Pocket Medicine 5th Edition - The Massachuset PDF

Pocket
MEDICINE
Fifth Edition
Edite d by
MARC S. SABATINE, MD, MPH

ASSOCIATE PROFESSOR OF MEDICINE
HARVARD MEDICAL SCHOOL
The Massachusetts General Hospital

Handbook of Internal Medicine
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Library of Congress Cataloging-in-Publication Data
Pocket medicine (Sabatine)

Pocket medicine / [edited by] Marc S. Sabatine. — Fifth edition.
p . ; cm.
Preceded by Pocket medicine / edited by Marc S. Sabatine. 4th ed.
c2 011.
Includes bibliograp hical references and index.
ISBN-13: 978 -1-4511-8 2 37-8
ISBN-10: 1-4511-8 2 37-6
ISBN-13: 978 -1-4511-8 8 8 7-5
ISBN-10: 1-4511-8 8 8 7-0
I. Sabatine, Marc S., editor of comp ilation. II. Title.
[DNLM: 1. Internal Medicine–Handbooks. 2 . Clinical Medicine–Handbooks. WB 39]
RC55
616–dc2 3
2 013019655
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10 9 8 7 6 5 4 3 2 1
CONTENTS
Contributing Authors
Fore word
Preface
CARDIOLOGY
Ne al A. Chatte rje e , Ada Ste fane scu, William J. Hucke r, David M. Dudzinski, Marc S.
Sabatine , Miche lle O’Donog hue
Electrocardiograp hy
Chest Pain
Noninvasive Evaluation of CAD
Coronary Angiograp hy and Revascularization
Acute Coronary Syndromes
PA Catheter and Tailored Therap y
Heart Failure
Cardiomyop athies
Valvular Heart Disease
Pericardial Disease
Hyp ertension
Aortic Aneurysms
Acute Aortic Syndromes
Arrhythmias
Atrial Fibrillation
Syncop e
Intracardiac Devices
Cardiac Risk Assessment for Noncardiac Surgery
Perip heral Artery Disease
PULMONARYQ
Ian J. Barbash, Kathryn A. Hibbe rt, Atul Malhotra

Dysp nea
Pulmonary Function Tests
Asthma
Anap hylaxis
Chronic Obstructive Pulmonary Disease
Hemop tysis
Bronchiectasis
Solitary Pulmonary Nodule
Obstructive Sleep Ap nea
Interstitial Lung Disease
Pleural Effusion
Venous Thromboembolism
Pulmonary Hyp ertension
Resp iratory Failure
Mechanical Ventilation
Acute Resp iratory Distress Syndrome
Sep sis
GASTROENTEROLOGY
Zachary A. Zator, Andre w S. de Le mos, Lawre nce S. Frie dman
Esop hageal and Gastric Disorders

Gastrointestinal Bleeding
Diarrhea, Constip ation and Ileus
Diverticular Disease
Inflammatory Bowel Disease
Intestinal Ischemia
Pancreatitis
Abnormal Liver Tests
Hep atitis
Acute Liver Failure
Cirrhosis
Hep atic Vascular Disease
Ascites
Biliary Tract Disease
NEPHROLOGY
Andre w S. Alle g re tti, Andre w L. Lundquist, Hasan Bazari
Acid-Base Disturbances
Sodium and Water Homeostasis
Potassium Homeostasis
Renal Failure
Glomerular Disease
Urinalysis
Nep hrolithiasis
HEMATOLOGY-ONCOLOGY
Andre w M. Brunne r, She he ryar K. Kabraji, Mark M. Awad, Andre w J. Ag uirre , Danie l J.
De Ang e lo, David P. Ryan
Anemia
Disorders of Hemostasis
Platelet Disorders
Coagulop athies
Hyp ercoagulable States
Disorders of Leukocytes
Transfusion Therap y
Myelodysp lastic Syndromes
Myelop roliferative Neop lasms
Leukemia
Lymp homa
Plasma Cell Dyscrasias
Hematop oietic Stem Cell Transp lantation
Lung Cancer
Breast Cancer
Prostate Cancer
Colorectal Cancer
Chemotherap y Side Effects
Pancreatic Tumors
Oncologic Emergencies
Cancer of Unknown Primary Site
INFECTIOUS DISEASES
Ana A. We il, Emily P. Hyle , Ne sli Basg oz

Pneumonia
Fungal Infections
Infections in Immunosup p ressed Hosts
Urinary Tract Infections
Soft Tissue and Bone Infections
Infections of the Nervous System
Bacterial Endocarditis
Tuberculosis
HIV/AIDS
Tick-Borne Diseases
Fever Syndromes
ENDOCRINOLOGY
Ke lly B. Laute r, Marc N. We in, Michae l Mannstadt
Pituitary Disorders
Thyroid Disorders
Adrenal Disorders
Calcium Disorders
Diabetes Mellitus
Lip id Disorders
RHEUMATOLOGY
Zachary S. Wallace , Eli Miloslavsky, Robe rt P. Friday
Arthritis—Overview
Rheumatoid Arthritis
Adult Onset Still’s Disease & Relap sing Polychondritis
Crystal Dep osition Arthritides
Seronegative Sp ondyloarthritis
Infectious Arthritis & Bursitis
Connective Tissue Diseases
Systemic Lup us Erythematosus
Vasculitis
IgG4-Related Disease
Cryoglobulinemia
Amyloidosis
NEUROLOGY
Michae l P. Bowle y, Todd M. He rring ton, Eyal Y. Kimchi, Sarah Wahlste r, Trace y A. Cho
Change in Mental Status
Seizures
Alcohol Withdrawal
Stroke
Weakness & Neuromuscular Dysfunction
Headache
Back and Sp inal Cord Disease
CONSULTS
Kiran H. Lag ise tty, Je nnife r F. Tse ng , Kathe rine T. Che n, Ste lla K. Kim
Surgical Issues
Ob/Gyn Issues
Op hthalmic Issues
APPENDIX
ICU Medications & Treatment of Hyp otension/Shock
Antibiotics
Formulae and Quick Reference
ABBREVIATIONS
INDEX
PHOTO INSERTS
Radiology
Echocardiograp hy & Coronary Angiograp hy
Perip heral Blood Smears & Leukemias
Urinalysis
ACLS
CONTRIBUTING AUTHORS
Andrew J. Aguirre, MD, PhD
Hematology-Oncology Fellow, Dana-Farber/Partners CancerCare

Hematology/Oncology Program
Andrew S. Allegretti, MD
Internal Medicine Resident, Massachusetts General Hosp ital
Mark M. Awad, MD, PhD
Hematology-Oncology Fellow, Dana-Farber/Partners CancerCare
Hematology/Oncology Program
Ian J. Barbash, MD

Nesli Basgoz, MD
Associate Chief and Clinical Director, Infectious Disease Division, Massachusetts

General Hosp ital
Associate Professor of Medicine, Harvard Medical School
Hasan Bazari, MD
Clinical Director, Nep hrology Unit, Massachusetts General Hosp ital

Program Director, Internal Medicine Residency, Massachusetts General Hosp ital
Michael P. Bowley, MD, PhD
Neurology Resident, Partners Neurology Residency
Andrew M. Brunner, MD
Neal A. Chatterjee, MD
Katherine T. Chen, MD, MPH
Associate Professor of Obstetrics, Gynecology, and Rep roductive Science

Associate Professor of Medical Education
Vice-Chair of Ob/Gyn Education, Career Develop ment, and Mentorship
Icahn School of Medicine at Mount Sinai, New York
Tracey A. Cho, MD
Associate Program Director, Partners-Harvard Neurology Residency

Assistant Professor of Neurology, Harvard Medical School
Assistant Neurologist, Massachusetts General Hosp ital
Andrew S. de Lemos, MD
Transp lant Hep atology Fellow, Massachusetts General Hosp ital
Daniel J. DeAngelo, MD, PhD
Adult Leukemia Program, Dana-Farber Cancer Institute & Brigham and Women’s
Hosp ital
David M. Dudzinski, MD, JD

Cardiology Fellow, Massachusetts General Hosp ital
Robert P. Friday, MD, PhD
Attending Physician, Rheumatology Unit, Massachusetts General Hosp ital

Associate Director, Rheumatology Fellowship Program, Massachusetts General
Hosp ital
Instructor in Medicine, Harvard Medical School
Lawrence S. Friedman, MD
Anton R. Fried, MD, Chair, Dep artment of Medicine, Newton-Wellesley Hosp ital
Assistant Chief of Medicine, Massachusetts General Hosp ital
Professor of Medicine, Harvard Medical School
Professor of Medicine, Tufts University School of Medicine
Todd M. Herrington, MD, PhD
Kathryn A. Hibbert, MD
Pulmonary and Critical Care Fellow, Harvard Medical School
William J. Hucker, MD, PhD
Cardiology Fellow, Massachusetts General Hosp ital

Emily P. Hyle, MD
Assistant in Medicine, Infectious Disease Division, Massachusetts General Hosp ital

Instructor in Medicine, Harvard Medical School
Sheheryar K. Kabraji, BM, BCh
Stella K. Kim, MD
Director, Clinical Research in Op thalmology

Director, Op thalmology Residency Rotation Program
Associate Professor of Op thalmology
UT MD Anderson Cancer Center
Eyal Y. Kimchi, MD, PhD

Kiran H. Lagisetty, MD
Surgical Resident, Beth Israel Deaconess Medical Center
Kelly B. Lauter, MD, PhD

Andrew L. Lundquist, MD
Nep hrology Fellow, BWH/MGH Joint Nep hrology Fellowship Program
Atul Malhotra, MD
Associate Physician, Divisions of Pulmonary & Critical Care and Sleep Medicine,
Brigham and Women’s Hosp ital
Michael Mannstadt, MD
Attending Physician, Endocrine Unit, Massachusetts General Hosp ital

Assistant Professor of Medicine, Harvard Medical School
Eli Miloslavsky, MD
Rheumatology Fellow, Massachusetts General Hosp ital
Michelle O’Donoghue, MD, MPH
Investigator, TIMI Study Group and Associate Physician, Cardiovascular Division,

Brigham and Women’s Hosp ital
Affiliate Physician, Cardiology Division, Massachusetts General Hosp ital
Assistant Professor of Medicine, Harvard Medical School
David P. Ryan, MD
Clinical Director, Massachusetts General Hosp ital Cancer Center
Chief of Hematology/Oncology, Massachusetts General Hosp ital
Marc S. Sabatine, MD, MPH

Chairman, TIMI Study Group and Physician, Cardiovascular Division, Brigham and
Women’s Hosp ital
Affiliate Physician, Cardiology Division, Massachusetts General Hosp ital
Ada Stefanescu, MD, CM

Jennifer F. Tseng, MD, MPH
Chief, Division of Surgical Oncology, Beth Israel Deaconess Medical Center

Associate Professor of Surgery, Harvard Medical School
Sarah Wahlster, MD
Zachary S. Wallace, MD

Ana A. Weil, MD, MPH
Marc N. Wein, MD, PhD
Endocrinology Fellow, Massachusetts General Hosp ital
Zachary A. Zator, MD
FOREWORD
To the 1st Edition
It is with the greatest enthusiasm that I introduce Pocke t Me dicine . In an era of

information glut, it will logically be asked, “Why another manual for medical house
o cers?” Yet, desp ite enormous information readily available in any number of
textbooks, or at the p ush of a key on a comp uter, it is often that the harried house
o cer is less help ed by the descrip tion of di erential diagnosis and therap ies than one
would wish.
Pocke t Me dicine is the joint venture between house sta and faculty exp ert in a
number of medical sp ecialties. This collaboration is designed to p rovide a rap id but
thoughtful initial ap p roach to medical p roblems seen by house o cers with great
frequency. Questions that frequently come from faculty to the house sta on rounds,
many hours after the initial interaction between p atient and doctor, have been
anticip ated and imp ortant p athways for arriving at diagnoses and initiating therap ies
are p resented. This ap p roach will facilitate the evidence-based medicine discussion that
will follow the workup of the p atient. This well-conceived handbook should enhance the
ability of every medical house o cer to p rop erly evaluate a p atient in a timely
fashion and to be stimulated to think of the evidence sup p orting the diagnosis and the
likely outcome of therap eutic intervention. Pocke t Me dicine will p rove to be a worthy
addition to medical education and to the care of our p atients.
DENNIS A. AUSIELLO, MD
Physician-in-Chie f, Massachuse tts Ge ne ral Hospital
Jackson Profe ssor of Clinical Me dicine , Harvard Me dical School
PREFACE
To my pare nts, Matt and Le e Sabatine , to the ir name sake

g randchildre n Matte o and Natalie , and to my wife Je nnife r
Written by residents, fellows and attendings, the mandate for Pocke t Me dicine was to
p rovide, in a concise a manner as p ossible, the key information a clinician needs for
the initial ap p roach to and management of the most common inp atient medical
p roblems.
The tremendous resp onse to the p revious editions suggests we were able to help ll
an imp ortant need for clinicians. With this fth edition come several major
imp rovements including a thorough up dating of every top ic, the addition of several
new top ics (including treatment of anap hylaxis, ap p roach to inp atient nutritional
issues, chemotherap y side e ects, and workup of a fever in a recent traveler), and
inclusion of additional p hotomicrograp hs. We have also added a new section on
Consults in which non-internal medicine sp ecialists p rovide exp ert guidance in terms
of establishing a di erential diagnosis for common p resenting symp toms and
initiating an evaluation in anticip ation of calling a consult. As always, we have
incorp orated key references to the most recent high-tier reviews and imp ortant studies
p ublished right up to the time Pocke t Me dicine went to p ress. We welcome any
suggestions for further imp rovement.
Of course medicine is far too vast a eld to ever summarize in a textbook of any
size. Long monograp hs have been devoted to many of the top ics discussed herein.
Pocke t Me dicine is meant only as a starting p oint to guide one during the initial p hases
of diagnosis and management until one has time to consult more de nitive resources.
Although the recommendations herein are as evidence-based as p ossible, medicine is
both a science and an art. As always, sound clinical judgement must be ap p lied to
every scenario.
I am grateful for the sup p ort of the house o cers, fellows, and attendings at the
Massachusetts General Hosp ital. It is a p rivilege to work with such a knowledgeable,
dedicated, and comp assionate group of p hysicians. I always look back on my time
there as Chief Resident as one of the best exp eriences I have ever had. I am grateful to
several outstanding clinical mentors, including Hasan Bazari, Larry Friedman, Nesli
Basgoz, Mort Swartz, Eric Isselbacher, Bill Dec, Mike Fifer, and Roman DeSanctis, as
well as the late Charlie McCabe and Peter Yurchak.
This edition would not have been p ossible without the help of two individuals in the
TIMI Study Group Chairman’s O ce. Melinda Cuerda, my academic coordinator, was
an invaluable resource for this edition. She shep herded every asp ect of the p roject from
start to nish, with an incredible eye to detail to ensure that each p age of this book
was the very best it could be. Pamela Melhorn, my executive assistant, exp ertly
manages the Chairman’s O ce, miraculously coordinating the comp lex clinical,
research, and educational missions.
Lastly, sp ecial thanks to my p arents for their p erp etual encouragement and love
and, of course, to my wife, Jennifer Tseng, who, desp ite being a surgeon, is my closest
advisor, my best friend and the love of my life.
I hop e that you nd Pocke t Me dicine useful throughout the arduous but incredibly
rewarding journey of p racticing medicine.
MARC S. SABATINE, MD, MPH
ELECTROCARDIOGRAPHY
Approach (a systematic approach is vital)
• Rate (? tachy, brady) and rhythm (? relationship between P and QRS)

• Intervals (PR, QRS, QT) and axis (? LAD or RAD)
• Chamber abnormality (? LAA and/or RAA, ? LVH and/or RVH)
• QRST changes (? Q waves, p oor R-wave p rogression V1–V6, ST ↑/↓ or T-wave Δs)
Figure 1-1 QRS axis
Left axis deviation (LAD)

• Definition: axis beyond –30° (S > R in lead II)
• Etiologies: LVH, LBBB, inferior MI, WPW
• Left anterior fascicular block: LAD (–45 to –90°) and qR in aVL and QRS <12 0
msec and no other cause of LAD (eg, IMI)
Right axis deviation (RAD)
• Definition: axis beyond +90° (S > R in lead I)
• Etiologies: RVH, PE, COPD (usually not > +110°), sep tal defects, lateral MI, WPW
• Left posterior fascicular block: RAD (90–18 0°) and rS in I & aVL and qR in III &
aVF and QRS <12 0 msec and no other cause of RAD
Prolonged QT interval (NEJM 2008; 358:169; www.torsades.org)
• QT measured from beginning of QRS comp lex to end of T wave (measure longest QT)
• QT varies w/ HR → correct w/ Bazett formula: QTc = QT/√RR (in sec), formula

inaccurate at very high and low HR (nl QTc <440 msec and <460 msec )
• QT p rolongation a/w ↑ risk TdP (esp . >500 msec); p erform baseline/serial ECGs if
using QT p rolonging meds, no estab guidelines for stop p ing Rx if QT p rolongs
• Etiologies:
Antiarrhythmics: class Ia (p rocainamide, disop yramide), class III (amiodarone,

sotalol)
Psych drugs: antip sychotics (p henothiazines, halop eridol, atyp icals), Li, ? SSRI,
TCA
Antimicrobials: macrolides, quinolones, azoles, p entamidine, atovaquone,

atazanavir
Other: antiemetics (drop eridol, 5-HT3 antagonists), alfuzosin, methadone,

ranolazine
Electrolyte disturbances: hyp oCa (nb, hyp erCa a/w ↓ QT), ? hyp oK, ? hyp oMg
Autonomic dysfxn: ICH (deep TWI), stroke, carotid endarterectomy, neck

dissection
Congenital (long QT syndrome): K, Na, Ca channelop athies (Circ 2 013;12 7:12 6)
Misc: CAD, CMP, bradycardia, high-grade AVB, hyp othyroidism, hyp othermia,
BBB
Left ventricular hypertrophy (LVH) (Circ 2009; 119:e251)
• Etiologies: HTN, AS/AI, HCMP, coarctation of aorta
• Criteria (all w/ Se <50% , Sp >8 5% ; accuracy affected by age, sex, race, BMI)
Romhilt-Estes p oint-score system: 4 p oints = p robable, 5 p oints = definite ↑

Amp litude (any of the following): largest R or S in limb leads ≥2 0 mm or S in
V1 or V2 ≥30 mm or R in V5 or V6 ≥30 mm (3 p oints)
ST disp lacement op p osite to QRS deflection: w/o dig (3 p oints); w/ dig (1 p oint)
LAA (3 p oints); LAD (2 p oints); QRS duration ≥90 msec (1 p oint)

Intrinsicoid deflection (QRS onset to p eak of R) in V5 or V6 ≥50 msec (1
p oint)
Sokolow-Lyon: S in V1 + R in V5 or V6 ≥35 mm or R in aVL ≥11 mm
Cornell: R in aVL + S in V3 >2 8 mm in men or >2 0 mm in women
If LAD/LAFB, S in III + max (R+S) in p recordium ≥30 mm
Right ventricular hypertrophy (RVH) (Circ 2009; 119:e251)

• Etiologies: cor p ulmonale, congenital (tetralogy, TGA, PS, ASD, VSD), MS, TR
• Criteria (all tend to be insensitive, but highly sp ecific, excep t in COPD)

R > S in V1 or R in V1 ≥7 mm, S in V5 or V6 ≥7 mm, drop in R/S ratio across
p recordium
RAD ≥ +110° (LVH + RAD or p rominent S in V5 or V6 → bive ntricular

hyp ertrop hy)
Ddx of dominant R wave in V1 or V2
• Ventricular enlargement: RVH (RAD, RAA, deep S waves in I, V5, V6); HCMP
• Myocardial injury: p osterior MI (anterior Rw = p osterior Qw; often with IMI)
• Abnormal dep olarization: RBBB (QRS >12 0 msec, rSR′); WPW (↓ PR, Δ wave, ↑
QRS)
• Other: dextroversion; Duchenne muscular dystrop hy; lead misp lacement; nl variant
Poor R wave progression (PRWP) (Am Heart J 2004; 148:80)

• Definition: loss of anterior forces w/o frank Q waves (V1–V3); R wave in V3 ≤3 mm
• Possible etiologies (nonsp ecific):
old anterosep tal MI (usually w/ R wave V3 ≤1.5 mm, ± p ersistent ST ↑ or TWI

V2 & V3) cardiomyop athy
LVH (delayed RWP with p rominent left p recordial voltage), RVH, COPD (which
may also have RAA, RAD, limb lead QRS amp litude ≤5, S IS IIS III w/ R/S ratio
<1 in those leads)
LBBB; WPW; clockwise rotation of the heart; lead misp lacement; PTX
Pathologic Q waves
• Definition: ≥30 msec (≥2 0 msec V2 –V3) or >2 5% height of R wave in that QRS
comp lex
• Small (sep tal) q waves in I, aVL, V5 & V6 are nl, as can be isolated Qw in III, aVR,
V1
• “Pseudoinfarct” p attern may be seen in LBBB, infiltrative dis., HCMP, COPD, PTX,
WPW
ST elevation (STE) (NEJM 2003; 349:2128; Circ 2009; 119:e241 & e262)
• Acute MI (up ward convexity ± TWI) or p rior MI with p ersistent STE
• Coronary spasm (Prinzmetal’s angina; transient STE in a coronary distribution)

• Myopericarditis (diffuse, up ward concavity STE; a/w PR ↓; Tw usually up right)
• HCMP, Takotsubo CMP, ventricular aneurysm, cardiac contusion

• Pulmonary embolism (occ. STE V1–V3; typ ically associated TWI V1–V4, RAD,
RBBB)
• Repolarization abnormalities
LBBB (↑ QRS duration, STE discordant from QRS comp lex)
dx of STEMI in setting of LBBB: ≥1 mm STE concordant w/ QRS (Se 73% , Sp

92 % ), STD ≥1 mm V1–V3 (Se 2 5% , Sp 96% ) or STE ≥5 mm discordant w/
QRS (Se 31% , Sp 92 % ) (“Sgarbossa criteria,” NEJM 1996;334:48 1)
LVH (↑ QRS amp litude); Brugada syndrome (rSR′, downslop ing STE V1–V2 )
Hyp erkalemia (↑ QRS duration, tall Ts, no Ps)
• aVR: STE >1 mm a/w ↑ mort in STEMI; STE aVR > V1 a/w left main disease
• Early repolarization: most often seen in V2 –V5 & in young adults (Ann Eme rg Me d
2 012 ;60:45)
J p oint ↑ 1–4 mm; notch in downstroke of R wave; up ward concavity of ST; large
Tw;
ratio of STE / T wave amp litude <2 5% ; p attern may disap p ear with exercise
? early rep ol in inf leads may be a/w ↑ risk of VF (NEJM 2 009;361:2 52 9; Circ
2 011;12 4:2 2 08 )
ST depression (STD)
• Myocardial ischemia (± Tw abnl) or acute true p osterior MI (V1–V3)
• Digitalis effect (downslop ing ST ± Tw abnl, does not correlate w/ dig levels)
• Hyp okalemia (± U wave)
• Rep olarization abnl in a/w LBBB or LVH (usually in leads V5, V6, I, aVL)
T wave inversion (TWI; generally ≥1 mm; deep if ≥5 mm) (Circ 2009; 119:e241)
• Ischemia or infarct; Wellens’ sign (deep early p recordial TWI) → p roximal LCA
lesion
• Myop ericarditis; CMP (Takotsubo, ARVC, ap ical HCM); MVP; PE (esp . if TWI V1–
V4)
• Rep olarization abnl in a/w LVH/RVH (“strain p attern” ), BBB
• Posttachycardia or p ostp acing

• Electrolyte, digoxin, PaO 2 , PaCO 2 , p H or core temp erature disturbances
• Intracranial bleed (“cerebral T waves,” usually w/ ↑ QT)

• Normal variant in children (V1–V4) and leads in which QRS comp lex p redominantly
Low voltage
• QRS amp litude (R + S) <5 mm in all limb leads & <10 mm in all p recordial leads
• Etiologies: COPD (p recordial leads only), p ericardial effusion, myxedema, obesity,

p leural effusion, restrictive or infiltrative CMP, diffuse CAD
CHEST PAIN
Initial approach
• Focused history: quality & severity of p ain; location & radiation; p rovoking &
p alliating factors; intensity at onset; duration, frequency & p attern; setting in
which it occurred; associated sx; cardiac hx and risk factors
• Targeted exam: VS (including BP in both arms), cardiac gallop s, murmurs or rubs;

signs of vascular disease (carotid or femoral bruits, ↓ p ulses), signs of heart
failure; lung & abdominal exam; chest wall exam for rep roducibility of p ain
• 12-lead ECG: obtain w/in 10 min; c/w p riors & obtain serial ECGs; consider
p osterior leads (V7–V9) to reveal p osterior MI if hx c/w ACS but ECG unrevealing
or ST ↓ V1–V4
• Cardiac biomarkers (Tn ± CK-MB): ✓ Tn at baseline & 3–6 h after sx onset
troponin: >95% Se, 90% Sp ; level >99th % ile w/ rise & fall in ap p rop . setting
is dx of MI detectable 1–6 h after injury, p eaks 2 4 h, may remain elevated for 7–
10 d in STEMI hig h-se ns. Tn: 98 % Se, 90% Sp w/in 3 h of admit, 90% Se w/in 1 h
( JAMA 2 011;306:2 68 4)
Causes for ↑ Tn other than ACS (= “typ e 1 MI” ): (1) Sup p ly-demand mismatch not
due to Δ in CAD (= “typ e 2 MI” ; eg, ↑↑ HR, shock, HTN crisis, sp asm, HCM,
severe AS), (2 ) non-ischemic injury (myocarditis/toxic CMP, cardiac contusion)
or (3) multifactorial (PE, sep sis, severe HF, renal failure, Takotsubo, infilt dis.)
(Circ 2 012 ;12 6:2 02 0)
CK-MB: less Se & Sp (skel. muscle, tongue, diap hragm, intestine, uterus, p rostate),
useful for dx of p ost-PCI/CABG MI or MI if Tn already elevated
• CXR; other imaging (echo, PE CTA, etc.) as indicated based on H&P and initial
testing
• If low p rob of ACS (eg, ECG & Tn) & stable → noninvasive fxnal or imaging test
• Coronary CT angio (CCTA): NPV 98 % for signif CAD, but PPV 35% for ACS; help ful
to r/o CAD if low-intermed p rob of ACS. CCTA vs. noninv. fxnal test for ischemia
→ ↓ time to dx & LOS, but ↑ p rob of cath/PCI, contrast exp osure & ↑ radiation
(NEJM 2 012 ;366:1393 & 367:2 99; JACC 2 013;61:8 8 0). “Trip le r/o” CT angiogram
for CAD, PE, AoD.
NONINVASIVE EVALUATION OF CAD
Stress testing (Circ 2007; 115:1464; JACC 2012; 60:1828)

• Indications: dx CAD, evaluate Δ in clinical status in Pt w/ known CAD, risk stratify
s/p ACS, evaluate exercise tolerance, localize ischemia (imaging required)
• Contraindications (Circ 2 002 ;106:18 8 3; & 2 012 ;12 6:2 465)

Absolute: AMI w/in 48 h, high-risk UA, acute PE, severe sx AS, uncontrolled HF,
uncontrolled arrhythmias, myop ericarditis, acute aortic dissection
Relative: left main CAD, mod valvular stenosis, severe HTN, HCMP, high-degree
AVB, severe electrolyte abnl
• Exercise: standard Bruce (↑ sp eed & incline q3min), modified Bruce (begins w/o
treadmill incline), submax (if <3 wk p ost-MI) or sx-limited; hold
nitrates/βB/CCB/ranolazine if trying to dx CAD, but give when assessing if Pt
ischemic on meds
• Pharmacologic: if unable to exer., low exer. tol, or recent MI. Se & Sp exercise.
Preferred if LBBB (requires imaging since ECG not interp retable). Coronary
vasodilators (will reveal CAD, but not tell you if Pt ische mic): regadenoson,
dip yridamole or adenosine (may p recip itate bradycardia and bronchosp asm).
Chronotrope s/inotrope s (more p hysiologic): dobutamine (may p recip itate
tachyarrhythmias).
• Imaging: used if uninterp retable ECG (p aced, LBBB, resting ST ↓ >1 mm, dig.,
LVH, WPW), after indeterminate ECG test, p harmacologic tests, or localization of
ischemia
SPECT (eg, 99m Tc-sestamibi), PET (rubidium-8 2 ; usually w/ p harm test), echo,
MRI
Test results
• HR (must achieve ≥8 5% of max p red HR [2 2 0-age] for e xe r. test to be dx), BP

resp onse, p eak double product (HR × BP; nl >2 0k), HR recovery (HRp eak –
HR1 min later ; nl >12 )
• Max exercise capacity achieved (METS or min)
• Occurrence of symptoms (at what level of exertion and similarity to p resenting sx)
• ECG Δs: downsloping or horizontal ST ↓ (≥1 mm) 60–8 0 ms after QRS p redictive of
CAD (but does not localize ischemic territory); however, STE highly p redictive &
localizes
• Duke treadmill score = exercise min – (5 × max ST dev) – (4 × angina index) [0

none, 1 nonlimiting, 2 limiting]; score ≥5 → <1% 1-y mort; –10 to + 4 → 2 –
3% ; ≤ –11 → ≥5%
• Imaging: radionuclide defects or echocardiograp hic regional wall motion

abnormalities
reversible defect = ischemia; fixed defect = infarct; transient isch dilation =
severe CAD
false : breast → ant “defect” and diap hragm → inf “defect”
false may be seen if balanced (eg, 3VD) ischemia (global ↓ p erfusion w/o
regional Δs)
High-risk test results (PPV ~50% for LM or 3VD, ∴ consider coronary angio)
• ECG: ST ↓ ≥2 mm or ≥1 mm in stage 1 or in ≥5 leads or ≥5 min in recovery; ST
↑; VT
• Physiologic: ↓ or fail to ↑ BP, <4 METS, angina during exercise, Duke score ≤ –11;
↓ EF
• Radionuclide: ≥1 lg or ≥2 mod. reversible defects, transient LV cavity dilation, ↑
lung up take
Myocardial viability (Circ 2008; 117:103; Eur Heart J 2011; 31:2984 &
2011; 32:810)
• Goal: identify hibernating myocardium that could regain fxn after revascularization
• Op tions: MRI (Se ~95% , Sp ~8 5% ), PET (Se ~90% , Sp ~65% ), dobutamine

stress
echo (Se ~8 0% , Sp ~8 0% ); SPECT/rest-redistribution (Se ~8 5% , Sp ~70% )
In Pts w/ LV dysfxn, viabil. doesn’t p redict ↑ CABG benefit vs. med Rx (NEJM
2 011;364:1617)
CT & MR coronary angio (NEJM 2008; 369:2324; Circ 2010; 121:2509; Lancet
2012; 379:453)
• Image quality best at slower & regular HR (? give bB if p ossible, goal HR 55–60)
• Calcium generates artifact for CT angiograp hy
• MRI: angiograp hy, p erfusion, LV fxn, enhancement (early = microvasc obstr; late
= MI)
Coronary artery calcium score (CACS; Circ 2 010;12 2 :e58 4; NEJM 2 012 ;366:2 94;
JAMA 2 012 ;308 :78 8 )
• Quantifies extent of calcium; thus e stimate s p laque burden (but not % coronary
stenosis)
• ? Risk strat. (<100 = low; >300 = high) in asx Pts w/ intermed risk (10–2 0% 10-
y risk)
• ? Value as screening test to r/o CAD in sx Pt (CACS <100 → 3% p robability of

signif CAD; but interp retation affected by age, gender)
CORONARY ANGIOGRAPHY AND REVASCULARIZATION
Indications for coronary angiography in stable CAD or asx Pts
• CCS class III–IV angina desp ite medical Rx or angina + systolic dysfxn
• High-risk stress test findings (see p rior top ic)

• Uncertain dx after noninvasive testing (& comp elling need to determine dx),
occup ational need for definitive dx (eg, p ilot) or inability to undergo noninvasive
testing
• Systolic dysfxn with unexp lained cause
• Survivor of SCD, p olymorp hic VT, sustained monomorp hic VT

• Susp ected sp asm or nonatherosclerotic cause of ischemia (eg, anomalous coronary)
Precath checklist
• Document p erip heral arterial exam (radial, femoral, DP, PT p ulses; bruits); NPO >6
h
• ✓ CBC, PT, & Cr; give IVF (± bicarb, ± acetylcysteine; see “CIAKI” ); blood bank
samp le
• ASA 32 5 mg × 1; consider clop i 600 mg ≥2 –6 h before PCI or, if ACS, ticagrelor

p re- or p eri-PCI or p rasugrel p eri-PCI; cangrelor (IV P2 Y 12 inhib) ↓ p eri-PCI
ischemic events vs. clop i w/o p reload (NEJM 2 013;368 :1303); consider statin
p reRx (Circ 2 011;12 3:162 2 )
Coronary revascularization in stable CAD (Circ 2011; 124:e574)
• Op timal med Rx (OMT) should be initial focus if stable, w/o critical anatomy, & w/o
↓ EF
• PCI: ↓ angina more quickly c/w OMT; does not ↓ D/MI (NEJM 2 007;356:1503); in
Pts w/ ≥1 stenosis w/ FFR ≤0.8 (see below), ↓ urg revasc c/w OMT (NEJM
2 012 ;367:991); may be noninferior to CABG in unp rotected left main dis. (NEJM
2 011;364:1718 )
• CABG: in older studies, ↓ mort. c/w OMT if 3VD, LM, 2 VD w/ critical p rox LAD,
esp . if ↓ EF; more recently, if EF <35% ↓ CV death vs. OMT (NEJM
2 011;364:1607) insufficient evidence to sup p ort routine viability assessment (NEJM
2 011;364:1617) in diabetics w/ ≥2 VD, ↓ D/MI, but ↑ stroke c/w PCI (NEJM
2 012 ;367:2 375)
• If revasc deemed necessary, PCI if limited # of discrete lesions, nl EF, no DM, p oor
op erative candidate; CABG if extensive or diffuse disease, ↓ EF, DM or valvular
disease; if 3VD/LM: CABG ↓ D/MI & revasc but trend toward ↑ stroke c/w PCI
(Lance t 2 013;38 1:62 9); SYNTAX score II help s identify Pts who benefit most from
CABG (Lance t 2 013;38 1:639)
PCI
• Balloon angioplasty (POBA): effective, but c/b dissection & elastic recoil &
neointimal hyp erp lasia → restenosis; now reserved for small lesions & ? some SVG
lesions
• Bare metal stents (BMS): ↓ elastic recoil → 33–50% ↓ restenosis & rep eat revasc (to
~10% by 1 y) c/w POBA; requires ASA lifelong & P2 Y 12 inhib × ≥4 wk
• Drug-eluting stents (DES): ↓ neointimal hyp erp lasia → ~75% ↓ restenosis, ~50%
↓ rep eat revasc (to <5% by 1 y), no ↑ D/MI c/w BMS (NEJM 2 013;368 :2 54); next
generation DES may ↓ rep eat revasc & stent thrombosis; require P2 Y 12 inhib ≥1 y
(Circ 2 007;115:8 13)
• Radial access ↓ vasc. comp lic. vs. femoral, but no ∆ D/MI/CVA (Lance t
2 011;377:1409)
• Fractional flow reserve [FFR; ratio of max flow (induced by IV or IC adenosine)

distal vs. p roximal to a stenosis] guided PCI (<0.8 ) → ↓ # stents & ↓ D/MI/revasc
(NEJM 2 009;360:2 13)
Post-PCI complications
• Postp rocedure ✓ vascular access site, distal p ulses, ECG, CBC, Cr

• Bleeding
he matoma/ove rt ble e ding : manual compression, reverse/stop anticoag
re trope ritone al ble e d: may p /w ↓ Hct ± back p ain; ↑ HR & ↓ BP late; Dx w/
abd/p elvic CT (I– ); Rx: reverse/stop anticoag (d/w interventionalist),
IVF/PRBC/p lts as required
if bleeding uncontrolled, consult p erforming interventionalist or surgery

• Vascular damage (~1% of dx angio, ~5% of PCI; Circ 2 007;115:2 666)
p seudoaneurysm: triad of p ain, exp ansile mass, systolic bruit; Dx: U/S; Rx (if
p ain or >2 cm): manual or U/S-directed comp ression, thrombin injection or
surgical rep air
AV fistula: continuous bruit; Dx: U/S; Rx: surgical rep air
LE ischemia (emboli, dissection, clot): cool, mottled extremity, ↓ distal p ulses; Dx:
p ulse volume recording (PVR), angio; Rx: p ercutaneous or surgical rep air
• Peri-PCI MI: >5× ULN of Tn/CK-MB + either sx or ECG/angio Δs; Qw MI in <1%
• Renal failure: contrast-induced manifests w/in 2 4 h, p eaks 3–5 d (see “CIAKI” )
• Cholesterol emboli syndrome (typ ically in middle-aged & elderly and w/ Ao

atheroma)
renal failure (late and p rogressive, eos in urine); mesenteric ischemia (abd p ain,
LGIB, p ancreatitis); intact distal p ulses but livedo p attern and toe necrosis
• Stent thrombosis: mins to yrs after PCI, typ ically p /w AMI. Due to mech p rob.
(stent underexp ansion or unrecognized dissection, typ ically p resents early) or d/c
of antiplt Rx (esp . if d/c both ASA & P2 Y 12 inhib; JAMA 2 005;2 93:2 12 6). Risk of
late stent thrombosis may be higher with DES than BMS ( JACC 2 006;48 :2 58 4).
• In-stent restenosis: mos after PCI, typ ically p /w gradual ↑ angina (10% p /w ACS).
Due to combination of elastic recoil and neointimal hyp erp lasia; ↓ w/ DES vs.
BMS.
ACUTE CORONARY SYNDROMES
Ddx (causes of myocardial ischemia/infarction other than atherosclerotic plaque

rupture)
• Nonatherosclerotic coronary artery disease
Sp asm: Prinzmetal’s variant, cocaine-induced (6% of CP + cocaine use r/i for MI)
Dissection: sp ontaneous (vasculitis, CTD, p regnancy), aortic dissection with
retrograde extension (usually involving RCA → IMI) or mechanical (catheter,
surgery, trauma)
Embolism: endocarditis, p rosthetic valve, mural thrombus, AF, myxoma;

thrombosis
Vasculitis: Kawasaki syndrome, Takayasu arteritis, PAN, Churg-Strauss, SLE, RA
Congenital: anomalous origin from aorta or PA, myocardial bridge (intramural

segment)
• Fixed CAD but ↑ myocardial O 2 demand (eg, ↑ HR, anemia, AS) → “demand”
ischemia
• Myocarditis; Takatsubo/stress CMP; toxic CMP; cardiac contusion
Clinical manifestations ( JAMA 2005; 294:2623)
• Typical angina: retrosternal p ressure/p ain/tightness ± radiation to neck, jaw or

arms
p recip . by exertion, relieved by rest or NTG; in ACS, new-onset, crescendo or at

rest
• Associated symptoms: dysp nea, diap horesis, N/V, p alp itations or lightheadedness
• Many MIs (~2 0% in older series) are initially unrecognized b/c silent or atyp ical sx
Physical exam
• Signs of ischemia: S 4, new MR murmur 2 ° p ap . muscle dysfxn, p aradoxical S 2 ,

diap horesis
• Signs of heart failure: ↑ JVP, crackles in lung fields, S 3, HoTN, cool extremities
• Signs of other areas of atherosclerotic disease: carotid or femoral bruits, ↓ distal

p ulses
Diagnostic studies
• ECG: ST ↓/↑, TWI, new LBBB, hyp eracute Tw. Qw/PRWP may suggest p rior MI, ∴
CAD ✓ ECG w/in 10 min of p resentation, with any Δ in sx and at 6–12 h;
comp are w/ baseline
dx of STEMI if old LBBB: ≥1 mm STE concordant w/ QRS (Se 73% , Sp 92 % ), STD

≥1 mm V1–V3 (Se 2 5% , Sp 96% ) or STE ≥5 mm discordant w/ QRS (Se 31% ,
Sp 92 % )
• Cardiac biomarkers (Tn p referred, or CK-MB): ✓ Tn at baseline & 3–6 h after sx

onset; a rise to >99th % ile in ap p rop . clinical setting dx of MI (see “Chest Pain” );
nb, in Pts w/ ACS & ↓ CrCl, ↑ Tn still p ortends p oor p rognosis (NEJM
2 002 ;346:2 047)
• If low p rob, stress test, CT angio or rest p erfusion imaging to r/o CAD (see “Chest
Pain” )
• TTE (new wall motion abnl) suggestive of ACS; coronary angio gold standard for
CAD
Prinzmetal’s (variant) angina
• Coronary sp asm → transient STE usually w/o MI (but MI, AVB, VT can occur)
• Pts usually young, smokers, ± other vasosp astic disorders (eg, migraines,
Raynaud’s)
• Angiograp hy → nonobstructive CAD, focal sp asm w/ hyp erventilation, acetylcholine

• Treatment: high-dose CCB, nitrates (+SL NTG p rn), ? a-blockers; d/c smoking
• Cocaine-induced vasosp asm: use CCB, nitrates, ASA; ? avoid bB, but data weak and
labetalol ap p ears safe (Archive s 2 010;170:8 74; Circ 2 011;12 3:2 02 2 )
Approach to triage
• If hx and initial ECG & biomarkers non-dx, rep eat ECG & biomarkers 3–6 h later
• If remain nl and low likelihood of ACS, search for alternative causes of chest p ain
• If remain nl, have ruled out MI, but if susp icion for ACS based on hx, then still need
to r/o UA w/ stress test to assess for inducible ischemia (or CTA to r/o CAD);
if low risk (age ≤70; p rior CAD, CVD, PAD; rest angina) can do as outPt w/in
72 h (0% mortality, <0.5% MI, Ann Eme rg Me d 2 006;47:42 7)
if not low risk, admit and initiate Rx for p ossible ACS and consider stress test or
cath
Coronary angiography (Circ 2007; 116:e148 & 2012; 126:875)
• Conservative strategy = selective angiograp hy. Medical Rx with p re-d/c stress test;
angio only if recurrent ischemia or strongly ETT. Indicate d for: low TIMI risk
score, Pt or p hysician p reference in absence of high-risk features, low-risk women
(JAMA 2 008 ;300:71).
• Invasive strategy = routine angiograp hy w/in 72 h

Imme diate (w/in 2 h) if: refractory/recurrent ischemia, hemodynamic or electrical
instability
Early (w/in 24 h) if: Tn, ST Δ, TRS ≥3, GRACE risk score >140 (NEJM
2 009;360:2 165)
De laye d (ie , acce ptable anytime w/in 72 h) if: diabetes, EF <40% , GFR <60, p ost-
MI angina, PCI w/in 6 mo, p rior CABG or high-risk stress results
32 % ↓ rehosp for ACS, nonsignif 16% ↓ MI, no Δ in mortality c/w cons. (JAMA
2 008 ;300:71)
↑ p eri-PCI MI counterbalanced by ↓↓ in sp ont. MI
Mortality benefit seen in some studies, likely only if cons. strategy w/ low rate of
angio
Figure 1-2 Ap p roach to UA/NSTEMI
STEMI
Requisite STE (at J point)
• ≥2 contiguous leads w/ ≥1 mm (excep t for V2 –V3: ≥2 mm in and ≥1.5 mm
in )
• New or p resumed new LBBB
Reperfusion (“time is muscle”)

• Immediate rep erfusion (ie, op ening occluded culp rit coronary artery) is critical
• In PCI-cap able hosp ital, goal should be primary PCI w/in 90 min of 1st medical
contact
• In non-PCI-cap able hosp ital, consider transfe r to PCI-cap able hosp ital (see below),
o/w fibrinolytic therapy w/in 30 min of hosp ital p resentation
• Do not let decision regarding me thod of rep erfusion delay time to rep erfusion
Primary PCI (NEJM 2007; 356:47)
• Indic: STE + sx <12 h; ongoing ischemia 12 –2 4 h after sx onset; shock regardless

of time
• Sup erior to lysis: 2 7% ↓ death, 65% ↓ reMI, 54% ↓ stroke, 95% ↓ ICH (Lance t
2 003;361:13)
• Thrombus asp iration during angio p rior to stenting ↓ mortality (Lance t

2 008 ;371:1915)
• Do not intervene on nonculp rit lesions; risk stratify w/ imaging stress (Circ
2 011;12 4:e574)
• Transfe r to center for 1° PCI may also be sup erior to lysis (NEJM 2 003;349:733), see
below
Fibrinolysis
• Indic: STE/LBBB + sx <12 h; benefit if sx >12 h less clear; reasonable if p ersist.
sx & STE
• Mortality ↓ ~2 0% in anterior MI or LBBB and ~10% in IMI c/w rep erfusion Rx

• Prehosp ital lysis (ie, ambulance): further 17% ↓ in mortality ( JAMA
2 000;2 8 3:2 68 6)
• ~1% risk of ICH; high-risk group s include elderly (~2 % if >75 y), women, low wt
• Although age not contraindic., ↑ risk of ICH in elderly (>75 y) makes PCI more
attractive
Nonprimary PCI
• Facilitated PCI: up stream lytic, GPI or GPI + ½ dose lytic before PCI offers no
benefit
• Rescue PCI if shock, unstable, failed rep erfusion or p ersistent sx (NEJM
2 005;353:2 758 )
• Routine angio ± PCI w/in 2 4 h of successful lysis: ↓ D/MI/revasc (Lance t

2 004;364:1045) and w/in 6 h ↓ reMI, recurrent ischemia, & HF comp ared to w/in
2 wk (NEJM 2 009;360:2 705);
∴ if lyse d at non-PCI capable hospital, conside r transfe r to PCI-capable hospital

ASAP e sp. if hig h-risk pre se ntation (e g , ante rior MI, infe rior MI w/ low EF or RV
infarct, e xte nsive STE or LBBB, HF, ↓ BP or ↑ HR)
• Late PCI (median day 8 ) of occluded infarct-related artery: no benefit (NEJM
2 006;355:2 395)
LV failure (~25% )
• Diurese to achieve PCWP 15–2 0 → ↓ p ulmonary edema, ↓ myocardial O 2 demand
• ↓ Afterload → ↑ stroke volume & CO, ↓ myocardial O 2 demand
can use IV NTG or nitrop russide (risk of coronary steal) → short-acting ACEI
• Inotrop es if HF desp ite diuresis & ↓ afterload; use dop amine, dobutamine or
milrinone
• Cardiogenic shock (~7% ) = MAP <60 mmHg, CI <2 L/min/m 2 , PCWP >18
mmHg; inotrop es, mech sup p ort [eg, VAD, IABP (trial w/o benefit NEJM
2 012 ;367:12 8 7)] to keep CI >2 ; p ressors to keep MAP >60; if not done already,
coronary revasc (NEJM 1999;341:62 5)
IMI complications (Circ 1990; 81:401; NEJM 1994; 330:1211; JACC 2003; 41:1273)
• Heart block (~2 0% , occurs because RCA typ ically sup p lies AV node)
40% on p resent., 2 0% w/in 2 4 h, rest by 72 h; high-grade AVB can develop

abrup tly
Rx: atrop ine, ep i, aminop hylline (100 mg/min × 2 .5 min), temp wire
• RV infarct (30–50% , but only ½ of those clinically signif). HoTN; ↑ JVP,

Kussmaul’s; 1 mm STE in V4R; RA/PCWP ≥0.8 ; RV dysfxn on TTE; p rox RCA
occl.
Rx: op timize p reload (RA goal 10–14, BHJ 1990;63:98 ); ↑ contractility
(dobutamine); maintain AV synchrony (p acing as necessary); rep erfusion (NEJM
1998 ;338 :933); mechanical sup p ort (IABP or RVAD); p ulmonary vasodilators
(eg, inhaled NO)
Mechanical complications (incid. <1% for each; typically occur a few days post-
MI)
• Free wall rupture: ↑ risk w/ lysis, large MI, ↑ age, , HTN; p /w PEA or hyp oTN,
p ericardial sx, tamp onade; Rx: volume resusc., ? p ericardiocentesis, inotrop es,
surgery
• VSD: large MI in elderly; AMI → ap ical VSD, IMI → basal sep tum; 90% w/ harsh
murmur ±
thrill (NEJM 2 002 ;347:142 6); Rx: diuretics, vasodil., inotrop es, IABP, surgery,
p erc. closure
• Papillary muscle rupture: more common after inf MI (PM p ap . muscle sup p lied by
PDA alone) than ant MI (AL p ap . muscle sup p lied by diags & OMs); 50% w/ new
murmur, rarely a thrill, ↑ v wave in PCWP tracing; asymmetric p ulmonary edema.
Rx: diuretics, vasodilators, IABP, surgery.
Arrhythmias post-MI
• Treat as p er ACLS for unstable or symp tomatic bradycardias & tachycardias
• AF (10–16% incidence): β-blocker or amio, ± digoxin (p articularly if HF), hep arin
• VT/VF: lido or amio × 6–2 4 h, then reassess; ↑ βB as tol., rep lete K & Mg, r/o
ischemia;
early monomorp hic (<48 h p ost-MI) does not carry bad p rognosis
• Accelerated idioventricular rhythm (AIVR): slow VT (<100 bp m), often seen after
successful rep erfusion; typ ically self-terminates and does not require treatment
• May consider backup transcutaneous pacing (TP) if: 2 ° AVB typ e I, BBB
• Backup TP or initiate transvenous pacing if: 2 ° AVB typ e II; BBB + AVB
• Transvenous pacing (TV) if: 3° AVB; new BBB + 2 ° AVB typ e II; alternating
LBBB/RBBB (can bridge w/ TP until TV, which is best accomp lished under
fluoroscop ic guidance)
Prognosis
• In registries, in-hosp ital mortality is 6% w/ rep erfusion Rx (lytic or PCI) and ~2 0%

w/o
• Predictors of mortality: age, time to Rx, anterior MI or LBBB, heart failure (Circ
2 000;102 :2 031)
PREDISCHARGE CHECKLIST AND LONG-TERM POST-ACS MANAGEMENT
Risk stratification
• Stress test if anatomy undefined; consider stress if signif residual CAD p ost-PCI of
culp rit
• Assess LVEF p rior to d/c; EF ↑ ~6% in STEMI over 6 mo ( JACC 2 007;50:149)
Medications (barring contraindications)

• Aspirin: 8 1 mg daily
• P2Y12 inhib (eg, clop i, p rasugrel or ticagrelor): ≥12 mo if stent (min 1 mo after
BMS); some PPIs interfere w/ biotransformation of clop i and ∴ p lt inhibition, but
no convincing imp act on clinical outcomes (Lance t 2 009;374:98 9; NEJM
2 010;363:1909); use w/PPIs if h/o GIB or multip le GIB risk factors ( JACC
2 010;56:2 051)
• β-blocker: 2 3% ↓ mortality after MI
• Statin: high-intensity lip id-lowering (eg, atorvastatin 8 0 mg, NEJM 2 004;350:1495)

• ACEI: lifelong if HF, ↓ EF, HTN, DM; 4–6 wk or at least until hosp . d/c in all STEMI
? long-term benefit in CAD w/o HF (NEJM 2 000;342 :145 & 2 004;351:2 058 ; Lance t
2 003;362 :78 2 )
• Aldosterone antag: 15% ↓ death if EF <40% & either DM or s/s of HF (NEJM
2 003;348 :1309)
• Nitrates: standing if symp tomatic; SL NTG p rn for all

• Oral anticoagulants: if warfarin needed in addition to ASA/clop i (eg, AF or LV
thrombus), target INR 2 –2 .5. ? stop ASA if at high bleeding risk on trip le Rx
(Lance t 2 013;38 1:1107). Low-dose rivaroxaban (2 .5 mg bid) in addition to ASA &
clop i → 16% ↓ D/MI/stroke and 32 % ↓ all-cause death, but ↑ major bleeding and
ICH (NEJM 2 012 ;366:9).
ICD (NEJM 2008; 359:2245)

• If sust. VT/VF >2 d p ost-MI not due to reversible ischemia
• Indicated in 1° p revention of SCD if p ost-MI w/ EF ≤30–40% (NYHA II–III) or ≤30–

35% (NYHA I); need to wait ≥40 d after MI (NEJM 2 004;351:2 48 1 &
2 009;361:142 7)
Risk factors and lifestyle modifications (Circ 2011; 124:2458)
• Low chol. (<2 00 mg/d) & fat (<7% saturated) diet; LDL goal <70 mg/dL; ? Ω ;-3
FA
• BP <140/90 mmHg; smoking cessation
• If diabetic, tailor HbA1c goal based on Pt (avoid TZDs if HF)
• Exercise (30–60 min 5–7 ×/wk); cardiac rehab; BMI goal 18 .5–2 4.9 kg/m 2
• Influenza vaccination (Circ 2 006;114:1549); screen for dep ression

PA CATHETER AND TAILORED THERAPY
Rationale
• Cardiac outp ut (CO) = SV × HR; SV dep ends on LV end-diastolic volume (LVEDV)

∴ manip ulate LVEDV to op timize CO while minimizing p ulmonary edema
• Balloon at tip of catheter inflated → floats into “wedge” p osition. Column of blood
extends from tip of catheter, through p ulmonary circulation, to a p oint just
p roximal to LA. Under conditions of no flow, PCWP LA p ressure LVEDP,
which is p rop ortional to LVEDV.
• Situations in which these basic assump tions fail:
(1) Catheter tip not in West lung zone 3 (and ∴ PCWP = alveolar p ressure ≠ LA
p ressure); clues include lack of a & v waves and if PA diastolic p ressure < PCWP
(2 ) PCWP > LA p ressure (eg, mediastinal fibrosis, p ulmonary VOD, PV stenosis)
(3) Mean LA p ressure > LVEDP (eg, MR, MS)
(4) Δ LVEDP-LVEDV relationship (ie, abnl comp liance, ∴ “nl” LVEDP may not be
op timal)
Indications ( JACC 1998; 32:840 & Circ 2009; 119:e391)
• Diagnosis and evaluation

Ddx of shock (cardiogenic vs. distributive; esp . if trial of IVF failed or is high risk)
and of p ulmonary edema (cardiogenic vs. not; esp . if trial of diuretic failed or is
high risk)
Evaluation of CO, intracardiac shunt, p ulmonary HTN, MR, tamp onade

Evaluation of unexp lained dysp nea (PAC during p rovocation w/ exercise,
vasodilator)
• Therapeutics (Circ 2 006;113:102 0)
Tailored therap y to op timize PCWP, SV, S vO 2 in heart failure (incl end-stage) or

shock
Guide to vasodilator therap y (eg, inhaled NO, nifedip ine) in p ulm HTN, RV
infarction
Guide to p eriop erative management in some high-risk Pts, p retransp lantation
• Contraindications
Absolute: right-sided endocarditis, thrombus/mass or mechanical valve; PE
Relative: coagulop athy (reverse), recent PPM or ICD (p lace under fluoroscop y),
LBBB (~5% risk of RBBB → CHB, p lace under fluoro), biop rosthetic R-sided
valve
Efficacy concerns (NEJM 2006; 354:2213; JAMA 2005; 294:1664)
• No benefit to routine PAC use in high-risk surgery, sep sis, ARDS
• No benefit in decomp ensated HF ( JAMA 2 005;2 94:162 5); untested in cardiogenic

shock
• But: ~½ of CO & PCWP clinical estimates incorrect; CVP & PCWP not well correl.;
∴ use PAC to (a) answer hemodynamic ? and then remove, or (b) manage
cardiogenic shock
Placement
• Insertion site: R internal jugular or L subclavian veins for “anatomic” flotation

into PA
• Inflate balloon (max 1.5 mL) when advancing and to measure PCWP
• Use resistance to inflation and p ressure tracing to avoid overinflation & risk of PA
rup ture
• Deflate the balloon when withdrawing and at all other times
• CXR should be obtained after p lacement to assess for catheter p osition and PTX
• If catheter cannot be successfully floated (typ ically if severe TR or RV dilatation) or
if another relative contraindication exists, consider fluoroscop ic guidance
Complications
• Central venous access: p neumo/hemothorax (~1% ), arterial p uncture (if
inadvertent cannulation w/ dilation → surgical/endovasc eval), air embolism,
thoracic duct injury
• Advancement: atrial or ventricular arrhythmias (3% VT; 2 0% NSVT and >50%

PVC), RBBB (5% ), catheter knotting, cardiac p erforation/tamp onade, PA rup ture
• Maintenance: infection (esp . if catheter >3 d old), thrombus, p ulm infarction
(≤1% ), valve/chordae damage, PA rup ture/p seudoaneurysm (esp . w/ PHT),
balloon rup ture
Intracardiac pressures
• Transmural p ressure ( p reload) = measured intracardiac p ressure – intrathoracic

p ressure
• Intrathoracic p ressure (usually slightly ) is transmitted to vessels and heart
• Always measure intracardiac pressure at end-expiration, when intrathoracic

p ressure closest to 0 (“high p oint” in sp ont. breathing Pts; “low p oint” in Pts on
p ressure vent.)
• If ↑ intrathoracic p ressure (eg, PEEP), measured PCWP ove re stimate s true transmural
p ressures. Can ap p rox by subtracting ~½ PEEP (× ¾ to convert cm H 2 O to
mmHg).
• PCWP: LV p reload best estimated at a wave; risk of p ulmonary edema from avg
PCWP
Cardiac output
• Thermodilution: saline injected in RA. Δ in temp over time measured at thermistor

(in PA) is integrated and is 1/CO. Inaccurate if ↓ CO, sev TR or shunt.
• Fick method: O 2 consump tion ( O 2 ) (L/min) = CO (L/min) × ∆ arteriovenous O 2

content
∴ CO = O2 / C(a-v)O2
O 2 ideally measured (esp . if ↑ metab demands), but freq estimated (12 5
mL/min/m 2 )
C(a-v)O 2 = [10×1.36 mL O 2 /g of Hb × Hb g/dL × (S a O 2 –S vO 2 )]. S vO 2 is ke y

variable that Δs.
If S VO 2 >8 0% , consider if the PAC is “wedged” (ie, p ulm vein sat), L→R shunt,
imp aired O 2 utilization (severe sep sis, cyanide, carbon monoxide), ↑↑ FiO 2 .
Tailored therapy in cardiogenic shock (Circ 2009; 119:e391)
• Goals: op timize both MAP and CO while ↓ risk of p ulmonary edema

MAP = CO × SVR; CO = HR × SV (which dep ends on p reload, afterload and
contractility)
p ulmonary edema when PCWP >2 0–2 5 (↑ levels may be tolerated in chronic HF)
• Optimize preload = LVEDV LVEDP LAP PCWP (NEJM 1973;2 8 9:12 63)
goal PCWP ~14–18 in acute MI, ≤14 in acute decompensated HF
op timize in individual Pt by measuring SV w/ different PCWP to create Starling

curve
↑ by giving NS (albumin w/o clinical benefit over NS; PRBC if significant anemia)
↓ by diuresis (qv), ultrafiltration or dialysis if refractory to diuretics
• Optimize afterload wall stress during LV ejection = [(~SBP × radius) / (2 ×
wall thick.)] and ∴ ∝ MAP and ∝ SVR = (MAP – CVP / CO); goals: MAP >60,
SVR 800–1200
MAP >60 & SVR ↑: vasodilators (eg, nitrop russide, NTG, ACEI, hydral.) or wean
p ressors
MAP <60 & SVR ↑ (& ∴ CO ↓): temp orize w/ p ressors until can ↑ CO (see below)
MAP <60 & SVR low/nl (& ∴ inap p rop riate vasop legia): vasop ressors (eg,
norep inep h-rine [a, b], dop amine [D, a, b], p henylep hrine [a] or vasop ressin
[V1] if refractory)
• Optimize contractility ∝ CO for given p reload & afterload; goal CI = (CO / BSA)
>2.2
if too low desp ite op timal p reload & vasodilators (as MAP p ermits):
inotrope s: eg, dobutamine (mod inotrop e & mild vasodilator) or milrinone

(strong inotrop e & vasodilator, incl p ulm), both p roarrhythmic, or ep i (strong
inotrop e & p ressor)
me chanical support de vice s: eg, IABP, p ercutaneous or surgical VAD (left-sided,

right-sided or both) or ECMO (Circ 2 011;12 3:533)
HEART FAILURE
Definitions (Braunwald’s Heart Disease, 9th ed., 2012)
• Failure of heart to p ump blood forward at sufficient rate to meet metabolic demands
of p erip heral tissues, or ability to do so only at abnormally high cardiac filling
p ressures
• Low outp ut (↓ cardiac outp ut) vs. high outp ut (↑ stroke volume ± ↑ cardiac outp ut)
• Left-sided (p ulmonary edema) vs. right-sided (↑ JVP, hep atomegaly, p erip heral
edema)
• Backward (↑ filling p ressures, congestion) vs. forward (imp aired systemic p erfusion)
• Systolic (inability to exp el sufficient blood) vs. diastolic (failure to relax and fill
normally)
• Reduced (HFrEF) vs. p reserved (HFp EF) left ventricular ejection fraction
• Some degree of systolic and diastolic dysfxn, may occur regardless of ejection
fraction
Figure 1-3 Ap p roach to left-sided heart failure
History
• Low outp ut: fatigue, weakness, exercise intolerance, Δ MS, anorexia
• Congestive: left-sided → dysp nea, orthop nea, p aroxysmal nocturnal dysp nea right-
sided → p erip heral edema, RUQ discomfort, bloating, satiety
Functional classification (New York Heart Association class)
• Class I: no sx w/ ordinary activity; class II: sx w/ ordinary activity; class III: sx w/

minimal activity; class IV: sx at rest
Physical exam (“2-minute” hemodynamic profile; JAMA 1996; 275:630 &
2002; 287:628)
• Congestion (“dry” vs. “wet”)

↑ JVP (~8 0% of the time JVP >10 → PCWP >2 2 ; J He art Lung Trans
1999;18 :112 6)
hep atojugular reflux: >4 cm ↑ in JVP for ≥15 sec w/ abdominal p ressure
Se/Sp 73/8 7% for RA >8 and Se/Sp 55/8 3% for PCWP >15 (AJC
1990;66:1002 )
Abnl Valsalva resp onse: square wave (↑ SBP w/ strain), no overshoot (no ↑ BP
after strain)
S 3 (in Pts w/ HF → ~40% ↑ risk of HF hosp . or p ump failure death; NEJM
2 001;345:574)
rales, dullness at base 2 ° p leural effus. (ofte n abse nt in chronic HF due to
lymp hatic comp ensation) ± hep atomegaly, ascites and jaundice, p erip heral
edema
• Perfusion (“warm” vs. “cold”)
narrow p ulse p ressure (<2 5% of SBP) → CI <2 .2 (91% Se, 8 3% Sp ; JAMA

198 9;2 61:8 8 4)
soft S 1 (↓ dP/dt), p ulsus alternans, cool & p ale extremities, ↓ UOP, muscle
atrop hy
• ± Other: Cheyne-Stokes resp ., abnl PMI (diffuse, sustained or lifting dep ending on
cause of HF), S 4 (diast. dysfxn), murmur (valvular dis., ↑ MV annulus, disp laced
p ap illary muscles)
Evaluation for the presence of heart failure

• CXR (see Radiology insert): p ulm edema, p leural effusions ± cardiomegaly,
cep halization, Kerley B-lines
• BNP/NT-p roBNP can help exclude HF; levels ↑ w/ age, ↓ w/ obesity, ↓ renal fxn, AF
• Evidence of ↓ organ p erfusion: ↑ Cr, ↓ Na, abnl LFTs

• Echo (see inserts): ↓ EF & ↑ chamber size → systolic dysfxn; hyp ertrop hy, abnl MV
inflow, abnl tissue Dop p ler → ? diastolic dysfxn; abnl valves or p ericardium;
estimate RVSP
• PA catheterization: ↑ PCWP, ↓ CO and ↑ SVR (in low-outp ut failure)
Evaluation of the causes of heart failure
• ECG: evidence for CAD, LVH, LAE, heart block or low voltage (? infiltrative
CMP/DCMP)
• Coronary angio (or noninvasive imaging, eg, CT angio); if no CAD, w/u for CMP
Precipitants of acute heart failure

• Dietary indiscretion or medical nonadherence (~40% of cases)
• Myocardial ischemia or infarction (~10–15% of cases); myocarditis
• Renal failure (acute, p rogression of CKD, or insufficient dialysis) → ↑ p reload
• Hypertensive crisis (incl. from RAS), worsening AS → ↑ left-sided afterload
• Drugs (bB, CCB, NSAIDs, TZDs), chemo (anthracyclines, trastuzumab), or toxins

(EtOH)
• Arrhythmias; acute valvular dysfxn (eg, endocarditis), esp . mitral or aortic

regurgitation
• COPD or PE → ↑ right-sided afterload; anemia, systemic infection, thyroid disease
Treatment of acute decompensated heart failure
• Assess degree of congestion & adequacy of p erfusion

• For congestion: “LMNOP”
Lasix IV w/ monitoring of UOP; total daily dose 2 .5× usual daily PO dose → ↑
UOP, but transient ↑ in renal dysfxn vs. 1× usual dose; clear diff between cont
gtt vs. q12 h dosing (NEJM 2 011;364:797)
Morp hine (↓ sx, venodilator, ↓ afterload)

Nitrates (venodilator)
Oxygen ± noninvasive vent (↓ sx, ↑ Pa O 2 ; no ∆ mortality; see “Mechanical

Ventilation” )
Position (sitting up & legs dangling over side of bed → ↓ p reload)
• For low perfusion, see below
• Adjustment of oral meds
ACEI/ARB: hold if HoTN, consider Δ to hydralazine & nitrates if renal

decomp ensation
βB: reduce dose by at least ½ if mod HF, d/c if severe HF and/or need inotrop es
Treatment of advanced heart failure (Circ 2009; 119:e391)
• Consider PAC if not resp to Rx, unsure re: vol status, HoTN, ↑ Cr, need inotrop es
• Tailored Rx w/ PAC (qv); goals of MAP >60, CI >2 .2 (MVO 2 >60% ), SVR <8 00,
PCWP <18
• IV vasodilators: NTG, nitrop russide (risk of coronary steal if CAD; p rolonged use →
cyanide/thiocyanate toxicity); nesiritide (rBNP) not rec for routine use (NEJM
2 011;365:32 )
• Inotropes (p rop erties in addition to ↑ inotrop y listed below)
dobutamine: vasodilation at doses ≤5 µg/kg/min; mild ↓ PVR; desensitization

over time
dop amine: sp lanchnic vasodil. → ↑ GFR & natriuresis; vasoconstrictor at ≥5

µg/kg/min
milrinone: p rominent systemic & p ulmonary vasodilation; ↓ dose by 50% in renal
failure
• Ultrafiltration: similar wt loss to aggressive diuresis, but ↑ renal failure (NEJM
2 012 :367:2 2 96)
• Mechanical circulatory support (Circ 2 011;12 3:533)
Intra-aortic balloon p ump (IABP): inflates in diastole & deflates in systole to ↓
imp edance to LV ejection of blood, ↓ myocardial O 2 demand & ↑ coronary
p erfusion
ventricular assist device (LVAD ± RVAD): as bridge to recovery (NEJM
2 006;355:18 73) or transp lant (some temp orary typ es can be p laced
p ercutaneously = PVAD), or as destination therap y (45–50% ↓ mort. vs. med
Rx; NEJM 2 009;361:2 2 41)
• Cardiac transp lantation: 15–2 0% mort. in 1st y, median survival 10 y
• Utility of BNP-guided Rx remains debated (Circ 2 013;301:500 & 509)
• Imp lantable PA p ressure sensor in NYHA III → ~30% ↓ risk of hosp (Lance t
2 011;377:658 )
Heart failure with preserved EF (HFpEF; “Diastolic HF”) (Circ 2011; 124:e540)
• Ep idemiology: ~½ of Pts w/ HF have normal or only min. imp aired systolic fxn (EF
≥40% ); risk factors for HFp EF incl ↑ age, , DM, AF. Mortality to those w/
systolic dysfxn.
• Etiologies (imp aired relaxation and/or ↑ p assive stiffness): ischemia, p rior MI, LVH,
HCMP, infiltrative CMP, RCMP, aging, hyp othyroidism
• Precip itants of p ulmonary edema: volume ove rload (p oor comp liance of LV →
sensitive to even modest ↑ in volume); ische mia (↓ relaxation); tachycardia (↓ filling
time in diastole), AF (loss of atrial boost to LV filling); HTN (↓ afterload → ↓
stroke volume)
• Dx w/ clinical s/s of HF w/ p reserved systolic fxn. Dx sup p orted by evidence of diast
dysfxn:
(1) echo: abnl MV inflow (E/A reversal and Δs in E wave deceleration time) & ↓
myocardial relax. (↑ isovol relax. time & ↓ early diastole tissue Dop p ler vel)
(2 ) exercise-induced ↑ PCWP (± ↓ resp onse chronotrop ic & vasodilator reserve)
• Treatment: diuresis for vol overload, BP control, p revention of tachycardia and
ischemia;
no benefit to: ACEI/ARB (NEJM 2 008 ;359:2 456), PDE5 inhib ( JAMA
2 013;309:12 68 )
sp ironolactone imp roves LV fxn, but not sx ( JAMA 2 013;309:78 1)
combined ARB/nep rilysin (neutral endop ep tidase) inhib under study (Lance t
2 012 ;38 0:138 7)
CARDIOMYOPATHIES
Dise ase s with me chanical and/or e le ctrical dysfunction of the myocardium

DILATED CARDIOMYOPATHY (DCMP)
Definition and epidemiology (Circ 2006; 113:1807)
• Ventricular dilatation and ↓ contractility ± ↓ wall thickness
• Incidence: 5–8 /100,000/yr; p revalence: 1/2 500. Most common reason for heart
transp lant.
Etiologies (NEJM 2000; 342:1077; Circ Res 2012; 111:131)

• Ischemia/infarct: systolic dysfxn & dilation due to p oor remodeling p ost-MI
• Valvular disease: systolic dysfxn due to chronic volume overload in MR & AI
• Familial (~2 5% ): mutations in cytoskeletal, nuclear and filament p roteins (NEJM
1992 ;362 :77)
• Idiopathic (~2 5% ): ? undiagnosed infectious, alcoholic or genetic cause
• Infectious myocarditis (10–15% , autoimmune resp onse; Lance t 2 012 ;379:738 )

Viruses (p arvoB19 & HHV6 > coxsackie, adeno, echo, CMV, HCV): from subacute
(dilated LV, mild–mod dysfxn) to fulminant (nondil., thick, edematous LV, sev
dysfxn)
Bacterial, fungal, rickettsial, TB, Lyme (mild myocarditis, often with AVB)
HIV: ~8 % of asx HIV ; due to HIV, other virus or antiretrovirals; HIV also
associated w/ p remature CAD (Circ 2 008 ;118 :e36; He art 2 009;95:1193)
Chagas: ap ical aneurysm ± thrombus, RBBB, megaesop hagus/colon (NEJM

1993;32 9:639)
• Toxic: alcohol (5% ) typ . 7–8 drinks/d × >5 y, but variable; cocaine; XRT (usu
RCMP);
anthracyclines (risk ↑ >550 mg/m 2 , may manifest late), cyclop hosp hamide,
trastuzumab
• Infiltrative (5% ): often mix of DCMP + RCMP (qv) with thickened wall
amyloidosis, sarcoidosis, hemochromatosis, tumor
• Autoimmune: collag e n vasc. dis. (3% ): PM, SLE, scleroderma, PAN, RA, Wegener’s;
pe ripartum (last month → 5 mo p ostp artum; JACC 2 011;58 :659): ~1:3000 p reg. ↑
risk w/ multip arity, ↑ age, Afr Am; stnd HF Rx excep t if p reg then select drugs
based on safety; ? bromocrip tine to ↓ p rolactin; ~½ normalize EF; even if nl EF
~30% recur w/ next p reg
Idiop athic giant cell myocarditis (GCM): avg age 42 y, fulminant, VT (NEJM
1997;336:18 60)
Eosinop hilic (variable p erip heral eos): hyp ersensitivity (mild HF) or acute
necrotizing eosinop hilic myocarditis (ANEM; STE, effusion, severe HF)
• Stress-induced (Takotsubo = ap ical ballooning): mimics MI (p ain, ± STE & ↑ Tn;
deep TWI & ↑ QT); mid/ap ex dyskinesis; ? Rx w/ bB, ACEI; usu. imp roves over
wks (JAMA 2 011;306:2 77)
• Tachycardia: likelihood ∝ rate/duration; often resolves w/ rate cntl (Circ

2 005;112 :1092 )
• Arrhythmogenic right ventricular cardiomyopathy (ARVC): fibrofatty rep lacement

of RV → dilation (dx w/ MRI); ECG: ± RBBB, TWI V1–V3, e wave; risk VT (Lance t
2 009;373:12 8 9)
• Metab/other: hyp othyroid., acromegaly, p heo, OSA, thiamine, selenium or
carnitine defic
Clinical manifestations
• Heart failure: both congestive & p oor forward flow sx; signs of L- & R-sided HF
diffuse, laterally displaced PMI, S3, ± MR or TR (annular dilat., disp laced p ap .

muscle)
• Embolic events (~10% ), sup raventricular/ventricular arrhythmias, & p alp itations
• Chest p ain can be seen w/ some etiologies (eg, myocarditis)
Diagnostic studies and workup

• CXR: moderate to marked cardiomegaly, ± p ulmonary edema & p leural effusions
• ECG: may see PRWP, Q waves or BBB; low-voltage; AF (2 0% ); may be normal
• Echocardiogram: LV dilatation, ↓ EF, re g ional or g lobal LV HK ± RV HK, ± mural

thrombi
• Cardiac MRI: up to 76% Se, 96% Sp for myocarditis or infiltrative dis. ( JACC
2 005;45:18 15); extent of midwall fibrosis correlated w/ mortality in NICMP
( JAMA 2 013;309:8 96)
• Laboratory evaluation: TFTs, iron studies, HIV, SPEP, ANA; others p er clinical
susp icion; viral serologies not recommended ( JACC 2 012 ;59:779)
• Family hx (2 0–35% w/ familial dis.), genetic counseling ± genetic testing ( JAMA

2 009;302 :2 471)
• Stress test: useful to r/o ischemia (low false rate), high false rate, even w/
imaging
• Coronary angiograp hy to r/o CAD if risk factors, h/o angina, Qw MI on ECG,

equivocal ETT; consider CT angiograp hy (JACC 2 007;49:2 044)
• ? Endomyocardial biop sy (JACC 2 007;50:1914): yield 10% (of these, 75%

myocarditis, 2 5% systemic disease); 40% false rate (p atchy dis.) & false
(necrosis → inflammation)no p roven Rx for myocarditis; ∴ biop sy if: acute &
hemodyn comp romise (r/o GCM, ANEM); arrhythmia or RCMP features (r/o
infiltrative); or susp ect toxic, allergic, tumor
Treatment (see “Heart Failure” for standard HF Rx)
• Imp lantation of devices may be temp ered by p ossibility of reversibility of CMP
• Immunosup p ression: for giant cell myocarditis (p rednisone + AZA), collagen

vascular disease, p erip artum (? IVIg), & eosinop hilic; no p roven benefit for viral
myocarditis
• Prognosis differs by etiology (NEJM 2 000;342 :1077): p ostp artum (best),

ischemic/GCM (worst)
HYPERTROPHIC CARDIOMYOPATHY (HCMP)
Definition and epidemiology
• LV (usually ≥15 mm) and/or RV hyp ertrop hy disp rop ortionate to hemodynamic
load
• Prevalence: 1/500; 50% sp oradic, 50% familial, most asymp tomatic
• Ddx: LVH 2 ° to HTN, AS, elite athletes (wall usually <13 mm & symmetric and nl/↑
rates of tissue Dop p ler diastolic relaxation; Circ 2 011;12 3:2 72 3), Fabry dis. (↑ Cr,
skin findings)
Pathology
• Autosomal dominant mutations in cardiac sarcomere genes (eg, b-myosin heavy
chain)
• Myocardial fiber disarray with hyp ertrop hy, which creates arrhythmogenic substrate
• Morp hologic hyp ertrop hy variants: asymmetric sep tal; concentric; midcavity;
ap ical
Pathophysiology
• Subaortic outflow obstruction: narrowed tract 2 ° hyp ertrop hied sep tum + systolic
anterior motion (SAM) of ant. MV leaflet (may be fixed, variable or nonexistent)
and p ap illary muscle disp lacement. Gradient (∇) worse w/ ↑ contractility
(digoxin, b- agonists, exercise, PVCs), ↓ p reload or ↓ afterload.
• Mitral regurgitation: due to SAM (mid-to-late, p ost.-directed regurg. jet) and/or abnl
mitral leaflets and p ap illary muscles (p ansystolic, ant.-directed regurg. jet)
• Diastolic dysfunction: ↑ chamber stiffness + imp aired relaxation
• Ischemia: small vessel dis., p erforating artery comp ression (bridging), ↓ coronary
p erfusion
• Syncop e: Δs in load-dep endent CO, arrhythmias

Clinical manifestations (70% are asymptomatic at dx)
• Dyspnea (90% ): due to ↑ LVEDP, MR, and diastolic dysfunction
• Angina (2 5% ) even w/o ep icardial CAD; microvasc. dysfxn (NEJM 2 003;349:102 7)
• Arrhythmias (AF in 2 0–2 5% ; VT/VF) → p alp itations, syncop e, sudden cardiac

death
Physical exam
• Sustained PMI, S 2 p aradoxically sp lit if severe outflow obstruction, S 4 (occ.

p alp able)
• Systolic murmur: crescendo-decrescendo; LLSB; ↑ w/ Valsalva & standing (↓
p reload)
• ± mid-to-late or holosystolic murmur of MR at ap ex

• Bifid carotid p ulse (brisk rise, decline, then 2 nd rise); JVP w/ p rominent a wave
• Contrast to AS, which has murmur that ↓ w/ Valsalva and ↓ carotid p ulses
Diagnostic studies
• CXR: cardiomegaly (LV and LA)
• ECG: LVH, anterolateral and inferior p seudo-Qw, ± ap ical giant TWI (ap ical
variant)
• Echo: no absolute cutoffs for degree of LVH but sep tum/p ost. wall ≥1.3 suggestive,
as is sep tum >15 mm; other findings include dynamic outflow obstruction, SAM,
MR
• MRI: hyp ertrop hy + p atchy delayed enhancement (useful for dx & p rog) ( JACC CV
Imag 2 012 ;2 :370)
• Cardiac cath: subaortic p ressure ∇; Brocke nbroug h sig n = ↓ p ulse p ressure p ost-
PVC (in contrast to AS, in which p ulse p ressure ↑ p ost-PVC)
• ? Genotyp ing for family screening, but p athogenic mutation ID’d in <½ (Circ
2 011;12 4:2 761)
Treatment (Circ 2011; 124:e783 & 2012; 125:1432; Lancet 2013; 381:242)
• Heart failure
inotropes/chronotropes: b-blockers, CCB (verap amil), disop yramide
Careful use of diuretics, as may further ↓ p reload. Vasodilators only if systolic

dysfxn. Avoid digoxin.
If sx refractory to drug Rx + obstructive p hysiology (∇ >50 mmHg):
(a) Surgical myectomy: long-term ↓ symp toms in 90% (Circ 2 005;112 :48 2 )
(b) Alcohol sep tal ablation (Circ CV Inte rv 2 011;4;2 56; JACC 2 011;58 :2 32 2 ):
gradient ↓ by ~8 0% , only 5–2 0% remain w/ NYHA III–IV sx; 14% require
rep eat ablation or myectomy. Good alternative for older Pts, multip le
comorbidities. Comp lic: transient (& occ. delayed) 3° AVB w/ 10–2 0% req. PPM;
VT due to scar formation.
No clear benefit of dual-chamber p acing ( JACC 1997;2 9:435; Circ 1999;99:2 92 7)
If refractory to drug therap y and there is nonobstructive p athop hysiology:

transp lant
• Acute HF: can be p recip . by dehydration or tachycardia; Rx w/ fluids, bB,

p henylep hrine
• AF: rate control with bB, maintain SR with disop yramide, amiodarone
• SCD: ICD ( JACC 2 003;42 :168 7). Risk factors: h/o VT/VF, FHx SCD,
unexp lained syncop e, NSVT, ↓ SBP or rel HoTN (↑ SBP <2 0 mmHg) w/ exercise,
LV wall ≥30 mm, extensive MRI delayed enhancement. EPS not useful. Risk 4% /y
if high-risk (JAMA 2 007;2 98 :405).
• Counsel to avoid dehydration, extreme exertion
• Endocarditis p rop hylaxis not recommended (Circ 2 007;16:1736)
• First-degree relatives: p eriodic screening w/ echo, ECG (as timing of HCMP onset
variable). Genetic testing if known mutation.
RESTRICTIVE CARDIOMYOPATHY (RCMP)
Definition (Circ 2006; 113:1807)
• Imp aired ventricular filling with ↓ comp licance in nonhyp ertrop hied, nondilated
ventricles; normal or ↓ diastolic volumes, normal or near-normal EF; must r/o
p ericardial disease
Etiology ( JACC 2010; 55:1769)
• Myocardial processes
Autoimmune (scleroderma, p olymyositis-dermatomyositis)
Infiltrative diseases (see p rimary entries for extracardiac manifestations, Dx, Rx)
Amyloidosis (CIrc 2 011;12 4:1079): age at p resentation ~60 y; : = 3:2 AL

(MM, light-chain, MGUS, WM); familial (transthyretin, TTR); AA/senile (TTR,
ANP) ECG: ↓ QRS amp litude (50% ), p seudoinfarction p attern (Qw), AVB (10–
2 0% ), hemiblock (2 0% ), BBB (5–2 0% )
Echo: biventricular wall thickening (ye t w/ low voltag e on ECG), granular
sp arkling texture (30% ), biatrial enlargement (40% ), thickened atrial
sep tum, valve thickening (65% ), diastolic dysfxn, small effusions
Normal voltage & normal sep tal thickness has NPV ~90%
MRI: distinct late gadolinium enhancement p attern ( JACC 2 008 ;51:102 2 )
Sarcoidosis: age at p resent. ~30 y; more common in blacks, N. Europ eans,

women
5% of those w/ sarcoid have overt cardiac involvement; cardiac w/o systemic
in 10%
ECG: AVB (75% ), RBBB (2 0–60% ), VT; PET: ↑ FDG up take in affected area
Echo: regional WMA (p articularly basal sep tum) with thinning or mild
hyp ertrop hy
Nuclear imaging: gallium up take in areas of sestaMIBI p erfusion defects;
cardiac MR
Hemochromatosis: in middle-aged men (esp . N. Europ ean); 15% p /w cardiac sx

Storage diseases: Gaucher’s, Fabry, Hurler’s, glycogen storage diseases
Diabetes mellitus
• Endomyocardial processes
Chronic eosinop hilic: Löffler’s endocarditis (temp erate climates; ↑ eos; mural
thrombi that embolize); endomyocardial fibrosis (trop ical climates; var. eos;
mural thrombi)
Toxins: radiation (also p /w constrictive p ericarditis, valvular dis, ostial CAD),
anthracyclines
Serotonin: carcinoid, serotonin agonists, ergot alkaloids
Metastatic cancer
Pathology & pathophysiology
• Path: normal or ↑ wall thickness ± infiltration or abnormal dep osition
• ↓ myocardial comp liance → nl EDV but ↑ EDP → ↑ systemic & p ulm. venous
p ressures
• ↓ ventricular cavity size → ↓ SV and ↓ CO
Clinical manifestations (Circ 2000; 101:2490)
• Right-sided > left-sided heart failure with p erip heral edema > p ulmonary edema
• Diuretic “refractoriness”
• Thromboembolic events
• Poorly tolerated tachyarrhythmias; VT → syncop e/sudden cardiac death
Physical exam
• ↑ JVP, ± Kussmaul’s sign ( JVP ↑ w/ insp iration, classically seen in constrictive

pe ricarditis)
• Cardiac: ± S 3 and S 4, ± murmurs of MR and TR
• Congestive hep atomegaly, ± ascites and jaundice, p erip heral edema

