Imir Studyguide2014

INTERNAL MEDICINE IN-REVIEW
STUDY GUIDE
2.2 EDITION
Companion to the Online Study System

InReviewIM.com
Senior Editor
Norman H. Ertel, MD
Associate Editors
James M. Horowitz, MD
Miguel A. Paniagua, MD, FACP
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in the materials.
The developments in medicine are always changing, from clinical experiences, new research, and
changes in treatment and drug therapy. The Internal Medicine In-Review team use reasonable efforts
to include information that is complete and within accepted standards at the time of publication.
However, the faculty, authors, publisher, nor any other party who has been involved in the preparation
of Internal Medicine In-Review make no representations, warranties, or assurances as to the accuracy,
currency, or completeness of the information provided. Users of Internal Medicine In-Review are
encouraged to conrm the information contained with other sources. The publishers of this guide
shall not be liable for any damages or injury resulting from your access to this guide, or from your
reliance on any information provided in this guide. This Study System is intended for U.S. physicians
only and is not in any means intended for use by the general public.
ISBN 978-0-9858025-1-6
2014 Published by Educational Testing & Assessment Systems, a product of SanovaWorks
Edited by Norman H. Ertel, MD
All rights reserved. No part of this book may be reproduced
in any form or by any means, without permission in writing
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Printed in the United States of America
Challenge Yourself with These Case Study Questions
2. An 80 year-old woman presents with dysphagia, epigastric pain, and frequent belching. Her symptoms are particularly
bothersome in the morning after eating breakfast. Her esophagram is shown. What is the most likely manometric finding?
a. Aperistalsis with lack of lower esophageal relaxation

b. Aperistalsis with a hypotonic lower esophageal sphincter
c. Abnormal tertiary contractions
d. Large propagating peristaltic waves
e. Normal peristalis
3. A 40-year-old competitive athlete has noticed intermittent irregular pulse while running but no other associated symptoms.
On examination he has normal cardiopulmonary exam and BP is recorded as 122/78. EKG and echo are normal. He was set
up for a Holter monitoring and a strip from Holter (while asleep) shows Wenckebach 2 heart block. Which of the following would
be the most appropriate next step in management?
a. Angiography
b. Pacemaker For More Free MCQs
c. Thallium stress test & to Find Out How You Did, Visit
d. Exercise stress test
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Users Guide
Created for first-year residents to use throughout the duration of their residency training, the Internal Medicine In-
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keep in mind the following:
Need a refresher? Internal Medicine In-Review is not meant to be a reference guide with an intimidating sizethe quick,
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You will notice redundancy between chapters. Repetition has been purposely integrated to further your learning.
Compiled of 17 chapters, the Study Guide covers the American Board of Internal Medicine (ABIM) certification exam
blueprint. You will also note a pain management chapter, which is not expressly identified as a content area covered on the
ABIM certification exam; however, pain management can be found throughout many of the medical-content categories,
including the 3% of the exam referred to as Miscellaneous.
Each chapter is followed by a series of Notes
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ERR A T A
The following errata is a list of errors and their corrections for the enclosed Internal Medicine In-Review Study Guide. Please visit the Online Study System for the fully
updated 2nd Edition, which includes optimizations and improvements to the Study Guide not listed below. You can download a PDF of the 2nd Edition at InReviewIM.com.
Module 1
Page # Section Correction
4 Urinary Incontinence Under Anticholinergics, include oxybutynin, tolterodine, darifenacin, solifenacin, trospium, and fesoterodine
18 OTC Pain Medications Subsection of NSAIDs, add New generation NSIADs such as Cyclooxygenase-2 ( Cox-2 ) inhibitors such as celecoxib can
provide better safety profile compared to traditional NSAIDs
21 Complementary and Alterna- Under Evaluation of patients for abuse potential add: ioids titration to long acting meds. Under Complementary and
tive Medicine (CAM) Alternative Medicine (CAM) add Physical Therapy, Chiropractor, aqua therapy, bio feedback
26 Headache and Facial Pain Under Surgical therapy is reserved to TN that is refractory to medical therapy change as follows: Nerve blocks, Microvas-
cular decompressin, Nerve Ablation, Chemical, Radiofrequency ablation, Gama Knife Radiosurgery
28 Treatment of Low Back Pain Under Subacute and Chronic Low Back PainAdd line between exercise and surgery lines as follow:- Interventional pain
procedures such as nerve blocks, Epidural injections, Sacro-Iliac joint injections, Facet nerve blocks, Radio frequency abla-
tion etc.
28 Neck Pain Add interventional approaches in multifaceted therapy as follow: Interventional pain procedures such as nerve blocks,
Epidural injections, Facet nerve blocks, Radio frequency ablation etc
31 Hip Pain Under Trochanteric Bursitis add: Bursa injection for Trochanteric bursitis not responding to conservative treatment
33 Knee Pain Subsection of Remember: Change Acute knee pain secondary to trauma can be a result of injuries to Acute knee pain
secondary to trauma can be a result of sports injuries
35 Fibromyalgia Syndrome Update diagnostic criteria of Fibromyalgia. As follow: Remove elicits painful response at 10 or more of the 18 tender points:
Occiput area, upper back, neck, upper chest, elbows hips, and knees update with 2010 PRELIMINARY DIAGNOSTIC CRI-
TERIA (EXCERPT) AS PER AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) includes A patient satisfies diagnostic criteria for
fibromyalgia if the following 3 conditions are met: Widespread pain index (WPI) 7 and symptom severity (SS) scale score
5 or WPI 3 - 6 and SS scale score 9. Symptoms have been present at a similar level for at least 3 months. The patient
does not have a disorder that would otherwise explain the pain. Add: Muscle relaxant in medications list
44 History: Table 3.1 Under Conductive hearing loss, include foreign bodies as a cause
Under Sensory hearing loss, include furosemide as a cause
51 Sinusitis: Treatment After silver nitrate can be applied topically to cauterize the bleeding site of a patch can be applied, include before apply-
ing silver nitrate, numb the nose bleed with lidocaine.
79 Intrauterine Devices In the first bullet point, include (LNG) after levonorgestrel
Module 2
3 Acute Ischemic Stroke Under Evaluation and Treatment new guidelines, change If <3 hours to If >3 to 4 1/2 hrs since..
6 Demyelinating Diseases Add Guillen Barre (GBS) Syndrome
(Other)
10 Movement Disorders (Other) Under Huntington disease change between 20 to 40 years of age to age less than 40 years of age
12 Normal Pressure Hydroceph- Add last bullet: Clinical Pearl 3 Ws as a pneumonic - Wet, Wobbly, Weird
alus (NPH) See it everywhere, will help people to remember
116 Hematology Chapter Please see additional sections to the hematology chapter by viewing the Online Study Guide at IMInReview.com
Module 3
30 Meningitis Replace first bullet with, The classic triad is fevers, altered mental status, and stiff neck.Include the word often at the
beginning of the sixth bullet so that it reads, Often, normal CSF glucose essentially rules out acute bacterial meningitis
(ABM)
32 Encephalitis: Table 14.2 Bullet point that says, PMN predominance early, later shifting to lymphocytes under HSV-1: Historical/Laboratory Clues
should be replaced with, PMN predominance late (after 1 week after onset) for most people, with lymphocytic predomi-
nance typically at the time of presentation
33 Neurosyphilis IV penicillin G is preferred therapy should be changed to, IV penicilli G is the required therapy. Those that cannot tolerate
it should be desensitized. All other regiments are suboptimal and with high failure rates
36 Community Acquired Pneu- Oral anaerobes should not be italicized
monia (CAP): Table 14.4 Under treatment for Oral anaerobes, current options should be replaced with the following, clindamycin or a beta-lactam
+ clindamycin/metronidazole or ampicillin/sulbactam or moxifloxacin
2017 Educational Testing and Assessment Systems (ETAS). All Rights Reserved. This document contains proprietary information, images, and marks of ETAS. iPhone is
E R R A T A
Module 3
44 Acute Infectious Diarrheas: E. Replace erythromycin with azithromycin in the following sentence, Treat Campylobacter with erythromycin or a
Coli quinolone.
45 Urinary Tract Infections Remove antibiotic therapy is option from the 6th bullet point
48 Epididymitis The last bullet, which starts with Blastomyces should be treated has a misspelling. Itraconozole should be
replaced with itraconazole
90 Barrett Esophagus Under Screening and Diagnosis add after esophageal adenocarcinoma Risk factors : age> 50 years, white, male,
obesity, chronic GERD
90 Barrett Esophagus Under Treatment Add: UPDATED GUIDELINE: Endoscopic therapy with RFA, endoscopic mucosal resection (EMR) and
photodynamic therapy (PDT) should be attempted in high-grade Barretts before surgery [1]
91 Esophageal Carcinoma Please see new additions to the Disorders of the Esophagus chapter by viewing the Online Study Guide at IMInReview.
com
92 Esophageal Motility Disorders Under Diffuse Esophageal Spasm and Nutcracker Esophagus add: Chest pain, dysphagia, globus sensation, regur-
gitation
add after second bullet Barium swallow shows cock-screw esophagus After channel blockers ADD: proton pump
inhibitors, botulinum toxins, and antidepressants
93 Infectious, Pill-induced, and Delete this statement: Candida albicans is the most common organism causing esophagitis in immunocompetent
Eosinophilic Esophagitis patients
Replace with: The most common cause of esophagitis in immunocompetent patients is GERD, about 20-30% of cases.
ADD: Fungal (Candida albicians) and Viral (HSV and CMV) esophagitis are seen in immune-compromised patients
93 Disorders Of The Stomach And Add Classification: Gastric ulcer (worsens with eating, in the upper Epigastric region) Duodenal ulcer (improves with
Duodenum eating, but worsens 3 hours after eating)
94 Helicobacter Pylori Infection After Urea breath testing ADD: Diagnosed by the Urea breath test : patient drinks C-13 0r C-14 labelled urea which
the bacterium metabolizes, producing labelled carbon dioxide that can be detected in the breath
95 Gastric Polyps, Subepithelial After: Weight loss, Add: bleeding, dysphagia, and upper abdominal pain
Lesions, and Adenocarcinoma Add bullet: Diagnosis: gastroscopic exam using a fiberoptic camera to visualize the gastric tissue is standard diagnostic
method; followed by biopsy. Add bullet: Prognosis : less than 10% 5-year survival rate.
96 Disorders Of The Intestines Please see additional sections to the Disorders Of The Intestines chapter by viewing the Online Study Guide at
IMInReview.com
102 Chronic Pancreatitis After ANA titer ADD: for a duration of 4-6 weeks, and repeated imaging used to monitor for improvement -Recent
update guidelines: Patients with IgG4 autoimmune pancreatitis have a higher risk of relapse if not maintained on an
immunosuppressant, and should be maintained on azathioprine
102 Chronic Pancreatitis Under Diagnosis: DELETE: Contrast-enhanced helical computed tomography (CT) scanning is the preferred method to
diagnose and stage pancreatic cancer ADD: Transabdominal Ultrasound is the first line because of its higher sensitiv-
ity (>90%) for all pancreatic tumors; in contrast, triple-phase helical multi-detector row CT abdomen is 100% sensitive
for tumors >2cm, but 77% sensitive for tumors <2cm.
105 Disorders Of The Liver, Please see additional sections to the Disorders Of The Liver, Gallbladder, And Bile Ducts chapter by viewing the Online
Gallbladder, And Bile Ducts Study Guide at IMInReview.com
119 Medical Oncology Please see additional content added to Medical Oncology chapter by viewing the Online Study Guide at IMInReview.
com
Any questions about the content of Internal Medicine In-Review should be directed to Educational Testing and Assessment Systems, Inc.
which controls the content and owns all copyrights in the materials.
The developments in medicine are always changing, from clinical experiences, new research, and changes in treatment and drug therapy.
The Internal Medicine In-Review team use reasonable efforts to include information that is complete and within accepted standards at the
time of publication. However, the faculty, authors, publisher, nor any other party who has been involved in the preparation of Internal Medicine
In-Review make no representations, warranties, or assurances as to the accuracy, currency, or completeness of the information provided.
Users of Internal Medicine In-Review are encouraged to confirm the information contained with other sources. The publishers of this guide
shall not be liable for any damages or injury resulting from your access to this guide, or from your reliance on any information provided in this
guide. This Study System is intended for U.S. physicians only and is not in any means intended for use by the general public.
STUDY GUIDE
2.2 EDITION
MODULE 1
STUDY GUIDE
2.2 EDITION
MODULE 2
FACULTYv
STUDY GUIDE
2.2 EDITION
MODULE 3
1 General Internal Medicine
Fred Buckhold, MD
C o n t e n t s
1.1 ROUTINE CARE OF THE HEALTHY PATIENT . . . . . 2
1.2 GERIATRIC MEDICINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3 PERI-OPERATIVE MEDICINE . . . . . . . . . . . . . . . . . . . . . 5
1.4 PATIENT SAFETY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.5 PROFESSIONALISM AND ETHICS . . . . . . . . . . . . . . . . 6
1.6 PALLIATIVE CARE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.7 COMMON SYMPTOMS . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.8 MEN'S HEALTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
GENERAL INTERNAL MEDICINE1
1.1 ROUTINE CARE OF THE HEALTHY PATIENT
Screening
Assessing patients for risk or presence of asymptomatic disease and identifying lifestyle
choices that have health consequences.
Often based on prevalence of diseases
The United States Preventative Services Task Force (USPSTF) has recommendations on
which screening measures are effective
Screening During History and Physical Exam
Measure height and weight (for BMI/obesity)
Measure blood pressure (for hypertension)
Assess for tobacco, alcohol, and drug use
Detailed sexual history, including risk factors for STDs
Screening Tests
Papanicolaou test every 3 years starting at age 21, stopping age 65
Chlamydia for sexually active women under age of 25
Routine HIV screening for ages 13 to 64
Biennial mammograms for women age 50 to 74
Cholesterol screening (Total and HDL) every 5 years in men >35 years and women >45
years
Fasting glucose if sustained blood pressure >135/80 mmHg
Colonoscopy every 10 years above age of 50 until age 74; may also have occult blood
testing yearly or flexible sigmoidoscopy every 5 years
Abdominal aortic aneurysm for male adults between 65 to 75, if history of smoking present
Osteoporosis (via BMD) in women >65, or 60 to 64 if body weight below 70 kg
Family History
Taking a Family History
Screen for diseases that family members have
Inquire specifically about early onset cardiovascular disease and 1st and 2nd degree
relatives with cancer (and what type/age of onset)
Genetic Testing
More useful for high risk populations, or if suspected
Testing should aid in diagnosis and/or management
BRCA or FAP mutation may lead to aggressive screening and interventions
2INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

Immunizations
Table 1.1: Immunizations

Vaccine Frequency Indications
(blank indicates universal)
Hepatitis A 2 doses once Men who have sex with men
Injection drug users
Occupational (food handlers)
Travel to endemic areas
Chronic liver disease
Hepatitis B 3 doses Sexually active young adults
Healthcare or public safety
workers
Travel
Human papillomavirus vaccine Females 19-26 years, males 19-21
years, consider 22-26 3 doses
Influenza Annually
Measles-Mumps-Rubella Should have as a child May have to check serologies
if unsure of history; adults born
before 1957 considered immune
Meningococcal vaccine 1 dose 1st year college students
HIV or asplenia
Pneumococcal vaccine 1 or 2 doses Age >65
Chronic lung disease, diabetes,
chronic liver disease, asplenia
Tetanus-Diphtheria-Acellular Every 10 years Tdap booster once, followed
Pertussis (Td or Tdap) by Td every 10 years
Varicella 2 doses
Zoster 1 dose Age 60 and above
Lifestyle Risk Factors

Behavioral Counseling
Brief interventions at office visits can be effective
Use the 5 As: Assess, Advise, Agree, Assist, Arrange
Physical Inactivity
Should encourage 30 minutes of aerobic exercise 5 times weekly
Strengthening exercise at least twice weekly
Encourage activity to reduce sedentary behavior for those with chronic disease or in ages
>65 years
Substance Use Disorders
Tobacco
Assess at each visit
Brief counseling and possibly medication
Routinely screen for alcohol misuse and abusemost frequently in young adults and
smokers
Can use CAGE questionnaire
If at-riskbrief counseling
If dependencereferral to treatment
Illicit drugs: Look for behavior changes, legal troubles, and medical sequelae
Referral or brief counseling
Sexual Behavior
History oriented to high risk practices (men who have sex with men, multiple partners,
contact with sex workers)
Counsel of safe sex practices (use of barrier protection vs. birth control for prevention of
STDs)
Offer screening for STDs as appropriate
Domestic Violence
Screen if suspected
Intervene if possible; assessing for safety, clear documentation of injuries, and providing
resources
1.2 GERIATRIC MEDICINE

Functional Assessment
Hearing loss screening
Patient reported
Test by whispering in ear while using distraction in other ear
Screen for vision loss
Screen for depression
Probe for deficits in activities of daily living
Inquire for falls
Get up and go good for screening
To reduce risk of falls:
Monitor meds, stop centrally acting ones
Muscle strengthening and balance exercises
Calcium and vitamin D
Improve living environment
Urinary Incontinence
Stress: Loss of sphincter tone, worse with cough
Pelvic floor exercises
Estrogen cream
Surgery
Urge: Spastic/overactive detrusor muscle
Timed voiding
Anticholinergics: oxybutynin, tolterodine, darifenacin, solifenacin, trospium, and
fesoterodine
In men: Consider overflow incontinence from bladder retention from BPH
Pressure Ulcers
Prevent them at all costs, aimed at reducing friction, shear stress, and skin moisture.
May need debridement and antibiotics for stage III-IV ulcers

1.3 PERI-OPERATIVE MEDICINE
There are few limiting factors that would prevent a patient from being an operative candidate.
Evaluation goal is risk reduction if possible, and perform testing only if it will change pre-operative
management.
Cardiac Evaluation
ACC/AHA algorithm
1. Emergent surgery to OR
2. Active cardiac condition (ACS, ventricular arrhythmia, decompensated heart failure)
treat condition
3. Low risk surgery to OR
4. Assess functional capacity (can walk up a flight of stairs or hill go to OR)
5. If unable to assess or perform at functional capacity, assess risk factors; if 3 or more
consider testing if it will change management
Risk factors
High risk surgery
Creatinine >2.0
Ischemic heart disease
History of stroke
Diabetes requiring insulin
LV systolic dysfunction with EF <35%
If patient has coronary revascularization prior to surgery (either due to pre-operative
assessment or not), needs to be on anti-platelet agents for 4 to 6 weeks for bare metal
stent, 12 months for drug eluting stent
Both aspirin and clopidogrel should be stopped about 5 days before planned surgery
Maintain b-blocker dose if already takingno need to add before surgery
Consider stopping lisinopril
Pulmonary Evaluation
Risk factors associated with pulmonary complications
Type of surgery (emergent vs. non-emergent) and surgery duration
Location (intrathoracic and upper abdominal highest risk)
Use of general anesthesia, long acting neuromuscular blockers, and NG tubes
Only measure to reduce morbidity/mortality is incentive spirometry postoperatively
Only do diagnostic spirometry pre-operatively if having lung resection
Chest radiograph not needed
VTE Prophylaxis
Should be applied to most surgical patients (mechanical and pharmacologic)
Usually LMWH or heparin is sufficient
Higher risk surgeries (hip or knee arthroplasty, hip fracture, trauma, spinal injury):
Therapeutic warfarin for INR 2-3 or fondaparinux
Glycemic Control
Diabetics should be monitored closely peri-operatively
Data unclear on optimal regimen, likely benefit if blood sugar remains less than 180 mg/dL
Continue insulin regimen (basal, no bolus) for type 1 diabetics
Halve insulin for type 2 diabetics the day of surgery
Metformin and other agents should be stopped 1 to 3 days prior to operation
Other Considerations
Surgery in a hyperthyroid patient may induce thyroid storm
May use steroids to block this effect
Stress steroids may be required for steroid-dependent patients
Dialysis patients should ideally be dialyzed the day prior to surgery
Delirium commonly occurs in patients at risk
1.4 PATIENT SAFETY

Data on adverse events
IOM report (To Err is Human) 100,000 deaths annually from medical error
Majority are medication related
Principles of patient safety
Root cause analysis to define cause
Redundancy in system
Checklists
Time-outs
Electronic medical records
Quality improvement models
Most common PDSA; Plan Do Study Act
6 sigma
Total quality management
Diagnostic error
Heuristics (mental shortcuts) lead to diagnostic mistakes
Availability
Anchoring
Blind obedience
Can be reduced by recognizing types of heuristics, completeness of differential
diagnosis, and by considering alternative diagnosis along with working diagnosis
National Patient Safety Goals
Mandated by Joint Commission in 2009
Emphasize areas of risk in patient care, including medication safety, patient hand-
offs, infection control
1.5 PROFESSIONALISM AND ETHICS

Professionalism 3 principles from the Charter of Medical Professionalism
Primacy of patient welfare
Patient autonomy
Social justice
Assessing decision-making capacity
Does the patient have the ability (medical or psychological) to make decisions
Multiple modalities based on stringency best tests find rationality in choice
Why are you choosing this?

Does the decision make sense?
Advance directives and surrogate decision-making
Advance directives instructions on types of care to be provided. May be vague
Surrogate decision maker healthcare proxy or power of attorney; typically a family
member
Makes decisions on behalf of patient with patients known preferences in mind
Informed consent 3 elements
Disclosure of all relevant information benefits, risks, alternatives within reason
Adequate understanding by the patient
Voluntary decision
Withholding or withdrawing care
Justifiable if futile
Ideally should be discussed with patient as early as possible
Should try to involve family and patient as much as possible
Physician-assisted suicide and euthanasia
Physician-assisted suicide illegal except in Washington and Oregon
Euthanasia (physician directly administering a substance causing death) is illegal
Patient inquiries should be a means to assessing need for care
Confidentiality
Strive to maintain at all costs; consent must be obtained to release patient health
information
Conflicts of interest
Occurs when other interests to provider may potentially or does interfere with
providers duty to patient
Can be handled by:
Disclosure making conflict known
Avoidance avoiding conflict
Medical error reporting
When error occurs inform patient
Sexual contact between physician and patient is unethical, even with former patients
The impaired physician and colleague responsibility
Ethical responsibility to report suspected impairment
1.6 PALLIATIVE CARE

Assessment
Center around terminal diagnosis, expected symptoms, and ways to alleviate symptoms
Performance scales aid in prognosis
Consider stopping medical devices
Symptom Management
Pain: Aspirin, acetaminophen, or NSAIDs initially, at labeled dosing. For severe pain, opioids
are reasonable
Can use combination regimen of long acting and short acting opioids
Oral is preferred, avoid meperidine and opioid agonists/antagonists
Liquid morphine may be helpful for those with difficulty swallowing
Monitor for side effects
Surgery may be useful for visceral pain
Appropriate agents for neuropathic pain include TCAs, dual acting anti-depressants,
tramadol, gabapentin, pregabalin
Dyspnea: Treat the symptom
Use short acting opioid if on chronic therapy for symptom relief
Morphine also helpful
Do not use benzodiazepines
Oxygen for hypoxemia
Nutrition: Appetite may wane, but important to consider social element of eating
If not near death, stimulants are appropriate - megestrol and medroxyprogesterone
Unclear benefit of enteral/parental feeding
Depression: Difficult to diagnose
Patients noting low mood and low interest are more likely to be depressed
Treat with SSRIs or TCAs
Altered mental status
Consider medication, especially opioids
Consider prognosis before full evaluation
Haloperidol may be used for symptoms, can also use benzodiazepine with monitoring
Caregiver stressors and bereavement
Must be closely monitored
If symptoms of bereavement continue for 6 months, high risk for complicated grief and
depression may need treatment medically or with therapy
1.7 COMMON SYMPTOMS

Chronic Pain
Characterizing and assessing pain
Somatic pain: Inflammatory, responds to NSAIDs
Central sensitization pain abnormal processing of sensation by CNS; allodynia and
hyperalgesia is common
Opioids and NSAIDs often not helpful
Cognitive therapy, serotonin-norepinephrine reuptake inhibitors, and TCAs are
helpful
Evaluate and treat comorbid depression and anxiety
If history or physical suggest possible etiology for pain, evaluate with appropriate tests,
otherwise none is needed
Managing pain
The World Health Organizations Analgesic Ladder is a useful construct
Start with non-opioids (NSAIDs, aspirin, acetaminophen), before starting mild
opioids (codeine), followed by strong opioids (morphine, fentanyl) with careful
consideration of side effects and potential for abuse
Liquid morphine effective for those with difficulty swallowing
Tramadol is an effective alternative

Non-pharmacologic
Ice for inflammatory pain
Heat for chronic pain
Graded exercise
Electrical nerve stimulation
Acute and Chronic Cough

Acute (less than 3 weeks) commonly:
Usually infectious, use other clues for diagnosis
Viral URI
Viral or bacterial pneumonia unlikely unless abnormal vital signs (fever, HR >100
BPM, respirations >24/min) or physical exam findings
Bacterial sinusitis 7 days or more of symptoms
Rhinitis with post-nasal drip
Acute bronchitis non-productive cough, likely viral, symptomatic care
Influenza if in season (fall/winter), concomitant fever, malaise, cough, sore throat
Chronic (more than 8 weeks) or sub-acute (3 to 8 weeks). Most commonly:
Asthma confirmed when improved with asthma treatment
GERD therapeutic trial with PPI is reasonable
Post nasal drip/upper airway cough syndrome
If cause unclear, 1st step is empiric therapy with antihistamine/decongestant
Alternative diagnoses
ACE inhibitor
Chronic bronchitis (if sputum production)
Non-asthmatic eosinophilic bronchitis
Smoking (improves with cessation)
Cough in the immunocompromised patient
Consider opportunistic infections, tuberculosis, and pneumocystis pneumonia
Hemoptysis
Malignancy, infection, elevated pulmonary pressure, or idiopathic
Should have chest X-ray
If male, older than 40 years, symptoms >1 week, or 40 pack year smoker chest CT
and bronchoscopy
If massive bleeding needs emergent/critical care
Chronic Fatigue and Chronic Fatigue Syndrome

Defined as disabling fatigue lasting more than 6 months
Etiology unknown
Rule out other factors (OSA or other sleep disturbance, depression, anemia, drugs,
hypothyroid, chronic disease)
Cognitive behavioral therapy and graded exercise are effective therapies
Antidepressants might be helpful
Dizziness
Helpful exam maneuvers
Orthostatics for lightheadedness
Dix-Hallpike for positional vertigo
Neurologic and ear assessment for vertigo
Vestibular and Peripheral Nerve Causes of Dizziness
Usually related to vertigo
BPPV use Epley maneuver to improve
Vestibular neuronitis likely after viral infection; symptoms not self limiting
May respond to steroids
Meniere vertigo with hearing loss and tinnitus
Thiazide diuretics to treat
Central Nervous System Causes of Dizziness
Rarely tumor
Vascular disease of posterior cerebral arteries; consider when other vascular risk factors
present
Migraine headaches
MRI may be helpful if symptoms or exam suggest
Disequilibrium Gait Unsteadiness
Multifactorial peripheral neuropathy, poor eyesight, medications
Safety features added to homes, assistive devices, and reducing polypharmacy helpful
Non-specific Dizziness
May be related to other systemic problems (hypoglycemia, hyperventilation)
Associated with psychiatric illness
Insomnia
Often related to co-morbidities
Take a detailed history involving time going to sleep, duration, wakefulness upon waking
Non-drug therapies (sleep restriction, cognitive therapy, sleep journal) likely more effective
than drug therapies
Can use medication, preferably not benzodiazepines
Syncope
Transient loss of consciousness due to lack of cerebral blood flow. Pre-syncope is the sensa-
tion of almost losing consciousness. Pathophysiology typically the same for both.

Table 1.2: Syncope
Etiology/Cause of Syncope Clues
Vasovagal Symptoms occur after sudden pain, fear, or
unpleasant sensation
After prolonged standing
Situational Based on history
Carotid-sinus Occurs with head rotation or palpation of carotid
sinus
Psychiatric disorders Somatic symptoms, high frequency of occurrences
Associated with anxiety, depression, panic disorder
Orthostatic hypotension Occurs when standing from supine/sitting
Medication Consider when polypharmacy, many centrally acting
drugs, or that affect QT interval
Neurologic (stroke, seizure, etc.) Migraines
Symptoms suggestive of posterior stroke
Seizure
Structural heart disease (outflow obstruction or Atrial myxoma or thrombus symptoms with posi-
ischemia) tional changes, no orthostasis
Exertional symptoms structural changes in heart
(AS, MS, HOCM)
Arrhythmia Brief LOC with no prodrome
Family history of sudden death
Idiopathic Other causes ruled out
Adapted from Kapoor W, NEJM 343:1856-62.
Patients with high index of suspicion for heat disease (based on previous history or ECG
changes) should be admitted for evaluation
Evaluation should be based on suspected underlying condition
Chest Pain
Priority in differential diagnosis depends on situation
Majority of CP in ambulatory clinic musculoskeletal
In emergency settings acute coronary syndrome
Differential is broad; clues to diagnosis include:
Ischemic changes to heart: Substernal pain or tightness with radiation; ECG and
biochemical changes
Reproducible, sharp pain, negative ECG, or positional-related makes ischemia
unlikely
Aortic dissection abrupt onset, tearing chest pain, pulse differential, wide
mediastinum on chest X-ray if considering, order MRI, angiography, or chest CT (not
echo)
Pulmonary embolism pleuritic pain, sudden onset, dyspnea, tachycardia, and risk
factors; CT angio is reasonable if intermediate or high suspicion
Pneumonia fever, productive cough, infiltrate on chest X-ray
Gastroesophageal reflux often mimics ischemic heart disease, always consider cardiac
disease. Trial of proton pump inhibitor if cardiac disease ruled out
Musculoskeletal reproducible tenderness, otherwise normal exam
Panic attack or anxiety
Hyperlipidemia
Screening males >35, females >45
Components of cholesterol profile
LDL main substrate for atherogenic disease. Usually elevated due to dietary/lifestyle
or genetic causes, also consider hypothyroidism, nephrotic syndrome, obstructive liver
disease, and certain medications
Primary target of cholesterol lowering therapy
Triglycerides not reliable predictor of cardiovascular disease; if high, may affect
estimation of LDL (LDL not usually measured directly)
Must treat if above 500 mg/dL to decrease risk of pancreatitis
HDL higher levels correlate with decreased incidence of cardiovascular disease; no
evidence that raising improves CAD risk
Treatment
Lifestyle modifications 1st choice restriction of fat, more plant stenosis, exercise
Statins are mainstay of secondary prevention (for those who have CAD), and should be
considered for primary prevention if risk is high enough
Must be vigilant for effects of myopathy and myalgia, elevated liver enzymes, and
rhabdomyolysis
Other drugs fibrates (mainly gemfibrozil), ezetimibe, and niacin may be used to
further reduce LDL or improve HDL, but benefit on atherogenic disease is uncertain
Goals to treat with medication
Use Framingham Risk Score (FRS) to assess 10 year cardiovascular risk
Risk factors for CVD
Cigarette smoking
Hypertension
Age (men 45, women 55)
Low HDL (<40 mg/dl)
Family history male relative with CAD <55, female <65
If CVD present, treat LDL 100 mg/dL
If FRS 10 to 20%, 2 risk factors, treat if LDL 130 mg/dL
If FRS <10%, 2 risk factors, treat LDL 160 mg/dL
If FRS <10%, 0 to 1 risk factors, treat LDL 190 mg/dL
If LDL is lower than above numbers, but elevated, start lifestyle changes
Obesity
Defined as BMI >30
Obesity confers higher risk of chronic disease
Evaluation should probe for causes, including:
Medication induced
Endocrine hypothyroid, excess cortisol, polycystic ovarian syndrome
Other cardiovascular comorbidities (hypertension, diabetes, dyslipidemia)
Treatment
Diet and exercise
Behavior modification
Orlistat and sibutramine can be used as supplement to above
Sibutramine should not be used in hypertensive patients

Bariatric surgery has been shown to reduce incidence of diabetes, hypertension, sleep
apnea, and hyperlipidemia
Monitor long term for nutrient deficiencies, especially vitamin B12, vitamin D,
calcium, iron, folate
1.8 MEN'S HEALTH

Erectile dysfunction is often due to organic factors similar to cardiovascular disease
(smoking, hypertension, and diabetes)
Try to identify comorbid disease
Treat initially with phosphodiesterase -5 inhibitors, if no contraindications (i.e., not on
nitrates)
Premature ejaculation treat with SSRIs or behavioral techniques
Decreased libido
Hormone defect (testosterone or hyperprolactinemia)
Psychiatric illness (depression)
Medications
Benign prostatic hyperplasia (BPH)
Enlargement of prostate causing obstruction of urine flow can lead to overflow
incontinence
Large, boggy prostate on exam
Consider mitigating factors fluid ingestion, medications, neurologic/cognitive
impairments
Treat with alpha-antagonists or 5 alpha reductase inhibitors
Surgery last option
Acute testicular/scrotal pain
Consider torsion if suspicious surgery (no imaging). Absent cremasteric reflex very
sensitive
Epididymitis and orchitis may be due to chlamydia/gonorrhea
Treat with antimicrobials, acetaminophen, or NSAIDs
Chronic prostatitis -blockers are effective treatment
Hernias palpated or visualized in inguinal canal
Surgical management
REFERENCES & SUGGESTED READINGS
1. U.S. Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task
Force Recommendation Statement. Ann Intern Med2009;151:716-726.
2. U.S. Preventive Services Task Force.Screening for Colorectal Cancer: U.S. Preventive Services Task
Force Recommendation Statement. AHRQ Publication 08-05124-EF-3, October 2008. http://www.
uspreventiveservicestaskforce.org/uspstf08/colocancer/colors.htm
3. Screening for Cervical Cancer, Topic Page. April 2012. U.S. Preventive Services Task Force. http://
www.uspreventiveservicestaskforce.org/uspstf/uspscerv.htm
4. Centers for Disease Control and Prevention. Recommended adult immunization scheduleUnited
States, 2012. MMWR 2012;61(4).
5. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann KE, Freeman WK, Froehlich
JB, Kasper EK, Kersten JR, Riegel B, Robb JF. ACC/AHA 2007 guidelines on perioperative car-
diovascular evaluation and care for noncardiac surgery: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee
to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac
Surgery).Circulation. 2007;116:e418e499.
6. McGlynn EA, et al. The quality of health care delivered to adults in the United States. N Engl J Med.
348:2635.
7. Snyder L, Leffler C; Ethics and Human Rights Committee; American College of Physicians. Ethics
Manual: fifth edition. Ann Intern Med. 2005;142(7):560-582.
8. Qaseem A, Snow V, Shekelle P, et al; Clinical Efficacy Assessment Subcommittee of the American
College of Physicians. Evidence-Based Interventions to Improve the Palliative Care of Pain, Dyspnea,
and Depression at the End of Life: A Clinical Practice Guideline from the American College of
Physicians. Ann Intern Med. 2008;148(2):141-146.
9. Keith M. Swetz, Arif H. Kamal, Deborah Cotton, Darren Taichman, Sankey Williams; Palliative Care.
Annals of Internal Medicine. 2012 Feb;156(3):ITC2-1.
10. Irwin R, Madision JM. The Diagnosis and Treatment of Cough. N Engl J Med. 343:1715-1721.
11. Kapoor WN. Syncope. N Engl J Med. 343; 1856-1862.
12. Barbara Turner, Sankey Williams, Darren Taichman, Laurie Kopin, Charles Lowenstein; Dyslipidemia.
Annals of Internal Medicine. 2010 Aug;153(3):ITC2-1.
13. Christine Laine, David R. Goldman, George A. Bray, Jennifer F. Wilson; Obesity. Annals of Internal
Medicine. 2008 Oct;149(7):ITC4-1.
14. Daroff R. Dizziness and Vertigo. Harrisons Principles of Internal Medicine. 17th ed. Ed. Fauci A et al.
New York: McGraw-Hill, 2008.
15. Fields HL and Martin JB. Pain: Pathophysiology and Management. Harrisons Principles of Internal
Medicine. 17th ed. Ed. Fauci A et al. New York: McGraw-Hill, 2008.

NOTES
NOTES

2 Pain Management
Howard S. Smith, MD
Plinio P. Silva, MD, MPH
Intikhab Mohsin, MD
C o n t e n t s
2.1 WHY PAIN MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . 18
2.2 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.3 OTC, RX, AND ALTERNATIVE PAIN MANAGEMENT. . 18
2.4 HEADACHE AND FACIAL PAIN . . . . . . . . . . . . . . . . . .23
2.5 CHRONIC MUSCULOSKELETAL PAIN AND OTHER

COMMON CHRONIC PAIN CAUSES . . . . . . . . . . . . . .27
2.6 OTHER TYPES OF COMMON CHRONIC PAIN . . . .35
2.7 ACUTE AND CHRONIC PAIN IN DIFFERENT

PATIENT POPULATIONS . . . . . . . . . . . . . . . . . . . . . . . .35
PAIN MANAGEMENT17
2.1 Why Pain Management
Though Pain Management is not expressly identified as a content area covered on the
American Board of Internal Medicine (ABIM) certification exam, pain management can be found
throughout many of the medical-content categories, including the 3% of the exam referred to as
Miscellaneous. Beyond exam study, we firmly believe that pain management knowledge is cru-
cially important for healthcare providers in their day-to-day practice.
We have started the chapter with a section on over-the-counter (OTC), Rx, and alternative
pain management. This section will help you understand drug-drug interactions at-a-glance, along
with which OTC analgesics are safe and effective for certain pathologies, diseases, and symptoms.
From there we will dive into an in-depth look at different pain areas.
2.2 INTRODUCTION
The study of pain is defined by the International Association for the Study of Pain (IASP) as
an unpleasant sensory and emotional experience associated with actual or potential tissue
damage, or described in terms of such damage
Acute pain is a physiologic response following a cascade of molecular events initiated by
initial tissue injury
Initially acute pain plays a protective role against further tissue damage, but can progress to
a chronic disease if it persists despite apparent healing
Acute and chronic pain are commonly encountered in clinical practice and present
challenges to the internal medicine physician
The 2011 Institute of Medicine (IOM) report, Relieving Pain in America: A Blueprint for
Transforming Prevention, Care, Education, and Research:
Reported that pain affects as many as 100 million Americans and cost $635 billion
annually
Called for a cultural transformation that would increase awareness and prevention;
improve assessment and management; emphasize patient education; and address
disparities in different patient subgroups
2.3 OTC, RX, AND ALTERNATIVE PAIN MANAGEMENT

OTC Pain Medications
Are used universally and benefit many patients
Are generally safe and effective for short-term use when taken as directed
Classes include:
Nonsteroidal anti-inflammatory drugs (NSAIDs):
Salicylates an example is aspirin
Propionic acid derivatives examples are ibuprofen, naproxen sodium, ketoprofen
New generation NSIADs such as Cyclooxygenase-2 ( Cox-2 ) inhibitors such as
celecoxib can provide better safety profile compare to traditional NSAIDs
Aminophenols an example is acetaminophen
Are used to treat mild to moderate pain

OTC pain medications treat pain that is commonly associated with many conditions
including colds, flu, sore throat, headache, muscular aches, postoperative pain, arthritis,
menstrual cramps, dental pain, and back pain
Acetaminophen, an analgesic and antipyretic agent, does not have anti-inflammatory
properties of NSAIDs. However, acetaminophen effectively treats mild to moderate
pain without increasing the risk for gastrointestinal complications, such as gastric
irritation, gastric erosions, bleeding, or ulcers when compared with NSAIDs
As a medical professional, it is important to:
Know the precise amounts of all substances in an OTC formulation
Know the maximum daily dose of all agents contained in OTC formulations
Stay abreast of the latest evidence and dosing in order to give patient up-to-date
advice and recommendations
Advise patients to communicate the exact quantity of OTC medications used
Counsel patients about the reason for use of the medication, frequency of
administration, anticipated effect on symptoms, possible drug interactions, and
potential adverse effects (especially severe ones)
Counsel patients to follow the labeled dosage and to not take more than the
recommended labeled dose or the dose that is recommended by you, as this will help
patients to prevent reaching toxic dose levels
Emphasize the importance of reading the package labeling sections
One of the FDA proposed changes requires that all OTC products containing
NSAIDs or acetaminophen (including combination products) list these ingredients
on the products principal display panel and to also specify the potential for liver
toxicity (in the case of acetaminophen) or GI complications (in the case of NSAIDs)
when these products are taken with 3 or more alcoholic drinks daily
Monitor renal and liver function periodically
Educate parents and caregivers to keep OTC pain medications out of the reach of
young children by storing these medicines in a high location that is out of the childs
eye sight
Instruct the patient to avoid using more than 1 medicine that contains the same active
ingredient at the same time
When recommending acetaminophen, inform patients of the following:
Advise patients to be mindful of alcoholic intake and discuss the use of alcohol
while taking acetaminophen-containing medications, as liver damage may occur
if the patient consumes more than the FDAs recommended amount of alcoholic
consumption (3 or more drinks) each day while using acetaminophen. Again,
patients should not exceed labeled dosing
Educate patients of the potential increased risk for bleeding if acetaminophen is
taken with warfarin, a blood-thinning drug. Acetaminophen and warfarin combined
may cause International Normalized Ratio (INR) elevation. Increased INR levels can
be an indicator for early signs of internal bleeding
Instruct patients to ask you or a pharmacist when they are not sure whether a
drug contains OTC pain relievers, such as acetaminophen. Also explain to the
patient that severe liver damage may occur if the patient takes excessive amounts
of acetaminophen, especially if the patient takes acetaminophen along with other
drugs containing acetaminophen
PAIN MANAGEMENT19
Further, educate patient regarding the existence of OTC medications that combine
2 or more active ingredients. Patients may not realize that the product contains
1 or more ingredient(s) that they are also taking in the form of another OTC or
prescription medication, which may increase the risk of overdose. To reduce this
problem, you may consider recommending a single-ingredient product whenever
possible
When recommending NSAIDs, inform patients of the following:
Factors associated with the increased risk of NSAID-induced GI complications
are older age, higher daily dosage, history of gastrointestinal or GI ulcer, history
of GI hemorrhage, dyspepsia, NSAID intolerance, use of corticosteroids, use of
anticoagulants, alcohol consumption, and poor general health
Individuals who have severe kidney or liver disease, hypertension, GI ulcers, or who
take certain medications such as anticoagulants should not take OTC NSAIDs in
order to reduce their risk for side effects
Advise patients with peptic ulcer disease to avoid taking NSAIDs for pain relief,
as it increases the risk of gastrointestinal (GI) complications, ranging from mild
dyspepsia to more severe problems such as gastrointestinal hemorrhage
NSAIDs with long-term use may cause renal injury. The use of aspirin, even low-
dose aspirin, can affect renal function in the elderly. Therefore, NSAIDs should
be used with caution in the elderly population because of the higher incidence
of cardiovascular and GI disease, age-related decline in renal function and the
likelihood of polypharmacy
Certain NSAIDs have drug-drug interactions with antihypertensive medications,
which may result in elevated blood pressure and/or decrease in renal function.
Therefore, advise patients with hypertension to avoid NSAIDs. Further, educate
patients with hypertension regarding the use of acetaminophen for pain relief
instead of NSAIDs while using antihypertensive medication. Acetaminophen does
not affect blood pressure or have drug-drug interactions with antihypertensive
medications
Ibuprofen and naproxen sodium may reduce the rate of renal clearance of lithium,
increasing serum levels of lithium and an individuals risk for toxicity
Aspirin may potentiate hypoglycemic effects of sulfonylureas
Prescription Pain Medications (Rx)

Widely used for treatment of moderate to severe acute and chronic pain
Judicious prescription practices are important to decrease adverse effects of prescription
pain medications
Opioids used for the treatment of persistent non-cancer pain are of special importance
given their abuse potential
Inform patients of any side-effects and be aware of any OTC analgesic they are taking to
avoid overdose
The following practices are important prior to initiating chronic opioid therapy:
Informed consent
Opioid treatment agreement that includes a clause that opioids will be obtained from
only 1 physician

Goal directed therapy and periodic re-evaluation of treatment strategy are important
Evaluation of patients for abuse potential
Urine drug test
Psychological assessment
Opioids titration to long acting meds
Development of a strong doctor-patient relationship that will allow open
communication
Complementary and Alternative Medicine (CAM)

Emerging as potential adjuvant to conventional therapy in the treatment of chronic pain
Physical Therapy, Chiropractor, aqua therapy, bio feedback
Acupuncture is the most widely used CAM modality
Acupuncture successfully employed for treatment of migraine and tension-type
headaches, fibromyalgia, musculoskeletal pain, and pain during pregnancy
Herbal medicine
Commonly used for the treatment of chronic pain
Treating physician must be aware of medicines to monitor for potential adverse effects
and potential interactions with conventional medical therapies
Table 2.1: Common Drug-Drug Interactions Between OTC Pain Relievers

and Prescription Drugs
OTC Pain Relievers Prescription Drug Common Drug-Drug Interactions
Acetaminophen and all Warfarin May increase the risk of bleeding
NSAIDs
Acetaminophen Isoniazid Isoniazid prevents the metabolism of
acetaminophen
All NSAIDs Cyclosporine NSAIDs reduce the renal clearance of cyclosporine,
resulting in increased serum levels
All NSAIDs Antihypertensives NSAIDs may increase blood pressure and interact
with antihypertensives. NSAIDs, such as aspirin,
interact with antihypertensives (angiotensin-con-
verting enzyme [ACE] inhibitors and -blockers)
All NSAIDs Methotrexate NSAIDs may increase serum levels of methotrexate
and lead to an increased risk of methotrexate
toxicity
Ibuprofen and naproxen Lithium Ibuprofen and naproxen sodium reduces the rate
sodium of renal clearance of lithium, increases serum levels
of lithium, and may increase an individuals risk for
toxicity
Aspirin Sulfonylureas Aspirin may potentiate hypoglycemic effects of
sulfonylureas
Aspirin and other Valproic acid Aspirin and other salicylates reduce elimination of
salicylates valproic acid, thus increasing the concentration of
valproic acid in the blood. Due to the increased
levels of valproic acid, valproic acid toxicity may
occur
Adapted from Montauk SL, Rheinstein PH. Appropriate use of common OTC analgesics and cough and cold medications.
Leawood, Kan.:American Academy of Family Physicians; 2002.
PAIN MANAGEMENT21
Table 2.2: OTC Pain Relievers With Certain Symptoms, Diseases, and Conditions*
Disease/Condition/Symptom Preferred Analgesic Therapeutic Note
Asthma Acetaminophen Use with caution: Aspirin,

ibuprofen, naproxen sodium
Musculoskeletal (back, hip, Acetaminophen or ibuprofen N/A
elbow, shoulder, etc.) pain
Bleeding disorders Acetaminophen or non-aspirin Use with caution: Aspirin,
salicylates ibuprofen, naproxen sodium
Congestive heart failure Acetaminophen Use with caution: Effervescent
aspirin tablets (with high
sodium content), and non-
salicylate NSAIDs
Dental pain Ibuprofen. Alternative treatment Use with caution: Aspirin
includes acetaminophen or ibuprofen if extraction is
planned
Dysmenorrhea Ibuprofen, naproxen sodium, N/A
acetaminophen
Gout Acetaminophen or non-salicylate Use with caution: Salicylates
NSAIDs
Headache Acetaminophen, aspirin, or ibuprofen N/A
Hepatic impairment Acetaminophen Use with caution: All NSAIDs
Hypertension Acetaminophen Use with caution: All NSAIDs
Lithium therapy Acetaminophen or aspirin Use with caution: Ibuprofen
and naproxen sodium
Methotrexate therapy Acetaminophen Use with caution: All NSAIDs
Migraine Ibuprofen or ASA. Alternative treat- Avoid coated aspirin due to
ment includes acetaminophen delayed onset
Acute sore throat pain (asso- Acetaminophen. Alternative treat- N/A
ciated with upper respiratory ment includes aspirin or ibuprofen
tract infection), Pain (associ-
ated with the cold and flu)
Type 2 diabetes managed Acetaminophen or ibuprofen Use with caution: Naproxen
with 1st generation (however, patients with diabetes are sodium, salicylates
sulfonylureas at risk of renal dysfunction resulting
from NSAID use)
Oral anticoagulant therapy Acetaminophen or non-aspirin salicy- Use with caution: Aspirin,
lates (patients taking anticoagulants ibuprofen, naproxen sodium
who also take acetaminophen regu-
larly or at higher doses should be
monitored)
Osteoarthritis or tendonitis Acetaminophen or ibuprofen N/A
Peptic ulcer disease Acetaminophen Use caution with: All NSAIDs
Renal impairment Acetaminophen Use caution with: All NSAIDs
Rheumatoid arthritis Acetaminophen, NSAIDs like N/A
ibuprofen and naproxen sodium
Urticaria, Rash, Pruritic Rash Acetaminophen Salicylates
Adapted from: APhA. Self-Limited Pain Protocol Panel. APhA drug treatment protocols: self-care of self-limited pain. J Am
Pharm Assoc. 1999;39:321-330.

Rowland, M. The pharmacists role in pain relief. Pharmacy Post Clinical Report. June 2003.
*Labeled dosage should always be recommended unless otherwise suggested by the physi-
cian. Please refer to the Table on Drug-Drug Interactions of Common OTC Analgesics for addi-
tional information.
2.4 HEADACHE AND FACIAL PAIN

General Approach
General history: Previous episodes, acuity, timing, severity, and medications
Red flags: Very abrupt and severe (worst headache in patients life), fever, focal neurological
signs, and mental status changes such as cognitive dysfunction and diminished level of
consciousness
Physical exam (usually normal). Red flags: Neck stiffness, papilledema, or other focal deficits
are concerning
Imaging
Controversial and generally not helpful for diagnosis
Indicated for patients with red flags on general history or physical exam
Consider in the following settings:
Poor response or worsening in setting of appropriate therapy
New onset of headache in patients at extremes of age
Recent change in quality, severity, or timing of chronic headache
Association with exercise or other factors that would increase intracranial pressure (ICP)
Migraine
High morbidity in general population
Usually unilateral, gradual in onset, throbbing, lasts hours to days, and associated with
significant impairment in function
Aura (often visual), nausea, and vomiting are generally observed
Photophobia and phonophobia are often presentpain is usually relieved by removal of
these stimuli
History alone is often enough to establish diagnosis
Acute Treatment for Migraine
Trigger identification and avoidance
Initial trial with nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen at
labeled dosage
If poor response, triptans and ergots are appropriate options
If nausea and/or vomiting is severe enough to limit oral therapy, sumatriptan can be
given subcutaneously or intranasally
Early treatment may lead to improved outcomes
Prophylactic Treatment for Migraine
Appropriate in patients with frequent attacks, long lasting attacks, and attacks associated
with profound functional disability
Improves control of migraine episodes
Lowers incidence of analgesic rebound headache
General classes used for prophylaxis:
PAIN MANAGEMENT23
Antihypertensives (-blockers, ACE-I, calcium channel blockers)
Antidepressants (amitriptyline, venlafaxine)
Anticonvulsants (topiramate, valproate, gabapentin)
Avoid opioids for prophylaxis given higher associated risk of chronic daily headache,
dependence, and abuse potential
Tension-type Headache (TTH)

Bilateral pressure of waxing and waning pattern and varying duration
Degree of functional incapacitation is patient and episode dependent
Associated with stress, anxiety, and depression
Acute Treatment for TTH
Episodic TTH can be treated with analgesics agents:
Acetaminophen or NSAIDs like ibuprofen or naproxen sodium
Caffeine-containing combination agents can be used as second line therapy
Severe TTH: Can be treated with intramuscular ketorolac
Medications containing opioids, muscle relaxants, and triptans should be avoided
Prophylactic Treatment for TTH
Mainstay of therapy is the tricyclic antidepressant (TCA) amitriptyline
Mirtazapine and venlafaxine can be used as second line therapy
Side effects are a major limiting factor
Patients with frequent episodic TTH are at high risk for developing medication overuse head-
ache (MOH). Limit medication use and consider prophylactic therapy in the setting of frequent
episodes.
Chronic Daily Headache

Non-specific type of headache
Descriptive term that encompasses different subtypes of primary headaches
Definition: Duration of 4 hours or longer, 15 days or more per month, and longer than 3
months without obvious organic cause
5 subtypes:
1. Chronic migraine headache
2. Chronic tension-type headache
3. Medication overuse headache
4. Hemicrania continua
5. Daily persistent headache
Diagnosis usually reached with full headache history and associated symptoms
Treatment regimen dictated by specific headache type (e.g., botulinum toxin type
A injections are Federal Drug Administration [FDA]-approved for chronic migraine
headaches)
Trigeminal Autonomic Cephalalgias

Multiple short lasting episodesunilateral and severe
Associated with autonomic symptoms (often ipsilateral)
Periorbital erythema and lacrimation
Rhinorrhea and nasal congestion

Facial diaphoresis and/or pallor
Palpebral edema
Horners syndrome (rare)
Very selective response to therapeutic approaches
Cluster Headache
Characteristics
Deep periorbital or temporal pain with sudden progression
Severe pain that is unilateral and bursting in quality
Multiple cluster attacks a day lasting 15 minutes to 180 minutes
Patients are usually restless and/or agitated
May be accompanied by nausea, photophobia, and phonophobia
More common in smokers and in men
Alcohol intake may be a trigger
Acute Treatment for Cluster Headache
First-line: 100% oxygen and subcutaneous sumatriptan. Intranasal route is also a viable
option if subcutaneous (SQ) injection is contraindicated
If no response or contraindication to sumatriptansubcutaneous octreotide can be used
Prophylactic Treatment for Cluster Headache
Start at onset of first episode to prevent/decrease further cluster episodes during same
cluster period
Active cluster period
<2 months, glucocorticoids alone is appropriate
>2 months, choose verapamil
Paroxysmal Hemicrania
Characteristics
Sudden onset of severe periorbital or temporal pain
Pain is sharp and throbbing
Multiple attacks a day (up to 40) lasting 2 minutes to 30 minutes
Possible nausea, photophobia, and phonophobia
Treatment for Paroxysmal Hemicrania
Solely prophylactic as acute episodes are too short to be successfully treated
Indomethacin is the mainstay of therapy
Short-lasting Unilateral Neuralgiform Headache (SUNCT) Attacks With Conjunctival
Injection and Tearing
Characteristics of SUNCT
Sudden onset of severe periorbital pain
Pain is sharp and burning in quality
Multiple attacks a day (up to 200) lasting from seconds to minutes
May be triggered by cutaneous stimulation
Acute Treatment of SUNCT
Intravenous lidocaine
Prophylactic Treatment of SUNCT
PAIN MANAGEMENT25
Lamotrigine, topiramate, or gabapentin
Trigeminal Neuralgia (TN)

2 etiology categories
1. Classic: Idiopathic or associated with vascular compression
Diagnostic criteria
Paroxysmal attacks of pain lasting from less than a second up to 2 minutes
Affects 1 or more divisions of Trigeminal (V) nerve
At least 1 of the following:
Pain is stabbing, sharp, severe, and superficial
Triggered by focal stimulation or other trigger factors
Attacks are similar or same in the individual patient (stereotyped) followed by
refractory period
No obvious clinical neurologic deficit
Not caused by another disorder
2. Secondary: Caused by diagnosed structural lesion that is not related to the vasculature
Pain essentially indistinguishable from Classic TN
Cause is a structural lesion that is not associated with vascular compression
No refractory period following attack
May be associated with sensory impairment of affected region (trigeminal branch)
Utility of imaging is controversial, but may be useful in distinguishing Classic from
Secondary TN
Treatment of TN
Medical therapy is first-line treatment
Classic TN: Carbamazepine, oxcarbazepine, baclofen
Surgical therapy is reserved to TN that is refractory to medical therapy
Microvascular decompression
Nerve ablation
Rhizotomy
Gamma knife radiosurgery
Peripheral neurectomy and nerve block
Headache Secondary to Changes in Intracranial Pressure or Volume

Idiopathic Intracranial Hypertension (Pseudotumor Cerebri)
Highest incidence seen in overweight/obese women of childbearing age
Headache
The most common symptom
Pain is generally described as unilateral, severe, and throbbing
Often confused with other diagnosis: Migraines, TTH, MOH
Other associated signs and symptoms: Papilledema, vision loss (especially visual field
loss that can then be followed by visual acuity loss), diplopia, pulse synchronous tinnitus,
retrobulbar pain, cranial nerve (CN) palsy (especially the abducens nerve CN VI)
Symptoms are thought to be secondary to increase in ICP
Initial evaluation must rule out other causes of increased ICP (mass lesion, obstruction of
cerebrospinal fluid (CSF) outflow, increased CSF production)
Treatment: Symptom management and prevention of vision loss

Thunderclap Headache (TCH)
Severe, sudden headache (In a clap of thunder)
Requires urgent evaluation to rule out secondary cause, especially subarachnoid
hemorrhage
Etiologies of Secondary Thunderclap Headache
1. Subarachnoid hemorrhage
2. Unruptured intracranial aneurysm (sentinel headache)
3. Cerebral venous thrombosis
4. Cervical artery dissection
5. Spontaneous intracranial hypotension
6. Pituitary apoplexy
7. Retroclival hematoma
8. Ischemic stroke
9. Acute hypertensive crisis
10. Colloid cyst of the third ventricle
11. Infection (encephalitis, meningitis)
12. Cerebral vasoconstrictions
If secondary cause ruled out, then a diagnosis of primary thunderclap headache can be con-
sidered.
Primary Thunderclap Headache Diagnostic Criteria

Pain is severe, sudden in onset reaching maximum intensity in less than a minute
Pain lasts from 1 hour to 10 days
May recur during the 1st week, but not over the following weeks or months
Not secondary to any other disorder
In addition to standard clinical evaluation, studies used to help elucidate the etiology of TCH
include: Computerized axial tomography (CT) scan, lumbar puncture, magnetic resonance imag-
ing (MRI), magnetic resonance angiography (MRA), and angiography.
2.5 CHRONIC MUSCULOSKELETAL PAIN AND OTHER COMMON

CHRONIC PAIN CAUSES
Low Back Pain
1 of the most common reasons for outpatient clinic visits
Often seen in patients ages 35 to 55
Low back pain is classified as:
Acute: 2 to 4 weeks
Subacute: <12 weeks
Chronic: >12 weeks
Risk factors: Psychological or physical stress, heavy lifting, smoking, obesity, and psychiatric
illness (depression and anxiety)
History and physical examination are very important with special focus to rule out systemic
disease as a primary cause
PAIN MANAGEMENT27
Red flags associated with systemic disease: Older age, cancer history, weight loss, pain >30
days, or poor response to therapy, urinary and stool incontinence
Imaging is usually not helpful early in course of disease, as most episodes are self-resolving
Imaging is indicated if pain persists for >4 to 6 weeks
Plain film of spine should be done first, followed by CT/MRI if necessary
CT/MRI helpful if pain persists for >12 weeks or if there is a high suspicion of systemic
disease (especially cancer and red flags listed)
Treatment of Low Back Pain
Acute Low Back Pain
Usually has an excellent prognosis
Avoid bed rest
Treatment: Reasonable first-line analgesic choice is acetaminophen to help treat
symptoms and improve mobility. NSAIDs may also be considered, but there is
an associated higher incidence of side effects (see OTC, Rx, and Alternative Pain
Management). Muscle relaxants such as cyclobenzaprine can also be considered
If pain persists, initial therapy with opioids can be helpful; however, short course of
scheduled around the clock therapy is preferred over an as-needed (PRN) basis
Subacute and Chronic Low Back Pain
Evaluate for cause based on history and clinical assessment as outlined above
Avoid bed rest
Treatment with NSAIDs or acetaminophen during exacerbation
Limit opioids to short courses of scheduled therapy and to patients with low abuse
potential
Assess and treat exacerbating factors and co-morbid conditions: Psychosocial stress,
depression, and anxiety
A trial of tricyclic antidepressants may be of benefit even for those not suffering with
depression
Exercise has been shown to be beneficial, including yoga, aerobic, and physical therapy
Surgery generally not recommended. Early benefits usually seen but these usually do not
persist
Interventional pain procedures such as nerve blocks, Epidural injections, Sacro-Iliac joint
injections, Facet nerve blocks, Radio frequency ablation etc.
Neck Pain
Spontaneous or traumatic in origin
Usually secondary to cervical spine disease or soft tissue injury:
Myofascial pain
Cervical radiculopathy with or without spinal stenosis
Axial pain or facet joint arthrosis
Red flags: Fever, cancer history (with or without metastasis), and rapid progression of
symptoms
Rule out neurologic compromise by physical examination
Multifaceted therapy is best approach:
Pharmacotherapy: Acetaminophen or NSAIDs are first-line treatments
Muscle relaxant can be added if spasms are evident
Physical therapy with postural correction and rest
Elimination of ongoing stress or inciting factors

Interventional pain procedures such as nerve blocks, Epidural injections, Facet nerve
blocks, Radio frequency ablation etc.
If poor response to above therapy and unclear diagnosis, more thorough evaluation for
neuropathic component of pain is necessary
Burning pain with weakness, numbness, and loss of reflexes
Can be treated with antidepressants
Moderate, chronic, and refractory pain can be treated with trigger point injections, surgery,
and opioids
Shoulder Pain
Common complaint that affects majority of adults at some point in life
Deep, ache-like pain on lateral arm at point of deltoid insertion (referred pain)
Also associated with difficulty abducting arm above level of the head, pain with pressure on
shoulder area (sleeping on affected side), and reaching towards their back
Important to evaluate for history of trauma, overuse, or other inciting factor
All patients should be evaluated with a plain film radiograph
Traumatic injury should be treated with reduction (closed or open) and immobilization
Specific therapy depends on diagnosis
Non-traumatic injury can be treated with:
Rest and NSAIDs or acetaminophen for symptomatic relief
Gentle exercises followed by strengthening exercises and possible physical therapy
Differential Diagnosis
Fracture
Dislocation
Impingement
Acromioclavicular arthritis
Biceps tendinitis
Rotator cuff tear
Instability
Superior labrum anterior posterior lesion
Frozen shoulder
Cervical disk
Elbow Pain
Presentation depends on etiology and final diagnosis
Most common diagnosis and associated presentations
Epicondylitis (lateral vs. medial)
Local tenderness at muscle origin and/or tendon
Pain worse in morning and associated with tearing sensation
Secondary to avascular necrosis of common extensor or flexor tendon
Treatment: Rest, ice, splinting, NSAIDs or acetaminophen, possible steroid injection,
possible surgery
Ulnar neuropathy
Elbow pain and tenderness that is medially located (where ulnar nerve courses
medial epicondyle)
PAIN MANAGEMENT29
Associated with hypoesthesia in the ulnar nerve distribution (medial half of 4th digit
and the 5th digit), can progress to hand weakness secondary to intrinsic muscle
atrophy
Treatment: Rest, therapy, gliding of ulnar nerve
Ulnar nerve subluxation
Snapping sensation with elbow flexion and extension
Paresthesias, especially shock like sensation, in ulnar distribution
Treatment: Rest, flexion avoidance, and possible surgery if it persists
Radial nerve/peripheral interosseous nerve compression
Deep, ache like pain, distributed over extensor surface of forearm
Treatment: Rest, therapy, gliding of radial nerve, and surgical decompression may
be needed
Elbow instability
Traumatic dislocation or repetitive injury (exercise)
Treatment: Physical therapy
Fracture
Associated with acute trauma
Treatment: Reduction and immobilization, possibly open reduction and internal
fixation (ORIF)
Synovitis
Associated with elbow swelling and painful flexion/extension
Treatment: Rest, ice, splinting, NSAID therapy, steroid injection, possible surgery
Arthritis
Trauma or history of inflammation (rheumatoid arthritis)
Treatment: Rest, ice, splinting, acetaminophen as first-line therapy before trying
NSAIDs, possible steroid injection, possible surgery
Olecranon bursitis
Inflammation of olecranon bursa
Localized swelling on posterior forearm at elbow
Treatment: Usually self-limiting so observation is warranted, antibiotics are
indicated if cellulitis is present, incision and drainage (I&D) with bursectomy if no
improvement or systemic symptoms are seen
Wrist and Hand Pain

Carpal Tunnel Syndrome
Common cause of upper extremity neuropathy
Pain and/or symptoms result from compression of median nerve
Presents with hand paresthesia and/or hypoesthesia in the distribution of median nerve
Palmar surface 1st digit to lateral half of 4th digit
Dorsal surface 2nd digit to 4th digit distal to the distal interphalangeal joints (DIP)
Can eventually progress to thenar muscles weakness and atrophy
Treatment
Start conservatively with wrist splinting, NSAIDs or acetaminophen, diuretics, and
possible steroid injection
If conservative treatment fails then surgical release of transverse carpal ligament can
be performed

Ulnar Tunnel Syndrome
Caused by compression of ulnar nerve in Guyons canal (fascial band between pisiform
and hamate)
Presents with paresthesia and hypoesthesia in 5th digit and medial half of 4th digit
Can be seen in long distance cyclers, prolonged use of screwdrivers and pliers, golfers,
and racquet sports players
Treatment: Rest, avoiding inciting factors, splinting, NSAIDs, steroid injections,
occupational therapy, and ultimately surgery if conservative treatment fails
Cubital Tunnel Syndrome
Most common site of ulnar nerve compression
Injury can develop after prolonged elbow flexion, compression secondary to osteoarthritis
or inappropriate growth after elbow fracture
Patients usually present with medial elbow pain and paresthesia radiating to the 4th and
5th digits
Can eventually progress to intrinsic hand weakness (grip strength)
Treatment: Sling with immobilization to avoid elbow flexion, decreasing activities that
involve elbow flexion, and possible treatment with NSAIDs or acetaminophen
Referred Pain
Hand pain can be a presentation of myocardial infarction or stable/unstable angina as
referred pain, especially when associated with activity
Cervical disk disease
Usually presents with pain radiating from cervical area to hand
Pain path usually follows distribution of nerve root being compressed
Hip Pain
Trochanteric Bursitis
Inflammation of trochanteric bursa
Presents as lateral pain that is worsened by pressure/palpation
Treatment: Localized physical therapy, NSAIDs, and rest
Hip Arthritis
Generally presents as pain radiating to groin that is worsened by movement of hip joint
and relieved by rest
Eventually leads to decreased range of motion
Can be caused by many factors, such as osteoarthritis, osteonecrosis, trauma, sepsis, and
rheumatoid arthritis
Treatment
Initially conservative with rest, physical therapy, acetaminophen or NSAIDs, and
physical support (i.e., cane in opposite hand)
obesity is present, weight loss can significantly improve pain
If
Surgical treatment with total joint replacement may eventually become necessary if
pain is refractory to conservative measures
Avascular Necrosis (AVN)
Etiology is generally unknown
Associated with alcohol intake, steroid use, trauma, and sickle cell disease (S or SC)
Presents as groin pain and/or a limp
PAIN MANAGEMENT31
Treatment largely surgical, although initially analgesics and physical support can be
helpful
Occult Hip Fracture
Usually secondary to osteoporosis
More common in women
Generally associated with previous trauma (even if minor)
Presents as hip/groin pain and inability to bear weight on affected side
Treatment is surgical stabilization of femoral head and treatment of osteoporosis to
decrease likelihood of future fractures
Malignancy
Presents as constant pain generally not associated with activity
Can be site of primary malignancy or metastasis (especially in patients with a history of
cancer)
Treatment: Surgical intervention may decrease likelihood of future fractures
Infection
Presents with constant joint pain associated with decrease in movement of joint, inability
to bear weight, and generally worse at night
Fevers and history of bacteremia are helpful in making diagnosis
Generally presents with elevated white blood cells (WBC), c-reactive protein (CRP), and
erythrocyte sedimentation rate (ESR)
Aspiration of joint effusion can aid greatly in diagnosis with analysis of aspirate
Treatment: Intravenous (IV) antibiotics and pain relief
Knee Pain
Patellofemoral Syndrome
Presents as anterior knee pain exacerbated by prolonged sitting
Secondary to trauma, overuse or poor alignment of patella and femur resulting in
repetitive irritation
Treatment
Analgesic medication, commonly restricted to acetaminophen or aspirin, for 3 to 4
weeks, followed by a taper
For refractory pain, corticosteroid injections and surgery are options
Pes Anserine Bursitis
Presents as anteromedial knee pain
Usually caused by an abnormal gait or trauma resulting in inflammation of the bursa
between the pes anserine tendons and the medial collateral ligament (MCL)
Treatment
Address abnormal gait, ice, and avoidance of knee flexion. NSAIDs can be used for
pain but low vasculature in this region may prevent adequate therapeutic effect
pain persists for more than 6 to 8 weeks, local anesthetic and methylprednisolone
If
injections are used second as second-line
Prepatellar Bursitis
Presents with anterior knee pain and a swollen knee
Often caused by trauma or after prolonged and frequent pressure, such as kneeling
Can also be caused by urate crystal accumulation
Knee range of motion is generally preserved

Aspiration should be done to rule out infectious or crystal induced arthropathy etiology
and as a therapeutic measure
Treatment
Aspiration to reduce pressure and pain, compression dressing, ice, NSAIDs, and
avoidance of knee flexion
40% will require corticosteroid injection once infection and gout are ruled out
5% will go on to develop chronic bursitis and may require a bursectomy
Iliotibial Band Tendinitis
Presents as lateral knee pain
Common sport-associated injury (e.g., running, cycling)
Caused by repetitive friction of a tight iliotibial band with the lateral femoral condyle
Treatment: Ice, rest, NSAIDs or acetaminophen, and progressive stretching of iliotibial
band
Osteoarthritis
Presents as knee pain that is worsened by activity and relieved by rest, and morning
stiffness that improves with activity
An effusion is often present
Predisposing factors: Family history, obesity, genu valgum, genu varum, previous knee
trauma, or injury to meniscus
Treatment
Rest, ice, elevation, avoiding repetitive impact and physical therapy aiming
at strengthening the quadriceps muscle. In addition, glucosamine sulfate and
acetaminophen or NSAID course with taper
If pain is refractory to above treatment, a second NSAID course with a different
NSAID can be attempted along with local injection of corticosteroid and local
anesthetic
Surgical reconstruction of the knee joint is indicated when pain is refractory to
conservative treatment, severe disability, cartilage destruction reaches 80 to 90% or
the patient develops angulation of lower extremity
Popliteal Cyst (Bakers Cyst)
Presents with posterior knee pain associated with popliteal fossa distention and
hypoesthesia
Over time, recurrent effusions can result in a protrusion of the posterior capsule into
the posterior fossa and subsequent cyst formation
Treatment targeted towards identifying and treating source of effusion
Surgical therapy is necessary if cyst persists or venous compression is identified
Remember: Acute knee pain secondary to trauma can be a result of sports injuries to anterior
cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), lat-
eral collateral ligament (LCL), or meniscus. In addition, the differential of acute knee pain includes
septic arthritis, gout and pseudogout.
Ankle and Foot Pain

Tarsal Tunnel Syndrome
Caused by entrapment of posterior tibial nerve or its branches (medial calcaneal nerve,
medial plantar nerve, lateral plantar nerve, and first branch of lateral plantar nerve)
PAIN MANAGEMENT33
Nerve compression can occur before or after terminal branch division
Usually presents with medial mid foot pain
Roughly half of patients may have a positive Tinels sign
Compression of the lateral plantar nerve occurs most often (e.g., Joggers foot) and
causes stabbing pain in the medial sole when walking or running
Treatment
Conservative: NSAIDs, icing, massage, shoe modification, steroid injections
Surgical release
Arthritis
Inflammatory or osteoarthritis
Rheumatoid arthritis affecting the foot and ankle can be seen in up to 90% of cases
Gout and pseudogout are commonly seen involving the foot
Treatment may include: NSAIDs or acetaminophen, colchicines, steroid injection
Osteoarthritis of foot and ankle usually involves the first MTP joint and naviculocuneiform,
intercuneiform, and metatarsocuneiform joints
Treatment: NSAIDs or acetaminophen and shoe modification
Plantar Fasciitis
Inflammation of foot plantar fascia
Chronic plantar fasciitis is usually characterized by marked collagen degeneration
Pain and tenderness may be maximal over the origin of the plantar fascia on the medial
calcaneal tuberosity and along the fascia 1 cm to 2 cm distal to the origin
Associated with obesity, foot deformities, and middle age
Typically presents with pain at the distal portion of the heel pad (calcaneus) that is worse
in the morning or when standing after rest
Treatment modalities vary and include: Ice, rest, casting, NSAIDs or acetaminophen,
possible steroid injections, physical therapy, and orthotics
Most cases resolve after a period of conservative treatment
Other Heel and Foot Pain

Mortons metatarsalgia (Mortons neuroma)
Lancinating, shock-like pain between the 3rd and 4th toes upon mechanical stress
Calcaneal stress fracture
Progressively worsening heel pain
Usually follows increase in activity level or change to a harder walking and/or exercise
surface
Heel pad syndrome (fat pad atrophy)
Deep, bruise like pain in the mid heel area usually most intense over central portion of
heel fat pad
Without medial calcaneal tuberosity and plantar fascia tenderness
Achilles tendinopathy
Posterior heel pain
Sinus tarsi syndrome
Anterolateral ankle pain and/or lateral midfoot heel pain
Usually secondary to excessive motions of the subtalar joint or trauma

Results in subtalar joint synovitis and infiltration of fibrotic tissue into the sinus tarsi
space (anterior to lateral malleolus)
Calcaneal periostitis
Pain and tenderness over calcaneus
Haglund deformity related pain
A prominence of the calcaneus that may cause bursa inflammation between the
calcaneus and Achilles tendon
2.6 OTHER TYPES OF COMMON CHRONIC PAIN

Chronic Functional Abdominal Pain
Defined as continuous or almost continuous pain without evidence of organic disease that
has been present for 6 months, and interferes with daily functions
The cause of chronic functional abdominal pain is poorly understood but may be due to the
persistence of nerve sensitization after an initial event such as surgery or inflammation
Chronic functional abdominal pain is generally a diagnosis of exclusion. A broad differential
must first be ruled out
The psychosocial aspect of chronic functional abdominal pain is also very important to
consider
Treatment varies but generally includes multimodal therapeutic approaches with physical,
occupational, behavioral therapies, and medications
Avoid use of opioids and barbiturates
Fibromyalgia Syndrome
Pain-amplification syndrome in highly sensitive patients
Both sensory abnormalities and psychosocial exacerbating factors have been described
2010 PRELIMINARY DIAGNOSTIC CRITERIA (EXCERPT) AS PER AMERICAN COLLEGE OF
RHEUMATOLOGY (ACR) includes a patient satisfies diagnostic criteria for fibromyalgia if
the following 3 conditions are met:
Widespread pain index (WPI) 7 and symptom severity (SS) scale score 5 or WPI 3 -
6 and SS scale score 9
Symptoms have been present at a similar level for at least 3 months
The patient does not have a disorder that would otherwise explain the pain
Treatment
Medication based treatment
Tricyclic antidepressants
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine
reuptake inhibitors (SNRIs)
Lidocaine trigger point injection
Pregabalin and gabapentin
Muscle relaxant
Non medication treatment
Low to moderate intensity exercise has been shown to improve physical symptoms
and functional capacity
Extensive patient education is also beneficial
PAIN MANAGEMENT35
2.7 ACUTE AND CHRONIC PAIN IN DIFFERENT PATIENT
POPULATIONS
Women and Pain
Women may have higher prevalence of chronic pain conditions
Evidence suggests that the pathophysiology and experience of chronic pain in women is
different than chronic pain in men. This is thought to be secondary to the expression of
different pain receptors
Spinal cord Mu opioid receptor and Kappa opioid receptor heterodimers may represent
unique targets for providing analgesia in women
Rates of oral and or facial pain, migraines, and fibromyalgia are higher in women when
compared to rates of the same conditions in men
Pathologies specific to women
Menstrual migraines
Chronic pelvic pain
OTC treatments
NSAIDs for short-term treatment reduce swelling and relieve pain
Non-opioid analgesic acetaminophen reduces fever, relieves pain due to headaches,
back pain, sore muscles, and joint pain; can be used in combination with opioid
medications
Pregnancy and OTC analgesics
Acetaminophen: 1st/2nd/3rd trimesters - Category B
Non-salicylate NSAIDs: 1st and/or 2nd trimester - Category B; 3rd trimester Category D
Aspirin should generally be avoided
Analgesics should be used in the smallest, most effective dose for pain relief
Breastfeeding
Acetaminophen and non-salicylate NSAIDs are considered safe
Salicylates can be excreted in human milk
The use of high doses of aspirin can produce effects in the nursing infant
Ethnic Differences
Significant disparities exist on the treatment of pain in minority groups
Minority groups are less likely to be prescribed opioid therapy for severe pain
Minority patients are at risk for under-treatment of acute pain across life span and
treatment settings
They receive less analgesic therapy in general
Pain management and assessment have also been found to be less than adequate for
minority groups in emergency department settings
Different ethnic groups may have slightly different expression of drug metabolizers leading
to higher or lower drug levels than those seen in other patients
This is particularly important with codeine, as a patient who has decreased expression
of the CYP2D6 will not be able to convert codeine (pro-drug) to morphine, its active
metabolite. Therefore these patients will not receive appropriate therapeutic benefit

Pain in the Pediatric Patient
Assessment of pain, especially chronic pain, in the pediatric patients is challenging
Many tools are available to facilitate evaluation
In older children, self-report can also be reliably used
Treatment
Nonpharmacologic: Psychosocial, cognitive behavioral therapy, parental education, and
support
Pharmacologic
Organ development, different body composition and plasma protein levels must be
taken into consideration (especially in neonates) for drug metabolism, clearance,
and plasma concentrations
Acetaminophen
Common use in pediatrics because of excellent safety profile and few side
effects, if taken at labeled dosage
Often combined with opioids for the treatment of moderate/severe pain
Weight dosing is extremely important to avoid toxicity
NSAIDs
Pharmacology is similar in children and adults
Children have lower incidence of renal and gastrointestinal (GI) associated
adverse effects
Ibuprofen is commonly used for treatment of mild/moderate pain, and
ketorolac is often used for treatment of acute pain
Opioids
Dosing is dependent on the childs age as plasma clearance and drug
metabolism vary accordingly
Children are at greater risk for developing respiratory distress secondary to
opioids administration and should always be monitored
Geriatrics and Chronic Pain

Patient population frequently affected by chronic pain
Pharmacokinetic and pharmacodynamic changes with age are important to consider
Acetaminophen and NSAIDs
No adjustment in labeled dosage is necessary for older patients who take
acetaminophen for mild to moderate musculoskeletal pain
NSAIDs are associated with GI ulcers, bleeding, and gastrointestinal perforation
Acetaminophen is a better choice for relief of pain from osteoarthritis because of
decreased risk of gastrointestinal problems
The effects of NSAIDs on prostaglandin synthesis can significantly interfere with the
effects of many different types of antihypertensive medications that the geriatric
patient uses including: Diuretics, -blockers, ACE inhibitors, vasodilators, central
alpha-agonists and peripheral alpha-antagonists
Elderly patients show different patterns of drug distribution due to different body
composition, lower muscle mass, and total body water but increased fat mass
PAIN MANAGEMENT37
Elderly may be more sensitive to higher doses of opioids and exercising caution with slow
increase in doses is safer
Alcohol Use and OTC Analgesics

Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive
acetaminophen use. Therefore, healthcare professionals should inform their patients
who regularly consume large amounts of alcohol not to exceed recommended doses of
acetaminophen
The concurrent use of alcohol and NSAIDs has been associated with an increased risk of GI
bleeding and increases an individuals risk ratio for developing gastrointestinal complications
than alcohol abuse or NSAID use alone
Approximately 15% of patients treated with NSAIDs have borderline elevations of serum
transaminases, LDH, and alkaline phosphatase. NSAIDs are highly protein-bound and some
are extensively metabolized by the liver. Metabolic activity and/or plasma protein binding
may be altered in patients with hepatic impairment, which may result in a dosage reduction
for some patients
The combination of acetaminophen and alcohol, especially moderate to heavy alcohol
use, may result in a significant risk of hepatotoxicity. However, hepatotoxicity with
acetaminophen occurs almost exclusively in the setting of massive overdose. Therefore,
advise patient to strictly adhere to dosing as indicated on the medication label
Patients should be counseled about the risks of combining alcohol and OTC pain relievers
and be encouraged to not exceed the recommended label daily dose of these medications
When communicating with patients about the use of OTC pain medications and discussing
responsible dosing, especially if alcohol use is involved, it is important for you to:
Address with patients the responsible use of products containing acetaminophen and
NSAIDs
Inform patients about the potential risks of the NSAIDs and acetaminophen
Educate patients to always read package labeling and follow the label carefully
Emphasize the importance of reading the package labeling sections labeled
Warnings and Directions. One of the FDA proposed changes requires that all OTC
products containing NSAIDs or acetaminophen (including combination products)
to list these ingredients on the products principal display panel and to also specify
the potential for liver toxicity (in the case of acetaminophen) or GI complications
(in the case of NSAIDs) when these products are taken with 3 or more alcoholic
drinks daily
Stay current on OTC usage patterns, trends, proper storage, and risks with improper
use of OTC drugs because of the high occurrence of OTC medication use
Instruct patients to ask you or a pharmacist when they are not sure whether a drug
contains acetaminophen. Inform patients that severe liver damage may occur if taken
with other drugs containing acetaminophen

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NOTES
PAIN MANAGEMENT41
NOTES

NOTES
PAIN MANAGEMENT43
NOTES

3 Otorhinolaryngology:
Ear, Nose, & Throat
Sarah Boutwell, MD
Dary Costa, MD
Jastin Antisdel, MD
C o n t e n t s
3.1 EVALUATION OF HEARING LOSS . . . . . . . . . . . . . . . 44
3.2 TINNITUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.3 OTITIS MEDIA AND OTITIS EXTERNA . . . . . . . . . . . 46
3.4 CERUMEN IMPACTION . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.5 UPPER RESPIRATORY TRACT DISORDERS . . . . . . 47
3.6 EPISTAXIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.7 ORAL HEALTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
3.8 TEMPOROMANDIBULAR DISORDERS (TMD) . . . . 55
OTORHINOLARYNGOLOGY: EAR, NOSE, & THROAT 43
3.1 EVALUATION OF HEARING LOSS
History
Hearing loss is a common complaint, especially in the elderly. Determining the cause of the
hearing loss (conductive, sensorineural or mixed) may direct treatment
The most common causes of conductive hearing loss are:
Otosclerosis (stiffening of the ossicles)
Cerumen impaction
Otitis media
Sensorineural hearing loss is frequently due to presbycusis (high frequency hearing loss of
aging) or noise exposure. An audiogram will determine the severity and type of hearing loss
by measuring the softest sounds (in decibels) the patient can hear. A difference between
the air conduction thresholds and bone conduction thresholds suggests a conductive
hearing loss. Bone and air thresholds are usually the same in patients with sensorineural
hearing loss
Table 3.1: Types of Hearing Loss

Definition Cause
Conductive External or middle ear dysfunc- Obstruction such as cerumen
tion causing impairment of the impaction or foreign bodies
passage of sound vibrations to Mass loading (e.g., middle ear
the inner ear effusion)
Stiffness (osteosclerosis)
Discontinuity (ossicular
disruption)
Sensory Detiroration of the cochlea Loss of hair cells from the

organ of Corti
Noise exposure
Head trauma
Systemic disease
Neural Lesions involving the 8th CN, Acoustic neuroma

auditory nuclei, ascending tracts, Multiple sclerosis
or auditory cortex Auditory neuropathy
Table 3.2: Diagnostic Evaluation

Classification of Hearing Loss Voice Level Decibel Range
Normal Soft whisper 0-20
Mild Soft spoken voice 21-40
Moderate Normal spoken voice 41-55
Moderately Severe 56-70
Severe Loud spoken voice 71-90
Profound Shout >90

Physical Exam
Otoscopic Exam
Evaluate for cerumen impaction, otitis externa, tympanic membrane integrity, and otitis
media with effusion
Weber Test
Place a vibrating 256 Hz tuning fork in the middle of the forehead. A normal patient will
not notice a difference in 1 ear versus the other. The sound is louder in the effected ear of
a patient with conductive hearing loss. The sound is louder in the normal ear of a patient
with sensorineural hearing loss
Rinne Test
Place a vibrating 512 Hz tuning fork on the mastoid process behind the ear. When ringing
is no longer heard, the tuning fork is moved just outside the auditory canal. A normal or
positive Rinne test is when the ringing outside the auditory canal is louder than the initial
sound heard when the tuning fork is on the mastoid process. A negative Rinne test, or
decreased sound outside the auditory canal, indicates conductive hearing loss
Treatment
Options depend on the etiology of the hearing loss. In conductive hearing loss, treatment
is directed at restoring the patency of the auditory canal by cerumen removal, reduction
in swelling and treating infectious processes if present. Sensorineural hearing loss is
typically treated by reducing background noise, sound amplification devices, and cochlear
implants if hearing loss is severe bilaterally
3.2 TINNITUS
The sensation of sound in the ears, such as ringing or roaring, without external stimulus. It
may accompany hearing loss
Cause
Often caused by damage to the stereocilia, which can release an electrical signal to the
auditory nerve that is interpreted as sound. Damage can be caused by age related changes
or exposure to loud noise. Objective or pulsatile tinnitus requires imaging studies of the
temporal bone for evaluation
Treatment
Treatment is aimed at reducing annoyance caused by tinnitus and not resolution. It is
often masked by using background noise, such as using a hearing aid to introduce a more
pleasant noise into the ear
3.3 OTITIS MEDIA AND OTITIS EXTERNA
Otitis Media
An inflammatory process of the middle ear. It can be classified into acute otitis media
(AOM), which can be bacterial or viral and has associated symptoms of fever or pain. Otitis
media with effusion (OME) is middle ear fluid without fever or pain
Etiology
The most common bacterial causes of AOM are Streptococcus pneumonia, Haemophilus
influenza, and Moraxella catarrhalis. OME can develop after an episode of AOM
Presentation
AOM presents with otalgia, fever, and bulging tympanic membrane. OME includes
persistent hearing loss and dull or immobile tympanic membrane
Treatment
AOM is treated with antibiotic therapy, although observation for fever or progressive
symptoms is acceptable for 2 days. Amoxicillin is generally the 1st choice, although
ampicillin, amoxicillin-clavulinic acid, or trimethoprim/sulfizoxazole are also acceptable
treatments. OME is managed by observation or nasal decongestants. If middle ear fluid
persists then tympanostomy tubes can be considered. Untreated AOM will rarely extend
into the surrounding soft tissue or the central nervous system leading to meningitis or
intracranial abscess
Otitis Externa
A painful inflammation of the ear canal with purulent ear drainage. Malignant otitis externa
is a severe form usually in immunocompromised or diabetic patients that leads to invasion
of adjacent bone
Etiology
Pseudomonas aeruginosa is the most common cause of acute otitis externa, although
other aerobic Gram Negative species or funguses are other common causes
Presentation
Acute otitis externa (AOE) presents with fever, irritability, and acute pain, with inflamed
ear canal and tenderness of the ear. AOE is commonly called swimmers ear that is
contracted from swimming in water contaminated with aerobic Gram Negative species
Treatment
The commonly indicated bacteria are sensitive to acidic environments so that topical
agents with low pH, such as in acetic acid solutions, are most effective. Topical antibiotic
solutions may also be used. If the canal is swollen shut, a small foam wick may be placed
in the ear canal to allow penetration of the antibiotic drops

3.4 CERUMEN IMPACTION
Cerumen is a protective wax material secreted by the ear canal
Most people produce the dominant sticky type of ear wax, in which case the ear canal is
largely self-cleaning unless external factors interfere
Cerumen impaction can be caused or exacerbated by foreign bodies intended to remove
ear wax, however, in actuality, they are causing wax to be pushed further into the ear canal
and causing irritation or pain
Treatment is aimed at gentle removal of the ear wax either by manual disimpaction by
a clinician with a curette or water jet irrigator. Hydrogen peroxide solutions with gentle
irrigation can also be used at home
3.5 UPPER RESPIRATORY TRACT DISORDERS

Sinusitis
Inflammation of the sinuses
Normally ciliary activity clears sinuses of mucus so the sinuses are largely sterile. If the
sinuses become obstructed than mucus can accumulate producing signs and symptoms of
sinusitis and increasing susceptibility to sinus infection by bacteria
Sinusitis is a very common primary care office complaint and can be classified by its
duration (acute or chronic), the etiology, and the pathogen
Acute Rhinosinusitis
Sinusitis of less than 4 weeks durationtypically it occurs secondary to a viral upper
respiratory infection
Etiology
Sinusitis is caused by obstruction either from infectious causes such as viruses, or non-
infectious causes such as allergic rhinitis, barotraumas, and exposure to chemical irritants
Less common causes of obstruction can occur from polyps, sinus tumors, granulomatous
disease, and cystic fibrosis leading to decreased mucus clearance
Viral sinusitis from common pathogens such as rhinovirus, parainfluenza, and influenza is
more common than bacterial causes
Bacterial sinusitis is most commonly caused by Streptococcus pneumonia and
Haemophilus influenza; however, MRSA is an emerging cause of bacterial sinusitis
Diabetics and other immunocompromised individuals are more likely to have atypical or
polymycrobial infections such as fungal or Pseudomonas infections
Presentation
Most cases of acute sinusitis occur after a viral URI
Symptoms typically include nasal drainage, congestion, facial pain or pressure, and
headache
Purulent discharge with fever is more common with bacterial sinusitis
Tooth pain, especially in the upper molars, is more commonly associated with bacterial
sinusitis
Pain may localize to tenderness with palpation over the affected sinuses
Bacterial sinusitis can be reliably diagnosed in patients with symptoms lasting greater
than 10 days
Treatment
Most cases of acute sinusitis improve without antibiotics. Generally supportive care with
decongestants, nasal glucocorticoids, and nasal lavage is preferred in patients with mild
to moderate symptoms
Adult patients who do not improve after 7 days or who have severe symptoms should be
started on antibiotics. However, patients with mild to moderate symptoms and duration of
symptoms less than 7 days showed that antibiotics had no significant impact on cure rates
Treatment targeted at the most common pathogens includes antibiotics such as
amoxicillin and augmentin
If severe disease develops or intracranial complications occur, patients should undergo
surgical intervention and IV antibiotic administration
Chronic Sinusitis
The presence of sinus inflammation symptoms lasting more than 12 weeks
It is increasingly thought that underlying inflammation is the cause of chronic sinusitis
more than it being primarily an infectious process
The natural history of the illness is constant nasal congestion and sinus pressure with
intermittent flares
Patients should have a CT sinus to evaluate for possible structural obstructions such as
polyps. Patients should also be evaluated by an otolaryngologist to visualize the sinuses
and collect direct cultures
Antibiotic treatment is directed by culture data and is often a prolonged 3 to 4 week
course; however, appropriate treatment with concurrent topical/oral glucocorticoids and
mechanical irrigation is important
Surgery may be indicated if therapy fails
Allergic Rhinitis
After exposure to an allergen, patients develop allergic rhinitis symptoms
Approximately 20% of the North American population is affected and may occur in
seasonal variations
It is more common in people with a family history or individuals with a personal history of
asthma, eczema, or urticaria
Symptoms generally present before 40 years of agesymptoms will gradually decline with
age
Etiology
Allergic rhinitis is a Type I allergic reaction with mast cell degranulation. Degranulation
occurs after the patient is sensitized by as antigen, develops B-cell memory, and then has
a re-exposure. IgA in the mucosal surface is responsible in large part for the rhinorrhea
present in allergic rhinitis. The most typical pollen allergens are caused by trees, grasses,
and weeds that depend of wind for pollinationthese are typical causes of seasonal
allergies. Perennial allergies can be caused by animal dander, cockroaches, mold, dust,
and dust mites
Presentation
Patients present with episodic sneezing, rhinorrhea, nasal passage obstruction, itching of
the eyes, nose, or throat, and tearing of the eyes. On exam the nasal turbinates appear
boggy and pale, conjunctiva is injected, and oropharynx unremarkable. Nasal polyps are
sometimes noted

Treatment
Diagnosis of allergic rhinitis is largely made by history and can identify likely allergens by
annual timing of symptoms
Skin testing can be used to identify specific allergens
Serum levels of IgE are often elevated
Treatment is aimed at prevention of symptoms. Avoiding the allergen if possible is the
most effective method
Oral H1 antihistamines (fexofenadine, loratadine, cetirizine, diphenhydramine) assist
in managing itching, sneezing, rhinorrhea, and ocular manifestations; however, H1
antihistamines do not treat nasal congestion. Newer H1 antihistamines are more selective
and less likely to cause sedation. To treat nasal congestion, topical adrenergic agents
such as phenylephrine can be used for the short term, but can cause rebound rhinitis after
prolonged use. Oral adrenergic agents such as pseudoephedrine can be used to treat
nasal congestion, but also are most effective if used for short term. A leukotriene inhibitor
such as montelukast is helpful in treating allergic rhinitis. Intranasal glucocorticoids (e.g.;
beclomethasone, fluticasone, budesonide) are the most effective methods of treating
nasal congestion, rhinorrhea, and itching
Pharyngitis
Sore throat caused by either a viral or bacterial infection
One of the most common presenting complaints in primary care
Etiology
Pharyngitis is a typical-presenting symptom for respiratory viruses, and viruses are the
most common cause of pharyngitis
Rhinoviruses account for approximately 20% of all acute pharyngitis cases and 5% of all
cases are caused by coronaviruses
Other frequent viral pathogens include influenza, parainfluenza, and adenovirus
Less common viral causes of pharyngitis include herpes simplex virus 1 and 2,
cytomegalovirus, Epstein-Barr virus, and acute HIV infection
Bacterial pharyngitis accounts for approximately 5 to 15% of all acute pharyngitis cases
Most cases in adults (5 to 15%) is Group A hemolytic Streptococcus pyogenes, which is
associated with rheumatic fever and acute glomerulonephritis
Other causes of strep pharyngitis include Group C and G Streptococcus infections, which
are non-rheumatogenic
Fusobacterium necrophorum is almost as common as strep pharyngitis and can cause
Lemierres disease, an infectious thrombophlebitis of the jugular vein
Depending on a patients exposure, other bacterial agents should be considered such as
Neisseria gonorrhoeae, Corynebacterium diptherieae, Corynebacterium ulcerans, Yersinia
enterocolitica, Treponema pallidum (as seen in secondary syphilis), Mycobacterium
pneumonia, and Corynebacterium pneumoniae
Presentation
In a viral URI setting, acute pharyngitis, as caused by rhinovirus or cornovirus, is usually
mild and associated with other nonspecific URI symptoms such as rhinorrhea, congestion,
and cough
Viral pharyngitis is typically not associated with fever, tender cervical adenopathy, or
pharyngeal exudates
Viral pharyngitis can be severe when caused by influenza or adenovirus and will be
associated with fever, myalgias, headache, and cough
Adenovirus may additionally be associated with conjunctivitis in about 1/3 to 1/2 of
patients infected
More rare causes of viral pharyngitis can be distinguished by physical exam findings
HSV infection has vesicles and shallow ulcers on the palate, as well as pharyngeal
exudates and inflammation
The small vesicles associated with Coxsackie virus are found on the uvula and soft palate
and form small white ulcers after rupture
Both EBV and CMV can have exudative pharyngitis with fever, fatigue, lymphadenopathy,
and enlarged spleen making it difficult to distinguish clinically from acute Streptococcal
pharyngitis
In the setting of acute HIV infection, patients frequently develop a flu-like prodrome with
myalgias, arthralgias, malaise, fever, pharyngitis, and sometimes a maculopapular rash
The presentation of bacterial Streptococcal pharyngitis is similar in group A, C, and G with
a wide variance in severity of symptoms. Patients present with fever, chills, and abdominal
pain in addition to the pharyngeal pain, but no cough
On exam there is tonsillar enlargement and exudates with tender cervical
lymphadenopathy
The Centor Criteria are typically used to distinguish Streptococcal pharyngitis and
determine antibiotic usage. Some strains of Streptococcal pyogenes can present with
a strawberry tongue and erythematous rash
Other bacterial causes of pharyngitis typically present with exudates but generally
are non-specific in their clinical findings and must be distinguished based on history
alone
Treatment
Determined by the etiology. Viral pharyngitis is managed by supportive care. However,
bacterial often requires antibiotic therapy
Throat swab culture is the gold standard for diagnosis, but rapid-antigen testing can
have up to a 90% specificity, although sensitivity is only 65 to 90% depending on clinical
presentation and collection technique
The Centor Criteria is used to raise the sensitivity of testing and determine
appropriateness of antibiotic usage. A score of less than 2 points directs against antibiotic
usage. A score of 2 to 3 points should receive a throat swab and antibiotic usage dictated
by results of culture data. Scores greater than 3 points should empirically be started on
antibiotic therapy
Table 3.3: Centor Criteria for Antibiotic Usage

Sign or Symptom Point Value
History of fever Add 1
Tonsillar exudates Add 1
Tender anterior cervical lymphadenopathy Add 1
Absence of cough Add 1
Age <15 years Add 1
Age >44 years Subtract 1

Prompt treatment of S. pyogenes with antibiotics reduces the risk of rheumatic fever;
however, rheumatic fever is a rare sequelae even among untreated patients. Treatment
within 48-hours of the onset of symptoms typically reduces the duration of symptoms, as
well as reducing the potential spread of disease
Penicillin IM for 1 dose or PO for 10 days is the treatment of choice for Strep pharyngitis,
although erythromycin and azithromycin are commonly usedresistance has been
growing to these antibiotics. Complications from failure to treat include rheumatic fever,
as noted, and local invasions into the surrounding structures, sometimes with abscess
development. Acute glomerulonephritis is another complication, which is not preventable
by antibiotic treatment
In viral pharyngitis, patients suffering from influenza antivirals like oseltamivir, zanamivir,
amantadine, or rimantadine started within the 1st 36 to 48 hours of symptoms, which
reduces the duration and severity of illness. Oseltamivir and zanamivir are active against
both Influenza A and B. HSV infections can be treated by acyclovir, but treatment is
typically reserved for immunocompromised patients
3.6 EPISTAXIS
Sinusitis
This is a common primary care problem of bleeding from the anterior nasal cavity, usually
unilaterally. Posterior or bilateral bleed is a matter of medical urgency and should be
evaluated immediately
Etiology
Most commonly caused by nasal trauma such as nose picking, foreign bodies, or nose
blowing. Other causes include rhinitis, dry air, nasal septum deviation, atherosclerotic
disease, hypertension, neoplasia, cocaine abuse, alcohol use, and Osler-Webb-Rendu
syndrome (hereditary hemorrhagic telangectasias)
A less common cause is anticoagulation
The most common location is in the anterior septum in a confluence of superficial veins
called Kiesselbach plexus
Presentation
Bleeds are typically unilateral and self limiting. Patients with epistaxis typically have higher
blood pressures, but values usually return to normal once bleed has resolved. Laboratory
values such as platelet counts and INR can be useful in evaluating cause of an acute bleed
Treatment
Direct pressure on the site of the bleed for 15 minutes by compression of nares treats the
majority of cases
Nasal packing or pneumatic sealant can also be used to compress bleeding sites difficult
to compress externally
Sitting upwards reduces venous pressure, and leaning forward decreases the amount of
blood swallowed
A topical decongestant such as phenylephrine acts as a vasoconstrictor. Topical cocaine
can also be used as both vasoconstrictor and anesthetic. Silver nitrate can be applied
topically to cauterize the bleeding site or a patch can be applied. Before
applying silver nitrate, numb the nose bleed with lidocaine
If bleeding continues or bleed originates in the posterior nasal cavity, an otolaryngology
consult for packing and hospitalization for monitoring and pain control is advised
In the case of life-threatening hemorrhage, surgical intervention such as ligation of the
nasal arterial supply or endovascular embolization may be necessary
Antibiotic coverage for staphylococcal infection is necessary while packing is in place
3.7 ORAL HEALTH

Oral infections and ulcers: The most common oral infections are from periodontal diseases
such as gingivitis. The next most common infections include HSV, such as with cold sores or
Candidal species
HSV: Can affect the lips, tongue, or buccal mucosa causing irritating and painful vesicles
that progress to painful shallow ulcers. Topical antivirals such as acyclovir can be used on
cold sores, but primary infections may require PO or IV antivirals depending on extent and
host immunocompetency
Oral candidiasis or thrush: Most commonly caused by Candida albicans. Thrush is
uncommon in immunocompetent adults, although individuals on prolonged glucocorticoids
or antibiotics may develop thrush. Patients develop sore throat and burning in the
mouth and throatexam will reveal white plaques. Treatment is typically oral nystatin or
fluconazole, although IV formulations can be used in resistant cases
Vincents angina or trench mouth: Acute necrotizing ulcerative gingivitis with very
inflamed, painful gingival and ulcerations of the papillae between teeth that bleed easily.
Patients frequently have halitosis from the anaerobic bacterial pathogen causing disease.
Other common symptoms are fever, malaise, and lymphadenopathy. Debridement and oral
penicillin plus metronidazole or clindamycin is the treatment of choice
Ludwigs angina: A dangerous cellulitis of the sublingual and submandibular spaces that
is rapidly progressive. Infection source is typically an infected tooth, especially in the lower
jaw. Patients present with a constellation of symptoms including dysphagia, odynophagia,
edema, tongue displacement with possible airway obstruction, fever, dysarthria, and
drooling. The classic sign is a hot potato voice. Patients may require airway protection
temporarily with intubation or tracheostomy. Treatment is broad spectrum IV antibiotics
such as ampicillin/sulbactam, penicillin, and metronidazole
Lemierres disease: Or septic thrombophlebitis of the jugular vein can be a complication of
Fusobacterium necrophorum infection. The deep pharyngeal tissue becomes infected and
drains into the lateral pharyngeal space and then the internal jugular vein. Patients typically
present initially with pharyngitis, but then neck swelling, stiffness, pain, and dysphagia
develop. Sepsis usually develops within a week of sore throat and may develop distant
emboli. Mortality is significant. Treat with IV penicillin or clindamycin with concurrent
abscess drainage. Anticoagulation is recommended to prevent emboli, but data is not clear
on the benefits of anticoagulation therapy
Oral Tumors
Include tumors from the lips, the hard and soft palate, the tongue, salivary glands, or even
the gingiva and oral cavity floor. The anterior 2/3s of the tongue and the floor of the mouth
are the most common location for oral tumors

Epidemiology
Oral tumors are more common in developing countries and represent 3% of new cancer
cases in the US
Squamous cell cancers are the most common, and more than 50% of oral cancers contain
oncogenic HPV. HPV-positive oral tumors are typically poorly differentiate, basaloid
histopathology, with poor response to chemotherapy and radiation. HPV-16 causes
occasional chromosome loss or gross deletions, and show an increased survival after
chemoradiotherapy
Alcohol, age >50 years, and tobacco exposure represent other risk factors for oral
tumors, with a heavy prevalence of p53 mutations in alcohol and tobacco users. Smoking
is almost exclusively the cause or oral cavity floor, larynx, and hypopharynx cancer
Diagnosis
Signs and symptoms are associated with local invasion, and will change depending on the
location within the oral cavity. Patients may present with swelling, pain, otalgia, dysphagia,
odynophagia lasting weeks, and soreness in oral cancers
Physical examination includes careful inspection of all oral mucosal surfaces, palpation of
the tongue, mouth floor, and examining for lymphadenopathy. Most commonly visualized
pre-malignant lesions are leukoplakia and erythroplakia. A suspicious lesion should be
biopsied for final diagnosis. MRI and CT are useful for staging
Treatment
Local resection is principally used for localized small tumors. Radiotherapy is utilized as
a single treatment for T1 and T2 tumors, almost always including regional lymph nodes.
For T1 lesions, control is gained in greater than 90% of cases with radiotherapy, and 70 to
85% of T2 cases gain control
Tonsillar cancer often has better remission rates as it is detected sooner and can respond
to the radiotherapy more readily
Patients with squamous cell at the tongue base are more difficult to treat as they present
later; 75% of patients present with Stage III or IV disease. Chemoradiotherapy is the
treatment of choice
Dental Infection
Dental caries and periodontitis are the sequelae of plaque build-up and bacterial infection
leading to the destruction of involved tissues. Plaque is a biofilm composed largely of
normal oral bacteria
Dental Caries
Defined as inclusions in the mineralized tooth from acidic byproducts of bacterial
metabolism
Caries progress inward from the surface, eventually involving the dentin and then the
pulp from which infection can extend into the periodontal tissues at the root
Streptococcus mutans is the dominant organism causing caries, but other organisms such
as Lactobacillus acidophilus, Streptococcus salivarius, and actinomyces also contribute to
the formation of dental carries
Monosaccharides and disaccharides such as glucose, sucrose, lactose, and maltose
provide appropriate substrate for glycolysis and contribute to bacterial acid production
Bacteria can utilize sucrose to synthesize polyglycans that increase adherence and
aggregation of bacteria on the tooth surface. This polyglycan can also be utilized
by bacteria as a food source when dietary food sources are absent. This prolongs
acid production beyond the period of substrate clearance, increasing the chance of
developing dental caries
Complications of dental caries include extension of infection into the pulp, necrosis of the
pulp, extension into the root canal and the periapical area of the periodontal ligament
Further involvement can result in periapical abscess, nonsuppurating inflammation, or
cyst. If the infection goes unchecked, it may result in cellulitis, osteomyelitis, or septic
thrombophlebitis (Lemierres disease)
Incidence of new dental caries can be affected by 50 to 60% via systemic ingestion of
fluoride or 35 to 40% by topical application
Periodontal disease includes gingivitis and chronic periodontitis, both of which are caused
by plaque build-up
Gingivitis represents an earlier, reversible form of chronic periodontitis. Gingivitis refers to
inflammation of the gingiva, or gum line. Onset of disease occurs within 2 weeks of poor
tooth hygiene
Chronic periodontitis, the progression of gingivitis, with permanent bone resorption leads
to the loss of tooth support
Abscess can also develop when chronic inflammations flare at the neck of the tooth in a
single location. It accounts for the majority of tooth loss in people older than 35 years
With periodontal disease there is evidence of inflammatory infiltrate into the gingival, but
no direct invasion by bacteria in the early stages
Gram Negative anaerobic bacteria are predominantly responsible for periodontal disease.
Infections are typically microbial and include Porphyromonas gingivalis and Treponema
denticola, which grow synergistically
Halitosis
A foul odor that comes from the nasal passages or oral cavity
The bacterial decay of food and cellular debris produces sulfur compounds creating the
odor
Halitosis is associated with periodontal disease, dental caries, acute gingivitis, oral
abscess, and tongue coating
Less common causes include esophageal diverticulum with retained food particles,
esophageal stasis, sinusitis, lung abscess, and pockets of decay in tonsillar crypts
There are also systemic diseases that can cause halitosis such as renal failure (ammoniac),
hepatic failure (fishy), and ketoacidosis (fruity)
Helicobacter pylori infection can also create ammoniac breath
Treatment is aimed at correcting poor hygiene including tongue brushing and treating
infection
Tongue Syndromes
Glossitis
A red, smooth surfaced tongue caused by inflammation and subsequent loss of filiform
papillae. Typically non-painful, it is often associated with nutritional deficiencies such as
niacin, riboflavin, iron, or vitamin E. It may also be caused by drug reactions, dehydration,
foods, and even autoimmune reactions. If no cause is identified, empiric nutritional
replacement therapy is often the best first-line therapy

Glossodynia
A painful burning of the tongue which occurs both with and without concurrent glossitis.
In the presence of glossitis, it is associated with diabetes, diuretics, tobacco, xerostomia,
and candidiasis. Burning mouth syndrome is glossodynia without and identifiable cause.
Glossodynia is most common in post menopausal women, and is typically benign. If
symptoms are unilateral or suggest involvement of a cranial nerve, imaging of the brain is
reasonable to identify possible neuropathology. Treatments include alpha-lipoic acid and
clonazepam, as well as behavioral therapy
Leukoplakia
A white lesion that cannot be removed by rubbing. Often they are caused by chronic
irritation such as from dentures or tobacco, but about 2 to 6% represent dysplasia or
early invasive squamous cell carcinoma. Any enlarging areas of leukoplakia should be
biopsied
Erythroplakia
Similar to leukoplakia, but also have erythema underlying it. 90% of erythroplakia cases
are associated with dysplasia or squamous cell carcinoma. Risk factors include alcohol
and tobacco use. All erythroplakia lesions should be biopsied
Oral Lichen Planus
A lacy leukoplakia often with an erosive component caused by chronic inflammatory
autoimmune disease. It is present in 0.5 to 2% of the population. Lesions are often difficult
to differentiate between lichen planus and infectious or cancerous lesions. Exfoliative
cytology or biopsy is indicated if squamous cell carcinoma is suspected, but only about
1% of lichen planus evolves into SCC. Treatment is aimed at reducing inflammation with
corticosteroids, cyclosporines, and retinoids
Hairy Leukoplakia
Slightly raised leukoplakic are on the edge of the tongue with a corrugated surface. It is a
common early finding in HIV infection and responds clinically to zidovudine or acyclovir
3.8 TEMPOROMANDIBULAR DISORDERS (TMD)