Diagnostic studies
• CXR: normal ventricular chamber size, enlarged atria, ± p ulmonary congestion

• ECG: low voltage, p seudoinfarction p attern (Qw), ± arrhythmias
• Echo: symmetric wall thickening, biatrial enlarge., ± mural thrombi, ± cavity

oblit. w/ diast dysfxn: ↑ early diast (E) and ↓ late atrial (A) filling, ↑ E/A ratio, ↓
decel. time
• Cardiac MRI/PET: may reveal inflammation or evidence of infiltration (but
nonsp ecific)
• Cardiac catheterization
Atria: M’s or W’s (p rominent x and y descents)

Ventricles: dip & plateau (rap id ↓ p ressure at onset of diastole, rap id ↑ to early
p lateau)
Concordance of LV and RV p ressure p eaks during resp iratory cycle (vs.

discordance in constrictive p ericarditis; Circ 1996;93:2 007)
• Endomyocardial biop sy if susp ect infiltrative p rocess
• Restrictive cardiomyop athy vs. constrictive p ericarditis: see “Pericardial Disease”

Treatment (in addition to Rx’ing underlying disease)
• Gentle diuresis. May not tolerate CCB or other vasodilators.
• Control HR (but can ↓ CO); maintain SR (help s filling). Digoxin ↑ arrhythmias in

amyloid.
• Anticoagulation (p articularly with AF or low CO)
• Transp lantation for refractory cases

VALVULAR HEART DISEASE
AORTIC STENOSIS (AS)
Etiology
• Calcific: p redominant cause in Pts >70 y; risk factors include HTN, ↑ chol., ESRD
• Congenital (ie, bicusp id AoV w/ p remature calcification): cause in 50% of Pts <70
y
• Rheumatic heart disease (AS usually accomp anied by AI and MV disease)
• AS mimickers: subvalvular (HCMP, subAo membrane) or sup ravalvular stenosis
Clinical manifestations (usually indicates AVA <1 cm2 or concomitant CAD)

• Angina: ↑ O 2 demand (hyp ertrop hy) + ↓ O 2 sup p ly (↓ cor p erfusion p ressure) ±
CAD
• Syncope (e xe rtional): p erip heral vasodil. w/ fixed CO → ↓ MAP → ↓ cerebral

p erfusion
• Heart failure: outflow obstruct + diastolic dysfxn → p ulm. edema; esp . if ↑ HR/AF
(↓ LV fill.)
• Acquired vWF disease (~2 0% of sev. AS): destruction of vWF; GI angiodysp lasia
• Natural hx: usually slowly p rogressive (AVA ↓ ~0.1 cm 2 /y, but varies; Circ
1997;95:2 2 62 ), until sx develop ; mean survival based on sx: angina = 5 y;
syncop e = 3 y; CHF = 2 y
Physical exam
• Midsystolic crescendo-decrescendo murmur at RUSB, harsh, high-p itched, radiates
to carotids, ap ex (holo-systolic = Gallavardin effect), ↑ w/ p assive leg raise, ↓ w/
standing & Valsalva. In contrast, dynamic outflow obstruction (HCMP) ↓ w/ leg
raise, ↑ w/ standing, Valsalva.
• Ejection click after S1 sometimes heard with bicuspid AoV
• Signs of severity: late -pe aking murmur, p aradoxically sp lit S 2 or inaudible A2 ,

small and delayed carotid p ulse (“pulsus parvus e t tardus” ), LV heave, S4
(occasionally p alp able)
Diagnostic studies
• ECG: may see LVH, LAE, LBBB, AF (in late disease)
• CXR: cardiomegaly, AoV calcification, p oststenotic dilation of ascending Ao,

p ulmonary congestion
• Echo: valve morp hology, estim p ressure gradient & calculate AVA, EF
• Cardiac cath: usually to r/o CAD (in ~½ of calcific AS); for hemodyn. if disp arity
between exam & echo: ✓ p ressure gradient (∇) across AoV, calc AVA (underestim.
if mod/sev AI)
• Dobutamine challenge during echo or cath if low EF and ∇ <30 to differentiate:

afte rload mismatch: 2 0% ↑ SV & ∇, no Δ AVA (imp lies contractile reserve & ↑ EF
p ost-AVR)
pse udoste nosis: 2 0% ↑ SV, no Δ in ∇, ↑ AVA (imp lies low AVA artifact of LV
dysfxn)
limite d contractile re se rve : no Δ SV, ∇ or AVA (imp lies EF p rob. will not imp rove
w/ AVR)
Treatment (Circ 2008; 118:e523; Lancet 2009; 373:956; EHJ 2012; 33:2451)
• Management decisions are based on symptoms: once they develop AVR is needed.
If asx, HTN can be cautiously Rx’d; statins have not been p roven to ↓ p rogression.
• AVR: indicated in sx AS (almost invariably severe; if not, look for another cause of
sx) & asx severe AS + EF < 50% . May consider if asx but either sx or ↓ BP w/
exercise (can care fully exercise asx AS to uncover sx, do not exercise sx AS) or
extremely severe (AVA <0.6 cm 2 , mean ∇ >60 mmHg, aortic jet >5 m/s).
Reasonable if asx mod-severe AS and undergoing CV surgery.
• Medical (if not AVR candidate or to temp orize): careful diuresis p rn, control HTN,
maintain SR; digoxin if ↓ EF & HF or if AF; avoid venodilators (nitrates) &
inotrop es (bB/CCB) if severe; avoid vigorous p hysical exertion once AS mod–
severe;
? nitrop russide if p /w CHF w/ sev. AS, EF <35% , CI <2 .2 , & nl BP (NEJM
2 003;348 :1756)
• IABP: stabilization, bridge to surgery
• Balloon AoV valvotomy (BAV): 50% ↑ AVA & ↓ p eak ∇, but 50% restenosis by 6–
12 mo &
↑ risk of p eri-PAV stroke/AI (NEJM 198 8 ;319:12 5), ∴ bridge to AVR or p alliation
• Transcatheter AoV replacement (TAVR): sx, hemodyn, & mortality to surgical

AVR, but ↑ (mostly early) risk of vasc comp lic and stroke/ TIA; p aravalvular
leaks in ~7% (NEJM 2 012 ;366:168 6); in nonop erative Pts, 44% ↓ mortality vs.
standard Rx (NEJM 2 012 ;366:1696)
AORTIC INSUFFICIENCY (AI)
Etiology (Circ 2006; 114:422)
• Valve disease (43% )

rheumatic heart disease (usually mixed AS/AI and concomitant MV disease)
bicuspid AoV: natural hx: 1⁄3→ normal, 1⁄3 → AS, 1⁄6 → AI, 1⁄6 → endocarditis
→ AI infective endocarditis
valvulitis: RA, SLE; anorectics (fen/p hen) & other serotoninergics (NEJM
2 007;356:2 9,39), XRT
• Root disease (57% )
HTN
aortic aneurysm or dissection, annuloaortic ectasia, Marfan syndrome

aortic inflammation: giant cell, Takayasu’s, ankylosing sp ond., reactive arthritis,
syp hilis
• Acute: sudden ↓ forward SV and ↑ LVEDP (noncomp liant ventricle) → p ulmonary
edema ± hyp otension and cardiogenic shock
• Chronic: clinically silent while LV dilates (to ↑ comp liance to keep LVEDP low) more
than it hyp ertrop hies → chronic volume overload → LV decomp ensation → CHF
• Natural hx: variable p rogression (unlike AS, can be fast or slow); once
decomp ensation begins, p rognosis p oor w/o AVR (mortality ~10% /y)
Physical exam
• Early diastolic decrescendo murmur at LUSB (RUSB if dilated Ao root); ↑ w/
sitting forward, exp ir, handgrip ; severity of AI ∝ duration of murmur (excep t in
acute and severe late); Austin Flint murmur: mid-to-late diastolic
rumble at ap ex (AI jet interfering w/ mitral inflow)
• Wide pulse pressure due to ↑ stroke volume, hyp erdynamic p ulse → many of
classic signs (see table); p ulse p ressure narrows in late AI with ↓ LV fxn; bisferiens
(twice-beating) arterial p ulse
• PMI diffuse and laterally disp laced; soft S 1 (early closure of MV); ± S 3 (≠ ↓ EF but
rather just volume overload in AI)
Diagnostic studies
• ECG: can see LVH, LAD, abnl rep ol; CXR: cardiomegaly ± ascending Ao dilatation
• Echo: severity of AI (severe = width of regurgitant jet >65% LVOT, vena contracta
>0.6 cm, regurg fraction ≥50% , regurg orifice ≥0.3 cm 2 , flow reversal in
descending Ao); LV size & fxn
Treatment (Circ 2008; 118:e523; EHJ 2012; 33:2451)
• Acute decomp ensation (consider ischemia and endocarditis as p ossible p recip itants):
surg e ry usually urgently needed for acute severe AI which is p oorly tolerated by LV
IV afterload reduction (nitrop russide) and inotrop ic sup p ort (dobutamine)
± chronotrop ic sup p ort (↑ HR → ↓ diastole → ↓ time for regurgitation)

p ure vasoconstrictors and IABP contraindicated
• In chronic AI, management decisions based on LV size and fxn (and before sx occur)
• Surgery (AVR, rep lacement or rep air if p ossible)
sx (if equivocal, consider stress test) severe AI (if not severe, unlikely to be cause
of sx)
asx severe AI and EF ≤ 50% or LV dilation (end syst. diam. >50–55 mm or end
diast. diam. >70–75 mm, esp . if p rogression) or undergoing cardiac surgery
• Transcatheter AoV rep lacement (TAVR) being exp lored ( JACC 2 013;61:1577)
• Medical therap y: vasodilators (nifedip ine, ACEI/ARB, hydralazine) if severe AI w/ sx

or LV dysfxn & Pt not op erative candidate or to imp rove hemodynamics before
AVR; no clear benefit on clinical outcomes or LV fxn when used to try to p rolong
comp ensation in asx severe AI w/ mild LV dilation & nl LV fxn (NEJM
2 005;353:1342 )
MITRAL REGURGITATION (MR)
Etiology (Lancet 2009; 373:1382; NEJM 2010; 363:156)
• Leaflet abnormalities: myxomatous degeneration (MVP), endocarditis, calcific
RHD, valvulitis (collagen-vascular disease), congenital, anorectic drugs, XRT

• Functional: inferoap ical papillary muscle displacement due to ischemic LV
remodeling or other causes of DCMP; LV annular dilation due to LV dilation
• Rup tured chordae tendinae: myxomatous, endocarditis, sp ontaneous, trauma
• Acute p ap illary muscle dysfxn b/c of ischemia or rupture during MI [usu.
p osteromedial p ap illary m. (sup p lied by PDA only) vs. anterolateral (sup p l. by
diags & OMs)]
• HCMP: (see “Cardiomyop athy” )

• Acute: pulmonary edema, hyp otension, cardiogenic shock (NEJM 2 004;351:162 7)

• Chronic: typ ically asx for yrs, then as LV fails → p rogressive DOE, fatigue, AF, PHT
• Prognosis: 5-y survival w/ medical therap y is 8 0% if asx, but only 45% if sx

Physical exam
• High-pitched, blowing, holosystolic murmur at apex; radiates to axilla; ± thrill;

↑ w/ handgrip (Se 68 % , Sp 92 % ),
↓ w/ Valsalva (Se 93% ) (NEJM 198 8 ;318 :1572 )
ant. leaflet abnl → p ost. jet heard at sp ine
p ost. leaflet abnl → ant. jet heard at sternum

• ± diastolic rumble b/c ↑ flow across valve
• Lat. disp l. hyp erdynamic PMI, obscured S 1, widely sp lit S 2 (A2 early b/c ↓ LV
afterload, P2 late if PHT); ± S 3
• Carotid up stroke brisk (vs. diminished and delayed in AS)

Diagnostic studies (NEJM 2005; 352:875)
• ECG: may see LAE, LVH, ± atrial fibrillation
• CXR: dilated LA, dilated LV, ± p ulmonary congestion
• Echo: MV anatomy (ie, etiol); MR severity: jet area (can underestimate eccentric
jets), jet width at origin (vena contracta) or effective regurgitant orifice (ERO;
p redicts survival); LV fxn (EF should be supranormal if comp ensated, ∴ EF <60%
w/ sev. MR = LV dysfxn); TEE if TTE inconclusive or p re/intraop to guide rep air
vs. rep lace
• Cardiac cath: p rominent PCWP c-v waves (not sp ec. for MR), LVgram for MR
severity & EF
Treatment (Circ 2008; 118:e523; NEJM 2009; 361:2261; EHJ 2012; 33:2451)
• Acute decomp ensation (consider ischemia and endocarditis as p recip itants)

IV afterload reduction (nitrop russide), ± inotrop es (dobuta), IABP, avoid
vasoconstrictors
surg e ry usually needed for acute severe MR as p rognosis is p oor w/o MVR
• Surgery (rep air [p referred if feasible] vs. rep lacement w/ p reservation of mitral
ap p aratus)
sx severe MR, asx severe MR and EF 30–60% or LV sys. diam. >40 mm
consider MV re pair for asx severe MR w/ p reserved EF, esp . if new AF or PHT
if AF, maze p rocedure or p ulm vein isolation may → NSR and p revent future
stroke
• In Pts undergoing CABG w/ mod–sev fxnal MR, consider annulop lasty ring
• Percutaneous MV rep air: edge-to-edge clip less effective than surgery, but ? consider
for elderly, fxnal MR or low EF (NEJM 2 011;364:1395); p ercutaneous valve under
study
• Medical: clinical benefit in asx Pts; bB p reserve LV fxn ( JACC 2 012 ;60:8 33); if sx
but not op erative candidate ↓ preload (↓ HF and MR by ↓ MV orifice): diuretics,
nitrates (esp . if ischemic/fxnal MR); if LV dysfxn: ACEI, bB, ± BiV p acing;
maintain SR
MITRAL STENOSIS (MS)
Etiology (Lancet 2012; 379:953)
• Rheumatic heart disease (RHD): fusion of commissure s → “fish mouth” valve
from autoimmune rxn to b strep infxn; seen largely in develop ing world today
• Mitral annular calcification (MAC): encroachment up on leaflets → functional MS
• Congenital, infectious endocarditis w/ large lesion, myxoma near MV, thrombus
• Valvulitis (eg, SLE, amyloid, carcinoid) or infiltration (eg, mucop olysaccharidoses)
Clinical manifestations (Lancet 2009; 374:1271)

• Dyspnea and pulmonary edema (if due to RHD, sx usually begin in 30s)
p recip itants: exercise, fever, anemia, volume overload (incl. p regnancy),
tachycardia, AF
• Atrial fibrillation: onset often p recip itates heart failure in Pts w/ MS

• Embolic events: commonly cerebral, esp . in AF or endocarditis
• Pulmonary: hemop tysis, frequent bronchitis (due to congestion), PHT, RV failure

• Ortner’s syndrome: hoarseness from LA comp ression of recurrent laryngeal nerve
Physical exam
• Low-pitched mid-diastolic rumble at apex w/ p resystolic accentuation (if not in

AF); best heard in L lat decubitus p osition during exp i- ration, ↑ w/ exercise;
severity p rop ortional to duration (not intensity) of murmur
• Opening snap (high-p itched early diastolic sound at ap ex) from fused leaflet tip s;
MVA p rop ortional to S 2 –OS interval (tighter
valve → ↑ LA p ressure → shorter interval)
• Loud S 1 (unless MV calcified)

Diagnostic studies
• ECG: LAE (“P mitrale” ), ± AF, ± RVH
• CXR: dilated LA (straightening of left heart border, double density on right, left
mainstem bronchus elevation)
• Echo: estimate p ressure gradient (∇), RVSP, valve area, valve echo score (0–16,
based on leaflet mobility & thick., subvalvular thick., Ca ++); exer. TTE (to assess
∆ RVSP and ∇) if sx & severity of MS at rest discrep ant; TEE to assess for LA
thrombus before PMV
• Cardiac cath: ∇ from simultaneous PCWP & LV p ressures, calculated MVA; LA

p ressure tall a wave and blunted y descent; ↑ PA p ressures
Treatment (NEJM 1994; 331:961; Circ 2002; 105:1465 & 2008; 118:e523; EHJ
2012; 33:2451)
• Medical: Na restriction, cautious diuresis, bB, sx-limited p hysical stress
• Antibiotic Pp x recommended if h/o RHD w/ valvular disease for 10 y or until age 40
• Anticoag if: AF, p rior embolism, LA thrombus; ? LA >55 mm or lg LA w/ sp ont

contrast
• Mechanical intervention if: heart failure sx w/ MVA ≤1.5, or
heart failure sx w/ MVA >1.5 but ↑ PASP, PCWP, or MV ∇ w/ exercise, or

asx Pts w/ MVA ≤1.5 and PHT (PASP >50 or >60 mmHg w/ exercise) or new-
onset AF
• Percutaneous mitral valvotomy (PMV): p referred Rx if RHD; MVA doubles, ∇↓ by

50% ; MVR if valve score <8 , ≤ mild MR, AF or LA clot
• Surgical (MV rep air if p ossible, o/w rep lacement): consider in sx Pts w/ MVA ≤1.5
if PMV unavailable/contraindicated (mod. MR, LA clot), or valve morp hology

unsuitable
• Pregnancy: if NYHA class III/IV → PMV, o/w medical Rx w/ low-dose diuretic & bB
MITRAL VALVE PROLAPSE (MVP)
Definition and Etiology
• Billowing of MV leaflet ≥2 mm above mitral annulus in p arasternal long axis echo

view
• Leaflet redundancy from myxomatous p roliferation of sp ongiosa of MV ap p aratus
• Idiop athic, familial and a/w connective tissue diseases (eg, Marfan’s, Ehlers-Danlos)
• Prevalence 1–2 .5% of gen. p op ulation, > (NEJM 1999;341:1), most common
cause of MR
Clinical manifestations (usually asymptomatic)

• MR (from leaflet p rolap se or rup tured chordae); infective endocarditis; embolic
events
• Arrhythmias, rarely sudden cardiac death

Physical exam
• High-p itched, midsystolic click ± mid-to-late systolic murmur
• ↓ LV volume (standing) → click earlier; ↑ LV volume or afterload → click later,

softer
Treatment
• Endocarditis p rop hylaxis no longer recommended (Circ 2 007:116:1736)

• Asp irin or anticoagulation if p rior neurologic event or atrial fibrillation
TRICUSPID REGURGITATION
• Primary etiol: rheumatic, CTD, radiation, IE, Ebstein’s anomaly, carcinoid, tumors
• Fxnal etiol: RV and/or p ulm HTN (may be 2 ° to L-sided dis.), RV dilation and/or
infarct
• Consider rep air, annuop lasty or rep lacement for sx and severe TR (eg, ERO ≥0.40
cm 2 )
PROSTHETIC HEART VALVES
Mechanical (60% )
• Bileaflet (eg, St. Jude Medical); tilting disk; caged-ball
• Very durable (2 0–30 y), but thrombogenic and ∴ require anticoagulation

consider if age <~65 y or if anticoagulation already indicated ( JACC
2 010;55:2 413)
Bioprosthetic (40% )
• Bovine pericardial or p orcine heterograft (eg, Carp entier-Edwards), homograft
• Less durable, but min. thrombogenic; consider if >~65 y, lifesp an <2 0 y or
anticoag
Physical exam
• Normal: crisp sounds, ± soft murmur during forward flow (normal to have small
∇)
• Abnormal: regurgitant murmurs, absent mechanical valve closure sounds
Anticoagulation & antiplatelet therapy (Circ 2008; 118:e523; JAMA

2012; 308:2118)
• Assess for hig h-risk fe ature s: p rior thromboembolism, AF, EF<30–35% ,
hyp ercoagulable
• Warfarin: low-risk mech AVR: INR 2 –3 (consider 2 .5–3.5 for 1st 3 mo)
mech MVR or high-risk mech AVR: INR 2 .5–3.5
high-risk biop rosthetic: INR 2 –3 (and consider in low-risk for 1st 3 or even ? 6
mo)
• ASA (75–100 mg) for all p rosthetic valves; avoid adding to warfarin if h/o GIB,
uncontrolled HTN, erratic INR or >8 0 y; ASA + clopidogrel (or warfarin) × 3–6
mo after TAVR
• If thrombosis, ↑ intensity (eg, INR 2 –3 → 2 .5–3.5; 2 .5–3.5 → 3.5–4.5; add ASA if

not on)
Correction of overanticoagulation (Circ 2008; 118:e626)
• Risk from major bleeding must be weighed against risk of valve thrombosis
• Not bleeding: withhold warfarin, give vit K 1–2 .5 mg PO only if INR 5–10, ✓ serial
INRs
• Bleeding or INR >10: FFP ± low-dose (1 mg) vit K IV
Endocarditis prophylaxis: for all prosthetic valves (see “Endocarditis”)
Complications
• Structural failure (r/o endocarditis); mechanical valves: rare excep t for Bjork-Shiley;
biop rosthetic valves: up to 30% fail rate w/in 10–15 y, mitral > aortic
• Paravalvular leak (r/o endocarditis); small ce ntral jet of regurg is normal in mech.
valves
• Obstruction from thrombosis or p annus ingrowth: ✓ TTE, TEE and/or fluoroscop y if
? clot significantly sx pannus ingrowth: remove w/ surgery
thrombosis: surgery if L-sided valve & either severe sx or lg (? >1 cm) clot
burden; lytic often ine ffe ctive for L-sided thrombosis & 12 –15% risk of stroke;
consider UFH ± lytic (? low-dose tPA via slow infusion, JACC CV Imag ing
2 013;6:2 06) if mild sx & small clot burden or p oor surg candidate; lytic
reasonable for R-sided
• Infective endocarditis ± valvular abscess and conduction system dis. (see

“Endocarditis” )
• Embolization (r/o endocarditis); risk ~1% /y w/ warfarin (vs. 2 % w/ ASA, or 4%

w/o meds)
mech MVR 2 × risk of embolic events vs. mech AVR (Circ 1994;8 9:635)
• Bleeding (from anticoag), hemolysis (esp . w/ caged-ball valves or p aravalvular
leak)
HEART VALVES (superior view, JAMA 1976; 235:1603)
PERICARDIAL DISEASE
GENERAL PRINCIPLES
Anatomy
• 2 -layered (p arietal & visceral) tissue sac surrounding heart & p roximal great vessels
Disease states
• Inflammation (w/ or w/o fluid accumulation) → p ericarditis
• Fluid accumulation → effusion ± tamp onade
• Decrease in comp liance (sequela of inflammation) → constrictive p ericarditis

• Tamp onade and constriction characterized by increased ventricular interdep endence
PERICARDITIS AND PERICARDIAL EFFUSION
Clinical manifestations (NEJM 2004; 351:2195)
• Pericarditis: retrosternal chest p ain that is p leuritic, p ositional (↓ by sitting

forward), radiates to trap ezius; may be abse nt in tuberculous, neop lastic, p ost-
XRT and uremic p ericarditis; ± fever; ± s/s of systemic etiologies
• Effusion: ranges from asx to tamp onade (see below)
Physical exam
• Pericarditis: multip hasic friction rub best heard at LLSB w/ diap hragm of
stethoscop e. Notoriously variable and evanescent leathery sound w/ up to 3
comp onents: atrial contraction, ventricular contraction, ventricular relaxation
(NEJM 2 012 ;367:e2 0).
• Effusion: distant heart sounds, dullness over left p osterior lung field due to
comp ressive atelectasis from p ericardial effusion (Ewart’s sign)
Diagnostic studies (EHJ 2004; 25:587; Circ 2006; 113:1622 & 2010; 121:916)
• ECG: may show diffuse STE (concave up) & PR dep ression (excep t in aVR: ST ↓ & PR
↑), TWI; classically and in contrast to STEMI, TWI do not occur until STs normalize
Stages: (I) STE & PR ↓; (II) ST & PR normalize; (III) diffuse TWI; (IV) Tw normalize
ECG may show evidence of large effusion w/ low voltage & electrical alternans
(beat-to- beat Δ in QRS amp litude and/or axis due to swinging heart)
• CXR: if large effusion (>2 50 mL of fluid) → ↑ cardiac silhouette w/ “water-bottle”

heart and ep icardial halo
• Echocardiogram: p resence, size, & location of e ffusion; p resence of tamponade

physiolog y; p ericarditis itself w/o sp ec. abnl (∴ echo can be nl), although can see
p ericardial stranding (fibrin or tumor); can also detect LV/RV dysfxn (myocarditis
?)
• CT will reveal p ericardial effusions, often ap p earing larger than on

echocardiograp hy
• CK-MB or trop onin ( in ~30% , JACC 2 003;42 :2 144) if myop ericarditis.
Consider CRP/ESR.
Workup for effusion
• r/o infxn: usually ap p arent from Hx & CXR; ? value of ✓ acute and convalescent
serologies
• r/o noninfectious etiologies: BUN, Cr, ANA, RF, HIV, screen for common
malignancies
• Pericardiocentesis if susp ect infxn or malignancy or large effusion (>2 cm) or
recurrent
✓ cell counts, TP, LDH, glc, Gram stain & Cx, AFB, cytology
ADA, PCR for MTb, and sp ecific tumor markers as indicated by clinical susp icion
“exudate” criteria: TP >3 g/dL, TPeff/TPserum >0.5, LDH eff/LDH serum >0.6 or
glc <60 mg/dL high Se (~90% ) but ve ry low Sp (~2 0% ); overall low utility
(Che st 1997;111:12 13)
• Pericardial bx if susp icion remains for malignancy or tuberculosis
Treatment of pericarditis (EHJ 2004; 25:587; Circ 2006; 113:1622)

• NSAIDs (eg, ibup rofen 600–8 00 mg tid × 7–14 d then tap er) ± colchicine 1–2 mg
× 1 → 0.5–1 mg bid × 3 mo (Circ 2 005;112 :2 012 ; He art 2 012 ;98 :1078 ); sx
usually subside in 1–3 d
• Steroids (usually systemic; occ. intrap ericardial) only for systemic rheum or
autoimmune disorder, uremic, p reg., contraindication to NSAID, or refractory
idiop athic dis.
Systemic steroids ap p ear to ↑ rate of p ericarditis recurrence (Circ 2 008 ;118 :667).
• Avoid anticoagulants
• Infectious effusion → p ericardial drainage (p referably surgically) + systemic

antibiotics
• Acute idiop athic effusion self-limited in 70–90% of cases
• Recurrent p ericarditis (Circ 2 007;115:2 739)
risk factors: subacute, lg effusion/tamp onade, T >38 °C, lack of NSAID resp onse
after 7 d treatment: add colchicine 0.5–1 mg bid × 6 mo (Annals 2 011;155:409)
• Recurrent effusion: consider p ericardial window (p ercutaneous vs. surgical)

PERICARDIAL TAMPONADE
Etiology
• Any cause of p ericarditis but esp . malignancy, uremia, idiopathic, p roximal aortic
dissection with rup ture, myocardial rup ture
• Rap idly accumulating effusions most likely to cause tamp onade as no time for
p ericardium to stretch (eg, to ↑ comp liance) and accommodate ↑ intrap ericardial
fluid volume
Pathophysiology (NEJM 2003; 349:684)
• ↑ intrap ericardial p ressure, comp ression of heart chambers, ↓ venous return → ↓
CO
• Diastolic p ressures ↑ & equalize in all cardiac chambers → minimal flow of blood
from RA to RV when TV op ens → blunted y descent
• ↑ ventricular interdep endence → p ulsus p aradoxus (p athologic exaggeration of nl
p hysio)
Insp iration → ↓ intrap ericardial & RA p ressures → ↑ venous return → ↑ RV size
→ sep tal shift to left. Also, ↑ p ulmonary vascular comp liance → ↓ p ulm venous
return. Result is ↓ LV filling → ↓ LV stroke volume & blood p ressure.
• Cardiogenic shock (hyp otension, fatigue) without pulmonary edema
• Dysp nea (seen in ~8 5% ) may be due to ↑ resp iratory drive to augment venous
return
Physical exam ( JAMA 2007; 297:1810)
• Beck’s triad (p resent in minority of cases): distant heart sounds, ↑ JVP,

hypotension
• ↑ JVP (76% ) w/ blunted y descent
• Reflex tachycardia (77% ), hyp otension (2 6% ; occasionally hyp ertensive), cool

extremities
• Pulsus paradoxus (Se 8 2 % , Sp 70% ) = ↓ SBP ≥10 mmHg during insp iration
LR 3.3 (5.9 if p ulsus >12 ), LR 0.03
Ddx = PE, hyp ovolemia, severe COPD, constriction (~ 1⁄3), RV infarct
Can be absent if p re-existing ↑ LVEDP, arrhythmia, severe AI, ASD, regional

tamp onade
• Distant heart sounds (2 8 % ), ± p ericardial friction rub (30% )

• Tachyp nea but clear lungs
Diagnostic studies
• ECG: ↓ voltage (seen in 42 % ), electrical alternans (2 0% ), ± signs of p ericarditis
• CXR: ↑ cardiac silhouette (8 9% )
• Echocardiogram: effusion, IVC p lethora, septal shift with insp iration
diastolic collapse of RA (Se 8 5% , Sp 8 0% ) and/or RV (Se <8 0% , Sp 90% )
respirophasic Δ’s in transvalvular velocities (↑ across TV & ↓ across MV w/

insp ir.)
p ostsurgical tamp onade may be localized and not easily visible
• Cardiac cath (right heart and p ericardial): elevation (15–30 mmHg) and equalization
of
intrap ericardial and diastolic p ressures (RA, RV, PCWP), blunted y descent in RA
↑ in stroke volume p ostp ericardiocentesis = ultimate p roof of tamp onade

if RA p ressure remains elevated after drainage, may have effusive-constrictive
disease (NEJM 2 004;350:469) or myocardial dysfxn (eg, from concomitant
myocarditis)
Treatment
• Volume (but be careful as overfilling can worsen tamp onade) and inotrop es
(avoid bB)
• Avoid vasoconstrictors as will ↓ stroke volume & p otentially ↓ HR
• Pericardiocentesis (excep t if due to aortic or myocardial rup ture, in which case

consider removing just enough fluid to reverse PEA en route to emergent surgery)
CONSTRICTIVE PERICARDITIS
Etiology (Circ 2011; 124:1270)
• Any cause of p ericarditis (~1–2 % incidence overall after acute p ericarditis)
• Highest risk w/ TB, bacterial, neoplastic, connective tissue, p ostcardiac surgery

• Viral/idiopathic, as most common cause of p ericarditis, also account for signif
p rop ortion
Pathophysiology
• Adhesion of visceral and p arietal p ericardial layers → rigid p ericardium that limits
diastolic filling of ventricles → ↑ systemic venous p ressures
• Venous return is limited only after early rap id filling p hase; ∴ rap id ↓ in RA
p ressure with atrial relaxation and op ening of tricusp id valve and promine nt x and
y de sce nts
• Kussmaul sign: JVP does not decrease with insp iration (↑ venous return with
insp iration but negative intrathoracic p ressure not transmitted to heart because of
rigid p ericardium)
• Right-sided > left-sided heart failure (systemic congestion > p ulmonary congestion)
Physical exam
• ↑ JVP with prominent y descent, Kussmaul sign (Ddx: tricusp id stenosis, acute
cor p ulmonale, RV failure and RV infarct, RCMP)
• Hep atosp lenomegaly, ascites, p erip heral edema. Consider on Ddx of idiop athic
cirrhosis.
• PMI usually not p alp able, pericardial knock, usually no p ulsus p aradoxus
Diagnostic studies
• ECG: nonsp ecific, AF common (up to 33% ) in advanced cases
• CXR: calcification (MTb most common), esp . in lateral view (although not sp ecific)
• Echocardiogram: ± thickened p ericardium, “septal bounce” = abrup t disp lacement

of sep tum during rap id filling in early diastole
• Cardiac catheterization
atria: Ms or Ws (p rominent x and y descents)
ventricles: dip-and-plateau or square-root sign (rap id ↓ p ressure at onset of

diastole, rap id ↑ to early p lateau)
discordance between LV & RV p ressure p eaks during resp iratory cycle (Circ
1996;93:2 007)
• CT or MRI: thickened p ericardium (>4 mm; Se ~8 0% ), w/ tethering (Circ

2 011;12 3:e418 )
Treatment
• Diuresis for intravascular volume overload; surgical p ericardiectomy in advanced

cases
• ? MRI able to p redict reversibility with anti-inflammatory agents (Circ

2 011;12 4:18 30)
HYPERTENSION
BP should be determined by making ≥2 measurements sep arated by >2 min.

Confirm stage 1 w/in 2 mo; can Rx stage 2 immediately.
Epidemiology ( JAMA 2003; 290:199 & 2010; 303:2043)
• Prevalence 30% in U.S. adults; >68 million affected (2 9% in whites, 33.5% in

blacks)
• Only 50% of p atients with dx of HTN have adequate BP control
Etiologies
• Essential (95% ): onset 2 5–55 y; FHx. Unclear mechanism but ? additive

microvasc
renal injury over time w/ contribution of hyp eractive symp athetics (NEJM
2 002 ;346:913).
↑ Age → ↓ arterial comp liance → syst HTN. Genetics also involved (Nature
2 011;478 :103).
• Secondary: Consider if Pt <2 0 or >50 y or if sudden onset, severe, refractory HTN

Standard workup
• Goals: (1) identify CV risk factors or other diseases that would modify p rognosis or
Rx;
(2 ) reveal 2 ° causes of hyp ertension; (3) assess for target-organ damage
• History: CAD, HF, TIA/CVA, PAD, DM, renal insufficiency, sleep ap nea,
p reeclamp sia; FHx for HTN; diet, Na intake, smoking, alcohol, p rescrip tion
and OTC meds, OCP
• Physical exam: ✓ BP in both arms; funduscop ic exam, cardiac (LVH, murmurs),
vascular (bruits, radial-femoral delay), abdominal (masses or bruits), neuro exam
• Testing: K, BUN, Cr, Ca, glc, Hct, U/A, lip ids, TSH, urinary albumin:creatinine (if ↑
Cr, DM, p erip heral edema), ? renin, ECG (for LVH), CXR, TTE (eval for valve abnl,
LVH)
Complications of HTN
• Each ↑ 20 mmHg SBP or 10 mmHg DBP → 2× ↑ CV complications (Lance t
2 002 ;360:1903)
• Neurologic: TIA/CVA, rup tured aneurysms, vascular dementia

• Retinop athy: stage I = arteriolar narrowing; II = cop p er-wiring, AV nicking; III =
hemorrhages and exudates; IV = p ap illedema
• Cardiac: CAD, LVH, HF, AF

• Vascular: aortic dissection, aortic aneurysm (HTN = key risk factor for aneurysms)
• Renal: p roteinuria, renal failure

Treatment (Lancet 2012; 380:591)
• Goal: <140/90 mmHg; if DM or CKD goal is <130/8 0 mmHg (nb, in DM, target of
<12 0 does not ↓ CV risk & ↑ adverse events; NEJM 2 010;362 :1575)
• Tre atme nt re sults in 50 % ↓ HF, 40 % ↓ stroke , 20 –25% ↓ MI (Lance t

2 000;356:1955); benefits of Rx’ing stage II HTN extend to Pts >8 0 y, goal BP
<150/8 0 (NEJM 2 008 ;358 :18 8 7)
• Lifestyle modifications (each ↓ SBP ~5 mmHg)
weight loss: goal BMI 18 .5–2 4.9; aerobic exercise: ≥30 min exercise/d, ≥5 d/wk
diet: rich in fruits & vegetables, low in saturated & total fat (DASH, NEJM
2 001;344:3)
sodium restriction: ≤2 .4 g/d and ideally ≤1.5 g/d (NEJM 2 010;362 :2 102 )
limit alcohol consump tion: ≤2 drinks/d in men; ≤1 drink/d in women & lighter-
wt Pts
• Pharmacologic options (if HTN or p re-HTN + diabetes or renal disease)
Pre-HTN: ARB p revents onset of HTN, no ↓ in clinical events (NEJM

2 006;354:168 5)
HTN: choice of the rapy controve rsial, concomitant dise ase and stag e may he lp g uide
Rx
uncomplicated: thiazide if likely salt sensitive (eg, elderly, black, obese), o/w
start w/ ACEI or CCB (NEJM 2 009;361:2 153). bB not first line (Lance t
2 005;366:1545).
+high-risk CAD: ACEI or ARB (NEJM 2 008 ;358 :1547); ACEI + CCB sup erior to
ACEI + thiazide (NEJM 2 008 ;359:2 417) or bB + diuretic (Lance t 2 005;366:8 95)
+angina: bB, CCB, nitrates
+post-MI: ACEI, bB ± aldosterone antagonist (see “ACS” )
+HF: ACEI/ARB, bB, diuretics, aldosterone antagonist (see “Heart Failure” )
+2° stroke prevention: ACEI (Lance t 2 001;358 :1033); ? ARB (NEJM

2 008 ;359:12 2 5) +diabetes mellitus: ACEI or ARB; can also consider
diuretic, bB or CCB
+chronic kidney disease: ACEI/ARB (NEJM 1993;32 9:1456 & 2 001;345:8 51 &
8 61)
• Tailoring therapy
if stage 1, start w/ monoRx; if not at goal, Δ to different class rather than adding
2 nd agent
if stage 2 , consider starting w/ combo (eg, ACEI + CCB; NEJM 2 008 ;359:2 417) as
most will require ≥2 drugs; low–mod doses of 2 drugs generally p referred over
max dose of 1 drug (b/c of dose-related AEs)
if resistant [= HTN desp ite ≥3 drugs (incl diuretic) at op t doses], consider
noncomp liance, volume overload, secondary causes; ? renal artery denervation
(Lance t 2 010;376:1903)
• Secondary causes
Renovascular: control BP w/ diuretic + ACEI/ARB (watch for ↑ Cr w/ bilat. RAS)
or CCB Atherosclerosis risk-factor modification: quit smoking, ↓ chol. If
refractory HTN, recurrent flash p ulm edema, worse CKD, consider revasc
For atherosclerosis: stenting ↓ restenosis vs. PTA alone, but no clear
imp rovement in BP or renal function vs. med Rx (NEJM 2 009;361:1953;
Annals 2 009;150:8 40)
For FMD (usually more distal lesions): PTA ± bailout stenting

Renal parenchymal disease: salt and fluid restriction, ± diuretics
Endocrine etiologies: see “Adrenal Disorders”
• Pregnancy: methyldop a, labetalol, nifedip ine, hydralazine; avoid diuretics;

ACEI/ARB
HYPERTENSIVE CRISES
• Hypertensive emergency: ↑ BP → acute target-organ ischemia and damage
neurologic damage: encep halop athy, hemorrhagic or ischemic stroke, p ap illedema
cardiac damage: ACS, HF/p ulmonary edema, aortic dissection

renal damage: p roteinuria, hematuria, acute renal failure; scleroderma renal crisis
microangiop athic hemolytic anemia; p reeclamp sia-eclamp sia
• Hypertensive urgency: SBP >18 0 or DBP >12 0 (?110) w/ min. or no target-organ
damage
Precipitants
• Progression of essential HTN ± medical noncomp liance (esp . clonidine) or Δ in diet

• Progression of renovascular disease; acute glomerulonep hritis; scleroderma;
p reeclamp sia
• Endocrine: p heochromocytoma, Cushing’s
• Symp athomimetics: cocaine, amp hetamines, MAO inhibitors + foods rich in

tyramine
• Cerebral injury (do not treat HTN in acute ischemic stroke unless Pt getting lysed,
extreme
BP (>2 2 0/12 0), Ao dissection, active ischemia or HF (Stroke 2 003;34:1056)

Treatment (Chest 2007; 131:1949)
• Tailor goals to clinical context (eg, more rap id lowering for Ao dissection)
• Emergency: ↓ MAP by ~2 5% in mins to 2 h w/ IV agents (may need arterial line for

monitoring); goal DBP <110 w/in 2 –6 h, as tolerated
• Urgency: ↓ BP in hours using PO agents; goal normal BP in ~1–2 d

• Watch UOP, Cr, mental status: may indicate a lower BP is not tolerated
AORTIC ANEURYSMS
Definitions
• True aneurysm (dilation of all 3 layers of aorta) vs. false (rup ture contained by
adventitia)
• Location: root (annuloaortic ectasia), thoracic aortic aneurysm (TAA),

thoracoabdominal aortic aneurysm (TAAA), abdominal aortic aneurysm (AAA)
• Type: fusiform (circumferential dilation) vs. saccular (localized dilation of aortic
wall)
Epidemiology (Circ 2010; 121:e266; Nat Rev Cardiol 2011; 8:92)
• In U.S., ~15,000 deaths/y from aortic rup tures; overall ~50,000 deaths/y from Ao
disease
• TAA: : ~1.7:1; ~60% root/ascending Ao; 40% descending Ao; arch & TAAA
rarer
Risk factors: HTN; atherosclerosis; congenital (bicuspid AoV, Turner’s);
connective tissue diseases (Marfan, Ehlers-Danlos typ e IV, Loeys-Dietz);
aortitis (Takayasu’s, GCA, sp ondyloarthritis, IgG4, syp hilis); familial
syndromes; chronic AoD; trauma
• AAA: ~4–8 % p rev. in those >65 y; 5–10× more common in vs. ; mostly
infrarenal
Risk factors = similar to atherosclerosis: smoking, HTN, hyp erlip idemia, age,
FHx
Pathophysiology (NEJM 2009; 361:1114; Nat Med 2009; 15:649)
• LaPlace’s law: tension across a cylinder ∝ [(ΔP × r) / (wall thickness)]
• TAA: medial degeneration = muscle ap op tosis, elastin fiber weakening, mucoid

infiltration
• AAA: atherosclerosis & inflammation → matrix degeneration → medial weakening

• Inflammatory and infectious (“mycotic” ) aneurysms relatively rare
Screening (Annals 2005; 142:203; JAMA 2009; 302:2015; Circ 2010; 121:e266)
• TAA: no consensus guidelines; ? screen if bicusp id AoV or first-degree relative
• AAA: ✓ for p ulsatile abd mass; U/S >60 y w/ FHx of AAA & 65–75 y w/
p rior tobacco
Diagnostic studies (Circ 2005; 111:816 & 2010; 121:e266)
• Contrast CT: quick, noninvasive, high Se & Sp for all aortic aneurysms
• TTE/TEE: TTE most useful for root and p roximal Ao; TEE can visualize other sites of
TAA
• MRI: p referred over CT for aortic root imaging for TAA; also useful in AAA but time-
consuming; noncontrast “black blood” MR to assess aortic wall
• Abdominal U/S: screening and surveillance test of choice for infrarenal AAA
Treatment (Circ 2006; 113:e463; 2008; 177:1883; 2010; 121:1544 & e266)
• Risk factor modification: smoking cessation, statin to achieve LDL-C <70 mg/dL
• BP control: bB (↓ dP/dt) ↓ aneurysm growth (NEJM 1994;330:1335); ACEI a/w ↓
risk of rup ture (Lance t 2 006;368 :659), ARB may ↓ rate of aortic root growth in
Marfan (NEJM 2 008 ;358 :2 78 7); no burst activity/exercise requiring Valsalva
maneuvers (eg, heavy lifting)
• Indications for surgery: individualize based on FHx, body size, gender
TAA: sx; asc Ao ≥5.5 cm (? 5.0 cm Marfan, bicusp id AoV; 4.2 –4.4 cm Loeys-
Dietz); descending >6 cm; ↑ >0.5 cm/y; aneurysm ≥4.5 cm and p lanned AoV
surgery
AAA: infrarenal ≥5.5 cm (NEJM 2 002 ;346:1437) but consider ≥5.0 cm in ; sx;
↑ >0.5 cm/y; inflam/infxn
• Endovascular aneurysm repair (EVAR) (NEJM 2 008 ;358 :494; Circ 2 011;12 4:2 02 0)
↓ short-term mort., bleeding, LOS; but long-term graft comp lic. (3–4% /y;
endoleak, need for reintervention, rup ture) necessitate p eriodic surveillance, with
no p roven Δ in overall mortality, excep t ? in those <70 y (NEJM
2 010;362 :18 63, 18 8 1 & 2 012 ;367:198 8 )
Guidelines sup p ort op en rep air or EVAR for infrarenal AAA in good surg
candidates
In Pts unfit for surgery or high p eri-op risks: ↓ aneurysm-related mortality but no
Δ in overall mortality over medical Rx (NEJM 2 010;362 :18 72 ). EVAR
noninferior (? sup erior) to op en rep air in rup tured AAA w/ favorable anatomy
(Ann Surg 2 009;2 50:8 18 ).
TEVAR (thoracic EVAR) for descending TAA ≥5.5 cm may ↓ p eri-op morbidity, no
p roven mortality benefit (Circ 2 010;12 1:2 78 0; JACC 2 010;55:98 6; J Thorac CV
Surg 2 010;140:1001)
Complications (Circ 2010; 121:e266; Nat Rev Cardiol 2011; 8:92)
• Pain: gnawing chest, back or abdominal p ain; new or worse p ain may signal
rup ture
• Rupture: risk ↑ w/ diameter, , current smoking, HTN
TAA: ~2 .5% /y if <6 cm vs. 7% /y if >6 cm; AAA: ~1% /y if <5 cm vs. 6.5% /y
if 5–5.9 cm
rup ture p /w severe constant p ain and hemorrhagic shock; ~8 0% mortality at 2 4

h
• Acute aortic syndromes (qv)
• Thromboembolic ischemic events (eg, to CNS, viscera, extremities)
• Compression of adjacent structures (eg, SVC, trachea, esop hagus, laryngeal nerve)
Follow-up (Circ 2010; 121:e266; Nat Rev Cardiol 2011; 8:92; JAMA 2013; 309:806)
• Exp ansion rate ~0.1 cm/y for TAA, ~0.3–0.4 cm/y for AAA
• AAA: q3y if 3–3.9 cm; q6–12 mo if 4.0–5.4 cm (? q2 y if 4–4.4)
• TAA: 6 mo after dx to ensure stable, then annually.
• Screen for CAD, PAD and aneurysms elsewhere, esp . p op liteal. About 2 5% of Pts w/
TAA will also have AAA, and 2 5% of AAA Pts will have a TAA: consider p an-Ao
imaging.
ACUTE AORTIC SYNDROMES
Definitions (Circ 2003; 108:628 & 2010; 121:e266; Eur Heart J 2012; 33:26)
• Aortic dissection: intimal tear → blood extravasates into Ao media (creates false
lumen)
• Intramural hematoma (IMH): vasa vasorum rup ture → medial hemorrhage that
does not communicate with aortic lumen; 6% of aortic syndromes; clinically
identical to AoD
• Penetrating ulcer: atherosclerotic p laque p enetrates elastic lamina → medial
hemorrhage
Classification (proximal twice as common as distal)

• Proximal: involves ascending Ao, regardless of origin (= Stanford A, DeBakey I &
II)
• Distal: involves descending Ao only, distal to L subclavian art. (= Stanford B,
DeBakey III)
Risk factors
• Hypertension (h/o HTN in >70% of dissections); male sex (~70% ); cocaine
• Connective tissue disease: Marfan (fibrillin-1): arachnodactyly, joint disloc.,

p ectus, ectop ia lentis, MVP; Ehle rs-Danlos typ e IV (typ e III p rocollagen):
translucent skin; bowel or uterine rup ture; Loe ys-Die tz (TGFbR); annuloaortic
ectasia, familial AoD; PCKD
• Congenital aortic anomaly: bicusp id AoV, coarctation (eg, in Turner’s syndrome)

• Aortitis (eg, Takayasu’s, GCA, Behçet’s, syp hilis, now rare); pregnancy (typ . 3rd
trim.)
• Trauma: blunt, deceleration injury; IABP, cardiac or aortic surgery, cardiac

catheterization
Diagnostic studies (Circ 2005; 112:3802; & 2010; 121:e266; Annals 2006; 166:1350)
• Check bilateral BP and radial p ulses for symmetry

• CXR: abnl in 60–90% (↑ mediastinum, left p l effusion), but cannot be used to r/o
dissection
• CT: quick, noninvasive, readily available, Se ≥93% & Sp 98 % ; however, if &

high clin. susp icion → additional studies (2 ⁄3 w/ AoD have ≥2 studies; AJC
2 002 ;8 9:12 35)
• TEE: Se >95% p rox, 8 0% for distal; can assess cors/p eric/AI; “blind sp ot” behind
trachea
• MRI: Se & Sp >98 % , but time-consuming test & not readily available
• Aortography: Se ~90% , time-consuming, cannot detect IMH; can assess branch

vessels
• D-dimer: Se/NPV ~97% ; ? <500 ng/mL to r/o dissec (Circ 2 009;119:2 702 ); does
not r/o IMH
Treatment (Lancet 2008; 372:55; Circ 2010; 121:1544; JACC 2013; 61:1661)
• Initial Medical: ↓ dP/dt targeting HR ~60 & central BP 100–12 0 (or lowest that
p reserves p erfusion; r/o p seudohyp otension, eg, arm BP ↓ due to subclavian
dissection)
first with IV bB (eg, p rop ranolol, esmolol, labetalol) to blunt reflex ↑ HR &
inotrop y that would occur in resp onse to vasodilators; verap /dilt if bB
contraindic.
then ↓ SBP with IV vasodilators (eg, nitrop russide)
control p ain with MSO 4 p rn to blunt symp athetic resp onse
• Proximal: surgery (root rep lacement); all acute; chronic if c/b p rogression, AI or
aneurysm
• Distal: med Rx unless c/b p rogression, branch artery involvement → malp erfusion/
ischemia, refractory HTN, refractory p ain, rap id ↑ aneurysm size, rap id ↑ false
lumen size. Rep eat imaging: routinely (eg, 7 d, 3 wk, then q yr) & with any clinical
or significant lab Δ. If comp lic., endovascular rep air (covered stent graft to seal
off entry, fenestrate flap , op en occluded branch) p referred over surgery due to
p ossible ↓ mort. ( JACC 2 013;61:1661).
Complications
• Rupture: p ericardial sac → tamp onade (avoid p ericardiocentesis unless PEA); blood
in p leural sp ace, mediast., retrop eritoneum; ↑ in hematoma on imaging p ortends
rup ture.
• Malperfusion (obstruction of branch artery)
can be static (avulsed/thrombosed) or dynamic (Δs in p ressure in true vs. false

lumen)
coronary → MI (usually RCA → IMI, since dissection often along outer Ao
curvature)
innominate/carotid → CVA, Horner; intercostal/lumbar → sp inal cord

ischemia/p arap legia
innominate/subclavian → up p er extremity ischemia; iliac → lower extremity

ischemia
celiac/mesenteric → bowel ischemia; renal → acute renal failure, refractory HTN
• AI: due to annular dilatation or disrup tion or disp lacement of leaflet by false lumen
• Mortality: 1–2 % /h × 48 h for acute p roximal; 10% at 30 d for acute distal

ARRHYTHMIAS
BRADYCARDIAS, AV BLOCK AND AV DISSOCIATION
Sinus bradycardia (SB) (NEJM 2000; 342:703)
• Etiologies: meds (incl bB, CCB, amio, Li, dig), ↑ vagal tone (incl. athletes, sleep ,
IMI), metabolic (hyp oxia, sep sis, myxedema, hyp othermia, ↓ glc), OSA, ↑ ICP
• Treatment: usually none required; atrop ine, b1 agonists or temp . p acing if

symp tomatic
• Most common cause of sinus p ause is blocke d pre mature atrial be at

Sick sinus syndrome (SSS)
• Features may include: p eriods of unp rovoked SB, SA arrest, p aroxysms of SB and
atrial
tachyarrhythmias (“tachy-brady” syndrome), chronotrop ic incomp etence w/ ETT

• Treatment: meds alone usually fail (adeq. control tachy → unaccep table brady);
usually need combination of meds (bB, CCB, dig) for tachy & PPM for brady
AV dissociation
• De fault: slowing of SA node allows subsidiary p acemaker (eg, AV junction) to take

over
• Usurpation: acceleration of subsidiary p acemaker (eg, AV junctional tach, VT)
• 3° AV block: atrial p acemaker unable to cap ture ventricles, subsidiary p acemaker

emerges distinguish from isorhythmic dissociation (A V rate, some P waves
nonconducting)
Temporary pacing wires

• Consider w/ bradycardia with hemodyn instability or unstable escap e rhythm when
p erm p acer not readily available. Risks: RV p erf, VT, PTX, CHB if existing LBBB,
etc.
• Consider instead of PPM for sx bradycardia due to reversible cause (bB/CCB O/D,
Lyme, myocarditis, SBE, s/p cardiac surgery/trauma), TdP, acute MI (sx brady,
high grade AVB)
SUPRAVENTRICULAR TACHYCARDIAS (SVTS)
Arise above the ve ntricle s, ∴ narrow QRS unle ss abe rrant conduction or pre -e xcitation.
Figure 1-4 Ap p roach to SVT (adap ted from NEJM 2 012 ;367:1438 )
• Cathe te r ablation: high overall success rate (AFL/AVNRT ~95% , AVRT ~90% , AF
~8 0% )
Comp lications: stroke, MI, bleeding, p erforation, conduction block (JAMA

2 007;2 90:2 768 )
ACCESSORY PATHWAYS (WOLFF-PARKINSON-WHITE)
Definitions
• Accessory pathway (byp ass tract) of conducting myocardium connecting atria &
ventricles, allowing imp ulses to byp ass normal AVN delay
• Preexcitation (WPW) pattern: ↓ PR interval, ↑ QRS width w/ Δ wave (slurred

onset, can be subtle ), ST & Tw abnl (can mimic old IMI); only se e n w/ pathways
that conduct ante g rade (if p athway only conducts retrograde then
ECG will be normal during SR; “concealed” byp ass tract)
PAC can exaggerate p reexcitation if AV node conduction slowed
• WPW syndrome: accessory p athway + p aroxysmal tachycardia
Classic tachycardias of WPW
• Orthodromic AVRT: narrow-comple x SVT (typ ically), conducting ↓ AVN & ↑

accessory p athway; requires retrograde conduction and ∴ can occur w/ concealed
byp ass tracts
• Antidromic AVRT (rare): wide -comple x SVT, conducting ↓ accessory p athway & ↑
AVN;
requires antegrade conduction and ∴ should see WPW p attern during SR
• AF w/ rap id conduction down accessory p athway; ∴ wide-comp lex irregular SVT;

requires antegrade conduction; ∴ should see WPW p attern in SR. Rarely can
degenerate into VF.
Treatment
• AVRT: vagal, bB, ? CCB; caution w/ adenosine (can p recip . AF); have de fibrillator
re ady
• AF/AFL w/ conduction down accessory p athway: need to Rx arrhythmia and ↑

p athway
refractoriness; use procainamide, ibutilide, amio, flecainide or DCCV; avoid CCB

& bB (ineffective), dig/adenosine (can ↓ refractoriness of p athway → ↑ vent. rate
→ VF)
• Long term: Rx sx tachycardias w/ RFA, antiarrhythmics (IA, IC) if not candidate for
RFA;
consider RFA if asx but AVRT or AF inducible on EPS (NEJM 2 003;349:18 03) of if
rap id conduction p ossible (✓ w/ EPS if p reexcitation p ersists desp ite exercise
testing)
risk of SCD related to how short RR interval is in AF and if SVT inducible w/
exercise
WIDE-COMPLEX TACHYCARDIAS (WCTS)
Etiologies (Lancet 2012; 380:1520)
• Ventricular tachycardia (VT)
• SVT conducted with aberrancy: either fixed BBB, rate-dep endent BBB (usually
RBBB), conduction via an accessory p athway or atrially triggered ventricular
p acing
Monomorphic ventricular tachycardia (MMVT)
• All beats look similar; p redominantly up ward in V1 = RBBB-typ e vs. downward =
LBBB-typ e
• In structurally abnormal heart: prior MI (scar); CMP; myocarditis;
arrhythmogenic RV CMP (ARVC): incomp lete RBBB,

ε wave (terminal notch in QRS) & TWI in V1–V3 on resting ECG, LBBB-typ e VT, dx
w/ MRI (Lance t 2 009;373:12 8 9)
• In structurally normal heart (w/ normal resting ECG):
RVOT VT: LBBB-typ e VT w/ inferior axis; typ ically ablate
idiopathic LV VT: RBBB-typ e VT w/ sup erior axis; resp onds to verap amil
Polymorphic ventricular tachycardia (PMVT)

• QRS morp hology changes from beat to beat
• Etiologies: ischemia; CMP; catecholaminergic;
torsades de pointes (TdP = “twisting of the p oints,” PMVT + ↑ QT): ↑ QT

acquired (meds, lytes, stroke, see "ECG") w/ risk ↑ w/ ↓ HR, freq PVCs (p ause
dep endent) or cong e nital (K/Na channelop athies) w/ resting Tw abnl & TdP
triggered by symp athetic stimulation (eg, exercise, emotion, sudden loud noises)
(Lance t 2 008 ;372 :750).
Brugada syndrome (Na channelop athy): > ; p seudo-RBBB w/ STE in V1–

V3 (p rovoked w/ class IA or IC) on resting ECG
Diagnostic clues that favor VT (assume until proven o/w)
• Prior MI, CHF or LV dysfunction be st pre dictors that WCT is VT (Am J Me d

1998 ;8 4:53)
• Hemodynamics and rate do not reliably distinguish VT from SVT
• MMVT is regular, but initially it may be slightly irregular, mimicking AF w/

aberrancy; g rossly irregularly irregular rhythm suggests AF w/ aberrancy
• ECG features that favor VT (Circ 1991;8 3:1649)
AV dissociation (indep endent P waves, cap ture or fusion beats) p roves VT

ve ry wide QRS (>140 ms in RBBB-typ e or >160 in LBBB-typ e); e xtre me axis
de viation
QRS morpholog y atypical for BBB RBBB-typ e: absence of tall R′ (or p resence of
monop hasic R) in V1, r/S ratio <1 in V6 LBBB-typ e: onset to nadir >60–100
ms in V1, q wave in V6
concordance (QRS in all p recordial leads w/ same p attern/direction)
Long-term management ( JACC 2006; 48:1064)
• Workup : echo to ✓ LV fxn, cath or stress test to r/o ischemia, ? MRI and/or RV bx
to
look for infiltrative CMP or ARVC, ? EP study to assess inducibility
• ICD: 2 ° p revention after documented VT/VF arrest (unless due to reversible cause)
1° p rev. if high risk, eg, EF <30–35% , ARVC, Brugada, certain LQTS, severe
HCMP. See “Intracardiac Devices.” ? Wearable vest if revers. etiol. waiting for
ICD (Circ 2 013;12 7:8 54).
Antitachycardia p acing (ATP = burst p acing faster than VT) can terminate VT w/o
shock
• Meds: bB, antiarrhythmics (eg, amio, mexiletine) to sup p ress VT which could trigger
shock
• If med a/w TdP → QT >500 ± VPBs: d/c med, rep lete K, give Mg, ± p acing (JACC
2 010;55:934)
• Radiofrequency ablation if isolated VT focus or if recurrent VT triggering ICD
firing; ablation before ICD imp lantation ↓ discharge rate by 40% (Lance t
2 010;375:31)
ATRIAL FIBRILLATION
Classification (Circ 2006; 114:e257 & 2011; 123:104)
• Paroxysmal (self-terminating, usually <48 h) vs. persistent (sustained >7 d or

terminated after Rx) vs. permanent (typ ically >1 y and when cardioversion has
failed or is foregone)
• Valvular (rheumatic MV disease, p rosthetic valve or valve rep air) vs. nonvalvular
• Lone AF = age <60 y and w/o clinical or echo evidence of cardiac disease
(including HTN)
Epidemiology and etiologies (Annals 2008; 149:ITC5-2)
• 1–2 % of p op . has AF (8 % of elderly); lifetime risk 2 5% ; mean age at p resentation
~75 y
• Acute (up to 50% w/o identifiable cause)
Cardiac: HF, myo/p ericarditis, ischemia/MI, hyp ertensive crisis, cardiac surgery
Pulmonary: acute p ulmonary disease or hyp oxia (eg, COPD flare, PNA), PE, OSA
Metabolic: high catecholamine states (stress, infection, p ostop , p heo),

thyrotoxicosis
Drugs: alcohol (“holiday heart” ), cocaine, amp hetamines, theop hylline, caffeine
Neurogenic: subarachnoid hemorrhage, ischemic stroke
• Chronic: ↑ age, HTN, ischemia, valve dis. (MV, TV, AoV), CMP, hyp erthyroidism,
obesity
Evaluation
• H&P, ECG, CXR, TTE (LA size, thrombus, valves, LV fxn, p ericardium), K, Mg, FOBT
before anticoag, TFTs; r/o MI not necessary unless other ischemic sx
Figure 1-5 Ap p roach to acute AF
(Adap ted from NEJM 2 004;351:2 408 ; JACC 2 006;48 :e149)

Strategies for recurrent AF (Circ 2011; 123:104; Lancet 2012; 379:648)
• Rate control: goal HR <110 at rest if EF >40% and asx (NEJM 2 010;362 :1363)
AV node ablation + PPM as a last resort (NEJM 2 001;344:1043; 2 002 ;346:2 062 )
• Rhythm control: no clear survival benefit vs. rate cntl (NEJM 2 002 ;347:18 2 5 &
2 008 ;358 :2 667)
Consider if sx w/ rate cntl, difficult to cntl rate, ? unable to anticoag, ? benefit in

CRT
Cardioversion
• Consider p harm or electrical cardioversion w/ 1st AF ep isode or if sx;

if AF >48 h, 2 –5% risk stroke w/ cardioversion (pharmacolog ic or e le ctric) ∴
either TEE to r/o thrombus or ensure therap eutic anticoagulation for ≥3 wk p rior
• Likelihood of success ∝ AF duration & atrial size; control p recip . (eg, vol status,
thyroid)
• Consider p re-Rx w/ antiarrhythmic drugs (esp . if 1st cardioversion attemp t fails)

• For p harmacologic cardioversion, class III and IC drugs have best p roven efficacy
• If SR returns (sp ont. or w/ Rx), atria may be me ch. stunne d; also, high risk of
recurrent AF over next 3 mo. ∴ Anticoag postcardioversion ≥4–12 wk (? unless
<48 h and low risk).
Nonpharmacologic therapy
• Radiofrequency ablation (circumferential p ulm. vein isolation; Lance t

2 012 ;38 0:1509): ~8 0% success; reasonable alternative to AAD in sx p ersistent or
p aroxysmal AF w/o ↑↑ LA or ↓ EF (NEJM 2 012 ;367:158 7; RAAFT 2 , HRS 2 012 )
• Surgical “maze” p rocedure (70–95% success rate) op tion if undergoing cardiac

surgery
• LA ap p endage closure/resection: reasonable if another indication for cardiac surgery

p ercutaneous closure noninferior to warfarin, ↓ risk of ICH, but w/ p rocedural
comp lic; additional studies & ap p roaches underway (Lancet 2 009;374:534;
PREVAIL, ACC 2 013)
Oral anticoagulation (Chest 2012; 141:e531S; EHJ 2012; 33:2719; Circ

2013; 127:1916)
• All valvular AF as stroke risk very high
• Nonvalvular AF: stroke risk ~4.5% /y; anticoag → 68 % ↓ stroke; use a risk score to
guide Rx:
CHADS2 : CHF (1 p oint), HTN (1), Age ≥75 y (1), DM (1), p rior Stroke/TIA (2 )
CHA2 DS2 -VASc: adds 65–74 y (1), >75 y (2 ); vasc dis. (1); sex (1)
score >2 → anticoag; score 1 → consider anticoag or ASA (? latter reasonable

if risk factor 65–74 y, vasc dis. or ); antithrombotic Rx even if rhythm cntl
• Rx options: factor Xa or direct thrombin inhib (non-valv only; no monitoring

required) or warfarin (INR 2 –3; w/ UFH bridge if high risk of stroke); if Pt refuses
anticoag, consider
ASA + clop i or, even less effective, ASA alone (NEJM 2 009;360:2 066)
SYNCOPE
Definition
• Symp tom of sudden transient loss of consciousness due to global cerebral

hyp op erfusion
• If CPR or cardioversion required, then SCD and not syncop e (different p rognosis)
Etiologies (NEJM 2002; 347:878; JACC 2006; 47:473; Eur Heart J 2009; 30:2631)
• Neurocardiogenic (a.k.a. vasovagal, ~2 0% ; NEJM 2 005;352 :1004): ↑ symp athetic
tone → vigorous contraction of LV → mechanorecep tors in LV trigger ↑ vagal tone
(hyp eractive Bezold-Jarisch reflex) → ↓ HR (cardioinhibitory) and/or ↓ BP
(vasodep ressor)
cough, deglutition, defecation, & micturition → ↑ vagal tone and thus can be
p recip itants
related disorder: carotid sinus hyp ersensitivity (exagg vagal resp to carotid
massage)
• Orthostatic hypotension (10% )

hyp ovolemia/diuretics, deconditioning; vasodilat. (esp . if combined w/
chronotrop es)
autonomic neurop athy [1° = Parkinson’s, Shy-Drager, Lewy body dementia, POTS
(dysautonomia in the young); 2 ° = DM, EtOH, amyloidosis, CKD] (NEJM
2 008 ;358 :615)
• Cardiovascular
Arrhythmia (15% )
Bradyarrhythmias: SSS, high-grade AV block, chronotrop es, PPM

malfunction
Tachyarrhythmias: VT, SVT (syncop e rare unless structural heart disease or
WPW)
Me chanical (5% )
Endocardial/Valvular: AS, MS, PS, p rosthetic valve thrombosis, myxoma

Myocardial: p ump dysfxn from MI or outflow obstruction from HCMP (but
usually VT)
Pericardial: tamp onade

Vascular: PE, PHT, aortic dissection, rup tured AAA, subclavian steal
• Neurologic (10% ): seizure (technically not syncop e), TIA/CVA, vertebrobasilar
insufficiency, dissection of cerebral arteries, migraine, narcolep sy
• Misc. causes of LOC (but not syncop e): hyp oglycemia, hyp oxia, anemia,
p sychogenic
Workup (etiology cannot be determined in ~40% of cases)
• H&P incl. orthostatic VS have hig he st yie ld and most cost e ffe ctive (Archive s
2 009;169:12 99)
• History (from Pt and witne sse s if available)
activity and p osture before the incident
p recip itating factors: exertion (AS, HCMP, PHT), p ositional Δ (orthostatic

hyp otension), stressors such as sight of blood, p ain, emotional distress, fatigue,
p rolonged standing, warm environment, N/V,
cough/micturition/defecation/swallowing (neurocardiogenic), head turning or
shaving (carotid sinus hyp ersens.); arm exercise (subclavian steal)
p rodrome (eg, diap horesis, nausea, blurry vision): cardiac <~5 sec, vasovagal
>~5 sec
associated sx: chest p ain, p alp ., neurologic, p ostictal, bowel or bladder

incontinence (convulsive activity for <10 sec may occur w/ transient cerebral
HoTN & mimic seizure)
• PMH: p rior syncop e, p revious cardiac or neurologic dis.; no CV disease at baseline
→ 5% cardiac, 2 5% vasovagal; CV disease → 2 0% cardiac, 10% vasovagal
(NEJM 2 002 ;347:8 78 )
• Medications that may act as precipitants

vasodilators: a-blockers, nitrates, ACEI/ARB, CCB, hydralazine, p henothiazines,
antidep .
diuretics; chronotrop es (eg, bB and CCB)
p roarrhythmic or QT p rolonging: class IA, IC or III antiarrhythmics (see “ECG” )
p sychoactive drugs: antip sychotics, TCA, barbiturates, benzodiazep ines, EtOH

• Family history: CMP, SCD, syncop e (vasovagal may have genetic comp onent)
• Physical exam
VS including orthostatics ( if sup ine → standing results in >2 0 mmHg ↓ SBP,

>10 mmHg ↓ DBP, or >10–2 0 bp m ↑ HR), BP in both arms
cardiac: HF (↑ JVP, disp l. PMI, S 3), murmurs, LVH (S 4, LV heave), PHT (RV
heave, ↑ P2 )
vascular: ✓ for asymmetric p ulses, carotid/vertebral/subclavian bruits; carotid

sinus massage to assess for carotid hyp ersensitivity (if no bruits)
neurologic exam: focal findings, evidence of tongue biting; FOBT
• ECG (abnormal in ~50% , but only definitively identifies cause of syncop e in ~10% )
Conduction: SB, sinus p auses/sinus arrhythmia, AVB, BBB/IVCD
Arrhythmia: ectop y, ↓ QT, p reexcitation (WPW), Brugada, e wave (ARVC), SVT/VT

Ischemic changes (new or old): atrial or ventricular hyp ertrop hy
Other diagnostic studies (consider based on results of H&P and ECG)
• Ambulatory ECG monitoring: if susp ect arrhythmogenic syncop e
Holter monitoring (continuous ECG 2 4–48 h): useful if fre que nt events arrhythmia
+ sx (4% ); asx but signif. arrhythmia (13% ); sx but no arrhythmia (17% )
Event recorder (activated by Pt to record rhythm strip ): limited role as only useful
if established p rodrome (because must be Pt activated)
Loop recorders (continuously saves rhythm, ∴ can be activated afte r an event):
useful for ep isodes (including w/o p rodrome) likely to occur w/in month.
Implantable loop recorders (inserted SC; can record up to 3 y): useful for
infrequent ep isodes (<1/mo); recommended for recurrent syncop e w/o p rodrome
• Echo: consider to r/o structural heart disease (eg, CMP [incl HCMP & ARVC],
valvular disease [incl AS, MS, MVP], myxoma, amyloid, PHT, ± anomalous
coronaries)
• ETT: esp . w/ exertional syncop e; r/o ischemia- or catecholamine-induced
arrhythmias
• Cardiac catheterization: consider if noninvasive tests suggest ischemia

• Electrop hysiologic studies (EPS): consider in high-risk Pts in whom tachy or brady
etiology is strongly susp ected, but cannot be confirmed;
50% abnl (inducible VT, conduction abnormalities) if heart disease, but ?
significance
3–2 0% abnl if abnl ECG; <1% abnl if normal heart and normal ECG (Annals
1997;12 7:76)
• ? Tilt table testing: utility is debated due to p oor Se/Sp /rep roducibility; consider
only if vasovagal dx susp ected but can’t be confirmed by hx
• Cardiac MRI: help ful to dx ARVC if suggestive ECG, echo (RV dysfxn) or FHx of
SCD
• Neurologic studies (cerebrovascular studies, CT, MRI, EEG): if H&P suggestive; low
yield
Figure 1-6 Ap p roach to syncop e
High-risk features (usually admit w/ telemetry & testing; J Emerg Med

2012; 42:345)
• Age >60 y, h/o CAD, HF/CMP, valvular or congenital heart dis., arrhythmias, FHx
SCD
• Syncop e c/w cardiac cause (lack of p rodrome, exertional, resultant trauma) or

recurrent
• Comp laint of chest p ain or dysp nea; abnl VS or cardiac exam
• ECG suggesting tachy or brady-induced syncop e; Pt w/ PPM/ICD
Treatment
• Arrhythmia, cardiac mechanical or neurologic syncop e: treat underlying disorder

• Vasovagal syncop e: no p roven benefit for midodrine, fludrocortisone, disop yramide,
SSRI ? 16 oz of H 2 O before at-risk situations (Circ 2 003;108 :2 660)
no p roven benefit w/ bB (Circ 2 006;113:1164)

? benefit w/ PPM if ≥3 ep isodes/2 y & loop recorder w/ asystole >3 sec (Circ
2 012 ;12 5:2 566)
• Orthostatic syncop e: volume rep lete (eg, 500 mL PO q a.m.); if chronic → rise from
sup ine to standing slowly, comp ressive stockings, midodrine, fludrocortisone, high
Na diet
Prognosis (Ann Emerg Med 1997; 29:459; NEJM 2002; 347:878)
• 2 2 % overall recurrence rate if idiop athic, else 3% recurrence
• Cardiac syncop e: 2 -fold ↑ in mort., 2 0–40% 1-y SCD rate, median survival ~6 y
• Unexp lained syncop e w/ 1.3-fold ↑ in mort., but noncardiac or unexp lained syncop e
w/ nl
ECG, no h/o VT, no HF, age <45 → low recurrence rate and <5% 1-y SCD rate
• Vasovagal syncop e: Pts not at increased risk for death, MI or stroke
• ✓ state driving laws and MD rep orting requirements. Consider ap p rop riateness of
Pt involvement in exercise/sp ort, op erating machinery, high-risk occup ation (eg,
p ilot).
INTRACARDIAC DEVICES
Cardiac resynch therapy (CRT)/Biventricular (BiV) pacing (Circ 2012; 126:1784)

• 3-lead p acemaker (RA, RV, coronary sinus to LV); R>S in V1 suggests ap p rop LV
cap ture
• Synchronize & enhance LV fxn (↑ CO, ↓ adverse remodeling)
• Indic: LVEF ≤35% + NYHA II–IV desp ite med Rx + SR + LBBB ≥150 ms (also
reasonable if e ithe r LBBB ≥12 0 ms or no LBBB but QRS ≥150 ms + NYHA III–
IV); consider in AF, but rate cntl → ~100% vent cap ture; ? NYHA I w/ LVEF
≤30% + LBBB ≥150 ms; ? EF ≤50% w/ AVB + indic for PPM (NEJM
2 013;368 :158 5)
• Benefits: ↓ HF sx, ↓ HF hosp ., ↑ survival (NEJM 2 005;352 :1539; 2 010;363:2 38 5)
Implantable cardiac defibrillator (ICD) (NEJM 2003; 349:1836; JACC 2009; 54:747)
• RV lead: defib & p acing (± antitachycardia p acing [ATP] = burst p acing > VT rate
to stop VT); ± RA lead for dual chamber PPM. Wearable vest & SC ICD exist (Circ
2 013;12 7:8 54).
• Pt selection (NEJM 2 004;350:2 151 & 351:2 48 1; 2 005;352 :2 2 5; 2 009;361:142 7;
Circ 2 012 ;12 6:178 4)
2 ° p revention: survivors of VF arrest, unstable VT w/o reversible cause (NEJM
1997;337:1576); structural heart disease & sp ontaneous sustained VT (even if
asx)
1° p revention: LVEF ≤30% & p ost-MI or LVEF ≤35% & NYHA II-III (wait: ≥40 d
if p ost-MI, ? until stabilized on meds for NICMP, or if p resumed reversible) or
LVEF ≤40% & inducible VT/VF; life e xpe ctancy must be >1 y; consider for
HCM, ARVC, Brugada, sarcoid, LQTS, Chagas or congenital heart disease if risk
factors for SCD
• Benefits: ↓ mortality from SCD c/w antiarrhythmics or p lacebo

• Risks: inap p rop shock in ~15–2 0% at 3 y (most commonly d/t misclassified SVT);
infxn
• ICD discharge: ✓ device to see if ap p rop ; r/o ischemia; 6-mo driving ban (✓ state
law); if recurrent VT, ? drug Rx (eg, amio + bB, JAMA 2 006;2 95:165) or VT
ablation (NEJM 2 007;357:2 657); ablation at time of ICD ↓ risk of VT by 40%
(Lancet 2 010;375:31)
Device infection (Circ 2010; 121:458; JAMA 2012; 307:1727; NEJM

2012; 367:842)
• Presents as pocke t infe ction (warmth, erythema, tenderness) and/or se psis w/

bacte re mia
• Incidence ~2 % over 5 y; if S. aure us bacteremia, infxn in ≥35%
• TTE/TEE used to help visualize comp lic. (eg, vegetation), but even TEE does not
r/o
• Treatment: abx and removal of system; Pp x: no rec for routine abx p rior to invasive
p roc.
CARDIAC RISK ASSESSMENT FOR NONCARDIAC SURGERY
Preoperative evaluation
Figure 1-7 ACC/AHA ap p roach to p reop erative cardiovascular evaluation for

noncardiac surgery
Preoperative testing and assessment
• ECG if ≥1 risk factor and p lanned vascular surgery or if known vascular disease
and intermediate risk surgery. ? p rior to any vascular surgery.
• TTE if dysp nea of unknown origin or if HF w/ ↑ dysp nea and no TTE in p ast 12 mo
• Stress test if active cardiac issues (see above) or vascular surgery w/ ≥3 risk factors
& it will Δ mgmt. Overall low PPV to p redict p eriop CV events.
• ? consider CXR and ECG in p reop evaluation of severely obese Pts (Circ
2 009;12 0:8 6)
• Comorbidity indices (eg, Charlson index) may p redict mortality (Am J Med Qual
2 011;2 6:461)
Pre- & perioperative management
• Coronary revascularization should be based on standard indications (eg, ACS,

refractory sx, lg territory at risk). Has not been shown to Δ risk of death or
p ostop MI when done p rior to elective vasc. surgery based on p erceived cardiac
risk (NEJM 2 004;351:2 795) or documented extensive ischemia (AJC
2 009;103:8 97), but systematic angio ↓ 2 –5 y mortality in a vascular surgery trial
( JACC 2 009;54:98 9).
• Continue ASA: ↓ MACE in Pts w/ cardiac risk factors (Br J Anaesth 2 010;104:305)
• Given need for dual antip latelet Rx after stenting, wait 4–6 wk after BMS and ideally
>12 mo after DES before discontinuing ADP recep tor blockade
• If p ossible, wait >4–6 wk after MI (even if ETT or ETT & revascularized). If
no
revasc, wait 6 mo before elective surgery.

• Preop statins: ↓ ischemia & CV events in Pts undergoing vascular surg (NEJM
2 009;361:98 0); may reduce AF, MI, LOS in statin-naïve Pts (Arch Surg
2 012 ;147:18 1)
Perioperative β-blocker (Circ 2009; 120:2123; JAMA 2010; 303:551; Am J Med

2012; 125:953)
• Conflicting evidence: some studies show ↓ death & MI (NEJM 1996;335:1713 &
1999;341:178 9), another showed ↓ MI, but ↑ death & stroke and ↑
bradycardia/HoTN (Lancet 2 008 ;371;18 39)
• ? consider if CAD, stress test, or ≥2 cardiac risk factor, esp . if vascular surgery
• Ideally initiate we e ks p rior to surgery and titrate slowly and carefully to achieve
desired individual HR and BP goal (? HR ~55–65). Avoid bradycardia and
hyp otension. Do not discontinue bB abrup tly p ostop , as may cause symp athetic
activation from withdrawal.
Postoperative monitoring
• ✓ Postop ECG if known CAD or high-risk surgery. Consider if >1 risk factor for
CAD.
• ✓ Postop trop onin only if new ECG Δs or chest p ain suggestive of ACS
PERIPHERAL ARTERY DISEASE (PAD)
Clinical features
• Prev. ↑ w/ age: <1% if <40 y, ~15% if ≥70 y; risk factors incl. smoking, DM,
HTN, chol
• Claudication (dull ache, often in calves) p recip by walking and relieved by stop p ing
(vs. sp inal stenosis, qv); Leriche synd = claudication, ↓ or femoral p ulses, &
erectile dysfxn
• Critical limb ischemia (CLI): rest pain (↑ w/ elevation b/c ↓ p erfusion), ulcer
(typ ically at p ressure foci, often dry; in contrast, venous ulcers are more often at
medial malleolus, wet, and with hemosiderin dep osition) or gangrene, due to
PAD, and >2 -wk duration (imp lies chronicity vs. acute limb ischemia, see below)
Diagnosis
• ↓ p erip heral p ulses; other signs of chronic PAD: hair loss, skin atrop hy, nail
hyp ertrop hy
• Ankle:brachial index (ABI): nl 1–1.4; borderline 0.91–0.99; abnl ≤0.90; if >1.4,

non-dx p ossibly due to calcified noncomp ressible vessel → ✓ PVR. If ABI abnl →
segmental ABI w/ PVR to localize disease. If sx but nl ABI, ✓ for ↓ lower
extrem BP after exercise.
• Dup lex arterial U/S; CTA w/ distal run-off; MRA or angio
Treatment (JACC 2013; 61:1555; JAMA 2013; 309:453)

• Risk factor modification. Sup ervised exercise Rx. Screen for CAD.
• Cilostazol (if no HF) & ? ACEI to ↓ sx. ASA or clop i to ↓ D/MI/stroke if claud. or ABI
<0.9.
• Revasc if CLI or limiting/refractory claudication
Acute limb ischemia (ALI)
• Sudden decrement in limb p erfusion that threatens viability; viable (no immed threat
of tissue loss): audible art. Dop p ler signals, sensory & motor OK thre ate ne d
(salvage requires p romp t Rx): loss of arterial Dop p ler signal, sensory or motor
• Etiologies: embolism > acute thrombosis (eg, athero, APLA, HITT), trauma to artery
• Clinical manifestations (6 Ps): p ain (distal to p roximal, ↑ in severity),

p oikilothermia, p allor, p ulselessness, p aresthesias, p aralysis
• Testing: thorough p ulse & neuro exam; arterial Dop p ler; angiograp hy, either CT w/
bilateral run-off through feet or arteriograp hy
• Urgent consultation w/ vascular medicine and/or vascular surgery

• Treatment: immediate anticoagulation ± intraarterial lytic; angiop lasty or surgery
NOTES
DYSPNEA
Evaluation
• History: quality of sensation, temp o, p ositional dep endence, exac./allev. factors,
exertion
• Cardiop ulmonary exam, S a O 2 , CXR (see Ap p endix & Radiology inserts), ECG
p redictors of CHF: h/o CHF, PND, S 3, CXR w/ venous congestion, AF ( JAMA
2 005;2 94:1944) dysp nea w/ nl CXR → CAD, asthma, PE, PHT, early ILD, anemia,
acidosis, NM disease
• Based on results of initial evaluation: PFT, chest CT, TTE, cardiop ulmonary testing
• BNP & NT-proBNP ↑ in CHF (also ↑ in AF, RV strain from PE, COPD flare, PHT,
ARDS) BNP <100 p g/mL to r/o CHF (90% Se), >400 to r/i (NEJM 2 002 ;347:161)
NT-p roBNP <300 p g/mL to r/o CHF (99% Se); age-related cut p oints to r/i: >450
p g/mL (<50 y), >900 (50–75 y), >18 00 (>75 y) (EHJ 2 006;2 7:330)
↑ in chronic heart failure, ∴ need to comp are to known “dry BNP”

PULMONARY FUNCTION TESTS (PFTs)
• Spirometry: evaluate for obstructive disease
Flow-volume loop s: diagnose and/or localize obstruction
Bronchodilator: indicated if obstruction at baseline or asthma clinically susp ected

Methacholine challenge: help s dx asthma if sp irometry nl, >2 0% ↓ FEV1 →
asthma
• Lung volumes: evaluate for hyp erinflation or restrictive disease including NM
causes
• D LCO: evaluates functional surface area for gas exchange; help s differentiate causes
of obstructive and restrictive diseases and screens for vascular disease & early ILD
Figure 2-1 Approach to abnormal PFTs

ASTHMA
Definition and epidemiology
• Chronic inflam. disorder w/ airway hyperresponsiveness + variable airflow

obstruction
• Affects ~5% p op ulation; ~8 5% of cases by age 40 y

• Classic triad = wheezing, cough and dyspnea; others include chest tightness,
sp utum; symp toms typ ically chronic with e pisodic e xace rbation
• Precip itants (triggers)
re spiratory irritants (smoke, p erfume, etc.) & alle rg e ns (p ets, dust mites, p ollen,
etc.)
infe ctions (URI, bronchitis, sinusitis)
drug s (eg, ASA & NSAIDs via leukotrienes, bB via bronchosp asm, MSO 4 via
histamine) emotional stress, cold air, exercise (increase in ventilation dries out
airways)
Physical examination
• Wheezing and p rolonged exp iratory p hase
• Presence of nasal p olyp s, rhinitis, rash → alle rg ic compone nt

• Exacerbation → ↑ RR, ↑ HR, accessory muscle use, diap horesis, p ulsus p aradoxus
Diagnostic studies
• Peak exp flow (PEF): ≥60 L/min ↑ after bronchodil or ≥2 0% diurnal variation c/w
asthma. <8 0% p ersonal best c/w p oor control, <50% c/w severe exacerbation.
• Spirometry: ↓ FEV1, ↓ FEV1/FVC, coved flow-volume loop ; lung volumes: ± ↑ RV &
TLC
bronchodilator resp onse (↑ FEV1 ≥12 % & ≥2 00 mL) strongly suggestive of

asthma methacholine challenge (↓ FEV1 ≥2 0% ) if PFTs nl: Se >90% (AJRCCM
2 000;161:309)
• Sp utum: eos >3% has 8 6% Se, 8 8 % Sp ; can also see Curschmann’s spirals (mucus
casts of distal airways) and Charcot-Le yde n crystals (eosinop hil
lysop hosp holip ase)
• Allergy susp ected → consider ✓ serum IgE, eos, skin testing/RAST
Ddx (“all that wheezes is not asthma … ” )
• Hyp erventilation & p anic attacks

• Up p er airway obstruction or inh foreign body; laryngeal/vocal cord dysfxn (eg, 2 °
to GERD)
• CHF (“cardiac asthma” ); COPD, bronchiectasis; ILD (including sarcoidosis);

vasculitis; PE
“Asthma plus” syndromes (Lancet 2002; 360:1313)
• Atop y = asthma + allergic rhinitis + atop ic dermatitis

• ASA-sensitive asthma (Samter’s syndrome) = asthma + ASA sensitivity + nasal
p olyp s
• ABPA = asthma + p ulmonary infiltrates + allergic rxn to Aspe rg illus
• Churg-Strauss = asthma + eosinop hilia + granulomatous vasculitis
“Reliever” medications (used p rn to quickly relieve sx)

• Short-acting inh β2 -agonists (SABA): albuterol Rx of choice
• Short-acting inh anticholinergics (ip ratrop ium) ↑ β2 -agonist delivery → ↑

bronchodilation
“Controller” meds (taken daily to keep control) (NEJM 2009; 360:1002)

• Inh corticosteroids (ICS): Rx of choice ( JAMA 2 001;2 8 5:2 58 3). PRN ? as good as
daily for mild asthma (NEJM 2 005;352 :1519 & 2 007;356:2 040). PO steroids may
be needed for severely uncontrolled asthma, but avoid if p ossible b/c systemic side
effects.
• Long -acting inh β2 -agonists (LABA; eg, salmeterol): ↑ PEF when added to ICS (Lance t
2 009;374:1754). Excep t for exercise-induced asthma, should not be used w/o ICS
(may ↑ mortality, esp . in African Americans) (Che st 2 006;12 9:15; Annals
2 006;144:904). Clinical relevance of β2 -recep tor p harmacogenetic interaction not
validated (Lance t 2 009;374:1754).
• Long -act inh anticholinergics (LAA; eg, tiotrop ium): add-on if sx desp ite ICS
(sup erior to ↑ ICS, to adding LABA; NEJM 2 010;363:1715) or if sx desp ite
ICS+LABA (NEJM 2 012 ;367:1198 )
• Nedocromil/cromolyn: limited use in adults. Useful in young Pts, exercise-induced

bronchosp asm; ineffective unless used before trigger or exercise exp osure.
• Theophylline: useful if hard to control sx; PO convenient, but high side-effect p rofile
• Leukotriene antagonists (LTA): some Pts very resp onsive, esp . ASA-sens (AJRCCM
2 002 ;165:9) and exercise-induced (Annals 2 000;132 :97). May be noninf to ICS
initial Rx and LABA add-on Rx (NEJM 2 011;364:1695).
• Anti-IgE: for uncontrolled mod-to-severe allergic asthma (↑ IgE) on ICS ± LABA

(NEJM 2 006;354:2 68 9; Annals 2 011;154:573); not cost-effective for most Pts (
JACI 2 007;12 0:1146)
Other
• Behavior modification: identify and avoid triggers; PPI w/o benefit (NEJM
2 009;360:148 7)
• Immunotherap y (eg, desensitization): may be useful if significant allergic comp onent

• TNF antagonists may be help ful in Pts w/ refractory asthma (NEJM 2 006;354:697)
• Anti-IL5 (mep olizumab) ↓ exac. w/ sev asthma (Lance t 2 012 ;38 0:651), not yet FDA
ap p roved
• Anti-IL13 (lebrikizumab) ↑ FEV1 (NEJM 2 011;365:108 8 ), not yet FDA ap p roved
• Bronchial thermop lasty (exp ’tal): radiofrequency destruction of airway smooth

muscle no Δ in FEV1, but ↓ in sx and # of exacerbations (NEJM 2 007;356:132 7)
Principles of treatment
• Education and avoidance of environmental triggers for all Pts; yearly flu shot
• Use quick-relief rescue medication as needed for all Pts

• Goal to achieve complete control = daily sx ≤2 /wk, Ø nocturnal sx or limitation
of activity, reliever med ≤2 /wk, nl PEF or FEV1; p artly controlled = 1–2 of the
above p resent in a wk; uncontrolled = ≥3 of the above p resent in a wk
• Step up treatment as needed to gain control, step down as tolerated

• If PEF ↓ 15% × 2 d or ↓ 30% , 4× ICS dose ↓ need for PO steroids (AJRCCM
2 009;18 0:598 )
• Variants in glucocorticoid-induced transcrip t 1 gene a/w resp to ICS (NEJM
2 011;365:1173)
EXACERBATION
Evaluation
• History: baseline PEF, steroid requirement, ED visits, hosp ital admissions, p rior
intubation Current exacerbation: duration, severity, p otential p recip itants, meds
used
Risk factors for life -thre ate ning : p rior intubation, h/o near-fatal asthma, ED
visit/hosp for asthma w/in 1 y, current/recent PO steroids, not using ICS,
overdep endent on SABA, Ψ, h/o noncomp l
• Physical exam: VS, p ulm, accessory muscle use, p ulsus p aradoxus, abdominal
p aradox
Assess for barotrauma: asymmetric breath sounds, tracheal deviation,
subcutaneous air → p neumothorax, p recordial (Hamman’s) crunch →
p neumomediastinum
• Diagnostic studies: PEF (used to follow clinical course); SaO2 ; CXR to r/o PNA or
PTX ABG if severe: low Pa CO 2 initially; nl or high Pa CO 2 may signify tiring
Initial treatment (NEJM 2010; 363; 755)

• Oxygen to keep S a O 2 ≥90%
• Inhaled SABA (eg, albuterol) by MDI (4–8 p uffs) or nebulizer (2 .5–5 mg) q2 0min
• Corticosteroids: p rednisone 0.5–1 mg/kg PO; IV if imp ending resp arrest
• Ipratropium MDI (4–6 p uffs) or nebulizer (0.5 mg) q2 0min if severe (Che st
2 002 ;12 1:1977)
• Ep inep hrine (0.3–0.5 mL SC of 1:1000 dilution) no advantage over inh SABA
• Montelukast IV ↑ FEV1 but did not Δ rate of hosp ( J Alle rg y Clin Immunol
2 010;12 5:374)
• Re asse ss afte r 6 0 –90 min of Rx

Mild-mod exacerbation: cont SABA q1h
Severe exacerbation: SABA & ip ratrop ium q1h or continuously; ± Mg 2 g IV over

2 0 min (Lance t 2 003;361:2 114); ± heliox (60–8 0% )
• De cide disposition within 4 h of pre se ntation and afte r 1–3 h of Rx
Figure 2-2 Disp osition of p atients after initial treatment of asthma exacerbation
ICU-level care
• High-dose steroids: methylp rednisolone 12 5 mg IV q6h (Archive s 198 3;143:132 4)
• Invasive ventilation:
large ET tube, Pp lat <30 cm H 2 O (p redicts barotrauma better than PIP), max exp
time
PEEP individualized to Pt p hysiology

p aralysis, inhalational anesthetics, bronchoalveolar lavage w/ mucolytic, heliox
(60–8 0% helium) and ECMO have been used with success
• NPPV likely imp roves obstruction (Che st 2 003;12 3:1018 ), but controversial and
rarely used
ANAPHYLAXIS
Definition and pathophysiology (Ann Emerg Med 2006; 47:373)
• Severe, rap id-onset (mins to hrs), p otentially life-threatening systemic allergic

resp onse
• IgE-mediated mast cell degranulation with release of histamine, tryp tase and TNF
• Precip itates systemic reactions (bronchosp asm, tissue swelling, fluid shifts,
vasodilation)
• Common triggers: p enicillins, cep halosp orins, shellfish, nuts, insect stings, IV
contrast (not truly an IgE-mediated mechanism, but clinically similar)
Diagnosis: any of the three following criteria

1) Acute illness with skin ± mucosal involvement (rash, flushing, hives), AND at least
one of:
• Resp iratory comp romise (wheeze, stridor, dysp nea, hyp oxemia)
• Hyp otension or hyp op erfusion (syncop e, incontinence)
2 ) Two or more of the following after exp osure to a likely allergen: skin/mucosal
involvement, resp iratory comp romise, ↓ BP or hyp op erfusion, GI symp toms
3) Hyp otension after exp osure to known allergen for that Pt
Treatment
• Epinephrine: IM or SC 0.3–0.5 mL of 1:1000 dilution (1 mg/mL) q5–2 0min; if

HoTN or cardiac arrest, IV (or via ETT) 2 .5–10 mL of 1:10,000 dilution q5min ±
gtt
• Airway management: sup p l O 2 ± intubation (or cricothyroidotomy if laryngeal

edema) β2 -agonists (stacked or continuous nebulizers) for refractory bronchosp asm
• Fluid resuscitation w/ lg volume of crystalloid (may extravasate up to 35% of blood

volume)
• Antihistamines relieve hives & itching, no e ffe ct on airway or he modynamics H1RA

(dip henhydramine 50 mg IV/IM) ± H2 RA (eg, ranitidine 50 mg IV)
• Corticosteroids have no immediate effect but may help p revent relap se:
methylp rednisolone 12 5 mg IV q6h if severe or p rednisone 50 mg PO
• Glucagon (1–5 mg IV over 5 min) if inotrop ic or chronotrop ic sup p ort needed in Pt
taking bB
• Avoid unop p osed a-adrenergic vasop ressors

Disposition
• Mild rxn limited to urticaria or mild bronchosp asm can be observed for ≥6 h;
admit all others
• Watch for bip hasic reaction; occurs in 2 3% , typ ically w/in 8 –10 h but up to 72 h
• At time of d/c: education re: allergen avoidance, instruction and Rx for Ep iPen,
allergist f/u
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Definition and epidemiology (NEJM 2 004;350:2 6)

• Progressive airflow limitation caused by airway and p arenchymal inflammation
Pathogenesis (Lancet 2003; 362:1053)
• Cigarette smoke (centrilobular emp hysema, affects 15–2 0% of smokers)

• Recurrent airway infections
• ɑ1-antitryp sin defic.: early-onset p anacinar emp hysema, 1–3% of COPD cases.
Susp ect if age <45, lower lungs affected, extrathoracic manifestations (liver
disease [not if MZ subtyp e], FMD, p ancreatitis). ✓ serum AAT level (nb, acute
p hase reactant).
• Chronic cough, sp utum p roduction, dysp nea; later stages → freq exac., a.m. HA, wt
loss
• Exacerbation triggers: infxn, other cardiop ulmonary disease, incl. PE (Annals

2 006;144:390)
Infxn: overt tracheobronchitis/p neumonia from viruses, S. pne umoniae , H.

influe nzae , M. catarrhalis or triggered by changes in strain of colonizers (NEJM
2 008 ;359:2 355)
• Physical exam: ↑ AP diameter of chest (“barrel-chest” ), hyp erresonance, ↓

diap hragmatic excursion, ↓ breath sounds, ↑ exp iratory p hase, rhonchi, wheezes
during exacerbation: tachyp nea, accessory muscle use, p ulsus p aradoxus, cyanosis
Diagnostic studies
• CXR (see Radiology inserts): hyp erinflation, flat diap hragms, ± interstitial
markings & bullae
• PFTs: Obstruction: ↓↓ FEV1, ↓ FVC, FEV1/FVC <0.7 (no sig Δ post
bronchodilator), exp iratory scoop ing of flow-volume loop ; Hyperinflation: ↑↑
RV, ↑ TLC, ↑ RV/TLC;
Abnormal gas exchange: ↓ DLCO (in emp hysema)
• ABG: ↓ Pa O 2 , ± ↑ Pa CO 2 (in chronic bronchitis, usually only if FEV1 <1.5 L) and

↓ pH
• ECG: PRWP, S1S2 S3, R-sided strain, RVH, ↑ P waves in lead II (“P p ulmonale” )
Chronic treatment (NEJM 2010; 362:1407; Lancet 2012; 379:1341)
• Bronchodilators (first-line the rapy): anticholinergics, β2 -agonists (BA), theop hylline
Long-acting (LA) anticholinergic (LAA, tiotrop ium): ↓ exac., ↓ admit, ↓ resp

failure (NEJM 2 008 ;359:1543), better than ip ratrop ium or LABA as mono Rx
(NEJM 2 011;364:1093)
LABA: ~15% ↓ in exacerbations, ↓ FEV1 decline, trend toward ↓ mort. (NEJM
2 007;356:775)
LABA + inh steroid: ? ↓ mort. (NEJM 2 007;356:775; AJRCCM 2 008 ;177:19)
LAA + LABA + inh steroid: ↑ FEV1, ↓ COPD admits (Annals 2 007;146:545)
• Corticosteroids (inhaled, ICS): ~2 0% ↓ in exacerb if FEV1 <2 .0 L (Che st

2 009;136:102 9) may slow ↓ FEV1, but more so in combo with LABA (NEJM
2 007;356:775); ↑ in PNA (not seen w/ budesonide; Lance t 2 009;374:712 ); no Δ in
mort. w/ ICS alone (NEJM 2 007;356:775)
• Antibiotics: daily azithro ↓ exacerb, but not yet routine (NEJM 2 011;365:68 9 &
2 012 ;367:340)
• Mucolytics: no Δ FEV1, but ? ↓ exacerbation rate (Lance t 2 008 ;371:2 013)
• Oxygen: if Pa O 2 ≤55 mmHg or S a O 2 ≤8 9% (during rest, exercise or sleep ) to

p revent cor p ulmonale; only Rx p roven to ↓ mortality (Annals 198 0;93:391;
Lance t 198 1;i:68 1)
• Prevention: Flu/Pneumovax; smoking cessation (eg, varenicline, bup rop ion) → 50%
↓ in lung function decline (AJRCCM 2 002 ;166:675) and ↓ long-term mortality
(Annals 2 005;142 :2 2 3)
• Rehabilitation: ↓ dysp nea and fatigue, ↑ exercise tolerance, ↓ QoL (NEJM

2 009;360:132 9)
• Exp erimental
Lung volume reduction surgery: ↑ exer. cap acity, ↓ mort. if FEV1 >2 0% , up p er-
lobe, low exer. cap acity (NEJM 2 003;348 :2 059); bronchoscop ic w/
endobronchial valves w/ mixed benefits: ↑ lung fxn but ↑ PNA, exacerb,
hemop tysis (NEJM 2 010;363:12 33)
Roflumilast (PDE-4 inhibitor): ↑ FEV1 when added to standard Rx (Lance t
2 009;374:68 5&695)
Nocturnal BiPAP: may imp rove survival, ? decrease QoL (Thorax 2 009;64:561)
• Lung transp lant: ↑ QoL and ↓ sx (Lance t 1998 ;351:2 4), ? survival benefit (Am J
Transplant 2 009;9:1640)
Staging and prognosis
• FEV1: 50–8 0% p redicted → 3-y mort. ~11% ; 30–50% → ~15% ; <30% → ~2 4%
• BODE 10-p t scale (Lance t 2 009;374:704); HR 1.62 for resp mort., 1.34 mort. for
each 1-p t ↑ BMI: ≤2 1 (+1)
Obstruction (FEV1): 50–64% (+1), 36–49% (+2 ), ≤35% (+3)
Dysp nea (MMRC scale): walking level (+1), after 100 yd (+2 ), with ADL (+3)
Exs cap acity (6-min walk): 2 50–349 m (+1), 150–2 49 (+2 ), ≤149 (+3)
sup erior to FEV1 (NEJM 2 004;350:1005); can p redict survival from LVRS (Che st
2 006;12 9:8 73)
• mMRC score: ≥2 defined as walking slowly b/c breathlessness or having to stop to
catch breath walking level
• Ratio of diam PA/aorta >1 associated with ~3× ↑ risk of exacerbations (NEJM
2 012 ;367:913)
EXACERBATION
HEMOPTYSIS
Definition and pathophysiology
• Exp ectoration of blood or blood-streaked sp utum
• Massive hemoptysis: ~>600 mL/2 4–48 h; gas exchange more imp ortant than
blood loss
• Massive hemop tysis usually from tortuous or invaded bronchial arteries
Diagnostic workup
• Localize bleeding site
Rule out GI or ENT source by exam, history; may require endoscop y
Pulmonary source: determine whether unilateral or bilateral, localized or diffuse,

parenchymal or airway by CXR or chest CT, bronchoscop y if necessary
• PT, PTT, CBC to rule out coagulopathy
• Sp utum culture/stain for bacteria, fungi and AFB; cytology to r/o malignancy
• ANCA, anti-GBM, urinalysis to ✓ for vasculitis or pulmonary-renal syndrome
Treatment
• Mechanism of death is asp hyxiation not exsanguination; maintain gas exchange,

reverse coagulation and treat underlying condition; cough sup p . may ↑ risk of
asp hyxiation
• Massive hemop tysis: p ut bleeding side dep endent; selectively intubate nl lung if
needed Ang iog raphy: Dx & Rx (vascular occlusion balloons or selective embol of
bronchial art) Rig id bronchoscopy: allows more interventional op tions
(electrocautery, laser) than flex. Surgical resection
BRONCHIECTASIS
Definition and epidemiology (NEJM 2002; 346:1383)

• Obstructive airways disease of bronchi and bronchioles, chronic transmural inflamm
w/ airway dilatation and thickening, collap sibility, mucus p lugging w/ imp aired
clearance
• Frequency: > ; in the U.S. more frequent in Asian Americans (Che st

2 012 ;142 :432 )
Initial workup
• H&P: cough, dysp nea, cop ious sp utum p roduction, ± hemop tysis, insp iratory
“squeaks”
• CXR: scattered or focal; rings of bronchial cuffing; “tram track” of dilated, thick
airways
• PFTs: obstructive p attern
• Chest CT: dilation and thickening of airways; ± cystic changes, infiltrates,

adenop athy
Treatment
• Treat underlying condition; mucolytics & bronchodilators
• Antibiotics: CF Pts often have multip le drug-resistant organisms (Pse udomonas,

Burkholde ria ce pacia, S. aure us) and require IV antibiotics during exacerbations.
Azithro shown to ↓ exacerb. in non-CF bronchiectasis (Lance t 2 012 ;38 0:660; JAMA
2 013;309:12 51).
• Emerging data on gene-based targeted therap ies in CF (NEJM 2 011;365:1663)

SOLITARY PULMONARY NODULE
Principles
• Definition: single, <3 cm, surrounded by normal lung, no LAN or p leural effusion
• Often “incidentalomas,” esp with ↑ CT use, but may still be early, curable
malignancy
Initial evaluation
• History: h/o cancer, smoking, age (<30 y = 2 % malignant, +15% each decade
>30)
• CT: size/shap e, Ca 2 +, LAN, effusions, bony destruction, compare w/ old studies
Ø Ca → ↑ likelihood malignant; laminated → granuloma; “p op corn” →

hamartoma
• High-risk features for malignancy: ≥2 .3 cm diameter, sp iculated, >60 yo, >1 p p d
current smoker, no p rior smoking cessation (NEJM 2 003;348 :2 535)
Diagnostic studies
• PET: detects metab. activity of tumors, 97% Se & 78 % Sp for malig. (esp . if >8
mm) also useful for surgical staging b/c may detect unsusp ected mets (JAMA
2 001;2 8 5:914) useful in deciding which lesions to bx vs. follow w/ serial CT ( J
Thor Oncol 2 006;1:71)
• Transthoracic needle biopsy (TTNB): if tech. feasible, 97% will obtain definitive
tissue dx (AJR 2 005;18 5:12 94); if noninformative or malignant → resect
• Video-assisted thoracoscopic surgery (VATS): for p ercutaneously inaccessible

lesions; highly sensitive and allows resection; has rep laced thoracotomy
• Transbronchial bx (TBB): most lesions too small to reliably samp le w/o

endobronchial U/S (Che st 2 003;12 3:604); bronch w/ brushings low-yield unless
invading bronchus; navigational bronchoscop y w/ 70% yield, ↑ sens w/ larger
nodules (Che st 2 012 ;142 :38 5)
• PPD, fungal serologies, ANCA
Management (for solid SPN >8 mm; if ≤8 mm, serial CT) (Chest 2013; 143:840)
• Low risk (<5% , see ref): serial CT (freq dep ending on risk); shared decision w/ Pt
re: bx
• Intermediate risk (5–60% ): PET, if → follow low-risk p rotocol; if → high-

risk p rotocol
• High risk (and surgical candidate): TBB, TTNB, or VATS → lobectomy if malignant
• Ground-glass nodules: longer f/u b/c even if malignant can be slow-growing and
PET
OBSTRUCTIVE SLEEP APNEA (OSA)
• Rep etitive p haryngeal collap se during sleep causing ap nea (≥10 s) or hyp op nea
(airflow reduction) ± desaturation, arousals from sleep → daytime sleep iness
• Ap nea-hyp op nea index = avg # ap neas and hyp op neas p er hr of sleep
• Sleep -induced loss of activity of p haryngeal dilator muscles → p haryngeal collap se

→ arousal → activation of symp athetic nervous system; p henotyp es vary across
OSA Pts
• Ap nea → negative intrathoracic p ressure → ↑ p reload, ↑ afterload → HTN, CV
sequelae
• Risk factors: obesity (p resent in 70% ), male, age, alcohol, smoking, black race
Clinical manifestations (Lancet 2002; 360:237; Lancet Resp Med 2013; 1:61)
• Snoring, witnessed ap neas/gasp ing, daytime sleep iness

• Cardiovascular: HTN ( JAMA 2 012 ;307:2 169); a/w ↑ risk of stroke and death
(NEJM 2 005;353:2 034) & p ossibly CAD & endothelial dysfxn (AJRCCM
2 001;163:19; Circ 2 008 ;117:2 2 70)
• Neurocognitive: ↓ cognitive p erformance, ↓ QoL, ↑ motor vehicle and work

accidents (NEJM 1999;340:8 47; AJRCCM 2 001;164:2 031)
Diagnosis and treatment
• Polysomnography (sleep study); can do home-testing. If , trial of CPAP.
• CPAP: ↓↓ ap nea/hyp op nea, ↓ BP (Lance t 2 002 ;359:2 04), ↓ sleep iness, ↑

p erformance (AJRCCM 2 012 ;18 6:677), ↑ EF in Pts with CHF (NEJM
2 003;348 :12 33), ↓ metab syndrome (NEJM 2 011;365:2 2 77), ↓ mortality after
stroke (AJRCCM 2 009;18 0:36)
• Oral ap p liances can p revent retroglossal collap se. Offer if refusing CPAP.
• Avoid alcohol and sedatives
• Surgery (eg, uvulop alatop haryngop lasty, UPPP) of limited benefit (Che st
1997;111:2 65)
INTERSTITIAL LUNG DISEASE
WORKUP OF ILD
Rule out mimickers of ILD
• Congestive heart failure (✓ BNP, trial of diuresis)

• Infection: viral, atyp ical bacterial, fungal, mycobacterial, p arasitic
• Malignancy: lymp hangitic carcinomatosis, bronchoalveolar, leukemia, lymp homa
History and physical exam
• Occup ational, travel, exp osure (including tobacco), meds, FHx, p recip itating event
• Temp o (acute → infxn, CHF, hyp ersens p neumonitis, eos PNA, AIP, COP, drug-
induced)
• Extrap ulmonary s/s (skin Ds, arthralgias/arthritis, clubbing, neurop athies, etc.)
Diagnostic studies (see Ap p endix & Radiology inserts)

• CXR and high-resolution chest CT: reticular, nodular or ground glass p attern
up p er → coal, silicon, hyp ersens, sarcoid, TB, RA; lower → IPF, asbestos,
scleroderma adenop athy → sarcoidosis, berylliosis, silicosis, malignancy, fungal
infections p leural disease → collagen-vascular diseases, asbestosis, infections, XRT
• PFTs: ↓ DLCO (e arly sig n), restrictive p attern (↓ volumes), ↓ Pa O 2 (esp . w/ exercise);
if also obstructive, consider sarcoid, LAM, silicosis
• Serologies: ✓ ACE, ANA, RF, ANCA, anti-GBM, HIV
• Bronchoalveolar lavage: dx infxn, hemorrhage, eosinop hilic syndromes, PAP
• Biop sy (transbronch, CT-guided, VATS, op en) if no clear p recip itant and w/u
unrevealing
ETIOLOGIES OF ILD
Sarcoidosis (NEJM 2007; 357:2153; JAMA 2011; 305:391)

• Prevalence: African Americans, northern Europ eans and females; onset in 3rd–4th
decade
• Pathop hysiology: dep ression of cellular immune system p erip herally, activation
centrally
• Löfg re n’s syndrome : erythema nodosum + hilar adenop athy + arthritis (good
p rognosis)
• Diagnostic studies: LN bx → noncaseating granulomas + multinucleated giant cells

18 FDG PET can be used to identify extent and p otentially targets for dx bx ↑ ACE
(Se 60% , 90% w/ active dis., Sp 8 0% , false in granulomatous diseases)
• To assess extent: CXR, PFTs, full op htho exam, ECG, CBC (lymp hop enia, ↑ eos), Ca,
2 4-h urine for Ca, LFTs; ± Holter, echo, cardiac MRI, brain MRI, etc., based on
s/s
• Rx: steroids (eg, p rednisone 2 0–40 mg/d) if sx or extrathoracic organ dysfxn
(imp roves sx, but doesn’t Δ long-term course); hydroxychloroquine for extensive
skin disease; anti-TNF, MTX, AZA, mycop henolate or cyclop hosp hamide for
chronic/refractory disease
• Prognosis: ~ 2 /3 sp ontaneously remit w/in 10 y (60–8 0% of stage I, 50–60% stage
II, 30% stage III), w/ relap ses uncommon; ~ 1/3 have p rogressive disease
Iatrogenic
• Amiodarone (~10% ; dose & duration dep end.): chronic interstitial p neumonia ↔
ARDS; bx → vacuolized Mf w/ lamellar inclusions on EM; Rx: d/c amio, give
steroids
• Other drugs: nitrofurantoin, sulfonamides, thiazides, INH, hydralazine, gold
• Chemo: bleomycin (triggered by hyp eroxia), busulfan, cyclop hosp hamide, MTX, etc.
• XRT: COP/BOOP w/ sharp ly linear, nonanatomic boundaries; DAH
Idiopathic interstitial pneumonias (IIPs) (AJRCCM 2005; 172:268)
• Definition: ILD of unknown cause; dx by radiograp hic, histologic and clinical

features
UIP, usual interstitial PNA (IP); IPF, idiop athic p ulm fibrosis (Lance t
2 011;378 :1949); NSIP, nonsp ecific IP; COP, cryp togenic organizing PNA; BOOP,
bronchiolitis obliterans w/ organizing PNA; AIP, acute IP (Hamman-Rich syndrome);
DIP, desquamative IP; RB-ILD, resp bronchiolitis-assoc ILD.
• Rx for UIP/IPF: ?? NAC (NEJM 2 005;353:2 2 2 9); p red + AZA harmful (NEJM
2 012 ;366:1968 )
Exp erimental: tyrosine kinase inhib (NEJM 2 011;365:1079); p irfenidone (Lance t

2 011;377:1760; not avail in U.S.); ? sildenafil (NEJM 2 010;363:62 1);
thalidomide for cough (Annals 2 012 ;157:398 )
• Steroids for other IIPs: NSIP (esp . cellular typ e) and COP (AJRCCM 2 000;162 :571); ?
benefit for AIP and DIP/RB-ILD (for which Pts should stop smoking)
Environmental & occupational exposures (NEJM 2000; 342:406; Lancet

2012; 379:2008)
• Pneumoconioses (inorganic dusts)
Coal worker’s: up p er lobe coal macules; may p rogress to massive fibrosis
Silicosis: up p er lobe op acities ± eggshell calcification of lymp h nodes; ↑ risk of

TB
Asbestosis: lower lobe fibrosis, calcified p leural p laques, DOE, dry cough, rales on
exam. Asbestos exp osure also → p leural p laques, benign p leural effusion,
diffuse p leural thickening, rounded atelectasis, mesothelioma, lung Ca (esp . in
smokers).
Berylliosis: multisystemic granulomatous disease that mimics sarcoidosis
• Hypersensitivity pneumonitides (organic dusts): loose, noncaseating g ranulomas
Antigens: farmer’s lung (sp ores of thermop hilic actinomyces); p igeon fancier’s
lung (p roteins from feathers and excreta of birds); humidifier lung (thermop hilic
bacteria)
Collagen vascular diseases (NEJM 2006; 355:2655)
• Rheumatologic disease
Scleroderma: fibrosis in ~67% ; PHT seen in ~10% of CREST Pts
PM-DM: ILD & weakness of resp iratory muscles; MCTD: PHT & fibrosis
SLE & RA: p leuritis and p leural effusions more often than ILD; SLE can cause DAH
• Vasculitis (can p /w DAH)
Wegener’s granulomatosis ( c-ANCA) w/ necrotizing granulomas
Churg-Strauss syndrome ( c- or p -ANCA) w/ eosinop hilia & necrotizing

granulomas
Microscop ic p olyangiitis ( p -ANCA) w/o granulomas
• Goodpasture’s syndrome = DAH + RPGN; typ ically in smokers; anti-GBM in

90%
• Lymphangioleiomyomatosis (LAM): cystic, ↑ in , Rx w/ sirolimus (NEJM

2 011;364:1595)
Pulmonary infiltrates w/ eosinophilia (PIE) = eos on BAL ± periph. blood
• Allergic bronchopulmonary aspergillosis (ABPA): allergic reaction to Aspe rg illus

Criteria: asthma, p ulm infiltrates (transient or fixed), skin rxn & serum
p recip itins to Aspe rg illus, ↑ IgE to Aspe rg illus & total (>1000), ↑ eos, central
bronchiectasis
Rx: steroids ± itraconazole for refractory cases (NEJM 2 000;342 :756)
• Löffler’s syndrome: p arasites/drugs → transient p ulm infilt + cough, fever,

dysp nea, eos
• Acute eosinop hilic PNA (AEP): acute hyp ox febrile illness; Rx: steroids, tobacco
cessation
• Chronic eosinop hilic p neumonia (CEP): “p hotonegative” of CHF, typ ically in women
• Other: Churg-Strauss syndrome; hyp ereosinop hilic syndrome
Miscellaneous
• Pulm alveolar p roteinosis (PAP): accum of surfactant-like p hosp holip ids;

smokers; white & gummy sp utum; BAL milky fluid (NEJM 2 003;349:2 52 7); Rx w/
lung lavage & GMCSF
• Langerhans cell granulomatosis (LCG): young smokers; ap ical cysts; PTX (2 5% )
• Lymp hocytic interstitial PNA: p olyclonal B-cell infiltration (? lymp homa); Rx:
steroids
PLEURAL EFFUSION
Pathophysiology
• Systemic factors (eg, ↑ PCWP, ↓ oncotic p ressure) → transudative effusion
• Local factors (ie, Δ p leural surface p ermeability) → e xudative effusion

Transudates
• Congestive heart failure (40% ): 8 0% bilateral, ± cardiomegaly on CXR
occasionally exudative (esp . after aggressive diuresis or if chronic), but ~75% of
exudative effusions in CHF Pts found to have non-CHF cause (Che st
2 002 ;12 2 :1518 )
• Constrictive pericarditis (knock on exam, calcification or thickening on imaging)
• Cirrhosis (“hep atic hydrothorax” ): diap hragmatic defect w/ p assage of ascitic fluid
often right-sided (2 /3) & massive (even w/o marked ascites)
• Nep hrotic syndrome: usually small, bilateral, asymp tomatic (r/o PE b/c hyp ercoag)
• Other: PE (usually exudate), malignancy (lymp hatic obstruction), myxedema, CAPD

Exudates
• Lung parenchymal infection (25% )

bacterial (p arap neumonic): can evolve along sp ectrum of e xudative (but sterile) →
fibropurule nt (infected fluid) → org anization (fibrosis & formation of rigid p leural
p eel). Common causes: Stre p pne umo, Staph aure us, Stre p mille ri, Kle bsie lla,
Pse udomonas, Hae mophilus, Bacte roide s, Pe ptostre ptococcus, mixed flora in
asp iration p neumonia.
mycobacterial: >50% lymp hs 8 0% of the time, ADA >40, p leural bx ~70% Se
fungal, viral (usually small), p arasitic (eg, amebiasis, echinococcosis,

p aragonimiasis)
• Malignancy (15% ): p rimary lung cancer most common, metastases (esp . breast,
lymp homa, etc.), mesothelioma (✓ serum osteop ontin levels; NEJM 2 005;353:15)
• Pulmonary embolism (10% ): effusions in ~40% of PEs; exudate (75% ) >
transudate (2 5% ); hemorrhagic—must have hig h suspicion b/c pre se ntation hig hly
variable
• Collagen vascular disease: RA (large), SLE (small), Wegener’s, Churg-Strauss
• Gastrointestinal diseases: p ancreatitis, esop hageal rup ture, abdominal abscess
• Hemothorax (Hcteff/Hctblood >50% ): trauma, PE, malignancy, coagulop athy,

leaking aortic aneurysm, aortic dissection, p ulmonary vascular malformation
• Chylothorax (triglycerides >110): thoracic duct damage due to trauma, malignancy,

LAM
• Other:
p ost-CABG: left-sided; initially bloody, clears after several wks
Dressler’s syndrome (p ericarditis & p leuritis p ost-MI), uremia, p ostradiation

therap y
Asbestos exp osure: benign; eosinop hils
Drug-induced (eg, nitrofurantoin, methysergide, bromocrip tine, amiodarone):

eos
Uremia; p ost-XRT; sarcoidosis
Meigs’ syndrome = benign ovarian tumor → ascites & p leural effusion
Yellow-nail syndrome: yellow nails, lymp hedema, p leural effusion, bronchiectasis

Diagnostic studies
• Thoracentesis (NEJM 2 006;355:e16)
Indications: all effusions >1 cm in decubitus view if susp ect due to CHF, can
diurese and see if effusions resolve (75% do so in 48 h) asymme try, fe ve r, che st
pain or failure to re solve → thoracentesis parapneumonics should be tapped
ASAP (cannot exclude infxn clinically)
Diag nostic studie s: ✓ total p rotein, LDH, glucose, cell count w/ differential, Gram
stain & culture, p H; remaining fluid for additional studies as dictated by clinical
scenario
Complications: PTX (5–10% ), hemothorax (~1% ), re-exp ansion p ulm edema (if
>1.5 L removed), sp leen/liver lac.; p ost-tap CXR not routinely needed (Annals
1996;12 4:8 16)
↓ PTX w/ U/S and exp erienced sup ervisor (Che st 2 009;135:1315; Archive s
2 010;170:332 )
• Transudate vs. exudate (Annals 1972 ;77:507)
Light’s criteria: exudate = TPeff/TPserum >0.5 or LDH eff/LDH serum >0.6 or
LDH eff >2 /3 ULN of LDH serum ; 98 % Se, 8 3% Sp ; best Se of all methods
(Che st 1995;107:1604); however, will misidentify 2 5% of transudates as
exudates; ∴ if clinically susp ect transudate but meets criterion for exudate,
confirm w/ test w/ higher Sp
exudative criteria w/ better Sp : serum-effusion alb gradient ≤1.2 , Se 8 7% , Sp

92 % ; serum-effusion TP gradient ≤3.1, Se 8 4% , Sp 91% ; chol eff >45 mg/dL
and LDH eff >2 00, 90% Se, 98 % Sp (no serum required)
CHF effusions: TP may ↑ with diure sis or chronicity → “p seudoexudate” ; alb gradient
≤1.2 , chol eff >60 mg/dL (Se 54% , Sp 92 % ) or clin judgment to distinguish
(Che st 2 002 ;12 2 :152 4)
• Complicated vs. uncomplicated parapneumonic (Che st 1995;108 :2 99)
comp licated = Gram stain or culture or p H <7.2 or glucose <60
comp licated p arap neumonic effusions usually require drainag e to achieve

resolution
emp yema = frank p us, also needs drainage to achieve resolution
• Additional p leural fluid studies (NEJM 2 002 ;346:1971)
NT-p roBNP ≥1,500 p g/mL has 91% Se & 93% Sp for CHF (Am J Me d
2 004;116:417)
WBC & diff.: exudates tend to have ↑ WBC vs. transudates but nonsp ecific
neutrop hils → p arap neumonic, PE, p ancreatitis lymp hocytes (>50% ) → cancer,
TB, rheumatologic eos (>10% ) → blood, air, drug rxn, asbestos,
p aragonimiasis, Churg-Strauss, PE
RBC: Hcteff 1–2 0% → cancer, PE, trauma; Hcteff/Hctblood >50% → hemothorax
AFB: yield in TB 0–10% w/ stain, 11–50% w/ culture, ~70% w/ p leural bx
adenosine deaminase (ADA): seen w/ granulomas, >70 suggests TB, <40 excludes
TB
cytology: ideally ≥150 mL and at least 60 mL should be obtained (Che st
2 010;137:68 )
glucose: <60 mg/dL → malignancy, infection, RA
amylase: seen in p ancreatic disease and esop hageal rup ture (salivary amylase)
rheumatoid factor, C H 50, ANA: limite d utility in dx collagen vascular disease
triglycerides: >110 → chylothorax, 50–110 → ✓ lip op rotein analysis for

chylomicrons
cholesterol: >60; seen in chronic effusions (eg, CHF, RA, old TB)
creatinine: effusion/serum ratio >1 → urinothorax

fibulin-3: ↑ p lasma and/or effusion levels → mesothelioma (NEJM 2 012 ;367:1417)
• Chest CT; p leural biop sy; VATS

• Undiagnosed p ersistent p leural effusions (Clin Che st Me d 2 006;2 7:309)
Transudative : most commonly CHF or hep atic hydrothorax. ✓ s/s CHF or

cirrhosis, NT-p roBNPeff; consider intrap eritoneal injection of technetium-99m
sulfur colloid
Exudative (ensure using Sp test listed above): most commonly malig, emp yema,
TB, PE. ✓ s/s malig, chest CT (I+), ADA or IFN-g release assay; consider
thoracoscop y.
Treatment
• Symp tomatic effusion: therap eutic thoracentesis, treat underlying disease p rocess
• Parap neumonic effusion (Che st 2 000;118 :1158 )
uncomp licated → antibiotics for p neumonia
>1/2 hemithorax or complicated or empyema → tube thoracostomy (otherwise

risk of organization and subsequent need for surgical decortication)
loculated→ tube thoracostomy or VATS; intrap leural t-PA + DNase ↓ need for
surgical referral (NEJM 2 011;365:518 )
• Malignant effusion: serial thoracenteses vs. tube thoracostomy + p leurodesis

(success rate ~8 0–90% ) vs. indwelling p leural catheter ( JAMA 2 012 ;307:2 38 3);
choice of p leurodesis agent (talc, bleo, doxy) controversial; systemic steroids & p H
<7.2 a/w ↑ p leurodesis failure rate
• TB effusions: effusion will often resolve sp ontaneously; however, treat Pt for active
TB
• Hep atic hydrothorax
Rx: Δ p ressure gradient (ie, ↓ ascitic fluid volume, NIPPV)

avoid chest tubes; p rn thoracenteses, p leurodesis, TIPS or VATS closure of
diap hragmatic defects if medical Rx fails; NIPPV for acute short-term
management
sp ontaneous bacterial emp yema (SBEM) can occur (even w/o SBP being p resent),
∴ thoracentesis if susp ect infection
transp lant is definitive treatment and workup should begin immediately
VENOUS THROMBOEMBOLISM (VTE)
Definitions
• Proximal deep venous thrombosis (DVT): thrombosis of p op liteal, femoral or iliac

veins
(nb, “sup erficial” femoral vein p art of deep venous system)
• Pulmonary embolism (PE): thrombosis originating in venous system and embolizing

to p ulmonary arterial circulation; 1 case/1000 p erson y; 2 50,000/y (Archive s
2 003;163:1711)
Risk factors
• Virchow’s triad for thrombogenesis
stasis: bed rest, inactivity, CHF, CVA w/in 3 mo, air travel >6 h (NEJM
2 001;345:779)
injury to endothelium: trauma, surgery, p rior DVT, inflammation

thrombophilia: APC resistance, p rotein C or S deficiency, APS, p rothrombin gene
mutation,↑ factor VIII, hyp erhomocysteinemia, HIT, OCP, HRT, tamoxifen,
raloxifene
• Malignancy (12 % of “idiop athic” DVT/PE)

• History of thrombosis (greater risk of recurrent VTE than genetic thrombop hilia)
• Statin therap y ↓ risk (NEJM 2 009;360:18 51)
Clinical manifestations—DVT
• Calf p ain, swelling (>3 cm c/w unaffected side), venous distention, erythema,
warmth, tenderness, p alp able cord, Homan’s sign (calf p ain on dorsiflexion,
seen in <5% of Pts), phle g masia ce rule a dole ns: stagnant blood → edema,
cyanosis, p ain
• 50% of Pts with sx DVT have asx PE

Diagnostic studies—DVT
• D-dimer: <500 help s r/o; ? use 1000 as threshold if low risk (Annals 2 013;158 :93)
• Comp ression U/S >95% Se & Sp for sx DVT (lower for asx DVT); survey whole leg
rather than just p roximal if ≥mod p rob ( JAMA 2 010;303:438 ); venograp hy
rarely used
Figure 2-3 Approach to suspected DVT (Chest 2012; 141:e351S)
Clinical manifestations—PE
• Dysp nea (73% ), p leuritic chest p ain (66% ), cough (37% ), hemop tysis (13% )
• ↑ RR (>70% ), crackles (51% ), ↑ HR (30% ), fever, cyanosis, p leural friction rub,

loud P2
• Massive : syncop e, HoTN, PEA; ↑ JVP, R-sided S 3, Graham Steell (PR) murmur
Diagnostic studies—PE (NEJM 2010; 363:266)
• CXR (limited Se & Sp ): 12 % nl, atelectasis, effusion, ↑ hemidiap hragm, Hamp ton
hump (wedge-shap ed density abutting p leura); Westermark sign (avascularity
distal to PE)
• ECG (limited Se & Sp ): sinus tachycardia, AF; signs of RV strain → RAD, P
p ulmonale, RBBB, S IQ IIITIII & TWI V1–V4 (McGinn-White p attern, Che st
1997;111:537)
• ABG: hyp oxemia, hyp ocap nia, resp iratory alkalosis, ↑ A-a gradient (Che st
1996;109:78 ) 18 % w/ room air Pa O 2 8 5–105 mmHg, 6% w/ nl A-a gradient
(Che st 1991;100:598 )
• D-dimer: high Se, p oor Sp (~2 5% ); ELISA has >99% NPV and can be used to
r/o PE in Pts w/ “unlikely” p retest p rob. ( JAMA 2 006;2 95:172 )
• Echocardiograp hy: useful for risk stratification (RV dysfxn), but not dx (Se <50% )
• V/Q scan: high Se (~98 % ), low Sp (~10% ). Sp imp roves to 97% for high p rob VQ.
Use if p retest p rob of PE high and CT not available or contraindicated. Can also
exclude PE if low p retest p rob, low p rob VQ, but 4% false ( JAMA
1990;2 63:2 753).
• CT angiography (CTA; see Radiology inserts): Se ~90% & Sp ~95% w/ MDCT

(NEJM 2 006;354:2 317); PPV & NPV >95% if imaging concordant w/ clinical
susp icion, ≤8 0% if discordant (∴ need to consider both); CT may also p rovide
other dx
• Lower extremity comp ression U/S shows DVT in ~9% , sp aring CTA, but when
added to CTA, does not Δ outcomes (Lance t 2 008 ;371:1343)
• Pulmonary angio: ? gold standard (morbidity 5% , mortality <0.5% ), infrequently

p erformed
• MR angiograp hy: Se 8 4% (segmental) to 100% (lobar) (Lance t 2 002 ;359:1643); if

add MR venograp hy, Se 92 % , Sp 96% (Annals 2 010;152 :434)
Figure 2-4 Approach to suspected PE using CTA
Workup for idiopathic VTE
• Thrombophilia workup: ✓ if FH, consider if age <50 y or on OCP/HRT. Send

p anel 2 wk after comp lete anticoagulation, as thrombus, hep arin and warfarin Δ
results. Nb, does not change management after 1st idiop athic DVT if p lan for long-
term anticoagulation ( JAMA 2 005;2 93:2 352 ; Blood 2 008 ;112 :4432 ; Am J Me d
2 008 ;12 1:458 ).
• Malignancy workup: 12 % Pts w/ “idiop athic” DVT/PE will have malignancy; age-
ap p rop riate screening adequate; avoid extensive w/u (NEJM 1998 ;338 :1169)
Risk stratification for Pts with PE

• Clinical: hyp otension and/or tachycardia (~30% mortality), hyp oxemia
• CTA: RV / LV dimension ratio >0.9 (Circ 2 004;110:32 76)
• Biomarkers: ↑ trop onin (Circ 2 002 ;106:12 63), ↑ BNP (Circ 2 003;107:1576) a/w ↑
mortality
• Echocardiogram: RV dysfxn (controversial in absence of hyp otension)
• Simp lified PE Severity Index: 0 RFs → 1.1% mort.; ≥1 → 8 .9% mort (Archive s
2 010;170:138 3) RFs: age >8 0 y; h/o cancer; h/o HF or lung disease; HR ≥110;
SBP <100; S a O 2 <90%
Treatment of VTE (Lancet 2012; 379; 1835; Chest 2012; 141:e419S)
• LE DVT: p roximal → anticoagulate; distal: anticoagulate if severe sx or risk for

extension, o/w may consider serial imaging (although if bleeding risk low, many
would anticoagulate)
• UE DVT: anticoagulate (same guidelines as LE; NEJM 2 011;364:8 61). If catheter-

associated, need not remove if catheter functional and ongoing need for catheter.
• Sup erficial venous thrombosis: anticoagulate (esp . if extensive clot) as 10%

exp erience thromboembolic event w/in 3 mo (Annals 2 010;152 :2 18 )
• Acute anticoagulation options (initiate imme diate ly if hig h clinical suspicion!)
LMWH (eg, enoxap arin 1 mg/kg SC bid or daltep arin 2 00 IU/kg SC qd)
Preferred over UFH excep t: renal failure (CrCl <2 5), ? extreme obesity,
hemodynamic instability or bleed risk (Cochrane 2 004;CD001100)
No need to monitor anti-factor Xa unless concern re: dosing (eg, renal insuffic.)
Attractive op tion as outPt bridge to long-term oral anticoagulation
Fondaparinux: 5–10 mg SC qd (NEJM 2 003;349:1695); use if HIT ; avoid if

renal failure
IV UFH: 8 0 U/kg bolus → 18 U/kg/h → titrate to PTT 1.5–2 .3 × cntl (eg, 60–8 5
sec)
Rivaroxaban: 15 mg bid (for 1st 3 wk) LMWH followed by warfarin (NEJM

2 010;363:2 499 & 2 012 ;366:12 8 7); effect wears off w/in 2 4 h, but not easily
immediately reversed
Direct thrombin inhibitors (eg, argatroban, lep irudin) used in HIT Pts
• Early ambulation
• DVT & low-risk PE can be treated comp letely as outPt (Lance t 2 011;378 :41)
• Thrombolysis (eg, TPA 100 mg over 2 h or wt-adjusted TNK bolus)
Use if PE a/w hemodynamic comp romise (“massive PE” )
Consider if PE w/o hemodynamic comp romise, but high-risk (“submassive PE,” eg,
marked dysp nea, severe hyp oxemia, RV dysfxn on echo, RV enlargement on
CTA) and low bleed risk. Risk of ICH ~1% and no p roven mortality benefit
(NEJM 2 002 ;347:1143; Cochrane 2 006:CD004437).
Consider if extensive (eg, iliofemoral) acute DVT and catheter-directed Rx not
available
• Catheter-directed therapy (fibrinolytic & thrombus fragmentation/asp iration)

Consider if extensive vs. in all acute DVT as ↓ p ostthrombotic synd (Lance t
2 012 ;379:31)
Consider if PE w/ hemodynamic comp romise or high risk and not candidate for
systemic fibrinolytic therap y or surgical thrombectomy (Circ 2 011;12 4:2 139)
• Thrombectomy: if large, p roximal PE + hemodynamic comp romise + contra. to
lysis;
consider in exp erienced ctr if large p rox. PE + RV dysfxn ( J Thorac CV Surg
2 005;12 9:1018 )
• IVC filter: if anticoagulation contraindication, failure or bleed, or ? ↓ CP reserve;

temp . filter if risk time limited; adding filter to anticoagulation → PE ↓ 1/2 , DVT
↑ 2 ×, no mort. diff. (NEJM 1998 ;338 :409; Circ 2 005;112 :416)
• Long-term anticoagulation options

Warfarin (goal INR 2 –3): start same day as hep arin unless instability and ? need
for lytic, catheter-based Rx or surgery; overlap ≥5 d w/ hep arin & until INR
≥2 × ≥2 4 h
Rivaroxaban (after 15 mg bid for 1st 3 wk, then 2 0 mg qd) warfarin (see refs
above)
Dabigatran (NEJM 2 009;361:2 342 ) and idrabiotap arinux (weekly SC FXa inhib;
Lance t 2 012 ; 379:12 3) both ap p ear warfarin, but neither FDA ap p roved
VTE a/w cancer: LMWH × 3–6 mo, then LMWH/warfarin indefinitely or until
cancer cured (NEJM 2 003;349:146); ✓ head CT for brain mets if melanoma,
renal cell, thyroid, chorioCA
• Duration of anticoagulation:
Sup erficial venous thrombosis: 4 wk
1st p rox DVT or PE 2 ° reversible/time-limited risk factor or distal DVT: 3 mo
1st unprovoke d p rox DVT or PE: ≥3 mo, then reassess; if low bleed risk →
indefinite Rx w/ warfarin; extended Rx w/ newer agents under study: c/w
p lacebo ap ixaban (either 2 .5 or 5 mg) ↓↓ VTE w/o ↑ major bleeding (NEJM
2 013;368 :699); rivaroxaban (2 0 mg qd) or dabigatran (150 mg bid) also ↓↓ VTE
but ↑ major bleeding (NEJM 2 010;363:2 499 & 2 013;368 :709)
2 nd VTE event: indefinite warfarin (NEJM 1997;336:393 & 2 003;348 :142 5)
Can be guided by D-dimer testing at 1 & 3 mo (NEJM 2 006;355:178 0; Blood

2 010;115:48 1)
Afte r 6–18 mo of anticoag for unp rovoked VTE, if decide to stop anticoag (eg, b/c
of bleeding) ASA ↓ risk of recurrent VTE by 32 % (NEJM 2 012 ;366:1959 &
367:1979)
Complications & prognosis
• Postthrombotic syndrome (2 5% ): p ain, swelling; ↓ with comp ression stockings × 3

mo
• Recurrent VTE: 1% /y (after 1st VTE) to 5% /y (after recurrent VTE)
after only 6 mo of Rx: 5% /y & >10% /y, resp ectively
p redictors: abnl D-dimer 1 month after d/c anticoag (NEJM 2 006;355:178 0);
U/S after 3 mo of anticoag (Annals 2 002 ;137:955); thrombin generation >400
nM ( JAMA 2 006;2 96:397)
• Chronic thromboembolic PHT after acute PE ~3.8 % (NEJM 2 004;350:2 2 57),

consider thromboendarterectomy
• Mortality: ~10% for DVT and ~10–15% for PE at 3–6 mo (Circ 2 008 ;117:1711)
PULMONARY HYPERTENSION (PHT)
PA me an pre ssure >25 mmHg at re st
Pathobiology (NEJM 2004; 35:1655)
• Smooth muscle & endothelial cell p roliferation; mutations in bone morp hogenic
p rotein recep tor 2 (BMPR2) in ~50% familial & ~2 6% sp oradic cases of IPAH
(NEJM 2 001;345:319)
• Imbalance between vasoconstrictors and vasodilators
↑ vasoconstrictors: thromboxane A2 (TXA2 ), serotonin (5-HT), endothelin-1 (ET-1)
↓ vasodilators: p rostacyclin (PGI2 ), nitric oxide (NO), vasoactive p ep tide (VIP)
• In situ thrombosis: ↑ TXA2 , 5-HT, PAI-1; ↓ PGI2 , NO, VIP, tissue p lasminogen
activator
• Dysp nea, exertional syncop e (hyp oxia, ↓ CO), exertional chest p ain (RV ischemia)
• Symp toms of R-sided CHF (eg, p erip heral edema, RUQ fullness, abdominal
distention)
• WHO class: I=asx w/ ordinary activity; II=sx w/ ord. activ.; III=sx w/ min activ.;
IV=sx at rest
Physical exam
• PHT: p rominent P2 , R-sided S 4, RV heave, PA tap & flow murmur, PR (Graham
Steell), TR
• ± RV failure: ↑ JVP, hep atomegaly, p erip heral edema
Diagnostic studies & workup (Circ 2009; 119:2250)
• IPAH ye arly incide nce 1–2 pe r million, ∴ r/o 2° cause s

• CXR and high-resolution chest CT: dilatation & p runing of p ulmonary arteries,
enlargement of RA and RV; r/o p arenchymal lung disease
• ECG: RAD, RBBB, RAE (“P p ulmonale” ), RVH (Se 55% , Sp 70% )
• PFTs: ↓ DLco, mild restrictive p attern; r/o obstructive and restrictive lung disease
• ABG & p olysomnograp hy: ↓ Pa O 2 and S a O 2 (esp . w/ exertion), ↓ Pa CO 2 , ↑ A-a

gradient; r/o hyp oventilation and OSA
• TTE: ↑ RVSP (but over or under by ≥10 mmHg in 1/2 of PHT Pts; Che st
2 011;139:98 8 ), flattened (“D” ) sep tum, TR, PR; r/o LV dysfxn, MV disease and
congenital heart disease
• RHC: ↑ RA, RV, & PA p ressures, nl PCWP (unless due to L-sided heart disease), ↑
transp ulm gradient (PAP-PCWP >12 –15, but can be nl if due to LV or valvular
dis.), ↑ PVR, ↓ CO; r/o ↑ L-sided p ressures shunt
• CTA (large/med vessel), V/Q scan (small vessel to r/o CTEPH), ± p ulmonary
angiogram: r/o PE and chronic thromboembolic disease
• Vasculitis labs: ANA (~40% in PAH), RF, anti-Scl-70, anticentromere, ESR
• LFTs & HIV: r/o p ortop ulmonary and HIV-associated PAH

• 6-min walk test (6MWT) or cardiop ulmonary exercise testing to establish fxnl
cap acity
Treatment (NEJM 2004; 351:1425; JIM 2005; 258:199; Circ 2009; 119:2250)
• Princip les
1) p revent and reverse vasoactive substance imbalance and vascular remodeling
2 ) p revent RV failure: ↓ wall stress (↓ PVR, PAP, RV diam); ensure adeq. systemic
DBP
• Supportive
Oxygen: maintain S a O 2 >90–92 % (reduces vasoconstriction)
Diuretics: ↓ RV wall stress and relieve RHF sx; g e ntle b/c RV is p reload dep endent
Digoxin: control AF, ? counteract neg. inotrop ic effects CCB
Dobutamine and inhaled NO for decomp ensated PHT
Anticoagulation: ↓ VTE risk of RHF; ? p revention of in situ microthrombi; ? mort.

benefit even if in NSR (Circ 198 4;70:58 0; Che st 2 006;130:545)
• Vasodilators (right heart catheterization p rior to initiation) acute vasore activity te st:
use inhaled NO, adenosine or p rostacyclin to identify Pts likely to have a long-term
resp onse to oral CCB ( vasoreactive resp onse defined as ↓ PAP ≥10 mmHg to
a level <40 mmHg with ↑ or stable CO); ~10% Pts are acute resp onders; no
resp onse → still candidates for other vasodilators (NEJM 2 004;351:142 5)
• Treat underlying causes of 2 ° PHT; can use vasodilators, although little evidence
• Refractory PHT:
balloon atrial sep tostomy: R→L shunt causes ↑ CO, ↓ S a O 2 , net ↑ tissue O 2
delivery
lung transp lant (single or bilateral); heart-lung needed if Eisenmenger p hysiology
Figure 2-5 Treatment of PAH (modified from JACC 2009; 54:S78)
Management of ICU patient
• Avoid overly aggressive volume resuscitation
• Caution with vasodilators if any L-sided dysfunction

• May benefit from inotrop es/chronotrop es
• Consider fibrinolysis if acute, refractory decomp ensation (eg, TPA 100 mg over 2 h)
Prognosis
• Median survival after dx ~2 .8 y; PAH (all etiologies): 2 -y 66% , 5-y 48 % (Che st

2 004;12 6:78 -S)
• Poor p rognostic factors: clinical evidence of RV failure, rap idly p rogressive sx,
WHO (modified NYHA) class IV, 6MWT <300 m, p eak VO 2 <10.4 mL/kg/min, ↑
RA or RV or RV dysfxn, RA >2 0 or CI <2 .0, ↑ BNP (Che st 2 006;12 9:1313)
• Lung transp lant: 1-y survival 66–75% ; 5-y survival 45–55% (Che st 2 004;12 6:63-S)
RESPIRATORY FAILURE
• A-a gradient = P AO2 – P aO2 : normal (on room air) = “4 + age/4” or “2 .5 + (0.2
× age)” hyp oxemia + normal A-a gradient → p roblem is excess Pa CO 2 (ie,
hyp oventilation)
• V/Q mismatch and shunt rep resent sp ectrum w/ both coexisting in alveolar disease
100% O 2 can overcome V/Q mismatch but not large shunt b/c sigmoidal Hg-O 2
curve
Figure 2-6 Workup of acute hypoxemia
• Cyanosis: seen when >4 g/dL of reduced Hb in blood vessels of skin/mucous

membranes central: ↓ S a O 2 (p ulm disease, shunt); abnl Hb [metHb, sulfHb, COHb
(not true cyanosis)] p erip heral: ↓ blood flow → ↑ O 2 extraction (eg, ↓ CO, cold,
arterial or venous obstruction)
CO binds to Hb more avidly than does O 2 . Pulse oximeter (Ox) misreads COHb as
HbO 2 → falsely nl sat. Oxidizing drugs Δ Hb (ferrous) to MetHb (ferric), which
cannot carry O 2 . Pulse ox misreads MetHb as HbO 2 . Cyanide inhibits mitochondrial
O 2 use → cellular hyp oxia but p ink skin and ↑ ve nous O 2 sat.
MECHANICAL VENTILATION
Indications
• Imp rove gas exchange
↑ oxygenation
↑ alveolar ventilation and/or reverse acute resp iratory acidosis
• Relieve resp iratory distress
↓ work of breathing (can account for up to 50% of total oxygen consump tion)
↓ resp iratory muscle fatigue

• Ap nea, airway p rotection, p ulmonary toilet
Choosing settings (NEJM 2001; 344:1986)

1. Choose method (including p otentially noninvasive ventilation, see later)
2 . Pick ventilator mode, and (if ap p rop riate) volume targeted or p ressure targeted
3. Set or ✓ remaining variables (eg, Fi O 2 , PEEP, I:E time, flow, airway p ressures)
Tailoring the ventilator settings
• To imp rove oxygenation: op tions include ↑ Fi O 2 , ↑ PEEP
First, ↑ Fi O 2 . If >0.6 and oxygenation remains subop timal, then try ↑ PEEP:
If ↑ Pa O 2 /Fi O 2 and Pp lat stable, suggests recruitable lung (ie, atelectasis).

Continue to ↑ PEEP until either can ↓ Fi O 2 to <0.6 or Pp lat ≥30 cm H 2 O. If
PEEP 2 0 & Fi O 2 1.0 and oxygenation remains subop timal, consider rescue/exp t
strategies (see “ARDS” ).
If ↑ PEEP yields no Δ or ↓ Pa O 2 /Fi O 2 or ↑ Pa CO 2 , suggests additional lung not

recruitable and instead overdistending lung → ↑ shunt & dead sp ace; ∴ ↓ PEEP
• To imp rove ventilation: ↑ VT or insp iratory p ressure, ↑ RR (may need to ↓ I time).

Nb, tolerate ↑ Pa CO 2 (p ermissive hyp ercap nia) in ALI/ARDS (qv) as long as p H
>7.15.
Acute ventilatory deterioration (usually ↑ PIP)
• Resp onse to ↑ PIP: disconnect Pt from vent., bag, auscultate, suction, ✓ CXR & ABG
Figure 2-7 Approach to acute ventilatory deterioration

Weaning from the ventilator (NEJM 2012; 367:2233)
• Perform daily assessment of readiness for sp ontaneous breathing trial (SBT)

• Clinical screening criteria: VS stable, minimal secretions, adequate cough, cause of
resp iratory failure or p reviously failed SBT reversed
• Vent p arameters: Pa O 2 /Fi O 2 >2 00, PEEP ≤5, f/VT <105, VE <12 L/min, VC >10
mL/kg rap id shallow breathing index (f/VT) >105 p redicts failure; NPV 0.95
(NEJM 1991;32 4:1445)
• Daily awakening trial (d/c all sedation; Lance t 2 008 ;371:12 6): op en eyes & w/o:
agitation, RR >35, S a O 2 <8 8 % , resp distress or arrhythmias (if fail, restart
sedation at 1/2 p rior dose).
• SBT = CPAP or T p iece × 30–12 0 min
failure if: deteriorating ABGs, ↑ RR, ↑ or ↓ HR, ↑ or ↓ BP, diap horesis, anxiety
• Tolerate SBT → extubation. Fail SBT → ? cause → work to correct → retry SBT qd
Complications
• Oxygen toxicity (theoretical); p rop ortional to duration + degree of ↑ oxygen (Fi O 2
>0.6)
• Ventilator-associated p neumonia (~1% /day, mortality rate ~30% )
typ ical p athogens: MRSA, Pse udomonas, Acine tobacte r and Ente robacte r sp ecies
p reventive strategies (AJRCCM 2 005;171:38 8 ): wash hands, HOB elevated, non-
nasal intub., enteral nutrition rather than TPN, routine suction of subglottic
secretions, avoid unnecessary abx & transfusions, routine oral antisep tic, stress-
ulcer p rop hylaxis w/ ? sucralfate (↓ VAP, ↑ GIB) vs. H 2 RA/PPI, ? silver-coated
tubes ( JAMA 2 008 ;300:8 05)
• Laryngeal
edema: for Pts vent >36 h; ? p redicted by cuff leak test. Methylp rednisolone
2 0 mg IV q4h starting 12 h p re-extub. → ↓↓ edema and 50% ↓ in reintubation
(Lance t 2 007;369:1003)
ulceration: consider trache ostomy for p atients in whom exp ect >14 d of mech vent
→ ↓ duration mech vent, ↓ # ICU days (BMJ 2 005;330:12 43); no benefit to
p erforming at ~1 wk vs. waiting until ~2 wk ( JAMA 2 010;303:148 3)
• Malnutrition (for all critically ill Pts): e nte ral nutrition initiated early is safe but not
necessary ( JAMA 2 012 ;307:795), but bolus may ↑ risk of VAP & C diff. ( JPEN
2 002 ;2 6:174); no clear benefit to ✓ing gastric residuals ( JAMA 2 013;309:2 49);
pare nte ral nutrition should be delayed until after day 8 to ↓ risk of infections,
cholestasis, RRT, ventilator days (NEJM 2 011;365:506)
• Oversedation/delirium: BDZs and p olyp harmacy are risk factors

p rop ofol: HoTN in ~2 5% ; propofol infusion syndrome (PRIS) ? esp . w/ high (>5
mg/kg/h) & p rolonged (>48 h) infusions & concom vasop ressors → ↑ AG,
cardiac dysfxn, rhabdomyolysis, ↑ triglycerides, & renal failure (Crit Care
2 009;13:R169)
dexmedetomidine: ↑ vent-free days, but brady & HoTN c/w BDZ ( JAMA
2 012 ;307:1151)
ACUTE RESPIRATORY DISTRESS SYNDROME
New “Berlin” definition ( JAMA 2012; 307:2526)

• Acute onset within 1 wk of clinical insult or worsening resp iratory status
• Bilateral infiltrates without alternative exp lanation (eg, effusion, atelectasis,

nodules)
• Edema not fully explained by fluid overload or congestive heart failure

• Hypoxemia: Pa O 2 /Fi O 2 determined with 5 cm H 2 O of PEEP
Pa O 2 /Fi O 2 2 00–300 = mild ARDS (may be on NIPPV), 100–2 00 = mod, <100

= severe
• Chest CT: heterogeneous lung with densities greater in dep endent areas
• Lung bx: diffuse alveolar damage (DAD); Ø req, may give useful dx info (Che st
2 004;12 5:197)
Pathophysiology
• ↑ intrap ulmonary shunt → hyp oxemia (∴ Rx w/ PEEP to p revent derecruitment)
• ↑ increased dead sp ace fraction (see Ap p endix), p redicts ↑ mort. (NEJM

2 002 ;346:12 8 1)
• ↓ comp liance: VT/(Pp lat – PEEP) <50 mL/cm H 2 O
Treatment (p rimarily sup p ortive) (Lancet 2007; 369:1553; NEJM 2007; 357:1113)
• Goal is to maintain gas exchange, sustain life, & avoid ventilator-induced lung injury
(VILI)
• Fluid balance: target CVP 4–6 cm H 2 O (if nonoliguric & normotensive) → ↑
vent/ICU-free days, but no Δ mortality (NEJM 2 006;354:2 564); PA catheter
unp roven (NEJM 2 006;354:2 2 13); using BNP >2 00 to trigger diuresis (UOP goal
4.5–9 mL/kg/h × 3 h) ↓ time to extubation (AJRCCM 2 012 ;18 6:12 56)
• Steroids: debate continues. Adverse effects include neuromuscular weakness, p oor glc
control, ? infection. Benefit may vary by time since ARDS onset:
<72 h: older studies w/o benefit (NEJM 198 7;317:1565); ? ↓ mortality, ↑
vent/ICU-free days in more recent, controversial study (Che st 2 007;131:954)
7–13 d: ? benefit → ↑ vent/ICU-free days, no mortality difference (NEJM

2 006;354:1671)
≥14 d: ↑ mortality (NEJM 2 006;354:1671)

• Paralysis: if Pa O 2 /Fi O 2 <150, cisatracurium × 48 h ↓ mortality (NEJM
2 010;363:1107)
• Experimental ( JAMA 2 010;304:2 52 1)
Inhale d NO or prostacyclins: ↑ Pa O 2 /Fi O 2 , no ↓ mort. or vent-free days (BMJ

2 007;334:779)
Prone : ↑ Pa O 2 , but ↑ comp lications and no ↓ mortality ( JAMA 2 009;302 :1977); ?

↓ mortality if Pa O 2 /Fi O 2 <100 (Inte ns Care Me d 2 010;36:58 5)
Hig h-fre q oscillatory ve nt: no benefit and p ossible harm (NEJM 2 013;368 :795, 8 06,
& 8 63)
Lung re cruitme nt: ap p ly CPAP 40–45 cm H 2 O × 2 min to recruit lung and then ↑
PEEP to maintain; sicker Pts had ↑ recruitable lung (NEJM 2 006;354:1775, 18 39)
ECMO: may be useful in refractory ARDS, but no good trial data (NEJM
2 011;365:1905)
Esoph manome try: adjust PEEP according to esop h p ressure ( p leural p ressure)
to maintain p ositive transp ulm p ressure → ↑ Pa O 2 /Fi O 2 , ↑ comp liance and
p ossible outcome benefit (NEJM 2 008 ;359:2 095); help ful in obese Pts or w/ ↑
abdominal p ressure
Prognosis
• Mortality ~40% overall in clinical trials; 9–15% resp . causes, 8 5–91% extrap ulm
(MODS)
• ↑ BNP & trop onin a/w ↑ mortality (Che st 2 007;131:964; PLoS One 2 012 ;7:e40515)
• Survivors: PFTs ~normal, ↓ DLCO, muscle wasting, weakness p ersists (NEJM
2 003;348 :68 3), ↓ exercise tolerance, ↓ QoL, ↑ p sych morbidity (NEJM
2 011;364:12 93)
SEPSIS
Fluids & vasoactive drugs

• Early goal-directed therapy (“Rivers Protocol,” NEJM 2 001;345:1368 ), confirm.
trials p ending
Insert arterial & central venous lines (NEJM 2 007;356:e2 1; PAC not needed) and ✓
MAP, CVP & S cvO 2 (central venous O 2 sat, nl 60–8 0% ) which measures O 2
consump tion vs. delivery (less invasive than mixed venous) w/ low S CVO 2 → ↓
O 2 delivery (↓ S a O 2 , nl S a O 2 but ↓ CO or anemia) or excessive O 2
consump tion
Target MAP ≥65 mmHg, CVP 8 –12 mmHg, & UOP ≥0.5 mL/kg/h using fluid (eg,
500 mL NS q30min) and vasop ressors as needed
Target S cvO 2 ≥70% using PRBCs & inotrop es (dobutamine, ↑ dose as needed
q15min)
When done w/in first 6 h for severe sep sis & sep tic shock, 42 % ↓ mortality
• Lactate clearance (≥2 0% / 2 h) as effective as S cvO 2 to guide resuscitation ( JAMA

2 010;303:739)
• Crystalloid better than colloid for resuscitation (NEJM 2 004;350:2 2 47 &
2 012 ;367:12 4 & 1901)
• Norep i ↓ arrhyth. & mort. c/w dop amine (NEJM 2 010;362 :779; Crit Care Me d
2 012 ;40:72 5)
• Vasop ressin added to low-dose norep inep hrine not sup erior to high-dose
norep inep hrine (NEJM 2 008 ;358 :8 77); consider if HoTN refractory to
catecholamine vasop ressors
• Use PRBC w/ caution, may ↑ mortality/morbidity, ↑ risk of ARDS (Crit Care Me d
2 005;33:1191); ∴ goal Hb 7 unless active cardiac ischemia (NEJM 1999;340:409)
• After early resuscitation, if ALI/ARDS, target CVP 4–6 mmHg as additional fluids
may be harmful → ↑ ventilator/ICU days (NEJM 2 006;354:2 564; Che st
2 008 ;133:2 52 )
• Pulse p ressure variation >13% with resp iration → likely volume-resp onsive (Che st
2 008 ;133:2 52 ); only validated in p assive, intubated Pts and studied in higher tidal
volumes
Antibiotics
• Start emp iric IV abx w/in 1 h of recognition of severe sep sis or sep tic shock; every
hour delay in abx admin a/w 8 % ↑ in mortality (Crit Care Me d 2 006;34:158 9)
• If p ossible, obtain 2 sets of BCx before urgently starting abx (but do not delay abx)
• Typ ically want broad gram-p ositive and gram-negative coverage, including MRSA
and highly resistant gram-negative bacilli ± anaerobes
Steroids (NEJM 2003; 348:727; JAMA 2009; 301:2362)
• Cortisol secretion help s p redict mortality, but treatment of adrenal insufficiency is

unp roven ( JAMA 2 000;2 8 3:1038 ; NEJM 2 008 ;358 :111)
• Earlier study showed possible mortality benefit w/in 8 h of severe sep tic shock (SBP
<90 for >1 h desp ite fluids & p ressors) if p ost ACTH stim cortisol Δ ≤ 9 µg/dL
( JAMA 2 002 ;2 8 8 :8 62 )
• No mortality benefit to early (<72 h) emp iric corticosteroids in all Pts w/ sep tic
shock, regardless of ACTH stim; faster resolution of shock, more sup erinfection
(NEJM 2 008 ;358 :111)
• ? hydrocortisone 50–100 q6–8 h ± fludrocortisone 50 µg daily in sep tic shock
refractory to fluids & p ressors, regardless of ACTH stim (Crit Care Me d
2 008 ;36:2 96)
Activated protein C
• No longer FDA ap p roved, no imp rovement in mortality (NEJM 2 012 ;366:2 055)
Intensive glycemic control (NEJM 2010; 363:2540)

• No evidence of imp roved outcomes in MICU p op ulation w/ intensive glycemic
control
• Intensive glycemic control to goal 8 0–110 mg/dL in surg ical ICU p op ulation →
mortality benefit, greatest if >3-d ICU stay (NEJM 2 001;345:1359)
• Rep eat studies suggest intensive glycemic control → either no Δ or ↑ increased

mortality, and definite ↑ hyp oglyc. ( JAMA 2 008 ;300:933; NEJM 2 006;354:449;
2 008 ;358 :12 5; 2 009;360:12 8 3)
• Hyp oglycemia associated with mortality (NEJM 2 012 ;367:1108 )
• Reasonable to keep glc <150 mg/dL in severe sep sis, using validated p rotocol (Crit
Care Me d 2 008 ;36:2 96)
NOTES
ESOPHAGEAL AND GASTRIC DISORDERS
DYSPHAGIA
Definitions
• Orop haryngeal: inability to p rop el food from mouth through UES into esop hagus
• Esop hageal: difficulty swallowing & p assing food from esop hagus into stomach
Figure 3-1 Etiologies of and ap p roach to dysp hagia (NCP Gastrohe p 2 008 ;5:393;
Ne urog astro 2 012 ;2 4:57)
Achalasia
• Etiologies: idiop athic (most common), p seudoachalasia (due to GE jxn tumor),

Chagas
• Sx: dysp hagia (solid & liquid), chest p ain (1/3 of Pts), regurgitation
• Dx: barium swallow → dilated esop hagus w/ distal “bird’s beak” narrowing;
manometry → simultaneous, low amp litude contractions of esop hageal body,
incomp lete relaxation of lower esop hageal sp hincter (± LES hyp ertension); EGD →
r/o p seudoachalasia (retroflex)
• Rx: exp ert p neumatic dilation (≤4% eso p erf) lap Heller myotomy (NEJM
2 011;364:18 68 )
Other esophageal disorders

• Webs (up p er/mid esop h; congenital, GVHD, Fe-defic anemia); Rings (lower; ? due to
GERD); Zenker’s diverticulum (p haryngoesop h jxn); dx w/ barium swallow; Rx:
endo/surg
• Infxn esop hagitis: odynop hagia > dysp hagia; often immunosup p w/ Candida, HSV,
CMV
• Pill esop hagitis: odynop hagia > dysp hagia; NSAID, KCl, bisp hosp ., doxy &
tetracycline
• Eosinop hilic esop hagitis (Clin Gastro & He p 2 012 ;10:1066): seen in young or middle-
aged, p redom . Dx req >15 eos/hp f on bx & exclude GERD (eg, emp iric PPI
trial). Rx: 3Ds: Diet (elim milk, soy, eggs, wheat, nuts, fish); Drugs (swallow inh
steroids), Dilation
GASTROESOPHAGEAL REFLUX DISEASE (GERD)
Pathophysiology
• Excessive transient relaxations of lower esop hageal sp hincter (LES) or incomp etent
LES
• Mucosal damage (esop hagitis) due to p rolonged contact w/ acid can evolve to
stricture
• Risk factors: hiatal hernia, obesity, gastric hyp ersecretory states, delayed emp tying
• Precip itants: sup ine p osition, fatty foods, caffeine, alcohol, cigarettes, CCB,
p regnancy
• Esop hageal: heartburn, atyp ical chest p ain, regurgitation, water brash, dysp hagia
• Extraesop hageal: cough, asthma (often p oorly controlled), laryngitis, dental
erosions
Diagnosis (Gastro 2 008 ;135:138 3; Am J Gastro 2 010;105:747; Annals 2 012 ;157:8 08 )
• Based on hx & emp iric trial of PPI (Se & Sp : 78 % & 54% ) (Annals 2 004;140:518 )
• EGD if: (1) failure to resp ond to bid PPI; (2 ) alarm features: dysp hagia, vomiting,
wt loss, evid of blood loss; or ? (3) >50 y w/ sx ≥5 y + nocturnal sx, hiatal
hernia, obesity, cigs
• If dx uncertain & EGD nl → high res manometry w/ 2 4-h esop h p H monitoring ±

imp edance
Treatment (NEJM 2 008 ;359:1700)

• Lifestyle: avoid p recip itants, lose weight, avoid large & late meals, elevate head of
bed
• Medical: PPI achieve relief in 8 0–90% (titrate to lowest dose that achieves sx control)
surgery among Pts who initially resp ond to acid sup p ression (JAMA
2 011;305:1969)
• Refractory: confirm w/ p H testing: if acidic or sx correlate w/ reflux ep isodes →
surgical fundop lication (imp lantation of magnetic esop hageal sp hincter device
being studied; NEJM 2 013;368 :719); if nl p H or no sx correlation → TCA, SSRI or
baclofen (Gastro 2 010;139:7.e3)
Complications (NEJM 2 009;361:2 548 ; Gastro 2 011;140:108 4 & e18 )
• Barrett’s esop hagus: dx by bx of intestinal metap lasia above GE jxn. Screen for BE if
≥2 of the following risk factors: >50 y, male, white, chronic GERD, hiatal hernia,
high BMI.
• Esop hageal adenocarcinoma: risk ~0.12 % /y if Barrett’s, ~2 .3% /y if low-grade

dysp lasia, ~6% /y if high-grade dysp lasia; ~40% of Pts w/ esop h adenoca rep ort
no hx of GERD sx
• Management: Barrett’s w/o dysp lasia: surveillance EGD q3–5 y; low-grade

dysp lasia: q 6– 12 mo. 4 quadrant bx q 2 cm. Chemop reventive benefit of ASA
under study.
High-grade dysp lasia: U/S to r/o invasive cancer; endoscop ic mucosal resection of
any visible mucosal irregularity + ablation of dysp lasia (radiofrequency or
p hotodynamic).
DYSPEPSIA (“INDIGESTION”)
Definition
• Up p er abdominal sx: discomfort, p ain, fullness, early satiety, bloating, burning
Etiologies
• Functional (“nonulcer dysp ep sia” or NUD ~60% ): some combination of visceral
afferent hyp ersensitivity & abnormal gastric motility (Rome III criteria in Gastro
2 006;130:1377)
• Organic (~40% ): GERD, PUD, rarely gastric cancer, other (meds, diabetic gastro-
p aresis, lactose intolerance, biliary p ain, chronic p ancreatitis, mesenteric
ischemia)
• Alarm fe ature s that suggest organic cause & warrant EGD: see list above under GERD
Treatment of functional dyspepsia (Gastro 2 005;12 9:1756; Alim Pharm The r

2 012 ;36:3)
• H. pylori eradication → emp iric Rx if serology, NNT = 14 (Cochrane 2 006(2 )

CD002 096)
• PPI effective in some (? misdx GERD), others: TCA, p rokinetics, busp irone
PEPTIC ULCER DISEASE (PUD)
Epidemiology & etiologies (Lance t 2 009;374:1449)

• Lifetime p revalence ~10% , but incidence ↓ (H. pylori and p otent acid sup p ression
Rx). However, hosp for comp lic unD’d in general and ↑ in elderly, likely 2 ° to ↑
NSAID use.
• H. pylori infection: 8 0% of duodenal ulcers (DU) and 60% of gastric ulcers (GU)
~50% of p op ulation colonized w/ H. pylori, but only 5–10% will develop PUD
• ASA & NSAIDs: 45% erosions, 15–30% GU, 0.1–4% UGIB
• Hyp ersecretory states (often mult. recurrent ulcers): gastrinoma (Zollinger-Ellison
syndrome, also p /w diarrhea, <1% of PUD), carcinoid, mastocytosis
• Malignancy: 5–10% of GU
• Other: smoking, stress ulcers, XRT, chemo, CMV/HSV (immunosup p ),
bisp hosp honates; steroids alone generally not a risk factor, but may exacerbate
NSAID-induced ulceration
• Epigastric abdominal pain: relieved with food (DU) or worsened by food (GU)
• Comp lications: UGIB, p erforation & p enetration, gastric outlet obstruction

Diagnostic studies
• Test for H. pylori

Stool antigen or EGD + rap id urease test now dx tests of choice & to confirm erad
(4–6 wk p ost txment); false if on abx, bismuth, PPI, so stop p rior to testing
if p ossible
Serology: ↓ utility, useful only to exclude infection in low p revalence areas (most
of U.S.)
• EGD req to def make dx; consider if fail emp iric Rx or alarm features; bx GU to r/o
malig; relook in 6–12 wk if ap p arently benign ulcer >2 .5 cm, comp licated or sx
p ersist
Treatment (NEJM 2 010;362 :1597, Gut 2 012 ;61:646)

• If H. pylori , eradicate:
Trip le Rx: clarith+[amox, MNZ or levoflox]+PPI bid × 10–14 d (if clarith resist
rate <2 0% )
Quadrup le Rx: MNZ + TCN + bismuth + PPI (if clarith resist rate >15% or
amox allergy) erad vs. trip le 93 vs. 70% , clarith sens 95 vs. 8 5% , resist 91 vs.
8 % (Lance t 2 011;377:905)
Sequential Rx: PPI + amox × 7 d → PPI + clarith + MNZ × 7 d (Lance t

2 013;38 1:2 05)
Besides PUD, test & Rx if: gastric MALT lymp homa, atrop hic gastritis, FHx
gastric ca
• If H. pylori : gastric acid sup p ression w/ PPI
• Discontinue ASA and NSAIDs; add PPI

• Lifestyle changes: d/c smoking and p robably EtOH; diet does not seem to p lay a role
• Surgery: if refractory to med Rx (1st r/o NSAID use) or for comp lications (see above)
Prophylaxis if ASA/NSAID required (JACC 2 008 ;52 :1502 )
• PPI if (a) h/o PUD/UGIB; (b) also on clop idogrel (although ? ↓ antip lt effect); (c) ≥2
of the following: age >60, steroids or dysp ep sia; p rior to start test & Rx H. pylori
• Consider misop rostol; consider H2 RA if ASA monotherap y (Lance t 2 009;374:119)
• Consider Δ to COX-2 inhibit (↓ PUD & UGIB but ↑ CV events) if low CV risk & not on
ASA
• Stress ulcer: risk factors = ICU & coagulop athic, mech vent, h/o GIB, steroid use;
Rx w/ PPI
GASTROINTESTINAL BLEEDING
Definition
• Intraluminal blood loss anywhere from the orop harynx to the anus
• Classification: upper = above the ligament of Treitz; lower = below the ligament of
Treitz
• Signs: hematemesis = blood in vomitus (UGIB); hematochezia = bloody stools

(LGIB or rap id UGIB); melena = black, tarry stools from digested blood (usually
UGIB, but can be anywhere above and including the right colon)
Etiologies of upper GI bleed (UGIB)
• Peptic ulcer disease (50% ): H. pylori, NSAIDs, gastric hyp ersecretory states
• Varices (10–30% ): esop hageal ± gastric, 2 ° to p ortal HTN. If isolated gastric → r/o
sp lenic vein thrombosis.
• Gastropathy/gastritis/duodenitis (15% ): NSAIDs, ASA, alcohol, stress, p ortal

hyp ertensive
• Erosive esophagitis/ulcer (10% ): GERD, XRT, infectious (CMV, HSV or Candida if
immunosup p ressed), p ill esop hagitis (bisp hosp honate, NSAIDs; ± odynop hagia)
• Mallory-Weiss tear (10% ): GE junction tear due to retching against closed glottis
• Vascular lesions (5% )
Dieulafoy’s lesion: sup erficial ectatic artery usually in cardia → sudden, massive
UGIB
AVMs, angioectasias, hered. hemor. telangiectasia: submucosal, anywhere in GI
tract
Gastric antral vascular ectasia (GAVE): “watermelon stomach,” tortuous, dilated

vessels; a/w cirrhosis, atrop hic gastritis, CREST syndrome
Aortoenteric fistula: AAA or aortic graft erodes into 3rd p ortion of duodenum; p /w
“herald bleed” ; if susp ected, diagnose by endoscop y or CT
• Neop lastic disease: esop hageal or gastric carcinoma, GIST
• Orop haryngeal bleeding and ep istaxis → swallowed blood