Sinusitis
Affects 3 to 7% of the population and is a musculoskeletal disorder affecting the
temporomandibular joint, and may include the masticatory muscles
TMD can be acute, recurrent, or chronic
Women of childbearing age are more likely to experience TMD, and incidence declines after
55 years
Etiology
The cause of TMD is multifactorial with genetics, trauma, and stress all playing a part
TMD is the perpetuated by stress, harmful habits such as clenching or grinding,
poor posture, and poor sleep habits. Bruxism, the grinding of teeth during sleep, can
simultaneously be a predisposing and perpetuating cause of TMD. However, malocclusion
has not been shown to increase TMD incidence
Presentation
Patients typically present with jaw, face, and head pain. They may have difficulty opening
their jaw or experience catching or sticking with accompanying joint popping and clicking
Global headache, shoulder, and neck pain are also common as well as tooth sensitivity,
malocclusion, and abnormal tooth wear
Occasionally tinnitus, dizziness, and hearing loss are noted
CT can show bony tissue degenerative changes while MRI can evaluate for soft and hard
tissue abnormalities
Treatment
Conservative management is the most common method of treatment; less than 5%
of cases require treatment. A combination of self-care, physical therapy, splinting, and
medication with muscle relaxants and NSAIDs can provide significant relief of pain. Short
courses of oral steroids and opiates can be used in patients with moderate to severe pain
who are not responding to initial therapy; joint injections with steroid can also be useful.
Alternative therapy such as massage has also shown beneficial effects
Self-care Recommendations
The rest of the muscles and joints allow healing
Soft food enables muscles and joints to heal
Not chewing gum lessens muscle fatigue and joint pain
Relax your facial muscles: "Lips relaxed teeth apart"
No clenching; it irritates joints and muscles
Yawning against pressure prevents locking open and jaw pain
Moist heat for 20 minutes promotes healing and relaxation
Ice is for severe pain and new injuries (less than 72 hours)
Heat and ice5 seconds of heat, 5 seconds of icefor pain relief
Good posture; avoid head-forward position
Sleeping position: Side lying, with good pillow support
Jaw exercise: Open and close against finger pressure
Exercise: 20 to 30 minutes at least 3 times a week
Acupressure massage between thumb and forefinger
Over-the-counter analgesics
Yoga and meditation for stress reduction
Massage promotes healing and relaxation
An athletic mouth guard can give temporary relief
Avoid long dental appointments
Do not cradle the telephoneit aggravates the neck and jaw

1. Johnston C, Harper G, Landefeld C. Chapter 4. Geriatric Disorders. In: Papadakis MA, McPhee SJ,
Rabow MW, eds. CURRENT Medical Diagnosis & Treatment 2013. New York: McGraw-Hill; 2013.
2. Ropper AH, Samuels MA. Chapter 15. Deafness, Dizziness, and Disorders of Equilibrium. In: Ropper
AH, Samuels MA, eds. Adams and Victor's Principles of Neurology. 9th ed. New York: McGraw-Hill;
2009.
3. Pai S, Parikh SR. Chapter 49. Otitis Media. In: Lalwani AK, ed. CURRENT Diagnosis & Treatment in
OtolaryngologyHead & Neck Surgery. 3rd ed. New York: McGraw-Hill; 2012.
4. Ray CG, Ryan KJ. Chapter 59. Eye, Ear, and Sinus Infections. In: Ray CG, Ryan KJ, eds. Sherris
Medical Microbiology. 5th ed. New York: McGraw-Hill; 2010.
5. Lustig LR, Schindler JS. Chapter 8. Ear, Nose, & Throat Disorders. In: Papadakis MA, McPhee SJ,
6. Rubin MA, Ford LC, Gonzales R. Chapter 31. Pharyngitis, Sinusitis, Otitis, and Other Upper
Respiratory Tract Infections. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J,
eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.
7. Austen KF. Chapter 317. Allergies, Anaphylaxis, and Systemic Mastocytosis. In: Longo DL, Fauci AS,
Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th
ed. New York: McGraw-Hill; 2012.
8. Rubin MA, Ford LC, Gonzales R. Chapter 31. Pharyngitis, Sinusitis, Otitis, and Other Upper
Respiratory Tract Infections. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J,
eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.
9. Lustig LR, Schindler JS. Chapter 8. Ear, Nose, & Throat Disorders. In: Papadakis MA, McPhee SJ,
10. Goddard G. Chapter 26. Temporomandibular Disorders. In: Lalwani AK, ed. CURRENT Diagnosis &
Treatment in OtolaryngologyHead & Neck Surgery. 3rd ed. New York: McGraw-Hill; 2012.
NOTES

4 OPHTHALMOLOGY
Mohamed Abou Shousha, MD

Matthew D. Council, MD
C o n t e n t s
4.1 BASIC ANATOMY AND FUNCTION . . . . . . . . . . . . . . 60
4.2 BASIC EYE EXAMINATION . . . . . . . . . . . . . . . . . . . . . . . 61
4.3 COMMON CAUSES OF VISUAL LOSS . . . . . . . . . . . . . 61
4.4 AGE RELATED MACULAR DEGENERATION . . . . . 63
4.5 GLAUCOMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.6 DIABETIC RETINOPATHY . . . . . . . . . . . . . . . . . . . . . . . 66
4.7 ACUTE LOSS OF VISION . . . . . . . . . . . . . . . . . . . . . . . . 68
4.8 OCULAR INFECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.9 EYELID DISEASES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.10 RED EYE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.11 EYE IN RHEUMATOLOGICAL DISEASES . . . . . . . . . 72
4.12 OCULAR EMERGENCIES . . . . . . . . . . . . . . . . . . . . . . . . .72
OPHTHALMOLOGY59
4.1 BASIC ANATOMY AND FUNCTION
Eyelids: Provide protection to the eye. They evenly spread the tear film on the ocular
surface. Eyelid margins carry meibomian glands, which provide an important component of
the tear film. Dysfunction of these glands can cause a form of blepharitis and dry eye
Conjunctiva: Lines the inner aspect of the eyelids and covers the sclera. The conjunctiva
secretes an important component of the tear film and provides the immune surveillance of
the ocular surface
Cornea: It is the transparent avascular anterior surface of the eye. It transmits and focuses
light on the photoreceptors of the retina. Minor irregularities or opacities in the cornea can
significantly affect visual acuity. The cornea is very densely innervated, and thus corneal
diseases such as an abrasion can be associated with severe pain
Anterior chamber angle: It is the angle between the cornea anteriorly and the iris
posteriorly and is responsible for draining out the aqueous humor and thus maintaining a
normal intraocular pressure. Dysfunction in this area can cause a form of glaucoma
Crystalline lens: Together with the cornea, it focuses incoming light on the photoreceptors
of the retina. Contraction of the ciliary muscle surrounding the lens allows accommodation
of the lens, the ability to focus on objects at different distances from the eye
Uvea: Composed of the iris, ciliary body and choroid. The iris forms the pupil, which
continuously controls the amount of light entering the eye similar to the shutter of a
camera. The ciliary body secretes the aqueous humor, which provides nutrition to the
avascular cornea and lens. The choroid provides nutrition to the outer layers of the retina
Retina: Has the photoreceptors, which convert light to electrical impulses. The peripheral
part of the retina provides night vision and visual field. The central part of the retina, the
macula, is the most sensitive part, providing fine central vision
Optic nerve: Carries the electrical impulses from the retina to the brain. The optic nerve
head can be visualized during direct ophthalmoscopy and is seen nasal to the macula. The
optic nerve is surrounded by the 3 meningeal sheaths of the brain and its subarachnoid
space is connected to that of the brain
Orbit: The skull socket, which contains and protects the eye globe, part of the optic nerve,
the extraocular muscles, nerves, and blood vessels. The orbital apertures are continuous
with the intracranial cavity

Cornea
Figure 4.1: Schematic figure of the eye globe
Iris Anterior chamber angle
Canal of
Schlemm
Lens Sclera
Vitreous humor
Choroid
Retinal
pigment
epithelium
Macula
Retina
Optic nerve
Fovea
4.2 BASIC EYE EXAMINATION

Test visual acuity of each eye with the patients glasses or reading glasses, if available
Test confrontational visual fields for each eye
Inspect the eyelids, conjunctiva, sclera, cornea, and iris
Test the motility of the extraocular muscles
Assess anterior chamber depth and clarity
Test the pupils for direct and consensual light reflexes
Assess the crystalline lens for clarity
Examination of the fundus using a direct ophthalmoscope
4.3 COMMON CAUSES OF VISUAL LOSS

I- Refractive Errors
Clear vision is achieved by focusing the image of an object on the macula. Failure of this
focusing is called refractive error and is the most common cause of reversible decrease in vision.
Eyeglasses or contact lenses can correct most of refractive errors. Refractive surgery such as
LASIK (laser-assisted in situ keratomileusis) can also be used to correct refractive errors.
Amblyopia or lazy eye: Irreversible decrease of vision in 1 eye secondary to
underdevelopment of the visual cortex. Usually caused by uncorrected refractive errors
or misalignment of the eyes during childhood. Can be prevented by early screening and
intervention
Myopia (Nearsightedness): Blurring of distance vision. Image of the distant object is
focused anterior to the macula. Near vision is preserved unless the myopia is severe
Hyperopia (Farsightedness): Blurring of near vision. Image of the distant object is focused
posterior to the macula. Far vision is preserved in mild hyperopia. Accommodation can
compensate for mild hyperopia but may lead to eye strain and headaches. Compensatory
accommodation in children can result in crossed eyes (accommodative esotropia)
OPHTHALMOLOGY61
Astigmatism: Astigmatism occurs when the curvatures of the cornea (or the lens) at
different axes are not equal (the shape of an American football instead of a basketball),
resulting in failure to focus the image on the macula
Presbyopia: Progressive age related diminution of near vision secondary to a decrease in
the amplitude of accommodation. Usually starts in the 4th decade. Vision is fully corrected
by appropriate reading glasses
II- Cataract
Opacification of the crystalline lens.
Types
Senile (age-related) cataract: The most common type
Secondary: May be seen with trauma, corticosteroids, uveitis, radiation, diabetes mellitus, or
systemic diseases such as Wilsons disease or neurofibromatosis type 2
Congenital or developmental: Usually leads to amblyopia and nystagmus
Symptoms
Painless, slowly progressive blurring of vision that is usually bilateral yet often
asymmetrical
Glare (often with bright sun light or automobile headlights at night)
Decreased color vision
Some patients initially notice frequent changes in their eyeglass prescriptions and
improvement of near vision in a phenomenon known as second sight
Signs
Decreased visual acuity
Direct ophthalmoscopy: Clouding of the lens, dim or absent red reflex, difficulty
visualizing the retina
Figure 4.2: Senile cataract

Treatment
Surgical removal of the lens followed by placement of an intraocular lens
Surgery is indicated if the decrease in vision affects a patients ability to perform his/her
activities of daily living. The ophthalmologist may sometimes advise earlier or delayed
intervention depending on other ocular comorbidities
Cataract surgery is usually an outpatient surgery

Anesthesia: MAC (monitored anesthesia care) and topical eye drops with or without
local injections of anesthetic agents (intraocular or retro/peri-bulbar injections). General
anesthesia is rarely needed. Sedation is sometimes needed in anxious uncooperative
patients
The risk of serious bleeding is low. Discussion of benefit to risk ratio of discontinuing
anticoagulation perioperatively must be addressed by the ophthalmologist and the
internist. Anticoagulation can often be continued in routine cataract surgeries
4.4 AGE RELATED MACULAR DEGENERATION (AMD)

AMD is a major global public health problem. 12% of Caucasian males and 16% of Caucasian
females older than 80 years in the US suffer from the disease
It is the leading cause of legal blindness in the elderly Caucasian population in the US. It
accounts for around 54% of all cases
Risk factors are age, Caucasian race, family history, smoking, and hypertension
Types
1- Dry type (atrophic, non-exudative): 90% of cases
Symptoms
Gradual loss of central vision (usually over months or years)
Distortion of vision
An Amsler grid can be used to assess the progression of the disease. It is a grid of
horizontal and vertical lines. A change or distortion in the lines may indicate progression
of the disease, which may require treatment
Signs
Figure 4.3: Drusen in age-related macular

degeneration
Drusen are small yellow or white spots in the macula. They are usually bilateral but may
be asymmetric
In advanced cases, sharply demarcated areas of retinal atrophy (geographic atrophy) are
seen
OPHTHALMOLOGY63
2- Neovascular or exudative (wet): 10% of cases
Symptoms
Central visual loss, which may be rapidly progressive
Signs
Macular drusen, retinal pigment epithelial detachment
Choroidal neovascularization with retinal hemorrhages
Subretinal fibrosis and scar
Screening
A comprehensive eye exam by an ophthalmologist is recommended every 2 years for
people under age 65 and annually for those over age 65
Prevention
A diet rich in leafy green vegetables may lower the risk of AMD
Cessation of smoking
Protective measures against exposure to excessive sunlight
Control of hypertension
Treatment
Dry AMD:
High dose antioxidant vitamins and minerals (vitamin C and E, beta-carotene, zinc, and
copper AREDS formula): Can decrease the risk of AMD progression in moderate and
advanced AMD. Note that there is an increased risk of lung cancer with beta-carotene in
smokers and ex-smokers
Amsler grid: Should be provided for self-test on a regular basis
Low vision aids
Surgery: Miniature intraocular telescope implantation or macular translocation surgery
may be of benefit
Wet AMD:
Intravitreal injections of Anti-VEGF (vascular endothelial growth factor): The current
standard of care
Intravitreal injections of steroids
Thermal laser photocoagulation or photodynamic therapy (PDT) may sometimes be
used
4.5 GLAUCOMA
Glaucoma is a progressive optic neuropathy characterized by visual field loss and optic
disc cupping. It is usually associated with elevated intraocular pressure, which is the key
modifiable factor
Glaucoma is the 2nd leading cause of legal blindness in the US after AMD and the leading
cause among African Americans
Primary Open Angle Glaucoma

Accounts for 74% of all patients with glaucoma
More than 2.25 million Americans aged 40 years and older have the disease. About 50% of
those are undiagnosed
Risk factors include high intraocular pressure, age, African American race, family history,
diabetes, and myopia

Symptoms
Usually asymptomatic without redness or pain. Headache or eye pain is only present
when the pressure is severely elevated
Loss of peripheral vision
Central vision is preserved until late in the disease course
Signs
Visual acuity is likely to be normal except in advanced glaucoma
Relative afferent pupillary defect indicates substantial progression
Direct ophthalmoscopy will usually show optic cupping (cup/disc ratio 0.5)
Tonometry shows elevated intraocular pressure
Perimetry by the ophthalmologist can detect visual field defects
Screening
Screening is recommended for high-risk groups. A comprehensive eye exam by an
ophthalmologist is recommended every 2 years from the age of 45 to 65 and every year
afterwards
Treatment
Medical therapy: Topical prostaglandin analogues, b-blockers, a-2 agonists, carbonic
anhydrase inhibitors and/or miotics. These medications may have systemic side effects
Laser trabeculoplasty: Enhances aqueous outflow and lowers IOP
Surgical: Trabeculectomy or tube shunt surgeries
Table 4.1: Side Effects of Common Ocular Medications

Medication Side Effects Contraindications
b-adrenergic Bronchospasm, bradycardia, hypoten- Asthma and obstructive airways dis-
blocking agents sion, fatigue, depression, and decreased ease, bradycardia, congestive cardiac
libido failure, and 2nd or 3rd degree heart
block
a-agonists Hypotension, dry mouth, dizziness, and Children, as the drugs may cross the
fatigue blood-brain barrier
Prostaglandin Periocular skin pigmentation, growth Pregnancy, as animal studies have
analogues of lashes, possible flare of uveitis, or shown potential teratogenic effects
herpetic eye disease
Oral carbonic Paresthesia, fatigue, depression, hypoka- Allergy to Sulfa
anhydrase lemia, acidosis, diarrhea, nausea, aplastic
inhibitors anemia (rare)
Corticosteroids Glaucoma, cataract, and worsening of Infection
infections
Acute Angle-closure Glaucoma

Occlusion of the trabecular meshwork that drains the aqueous humor out of the eye by the
peripheral iris results in a rapid and often severe rise in the intraocular pressure
High prevalence in individuals of Far Eastern descent
OPHTHALMOLOGY65
Symptoms
Haloes around lights, eye pain, and headache
Precipitating factors include being in a dark room, reading, emotional stress, and
medications causing mydriasis such as topical mydriatics, systemic parasympathetic
antagonists, or sympathetic agonists (e.g., cold remedies)
Signs
Reduced vision (often less than 20/200)
Ciliary hyperemia (violaceous circumcorneal injection) and corneal edema
Anterior chamber is shallow
Nonreactive mid-dilated pupil
Intraocular pressure is usually very high (50 to 100mmHg)
Treatment
Immediate referral to an ophthalmologist
Supine position to encourage the lens to shift posteriorly under the influence of gravity to
break the attack
Systemic: Intravenous acetazolamide, mannitol, or glycerol. Analgesia and an antiemetic
may be required
Topical: a-agonists, b-blockers, steroids, pilocarpine
Central corneal indentation with an indentation lens can force aqueous into the angle and
may break an attack
In resistant cases: Emergency laser or surgical iridotomy, lens extraction, or
trabeculectomy
4.6 DIABETIC RETINOPATHY

Around 1/3 of diabetics aged 40 years or older have diabetic retinopathy and 4% have
vision-threatening complications related to diabetic retinopathy
More common in type 1 diabetes. Nearly all patients with type 1 diabetes and >60% of
patients with type 2 diabetes have diabetic retinopathy during the 1st 2 decades of their
disease
Risk factors: Duration of diabetes (the most important risk factor), poor control of diabetes,
hypertension, nephropathy, hyperlipidemia, and smoking. Pregnancy is not a risk factor but
can be associated with rapid progression of diabetic retinopathy

Diagnosis
Figure 4.4: Background diabetic retinopathy.

a = blot hemorrhage. b = cotton wool spot
Non-proliferative
Microaneurysms: Tiny red dots in the retina (the earliest sign)
Retinal hemorrhages: Flame-shaped and dot/blot hemorrhages
Exudates: Waxy yellow lesions with relatively distinct margins
Cotton wool spots: Small, whitish, fluffy superficial lesions
Diabetic Maculopathy
Macular edema, exudates or ischemia: The most common cause of visual impairment
Proliferative Retinopathy
Retinal neovascularization: New blood vessels form in response to retinal ischemia. New
blood vessels may bleed spontaneously resulting in retinal and vitreous hemorrhages and
subsequent retinal fibrosis and detachment
Iris neovascularization: May cause occlusion of the trabecular meshwork and neovascular
glaucoma
Screening
A dilated comprehensive eye examination by an ophthalmologist is indicated immediately
after the diagnosis of diabetes type 2 is made. An examination is indicated within 35 years
of the diagnosis of type 1 diabetes
Subsequent examinations for both type 1 and type 2 diabetic patients should be repeated
annually. Examinations will be required more frequently if retinopathy is progressing
Treatment
Improved glycemic and blood pressure control can prevent and delay the progression of
diabetic retinopathy
Laser photocoagulation therapy prevents loss of vision in patients with severe non-
proliferative, proliferative diabetic retinopathy and/or macular edema
OPHTHALMOLOGY67
4.7 ACUTE LOSS OF VISION
Transient Loss of Vision (Amaurosis Fugax)
Embolic: Occlusion of blood supply to the retina or the visual pathway (atrial fibrillation,
carotid thrombus)
Vasospasm: Migraine or hypertensive emergency
Hypoperfusion: Low blood pressure, shock, or orthostatic hypotension
Functional disorder: Hysterical and malingering
Sustained Loss of Vision

Media opacity: Corneal edema, hyphema (blood in anterior chamber) and vitreous
hemorrhage (e.g., in diabetic retinopathy)
Retinal disease: Retinal detachment, retinal vascular occlusions (e.g., central retinal artery or
vein occlusion) and retinal hemorrhages
Optic nerve disease: Optic neuritis (MS, SLE, sarcoidosis), acute glaucoma, ischemic optic
neuropathy, and giant cell arteritis
Visual pathway disorder: Stroke
4.8 OCULAR INFECTIONS

Herpes Simplex Keratitis
The most common infectious cause of corneal blindness in developed countries
Symptoms
Unilateral discomfort, redness, photophobia, watering, and blurred vision
Recurrence is common
Signs
Linear branching (dendritic) corneal ulcer. Often located centrally. Can be seen with
fluorescein stain
Figure 4.5: Herpetic corneal dendrite (ulcer) stained

with fluoroscein

Treatment
Antiviral eye drops (e.g., topical ganciclovir)
Most uncomplicated cases resolve by 2 weeks

Oral antiviral therapy may be indicated, especially in immunodeficient patients
Topical steroids may exacerbate the keratitis
Herpes Zoster Ophthalmicus

Shingles involving the V1 dermatome supplied by the ophthalmic division of the 5th cranial
nerve (trigeminal). Involvement of the skin of the tip, side and root of the nose correlates
strongly with ocular involvement
Presentation
Acute keratitis: Dendritic lesions
Can also cause conjunctivitis, episcleritis, scleritis, uveitis, optic neuritis and cranial nerve
palsies
Treatment
Oral antiviral (e.g., acyclovir)
Systemic steroids: Used only in conjunction with systemic antivirals. Have a moderate
effect in reducing acute pain and accelerating skin healing. No effect on the incidence or
severity of postherpetic neuralgia
Ocular Manifestations of HIV

HIV Retinal Microangiopathy
Develops in up to 70% of AIDS patients with declining CD4+ count
Symptoms: None
Signs: Cotton wool spots and retinal hemorrhages
Cytomegalovirus (CMV) Retinitis
Is the most common opportunistic ocular infection in AIDS
Symptoms: Floaters and blind spots. Up to 50% of patients are asymptomatic
Signs: Well-demarcated, geographic, confluent areas of retinal whitening associated
with retinal hemorrhages
Treatment: Systemic and intravitreal antiviral treatment (e.g., ganciclovir)
Other Ocular Manifestations of AIDS
Kaposi sarcoma, molluscum contagiosum, herpes zoster ophthalmicus, conjunctival squamous
cell carcinoma, and progressive outer retinal necrosis.
4.9 EYELID DISEASES

Blepharitis
(see Red Eye Table )
Chalazion
Chronic, sterile, granulomatous inflammation of the meibomian glands of the eyelid. A
secondarily infected chalazion is referred to as an internal hordeolum
Symptoms
Gradually enlarging painless nodule. Painful if infected
Signs
A nodule within the eyelid that may be tender if inflamed
OPHTHALMOLOGY69
Treatment
Warm compresses: At least a 3rd of chalazia resolve spontaneously
Persistent lesions may be treated with surgery (incision and curettage) or intralesional
steroid injection
Recurrent chalazia should be biopsied to rule out masqueraders such as sebaceous cell
carcinoma of the eyelid
Stye (External Hordeolum)

An acute staphylococcal abscess of a lash follicle
Diagnosis
A tender swelling in the lid margin pointing anteriorly, usually with a lash at the apex
Treatment
Topical antibiotics, hot compresses, and epilation of the associated lash
Eyelid Basal Cell Carcinoma (BCC)

The most common eyelid malignancy. Slow growing and locally invasive but does not
usually metastasize. 90% of basal cells occur in the head and neck and about 10% of these
involve the eyelid
Risk factors: Old age, fair skin, inability to tan, and chronic exposure to sunlight
Presentation
Firm, pearly nodule with small, dilated blood vessels on the surface
Treatment
Excision with safety margins. Recurrences after incomplete excisions can be more
aggressive
Eyelid Squamous Cell Carcinoma

Much less common but more aggressive than basal cell carcinoma with metastasis to
regional lymph nodes in about 20% of cases

4.10 RED EYE
Table 4.2: Red Eye
Symptoms Signs Management
Subconjunctival Mild soreness or for- Unilateral bright red patch None needed
Hemorrhage eign body sensation under the conjunctiva
Blepharitis Usually bilateral Scales and crusting around Warm compresses
ocular discom- lashes and eyelid scrubs
fort and irritation.
Burning, crusting Hyperemic and greasy anterior Oral tetracyclines
of lashes; worse lid margins
in morning with Topical antibiotics and
remissions and Capping of meibomian gland steroids
exacerbations orifices with oil globules
Keratoconjunctivitis Foreign body sensa- Schirmer test with reduced tear Artificial tears
sicca (dry eye) tion, burning, tearing. production
Typically worse at Punctual occlusion
end of day Corneal fluorescein staining
shows fine diffuse erosions Topical cyclosporine
Viral Excessive watery Follicles on conjunctival lining Supportive
conjunctivitis discharge, irritation, of the eyelid (e.g., artificial tears)
pruritus. Usually
starts unilateral then Preauricular lymphadenopathy Avoid close contact
becomes bilateral with people for 7 to 14
Sometimes associated with days
sore throat
Bacterial Thick purulent Mucopurulent discharge Topical antibiotics.
conjunctivitis discharge, irritation, Most common organ-
pruritus. Unilateral Sticking of the eye lashes ism: S. pneumoniae,
or bilateral together S. aureus, and
H. influenza
Allergic Clear discharge, Watery discharge Topical antihistamine/
conjunctivitis pruritus. Bilateral mast cell stabilizers
Papillae (red dots) on the con-
junctival lining of the eyelid
Corneal abrasion Pain, photophobia, Corneal staining with fluorescein Prophylactic antibiotic
watering, blurred eyedrops or ointment
vision. Unilateral
Episcleritis Redness and Inflammation of superficial Topical steroid or oral
tenderness. Usually episcleral vessels NSAID
unilateral
Scleritis Deep aching eye Inflammation of deep episcleral Periocular steroid
pain vessels. Scleral Nodule injections, systemic
steroids, and/or sys-
temic immunosup-
pressive agents
Uveitis Pain, photophobia, Ciliary (circumcorneal) injection Topical, periocular and
blurred vision, which has a violaceous hue systemic steroids
floaters
Cell and flare in the anterior Immunosuppresive
chamber agents
Hypopyon (settling of cells in Work up to determine

the inferior part of the anterior cause
chamber) in severe cases
Other causes of red eye: Foreign body in the eye, pinguecula, pterygium, thyroid-related eye disease,
eyelid malposition, keratitis (herpetic, bacterial), acute angle-closure glaucoma
OPHTHALMOLOGY71
4.11 EYE IN RHEUMATOLOGICAL DISEASES
Table 4.3: Eye in Rheumatological Diseases

Keratoconjunctivitis sicca Sjgren's syndrome, rheumatoid arthritis, systemic lupus erythematosus,
(dry eye) polyarteritis nodosa, scleroderma
Episcleritis and Scleritis Rheumatoid arthritis, systemic lupus erythematosis, Wegeners granuloma-
tosis, polyarteritis nodosa, relapsing polychondritis
Uveitis Sarcoidosis, seronegative spondyloarthropathies, Bhcet disease, Lyme
disease, juvenile rheumatoid arthritis
Keratitis Systemic lupus erythematosis, Wegeners granulomatosis, polyarteritis
nodosa
Anterior ischemic optic Giant cell arteritis
neuropathy
4.12 OCULAR EMERGENCIES

Retinal Artery Occlusion
Occlusion of the central retinal artery or one of its branches with a thrombus or embolus.
Symptoms
Sudden and profound painless loss of vision in 1 eye
Vision loss can be confined to a sector of the visual field in cases with branch artery
occlusion
Spontaneous dislodgment of the embolus can occur resulting in regaining of vision
(amaurosis fugax). This is a form of transient ischemic attack (TIA)
Signs
Narrowing of the retinal arteries and veins with segmentation of the blood column
Cherry red spot at the center of the fovea is seen surrounded by cloudy white ischemic
retina
Emboli can sometimes be seen
Treatment
The aim is to dislodge the emboli before retinal infarction occurs.
Ocular massage, intravenous mannitol, sublingual isosorbide dinitrate, topical
apraclonidine, topical timolol and intravenous acetazolamide
STAT ophthalmology consultation
Anterior chamber paracentesis by an ophthalmologist
Intra-arterial thrombolysis
Note that the risk of stroke is high. Stroke workup and prophylaxis is advisable
Acute Angle Closure Glaucoma

1. Eye Trauma
Chemical burns to the eye (EMERGENCY!!)
Requires emergency treatment before completing a thorough history and examination.
Alkali burns are the most serious as alkali causes denaturation of proteins and rapidly
penetrates into the eye. The most commonly involved alkalis are ammonia, sodium
hydroxide, and lime

Immediate treatment
Copious irrigation with sterile normal saline or lactated Ringers is crucial until pH is
neutral (use tap water if necessary to avoid delay). This will often take several liters of
fluid
The speed and efficacy of irrigation is the most important prognostic factor
A topical anesthetic prior to irrigation improves comfort and facilitates cooperation
Eversion of the upper eyelid is imperative to identify and remove any retained particles
STAT ophthalmology consultation
2. Corneal Foreign Body or Abrasions
Symptoms
Sudden eye discomfort, tearing and photophobia. History suggestive of a foreign body is
usually elicited
Signs
Careful slit lamp exam and fluorescein staining of the cornea to detect the foreign body
Eversion of the upper eyelid may be necessary to reveal hidden foreign bodies
Treatment
Foreign body can be removed with a 25 gauge needle held parallel to the cornea under
the slit lamp microscope
Prophylactic antibiotic eye drops are advisable
Foreign bodies from grinding metals raise suspicion for an intraocular foreign body/
ruptured globe. A CT scan of the orbit and ophthalmology consult are advisable in such
cases
3. Hyphema
Hemorrhage into the anterior chamber of the eye.
Symptoms: Blurry vision after a severe blunt trauma
Signs: Red blood cells sediment inferiorly in the anterior chamber with a resultant fluid
level
Treatment is aimed at prevention of secondary hemorrhage and control of any elevation
of intraocular pressure. Ophthalmology consult is required. An occult ruptured globe
must be ruled out
4. Ruptured Globe
Caused by penetrating as well as severe blunt trauma
Prolapse of intraocular structures such as the lens, iris, vitreous, or retina is usually evident
Note that an anterior rupture may be masked by extensive subconjunctival hemorrhage
An occult posterior rupture can be associated with little damage to the anterior segment
but should be suspected if there is an asymmetry of the anterior chamber depths in the
setting of trauma
Cover the eye with a protective eye shield and get STAT ophthalmology consultation
Consider CT orbit to rule out intraocular and/or intraorbital foreign bodies, especially if
the nature of the injury is suggestive
Antiemetic as needed to prevent worsening of rupture
OPHTHALMOLOGY73
NOTES

5 Gynecology & Womens Health
Anne Davis, MD
C o n t e n t s
5.1 SEXUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
5.2 CONTRACEPTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
5.3 VAGINITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.4 BREAST PAIN (MASTALGIA) . . . . . . . . . . . . . . . . . . . . 80
5.5 BREAST MASS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
5.6 ABNORMAL UTERINE BLEEDING . . . . . . . . . . . . . . . . 81
5.7 DYSMENORRHEA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.8 MENOPAUSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
GYNECOLOGY & WOMEN'S HEALTH75
5.1 SEXUALITY
Sexual Functioning
Most women describe themselves as heterosexual, about 4% as bisexual, and about 2% as
lesbian; however, about 12% of women report sexual experience with another woman
Most heterosexual women in the US begin having vaginal intercourse around age 17; 98% of
women will have intercourse at least once
Most couples are satisfied with their sexual relationships and report sex from a few times a
week to a few times a month. Even those having sex much less frequently can report high
sexual satisfaction
Important components of the sexual response (desire, arousal, and orgasm) are similar
in women and men, but may not occur in a linear manner. For example, many women
experience arousal before desire
Low Interest in Sex

Low interest in sex is common and is only a problem if associated with distress
Decreased desire may be related to depression or anxiety, co-existing medical illnesses, life
stresses, relationship, sexual boredom, or sexual pain
Medications that can decrease interest in sex include SSRIs and anti-hypertensives, among
others. There is no clear link between hormonal contraception and libido
There is no strong relationship between endogenous testosterone and libido in women
Low Arousal and Difficulty With Orgasm

As with desire, low arousal and problems with orgasm are only a problem if associated with
distress. Sexual satisfaction in women is not tightly linked to the occurrence of orgasm
Poor sexual stimulation is a common cause of low arousal and lack of orgasm; this can be
addressed through couple communication
Medications interfering with libido can also lead to problems with arousal and orgasm
Pain During Sex (Dyspareunia)

External pain can be caused by urogenital atrophy after menopause, vaginitis, low arousal,
vestibulitis, or vaginismus (muscular tightening of the vaginal opening)
Internal pain has many causes related to pelvic pathology. Common sources include ovarian
cysts, myomas, surgical scarring, and endometriosis
Treatment of Sexual Problems

In most cases sexual problems improve, but may not resolve, with supportive counseling
from a primary care provider or therapist
No pharmacotherapy has been approved for low libido in women
Decreased estrogen in menopause can hinder arousal in some women if urogenital
atrophy causes dryness and decreased tissue elasticity. These changes can be treated with
lubricants and estrogen replacement, either local or systemic
Pain should be addressed through treatment of its source

5.2 CONTRACEPTION
More couples need access to effective contraception; half of all pregnancies in the US are
unplanned
The most effective methods are sterilization, which is permanent, and long-acting reversible
contraception (LARC) methods of the IUD and implants
LARC methods have failure rates of less than 1% per year. Methods such as pills, rings,
patches, and injections require daily, weekly, or monthly effort by the user as well repeat
visits to a pharmacy. With typical use, these methods are associated with pregnancy rates
20 times higher than sterilization or LARC
Effective contraception is especially important for women with medical conditions that
increase maternal and fetal risk with pregnancy; such pregnancies have better outcomes
when planned
Combined Hormonal Methods: Pill, Patch, Ring

Oral contraceptives (OCs) are the most commonly used method in younger women in
the US. Women after 35 most often rely on sterilization. There are many OC formulations
available. Most OCs contain a synthetic estrogen and progestin; 1 OC contains only a
progestin. OCs vary in their doses of estrogenic and progestin doses. Currently available
OCs with varying doses have comparable safety profiles
OCs prevent pregnancy primarily by preventing ovulation. All combined methods (estrogen
plus progestin) are immediately reversible, baseline fertility returns completely after only a
few weeks
OCs have at least 3 weeks of active pills and 1 week or fewer of placebo pills (or pill free
interval). Bleeding occurs during use of the placebos or pill-free interval. OCs can be taken
safely with a pill-free interval every few months or without a pill-free interval (continuously)
OCs can be started without a back-up method during the 1st 7 days after spontaneous
menses begins. If started at some other time, a pregnancy test should be performed and
if negative OCs may be started with a back-up method such as condoms for 1 week. OCs
given inadvertently in early pregnancy are not harmful because contraceptive steroids
are not teratogenic. If a pill is missed, 2 pills may be taken the next day without reducing
efficacy
The contraceptive ring combines an estrogen and progestin and is placed in the vagina
for 3 weeks. It is removed and a new ring is placed 1 week later. The contraceptive patch
combines an estrogen and progestin and is worn on the skin, 1 week per patch for 3 weeks
of the month; it too is removed for a week then restarted with a new patch
Side Effects
Many women experience some unpredictable, or breakthrough, bleeding in the 1st months
of use with OCs, patches and rings which usually resolves. Combined hormonal methods
do not cause weight gain or clinically important psychological changes
Table 5.1: Drug Interactions
Medicines that can decrease the efficacy of hormonal
contraception
Griseofulvin
Rifampin
Carbamazepine
Phenobarbital
Dilantin
Oxcarbazepine
Bosentan
Safety
Combined hormonal contraceptives are Safety of contraception for women with medical
much safer than pregnancy. Serious conditions: Where to go to know
complications of use are largely related to
U.S. Medical Eligibility Criteria for Contraceptive Use,
thrombotic effects of estrogens
2010
Users experience a very small absolute Adapted from the World Health Organization Medical
risk of venous thrombosis, embolism, Eligibility Criteria for Contraceptive Use, 4th edition
stroke or myocardial infarction. These risks www.cdc.gov
increase for women who smoke and use

methods with estrogens, more dramatically after age 35, and women with a personal
or family history of thrombosis, hypertension, personal history of stroke or MI, diabetes
with vascular disease, migraine with aura, SLE with vascular disease, cardiac disease or
smoking after age 35 years
Other contraindications include active gallbladder disease, liver dysfunction, and
hormonally sensitive cancers (breast, endometrial). Combined methods are not
contraindicated for women with a family history of breast cancer
Use of OCs reduces the risk of ovarian and endometrial cancer, improves acne, decreases
menstrual bleeding and dysmenorrhea, lowers risk of PID, and prevents some forms of
ovarian cysts
Progestin Only Methods: Injectable and Implants

Depo-medroxyprogesterone acetate (DMPA) is administered IM every 3 months. The
contraceptive implant is a 3 cm flexible rod placed subdermally in the upper arm for 3
years. Both methods have a failure rate of less than 1% per year
Erratic bleeding is normal with injectable DMPA or the implant. With DMPA bleeding
decreases dramatically; 75% of women report amenorrhea after 1 year
DMPA is associated with weight gain of approximately 5 pounds per year. Implant use
is not associated with weight gain. DMPA, but not the implant, causes small, reversible
decreases in bone density
Full return to fertility occurs immediately after implant removal, but may not occur until 18
months after DMPA
Because progestin-only methods are not pro-thrombotic they are safe when estrogen
is contraindicated due to thrombosis risk. For instance, DMPA and implants can be used
in women with a history of VTE. Highly-effective methods are essential for women anti-
coagulated with coumadin, a potent teratogen

Intrauterine Devices
Two intrauterine devices are available. The T380A (Copper) IUD contains no hormones and
may be used for 10 years. The levonorgestrel (LNG) IUD elutes a progestin for 5 years
Both types of IUD prevent fertilization because copper is spermicidal and progestins
change cervical mucous to stop sperm penetration
The copper IUD may cause longer, heavier menses or more cramping, however, in many
women their menses does not change. After an initial period of erratic bleeding, the LNG
IUD reduces menstrual flow substantially
After removal, full fertility returns with both devices. The modern IUD does not increase the
risk of pelvic inflammatory disease or tubal infertility
Women who have never been pregnant may safely use either IUD
Barrier Methods
Male latex condoms are widely used for contraception and are easy obtained over the
counter. Polyurethane condoms are as effective as latex versions. Female condoms are also
available
Condom use reduces, but does not eliminate, the risk of STI acquisition
Typically, at least 15% of couples that use condoms as their only method will experience a
pregnancy during a year
Other barrier methods include the female diaphragm and cervical cap. These methods must
be used with a spermicide. Failure rates are high, about 20% per year
Emergency Contraception
Emergency, or post-coital, contraception reduces the risk of pregnancy after intercourse
primarily by inhibiting ovulation. Women over 17 may obtain EC without a prescription
EC contains progestin in a dose higher than OCs, without estrogen, and will reduce the risk
of pregnancy related to unprotected intercourse in the previous 72 hours
A newer form of EC, ulipristal acetate, is effective for 5 days after unprotected sex
A copper IUD is effective for EC up to 7 day after unprotected sex
5.3 VAGINITIS
Women with vaginitis describe symptoms with some combination of abnormal discharge,
irritation or itching, odor and occasionally pain. Some forms of vaginitis are due to sexually
transmitted infections. A directed physical exam and wet preparation should guide diagnosis and
treatment. Asymptomatic yeast or BV detected by PAP testing or exam does not require treatment.
Yeast Vaginitis or Vulvitis

Symptoms: Cheesy or curdy white vaginal discharge and itching, can be intense
Predisposing factors: Immunosuppression, recent antibiotics
Exam: Erythematous vulva or vagina, white curdy discharge
Wet mount: Many WBCs, hyphae on KOH prep, pH is low
Not sexually transmitted
Treatment: Oral or topical anti-fungal, latter is OTC
Bacterial Vaginosis
Symptoms: Discharge, fishy odor especially after intercourse
Pre-disposing factors: Previous BV, tends to recur
Exam: Thin, grey vaginal discharge
Wet mount: + odor with KOH added, Clue cells on saline prep, pH high
Not sexually transmitted
Oral or topical metronidazole, avoid alcohol with oral form
Trichomoniasis
Symptoms: Itching, can be intense
Predisposing factors: New partner
Exam: Greenish, frothy vaginal discharge, erythematous vagina and cervix (strawberry
cervix)
Wet mount: WBCs, motile flagellated trichomonads, pH is high
Treatment: Oral metronidazole 1 dose, also for partner
Sexually transmitted
Herpes
Symptoms: Focal edema, pain and vesicles that ulcerate, primary infection may occur with
fever and adenopathy
Predisposing factors: New partner
Exam: Swollen, tender area on perineum, cervical, labial or perineal blisters or ulcers, vaginal
discharge
Wet mount: WBCs, pH is low
Treatment: Oral acyclovir or valacyclovir
Sexually transmitted, symptoms may be due to primary or recurrent HSV
Atrophic Vaginitis
Symptoms: Painful intercourse, irritation with urination, discharge, itching
Predisposing factors: Menopause
Exam: Thinned vulvar tissues, narrowed introitus, erythema
Wet mount: WBCs
Treatment: Lubricants, systemic or topical estrogen replacement
5.4 BREAST PAIN (MASTALGIA)

Breast pain can be cyclical or non-cyclical. Most women with breast pain do not have
cancer, but cancer can present with breast pain. Any woman who presents with a breast
complaint should have a complete exam of both breasts and axillae
Cyclical breast pain is usually hormonal in etiology, bilateral, begins in the luteal phase and
dissipates with menses. This pain is usually mild but can be stronger
Cyclic mastalgia with a normal exam can be treated with a well-fitting bra, warm or
cold packs, acetaminophen, or NSAIDs
Non-cyclical pain is more likely to be unilateral, related to a breast or chest wall lesion.
Breast-related causes include: Large breasts, hormone replacement therapy, pregnancy,
ductal ectasia, breast cancer, especially inflammatory, mastitis (usually in lactating women),
and surgical scarring. The etiology will guide treatment

5.5 BREAST MASS
In most women who present with a breast mass there is no underlying cancer. Every
woman who presents with a breast mass should have a complete exam and if needed,
imaging. Breast cancer is strongly related to age. Abnormal physical findings are more likely
to indicate cancer in older women and in women with a family history of breast cancer
Physical findings suggestive of malignancy include skin changes (peau dorange,
retraction), a mass, nipple ulceration or bloody nipple discharge. Lymphadenopathy
may also be present
Galactorrhea is not associated with cancer and is usually bilateral
Cancerous lesions are more likely to be isolated, hard, irregular, and fixed
Benign masses: These are most commonly fibroadenomas and cysts
Imaging: A diagnostic mammogram should be the first test ordered in women over 30
with a new breast mass. Targeted ultrasound, combined with mammography, may aid in
evaluation of a breast mass in a woman over 30. Ultrasound is the first step to evaluate a
mass in a woman under 30
As yet, there is no clear role for MRI in the diagnostic evaluation of breast lesions
A suspicious finding on physical exam should be evaluated for biopsy, even if a diagnostic
mammogram is negative
5.6 ABNORMAL UTERINE BLEEDING

Most women have a menstrual cycle of 21 to 35 days in length, bleeding lasts on average
for 5 days, and usual blood loss per cycle is less than 80 mL. Disorders of the menstrual
cycle include absence of menstrual bleeding (amenorrhea), fewer menses than normal
(oligomenorrhea), bleeding between menses (intermenstrual bleeding) or heavy menstrual
bleeding. The work-up of irregular or heavy bleeding should include cervical cytology and
endometrial sampling to rule out cancer in women over 35. Ultrasonography is helpful for
anatomic causes
Amenorrhea can be primarynever experiencing a periodor secondary when periods
disappear after establishment of menses
Primary amenorrhea may be a normal variant in adolescents who start menarche later
Secondary amenorrhea and oligomenorrhea: Pregnancy should be ruled out
first. Common causes include endocrinopathies such as PCOS, thyroid disorders,
hyperprolactinemia, low BMI, vigorous sustained exercise. Premature ovarian failure is
an uncommon but important cause and is diagnosed by elevated gonadotropins (FSH)
Thyroid disorders can lead to a variety of menstrual disorders, from amenorrhea to
heavy, frequent menses with anemia
Hyperprolactinemia, from adenomas or medications, can cause oligomenorrhea and
amenorrhea. Galactorrhea is often present with bilateral milky white breast discharge
Intermenstrual Bleeding
Occurs between regular menstrual cycles. Rule out pregnancy. Other causes include
cervical or endometrial polyps, myomas, cervicitis (chlamydial is common), endometrial
hyperplasia or cancer, or cervical dysplasia/cancer
Heavy Menstrual Bleeding (HMB)
May lead to severe anemia. A complete blood count should be included. Start iron
empirically
Can be due to endocrinopathies, hemoglobinopathies, or anatomic causes
Endocrinopathies include hypothyroidism and PCOS. Von Willebrand disease is the most
common inherited coagulopathy
Anatomic causes include uterine polyps and myomas (especially when impinging on the
uterine cavity-submucous)
Treatment
Amenorrhea and oligomenorrhea treatment Polycystic ovarian syndrome (PCOS)
will depend on the etiology such as correction Associated with infrequent, irregular and sometimes
heavy menstrual flow due to anovulation. Diagnosis:
of thyroid disease and hyperprolactinemia.
Typical ovarian appearance on sonography, clinical evi-
Primary ovarian failure requires hormone dence of hyperandrogenism such as hirsutism and acne,
replacement and careful discussion of fertility with menstrual irregularity. Many patients are also obese
implications. Menstrual irregularities due to and abnormalities of lipids and insulin resistance may be
present. Infertility may occur.
PCOS can be managed with weight loss and
OCs in women not seeking pregnancy
HMB should be treated initially with iron replacement. When not associated with a hormonal
etiology or cancer, HMB can be treated with non-hormonal treatments such tranexamic
acid, or NSAIDs or hormonal treatments such as OCs, DMPA or the hormonal IUD. Surgical
treatments include endometrial ablation, myomectomy or hysterectomy
5.7 DYSMENORRHEA
Dysmenorrhea refers to pain with menstrual bleeding. Primary dysmenorrhea is pain in the
absence of an anatomic cause. Primary dysmenorrhea is very common in young women; 85% of
adolescents experience menstrual pain and 15% describe it as severe.
Primary dysmenorrhea: May be associated with nausea, vomiting, and inability to participate
in normal activities. Related to over-production of uterine prostaglandins. Effective
treatments include NSAIDs, acetaminophen, and hormonal therapy with OCs, DMPA
Secondary dysmenorrhea may also respond to NSAIDs, acetaminophen, and hormonal
treatments; however, when due to another etiology that must be addressed: Myomas,
endometriosis
Table 5.2: OTC Pain Relievers for Dysmenorrhea

For treatment of primary symptoms
Ibuprofen
Naproxen sodium
Acetaminophen
Recommend labeled dosing of OTC analgesics

5.8 MENOPAUSE
Menopause is defined as the absence of spontaneous menses for 1 year. The average age at
menopause is 50 years old in the US.
The diagnosis is clinical. FSH levels are elevated in menopause. Perimenopause can be a
process of several years normally associated with dramatic hormonal fluctuations; hormonal
testing is not helpful
Most common symptoms are hot flushes/night sweats and vaginal dryness. Not all women
get hot flushes, but this is the most bothersome symptom. Other changes: Decreased bone
density and long-term increased risk of fracture
Replacement Therapy: Treatment of Symptoms: Systemic

For women with a uterus, estrogen must be given with a progestin to protect against
endometrial hyperplasia and cancer. For women without a uterus, estrogen can be given
alone
Systemic estrogens: Give continuously via transdermal, oral, vaginal ring, cream routes. Start
with lowest dose and work your way up for symptoms
Progestins: Use continuously, use recommended doses via oral or transdermal routes
Estrogens and progestins are available separately in or combination products
Estrogens reduce hot flushes and vaginal dryness by 90%, alternatives that do not work as
well but are better than placebo include clonidine, progestins alone, SSRI, or gabapentin
No clear guidelines on how long to continue, try to taper off when patient ready
Replacement Therapy: Treatment of Vaginal Symptoms: Local

Vaginal pills (estradiol 10 mg twice a week) or 1/2 g cream can be used without increase
risk of systemic risks, safe with personal hx breast cancer
Indications
Symptomatic hot flushes or vaginal dryness, not prevention of heart disease or osteoporosis
Contraindications
Elevated risk of CVA, MI, DVT, current breast cancer any age, active liver disease (local
therapy in vagina likely acceptable risk in any of these conditions)
Risks
Different for women in their 50s and women 60 and older
Younger women estrogen only (no uterus): No increased risk of breast cancer, very
small increase VTE, increased risk of heart disease and stroke very small, if any
Younger women estrogen and progestin (with uterus): Estrogen and progestin very
small increased risk of breast cancer after 4 to 5 years of use. Small increase risk VTE,
risk of heart disease and stroke very small if any
Older women: Increase risk VTE, MI, CVA as well as breast CA. Absolute risks for all
outcomes low but serious outcomes. Higher threshold to start replacement
NOTES

6 Dermatology
Adam Friedman, MD, FAAD

Lorraine Rosamilia, MD, FAAD
C o n t e n t s
6.1 COMMON DIAGNOSTIC TESTS . . . . . . . . . . . . . . . . . . 87
6.2 COMMON DERMATOSES . . . . . . . . . . . . . . . . . . . . . . . . 87
6.3 INFLAMMATORY DISEASES OF THE ADNEXA . . 97
6.4 FUNGAL SKIN AND NAIL INFECTIONS . . . . . . . . . 100
6.5 BACTERIAL INFECTIONS . . . . . . . . . . . . . . . . . . . . . . 103
6.6 VIRAL INFECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
6.7 STDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6.8 PARASITES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
6.9 BITES AND STINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
6.10 COMMON NEOPLASMS . . . . . . . . . . . . . . . . . . . . . . . . 123
6.11 BENIGN TUMORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
6.12 PRURITUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
6.13 URTICARIA/ANGIOEDEMA . . . . . . . . . . . . . . . . . . . . . 127
6.14 COLLAGEN VASCULAR/CONNECTIVE TISSUE

DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
DERMATOLOGY85
6.15 AUTOIMMUNE BLISTERING DISEASES . . . . . . . . . 134
6.16 ALOPECIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
6.17 CUTANEOUS MANIFESTATIONS OF INTERNAL .

DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
6.18 SELECTED DERMATOLOGIC EMERGENCIES . . . 145
6.19 SPECIAL POPULATIONS . . . . . . . . . . . . . . . . . . . . . . . 146
6.20 HIGH YIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

6.1 COMMON DIAGNOSTIC TESTS
Table 6.1: Dermatologic Diagnostic Examinations

Test Diagnosis
Tzanck Herpes virus, Langerhans cells (useful for Langerhans cell histiocytosis)
KOH Fungi or yeast
Cultures Bacterial or viral
Gram Stain Bacteria, eosinophils (useful for erythema toxicum neonatorum)
Patch Allergic contact dermatitis (ACD)
Mineral Oil preparation Scabies (mite, feces, ova)
Biopsy
Shave Epidermal processes: Includes but not limited to seborrheic keratoses,

basal cell carcinoma, squamous cell carcinoma, cutaneous T-cell
lymphoma (looking for atypical lymphocytes in the epidermis)
Punch Includes but not limited to sarcoidosis, granuloma annulare, metastatic

cancer
Wedge Deep processes (panniculitis, deep fungal infections)
Excisional Dysplastic nevi, melanoma
6.2 COMMON DERMATOSES

Eczematous
Atopic Dermatitis
Figure 6.1: Flexural fissured erythematous

plaque of eczema
Major features
Pruritus
Facial and extensor involvement in infants and children
Flexural lichenification (increased skin markings) in adults
DERMATOLOGY87
Chronic or relapsing dermatitis
Personal/family history of atopy
Eye findings: Keratoconus may be associated, anterior and posterior cataracts (usually
secondary to long term steroid use)
Infections
Eczema herpeticum
Figure 6.2: Eczema herpeticum
Molluscum contagiosum
HPV
T. rubrum and P. ovale
S. aureus in 90%
Impaired innate antimicrobial peptides
Human B-defensin and cathelicidins Decreased in AD patients
May explain increased colonization
Elevated IgE
Most AD patients DO NOT have food allergy
Contact Dermatitis
Florist dermatitis - Compositae Sesquiterpene lactone
Causes: Ragweed, chrysanthemum, feverfew, liverwort, lettuce, sage, artichoke,
marigold, sunflower, philodendron, Peruvian lily, and others
Patch test with Sesquiterpene lactone mix
Chromium
Cement and tanned leather
Blackjack felt dermatitis
Cross-reacts with nickel
Cobalt
Vitamin B12 injections
Cross-reacts with nickel
Colophony Resin from tree sap used for adhesion
Bandages
Turpentine lacquer and varnish
Mascara, chewing gum, and newspapers
Preservatives
Quaternium-15 #1 cause of preservative dermatitis
Imidazolidinyl urea #2 culprit

Quaternium-18-bentonite - ivy block
Parabens
Most common preservative overall
Glutaraldehyde
Cold sterilizing agent healthcare workers
Latex
Cross-reactions
Avocado, banana, chestnut most commonly Kiwi, passion fruit, mango, fig,
cantaloupe, and others
Cerebral palsy patients commonly have latex allergy
Chemicals that penetrate latex gloves
Nickel, cobalt, formaldehyde, acrylates, epoxy resin, thioglycollate, glutaraldehyde
Nickel
Dimethylglyoxime test to check for nickel (turns metal pink)
Poison ivy/oak: Toxicodendron sp.
Pentadecylcatechol from oleoresin or urushiol
Cross reactions
Cashew; lacquer tree; mango rind (not juice); Indian marking tree; gingko leaves
(not the supplement); Brazilian pepper; Rengas tree (black varnish)
Stasis Dermatitis
Subacute to chronic dermatitis with hemosiderin (brown), dilated capillaries in fibrotic
dermis
May be exacerbated by application of topical steroids or topical antibiotics if a
concomitant allergic contact dermatitis is present
Often confused for cellulitis (bilateral cellulitis of the leg is usually stasis dermatitis)
Pigmented Purpuras
Figure 6.3: Schambergs pigmented purpura
Chronic capillaritis; superficial vessels dilated with endothelial cell hypertrophy and
surrounding extravasated red blood cells
Variants include:
Progressive pigmentary dermatosis of Schamberg
DERMATOLOGY89
Lichen aureus
Eczematoid purpura of Doucas and Kapetanakis
Lichenoid dermatitis of Gougerot and Blum
Purpura annularis telangiectodes of Majocchi
Lichen Planus (LP)
Figure 6.4: Lichen planus
Inflammatory disorder that affects the skin, mucous membranes, nails, and hair
The Ps: Purple, polygonal, pruritic, papule, planar
Wickhams striae fine, whitish reticulated networks on surface of well-developed plaques
Prevalence: <1%, no racial preference
Many clinical subtypes:
Annular (more common in darker skin), atrophic, linear, erosive, hypertrophic (shins)
Erosive mucous membrane disease more common in patients with hepatitis C
infection
Graham-Little syndrome
Follicular lichen planus of skin and/or scalp
Multifocal cicatricial alopecia of scalp
Nonscarring alopecia of axillary and pubic areas
LP of the nails
10 to 15% of cases
Usually in combination with other LP lesions on skin
20-nail dystrophy (trachyonychia)
Thinning, longitudinal ridging, and distal splitting of nail plate (onychoschizia)
Also, onycholysis, longitudinal striation (onychorrhexis), subungual hyperkeratosis, or
anonychia
Drug-related
b-blockers
Antimalarials
Captopril
Gold
Penicillamine
HCTZ
NSAIDs

Psoriasis
Figure 6.5: Psoriasis
Affects approximately 2% of population of US

Usually begins in 3rd decade of life
An early onset predicts more severe disease
Early onset more likely with positive family history
Clinical Manifestations
Sharply demarcated papules and plaques
Non-coherent silvery scales
Auspitz sign bleeding upon removal of scale
Koebnerization, stimulation of clinical disease due to external trauma, is seen in 20%
Woronoff ring: Area of blanching around psoriatic plaques secondary to decrease in
prostaglandin, PGE
Clinical subtypes
Guttate
Figure 6.6: Guttate psoriasis
Small (0.5 to 1.5 cm) lesions over upper trunk and proximal extremities
Early age of onset/young adults
Streptococcal throat infection frequently precedes eruption
Generalized pustular
Fever, lasting several days, with eruption of sterile pustules 2 to 3 mm diameter
paralleling the fever
DERMATOLOGY91
Fingertips may become anonychia and atrophic
Hypocalcemia, albuminemia, and leukocytosis
Can be induced following cessation of systemic steroids
Psoriatic nail disease
Figure 6.7: Nail psoriasis - Pits and onycholysis
May be of nail matrix or nail bed origin

Fingernails involved in 50%, toenails in 35%
Nail changes more frequent (80 to 90%) in patients with arthritis
Psoriatic nail changes of matrix pits (the most common nail change of psoriasis
and representing focal psoriasis of the proximal matrix) and leukonychia
Pits in psoriasis are generally more randomly distributed than the regular rows
of pits seen in alopecia areata
Psoriatic nail changes of nail bed origin include: Salmon spots, oil spots,
onycholysis, subungual hyperkeratosis, and splinter hemorrhages
Drugs that exacerbate:
Steroid withdrawal
Lithium
b-blockers
Interferons
ACE inhibitors
G-CSF
Systemic associations
Psoriatic arthritis
Crohns disease and ulcerative colitis
HTN, obesity, diabetes, and chronic oropharyngeal infections found more frequently
in psoriatic patients
Increased risk of lymphoma
Treatment
Topical agent examples:
Vitamin D3 analogues
Calcipotriol, tacalcitol, calcitriol
Inhibit keratinocyte proliferation and induce terminal differentiation
Anti-inflammatory

Tazarotene
Retinoid
Reduces scaling and plaque thickness, with little effectiveness on erythema
Topical steroids
Systemic agent examples:
Methotrexate
Synthetic analog of folic acid that competitively inhibits dihydrofolate reductase
Inhibits S phase of cell cycle (like hydroxyurea)
Leukopenia and thrombocytopenia indicate overdose leucovorin rescue
required
Careful in kidney dysfunction renal excretion
Acute interstitial pneumonitis (rare)
Hepatotoxicity; exclude those with liver disease or alcohol abuse
Cyclosporine
Inhibits release of cytokines, specifically IL-2, by binding and deactivating
calcineurin
Effective in erythrodermic and generalized pustular psoriasis
SE
Hypertension (treat with ACE-inhibitors)
Elevated triglycerides
Hyperkalemia
Hypomagnesemia
Hepatotoxicity
Hypertrichosis (common), gingival hyperplasia, trichomegaly, nausea, vomiting,
diarrhea, arthralgia, myalgia, tremor, acne, sebaceous hyperplasia, and fatigue
may occur
Metabolized by P450, thus erythromycin or ketoconazole will increase drug
levels
Biologics
Biologic therapy refers to proteins synthesized through recombinant DNA
techniques as immunomodulating agents
Recombinant human cytokines, humanized monoclonal antibodies, or specific
molecular receptors
Psoriasis is currently the major target for biologic therapies
With regard to psoriasis therapy, there are 3 classes of biologics: The T-cell
targeting drugs (alefacept), the TNF-inhibiting drugs (etanercept, adalimumab,
and infliximab), and newest, il-12/23 (ustekinumab)
Seborrheic Dermatitis
Related to Malassezia furfur and sebum production
Seen in infants and post-pubertal
Face/scalp/chest/back/intertriginous areas
Salmon colored, waxy scaling patches and plaques
Severe cases in: HIV, Parkinsons
Seborrheic dermatitis like: Langerhans cell histiocytosis
Treatment: Topical steroids, ketoconazole, topical tacrolimus/pimecrolimus
DERMATOLOGY93
Pityriasis Rosea
Figure 6.8: Herald patch of pityriasis rosea
Associated with HHV-6 and 7; may be a viral exanthem

Herald patch (precedes eruption)
Clears within 6 to 8 weeks
Tends to be in body folds, e.g., Christmas tree distribution
Usually spares lower extremities
Erythromycin can accelerate clearance of PR
Variant: Inverse PR (involves face, axillae, inguinal areas)
Always check an RPR in PR (Ddx secondary syphilis)
PR-like drug eruption: ACEI, gold
Pityriasis rosea may cause premature delivery with neonatal hypotonia and possibly fetal
death especially in the 1st 15 weeks of gestation
Erythema Multiforme
Target lesion = dusky center, white ring, with surrounding erythema; tend to occur on face,
mucosal, acral sites, genitalia
Note: Steven Johnson syndrome (SJS) and toxic epidermolytic necrolysis (TEN) are
now thought to be variants within a spectrum; erythema multiforme is considered
distinct, though with clinical overlap
Erythema multiforme minor
#1 cause = HSV; outbreak precedes EM by 3 to 14 days
No systemic or mucosal involvement
Erythema multiforme major
Caused by infection in 90% (HSV, Mycoplasma), rarely drugs
Has systemic or mucosal involvement
Full development of all lesions in 24 to 72 hours, last at least a week
Does not progress to TEN
Rowell syndrome
Patients with SLE develop lesions of erythema multiforme
Drug Reactions
Drug eruptions (adults > children)
Drug exanthem

Figure 6.9: Morbilliform drug eruption
Includes morbilliform drug eruption (i.e., maculopapular)

Classically occurs 7 to 14 days after exposure; commonly from PCN/sulfa/anti-
convulsant/allopurinol/cephalosporin
Occurs faster upon re-exposure
Will occur when PCN (amoxicillin) given for mononucleosis
Serum-sickness like eruption (fever, arthralgias, urticarial, or morbilliform rash) can
occur 1 to 3 weeks; after cefaclor most commonly
Urticaria/angioedema (discussed in detail below)
Most common cause of anaphylaxis: ASA
Hypersensitivity vasculitis
Palpable purpura non-blanching erythematous papules
Papules, urticaria, angioedema, pustules, vesicles, ulcers, necrosis, and livedo reticularis
Usually occurs on lower extremities or over dependent areas such as the back and
gluteal regions
Drug induced:
Penicillin
Sulfonamides
Thiazides
Allopurinol
Phenytoin
NSAIDs
PTU and hydralazine in association with ANCA
Streptokinase
Radiocontrast media
Monoclonal antibodies
G-CSF
Erythroderma
High BSA with erythema
Medical emergency due to inability to thermoregulate
Stevens-Johnsons syndrome/toxic epidermal necrolysis (SJS/TEN), rarely from EM-Major
BSA = % of skin with epidermal detachment (<10% in EM-Major, 10 to 30% in SJS, >30%
in TEN)
7 to 21 days after exposure
Path: Apoptotic keratinocytes to full epidermal necrosis
SJS in 1/106 of general population, 1/1000 of HIV/AIDS (acquired glutathione
deficiency)
DERMATOLOGY95
Hypersensitivity syndromes
Seen most often with anticonvulsants and sulfonamides, and less commonly with
allopurinol, dapsone, and gold
Reactions present with fever, rash with facial edema, eosinophilia,
lymphadenopathy, hepatitis, and nephritis
Pathogenesis of anticonvulsant hypersensitivity is related to the individuals inability
to detoxify arene oxide metabolites of these medications, due to lack of epoxide
hydrolase
Diphenylhydantoin, phenobarbital, and carbamazepine are known to cross-
react, whereas valproic acid generally does not cross react
DRESS (Drug reaction with eosinophilia and systemic symptoms)
Also known as drug/dilantin hypersensitivity syndrome
Most common from aromatic antiepileptic agents
Phenytoin, carbamazepine,and phenobarbital (these 3 cross-react) and the
sulfonamides, allopurinol
Predisposed to by epoxide hydrolase deficiency (anti-epileptics), slow acetylator
(sulfas)
Can be difficult to distinguish from serum sickness
15 to 40 days after exposure
Clinically, facial edema is hallmark
Usually see elevation in LFTs (liver most commonly involved)
Possible role of HHV-6 and 7 has been proposed
Monitor TFTs for 12 weeks; hypothyroidism possible
10% mortality
Acute generalized exanthematous pustulosis (AGEP)
Non-follicular, sterile pustules on erythematous background; ddx pustular psoriasis,
candidiasis
Caused by beta-lactams, macrolides, terbinafine
<4 days after exposure
Can be associated with elevated WBC (18 to 25)
Patch testing positive in 80%
Can see upregulated IL-8 (neutrophil chemoattractant)
Specific Drug Eruptions

Systemic lupus-like eruption
Anticonvulsants
Isoniazid
Hydralazine
Minocycline
Procainamide
Penicillin
D-penicillamine
Subacute cutaneous lupus-like eruption
Azathioprine
Glyburide
Griseofulvin
Terbinafine

Hydrochlorothiazide
Penicillin
Penicillamine
Acne-inducing drugs
ACTH
Steroids
Halogens
Lithium
INH
Dilantin
6.3 INFLAMMATORY DISEASES OF THE ADNEXA

Acne
Pathogenesis
Follicular hyperkeratosis
Microcomedone is precursor lesion
Human sebum is rich in triglycerides
P. acnes makes an enzymatic lipase which cleaves triglycerides into free fatty acids
P. acnes can activate complement and PMNs chemotaxis
IL-1 contributes
Toll-like receptors
Recognize bacterial patterns
P. acnes activates TLR-2
Certain retinoids downregulate TLR-2
Clinical
Acne vulgaris
Open = "black head" and closed = "white head"
Inflammatory lesions are papules, pustules and nodules
Figure 6.10: Acne vulgaris
DERMATOLOGY97
Acne fulminans
Explosive: Trunk > face
Leukocytosis, fever, arthralgias
Lytic bone changes
Sternoclavicular joints and chest wall inflammation
Tx with prednisone and isotretinoin
Chloracne
Malar, postauricular, scrotum
Cutting oils and dioxin
Acne-like induced eruptions
Halogens, bromide, and iodide
Androgenetic hormones such as testosterone, ACTH, corticosteroids
Isoniazid (INH)
Lithium
Erbitux
Phenytoin
Cyclosporine
Vitamins B2, B6, and B12
Treatment
Erythromycin and clindamycin less effective against P. acnes
Tetracyclines below MIC can inhibit PMNs, cytokines and P. acnes production of lipase
Risk of photosensitivity demecycline > doxycycline > tetracycline > minocycline
Unlike other tetracyclines, doxycycline is excreted via the GI tract rather than the
kidneys, and thus is the tetracycline of choice in renal-compromised patients
Minocycline can cause hyperpigmentation of the skin. Three types are generally
described:
Blue-black discoloration: Appearing in areas of prior skin injury, such as acne scars
Blue-gray discoloration: Often at the lower anterior legs and forearms
Muddy brown discoloration: Found on sun-exposed areas. The least common type
of hyperpigmentation
Only rifampin reduces OCP efficacy in studies
Isotretinoin
120-150 mg/kg total dose
SE: Pseudotumor with TCN
Large study failed to show increased risk of suicide
Large study failed to show association with IBD
Hormonal
Estrogen
Ethinyl estradiol most common
Desogestrel, norgestimate and gestodene lowest andro properties
Combo works best
Anti-androgen
Spironolactone

Rosacea
Clinical
Figure 6.11: Papulopustular rosacea
Papules and papulopustules in central region of face against a vivid background of

telangiectases
Later, diffuse hyperplasia of connective tissue with enlarged sebaceous glands
Localized to nose, cheeks, chin, forehead, glabella; less commonly affected areas include
the retroauricular, V-shaped chest area, neck, back, scalp
Flushing and blushing evoked by UV, heat, cold, chemical irritation, strong emotions,
alcoholic beverages, hot drinks, and spices
Variants of rosacea
Persistent edema of rosacea (rosacea lymphedema or Morbihans disease)
Often misdiagnosed as cellulitis
Ophthalmic rosacea
Blepharitis, conjunctivitis, iritis, keratitis (inflammation of cornea)
The treatment of choice for ocular rosacea is oral antibiotics
Granulomatous rosacea
Dozens of brown-red papules or nodules on diffusely reddened skin, frequently
involving lower eyelids
Steroid rosacea
Steroid atrophy with resultant telangiectases
Flaming red, scaling, papule-covered face
Withdrawal of steroid accompanied by exacerbation of disease
Slow tapering of steroid over months is required
Rosacea fulminans (Pyoderma faciale)
Occurs almost exclusively in post-adolescent women; lots of flushing and blushing
Perioral dermatitis
May be triggered or exacerbated by topical steroid use
Spares vermillion border
Phymas
Rhinophyma
Occurs almost exclusively in men
Gnathophyma: Chin swelling
Metophyma: Forehead and nose saddle
DERMATOLOGY99
Otophyma: Earlobes
Blepharophyma: Eyelids
Treatment
Topical
Antibiotics often effective
Topical metronidazole active against papules and pustules, but not telangiectasia
and flushing
Topical sulfur-based preparations
Azelaic acid
Sunscreen
Systemic
Antibiotics generally responds well Tetracyclines
Isotretinoin indicated in phymas; but rosacea often rapidly recurs after
discontinuation of isotretinoin
Hidradenitis Suppurativa
Component of follicular occlusion triad
Acne conglobata, hidradenitis suppurativa, and dissecting cellulitis of the scalp
Associated with smoking and being overweight
Hidradenitis suppurativa severity predictors
Atypical locations more common in men than in women
Men have more severe disease
Increased body mass index
Atypical locations
A personal history of severe acne
Absence of a family history of HS were associated with more severe disease
Clinical: Recurrent, inflamed cystic nodules in intertriginous areas. Chronic inflammation can
lead to the formation of sinus tracts
Treatment: Topical antibiotics (i.e., clindamycin), antibacterial washes, oral antibiotics
(rifampin + clindamycin > tetracycline class), oral retinoids
6.4 FUNGAL SKIN AND NAIL INFECTIONS

Superficial Fungal Infections
Tinea Versicolor
Malassezia globosa #1 cause Lipophilic
Clinical: White or brown flat, small scaly plaques in seborrheic distribution (usually spares
face)
Woods lamp yellow
Tx: Topical antifungals and selenium sulfide-containing shampoos
Tinea Nigra
Phaeoannellomyces werneckii
Palms, soles
Dark organisms in stratum corneum

Dermatophytosis
Dermatophytes: Group of closely related filamentous fungi, which colonize keratin such as
the stratum corneum of the epidermis, hair, nails, feathers of various animals
3 subtypes: Microsporum, Epidermophyton (never impacts hair bearing areas), and
Trichophyton
T. capitis Dermatophyte infection of the scalp and hair, generally seen in childhood
Significant posterior cervical lymphadenopathy is noted
Ectothrix
Fluorescent (mostly microsporum)
Non-fluorescent (mostly trichophyton)
Endothrix = Black dot ringworm invades the hair shaft so breaks
Favus = Scutula - yellowish cups with hair penetrating though
T. schoenleinii, violaceum, gypseum
Kerion
Boggy, oozing inflammatory reaction to fungus
Regional lymphadenopathy
Scarring alopecia may result
May need prednisone
T. corporis
Figure 6.12: Tinea corporis

Figure 6.13: Tinea corporis
Organisms invade stratum corneum generally causing an annular lesion with an

erythematous raised, scaly advancing border, the center of the lesion may show
clearing
DERMATOLOGY101
Majocchis granuloma
Indurated, pink plaque with prominent hair follicles caused by T. rubrum
Needs systemic antifungals
T. barbae
In men, the bearded area of the face and neck, generally inflammatory
Associated with exposure to animals
T. cruris
Mainly seen in males, involves the groin, perineal and perianal skin
Direct or indirect contact
T. pedis - 3 clinical subtypes:
Moccasin
Interdigital
Bullous
Interweb infections often involve fungi, yeast, gram negative and positive bacteria
Onychomycosis
Fungal infection of the nails due to dermatophyte, yeast, or nondermatophyte
Clinical subtypes
Distal lateral subungual onychomycosis
Infection begins distally and involves the nail bed, nail plate and lateral nail
fold; thick nail with debris, loose or cracked nail plate
Proximal white subungual onychomycosis
Rarest form of onychomycosis
AIDS marker
Organisms enter the cuticle and infect the proximal part of the nail bed
causing white islands that slowly invade the nail plate
White Superficial Onychomycosis
Organism invades the surface of the nail plate of toenails only
Irregular white chalky opaque patches on the nail
Candidiasis
Candida albicans, C. glabrata (fluconazole resistant), C. parapsilosis, C. tropicalis, C. krusei,
C. dubliniensis (thrush in HIV)
Most common fungal opportunistic infection, may be difficult to evaluate; yeast are
ubiquitous and part of endogenous flora
Prototypically bright red, moist patches with satellite pustules
Intertriginous involvement or thrush
Factors contributing to candida infection:
Impaired epithelial cell barrier, systemic illness, neutrophil and macrophage disorders,
immune disorders, therapeutic agents, congenital or acquired endocrine disorders,
malignancies, indwelling catheters, hyperalimentation, heat, humidity, and friction
Clinical variants
Angular cheilitis: A classic complication of childhood diabetes, presents as a white
curd-like material adherent to red, fissured oral commissures
Median rhomboid glossitis
Chronic paronychia: Involves the proximal nailfold; erythema, swelling, separation
from the nail margin with nail dystrophy
C. parapsilosis

Super infection by bacterial organisms, most commonly S. aureus, may occur
causing an acute paronychia
Erosio interdigitalis blastomycetica: Interdigital infection between the 3rd and 4th
fingers or 4th and 5th toes
Figure 6.14: Erosio interdigitalis blastomycetica
Genital infections: Vulvovaginitis and candida intertrigo of the inframammary region

in women
In contrast, balanitis and phimosis in men are relatively less common
Treatment includes control of blood sugar and topical or systemic antifungals
6.5 BACTERIAL INFECTIONS

Anthrax
Figure 6.15: Malignant pustule of anthrax
DERMATOLOGY103
Bacillus anthracis Spore-forming, gram+ rod
Animal exposure
Exotoxins
Edema toxin = Edema factor (EF) + protective antigen (PA)
EF causes gelatinous edema by increasing camp
Lethal toxin = Lethal factor (LF) + PA
LF can cause shock and death in disseminated disease by release of TNF and IL-1
PA allows entry of exotoxins into the cells
Antibodies to PA will prevent LF and EF action
3 clinical forms:
Inhalational, GI, and cutaneous
Cutaneous
Malignant pustule followed by bullae and eschar
Treatment
ConventionalPCN
Bioterrorismciprofloxacin or doxycycline
Borrelia
Lyme
Tick-borne
Organism: B. burgdorferi
Vector: Ixodes dammini, pacificus, ricinus
Figure 6.16: Ixodes
Clinical: Erythema migrans, chronica atrophicans (rare, chronic disease resulting in acral
sclerodermoid changes
Treatment: Doxycycline Amoxicillin for kids and pregnant women
Relapsing fever
Louse-borne
Organism: B. recurrentis
Vector: Pediculus humulus
Clinical fever, HA, systemic disease
Treatment: Doxycycline
Relapsing fever
Tick-borne
Organism: B. duttonii
Vector: Ornithodoros soft tick
Same symptoms as above
Treatment: Doxycycline

Botryomycosis
Staph, E. coli, pseudomonas, and proteus
Granulomatous nodules or plaques
Clinical setting: Immunosuppression
Staphylococcus aureus
Toxic shock syndrome
Enterotoxins B and C
TSST-1 in menstrual cases
Scarlatiniform eruption and desquamation with sepsis
Staph scalded skin syndrome
Exfoliative toxin A and B
Bind to Desmoglein-1 (a transmembrane adhesion molecule in the epidermis)
At risk populations: Kids and renal disease patients
Nikolsky sign + in non-lesional skin
Culture of bullae useless no organism present (toxin mediated)
Bullous impetigo
Exfoliative toxin A and B
Others: Sycosis barbae, Botryomycosis, Acute paronychia, Felon, Endocarditis
Strep spp.
Group A Strep
Blistering distal dactylitis
Dorsal fingers and toes
Tense blisters
Perianal strep
Bright red and well-demarcated
Scarlet fever
Erythrogenic toxin A, B, and C
Strep throat
Exudative pharyngitis and strawberry tongue
Sandpaper rash starts on head and neck
Pastias lines
Linear petechiae in axillae and antecubital fossae
Purpura fulminans
Hemorrhagic infarction from DIC
Geographic areas of purpura
Others: Non-bullous impetigo, erysipelas, cellulitis (see Figure), necrotizing fasciitis,
Strep toxic-shock-like syndrome, endocarditis
DERMATOLOGY105
Figure 6.17: Cellulitis
Meningococcemia
N. meningitides
Gram negative diplococcus
Those at risk: Children and those with complement deficiencies (C3-5)
Petechiae may be 1st sign
IV PCN or ceftriaxone
Rhinoscleroma
Klebsiella pneumoniae rhinoscleromatis
Plaques on external nares
Mikulicz cells on path
Tx: Cipro
Pseudomonal Skin Infections

Ecthyma gangrenosum
P. aeruginosa (PA)
At risk: Immunocompromised patients
Starts as hemorrhagic vesicle, pustule, and develops to necrosis
Assume sepsis
Green nails
PA
Pyocyanin virulence factor/cause of color
Gram negative toe web infection
PA, E. coli, proteus
Typically starts with dermatophytosis
Blastomycosis-like pyoderma
PA and S. aureus
Hot tub folliculitis
PA
Self-limiting 1 to 4 days after soaking
Rarely patients get malignant otitis from PA

Rickettsial
Table 6.2: Rickettsial Diseases
Causative Organism Vector
Rocky Mountain R. rickettsii 1.) Western US - Dermacentor andersoni
spotted fever 2.) Eastern US - Dermacentor variabilis
Rickettsialpox R. akari Liponyssoides sanguineus - Mite of the
house mouse
Epidemic typhus R. prowazekii Pediculus humanus corporis - human
body louse
Endemic typhus R. typhi Xenopsylla cheopis - rat flea
Scrub fyphus Orientia tsutsugamushi Chiggers - trombiculid mite larvae
Q Fever Coxiella burnetii Dried tick feces which are inhaled
Ehrlichiosis 1.) E. chaffeensis 1.) Amblyomma anericanum
1.) Human monocytic 2.) Human Granylocytic 2.) Ixodes sapularis, Ixodes pacificus
ehrlichiosis Ehrlichiosis (HGE) agent
2.) Human granulocytic
ehrlichiosis
Caused by obligate intracellular coccobacilli

Transmitted by arthropod vectors
Tx: Tetracyclines (doxycycline preferred)
Mycobacterial
Leprosy
Figure 6.18: Leprosy
DERMATOLOGY107
Table 6.3: Leprosy
TT BT BB BL LL
TH1 cytokine TH2 cytokine
profile: profile IL-4, IL-10
IFN-, IL-2, IL-12 Multibacillary
Paucibacillary Lepromin test-
Lepromin test+
3 lesions 310 lesions that Many lesions Lesions too Generalized and
are smaller than distributed numerous to symmetrical
TT lesions asymmetrically count; smaller distribution
predominate
Anesthetic Similar to TT Less anesthesia Minimal or no No loss of
and anhidrotic than TT sensory defects sensation or
sweating
lesions
Table 6.4: Treatment (WHO Recommendations)

Paucibacillary Dapsone 100 mg po qd for 6 months
Rifampin 600 mg po q monthly for 6 months
Multibacillary Dapsone 100 mg po qd for 12 months
Clofazimine 50 mg po qd for 12 months
Rifampin 600 mg po q monthly for 12 months
Clofazimine 300 mg po q monthly for 12 months (supervised)
Causative organism: Mycobacterium leprae

Transmitted from human to human most likely via respiratory secretions
Spectrum of disease based on cell mediated immune response
Armadillos may be a nonhuman source of infection
Miliary tuberculosis of the skin
Hematogenous spread of mycobacteria from fulminant tuberculosis of the lung or
meninges
Immunosuppressed host HIV, infants
Tuberculin test is negative (anergic)
Disseminated erythematous macules, papules, nodules, or purpuric lesions
Atypical mycobacteria
M. fortuitum, M. chelonei, M. abscessus
Rapid growers
Found in soil, water, dust, and animals
Infections occur after exposure to contaminated surgical instruments or following
trauma
Typically presents with a single or multiple erythematous subcutaneous nodules on
an extremity
Treatment: Surgical drainage/debridement followed by course of antimicrobial
therapy (amikacin, clarithromycin, ciprofloxacin, imipenem, and others)
M. Marinum
Swimming pool/aquarium granuloma
Begins as small papule at site of inoculation and evolves into a nodule or
granulomatous plaque, often with a verrucous surface
Treatment: Minocycline

Table 6.5: Tuberculosis of the Skin (Summary)
Tuberculous Tuberculosis Lupus Scrofuloderma Tuberculous Tuberculosis
Chancre Verrucosa Vulgaris Gumma Cutis Orificialis
Cutis
Primary Exogenous Hematogenous, Contiguous Hematogenous Autoinoculation
(exogenous) re-infection lymphatic, or spread spread from underlying
inoculation contiguous onto skin from advanced visceral
spread from underlying tuberculosis
distant site tuberculous
of tuberculous infection
infection
Non-sensitized Sensitzed host Sensitized host Sensitized host Immuno- Sensitized host
host with strong with moderate with low immunity suppressed with diminishing
immunity to high host immunity
immunity
Pauci- or Paucibacillary Pauci-bacillary Multi- or pauci- Multi-bacillary Multi-bacillary
Multi-bacillary, bacillary
depending
on stage
of infection
and strength
of immune
response
Painless red- Slowly growing B
rownish-red Subcutaneous Subcutaneous Punched-out
brown papule verrucous plaque nodules with abscesses ulcers with
that ulcerates plaques with Apple-jelly purulent or May form undermined
Tuberculous irregular color on caseous drainage fistulas and edges
primary borders diascopy May develop ulcers On ucocutaneous
complex: Typically on H
ead/neck sinuses and Typically on junctions of
regional hand involvement in ulcers with trunk, head, or mouth, genitalia
hadenopathy, 90% of cases granulating extremities
3-8 weeks bases
post infection Occurs most
commonly over
cervical lymph
nodes
DERMATOLOGY109
6.6 VIRAL INFECTIONS
DNA Viruses
CMV
Infection during 1st and 2nd trimester - highest risk for permanent abnormalities
Small for gestational age, microcephaly, retinitis, colobomas, intracranial
calcifications
#1 infectious cause of deafness and mental retardation in US
Most common congenital viral infection
Part of TORCH syndrome with blueberry muffin baby purpura
EBV
Infects B lymphocytes
Infectious mononucleosis

Figure 6.19: Mononucleosis
Fever, pharyngitis, and lymphadenopathy

Malaise, headache, myalgias, hepatosplenomegaly
Commonly morbilliform eruption after treatment with ampicillin
Affects teenagers and young adults
Oral hairy leukoplakia
Raised white plaque on lateral tongue
HIV and other immunocompromised states
Exanthem subitum
HHV 6,7
High fever followed by pink macules and papules resolves with fever (1 to 2 days)
Starts on trunk

Human Papillomavirus (HPV)
Figure 6.20: Condyloma
Genome encodes E (early) and L (late proteins)

E proteins (E1-8): Participate in viral DNA replication
L proteins (L1-L2): Structural proteins form virion (the outer shell of the virus)
Herpes Simplex Virus (HSV-1, HSV-2)

Clinical Presentations

Figure 6.21: Herpes simplex 1
Primary gingivostomatitis
Seen in children and young adults following primary HSV infection (usually HSV-1);
occurs in only 1% of primary HSV infections of the lips or face
Presents with fever, sore throat, and painful vesicles/erosions on the tongue, palate,
buccal, and gingival mucosa
Erosions are covered with characteristic gray membrane
Primary genital herpes
Most cases caused by primary infection with HSV-2
Multiple painful erosions, often bilateral, on the ano-genital mucosa
Painful inguinal lymphadenopathy
DERMATOLOGY111
Minority of cases may have concomitant aseptic meningitis with fever, nuchal rigidity,
headache, photophobia
Dysuria and vaginal/urethral discharge may be present
Severity of symptoms peaks at days 8 to 10
Herpes gladiatorum
Affects wrestlers and rugby players
Most common locations: Face, lateral neck, medial arm
Neonatal herpes simplex
Majority of cases acquired during delivery as neonate passes through infected vaginal
canal
Clinical spectrum ranges from localized skin lesions to multi-systemic infection with
encephalitis, hepatitis, pneumonia, and coagulopathy
Herpes simplex treatment
Acyclovir
Guanosine analogue
Inhibits viral DNA polymerase after being phosphorylated by viral thymidine kinase
(TK), and 2 additional viral kinases
Famciclovir
Prodrug of penciclovir; Increased bioavailability and longer half-life
Also dependent on viral TK for activity
Valacyclovir
Viral TK-dependent; same mechanism of action as acyclovir
Thrombotic thrombocytopenic purpura reported using high doses in
immunosuppressed patients
Acyclovir-resistant HSV* treatment
*Most commonly due to TK-deficient strains of HSV
Foscarnet directly inhibits viral DNA polymerase (without requiring
phosphorylation by TK)
Cidofovir inhibits viral DNA polymerase in a TK-independent fashion
Varicella (Varicella-Zoster Virus)

Distinguishing features (compared to smallpox):
Absent or mild prodrome
Lesions begin on face and spread to trunk
Centripetal distribution with fewest lesions on extremities
Dew drops on a rose petal superficial vesicle with erythematous halo
Lesions in different stages of evolution
Rapid evolution (<24 h) of lesions from macule-papule-vesicle-crust
Varicella in pregnancy
1st 20 weeks of gestation: Congenital varicella syndrome - hypoplastic limbs, ocular
and CNS abnormalities
5 days before and 2 days after delivery: Neonatal varicella
Neonate develops varicella at 5 to 10 days of age because of inadequate
transplacental delivery of maternal anti-varicella antibodies
Treat with VZIG + IV-acyclovir

Herpes Zoster (Varicella-Zoster Virus)
Ramsay Hunt syndrome
Caused by VZV infection of the geniculate ganglion
Zoster involves the external ear
Facial paralysis ipsilateral
Tinnitus or other auditory symptom
Figure 6.22: Herpes zoster
Other Human Herpes Viruses

HHV-6: Causes roseola infantum = exanthem subitum = Sixth disease
HHV-7: Also causes roseola
HHV-8: Oncogenic virus: Kaposis sarcoma, Castleman syndrome
Milkers Nodule
Paravaccinia virus
Cows
1 cm nodule on arm or finger
No treatment necessary
Molluscum
Poxvirus
Clinical: Umbilicated white papules
Orf
Parapoxvirus
Sheep and goats
Dorsal index finger
6 stages: Papular, target, acute, regenerative, papillomatous, regressive
DERMATOLOGY113
Parvovirus B19 (the only ssDNA virus)
Figure 6.23: Reticulated erythema of Fifth disease
Erythema infectiosum or fifth disease

Clinical: Children - slapped cheek erythema progressing to lacy reticular truncal erythema
(no longer infectious at this point)
Arthropathy in adult
Hydrops and spontaneous abortion
Purpuric gloves and stocking syndrome
Aplastic crisis in sickle cell patients
Smallpox
Poxvirus - Variola
Incubation is an average of 12 days
Virus replicates during this time
Not contagious
Prodrome -3 days of fever, malaise, HA, back pain, and vomiting
Rare swimming trunk petechiae is pathognomonic
Generalized centrifugal eruption
Over 2 weeks
Lesions in same stage
Umbilicated lesion
Head and extremities > trunk
Most infectious during the 1st 7 to 10 days following rash onset
Contagious until scabs fall off
RNA Viruses
Measles
Paramyxovirus
Clinical
Prodrome fever, cough, coryza, and conjunctivitis
Enanthem: Koplik spots
Exanthem: Morbilliform eruption starting on face
Hand-foot-and-mouth disease
Coxsackievirus A16 or enterovirus 71
Oraloral and fecaloral mode of transmission

Erythematous papules with grayish vesicle and surrounding red areola are
characteristic cutaneous lesions
Herpangina
Group A coxsackievirus
Fever, headache, cervical lymphadenopathy
Gray-white papulovesicles in oral mucosa that ulcerate (commonly present on tonsillar
fauces, palate)
Table 6.6 RNA Viruses

Virus Group Major Examples
Paramyxovirus Measles, mumps
Togavirus Rubella
Rhabdovirus Rabies
Retrovirus HIV, HTLV
Picornavirus Enterovirus: Coxsackie virus
(Hand-foot-and-mouth disease)
6.7 STDS
Primary Syphilis Chancroid Granuloma Inguinale Lymphogranuloma
Venereum
Causative T. pallidum H. ducreyi Calymmatobacterium Chlamydia
Organism granulomatis trachomatis L1, L2, L3
Characteristic Painless chancre Soft, painful/tender Primary lesion: Papule, Painless, soft
Clinical with ham-col- chancre with subcutaneous nodule erosion that heals
Features ored base and ragged edges (pseudobubo), or spontaneously
sharply defined, ulcer
indurated border School of fish on Secondary inguinal
Gram or Giemsa 4 clinical forms: adenopathy with fluc-
Chancre has stain Ulcerovegetative tuant, tender nodes
cartilage-like (most common), above and below
consistency and nodular, hypertrophic, Pouparts ligament
exudes clear fluid and cicatricial groove sign (can be
bilateral)
Bilateral Donnovan bodies
(safety-pin shaped Serologic diagnosis
intracytoplasmic inclu- by complement fixa-
sions in macrophages) tion test
seen on microscopy
Treatment Penicillin Azithromycin TMP-SMX Doxycycline
Ceftriaxone Doxycycline
Ciprofloxacin Erythromycin
Erythromycin Ciprofloxacin
DERMATOLOGY115
Chancroid
H. ducreyi
Gram negative rod - School of fish appearance
Painful ulcer
Tx: Azithromycin
Lymphogranuloma Venereum
Chlamydia trachomatis L1, 2, 3
Painless erosion that heals spontaneously
Fluctuant inguinal lymphadenopathy
Groove sign
Dx: Complement fixation test
Tx: Doxycycline x 3 weeks
Granuloma Inguinale Klebsiella Granulomatis (Formerly Calymmatobacterium

Granulomatis)
Gram negative rod
Safety pin appearance (intracytoplasmic inclusions in macrophages)
Treatment with sulfamethoxazole and trimethoprim or doxycycline for 3 weeks
Gonococcemia
N. gonorrhoeae
Hemorrhagic pustules on red bases
Arthralgias
May have C5-C9 deficiency
Treatment with ceftriaxone
Syphilis
T. pallidum
Primary
Figure 6.24: Painless chancre of primary syphilis
Chancre 10 days to 3 months after exposure

Lasts 3 to 12 weeks

Secondary

Figure 6.25: Secondary syphilis
Figure 6.26: Secondary syphilis
4 to 12 weeks
Skin and mucous membranes - pityriasis rosea-like
Ham-colored macules on palms
Condyloma lata
Split papules - oral commissures
Moth-eaten alopecia
Tertiary
Cardiovascular and neurological sequelae in some
DERMATOLOGY117
Congenital ~ Secondary syphilis
Early <2 years
SGA
Saw-tooth metaphysis
Snuffles
Rhinitis
Rhagades
Parrots lines
Late >2 years (think bony abnormalities)
Mulberry molars
High-arched palate
Hutchinsons teeth (wide spaces and peg-shaped)
Saddle nose
Saber shins
Cluttons joints (non-tender edema of knees)
Higoumenakis sign (UL medial clavicle enlargement)
Hutchinsons triad Hutchinsons teeth deafness interstitial keratitis
Serology
Nontreponemal tests
VDRL: 4 to 5 weeks after inoculation
May revert in latency
RPR: Similar to VDRL
Treponemal
FTA-ABS: 3 weeks after inoculation
Remains + after treatment
Most sensitive test
MHA-TP
Similar to FTA-ABS, but less sensitive
Treatment
Primary and secondary without end-organ damage
Benzathine PCN G 2.4 mil U IM X 1 doxycycline 100 mg BID x 2 week if PCN
allergic
Tertiary without neuro diseasebenzathine PCN G 2.4 mil U IM weekly X 3
Jarisch-Herxheimer reaction
Fever, HA, LAD, skin lesions, myalgias, WBCs
Caused by TNF-alpha and other cytokines being released when spirochetes are
phagocytosed

6.8 PARASITES
Leishmaniasis
Old WorldL. major, tropica, aethiopica, infantum, donovani
New WorldL. mexicana, braziliensis, amazonensis
Mucocutaneous
Figure 6.27: Leishmaniasis
Figure 6.28: Leishmaniasis
Old WorldL. aethiopica

New WorldL. braziliensis
Visceral
L. donovani
L. infantum
Vector
Sandflies
Old WorldPhlebotomus
New WorldLutzomyia
Diagnosis
Culture in Novy-MacNeal-Nicolle (NNN) medium
Histology
Amastigotes in histiocyte cytoplasm
Giemsa stain - Kinetoplast
Treatment
Pentavalent antimony/sodium stibogluconate
Monitor for cardiac side effects
DERMATOLOGY119
Trypanosomiasis
African
T. brucei gambiense in West Africa
T. brucei rhodesiense in East Africa
Vector: Tsetse fly/Glossina
Winterbottoms sign
Posterior cervical LAD
American (Chagas disease)
T. cruzi
Vector: Reduviid beetle aka assassin bug
Clinical: Romana sign
Eyelid edema and conjunctivitis at site of inoculation
Chronic: Cardiac infiltration
GI: Toxic megacolon
Filariasis
Lymphedema and elephantiasis
Brugia malayi and timori; Wuchereia bancrofti
Vectors: Mosquitos - Aedes, anopheles, culex, and mansonia
Dracunculiasis
D. medinensis Cyclops copepods
Worms under the skin
Tx: Slowly remove parasite
Loa Loa
Mango or deer flies
Vector: Chrysops
Clinical: Calabar swellings = dead filarial in microvasculature causing nonpitting edema of
cheeks
Eye worm
Treatment with diethylcarbamazine
Onchocerciasis
O. volvulus
Vector: Black flies aka Simulium
Pruritic papules
Chronic: Leopard skin, onchocercoma (nodules of organism)
River Blindness: # 1 cause of acquired blindness worldwide
Treatment with ivermectin
Mazzotti reaction: Symptom complex seen in patients after undergoing treatment of
onchocerciasis with the medication diethylcarbamazine (DEC)
Life-threatening, and are characterized by fever, urticaria, swollen and tender lymph
nodes, tachycardia, hypotension, arthralgias, oedema, and abdominal pain
Strongyloidiasis
S. stercoralis
Larvae penetrates through skin or mucous membrane

Clinical entity - Larva currens (STRONG CURRENt)
Serpiginous urticarial plaques on lower extremities
Disseminated - thumbprint purpura on periumbilical skin along with petechiae
Cercarial Dermatitis
Swimmers itch
Penetrate skin while swimming in northern US or Canadian waters
Pruritic papules on non-covered skin
Seabathers Eruption
Edwardsiella lineatasea anemone
Linuche unguiculatathimble jellyfish
Eruption is on covered skin - pressure from clothing releases toxin
6.9 BITES AND STINGS

Overview
Eruptions are caused by venom, bites, allergic/irritant response, or systemic reactions
Mites, spiders, ticks, and scorpions = arachnids (8 legs)
Lice and bees/wasps = insects (6 legs)
Mites
Scabies
Figure 6.29: Scabies
Extremely pruritic burrows/papules in skin folds and acral webs, transmitted through
physical contact, particularly in crowded jails, college housing, and nursing homes
Can have atypical presentation in infants bullous, involve the genitals
Testing = scabies prep skin scraping showing scabies mites, eggs, or feces
Treatment = permethrin 5% cream repeated in 7 days, severe cases oral ivermectin,
linens/clothing washed in hot water
Ticks
Lyme disease
Transmitted by deer ticks, most common vector-borne disease in the US
Clinical
Early localized = erythema migrans (expanding targetoid rash) 1 to 2 weeks after bite
DERMATOLOGY121
Early disseminated = within 6 months of bite, disseminated rash, polyarthritis, Bells
palsy
Late/chronic = months to years later, neurologic and rheumatologic symptoms
Serologic testing = unhelpful acutely
Treatment = single dosage doxycycline if within 72 hours of confirmed bite to prevent
Lyme, otherwise doxycycline (amoxicillin if allergic) x 10 to 14 days
Rocky Mountain Spotted Fever
Transmitted by dog/wood ticks, most common fatal tick-borne illness in US
Clinical
Acral petechial rash spreading centrally within a week of bite, fever, and headache
may precede
Serologic testing = unreliable
Treatment: Doxycycline x 7 to 14 days (chloramphenicol if severely allergic),
delayed treatment leads to hospitalization, death in up to 5% of cases (vascular
damage, shock)
Spiders
Black widow
Figure 6.30: Black widow spider
Painful edematous bite without necrosis, caused by a neurotoxin mimicking acute

abdomen
Treatment: Supportive therapy, specific IV antivenin (effective within 4 days of bite),
rarely fatal
Brown recluse
Usually painless bite with necrotic skin lesion (erythema/ischemia/thrombosis = red/
white/blue), flu-like symptoms, hemolytic anemia, and possible shock/death
Treatment: Ice and supportive measures, specific anti-venoms not available
Lice
Transmitted through physical contact, extreme pruritus and localized lymphadenopathy
Head lice Most common louse, laying eggs at the base of hair (nits)
Pubic (crab) lice Different body type than other lice (crab-like); macula cerulea =
bluish macules in groin (characteristic)
Human body lice Located on clothing, not body. Vector for trench fever, epidemic
typhus, and relapsing fever
Treatment: Comb removal of lice/nits, topical permethrin or malathion (flammable) all
repeated twice within a week, discarding or laundering clothing/linens in hot water

6.10 COMMON NEOPLASMS
Premalignant and Malignant Tumors
Typically in sun exposed/sun damaged skin as a new or evolving skin lesion (change of
color, size, shape, or new bleeding or irritation)
Actinic keratosis
Keratotic sandpaper-like papules commonly on face and upper extremities, often
treated with cryotherapy with liquid nitrogen
Basal cell carcinoma
Pearly telangiectatic pink papules, nodules, patches/plaques; often with rolled border,
rarely invasive
Figure 6.31: Basal cell carcinoma
Can have pigmented variant

Figure 6.32: Pigmented basal cell carcinoma
DERMATOLOGY123
Squamous cell carcinoma
Keratotic papules, nodules, patches/plaques; higher risk of invasion if scalp/face
Figure 6.33: Squamous cell carcinoma
Nonmelanoma skin cancer treatment = electrodesiccation and curettage, simple

excision, or Mohs surgery depending on tumor site and subtype, level of invasion, and
size of lesion
Melanoma
Figure 6.34: Nodular melanoma
Brown to black (but can be any color) macule, papule, or nodule with differing clinical
features than patients other skin lesions/nevi, local and distant metastatic potential,
can occur anywhere on skin/mucosa
A(symmetry), B(order), C(olor), D(iameter), E(volving)
Complete excisional biopsy required for tumor depth (Breslow, determines prognosis)
Treatment: Wide local excision, possible sentinel lymph node sampling and body
imaging, adjuvant therapies inconsistently effective for metastatic disease, but targeted
biologic agents evolving
Risk factors for the development of MM include sun exposure with tendency to freckle
and sunburn, fair skin complexion, light colored eyes and hair, presence of large
number of nevi, as well as family and personal history of melanoma
The most important mutated gene associated with a predisposition to develop MM is
the CDKN2A (located on chromosome 9p21)

Sun Protection and Skin Cancer Prevention
Risks of skin cancer
Number of blistering sunburns and cumulative exposure to UV light
Fairer skin type, genetic factors
Geographic locale tanning bed use (artificial UVA/some UVB light)
Skin cancer prevention/sun protection
Seeking shade, particularly 10 am to 2 pm hours when UV light most potent
Sun protective clothing, labeled with UPF (ultraviolet protection factor)
Sunscreen of SPF (sun protection factor, against UVB rays) >30, with added broad
spectrum (against UVA rays) and water resistant labeling, applied before sun
exposure and reapplied at least every 2 hours
Avoidance of tanning bed use except if prescribed by a doctor for inflammatory skin
disease or part of psychiatric therapy
Nightly topical retinoid
6.11 BENIGN TUMORS

Nevus: Tan to brown papules with genetic and/or environmental triggers, any part of the
body
Seborrheic keratosis: Waxy tan to brown mammillated papules and plaques, often involving
the trunk, increasing in number over time particularly in susceptible families
Figure 6.35: Seborrheic keratosis
Skin tag (acrochordon): Fibrous growth of skin, often multiple tan pedunculated papules
particularly in areas of friction, with genetic and metabolic syndrome link
Corn (clavus): Keratotic firm inverted growth, often on plantar surface, due to friction or
pressure
Epidermoid and pilar cyst: Epidermoid cysts are nodules often with central punctum often
on trunk; pilar cysts are dermal nodules with no punctum commonly on the scalp; all have
potential for growth and rupture
Neurofibroma: Pink fleshy papules, sometimes tender; multiple in neurofibromatosis
syndromes
DERMATOLOGY125
Pyogenic granuloma: Enlarging, easily traumatized red friable papules, can favor the face
and digits, more common in children, pregnancy, and with certain HIV drugs; self-resolving
but often removed because of tenderness (particularly periungual), and bleeding
Venous lake: Dark red to purple papule made of blood vessels, commonly on the lip
Cherry angioma: Red papules favoring the trunk, typically increasing in number over time
Dermatofibroma: Firm dusky pink to brown papules with dimple sign on exam, commonly
on legs of females, sometimes precipitated by trauma
Hypertrophic scars and keloids: Hypertrophic scars are firm pink shiny plaques within the
confines of an established scar; keloids grow bulbously beyond the original scar and can
often occur at piercing sites
Sebaceous hyperplasia: Pink to orange doughnut-shaped small papules on the face of
adults
Digital mucous cyst: Tense shiny nodule near DIP, representing joint fluid leakage because
of osteoarthritis/injury; drainage of the viscous fluid can temporarily relieve pressure but
ortho/hand surgeon intervention is often needed to ultimately prevent recurrence
6.12 PRURITUS
Overview
Pruritus
Transmitted via unmyelinated C and A delta fibers
Skin and cornea only tissues that itch
Histamine #1 mediator
Others include papain, trypsin, serotonin, bradykinin, kallidin, kallikrein, substance P, VIP
Prostaglandins exaggerate existing itch
Opiates have both central and peripheral itch-producing action
Conditions that Cause Pruritus

Chronic renal disease
80% of those on dialysis
Secondary hyperparathyroidism is an occasional cause of uremic pruritus
Increased population of mast cells in skin
Tx
Emollients, antihistamines ineffective
UV phototherapy may benefit
Cholestasis
High level of bile salts
Tx: Cholestyramine causes symptomatic improvement
Endocrine disease
Thyrotoxicosis
Increased skin blood flow which raises skin temperature
Hypothyroidism
Pruritus secondary to the dry skin
Postmenopausal pruritus may be generalized or localized, usually in anogenital area
Malignancy
Most common association: Hodgkins disease and polycythemia vera

Polycythemia vera
50% have water-induced pruritus
Referred to as bath itch or aquagenic pruritus
May precede development of PV by years
Itch is independent of temperature of water
HIV infection
Eosinophilic pustular folliculitis
Pruritus of HIV
May respond to UVB, PUVA, or dapsone
Workup of Generalized Pruritus

Physical exam, including pelvic and rectal
CBC
Stool for O&P, occult blood
CXr
Thyroid, renal, and liver function tests
Drug history/testing
6.13 URTICARIA/ANGIOEDEMA
Urticaria
Figure 6.36: Urticaria
Individual lesions called wheals; may have pale centers (not dusky, so not targetoid)
By definition lesions should last <24-hours
Ask the patient: Do they move around?
Note: Chronic urticaria defined as 6 weeks
Urticaria may be a disease spectrum with depth of swelling causing urticaria, angioedema
(deeper in dermis/subq), or both
Type I hypersensitivity
Often caused by: Idiopathic, drug, food, infection (GAS, viral, parasites)
DERMATOLOGY127
Primary effector cell = mast cell
Pre-formed mediators = histamine, heparin, tryptase, chymase
Newly formed mediators = prostaglandins, leukotrienes, PAF
Types of urticria:
Physical urticaria
Dermatographism
Pressure urticaria
Cold urticaria
Solar urticaria
Angioedema
Figure 6.37 Angioedema
Look for stridor, GI/respiratory symptom

Can be caused by ACE inhibitors at any time
C1 esterase inhibitor deficiency
Never causes urticaria
Screen for with C4 level
Can be inherited or acquired
Treat with danazol
Acquired
See in lymphoproliferative and rheumatological disease
Serum C1q decreased
C2 and C4 are decreased in both forms
Treatment
Androgen therapy: Danazol or stanozolol as prevention
Fresh frozen plasma or C1INH should be given in acute attacks
Diagnosis review
Screen with C3 and C4 levels C4 low, C3 normal in angioedema
C1q level low in acquired, but normal in hereditary

Anaphylaxis
Nonimmunologic urticaria (anaphylactoid drug reaction)
Caused by direct mast cell granulation
Mnemonic PROMS = polymyxin B, radiocontrast, opioids, muscle relaxants, salicylates/
NSAIDs
Urticarial Vasculitis
Clinically indistinguishable from urticaria, but last >24-hours
Hypocomplementemic urticarial vasculitis syndrome
Defined by low serum complement levels plus presence of anti-C1q precipitin (in 100%),
decrease in C1 activity
6.14 COLLAGEN VASCULAR/CONNECTIVE TISSUE DISEASE

*Specifically, most used to refer to spectra of: SLE/RA/dermatomyositis/Sjgren/scleroderma.
**Note: Skin changes non-specific for CVD includes: Raynauds, non-scarring alopecia, livedo
reticularis, pericuticular erythema, telangiectasia, palpable purpura (leukocytoclastic vasculitis)
especially in SLE and RA.
Lupus Erythematosus
Acute
Types: Malar erythema butterfly rash, diffuse erythemas, bullous
Figure 6.38: Malar erythema of acute lupus

erythematosus
These acute findings are usually associated with SLE, but there is overlap
Systemic lupus erythematosus (SLE)
Know the 11 criteria, 4/11 = SLE;
4 skin findings: Malar, discoid, oral ulcers, photosensitivity
2 antibodies: ANA (99% sensitive) and anti-Smith (or anti-dsDNA) (specific)
5 systems: Heme (hemolytic anemia, leukopenia, or thrombocytopenia), renal
(proteinuria), neuro (seizures or psychosis), rheum (arthritis), and cards/Pulm
(serositis)
Note- ANA patterns: Homogeneous (anti-histone), peripheral (anti-dsDNA, SLE
with renal dz), speckled, nucleolar (ribosomal RNA, scleroderma), centromeric
(Only centromeric is specific: CREST)
Lupus band test = DIF shows DEJ IgG deposits in normal, non-sun-exposed skin of
SLE
DERMATOLOGY129
Drug-induced lupus
Resolves in days to months
Most common: Hydralazine (5%), procainamide (15 to 25% of patients taking the
drug), quinidine
Has been reported with minocycline
Anti-histone Ab in 95% - this is positive in 50% of SLE
Subacute
Types: Annular (and polycyclic), urticarial, papulosquamous
Subacute cutaneous lupus (SCLE)
Strong anti-Ro association, tend to be ANA positive
Can develop Sjgren; half may meet criteria for lupus
Drug-induced by HCTZ, terbinafine (Lamisil) > Ca channel blockers, NSAIDs,
griseofulvin, antihistamines
Neonatal lupus erythematosus
Risk of 3rd degree heart block (15 to 30%)
Check for Ro (most common in 95%), La, anti-U1-RNP
Mother usually asymptomatic, usually Ro positive (1% risk)
25% risk of next child developing
Chronic
Types: Discoid, panniculitis, hypertrophic/lichenoid
Discoid lupus (DLE)
Figure 6.39: Discoid lupus
Young adults, women:men 2:1

Dull red macules with adherent scales extending into patulous follicles
Plugged follicles
Patches heal with atrophy, scarring, dyspigmentation, and telangiectasia

Lupus profundus (panniculitis)
Deep dermal and subcutaneous nodules, rubbery-firm, sharply defined, and
nontender
Upper arms, chest, buttocks, thighs
Lupus erythematosus tumidus (Tumid lupus)
Non-scarring
On face/trunk, annular plaques
Pregnancy and SLE
Miscarriages occur with greater frequency
LE may worsen, or go into remission during pregnancy
Fetal death risk increased with anti-cardiolipin or anti-Ro antibodies
Postpartum period shows the highest risk to the patient
Dermatomyositis
Clinical signs
Gottrons papules = lichenoid papules over MCPs, DIPs, PIPs
Gottrons sign = pink/red/purple atrophic or scaling eruption over knuckles, knees,
elbows
Figure 6.40: Gottrons sign
Shawl sign = erythema and scale +/- poikiloderma over shoulders
Figure 6.41: Shawl sign
On physical exam: Proximal muscle weakness (e.g., cannot lift arms)
DERMATOLOGY131
Non-specific: Heliotrope rash (ddx contact dermatitis, trichinosis), poikiloderma,
mechanics hands, malar erythema
Remember: Amyopathic dermatomyositis (atypical case without muscle
involvement)
Frayed cuticular changes in DM = Samitz sign
Important: r/o underlying malignancy (especially likely if age >50)
R/o paraneoplastic syndrome, in women: Ovarian/breast cancer; Men: GI, respiratory
cancer
Antibodies: Anti-Jo-1 (predicts lung involvement), anti-Mi-2 (predicts benign course, less
lung involvement), anti-Ku (DM/scleroderma overlap)
Can see elevated CK and aldolase
Scleroderma
Figure 6.42: Digital tapering of systemic sclerosis
Localized (morphea)
Figure 6.43: Morphea
Can be associated with anti-ssDNA antibodies