Etiologies of lower GI bleed (LGIB)
• Diverticular hemorrhage (33% ): 60% of diverticular bleeding localized to right colon
• Neop lastic disease (19% ): usually occult bleeding, rarely severe
• Colitis (18 % ): infectious, ischemic, radiation, inflammatory bowel disease (UC >>
CD)
• Angiodysp lasia (8 % ): most commonly located in ascending colon and cecum
• Anorectal (4% ): hemorrhoids, anal fissure, rectal ulcer
• Other: p ostp olyp ectomy, vasculitis

• UGIB > LGIB: N/V, hematemesis, coffee-ground emesis, ep igastric p ain, vasovagal,
melena
• LGIB > UGIB: diarrhea, tenesmus, BRBPR, hematochezia (11% UGIB; Gastro
198 8 ;95:1569)
Initial management
• Assess severity: tachycardia (can be masked by bB use) suggests 10% volume loss,
orthostatic hyp otension 2 0% loss, shock >30% loss
• Resuscitation: p lacement of 2 large-bore (18 -gauge or larger) intravenous lines

Volume rep lacement: NS or LR to achieve normal VS, UOP, & mental status
• Transfuse: blood bank samp le for typ e & cross; use O-neg if emerg; transfuse as
needed; for UGIB (esp . w/ p ortal HTN) use more restrictive Hb goal (eg, 7 g/dL)
(NEJM 2 013;368 :11)
• Reverse coagulopathy: FFP & vit K to normalize PT; p lts to keep count >50,000
• Triage: consider ICU if unstable VS or p oor end organ p erfusion
Intubation for emergent EGD, if ongoing hematemesis, shock, p oor resp status, Δ
MS
? OutPt management if SBP ≥110, HR <100, Hb ≥13 ( ) or ≥12 ( ), BUN

<18 , melena, syncop e, heart failure, liver disease (Lance t 2 009;373;42 )
Workup
• History: whe re (anatomic location) & why (etiology)
acute or chronic, p rior GIB, # of ep isodes, other GI dx
hematemesis, vomiting prior to hematemesis (Mallory-Weiss), melena,

hematochezia
abdominal p ain, wt loss, anorexia, Δ in stool caliber
gastric irritants (ASA/NSAIDs), antip latelet drugs, anticoagulants, known

coagulop athy
alcohol (gastrop athy, varices), cirrhosis, known liver disease, risk factors for liver
disease
abdominal/rectal radiation, history of cancer, p rior GI or aortic surgery
• Physical exam: VS most important, orthostatic Ds, JVP
localizable abd tenderness, p eritoneal signs, masses, LAN, signs of p rior surgery
signs of liver disease (hep atosp lenomegaly, ascites, etc.)

rectal exam: masses, hemorrhoids, anal fissures, stool ap p earance, color, occult
blood
p allor, jaundice, telangiectasias (alcoholic liver disease or hered. hemor.

telangiectasia)
• Lab studies: Hct (may be normal in first 2 4 h of acute GIB before equilibration)
↓ 2 –3% → 500 mL blood loss; low MCV → Fe deficient and chronic blood loss;
p lt, PT,
PTT; BUN/Cr (ratio >36 in UGIB b/c GI resorp tion of blood ± p rerenal
azotemia); LFTs
Diagnostic studies
• Nasogastric tube can aid localization: fre sh blood → active UGIB; coffe e g rounds →
recent UGIB; nonbloody bile → ? lower source, but does not exclude active UGIB
(~15% missed); occult blood testing of no value
• UGIB: EGD w/in 2 4 h for dx and p oss Rx; ↓ LOS & need for surgery, consider
erythro 2 50 mg IV 30 min p rior → emp ty stomach of blood → ↑ Dx/Rx yield (Am
J Gastro 2 006;101:12 11)
• LGIB: first r/o UGIB before attemp ting to localize p resumed LGIB (10–15% actually
UGIB, 3–5% small bowel), the n colonoscop y (identifies cause in >70% ); consider
rap id p urge w/ PEG solution 4 L over 2 h; no clear benefit of colonoscop y w/in 12
vs. 36–60 h (AJG 2 010;105;2 636); CT angio p romising (Radiolog y 2 010;2 62 :109)
• Unstable or recurrent UGIB & LGIB:
tagged RBC scan: can localize bleeding rates ≥0.1 mL/min for surg but unreliable
arteriography: can localize if bleeding rates ≥0.5 mL/min and can Rx (coil, vaso,
glue) emergent exp loratory lap arotomy (last resort)
Obscure GIB (Gastro 2 007;133:1694; GIE 2 010;72 :471)
• Definition: continued bleeding (melena, hematochezia) desp ite EGD & colo; 5%
of GIB
• Etiologies: Dieulafoy’s lesion, small bowel angiodysp lasia, ulcer or cancer, Crohn’s
disease, aortoenteric fistula, Meckel’s diverticulum (2 % of p op ., remnant of
vitelline duct w/ ectop ic gastric mucosa), hemobilia
• Diagnosis: rep eat EGD w/ p ush enteroscop y/colonoscop y when bleeding is active
If , video cap sule to evaluate small intestine (Gastro 2 009;137:1197)
If still , consider 99m Tc-p ertechnetate scan (“Meckel’s scan” ), enteroscop y
(single-balloon, double-balloon or sp iral), tagged RBC scan and arteriograp hy
DIARRHEA, CONSTIPATION AND ILEUS
ACUTE DIARRHEA (<4 wk)

Evaluation (NEJM 2 009;361:1560; Gastro 2 009;136:18 74)
• Hx: stool freq, bloody, abd p ain, duration of sxs [~1 wk for viral & bacterial
(excep t C. diff), >1 wk for p arasitic], travel, food, recent abx
• PEx: vol dep letion (VS, UOP, axillae, skin turgor, MS), fever, abd tenderness, ileus,
rash
• Furthe r e valuation if warning signs: fever, signific abd p ain, blood or p us in stools,
>6 stools/d, severe dehydration, immunosup p , elderly, duration >7 d, hosp -
acquired
• Etiology established in only ~3% of community-acquired diarrhea

• Laboratory: fecal WBC (high false & ; ✓ fecal calp rotectin or lactoferrin
Se/Sp >90% ), stool cx, BCx, lytes, C. diff (if recent hosp or abx), stool O&P (if
>10 d, travel to endemic area, exp osure to unp urified H 2 O, community outbreak,
daycare, HIV or MSM)
± stool ELISAs (viruses, Crypto, Giardia), serologies (E. histolytica), sp ecial stool cx
• Imaging/endoscopy: CT/KUB if ? toxic megacolon; sig/colo if immunosup p or cx
• Ddx: infxn vs. p reformed toxin vs. med-induced vs. initial p resentation of chronic
diarrhea
Treatment
• If none of the above warning signs and Pt able to take POs → sup p ortive Rx only:
oral hydration, lop eramide, bismuth subsalicylate (avoid anticholinergics)
• If moderate dehydration: 50–2 00 mL/kg/d of oral solution (1/2 tsp salt, 1 tsp
baking soda, 8 tsp sugar, & 8 oz OJ diluted to 1 L w/ H 2 O) or Gatorade, etc. If
severe, LR IV.
• For traveler’s diarrhea, bismuth or rifaximin useful for p rop hylaxis & emp iric Rx
• Empiric abx for non–hosp ital-acquired inflammatory diarrhea reasonable: FQ × 5–7 d
abx rec for Shig e lla, cholera, Giardia, amebiasis, Salmone lla if Pt >50 y or
immunosup p or hosp italized, ? Campylobacte r (if w/in 4 d of sx onset)
avoid abx if susp ect E. coli O157:H7 as may ↑ risk of HUS

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA (CDAD)
Pathogenesis
• Ingestion of C. difficile sp ores → colonization when colonic flora Dd by abx or chemo

→ release of toxin A/B → colonic mucosal necrosis & inflammation →
p seudomembranes
• ↑ toxigenic strain (NAP 1/02 7) ↑ mort. & length of hosp (esp . in elderly) (NEJM
2 008 ;359:1932 )
• Additional risk factors: elderly, nursing home residents, IBD, PPI (CID 2 011;53:1173)
Clinical manifestations (a sp ectrum of disease)

• Asx colonization: <3% healthy adults; ~2 0% in hosp italized p atients on antibiotics
• Acute watery diarrhea (occ bloody) ± mucus, often w/ lower abd p ain, fever, ↑↑↑
WBC
• Pseudomembranous colitis: above sx + p seudomembranes + bowel wall thickening

• Fulminant colitis (2 –3% ): toxic megacolon (colon dilatation ≥6 cm on KUB,
colonic
atony, systemic toxicity) and/or bowel p erforation

Diagnosis
• Only test if symptomatic; test liquid stool (unless concern for ileus)
• Stool EIA: detects toxin B and/or A (1–2 % strains make A); fast (2 –6 h); most often
used
• PCR: quick, becoming test of choice (Mayo 2 012 ;8 7:643)

• Alternative is 2 -step method: ✓ glutamate dehydrogenase (GDH) EIA (high Se,
even if no toxin p roduction), then if , ✓ cytotoxin assay or toxigenic cx
• Consider flex sig if dx uncertain and/or evidence of no imp rovement w/ standard Rx
Treatment (Infe ct Control Hosp Epide miol 2 010;31:431)
• Start contact p recautions; if p ossible d/c abx ASAP; stop antimotility agents
• Mild-Moderate (WBC <15k, Cr <1.5 × baseline, age <65 y and no p eritoneal sx):
MNZ 500 mg PO tid × 10–14 d
• Severe (WBC >15k or Cr >1.5× baseline or age ≥65 y): vanco 12 5 mg PO qid ×
10–14 d
• Complicated (ileus, malabsorp tion, shock, megacolon, p eritonitis): vanco 500 mg

PO q6h and MNZ 500 mg IV q8 h; PR vanco if ileus, but avoid if evidence of toxic
megacolon; abd CT & urgent surg consult re: colectomy; ? IVIG fidaxomicin 2 00
mg bid noninferior to vanco PO & ↓ rate of recurrence (NEJM 2 011;364:42 2 )
• If Pt needs to stay on original abx, continue C. diff. Rx for ≥7 d p ost-abx cessation
• Stool carriage may p ersist 3–6 wk p ostcessation of sx and should not trigger further
Rx
• Recurrent infection: 15–30% risk after d/c of abx, most w/in 2 wk of stop p ing
abx
1st relap se: if mild; rep eat 14-d course of MNZ or vanco
2 nd relap se: PO vanco tap er for 6 wk

>2 relap ses: vanco tap er & adjunctive Rx such as S. boulardii, p robiotics,
rifaximin, nitazoxanide, fidaxomicin or cholestyramine (binds vanco so cannot
take concurrently)
Fecal transp lant in refractory disease ap p ears safe and effective (Clin Gas He p
2 011;9:1044; NEJM 2 013;368 :407)
• Probiotics may p revent CDAD by 66% in non-immunosup p ressed Pts (Annals

2 012 ;157:8 78 )
CHRONIC DIARRHEA (>4 wk; Gastro 2004; 127:287)
Medications (cause ↑ secretion, ↑ motility, Δ flora, ↑ cell death or inflammation)

• PPI, colchicine, abx, H2 RA, SSRIs, ARBs, NSAIDs, chemo, caffeine
Osmotic (↓ diarrhea with fasting, fecal fat, ↑ osmotic gap )
• Lactose intolerance: seen in 75% nonwhites & in 2 5% whites; can be acquired after
gastroenteritis, med illness, GI surgery. Clinical: bloating, flatulence, discomfort,
diarrhea. Dx: hydrogen breath test or emp iric lactose-free diet. Rx: lactose- free
diet, use of lactose-free dairy p roducts and lactase enzyme tablets.
• Other: lactulose, laxatives, antacids, sorbitol, fructose
Malabsorption (↓ diarrhea with fasting, ↑ fecal fat, ↑ osmotic gap )

• Celiac disease (NEJM 2 012 ;367:2 419)
Immune rxn in genetically p redisp osed Pts (~1% p op ) to gliadin, a comp onent of
gluten (wheat p rotein) → small bowel inflammatory infiltrate → cryp t
hyp erp lasia, villus atrop hy → imp aired intestinal absorp tion
Other s/s: Fe/folate defic anemia; osteop orosis; dermatitis herp etiformis (p ruritic
p ap ulovesicular); ↑ AST/ALT
Dx: IgA tissue transglutaminase or endomysial Abs ~90% Se & >98 % Sp (JAMA
2 010;303:1738 ). Small bowel bx and clinical/serologic resp onse to gluten-free
diet definitive.
Rx: gluten-free diet; 7–30% do not resp ond to diet → ? wrong dx or noncomp liant
Comp lic: ~5% refractory (sx desp ite strict dietary adherence), risk of T-cell lym-
p homa and small bowel adenocarcinoma
• Whipple’s disease: infxn w/ T. whipple i (NEJM 2 007;365:55)

Other s/s: fever, LAN, edema, arthritis, CNS Ds, gray-brown skin p igmentation, AI
& MS, oculomasticatory myorhythmia (eye oscillations + mastication muscle
contract)
Rx: (PCN + strep tomycin) or 3rd-gen cep h × 10–14 d → Bactrim for ≥1 y
• Small Intestinal bacterial overgrowth (SIBO; Inf Dis Clin 2 010;2 4:943): ↑ SI
bacteria from incomp etent/absent ileocecal valve, s/p RYGB, scleroderma,
diabetes, s/p vagotomy → fat & CHO malabsorp tion. Dx: 14C-xylose & H +
breath tests; Rx: cycled abx (eg, MNZ, FQ, rifaximin)
• Pancreatic insufficiency: most commonly from chronic p ancreatitis or p ancreatic

cancer
• ↓ bile acids due to ↓ synthesis (cirrhosis) or cholestasis (PBC) → malabsorp tion
• Other: s/p short bowel resection (short bowel syndrome), Crohn’s disease, chronic
mesenteric ischemia, eosinop hilic gastroenteritis, intestinal lymp homa, trop ical
sp rue
Inflammatory ( FOB, fever, abd p ain, fecal WBC or lactoferrin or calp rotectin)
• Infections: p articularly p arasitic (incl above p athogens & Strong yloide s), CMV, TB
• Inflammatory bowel disease

• Radiation enteritis, ischemic colitis, neop lasia (colon cancer, lymp homa)
Secretory (nocturnal diarrhea freq described, no Δ diarrhea after NPO, normal osmotic
gap )
• Hormonal: VIP (VIPoma, Verner-Morrison), serotonin (carcinoid), thyroxine,
calcitonin (medullary cancer of the thyroid), gastrin (Zollinger-Ellison), glucagon,
substance P
• Laxative abuse
• Neop lasm: carcinoma, lymp homa, villous adenoma

• ↓ bile acids absorp tion (s/p ileal resection, Crohn’s) → colonic exp osure & ↑
secretion
• Lymp hocytic colitis, collagenous colitis (may be a/w meds, including NSAIDs)
Motility (normal osmotic gap )

• Irritable bowel syndrome (10–15% of adults; BMJ 2 012 ;345:e58 36; NEJM
2 012 ;367:162 6)
Due to altered intestinal motility/secretion in resp onse to luminal or
environmental stimuli w/ enhanced p ain p ercep tion and dysregulation of the
brain–gut axis
Rome III criteria: recurrent abd p ain ≥3 d/mo over last 3 mo plus ≥2 of
following: (i) imp rovement w/ defecation, (ii) onset w/ Δ freq of stool, (iii) onset
w/ Δ in form of stool
Rx sx-guided (AJG 2 009;104:51)

Pain: antisp asmodics, TCA, SSRI
Bloating : rifaximin (NEJM 2 011;364:2 2 ), p robiotics
Diarrhe a: lop eramide, alosetron (5-HT3 antagonist) for women (↑ risk of
ischemic colitis), rifaximin
Constipation: ↑ fiber 2 5 g/d, lubip rostone (Cl – channel activator)

• Scleroderma; diabetic autonomic neurop athy; hyp erthyroidism; amyloidosis; s/p
vagotomy
Figure 3-2 Workup of chronic diarrhea

CONSTIPATION & ADYNAMIC ILEUS
Constipation (Gastro 2 013;144:2 11 & 2 18 )

• Definition (Rome III): ≥2 of the following during last 3 mo at least 2 5% of time:
straining, lump y/hard stools, incomp lete evacuation, sensation of anorectal
obstruction, manual maneuvers to facilitate defecation, stool frequency <3 p er wk
• Etiology
Functional: normal transit, slow transit, p elvic floor dysfunction, constip ation-
p redom IBS
Meds: op ioids, anticholinergics (TCAs & antip sychotics), Fe, CCB, diuretics,
NSAIDs
Obstruction: cancer, stricture, rectocele, anal stenosis, extrinsic comp ression
Metabolic/endo: DM, hyp othyroid, uremia, p reg, p anhyp op it, p orp hyria, ↑ Ca, ↓
K, ↓ Mg
Neuro: Parkinson’s, Hirschsp rung’s, amyloid, MS, sp inal injury, autonomic

neurop athy
• Diagnosis: H&P w/ DRE. Labs: consider CBC, electrolytes w/ Ca, TSH
Colonoscop y if alarm sx: wt loss, FOBT, fever, FHx of IBD or colon cancer.
Sigmoidoscop y if no alarm sx & <50 y
For functional constip ation: Sitzmark study, anorectal manometry, defecograp hy

• Treatment: Bulk laxatives (fiber ~2 0 g/d) → osmotic laxative → stimulant laxative
Bulk laxatives (p syllium, methylcellulose, p olycarbop hil): ↑ colonic residue, ↑

p eristalsis
Osmotic laxatives (Mg, sodium p hosp hate [avoid if CKD], lactulose): ↑ water in
colon
Stimulant laxatives (senna, castor oil, bisacodyl, docusate sodium): ↑ motility &
secretion
Enema/sup p ository (p hosp hate, mineral oil, tap water, soap suds, bisacodyl)
Lubip rostone (see “IBS” ). Methylnaltrexone and alvimop an for op ioid-induced

(AJG 2 011;106:8 35)
Linaclotide ↑ stool freq, ↓ straining/bloating (NEJM 2 011;365;6:52 7)
Acute pseudo-obstruction (adynamic ileus)
• Definition: loss of intestinal p eristalsis in absence of mechanical obstruction

Ogilvie’s = acute colonic adynamic ileus in p resence of comp etent ileocecal valve
• Precip itants: intra-abd p rocess (surgery, p ancreatitis, p eritonitis); severe medical

illness
(eg, PNA, sep sis); intestinal ischemia; meds (op iates, anticholinergics); electrolyte
abnl
• Clinical manifestations: abd discomfort, N/V, hiccup s, abd distention, ↓ or absent

bowel
sounds, no p eritoneal signs (unless p erforation); cecum ≥10–12 cm → ↑ risk of

rup ture
• Dx: sup ine & up right KUB vs. CT→ gas-filled loop s of small & large intestine. Must
exclude mechanical obstruction (absence of gas in rectum).
• Treatment: NPO, mobilize (walk, roll), d/c Rxs that ↓ intestinal motility, enemas;
decomp ression (NGT, rectal tube, colonoscop e); neostigmine (for colonic),
methylnaltrexone (for small bowel, ? colonic)
NUTRITION IN HOSPITALIZED PATIENTS
Pathophysiology
• When acutely ill, catabolism > anabolism, carbohydrates p referred due to ↓ fat
metab
• When recovering, anabolism > catabolism, so body restores p rotein and muscle loss
Critical illness (see “Mech Ventilation” for recs in that setting) (JPEN 2 009;33:2 77)
• Goals not well validated but 18 –30 kcal/kg/d & 1.2 –1.5g/kg/d p rotein
• Enteral: start w/in 2 4–48 hrs of admission, trend toward ↓ infxns and mortality in
early (<48 h) feeding in critically ill Pts who are adequately nourished at
p resentation Contraindic: inadequate volume resusc, intestinal obstruction, major
GIB, severe vomiting, ischemic bowel
• Parenteral: start if unable to tolerate enteral w/in 7 d or evidence of p rotein/cal
malnutrition on admission; may be beneficial in those below calorie goal w/
enteral (Lance t 2 013;38 1:38 5) Contraindic: hyp erosmolality, severe electrolyte
disturbances, severe hyp erglycemia; sep sis is re lative contraindication
End-stage liver disease (Clin Gastro & He p 2 012 ;10:117)
• Nutrition status p redicts morbidity/mortality; malnutrition in 50–90% of cirrhotics
• Protein requirement hig he r than healthy adults (1–1.5 g/kg/d vs. 0.8 g/kg/d);
p rotein restrict only if acute hep atic encep halop athy Sup p lement vitamins ADEK,
zinc, selenium; do not carbohydrate restrict
Refeeding syndrome (BMJ 2 008 ;336;1495)

• Fluid/electrolyte shifts in malnourished Pts receiving artificial nutrition;
hyp op hosp hatemia is hallmark, but also ↓ K & Mg, hyp erglycemia, ↓ thiamine,
hyp ervolemia
• Prevention: (1) thiamine 300 mg PO qd, vit B comp lex tid, MVI; (2 ) start feeding at
~10 kcal/kg/d (or 2 5% of estim goal) & ↑ over 3–5 d; advance only when
electrolytes are w/in nl range; (3) follow electrolytes and volume status,
rehydrating and rep leting
DIVERTICULAR DISEASE
DIVERTICULOSIS
Definition & pathobiology (Lance t 2 004;363:631)
• Acquired herniations of colonic mucosa and submucosa through the colonic wall
• Existing dogma is low-fiber diet → ↑ stool transit time and ↓ stool volume → ↑
intraluminal p ressure → herniation where vasa recta p enetrate, but now ?’d
(Gastro 2 012 ;142 :2 66)
Epidemiology
• Prevalence higher w/ ↑ age (10% if <40 y; 50–66% if >8 0 y); “Westernized”
societies
• Left side (90% , mostly sigmoid) > right side of colon (excep t in Asia, where R > L)
• Usually asx, but 5–15% develop diverticular hemorrhage and <5% diverticulitis
• Nuts, etc. intake in asx diverticulosis does not ↑ risk of diverticulitis (JAMA
2 008 ;300:907)
DIVERTICULITIS
Pathophysiology (NEJM 2 007;357:2 057)

• Retention of undigested food and bacteria in diverticulum → fecalith formation →
obstruction → comp romise of diverticulum’s blood sup p ly, infection, p erforation
• Uncomplicated: microp erforation → localized infection
• Complicated (2 5% ): macrop erforation → abscess, p eritonitis, fistula (65% w/

bladder), obstruction, stricture
• LLQ abdominal pain, fever, nausea, vomiting, constip ation
• PEx ranges from LLQ tenderness ± p alp able mass to p eritoneal signs & sep tic shock
• Ddx includes IBD, infectious colitis, PID, tubal p regnancy, cystitis, colorectal cancer
Diagnostic studies
• Plain abdominal radiograp hs to r/o free air, ileus or obstruction
• Abdominal CT (I+O +): >95% Se & Sp ; assess comp licated disease (abscess,
fistula)
• Colonoscop y contraindicate d acutely ↑ risk of p erforation; do 6 wk after to r/o

neop lasm
Treatment (Am J Gastro 2 008 ;103:1550)

• Mild: outPt Rx indicated if Pt has few comorbidities and can tolerate POs
PO abx: (MNZ + FQ) or amox/clav for 7–10 d; liquid diet until clinical
imp rovement, though recent evidence suggest abx may be unnecessary (Br J Surg
2 012 ;99:532 )
• Severe: inPt Rx if cannot take POs, narcotics needed for p ain, or comp lications
NPO, IV fluids, NGT (if ileus)
IV abx (GNR & anaerobic coverage): amp /gent/MNZ or p ip eracillin-tazobactam
• Abscesses >4 cm should be drained p ercutaneously or surgically
• Surgery: if p rogression desp ite med Rx, undrainable abscess, free p erforation or
p ossibly recurrent disease (≥2 severe ep isodes)
• Colonic stricture: late comp lication of diverticulitis; Rx w/ endoscop ic dilation vs.

resection; colonoscop y after 6 wk to exclude neop lasm
Prevention
• Low-fibe r diet immediately after acute ep isode; hig h-fibe r diet when >6 wk w/o sx
• Consider mesalamine ± rifaximin if multip le ep isodes
• Risk of recurrence 10–30% w/in 10 y of 1st ep isode; more likely 2 nd ep isode

comp licated
DIVERTICULAR HEMORRHAGE (ALSO SEE “GASTROINTESTINAL BLEEDING”)
Pathophysiology
• Intimal thickening and medial thinning of vasa recta as they course over dome of
diverticulum → weakening of vascular wall → arterial rup ture
• Diverticula more common in left colon; but ble e ding dive rticula more ofte n in rig ht
colon
• Painless hematochezia/BRBPR; can have abdominal cramp ing
• Usually stop s sp ontaneously (~75% ) but resolution may occur over hrs–days;
~2 0% recur
Diagnostic studies
• Colonoscop y: rap id p rep w/ PEG-based solution via NGT (4–6 L over 2 –4 h)
• Arteriograp hy ± tagged RBC scan if severe bleeding

Treatment
• Colonoscop y: ep inep hrine injection ± electrocautery (NEJM 2 000;342 :78 ),

hemoclip , banding
• Arteriograp hy: intra-arterial vasop ressin infusion or embolization
• Surgery: if above modalities fail & bleeding is p ersistent & hemodynamically

significant
INFLAMMATORY BOWEL DISEASE
Definition
• Ulcerative colitis (UC): idiop athic inflammation of the colonic mucosa
• Crohn’s disease (CD): idiop athic transmural inflammation of the GI tract, skip are as
• Indeterminate colitis: in 5–10% of chronic colitis, cannot distinguish UC vs. CD even
w/ bx
Epidemiology & pathophysiology (NEJM 2 009;361:2 066; Gastro 2 011;140:178 5)

• 1.4 million p eop le in U.S.; p rev 1:1000 UC & 1:3000 CD; ↑ incidence in Caucasians,
Jews
• Age of onset 15–30 y in UC and CD; CD is bimodal and has second p eak at 50–70 y
• Smokers at ↑ risk for CD, whereas nonsmokers & former smokers at ↑ risk for UC
• Genetic p redisp osition + disrup tion of intestinal barrier (ep ithelial or ↓ defenses) ±
Δ in gut microbiota → acute inflam w/o immune downregulation or tolerance →
chronic inflam
ULCERATIVE COLITIS (NEJM 2011; 365:1713; Lancet 2012; 380:1606)
• Grossly bloody diarrhea, lower abdominal cramp s, urgency, tenesmus
• Severe colitis (15% ): p rogresses rap idly over 1–2 wk with ↓ Hct, ↑ ESR, fever,
hyp otension, >6 bloody BMs p er day, distended abdomen with absent bowel
sounds
• Extracolonic (>2 5% ): erythema nodosum, p yoderma gangrenosum, ap hthous
ulcers, uveitis, ep iscleritis, thromboembolic events (esp . during a flare; Lance t
2 010;375:657), AIHA, seroneg arthritis, chronic hep atitis, cirrhosis, PSC (↑ risk
cholangio CA, CRC)
Diagnosis
• Colonoscopy: involves rectum (95% ) & extends p roximally and contig uously within
colon
• Classify by location: p roctitis (2 5–55% ), left-sided colitis (50–70% ) and p ancolitis

(2 0% )
• Ap p earance: granular, friable mucosa with diffuse ulceration; pse udopolyps
• Microscop y: sup erficial chronic inflammation; cryp t abscesses & architectural

distortion
Complications
• Toxic megacolon (5% ): colon dilatation (≥6 cm on KUB), colonic atony, systemic
toxicity, & ↑ risk of p erf. Rx w/ IV steroids & broad-sp ectrum abx; surgery if fail
to imp rove w/in 48 –72 h
• Stricture (5% ): occurs in rectosigmoid after rep eated ep isodes of inflammation
Prognosis
• 50% of Pts in remission at any given time; intermittent exacerbations in 90% ;
continual active disease in ~18 % . Rate of colectomy at 10 y is 2 4% .
• Mortality rate of severe UC flare is <2 % , & overall life exp ectancy in UC = non-
UC Pts
CROHN’S DISEASE (Lancet 2012; 380:1590)
• Abdominal pain, fever, malaise, wt loss
• Mucus-containing, nongrossly bloody diarrhea; N/V, bloating, obstip ation

• ↓ albumin, ↑ ESR/CRP, ↓ Hct (due to Fe, B 12 , folate deficiency; chronic
inflammation)
• Extracolonic as in UC
Diagnosis
• EGD/colonoscopy + small bowel imaging (eg, video cap sule endoscop y [if no
stricture] or CT/MR-enterograp hy); CD can affect any p ortion of GI tract with skip
le sions
• Classify by location: small bowel (47% ), ileocolonic (2 1% ), colonic (2 8 % ); up p er

tract rare
• Appearance: nonfriable mucosa, cobblestoning, aphthous ulcers, deep & long

fissures
• Microscopy: transmural inflammation with mononuclear cell infiltrate,
noncaseating granulomas (seen in <2 5% of mucosal biop sies), fibrosis, ulcers,
fissures
Complications
• Perianal disease: fissures, fistulas, p erirectal abscesses (up to 30% of Pts)
• Stricture: small bowel, p ostp randial abd p ain; can lead to comp lete SBO
• Fistulas: p erianal, enteroenteric, rectovaginal, enterovesicular, enterocutaneous
• Abscess: fever, tender abd mass, ↑ WBC; ste roids mask sx, ∴ need high-level
susp icion
• Malabsorption: ileal disease/resection: ↓ bile acids abs → gallstones; ↓ fatty acid

abs → Ca oxalate kidney stones; ↓ fat soluble vitamin abs → vit Δ deficiency →
osteop enia
Prognosis
• Variable at 1 y: ~50% in remission, ~2 0% flared, ~2 0% low activity, ~10%

chronic active
• At 2 0 y, majority will have required some surgery; overall life exp ectancy is slightly
↓
MANAGEMENT (Gastro 2011; 140:1827)
Initial evaluation
• H&P (✓ for intestinal & extraintestinal manifestations) and endoscop y as above
• Laboratory: ESR, CRP, CBC, LFTs, Fe, B 12 , folate, vit D. Fecal calp rotectin ap p ears
useful for Ddx IBD vs. IBS & may p redict IBD flare (Infl Bowe l Dis 2 012 ;18 :2 2 18 ).
• Exclude other etiologies: infectious/ischemic colitis, med adverse effect, intestinal
lymp homa/carcinoma, colon cancer, IBS, vasculitis, Behçet’s, celiac disease, SIBO
• Rule out infection before treating with immunosup p ressants and biologics
Goals of treatment
• Avoid NSAIDs (both UC and CD)
• Induce remission of acute flare → maintain remission; mucosal healing 1° goal

• Convention has been step up Rx (least → most toxic). Recent shift to early and/or
combined immunomodulation to imp rove disease outcome (Lance t 2 008 ;371:660;
NEJM 2 010;362 :138 3).
Complications of therapy (Clin Gastro He p 2 009;7:8 74)
• Anti-TNFα: reactivation TB; must doc PPD p rior to Rx. Exclude viral hep atitis.
Small ↑’d risk of NHL. Other: infusion rxn; lup us-like rxn, p soriasis, MS, CHF.
• 6MP/AZA: BM sup p ression, lymp homa, p ancreatitis, hep atitis; ✓ TPMT genotyp e
p rior to dosing to ↓ risk of generation of toxic metabolites
• 5-ASA: diarrhea, abd p ain, p ancreatitis. If sx, consider 3-d holiday.
Cancer screening (Gastro 2 010;138 :738 )
• Colon cancer: risk in UC ~2 % at 10 y, ~8 % at 2 0 y, ~18 % at 30 y. Similar for

colonic CD, p lus risk of small bowel cancer as well. Dysp lasia best marker for
risk. Other risk factors include: PSC, FHx, greater extent of disease, stricture,
& p seudop olyp s.
• Surveillance: colonoscopy w/ random bx 8 y after dx to eval for dysp lasia, q1–3y
thereafter based on risk factors. If high-grade dysp lasia or dysp lasia assoc.
lesion/mass → colectomy. Chemop rop hylaxis: 5-ASA & ursodeoxycholic acid (if
PSC) ? beneficial (AJG 2 011;106:731; Alime nt Pharmacol The r 2 012 ;35:451).
INTESTINAL ISCHEMIA
ACUTE MESENTERIC ISCHEMIA (25% )

Etiologies
• SMA embolism (50% ): from LA (AF), LV (↓ EF) or valves; SMA most p rone to
embolism
• Nonocclusive mesenteric ischemia (2 5% ): transient intestinal hyp op erfusion due

to ↓ CO, atherosclerosis, sep sis, drugs that ↓ gut p erfusion (p ressors, cocaine, dig,
diuretics)
• SMA thrombosis (10% ): usually at site of atherosclerosis, often at origin of artery
• Venous thrombosis (10% ): hyp ercoagulable states, p ortal hyp ertension, IBD,
malignancy, inflammation (p ancreatitis, p eritonitis), p regnancy, trauma, surgery
• Focal segmental ischemia of the small bowel (<5% ): vascular occlusion to small
segments of the small bowel (vasculitis, atheromatous emboli, strangulated
hernias, XRT)
• Occlusive: sudden abd pain out of proportion to abdominal tenderness on exam

at leastinitially (2 –4 h) until severe ischemia → frank infarction w/ p eritoneal signs
• Nonocclusive: abd distention & p ain, though up to 2 5% may be p ain-free, N/V;
often in setting of CHF ± h/o chronic mesenteric ischemia sx
• Hematochezia due to mucosal sloughing (right colon sup p lied by SMA)
• “Intestinal angina” : p ostp randial abd p ain, early satiety, & ↓ wt from gastric
vascular “steal” ; may occur wks to mos before onset of acute p ain in Pts w/
chronic mesenteric ischemia
Physical exam
• May be unremarkable, or may only show abdominal distention; FOBT ~75% of
Pts
• Bowel infarction suggested by p eritoneal signs (diffuse tenderness, rebound,

guarding)
Diagnostic studies
• Dx relies on high level of susp icion; rap id dx essential to avoid infarction (occurs
w/in h)
• Laboratory: often nl; ~75% ↑ WBC; ↑ amylase, LDH, p hosp hate, D-dimer; ~50%
acidosis w/ ↑ lactate (late)
• KUB: nl early before infarct; “thumbp rinting,” ileus, p neumatosis in later stages
• CT angiography (arterial p hase imaging): noninvasive test of choice; can detect

thrombi in mesenteric vessels, colonic dilatation, bowel wall thickening,
p neumatosis/ p ortal venous gas; ve nous p hase imaging for dx of mesenteric vein
thrombosis
• Angiography: gold standard; p otentially therap eutic; indicated if vasc occlusion

susp ected
Treatment
• Fluid resuscitation, optimize hemodynamics (minimize p ressors); broad-sp ectrum

abx
• Emergent surgery for p romp t resection of necrotic bowel if evidence of p eritonitis
• Anticoagulation for arterial & venous thrombosis and embolic disease
• Papaverine (vasodilator) catheter-directed infusion into SMA, typ ically in nonocclu-

sive ischemia when sp asm is considered the p rimary cause of the ischemia
• SMA embolism: consider fibrinolytic; if no quick imp rovement → surgical
embolectomy if p ossible, o/w aortomesenteric byp ass
• SMA thrombosis: p ercutaneous or surgical revascularization (J Vasc Surg
2 009;50:341)
• Nonocclusive: correct underlying cause (esp . cardiac)
• Consider angiop lasty/stent vs. surg revasc in cases of chronic mesenteric ischemia if:
≥2 vessels or occl SMA, sup p ortive clinical hx, & other etiologies for abd p ain
excluded
Prognosis
• Mortality 2 0 to >70% if bowel infarcted; dx p rior to infarction strongest p redictor
of survival
ISCHEMIC COLITIS (75% )
Definition & pathophysiology
• Nonocclusive disease 2 ° to Ds in systemic circulation or anatomic/fxnal Ds in local

mesenteric vasculature; often underlying etiology unknown, frequently seen in
elderly
• “Watershed” areas (sp lenic flexure & rectosigmoid) most suscep tible, 2 5% involve
R side
Clinical manifestations, diagnosis, & treatment
• Disease sp ectrum: reversible colop athy (35% ), transient colitis (15% ), chronic
ulcerating colitis (2 0% ), resulting stricture (10% ), gangrene (15% ), fulminant
colitis (<5% )
• Usually p /w cramping LLQ pain w/ overtly bloody stool; fever and p eritoneal
signs should raise clinical susp icion for infarction
• Dx: r/o infectious colitis; consider flex sig/colonoscopy if sx p ersist and no

alternative etiology identified (only if p eritonitis not p resent, o/w avoid
overdistention of colon)
• Treatment: bowel rest, IV fluids, broad-spectrum abx, serial abd exams; surgery
for infarction, fulminant colitis, hemorrhage, failure of med Rx, recurrent sep sis,
stricture
• Resolution w/in 48 h w/ conservative measures occurs in >50% of cases
PANCREATITIS
Pathogenesis
• Acinar injury via direct or indirect toxicity → release or imp aired secretion (ie, duct
obstruction) of enzymes → autodigestion → fat necrosis
• Profound acute inflammatory resp onse
Etiologies
• Gallstones (40% ): > , usually small stones (<5 mm) or microlithiasis
• Alcohol (30% ): > , usually chronic, w/ acute flares
• Drugs (via hyp ersens, toxic metab or direct toxicity): furosemide, thiazides, sulfa,
ddI, ? DPP- 4 inhib, asp araginase, estrogen, 6-MP/AZA, ACEI, dap sone, 5-ASA,
valp roic acid
• Obstructive: p anc/amp ullary tumors, mets (breast, lung), annular p ancreas,

divisum w/ concurrent minor p ap illa stenosis and ascaris
• Metabolic: hyp ertriglyceridemia (TG >1000 and usually ~4500; seen w/ typ es I, IV,
& V familial hyp erlip idemia), hyp ercalcemia
• Infections: coxsackie, mump s, EBV, CMV, HAV, HBV, mycop lasma, TB,
candida/toxo/cryp to
• Autoimmune: can p /w chronic disease or p anc mass; ↑ IgG4, ANA, duct abnl
• Ischemia: vasculitis, cholesterol emboli, hyp ovolemic shock, cardiop ulmonary

byp ass
• Post ERCP: ~5% w/ clinical, overt p ancreatitis; 35–70% with asx ↑ amylase;
p revent w/ indomethacin 100 mg PR immediately after ERCP (NEJM
2 012 ;366:1414)
• Post trauma: blunt abd trauma, p ancreatic/biliary surgery
• Familial: autosomal dominant w/ variable p enetrance (PRSS1, CFTR, SPINK1 genes)
• Scorp ion sting (in Trinidad): mechanism believed to be hyp erstimulation of p ancreas
• Epigastric abdominal pain, radiating to back, constant, some relief w/ leaning

forward
• Nausea and vomiting
• Ddx: acute cholecystitis, p erforated viscus such as DU, intestinal obstruction, mesen-
teric ischemia, IMI, AAA leak, distal aortic dissection, rup tured ectop ic p regnancy
Physical exam
• Abdominal tenderness and guarding, ↓ bowel sounds (adynamic ileus) ± p alp able
abdominal mass; ± jaundice if biliary obstruction
• Signs of retrop eritoneal hemorrhage (Cullen’s = p eriumbilical; Grey Turner’s =
flank) rare
• Fever, tachycardia, hyp otension ± shock
Diagnostic studies (Gastro 2 007;132 :2 02 2 )
• Laboratory
↑ amylase: levels >3× ULN suggestive of p ancreatitis; level ≠ severity
false : acute on chronic (eg, alcoholic); hyp ertriglyceridemia (↓ amylase

activity)
false : other abd or salivary gland p rocess, acidemia, renal failure,
macroamylasemia (amylase binds to other p roteins in serum, cannot be
filtered by kidneys)
↑ lipase: more sp ecific than amylase

false : renal failure, other abd p rocess, diabetic ketoacidosis, HIV,
macrolip asemia
ALT >3 × ULN suggests gallstone p ancreatitis (Am J Gastro 1994;8 9:18 63); AΦ ,
bili not help ful
Other labs (see “Prognosis” ): ↑ WBC, ↑ or ↓ Hct, ↑ BUN, ↓ Ca, ↑ glc, ↑ CRP
• Imaging studies
KUB/CXR: can see “sentinel loop ” air in small bowel in LUQ, atelectasis, effusion
Abd CT: not required for dx, but test of choice to make dx. Help s exclude other dx,
stage severity, & r/o comp lications. CT w/ IV contrast on day 3 of p resentation
in severe cases to evaluate for p ancreatic necrosis (avoid on p resentation b/c
theoretical concern of ↑ necrosis w/ IV contrast; defer if concomitant AKI).
Abd U/S: typ ically not useful to visualize p ancreas (obscured by bowel gas), but
help ful to investigate biliary etiology (ie, gallstones and BD dilatation); can see
p seudocyst
MRI/MRCP: can detect necrosis; also used to assess for stones & ductal disrup tion
Endoscop ic U/S (EUS): limited role acutely; useful for occult biliary disease
(microlithiasis)
Treatment (Lance t 2 008 ;371:143; AJG 2 012 ;107:1146)
• Sup p ortive therap y: in mild cases, bowel rest is usually sufficient
Fluid resuscitation LR may be sup erior to NS (↓ SIRS, CRP at 2 4 h;

contraindicated if ↑ Ca); at least 2 50 mL/h, may need up to 10 L/d if severe;
titrate to UOP ≥0.5 mL/kg/h
Nutrition: if mild, initiate oral nutrition when p ain, nausea allow.
If severe and NPO >7 d exp ected, early (w/in 48 h) enteral nutrition indicated and
p referred over TPN; ↓ infectious comp lications & disease severity, & trend
toward ↓ mortality (BMJ 2 004;32 8 :1407). Ideally NJ tube, but NG okay.
Analgesia: IV mep eridine, morp hine, hydromorp hone (theoretical risk of

sp hincter of Oddi sp asm by op iates, but has not been shown to adversely affect
outcome)
• Prop hylactic systemic abx (eg, imip enem) to ↓ mortality & p revent conversion of
sterile to infected necrosis controversial (Am J Surg 2 009;197:8 06; Gastro
2 007;132 :2 02 2 ); ? reserve for severe p ancreatitis w/ >30% necrosis by CT, & no
>14 d
• Debridement: infected necrosis usually requires p ercut, endoscop ic or surgical

debridement. Imp roved outcomes by delaying surgery ≥2 wk if p ossible to allow
organization of necrosis. CCY if gallstones (w/in 48 h if mild, o/w w/in 14 d; Surg
2 009;145:2 60; Ann Surg 2 010;2 51:615)
• ERCP + sp hincterotomy: in acute setting, reserved for severe cholangitis/sep sis and
T bili >5 (ie, p resump tive obstructive BD stone). Otherwise, early ERCP does not
reduce risk of local or systemic p ancreatitis comp lications (Ann Surg
2 007;2 45:10).
Complications
• Systemic: shock, ARDS, renal failure, GI hemorrhage, DIC
• Metabolic: hyp ocalcemia, hyp erglycemia, hyp ertriglyceridemia

• Acute fluid collection (30–50% ): seen early, no cap sule, no Rx required
• Pseudocyst (10–2 0% ): fluid collection, p ersists for 4–6 wk, encap sulated suggested
by p ersistent p ain & elevation of amylase or lip ase, or mass on exam most resolve
sp ont.; if >6 cm or p ersists >6 wk + p ain → endo/p erc/surg drainage
• Sterile pancreatic necrosis (2 0% ): area of nonviable p ancreatic tissue ?

p rop hylactic abx (see above); sup p ortive measures, surgery if Pt unstable
• Infection (5% of all cases, 30% of severe): usually 2 ° enteric GNR

infected pancreatic necrosis: new SIRS after 7 d typ ical; p erc drainage followed
by min invasive surg debridement or endoscop ic necrosectomy sup erior to op en
necrosectomy; FNA no longer routinely recommended (Pancre as 2 012 ;41:1176)
pancreatic abscess: circumscribed collection of p us (usually w/o p ancreatic
tissue) treat with abx + drainage (CT-guided if p ossible), usually seen ≥4 wk
into course
• Ascites or pleural effusion: occurs due to disrup ted p ancreatic duct; consider early
ERCP w/ stent across duct; can also occur from draining p seudocyst
Prognosis (Gastro 2 007;132 :2 02 2 )

• Severe p ancreatitis (2 0% ) = organ failure or local comp lications (necrosis,
p seudocyst)
• Scoring systems: HAPS, BISAP, APACHE II, Ranson’s criteria, CT Severity Index
HAPS: no abd tenderness or rebound on exam p lus nl Hct and Cr on admission

p redicts non-severe course w/ 98 % accuracy (Clin Gas He p 2 009;6:702 )
BISAP: 5-p oint scoring system on admission (BUN >2 5, GCS <15, SIRS, age
>60, and p leural effusion) identifies Pts at risk for ↑’d mortality (Am J Gastro
2 009;104:966)
APACHE II (www.mdcalc.com/ap ache-ii-score-for-icu-mortality): severe if

score ≥8
Chronic pancreatitis (Lance t 2 011;377:118 4)
• 70–8 0% due to EtOH, also consider autoimmune p ancreatitis. Smoking major risk
factor.
• Often, but not always, recurrent acute attacks → inflammatory infiltrate → fibrosis
→ exocrine then endocrine insufficiency (eg, diabetes)
• Sxs include ep igastric p ain, N/V; over time will be p ainless and p /w steatorrhea and
wt loss
• Amylase/lip ase ↑ early, but may be nl later. fecal fat, ↓’d stool elastase &
chymotryp sin, Ca 2 + in p ancreas on KUB/CT.
• ERCP/MRCP/EUS high Se for dx: stricture, dilated ducts, honeycombing of

p arenchyma
• Treatment is low-fat diet and enzyme rep lacement. Avoid EtOH & tobacco. Analgesia
w/ NSAID ± mild op ioid (eg, tramadol). Surgery in selected cases.
ABNORMAL LIVER TESTS
Tests of hepatocellular injury or cholestasis
• Aminotransferases (AST, ALT): intracellular enzymes released 2 °

necrosis/inflammation
ALT more sp ecific for liver than is AST (heart, skeletal muscle, kidney, brain,
RBC/WBC)
ALT > AST → viral hep atitis or fatty liver/nonalcoholic steatohep atitis
(p recirrhotic)
AST: ALT >2 :1 → alcoholic hep atitis, cirrhosis; nonhep atic source
ALT/AST >15× ULN → etiologies of acute liver failure (↑↑↑ LDH →
ischemia/toxic)
• Alkaline phosphatase (AΦ ): enzyme bound in hep atic canicular membrane
besides liver, also found in bone, intestines, kidney and p lacenta

confirm liver origin with: ↑ 5′-NT, ↑ GGT or AΦ heat fractionation
↑ levels seen with biliary obstruction or intrahep atic cholestasis (eg, hep atic
infiltration)
Tests of hepatic function
• Albumin: marker for liver p rotein synthesis, ↓ slowly in liver failure (t1/2 ~2 0 d)
• Prothrombin time (PT): dep ends on synthesis of coag factors by liver (excep t FVIII);
b/c t1/2 of some factors (eg, V, VII) is short, ↑ PT can occur w/in hrs of liver
dysfxn
• Bilirubin: p roduct of heme metab (unconjugated, “indirect” ) carried by alb to liver

where taken up for conjugation (“direct” ) to make soluble, then excreted into bile;
most sensitive test to detect p arenchymal disease; in those w/ normal LFTs, high nl
Tbili (? marker of ↑ heme oxygenase) a/w ↓ resp disease & death (JAMA
2 011;305:691)
Patterns of liver injury
• Hepatocellular: ↑↑ aminotransferases, ± ↑ bilirubin or AΦ
↑↑↑ ALT & AST (>1000): severe viral hep atitis, drugs, ischemia, Wilson’s, AIH
• Cholestasis: ↑↑ AΦ and bilirubin, ± ↑ aminotransferases
• Isolated hyperbilirubinemia: ↑↑ bilirubin (direct or indirect), nl AΦ and

aminotransferases
• Infiltrative: ↑ AΦ , ± ↑ bilirubin or aminotransferases
• Jaundice is a clinical sign seen when bilirubin >2 .5 mg/dL (esp . in sclera or under
tongue); if hyp erbilirubinemia conjugated → ↑ urine bilirubin
Figure 3-3 Ap p roach to abnormal liver tests with hep atocellular p attern
• Acute workup: toxins (EtOH, acetaminop hen); vascular abnl (U/S w/ Dop p ler); viral
te sts: IgM anti-HAV, HBsAg, IgM anti-HBc, HBV DNA, HCV RNA, anti-HEV, ±
EBV, CMV, HSV, VZV; autoimmune (ANA, ASMA, ALKM); ce ruloplasmin
• Chronic workup: HBsAg, anti-HCV; Fe, TIBC; glc, HbA1c, TG; ANA, ASMA, ALKM;
anti-tissue transglutaminase; cerulop lasmin & ɑ1-AT; TSH; vascular abnl (U/S w/
Dop p ler)
Figure 3-4 Ap p roach to abnormal liver tests with cholestatic p attern
Figure 3-5 Ap p roach to abnormal liver tests with isolated hyp erbilirubinemia
Figure 3-6 Ap p roach to abnormal liver tests with infiltrative p attern
Abnormal liver tests in asymptomatic patients (Clin Live r Dis 2 009;13:167)

• Careful review of history (meds, EtOH/drug use, exp osures, risk factors for liver
disease) and p hysical exam. Evaluate for any clues to etiology 1st (eg, d/c med and
rep eat LFTs).
• Confirm hep atic source: if p rimarily ↑ AΦ (✓ GGT) or AST > ALT (✓ CK, aldolase,
TFT)
• Hepatocellular
Evaluate for most common causes: hep atitis A/B/C, hemochromatosis; screen for
evidence of chronic liver disease (p latelets, PT/INR, albumin)
If evaluation → lifestyle modification (wt loss, DM control) + rep eat test 6

mo
If evidence of chronic liver disease or p ersistent lab abnl, screen for less common
causes: AIH, Wilson’s, celiac, ɑ1-AT; ✓ U/S & consider liver bx
If still → liver bx if ALT or AST >2 × ULN for >6 mo; o/w observe
• Cholestatic: ✓ RUQ U/S, AMA
if biliary dilatation or obstruction → MRCP
if AMA and U/S , or AMA and U/S w/ abnl p arenchyma → liver bx
if AMA & U/S : AΦ >1.5× ULN → consider bx; AΦ <1.5× ULN → observe
• Isolated hyperbilirubinemia: ✓ conjugated vs. unconjugated
conjugated → p erform abdominal U/S → MRCP if dilatation or obstruction; if nl

ultrasound ✓ AMA and consider MRCP or liver bx
unconjugated → ✓ Hct, retic count, smear, LDH, hap toglobin
Common medications that cause abnormal liver tests (http ://livertox.nlm.nih.gov)

HEPATITIS
VIRAL
Hepatitis A (ssRNA; 30–45% of acute viral hep atitis in U.S.)
• Transmission: fecal–oral route; contaminated food, water, shellfish; daycare ctr

outbreaks
• Incubation: 2 –6 wk; no chronic carrier state

• Sx: ↓ ap p etite, malaise, fever, N/V, RUQ p ain, ± jaundice; rarely fulminant
• Diagnosis: acute hep atitis = IgM anti-HAV; p ast exp osure = IgG anti-HAV
( IgM)
• Treatment for acute HAV sup p ortive. Prevention: vaccinate children & Pts w/ chronic
HBV, HCV (? if cost-effective) or other chronic liver disease (2 doses at 0, 6–12
mo)
• Postexp osure p p x: age 1–40 y → vaccine; age <1 or >40 y or immunosup p → Ig
Hepatitis B (dsDNA; ~45% of acute viral hep atitis in U.S.; Lance t 2 009;373:58 2 )
• Transmission: blood (IVDU, transfusion), sexual, p erinatal
• Incubation: 6 wk–6 mo (mean 12 –14 wk)

• Acute infxn: 70% subclinical, 30% jaundice, <1% fulminant hep atitis (up to 60%
mortality)
• Chronic infxn: <5% (adult-acquired; higher if immunosup p ), >90% (p erinatally

acquired); ~40% chronic carriers → cirrhosis; ↑ risk of cirrhosis if HCV, HDV or
HIV coinfection
• Hep atocellular carcinoma (w/ or w/o concurrent cirrhosis); ↑ risk w/ p erinatal
transmission & ↑’d HBV DNA. Screen chronic carriers w/ AFP & U/S vs. MRI
q6mo.
• Extrahep atic syndromes: PAN (<1% ), MPGN, arthritis, dermatitis, PMR
• Serologic and virologic tests
HBsAg: ap p ears before sx; used to screen blood donors; p ersists >6 mo =
chronic HBV
HBeAg: evidence of viral rep lication and ↑ infectivity
IgM anti-HBc: first Ab to ap p ear; indicates acute infection window p eriod =

HBsAg become , anti-HBs not yet , anti-HBc only clue to infection
IgG anti-HBc: indicates p revious (HBsAg ) or ongoing (HBsAg ) HBV

infection
anti-HBe: indicates waning viral rep lication, ↓ infectivity
anti-HBs: indicates resolution of acute disease & immunity (sole marker after vac)
HBV DNA: p resence in serum correlates w/ active viral rep lication in liver
Figure 3-7 Serologic course of acute HBV infection with resolution

• Treatment for acute HBV: sup p ortive; hosp italize for Δ MS or ↑ INR (liver
transp lant ctr)
• Treatment for chronic HBV if: (1) HBeAg w/ DNA >2 0,000 IU/mL & elevated
ALT; (2 ) HBeAg w/ DNA >2 000 IU/mL & elevated ALT or liver bx
demonstrates stage ≥2 fibrosis (NEJM 2 008 ;359:148 6; He p 2 009;50:661; Clin Gas
He p 2 011;9:2 8 5)
• 1st line is nucleo(s/t)ide analogues: entecavir or tenofovir; well tolerated & low
resistance (1% for entecavir at 5 y in Rx-naïve Pts); at 5 y HBeAg seroconversion
is 30–40% & loss of HBsAg is 5–10% (Gastro 2 012 ;142 :1360; Lance t
2 013;38 1:468 )
• PEG IFNɑ-2 a: best rate of HBeAg seroconversion at 1 y (2 7% ), low tolerability

limits use
• Goal: if HBeAg → HBeAg , anti-HBe ; if HBeAg or seroconversion

or Asian Pt → indefinite tx or until HBsAg clears (if ever)
• If undergo liver transp lant: HBIG + nucleo(s/t)ide analogue effective in p reventing

reinfection
• HIV/HBV coinfe ction: Rx w/ 2 drugs active against both HBV & HIV (NEJM
2 007;356:1445)
• If inactive carrier scheduled to receive immunosup p ression/chemotherap y → Rx

• Prevention: vaccinate all infants & children and at-risk adults (3 doses 0, 1 & 6–12
mo)
• Postexp osure (risk infxn ~30% ) p p x: HBIG → vaccine (if unvac or known
nonresp onder)
Hepatitis C (ssRNA; ~10% of acute viral hep atitis in U.S.; NEJM 2 011;364:2 42 9)
• Transmission: blood (IVDU, transfusion) >> sexual; 2 0–30% w/o clear p recip itant
• Incubation: 1–5 mo; mean 6–7 wk
• Natural hx
acute infxn: 8 0% subclinical; 10–2 0% sx hep atitis w/ jaundice; fulminant

hep atitis very rare; p rob of sp ont clearance a/w IL28 B & HLA class II genotyp es
(Annals 2 013;158 :2 35)
chronic: up to 8 5% → chronic hep atitis, 2 0–30% of whom develop cirrhosis
(after ~2 0 y) ↑ risk of cirrhosis in men, EtOH, HIV; HCC in 2 –5% of
cirrhotics/y
• Extrahep atic syndromes: cryoglobulinemia, p orp hyria cutanea tarda (blistering rash
in sun-exp osed areas), MPGN, MGUS, IPF, NHL and DM
• Serologic, virologic, & genetic tests

anti-HCV (ELISA): in 6 wk, does not = recovery or immunity; can be after
recovery
HCV RNA: w/in 2 wk, marker of active infection
HCV RIBA: used to confirm anti-HCV ELISA in Pts w/ undetectable HCV RNA
HCV genotyp e (1–6): guides duration & p redicts resp onse to Rx
• Dx: acute hep atitis = HCV RNA, ± anti-HCV; re solve d = HCV RNA, ±
anti-HCV; chronic = HCV RNA, anti-HCV
• Treatment indications (He p 2 009;49:1335 & 2 011;54:1433; NEJM 2 013;368 :1907)
Acute: if no sp ont. clearance at 8 –12 wk, consider PEG-IFNɑ-2 a/b ± RBV × 12 –

2 4 wk
Chronic: RNA , p lus bx w/ either chronic hep atitis & fibrosis stage >1 or
comp ensated liver disease (in genotyp e 2 or 3, may p roceed to Rx w/o bx b/c
high resp onse rate)
• Triple therapy (genotyp e 1): PEG-IFN ɑ-2a/b, RBV, & protease inhibitor (PI), either
bocep revir (BOC) or telap revir (TVR) (NEJM 2 011;364:1195 & 2 405). Rx 2 4–48
wk; SVR rate 30–8 0% based on variables such as advanced fibrosis, IL28 B
genotyp e, p rior resp onse to IFN and rap id virologic resp ( RNA at wk 4 [TVR] or
wk 8 [BOC]) (Gastro 2 012 ;142 :1314)
• Dual therapy (genotyp es 2 & 3): PEG-IFNɑ-2 a/b + RBV; Rx 2 4 wk; SVR rate ~8 0%
• Goal is sustaine d virolog ic re sponse (SVR) = viremia 2 4 wk after comp letion of Rx
• IFN-free regimens incl. rep lic. comp lex, p olymerase, & microRNA-12 2 inhibs. &
other direct acting antivirals under study (NEJM 2 012 ;366:2 16; 2 013;368 :34, 45,
168 5, 18 67 & 18 78 )
• Risks of Rx: flu-like sx, p sych sx (if dep ressed can give SSRI), thyroid dysfxn,
marrow sup p ression (can give EPO & G-CSF), hemolysis (RBV), sexual dysfxn; PIs
w/ sig drug-drug interactions, worsen anemia, & TVR a/w rash/p ruritus in 6% ,
DRESS/SJS in <1%
• Contraindic.: decomp ensated cirrhosis, p reg, severe p sych illness, active substance
abuse, severe cardiac/p ulm disease, uncontrolled DM, seizure d/o, autoimmune
disease
• CDC rec screening for HCV in anyone born 1945–1965 (Annals 2 012 ;156:2 63)
• Vaccinate all chronic HCV p atients against HBV and HAV if not immune
• Postexp osure (needlestick risk ~3% ) p p x: none; if HCV RNA → , consider Rx
w/in 3 mo
Hepatitis D (RNA)
• Transmission: blood or sexual; endemic in Africa & E. Europ e

• Pathogenesis: requires HBV to cause either simultaneous or sup erimp osed infection
• Natural hx: in HBV ↑ severity of infxn and ↑ p rogression to cirrhosis and HCC in
chronic carriers; clears w/ HBV
• Serologic/virologic tests: anti-HDV; follow HDV RNA during Rx (high relap se rate)
Hepatitis E (ssRNA; NEJM 2 012 ;367:12 37; Lance t 2 012 ;379:2 477)
• In endemic areas most common cause of acute viral hep atitis

• Transmission: fecal–oral; travelers to central & SE Asia, Africa and Mexico, exp . to
swine
• Natural hx: acute hep atitis w/ ↑ mort. (10–2 0% ) if p regnant; rare chronic in
transp lant Pts
• Dx: IgM anti-HEV (through CDC)
• Extrahep atic sx: arthritis, p ancreatitis, neuro (GBS, inflam p olyradic.,

meningoencep h.)
Other viruses (HGV, CMV, EBV, HSV, VZV)

AUTOIMMUNE HEPATITIS (AIH)
Classification (J He p 2 011;55:171; He p 2 010;51:1)

• Typ e 1: antismooth muscle Ab (ASMA), ANA; antisoluble liver antigen (anti-SLA),
a/w more severe disease and relap sing disease
• Typ e 2 : anti–liver/kidney microsome 1 (anti-LKM1) or liver/cytosol (LC1); kids (2 –
14 y)
• Overlap syndrome: AIH + PBC or PSC; Rx-induced: minocycline, nitrofurantoin,
infliximab
Diagnosis and treatment
• 70% female; 40% p resent acutely (occ. fulminant); 34% asx; ALT can be >1000
• Extrahep atic syndromes: thyroiditis, arthritis, UC, Sjögren’s, Coombs’ hemolytic
anemia
• Dx: scoring system combining serologies, ↑ IgG, viral hep atitis, & characteristic
liver bx (lymp hop lasmacytic infiltrate & interface hep atitis) has high Sp & mod Se
(He p 2 008 ;48 :169)
• Rx: if LFTs 10× ULN, or if 5× ULN w/ IgG 2 × ULN, or bridging/multiacinar
necrosis on bx
• Prednisone + azathiop rine → 65% remission w/in 3 y; 50% relap se on withdrawal

of meds at 6 mo; up to 90% by 3 y; ∴ most will require long-term Rx; consider
substituting budesonide for p red in noncirrhrotics w/ Rx-naive AIH (Gastro
2 010;139:1198 )
• Liver transp lant for ESLD; recurs in ~30% of Pts, but generally easily treated
OTHER CAUSES OF HEPATITIS OR HEPATOTOXICITY
Alcoholic hepatitis (NEJM 2 009;360:2 758 ; Clin Liv Dis 2 012 ;16:371)
• Sxs: can range from asx hep atomegaly to decomp ensation w/ ascites,
encep halop athy and death. AST & ALT usually <300–500 w/ AST:ALT > 2 :1, in
p art b/c concomitant B 6 defic (ALT can be normal); ↓ p lt, ↑ iron sat, ↑’d Tbili &
INR indicate severe hep atitis.
• Rx: if discriminant fxn (= 4.6 × [PT-control] + Tb in mg/dL) >32 or
encep halop athy
methylp rednisolone 32 mg/d × 4 wk → 4–6 wk tap er; ↓ death (NEJM
1992 ;32 6:507) contraindications: GIB, chronic HBV, severe infections such as
sep sis
p entoxifylline 400 mg tid ↓ mortality due to reduction in HRS (Coch
2 009;4:CD007339)
NAC + steroids ↓ 30-d but not 6-mo mortality (NEJM 2 011;365:178 1)

• Lille model p redicts nonresp onse to corticosteroids & mortality, p owered by Δ Tb
from day 1 → 7; nonresp onders have 6-mo survival of 2 5% (www.lillemodel.com;
He p 2 007;45:1348 )
Acetaminophen hepatotoxicity (NEJM 2 008 ;359:2 8 5; BMJ 2 011;342 :d2 2 18 )

• Normal metabolism via glucuronidation and sulfation → nontoxic metabolites
• Overdose (usually >10 g): CYP2 E1 hydroxylation → reactive electrop hilic sp ecies
(NAPQI) that are scavenged by glutathione until reserves exhausted →
hep atotoxicity
• CYP2 E1 induce d by fasting and alcohol allowing for “therap eutic misadventure” in
malnourished alcoholics taking even low doses (2 –6 g) of acetaminop hen
• Liver dysfunction may not be ap p arent for 2 –6 d
• Rx: NG lavage, activated charcoal if w/in 4 h. Consider early transfer to transp lant
ctr.
N-acetylcysteine: administer up to 72 h after ingestion, if time of ingestion

unknown or if chronic ingestion >4 g/d
Rumack-Matthew nomogram
(www.tylenolp rofessional.com/assets/Nomogram.p df) p redicts risk of
hep atotoxicity from serum level of acetaminop hen when time of ingestion is
known
Low threshold to start NAC even w/ low or undetectable serum acetaminop hen
levels
PO NAC (p referred): 140 mg/kg loading dose → 70 mg/kg q4h × 17 additional

doses
IV NAC: 150 mg/kg over 1 h → 50 mg/kg over 4 h → 100 mg/kg over 16 h; risk
of anap hylaxis; use if unable to tolerate POs, GIB, p reg, fulminant hep atic
failure
Ischemic hepatitis
• “Shock liver” w/ AST & ALT >1000 + ↑↑ LDH; delayed ↑↑ Tbili
• Seen in HoTN & CHF; often requires ↑ venous + ↓ p ortal/arterial p ressure +

hyp oxia
Nonalcoholic fatty liver disease (NAFLD, a sp ectrum of disease; He p 2 012 ;55:2 005)
• Definition: fatty infiltration of liver and absence of EtOH or other cause of steatosis
(TPN, rap id wt loss or Rxs such as HAART, tamoxifen, amiodarone, MTX)
NAFL = steatosis, inflammation; NASH = steatosis + inflammation ± fibrosis

on liver bx
• NAFLD: 10–30% of U.S. p op . & over 60% in T2 DM & obesity
• NASH: 2 –5% of NAFLD & risk of cirrhosis in NASH w/ fibrosis on bx is 30% at 10 y
• Pathop hys: hep atic lip otoxicity w/ oxidant stress & inflammatory resp onse; PNPLA3
high-risk SNP confers ↑ risk of hep atic fat content, NASH, & fibrosis (He p
2 011;53:18 8 3)
• Clinical: 8 0% asx, ↑ ALT > AST, but nl ALT/AST does not exclude p oss. of NASH on
bx
• Dx: based on clinical variables & imaging. Liver bx remains gold standard. NAFLD
fibrosis score (www.nafldscore.com) = clinical variables to p redict NASH w/
advanced fibrosis.
• Rx: wt loss, exercise, DM/lip id control (statins; Lance t 2 010;376:1916); p ioglitazone

+ vit E ↓ steatosis & inflam, not fibrosis (NEJM 2 010;362 :1675). Pentoxifylline
under study (He p 2 011;54:1610).
ACUTE LIVER FAILURE
Definition
• Acute hep atic disease + coagulop athy + encep halop athy; w/o known p re-existing
liver dis.
• Fulminant = develop s w/in 8 wk; subfulminant = develop s between 8 wk and 6 mo
Etiology (Lance t 2 010;376:190)

• Viral (12 % of cases)
HAV, HBV, HCV (rare), HDV + HBV, HEV (esp . if p regnant)
HSV (immunosup p Pt), EBV, CMV, adenovirus, p aramyxovirus, p arvovirus B19
• Drugs/toxins (nearly 8 0% of cases; He p 2 010;52 :2 065)
Drugs: acetaminop hen (most common cause; >40% of all cases), p henytoin, INH,
rifamp in, sulfonamides, tetracycline, telithromycin, amiodarone, PTU, valp roate
Toxins: fluorinated hydrocarbons, CCl 4, Amanita phalloide s
• Vascular: ischemic hep atitis, Budd-Chiari syndrome, hep atic SOS, malignant
infiltration
• Autoimmune hepatitis (initial p resentation)
• Misc.: Wilson’s, acute fatty liver of p regnancy (HELLP, Reye’s), idiop athic (up to
2 0% )
• Initial p resentation usually nonsp ecific, w/ nausea, vomiting, malaise, followed by

jaundice
• Neurologic
encephalopathy: stage I = DMS; stage II = lethargy, confusion; stage III =

stup or; stage IV = coma
asterixis in stage I/II/III encep halop athy; hyp erreflexia, clonus, rigidity in stage
III/IV
cerebral edema → ↑ ICP, ↓ CPP → cerebral hyp oxia, uncal herniation, Cushing’s
reflex (hyp ertension + bradycardia), p up illary dilatation, decerebrate
p osturing, ap nea
• Cardiovascular: hypotension with low SVR
• Pulmonary: respiratory alkalosis, imp aired p erip heral O 2 up take, p ulm edema,
ARDS
• Gastrointestinal: GIB (↓ clotting factors, ↓ p lt, DIC), p ancreatitis (? due to ischemia)
• Renal: ATN, hepatorenal syndrome, hyp onatremia, hyp okalemia,

hyp op hosp hatemia
• Hematology: coagulopathy (due to ↓ synthesis of clotting factors ± DIC)
• Infection (~90% of Pts): esp . with Staph, Stre p, GNRs and fungi (↓ immune fxn,
invasive p rocedures); SBP in 32 % of Pts; fe ve r and ↑ WBC may be abse nt
• Endocrine: hypoglycemia (↓ glc synthesis), metabolic acidosis (↑ lactate), adrenal
insuf.
Workup (He p 2 012 ;55:965)

• Viral serologies (see “Acute Hep atitis Workup ” )
• AIH serologies, cerulop lasmin & serum/urine cop p er, p regnancy test, arterial NH3
• Toxicology screen (acetaminop hen levels q1–2 h until p eak determined)
• Imaging studies (RUQ U/S or abd CT, Dop p ler studies of p ortal and hep atic veins)
• Liver biop sy (unless p recluded by coagulop athy → in which case consider
transjugular)
Treatment (He p 2 012 ;55:965)

• ICU care at liver transplant ctr for hemodynamic & ventilatory sup p ort; CVVH for
ARF
• IV N-acetylcysteine (same dose as for acetaminop hen): all Pts w/ hep atic failure
and grade 1–2 encep h: ↑ cerebral blood flow and ↑ transp lant-free survival (Gastro
2 009;137:8 56)
• Cerebral edema: rare w/ NH 3 <75 mM/L, invariable if >2 00 mM/L; consider ICP
monitoring if stage III/IV encep h; if ↑ ICP → mannitol 0.5–1.0 mg/kg;
p rop hylactic 3% saline for goal Na 145–155 mEq/L if NH 3 >150 mM/L, grade
3/4 encep h, ARF or on vasop ressors; barbiturates & hyp othermia if ↑ ICP
refractory to osmotic agents
• Encep halop athy: intubate for grade III or IV; lactulose (avoid diarrhea &
overdistension)
• Coagulop athy: vit K; FFP/p lts/cryo if active bleeding; ? recomb. factor VIIa; PPI
p rop hylaxis
• Infection: low threshold for abx (broad sp ectrum, eg, vancomycin & 3rd-gen cep h.),
albeit no p roven mortality benefit to emp iric abx
• Treatment of sp ecific causes: nucleo(s/t)ides for HBV; steroids for AIH; consider
p lasma exchange for Wilson’s; IV acyclovir for HSV; gastric lavage & PCN-G for
Amanita phalloide s; delivery of child for p regnancy related; TIPS and anticoag for
Budd-Chiari
• Liver transp lantation if p oor p rognosis w/ grade II or III encep halop athy (see
below)
Prognosis
• Non-acetaminop hen ALF mortality ~8 0% , acetaminop hen-induced ALF mortality

~30%
• Predictors of p oor outcome
Acetaminop hen-induced: p H <7.3 after fluids or INR >6.5, Cr >3.4, or grade

III/IV encep h.
Non-acetamin.-induced: INR >6.5 or 3 of the following: non-A/B viral hep ; other

drug toxicity; time from jaundice to encep h. >7 d; age <10 or >40 y; INR
>3.5; Tbili >17.4
• ALFED model: NH 3, Tbili, INR, & ≥2 encep h (Gut 2 012 ;61:1068 ) & ALFSG index:
coma grade, INR, Tbili, PO 4, & serum CK18 (Gastro 2 012 ;143:12 37) are new
indices for p redicting need for liver Tx and mortality
• ~2 5–30% of Pts w/ ALF undergo liver transp lantation w/ 5-y survival rate of 70%
CIRRHOSIS
Definition (He p 2 011;54:18 64 & 2 012 ;56:198 3; J He p 2 012 ;56:S13)

• Definition: fibrosis and regenerative nodules resulting from hep atocellular injury
• Decompensated = jaundice, variceal bleed, encep halop athy, ascites; worse

p rognosis
Etiologies
• Alcohol (~60–70% ): Laennec’s cirrhosis; micronodular
• Viral hepatitis (~10% ): chronic HBV, HCV, HDV infection
• Autoimmune hepatitis: female, ↑ IgG, ANA, antismooth muscle Ab
• Metabolic diseases (~5% ): hemochromatosis, Wilson’s disease, ɑ1-AT deficiency
• Biliary tract diseases (~5% ): p rimary biliary cirrhosis, secondary biliary cirrhosis
(calculus, neop lasm, stricture, biliary atresia), p rimary sclerosing cholangitis
• Vascular diseases: Budd-Chiari syndrome, R-sided CHF, constrictive p ericarditis,
sinusoidal obstruction syndrome
• Nonalcoholic fatty liver dis. (NAFLD, 10–15% ) cause of most “cryp togenic
cirrhosis”
• Subclinical or may p /w liver dysfunction (jaundice, coagulop athy, encep halop athy)
and/or p ortal HTN (ascites, varices); 35% p /w fever (SBP, acute EtOH); 2 5% p /w
hematemesis
Physical exam
• Liver: initially enlarged, p alp able (L lobe p redom), firm; e ve ntually shrunken and
nodular
• Signs of liver failure: jaundice (bili >2 ), sp ider angiomata & p almar erythema (↑
estradiol), Dup uytren’s contractures, white nail lines (Muehrcke’s lines) &
p roximal nail beds (Terry’s nails), ↑ p arotid & lacrimal glands, gynecomastia,
testicular atrop hy, asterixis, encep halop athy, fetor hep aticus, clubbing,
hyp ertrop hic osteoarthrop athy
• Signs of p ortal hyp ertension: sp lenomegaly, ascites, dilated sup erficial abdominal
veins (cap ut medusae), ep igastric Cruveilhier-Baumgarten venous hum
Laboratory studies
• ↑ bilirubin, ↑ PT (p oor correlation w/ bleeding; factor VIII nl as not synthesized by

liver), ↓ alb, ± ↑ aminotransferases (AST > ALT if late) and ↑ AΦ (variable), ↓
Na, ↑ γ-glob
• Anemia (marrow sup p ression, hyp ersp lenism, Fe and/or folate defic.), neutrop enia
(hyp ersp lenism), thrombocytop enia (hyp ersp lenism, ↓ Tp o p roduction by liver,
EtOH tox)
Workup
• Abdominal U/S w/ Doppler: liver size (↑ L & caudate lobe), r/o HCC, ascites, ✓
p atency of p ortal, sp lenic and hep atic veins
• Assess fibrosis: biomarkers (eg, FibroSURE = p anel of 6 markers validated in HCV,

↑ score p redictive of fibrosis); U/S or acoustic radiation force imp ulse or MR
elastograp hy
• Determine etiology: hep atitis serologies (HBsAg, anti-HBs, anti-HCV), autoimmune
hep atitis studies (IgG, ANA, anti–smooth muscle Ab), Fe and Cu studies, ɑ1-AT,
AMA
• ± Liver bx: p ercutaneous or transjugular (consider if ascites or coagulop athy) used
to dx etiology and p resence of cirrhosis
Ascites (see “Ascites” for details on dx eval; He p 2 009;2 9:2 08 7)

• Due to p ortal HTN (defined as hep atic venous p ressure gradient [HVPG] >5 mmHg)
• Develop s in 60% w/in 10 y; ~50% mortality at 5 y

• Treatment (Am J Gastro 2 009;104:18 02 ): ↓ Na intake (1–2 g/d); free H 2 O restrict if
Na <12 5
Diuretics: goal 1 L/d; urine Na/K >1 imp lies effective aldo block; sp ironolactone
± furosemide in 5:2 ratio (eg, 100 & 40 mg daily); ↑ doses in p rop ortion
NSAID as interferes w/ diuretic action (common cause of refractory ascites)
• Refractory ascites (Clin Gas He p 2 011;9:931): seen in 5–10% of Pts; 2 -y survival is

2 5%
Diuretic resistant on 2 g Na diet or diuretic-induced comp lic (Cr >2 , Na <12 5, ↑
or ↓ K, encep h)
Large-volume paracentesis (LVP); if >5 L, rep lace w/ 8 –10 g/L of alb → ↓ risk
of p aracentesis-induced circ. dysfxn (AKI & lyte abnl) & ? ↓ mortality (He p
2 012 ;55:1172 )
Beware LVP if SBP as ↑ risk of ARF → consider dx tap to r/o SBP first
Transjugular intrahepatic portosystemic shunt (TIPS) (Clin Gas He p

2 011;9:936)
↓ ascites in 75% , ↑ CrCl, ↑ encep h, survival benefit over LVP remains

controversial
Contraindic: grade II encep h, CHF or p ulm HTN, active infxn or biliary

obstruction
Comp lications include te chnical: bleeding, fistula; re late d to ste nt: thrombosis
w/in 2 4 h rare, 1 y p atency w/ coated stents ~8 0% , infxn (endotip sitis);
shunting : new or ↑ encep h in 2 0–30% , hemolysis (He p 2 010;51:306)
• Hep atic hydrothorax: 2 ° diap hragmatic defect; often unilateral, R > L, ± ascites
Treatment: chest tube due to ↑ comp lications; Rx same as ascites
Sp ont e mpye ma can occur (even w/o SBP) → dx thoracentesis; Rx same as for SBP
Spontaneous bacterial peritonitis (SBP; see “Ascites” for details; J He p 2 010;53:397)
• Develop s in ~2 0% ; 2 0% mortality; risk factors: AFTP <1 g/dL, hx of SBP, current

GIB
• Can p /w encep halop athy, abd p ain, fever, but ofte n (25% ) asx; consider
p aracentesis in all hosp italized cirrhotics w/ ascites
• Micro: 70% GNR (E. coli, Kle bs), 30% GPC (Ente rococcus, S. pne umo), nosocomial
(fungi, Pse ud); ~40% culture
• Rx: 3rd gen. cep h (eg, cefotaxime 4g/d total dose) or amox/clav × 5 d, if
encep h/AKI can use FQ (cip ro/oflox) but avoid if already on for p p x or in ↑ FQ
resist. areas IV albumin 1.5 g/kg at time of dx & 1 g/kg on day 3 → ↑ survival
(NEJM 1999;341:403) If not imp roving, rep eat p aracentesis at 48 h: ~2 5% ↓ PMN
count = Rx success
• Pp x: if h/o SBP or AFTP <1.5 + Na <130, Cr >1.2 or Child-Pugh B (Am J Gastro
2 009;4:993) norfloxacin 400 mg PO qd or Bactrim DS qd
Gastroesophageal varices ± UGIB (see also “GIB” ; NEJM 2 010;362 :8 2 3)
• Present in 60% of decomp ensated cirrhotics; incidence of bleeding is 2 4% by 2 y;

bleeding risk if HVPG >12 mmHg; screen all cirrhotics at time of dx
• 1° p revention of UGIB: med-to-large varices or “red wale” marks or Child-Pugh B or
C
nonselective b-blockers: ~50% ↓ risk of bleeding ± ↓ mortality; typ ically
nadolol or p rop ranolol (consider carvedilol if systemic HTN as ɑ1 blockade ↓
intrahep atic vasc resist.; He p 2 010;54:2 2 14); titrate to 2 5% ↓ HR; EGD req.
to document imp rovement
endoscopic variceal ligation (EVL): ↓ bleeding & death bB (Ann He p
2 012 ;11:369) q1–2 wk until gone → survey EGD at 3 mo → q6–12 mo; adding bB
only ↑ side effects
bB vs. EBL: choice based on Pt/p hysician p reference, bB often 1st (He p
2 008 ;47:1764)
• 2 ° p revention: for all Pts after 1st bleed b/c ~50% rebleed & ~30% mortality bB +
EBL > either alone (Annals 2 008 ;149:109); TIPS if refractory or consider in Child-
Pugh B or C w/in 72 h of admission for esop h variceal bleed (↑ 1-y survival;
NEJM 2 010;362 :2 370)
Portosystemic (hepatic) encephalopathy (PSE) (Clin Gas He p 2 012 ;10:12 08 )

• Pathogenesis: failure of liver to detoxify NH 3 + other substances (eg, ADMA; J He p
2 013;58 :38 ) that cause cerebral edema, ↓ O 2 consump tion, ↑ ROS → brain dysfxn
• Precip itants: ↑ dietary p rotein, constip ., GIB, med nonadherence, infxn, azotemia, ↓
K, Δ volume/water, hyp oxia, HCC, p ortosystemic shunt, meds, PVT
• Stages: (1) confusion; (2 ) drowsiness; (3) stup or; (4) coma
• Dx: asterixis can be seen; NH 3 p oor Se for dx & monitoring Rx; remains a clinical dx
• Treatment: identify/correct p recip itants, restrict dietary p rotein acutely (60–8 0 g/d),
lactulose (acidification of colon: NH 3 → NH 4+) w/ goal 2 –4 stools/d ± rifaximin
550 mg bid (↓ gut bacteria → ↓ NH 3 p rod); correct zinc deficiency
• 2 ° p revention: lactulose ± rifaximin 550 bid (Gastro 2 009;137:8 8 5; NEJM

2 010;362 :1071)
Hepatorenal syndrome (HRS) (NEJM 2 009;361:12 79; Crit Care 2 012 ;16:R2 3(1))
• Pathop hys: renal vasoconstriction w/ ↓ renal blood flow; kidney histologically nl

• Criteria: (1) cirrhosis w/ ascites; (2 ) Cr >1.5 mg/dL; (3) imp rovement in Cr (to
≤1.5) after d/c diuretic & volume exp ansion (1 g/kg/d of albumin × 2 d); (4)
shock (p rerenal azotemia/ATN); (5) nep hrotoxic meds; (6) organic kidney dis
(eg, GN) or obstruction
Type I: Cr >2 .5 or 1.5× baseline in <2 wk; usually occurs in severe liver
failure, often following p recip itating event (see later); median survival 2 wk
Type II: more indolent course, median survival 6 mo; liver failure p resent < in
typ e I
• Precip itants: GIB, overdiuresis, infection, p aracentesis, drugs (aminoglycosides,

NSAIDs)
• Rx: Typ e 1: octreotide (100–2 00 mcg SC tid) + midodrine (7.5–12 .5 mg PO tid,
titrate to ↑ MAP 15 mmHg) + 2 0–40 g/d albumin or terlip ressin + albumin (He p
2 010;51:576); definitive Rx = liver tx. Typ e 2 w/ refractory ascites → TIPS.
Hepatocellular carcinoma (HCC) (He p 2 011;53:102 0; Lance t 2 012 ;379:12 45)
• Ep i: worldwide, 6th most p revalent cancer, 3rd most frequent cancer-related death,
8 0% of cases due to HCV/HBV cirrhosis, in which annual risk of HCC is ~3–8 %
(Gastro 2 012 ;142 :12 64). ↑’d risk w/ cirrhosis of any typ e but esp . w/ viral, HFE,
PBC, ?ɑ1-AT.
• Clinical: asx vs. hep atic decomp ensation (eg, ascites, PSE), PVT w/ tumor thrombus
• Dx: screen cirrhotics q6mo w/ U/S ± AFP, though many centers choose dual p hase
CT/MRI (if arterial enhancing & venous p hase or delayed washout, no bx req for
dx)
• Rx: radiofre que ncy ablation (RFA) for HCCs <3 cm in size; consider re se ction if
single lesion <2 cm and Child-Pugh A w/o p ortal HTN; transarte rial
che moe mbolization (TACE) p referred for large cancers (not curative) or if not
amenable to RFA (near IVC/lung); consider live r transplant if up to 3 HCCs ≤3 cm
or 1 HCC ≤5 cm
• Comp lications of Rx in 2 –11% , p rocedure mortality ~0.5% . RFA → PVT, colon
p erforation, abscess, skin burn, PTX, subcap sular hematoma, AKI, diap hragm
injury. TACE → p ostembolization syndrome (PES) = nausea, RUQ p ain, ileus,
fever, ↑ ALT/AST; self-limited, resolves w/in 1 wk. Other: hep atic ischemia,
abscess (2 % ), biliary tree injury, cholecystitis, gastroduodenal ulceration (~5% ),
kidney injury (2 % ).
Other complications
• Coagulopathy (NEJM 2 011;365:147): comp lex balance of p ro- & anti-hemostatic
drivers ↑ bleeding: ↓ p lts (sequestration & ↓ Tp o) & ↓ clotting factors, renal dysfxn
↑ clotting: ↑ vWF & factor VIII, ↓ p rotein C, S, ATIII
• Hepatopulmonary syndrome (HPS) (NEJM 2 008 ;358 :2 378 )
Definition/etiology: abnl p ulm gas exchange (A-a gradient ≥15 or Pa O 2 <8 0) +

intrap ulm vascular shunting w/o intrinsic p ulm disease; ? due to ↑ p ulmonary
NO
S/S: p latyp nea-orthodeoxia, clubbing, cyanosis
Dx w/ contrast echo showing p ulm A-V shunt (op ac. in LA 3–6 cycles after RA)
Rx: O 2 ; p otential embolization if large vessel on CT, ? TIPS, liver tx only

definitive Rx
• Portopulmonary hypertension (POPH) ( J Clin Gastr 2 011;45:703): ↑ PAP (MPAP

>2 5 mmHg), PVR >2 40 dyns/cm 5 and PAOP <15 mmHg. Due to p ulm
vasoconstriction from ↑ endothelin in ESLD. If PASP ≥40 mmHg by TTE → RHC.
• Cirrhotic cardiomyopathy: ↓ inotrop ic & chronotrop ic resp onse, ↓ systolic and

diastolic fxn, p rolonged QT, hyp erkinetic circulation; ↑ trop onin, BNP (JACC
2 010;56:539)
• Infxn: Kup ffer cell (hep atic mΦ ) dysfxn, ↓ op sonic activity; vaccinate for HAV &
HBV, influenza yearly, p neumococcal vaccine, avoid PPIs? (Alim Pharm The r
2 012 ;36:8 66)
• Endocrine: diabetes (15–30% ) due to altered glc & insulin metabolism; ↑ frequency of
adrenal insufficiency in ESLD (He p 2 012 ;55:12 8 2 )
Prognosis
• MELD (Model for End-Stage Liver Disease): used to stratify Pts on liver tx list & to
p redict 3-mo survival in Pts w/ cirrhosis and some acute forms of liver disease.
Based on Cr, INR, & total bili. Calculator:
www.mayoclinic.org/meld/mayomodel6.html (Gastro 2 011;14:1952 ). If MELD
<2 1 additional p redictors of mortality include Na <130 (NEJM 2 008 ;359:1018 ;
Clin Gastro He p 2 009;7:12 36), refractory ascites, ↑ HVPG and low QoL.
Liver transplantation
• Undertake evaluation when MELD ≥15
• Indic: recurrent/severe encep h, refractory ascites, SBP, recurrent variceal bleeding,

HRS, HPS, HCC (if no single lesion is >5 cm or ≤3 lesions with largest ≤3 cm),
acute liver failure
• Contraindic: inadequate social sup p ort, active substance abuse (EtOH w/in 6 mo),
sep sis, significant comorbidity (eg, PoPH w/ MPAP ≥45 mmHg refractory to Rx),
extrahep atic cancer, p ersistent noncomp liance
• Survival: 1-y up to 90% , 5-y up to 8 0% , though lower with HCV; autoimmune liver
disease, such as AIH/PBC/PSC may recur in 10–30% of allografts
OTHER ETIOLOGIES OF CIRRHOSIS
Hemochromatosis (He p 2 011;54:32 8 ; BMJ 2 011;342 :2 18 )

• Recessive disorder of iron sensing or transport leading to tissue iron deposition
• HFE mutations (8 5% of cases), typ ically C2 8 2 Y homozygotes (~0.5% of N.

Europ ean Caucasians), rarely C2 8 2 Y/H63D comp ound heterozygotes; C2 8 2 Y
homozygotes: 2 8 % of develop sx (8 8 % lab abnl), and 1% of develop sx
(due to menses ↓ Fe load → later p resentation). C2 8 2 Y/H63D: only 1.5% manifest
dis.
• Non-HFE mutations: hemojuvelin, hep cidin, transferrin recep tor 2 , & ferrop ortin
• 2 ° Fe overload: thalassemia, PRBC transfusion, MDS, EtOH, NASH (NEJM
2 012 ;366:348 )
• Sx: fatigue & arthralgias. In advance d dise ase (rare): bronze skin (melanin + iron),
hyp ogonadism (esp . in juvenile onset), DM, arthrop athy (MCP), CHF, infxns
(Vibrio, Liste ria, Ye rsinia), cirrhosis (↑ risk if EtOH/fatty liver disease; 15% risk of
HCC). Disease also a/w ALS (H63D homozygotes) & p orp hyria.
• Dx: fasting iron sat >45% (iron/TIBC × 100% ); ↑ ferritin (acute p hase reactant, so
p oor Sp ; often nl in young Pts). If ↑ iron sat. → ✓ HFE to confirm dx, imaging by
MRI (black liver) If HFE & ferritin >1000 ng/mL or ↑ LFTs → liver bx for
quant Fe index & to stage fibrosis
• Treatment: p hlebotomy (2 50 mL = 1 unit, ~2 50 mg of Fe) qwk until Fe sat <50%

& ferritin 50–100 μg/L, then q3–4mo; avoid vit C, PPI (↓ intestinal iron transp ort);
deferoxamine or deferasirox if p hleb. contraindic.; genetic counseling
Wilson’s disease (J He p 2 012 ;56:671)
• Recessive disorder of cop p er transp ort (mutation in ATP7B) → cop p er overload;

p rimarily affects liver, but also other tissues (brain, eye)
• Ep idemiology: 1 in 40,000, majority p resent b/t 5 & 35 y/o, only 3% of Pts p resent
>40 y/o
• Extrahep atic s/s: neuro ψ disease, p arkinsonism & movement disorder
(hep atolenticular disease), Kayser-Fleischer rings ( in 99% w/ neuro ψ but in
<50% w/ hep atic disease), Coombs hemolytic anemia, renal disease
• Dx: ↑ 2 4-h urine Cu, ↓ serum cerulop lasmin (Se 90% ), rarely p enicillamine
challenge w/ ↑ urine Cu excretion, liver bx w/ hep atic Cu content. In acute live r
failure , AΦ /bili <4 + AST/ALT >2 .2 better Se & Sp than urine Cu or
cerulop lasmin (He patolog y 2 008 ;4:1167).
• Treatment: chelation w/ p enicillamine + p yridoxine; 2 nd line trientine (↓ toxicity
w/ similar efficacy). Zinc: ↓ intestinal Cu transp ort and can help delay disease;
best used if asx or in conjunction w/ chelation (must give 4–5 h ap art from
chelators).
ɑ1-antitryp sin deficiency (ɑ1-AT) (NEJM 2 009;360:2 749; Clin Gas He p 2 012 ;10:575)
• Abnl ɑ1-AT → p olymerization in liver (cirrhosis) & uninhibited p rotease activity in

lung (emp hysema). Affects 1/3000 of Europ ean ancestry. Varied p resentations:
neonatal hep atitis in infants; cholestatic jaundice in kids; ↑ AST/ALT or cirrhosis
in kids/adults.
• Extrahep atic disease: emp hysema, necrotizing p anniculitis, ANCA vasculitis

(Wegener)
• Dx: serum ɑ1-AT level (acute p hase reactant), level <50% of nl typ ically diagnostic;
gold standard = p henotyp ing of p rotease inhibitor (Pi); Z is high-risk allele (ZZ =
liver dis); S is “slow” allele (SZ = liver or lung dz); M is nl (MZ ? ↑ risk of dis);
null/null → no ɑ1-AT p rotein, ∴ only emp hysema and not liver dis (no
p olymerization)
liver bx shows characteristic PAS cytop lasmic inclusion bodies
• Treatment: standard Rx for cirrhosis/chronic liver dis.; ɑ1-AT rep lacement for
emp hysema
Primary biliary cirrhosis (PBC) (He patolog y 2 009;50:2 91; Lance t 2 011;377:1600)
• Autoimmune destruction of intrahe patic bile ducts; may be triggered by certain infxns
or toxins; a/w X monosomy, variants in IL12 ɑ & IL12 recep tor genes (NEJM
2 009;360:2 544)
• Ep i: 40–60 y/o; a/w Sjögren’s, Raynaud’s, scleroderma, celiac & thyroid disease
• Sx (late): fatigue, p ruritus, jaundice, steatorrhea, xanthelasma, autonomic & cog

dysfxn
• Ddx: PSC, autoimmune hep atitis (overlap syndrome), sarcoid, meds, idiop athic
adult ductop enia, biliary stricture/cancer
• Dx: ↑ AΦ , ↑ bili, ↑ IgM, ↑ chol, antimitochondrial Ab (AMA) in 95% . If

AMA, liver bx not needed due to high Se & Sp . 0.5% gen p op AMA & nl LFTs
→ 10% develop PBC at 6 y. If AMA , liver bx (Pts often ANA, smooth
muscle Ab; same p rognosis as AMA).
• Rx: ursodeoxycholic acid (13–15 mg/kg/d) regardless of stage
~2 5% comp lete resp onse, ↑ survival & ↓ histologic change & comp lications (eg,
varices) (Gastro 2 005;12 8 :2 97). Trials of colchicine, MTX, budesonide if
refractory to urso.
Pruritus: cholestyramine (give 2 –4 h after UDCA); if refractory sx: naltrexone,

rifamp in
Fat-soluble vitamins; screen/Rx osteop orosis (risk indep endent of vit Δ deficiency)
If ESLD: liver tx: ~2 0% recur but no imp act on long-term survival
Primary sclerosing cholangitis (PSC) (Live r Transpl 2 008 ;14:735)
• Diffuse inflammation of intrahe patic and e xtrahe patic bile ducts leading to fibrosis &
stricturing of biliary system. A/w HLA-B8 and -DR3 or -DR4, frequent
autoantibodies but p oor resp onse to immunomodulator Rx suggesting
nonautoimmune p athogenesis.
• Ep i: > (2 0–50 y). ~70% of Pts w/ PSC have IBD (usually UC); only 1–4% w/
UC get PSC.
• Clinical sx: fatigue, p ruritus, jaundice, fevers, RUQ p ain, cholangioca., ↑ Tb, ↑ AΦ
• Ddx: extrahep atic obstruction, PBC, may also have overlap w/ AIH and similar
p resentation to IgG4 autoimmune cholangitis (steroid resp onsive) (Gastro
2 008 ;134:706)
• Dx: MRCP ± ERCP → multifocal be ade d bile duct stricture s, but may miss dx if
confined to small intrahep atic ducts (~2 % “small duct PSC” : better p rognosis,?
different disease). Liver bx may show “onion-skin” fibrosis around bile ducts, but
not necessary for dx, p lays role in excluding autoimmune sclerosing cholangitis.
• Treatment: sup p ortive care, fat-soluble vitamins; no meds have imp roved survival
Ursodeoxycholic acid may ↓ colon CA risk in Pts w/ UC & imp rove LFTs in Pts
w/o UC Dominant stricture: endoscop ic dilation, short-term stenting or surgical
resection Cholangiocarcinoma (2 0% ): ? biannual surveillance w/ MRCP/RUQ U/S
and CA19-9 Liver transp lantation: ~30% recurrence, though if UC, colectomy may
↓ recurrence
HEPATIC VASCULAR DISEASE
Portal vein thrombosis (PVT) (Al Phar The r 2 009;30:8 8 1; J He patol 2 012 ;56:S1)
• Definition: thrombosis, constriction or invasion of p ortal vein → p ortal HTN →
varices. Isolated sp lenic vein thrombosis (eg, 2 ° to p ancreatitis) → isolated gastric
varices.
• Etiologies: cirrhosis, neop lasm (p ancreas, HCC), abdominal infxn → p ylep hlebitis
(infected thrombosis of PVT), hyp ercoag state (incl MPS), p ancreatitis, IBD,
surgery, trauma
• Clinical manifestations
acute PVT: can p /w p ain; often asx and dx as incidental finding on U/S or CT if
mesenteric vein involved may p /w intestinal infarct; if fever consider
p ylep hlebitis
chronic PVT: asx/incidental finding; may p /w s/s of p ortal HTN → hematemesis
2 ° variceal bleeding, sp lenomegaly, mild encep h; ascites uncommon unless
cirrhosis
• Diagnostic studies: LFTs usually normal; U/S w/ Dop p ler, MRA, CT (I+),
angiograp hy;
“p ortal cavernoma” network of hep atop edal collaterals in chronic PVT—can
rarely cause biliary obstruction and cholestatic LFTs = p ortal cholangiop athy
(may require surgery)
• Treatment: eval for underlying cause (cirrhosis, MDS, hyp ercoag); if cirrhotic, Rx
less clear
acute: LMWH → warfarin × 6 mo, or indefinitely if irreversible cause (excep t
cirrhosis),
chronic: anticoag if noncirrhotic or hyp ercoag state; unclear if benefit > bleed
risk
ppx: LMWH may p revent PVT & liver decomp in advanced cirrhosis (Gastro
2 012 ;143:12 53)
Varices: screen at dx; no evidence for 1° p p x of bleed; if bleed endoscop ic Rx and

bB. If refractory bleed consider TIPS, shunt. Isolated gastric varices 2 ° sp lenic
vein thrombosis: sp lenectomy is curative.
Budd-Chiari syndrome (J He patol 2 012 ;56:S1)
• Occlusion of hep atic vein(s) or IVC → sinusoidal congestion and p ortal HTN
• Etiol: ~50% due to myelop roliferative disorder a/w JAK2 mutations (esp . P. ve ra),
other hyp ercoag state, tumor invasion (HCC, renal, adrenal), IVC webs, trauma,
1/ idiop athic
4
• Symp toms: hep atomegaly, RUQ p ain, ascites, dilated venous collaterals
• Dx: ± ↑ aminotransferases & AΦ ; Dop p ler U/S of hep atic veins (8 5% Se & Sp ); CT
(I+) or MRI/MRV → vein occlusion or ↑ caudate lobe (sep arate venous drainage);
“sp ider- web” p attern on hep atic venograp hy; liver bx showing congestion (r/o
right-sided CHF)
• Treatment: anticoag (LMWH → warfarin); consider thrombolysis acutely; if short
stenosis stent may be p ossible; consider TIPS (↑ occlusion risk c/w side-to-side
p ortocaval shunt); liver transp lant if hep atic failure or failed shunt (J Gastro Surg
2 012 ;16:2 8 6)
Sinusoidal obstruction syndrome (SOS) (J He patol 2 012 ;56:S1)

• Occlusion of hepatic venules and sinusoids (formerly veno-occlusive disease)
• Etiologies: HSCT, chemo (esp . cyclop ho), XRT, Jamaican bush tea
• Clinical manifestations: hep atomegaly, RUQ p ain, ascites, weight gain, ↑ bilirubin
• Dx: U/S w/ reversal of p ortal flow, but often not help ful; dx made clinically (↑ bili,
wt gain/ascites and RUQ p ain) or, if necessary, by liver bx or HVPG (>10 mmHg)
• Treatment (2 0% mortality): sup p ortive; ? defibrotide (adenosine agonist ↑ TPA

levels)
• Pp x: defibrotide; ursodeoxycholic acid for high-risk HSCT p op ; ? use of low-dose
hep arin
Figure 3-8 Hep atic vasculature

ASCITES
Pathophysiology
• Portal hyp ertension → systemic vasodilatation (? due to release of NO) → ↓ effective

arterial volume → renal Na retention
• ↓ serum oncotic p ressure from hyp oalbuminemia; ↑ hep atic lymp h p roduction
Symptoms
• ↑ abd girth, wt gain, new abd hernia, abd p ain, dysp nea, nausea, early satiety
Evaluation (JAMA 2 008 ;2 99:1166; He patolog y 2 009;2 9:2 08 7)
• Physical exam: flank dullness (NPV ~90% ; >1500 mL needed), shifting dullness (Se
~8 3% )
• Radiologic: U/S detects >100 mL; MRI/CT (also help with Ddx)
• Paracentesis (NEJM 2 006;355:e2 1; Dig Dis Sci 2 007;52 :3307): p erform in all Pts w/
new ascites and consider in all hosp italized cirrhotics w/ ascites; comp lic. <1%
(bleeding, but risk not related to PT or p lt count; He patolog y 2 004;40:48 4); U/S ↑
success but does not ↓ comp lic.
• Serum-ascites albumin gradient (SAAG): ~95% acc. for p ortal HTN (Annals
1992 ;117:2 15)
≥1.1 g/dL → p ortal hyp ertension related; <1.1 g/dL → non–p ortal hyp ertension
related
if p ortal HTN + another cause (seen in ~5% of cases) SAAG still ≥1.1
if known cirrhosis and SAAG <1.1 but no other readily identifiable cause, likely
just cirrhosis (Am J Gastro 2 009;104:1401)
• Ascites fluid total p rotein (AFTP): useful when SAAG ≥1.1 to distinguish cirrhosis
(AFTP <2 .5 g/dL) from cardiac ascites (AFTP ≥ 2 .5 g/dL)
• Rule out infection: cell count w/ diff + Gram stain/cx define bacterial p eritonitis
(see later); bedside inoculation of cx bottles ↑ yield to 90% (Gastro 198 8 ;95:1351)
fungal cx if p rolonged hosp , abx use; AFB cx + adenosine deaminase to r/o TB
• Other tests: amylase (p ancreatitis, gut p erforation); triglycerides (chylous ascites);

cytology (p eritoneal carcinomatosis, ~95% Se w/ 3 samp les); LDH, glc, CEA, AΦ
(p erforation)
Treatment
• If 2° to portal HTN (see “Cirrhosis” for details): ↓ Na intake + diuretics

(sp ironolactone + furosemide); if refractory → large-volume p aracentesis or TIPS
• If non–p ortal HTN related: dep ends on underlying cause (TB, malignancy, etc.)
• Vap tans ↑ Na, mobilize ascites, but no morb/mort benefit (Al Pharm & The r
2 012 ;36:619)
Bacterial peritonitis (Gut 2 012 ;61:2 97)
• SBP/CNNA: seen in cirrhosis (qv) b/c ascites have ↓ op sonins; rare in other causes
• NNBA: often resolves w/o Rx; follow closely → Rx only if sx or p ersistently culture
• Secondary intra-abdominal abscess or p erforation so often p olymicrobial ascitic

fluid TP >1 g/dL, glc <50 mg/dL, LDH >2 2 5 U, CEA >5, AΦ >2 40 Rx: 3rd-
gen. cep h + metronidazole; urgent abdominal imaging ± ex lap
• Peritoneal dialysis-associated: cloudy fluid, abd p ain, fever, nausea p athogens:
70% GPC, 30% GNR; Rx: vanc + gent (IV load, then administer in PD)
BILIARY TRACT DISEASE
CHOLELITHIASIS (GALLSTONES)
Epidemiology & pathogenesis (J He p 2 008 ;48 :S12 4)
• >10% adults in the U.S. have gallstones; a/w ↑ overall mortality (Gastro
2 011;140:508 )
• Bile = bile salts, p hosp holip ids, cholesterol; ↑ cholesterol saturation in bile +
accelerated nucleation + gallbladder hyp omotility → gallstones
• Risk factors: ; South, Central, Native American; ↑ age (>40 y), obesity,
p regnancy, TPN, rap id ↓ wt; drugs (OCPs, estrogen, clofibrate, octreotide,
ceftriaxone); ileal disease
• ? statin use >1 y ↓ risk of sx gallstones & cholecystectomy (JAMA 2 009;302 :2 001)
Types of gallstones
• Cholesterol (90% ): 2 subtyp es

mixed: contain >50% cholesterol; typ ically smaller, multip le stones
p ure: 100% cholesterol; larger, yellow, white ap p earance
• Pigment (10% )
Black: unconjugated bilirubin (chronic hemolysis, cirrhosis) and calcium
Brown: stasis & infection in bile ducts → bacteria deconjugate bilirubin →

p recip itates w/ calcium; seen w/ duodenal diverticula, biliary strictures,
p arasites
• May be asx; biliary p ain in ~2 % /y; once sx, rate of comp lications ~2 % /y
• Biliary pain (“colic”) = episodic RUQ or epigastric abd pain that begins
abrup tly, is continuous, resolves slowly and lasts for 30 min–3 h; ± radiation to
scap ula; nausea
• May be precipitated by fatty foods
• Physical exam: afebrile, ± RUQ tenderness or ep igastric p ain
Diagnostic studies
• RUQ U/S: Se & Sp >95% for stones >5 mm; can show comp lications
(cholecystitis); should be p erformed only after fasting ≥8 h to ensure distended,
bile-filled gallbladder
Treatment
• Cholecystectomy (CCY), usually lap aroscop ic, if symp tomatic
• CCY in asx Pts w/: GB calcification (~7% risk of ca) (Surg e ry 2 001;12 9:699), GB
p olyp s >10 mm, Native American, stones >3 cm or bariatric surgery or cardiac
transp lant candidates
• Ursodeoxycholic acid (rare) for cholesterol stones w/ uncomp licated biliary p ain or
if p oor surgical candidate; also reduces risk of gallstone formation with rap id wt
loss
• Biliary p ain: NSAIDs (eg, diclofenac 50 mg IM) drug of choice, efficacy op iates &
↓ comp lications (Alime nt Pharmacol The r 2 012 ;35:1370)
Complications
• Cholecystitis: 2 0% of sx biliary p ain → cholecystitis w/in 2 y
• Choledocholithiasis → cholangitis or gallstone p ancreatitis
• Mirizzi’s syndrome: common hep atic duct comp ression by cystic duct stone →
jaundice, biliary obstruction
• Cholecystenteric fistula: stone erodes through gallbladder into bowel
• Gallstone ileus: SBO (usually at term ileum) due to stone in intestine that p assed thru
fistula
• Gallbladder carcinoma (~1% in U.S.)
CHOLECYSTITIS (NEJM 2008; 358:2804)
Pathogenesis
• Acute cholecystitis: stone imp action in cystic duct → inflammation behind

obstruction → GB swelling ± secondary infection (50% ) of biliary fluid
• Acalculous cholecystitis: gallbladder stasis and ischemia → inflammatory resp onse;

occurs mainly in critically ill, hosp . Pts (p ostop major surgery, TPN, sep sis,
trauma, burns, op iates, immunosup p ression, infxn [eg, CMV, Crypto,
Campylobacte r, typ hoid fever])
• History: RUQ/ep igastric p ain ± radiation to R shoulder/back, nausea, vomiting,

fever
• Physical exam: RUQ tenderness, Murp hy’s sign = ↑ RUQ p ain and insp iratory
arrest with deep breath during p alp ation of R subcostal region, ± p alp able
gallbladder
• Laboratory evaluation: ↑ WBC, ± mild ↑ bilirubin, AΦ , ALT/AST and amylase;

AST/ALT >500 U/L, bili >4 mg/dL or amylase >1000 U/L → choledocholithiasis
Diagnostic studies
• RUQ U/S: high Se & Sp for stones, but need spe cific sig ns of chole cystitis: GB wall
thickening >4 mm, p ericholecystic fluid and a sonograp hic Murp hy’s sign
• HIDA scan: most Se test (8 0–90% ) for acute cholecystitis. IV inj of HIDA (selectively
secreted into biliary tree). In acute cholecystitis, HIDA enters BD but not GB. 10–
2 0% false (cystic duct obstructed from chronic cholecystitis, lengthy fasting,
liver disease).
Treatment
• NPO, IV fluids, nasogastric tube if intractable vomiting, analgesia

• Antibiotics (E. coli, Kle bsie lla and Ente robacte r sp . are usual p athogens) ([2 nd- or
3rd-generation cep halosp orin or FQ] + MNZ) or p ip eracillin-tazobactam
• Early CCY (usually w/in 72 h). Delaying surgery 2 –3 mo ↓ op erative time w/o Δ
rate of comp lications or conversion to op en p rocedure (Am J Surg 2 008 ;194:40).
• If unstable for surgery, EUS-guided transmural or ERCP-guided transcystic duct

drainage is equivalent to cholecystostomy (Gastro 2 012 ;142 :8 05)
• Intraop erative cholangiogram or ERCP to r/o choledocholithiasis in Pts w/ jaundice,

cholangitis or stone in BD on U/S
Complications
• Gangrenous cholecystitis: necrosis w/ risk of emp yema and p erforation
• Emp hysematous cholecystitis: infection by gas-forming organisms (air in GB wall)
• Post CCY: bile duct leak, BD injury or retained stones, cystic duct remnant, sp hincter
of Oddi dysfxn
CHOLEDOCHOLITHIASIS
Definition
• Gallstone lodged in bile duct (BD)
Epidemiology
• Occurs in 15% of Pts w/ gallbladder stones; can form de novo in BD
• Asymp tomatic (50% )
• RUQ/ep igastric p ain due to obstruction of bile flow → ↑ BD p ressure, jaundice,

p ruritus, nausea
Diagnostic studies
• Labs: ↑ bilirubin, AΦ ; transient sp ike in ALT or amylase suggests p assage of stone
• RUQ U/S: BD stones seen ~50% of cases; usually inferred from dilated BD (>6 mm)
• ERCP p referred dx modality when likelihood high; cholangiogram (p ercutaneous,
op erative) when ERCP unavailable or unsuccessful; EUS/MRCP to exclude BD
stones when susp icion low
Treatment
• ERCP & p ap illotomy w/ stone extraction (± lithotrip sy)
• CCY typ ically w/in 6 wk unless contraindication (>15% Pts will develop indication
for CCY if left unRx’d)
Complications
• Cholangitis, cholecystitis, p ancreatitis, stricture

CHOLANGITIS
Definition & etiologies
• BD obstruction → infection p roximal to the obstruction
• Etiologies: BD stone (~8 5% )

Malignant (biliary, p ancreatic) or benign stricture
Infection w/ fluke (Clonorchis sine nsis, Opisthorchis vive rrini)
• Charcot’s triad: RUQ p ain, jaundice, fever/chills; p resent in ~70% of Pts

• Reynolds’ p entad: Charcot’s triad + shock and Δ MS; p resent in ~15% of Pts
Diagnostic studies
• RUQ U/S
• Labs: ↑ WBC, bilirubin, AΦ , amylase; BCx
• ERCP; p ercutaneous transhep atic cholangiogram (if ERCP unsuccessful)
Treatment
• Antibiotics (broad sp ectrum) to cover common bile p athogens (see above) amp icillin
+ gentamicin (or levofloxacin) ± MNZ (if severe); carbap enems; p ip /tazo
• ~8 0% resp ond to conservative Rx and abx → biliary drainage on elective basis
• ~20% require urgent biliary decompression via ERCP (p ap illotomy, stone

extraction and/or stent insertion). If sp hincterotomy cannot be p erformed (larger
stones), decomp ression by biliary stent or nasobiliary catheter can be done;
otherwise p ercutaneous transhep atic biliary drainage or surgery.
ACID-BASE DISTURBANCES
GENERAL
Definitions
• Acidemia → p H <7.36, alkalemia → p H >7.44
• Acidosis → p rocess that increases [H+]; alkalosis → p rocess that decreases [H+]
• Primary disorders: metabolic acidosis or alkalosis, resp iratory acidosis or alkalosis

• Comp ensation
resp iratory: hyp er- or hyp oventilation alters Pa CO 2 to counteract 1° metabolic
p rocess renal: excretion/retention of H+/HCO 3 to counteract 1° resp iratory
p rocess resp iratory comp ensation occurs in minutes; renal comp ensation takes
hours to days compe nsation ne ve r fully corre cts pH; if p H normal, consider
mixed disorder
Workup
• Determine primary disorder: ✓ p H, Pa CO 2 , HCO 3
• Determine if degree of compensation is ap p rop riate

Mixed disorders (more than one p rimary disorder at the same time)
• If comp ensation less or greater than p redicted, may be 2 disorders:
Pa CO 2 too low → concomitant 1° resp . alk.
Pa CO 2 too high → concomitant 1° resp . acid.
HCO 3 too low → concomitant 1° met. acid.
HCO 3 too high → concomitant 1° met. alk.
• Normal p H but …
↑ Pa CO 2 + ↑ HCO 3 → resp . acid. + met. alk.
↓ Pa CO 2 + ↓ HCO 3 → resp . alk. + met. acid.
normal Pa CO 2 & HCO 3, but ↑ AG → AG met. acid. + met. alk.
normal Pa CO 2 , HCO 3, & AG → no disturbance or non-AG met. acid. + met. alk.
• Cannot have resp . acid. (hyp oventilation) and resp . alk. (hyp erventilation)
simultaneously
Figure 4-1 Acid-base nomogram

• ABG vs. VBG: concordant for p H (~0.04), HCO 3 (~2 mEq) but not Pa CO 2 (~8 ±17
mmHg) VBG can be used to scre e n for hyp ercarbia w/ Pa CO 2 cutoff ≥45 mmHg
(100% Se), but does not accurately assess de g re e of hyp ercarbia (Am J Eme rg Me d
2 012 ;30:8 96)
METABOLIC ACIDOSIS
Initial workup (Nat Re v Ne phol 2 010;6:2 74)
• ✓ anion gap (AG) = Na+ – (Cl - + HCO 3-) = unmeasured anions - unmeasured
cations
if ↑ glc, use measured not corrected Na
exp ected AG is [albumin] × 2 .5 (ie, 10 if albumin is 4 g/dL, 7.5 if albumin is 3
g/dL)
↑ AG → ↑ unmeasured anions such as organic acids, p hosp hates, sulfates
↓ AG → ↓ alb or ↑ unmeasured cations (Ca, Mg, K, Li, bromine, immunoglobulin)
• If ↑ AG, ✓ delta-delta (ΔΔ = DAG/DHCO 3) to assess if there is an additional

metabolic acid-base disturbance; DAG = (calculated AG – exp ected AG), DHCO 3 =
(2 4 – HCO 3)
ΔΔ = 1–2 → p ure AG metabolic acidosis
ΔΔ < 1 → AG metabolic acidosis and simultaneous non-AG acidosis

ΔΔ > 2 → AG metabolic acidosis and simultaneous metabolic alkalosis
Workup for AG metabolic acidosis

• ✓ for ketonuria (dip stick acetoacetate) or p lasma b-hydroxybutyrate (bOHB) nb,
urine acetoacetate often not p resent in early ketoacidosis due to shunting to bOHB;
∴ acetoacetate may later turn , but does not signify worsening disease
• If ketones, ✓ renal function, lactate, toxin screen, and osmolal gap
• Osmolal gap (OG) = measured osmoles – calculated osmoles
calculated osmoles = (2 × Na) + (glucose / 18 ) + (BUN / 2 .8 ) (can +

[EtOH/4.6] if have EtOH level and want to test if other ingestions)
OG >10 → suggests ingestion (see below)
for methanol/ethylene glycol: early on, OG p recedes AG; later OG may be nl

with AG
Workup for non-AG metabolic acidosis (CJASN 2 012 ;7:671)
• Evaluate history for causes (see above)
• ✓ urine anion gap (UAG) = (U Na + U K) – U Cl
UAG = unmeasured anions – unmeasured cations; as NH 4+ is p rimary

unmeasured cation, UAG is indirect assay for renal NH 4+ excretion (NEJM
198 8 ;318 :594)
• UAG → ↑ renal NH 4+ excretion → ap p rop riate renal resp onse to acidemia
Ddx: GI causes, p roximal RTA, ingestions or dilutional
• UAG → failure of kidneys to secrete NH 4+ Ddx: distal or hyp oaldo RTA, early
renal failure
nb, p lasma K usually ↓ in distal and ↑ in hyp oaldo RTA
• UAG evaluation assumes Pt volume rep lete (U Na >2 5) & no AG met. acid. (which
causes UAG due to excretion of organic anions)
Renal tubular acidoses (RTAs) (JASN 2 002 ;13:2 160; Int J Clin Pract 2 011;65:350)
• Proximal (Typ e II): ↓ p roximal reabsorp tion of HCO 3
1° (Fanconi’s syndrome = ↓ p roximal reabsorp tion of HCO 3, PO 4, glc, amino

acids), p arap rotein (multip le myeloma, amyloidosis), meds (acetazolamide,
heavy metals, ifosfamide), renal transp lant, ↓ Vit D, NRTIs
• Distal (Typ e I): defective distal H+ secretion

1°, autoimmune (Sjögren’s, RA), nep hrocalcinosis, meds (amp ho, Li, ifosfamide);
normally a/w ↓ K; if with ↑ K → sickle cell, obstruction, SLE, renal transp lant
• Hypoaldo (Typ e IV): ↑ K → ↓ NH 3 synthesis/delivery → ↓ urine acid carrying

cap acity
↓ renin: diabetic nep hrop athy, NSAIDs, chronic interstitial nep hritis, HIV
normal renin, ↓ aldo synthesis: 1° adrenal disorders, ACEI, ARBs, hep arin
↓ resp onse to aldosterone

meds: K-sp aring diuretics, TMP-SMX, p entamidine, calcineurin inhibitors
tubulointerstitial disease: sickle cell, SLE, amyloid, diabetes

• Combined (Typ e III): rarely discussed or clinically relevant, also called juvenile RTA,
has distal & p roximal features, can be due to carbonic anhydrase II deficiency
Figure 4-2 Approach to metabolic acidosis

Treatment of severe metabolic acidoses (pH <7.2) (Nat Re v Ne phol 2 012 ;8 :58 9)
• DKA: insulin & IVF; AKA: dextrose, IVF, rep lete K, Mg, PO 4 as needed
• Lactic acidosis: treat underlying condition, avoid vasoconstrictors
• Renal failure: hemodialysis

• Methanol & ethylene glycol: early fomep izole, vit. B 6 (ethylene glycol), folate
(methanol), hemodialysis (esp . if late p resentation) (NEJM 2 009;360:2 2 16)
• Alkali therap y: NaHCO 3 (eg, three 50-mmol amp s in 1 L D5W) to get serum HCO 3
>8 and p H >7.2 (estimate mmol of HCO 3 needed as 8 -[HCO 3]serum × wt ×
0.5) side effects: ↑ volume, ↑ Na, ↓ ICa, ↑ Pa CO 2 (& ∴ intracellular acidosis),
overshoot
No p roven benefit in lactic acidosis or DKA (Annals 198 6;105:8 36 &

1990;112 :492 )
• THAM (p roton accep tor) in Pts w/ ↑ Pa CO 2

METABOLIC ALKALOSIS
Pathophysiology
• Saline-resp onsive etiologies require initiating e ve nt and mainte nance phase
• Initiating e ve nt: gain of HCO 3 or loss of acid
loss of H+ from GI tract or kidneys

exogenous alkali: iatrogenic HCO 3 administration, milk alkali syndrome
contraction alkalosis: diuresis → excretion of HCO 3-p oor fluid → extracellular

fluid “contracts” around fixed amount of HCO 3 → ↑ HCO 3 concentration
posthypercapnia: resp iratory acidosis → renal comp ensation with HCO 3

retention; rap id correction of resp iratory disorder (eg, with intubation) →
transient excess HCO 3
• Mainte nance phase
volume depletion → ↑ p roximal reabsorp tion of NaHCO 3 and ↑ aldosterone (see

next)
hyperaldosteronism (either 1° or 2 °) → distal Na reabsorp tion in exchange for

K+ and H+ excretion (and consequent HCO 3 retention)
hypokalemia → transcellular K+/H+ exchange; intracellular acidosis in renal

p roximal tubular cells p romotes bicarbonate reabsorp tion and ammoniagenesis
Workup
• Check volume status and U Cl
U Cl <2 0 mEq/L → saline-resp onsive
U Cl >2 0 mEq/L → saline-resistant (unless currently receiving diuretics)
(U Na unreliable determinant of volume status as alkalemia → ↑ HCO 3 excretion

→ ↑ Na excretion; negatively charged HCO 3 “drags” Na+ along)
If U Cl >2 0 and volume rep lete, ✓ blood pressure
Figure 4-3 Ap p roach to metabolic alkalosis
Treatment of severe metabolic alkalosis (pH >7.6)
• If volume dep letion: d/c diuretics and correct volume deficit with isotonic saline If
cardiop ulmonary disease p recludes hydration, can use KCl, acetazolamide, HCl
• If NGT drainage that cannot be stop p ed: PPI
• Hyp eraldosteronism: treat underlying condition

RESPIRATORY ACIDOSIS
Etiologies
• CNS depression: sedatives, CNS trauma, O 2 in chronic hyp ercap nia (↓ hyp oxemic
drive), central sleep ap nea
• Neuromuscular disorders: myasthenia gravis, Guillain-Barré, p oliomyelitis, ALS,

muscular dystrop hy, severe hyp op hosp hatemia, high sp inal cord injury, drugs
(p aralytics)
• Upper airway abnormalities: acute airway obstruction, laryngosp asm, obstructive
sleep ap nea, esop hageal intubation
• Lower airway abnormalities: asthma, COPD
• Lung p arenchyma abnormalities (often cause hyp oxia → ↑ RR → resp . alk., but
eventual muscle fatigue → resp . acid.): p neumonia, p ulmonary edema, restrictive
lung disease
• Thoracic cage abnormalities: p neumothorax, flail chest, kyp hoscoliosis
• Post infusion of bicarbonate in acidemic Pt w/ limited ability to ↑ minute ventilation

RESPIRATORY ALKALOSIS
Etiologies (NEJM 2 002 ;347:43)

• Hypoxia → hyperventilation: p neumonia, p ulm. edema, PE, restrictive lung disease
• Primary hyperventilation
CNS stimulation, p ain, anxiety, fever, trauma, stroke, voluntary
drugs: salicylates, p rogesterone, methylxanthines, nicotine p regnancy, sep sis,
hep atic failure
• Pseudorespiratory alkalosis: ↓ p erfusion w/ p reserved ventilation (eg, CPR, severe
HoTN) → ↓ delivery of CO 2 to lungs for excretion; low Pa CO 2 but ↑ tissue CO 2
SODIUM AND WATER HOMEOSTASIS
OVERVIEW
General
• Disorders of serum sodium are generally due to Ds in total body wate r, not sodium
• Hyp er- or hyp o-osmolality → rap id water shifts → Ds in brain cell volume → Δ MS,
seizures
Key hormones
• Antidiuretic hormone (ADH): p rimary hormone that regulates sodium conce ntration
stimuli for secretion: hyp erosmolality, ↓↓ effective arterial volume (EAV),
angiotensin II action: insertion of aquap orin-2 channels in collecting ducts →
p assive water reabsorp tion urine osmolalityis an indirect functional assay of the
ADH-renal axis U osm range: 60 mOsm/L (no ADH) to 12 00 mOsm/L (maximal
ADH)
• Aldosterone: p rimary hormone that regulates total body sodium (and ∴ volume)
stimuli for secretion: hyp ovolemia (via renin and angiotensin II), hyp erkalemia
action: iso-osmotic reabsorp tion of sodium in exchange for p otassium or H +
HYPONATREMIA
Pathophysiology
• Excess of water relative to sodium; almost always due to ↑ ADH
• ↑ ADH may be appropriate (eg, hyp ovolemia or hyp ervolemia with ↓ EAV)
• ↑ ADH may be inappropriate (SIADH)
• Rarely, ↓ ADH (ap p rop riately sup p ressed), but kidneys unable to maintain nl
[Na]serum
1° polydipsia: ingestion of massive quantities (usually >12 L/d) of free H 2 O

overwhelms diluting ability of kidney (normal dietary solute load ~750
mOsm/d, minimum U osm = 60 mOsm/L → excrete in ~12 L; if H 2 O ingestion
exceeds this amount → H 2 O retention)
“te a & toast” and “be e r potomania”: ↓↓ daily solute load, ↑ free H 2 O →
insufficient solute to excrete H 2 O intake (eg, if only 2 50 mOsm/d, minimum
U osm = 60 mOsm/L → excrete in ~4 L; if H 2 O ingestion exceeds this amount
→ H 2 O retention)
Workup (NEJM 2 000;342 :158 1; JASN 2 012 ;2 3:1140)
• History: (1) acute vs. chronic (>48 h); (2 ) sx severity; (3) risk for neuro
comp lications (alcoholism, malnourished, cirrhosis, older females on thiazides,
hyp oxia, hyp oK)
• Measure plasma osmolality
Hypotonic hyponatre mia most common scenario; true excess of free H 2 O relative to
Na Hype rtonic hyponatre mia: excess of another effective osmole (eg, glc,
mannitol) that draws H 2 O intravascularly; each 100 mg/dL ↑ glc >100 mg/dL
→ ↓ [Na] by 2 .4 mEq/L Isotonic hyponatre mia: rare lab artifact from
hyp erlip idemia or hyp erp roteinemia
• For hyp otonic hyp onatremia, ✓ volume status (vital signs, orthostatics, JVP, skin
turgor, mucous membranes, p erip heral edema, BUN, Cr, uric acid)
• U osm diagnostically useful in limited circumstances, because almost always >300

excep tions: U osm <100 in 1° p olydip sia & ↓ solute intake moreover, U osm >300
≠ SIADH; must determine if ↑ ADH ap p rop riate or inap p rop riate however, U osm
imp ortant when deciding on tre atme nt (see below)
• If euvolemic and ↑ U osm , evaluate for glucocorticoid insufficiency and

hyp othyroidism
Figure 4-4 Approach to hyponatremia

Hypovolemic hypotonic hyponatremia (ie, ↓↓ total body Na, ↓ TBW)
• Renal losses (U Na >2 0 mEq/L, FENa >1% ): diuretics (esp . thiazides, as loop
diuretics
↓ tonicity of medullary interstitium and imp air urine concentrating ability), salt-
wasting nep hrop athy, cerebral salt wasting, mineralocorticoid deficiency
• Extrarenal losses (U Na <10 mEq/L, FENa <1% ): GI losses (eg, diarrhea), third-
sp acing (eg, p ancreatitis), inadequate intake, insensible losses
Euvolemic hypotonic hyponatremia (ie, ↑ TBW relative to total body Na)

• SIADH (eu- or mild hyp ervolemia, inap p rop ↑ U Osm , normal U Na , ↓ BUN & UA)
malignancy: lung, brain, GI, GU, lymp homa, leukemia, thymoma, mesothelioma
pulmonary: p neumonia, TB, asp ergillosis, asthma, COPD, PTX, p ressure

ventilation
intracranial: trauma, stroke, hemorrhage, infxn, hydrocep halus, Guillan-Barré

syndrome
drugs: antip sychotics, antidep ressants (esp . SSRIs), chemotherap y, AVP, MDMA
miscellaneous: p ain, nausea, p ostop erative state
• Endocrinopathies: ↑ ADH activity seen in g lucocorticoid de ficie ncy (co-secretion of

ADH & CRH) and se ve re hypothyroidism/myxe de ma coma (↓ CO & ↓ GFR)
• Psychogenic polydipsia (U osm <100, ↓ uric acid): usually requires intake >12 L/d
• Low solute (↓ U Na , ↓ U osm ) “tea & toast” ; “beer p otomania”
• Reset osmostat: chronic malnutrition (↓ intracellular osmoles) or p regnancy

(hormonal effects) → ADH p hysiology reset to regulate a lower [Na]serum
Hypervolemic hypotonic hyponatremia (ie, ↑ total body Na, ↑ ↑ TBW)
• CHF (↓ CO → ↓ EAV; U Na <10 mEq/L, FENa <1% )
• Cirrhosis (sp lanchnic arterial vasodilation + ascites → ↓ EAV; U Na <10 mEq/L,

FENa <1% )
• Nephrotic syndrome (hyp oalbuminemia → edema → ↓ EAV; U Na <10 mEq/L,
FENa <1% )
• Advanced renal failure (diminished ability to excrete free H 2 O; U Na >2 0 mEq/L)
Treatment (Curr Opin Ne phrol Hype rte ns 2 010;19:493)

• Approach: dep ends on volume status, acuity of hyp oNa, and if symptomatic
Asx or chronic symp tomatic: correct [Na]serum at rate of ≤0.5 mEq/L/h
Acute sx: initial rap id correction of Na (2 mEq/L/h for the first 2 –3 h) until sx
resolve
Rate of ↑ Na should not e xce e d 6 (chronic) to 8 (acute) mEq/L/d to avoid central
p ontine myelinolysis/osmotic demyelination syn. (CPM/ODS: p arap legia,
dysarthria, dysp hagia)
• Frequent lab draws and IVF rate adjustments are cornerstones of treatment
• Overly rapid correction: can lead to CPM/ODS. Should be emergently reversed w/
dDAVP ± D5W; p artial neurologic recovery p ossible (CJASN 2 008 ;3:331)
• Effect of IV fluids (http ://www.medcalc.com/sodium.html)
howe ve r, above assumes entire infusate retained without any output of Na or H 2 O if

Pt euvolemic, as in SIADH, infused Na will be excreted eg, 1 L NS (154 mEq of Na
or 308 mOsm of solute in 1 L free H 2 O) given to Pt with SIADH with U osm = 616
→ 308 mOsm solute excreted in 0.5 L H 2 O → net gain 0.5 L H 2 O → ↓ [Na]serum
∴ normal saline can worse n hyp onatremia 2 ° SIADH if U osm > infusateosm
• Hypovolemic hyponatremia: volume rep letion with normal saline at a slow rate.
Once volume rep lete → stimulus for ADH removed → kidneys excrete free H 2 O →
serum Na will correct very rap idly (D5W ± ddAVP if overcorrection) (KI
2 009;76:58 7).
• SIADH (NEJM 2 007;356:2 064): free water restrict + treat underlying cause
hypertonic saline (± loop diuretic) if sx or Na fails to ↑ w/ free H 2 O restriction

1 L hyp ertonic saline (3% NaCl) will raise [Na]serum by ~10 mEq (see above)
~50 mL/h will ↑ [Na] by ~0.5 mEq/L/h; 100–2 00 mL/h will ↑ [Na] by ~1–2
mEq/L/h formula only p rovides estimate; ∴ recheck serum Na frequently (at
least q2 h)
salt tabs: p articularly if chronic and no CHF
aquaresis: conivap tan (IV V1a & V2 vasop ressin recep tor antag) or tolvap tan
(oral V2 antag; NEJM 2 006;355:2 099); used for symp tomatic SIADH resistant to
above Rx but rate of correction can be rap id (AJKD 2 010;56:32 5)
demeclocycline: causes nep hrogenic DI, ↓ U osm
• Hypervolemic hyponatremia: free water restrict

mobilize excess Na & H 2 O (use loop diuretics; avoid thiazides) & ↑ EAV
(vasodilators to ↑ CO in CHF, colloid infusion in cirrhosis)
aquaresis: tolvap tan effective and safe, however no p roven mortality benefit,
hyp oNa recurs after stop p ing drug, exp ensive and must monitor for
overcorrection (JASN 2 010;2 1:705; J He patol 2 012 ;56:571)
HYPERNATREMIA
Pathophysiology (NEJM 2 000;342 :1493)

• Deficit of water relative to sodium; by definition, all hyp ernatremic Pts are
hyp ertonic
• Usually loss of hypotonic fluid (ie “dehydration” ); occasionally infusion of
hyp ertonic fluid
• And impaired access to free water (eg, intubation, Δ MS, elderly): hyp ernatremia is
a p owerful thirst stimulus, ∴ usually only develop s in Pts w/o access to H 2 O
Workup
• ✓ U osm , U Na , volume status (vital signs, orthostatics, JVP, skin turgor, BUN, Cr)
Figure 4-5 Ap p roach to hyp ernatremia
Extrarenal H2 O loss (U osm >700–800)
• GI H2 O loss: vomiting, NGT drainage, osmotic diarrhea, fistula
• Insensible loss: fever, exercise, ventilation
Renal H2 O loss (U osm <700–800)
• Diuresis: osmotic (glc, mannitol, urea), loop diuretics
• Diabetes insipidus (J Clin Endocrinol Me tab 2 012 ;97:342 6)
ADH deficiency (central) or resistance (nep hrogenic)

Central: hyp othalamic or p osterior p ituitary disease (congenital, trauma/surgery,
tumors, infiltrative/IgG4); also idiop athic, hyp oxic encep halop athy, anorexia,
EtOH
Nephrogenic (Annals 2 006;144:18 6)
congenital (ADH recep tor V2 mutation, aquap orin-2 mutation; Pe diatr Ne phrol
2 012 ;2 7:2 18 3)
drugs: lithium, amp hotericin, demeclocycline, foscarnet, cidofovir metabolic:

hypercalcemia, severe hypokalemia, p rotein malnutrition, congenital
tubulointerstitial: postobstruction, recovery phase of ATN, PKD, sickle cell,
Sjögren’s, amyloid, p regnancy (p lacental vasop ressinase)
DI usually p resents as se ve re polyuria and mild hype rnatre mia
Other (U osm >700–8 00)
• Na overload: hyp ertonic saline (eg, resuscitation w/ NaHCO 3), mineralocorticoid

excess
• Seizures, ≠ exercise: ↑ intracellular osmoles → H 2 O shifts → transient ↑
[Na]serum
Treatment
• Restore access to H2 O or sup p ly daily requirement of H 2 O (≥1 L/d)
• Replace free H2 O deficit (also rep lace concurrent volume deficit if ap p rop riate):
eg, 1 L D5W given to 70-kg man w/ [Na] = 160 mEq/L will ↓ [Na]serum by 3.7
mEq
• Rate of Ø of Na should not exceed 0.5 mEq/L/h to avoid cerebral edema shortcut:
in 70-kg man, 12 5 mL/h of free H 2 O will ↓ [Na] by ~0.5 mEq/L/h
• 1/2 NS (77 mEq/L) or 1/4 NS (38 mEq/L) p rovides both volume & free H 2 O (500 or
750 mL of free H 2 O p er L, resp ectively); can give free H 2 O via NGT/OGT
• Formulas p rovide only estimates; ∴ recheck serum Na frequently
• DI and osmotic diuresis: see “Polyuria” section below
• Na overload: D5W + diuretic

POLYURIA
• Polyuria defined as >3 L UOP p er day
• Due to an osmotic or a wate r diure sis; almost always due to osmotic diuresis in
inp atients
Workup
• Perform a timed urine collection (6 h sufficient) and measure U osm
• 2 4-h osmole excretion rate = 2 4-h UOP (actual or estimate) × U osm
>1000 mOsm/d → osmotic diuresis
<8 00 mOsm/d → water diuresis

Osmotic diuresis
• Etiologies
Glucose (uncontrolled diabetes mellitus)
Mannitol
Urea: recovering ARF, ↑ p rotein feeds, hyp ercatabolism (burns, steroids), GI bleed
NaCl administration
Prop ylene glycol

Water diuresis
• Etiologies: diabetes insipidus (DI) (Na serum >140) or 1° polydipsia (Na serum
<140) see “Hyp ernatremia” above for list of causes of central and nep hrogenic DI
• Workup of DI: U osm <300 (comp lete) or 300–600 (p artial)
water deprivation test (start in a.m., ✓ Na serum , Posm , U osm , UOP q1–2 h)
Dep rive until Posm >2 95, then ✓ U osm . If U osm <300, then administer
vasop ressin (5 U SC) or dDAVP (10 µg intranasal), then check U osm in 1–2 h:
U osm ↑ by >50% = central DI U osm unchanged = nep hrogenic DI
✓ ADH level before and after water dep rivation to evaluate p rop er resp onse
Figure 4-6 Approach to polyuria

Treatment
• 1º polydipsia: treat p sychiatric illness, check meds, restrict access to free H 2 O
• Osmotic diuresis: address underlying cause, rep lace free H 2 O deficit (see
“Hyp ernatremia” for formula to calculate) and ongoing losses
• DI:
central DI: desmop ressin (dDAVP)
nep hrogenic DI: treat underlying cause if p ossible; Na restriction + thiazide (mild
volume dep letion → ↓ delivery of filtrate to dysfxnal diluting segment of
kidney), consider amiloride for lithium-induced DI (Kid Int 2 009;76:44)
p regnancy-induced DI: due to vasop ressinase from p lacenta, ∴ Rx w/ dDAVP

POTASSIUM HOMEOSTASIS
Overview (Annals 2 009;150:619)

• Renal: p otassium excretion regulated at distal nephron (collecting tubule) distal Na
delivery & urine flow: Na absorp tion → lumen electronegative → K secretion
metabolic alkalemia and aldosterone: increase Na absorp tion and K secretion
• Transcellular shifts: most common cause of acute change in serum p otassium Acid-
base disturbance: K+/H+ exchange across cell membranes Insulin → stimulates
Na-K ATPase → hyp okalemia (mitigates p ostp randial ↑ K) Catecholamines →
stimulate Na-K ATPase → hyp okalemia; reversed by b-blockers Digoxin → blocks
Na-K ATPase → hyp erkalemia Massive necrosis (eg, tumor lysis, rhabdo, ischemic
bowel) → release of intracellular K Hyp o- or hyp erkalemic p eriodic p aralysis:
rare disorders due to channel mutations
• Diet: alone rarely causes ↑ or ↓ K (total body store ~3500 mEq, daily intake ~100
mEq)
HYPOKALEMIA
Transcellular shifts
• Alkalemia, insulin, catecholamines, hyp okalemic/thyrotoxic p eriodic p aralysis,

acute ↑ in hematop oiesis (megaloblastic anemia Rx w/ B 12 , AML crisis),
hyp othermia, chloroquine, barium/cesium intoxication, antip sychotic overdose
(risp eridone, quetiap ine)
GI potassium losses (U K<2 5 mEq/d or <5 mEq/L or TTKG <3)
• GI losses plus metabolic acidosis: diarrhea, laxative abuse, villous adenoma

• Vomiting & NGT drainage usually manifest as re nal losse s due to 2 ° hyp eraldo &
met. alk.
Renal potassium losses (U K>30 mEq/d or >15 mEq/L or TTKG >7)
• Hyp otensive or normotensive acidosis: DKA, RTA [p roximal RTA (typ e II) and some
distal RTAs (typ e I)] alkalosis: diuretics, vomiting/NGT drainage (via 2 °
hyp eraldosteronism) Bartter’s syndrome (loop of Henle dysfxn → furosemide-like
effect; NEJM 1999;340:1177)
Gitelman’s syndrome (distal convoluted tubule dysfxn → thiazide-like effect)
↓ Mg: ? release Mg-mediated inhib. of ROMK channel ∴ ↑ K secretion (JASN

2 007;18 :2 649)
• Hyp ertensive: mineralocorticoid excess
1° hyp eraldosteronism (eg, Conn’s syndrome, glucocorticoid-remediable

aldosteronism)
2 ° hyp eraldosteronism (eg, renovascular disease, renin-secreting tumor)
nonaldosterone mineralocorticoid (eg, Cushing’s, Liddle’s, exogenous

mineralocort., licorice, congenital adrenal hyp erp lasia)
• Nausea, vomiting, ileus, weakness, muscle cramp s, rhabdomyolysis, p olyuria
• ECG: U waves, ± ↑ QT interval, ventricular ectop y (PVCs, VT, VF)
Workup (NEJM 1998 ;339:451)

• Rule-out transcellular shifts
• ✓ 2 4-h U K and transtubular potassium gradient (TTKG) = (U K/PK) / (U osm /Posm )
U K >30 mEq/d or >15 mEq/L or TTKG >7 → renal loss
U K <2 5 mEq/d or <15 mEq/L or TTKG <3 → extrarenal loss
• If renal losses, ✓ BP, acid-base, U Cl (U Na unreliable for volume status w/

alkalemia)
Figure 4-7 Ap p roach to hyp okalemia

Treatment
• If true potassium de ficit: potassium repletion (↓ 1 mEq/L 2 00 mEq total body

loss) KCl 40 mEq PO q4–6h if nonurgent, KCl 10 mEq/h IV if urgent, recheck K
freq
• Beware of excessive p otassium rep letion if transcellular shift cause of hyp okalemia
• Treat underlying cause (if hydration needed, avoid dextrose-containing solutions as

dextrose → ↑ insulin → intracellular p otassium shifts)
• Rep lete low Mg: IV Mg-SO 4 1–2 g q2 h (oral Mg-oxide p oorly tolerated b/c diarrhea)
Causes of low Mg: GI loss (diarrhea, byp ass, p ancreatitis, malnutrition, PPI);
renal loss (diuretics, nep hrotoxic drugs, EtOH, ↑ Ca, 1° wasting syndromes,
volume exp ansion)
HYPERKALEMIA
Transcellular shifts (BMJ 2 009;339:1019)

• Acidemia, insulin defic. (DM), b-blockers, dig intox., massive cellular necrosis
(tumorlysis, rhabdo, ischem. bowel, hemolysis), hyp erkalemic p eriodic p aralysis,
succinylcholine
Decreased GFR
• Any cause of oliguric or anuric AKI or any cause of end stage renal disease
Normal GFR but with Ø renal K excretion

• Normal aldosterone function
↓ EAV (K excretion limited by ↓ distal Na delivery & urine flow): CHF, cirrhosis
excessive K intake: in conjunction with imp airment in K excretion or
transcellular shift ureterojejunostomy (absorp tion of urinary K in jejunum)
• Hypoaldosteronism: same as etiologies of hyp oaldo RTA (typ e IV)

↓ renin: diabetic nep hrop athy, NSAIDs, chronic interstitial nep hritis, HIV normal
renin, ↓ aldo synthesis: 1° adrenal disorders, ACEI, ARBs, hep arin
↓ resp onse to aldosterone meds: K-sp aring diuretics, TMP-SMX, p entamidine,

calcineurin inhibitors tubulointerstitial disease: sickle cell, SLE, amyloid,
diabetes
• Weakness, nausea, p aresthesias, p alp itations

• ECG: p eaked T waves, ↑ PR interval, ↑ QRS width, loss of P wave, sine wave
p attern, PEA/VF (ECG: low sensitivity, cardiac arrest can be first electrical
manifestation!)
Workup (Crit Care Me d 2 008 ;36:32 46)
• Rule out p seudohyp erkalemia (IVF with K, hemolysis during venip uncture, ↑ p lt or
WBC)
• Rule out transcellular shift
• Assess GFR, if normal: Consider ↓ distal Na delivery and urine flow

✓ transtubular K gradient (TTKG) = (U K/PK)/(U osm /Posm ) <6 c/w hyp oaldo
(JASN 2 008 ;19:42 4)
• Rate of onse t imp ortant to note when establishing a treatment p lan
• Calcium help s p revent/treat cardiac comp lications; ∴ should be initial Rx, esp . if
ECG Ds
• Insulin, bicarbonate (esp . if acidemic), and b2 agonists should follow to ↓ p lasma K
• Treatments that eliminate total body K essential as other Rxs will wear off with
time; Kayexalate ± diuretics may be effective in many cases, but emergent
hemodialysis should be considered in life-threatening situations
• Patient information for diet education:

http ://www.kidney.org/atoz/content/p otassium.cfm
RENAL FAILURE
ACUTE KIDNEY INJURY (AKI)
Definition (CJASN 2 008 ;3:8 44; KI Suppl 2 012 ;2 :19)

• AKI: abrup t (<48 h) ↑ Cr ≥0.3 mg/dL, ↑ Cr ≥50% , or UOP <0.5 mL/kg/h for ≥6
h additional gradations based on further ↑ Cr & ↓ UOP, but not used clinically
• Cannot estimate GFR using Cr in setting of AKI or D’ing Cr (requires steady state)
Workup (Lance t 2 012 ;38 0:756)
• H&P: recent p rocedures & meds; thirst; VS & vol status; s/s of obstruction, vasc or
systemic dis.; ischemia (p rerenal & ATN) accounts for >50% of in-hosp ital AKI
• Urine evaluation: outp ut, urinalysis, sediment, electrolytes, and osmolality
• Fractional excretion of sodium (FENa) = (U Na /PNa )/(U Cr /PCr )
<1% → p rerenal, contrast, HRS or glomerulonep hritis; >2 % → ATN In setting

of diuretics, ✓ FEUN = (U UN/PUN)/(U Cr /PCr ); <35% → p rerenal
• Renal U/S or CT: r/o obstruction & eval kidney size to estimate chronicity of kidney
disease
• Serologies (if indicated): see “Glomerular Disease”
• Renal bx: may be necessary if cause remains unclear (esp if hematuria and/or
p roteinuria)
Contrast-induced acute kidney injury (CIAKI)
• Risk factors: CKD, DM, CHF, age, hyp otension, ↑ contrast volume (JACC
2 004;44:1393)
• Clinical: Cr ↑ 2 5% or 0.5 mg/dL w/in 48 h, p eaks in 3–5 d, resolves in 7–10 d
• Prevention (NEJM 2 006;354:379; JAMA 2 006;2 95:2 765; KI Suppl 2 012 ;2 :69)
Isotonic IV fluids (unless contraindic, eg, CHF): 3 mL/kg/h × 1 h before, 1

mL/kg/h × 6 h after (JAMA 2 004;2 91:2 32 8 ); NaHCO 3 ? more effective than
NaCl (Annals 2 009;151:631)
Hold ACEI/ARB (AJKD 2 012 ;60:576), NSAIDs, diuretics

N-acetylcysteine 12 00 mg PO bid on day p rior to & day of contrast; safe & ∴
reasonable in high-risk Pts, but benefit remains unclear (JACC CV Inte rv
2 009;2 :1116; Circ 2 011;12 4:12 50) Minimize contrast volume and consider iso-
osmolar contrast (JACC 2 006;48 :692 ) ? high-dose statin (Circ 2 012 ;12 6:3008 )
No p roven benefit to Pp x RRT in addition to above, may be harmful (Am J Me d
2 012 ;12 5:66)
• Gadolinium: can cause AKI in stage IV CKD (Ne ph Dial Trans 2 006;2 1:697), no
effective Pp x Nep hrogenic systemic fibrosis: fibrosis of skin, joints, eyes, and
internal organs ~2 –4 wk p ost exp osure in Pts w/ mod-severe CKD (JACC
2 009;53:162 1). ? role of p ostgado HD (Radiat Me d 2 006;2 4:445). Rx is ↑ renal
function, p hysical therap y. Can be irreversible.
Treatment
• Treat underlying disorder (see relevant sections); ? steroids if AIN (KI 2 008 ;73:940)
• Prerenal: Isotonic IVF alb (NEJM 2 004;350:2 2 ), HES (starch) nep hrotoxic (NEJM
2 012 ;367:12 4)
• Avoid nep hrotoxic insults; review dosing of renally cleared drugs

• Op timize hemodynamics (both MAP & CO); may take 1–2 wk to recover from ATN
• Watch for and correct volume overload, electrolyte (↑ K, ↑ PO 4), & acid/base status
• If obstruction is diagnosed and relieved, watch for:
Hyp otonic diuresis (2 ° buildup of BUN, tubular damage); Rx w/ IVF (eg, 1/2 NS)
Hemorrhagic cystitis (rap id Δ in size of bladder vessels); avoid by decomp ressing

slowly
• Indications for urgent dialysis (when condition refractory to conventional therap y)
Acid-base disturbance: acidemia
Electrolyte disorder: generally hyp erkalemia; occasionally hyp ercalcemia, tumor

lysis
Intoxication: methanol, ethylene glycol, lithium, salicylates (Kid Int 2 009;75:1349)
Overload of volume (CHF)

Uremia: p ericarditis, encep halop athy, bleeding
• No benefit to dop amine (Annals 2 005;142 :510), diuretics (JAMA 2 002 ;2 8 8 :2 547), or
mannitol
CHRONIC KIDNEY DISEASE (CKD)
Definition and etiologies (Lance t 2 012 ;379:165)

• ≥3 mo of reduced GFR (<60) and/or kidney damage (p ath, markers, imaging)
• Prevalence 13% in U.S.; Cr p oor estimate of GFR; ∴ use p rediction equation, eg,
MDRD or CKD-EPI: www.kidney.org/p rofessionals/KDOQI/gfr_calculator.cfm nb,
equation may underestimate GFR in Pts w/ normal renal fxn, esp MDRD
• Etiologies: DM (45% ), HTN/RAS (2 7% ), glomerular (10% ), interstitial (5% ), PKD
(2 % ) (NEJM 2 008 ;359:1477), congenital, drugs, myeloma, p rogression of AKI
(JAMA 2 009;302 :1179)
• Presence and degree of albuminuria a/w worse outcomes indep endent of GFR
• Rates of all-cause mortality and CV events increase with each stage of CKD and are
significantly higher than the rate of p rogression to kidney failure (NEJM
2 004;351:12 96)
Treatment (Annals 2 009;150:ITC2 -1; NEJM 2 010;362 :57)
• General: nep hrology referral when GFR <30 and access p lanning (avoid subclavian
lines; p reserve an arm for access by avoiding blood draws, BP measurements,
IVs); Rx CV risk factors (eg, smoking, LDL-C; Lance t 2 011;377:2 18 1), vaccines
(flu, PNA, HBV)
• Dietary restrictions: Na (if HTN), K (if oliguric or hyp erkalemic), PO 4, ? moderate

p rotein restriction, strict glc control in DM
• BP Control: goal <130/8 0, start with ACEI (or ARB), effective in DM & nondiabetic
CKD (NEJM 2 004;351:1952 ); likely no benefit of ACEI + ARB (BMJ
2 013;346:f360). For outPts, ✓ Cr & K in 1–2 wk, d/c if Cr ↑ 30% or K >5.4 (after
dietary Δ & loop diuretic).
• Metabolic acidosis: sodium bicarbonate or sodium citrate if low HCO 3 (JASN

2 009;2 0:2 075)
• Anemia: goal Hb ~10 g/dL, worse outcomes if higher (NEJM 2 006;355:2 08 5 &
2 009;361:2 019) ep oetin (start 8 0–12 0 U/kg SC, divided 3×/wk) or darbep oetin
(0.45 µg/kg q wk) iron sup p lementation to keep transferrin sat >2 0% (often given
IV in HD Pts)
• Uremic bleeding: desmop ressin (dDAVP) 0.3 µg/kg IV or 3 µg/kg intranasally
• 2° Hyperparathyroidism: ↑ PO 4, ↓ Ca, ↓ calcitriol → ↑ PTH → renal osteodystrop hy
p hosp horus binders (take with me als!) (NEJM 2 010;362 :1312 )

if ↑ PO 4 and ↓ Ca → calcium acetate (PhosLo) or calcium carbonate
if refractory ↑ PO 4 or in setting of ↑ Ca → sevelamer (Renagel), lanthanum
(Fosrenol)
if severe ↑ PO 4 → aluminum hydroxide (Amp hojel), short-te rm use only
vit. Δ or analogue (p aricalcitol) if 2 5-(OH)D <30, stop if ↑ Ca (AJKD

2 009;53:408 ) calcitriol or p aricalcitol if Ca-PO 4 p roduct <55 (? ↑ survival in HD
Pts, NEJM 2 003;349:446) cinacalcet (p arathyroid calcium-sensing recep tor agonist)
if PTH remains elevated desp ite p hosp horus binders ± vit. Δ analogue (NEJM
2 004;350:1516; NDT 2 011;2 6:132 7) p arathyroidectomy
• Consider transplant evaluation

DIURESIS
General considerations
• Increases Na excretion for treatment of HTN or edema in CHF, renal failure, and
cirrhosis
• Daily wt most effective method of documenting successful diuresis
Loop diuretics (NEJM 1998 ;339:38 7)

• Drugs: furosemide (Lasix), torsemide, bumetanide (Bumex), ethacrynic acid
• Mechanism: inhibit Na-K-2 Cl transp orter in thick ascending limb (ThAL) Transient,
immediate venodilation may aid in p ulmonary congestion (NEJM 1973;2 8 8 :108 7)
Resp onse is fxn of amt of drug excreted; ∴ ↑ dose needed in renal insufficiency,
CHF Sigmoidal dose resp onse curve; ∴ ↑ dose until induce diuresis, ↑↑ dose
beyond that p oint yields diminishing returns comp ared with ↑ frequency of dosing
• Dosing: PO bioavailability of furosemide ~50% , ∴ IV dose ~2 × as p otent as PO

dose torsemide & bumetanide ~90% bioavailability; use ethacrynic acid if sulfa
allergy 40 mg furosemide PO 2 0 mg furosemide IV 2 0 mg torsemide PO
1 mg bumetanide dose furosemide bid-qid; qd dosing can lead to initial
diuresis → antinatriuresis Continuous vs. bolus IV: similar results in acute CHF
(NEJM 2 011;364:797)
? ↑ diuresis w/ co-administration of albumin if ↓ serum albumin (Crit Care Me d

2 005;33:168 1)
Thiazide diuretics (NEJM 2 009;361:2 153)

• Drugs: hydrochlorothiazide (HCTZ), chlorothiazide (Diuril), metolazone (Zaroxolyn)
• Mechanism: inhibit Na-Cl cotransp orter in the distal convoluted tubule (DCT)
synergistic with loop diuretic, esp . if chronic loop use
↓ effect when GFR <30, e xce pt me tolazone which is still effective in renal
insufficiency
• Dosing: give p rior to loop diuretic, typ ically ~30 min before
K-sparing diuretics
• Drugs: sp ironolactone (Aldactone), amiloride, triamterene, ep lerenone
• Mechanism: ↓ Na reabsorp tion in collecting duct (amiloride/triamterene inhibit

p rincip al cell Na channel [ENaC]; sp ironolactone/ep lerenone inhibit
mineralocorticoid recep tor). Relatively weak natriuretic activity, useful in
combination with thiazide or in cirrhosis.
Disease state specific regimens

• Renal insufficiency: loop diuretic (↑ dose to achieve effective delivery to ThAL) ±
thiazide
• CHF: loop diuretic (↑ frequency over ↑ dose) + thiazide (watch K & Mg)
• Nep hrotic syndrome: urinary albumin binds secreted loop diuretic, use 2 –3 ×
normal dose
• Cirrhosis: sp ironolactone (blocks 2 ° hyp eraldosteronism) + lasix in 2 .5:1 ratio
• Severe metabolic alkalosis: acetazolamide & treat underlying cause
Adverse effects
• Loop : ± ↑ Na, ↓ K, ↓ Mg, ↓ Ca, hyp eruricemia, ototoxicity, hyp ersensitivity (sulfa)
• Thiazide: ↓ Na, ↓ K, ↓ Mg, ↑ Ca, hyp erlip idemia, p ancreatitis, ↑ glucose
• K-sp aring: ↑ K (esp . w/ ACEI), metabolic acidosis, gynecomastia (sp ironolactone)
RENAL REPLACEMENT AND DIALYSIS
General
• Substitutes for renal solute and fluid removal; Acute : CVVH vs. HD; Chronic: PD vs.
HD
Hemodialysis (HD) (NEJM 2 010;363:18 33)
• Physiology: blood flows along one side of se mipe rme able membrane, dialysate along
other
Fluid removal (ie, Na + H 2 O) via transmembrane p ressure (TMP) gradient
Solute removal via transmembrane concentration gradient and inversely

p rop ortional to size (∴ effective removal of K, urea, and Cr, but not PO 4)
• Typ ical orders: duration, volume removal goals, K and Ca in dialysate bath,
anticoagulation
• 6× vs. 3×/wk imp roved HTN, LV mass, QoL, but ↑ vasc issues (NEJM
2 010;363:2 2 8 7); w/ 3×/wk HD, ↑ adverse outcomes after 2 d interval (NEJM
2 011;365:1099)
• Comp lications: HoTN, arrhythmia, access issues (clot, stenosis, infxn, recirculation),
disequilibrium syndrome (sx of cerebral edema due to H 2 O shifts after removal of
p lasma urea during dialysis, esp . in new HD Pts w/ ↑ ↑ BUN), high outp ut HF
• Fever w/ catheter: emp iric abx (vanc + AG qHD). GPC > GNR > mixed/fungal.
Catheter removal, rep lacement, or “lock” abx. Consider metastatic infxn w/u
(AJKD 2 004;44:779).
Continuous veno-venous hemofiltration (CVVH) (NEJM 2 012 ;367:2 6)
• Physiology: he mofiltration rather than dialysis. Blood under p ressure p asses down
one side of hig hly pe rme able membrane allowing H 2 O and solutes to p ass across
membrane via TMP gradient (convective clearance). Filtrate discarded.
Rep lacement fluid infused (solute concentrations similar to p lasma, excep t no K,
urea, Cr, PO 4). Fluid balance p recisely controlled by adjusting filtrate/rep lacement
fluid.
• Access: double-lumen central venous catheter
• Typ ical orders: volume goals, rep lacement fluid buffer: HCO3 (requires hep arin to
p revent machine from clotting) vs. citrate (hep atically metabolized to HCO 3;
p rovides anticoagulation w/ in machine via Ca chelation; ∴ requires Ca infusion)
• Comp lications: hyp otension, ↓ PO 4, access comp lications; ↓ ICa (citrate toxicity in
Pts with hep atic dysfunction → look for ↓ ICa but normal/ ↑ serum Ca and AG met
acidosis)
• Potential advantages over HD: less hyp otension, better volume control, removal of
inflammatory mediators; however, no survival advantage (Lance t 2 006;368 :379)
• No advantage for high intensity CVVH over standard intensity (NEJM 2 008 ;359:7)
Peritoneal dialysis (PD) (Pe rit Dial Int 2 001;2 1:2 5)

• Physiology: p eritoneum acts as membrane. Fluid balance controlled by choosing
dialysate [glc] (higher concentrations p ull more fluid into p eritoneum); longer
dwell times p ull less fluid as glc equilibrates across p eritoneum
• Access: p ermanent catheter inserted in OR
• Typ ical orders for CAPD (continuous ambulatory p eritoneal dialysis):
PD fluid = dextrose (1.5% , 2 .5% , or 4.2 5% ), buffer (lactate), Na+, Ca 2 +,

Mg 2 +
infuse 10 min, dwell 90 min–5.5 h, drain 2 0 min

• Can use overnight cycler device that infuses & drains more rap idly, with shorter
dwells, while Pt sleep s. Called automated or continuous cycling p eritoneal dialysis
(APD, CCPD).
• Comp lications: hyp oalbuminemia; right-sided p leural effusion Peritonitis: abd

p ain, tenderness, cloudy drainage (WBC >100 and >50% PMNs) sp ectrum: 60–
70% GPC, 15–2 0% GNR, remainder no bacteria or fungal Rx: abx IV or in PD,
catheter removal for certain p athogens (eg, yeast, Pse udomonas) Hyp erglycemia:
exacerbated by inflammation, long dwell times, and higher [glc]
Kidney transplantation (NEJM 1994;331:365)
• Rx of choice for ESRD; contraindic: active malig, infxn, ischemia, noncomp l, subst
abuse
• Immunosup p ression: calcineurin inhib (tacrolimus, CsA), antimetabolite (AZA,

MMF), p rednisone, ± mTOR inhibitor (sirolimus) (NEJM 2 004;351:2 715)
• Late renal dysfxn: usual AKI causes + calcineurin tox, rejection, BK virus,
recurrence of 1° disease; usual w/u + immunosup p levels, BK virus load, U/S,
then bx if no other cause
• ↑ risk of infxn (incl op p ortunistic such CMV, JC, BK viruses) & malignancy (incl
PTLD)
• ↑ CVD risk due to HTN (calcineurin inhib, RAS), DM & dyslip idemia (immunosup p
meds)
GLOMERULAR DISEASE
GLOMERULONEPHRITIS (GN)
Definition (NEJM 1998 ;339:8 8 8 ; Lance t 2 005;365:1797)

• Patholog ically: intraglomerular inflammation (ranging from focal p roliferative
[<50% of glomeruli] to diffuse p roliferative to crescentic) (Lance t 2 006;368 :404)
• Clinically: hematuria w/ dysmorp hic RBCs or RBC casts, ± subnep hrotic p roteinuria
often w/ renal failure, HTN, edema
• Prog re ssion: acute GN days; rap idly p rogressive GN (RPGN) wks; chronic GN
mos; can simp ly have asx hematuria
• Crescentic GN (p athologic descrip tion) RPGN (clinical descrip tion)
Workup (Archive s 2 001;161:2 5)

• Acute GN/RPGN ± lung he morrhag e is an e me rg e ncy → requires early Dx and Rx
• ANCA (Lance t 2 006;368 :404), anti-GBM, comp lement levels
• Dep ending on clinical hx: ANA, ASLO, BCx, cryocrit, hep atitis serologies, skin bx
• Consider GN mimics
thrombotic microangiop athy: ↓ Hct & Plts, schistocytes on smear, ↑ LDH
cholesterol emboli (Lance t 2 010;375:1650): p urp le toes, livedo, ↓ C3/C4, eos,
p rior cath AIN: rash, new drug exp osure, urine WBCs (incl eos) ± WBC casts
(and UCx) myeloma: anemia, hyp ercalcemia, lytic bone lesions,
SPEP/serum free light chains
• Renal biop sy with immunofluorescence (IF) ± electron microscop y (EM)
Figure 4-8 Ap p roach to glomerulonep hritis
Treatment (Kid Int Sup 2 012 ;2 :143)

• If acute GN/RPGN susp ected, give 1 g methylp rednisolone IV qd x 3 d ASAP while
awaiting bx results, further Rx based on underlying disease (AJKD 198 8 ;11:449)
• SLE nep hritis: steroids + cyclop hosp hamide (CYC) or MMF (JASN 2 009;2 0:1103)
• ANCA or anti-GBM: p ulse steroids + CYC (or rituximab) ± p lasmap heresis

(JASN 2 007;18 :2 18 0; NEJM 2 010;363:2 2 1)
• See “Vasculitis” for further disease sp ecific treatment details

ASYMPTOMATIC GLOMERULAR HEMATURIA
Definition and etiologies
• Hematuria ± p roteinuria of glomerular origin w/o renal insufficiency or systemic

disease (nonglomerular hematuria more common; see “Hematuria” )
• Ddx: any cause of GN (esp . IgA); also consider Alp ort’s (X-linked, deafness, renal
failure), thin basement membrane nep hrop athy (autosomal dominant, benign;
JASN 2 006;17:8 13)
IgA nephropathy (NEJM 2 002 ;347:738 ; JASN 2 005;16:2 08 8 )

• Most common cause of GN; male p redominance w/ p eak incidence 2 0–30s
• Wide range of clinical p resentations: asx hematuria (30–40% ), gross hematuria ~1–
3 d after URI (30–40% ), chronic GN (10% ), nep hrotic syndrome (5% ), RPGN
(<5% )
• Though clinical p resentation can be highly suggestive, definitive dx only w/ bx
• Prognosis: 2 5–30% will reach ESRD w/in 2 0–2 5 y of p resentation

• Treatment: ACEI/ARB, ± fish oils (JASN 1999;10:1772 ); steroids (JASN
2 012 ;2 3:1108 ); ± cytotoxic therap y for crescentic GN and nep hrotic sx, consider
for p rogressive chronic GN
NEPHROTIC SYNDROME
Definition (NEJM 1998 ;338 :12 02 )

• Proteinuria >3.5 g/d, albumin <3.5 mg/dL, edema, ↑ cholesterol
Primary glomerular diseases (group ed by p athology)

• Focal segmental glomerulosclerosis (40% ; NEJM 2 011;365:2 398 ;): 1º (? ↑ soluble
urokinase recep tor; Nat Me d 2 011:17;952 ), HIV (collap sing variant), NSAIDs,
lymp homas, p amidronate, heroin, congenital, ↑ filtration from p rior nep hron
loss, obesity, vesicoureteral reflux, anabolic steroids, genetic (tryp anolytic Ap oL1
mutation in AA; Scie nce 2 010;32 9:8 41)
• Membranous nephropathy (30% ; JASN 2 012 ;2 3:1617) idiop athic (p hosp holip ase
A2 recep tor Abs; NEJM 2 009;361:11), infxn (esp . HBV, also HCV, syp hilis),
autoimmune (esp . SLE), carcinomas, drugs (NSAIDs, p enicillamine)
• Minimal change disease (2 0% , more common in children; NDT 2 003;18 :vi52 )
idiop athic, NSAIDs, Hodgkin’s disease, & other lymp hop roliferative disorders
• Membranoproliferative GN (5% , mixe d nep hrotic/nep hritic features; NEJM
2 012 ;366:1119) Immune comp lex-mediated: infection (esp . HCV ± cryos, IE,
HBV, “shunt” nep hritis, other chronic infxns), SLE, cryos, Sjögren’s, lymp homas,
dysp roteinemia, idiop athic Comp lement-med (rare); abnl C3 convertase activity,
dense dep osit dis, C3GN
• Fibrillary-immunotactoid glomerulopathy (1% ; Kid Int 2 003;63:1450)
• Mesangial proliferative GN (? atyp ical forms of MCD/FSGS, 5% ) IgM, C1q

nep hrop athy
Systemic diseases
• Diabetes mellitus: nodular glomerulosclerosis (Kimmelstiel-Wilson lesion); large

kidneys hyp erfiltration → microalbuminuria → dip stick → nep hrotic range
(10–15 y) concomitant p roliferative retinop athy seen in 90% of typ e 1 and 60% of
typ e 2
• Amyloidosis: AL or light chain amyloid or AA amyloid secondary to inflammation
• SLE: typ ically with membranous nep hrop athy (WHO class V)
• Cryoglobulinemia: typ ically with membranop roliferative GN
Workup (Archive s 2 001;161:2 5; BMJ 2 008 ;336:118 5)

• Urine sediment: usually benign; ± oval fat bodies (“Maltese crosses” ; NEJM
2 007;357:8 06)
• Measure p roteinuria: 2 4-h urine collection or urine p rot/Cr ratio (not accurate in
AKI)
• r/o 2 ° causes: ↑ HbA1C + retinop . → p resump t. dx of diab. nep hrop .; ✓ ANA, anti-
dsDNA, C3/C4, SPEP/free light chains, fat p ad bx, cryocrit, HBV/HCV, HIV, RPR,
PLA2 recep t. Ab
• Renal biop sy
Treatment (Kid Int Sup 2 012 ;2 :143; NEJM 2 013;368 :10)
• General: p rotein sup p l.; diuretics for edema; treat hyp erlip idemia, Na restriction
(<2 g/d)
• ACEI/ARB: decrease p roteinuria → slow nonimmunologic p rogression of renal

disease
• 1° glomerular dis: steroids ± cytotoxic therap y; cancer screening if membranous
nep h.
• Secondary causes: treat underlying disease

• Watch for malnutrition (p rotein loss), thrombosis (in ~2 5% , esp . renal vein, b/c
loss of ATIII & other endogenous anticoags), infxn (esp . encap s. organisms b/c loss
of Ig)
URINALYSIS
PROTEINURIA
• Urine dipstick
1+ 30 mg/dL, 2 + 100 mg/dL, 3+ 300 mg/dL, 4+ >2 g/dL;

interp retation dep ends on SG; eg, 3+ in very concentrated urine might not
indicate heavy p roteinuria
Insensitive for microalbuminuria and myeloma light chains
• Spot urine: p rotein (mg/dL)/creatinine (mg/dL) g/d of p roteinuria (NEJM

198 3;309:1543) unlike urine dip stick, will accurately measure myeloma light
chains reliable surrogate for 2 4-hr urine, esp . 1st morning void (JASN
2 009;2 0:436); inaccurate if AKI dep ends on Cr p roduction, ∴ underestimates if
muscular, overestimates if cachectic
• Microalbuminuria (30–300 mg/2 4h or mg/L or mg/mg of Cr): early sign of

glomerular vascular disease; marker for ↑ risk of CV adverse outcomes (JAMA
2 001;2 8 6:42 1)
• Orthostatic p roteinuria: typ ically in adolescents; ~90% of young with isolated

p roteinuria have orthostatic p roteinuria; typ ically resolves sp ontaneously
HEMATURIA
• Wide, overlap p ing ages for various etiologies, but general guide for common causes:
<2 0 y: GN, UTI, congenital; 2 0–60 y: UTI, nep hrolithiasis, cancer
>60 y : p rostatitis, cancer, UTI; >60 y : UTI, cancer
Workup (J Urol 2 012 ;18 8 (6 sup p l):2 473)
• Urine dipstick: if ≥3 RBCs; dip stick and sediment → myo- or

hemoglobinuria
• Urine sediment: dysmorp hic RBCs or RBC casts → GN → consider renal bx