Melorheostosis = thickening/sclerosis of bones, usually in 1st big toe
3 forms: Plaque, linear, generalized
CREST syndrome
Calcinosis, Raynauds, esophageal dysmotility, sclerodactyly, telangiectasias
(matted)

Anti-centromere ab
Progressive systemic sclerosis (scleroderma)
May see CREST findings, plus tightened face, fixed bird-like facies, pursed lips,
confetti depigmentation, loss of skin creases, digital ulceration, distal pterygium,
Raynauds
Systemic involvement: Interstitial lung disease, pulmonary HTN, esophageal
dysmotility, cardiomyopathy, renal crisis, sicca syndrome
May have early edematous phase (pitting of digits before sclerosis)
Anti-Scl-70 Ab
#1 mortality = lung disease, scleroderma renal crisis
Sjgren
Keratoconjunctivitis sicca
Xerostomia
Rheumatoid arthritis
More than 90% women
Vasculitis palpable purpura
Patients develop lymphoreticular malignancy such as NHL
Anti-Ro and La, anti-a-fodrin
Mixed Connective Tissue Disease (MCTD)

Anti U1-RNP
Different from overlap of 2 concurrent CTDs
Rheumatoid Arthritis
Can be associated with vasculitis
Can be underlying cause of epidermolysis bullosa acquisita
Rheumatoid nodule
Figure 6.44: Rheumatoid nodule
Rheumatoid arthritis neutrophilic dermatosis
DERMATOLOGY133
Relapsing Polychondritis
On ears, recognized by only affecting cartilage
Can also affect nose, larynx
Can see Ab to type II collagen (but found in <50%) - Car-2-lage
Concern regarding tracheal involvement
Can be associated with MAGIC syndrome (Mouth And Genital ulcers and Inflamed Cartilage
= relapsing polychondritis + Behets)
6.15 AUTOIMMUNE BLISTERING DISEASES

Pemphigus Family: Intraepidermal Blisters
Figure 6.45: Pemphigus vulgaris
Pemphigus foliaceus - superficial, rarely appreciate intact vesicles. Bran flake-like crust
Pemphigus vulgaris (mucocutaneous)
Pemphigus erythematosus (lupus overlap)
Paraneoplastic (associated with NHL, CLL, thymoma, sarcoma, Castleman)
Drug induced
Thiol-containing drugs: Captopril, penicillamine, thioproline
Drugs with disulfide bonds: Gold, pyritinol
Drugs that have the potential to release sulfur moieties: Penicillins, piroxicam,
cephalosporins
Pyrazoline derivatives and enalapril (possibly secondary to an amide group),
indomethacin, rifampin
Figure 6.46: Paraneoplastic pemphigus

Clinical manifestations and diagnosis: Painful pink patches/plaques with erosions (few intact
bullae), mucosal ulcerations, bacterial superinfection/sepsis possible
Diagnosed by skin biopsy/immunofluorescence
Treatment: Systemic steroids, other immunosuppressants, sometimes rituximab
Subepidermal Blisters
Clinical manifestations and diagnosis: Tense/ruptured bullae, diagnosed by skin biopsy/
immunofluorescence
Bullous pemphigoid occurs in elderly and can look like urticaria (hives)
Dermatitis herpetiformis (DH) extremely pruritic on extremities, often with concurrent
celiac disease
Linear IgA has necklace-like linked bullae, can be caused by vancomycin
Bullous lupus form of acute lupus
Treatment: Systemic and topical steroids, dapsone, and gluten-free diet very helpful in DH
6.16 ALOPECIA
Non-scarring Alopecia
Alopecia areata
Genetics
High frequency of family history, especially in patients with early onset (37%)
Twin concordance = 55% (identical twins)
Immunologic factors
Major associations: Vitiligo and thyroid disease (10%), with increased prevalence of
antithyroid antibodies and thyroid microsomal antibodies in AA
Other autoimmune diseases shown to be associated: Pernicious anemia, diabetes,
LE, myasthenia gravis, RA, polymyalgia rheumatica, ulcerative colitis
Emotional stress
May be precipitating factor in some cases
Clinical features
Pull test may be positive at margins, indicating early disease
Usually asymptomatic, but some patients perceive pruritus, tenderness, burning, or
pain preceding hair loss
PATTERNS: Patchy (most common); reticulated; ophiasis (parietal/temporal/occipital);
ophiasis inversus (sisapho bandlike pattern in fronto parietotemporal scalp)
Areata partial loss of scalp hair
Totalis total loss of scalp hair
Universalis 100% loss on scalp, eyebrows, eyelashes, and rest of body
Initial regrowth is white, followed by repigmentation
Nail dystrophy (10 to 66%), seen in one, some, or all nails, preceding, coinciding, or
occurring after hair disease
Pitting with irregular pattern or in organized rows
Trachyonychia: Longitudinal striations resulting in sandpaper appearance
Red-spotted lunula
DERMATOLOGY135
Treatment: Intralesional steroids, topical steroid, systemic steroid, PUVA, topical
immunotherapy (e.g., anthralin, diphenylcyclopropenone, squaric acid dibutyl ester),
minoxidil
Triangular Alopecia
Congenital or childhood
Complete absence of hair or vellus hairs in triangular pattern in the temporal area,
frequently bilateral
Androgenetic Alopecia
AD, polygenetic with variable penetrance
Progressive miniaturization of hair, increased telogen hairs
Males bitemporal, vertex
Females preserved anterior hair line, Christmas-tree pattern with widened hair part at
vertex
Type II 5-alpha reductase activity in dermal papilla and outer root sheath
TX: Minoxidil, finasteride, oral contraceptive pills, spironolactone, flutamide, cyproterone
acetate, transplant
Trichotillomania
Compulsive hair pulling, irregular broken hairs within a geometric localized area
TX: Chlorimipramine, SSRI
Acquired Progressive Kinking

Post-pubescent male with androgenetic alopecia, gradual curling and darkening of frontal,
temporal and auricular regions progression to androgenetic alopecia
Associated with AIDS, retinoids
Syphilis
Secondary syphilis, 3 to 7% occurrence rate
Moth-eaten non-scarring with indistinct margins or diffuse alopecia
Telogen Effluvium
Early and excessive loss of club hairs from the normal resting follicles in the scalp
Physical stress such as: Surgery, anemia, traction or systemic illness - generally 3 months
prior to onset
Psychological stress
Endocrine causes such as: Hypo or hyperthyroidism or peri-/postmenopausal states
Nutritional deficiencies: Biotin, iron, protein (kwashiorkor), zinc, essential fatty acid or calorie
deficiency (marasmus or starvation diets)
Hypervitaminosis A
Drugs implicated:
Amphetamines
Aminosalicylic acid
Angiotensin-converting enzyme inhibitors
Anticoagulants
b-blockers
Bromocriptine

Carbamazepine
Cimetidine
Danazol
Etretinate
Interferon
Lithium
Oral contraceptives
Valproic acid
Clinical
Diffuse loss
Only rarely involves greater than 50% of the scalp
Takes 612 months for hair density to return to normal therapy
Anagen Effluvium
Frequently seen following administration of cancer chemotherapeutic agents
Stimulus induces the abrupt cessation of mitotic activity in rapidly dividing hair matrix
cells; hair shaft thins and then breaks at skin surface
Occurs within days to weeks of the stimulus
Entirely reversible with cessation of drug therapy
Causes
Antimetabolites
Alkylating agents
Mitotic inhibitors
Examples: Doxorubicin, the nitrosoureas, and cyclophosphamide
Alopecia (Scarring)
Pseudopelade of Brocq
Figure 6.47: Scarring alopecia with Pseudopelade of

Brocq
DERMATOLOGY137
Alopecia in small patches foot prints in the snow to large patches
Controversy regarding distinct entity versus end-stage of various scarring alopecias
Follicular degeneration syndrome
Hair loss mostly on vertex in black females +/ history of chemical relaxers
Previously known as hot comb alopecia but can occur without use of hot combs
Lichen planopilaris
Figure 6.48: Lichen planopilaris
Alopecia with perifollicular erythema

Morphea (en coup de sabre)
Linear morphea with linear scarring alopecia of the frontal scalp
Parry-Romberg syndrome (linear morphea, progressive facial hemiatrophy,
exophthalmos)
Folliculitis decalvans
Inflammation, boggy induration, crust, pustules on scalp
Dissecting folliculitis (Perifolliculitis Capitis Abscedens et Suffodiens of Hoffman)
African American males
Deep inflammatory boggy nodules +/ sinus tracts on the occipital region
Acne keloidalis nuchae
African American male
Follicular papules and pustules persistent firm papule or plaque at neck/occipital
scalp
Traction alopecia
Prolonged tension on the hair from braiding, ponytails, rolling curlers, twisting with
fingers
Other Alopecia
Meralgia paresthetica
May have alopecia of the anesthetic area of the outer thigh
Hypothyroidism
Hair coarse, dry, brittle, and sparse
Telogen hairs 3x more prevalent
Hyperthyroidism
Hair becomes extremely fine and sparse
Alopecia neoplastica
Hair loss from metastatic tumors
Usually breast carcinoma

6.17 CUTANEOUS MANIFESTATIONS OF INTERNAL DISEASE
Internal Malignancy
Lung CA
Tripe palms thick palms with accentuated skin lines and fissures
Erythema gyratum repens pruritic maze-like circular red plaques all over body,
migrate daily and rapidly; resolves with treatment of underlying carcinoma
Hypertrichosis lanuginosa acquisita diffuse eruptive downy hair growth starting on
face
Gastrointestinal CA
Sign of Leser-Trlat (gastric adenocarcinoma) eruptive seborrheic keratoses, often
pruritic
Tripe palms and severe acanthosis nigricans (gastric adenocarcinoma)
Necrolytic migratory erythema (glucagonoma tumor) psoriasiform eroded eruption
with more intertriginous and acral involvement; most patients are metastatic at time of
skin diagnosis
Lymphoproliferative
Paraneoplastic pemphigus (NH lymphoma, CLL, thymoma, Castlemans, sarcoma)
severe mucosal erosions
Sweet syndrome (AML) beefy plaques especially on dorsa of hands
Genitourinary, breast, or lung CA
Dermatomyositis
Sun-exposed scaly pink plaques, heliotrope purple hue around eyes, ragged
cuticles, Gottrons papules (pink papules over dorsal hand joints), Gottrons sign
(pink papules and nodules over elbows)
Proximal muscle weakness
Requires CA screening yearly for 5 years after rash appears
Cardiovascular Disease
Hypertension, venous stasis stasis dermatitis stasis dermatitis on legs, resembles cellulitis
but shows bilateral involvement with background stasis changes; often confused for
bilateral cellulitis
General hyperlipidemia various types of xanthomas
Hypertriglyceridemia eruptive xanthomas
Metabolic syndrome acanthosis nigricans, skin tags (*patients with psoriasis carry a higher
risk of metabolic syndrome then the general population
Superior vena cava syndrome facial edema and dilated veins on skin superior to the heart
on the upper chest
DERMATOLOGY139
Endocrine Disease
Hypothyroidism
Cool, dry, pale skin, xerosis, hypohidrosis, yellowish hue secondary to carotenemia
Generalized myxedema swollen waxy appearance to skin and lips, broad nose,
macroglossia
Dry, brittle, coarse, straw-like hair
Hyperthryoidism
Thyroid acropachy clubbing of fingers associated with soft tissue swelling and
periosteal new bone formation
Localized or generalized hypertrichosis, wispy fine hair
Thyroid dermopathy (pretibial myxedema) bilaterally symmetric, non-pitting
yellowish-brown to red waxy papules, nodules, and plaques most commonly on lower
extremities (but can occur on any area of skin)
Figure 6.49: Myxedema
Diabetes mellitus
Acanthosis nigricans, diabetic limited joint mobility (cheiroarthropathy), necrobiosis
lipoidica (NL), scleredema, diabetic bullae (bullosis diabeticorum), diabetic dermopathy
(shin spots or pigmented pretibial papules), eruptive xanthomas, granuloma annulare
(generalized and perforating forms), skin tags, perforating dermatoses
Can also be associated with other autoimmune skin conditions like vitiligo

Figure 6.50: Necrobiosis lipoidica
Figure 6.51: Eruptive xanthomas
Figure 6.52: Granuloma annulare
Rheumatologic Disease
Lupus
Photosensitive eruptions butterfly rash (acute systemic lupus), discoid (scarring
especially on face and inside ears), annular (subacute cutaneous lupus)
Vasculitis palpable purpura
Alopecia, often scarring
Dermatomyositis
Photosensitive eruption, heliotrope, Gottrons papules, ragged cuticles
DERMATOLOGY141
Gastrointestinal Disease
Inflammatory bowel disease
Erythema nodosum; ulcerative colitis (UC) > Crohns
Cutaneous/metastatic Crohns vegetative ulcerating plaque with histologic features of
Crohns (granulomatous)
Pyoderma gangrenosum ulceration with underminable rolled dusky borders; +
pathergy (do not debride); UC > Crohns
Gingival hyperplasia and cobblestoning (Crohns)
Pyoderma vegetans (UC)
Vasculitis/Polyarteritis nodosa (Crohns)
Celiac disease
Dermatitis herpetiformis very pruritic, especially on elbows
Over 90% of people with the rash have gluten-sensitive enteropathy
15 to 25% celiac patients develop dermatitis herpetiformis
Skin disease responds to gluten-free diet (and dapsone)
Hepatitis C
Porphyria cutanea tarda sun-exposed papules, bullae, tiny cysts and scars, werewolf-
like hair growth on face, 24-hour urine porphyrins is test of choice
Lichen planus purple polygonal pruritic papules, classic area is wrists but can occur
anywhere on skin, Wickham striae (can see in mouth), oral erosions (most commonly in
setting of Hep C)
Necrolytic acral erythema psoriasiform plaques on dorsa of feet

Figure 6.53: Porphyria cutanea tarda
Pulmonary Disease
Sarcoidosis
Lupus pernio plum-colored nodules especially on nose, cheeks, and ears
Erythema nodosum
Wegener granulomatosis
Palpable purpura on legs, skin ulcers, erythema nodosum
Oral ulcers and gingival hyperplasia (strawberry-like)
Pulmonary hypertension
Clubbing

Figure 6.54: Papular sarcoidosis
Figure 6.55: Plaque sarcoidosis
Figure 6.56: Erythema nodosum
Renal Disease
Renal failure
Pruritus best treated with light therapy
Nephrogenic systemic fibrosis (NSF) thickening of skin (excluding face), caused by
renal insufficiency paired with exposure to MRA with gadolinium contrast
DERMATOLOGY143
Calciphylaxis purple necrotic plaques (the more proximal, the more deadly), caused
by calcifications of vessels and thrombosis, often results in severe wounds, infection,
and death
Perforating dermatoses crusted papules on skin (especially arms) representing
extruding material from the body
Neurologic Disease
Alzheimers, Parkinsons, stroke seborrheic dermatitis, increased risk of melanoma
Neurocutaneous syndromes
Neurofibromatosis neurofibromas, skin freckling (axilla), caf au lait macules, Lisch
nodules in iris, scoliosis, seizures
Tuberous sclerosis facial papules (adenoma sebaceum), ash leaf macules
(hypopigmented), Shagreen patch (thick leathery truncal plaque), intracranial tubers
causing various neurologic symptoms
Pregnancy-related Dermatoses: Usually Late in Pregnancy

Polymorphous eruption of pregnancy (formerly PUPPP) pruritic papules starting in striae
Pemphigoid gestationis hive-like lesions and bullae starting periumbilically; associated with
Grave disease
Intrahepatic cholestasis of pregnancy pruritus, abnormal bile acids/cholelithiasis, low
maternal K+
Pustular Psoriasis of Pregnancy/Impetigo Herpetiformis

Late 1st trimester to 3rd trimester
Clinical
Often begins in intertriginous regions and spreads to trunk and extremities
Spares face, palms, and soles
Erythematous plaque with ring of pustules that enlarges at periphery and erodes or
crusts at periphery
Mucosa can be involved
Onycholysis
Remits quickly postpartum
Recurs with subsequent pregnancies, menses, and OCPs
Fetus at risk for placental insufficiency
Laboratory
Hypocalcemia, leukocytosis, elevated ESR
Treatment
Prednisolone 80 mg/d decreases mortality risk for mother
Treat hypocalcemia
May require early delivery

6.18 SELECTED DERMATOLOGIC EMERGENCIES
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (TEN)
Figure 6.57: Steven Johnson syndrome
Causes: Medications (sulfa drugs, anticonvulsants, allopurinol, NSAIDs), infections (HSV,

mycoplasma)
Clinical manifestations: Targetoid and eroded pink papules, plaques, and mucosal
ulcerations, occurring 1 to 3 weeks after starting offending medication, can progress to full
skin sloughing (TEN)/death
Diagnosis and management: Clinical features (+/- skin biopsy), treatment = avoidance
triggers, prompt supportive therapy to avert infection and shock
DRESS (Drug Reaction With Systemic Symptoms and Eosinophilia)
Figure 6.58: Morbilliform eruption of DRESS
Causes: Medications (anticonvulsants, antibiotics, allopurinol); valproic acid safe

Clinical manifestations: Rapidly-progressive drug rash and facial edema, usually within 2 to 8
weeks of drug exposure, recurs quickly with re-exposure
Diagnosis and management: Clinical features and eosinophilia/possible liver and renal
dysfunction, treatment = prompt drug withdrawal, long taper of steroid usually required
DERMATOLOGY145
Erythroderma
Causes: Psoriasis, atopic dermatitis, drug eruption, cutaneous lymphoma, paraneoplastic,
idiopathic
Clinical manifestations: Diffusely erythematous scaly skin, sometimes with ectropion
Diagnosis and management: Clinical history and skin biopsy; treatment = etiology-based,
often topical and systemic steroids and antihistamines, IV fluids
6.19 SPECIAL POPULATIONS

Skin in Elderly Patients
Common clinical problems of aging skin: Photoaging (wrinkles, lentigines, actinic purpura),
seborrheic keratoses, actinic keratoses, xerosis (dry skin), pruritus, brittle hair and nails,
pattern hair loss
Dermatologic Diseases in the Immunosuppressed

HIV: Pruritus, eosinophilic folliculitis, facial lipoatrophy (see Figure on nasolabial lipoatrophy),
Kaposi sarcoma (see Figure on Kaposi's sarcoma), infection (diffuse molluscum, warts,
herpes, scabies, oral hairy leukoplakia/EBV)
Figure 6.59: Nasolabial lipoatrophy
Figure 6.60: Kaposis sarcoma
Transplant patients: Skin cancer (highest risk is for squamous cell carcinoma 36 fold),
graft-versus host disease (GVHD), disseminated infections

6.20 HIGH YIELD
Childhood Viral Exanthems
First disease Rubeola/measles Paramyxovirus
Second disease Scarlet fever Streptococcus (not viral)
Third disease Rubella Togavirus
Fourth disease Dukes disease not specific
Fifth disease Erythema infectiosum Parvovirus B19
Sixth disease Roseola/Exanthem subitum HHV-6/7
Human Herpes Viruses

HHV-1 = HSV-1
HHV-2 = HSV-2
HHV-3 = VZV
HHV-4 = EBV
HHV-5 = CMV
HHV-6 = related to pityriasis rosea and roseola, DRESS
HHV-7 = related to pityriasis rosea and roseola, DRESS
HHV-8 = related to Kaposis sarcoma, Castleman disease, primary effusion lymphoma
Alpha = HHV-1,2,3 (herpes ones)
Beta = HHV-5,6,7 (CMV, roseola)
Gamma = HHV-4 and 8 (oncogenic ones)
Causes of Gingival Hyperplasia

Drugs: Phenytoin, Ca channel blockers, cyclosporine
Diseases: AML, sarcoid, Wegeners, scurvy, pregnancy, upper airway disease
HCV Skin Associations

(By direct effect and as consequence of associated hepatic damage)
Cutaneous necrotizing vasculitis (as in type II cryoglobulinemia), usually presents with
palpable purpura, can see livedo reticularis, urticaria
Porphyria cutanea tarda (may have HCV association)
Lichen planus stronger association with mucosal/ulcerative LP
Cutaneous B-cell lymphoma
Xerostomia
Erythema multiforme (possibly)
Pruritus (in 15% of patients with HCV)
Necrolytic Acral Erythema
HIV Skin Associations

Exuberant seborrheic dermatitis
Kaposis sarcoma
Molluscum contagiosum (giant, diffuse)
HIV-associated eosinophilic pustular folliculitis
Diffuse tinea corporis
Herpes zoster (and disseminated zoster)
Lipodystrophy associated with protease inhibitors (specifically indinavir)
Bacillary angiomatosis
DERMATOLOGY147
TB and atypical mycobacteria (esp. MAC)
Cryptococcosis
Toxoplasmosis
Reactive arthritis (psoriasiform)
Diffuse verruca vulgaris/ condyloma acuminata
Pruritus
Can also see: Acquired ichthyosis, drug reactions, and psoriasis
Dermatology Conditions Associated With Diabetes

Acanthosis nigricans
Diabetic dermopathy (shin spots)
Necrobiosis lipoidica (NLD)
Scleredema
Granuloma annulare
Yellow skin (carotenodermia)
Diabetic bullae (bullous diabeticorum)
Acrochordon
Necrotizing fasciitis
Malignant external otitis
Erythrasma
Mucormycosis
Diseases With Body Lice as a Vector

Body lice = Pediculus humanus var. corporis
Louse-borne epidemic typhus (Rickettsia prowazekii)
Relapsing fever (Borrelia recurrentis)
Trench fever (Bartonella quintana)
Types of Cutaneous TB
From external exposure:
Primary inoculation
Tuberculosis verrucosa ctis
Tuberculosis cutis orificialis (orificial TB)
From hematogenous spread:
Lupus vulgaris
Miliary tuberculosis
From direct extension:
Scrofuloderma
Reactive eruptions to TB (tuberculid eruptions):
Papulonecrotic tuberculid
Lichen scrofulosorum
Erythema induratum
Causes of Urticaria
Mnemonic = Mr. Hives still seeks drugs and graft
Viral (MR. HIVES) = Measles, Rubella, Hepatitis, Infectious mono (including EBV, CMV, HIV),
Viral other, E. infectiosum/Subitum

Bacterial (STILL) = Scarlet fever, Toxic shock/strep, Infectious bacterial other (rose spots,
salmonella), Lyme, Lues (syphilis)
Inflammatory (SEEKS) = SLE, Erythema marginatum, Erythema multiforme, Kawasakis,
Stills/serum sickness
Is of Urticaria
Infection (viral)
Iatrogenic
Inherited
Immunologic
Idiopathic
Ingestion (food, drug)
Injection
Inhalation
Infestation
Physical causes (pressure, cold)
Dermatome Review
Thumb = C6
Nipple = T4
Umbilicus = T10
Top of feet = L5
Bottom of feet = S1
Etiologies of Vasculitis (CTD SING)

CTD (SLE, RA)
Thrombotic (TTP, DIC, septic emboli, HSP, cryo)
Drugs (including serum sickness)
Syndromes (Schnitzlers, Muckle-Wells, Finklesteins disease)
Infection (HCV, HBV, Strep, GC, HIV)
Neoplasms (Hodgkins, multiple myeloma, leukemia)
Granulomatous/Inflammatory (Churg-Strauss, Wegeners, MPA)
DERMATOLOGY149
1. Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatricks dermatology in general medicine. 5th ed.
New York: McGraw-Hill, Health Professions Division, 1999.
2. Ingham E et al. Proinflammatory levels of interleukin-1 alpha-like bioactivity are present in the major-
ity of open comedones in acne vulgaris. J Invest Dermatol. 1992; 98: 895-901.
3. Kim J et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J
Immunol. 2002; 169:1535-1541.
4. Andrews diseases of the skin, 9th ed. Philadelphia: WB Saunders, 2000.
5. Goldstein SM and Wintroub BU, Adverse cutaneous reactions to medications. Baltimore: Williams
and Wilkins, 1996; 55-57.
6. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001.
7. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001.
8. Elder D et al. Levers histopathology of the skin, 8th ed. Philadelphia: Lipincott Raven, 2001; 295.
9. Webster G Fetal. Suppression of polymorphonuclear leukocytechemoactic factor production in
Propionibacterium acnes by subminimal inhibitory concentrations of tetracycline, ampicillin, minocy-
cline and erythromycin. Antimicrob agents chemother. 1982; 21:770-772.
10. Wolverton,SE.Comprehensivedermatologicdrugtherapy.Philadelphia:WBSaunders,2001.
11. Dermatology in General Medicine, 5th Edition. New York, McGraw-Hill,1999.
12. Andrews Diseases of the Skin, 9th Edition. Philadelphia:WB Saunders,2000.
13. http://www.cdc.gov/lyme/
14. http://www.cdc.gov/rmsf/
15. http://www.cdc.gov/parasites/lice/
16. Goldsmith L, et al. Fitzpatricks Dermatology in General Medicine 8e, New York: McGraw Hill, 2012.
17. Rigopoulos D, et al. Skin signs of systemic diseases. Clin Dermatol. 2011; 29(5): 531-40.
18. Thiers BH, et al. Cutaneous manifestations of internal malignancy. CA Cancer J Clin. 2009; 59(2):
73-98.

NOTES
DERMATOLOGY151
NOTES

7 Neurology
Matthew J. Mandel, MD
c o n t e n t s
7.1 NEUROLOGIC EXAMINATION . . . . . . . . . . . . . . . . . . . . 2
7.2 IMAGING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
7.3 STROKE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
7.4 DEMYELINATING DISEASES . . . . . . . . . . . . . . . . . . . . . 4
7.5 EPILEPSY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
7.6 MOVEMENT DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . 8
7.7 DEMENTIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
7.8 NEURO-ONCOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
7.9 NEUROMUSCULAR DISORDERS . . . . . . . . . . . . . . . . . 14
7.10 DISORDERS OF THE SPINAL CORD . . . . . . . . . . . . . 15
7.11 HEAD INJURY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
NEUROLOGY1
7.1 Neurologic Examination
The neurologic examination has 7 basic parts: 1. Mental status 2. Cranial nerves 3. Motor
4. Sensory 5. Reflexes 6. Coordination 7. Gait
The general purpose of performing a neurologic exam is to localize the lesion; can be
thought of as a "poor mans MRI"
Mental Status
Abnormalities on mental status testing indicate a problem in higher cortical areas (ex.:
decreased attention testing localizes to the frontal lobe)
Assess with a mini-mental status examination including: Alertness, orientation,
concentration, memory, calculations, abstract reasoning, fund of knowledge
Cranial Nerves
Abnormalities on cranial nerve testing indicate a problem in the brainstem (composed of
the midbrain, pons, and medulla)
II = optic n; III = oculomotor n; IV = trochlear n; V = trigeminal n; VI = abducens n; VII = facial
n; VIII = vestibulochoclear n; IX = glossopharyngeal n; X = vagus n; XI = accessory n;
XII = hypoglossal n
Motor
Abnormalities on motor testing could indicate a problem anywhere from the neurons that
form the corticospinal tracts to the neuromuscular junction to the muscle itself
Strength is graded on a 5-point (MRC) scale: 5/5 = normal; 3/5 = able to move vs. gravity
but not vs. resistance; 1/5 = twitch
Sensory
Abnormalities on sensory testing could indicate a problem anywhere from the sensory
receptors to the higher cortical areas where sensory input is processed
Assessments of light touch, pin, vibration, and proprioception should be performed
Reflexes
Abnormalities of reflex testing indicate problems at various spinal cord levels
Coordination
Abnormalities on coordination testing indicate problems with the cerebellum
Gait
Gait is multifactorial; does not necessarily localize to any 1 area of the CNS; however,
certain gaits are characteristic of specific neurologic conditions (ex.: shuffling gait think
Parkinson's disease)

7.2 Imaging
CT Scans
Often obtained in the emergency room
Rapid; takes a few minutes to perform
Very good for detecting blood
MRI Scans
Depending on protocol, can take up to 45 minutes to perform study
Different sequences appropriate for different conditions
T1 = anatomy
T2 FLAIR = multiple sclerosis
Diffusion weighted imaging (DWI) = stroke
7.3 Stroke
Classification (By Pathophysiology)
Ischemic - due to thromboembolic occlusion of blood flow
Hemorrhagic extravasation of blood into the brain parenchyma (ICH) or spaces (SAH)
Ischemic Stroke
Acute Ischemic Stroke
Definition
Rapid onset of focal neurologic deficits in a neuroanatomical distribution (i.e., MCA
syndrome, ACA syndrome)
If the neurologic deficits last <24-hours the condition is technically called a transient
ischemic attack (TIA)
Evaluation and Treatment
If <3 hours since the onset of symptoms, rapid evaluation and diagnosis is critical as
administration of tPA can lead to revascularization
Brief history from patient or family members present in the ER; most important to
establish time of onset
Performance of NIH Stroke Scale
Non-contrast head CT to make sure no hemorrhage
Coagulopathy labs PT/INR, platelets
Rapid evaluation and diagnosis is critical as administration of tPA in <3 hours from
onset can lead to revascularization
If If >3 to 4 1/2 hrs since the onset of symptoms, tPA is contraindicated as the risk of
secondary hemorrhage outweighs the benefits of potential revascularization
Orders: Admit, ASA 325 mg po, statin, hold antihypertensive meds, MRI brain/
MRA head and neck, telemetry, UA/Umicro/Utox, CXR, EKG, TTE, carotid dopplers,
swallow evaluation, HbA1c, fasting lipids, DVT ppx, PPI, nicotine patch, maintain
normoglycemia, PT/OT
NEUROLOGY3
Secondary Prevention
The same vascular risk factors that put a patient at risk for myocardial infarction, put a
patient at risk for TIA and stroke. Good control of HTN, diabetes, cholesterol, and weight
will minimize the occurrence of stroke/TIA. Regular physical activity and minimization of
tobacco and ETOH consumption also minimize the occurrence of stroke/TIA
Coagulopathies and Afib can increase the chance of embolus formation and subsequent
stroke
Hemorrhagic Stroke
Intracerebral Hemorrhage (ICH)
Etiology
Most commonly due to HTN; if patients blood pressure acutely rises above their normal
chronic hypertensive level, suspect hemorrhage (acute reactive HTN)
Treatment
BP control
Prognosis
Small ICH (<30 mL) favorable outcome
Large ICH often death
Subarachnoid Hemorrhage (SAH)
Etiology
Most commonly aneurysmal (in the Circle of Willis)
Diagnosis
Classic history = sudden onset of worst headache of life (i.e., thunderclap headache)
Non-contrast head CT to reveal blood is the initial test of choice and will make the
diagnosis in 95% of cases. However, if the scan is negative, an LP must be performed to
diagnose the remaining 5% of cases
Graded clinically 1 (asymptomatic or minimal headache/slight neck stiffness) - 5 (deep
coma; decerebrate rigidity) on the Hunt & Hess Scale
Treatment
Medical: Admit to NICU, CT angiogram, amicar until intervention (started in ED), seizure
prophylaxis, SBP<140, nimodipine 30/60 mg po Q4, fluids, blood glucose control, check
UA, umicro, utox, HbA1c, TTE, serial trop and EKG, hold lovenox until 24-hours after
intervention. SCDs for DVT ppx until then
Surgical: Clipping (open procedure) or coiling (neurointerventional) of aneurysm
7.4 Demyelinating Diseases

Multiple Sclerosis
Epidemiology
2:1 predominance F>M
Can occur at any age but most common onset between 20 to 40 years of age
Presenting Signs and Symptoms
Depends on location of the lesion; most commonly pain in 1 eye (optic neuritis), double
vision, limb weakness, bowel/bladder disturbance

Diagnosis
Diagnosis is made by fulfilling the McDonald criteria, which utilizes a combination of
physical exam, MRI, and CSF findings to demonstrate the occurrence of lesions separated
in space and time
Physical exam: A constellation of neurologic deficits not fitting an anatomical
distribution
MRI: T1 gadolinium enhancing lesions = acute; T2 FLAIR sequence will demonstrate
the majority of lesions in MS
Lumbar puncture: Oligoclonal bands (OCBs) in CSF; elevated IgG index
Sarcoid, ADEM (acute disseminated encephalomyelitis), B12 deficiency, tropical spastic
paraparesis (caused by the HTLV-1 virus)
Clinical Course
Relapsing-remitting secondary progressive
The majority of patients, especially younger patients, present with a relapsing-
remitting course where they have periods of acute neurologic exacerbations followed
by a return to normalcy. If exacerbations are frequent, residual neurologic deficits
will be permanent (and therefore present between attacks). About 50% of initially
relapsing-remitting patients will transition to a secondary progressive clinical course
after 10 years. Secondary progressive disease is characterized by progressively
increasing neurologic deficits without acute exacerbations
Other clinical courses include:
Primary progressive progressive increase in neurologic deficits from disease onset
without acute exacerbations; usually occurs in patients who are older at the time of
diagnosis
Progressive relapsing acute relapses superimposed on a progressive course from
the time of disease onset
Treatment
Acute exacerbations
IV methylprednisolone for 37 days followed by oral prednisone taper
Disease-modifying therapies (FDA approved)
First-line
Injectibles = Interferon beta-1a (avonex, rebif), inteferon beta-1b (betaseron,
extavia), glatiramer acetate (copaxone)
Orals = Fingolimod (gilenya)
Second-line
Infusions = Natalizumab (tysabri), mitoxantrone (novantrone)
Symptomatic management
Fampridine (ampyra): Indicated to improve walking in MS
Dextromethorphan/quinidine (neudexta): Indicated for pseudobulbar affect
(involuntary laughing)
Off label symptomatic treatments often include: Baclofen (spasticity), SSRIs
(depression), ditropan (incontinence)
NEUROLOGY5
Demyelinating Diseases (Other)
MS is by far the most common demyelinating disease
Other demyelinating diseases include:
NMO (neuromyelitis optica) lesions in optic nerve and spinal cord without lesions in
the brain
ADEM (acute disseminated encephalomyelitis) single episode of severe acute
demyelination; postinfectious/postvaccinal
Guillen Barre (GBS) Syndrome
7.5 Epilepsy
Seizures
Partial Seizure
Synonymous with focal; i.e., there was a well defined focus of seizure onset
Simple Partial
Preservation of consciousness
The aura (dj vu, nausea, etc.) that precedes certain epileptic events is actually a
simple partial seizure in and of itself
Complex Partial
Impairment of consciousness
The patient can display unusual behaviors (lip smacking, chewing, swallowing, etc.) while
the seizure is occurring, which can be perceived by others as mental illness or drug use.
Often preceded by an aura and followed by amnesia for the period of time immediately
preceding and immediately following the seizure event
Generalized Seizure
No defined focus of seizure onset; i.e., diffuse seizure activity
Primary Generalized
Onset of diffuse seizure activity is immediate
Absence
Typical history is a school aged child who the teacher believes is not paying attention
or is day-dreaming; EEG reveals frequent epiletiform activity (3 Hz spike and wave)
throughout the day; treatment = ethosuximide
Tonic-clonic
This is the classic Grand Mal seizure comprised of a phase where the muscles tense up
(tonic phase) followed by a phase where the muscles continuously contract and relax
(clonic phase). Often preceeded by an aura and followed by a postitcal (i.e., sleepy)
period
Although the generalized tonic clonic (GTC) seizure looks like a medical emergency (and
truly is sometimes), the majority of cases pass on their own before acute benzodiazepine
treatment can be administered
Secondary Generalized
Onset of diffuse seizure activity occurred after the spread of focal seizure activity
Other Commonly Encountered Epilepsy Syndromes

Temporal lobe epilepsy

Sometimes employed by defense attorneys as an explanation for their clients criminal
activity; treatment = removal of seizure focus
Frontal lobe epilepsy
Bizarre movements and vocalizations can occur and therefore this condition is often
misdiagnosed as a pseudoseizure
Wests syndrome
Begins in infancy or toddler years, most commonly secondary to tuberous sclerosis,
characterized by trunk flexion/mental retardation/myoclonus, treatment = ACTH
Febrile seizures
Generally occur between 6 months and 6 years of age; increased chance of developing
adult epilepsy if febrile seizures are prolonged, focal, there are neurologic deficits on
exam, or there is a family history of seizures
Risk Factors, Differential Diagnosis, Diagnostic Evaluation,

and Treatment for Seizures
Risk Factors
Family history of seizures, prior severe head injury or intracranial infection (leading to
seizure focus), drugs (cocaine intoxication, ETOH/benzodiazepine withdrawal, opiod use
lowers seizure threshold)
Syncope, stroke, panic attack, pseudoseizure (suspect if hip thrusting), malingering
Diagnostic Evaluation
History ask about risk factors above
MRI (Brain) can reveal focal causes such as tumor or AVM; thin cuts through temporal
lobe if suspect TLE
Electroencephalography (EEG) seizures are an intermittent event so failure to capture
a seizure on EEG does not mean the patient is not having seizures
Treatment
Antiepileptic drugs (AEDs) have multiple effects on the brain
Types (based on mechanism):
Na channel blockers (phenytoin, valproate, carbamazepine)
GABA agonist (phenobarbital)
Unknown mechanism (gabapentin, levetiracetam, topiramate)
Selection depends on type of seizure; quick reference:
Phenytoin complex partial; GTC
Valproate complex partial; GTC; migraine; mood stabilization
Carbamazepine complex partial; GTC
Phenobarbital complex partial; GTC
Gabapentin complex partial; pain (neuropathic)
Levetiracetam complex partial; GTC
Topiramate complex partial; GTC; headache
Surgery consider surgery when there is a discrete/localized focus where seizures are
known to originate from (i.e., TLE). Surgery should also be considered when a patient
is on multiple AEDs and the seizures are still not controlled, as it is highly unlikely that
addition of another AED will result in seizure control in this scenario
NEUROLOGY7
Status Epilepticus
Definition and Diagnosis
Official definition is repetitive seizures occurring for at least 30 minutes without full
recovery between attacks. However, it is important to treat possible status epilepticus
fast and aggressively as the earlier treatment is initiated, the more likely it is that the
status epilepticus will break/resolve. Any seizure lasting more than a few minutes should
be regarded as status epilepticus
Status is a neurologic emergency because ongoing seizures will cause permanent
neurological damage due to neurotransmitter toxicity, failure to meet metabolic demands,
and systemic complications
Etiology
Consider subtherapeutic AED levels (in a patient with prior epilepsy) > stroke/CNS tumor
> toxic - metabolic (including hyperglycemia or hypoglycemia, low Ca/Na/Mg/P, high
BUN/Creat; medications) > ETOH > hypoxia > infection > TBI. One-third of cases are
idiopathic
Treatment
ABCs
IV access; send blood for chemistries/cbc/lfts/AED-levels; ABG, Utox
Thiamine 100 mg IV and D50 50 mL IV (unless fingerstick for glucose)
Lorazepam 4 mg IV x 1 over 2 min (may give additional 2 x 2 mg each after 5 min (total
of 8 mg) if still seizing
Load with fosphenytoin 20 mg/kg at 150 mg/min; monitor EKG/BP
Often, the above management will suffice in the acute setting. However, if seizures
persist, patients may receive: Midazolam, propofol, IV valproate, IV phenobarbital, IV
pentobarbital
Obtain cEEG as soon as possible
7.6 Movement Disorders

Parkinson's Disease
Pathology
Degeneration of the substantia nigra (of the midbrain) with a resulting lack of dopamine
Characterized by the presence of Lewy bodies (made up of alpha-synuclein protein) in
neurons
Demographics and Epidemiology
Age of onset typically after 50 years old
Male predominance (slight)
Incidence (Annual) = 20 / 100,000; Prevalence = 200/100,000; 500,000 people affected
in US
Genetics
Most cases of Parkinsons are idiopathic, however, familial cases exist (associated genes =
alpha-synuclein; young age of onset, rapid clinical course), parkin gene (typical onset <40
years old), PINK1 (onset = 30 to 40 years old, slow progression), LRRK2 gene
Suspect familial Parkinsons in patients with early onset disease (age = <40)

Clinical Features
Diagnosis is usually made based on clinical symptoms
The 4 cardinal features of Parkinson's disease are:
Bradykinesia - slowness of movement
Rigidity increased muscle tone; cogwheel rigidity is classic
Tremor often begins with unilateral pill rolling tremor
Postural instability frequent falls, assess with pull test
A good way to remember the clinical features of Parkinsons is to think of an average
elderly person. Although all elderly people certainly do not have Parkinson's disease,
they generally exhibit Parkinsonian features: i.e., walk with a slow, shuffling gait, stooped
posture, slowed movements, may have a tremor, fall risk
Treatment
Levodopa/carbidopa (sinemet)
Initially, use of sinemet often relieves all of the symptoms of Parkinson's disease;
however, this therapy typically becomes less effective over time
Dopamine agonists (bromocriptine, pergolide, pramipexole, ropinirole)
Can be used in conjunction with levodopa/carbidopa therapy
Used in patients with a declining response to levodopa therapy
MAO-B inhibitors (selegeline, rasagiline)
Can be used in conjunction with levodopa/carbidopa therapy
Anticholinergics
Sometimes used for later stage disease; for treatment of motor symptoms
COMT inhibitors (entacapone)
Surgical ablation/DBS
Types of surgery include lesional ablation and deep brain stimulator placement
Surgery is performed in PD to attempt to reduce tremor
Tragets for PD surgery include: Subthalamic nucleus, globus pallidus, ventral
intermediate nucleus, and ventrolateral nucleus of thalamus
Secondary Parkinsonism
In addition to idiopathic Parkinson's disease, a Parkinsonian phenotype (including
bradykinesia, rigidity, tremor, and postural instability) can be secondary to a variety of
primary insults including:
Drugs - neuroleptics, antiemetics, and lithium; removal of the offending agent = 1st step
in treatment
Toxins - MPTP
Hydrocephalus
Infections - postencephalitic parkinsonism
Metabolic Wilson disease
Trauma
Vascular
Parkinsons-Plus Syndromes
Feature the classic Parkinsonian phenotype (bradykinesia, rigidity, tremor, and postural
instability) with additional features (such as dysautonomia, supranuclear gaze palsy, etc.;
specific to the particular syndrome) that distinguish them from simple idiopathic Parkinson's
disease
NEUROLOGY9
Suspect these syndromes if there is a symmetrical onset of symptoms (vs. classic idiopathic
Parkinsons that often begins unilaterally)
These conditions generally respond less well to anti-Parkinsons drugs and are more rapidly
progressive than classic idiopathic Parkinson's disease
Examples of Parkinsons-Plus syndromes include:
Multiple system atrophy (MSA)
Autonomic features commonly occur
Progressive supranuclear palsy (PSP)
Difficulty with vertical (typically upward) gaze
Corticobasal degeneration
Alien hand syndrome (i.e., patient believes their limb is not theirs and cannot
control its movements) occurs in 60% of those diagnosed with CBD
Movement Disorders (Other)

Essential tremor
Tremor present during movement of the limb (i.e., kinetic tremor)
Worsened with stress/anxiety; improved with ETOH
Huntington disease
Characterized by progressive dementia and chorea in individuals with a family history
of the disorder; usually begins between 20 to 40 years of age
Autosomal dominant inheritance; 100% penetrance; triplet (CAG) repeat disorder
carried on chromosome 4
Anticipation the disease occurs earlier and earlier in successive generations (related
to expansion in size of the triplet repeat)
Pathologically there is atrophy of the caudate
Prognosis progressive to death in 10 to 15 years
Restless leg syndrome (RLS)
Can occur at any age
Uncomfortable sensation in the limbs temporarily alleviated by moving
Worsened by prolonged periods of rest; generally worse at night
Treatment = dopamine agonist (ropinerole/requip)
Periodic limb movements of sleep
Brief and characteristic triple flexion movement of toe/ankle/knee/hip
May cause insomnia
7.7 Dementia
Reversible and Nonreversible Causes of Dementia
Reversible: Vitamin B12, thyroid disease, neurosyphilis, neoplasms, NPH (normal pressure
hydrocephalus), subdural hematoma
Nonreversible: Alzheimer's disease, Lewy body disease, Parkinson's disease, Pick disease,
PSP (progressive supranuclear palsy), HIV-associated dementia, CJD (Creutzfeldt-Jakob
disease), some vascular diseases

Mild Cognitive Impairment (Amnestic Type)
Subjective memory complaints
Impaired memory testing (often delayed recall on examination)
Pathology = hippocampal atrophy
Often a prodrome for Alzheimer's disease
15%/year convert to Alzheimer's disease
25% of MCI patients never convert to Alzheimer's disease
Alzheimer's Disease
Clinical Description and Diagnosis of Alzheimer's Dementia
Multiple cognitive deficits; memory impairment + impairment in at least 1 other cognitive
sphere (aphasia, apraxia, agnosia)
In addition to cognitive impairment, the patient may also have hallucinations/delusions,
mood disturbances (i.e., depression, agitation), sleep/wake cycle disturbances
In making the diagnosis, the physician must make sure the symptoms are not due to
delirium or another CNS/general medical condition
Incidence and Prevalence
Incidence = 53 new cases per year/1,000 people (age 65 to 74); 170 new cases per
year/1,000 people (age 75 to 84); 231 new cases per year/1,000 people (age >85)
Prevalence = 231 cases/1,000 people (age >65)
Risk Factors
Age some statistical models predict that everyone would develop Alzheimer's disease if
they were to live long enough
F>M
African American ancestry have twice the risk of developing AD as Caucasians
MCI (of amnestic type)
Family history
Lower level of education education is protective vs. Alzheimer's disease, possibly due to
the individual having a greater cognitive reserve
Head trauma
Apolipoprotein genotype
Progression of Alzheimer's Dementia
Gradual onset with progressive decline; average duration of illness = 10 years from onset
to death
Pathology
Early neuronal loss in medial temporal lobe
Senile plaques/amyloid deposition (= primarily AB-42 peptide)
Neurofibrillary tangles made of tau protein and ubiquitin
Treatment
Cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine)
Used for mild to moderate AD (except donepezil which is also approved for severe AD)
NMDA receptor antagonist (memantine) approved for moderate to severe AD
NEUROLOGY11
Lewy Body Dementia
Characterized by dementia and Parkinsonism progressing simultaneously (in contrast to
dementia superimposed on Parkinson's disease where the Parkinson's disease is present
long before the onset of dementia)
Classic features = fluctuating attention/alertness, visual hallucinations, Parkinsonian type
motor impairment
Lewy body = an abnormal aggregation of alpha-synuclein, neurofilament, and ubiquitin
proteins
An immunoperoxidase stain for ubiquitin turns the Lewy bodies brown
Prognosis: Slowly progressive
Frontotemporal Lobar Degeneration

Consider this diagnosis when there is an early onset of frontal lobe symptoms (including
behavioral changes such as apathy or disinhibition and/or the presence of primitive reflexes
due to frontal release)
As the name suggests, condition is characterized by atrophy in the frontal lobes and
(anterior) temporal lobes
Picks disease = a specific type of frontotemporal lobar degeneration; characterized
pathologically by Pick bodies (= large aggregates of tau protein and ubiquitin) and Pick
cells (= ballooned neurons)
Normal Pressure Hydrocephalus (NPH)

Etiology is idiopathic; some investigators believe it is caused by decreased CSF absorption
at arachnoid villi intermittently increased intracranial pressure distention of lateral
ventricles normalization of CSF pressure (with now wider ventricles)
The 3 cardinal features of NPH:
1. Gait impairment patients develop a magnetic gait appear glued to the floor
2. Dementia subcortical dementia characterized by apathy and slowness
3. Urinary incontinence
In making the diagnosis, a large volume spinal tap may be helpful if patient has NPH, may
see an immediate improvement in their gait with the procedure
Treatment = ventriculoperitoneal shunt
Vascular Dementia
= Multi-infarct dementia caused by multiple small infarcts disrupting neural networks
Risk factors = the same risk factors as for MI/CVA (i.e., HTN, smoking, diabetes, etc.)
Consider this diagnosis whenever there are focal neurologic signs in addition to dementia
Typically, there is a step-wise decline in cognitive functioning (vs. AD with its more
steadily progressive decline)
Sundowning Delirium
Is a delirium on dementia; i.e., patients with dementia (an already pathologic brain) are at
increased risk of evening agitation/confusion
Exacerbated by pain, fecal impaction, malnutrition, polypharmacy, poor sleep, infections,
unfamiliar environment

7.8 Neuro-oncology
Gliomas
= Tumors of glial cells including astrocytomas, oligodendrogliomas, and ependymomas
Astrocytomas
Grade I IV
Grade I = JPA (Juvenile pilocytic astrocytoma), characterized by Rosenthal fibers
(eosinophilic, intracytoplasmic inclusions), can be surgically resected
Grade II IV = are infiltrating and cannot be completely surgically resected, require
chemotherapy and radiation
Grade IV = GBM (Glioblastoma multiforme); very poor prognosis, death within 12 to 15 months
Oligodendrogliomas
Grade II-III
Generally grow more slowly than astrocytomas
Characteristically have a fried egg appearance on pathology
1p19q deletion = good response to radiation and/or chemotherapy
Ependymomas
Grade I-III
As name suggests, comes from the ependymal lining of the ventricles; often infratentorial
(4th ventricle = most frequent site); spread is via the CSF
More common in children although can occur at any age
Characterized pathologically by perivascular pseudorosettes, Flexner-Wintersteiner true
rosettes, and GFAP + staining
Treatment = surgery + radiation
Meningiomas
= Tumors of the arachnoid cells of the meninges
Generally slow growing with symptoms caused by mass effect of tumor on neighboring
brain structures
On imaging, the tumors are extra-axial (i.e., outside the brain proper because they arise
from the meninges) and exhibit homogeneous enhancement with a dural tail (where they
are connected to the meninges)
Treatment = surgery + radiation
Central Nervous System Lymphoma

Most CNS lymphomas are B cell
Can be either primary CNS lymphoma or associated with systemic lymphoma
Think of CNS lymphoma particularly in those who are immunocompromised
Strong initial response to steroids but then recur; should avoid steroids until after make the
diagnosis b/c steroids can make the biopsy non-diagnostic
In those with HIV and CNS lymphoma, prognosis is about 3 months
Metastatic
Metastatic cancer to the brain is much more common (about 10:1) than primary cancer of
the brain
Incidence increases with age
Cancers that met. brain include: Lung (both SCLC & NSCLC), breast, melanoma, and renal
cell carcinoma
NEUROLOGY13
Paraneoplastic Syndromes
Paraneoplastic syndromes are syndromes associated with humoral factors excreted by
tumor cells or by an antibody response against the tumor
Typically occur in middle aged/older patients
Typically occur in lung cancer, breast cancer, ovarian cancer, and lymphoma
Anti-Ri antibody = opsoclonus-myoclonus syndrome
Anti-Yo antibody = subacute cerebellar cortical degeneration syndrome
7.9 Neuromuscular Disorders

Peripheral Neuropathies
As the name suggests, peripheral neuropathies are conditions in which there is damage to
the nerves of the peripheral nervous system
Peripheral neuropathies can include:
Mononeuropathies neuropathy affecting a single nerve (ex.: Carpal tunnel syndrome)
Mononeuritis multiplex neuropathy affecting individual noncontiguous nerve trunks
Polyneuropathies neuropathy affecting various nerve cells in different parts of the
body (ex.: diabetic neuropathy).
Autonomic neuropathy a polyneuropathy of the autonomic nervous system;
involvement of internal organs
Neuritis inflammation of nerves of the peripheral nervous system
Brachial Plexopathy
Think of this condition in patients who have acute or subacute onset of severe
pain and weakness following vaccination
Often a single nerve is affected
Recovery = generally good
Motor Neuron Disease

Amyotrophic Lateral Sclerosis (ALS)
= Lou Gehrigs disease
Can be familial (5% of overall cases) and 20% of these familial cases are related to a
defect on chromosome 21 (of the superoxide dismutase gene). The large majority of
cases are sporadic and idiopathic
M:F ratio = 2:1
Pathology = degeneration of anterior horn cells (lower motor neurons) of the spinal cord
and the corticospinal tracts (upper motor neurons)
Rapidly progressive weakness and atrophy. Muscle fasiculations are characteristic.
Patients experience dysphagia and dysarthria
Death in approx. 2 years due to diaphragmatic weakness/decline in breathing ability
Classically, sensory functions, eye movements, and sphincter functions are not affected
Riluzole is FDA approved for treatment of ALS; = approx. 2 to 3 month prolonged
survival

Neuromuscular Junction Disorders
Myasthenia Gravis
Caused by autoantibodies (binding, blocking, and modulating) to the postsynaptic muscle
acetylcholine receptor. Anti-MuSK antibodies are also found in many cases previously
considered to be seronegative
Fluctuating muscle weakness is characteristic; fatigability is characteristic (muscles
become weaker with use)
Ocular onset is the most common pattern
Can have ptosis, diplopia, dysphagia, dysarthria, limb weakness, shortness of breath
Often associated with other autoimmune diseases: Thyroid disease, SLE, rheumatoid
arthritis, pernicious anemia, and thymoma
Treatment = AchE inhibitors (pyridostigmine), prednisone, azathioprine, IVIG/
plasmapheresis, cyclosporine, cyclophosphamide, thymectomy
Lambert-Eaton Myasthenic Syndrome
Caused by autoantibodies to the presynaptic calcium channels
Proximal limb weakness that becomes stronger with use (facilitation)
Is a paraneoplastic syndrome; look for occult malignancy (SCLC)
Treatment of underlying cancer relieves the symptoms
Myopathies
As the name suggests, myopathies are primary disorders of the muscle; weakness and
cramping are common
Myopathies can be due to a variety of causes including:
Inherited (muscular dystrophy)
Inflammatory (dermatomyositis, polymyositis, and inclusion body myositis)
Toxins (related to alcohol, corticosteroids, narcotic use)
Metabolic/mitochondrial
Endocrine-related (thyroid, parathyroid, adrenal, and pituitary disorders)
Paraneoplastic
Critical illness
7.10 Disorders of the Spinal Cord

Infectious Myelopathy
Multiple viruses and bacteria can infect the spinal cord including HIV (most common viral
cause), HTLV-1 (transmitted like HIV, causes tropical spastic paraparesis that looks clinically
like MS, endemic in the Caribbean), herpes virus, West Nile virus, poliomyelitis (post-polio
syndrome = progressive weakness occurring years to decades after the acute illness), Lyme,
syphilis
Metabolic Myelopathies
Vitamin B12 deficiency (occurs after nitrous oxide exposure at dentists office, get subacute
combined degeneration of posterior columns and corticospinal tracts), vitamin E deficiency,
and copper deficiency all affect the spinal cord
NEUROLOGY15
Compressive Myelopathies
Metastatic cancer of breast, lung, kidney, prostate; areas affected = lumbar > thoracic >
cervical; txt = dexamethasone (10-100 mg loading dose 24 mg q6h)
Primary neoplasms of the spinal cord (meningioma, schwannoma, neurofibroma,
ependymoma)
Spondylosis (degenerative disease of vertebrae leading to compression; often C5-C6 or
C6-C7 levels)
Epidural abscess (60% of cases = staph aureus)
Trauma
Conus Medullaris Syndrome vs. Cauda Equina Syndrome

Conus medullaris syndrome: Pain may only be mild, symmetric saddle distribution sensory
deficit, loss of Achilles reflex, early and severe bowel/bladder dysfunction, impaired
erection/ejaculation, onset = sudden and bilateral
Cauda equina syndrome: Pain is severe and radicular, unilateral/asymmetric distribution
sensory deficit, loss of Achilles and patellar reflexes, late and mild bowel/bladder
dysfunction, less severe sexual dysfunction, onset = gradual and unilateral
7.11 Head Injury

Subdural Hematoma (SDH)
SDH is due to tearing of the bridging veins; elderly are at significantly increased risk after
falls because atrophied brain does not completely fill the cranium
Acute: Patient may be comatose from the time of head injury; diagnose with non-contrast
head CT; treatment = craniotomy
Chronic: Trauma is remote/forgotten until weeks later patient develops headaches/
confusion/seizures/hemiparesis
Concussion
Definition: Any brief loss or alteration of consciousness 2/2 head trauma; a functional
impairment due to jarring of the brain
Grading of concussions
Grade 1 = no LOC (loss of consciousness), confusion = transient, time to symptom
resolution <15 minutes
Grade 2 = no LOC, confusion = transient, time to symptom resolution >15 minutes
Grade 3 = + LOC
Returning to play after concussion
Grade 1: May return to play if symptoms resolve in <15 minutes
Grade 2: May return to play in 1 week
Grade 3: May return to play in 1 to 2 weeks

References & SUGGESTED READINGS
4. Flaherty, Alice, Natalia Rost. The Massachusetts General Hospital Handbook of Neurology 2nd
Edition. Philadelphia, 2007. Print.
5. Roland, Lewis. Merrits Neurology 11th Edition. Philadelphia: Lippincott Williams & Wilkins, 2005. Print.
6. Ropper, Allan, Martin Samuels. Adams & Victors Principles of Neurology 9th Edition. New York:
McGraw Hill, 2009. Print.
NEUROLOGY17
NOTES

NOTES
NEUROLOGY19
NOTES

8 Psychiatry: Mental & Behavioral Health
Radu V. Saveanu, MD
Kathleen Molly McShane, MD, MPH
Luis Chaves, MD
Harvey Chitiva, MD
C o n t e n t s
8.1 ANXIETY DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
8.2 DEPRESSIVE DISORDERS . . . . . . . . . . . . . . . . . . . . . . . 24
8.3 BIPOLAR DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
8.4 SOMATOFORM DISORDERS . . . . . . . . . . . . . . . . . . . . 27
8.5 EATING DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
8.6 ATTENTION-DEFICIT/HYPERACTIVITY DISORDER . . 31
8.7 SCHIZOPHRENIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
8.8 AUTISM SPECTRUM DISORDERS . . . . . . . . . . . . . . . . 33
8.9 Common Psychiatric Medications . . . . . . . . . 34
PSYCHIATRY: MENTAL & BEHAVIORAL HEALTH19
8.1 ANXIETY DISORDERS
Generalized Anxiety Disorder (GAD)
Excessive anxiety and worry about a number of activities, occurring more days than not, for
at least 6 months
The worry is difficult to control
At least 3 of the following 6 symptoms are present:
Restlessness or feeling keyed up
Difficulty concentrating or mind going blank
Irritability
Easily fatigued
Muscle tension
Sleep disturbance
Treatment
Medications
SSRIs and SNRIs (see Table on Common Antidepressants)
Benzodiazepineslong acting (e.g., clonazepam) is preferred over short acting (e.g.,
alprazolam) to avoid withdrawal-induced anxiety and to lower risk of abuse (see
Table on Common Anxiolytics)
Buspironea nonbenzodiazepine anxiolytic, useful if history of substance abuse
Psychotherapy
Cognitive behavioral therapy to correct cognitive distortions (e.g., catastrophizing)
and to teach relaxation techniques and desensitization
Panic Disorder With or Without Agoraphobia

Panic Attack
A discrete period of intense fear or discomfort, reaching a peak within 10 minutes,
typically lasting 5 to 30 minutes (see Table on Panic Attack Symptoms)
Table 8.1: Panic Attack Symptoms

(At Least 4 Symptoms Needed for Diagnosis)
1. Feeling dizzy, lightheaded, or faint 7. Chest pain or discomfort
2. Derealization (feelings of unreality) or deper- 8. Nausea or abdominal distress
sonalization (being detached from oneself) 9. Palpitations, tachycardia
3. Fear of losing control or going crazy 10. Sweating
4. Fear of dying 11. Trembling or shaking
5. Sensations of shortness of breath or smothering 12. Paresthesia
6. Feeling of choking 13. Chills or hot flushes
Diagnosis
Recurrent unexpected panic attacks
1 or more of the following:
Concern about having additional attacks
Worry about the implications or the consequences (e.g., losing control, having a heart
attack)

Change in behavior because of the attacks
Specify whether agoraphobia is present
Agoraphobia
Anxiety about having a panic attack while being in places or situations from which escape
might be difficult or embarrassing or in which help may not be available
Situations are avoided, or endured with marked distress
Agoraphobic fears include being outside the home alone, being in a crowd, standing in
line, being on a bridge, traveling in a bus, train or car
Can lead to patient being homebound
Treatment
Medications
SSRIs and venlafaxine (SNRI)initiate at lower dosage since they can cause increase
in anxiety in the 1st 1 to 2 weeks
TCAs and MAOIs are effective, but have significant side effects (see Table on
Common Antidepressants)
Benzodiazepinesalprazolam and clonazepam are effective; may require high doses
Psychotherapy
Cognitive behavioral therapy
Relaxation and exposure techniques
Post-traumatic Stress Disorder (PTSD)

Experiencing or witnessing an event that involves death, threat to life, or serious injury to
self or others
Response involves fear, helplessness, or horror
Symptoms occur for at least 1 month (if symptoms are less than 1 month, then diagnosis is
acute stress disorder)
For symptoms, see Table on PTSD Diagnostic Criteria
Table 8.2: PTSD Diagnostic Criteria
PTSD Symptom Category Symptoms
Re-experiencing 1. Recurrent and intrusive thoughts
(at least 1 symptom) 2. Recurrent and distressing dreams of the trauma
3. Intense psychological distress at cues that recall or symbolize
the traumatic event
4. Physiological reactivity on exposure to cues that recall or sym-
bolize the traumatic event
5. Flashbacks
Avoidance 1. Avoiding thoughts, feelings or conversations associated with the
trauma
(at least 3 symptoms)
2. Avoiding activities, places or people associated with the trauma
3. Markedly diminished interest or participation in significant activities
4. Feelings of detachment or estrangement from others
5. Inability to recall important aspects of the trauma
6. Restricted range of affect
7. Sense of foreshortened future
Increased Arousal 1. Difficulty falling or staying asleep
(at least 2 symptoms) 2. Difficulty concentrating
3. Irritability or outbursts of anger
4. Hypervigilance
5. Exaggerated startle response
Acute PTSDif duration of symptoms is less than 3 months

Chronic PTSDif duration of symptoms is 3 months or more
Treatment
Combination of medications and psychotherapy is best
Medications
First-line: SSRIs and SNRIs (see Table on Common Antidepressants)
Prazosin (usual dosage 1-10 mg) has been shown to decrease nightmares and
improve sleep
Psychotherapy
Cognitive behavioral therapy incorporating exposure therapy
Eye Movement Desensitization and Reprocessing (EMDR)patient focuses on
traumatic memory while eyes track side-to-side and therapist supplies positive
associations in order to replace the negative ones
Specific Phobia
There is marked and persistent fear that is excessive and unreasonable cued by the
presence or anticipation of a specific object or situation (e.g., flying, heights, animals,
injections, seeing blood)
Exposure to the stimulus provokes an immediate anxiety response, which may be a
situationally bound panic attack (unlike panic disorder, where panic attacks are unexpected)
Realization that the fear is excessive or unreasonable
Phobias are among the most common of all psychiatric disorders, affecting 5 to 10% of the
population

Treatment
Psychotherapy using systematic desensitization
Social Anxiety Disorder

Social anxiety disorder, or social phobia, is a fear of social situations or performance
situations, such as public speaking
The patient fears acting in an embarrassing or humiliating manner in social settings
Symptoms include blushing, trembling, sweating, tachycardia, elevated blood pressure, and
situationally bound panic attacks
Individuals avoid social interactions and feel easily scrutinized and criticized by others
Treatment
SSRIs
TCAs
Benzodiazepines
b-blockers (e.g., propranolol, usual dosage 20-80 mg) are used for performance situations
Obsessive Compulsive Disorder (OCD)

Obsessions or compulsions or both are present
Obsessions
Recurrent and persistent thoughts, impulses, or images that are intrusive and
inappropriate and that cause marked anxiety or distress
Attempts are made to ignore the thoughts or to neutralize them with some other
thought or action
Compulsions
Repetitive behaviors or mental acts that the patient feels driven to perform in response
to an obsession or according to rigid rules
The obsessions or compulsions are recognized as excessive or unreasonable
The obsessions or compulsions are time-consuming (over 1 hour a day)
OCD is underreported, with long delay between onset and presentation for treatment
Table 8.3: Common Obsessions and Compulsions

Obsessions Compulsions
Contamination or illness Checking door locks, oven, etc.
Violent images Cleaning or washing
Fear of harming other or harming self Counting objects
Perverse or forbidden sexual thoughts, images or Hoarding or collecting things
impulses Ordering or arranging things
Symmetry or exactness Repeating things (words silently, tapping)
Treatment
Behavioral therapy
Create hierarchy of fears
Prevent patient from completing the compulsive behaviors
Medications
FDA approved SSRIs: Fluvoxamine, fluoxetine, sertraline, paroxetine
FDA approved TCA: Clomipramine
Neurosurgery for severe cases
Deep brain stimulation (DBS)
Bilateral cingulotomy
8.2 DEPRESSIVE DISORDERS

Major Depressive Disorder (MDD)
Presence of 1 major depressive episode
There has never been a manic episode, a mixed episode, or a hypomanic episode
Major Depressive Episode (MDE)
5 of the following symptoms for 2 weeksat least 1 needs to be either depressed mood
or loss of interest or pleasure:
1. Depressed mood Mnemonic: SIGECAPS
2. Diminished interest or pleasure in activities S: Sleep
3. Weight loss, or decrease or increase in appetite I: Interest
G: Guilt
4. Insomnia or hypersomnia
E: Energy
5. Psychomotor agitation or retardation C: Concentration
6. Fatigue or loss of energy A: Appetite
P: Psychomotor
7. Feelings of worthlessness or excessive or inappropriate guilt
S: Suicidal
8. Poor concentration or indecisiveness
9. Recurrent thoughts of death, suicidal ideation without plan, or
suicidal plan or suicidal attempt
Epidemiology
Lifetime prevalence: 16.5% (higher in females than males)
Point prevalence: 5 to 9% for women and 2 to 3% for men
If 1 previous MDE, then there is a 60% chance of having a 2nd episode.
If 2 previous episodes, then there is a 70% chance of having a 3rd one.
If 3 previous episodes, then there is a 90% chance of having a 4th one
20 to 25% of patients with certain general medical conditions (e.g., diabetes, myocardial
infarction, carcinomas, stroke) will develop MDD
Up to 15% of individuals with severe MDD may commit suicide
Comorbidities
Substance use disorders, anxiety disorders, and eating disorders (anorexia and bulimia
nervosa)
Anxiety can present as an associated symptom or as part of a separate comorbid anxiety
disorder (panic disorder, obsessive-compulsive disorder, etc.)

Treatment
Goal of treatment is symptom remission
Psychotherapy in mild to moderate depression
Cognitive behavioral therapy (CBT)
Interpersonal psychotherapy (ITP)
Medications
First-line: SSRIs, SNRIs, bupropion, mirtazapine (see Table on Common
Antidepressants)
Second-line: TCAs, MAOIs (avoid these if suicidal, due to risk of lethal overdose)
Common augmentation strategies: 2nd generation antipsychotics, lithium,
liothyronine (synthetic T3)
Electroconvulsive therapy (ECT)
Failure of multiple antidepressants
Severe depression
Psychotic symptoms
Suicidal ideation
Also helpful in treating catatonia and mania
Contraindications: No absolute contraindication for ECT
Relative contraindications: Recent CVA, brain tumor, spine compression fracture
Dysthymic Disorder
Depressed mood for most of the day, for more days than not, for at least 2 years
Presence of 2 of the following:
Poor appetite or overeating
Insomnia or hypersomnia
Low energy or fatigue
Low self-esteem
Poor concentration or difficulty making decisions
Feelings of hopelessness
Often described as a chronic, low-grade depression
Epidemiology
Lifetime prevalence: 6%
More frequent in females2:1
Treatment
Similar to MDD
8.3 BIPOLAR DISORDERS
Bipolar I Disorder
Occurrence of 1 or more manic or mixed episodes
Episodes of depression frequently occur but are not required for the diagnosis
Manic Episode
1 week (or any duration if hospitalized) of abnormally Mnemonic: DIG FAST
and persistently elevated, expansive, or irritable mood, D: Distractibility
together with 3 (4 if the mood is irritable) of the following I: Impulsive pleasurable activities
G: Grandiosity
symptoms:
F: Flight of ideas
Inflated self-esteem or grandiosity A: Activities towards goals
Decreased need for sleep S: Sleep
More talkative T: Talkativeness
Flight of ideas or subjective experience that thoughts

are racing
Distractibility
Increase in goal-directed activity or psychomotor agitation
Involvement in activities that have a high potential for painful consequences (e.g.,
sexual indiscretions, or foolish business investments)
Epidemiology
Lifetime prevalence: 0.4 to 1.6%
Suicide: 10 to 15% of patients
Course
Average age at onset: 20
>90% of patients who have a single manic episode will have more episodes
60 to 70% of manic episodes occur immediately before or after a MDE
On average, 4 episodes occur in 10 years in patients without treatment
Treatment
Mood stabilizers (see Table on Common Mood Stabilizers)
Lithium is very effective and still considered the gold standard
2nd-generation antipsychotics (see Table on Common Antipsychotics) for their mood
stabilizing effects
Avoid antidepressants for risk of switching to mania
Mixed Episode
Symptoms of a manic episode plus a major depressive episode during at least 1 week
Bipolar II Disorder
1 major depressive episode and at least 1 hypomanic episode
Hypomanic Episode
Criteria are the same than for manic episode except for:
Episode lasts at least 4 days
Episode is not severe enough to cause marked impairment in social or occupational
functioning, or to necessitate hospitalization, and there are no psychotic features
Treatment
Similar to bipolar I

Cyclothymic Disorder
Diagnosis
2 years with numerous periods with hypomanic symptoms and depressive symptoms
that do not meet criteria for a manic episode or major depressive episode
During that 2-year period the person has not been without symptoms for more than 2
months at a time
Table 8.4: Presence of Mood Episodes in Bipolar Disorders

Manic Episodes Mixed Episodes Hypomanic Depressive
Episodes Episodes
Bipolar I Disorder x x x x
Bipolar II Disorder x x
8.4 SOMATOFORM DISORDERS

Include somatization disorder, conversion disorder, hypochondriasis, body dysmorphic
disorder, and pain disorder
Medical symptoms are excessive for the degree of objective disease
The symptoms or deficits are not intentionally produced or feigned as in factitious disorder
or malingering (see Other Related Disorders)
The symptoms or deficits cause clinically significant distress or impairment in social,
occupational or other important areas of functioning or warrant medical evaluation
Treatment focuses on management of symptoms rather than cure
Somatoform disorder is a diagnosis of exclusion
Somatization Disorder
Multiple recurrent somatic complaints starting before age of 30
Pain symptoms in at least 4 sites, and 2 or more GI symptoms, 1 sexual or reproductive
symptom, and 1 pseudoneurological symptom
The disorder usually results in significant medical diagnostic testing, medical intervention
and other iatrogenic problems
Treatment
Regularly scheduled appointments with the primary care physician to lessen frequency of
ER visits and doctor shopping
Screen for and treat co-morbid psychiatric disorders
Conversion Disorder
Symptoms present as voluntary motor or sensory dysfunction suggestive of a neurologic or
other general medical condition
Psychological factors are prominent, and the initiation or exacerbation of the symptoms is
preceded by conflicts or stressors
The symptoms are not fully explained after clinical assessment as a medical condition or
culturally sanctioned phenomenon
Common symptoms include sudden paralysis, abnormal movements, aphonia, blindness,
deafness, or pseudoseizures
Treatment
Reassure the patient and inquire about stressors
Focus on regaining function and suggest the course of impairment is brief
Direct confrontation is not recommended
Screen for domestic violence
Hypochondriasis
Preoccupation with fears of having a serious disease based on the patients
misinterpretation of bodily symptoms for at least 6 months
Preoccupation persists despite appropriate medical evaluation and reassurance
Preoccupation is not delusional, not consistent with body dysmorphic disorder, and is not
better accounted for by another psychiatric disorder
Treatment
Manage psychological stressors in collaboration with a psychiatrist
Reassure and validate distress
Body Dysmorphic Disorder

Preoccupation with an imagined or grossly exaggerated body defect
Psychiatric disorders such as anorexia nervosa, OCD, etc. cannot account for the
preoccupation and the impairment
Patients frequently consult multiple primary care physicians, dermatologists, and plastic
surgeons
Treatment
SSRIs and cognitive behavioral therapy
Pimozide is helpful for delusional belief of parasitic infestation
Pain Disorder
Pain is the prominent clinical presentation for at least 6 months
Psychological factors have a significant role in the outset, severity, exacerbation, or
perpetuation of the pain syndrome
The pain is not a component of somatization disorder
Co-morbid MDD is extremely common
Treatment
Refer to multidisciplinary pain clinic
Cognitive and biofeedback therapy
TCAs for pain and comorbid psychiatric conditions
Limit inappropriate use of analgesics
Other Related Disorders

Factitious Disorder
Voluntary and deliberate production of signs or symptoms of physical or psychological
disease in order to assume the sick role
Associated with history of childhood trauma
Often there is a history of genuine physical illness in the patient or a close relative during
childhood
Patients are commonly healthcare workers (i.e., nurses)
Patients often undergo multiple hospitalizations and surgeries

Munchausens syndrome is the most extreme form of chronic factitious disorder with
predominantly physical signs and symptoms. It is more common in men
Treatment
Avoid unnecessary treatment
Address underlying emotional needs and/or psychiatric illness
Malingering
Intentional production of false or exaggerated physical or psychological symptoms
Unlike factitious disorder, malingering is motivated by external incentives such as avoiding
work, obtaining financial compensation or drugs, evading criminal prosecution, etc.
Marked discrepancy exists between claimed disability and objective findings
Patient likely has anti-social personality disorder and is uncooperative with evaluation and
treatment
Treatment
After careful investigation, confront the patient
8.5 EATING DISORDERS

Significantly more prevalent in women
Onset in teenage or young adult years
Both anorexia nervosa and bulimia nervosa have primary symptom of preoccupation with
weight and body image
Prevalence is 4% and is increasing
Approximately 50% of patients with anorexia nervosa also have symptoms of bulimia
nervosa
A diagnosis of bulimia is not made if criteria for diagnosis of anorexia nervosa are present
Comorbid MDD is common
Bupropion is contraindicated due to increased risk of seizures
Anorexia Nervosa
Diagnostic Criteria (Must Meet All 4 Criteria)
1. Refusal to maintain normal weight for age and height (less than 85% of ideal weight)
2. Intense fear of gaining weight
3. Disturbance in the way body weight or shape is experienced or denial of the seriousness
of the current low body weight
4. Amenorrhea in postmenarcheal females who are not on OCPs
Types
Restricting type (limits food intake to avoid weight gain)
Binge-eating/purging type (self-induced vomiting or misuse of laxatives or diuretics)
Table 8.5: Medical Complications of Anorexia Nervosa
Bradycardia Depletion of fat
Hypotension Muscle wasting (including cardiac muscle in severe
wasting)
Hypothermia
Lanugo (fine hair of the body)
Hypokalemia
Hypercortisolemia
Arrhythmias and sudden death
Osteoporosis
Leukopenia
Treatment
Hospitalization to reestablish weight and correct metabolic abnormalities
Behavioral modification, cognitive behavioral therapy, family therapy
SSRI for co-morbid depression
Bulimia Nervosa
Diagnostic Criteria
Recurrent episodes of binge eating characterized by both:
1. Eating, in a discrete period of time, an amount of food that is definitely larger than
most people would eat during a similar circumstances
2. A sense of lack of control over eating during the episode
Recurrent inappropriate compensatory behaviors to prevent weight gain: Self-induced
vomiting, diet pills, fasting, misuse of laxatives, diuretics, enemas, and or excessive
exercise
2 episodes of binge eating and purging/severe compensatory behaviors per week for a
minimum of 3 months
Types
Purging type (self-induced vomiting or the misuse of laxatives, diuretics, or enemas)
Nonpurging type (fasting or excessive exercise)
Table 8.6: Medical Complications of Bulimia Nervosa

Dental disease including erosion of dental enamel Melanotic stool if abusing laxatives
and dental carries Esophageal and gastric irritation and bleeding
Parotid and salivary gland hypertrophy Hyperamylasemia
Hypochloremic-hypokalemic metabolic alkalosis May have comorbid depressive or anxiety disorder
due to vomiting
Treatment
SSRIs treat binge-eating component, regardless of whether there is comorbid depression

8.6 ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)
Definition
Syndrome with prominent deficits of executive functions including inattention, distractibility,
restlessness, over-activity, and impulsiveness
Affects 5 to 12% of children worldwide. Male to female ratio = 3-5:1
Females have a slightly higher incidence of inattentive symptoms while boys have a higher
incidence of disruptive symptoms, leading many times to earlier referral
Hyperactive symptoms tend to decrease with age, inattentive ones tend to persist
Comorbid disorders: Conduct, anxiety, learning and mood disorders
Types/Diagnostic Criteria
Diagnosis is made clinically, supported by reports (scales) from teachers and parents
Some symptoms must have been present before the age of 7
There has to be evidence of impairment in social, academic or occupational functioning.
Impairment MUST be present in at least 2 settings (school/home/work)
Symptoms must have persisted for at least 6 months
Table 8.7: ADHD Types

Inattentive At least 6 of the following 9:
1. Poor attention to details
2. Difficulty sustaining attention
3. Patient does not seem to listen when spoken to
4. Patient does not follow instructions or fails to finish duties
5. Difficulty organizing tasks
6. Avoids tasks that require sustained mental effort
7. Losing things necessary for tasks
8. Easily distracted by extraneous stimuli
9. Forgetfulness
Hyperactive/Impulsive At least 6 of the following 9:
1. Often fidgets with hands or feet
2. Unable to remain seated when expected to
3. Restlessness
4. Difficulty engaging in leisure activities quietly
5. Often on the go
6. Often excessively talking
7. Often blurts out answers before questions have been completed
8. Often has difficulty awaiting turn
9. Often interrupts or intrudes on others
Combined Symptoms of inattention AND hyperactivity
Not Otherwise Prominent symptoms of inattention or hyperactivity that do not meet the
Specified criteria for ADHD
Treatment
First-line: Stimulants: Amphetamines (e.g., Adderall) and methylphenidate (e.g., Ritalin,
Focalin, Concerta)
Most common side effects of stimulants: Decreased appetite and insomnia. Usually
managed with clonidine or guanfacine
Also first-line: Atomoxetine (Strattera), a norepinephrine reuptake inhibitor
Atomoxetine usually started if anxiety is a prominent feature. It is less associated with
insomnia or decreased appetite
Second-line: -2 receptor agonists (clonidine and guanfacine) and bupropion
SSRIs usually started for comorbid depression or anxiety
Psychotherapy recommended when behavioral problems, depression, or anxiety are
prominent features
8.7 SCHIZOPHRENIA
2 of the following symptoms for 1 month:
Delusions (false fixed beliefs resistant to reason or confrontation and not explained by
patients culture)
Hallucinations (false sensory perceptions in the absence of external stimulus)
Disorganized speech
Grossly disorganized or catatonic behavior
Negative symptoms (affective flattening, alogia, or avolition)
Continuous signs of the disturbance persist for at least 6 months
Epidemiology
Prevalence: 1% worldwide
Men=women
Peak ages of onset: 18 to 25 for males, 25 to 35 years for females
Etiology
Increased dopaminergic activity
Serotonin and glutamate also involved
Psychiatric Comorbidities
Nicotine dependence: 80 to 90%
Anxiety disorders (OCD, panic disorder)
Schizotypal, schizoid, and paranoid personality disorder
Predictors of Good Prognosis

Late onset
Acute onset
Good premorbid functioning
Good social support
Positive symptoms (hallucinations, delusions)
Pharmacological Treatment
Typical or atypical antipsychotics (see Table on Common Antipsychotics)

Atypical antipsychotics target negative symptoms, have fewer side effects and lower risk
for Neuroleptic Malignant Syndrome (NMS)
Table 8.8: Differential Diagnosis of Schizophrenia

Brief Schizophreniform Schizophrenia Schizoaffective Disorder
Psychotic Disorder
Disorder
Psychotic <1 month 1-6 months >6 months 1. Criteria for schizophrenia
Symptoms 2. Criteria for MDD or bipolar
3. 2 weeks of psychosis without
mood symptoms
8.8 AUTISM SPECTRUM DISORDERS a.k.a. Pervasive Developmental Disorders (PDD)

Definition
Developmental disorders with presence of severeandpervasive impairments in 3 areas:
1. Social skills 2. Communication and play 3. Interests/activities (stereotyped behavior)
Differential diagnosis include: Mental retardation, learning disorders, selective mutism, early-
onset schizophrenia, social anxiety, OCD, and schizoid or avoidant personality disorders
Clinical presentation varies from very impaired to somewhat functioning and independent
Associated symptoms include: Aggressiveness, anxiety, and obsessive-compulsive
behaviors
About 35% of patients with autism have comorbid seizure disorders
Types
Autistic Disorder
Affects all 3 major areas seen in the PDD
Delays must be present before the age of 3
No specific laboratory test for autism but conditions such as Fragile X and tuberous
sclerosis should be excluded
Diagnosis is made clinically, supported by complete history of pregnancy, neonatal, and
developmental history, along with scales provided to parents
Chief complaint is usually a concern due to unusual sensitivities to the environment (e.g.,
light, sounds, labels of clothes) or that child might be deaf
Language is typically significantly delayed or absent in the 1st years
Unusual behaviors (e.g., stereotyped movements, extreme rigidity with schedules) are
common
Prevalence: 1 in 1,000
3 to 4 times more common in males than females, but in females it tends to be more
associated to severe mental retardation
50% have severe-profound mental retardation; 30% mild-moderate; 20% have normal IQ
Retts Disorder
Early growth and development is normal followed by a deceleration in head growth after
the age of 5 months. The only PDD with decreased life expectancy
Loss of previously acquired skills in language, social skills, and hand skills
Patients develop stereotyped hand movements (wringing, washing-like movements)
Aspergers Disorder
Similar to autistic disorder but there is no significant delay in language or cognition
Social deficits become more prominent as the child enters preschool
PDD-Not Otherwise Specified (NOS)
Impairment in all 3 areas (social, language, and stereotyped behavior) but not enough to
meet criteria for one of the other PDDs
Childhood Disintegrative Disorder
Apparently normal development for the 1st 2 years of life, followed by a marked
regression in development (language, social, play, motor skills) before the age of 10
Treatment
There are no specific medications for PDDs and no medication treats the core symptoms.
Management depends on the clinical presentation:
If anxiety is present, patients might require use of SSRIs
If behavioral problems/aggressive behaviors are present, atypical antipsychotics
including risperidone can be used
Lithium, anxiolytics (e.g., benzodiazepines) and mood stabilizers have been used in
these patients with varying degrees of success
Structured environment and behavioral methods are most effective
8.9 Common Psychiatric Medications
Table 8.9: Common Antidepressants

Antidepressant Medication Daily Dose Side Effects
Type Name Range (mg) *Comments
Selective serotonin Citalopram 20-40 Sexual dysfunction (the most common side
reuptake inhibitors effect in long-term treatment)
(SSRIs) Escitalopram 10-20
Headaches
Fluoxetine 20-80
GI (nausea, vomiting, diarrhea)
Fluvoxamine 50-300
Anxiety (when starting or stopping SSRI, so
Paroxetine 20-50 titrate slowly)
Sertraline 50-200 Insomnia/sedation
Impaired platelet aggregation
Hyponatremia
SIADH
Suicidality (in children and young adults)
Serotonin Venlafaxine 75-375 Sexual dysfunction
norepinephrine GI (nausea, constipation)
reuptake inhibitors Desvenlafaxine 50-100
(SNRIs) Dry mouth
Duloxetine 60-120 Sweating
Elevated blood pressure
*Helpful in chronic pain
*Duloxetine should not be used in patients
with active alcohol abuse

Table 8.9: Common Antidepressants cont.
Antidepressant Medication Daily Dose Side Effects
Type Name Range (mg) *Comments
Norepinephrine and Bupropion 100-450 Headache
dopamine reuptake Insomnia
inhibitor (NDRI)
Nausea
Irritability
Anxiety
Seizures
*Used for ADHD and smoking cessation
Noradrenergic Mirtazapine 15-45 Somnolence
and specific Dry mouth
serotonergic
antidepressant Increased appetite/weight gain
(NaSSA) *Used for insomnia
Serotonin Trazodone 50-400 Sedation
Antagonist/reuptake Orthostatic hypotension
inhibitor (SARI)
Dizziness
Priapism (rare but potentially serious)
*Commonly used for insomnia
Tricyclic Imipramine 150-300 Anticholinergic effects
antidepressants Orthostatic hypotension
(TCAs)
Amitriptyline 150-300 Tachycardia
Prolonged QT interval
Arrhythmias (in overdose)
Monamine oxidase Phenelzine 45-90 Orthostatic hypotension
inhibitors (MAOIs)
Insomnia
Tranylcypromine 20-60 Weight gain
Sexual dysfunction
Tyramine-induced hypertensive crisis
*Must avoid many foods and medications
(sympathomimetics, opioids, etc.)
Table 8.10: Common Antipsychotics
Type Medication Name Daily Dose Side Effects *Comments
Range (mg)
1st-generation Haloperidol 1-20 Acute dystonia
antipsychotics Akathisia
(typicals)
Tardive dyskinesia
Hyperprolactinemia
Chlorpromazine 100-1,000 Sedation
Hypotension
Q-T interval prolongation
Decrease in seizure threshold
Anticholinergic effects
2nd-generation Aripiprazole 10-30 Headache
antipsychotics Somnolence
(atypicals)
Akathisia
Clozapine 50-900 Sedation
Orthostatic hypotension
Metabolic syndrome
Agranulocytosis (requiring frequent labs)
Hypersalivation
Dose-dependent seizures
*Used in treatment-resistant schizophrenia
*Decreases suicidal risk
Olanzapine 5-20 Metabolic syndrome
Quetiapine 50-800 Somnolence
Risperidone 1-6 Extrapyramidal symptoms
Hyperprolactinemia
Ziprasidone 40-160 Q-T interval prolongation

Table 8.11: Common Mood Stabilizers
Medication Name Daily Dose Range (mg) Side Effects *Comments
Lamotrigine 100-400 Stevens-Johnson syndrome
Concurrent use of valproic acid doubles serum
lamotrigine concentration
Skin rash in 10% of patients
*Beneficial for depressive episodes in Bipolar I or II
Disorder
Lithium 900-1,800 Polyuria and polydipsia
Theraputic level: 0.5 Fine tremor
1.2 mEq/L Nausea and diarrhea
Acne
Hypothyroid
Diabetes insipidus
Benign leukocytosis
Narrow therapeutic index
Teratogenic: Ebstein anomaly
*Decreases suicidal risk
*Renally excreted
Valproic Acid 1,000-2,000 Hepatotoxicity
Max 60 mg/kg/d Pancreatitis
Theraputic level: 50 GI distress
125 mg/mL Thromocytopenia
Weight gain
Alopecia
Teratogenic neural tube defects
Table 8.12: Common Anxiolytics

Medication Name Daily Dose Side Effects *Comments
Range (mg)
Alprazolam 0.5-6 Drowsiness
Clonazepam 0.5-4 Respiratory depression
Lorazepam 0.5-6 Tolerance, dependence
Discontinuation syndrome
Withdrawal seizures
Abuse potential
Buspirone 15-60 Dizziness
Headache
Serotonin syndrome
*Not addictive or sedative
*Acts on serotonin and dopamine receptors (not GABA)
Medication Induced Syndromes
Serotonin Syndrome
Due to:
Combination of SSRIs+ MAOI, L-tryptophan, or lithium
Overdose of MAOIs
Symptoms: Mental status changes, confusion, restlessness, hyperreflexia, tremor, ataxia,
nausea, diarrhea
Caution when using: Meperidine, tramadol, triptans, dextromethorphan
Treatment: Supportive measures, stop causing medications, benzodiazepines
Serotonin Discontinuation (or Withdrawal) Syndrome
Due to abrupt discontinuation of medication
Occurs within 48-hours of stopping antidepressant
Venlafaxine, fluvoxamine, and paroxetine have higher risk due to short half-lives
Symptoms include anxiety, irritability, nausea, headaches, insomnia, fatigue, dysphoria, flu-
like symptoms
Treatment: Fluoxetine at low dose (10-20 mg daily) for 1 to 2 weeks and then discontinue
Neuroleptic Malignant Syndrome (NMS)
A life-threatening reaction to an antipsychotic medication Mnemonic: FEVER
All antipsychotics may cause the syndrome, however, it is more F: Fever
frequently associated with potent antipsychotics (haloperidol) E: Encephalopathy
V: Vitals unstable
Some antiemetic medications such as metoclopramide can
E: Elevated CPK
cause the syndrome R: Rigidity
Treatment: Stop antipsychotic, cooling blankets, supportive
measures, muscle relaxants (dantrolene), or dopamine agonists
(bromocriptine, amantadine)
Re-challenging with the same medication will likely induce NMS again
REFERENCES & Suggested Readings

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edition,
text revision. Washington: American Psychiatric Association, 2000. Print.
2. Pliszka S, AACAP Work Group on Quality Issues. Practice parameters for the assessment and
treatment of children and adolescents with ADHD. Journal of the American Academy of Child &
Adolescent Psychiatry, 46:7, 2007: 894-921.
3. Sadock B, Sadock V. Kaplan & Sadocks Synopsis of Psychiatry. 10th Edition. Philadelphia: Lippincott
Williams & Wilkins, 2007. Print.
4. Sadock B, Sadock V, Sussman N. Kaplan & Sadocks Pocket Handbook of Psychiatric Drug
Treatment. 5th Edition. Philadelphia: Lippincott Williams & Wilkins, 2011. Print.
5. Stahl S. Stahls Essential Psychopharmacology. 3rd Edition. New York: Cambridge University Press,
2008. Print.
6. Stern T, Herman J. Massachusetts General Hospital Psychiatry Update and Board Preparation. 2nd
Edition. New York: McGraw-Hill, 2004. Print.
7. Tanguay P.E. Dulcans Textbook of Child and Adolescent Psychiatry. Chapter 13, Autism Spectrum
Disorders. American Psychiatric Publishing, Inc, 2010.
8. Volkmar F, AACAP Work Group on Quality Issues. Practice parameters for the assessment and
treatment of children, adolescents, and adults with autism and other pervasive developmental disor-
ders. Journal of the American Academy of Child & Adolescent Psychiatry, 38:12, 1999: 32S-54S.

NOTES
NOTES

9 Nephrology/Urology
Alexandra Voinescu, MD
C o n t e n t s
9.1 Clinical Evaluation of Kidney Function . 42
9.2 Fluids and Electrolytes . . . . . . . . . . . . . . . . . . . 48
9.3 Acid-base Disorders . . . . . . . . . . . . . . . . . . . . . . . . 55
9.4 Tubulointerstitial Disease . . . . . . . . . . . . . . . . 59
9.5 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
9.6 Genetic Disorders and Kidney Disease . . . 68
9.7 Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . 73
9.8 Kidney Stones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
9.9 The kidney in Pregnancy . . . . . . . . . . . . . . . . . . . 85
9.10 Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . 91
9.11 Glomerular Diseases . . . . . . . . . . . . . . . . . . . . . . . 95
NEPHROLOGY/UROLOGY41
9.1 Clinical Evaluation of Kidney Function
Estimation of the Glomerular Filtration Rate (GFR)
The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF K/DOQI)
chronic kidney disease (CKD) guidelines define CKD as either kidney damage (proteinuria,
hematuria, or structural abnormalities of the kidney) with or without impaired GFR, or
impaired eGFR <60 mL/min per 1.73m2 with or without kidney damage that persists for
over 3 months
Estimation of GFR is used clinically to assess the degree of kidney impairment and to
measure disease progression to determine prognosis and effects of treatment
The GFR is equal to the sum of the filtration rates in all of the functioning nephrons. Thus,
the GFR gives a rough measure of the number of functioning nephrons
Measurement of GFR is complex, time consuming, and cumbersome to do in routine clinical
practice. Although GFR cannot be measured directly, the best method for estimating GFR
is measurement of the urinary clearance of an ideal filtration marker
Inulin is the gold standard filtration marker, as it is freely filtered at the glomerulus, and is
neither secreted, reabsorbed, synthesized, nor metabolized by the kidney
Other less cumbersome methods for measuring clearance have been developed, using
alternative exogenous markers, such as iothalamate, iohexol, DTPA, or EDTA
Serum Creatinine
The most widely used indirect measure of GFR
Creatinine, a metabolic product derived from the metabolism of creatine in the skeletal
muscle and from dietary meat intake, is released into circulation at a relatively constant
rate
Creatinine is freely filtered in the glomeruli, and is not reabsorbed or metabolized by the
kidney
10 to 30% of the creatinine in the bloodstream is not filtered in the glomeruli, but is
secreted in the urine by the organic cation secretory pathways in the proximal tubules
Because production of creatinine is constant, the serum creatinine level depends on the
rate of clearance, which mainly reflects the GFR
There are many limitations of using creatinine to estimate GFR. A reduction in muscle
mass (e.g., malnutrition, liver failure, or muscle wasting) can cause a disproportionately
low creatinine level that results in overestimation of the GFR. Early in the course of
chronic kidney disease, there is an enhanced tubular creatinine secretion by as much as
50%, which may result in overestimation of the GFR. In addition, creatinine secretion can
be blocked by different drugs (e.g., trimethoprim, cimetidine), resulting in a rise in the
serum creatinine of as much as 0.4 to 0.5 mg/dL and an underestimation of the GFR
Creatinine Clearance
Usually determined from a 24-hour urine collection
Limitations of using creatinine clearance include inaccurate urine collection and variation in
the degree of creatinine secretion, which increases as GFR decreases
The accuracy of 24-hour urine collection can be estimated from comparing the total urine
creatinine excretion with the normal rate of creatinine excretion (20 to 25 mg/kg/24 h in
men, and 15 to 20 mg/kg/24 h in women)

Estimated GFR Formulas
Different estimation equations have been developed as alternative methods of estimating
GFR (see Table on Estimated GFR Equations)
The most widely used equations in the US are the Cockcroft-Gault and the Modification
of Diet in Renal Disease (MDRD) Study equation
The CKD-EPI equation provides a more accurate estimate of GFR among individuals with
normal or only mildly reduced GFR (above 60 mL/min per 1.73 m2)
Table 9.1: Estimation GFR Equations

Cockcroft-Gault Equation
Ccr = ([140 - age] weight)/72 (Scr) 0.85 (if the patient is female)
Modification of Diet in Renal Disease Study Equation
GFR = 170 (Scr)-0.999 (age)-0.176 (BUN)-0.170 (alb)-0.318 0.762 (if the patient is female) or
1.18 (if the patient is African decent)
Abbreviated Modification of Diet in Renal Disease Study Equation
GFR = 175 (Scr)-1.154 (age)-0.203 0.742 (if the patient is female) or 1.212 (if the patient is African
decent)
CKD-EPI
GFR = 141 min (Scr/k, 1)alpha max (Scr/k, 1)-1.209 0.993 Age 1.018 (if the patient is female) 1.159
(if the patient is African decent)
k is 0.7 for females and 0.9 for males, alpha is -0.329 for females and -0.411 for males, min indicates the
minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1
Blood Urea Nitrogen (BUN)

Usually measured simultaneously with creatinine to evaluate kidney function
The normal BUN/creatinine ratio is 10/1 to 15/1
40 to 50% of the filtered urea is passively reabsorbed, especially in the proximal tubule
Conditions that decrease renal perfusion, such as volume depletion of heart failure, are
associated with increase in urea reabsorption, resulting in a disproportionate increase in the
BUN/creatinine ratio (20/1 or higher)
A high protein diet, increased tissue breakdown due to hemorrhage, trauma, or
glucocorticoid therapy may cause an increase in the BUN level and a subsequent
underestimation of kidney function
A low protein diet or liver disease can cause a decrease in the BUN level and a subsequent
overestimation of kidney function
In patients with severe kidney disease, the urea clearance significantly underestimates the
GFR, and the creatinine clearance significantly overestimates the GFR. In these patients,
GFR can be estimated to average both the creatinine and urea clearance
Interpretation of Urinalysis
Dipstick Analysis
Specific Gravity
Reflects the relative proportion of dissolved solutes to total volume
Depends on both the number and weight of the dissolved particles
Normal range is 1.003 to 1.030
Values decrease with age as the kidneys ability to concentrate urine decreases
Is also influenced by protein, glucose, mannitol, diuretics, radiocontrast media, and some
antibiotics
Low values (<1.010) are consistent with dilute urine, which may be seen in overhydration
or diabetes insipidus
High values (>1.030) are consistent with concentrated urine
pH
The physiologic urine pH ranges between 4.5 to 8.0
A very alkaline urine (pH >7.0) is associated with urinary tract infections with a urea-
splitting organism, vegetarian diet, metabolic alkalosis
A low urine pH (pH <5.0) is associated with metabolic acidosis and with the ingestion of
large amounts of meat
A urine pH above 5.5 in the setting of metabolic acidosis suggests impairment in the
acidification process, indicating the presence of 1 of the forms of renal tubular acidosis
Glucose
Glycosuria occurs in the presence of uncontrolled hyperglycemia, when the filtered
glucose load is increased to a level that exceeds proximal glucose reabsorptive capacity
The renal threshold for glucose is generally 160 to 180 mg/dL
Renal glycosuria, associated with normal plasma glucose concentration, is seen with a
defect in proximal tubular reabsorption of glucose, such as Fanconi syndrome
Ketones
The dipstick reveals the presence of acetoacetate and acetone, but not the beta-
hydroxybutyrate (often 80% of total serum ketones in ketosis)
Urine ketones are associated with diabetic and alcoholic ketoacidosis, prolonged fasting
or starvation
False positive results may occur in patients taking different drugs, such as levodopa or
drugs that contain free sulfhydryl groups (e.g., captopril, mesna)
Leukocyte Esterase
Detects the presence of leukocytes in the urine
The test threshold is 5 to 15 white blood cells per high-power field (WBCs/hpf)
False positive results can occur with vaginal contamination
False negative results can occur with glycosuria, vitamin C, cephalexin and tetracycline
therapy, or excessive oxalate excretion
Nitrite
Dietary nitrates are normally excreted in the urine
The dipstick reveals the presence of bacteria which have the capability of reducing
nitrates to nitrites due to nitrate reductase activity, which is present in most gram-
negative urinary pathogens
False negative results occur in the presence of organisms that do not produce nitrite,
when vitamin C is present, or when urine has not been retained in the bladder long
enough (approximately 4 hours) to permit sufficient production of nitrite from nitrate
Bilirubin
Only conjugated bilirubin is passed into the urine
The dipstick is positive in patients with jaundice due to hepatobiliary disease, but is
negative in patients with jaundice due to hemolysis

Urobilinogen
A colorless pigment produced in the gut from metabolism of bilirubin
Some urobilinogen is excreted in feces and the rest is absorbed and excreted in the urine
Urine excretion is increased in patients with jaundice, except of obstructive jaundice, since
bilirubin does not reach the bowel
Blood
Dipstick urinalysis is sensitive for erythrocytes, hemoglobin, and myoglobin
The test is positive with hematuria, hemoglobinuria deriving from intravascular hemolysis
or myoglobinuria secondary to rhabdomyolysis
Protein
The dipstick is sensitive to very small urine protein concentration (the lower limit of
detection is 0.20 g/L)
Albumin is the only protein that is detected on dipstick urinalysis
The urine dipstick does not detect immunoglobulin proteins (e.g., monoclonal light
chains). The addition of sulfosalicylic acid to the urine supernatant (in an 1:3 ratio) will
detect all proteins, including light chains, or Bence Jones proteins, with the degree of
turbidity noted being proportional to the protein concentration
False positive results can be seen in the presence of highly concentrated or extremely
alkaline (pH 9) urine
Microscopic Examination of the Urinary Sediment

Urine microscopy is indicated in all patients with acute kidney injury
A mid-stream, clean catch urine specimen should be collected when possible and
examined within 30 to 60 minutes
A high urine concentration and a low urine pH help to preserve formed elements
The urine sediment (prepared from 10 mL of urine) should be examined under a phase
contrast microscope at low power (100x) and high power magnification (400x)
The urinary sediment is examined for cells, casts, crystals, and bacteria
In a normal patient, one high power field may contain 0 to 4 white blood cells and 0 to 2
red blood cells, and 1 cast may be seen in 10 to 20 low powered fields. Crystals of calcium
oxalate, uric acid, or phosphate may also be present
Cellular Elements
The cells found in the urinary sediment include red blood cells, leukocytes, and epithelial
cells
Erythrocytes
Microscopic hematuria is commonly defined as the presence of more than 2 red blood
cells per high power field in a spun urine sediment
The differential diagnosis of hematuria is broad, and can be categorized in glomerular and
nonglomerular hematuria
Glomerular hematuria is characterized by the presence of dysmorphic erythrocytes
and acanthocytes
Hematuria that is accompanied by red blood cell casts, proteinuria, or both is most
likely glomerular in origin
Nonglomerular hematuria is associated with isomorphic erythrocytes that appear
normal on urine microscopy
Leukocytes
Pyuria (presence of WBCs) is defined as increased amount of leukocytes in the urine
(>4/hpf)
Pyuria can arise from several conditions, by far the most common being infection
Sterile (culture-negative) pyuria can be seen in active tuberculosis infection, severe sepsis,
interstitial nephritis, and nephrolithiasis
Wright or Hansel staining of the urine sediment can reveal eosinophiluria, which may
occur in acute interstitial nephritis, in various types of glomerulonephritis, chronic
pyelonephritis, septic emboli, acute atheroembolic disease of the kidney
Epithelial Cells
Renal tubular cells derive from the exfoliation of the tubular epithelium
The presence of renal tubular cells, especially in association with casts, indicates a renal
source of injury, such as acute tubular necrosis, pyelonephritis, acute interstitial nephritis,
and acute cellular rejection
Casts
Are cylindrical bodies that form in the distal tubules and collecting tubules where Tamm-
Horsfall glycoprotein precipitates and entraps cells present in the urinary space
Hyaline casts and fine granular casts can be seen in normal individuals and in patients
with renal disease
Coarse granular casts, result from degeneration of embedded cells, are nonspecific but
usually pathologic
Waxy casts are believed to result from the degeneration of cellular casts, and, thus, can
be seen in a variety of kidney disease
Red blood cell casts are a hallmark of proliferative glomerulonephritis
White blood cell casts are seen in pyelonephritis, acute interstitial nephritis, but can also
be seen in glomerulonephritis
Pigmented casts derive their distinctive color from bilirubin or hemoglobin and are found
in hyperbilirubinemia or hemoglobinuria
Crystals
Many different forms of crystals can be observed in normal patients and in those with
defined diseases
Uric Acid Crystals
Are found only in acid urine, a milieu that favors the conversion of the relatively soluble
urate salt into the insoluble uric acid
May have different forms, including rhomboidal, rectangular, or needles
Calcium Oxalate Crystals
The formation of these crystals is not dependent upon the urine pH
Are small, uniform, described as envelope shape
Calcium Phosphate
Only form in a relatively alkaline urine
Are usually narrow rectangular needles
Cystine Crystals
Precipitate only in acid urine
Have a hexagonal shape
Are diagnostic of cystinuria

Calcium Magnesium Ammonium Pyrophosphate (So-called Triple Phosphate) Crystals
Have an appearance of coffin lids
They are found only in alkaline urine
Imaging Studies
The most commonly radiologic studies used to evaluate the patient with renal disease
include:
Plain Film of the Abdomen
Can identify radiopaque kidney stones (calcium-containing, struvite, and cysteine stones),
but will miss radiolucent uric acid stones
Renal Ultrasonography
Inexpensive and safe, does not require contrast agents, but it is highly dependent on the
operators skills
Can differentiate from intrinsic renal parenchymal disease and renal cysts from solid
tumors
Commonly used to screen for and diagnose polycystic kidney disease
Also used to delineate renal or perinephric abscesses, or other complications of
pyelonephritis
Advanced chronic kidney disease is accompanied by scarring and thinning of the renal
cortex with small kidneys
Doppler renal ultrasonography measures blood flow or velocity in the main renal artery
Doppler is also used to obtain the resistive index (RI = peak systolic velocity-end diastolic
velocity/peak systolic velocity). Normal RI is <0.7. A high resistive index may indicate
intravascular disease, but may also be seen in acute tubular necrosis, obstruction or acute
rejection of the transplanted kidney
CT Scanning
Non-contrast helical CT is the gold standard for the radiologic diagnosis of nephrolithiasis
Can distinguish a neoplastic lesion from a simple cyst
CT is useful in the diagnosis of pyelonephritis and its complications, and in the diagnosis
of renal vein thrombosis
MRI
Used to evaluate complex masses, especially where CT is not definitive
Also used in staging kidney neoplasms, especially in evaluating for renal vein or inferior
vena caval extension of tumor
MR angiography is a reliable technique for diagnosis of renal artery stenosis, with
sensitivity and specificity of more than 90%
Intravenous Urogram
Used in the evaluation and diagnosis of certain diseases, such as medullary sponge
kidney, and papillary necrosis
Renal Arteriography
Used for evaluation of the renal arteries to assess possible renal artery stenosis, and to
correct it with angioplasty
Also used in the evaluation of medium to large vessel vasculitis and detection of renal
infarction
Renal Venography
Not routinely performed
Useful for the diagnosis of renal vein thrombosis
Radionuclide Scans
Can be used to calculate glomerular filtration rate (GFR) and effective renal plasma flow
(ERPF), even in cases of impaired renal function
Captopril renogram is a screening test for renovascular disease
The diuretic renogram can be obtained in cases of suspected obstructive uropathy
Voiding Cystourethrography
Can be used to detect vesicoureteral reflux
Retrograde or Anterograde Pyelography
May be used to diagnose urinary tract infections
Kidney Biopsy
Kidney biopsy is performed when histologic confirmation is needed to help diagnose and
treat different kidney diseases
Kidney biopsy is indicated in patients with nephrotic syndrome, in patients with renal
disease in the setting of a systemic disorder, in any patient with acute renal failure in
whom the diagnosis in not clear, and in renal transplant dysfunction. Some patients with
non-nephrotic proteinuria associated with hematuria, and patients with unexplained
chronic kidney disease may also benefit
Renal biopsy is often performed into the lower pole of kidney under direct ultrasound or
CT guidance
Complications of renal biopsy include pain (particularly if a large perinephric hematoma
develops), gross hematuria (1.5% of cases) and the need for blood transfusion (1%).
If hemorrhage is severe and prolonged, angiography should be used to identify the
feeding artery, which can be embolized. Other complications include arteriovenous
fistula, and Page kidney, complication in which subcapsular hematoma compresses the
kidney provoking ischemia and high renin hypertension; surgical decompression may be
necessary
Contraindications to renal biopsy include uncontrolled blood pressure, uncontrolled
bleeding diathesis, uncooperative patient, multiple renal cysts, acute pyelonephritis, renal
neoplasm, and solitary kidney
Most contraindications to renal biopsy are relative rather than absolute
9.2 Fluids and Electrolytes

Disorders of Serum Sodium
Hyponatremia is one of the most common electrolyte abnormalities encountered in clinical
practice
Hyponatremia is defined as a serum sodium concentration less than 135 meq/L, but can
vary to a small degree in different clinical laboratories
The plasma sodium concentration is the main determinant of the plasma osmolality. Thus,
hyponatremia usually represent a marker of hypoosmolality
In some patients, hyponatremia can be seen with normal or high serum osmolality, rather
than with hypoosmolality
Hyponatremia With Normal Serum Osmolality
Can be seen with severe hyperlipidemia and hyperproteinemia

Plasma is normally composed of 93% water and 7% proteins and lipids. Hyperproteinemia
or hyperlipidemia decreases the aqueous fraction of the plasma sample and causes an
artifactual low plasma sodium concentration despite a normal sodium concentration in
plasma water, phenomenon called pseudohyponatremia
Isosmotic hyponatremia can also occur after the systemic absorption of an isosmotic
or near isosmotic but non-sodium-containing irrigant fluid during endoscopic prostate,
bladder, or intrauterine surgery
Hyponatremia With High Serum Osmolality
Is seen due to marked hyperglycemia or due to the administration and subsequent
retention of hypertonic mannitol
Serum sodium concentration is expected to decrease by 1.6 meq/L for every 100 mg/dl in
blood glucose. Similarly, as blood sugar decreases, serum sodium would be expected to
increase by 1.6 meq/L for every 100 mg/dl fall in blood glucose level
Hyponatremia With Low Serum Osmolality
Diseases in Which Renal Water Excretion is Impaired
Hypoosmotic hyponatremia associated with effective circulatory volume (ECV) depletion
Gastrointestinal losses: Vomiting, diarrhea, tube drainage
Renal losses: Diuretics, salt-wasting nephropathy, mineralocorticoid deficiency
Skin losses: Burns
Edematous states: Congestive heart failure, nephrotic syndrome, cirrhosis
Hypoosmotic hyponatremia associated with normal ECV
Syndrome of inappropriate ADH secretion
CNS disease: Infections, subarachnoid hemorrhage, neoplasm (primary or
metastatic)
Carcinoma: Small cell lung, duodenum, pancreas
Drugs: Cyclophosphamide, carbamazepine, vincristine, vinblastine, haloperidol,
thioridazine, SSRIs, amitriptyline
Pulmonary disease
Postoperative patient
Severe nausea
Cortisol deficiency
Hypothyroidism
Renal failure
Decreased solute intake
Diseases in Which Renal Water Excretion is Normal
Primary polydipsia
Reset osmostat: Pregnancy, psychosis
Evaluation of Hyponatremia
Plasma osmolality
Low: True hyponatremia
Normal or high
Urine osmolality
Less than 100 msom/kg: Primary polydipsia, reset osmostat
More than 100 mosm/kg: Other causes of true hyponatremia
Urine sodium concentration
Less than 25 meq/L: ECV depletion
More than 40 meq/L: SIADH, diuretics, renal failure
Causes of Acute Hypotonic Hyponatremia