• If no evidence of glomerulonep hritis:
r/o UTI and non-GU causes (GI or vaginal bleed)
Urine cytology (Se ~70% , Sp ~95% ), not adequate substitute for cystoscop y
Renal imaging: helical CT ± contrast (r/o nep hrolithiasis and neop lasia of up p er
tract), cystoscop y (r/o bladder neop lasia, esp . ≥35 y), ± MRI, retrograde
p yelogram, U/S
NEPHROLITHIASIS
Types of stones and risk factors (J Clin Endocrinol Me tabol 2 012 ;97:18 47)
• Calcium (Ca oxalate > Ca p hosp hate): 70–90% of kidney stones
Urine findings: ↑ Ca, ↑ oxalate (Ca-ox only), ↑ p H (Ca-p hos only), ↓ citrate, ↓
volume
2 ° hyp ercalciuria: 1° hyp erp arathyroidism, distal RTA, sarcoid

2 ° hyp eroxaluria: Crohn’s, ileal disease w/ intact colon, gastric byp ass
Diet: ↑ animal p rotein, ↑ sucrose, ↑ Na, ↓ K, ↓ fluid, ↓ fruits/vegetables, ↑ vit. C,
↓ Ca
• Uric acid: 5–10% of kidney stones, radiolucent on p lain film
Urine findings: ↑ uric acid, ↓ p H (eg, from chronic diarrhea)
• Magnesium ammonium phosphate (“struvite” or “trip le p hosp hate” )

Chronic up p er UTI w/ urea-sp litting organisms (eg, Prote us, Kle bs) → ↑ urine
NH 3, p H >7
• Cystine: inherited defects of tubular amino acid reabsorp tion
• Hematuria (absence does not exclude diagnosis), flank p ain, N/V, dysuria, frequency
• Ureteral obstruction (stones >5 mm unlikely to p ass sp ont.) → AKI if solitary
kidney
• UTI: ↑ risk of infection p roximal to stone; urinalysis of distal urine may be normal
Workup
• Noncontrast helical CT scan (ureteral dilation w/o stone suggests recent p assage)
97% sens. 96% sp ec. (AJR 2 008 ;191:396)
• Strain urine for stone to analyze; U/A & UCx; electrolytes, BUN/Cr, Ca, PO 4, PTH
• 2 4-h urine × 2 (>6 wk after acute setting) for Ca, PO 4, oxalate, citrate, Na, Cr,
p H, K, vol.
Acute treatment (NEJM 2 004;350:68 4)
• Analgesia (narcotics ± NSAIDs; combination sup erior, Ann Eme rg Me d

2 006;48 :173), ensure adequate fluid rep letion, antibiotics if UTI
• Consider alp ha blocker > CCB to p romote ureteral relaxation (Lance t
2 006;368 :1171)
• Indications for immediate urologic eval and/or hosp: obstruction (esp . solitary or
transp lant kidney), urosep sis, intractable p ain or vomiting, significant AKI
• Urologic Rx: lithotrip sy (NEJM 2 012 :367:50), stent, p erc nep hrostomy,
ureteroscop ic removal
Chronic treatment (J Clin Endocrinol Me tabol 2 012 ;97:18 47)
• Increase fluid intake (>2 L/d) for goal UOP 2 L/d
• Calcium stones: 2 4-h urine identifies specific urinary risk factors to treat
↓ Na and meat intake (NEJM 2 002 ;346:77), thiazides: decrease urine Ca

Dep ending on 2 4-h urine: K-citrate, dietary oxalate restriction, allop urinol
High dietary Ca is likely beneficial by ↓ oxalate absorp ., unclear role of Ca

sup p lements
• Uric acid: urine alkalinization (K-citrate), allop urinol
• Magnesium ammonium p hosp hate: antibiotics to treat UTI, urologic intervention,

acetohydroxamic acid: urease inhibitor, reserve for exp erienced clinician, p oorly
tolerated
• Cystine: urine alkalinization (K-citrate), D-p enicillamine, tiop ronin
NOTES
ANEMIA
↓ in RBC mass: Hct <41% or Hb <13.5 g /dL (me n); Hct <36 % or Hb <12 g /dL
(wome n)
• Symp toms: ↓ O 2 delivery → fatigue, exertional dysp nea, angina (if CAD)
• Signs: p allor (mucous membranes, p almar creases), tachycardia, orthostatic

hyp otension
• Other findings: jaundice (hemolysis), splenomegaly (thalassemia, neop lasm,
chronic hemolysis), petechiae/purpura (bleeding disorder), glossitis (iron, folate,
vitamin B 12 defic.), koilonychia (iron defic.), neurologic abnormalities (B 12
defic.)
Diagnostic evaluation
• History: bleeding, systemic illness, drugs, exp osures, alcohol, diet (including pica),
FHx
• CBC w/ diff.; RBC p arams incl. retics, MCV (nb, mixed disorder can → nl MCV),
RDW
• Reticulocyte index (RI) = [reticulocyte count × (Pt’s Hct/nl Hct)]/maturation factor

maturation factors for a given Hct: 45% = 1, 35% = 1.5, 2 5% = 2 , 2 0% = 2 .5
RI >2 % → adequate marrow resp onse; RI <2 % → hyp op roliferation
• Peripheral smear: select area where RBCs evenly sp aced and very few touch each
other; ✓ RBC size, shap e, inclusions (see Ap p endix & Perip heral Smear inserts),
WBC morp hology, p lt count
• Additional labs as indicated: hemolysis labs (if RI >2 % ), iron/TIBC, ferritin, folate,
B 12 , LFTs, BUN and Cr, TFTs, Hb electrop horesis, enzyme analyses, gene mutation
screens
• Bone marrow (BM) aspirate and biopsy (bx) with cytogenetics as indicated
Figure 5-1 Approach to anemia

MICROCYTIC ANEMIAS
Figure 5-2 Approach to microcytic anemias
Iron deficiency (NEJM 1999;341:198 6; Gut 2 011;60:1309)
• ↓ marrow iron & dep leted body iron stores → ↓ heme synthesis → microcytosis →
anemia
• Sp ecial clinical manifestations: angular cheilosis, atrop hic glossitis, p ica

(consump tion of nonnutritive substances such as ice, clay), koilonychia (nail
sp ooning) Plummer-Vinson syndrome (iron deficiency anemia, esop hageal web &
atrop hic glossitis)
• Etiologies: chronic bleeding (GI—incl. cancer, menstrual, p arasites, etc.), ↓ supply

(malnutrition; ↓ absorp . due to celiac sp rue, Crohn’s, ↑ gastric p H, subtotal
gastrectomy), ↑ demand (p reg., Ep o). Rare Fe refractory genetic disorder due to
hep cidin dysregulation (Nat Ge ne t 2 008 ;40:569).
• Diagnosis: ↓ Fe, ↑ TIBC, ↓ ferritin (esp . <15), ↓ transferrin sat (Fe/TIBC; esp .
<15% ), ↑ soluble transferrin recep tor; ↑ p lt; unless hx c/w other etiology, initiate
workup for GIB; incl. H. pylori serology, ? celiac sp rue labs (anti-TTG, antigliadin,
antiendomysial Ab)
• Treatment (Fe sup p lementation): oral Fe tid (~6 wk to correct anemia; ~6 mo to

rep lete Fe stores); in cases of excessive/p ersistent GI losses or for dialysis or
cancer Pts p rior to Ep o Rx, IV iron (Fe-sucrose, -gluconate, -dextran) should be
considered
Thalassemias (Lance t 2 013;379:373)
• ↓ synthesis of ɑ- or β-globin chains of Hb → ≠ subunits → destruction of RBCs and

erythroid p recursors; ∴ anemia from hemolysis and ineffective erythrop oiesis
• ɑ-thalassemia: deletions in ɑ-globin gene comp lex on chr. 16 (nl 4 ɑ genes)

3 ɑ → ɑ-thal-2 trait = silent carrier; 2 ɑ → ɑ-thal-1 trait or ɑ-thal minor = mild
anemia
1 ɑ → HbH (β4) disease = severe anemia, hemolysis and sp lenomegaly
0 ɑ genes → Hb Barts (γ4) = intrauterine hyp oxia and hydrop s fetalis
• β-thalassemia: mutations in β-globin gene on chr. 11 → absent or ↓ gene p roduct

1 mutated β gene → thal minor (or trait) = mild anemia (no transfusions)
2 mutated β genes → thal intermedia (occasional transfusions) or thal major ( =
Cooley’s anemia; transfusion dep endent) dep ending on severity of mutations
• Sp ecial clinical manifestations (in severe cases): chip munk facies, p athologic
fractures, hep atosp lenomegaly (due to extramedullary hematop oiesis), high-outp ut
CHF, bilirubin gallstones, iron overload syndromes (from chronic transfusions)
• Diagnosis: MCV <70, normal Fe, MCV/RBC count<13 [Mentzer Index, 60% Se,
98 % Sp ; (Ann He m 2 007;8 6:48 6)], ± ↑ retics, basop hilic stip p ling; Hb
electrophoresis: ↑ HbA2 (ɑ2 δ 2 ) in β-thal; normal p attern in ɑ-thal trait
• Treatment: folate; transfusions + deferoxamine, deferasirox (oral iron chelator);

sp len-ectomy if ≥50% ↑ transfusions; consider allo-HSCT in children w/ severe β-
thal major
Anemia of chronic inflammation (see below)
Sideroblastic anemia
• Defective heme biosynthesis within RBC p recursors

• Etiologies: hereditary/X-linked (ALAS2 mutations), idiopathic, MDS-RARS,
reversible (alcohol, lead, isoniazid, chloramp henicol, cop p er deficiency,
hyp othermia)
• Sp ecial clinical manifestations: hep atosp lenomegaly, iron overload syndromes

• Dx: review social, work & TB hx; can be microcytic, normocytic or macrocytic;
variable p op of hyp ochromic RBCs; ↑ Fe, nl TIBC, ↑ ferritin, basop hilic stip p ling,
RBC Pappenheimer bodies (Fe-containing inclusions), ring sideroblasts (w/ iron-
laden mitochondria) in BM
• Treatment: treat reversible causes; trial of p yridoxine, sup p ortive transfusions for
severe anemia; high-dose p yridoxine for some hereditary cases
NORMOCYTIC ANEMIAS
Pancytopenia (see below)

Anemia of chronic inflammation (ACI; NEJM 2 005;352 :1011; 2 009;361:1904)
• ↓ RBC p roduction due to imp aired iron utilization and functional iron deficiency
from ↑ hepcidin; cytokines (IL-6, TNF-a) cause ↓ Ep o resp onsiveness/p roduction
• Etiologies: autoimmune disorders, chronic infection, inflammation, HIV, malignancy
• Dx: ↓ Fe, ↓ TIBC (usually normal or low transferrin sat), ± ↑ ferritin; usually
normochromic, normocytic (~70% of cases) but can be microcytic if p rolonged
• Coexisting iron deficiency common. Dx clues include ↓ serum ferritin levels, absence
of iron staining on BM bx, resp onse to a trial of oral iron and/or ↑ soluble
transferrin recep tor/ferritin index (Blood 1997;8 9:1052 ).
• Treatment: treat underlying disease ± iron and/or erythrop oiesis-stimulating agent
(ESA, eg, Ep o). Iron if ferritin <100 or Fe/TIBC <2 0% . Consider ESA if Ep o
<500. Avoid ESA in cancer if treatment goal is cure (Le uk Re s 2 012 ;36:939).
Unclear if one should treat highly sx Pts w/ goal Hb 10–12 g/dL; weigh risk of
thrombosis.
Anemias of chronic disorders

• Anemia of chronic inflammation (see above)
• Anemia of chronic kidney disease: ↓ Ep o; treat w/ Ep o (see “Chronic Kidney

Disease” )
• Endocrine deficiencies: hyp ometabolism and ↓ O 2 demand with thyroid, p ituitary,
adrenal, or p arathyroid disease → ↓ Ep o; can be normocytic or macrocytic
Sideroblastic anemia (see above)

Pure red cell aplasia
• Destructive antibodies or lymp hocytes → ineffective erythrop oiesis
• Associated with thymoma, CLL and p arvovirus infection
• Diagnostic studies: lack of erythroid precursors on BM bx, other lines normal

• Treatment: thymectomy if thymus enlarged; IVIg if p arvovirus infection;
immunosup p ression if CLL or idiop athic; sup p ortive care with PRBC transfusions;
? erythrop oietin recep tor agonist if due to antierythrop oietin Ab (NEJM
2 009;361:18 48 )
MACROCYTIC ANEMIAS
include s me g aloblastic and nonme g aloblastic cause s
Megaloblastic anemia
• Impaired DNA synthesis → cytop lasm matures faster than nucleus → ineffective
erythrop oiesis and macrocytosis; due to folate or B12 deficiency; MDS
• ✓folate and vitamin B12; ↑ LDH & indirect bilirubin (due to ineffective
erythrop oiesis)
• Smear: neutrophil hypersegmentation, macro-ovalocytes, anisocytosis,
p oikilocytosis
Folate deficiency
• Folate p resent in leafy green vegetables and fruit; total body stores sufficient for 2–3
mo
• Etiologies: malnutrition (alcoholics, anorectics, elderly), ↓ absorp tion (sp rue),

imp aired metabolism (methotrexate, p yrimethamine, trimethop rim), ↑
requirement (chronic hemolytic anemia, p regnancy, malignancy, dialysis)
• Diagnosis: ↓ folate; ↓ RBC folate, ↑ homocyst. but nl methylmalonic acid (unlike

B 12 defic.)
• Treatment: folate 1–5 mg PO qd for 1–4 mo or until comp lete hematologic recovery;
critical to r/o B 12 de ficie ncy first (se e be low)
Vitamin B12 deficiency (NEJM 2 013;368 :149)
• B 12 p resent only in foods of animal origin; total body stores sufficient for 2–3 y
• Binds to intrinsic factor (IF) secreted by gastric p arietal cells; absorbed in terminal
ileum
• Etiologies: malnutrition (alcoholics, vegans), pernicious anemia (PA, autoimmune

disease against gastric p arietal cells, a/w p olyglandular endocrine insufficiency
and ↑ risk of gastric carcinoma), other causes of ↓ absorp tion (gastrectomy, sp rue,
Crohn’s disease), ↑ comp etition (intestinal bacterial overgrowth, fish tap eworm)
• Clinical manifestations: neurologic changes (subacute combined degeneration)

affecting p erip heral nerves, p osterior and lateral columns of the sp inal cord and
cortex → numbness, p aresthesias, ↓ vibratory and p ositional sense, ataxia,
dementia
• Dx: ↓ B 12 ; ↑ homocysteine and methylmalonic acid; anti-IF Ab; Schilling test; ↑

gastrin in PA
• Treatment: 1 mg B 12 IM qd × 7 d → q wk × 4–8 wk → q month for life neurologic
abnormalities are reversible if treated w/in 6 mo folate can reverse he matolog ic
abnormalities of B 12 deficiency but not ne urolog ic changes (and can lead to “steal”
of B 12 stores → worsening of neuro comp lications) oral sup p lementation (2 mg
qd) ap p ears feasible as well (Blood 1998 ;92 :1191) even w/o IF
Nonmegaloblastic macrocytic anemias
• Liver disease: often macrocytic, may see target cells

• Alcoholism: BM sup p ression & macrocytosis indep endent of folate/B 12 defic. or
cirrhosis
• Reticulocytosis
• Other causes: hyp othyroidism; MDS; meds that imp air DNA synthesis (zidovudine,
5-FU, hydroxyurea, Ara-C); hereditary orotic aciduria; Lesch-Nyhan syndrome.
PANCYTOPENIA
Etiologies
• Hyp ocellular bone marrow (nl cellularity ~100 – age): aplastic anemia,
hyp op lastic MDS
• Cellular bone marrow: MDS, aleukemic leukemia, PNH, severe megaloblastic anemia
• Marrow rep lacement (myelop hthisis): myelofibrosis, metastatic solid tumors,

granulomas
• Systemic diseases: hyp ersp lenism, sep sis, alcohol, toxins
• Anemia → fatigue
• Neutrop enia → recurrent infections
• Thrombocytop enia → mucosal bleeding & easy bruisability
Aplastic anemia = stem cell failure (Lance t 2 005;365:1647; Blood 2 012 ;12 0:118 5)
• Ep idemiology: 2 –5 cases/106/y; bip hasic (major p eak in adolescents, 2 nd p eak in

elderly)
• Diagnosis: p ancytop enia w/ ↓ retics, BM bx w/ cytogenetics showing hyp ocellularity
• Etiologies: idiopathic (1/2 – 1/3 of cases)
stem cell destruction: radiation, chemotherapy, chemicals (eg, benzene)

idiosyncratic med rxn (eg, chloramp henicol, NSAIDs, sulfa drugs, gold,
carbamazep ine, antithyroid)
viruses (HHV-6, HIV, EBV, p arvovirus B19); also post-hepatitis (non A, B or C)
immune disorders (SLE, GVHD p ost-HSCT, thymoma)
PNH (see below); Fanconi’s anemia (congenital disorder w/ p ancytop enia,

macrocytic anemia, ↑ risk of MDS, AML, & SCC of head & neck, and multip le
p hysical anomalies);
shortened telomeres: seen w/ telomerase (TERT, TERC) mut (10% of ap lastic

anemia), dyskeratosis congenita/DKC1 mut; a/w IPF, cirrhosis (NEJM
2 009;361:2 353)
• Treatment and p rognosis
allogeneic HSCT: for young Pts → ~8 0% long-term survival and significantly ↓

risk of malignant evolution, but has risk of transp lant-related morbidity &
mortality; if p ossible avoid transfusions (and alloimmunization) p retransp lant
immunosuppression (CsA/tacrolimus, ATG): 70–8 0% resp ond, with 8 0–90% 5-y

survival in resp onders (96% vs. 76% w/ horse vs. rabbit ATG; NEJM
2 011;365:430); 15–2 0% 10-y incidence of clonal disorders (mostly MDS, AML,
PNH)
TPO mimetics (eg, eltrombop ag) may be op tion in refractory disease (NEJM
2 012 ;367:11)
supportive care: transfusions, antibiotics, p ossible utility of G-CSF and Ep o
Myelodysplastic syndromes (MDS) (qv)
Paroxysmal nocturnal hemoglobinuria (PNH) (Blood 2 009;113:652 2 )

• Acquired clonal stem cell disorder = inactivating somatic mutation of PIG-A gene →
deficiency of GPI-anchor for CD55 & CD59 (inhib of comp lement) → comp lement-
mediated RBC lysis, p lt aggreg., & hyp ercoagulability
• Clinical: intravascular hemolytic anemia, hypercoagulability (venous > arterial;

esp . intraabdominal, cerebral), smooth muscle dystonias, deficient hematopoiesis
(cytop enias); a/w ap lastic anemia, MDS and evolution to AML
• Dx: flow cytometry (↓ CD55 & CD59) on RBCs and granulocytes; urine
hemosiderosis
• Treatment: sup p ortive care (iron, folate, transfusions); consider anti-coagulation
allogeneic HSCT for hyp op lasia or severe thrombosis eculizumab (Ab inactivates
terminal comp lement C5s): ↓ hemolysis, imp roves QoL & stabilizes Hb levels
(NEJM 2 004;350:552 & 2 006;355:12 33; Lance t 2 009;373:759); must have
meningococcal vaccination
Myelophthisic anemia (see also “Primary Myelofibrosis” )
• Infiltration of bone marrow by cancer, leukemia, infection, fibrosis (p rimary

myelofibrosis), granulomas, lysosomal storage disorders
HEMOLYTIC ANEMIAS
• ↑ reticulocyte count (RI >2 % ), ↑ LDH, ↓ hap toglobin (8 3% Se, 96% Sp ), ↑ indirect
bili
• Autoimmune hemolysis: Coombs’ test = direct antiglobulin test (DAT) → if

agglutination occurs when antisera against Ig or C3 are ap p lied to p atient RBCs
• Intravascular: ↑↑ LDH, ↓↓ hap toglobin; hemoglobinemia, hemoglobinuria,

hemosiderinuria
• Extravascular: sp lenomegaly
• Family h/o anemia; p ersonal or family h/o cholelithiasis
Glucose-6-phosphate dehydrogenase (G6PD) deficiency (Lance t 2 008 ;371:64)
• X-linked defect of metabolism (G6 PD mutations) w/ ↑ suscep tibility to oxidative

damage
• Most common in of African or Mediterranean descent (malaria-endemic areas)
• Hemolysis p recip itated by drugs (sulfonamides, dap sone, p rimaquine, doxorubicin,

methylene blue), infection, DKA or foods (fava beans in children)
• Diagnosis: smear may show RBC Heinz bodies (oxidized Hb) that result in bite cells
once removed by sp leen; ↓ G6PD levels (may be normal afte r acute he molysis as
older RBCs have already lysed and young RBCs may still have near normal levels)
Sickle cell anemia (Lance t 2 010;376:2 018 )

• Recessive β-globin mutation → structurally abnl hemoglobin (HbS). ~8 % African
Americans heterozygotes (“sickle trait” ; usually w/o sx); ~1/400 homozygotes
(sickle cell disease).
• ↓ O 2 → HbS p olymerizes → RBC sickles, ↓ RBC deformability → hemolysis &

microvascular occlusion
• Anemia: chronic hemolysis ± acute ap lastic (p arvo. B19) or sp lenic sequestration
crises
• Vaso-occlusion and infarction: p ainful crises, acute chest syndrome, CVA, sp lenic
sequestration, hand-foot syndrome, renal p ap illary necrosis, asep tic necrosis,
p riap ism
• Infection: sp lenic infarction → overwhelming infection by encapsulated organisms;
infarcted bone → osteomyelitis (Salmone lla, Staph. aure us)
• Diagnosis: sickle-shap ed RBCs and Howell-Jolly bodies on smear; Hb electrop horesis

• Treatment: hydroxyurea causes ↑ HbF → ↓ p ainful crises, acute chest ep isodes and
may ↓ mortality (NEJM 2 008 ;358 :1362 ); allogeneic HSCT may have a role in
young Pts w/ severe disease (Blood 2 000;95:1918 ) and adults (NEJM
2 009;361:2 309)
• Sup p ortive care: folic acid qd; p neumococcal, meningococcal, H. flu & HBV
vaccination; p ain crises treated with hydration, oxygen and analgesia; simp le or
exchange transfusion for TIA or stroke, severe acute chest syndrome, or p reop
(goal Hb 10 g/dL)
Hereditary spherocytosis (HS) (Br J He matol 2 004;12 6:455)

• Defect in a cytoskeletal p rotein of RBC membrane → membrane loss mutations in
ankyrin, a- and β-sp ectrin, band 3 and p allidin have been identified
• Most common in N. Europ ean p op ulations (1/5000 births); FHx (75% of Pts)
• Anemia, jaundice (mostly neonates), sp lenomegaly, p igmented gallstones

• Diagnosis: sp herocytes on smear, osmotic fragility test (~8 0% Se), ↓ eosin-5-
maleimide (EMA) binding (92 % Se; 99% Sp )
• Treatment: folate, transfusions, sp lenectomy for moderate and severe HS (balance w/
↑ risk of future thrombosis and infection (J Thromb Hae most 2 008 ;6:12 8 9)
Paroxysmal nocturnal hemoglobinuria (see above)

Autoimmune hemolytic anemia (AIHA)
• Acquired, antibody-mediated RBC destruction
• Warm AIHA: IgG Abs op sonize RBCs at body te mp → removal by sp leen Etiologies:
idiop athic, lymp hop roliferative (CLL, NHL), autoimmune (SLE), drugs
• Cold AIHA: IgM Ab binds to RBCs at te mp <37°C → complement fixation →

intravascular hemolysis and acrocyanosis on exp osure to cold
Etiologies: idiop athic, lymp hop rolif. disorders (eg, Waldenström’s; monoclonal),
Mycoplasma pneumoniae infxn and infectious mononucleosis (p olyclonal)
• Diagnosis: sp herocytes on smear, Coombs’; ✓ cold agglutinin titer,
sp lenomegaly
• Treatment: treat underlying disease
warm AIHA: corticosteroids ± sp lenectomy, IVIg, cytotoxic agents, rituximab
cold AIHA: avoid cold; steroids ineffective; rituximab (Blood 2 004;103:2 92 5)

Drug-induced hemolytic anemia
• Acquired, antibody-mediated, RBC destruction p recip itated by a medication:
abx: cep halosp orins, sulfa drugs, rifamp in, ribavirin
CV: methyldop a, p rocainamide, quinidine, thiazides
TCAs, p henothiazines, NSAIDs, sulfonylureas, MTX, 5-FU, rasburicase (G6PD

defic.)
• Diagnosis: Coombs’ usually negative, ↑ LDH
• Treatment: discontinue offending agent

Microangiopathic hemolytic anemia (MAHA)
• Intra-arteriolar fibrin damages RBCs → acquired intravascular hemolysis
• Etiologies: hemolytic-uremic syndrome (HUS), thrombotic thrombocytopenic

purpura (TTP), disseminated intravascular coagulation (DIC), malignancy,
malignant HTN, eclamp sia/HELLP, mech. cardiac valves, infected vascular
p rostheses
• Diagnosis: schistocytes ± thrombocytop enia ± abnormalities a/w sp ecific

disorders (eg, ↑ PT in DIC, ↑ Cr in HUS, ↑ LFTs in HELLP)
• Treatment: treat underlying abnormality; urgent plasma exchange for TTP
Hypersplenism
• Stasis/trap p ing in sp leen → mf attack & remodeling of RBC → sp herocytosis →
hemolysis
DISORDERS OF HEMOSTASIS
Figure 5-3 Approach to abnormal hemostasis
Figure 5-4 Coagulation Cascade

Purpura (nonblanching p urp le/red lesions due to extravasation of RBCs into dermis)
• Nonpalpable (macular; ≤3 mm in diameter = p etechiae; >3 mm = ecchymoses)
platelet disorder: thrombocytop enia, defect in p latelet fxn
thromboemboli: DIC, TTP, cholesterol or fat emboli
trauma or vascular fragility: amyloidosis, Ehlers-Danlos, scurvy

• Palpable (p ap ular); vasculitis: leukocytoclastic, HSP, PAN, RMSF;
infectious emboli: meningococcemia, bacterial endocarditis
• Purpura fulminans (aka retiform p urp ura): purpura + hypotension + DIC;

typ ically due to infxn/sep sis, p rotein C or S deficiency or APS (see section on DIC)
PLATELET DISORDERS
THROMBOCYTOPENIA (PLT COUNT <150,000/µL)
Etiologies
• ↓ production
hypocellular bone marrow: ap lastic anemia (qv), rarely MDS, drugs (eg,
thiazides, antibiotics), alcohol, cirrhosis
hypercellular bone marrow: MDS, leukemia, severe megaloblastic anemia
marrow replacement: myelofibrosis, hematologic and solid malignancies,

granulomas
• ↑ destruction
immune-mediated (distinguish p rimary from secondary; Blood 2 009;113:2 38 6)

Primary (idiop athic): immune thrombocytop enic p urp ura (ITP, see below)
Secondary: infxn (HIV, HCV, HSV), collagen vascular diseases (SLE), APS,
lymp hop roliferative (CLL, lymp homa), drugs (many, including heparin,
abciximab, quinidine, sulfonamides, vancomycin), alloimmune
(p osttransfusion)
non–immune-mediated: MAHA (DIC, HUS, TTP), ticlop idine/clop idogrel,

vasculitis, p reeclamp sia/HELLP, cardiop ulm byp ass, CVVH, IABP, cavernous
hemangioma
• Abnormal distribution or pooling: sp lenic sequestration, dilutional, hyp othermia
• Unknown: ehrlichiosis/anap lasmosis, babesiosis, RMSF
• H&P: meds, infxns, underlying conditions, sp lenomegaly, lymp h nodes, bleeding hx

• CBC with differential: isolated thrombocytop enia vs. multilineage involvement
• Peripheral smear
↑ destruction → look for large p lts, schistocytes (see “Perip heral Smear” inserts)
↓ p roduction → rarely limited to p latelets → look for blasts, hyp ersegmented

PMNs, leukoerythroblastic Ds; can see inclusion bodies (anap lasma), p arasites
(babesia)
r/o pseudothrombocytopenia due to p latelet clump ing (✓ p latelet count in non–

EDTA-containing tube, eg, citrate-containing yellow top tube)
Figure 5-5 Ap p roach to thrombocytop enia

• Additional laboratory evaluations as indicated (eg, viral titers, flow cytometry, ANA,
APLA)
if anemia: ✓ reticulocyte count, LDH, hap toglobin, bilirubin to detect hemolysis
if hemolytic anemia: ✓ PT, PTT, fibrinogen, D-dimer, Coombs, ANA
BM bx for unexp lained thrombocytop enia, esp . if associated with sp lenomegaly
Primary immune thrombocytopenic purpura (ITP) (Blood 2 010;115:168 )
• Primary ITP: isolated thrombocytop enia due to immune p lt de struction & ↓

production (auto-Ab to megakaryocytes); (2 ° ITP a/w disease/drug exp osure; Rx
underlying disorder)
• Primary ITP is diag nosis of e xclusion; no robust clinical or lab p arameters, but
typ ically:
CBC: isolated ↓ p lt (<100,000/µL); 10% have ITP + AIHA = Evans syndrome
Perip heral smear: large p latelets
BM bx: ↑ megakaryocytes; p erform in adults >60 y to r/o myelodysp lasia
R/o othe r e tiolog ie s: viral serologies (HIV, HCV, HBV, EBV), H. pylori Ab, ANA,
p regnancy test, APLA, TSH, p arvovirus, & CMV PCR. Anti-plt Ab te sts not use ful.
• Clinical manifestations: insidious onset of mucocutaneous bleeding; : = 3:1
• Treatment: goals based on individual Pt rarely indicated if p lt >50,000/µL unless

bleeding, trauma/surgery, anticoag, comorbidities steroids, IVIg, & sp lenectomy
mainstay of initial Rx; romip lostim/eltrombop ag if refractory
• Pathop hysiology (typ e II): Ab binds hep arin-PF4 → immune comp lex binds to p lt →
plt activation, further PF4 release → p lt aggregates removed from circulation →
thrombocytopenia; p rocoagulants released by p lts and tissue factor released by
endothelial cells damaged by HIT Abs → prothrombotic state
• Diagnosis (ne e d clinical + patholog ic)
Clinical: p lt <100k or ↓ 50% from baseline; or venous (DVT/PE) or arterial

(limb ischemia, CVA, MI) thrombosis (4:1 ratio); skin necrosis; ? ↑ hep arin
resistance
Pathologic: HIT Ab using PF4-hep arin ELISA (≥90% Se, IgG-sp ecific ELISA
Sp 94% ), may confirm w/ functional p lt aggregation (serotonin-release) assay
(>90% Sp )
Pretest p rob w/ “4T’s” criteria (Blood 2 012 ;12 0:4160): ≤3 p oints → 99% NPV,
investigate other causes; 4–5 p oints 2 2 % PPV & 6–8 p oints 64% PPV, ✓ lab test
and rep lace UFH
• Treatment of HIT (typ e II) (Che st 2 012 ;141:e495S; Blood 2 012 ;119:2 2 09; NEJM
2 013;368 :737)
Discontinue heparin (including flushe s, LMWH prophylaxis, he parin-impre g nate d
line s)
Avoid p lt transfusions if not actively bleeding (anecdotally linked w/ thrombotic

events)
Nonheparin anticoag (argatroban, bivalirudin; NEJM 2 013;368 :737) re g ardle ss
of thrombosis; start warfarin when p lt >150k, overlap ≥5 d (✓ chromogenic Xa
to titrate)
thrombosis (HITT): anticoagulate for ≥ 3–6 mo
thrombosis (HIT): screen for DVT; unclear duration of subsequent anticoag

(until p lt count recovers, often ~2 –3 mo if no clot); 25–50 % thrombosis rate
w/in 30 d
• Hep arin use if h/o HIT: if PF4 Ab (typ ically >100 d after dx) → re-exp osure to
UFH reasonable (eg, for surgery); HIT recurrence low
Hemolytic-uremic syndrome (HUS) & thrombotic thrombocytopenic purpura (TTP)

• Definition: vascular occlusive disorders w/ systemic (TTP) or intrarenal (HUS) p lt
aggreg.
→ thrombocytop enia & mechanical injury to RBCs (MAHA) (NEJM 2 002 ;347:58 9)
HUS triad = thrombocytop enia + MAHA + renal failure
TTP pentad (all 5 in only ~5% ) = thrombocytop enia + MAHA (100% ) ± Δ MS

(65% ) ± renal failure (50% ) ± fever (2 5% )
• Pathop hysiology: mechanism in most HUS cases is distinct from TTP (NEJM
1998 ;339:1578 )
HUS: Shiga toxin binds & activates renal endothelial cells & p lts → intrarenal
thrombi
TTP: ↓ ADAMTS13 p rotease activity or inhibitor→ p ersistence of large vWF

multimers on endothelial surface → adhesion and aggregation of p assing
p latelets → thrombosis
• Clinical manifestations and associations
HUS: usually in children; p rodrome of bloody diarrhea due to enterohemorrhagic
E. coli
TTP: usually in adults; idiopathic, drugs (CsA, tacrolimus, gemcitabine,

mitomycin-C, ticlop idine, clop idogrel, quinine), HIV, p regnancy, HSCT,
autoimmune disease, familial
• Dx: unexp lained thrombocytopenia (typ ically <2 0k) + MAHA → sufficie nt for dx
schistocytes (>2 –3/hp f), Coombs, normal PT/PTT & fibrinogen, ↓↓
ADAMTS13 ↑↑ LDH (tissue ischemia + hemolysis), ↑ indirect bili., ↓↓ hap toglobin,
↑ Cr (esp . in HUS)
Biop sy: arterioles filled with p latelet hyaline thrombi

Ddx: DIC, vasculitis, malignant hyp ertension, p reeclamp sia/HELLP syndrome
• Treatment: urgent plasma exchange ± glucocorticoids if susp ected; FFP if delay to
p lasma exchange (Blood 2 010;116:4060); ? eculizumab in HUS (NEJM
2 011;364:2 561); plt transfusions contraindicate d → ↑ microvascular thrombosis
(NEJM 2 006;354:192 7)
Disseminated intravascular coagulation (DIC): see “Coagulop athies”

DISORDERS OF PLATELET FUNCTION
Tests of platelet function

• Bleeding time: global screen of p latelet function; not re liable and rare ly use d
• Platelet aggregation tests: measure aggregation in resp onse to agonists (eg, ADP)
von Willebrand’s disease (vWD) (NEJM 2 004;351:68 3 & 2 012 ;367:1954)

• von Willebrand’s factor (vWF) function = p latelet glue & p lasma carrier of factor
VIII
• vWD most common inherited (usually auto dom) bleeding disorder; ~8 5% (typ e 1)
have p artial quantitative defic of vWF, ~15% (typ e 2 ) have qualitative defic in
vWF
• Acquired vWD: a/w many disorders (malig, MPN w/ ↑ p lt count; autoimmune; hyp o-
thyroidism; drugs) and caused by different mechanisms (anti-vWF Abs, ↑ clearance,
↓ synthesis); Heyde’s syndrome = vWF destruction by severe AS, a/w GI
AVMs/bleed
• Diagnosis: ↓ vWF:Ag, ↓ vWF activity (measured by ristocetin cofactor assay), ↓

factor VIII, ± ↑ PTT, ± ↓ p latelets; confirm with vWF multimer analysis
• Clinical condition, factor VIII levels and ristocetin cofactor assay useful to guide Rx
decision
• Rx: desmopressin (dDAVP, IV/IN) → ↑ endothelial cell release of vWF; efficacy

dep ends on typ e (avoid in Typ e 2 ), ∴ ✓ resp onse before use w/ subseq. bleeding
or p rocedures;
vWF replacement: cryop recip itate, factor VIII concentrates rich in vWF, recomb.
vWF
Uremic bleeding
• Uremia → p latelet dysfunction including ↓ aggregation, imp aired adhesiveness

• Treatment: dDAVP, cryop recip itate, correct anemia (imp roves p lt aggregation and
adhesion by increasing p lt interactions with endothelium), consider holding anti-

p lt agents
COAGULOPATHIES
Further coagulation tests

• Mixing study: useful if ↑ PT or PTT; mix Pt’s p lasma 1:1 w/ normal p lasma and
retest PT/PTT normalizes → factor deficiency; PT/PTT remains elevated → factor
inhibitor
• Coagulation factor levels: useful if mixing study suggests factor deficiency
DIC → all factors consumed; ∴ ↓ factors V and VIII liver disease → ↓ all factors
e xce pt VIII; ∴↓ factor V, normal factor VIII vitamin K deficiency → ↓ factors II,
VII, IX, X (and p rotein C, S); ∴ normal V and VIII
• DIC screen: fibrinogen (consumed), fibrin degradation p roducts (FDPs, due to

intense fibrinolysis), D-dimer (more sp ecific FDP test that detects degradation of X-
linked fibrin)
Hemophilias (NEJM 2 001;344:1773)

• X-linked recessive factor VIII (hemop hilia A) or factor IX (hemop hilia B) deficiency
• Classification: mild (5–2 5% normal factor activity), moderate (1–5% ) or severe

(<1% )
• Clinical manifestations: hematomas, hemarthroses, bruising, bleeding (mucosal, GI,

GU)
• Diagnosis: ↑ PTT (normalizes w/mixing study), normal PT & vWF, ↓ factor VIII or IX
• Treatment: p urified/recomb. factor VIII or IX concentrate, desmop ressin (mild

disease), aminocap roic acid; recomb. factor VIIa if factor inhib., cryo (only has
factor VIII)
Coagulation factor inhibitors
• Etiologies: hemop hilia (treated with factor rep lacement); p ostp artum;
lymp hop roliferative disorders and other malignancies; autoimmune diseases; most
commonly anti–factor VIII
• Diagnosis: ↑ PTT (does not normalize w/mixing study); Bethesda assay quantitates
titer
• Treatment: high titer → recomb. factor VIIa, p orcine factor concentrates, activated
p rothrombin comp lex; others → high-p urity human factor, p lasmap heresis,
immunosup p . w/ steroids, cyclop hosp hamide and/or rituximab (Curr Opin
He matol 2 008 ;15:451)
Disseminated intravascular coagulation (DIC) (NEJM 1999;341:58 6)
• Etiologies: trauma, shock, infection, malignancy (esp . APL), obstetric comp lications
• Pathogenesis: massive activation of coagulation that overwhelms control mechanisms

thrombosis in microvasculature → ischemia + microangiop athic hemolytic
anemia acute consump tion of coagulation factors and p latelets → bleeding chronic
DIC → able to rep lete factors and p latelets → thrombosis
• Diagnosis: ↑ PT, ↑ PTT, ↓ fibrinogen (may be nl b/c acute p hase), FDP/D-dimer,
↓ p lts, schistos, ↑ LDH, ↓ hap to; chronic DIC: FDP/D-dimer, variable p lts,
other labs nl
• Treatment: treat underlying p rocess; sup p ort with FFP, cryoprecipitate (goal
fibrinogen
>100 mg/dL) and platelets; no role for activated p rotein C in sep sis (NEJM
2 012 ;366:2 055)
Vitamin K deficiency
• Etiologies: malnutrition, ↓ absorp tion (antibiotic sup p ression of vitamin K-
p roducing intestinal flora or malabsorp tion), liver disease (↓ stores), warfarin
HYPERCOAGULABLE STATES
Suspe ct in Pts with ve nous or arte rial thrombosis at young ag e or unusual locations,
re curre nt thrombose s or pre g nancy loss or FHx
Diagnostic evaluation (not routinely required for initial VTE)

• APC resistance screen; p rothrombin PCR test; functional assays for p roteins C and S,
ATIII; homocysteine level; factor VIII levels; anticardiolip in and lup us
anticoagulant Ab. Also consider nep hrotic syndrome, PNH (esp . if mesenteric
thrombus).
• Consider JAK2 mutation testing if susp ect MPN or sp lanchnic thrombosis.
• Proteins C & S and ATIII levels are affected by acute thrombosis and anticoagulation
∴ levels best assessed ≥2 wk after comp leting anticoagulation course
• Age-ap p rop riate malignancy screening ( in 7–10% in “idiop athic” DVT; Annals
2 008 ;149:32 3)
Treatment
• Asx w/ inherited risk factor: consider p rop hylactic anticoag. if develop s acquired
risk factor
• Thrombosis w/ inherited risk factor: see “Venous Thromboembolism”
Antiphospholipid syndrome (APS) ( J Thromb Hae most 2 006;4:2 95; NEJM
2 013;368 :1033)
• Definition: dx requires ≥1 clinical & ≥1 laboratory criteria

Clinical: thrombosis (any) or comp lication of p regnancy (≥3 sp ont. abortions
before 10 wk or ≥1 fetal loss after 10 wk or p remature birth before 34 wk)
Laboratory: moderate–high titer anticardiolip in (ACL), lup us

anticoagulant (LA) or β2 -glycop rotein-I (β2 -GP-I) Ab on ≥2 occasions at least
12 wk ap art
• Clinical: DVT/PE/CVA, recurrent fetal loss, thrombocytopenia, hemolytic anemia,

livedo reticularis; “catastrophic APS” = ≥3 organ systems in <1 wk w/
APLA & tissue microthrombi (Lupus 2 003;12 :530) → 44% mortality (Arth Rhe um
20 0 6 ;54:2 568 )
• Antiphospholipid antibodies (APLA) ✓ if: SLE, ag e <40 y & arte rial thromb,
re curre nt ve nous thromb, spontane ous abortion
ACL: Ab against cardiolip in, a mitochondrial p hosp holip id; IgG more sp ecific
than IgM
LA: Ab that p rolongs p hosp holip id-dep endent coagulation reactions; ∴ ↑ PTT that
does not correct with mixing study but does correct with excess p hosp holip ids or
p latelets; PT not affected b/c the reaction contains much more p hosp holip id
β2 -GP-I: Ab against β2 -glycop rotein-I, IgG or IgM
False VDRL: nontrep onemal test for syp hilis in which cardiolip in is p art of
Ag comp lex
Clinical significance of different Abs in p athogenesis uncertain
Risk of thromboembolic p henomena may increase with titer of APLs

• Etiologies: p rimary (idiop athic) or secondary due to autoimmune syndromes (eg,
SLE), malignancy, infections, drug reactions
• Treatment: UFH/LMWH → warfarin after thromboembolic event (lifelong for most

Pts)
Intensity of anticoagulation controversial (Arthritis Rhe um 2 007;57:148 7)
Initial ve nous thrombosis: INR 2 –3 (NEJM 2 003;349:1133; J Thromb Hae most
2 005;3:8 48 )
Initial arte rial thrombosis: typ ically INR 2 –3 + ASA 8 1, although some treat to
INR 3–4
Re curre nt thrombosis on warfarin: INR 3–4 vs. LMWH (Arth Rhe um 2 007;57:148 7)
Consider ASA p rop hylaxis for high-risk asx Pt (eg, SLE)

DISORDERS OF LEUKOCYTES
TRANSFUSION THERAPY
Transfusion reactions
• For all reactions (excep t minor allergic): stop transfusion; send remaining blood
p roduct and fresh blood samp le to blood bank
• Acute hemolytic: fever, hyp otension, flank p ain, renal failure <2 4 h after
transfusion
Due to ABO incomp atibility → p reformed Abs against donor RBCs

Treatment: vigorous IVF, maintain UOP with diuretics, mannitol or dop amine
• Delayed hemolytic: generally less severe than acute hemolytic; 5–7 d after
transfusion
Due to undetected allo-Abs against minor antigens → anamnestic resp onse
Treatment: usually no sp ecific therap y required; dx is imp ortant for future
transfusion
• Febrile nonhemolytic: fever and rigors 0–6 h after transfusion
Due to Abs against donor WBCs and cytokines released from cells in blood p roduct
Treatment: acetaminop hen ± mep eridine; r/o infection and hemolysis
• Allergic: urticaria; rarely, anaphylaxis: bronchosp asm, laryngeal edema,

hyp otension Reaction to transfused p roteins; anap hylaxis seen in IgA-deficient Pts
w/ anti-IgA Abs
Treatment: urticaria → dip henhydramine; anap hylaxis → ep inep hrine ±

glucocorticoids
• Transfusion-related acute lung injury (TRALI): noncardiogenic p ulmonary edema
Due to donor Abs that bind recip ient WBCs, which then aggregate in p ulmonary
vasculature and release mediators causing ↑ cap illary p ermeability Treatment: see
“ARDS”
MYELODYSPLASTIC SYNDROMES (MDS)
Myeloid neoplasm overview (Blood 2 009;114:937)

• 5 categories based on BM morp hology, clinical characteristics and genetics
Myelodysplastic syndromes (MDS) overview (NEJM 2 009;361:18 72 )
• Acquired clonal stem cell disorder → ineffective hematop oiesis → cytopenias,

dysmorphic blood cells and precursors, variable risk of leukemic
transformation
• Ep idemiology: >10,000 cases/y; median age ~65 y; male p redominance (1.8 ×)

• Idiopathic or 2 ° to chemo w/ alkylating agents; ↑ risk w/ radiation, benzene
• Clinical manifestations: anemia (8 5% ), neutrop enia (50% ), thrombocytop enia (40–

65% )
• Diagnosis: dysp lasia (usually multilineage) in p erip heral smear (ovalomacrocytes,
pseudo-Pelger-Huët anomaly) and bone marrow (≥10% dysp lasia with blasts ±
RS)
• Both cytogenetic [eg, del(5q), mono 7, del(7q), trisomy 8 , del(2 0q)] and molec abnl
(eg, TP53, EZH2 , ETV6, RUNX1, ASXL1, SF3B1) have p rognostic signif (NEJM
2 011;364:2 496)
• Prior to dx MDS: exclude AML (≥2 0% blasts) and CMML (monocyte count >1 ×
109/L); r/o 2 ° BM Ds due to defic. of B 12 , folate, cop p er; viral infections (eg,
HIV); chemotherap y; alcohol abuse; lead or arsenic toxicity
• Rx (Am J He matol 2 012 ;8 7:692 ): intensity based on IPSS-R (qv), age, p erformance
status (PS)
Poor PS, any risk → sup p ortive care = transfusions, G-CSF, Ep o, abx if needed
Low/intermediate risk → Ep o (esp . if Ep o level <500); lenalidomide (esp . for 5q
syndrome; NEJM 2 005;352 :549); DNA hyp omethylating agents (azacitidine or
decitabine)
Intermediate/high risk → DNA hyp omethylating agents (survival advantage w/
azacytidine; Lance t Oncol 2 009;10:2 2 3), combination chemo (akin to AML Rx)
or allogeneic HSCT if age <55 (consider reduced-intensity transp lant for ages
55–75)
Hyp op lastic MDS (rare) → can consider immunosuppression (CsA, ATG,

p rednisone)
• Prognosis: IPSS correlates with survival and progression to AML
MYELOPROLIFERATIVE NEOPLASMS (MPN)
General (NEJM 2 006;355:2 452 ; Nat Re v Clin Oncol 2 009;6:62 7; Am J He matol

2 012 ;8 7:2 8 5)
• Results from clonal exp ansion of multip otent hematop oietic stem cell
• A typ e of myeloid neop lasm (see MDS for classification)
• Different from MDS in that the cells are not dysp lastic (ie, normally develop ed)
• 8 categories of MPN: p olycythemia vera (PV); essential thrombocythemia (ET);
p rimary myelofibrosis (PM); chronic myelogenous leukemia (CML), BCR-ABL1
; chronic neutrop hilic leukemia; chronic eosinop hilic leukemia, not otherwise
sp ecified; mastocytosis; myelop roliferative neop lasms, unclassifiable
• Gain of fxn mutations in JAK2 V617F ( Janus kinase) p resent in many cases (PV
~95% , ET ~50% , PMF ~50% ; NEJM 2 005;352 :1779) and BCR-ABL fusion in all
cases of CML; KIT mutations in virtually all systemic mastocytosis; MPL and TET2
mutations w/ lower frequency; genetic lesions are useful as a clonal marker and dx
tool
POLYCYTHEMIA VERA (PV)
Definition
• ↑ in RBC mass ± ↑ granulocytes and p latelets in the absence of p hysiologic stimulus
Etiologies of erythrocytosis
• Relative ↑ RBC (↓ p lasma): dehydration; “stress” erythrocytosis (Gaisböck’s
syndrome)
• Absolute ↑ RBC: 1° (PV, other MPD) or 2 ° due to hypoxia; carboxyhemoglobinemia;
inappropriate erythropoietin (renal, hep atic, cerebellar tumors); Cushing’s
syndrome
Clinical manifestations (common between PV and ET)

• Symp toms → often termed “vasomotor symp toms”
hyperviscosity (erythrocytosis): headache, dizziness, tinnitus, blurred vision
thrombosis (hyp erviscosity, thrombocytosis): transient visual disturbances

(amaurosis, ocular migraine); Budd-Chiari syndrome; erythromelalgia = intense
burning, p ain and erythema of extremities due to microvascular thrombi; ↑ risk
of DVT, MI, stroke. Risk of thrombosis highly correlated with ↑ WBC in PV and
ET (see below).
bleeding (abnormal p latelet function): easy bruising, ep istaxis, GI bleeding
↑ histamine from basop hils → pruritus, p ep tic ulcers; ↑ uric acid (cell turnover)
→ gout
• Signs: plethora, splenomegaly, hyp ertension, engorged retinal veins
• Hb >18 .5 g/dL (men), >16.5 g/dL (women)
• ✓ Ep o to rule out secondary causes of erythrocytosis; if Epo ↓, PV likely If Ep o ↑,

then ✓ SaO 2 or PaO 2 , carboxyhemoglobin, BM exam
• JAK2 V617F mutation screen on p erip heral blood is p ositive in ~95% of PV and
JAK2 exon 12 mutations are p resent in the remainder of Pts
• ± ↑ WBC, p latelets, basop hils; ↑ uric acid, leukocyte alkaline p hosp hatase, vit B 12
• Perip heral smear → no morp hologic abnormalities
• BM bx → hyp ercellular, megakaryocytic hyp erp lasia, ↓ iron, absence of Ph

chromosome
Treatment
• Phlebotomy to moderate degree of Fe defic., goal Hct <45% (NEJM 2 013;368 :2 2 ),

consider <42 % in
• Low-dose ASA in all Pts (NEJM 2 004;350:114)

• Hydroxyurea if high risk of thrombosis (age ≥60, p rior thrombosis) or sx throm-
bocytosis (p lt >1.5 × 106/µL)
• PEG IFNa-2 a yields high resp onse rate w/ limited toxicity (Blood 2 008 ;112 :3065)
• Sup p ortive: allop urinol (gout), H 2 -blockers/antihistamines (p ruritus)

Prognosis
• Median survival w/ Rx 9–12 y. ↑ age, WBC p redict ↓ survival (Br J Hae matol
2 013;160:2 51)
• Post-PV myelofibrosis (sp ent p hase) occurs in 10–2 0% of cases, usually after 10 y
• Risk of transformation into acute leukemia (2 -5% ; higher if p revious cytoreductive

chemo)
ESSENTIAL THROMBOCYTHEMIA (ET)
Definition
• Sustained ↑ in p latelets (>450,000/µL) ± ↑ RBC and granulocytes
Etiologies of thrombocytosis
• 1° = ET or other MPN; myelodysp lastic syndromes (5q-syndrome)
• 2 ° = reactive thrombocytosis: inflammation (RA, IBD, vasculitis), infection, acute
bleeding, iron deficiency, p ostsp lenectomy, neop lasms (p articularly Hodgkin
lymp homa)
• Of p atients with p lt >106/µL, <1 in 6 will have ET
Clinical manifestations (see “Polycythemia Vera” )
• Thrombosis with erythromelalgia (risk of thrombosis highest in Pts with WBC

>8 700), bleeding, p ruritus; mild sp lenomegaly; migraine, TIA; early fetal loss
• Perip heral smear: large hyp ogranular p latelets

• BM bx: megakaryocytic hyp erp lasia; absence of Philadelp hia chromosome and lack
of collagen fibrosis; normal iron stores
• JAK2 V617F p resent in ~50% of ET
• Patients should not meet WHO criteria for diagnosis of CML, PV, PMF or MDS
Prognosis
• Low-risk Pts have overall survival control p op ulation. Risk of transformation

into acute leukemia ~2 –3% .
PRIMARY MYELOFIBROSIS (PMF)
Definition
• Clonal myelop roliferation with reactive marrow fibrosis & extramedullary

hematop oiesis
• Formerly known as agnogenic myeloid metap lasia with myelofibrosis
Etiologies of myelofibrosis
• Myelop roliferative neop lasm = p rimary myelofibrosis; p ost-PV/ET myelofibrosis
• Other hematologic: eg, CML, AML, ALL, MDS
• Metastatic malignancies: eg, breast, p rostate
• Autoimmune: eg, SLE and other collagen vascular disorders

• Other: toxins (eg, benzene); radiation; granulomas from infection (eg, TB, fungal) or
sarcoid; dep osition diseases (eg, Gaucher’s disease)
Clinical manifestations (NEJM 2 000;342 :12 55; BJH 2 012 ;158 :453)
• Ineffective erythrop oiesis → anemia; extramedullary hematop oiesis → massive

splenomegaly (abdominal p ain, early satiety) ± hep atomegaly
• Tumor bulk and ↑ cell turnover → fatigue, weight loss, fever, sweats
Diagnostic evaluation (NEJM 2 006;355:2 452 ; JAMA 2 010;303:2 513)
• Anemia with variable WBC and p latelet counts

• Perip heral smear → “leukoerythroblastic” (teardrop cells, nucleated RBCs,
immature WBCs); large abnormal p latelets
• BM asp irate → “dry” tap; BM bx → severe fibrosis, rep lacement by reticulin &
collagen
• JAK2 V617F p resent in ~50% of PMF; MPL mutations in ~11% of JAK2 Pts
• No BCR-ABL translocation; also does not meet criteria for PV or MDS
Treatment (Blood 2 011;117:3494)

• In absence of adverse p rognostic factors (eg, anemia or sx) → no treatment
• Allogeneic HSCT only p otential cure → consider in young Pts with p oor p rognosis
• Sup p ortive care: transfusions; inconsistent benefit from androgens or Ep o;

sp lenectomy for blood counts refractory to transfusion or p ainful sp lenomegaly
• Hydroxyurea for significant leukocytosis or thrombocytosis
• Ruxolitinib (JAK1/JAK2 inhibitor) ↓ sx, ↓ sp lenomegaly, ↑ survival (NEJM

2 012 ;366:78 7 & 799)
• Thalidomide and lenalidomide (imp rove red cell count)
Complications and prognosis
• Median survival ~5 y; transformation into AML occurs at a rate of ~8 % /y
• International Working Group (IWG) p oor p rognostic factors: age >65, WBC >2 5k,
Hgb <10, blasts >1% , symp toms (Blood 2 009;113:2 8 95). Stratification
based on IWG factors allows p rognostication at any p oint during clinical course
(Blood 2 010;115:1703).
LEUKEMIA
ACUTE LEUKEMIA
Definition
• Clonal p roliferation of hematop oietic p rogenitor with ↓ ability to differentiate into

mature elements → ↑ blasts in bone marrow and p erip hery → ↓ RBCs, p latelets
and neutrop hils
Epidemiology and risk factors
• Acute myelogenous leukemia (AML): ~14,000 cases/y; median age 66 y; >8 0% of

adult acute leukemia cases
• Acute lymp hocytic leukemia (ALL): ~6000 cases/y; median age 14 y; bimodal with
2 nd p eak in adults
• Risk factors: radiation, chemo (alkylating agents, top o II inhib), benzene, smoking
• Acquired hematop oietic diseases: MDS, MPN (esp . CML), ap lastic anemia, PNH
• Inherited: Down’s & Klinefelter’s, Fanconi’s anemia, Bloom syndrome, ataxia
telangiectasia
• Cytop enias → fatigue (anemia), infection (neutrop enia), bleeding
(thrombocytop enia)
• More common in AML (e sp. monocytic le uke mias):

leukostasis (when blast count >50,000/µL): occluded microcirculation → local
hyp oxemia and hemorrhage → dysp nea, hyp oxia, headache, blurred vision,
TIA/CVA; look for hype rviscosity re tinopathy (vascular engorgement, exudates,
hemorrhage)
DIC (esp . with APL)
leukemic infiltration of skin, gingiva (esp . with monocytic subtyp es)

chloroma: extramedullary tumor of leukemic cells, virtually any location
• More common in ALL:
bone p ain, lymp hadenop athy, hep atosp lenomegaly (also seen in monocytic AML)
CNS involvement (up to10% ): cranial neurop athies, N/V, headache anterior
mediastinal mass (esp . in T-cell); tumor lysis syndrome (qv)
Diagnostic evaluation (Blood 2 009;114:937)
• Peripheral smear: anemia, thrombocytop enia, variable WBC (50% p /w ↑ WBC) +

circulating blasts (seen in >95% ; Auer Rods in AML)
• Bone marrow: hyp ercellular with >2 0% blasts; cytogenetics, flow cytometry
• Presence of certain cytogenetic anomalies, eg, t(15;17), t(8 ;2 1), inv(16) or t(16;16),
are sufficient for dx of AML re g ardle ss of the blast count
• ✓ for tumor lysis syndrome (rap id cell turnover): ↑ UA, ↑ LDH, ↑ K, ↑ PO 4, ↓ Ca
• Coagulation studies to r/o DIC: PT, PTT, fibrinogen, D-dimer, hap toglobin, bilirubin
• LP (w/ co-admin of intrathecal chemotherapy to avoid seeding CSF w/ circulating

blasts) for Pts w/ ALL (CNS is sanctuary site) and for Pts w/ AML w/ CNS sx
• TTE if p rior cardiac history or before use of anthracyclines
• HLA typing of Pt, siblings and p arents for p otential allogeneic HSCT candidates
ACUTE MYELOGENOUS LEUKEMIA (AML)
Classification (FAB no longer used clinically; Blood 2 009;114:937)

• Features used to confirm myeloid lineage and subclassify AML to guide treatment:
morp hology: blasts, granules, ± Auer rods (eosinop hilic needle-like
inclusions) cytochemistry: myeloperoxidase and/or nonspecific esterase
• Immunop henotyp e: myeloid antigens → CD13, CD33, CD117; monocytic antigens →

CD11b, CD64, CD14, CD15
• Cytogenetics: imp ortant for p rognosis. Intermed. risk = no favorable/unfavorable
features.
Treatment (Blood 2 010;115:453; JNCCN 2 012 ;10:98 4; Lance t 2 013;38 1:48 4)
• Induction chemo followed by consolidation Rx
• Induction chemo: “7 + 3” = cytarabine × 7 d + ida/daunorubicin × 3 d.

Cytarabine dose: continuous intermed. high dose (NEJM 2 011;364:102 7).
Daunorubicin dose: age <60 → high (90 mg/m 2 ); age >60 → standard (60 or 45
mg/m 2 ) (NEJM 2 009;361:12 49). Gemtuzumab ozogamicin (ɑ-CD33) ? benefit in
fav/int risk AML (Lance t 2 012 ;379:1508 )
• ✓ for comp lete remission (CR) = normal p erip heral counts, <5% BM blasts CR ≠
cure; ∴ must always f/u induction with consolidation Rx
• If CR: consolidation Rx based on risk stratification (age, genetics, PS): chemo

(eg, high dose cytarabine) if favorable risk; othe rwise → allo-HSCT ( JAMA
2 009;301:2 349)
• If CR: reinduction with similar chemotherap y (“5 + 2 ” ) or alternative regimen
• If relap se after CR: salvage chemo → allogeneic HSCT (↓ intensity conditioning if

>60 y)
• Sup p ortive care: hydration + allop urinol or rasburicase for tumor lysis
p rop hylaxis; transfusions; antibiotics for fever and neutrop enia; antifungals for
p rolonged fever & neutrop enia; hydroxyurea ± leukop horesis for leukostasis
Prognosis
• CR achieved in 70–8 0% of Pts <60 y and in 40–50% for Pts >60 y
• Overall survival dep ends on p rognostic factors: ranges from ~50% for Pts <60 y
w/ favorable p rognostic factors to <10% for Pts >60 y w/ p oor p rognostic
factors
• Poor p rognostic factors: age >60, unfavorable cytogenetics (see above), FLT3-ITD
, p oor p erformance score, antecedent MDS/MPN, therap y-related AML; genetic
p rofiling (NEJM 2 012 ;366:1079)
Acute promyelocytic leukemia (APL) (Blood 2 009;113:18 75)

• Rare disease w/ only ~1000 cases/y in the U.S. but biolog ically and clinically distinct
• Atyp ical p romyelocytes (large, granular cells; bilobed nuclei) in blood and bone
marrow
• Defined by translocation of retinoic acid recep tor: t(15; 17); PML-RARɑ (>95% of
cases)
• Medical emergency with DIC and bleeding common; sup p ortive care measures
crucial
• Remarkable resp onses to all-trans-retinoic acid (ATRA), which induces

differentiation, and arsenic trioxide (ATO); early initiation of ATRA is critical as
soon as APL suspe cte d; ATO highly active as first-line therap y or in treatment of
refractory disease.
• Induction regimen: anthracycline + ATRA ± cytarabine → CR in ~90% ; or ATRA +

ATO alone (ASH 2 012 ; JCO 2 009;2 7:504)
• Differentiation (ATRA) syndrome: ~2 5% of Pts; fever, p ulm infiltrates, SOB, edema,
HoTN, AKI; tx w/ dexamethasone 10 mg bid, sup p ortive care (eg, diuresis) (Blood
2 008 ;113:775)
• Consolidation Rx: eg, ATO → anthracycline + ATRA (Blood 2 010;116:3751)
• Role of maintenance Rx (eg, ATRA + 6MP + MTX) currently controversial

• Best p rognosis of all AMLs: >90% cure; WBC >10,000/µL = ↓ p rognosis (Blood
2 000;96:12 47)
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Classification
• Lymp hoblastic neop lasms may p resent as acute leukemia (ALL) with >20% BM
blasts or as lymp hoblastic lymp homa (LBL) w/ mass lesion & <2 0% BM blasts.
ALL and LBL are considered the same disease with different clinical p resentations.
• Morp hology: no granules (granules seen in myeloid lineage)
• Cytochemistry: terminal deoxynucleotidyl transferase (TdT) in 95% of ALL
• Cytogenetics (Blood 2 010;115:2 06): t(9;2 2 ) = Philadelp hia chrom (Ph) ~2 5% of

adults w/ ALL
• Immunohistochemistry: 3 major p henotyp es (Burkitt’s usually treated differently)
Treatment (NEJM 2 006;354:166; JCO 2 011;2 9:532 )

• Induction chemo: multip le accep table regimens including combination of
anthracycline, vincristine, steroids, cyclop hosp hamide, ± asp araginase
• CNS prophylaxis: intrathecal MTX/cytarabine ± cranial irradiation or systemic

MTX
• Postremission therapy op tions:

consolidation/intensification chemo (~7 mo) followed by maintenance chemo (~2 –
3 y) high-dose chemo w/ allo HSCT considered for all Pts in CR1 w/ available
donor p ediatric regimens in young adults (<30 y); consider allo SCT for all Pts
<50 (controversial)
• If relap se → salvage chemo followed by allogeneic HSCT if able
• Ph t(9;2 2 ) → add imatinib or dasatinib, followed by allogeneic HSCT
• MLL-AF4 t(4;11) or hyp odip loidy (<44 chromosomes) → consider for allogeneic
HSCT
• Infusion of chimeric antigen recep tor–modified T cells p romising (NEJM
2 013;368 :1509)
Prognosis
• CR achieved in >8 0% of adults
• Cure achieved in 50–60% if good p rog. factors vs. 10–30% w/ p oor p rog. factors
• Good p rognostic factors: younger age, WBC <30,000/µL, T-cell immunop henotyp e,
absence of Ph chromosome or t(4;11), early attainment of CR
• Gene exp ression p atterns may be useful in p redicting chemo resistance (NEJM
2 004;351:533)
CHRONIC MYELOGENOUS LEUKEMIA (CML)
Definition (Blood 2 009;114:937)

• Myeloproliferative neoplasm with clonal overp roduction of hematop oietic myeloid
stem cells that can differentiate
• Philadelphia chromosome (Ph) = t(9;2 2 ) → BCR-ABL fusion → ↑ Abl kinase
activity
BCR-ABL required for Dx of CML
• “Atyp ical CML” (BCR-ABL ) now considered a sep arate disease and reclassified
as MDS/MPN (see “Myelodysp lastic Syndromes” )

• ~5400 new cases/y in U.S.; median age ~64 at p resentation; ~15% of adult
leukemias
• ↑ risk with irradiation; no clear relation to cytotoxic drugs
• Trip hasic clinical course; 8 5% p resent in the chronic p hase

• Chronic phase: often asymp tomatic but common features are fatigue, malaise,
weight loss, night sweats, abdominal fullness (splenomegaly 50% )
• Accelerated phase: refractory leukocytosis, thrombocytop enia and worsening sx →

fever, wt loss, ↑ sp lenomegaly, bone p ain, bleeding, infections, p ruritus
(basop hilia)
• Blastic phase acute leukemia → severe constitutional symp toms, infection,

bleeding and p ossible leukostasis (see “Acute Leukemia” )
• Peripheral smear: leukocytosis (often >100,000/µL), left-shifted with all stag e s of

mye loid maturation; anemia, thrombocytosis, basophilia
• Bone marrow: hyp ercellular, ↑ myeloid to erythroid ratio, ↓ leuk alkaline

p hosp hatase
• Chronic: <10% blasts (p erip heral or BM)
• Accelerated: 10–2 0% blasts, >2 0% basos, p lts <100k, ↑ sp leen size, karyotyp ic
p rog.
• Blastic: >2 0% blasts (2 ⁄3 myeloid, 1⁄3 lymp hoid), may see extramedullary
leukemia
Treatment (NEJM 2 010;362 :2 2 60; Blood 2 011;118 :12 08 & 2 012 ;12 0:1390)
• Tyrosine kinase inhibitor (TKI): imatinib, dasatinib, nilotinib, bosutinib, p onatinib

are selective inhibitors of BCR-ABL (JCO 2 010;2 8 :42 8 ; Blood 2 012 ;12 0:1390).
Imatinib, nilotinib, & dasatinib ap p roved as initial Rx.
Resistance = recurrent dis. on TKI, often result of BCR-ABL mutation or

amp lification.
Nilotinib, dasatinib, bosutinib, & p onatinib ap p roved for resistant disease, w/

only p onatinib effective on T315I resistance mutation (NEJM 2 012 ;367:2 075).
Side effects include nausea, diarrhea, muscle cramp s, cytop enias, ↓ PO 4, ↑ QT,
rarely CHF; dasatinib also a/w p ericardial & p leural effusions, nilotinib w/ ↑
bili & lip ase.
• Chronic phase: TKI; continued indefinitely in resp onders (Blood 2 012 ;12 0:1390)
• Accelerated phase: TKI up front, consider allogeneic HSCT
• Blastic phase: TKI + HSCT vs. ALL or AML induction (based on cell typ e) + HSCT
• Allogeneic HSCT: consider for Pts w/ available donor who p resent in accelerated or
blastic p hase; reasonable op tion for Pts with relap sed/refractory disease to TKIs
Prognosis
• Chronic p hase CML Rx’d w/ imatinib: 8 9% overall survival, 95% survival free of
CML-related deaths, 7% p rogression to blast p hase at 5 y (NEJM 2 006;355:2 408 )
• Accelerated p hase CML Rx’d w/ imatinib: ~50% overall survival at 4 y (Cance r

2 005;103:2 099)
• Poor p rognostic factors: ↑ age, ↑ p latelet count, ↑ sp leen size, ↑ p ercentage of blasts
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Definition (NEJM 2 005;352 :8 04; Blood 2 008 ;111:5446)

• Monoclonal accumulation of functionally incomp etent mature B lymp hocytes
• CLL (>5000/µL malignant cells) & small lymp hocytic lymp homa (SLL; <5000/µL
malignant cells, but + LAN ± sp lenomegaly) now classified as same disease
• Monoclonal B lymp hocytosis (<5000/µL, nodes <1.5 cm, nl RBC and Plt counts):
observe

• ~16,000 new cases/y; median age at dx is 72 y; most common adult leukemia
• ↑ incidence in 1st-degree relatives; no known association with radiation, chemicals,
drugs
• Symp toms: often asx & identified when CBC reveals lymp hocytosis; 10–2 0% p /w
fatigue, malaise, night sweats, weight loss (ie, lymp homa “B” sx)
• Signs: lymphadenopathy (8 0% ) and hepatosplenomegaly (50% )
• Autoimmune hemolytic anemia (AIHA) (~7% ) or thrombocytopenia (ITP) (~1–

2% )
• Hyp ogammaglobulinemia ± neutrop enia → ↑ suscep tibility to infections
• Bone marrow failure in ~13% ; monoclonal gammop athy in ~5%

• Aggressive transformation: ~5% develop Richter’s syndrome = transformation
into high-grade lymp homa (usually DLBCL) and sudden clinical deterioration
Diagnostic evaluation (see “Lymp homa” for general ap p roach)
• Peripheral smear: lymphocytosis (>5000/µL, mature-ap p earing small cells)

“smudge” cells from damage to abnl lymp hs from shear stress of making blood
smear
• Flow cytometry: clonality with dim surface Ig (sIg); CD5+, CD19+, CD2 0(dim),
CD2 3+. CD38 + or ZAP70+ a/w unmutated Ig variable heavy chain region &
worse p rognosis.
• Bone marrow: normo- or hyp ercellular; infiltrated w/ small B-cell lymp hocytes
(≥30% )
• Lymph nodes: infiltrated w/ small lymp hocytic or diffuse small cleaved cells = SLL
• Genetics: del 11q2 2 -2 3 & 17p 13 unfavorable; trisomy 12 neutral; del 13q14 and
mut Ig VH favorable. Nine significantly mutated genes, including TP53, NOTCH1,
MYD8 8 and SF3B1. Key role for sp liceosome mutations (NEJM 2 011;365:2 497;
JCI 2 012 ;12 2 :3432 ).
Treatment
• Treatment is p rimarily palliative → early stage disease can be followed w/o Rx
• Indications for treatment: Rai stages III/IV, Binet stage C, disease-related sx,
p rogressive disease, AIHA or ITP refractory to steroids, recurrent infections
• Op tions:
purine analogues: fludarabine (“F” ), p entostatin (“P” )
alkylating agents: cyclop hosp hamide (“C” ), bendamustine (“B” ), CVP, CHOP; ?
chlorambucil for elderly (lower resp onse vs. F, but survival; NEJM
2 000;343:1750)
± monoclonal Ab against CD2 0 (rituximab, “R” ) or CD52 (alemtuzumab, esp .

w/ 17p -) combination re g ime ns (eg, FR, FCR, BR) sup erior to monoRx (Lance t
2 007;370:2 30)
• Novel Rx refractory dis.: ofatumumab (ɑ-CD2 0), ibrutinib (BTK inhib), CAL101 (PI3K
inhib)
• Consider allo-HSCT in p53 mut or refractory CLL (BBMT 2 009;15:53; BJH

2 012 ;158 :174)
• Sup p ortive care: PCP, HSV, VZV p rop hylaxis; CMV monitoring for Pts receiving
anti-CD52 ; AIHA/ITP → steroids; recurrent infections → IVIg
Prognosis (NEJM 2 004;351:8 93; JCO 2 006;2 4:4634 & 2 010;2 8 :4473; Blood
2 008 ;111:8 65)
• Survival varies substantially. Median overall survival ~10 y (Am J He matol
2 011;12 :98 5)
• Favorable p rognosis: 13q14 deletion (~50% of CLL cases)
• Factors a/w worse p rognosis include:
unfavorable cytogenetics (eg, 17p -/TP53 mutation)
unmutated (<2 % c/w germline) Ig VH gene (<8 –10 y vs. >2 0–2 5 y if mutated)
high (>2 0–30% ) Zap -70 exp ression (p art of T cell recep tor; correlated w/
unmutated Ig VH)
CD38 >30% or CD49d <30% (correlated with unmutated Ig VH)
higher β2 -microglobulin levels (correlate with disease stage and tumor burden)
LYMPHOMA
Definition
• Malignant disorder of lymp hoid cells that reside p redominantly in lymp hoid tissues
• Hodgkin lymphoma (HL) is distinguished from non-Hodgkin lymphoma (NHL) by

the p resence of Reed-Sternberg (RS) cells
• Lymp hadenop athy (nontender)
HL: sup erficial (usually cervical/supraclavicular) ± mediastinal

lymp hadenop athy; nodal disease with orderly, anatomic spread to adjacent
nodes
NHL: diffuse; nodal and extranodal disease with noncontiguous spread;
symp toms reflect involved sites (abdominal fullness, bone p ain)
• Constitutional (“B” ) symp toms: fever (>38 °), drenching sweats, ↓ weight (>10%
in 6 mo)
HL: p eriodic, recurrent “Pel-Ebstein” fever; 10–15% have p ruritus; ~35% “B”
symp toms
NHL: “B” symp toms vary between typ es, ~15–50%
Diagnostic and staging evaluation
• Physical exam: lymp h nodes, liver/sp leen size, Waldeyer’s ring, testes (~1% of
NHL), skin
• Pathology: excisional lymph node bx (not FNA b/c need surrounding architecture)
with immunop henotyp ing and cytogenetics; BM bx (excep t in HL clinical stage
IA/IIA with favorable features or CLL clone by flow); LP if CNS involvement
clinically susp ected
• Lab tests: CBC, BUN/Cr, LFTs, ESR, LDH, UA, Ca, alb; ✓ HBV & HCV (and must ✓
HBsAg & anti-HBc if p lanning rituximab Rx as can lead to HBV reactivation);
consider HIV, HTLV, & EBV serologies and connective tissue diseases autoAbs
• Imaging: chest/abd/pelvic CT, but doesn’t reliably detect sp leen/liver involvement
consider PET-CT scans (esp . in HL, DLBCL). PET resp onse to Rx can be p rognostic
(Blood 2 006;107:52 ; JCO 2 007;2 5:3746); has role to assess PR/CR after
treatment.
Head CT/MRI only if neurologic symp toms.

HODGKIN LYMPHOMA (HL) (NEJM 2010; 363:653)
• ~9,000 cases/y; bimodal distribution (15–35 & >50 y); ↑ ; role of EBV in subsets
of HL, esp . immunocomp romised p atients
Pathology
• Affected nodes show RS cells (<1% ) in background of non-neop lastic inflammatory

cells
• Classic RS cells: bilobed nucleus & p rominent nucleoli with surrounding clear sp ace
(“owl’s eyes” ). RS cells are clonal B-cells: CD15+, CD30+, CD2 0– (rarely +).
• Nonclassical (5% ): nodular lymp hocyte p redominant (NLP); involves p erip heral LN
8 0% p resent in stages I–II and Rx can be RT alone or combination chemo + RT

w/ 8 0% 10-y p rogression-free survival, 93% overall survival ( JCO
1997;15:3060)
Consider rituximab as most NLP RS cells are CD2 0+

Stages III–IV treated with combination chemo (see below)
Treatment (Lance t 2 012 ;38 0:8 36)
• Stages I–II: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) ± RT
Lower intensity regimens comp arable efficacy if favorable p rognosis (NEJM

2 010;363:640)
• Stages III–IV: ABVD × 6 cycles or escalated BEACOPP (bleomycin, etop oside,

doxorubicin, cyclop hosp hamide, vincristine, p rocarbazine and p rednisone)
• Refractory/relap sed disease: salvage chemo + auto HSCT, ± RT
• Late effects include ↑ risk for:
second cancers: bre ast (if RT), ∴ annual screening at age 40 or 8 –10 y p ost RT;
lung , ? role of screening CXR or CT (controversial); acute le uke mia/MDS; NHL
cardiac disease (if RT or anthracycline), ? role of echo/stress at 10 y

(controversial)
pulmonary toxicity (if bleomycin)
hypothyroidism (if RT), ∴ annual TSH (if neck RT)

NON-HODGKIN LYMPHOMA (NHL)
• ~70,000 new cases/y; median age at dx ~65 y; p redominance; 8 5% B-cell

origin
• Associated conditions: immunodeficiency (eg, HIV, p osttransp lant); autoimmune
disorders (eg, Sjögren’s, RA, SLE); infection (eg, EBV, HTLV-I, H. pylori)
• Burkitt’s lymp homa: (1) endemic or African (jaw mass, 8 0–90% EBV-related); (2 )
sp oradic or American (2 0% EBV-related); (3) HIV-related
Treatment (Lance t 2 012 ;38 0:8 48 )
• Treatment and p rognosis determined by histop athologic classification rather than

stage
• Rituximab (antibody to CD2 0; NEJM 2 012 ;366:2 008 ) if CD2 0+; no role if tumor is
CD2 0–
• Indolent: goal is sx management (bulky dis., cytop enias, “B” sx); not curable w/o
allo HSCT
Op tions include radiation for localized disease, rituximab ± chemo

(bendamustine, CVP, fludarabine)
For MALT → treat H pylori if
Rituximab maintenance ↑ survival in relap sed disease (JNCI 2 009:101:2 48 );

growing role for rituximab maintenance in indolent and aggressive disease
(Lance t 2 011;377:42 )
• Aggressive (DLBCL, 30–40% of NHL): goal is cure (JCO 2 005;2 3:638 7)

R-CHOP (rituximab, cyclop hosp hamide, doxorubicin = hydroxydaunorubicin,
vincristine = Oncovin, p rednisone) (NEJM 2 002 ;346:2 35 & 2 008 ;359:613) 10-y
p rogression-free survival = 45% ; overall survival = 55% (Blood
2 010;116:2 040)
? R-ACVBP (ritux, doxorubicin = Adriamycin, cyclop hosp h, vindesine, bleo,
p rednisone) ↑ 3-y OS vs. R-CHOP, but ↑ adverse events (Lance t 2 011;378 :18 58 )
+ Radiation for localized or bulky disease
Consider CNS prophylaxis w/ intrathecal or systemic high-dose methotrexate if

p aranasal sinus, testicular, breast, p eriorbital, p aravertebral or bone marrow
involved; ≥2 extranodal site + ↑ LDH may also warrant
Refractory/relap sed disease: salvage chemo; high-dose chemo + auto-HSCT (NEJM
1995;333:1540); allo-HSCT if beyond 2 nd relap se
• Highly aggressive
Burkitt’s: intensive short-course chemotherap y (Blood 2 004;104:3009)
Low risk defined as nl LDH & single focus of disease <10 cm; all others high risk
Low risk Rx = CODOX-M (cyclop hosp hamide, vincristine, doxorubicin, high-dose

methotrexate ± rituximab) (Le uk Lymph 2 004;45:761)
High risk Rx = CODOX-M/IVAC (above w/ ifosfamide, etop oside, high-dose

cytarabine), hyp er-CVAD (cyclop hosp hamide, vincristine, doxorubicin,
dexamethasone)
All Pts receive CNS p rop hylaxis & tumor lysis syndrome p rop hylaxis
Lymp hoblastic lymp homa (B or T cell): treated like ALL (see “Acute Leukemia” )
Prognosis
• Indolent: typ ically incurable, but long median survival
• Aggressive: ↑ chance of cure, but overall worse p rognosis

HIV-associated NHL (Blood 2 006;107:13)
• HIV imp arts 60–100× relative risk
• NHL is an AIDS-defining malignancy along with Kap osi’s, cervical CA, anal CA
• Concurrent HAART & chemotherap y likely p rovide survival benefit
• DLBCL & immunoblastic lymp homa (67% ): CD4 <100, EBV-associated Treat as
immunocomp etent (CHOP-R), but avoid rituximab if CD4 <100 Alternative
regimens include R-EPOCH (etop , p red, vincristine, cyclop hos, doxorubicin)
• Burkitt’s (2 0% ): can occur with CD4 >2 00 Treat as immunocomp etent; p rognosis is
not significantly worse
• Primary CNS lymp homa (16% ): CD4 <50, EBV-associated (also seen in Pts w/o
HIV) Treat with high-dose methotrexate + steroids ± RT
• Primary effusion lymp homa (<5% ): HHV8 driven; also can be seen in other
immunosup p . Pts such as s/p solid organ transp lant or w/ chronic HBV. Treat
with standard CHOP (often CD2 0–), but p oor p rognosis.
PLASMA CELL DYSCRASIAS
MULTIPLE MYELOMA (MM)
Definition and epidemiology (NEJM 2 011;364:1046)

• Malignant neop lasm of plasma cells p roducing a monoclonal Ig = “M protein”
• ~2 1,700 new cases and ~10,710 deaths/y in U.S. (2 012 ); median age at diagnosis
69 y
• African American:Caucasian ratio 2 :1
Clinical manifestations (CRAB criteria)

• Hyp erCalcemia due to ↑ osteoclast activity
• Renal disease: multip le mechanisms include toxic effect of filtered light chains →
re nal failure (cast nep hrop athy) or type II RTA; amyloidosis or light chain
dep osition disease → ne phrotic syndrome ; hyp ercalcemia, urate nep hrop athy, typ e
I cryoglobulinemia
• Anemia (normocytic) due to bone marrow involvement and autoimmune Ab

• Bone p ain due to ↑ osteoclast activity → lytic lesions, p athologic fx
• Recurrent infxns due to relative hyp ogammaglob. (clonal p lasma cells sup p ress nl
Ig)
• Neurologic: cord comp ression; POEMS (p olyneurop athy, organomegaly,
endocrinop athy, M p rotein, skin changes) syndrome
• Hyp erviscosity: usually when IgM >4 g/dL, IgG >5 g/dL, or IgA >7 g/dL
• Coagulop athy: inhibition of or Ab against clotting factor; Ab-coated p latelets
• Amyloidosis (see “Amyloidosis” )

• Symptomatic MM criteria (all 3 must be met)

1) M p rotein in serum or urine (no sp ecific level required)
2 ) bone marrow clonal p lasmacytosis (≥10% ) or p resence of a p lasmacytoma
3) myeloma-related organ or tissue imp airment (ROTI) = lytic bone lesions, Ca
>11.5 g/dL, Cr >2 mg/dL, or Hb <10
• Variants
smoldering MM: M p rotein >3 g/dL and/or p lasmacytosis >10% , but asx & no
ROTI risk of p rog.: M p rotein concen., subtyp e & free light chain ratio (NEJM
2 007;356:2 58 2 )
solitary bone p lasmacytoma: 1 lytic lesion w/o M p rotein, p lasmacytosis, or

other ROTI
extramedullary (nonosseous) p lasmacytoma: usually up p er resp iratory tract
p lasma cell leukemia: p lasma cell count >2 000/µL in p erip heral blood
nonsecretory MM (~2 % of MM Pts): no M p rotein, but marrow p lasmacytosis &

ROTI
• Ddx of M comp onent: MM, MGUS (see below), CLL, lymp homa, cirrhosis,
sarcoidosis, RA
• Perip heral smear → rouleaux (see insert); ✓ Ca, alb, Cr; ↓ anion gap , ↑ globulin, ↑
ESR
• Protein electrophoresis and immunofixation
serum protein electrophoresis (SPEP): quantitates M comp onent; in ~8 0%
of Pts
urine p rotein electrop horesis (UPEP): detects the ~2 0% of Pts who secrete only
light chains ( = Bence Jones p roteins), which are filtered rap idly from the blood
immunofixation: shows comp onent is monoclonal and identifies Ig typ e → IgG
(50% ), IgA (2 0% ), IgD (2 % ), IgM (0.5% ), light chain only (2 0% ), nonsecretors
(<5% )
serum-free light chain assay: imp ortant test for dx and follow-up of resp onse to
Rx
• β2 -microglobulin and LDH levels reflect tumor burden
• BM bx cytogenetics: normal karyotyp e better than abnl. Standard risk =

hyp erdip loidy or t(11;14); high risk = hyp odip loidy, del. 17p 13 (~10% of Pts),
t(4;14) & t(4;16)
• Gene mutations include TP53, NRAS, KRAS, BRAF & NK-kB p athway (Nature
2 011;471:467)
• Skeletal survey (p lain radiograp hs) to identify lytic bone lesions and areas at risk
for p athologic fracture; bone scan is not use ful for de te cting lytic le sions
Treatment (NEJM 2 011;364:1046; Am J He matol 2 012 ;8 7:79)
• Not indicated for smoldering MM or asx stage I disease
• Decisions generally dictated by risk stratification and transplant e lig ibility

• Active agents include: bortezomib (V), dexamethasone (D), p rednisone (P),
lenalidomide (R), thalidomide (T), melp halan (M), cyclop hosp hamide (C),
doxorubicin, carfilzomib (Cz)
• Induction Rx regimens w/ best resp onse rate incl. those w/ p roteasome inhib (V, Cz)
& immunomod (R), but many 2 - or 3-drug op tions used based on comorbidities
and risk. Proteasome inhib containing regimens incl. MPV, RVD, VCD & CzRD.
• If not transp lant eligible: induction chemo ↑ survival, not curative; consider maint
chemo
• If transp lant e lig ible : induction chemo (eg, RVD, VCD, RD, VTD; Lance t
2 010;376:2 075) then high-dose chemo + auto-HSCT. Not curative, but ↑ survival
c/w chemo (NEJM 2 009;360: 2 645). Timing of HSCT (up front vs. relap se) under
study. Offer if <70 y w/ good p erf. status & no p rohibitive comorbidities. Maint
Rx w/ R or V until p rogression or intolerance. Role of tandem auto-HSCT & allo-
HSCT remains controversial (NEJM 2 003;349:2 495).
• Local radiation for solitary or extramedullary p lasmacytoma
• Adjunctive Rx
bone : bisphosphonates (JCO 2 007;2 5:2 464); XRT for sx bony lesions
re nal: avoid NSAIDs & IV contrast; consider p lasmap heresis for acute renal failure
hype rviscosity syndrome : p lasmap heresis; infxns: consider IVIg for recurrent
infections
• Common toxicities of Rx: melp halan → myelosup p ression; lenalidomide → low p lts
& thromboembolism; bortezomib → p erip h. neurop athy; steroids →
hyp erglycemia, infxn
MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (MGUS)
Definition and epidemiology (NEJM 2 006;355:2 765)

• M p rotein <3 g/dL, no urinary Bence Jones p roteins, marrow p lasmacytosis
<10% , no ROTI
• Prevalence ~3% in p op ulation >50 y of age, ~5% in p op ulation >70 y of age,
and
7.5% in p op ulation >8 5 y of age (NEJM 2 006;354:1362 )
Management
• ✓ CBC, Ca, Cr, SPEP, serum free light chains, UPEP w/ immunofixation (to exclude
MM)
• Close observation: rep eat SPEP in 6 mo, then yearly thereafter if stable
Prognosis (NEJM 2 002 :346:564)
• ~1% /y or ~2 5% lifetime risk → MM, WM, amyloidosis, or malign.

lymp hop roliferative dis.
• Abnormal serum-free light chain ratio: ↑ risk of p rogression to MM (Blood

2 005;105:8 12 )
WALDENSTRÖM’S MACROGLOBULINEMIA (WM)
Definition (Blood 2 009;114:2 375)

• B-cell neop lasm (lymp hop lasmacytic lymp homa) that secretes monoclonal IgM
• MYD8 8 (NF-кB p athway) L2 65P somatic mutation found in 91% of Pts w/ WM and
could be used to distinguish WM from MM (NEJM 2 012 ;367:8 2 6)
• No e vide nce of bone le sions (IgM M comp onent + lytic bone lesions = “IgM
myeloma” )
• Fatigue from anemia is most common sx
• Tumor infiltration: BM (cytop enias), hep atomegaly, sp lenomegaly,
lymp hadenop athy
• Circulating monoclonal IgM
hyperviscosity syndrome (~15% )

neurologic: blurred vision (“sausage” retinal veins on funduscop y), HA, dizziness,
Δ MS
cardiop ulmonary: congestive heart failure, p ulmonary infiltrates

typ e I cryoglobulinemia → Raynaud’s phenomenon
p latelet dysfxn → mucosal bleeding

• IgM deposition (skin, intestine, kidney); amyloidosis and glomerulop athy
• Autoantibody activity of IgM

chronic AIHA (p rominent rouleaux; 10% Coombs’ = AIHA)
peripheral neuropathy: may be due to IgM against myelin-associated

glycop rotein
• SPEP + immunofixation with IgM >3 g/dL; 2 4-h urine for UPEP (only 2 0% have
UPEP)
• Bone marrow biop sy: ↑ p lasmacytoid lymp hocytes; β2 -microglobulin for p rognostic
eval
• Relative serum viscosity: defined as ratio of viscosity of serum to H 2 O (nl ratio
1.8 ) hyp erviscosity syndrome when relative serum viscosity >5–6
Treatment
• Hyp erviscosity: plasmapheresis
• Symp toms (eg, p rogressive anemia): rituximab ± chemotherap y (eg,

cyclop hosp hamide, chlorambucil, fludarabine, cladribine, bendamustine) or
bortezomib
• Thalidomide, alemtuzumab, everolimus, ibrutinib & auto-HSCT are investigational

Rx
HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)
Transplantation of donor pluripote nt ce lls that can re constitute all re cipie nt blood line ag e s
• Types of Allo HSCT: base d on donor/re cipie nt matching of major HLA antig e ns on Chr.
6 (4 p rincip al genes for serotyp ing: HLA-A, -B, -C, & -DR; each w/ 2 alleles ∴ 8
major Ag)
Matche d re late d (sibling matched at 8 /8 major Ag): lowest risk of GVHD;

p referred donor
Mismatche d re late d (eg, 1/8 Ag mismatch) or haploide ntical (mismatch at 4/8 Ag):
easiest to find, but ↑ risk of GVHD, rejection; ∴ need additional
immunosup p ression
Matche d unre late d: ↑ risk of GVHD; ∴ matching of 10 HLA alleles (DQ also) to ↓
risk; chance of match correlates w/ ethnicity
Umbilical cord blood: HSC p rocessed at birth & stored; ↓ risk of GVHD; tolerate
mismatch but much slower immune reconstitution (Blood 2 010;116:4693)
• Graft-vs.-host disease (GVHD): unde sirable side effect of allo HSCT allogeneic T cells
view host cells as foreign; ↑ incid. w/ mismatch or unrelated donors
• Graft-vs.-tumor (GVT) effect: de sire d in allo-SCT; graft T cells attack host tumor
cells
Indications (NEJM 2 006;354:18 13; BMT 2 010;45:12 59)
• Malignant disease:
Auto HSCT allows higher ablative chemo doses and then rescues the
hematop oietic system (used mostly for lymp homa, multip le myeloma, testicular
cancer)
Allo HSCT p roduces graft-versus-tumor (GVT) effect, in addition to hematop oietic

rescue (used for AML, ALL, CML, CLL, MDS, lymp homa)
• Nonmalignant disease: allo HSCT rep laces abnl lymp hohematop oietic system w/
one from nl donor (eg, immunodef., ap lastic anemia, hemoglobinop athies, ?
autoimmune dis.)
Transplantation procedure
• Preparative regimen: che mothe rapy and/or immunosuppre ssion p rior to

transp lantation
myeloablative (traditional): chemotherap y and/or total body irradiation. Goal is
e radication of underlying disease for which transp lant is being p erformed.
reduced intensity conditioning (RIC or “mini” ): lower dose conditioning → ↓

toxicity to allow Pts w/ comorbidities or ↑ age to tolerate HSCT. Goal to p roceed
w/ transp lant when in disease remission. Dep ends mostly on GVT; ↓ mortality
w/ RIC, but ↑ relap se.
• Sources of stem cells:
bone marrow (BM): original source of HSCT, now less commonly used than PBSC
peripheral blood stem cells (PBSC): easier collection, most commonly used
source
BM vs. PBSC survival; BM ↓ chronic GVHD, PBSC ↓ graft failure (NEJM

2 012 ;367:148 7)
umbilical cord blood (UCB): less stringent HLA-matching requirements, but fewer
cells available from single donor (∴ 2 donors combined in adults); slower
engraftment
haploidentical: most available; newer regimens starting to make safer/more
common
• Engraftment: absolute neutrop hil count (ANC) recovers to 500/µL w/in ~2 wk w/

PBSC, ~3 wk w/ BM, ~4 wk w/ UCB. G-CSF accelerates recovery by 3–5 d in all
scenarios.
Eng raftme nt syndrome : fever, rash, noncardiogenic p ulm edema, abnl LFTs, AKI,
wt gain. Dx of exclusion: r/o infection, GVHD; Rx w/ IV steroids.
Complications
• Either direct chemoradiotoxicities associated with p rep arative regimen or
consequences of interaction between donor and recipient immune systems
• Sinusoidal obstruction syndrome (SOS): incidence ~10% , mortality ~30%

Previously known as veno-occlusive disease (VOD)
Mechanism: direct cytotoxic injury to hep atic venules → in situ thrombosis
Symp toms: tender hep atomegaly, ascites, jaundice, fluid retention with severe
disease → liver failure, encep halop athy, hep atorenal syndrome
Diagnosis: ↑ ALT/AST, ↑ bilirubin; ↑ PT with severe disease; Dop p ler U/S may
show reversal of p ortal vein flow; ↑ hep atic wedge p ressure; abnl liver bx
Treatment: sup p ortive; p rop hylaxis with ursodiol; defibrotide
• Idiopathic pneumonia syndrome (IPS): up to 70% mortality (Curr Opin Oncol

2 008 ;2 0:2 2 7)
Mech: alveolar injury due to direct toxicity → fever, hyp oxia, diffuse p ulmonary
infiltrates
Diffuse alveolar hemorrhage (DAH): subset of IPS
Diagnosis: bronchoscop y to exclude infection; ↑ bloody lavage fluid seen with DAH
Treatment: high-dose corticosteroids, etanercep t (Blood 2 008 ;112 :3073)
• Acute GVHD (usually within 6 mo of transp lant; Lance t 2 009;373:1550)
Clinical grades I–IV based on scores for skin (severity of maculop ap ular rash),
liver (bilirubin level) and GI (volume of diarrhea); bx sup p orts diagnosis
Prevention: immunosuppression (MTX + CsA or tacrolimus) or T-cell dep letion of

graft
Treatment: grade I → none; grades II–IV → associated with ↓ survival and ∴

treated with immunosup p ressants (corticosteroids, CsA, tacrolimus, rap amycin,
MMF)
• Chronic GVHD (develop ing or p ersisting beyond 3 mo p osttransp lant)

Clinical: malar rash, sicca syndrome, arthritis, obliterative bronchiolitis, bile duct
degeneration, cholestasis and many others. More common w/ PBSC than BM.
Treatment: immunosup p ressants; rituximab; p hotop heresis

• Graft failure
Primary = p ersistent neutrop enia without evidence of engraftment
Secondary = delayed p ancytop enia after initial engraftment; either immune

mediated via immunocomp etent host cells (graft rejection) or non–immune
mediated (eg, CMV)
• Infectious complications
due to regimen-induced p ancytop enia and immunosup p ression
auto HSCT recip ients: no immunosup p ression ∴ at ↑ risk only p re-

/p ostengraftment
both p rimary infections and reactivation events occur (eg, CMV, HSV, VZV)
LUNG CANCER
(NEJM 2008; 359:1367; JCO 2012; 30:863; J Thorac Oncol 2012; 7:924; Nature
2011; 489:519; Cell 2012; 150:1107)

• Most common cause of cancer-related death for both men and women in the U.S.
• Cigarette smoking: 8 5% of lung cancers occur in smokers; risk ∝ total p ack-yrs, ↓

risk after quitting/reducing, but not to baseline (Int J Cance r 2 012 ;131:12 10)
squamous & small cell almost exclusively in smokers adenocarcinoma most
common typ e in nonsmokers bronchioalveolar carcinoma associated with women,
nonsmokers, EGFR mutations
• Asbestos: when combined with smoking, synergistic ↑ in risk of lung cancer

• Radon: risk to general p op ulation unclear
• ~10% are asx at p resentation and are detected incidentally by imaging
• Endobronchial growth of 1° tumor: cough, hemoptysis, dyspnea, wheezing, p ost–

obstructive p neumonia; more common with squamous or small cell (central
location)
• Regional spread
pleural effusion, p ericardial effusion, hoarseness (recurrent laryngeal nerve

p alsy), dysp hagia (esop hageal comp ression), stridor (tracheal obstruction)
Pancoast’s syndrome: ap ical tumor → brachial p lexus involvement (C8 , T1, T2 )

→ Horner’s syndrome, shoulder p ain, rib destruction, atrop hy of hand muscles
SVC syndrome (NEJM 2 007;356:18 62 ): central tumor → SVC comp ression → face
or arm swelling (>8 0% ), venous distention of neck & chest wall (~60% ),
dysp nea/cough (~50% ), HA (~10% ); Rx = steroids & diuretics, RT ± chemo
after tissue dx, SVC stent for severe sx, fibrinolytic + anticoag if thrombus
• Extrathoracic metastases: brain, bone, liver, adrenal
• Paraneoplastic syndromes
Endocrine :
ACTH (SCLC) → Cushing’s syndrome; ADH (SCLC) → SIADH
PTH-rP (squamous cell) → hypercalcemia

Ske le tal: digital clubbing (non–small cell), hypertrophic pulmonary
osteoarthropathy (adenocarcinoma) = symmetric p olyarthritis and
p roliferative p eriostitis of long bones
Ne urolog ic (SCLC): Eaton-Lambert, p erip heral neurop athy, cerebellar

degeneration, limbic encep halitis
Cutane ous: acanthosis nigricans, dermatomyositis
He matolog ic: hyp ercoagulable state (adenocarcinoma), DIC, marantic endocarditis
Screening (JAMA 2 011;306:18 65; NEJM 2 011;365:395)

• No benefit to CXR or sp utum cytology, even in high-risk Pts
• Low-dose chest CT in >30 p ack-y smokers age 55–74 y → 2 0% ↓ in lung cancer–
related mortality vs. CXR; number needed to screen = 32 0; high false rate
Diagnostic and staging evaluation (NCCN Guide line s v.3.2 012 )

• Initial imaging: chest CT (include liver and adrenal glands) w/ contrast if p ossible
• Tissue
bronchoscopy (for central lesions) or CT-guided needle bx (for p erip heral lesions
or accessible sites of susp ected metastasis)
mediastinoscop y (lymp h node bx), VATS (eval. of p leura p erip heral lesions),
thoracentesis (cell block for cytology) or sp utum cytology (for central lesions)
• Staging
Intrathoracic: mediastinoscopy (± p receded by U/S-guided transesop h. or

transbronch. needle asp iration; JAMA 2 010;304:2 2 45) or VATS; thoracentesis if
p leural effusion
Extrathoracic: PET-CT more Se than CT alone for detecting mediastinal and distant
mets as well as bone mets (NEJM 2 009;361:32 ); brain MRI for all Pts (excep t IA)
• Genetic testing for EGFR mutations and ALK rearrang. for stage IV nonsquam
NSCLC
• PFTs w/ quantitative V/Q if p lanned treatment includes surgical resection; need to

have 30% of normal, p redicted lung fxn afte r resection
NSCLC treatment (NCCN Guide line s v.3.2 012 )
• Stages I & II: surgical resection + adjuvant chemo (surgery alone for stage IA)
(NEJM 2 004;350:351 & 2 005;352 :2 58 9)
• Stage III: chemoradiation is main treatment modality
IIIA viewed as p otentially resectable (Lance t 2 009;374:379) and IIIB as

unresectable neoadjuvant chemoradiation may convert unresectable → resectable
• Stage IV: chemotherapy ↑ survival vs. best sup p ortive care
backbone of therap y is p latinum-based doublet; cisp latin/p emetrexed better for
adenocarcinoma; cisp latin/gemcitabine better for squamous (JCO 2 008 ;2 6:3543)
bevacizumab (anti-VEGF mAb) + chemo ↑ median survival by 2 mo; ↑ risk of
bleeding, ∴ do not use if untreated or hemorrhagic brain mets (JCO
2 009;2 7:52 55) or squamous cell (hemop tysis) (NEJM 2 006;355:2 542 )
if EGFR mutation (a/w imp roved p rognosis): EGFR tyrosine kinase inhibitor (TKI,
eg, erlotinib) first-line Rx (Lance t 2 008 ;372 :18 09; NEJM 2 010;362 :2 38 0 &
2 011;364:947)
if ALK rearrangement: ALK TKI (eg, crizotinib) first-line Rx (Lance t Oncol
2 011;12 :1004)
TKI toxicities: rash & diarrhea (common); lung & liver injury (rare but p otentially
serious) p alliative radiation used to control local sx caused by tumor or
metastasis solitary brain metastasis: surgical resection + brain radiation may ↑
survival
SCLC treatment (NCCN Guide line s v.2 .2 013)
• SCLC usually disseminated at p resentation, but can be very resp onsive to

chemoradiation
• Chemotherapy (p latinum + etop oside) is p rimary treatment modality
• Thoracic radiation added to chemotherap y imp roves survival in limited stage

disease
• Prophylactic cranial irradiation (PCI) imp roves survival for limited stage disease
in comp lete remission (NEJM 1999;341:476)
BREAST CANCER
Epidemiology and genetics (risk assessment tool: www.cancer.gov/bcrisktool/)

• In U.S., most common cancer in women; 2 nd leading cause of cancer death in
women
• Age: incidence rates ↑ with age, with p ossible ↓ in slop e after menop ause
• Genetics (Nature 2 012 ;490:61): Mutations in TP53, PIK3CA and GATA3; HER2
amp lified. 15–2 0% have FHx → 2 × ↑ risk; ~45% of familial cases a/w
known germline mutation
BRCA1/2: 35–8 5% lifetime risk of breast cancer & ↑ risk of ovarian cancer; ? ↑
colon & p rostate cancer; p rog not worse than in noncarriers w/ breast ca (NEJM
2 007;357:115); BRCA2 : a/w ↑ male breast cancer & p ancreatic cancer. Rare
mutations in CHEK2, HRAS, TP53 a/w ↑ risk in familial breast cancer (Bre ast
Cance r Tre at Re s 2 011;12 7:309)
• Estrogen: ↑ risk with early menarche, late menop ause, late p arity or nullip arity
(NEJM 2 006;354:2 70); ↑ risk with p rolonged HRT (RR = 1.2 4 after 5.6 y, JAMA
2 003;2 8 9:32 43);
no ↑ risk shown with OCP use (NEJM 2 002 ;346:2 02 5)

• Benign breast conditions: ↑ risk w/ atyp ia (atyp ical ductal or lobular hyp erp lasia)
& p roliferative (ductal hyp erp lasia, p ap illoma, radial scar or sclerosing adenosis)
features; no ↑ risk w/ cysts, fibroadenoma or columnar changes (NEJM
2 005;352 :2 2 9)
• ↑ risk with h/o ionizing radiation to chest for treatment of Hodgkin lymp homa
• Breast mass (hard, irregular, fixed, nontender), nip p le discharge (higher risk if
unilateral, limited to one duct, bloody, associated with mass)
• Sp ecial typ es: Paget’s disease → unilateral nip p le eczema + nip p le discharge;
inflammatory breast cancer → skin erythema and edema (pe au d’orang e )
• Metastases: lymp h nodes, bone, liver, lung, brain
Screening (NEJM 2 011;365:102 5)
• Self breast exam (SBE): no p roven mortality benefit (JNCI 2 002 ;94:1445); not
recommended
• Clinical breast exam (CBE): benefit indep endent of mammograp hy not established
• Mammography: ~2 0–30% ↓ in breast cancer mortality (smaller abs. benefit in

women <50 y) (Lance t 2 006;368 :2 053; Annals 2 009;151:72 7); 75% of all abnl
findings benign; susp icious: clustered microcalcifications, spiculated, enlarging
adding U/S ↑ Se, but ↓ PPV (JAMA 2 008 ;2 99:3151)
• ACS/NCI recommend annual mammo + CBE beginning at age 40; USPSTF

recommends beginning at 50 and biennially (Annals 2 009;151:716), controve rsial
(NEJM 2 009;361:2 499)
• ↑ risk: screen earlier w/ CBE and mammo (age 2 5 in BRCA1/2 carrier, 5–10 y
before earliest FHx case, 8 –10 y after thoracic RT, up on dx of ↑ risk benign
disease)
• MRI: sup erior to mammo in high-risk Pts; consider annually if >2 0% lifetime risk
(eg, FHx, BRCA1/2, p rior chest RT) (Lance t 2 011;378 :18 04)
• Genetic testing should be considered in women with strong FHx

• Palpable breast mass: age <30 y → observe for resolution over 1–2 menstrual
cycles;
age <30 y, unchanging mass → U/S → asp iration if mass not simp le cyst;
age >30 y or solid mass on U/S or bloody asp irate or recurrence after asp iration
→ mammo (detect other lesions) and either fine-needle asp. or core-needle bx
clearly cancerous on exam or indeterminate read or atyp ia on bx → excisional
bx
• Suspicious mammogram with normal exam: stereotactically guided bx
• MRI: detects contralateral cancer in 3% of women w/ recently dx breast cancer &
negative contralateral mammogram (but PPV only 2 1% ) (NEJM 2 007;356:12 95);
whether to use routinely remains unclear
Staging
• Anatomic: tumor size, chest wall invasion, axillary LN mets (strong e st prog nostic
factor)
• Histopathologic: typ e (little p rognostic relevance) & grade; lymp hatic/vascular

invasion
In situ carcinoma: no invasion of surrounding stroma
Ductal (DCIS): ↑ risk of invasive cancer in ipsilate ral breast (~30% /10 y)
Lobular (LCIS): marker of ↑ risk of invasive cancer in e ithe r breast (~1% /y)
Invasive carcinoma: infiltrating ductal (70–8 0% ); invasive lobular (5–10% );

tubular, medullary and mucinous (10% , better p rognosis); p ap illary (1–2 % );
other (1–2 % )
Inflammatory breast cancer (see above): not a histologic typ e but a clinical
reflection of tumor invasion of dermal lymp hatics; very p oor p rognosis
Paget disease: ductal cancer invading nip p le ep idermis ± associated mass
• Biomarkers: determine estrogen, p rogesterone recep tor (ER/PR) and HER2/ne u

status for all invasive breast cancers
• Oncotyp e DX 2 1-gene risk recurrence score has p redictive and p rognostic value in
ER , node or Pts (JCO 2 007;2 5:52 8 7 & 2 010;2 8 :18 2 9; Lance t
2 011;378 :18 12 )
• Circulating tumor DNA may serve as biomarker of met tumor burden (NEJM
2 013;368 :1199)
Treatment
• Local control: surgery and radiation therapy (RT)

Bre ast-conse rving = lump ectomy + breast RT + axillary node dissection (ALND)
is equivalent to maste ctomy + ALND (NEJM 2 002 ;347:12 2 7); contraindications:
multicentric disease, diffuse microcalcifications, p rior RT, p regnancy, ? tumor
>5 cm
Se ntine l lymph node disse ction (SLND) p rior to ALND p referred if w/o p alp
axillary LNs; T1-2 w/ SLND & Rx w/ lump ect./RT/chemo may not need
ALND (JAMA 2 011;305:569)
Radiation the rapy (RT) after mastectomy for ≥4 LN, tumor >5 cm or
surgical margins → ↓ locoregional recurrence and ↑ survival (Lance t
2 011;378 :1707)
• Systemic therapy: for stage I-III excep t tumors <1 cm (comp lex risk assessment
needed). http ://www.adjuvantonline.com/index.jsp can guide use of chemo and/or
hormonal Rx.
Che mothe rapy (Lance t 2 008 ;371:2 9): in neoadjuvant setting usually
anthracycline-based (eg, adriamycin + cyclop hosp hamide). Sequential Rx w/
taxane (eg, p aclitaxel) → small ↑ survival (NEJM 2 007;357:1496;
2 010;362 :2 053 & 2 010;363:2 2 00).
Anti-HER2 the rapy (growing list of agents) in HER2 tumors (NEJM
2 012 ;366:176)
trastuzumab (Hercep tin; anti-HER2 mAb) ↑ survival (NEJM 2 001;344:78 3); give
after anthracycline or w/ taxane to avoid cardiotox (JCO 2 002 ;2 0:12 5 & NEJM
2 011;365:12 73) lap atinib (tyrosine kinase inhib. of HER2 & EGFR) +
trastuzumab ↑ survival after failing trastuzumab (JCO 2 012 ;30:2 58 5); dual
inhib. initial Rx ↑ resp onse (Lance t 2 012 ;379:633) p ertuzumab (anti-HER2 mAb,
p revents dimerization) ↑ p rogression-free survival when added to trastuzumab
as first-line Rx for metastatic dis. (NEJM 2 012 ;366:109) trastuzumab emtansine
(T-DM1, HER2 mAb conjugated to microtubule inhibitor) ↑ survival comp ared to
second-line lap atinib + cap ecitabine (NEJM 2 012 ;367:178 3)
Be vacizumab (anti-VEGF): ? in neoadjuvant Rx if HER2 (NEJM 2 012 ;366:2 99 &

310)
Hormonal (in ER/PR or unknown status)
tamoxifen: 39% ↓ recurrence and 30% ↓ breast cancer mortality in p re- and p ost-
menop ausal p atients; 10 y of Rx sup erior to 5 y (Lance t 2 011;378 :771 &
2 013;38 1:8 05)
aromatase inhibitors (AI) (anastrozole, letrozole, exemestane): ~18 % ↓

recurrence vs. tamoxifen in postme nopausal Pts (Lance t 2 005;365:60; NEJM
2 005;353:2 747)
everolimus ↑ p rogression-free survival if p ostmenop ausal & failed AI (NEJM
2 012 ;366:52 0)
2 nd-line: ovarian ablation with LHRH agonists (goserelin) or oop horectomy if

pre me nopausal; p ure antiestrogens (fulvestrant) if postme nopausal
Prevention (with selective estrogen recep tor modulator [SERM] or AI)
• Tamoxifen: ↓ risk contralat. breast CA as adjuvant Rx. Ap p roved for 1° p revent. if
↑ risk: ↓ invasive breast ca, but ↑ DVT & uterine CA; ? ↑ in mortality (Lance t
2 002 ;360:8 17 ).
• Raloxifene: ↓ risk of invasive breast cancer & vertebral fx, ↑ risk of stroke & DVT/PE
(NEJM 2 006;355:12 5); tamoxifen in p revention of breast cancer w/ ↓ risk of
DVT/PE & cataracts, trend toward ↓ uterine cancer ( JAMA 2 006;2 95:2 72 7 )
• Exemestane in high-risk p ostmenop ausal ↓ invasive breast ca by 65% (NEJM

2 011;364:2 38 1)
• BRCA1/2 : intensified surveillance as described above. Prop hylactic bilat.
mastectomy → ~90% ↓ risk; bilat. salp ingo-oop horectomy ↓ risk of ovarian and
breast cancer.
PROSTATE CANCER
Epidemiology and risk factors (NEJM 2 003;349:366)

• Most common cancer in U.S. men; 2 nd most common cause of cancer death in men
• Lifetime risk of p rostate cancer dx ~16% ; lifetime risk of dying of p rostate cancer
~3%
• More common with ↑ age (rare if <45 y), in African Americans and if FHx
• ↑ risk w/ BRCA2 (4.7) and BRCA1 (1.8 ) (JNCI 1999;91:1310 & 2 002 ;94:1358 )
Clinical manifestations (usually asymp tomatic at p resentation)
• Obstructive sx (more common with BPH): hesitancy, ↓ stream, retention, nocturia

• Irritative sx (also seen with p rostatitis): frequency, dysuria, urgency
• Perip rostatic sp read: hematuria, hematosp ermia, new-onset erectile dysfunction

• Metastatic disease: bone p ain, sp inal cord comp ression, cytop enias
Screening (NEJM 2 012 ;367:e11)

• Digital rectal exam (DRE): size, consistency, lesions
• PSA: 4 ng/mL cut p oint neither Se nor Sp ; can ↑ with BPH, p rostatitis, acute
retention, after bx or TURP, and ejaculation (no sig nificant ↑ afte r DRE, cystoscopy);
15% of men >62 y w/ PSA <4 & nl DRE have bx-p roven T1 cancer (NEJM
2 004;350:2 2 39)
• Per American Cancer Soc. men ≥50 y (or ≥ 45 y if African-Am or FHx) should
discuss PSA screening w/ their MD; USPSTF rec. against screening in asx males (no
reduction in p rostate cancer-related mortality) (NEJM 2 009;360:1310; Annals
2 012 ;157:12 0)
• Transrectal ultrasound (TRUS) guided biopsy, with 6–12 core sp ecimens
• Histology: Gleason grade (2 –10; low grade ≤6) = sum of the differentiation score
(1 = best, 5 = worst) of the 2 most p revalent p atterns in the bx; correlates with
p rognosis
• Imaging: to evaluate extrap rostatic sp read bone scan: for PSA >10 ng/mL, high
Gleason grade or clinically advanced tumor abdomen-p elvis CT: inaccurate for
detecting extracap sular sp read and lymp h node mets endorectal coil MRI:
imp roves assessment of extracap sular sp read
Prognosis
• PSA level, Gleason grade and age are p redictors of metastatic disease
• In surgically treated Pts, 5-y relap se-free survival >90% if disease confined to
organ, ~75% if extension through cap sule, and ~40% if seminal vesicle invasion
• PSA doubling time, Gleason, & time to biochemical recurrence p redict mortality
following recurrence. For local recurrence following RP, salvage RT may be
beneficial if low PSA.
• Metastatic disease: median survival ~2 4–30 mo; all become castrate resistant (in
15–2 0% discontinuation of antiandrogens results in p aradoxical ↓ in PSA)
• Long-term consequences of antiandrogen therap y include osteop orosis
Prevention
• Finasteride and dutasteride ↓ total p rostate cancers detected by bx, but ↑ number of
high Gleason grade tumors (NEJM 2 003;349:2 15 & 2 010;362 :1192 )
COLORECTAL CANCER (CRC)
Epidemiology and risk factors (Lance t 2 010;375:1030; CA Cance r J Clin 2 011;61:2 12 )

• 4th most common cancer in U.S. men & women; 2 nd leading cause of all cancer
death
• Rare before age 40, w/ 90% of cases occurring after age 50. ~75% are sp oradic.
• Family history: up to 2 5% of Pts have FHx. Risk dep ends on # of 1st-degree

relatives (w/ CRC or p olyp ) and their age at dx; ~5% have an identifiable
germline mutation
Familial adenomatous polyposis (FAP): mutation in APC gene → 1000s of p olyp s
at young age → ~100% lifetime risk; ↑ risk of thyroid, stomach, small bowel
cancers
Hereditary nonpolyposis colorectal cancer (HNPCC): most common hereditary

CRC (~3% of all CRC; NEJM 2 003;348 :919); mutations in DNA mismatch
rep air genes (eg, MSH2, MLH1) → microsatellite instability (MSI) → ↑ tumor
p rogression → ~8 0% lifetime risk; p redom. right-sided tumors; ↑ risk of
endometrial, ovarian, stomach, urothelial, small bowel and p ancreatic cancers.
Amsterdam criteria: ≥3 family members w/ HNPCC-related cancer, one of which

is dx before age 50, affecting 2 successive generations.
• Inflammatory bowel disease: ↑ risk with ↑ extent and duration of disease
• Other factors a/w ↑ risk of CRC: diet rich in animal fat, ? smoking, ?
diabetes/obesity
• COX-2: ↓ risk of adenomas w/ ASA & NSAIDs. ASA assoc. w/ ↓ CRC incidence, mets
and mortality (Lance t: 2 010;376:1741; 2 012 ;379:1591 & 1602 ). ↓ COX-2 -
exp ressing CRC after p rolonged ASA (NEJM 2 007;356:2 131). ASA effect limited to
PIK3CA-mut CRC (NEJM 2 012 ;367:1596). COX-2 inhib. effective but ↑ bleeding &
CV events (NEJM 2 006;355:8 73 & 8 8 5).
Pathology and genetics (NEJM 2 009;361:2 449; Nature 2 012 ;48 7:330)
• Adenoma → carcinoma sequence reflects accumulation of multip le genetic

mutations. ↑ risk of malig. w/ large (>2 .5 cm), villous, sessile adenomatous
p olyp s. Adenomas typ ically observed ~10 y p rior to onset of cancer (both
sp oradic & familial).
• Genetic p rofile in sp oradic CRC: APC (~8 0% ), KRAS (~40% ), TP53 (50–70% ), DCC
or SMAD4, or BRAF (~15% ); chrom instability (majority) or mismatch rep air
defic (10–15% )
• Up front genotyp ing may guide Rx; eg, benefit of anti-EGFR Ab cetuximab greater in
KRAS wild-typ e than KRAS mutant (NEJM 2 008 ;359:1757). BRAF mutation may
guide clinical trials.
• Distal colon: Δ bowel habits, obstruction, colicky abdominal p ain, hematochezia
• Proximal colon: iron defic. anemia, dull vague abd p ain; obstruction atyp ical due
to larger lumen, liquid stool and p olyp oid tumors (vs. annular distal tumors)
• Metastases: nodes, liver, lung, p eritoneum → RUQ tenderness, ascites,

sup raclavicular LN
• Associated with Stre ptococcus bovis bacteremia and Clostridium se pticum sep sis
Screening (NEJM 2 009;361:1179)
• Average risk: colonoscop y starting at age 50 & rep eat q10y strongly p referred
method
• ↑ risk: earlier and/or more frequent screening. FHx: age 40 or 10 y before index
dx, then q5y. IBD: 8 –10 y after dx, then q1–2 y. Known or susp ected familial
syndrome: genetic counseling & very early screening (eg, age 2 0–2 5 y), then q1–
2 y.
• Imaging
Colonoscopy: test of choice as examines entire colon; 90% Se for lesions >1 cm.
Flex sig less Se vs. colo and CTC (Gut 2 009;58 :2 41). If p olyp found, re ✓ in 3–5
y. Removal of adenomatous p olyp s associated with lower CRC mortality (NEJM
2 012 ;366:68 7).
Sigmoidoscopy: 2 1% ↓ incidence in CRC & 2 6% ↓ mortality in distal CRC (NEJM
2 012 ;366:2 345). Benefit may also be seen w/ 1-time flex-sig (Lance t
2 010;375:972 6).
CT colonography (CTC): c/w colonoscop y, ~90% Se for lesions ≥1 cm but
considerably less for smaller lesions (NEJM 2 008 ;359:12 07). In high-risk Pts, Se
only 8 5% for advanced neop lasia ≥6 mm (JAMA 2 009;301:2 453). At
p op ulation level, ↑ p articip ation w/ CTC, but ↓ yield vs. colonoscop y; ∴
similar screening overall (Lance t 2 012 ;13:55).
• Biochemical fecal testing

Occult blood (FOBT): ↓ mortality (NEJM 1993;32 8 :1365 & 2 000;343:1603); 3
card home testing more Se (2 4% vs. 5% ) than DRE/FOBT (Annals 2 005;142 :8 1).
Rep eat q1y.
Immunohisto for Hb: Se ~35% & ~8 0% for adv neop lasia & CRC (AJG
2 012 ;107:1570)
DNA: ↑ Se, Sp c/w FOBT, but less Se than colonoscop y (NEJM 2 004;351:2 704)
Staging (AJCC Cance r Stag ing Manual, 7th ed, 2 010)
• TNM staging: Size/dep th of p rimary (T), locoregional nodes (N), distant metastases
(M). Staging is comp lex and based on p athologic correlation with observed
survival data.
• Colonoscopy + biopsy/polypectomy + intraoperative and pathologic staging

essential for evaluating extracolonic sp read
• CT scans of chest and abdomen/p elvis (inaccurate for dep th of invasion & malignant
LN)
• Baseline CEA in Pt with known CRC has p rognostic significance and is useful to fol-
low resp onse to therap y and detect recurrence; not a screening tool
• Chemotherap y
FOLFOX (5-FU + leucovorin + oxaliplatin), FOLFIRI or Cap eOx (NEJM

2 004;350:2 343)
± Bevacizumab (anti-VEGFA mAb, NEJM 2 004;350:2 335) or cetuximab (anti-EGFR

mAb, NEJM 2 004:351:337; benefit limited to Pts w/o KRAS mutation; NEJM
2 008 ;359:1757)
Regorafenib (multikinase inhib.) ↑ survival in Pts w/ p rogressive metastatic CRC

(Lance t 2 013;38 1:303).
CHEMOTHERAPY SIDE EFFECTS
PANCREATIC TUMORS
Pathology and genetics (Annu Re v Pathol 2 008 ;3:157; Nature 2 012 ;491:399)
• Histologic typ es: adenocarcinoma, acinar cell carcinoma, endocrine tumors, cystic
neop lasms (eg, IPMN, see below); rarely, mets to p ancreas (eg, lung, breast, renal
cell)
• Pancreatic adenocarcinoma accounts for majority of p ancreatic cancer (~8 5% )
• Location: ~60% in head, 15% in body, 5% in tail; in 2 0% diffuse infiltration of
p ancreas
• Mutations in adenoca.: KRAS (>90% ), p16 (8 0–95% ), p53 (50–75% ), SMAD4
(~55% )
Epidemiology and risk factors (Lance t 2 011;378 :607)

• Pancreatic adenocarcinoma 4th leading cause of cancer death in U.S. men and
women
• 8 0% of p ancreatic adenocarcinomas occur in Pts 60–8 0 y

• Acquired risk factors: smoking (RR ~1.5; 2 0% Pts), obesity, chronic p ancreatitis, ?
diabetes
• Hereditary risk factors: genetic suscep tibility may p lay a role in 5–10% of cases
Hereditary chronic p ancreatitis: mutation in cationic tryp sinogen gene (PRSS1)
Familial cancer syndromes and gene mutations with ↑ risk: familial atyp ical
multip le mole melanoma (CDKN2A/p16 ), familial breast and ovarian cancer
(BRCA2), Peutz-Jeghers (LKB1), ataxia-telangiectasia (ATM), ? hereditary
colorectal cancer (HNPCC and FAP)
• Painless jaundice (w/ p ancreatic head mass), pain radiating to back, ↓ appetite &
wt
• New-onset atyp ical diabetes mellitus (2 5% ); unexp lained malabsorp tion or

p ancreatitis
• Migratory thrombop hlebitis (Trousseau’s sign), not sp ecific to p anc cancer (JCO
198 6;4:509)
• Exam: abd mass; nontender, p alp able gallbladder (Courvoisier’s sign, but more
often seen w/ biliary tract cancers); hep atomegaly; ascites; left sup raclavicular
(Virchow’s) node & p alp able rectal shelf (both nonsp ecific signs of carcinomatosis)
• Laboratory tests may show ↑ bilirubin, ↑ alk p hos, anemia
Diagnostic and staging evaluation (NCCN Guide line s v.2 .2 012 )
• Pancreatic protocol CT scan (I+ w/ arterial & venous p hase imaging) or MRI
• If no lesion seen → EUS, ERCP, MRI/MRCP may reveal mass or malignant ductal
strictures
• Biop sy p ancreatic lesion via EUS-guided FNA (p referred in p otential surgical

candidates) or CT-guided (p otential risk of seeding) or biop sy of p ossible
metastasis
• ↑ CA19-9 (nb, also ↑ in benign liver/biliary disease); may be useful to follow dis.
p ostop
Treatment of pancreatic adenocarcinoma (NEJM 2 010;362 :1605; Lance t
2 011;378 :607)
• Resectable: surgery ± adjuvant (neoadjuvant or p ostop erative) therap y
p ancreaticoduodenectomy = Whipple procedure = resection of p ancreatic head,

duodenum, CBD and gallbladder ± p artial gastrectomy
adjuvant therap y: ↑ survival but choice of regimen controversial (chemo vs.
chemo/RT and gemcitabine vs. 5-FU (J Surg Oncol 2 013;107:78 )
• Locally advanced: op timal strategy controversial. Gemcitabine alone vs. gemcitabine

+ RT ( JCO 2 008 ;2 6:2 14s; Ann Oncol 2 008 ;19:1592 ; JCO 2 011;2 9:4105).
• Metastatic: FOLFIRINOX (5-FU + leucovorin, irinotecan, oxalip latin) if good
p erform. status (NEJM 2 011;364:18 17); gemcitabine combination (eg, w/ nab-
p aclitaxel; JCO 2 011;2 9:4548 ) or monotherap y if p oor p erformance status (JCO
1997;15:2 403). Offer clinical trials.
• Palliative and sup p ortive care:
obstructive jaundice or gastric outlet obstruction: endoscop ic stenting or surgical
byp ass p ain: op iates, celiac p lexus neurolysis, radiation therap y weight loss:
p ancreatic enzyme rep lacement, nutrition consult, end-of-life discussions
Cystic lesions of the pancreas (NEJM 2 004;351:12 18 ; Oncolog ist 2 009;14:12 5)
• <10% of p ancreatic neop lasms. Dx w/ CT, ERCP, MRCP or EUS.
• Serous cystadenoma: usually benign; central scar or honeycomb ap p earance on

imaging
• Mucinous cystic neoplasm (MCN): p redominantly young females; multiloculated

tumors in body or tail w/ ovarian-typ e stroma and mucin-rich fluid w/ ↑ CEA
levels; p recancerous
• Intraductal papillary mucinous neoplasm (IPMN): neop lasm arising in main

p ancreatic duct or a branch; a/w ductal dilation w/ extrusion of mucinous
material. Uncertain p rogression to cancer (? 5–2 0 y). Surgery based on age, size,
location, dysp lasia.
ONCOLOGIC EMERGENCIES
FEVER AND NEUTROPENIA (FN)

Definition
• Fever: single oral temp ≥38 .3°C (101°F) or ≥38 °C (100.4°F) for ≥1 h
• Neutropenia: ANC <500 cells/µL or <1000 cells/µL with p redicted nadir <500
cells/µL
Pathophysiology and microbiology
• Predisp osing factors: catheters, skin breakdown, GI mucositis, obstruction
(lymp hatics, biliary tract, GI, urinary tract), immune defect a/w malignancy
• Most ep isodes thought to result from seeding of bloodstream by GI flora
• Neutrop enic enterocolitis (typ hlitis): RLQ p ain, watery/bloody diarrhea, cecal wall
thickening
• GNRs (esp . P. ae rug inosa) were historically most common

• Gram infections have recently become more common (60–70% of identified
organisms)
• Fungal sup erinfection often results from p rolonged neutrop enia & antibiotic use
• Infection with atyp ical organisms and bacterial meningitis is rare

Prevention
• Levofloxacin (500 mg qd) ↓ febrile ep isodes & bacterial infections in chemo-related

high-risk neutrop enic p atients; no difference in mortality (NEJM 2 005;353:977 &
98 8 )
• Exam: skin, orop harynx, lung, p erirectal area, surgical & catheter sites; avoid DRE
• Labs: CBC with differential, electrolytes, BUN/Cr, LFTs, U/A
• Micro: blood (p erip heral & through each indwelling catheter p ort), urine, & sp utum
cx; for localizing s/s → ✓ stool (C. difficile , cx), p eritoneal fluid, CSF (rare source)
• Imaging: CXR; for localizing s/s → CNS, sinus, chest or abdomen/p elvis imaging
• Caveats: neutrop enia → imp aired inflammatory resp onse → e xam and radiog raphic
finding s may be subtle ; absence of neutrop hils by Gram stain does not r/o infection
Risk stratification (factors that p redict lower risk)
• History: age <60 y, no symp toms, no major comorbidities, cancer in remission,

solid tumor, no h/o fungal infection or recent antifungal Rx
• Exam: temp <39°C, no tachyp nea, no hyp otension, no Δ MS, no dehydration
• Studies: ANC >100 cells/µL, anticip ated duration of neutrop enia <10 d, normal
CXR
Initial antibiotic therapy (Clin Infe ct Dis 2 011;52 :e56)
• Emp iric regimens including drug w/ antipseudomonal activity; consider VRE

coverage if colonized; OR 3.8 for VRE if VRE (BBMT 2 010;16:1576)
• PO abx may be used in low-risk Pts (<10 d neutrop enia, nl hep /renal fxn, no
N/V/D, no active infxn, stable exam): cip ro + amoxicillin-clavulanate (NEJM
1999;341:305)
• IV antibiotics: no clearly sup erior regimen; monotherap y or 2 -drug regimens can be
used
Monotherap y: ceftazidime, cefep ime, imip enem or merop enem

2 -drug therap y: aminoglycoside + antip seudomonal β-lactam
PCN-allergic: levofloxacin + aztreonam or aminoglycoside
• Vancomycin added in select cases (hyp otension, indwelling catheter, severe

mucositis, MRSA colonization, h/o quinolone p rop hylaxis), discontinue when
cultures × 48 h
Modification to initial antibiotic regimen

• Low-risk Pts who become afebrile w/in 3–5 d can be switched to PO antibiotics
• Emp iric antibiotics changed for fever >3–5 d or p rogressive disease (eg, add
vancomycin)
• Antifungal therap y is added for neutrop enic fever >5 d
lip osomal amp hotericin B, casp ofungin, micafungin, anidulafungin, voriconazole,

p osaconazole all op tions (NEJM 2 002 ;346:2 2 5; 2 007;356:348 )
Duration of therapy
• Known source: comp lete standard course (eg, 14 d for bacteremia)
• Unknown source: continue antibiotics until afebrile and ANC >500 cells/µL
• Less clear when to d/c abx when Pt is afebrile but p rolonged neutrop enia
Role of hematopoietic growth factors (NEJM 2 013;368 :1131)

• Granulocyte (G-CSF) and granulocyte-macrop hage (GM-CSF) colony-stimulating
factors can be used as 1° p rop hylaxis when exp ected FN incidence >2 0% or as 2 °
p rop hylaxis after FN has occurred in a p revious cycle (to maintain dose-intensity
for curable tumors). CSFs ↓ rate of FN but have not been shown to imp act
mortality.
• Colony-stimulating factors can be considered as adjuvant therap y in high-risk FN Pts

SPINAL CORD COMPRESSION
Clinical manifestations (Lance t Ne uro 2 008 ;7:459)

• Metastases located in vertebral body extend and cause ep idural sp inal cord
comp ression
• Prostate, breast and lung cancers are the most common causes, followed by renal
cell
carcinoma, NHL and myeloma
• Site of involvement: thoracic (60% ), lumbar (2 5% ), cervical (15% )

• Signs and symp toms: pain (>95% , pre ce de s ne uro Ds), weakness, autonomic
dysfunction (urinary retention, ↓ anal sp hincter tone), sensory loss
• Always take back p ain in Pts with solid tumors very seriously
• Do not wait for neurologic signs to develop before initiating evaluation b/c duration
& severity of neurologic dysfunction before Rx are best p redictors of neurologic
outcome
• Urgent whole-spine MRI (Se 93% , Sp 97% ); CT myelogram if unable to get MRI
Treatment
• Dexamethasone (10 mg IV × 1 stat, then 4 mg IV or PO q6h)
initiate imme diate ly while awaiting imaging if back p ain + neurologic deficits
• Emergent RT or surgical decomp ression if confirmed comp ression/neuro deficits
• Surgery + RT sup erior to RT alone for neuro recovery in solid tumors (Lance t
2 005;366:643)
• If p athologic fracture causing comp ression → surgery; if not surgical candidate →

RT
TUMOR LYSIS SYNDROME
Clinical manifestations (NEJM 2 011;364:18 44; BJH 2 010;149:578 )

• Large tumor burden or a rap idly p roliferating tumor → sp ontaneous or
chemotherap y-induced release of intracellular electrolytes and nucleic acids
• Most common w/ Rx of high-grade lymp homas (Burkitt’s) and leukemias (ALL,
AML, CML in blast crisis); rare with solid tumors; rarely due to sp ontaneous
necrosis
• Electrolyte abnormalities: ↑ K, ↑ uric acid, ↑ PO 4 → ↓ Ca
• Renal failure (urate nep hrop athy)

Prophylaxis
• Allop urinol 300 mg qd to bid PO or 2 00–400 mg/m 2 IV (adjusted for renal fxn) &
aggressive hydration p rior to beginning chemotherap y or RT
• Rasburicase (recombinant urate oxidase) 0.15 mg/kg or 6 mg fixed dose (excep t in

obese Pts) & aggressive hydration p rior to beginning chemotherap y or RT (see
below)
Treatment
• Avoid IV contrast and NSAIDs
• Allop urinol + aggressive IV hydration ± diuretics to ↑ UOP

• Consider alkalinization of urine w/ isotonic NaHCO 3 to ↑ UA solubility & ↓ risk of
urate nep hrop athy (controversial: may cause metabolic alkalosis or Ca 3(PO4)2
p recip itation)
• Rasburicase (0.1–0.2 mg/kg × 1, rep eat as indicated) for ↑↑ UA, esp . in aggressive
malig; UA level must be drawn on ice to quench e x vivo enzyme activity (JCO
2 003;2 1:4402 ; Acta Hae matol 2 006;115:35). Avoid in G6PD deficiency as results
in hemolytic anemia.
• Treat hyp erkalemia, hyp erp hosp hatemia and symp tomatic hyp ocalcemia
• Hemodialysis may be necessary; early renal consultation for Pts w/ renal insuffic. or
ARF
CANCER OF UNKNOWN PRIMARY SITE
• Bony mets: common p rimary tumors include breast, lung, thyroid, kidney, p rostate
NOTES
PNEUMONIA
• “Typ ical” : acute onset of fever, cough w/ p urulent sp utum, dysp nea, consolidation
on CXR
• “Atyp ical” (originally described as cx ): insidious onset of dry cough, extrap ulm
sx (N/V, diarrhea, headache, myalgias, sore throat), p atchy interstitial p attern on
CXR
• S/s & imaging do not reliably distinguish between “typ ical” (S. pne umo, H. flu) and
“atyp ical” (Mycoplasma, Chlamydia, Le g ione lla, viral); ↑ aminotransferases & ↓ Na
w/ Le g ione lla
Diagnostic studies
• Sputum Gram stain: utility debated. Good samp le (ie, sp utum not sp it) has <10
squamous cells/lp f. Purulent samp le has >2 5 PMNs/lp f.
• Sputum bacterial culture: transp ort to lab w/in 1–2 h of collection
• Blood cultures (be fore antibiotics!): in ~10% of inPts, dep ending on p athogen
• CXR (PA & lateral; see Radiology inserts) → tap effusions if >5 cm or severe PNA
• Other: SaO2 or Pa O 2 , arterial p H (if severe), CBC w/ diff, Chem-2 0; HIV test (if
unknown)
• Other micro based on clinical susp icion (p aired serologies available for most
atyp icals):
Mycoplasma: PCR of throat or sp utum/BAL be fore first dose abx
Le g ione lla urinary Ag (detects L. pne umophila L1 serotyp e, 60–70% of clinical

disease)
S. pne umoniae urinary Ag (Se 50–8 0% , Sp >90% )
MTb: induced sp utum for AFB stain and mycobacterial cx (e mpiric re spiratory
isolation while pe nding ); avoid quinolones if susp ect TB; request rap id DNA p robe
if stain
Induced sp utum for PCP if HIV or known ↓ cell-mediated immunity
• Viral testing (DFA or PCR) on nasop haryngeal swab or sp utum; rarely viral cx
• Bronchoscop y: consider if immunosup p ., critically ill, failing to resp ond, or chronic
p neumonia. Also if susp ected TB or PCP, but inadequate or sp utum cx. Some
p athogens need sp ecific cx (eg, Le g ione lla on BCYE); collaborate with lab.
• Reasons for failure to imp rove on initial Rx:
Insufficient time: may take ≥72 h to see clinical imp rovement
Insufficient drug levels: eg, vanco trough <15–2 0 µg/mL (needed for lung
p enetration)
Resistant organisms (or sup erinfxn): eg, MRSA, Pse udomonas; consider
bronchoscopy
Wrong dx: fungal/viral, chemical p neumonitis, PE, CHF, ARDS, DAH, ILD;
consider CT
Parap neumonic effusion/emp yema/abscess: esp . seen w/ strep ; if CXR ,

consider CT (dx tap ± chest tube if effusion p resent, esp . if loculated)
Metastatic infection (eg, endocarditis, meningitis, arthritis)

Prognosis
• Pneumonia and influenza are the 8 th leading cause of death in the U.S.
• For low-risk Pts, can discharge immediately after switching to PO abx (CID
2 007;44:S2 7)
• CXR resolves in most by 6 wk; consider f/u to r/o underlying malignancy (esp . if
age >50 y or smoker, Archive s 2 011;171:1192 ) or other dx
• Severe CAP (generally requiring ICU) defined as: sep tic shock, resp failure, or ≥3
of: RR ≥30, Pa O 2 /Fi O 2 ≤2 50, <36°C, HoTN, DMS, multilobar, WBC <4k, p lt
<100, BUN ≥19.9, metabolic acidosis, ↑ lactate (ATS/IDSA criteria, CID
2 007;44:S2 7)
• SMART-COP risk score: SBP <90 (2 p oints), Multilobar infiltrates, Alb <3.5 g/dL,
RR ≥30, Tachycardia (HR >12 5), Confusion, O2 sat <90% (2 p oints), arterial
pH <7.35 (2 p oints) score ≥3 p oints has Se ~60–90% & Sp 45–75% for need for
ICU care (CID 2 008 ;47:375)
Prevention
• Pneumococcal vaccine (PPSV2 3): all p ersons >65 y of age. If high-risk comorbidity,
give at younger age and consider additional vaccination with PCV13.
• VAP p recautions: HOB >30°, chlorhexidine rinse; asp iration p recautions in high-
risk Pts
• Tdap booster: 1 time dose in adults with uncertain vaccination history (MMWR 2 012 ;
61:468 )
VIRAL RESPIRATORY INFECTIONS
URI, bronchitis, bronchiolitis, pne umonia (Lance t 2 011;377:12 64)
Microbiology & epidemiology
• Typ ical p athogens: short, mild = rhinovirus, coronavirus; longer, more severe or
comp licated = influenza, p arainfluenza, resp iratory syncytial virus (RSV),
adenovirus, metap neumovirus. Can be esp . severe in immunosup p .
• Seasonal flu: 365,000 hosp , 51,000 deaths p er y in U.S.; most >65 y (NEJM
2 008 ;359:2 579)
• Pandemic 2 009 H1N1 (swine): more severe in younger and obese Pts (JAMA
2 009;302 :18 96)
• Sp oradic 2 011 H3N2 : adults exp osed to swine (also human-to-human) (MMWR
2 011;60:1615)
• H5N1 influenza (avian): ongoing small outbreaks globally.
• For weekly influenza up dates: http ://www.cdc.gov/flu/weekly

Diagnosis
• Primarily clinical: cough, fever, myalgias, arthralgias, rhinorrhea, p haryngitis (in

contrast, viral bronchitis p /w cough ± low-grade temp ; usually benign & self-
limited)
• Resp iratory viral p anel on nasal washing or sp utum/BAL
• Rap id influenza test on nasal swab: Se ~50–70% (? lower for p andemic flu), Sp
>95%
• DFA (Se ∼8 5% ), RT-PCR (gold standard) avail. for influenza (PCR distinguishes
typ e)
Treatment (NEJM 2008; 359:2579)
• Seasonal influenza: treat with neuraminidase inhib. (oseltamivir, zanamivir), which

are effective vs. A & B, but resistance emerging. M2 inhib. (amantadine,
rimantadine) not recommended due to widesp read resistance (MMWR 2 011;60:1).
• Pandemic H1N1: nearly 100% sens. to oseltamivir. H5N1: Uncertain resistance

p attern.
H7N9: newly emerging in Asia (NEJM 2 013;368 :18 8 8 )
• Oseltamivir dosed 75 mg PO bid × 5 d. Must start w/in 48 h of sx for low-risk; for

critically ill or immunosup p ., start ASAP even if >48 h.
• Consider inhaled ribavirin for RSV in immunosup p . (eg, BMT, lung tx); limited
adult data
Prevention
• Inactivated influenza vaccine: incl. H1N1. Rec for all >6 mo of age and esp . if
p regnant, >50 y, immunosup p ., or HCW (MMWR 2 012 ;61:613)
• Isolation, drop let p recautions for inPts strongly recommended

• Prop hylaxis for high-risk contacts of confirmed influenza: oseltamivir 75 mg PO
daily × 10 d
FUNGAL INFECTIONS
Candida species
• Microbiology: normal GI flora; C. albicans & nonalbicans sp p . (consider azole

resistance if h/o Rx or nonalbicans; C. parapsilosis ↑ echinocandin resistant). Sensi
testing available.
• Risk factors: neutrop enia, immunosup p ., broad-sp ectrum abx, intravascular
catheters (esp . if TPN), IVDU, abd surgery, DM, renal failure, age >65
Mucocutaneous: cutaneous (eg, red, macerated lesions in intertriginous zones); oral
thrush (exudative, erythematous or atrop hic; if unexp lained, r/o HIV);
esop hageal (odynop hagia; ± oral thrush); vulvovaginal, balanitis
Candiduria: typ ically colonization due to broad-sp ectrum abx and/or indwelling
catheter
Candidemia (#4 cause of health care assoc. bloodstream infxn): r/o retinal
involvement (req ↑ Rx); endocarditis rare but serious (esp . w/ nonalbicans &
p rosthetic valve)
Hep atosp lenic: intestinal seeding of p ortal & venous circulation; esp . in acute
leukemia
Hematogenous dissemination: lung, brain, meninges, etc.
Cryptococcus (CID 2010; 50:291)
• Epidemiology: immunosup p . (esp . AIDS) most suscep tible; can occur in healthy
host, esp . elderly, EtOH, DM. If from Pacific NW, consider C. g atti (↑ mortality in
healthy host).
CNS (meningitis): HA, fever, meningismus, ↑ ICP, CN abnl, ± stup or, often
subacute. Dx: CSF CrAg, India ink stain, fungal cx. Cell counts vary; serum
CrAg >1:8 Se/Sp in AIDS.
Other sites: p ulm, GU, cutaneous, CNS cryp tococcoma. With any crypto dx, LP all
Pts.
• Treatment
CNS: If ↑ ICP, rep eat large-volume LPs or temp . lumbar drain; few require VP
shunt
In HIV or immunosup p . Pts, CNS Rx has induction (amp ho ±

flucytosine), consolidation and maintenance (fluconazole) p hases (NEJM
2 013;368 :12 91). If r/o CNS disease, then fluconazole. Dosing and duration
vary by host.
Non-CNS disease in healthy Pts: fluconazole vs. observation, based on clinical
setting
Histoplasmosis (CID 2007; 45; 807)
• Endemic: central & SE U.S. (esp . in areas w/ bird & bat drop p ings), river banks
elsewhere
Acute: often subclinical, but may see mild to severe PNA ± cavitary & hilar LAN
Chronic p ulm: ↑ p roductive cough, wt loss, night sweats, ap ical infiltrates,

cavitation
Disseminated (typ ically in immunosup p .): fever, wt loss, HSM, LAN, oral ulcers,
skin lesion, fibrosing mediastinitis, reactive arthritis, p ericarditis
• Treatment: itraconazole (monitor levels); amp ho ± steroids if severe or
immunosup p .
Coccidioidomycosis (CID 2005; 41:1217)

• Endemic: SW U.S. (San Joaquin or “Valley” fever)
Acute: 50–67% subclinical; PNA w/ cough, chest p ain, fever, arthralgias, fatig ue
Chronic p ulm: nodule(s), cavity or p rogressive fibrocavitary PNA (can be asx or

sx)
Disseminated (typ ically in immunosup p .): fever, malaise, diffuse p ulmonary
p rocess, bone, skin, & meningeal involvement
• Treatment: monitor mild disease closely q3–6mo; for severe disease: fluconazole,
itraconazole or amp hotericin
Blastomycosis (CID 2008; 46:1801)
• Endemic: south central, SE and midwest U.S.
Acute: 50% subclinical; cough, multilobar PNA; can p rogress to ARDS

Chronic p ulm: cough, wt loss, malaise, CT w/ masses & fibronodular infiltrates
Disseminated: (2 5–40% of all but >> in immunosup p .): verrucous & ulcerated
skin lesions, bone, & GU involvement; CNS rare unless immunosup p .
• Treatment: itraconazole (monitor levels); amp ho B if severe, disseminated or
immunosup p .
Aspergillosis (CID 2008; 46:327; NEJM 2009; 360:1870)

• ABPA; hypersensitivity pneumonitis: see “Interstitial Lung Disease”
• Aspergilloma: usually in p re-existing cavity (from TB, etc.); most asx, but can lead
to hemop tysis; sp utum cx in <50% ; CT → mobile intracavitary mass with air
crescent
Rx: antifungals w/o benefit; embolization or surgery for p ersistent hemop tysis
• Necrotizing tracheitis: white necrotic p seudomembranes in Pts w/ AIDS or lung Tx
• Chronic necrotizing: seen in COPD, mild immunosup p .; subacute sp utum, fever, wt

loss; CT: infiltrate ± nodule ± thick p leura; lung bx → invasion
• Invasive/disseminated: seen if immunosup p . (neutrop enia, s/p transp lant, steroid
Rx, AIDS esp . w/ steroids or neutrop enia); s/s PNA w/ che st pain & he moptysis;
CT: nodules, halo sign, air crescent sign; BAL + galactomannan; lung bx if dx
inconclusive
• Rx (necrotizing/invasive): voriconazole PO p referred to amp ho; monitor serum
levels
Zygomycetes (eg, Mucor, Rhizopus)

• Epidemiology: diabetes mellitus (70% ), heme malignancy, s/p transp lant, chronic
steroids, deferoxamine or iron overload, trauma, h/o voriconazole Rx or Pp x
• Clinical manifestations: rhinocerebral = p eriorbital/forehead p ain (more
extensive than orbital cellulitis), ± fever (may ap p ear nontoxic at first),
exop hthalmos, ↓ EOM, CNs (V > VII); nasal turbinates ± black eschar but exam
can be quite nl. Also, pulmonary (PNA w/ infarct & necrosis); cutaneous
(indurated p ainful cellulitis ± eschar); GI (necrotic ulcers).
• Treatment: Serial debridement + amp ho (? + p osaconazole). High mortality

desp ite Rx.
Fungal diagnostics
• Culture: Candida grows in blood/urine Cx, but ↓ Se of BCx if deep tissue infection;
others (eg, Crypto, Histo) ↓↓ Se of BCx; if susp ect Coccidio alert lab (biohazard)
• Antibody detection: Histo, Blasto, Coccidio, Aspe rg illus. Se variable (best for
Coccidio).
• Antigen detection
Histo urine/serum Ag: Se of urine Ag 90% (serum 8 0% ) if dissem; Sp limited by
X-react
Crypto Ag (serum, CSF): serum Ag >90% Se & Sp in invasive infxn, less for p ulm
only
1,3-b-D-glucan: Se for many fungal infxns (Candida, Aspe rg illus, Histo, Coccidio,
Fusarium, Pne umocystis, Sporothrix; but not Crypto, Blasto, Mucor, Rhizopus); not
Sp
Galactomannan: more sp ecific for Aspe rg illus, but Se <50% . ↑ Se on BAL.
• Biopsy (ie, histop athology): nb, no grinding of tissue if Zygomycetes susp ected
INFXNS IN IMMUNOSUPPRESSED HOSTS
Overview
• Many immunop henotyp es, meds or systemic diseases p redisp ose to infection
• Many Pts have ≥1 risk (eg, DM, ESRD, transp lant, extremes of age); duration of risk
varies
• The following is not an exhaustive list, but a delineation of common or classic

etiologies
URINARY TRACT INFECTIONS
Definitions
• Anatomic
lower: urethritis, cystitis (sup erficial infection of bladder)

upper: p yelonep hritis (inflam of renal p arenchyma), renal/p erinep hric abscess,
p rostatitis
• Clinical
uncomplicated: cystitis in immunocomp etent nonp regnant women w/o underlying
structural or neurologic disease
complicated: up p er tract infection in women or any UTI in men or p regnant
women or UTI with underlying structural disease or immunosup p ression
Microbiology
• Uncomp licated UTI: E. coli (8 0% ), Prote us, Kle bsie lla, S. saprophyticus (CID
2 004;39:75). In healthy, nonp regnant women, lactobacilli, enterococci, Group B
strep and coag-neg stap h (excep t S. saprophyticus) usually contaminants (Annals
2 012 ;156:ITC3).
• Comp licated UTI: E. coli (30% ), enterococci (2 0% ), PsA (2 0% ), S. e pi (15% ), other

GNR
• Catheter-associated UTI: yeast (30% ), E. coli (2 5% ), other GNR, enterococci, S. e pi
• Urethritis: Chlamydia trachomatis, Ne isse ria g onorrhoe ae , Ure aplasma ure alyticum,
Trichomonas vag inalis, Mycoplasma g e nitalium, HSV
• S. aure us: uncommon p rimary urinary p athogen in absence of catheter or recent

instrumentation; ∴ consider bacteremia w/ hematogenous seeding
• Cystitis: dysuria, urgency, frequency, hematuria, Δ in urine color/odor,

sup rap ubic p ain; fever usually abse nt. R/o vaginitis with symp toms of cystitis
and urethritis.
• Urethritis: similar to cystitis excep t ure thral discharg e can be p resent
• Prostatitis
chronic: similar to cystitis excep t symptoms of obstruction (hesitancy, weak

stream)
acute: p erineal p ain, fever, tenderness on p rostate exam
• Pyelonephritis: fever, chills, flank or back p ain, nausea, vomiting, diarrhea
• Renal abscess (intrarenal, p erinep hric): identical to p yelonep hritis w/ pe rsiste nt

fe ve r de spite appropriate antibiotics
Diagnostic studies
• Urinalysis: pyuria + bacteriuria ± hematuria ± nitrites

• Urine Cx (from clean-catch midstream or straight-cath sp ecimen): obtain cx only if
sx
Significant bacterial counts: typ ically ≥105 CFU/mL in women, ≥103 CFU/mL in
men or catheterized Pts. Counts may vary dep ending on dilution & stage of
infxn; interp ret in context of symp toms and host.
Pyuria & UCx = sterile p yuria → urethritis, nep hritis, renal tuberculosis,
foreign body
• Blood cultures: obtain in febrile Pts; consider in comp licated UTIs
• DNA detection/cx for C. trachomatis/N. g onorrhoe ae in high-risk Pts or sterile p yuria
• If ? p rostatitis: 1st void, midstream, p rostatic exp ressage & p ostp rostatic massage
UCx
• Abdominal CT: r/o abscess in Pts with p yelo who fail to defervesce after 72 h
• Urologic w/u (renal U/S w/ PVR, abd CT, voiding cystograp hy) if recurrent UTIs in
men
SOFT TISSUE AND BONE INFECTIONS
CELLULITIS
Infe ction of supe rficial and de e p de rmis and subcutane ous fat
Microbiology & clinical (NEJM 2004; 350:904; CID 2005; 41:1373)

• Primarily strep and stap h, including MRSA; may include GNRs in
diabetics/immunosup p .
• Community-acquired MRSA (CA-MRSA) (NEJM 2 005;352 :148 5 & 2 006;355:666)
Up to 75% of p urulent skin/soft tissue infxns, dep ending on local ep i (rap idly
increasing)
Clinically indistinguishable from MSSA, often assoc. w/ p urulent drainage or
exudate
High-risk group s: athletes, military, p rison, MSM, communities w/ high

p revalence
Often TMP-SMX sensitive; variably clindamycin sensitive (may falsely ap p ear
suscep tible on lab testing, requires confirmation w/ D-test; NEJM 2 007;357:38 0)
• Erythema, edema, warmth, p ain (rubor, tumor, calor, dolor)
• Lymp hangitis (p roximal red streaking) and regional lymp hadenop athy
• Toxic shock syndrome can occur w/ stap h or strep infxn. Fever, HA, N/V, diarrhea,
myalgias, p haryngitis, diffuse rash w/ desquamation, HoTN, shock. BCx may be
.
• Bites: skin and oral flora (incl anaerobes) + sp ecial exp osures:
Diagnosis
• Largely clinical diagnosis; BCx low yield (Se <5% in simp le cellulitis) but useful if
• Asp irate of bulla or p us from furuncle or p ustule may p rovide microbiologic dx
Treatment
• Limb elevation; erythema may worse n after starting abx b/c bacterial killing →
inflam.
• I&D if abscess is p resent in addition to cellulitis
• Worse outcomes if vasc. insuff., edema, immunosup p ., resistant orgs. or deep er

infxn
• In obese Pts, adequate drug dosing imp ortant to avoid treatment failure (J Infect
2 012 ;2 :12 8 )
OTHER CUTANEOUS INFECTIONS
“DIABETIC FOOT” = INFECTED NEUROPATHIC FOOT ULCER
Le ading cause of DM-re late d hosp. days & nontrauma amputations
Microbiology
• Mild (sup erficial, no bone or joint involvement): usually S. aure us or aerobic

strep tococci
• Limb- or life-threatening = deep , bone/joint involvement, systemic tox., limb

ischemia
• Mono- or p olymicrobial with aerobes + anaerobes
aerobes = S. aure us, strep , enterococci and GNR (including Pse udomonas)
anaerobes = anaerobic strep tococci, Bacte roide s, Clostridium (rare)
• Clinical dx: ≥2 classic s/s of inflammation (erythema, warmth, tenderness [may be

absent in neurop athy], p ain or induration) or p urulent secretions ± crep itus
(indicating gas and ∴ mixed infection w/ GNR & anaerobes or Clostridium)
• Comp lications: osteomyelitis, systemic toxicity (fever, chills, leukocytosis,

hyp erglycemia)
Diagnostic studies
• Avoid sup erficial swabs (only help ful if for S. aure us and susp ect infxn); wound
cx (eg, deep tissue samp le or curettage at ulcer base after débridement) has ↑ Se
• Blood cx should be obtained in all Pts, in 10–15%
• Osteomyelitis should always be ruled out: p robe to bone test for all op en wounds
in a diabetic foot (high Sp but low Se); imaging (see below); bone biopsy best
Treatment (CID 2012; 54:e132)
• Elevation, non–weight-bearing status, wound care, glycemic control, antibiotics
• Evaluation and treatment for venous insufficiency and arterial ischemia
• Many require surgery: early, aggressive and rep eated débridement;

revascularization or amp utation may be necessary
• Management by multidiscip linary team imp roves outcomes (Circulation
2 006;113:e463)
NECROTIZING FASCIITIS
Definition
• Infection and necrosis of sup erficial fascia, subcutaneous fat and deep fascia
(necrosis of arteries and nerves in subcutaneous fat → gangrene)
• Fournier’s gangrene: necrotizing fasciitis of the male genitalia or female p erineum
Epidemiology
• Affects healthy individuals but ↑ risk: DM, PVD, EtOH abuse, IDU, immunosup p .,
cirrhosis
Microbiology
• Typ e I (after abd/p erineal surgery or trauma; in DM, PVD): p olymicrobial (w/
anaerobes)
• Typ e II (usually extremities): Stre p pyog e ne s ± CA-MRSA, often healthy w/o obvious
p ortal of entry; up to 1/2 have toxic shock syndrome (TSS)
• Need hig h de g re e of clinical suspicion because of nonsp ecific p hysical exam
• Most common sites: extremities, abdominal wall and p erineum, but can occur
anywhere
• Cellulitic skin Ds with p oorly defined margins + rapid spread + systemic toxicity
• Pain out of proportion to ap p arent cellulitis; skin hyp eresthetic and later anesthetic
• Bullae, darkening of skin to bluish-gray ± crepitus or radiograp hically visible
gas
Diagnostic signs
• Clinical dx sufficient to initiate urgent surgical exploration
• Asp iration of necrotic center; BCx; Gram stain; ✓ CK for tissue necrosis
• Imaging: non-contrast CT, but do not delay therap y (Arch Surg 2 010;145:452 )
• Microbiologic dx from Gram stain and culture of surgical sp ecimens
Treatment
• Definitive treatment is surgical débridement of necrotic tissue and fasciotomy
• Typ e I: breadth of GNR coverage determined by host, p rev hosp , p rev Rx and initial
Gram stain; eg, carbap enem or (3rd-gen cep h + amp + [clinda or
metronidazole])
• Typ e II: PCN + clinda. If ↑ risk of CA-MRSA, + vanco. If concern for strep , IVIG.
Prognosis
• Generally fatal if untreated; rep orted mortality 2 0–50%

CLOSTRIDIAL MYONECROSIS (GAS GANGRENE)
Definition
• Life-threatening, fulminant clostridial infection of skeletal muscle
• Wound contamination w/ clostridial sp ores after trauma (p enetrating or crush

injury)
• Most commonly C. pe rfring e ns; C. se pticum assoc w/ cancer (GI, heme), even w/o
trauma
• Incubation p eriod 6 h to 2 –3 d
• Sense of heaviness/p ain, often at site of trauma; rap id worsening; marked systemic
toxicity
• Bronze skin discoloration, tense bullae, serosanguineous or dark fluid and necrotic
areas
• Crepitus p resent but not p rominent (gas is in muscle), may be obscured by edema
Diagnostic studies
• Gram stain: lg, Gram bacilli w/ blunt ends (can be Gram-variable ), few p olys
• Bacteremia in ~15%
• Plain radiograp hs: gas dissecting into muscle
Treatment
• Surgical exploration with débridement, fasciotomies and amp utation if necessary
• Antibiotics: high-dose penicillin G 2 4 MU IV divided q2 –3h + clinda 900 mg IV

q8 h
OSTEOMYELITIS
Infe ction of bone due to he matog e nous se e ding or dire ct spre ad from contig uous focus
Microbiology (NEJM 1997; 336:999; Lancet 2004; 364:369)
• Hematogenous: S. aureus; mycobacterial infection of vertebral body = Pott’s

disease
• Contiguous focus (may be acute or chronic)

op en fracture, orthop edic surgery, etc.: S. aureus and S. epi
skin breakdown + vasc. insuffic. (eg, diabetic foot): polymicrobial (aerobic +
anaerobic GPC & GNR)
• Surrounding soft-tissue comp romise ± fistula to sup erficial skin
• ± Fever, malaise and night sweats (more common in hematogenous than contiguous)
• Vertebral osteomyelitis (seen in Pts >50 y): unremitting, focal back p ain, usually
fever (NEJM 2 010;362 :102 2 )
Diagnostic studies (JAMA 2008; 299:806)
• Identification of the causative organism is key

• Culture from tissue (surgical samp ling/needle bx), not swabs of ulcers or fistulae
drainage
• High susp icion in diabetic foot (see above) if can p robe ulcer to bone or ulcer >2
cm 2
• Blood cultures (more often with acute hematogenous osteomyelitis)
• ESR >70 greatly increases likelihood of osteo (JAMA 2 008 ;2 99:8 06)
• Imaging
Plain radiograp hs: normal early in disease; lytic lesions seen after 2 –6 wk
MRI: can detect very early changes (overall Se 90% , Sp 8 2 % ; Archive s

2 007;167:12 5)
CT: can demonstrate p eriosteal reaction and cortical and medullary destruction
CT & MRI very Se but ↓ Sp ; false if contig focus w/ p eriosteal reaction,

Charcot Ds
Radionuclide imaging: very Se but non-Sp (false if soft tissue inflammation)
Treatment
• Antibiotics (based on cx data) × 4–8 wk
• Surgery should be considered for any of the following: acute osteo that fails to
resp ond to medical Rx, chronic osteo, comp lications of p yogenic vertebral osteo
(eg, early signs of cord comp ression, sp inal instability, ep idural abscess) or
infected p rosthesis
EPIDURAL ABSCESS
Etiology
• Hematogenous sp read (2 /3): skin infection, soft tissue (dental abscess) or

endocarditis
• Direct extension (1/3): vertebral osteo, sacral ulcer, sp inal anesthesia or surgery, LP
• Risk factors: diabetes, renal failure, alcoholism, IVDU, immunosup p .

• S. aureus most common p athogen, increasing incidence of MRSA
• Back pain (unremitting including midline) + often fever ± nerve root or cord signs
Diagnostic studies
• MRI
• Asp iration of abscess fluid for Gram stain & cx or op erative Gram stain & cx
• Blood cx (frequently )
Treatment
• Antibiotics ± surgery (decomp ressive laminectomy and débridement) for failure to
imp rove on medical Rx or early s/s of cord comp ression (w/ vertebral osteo and
ep idural abscess, may see p arap legia 48 –72 h after first signs)
INFECTIONS OF THE NERVOUS SYSTEM
ACUTE BACTERIAL MENINGITIS

Definition
• Bacterial infection of the subarachnoid sp ace
Clinical manifestations (NEJM 2006; 354:44; Lancet 2012; 380:1684)
• Fever (77% ), headache (8 7% ), stiff neck (31% ), photosensitivity, Δ MS (69% )

(defined as GCS <14), seizures (5% ); 2 of 4 (fever, HA, stiff neck, Δ MS) p resent
in 95%
• Presentation may be atypical (eg, lethargy w/o fever) in elderly and immunosup p .
Physical exam
• Nuchal rigidity (Se 31% ), Kernig’s sign (Pt sup ine, hip flexed at 90°, knee flexed at
90°; if p assive extension of knee results in resistance), Brudzinski’s sign (Pt
sup ine and limbs sup ine; if p assive neck flexion → involuntary hip and/or
knee flexion)
nb, Kernig’s or Brudzinski’s signs in only ~10% of Pts (Lance t

2 012 ;38 0:168 4)
• ± Focal neuro findings (~30% ; hemip aresis, ap hasia, visual field cuts, CN p alsies)
• ± Funduscop ic findings: p ap illedema, absent venous p ulsations
• ± Rash: maculop ap ular, p etechial or p urp uric
Diagnostic studies (Lancet 2012; 380:1684)

• Blood cultures ¥ 2 before abx
• WBC count: >10,000 in >90% of bacterial meningitis in healthy hosts
• Conside r head CT to r/o mass effect before LP if p resence of high-risk feature (age
>60 y, immunosup p ., h/o CNS disease, new-onset seizure, Δ MS, focal neuro
findings, p ap illedema); absence of all these has NPV 97% ; however, in Pts w/
mass effect, herniation may occur w/o LP and may not occur even w/ LP (NEJM
2 001;345:172 7)
• Lumbar puncture (NEJM 2 006;355:e12 )
CSF Gram stain has 30–90% Se; cx 8 0–90% Se if LP done p rior to abx role of
CSF PCR for common bacterial causes (? ~90% Se if w/in 2 h) to be defined
rep eat LP only if no clinical resp onse after 48 h of ap p rop riate abx or CSF
shunt
Opening pressure typ ically ↑ in bact meningitis; must measure w/ Pt’s legs
extended
Rule of 2s: CSF WBC >2 k, glc <2 0, & TP >2 00 has >98 % Sp for bacterial
meningitis
Recurrent meningitis
• Bacterial: consider CSF leak, dermal sinus or other congenital/acquired anatomic
defects
• Viral: HSV-2 (causes majority of Mollaret’s meningitis)

• Asep tic (see below): leak from cyst/tumor/lesion with dermoid/ep idermoid elements,
autoimmune (eg, SLE, Behçet’s), medications
• Additional CSF studies based on clinical susp icion: AFB smear & cx, India ink p rep ,
cryp tococcal Ag, fungal cx, VDRL, PCR (eg, of HSV, VZV, enteroviral), cytology
Prognosis
• For community-acquired S. pne umo mort. 19–37% ; 30% have long-term neuro
sequelae
ASEPTIC MENINGITIS
Definition
• Negative bacterial micro data, CSF p leocytosis with ap p rop riate blood & CSF
cultures (asep tic meningitis can be neutrop hilic, though less common)
• Asep tic = less likely to be bacterial, but can be infectious or noninfectious
Etiologies (Neurology 2006; 66:75)

• Viral: enteroviruses (most common), HIV, HSV (typ e 2 > 1), VZV, mump s,
lymp hocytic choriomeningitis virus, encep halitis viruses, adenovirus, p olio, CMV,
EBV
• Parameningeal focus of infection (eg, brain abscess, ep idural abscess, sep tic
thrombop hlebitis of dural venous sinuses or subdural emp yema)
•Partially treated bacterial meningitis

• TB, fungal, spirochetal (Lyme, syp hilis, lep tosp irosis), rickettsial, Coxie lla,
Ehrlichia
• Medications: TMP/SMX, NSAIDs, IV Ig and antilymp hocyte Ig, PCN, INH,

lamotrigine
• Systemic illness: SLE, sarcoidosis, Behçet’s, Sjögren’s syndrome, RA
• Neoplasm: intracranial tumors (or cysts), lymp homatous or carcinomatous

meningitis (CSF cytology or flow may be reactive and dx may require meningeal
bx)
Empiric treatment
• No abx if susp ect viral (cell count <500 w/ >50% lymp hs, TP <8 0–100 mg/dL,
normal glc, Gram stain, not elderly/immunosup p .); o/w start emp iric abx,
wait for cx data
• If susp ect MTb: antimycobacterial Rx + dexamethasone (NEJM 2 004;351:1741)
• If susp ect fungal: amp ho lip id formulation, ± 5-fluorouracil

ENCEPHALITIS
Definition
• Infection of brain p arenchyma with evidence of neurologic dysfunction
Etiologies (sp ecific etiology found in <20% of cases; Neurology 2006; 66:75; CID
2008; 47:303)
• HSV-1 (~9% ): all ages/seasons; MRI: temp oral lobe lesions/edema; EEG: temp oral
focus
• VZV (~9% ): 1° or reactivation; ± vesicular rash; all ages (favors elderly), all
seasons
• Arboviruses (~9% ): Eastern/Western equine, St. Louis, Jap anese, Powassan, W. Nile
(NEJM 2 005;353:2 8 7): mosquito vector, bird reservoir; fever, HA, flaccid
paralysis, rash. Risk factors for severe dis: renal dis., cancer, EtOH, DM, HTN (Am
J Trop Me d Hyg 2 012 ;8 7:179).
• Enteroviruses (coxsackie, echo): viral syndrome; p eaks in late summer/early fall

• Others: CMV, EBV, HIV, JC virus (PML), measles, mump s, rubella, rabies, flu,
adenovirus
• Nonviral mimics: bacterial endocarditis, brain abscess, toxop lasmosis, TB, toxins,
vas-culitis, hematologic malignancies, Whip p le’s disease, subdural hematoma,
encep halomyelitis (eg, ADEM), p araneop lastic syndromes, seizure, mitochondrial
disorders, autoimmune anti N-methyl-D-asp artate recep tor (esp . if <30 y, CID
2 012 ;54:8 99)
• Fever, HA, Δ MS, ± seizures and focal neuro findings (latter atyp ical for viral
me ning itis)
Diagnostic studies (etiologic dx made in only about 2 5% of cases)
• Vaccine hx, dilated retinal exam, ELISA or DFA nasal/resp swabs for viruses,
serologies
• Lumbar puncture: lymp hocytic p leocytosis; PCR for HSV (95% Se & Sp at 2 –3 d),
VZV, CMV, EBV, HIV, JC, adeno/enterovirus, W. Nile (<60% Se); W. Nile CSF IgM
8 0% Se
• MRI (CT if MRI unavailable); W. Nile w/ thalamic hyp erintensity
• EEG to r/o seizure; findings in encep halitis are nonsp ecific
Treatment
• HSV, VZV: acyclovir 10 mg/kg IV q8 h (often emp iric Rx given frequency of
HSV/VZV)
• CMV: ganciclovir ± foscarnet; sup p ortive care for most other etiologies
BELL’S PALSY
Definition & etiology
• Acute idiop athic unilat. facial nerve palsy (CN VII), often p resumed HSV-1
reactivation
• Unilateral facial muscle weakness, hyperacusis, ↓ taste/lacrimation/salivation

Diagnosis
• Dx of exclusion: r/o brainstem lesion, Lyme, zoster (incl sine he rpe te ), HIV/AIDS,
sarcoid
Treatment (NEJM 2007; 357:1598; JAMA 2009; 302:985)

• ~8 0% recover sp ontaneously by 9 mo (much lower rate in DM)
• Corticosteroids (p rednisolone 2 5 mg PO bid × 10 d) started w/in 72 h of sx onset

imp rove odds of recovery (note: no conclusive data for use in DM, immunosup p .)
• No conclusive data to sup p ort the use of acyclovir or valacyclovir, though often
p rescribed
ZOSTER
Definition & etiology
• Zoster = herp es zoster = shingles: acute, unilat., painful dermatomal skin

eruption
• VZV reactivation in p erip heral nerve distribution from latency in dorsal root
ganglion
• Neuritic pain in a dermatomal distribution, then acute dermatomal eruption of
clustered rash (vesicles > p ap ules/p ustules > macules) in varying stages of
evolution
• Consecutive dermatomes may be seen in all Pts; more widesp read in immunosup p .
• Lesions in V1 distribution of facial nerve require urgent op hthalmologic evaluation
• Post-herp etic neuralgia (PHN) = severe p ain lasting >90 d after ep isode; may last
mos to y, more frequent w/ ↑ age and delay of antiviral Rx
Diagnosis
• Ap p earance of rash; DFA is most Se from scrap e of newly unroofed vesicle. Tzanck
does not distinguish HSV or VZV, cx insensitive for VZV (unlike HSV).
Treatment
• Rx if can initiate w/in 72 h of skin lesions in healthy Pt or at any time in

immunosup p .
• Valacyclovir or famciclovir × 7–14 d, or until lesions fully crusted; acyclovir 10
mg/kg IV q8 h if dissem. or high-risk Pt (medically ill, immunosup p ., V1 zoster w/
op hthalmic s/s, etc.)
• Prevention: vaccine ap p roved for Pts >50 y (↓ lifetime risk from 2 0% to 10% , also
↓ PHN)
BACTERIAL ENDOCARDITIS
Definition
• Infection of endothelium of heart (including but not limited to the valves)
• Acute (ABE): infxn of normal valves w/ virulent organism (eg, S. aure us, group A or
other β-hemolytic strep , Stre p pne umo)
• Subacute (SBE): indolent infxn w/ less virulent organism (eg, S. viridans); often abnl
valves
Predisposing conditions
• Abnormal valve
Hig h risk: p rior endocarditis, rheumatic valvular disease, AoV disease (incl.
bicusp id), comp lex cyanotic lesions, p rosthesis (annual risk 0.3–1% )
Me dium risk: MV disease (including MVP w/ MR or leaflet thickening), HCMP
• Abnormal risk of bacteremia: IDU, indwelling venous catheters, p oor dentition,

hemodialysis, DM, intracardiac devices (eg, p acemaker, ICD)
Clinical manifestations (Archives 2009; 169:463)
• Persistent bacteremia: fever (8 0–90% ), chills, night sweats, anorexia, wt loss,

fatigue
• Valvular or perivalvular infection: CHF, conduction abnormalities
• Septic emboli: systemic emboli (eg, to p erip hery, CNS, kidneys, sp leen or joints),
stroke,
PE (if right-sided), mycotic aneurysm, MI (coronary artery embolism)

• Immune complex phenomena: arthritis, glomerulonep hritis, RF, ↑ ESR
• SBE: can p /w fatigue, nonsp ecific sx in Pts w/o risk factors; ∴ need high index of
susp icion
Physical exam
• HEENT: Roth spots (retinal hemorrhage + p ale center), petechiae (conjunctivae,
p alate)
• Cardiac: murmur (8 5% ), new valve regurgitation (40–8 5% ) ± thrill (fenestrated

valve or rup tured chordae), muffled sounds (PV). Fre que nt e xams for Δ murmurs,
s/s CHF.
• Abdomen: tender sp lenomegaly; musculoskeletal: arthritis, vertebral tenderness
• Extremities (typically se e n in SBE, not ABE)

Janeway lesions (sep tic emboli → nontender, hemorrhagic macules on p alms or
soles)
Osler’s nodes (immune comp lexes → tender nodules on p ads of digits)
proximal nail bed sp linter hemorrhages (8 –15% ); p etechiae (33% ); clubbing
• Neuro: Δ MS or focal deficits
• Devices: erythema, tenderness or drainage at catheter site, PM/ICD p ocket tenderness
Diagnostic studies
• Blood cultures (be fore abx): at least 3 sets (aerobic & anaerobic bottles) from
different sites, ideally sp aced ≥1 h ap art. ✓ BCx (at least 2 sets) after
ap p rop riate abx have been initiated to document clearance; rep eat q2 4–48 h until
.
• CBC w/ diff (↑ WBC common in ABE; anemia in 90% SBE), ESR, RF, BUN/Cr, U/A,
& UCx
• ECG (on admission and at regular intervals) to assess for new conduction
abnormalities
• Echocardiogram: obtain TTE if low clinical susp icion, exp ect good image quality;
TEE if (i) mod-to-high susp icion, (ii) high-risk Pt (p rosthetic valve, p rior IE,
congenital heart dis), (iii) TTE nondx, (iv) TTE but high-risk endocarditis, or
(v) susp ect p rogressive or invasive infection (eg, p ersistent bacteremia or fever,
new conduction abnl, etc.) (Circ 2 005;111:e394)
• Cx endocarditis: may be due to abx p rior to BCx. PCR, bacterial 16S ribosomal
RNA, serologies may be help ful. Detailed hx: animal exp osure, travel,
unp asteurized dairy, etc. Seek ID eval (Me d 2 005;8 4:162 ; NEJM 2 007;356:715).