Self-induced water intoxication, in psychotic patients with marked polydipsia
Excess water consumption by marathon runners
Use of the illicit drug ecstasy (3,4-methylenedioxymethamphetamine), which stimulates
both thirst and vasopressin release
Excessive hypotonic fluid administration to patients with an impaired ability to excrete an
acute water load, most commonly in the postoperative period
Neurosurgical hyponatremia, especially in the setting of subarachnoid hemorrhage
Symptoms of Hyponatremia
Clinical manifestations of acute hyponatremia include neurological symptoms induced by
cerebral edema
Nausea and malaise may be seen at a serum sodium concentration of 125 to 130 meq/L
Headache, lethargy, seizures, and coma may occur at a serum sodium concentration of 115
to 120 meq/L
Due to cerebral adaptation, neurological symptoms are less severe in the setting of chronic
hyponatremia, and include the following: Fatigue, nausea, gait disturbances, and attention
deficit
Treatment of Hyponatremia
Symptomatic Hyponatremia
Acute, life-threatening hyponatremia requires an aggressive treatment with hypertonic
saline
Usually 4 to 5 meq/L increase in serum sodium concentration is adequate to prevent
permanent neurologic sequelae
Dose: 100 mL or 2 mL/kg bolus infusion of 3% saline, repeated up to two times if
necessary
Loop diuretics can also be added in this setting
Patients with mild and moderate neurological symptoms may require hypertonic saline,
but there is no need for an aggressive approach
The goal is an increase in serum sodium concentration of less than 10 meq/L in the 1st
24 hours and less than 18 meq/L in the 1st 48 hours
Patients with symptomatic hypovolemic hyponatremia can be treated with 0.9% NaCl
An overly rapid increase in the serum sodium concentration can lead to osmotic
demyelination
Asymptomatic Hyponatremia
Hypovolemic hyponatremia: Isotonic 0.9% NaCl
Hypervolemic hyponatremia: Fluid restriction with and without loop diuretic therapy, IV
vaptans
Normovolemic hyponatremia: Fluid restriction, demeclocycline, tetracycline antibiotic,
which antagonizes the action of ADH, vaptans

Vasopressin Antagonists (Vaptans)
The vasopressin receptor antagonists V1 and V2 have developed as a new approach to
treat hyponatremia. They cause an increase in water excretion with little or no change in
the urine sodium excretion
The intravenous V1 and V2 receptor antagonist conivaptan is approved for use in SIADH,
and it is contraindicated in heart failure and cirrhosis
The oral V2 receptor antagonist tolvaptan is approved for treatment of euvolemic and
hypervolemic hyponatremia associated with heart failure and cirrhosis
Hypernatremia
Hypernatremia is defined as a serum sodium concentration greater than 145 meq/L, and
represents a deficiency of total body water relative to total body sodium
Etiology of Hypernatremia
Water Loss
Insensible losses
Increased sweating: Fever, exercise
Burns
Respiratory losses
Renal losses
Central diabetes insipidus
Nephrogenic diabetes insipidus
Osmotic diuresis
Gastrointestinal losses
Osmotic diarrhea
Hypothalamic disorders
Primary hypodipsia
Water loss into cells
Severe exercise, seizures, rhabdomyolysis
Sodium Retention
Administration of hypertonic NaCl or NaHCO3
Ingestion of NaCl tablets
Assessment of Polyuria
Polyuria is generally defined as a urine volume above 2.5 L/d
Polyuria is mediated by excessive excretion of water (water diuresis) or solutes, such as
sodium, urea, glucose (solute diuresis)
Water diuresis (urine osm <150 mosm/kg)
Primary polydipsia
Central diabetes insipidus
Nephrogenic diabetes insipidus
Solute diuresis (urine osm >300 mosm/kg)
Saline loading
Post-obstructive diuresis
Hyperglycemia
High-protein tube feedings
Renal salt wasting
Diabetes insipidus
Central diabetes insipidus (CDI) is caused by inadequate secretion of AVP from the
posterior pituitary gland in response to osmotic stimulation
Nephrogenic diabetes insipidus (NDI) is associated with resistance to the antidiuretic
action of AVP due to a defect within the kidney
Causes of CDI
Neurosurgical procedures
Head trauma
Hypoxic encephalopathy
Malignancy: Primary (craniopharyngioma) or metastatic (breast, lung)
Meningitis, encephalitis
Pituitary infiltrative diseases (histiocytosis X, sarcoidosis)
Idiopathic
Causes on NDI
Electrolytes abnormalities (hypokalemia, hypercalcemia)
Drugs: Demeclocycline, lithium, ifosfamide, foscarnet, amphotericin B
Chronic tubulointerstitial disease
Pregnancy
CDI and NDI are both characterized by polyuria and polydipsia as well as an absence
of change in urine osmolality in response to water deprivation. Subcutaneous
administration of antidiuretic hormone causes an increase in urine osmolality in
patients with CDI but causes no change in urine osmolality in patients with NDI
Treatment of Hypernatremia
Treat underlying disease
Patients with evidence of hemodynamic collapse should receive isotonic fluids (normal
saline) until hemodynamically stable
Calculate free water deficit
Free water deficit = TBW x (plasma Na/140 1)
Correction should occur slowly; aim for a decrease in serum sodium of 0.5 meq/L/hour
Disorders of Serum Potassium

Hypokalemia
Defined as plasma potassium concentration less than 3.5 meq/L (3.5 mmol/L)
Most often is caused by the loss of potassium from the body, but can also result from
redistribution of potassium from the extracellular fluid space to the intracellular space
Hypokalemia can be divided into the following categories:
Pseudohypokalemia
Seen in patients with many metabolically active blood cells, such as in the setting of acute
myeloid leukemia and a high white blood cell count. If the blood is allowed to stand at
room temperature prior to measurement of the potassium concentration, the measured
value may be below 1 meq/L even though the patients have no symptoms. This can be
prevented by either rapid separation of the plasma from the cells following venipuncture,
or storage of the blood at 4C before assay

Cell Shifts
Caused by excess of insulin, increase endogenous catecholamine release (in the setting of
acute myocardial infarction) which promotes potassium entry into cells by increasing the
activities of the Na-K-ATPase pump, administration of beta agonists for asthma
Treatment of megaloblastic anemia with vitamin B12 or folic acid
Increase in extracellular pH
Inadequate Intake
Low dietary intake of potassium
Clay ingestion (binds dietary potassium and decreases potassium absorption)
Gastrointestinal Losses
Diarrhea, vomiting, gastrointestinal fistulas, laxative abuse
Renal Losses
Hypokalemia due to renal losses is primarily due to 2 factors: 1. Increased distal delivery of
sodium 2. Water increased mineralocorticoid activity
Loop and thiazide diuretics
Bartter and Gitelman syndrome
Sodium reabsorption with a non-reabsorbable anion (vomiting, proximal RTA,
penicillin derivatives)
Mineralocorticoid excess
Hypomagnesemia
Increases Sweat Losses
Role of potassium in the electric potential of cellular membranes determines the
major signs and symptoms of hypokalemia
Generalized muscle weakness and paralysis, including intestinal ileus
Many cardiac arrhythmias can be induced by hypokalemia (atrial tachycardia,
atrioventricular dissociation, ventricular tachycardia, and ventricular fibrillation)
Electrocardiographic findings in patients with hypokalemia include ST-segment
depression, T-wave flattening, and the development of U wave
Rhabdomyolysis
Renal dysfunction
Impaired concentrating ability, leading to polyuria and polydipsia
Tubulointerstitial disease and renal failure
Treatment of Hypokalemia
A decrease in the serum potassium concentration from 4 to 3 meq/L is associated with a
deficit of 200 to 300 meq; a serum potassium concentration of 2 meq/L reflects a deficit
of approximately 400 to 500 meq, and a level <2 meq/L is associated with a deficit in
excess of 600 meq
If the degree of hypokalemia is not severe and the patient is asymptomatic, oral
supplementation is adequate
If hypokalemia is severe or the patient is symptomatic (muscle weakness, cardiac
arrhythmias), intravenous potassium should be administered
Hyperkalemia
Defined as a potassium level of 5.5 mmol/L or higher
Causes of hyperkalemia
1. Pseudohyperkalemia can be caused by the mechanical release of potassium from cells
during phlebotomy or with severe thrombocytosis or leukocytosis due to release of
potassium from these cellular elements
2. Excessive dietary intake
3. Cellular redistribution
Tissue damage (rhabdomyolysis, trauma, burns, tumor lysis syndrome, hemolysis)
Metabolic acidosis (mineral acidosis associated with ammonium chloride or
hydrochloric acid results in potassium efflux from cells because of the relative
impermeability of the chloride anion)
Severe exercise
Drugs: Succinylcholine, digitalis, beta-adrenergic blockade
Insulin deficiency and hyperglycemia (potassium movement via solvent drag)
4. Decreased urinary excretion
Renal failure
Effective circulating volume depletion
Hypoaldosteronism state
Drugs: NSAIDs, ACEI, ARB, renin inhibitors, cyclosporine and tacrolimus, amiloride,
triamterene, spironolactone, heparin
Muscle weakness, paralysis and respiratory failure
Cardiac arrhythmias
Electrocardiographic findings in patients with hyperkalemia include peak T waves,
lengthening of the PR and QRS intervals, development of a sine wave, ventricular
fibrillation and asystole
Treatment of Hyperkalemia
Stabilization of excitable membranes with intravenous calcium gluconate
Increased potassium entry into the cells with insulin, beta adrenergic agonists, or sodium
bicarbonate
Removal of the potassium: Potassium wasting diuretics, cation-exchange resin
(Kayexalate), dialysis

Hypophosphatemia
Table 9.2: Causes of Hypophosphatemia

Redistribution of phosphate from the extracellular fluid into cells
Refeeding
Increased insulin secretion during carbohydrate refeeding in malnourished patients causes increase
phosphate intake and utilization
Respiratory alkalosis
Increased intracellular pH stimulates glycolysis and increases the formation of phosphorylated
carbohydrates
Decreased phosphate intake
Decreased intestinal absorption
Steatorrhea or chronic diarrhea
Vitamin D deficiency
Antacids containing aluminum or magnesium
Increased renal excretion
Hyperparathyroidism
Fanconi syndrome
Primary renal phosphate wasting
Osmotic diuresis (most often due to glycosuria)
Posttransplantation
Treatment
Phosphate repletion is indicated when serum phosphate level is less than 2 mg/dL
Intravenous phosphorus repletion is reserved for patients with severe hypophosphatemia
(<1 mg/dL)
Intravenous phosphate is potentially dangerous, since it can precipitate with calcium and
produce various adverse effects, including hypocalcemia, renal failure due to calcium
phosphate precipitation, and potentially fatal arrhythmias
9.3 Acid-base Disorders

Evaluation of all acid-base disorders begins by establishing which acid-base disorder is
present, the cause of each disorder, and whether adequate compensation is present
The acid-base status of the body is tightly controlled to maintain pH within a normal range
of 7.35 to 7.45
The lung and kidney help maintain acid-base equilibrium/lungs via CO2 and kidneys via
HCO -
3
Primary changes in serum concentrations of fixed acid or base, reflected in the serum
bicarbonate concentration, result in either metabolic acidosis or alkalosis
Primary changes in ventilation, which affects the partial pressure of arterial carbon dioxide
(PaCO2), result in either respiratory acidosis or alkalosis
1. Steps involved for interpreting acid-base disorder:
Simultaneous measurement of arterial blood gases and serum electrolytes
The arterial blood gases provides a direct measurement of PCO2 and pH
The bicarbonate concentration is calculated using the Henderson equation:
H+ = 24 x PCO2/HCO3-
The total serum CO2 is directly measured from venous blood specimen and should
be compared to the calculated bicarbonate to ensure accuracy
2. Is the pH low or high?
pH <7.4 indicates acidosis
pH >7.4 indicates alkalosis
3. Is the primary disturbance metabolic (HCO3) or respiratory (PCO2)?
Look at the PCO2 and serum CO2 to see which one is consistent with the pH, and
to determine if the primary disorder is respiratory or metabolic
4. Is compensation appropriate?
Yes simple acid-base disorder
No mixed acid-base disorder
Table 9.3: Expected Compensations for Simple Acid-base Disorders

Metabolic acidosis compensation
Expected PCO = (1.5 x HCO -) + 8
2 3
PCO2 = HCO3+15
PCO2 = last digits of pH
Metabolic alkalosis compensation
Expected PCO = (0.9 x HCO -) + 20
2 3
PCO2 = HCO3- + 15
PCO2 increases 7 mmHg for each 10 meq/L increase in HCO3-
Respiratory acidosis compensation
HCO3- increases by 1 meq/L for each 10 mmHg increase in PCO2 (acute)
HCO - increases by 4 meq/L for each 10 mmHg increase in PCO (chronic)
3 2
Respiratory alkalosis compensation
HCO3- decreases by 2 meq/L for each 10 mmHg decrease in PCO2 (acute)
HCO - decreases by 4 meq/L for each 10 mmHg decrease in PCO (chronic)
3 2
Metabolic Acidosis
Characterized by a fall in serum bicarbonate concentration, and is normally compensated
by increased ventilation, with decrease in PCO2
Can be caused by loss of HCO3- stores (diarrhea, renal tubular acidosis), increase in
endogenous production of acid (lactic acid, ketoacids), or progressive accumulation of
endogenous acids (renal failure)
The anion gap (AG) is a useful tool in the differential diagnosis of metabolic acidosis
+ - -
AG = Na - (Cl + HCO3 )
AG represents the unmeasured anions that are normally present in serum and
unaccounted for by the serum electrolytes measured on the electrolyte panel
The normal AG is 12 +/- 2
The unmeasured anions present in serum include phosphates, sulfates, organic acids,
and negatively charged plasma proteins

Metabolic acidosis is classified as either normal anion gap (in which HCO3- has been
effectively replaced by Cl-) or high anion gap (in which AG increases due to accumulation
of excess acid anions, such as lactate or acetoacetate)
Low AG may be caused by increase in unmeasured cations (IgG paraproteins in
multiple myeloma), ingestion of bromide, or due to decrease in unmeasured anions
(hypoalbuminemia)
Normal Anion Gap (Hyperchloremic) Metabolic Acidosis

Common causes include:
Gastrointestinal loss of bicarbonate: Diarrhea and fistulas
+
Renal loss of bicarbonate or failure to excrete NH4 : Renal tubular acidosis
Miscellaneous: Ureteral diversion, hyperalimentation, ammonium chloride ingestion,
dilutional acidosis
Urine anion gap (UAG) can help distinguish between the gastrointestinal and renal causes
of metabolic acidosis
The majority of acid excreted in the urine is bound to ammonia as ammonium
Electroneutrality is preserved by coupling ammonium ion to chloride, forming
ammonium chloride
Net acid excretion is accurately derived from direct measurement of urine ammonium,
but measurement of urine ammonium is not a commonly available study. This value
can be indirectly assessed by calculating the urine anion gap (UAG)
+ + -
UAG = (Na + K ) Cl
In metabolic acidosis of extrarenal origin, the expected response by the kidney is to
increase ammonium production and excretion, resulting in a negative UAG
A positive UAG suggests renal tubular disorders (dRTA)
Renal Tubular Acidosis (RTA)

Proximal RTA is uncommon in adults, and is usually characterized by diffuse proximal
tubular dysfunction, known as Fanconi syndrome (glycosuria, generalized aminoaciduria,
phosphaturia, and uricosuria)
Causes of proximal RTA include myeloma, cystinosis, lead, tetracycline, ifosfamide, and
acetazolamide
Correction of acidosis in patients with proximal RTA is often difficult even with
administration of large amounts of sodium bicarbonate, because bicarbonate is rapidly
excreted in the urine. The addition of a thiazide diuretic may be helpful by inducing mild
volume depletion, resulting in decrease in the filtered load of bicarbonate
Hypokalemic Distal RTA
Characterized by the inability to acidify the urine maximally (to pH <5.5) in the setting of
systemic acidosis
This condition results from decrease distal acidification (diminished net tubular H+
secretion)
The causes of distal RTA include Sjgren syndrome, toluene sniffing, amphotericin B, or
hypergammaglobulinemia
Associated with nephrocalcinosis and osteomalacia
Treatment includes administration of alkali therapy (1 to 2 meq/kg daily) in the form of
potassium citrate, which is also beneficial in the setting of hypokalemia or calcium stone
disease
Hyperkalemic Distal RTA
Results from aldosterone deficiency or resistance
There is both impaired hydrogen secretion and decreased urine ammonium excretion
May be caused by diabetes mellitus, interstitial nephritis, and drugs (spironolactone,
amiloride, triamterene, or cyclosporine)
High Anion Gap Metabolic Acidosis

Has several causes:
1. Ketoacidosis
Diabetic ketoacidosis, caused by increased fatty acid metabolism and the
accumulation of ketoacids (acetoacetate and beta-hydroxybutyrate)
Alcoholic, starvation ketoacidosis
2. Lactic acidosis
Caused by increased production of lactic acid during anaerobic metabolism or
decreased lactate utilization
Type A lactic acidosis results from tissue hypoperfusion in the setting of shock
Type B lactic acidosis results from inability of tissue to utilize oxygen; has been
reported with drug use (metformin, propofol, nucleoside reverse transcriptase
inhibitors), liver failure and malignancy
3. Drug and toxin-induced acidosis
Salicylate intoxication generates several organic acids, including salicylic acid, lactic
acid, and ketoacids
Ethylene glycol intoxication produces oxalic acid
Methanol intoxication produces formic acid
These toxic agents are osmotically active and may result in an increase in osmolar gap
Osmolar gap: Measured osmolality calculated osmolality (normal is <10)
Calculated Osm = 2 x Na + glucose/18 + BUN/2.8
Isopropyl alcohol intoxication results in an osmolar gap, with no acid-base disorder
associated
Metabolic Alkalosis
A primary acid-base disturbance characterized by increased plasma bicarbonate level with
an increase in PCO2 as a result of compensatory alveolar hypoventilation
The maintenance of metabolic alkalosis represents a failure of the kidney to eliminate
bicarbonate at the normal capacity
Causes of metabolic alkalosis:
Exogenous administration of bicarbonate (administration of sodium bicarbonate, milk-
alkali syndrome, massive blood transfusion)
Acid loss
Gastrointestinal loss: Vomiting, nasogastric suctioning
Renal loss: Diuretics, administration of nonresorbable anions (e.g., intravenous
penicillin or carbenicillin), Bartter and Gitelman syndrome
Mineralocorticoid state
Measurement of a spot urine chloride is a more reliable index of the volume status than the
urinary sodium concentration
Urine chloride <25 meq/L: Vomiting, nasogastric suction, diuretics (late)

Urine chloride >40 meq/L: Diuretics (early), primary mineralocorticoid excess, Bartter
or Gitelman syndrome
Treatment
Chloride-responsive alkalosis typically responds to volume replacement
Chloride-unresponsive alkalosis (e.g., mineralocorticoid excess) does not respond to
saline administration
Respiratory Acidosis
The primary defect in respiratory acidosis is an increase in PCO2
Causes of respiratory acidosis:
Central: Drugs (sedatives, narcotics), respiratory center hypoperfusion (infection,
ischemia), obstructive sleep apnea
Lungs/airways: Obstruction/asthma, pneumonia, pulmonary edema, COPD, ARDS,
barotraumas
Neuromuscular: Poliomyelitis, kyphoscoliosis, muscular dystrophy, multiple sclerosis
Prediction of HCO3 in respiratory acidosis
HCO3 increases by 1 meq/L for each 10 mmHg increase in PCO2 (acute)
HCO3 increases by 4 meq/L for each 10 mmHg increase in PCO2 (chronic)
Respiratory Alkalosis
Characterized by a decrease in PCO2
Causes of respiratory alkalosis:
CNS stimulation: Anxiety, pain, fever, cerebrovascular accident, tumor, meningitis,
encephalitis
Hypoxemia: High altitude, pneumonia, pulmonary edema, aspiration, pulmonary
embolus
Drugs or hormones: Salicylates, progesterone, nicotine, xanthenes
Stimulation of chest receptors: Pneumonia, pneumothorax, pulmonary embolism
Others: Pregnancy, liver failure, septicemia, mechanical hyperventilation
Prediction of HCO3 in respiratory alkalosis
HCO3 decreases by 2 meq/L for each 10 mmHg decrease in PCO2 (acute)
HCO3 decreases by 4 meq/L for each 10 mmHg decrease in PCO2 (chronic)
Treatment of respiratory alkalosis is directed at correcting the primary cause. In addition,
sedation or rebreathing into a paper bag can increase the arterial PCO2, resulting in partial
correction of hypocapnia
9.4 Tubulointerstitial Disease

Chronic Tubulointerstitial Nephritis
Represents a diverse group of renal diseases with predominant involvement of the
interstitium and tubules, characterized histologically by progressive scarring of the
tubulointerstitium, with tubular atrophy, macrophage and lymphocytic infiltration and
interstitial fibrosis. As chronic interstitial damage progresses, the glomeruli may become
secondarily involved as a result of glomerular hypertension and hyperfiltration, resulting in
periglomerular fibrosis, segmental sclerosis, and ultimately, global sclerosis
There are many causes of primary as well as secondary causes of chronic tubulointerstitial
nephritis
Table 9.4: Causes of Chronic Tubulointerstitial Nephritis

Primary
1. Immune-mediated 5. Hereditary disorders
Sjgren syndrome Polycystic kidney disease
Sarcoidosis Medullary sponge kidney
Systemic lupus erythematosus
Renal allograft rejection 6. Drugs/toxins
Vasculitis Analgesics
Calcineurin inhibitors (cyclosporine, tacrolimus)
2. Infection Cisplatin
Bacterial: Chronic pyelonephritis, leptospirosis, Lithium
Rickettsia, schistosomiasis Chinese herbs
Viral: Adenovirus, Epstein-Barr, cytomegalovirus, Heavy metals (lead, cadmium, mercury)
polyoma BK virus
7. Obstructive disorders
3. Hematologic disorders
Tumors
Sickle cell disease
Nephrolithiasis
Light chain disease
Vesicoureteral reflux
Amyloidosis
Lymphoproliferative disease
4. Metabolic disorders
Hypercalcemia/nephrocalcinosis
Hypokalemia
Hyperuricemia
Hyperoxaluria
Cystinosis
Secondary
Secondary chronic tubulointerstitial nephritis includes diseases in which the primary pathogenic process
begins in the glomerular, vascular, or tubular systems followed by damage to the tubulointerstitial
compartment
Clinical Manifestations and Diagnosis

The clinical course of chronic tubulointerstitial nephritis is usually lent, with progression to
end stage renal disease occurring over years
Most patients with chronic tubulointerstitial disease have a bland urine sediment and non-
nephrotic range proteinuria
There is increased urinary excretion of low-molecular weight proteins commonly
associated with tubular injury, such as lysozyme, beta2-microglobulin, uromodulin
(Tamm-Horsfall mucoprotein) and retinol-binding proteins

Other tubular defects may result in proximal tubule defects (with aminoaciduria,
phosphaturia, Fanconi syndrome, proximal renal tubular acidosis) or distal tubular defects
(especially type IV RTA)
Many diseases are associated with the inability to conserve salt on a low salt diet,
resulting in salt wasting syndromes
Urinary concentration defect appears early in course of disease, associated with polyuria
and nocturia, and can result in nephrogenic diabetes insipidus
Hypertension is another common clinical feature
Renal ultrasonography shows shrunken, hyperechoic kidneys
Kidney biopsy findings include interstitial fibrosis, lymphocytic infiltration, tubular atrophy,
glomerulosclerosis, and cast formation within tubular lamina, which contain desquamated
tubuloepithelial cells embedded in Tamm-Horsfall protein
Causes of Primary Chronic Tubulointerstitial Disease
Immunologic Diseases
Sjgren Disease
Renal involvement in patients with Sjgren syndrome has been reported in 20 to 65%
patients with Sjgren syndrome
Renal disease is usually characterized by interstitial nephritis
The clinical manifestations of the interstitial nephritis include increase in the plasma
creatinine level, relatively benign urinalysis, and abnormalities in tubular function, including
the Fanconi syndrome, distal (type 1) renal tubular acidosis, nephrogenic diabetes
insipidus (tubular resistance to antidiuretic hormone), and hypokalemia without renal
tubular acidosis (sodium-wasting can result in enhance potassium secretion due to
increase in sodium delivery to the potassium secretory site in the collecting tubules, and
as a result of volume depletion, which enhances the release of aldosterone)
Glomerular diseases are much less common, and include membranoproliferative
glomerulonephritis and membranous nephropathy
Sarcoidosis
Hypercalciuria and hypercalcemia are frequently present in patients with sarcoidosis as a
consequence of enhanced production of calcitriol (1,25-dihydroxy vitamin D) by activated
mononuclear cells (particularly macrophages) in the lung and lymph nodes
Hypercalcemia may result in nephrogenic diabetes insipidus, nephrolithiasis,
nephrocalcinosis, and renal failure
Acute interstitial nephritis with mononuclear cells and noncaseating granulomas is
relatively common in sarcoidosis
Glomerular diseases are rare in sarcoidosis, and include membranous nephropathy, IgA
nephropathy, minimal change disease, a proliferative/crescentic glomerulonephritis, and
focal glomerulosclerosis
Retroperitoneal lymph node involvement, retroperitoneal fibrosis, and ureteral
involvement occasionally produce ureteral obstruction in patients with sarcoidosis
Systemic Lupus Erythematosus
Tubulointerstitial disease is occasionally the only manifestation of lupus nephritis
The presence of interstitial inflammation with or without associated immune deposits
along the tubular basement membrane is more often seen with concurrent glomerular
disease
Analgesics
Analgesic nephropathy is responsible for 20% of cases of tubulointerstitial disease
Analgesic nephropathy develops in patients who abuse the compound analgesics
containing aspirin or antipyrine, combined with phenacetin, acetaminophen (paracetamol)
or salicylamide, and caffeine and codeine
Many studies suggest a dose-dependent risk for developing analgesic nephropathy with
compound analgesics; the total amount of phenacetin necessary to cause analgesic
nephropathy >3.0 kg
The main site of renal injury is medulla, which becomes vulnerable because of the
concentration of toxic metabolites built up by the counter-current mechanism and
because of the low oxygen tension present in this region
Aspirin and NSAIDs can result in the reduction of vasodilatory prostaglandins, with
decreased local renal blood flow within the medulla
Phenacetin is converted to acetaminophen, which causes cellular depletion of
glutathione, and results in the formation of oxidative and alkylating metabolites
Caffeine can be metabolized to adenosine, with vasoconstrictive effects within the
kidney
The result is papillary ischemia and eventually papillary necrosis
Patients with analgesic nephropathy present with slowly progressive chronic kidney
disease, with bland urinalysis or with sterile pyuria and/or mild proteinuria (usually less
than 1.5 g/d)
Intravenous pyelography shows papillary necrosis when part or all of the papilla has
sloughed
CT scan without contrast shows bilateral reduced renal size, bumpy renal contours, and
bilateral papillary calcifications (small, indented calcified kidneys)
Analgesic nephropathy is associated with increased risk of transitional cell carcinoma of
the uroepithelium. This should be further investigated especially in patients with gross
hematuria
Other causes of papillary necrosis can be remembered by the mnemonic POSTCARD
(Pyelonephritis, Obstruction, Sickle cell disease or trait, Tuberculosis, Chronic alcoholism
with cirrhosis, Analgesics, Renal vein thrombosis, and Diabetes mellitus)
Lithium
Chronic lithium ingestion has been associated with polyuria, polydipsia, and nephrogenic
diabetes insipidus, and less frequently, with chronic tubulointerstitial nephropathy
Nephrogenic diabetes insipidus appears to result from lithium accumulation in collecting
tubule cells after entering these cells through sodium channels in the luminal membrane,
interfering with the ability of antidiuretic hormone (ADH) to increase water reabsorption
by inhibiting adenylate cyclase and hence cAMP production, and also by decreasing the
apical membrane expression by aquaporin 2 water channels
In patients who develop nephrogenic diabetes insipidus, lithium therapy should be
discontinued, if possible. If lithium therapy is continued, concomitant amiloride therapy is
recommended, as amiloride can block lithium uptake through the sodium channels in the
collecting duct, and can reduce the urine output by up to 50%
15 to 20% of the patients on chronic lithium therapy develop chronic tubulointerstitial
disease

Chronic tubulointerstitial disease is characterized histologically by a focal chronic
interstitial nephropathy with interstitial fibrosis, tubular atrophy, and glomerular sclerosis.
A characteristic finding is the presence of microcystic changes in the distal tubule
The course of the renal disease after discontinuation of lithium is unpredictable
Lithium treatment can also induce impairment in distal urinary acidification (distal RTA),
minimal change disease, focal segmental glomerulosclerosis
Lead
Chronic exposure to high levels of lead is associated with a progressive chronic interstitial
nephritis
Majority of chronic exposures are occupational, and seen in the manufacturing or use of
lead-containing paints, ammunitions, radiators, batteries, wires, ceramic glaze, and metal
cans. Environmental exposure can also occur in other settings, such as lead pipes in
drinking water lines, or consuming crops grown in lead-contaminated soils
The early stages observed with chronic lead exposure results in proximal tubular
intranuclear inclusion bodies composed of a lead-protein complex as a result of proximal
reabsorption with subsequent intracellular lead accumulation
Early clinical manifestations are primarily limited to proximal tubular dysfunction, resulting
in hyperuricemia (from diminished uric acid secretion), aminoaciduria or renal glycosuria
Prolonged lead exposure leads to chronic kidney disease, a relatively normal urinalysis,
hypertension, and gout
Diagnosis of chronic lead intoxication is made by the calcium EDTA lead chelation test.
Urinary lead excretion of more than 600 mcg per 3 days after administration of calcium
EDTA intravenously over 1 to 2 hours indicates a lead body burden capable of causing
lead nephropathy
Treatment involves the use of calcium EDTA chelation together with removal of the
source of lead
Hyperuricemia
Renal dysfunction is often associated with hyperuricemia
Chronic urate nephropathy is characterized by tubulointerstitial fibrosis, often with
arteriolosclerosis and glomerulosclerosis. Precipitated uric acid crystals can often be
found in the tubules and in the interstitium (particularly in the medulla)
Clinically, patients present with hypertension, mild proteinuria, and unremarkable urinary
sediment
Uric acid nephropathy should be considered if there is a disproportionate elevation of
serum uric acid in relation to the degree of renal failure
Treatment consists of lowering uric acid with xanthine oxidase inhibitors (allopurinol) with
a target serum uric of 5.5 mg/dL or lower
9.5 Hypertension
Epidemiology
Affects almost 30% of the adult population in the US
Is a common risk factor for cardiovascular disease and progressive chronic kidney disease
Less than 50% of hypertensive patients have adequate blood pressure control
Definitions
The Joint National Committee (JNC 7) guidelines proposed the following definitions based
upon the average of 2 or more blood pressure readings obtained at 2 or more visits:
Normal blood pressure: Systolic <120 mmHg and diastolic <80 mmHg
Prehypertension: Systolic 120-139 mmHg or diastolic 80-89 mmHg
Hypertension as 140/90 mmHg or higher
Stage 1 hypertension: Systolic 140-159 mmHg or diastolic 90-99 mmHg
Stage 2: Systolic 160 or diastolic 100 mmHg
The definition of hypertension based upon ambulatory blood pressure monitoring:
A 24-hour average above 135/85 mmHg
Daytime (awake) average above 140/90 mmHg
Nighttime (asleep) average above 125/75 mmHg
Isolated systolic hypertension
Hypertension is only systolic, with normal diastolic blood pressure
It is usually seen in elderly patients and is a result of decreased arterial elasticity
Malignant hypertension is defined as marked hypertension with retinal hemorrhages,
exudates, or papilledema, and by evidence of renal damage
Risk Factors
Race (hypertension is more prevalent in African decent population)
Family history of hypertension in maternal, paternal, or both parents
Excess alcohol intake
High sodium intake
Obesity, weight gain, and physical inactivity
Dyslipidemia
Vitamin D deficiency
Complications
Left ventricular hypertrophy is seen commonly in patients with hypertension, and is
associated with increased risk of cardiovascular events, especially heart failure and stroke
Hypertension is the most common risk factor for ischemic stroke
Heart failure (patients with hypertension have a 3-fold higher risk of heart failure than
normotensive subjects)
Hypertension is a risk factor for chronic kidney disease and end-stage renal disease
Evaluation
Office Blood Pressure Measurement
Adequate measurement and interpretation of the blood pressure is essential in the
diagnosis and management of hypertension
In adults, classification of hypertension is based on an average of 2 or more readings
obtained 5 minutes apart, at 2 or more visits
Single office blood pressure measurement is not able to detect white coat hypertension,
masked hypertension, and labile hypertension
White coat hypertension is responsible to 20 to 25%of patients diagnosed with stage 1
office hypertension. Repeat blood pressure measurements are normal at home, at work,
or by ambulatory blood pressure monitoring

Masked hypertension, characterized by elevated out-of-office readings despite normal
office readings, occurs in more than 10% of the general population. These patients are
thought to be at increased risk of cardiovascular events, and should be treated
Labile hypertension describes an intermittent form of hypertension
Ambulatory Blood Pressure Monitoring
Ambulatory blood pressure monitoring allows multiple blood pressure readings over a
prolonged period of time
It evaluates mean 24-hour blood pressure, mean daytime and mean nighttime blood
pressure, the average difference between waking and sleeping blood pressure to evaluate
for nocturnal dipping (characterized as a decrease in mean arterial blood pressure of
>10% during sleep), and blood pressure variability
Failure of the blood pressure to decrease by at least 10% during sleep, known as non-
dipping, as well as an excessive morning surge in blood pressure, are associated with
increased cardiovascular risk
This method is used in the following situations: White-coat hypertension, suspected
episodic hypertension (e.g., pheochromocytoma), hypertension resistant to increasing
medications, and hypotensive symptoms while taking antihypertensive medications
Evaluation, Physical Examination, and Laboratory Studies
A careful history should be obtained in all patients with hypertension to determine the
natural course of the blood pressure, the presence of precipitating or aggravating factors
(such as alcohol use, different types of medications), the presence of family history of
hypertension, lifestyle factors that may exacerbate hypertension, and the extent of target
organ damage such as cardiovascular disease, or kidney disease
Physical examination includes: Measurement of vital signs, BMI, funduscopic examination,
cardiopulmonary examination, auscultation of the major blood vessels to identify bruits,
abdominal examination, neurologic examination, and evaluation of the extremities for
edema and circulatory abnormalities
Laboratory evaluation should include the followings:
Complete blood count
Routine blood chemistries (glucose, creatinine, electrolytes), and estimated
glomerular filtration rate
Lipid profile (total and HDL-cholesterol, triglycerides)
Urinalysis
Electrocardiogram
Microalbuminuria (known to be an independent risk factor for cardiovascular disease)
Echocardiography is useful in patients with manifestations of hypertensive heart
disease, such as left ventricular hypertrophy, heart failure, or diastolic dysfunction
Management
The goal of treatment of hypertension is to reduce cardiovascular morbidity and mortality
by lowering blood pressure
Treatment of hypertension should involve both nonpharmacologic therapy (also called
lifestyle modification) and antihypertensive drug therapy for all patients with stage 1 or
greater hypertension
Lifestyle modifications include the followings: Dietary salt restriction, the DASH diet
(increased intake of fruits and vegetables and low-fat dairy products), weight loss, physical
activity, limit daily alcohol intake (limit to less than 2 drinks per day for men and <1 drink for
women), and smoking cessation
Lifestyle modifications lower not only blood pressure, but can also modify additional
cardiovascular risk factors, such as obesity, diabetes, and dyslipidemia
Antihypertensive Drugs
Antihypertensive drugs should be started if the systolic pressure is persistently
140 mmHg and/or the diastolic pressure is persistently 90 mmHg despite attempted
nonpharmacologic strategy
Therapy with 2 antihypertensive drugs should be considered in patients with a baseline
blood pressure above 160/100 mmHg
Most antihypertensive agents reduce blood pressure by 15 to 20%, and all classes of
antihypertensive drugs decrease cardiovascular morbidity and mortality compared with
placebo
Some patients may have specific indications for use of certain antihypertensive drugs that
are unrelated to essential hypertension
If there is no specific indication, monotherapy is generally initiated with the following class
of medications: Thiazide diuretics, long-acting calcium channel blockers (most often a
dihydropyridine), and angiotensin-converting enzyme (ACE) inhibitors or angiotensin II
receptor blockers (ARBs)
ACEI and ARBs are indicated in patients with heart failure, systolic dysfunction, post-
myocardial infarction and in proteinuric kidney disease
Diuretics are used in patients with salt-sensitive hypertension and in patients with systolic
hypertension. In addition, aldosterone antagonists (spironolactoneor eplerenone) are
indicated in selected patients with advanced heart failure who have relatively preserved
kidney function
-blockers are used in patients with coronary artery disease, for rate control in patients
with atrial fibrillation, angina pectoris, or in patients with migraine headaches
Calcium channel blockers are used in patients with angina and in systolic hypertension.
The non-dihydropyridine calcium channel blockers (verapamil, diltiazem) can be given for
rate control in patients with atrial fibrillation
Calcium channel blockers and diuretics are more effective in patients who are likely
to be sodium sensitive, such as older patients, African decent patients, and those with
lower pretreatment plasma renin activity. On the other hand, ACE inhibitors or -blockers
may be more effective in younger patients, Caucasian patients, and those with higher
pretreatment plasma renin activity
a-blockers are given in patients with benign prostatic hyperplasia
Adverse effects (see Table on Antihypertensive Drugs - Adverse Effects)

Table 9.5: Antihypertensive Drugs - Adverse Effects
Class of Drug Adverse Effects
Thiazide diuretics Hypokalemia, hyperuricemia, hyponatremia (espe-
cially in elderly patients), hyperglycemia, hyperlipid-
emia, hypercalcemia
Aldosterone antagonists Hyperkalemia, painful gynecomastia, impotence in
men and diminished libido and menstrual irregulari-
ties in women
ACE inhibitor Cough, angioedema, hyperkalemia, increased cre-
atinine level in patients with bilateral renal artery
stenosis, rash, loss of taste
ARBs Hyperkalemia, angioedema (rare), increased cre-
atinine level in patients with bilateral renal artery
stenosis
Calcium channel blockers Headache, flushing, gingival hyperplasia, edema,
constipation
b-blockers Bronchospasm, bradycardia, heart failure, impaired
peripheral circulation, insomnia, depression, fatigue,
decreased exercise tolerance, hypertriglyceridemia,
may prolong hypoglycemia in diabetics
a-blockers Headache, drowsiness, fatigue, weakness, postural
hypotension
Secondary Hypertension
Should be considered in patients who present with atypical clinical features and are
resistant to antihypertensive therapy
The most common causes of secondary hypertension include primary aldosteronism,
renovascular disease, and pheochromocytoma
Primary Aldosteronism
Primary aldosteronism consists of a heterogeneous group of disorders characterized
by hypokalemic alkalosis with potassium wasting, increased plasma aldosterone and
suppressed plasma renin activity
Primary aldosteronism affects approximately 10 to 15% of patients with hypertension
Screening is recommended in the following settings: Spontaneous hypokalemia,
hypertension with an adrenal mass found incidentally on a routine abdominal CT scan,
hypertension in first-degree relatives of patients with primary hyperaldosteronism
Diagnosis
Plasma aldosterone concentration (>15 ng/dL)
The aldosterone to renin ratio (ARR) (>20)
After correction of hypokalemia and adherence to a high-sodium diet for 3 days,
24-hour urine sodium >200 mEq and urine aldosterone >12 g/24 h
High-resolution CT scan or MRI should be performed to identify an adenoma
Adrenal vein sampling is the gold standard to establish a lateralizing adenoma or
hyperplastic gland. However, adrenal vein sampling is very difficult and highly operator
dependent
Treatment
Laparoscopic adrenalectomy
Patients who are poor candidates for surgery should be treated medically with
spironolactone or eplerenone
Renovascular Disease
Renovascular hypertension is defined as hypertension secondary to narrowing of one or
more of the renal arteries
85% of patients have occlusive atherosclerotic renovascular disease
Screening for renovascular disease
Duplex ultrasound
Magnetic resonance angiography
CT angiography
Treatment: Surgical revascularization, percutaneous transluminal angioplasty with stent
placement, and medical therapy
Pheochromocytomas
Pheochromocytomas are catecholamine-secreting tumors that arise within the adrenal
glands, but approximately 10% are extra-adrenal (paraganglioma)
Overproduction of catecholamines can cause labile or paroxysmal hypertension,
diaphoresis, headache, palpitations, and anxiety
10% of patients with pheochromocytomas have metastatic disease, particularly to bone,
lungs, liver, and regional lymph nodes
Complications of pheochromocytomas include myocardial infarction, stroke, and
cardiovascular collapse
Diagnosis of pheochromocytoma includes the measurement of urinary catecholamines,
urinary and plasma metanephrines, clonidine suppression test, MRI or CT scanning which
can localize the tumor, and scintigraphy with 123-I-metaiodobenzylguanidine (MIBG), which
can be used to confirm positive findings on CT and MRI scanning
Treatment of choice is surgical resection
Preoperative and postoperative hypertension should be treated with a combination of alpha
and b-blockers
9.6 Genetic Disorders and Kidney Disease

Cystic Disorders
Autosomal-dominant Polycystic Kidney Disease
The most common inherited disease, occurring in approximately 1 in every 500 to 1,000
live births
This disease is caused by mutations in PKD1 or PKD2 genes
PKD1 and PKD2 encode proteins called polycystin-1 and polycystin-2, respectively
PKD1 makes up about 85% of the cases and is localized on chromosome 16. PKD2 is on
chromosome 4 and accounts for 10 to 15% of affected families
PKD1-related disease seems to be more severe than PKD2-related disease

The clinical hallmark is tremendous cystic enlargement of both kidneys, which leads to
loss of renal function overtime
Renal manifestations
Renal size
Kidney size increases with age. Massive renal enlargement can lead to back
and flank pain, and can cause compression of local structures, resulting in such
complications as inferior vena cava compression and digestive symptoms
Pain related to the kidney can be caused by:
Cyst hemorrhage and may be associated by hematuria
Infections (cystic or parenchymal)
Nephrolithiasis (majority of stones are uric acid and/or calcium oxalate)
Hypertension
Is an early and common presentation of ADPKD, occurring in 60 to 70% of the
patients with normal renal function
The renin-angiotensin system is activated early in the course of ADPKD, likely
secondary to cyst expansion, leading to narrowing of neighboring intrarenal
vessels, and resulting in bilateral intrarenal ischemia
Many patients with ADPKD have a mild concentrating defect, and declines with age
and level of kidney function
Proteinuria is not a major feature of ADPKD and is usually less than 1 g/24 h
Renal failure
Patients with ADPKD maintain normal GFR for decades with significant cyst and
kidney enlargement occurring before loss of kidney function. Once the glomerular
filtration rates starts to decline, the average reduction is 4-6 mL/min/year
Negative prognostic indicators for the progression to ESRD include genetic
factors (PKD1 vs. PKD2), male gender, early onset of symptoms, the presence of
hypertension, and increased renal size
Extrarenal manifestations
Polycystic liver disease
Females develop cysts at an earlier age and have worse disease, suggesting a
direct role of estrogen exposure in hepatic cyst growth
Cyst volume increases with age
Many patients remain asymptomatic with preserved hepatic function
Severe hepatic enlargement may result in symptoms of shortness of breath,
abdominal distension, early satiety, and, rarely, inferior vena cava compression
Intracranial aneurysms
Occur in approximately 8% of the ADPKD population
The most serious complication of ADPKD is rupture of an cerebral aneurysm,
resulting in subarachnoid or intracerebral hemorrhage, and high mortality rates
Routine screening is recommended for high-risk patients, such as those with
a previous rupture, with a positive family history of an intracerebral bleed or
intracranial aneurysm, patients with high-risk occupations, and prior to major
elective surgery that would likely to be associated with hemodynamic instability
with hypertension
Screening modalities for cerebral aneurysm include high-resolution CT
angiography (CTA) or magnetic resonance angiography (MRA)
Valvular heart disease include mitral valve prolapse and aortic regurgitation
Screening and Diagnosis
Among at risk individuals, renal ultrasonography is usually the initial modality used for
screening and diagnosis
Ultrasonographic criteria for the diagnosis of ADPKD for at-risk individuals from families
of unknowngenotype
Among individuals between 15 and 39 years of age, at least 3 unilateral or bilateral
cysts
Among individuals 40 to 59 years of age, 2 cysts in each kidney
Among individuals 60 years or older, 4 cysts in each kidney
Ultrasonographic criteria for the diagnosis of ADPKD for at-risk individuals for type 1
ADPKD
Among individuals between 15 and 30 years of age, at least 2 unilateral or bilateral
cysts
Among individuals 30 to 50 years of age, 2 cysts in each kidney
Among individuals 60 years or older, 4 cysts in each kidney
In the absence of a family history, more strict criteria is required for diagnosis. The
diagnosis should be strongly suspected in the presence of multiple and bilateral cysts
(arbitrarily defined as 10 or more cysts in each kidney) in the absence of findings
suggestive of a different renal cystic disease
Genetic testing
Can be done when the imaging results are equivocal and/or a definitive diagnosis is
required
Direct DNA analysis of the PKD1 and PKD2 genes can be performed by linkage or
sequence analysis
Treatment
Treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor
blockers (ARBs) may lower the blood pressure and slow the rate of progression of
ADPKD, especially in patients with proteinuria
No specific therapy has been proven to prevent or delay progression of ADPKD.
Promising specific therapies that are being evaluated include vasopressin V2 receptor
antagonists (which reduces renal epithelial cell intracellular cAMP levels), mTOR inhibitors,
somatostatin, and EGF receptor antagonists
Renal cyst infection requires prolonged courses of treatment (up to 4 weeks)
with antibiotics that penetrate the cysts, such as trimethoprim-sulfamethoxazole,
fluoroquinolones, chloramphenicol, or vancomycin
Pain related to cyst hemorrhage is usually treated with analgesics, bed rest, and hydration
Autosomal-recessive Polycystic Kidney Disease
An inherited disease characterized by cystic dilations of the renal collecting ducts and
congenital hepatic fibrosis
The estimated incidence of ARPKD is 1:10,000 to 1:40,000 births
ARPKD is caused by mutations in the PKHD1 gene on the chromosome 6 that encodes
for fibrocystin (polyductin)

Approximately 30% of the children have severe disease in utero, with enlarged kidneys,
oligohydramnios and the absence of urine in the fetal bladder, with resultant lung
hypoplasia, pulmonary insufficiency and perinatal death
Older patients develop hepatic fibrosis, which can progress to portal hypertension and its
associated complications (ascites and esophageal varices)
Growth retardation occurs in 25% of patients
More than 60% of patients have hypertension
80% of children are predicted to survive into their twenties once they have survived the
neonatal period
The outcome of ARPKD is dependent on the degree of renal and hepatic involvement.
ARPKD children are candidates for liver or combined liver and kidney transplantation in
advanced cases
Tuberous Sclerosis
Tuberous sclerosis complex is an autosomal dominant genetic disorder with an incidence
of approximately 1 in 5,000 to 10,000 live births
It is caused by mutations in 2 separate genes: 1. TSC1 and 2. TSC2
TSC is characterized by the development of variety of benign tumors in multiple organs,
including the brain, skin, eyes, heart, kidney, lung, and liver
In 1998, a TSC consensus conference of international experts revised the diagnostic
criteria
Major features include:
Skin: Facial angiofibromas or forehead plaque, nontraumatic ungual or periungual
fibromas, hypomelanotic macules (3 or more), and shagreen patch (connective tissue
nevi)
Ocular: Retinal nodular hamartomas
Central nervous system: Glioneuronal hamartoma (cortical tuber), subependymal
nodule, subependymal giant cell astrocytoma
Cardiac: Rhabdomyoma
Lungs: Lymphangiomyomatosis
Kidney: Renal angiomyolipoma
Minor features include:
Confetti skin lesions (multiple 1 to 2 mm hypomelanotic macules)
Gingival fibromas
Multiple randomly-distributed pits in dental enamel
Hamartomatous rectal polyps
Multiple renal cysts
Nonrenal hamartomas
Bone cysts
Retinal achromic patch
Cerebral white matter radial migration lines
A definitive diagnosis of tuberous sclerosis entails the presence of any 2 major features or
1 major feature and 2 minor features
Noncystic Disorders
Alport Syndrome
Alport syndrome is a generalized, inherited disease of basement membrane that results
from mutations in genes encoding the alpha-3, alpha-4, and alpha-5 chains of type IV
collagen
These alpha IV collagen chains are normally located in various basement membranes of
the kidney, cochlea, and eye
X-linked Alport syndrome is the predominant form of the disease, accounting for
approximately 85% of patients and arises from mutation in the COL4A5 gene on the X
chromosome
Autosomal recessive disease occurs in 15% of cases and arises from mutations affecting
both alleles of COL4A3 and COL4A4
Autosomal dominant disease occurs in 5% of patients and arises from heterozygous
mutations in the COL4A3 or COL4A4 genes
Clinical Features
Renal manifestations
The cardinal finding is persistent microscopic hematuria
Some patients develop recurrent episodes of gross hematuria, often precipitated by
upper respiratory infections
The serum creatinine and blood pressure are normal, and proteinuria is absent in
early childhood
Progressive renal failure, hypertension, and significant proteinuria develop with time.
End stage renal disease develops in the second or 3rd decade of life
Patients with autosomal recessive disease have a similar clinical presentation and
course as those with X-linked disease, whereas, patients with autosomal dominant
disease generally have a slower decline in renal function
Bilateral sensorineural hearing loss is common in Alport syndrome
Ocular defects
Anterior lenticonus is a forward protrusion of the anterior surface of the ocular lens
Corneal changes include posterior polymorphous dystrophy and recurrent corneal
erosions
Retinal flecks are small yellow or white dots scattered around the macula or in the
periphery of the retina
Diagnosis
Can be made by either a skin biopsy or a renal biopsy
Routine immunofluorescence examination for immunoglobulins and complement
components is negative, but staining for the alpha 5 (IV)-chain can be done and shows
no staining of the GBM with the alpha 5 antibody in X-linked males
Electron microscopy shows variable thickening, thinning, basket-weaving, and lamellation
of the GBM
Thin Basement Membrane Nephropathy (Benign Familial Hematuria)
An inherited disorder caused by several mutations of the type IV collagen genes COL4A3
and COL4A4

A family history of hematuria is noted in 30 to 50% of cases. The clinical manifestations
include persistent or intermittent asymptomatic microscopic hematuria. Overt proteinuria
and hypertension are unusual in thin basement membrane nephropathy
Renal biopsy shows diffuse thinning of the glomerular basement membranes on electron
microscopy
Long-term prognosis is excellent in majority of patients
Fabry Disease
An X-linked disorder caused by mutation of the -galactosidase A gene on chromosome
X. Deficiency of the -galactosidase A enzyme causes accumulation of glycosphingolipids
in all body fluids and tissues, resulting in organ dysfunction
Neuropathic pain and limb paresthesias
Telangiectasias and angiokeratomas
Later manifestations include concentric left ventricular hypertrophy, heart failure,
coronary artery disease, cerebrovascular accidents
Renal manifestations include proteinuria and progressive renal failure
Renal histology shows vacuolization and foamy appearance of visceral glomerular
epithelial cells (podocytes) and distal tubular epithelial cells due to accumulation of
glycosphingolipids
Intravenous replacement with recombinant human -galactosidase A is effective in
treating Fabry disease
9.7 Acute Kidney Injury

Definition
Acute renal failure has been defined as an abrupt decrease in renal function characterized
by progressive azotemia (best measured by serum creatinine), which may or may not be
associated with oliguria
The literature is full of different definitions of acute renal failure. In an attempt to create a
standardized definition, the Acute Dialysis Quality Initiative (ADQI) proposed a consensus
graded definition, called the RIFLE criteria
Table 9.6. RIFLE Criteria

RIFLE Criteria GFR Criteria UOP Criteria
Risk 1.5-fold increase in the serum Urine output <0.5 mL/kg/h for 6
creatinine or GFR decrease by hours
25%
Injury 2-fold increase in the serum cre- Urine output <0.5 mL/kg/h for 12
atinine or GFR decrease by 50% hours
Failure 3-fold increase in the serum Urine output of <0.3 mL/kg/h for
creatinine or GFR decrease by 24 hours, or anuria for 12 hours
75%
The Acute Kidney Injury Network (AKIN) proposed the term acute kidney injury (AKI) to
represent the entire spectrum of acute renal failure. The proposed diagnostic criteria are an
abrupt increase in the serum creatinine concentration of at least 0.3 mg/dL from baseline,
or a percentage increase in serum creatinine concentration of 50% over a period of less
than 48-hours, or oliguria of less than 0.5 mL/kg per hour for more than 6 hours
Table 9.7. AKIN Criteria

Serum Creatinine UOP
Stage I Increase in creatinine 1.5 to 2-fold <0.5 mL/kg per h for >6 h
Stage II Increase in creatinine 2 to 3-fold <0.5 mL/kg per h for >12 h
Stage III Increase in creatinine >3 times or <0.3 mL/kg per h for >24 h or
dialysis dependent anuria >12 h
Epidemiology
Incidence of acute kidney injury: 500/100,000 person years
Occurs in 5 to 10% of hospitalized patients and up to 20% of ICU admissions
Patients with acute kidney injury have an increased long-term risk for CKD progression or
death compared with hospitalized patients without AKI
Clinical Manifestations and Evaluation

History should include evaluation of any nephrotoxic exposure (iodinated contrast agents,
NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers), use of
new medications, volume depletion, hypotensive episodes
Some patients develop symptoms directed related to the kidney (flank pain, hematuria) or
extrarenal symptoms (edema, hypertension, uremic symptoms)
Physical exam: Check BP/pulse (with orthostatics), look for edema, skin rashes, check fundi
and skin for evidence of thromboemboli
Laboratory data: CBC, serum electrolytes, CPK, uric acid, LFTs, toxicology screen, serologic
work-up if glomerulonephritis is suspected
Urinalysis
Urine sodium, fractional excretion of sodium (FENa), which measures the percent of filtered
sodium that is excreted in the urine
Urine sodiumxPlasma creatinine
FENa, percent = x100
Plasma sodium x Urine creatinine
The FENa and the urine sodium concentration are difficult to interpret with concurrent
diuretic therapy. The fractional excretion of urea (FEurea) may be most useful in this setting
Imaging studies: Renal ultrasound is indicated in all patients with AKI to define kidney
anatomy and echogenicity and to rule out hydronephrosis
Renal biopsy should be considered when the diagnosis remains unclear after ruling out
prerenal and postrenal causes. Biopsy if glomerulonephritis is suspected

Classification
Prerenal Azotemia
True volume depletion
Lack of oral intake, vomiting
GI loss: Bleeding, diarrhea
Urinary losses: Diuretics, osmotic diuresis, salt-wasting nephropathies
Cutaneous losses: Burns, sweats
Third space sequestration (crush injury)
Reduction in effective circulating volume
Congestive heart failure
Cirrhosis
Nephrotic syndrome
Shock
Renal vasoconstriction
Hypercalcemia
Hepatorenal syndrome
Altered renal hemodynamics
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
decrease postglomerular arteriolar constriction
NSAIDs decrease preglomerular arteriolar dilatation
Increase renal vein pressure
Abdominal compartment syndrome
Diagnosis
BUN/creatinine ratio greater than 20 to 1 due to increased water and urea reabsorption
Low urine sodium concentration (usually less than 20 mEq/L)
Low urine fractional excretion of sodium (FENa <1%)
FEurea <35%
Urine osmolality >500 mOsm/kg
Urine creatinine/plasma creatinine ratio >40
Treatment
Volume depletion: IV fluid resuscitation
Reduced effective volume: Treatment of the underlying disease process; maximize
cardiac output
Intrinsic Causes of Acute Kidney Injury

Include disorders involving tubulointerstitium, large renal vessels, renal microvasculature,
and glomeruli
Acute Tubular Necrosis
The most common cause of intrarenal disease in the hospital setting
Results from ischemia (prolonged hypotension) or nephrotoxic injury to renal tubules
Many exogenous toxins (aminoglycosides, amphotericin B, cisplatin, radiocontrast media,
pentamidine, IVIG, mannitol, hetastarch) and endotoxins (hemoglobinuria, myoglobinuria,
uric acid, bilirubin, and bile salt) can cause tubular damage
Diagnosis
BUN/creatinine ratio is normal, usually less than 20 to 1
Urinalysis shows muddy brown granular casts and epithelial cell casts
High urine sodium concentration (usually >40 meq/L) is caused by tubular injury and
decreased sodium reabsorption
High urine fractional excretion of sodium (FENa >2%)
FEUrea is between 50 to 65%
Urine osmolality <450 mOsm/kg
Urine creatinine/plasma creatinine ratio <20 (measure of tubular water reabsorption)
Treatment
Supportive care, hemodynamic support
Loop diuretics have not shown any benefit in preventing AKI or improving outcomes
in oliguric patients, but are routinely used in management of fluid overload and
hyperkalemia before initiation of renal replacement therapy
Several different agents have been studied in an attempt to prevent or ameliorate AKI,
including renal vasodilators, adenosine antagonists, or free radical scavengers. However,
no strategy showed improved benefit in improving outcomes or mortality
Contrast-induced Nephropathy
Defined as a sudden decline in kidney function within 24 to 48-hours of IV contrast
exposure
Kidney injury is usually non-oliguric
Creatinine peaks within 7 days and usually returns to baseline within 10 days
Caused by renal vasoconstriction leading to medullary ischemia, direct tubular
cytotoxicity of contrast, and the generation of reactive oxygen species, which contribute
to cell damage
Risk Factors
Underlying renal insufficiency (serum creatinine >1.5 mg/dl)
Diabetes mellitus
Poor renal perfusion: Intravascular volume depletion, congestive heart failure, liver failure
Multiple myeloma
High dose of contrast used
Prevention
Use of less nephrotoxic contrast agents (such as low-osmolal or iso-osmolal contrast
agents)
Avoid volume depletion and nonsteroidal anti-inflammatory drugs
Expansion of the intravascular space and enhanced diuresis with IV bicarbonate (bolus of
3 mL/kg of isotonic bicarbonate for 1 hour prior to the procedure, followed by 1 mL/kg/h
for 6 hours after the procedure) or normal saline (1 mL/kg/hour, 6 to 12 hours prior to the
procedure, and continued 6 to 12 hours after contrast administration)
N-acetylcysteine 1,200 mg orally twice daily the day before and the day of the procedure
Prophylactic renal replacement therapies for the prevention of contrast-induced
nephropathy have no proven benefit
Trial of pharmacologic agents, including furosemide, fenoldopam, dopamine, mannitol,
calcium channel blockers, have failed to show benefit
Pigment Nephropathy
Acute tubular injury can occur from release of non-protein heme pigment released from
myoglobin or hemoglobin

Heme pigment may cause injury to the kidneys in multiple ways: Vasoconstriction, with a
decrease in blood flow in the outer medulla, direct proximal tubular cell injury, or due to
tubular obstruction, possibly in association with uric acid
Causes of rhabdomyolysis: Traumatic muscle injury (extreme exercises, trauma,
seizures, neuroleptic malignant syndrome, malignant hyperthermia), exogenous toxins
(including alcohol, illicit drugs, medications: Statins, zidovudine), hereditary myopathies
and inflammatory muscle diseases, infections, electrolyte abnormalities (hypokalemia,
hypophosphatemia), endocrine causes (thyroid diseases, pheochromocytoma)
Renal injury often associated with CPK greater than 10,000
Release of intracellular electrolytes results in hyperkalemia, hyperphosphatemia, and
hyperuricemia
Sequestration of fluid and calcium into injured muscles leads to volume depletion and
hypocalcemia
The positive dipstick for blood in the absence of visible red cells by urine microscopy is
compatible with both rhabdomyolysis and hemolysis. These patients have a red to brown
color of the urine supernatant, and urine sediment shows pigmented granular casts
Treatment
Aggressive IV hydration, with target urine output of 250 to 300 mL/h
Alkalinize urine to pH above 6.5 with isotonic sodium bicarbonate, as tubular toxicity
of myoglobin is reduced in alkaline urine. Alkalinization can worsen hypocalcemia, by
increasing the percentage of calcium bound to albumin, thus reducing the free or ionized
calcium
Acute Interstitial Nephritis (AIN)
Usually caused by a hypersensitivity reaction to a drug, especially beta-lactam antibiotics
Less commonly, AIN can be caused by an infection or by autoimmune disorders
Table 9.8: Causes of AIN

Drugs
Antibiotics (penicillin, cephalosporins, rifampin, and sulfonamides)
Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, diuretics, proton
pump inhibitors, H2 antagonists, phenytoin, allopurinol
Infections
Bacteria (streptococci, staphylococci, Legionella, Brucella, and salmonella)
Viruses (Epstein-Barr virus, cytomegalovirus, HIV, polyomavirus)
Systemic Diseases
Sarcoidosis
Sjgren syndrome
Systemic lupus erythematosus
Idiopathic (up to 30% of AIN)
TINU syndrome: Tubulointerstitial nephritis and uveitis
Clinical Presentation
Acute renal failure after starting a new medication (the onset ranges from days to weeks
after initiation of the drug)
The classic signs of drug-induced AIN includes: Fever, macular rash, and eosinophilia
Dipstick evaluation is positive for proteinuria and hematuria
Urinary sediment shows RBCs (RBC casts or dysmorphic RBCs are usually not seen),
WBC and WBC casts
The presence of eosinophiluria suggests AIN, but urine eosinophils may also be seen with
acute glomerulonephritis, acute pyelonephritis, and atheroembolic renal disease
Mild proteinuria is seen (nephrotic-range proteinuria can be induced by NSAIDs when
there is a coexistant glomerular lesion which resembles minimal change disease)
Oliguria is often present (which may be related to severe interstitial inflammation causing
tubular obstruction and impeding the urine flow)
Tubular defects (Fanconi syndrome, renal tubular acidosis) are rarely seen in AIN
Renal biopsy is often required to establish a definitive diagnosis of AIN
The hallmark of AIN is the infiltration of the interstitial space by inflammatory cells (mostly
T-cells and monocytes) with sparing of glomeruli
Treatment
Discontinuation of offending agent
Patients who do not show improvement of renal function after discontinuation of the
offending drug may be treated with corticosteroids; however, their role in the treatment
of AIN remains controversial
Atheroembolic Renal Disease
AKI results from cholesterol emboli, which dislodge in medium or small renal arteries
Occurs spontaneously or following a catheter manipulation in aorta or surgery
Clinical manifestations usually appear 1 to 14 days after the inciting event, but the onset
can be delayed for weeks
Skin manifestations include livedo reticularis, purple toes, skin ulcerations and nodules
Other extrarenal manifestations include abdominal pain, pancreatitis, transient cerebral
ischemia
Renal impairment is usually subacute and advances in a stepwise fashion over a period of
several weeks, leading to need for dialysis in up to 40% of patients
Laboratory findings include increased ESR, leukocytosis and anemia, eosinophilia,
eosinophiluria, and hypocomplementemia
Treatment: Supportive care only; prognosis is poor (only half of the patients needing
dialysis regain sufficient renal function to come off dialysis)
Postrenal Azotemia
Results from obstruction of the ureters (calculi, infiltration of the ureteric wall by
malignancy, or external ureteral obstruction due to retroperitoneal fibrosis), from
obstruction of the bladder neck (prostatic hypertrophy, neurogenic bladder, or due to
treatment with anticholinergic agents), or less commonly from acute lower urinary tract
obstruction (urethral spasm, calculi or blood clots)
If obstruction is complete, anuria will result
Partial obstruction may result in polyuria due to loss of tubular function or excretion of
retained solutes

Diagnosis
Ultrasonography is the test of choice because it is safe, inexpensive, and has a high
sensitivity and specificity for detecting hydronephrosis. It may not be able to detect
obstruction in the 1st 48 hours when hydronephrosis has not, as yet, developed
Intravenous pyelography provides both functional and anatomic data, especially for the
ureters. However, it involves the use of intravenous contrast load and in patients with low
GFR, kidneys may not be visualized because the suppressed GFR may not allow excretion
of the contrast material
Computer tomography is able to diagnose hydronephrosis, ureteral stones, or extrinsic
causes of obstruction (e.g., retroperitoneal fibrosis)
Isotopic renography avoids the risks associated with radiocontrast agents, and provides a
functional assessment of the obstructed kidney; however, anatomic visualization is poor
Treatment
Emergent relief of obstruction is indicated in the presence of acute kidney injury or
urosepsis
Urethral or bladder neck obstruction is relieved by transurethral or suprapubic catheter
placement
Ureteric obstruction can be relieved by placement of a percutaneous nephrostomy tube
or ureteral stent placement
Recovery of renal function has been shown after release of obstruction of more than 60
days duration
Release of obstruction may result in postobstructive diuresis, marked polyuria with loss
of water, sodium, potassium, phosphate, and divalent cations. It is caused by combination
of damage to the tubular salt, solute, and water reabsorption, as well as the effects of
volume expansion, urea accumulation, and accumulation of natriuretic factors
Acute Kidney Injury in Special Clinical Settings

Hepatorenal Syndrome (HRS)
A form of volume-unresponsive, refractory prerenal azotemia, that occurs in patients with
advanced liver cirrhosis or those with fulminant hepatic failure
The syndrome is characterized by intense renal vasoconstriction with concomitant
peripheral arterial vasodilation
2 types of HRS have been identified:
Type 1 HRS is defined by doubling of initial serum creatinine to a level >2.5 mg/dL or
by 50% reduction in creatinine clearance to a level <20 mL/min in <2 weeks
Type 2 HRS is a moderate, steady renal failure with a serum creatinine of >1.5 mg/dL
Precipitating factors include bacterial infections, large volume paracentesis without
albumin infusion, gastrointestinal bleed, and acute alcoholic hepatitis
Diagnosis of HRS should require the following criteria (see Table on Diagnosis of HRS
Criteria)
Table 9.9: Diagnosis of HRS Criteria
1. Cirrhosis with ascites
2. Serum creatinine >1.5 mg/dL
3. No improvement of serum creatinine (decrease to a level of 1.5 mg/dL) after at least 2 days with
diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg
of body weight daily up to a maximum of 100 g/d
4. Absence of shock
5. No current or recent treatment with nephrotoxic drugs
6. Absence of parenchymal kidney disease, as indicated by proteinuria >500 mg/24 h, microhematuria
(>50 RBC/hpf), and/or abnormal renal ultrasonography
Treatment
Given the dismal prognosis of patients with type 1 HRS, aggressive treatment is indicated
only in patients who are waiting for a liver transplant or for patients undergoing
evaluation to determine candidacy for transplantation
Several systemic and splanchnic vasoconstrictors have been used in HRS, including
vasopressin, vasopressin analogues (ornipressin and terlipressin), somatostatin analogue
(octreotide), and alpha-adrenergic agonists (midodrine and norepinephrine)
Transjugular intrahepatic portosystemic shunt (TIPS) has been shown to improve the
renal function of patients who receive this treatment because of refractory ascites,
variceal bleeding, refractory hepatic hydrothorax, and pre-surgical portal decompression
Renal replacement therapy can be considered as a bridge to liver transplantation
Liver transplantation is the best treatment for suitable patients with HRS because it cures
the diseased liver and the renal dysfunction
Tumor Lysis Syndrome (TLS)
A constellation of metabolic abnormalities (hyperuricemia, hyperkalemia,
hyperphosphatemia, and hypocalcemia) that develops after administration of
cytotoxic chemotherapy or occasionally occurs spontaneously in patients with tumors
characterized by high cellular proliferation and rapid cellular turnover
More commonly seen in hematologic malignancies, such as non-Hodgkin lymphoma
(in particular Burkitt lymphoma), acute lymphoblastic leukemia (ALL), acute myeloid
leukemia (AML)
Can also develop in solid tumors, such as small cell lung cancer, germ cell tumors, and
melanoma

Diagnosis
Table 9.10: Diagnosis of TLS

Laboratory TLS (2 or more laboratory changes must be observed within 3 days before or 7 days after
cytotoxic therapy):
Uric acid >8 mg/dL or 25% increase from baseline
Potassium >6 mEq/L or 25% increase from baseline
Phosphorus >6.5 mg/dL or 25% increase from baseline
Calcium <7 mg/dL or 25% decrease from baseline
Clinical TLS is defined as the presence of laboratory TLS and 1 or more of the following associated
complications:
Creatinine >1.5 times the upper limit of normal
Cardiac arrhythmias or sudden death
Seizures
Acute kidney injury results from hyperuricemia and hyperphosphatemia, causing tubular
obstruction with uric acid and calcium phosphate crystals. Uric acid may also activate
proinflammatory cells (neutrophils and macrophages), and may directly damage renal
tubular epithelial cells
Treatment of TLS is focused on preventing clinical complications, including AKI
Volume expansion with crystalloid solutions and forced diuresis are used to promote
urine flow and excretion of uric acid, potassium, and phosphorus
Urine alkalinization can increase the solubility of uric acid, but does not increase xanthine
solubility (a purine metabolite that can also precipitate in the renal tubules), may increase
calcium-phosphate crystallization, and may result in metabolic alkalosis
Drugs that lower uric acid levels include allopurinol and rasburicase
Purine metabolites of nucleic acids are broken down by xanthine oxidase to
hypoxanthine, xanthine, and finally uric acid. Allopurinol inhibits xanthine oxidase, thus
decreasing uric acid production. Therefore, allopurinol is more effective at preventing
hyperuricemia than decreasing preexistent hyperuricemia
Rasburicase is recombinant urate oxidase that can convert uric acid to a more soluble
metabolite, allantoin. Rasburicase is contraindicated in pregnancy and in patients with
glucose-6-phosphate dehydrogenase (G6PD) deficiency
Renal replacement therapy may be indicated in patients with refractory, life-threatening
electrolytes abnormalities, especially in the presence of volume overload and renal failure
HIV Infection Treated with HAART
Rhabdomyolysis can be seen in patients treated with zidovudine or didanosine
Tenofovir, abacavir, didanosine, lamivudine, and stavudine have been linked to the
development of proximal tubular dysfunction, including Fanconi syndrome
Acute interstitial nephritis has been described in patients taking indinavir, abacavir,
ritonavir, and atazanavir
Urinary obstruction can develop secondary to stones associated with drugs, such as
indinavir
Renal function should be monitored closely in all patients with HIV receiving any
antiretroviral agent
9.8 Kidney Stones
Epidemiology
Kidney stones are common in industrialized countries, with an annual incidence of over 1 in
1,000 persons
Stone formation is more common in males than females (at a ratio of 2-4:1) and is more
common in Caucasian population
The peak incidence occurs in the 3rd decade of life
Renal stones generally consist of calcium salts (>70%), uric acid, cystine, or struvite
Recurrent rates are high: 40 to 50% by 5 years, and 50 to 60% by 10 years
Calcium Stones
Calcium oxalate and calcium phosphate stones are the most common stones seen in clinical
practice
Several risk factors have been described in patients with calcium containing stones:
Hypercalciuria
The most common metabolic abnormality described in patients with calcium-containing
stones, occurring in 50 to 70% of all patients with calcium stones
See Table for Causes of Hypercalciuria
Table 9.11. Causes of Hypercalciuria

Associated with high serum calcium:
Primary hyperparathyroidism
Granulomatous diseases (sarcoidosis, tuberculosis)
Vitamin D ingestion
Malignant tumors
Immobilization
Hyperthyroidism
Associated with normal serum calcium:
Distal renal tubular acidosis
Idiopathic hypercalciuria
Patients with idiopathic hypercalciuria have enhanced intestinal calcium absorption, and
may also have decreased renal tubular reabsorption, and increased calcium mobilization
from bone
Prevention is directed toward increasing the solubility of calcium in the urine:
High fluid intake (2-2.5L/d) to reduce the calcium concentration
Dietary sodium restriction reduces urine calcium excretion
Dietary protein restriction
Moderation of calcium intake (calcium binds to gastrointestinal oxalate and thus
prevents oxalate absorption)
Thiazide diuretics stimulate distal nephron calcium reabsorption and are the first-line
therapy for idiopathic hypercalciuria. Diuretic-induced hypokalemia can predispose
to hypocitraturia, a risk factor to stone pathogenesis. If hypokalemia develops,
potassium citrate supplements (Urocit K 20 to 40 mmol daily) can be given

Hyperoxaluria
Is found in up to 20% of calcium stone formers
The upper limit of normal for oxalate excretion is 45 mg/d in an adult
Several conditions have been associated with increased urinary oxalate excretion:
Excessive dietary intake (spinach, rhubarb, chocolate, black tea, nuts, cocoa, beets)
High doses of vitamin C (as vitamin C is metabolized to oxalate)
Enteric oxaluria, seen in patients with malabsorption syndromes, results in decreased
intestinal free calcium concentration (since calcium is complex to fatty acids), with
subsequent increased gastrointestinal absorption of oxalate
Primary oxaluria (PHO) is a rare autosomal recessive disorder in which hyperoxaluria
results from disturbances in the oxalate biosynthetic pathway. Type 1 hyperoxaluria
is characterized by defective conversion of glyoxylate to glycine, which results in
increased availability of glyoxylate for conversion to oxalate. This results in excess
oxalate secretion in the urine, recurrent calcium oxalate calculi, and progressive renal
failure
Hypocitraturia
Citrate functions as a stone formation inhibitor because it reduces the supersaturation of
calcium oxalate by binding to calcium
Hypocitraturia is found in up to 20% of stone formers and can be idiopathic or
associated with chronic diarrheal states, distal renal tubular acidosis, and diuretic-induced
hypokalemia. All of these conditions are associated with an intracellular acidosis, which
increases citrate reabsorption in the proximal tubule
Alkali therapy with potassium citrate or orange juice can be used to increase urinary
citrate
Urine pH should be monitored because calcium phosphate precipitation can occur if the
pH exceeds 7.0
Magnesium Ammonium Phosphate (Struvite) Stones

Struvite stones form in the renal pelvis and calices when there is recurrent urinary tract
infection with an urea-splitting organism, usually a Proteus species
Struvite stones tend to branch and enlarge quickly and can produce staghorn calculi that
can fill the entire renal collecting system
Treatment of these stones include surgical removal and antibiotic therapy to eradicate urea-
splitting bacteria
Surgical stone removal is difficult and any retained fragments will contain bacteria that will
start creation of a new stone. Patients with struvite stones need long-term follow-up and
surveillance for urinary tract infection
Cystine Stones
Cystinuria is an autosomal recessive disorder characterized by impaired transport of cystine
and the dibasic amino acids ornithine, lysine, and arginine in the renal proximal tubules and
gastrointestinal tract, of which cystine is the least soluble and therefore the most likely to
precipitate as a stone
Patients with cystinuria start developing stones during the 1st to 3rd decade
Urine alkalinization with potassium citrate is indicated to increase cystine solubility
Protein restriction will also decrease cystine load
Chelating drugs, such as penicillamine and mercaptopropionylglycine (tiopronin), solubilize
cystine by forming disulfide bonds with cystine
Uric Acid Stones

Accounts for 10% of all renal stones in the US
10 to 15% of patients with gout develop uric acid stones
Hyperuricosuria (especially when urine uric acid excretion is more than 1,000 mg/24 h) may
cause uric acid stones
Hyperuricosuria can occur with gout, myeloproliferative disease, or with use of uricosuric
drugs, such as probenecid and aspirin
Uric acid salts are poorly soluble in acid urine, and a pH of 6 to 7 is optimal to prevent urate
stone formation
Treatment includes fluids, alkali administration, low purine diet, and allopurinol
It may be beneficial to treat hyperuricosuria to prevent calcium stone formation, as
hyperuricosuria may promote calcium oxalate renal stones by heterogeneous nucleation or
adsorption of macromolecular inhibitors
Include the following: Asymptomatic microscopic hematuria, renal colic (sudden onset of
flank pain, associated with nausea, vomiting, or urinary frequency and urgency), recurrent
urinary tract infection, or obstructive uropathy
Stones <5 mm in diameter will generally pass with hydration alone, but passage of stones
greater than 7 mm in diameter is uncommon and requires urologic consultation
Laboratory Studies
All patients with nephrolithiasis should undergo a basic evaluation, including serum
chemistry analysis, calcium, uric acid level, intact parathyroid hormone level (if calcium level
is high or high normal), urinalysis with sediment examination (e.g., presence of hexagonal
crystals of cystinuria), and urine culture to exclude infection with a urea-splitting organism
Patients with recurrent stones or multiple stones on 1st presentation, or patients with
non-calcium-based stones, require a more complete evaluation to evaluate for metabolic
abnormalities that can contribute to stone formation. 24-hour urine studies should be
obtained for calcium, uric acid, citrate, sodium, and oxalate excretion. A 24-hour urine
creatinine clearance collection should also be performed to ensure the adequacy of
collection
Imaging Studies
A plain film of the abdomen may reveal only radiopaque stones
Renal ultrasound may not reveal small stones or stones in the ureters and urethra
Intravenous pyelography has a high sensitivity and specificity in the diagnosis of renal
stones, but requires intravenous iodinated contrast agents
Noncontrast helical CT of the abdomen and pelvis has become the gold standard test for
diagnosis kidney stones because of its superior sensitivity and specificity in identifying
ureteric stones

Management
Emergency urologic referral is indicated in the setting of urosepsis and bilateral disease
manifesting as acute renal failure
Other indications for surgical referral include failure to pass a stone within 4 to 6 weeks,
persistent obstruction, stones >7 mm which are unlikely to pass spontaneously, staghorn
calculi
Surgical management options include extracorporeal shock-wave lithotripsy (which may
require ureteral stent placement if patient is symptomatic), ureteroscopy with stone
fragmentation (usually recommended when stones are located in the distal ureter), and
percutaneous nephrolithotomy (indicated for staghorn calculi, and stones that are resistant
to ESWL)
9.9 The kidney in Pregnancy

Kidney Anatomy and Physiology in Pregnancy
Kidney increases in size, in part due to the increase in renal vascular and interstitial volume
There is dilation of the calyces, renal pelvis, and the ureters, mediated by the effect of
progesterone, and with progression of pregnancy, as a result of mechanical compression of
the ureters at the pelvic brim
Renal Hemodynamics
Normal pregnancy is characterized by widespread vasodilation, with increased arterial
compliance and reduced systemic vascular resistance. These hemodynamic changes are
accompanied by increases in renal blood flow and glomerular filtration rate
The physiologic increase in GFR is associated with a decrease in serum creatinine
concentration, which falls by an average of 0.4-0.5 mg/dL
Because the rise in renal plasma flow is slightly more pronounced than the increase in GFR,
filtration fraction decreases slightly during pregnancy
In response to renal vasodilation, there is stimulation of all components of the renin-
angiotensin system. The increased renin release causes an increase in aldosterone
production, with sodium retention and a slight decrease in serum potassium level
Other Changes in Pregnancy

Pregnancy is associated with decrease in tubular reabsorption of glucose, amino acids, and
beta microglobulin, which may result in glycosuria and aminoaciduria
Urine protein excretion increases during pregnancy to 300 mg/24-hours
The plasma osmolality in normal pregnancy decreases by ~10 mosmol/kg below
nonpregnancy levels. The osmotic thresholds for arginine vasopressin release (and thirst)
are reduced to recognize the reduced plasma osmolality as normal
The metabolic clearance rate of arginine vasopressin is increased in pregnancy due to
the release of placental vasopressinase. As a result of increased metabolism of arginine
vasopressin, pregnant women may develop syndrome of transient diabetes insipidus
Minute ventilation rises in early pregnancy and continues to increase until term, resulting in
a modest fall in the PCO2 and mild respiratory alkalosis. These changes are probably the
result of direct stimulation of the central respiratory centers by progesterone. The metabolic
compensation results in an increase in renal bicarbonate excretion, with a decrease in
plasma bicarbonate concentration by approximately 4 mmol/L
There is a small reduction in serum anion gap during pregnancy
Hypertensive Disorders Associated With Pregnancy

Classification of hypertensive disorders in pregnancy
Preeclampsia
Gestational hypertension
Chronic hypertension
Chronic hypertension with superimposed preeclampsia
Preeclampsia
A syndrome of pregnancy characterized by hypertension (>140/90 mmHg) and
proteinuria (>300 mg/d) after 20 weeks of gestation, but often closer to term
Eclampsia is the convulsive form of preeclampsia
5 to 8% of all pregnancies are complicated by preeclampsia
Risk factors for preeclampsia include nulliparity, preeclampsia in a previous pregnancy,
multiple gestations, family history of preeclampsia, and extremes of reproductive age.
Women with preexisting medical conditions, such as hypertension, diabetes mellitus,
obesity, preexisting kidney disease, thrombophilic diseases (particularly the factor V
Leiden mutation and antiphospholipid antibody syndrome) also have an increased risk of
preeclampsia
Pathophysiology
The pathogenesis of preeclampsia is complex, involving both maternal and fetal/placental
factors
The first stage is asymptomatic, characterized by abnormal development of the placental
vasculature as a result of failure of trophoblast remodeling of uterine spiral arteries.
These abnormalities result in constricted spiral arteries and placental underperfusion,
hypoxia, and ischemia. Placental ischemia may lead to the release of various factors, such
as reactive oxygen species, cytokines, antiangiogenic factors (sFlt-1, soluble endoglin)
that cause maternal systemic endothelial damage, increased vascular permeability,
vasoconstriction, intravascular coagulation, resulting in end-organ damage and/or
hypoperfusion
Headaches
Visual abnormalities (scotoma, photophobia)
Upper abdominal or epigastric pain
Shortness of breath, chest pain, pulmonary edema
Oliguria
Edema of face/hands
Fetal growth retardation
Laboratory Abnormalities
Creatinine level >0.8 mg/dl
Proteinuria >300 mg/d

Plasma uric acid >5.5 mg/dl is indicative of preeclampsia
Low hemoglobin level (due to microangiopathic hemolytic anemia)
Hematocrit >40% reflects plasma volume concentration
Thrombocytopenia (<100,000/microL)
Elevated liver enzymes (twice the upper limit of normal)
HELLPsyndrome (Hemolysis, Elevated Liver enzymes, Low Platelet count) represents a
severe form of preeclampsia
Prevention
Low dose aspirin is associated with 10 to 15% reduction in relative risk of adverse maternal
and fetal outcomes. Aspirin should be used for women at moderate to high risk of
developing preeclampsia
Calcium supplementation may be beneficial for preeclampsia prevention in high-risk
patients, particularly those who have a low calcium diet
Antioxidant supplementation (such as vitamin C, vitamin E), showed no benefit in
preventing preeclampsia
Management
Delivery should be considered in all cases at term
In cases remote from term, management includes bed rest, antihypertensive therapy,
close monitoring of maternal and fetal conditions, seizure prevention with magnesium
sulfate, and appropriately timed delivery
Delivery should be considered, regardless of gestational age, when there are signs of
progressive evidence of maternal organ dysfunction: Worsening renal or hepatic function,
worsening of thrombocytopenia, development of neurologic symptoms/signs or inability
to control blood pressure
Antihypertensive medications are indicated for the treatment of severe hypertension
(systolic pressures 150 mmHg and diastolic blood pressures 100 mmHg)
Parenteral therapy is recommended when delivery is likely to take place in the next
24-hours. An oral agent is usually used when delivery can be safely postponed
Table 9.12: Drugs Used in the Treatment of Hypertension in Preeclampsia

Acute Chronic
Hydralazine (IV or IM) Methyldopa
Labetalol (IV) Labetalol, other b-blockers
Nifedipine (SC) Calcium channel blockers
Diazoxide (IV, rarely used) Clonidine
a-blockers
Hydralazine
Seizure prophylaxis is recommended in patients with moderate to severe preeclampsia.

The benefit of seizure prophylaxis is less clear in mild preeclampsia
Magnesium sulfate has been shown to be superior to phenytoin or diazepam for
prevention of recurrent seizures
The dose of magnesium should be adjusted in women with renal insufficiency (with
serum creatinine >1.0 mg/dL). Close monitoring of the serum magnesium levels every 6
hours is usually required
Gestational Hypertension
Defined as de novo hypertension developing in the latter half of pregnancy not
associated with the systemic features of preeclampsia (e.g., proteinuria), returning to
normal within 3 months postpartum
May be early manifestation of preeclampsia or early unrecognized chronic hypertension
Approximately 15 to 45% of women diagnosed with gestational hypertension develop
preeclampsia
Progression to preeclampsia is more likely to occur if gestational hypertension appears
early in the pregnancy, or if there is a history of prior miscarriage or hypertension during
a previous pregnancy
Baseline urinalysis and blood chemistries are indicated to rule out preeclampsia
Chronic Hypertension
Present in up to 5% of pregnancies
Risk of superimposed preeclampsia is 10 to 25% compared with 5% of normotensive
pregnancies
Patients with mild essential hypertension (systolic 140 to 159 or diastolic 90 to 99 mmHg)
without evidence of target organ damage may have their antihypertensive drugs tapered
during pregnancy, since blood pressure usually decreases as pregnancy progresses, with
close monitoring of the maternal blood pressure response
A subgroup of women with mild hypertension and associated comorbidities (such as
chronic kidney disease, diabetes mellitus) or in the presence of target-organ damage
(e.g., microalbuminuria, left ventricular hypertrophy) are at greater risk of maternal or
fetal complications and may benefit from antihypertensive therapy
Severe hypertension (blood pressure >160/105 mmHg), should be treated to protect the
mother from serious complications, such as stroke, heart failure, or renal failure
Table 9.13: Drugs Indicated in Pregnancy

Drug Dose
Methyldopa Starting dose 250 mg bid, maximum 500 mg qid
Labetalol Starting dose 100 mg bid, maximum 200 mg qid
Nifedipine XL (other nondihydropyridine calcium Starting dose 30 mg qd, maximum 90 mg qd
antagonists have been used as well)
Thiazide diuretics Can be used as long as volume depletion is avoided
Drugs Contraindicated in Pregnancy

Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers
(ARBs) are contraindicated at all stages of pregnancy
Exposure to ACE inhibitors (and probably ARBs) in the 1st trimester may increase the risk
of fetal cardiovascular and central nervous system malformations. Later in pregnancy, ACE
inhibitor use can cause impaired fetal/neonatal renal function, resulting in oligohydramnios
during pregnancy, and anuria and renal failure after delivery

Kidney Disease in the Pregnant Patient
Pregnant normotensive women with preserved or only mild decrease in renal function
(serum creatinine <1.4 mg/dl) and minimal proteinuria are less likely to develop permanent
deterioration in renal function. There is an increased incidence of superimposed
preeclampsia and late pregnancy hypertension, as well as increased proteinuria in the 2nd
half of pregnancy
Pregnancy in women with moderate or severe renal impairment (with serum creatinine
>1.5 mg/dl) is associated with increased fetal and maternal complications, but also with
deterioration in kidney function that may be irreversible
Diabetes Mellitus
Diabetic women with microalbuminuria have an increase in urinary protein excretion, and up
to 30% of patients may develop nephrotic range proteinuria. Postpartum, urinary albumin
excretion typically returns to pre-pregnancy values
Patients with normal blood pressure and preserved renal function have a good outcome,
but they have an increased risk of preeclampsia and urinary tract infection
In patients with diabetic nephropathy and preserved kidney function, deterioration of renal
function during pregnancy is uncommon
Patients with overt nephropathy and impaired renal function have a high incidence of
premature delivery and deterioration in renal function
Tight glucose control is associated with improved fetal outcome. Women taking
angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be
switched to other agents before conception
Chronic Glomerulonephritis
In general, pregnancy in patients with preserved renal function and normal blood pressure
has a good prognosis
Patients with scleroderma and periarteritis nodosa are at risk of increased maternal death
and poor fetal outcomes; thus, they should be counseled to avoid pregnancy
Systemic Lupus Erythematosus (SLE)

SLE is associated with significant maternal and fetal risk and tends to exacerbate during
pregnancy. In general, patients with SLE, especially those with active disease, have an
increased risk for mortality, preeclampsia, and preterm birth and fetal loss
The prognosis for both mother and child is best if disease has been in remission for 6
months before conception
Pregnancy in women with lupus nephritis is associated with an increased risk of fetal loss
and with worsening of both renal and extrarenal manifestations of SLE
Patients with SLE are more likely to have clinically significant titers of antiphospholipid
antibodies and lupus anticoagulant, which are associated with spontaneous fetal loss, early
severe preeclampsia, fetal growth restriction, pregnancy-related maternal thrombosis
For women with antiphospholipid antibodies with no prior history of thrombosis, low dose
daily aspirin is recommended. If there is history of prior thrombotic events, combination
therapy with subcutaneous heparin is recommended
Appropriate therapy for lupus nephritis during pregnancy includes steroids and azathioprine
Cyclophosphamide and mycophenolate mofetil (MMF) are contraindicated in pregnancy
Polycystic Kidney Disease
Pregnancy in women with autosomal-dominant polycystic kidney disease is uneventful if
renal function is preserved
Patients with hypertension and impaired renal function are at risk for preeclampsia and
premature delivery
Chronic Pyelonephritis
Bacteriuria in pregnancy may lead to acute exacerbations but otherwise is well tolerated
Frequent urine cultures are usually recommended
Chronic suppressive antibiotic therapy may be necessary
Acute Kidney Injury

Early in pregnancy (12 to 18 weeks), the most common causes of acute kidney injury include
prerenal diseases due to hyperemesis gravidarum or acute tubular necrosis, in association
with a septic abortion
Later in pregnancy, acute kidney injury may result from thrombotic microangiopathies,
acute fatty liver of pregnancy, renal cortical necrosis, pyelonephritis, urinary tract
obstruction or nephrolithiasis
Thrombotic Microangiopathy
Acute kidney injury associated with microangiopathy and thrombocytopenia can be caused
by thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) or
severe preeclampsia with the HELLP syndrome
TTP associated with ADAMTS13 deficiency occurs predominantly in the 2nd and 3rd
trimesters
Pregnancy-associated HUS occurs more commonly in the postpartum period. Mutations
in genes that encode proteins involved in complement alternative pathway have been
associated with pregnancy-associated HUS
Treatment of TTP/HUS includes plasma infusion/exchange and other modalities used in
non-pregnant patients
Management of End-stage Renal Disease During Pregnancy

Dialysis
The reported frequency of conception among women of child-bearing age on dialysis
ranges from 0.3 to 1.5% per year
Improvements in management have resulted in an enhanced frequency of live births
Better outcomes are associated with increase dialysis (e.g., using nocturnal dialysis of
3 to 6 sessions/week; 6 to 8 hours) and improved management of anemia (e.g., use of
erythropoietin, blood transfusions)
Possible maternal complications include accelerated hypertension, and mortality
Common fetal complications of this therapy include intrauterine growth restriction and
polyhydramnios-related preterm labor
Kidney Transplantation
Fertility generally returns after renal transplantation. However, the rates of both
pregnancy and successful pregnancy (i.e., resulting in a live birth) remain far lower than in
the general population
In addition, there is an increased risk of intrauterine growth restriction, preterm delivery,
and preeclampsia in transplant recipients

Patients are advised to wait at least 1 year after living related donor transplantation and 2
years after deceased transplantation before conceiving
The renal allograft should be functioning well, with a stable serum creatinine level of less
than 1.5 mg/dL and urinary protein excretion less than 500 mg/d
Immunosuppressive regimens may need to be adjusted prior to conceiving.
Mycophenolate mofetil (MMF) and sirolimus are contraindicated in pregnancy
General pregnancy does not have long-term adverse effects on graft survival
9.10 Chronic Kidney Disease

The NKF K/DOQI CKD guidelines define CKD as either kidney damage (proteinuria,
hematuria, or structural abnormalities of the kidney) with or without impaired GFR, or
impaired eGFR <60 mL/min per 1.73 m2 with or without kidney damage that persists for
over 3 months
The KDOQI work group also established the following stages of CKD:
Stage I: Kidney damage with normal or increased GFR
Stage II: Kidney damage with mild decrease in GFR (60-89 mL/min/1.73 m2)
Stage III: Moderate decrease in GFR (30-59 mL/min/1.73 m2)
Stage IV: Severe decrease in GFR (15-29 mL/min/1.73 m2)
Stage V: Kidney failure (<15 mL/min/1.73 m2 or dialysis)
Etiology
Diabetes mellitus
Hypertension
Glomerulonephritis
Genetic or congenital
Urologic
Usually asymptomatic until the late stages of renal failure
Are nonspecific, can mimic many other clinical conditions, and include the following:
Anorexia, nausea, vomiting, and dysgeusia
Fatigue, weakness, lethargy
Pruritus
Insomnia, irritability, paresthesias, mental status changes due to encephalopathy
Dyspnea and peripheral edema (from fluid overload), chest pain from pericarditis
Physical examination findings:
Uremic fetor (foul-smelling breath similar to urine or fish)
Pallor
Signs of volume overload
Pericardial friction rub
Asterixis
Metabolic abnormalities are often seen
Anemia
Metabolic acidosis
Hyperkalemia
Hypocalcemia, hyperphosphatemia, and renal bone disease
General Management
Early referral to nephrologist has been shown to improve outcomes and allows for early
intervention
Management of patients with CKD involves the following issues:
Prevention or Slowing the Progression of Renal Disease
ACE inhibitors and angiotensin receptor blockers (ARBs) decrease intraglomerular
pressure and hyperfiltration; may be associated with hyperkalemia
Management of hypertension
2011 KDIGO clinical guideline recommendations for management of blood pressure in
CKD patients depending upon the degree of proteinuria
Blood pressure <130/80 mmHg in patients with proteinuric CKD (500 to 1,000 mg/d
or more)
Blood pressure <140/90 mmHg in patients with nonproteinuric CKD (less than 500
to 1,000 mg/d)
The proteinuria goal is less than 1,000 mg/d
Dietary protein restriction
In theory, reduced protein intake decreases intraglomerular pressure and metabolic
demands on the kidney, but its benefit in delaying progression of CKD in humans
remains controversial
Recommended protein intake: 0.8 to 1.0 g/kg per day of high biologic value protein,
with the lower value used in patients with progressive CKD
Treatment of hyperglycemia
Goal of glycated hemoglobin should be less than 7%
Modify other cardiovascular risk factors (hyperlipidemia, hyperuricemia, tobacco use)
Prevention/Treatment of the Complications of CKD (Volume Overload, Anemia,
Hyperkalemia, Metabolic Acidosis, Renal Bone Disease)
Volume Overload
Results from the inability of kidney to excrete water and salt
Treatment includes dietary sodium restriction and diuretic therapy, usually with a loop
diuretic given daily
Anemia
Anemia of chronic kidney disease is normocytic and normochromic, and results from
decreased production of erythropoietin by the kidney, and to shortened red cell survival
Anemia is common in patients with CKD with GFR <60 mL/min
Anemia is a contributing factor in many of the symptoms associated with reduced kidney
function. These include fatigue, decreased functional capacity and quality of life, dyspnea,
and cardiovascular consequences, such as left ventricular hypertrophy
The evaluation of anemia in patients with CKD should begin when the Hgb level is less
than 12 g/dL in females, and less than 13.5 g/dL in adult males
The evaluation of anemia should rule out other causes, and includes reticulocyte count,
serum iron, total iron binding capacity, percent transferring saturation, serum ferritin,
peripheral smear, and Hemoccult stool
Treatment of anemia includes the use of erythropoiesis-stimulating agents (ESAs)
ESAs should be initiated when the Hgb level is <10 g/dL; goal maintaining Hgb levels
between 10 and 11 g/dL

Clinical data suggest that hemoglobin levels above 13 g/dL are associated with increased
morbidity and mortality
Almost 50% of CKD patients are also iron deficient
The recommended transferring saturation and ferritin concentration are 20 to 50% and
100-500 mg/dL, respectively
Iron absorption from the intestinal tract is impaired in CKD patients, because of increased
hepcidin, a 25-amino acid protein produced in the liver
Several IV iron preparations are available to treat CKD patients with iron deficiency
anemia
Metabolic Acidosis
Results from inability of kidney to excrete acid load
Chronic acidosis can increase skeletal muscle breakdown and diminish albumin synthesis,
resulting in muscle weakness and poor nutritional status
Bone buffering of the excess hydrogen ions is associated with the release of calcium and
phosphate from bone, resulting in worsening of the bone disease
Alkali therapy, recommended to maintain the serum bicarbonate concentration above
23 meq/L, can be done with sodium bicarbonate 1,300 mg twice a day or sodium citrate
0.5-1 mL/kg in 3 divided doses
Hyperkalemia
Results from the inability of the kidney to excrete potassium load in the setting of a high
potassium diet, increased tissue breakdown, or use of medications (such as ACEI, ARB or
NSAIDs)
Long-term treatment includes ingestion of a low potassium diet (less than 40 to 70 meq/
day [1,500 to 2,700 mg/d]), use of loop diuretics, and discontinuation of drugs that raise
the serum potassium concentration
Mineral and Bone Disorder
Renal bone disease develops early in the course of CKD. Disturbances of mineral and
bone metabolism have been linked to cardiovascular disease and vascular calcifications
The term chronic kidney disease-mineral and bone disorder (CKD-MBD) refers to a
syndrome of bone and extraskeletal calcification that occurs in patients with CKD
Renal bone disease is caused by secondary hyperparathyroidism, induced by the
combined effects of hypocalcemia, deficiency of 1,25-dihydroxyvitamin, and phosphorus
retention/hyperphosphatemia. In addition, phosphate retention was found to stimulate
production of another hormone, fibroblast growth factor 23 (FGF 23), a hormone
produced by the osteocytes. FGF 23 interferes with the synthesis of vitamin D and
inhibits renal tubular phosphate transport
Parathyroid hormone (PTH) has many physiologic effects that allows to restore calcium
and phosphate to normal
Inhibits sodium/phosphate cotransport in the proximal tubule, with increase in
phosphate excretion
Stimulates 1-alpha hydroxylase and increases the production of 1,25-dihydroxyvitamin
D (calcitriol), which, in turn, increases intestinal calcium absorption
Increases mobilization of calcium from mineralized bone and decreases urine calcium
excretion
The principal types of renal bone disease include osteitis fibrosa, osteomalacia, and
adynamic bone disease
Clinical manifestations of renal osteodystrophy
Bone pain and fractures
Muscles weakness and myopathy
Spontaneous tendon rupture
Pruritus (associated with severe hyperparathyroidism, and a high calcium-phosphorus
product)
Metastatic and extraskeletal calcifications
Renal Bone Disease
The initial step in the treatment of renal bone disease should include dietary phosphate
restriction
An intake of approximately 800 mg/d is recommended by the K/DOQI guidelines
The K/DOQI guidelines recommend that serum phosphorus levels should be between 2.7
and 4.6 mg/dL among patients with stage 3 and 4 CKD, and between 3.5 and 5.5 mg/dL
among those with stage 5 CKD
Many patients require phosphate binders to reduce the amount of phosphorus absorbed
and achieve a normal phosphate concentration
Calcium-based binders: Calcium carbonate, calcium acetate
Non-calcium-based binders: Sevelamer hydrochloride, lanthanum carbonate
Aluminum-based binders should be avoided because of the gradual induction of
aluminum toxicity
If the target PTH level is not achieved, despite dietary phosphate restriction and intestinal
phosphate binders, administration of vitamin D compounds is recommended:
1,25-OH-vitamin D (calcitriol), or
Synthetic vitamin D analogues (paricalcitol or doxercalciferol)
Vitamin D analogs can induce hypercalcemia and hyperphosphatemia and therefore
should be used with caution
The goal iPTH levels varies, based on stage of CKD
Stage III: iPTH = 35-70
Stage IV: iPTH = 70-110
Stage V: iPTH = 150-300
Calcimimetics are agents that allosterically increase the sensitivity of the calcium-
sensing receptor in the parathyroid gland to calcium. Cinacalcet is currently the only
available calcimimetic, is curently approved only for dialysis patients, but may become
an emerging option in the treatment of secondary hyperparathyroidism in predialysis
patients with CKD
Preparation of the Patient for Renal Replacement Therapy
The 2006 K/DOQI guidelines recommend that patients with a GFR less than 30 mL/min
should be educated concerning different choices of renal replacement therapy, such as
hemodialysis (in-center or at home), peritoneal dialysis, and renal transplantation (living or
deceased donor)
Renal Transplantation
Kidney transplantation is the treatment of choice for end-stage renal disease
Patients can be listed for cadaveric transplant when eGFR is less than 20 mL/min
Contraindications to transplantation include: Recent or metastatic malignancy, current
untreated infection, history of nonadherence, inability to give informed consent, and
active use of illicit drugs
Graft survival rates exceeds 95% at 1 year and 80% at 5 years

Dialysis
The timing of initiation of dialysis is unclear and there is no specific threshold GFR level
that has been established for the initiation of dialysis. Many clinicians initiate dialysis when
eGFR is less than 15 mL/min in diabetic patients and less than 10 mL/min in nondiabetic
patients
There are a number of clinical situations that require initiation of dialysis:
Pericarditis
Progressive uremic encephalopathy or neuropathy
A clinically significant bleeding diathesis attributable to uremia
Volume overload not responsive to diuretics
Persistent metabolic disturbances (hyperkalemia, metabolic acidosis) that are
refractory to medical management
Persistent nausea and vomiting
Evidence of malnutrition
Hemodialysis
Requires a stable access to the bloodstream to permit dialysis to be performed
Arteriovenous (AV) fistula
Synthetic arteriovenous fistulas (AV grafts)
Double-lumen, cuffed tunneled catheters
All patients should be referred to an access surgeon when the estimated GFR drops
below 20 to 25 mL/min
The 2006 K/DOQI guidelines recommend that a fistula be placed at least 6 months prior
to the anticipated start of hemodialysis
AVF is the preferred form of vascular access given higher long-term patency rates and
lower rate of infections
Peritoneal dialysis
Can be continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal
dialysis (APD) done over 8 to 10 hours
Peritoneal dialysis catheters should be placed 2 weeks before beginning dialysis to avoid
the risk of fluid leak
Major risk is peritonitis; occurs at a rate of 0.77 episodes per patient per year
9.11 Glomerular Diseases

Pathophysiology
Glomerular diseases represent a group of disorders that cause alteration in the glomerular
filtration barrier
The glomerular capillary wall is the filtering membrane that consists of the following
structural elements:
The innermost part of the glomerular capillary wall, in contact with the vascular space,
is covered by a fenestrated capillary endothelium, coated with a layer of polyanionic
glycosaminoglycans and glycoproteins
The endothelial cells are attached to the glomerular basement membrane (GBM),
composed of a complex meshwork of different matrix proteins, such as type IV
collagen, laminin, fibronectin, polyanionic proteoglycans (mostly heparan sulfate), and
other glycoproteins
Visceral epithelial cells (or podocytes) are structurally complex cells that possess
interdigitating processes (foot processes), which are attached to proteoglycans in
the GBM via adhesion proteins (integrins). The pores between the foot processes (slit
pores) are closed by a thin membrane called the slit diaphragm. A number of proteins
have been found to be part of the slit diaphragms, including nephrin, neph1, neph2,
FAT1, FAT 2, podocin, TRPC6, and tight junction proteins
Mesangium composed of the mesangial matrix (similar in composition to the GBM but
less well organized) and the mesangial cells, which are contractile, phagocytic cells,
capable of proliferation, of laying down matrix and collagen, and of secreting many
biologically active mediators
Injury to the visceral epithelial cells (e.g., foot process effacement or detachment of
podocytes from the underlying GBM) or injury to the GBM (such as thickening of the GBM
due to increased synthesis of its protein components in diabetic glomerulosclerosis, or due
to deposition of amorphous electron-dense material, most often immune complexes) can
alter the permeability of the capillary wall, and results in proteinuria
Rupture of the capillary wall or cellular proliferation of the mesangial or endothelial cells
causes hematuria
Rupture of the GBM following an immune/inflammatory injury can result in necrosis and
crescent formation. These are accumulations of cells composed of proliferating parietal
epithelial cells and infiltrating leukocytes
Majority of patients who develop glomerular disease present with 1 of 2 patterns of
kidney disease, nephritic or nephrotic, based upon the urine sediment and the degree of
proteinuria
Nephritic Pattern
Nephritic disorders are commonly associated with systemic diseases and are often
caused by immune-complex deposition in the glomerular capillaries
Usually characterized by azotemia, oliguria, hypertension, proteinuria (ranging from
normal protein excretion to the nephrotic range) and active urine sediment characterized
by the presence of red cells (some with a dysmorphic appearance and acanthocytes) and
occasionally white blood cells, with or without red cell or mixed cellular casts, and variable
degrees of proteinuria, ranging from normal protein excretion to the nephrotic range (i.e.,
both nephritic and nephrotic)
Common glomerular diseases presenting as nephritic syndrome include:
Poststreptococcal glomerulonephritis, other postinfectious diseases (endocarditis,
shunt nephritis, abscesses), IgA nephropathy, systemic lupus erythematosus, vasculitis,
Goodpastures disease
Serologic work-up include antistreptococcal antibodies, antinuclear antibodies, anti
double-stranded DNA antibodies, ANCA, antibodies, anti-GBM antibodies, cryoglobulins,
hepatitis B or C virus antibodies, and complement levels

Nephrotic Pattern
Characterized by proteinuria (usually above 3.5 g/24 h) and lipiduria, but few cells or
casts other than fatty casts
Some patients develop nephrotic syndrome, defined by the presence of proteinuria
(>3.5 g/24 h), hypoalbuminemia, edema, and hyperlipidemia
Urinary losses of anticoagulant proteins (e.g., protein C, protein S, antithrombin III) may
result in hypercoagulable state
Loss of immunoglobulins may result in a relative immune-deficient state
Patients with nephrotic pattern in the urinalysis may have either a primary renal disease
(e.g., minimal change disease, focal segmental glomerulosclerosis, idiopathic membranous
nephropathy, or membranoproliferative glomerulonephritis) or a systemic disease that
affects the kidneys (e.g., systemic lupus erythematosus, amyloidosis, hepatitis B or C virus
infection, or HIV infection)
Serologic work-up includes: Antinuclear antibodies (ANA), anti-double-stranded DNA
antibodies, complement levels, serum and urine immunofixation and serum free light
chain ratio analysis, hepatitis B and C and HIV serology, cryoglobulin levels
Primary Nephrotic Syndrome

Minimal Change Disease (MCD)
The most common cause of nephrotic syndrome in children and accounts for 10 to 15% of
all cases of primary nephrotic syndrome in adults
Majority of cases are idiopathic, but can be associated with hematologic malignancies
(Hodgkin lymphoma and other less-common lymphomas or leukemias) or solid tumors
(thymoma, malignancies of the kidney, lung, duodenum, and pancreas), infections
(syphilis, tuberculosis, ehrlichiosis), allergy, and some drugs (nonsteroidal anti-
inflammatory drugs, D-penicillamine, lithium, or pamidronate)
Although pathogenesis is unknown, systemic T-cell dysfunction appears to produce
increasing levels of a circulating factor (perhaps a cytokine), which can directly affect the
glomerular capillary wall, resulting in foot process fusion
Pathology
Light microscopy (LM) and immunofluorescence (IF) findings are normal
Electron microscopy (EM): Diffuse effacement of the epithelial foot processes
Clinical manifestations
MCD is characterized by the sudden onset over days to a few weeks of the signs
and symptoms of the nephrotic syndrome, often following an upper respiratory or
systemic infection
Microscopic hematuria is present in less than 15% of patients with MCD
Acute renal failure can develop in some patients, as a result of volume contraction,
interstitial edema, and the use of NSAIDs
Treatment
Corticosteroid therapy is the treatment of choice, and leads to complete remission of
proteinuria in 90% of adults with MCD
As few as 25% of patients will have a long-term remission, 25 to 30% have infrequent
relapses (no more than 1 a year), and the remainder have frequent relapses, or
resistance to steroid treatment
Immunosuppressive agents (cyclophosphamide, cyclosporine, tacrolimus, and
mycophenolate mofetil) have been used in patients with frequent relapses, as well as
in corticosteroid-resistant patients
Focal Segmental Glomerulosclerosis (FSGS)
Accounts for 30 to 35% of cases of adult nephrotic syndrome
The most common primary glomerular disease that causes end-stage kidney disease in
the US
The yearly incidence of primary FSGS has increased over the past 2 decades
Idiopathic FSGS is more prevalent among African American and Hispanic population
FSGS may be primary (idiopathic) or may be associated with other conditions:
Reduced nephron numbers (unilateral renal agenesis, postnephrectomy, reflux
interstitial nephritis) thought to represent an adaptive response to glomerular
hypertrophy or hyperfiltration
HIV disease (usually collapsing variant)
Toxins (heroin, interferon, lithium, and pamidronate)
Glomerulomegaly (morbid obesity, cyanotic congenital heart disease, or hypoxic
pulmonary disease)
Familial FSGS described in patients with mutations involving various slit diaphragm
proteins (alpha-actinin 4, podocin, nephrin, or TRPC6)
The pathogenesis of primary FSGS involves injury to the visceral epithelial cell or
podocyte. Injury may be caused by a circulating toxin, such as the soluble urokinase
receptor (suPAR)
Pathology
LM: Segmental areas of mesangial collapse and sclerosis in some but not all glomeruli
(focal); sclerotic changes occur first in juxtamedullary glomeruli
IF: No true immune complex deposits, except for nonspecific binding of IgM and C3
in the mesangium associated with sclerotic lesions
EM: Diffuse fusion of the epithelial cell foot processes
In addition to classic FSGS, variants include collapsing, tip, perihilar, and cellular.
Collapsing FSGS is usually but not always associated with HIV infection, and it is
characterized by collapse and sclerosis of the entire glomerular tuft, associated often with
severe tubular injury with proliferative microcyst formation and tubular degeneration.
The collapsing variant has a worse prognosis than other variants. The tip variant has the
defining pathologic lesion located at the tip of the glomerulus near the proximal tubule,
and is considered the most steroid responsive variant
Proteinuria is the hallmark of primary FSGS
Patients with FSGS also present with microscopic hematuria, hypertension, and renal
failure
Predictors of poor outcome in primary FSGS include: Nephrotic range proteinuria, renal
failure, and failure to respond to corticosteroid treatment
Treatment
Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers
(ARBs) are the principal treatment agents used for non-nephrotic patients
Nephrotic patients with primary FSGS should receive immunosuppressive therapy
with corticosteroids

30 to 50% of patients with primary FSGS are resistant to an adequate course of
steroids, whereas the others are steroid sensitive or steroids dependent
Cyclosporine and tacrolimus are beneficial in steroid-resistant FSGS because they
both lower proteinuria and delay progression of the disease
Prognosis: Up to 50% of patients with FSGS and persistent nephrotic-range proteinuria
develop ESRD within 5 years
Membranous nephropathy (MN)
Accounts for the nephrotic syndrome in approximately 30% of adults
Can occur as an idiopathic (primary) or secondary disease
Idiopathic MN is more common in white males over the age of 40 years
Secondary MN may be caused by autoimmune diseases, (lupus nephritis or autoimmune
thyroiditis), infections (hepatitis B or C, syphilis, malaria), drugs (gold, penicillamine,
captopril, nonsteroidal anti-inflammatory drugs, and possibly anti-tumor necrosis factor
agents), and malignancies (colon, lung, and melanoma)
Pathology
LM: Diffuse thickening of the glomerular basement membrane (GBM) throughout all
glomeruli; "spikes" of GBM extending between the immune deposits are seen with
silver stain
IF: Diffuse granular pattern of IgG and C3 staining along the GBM
EM: Subepithelial electron dense immune deposits, effacement of the foot processes
of the overlying podocytes, and expansion of the GBM by deposition of new
extracellular matrix between the deposits (which are the "spikes" observed by LM)
Almost 80% of patients with MN present with the nephrotic syndrome
Microscopic hematuria is present in almost 50% of the patients
Renal function is usually preserved at presentation
Prognosis
Low risk of progression: Protein excretion less than 4 g/d on a 24-hour urine
collection and normal renal function for a 6-month follow-up period
Moderate risk of progression: Protein excretion is between 4 and 8 g/d on a 24-hour
urine collection, and normal or near normal renal function that remains stable over 6
to 12 months of observation
High risk of progression: Protein excretion is greater than 8 g/d and persists for 3
months and/or renal function is reduced or declines over 3 months of observation
Treatment
Nonimmunosuppressive therapy is indicated for all patients with idiopathic MN
Patients with persistent proteinuria would benefit from using an ACE inhibitor or an
ARB
Patients with low risk of progression are usually not treated with immunosuppressive
therapy, since they have an excellent long-term prognosis and often undergo
spontaneous partial or complete remission
Patients with moderate and high risk of progression should be treated with
immunosuppressive therapy using cyclophosphamide-based or calcineurin inhibitor-
based regimens
Resistant patients (patients with moderate or high risk disease who fail an adequate
trial of treatment with both cyclophosphamide-based and calcineurin inhibitor-based
regimens) can be given a trial of rituximab
Secondary Nephrotic Syndrome

Diabetic Nephropathy
Diabetic nephropathy is the main cause of end-stage renal disease in many Western
countries
It develops within 10 to 20 years after onset of type 1 diabetes and within 5 to 10 years
after onset of type 2 diabetes
This condition occurs in 30 to 40% of patients with type 1 diabetes and in 10 to 20% of
patients with type 2 diabetes mellitus
Diabetic nephropathy is more prevalent in African American, Native Americans,
and Mexican Americans when compared with Caucasians. Other risk factors for the
development of diabetic nephropathy include family history of diabetes, higher systemic
blood pressure, poor glycemic control, smoking, older age and obesity
Clinical manifestations of diabetic nephropathy include albuminuria, less often hematuria,
and progressive chronic kidney disease
Microalbuminuria (also called high albuminuria) is defined as the excretion of 30 and
300 mg/d or between 30 and 300 mg/g creatinine in at least 2 of 3 consecutive urine
samples obtained within a 6-month period
Factors that can transiently cause microalbuminuria include exercise, fever, heart failure,
and poor glycemic control
Macroalbuminuria (also called very high albuminuria) is defined as urinary albumin
excretion above 300 mg/d or above 300 mg/g creatinine on a random urine sample
Annual screening for microalbuminuria is recommended for all diabetic patients
Microalbuminuria is a predictor for progression of nephropathy as well as for increased
cardiovascular disease in patients with type 1 and 2 diabetes
Pathology
Mesangial expansion
Glomerular basement membrane thickening
Glomerular sclerosis, which may have a nodular appearance (the Kimmelstiel-Wilson
lesion)
Treatment goals
Good glycemic control can prevent or slow the progression of diabetic nephropathy
Decrease protein excretion to less than 500 to 1,000 mg/d
Decrease the blood pressure to less than 130/80 mmHg and even lower levels for
patients with proteinuria more than 1,000 mg/d
ACE inhibitors and ARBs also have been shown to slow the progression of diabetic
kidney disease
Amyloidosis
Refers to a group of conditions characterized by extracellular deposition of fibrillary
structures composed of a variety of proteins, many of which circulate as constituents of
plasma
The major forms of amyloidosis include the AL (primary) and AA (secondary) amyloidosis

AL amyloidosis, the most common form in developed countries, is due to deposition of
protein derived from immunoglobulin light chain fragments
AL amyloidosis can occur alone or in association with multiple myeloma, Waldenstrms
macroglobulinemia or non-Hodgkin lymphoma
AA amyloidosis, the most common form in developing countries, is caused by deposition
of fragments of the acute phase reactant serum amyloid A
AA amyloidosis may develop secondary to chronic inflammatory states, such as chronic
infections, rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and
familial Mediterranean fever
Other types of amyloidosis include dialysis-related amyloidosis (accumulation of beta2-
microglobulin), hereditary amyloidosis, and age-related systemic amyloidosis
Clinical manifestations vary depending upon the type of amyloid and the distribution of
deposition
Renal manifestations include proteinuria (heavy proteinuria with glomerular involvement),
progressive chronic kidney disease and little proteinuria in patients with vascular deposits,
or less frequently, evidence of tubular dysfunction in patients with tubular deposition
(such as distal renal tubular acidosis, or nephrogenic diabetes insipidus)
Multiple Myeloma
Renal disease is common in multiple myeloma
Types of renal diseases can be classified by the primary site of injury
Glomerular disease caused by amyloidosis and light and/or heavy chain deposition
disease
Tubular disease: Light chain cast nephropathy (also known as myeloma kidney),
associated with distal or proximal tubular dysfunction
Interstitial disease due to plasma cell infiltration
Myeloma cast nephropathy
Is present in 40 to 50% of patients with multiple myeloma
Occurs in the presence of excess free light chains in the plasma and urine
Renal impairment results from direct tubular toxicity and from intratubular cast
formation in the distal tubules (these casts contain precipitated light chains and
Tamm-Horsfall mucoprotein, which is normally secreted by the tubular cells in the
thick ascending limb of the loop of Henle and constitutes the matrix of all urinary
casts)
Many patients develop acute kidney injury that may be caused by dehydration,
hypercalcemia, intravenous radiocontrast agents, or NSAIDs use
Treatment should include chemotherapy to decrease light chain production (e.g.,
bortezomib, thalidomide and dexamethasone), volume expansion, and maybe
plasmapheresis
HIV-associated Nephropathy
Renal disease is a common manifestation of HIV infection
The most common form of HIV-associated nephropathy (HIVAN) is a collapsing form of
focal segmental glomerulosclerosis, associated with severe cystic tubular lesions, leading
to chronic kidney disease
HIVAN usually is seen in African decent patients and is known to be a leading cause of
end-stage renal disease in this population
The pathogenesis of HIVAN is not well understood, but may involve direct viral infection
of glomerular endothelial, mesangial and tubular cells
Patients with HIVAN present with nephrotic syndrome, renal failure and rapid progression
to end-stage renal disease
The renal ultrasound shows large echogenic kidneys
Therapies that could slow the progression of HIVAN include HAART therapy and
angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). The
role of corticosteroids, cyclosporine or other immunosuppressants in HIVAN is uncertain
Other renal conditions associated with HIV infection include:
Membranous nephropathy, associated with concurrent infection with hepatitis B and
C infection or syphilis
Membranoproliferative glomerulonephritis, associated with concurrent hepatitis C
infection or mixed cryoglobulinemia
IgA nephropathy
A lupus-like, immune complex mediated glomerulonephritis
Interstitial nephritis, due cytomegalovirus infection or a reaction to a medication (e.g.,
TMP-SMX)
Amyloidosis due to chronic infection
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)
Nephritic Syndromes
IgA Nephropathy
IgA nephropathy is the most common cause of glomerulonephritis in most countries
IgA nephropathy is common in Asian and Caucasian population, and is rare in African
decent patients
Pathology
LM: Diffuse mesangial proliferation and matrix expansion with proliferative
glomerulonephritis and crescents in more severe disease
IF: Prominent, globular deposits of IgA (often accompanied by C3 and IgG) in the
mesangium
EM: Electron-dense deposits located predominantly in the mesangium
Clinical manifestations of IgA nephropathy are limited to the kidney. Mesangial IgA
deposition, which is often clinically silent, may also be associated with cirrhosis, celiac
disease, ankylosing spondylitis, or HIV infection. In addition, IgA nephropathy may also
be seen with other glomerular diseases, such as minimal change disease and Wegeners
granulomatosis
Gross hematuria, usually following an upper respiratory or gastrointestinal infection
Microscopic hematuria with or without proteinuria
Rarely, patients with IgA nephropathy can develop acute kidney injury with or
without oliguria, due to crescentic IgA nephropathy, or to gross hematuria causing
tubular occlusion by red cells
Treatment
Nonimmunosuppressive therapies with angiotensin converting enzyme (ACE)
inhibitors or angiotensin II receptor blockers (ARBs), and fish oil are indicated for
patients with isolated hematuria, minimal proteinuria (less than 1,000 mg/d) and
normal kidney function

Patients with more active or progressive disease (increasing serum creatinine level,
persistent proteinuria more than 1,000 mg/d, morphologic evidence of active
disease (proliferative or necrotizing glomerular changes) should be treated with
corticosteroid therapy
Combined immunosuppressive therapy can be given in patients with more severe
disease (rapidly progressive clinical course and/or histologic evidence of severe
active inflammation)
Membranoproliferative Glomerulonephritis
Membranoproliferative glomerulonephritis (MPGN) is characterized by diffuse proliferative
lesions and thickening of glomerular capillary walls as a result of immune complex
deposition, peripheral mesangial cell interposition, and duplication of GBMs
MPGN may be primary (idiopathic) or secondary to systemic autoimmune disorders such
as SLE or Sjgren syndrome, infections such as hepatitis C, or cryoglobulinemia
Clinical manifestations of MPGN include microscopic hematuria and proteinuria, nephrotic
syndrome, or severe glomerulonephritis with hypertension and rapidly deteriorating renal
function. The majority of patients develop hypocomplementemia (low C3)
MPGN is traditionally classified based upon electron microscopy (EM) findings as MPGN
types I, II, and III
MPGN type I involves the presence of immune deposits in the mesangium and
subendothelial space
MPGN type II or dense deposit disease (DDD) is characterized by dense ribbon-like
deposits along the basement membranes, tubules, and Bowman's capsule of the
kidneys
MPGN type III is similar to MPGN type I except that subepithelial deposits are noted
as well as subendothelial deposits
Treatment of idiopathic MPGN includes corticosteroids and other immunosuppressive
agents, antiplatelet agents or anticoagulants
Secondary MPGN associated with hepatitis C virus infection can be treated with
pegylated interferon-alfa 2a alone or in association with ribavirin
Poststreptococcal Glomerulonephritis
Typically develops after an incubation period of 2 weeks after throat infections and longer
(several weeks) after skin infections
The clinical findings vary from microscopic hematuria to the full-blown acute nephritic
syndrome (gross hematuria, proteinuria, edema, hypertension, and acute kidney injury)
Antistreptolysin O (ASO) antibody titers are increased in approximately 75% of patients
with poststreptococcal glomerulonephritis following throat infections, and 73% of post
impetigo cases have anti-DNAse B antibodies
Pathology
LM: Diffuse endocapillary glomerulonephritis with proliferation of mesangial and
endothelial cells
IF: Glomerular immune deposits of IgG and C3 distributed in a diffuse granular
pattern within the mesangium, and glomerular capillary walls
EM: Dome-shaped subepithelial electron-dense deposits/humps
Treatment is supportive and includes fluid and salt restriction, and diuretic therapy
Most patients, especially children, have an excellent outcome. Some patients with severe
glomerular damage develop persistent proteinuria and hypertension that require long-
term therapy
Lupus Nephritis (LN)
40 to 50% of patients with SLE develop renal abnormalities early in their course
Clinical manifestations include microhematuria, proteinuria, hypertension, and progressive
renal dysfunction
The ISN classification system divides glomerular disorders associated with SLE into 6
different classes based on kidney biopsy histopathology:
Class I: Minimal mesangial LN
Normal glomeruli by LM, but mesangial immune deposits by IF
Class II: Mesangial proliferative LN
Mesangial hypercellularity with mesangial immune deposits
Class III: Focal LN
III (A): Purely active lesions: Focal proliferative LN
III (A/C): Active and chronic lesions: Focal proliferative and sclerosing LN
III (C): Chronic inactive lesions with glomerular scars: Focal sclerosing LN
Class IV: Diffuse LN
IV-S (A) or IV-G (A): Purely active lesions: Diffuse segmental (S) or global (G)
proliferative LN
IV-S (C) or IV-G (C): Inactive with glomerular scars: Diffuse segmental of global
sclerosing LN
Class V: Membranous LN
Class VI: Advanced sclerosing LN
90% of glomeruli globally sclerosed without residual activity
Treatment
Class I and II disease is associated with excellent prognosis, and immunosuppressive
therapy in these patients is not indicated
The patients with active focal proliferative LP (ISN class IIIA and III A/C), active
diffuse proliferative LN (ISN class IV A and IV A/C), and membranous lupus (ISN
class V) are usually treated with immunosuppressive therapy
Anti-glomerular Basement Membrane Antibody Disease
Anti-GBM antibody disease is caused by antibodies to a noncollagenous (NC1) domain of
type IV collagen, which is highly expressed in the GBM and alveoli
The pulmonary-kidney presentation of anti-GBM antibody disease, known as Goodpasture
syndrome, causes pulmonary hemorrhage with rapidly progressive glomerulonephritis
40% of patients with anti-GBM antibody disease also have ANCA-associated vasculitis
Pathology
LM: Crescentic glomerulonephritis
IF: Linear deposition of IgG along the glomerular capillaries and occasionally the distal
tubules
Treatment includes plasmapheresis in conjunction with cyclophosphamide and
prednisone
Small-vessel Vasculitis
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides include
granulomatosis with polyangiitis (Wegeners), which can be abbreviated as GPA,
microscopic polyangiitis (MPA), the Churg-Strauss syndrome (CSS) and renal limited
vasculitis

Antiproteinase-3 (anti-PR3) antibodies are usually detected in patients with Wegener,
whereas anti-myeloperoxidase (anti-MPO) antibodies are usually found in those with
microscopic polyangiitis
Renal histology shows the presence of a focal necrotizing, often crescentic, pauci-immune
glomerulonephritis
Treatment includes immunosuppressive therapy, such as cyclophosphamide or rituximab,
and glucocorticoids
Plasma exchange is indicated in the following conditions:
Patients with GPA or MPA who have anti-GBM antibodies as well as ANCA
Pulmonary hemorrhage
Patients who have advanced renal dysfunction at presentation, as defined by a serum
creatinine level above 5.7 mg/dL and/or dialysis dependence
Thrombotic Microangiopathy
Thrombotic microangiopathy is characterized by an acute syndrome of microangiopathic
hemolytic anemia, thrombocytopenia, and variable signs of organ injury due to platelet
thrombosis in the microcirculation
Thrombotic microangiopathy may manifest as thrombotic thrombocytopenic purpura
(TTP) or hemolytic-uremic syndrome (HUS)
Most patients with TTP have a severe deficiency of ADAMTS13
ADAMTS13 is a protease responsible for cleaving unusually large von Willebrand
factor (ULVWf) multimers. Persistence of these multimers in patients with ADAMTS13
deficiency is thought to promote platelet agglutination and thrombus formation in the
microvasculature
HUS is usually caused either by infection with Shiga toxinproducing Escherichia coli or
by complement dysregulation caused by genetic mutations
Patients with idiopathic TTP-HUS are treated with plasma exchanges
SUGGESTED READINGs
1. Bagshaw SM, Haase M, Hasse-Fielitz A, Bennett M, Devarajan P, Bellomo R. A Prospective
Evaluation of Urine Microscopy in Septic and Non-septic Acute Kidney Injury. Nephrology Dialysis
Transplantation. Vol 27(2), p582-588.
2. Bevc S, Hojs R, Ekart R, Zavrsnik M, Gorenjak M, Puklavec L. Simple Cystatin C Forumla for
Estimation of Glomerular Filtration Rate in Overweight Patients with Diabetes Mellitus Type 2 and
Chronic Kidney Disease. Experimental Diabetes Research. Vol 2012.
3. Molitoris BA. Measuring Glomerular Filtration Rate in Acute Kidney Injury: Yes, But Not Yet. Critical
Care. 2012, 16:158.
4. Daugirdas JT, Leypoldt JK, Akonur A, Greene T, Depner TA, the FHN Trial Group. Improved Equation
for Estimating Single-pool Kt/V at Higher Dialysis Fequencies. Nephrology Dialysis Transplantation.
2012.
5. Reidenberg MM. Early Research on Renal Function and Drug Action. The Journal of Clinical
Pharmacology. 2011.
6. Kovesdy CP. Significance of Hypo- and Hypernatremia in Chronic Kidney Disease. Nephrology
Dialysis Transplantation. Vol 27(3):891-898.
7. Atta MG. Dilutional Hyponatremia in Cirrhosis: Updating the Standard of Care. Nephrology Times.
April 2012, 5(4), p12-14.
8. Franco MCP, Oliveira V, Ponzio B, Rangel M, Palomino Z, Gil FZ. Influence of Birth Weight on
the Renal Development and Kidney Diseases in Adulthood: Experimental and Clinical Evidence.
International Journal of Nephrology. Vol 2012.
9. Thomas W, Griffiths M, Nelson-Piercy C, Sinnamon K. Pre-eclampsia Before 20-week Gestation:
Diagnosis, Investifation and Management. Clinical Kidney Journal. Oct 2012.
10. Bushinsky DA, Wolf MS. Mineral Metabolism: Confusion to Clarity. Current Opinion in Nephrology &
Hypertension. Jul 2012, Vol 21(4), p353-354.
11. Bushinsky DA. Clinical Application of Calcium Modeling in Patients With Chronic Kidney Disease.
Nephrol Dial Transplant (2012) 27:10-13.
12. Riggs MM, Peterson MC, Gastonguay MR. Multiscale Physiology-based Modeling of Mineral Bone
Disorder in Patients With Impaired Kidney Function. The Journal of Clinical Pharmacology. 2012.
13. Dash A, Fatima H, Grewal M, Galphin C, Paueksakon P. Renal Injury Due to Anti-glomerula Basement
Membrane Antibody-mediated Glomerulonephritis Without Circulation Antibody. Clin Kidney J
(2012) 0:1-4.
14. Oda T, Yoshizawa N, Yamakami K, Sakurai Y, Takechi H, Yamamoto K, Oshima N, Kumagai H. The
Role of Nephritis-associated Plasmin Receptor in Glomerulonephritis Associated With Streptococcal
Infection. Journal of Biomedicine and Biotechnology. 2012.
15. Shah S, Weber-Shrikant E, Panesar M. Discontinuation of Antiretroviral Therapy Causing Progression
to End-stage Renal Disease in an HIV Patient Diagnosed With Immune Complex 'Lupus-like'
Glomerulonephritis. Clinical Kidney Journal. Vol 5(3) p276-278.
16. Villaverde RV, Darioli V, Hirschel B, McKee TA, Lobrinus JA, Moll S. Kidney Light Chain Disease in
Patients With the Acquired Immunodeficiency Syndrome. Clinical Kidney Journal. Vol 5(1)p59-62.

NOTES
NOTES

10 Hematology
Wasseem El-Aneed, MD
C o n t e n t s
10.1 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
10.2 HEMATOPOIETIC STEM CELLS AND THEIR

DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
10.3 TRANSFUSION MEDICINE . . . . . . . . . . . . . . . . . . . . . . . 115
10.4 HEMATOLOGIC ISSUES OF PREGNANCY . . . . . . . 116
10.5 MULTIPLE MYELOMA AND RELATED DISORDERS . . 117
HEMATOLOGY 109
10.1 INTRODUCTION
The hematology chapter focuses on high-yield information regarding 4 important topics: Any
topics that are not covered in this chapter can be found throughout the study guide, as hematol-
ogy may be viewed as a cross-content category.
10.2 HEMATOPOIETIC STEM CELLS (HSCs) And Their DISORDERS

Blood Cell Production
RBC: Regulated by Erythropoietin
Includes maturation of pluripotent stem cellthe cells lose their nucleus (reticulocyte) and
then RNA (mature RBC), and live 120 days after (ingested by macrophages in the spleen)
The process is controlled by erythropoietin: Produced by the kidney, increased with
impaired oxygen delivery to the kidney (ex.: anemia, renal artery stenosis)
WBC
Pluripotent stem cells that differentiate in myeloid cells (eventually granulocytes,
monocytes, erythrocytes and megakaryocytes) and lymphocytic cells (B- or T-cells).
Beside erythropoietin, there are numerous hematopoietic growth factors that affect this
process
Platelets: Thrombopoietin stimulate megakaryopoiesisfragmentation of megakaryocyte
produces platelets. Thrombopoietin is produced by the liver and its synthesis is increased
with inflammation and specifically by interleukin 6
Bone Marrow Failure

Congenital (in childhood) or acquired (drugs, toxins, infections, or idiopathic)
May affect 1 cell-line or cause pancytopenia
Neutropenia
ANC <1500/microL defines neutropenia for adults
Severe with <500/microLwhen ANC <200: No inflammatory response
Causes
Production
Drug induced: Alkylating agents (cyclophosphamide), antimetabolites
(methotrexate, 6-mercaptopurine), other agents such as chloramphenicol,
penicillins, sulfonamides antithyroid drugs
Myelofibrosis
Infection: HIV, viral hepatitis, infectious mononucleosis
Nutritional deficiency: B12, folate
Peripheral destruction
Antineutrophil antibodies, splenic or lung trapping
Drugs: a-methyldopa, phenylbutazone, some phenothiazines
Autoimmune disorders: Rheumatoid arthritis, lupus erythematosus
Course and diagnosis
Likely acquired and self-limited in adults, bone marrow aspirate: Hypocellular in
drug-induced and postinfectious neutropenia or early onset of aplastic anemia.
Hypercellular: May indicate peripheral destruction
Dysplastic morphologic findings suggest myelodysplasia

Megaloblastic anemia and thrombocytopenia suggest the presence of vitamin B12 or
folate deficiency
Note: Cyclic neutropenialifelong history of neutrophil counts that decrease to zero
(or near zero) for a few days once every 3 weeks and then rebound
Treatment
Stopping the offending agent or treating the causative agent
Fever in these patients should promote immediate administration of antibiotics (to
covet staphylococci), antifungal, adding Gram Negative coverage can be added
when fever doesnt resolve in 48 hours. Colony-stimulating agents should be tried in
critically ill patients
Aplastic Anemia
Definition: Pancytopenia with bone marrow hypocellularity.
Epidemiology
Men and women are affected with equal frequency
Major peak in 20s and a second rise in older adults
Etiology
Most cases of aplastic anemia are idiopathic up to 70%
Other causes include:
Radiation: Radiation damages DNA
Chemicals: Benzene is a notorious cause of bone marrow failure (benzene
is associated with aplastic anemia, acute leukemia, and blood and marrow
abnormalities). Benzene is no longer available as a household solvent
Drugs: Especially psychotropics, penicillamine, allopurinol, and gold
Infections: Parvovirus B19, HIV, CMV, EBV
Pregnancy: Very rare, resolve with delivery or abortion
Paroxysmal nocturnal hemoglobinuria: An acquired mutation in the PIG-A gene
clinically manifested as hemolytic anemia and venous thrombosis (intraabdominal
and cerebral), diagnosed with flow cytometry ( CD55 & CD59). These patients
are likely to develop frank marrow aplasia and pancytopenia; if diagnosis of
aplastic anemia comes first, a hemolytic PNH may develop years after recovery of
blood counts
Treatment
Allogeneic bone marrow transplantation (for young patients)
Immunosuppressants in combination with steroids and cyclosporine
Correcting the underlying disorder - thymectomy if thymoma is found
Supportive care (transfusion, antibiotics)
Note: Patients are at risk of developing acute leukemia
Pure Red Cell Aplasia
Rare disease, likely idiopathic, may occur in association with thymomas, MDS, SLE
Another possible cause is development of cross-reacting antibodies that attack
erythrocytes precursors in patients receiving recombinant erythropoietin
Treatment is directed as for aplastic anemia, IVIG is indicated when Parvovirus is detected
Myelodysplastic Syndromes
Group of disorders characterized by:
Ineffective blood cell production
Variable progression to acute leukemia
HEMATOLOGY 111
Most of the patients are >60 years old
Idiopathic or related to alkylating agents, radiation, or benzene
Clinically presented with symptoms related to pancytopenia (weakness, infection, bleeding)
Macrocytic anemia is the most common presentation
Diagnosis: Macrocytosis, hypergranular WBC and blasts may be seen, PLTs are giant. Bone
marrow biopsy: Hypercellular
Note: If >20% blasts present in peripheral blood, then the diagnosis is AML
Note: Deletion of chromosome 5q or 20q has favorable prognosis
Treatment
Bone marrow transplant in young patients
Chemotherapy with demethylating agents like azacitidine and decitabine
Supportive therapy
Growth factors have been used with variable response
5q disease: Generally responds to Lenalidomide
Myeloproliferative Disorders
Definition: Clonal malignancy that results from clonal expansion of multipotent HSCs, in which
the regulation of cells proliferation is impaired. There are 4 major types:
1. Essential thrombocythemia
2. Polycythemia vera
3. Chronic myeloid leukemia (CML)
4. Myelofibrosis
Essential Thrombocythemia
PLT >600,000 with normal CBC counting
Patients are at risk of thrombosis (venous and arterial) and hemorrhage. Life expectancy
may not be affected in majority of patients
Patients are likely in the 5th or 6th decade
Symptoms: Bleeding and splenomegaly
Diagnosis
Ht >60%
Mainly by excluding secondary erythrocytosis (normal to low erythropoietin)
The JAK2 mutation is present in more than 90% of the patients
Splenomegaly
Other findings will be helpful like PLT >400,000 and neutrophils >10,000
Treatment
Phlebotomy to Ht <45% found to reduce mortality though it may increase risk of
thrombosisgive ASA
Other supportive treatments include hydroxyurea (to keep PLT <400,000),
allopurinol, low dose ASA
Prognosis
Depends on leukemic transformation and thrombosis/bleeding events
Chronic Myeloid Leukemia (CML)
Definition: Myeloproliferative disorder characterized by overproduction of myeloid cells.
Present with patients >50 years old
Signs and symptoms
Fatigue, night sweats, and low-grade fever

Splenomegaly
Blurred vision, respiratory distress and TIA/CVA likely related to leukostasis. Priapism
can happen but is rare
Sternal tenderness
May have lymphadenopathy
Note: With symptoms related to leukostasisWBC count is >250,000
Diagnosis
Laboratory tests
WBC 150,000/mcL or more
Hematocrit is usually normal at presentation, RBC with normal morphology, PLT
normal to elevated, blasts usually <5%
Basophilia and eosinophilia may be present
Bone marrow aspirate and biopsy (not necessary for diagnosisdone for prognosis):
Hypercellular, with left-shifted myelopoiesis
Cytogenetics in bone marrow show Philadelphia chromosome
When blasts >20% of bone marrow blast phase of CML
The diagnosis is confirmed by finding BCR-ABL gene in peripheral blood
Philadelphia chromosome: Chromosomal translocation t(9;22), produces fusion
protein BCR-ABL, found in 90 to 95% of CML. Treatment is directed against this gene
product
Treatment
Treatment is an emergency when symptomatic leukocytosis occurs
Imatinib mesylate (Gleevec): Targets the gene product of Philadelphia chromosome;
BCR-ABL induces apoptosis in cells expressing BCR-ABL
Dasatinib and nilotinib are other tyrosine kinase inhibitors that are used for imatinib-
resistant CML
Allogeneic transplantation is recommended if there is suboptimal response and it is
the only curative treatment available
Note: CML can be classified by blast percentage into chronic (<10%), accelerated (10
to 20%), or blastic (>20%)
Myelofibrosis
Definition: Chronic myeloproliferative disorder characterized by overproduction of atypical
megakaryocytes that stimulate a non-clonal proliferation of fibroblasts.
Affects adults >50 years old
Signs and symptoms
Fatigue due to anemia
Splenomegaly
Bleeding and bone pain
Liver is enlarged in more than 50% of cases
Thrombocytopenia leads to bleedinghematopoiesis in the liver leads to portal
hypertension with ascites
Tests
CBC: Pancytopenia
Smear: The typical teardrop RBC with nucleated RBC
Bone marrow aspirate: Typically dry (no aspirate can be obtained). Biopsy: Fibrosis
HEMATOLOGY 113
Treatment
Supportive: Transfusions, splenectomy, and hydroxyurea
The only curative treatment is allogeneic bone marrow transplant
Prognosis
Median survival is only 5 years. Severe anemia on presentation indicates poor
prognosis
Acute Myeloid Leukemia (AML)

Definition: Clonal disorder of early myeloid cells.
Affects adults age >65 yearsmay follow MDS
Signs and symptoms
Fatigue, easy bruising
Mucosal bleeding
Fever and infection
Note: Lymphadenopathy and splenomegaly, if present, suggest an alternative diagnosis
Tests and diagnosis
Initial laboratory findings usually show leukocytosis and circulating blasts, anemia, and
thrombocytopenia
Auer rods (eosinophilic needle shaped crystals) inside peripheral blood cells are
diagnostic
Bone marrow blasts >20%
Cytogenetics and karyotype for classification: t(8;21), t(15;17) have favorable prognosis
Classification
M0: No differentiation
M1: Myeloid without maturation
M2: Myeloid with maturation
M3: Promyelocytic leukemia t(15;17)peroxidase stain intensely positive
M4: Myelomonocytic leukemia
M5: Monocytic, associated with DIC
M6: Erythroleukemia
M7: Megakaryoblastic
Treatment
Supportive: Transfusion, antibiotics for fever, hydration and allopurinol for tumor lysis
prophylaxis
Hydroxyurea or leukapheresis if leukostasis presents
Induction chemotherapy: Cytosine and arabinoside (ara-C) and daunorubicin
Consolidation therapy: Usually with higher dose of (ara-C)
Above treatment achieve about 50% remission
Bone marrow transplant: For patients <60 years old
Acute Lymphoblastic Leukemia (ALL)

Definition: Clonal disorder of early lymphocytic precursor (B or T).
ALL is a disease that affects children (under 20). Another peak in the 6th decade (adult
ALL is more aggressive)

Signs and symptoms: Similar to AML
Signs of anemia, thrombocytopenia
Hepatosplenomegaly
Lymphadenopathy
CNS involvement is common
Tests
As with AML, circulating blasts are key, B-cell ALL (75%) is more common than T-cell
Lymphocytosis, neutropenia, anemia, and thrombocytopenia
LP (done for AML only if CNS symptom presents)
Bone marrow aspirate and biopsy and flow cytometry
Treatment
Induction: Prednisone, vincristine, anthracyclines, L-asparaginase, 6-mercaptopurine,
and high-dose cytarabine. Consolidation: High-dose cytarabine. Maintenance:
6-mercaptopurine and methotrexate
CNS prophylaxis consisting: Intrathecal chemotherapy with or without cranial
irradiation should always be given
Note: Philadelphia chromosome carries unfavorable prognosis in ALL
10.3 TRANSFUSION MEDICINE

General Considerations
Whole blood transfusion is rarely done
1 unit of PRBC should increase the Hg by 1g/dL
Platelets are generally infused for thrombocytopenia + bleeding, unless PLT <10,000,
50,000 is needed for procedures
WBC transfusion is rarely used; instead Granulocyte colony-stimulating factor is used
FFP coagulation factors (ex.: Reverse warfarin effect)
Cryoprecipitate fibrinogen (ex.: DIC)
What is alloimmunization?
Alloimmunization means forming antibodies to transfused RBC antigens, usually
happens in 10% of transfused patients and logically this increases with the number
of units infused. As a result, development of delayed hemolytic transfusion reactions
occurs. Alloimmunization is minimized by ABO/Rh blood transfusion compatibility
Transfusion Reactions
Acute Hemolytic Transfusion Reaction
ABO incompatibility (medical emergency), within minutes to hours
Symptoms: Chills, backache, tachypnea, hypotension
Stop transfusion; send the bag for type and cross, vigorous hydration
Labs: Coombs, Hg, bilirubin, HDL, haptoglobin
Delayed Hemolytic Transfusion Reaction
Rh incompatibility
Happens a week after transfusion
Symptoms are mild including fever and elevated unconjugated bilirubin. No treatment is
needed
HEMATOLOGY 115
Allergic Reaction
Causes urticaria and possible bronchospasm
Seen in IgA deficient patients (they form anti IgA-antibodies)should receive transfusion
from IgA-deficient donors
Febrile Nonhemolytic Reaction
The most common reactionnonhemolytic reaction to the transfused WBCtreat with
acetaminophen and diphenhydramine. Leukocyte depleted units can be used to minimize
this reaction
Acute Lung Injury
Respiratory distress typically 1 to 2 hours (up to 6 hours) after transfusion of FFP
Caused by donor antibodies to recipient leukocyte
Treat supportively (including intubation. Recovery is expected in 4 days)
Other Considerations
Transfusion dependant thalassemia patients develop hemosiderosis. Diagnosed with
elevated ferritinliver biopsy may be necessary. Treat with chelating agents
CMV negative blood should be given to transplant patients
GVH reaction: In immunocompromised patients, lymphocytes in donated blood attack the
host tissues
10.4 HEMATOLOGIC ISSUES OF PREGNANCY

Gestational Anemia
Hg during pregnancy drops because of the increase of plasma volume without a similar
increase in the erythrocyte mass
Anemia in pregnancy is defined as hemoglobin less than 11.0 g/dL (except in the 2nd
trimesterthe cut-off is 10.5)
Iron Deficiency Anemia

Iron requirements increase during pregnancy to meet fetal/maternal demand. Daily iron
ingestion of 30 mg of elemental iron is needed in the 2nd and 3rd trimester of pregnancy
Usual findings of hypochromic/microcytic RBC may not be evident initially but iron studies
confirm the diagnosis
Treat with 60-100 mg of elemental iron
Vitamin C enhances iron absorption
Folic Acid Deficiency Anemia

Daily need of folic acid increases during pregnancy, 0.4 mg of daily folate is recommended
Folic acid is recommended in the periconceptional period: reduce the risk of neural tube
defect
Increase MCV and hypersegmented neutrophils. Though macrocytosis might be masked by
accompanied iron deficiency anemia
Treat with 1 mg folic acid daily
Sickle Cell Disease in Pregnancy

Crisis becomes more painful, there is increased risk of infection

Refer to maternal fetal medicine specialist and a hematologist
Transfusion is controversial
Hydroxyurea is contraindicated and ideally should be stopped three month before
conception
Sickle cell trait patients have no increase of pregnancy incidents
Thrombocytopenia in Pregnancy
Mild thrombocytopenia is generally benign and doesnt require further investigation. Usually
develops late in the term of pregnancy
Most common cause is preeclampsia, HEELP syndrome should be excluded
ITP might be difficult to diagnose and generally a Dx of exclusion
ITP should be treated with prednisone when PLT count < 50K, watch for gestational
diabetes
TTP is treated with plasmapheresis
Thrombophilia, Venous Thromboembolism, and Pregnancy

1 in 1000 pregnancies
Estrogen stimulates coagulation factors and decreases activity of the fibrinolytics
Almost 50% of pregnant women who are diagnosed with DVT during pregnancy have
inherited thrombophilic defect
Diagnosis of DVT is no difference from non-pregnant patients
Unfracture heparin and LMWH can be used during pregnancy (both has no teratogenic
effect and cant cross placenta)
Heparin, bed rest, and analgesia are the treatments of DVT, transition to warfarin is delayed
to postpartum stage. Treatment should be continued 6-12 weeks postpartum
10.5 MULTIPLE MYELOMA AND RELATED DISORDERS

Multiple Myeloma
Neoplasm of plasma cells, produce M protein
Clinically manifest as:
Anemia due to bone marrow involvement
Bone pain from invading bone marrow and release of osteoclast activating factor (thus
lytic lesions and increased calcium)
Recurrent infection secondary to immunoglobulin suppression (total immunoglobulin is
elevated)
Renal failure, multifactorial (increase Ca, toxic effect of light chains, amyloidosis, type II
RTA may develop)
Hyperviscosity
Dx
SPEP and UPEP looking for M spike, if present serum viscosity should be done
Skeletal survey to identify lytic lesions
Marrow biopsy to confirm diagnosis
Note: Hyperviscosity syndrome clinically: blurred vision, fatigue, mucosal bleeding,
headache, heart failure, and AMS. Should be treated with plasmapheresis
HEMATOLOGY 117
Table 10.1: You May Depend on the WHO Criteria for Diagnosis
(One major and one minor or three minor criteria)
Major Criteria Minor Criteria
Plasmacytoma on tissue biopsy Bone marrow clonal plasma cells 10%-30%
Bone marrow clonal plasma cells >30% M-protein less than as mentioned in major criteria
High M protein (IgG >3.5 g/dL [35 g/L], IgA >2.0 g/ Lytic bone lesions
dL [20 g/L], Bence-Jones proteinuria >1.0 g/24 h) Immunoglobulins to <50% of normal
Note that b2-microglubulin predict survival

There are two different systems for staging
ISS
Stage I b2-microglubulin < 3.5 & albumin > 3.5
Stage III b2-microglubulin > 5.5
Stage II when doesnt fit neither of above
Durie-Salmon Criteria
Stage I Hb > 10 mg/dL & Ca 12 mg/dL & < 1 lytic lesion & IgG < 5g/L or light
chains (urine) < 4g/24h
Stage III Hb <8.5 or Ca > 12 or > 5 lytic lesions or IgG > 7g/L or urine light change >
12g/24h
Tx
Monitor for stage I
Chemo for non-transplant eligible
Transplant eligible should receive high dose chemo followed by stem cell transplant.
Plasmacytomas can be treated by local radiation
Monoclonal Gammopathy of Undetermined Significance

Common, 1% of population, up to 15% elderly >15-years-old. Basically it the presence of M
spike without a criteria to make Dx of MM. Likely to be discovered by routine labs
Major differences from MM include absence of bony lesions, M protein if found less than
3 g/dL and bone biopsy with less than 10% of plasma cells. There is no increase risk of
infection or renal failure (no Bence-Jones proteinuria)
No Tx necessary, observe every six month with SPEP, UPEP, CBC, Cr and Ca to watch for
possible progression to MM
Immunoglobulin Light-chain (AL) Amyloidosis

Immunoglobulin light chain or a fragment of a light chain (produced by the clonal plasma
cell and considered the insoluble fibrils that cause amyloidosis with extracellular deposition)
Tissue biopsy demonstrates apple-green birefringence when stained with Congo red and
viewed under a polarizing microscope
Treatment with prednisone and melphalan, definitive treatment should be directed towards
MM
Waldenstrom Macroglobulinemia
Bone marrow infiltrates with neoplastic B-cells that secrete monoclonal IgM
Symptoms include anemia (from bone marrow infiltrate), hyperviscosity secondary to high
levels of IgM, lymphadenopathy, splenomegaly and hepatomegaly. Organomegaly and
absence of bone lytic lesions help to differentiate it from MM
SPEP shows a spike of IGM, bone marrow biopsy confirms the diagnosis

SUGGESTED READINGs
1. Bagher KM, Sadeh M, Hekmati Moghaddam S. Hematologic Indices, Inflammatory Markers,
Symptoms and Routine Diagnostic Tests in Childhood Brucellosis. Iranian Journal of Pediatric
Hematology Oncology. 2(1), 2012.
2. Kurugol Z, Onen SS, Koturoglu G. Severe Hemolytic Anemia Associated With Mild Pneumonia
Caused by Mycoplasma pneumonia. Case Reports in Medicine. Vol. 2012, p3.
3. Sugimoto-Sekiguchi H, Tashior H, Shirasaki R, Arai T, Yamamot T, Oka Y, Akiyama N, Kawasugi K,
Shirafuji N. Colonic EBV-associated Lymphophoproliferative Disorders in a Patient Treated With
Rabbit Antithymocyte Globulin for Aplastic Anemia. Case Reports in Gastrointestinal Medicine. Vol
2012, p 6.
4. Alwazeer MR, Imran H, Wilson F, Siddiqui AH. Pancytopenia After Packed Red Blood Cell
Transfusion for Sever Iron Deficiency Anemia in a Toddler. Journal of Pediatric Hematology/
Oncology. Vol 34(3), p125-126, 2012.
5. Aats EO, van Wageningen B, Janssen IMC, Berends FJ. Prevalence of Anemia and Related
Deficiencies in the First Year Following Laparoscopic Gastric Bypass for Morbid Obesity. Journal of
Obesity. Vol 2012, p7.
6. Javazon EH, Radhi M, Gangadharan B, Perry J, Archer D. Hematopoietic Stem Cell Function in a
Murine Model of Sickle Cell Disease. Anemia. Vol 2012, p9.
7. Karlsson T. Iron-restricted Erythropoiesis in a Population of Elderly Hospitalized Anemic Patients.
Open Journal of Blood Diseases, 2012, 2, 30-33.
8. Lazarchick J. Update on Anemia and Neutropenia in Copper Deficiency. Current Opinion in
Hematology. Jan 2012, Vol 19(1), p58-60.
9. Steinberg M, Forge BG, Higgs DR, Weatherall DJ. Disorders of Hemoglobin: Genetics,
Pathophysiology, and Clinical Management. J R Soc Med. 2012, Nov; 94(11), p602-603.
10. Kinsella F. Drug-induced Platelet Disorders. Adverse Drug Reaction Bulletin. Feb 2012, Issue 272,
p1047-1050.
11. Midaglia L, Rodriguez Ruiz M, Munoz-Garcia, D. Severe Haematological Complications During
Treatment With Natalizumab. Multiple Sclerosis Journal. 2011.
12. Stonwell SR, Winkler AM, Maier CL, Arthur CM, Smith NH, Girard-Pierce KR, Cummings RD, Zimring
JC, Henderickson JE. Initiation and Regulation of Complement During Hemolytic Transfusion
Reactions. Clinical and Developmental Immunology. Vol 2012(2012).
13. Miraflor E, Yeung L, Strumwasser A, Liu TH, Victorino GP. Emergency Uncrossmatched Transfusion
Effect on Blood Type Alloantibodies. Journal of Trauma and Acute Care Surgery. Jan 2012, 72(1),
p48-53.
14. Jardim DL, Rodrigues CA, Novis YAS, Rocha VG, Hoff PM. Oxaliplatin-related Thrombocytopenia.
Annals of Oncology. Vol 23(8), p1937-1942.
15. Stavropoulos-Giokas C, Dinou A, Papassavas A. The Role of HLA in Cord Blood Transplantation.
Bone Marrow Research. Vol 2012(2012).
16. Mehta P. Stem Cells and Cancer Stem Cells: Therapeutic Applications in Disease and Injury, Vol. 2.
JAMA 2012;307(10):1087.
17. Mavroudi I, Papadaki HA. Genetic Associations in Acquired Immune-Mediated Bone Marrow
Failure Syndromes: Insights in Aplastic Anemia and Chronic Idiopathic Neutropenia. Clinical and
Developmental Immunology. Vol 2012.
HEMATOLOGY 119
NOTES

11 Medical Oncology
Mustafa Hyder, MD
Genevieve Moyer, MD
Iba Al Wohoush, MD
Chukwuemeka Charles Ezeoke MD, LT (USN)
C o n t e n t s
11.1 CANCER RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
11.2 LUNG CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
11.3 GENITOURINARY CANCER . . . . . . . . . . . . . . . . . . . . . 126
11.4 ONCOLOGIC EMERGENCIES. . . . . . . . . . . . . . . . . . . . 131
11.5 LYMPHOID MALIGNANCIES . . . . . . . . . . . . . . . . . . . . 135
11.6 BREAST CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
11.7 OVARIAN CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
11.7 CERVICAL CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . .140
11.8 CANCER OF UNKNOWN PRIMARY SITE . . . . . . . . 141
11.9 EFFECTS OF CANCER AND CANCER THERAPY. . 141
11.10 GASTROINTESTINAL MALIGNANCIES . . . . . . . . . . 142
MEDICAL ONCOLOGY119
11.1 CANCER RISK
Environmental Risk Factors
Chemical carcinogens can lead to cancer either by DNA damage (genotoxic) or by a variety
of non-genotoxic mechanisms
Table 11.1: Genotoxic and Non-genotoxic Mechanisms

Genotoxic Non-genotoxic
Nicotine derived nitrosamines Ethanol
Polycyclic aromatic hydrocarbons (fuel, tobacco, Tetradecanoyl phorbol acetate (horticulture,
charbroiled food) rubber, gasoline)
Aromatic amines (dyes) Diethylstilbestrol
Fungal toxins (aflatoxin) Arsenic
Sunlight Asbestos
Dioxins (herbicides)
Genetic Susceptibility Risk Factors

Knudson two-hit hypothesis: Multiple genetic defects are required for a cell to develop
malignant potential
DNA of normal cells contains both oncogenes (genes that promote tumor formation) and
tumor-suppressor genes
Both alleles must be mutated to affect expression of that gene
In familial cancer syndromes, individuals inherit a defect to 1 allele. These individuals are at
an increased risk for developing cancer because they only require 1 acquired genetic insult
as opposed to 2 before the cascade of malignant transformation begins
Table 11.2: Familial Cancer Syndromes

Syndrome Tumor(s) Gene(s)
Ataxia telangiectasia Breast ATM
Autoimmune Lymphoma FAS
lymphoproliferative syndrome
Bloom Several BLM
Cowden Breast, thyroid PTEN
Familial adenomatous polyposis Intestinal, colorectal APC
Familial melanoma Melanoma, pancreatic
Familial Wilms tumor Kidney WT1
Hereditary breast/ovarian Breast, ovarian, colon, prostate BRCA1, BRCA2
Hereditary diffuse gastric cancer Stomach
Hereditary multiple exostoses Exostoses, chondrosarcoma EXT1, EXT2
Hereditary prostate cancer Prostate HPC1

Table 11.2: Familial Cancer Syndromes (cont.)
Syndrome Tumor(s) Gene(s)
Hereditary retinoblastoma Retinoblastoma, osteosarcoma RB1
Hereditary nonpolyposis colon Colon, endometrial, ovarian, stomach,
cancer small bowel, ureter
Hereditary papillary renal Kidney MET
carcinoma
Juvenile polyposis GI, pancreatic SMAD4
Li-Fraumeni Sarcoma, breast TP53
Multiple endocrine neoplasia, Pituitary, parathyroid, pancreas MEN1
type 1
Multiple endocrine neoplasia, Medullary thyroid, pheochromocytoma RET
type 2
Neurofibromatosis, type 1 Neurofibroma, neurofibrosarcoma NF1
Neurofibromatosis, type 2 Vestibular schwannoma, meningioma NF2
Nevoid basal cell carcinoma Basal cell carcinoma, medulloblastoma PTCH
syndrome (Gorlin syndrome)
Tuberous sclerosis Angiofibroma, renal angiomyolipoma TSC1, TSC2
Von Hippel-Lindau Kidney, cerebellum, pheochromocytoma VHL
Breast Cancer
Familial cancer syndromes associated with breast cancer:
Those associated with BRCA1/BRCA2 mutations
Li-Fraumeni syndrome
Mutation in TP53 gene
p53 protein is the guardian of the genome and mutations can lead to a wide
spectrum of neoplasms occurring at a young age
Autosomal dominant
Cancer occurs in 90% of women before 60 years
Management: Genetic counseling and testing to confirm.
Diagnosis : 3 criteria: diagnosis of sarcoma at a young age (below 45) + cancer
diagnosis in a 1st degree relative < 45 years old + cancer diagnosis in ANOTHER
1st degree relative < 45 years old
Cowden syndrome
High risk of benign fibrocystic breast disease
25 to 50% lifetime risk of breast cancer
Mutations in PTEN, tumor suppressor gene
Manifestations : predisposition to endometrial, breast, thyroid carcinoma with skin
tumors, macrocephaly, intestinal polyps, and benign skin tumors
Offspring of individual with germline mutation has 50% chance of inheriting mutation
Hereditary Colorectal Cancer Syndromes
Main high risk colorectal cancer syndromes:
Lynch syndrome (hereditary nonpolyposis colorectal cancer)
Polyposis syndromes
MEDICAL ONCOLOGY121
Classical familial adenomatous polyposis
Attenuated familial adenomatous polyposis
Peutz-Jeghers syndrome
Juvenile polyposis
MUTYH-associated polyposis
Lynch syndrome
Most common genetically determined colon cancer risk factor
2 to 4% all CRC cases
Germline mutation in DNA mismatch repair gene
Microsatellite instability
80% lifetime risk of developing colorectal cancer (mean age of diagnosis is 44 years)
The Amsterdam criteria developed in 1990 was previously used, but was replaced
by the Bethesda criteria (developed in 1996) due to its low sensitivity in detection
(about 50%)
The Bethesda criteria is 89% sensitive, and 80 % specific , and recommends that
patients with colon cancer should be tested for microsatellite instability and should
further be tested for germline MMR
Most common extra-colonic cancer in Lynch is endometrial cancer
Classical and attenuated FAP
Autosomal dominant
Germline mutation in APC gene
Less than 1% of all CRC
>100 polyps on colonoscopy is diagnostic of classical FAP
Lifetime cancer risk approaches 100% by age 50
Attenuated typically has later onset and <100 polyps
Lifetime risk 70% by age 80
Prophylactic proctocolectomy in 2nd decade is recommended
Risk Assessment and Genetic Counseling

Familial Breast Cancer Syndromes
Criteria for further genetic risk evaluation in person affected with breast cancer
Early-age-onset (<50)
Triple negative cancer (ER, PR, HER2)
2 breast cancer primaries
1 or more 1st, 2nd, or 3rd degree relatives with breast cancer at age <50
1 or more 1st, 2nd, or 3rd degree relatives with epithelial ovarian cancer at any age
2 or more 1st, 2nd, or 3rd degree relatives with breast cancer and/or pancreatic
cancer at any age
Of Ashkenazi Jewish descent
Ovarian cancer or other malignancy
Male
Criteria for further genetic risk evaluation in person without breast cancer
Family history of:
2 or more breast primaries in a single individual or 2 different individuals on same
side of family

1 or more ovarian cancer primary malignancies
1st or 2nd degree relative with breast cancer before 45 years of age
A known mutation in a breast cancer susceptibility gene within the family
Male breast cancer
Breast cancer plus other malignancy
After referral for genetic counseling:
BRCA, TP53 and PTEN gene mutation testing
If no mutations are found, breast cancer risk can be estimated according to the
modified Gail model
Factors affecting risk according to Gail model:
Age, age at menarche, age at 1st live birth, number of breast biopsies,
presence of atypical hyperplasia, number of first-degree relatives with breast
cancer, race/ethnicity
If life expectancy is >10 years, risk reductive interventions can be discussed
Lifestyle modifications
Risk reduction surgery
Mastectomy
Salpingo-oophorectomy
Selective estrogen receptor modulators (SERM) tamoxifen, raloxifene
Aromatase inhibitors (Arimidex)
Hereditary Colorectal Cancer Syndromes
Criteria for further genetic risk evaluation for high-risk colorectal cancer syndrome:
Onset less than 50 years of age
Presence of other colorectal or Lynch syndrome associated tumor at any age
Cancer with microsatellite instability on histology and less than 60 years of age
1 or more first-degree relatives with a Lynch syndrome associated cancer and age
less than 50
2 or more first- or second-degree relatives with Lynch syndrome related cancer at
any age
3 or more relatives with colorectal cancer (1 being a first-degree relative of the other
2 with two successive generations affected and 1 relative being diagnosed before age
50)
>10 adenomas in same individual
Multiple GI hamartomatous polyps
Family member with known diagnosis of hereditary syndrome
After referral for genetic counseling:
Identification of at-risk family members and predictive testing
Surveillance guidance
Chemoprevention with aspirin/NSAIDs
MEDICAL ONCOLOGY123
11.2 LUNG CANCER
Lung cancer is the most prevalent cancer and the number one cause of cancer deaths. t is
divided into small cell, oat cell, and non-small cell lung cancer. 80-90% of cases is due to tobacco
smoke; while 10-15% is from non-smoking
Initial presentation may be based on signs, symptoms or laboratory abnormalities
Signs and symptoms
Cough, weight loss, dyspnea, chest pain, hemoptysis, bone pain, clubbing, fever,
weakness, superior vena cava obstruction, dysphagia, wheezing, stridor
Horners syndrome: Ptosis, myosis, anhydrosis
Pancoast or superior sulcus tumor: Local extension of a tumor growing in the apex
of the lung with involvement of the 8th cervical and 1st and 2nd thoracic nerves
with shoulder pain, and destruction of 1st and 2nd ribs
Paraneoplastic Eaton-Lambert: Proximal muscle weakness, autonomic dysfunction,
cranial nerve, or bulbar symptoms
Strength improves with serial effort
Trousseaus syndrome: Migratory venous thrombophlebitis
1/3 present with symptoms of distant metastases
Laboratory abnormalities
Anemia, elevated alkaline phosphatase, elevated transaminases, hypercalcemia
12% present with paraneoplastic endocrinopathies
Hypercalcemia from ectopic production of PTH or PTH-related peptide
(Squamous cell)
Hyponatremia from SIADH or atrial natriuretic peptide secretion In small cell
lung carcinoma
Treated with demeclocycline if unresponsive to fluid restriction
Hypokalemia from ectopic ACTH secretion (small cell, carcinoid)
Staging
Table 11.3: Staging
T N M
x Cannot be assessed Can not be assessed Can not be assessed
0 No evidence of primary No nodes No metastasis
Tis Carcinoma in situ
1 <3 cm Ipsilateral non-medias- A: Local
tinal or subcarinal B: Distant
2 3-7 cm Ipsilateral mediastinal
or subcarinal
3 >7 cm Contralateral,
supraclavicular
4 Invasion of mediastinum, heart or STAGE
great vessels, recurrent laryngeal
nerve, esophagus, vertebra
Adapted from NCCN guidelines, Small Cell Lung Cancer.

T and M Categories
T1 (<2 cm) T2 (>5-7 cm) T4 (small lobe nodule) T4 (pleural effusion)

T/M: T1a T/M: T2b T/M: T3 T/M: M1a
N0: IA N0: IIA N0: IIB N0: IV
N1: IIA N1: IIB N1: IIIA N1: IV
N2: IIIA N2: IIIA N2: IIIA N2: IV
N3: IIIB N3: IIIB N3: IIIB N3: IV
T1 (>2-3 cm) T2 (>7 cm) T4 (extension) M1 (contralateral lung)
T/M: T1b T/M: T3 T/M: T4 T/M: M1a
N0: IA N0: IIB N0: IIIA N0: IV
N1: IIA N1: IIIA N1: IIIA N1: IV
N2: IIIA N2: IIIA N2: IIIB N2: IV
T2 (<5 cm) T3 (invasion) M1 (ipsilateral lung) M1 (distant)
T/M: T2a T/M: T3 T/M: T4 T/M: M1b
N0: IB N0: IIB N0: IIIA N0: IV
N1: IIA N1: IIIA N1: IIIA N1: IV
N2: IIIA N2: IIIA N2: IIIB N2: IV
MEDICAL ONCOLOGY125
Non-small Cell Lung Cancer
85% of lung cancers
Squamous and non-squamous (adenocarcinoma, large cell, other)
Squamous cell: more centrally-located, more common in men who are smokers, than
women
Large cell: has twice odds ratio in smoking women than in men.
Adenocarcinoma: Most common type of lung cancer and is the most frequent cell type in
non-smokers
Treatment
Varies depending on the stage, patients karnofsky performance status, and cancer subtype.
Different treatment modalities include surgery, chemotherapy, radiation therapy, palliative
care
Surgery
Figure 11.1: Non-small Cell Lung Cancer Treatment
Pulmonary Function Test
FEV1 >2L or
FEV1 1.5 - 2L FEV1 <1.5L
80% predicted
Exertional dyspnea Exertional dyspnea No surgery
Yes No Yes No
Pneumonectomy Lobectomy
DLCO >80 DLCO <80 DLCO <80 DLCO >80
Pneumonectomy Lobectomy
Further physiologic
testing
Best chance for cure

Sleeve lobectomy, lobectomy, or pneumonectomy
Only recommended for stage I or II disease
Evaluation for resection candidacy

Radiation Therapy
Can be used in 3 clinical settings
Adjuvant
Primary local treatment if unresectable
Palliative
Chemotherapy
Stage IB, II and III: In patients with completely resected NSCLC, adjuvant chemotherapy
has been shown to improve survival
Stage III: Concurrent chemoradiation is superior to sequential therapy
Stage IV: Platinum-based chemotherapy as palliation
Targeted therapies
Bevacizumab: Anti-VEGF
Erlotinib: EGFR inhibitor
Crizotinib: ALK inhibitor
Small Cell Lung Cancer

Nearly all attributable to cigarette smoking
Less common but more aggressive than NSCLC
Limited stage: Disease confined to ipsilateral hemithorax that can be safely encompassed
within a radiation field
Extensive stage: Beyond ipsilateral hemithorax
Treatment
Surgery only appropriate for 2 to 5% with stage 1 disease
Limited stage: Chemotherapy + radiotherapy
Extensive stage: Chemotherapy for palliation
Chemotherapy: Etoposide and cisplatin
11.3 GENITOURINARY CANCER

Prostate Cancer
2nd most common cancer and 2nd most common cause of death in the U.S
1 in 6 men diagnosed, only 1 in 30 will die of disease
Screening
No evidence that the potential benefits of prostate cancer screening outweighs the
harms of testing
When to discuss pros and cons and decide whether or not to screen:
Age 45 in African-Americans or individuals with first-degree relatives who
developed prostate cancer before age 65
Age 40 in individuals with more than 1 first-degree relative who developed prostate
at an early age
Otherwise at age 50
Screening: PSA blood test +/- DRE
PSA <2.5: Retesting every 2 years
PSA >2.5: Yearly testing
PSA >4: Biopsy
MEDICAL ONCOLOGY127
Diagnosis
Men with prostatic nodules, indurations, or asymmetry should be referred to a urologist
or abnormally elevated PSA
Transrectal ultrasound (TRUS) guided needle biopsy (minimum of 12 core samples)
The urologist should perform a Transrectal ultrasound (TRUS) guided needle biopsy
Repeat Biopsy is indicated if the first biopsy is negative, and the PSA continues to rise
Histology
95% tumors are adenocarcinomas
5% are squamous or transitional cell, rarely sarcomas
Gleason grading system
Based on dominant and secondary histology
Each receive a score from 1 (well-differentiated) to 5 (undifferentiated)
Scores are added
After confirmed biopsy, MRI is imaging modality used to complete staging
Table 11.4: Staging

T N M
1 No palpable or visible tumor Positive lymph nodes Distant Metastases
2 Tumor confined to prostate
3 Tumor extends from prostate capsule
to seminal vesicles
4 Involvement of structures other than
seminal vesicles
Treatment
Watchful waiting
Serial DRE, PSA, biopsies
Radical Prostatectomy
Patients with life expectancy >10 years
Commonly complicated by impotence and/or incontinence
Radiation
External beam
Brachytherapy: Implantation of radioactive seeds into prostate
Medications
Testosterone-lowering agents: Leuprolide, goserelin, degarelix
Used in metastatic disease in individuals with noncastrate levels of testosterone
(>150 ng/dL)
Associated with hot flushes, impotence, depression, insulin resistance, obesity,
increased cardiovascular disease risk and osteoporosis
Assess fracture risk with FRAX scale, supplement with calcium and vitamin D,
treatment with bisphosphonate or denosumab
Antiandrogens: Flutamide, bicalutamide, nilutamide
Primarily used to reduce side effects of testosterone-lowering agents

Sipuleucel-T
Cancer vaccine in which T-cells are collected from patient, exposed to prostatic
acid phosphatase and re-infused into patient
Prevention: 5-alpha reductase inhibitors can reduce prevalence of prostate cancer
by 25%.
Diet, life style modification such as smoking cessation help reduce risk of cancer
Testicular Cancer
Most commonly presents as painless testicular mass
Testicular mass in male >50 is lymphoma until proven otherwise
Histology
2 main histologic types: 1. Seminoma 2. Nonseminoma
Nonseminomatous further broken down into 4 histologic subtypes: Embryonal,
teratoma, choriocarcinoma, endodermal sinus (yolk sac) tumor
Embryonal: Secrete tumor markers hCG, AFP or both
Teratoma: Contains cell types from 2 or more germ layers: Ectoderm, mesoderm, or
endoderm
Choriocarcinoma: Cytotrophoblast or syncytiotrophoblast
Secrete tumor marker hCG
Endodermal sinus or yolk sac tumor
Secrete AFP
Table 11.5: Seminoma and Nonseminoma

Seminoma Nonseminoma
4th decade of life 3rd decade of life
Indolent Tend to metastasize to retroperitoneal lymph
nodes or lungs
May have elevated hCG (elevated AFP suggests May have elevated hCG or AFP
occult nonseminoma)
LDH elevated in 80% of advanced cases LDH elevated in 50-60% of cases with metastases
MEDICAL ONCOLOGY129
Evaluation
Figure 11.2: Testicular Cancer Evaluation
Testicular discomfort
or swelling
Trial of antibiotics
Painless Testicular
Mass No Resolution Resolution
TESTICULAR ULTRASOUND
No further testing
MEASUREMENT OF AFP, BETA-HCG,
AND LDH CHEST X-RAY
Normal
Suspicious testicular lesion + Other abnormal findings
Elevated/rising beta hCG +
Symptomatic metastatic disease
Testicular biopsy versus orchiectomy
(malignancy on biopsy should be
followed by orchiectomy)
Chemotherapy
Histologic confirmation of malignancy
CT abdomen and pelvis

(include chest if abnormal CSR)

Treatment
Table 11.6: Testicular Cancer Treatment
Stage Seminoma Nonseminoma
Confined to testis with no Observation, Chemotherapy Retroperitoneal lymph node
vascular invasion or Radiation therapy (RT) dissection (RPLND) or observation
IA
Extension to vascular/ Observation, Chemotherapy RPLND or Chemotherapy
lymphatics, tunica albuginea, or Radiation
spermatic cord or scrotum
IB
Retroperitoneal lymph nodes RT RPLND +/- Chemotherapy
<2 cm
IIA
Retroperitoneal lymph nodes RT or Chemotherapy Chemotherapy followed by RPLND
2-5 cm
IIB
Retroperitoneal lymph nodes Chemotherapy Chemotherapy followed by RPLND
>5 cm
IIC
Distant metastases Chemotherapy Chemotherapy
III
Bladder Cancer
Epidemiology
Up to 50% can be attributed to tobacco; up to 30% develop cancer when exposed to
benzidine
Most common form is transitional cell carcinoma
In developing countries parasitic infection with Schistosoma haematobium is a
common cause for squamous cell carcinoma of the bladder
Clinical presentation
Classically: Painless hematuria in male smoker >50 years old
Irritative symptoms such as dysuria, frequency, or urgency
Obstruction with flank pain and symptoms of metastatic disease can occur but are rare
Evaluation
Cystoscopy is imaging modality of choice
Ultrasound, CT, and/or MRI can be used to document full extent of disease
Histology
90% transitional or urothelial
3% squamous (most common in distal third of urethra)
2% adenocarcinoma
1% small cell
MEDICAL ONCOLOGY131
Treatment
Dependent upon whether tumor is superficial or muscle-Invasive
Superficial
Endoscopic resection (transurethral resection of bladder tumor or TURBT) with
or without intravesical therapy (bacillus Calmette-Guerin instillations)
Indication for BCG therapy: Recurrent disease, >40% involvement, diffuse
carcinoma in situ
Muscle-invasive: Radical cystectomy
Removal of pelvic lymph nodes
Males: Removal of prostate, seminal vesicles, proximal urethra
Females: Removal of urethra, uterus, fallopian tubes, ovaries, anterior vaginal
wall
Requires creation of continent cutaneous reservoir or orthotopic neobladder
Consideration of chemotherapy for nodal disease, extravesical extension, or
vascular invasion
Renal Cancer
Epidemiology
Strongest association is with cigarette smoking
35% of individuals with von Hippel-Lindau (VHL) will develop RCC
80-85% develop within the renal cortex; 8% develop as transitional cell carcinoma of
the pelvis
Histology
Table 11.7: Renal Cancer Histology

Carcinoma Type Cell of Origin
Clear cell (predominant) Proximal tubule
Papillary cell Proximal tubule
Chromophobic Cortical collecting duct
Oncocytic (benign) Cortical collecting duct
Collecting/Bellini duct (aggressive) Medullary collecting duct
Classic triad: Hematuria, abdominal pain, and palpable mass
Stauffer syndrome: Paraneoplastic syndrome with erythrocytosis, hypercalcemia and
hepatic dysfunction
Evaluation
Any solid renal mass should be considered malignant until proven otherwise
If no metastases, surgery is indicated
Non renal-cell malignancies of the kidney: Transitional cell carcinoma of the renal pelvis,
sarcoma, lymphoma, Wilms tumor
Radiographic testing: Abdominal ultrasound or CT is first-line test
Ultrasound is less sensitive than CT for differentiating a benign cyst from a tumor.
A cyst is all of the following: (1). No echoes within the cyst (anechoic) (2). Strong
posterior wall echo indicating good transmission through a cyst. (3). Rounded, with
demarcated smooth walls

Malignancy is confirmed on CT by thick irregular walls or septa enhancing after
contrast injection
Staging
Stage I: Limited to kidney and <7 cm
Stage II: Limited to kidney and between 7 and 10 cm
Stage III: Lymph node involvement
Stage IV: Distant metastases
Treatment
Stage I and II (selected stage III) disease: Radical nephrectomy (kidney, adrenal gland,
hilar lymph nodes)
Stage IV disease
Cytokine therapy: IL-2 or IFN-alpha
Produces regressions in 10 to 20% of patients and durable remission in small
proportion of cases
Antiangiogenic therapy: Bevacizumab, sorafenib, sunitinib
Inhibit VEGF and PDGF receptor signaling
Temsirolimus and everolimus: Inhibit mammalian target of rapamycin (mTOR)
11.4 ONCOLOGIC EMERGENCIES

Structural Urgencies and Emergencies
Superior Vena Cava Syndrome
Obstruction of the superior vena cava leading to:
Neck, facial, chest and upper extremity swelling
Exacerbated by bending forward or lying down
Hoarseness, headaches, hemoptysis
Life threatening sequelae
Tracheal obstruction
Cerebral edema with seizures
Usually a result of lung cancer, lymphoma or metastatic tumors
Diagnosis
Clinical
Chest X-ray: Superior mediastinum widening
CT: Decreased opacification of central venous structures and collateral venous
circulation
Treatment
Non-small cell lung cancer and metastatic solid tumors: Radiation
Small cell lung cancer, lymphoma or germ cell tumor: Chemotherapy
Diuretics, low-salt diet, head elevation, oxygen
Glucocorticoids effective for lymphoma only
MEDICAL ONCOLOGY133
Brain Metastases with Increased Intracranial Pressure
Most commonly:
Lung 16 to 20 percent
Melanoma 7 percent
Renal cell cancer 7 to 10 percent
Breast cancer 5 percent
Symptoms
Headache, nausea, vomiting, behavior change, seizure
Diagnosis
Contrast-enhanced MRI is more sensitive than non-contrast or T2-weighted MRI or
contrast-enhanced CT scan
MRI with gadolinium is most sensitive in evaluating meningeal involvement and small
lesions
Treatment
Dexamethasone 6 mg IV Q6H (indicated only in patients with increased intracranial
pressure or edema on imaging)
Intubation with hyperventilation to maintain PCO2 between 25 and 30 mmHg
Mannitol 1-1.5 g/kg IV Q6H
Head elevation, fluid restriction, and hypertonic saline with diuretics
Shunt placement for patients with hydrocephalus
Whole brain radiation in patients with multiple lesions
Surgical excision for single brain metastases if extra-cranial disease is controlled
Should be followed by whole-brain radiation
Stereotactic radiosurgery for inaccessible or recurrent lesions
Spinal Cord Compression
Most common culprits are lung, breast, prostate, multiple myeloma, lymphoma,
melanoma, thyroid, renal cell, and GU cancers
Mnemonic: BLT with pickles, mustard, and relish: Breast, Lung, Thyroid, Prostate,
Myeloma/Melanoma, and Renal cell
Thoracic spine is the most common site (70%)
75% who receive treatment while still ambulatory will remain ambulatory, while only 10%
of those with paraplegia recover ambulatory ability
Symptoms
Back pain and tenderness
Radicular pain
Lhermitte sign: Tingling or electric sensation down back with neck flexion
Loss of bowel or bladder
Gait abnormalities or ataxia
Physical findings
Pain on percussion
Weakness or spasticity
Extensor plantar reflex or brisk deep tendon reflexes
Absence of anal wink
Cauda equina syndrome: Compression at level of nerve roots leaving spinal cord
Low back pain, saddle anesthesia, rectal and bladder dysfunction, sexual
impotence, absent Achilles reflex, and lower extremity weakness

Radiologic findings
Winking owl sign: Erosion of vertebral pedicles
Earliest radiologic finding of vertebral tumor
MRI of cervical, thoracic and lumbar spin is imaging modality of choice
Patients with poor MRI images or who cannot undergo MRI promptly should
undergo myelography
Treatment
Patients found to have physical exam findings consistent with cord compression
should be started on dexamethasone mg IV Q6H immediately and prior to radiologic
confirmation
Radiation
Surgery indications
Unknown etiology
Failure of radiation
Radio-resistant tumor such as melanoma or renal cell
Pathologic fracture dislocation
Chemotherapy indications
Chemo-sensitive tumors (lymphoma, small cell lung cancer)
Already have received radiotherapy
Not surgical candidates
Metabolic Urgencies and Emergencies

Tumor-Lysis Syndrome
Caused by destruction of a large number of rapidly proliferating cells
Most common malignancies include Burkitts lymphoma and ALL
Manifestations
Hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia
Acidosis
Acute renal failure
Secondary to precipitation of calcium phosphate crystals
Occurs 1 to 5 days after chemotherapy and on occasion, spontaneously
Treatment
Allopurinol: Xanthine oxidase inhibitor
Prevents oxidation of hypoxanthine and xanthine to uric acid
Rasburicase: Recombinant urate oxidase
Converts uric acid to allantoin, a more soluble metabolite
Contraindicated in individuals with G-6-PD deficiency
Urinary alkalinization
Aggressive hydration
Dialysis
Hypercalcemia
Serum calcium above 11.5 mg/dL
An ominous prognostic indicator when associated with malignancy and 6 month
untreated survival
Symptoms
Fatigue, depression, confusion, increased urination and dehydration, short QT interval
and arrhythmias, abdominal discomfort
MEDICAL ONCOLOGY135
Etiology
Production of PTHrP (parathyroid hormone related protein) by solid tumor
Squamous cell carcinoma of the lung, multiple myeloma, and breast cancer are
most common culprits
The mechanisms of hypercalcemia are due to:
Production of 1, 25-dihydroxyvitamin D
Local release of cytokines secondary to osteolytic metastasis
PTH-rP secretion by the tumor cells
Findings
Elevated urinary cyclic AMP, hypophosphatemia, increased urinary phosphate
clearance
Low-normal levels of 1,25(OH)2 vitamin D
Differentiating between hyperparathyroidism and hypercalcemia of malignancy
Table 11.8: Differentiating Between Hyprparathyroidism and Hypercalcemia of Malignancy

Hyperparathyroidism Hypercalcemia of Malignancy
Undetectable PTHrP Detectable PTHrP
Elevated PTH Low PTH
Elevated 1,25(OH)2 D Low 1,25(OH)2 D
No known malignancy or suspected lesion Likely to already have cancer diagnosis
Treatment
Hydration with normal saline until euvolemic, then hydration with loop diuretic
Bisphosphonates
Pamidronate and zoledronate
Onset of action is 1 to 2 days
Dialysis
Control of underlying malignancy
In patients with end stage malignancy, consider withholding treatment for elevated
calcium as it can provide a sedating effect
Chemotherapy-related Toxicities
Neutropenia and infection
Patients with intermediate and high risk malignancies or treatment regimens should be
on bacterial, fungal, and viral prophylaxis while neutropenic
Includes patients with liquid tumors and those with neutropenia lasting longer than
7 days
Patients at increased risk for pneumocystis jirovecci should also receive prophylactic
Bactrim, dapsone, aerosolized pentamidine, or atovaquone
Includes allogeneic stem cell recipients, patients with acute lymphocytic leukemia,
or those receiving alemtuzumab
Febrile neutropenia
Single temperature >38.3 or >38.0 for over 1 hour
Less than 500 neutrophils or <1,000 neutrophils with predicted decline to <500
over next 48-hours

Should receive empiric broad-spectrum antibiotics and evaluation for occult
infection
Human antibody infusion reactions
Caused by rituximab, gemtuzumab, trastuzumab
Leads to fever, chills, asthenia, bronchospasm, hypotension, ARDS
Lab findings include increased liver enzymes, D-dimer, LDH, PT, PTT
Treated with diphenhydramine, hydrocortisone, and acetaminophen
Hemolytic-Uremic syndrome
Caused by cisplatin, bleomycin, gemcitabine
Leads to microangiopathic hemolytic anemia, thrombocytopenia, and renal failure
Lab findings include anemia, schistocytes on peripheral smear, reticulocytosis,
decreased haptoglobin and increased LDH, increased bilirubin, negative Coombs test,
elevated creatinine
Treated with plasmapheresis and or rituximab
Lung injury
Bleomycin, methotrexate, busulfan, gemcitabine, mitomycin, vinorelbine, docetaxel,
ifosfamide, temsirolimus, tyrosine kinase inhibitors such as imatinib, erlotinib, gefitinib,
radiation
Potentiated by high FiO2 states
Treated with glucocorticoids
GI injury
Neutropenic enterocolitis or typhlitis caused by necrosis of the cecum
Leads to right lower quadrant abdominal pain, abdominal distention, watery diarrhea
Diagnosed by CT scan showing bowel wall thickening and edema and ascites
Treated with broad spectrum antibiotics
GU injury
Hemorrhagic cystitis
Chemical irritation from cyclophosphamide or ifosfamide which are both
metabolized to acrolein or
Viral: Polyoma virus BKV or adenovirus type 11
Causes gross hematuria and irritative symptoms
Treated with mesna and bladder irrigation
Skin changes
Chemotherapy-induced acral erythema/palmar-plantar erythrodysesthesia/hand-foot
syndrome
Caused by: Fluorouracil, capecitabine, cytarabine, doxorubicin, sorafenib and seniti
Involves swelling, pain, desquamation and paresthesias of palms and soles of hands and
feet
Treated with wound care and pain medication
Neuropathy
Most commonly implicated agents:
Platinum based (cisplatin, carboplatin)
Plant alkaloids (vincristine, vinblastine, vinorelbine, etoposide)
Taxanes: Paclitaxel, docetaxel
Bortezomib
Often requires dose reduction or therapeutic substitutions
MEDICAL ONCOLOGY137
11.5 Lymphoid Malignancies
Introduction
Solid tumors of the immune system
Lymphocytes transformed to malignant cells. Can be T, B, NK cells. Majority originate from
B-cells
Hodgkins (HL) vs. Non-Hodgkins lymphomas (NHL)
Epidemiology
HL: Bimodal incidence with peaks at 30 years and then after 50 years of age
NHL: More frequent in elderly and in males
Common Signs and Symptoms

Painless lymphadenopathy
Systemic B symptoms: Fever, night sweats, weight loss (>10% in less than 6 months)
Less common: Fatigue, pruritus, abdominal pain due to organomegaly, reduced appetite
Diagnosis
Biopsy (incisional or excisional), immunohistochemistry or flow cytometry
If no accessible nodes, can do FNA or core needle biopsy
If isolated splenomegaly, often recommend splenectomy
Imaging: CT chest, abdomen, and pelvis. Otherwise, PET-CT
Labs: CBC with differential, CMP, LDH, ESR, peripheral smear
Hodgkins Lymphoma (HL)
~ 8,000 new diagnoses each year in the US
Reed Sternberg cell: Malignant B-cells that express CD15 & CD30
4 types of HL: Nodular sclerosis, mixed cellularity, lymphocyte deplete, lymphocyte rich
Nodular sclerosing is most common in the US
Symptoms
Non-tender lymphadenopathycommonly in neck, axilla, supraclavicular area
Systemic B symptoms
Diagnosis
CBC, ESR, bone marrow biopsy, CT chest, abdomen, and pelvis
Treatment
Early Stage HL (Stage I: Single lymph node; Stage II: 2 or more nodal regions on same
side of diaphragm)
Chemotherapy with ABVD (anthracycline, bleomycin, vinblastine, dacarbazine) and
IFRT (involved field radiation therapy)
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,
procarbazine, and prednisone)
85 to 95% disease free survival at 5 years
Advanced Stage HL
Chemotherapy with ABVD, and if bulky disease, radiation therapy
Relapsed HL
If relapse >1 year, systemic chemotherapy
If relapse <1 year, aggressive chemotherapy. Consider autologous stem cell
transplantation (auto SCT)

Complications of treatment
Radiation therapy - secondary malignancies, hypothyroidism if given near head or
neck. Secondary myelodysplastic syndrome or leukemia
Non-Hodgkins Lymphoma (NHL)
Growth of a clonal population of lymphocytes, most often B-cells
Several different types including (in percentage of NHL): Diffuse large B-cell lymphoma
(31%), follicular lymphoma (22%), MALT lymphoma (7.6%), mature T-cell lymphoma (7.6%)
Symptoms
Painless lymphadenopathy
Systemic B symptoms
Diagnosis
CBC, LDH, CMP, excisional biopsy or FNA, bone marrow biopsy, beta-2 microglobulin,
serum protein electrophoresis
Consider HIV and hepatitis panel due to association with some NHL
Treatment
Generally, indolent (low-grade) NHL is not incurable and aggressive (high-grade) NHL is
curable
Indolent NHL
Subtypes are: Follicular Lymphoma, Waldenstrom Macroglobulinemia, Marginal Zone
Lymphoma, Primary Cutaneous Anaplastic Large Cell Lymphoma
Early stage indolent - IFRT or IFRT + chemotherapy
Advanced stage indolent - rituximab + chemotherapy (e.g., R-CHOP)
Relapsed indolent - aggressive salvage chemotherapy
Aggressive NHL
Early stage - R-CHOP + IFRT
Advanced stage - R-CHOP or anthracycline containing regimen
Relapsed - salvage chemotherapy and then SCT
Specific treatment examples
In diffuse large B-cell lymphoma (aggressive NHL)
Rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP)
In follicular lymphoma (indolent NHL)
Ranges from watchful waiting for asymptomatic patients to chemotherapy and
IFRT in local disease. Include rituximab if CD20 (+)
In MALT lymphoma
In cases of gastric MALT, 95% are associated with H. pylori and treatment of infection
can achieve remission. If antibiotics are not successful, radiation is often used
Chronic Lymphocytic Leukemia (CLL)
Most common adult leukemia in the west
More frequent in Caucasians and males
It presents primarily in the lymph nodes, and is a stage of small lymphocytic lymphoma, a
type of B-cell lymphoma
Growth of monoclonal B-cell that is CD5 (+) and CD23
Symptoms
Lymphadenopathy
Fatigue
Frequent infections
B symptoms
MEDICAL ONCOLOGY139
Diagnosis
CBC, CMP, peripheral blood smear, flow cytometry, bone marrow biopsy, LDH, uric acid,
beta-2 microglobulin, SPEP, CT chest, abdomen, and pelvis
Absolute lymphocytosis > 4 x 10^9/L
CD5 and CD23 antigen positive
Smear may show smudge cells
Treatment
Asymptomatic - watchful waiting
Bone marrow failure with developing cytopenias - various treatments including:
fludarabine, chlorambucil, cyclophosphamide, rituximab
Complications
Often develop autoimmune hemolytic anemia, autoimmune thrombocytopenia (ITP),
red cell aplasia, and/or hypogammaglobulinemia that require treatment per standard
guidelines, irrespective of CLL treatment
11.6 Breast Cancer

Epidemiology
Lifetime risk is 1 in 8 for women with highest prevalence found in ages 60-70 years old
Most frequent cancer diagnosis in females. Second to lung cancer in mortality
Highest incidence in Northern Europe and US
Mortality rates higher in African-American females - disparities in access
Risk Factors
Genetics
BRCA-1 - involved in gene repair. 60 to 80% lifetime chance of breast cancer if mutated
BRCA-2 - increases risk
Li-Fraumeni syndrome - inherited mutations in p53 tumor suppressor gene. Increases
risk of breast cancer as well as other cancers
Protective: Late menarche, earlier 1st pregnancy, earlier menopause. Decreased lifetime
exposure to estrogen
Increased risk: Smoking, moderate alcohol intake, nulliparity, previous radiation therapy in
younger women
Risk Reduction
If strong family history, especially if Ashkenazi Jewish decent, recommend genetic
counseling
If BRCA-1 or BRCA-2 (+), prophylactic mastectomy can significantly reduce risk;
oophorectomy also reduces risk
Screening mammogram with or without clinical breast exam every 1 to 2 years for >40
years of age
Possible benefits: Decreased fat diet, decreased alcohol consumption, weight loss,
exercise

Non-invasive Breast Cancer
DCIS (Ductal Carcinoma In Situ)
Malignant cell proliferation within breast ducts
Diagnosis
Mammogram shows clusters of micro-calcifications
Core biopsy helps identify architecture. FNA cannot distinguish architecture to determine
whether invasive or not
Treatment
Lumpectomy and chest wall irradiation. Tamoxifen after surgery and radiation further
reduce rates of recurrence
LCIS (Lobular Carcinoma In Situ)
Proliferation of malignant epithelial cells within breast lobules
Diagnosis
Not associated with mammographic abnormality
Not detectable on physical exam
Usually an incidental finding
Core biopsy for architecture
Not a pre-malignant lesion, but marker for future risk of invasive cancer (usually invasive
ductal)
Often multicentric with increased incidence of bilaterality
Treatment
Observation alone. Can use tamoxifen or raloxifene for reduction of future risk
Invasive Breast Cancer

Most important prognostic factor is metastases to axillary lymph nodes. Sentinel node
dissection is important
Treatment
Breast conserving therapy with subsequent breast radiation or mastectomy
Depends on size and location of cancer, and on breast size and patient preference
Adjuvant chest wall and axillary radiation if: 1. Positive surgical margins 2. Tumor >5 cm
3. 4 or more lymph nodes (+)
Adjuvant chemotherapy: Recommended if node (+), or if node (-) and tumor is >1 cm
Adjuvant hormone therapy: If ER or PR (+), selective estrogen receptor modulators
(SERM), tamoxifen or raloxifene; or if post-menopausal then aromatase inhibitors,
anastrozole or letrozole
Note: Aromatase inhibitors are not used in pre-menopausal women
Alternatives in ER-positive pre-menopausal patients: Oophorectomy, chemical
ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonist
(ex.: goserelin)
If HER2/neu (+), monoclonal antibody, trastuzumab given in addition to
chemotherapy
MEDICAL ONCOLOGY141
Metastatic Breast Cancer
If prior lumpectomy, consider mastectomy and radiation
Hormonal therapy
If post-menopausal ER (+) and:
>1 year past previous anti-estrogen therapy aromatase inhibitor or SERM
<1 year past previous anti-estrogen therapy aromatase inhibitors are first-line
pre-menopausal ER (+):
If
LHRH agonist + SERM
Consider oophorectomy
If rapidly progressive or refractory disease: Combination chemotherapy
If Her2/neu (+): Trastuzumab + chemotherapy
If metastases to bone: Include bisphosphonates e.g., zoledronate or pamidronate
Prognosis
Depends on stage of cancer (TNM), grade, patients age, and performance status, and
recurrence of disease
Nottingham Prognostic Index is used after surgery for breast cancer
NPI = [0.2 x S] + N + G
Where: S is the size of the index lesion in centimetres. N is the number of lymph nodes
involved: 0 =1, 1-3 = 2, >3 = 3. G is the grade of tumour: Grade I =1, Grade II =2, Grade III
=3
Score 5-year survival
>/=2.0 to </=2.4 93%
>2.4 to </=3.4 85%
>3.4 to </=5.4 70%
>5.4 50%
11.7 Ovarian Cancer

Epidemiology
Leading cause of death from gynecologic malignancies
Represents the 6th most commonly diagnosed cancer among women around the world
Risk Factors
Age
Family history
Cigarette smoking and alcohol consumption
Postmenopausal hormone-replacement therapy
Protective: Increasing parity, oral contraceptive use, oophorectomy
Lactaction, incomplete pregnancies, and surgeries (hysterectomy and tubal ligation) may
confer a week protective effect against the cancer
Infertility may contribute as a risk for nulliparous women
Diagnosis
Family history: Breast, ovarian, and/or colon cancer
Abdominal swelling and/or tenderness
Abnormal vaginal bleeding
Pelvic or transvaginal ultrasounds - mass may be present
CA-125 blood test
Treatment
Surgery to remove the ovaries, along with additional areas where it has spread (often
spread to omentum)
Chemotherapy may be intitial treatment in advanced cases
Follow-up with pelvic exam and serum CA-125 blood tests
11.8 Cervical Cancer

Epidemiology
5th most deadly cancer in women
Estimated to affect 16 out of 100,000 women per year
Risk factor: Human papillomavirus (HPV)
Prevention
HPV vaccine for women 9-26; however, does not protect against ALL strains and does not
treat exisiting HPV

Pap smear, with the exception of patients following hysterectomy
HPV DNA testing
Colposcopy: If abnormal pap smear
If precancerous changes in cells: Physical exam, cystoscopy, chest X-ray, blood tests, CT/
PET scan
Symptoms may include: Foul-smelling vaginal discharge, back painm leg swelling, bleeding
Treatment
Loop electrosurgical excision procedure (LEEP)
Cervical cone biopsy
Simple or radical hysterectomy
Radiation
Chemotherapy
11.9 Cancer of Unknown Primary Site

Diagnostic and Prognostic Considerations
Tumor detected at 1 or more sites with evaluation that does not detect a primary site
Thorough initial evaluation with history, physical including pelvic and prostate examination,
CBC, urinalysis, CMP, CT chest/abdomen/pelvis, mammography, PET-scan
Pathology for biopsy with special stains may aid diagnosis
Most easily accessible site may be used for biopsy
Tumor markers are not useful for diagnosis, may aid in prognosis
Unfavorable prognosis: Multiple metastatic sites, adenocarcinoma histology, low-
performance status, older age
MEDICAL ONCOLOGY143
Subsets of Treatable Cancer of Unknown Primary
Axillary Lymphadenopathy in Women
Women presenting with this should be treated as Stage II or III breast cancer
MRI can help identify primary even when mammogram is normal
Inguinal Lymphadenopathy
Lymph node biopsy of most accessible node
Superficial lymph node dissection with or without subsequent chemotherapy based on
cell type seen in pathology
Cervical Lymphadenopathy
Panendoscopy, panorex, CT head and neck for diagnosis
If squamous cell seen on pathology, treat as head and neck cancer
Peritoneal Carcinomatosis in Women
Peritoneal carcinomatosis with malignant ascites should prompt treatment for ovarian
cancer
Treat as Stage III ovarian cancer with cytoreductive surgery and chemotherapy
Poorly Differentiated Carcinoma
Young males with midline tumor location in mediastinum and peritoneum, elevated
human chorionic gonadotropin and alpha fetoprotein should be treated as testicular
cancer with poor prognosis
Treat with chemotherapy and surgical resection of residual disease
11.10 Effects of Cancer and Cancer Therapy

Cardiac Issues
Trastuzumab, mitoxantrone, ifosfamide, cyclophosphamide, anthracycline: Congestive heart
failure
5-fluorouracil: Cardiac arrhythmias, myocardial ischemia
Radiation therapy to the mediastinum: Cardiomyopathy, valvular heart disease
Pulmonary Issues
Bleomycin induced pneumonitis. Higher risk when associated with: Age >70, higher doses,
underlying pulmonary disease, prior mediastinal radiation, renal dysfunction
Radiation pneumonitis: Risk increases with prior chemotherapy, withdrawal of
corticosteroids
Chemotherapy
Related infertility can be managed by storage of sperm/eggs/embryos
Hormonal imbalance from chemotherapy related side effects can cause significant
morbidity
Problems with cognition have been reported after chemotherapy
Radiation therapy to the neck should prompt evaluation for hypothyroidism

11.11 Gastrointestinal Malignancies
Colorectal Cancer
3rd most common malignancy in the US. Incidence declining with screening; and second
most common causes of cancer death; Incidence declining with screening
Predisposing Factors
Hereditary cancer syndromes: Familial adenomatous polyposis, hereditary non-polyposis
colon cancer, Peutz Jeghers
Inflammatory bowel disease Crohn disease, ulcerative colitis
Personal history of polyps - adenomatous, villous, tubulovillous
Family history of colorectal cancer
Signs and Symptoms
Anemia, melena, hematochezia, abdominal pain, change in bowel habits
RUQ pain, abdominal bloating, early satiety, weight loss
Staging and Diagnosis
AJCC TNM staging and Dukes staging for colorectal cancer
Survival rates increase with number of nodes analyzed at least 12 should be examined
for accurate staging
Colonoscopy is the gold standard screening test
Rectal cancer has a poorer prognosis and higher rates of local recurrence due to lack of
serosa
Treatment
Surgical resection is mostly curative in limited disease
Adjuvant therapy for Stage II & III disease to check growth of micro metastases
High-risk features include higher T stage (T4 v T3), suboptimal (<12) lymph node retrieval,
presence of lymphovascular invasion, bowel obstruction or bowel perforation, and poorly
differentiated histology. These also benefit from adjuvant therapy
Adjuvant therapy with FOLFOX-5FU, oxaliplatin and leucovorin now approved for Stage
II, III colon cancer
Administering biological agents such as monoclonal antibodies with standard
chemotherapy improves overall survival in patients with metastatic cancer
Surveillance
History, physical examination and CEA every 3 to 6 months for 1st 2 years, every 6
months for subsequent 3 years
Colonoscopy at 1 year with repeat in 1 year if abnormal. Or 3 years if negative for polyps,
followed by colonoscopy every 5 years
CT chest/abdomen/pelvis annually for 3 years for poorly differentiated tumors
Gastric Cancer
Male sex
Age
Smoking
Family history of gastric cancer
Familial adenomatous polyposis
H. pylori infection (main cause)
MEDICAL ONCOLOGY145
Partial gastrectomy
Atrophic gastritis
High salt intake
Signs and Symptoms
Anemia
Melena
Hematemesis
Abdominal pain
Palpable abdominal mass
Nausea
Vomiting
Weight loss
Upper endoscopy with biopsy is gold standard
AJCC and TNM staging is used
Treatment
Local disease: Stage 0-1b - surgery with curative intent
For resectable disease: Adjuvant therapy is concurrent chemotherapy with 5-FU,
Leucovorin, and radiation therapy
Neoadjuvant therapy is with epirubicin, cisplatin and 5-FU, followed by postoperative
adjuvant therapy
Adjuvant capecitabine plus oxaliplatin treatment after curative gastrectomy should be
considered as a treatment option for patients with operable gastric cancer
Neoadjuvant, adjuvant and radiation therapy have been shown to improve overall survival
Metastatic disease or recurrent disease: Incurable. Single agents epirubicin, oxaliplatin,
capecitabine, docetaxel or combination regimens. No standard regimen exists
Surveillance
Every 3 to 4 months for 3 years followed by annual visits
CEA, CT scans, bone density, serum B12 levels, iron, folate, calcium level monitoring for
post gastrectomy patients
Esophageal Cancer
Two types : squamous cell, and adenocarcinoma
Risk factors for adenocarcinoma: smoking, obesity, GERD
Risk factors for squamous: smoking, alcohol, unhealthy diet
BOTH: Age> 60, male sex, HPV, Plummer-Vinson Syndrome
Signs and Symptoms
Dysphagia, initially for solids then to liquids, weight loss, odynophagia, retrosternal pain,
hoarseness of voice, cough
Barium swallow, esophagogastroduodenoscopy with biopsy is gold standard
AJCC TNM staging
Treatment
Esophagectomy in lymph node negative disease
Preoperative chemoradiation therapy followed by surgery increases overall survival when
compared to surgery alone
Metastatic disease: No standard regimen

Surveillance
History and physical examination every 3 months for 1st 2 years, every 6 months for
subsequent 3 years
Colonoscopy at 1 year with repeat in 1 year if abnormal or 3 years if negative for polyps,
followed by colonoscopy every 5 years
CT chest/abdomen/pelvis every 6 months for 1 to 3 years
Pancreatic Cancer
Subtypes: adenocarcinoma, and neuroendocrine tumors; Fourth cause of cancer death in the U.S
Smoking, family history
Chronic pancreatitis, diabetes, obesity
Signs and Symptoms
Abdominal pain, pain radiating to the back, bloating, nausea
Weight loss, anorexia
Jaundice
High-resolution spiral dynamic phase CT abdomen, liver function panel, endoscopic
ultrasound
AJCC TNM staging
Treatment
Whipples procedure for resectable disease (cholecystectomy, partial gastrectomy,
resection if proximal jejunum, portion of pancreas and gastrojejunostomy)
Neoadjuvant chemotherapy for locally advanced resectable, and locally advanced
unresectable disease with gemcitabine and 5-FU
Metastatic disease: Gemcitabine is standard regimen. Addition of Erlotinib has shown
minimal improvement in overall survival
Surveillance
History and physical examination every 3 months for 1st 2 years, every 6 months for
subsequent 3 years
CA 19-9, CT chest/abdomen/pelvis at each follow-up
Prognosis
Poor:
<5% 5-year survival rate
25% 1-year survival rate
My suggested readings
American Joint Committee in Cancer: AJCC: https://cancerstaging.org/Pages/default.
aspx
National Guidelines Clearinghouse.
http://www.guideline.gov/
http://www.Uptodate.com
American Cancer Society : http://www.cancer.gov
Wikipedia, the free encyclopedia, Colorectal cancer
Wikipedia, the free encyclopedia, gastric cancer
Wikipedia, the free encyclopedia, breast cancer
Wikipedia, the free encyclopedia, esophageal cancer
MEDICAL ONCOLOGY147
References & Suggested Readings
1. Rajput, A., Romanus, D., Weiser, M.R., terVeer, A., Niland, J., Wilson, J., Skibber J.M., Wong Y.N.,
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Journal of Surgical Oncology. 102(1), 3-9.
2. Dotan E, Cohen SJ. (2011). Challenges in the management of stage II colon cancer. Seminars in
Oncology. 38(4), 511-20.
3. Andr T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J,
Rivera F., (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant
treatment in stage II or III colon cancer in the MOSAIC trial. Journal of Clinical Oncology. 27(19),3109-
16.
4. Thrlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-
Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A. (2005). A compari-
son of letrozole and tamoxifen in postmenopausal women with early breast cancer. New England
Journal of Medicine. 253:2747-57.
5. Su Y, Yang WB, Li S, Ye ZJ, Shi HZ, Zhou Q. (2012). Effect of angiogenesis inhibitor bevacizumab on
survival in patients with cancer: a meta-analysis of the published literature. PLoS One. 7(4):e35629.
6. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe
JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ., (2006)
Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. MAGIC
Trial Participants. New England Journal of Medicine. 355(1),11-20.
7. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W,
Wolter J, Pegram M, Baselga J, Norton L. (2001). Use of chemotherapy plus a monoclonal anti-
body against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of
Medicine. 344(11):783-92.
8. Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ,
Kim YH, Ji J, Yeh TS, Button P, Sirzn F, Noh SH., (2012). Adjuvant capecitabine and oxaliplatin for
gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomized controlled trial.
Lancet. 379(9813), 315-21.
9. Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J,
Kocha W, Minsky BD, Roth JA. (1998). Chemotherapy followed by surgery compared with surgery
alone for localized esophageal cancer. New England Journal of Medicine. 339(27),1979-84.
10. Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker
D, Mayer R. (2008) Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy,
and surgery compared with surgery alone for esophageal cancer: CALGB 9781. Journal of Clinical
Oncology. 26(7):1086-92.
11. Basic & Clinical Pharmacology, (12th ed.). (2011). McGraw-Hill Medical.
12. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff
RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W. (2007).
Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic
cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of
Clinical Oncology. 25(15):1960-6.
13. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke
C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO,
Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. (2007). Adjuvant chemotherapy with
gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a
randomized controlled trial. JAMA. 297(3):267-77.
14. Harrisons Principles of Internal Medicine, (18th ed). (2011). McGraw-Hill Professional.
15. The Washington Manual Hematology and Oncology Subspecialty Consult, (2nd ed.). (2008).
Lippincott, Williams & Wilkins.

16. Bugat R, Bataillard A, Lesimple T, Voigt JJ, Culine S, Lortholary A, Merrouche Y, Ganem G, Kaminsky
MC, Negrier S, Perol M, Lafort C, Bedossa P, Bertrand G, Coindre JM, Fizazi K. (2002). Summary of
the Standards, Options and Recommendations for the management of patients with carcinoma of
unknown primary site. British Journal of Cancer. 89 Suppl 1:S59-66.
17. Monsuez JJ, Charniot JC, Vignat N, Artigou JY. (2010). Cardiac side-effects of cancer chemotherapy.
International Journal of Cardiology. 144(1):3-15.
18. NCCN guidelines for breast cancer (accessed on 7/30/12)
19. NCCN guidelines for colon cancer (accessed on 8/24/2012)
20. NCCN guidelines for esophageal cancer (accessed on 8/25/2012)
21. NCCN guidelines for Hodgkin lymphoma (accessed on 7/30/12)
22. NCCN guidelines for Non-Hodgkins lymphomas (accessed on 7/30/12)
23. NCCN guidelines for pancreatic cancer (accessed 8/25/2012)
24. Harrisons Online, Chapter 276, Oncologic Emergencies, Structural-Obstructive Oncologic
Emergencies.
25. Harrisons Online, Chapter 276, Oncologic Emergencies, Metabolic Emergencies.
26. Harrisons Online, Chapter 353, Disorders of the Parathyroid Gland and Calcium Homeostasis,
Hypercalcemia.
27. Harrisons Online, Chapter 276, Oncologic Emergencies, Treatment-Related Emergencies.
28. NCCN guidelines, prevention and treatment of cancer-related infections.
29. NCCN guidelines, genetic/familial high-risk assessment: breast and ovarian.
30. NCCN guidelines, colorectal cancer screening.
31. Harrisons Online, Chapter 89, Neoplasms of the Lung, Clinical Manifestations.
32. Harrisons Online, Chapter 95. Benign and Malignant Disease of the Prostate.
33. American Cancer Society website: http://www.cancer.org/Cancer/ProstateCancer/MoreInformation
ProstateCancerEarlyDetection/prostate-cancer-early-detection-acs-recommendations
34. NCCN Guidelines prostate cancer early detection.
35. Goodman and Gillmans The Pharmacological Basis of Therapeutics, chapter 67, Carcinogens and
Chemoprevention.
MEDICAL ONCOLOGY149
NOTES

12 Endocrinology, Diabetes, &
Metabolism
Yashaswini Yeragunta, MD
Edward Kessler, MD
C o n t e n t s
12.1 ADRENAL GLAND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
12.2 DISORDERS OF THE PITUITARY GLAND . . . . . . . 152
12.3 DISORDERS OF THE THYROID GLAND . . . . . . . . . 155
12.4 CALCIUM AND BONE DISORDERS . . . . . . . . . . . . . . 161
12.5 Hypercalcemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
12.6 HYPOCALCEMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
12.7 DIAGNOSIS AND CLASSIFICATION OF DIABETES
MELLITUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
12.8 REPRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
ENDOCRINOLOGY, DIABETES, & METABOLISM149
12.1 ADRENAL GLAND
The adrenal cortex produces 3 classes of steroids: Glucocorticoids (i.e., cortisol),
mineralocorticoids (i.e., aldosterone) and androgen (dehydroepiandrosterone)
The diagnostic test of choice for glucocorticoid excess is the dexamethasone suppression
test
The diagnostic test of choice of glucocorticoid deficiency is cosyntropin stimulation test
Mineralocorticoid deficiency is characterized by renin excess
Mineralocorticoid excess is heralded by renin suppression
Cushing Syndrome
Disorder of glucocorticoids excess, which can either be ACTH driven (pituitary tumor or
ectopic ACTH tumor), non-ACTH driven (adrenal adenoma or hyperplasia), or iatrogenic
(use of exogenous steroids, which is most common)
Most commonly seen in women or prepubertal aged men
McCune-Albright syndrome is glucocorticoid excess, non ACTH driven, associated with
polyostotic fibrous dysplasia, unilateral caf-au-lait spots, and precocious puberty
Clinical Features
Common symptoms include: Skin manifestations (bruising, striae, acne), diabetes, truncal
obesity, proximal myopathy, hirsutism, and hypertension
Due to hypercoagulable state, they are at high risk for venous thromboembolism
Increased rate of cardiovascular disease and osteoporosis with vertebral fractures are
noted in patients with Cushings even after effective treatment
Diagnosis
See Figure on Diagnosis of Cushing Syndrome
Figure 12.1: Diagnosis of Cushing Syndrome
High index of clinical suspicion
Check urine 24 hr cortisol

Dexamethasone suppression test*
Midnight cortisol >130 nmol/L
Check ACTH
Confirmatory testing can be done
by low dose dexamthesone
suppression test
HIGH LOW
Ectpoic ACTH Adrenal

Pituitary tumor Adrenal mass
source hyperplasia
(micro or
macro)

Low dose dexamethasone test is performed by dexamethasone 0.5 mg IV q6 hours for 2
days and plasma cortisol level is >50 mg/dl
Inferior petrosal sinus sampling, CT abdomen/pelvis and octreotide scan may be
considered when there is a negative MRI for negative pituitary scan with an elevated
ACTH level
Dexamethasone suppression test is done by administering 1 mg dexamethasone at 11 pm
and morning cortisol is >50 nmol/L at 8 am
Treatment
Treatment is based on underlying cause
For non ACTH driven tumors, depending on tumor size either a minimally invasive
approach or open surgical approach for adrenal tumors
Pituitary tumors (ACTH driven) are best treated by transsphenoidal resection
If unknown origin or ectopic ACTH secretion, treatment entails medical suppression prior
to surgical intervention such as bilateral adrenalectomy
In select patients (complications such as psychosis or hypertension), consider medical
suppression therapy prior to surgical intervention
In non surgical candidates, medical treatment includes metyrapone and ketoconazole
Post operatively, hydrocortisone replacement must be started immediately with cautious
taper to avoid cortisol withdrawal syndrome
Cortisol withdrawal syndrome is characterized by hypotension, nausea, fatigue, myalgias,
arthralgias, and dry skin
Mineralocorticoid Excess
Most common etiology is adrenal hyperplasia
Other causes include adrenocortical carcinoma and congenital adrenal hyperplasia
Liddles syndrome is a rare autosomal dominant mutation in sodium channel with features
of aldosterone excess (hypertension, metabolic alkalosis, hypokalemia), but found to have
low renin and aldosterone levels
Diagnosis
Screening for mineralocorticoid excess in setting of hypokalemic hypertension, early
onset of hypertension age prior to 40 years of age and hypertension associated with
drug resistance
Test for renin and aldosterone levels after stoppage for any mineralocorticoid active
drugs (i.e., spironolactone and ACEI/ARB) for at least 4 weeks
The test is positive if ratio is >750 pmol/L: ng/mL per hour with high/normal aldosterone
Aldosterone to plasma renin activity levels >20 in patients off ACEI/ARBS and >10 in
patients on ACEI and ARBS is indicative of hyperaldosteronism
Adrenal Incidentaloma
Defined as an adrenal mass, generally 1 cm or more in diameter that is discovered
serendipitously during a radiologic examination performed for indications other than an
evaluation for adrenal disease
Incidence increases with age, for example incidence between ages 20 to 29 is
approximately 0.2%, as compared with approximately 7% in a patient over 70 years of age
Functional assessment may reveal: Subclinical Cushing syndrome, clinically silent
pheochromocytoma, primary aldosteronism
Assessment of malignant potential
Size of the mass and imaging are major predictors of malignant potential
Size greater than 4 cm or growth greater than 1 cm on repeat imaging (at 6, 12, 24
month intervals) is commonly recommended to be resected
Adrenal tumors should be removed if they are functional
Imaging phenotype
Lipid content and time of washout aid distinguishing adenomas from non adenomas
Metastatic disease
Carcinomas of lung, breast, colon, esophagus, pancreas, and liver frequently
metastasize to the adrenals and are frequently bilateral
Because of the high cost, FDG-PET is not recommended routinely for evaluation with
no history of malignancy
Fine needle aspiration biopsy
To be used with caution for pheochromocytoma as it can precipitate crisis, hence
definitive biochemical functional assessments should be performed prior to biopsy
12.2 DISORDERS OF THE PITUITARY GLAND

Multiple Endocrine Neoplasia
Autosomal dominant inheritance
MEN 1: Involves pituitary, parathyroid, and pancreas (gastrinoma-Zollinger Ellison syndrome
most common)
Presents in 40 to 50 year old age group and due to mutation of chromosome 11 at q13 locus
Screening of first degree relatives may be offered in confirmed cases
Once established screen 1 to 2 years from 15 years of age is the recommendation
MEN 2A: Involves medullary carcinoma of thyroid, hyperparathyroidism, and
pheochromocytoma
Total thyroidectomy is the standard of care for thyroid medullary carcinoma
MEN 2B: Involves medullary carcinoma of thyroid, pheochromocytoma, and multiple
mucosal neuromas
Both MEN 2 subtypes are associated with mutation in RET proto-oncogene and is used as a
screening tool
Hypopituitarism
Micro are defined as tumors >10 mm radiologically and micro are <10 mm
Pituitary adenomas, radiation, trauma, and surgery are common etiologies of
hypopituitarism
Clinical effects of hypopituitarism depend on concomitant hormone deficiency
Growth Hormone Deficiency
Regulated by growth hormone-releasing hormone
Short stature in children; in adults causes decreased strength, libido, increased body fat,
decreased cardiac output
Treatment with GH replacement improves all the above complaints but can have
unfavorable effects such as arthralgias and fluid retention, hypertension, gynecomastia,
and acromegaly

TSH Deficiency
Hypothyroidism and manifestation and therapies are discussed in detail in the thyroid
portion of this chapter
Gonadotropin Deficiency
This is the most common deficiency detected probably due to the obvious clinical
manifestations warranting medical attention
It causes amenorrhea, lack of libido, infertility, and osteopenia
Gonadotropin deficiencies are noted not only in pituitary tumors/malfunction but also in
severe critical ill states like anorexia nervosa
Prolactinoma
Etiologies are due to prolactin excess from the gland or any mechanism interfering with
dopamine inhibiting release of prolactin
Medications that interfere with dopamine include tricyclic antidepressants,
metoclopramide, cocaine, and opiates
Natural states of hyperprolactinemia are pregnancy, newborn, sleep, and intercourse
Oligomenorrhea, amenorrhea, or galactorrhea in females
Erectile dysfunction, lack of libido, mass effects like headache, and visual changes in men
Laboratory detection is by serum prolactin levels >200 ug/L, excluding any offending
drugs
MRI is imaging of choice
Treatment
Bromocriptine and cabergoline suppress prolactin as dopamine agonists
These medications have also demonstrated reduction in tumor size
Side effects are multiple and include constipation, dry mouth, insomnia, nausea, vomiting,
and hypotension
Surgery is an option for refractory to medical therapy patients
Diabetes Insipidus
Characterized by deficiency of vasopressin
Suspected in situations with high urine output (greater than 50mL/kg) and urine osmolality
<300 mOsmol/L
Etiology
Central - genetic, inherited, tumor, craniopharyngioma, cancer, infectious causes,
aneurysms, Sheehan syndrome, autoimmune
Nephrogenic - resistance to vasopressin
Drug induced - lithium, demeclocycline, amphotericin B, and antibiotics (i.e.,
aminoglycosides)
Clinical Features
Symptoms include polyuria, polydipsia, enuresis, and excessive thirst
Serum osmolarity <300 mOsmol/L
Water deprivation test:
Measure osmolarity (serum and urine) at baseline and every 2 hours until serum
osmolarity is >295 mOsmol/kg and the patient has lost no more than 3% body
weight. Subsequently, after administration of 5 ug of desmopressin intranasally or
intravenously, the osmolarity is re-measured
Healthy patients, during water deprivation, will increase urine osmolarity >800 mOsmol/
kg as an appropriate response, whereas patients with DI, will not have a rise in urine
osmolarity >300 mOsmol/kg
In patients with central DI, there will be rise in osmolarity of 50% or greater in osmolarity
in response to desmopressin
In nephrogenic DI, there will be little or no response in urine osmolarity to desmopressin
Treatment
Nephrogenic DI treatment includes high dose desmopressin, thiazides and NSAIDs
(i.e., indomethacin)
Central DI requires desmopressin replacementavailable in subcutaneous, intranasally, or
oral forms
Acromegaly
Caused by excessive GH secretion from pituitary or hypothalamic cause
Clinical Features
Enlargement of nose, lip, tongue, frontal bossing, enlargement of hands and feet,
amenorrhea, cardiomegaly, cardmyopathy, hypertension, diabetes
Diagnosis
Diagnosis is established by IGF-1 levels which has high sensitivity
Direct measurement of GH secretion is futile due to pulsatile nature of GH
Oral glucose tolerance test is confirmatory
Treatment
Surgical resection (transphenoidal approach) is primary treatment for GH secreting
adenomas
Current medical therapies include dopamine agonists (i.e., cabergoline), octreotide
(decreases GH and IGF levels) and pegvisomant (synthetic GH analogue, blocks GH
receptor)
Radiation therapy can be offered in recalcitrant or unresectable cases
Early screening colonoscopy with close follow up every 3 to 5 years is recommended due
high propensity of colonic polyps

12.3 DISORDERS OF THE THYROID GLAND
Thyroid Physiology
Figure 12.2: Thyroid Physiology
Hypothalamus
TRH
Pituitary
T3 + T4
TSH
Liver
T3 + T4
Thyroid
Hypothyroidism
Clinical Features
Depression
Fatigue
Delayed DTR
Bradycardia
Diastolic hypertension
Constipation
Menorrhagia
Dry skin
Thin hair
Cold intolerance
Weight gain
Etiology
Most common cause is iodine deficiency, autoimmune disorders (Hashimotos) and
Iatrogenic
Other causes include medications like iodine, amiodarone, lithium, congenital
hypothyroidism, and dyshormonogenesis, infiltrative disorders (i.e., amyloid, sarcoid and
scleroderma), postpartum thyroiditis
Secondary causes include hypopituitarism or hypothalamic disease (i.e., tumors, surgery,
irradiation, trauma and ischemia)
Diagnosis
Figure 12.3. Approach to Diagnosis of Hypothyroidism
TSH, T4
High TSH, High TSH Low TSH

fT4 WNL Low fT4 Low fT4
Subclinical Primary Secondary (pitu-

hypothyroidism hypothyroidism itary) vs. tertiary
(hypothalamus)
hypothyroidism
Check anti-TPO Check anti-TPO
MRI brain
Repeat eval in Autoimmune Secondary causes

1-2mo hypothyroidism Surgery
Radiation
Medications
Congenital
Iodine deficiency
Infiltrative disease
Etiologies of falsely low T3/T4: Lab error, cirrhosis, nephrotic syndrome, severe illness,
and medications
Etiologies of falsely high TSH: Exercise, sleep deprivation, recovery from nonthyroidal
illness, elderly
Treatment
Treatment for hypothyroidism is based on levothyroxine replacement
Adults require around 1.7 microg/kg of body weight
The American Thyroid Society recommends starting full replacement in patients younger
than 50 years
Patients 50 years or older should be started at 25-50 mcg daily
Re-evaluate thyroid function studies at 6 to 8 week intervals and titrate levothyroxine
Special situations
Sick euthyroid syndrome noted in the setting of severe stress (shock, surgery,
malnutrition) due to increased metabolism or inhibition of thyroid hormone binding.
Laboratory findings include normal TSH, low T4, and increased reverse T3
Treatment with thyroid hormone replacement is not indicated. Treat the underlying
cause
Thyrotoxicosis
Defined as an excess of thyroid hormones. Thyrotoxicosis is not synonymous with
hyperthyroidism, which is the result of excess thyroid function

Etiologies
Primary causes include Graves' disease, toxic multinodular goiter, toxic adenomas, thyroid
carcinoma, struma ovarii, and iodine excess
Secondary causes include pituitary adenoma, gestational thyrotoxicosis, and thyroid
hormone resistance
Causes of thyrotoxicosis without hyperthyroidism are subacute thyroiditis and thyroid
destruction due to amiodarone and radiation
Graves' disease is autoimmune phenomenon cause by TSI
Clinical features include weight loss, anxiety, insomnia, tremors, palpitations, tachycardia,
dyspnea, diarrhea, and irregular menses
Graves' disease has more specific findings that can include ophthalmopathy like lid
retraction, periorbital edema, conjunctival injection, proptosis, pretibial myxedema, and
acropachy
Diagnosis
Figure 12.4. Approach to Diagnosis of Thyrotoxicosis
Check TSH/T4
Low TSH, High FT4 Low TSH, FT4 WHL High TSH, High FT4
Primary Central vs. thyroid

Check T3 Level
thyrotoxicosis hormone resistance
Diffuse goiter,
t3 thyrotoxicosis High Normal
dermatopathy,
ophthalmopathy
Subclinical
hypterthyroidism
Negative Recheck labs in

6-12 weeks
Check anti TPO, TSI

Positive Negative
and TPII
Radioactive iodine
Graves' disease
uptake scan
Single focus of Multiple foci

Diffuse Low
uptake of uptake
Toxic multinodular Destructive

Graves' disease Toxic adehoma thyroiditis vs
goiter
exogenous
hormone
exposure
Treatment
Graves'
1. Antithyroid medications (methimazole, carbimazole, and PTU)
2. b-blocker for symptom control
3. Therapeutic radioactive iodine
Antithyroid medications (ATM)
All medications inhibit TPO function
Propylthiouracil additionally inhibits deiodination of T4 to T3
Clinical exam, and unbound free T4 every 4 weeks to aid titration of
medications

TSH is not an index of treatment response
Levothyroxine may or may not be started
Follow for relapse annually
Short term treatment in preparation for thyroidectomy
Radioactive iodine (RAI)
Stop ATM at least 2 days prior to RAI
Usually only requires 1 treatment dose for remission
Signs/symptoms may last for 3 months post treatment
Contraindications: Pregnancy, breast feeding
Thyroidectomy: Subtotal/near-total: Offered for relapse or treatment failure; preferred if
large goiter
Special situations
Graves' ophthalmopathy: Treatment with adjunctive steroid regimen; artificial tears
Thyrotoxic crisis: Caused by stroke, trauma, surgery, infection, DKA, radioactive
iodine treatment; supportive care and treatment of underlying cause, may consider
PTU
Thyroiditis
Acute
Rare presentation typically due to infectious etiologiesmost commonly related to
presence of piriform sinus in youth, but also concerning for malignancy in elderly
Typical signs/symptoms: Neck/thyroid pain with radiation to ears
Lab evaluation: TSH/T4 normal; diagnosis guided by biopsy, stain, and culture results
Subacute (De Quervains, Granulomatous, or Viral Thyroiditis)
Viral etiology (mumps, Coxsackie, adenovirus, influenza, echovirus, etc.)
Diagnosis: Clinical presentation vague and similar to URI/pharyngitis
Lab evaluation: Vary by stages, early stage (thyrotoxic phase with elevated T4 and T3,
low TSH; hypothyroid phase with elevated TSH and low T4/T3 and recovery phase with
normal thyroid function tests)
Treatment for pain and fever: Acetaminophen may reduce pain and fever; aspirin or
NSAIDs may treat inflammation and fever; refractory treatment include steroids
Silent
Minimal symptoms hence silent
Most commonly occurs post partum (3 to 6 months); Similar course as subacute
thyroiditis
Initial toxicosis lasts 2 to 4 weeks and hypothyroidism lasts 4 to 12 weeks
Associated with type 1 DM
Painless goiter, differentiated from subacute thyroiditis with normal ESR and +TPO
antibodies
No treatment until symptom of thyrotoxicosis manage with b-blocker; levothyroxine
replacement in hypothyroid phase
Drug Induced
Common inciting agents include interferon alpha, IL-2, and amiodarone
Chronic
Hashimotos thyroiditis: Most commonly seen in women. Usually painful. Autoimmune in
origin
Riedels thyroiditis: Usually painless goiter with compressive symptoms on the esophagus,
trachea. Hard on palpation and easily mistaken for malignancy
FNA biopsy is usually inadequate and open biopsy is required for diagnosis
Treatment is usually surgical
Sick euthyroid syndrome
Noted mostly in people with critical illness
Impaired conversion of T4 to T3 resulting in normal TSH, normal T4, but low T3 with
elevation in reverse T3. Fluctuations noted in TSH. Deficiencies usually correct after
treating critical illness
Goiter and Nodules

Goiter is enlargement of the thyroid gland
Multiple etiologies related to thyroid hormone dysgenesis leads to elevated TSH which
causes gland hyperplasia and hence goiter
Diffuse Non-toxic Goiter
Diffuse enlargement with no nodules and biochemical euthyroid state
Most commonly secondary to Iodine deficiency
Asymptomatic, symmetric, enlarged, non-tender
Lab findings include normal TSH, low T4, and normal T3
Treatment is iodine or thyroid hormone replacement, which may or may not lead to
resolution of the goiter
Surgery rarely indicated except for complications like obstruction/compression of
surrounding tissues
Radioactive iodine is effective in majority of the patients in reducing goiter size. Patients
should be followed-up for hypothyroidism
Non-toxic Multinodular Goiter (NTMN)
Multifactorial etiology
Usually asymptomatic and euthyroid
Symptoms such as pain, dysphagia, swelling, respiratory distress, and hoarseness with
NTMN concerning for cancer
Diagnosis: Exam with multiple variant nodules, TSH usually normal
Ultrasound guided biopsy for diagnosis
Treatment includes levothyroxine with glandular suppression and need to monitor for
thyrotoxicosis
Caution with iodine containing substances like contrast agents due to risk of inducing
Jod-Basedow phenomenon (Thyroid hyperfunction)
Surgery is highly effective
Toxic Multinodular Goiter
Multifactorial etiology
Presentation is variable and may include tachycardia, palpitations, dyspnea, anxiety, and
tremors
TSH low, T4 normal to high, T3 greater than T4
Thyroid scan shows multiple regions of variable uptake
Treatment is essentially symptom driven
Radioactive iodine to decrease the mass and separate active nodules. b-blocker and anti-
thyroid drugs help with overall thyrotoxicosis symptom control

Toxic Adenoma
TSH receptor mutation leads to hyperfunctioning gland
Diagnosis is by thyroid scan with hyperfunctioning focal nodule
Treatment is with radioiodine ablation (i-131). Surgery is also effective
Thyroid Neoplasms
Benign
Follicular adenoma
Based on morphology, micro- (fetal), normal- (simple), macrofollicular (colloid), trabecular
(embryonal), and Hrthle cell variant (oncolytic)
Frequently, nodules noted to be thyroid cysts diagnosed on ultrasound or aspiration,
prone to recurrence and may necessitate excision
Pregnancy and Thyroid

During pregnancy, elevation of BHCG and estrogen lead to activation of the TSH receptor
and elevation of TBG respectively
In addition, there is an increased metabolism of T3 and T4 by placenta
May lead to maternal and fetal hypothyroidism, which is of concern especially during the 1st
trimester due to fetal dependence on maternal thyroid hormone necessitating early thyroid
function assessment
Pregnant patients with Graves disease are often treated with PTU during 1st trimester and
later changed to methimazole due to teratogenicity of the respective agents
Monitor TSI during pregnancy to aid titration/discontinuation of medications
Elevated TSI is associated with fetal Graves' disease
12.4 CALCIUM AND BONE DISORDERS

Regulation of calcium metabolism
Hypercalcemia
Hypocalcemia
Osteoporosis
Osteomalacia
Paget disease of the bone
Hypophosphatemia
Etiologies: Reduced or impaired absorption in the intestine due to intake of sevelamer or
aluminum containing antacids
Depressed renal reabsorption in primary or secondary hyperparathyroidism and
hypercalcemia of malignancy
Rapid redistribution responsible for low serum availability due to insulin therapy,
catecholamines, intravenous glucose, after parathyroidectomy, leukemic blast crisis, and
catecholamine surge
Clinical manifestations include but are not limited to lethargy, confusion, hallucinations,
paresthesia, including visceral malfunction such as cardiomyopathy and respiratory
compromise due to muscle fatigue
Serious consequences like paralysis and seizures are noted at very low levels (less than
1 mg/dl)
Treatment includes aggressive replacement using sodium or potassium phosphate salts
Treat underlying cause and concomitant electrolyte and nutritional deficits including vitamin D
Hyperphosphatemia
Most common etiology is renal failureacute or chronic
Also noted in hypoparathyroidism, hypomagnesemia, pseudohypoparathyroidism, crush
injuries, rhabdomyolysis, hyperthermia, and acidosis causing transcellular shifts
Clinical manifestations are due to calcium binding resulting in hypocalcemia, which may
lead to tetany, seizures, etc.
Treatment
Phosphate binders (i.e., sevelamer) limit intestinal absorption
Fluid resuscitation aid renal clearance
Consider hemodialysis in severe and/or symptomatic hypocalcemia
Parathyroid Hormone
Secreted by the parathyroids
Acts on the kidney to produce 1,25 vitamin D, which enhances renal calcium reabsorption
and on the bone osteoclasts to increase serum calcium concentration
Indirectly influences intestinal calcium absorption via 1,25 vitamin D
The serum ionized calcium level closely regulates PTH level through a negative feedback
mechanism
Calcitonin is a PTH antagonist secreted by the thyroid and inhibits osteoclast bone
resorption
12.5 Hypercalcemia
Causes
Hyperparathyroidism mainly causing raised PTH level, resulting in raised calcium levels
Granulomatous diseases like sarcoidosis and lymphomaelevated vitamin D levels leads to
increased absorption
Genetic causes such as familial hypocalciuric hypercalcemia with impaired parathyroid and
renal calcium receptors
Increased intake (i.e., milk-alkali syndrome)
Malignancy (i.e., breast cancer, myeloma, lytic lesions)
Medications (i.e., thiazide diuretics)
Rapid increase in calcium level has more pronounced clinical presentations, including
lethargy, altered mental status, seizures, and may result in coma if untreated
Chronic elevation of calcium level can lead to varied presentation like renal stones, gastritis,
pancreatitis, constipation, and fractures
Laboratory Detection
Intact PTH assay helpful to diagnose various etiologies such as primary hyperparathyroidism
or rapid bone turnover
Treatment
IVF resuscitation
Loop diuretics (i.e., furosemide) should be used only after adequate volume replacement

Bisphosphonates (i.e., zoledronic acid and pamidronate) are very effective and act via
inhibiting bone resorption
Zoledronic acid has the fastest onset of action and long half life (198 hours)
Calcitonin, especially in patients with poor kidney function in which bisphosphonates are
relatively contraindicated
In hypervitaminosis D, glucocorticoids are the treatment of choice as it reduces production
of vitamin D
In hypercalcemia of malignancy, it is important to treat the underlying malignancy
12.6 HYPOCALCEMIA
Serum calcium level drops by 0.8 mg/dl for every 1 gm/dl drop in serum albumin
It is important to distinguish true hypocalcemia from falsely low secondary to low albumin
Most common etiology is chronic kidney disease, with its low vitamin D level and
hyperphosphatemia
Also noted in electrolyte abnormalities like hypomagnesemia, hypoparathyroidism from
genetic causes, and chronic vitamin D deficiency from poor PO intake
Includes tetany, carpopedal spasm, Chvosteks sign (tapping of facial nerve leading to
twitching)
Prolong QT leading to life-threatening ventricular abnormalities
Laboratory evaluation begins with measuring serum albumin and Ionized calcium level to
assess accurately hypocalcemia
Next is to measure PTH level and determine if there is an appropriate response to
hypocalcemia
Vitamin D level should be assessed as well as other possibilities including CKD
Treatment
Calcium carbonate supplements offer the highest elemental calcium
Per FDA, dietary calcium requirements around 1,000 mg for men and premenopausal
women
Achlorhydric patients (like those on PPI) have difficulty absorbing calcium
In case of dangerously low Ionized calcium (ionized calcium below 1.15 mg/dl) with EKG
abnormalities, monitor patients with aggressive replacement using intravenous infusion of
calcium gluconate/chloride with dextrose
Concomitant vitamin D supplementation is beneficial
Less expensive ergocalciferol or the more expensive active form of vitamin D3 can be
utilized
12.7 DIAGNOSIS AND CLASSIFICATION OF DIABETES MELLITUS
Diabetes mellitus is a disease based on insulin deficiency or increased resistance to insulin
actions. It is presently classified on the basis of pathogenesis.
Type 1: Immune medicated, associated with beta cell destruction
Type 2: Varying degrees of insulin resistance with subsequent deficiencies secondary to
secretory defect
Gestational diabetes mellitus: Onset of hyperglycemia during gestation
Other types: Genetic defects leading to maturity onset diabetes of the young
Diseases of exocrine pancreas secondary to chronic pancreatitis, cystic fibrosis, and
hemochromatosis
Diagnosis
Present if any 1 of the following are there:
New onset Hba1c >/=6.5 gm% or fasting blood glucose >/=126 mg/dl or random glucose
>/=200 mg/dl
2 hour plasma glucose is greater than/equal to 200 mg/dl
For gestational diabetes:
Fasting > equal to 92 mg/dl
1 hr > equal to 180 mg/dl
2 hr > equal to 153 mg/dl
Performed at 24 weeks of gestation
Treatment
Goals
Hemoglobin A1C: <7.0 gm%
Pre-prandial plasma glucose: 70-130 mg/dl
Postprandial plasma glucose: <180 mg/dl
Blood pressure: <130/80 mmHg
LDL: 100 mg/dl (with extensive cardiovascular disease <70 mg/dl)
HDL-cholesterol
Men: >40 mg/dl
Women: >50 mg/dl
Triglycerides: <150 mg/dl
Oral Hypoglycemic Agents
Insulin
Short acting - regular insulin
Onset of action: 30 min
Duration of action: 4 to 8 hrs
Lispro insulin
Onset of action: <15 min
Peak of action: 1 hr
Intermediate acting - NPH insulin
Onset of action: 2 to 4 hrs
Peak of action: Within 8 to 10 hrs

Long acting- Glargine insulin
Onset of action: 2 to 3 hrs
Peak of action: None
Detemir insulin
Onset of action: 1 hr
Peak of action: None
Complications
Acute
DKA (Diabetic Ketoacidosis)
Secondary to insulin deficiency from various causesmost commonly dietary, medication
non-compliance, infection, pancreatitis, and other stress states. Imbalance between
endogenous production and glucagon overproduction leading to hyperglycemia, ketosis,
and anion gap metabolic acidosis
Laboratory findings: Blood glucose >250 mg/dl, serum ketones at a dilution of 1:8 or
greater, hyperkalemia (serum potassium of 5-8 meq/slight hyponatremia, serum sodium
of approximately 130 meq/l), hyperphosphatemia (serum phosphate level of 6-7 mg/dl).
Acidosis maybe severe with pH 6.9-7.2 and serum bicarbonate between 5-15 meq/dl
HONK (Hyperosmolar Nonketotic State)
Secondary to similar etiologies as DKA. Relative insulin deficiency but without significant
ketone production
Laboratory findings: Hyperglycemia >600 mg/dl, serum osmolarity >310 mOsm/kg,
bicarbonate >15 meq/L and normal anion gap
Treatment: Similar for both conditions essentially based on degree of severity with goals
to restore plasma volume deficit, reduce blood glucose, and replenish electrolytes
Plasma Volume Deficit
Around 4-5 L. Usually with 0.9% normal saline or 0.45% normal saline (if serum sodium is
>150 mEq/L). Switch to dextrose 5% once blood glucose <250 mg/dl
Insulin Replacement
IV regular insulin is preferred. Continuous drip is to be titrated based on hourly blood
sugar levels. In HONK, relatively less overall requirement in comparison to DKA
Electrolyte replacement, especially potassium and phosphorus, as needed
Chronic
Ophthalmological complications: Retinopathy, macular edema, cataracts
Nephropathy: Proteinuria/microalbuminuria 30 to 300 ug albumin/24 hrs to overt
proteinuria >300 mg/d. ACEI and ARB. This can be effectively type 4 renal tubular
acidosis, ESRD
Neuropathy
Distal symmetric nephropathy
Isolated peripheral neuropathy
Painful diabetic neuropathy
Autonomic neuropathy
Cardiovascular disease: Coronary artery disease
Gastrointestinal: Gastroparesis
Sexual dysfunction
Dermatologic manifestations: Acanthosis nigricans
12.8 REPRODUCTION
Male Physiology
Hypothalamus produces gonadotropin releasing hormone (GNRH) which acts on the
pituitary to produce luteinizing hormone (LH) and follicular stimulating hormone (FSH)
LH stimulates Leydig cells to produce testosterone
FSH stimulates Sertoli cells which aid in spermatogenesis and inhibin B, which provides
feedback inhibition on FSH release
Most testosterone bound to sex hormone binding globulin (SHBG); less than 5% of
testosterone remains unbound or bound to albumin
Hypogonadism
Etiologies
Primary etiologies: Genetic (i.e., Klinefelters), androgen resistance, infection, medication/
toxins (alcohol, azoles, androgen-inhibition, chemotherapy, etc.), and trauma
Secondary etiologies: Multifactorial and affecting hypothalamus/pituitary including
masses (tumors), systemic/infiltrative disease (hemochromatosis, amyloid, etc.), ischemic
insults, malnutrition, and medication/toxins
In pre-/peri-pubertal states, features include small testes, delayed/arrested maturation,
infertility, lack of secondary sexual characteristics
In post pubertal states: Infertility, erectile dysfunction, decreased libido, small testes,
fatigue, loss of secondary sexual characteristics, and muscular atrophy
Laboratory Evaluations
GNRH, LH, FSH, prolactin, free testosterone levels; may consider karyotype if elevated
GNRH
Treatment
Address primary etiology; testosterone replacement

Figure 12.5: Approach to Diagnosis of Hypogonadism
Signs/symptoms of
hypogonadism
Free testosterone
Normal or elevated
Low testosterone
testosterone
Suspect androgen
Obtain FSH, LH
resistance
Elevated FSH
Low FSH and LH Normal FSH, LH
and/or LH
Secondary Dysfunctional feedback Primary

hypogonadism inhibition hypogonadism
Obtain MRI, prolactin, Prolactin level consider

Obtain karyotype
consider olfactory test MRI, hormone
GNRH stimulation test stimulation assessment
Consider
Above normal and age testosterone
>60 consistent with replacement
ADAM syndrome
Testosterone Replacement
Preparations include intramuscular injections and topical applications
Requires serial assessment of testosterone levels, hemoglobin, hematocrit, lipids, and PSA
Contraindications: Breast cancer, hypersensitivity, and prostate cancer
Erectile Dysfunction
Etiologies
Organic: Inflammation/infection, vaso-occlusive disease, trauma, endocrine disorders (DM,
hypogonadism, hyperprolactinemia), drug/medications
Psychogenic: Anxiety, depression, stress-related disorders
Insufficient erection for intercourse; often times associated with older age, systemic
disease (especially atherosclerosis, peripheral arterial disease, DM), and smoking history
Diagnosis
History/exam (secondary sexual characteristics, hair distribution, heralding signs of other
systemic illnesses, cardiovascular assessment, etc.)
Labs: Testosterone level, prolactin level, GNRH level, BMP, CBC, and lipids
Other tests: Nocturnal tumescence, vascular studies (Doppler, angiography), neurological
evaluation, and psychological evaluation
Treatment
Address underlying etiology
Patient education: Lifestyle counseling, avoid recreational drugs/substances
Therapies
Oral phosphodiesterase inhibitors (sildenafil, vardenafil, etc.)
Onset within 60 to 120 min
Caution with patients with renal dysfunction, co-administration with medications
(nitrates, alpha blockade, azole antibiotics, and other medications metabolized by
CYP3A4 pathway)
Side effects: Bluish visual disturbance and headache
Other therapies: Intraurethral suppositories, intracavernosal injections, prosthesis
implantation, vacuum assist devices
Female Physiology
LH acts on theca cells which release androgens (i.e., androstenedione, testosterone)
FSH acts on granulosa cells leading to increased aromatase and inhibin B; aromatase
converts androgens to estradiol leading to ovulation
Granulosa cells form corpus luteum post ovulation, which secrete progesterone
Unless the egg is fertilized, the corpus luteum regresses, leading to progesterone
withdrawal and then menstruation
Polycystic Ovarian Syndrome (PCOS)
Commonly diagnosed in puberty
Etiologies
Unclear, related to androgen hormone imbalance, amenorrhea, obesity, insulin resistance,
and hirsutism
Irregular menstrual cycles, virilization (i.e., voice changes, decreased breast size, acne, etc.)
Diagnosis
Rotterdam criteria - 2 of 3 of the following:
Irregular/absent ovulation
Elevated androgen levels
Enlarged ovaries with at least 12 follicles
R/O Cushings, hyperprolactinemia, and CAH (congenital adrenal hyperplasia)
Additional tests: Glucose oral tolerance test, fasting lipids
Treatment
Planning for fertility: Metformin (off-label); clomiphene second line
No desire for pregnancy: First-line is spironolactone and oral contraceptive (progesterone
only); second-line: Androgen antagonist
Improvement in hirsutism: Requires at least 3 months of therapy and mechanical removal
(waxing, shaving, etc.)
Amenorrhea
Primary: No menses by age 16 years
Secondary: No menses for 3 months in a female with previous menstrual cycles

Etiologies
Primary: Genetic abnormalities (i.e., Turners, mullerian agenesis), endocrinopathy
(hypopituitarism), androgen resistance
Secondary: Pregnancy, excessive weight loss/malnutrition, Ashermans syndrome, chronic
inflammatory disease (rheumatoid, Crohns, ulcerative colitis, etc.), hyperprolactinemia,
hypothyroidism, PCOS
Diagnosis
For primary amenorrhea
Assess for secondary sexual characteristics
If present: Ultrasonography of uterus
If abnormal karyotype (androgen insensitivity 46 XY, mullerian agenesis 46
XX)
If normal evaluate for outflow obstruction (imperforate hymen, vaginal
septum) and workup as secondary amenorrhea
Not present: Measure FSH and LH
FSH >20 and LH >40 hypergonadotropic hypogonadism
Obtain karyotype (ovarian failure 46 XX, Turners 45 XO)
FSH <5 and LH <5 hypogonadotropic hypogonadism
Consider MRI head to evaluate for CNS mass or defect
Psychiatric assessment: Depression, anorexia
Endocrine assessment: TRH, TSH, OGTT
For secondary amenorrhea
Obtain B HCG
If B HCG is negative, proceed with endocrine evaluation (TRH, TSH, prolactin,
cortisol)
Normal TSH, elevated prolactin MRI head
Abnormal TSH, normal prolactin thyroid disease
If normal TSH and prolactin, then proceed to progesterone withdrawal challenge
Progesterone withdrawal challenge
If withdrawal bleed, its normogonadotropic hypogonadism (androgen insensitivity,
PCOS, Cushings syndrome, outflow obstruction)
If there is no bleed proceed to estrogen/progesterone challenge
Estrogen/progesterone challenge
If no withdrawal bleed, then its outflow obstruction
If withdrawal bleed then proceed to obtain FSH, LH
Obtain FSH, LH
FSH/LH <5 respectively MRI
FSH >20, LH>40 diagnosis is hypogonadotropic hypogonadism premature vs.
post menopausal ovarian failure
References & Suggested READINGS
1. Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;
356(6):601-610. [PMID: 17287480]
2. Young WF Jr. Management approaches to adrenal incidentalomas: a view from Rochester,
Minnesota. Endocrinol Metab Clin North Am. 2000;29:159-185.
3. Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass
(incidentaloma). Ann Intern Med. 2003;138:424-429.
4. David M. Nathan, MD, John B. Buse, MD, PHD, Mayer B. Davidson, MD, Ele Ferrannini, MD,
Rury R. Holman, FRCP, Robert Sherwin, MD and Bernard Zinman, MD. Medical Management of
Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment
of Therapy. A consensus statement of the American Diabetes Association and the European
Association for the Study of Diabetes.
5. Jameson JL. Chapter 338. Principles of Endocrinology. In: Longo DL, Fauci AS, Kasper DL,
Hauser SL, Jameson JL, Loscalzo J, eds. Harrisons Principles of Internal Medicine. 18th ed. New
York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=9139719. Accessed
September 12, 2012.
6. McPhee S, Papadakis M., Rabow M. Current Medical Diagnosis and Treatment. 5th ed. 2012
7. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules
and Differentiated Thyroid Cancer, November 2009.
8. Bahn R., Burch, H., Cooper D., Garber J., Greenlee C., Klein I., Laurberg P., McDougall R., Montori
V., Rivkees S., Ross D., Sosa J., Stan M. Hyperthyroidism and Other Causes of Thyrotoxicosis:
Management Guidelines of the American Thyroid Association and American Association of
Clinical Endocrinologists. The American Thyroid Association and American Association of Clinical
Endocrinologists. Taskforce on Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid, V. 21,
Num. 6, 2011.

NOTES
NOTES

13 Rheumatology/Orthopedics
Saakshi Khattri, MD
C o n t e n t s
13.1 Patient with Suspected Rheumatic Disease . . . 2
13.2 MEDICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
13.3 Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . 7
13.4 Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
13.5 Fibromyalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
13.6 Seronegative Spondyloarthropathies . . . 11
13.7 Systemic Lupus Erythematosus . . . . . . . . . . . . 12
13.8 Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
13.9 Sjgren Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
13.10 Mixed Connective Tissue Disease . . . . . . . . . . . 17
13.11 Crystal-induced Arthropathies . . . . . . . . . . . 17
13.12 Infectious Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . 19
13.13 Idiopathic Inflammatory Myopathies . . . . . 21
13.14 Systemic Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . 22
13.15 Other Systemic Autoinflammatory

Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
RHEUMATOLOGY/ORTHOPEDICS1
13.1 Patient with Suspected Rheumatic Disease
Localized vs. Diffuse Rheumatic Pain
Localized rheumatic pain
Arising from joint or periarticular structures (bursitis, tendinitis, or muscle involvement
for e.g., rotator cuff tear)
Diffuse rheumatic pain
Seen in fibromyalgia
Pain in multiple joints (e.g., RA, Psoriatic arthritis)
Arthralgia, Arthritis, Bursitis, and Tendinitis/Tendonitis

Arthralgia: Pain but no evidence of synovitis/swelling or inflammation
Arthritis: Pain, swelling, redness of affected joint
Bursitis: Inflammation of the fluid-filled sac (bursa) that lies between a tendon and skin, or
between a tendon and bone
Tendinitis: Inflammation or irritation of a tendon
Approach to Patient
Duration of symptoms: Acute or chronic
Number of joints involved: Single (monoarticular), 2 to 4 (oligoarticular), or >5 (polyarticular)
Symmetric vs. asymmetric
Constitutional symptoms: Fevers, chills, malaise, weight loss, and myalgias
Extra-articular involvement: Rash is common in several rheumatic conditions, e.g., malar
rash in SLE, purpura in some vasculitis
Inflammatory vs. noninflammatory (elevated ESR, CRP)
Comorbidities
Laboratory Evaluation
Routine blood work like CBC, comprehensive metabolic panel (creatinine, liver functions,
albumin)
Thrombocytosis, hypoalbuminemia, anemia may suggest an systemic inflammatory process
Leukopenia especially lymphopenia is seen in SLE
Inflammatory markers (ESR, CRP)
Based on history and exam, testing for antibodies like ANA, SSA, SSB, anti-Smith, anti-
dsDNA, ANCA, RNP, anti-Jo1 is done when one suspects a rheumatic condition (discussed
in detail in later sections)
Synovial fluid analysis: WBC count, crystals, gram stain, and culture if septic arthritis is a
concern
Urine analysis looking for protein and RBC casts (in patients with SLE, suspected vasculitis)
Radiological Evaluation
X-ray studies of involved joints (looking for periarticular osteopenia, erosions, soft tissue
swelling, osteophytes)
Musculoskeletal ultrasound is increasingly being used to image joints and soft tissues and
perform ultrasound guided joint aspirations and steroid injections
MRI can be used in certain conditions, e.g., diagnosis avascular necrosis of a joint or
sometimes in RA

CT scan is not a good imaging modality for joint imaging, reserved to evaluate pulmonary
involvement in rheumatic diseases, e.g., scleroderma, ILD associated with RA
Approach to Patients With Multisystem Illness

History and physical exam
Presence of morning stiffness
Joint exam looking for number of swollen joints, number of tender joints
Blood work: Anemia of chronic disease, elevated ESR/CRP, presence of RF, anti-CCP
antibodies
Radiological evaluation may reveal erosions
Evaluating for extra-articular manifestations: ILD is seen in RA may need PFTs, chest
CT scan
Dermatologic lesions in rheumatic conditions
Palpable purpura
ANCA vasculitis
SLE
Cryoglobulinemia
Hypersensitivity vasculitis
Maculopapular rash
Adult onset Still disease
Kawasaki disease
Urticaria like rash
SLE
Urticarial vasculitis
Subcutaneous nodular lesions
Sarcoidosis
Behet's disease
Lupus profundus
Polyarteritis nodosa
Fever and rheumatic conditions
Fever is seen in several rheumatic conditions and in fact fever of unknown origin (FUO)
includes several rheumatic conditions, namely;
1. Rheumatoid arthritis
2. SLE
3. Vasculitis
4. Adult onset Still disease
5. Polymyalgia rheumatic
6. Temporal arteritis
7. Reactive arthritis
8. Rheumatic fever
Inflammatory eye disease and rheumatic diseases
Conjunctivitis: Seen in reactive arthritis (triad of conjunctivitis, urethritis, and arthritis)
Uveitis
1. Ankylosing spondylitis
2. Behet's disease
3. Juvenile idiopathic arthritis
4. Psoriatic arthritis
5. Sarcoidosis
6. SLE
7. Vasculitis like Kawasaki, Cogan syndrome
8. Inflammatory bowel disease
Scleritis
1. Rheumatoid arthritis
2. Wegeners vasculitis
3. Inflammatory bowel disease
4. Ankylosing spondylitis
5. Relapsing polychondritis
6. Behets disease
13.2 Medications
Acetaminophen
Inhibits prostaglandin synthesis centrally, resulting in analgesic effects and alleviation of pain
Acetaminophen is well tolerated when used as directed
May cause International Normalized Ratio (INR) elevation when given concurrently with
warfarin
When communicating with patients about the use of OTC pain medications and discussing
responsible dosing, it is important for you to:
Know the precise amounts of all substances in an OTC formulation
Know the maximum daily dose of all agents contained in OTC formulations
Monitor renal and liver function periodically
Stay abreast of the latest evidence and dosing in order to give patient up-to-date
advice and recommendations
Counsel patients about the reason for use of the medication, frequency of
administration, anticipated effect on symptoms, and possible drug interactions and
potential adverse effects
Advise patients to communicate the quantity of OTC medications used
Emphasize the importance of reading the package labeling sections labeled Warnings
and Directions. One of the FDA proposed changes requires that all OTC products
containing NSAIDs or acetaminophen (including combination products) to list these
ingredients on the products principal display panel and to also specify the potential
for liver toxicity (in the case of acetaminophen) or GI complications (in the case of
NSAIDs) when these products are taken with 3 or more alcoholic drinks daily
Educate parents and caregivers to keep OTC pain medications out of the reach of
young children by storing these medicines in a high location that is out of the childs
eye sight
Instruct patients to avoid using more than 1 medicine that contains the same active
ingredient

Educate patients of the increased risk for bleeding if acetaminophen is taken with
warfarin, a blood thinning drug
Monitor a patients PT or INR level when a patient is on warfarin and other medications
are started, discontinued or taken regularly. Acetaminophen taken with warfarin
may increase a patients International Normalized Ratio (INR), which may indicate an
increased risk for bleeding
Anti-inflammatory Agents
NSAIDs: Inhibit cyclooxygenase (COX) thereby decreasing prostaglandins with resultant
anti-inflammatory effects
GI side effects (gastritis, dyspepsia, peptic ulcer disease) are the most common
complications
Need to monitor electrolytes and renal functions
Selective COX-2 inhibitors are associated with adverse cardiovascular outcome
Corticosteroids: Anti-inflammatory effects through various mechanisms (upregulation of
the production of anti-inflammatory proteins, inhibit pro-inflammatory cytokines, decrease
eosinophils, and migration of neutrophils to sites of inflammation)
Intravenous pulse methylprednisolone used for severe life threatening complications of
SLE, vasculitis, and myositis
High dose prednisone 1 mg/kg/d used for controlling severe manifestations of
rheumatic conditions
Prolonged use of steroids results in suppression of adrenal glands
Side effects include GI complications, thinning of skin, osteoporosis, and increased risk
of infections
Immunosuppressive Agents and Disease-modifying Antirheumatic Drugs

Methotrexate: Inhibits dihydrofolate reductase
Given as a weekly dose either oral or subcutaneously
Folic acid is given daily to prevent side effects
Liver function needs to be monitored while on methotrexate
Women of child-bearing age need to use contraception and breast feeding is not
allowed while taking methotrexate
Starting dose is 7.5-10 mg/weekly, which can be slowly tapered to maximum dose of
20-25 mg/weekly
Hydroxychloroquine: Used to treat cutaneous manifestations of SLE and as a part of
combination DMARD therapy in rheumatoid arthritis
Baseline macula exam should be done before starting therapy and repeat exam every
6 to 12 months done while on therapy
G-6-P-D levels should be checked prior to initiating therapy as G-6-P-D deficiency
results in hemolytic anemia
Dose is 200-400 mg daily
Sulfasalazine: Used to treat rheumatoid arthritis and spondyloarthropathies
Starting dose is 500 mg a day, which can be slowly increased to maximum dose of 3 g
daily as tolerated
Nausea, vomiting, and dyspepsia are common side effects
Leukopenia, anemia, and thrombocytopenia can also occur
Leflunomide: Inhibits dihydro-orotate dehydrogenase
Daily dosing 10-20 mg
Has a long half-life
If women on leflunomide decide to get pregnant then there is a need to administer
cholestyramine to clear leflunomide from system
Azathioprine: Blocks purine synthesis
Nausea and vomiting are common side effects
Enzyme thiopurine-S-methyltransferase (TPMT) deactivates active metabolite of
azathioprine and should be measured prior to starting therapy, deficiency of that
enzyme is an absolute contraindication to starting therapy
Bone marrow suppression is a rare complication
Used to treat SLE, rheumatoid arthritis, as steroid sparing agent in myositis, can be
used in maintenance phase of lupus nephritis and vasculitis
Dose is 50-150 mg/d
Cyclophosphamide: Depletes B- and T-cells
Used to treat systemic vasculitis, lupus nephritis, ILD occurring as a complication of
systemic sclerosis
Can be given as daily oral dosing or monthly infusions (NIH protocol) or infusions every
2 weeks (EURO-lupus protocol)
Oral dose is 2 mg/kg/d
Intravenous dose is 500-1,000 mg/m2 body surface area
Dose should be adjusted based on creatinine clearance
Fall in WBC is noted 7 to 10 days after IV administration and if WBC level falls below
1,500 then dose should be reduced on subsequent infusions
Ovarian failure is the most serious side effect of this therapy and risk increases with age
of women
Mycophenolate mofetil: Inhibits inosine monophosphate dehydrogenase
Used to treat SLE, myositis, and vasculitis
1.5-3 g/d is standard dosing
GI side effects are common
Teratogenic to fetus
Cyclosporine: Inhibits T-cells
Used to treat RA and SLE
Elevations in BP and worsening renal functions are some of its side effects
Daily dose is 2.5 mg/kg-4.5 mg/kg
Biologic Agents
Tumors necrosis factor a inhibitors: Include etanercept, adalimumab, infliximab, golimumab,
certolizumab
Given as weekly or monthly subcutaneous injections (infliximab is given as a monthly
infusion)
Used to treat RA, psoriatic arthritis, ankylosing spondylitis
Associated with reactivation of TB, so checking for latent TB is important before
starting therapy
In rare cases, use is associated with a demyelinating syndrome involving CNS
Risk of cancer such as lymphoma has been noted with use
Abatacept: Inhibits T-cell costimulation by binding to B7 protein

Administered intravenously, recently a subcutaneous form of abatacept has been
introduced that is administered as a weekly injection
Used to treat RA
Reactivation of TB is a concern; hence all patients should be tested for latent TB
Infusion reaction, infections are other concerns
Rituximab-monoclonal antibody against CD20
Used to treat SLE, RA, ANCA vasculitis
2 infusions of 1,000 mg given 2 weeks apart is standard dosing regime though 375 mg/m2
administered in 4 weekly infusions can also be used
Patients should be monitored for infections
Anakinra: IL-1 receptor antagonist
Used to treat RA and adult onset still disease
It is a daily subcutaneous injection
Injection site reaction is a common side effect of this medication
Tocilizumab: Monoclonal antibody against IL-6 receptor
Used to treat RA
Given as an intravenous infusion every 4 weeks
Associated with increased triglyceride levels in some patients
Increased infection risk and reactivation of TB are other complications
Bowel perforation was a rare complication noted in trials
13.3 Rheumatoid Arthritis

Pathophysiology
Etiology is poorly understood
Role of genetics- HLA-DR4, HLA-DR1
Inflammation initiated by activated T-lymphocytes, macrophages with resultant production
of inflammatory cytokines (TNF-alpha, IL-1)
Role of environmental factors like cigarette smoke
Disease Course
Starts in small joints of the hands progressively involving larger joints
Early in the disease soft tissue synovial swelling is seen in the joints
If left untreated, later in the disease erosions develop
In late established disease typical RA deformities arise (ulnar deviation of fingers, swan-neck
deformity, boutonnieres deformity, Z-shaped thumb)
Epidemiology
1% of the population
Females:Males = 3:1
Women in child-bearing age group, men in 6th to 8th decade
Increases with age
Prognostic Factors
Poor prognostic markers are:
RF positivity
Poor functional status
Extra-articular involvement
Erosive disease
Persistently elevated ESR/CRP
Diagnosis
Symmetric joint inflammation
Most commonly there is small joint involvement (wrists, MCPs, PIPs)
Typical deformities like ulnar deviation, swan-neck, boutonnieres deformity, Z-shaped
thumb
Morning stiffness lasting >60 min
Involvement of large joints occurs later in the disease - Bakers cyst can be seen in the
knees posteriorly
Evaluation
Routine labs like CBC (looking for anemia, thrombocytosis), liver function test could show
a globulin gap
ESR, CRP: Inflammatory markers
Specific antibodies: Rheumatoid factor, anti-CCP antibody
Radiology: X-rays of affected joints could show erosions, periarticular osteopenia
Complications and Extra-articular Manifestations

Systemic manifestations like fatigue, malaise, weight loss, low grade fevers
Rheumatoid nodules: Subcutaneous, seen in extensor surfaces and pressure points. Firm,
non-tender
Infection: Due to inherent immunosuppression or as a result of treatment
Cervical instability: C1-C2 articulation involved- erosions and ligament damage can result in
subluxation. Patients with longstanding RA should have C-spine flexion/extension X-rays
looking for subluxation
Coronary artery disease: From chronic inflammation, side-effect of chronic prednisone use,
and sedentary lifestyle
Secondary Sjgrens syndrome: Dry eyes and mouth
Eye manifestations: Scleritis, which results in painful red eye
Feltys syndrome: Triad of RA, neutropenia, and splenomegaly
Vasculitis: Leukocytoclastic vasculitis, pyoderma gangrenosum
Pulmonary manifestations: Interstitial lung disease carries a poor prognosis, other
manifestations include rheumatic nodules in the lung, pleural effusions
Management
NSAIDs: Symptomatic relief, minor anti-inflammatory role
Corticosteroids: Most potent anti-inflammatory agents in RA, fast acting
Most commonly used steroid is prednisone
Use lowest dose possible for smallest duration of time to control inflammation and
prevent side effects
May need GI prophylaxis to prevent gastritis with steroid use (PPI, H2 blockers)
Need prophylaxis for osteoporosis if >7.5 mg being used daily for >3 months

Disease modifying antirheumatic drugs (DMARDs) methotrexate is the preferred DMARD,
others are sulfasalazine, hydroxychloroquine, leflunomide, azathioprine
Biologic Therapy: TNF-alpha blockers such as etanercept, adalimumab, infliximab (most
commonly used)
IL-1 blocker such as anakinra (though less commonly used)
CTLA-4 fusion protein that blocks T-lymphocyte stimulation (abatacept)
IL-6 blocker such as tocilizumab
CD-20 inhibitor rituximab
Surgical therapy: Synovectomy for chronic synovial hypertrophy, joint replacement for
destroyed joints, arthrodesis or surgical joint fusion for unstable and painful joints
Pregnancy and Rheumatoid Arthritis

RA usually improves during pregnancy
For managing flares during pregnancy, lowest possible dose of steroids should be used
Intra-articular steroid injection is a better alternative if 1 or 2 joints are involved
Sulfasalazine can be a safe option during pregnancy
Hydroxychloroquine can be used but it is category C
NSAID use can result in premature closure of ductus arteriosus if used in 3rd trimester
13.4 Osteoarthritis
Pathophysiology
Damaged cartilage is unable to repair itself as a result; there is progressive cartilage
degradation with time
There is sclerosis of the underlying bone
Growth of osteophytes at margins
Joint space narrowing due to cartilage loss
Risk Factors
Increasing age
Previous joint injury
Obesity
Sex: Woman have greater risk of OA compared to men
African Americans have greater risk of OA compared to Caucasians
Family history
Clinical Features
Pain in affected joint that increases with activity, improves with rest or OTC analgesics
Stiffness in affected joint that can be seen in the morning or after periods of inactivity but
lasting less than 30 min
Joint instability especially a feeling of legs giving way in knee OA
In knee OA complaints of pain upon walking up or down the stairs
In hand OA with disease progression holding, gripping, opening jars become increasingly
difficult activities to do
Crepitus over affected joint
Bony enlargement of affected joint
Classification
Primary osteoarthritis: Results from increasing age, family history
Secondary osteoarthritis: Pre-existing conditions that cause cartilage damage like metabolic
disorders (hemochromatosis, Wilsons disease, alkaptonuria), or connective tissue disorders
like Marfan or Ehlers-Danlo syndromes
Erosive inflammatory osteoarthritis: A type of OA where erosions and increased
inflammatory markers are seen
Diagnosis
Examination of affected joint may reveal crepitus
Imaging studies reveal joint space narrowing, osteophytes, bony sclerosis, subchondral cysts
Negative RF, CCP
Synovial fluid aspiration reveals non-inflammatory fluid with WBCs <1,000
Management and Treatment

Nonpharmacologic interventions: Assistive devices like cane, walker that help unload
affected joints, muscle strengthening exercises like quadriceps strengthening for knee OA,
referral to physical therapy
Pharmacologic therapy: Acetaminophen or NSAIDs for initial treatment
Intra-articular injection: Intra-articular injection of steroid into the joint results in
symptomatic relief, which can last as long as 3 months. Recently intra-articular hyaluronan
injections for knee OA are being used for symptomatic relief
Surgical intervention: Joint replacement is warranted when pharmacological therapy fails to
control symptoms
13.5 Fibromyalgia
Introduction
Wide spread pain in all 4 quadrants for longer than 3 months
Insufficient, poor, or non restorative sleep
Fatigue
Personality changes
Epidemiology
Prevalence is 3 to 5% amongst women, 1% amongst men
Diagnosis and Evaluation

Characteristic history of wide spread pain, myalgias, arthralgias, fatigue, poor sleep, can be
associated with irritable bowel syndrome and headaches
Presence of tender points- 11/18 tender points as per old ACR diagnostic criteria
Treatment
Nonpharmacologic therapy: Aquatic therapy, aerobic exercises, tai-chi, yoga, meditation,
biofeedback therapy

Pharmacologic therapy: Tricyclic antidepressants are first-line (amitriptyline), serotonin
reuptake inhibitors (fluoxetine), serotonin/norepinephrine reuptake inhibitors (venlafaxine,
duloxetine)
Muscle relaxants like cyclobenzaprine can also be used
Others: Gabapentin, anxiolytics like alprazolam, lorazepam can also be considered
13.6 Seronegative Spondyloarthropathies

Pathophysiology
Genetic predisposition - HLA-B27
Environmental triggers
Classification
Ankylosing Spondylitis: Inflammatory low back pain associated with morning stiffness >30
min that improves with exercise and recurs with rest
Schobers test <5 cm increase on flexion at LS spine
Ankylosis at cervical spine results in increased occipito-wall distance
Impaired chest expansion <5 cm due to involvement of costovertebral and
costochondral joints
Inflammation at tendon insertions resulting in enthesitis (ischial tuberosity, iliac crests,
greater trochanter, Achilles tendon)
Ocular involvement in form of uveitismost common extra-articular finding
Radiological findings: Sacroiliitis and subsequent fusion of SI joints, shiny corners or
Romanus lesions as a result of inflammation at the site of insertion of annulus fibrosis
on vertebral bodies, squaring of vertebrae, syndesmophytes, and finally bamboo spine
formation
Reactive arthritis: Triggered by bacterial infection in the genitourinary or gastrointestinal
tract
Develops 2 to 4 weeks after gastroenteritis from Salmonella, Shigella, Yersinia,
Clostridium difficile, or Campylobacter or genitourinary infection from chlamydia
Triad of conjunctivitis, urethritis, and arthritis
Dactylitis that results in swelling of entire digit from synovitis and enthesitis is seen, also
called sausage digit
Enteropathic arthritis: Develops in 20% patients with inflammatory bowel disease (Crohns
or Ulcerative colitis)
Erythema nodosum and pyoderma gangrenosum can be seen
Psoriatic arthritis: Present wit oligo or mono arthritis
DIP joints are commonly involved
Arthritis mutilans wherein a pencil in cup deformity is noted on X-rays is seen in 1 to 5%
individuals
Dactylitis or sausage digits, enthesitis are other findings
Nail pitting and skin psoriasis is also seen
Extra-articular manifestations such as eye involvement (iritis, episcleritis, scleritis) is
noted
Treatment
Ankylosing spondylitis: NSAIDs reduce pain and stiffness and recent studies show that they
can prevent progression of ankylosis
DMARDs like methotrexate and sulfasalazine are also used but studies have not shown
any benefit
TNF inhibitors like etanercept, adalimumab, and infliximab have shown promising
results
Physical therapy to improve range of motion
Reactive arthritis: NSAIDs is mainstay of treatment
Antibiotics should be used for active infection
Steroids have not shown to provide any benefit
Enteropathic arthritis: Treatment of underlying inflammatory bowel disease results in
improvement of arthritis
Psoriatic arthritis: NSAIDs help decrease pain
DMARDs like methotrexate, leflunomide, or sulfasalazine can be tried
Biologics like etanercept, adalimumab, infliximab, and golimumab have shown
promising results
13.7 Systemic Lupus Erythematosus

Pathophysiology
Antigen driven immune mediated disease characterized by high affinity IgG antibodies to
dsDNA and nuclear proteins
Immune complex deposition (comprising of IgM, IgG, IgA, complement components)
dsDNA plays major role in lupus nephritis
Abnormalities in T-cell function, B-cell function, programmed cell death (apoptosis),
immune complex clearance, complement function and complement deficiencies all play a
role in pathogenesis
Epidemiology
Primarily a disease of young women
Peak incidence between 20 to 40
Female:Male = 6-10:1
Risk Factors
Common in African Americans
Environmental trigger like exposure to ultraviolet light
Association with HLA-DR2, DR3
Cutaneous Involvement
Photosensitive skin rash
Malar rash on cheeks, nose, sparing nasolabial fold
Discoid rash that heals with hyper or hypo pigmentation and causes scarring
Other skin manifestations include livedo reticularis, lupus panniculitis also called lupus
profundus
Oral and/or nasal ulcers that are generally painless

Joint Involvement
Polyarthralgias and polyarthritis
Non-erosive in nature involving small joints like PIPs, MCPs
Jaccouds arthropathy notedreducible ulnar deviation similar in appearance to RA;
however, due to tendon, ligament laxity and not erosions
Renal Involvement
Lupus nephritis (classes 1 to 6)
Urine analysis shows red blood cell casts, proteinuria
Neurologic Involvement
Seizures, psychosis, encephalopathy, stroke, coma, transverse myelitis, peripheral
neuropathy, mononeuritis multiplex
Cognitive impairment is most common manifestation
Headaches that are non responsive to acetaminophen are likely from SLE
Cardiopulmonary Involvement
Pericardial and pleural effusions
Libman- sacks endocarditis
Myocarditis
Coronary arteritis
Pulmonary hypertension can be seen
Interstitial lung disease
Shrinking lung syndrome
Hematologic Involvement
Anemia: Hemolytic anemia with increased reticulocyte count, positive coombs test, low
haptoglobin, and elevated LDH
Other causes of anemia: Iron deficiency, anemia of chronic diseases
Thrombocytopenia
Leukopenia and especially lymphopenia can also be seen
Gastrointestinal Involvement
Pancreatitis is a rare manifestation
Ischemic colitis, mesenteric vasculitis, and protein losing enteropathy are other
manifestations

ACR classification criteria for SLE need to have 4 or more from 11 features. These include:
1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral/nasal ulcers
5. Arthritis
6. Serositis
7. Renal involvement (>0.5 g/d proteinuria or casts)
8. Neurologic involvement
9. Hematological involvement (hemolytic anemia, leukopenia, lymphopenia,
thrombocytopenia)
10. Immunologic involvement (dsDNA or anti-smith antibody, positive test for
antiphospholipid antibodies)
11. Anti-nuclear antibody
A thorough history and physical exam is needed in anyone suspected of having SLE
ANA, dsDNA, anti-Smith antibodies are tested
CBC, creatinine, and BUN levels are checked
Urine analysis looking for casts, proteinuria is checked
A spot urine protein to creatinine ratio is checked to determine degree of proteinuria
Other rheumatic disorders like rheumatoid arthritis, myositis, fibromyalgia
Viral infections can mimic lupus
Drug induced lupus should also be in differential (drugs like hydralazine, isoniazid,
minocycline have been implicated)
Treatment
NSAIDs
Used for pain relief especially from arthralgia/arthritis, myalgias, and headaches
In patients with kidney involvement, they should be avoided
Aseptic meningitis can be seen in some circumstances
Hydroxychloroquine
Antimalarial agent
Most frequently prescribed for lupus
First-line treatment option especially in mild disease (cutaneous, musculoskeletal
involvement)
Starting dose 200 mg daily, which is increased to 400 mg daily
Slow response taking 6 to 8 weeks
Eye exam at baseline and at 6-12 m period due to macular toxicity from cumulative dose
Corticosteroids
Provide immediate relief of symptoms
Smaller doses (5-30 mg daily) are effective in treating mild-moderate manifestations of
lupus such as arthritis, skin manifestations
Higher doses 1 mg/kg body weight are needed for severe manifestations like nephritis,
CNS manifestations, hematological manifestations
Intravenous pulse methylprednisolone can be given for life threatening manifestations (1 g
every 24 hr for 3 d)
Immunosuppressive Agents
Azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, cyclophosphamide,
leflunomide, and belimumab are other drugs used
Systemic Lupus Erythematosus and Pregnancy
No effect on disease activity
Lupus patients that have positive Ro antibody are at risk for complete heart block in the
fetus, neonatal lupus rash is also seen in newborns (it is transient and resolves without
scarring)
Thrombocytopenia is a common hematological finding in pregnant women
Presence of antiphospholipid antibodies and lupus anticoagulant can result in pregnancy
loss, preeclampsia, placental insufficiency

Prognosis
With early detection and treatment prognosis is better but still 10-year survival is around 50%
Early death is due to disease activity, infections, and renal involvement
Late deaths are due to cardiovascular involvement
13.8 Systemic Sclerosis

Pathophysiology
Characterized by immune system activation, endothelial dysfunction, and enhanced
fibroblast activity
Endothelial cell activation and vascular damage from unknown factors
Extravasation of inflammatory cells
Activation of fibroblasts
Epidemiology
Annual incidence in the US of about 20 cases per 1 million adults
Women are 4 times more likely to develop systemic scleroderma
African Americans are at greater risk
Presents in 3rd and 4th decades of life
10-year survival rate is 70 to 80%
Classification
Limited scleroderma: Raynauds phenomenon, GERD, swelling, and puffiness of fingers
Can be initial manifestation
Later skin thickening and tethering occurs
Anti-centromere antibody present
CREST syndrome is seen in a subgroup of patients with limited disease: Calcinosis,
Raynauds, esophageal dysmotility, sclerodactyly and telangiectasias
Pulmonary hypertension is seen as a complication in limited scleroderma
Diffuse cutaneous systemic sclerosis: Raynauds phenomenon, systemic symptoms like
malaise, arthralgias, weigh loss, skin findings (swelling then thickening and tethering, which
is more widespread)
Internal organ involvement (lung, scleroderma renal crisis, HTN, tendon friction rubs)
RNA polymerase antibody and anti-scl-70 seen in diffuse scleroderma
ILD is commonly seen in diffuse scleroderma
Systemic sclerosis sine scleroderma: Internal organ manifestations without skin thickening
Localized scleroderma: En coup de saber (linear scleroderma)
Clinical Findings
Cutaneous involvement: Telangiectasias, digital ulceration, nailfold capillary abnormalities,
skin thickening and tethering, calcinosis, salt pepper pigmentation of skin (hypo/
hyperpigmentation areas), reduced oral aperture, sclerodactyly
Vascular involvement: Raynauds phenomenon
Musculoskeletal involvement: Muscle contractures (prayer sign), tendon friction rubs,
arthralgias, myalgias, can have myositis if they have overlap syndrome
Gastrointestinal involvement: GERD, watermelon stomach, bacterial overgrowth,
malabsorption, pseudo-obstruction
Pulmonary involvement: ILD, pulmonary HTN
Cardiac involvement: Myocardial fibrosis resulting in conduction defects, CHF
Renal involvement: Renal crisis
Diagnosis
Based on history and clinical exam (findings outlined in earlier section)
Presence of ANA, anti-centromere, RNA-polymerase and anti-scl-70 antibodies
Pregnancy and Systemic Sclerosis

Pregnancy in systemic sclerosis may be uneventful with good maternal and fetal outcomes.
High-risk obstetric monitoring program is important, close monitoring for renal crisis is
important, as that is a complication
Women who have diffuse scleroderma are at a greater risk for developing serious
cardiopulmonary and renal problems within 3 years after disease diagnosis so they should
delay pregnancy until the disease stabilizes
Scleroderma Spectrum Disorders

Scleromyxedema
Eosinophilic fasciitis
Nephrogenic systemic sclerosis
Scleredema
Paraneoplastic syndrome
Toxic oil syndrome (contaminated rapeseed oil)
Eosinophilia myalgia syndrome (contaminated l-tryptophan)
Chronic graft versus host disease
13.9 Sjgren Syndrome

Pathology
Autoimmune disease characterized by lymphocytic infiltration and destruction of
the salivary and lacrimal glands and systemic production of autoantibodies to the
ribonucleoproteins SSA or Ro and SSB or La
Epidemiology
Women are commonly affected >90%
Mean age of onset 40 to 50 years
Sicca symptoms: Dry eyes (xerophthalmia) and dry mouth (xerostomia)
Lack of salivary secretions result in tooth decay, periodontal disease
Salivary gland swelling (parotid and submandibular glands)
Dryness of the vagina resulting in dyspareunia
Arthralgias, myalgias
Leukocytoclastic vasculitis (small vessel vasculitis) maybe seen
Raynauds phenomenon

Renal involvement: Proteinuria, renal tubular acidosis, and glomerulonephritis can be seen
Obstructive lung disease or interstitial lung disease are the lung manifestations seen in this
condition
CNS involvement is rare, can develop peripheral neuropathy, white matter lesions seen on
MRI are commoner but asymptomatic
Diagnosis
New criteria for diagnosis requires at least 2 of the 3:
Positive Ro or La antibody or positive RF and ANA (>1:320)
Positive lip biopsy showing focal lymphocytic sialadenitis
Ocular staining score 3 for keratoconjunctivitis sicca
Treatment
Symptomatic: Use of artificial tears for dry eyes
Pilocarpine and cevimeline are approved for use for dry mouth
Recent studies have shown a potential role for hydroxychloroquine
13.10 Mixed Connective Tissue Disease

Characterized by features of scleroderma, SLE, RA, and myositis
Arthralgias or arthritis, skin changes limited to hands
Raynauds phenomenon
GERD maybe present
Restrictive pattern on PFTs
Diagnosis
Presence of anti-RNP antibody
Treatment
Corticosteroids are usually used
Mild cases with arthralgias or arthritis can be treated with aspirin or other nonsteroidal anti-
inflammatory drugs
13.11 Crystal-induced Arthropathies

Gout
Epidemiology
Predominantly a disease seen in men
Peak onset 5th decade
Seen in women after menopause
Pathophysiology
Increased serum uric acid that results in precipitation of uric acid in joints inciting an
inflammatory response
Heralded by rapid onset of pain, redness, swelling and warmth of affected joint/joints
First attack usually involves 1st metatarsophalangeal joint (podagra), gout can then
progress to involve midfoot, ankle, knee.
Joints of upper extremity occur later in the course of the disease
Hyperuricemia; however, during an acute attack uric acid levels may fall due to deposition
in joints
Definitive diagnosis is made by synovial fluid aspiration and analysis, which shows
leukocytosis with predominance of neutrophils (>15,000 cells) and needle shaped crystals
that demonstrate negative birefringence under polarized light (yellow when light is
parallel to crystals and blue when perpendicular)
Presence of tophaceous deposits around olecranon, pinna
Treatment and Prevention
Aimed at pain relief and resolution of attack: NSAIDs, colchicine, or steroids can be used
Preventing future attacks: Colchicine and uric acid lowering medications (allopurinol and
febuxostat both are xanthine oxidase inhibitors), more recently pegloticase has been
approved for lowering uric acid levels. Drugs that cause increased secretion of uric acid in
urine such as probenecid and sulfinpyrazone can also be tried
Goal of treatment is to lower uric acid to <5 mg/dl
Dietary changes such as avoiding alcohol especially beer, purine rich foods like red meat,
shellfish, lentils, and beans. Increase dairy, fruits, and vegetable intake in diet
Calcium Pyrophosphate Dihydrate Deposition Disease

Pathophysiology
Deposition of CPPD crystals elicits an inflammatory response
Epidemiology
Hemochromatosis, Wilsons disease, hypomagnesemia, hypothyroidism,
hyperparathyroidism and renal osteodystrophy are often also associated with
chondrocalcinosis. History of trauma to a joint increases risk of developing
chondrocalcinosis
Seen in individuals greater than 60
Acute onset of pain, redness, and swelling of a joint, commonly affects knees, however,
can involve wrists and ankles
Diagnosis
Radiographic findings of chondrocalcinosis in 2 or more different joints (e.g., knee and
wrist)
Synovial fluid aspiration and analysis shows rhomboid shaped, positively birefringent
crystals, WBC >5,000
Treatment
Acute attack warrants use of prednisone
NSAIDs for pain control
Colchicine can be used for prophylaxis
Finding underlying cause if any (mentioned previously)

Basic Calcium Phosphate Deposition Disease
Associated with a number of clinical syndromes, including calcific tendinitis, Milwaukee
shoulder, and a severe form of OA
Can cause acute synovitis of small or large joints
BCP crystals are not detectable by polarized light microscopy
Alizarin red S staining can help in detection
Treatment includes symptomatic management with NSAIDs, local steroid injection. Physical
therapy can be tried to improve range of motion
13.12 Infectious Arthritis

Acute onset of painful, swollen and warm joint
Usually monoarticular and affects large joints
Fevers and chills
Pain on active as well as passive range of motion
Physical Examination
Warmth, swelling, and tenderness of affected joint
Inability to move affected joint
Redness of overlying skin
Laboratory Studies
Peripheral leukocytosis
Elevated ESR/CRP
About 50% have bacteremia - can have positive blood cultures
Aspiration of affected joint reveals turbid or purulent synovial fluid with leukocytosis (WBC
>50,000/mm3), majority are neutrophils, gram stain is positive and so are cultures
Risk Factors
Prosthetic joints
Injection drug use
Crystalline arthritis
HIV infection
Sexual activity (predisposes to gonococcal infection)
Systemic disease (e.g., SLE, DM)
Extremes of age (<5, >65)
Common Causes
Infection With Gram-Positive Organisms
Staphylococcus and Streptococcus are common causes
Staph is most common pathogen in native joints
MRSA infections are on the rise
Approximately 70% of infections are from Staph
Vancomycin is generally used given rates of MRSA infection
3rd generation cephalosporins can also be used
Infection With Gram-Negative Organisms
About 20% infection are from gram negative
Common in neonates, elderly, IV drug users and patients with comorbid conditions like
cancer, DM, transplant recipients
Aminoglycoside + ticarcillin or piperacillin
Disseminated Gonococcal Infection
Seen in a sexually active young person
Triad of polyarthritis, tenosynovitis and dermatitis
Synovial fluid cultures are negative
Most common presentation is of oligoarticular arthritis
Skin lesions are seen in 2/3rds and are pustular in nature
Neisseria gonorrhoeae can be cultured from the skin lesions
Urethral, cervical, rectal, pharyngeal cultures are positive in 70 to 90% cases
3rd generation cephalosporin like ceftriaxone are commonly used
Other options are fluoroquinolones
Infection With Brucella
Risk factors: Ingestion of unpasteurized milk and milk products, occupational exposure
(farmers, meat packers)
Can cause monarthritis or oligoarthritis
Sacroiliitis is also seen
Brucella melitensis is common pathogen
Prolonged course of antibiotics is needed to treat infection
Prosthetic Joint Infections
<4 weeks after surgery are due to hematogenous spread
>4 weeks after surgery are from low virulence organisms (staphylococcus epidermis)
Treatment requires antibiotics for at least 6 weeks and removal of infected prosthesis,
placement of a temporary spacer and revision arthroplasty after infection has resolved
All Causes of Septic Arthritis
All require drainage of affected joints (open surgical drainage and debridement)
Lyme Disease
Caused by Borrelia burgdorferi
Early disease presents as skin rash called erythema migrans
Can have systemic symptoms like malaise, fevers, and arthralgias
Early disseminated disease that occurs weeks to months after tick bite presents with
erythema migrans lesions, fevers, acute arthritis, carditis that manifests as AV block and
neurological manifestations of cranial nerve palsies and meningitis
Late disease occurs months to years after tick bite and presents with neurological
features (neuropathies, encephalopathy) and arthritis (usually monoarticular)
Measuring antibodies to Borrelia using ELISA (IgM 2/3 bands, IgG5/10 bands)
Goal of antibiotic therapy is to hasten resolution of signs and symptoms and prevent late
manifestations
Antibiotics that can be used are: Doxycycline, amoxicillin, and ceftriaxone is an IV option

13.13 Idiopathic Inflammatory Myopathies
Epidemiology
Bimodal distribution: Children between 10 to 15 and adults between age 40 to 60
Common in women
Classification
Polymyositis
Dermatomyositis
Inclusion body myositis
Myositis associated with malignancy
Necrotizing autoimmune myositis (NAM): From medications like statins
Muscle Involvement
Proximal, symmetrical muscle weakness
Pharyngeal muscle weakness can result in dysphagia and dysphonia
Cutaneous Involvement
Gottron papules over MCP and interphalangeal joints
Shawl sign: Erythema over posterior shoulders and neck
V-sign: Erythema over anterior chest and upper neck
Heliotrope rash over eyelids
Nailfold capillary changes
Mechanics hands: Fissuring of lateral and palmar aspect of hands
Calcinosis is seen in juvenile dermatomyositis
Cuticular overgrowth, periungual erythema
Cardiopulmonary Involvement
Lung involvement from ILD results in Velcro like crackles
Cardiac involvement may result in EKG abnormalities, cardiomyopathy and CHF
Additional Systemic Manifestations
Myalgias, arthralgias may occur
Diagnosis
Laboratory Studies
Elevated CPK, aldolase, AST, ALT
May have elevate ESR/CRP
Specific antibodies: Anti-jo1, anti-SRP, anti-Mi2
Imaging Studies
MRI to detect muscle inflammation
Electromyography
Increased insertional activity, fibrillations, spontaneous high frequency discharges,
polyphasic motor unit potentials
Muscle Biopsy
Most useful in making a diagnosis
Perivascular inflammatory infiltrate seen in dermatomyositis
Endomysial inflammatory infiltrate in polymyositis and inclusion body myositis
Intracellular red rimmed vacuoles seen in inclusion body myositis
Muscle fibers in various stages of necrosis and regeneration
Treatment
Steroids are first-line therapy, can start at 1 mg/kg/d
Can be given IV in severe cases
Methotrexate or azathioprine are used if patients do not respond to steroids or as steroid
sparing agents
IVIG has been tried
Other treatment options include rituximab and cyclophosphamide
Malignancy
All newly diagnosed myositis cases should have a through work-up to rule out any
underlying malignancy. Age appropriate malignancy workup (mammogram, colonoscopy),
CT scan of chest, abdomen and pelvis is also generally done
The 1st 5 years after DM diagnosis is when the risk for malignancy is greatest
13.14 Systemic Vasculitis

Large-vessel Vasculitis
Giant Cell Arteritis
Classic symptoms include headaches, jaw claudication, visual symptoms, malaise,
shoulder-hip pain that is worst in the morning and associated with stiffness lasting >1 hour
>50 years
ESR>50, other findings are anemia, thrombocytosis
Temporal artery may be enlarged, nodular or pulseless
Visual loss is irreversible, can be abrupt or preceded by amaurosis fugax, loss usually from
occlusion of posterior ciliary artery
Prednisone 1 mg/kg body weight should be started in anyone suspected of GCA
Temporal artery biopsy is gold standard for diagnosing and shows endothelial
proliferation, fragmentation of internal elastic lamina, infiltration with inflammatory cells
and giant cells
Polymyalgia Rheumatica
Related to GCA, not a vasculitis per se
Stiffness and achiness in shoulder, neck and hip region is noted
Rapid response to prednisone 20 mg daily
Takayasu Arteritis
Vasculitis affecting aorta and its major branches
Usually affects women
Presents as aortic or subclavian bruit, absent pulse, claudication, unequal blood pressures
extremities, HTN, light-headedness
Elevated ESR, thrombocytosis, anemia
MRI detects thickening of the wall of the aorta or its branches
CT angiography shows stenosis, vessel wall irregularities, occlusions

Prednisone 1 mg/kg/d is mainstay
Methotrexate and cellcept are other medications that have been tried in addition to
prednisone
Medium-sized Vessel Vasculitis

Polyarteritis Nodosa
Subacute onset of symptoms, weight loss, malaise, fevers, arthralgias
Lower extremity nodules, livedo reticularis and ulcerations can occur, mononeuritis
multiplex, and intestinal angina due to involvement of mesenteric vessels, testicular pain
or tenderness can also be seen
Association with hepatitis B
Not associated with glomerulonephritis
Other less common features are CHF, MI, CNS involvement manifesting as
encephalopathy and stroke
Elevated ESR,CRP, anemia, thrombocytosis is also noted
p-ANCA positive
Angiogram shows microaneurysms and areas of narrowing
Biopsy shows inflammatory infiltrate in vessel wall
Treatment of hepatitis B associated PAN is directed at treating hepatitis B with ribavirin
or interferon. Prednisone can be used to suppress inflammation, however, it can
potentially increase viral replication
Treatment for non-hepatitis B associated PAN is with prednisone
Cyclophosphamide is given in cases refractory to prednisone
Small-vessel Vasculitis
Wegener Granulomatosis
90% have nasal involvement as 1st manifestation of the disease, rhinorrhea, epistaxis,
bloody nasal crusts, cartilage inflammation may result in perforation, bony erosions of
sinus cavities
Conductive and sensorineural deafness, granulomatous inflammation of middle ear can
result in serous otitis media and compression of 7th cranial nerve
Orbital pseudotumor may result in proptosis and visual loss
Episcleritis, keratitis, uveitis
Intense inflammation of the gums (strawberry gums)
Pulmonary symptoms include cough, hemoptysis, shortness of breath, nodules, fleeting
pulmonary infiltrates, cavitary lesions in the lungs
Rapidly progressive glomerulonephritis
Arthritis
Skin involvement-digital ischemia, palpable purpura, nodules on extensor surfaces
Nonspecific symptoms like fevers, malaise, chills, weight loss
Elevated ESR/CRP, anemia, urine analysis shows RBC casts and proteinuria
Positive c-ANCA/pr-3-ANCA
Biopsygold standard in diagnosis: Lungs, kidneys, and upper respiratory tract
Treatment involves use of high dose steroids and cyclophosphamide
Cellcept or azathioprine can be used once remission is induced (for maintaining
remission)
All should receive PCP prophylaxis
Microscopic Polyangiitis
Nonspecific constitutional symptoms fevers, chills, arthralgias, malaise, myalgias
Rapidly progressive glomerulonephritis
Mononeuritis multiplex
Cutaneous involvement-palpable purpura, ulcers, nodules, livedo reticularis
Pulmonary involvement in the form of alveolar hemorrhage, infiltrates, effusions and
fibrosis can be seen
Elevated ESR/CRP
Positive p-ANCA/MPO type
Nerve conductions studies may reveal nerve involvement and sural nerve can be biopsied
for tissue diagnosis
Renal biopsy can be done and shows glomerulonephritis
Treatment is with a combination of prednisone and cyclophosphamide
Following induction of remission, azathioprine, or methotrexate can be used in
maintaining remission
Churg-Strauss Syndrome
3 phases of the disease are seen:
1. Prodrome phase-asthma, allergic rhinitis
2. Tissue infiltrate with eosinophils
3. Vasculitis phase-organ involvement
Asthma, eosinophilia, neuropathy, pulmonary infiltrates, sinus involvement is seen
Skin involvement in the form of palpable purpura, ulcers, nodules
Cardiac involvement manifesting as CHF is seen
Glomerulonephritis can be seen
Arthralgias and arthritis is also seen
Eosinophilia, elevated IgE, positive ANCA (either MPO or pr-3 type)
Steroids are first-line and are usually effective in controlling the disease
Cyclophosphamide can be used when glomerulonephritis or neuropathy is a
manifestation
Henoch-Schonlein Purpura
Acute onset fever, palpable purpura on lower extremities, abdominal pain
(intussusception in children, intestinal angina), hematuria and arthritis are seen
Age of onset <20
Diagnosis is confirmed on biopsy that shows IgA deposition
Elevated acute phase reactants
Elevated serum IgA
Symptomatic treatment with acetaminophen, aspirin, or NSAIDs
Resolves spontaneously in about 8 weeks
Steroids can be used if there are GI symptoms and renal involvement
Cryoglobulinemic Vasculitis
Skin involvement-livedo reticularis, palpable purpura
Arthralgias are prominent
Raynauds phenomenon
Peripheral neuropathy
Membranoproliferative glomerulonephritis can be seen
90% cases have concomitant hepatitis C

Positive cryoglobulins, low complements (especially C4), positive RF
Treating underlying cause, interferon for hepatitis C
Sometimes prednisone is used for neuropathy and when vital organs are involved
Rituximab has been successfully used in cryoglobulinemic vasculitis associated with
hepatitis C
Hypersensitivity Vasculitis
Affects only skin
Also called leukocytoclastic vasculitis
Purpura is the most common manifestation
Most common in lower extremity
Skin biopsy shows perivascular or extravascular inflammatory infiltrate
Treatment is usually aimed at identifying and removing offending agent
Colchicine, hydroxychloroquine maybe used for persistent cases
For severe cases prednisone can be started
13.15 Other Systemic Autoinflammatory Diseases

Relapsing Polychondritis
Unilateral or bilateral auricular chondritis, spares earlobe resulting in cauliflower ear with
recurrent attacks, hearing loss (conductive or sensorineural)
Nasal inflammation resulting in saddle nose deformity
Subglottic stenosis from tracheal inflammation
Eye involvement in form of scleritis, episcleritis
Arthritis
Aortic or mitral regurgitation from cartilaginous inflammation
Skin findings such as erythema nodosum, aphthous ulcers, purpura
Renal involvement in form of glomerulonephritis can be seen
Diagnosis
Clinical with the typical presentation of cartilage inflammation (chondritis, nasal
inflammation)
However, normocytic normochromic anemia and thrombocytosis are noted on blood
work
Elevated CRP/ESR
Tissue biopsy reveals features of cartilage inflammation
Treatment
Steroids are mainstay
Colchicine, dapsone, methotrexate can be used as steroid sparing agents
Cyclophosphamide used in refractory cases
Behet's Disease
Oral ulceration is a hallmark
Oral ulcers are painful
Genital ulcerations can also be seen
Skin manifestations include erythema nodosum, acneiform lesions
Pathergy phenomenon: Developing a nodule or ulcer 24 to 48-hours after a needle prick
to the forearm is seen
Ocular manifestation is noted: Includes anterior or posterior uveitis
Gastrointestinal manifestations are in form of aphthous ulcers in the GI tract
Non deforming arthritis is also noted
CNS involvement is seen in 10 to 20% patients and includes headaches, aseptic meningitis,
meningoencephalitis
Thrombophlebitis, vascular thrombosis can be seen
Large vessel vasculitis can be seen in rare cases
Diagnosis
Criteria for diagnosis includes recurrent oral ulceration that occurred at least 3 times over
a 12 month period plus 2 of the following:
1. Recurrent genital ulceration
2. Ocular involvement observed by an ophthalmologist
3. Skin lesions
4. Positive pathergy test
Treatment
Steroids: Mainstay
Colchicine can be used for recurrent ulcerations and as a steroid-sparing agent
Other immunosuppressive agents used are: Dapsone, thalidomide, methotrexate, and
cyclosporine
Cyclophosphamide is used for retinal vasculitis, CNS involvement, and arteritis
Adult-onset Still Disease

Daily fever with spike in afternoon, associated with shaking chills and sweats with return
to baseline
Salmon colored macular rash that manifests during febrile episode
Arthralgias and myalgias, arthritis can develop over time
Other manifestations include hepatosplenomegaly, lymphadenopathy, pericarditis,
pleuritis, pharyngitis, transaminitis
Diagnosis
Marked elevation of serum ferritin is commonly noted
Negative RF, ANA
Leukocytosis, thrombocytosis
Elevated ESR, CRP
Anemia of chronic disease
Elevated AST, ALT
Treatment
NSAIDs can be used but monitor liver function
Steroids 0.5-1 mg/kg/d with gradual taper
Anakinra 100 mg/sq daily has been used with success

References & Suggested readings
1. The Washington Manual. Subspeciality Consult Series- Rheumatology Subspeciality Consult.
2. John H.Klippel. Primer on the Rheumatic Diseases.
NOTES

14 Infectious Disease
Cheston Cunha, MD
C o n t e n t s
14.1 CNS INFECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
14.2 PHARYNGITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
14.3 PNEUMONIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
14.4 ENDOCARDITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
14.5 HEPATITIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
14.6 INFECTIOUS DIARRHEAS . . . . . . . . . . . . . . . . . . . . . . . 43
14.7 URINARY TRACT INFECTIONS . . . . . . . . . . . . . . . . . . 45
14.8 SEXUALLY TRANSMITTED DISEASES . . . . . . . . . . . 46
14.9 SKIN, SOFT TISSUE, AND BONE INFECTIONS . . . 50
14.10 NON-TB MYCOBACTERIAL INFECTIONS . . . . . . . . . 52
14.11 FUO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
14.12 VECTOR BORNE DISEASE . . . . . . . . . . . . . . . . . . . . . . . 55
14.13 TRANSPLANT ID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
14.14 ANTIBIOTICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Infectious Disease29
14.1 CNS INFECTIONS
Meningitis
The classic triad is fevers, altered mental status, and stiff neck
Typical organisms in adults, in order of frequency, are S. pneumoniae, N. meningitidis,
L. monocytogenes, H. influenzae
Empiric treatment consists of a 3rd generation cephalosporin and vancomycin for resistant
S. pneumoniae
Listeria occurs in patients >60 as well as patients with underlying malignancy. If listeria is
suspected, ampicillin must be added. Use chloramphenicol or TMP-SMX if PCN allergic
Imaging of the head should be performed prior to LP in patients with HIV, evidence of
increased ICP, seizure, or focal neurologic deficits
Often, normal CSF glucose essentially rules out acute bacterial meningitis (ABM)
Cryptococcal meningitis should be considered in patients with HIV (CD4 <200), patients
with lymphoma, or acute lymphocytic leukemia (ALL)
Treat cryptococcal meningitis with amphotericin B and oral flucytosine, then will need
lifelong fluconazole

Table 14.1: Meningitis - CSF Findings
Organism Cell Ct. RBCs Protein Glucose Gram Notes
(Cells/ Stain
mcL)/Diff.
S. pneumoniae 100-10K 0 Elevated Low GPC N. meningitidis is
N. meningitidis >90% GNC associated with
H. influenzae PMNs GNR purpura
N. meningitidis can
often have a negative
initial Gram stain
Consider septic
emboli from S. pneu-
moniae endocarditis
L. monocytogenes 100-10K Few Elevated Low GPR Only in elderly or
>90% (neg in patients with
PMNs 50%) malignancy
Although Gram stain
only identifies listeria
50% of time, culture is
always positive
Cryptococcus <300 0 Normal Low Neg. High opening pres-
lymphs to slightly sure is common
elevated Often associated with
neurological deficits
Diagnose with India
Ink stain of CSF/
Cryptococcal antigen
Negative
Cryptococcal antigen
effectively rules out
the diagnosis
M. tuberculosis <500 Few Elevated Low Neg. Often involves cranial
PMNs nerve VI
early, Lung lesions found
lymphs only 50% of time
late Diagnose with CSF
AFB smear/culture, or
TB PCR
Enterovirus <300 0 Normal Normal Neg. Occurs in summer
lymphs to slightly Often associated with
elevated sore throat, diarrhea,
facial/morbiliform
rash
Diagnose with CSF
PCR
Amebic 100-10K Few Elevated Low Neg. Motile WBCs on wet
(N. fowleri) >90% prep
PMNs Treat with
+/- amphotericin B
eosinophils
S. aureus 100-10K 0 Elevated Low GPC Associated with CNS
S. epidermidis >90% shunt infections
PMNs
INFECTIOUS DISEASE31
Encephalitis
Hallmark is fever, confusion/altered mental status (AMS) without stiff neck or focal
neurologic deficits
Table 14.2: Viral Encephalitis

Infectious Typical Historical/Laboratory Clues
Agent Time of
Year
HSV-1 Year-round Typically presents with confusion, AMS early, obtundation/seizures
later in disease course
May have history of Herpes labialis several weeks prior to CNS symptoms
EEG with frontal-temporal lobe activity (most sensitive initial test)
CT/MRI with temporal abnormalities later in disease course
RBCs in CSF only present later in disease course
PMN predominance late (after 1 week after onset) for most people,
with lymphocytic predominance typically at the time of presentation
Definitive diagnosis: CSF HSV PCR
Treatment: Acyclovir
St. Louis Summer Vector is Culex mosquitoes

Encephalitis Found along Mississippi river, but can occur anywhere
Tends to occur in patients > age 60
Only viral encephalitis associated with dysuria (20%)
Causes neurologic sequelae in 25% of cases
Predilection for the thalamic nuclei, brain stem, and the basal ganglia
Leukocytosis common
Definitive diagnosis: St. LE titers
Treatment: Supportive
West Nile Summer Vector is wild birds/Culex mosquitoes

Encephalitis Classically presents as encephalitis with flaccid paralysis
Often with thrombocytopenia and high ferritin
Transaminases will often be mildly increased
Leukopenia followed by lymphopenia common
Definitive diagnosis: CSF WNV PCR
Eastern Spring Vector is Culiseta melanura mosquito
Equine Summer Predilection for the thalamic nuclei and the basal ganglia
Encephalitis Found along the Eastern seaboard
Often presents with very high fever, rapid dense neurological deficits
Mortality up to 70%
Definitive diagnosis: EEE titers
Brain Abscess
Diagnosed on CT/ MRI
Often polymicrobial and secondary to suppurative lung disease (chronic bronchiectasis),
lung abscess, right to left cardiac shunts, mastoiditis, chronic sinusitis, or acute bacterial
endocarditis (ABE)
Treat empirically with 3rd generation cephalosporin in addition to metronidazole
If open trauma/neurosurgical procedure, add MRSA coverage

Table 14.3: Causes of Brain Abscesses
Organism Source/Notes
S. aureus Neurosurgical procedure, open trauma
S. epidermidis
Oral anaerobes Dental source, lung source, sinus source
Enterobacter Mastoid/otic source
Proteus
Actinomyces Dental source
Nocardia Lung source
Cysticercosis Ingestion of pork tapeworm Taenia solium, common in developing
countries. Causes new onset seizures
Toxoplasmosis Seen in immunocompromised hosts, typically multiple lesions
Neurosyphilis
Patients often asymptomatic
Can manifest with tabes dorsalis, optic symptoms/Argyll Robertson pupil, personality
change, auditory symptoms, cranial nerve palsies
Diagnose with elevated CSF VDRL titers (only 60% sensitive) and CSF pleocytosis (>20
cells/mcL in HIV patients, >5 cells/mcL in normal host) or CSF with increased protein
CSF FTA-ABS can often be falsely positive and can only be used to rule out disease
RPR titers should decline four-fold with treatment. Failure to do so should prompt LP to
evaluate for CNS involvement
IV penicilli G is the required therapy. Those that cannot tolerate it should be desensitized.
All other regiments are suboptimal and with high failure rates
14.2 PHARYNGITIS
Mycoplasma Pharyngitis
M. pneumoniae typically presents as acute sore throat (usually without exudate) and no
cervical lymphadenopathy
M. pneumoniae often associated with otitis or bullous myringitis
C. pneumoniae presents almost identically to M. pneumoniae, but patients will often report
laryngitis which is never present with pharyngitis caused by EBV, GAS, or M. pneumoniae
Diagnose M. pneumoniae/C. pneumoniae with elevations in their respective IgM titers
Treat M. pneumoniae/C. pneumoniae with doxycycline, respiratory quinolone, or a macrolide
Streptococcal Pharyngitis
Group A streptococcal (GAS) pharyngitis presents as acute sore throat (usually with
exudates), bilateral anterior cervical lymphadenopathy, and fever
Cough and hoarseness should essentially exclude GAS pharyngitis
Group A streptococcal pharyngitis is rare in patients over age 30
Diagnosis by throat culture (presence of many PMNs differentiates infection from simple
colonization of the pharynx), GAS probe, or elevated ASO titers
Rapid strep antigen test (RSAT) can miss up to 25% of Group A streptococcal pharyngitis
ASO titer may take up to a week to be positive
Treat Group A streptococcal pharyngitis with amoxicillin, clindamycin, or a macrolide
Treat within 10 days of onset to prevent acute rheumatic fever
Infectious Mononucleosis
Pharyngitis as part of the infectious mononucleosis syndrome is typically caused by EBV or CMV
EBV pharyngitis typically presents as acute sore throat (with or without exudate), extreme
fatigue, and bilateral posterior cervical lymphadenopathy
Diagnose EBV mononucleosis with monospot test, confirmed by elevated EBV IgM viral
capsid antigen (VCA) titer
Can differentiate between Group A streptococcal pharyngitis and EBV pharyngitis before
titers increase (may take up to 8 weeks for monospot to become positive), using ESR and
AST/ALT both of which are elevated early in EBV mono, but are normal in GAS
Other early lab clues that make EBV mono more likely are leukopenia, lymphocytosis
(classically atypical lymphs), with or without thrombocytopenia
Hoaglands sign (puffy upper eyelids) is an early clue to EBV mono, splenomegaly is a later
finding
Membranous Pharyngitis
C. diphtheriae pharyngitis presents as a membranous pharyngitis with little or no fever
Some cases develop marked enlargement of submandibular/anterior cervical lymph nodes
(bull neck)
Diagnose C. diptheriae pharyngitis with throat culture
Treatment is centered on rapid administration of diphtheria antitoxin (DAT) with adjunctive
penicillin or PO macrolide
14.3 PNEUMONIA
Community Acquired Pneumonia (CAP)
Typical CAP presents with cough, respiratory complaints, and fever unlike acute
exacerbation of chronic bronchitis (AECB) which lacks fever and has a clear CXR
Differentiate between typical and atypical by the presence of extrapulmonary findings
Diagnose with imaging, sputum culture/Gram stain (a single organism should predominate)
Normal hosts with CAP should not present with shock. This is not the case in asplenic
patients, or those with an underlying predisposition to hemodynamic compromise.
Nursing home acquired pneumonia (NHAP) is typically caused by H. influenzae, S. pneumoniae,
M. catarrhalis, or MDR aerobic Gram negative bacilli. It can be treated as CAP with a
carbapenem, respiratory quinolone, cephalosporin, or doxycycline

Table 14.4: Typical CAP
Organism Clinical Setting/Pearls Treatment
S. pneumoniae Causes 85% of CAP both in normal and immunocompromised Respiratory
hosts quinolone,
S. pneumoniae is the only CAP associated with Herpes labialis beta-lactam,
Bacteremia occurs in 10-15% of cases which can occasionally doxycycline, or
result in ABE, ABM, or septic arthritis cephalosporin
Asplenic patients are particularly susceptible to S. pneumoniae
and H. influenzae, presenting with rapid onset septic shock,
purpura fulminans, and DIC
In addition to sputum culture and Gram stain, can diagnose
S. pneumoniae with urinary antigen, blood culture, or pleural
fluid culture (if effusion/empyema present)
H. influenzae Relatively rare pathogens in normal hosts. These are much Respiratory
M. catarrhalis more common in patients with COPD, bronchogenic carcinoma, quinolone,
chronic smokers/alcoholics, or those with chronic bronchiectasis beta-lactam,
Diagnose H. influenzae by sputum culture doxycycline, or
Diagnose M. catarrhalis by sputum culture cephalosporin
If using a beta-lactam to treat M. catarrhalis it must be a beta-
lactamase resistant one
K. pneumoniae Occurs almost exclusively in cirrhotics Carbapenem

Patients become acutely ill with high fever, shaking chills, and (for ESBL pro-
productive cough (currant jelly sputum), often with chest pain ducers), other-
K. pneumoniae tends to involve the upper lobes, but can affect wise respiratory
any lobe (often multiple) quinolone, or
Typically cavitates (thick) on chest imaging in 5 to 7 days cephalosporin.
Forms lung abscesses in many cases For MDR
Can also present as a chronic pneumonia with cough, low strains, use
grade fevers, and weight loss over weeks, mimicking TB or colistin, poly-
melioidosis myxin B, or
tigecycline
B. pertussis Classically presents initially with 1 to 2 weeks of rhinorrhea, fol- Macrolide,
lowed by 2 to 4 weeks of paroxysmal coughing (often with respiratory
inspiratory whoop), then 1 to 2 weeks of convalescence with quinolone,
decreasing cough intensity/frequency doxycycline, or
Fever low or absent cephalosporin
Adults may present only with 2 to 6 weeks of cough without
whoop
Shaggy heart sign on CXR is often present
Only CAP to present with >60% lymphocytosis
Diagnose with DFA from nasopharyngeal swab as culture can
only be grown in Bordet-Gengou media
S. pyogenes Rare cause of CAP Beta-lactam,
(GAS) Presents as acute onset of high fever, shaking chills, and cough, clindamycin,
often with pleuritic chest pain or respiratory
Occurs in military recruits, closed chest trauma, or as a result of quinolone
acute extra-pulmonary GAS infection
Up to 66% of patients will give a history of antecedent pharyngitis
Causes moderate to large pleural effusions (serosanguinous)
Diagnose with sputum or pleural fluid Gram stain/culture
ASO titer may be negative if drawn too early in the disease
course
Table 14.4: Typical CAP (cont.)
S. aureus In CAP, S. aureus PNA only presents concurrently with viral Linezolid, van-
(CA-MRSA or influenza pneumonia comycin, mino-
MSSA) In addition to the manifestations of acute influenza, patients cycline, or anti-
develop rapid cavitation (<72 hours) on chest imaging, and Staphylococcal
cyanosis PCN if MSSA
S. aureus is not a pathogen causing CAP in the weeks following confirmed
recovery from viral influenza
Oral anaerobes Seen in patients with aspiration pneumonia Clindamycin or
Often accompanied by S. pneumoniae, H. influenzae, and a beta-lactam
M. catarrhalis + clindamycin/
Sputum Gram stain/culture often not diagnostic, diagnose on metronidazole
clinical findings/history or ampicillin/
Classically RLL, but location depends on position of patient sulbactam or
when aspiration occurred moxifloxacin
Pneumocystis Primarily seen in HIV patients, but can also present in patients TMP-SMX plus
jiroveci (PCP) on chronic immunosuppressants prednisone for
Typically presents subacutely with fever, cough, and dyspnea severe disease.
Often will become profoundly hypoxic despite a relatively clear Atovaquone,
CXR dapsone, or
Severe disease (need for adjunctive steroids) is described as primaquine in
pO2 <70 mmHg or A-a gradient >35 on ABG sulfa allergic
patients
Atypical CAP
Non-zoonotic atypical CAP is caused by Legionella sp., Mycoplasma pneumoniae, and
Chlamydophilia (Chlamydia) pneumoniae
Zoonotic atypical CAP is caused by Chlamydophilia (Chlamydia) psittaci, Coxilla burnetii,
and Francisella tularensis
Do not consider the zoonotic CAPs unless there is a clear history of recent vector exposure
Atypical CAP with significant splenomegaly is Q fever until proven otherwise
Atypical CAPs are systemic diseases with pulmonary manifestations. Symptoms noted in
the Table on Atypical CAP are found in addition to the usual cough, fever, and respiratory
complaints that accompany both typical and atypical pneumonia

Table 14.5: Atypical CAP
Legionella sp. Presents with acute onset of cough, high fever, and relative bradycardia Doxycycline,
Commonly Also associated with mental confusion, myalgias, diarrhea, and respiratory
L. pneumophila abdominal pain (can be severe) quinolone, or
Commonly occurs in elderly patients macrolide
Nosocomial Legionella occurs in clusters from a contaminated water
source, often near a ventilation system
Early in disease will often have hypophosphatemia, transaminitis,
increased ferritin, and increased CPK
Can also present with hyponatremia and microscopic hematuria
Rapid asymmetric development of infiltrates on CXR
Diagnose with Legionella DFA of respiratory secretions, or serum
IgM titers
Urinary antigen tests only for serotypes L. pneumophila 01-06, so a
negative result does not exclude the diagnosis
M. pneumoniae Presents with subacute onset of dry cough, low grade fever (<102 F), Doxycycline,
headache, and mild myalgias over several weeks respiratory
Can be accompanied by non-exudative pharyngitis (without hoarse- quinolone, or
ness), loose stools, or bullous myringitis macrolide
Highest incidence among young adults
Associated with E. multiforme
Can cause new onset asthma in adults
CXR shows ill-defined unilateral infiltrates without effusion
Cold agglutinins can be elevated transiently early in the disease course
Diagnose with serum IgM titers, throat culture (takes 2 to 3 weeks),
or PCR from nasopharyngeal swab or sputum if present
C. pneumoniae Similar in presentation to M. pneumoniae but with fewer GI Doxycycline,

complaints and is accompanied by hoarseness respiratory
Can cause outbreaks in nursing homes quinolone, or
Can cause new onset asthma in adults macrolide (not
Diagnose with serum IgM titers erythromycin)
C. psittaci Vector is psittacine birds Doxycycline or
Presents with Horders spots, severe headache, myalgias, and respiratory
relative bradycardia quinolone
Occasionally will present with splenomegaly
Associated with elevated transaminases
Can develop into culture negative SBE or obscure phlebitis
Diagnose with serum IgM IFA titers
C. burnetii Vector is parturient cats, sheep, or cattle Doxycycline,
(Q fever) Presents with splenomegaly and relative bradycardia respiratory
Associated with thrombocytosis and mildly increased transaminases quinolone, or
20% have anti-smooth muscle antibodies chloramphenicol
Diagnose with serum titers
F. tularensis Vector is tick, mosquito, or deerfly bite or direct contact with rabbits Doxycycline,
or deer respiratory
Presents with extremely acute onset of headache, myalgias quinolone,
WBC normal or low, LFTS are normal gentamicin, or
Most common form of infection is ulceroglandular tularemia which chloramphenicol
also has prominent skin manifestations (painful purple ulcer with
adenopathy)
Causes a bloody pleural effusion
Only cause of CAP with hilar lymphadenopathy (uni or bilateral)
Diagnose with serum titers
Viral CAP
Suspect S. aureus in patients with concurrent influenza and bacterial pneumonia. These
patients are toxic in appearance often with septic shock and marked hypoxia
In patients who recover from influenza pneumonia and then develop a bacterial pneumonia
7 to 10 days later, H. influenzae and S. pneumoniae are the likely pathogens and their course
is identical to normal hosts with uncomplicated H. influenzae or S. pneumoniae CAP
Table 14.6: Viral CAP

Pathogen Clinical Setting/Pearls Treatment
Influenza A/B Most common cause of viral pneumonia Oseltamivir
Presents with acute onset of fever, chills, malaise, and myalgias
Influenza alone may present with a clear chest initially both
on auscultation and imaging
Severe manifestations of viral influenza (particularly severe
myalgias, retro-orbital pain) is caused by Influenza A, while a
more mild course is suggestive of either A or B
Thrombocytopenia and leukopenia are common, and severe
Influenza A is associated with lymphopenia
Diagnose with rapid DNA probe, PCR, or DIA/EIA of respira-
tory secretions
Hantavirus Vector is dried rodent urine/feces Supportive,

pulmonary Initially presents as ILI with fevers, chills, headache, and myalgias unproven
syndrome Within 1 week, nausea, vomiting, and abdominal pain develops benefit for
(HPS) This is followed by the most severe phase of illness (car- ribavirin
diopulmonary phase), manifesting as dry cough, respiratory
distress as a result of non-cardiogenic pulmonary edema, and
shock, often leading to ATN
Severe cases are also accompanied by petechiae/hemorrhage
There is an initial leukopenia which is followed later in the dis-
ease course by thrombocytopenia and transaminase elevation
Diagnose with serum IgM titers or hantavirus PCR from respi-
ratory secretions
Severe acute Presents as ILI with fever, dry cough, myalgias, and diarrhea Supportive,
respiratory Classically presents with biphasic disease (influenza is not unproven
syndrome biphasic), with initial symptoms improving after several days. benefit for
(SARS) Fevers and severe dyspnea then returns 7-10 days after initial steroids
infection
CXR with bilateral interstitial findings
Diagnose with SARS serology or viral isolation
Nosocomial Pneumonia (NP)

Nosocomial pneumonia, including ventilator associated pneumonia (VAP), is defined as
development of pneumonia 5 or more days after being hospitalized
True NP occurs in 5 to 15 cases/1,000 hospital admissions. VAP occurs in between 10 to
25% of intubated patients
S. aureus often colonizes endotracheal tubes but is rarely a true pathogen in VAP
Legionella NP occurs in clusters. Its presentation and treatment is the same as Legionella
CAP

S. marcescens and Acinetobacter sp. are uncommon NP pathogens. S. marcescens is the
only NP with an upper lobe predominance
HSV-1 can present as failure to wean from a ventilator in a patient with persistent fevers,
leukocytosis and infiltrates despite 2 weeks of appropriate antibiotic therapy. Diagnose with
cytology by BAL
Table 14.7: Nosocomial Pneumonia

P. aeruginosa Presents as multiple infiltrates that rapidly cavitate in <72 Meropenem,
hours doripenem,
P. aeruginosa is the most virulent cause of NP so empiric NP levofloxacin,
coverage must cover Pseudomonas ciprofloxacin, or
Use meropenem, doripenem, colistin, or polymyxin B for MDR amikacin
P. aeruginosa
Diagnose with lung tissue biopsy or elastin fibers in respira-
tory secretions
K. pnemoniae Presents as a necrotizing pneumonia similar to P. aeruginosa Meropenem,
but takes 3 to 5 days to cavitate doripenem, or
Occurs primarily in alcoholics tigacycline
Chronic Pneumonia
Chronic pneumonias present with low grade fevers, chronic (usually non-productive) cough,
and are often accompanied by malaise, night sweats, and weight loss
Symptoms must be present for at least 4 weeks to be considered a chronic pneumonia
A PPD is considered positive in patients with HIV, have a solid organ transplant, are on
chronic immunosuppression, have evidence of old TB infection on CXR, or have recently
been in contact with someone with active TB if there is greater than 5 mm of induration
Patients with diabetes, leukemia, ESRD, residents of prisons, nursing homes and homeless
shelters, healthcare workers, and IVDA have a positive PPD if greater than 10 mm of
induration is present
Normal hosts without and TB risk factors are considered positive if there is 15 mm or
greater of induration on PPD testing
Table 14.8: Chronic Pneumonia
M. tuberculosis Presents with fever, weight loss (with intact appetite, vs. Isoniazid, rifampin,
(reactivation TB pres- malignancy), night sweats with or without hemoptysis ethambutol, and
ents as chronic PNA, Chest imaging shows bilateral apical fibro-cavitary lesions pyrazinamide.
primary TB presents No pleural effusion in reactivation TB (acute, primary TB is (treat with all 4
as acute PNA) lower lobe and commonly has effusions) initially, pending
ESR <70 mm/hr resistance studies)
Diagnose with sputum AFB positive and T-spot positive
Histoplasmosis Clinically resembles TB, but also presents with bilateral Itraconazole
hilar adenopathy (BHA)
Patients will often present with painful tongue ulcers
Geographic distribution: Mississippi River and Ohio River Valley
Diagnose with histoplasma urinary Ag
Blastomycosis Classic ulcerative/verrucous lesions develop on face/nose Itraconazole or
Organism may also involve bone or prostate amphotericin B
Right perihilar infiltrate typically seen on chest imaging
Diagnose with tissue biopsy
Coccidiomycosis Clinical presentation features prominent arthralgias and E. Amphotericin B
nodosum
Suspect Coccidiomycosis in patients with chronic pneu-
monia and eosinophilic meningitis
Chest imaging with thin walled cavities and BHA
Geographic distribution: California and American SW
Peripheral eosinophilia common
Diagnose with tissue biopsy
Nocardia Suspect Nocardia in patients with chronic pneumonia and TMP-SMX or
CNS mass lesions minocycline
Chest imaging with dense, central lower lobe infiltrates
Organism is weakly acid fast and aerobic
When stained, organism shows Chinese character forms
Diagnose with tissue biopsy/culture
Actinomyces Imaging demonstrates peripheral infiltrates Amoxicillin or
Commonly spreads to the chest wall/ribs creating fistulas doxycycline
Classic sulfur granules seen in chest wound drainage
As opposed to nocardia, actinomyces is anaerobic and not
acid fast
Diagnose with wound drainage culture
Melioidosis Clinically resembles TB, but imaging with lower lobe (not Ceftazidime
apical) involvement
Geographic distribution: Asia (exposure often decades
previously e.g., Vietnam veteran)
Diagnose with sputum culture of Burkholderia
(Pseudomonas) pseudomallei
Lung abscess Presents following aspiration pneumonia Clindamycin
Patients often with poor dentition and foul breath
Imaging with cavitary (thick walled) lung infiltrates
Requires prolonged antibiotic therapy until radiographic
resolution (1 to 3 months typically)
Diagnose with imaging/history
Rhodococcus equi Only consider R. equi in HIV patients TMP-SMX or
Presents like reactivation TB doxycycline
Diagnose on sputum stain: Filamentous forms fragment
into cocci and bacilli

14.4 ENDOCARDITIS
Acute Bacterial Endocarditis (ABE)
Clinical criteria for ABE are continuous, high grade bacteremia, fever, new or changed
murmur, and echocardiographic evidence of vegetation
Janeway lesions are classically present in ABE
ABE in a normal host is almost exclusively due to S. aureus infection and should be
empirically treated with vancomycin and gentamicin or amikacin
ABE in the IV drug abuser (IVDA) is typically caused by S. aureus, P. aeruginosa,
S. marscecens, and aerobic Gram negative bacilli
Treat ABE in the IVDA empirically with vancomycin and gentamicin or amikacin
Use ESR and teichoic acid antibody titers (for MRSA or MSSA only) as markers for effective
therapy and treat for 4 to 6 weeks
Subacute Bacterial Endocarditis (SBE)

Clinical criteria for SBE are continuous, high grade bacteremia, low grade fever (less
than 102 F in normal hosts), an unchanged murmur, and echocardiographic evidence of
vegetation
The most common cause of SBE originating from above the waist is viridans streptococci
The oral source of viridans streptococci bacteremia is almost always clinically inapparent
Bacteremia originating from below the waist is most commonly caused by enterococci
(group D streptococci)
S. bovis (nonenterococcal group D streptococci) SBE/bacteremia suggests an underlying
GI malignancy
Low back pain is common with SBE, particularly in enterococci SBE
Peripheral manifestation of SBE include Osler nodes, Roth spots, splinter hemorrhages,
conjunctival hemorrhages, and clubbing
Splenomegaly without hepatomegaly is almost always found in SBE
Non-specific laboratory tests associated with SBE are RF, ESR (often >100), false positive
VDRL, and microscopic hematuria
Bland emboli commonly occur with SBE. Embolization occurs to coronary arteries, CNS,
joints, kidneys, and spleen
Culture negative endocarditis is most commonly due to fastidious organisms that may
take weeks to grow under special conditions
The most important cause of true culture negative SBE is Q fever, which is always preceded
by Q fever CAP
Viridans streptococci SBE should be treated with ceftriaxone for 2 to 4 weeks
E. faecalis (Group D enterococci) SBE should be treated with ampicillin and gentamicin for
4 to 6 weeks. Substitute vancomycin for ampicillin in the PCN allergic patient
Prosthetic Valve Endocarditis (PVE)

Divide PVE into early (within 2 months) and late (more than 2 months) groups
PVE should be suspected in patients who have undergone prosthetic valve replacement
(PVR) and develop prolonged fevers and chills
Early PVE is typically caused by S. aureus (MSSA or MRSA) or Enterobacteriaceae
Fever of early PVE usually <102 F, and blood cultures are persistently/markedly positive
(3/4 - 4/4 sets)
Treat early PVE empirically with vancomycin and gentamicin. Patients will show clinical
improvement, but will not be cured without valve replacement
Late PVE is usually caused by viridans streptococci or S. epidermidis (CoNS) and presents
similarly to veridans streptococci SBE
Cultures of removed valve in late PVE may be negative, but Gram stain is always positive
Empirically treat late PVE with meropenem or with vancomycin and gentamicin
PVE caused by veridans streptococci may be cured with antibiotics alone
14.5 HEPATITIS
Acute Viral Hepatitis
Acute viral hepatitis typically presents with fever (<102 F), anorexia, and malaise often with
jaundice/dark urine. Subclinical infections do occur, recognizable only by mild transaminitis
and positive serology
Fulminant acute hepatitis is one of the few causes of transaminases greater than 1,000
Hepatitis A (HAV) and hepatitis E (HEV) viruses are transmitted via fecal-oral route and
tend to have more abrupt clinical onset that other hepatitis viruses
HAV is most common in developing countries where vaccines may not be readily available,
but outbreaks can occur in daycare centers, IVDAs, or rarely in hemophilia patients (clotting
factor contaminant)
Diagnose acute HAV infection with elevated HAV IgM
HAV is usually a self limited disease and does not progress to chronic hepatitis but may
cause fulminant hepatic failure
HEV is primarily found in Southeast/Central Asia, North Africa, the Middle East, and Central
America
Pregnant patients (3rd trimester particularly) that contract HEV can often develop
fulminant hepatitis
With the exception of pregnant females, HEV is usually a self limited disease and does not
progress to chronic hepatitis
Hepatitis B (HBV), hepatitis C (HCV), and hepatitis D (HDV) are blood-borne pathogens
Approximately 10% of acute HBV infection presents as serum sickness-like illness with
migratory polyarthritis, morbiliform or urticarial rash, glomerulonephritis, and angioedema
Hepatitis B surface antigen (HBsAg) becomes positive first in acute infection, remaining
elevated for weeks to months following infection. Elevation of antibody to hepatitis B core
antigen (Anti-HBc) IgM then becomes positive
Elevated Anti-HBc IgG can only indicate prior infection as vaccination results in HBsAg IgG
positivity
Diagnose acute HBV infection with HBsAg, HBV viral load by PCR, or hepatitis B envelope
antigen (HBeAg) IgM
Give hepatitis B immune globulin (HBIG) to newborns of mothers with positive HBsAg,
following needlestick or splash accident in non-vaccinated individuals, or to sexual contacts
of acute HBV patients who have not been vaccinated
HCV is much more common in its chronic form (55 to 85% risk of going on to have chronic
infection) and most HCV infections are asymptomatic (75%)

Suspect HSV, CMV, or EBV hepatitis in patients presenting with acute hepatitis who are
immunocompromised or have significant transaminitis with negative hepatitis virus testing
Hepatitis caused by CMV/EBV should be accompanied by bilateral posterior cervical
lymphadenopathy and atypical lymphocytes as part of a mono-like illness
Chronic Viral Hepatitis

Chronic viral hepatitis is often clinically asymptomatic and will often (not always) have
persistent/intermittent elevation of serum transaminases
The chance of HBV infection becoming chronic is inversely proportional to age, i.e., risk of
chronic HBV is 90% in neonates, <5% in adults
Important extra-hepatic manifestations of chronic HBV infection are polyarteritis nodosa
(PAN) and glomerulonephritis
HBV infection can create a window period several weeks after initial infection when
HBsAg is negative, use Anti-HBc IgM to confirm the diagnosis in these cases
Chronic HCV is rarely clinically evident before symptoms of cirrhosis begin
Important extra-hepatic manifestations of chronic HCV infection are cryoglobulinemia,
porphyria cutanea tarda, cutaneous vasculitis, and glomerulonephritis
Diagnose HCV with HCV RNA or anti-HCV Ab
Patients with chronic HCV should receive anti-viral agents if they have elevated HCV viral
load, elevated transaminases, and have not yet become end-stage cirrhotics
HDV infection occurs primarily in IVDAs and requires prior or concurrent HBV infection
Diagnose HDV infection with positive anti-hepatitis D virus (anti-HDV) IgM and positive
HBsAg, with positive Anti-HBc IgM indicating simultaneous HBV and HDV co-infection
14.6 INFECTIOUS DIARRHEAS

Acute Infectious Diarrheas
Clostridium Difficile
Caused by prior antibiotic/chemotherapy exposure and can occur up to 3 weeks
following the exposure
Diagnose with C. difficile stool toxin PCR
In addition to stopping the causative agent, uncomplicated C. difficile diarrhea can be
treated with 10 to 14 days PO metronidazole or PO vancomycin
C. difficile colitis, evidenced by marked leukocytosis, abdominal pain, and acidosis or
evidence of colitis on imaging should be treated with IV metronidazole
Severe cases may require colectomy
Vibrio
Vibrio cholera is the cause of cholera, an acute watery diarrhea that leads to significant
dehydration and acidosis
V. vulnificus typically presents as acute watery diarrhea and is classically transmitted via
contaminated oysters/mollusks
V. vulnificus can also cause sepsis/hemorrhagic bullae, particularly in patients with
underlying liver disease
Treat Vibrio sp. with doxycycline
E. coli
Enterotoxigenic E. coli (ETEC) typically presents as acute watery, voluminous diarrhea
without blood/mucus
ETEC is the most common cause of travelers diarrhea and can be treated with supportive
care and, if febrile, with 3 days of ciprofloxacin, levofloxacin, or azithromycin
Although most E. coli diarrhea has nonbloody stool, Enterohemorrhagic E. coli (EHEC)
type O157:H7 causes an invasive dysentery with bloody stools
E. coli O157:H7 is transmitted through undercooked beef/contaminated milk and is
associated with TTP/HUS
Do not treat E. coli O157:H7 with antibiotics as this increases the likelihood of HUS
Salmonella, Shigella, Campylobacter
Salmonella, Shigella, and Campylobacter all cause invasive, frequently bloody diarrhea
In addition to the diarrhea described above, Salmonella is often accompanied by fever
and abdominal pain
Salmonella is linked to raw dairy/contaminated eggs
S. typhi enteric fever is associated with relative bradycardia, Rose spots, headache, and
abdominal pain
There is an increased risk of Salmonella sp. disease in patients with sickle cell disease
(osteomyelitis), AIDS, leukemia, lymphoma, steroid use, or recent chemotherapy
Shigella sonnei is the primary cause of bacillary dysentery in the US
S. sonnei causes an invasive, bloody diarrhea and is typically spread via fecal oral route
and can be spread from person to person particularly in areas with poor hygiene
Treat Shigella sp. with ampicillin, TMP-SMX, or a quinolone
C. jejuni is transmitted via undercooked poultry
Campylobacter infection can lead to Guillain-Barre syndrome in up to 30% of cases
following the diarrheal illness (predilection for HLA-B27 positivity)
Treat Campylobacter with azithromycin or a quinolone
Amebic Dysentery
Entamoeba histolytica presents as subacute onset of bloody stools, often with mucus, but
can also cause a more chronic dysentery
May form collar-stud abscesses in the colon
Diagnose by stool or intestinal biopsy showing organism/trophozoites
Treat with metronidazole
Viral Diarrheas
Noroviruses typically cause outbreaks of profuse watery diarrhea in the winter months
and is water-borne (can be associated with raw shellfish)
Rotavirus is typically associated with contact with children (fecal-oral) and presents as a
self-limited watery diarrhea
Diagnosis of viral pathogens is based on history/exposure but can be confirmed with
ELISA
CMV is a cause of watery diarrhea and should be suspected primarily in patients on
systemic immunosuppression
To confirm CMV infection, a colonoscopy must be performed to look for CMV inclusion
bodies

Chronic Infectious Diarrheas
Giardia
G. lamblia causes subacute onset of watery diarrhea, abdominal cramping, flatulence, and
bloating
Associated with malabsorption in chronic cases
Diagnosis is via stool antigen test or visualizing trophozoites in stool. If this is unrevealing,
duodenal aspirate or biopsy should be performed using the string test or EGD
Treat Giardia with nitazoxanide or albendazole
Cryptosporidia, Cyclospora, Microsporidia, Isospora
Classically seen in HIV patients as a chronic, non bloody diarrhea lasting over 2 weeks
Cryptosporidia can cause a more acute, self-limited diarrheal illness in normal hosts who
have been traveling and in contact with the parasites reservoir (animals)
Cyclospora is often associated with flatulence/bloating like Giardia
Isospora belli is the only diarrhea causing protozoa with eosinophils in the stool. Treat
with TMP-SMX
14.7 URINARY TRACT INFECTIONS

Dysuria-pyuria syndrome (acute urethral syndrome) is caused by S. saprophyticus,
C. trachomatis, or E. coli and presents with dysuria, urinary frequency, and suprapubic pain
Pyuria is present but urine culture should demonstrate no growth or <10,000 colonies/mL
of E. coli, and is treated with doxycycline or a quinolone
Simple cystitis presents identically to the acute urethral syndrome but with fever (<102 F)
and bacteriuria in addition to pyuria and is treated for 1 to 3 days
Bacterial causes of cystitis commonly include Enterobacteriaceae, E. faecalis (Group D
enterococci), S. agalactiae (Group B streptococci), and S. saprophyticus, and is treated with
nitrofurantoin, TMP-SMX, amoxicillin, or a quinolone
Complicated UTIs (anatomical abnormality, males, etc.) should be treated for 10 to 14 days,
but treatment may fail and relapse/recurrence is common
Catheter associated bacteriuria (CAB) is typically asymptomatic and is best treated by
removing or changing the urinary catheter
Acute pyelonephritis presents with pyuria, bacteriuria, high fever (>102 F), unilateral CVA
tenderness and often bacteremia
The most common uropathogens causing acute pyelonephritis are Enterobacteriaceae
(treated with cephalosporin, quinolone, or aminoglycoside) or enterococci (treated with
ampicillin)
Infection with Proteus sp. should be suspected in patients with a urinary pH >6 and should
prompt an evaluation for GU struvite stones
Renal TB should be suspected in patients with persistent sterile pyuria and imaging that
demonstrates involvement of both the kidney and ureter
Pregnant patients with asymptomatic bacteriuria should always be treatednitrofurantoin is
the preferred treatment
Antibiotics that can be used in pregnancy for symptomatic UTIs are ampicillin,
aminoglycosides, or cephalosporins
14.8 SEXUALLY TRANSMITTED DISEASES
Urethritis
Manifests with a purulent urethral discharge. Differentiate gonococcal urethritis (GCU) from
nongonococcal (NGU) with gram stain and culture of the discharge. Discharge in NGU is
typically mucoid
GCU commonly occurs within 5 days of exposure and is accompanied by dysuria. It is
asymptomatic in 10% of males and 70% of females
Diagnose by seeing gram negative diplococci on Gram stain of urethral discharge in males,
use DNA probe or culture in females
N. gonorrhoeae infection can also involve the rectum, pharynx, and conjunctiva
Treat GCU with a single dose of 3rd generation cephalosporin or azithromycin. If no
response, consider NGU as diagnosis
NGU caused by Chlamydia trachomatis and less commonly Ureaplasma urealyticum,
Mycoplasma genitalium, or Trichomonas vaginalis
Diagnose NGU with culture of organism or DNA probe from cervical/urethral discharge.
Trichomonas can be identified on wet mount, and classically presents with strawberry
cervix
Treat all NGU except T. vaginalis with azithromycin x1 dose or doxycycline, quinolone, or
erythromycin for 1 week
Trichomonas should be treated with 2 gm metronidazole x1 dose or 2 gm tinidazole x1 dose.
Males are often asymptomatic and should be treated along with their partners
Ulcerative STDs
The chancre of primary syphilis resolves if untreated in approximately 3 to 6 weeks in a
normal host
Diagnosis based on dark field microscopy of chancre. VDRL/RPR titers take at least 1 week
to become positive, so a negative non-treponemal test does not exclude disease early on
Secondary syphilis is the result of disseminated T. pallidum. Although its manifestations are
myriad, its rash commonly involves the palms and soles and is almost always symmetric. It
may involve the oral/genital mucous membranes
Secondary syphilis is typically associated with generalized lymphadenopathy but can also
manifest as uveitis, condyloma lata, alopecia, etc.
Look for secondary syphilis 4 to 10 weeks following the initial ulcer and expect it to resolve
spontaneously 3 to 12 weeks after onset of symptoms
VDRL/RPR titers should be markedly elevated in secondary syphilis, aiding diagnosis, and
should be treated identically to primary syphilis
Latent syphilis is an asymptomatic state with a history of prior infection and elevated RPR/
VDRL. Early latent is <1 year from initial infection, late latent is >1 year or unknown
Treponemal tests will typically remain positive throughout the patients life even with
treatment, while non-treponemal titers should decrease by four-fold, or become completely
negative with treatment
Penicillin is always the preferred therapy for syphilis

Table 14.9: STDs
Organism Location/Type of Lesion Treatment
Syphilis (primary) Single or few clean based lesions with distinct Benzathine PCN IM
indurated borders or IV x 1 dose or
Treat secondary and Always painless PO doxycycline x 2
early latent the same Can develop bilateral painless inguinal adenopathy weeks
Haemophilus ducreyi Few ragged, undermined, draining ulcers (can start 3rd gen cepha-
(chancroid) as papules) which are painful losporin IM or
Also with painful unilateral inguinal lymphadenopathy azithhromycin x 1
dose
Herpes simplex (HSV) Painful grouped vesicles which can ulcerate PO acyclovir or
Associated with tender bilateral inguinal valacyclovir
lymphadenopathy
Can have low grade fever
Chlamydia trachomatis Unilateral painless papule that develops into an Doxycycline or
L1-3 serotypes ulcer and eventually, painless ipsilateral inguinal erythromycin x 3
(LGV) lymphadenopathy, often with draining sinus tracts weeks
Initial lesions disappear in 1 to 3 weeks, with lymph-
adenopathy developing in 2 to 6 weeks
Calymmatobacterium, Rare STD causing painless inguinal/genital ulcers Azithromycin q

now Klebsiella (pseudolymphadenopathy) known as groove week or doxycy-
granulomatosis (granu- sign cline until cured
loma inguinale or There is no true lymphadenopathy unlike LGV
Donovanosis)
Human papilloma virus Single or multiple verrucous papules on the ano- Prevent with
(HPV) genital region vaccination.
Types 16, 18, 31, 33, 35 high risk for cancer Topical therapy
Vaccine protects against types 6, 11, 16, 18 with cryotherapy/
Typically poor response to therapy laser/surgery/
imiquimod
PID/Salpingitis
Caused by N. gonorrhoeae, C. trachomatis, B. fragilis, or Enterobacteriaceae, and manifests
as lower abdominal pain, fever, and adnexal/cervical motion tenderness on pelvic exam
Must treat or infertility may develop along with other complications from scarring
N. gonorrhoeae and C. trachomatis PID patients can also develop perihepatitis (Fitz-Hugh-
Curtis Syndrome). PID with a hepatic rub is Fitz-Hugh-Curtis syndrome
Treat with moxifloxacin or doxycycline for 2 weeks
Imaging is required to evaluate for tuboovarian abscess which must typically be surgically
drained in addition to IV antibiotics
Epididymitis
Acute epididymitis presents as sudden onset unilateral testicular pain with fever
In young, sexually active males consider C. trachomatis, as the likely cause and treat with
doxycycline or levofloxacin
In older males P. aeruginosa, E. coli, and Enterobacteriaceae are the common pathogens
and can be treated with cefepime, meropenem, or levofloxacin
Chronic epididymitis presents as >2 weeks of epididymoorchitis with epididymal nodules
Mycobacterium tuberculosis and Blastomyces dermatidis are the most common organisms
in chronic epididymitis
Treat epididymal TB as you would pulmonary TB
Blastomyces should be treated with itraconazole or amphotericin B
Vaginitis
Bacterial vaginitis/vaginosis (BV) presents as a non-pruritic vaginal discharge with a fishy
odor
It is often polymicrobial (Gardnerella vagnialis, Mobiluncus, Prevotella, Mycoplasma hominis)
Diagnose with a positive whiff test, vaginal pH <4.5, and by visualizing clue cells on wet
mount
Treat with PO metronidazole or clindamycin for 7 days
Always treat pregnant females, since BV can result in premature rupture of membranes and
premature delivery. There is an increased risk of PID in non-pregnant females with BV
Partners do not need to be treated
Candidal vaginitis manifests as pruritic white plaques in the vagina often with an
erythematous base
Diagnose with KOH prep or culture and treat with a single dose of PO fluconazole or treat
with azole vaginal creams
HIV
General Principles
Acute HIV (primary HIV) infection presents as a flu-like illness 1 to 4 weeks following
inoculation that can mimic infectious mononucleosis
Primary HIV manifests as fever, generalized lymphadenopathy, non-exudative pharyngitis,
arthralgias or myalgias, and a morbilliform rash usually on the face/trunk but may involve
the palms/soles as well as the mucous membranes
Laboratory studies initially show lymphopenia followed by a lymphocytosis (no atypical
lymphs unlike mono), and thrombocytopenia, leukopenia, and mild elevation of the
transaminases may also be present
Diagnosis of acute HIV is by HIV RNA (>20,000 copies) as it takes up to 6 months (but
usually takes 6 to 8 weeks) for HIV antibodies to rise (seroconversion)
Patients with acute HIV will still need follow-up antibody testing to confirm diagnosis
Diagnose chronic HIV with ELISA screen and confirm with Western Blot
Unless acute HIV is suspected, a negative ELISA effectively rules out HIV infection
An indeterminate Western Blot may be seen in patients undergoing seroconversion,
patients with autoantibodies related to collagen vascular disease, or with HIV-2 infection.
A HIV RNA should be obtained to exclude seroconversion, and ELISA/Western Blot
testing should be repeated in several months
Rapid HIV testing is comparable to traditional ELISA/Western Blot accuracy, but must
always be confirmed by ELISA/Western Blot testing
Once HIV infection is confirmed, all patients should undergo testing including HIV viral
load, CD4 count, lipid profile, Toxoplasma IgG, RPR/VDRL, viral hepatitis serology, and
PPD (If >5 mm induration, and CXR without evidence of active TB they should be given 9
months of isoniazid for presumed latent TB infection)

When to start antiretroviral therapy (ART) is debatable but all guidelines agree on
starting if the CD4 count is <200, an AIDS defining illness is present, and compliance can
be assured
ART regimens are variable, but must always include at least 3 drugs to prevent resistance
HIV genotyping should be performed in patients who have previously been on ART
and stopped or have evidence of ART failure (rising viral load/falling CD4 count despite
compliance with ART)
Post exposure prophylaxis (PEP) should be given to individuals with skin break/mucous
membrane contact with blood of HIV positive patients. They should receive PEP
immediately and continue for 4 weeks. Regimens for PEP vary but always contain more
than 1 drug and usually include zidovudine
HIV testing should be performed following exposure for 6 months
Do not give PEP for exposure to a non-blood source
Opportunistic Infections in HIV - General Principles
AIDS is defined as CD4 count <200, CD4 <14% of total lymphocytes, or presence of an
AIDS defining opportunistic infection (OI)
Patients with a new diagnosis of HIV should be vaccinated against pneumococcus,
influenza, and hepatitis B as soon as possible. They should receive a hepatitis A vaccine if
they are co-infected with HCV. Routine adult vaccination (varicella, MMR, etc.) should also
be performed for the usual indications
HIV patients whose CD4 count is >500 are at risk for the same pathogens as normal
hosts, but as their CD4 counts drop, they are predisposed to certain conditions
CD4 >500: Increased risk of pneumococcal pneumonia, sinusitis, herpes zoster, TB,
molluscum contagiosum, eosinophilic folliculitis, extreme seborrheic dermatitis, and
sudden/severe pustular psoriasis
CD4 <500: Kaposis sarcoma (HHV-8), vaginal candidiasis, and ITP
CD4 <200: Oral hairy leukoplakia (EBV), oral candidiasis, Pneumocystis jiroveci
pneumonia (PCP), cryptococcal meningitis, and toxoplasmosis
CD4 <50: CMV retinitis and disseminated Mycobacterium avium complex (MAC) infection
Patients with CD4 counts <200 should be placed on TMP-SMX, which protects against
PCP and toxoplasmosis. Weekly azithromycin protects against MAC and should be given
to those with CD4 counts <50
Immune reconstitution inflammatory syndrome (IRIS) can unmask or worsen some OIs
including CMV, HSV, MAC, MTB, and PCP. ART should be continued during IRIS, but
severe cases require steroids
Opportunistic Infections in HIV - Specific Infections
CMV retinitis usually presents as unilateral (but often progresses to involve both eyes)
blurred vision, scotomata, and vision loss and has a classic cheese pizza or tomato
soup and milk appearance of retinal hemorrhage on fundus exam. Treat CMV retinitis
with valganciclovir, ganciclovir, or foscarnet
Progressive multifocal leukoencephalopathy (PML) manifests as subacute onset of
aphasia, ataxia, and focal neurologic deficits usually without headache or seizure.
Diagnose with MRI brain showing patchy demyelination of white matter. Caused by JC
virus reactivation. Treatment of PML is starting/maximizing ART, but neurologic deficits
are often not reversible
MAC typically manifests on subacute onset of fever, weight loss, and night sweats. Focal
disease can develop once ART is initiated as a result of IRIS
Toxoplasma gondii (toxoplasmosis) almost always presents as fever and headache. It
can be accompanied by confusion, seizures, and ataxia. Causes multiple ring enhancing
lesions on MRI (CNS lymphoma is ring enhancing but is usually a single lesion). Serum
toxoplasma titers and imaging provide diagnosis. Treat with pyrimethamine, sulfadiazine,
and leucovorin (not folic acid) for 6 weeks
Important Drug Concepts and Side Effects in HIV
Simvastatin and lovastatin are contraindicated with protease inhibitorspravastatin is
preferred in these patients
Severe, life threatening lactic acidosis can develop in patients taking NRTIs for prolonged
periods (particularly stavudine [d4T], zidovudine, or didanosine)
Efavirenz is teratogenic and should be avoided in pregnant patients. Use zidovudine (pre
and intrapartum) to prevent vertical transmission and breast feeding should be avoided
Indinavir is associated with crystalluria and hematuria
Abacavir is associated with a hypersensitivity reaction (only in HLA-B5701 positive
patients) manifesting with fever, systemic rash, malaise, abdominal pain, diarrhea, nausea,
and vomiting. Typically occurs within 10 days of initiating abacavir therapy
Stavudine and didanosine can cause often irreversible peripheral neuropathy or
pancreatitis
Zidovudine is associated with bone marrow suppression and myopathy
All protease inhibitors are associated with insulin resistance and hyperlipidemia
14.9 SKIN, SOFT TISSUE, AND BONE INFECTIONS

Uncomplicated Skin and Skin Structure Infections (uSSSIs)
uSSSIs include simple cellulitis, impetigo, lymphangitis, and erysipelas
Differentiate erysipelas from cellulitis by its clearly demarcated, indurated border
Impetigo is usually caused by S. pyogenes and manifests as vesiculopustular lesions that
develop a honey colored crust on the face and extremities
Treat these infections with a cephalosporin, quinolone. If MRSA suspected, use vancomycin,
linezolid, or minocycline
Complicated Skin and Skin Structure Infections (cSSSIs)

cSSSIs include necrotizing fasciitis (Fourniers gangrene if involving the scrotum), gas
gangrene, and mixed anaerobic/aerobic deep tissue infections
Necrotizing fasciitis presents in toxic appearing patients with high fevers and extremely
painful infected area without crepitus (may have foul smelling drainage)
Diagnose necrotizing fasciitis on CT/MRI of the affected area which will demonstrate
infection within 1 or more muscle compartments/fascial plane
Caused by Group A streptococci, Enterobacteriaceae, anaerobic streptococci, and
S. aureus, treat necrotizing fasciitis with prompt surgery along with carbapenem or
piperacillin/tazobactam. Clindamycin has anti-endotoxin effects and should be added if
GAS is suspected

Gas gangrene is usually caused by Clostridium sp. and presents following trauma as a
severely painful muscle infection (often out of proportion to its appearance) with little or no
fever
Bullae may be present (unlike necrotizing fasciitis) and wound discharge, if present, is
typically sweet smelling
Little, if any, gas is visible on plain films of involved area
Laboratory studies will often reveal a characteristic rapidly progressive hemolytic anemia as
well as elevated CPK
Diagnosis of gas gangrene is clinical and rapid surgical debridement is the treatment of
choice but PCN G, clindamycin, or ertapenem are used as antibiotic adjuncts
Mixed anaerobic/aerobic deep tissue infections are most common among diabetics (unlike
gas gangrene which is rare in diabetics) and will present with local pain at the infected site
as well as high fevers
They will often have evidence of gas on plain film, have marked crepitus on exam, and a
foul discharge if present
Treat mixed anaerobic/aerobic deep tissue infections with carbapenem or piperacillin/
tazobactam in addition to prompt surgical debridement
Sporothrix schenckii (Cutaneous Sporotrichosis)

Classically presents as an ascending infection following a skin break from a thorn
Initial lesion is a small, firm, mobile subcutaneous nodule, which then opens to form a friable
ulcer
Secondary lesions then develop along the extremity following the lymphatic drainage
channels, but do not involve the lymph nodes themselves. Spares the axilla because of the
increased temperature
S. schenckii can cause widespread lymphocutanoues disease with arthritis in HIV patients
with CD4 <200. Treat with itraconazole
Cutaneous Mucormycosis
Rhinocerebral mucor is seen primarily in poorly controlled diabetics. A black eschar is often
seen on the mucous membrane (nasal or hard palate)
In immunosuppressed or leukopenic hosts, cutaneous mucor presents as a black eschar on
the skin as a result of vascular invasion
Tissue stain (not culture) demonstrates the diagnostic broad, non-septate, ribbon like
branching hyphae
Treat with amphotericin B or itraconazole. Will often need surgical debridement
Bartonella henselae (Cat Scratch Disease - CSD)

CSD presents as subacute onset of fever following a cat bite or cat lick over an area of skin
with a micro-laceration, typically with local lymphadenopathy
Culture of any drainage or node is often negative, demonstrate organism on silver stain of
wound
CSD has 2 forms, 1. Invasive disease, which may present as FUO 2. Lymphoma and local
disease with lymphadenopathy alone
Characteristic macular star may be present on fundus exam in the invasive form
Treat invasive CSD with doxycycline or azithromycin, treat local CSD with azithromycin
Bites
Animal bites cause infection with P. multocida, GAS, Capnocytophaga canimorus (DF2), and
S. aureus. Treat with ertapenem, ampicillin/sulbactam, doxycycline, or amoxicillin/clavulanic
acid
Capnocytophaga canimorus (DF2) causes sepsis and DIC in asplenic patients bitten by cats
and dogs
Human bite wounds typically involve oral anaerobes, GAS, E. corrodens, and S. aureus.
Antibiotic therapy is identical to animal wound bites
Avoid primary closure of human bite wounds
If bitten by an animal suspected of being rabid, begin vaccination sequence immediately
(raccoon, skunk, bat, and fox bites are assumed to be rabid). If the animal is visibly rabid or
becomes rabid, give human rabies immune globulin (HRIG). If the animal can be watched
following a bite, it is possible to hold off on administration of HRIG/vaccination
Osteomyelitis
Acute osteomyelitis presents with tenderness over the infected bone, often with fever,
bacteremia, and leukocytosis. Bone scan or MRI will diagnose acute osteomyelitis in
conjunction with an ESR (often >100)
Debridement or bone biopsy is not needed for acute osteomyelitis and cure is possible with
4 to 6 weeks of antibiotics alone
Typical acute osteomyelitis organisms are S. aureus (treat with cephalosporin,
quinolone, or clindamycin if MSSA or linezolid, vancomycin, or minocycline if MRSA) and
Enterobacteriaceae (treat with cephalosporin or quinolone)
Chronic osteomyelitis typically occurs in diabetics or PVD patients and manifests as a deep
penetrating ulcer (sometimes with draining tract), normal WBC, and normal/low grade
(<102 F) fever
Plain films and ESR are sufficient for diagnosis, but MRI can also detect chronic
osteomyelitis. To isolate the causative organism, bone biopsy is the best test as blood
cultures are often negative and wound/ulcer cultures show superficial flora
P. aeruginosa is often cultured from the wound but is rarely a true pathogen unless history
of penetrating trauma through a humid, wet environment (stepping on a nail through the
bottom of a sneaker)
Definitive cure relies on surgical debridement, but can treat empirically with carbapenem,
piperacillin/tazobactam, or moxifloxacin. Use linezolid or minocycline for MRSA
Foul discharge from ulcer suggestive of B. fragilis infection requiring moxifloxacin or
ertapenem
Osteomyelitis is usually caused by Salmonella sp. in Sickle cell patients
14.10 NON-TUBERCULOUS MYCOBACTERIAL (NTM) INFECTION

Mycobacterium marinum (Swimming Pool Granuloma)
M. marinum presents as an area of tender erythema at the inoculation site which then
develops into a violaceous nodule that ulcerates and drains purulent material
Requires previous contact with fresh water source (swimming pool, fish tank, lake, etc.) and
may spread in a sporotrichoid fashion (20%)

Mycobacterium scrofulaceum (Scrofula)
M. scrofulaceum causes scrofula in adults (M. tuberculosis causes scrofula in children) which
manifests as chronic, cold, unilateral anterior cervical lymphadenopathy often with sinus
tracts
Diagnose by AF stain/culture of drainage and treat with surgical excision
Mycobacterium ulcerans
M. ulcerans begins as a firm, painless, mobile, subcutaneous nodule that evolves over 1 to 2
months into an enlarged fluctuant mass that eventually ulcerates with a undermined border
Geographic distribution: Africa primarily, but also present in Asia, Australia, and Central/
South America
Diagnose by AF stain/biopsy of ulcer
Mycobacterium leprae (Leprosy - Hansens Disease)

Leprosy presents as diffuse, anesthetic, white macules. Papules or nodules may occur and
symmetric peripheral neuropathy is a late complication
Lepromatous leprosy can result in the loss of eyebrows as well as thickening of the face
and earlobes (Leonine facies)
E. nodosum and polyclonal gammopathy is commonly present. Afebrile bacteremia is also
common and organism can be found in smears of the buffy coat
Diagnose by AF stain/biopsy of tissue
Rapidly Growing Mycobacteria (M. abscessus, M. chelonae, M. fortuitum)

Infection usually develops following inoculation from trauma, surgery, or injection
These organisms manifest as cold abscesses with draining fistulae
Often occur in nosocomial clusters and are associated with plastic surgery, breast implants,
and cardiac surgery. Remove any foreign body involved in these infections
Diagnose by AF stain/culture of wound drainage
Treat M. abscessus or M. chelonae with clarithromycin
14.11 FUO
Definition: Fever of unknown origin is defined as a temperature >101 F (38.3 C) x 3 weeks that
is undiagnosed after 3 days of hospitalization, 3 outpatient visits, or 1 week of intensive outpatient
investigation. Typically, the longer the period the fever remains undiagnosed, the less likely it is
infectious is origin.
Causes: 4 major categories: 1. Infectious 2. Malignancy 3. Rheumatologic 4. Other.
Table 14.10: Etiologies of FUO

Class Common Uncommon
Infectious Extrapulmonary TB, Intra-abdominal Toxoplasmosis, cat scratch disease
or pelvic abscess, subacute bacterial (CSD), EBV, Whipples disease, histo-
endocarditis (SBE), cytomegalovirus plasmosis, kala-azar
(CMV), Salmonella enteric fevers, HIV
Malignancy Lymphoma, renal cell carcinoma, CNS tumors, pancreatic cancer, colon
leukemias, hepatomas cancer, atrial myxoma
Rheumatologic Giant cell arteritis (GCA), adult onset Systemic lupus erythematosus (SLE),
Stills disease, periarteritis nodosa familial Mediterranean fever (FMF),
(PAN) vasculitis, Feltys syndrome, rheuma-
toid arthritis
Other Drug fever, alcoholic cirrhosis Subacute thyroiditis
Workup: Testing should be directed at any potential clues found on thorough history and
exam. It is important to also consider the patients age when directing the workup and consid-
ering the cause, i.e., malignancy is more likely in elderly patients with FUO; GCA should not be
considered in patients less than 50; SLE or RA rare to present later in life.
Table 14.11: FUO - Laboratory Tests

Test Clues
CBC Eosinophilia: Lymphoma, drug fever, PAN
Monocytosis: TB, CMV, lymphoma, carcinoma
Basophilia: Carcinoma, lymphoma
Leukopenia: SLE, miliary TB, lymphoma
Chronic lymphocytosis: CMV, EBV, CLL, toxoplasmosis
ESR >100 GCA, SBE, PAN, FMF, SLE, osteomyelitis, drug fever, lymphoma
SPEP Polyclonal gammopathy: HIV, atrial myxoma
Isolated alpha 1/2 spikes: Lymphoma
Imaging CT/MRI: Able to identify vertebral osteomyelitis, intra-abdominal
abscesses
PET: Able to identify neoplasm
Cardiac ECHO Able to identify atrial myxoma, SBE

LFTs Elevated transaminases: CMV, EBV, drug fever
Elevated alkaline phosphatase: PAN, hepatoma, lymphoma
Ferritin Very high levels suggestive of Stills disease
Bone marrow biopsy Helpful with liquid malignancies, can also aid in diagnosis of enteric
fevers, histoplasmosis, kala-azar, and miliary TB

14.12 VECTOR BORNE DISEASE
Rickettsia rickettsii (Rocky Mountain Spotted Fever - RMSF)
Vector is Dermacentor tick
Geographic distribution: Eastern and Southeastern US
Presents 3 to 12 days following tick bite with fever (with relative bradycardia), severe frontal
headache, and severe myalgias in back, legs, and abdominal muscles (can mimic an acute
abdomen)
Early in the disease course, patients develop periorbital edema and edema of dorsum of the
hands and feet. Acute deafness can occur in some cases
Characteristic rash starts 3 to 5 days after the bite as erythematous macules on wrists and
ankles then spreads over the body becoming petechiae/palpable purpura (involves palms
and soles)
Laboratory tests initially demonstrate a normal WBC or mild leukopenia followed by
leukocytosis, thrombocytopenia, and mild transaminitis
Myocarditis can develop resulting in hypotension, which is the most common cause of
death in RMSF
Diagnose with DFA of rash biopsy. Confirm with serum titers
Treat with doxycycline, which should be started as soon as possible based on clinical
suspicion and should not wait for biopsy/testing results
Malaria (Plasmodium falciparum, P. vivax, P. malariae, P. ovale)

Vector is the female Anopheles mosquito
Malaria presents with fever, rigors, headache, anorexia, and nausea/vomiting
Question the diagnosis of malaria if headache is not present
Laboratory tests are significant for hemolytic anemia, increased LDH, and
thrombocytopenia
Splenomegaly will only be present after 7 to 10 days
P. falciparum can become rapidly fatal in nonimmune patients, while P. vivax, P. malariae,
P. ovale are rarely fatal
Untreated P. vivax and P. ovale can persist and result in recurrent infection
Diagnose on thick and thin blood smear showing classic ring forms in RBCs
Treat severe malaria with quinidine/quinine and doxycycline
Treat all other Plasmodium sp. infection with chloroquine phosphate and add primaquine
phosphate for the hepatic phase of P. vivax and P. ovale. Use quinine sulfate and
doxycycline for chloroquine resistant strains
Babesia (Babesia microti)

Vector is the Ixodes tick
Geographic distribution: Northeastern US, typically during summer
B. microti infection presents as a malaria-like acute febrile illness with chills and myalgias in
normal hosts
Laboratory tests reveal hemolytic anemia, elevated LDH, elevated ESR, and elevated ferritin
Infection is more acute/severe in asplenic patients
Diagnose on thick and thin blood smear showing pathognomonic Maltese Crosses
Treat Babesia with azithromycin and atovaquone. Severe cases in asplenic patients may
require exchange transfusion
Ehrlichia chaffeensis (Human monocytic ehrlichiosis - HME)/Anaplasma (Ehrlichia)
phagocytophilium (Human granulocytic anaplasmosis - HGA)
HME vector is Ambylomma americanum (lone star tick). HGA vector is the Ixodes tick
HME/HGA presents acutely with chills, headache, malaise, myalgias, and fever
Clinically very similar to RMSF but without rash
Laboratory tests are notable for leukopenia with relative lymphopenia, thrombocytopenia,
low ESR, high ferritin, and elevated transaminases
Diagnose with serum PCR or classic mulberry shaped, basophilic morula in neutrophils
(HGA only). Otherwise use organism specific titers (no crossreactivity)
Treat HME and HGA with doxycycline
Borrelia burgdorferi (Lyme Disease)

Vector is the Ixodes tick
Geographic distribution: Northeastern US, upper Midwest, California, and Western Nevada,
typically during summer
Coinfection with HGA or Babesia may occur
Presents with erythema migrans within 2 weeks of tick bite sometimes with fever (<102),
arthralgias, meningismus, and headache
May also present with Bells palsy, myocarditis, meningitis, mild hepatitis, or arthritis (large,
weight bearing joints typically)
Treat Lyme carditis and resultant complete heart block with ceftriaxone
Diagnose with clinical history and IgM Lyme titers. If results equivocal, confirm with Western
blot (titers may take 4 to 6 weeks to rise)
Treat with doxycycline or beta-lactam, macrolides often fail
Dengue Fever (Break-bone Fever)

Vector is the Aedes mosquito
Geographic distribution: Tropics including Central America, South America, and the
Caribbean
The biphasic infection initially presents with rapid onset of high fever, severe myalgias/
arthralgias, headache, nausea/vomiting and a macular rash over the axilla and thorax
After several days the patient will often defervesce and show improvement in rash
A second fever may then develop (saddleback fever) along with a different morbilliform
rash that spares the palms and soles
Change in mental status, hypothermia, and thrombocytopenia predict development of
dengue hemorrhagic fever/shock
14.13 TRANSPLANT ID
General Principals
Transplant recipients can develop nosocomial/post-operative infections, reactivation of
latent infection, or infection from infected donor organs (donor derived infections)
Infections <1 Month Following Solid Organ Transplantation (SOT)

Most infections are related to surgical complications (wound infection, anastomotic leak,
etc.), nosocomial infections (line and catheter infections, legionella, etc.), or from donor
derived infections (rabies, lymphochoriomeningitis [LCM] virus, CMV, HSV, etc.)

3 components that determine the risk of infection in the post transplant patient are
epidemiologic exposure, net state of immunosuppression, and use of prophylactic
antimicrobials. Of these, the most critical is the net state of immunosuppression
C. difficile colitis can develop any time following transplant with a lower risk 6 months post
transplant
Table 14.12: Post Transplant Infections

Transplant Type Immediate Infection Usual Infection Later in
(Usually <1 Month Post-transplant) Transplant Course
(Uncommon <1 month)
Renal UTI/urosepsis CMV, BK virus

Liver Cholangitis, liver abscess. Candidal infection HCV, EBV, CMV
Lung Bronchial suture line infection, nosocomial H. capsulatum
PNA Aspergillus sp.
TB
Heart Mediastinitis/sternal wound infection, mycotic T. gondii
aneurysm, nosocomial PNA T. cruzi
Pancreas or pancreas/ Highest risk of wound infection CMV, BK virus
renal
Infections 1 to 6 Months Following SOT

This is the period of maximum immunosuppression and is the time with the greatest
incidence of primary or reactivation of infection
Expect infections from CMV, HSV, BK, HCV, EBV, listeria, nocardia, toxoplasmosis, T. cruzi,
strongyloides, PCP, TB, and cryptococcus during this time
Infections >6 Month Following SOT

Patients with good graft function are now at their lowest risk for infection
Community acquired respiratory and urinary pathogens are the usual infections at this time,
but Nocardia and Aspergillus sp., and late viral infections (CMV, JC virus causing PML, etc.)
can also present now
Skin cancer and lymphoma (post transplant lymphoproliferative disease - PTLD) also
develops at this time
Bone Marrow Transplants

BMT patients have similar complications to SOT recipients
Recipients of BMT are particularly susceptible to RSV, influenza, and adenovirus
Pre-engraftment phase (<1 month following BMT): Patients are at risk for nosocomial
infection, Candida, Aspergillus and other bacteria/fungi that are associated with leukopenia
Early post-engraftment phase (31 to 100 days following BMT): CMV is the greatest risk at
this time along with PCP (reduced risk if on prophylactic TMP-SMX), HHV-6 infection
Late post-engraftment phase (>100 days following BMT): VZV (40% of all BMT develop
VZV) and pneumococcal pneumonia are the 2 infections that are particularly important
in this population. Of the VZV cases, 30% become disseminated (can decrease risk with
antiviral prophylaxis)
14.14 ANTIBIOTICS
Syndrome specific antibiotic pearls are covered in each previous section. This section is
reserved for other high-yield Board pearls and notable side effects.
Pearls
Ertapenem is the only carbapenem that does not cover Pseudomonas aeruginosa
Daptomycin should not be used for pneumonia, as it is inactivated by the calcium in
surfactant
Of the cephalosporins, only ceftazidime (3rd GC), cefoperazone (3rd GC), and cefepime
(4th GC) are active against Pseudomonas aeruginosa
Table 14.13: Antibiotic Side Effects

Adverse Effect Antibiotic
Leukopenia Beta-lactams
Vancomycin
Anemia Beta-lactams (autoimmune hemolytic)
Chloramphenicol (dose related or aplastic)
Linezolid (aplastic)
TMP-SMX (megaloblastic anemia)
Thrombocytopenia TMP-SMX
Beta-lactams
Vancomycin
Drug induced SLE Minocycline (may not have anti-histone Ab)
Nitrofurantoin
Lowers seizure threshold Ciprofloxacin (not other quinolones)
Imipenem (not other carbapenems)
Encephalopathy Metronidazole
Hyperpigmentation Minocycline
Hypotension Amphotericin B
Pentamidine
Prolonged QTc Quinolones
Macrolides
Elevated CPK Daptomycin
Drug fever Can occur with any, but most common with
beta-lactams and sulfonamides
Crystaluria Acyclovir
Indinavir
Seratonin syndrome Linezolid (In patients on SSRIs)

NOTES
NOTES

15 Pulmonary Disease
Michael J. Sanley, MD
C o n t e n t s
15.1 ASTHMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
15.2 CHRONIC OBSTRUCTIVE PULMONARY DISEASE . 66
15.3 INTERSTITIAL LUNG DISEASE . . . . . . . . . . . . . . . . . . .68
15.4 OCCUPATIONAL AND ENVIRONMENTAL

LUNG DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
15.5 PLEURAL DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
15.6 ACUTE PULMONARY THROMBOEMBOLISM . . . . . 73
15.7 PULMONARY HYPERTENSION . . . . . . . . . . . . . . . . . . 74
15.8 PULMONARY NEOPLASTIC DISEASE . . . . . . . . . . . . 75
15.9 SLEEP DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
15.10 HIGH-ALTITUDE PULMONARY DISEASE . . . . . . . . 80
15.11 CRITICAL CARE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
PULMONARY DISEASE61
15.1 ASTHMA
Epidemiology
Affects roughly 300 million people worldwide
Common onset in childhood, but can have adult onset
Associated with atopy in most patients
Pathogenesis
Hallmark is chronic lower airway inflammation
Mucosal infiltration of inflammatory cells neutrophils and eosinophils
Thickening of basement membrane due to collagen deposition
Goblet cell hyperplasia leads to increased mucous production and plugging
Signs and Symptoms

Hallmark: Wheezing and dyspnea
May also present as cough (cough-variant asthma) particularly nocturnal or exercise
induced symptoms
Diagnostic Testing
Pulmonary function testing
Reduced FEV1, FEV1/FVC ratio, peak expiratory flow
Significant response to bronchodilator is an increase in FEV1 or FVC by 200 mL or
more or greater than or equal to 12%
Methacholine challenge decrease of FEV1 by 20% deemed positive for airway reactivity
Can be helpful in determining asthma as cause of chronic cough
Irritants and Asthma

Occupational asthma
Asthma symptoms after exposure to workplace over 200 agents identified
Type I hypersensitivity = immediate onset of symptoms
Type IV hypersensitivity = delay of 4 to 6 hours after exposure
Treat with inhaled corticosteroids and avoidance of exposure to identified agent
Reactive airways dysfunction syndrome
Also known as irritant-induced asthma
Symptoms after a single exposure to an irritant 24 to 48 hours after exposure
Common irritants: Chlorine gas, ammonia, bleach
Symptoms do not resolve away from causative agent
Asthma and Viral Infections

Unclear association with viral infections in the pathogenesis of asthma
Not likely a causative effect, but viral infection associated with exacerbations of asthma
Onset of exacerbation usually 2 to 4 days after onset of illness
Treat with short acting b2-agonists. Can use systemic corticosteroids in severe cases
Asthma and Gastroesophageal Reflux Disease

GERD can cause bronchoconstriction and chronic cough without underlying asthma
Bronchodilators in asthmatics can cause GERD as a side effect

Bronchopulmonary Aspergillosis
Allergic reaction to Aspergillus fumigatus
Intermittent eosinophilic infiltrates in lungs lead to mucoid plugs, leading to bronchiectasis
Diagnosed with skin test for Aspergillus
Treated with inhaled corticosteroids and oral steroids if needed. Add itraconazole to
prevent exacerbations
Exercise-induced Bronchospasm
Onset typically after exercise with resolution usually by 30 minutes
Treated with short acting b2-agonists prior to exercise
Vocal Cord Dysfunction

Often misdiagnosed as asthma
Inappropriate adduction of vocal cords with inspiration
Commonly in females 20 to 40
Inspiratory curve flattening on flow-volume loop
Treated with speech therapy
PULMONARY DISEASE63
Management
Table 15.1: Assessment of Asthma Control
Classification of Asthma Severity
>12 Years of Age
Components of Severity
Persistent
Intermittent Mild Moderate Severe
Symptoms 2 days/week >2 days/ Daily Throughout
week but not the day
daily
Nighttime 2x/month 3-4x/month 1x/week but Often 7x/
awakenings not nightly week
Short-acting 2 days/week >2 days/ Daily Several times
b2-agonist use week but not per day
Impairment daily, and not
for symptom
control (not more than 1x
Normal on any day
FEV1/FVC: prevention of
8-19 yr 85% EIB)
20-39 yr 80% Interference None Minor Some Extremely
40-59 yr 75% with normal limitation limitation limited
60-8 yr 70% activity
Lung function Normal FEV1 FEV1 >80% FEV1 >60% FEV1 <60%
between exac- predicted but <80% predicted
erbations FEV1/FVC predicted FEV1/FVC
FEV1 >80% normal FEV1/FVC reduced
predicted reduced 5% >5%
FEV1/FVC
normal
Risk Exacerbations 0-1/year 2/year
requiring oral
systemic Consider severity and interval since last exacerbation.
corticosteroids Frequency and severity may fluctuate over time for patients in any
severity category.
Relative annual risk of exacerbations may be related to FEV1

Recommended Step for Initiation Step 1 Step 2 Step 3 Step 4 or 5
Treatment and consider short course of
oral systemic corticosteroids
(See figure 4-5 for treatment
steps.) In 2-6 weeks, evaluate level of asthma control that is achieved and
adjust therapy accordingly.
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program: Expert panel report III:
Guidelines for the diagnosis and management of asthma. Published Bethesda, MD;2007. Accessed June 17. 2012.
Pharmacotherapy
Bronchodilators
b2-agonists relaxes airway smooth muscle, inhibits mast cell mediator release, and
airway edema. Improves mucociliary clearance. Decreases cough. Does not decrease
chronic inflammation
Short acting b2-agonists: Albuterol, levalbuterol, terbutaline
Long acting b2-agonists: Salmeterol, formoterol

Should not be used without inhaled corticosteroids as LABAs do not address
underlying airway inflammation
Anticholinergics
Ipratropium bromide
Prevent nerve induced bronchospasm and mucus secretion
Used in conjunction with b2-agonists when symptoms are not controlled
Theophylline
Inhibits phosphodiesterase in smooth muscle cells
Some evidence of anti-inflammatory effects
Oral medication given 1 to 2 times daily
Used in conjunction with short acting b2-agonists or inhaled corticosteroids in severe
asthma
Toxicity: Palpitations, diuresis, arrhythmias, seizures, and death
Avoid using with drugs that inhibit CYP450
Controller Therapy
Inhaled corticosteroids
Most effective anti-inflammatory agent in asthma
Side effects: Hoarseness and oral candidiasis
Systemic corticosteroids
Used for acute severe asthma
Oral is as effective as intravenous
Antileukotrienes
Montelukast and zafirlukast
Less effective than ICS
Useful as add-on therapy
Cromones
Cromolyn sodium and nedocromil sodium
Inhibit mast cell and sensory nerve action
Short duration, needs multiple daily dosing
Allergen Immunotherapy
May be helpful in patients with an identified allergen causing worsening of asthma
Attempts should be made to avoid allergens in the home
Alternative Therapies
Omalizumab, an anti IgE recombinant antibody, is available, but very expensive, reserved
for patients who do not respond to other therapy
Aspirin-sensitive Asthma
Affects 1% of patients with asthma
Aspirin causes worsening in symptoms and all non-selective COX-2 inhibitors should be
avoided
Asthma in Pregnancy
Rule of one-thirds: 1/3 of patients improve, 1/3 worsen, 1/3 remain stable
Short acting b2-agonists, inhaled corticosteroids and theophylline are safe in pregnancy
If systemic steroids needed, use prednisone as it is not activated by fetal liver
PULMONARY DISEASE65
Table 15.2: Stepwise Approach to Asthma Therapy
Persistent Asthma: Daily Medication
Intermittent
Consult with asthma specialist if Step 4 care or higher is required.
Asthma
Consider consultation at Step 3.
Step 6
Step 5 Preferred: Step up if

High-dose ICS needed
Step 4 Preferred: + LABA + oral
High-dose corticosteroid (first, check
Step 3 Preferred: ICS + LABA adherence,
Medium-dose AND environmental
Step 2 Preferred: ICS + LABA AND control, and
Low-dose Consider comorbid
Preferred: ICS + LABA or Alternative: Consider Omalizumab conditions)
Step 1 Low-dose ICS Medium-dose Medium- Omalizumab for patients
ICS dose ICS + for patients who have ASSESS
Alternative: either LTRA, who have allergies CONTROL
Preferred:
SABA PRN Cromolyn, Alternative: Theophylline, allergies
LTRA, Low-dose ICS or Zileuton Step down if
Nedocromil, or + either LTRA, possible
Theophylline Theophylline,
or Zileuton (and asthma
is well
controlled
Each step: Patient education, environmental control, and management of comorbidities. at least 3
Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma months)
(see notes).
Quick-Relief Medication for All Patients

SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3
treatments at 20-minute intervals as needed. Short course of oral systemic corticosteroids may be
needed
Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inad-
equate control and the need to step up treatment
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program: Expert panel report III:
Guidelines for the diagnosis and management of asthma. Published Bethesda, MD;2007. Accessed June 17. 2012.
15.2 CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Epidemiology
4th leading cause of death in the world
Very large economic and social burden
Risk Factors
#1 risk factor = smoking
Dose-response relationship the more you smoke, the higher your risk
Inhaled particles from other sources also increase risk (2nd hand smoke, wood/coal
furnaces, air pollution)
Alpha-1 antitrypsin deficiency
Pre-existing airway responsiveness (e.g., asthma)
Recurrent severe respiratory infections in childhood causing decreased lung function

Pathogenesis
Limitation of airflow from small airway obstruction and destruction of airspaces
(emphysema)
Mucus hypersecretion
Symptoms
Chronic cough
Dyspnea
Sputum production
Physical Findings
Signs of airflow limitation usually in more severe disease
Diagnosis
Spirometry: FEV1/FVC <70% predicted POST bronchodilator is diagnostic
Severity
GOLD 1 MILD: FEV1 greater than or equal to 80% predicted
GOLD 2 MODERATE: FEV1 between 50% and 80% predicted
GOLD 3 SEVERE: FEV1 between 30% and 50% predicted
GOLD 4 VERY SEVERE: FEV1 <30% predicted
Treatment
Smoking cessation
Stable disease
Bronchodilators
b2-agonists: Improves FEV1 and symptoms. Long acting more effective at
preventing symptoms
Anticholinergics improve symptoms, exacerbations, pulmonary rehab
Theophylline improves symptoms and exacerbations
Inhaled corticosteroids
Improves lung function, symptoms, quality of life, and exacerbations
More effective when combined with a bronchodilator
Pulmonary rehabilitation
Improves exercise capacity, perceived breathlessness, quality of life, decreases days
in hospital
Oxygen therapy
Indicated for resting SaO2 <88% at 2 visits over 3 weeks
Improves survival in patients who meet criteria
Lung volume reduction therapy
Improves survival in patients with severe upper lobe emphysema
Lung transplant
Indicated for very severe COPD with FEV1 <20%
Improves quality of life and functional capacity
Exacerbation acute change in dyspnea, cough or sputum production
Indications for hospitalization: Drastic change in symptoms, older age, frequent
exacerbations, serious comorbidities, severe underlying COPD
Oxygen therapy goal SaO2 >90%
PULMONARY DISEASE67
Short acting bronchodilators
Systemic corticosteroids oral prednisone 30-40 mg daily x 14 days
Antibiotics indicated for patients with:
All 3 cardinal symptoms (dyspnea, cough, and increased sputum purulence)
2 cardinal symptoms if 1 is sputum purulence, or
Patient requires mechanical ventilation
Mechanical ventilation
Non-invasive positive pressure ventilation (NIPPV): Reduces mortality, need for
endotracheal intubation and length of hospital stay
Invasive mechanical ventilation: Indicated for failure of NIPPV, respiratory or cardiac
arrest, altered mental status, aspiration, life-threatening hypoxemia, hemodynamic
instability
Discharge and follow-up
Criteria for discharge:
Decreased need for short acting bronchodilators less than every 4 hours
Ability to ambulate, eat, sleep without significant dyspnea
Clinically stable for 12 to 24 hours
Arrangements should be made for home care, oxygen as needed. Follow-up visit
should be scheduled within 4 to 6 weeks
15.3 INTERSTITIAL LUNG DISEASE

Definition and Classification
Group of conditions that affect lung parenchyma (alveoli, epithelium, capillary endothelium,
perivascular, and lymphatic tissues)
Over 200 individual diseases identified
Can classify into those diseases with known cause and those with unknown cause
(idiopathic)
Evaluation
Age/sex of patient important helps narrow differential
Exposure history smoking, drugs, radiation, occupational exposures
Onset usually over months to years, acute presentation uncommon
Radiologic findings
High-resolution CT scan more sensitive than chest radiograph
Reticular pattern most common interlacing linear opacities
Honeycombing series of cysts with shared walls commonly seen in idiopathic
pulmonary fibrosis
Cysts enlarged airspaces surrounded by wall
Nodules round, discrete opacities
Ground-glass opacities hazy increase in attenuation but can still see vasculature
Important to note distribution diseases often involve primarily upper vs. lower lung or
central vs. peripheral lung
Histopathologic diagnosis
Surgical biopsy has 90% diagnostic yield

Open lung biopsy vs. transbronchoscopic
Transbronchoscopic specimens with bronchoalveolar lavage usually sufficient for
carcinoma, sarcoidosis, eosinophilic pneumonia, infection
Important Interstitial Lung Diseases With Known Cause

Drug-induced ILD
Radiography: Reticular pattern with ground glass opacities
Symptoms: Fatigue, low grade fever, cough
Many identified drugs including amiodarone, isoniazid, sulfonamides, trazodone,
amphotericin B, methotrexate, bleomycin
Acute hypersensitivity-type reaction typically resolves with steroids and removal of
offending agent
Chronic drug-induced ILD presents with progressive dyspnea and few systemic
reactions. Treat with corticosteroids and removal of offending agent
Radiation-induced ILD
7 to 20% of patients undergoing radiation therapy
Increased radiation dose, pre-existing lung disease increase risk
Symptoms: Fever, cough, weight loss, dyspnea
Onset typically 1 to 6 months after radiation
Radiographic features: Alveolar opacification of irradiated portion of lung
Treat with long term corticosteroids: 80% response rate
Radiation fibrosis: Later onset (6 to 24) months and irreversible
Connective tissue disease
One of the more common known causes of ILD
Treatment of CTD ILD is disease specific
Up to 75% of systemic sclerosis patients have interstitial lung involvement
Up to 50% of rheumatoid arthritis patients have interstitial involvement
ILD may be the presenting complaint of connective tissue disease and should prompt
serologic evaluation when physical exam gives suspicion
Hypersensitivity pneumonitis
Allergic, inflammatory reaction to airborne allergens
Acute, subacute and chronic forms
Inflammatory cytokines lead to granuloma formation and possibly parenchymal fibrosis
Known antigens include bacterial and fungal elements from decaying organic matter
(e.g., farmers lung), mycobacteria (hot-tub lung), bird feathers, animal droppings,
aerosolized machine lubricants (machine operators lung)
Radiographic findings: Diffuse alveolar infiltrates with reticular pattern, ground-glass
opacification, centrilobular nodules
Histopathology: Acute = poorly formed granulomas, bronchiolitis. Chronic may be
difficult to differentiate from idiopathic pulmonary fibrosis
Treatment: Eliminate exposure, then steroids if no improvement or in patients with
hypoxemia
Lung transplant should be considered in patients with severe fibrotic changes
Smoking-related interstitial lung disease
Pulmonary Langerhans cell histiocytosis
Men ages 20 to 40
Symptoms: Cough, dyspnea, fever, weight loss, chest pain
PULMONARY DISEASE69
Pneumothorax in 25% of patients
Radiographic findings: Stellate nodules, reticular opacities, upper zone cysts,
preserved lung volume, sparing of costophrenic angles
HRCT combination of thin walled cysts and nodules virtually diagnostic in
appropriate patient
Fibrosis develops as disease progresses
Mainstay of treatment = smoking cessation
Improvement in 1/3 of patients, most have persistent or progressive disease
Desquamative interstitial pneumonia
Exclusively in smokers
Histology: Accumulation of macrophages in intraalveolar spaces, minimal fibrosis
Symptoms: Dyspnea and cough
HRCT diffuse hazy opacities
Treatment: Smoking cessation and glucocorticoids
70% 10-year survival
Interstitial Lung Disease With Unknown Cause

Idiopathic pulmonary fibrosis
Most common ILD without known cause
Symptoms: Exertional dyspnea, nonproductive cough
HRCT: Patchy basilar subpleural reticular opacities. Also traction bronchiectasis and
honeycombing
PFTs: Restrictive pattern
Diagnosis: Biopsy showing usual interstitial pneumonia with above radiographic
findings
No known effective therapy. Mortality 50% at 3 years. Consider lung transplant
Sarcoidosis
90% of patients with sarcoidosis have lung involvement
Staging by chest radiography
0 Normal
I Hilar lymphadenopathy
II Hilar lymphadenopathy with abnormal lung parenchyma
III No lymphadenopathy with abnormal lung parenchyma
IV Parenchymal fibrotic changes, alteration of lung architecture
Lofgren syndrome: Sarcoidosis with fever, erythema nodosum, polyarthralgia, hilar
lymphadenopathy
Diagnosis requires biopsy showing noncaseating granulomatous inflammation
Bronchoscopy has yield up to 90% with multiple biopsies
Treatment
Spontaneous resolution up to 2/3 of patients
Corticosteroids improve symptoms, lung function and radiographic findings
Methotrexate, hydroxychloroquine or azathioprine for non-responders
Lymphangioleiomyomatosis
Very rare, almost exclusive to young women
Many present with spontaneous pneumothorax
Chest radiograph reticulonodular infiltrates
HRCT diffuse, thin-walled small cysts throughout lung
Slowly progressive, lung transplantation is only chance for cure

15.4 OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE
15 to 20% of asthma and COPD burden likely due to environments or occupational
exposure
Approach
Requires an index of suspicion
Patient may report concern or coworkers with similar symptoms
Symptoms that improve away from work should raise suspicion
Work environment with known hazardous materials
Lack of improvement despite optimal medical therapy
Taking a detailed exposure history regarding materials contacted, length of exposure,
temporal relationship of symptoms to work exposure is important in diagnosis
Asbestos-associated Lung Disease

Diffuse interstitial fibrosis secondary to inhaled asbestos fibers
Heavily regulated in US, but more widespread use and exposure in developing countries
Cumulative exposure to fibers is main risk factor
Radiographic findings
Pleural plaques seen on chest radiograph
Diffuse pleural thickening and honeycombing seen with more progressive disease
Benign pleural effusion
Irregular and linear opacities
Clinical findings
Dyspnea, bibasilar crackles, digital clubbing
No specific therapy. Supportive care only
Asbestos and malignancy
Lung cancer more common (risk increases with exposure level)
Smoking has additive effect on risk
Mesothelioma
Short term exposure has been linked to development
No relation to smoking
Diagnosis can be made with pleural fluid cytology, but usually requires biopsy
No effective treatment
Silicosis
Seen in miners, stonecutters, sandblasters
Profuse military infiltration on chest radiograph. HRCT shows characteristic crazy paving
pattern diffuse ground-glass opacities with thickened intralobar and interlobular septa
Greater risk of active tuberculosis requires longer treatment of latent TB
Coal Workers Pneumoconiosis

Seen in ~10% of all coal miners with more than 20 years work
Coal dust contributes to development of COPD additive effect with smoking
PULMONARY DISEASE71
15.5 PLEURAL DISEASE
Causes of Pleural Effusion
Transpleural pressure imbalance
Increased capillary permeability
Impaired lymphatic drainage
Movement of peritoneal fluid across the diaphragm
Extravascular effusion
Pleural Fluid Analysis

Transudate vs. exudate
Lights criteria - exudative if:
Pleural fluid total protein/serum total protein ratio >0.5 and/or
Pleural fluid LDH >2/3 upper limit of normal serum LDH and/or
Pleural fluid LDH/serum LDH ratio >0.6
Table 15.3: Differential Diagnosis of Pleural Effusion

Causes of Transudative Effusion Include: Causes of Exudative Effusion Include:
Heart failure Lymphoma
Constrictive pericarditis Sarcoidosis
Hepatic hydrothorax Tuberculosis
Superior vena cava obstruction Chylothorax
Nephrotic syndrome Carcinoma
Hypoalbuminemia Fungal disease
Elevated pleural fluid amylase pancreatic vs. malignant effusion vs. esophageal rupture
Low pleural fluid glucose bacterial infection vs. malignancy vs. rheumatoid pleuritis
Cytology helpful in assessment for malignancy
Management
Parapneumonic effusions
Require thoracentesis for evaluation
Require chest tube placement if:
Loculated
Pleural fluid pH <7.2
Pleural fluid glucose <60 mg/dL
Positive gram stain or culture
Pus in pleural space (empyema)
Malignant pleural effusions
Can usually get diagnosis from cytology, but may require thoracoscopy
Symptomatic treatment with therapeutic thoracentesis
Small indwelling catheter can be inserted for repeated drainage
Consider pleurodesis to prevent re-accumulation

Pneumothorax
Primary spontaneous: Occurs without underlying lung disease or trauma
Treat with simple aspiration if symptomatic
Secondary spontaneous: Occurs without trauma but caused by underlying disease (e.g.,
emphysema)
Traumatic: Secondary to chest injury
Chest tube for any pneumothorax that measures >3 cm from lung to apex of thorax
Tension pneumothorax: Pressure in pleural space is positive thoughout respiratory cycle
Causes decreased venous return and cardiac output
EMERGENCY! Requires needle decompression with large bore needed in second
intercostal space until chest tube can be placed
15.6 ACUTE PULMONARY THROMBOEMBOLISM

Pulmonary embolism (PE) arises from deep venous thrombosis (DVT) which
thromboembolizes to pulmonary vasculature
Most commonly arises from lower extremities
DVT risk factors
Virchows triad: Venous stasis, vascular injury, hypercoagulability
DVT prevention
Low risk patients can use intermittent pneumatic compression (IPC) or compression
stockings. Also encourage ambulation
Moderate to high risk prophylactic heparin (unfractionated or low molecular weight
heparin [LMWH])
Diagnosis and evaluation of PE
Symptoms: Dyspnea, chest pain, hemoptysis
Classic EKG findings: Sinus tachycardia, S1 Q3 T3
S wave in lead I
Q wave in lead III
T wave inversion in lead III
Wells score for probability of PE: High >6 pts, Moderate 2 to 6 pts, low <2 pts
Clinical signs/symptoms of DVT = 3 pts
No alternative diagnosis more likely than PE = 3 pts
Heart rate >100 = 1.5 pts
Immobilization or surgery in past 4 weeks = 1.5 pts
Previous history of DVT or PE = 1.5 pts
Hemoptysis = 1 pt
Cancer treated within 6 months = 1 pt
Imaging
CT angiography requires contrast so contraindicated in renal failure
Ventilation/Perfusion (V/Q) scan normal scan indicates very low risk of PE
D-Dimer poor specificity, only helpful if negative to rule out
Treatment
Hemodynamically stable patient
Unfractionated heparin continuous IV infusion, weight based dosing, or
LMWH subcutaneous administration, cant be used in renal failure
PULMONARY DISEASE73
Warfarin for maintenance therapy
Continue heparin until INR 2-3 (need overlap of therapies for 4 to 5 days)
Duration of therapy:
Provoked DVT/PE (e.g., trauma, surgery) = 3 to 6 months
Initial unprovoked DVT/PE = 6 months
2nd unprovoked/cancer/hypercoagulable state = lifetime
Unstable PE
Consider thrombolytics if signs of shock, hemodynamic, or respiratory compromise
15.7 PULMONARY HYPERTENSION

Definition: Mean pulmonary artery pressure >25 mmHg
Signs and Symptoms

Exertional dyspnea, fatigue, syncope, peripheral edema, palpitations
Right sided gallop, tricuspid regurgitation murmur, increased P2, JVD, hepatomegaly and
ascites, peripheral edema
Right heart strain/failure
WHO Classifications
Group I: Pulmonary arterial hypertension
Idiopathic, familial, HIV associated, drug induced, portal hypertension, congenital shunts
Bone morphogenic protein receptor 2 (BMPR2) gene
Mutations seen in 50% of families with FPAH
Group II: Pulmonary hypertension owing to left heart disease
Group III: Pulmonary hypertension owing to lung diseases and hypoxia
Group IV: Chronic Thromboembolic Pulmonary Hypertension
Diagnose with V/Q scan or CT angiogram
Treatment: Pulmonary thromboendarterectomy significant improvement in survival
and quality of life
Group V: Pulmonary hypertension with unclear or multifactorial etiologies
Treatment of PAH
Anticoagulants - improved survival
Oxygen
Diuretics - symptomatic improvement and treatment of right heart failure associated with
PAH
Calcium channel blockers - benefit seen only in those patients that demonstrate positive
vasoreactivity on right heart catheterization
Prostacyclins - improved clinical measurements and survival
Epoprostenol, iloprost, treprostinil
Endothelin receptor antagonists - improvement in exercise capacity, functional class,
hemodynamics, and time to clinical worsening
Bosentan, ambrisentan
Phosphodiesterase inhibitors - improved 6 minute walk test and pulmonary vascular
resistance
Sildenafil, tadalafil

Prognosis and Follow-up
PAH (Group I) yields poor prognosis (~15% mortality in 1st year, on therapy)
Follow with serial echocardiogram and 6 minute walk test to assess functional capacity
15.8 PULMONARY NEOPLASTIC DISEASE

Evaluation of a Pulmonary Nodule
Solitary lung nodule = single, round, well-circumscribed opacity up to 3 cm in diameter
Nodule <8 to 10 mm much less likely to be malignant
Benign causes: Granuloma (healed vs. active), hamartoma, nonspecific inflammation,
AV malformation
Malignant causes: Adenocarcinoma, squamous cell carcinoma, metastasis, non-small
cell lung cancer, small cell lung cancer, bronchoalveolar cell carcinoma
Opacity >3 cm in diameter = lung mass
For follow-up imaging, determine risk of malignancy:
Nodule 2 to 3 cm more likely malignant, <4 mm virtually always benign
Smooth borders more likely benign, spiculated border more likely malignant
Smoking and history of malignancy higher risk of malignancy
For nodule >1 cm, get PET-CT, biopsy if positive
For nodule that is high risk for malignancy excise, may also require lobectomy
Nodules that are stable in size for 2 years are considered benign
Repeat CT follow-up for nodules <1 cm:
Nodule <4 mm: Low risk: No repeat CT needed; Higher risk: Repeat at 12 months
Nodule 4 to 6 mm: Low risk: Repeat at 12 months; Higher risk: Repeat at 6 to 12 and 18
to 24 months
Nodule >6 to 8 mm: Low risk: Repeat at 6 to 12 and 18 to 24 months; Higher risk:
Repeat at 3, 6, 12 and 24 months
Nodules 2 to 3 cm more likely malignant
Screening for Lung Cancer

Not recommended as it does not reduce mortality
Risk Factors for Lung Cancer

Cigarette smoking responsible for up to 90% of cases
Other known environmental causes:
Radon
Asbestos
Ionizing radiation
Polycyclic aromatic hydrocarbons
5 to 15% diagnosed incidentally with imaging
Most present with symptoms
Local tumor growth can cause:
Cough, hemoptysis, dyspnea
Pleural or chest wall pain
PULMONARY DISEASE75
Spread into thorax can cause:
Tracheal obstruction
Dysphagia due to esophageal compression
Hoarseness due to recurrent laryngeal nerve paralysis
Horners syndrome: Enophthalmos, ptosis, miosis and ipsilateral loss of sweating
Pancoasts syndrome: Tumor growth into apex of lung, affects C8-T2 nerves,
causing radiating pain down ulnar nerve
Superior vena cava syndrome
Extrathoracic metastasis can cause:
Brain metastasis: Headache, nausea, neurologic defects
Bone: Pathologic fracture
Spine: Cord compression syndrome
Liver: Abnormal LFTs, biliary obstruction, abdominal pain
Paraneoplastic syndromes
Syndrome of inappropriate anti-diuretic hormone (SIADH)
Cushing syndrome
Hypercalcemia
Clubbing
Hypertrophic osteoarthropathy
Eaton-Lambert syndrome
Migratory venous thrombophlebitis
Nonbacterial thrombotic endocarditis
Diagnosis and Staging

Diagnosis requires tissue biopsy
Classification important in determining therapy
Small cell lung cancer
2 stage system:
Limited-stage limited to 1 hemithorax and regional lymph nodes
Extensive stage anything beyond above boundaries
Non-small cell lung cancer
Uses tumor, node, metastasis (TNM) staging system
PET- CT should be used to help guide further evaluation of possible metastasis or
mediastinal involvement, which should be followed with biopsy of suspicious lesions

Table 15.4: Non-small Cell Lung Cancer Staging
Stage Tumor Node Metastasis
IA 1a tumor 2 cm 0 no node involvement 0
1b tumor >2 cm, but 3 cm 0 0
IB 2a tumor >3 cm but 5 cm 0 0
IIA 1a, 1b 1 involvement in ipsilat- 0
eral peribronchial, hilar or
intrapulmonary node
2a 1 0
2b tumor >5 cm but 7 cm 0 0
IIB 2b 1 0
3 tumor >7 cm OR invades chest 0 0
wall, diaphragm, phrenic nerve, medi-
astinal pleura, pericardium OR sepa-
rate tumor nodules in same lobe
IIIA 1, 2 2 involvement in ipsilat- 0
eral subcarinal or medi-
astinal node
3 1, 2 0
4 any size with involvement of 0, 1 0
mediastinum, heart, great vessels,
trachea, recurrent laryngeal nerve,
esophagus, vertebrae, separate nod-
ules in ipsilateral lobe
IIIB 4 2 0
Any T 3 0
IV Any T Any N 1a separate nodules
in a contralateral lobe,
pleural nodules or malig-
nant pleural effusion
1b distant metastasis
outside of thorax
Adapted from: Goldstraw, P, Crowley, J, Chansky, K, et al. The IASLC Lung Cancer Staging Project: Proposals for the
revision of the TNM stage groups in the forthcoming (seventh) edition of the TNM classification of malignant tumours.
J Thorac Oncol 2007; 2:706.
Treatment
Non-small cell lung cancer
Stage I-II: Resection if candidate. If not, radiation therapy
Adjuvant chemotherapy for stage II
Stage III: Local resection or radiation with systemic chemotherapy
Stage IV: Chemotherapy for palliative and improved survival
Median survival for untreated is 4 to 6 months, for treated is 8 to 10 months
Bevacizumab improves response rate, survival when added to chemotherapy
Small cell lung cancer
Chemotherapy is mainstay of treatment 60 to 80% response rate with 10 to 30%
complete response
In limited stage disease, addition of radiation therapy improves survival
High relapse rate
PULMONARY DISEASE77
Carcinoid Tumors
Neuroendocrine tumors, often present with cough, hemoptysis or bronchial obstruction
Treatment is surgical with 90% 10-year survival post resection if no nodal involvement
Atypical carcinoid histologic evidence of increased mitosis and dysplasia worse
prognosis with 60 to 70% 5 year survival
Common Metastatic Neoplasms to the Lung

Colon
Head and neck
Breast
Kidney
Thyroid
Melanoma
Mediastinal Masses
Anterior Mediastinal Masses
Thymoma
Lymphoma
Teratoma
Thyroid mass
Middle Mediastinal Masses
Vascular mass
Lymph node enlargement
Pleuropericardial cyst
Bronchogenic cyst
Posterior Mediastinal Masses
Neurogenic tumor
Meningocele
Meningomyelocele
Gastroenteric cyst
Esophageal diverticula
15.9 SLEEP DISORDERS

Obstructive Sleep Apnea
Definition: Excessive daytime sleepiness with at least 5 apneas/hypopneas per hour
Apnea = lack of airflow for at least 10 seconds
Hypopnea = reduction of flow by at least 50% for 10 seconds
Obstruction caused by collapse of upper airway by negative inspiratory pressure
Risk factors
Obesity
Shortening of mandible/maxilla
Male gender
Middle age
Myotonic dystrophy

Ehlers Danlos syndrome
Alcohol use
Complications
Elevated blood pressure
Increased risk of myocardial infarction and stroke
Insulin resistance and worsening of diabetes
Increased risk of motor vehicle and work accidents
Diagnosis
Signs/symptoms: Excessive daytime sleepiness, observed apneas/hypopneas by
partner, snoring, morning headaches, cognitive impairment, mood disorder
Polysomnography required to diagnose
Treatment
Behavioral measures: Limit alcohol intake, weight loss, avoid sleep positions that
worsen apnea (i.e., supine)
Positive airway pressure: Acts as a splint to keep airway open *MOST EFFECTIVE
Continuous positive airway pressure (CPAP) constant fixed pressure
Bi-level positive airway pressure (BiPAP) basal fixed pressure with increased
pressure (fixed) upon inspiration
Adaptive servo ventilation (ASV) like BiPAP, but inspiratory pressure is variable
Oral appliance
Pulls mandible forward to keep airway open
Must be fit by dental specialist
30 to 80% effective
Surgical options
Uvulopalatopharyngoplasty increases upper airway space
Not as effective as CPAP
Tracheostomy may be indicated for life threatening OSA, as it bypasses upper
airway completely
Central Sleep Apnea

Lack of airflow with lack of respiratory effort for at least 10 seconds
Hypercapnic
Hypoventilation with decreased response to hypercapnia
Non-hypercapnic
Normal or low waking PCO2 and increased response to hypercapnia
Often seen in heart failure or stroke
Treatment
Treat underlying conditions (i.e., heart failure)
Oxygen for non-hypercapnic CSA
CPAP
BiPAP with caution may cause hypocapnia
Acetazolamide carbonic anhydrase inhibitor causes metabolic acidosis shifts
hypercapnic ventilatory response
PULMONARY DISEASE79
15.10 HIGH-ALTITUDE PULMONARY DISEASE
Acute Mountain Sickness
Onset within 6 to 10 hours of ascent to high altitude
Symptoms: Lightheadedness, nausea, headache, tingling
Treatment: Descend to lower altitude (usually enough to relieve symptoms),
dexamethasone, acetazolamide
High-altitude Cerebral Edema

Ataxia, altered consciousness or both in person with acute mountain sickness or high-
altitude pulmonary edema
Treatment: Descent to lower altitude, dexamethasone
Can result in progression and brain herniation, death if untreated
High-altitude Pulmonary Edema

Most common cause of high-altitude death
Onset typically 24 to 48 hours after ascent to new altitude
50% of patients also have acute mountain illness, 14% have high-altitude cerebral edema
Symptoms
Early decreased performance, dry cough
Late resting tachycardia, tachypnea, frothy, blood tinged sputum, cyanosis
Treatment: Supplemental oxygen, descent to lower altitude
Hyperbaric chambers can be beneficial
Nifedipine if supplemental oxygen or descent not available
15.11 CRITICAL CARE

Respiratory Failure
Hypoxemic respiratory failure
Pulmonary shunt alveoli filled with blood, pus, or water, or collapsed
Treat with increased end expiratory pressure (PEEP) to recruit airspace
Ventilatory (hypercarbic) respiratory failure
Alveolar hypoventilation leads to increased systemic carbon dioxide
Caused by loss of respiratory drive, impaired respiratory muscle strength, increased
load on respiratory system
Noninvasive Positive Pressure Ventilation (NPPV)

Indications
Acute respiratory failure - first-line for acute respiratory failure in COPD
Weaning from invasive mechanical ventilation
Cardiogenic pulmonary edema
Respiratory failure in immunocompromised patient
This is due to complications associated with intubation (infection)
Postoperative respiratory failure
Consider trial in asthmatics with respiratory failure
Patient selection

Must be alert and cooperative, able to protect own airway
Contraindications
Respiratory or cardiac arrest
Excessive airway secretions
Shock
Upper GI bleed
Inability to cooperate/agitation
Poor mask fit/excessive air leak
Facial trauma/surgery
Invasive Mechanical Ventilation

Indications
Lack of improvement on NPPV (2 hours)
Compromised airway
Altered level of consciousness
Excessive secretions
Impaired cough (inability to clear secretions)
Shock/hemodynamic instability
Accessory respiratory muscle use (impending respiratory failure)
Severe respiratory acidosis
Severe hypoxemia
Respiratory rate >35/min
Management
Tidal volume goal 5-10 mL/kg ideal body weight
Respiratory rate 8 to 14/min
Be aware of auto-PEEP
Caused by incomplete exhalation, causes hyperinflation
Airflow vs. time waveform on ventilator will show inhalation before end of
expiratory phase
Commonly seen in COPD, asthma, ARDS, high minute ventilation or small ET tube
Ventilation problem solving
Respiratory acidosis
Increase respiratory rate or tidal volume
Respiratory alkalosis
Decrease respiratory rate or tidal volume
Poor oxygenation
Increase FiO2 or PEEP
Auto-PEEP
Decrease respiratory rate or tidal volume
Increase peak inspiratory flow rate this allows more time for exhalation by
adjusting the inspiration:respiratory ratio
Paralyze patient
Prophylaxis in mechanical ventilation
Stress ulcer prophylaxis H2-receptor antagonist or PPI
Semirecumbant positioning to reduce ventilator associated pneumonia
PULMONARY DISEASE81
Weaning
Patients should undergo daily awakening and spontaneous breathing trials to facilitate
extubation
Reduces time on ventilator, ICU time, hospital length of stay and 1-year mortality
Ventilator-associated Pneumonia
Definition: Onset of pneumonia at least 48 hours after initiation of invasive ventilation
Significant mortality 25 to 50%
Important to reduce risk: Elevate head of bed, consider limiting enteral feeding early in
disease, consider selective decontamination of GI tract and subglottic suction catheter
Acute Respiratory Distress Syndrome (ARDS)

Diagnostic criteria
PaO2/FIO2 200 mmHg
Acute onset
Bilateral infiltrates
Pulmonary capillary wedge pressure 18 mmHg
Causes
Pneumonia, sepsis, trauma, inhalation injury, near-drowning, transfusion, pancreatitis,
drug overdose
Treatment
Low tidal volume strategy: 6 mL/kg predicted body weight
End inspiratory plateau pressure <30 cm H20
PEEP important to keep alveoli from collapsing, but no proven benefit to high PEEP
Use PEEP to try to limit FiO2 to <60% to minimize lung toxicity
Use fluid restriction and diuretics to lower left atrial filling pressures while maintaining
adequate systemic perfusion
Sepsis
Diagnosis known infection plus at least 2 systemic inflammatory response syndrome
(SIRS) criteria:
Temperature >38 C (100.4 F) or less than 36 C (96.8 F)
Leukocyte count >12,000/L or less than 4,000/L
Respiratory rate >20/min
Heart rate >90/min
Severe sepsis = sepsis + evidence of 1 sepsis-induced organ dysfunction
Septic shock = sepsis-induced hypotension, persistent despite fluid resuscitation
Early goal directed therapy within 1st 6 hours
Early antibiotic initiation
Fluid resuscitation to goal central venous pressure of 8-12 mmHg
Initiation of vasopressors as needed for goal mean arterial pressure >65 mmHg
Urine output >0.5 mL/kg/hr
Central venous oxygen concentration >70%
Achieved by transfusion if hematocrit <30% or inotropic agents (dobutamine) if
>30%

Activated Protein C no longer recommended/removed from market due to increased
bleeding
Corticosteroids use in shock refractory to fluid resuscitation and vasopressors
Shock = Inadequate Tissue Perfusion
Table 15.5: Shock = Inadequate Tissue Perfusion

Form of Shock Cardiac Output Pulmonary Capillary Systemic Vascular Venous O2
Wedge Pressure Resistance Saturation
Hypovolemic Decreased Decreased Increased Decreased
Cardiogenic Decreased Increased Increased Decreased
Septic Increased Increased or Decreased Increased
decreased
Neurogenic Decreased Decreased Decreased Decreased
Hypoadrenal Decreased Increased or Normal to decreased Decreased
decreased
Acute Inhalational Injuries

Thermal injury causes airway edema, can be treated with inhaled racemic epinephrine
Important to note arterial blood gas as pulse oximetry may be misleading due to elevated
carboxyhemoglobin
Secondary pneumonia commonly caused by Staphylococcus aureus and Pseudomonas
aeruginosa
Combustion of plastics and acrylics think cyanide poisoning
Treat with sodium thiosulfate
Anaphylaxis
Symptoms: Urticaria, angioedema, hoarseness, stridor, tachycardia, bradycardia (severe
reaction), hypotension, cardiovascular collapse, respiratory arrest
Treatment: Intramuscular or subcutaneous epinephrine (0.3-0.5 mg of 1:1,000)
Use IV epinephrine (1:10,000) in anaphylactic shock
Important to monitor for recurrence
Common causes: Peanut, insect stings, medications, latex exposure
Hypertensive Emergencies
Elevated blood pressure with evidence of end organ dysfunction
Dont correct blood pressure too quickly no more than 25% in 1st hour
Dropping too low can cause hypoperfusion stroke due to cerebral autoregulation
IV medications include: Hydralazine, nitroprusside, nitroglycerin, labetalol, metoprolol,
esmolol, nicardipine
Hyperthermic Emergencies
Heat stroke
Signs/symptoms: Absence of sweat, altered consciousness, muscle rigidity, seizure
PULMONARY DISEASE83
Severe cases can cause rhabdomyolysis, disseminated intravascular coagulation, ARDS
Treat with cooling blankets, ice packs, cooled IV fluids, cold gastric lavage
Malignant hyperthermia
Caused by exposure to certain anesthetics and depolarizing muscle relaxants
Halothane, isoflurane, enflurane, desflurane, sevoflurane, succinylcholine,
decamethonium
Signs/symptoms: Increased muscle rigidity, tachycardia, hypercarbia, hypertension,
tachypnea, hyperthermia, arrhythmias
Inherited disorder important to note family history
Treatment: Removal of offending agent, supportive care, dantrolene every 5 to 10
minutes until resolution of symptoms
Neuroleptic malignant syndrome
Caused by exposure to certain antipsychotics and tranquilizers
Includes: Haloperidol, chlorpromazine, fluphenazine, clozapine, risperidone,
metoclopramide
Signs/symptoms: Muscle rigidity, hyperthermia, altered mental status, seizure,
arrhythmia, sialorrhea, diaphoresis
Onset typically within 2 weeks of drug initiation
Treatment: Removal of offending drug. Dantrolene for serious reactions
Hypothermia
Associated with tachycardia followed by worsening bradycardia, conduction abnormalities,
respiratory depression, altered mental status
EKG: Osborne waves
Treatment
Active external rewarming
Active core rewarming
Passive external rewarming
Poisonings and Overdoses

Alcohols
Methanol ingestion can cause ocular toxicity due to formic acid production
Ethylene glycol causes oxalic acid production, causes renal failure: Calcium oxalate
crystals in urine
Isopropyl alcohol no toxic metabolites
Laboratory values: Metabolic acidosis with osmolar gap
Treatment
Supportive care
Methanol or ethylene glycol ingestion - fomepizole IV, or ethanol IV or PO
Organophosphate
Pesticide exposure
Signs/symptoms: Increased salivation, tear production, urination, diarrhea, emesis,
miosis, bronchospasm
Testing: Elevated serum acetylcholinesterase levels
Treatment: Atropine
Acetaminophen
Hepatotoxicity occurs almost exclusively in the setting of massive overdose

May occur following ingestion of more than 7.5-10 grams in 8 hours or less
Antidote: N-acetylcysteine
Cyanide
Seen in excessive use of nitroprusside
Antidote: Sodium thiosulfate
Tricyclic antidepressants
Can cause cardiotoxicity with prolonged QRS interval and arrhythmia
Treatment: Sodium bicarbonate
Salicylates
Cause metabolic acidosis with respiratory alkalosis
Treatment: Alkalinization of urine or hemodialysis
Rhabdomyolysis
Breakdown of myocytes causes myoglobinuria and renal failure
Elevated CK, positive urine dipstick for blood suggests myoglobinuria
Treatment: Aggressive IV hydration, goal urine output 300 mL/hr. May require dialysis
Blood Sugar Control in the ICU

Intensive glucose control in medical ICU increases mortality
Goal blood sugar in medical ICU <180
Supportive Care in Critical Illness

Delirium
Associated with increased mortality, longer hospital stay
Should be addressed and monitored routinely in ICU
Limiting pharmacologic intervention (ex. sedation holidays) help improve ICU delirium
Prevention
Stress ulcer (gastric) prophylaxis
Risk factors: Mechanical ventilation >48 hours, coagulopathy, shock, sepsis, trauma,
burns, extended ICU stay
DVT prophylaxis with LMWH or UFH in appropriate patients
Pressure ulcer prophylaxis
Scheduled repositioning
Pressure relief devices
Barrier agents in moist areas
Early mobilization and physical therapy
Nutrition
Critically ill patients need 25 to 30 nonprotein kcal/kg/d and 1-1.5 kcal/kg/d
Malnutrition inhibits wound healing and immune function
Enteral feeding preferred over parenteral
End-of-life care
Important to involve family members early in structured family conference
Consensus among providers on diagnosis and prognosis important
Palliative care specialists can be very helpful in dealing with anxiety, bereavement
support
When patient is undergoing terminal ventilator weaning, provide close monitoring for
distress
Can treat respiratory distress with morphine IV or inhaled
PULMONARY DISEASE85
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NOTES
PULMONARY DISEASE87
NOTES

16 Gastroenterology
Elie Chahla, MD
Chukwuemeka Charles Ezeoke MD, LT (USN)
C o n t e n t s
16.1 DISORDERS OF THE ESOPHAGUS . . . . . . . . . . . . . . 90
16.2 DISORDERS OF THE STOMACH AND DUODENUM. .93
16.3 DISORDERS OF THE INTESTINES . . . . . . . . . . . . . . . 96
16.4 DISORDERS OF THE PANCREAS . . . . . . . . . . . . . . . 101
16.5 COLORECTAL NEOPLASIA . . . . . . . . . . . . . . . . . . . . .103
16.6 DISORDERS OF THE LIVER, GALLBLADDER, AND

BILE DUCTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .105
16.7 GASTROINTESTINAL BLEEDING . . . . . . . . . . . . . . . . . 111
GASTROENTEROLOGY89
16.1 DISORDERS OF THE ESOPHAGUS
Symptoms of Esophageal Disorders
Dysphagia
Definition of Dysphagia obstruction of passage of liquid or food through the esophagus
Classified as either oropharyngeal or esophageal
Oropharyngeal dysphagia arises from disorders that affect the function of the
oropharynx, larynx, and upper esophageal sphincter
Zenkers diverticulum typically is encountered in elderly patientsthey typically present
with regurgitation, dysphagia, and halitosis; They present with a triad of dysphagia,
regurgitation, and halitosis
Esophageal dysphagia arises within the body of the esophagus, the lower esophageal
sphincter, or cardia, and is most commonly due to mechanical causes or a motility
disturbance
The most common structural causes of dysphagia are Schatzkis rings, eosinophilic
esophagitis, and peptic strictures. Dysphagia also occurs in the setting of
gastroesophageal reflux disease without a stricture
Dysphagia for solids is usually caused by a structural lesion such as strictures, lower
esophageal ring, cancer and Plummer Vinson Syndrome: Include Plummer-Vinson
Syndrome: triad of esophageal web, iron deficiency anemia and cancer;; dysphagia for
both solids and liquids is usually caused by a motility disorder
For suspected esophageal dysphagia, endoscopy is the single most useful test.
Endoscopy allows better visualization than does barium radiography along with mucosal
biopsies, and therapeutic intervention
Videofluoroscopyis the most effective study for suspected oropharyngeal dysphagia
Noncardiac Chest Pain/Esophageal Origin
1. Pain persisting for more than 1 hour
2. Pain that typically occurs postprandially and reclining and wearing tight clothes
3. Lack of radiation of the pain
4. Associated esophageal symptoms (heartburn, regurgitation, dysphagia)
5. Pain relieved by antacid
Odynophagia and Globus Sensation
Definition: odynophagia as pain that occurs with swallowing
Odynophagia is the most common presenting symptom in infectious esophagitis, which
is most frequently caused by Candida Albicans, especially in the immunocompromised,
patients on chronic prednison
Globus sensation (also known as globus hystericus) is a feeling of a lump or tightness in
the throat; psychological factors account for most cases, GERD can be detected in many
affected patients
Gastroesophageal Reflux Disease

Pathogenesis
Gastroesophageal reflux disease (GERD) is caused by an insufficiency of physiologic
antireflux barriers at the gastroesophageal junction
The most common symptoms of GERD are heartburn (pyrosis), regurgitation, and
dysphagia

Diagnosis
Usually based upon clinical symptoms alone. The gold standard is exclusion of cardiac
chest pain first before diagnostic steps to rule in GERD)
Ambulatory pH monitoring (pH < 4 for > 4.5% of a 24-hour period)
EGD is warranted in patients with weight loss, dysphagia, odynophagia, and bleeding/
anemia (alarming features), and those refractory to acid-suppression therapy
Treatment
Lifestyle modifications: Elevation of the head of the bed, smoking cessation, weight loss,
and avoiding lying down after meals (reduce or stop soda, chocolate, coffee, spicy foods)
Medical treatment: The standard of care for GERD is proton pump inhibitor (PPI) therapy
(Given 30-60 minutes before meals for a duration for 8 weeks)
PPIs are safe in pregnancy-related GERD
UPDATED GUIDELINE [1]: Surgery is a long term treatment option in patients with GERD.
Consider bariatric surgery in obese women who are considered for surgery for GERD
Extraesophageal Manifestations of Gastroesophageal Reflux Disease
30% of patients evaluated for heartburn have evidence of extraesophageal reflux disease,
mainly asthma, cough, and laryngitis
Empiric PPI therapy usually helps in the diagnosis
Sources: 1.
1. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of
gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28. [184
references]
Barrett Esophagus
A complication of GERD in which normal squamous epithelium of the distal esophagus is
replaced by specialized columnar epithelium
It is a premalignant condition, affected patients have a 30-fold increased risk of
esophageal adenocarcinoma. Risk factors : age > 50 years, white, male, obesity, chronic
GERD.
Endoscopic surveillance is suggested for patients with Barretts esophagus as follows:
No dysplasia: 3 to 5 years
Low-grade dysplasia: 6 to 12 months
High-grade dysplasia in the absence of eradication therapy: 3 months
Treatment
Therapy with PPIs alone has not been shown to slow progression of Barrett
For low-grade dysplasia, radiofrequency ablation may be an appropriate therapeutic
alternative
UPDATED GUIDELINE: Endoscopic therapy with RFA, endoscopic mucosal resection
(EMR) and photodynamic therapy (PDT) should be attempted in high-grade Barretts
before surgery [1]
Esophagectomy is the only therapy for high-grade dysplasia
Source: 1. American Gastroenterological Association, Spechler SJ, Sharma P, Souza

RF, Inadomi JM, Shaheen NJ. American Gastroenterological Association medical
GASTROENTEROLOGY91
position statement on the management of Barrett's esophagus. Gastroenterology. 2011
Mar;140(3):1084-91
Esophageal Carcinoma
Two main types : are squamous cell carcinoma, and adenocarcinoma. Both types are becom-
ing equally prevalent in the United States. Major Risk factors: age, sex, smoking, alcohol, chronic
GERD, Barretts, diet, Plummer Vinson Syndrome. Signs and Symptoms: dysphagia, odynophagia,
dysphonia, cough as a result of laryngeal nerve injury.
Diagnosis and Staging
The diagnosis is usually established by endoscopic biopsy
Staging with a CT scan of the chest, abdomen and pelvis with contrast to evaluate for the
presence of metastatic disease
Patients without evidence of metastatic disease should undergo endoscopic
ultrasonography (EUS)
Treatment
Depending on staging, treatment modalities differ
Stage 0-1 (localized disease : endoscopic theray with RFA, EMR, PDT)
Stages I-IV: chemotherapy as adjuvant therapy
Esophagectomy and esophageal stenting is used as a palliative care measure in late stage
Prognosis
Because cancer is caught late, there is a low 15% 5 year survival rate with most patients
dying in the first year
Esophageal Motility Disorders

The upper 1/3 esophagus is composed of striated muscle whereas the lower 2/3 is
composed of smooth muscle
The upper esophageal sphincter and the lower esophageal sphincter are contracted at rest
Hypertonic (Spastic) Motility Disorders
Achalasia
Definition: Loss of peristalsis in the distal esophagus and a failure of lower esophageal
sphincter (LES) to relax with swallowing
Symptoms: Dysphagia for solids and liquids is the primary clinical feature
A barium swallow is the primary screening test
A manometric examination is the confirmatory test with 3 characteristic features:
1. Elevated resting LES pressure
2. Incomplete LES relaxation
3. Absence of peristalsis
Treatment: By disruption of the malfunctioning lower esophageal sphincter tone. Options
include: Medical therapy, botulinum toxin injection,dilation of LES, surgical myotomy

Figure 16.1: Achalasia Figure 16.2: Classic "Bird's Beak" of Achalasia
Pseudoachalasia mimics the manometric findings of achalasia but is caused by

obstruction by an underlying malignancy
Diffuse Esophageal Spasm and Nutcracker Esophagus
Signs and Symptoms: Chest pain, dysphagia, globus sensation, regurgitation
Diagnosis is made by clinical presentation and manometry
Barium swallow shows cock-screw esophagus
Characterized by intermittent nonperistaltic contractions in response to swallowing
Therapy with nitrates, calcium channel blockers, proton pump inhibitors, botulinum toxins,
and antidepressants
Hypotonic Motility Disorders
Scleroderma esophagus is a combination of aperistalsis of the esophageal body and a
hypotensive LES
Treatment is largely aimed at controlling acid reflux
Infectious, Pill-induced, and Eosinophilic Esophagitis

Infectious Esophagitis
The most common cause of esophagitis in immunocompetent patients is GERD, about
20-30% of cases.
Fungal (Candida albicians) and Viral (HSV and CMV) esophagitis are seen in immune-
compromised patients
Empiric antifungal therapy is indicated in patients with suspected esophagitis in the
presence of oral thrush
GASTROENTEROLOGY93
Figure 16.3: Upper endoscopy showing Candida
esophagitis
Pill-induced Esophagitis
Most common medications are tetracycline, iron sulfate, bisphosphonates, potassium,
NSAIDs, and quinidine
Taking a large fluid bolus prior to swallowing pills or remaining upright for 30 minutes
after taking medication might help
Eosinophilic Esophagitis
Emerged as an important cause of dysphagia that is amenable to treatment by
elimination of dietary allergens or topical glucocorticoids
16.2 DISORDERS OF THE STOMACH AND DUODENUM

CLASSIFICATION
Gastric ulcer (worsens with eating, in the upper Epigastric region)
Duodenal ulcer (improves with eating, but worsens 3 hours after eating)
Peptic Ulcer Disease (PUD)

The most common causes of peptic ulcer disease are Helicobacter pylori infection and
NSAIDs (accounting for >90% of ulcers)
Clinical Features, Diagnosis, and Complications
Symptoms include epigastric pain or indigestion (commonly asymptomatic)
Upper endoscopy with biopsy is the best way to diagnose malignant gastric ulcers
In young patients without alarm symptoms, recommendation for test and treat for
H. pylori first without endoscopy
The most common complication of PUD is gastrointestinal bleeding
Pneumonic POB for PUD complications: Perforation, Outlet obstruction, Bleeding
Management of PUD
PPI therapy is essential to heal ulcers
Long-term therapy for patients requiring chronic NSAID therapy
Duodenal PUD without complications does not require follow-up upper endoscopy
H. pylori antibody titers remain elevated and should not be ordered for follow-up

Dyspepsia
Dyspepsia is chronic recurrent discomfort in the upper mid-abdomen
Alarm features with dyspepsia:
1. Age >55 years with new-onset symptoms
2. Family history of gastrointestinal cancer
3. Unintentional weight loss
4. Gastrointestinal bleeding
5. Progressive dysphagia
6. Odynophagia
7. Iron-deficiency anemia
8. Persistent vomiting
9. Palpable mass or lymphadenopathy
10. Jaundice
Clinical Features
It is difficult to clinically distinguish organic from functional dyspepsia
The presence of alarm features should prompt further evaluation
Management
For patients younger than 55 years a test and treat approach for H. pylori infection is
recommended
Upper endoscopy is recommended for patients with alarm features
Helicobacter Pylori Infection

The prevalence may be as high as 80% in developing countries. The infection is most
commonly acquired through oral ingestion
Clinical Features
The clinical features of H. pylori infection range from asymptomatic gastritis to
gastrointestinal malignancy
Diagnostic Tests
The diagnosis of H. pylori can usually be established during endoscopy by 1 of 3 methods:
1. Biopsy urease test 2. Histology 3. Bacterial culture
Endoscopy is notindicated solely for the purpose diagnosis
Non invasive testing
Urea breath testing (Diagnosed by the Urea breath test: patient drinks C-13 0r C-14
labelled urea which the bacterium metabolizes, producing labelled carbon dioxide
that can be detected in the breath.)
Serology
Stool antigen assay
IgG serology is recommended as an initial approach to testing for H. pylori in
symptomatic patients. The stool antigen assay may be an alternative in patients not on
PPIs or bismuth
Treatment
Initial H. pylori therapy includes a PPI and 2 antibiotics (typically, clarithromycin and either
amoxicillin or metronidazole) for 2 weeks
Then PPI for 4 to 8 more weeks
GASTROENTEROLOGY95
Complications of Nonsteroidal Anti-inflammatory Drugs
Include dyspepsia, peptic ulcer disease, and strictures
Prevention and Treatment of NSAID-induced Injury
The risk of GI injury with COX-2 inhibitors is significantly lower than that of traditional
NSAIDs
Gastric Polyps, Subepithelial Lesions, and Adenocarcinoma

Gastric Polyps
Most patients with gastric polyps are asymptomatic, some patients may present with
obstruction or bleeding
There are no guidelines for endoscopic surveillance for patients with gastric adenomas;
follow-up endoscopy is strongly recommended
Gastric Adenocarcinoma
The incidence is decreasing, due to early recognition and modification of risk factors,
including treatment of H. pylori
Weight loss, bleeding, dysphagia, and upper abdominal pain are the most common
clinical manifestations
Most symptomatic patients have advanced disease at presentation
Diagnosis: gastroscopic exam using a fiberoptic camera to visualize the gastric tissue is
standard diagnostic method; followed by biopsy
Prognosis : less than 10% 5-year survival rate
Gastric Motility Disorders

Delayed gastric emptying (gastroparesis) should be considered in patients with recurrent
nausea, early satiety, bloating, and weight loss
Diagnosis
An upper endoscopy or barium radiograph should be performed to rule out mechanical
obstruction
Indications
Patients with chronic symptoms or negative findings on upper endoscopy should have a
gastric emptying study
Diabetic gastroparesis should be suspected in patients with diabetes for >10 years
Management
1. Smaller and more frequent meals are recommended
2. Electrolyte abnormalities should be corrected
3. Glycemic control tightened in diabetic patients
4. Exacerbating medications should be discontinued
16.3 DISORDERS OF THE INTESTINES

Diarrhea
Defined as a stool weight greater than 200 g/d
4 types of diarrhea: 1. Osmotic 2. Secretory 3. Inflammatory 4. Motility-related

Duration, Severity, and Characteristics
Acute diarrhea should last no more than 2 weeks
Chronic Diarrhea lasts >4 weeks
Small-bowel diarrhea is usually associated with less frequent large-volume stool
Large-bowel diarrhea is usually small-volume but more frequent bowel movements
Management
Persistent diarrhea despite no oral intake may imply a secretory cause
Supportive care with oral hydration and antidiarrheal medications is the standard for
most patients with acute diarrhea
Antibiotic is reserved for patients with diarrhea lasting >7 days or with symptoms of
fever, abdominal pain, or hematochezia
Travelers Diarrhea
The most common illness to affect visitors to developing countries and is most often due
to enterotoxigenic E. coli
Also manifests as cholera: diarrhea with flecks of mucus called rice water stools; also,
cause severe dehydration, death within 24 hours of onset
Shipboard epidemics of viral gastroenteritis are caused by Norwalk virus
Fat Malabsorption (Steatorrhea)

The gold standard for diagnosis of steatorrhea is quantitative measurement of stool fat.
Some of the most common diseases that cause fat malabsorption are:
Celiac Disease
Definition: An autoimmune disease of the small intestine
Patients may present with classic symptoms related to malabsorption, including diarrhea,
steatorrhea, weight loss, and vitamin deficiencies
They may also exhibit only minor GI complaints
Numerous extraintestinal conditions associated with celiac disease include dermatitis
herpetiformis, diabetes mellitus, and selective IgA deficiency
First line is anti-tissue transglutaminase (anti-tTG) has sensitivity (99%) and specificity
(>90%) FIRST; then, if EQUIVOCAL, be followed by an anti-endomysial antibodies
sensitivity: 90% and specificity: 99%.
Diagnosis: Definitive diagnosis requires small bowel biopsy beyond the duodenum bulb
or the jejunum (Blunting of Villi); gluten-free diet prior to diagnosis may result in false-
negative serologic test
Figure 16.4: Dermatitis herpetiformis rash
GASTROENTEROLOGY97
Therapy: Gluten-free diet for treatment of celiac disease or dermatitis herpetiformis (even
with the absence of GI manifestation)
Supplement deficient vitamins and nutrients
Noncompliance is the most common reason for failure and relapse
Small-intestine Bacterial Overgrowth
A condition in which colonic bacteria are present in increased numbers resulting in
excessive fermentation, inflammation, or malabsorption
Symptoms include flatulence, bloating, and constipation
May occur in association with anatomical abnormalities (surgical blind loop) or motility
disorders (scleroderma, diabetes mellitus)
The gold standard for diagnosis is an excessive bacterial growth in a jejunal aspirate; gold
standard: > 10^5 bacterial count ; normal -10^4)
D-xylose test :patient drinks D-xylose, and because it does not require enzyme for
digestion; presence in the urine and blood is a positive test for colonization of the bowel,
impairing absorption
Treatment includes antibiotics for 10 to 14 days
Short-bowel Syndrome
Malabsorptive state secondary to small bowel resection
Early management mostly involves replacement of fluid and electrolytes
Enteral feeding may be gradually introduced
Pancreatic Insufficiency
Patients with impaired pancreatic function present with symptoms of fat malabsorption;
symptoms include: steatorrhea, weight loss, anemia, hypoalbuminemia
Co-morbidities: Cystic fibrosis, inflammatory bowel disease, celiac disease.
Resolution of symptoms after an empiric trial of enzyme is often a confirmatory test
Inflammatory Bowel Disease

Idiopathic chronic inflammatory disease consisting of Ulcerative colitis (UC) and Crohns
disease (CD)
Risk Factors for Inflammatory Bowel Disease
IBD can present at any age, although the peak incidence occurs between the ages of 15
and 30 years. A second peak in the incidence of Crohns disease occurs between the ages
of 50 to 80. There is no gender specificity
Involves a genetic predisposition and a dysregulation of immunologic response
Clinical Manifestations of Inflammatory Bowel Disease
CD
Transmural inflammation
May involve the entire gastrointestinal tract with sparing of the rectum
Skip lesions with areas of normal mucosa juxtaposed with severe inflammation
Symptoms related to the transmural involvement include fistulas, phlegmon, abscess,
perianal disease, and/or malabsorption
Focal lesions with evidence of granulomas on pathology
UC
Bloody diarrhea with rectal urgency, discomfort, tenesmus, and cramps
Extends proximally from the anal verge and can progress to pancolitis involving the
cecum
The severity of the symptomatology often correlates with the anatomic extent of disease

Table 16.1: Differentiating Crohn's Disease from Ulcerative Colitis
Crohns Disease Ulcerative Colitis
Transmural inflammation that involves skip areas Crypt abscesses and superficial inflammation that
affects the colon and rectum
Symptoms may include: Crampy abdominal pain, Symptoms may include: Abdominal pain and
diarrhea, fever, fatigue, weight loss, tenesmus, fistulas sounds, persistent diarrhea, fever, weight loss,
tenesmus, blood and/or pus in stool
ASCA: 60% of patients ASCA: 10% of patients
P-ANCA: 0% of patients P-ANCA: 75% of patients
Risk factors: Family history, Jewish decent, smoking. Risk factors: Family history, Jewish decent. May
May occur at any age, but usually occurs between occur at any age, although there are peaks at 15
15 to 35 to 30 and 50 to 70
Table 16.2: Common Extraintestinal Manifestations

Musculoskeletal Ankylosing spondylitis, hypertrophic osteoarthropathy, osteoporosis, aseptic necrosis, etc.
Skin and Mouth Erythema nodosum, pyoderma gangrenosum, aphthous ulcers
Hepatobiliary Primary sclerosing cholangitis (PSC) and bile duct carcinoma
Ocular Uveitis iritis, episcleritis
Metabolic Growth retardation in children and adolescents
Modified from: Das KM. Relationship of extraintestinal involvements in inflammatory bowel disease: New insights into
autoimmune pathogenesis. Dig Dis Sci 1999; 44:1.
Diagnosis
Although several features may differentiate Crohn disease from ulcerative colitis, there is
significant overlap.
Treatment of Ulcerative Colitis
Table 16.3: Treatment of Ulcerative Colitis

Indication Treatment
Mild 5-aminosalicylic acid (5-ASA) agents: Mesalamine or sulfasalazine
Moderate Prednisone: Remission induction
Maintenance therapy with immunomodulators: 5-ASA agent, 6-mercaptopurine (6-MP)
or azathioprine
Severe IV corticosteroids or IV cyclosporine followed by oral cyclosporine
Surgery: Refractory disease
Treatment of Crohns Disease
Table 16.4: Treatment of Crohn's Disease

Indication Treatment
Mild to moderate 5-aminosalicylic acid (5-ASA) agents: Small- or large-bowel disease
Budesonide: Ileal or right colonic disease
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Moderate to severe Prednisone: Remission induction
Infliximab: Refractory disease
Maintenance therapy: 6-mercaptopurine (6-MP), azathioprine, or methotrexate
Severe IV corticosteroids: Remission
Infliximab: Corticosteroid-refractory disease
Surgery with colectomy: Extremely toxic patient or does not respond to
medication
Diagnosis:
Colonoscopy with biopsy; CT enterography
Guidelines for surveillance colonoscopy: concensus: 8-10 years after diagnosis; then every
year after that depending on the risk
Microscopic Colitis
Includes: Lymphocytic colitis or collagenous colitis
Peak incidence at age 65
Characterized by chronic diarrhea, often with abdominal pain and mild weight loss
Colonoscopy with tissue biopsies is required for diagnosis, mucosa usually normal on
gross visualization
Dysmotility Syndromes
Constipation
Alarm features include rectal bleeding, weight loss, a family history of colon cancer or
IBD, anemia, and acute onset in elderly patients
Ileus and Pseudo-obstruction
Usually after surgery (especially abdominal) and can be associated with metabolic
disturbances (electrolyte abnormalities, sepsis); medications (anticholinergics, narcotics, etc.)
Treatment depends on symptoms and etiology
Irritable Bowel Syndrome (IBS)

1. Diarrhea-predominant (IBS-D)
2. Constipation-predominant (IBS-C)
3. Mixed
4. Unsubtyped
Diagnosis is based solely on clinical grounds
Evaluation
Primary characteristic: Chronic abdominal pain and altered bowel habits
Abdominal pain in IBS can vary but should not be associated with any of the alarming
features
Rome III diagnostic criteria for IBS
Recurrent abdominal pain/discomfort at least 3 days per month in the last 3 months
associated with 2 or more of the following:
Improved with defecation
Onset associated with a change in frequency of stool
Onset associated with a change in appearance of stool

Treatment
Treatment of irritable bowel syndrome (IBS) varies with the severity and type of
symptoms
Treatment options include: Dietary modification, medications, psychological, and
alternative therapies
Antibiotics are not routinely recommended in patients with IBS
Colonic Diverticular Diseases

Diverticulosis
A herniation (diverticulum) of the intestinal wall
Uncomplicated diverticulosis is usually an incidental finding
The major complications of diverticular disease are diverticulitis and diverticular bleeding
Diverticular bleeding manifests as bright rectal bleeding in older patients > 60 years old
that resolves spontaneously
Asymptomatic diverticulosis does not warrant further evaluation
Diverticulitis
An inflammatory response following obstruction of a diverticulum
Characteristics: Left lower quadrant abdominal pain and fever
Colonoscopy should be avoided in the acute setting because of increased the risk for
perforation
After symptoms resolution, patients should undergo the procedures to rule out
malignancy (if no prior or recent procedure)
Treatment consists of antibiotic and symptom relief
Diverticular Bleeding
Occurs following rupture of an artery that has penetrated a diverticulumit is typically
painless, and usually stops without therapy
Intestinal Ischemic Disease

Acute Mesenteric Ischemia
Life-threatening condition that must be recognized and treated emergently
Usually develops from ventricular or left atrial thrombi in the context of atrial fibrillation
Symptoms: Poorly localized severe abdominal pain often out of proportion to physical
findings; peritoneal signs signify infarction
Diagnosis: Selective mesenteric angiography
Treatment: Surgical embolectomy or Intra-arterial thrombolysis if initiated within 12 hours
Chronic Mesenteric Ischemia
Symptoms: Postprandial abdominal pain and weight loss
Diagnosis: Conventional or magnetic resonance angiography
Treatment: Surgical reconstruction or angioplasty with stenting
Colonic Ischemia (Ischemic Colitis)
Caused by atherosclerosis, low-flow states
Symptoms: Left lower quadrant abdominal pain and self-limited bloody diarrhea
Diagnosis: Colonoscopy revealing patchy segmental ulcerations
Treatment: Supportive care with IV fluids and bowel rest
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16.4 DISORDERS OF THE PANCREAS
Acute Pancreatitis
The causes of acute pancreatitis US include:
1. Biliary obstruction and alcohol (most common about 80% of cases)
2. Sulfonamides, estrogens, didanosine (ddI), valproic acid, thiazide diuretics, and
furosemide
3. Hypertriglyceridemia (>1,000 mg/dL)
4. Endoscopic retrograde cholangiopancreatography (ERCP)
5. Cystic fibrosis (young people with pancreatitis) and pancreas divisum
Clinical Presentation and Diagnosis
Typical symptoms include: Sudden onset of epigastric pain, often radiating to the back
with nausea, vomiting, fever, and tachycardia
The serum amylase and lipase levels are elevated in 75 to 90% of patients (>3 times the
upper limit of normal)
Lipaseis preferred to amylase due to its longer half-life and increased specificity
Mildly increased amylase values can be caused by:
Renal insufficiency
Intestinal ischemia
Appendicitis
Parotitis
Prognostic Criteria for Acute Pancreatitis
Various scoring systems are used to identify at-risk patients and to determine prognosis;
these include the Ranson criteria, the Glasgow Scoring System, and the APACHE II
In the intensive care unit, the Severity of Organ Failure Assessment (SOFA) score has
been shown to be superior to the Ranson and APACHE score
On admission to the ED, 2006 guideline update has shown the APACHE score is more
sensitive to predicting mortality in acute pancreatitis
BISAP score is a reliable method in stratifying clinical severity of acute pancreatitis within
24-hours of hospital admission. It is a new scoring system that takes into consideration
the following clinical criteria:
Blood urea nitrogen level greater than 25 mg/dL
Impaired mental status
Systemic inflammatory response syndrome
Age >60 year
Pleural effusion
Management
Mild pancreatitis is treated with supportive care including pain control, intravenous fluids,
correction of electrolyte and metabolic abnormalities
Updated guidelines: use of Lactated Ringers solution is associated with reduction in
inflammation (84% vs 0%) compared to normal saline, and should be used in volume
repletion. Contrary to the belief against using opioids in causing sphincter of oddi spasms,
there is limited studies showing that morphine is a culprit; therefore, clinicians should use
fentanyl or Demerol, but should be wary of side-effects
Moderate-severe pancreatitis in addition to supportive care and intensive care unit
monitoring:
TPN or enteral jejunal feedings (preferred)

Antibiotics for cholangitis, infected pancreatic necrosis, and infected pseudocysts
Prophylactic antibiotics (imipenem or meropenem) for pancreatic necrosis
Complications
Pancreatic pseudocysts are the most common complication of acute pancreatitis
Symptomatic pseudocysts are treated with percutaneous or endoscopic or surgical
drainage
Chronic Pancreatitis
Chronic pancreatitis is an inflammatory disorder characterized by irreversible morphologic
changes
Chronic alcohol abuse is the most common cause in industrialized countries
Young adults with chronic pancreatitis require genetic tests for cystic fibrosis
Diagnosis
The diagnosis of chronic pancreatitis can be challenging since laboratory studies and
imaging procedures may be normal
The classic triad of pancreatic calcifications, steatorrhea, and diabetes strongly suggests
the diagnosis
The most sensitive test for pancreatic function is the secretin stimulation test
Normal amylase and lipase levels do not rule out chronic pancreatitis
Treatment
Directed at controlling pain and alleviating the manifestations of diabetes mellitus,
malabsorption, and steatorrhea
Initial therapy is administration of pancreatic enzymes
Corticosteroids can be used for autoimmune pancreatitis (a type of chronic pancreatitis
characterized by hypergammaglobulinemia, pancreatic enlargement, a positive ANA titer)
for a duration of 4-6 weeks, and repeated imaging used to monitor for improvement
Recent update guidelines: Patients with IgG4 autoimmune pancreatitis have a higher risk
of relapse if not maintained on an immunosuppressant, and should be maintained on
azathioprine
Pancreatic Adenocarcinoma
The initial presentation varies according to tumor location
Tumors in the pancreatic body or tail usually present with pain and weight loss
Those in the head typically present with jaundice, pain, weight loss, and steatorrhea
Diagnosis
Transabdominal Ultrasound is the first line because of its higher sensitivity (>90%) for all
pancreatic tumors; in contrast, triple-phase helical multi-detector row CT abdomen is 100%
sensitive for tumors >2cm, but 77% sensitive for tumors <2cm
All patients require biopsy of a pancreatic mass that can be obtained by endoscopic
ultrasonography with fine-needle aspiration biopsy
Serum tumor markers (CA 19-9) are not used to diagnose pancreatic cancer
Treatment
Surgical resection is appropriate for patients with resectable cancer
For advanced disease treatment is controversial
Survival rate is usually 6 months or less for patients with metastatic disease
Palliation of biliary obstruction should be considered
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Cystic Neoplasms of the Pancreas
Many pancreatic cysts are discovered incidentally when abdominal imaging is obtained for
unrelated indications
Treatment of benign lesions consists of observation and follow-up
Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors are rare neoplasms that can arise in the pancreas and in
other parts of the GI system
The hallmark is an excessive hormone secretion
The most common example of a functioning pancreatic neuroendocrine tumor is the
gastrinoma
16.5 COLORECTAL NEOPLASIA

Pathophysiology of Colorectal Neoplasia
The major factors that increase the risk of colon cancer include genetics, a personal or
family history of sporadic colorectal cancer or polyps, and inflammatory bowel disease
Genetics
Adenoma-to-carcinoma sequence
The progression from normal mucosa to adenoma to cancer takes approximately 15 years
Epidemiology and Risk Factors of Colonic Neoplasia

The 3rd most common cause of cancer death in both sexes
African Americans have more advanced stage at diagnosis and a worse overall prognosis
Environmental Factors
Obesity, smoking, alcohol use, and a sedentary lifestyle have been associated with an
increased risk for colorectal cancer
Hereditary Colon Cancer Syndromes
1. Familial adenomatous polyposis (FAP), which is an autosomal dominant disorder
requiring prophylactic colectomy
2. Gardner syndrome, which is a type of familial adenomatous polyposis with extraintestinal
manifestations, including osteomas, duodenal ampullary tumors, thyroid cancers, and
medulloblastomas
3. Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is the most
common of the hereditary colon cancer syndromes (autosomal dominant disorder)
If an inherited colon cancer syndrome is suspected, the patient and family members
should be referred for genetic testing
Acceptable Screening Strategies for the Average Risk Population

Yearly fecal occult blood testing (FOBT)
Sigmoidoscopy every 5 years (with or without FOBT)
Colonoscopy every 10 years

Screening and Surveillance for Colonic Neoplasia
Table 16.6: Screening and Surveillance for Colonic Neoplasia

Risk Profile When to Initiate Screening
Average risk Age 50
1st-degree relative with colon cancer age >60 Age 40
1st-degree relative diagnosed with an adenoma- Age 40 or 10 years younger than the earliest diag-
tous polyp or colon cancer at age <60 nosis in the family
CRC or adenomatous polyps in a 1st-degree rela- Age 40 or 10 years younger than the earliest diag-
tive before age 60 years or in 2 or more 1st-degree nosis in the family (colonoscopy every 5 years)
relatives
Genetic diagnosis of FAP or suspected FAP Age 10 to 12 years with annual sigmoidoscopy
Genetic or clinical diagnosis of HNPCC Colonoscopy every 1-2 years starting at age 20-25
years, or 10 years before the youngest case
Inflammatory bowel disease Cancer risk begins to be significant 8 years after
the onset of pancolitis, colonoscopy with biopsies
every 1-2 years thereafter
Surveillance of Patients With Colon Polyps or Cancer
Table 16.7: Surveillance of Patients with Colon Polyps or Cancer

Risk Profile When to Initiate Screening
Patients with 1 or 2 small tubular adenomas with Colonoscopy 5-10 years after the initial
low-grade dysplasia polypectomy
Patients with 3 to 10 adenomas, or 1 adenoma Colonoscopy 3 years after the initial polypectomy
>1 cm, or any adenoma with villous features or
high-grade dysplasia
Patients with >10 adenomas on a single examination Colonoscopy <3 years after the initial polypectomy
Patients with sessile adenomas that are removed Colonoscopy 2-6 months to verify complete
piecemeal removal
Clinical Presentation of Colonic Neoplasia

Rectal bleeding or change in bowel habits, other findings include pelvic pain or tenesmus,
weight loss, rectal or abdominal mass, hepatomegaly, and anemia
Bacteremia from Streptococcus bovis and Clostridium septicum has been associated with
colon cancer and should prompt colonoscopy
GASTROENTEROLOGY105
Staging of Colon Cancer
The TNM staging is the preferred staging system for colon cancer
Table 16.8: AJCC (TNM) Staging System

Stage 0 Earliest stage, not beyond the inner layer (mucosa) of the colon
Stage I Confined to muscularis propria
Stage II Extends into subserosa or directly invades other structures
Stage III Metastatic to regional lymph nodes
Stage IV Distant metastases
Modified from the American Joint Committee on Cancer (AJCC).
16.6 DISORDERS OF THE LIVER, GALLBLADDER, AND BILE DUCTS

Approach to the Patient With Abnormal Liver Chemistry Studies
Liver Injury Test Patterns
Liver injury is divided into 2 categories: 1. Hepatocellular injury 2. Cholestatic injury
Hepatocellular injury most often results in an elevation of serum ALT and AST
In cholestatic injury, an elevation of serum alkaline phosphatase occurs even without
jaundice. Profound injury results in elevation of the serum bilirubin and therefore jaundice
Gilbert syndrome (prevalence of 5 to 7%) is a benign disorder characterized by indirect
hyperbilirubinemia
Liver Function Tests
Synthetic liver function is measured by serum albumin and prothrombin time (or INR)
Elevation of ALT is more sensitive for diagnosing liver disease
Clinical Approach to Abnormal Liver Studies
Determination of the injury type and its severity
Detailed history and physical exam, looking for symptoms of liver disease (malaise,
jaundice, RUQ pain, weight loss, and nausea)
Duration of symptoms and/or laboratory findings to differentiate between acute and
chronic
Viral Hepatitis
Hepatitis A Virus
Transmitted via the fecal-oral route, and is more prevalent in low socioeconomic areas
Self-limited illness and rarely leads to fulminant hepatitis
Severity of infection can vary from a mild flu-like illness to fulminant hepatitis
Laboratory findings include marked increase in serum aminotransferases (usually >1,000
U/L), serum total and direct bilirubin, and alkaline phosphatase
Diagnostic test: IgM antibodies to HAV (IgM anti-HAV)
2011 Updated Guidelines on HAV Vaccination indications: travel to endemic countries, HIV
patients, chronic liver disease, exposure in outbreak, post-exposure prophylaxis, close
contact with international adoptees

Hepatitis B Virus
Hepatitis B is transmitted parenterally by percutaneous exposure
Causes 1/3 of cases of acute viral hepatitis and 15% of cases of chronic hepatitis
The diagnosis of acute hepatitis B is based upon the detection of HBsAg and IgM anti-HBc
The presence of hepatitis B e antigen and hepatitis B virus DNA are markers of active
viral replication
Patients with chronic hepatitis B are at high risk for hepatocellular carcinoma. Surveillance
with ultrasonography every 6 to 12 months is advised
Table 16.9: Serologic Markers for the Different

Phases of Acute Hepatitis B Infection
HBsAg HBeAg IgM IgG Anti- Anti- HBV Interpretation
anti- anti- HBs HBe DNA
HBc HBc
+ + + +++ Early phase
+ + Window phase
+ + + Recovery Phase
Management
Hepatitis B e antigen (HBsAg) positive
HBeAg positive
Alanine aminotransferase (ALT) <1x ULN
Every 3 to 6 month ALT - Every 6 to 12 month HBeAg
ALT 1-2x ULN
Every 3 month ALT - Every 6 month HBeAg - Possible biopsy and treat if
over 40
ALT >2x ULN - Hepatitis B virus (HBV) DNA>20,000 IU/mL
Every 1 to 3 month ALT, HBeAg for spontaneous conversion - Possible
biopsy and treatment
HBeAg negative
ALT >2x ULN - HBV DNA>20,000 IU/mL
Treat
ALT 1-2x ULN - HBV DNA 2,000-20,000 IU/mL
Possible biopsy and treatment
ALT <1x ULN - HBV DNA<20,000 IU/mL
Every 3 month ALT x3, followed by every 6 to 12 month ALT if still <1x ULN
Indications for hep B Vaccine: people born in endemic areas, patients with chronically
elevated aminotransferases, HIV, or HCV patients, household, family or sexual partners of
HBV patients, men who have sex with men, patients with multiple sexual partners, prison
inmates, IVDA, dialysis patients, and immunosuppressed patients
The 2008 NIH Guideline for Rx criteria : compensated cirrhotics with HBV DNA >2000,
patients with acute liver failure, decompensated cirrhosis, high HBV DNA in cirrhotics,,
chemotherapy patients, HBeAg-positive patients. Treatment options: Interferon,
lamivudine, Entecavir, tenofovir, telbivudine, etc.
GASTROENTEROLOGY107
Hepatitis C
85% develop chronic infection, 20 to 25% of those develop cirrhosis
Most patients with chronic infection are asymptomatic or have only mild nonspecific
symptoms
High-risk groups include IV drug abusers and recipients of blood transfusions prior to
1992
Measurement of anti-HCV is the initial diagnostic study. If positive, test for HCV RNA
Test for HCV in patients with vasculitis, cryoglobulinemia, glomerulonephritis, and
porphyria cutanea tarda
There are six different genotypes for HCV disease: genotypes 1, 2, 3, 4, 5, 6. Differentiating
between types 1a, and 1b is important because of resistance associated with treatment
Treatment should be offered for patients with compensated liver disease: Peginterferon
combined with ribavirin (plus protease inhibitor boceprevir or telaprevir in patients with
genotype 1)
The newest addition for treatment of HepC is sofosbuvir with interferon and ribavirin:
found to be 90% effective in genotypes 1, 4, 5, 6. Sofosbuvir and ribavirin is 70-95%
effective in genotypes 2 and 3.
The Updated guideline on monitoring treatment response is there is no indication for
periodic viral response to treatment with the newest treatments
Hepatitis D
Due to the dependence of HDV on HBV, the diagnosis of hepatitis D cannot be made in
the absence of HBV infection
Presentation as acute hepatitis or an exacerbation of preexisting chronic hepatitis
Prevention of HDV is vaccination against HBV, its helper virus.
No specific treatment exists; although there are limited evidence of foscarnet in treatment
Hepatitis E
Pregnant woman with acute infection, ADD: malnourished, and patients with chronic liver
diseases are at greatest risk for severe hepatitis or fulminant liver failure
Spread is by fecal-oral route, and outbreaks
Vaccines for Hep E prevention have been developed, but not yet commercially available
Prevention is by using healthy eating and hand hygiene habits when traveling to endemic
countries
Treatment is mainly supportive
Alcohol- and Drug-induced Liver Disease

Alcohol-induced Liver Disease
Several characteristic (non diagnostic) laboratory abnormalities including elevations in
AST and ALT that do not exceed 300-500 U/L, with an AST/ALT ratio >2.0
Severity is assessed by calculating the discriminant function DF
Corticosteroids (prednisone 40 mg/d) are indicated for patients with a DF score 32
DF = (4.6 x [prothrombin time - control PT]) + (serum bilirubin)
Zieves Syndrome
A Variant of Alcohol-induced liver injury.
Occurs in young alcoholics who have no evidence of liver damage on imaging

Triad of elevated liver functions test, jaundice, elevated triglyceride, and hemolysis.
Treatment is supportive with resolution of symptoms after a few days of alcohol
cessation
Drug-induced Liver Injury (DILI)
Acetaminophen overdose induced liver injury and hepatotoxicity
Acetaminophen overdose may occur when taken at supratherapeutic doses and
happens almost exclusively in the setting of massive overdose, following the
ingestion of more than 7,500 to 10,000 mg over a period of 8 hours or less in adults
and adolescents
The principal toxic effect of acetaminophen overdose is hepatic injury and
acetaminophen overdose is also associated with hepatotoxicity
Hepatotoxicity associated with supratherapeutic doses of acetaminophen may also
occur with:
Fasting or the inability to eat, and ingesting between 4,000 to 10,000 mg of
acetaminophen daily
Alcohol use individuals drinking alcohol and taking supratherapeutic doses of
acetaminophen (please see Pain Management chapter for further information
regarding alcohol and OTC analgesics)
Patients should be advised to follow labeled dosing to avoid toxicity
Treatment approved by the FDA for acetaminophen overdose is acetylcysteine.
Acetylcysteine should be initiated to prevent or limit liver injury in patients who have
already developed toxicity
Autoimmune Hepatitis
An inflammatory condition of the liver of unknown cause
Presents with weakness, fatigue, jaundice, anorexia, and incidental elevations of
aminotransferases discovered on routine laboratory testing
Up to 50% of patients have a concomitant autoimmune disease, such as thyroiditis,
ulcerative colitis, or synovitis
Liver biopsy is required for definitive diagnosis
Treat with prednisone and azathioprine
There is a high risk of relapse. Patients should be tapered off prednisone after repeated LFT
monitoring, and absence of symptoms
Metabolic Liver Disease

Nonalcoholic Fatty Liver Disease
Patients who lack a history of significant alcohol consumption but have liver biopsy findings
indistinguishable from alcoholic steatohepatitis
Nonalcoholic steatohepatitis (NASH) is a subset of NAFLD
Difference between NAFLD and NASH:
NAFLD: hepatic steatosis without inflammation
NASH: steatosis associated with inflammation.
NAFLD activity score (NAS) : <3 corresponds to NAFLD, >5 corresponds to NASH
Liver biopsy is the only way for diagnosis
Therapy involves weight reduction and lifestyle modification since there is no definitive
treatment
Updated Guidelines on NAFLD: Hepatitis A and B vaccination if they are not immune
GASTROENTEROLOGY109
Wilson Disease
Rare autosomal recessive disorder
Initial screening (when suspected) with liver function tests, a CBC, serum ceruloplasmin,
24-hour basal urinary copper, and slit-lamp examination for Kayser-Fleischer rings
Treatment of Wilson disease is directed at reducing the copper overload with the use of
copper chelators (penicillamine)
First-degree relatives should be screened
Hereditary Hemochromatosis
Hereditary hemochromatosis is an autosomal-recessive disorder (HFE Gene)
Initial evaluation involves measuring the transferrin saturation and the ferritin
HFE gene testing is indicated when the fasting serum transferrin >45%
A nondiagnostic HFE genotype does not rule out the diagnosis
Phlebotomy is the treatment of choice to achieve a Ferritin <50 ng/mL
Cholestatic Liver Disease

Primary Biliary Cirrhosis (PBC)
Autoimmune disease affecting women between the ages 40 to 60
Fatigue, pruritus, weight loss, hyperpigmentation, xanthomas are the typical features
Associated with other autoimmune diseases (typically: hypothyroidism, Sjgren disease,
Sicca syndrome, scleroderma)
Highly suspected with positive anti-mitochondrial antibody titers (AMA) and elevated
alkaline phosphatase
Diagnosis is confirmed by a liver biopsy
Treatment with ursodeoxycholic acid
Primary Sclerosing Cholangitis (PSC)
The disease should be considered in patients with IBD who have abnormal liver function
tests (typically alkaline phosphatase)
Up to 80% of patients with PSC have IBD
Diagnosis of PSC is established by cholangiography demonstrating multifocal strictures
and dilation string of beads of intrahepatic and extrahepatic bile ducts
Treatment with endoscopic therapy for extrahepatic dominant strictures
Patients with PSC and IBD are at higher risk for colon cancer
Figure 16.7: PSC with typical multifocal strictures -

MRCP

Figure 16.8: PSC with typical multifocal strictures -
ERCP
Cirrhosis
Presenting symptoms are related to hepatocyte dysfunction (jaundice, coagulopathy, and
edema) or due to increased portal venous pressure (ascites, bleeding esophageal varices,
hepatic encephalopathy, or hypersplenism)
The main causes of cirrhosis globally are Hepatitis B (30%), Hepatitis C (27%) and alcohol
(20%), nonalcoholic fatty liver disease
Portal Hypertension
Results from a combination of splanchnic vasodilation and increased resistance to blood
flow due to intrahepatic fibrosis
It is the pressure difference between the portal vein and the hepatic veins
Gastroesophageal Varices
Upper endoscopy is indicated for all new patients to screen for varices
Updated Guidelines for surveillance: EGD surveillance frequency is recommended yearly
in patients with decompensated cirrhosis; 1-2 years in patients with small varices, and 2-3
years in with patients with no varices on screening endoscopy
Hepatic venous pressure gradient is the best risk factor for the development of varices,
with values >10mmHg a red flag
Primary prophylaxis with non selective -blockers is indicated in patients with medium or
large varices
In patients with bleeding varices, Endoscopic variceal ligation or Trans-intrahepatic
portosystemic shunts (TIPS) should be considered
Ascites
Paracentesis should be performed for newly discovered ascites with calculation of the
serum-ascites albumin gradient (SAAG)
Table 16.10: Ascitic Fluid Interpretation

Ascitic Fluid Protein SAAG >1.1 SAAG <1.1
<2.5 g/dL Cirrhosis Nephrotic syndrome
>2.5 g/dL Right-sided heart failure, Malignancy, tuberculosis
Budd-Chiari syndrome
GASTROENTEROLOGY111
Spontaneous Bacterial Peritonitis
Ascitic fluid granulocyte count >250/L confirms SBP
Ascites in a cirrhotic who presents with fever, abdominal pain, altered mental status,
leukocytosis, azotemia
Treatment with antibiotics (3rd generation cephalosporin for at least 5 days) and albumin
infusion if 4-5L of fluids is removed to prevent renal damage
Hepatorenal Syndrome (HRS)
Diuretic therapy, paracentesis without volume expansion, and GI bleeding may precipitate
HRS
Lack of improvement of renal function following fluid challenge with administration of
11.5 L of normal saline suggests HRS
Almost all patients with HRS require liver transplantation
Hepatopulmonary Syndrome (HPS)
Suspected in patients with dyspnea, hypoxemia, and cirrhosis
Patients may exhibit platypnea (increased dyspnea sitting up and decreased dyspnea
lying flat)
HPS is different from portopulmonary hypertension (pulmonary hypertension secondary
to liver disease)
Hepatic Encephalopathy
Reversible decrease in level of consciousness or personality change with liver failure
Requires evaluation for bleeding, SBP (or other infections), and electrolyte disorders
Prevention by using lactulose their mechanism is by converting ammonia to unabsorbable
ammonium, for easy excretion, and they augment easy transit of contents through the gut
Antibiotics such as rifaximin are recommended to reduced the generation of ammonia by
gut bacteria in encephalopathy
Hepatocellular Carcinoma (HCC)
Patients with cirrhosis should have serum AFP measurement and abdominal
ultrasonography
Order imaging (CT or MRI) when serum AFP levels are >20 ng/mL or abdominal
ultrasonography is abnormal
A serum AFP level >500 ng/mL is diagnostic
Surveillance in patients with chronic liver disease with abdominal ultrasound every six
months is recommended for detection of HCC
AASLD Guidelines 2010: HCC diagnosis if nodules larger than 1cm in diameter on
ultrasound has appearance typical of HCC on MRI or CT
OR growth of a <1cm lesion found on ultrasound should be followed every 3 to 6 months,
and if no growth after 2 years, provider should revert to routine screening
Treatment with surgical resection or liver transplantation, sorafenib improves overall
survival in patients with advanced HCC
Fulminant Hepatic Failure

Rapid development of liver injury accompanied by mental status changes
Cerebral edema is the most common cause of death

Liver Transplantation
The evaluation for liver transplantation involves a multidisciplinary approach
Indications: HCC, decompensated cirrhosis, acute liver failure with MELD score of 10 or
Child-Pugh score of 7
Contraindications: severe cardiac and pulmonary disease, active drug and alcohol abuse,
malignancy outside the liver within five years of transplant evaluation
Amebic Liver Abscesses

Caused by Entamoeba histolytica
Clinical features include RUQ abdominal pain and fever
Metronidazole is the drug of choice
Pregnancy-related Liver Disease

Causes of jaundice during pregnancy
1st and 2nd trimesters: Viral hepatitis, drug induced
3rd trimester: Cholestasis of pregnancy, gallstones, acute fatty liver of pregnancy, and
HELLP syndrome
Cholestasis of pregnancy is the most common and most benign, ursodeoxycholic
acid is the treatment of choice
Acute fatty liver of pregnancy is rare, presenting symptoms are vague
May be associated with preeclampsia or eclampsia and coagulation abnormalities,
resolves rapidly after delivery
The HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) is
associated with preeclampsia or eclampsia, associated with microangiopathic
hemolytic anemia, the only treatment is immediate delivery
Gallstones and Acute Cholecystitis

Biliary pain is the most common cause of upper abdominal pain among patients aged >50
years
Select ultrasonography as the initial imaging modality
Complications of Gallstones
Acute Cholecystitis
Most common complication
Presentation with RUQ pain, fever, nausea/vomiting
Physical findings: + Murphy sign
Ultrasonography reveals pericholecystic fluid and a thickened gallbladder wall
If diagnosis is not definitive after ultrasonography, cholescintigraphy (HIDA scan) can
then be diagnostic
Surgery is required 24 to 48 hours
Acalculous Cholecystitis
In critically ill patients with comorbidities
Management is the same as acute calculous cholecystitis
Common Bile Duct Stones (Choledocholithiasis)
Most common cause of acute cholangitis
Charcot triad of cholangitis consisting of RUQ pain, fever, and jaundice, in advanced cases
mental status changes and shock may result
Reynolds pentad: Charcts triad + sepsis and altered mental status
GASTROENTEROLOGY113
ERCP is diagnostic and therapeutic but invasive, MRCP is a non invasive alternative
Treatment in acute cholangitis: Admit to ICU: start on broad-spectrum antibiotics: studies
showed beta-lactam therapy is less toxic and as effective as ampicillin and gentamycin
IV hydration
Mirizzi Syndrome
A condition where the cystic duct obstructs the common bile duct (extrinsic obstruction)
by enlargement of a gallstone in the cystic duct to the point it compresses the common
bile duct
Complications: obstructive jaundice, inflammation and cholecystocholedochal fistula
Diagnosis: Ultrasound or CT scan, and ERCP prior to Surgery
Treatment: cholecystectomy
16.7 GASTROINTESTINAL BLEEDING

Upper Gastrointestinal Bleeding
Peptic ulcer disease is the most common cause of non variceal upper GI bleeding
Other causes include: Gastritis, esophagitis, Mallory-Weiss tear, Gastric antral vascular
ectasia (GAVE syndrome, also called watermelon stomach), Dieulafoy lesion (from
superficial exposed arteriole)
Characteristic findings are hematemesis, melena, or bright-red blood per rectum (with
massive hemorrhage) or a high serum BUN/creatinine ratio
The hemoglobin concentration and hematocrit level are unreliable indicators of volume
status
Vital signs reveal tachycardia at 10% volume loss, orthostatic hypotension at 20% blood
loss, and shock at 30% loss
Management of Upper Gastrointestinal Bleeding
Fluid resuscitation with IV fluids and/or blood products
Correct coagulopathy with FFP or vitamin K, keep platelet count >50,000 L
Start a PPI before upper endoscopy
Upper endoscopy by a specialist
When endoscopic therapy is ineffective, interventional radiology or surgery should be
involved
Lower Gastrointestinal Bleeding

10% of rapid rectal bleeding has an upper GI source
Causes
Diverticular (painless and self-limited bleed)
Ischemic colitis (abdominal pain followed by passage of blood, elderly patients with risk
factors for atherosclerosis)
Angiodysplasia (silent bleed in elderly)
Hemorrhoids are unlikely to cause serious bleeding
Evaluation and Management
Dark or maroon-colored mixed with stool, bleeding source is right colon
Bright red blood, bleeding source is left colon

For patients with acute/severe hematochezia
Evaluate and resuscitation
Nasogastric tube aspiration
Aspirate bile/no blood, which leads to colonoscopy
All others
EGD. If negative, leads to colonoscopy
With massive rectal bleed angiography should be performed, angiographically evident
bleeding typically requires blood loss at a rate of 1 mL/min
In non-massive bleeding without clear identification of the source of bleed, technetium-
99m pertechnetate red blood cell scanning should be performed next which can identify
bleeding at much lower rates than angiography
For suspected small bowel bleeding, push enteroscopy or capsule endoscopy should be
performed
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NOTES
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17 Cardiovascular Disease
Ashraf Qaqa, MD
C o n t e n t s
17.1 Physical Examination . . . . . . . . . . . . . . . . . . . . . . . 118
17.2 Epidemiology of Cardiovascular Disease

(CVD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
17.3 Coronary Artery Disease (CAD) . . . . . . . . . . 122
17.4 Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
17.5 Myocardial Disease . . . . . . . . . . . . . . . . . . . . . . . . 130
17.6 Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
17.7 Pericardial Disease . . . . . . . . . . . . . . . . . . . . . . . . 138
17.8 Valvular Heart Disease . . . . . . . . . . . . . . . . . . . 139
17.9 Adult Congenital Heart Disease (CHD) . . 145
17.10 Disease of THE Aorta . . . . . . . . . . . . . . . . . . . . . . 147
17.11 Peripheral Arterial Disease (PAD) . . . . . . . 148
17.12 Pregnancy and Cardiovascular Disease . 150
CARDIOVASCULAR DISEASE117
17.1 Physical Examination
Cardiac Sounds
S1 is best heard at the heart apex
Conditions may affect the intensity of S1
S1 sound intensity will decrease in the following conditions:
Prolonged PR interval (1st degree block)
Low ejection fraction (systolic heart failure)
Acute aortic valve regurgitation (MV will close prematurely)
Conditions which affect leaflets mobility of the MV (thickening and calcification)
S1 sound intensity will increase in the following conditions:
If the PR interval shortens
Mitral valve stenosis (with mobile leaflets)
Cardiac hyperdynamic state (fever, anemia, hyperthyroidism)
S1 sound intensity will be variable in the following conditions:
Atrial fibrillation
Atrioventricular (AV) dissociation
The splitting of S2 (best heard at the left lower sternum using the diaphragm of the
stethoscope) normally occurs during inspiration
Conditions affect the intensity of S2 sound
S2 sound intensity will decrease in the following conditions:
Severe aortic stenosis
Pulmonic valve stenosis
2 sound intensity will increase in the following conditions:
S
Uncontrolled hypertension
Cardiac hyperdynamic state
Pulmonary embolism (P2 increased)
Conditions affect the splitting of S2 sound
Fixed splitting (the splitting of S2 can be heard during expiration and inspiration and
stays the same) atrial septal defect
Persistent splitting (the splitting does not disappear in expiration but gets wider with
inspiration) pulmonic stenosis, pulmonary embolism, right bundle branch block
(RBBB), left ventricular pacing (biventricular pacemaker or ectopic beat originating
from LV)
Paradoxical splitting (A2 after P2 and happens during expiration); Severe AS,
hypertrophic cardiomyopathy, left bundle branch block (LBBB), right ventricular pacing
(pacemaker or ectopic beat originating in right ventricle)
S3 is best heard by the bell of the stethoscope, at the apex (left ventricular gallop)
or at the lower sternum (right ventricular gallop)
S3 is normal in pregnant and young athletes, otherwise indicates ventricular failure
S4 results from filling of a stiff ventricle by strong atrial contraction
S4 is best heard by the bell at the apex (left ventricular S4) or left lower sternum
(right ventricular S4)

S4 can be heard in patients with cardiac ischemia, hypertensive and hypertrophic
heart disease, severe aortic stenosis, and severe pulmonary hypertension (right
atrial gallop)
Cardiac Murmurs
In general, the murmur will get louder if the flow across the valve increases
Squatting, for instance, will increase the venous return and the flow so it will intensify all
types of murmurs (except murmur associated with HOCM)
On the other hand, standing and Valsalva decrease the blood return and soften all
murmurs (except HOCH murmur which increases)
Murmurs Associated With Left Heart Lesions
Table 17.1: Murmurs Associated With Left Side Murmurs

Valve Disease Murmur Characteristics and Other Examination Findings
Aortic stenosis Mid-systolic to late peaking

Radiates to carotids
Soft S2 with paradoxical splitting, S4 can be heard
Valsalva and standing murmur but after PVC
HOCM Mid-systolic murmur
Does not radiate to carotids
Normal or bisferiens carotid pulse
Valsalva, standing, vasodilators (nitrate or exercise), and inotropes murmur
Squatting will the murmur
Mitral regurgitation Pansystolic murmur
Radiates to axilla or subscapular area
In acute MR, the murmur could be absent
Expiration murmur
Mitral valve prolapse Late systolic murmur
Radiates to LLS
Preceded by click (click-murmur syndrome)
Valsalva and standing murmur and the click happens early; closer to S1
Aortic regurgitation Early diastolic murmur
Soft S1 sound (indicates severe AR)
Austin Flint murmur (mitral stenosis murmur due to AR)
Exercise, handgrip, leaning forward murmur
Mitral stenosis Mid diastolic murmur
Preceded by opening snap
Loud S1 (diminish in advanced calcification)
Valsalva and standing make opening snap earlier (closer to S2)
Exercise and pregnancy (volume overload state) murmur
Murmurs Associated With Right Heart Lesions
Table 17.2: Murmurs Associated With Right Side Murmurs

Valve Disease Murmur Characteristics and Other Examination Findings
Pulmonic stenosis Ejection click preceding systolic murmur
Persistent splitting of S2 sound
Inspiration murmur
Tricuspid regurgitation Systolic murmur
Inspiration and squatting murmur
Tricuspid stenosis Diastolic murmur
Inspiration and squatting murmur
Murmurs Associated With Structural Cardiac Defects
Table 17.3: Murmurs Associated With Structural Cardiac Defects

Cardiac Defect Murmur Characteristics and Other Examination Findings
VSD Holosystolic murmur (very loud if the defect is small)
Associated with palpable thrill
Handgrip murmur
ASD Systolic ejection murmur ( flow across the pulmonic valve)
Fixed splitting of S2 sound
Aortic Coarctation Mid-systolic murmur heard at upper back
PDA Continuous murmur
Paradoxical splitting of S2 may occur
17.2 Epidemiology of Cardiovascular Disease (CVD)

Prevalence of CVD
CVD is the most common cause of death
Coronary artery disease (CAD) is the most common form of CVD death, followed by stroke
More than half of the cardiac deaths happen either before arriving to the hospital or in ER
Women and Cardiovascular Disease

The number of CVD-related deaths is increasing
Deaths related to coronary disease are more common than those from stroke
African Americans and Mexican American women have higher risk of CVD than Caucasian
women
Diabetes Mellitus (DM) and Cardiovascular Disease

DM significantly increases (2 to 4-folds) the risk of CVD
DM is considered a coronary artery disease equivalent
More than 1/3 of diabetic adults have some form of CVD
CVD is the most common cause of death in diabetics

Metabolic Syndrome and CVD
Obesity is an epidemic in the US
Obesity has been associated with premature cardiovascular morbidity and mortality
Obesity increases the risk of CAD, LV hypertrophy, arrhythmia, heart failure, and sudden
death
Metabolic syndrome diagnosis is increasing because of obesity and sedentary life style
About 1/3 of the adult population has metabolic syndrome
Patients with metabolic syndrome have insulin resistance ( fasting sugar), dyslipidemia
(high triglyceride or low HDL), obesity, and high blood pressure
Cancer and Cardiovascular Disease

Patients who had radiation therapy to the heart area are at risk of developing cardiac
complications (>10 years later)
Complications include: CAD, valve disease (mainly the aortic and mitral valves), diastolic
dysfunction, and restrictive cardiomyopathy, constrictive pericarditis, and conduction
abnormality
Patients with breast and lung malignant tumors are at the highest risk of severe recurrent
pericardial effusion
Systemic Inflammatory Conditions and Cardiovascular Disease

Chronic inflammatory diseases increase the risk of premature CAD (ex.: SLE)
Table 17.4: Cardiovascular Manifestation of Systemic Inflammatory Conditions

Inflammatory Condition Cardiovascular Manifestation
Rheumatoid arthritis Pericarditis (effusion or thickening)
Rheumatoid nodule on the valve
Increase risk of CAD (3-folds)
Ankylosing spondylitis Aortitis (aortic regurgitation)
Cardiac failure
Conduction abnormality (heart block)
SLE Pericarditis
Premature CAD
Libman-sack endocarditis
Myocarditis
If pregnant: Anti-Ro antibody risk of neonatal heart block
Antiphospholipid antibody risk of DVT, TIA, and stroke
syndrome
Scleroderma Raynaud's disease
Restrictive cardiomyopathy
Conduction abnormality
17.3 Coronary Artery Disease (CAD)
>50% obstruction in any epicardial coronary artery and mostly a result of atherosclerosis
If the stenosis is significant it will impair blood flow
Ischemia results when disequilibrium between myocardial oxygen supply and demand
occurs
As a consequence of ischemia, diastolic dysfunction happens followed by systolic
dysfunction, and then the EKG changes will appear and the symptoms of chest pain start
CAD may manifest as chronic stable CAD, acute coronary syndrome, heart failure, sudden
cardiac death, or silent disease (asymptomatic, but have EKG or imaging changes)
Chronic stable CAD is the most common type (50%) of ischemic heart disease
Coronary Artery Disease Risk Factors
Table 17.5: Coronary Artery Disease Risk Factors

Classification Risk Factors
Non-modifiable Aging
Male sex
Genetics/family history (history of premature CAD in first-degree relatives;
males <55 years and females <65 years)
Modifiable HTN (target <140/90, except if DM, or renal insufficiency target <130/80)
Smoking
DM (2 to 4-folds risk of CAD)
Metabolic syndrome
Dyslipidemia
Obesity (BMI >30)
Others levels of inflammatory markers (high sensitivity CRP commonly used in prac-
tice; if hs-CRP with positive risk factors, CAD surveillance)
Valve calcifications seen by 2D-echo (aortic sclerosis or mitral annular calcifica-
tion, if present, look for CAD and check for HTN)
Cocaine use
Sedentary life/Type-A personality
Depression ( sympathetic tone, catecholamine level, inflammatory mark-
ers, endothelial dysfunction, abnormal platelet activation, predict 1st MI)
Chronic Stable CAD

Presentation
Typical angina (retrosternal chest pain exacerbated by exercise and relieved by rest or
nitroglycerin)
Angina equivalent (shortness of breath on exertion)
Atypical chest pain (not brought up by exercise and not relieved by rest or NTG)
Diagnosis
Determine the likelihood of CAD (pre-test probability) based on the risk factors and
symptoms (typical vs. atypical angina)
Low no further testing

Intermediate noninvasive testing
High coronary angiography
ECG should be done 1st (normal ECG regular exercise stress test, abnormal ECG
echocardiographic or radionuclide imaging stress test)
Exercise stress test
Should be performed when possible because it gives information about functional
capacity and hemodynamic response
It is considered positive if the EKG during exercise shows horizontal or down
sloping ST segment depression (>2 mm), or blood pressure , or if sustained
ventricular tachyarrhythmia occurs (>30 sec), or if the patient developed heart
failure
Exercise stress test should not be done if baseline EKG shows ventricular paced
rhythm, LBBB, baseline ST depression, in patients with WPW syndrome, or if the
patient is on digoxin
Cardiac stress testing with imaging
Performed for patients with intermediate probability and abnormal baseline EKG
Exercise preferred over pharmacological agents, unless the patient is unable to
exercise
Exercise or pharmacological agents is used to increase the heart rate and
contractility and to induce coronary vasodilatation
Ischemia is assessed at the peak of heart rate and maximum exercise by visualizing
the myocardium and evaluating the contractility by echocardiography (stress
echocardiography) or by injecting radionuclide agent (thallium or technetium-
sestamibi) to evaluate myocardial perfusion (myocardial perfusion imaging [MPI])
Stress echocardiography detects ischemia by identifying ventricular regional wall
motion abnormality
MPI detects ischemia by identifying areas of decreased perfusion, transient increase
in LV size during exercise, and increase tracer uptake into the lung fields and
assessing the ventricular function (cardiac gating)
Medical treatment
Life style modification and risk factors reduction (low cholesterol diet, quit smoking,
regular exercise)
HbA1c target <7 if the patient is diabetic and has CAD
Aspirin cardiovascular events inpatients with CAD
Statin should be started if LDL >130 mg/dl (target LDL <100)
b-blockers are recommended to control BP and to control the angina ( mortality)
ACE inhibitors are recommended in diabetics or if the EF <40% ( mortality)
Nitrates angina symptoms (venodilator and coronary dilator), not given with
phosphodiesterase inhibitor (sildenafil), tolerance develops fast (should be stopped for
8 hours daily)
Ranolazine: New antianginal agent. The exact mechanism is unknown. Used in chronic
angina if uncontrolled after optimizing other antianginal agents. It's contraindicated in
hepatic impairment and prolonged QT ( QT interval)
Coronary revascularization
Indicated in angina refractory to medical treatment; if myocardial ischemic area is large,
left main disease, multivessel disease, impaired ejection fraction
Coronary revascularization can be by percutaneous coronary intervention for coronary
bypass surgery (CABG)
PCI has the limitation of restenosis; however, using drug-eluting stents (DES) decreases
neointimal hyperplasia and significantly reduces the restenosis to <15%. Antiplatelet
therapy with clopidogrel should be given for at least 12 months if DES was used, and at
least for 1 month in patients who received bare metal stents (BMS). Aspirin should be
given indefinitely decrease the rate of stent thrombosis
CABG is indicated in patients with left main artery disease and/or 3-vessel disease
2-vessel disease and 1 of the vessels is the proximal LAD (especially in patients with
EF <50% or demonstrable ischemia on nuclear or echo stress test) if the patient had
recovered sudden cardiac arrest or sustained ventricular tachyarrhythmia and the
coronary angiogram showed significant disease in any coronary artery
Generally diabetics and patient with reduced EF do better with surgical
revascularization in comparison to PCI/stenting
Antiplatelet should be held appropriately before elective CABG (clopidogrel 5 days,
tirofiban and eptifibatide about 6 hours, abciximab 24 to 48 hours and prophylactic
platelet transfusion)
Arterial grafts have better patency rate than venous graft
CABG associated with cognitive decline and neurological defects with no significant
difference between on-pump and off-pump (no aortic cannulation) approach
Refractory angina
Enhanced external counterpulsation is a treatment option for refractory angina
Transmyocardial laser revascularization; either percutaneous or through thoracotomy.
Its use is controversialit may reduce angina symptoms via unknown mechanism
Acute Coronary Syndrome (ACS)

ST segment elevation MI (STEMI), non-ST segment elevation MI (NSTEM), and unstable
angina
MI implies myocardial injury and necrosis, which result in cardiac enzymes leak that can be
detected in the serum
Troponin I and T are the main biomarkers (most specific) used to diagnose MI. Other
cardiac markers include CKMB and myoglobin (most sensitiveexcludes MI if negative)
Troponins stay elevated for at least a week so they cannot be used to evaluate recurrent
chest pain (e.g., patient had chest pain for a few days post MI had stent implantation,
myoglobin will be helpful in this situation to detect recurrent MI or stent thrombosis)
NSTEMI/unstable angina (UA)
Most patients with ACS have UA
Pathophysiology: Usually occurs as a result of acute plaque rupture but other causes
include vasospasm (Prinzmetal angina, cocaine abuse)
Presentation: Chest pain at rest, new onset angina, changing chronic angina
( frequency, in severity, longer duration, lower threshold). HF symptoms
Management
ECG should be done during 10 minutes from ER presentation if ACS suspected
Cardiac biomarkers should be measured (troponin start to increase in 3 hours and
peak in about 48 hours)

If initial EKG/cardiac biomarkers are normal serial ECG/biomarkers every 6 to 8
hours and reassessment of chest pain recurrent pain or biomarkers or change
in ECG (T inversion or ST depression) admission (continues EKG monitoring and
ACS protocol should be started)
If the follow-up cardiac biomarkers and ECG are negative with no recurrence of
chest pain arrange for stress test (to unmask ischemia, if any)
Medical treatment goals: To decrease cardiac oxygen consumption (b-blockers if
no contraindication, ACE inhibitor if blood pressure is high, and NTG/morphine to
relieve the pain), to maintain coronary flow and prevent thrombus formation and
progression
ST elevation myocardial infarction
Pathophysiology: Thrombus formation, which occlude the coronary artery flow. Usually
forms on top of rupture plaque or inside a coronary stent (stent thrombosis)
Presentation: Sudden onset severe retrosternal chest pain associated with ST- segment
elevation on the ECG. Biomarkers may be normal at initial presentation but increase
with time. Elderly (>75 years) patients more likely to have atypical presentation, silent
MI, LBBB and acute heart failure
Management
ECG should be done in 10 minutes from presentation
Relieving pain (morphine and NTG) and stabilizing blood pressure will ischemia
Reperfusion: The occluded artery should be opened as soon as possible to salvage
the myocardium. Reperfusion can be performed either directly by PCI (primary PCI)
or by fibrinolytics. PCI should be performed in <90 minutes (door to balloon time).
If the hospital has no PCI but can be transferred in <90 minutes to a PCI capable
hospital, the patient should be transferred. However, fibrinolytics should be the
treatment if the hospital has no PCI, the time needed to be transferred to other PCI
capable hospital is >90 minutes, and the patient presented within 12 hours since
chest pain started. Fibrinolytics should be administered within 30 minutes from the
1st patient contact (door to needle time)
Contraindication to fibrinolytics include previous intracranial bleed, cerebral AV
malformation or intracranial neoplasm, active bleeding, ischemic stroke in the past
3 months, and aortic dissection
Antiplatelet (aspirin, clopidogrel, and GP IIb/IIIa inhibitor) and parenteral
anticoagulants(heparin) shouldbe given to patients going for primary PCI
NTG sublingual should be given to relieve the pain; if failed, intravenous NTG can be
given. Contraindications: Hypotension, right ventricular failure, aortic stenosis, or if
phosphodiesterase inhibitor was taken <24 hours
Oral b-blockers prevent fatal arrhythmia and all patients should receive this therapy.
Contraindication to b-blockers include acute heart failure, cardiogenic shock,
bradycardia, heart block, or active asthma
ACE inhibitors should be administered to decrease cardiac remodeling
Statin should be started early with a high dose (e.g., atorvastatin 80 mg)
K+ and Mg++ are recommended to be >4 meq/L and 2.0 meq/L
Time of diagnosis is very crucial. The earlier the diagnosis the better the outcome.
The time since chest pain started is a very important prognostic factor (>12 hours
worse prognosis and less likely to benefit from reperfusion therapy)
Early risk stratification: Factors predicting mortality at presentation include:
Advanced age, heart failure at presentation, tachycardia, cardiogenic shock,
anterior MI, DM, renal failure and calculation of TIMI risk score for STEMI provides
precise information about the rate of in-hospital mortality
STEMI complications could be mechanical complication, usually after 48-hours and
include: Acute MR (papillary muscle rupture), VSD, free ventricular wall rupture
(risk: advanced age, 1st MI, NSAIDs, and steroid), pericarditis, and left ventricular
aneurysm
Conditions with normal coronaries and STEMI presentation include: Coronary
spasm, hypercoagulability, Takotsubo syndrome (stress induced cardiomyopathy),
cocaine use, collagen vascular disease, embolism, myocarditis, microvascular
disease
17.4 Heart Failure

Diagnosis and Evaluation of Heart Failure
Usually present with exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea,
dyspnea at rest
On cardiac examination, S3 sound can be heard and is an early pathologic sign that
indicates presence of heart failure
Lung crackles, jugular venous distention (indicates increased systemic venous pressure),
edema, hepatomegaly, pulsus alternans (advanced systolic dysfunction)are other findings
that support the diagnosis of heart failure
Cardiomegaly can be found in patients with chronic heart failure, but not in patients
with acute heart failure (acute MI, ruptured chordae), constrictive pericarditis, restrictive
cardiomyopathy, diastolic heart failure, or heart failure secondary to arrhythmias
Heart failure with preserved systolic function (diastolic heart failure) is an important under-
recognized cause of heart failure (the cause of heart failure in about 50% of patients)
Diagnostic testing
Echocardiography: The test of choice to assess the cardiac systolic and diastolic
function
Electrocardiography
BNP: Level <100 pg/mL indicates that the cause of shortness of breath is less likely
from the heart
Endomyocardial biopsy is indicated if a specific diagnosis is suspected or with new
onset cardiac failure and cardiogenic shock with no clear cause
Cardiac MRI can be helpful in identifying the cause of cardiomyopathies (ischemic,
infiltrative, arrhythmogenic right ventricular dysplasia)
Patients with new onset heart failure should be screened for hemochromatosis,
pheochromocytoma, thyroid disorder, and HIV

Therapeutic Options for Heart Failure
Table 17.6: Medications Used in Heart Failure Treatment

b-blockers Given to all patients with systolic heart failure, including asymptomatic
patients
It decreases mortality
b-blockers may exacerbate bronchospasm in patients with severe
COPD/asthmamore selective b-blockers (metoprolol, atenolol) can be
used in these patients
ACE inhibitor Decreases hospitalization, MI, morbidity and mortality in all patients,
including asymptomatic patients
May cause cough (increases bradykinin)
Maximizing the dose will not affect mortality
AR Blocker It can be given as an alternative to ACE inhibitors in patients who had
cough as a side effect
It may cause angioedema, hyperkalemia (less than ACE), renal impair-
ment as ACE (creatinine and K+ levels should be followed-up after
initiation of therapy)
Spironolactone Decreases mortality in patients with advanced heart failure (class III
and IV)
Contraindicated if K+ is above 5 or if the patient has renal failure
Eplerenone Can be used instead of spironolactone
Furosemide To manage volume overload
Bumetanide and torsemide can be used in patients who are resistant to
fursemide
Isosorbide dinitrate/ Decreases mortality in African American patients with advanced

hydralazine (BiDil) systolic heart failure
Implantable cardioverter-defibrillator (ICD) decreases mortality in patients with

symptomatic heart failure (class II and III) who have EF <35% or a history of
hemodynamically significant ventricular arrhythmia
Biventricular pacemaker (cardiac resynchronization therapy) improves the functional
capacity and heart failure symptoms
Decreases rates of readmissions and mortality
Indicated in symptomatic heart failure patients with EF <35% and who have wide QRS
(>120 ms)
Managing patients with heart failure symptoms who have preserved systolic function may
be viewed as controversial, but controlling exacerbating factors and managing volume
overload with diuretics is the mainstay of treatment. Candesartan has been suggested to
decrease the rate of hospitalization
Management of Chronic Heart Failure

Heart failure patients should be managed by a multidisciplinary team (heart failure
clinic with specialized heart failure nurses). This approach was found to decrease the
readmissions related to heart failure
Heart failure patients should have serial assessments of their functional status by NYHA
classification, 6-minute walking test, or cardiopulmonary exercise test
Volume status should be assessed serially by physical examination, patients weight, or
ultrasound of the inferior vena cava to assess its size. BNP can be measured if the volume
status is difficult to evaluate
Serial assessments of electrolytes, kidney function, and liver enzymes
Serial assessment of heart failure exacerbating factors
Reassessment of the systolic function by echocardiography should be performed only if
there is change in the clinical condition of the patient
Assessment of the patients prognosis will help in the management of heart failure and
discussing the different treatment options with the patient. There are several models that
can be used (ex.: Seattle Heart Failure Model [SHFM] is a calculator which estimates survival
at baseline, 1, 2, and 5 years in patients with systolic heart failure)
Acute Exacerbation of Chronic Heart Failure

Most common exacerbating factors are a high sodium diet and noncompliance to medicine,
followed by arrhythmias and superimposed infections. Uncontrolled hypertension and
cardiac ischemia are also important factors which should be considered in patients with
exacerbation
Cardiac ischemia is an important cause of heart failure exacerbation
Myocardial perfusion imaging may be needed in those patients with previous coronary
disease to look for reversible ischemia
Coronary angiography should be performed for patients who are newly diagnosed to
have heart failure and have a history or findings suggestive of cardiac ischemia
The volume status and signs of low cardiac output should be assessed carefully in patients
with decompensated heart failure
Patients with low cardiac output (cardiogenic shock) will have severe hypoperfusion and
signs of end organ damage (change in mental status, cool peripheries, and worsening of the
kidney function)
Treatment of cardiogenic shock should include inotropic support for patients with
inadequate perfusion
If hypoperfusion persists, an intra-aortic balloon pump should be considered
Volume status of the patient should be optimized at the same time
If the patient is still not improving, left ventricular assist device implantation may help
Cardiac transplantation would be the last resort for selected patients
Advanced Refractory Heart Failure

LVAD and cardiac transplantation are the only treatment options that can be life saving for
patients with advanced heart failure who, despite optimal therapy:
Developed cardiogenic shock
Were dependent on intravenous inotropic agents to keep an adequate organ perfusion
Functional capacity is severely limited by the heart failure or severe cardiac ischemia,
which is not amenable for surgical or percutaneous intervention
Have recurrent ventricular arrhythmias resistant to medical therapy

Other Therapies for Patients With Heart Failure
Ultrafiltration may help restore euvolemia in patients who have acute cardiac failure
decompensation and are resistant to diuretics
Vasopressin receptor blockers have recently been approved to treat heart failure associated
with hyponatremia
Specific Cardiomyopathies
Takotsubo cardiomyopathy (stress induced cardiomyopathy)
Is a transient acute cardiac systolic dysfunction with a similar presentation to
ST-segment elevation myocardial infarction (STEMI)
TTS usually affects elderly women and is characterized by a new cardiac motion
abnormality that commonly involves the apex of the left ventricle in the absence of
significant obstructive coronary artery disease
Acute, severe emotional or physical stress is believed to be the main precipitating
factor of TTS
Usually it is a benign condition and the systolic function returns to normal in few days
to few weeks
Acute myocarditis
Inflammation of the myocardium accompanied by myocellular necrosis
Can be asymptomatic or may be fulminantresults in severe heart failure symptoms
and cardiogenic shock
Usually the cardiac enzymes are elevated and the echocardiogram may show global
dysfunction and less frequently, regional motion abnormality
The treatment mainly is supportive
Tachycardia-mediated cardiomyopathy
Reversible left ventricular dysfunction usually results due to supraventricular
tachyarrhythmia. It has also been reported as a result of ventricular tachyarrhythmia
The myocardial high energy stores get depleted which will result in cellular and
structural changes
Treatment should be directed toward rate control
Cardiomyopathy is reversible, in weeks to months after heart rate control, in most
cases
Arrhythmogenic right ventricular dysplasia
An important cause of sudden death
Results from fibrofatty infiltration of the right ventricle
Right ventricle usually enlarged and has reduced systolic function while the left
ventricular function is preserved
ECG may show epsilon waves (positive deflection just after the QRS)
Usually diagnosed by cardiac MRI
Giant cell myocarditis
It causes congestive heart failure (biventricular enlargement) and frequently associated
with refractory ventricular arrhythmia
Usually presents as cardiogenic shock
A fatal form of myocarditis
Affects young adults
Heart transplant is the treatment of choice; however, it may recur after cardiac
transplantation
17.5 Myocardial Disease
Restrictive Cardiomyopathy
A non-dilated myocardial disease characterized by diastolic dysfunction with an increase in
filling pressureresults in pulmonary edema
Majority of the cases are idiopathic; however, amyloidosis is the most common identified
cause
Sarcoidosis and hemochromatosis are also important causes of restrictive cardiomyopathy.
Cardiac MRI is the diagnostic modality of choice to assist myocardial involvement
On examination: JVD, Kussmaul sign, ascites, and hepatomegaly
Echocardiographic findings that suggest amyloidosis include thickened valves, ventricular
hypertrophy (however, ECG will reveal low voltage), and pericardial effusion
Table 17.7: Differences Between Constrictive and Restrictive Disease

Constrictive Pericarditis Restrictive Cardiomyopathy
Large variation in ventricular filling pressure with Minimal variation in ventricular filling pressure with
respiration respiration
CT/ MRI will show thick pericardium Normal pericardial thickening
Elevated ventricular diastolic pressures Elevated diastolic pressure
Equalization of the diastolic pressure No equalization
BNP may be slightly elevated BNP IS HIGH (>800 pg/mL)
Treatment
Diuretics are used to treat the heart failure symptoms
b-blockers and non-dihydropyridines calcium channel blockers improve the relaxation
of the myocardium
Bradyarrhythmias and tachyarrhythmias should be avoided. A pacemaker is helpful in
symptomatic patients with bradycardia. Cardioverting patients with atrial fibrillation will
help improve the filling of the ventricle
Treatment of underlying cause will help in improving the diastolic function
In patients with hemochromatosis, frequent phlebotomy and chelating agents may
be helpful
In patients with sarcoidosis, the use of steroid therapy can improve survival
Stem cell transplant and cardiac transplantation in specific type of amyloidosis is
an option in patients with severe heart failure
Hypertrophic Cardiomyopathy
Genetic disordersusually inherited as autosomal dominant. Not all patients have family
history because of variable penetrance
Frequently affects African American males
Characterized by inappropriate left ventricular hypertrophic changes, which may affect any
region of the left ventricle, but can be diffuse
Interventricular septum is frequently the region that gets affected and may result in left
ventricular outflow obstruction with significant hemodynamic changes
The basal posterior segment usually spared

Patient has higher incidence of sudden death
Especially patients with a history of cardiac arrest or have a first-degree family history
of sudden death or ventricular tachycardia
Patients usually asymptomatic and diagnosed incidentally by screening echocardiograms
because of family history of the disease
Symptoms include chest pain, exertional shortness of breath, palpitation, dizziness, and
syncope
ECG usually shows LVH and ST-T wave changes
Echocardiogram will reveal hypertrophic changes, normal systolic function, relaxation
abnormality, and left atrial enlargement
Cardiac MRI (when the echocardiography is questionable) will reveal small areas of
hypertrophyby using gadolinium contrast, myocardial fibrosis can be detected
Asymptomatic patients have better prognosis. Symptoms result because of diastolic
dysfunction, outflow obstruction, atrial fibrillation, other arrhythmias, or because of dilated
cardiomyopathy (as the disease progresses)
Management
All patients with first-degree relatives affected should undergo screening
echocardiography
Once per year in adolescents
Every 5 years in adults
Patients with hypertrophic cardiomyopathy should avoid competitive sports and highly
strenuous activity
Vasodilators and inotropic agents should be avoided and diuretics should be used
cautiously
b-blocker is a first-line therapyimproves myocardial relaxation and increase LV
compliance
Asymptomatic patients who are at high risk of sudden death may benefit from
b-blocker
Amiodarone is the only drug proven to decrease the risk of cardiac sudden death
Patients with atrial fibrillation should be cardioverted back to sinus. Refractory and
recurrent rate should be controlleddioxin should be avoided
The implantable cardioverter defibrillator (ICD) has been used for the prevention of
sudden arrhythmic death in high risk patients
Myomectomy (either surgical or by alcohol ablation) should be the treatment in
patients who are refractory to medical treatment and symptomatic with outflow
obstruction
Cardiac Tumors
Most tumors of the heart have metastatic involvement
Primary heart tumors are very rare
Majority of primary cardiac tumors are benign
Usually diagnosed incidentally by echocardiogram
TEE or cardiac MRI/ CT is sometimes needed for better, more detailed images
Clinical manifestation may include constitutional symptoms, systemic embolization (stroke,
TIA), mechanical obstruction of the heart valve or outflow tract, valve regurgitation,
arrhythmia, and heart failure symptoms
Atrial myxoma is the most common type of primary tumors
Originate in the left atrium and widely differ in size
Can be part of the Carney complex (an autosomal dominant disorder which includes
cardiac and extracardiac neoplasms)
Myxoma should be resected to decrease the risk of systemic embolization and risk of
sudden death
17.6 Arrhythmias
Antiarrhythmic Agents
Table 17.8: Antiarrhythmics

Antiarrhythmic Mechanism of Action Drugs
Classification
IA Sodium channel blocker Procainamide, quinidine, disopyramide
IB Lidocaine, mexiletine
IC Flecainide, propafenone
II b-blocker Metoprolol, atenolol, propranolol
III Potassium channel blocker Sotalol, dofetilide, ibutilide, amiodarone
IV Calcium channel blocker Diltiazem, verapamil
Class IA
Causes QT prolongation
Chronic use of procainamide is associated with lupus
Disopyramide is effective in treating parasympathetic mediated atrial fibrillation
Class IB
They are not used in atrial fibrillation management because of minimal effect on the
atrium
Class IC
The QRS duration should be monitored since they may cause widening of QRS
Should not be used in patients with structural heart disease or post-MI ( mortality)
Not used alone in managing atrial fibrillation. Should be used with b-blocker or calcium
channel blocker to slow the conduction through the AV node since class IC may result
in conversion of atrial fibrillation to atrial flutter with 1:1 conduction
Class III
Sotalol: A mixture of isomers (l-sotalol and d-sotalol)
Contraindicated in decompensated heart failure and can cause QT prolongation
Dofetilide: Contraindicated if QT interval is prolonged at baseline. ECG should be
obtained at baseline and after each dose to follow the QT interval
If QTc exceeded 500 ms it should be stopped
Dofetilide is not contraindicated in heart failure

Bradycardia
HR is <60 BPM. ECG is needed to analyze the rhythm. If the bradycardia is associated with
symptoms (weakness, dyspnea, syncope), it is pathologic and the underlying cause should
be identified with 24-hour ECG monitoring or event monitoring and treated or a pacemaker
should be inserted
Low heart rate is normal finding and usually asymptomatic in athletes
Common causes include medications, electrolytes disturbances, hypothyroidism, coronary
disease, and Lyme disease
Sick Sinus Syndrome/Sinus Node Dysfunction

Affects mainly the elderly
Commonly associated with atrial fibrillation/flutter and this will result in tachycardia-
bradycardia syndrome
Treatment: Pacemaker
Atrioventricular Block
There is abnormal conduction of the electrical impulse through the AV node and
conduction system because of fibrosis and degeneration of the electrical conduction
system
Coronary artery disease and medications are also important causes to be excluded
Table 17.9: AV Blocks

1st-degree block PR Interval >200 ms Usually asymptomatic
2nd-degree block Mobitz-I (Wenckebach block): Progressive PR interval prolongation followed
by P wave, which is not conducted to ventricle. Frequently asymptomatic
and does not need treatment
Mobitz-II: PR interval is constant in several beats then followed by loss of
conduction of the P wave to the ventricle. If symptomatic and no reversible
cause pacemaker is indicated
3rd-degree block The atrial conductions are not conducted to ventricle. The atrial rate > ventricu-
lar rate. If no reversible cause, pacemaker is the treatment
AV Dissociation
The atrial and ventricle are beating independently. Usually the ventricular rate is the same or
higher than the atrial rate
Tachycardia
ECG should be obtained during the episode of palpitation.Holter monitor often needed to
record the tachycardia
Management: 3 steps are important to follow for appropriate management
Identify if the patient is stable or not; if hemodynamic instability is present,
cardioversion is the appropriate treatment
Check if the rhythm is regular (SVT or ventricular tachycardia) or irregular (atrial
fibrillation)
Calculate QRS duration: If QRS >120 ms (wide complex): Ventricular tachycardia (VT),
SVT with aberrant conduction or ventricular pre-excitation (accessory pathway). VT
should be differentiated from the other forms of wide complex tachycardia, otherwise
should be treated as VT. If QRS <120 (narrow complex): SVT. Adenosine, calcium
channel blocker or b-blocker is the treatment for stable patients
Atrial Fibrillation
Most common arrhythmia in clinical practice
It is either paroxysmal, persistent, or permanent
Clinical presentation: It can be asymptomatic but common symptoms at presentation
include palpitation, dyspnea, and dizziness. Thromboembolism may result in stroke,
acute limb ischemia, and renal embolism (acute kidney injury, decrease urine output, and
eosinophils in urine)
If the heart rate is not controlled it may result in tachycardia induced cardiomyopathies
Atrial fibrillation commonly associated with hypertension, valvular heart disease, coronary
heart disease, and cardiomyopathies
Atrial fibrillation is a common complication of cardiac surgery
Atrial fibrillation patients should be evaluated for reversible causes which include; thyroid
disorder, coronary artery disease, alcohol use, myocarditis, pericarditis, and pulmonary
embolism
Acute Management
If the patient is not stable or developed cardiac ischemia secondary to uncontrolled atrial
fibrillation, cardioversion should be performed
If the patient is stable the rate can be controlled using b-blocker or calcium channel
blocker. Digoxin can be added particularly in elderly and those with heart failure
AV nodal blocking agents are contraindicated in patients with preexisted atrial fibrillation
because it may increase the conduction through the accessory pathway and can lead to
ventricular fibrillation
If the patient has atrial fibrillation for less than 48 hours, synchronized cardioversion can
be performed without anticoagulation
If the patient has atrial fibrillation for longer than 48 hours or if the duration is unknown,
the patient can either be anticoagulated with intravenous heparin and can undergo
synchronized cardioversion if intra-cardiac clot was excluded by transesophageal
echocardiogram, or the anticoagulation can be continued for 3 weeks and the INR should
be between 2 to 3, then synchronized cardioversion can be arranged
All patients who underwent either mechanical or pharmacological cardioversion should
be anticoagulated for 4 weeks (atrial mechanical dissociation risk of clot formation post
cardioversion)
In patients who have pacemakers and intracardiac defibrillators cardioversion is safe but
pads should be away from them
Long-term Management
Rate control
Commonly using b-blocker and nondihydropyridine calcium channel blocker
The heart rate at rest should be less than 80. The heart rate when exercising should
be less than 115 beats/minute
Controlling the heart rate will prevent tachycardia induced cardiomyopathy

If controlling heart rate is not achievable after several agents were used, the only
choice will be atrioventricular junction ablation and permanent pacemaker
Rhythm control (maintaining sinus rhythm)
Does not improve survival and does not decrease risk of stroke but may improve the
quality of life
To maintain sinus rhythm, amiodarone is the preferred drug especially if there is
structural heart disease. Class IC also can be used but should be used with AV nodal
blocking agents
Radiofrequency ablation can be performed for patients who cannot tolerate the rate
control strategy and failed rhythm control. Success rate >80%
Maze procedure is a surgical procedure to treat atrial fibrillationusually performed if
other cardiac surgery is indicated. It has high success rate
Anticoagulation
Reduces the risk of stroke
CHADS2 should be calculated in patients with atrial fibrillation. One point is given
for the presence of chronic heart failure, hypertension, age above 75 years, diabetes
mellitus and 2 points for history of stroke or transient ischemic attack
If the risk of stroke is high according to CHADS2 (>2), warfarin is indicated and INR
should be maintained between 2 to 3
Atrial Flutter
Clinical Presentation and Evaluation
Common symptoms include palpitations, fatigue, dizziness, and mild dyspnea
Atrial flutter can be as a result of cardiac disease (post cardiac surgery, congenital
cardiac anomaly, cardiac ischemia, sick sinus disease, cardiomyopathies, HTN, valvular
disease) or associated with systemic disease (pulmonary embolism, chronic obstructive
pulmonary disease, diabetes, hyperthyroidism, obesity) or may result from substance
abuse (commonly alcohol and cocaine)
ECG is important to confirm the diagnosis and determining the type
Echocardiogram can help assess the systolic function, size of the atria, valve disease
(rheumatic mitral valve disease), and presence of intracardiac thrombus
Acute Management
If the patient is hemodynamically unstable, synchronized electrical cardioversion is the
appropriate treatment
Pharmacologic cardioversion (Class III antiarrhythmics: Ibutilide is the most effective) can
be tried in stable patients
If atrial flutter is more than 48 hours or of unknown duration, TEE or anticoagulation for 3
weeks should be performed before cardioversion (similar to atrial fibrillation)
Rate control can commonly be achieved using b-blockers and nondihydropyridine
calcium channel blockers
Chronic Management
If atrial flutter is recurrent, radiofrequency ablation is the treatment of choice with high
success rate
Anticoagulation therapy post ablation treatment is needed in patient with high CHADS2
score
Supraventricular Tachycardia
AV nodal reentrant tachycardia (AVNRT) is the most common followed by AV reentrant
tachycardia (AVRT). Atrial tachycardia is the least common
2 types of AVNRT:
Typical: The conduction to ventricle is through the slow pathway and retrograde
conduction through the fast pathway (short RP)
Atypical: The conduction to ventricle is through the fast pathway and retrograde
conduction through the slow pathway (long RP)
AVRT: There is accessory pathway conducts from the atrium to ventricle. If the accessory
pathway conducts anterograde, the ventricular preexcitation can be seen as delta waves.
However, if the accessory tracts only conducts retrograde, it will not be identified by ECG
and will be called concealed
Episodes of palpitation start and terminate abruptly. Symptoms can differ widely from
mild dyspnea to syncope
Frequently, event-monitor is needed to capture the arrhythmia
Underlying exacerbation condition should be excluded including anemia, hyperthyroidism,
and sepsis
Patient with WPW syndrome who had SVT should have the accessory pathway ablated
since they are at risk of sudden death (first-line therapy)
Acute Management
Carotid massage and other vagus-nerve stimulating maneuvers should be tried first in
stable patients
Adenosine (IV bolus, contraindicated in severe asthma) usually effective in terminating
AVNRT/AVRT
Other drugs include intravenous calcium channel blocker, intravenous b-blockers, and
amiodarone
Synchronized cardioversion should be the treatment in patients who are
hemodynamically unstable
Atrial tachycardia is usually resistant to cardioversion and adenosine (enhanced atomicity
mechanism)
Long-term Management
If SVT episodes are infrequent, observation and avoiding exacerbating factors would be
appropriate
b-blockers and calcium channel blockers can be used to decrease the recurrence.
However, they should be used cautiously in patients with WPW syndrome
Ablation has a high success rate (AVNRT/AVRT more success than atrial tachycardia)
Premature Ventricular Complexes

Usually asymptomatic but occasionally causes palpitation
It has no significance in young patients except if associated with cardiac disease. Then it is
associated with higher mortality
Management: Reassurance (if there is no associated cardiac disease). Treatment only in
symptomatic patient (b-blocker and calcium channel blocker). Radiofrequency ablation can
be the treatment in refractory PVCs with severe symptoms

Nonsustained Ventricular Tachycardia
It is ventricular tachycardia less than 30 seconds
Seen primarily in the elderly and patients with cardiomyopathies, especially if the systolic
function is depressed
It is associated with increased mortality except if it occurs in patients who have no
structural heart disease
Management: Reversible causes should be addressed first (e.g., ischemia). Symptomatic
patients managed mainly by b-blocker. Radiofrequency ablation can be used in patients
who are refractory for treatment
Suppression of NSVT did not decrease the risk of sudden death
Intra-cardiac defibrillator (ICD) is indicated in patients with EF <35% (decreases the risk of
sudden death)
Sustained Ventricular Tachycardia (V-tach)

V-tach more than 30 seconds
Usually results from myocardial scar (previous MI) and non-ischemic cardiomyopathy
ICD is the only treatment that decreases mortality. Indicated in patients with ischemic and
non-ischemic cardiomyopathy who have EF <35%
Other causes include: Idiopathic V-tach (usually benign, originates from the right ventricle
out-flow and suppressed by calcium channel blocker/b-blocker), arrhythmogenic right
ventricular dysplasia (MRI is diagnosticit shows fibrous and fatty tissue replacing part of
the right ventricular myocardium)
Sudden Cardiac Death (SCD)

Unexpected death in a short time period (<1 hour of symptom onset) secondary to cardiac
causes
Most deaths are related to cardiac arrhythmia (frequently ventricular fibrillation rhythm)
SCD most commonly associated with structural heart disease (MI and post-MI remodeling)
Left ventricular systolic dysfunction is the most important predictor of SCD
Acute management
ACLS guidelines should be followed
Defibrillation is the mainstay of the acute therapy of sudden death due to ventricular
arrhythmia. Amiodarone is the antiarrhythmic agent of choice if defibrillation was
unsuccessful
Induction of hypothermia limits neurologic injury in those patients
If the underlying cause of sudden death is asystole or pulses electrical activity than
reversible causes should be investigated
Long-term management
Secondary prevention using ICD, not antiarrhythmic agents, decreases mortality
Primary prevention using ICD is considered standard of care for most patients with
LVEF <35%
Long QTc Syndrome
Rare congenital disorderpredisposes patients to Torsade de Pointes and sudden death
The most common form is Romano-Ward syndrome (autosomal dominant pattern of
inheritance and not associated with deafness). The other less common form is Jervell-
Lange-Nielsen syndrome (autosomal-recessive pattern of inheritance and associated with
congenital deafness)
b-blockers are first-line therapy and have been shown to decrease overall mortality
ICD is indicated in patients with recurrent symptoms
Short QT Syndrome
QTc interval <300 ms and usually associated with peaked T waves
Inherited (ryanodine receptor mutation)
Polymorphic V-tach usually happens during emotional stress or activity
ICD placement may be considered to prevent V-tach and SCD
It is associated with increased sudden death
Brugada Syndrome
Brugada pattern is characterized by J-point elevation in V1-V3 and right bundle branch
block morphology
These changes can be intermittent and can be precipitated by several factors including
fever and electrolytes disturbances
If the Brugada pattern ECG changes associated with syncope, it is called Brugada
syndrome and has increased risk of sudden death
17.7 Pericardial Disease

Pericardial Effusion
Several causes include pericarditis, malignancy, radiation, trauma, infection (HIV, TB,
bacterial), hypothyroidism, connective tissue disease, and uremia
Cardiac tamponade can result from any type of pericarditis or bleeding into the pericardium
(chest trauma or during catheterization). It causes pulmonary congestion and decreases the
cardiac output
Symptoms depend on the size of effusion and the etiology. It can be asymptomatic
if small or may lead to shortness of breath if large. It also may be life threatening and
lead to hemodynamic instability if accumulates rapidly and in large amounts (cardiac
tamponade). Tachycardia, JVD, distant heart sound, pulsus paradoxus ( systolic
pressure with inspiration >10 mmHg), and hypotension can be detected by physical
examination of patients with tamponade
ECG: Will show low voltage and/or electrical alternant
Echocardiogram will show the size of effusion. If any right atrial collapse during expiration
or right ventricular collapse during diastole
Management: Identify and treat underlying cause. If tamponade, pericardiocentesis
should be performed and the fluid should be sent for gram stain/culture and cytologic
examination
Acute Pericarditis
Idiopathic (majority)other common causes include: Infectious, uremic, malignancy,
radiation, collagen vascular disease, post-MI, and medications
Past medical history should be reviewed for clues to specific etiologies

Clinical presentation: Pleuritic chest pain when supine and in setting forward. Radiation
to trapezius ridge is highly specific. Recent symptoms suggesting a viral syndrome is
common
On examination, friction rub can be heard in most patients
ECG stages include coved upward (in MI convex upward), diffuse ST-segment in all leads
(except aVR), PR-segment depression is also common normalization of the ECG ST
segment and T wave inversion normalization of the ECG
ESR, leukocytes, and mild lymphocytosis are common in acute idiopathic pericarditis.
cardiac biomarkers (concomitant myocarditis), AV block a clue for Lyme disease
diagnosis, QRS voltage and electrical alternans indicates associated effusion
Echocardiogram (look for effusion and to assess systolic function)
Post-MI pericarditis (few days post-MI or delayed few weeks [Dressler syndrome]),
incidence because of early reperfusion therapy
Management
Acute idiopathic pericarditis self-limitedthe majority has no significant
complications, treated with NSAIDs or acetaminophen at labeled doses. If not
adequate, colchicine or narcotic analgesics should be added
Prednisone should be avoided as initial treatment
Complications are infrequent and include: Tamponade, recurrent pericarditis, and
constrictive pericarditis
Relapsing and recurrent pericarditis: 15 to 30% of patients with acute pericarditis may
relapse and may need a 2nd 2-week course of an NSAID. Minority of patients may
develop recurrent episodes. They may need colchicine prophylaxis (should be worked
up for specific causes, especially autoimmune disorders)
Constrictive Pericarditis
Common causes include: Post-pericarditis, post-radiation, post-cardiac surgery, and
tuberculosis
Physical examination: Jugular venous distension, hepatomegaly, ascites, and peripheral
edema. Early diastolic knock and Kussmaul sign can also be found. Constrictive
pericarditis does not usually cause pulsus paradoxus
Calcification of the pericardium (in up to 50% of patients) can be best visualized on the
lateral projection. CT scan and cardiac MRI will show thickening in most cases
The diagnosis can be confirmed by cardiac catheterization which reveals elevation and
equalization of diastolic pressures in each of the cardiac chambers
Unlike cardiac tamponade, there is a prominent descent of the right atrial pressure tracing
Treatment of constrictive pericarditis requires surgical removal of the rigid pericardium
17.8 Valvular Heart Disease

Diagnosis and Evaluation of Valvular Heart Disease
Patient presentation varies according to severity and the acuteness of valve disease. Can
be diagnosed incidentally because heart murmur is heard or can present with heart failure
symptoms
Transthoracic echocardiography is the test of choice to assess the cardiac valves
Echocardiography is indicated in:
Symptomatic patients
Patients with heart murmur (continuous, at least moderate-intensity systolic murmur, or
diastolic murmur)
BNP has a prognostic value and helps with understanding the hemodynamic significance of
the valve lesion
General Approach in Managing Valvular Disease

If the patient is asymptomatic at follow-up, echocardiogram is indicated to assess the
progression of the valve lesion and to measure the ventricular size and pulmonary pressure
If the patient started to develop symptoms that are attributable to valve disease then
surgical or other valve intervention should be performed
Valve repair or replacement should be performed (in severe valve disease regardless of the
symptoms) if the patient is undergoing other heart surgery
Aortic Stenosis (AS)

Outflow obstruction leads to an increase in left ventricular (LV) systolic pressure left
ventricular hypertrophy diastolic compliance is reduced systolic function reduced
Calcific-aortic stenosis is the most common cause. Usually affects the elderly (2% of people
<65 years). It is not the normal aging process but active and complex disease process
which encompass inflammatory and proliferative changes
Other causes include congenital valvular AS (e.g., bicuspid aortic valveusually manifests in
adults) and rheumatic AS (rare in the US)
Risk factors for calcific-aortic stenosis include aging, dyslipidemia, diabetes, hypertension,
tobacco use, and male gender
Aortic sclerosis (thickening of the aortic leaflets without obstruction of the flow) is a
precursor for calcific AS
Increases in incidence with age (29% of individuals older than 65 years)
It is a marker of atherosclerosis and associated with increased risk of cardiac events
and cardiovascular mortality
Bicuspid aortic valve
The abnormal valve will cause turbulent flow with continuous trauma to the leaflets. It
ultimately will result in fibrosis, leaflet calcification and narrowing of the aortic orifice in
the 4th and 5th decades
The aortic root and thoracic aorta should be assessed for dilatation and coarctation,
respectively, using cardiac MRI or CT
Exertional dyspnea is the most common initial complaint
Ultimately, patients will experience the classic triad of angina, heart failure, andsyncope
( cerebral perfusion; can be precipitated by vasodilatation: Exercise, nitroglycerin)
Patient may have diminished carotid pulse amplitude (pulsus parvus et tardus)
Crescendo-decrescendo systolic murmur can be heard by auscultation (intensity does
not correlate with the severity of stenosis, but timing of the peak and murmur duration
indicates the severity)
A2 is usually diminished or absent
Paradoxical splitting may be present (as a result of late closure of A2)
Prominent S4 can be heard and indicates significant aortic stenosis in young patients

2
AS is considered severe (by echocardiography) if the valve area is less than 1 cm
transvalvular mean pressure gradient >40 mmHg, and transvalvular jet velocity above 4 ms
Management
Asymptomatic patients, even with severe stenosis, have an excellent prognosis for
survival but should have echocardiography every year (to follow the pulmonary
pressure, LV function, and dimensions)
Inducing symptoms by exercise stress test and measurements of BNP may help in
predicting the symptom onset
Symptomatic patients with severe AS have high risk of sudden cardiac death
Aortic valve replacement is the mainstay of treatment in patients with symptomatic
severe AS and in patients who have severe asymptomatic AS with systolic dysfunction,
and young women who have severe AS and are planning to get pregnant
Aortic Regurgitation
May result from valve disease or root pathology
Can be acute (medical emergency) or chronic
Acute Aortic Regurgitation
Common causes include: Aortic dissection (type A), infective endocarditis, chest trauma,
and malfunction of prosthetic valve
The LV is not dilated so acute change in volume load will result in rapid increase in the
end-diastolic pressure and pulmonary edema will develop
Typically patients present with sudden dyspnea which may rapidly progress to heart
failure, chest pain ( myocardial perfusion pressure), and cardiogenic shock
On examination S1 will be soft and S3 may be present. Short diastolic murmur can be
heard; however, if the patient has tachycardia it can be inaudible
Acute severe AR has high rates of morbidity and mortality
Transthoracic echocardiography should be the diagnostic modality of choice if acute AR
is suspected
Transesophageal echocardiogram, CT, or MRI should be performed if dissection is
suspected as mechanism of the acute AR
Intra-aortic balloon pump is contraindicated in AR
Surgical intervention is usually the treatment
Chronic Aortic Regurgitation
Causes gradual increase in ventricular volume which results in ventricular enlargement
and hypertrophy
In early stages the ejection fraction (EF) is normal or even increased and patients may
remain asymptomatic during this time. However, as AR progresses the left ventricle
cannot accommodate the increase in volume and diastolic pressure begins to rise,
resulting in symptoms. Later, LV will enlarge and the EF starts falling to normal and then
subnormal levels
Usually patients presents with palpitations, shortness of breath, and chest pain
On physical examination, the point of maximal impulse usually diffuses and is
hyperdynamic. Pulses are bounding. S3gallop (LV dysfunction), high-pitched diastolic
murmur (duration of murmur correlates with the severity) and Austin Flint murmur
(middiastolic low-pitched murmur results from early closure of the mitral valve by aortic
regurgitant jet) may be audible on auscultation
Bicuspid aortic valve, infective endocarditis, aortic valve prolapse, connective tissue
disorders, rheumatic fever, aortitis (ankylosing spondylitis, Behet disease, Giant cell
arteritis, Takayasu arteritis), rheumatoid arthritis (by forming granulomatous nodules
within the valve leaflets) are possible causes of AR
Aorticvalve replacement is recommended for patients:
With chronic severe AR who are symptomatic or resting EF of <55%
Who are asymptomatic, with LV end-systolic dimension >55 mm
Mitral Stenosis
Causes obstruction of the left ventricular inflow at the level of mitral valve
Rheumatic fever is the most common cause of mitral stenosis (commissural adhesion)
The clinical presentation of rheumatic mitral stenosis is usually between the 4th and 5th
decades but can present earlier if the disease is severe
Other etiologies include congenital mitral stenosis, carcinoid disease, systemic lupus
erythematosus,rheumatoid arthritis, severe mitral annular calcification, infective
endocarditis with large vegetation, left atrial myxoma, mechanical valve thrombus, or cor
triatriatum (congenital anomaly of the atrium)
Mitral valve is usually above 4 cm2. If the area started to decrease by valve pathology the
pressure gradient across the valve will start to rise to maintain the flow. If the pressure
gradient is more than 10 mmHg and the valve area less than 1 cm2, the stenosis is
considered severe
Clinical presentation includes dyspnea on minimal exertion or at rest. Hemoptysis (because
of bronchial venule rupture), hoarseness (the enlarged atrium will compress the recurrent
laryngeal nerve), frequent coughing (bronchial irritation by enlarge atrium), and atrial
fibrillation (risk of systemic embolization)
Physical examination will reveal jugular vein distension.Right ventricular lift can be felt in
patients with pulmonary hypertension. Opening snap (will be closer to S2 in severe MS)
followed by low pitch, and diastolic murmur, which is best heard at the apex (duration
correlates with the severity). The murmur gets louder near the end of diastole. The murmur
gets softer with Valsalva and louder with exercise. Diastolic murmur, because of pulmonary
regurgitation, can also be heard
Management
Rate control is very important in patients, especially with atrial fibrillation to prolong the
filling time of the ventricle
Percutaneous balloon valvotomy is indicated (if the valve morphology is favorable
for balloon valvotomy, otherwise surgical commissurotomy or MVR) in symptomatic
patients (mitral area less <1.5 cm2), asymptomatic with valve area 1.5 and have resting
pulmonary hypertension (PASP >50 mmHg), or exercise induced pulmonary HTN
(PASP >60 mmHg)
Mitral Regurgitation
Chronic MR
Common causes includemitral valve prolapse (MVP), rheumaticcardiac disease, infective
endocarditis, mitral annular calcification (mainly in elderly), cardiomyopathy (usually
because of dilatation of the annulus) and cardiac ischemia (causes dysfunctional papillary
muscle or tethering of the mitral leaflet)

The left atrium (LA) and ventricle dilate over time to accommodate the extra volume. In
addition, the left ventricle gets hypertrophic and the systolic function will be normal to
hyperdynamic. Ultimately the left atrial pressure increases and ventricular systolic function
decreases which will lead to pulmonary edema
On examination, patients usually have high-pitched pan-systolic murmur best heard at the
apex and radiates to axilla
S2 can be widely splitting because the aortic valve closes very early
S3 is frequently heard
P2 can be loud if pulmonary hypertension developed
Mid-systolic click followed by systolic murmur can be heard in MVP patients
Management
2D-echocardiography is the test of choice to diagnose and assess the severity of MR
and its effect on the LV function, dimension, atrial size, and pulmonary pressure
Yearly transthoracic echocardiography is indicated in patients with moderate MR and
every 6 months in patients who are asymptomatic with severe MR
Transesophageal echocardiography should be performed for patient with severe
MR who are going to have surgery to assess the etiology of MR and if valve can be
repaired
Treatment should include antihypertensive (to decrease afterload) and diuretics
If the patient has atrial fibrillation the rate should be controlled
In patients with dilated cardiomyopathy associated MR the use of biventricular
pacemaker can help decrease the regurgitation severity
Mitral valve repair is preferred over replacement, if possible
Mitral valve surgery is indicated:
In symptomatic patients with EF >30% and/or LV dimension at end systole (by
echocardiogram) <55 mm
In asymptomatic patients the surgery is indicated if the EF <60 and/or dimension
at end systole is >40 mm
If the asymptomatic patients developed new onset atrial fibrillation or the
pulmonary artery pressure started to increase
Acute MR
Ruptured chordae tendineae, papillary muscle dysfunction, a flail valve leaflet, or infective
endocarditis are frequent etiologies of acute MR
Severe dyspnea due to pulmonary edema and hypotension is a frequent initial
presentation of patients with significant acute MR
On examination, patients usually have signs of hypoperfusion (peripheral vasoconstriction,
pallor)
Tachycardiac with low volume pulse. The apex of the heart usually not displaced but
hyperdynamic
Auscultation of the heart may reveal soft decrescendo systolic murmur
Management
Electrocardiogramwill help in identifying the etiology (inferior MI)
Chest X-ray will show normal size cardiac silhouette with pulmonary edema changes
Echocardiogram will establish the diagnosis and identify the etiology of acute MR in
most cases
Usually patients are hemodynamically unstable and need urgent surgery. Temporary
hemodynamic support can be achieved by intra-aortic balloon pump
Mitral Valve Prolapse
MVP is the most common valvular pathology (prevalence of 2%)
The distribution is about the same in both genders
Most patients are asymptomatic but some patients may present with atypical chest
pain and symptoms related to autonomic dysfunction (palpitation, anxiety, orthostasis,
presyncope, syncope)
Usually it is a benign condition but infrequently complications may happen which include
mitral regurgitation (which can progress to sever form in spite of medical therapy),
endocarditis, arrhythmia and sudden cardiac death
The majority of patients with Marfan syndrome have MVP
On examination, midsystolic click can be heard (systolic buckling of the redundant mitral
leaflet) followed by short systolic murmur
MVP is diagnosed by transthoracic echocardiogram (shows thickening of the mitral leaflet
and mitral leaflet prolapsing into the left atrium more than 2 mm)
Tricuspid Valve Disease

Most common cause of the tricuspid regurgitation is left side heart failure which increases
the pulmonary pressure and results in dilation of the tricuspid annulus and malcoaptation of
the leaflets
Other important causes include core pulmonale, infective endocarditis, pacemaker, or
defibrillator wire crossing the valve, carcinoid, rheumatic valve disease, medications for
weight loss (fenfluramine and dexfenfluramine), to treat migraine (e.g., methysergide), and
to treat Parkinson's disease (e.g., pergolide)
Ebstein anomaly (displacement of the valve toward the apex)is the most common
congenital form of tricuspid regurgitation
The majority of patients are asymptomatic and diagnosed incidentally by echo to have mild
to moderate regurgitation. Severe regurgitation usually causes right sided heart failure and
may result in ascites and peripheral edema
Management includes treating overload state by diuretics and in severe cases valve
anuloplasty or bioprosthetic (not mechanical) valve replacement can be performed
Endocarditis
Should be suspected in patients with fever and new heart murmur
High risk patients include those with underlying valve disease, prosthetic valves, history of
infective endocarditis (IE), and immunosuppressed patients
Mechanical and bioprosthetic valves have the same long-term risk of infective endocarditis;
however, immediately after valve implantation the mechanical valve has higher risk
Endocarditis commonly leads to CNS embolization. The risk of embolization varies
according to valve and organism. Mitral valve infection and Staphylococcusspecies
infection are the most important determinants of embolization
Staph Aureus and Streptococcus species are common microorganisms to cause infective
endocarditis
Blood cultures are usually positive for microorganisms; however, culture-negative
endocarditis may result from partial treatment with antibiotics. Some organisms may result
in negative blood cultures and include Haemophilus,Actinobacillosiscardiobacterium
hominis, Eikenella corrodens, and Kingella

The clinical criteria to diagnose IE takes into consideration the clinical presentation and
patient risk factors, blood culture, and echocardiographic evidence of IE
Transesophageal echocardiogram has higher sensitivity and specificity for IE in comparison
to transthoracic echo
Initial management includes antibiotic therapy in stable patients
Surgery is the treatment in hemodynamically unstable patients, patients with heart failure
symptoms (severe regurgitation), AV block, resistant infection, fungal infection with large
vegetation, or recurrent embolization
Prophylaxis antibiotics are indicated in patients with:
Prosthetic valve
History of IE
Heart-transplanted patients with valve disease
Patients with unrepaired cyanotic congenital heart disease
Prosthetic Valves
There are 2 types of prosthetic valves: Bioprosthetic and mechanical valves
Bioprosthetic
Less durable than mechanical valves because of calcification and degeneration
All patients should be on low-dose aspirin
Warfarin is only indicated for mitral bioprosthetic valve in the first 3 months post surgery,
otherwise no anticoagulation is needed for bioprosthetic valves
Mechanical Valve
All patients should be anticoagulated with warfarin and should be on low-dose aspirin.
The INR target depends on the location of the valve and the patient risk factors
Mechanical aortic valve should have INR of 2 to 3 unless they are at higher risk
for thrombus formation (atrial fibrillation, depressed systolic function, history of
thromboembolism, or hypercoagulable state) the INR should be 2.5 to 3.5
For mechanical mitral valve (low-flow valve with large area) the INR should be 2.5 to 3.5
Prosthetic valve complication includes: Primary valve dysfunction, valve thrombosis,
endocarditis, thromboembolism, and hemorrhage
Transesophageal echocardiogram is the test of choice to evaluate the prosthetic valve
Surgery is the treatment of choice in patients with valve thrombus who present with
heart failure
17.9 Adult Congenital Heart Disease (CHD)

Adult patients with congenital cardiac disease are estimated to be more than a million
More patients with CHD are expected to live and be adult as a result of new surgical and
medical care advances
Table 17.10: Conginital Cardiac Defects
Atrial Septal Most common CHD in adults 2nd to bicuspid aortic valve
Defect Left to right shunt
Lead to right ventricle volume overload and pulmonary hypertension
Fixed wide splitting of S2, pulmonic systolic murmur usually present due to increased
flow across the pulmonary circulation, and prominent right ventricular impulse may
present
ECG: Shows incomplete right bundle branch block with right axis deviation (in secun-
dum ASD) and left axis deviation in primum ASD
Transthoracic echocardiography is the test of choicereveals right atrial dilation, elevat-
ed pulmonary pressure, and can detect the septum defect
Secundum, primum, and sinus venosus ASDs should be repaired if symptomatic, or evi-
dence of increased pulmonary flow in comparison to systemic flow (Qp:Qs 1.5:1)
Ventricular The most common type of VSD is perimembranoustype
Septal Small VSD are usually asymptomatic but may produce loud systolic murmur. It closes
Defect (VSD)
spontaneously and if persistent, it does not need closure
Echocardiogram can identify the size, location, and cardiac chamber changes associated
with the defect
Patent Frequently results because of maternal rubella infection
Ductus On physical examination, machinery-type continuous murmur (Gibson murmur) can be
Arteriosus heard and pulse pressure is widened
(PDA)
Color Doppler echocardiography is the test of choice to detect the PDA flow
If small and asymptomatic with no history of infective of endocarditis there is no treat-
ment, only observation
If moderate size with left ventricular overload, percutaneous closure of PDA is recom-
mended if there is no pulmonary hypertension. Otherwise, it is contraindicated to close it
Aortic Most commonly involves the descending aortic segment distal to left subclavian artery
Coarctation origin
More commonly affects males
Frequently associated bicuspid aortic valve. May also be associated with Turner syndrome
and intracranial aneurysm
Chest X-ray may show figure 3 sign (result from pre-stenotic and post-stenotic dilata-
tion of the aorta). Notching of the ribs (from collaterals) can be identified by X-ray
Echocardiogram with supra-sternal view can identify coarctation. Pressure gradient
across the narrowing should be measured
MRA and spiral CT is recommended to assess the entire aorta
Treatment: Surgical correction of the segment is indicated in patients with high-pressure
gradient across the coarctation (>20 mmHg)
Pulmonary Associated with Noonan syndrome
Stenosis Echocardiography is the test of choice to evaluate the right ventricle and Doppler evalu-
ation of the pulmonic valve will determine the severity of the stenosis
Balloon valvuloplasty is the treatment of choice
Tetralogy of Overriding aorta, VSD pulmonary outflow stenosis, and right ventricular hypertrophy.
Fallot (TOF) ASD may present in small portion (pentalogy of Fallot)
Cyanotic and cannot live without correction
Surgical repair before the age of 1 year
Sudden death, secondary to ventricular arrhythmias, is considered the most common
cause of late death post repair

17.10 Disease of THE Aorta
Aortic Atheroma
Atherosclerosis process of the aorta starts as fatty streaks at a young age. These changes
will progress with age and cause thickening and calcification of the aorta, which can be
detected by TEE
Aortic atheroma may cause stroke by embolization. Thick (>4 mm) non-calcified
atherosclerotic plaque of aorta proximal to subclavian artery carries the highest risk of
stroke
Management should include:
Risk factor modification and smoking cessation
Aspirin or warfarin
Statin
Abdominal Aortic Aneurysm

Often affects elderly men (women less affected) with smoking history
Most patients are asymptomatic; however, if symptoms develop (back pain, abdominal
pain) there is risk of rupture (high mortality rate)
The risk of rupture and rate of expansion increases significantly with increasing size of the
aneurysm
Screening abdominal ultrasonography should be done once for:
Men who are between 65 and 75 years of age and have smoked
Men above 60 with a significant family history of abdominal aneurysm
Medical management
Asymptomatic patients with aneurysm size less than 5.5 cm should undergo CT
angiogram every 6 months
Smoking cessation is the most important step to prevent aneurysm formation/
expansion
b-blocker and ACE inhibitor are frequently used in managing AAA to decrease the rate
of progression and risk of rupture, respectively
Simvastatin has been found to decrease the rate of expansion
Surgical repair of the AAA is indicated in:
Symptomatic patients
Asymptomatic with aneurysm size >5.5 cm
Asymptomatic with rate of enlargement more than 0.5 cm per year
Surgical repair is associated with increased perioperative mortality in comparison to
endovascular repair; however, the long-term mortality does not differ significantly. The
re-intervention rate and cost are higher in endovascular approach
Thoracic Aortic Aneurysm

Most are asymptomatic and discovered incidentally. But it may cause chest pain, back pain,
difficulty swallowing, change in voice, superior vena cava obstruction, tamponade, and
acute rupture
Management should include b-blocker and angiotensin receptor blocker
Surgical repair has high mortality rate (more than abdominal aneurysm repair) and
indicated in the following:
Patients with symptoms
Dissection
Enlargement >1 cm per year
If the size of the ascending and descending aorta is more than 5.5 cm and 6.5 cm
Marfan Syndrome
Autosomal dominant disorder resulting from fibrillin-1 gene mutation
Increased risk of aortic root dilation and dissection
Serial semiannual echocardiograms are recommended to follow the size of the aortic root
Medical management includes b-blocker and losartan (decreases the rate of aneurysmal
dilation)
Aortic root repair should be performed in Marfan patients if:
The aortic root size is >5 cm (>4.5 cm in women planning to get pregnant)
If the rate of expansion is >1 cm per year
Patients with Marfan should not be involved in heavy activity
Acute Aortic Syndromes

If the ascending aorta is involved it is considered type A and if it involves the aorta distal to
left subclavian artery than it is type B (Stanford classification)
Acute aortic syndrome should be suspected in patients presenting with new severe tearing
chest pain
Diagnosis commonly achieved by CT angiogram or TEE
Type-A dissection is surgical emergency while type-B is treated medically (intravenous
b-blocker and other intravenous antihypertensive agent and pain management)
Takayasu Arteritis
An infrequent large artery vasculitis (affects the aorta and the major branches) which
mainly affects women at young ages
The vascular clinical presentation depends on the arterial segments involved. Carotids
and vertebrobasilar involvement will result in neurological symptoms (headache, syncope,
TIA, stroke). If renal arteries are involved it will result in uncontrolled hypertension, arm
claudication, and inter-arm pressure difference as a result of subclavian artery involvement
17.11 Peripheral Arterial Disease (PAD)

Evaluation of Peripheral Arterial Disease
Most patients are asymptomatic and in symptomatic portion, atypical leg pain is more
frequent than classic intermittent claudication
Most of PAD caused by atherosclerosis
Differential diagnosis: Peripheral neuropathy, musculoskeletal disease, DVT, spinal stenosis
If the pain is at:
Buttock/hip level aorto-iliac stenosis
Thigh aortoiliac or common femoral artery stenosis
Calf superficial femoral artery
Foot tibial or peroneal artery
Severe bilateral aortoiliac disease impotence in men

Leriche syndrome: Claudication with decreased femoral pulses and impotence
Risk factors: Age, DM, smoking, hyperlipidemia
Physical examination: Decreased pulse size, delayed wound healing, cold feet, shiny
atrophied skin, and nail thickening
Diagnosis
Ankle brachial index (ABI) <0.90 has a high degree of sensitivity and specificity
ABI >1.3 indicates non-compressible arteries
If patient has high suspicion for PAD with normal ABI at rest, exercise ABI (look for drop
in ABI post exercise) should be performed
Ultrasonography and MRA can also be used to determine the site of obstruction
Low ABI >1.3 (regardless of symptoms present or not) is associated with increased
coronary artery disease, stroke, and mortality
Management of Peripheral Arterial Disease

Risk factor modification
Aggressive risk factor modification should be the initial step (smoking cessation
is the most important 1st step, statin to reduce LDL<100 mg/dL, and controlling
hypertension. ACE inhibitor and b-blocker [not-contraindicated in PAD] should be
given and to control diabetes)
PAD is CAD equivalent aspirin (81-325 mg) should be given (clopidogrel is an
alternative if allergic to aspirin). It decreases non-fatal MI, stroke, and cardiovascular
death
Treatment of symptomatic patients
In addition to risk factor modification, supervised exercise training sessions (half an
hour, more than 3 times a week) are helpful to increase the distance that can be
walked before claudication starts
Cilostazol can be used in symptomatic patients to improve the walking distance and
daily activity (avoid in heart failure)
Invasive treatments - surgery vs. endovascular (angioplasty/stenting) considered if:
Medical treatment failed
Severe disability
Non-healing foot ulcer
Feasible lesions for intervention
Acute Limb Ischemia

Results from thrombo-embolism (atrial fibrillation, left ventricular clot, or aortic aneurysm),
institute thrombosis, or occlusion of bypass graft
Treatment: Should include anticoagulation and either surgical embolectomy (increased risk
of future restenosis) or angiography with catheter based thrombolysis
17.12 Pregnancy and Cardiovascular Disease
Hemodynamic Changes in Pregnancy
plasma volume: Peak by the 2nd trimester (50% of baseline)
Heart rate increase by 20% above baseline, cardiac output (30 to 50%), vascular
resistance slight in blood pressure
venous pressure in lower extremities (80% have pedal edema)
Common normal cardiac symptoms during healthy pregnancy: exercise capacity,
dyspnea, palpitation (APC/VPC)
Physical examination of a healthy pregnancy may look like a patient with heart disease
( S1 and S2 intensity, + S3, + JV distention, systolic murmur [80% of pregnant]), and leg
edema
Normal ECG finding can be found in a healthy pregnancy (axis change, small Q-wave in
lead III, R/S wave ratio in V1-2, sinus tachycardia, arrhythmia)
Always vaginal delivery preferable except if contraindicated
Table 17.11: Contraindication to Vaginal Delivery

If on warfarin anticoagulation ( fetal ICH)
Severe dilated cardiomyopathy
Marfan syndrome with dilated aorta
Severe pulmonary hypertension
Severe obstructive disease (severe AS, MS, PS, coarctation of aorta)
Cardiovascular Disease Related to Pregnancy

Congenital heart disease is the most common heart disease in pregnant women in western
countries (ex.: ASD, VSD, PDA)
Gestational HTN: Develops between 20th week of pregnancy and resolves by the 6th week
post-partum
Preeclampsia suspected if + proteinuria (>300 mg/24 hrs)
Eclampsia if patient developed seizure (if above 34 weeks)
If less than 34 weeks then bed rest, IV MgSO4, blood pressure control, and
corticosteroids may help
MI in pregnancy: The incidence is low. May result from coronary atherosclerosis, coronary
dissection, vasculitis, or coronary embolization (atrial fibrillation, infective endocarditis,
prosthetic valves)
Treatment: Early cardiac catheterization with radiation protecting shield for the fetus
should be performed. Thrombolytics are contraindicated
Peripartum Cardiomyopathy
Dilated cardiomyopathy, EF (<45%), signs of heart failure in the last month of
pregnancy or within 5 months of delivery
75% are diagnosed within the 1st month postpartum
Increased risk in women >30 years, in patients with gestational hypertension, twin
pregnancy and use of tocolytic therapy

Management: No more pregnancy. Subsequent pregnancies are associated with relapse,
LV failure, and death. ACE inhibitor and ARB should be avoided in managing the heart
failure during pregnancy (teratogenic)
Majority (60%) of cases show complete or near-complete recovery within the first 6
months post-partum
Hypertrophic Cardiomyopathy (HOCM)
Pregnancy with HOCM should be managed with b-blocker. If there is associated atrial
fibrillation, the rate should be controlled and sometimes cardioversion is needed
Pulmonary HTN
Patients with Eisenmenger physiology ( pulmonary pressure, right to left shunt with
cyanosis) should be encouraged not to conceive. There is high mortality associated with
pregnancy
Aortic Dissection
Increased risk of dissection in pregnant women. Marfan syndrome women have the
highest risk especially if the aortic diameter is more than 4 cm, if the size of aorta is
increasing progressively, or there is a history of dissection in close relatives. b-blocker and
following the aortic diameter by echocardiography are both recommended
Valve Disease
Pregnant women tolerate regurgitant lesions better than stenotic lesions if not associated
with PHT. Most pregnant women develop symptoms during the 2nd and 3rd trimester.
Table 17.12: Valvular Diseases in Pregnancy

Mitral stenosis Usually rheumatic
pulmonary edema (treat by diuretics) and risk of atrial fibrillation (rate should
be controlled by b-blocker and digoxin, if unstable electric cardioversion can be per-
formed safely)
If patients developed hemodynamic instability percutaneous valvotomy can be
performed and usually deferred to 2nd or 3rd trimester to avoid fetus radiation
Most patients with mitral stenosis can undergo vaginal delivery and they tolerate
epidural anesthesia better than general anesthesia
Aortic stenosis Usually a result of bicuspid valve
AS, if severe, usually associated with high maternal mortality. Should be corrected
before conception
If diagnosed during pregnancy and symptoms developed diuretics should be tried. If
failed or the patient developed hemodynamic instability, percutaneous balloon val-
votomy should be performed
Spinal and epidural anesthesia should be avoided in those patients ( vasodilation)
Aortic Women with severe aortic regurgitation and signs of cardiac decompensation
regurgitation should undergo operative repair before conception
Digoxin, diuretics, and vasodilators can be used to manage the symptoms during the
pregnancy
Mitral Can be chronic (myxomatous degeneration or rheumatic disease) or acute (rupture
regurgitation of chordae tendineae)
Acute MR may produce flash pulmonary edema and life-threatening cardiac
decompensation
Women with severe regurgitation should have the valve repaired before pregnancy.
b-blocker,digoxin, diuretics, and vasodilators can be used to manage the symptoms
during the pregnancy
Prosthetic valve management
Bioprosthetic valve does not need anticoagulation
Mechanical valves need anticoagulation and this is associated with increased risk of
bleeding (maternal and fetal bleeding complication)
Coumadin crosses the placentashould be avoided in the 1st trimester (warfarin
embryopathy, incidence 4 to 10%). Heparin can be given during the 1st trimester and
after 36 weeks. Heparin infusions should be discontinued 4 hours before cesarean
sections
Arrhythmia
Premature atrial contractions and premature ventricular contraction are the most
common
There is an increase risk of SVT
Drugs should be avoided in the 1st trimester
Patients who have life-threatening ventricular arrhythmia should be managed by
implantable defibrillator
References & SUGGESTED READINGS

1. Crawford, Michael H., John P. DiMarco, and Walter J. Paulus.Cardiology. 3rd ed. London: Mosby,
2003. Print.
2. Baliga, Ragavendra R.Practical Cardiology: Evaluation and Treatment of Common Cardiovascular
Disorders. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2008. Print.
3. Hannaman, Robert A.MedStudy: Internal Medicine Review: Core Curriculum. Colorado Springs, CO:
MedStudy, 2005. Print.
4. MKSAP 15: Medical Knowledge Self-assessment Program. Philadelphia: American College of
Physicians, 2009. Print.
5. Chaitman, B. R. Ranolazine for the Treatment of Chronic Angina and Potential Use in Other
Cardiovascular Conditions.Circulation113.20 (2006): 2462-472.
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NOTES
NOTES
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INTERNAL MEDICINE IN-REVIEW

Companion to the Online Study System

a. Aperistalsis with lack of lower esophageal relaxation

1.1 ROUTINE CARE OF THE HEALTHY PATIENT . . . . . 2

1.2 GERIATRIC MEDICINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1.3 PERI-OPERATIVE MEDICINE . . . . . . . . . . . . . . . . . . . . . 5

1.4 PATIENT SAFETY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.5 PROFESSIONALISM AND ETHICS . . . . . . . . . . . . . . . . 6

1.6 PALLIATIVE CARE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1.7 COMMON SYMPTOMS . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1.8 MEN'S HEALTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

GENERAL INTERNAL MEDICINE1

2INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

Table 1.1: Immunizations

Lifestyle Risk Factors

GENERAL INTERNAL MEDICINE3

1.2 GERIATRIC MEDICINE

4INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

GENERAL INTERNAL MEDICINE5

1.4 PATIENT SAFETY

1.5 PROFESSIONALISM AND ETHICS

6INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

1.6 PALLIATIVE CARE

GENERAL INTERNAL MEDICINE7

1.7 COMMON SYMPTOMS

8INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

Acute and Chronic Cough

Chronic Fatigue and Chronic Fatigue Syndrome

GENERAL INTERNAL MEDICINE9

10INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

GENERAL INTERNAL MEDICINE11

12INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

1.8 MEN'S HEALTH

GENERAL INTERNAL MEDICINE13

14INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

GENERAL INTERNAL MEDICINE15

16INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

2.1 WHY PAIN MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . 18

2.3 OTC, RX, AND ALTERNATIVE PAIN MANAGEMENT. . 18

2.4 HEADACHE AND FACIAL PAIN . . . . . . . . . . . . . . . . . .23

2.5 CHRONIC MUSCULOSKELETAL PAIN AND OTHER

2.6 OTHER TYPES OF COMMON CHRONIC PAIN . . . .35

2.7 ACUTE AND CHRONIC PAIN IN DIFFERENT

2.3 OTC, RX, AND ALTERNATIVE PAIN MANAGEMENT

18INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

Prescription Pain Medications (Rx)

20INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

Complementary and Alternative Medicine (CAM)

Table 2.1: Common Drug-Drug Interactions Between OTC Pain Relievers

Disease/Condition/Symptom Preferred Analgesic Therapeutic Note

Asthma Acetaminophen Use with caution: Aspirin,

22INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

2.4 HEADACHE AND FACIAL PAIN

Tension-type Headache (TTH)

Chronic Daily Headache

Trigeminal Autonomic Cephalalgias

24INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

Trigeminal Neuralgia (TN)

Headache Secondary to Changes in Intracranial Pressure or Volume

26INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM

Primary Thunderclap Headache Diagnostic Criteria

2.5 CHRONIC MUSCULOSKELETAL PAIN AND OTHER COMMON

28INTERNAL MEDICINE IN-REVIEW l INREVIEWIM.COM