• Obtain culture data first
ABE → abx should start p romp tly after cx data obtained

SBE → if Pt hemodynamically stable, may delay abx to p rop erly obtain adequate
BCx data, esp . if p rior abx used
• Suggested empiric therapy (Circ 2 005;111:e394)

native valve ABE: vanco (± gent; no longer routinely recommended)
native valve SBE: ceftriaxone (or amp if ? enterococcus; eg, older or ob/gyn)
± gent
PVE: e arly (≤60 d): vanco + cefepime + gent; inte rme diate (60–365 d): vanco
+ gent; late (>1 y): vanco + CTX + gent
native or prosthetic cx : depends on host & epi, seek ID consultation
• Adjust abx regimen & duration based on valve (NVE vs. PVE); if p ossible, de-
escalate abx to organism-directed Rx guided by in vitro sensi's or local p atterns of
Rx-resist. Add rifamp in for PVE due to stap h sp p . (usually after BCx to ↓ risk
resistance develop s).
• Rep eat BCx qd until Pt defervesces and BCx ; usually 2 –3 d
• Fever may p ersist even >1 wk after ap p rop riate abx or due to metastatic sites
• Systemic anticoagulation relatively contraindicate d given risk of hemorrhage in

cerebral embolic strokes; w/o stroke, can continue short-acting anticoag for p re-
existing indication
• Monitor for comp lications of endocarditis (CHF, conduction block, new emboli, etc.,
which can occur even on abx) and of abx Rx (interstitial nep hritis, ARF,
neutrop enia, etc.)
• Duration of Rx: usually 4–6 wk. With NVE & sx <3 mo → 4 wk of abx; sx >3 mo
→ ≥6 wk. Uncomp licated right-sided NVE or PCN-S strep sp p → 2 wk may be
comp arable.
• Posthosp italization outPt IV abx monitoring; future endocarditis Pp x
Indications for surgery (EHJ 2009; 30:2369; Circ 2010; 121:1005 & 1141)
• Several days of abx (if p ossible) to ↓ recurrence of infection and imp rove structural
integrity of tissue to receive p rosthesis
• Severe valvular dysfunction → refractory CHF: e me rg e nt if refractory cardiogenic

shock (ie, desp ite ICU-level Rx); urg e nt (w/in days) if p ersistent refractory heart
failure; e le ctive (w/in wks) if asx severe AI or MR
• Uncontrolled infxn (urgent surgery w/in days): p eriannular abscess (10–40% NVE,
60– 100% PVE), fistula, worsening conduction, PVE w/ dehiscence, ↑ veg. size or
p ersistent sep sis (eg, BCx [? or fever] after ~1 wk of ap p rop riate IV abx and
no drainable metastatic focus or other identifiable cause)
• Organism: consider surgery for S. aure us, fungal or multiRx resistant organisms
• Systemic embolism (2 0–50% ): risk 4.8 /1000 Pt days in 1st wk, 1.7/1000 thereafter
urgent surgery if L-sided w/ >10 mm veg & severe AI/MR (NEJM 2 012 ;366:2 466)
or if recurrent emboli, embolism & >10 mm veg, or >15 mm veg desp ite
ap p rop . abx
ce re bral e mboli no longer considered contraindic to surgery unless hemorrhage
(then ideally wait 1 mo) or severe stroke (Stroke 2 006;37:2 094)
• PVE: esp . w/ valve dysfxn or dehiscence or S. aure us or GNR infection. Seek ID eval.
Prognosis
• NVE: non-IVDU S. aure us → 30–45% mortality; IVDU S. aure us (typ ically right-
sided) → 10–15% mortality; SBE → 10–15% mortality
• PVE → 2 3% mortality
• Aortic valve worse p rognosis than mitral valve

BACTEREMIA
Etiologies
• 1° infxn due to direct inoculation of the blood, frequently assoc w/ intravascular

catheters. Catheter-related bloodstream infection = same org from p erip heral cx
and cath tip cx or cx drawn from catheter (CID 2 009;49:1).
• 2 ° infxn due to infection in another site (eg, UTI, lung, biliary tree, skin) sp reading
to blood
Microbiology
• 1° infxn/indwelling catheters (ICHE 2 008 ;2 9:996): coag-neg stap h (incl S. e pi and
others) 34% , S. aure us 10% , enterococci 16% , Candida sp p . 12 % , Kle bsie lla sp p .
5%
• 2 ° infxn: dep endent on source
Risk factors for true bacteremia (JAMA 2012; 308:502)
• Pt: fever, shaking chills, IVDU, comorbidities, immunosup p , indwelling catheter,

SIRS
• Organism
more likely p athogenic: S. aure us, b-hemolytic strep , enterococci, GNR, S.

pne umo, Ne isse ria less likely p athogenic: coag-neg stap h (~10% ), dip htheroids,
Propionibacte rium (~0% )
• Time to growth: <2 4 h → higher risk, >72 h → lower risk (excep t for slow-
growing organisms such as HACEK group )
• Factors increasing the likelihood of endocarditis: high-grade bacteremia w/o
source, p ersisting after line removal or drainage of focal source, in hosts at risk
for endocarditis or w/ organisms known to cause IE (Duke criteria); emboli
Diagnosis
• Blood Cx: p rior to 1st abx dose if p ossible; 10 cc in each Cx bottle; add’l Cx if high
risk
Treatment
• 1° infxn: antibiotics based on Gram stain/culture results; tailor abx to sensitivities

emp iric therap y for GPC: vanco to cover coag-neg stap h and MRSA while awaiting
sensi
• 2° infxn: assess for p rimary source of infection and treat. Source control essential
for cure and to p revent recurrence.
• Persistently BCx: d/c indwelling catheters, consider metastatic infxn, infected

thrombosis or infected p rosthetic material (joint, abscess, vascular graft,
p acemaker, etc.)
TUBERCULOSIS
Epidemiology
• U.S.: 10–15 million infected (10× ↑ risk if foreign-born or minority); worldwide:

~2 billion
• After resurgence in U.S. 198 4–1992 , rates declined, though slower than CDC goals
• Multidrug resistant (MDR) TB: resistant to isoniazid (INH) and rifamp in (RIF). Can
occur as new (not p reviously treated) infxn if exp osed in former Soviet Rep ublics,
Russia, China
• Extensively drug resistant (XDR) TB resistant to INH, RIF, FQ and injectables
• Pts more likely to develop TB disease (NEJM 2 011;364:1441)
Hig h-pre vale nce populations (more likely to be exp osed to & infected): immigrant
from high-p revalence area, homeless, IDU or medically underserved, resident or
worker in jail or long-term facility, HCW at facility w/ TB, close contact to Pt
w/ active TB
Hig h-risk populations (infected & likely to p rogress to active disease): HIV ,
immunosup p . incl. biologics, uncontrolled DM & smoking, close contact w/
active TB Pt, underweight, CKD, organ Tx, IVU, EtOH, malnourished, cancer,
gastrectomy
Microbiology & natural history

• Transmission of Mycobacte rium tube rculosis via small-p article aerosols (drop let
nuclei)
• 90% of infected normal hosts will never develop clinically evident disease
• Localized disease: healing & calcification or p rogressive 1° TB (at site of infection)
• Hematogenous sp read: latent infection ± reactivation TB or p rogressive dissem. TB

Screening for prior infection
• Whom to screen: high-p revalence and high-risk p op ulations (HIV Pts should
have PPD testing as p art of initial evaluation and annually thereafter)
• How to screen: Mantoux tuberculin test (ie, p urified p rotein derivative or PPD)
inject 5-TU (0.1 mL) intermed. strength PPD intrade rmally → wheal; examine 48 –72
h
• How to interpret PPD: determine max. diameter of induration by p alp ation

• IFN-γ release assays (IGRA): (Ag-stimulated IFN-g release from Pt’s T-cells): can be
used for screening where you would use PPD (MMWR 2 010;59:1); ↑ Sp , esp . in
BCG Rx’d Pts (Annals 2 008 ;149:177). Does not distinguish active vs. latent, or
recent vs. remote infxn. Relies on host immune fxn; Se limited in immunosup p .
Lack of gold standard for latent TB infxn comp romises Se/Sp estimates (J Clin Epi
2 010;63:2 57; CID 2 011;52 :1031).
• Primary TB pneumonia: middle or lower lobe consolidation, ± effusion, ±

cavitation
• TB pleurisy: can occur w/ p rimary or reactivation. Due to breakdown of granuloma

w/ sp illing of contents into p leural cavity and local inflammation. Pulmonary
effusion ± p ericardial and p eritoneal effusions (tuberculous p olyserositis).
• Reactivation TB pulmonary disease: ap ical infiltrate ± volume loss ± cavitation

• Miliary TB: acute or insidious; due to widesp read hematogenous dissemination;
usually in immunosup p , DM, EtOH, elderly or malnourished. Constitutional sx
(fever, night sweats, weight loss) usually p rominent. Pulm disease w/ small millet
seed-like lesions (2 – 4 mm) on CXR or chest CT (latter more Se) p resent in 60–
8 0% of those w/ miliary TB.
• Extrapulmonary TB: lymp hadenitis, p ericarditis, p eritonitis, meningitis, nep hritis

± sterile p yuria, osteomyelitis (vertebral = Pott’s disease), hep atitis, sp lenitis,
cutaneous, arthritis
• TB and HIV: HIV at ↑ risk infxn, p rogressive 1° infxn and reactivation. Risk of
p rogression from infxn to disease >8 –10% /y, higher risk with ↓ CD4. Reinfection
(also w/ MDR) significant, esp . in hyp erendemic areas.
Diagnostic studies for active TB (high index of suspicion is key!)
• AFB smear (rap id dx) and culture (↑ Se & allows sensitivity testing) of sp utum,
BAL, p leura, etc.; avoid FQ if considering TB (can comp romise dx yield)
• PCR: 94–97% Se c/w smear; 40–77% Se c/w culture (JAMA 2 009;301:1014)
• CXR: classically fibrocavitary ap ical disease in reactivation vs. middle & lower lobe
consolidation in 1° TB, but distinction imp erfect. HIV assoc. w/ non-ap ical
disease regardless of timing (JAMA 2 005;2 93:2 740).
• Adenosine deaminase testing: useful in extrap ulmonary sites, best validated for
ascites
Preventive therapy (Annals 2009; 150:ITC6-1; NEJM 2010; 362:707)
• Prop hylaxis reduces incidence of subsequent disease by 65–75%
• Treat Pts who are based on guidelines listed above or any exp osed HIV or
immunocomp romised Pt
• R/o active disease in any Pt w/ suggestive s/s before starting INH. If HIV ,
routinely ask if cough, fever or night sweats; if yes → ✓ sp utum smear, CXR, CD4
• ✓ LFTs monthly (risk ↑ w/ age; Che st 20 0 5;128 :116 ): if 5× ULN or sx → stop TB

meds & reeval
Treatment of active tuberculosis (Annals 2009; 150:ITC6-1; NEJM 2013; 368:745)

• Isolate Pt p er infection control if hosp italized, modified isolation p er Dep t of Health
if outPt
• Use multip le drugs (see below) to which organism suscep tible; consult ID before
emp iric Rx if p ossible MDR-TB (susp ect if p rior TB Rx, from or travel to area w/
↑ rates of MDR, exp osure to p erson w/ likely MDR-TB, p oor Rx adherence) or if
INH resistance in community ≥4% (includes most of U.S.), extrap ulm. TB or HIV
(NEJM 2 008 ;359:636)
• Screen for HIV in Pts starting TB Rx; if HIV , consult ID re: timing of concurrent
HIV Rx
• Promote adherence to Rx; directly observed Rx cost-effective if high risk for

nonadherence
• Obtain monthly smears/cx on treatment until 2 consecutive are for TB
• Monthly clinical evaluation to monitor for Rx resp onse and adverse drug rxns
• “Paradoxical worse ning ” of sx can occur after starting Rx. More common w/
extrap ulm. TB (eg, tuberculoma, LAN) likely due to hyp ersensitivity resp onse to
killing of bacilli. More frequent/severe w/ concurrent immune reconstitution (eg,
HIV Pts started on ARVs, Pts taken off immunosup p ress, etc.). Must r/o tx
failure (rep eat Cx, imaging, etc.).
HIV/AIDS
Definition
• AIDS: HIV + CD4 <2 00/mm 3 or AIDS-defining op p ortunistic infection (OI) or

malignancy
Epidemiology
• ~1 million Americans living w/ HIV; ~34 million individuals worldwide
• 2 0% in U.S. are unaware of infection; 6th leading cause of death in 2 5–44-y age
group
• Routes: sexual (risk is 0.3% for male-to-male, 0.2 % for male-to-female, 0.1% for
female-to-male transmission), IVDU, transfusions, needle sticks (0.3% ), vertical
(15–40% w/o ARV)
• Postexp osure (risk infxn ~0.3% ) Pp x: 2 NRTIs (+ PI or NNRTI if high-risk) × 4 wk

Acute retroviral syndrome (ARS)
• Occurs in ~40–90% of Pts ~2 –6 wk after infxn; ± ELISA, viral load (2 wk

after infxn); early ART in ARS may be beneficial (NEJM 2 013;368 :2 07 & 2 18 )
• Mono-like syndrome (↑ mucocut. & neuro manifestations comp ared to EBV or CMV)
Diagnostic studies
• ELISA for HIV-1 Ab/Ag: 1–12 wk after acute infxn; >99% Se; 1° screening test
• Western blot: if ≥2 bands from HIV genome; >99% Sp ; confirmatory after

ELISA
• Rapid preliminary tests: 4 Ab tests; use saliva, p lasma, blood or serum; 99% Se &
96–99% Sp (Annals 2 008 ;149:153); PPV in low p rev p op ulations as low as 50%
• PCR (viral load): detects HIV-1 RNA in p lasma; assay range is 48 –10 million
cop ies/mL ~2 % false , but usually low # cop ies; in contrast, should be very
high (>750 k) in 1° infxn
• At least 1 time HIV screening recommended for all adult Pts (MMWR 2 006;55:1)
• CD4 count: not a dx test, b/c can be HIV w/ normal CD4 or be HIV w/ low
CD4
Approach to newly diagnosed HIV Pt
• Document HIV infection; counseling re: treatment op tions, adherence & disclosure
• H&P (including focus on h/o OIs, STDs); review all current meds
• Lab evaluation: CD4 count, PCR, HIV genotyp e, CBC w/ diff., Cr, lytes, LFTs, A1c &
fasting lip ids; PPD or IGRA, syp hilis & toxo screen & CMV IgG; HAV, HBV, & HCV
serologies; Chlamydia & gonorrhea screen; baseline CXR; Pap smear/anal p ap in
/
• ARVs should be given in consultation w/ HIV specialist (JAMA 2 010;304:32 1)
• Counseling re: strict adherence to ARVs is essential; genotyp e p rior to ART-
initiation
• All HIV Pts should be considered for ARVs; strongly recommended initiate Rx
for:
AIDS-defining illness, p regnancy, HIV-assoc. nep hrop athy, HCV/HBV co-infxn
CD4 £500/mm3 (NEJM 2 009;360:18 15 & 2 011;365:193; DHHS 2 012 ;

http ://aidsinfo.nih.gov)
Consider if CD4 >500; dep ends on Rx toxicity, adherence, p otential for
transmission
• Regimens for treatment-naïve Pts (DHHS guidelines Mar 2 9, 2 012 ;

http ://aidsinfo.nih.gov)
[NNRTI + 2 NRTI] or [PI (± low-dose ritonavir) + 2 NRTI] or [II + 2 NRTI]
• Initiation of ARVs may transie ntly worse n existing OIs for several wks due to immune
reconstitution inflammatory syndrome (IRIS)
Approach to previously established HIV Pt
• H&P (mucocutaneous, neurocognitive, OIs, malignancies, STDs); meds
• Review ARVs (p ast and current); if any must be interrup ted, stop all to ↓ risk of
resistance
• Failing regimen = unable to achieve undetectable viral load, ↑ viral load, ↓ CD4
count or clinical deterioration (with detectable viral load consider genotyp ic or
p henotyp ic assay)
COMPLICATIONS OF HIV/AIDS
Fever
• Etiologies (Infe ct Dis Clin North Am 2 007;2 1:1013)
infxn (82–90% ): MAC, TB, CMV, early PCP, Histo, Crypto, Coccidio, Toxo,
endocarditis
noninfectious: lymphoma, drug reaction. Non 1° HIV itself rarely (<5% ) cause
of fever.
• Workup : guided by CD4 count, s/s, ep i, & exp osures
CBC, chem, LFTs, BCx, CXR, UA, mycobact. & fungal cx, ✓ meds, ? ✓ chest & abd
CT
CD4 <100–2 00 → serum cryp to Ag, LP, urinary Histo Ag, CMV PCR or
antigenemia
p ulmonary s/s → CXR; ABG; sp utum for bacterial cx, PCP, AFB; bronchoscop y
diarrhea → stool for fecal leuks, culture, O&P, AFB; endoscop y
abnormal LFTs → abd CT, liver bx (for p athology and culture)

cytop enias → BM bx (include asp irate for culture)
Cutaneous
• Seborrheic dermatitis; eosinop hilic folliculitis; warts (HPV); HSV & VZV; MRSA skin
& soft tissue infxns; scabies; candidiasis; eczema; p rurigo nodularis; p soriasis;
drug erup tions
• Dermatop hyte infx: p rox subungual onychomycosis (at nail bed); p athognomonic for
HIV
• Molluscum contagiosum (p oxvirus): 2 –5 mm p early p ap ules w/ central

umbilication
• Kaposi’s sarcoma (KSHV or HHV8 ): red-p urp le nonblanching nodular lesions
• Bacillary angiomatosis (disseminated Bartone lla): friable violaceous vascular

p ap ules
Ophthalmologic
• CMV retinitis (CD4 usu <50); Rx: gan- or valganciclovir, ganciclovir imp lant or
cidofovir
• HZV, VZV, syp hilis (at any CD4 count) or Toxo: CD4 usually <100
Oral
• Aphthous ulcers; KS; thrush (oral candidiasis): curd-like p atches typ ically w/
burning or p ain; oral hairy leukoplakia: p ainless p roliferation of p ap illae w/
adherent white coating usually on lateral tongue, caused by EBV but not
p recancerous
Endocrine/metabolic
• Hypogonadism; adrenal insufficiency (CMV, MAC, TB, HIV or med-related); wasting

osteop enia/p orosis (at all CD4 counts); fragility fractures
• Lipodystrophy: central obesity, p erip heral lip oatrop hy, dyslip idemia,
hyp erglycemia
• Lactic acidosis: N/V, abd p ain; ? mitochondrial toxicity of AZT, d4T, ddI, other NRTI
Cardiac (JACC 2013; 61:511)

• Dilated CMP (10–2 0% ); PHT; CVD (NEJM 2 003;348 :702 ); p ericarditis/effusion, VTE
Pulmonary
• Pneumocystis jiroveci (PCP) pneumonia (CD4 <200) (NEJM 1990;32 3:1444)

constitutional sx, fever, night sweats, dysp nea on exertion, nonp roductive cough
CXR w/ interstitial p attern, ↓ Pa O 2 , ↑ A-a ∇, ↑ LDH, PCP sp utum stain,

β-glucan
Rx if Pa O 2 >70: TMP-SMX 15–2 0 mg of TMP/kg divided tid, avg dose = DS 2

tabs PO tid
Rx if Pa O 2 <70 or A-a gradient >35: prednisone before abx (40 mg PO bid; ↓
after 5 d) Alternative Rx if sulfa-allergy or renal insufficiency
Gastrointestinal & hepatobiliary
• Esophagitis: Candida, CMV, HSV, ap hthous ulcers, p ills; EGD if no thrush or

unresp onsive to emp iric antifungals
• Enterocolitis: bacte rial (esp if acute: shigella, salmonella, C. diff); protozoal (esp . if
chronic: Giardia, Entamoeba, etc.); viral (CMV, adeno); fung al (histo); MAC; AIDS
enterop athy
• GI bleeding: CMV, KS, lymp homa, histo; proctitis: HSV, CMV, LGV, N. g onorrhoe ae
• Hepatitis: HBV, HCV, CMV, MAC, TB, histo, drug-induced
• AIDS cholangiopathy: often a/w CMV or Cryptosporidium or Microsporidium (at ↓

CD4)
Renal
• HIV-associated nep hrop athy (collap sing FSGS); nep hrotoxic drugs (incl TDF)
Hematologic/oncologic (Lancet 2007; 370:59; CID 2007; 45:103)
• Anemia: ACD, BM infiltration by infxn or tumor, drug toxicity, hemolysis
• Leukopenia; thrombocytopenia (bone marrow involvement, ITP); ↑ globulin
• Non-Hodgkin lymphoma: ↑ frequency with any CD4 count, but incidence ↑ with ↓
CD4
• CNS lymphoma: CD4 count <50, EBV-associated

• Kaposi’s sarcoma (HHV-8 ): at any CD4 count, incidence ↑ as CD4 ↓, usu. MSM
Mucocutane ous (red-p urp le nodular lesions); pulmonary (nodules, infiltrates,
effusions, LAN); GI (bleeding, obstruction, obstructive jaundice)
• Cervical/anal CA (HPV); ↑ rates of liver (a/w HBV/HCV), gastric & lung CA
Neurologic
• Meningitis: Crypto (p /w HA, Δ MS, CN p alsy ± meningeal s/s; dx w/ CSF; serum

CrAg 90% Se), bact (inc. Liste ria), viral (HSV, CMV, 1° HIV), TB, histo, Coccidio,
lymp homa
• Neurosyphilis: meningitis, cranial nerve p alsies, dementia, otic or op htho s/s
• Space-occupying lesions: may p resent as HA, focal deficits or Δ MS. Workup : MRI,
brain bx if susp ect non-Toxo etiology (Toxo sero ) or no resp onse to 2 wk of
emp iric anti-Toxo Rx (if Toxo, 50% resp ond by d3, 91% by d14; NEJM
1993;32 9:995)
• AIDS dementia complex: memory loss, gait disorder, sp asticity (usually at CD4 ↓)
• Myelopathy: infxn (CMV, HSV), cord compression (ep idural abscess, lymp homa)
• Peripheral neuropathy: meds, HIV, CMV, demyelinating
Disseminated Mycobacterium avium complex (DMAC)

• Fever, night sweats, wt loss, HSM, diarrhea, p ancytop enia. Enteritis and mesenteric
lymp hadenitis if CD4 <150, bacillemia if <50. Rx: clarithromycin + ethambutol
± rifabutin.
Cytomegalovirus (CMV)
• Usually reactivation with ↓ CD4. Retinitis, esop hagitis, colitis, hep atitis,
neurop athies, encep halitis. Rx: ganciclovir, valganciclovir, foscarnet or cidofovir.
TICK-BORNE DISEASES
LYME DISEASE
Microbiology
• Infection with spirochete Borre lia burg dorfe ri (consider coinfection w/ Ehrlichia,
Babe sia)
• Transmitted by ticks (Ixode s, deer tick); infxn usually requires tick attached >36–
48h
Epidemiology
• Most common vector-borne illness in U.S.; p eak incidence in summer (May–Aug)
• Majority of cases in MN, WI, New England, northern mid-Atlantic, northern CA

• Humans contact ticks usually in fields with low brush near wooded areas
Diagnostic studies
• Often a clinical dx esp . in early disease; dx w/o EM requires confirmation testing (p er

IDSA)
• Serology (in right clinical setting): screen w/ ELISA, but false from other
sp irochetal disease, SLE, RA, EBV, HIV, etc.; false due to early abx or w/in 6
wk of infxn.
Confirm ELISA results w/ Western blot (↑ Sp )
• ✓ CSF if susp ected neuro disease: intrathecal Ab if

(IgGCSF/IgGserum )/(albCSF/albserum ) >1
• Prop hylaxis (best p revention is tick avoidance): p rotective clothing, tick ✓ q2 4h,
DEET
Chemop rop hylaxis w/ doxycycline 2 00 mg PO × 1 only if all of the following:

1. Ixode s scapularis tick attached ≥36 h
2 . Local Lyme carriage in ticks ≥2 0% (p eak season in New England, mid-Atl,

MN, WI)
3. Abx can be given w/in ≤72 h
4. No contraindication to doxy (eg, p reg, allergy, age <8 y)
If all the above met, NNT still 40–150 to p revent 1 case of Lyme (NEJM
2 001;345:79)
Regardless of Pp x, monitor for fever, flu-like sx, rash (erythema migrans) × 30 d
• Antibiotics: if clin. manifestations and serology (? and h/o tick bite if

nonendemic area)
local or early dissem. w/o neuro or cardiac involvement: doxycycline 100 mg PO

bid × 2 wk (range: 10–2 1 d); alternative (eg, p regnancy, doxy allergy): amox
500 mg PO tid or cefuroxime 500 mg PO bid × 14–2 1 d neuro (other than
isolated CN VII p alsy), cardiac, chronic arthritis: CTX 2 g IV qd × 2 –4 wk; alt
(eg, severe b-lactam allergy): doxy 100–2 00 mg PO bid × 2 –4 wk.
• Consider coinfection if severe/refractory sx, p ersistent fever, cytop enias

ROCKY MOUNTAIN SPOTTED FEVER (RMSF)
• Infection with Ricke ttsia ricke ttsii (Gram obligate intracellular bacterium)
• Transmitted by De rmace ntor variabilis, D. ande rsoni (dog tick); p eak in sp ring/early
summer
• Occurs in mid-Atl, SE, Midwest, New Engl, NW, Canada, Mexico, Central & S.
America
• Consider other rickettsial sp p .: R. akari (Rickettsial p ox), R. conorii (Mediterranean

sp otted fever), R. africae (African tick bite fever), R. fe lis (Flea rickettsiosis)
Clinical manifestations (typ ically w/in 1 wk of tick exposure)

• Nonsp ecific: fever, HA, DMS, myalgias, N/V, occasionally abdominal p ain
• Rash (2 –5 d afte r onset) = ce ntripe tal: starts on ankles and wrists → trunk, p alms &
soles; p rogresses from macular to maculop ap ular to p etechial
• Severe cases → vasculitis, hyp op erfusion/shock, end-organ damage; more likely in

elderly
• Up to 75% mortality if untreated, 5–10% even w/ Rx (esp . if delayed) (NEJM
2 005;353:551)
Diagnosis
• Usually a clinical dx; re quire s e arly clinical suspicion given risks of delayed Rx
• Acute illness dx by skin bx for rickettsiae (Se ~70% ); 7–10 d after sx onset, serology
Treatment
• Doxycycline 100 mg PO bid (g ive e mpirically if clinical suspicion)

EHRLICHIOSIS/ANAPLASMOSIS
Microbiology
• Gram obligate intracellular bacterium; human monocytic ehrlichiosis (E.

chaffe e nsis, HME); human granulocytic anaplasmosis (A. phag ocytophilum, HGA)
• Transmission: HME by Amblyomma ame ricanum, De rmace ntor variabilis; HGA by
Ixode s
Epidemiology
• HGA cases typ ically in RI, MN, CT, NY, MD; HME in SE, south central and mid-
Atlantic
• Peak incidence sp ring and early summer; can be transmitted by blood transfusion
Clinical manifestations (typ ically w/in 3 wk of tick exp osure)
• Asx or nonsp ecific: fever, myalgias, malaise, HA, cough, dysp nea; onset often acute
• Laboratory: leukop enia, thrombocytop enia, ↑ aminotransferases, LDH, Af, renal
insuff
• More severe disease can occur with bacterial sup erinfection in HGA
Diagnosis
• Acute: intraleukocytic morulae on p erip heral blood smear (rare); PCR; later:
serology
Treatment
• Start Rx based on clinical susp icion; definitive dx requires PCR (may not detect all
sp p .)
• Doxycycline 100 mg PO bid (often × 10 d); should defervesce in ≤48 h, else

reconsider dx
BABESIOSIS
• Infxn w/ p arasite Babe sia microti (U.S.), transmitted by Ixode s ticks; also a/w
transfusion
• Europ e & U.S. (more commonly MN, WI, coastal areas & islands of MA, NY, NJ, RI,
CT)
• Peak incidence June–August (MMWR 2 012 ;61:505)
Clinical manifestations (typ ically 1–4 wk after tick exposure; <9 wk if

transfusion)
• Range from asx to fevers, sweats, myalgias, & HA to severe hemolytic anemia,
hemoglobinuria, & death (degree of p arasitemia correlates roughly with severity)
• Risk factors for severe disease: asp lenia, ↓ cellular immunity, TNF inhib, ↑ age,
p regnancy
Diagnosis (NEJM 2012; 366:2397)

• Clinical syndrome + blood smear w/ intraerythrocytic parasites
• Rep eat smears (q12 –2 4h) if sx p ersist desp ite negative initial smear
• PCR serum if smear and high clinical susp icion, serum IgG can help but some
false
• Atovaquone & azithro for mild/mod illness; clinda & quinine if severe (more toxic)
• Duration dep ends on host; immunosup p Pts often need longer Rx
• Exchange transfusion if p arasitemia >10% , severe hemolysis or SIRS

TULAREMIA
Microbiology
• Infxn w/ Francise lla tulare nsis via contact w/ animal tissue, aerosol, tick/insect bite
Clinical manifestations (typ ically w/in 2 –10 d of exposure)

• Acute onset of fever, HA, nausea; ulcer w/ black eschar at site of entry; LAN; PNA
Diagnosis & treatment
• Hazardous and difficult to Cx, alert lab. Serology by wk 2 . PCR by research lab.
• Strep tomycin or gentamicin × 7–14 d; emp iric Rx may be needed given challenges
in dx
FEVER SYNDROMES
Te mpe rature >10 1° F or >38 .3° C
Diagnostic approach
• Thorough history including ROS, PMH/PSH, immunizations, including from

childhood
• Fever curve (consider holding antip yretics); less likely to mount fever if: chronic
renal or liver dis., extremes of age, p rotein calorie malnutrition, immunosup p .,
steroid use
• Exposures: travel, occup ation or hobbies, animals and insects, sexual contacts, TB;
consider age, geograp hy, season and incubation time in relation to exp osures
• Physical exam: comp lete exam w/ focus on mucuous membranes & conjunctiva;
cardiac murmurs; liver and sp leen size; skin, genitals, lymp h nodes, & joints;
comp lete neuro exam incl cranial nerves and meningeal signs
• If rash: location, duration, p rogression/∆ in ap p earance, was p rodrome p resent

FEVER OF UNKNOWN ORIGIN (FUO)
• Fever (as p er above def) on >1 occasion during ≥3 wk & no dx desp ite 1 wk of
evaluation
• More likely to be subtle manife station of common dise ase than an uncommon disease
• In Pts with HIV: >75% causes are infectious, but rare ly due to HIV itse lf
• Frequent reassessment needed to identify focal signs and p rogression of disease
Workup
• Focus by H&P, incl: CBC w/ diff, lytes, BUN, Cr, LFTs, ESR, CRP, ANA, RF,
cryoglobulin, LDH, CK, SPEP, 3 sets BCx (off abx), U/A, UCx, PPD or IGRA, HIV
Ab ± PCR, heterop hile Ab (EBV serologies if ), CMV antigen, Hep serologies if
LFTs abnl
• Stop unnecessary meds (only 2 0% with a med cause have eos or rash), reassess 1–3
wk
• Imaging: CXR, chest & abd CT, consider tagged WBC, gallium scan, PET, TTE, LENI
• Duke’s criteria for endocarditis (qv) have good Se & Sp in Pts with FUO
• Consider temp oral artery bx if ↑ ESR and age >60, p articularly if other s/s
• ? Bone marrow asp irate & bx (esp . if signs of marrow infiltration) or liver bx (esp .
if ↑ Af): even w/o localizing s/s, yield may be up to 2 4% (p ath and culture)
(Archive s 2 009;169:2 018 )
• Pursue abnormalities raised by above w/u (eg, bx, MRI, etc., for dx, not screening)
Treatment
• Emp iric abx not indicated (unless Pt neutrop enic)
• Emp iric glucocorticoids not indicated unless strong susp icion for sp ecific
rheumatologic dx
• Up to 30% of cases remain undiagnosed, most sp ontaneously defervesce (wks to mos)
FEVER AND RASH
Approach to diagnostic workup
• Meningococcemia, IE, RMSF, sepsis, toxic shock require immediate dx & Rx
• Workup : CBC w/ diff, lytes, BUN/Cr, LFTs, LDH, CK, U/A, HIV Ab ± PCR, BCx (off
abx)
• To narrow Ddx: characterize time course of rash, p rogression & morp hology (ie,
vesicular, maculop ap ular, p ustular, p urp uric, ulcerative)
• Erythema multiforme: symmetric “target” lesions often of p alms, soles, & mucous
memb
Infxn etiol: HSV 1/2 , Mycoplasma, syp hilis, tick borne diseases, etc.
Non-infxn etiol: meds (eg, NSAIDs, sulfa), malignancy, autoimmune & rheum
disease
• Erythema nodosum: tender erythematous or violaceous nodules usually symmetric

on LE
Infxn etiol: Strep , TB, EBV, Bartone lla, HBV, p sittacosis, fungal, L. ve ne re um, etc.
Non-infxn etiol: sarcoidosis, IBD, Behçet’s, other rheum, p regnancy/OCP use

• Pursue sp ecific dx based on exp osure hx & exam, including serologies, viral swab
PCR, antigen tests and p ossibly skin biop sy ± exam of vesicular or bullae fluid if
p resent
• Etiologies more broad in immunosup p . Pts, and dx ap p roach usually more extensive;
higher risk of critical illness due to disseminated or rap idly p rogressive infxns
Treatment
• Emp iric abx are not indicated (unless Pt neutrop enic or critically ill)
FEVER IN A RETURNED TRAVELER
• Febrile illness after recent travel outside of U.S./Canada; Ddx is extensive:
• Pts visiting friends and relatives abroad are most likely to contract illness during
travel
• Emerging p athogens: Influenza occurs year round in the trop ics. Chikungunya and
dengue w/ ↑ areas of transmission, hemorrhagic fevers p rimarily in Central
Africa.
• Consider domestic infxns, STIs, & non-infxn causes. Enteric p arasites rarely cause
fever.
Select clinical manifestations
• Malaria: nonsp ecific symp toms including diarrhea, myalgias, cough, altered mental
status
• Dengue: nonsp ecific symp toms including headache, severe myalgias, rash/p etechiae
• Typhoid: constip ation, abdominal p ain, p ossible rash, relative bradycardia
• Rickettsial disease: headache, myalgias, lymp hadenop athy, p ossible rash/eschar

Workup
• Routine testing: CBC w/ diff, lytes, LFTs, BCx, UA, rap id malaria test
• Fever in a traveler from a malaria zone is malaria until proven otherwise;

consider hospitalization and empiric Rx. One smear does not r/o malaria.
• Other tests based on s/s, labs, exp osure, incubation p eriod, geograp hy and
seasonality. O&P exam, CXR, blood smears for filaria/Babesiosis/Borre lia,
serologies, STI & HIV, PPD or IGRA, bone marrow asp irate, bx of lymp h nodes or
skin lesions, CSF studies.
NOTES
PITUITARY DISORDERS
HYPOPITUITARY SYNDROMES
Panhypopituitarism
• Etiologies
Primary: surgery, radiation, tumors (p rimary or metastatic), infection,

infiltration (sarcoid, hemochromatosis), autoimmune, ischemia (including
Sheehan’s syndrome caused by p ituitary infarction intrap artum), carotid
aneurysms, cavernous sinus thrombosis, trauma
Secondary (hyp othalamic dysfunction or stalk interrup tion): tumors (including
craniop haryngioma), infection, infiltration, radiation, surgery, trauma
Hormonal: acute → weakness, easy fatigability, hyp otension, p olyuria and
p olydip sia; chronic → bradycardia, sexual dysfxn, loss of axillary & p ubic hair,
wt loss, amenorrhea
Mass effect: headache, visual field Δs, cranial nerve p alsies, galactorrhea
Apoplexy (p ituitary hemorrhage or infarction, usually w/ underlying p ituitary

adenoma): sudden headache, N/V, visual field Δs, cranial nerve p alsies,
meningismus, Δ MS, hyp oglycemia, hyp otension
• Diagnostic studies
Hormonal studies
chronic: ↓ target gland hormone + ↓ or normal trop hic p ituitary hormone
acute : target gland hormonal studies may be normal partial hypopituitarism is
more common than panhypopituitarism
Pituitary MRI
• Treatment
Rep lace deficient target gland hormones
Most imp ortant deficiencies to recognize and treat in inPts are adre nal insufficie ncy
and hypothyroidism; if both p resent, treat with glucocorticoids first, then rep lace
thyroid hormone so as not to p recip itate adrenal crisis
↓ ACTH
• Adrenal insufficiency similar to 1° (see “Adrenal Disorders” ) e xce pt:
no salt cravings or hyp okalemia (b/c aldo p reserved)

no hyp erp igmentation (b/c ACTH/MSH is not ↑)
↓ TSH
• Central hyp othyroidism similar to 1° (see “Thyroid Disorders” ) e xce pt absence of

goiter
• Dx with free T4 in addition to TSH, as TSH may be low or inappropriate ly normal
↓ PRL
• Inability to lactate
↓ GH
• ↑ chronic risk for osteop orosis, fatigue, weight gain
• Dx with failure to ↑ GH w/ ap p rop riate stimulus (eg, insulin tolerance test, glucagon
stimulation)
• GH rep lacement in adults controversial (Annals 2 003;35:419)
↓ FSH & LH
• Clinical manifestations: ↓ libido, imp otence, oligomenorrhea or amenorrhea,

infertility
• Physical exam: ↓ testicular size; loss of axillary, p ubic and body hair
• Dx with: ↓ a.m. testosterone or estradiol (also assess SHBG, esp . in obese) and ↓ or
normal FSH/LH (all levels ↓ in acute illness, ∴ do not measure in hosp italized Pts)
• Treatment: testosterone or estrogen rep lacement vs. correction of the underlying

cause
↓ ADH (hyp othalamic or stalk disease): diabetes insip idus
• Typ ically from mass lesion extrinsic to sella; p ituitary tumor doesn’t typ ically
p resent w/ DI
• Clinical manifestations: se ve re p olyuria, mild hyp ernatremia (se ve re if ↓ access to
H 2 O)
• Diagnostic studies: see “Sodium and Water Homeostasis”

HYPERPITUITARY SYNDROMES
Pituitary tumors
• Pathop hysiology: adenoma → excess of trop hic hormone (if tumor fxnal, but 30–
40% not) and p otentially de ficie ncie s in other trop hic hormones due to
comp ression; cosecretion of PRL and growth hormone in 10% of p rolactinomas
• Clinical manifestations: syndromes due to oversecretion of hormones (see below)
± mass effect: headache, visual Ds, dip lop ia, cranial neurop athies
• Workup : MRI, hormone levels, ± visual field testing, consider MEN1 (see below)
if <10 mm, mass effect, no hormonal effects, can f/up q3–6mo
Hyperprolactinemia (NEJM 2 010;362 :12 19)

• Etiology
p rolactinoma (50% of p ituitary adenomas)

stalk comp ression due to nonp rolactinoma → ↓ inhibitory dop amine → ↑ PRL
(mild)
• Physiology: PRL induces lactation and inhibits GnRH → ↓ FSH & LH

• Clinical manifestations: amenorrhea, galactorrhea, infertility, ↓ libido, imp otence
• Diagnostic studies: ↑ PRL (✓ fasting levels), but elevated in many situations, ∴ r/o
p regnancy or exogenous estrogens, hyp othyroidism, dop amine agonists (p sych
meds, antiemetics), renal failure (↓ clearance), cirrhosis, stress, ↑ carb diet. MRI to
evaluate for tumor; visual field testing if MRI shows comp ression of op tic chiasm.
• Treatment
If asx (no HA, galactorrhea, hyp ogonadal sx) & microadenoma (<10 mm), follow
w/ MRI
If sx or macroadenoma (≥10 mm) op tions include:

me dical with dop amine agonist such as cabergoline (70–100% success rate) or
bromocrip tine (not as well tol); side effects include N/V, orthostasis, nasal
congestion, tricusp id valve regurgitation (✓ echo before & q1–2 y during Rx)
(JCEM 2 010:95:102 5)
surg ical: transsp henoidal surgery (main indications: failed or cannot tolerate
medical Rx, GH cosecretion or neurologic sx not imp roving); 10–2 0% recurrence
rate
radiation: if medical or surgical therap y have failed or are not tolerated
Acromegaly (↑ GH; 10% of adenomas; NEJM 2 006;355:2 558 )
• Physiology: stimulates secretion of insulin-like growth factor 1 (IGF-1)

• Clinical manifestations: ↑ soft tissue, arthralgias, jaw enlargement, headache, carp al
tunnel syndrome, macroglossia, hoarseness, sleep ap nea, amenorrhea, imp otence,
diabetes mellitus, acanthosis/skin tags, ↑ sweating, HTN/CMP, colonic p olyp s
• Diagnostic studies: no utility in che cking random GH le ve ls be cause of pulsatile

se cre tion
≠ IGF-1 (somatomedin C); ± ↑ PRL; OGTT → GH not sup p ressed to <1 (<0.3 if
newer assay) ng/mL; p ituitary MRI to evaluate for tumor
• Treatment: surgery, octreotide (long- and short-acting p rep arations), dop amine
agonists (if PRL co-secretion), p egvisomant (GH recep tor antagonist), radiation
• Prognosis: w/o Rx 2 –3× ↑ mortality, risk of p ituitary insufficiency, colon cancer

Cushing’s disease (↑ ACTH): 10–15% of adenomas; see “Adrenal Disorders”
Central hyperthyroidism (↑ TSH, ↑ ɑ-subunit): extremely rare; see “Thyroid

Disorders”
↑ FSH & LH: usually non-fxn, p resents as hypopituitarism b/c of comp ression effects
THYROID DISORDERS
Figure 7-1 Approach to thyroid disorders

HYPOTHYROIDISM
Etiologies
• Primary (>90% of cases of hyp othyroidism; ↓ free T4, ↑ TSH)
Goitrous: Hashimoto’s thyroiditis, after hyp erthyroid p hase of thyroiditis, iodine

defic, Li, amiodarone
Nongoitrous: surgical destruction, s/p radioactive iodine or XRT, amiodarone
• Central (↓ free T4, low/nl or slightly high TSH): hyp othalamic or p ituitary failure
(TSH levels ↓ or “normal,” can be slightly ↑ although functionally inactive due to
abnormal glycosylation)
Hashimoto’s thyroiditis
• Autoimmune destruction with p atchy lymp hocytic infiltration

• Associated with other autoimmune disease and may be p art of PGA syndrome typ e II
• antithyroid p eroxidase (anti-TPO) and antithyroglobulin (anti-Tg) Abs in >90%
Clinical manifestations (Annals 2 009;151:ITC61)
• Early: weakness, fatigue, arthralgias, myalgias, headache, dep ression, cold

intolerance, weight gain, constip ation, menorrhagia, dry skin, coarse brittle hair,
brittle nails, carp al tunnel syndrome, delayed DTRs (“hung up ” reflexes), diastolic
HTN, hyp erlip idemia
• Late: slow sp eech, hoarseness, loss of outer third of eyebrows, myxedema

(nonp itting skin thickening due to↑ glycosaminoglycans), p eriorbital p uffiness,
bradycardia, p leural, p ericardial, & p eritoneal effusions, atherosclerosis
• Myxedema crisis: hyp othermia, hyp otension, hyp oventilation, Δ MS (including
coma) hyp onatremia, hyp oglycemia; often p recip itated by infection or major
cardiop ulmonary or neurologic illness (Me d Clin North Am 2 012 ;96:38 5)
Diagnostic studies
• ↓ FT4; ↑ TSH in p rimary hyp othyroidism; antithyroid Ab in Hashimoto’s

thyroiditis
• May see hyp onatremia, hyp oglycemia, anemia, ↑ LDL, ↓ HDL and ↑ CK
• Screening recommended for p regnant women
Treatment of overt hypothyroidism
• Levothyroxine (1.5–1.7 µg/kg/d), re ✓ TSH q5–6wk and titrate until euthyroid;
sx can take mos to resolve; lowe r starting dose (0.3–0.5 µg/kg/d) if at risk for
ischemic heart disease or elderly; advise Pt to keep same formulation of
levothyroxine
↑ dose typ ically needed if: p regnancy (~30% ↑ by wk 8 ), initiation of estrogen

rep lacement, on meds that accelerate T4 catabolism (eg, p henytoin,
p henobarbital), p oor GI absorp tion (concomitant Fe or Ca sup p l, PPI,
sucralfate, cholestyramine, celiac disease, IBD)
• Myxedema coma: load 5–8 µg/kg T4 IV, then 50–100 µg IV qd; b/c p erip heral
conversion imp aired, may also give 5–10 µg T3 IV q8 h if unstable w/ bradycardia
and/or hyp othermia (T3 more arrhythmogenic); must give emp iric adre nal re place -
me nt the rapy first as ↓ adrenal reserves in myxedema coma
Subclinical hypothyroidism (Lance t 2 012 ;379:1142 )
• Mild ↑ TSH and normal free T4 with only subtle or no sx
• If TSH <7 or anti-TPO Ab, ~ 1⁄2 euthyroid after 2 y (JCEM 2 012 ;97:1962 ) if ↑
titers of antithyroid Abs, p rogression to overt hyp othyroidism is ~4% /y
• Rx controversial: follow exp ectantly or treat to imp rove mild sx or dyslip idemia
most initiate Rx if TSH >10 mU/L, goiter, p regnancy or infertility if TSH 5–10
mU/L Rx if ≤60 y (usually don’t Rx if ≥60 b/c ↑ risk CV comp lications)
HYPERTHYROIDISM
Etiologies (Lance t 2 012 ;379:1155)

• Graves’ disease (60–8 0% of thyrotoxicosis)
• Thyroiditis: thyrotoxic p hase of subacute (granulomatous) or p ainless (lymp hocytic)

• Toxic adenomas (single or multinodular goiter)
• TSH-secreting p ituitary tumor or p ituitary resistance to thyroid hormone (↑ TSH, ↑
free T4)
• Misc: amiodarone, iodine-induced, thyrotoxicosis factitia, struma ovarii (3% of

ovarian dermoid tumors and teratomas), hCG-secreting tumors (eg,
choriocarcinoma), large dep osits of metastatic follicular thyroid cancer
Clinical manifestations of hyperthyroidism
• Restlessness, sweating, tremor, moist warm skin, fine hair, tachycardia, AF, weight
loss, ↑ frequency of stools, menstrual irregularities, hyp erreflexia, osteop orosis,
stare and lid lag (due symp athetic overactivity)
• Apathetic thyrotoxicosis: seen in elderly who can p resent with lethargy as only sx
• Thyroid storm (extremely rare): delirium, fever, tachycardia, systolic hyp ertension
but wide p ulse p ressure and ↓ MAP, GI symp toms; 2 0–50% mortality
Laboratory testing
• ↑ FT4 and FT3 ; ↓ TSH (excep t in TSH-secreting tumors)
• RAIU scan is very useful study to differentiate causes (see table on p age 7-3); cannot
do if recent IV contrast or amio load b/c iodine blocks up take so ✓ autoantibodies
instead
• Rarely need to ✓ for autoantibodies excep t in p regnancy (to assess risk of fetal
Graves’)
• May see hyp ercalciuria ± hyp ercalcemia, ↑ AΦ , anemia
Graves’ disease (NEJM 2 008 ;358 :2 594)
• : ratio is 5–10:1, most Pts between 40–60 y at dx
• thyroid antibodies: TSI or TBII ( in 8 0% ), anti-TPO, antithyroglobulin; ANA
• Clinical manifestations in addition to those of hyp erthyroidism (see above):
goiter: diffuse, nontender, w/ thyroid bruit
ophthalmopathy (NEJM 2 009;360:994): Seen in 50% ; up to 90% if formally

tested. Periorbital edema, lid retraction, p rop tosis, conjunctivitis, dip lop ia
(EOM infiltration); associated w/ smoking. Stare and lid lag seen in any typ e of
hyp erthyroidism.
pretibial myxedema (3% ): infiltrative dermop athy
Thyroiditis (NEJM 2 003;348 :2 646; Me d Clin North Am 2 012 ;96:2 2 3)

• Acute: bacterial infection (very rare in U.S. excep t p ostsurgical)
• Subacute: transient thyrotoxicosis → transient hyp othyroidism → normal thyroid

fxn
painful (viral, granulomatous or de Quervain’s): fever, ↑ ESR; Rx = NSAIDs, ASA,
steroids
silent (p ostp artum, autoimmune including Hashimoto’s, or lymp hocytic):

p ainless, TPO Abs; if p ostp artum, can recur with subsequent p regnancies
other: amiodarone, p alp ation thyroiditis, after radiation
Treatment
• β-blockers: control tachycardia (p rop ranolol also ↓ T4 → T3 conversion)
• Graves’ disease: either antithyroid drugs or radioactive iodine (NEJM 2 005;352 :905)
methimazole: 70% chance of recurrence after 1 y; side effects include p ruritus,
rash, arthralgia, fever, N/V and ag ranulocytosis in 0.5% . PTU: 2 nd line (risk of
hep atocellular necrosis; TID dosing; slower effect). For both, need to ✓ LFTs,
WBC, TSH at baseline and in follow-up .
radioactive iodine (RAI) (NEJM 2 011;364:542 ): typ ically done as outPt; p reRx
selected Pts w/ CV disease or elderly w/ antithyroid drugs to p revent ↑
thyrotoxicosis, stop 3 d before to allow RAI up take; >75% of treated Pts
become hyp othyroid
surgery: less commonly chosen for Graves’, usually for Pts w/ obstructive goiter
or op hthalmop athy
• Toxic adenoma or toxic multinodular goiter: RAI or surgery (methimazole p reRx for
surgery, in selected p atients before RAI)
• Thyroid storm: β-blocker, PTU or methimazole, iop anoic acid or iodide (for Wolff-
Chaikoff effect) >1 h after PTU, ± steroids (↓ T4 → T3)
• Op hthalmop athy: can worsen after RAI, p revented by p rop hylactic Rx w/

p rednisone in high-risk Pts; can be Rx’d w/ radiation and/or surgical
decomp ression of orbits
Subclinical hyperthyroidism (Lance t 2 012 ;379:1142 )
• Mild ↓ TSH and normal free T4 with only subtle or no sx
• ~15% → overt hyp erthyroidism in 2 y; ↑ risk of AF, CHD (Archive s 2 012 ;172 :799),
osteop orosis
• Rx controversial: consider if TSH <0.1 mU/L and ↑ risk for CV disease or
osteop enic
NONTHYROIDAL ILLNESS (SICK EUTHYROID SYNDROME)
• TFT abnormalities in Pts w/ severe nonthyroidal illness (∴ in acute illness, ✓ TFTs

only if ↑ concern for thyroid disease); may have acquired transient central
hyp othyroidism
• If thyroid dysfxn susp ected in critically ill Pt, TSH alone not reliable; must measure
total T4, FT4, & T3 (J Endocrinol 2 010;2 05:1)
• Mild illness: ↓ T4 → T3 conversion, ↑ rT3 ⇒ ↓ T3; in severe illness: ↓ TBG &

albumin, ↑↑ rT3 ⇒ ↓↓ T3, ↑ degradation of T4, central ↓ TSH ⇒ ↓↓ T3 , ↓↓T4,
↓FT4, ↓TSH
• Recovery p hase: ↑ TSH followed by recovery of T4 and then T3
• Rep lacement thyroxine not help ful or recommended for critically ill Pts w/ ↓ T3 and
T4 unless other s/s of hyp othyroidism
AMIODARONE AND THYROID DISEASE
6 mg iodine pe r 20 0 mg table t; risk of thyroid dysfunction lowe r with lowe r dose s

✓ TSH prior to the rapy, at 4-mo inte rvals on amio, and for 1 y afte r if amio d/c’d
Hypothyroidism (occurs in ~10% ; more common in iodine-rep lete areas)

• Pathop hysiology
(1) Wolff-Chaikoff effect: iodine load ↓ I– up take, organification and release of T4 &
T3
(2 ) inhibits T4 → T3 conversion direct/immune-mediated thyroid destruction
• Normal individuals: ↓ T4; then escap e Wolff-Chaikoff effect and have ↑ T4, ↓ T3, ↑
TSH; then TSH normalizes (after 1–3 mo)
• Suscep tible individuals (eg, subclinical Hashimoto’s, ∴ ✓ anti-TPO) do not escap e

effects
• Treatment: thyroxine to normalize TSH; may need larger than usual dose
Hyperthyroidism (3% of Pts on amio; ∼10–2 0% of Pts in iodine -de ficie nt are as)
• Typ e 1 = underlying multinodular goiter or autonomous thyroid tissue
Jod-Basedow effect: iodine load → ↑ synthesis of T4 and T3 in autonomous tissue
• Typ e 2 = destructive thyroiditis
↑ release of p reformed T4 & T3 → hyp erthyroidism → hyp othyroidism →

recovery
• Dop p ler U/S: typ e 1 w/ ↑ thyroid blood flow; typ e 2 w/ ↓ flow
• Treatment: not absolutely necessary to d/c amio b/c amio ↓ T4 → T3 conversion

methimazole for typ e 1; steroids for typ e 2 often difficult to distinguish so Rx for
both typ ically initiated ( JCEM 2 001;8 6:3) consider thyroidectomy in severely ill
p atient
THYROID NODULES
• Prevalence 5–10% (50–60% if screen with U/S), ~5% malignant
• Features associated w/ ↑ risk of malignancy: age <2 0 or >70 y, , h/o neck XRT,
hard and immobile mass, cold nodule on RAIU, large size, worrisome U/S findings
(hyp oechoic, solid, irregular borders, microcalcifications, central blood flow),
cervical LAN
• Features associated w/ benign dx: FHx of autoimmune thyroid disease or goiter,

p resence of hyp othyroidism or hyp erthyroidism, nodule tenderness
• Screening U/S recommended for those with FHx of MEN2 or medullary thyroid
cancer, p ersonal h/o neck XRT, p alp able nodules or multinodular goiter
• Any evidence of tracheal deviation or comp ression → ✓ PFTs & refer to surgery
• FNA for nodules >10 mm (>8 mm if irregular borders), microcalcifications or
central vasculature; FNA any nodules in Pts with h/o neck XRT or FHx of MEN2 or
MTC
• Indeterminate p attern in 15–30% of FNA; gene exp ression p attern has Se 92 % & Sp
52 % for malignancy (NEJM 2 012 ;367:705)
• Sup p ressive Rx w/ high doses of levothyroxine less successful in iodine-sufficient

regions
• After comp lete surgical resection of thyroid cancer, RAI is administered (in Pts w/
low-risk thyroid cancer, this p ractice is controversial) (Lance t 2 013;38 1:1046 &
1058 )
Figure 7-2 Approach to thyroid nodules (Thyroid 2009; 19:1167; Am J Clin Pathol
2009; 132:658)
ADRENAL DISORDERS
CUSHING’S SYNDROME (HYPERCORTISOLISM)

Definitions
• Cushing’s syndrome = cortisol excess

• Cushing’s disease = Cushing’s syndrome 2 ° to p ituitary ACTH hyp ersecretion
Etiologies of hypercortisolism
• Most common is iatrogenic Cushing’s syndrome caused by exogenous glucocorticoids

• Cushing’s disease (60–70% ): p ituitary adenoma (usually microadenoma) or
hyp erp lasia
• Adrenal tumor (15–2 5% ): adenoma or (rarely) carcinoma
• Ectopic ACTH (5–10% ): SCLC, carcinoid, islet cell tumors, medullary thyroid
cancer, p heo
• Nonspe cific: glucose intolerance or DM, HTN, obesity, oligo- or amenorrhea,

osteop orosis
• More spe cific: central obesity w/ extremity wasting, dorsocervical fat p ads, rounded
facies
• Most spe cific: sp ontaneous bruising, p roximal myop athy, wide striae, hyp okalemia
• Other: dep ression, insomnia, p sychosis, imp aired cognition, facial p lethora, acne,
hirsutism, hyp erp igmentation (if ↑ ACTH), fungal skin infxns, nep hrolithiasis,
p olyuria
Figure 7-3 Approach to suspected Cushing’s syndrome (nb, very di cult to
diagnose as an inpatient)
CRH, corticotrop in-releasing hormone; DST, dexamethasone sup p ression test; UFC,
urinary free cortisol
Overnight 1 mg DST = give 1 mg at 11 p .m.; ✓ 8 a.m. serum cortisol (sup p ression if
<1.8 µg/dL); 1–2 % false (p rimarily used to evaluate subclinical Cushing’s in
adrenal “incidentalomas” ) (JCEM 2 008 ;93:152 6)
11 p m salivary cortisol = abnl if level ↑; 2 4-h UFC = abnl if level ↑, > 4× ULN
virtually diagnostic
48 -h LD DST + CRH = 0.5 mg q6h × 2 d, then IV CRH 2 h later; ✓ serum cortisol
15 min later ( = >1.4 µg/dL)
48 -h LD DST = 0.5 mg q6h × 2 d; ✓ 2 4-h UFC at base. & during last 2 4 h of dex
(sup p ress if <10% of base)
48 -h HD DST = 2 mg q6h × 2 d; ✓ 2 4-h UFC as p er LD DST
O/N HD DST = 8 mg at 11 p .m.; ✓ 9 a.m. serum cortisol (sup p ression if <32 % of
baseline)
CRH test = 1 µg/kg IV; ✓ cortisol and ACTH ( stim if > 35% ↑ in ACTH or
>2 0% ↑ in cortisol above baseline)
BIPSS, bilat. inferior p etrosal sinus vein samp ling; ✓ p etrosal:p erip heral ACTH ratio
( = 2 basal, >3 after CRH)
(J Clin Endocrinol Metab 2 008 ;93:152 6)
Treatment of Cushing’s syndrome
• Surgical resection of p ituitary adenoma, adrenal tumor or ectop ic ACTH-secreting

tumor
• If transsp henoidal surgery (TSS) not successful → p ituitary XRT, medical

adrenalectomy w/ mitotane, or bilat surgical adrenalectomy; ketoconazole (±
metyrap one) to ↓ cortisol
• Glucocorticoid rep lacement therap y × 6–36 mo after TSS (lifelong glucocorticoid +

mineralocorticoid rep lacement if medical or surgical adrenalectomy)
HYPERALDOSTERONISM
Etiologies
• Primary (adrenal disorders, renin indep endent increase in aldosterone) adrenal

hyp erp lasia (60% ), adenoma (Conn’s syndrome, 35% ), carcinoma (5% )
glucocorticoid-remediable aldosteronism (GRA; ACTH-dep . rearranged p romoter)
• Secondary (extra-adrenal disorders, ↑ aldosterone is renin dep endent)
Primary reninism: renin-secreting tumor (rare)
Secondary reninism
renovascular disease: RAS, malignant hyp ertension

edematous states w/ ↓ effective arterial volume: CHF, cirrhosis, nep hrotic syndrome
hyp ovolemia, diuretics, T2 D, Bartter’s (defective Na/K/2 Cl transp orter receiving
loop diuretic), Gitelman’s (defective renal Na/Cl transp orter receiving
thiazide diuretic)
• Nonaldosterone mineralocorticoid excess mimics hyp eraldosteronism

11β-HSD deficiency (→ lack of inactivation of cortisol, which binds to nonselective
mineralocorticoid recep tor)
Black licorice (glycyrrhizinic acid inhibits 11β-HSD), extreme hyp ercortisolism

(overwhelming 11β-HSD), exogenous mineralocorticoids
Liddle’s syndrome (constitutively activated/overexp ressed distal tubular renal Na
channel)
• Mild to moderate HTN (11% of Pts w/ HTN refractory to 3 drugs; Lance t
2 008 ;371:192 1), headache, muscle weakness, p olyuria, p olydip sia; no p erip heral
edema because of “escap e” from Na retention; malignant HTN is rare
• Classically hypokalemia (but often normal), metabolic alkalosis, mild

hyp ernatremia
Diagnostic studies
• 5–10% of Pts w/ HTN; ∴ screen if HTN + hyp okalemia, adrenal mass or refractory
HTN
• Screening: aldo (>15–2 0 ng/dL) and plasma aldo:renin ratio (>2 0 if 1°) obtain 8
a.m. p aired values (off sp ironolactone & ep lerenone for 6 wk); Se & Sp >8 5%
• ACEI/ARB, diuretics, CCB can ↑ renin activity → ↓ PAC/PRA ratio and βBs may ↑
PAC/PRA ratio;∴ avoid. ɑ-blockers generally best to control HTN during dx
testing.
• Confirm with sodium suppression test (fail to sup p ress aldo after sodium load) oral
salt load (+ KCl) × 3 d, ✓ 2 4-h urine ( if aldo >12 µg/d while Na >2 00
mEq/d) or 2 L NS over 4 h, measure aldo at end of infusion ( if aldo >5 ng/dL)
Figure 7-4 Ap p roach to susp ected hyp eraldosteronism

Treatment
• Adenoma → adrenalectomy vs. medical Rx w/ sp ironolactone or ep lerenone
• Carcinoma → adrenalectomy
• Hyp erp lasia → sp ironolactone or ep lerenone; GRA → glucocorticoids ±
sp ironolactone
ADRENAL INSUFFICIENCY
Etiologies
• Primary = adrenocortical disease = Addison’s disease
autoimmune: isolated or in assoc w/ PGA syndromes (see table on p age 7-2 )

infection: TB, CMV, histop lasmosis
vascular: hemorrhage (usually in setting of sep sis), thrombosis, HIT and trauma
metastatic disease: (90% of adrenals must be destroyed to cause insufficiency)
deposition diseases: hemochromatosis, amyloidosis, sarcoidosis

drugs: ketoconazole, etomidate (even after single dose), rifamp in, anticonvulsants
• Secondary = p ituitary failure of ACTH secretion (but aldosterone intact b/c RAA
axis) any cause of p rimary or secondary hyp op ituitarism (see “Pituitary
Disorders” )
glucocorticoid therap y (can occur after ≥2 wk of “sup p ressive doses” ; dose effect
variable; <10 mg p rednisone daily chronically can be sup p ressive)
megestrol (a p rogestin with some glucocorticoid activity)
Clinical manifestations (NEJM 1996;335:12 06)
• Primary or secondary: weakness and fatigability (99% ), anorexia (99% ),

orthostatic hypotension (90% ), nausea (8 6% ), vomiting (75% ), hyp onatremia
(8 8 % )
• Primary only (extra s/s due to lack of aldosterone and ↑ ACTH): marked orthostatic
hypotension (because volume-dep leted), salt craving, hyperpigmentation (seen in
creases, mucous membranes, p ressure areas, nip p les), hyperkalemia
• Secondary only: ± other manifestations of hyp op ituitarism (see “Pituitary

Disorders” )
Diagnostic studies (Annals 2 003;139:194)
• Early a.m. serum cortisol: <3 µg/dL virtually diagnostic; ≥18 µg/dL rules it out
(excep t in severe sep tic shock—see below)
• Standard (2 50 µg) cosyntropin stimulation test (testing ability of ACTH → ↑

cortisol)
normal = 60-min p ost-ACTH cortisol ≥18 µg/dL
abnormal in primary b/c adrenal gland diseased and unable to give adequate
outp ut
abnormal in chronic secondary b/c adrenals atrop hied and unable to resp ond
(very rarely, may be normal in acute se condary b/c adrenals still able to resp ond;
early a.m. cortisol can be used rather than p ost-stim value in these cases)
• Other tests to evaluate HPA axis (w/ guidance by endocrinologist): insulin-induced
hyp oglycemia (measure serum cortisol resp onse); metyrap one (blocks cortisol
synthesis
and therefore stimulates ACTH, measure p lasma 11-deoxycortisol and urinary
17-hydroxycorticosteroid levels)
• Other lab abnormalities: hyp oglycemia, eosinop hilia, lymp hocytosis, ±

neutrop enia
• ACTH: ↑ in 1°, ↓ or low-normal in 2 °
• Imaging studies to consider
p ituitary MRI to detect anatomical abnormalities
adrenal CT: small, noncalcified adrenals in autoimmune, enlarged in metastatic

disease, hemorrhage, infection or dep osition (although they may be normal-
ap p earing)
Adrenal insufficiency & critical illness (NEJM 2 003;348 :72 7; JAMA

2 009;301:2 362 )
• ↑ circulating cortisol desp ite ↓ ACTH due to ↓ clearance and p ossibly stimulation by
cytokines; ∴ dx of adrenal insufficiency p roblematic (NEJM 2 013;368 :1477)
• Nonetheless, reasonable to p erform ACTH stim ASAP in hyp otensive Pt susp ected to
have absolute adrenal insuffic.
• Initiate corticosteroids early: use dexamethasone 2 –4 mg IV q6h + fludrocortisone

50 µg daily p rior to ACTH stim; change to hydrocortisone 50–100 mg IV q6–8 h
once test comp leted.
• Rx of re lative adre nal insufficie ncy controversial (see “Sep sis” )
Treatment
• Acute insufficiency: volume resuscitation w/ normal saline + hydrocortisone IV as
above
• Chronic insufficiency
Hydrocortisone: 2 0–30 mg PO qd (2 ⁄3 a.m. 1⁄3 early p .m.) or p rednisone ~5 mg
PO qam
Fludrocortisone (not needed in 2 ° adrenal insufficiency): 0.05–0.1 mg PO qam
backup dexamethasone 4-mg IM p refilled syringe given to Pt for emergency

situations
PHEOCHROMOCYTOMA
Clinical manifestations (five Ps)
• Pressure (hyp ertension, p aroxysmal in 50% , severe & resistant to Rx, occ
orthostatic)
• Pain (headache, chest p ain)
• Palpitations (tachycardia, tremor, wt loss, fever)

• Perspiration (p rofuse)
• Pallor (vasoconstrictive sp ell)
• “Rule of 10” : 10% extra-adrenal (known as p araganglioma), 10% in children,
10% multip le or bilateral, 10% recur (↑ in p araganglioma), 10% malignant (↑ in

p araganglioma), 10% familial, 10% incidentaloma
• Emotional stress does not trigger p aroxysms, but abdominal manip ulation can
trigger
catecholamine release; some rep orts of IV contrast causing p aroxysms
• Associated with MEN2 A/2 B, von Hip p el Lindau, neurofibromatosis typ e 1, familial
p araganglioma (mutations in succinate dehydrogenase gene B, C and D)
Diagnostic studies
• 2 4° urinary fractionated metanep hrines & catechols: 90% Se, 98 % Sp (JCEM
2 003;8 8 :553). Screening test of choice if low-risk (as false with severe illness,
renal failure, OSA, labetalol due to assay interference, TCAs, medications
containing symp athomimetics).
• Plasma free metanep hrines: 99% Se, 8 9% Sp (JAMA 2 002 ;2 8 7:142 7). Screening test
of choice if high risk, but ↑ rate of false in low-p reval. p op ulation.
• Adrenal CT or MRI; consider MIBG scintigrap hy if CT/MRI , PET can be used to
localize nonadrenal mass, but usually easy to find
• Consider genetic testing in ap p rop riate circumstances (bilateral, young Pt, FHx,
extra-adrenal)
Treatment
• ɑ-blockade first (usually p henoxybenzamine) ± β-blockade (often p rop ranolol) →

surgery
• Preop erative volume exp ansion is critical due to p ossible hyp otension after tumor
excision
ADRENAL INCIDENTALOMAS
Epidemiology
• 4% of Pts undergoing abdominal CT scan have incidentally discovered adrenal mass;

p revalence ↑ with age
Differential diagnosis
• Nonfunctioning mass: adenoma, cysts, abscesses, granuloma, hemorrhage, lip oma,

myelolip oma, p rimary or metastatic malignancy
• Functioning mass: p heochromocytoma, adenoma (cortisol, aldosterone, sex
hormones), nonclassical CAH, other endocrine tumor, carcinoma
• Nonadrenal mass: renal, p ancreatic, gastric, artifact
Workup (NEJM 2 007;356:601; JCEM 2 010;95:4106)
• Rule out subclinical Cushing’s syndrome in all Pts using 1 mg overnight DST (Sp
91% ). Abnormal results require confirmatory testing.
• Rule out hyperaldosteronism if hype rte nsive w/ p lasma aldo & renin (see above)
• Rule out pheochromocytoma in ALL Pts (b/c of morbidity unRx’d p heo) using 2 4-h
urine fractionated metanep hrines and catecholamines or p lasma free
metanep hrines
• Rule out metastatic cancer and infection by history or CT-guided biop sy if susp icious
(in Pts w/ h/o cancer, ~50% of adrenal incidentalomas are malignant)
• CT and MRI characteristics may suggest adenoma vs. carcinoma
Be nig n fe ature s: size <4 cm; smooth margins, homogenous and hyp odense
ap p earance; unenhanced CT <10 Hounsfield units or CT contrast-medium
washout >50% at 10 min. Can follow such incidentalomas w/ p eriodic scans.
Suspicious fe ature s: size >4 cm or ↑ size on rep eat scan; irregular margins,
heterogeneous, dense or vascular ap p earance; h/o malignancy or young age
(incidentaloma less common). Such incidentalomas warrant resection or rep eat
scan at short interval.
CALCIUM DISORDERS
Pitfalls in measuring calcium
• Physiologically active Ca is free or ionized (ICa). Serum Ca reflects total calcium

(bound + unbound) and ∴ influenced by albumin (main Ca-binding p rotein).
• Corrected Ca (mg/dL) = measured Ca (mg/dL) + {0.8 × [4 − albumin (g/dL)]}
• Alkalosis will cause more Ca to be bound to albumin (∴ total Ca may be normal but
↓ ICa)
• Best to measure ionized Ca directly (but accuracy is lab de pe nde nt)
HYPERCALCEMIA
Clinical manifestations (“bones, stones, abdominal groans and p sychic moans” )

• Hypercalcemic crisis (usually when Ca >13–15): p olyuria, dehydration, ΔMS
Ca toxic to renal tubules → blocks ADH activity, causes vasoconstriction and ↓

GFR → p olyuria but Ca reabsorp tion → ↑ serum Ca → ↑ nep hrotoxicity and
CNS sx
• Osteop enia, fractures and osteitis fibrosa cystica (latter seen in severe hyp erp ara.
only →
↑ osteoclast activity → cysts, fibrous nodules, salt & p ep p er ap p earance on X-ray)
• Nep hrolithiasis, nep hrocalcinosis, nep hrogenic DI

• Abdominal p ain, anorexia, nausea, vomiting, constip ation, p ancreatitis, PUD
• Fatigue, weakness, dep ression, confusion, coma, ↓ DTRs, short QT interval
• 1° HPT: 8 0% asx, 2 0% nep hrolithiasis, osteop orosis, etc.
• Calciphylaxis (calcific uremic arteriop athy): calcification of media of small- to med-

sized blood vessels of dermis & SC fat → ischemia and skin necrosis (NEJM
2 007;356:1049).
Associated w/ uremia, ↑ PTH, ↑ Ca, ↑ PO 4 and ↑ (Ca × PO 4) p roduct. Dx by

biop sy.
Rx: aggressive wound care, keep Ca & PO 4 nl (goal <55), avoid vitamin Δ & Ca
sup p l. IV Na thiosulfate, cinacalcet, & p arathyroidectomy controversial.
Overall p ortends a p oor p rognosis

Diagnostic studies
• Hyp erp arathyroidism and malignancy account for 90% of cases of hyp ercalcemia
hyp erp arathyroidism more likely if asx or chronic hyp ercalcemia
malignancy more likely if acute or sx; malignancy usually overt or becomes so in

mos
• Ca, alb, ICa, PTH (may be inap p rop riately normal in 1° HPT & FHH), PO 4;
↑ or high nl PTH: 2 4-h U Ca >2 00 mg → HPT; 2 4-h U Ca <100 mg & FECa <0.01
→ FHH
↓ PTH: ✓ PTHrP, AΦ , & search for malig (eg, CT, mammogram, SPEP/UPEP) and
✓ vit D: ↑ 2 5-(OH)D → meds; ↑ 1,2 5-(OH)2 D → granuloma (✓ CXR, ACE, r/o
lymp h)
Treatment of asymptomatic 1° HPT (JCEM 2 009;94:335)
• Surgery if: age <50 y; serum Ca >1 mg/dL >ULN; CrCl <60 mL/min, DEXA T
score <-2 .5
• If surgery declined/deferred, can Rx with bisp hosp honates (↑ BMD but do not ↓ Ca &
PTH) or cinacalcet (↓ Ca & PTH but may not ↑ BMD)
• If not yet candidate for surgery: ✓ serum Ca & Cr annually and BMD q1–2 y
HYPOCALCEMIA
• Neuromuscular irritability: p erioral p aresthesias, cramp s, Chvostek’s
(tap p ing facial nerve → contraction of facial muscles), Trousseau’s (inflation
of BP cuff → carp al sp asm), laryngosp asm; irritability, dep ression, p sychosis, ↑
ICP, seizures, ↑ QT
• Rickets and/or osteomalacia: chronic ↓ vit Δ → ↓ Ca, ↓ PO 4 → ↓ bone/cartilage

mineralization, growth failure, bone p ain, muscle weakness
• Renal osteodystrophy (↓ vit Δ & ↑ PTH in renal failure): osteomalacia [↓

mineralization of bone due to ↓ Ca and 1,2 5-(OH)2 D] & osteitis fibrosa cystica
(due to ↑ PTH)
Diagnostic studies
• Ca, alb, ICa, PTH, 2 5-(OH)D, 1,2 5-(OH)2 D (if renal failure or rickets), Cr, Mg, PO 4,
Af, U Ca
Treatment (also treat concomitant vitamin Δ deficiency)
• Symp tomatic: Ca gluconate (1–2 g IV over 2 0 mins) + calcitriol (most effective in

acute hyp ocalcemia, but takes hrs to work) ± Mg (50–100 mEq/d)
• Asymp tomatic and/or chronic: oral Ca (1–3 g/d; Ca citrate better absorbed then Ca
carbonate, esp . if on PPI) & vitamin Δ (eg, ergocalciferol 50,000 IU PO q wk × 8 –
10 wk). In chronic hyp op ara., calcitriol is needed, consider also thiazide.
• Chronic renal failure: p hosp hate binder(s), oral Ca, calcitriol or analogue
(calcimimetic may be needed later to p revent hyp ercalcemia)
DIABETES MELLITUS
Definition (Diabe te s Care 2 010;33:S62 ; NEJM 2 012 ;367:542 )

• HbA1c ≥6.5 or fasting glc ≥12 6 mg/dL × 2 or random glc ≥2 00 mg/dL × 2 (× 1
if severe hyp erglycemia and acute metabolic decomp ); routine OGTT not
recommended (excep t during p regnancy)
• Blood glc higher than normal, but not frank DM (“p rediabetics,” ~40% U.S.
p op ulation)
HbA1c 5.7–6.4% or imp aired fasting glc (IFG): 100–12 5 mg/dL
Preventing p rogression to DM: diet & exercise (58 % ↓), metformin (31% ↓; NEJM
2 002 ;346:393), TZD (60% ↓; Lance t 2 006;368 :1096)
Categories
• Type 1: islet cell destruction; absolute insulin deficiency; ketosis in absence of
insulin; p revalence 0.4% ; usual onset in childhood but can occur throughout
adulthood; ↑ risk if FHx; HLA associations; anti-GAD, anti-islet cell & anti-
insulin autoAb
• Type 2: insulin resistance + relative insulin ↓; p revalence 8 % ; onset generally later

in life; no HLA associations; risk factors: age, FHx, obesity, sedentary lifestyle
• Type 2 DM p/w DKA (“ketosis-p rone typ e 2 diabetes” or “Flatbush diabetes” ): most
often seen in nonwhite, ± anti-GAD Ab, eventually may not require insulin (Endo
Re v 2 008 ;2 9:2 92 )
• Mature-Onset Diabetes of the Young (MODY): autosomal dom. forms of DM due to

defects in insulin secretion genes; genetically and clinically heterogeneous (NEJM
2 001;345:971)
• Secondary causes of diabetes: exogenous glucocorticoids, glucagonoma (3 Ds =

DM, DVT, diarrhea), p ancreatic (p ancreatitis, hemochromatosis, CF, resection),
endocrinop athies (Cushing’s disease, acromegaly), gestational, drugs (p rotease
inhibitors, atyp ical antip sychotics)
• Polyuria, p olydip sia, p olyp hagia with unexp lained weight loss; can also be
asymp tomatic
Complications
• Retinopathy
nonprolife rative : “dot & blot” and retinal hemorrhages, cotton-wool/p rotein
exudates
prolife rative : neovascularization, vitreous hemorrhage, retinal detachment,
blindness
treatment: p hotocoagulation, surgery, intravitreal bevacizumab injections

• Nephropathy: microalbuminuria → p roteinuria ± nep hrotic syndrome → renal
failure
diffuse glomerular basement membrane thickening/nodular p attern (Kimmelstiel-

Wilson)
usually accomp anied by retinop athy; lack of retinop athy suggests another cause
treatment: strict BP control using ACE inhibitors (NEJM 1993;32 9:1456 &
351:1941; Lance t 1997;349:178 7) or ARBs (NEJM 2 001;345:8 51 & 8 61), low-
p rotein diet, dialysis or transp lant
• Neuropathy: pe riphe ral: symmetric distal sensory loss, p aresthesias, ± motor loss
autonomic: gastrop aresis, constip ation, neurogenic bladder, erectile dysfxn,
orthostasis
monone uropathy: sudden-onset p erip heral or CN deficit (footdrop , CN III > VI >
IV)
• Accelerated atherosclerosis: coronary, cerebral and p erip heral arterial beds
• Infections: UTI, osteomyelitis of foot, candidiasis, mucormycosis, necrotizing

external otitis
• Dermatologic: necrobiosis lip oidica diabeticorum, lip odystrop hy, acanthosis

nigricans
Outpatient screening and treatment goals (Diabe te s Care 2 012 ;35:1364)
• ✓ HbA1C q3–6mo, goal <7% for most Pts. Can use goal HbA1C ≥7.5–8 % if h/o
severe hyp oglycemia or other comorbidities. Microvascular & macrovascular
comp lications ↓ by strict glycemic control in T1D (NEJM 1993;32 9:997 &
2 005;353:2 643) & T2 D (Lance t 2 009;373:1765; Annals 2 009;151:394).
• Microalbuminuria screening yearly with sp ot microalbumin/Cr ratio, goal <30

mg/g
• BP≤130/80 (? ≤140/8 5, Archive s 2 012 ;172 :12 96), benefit of ACE-I; LDL < 100,
TG <150, HDL >40; benefit of statins even w/o overt CAD (Lance t 2 003;361:2 005
& 2 004;364:68 5); ASA if age >50 ( ) or 60 ( ) or other cardiac risk factors
(Circ 2 010;12 1:2 694)
• Dilated retinal exam yearly; comp rehensive foot exam qy
Management of hyperglycemia in inpatients (for ICU Pts: see “Sep sis” )
• Identify reversible causes/exacerbaters (dextrose IVF, glucocorticoids, p ostop , ↑ carb

diet)
• Dx studies: BG fingersticks (fasting, qAC, qHS; or q6h if NPO), HbA1C
• Treatment goals: avoid hyp oglycemia, extreme hyp erglycemia (>18 0 mg/dL)
• Modification of outPt treatment regimen: In T1D, do not stop basal insulin (can →
DKA).
In T2 D: stop p ing oral DM meds generally p referred to avoid hyp oglycemia or

med interaction (excep t if short stay, excellent outPt cntl, no p lan for IV
contrast, nl diet)
• InPt insulin: can use outPt regimen as guide; if insulin naïve:
total daily insulin = wt (kg) ÷ 2 , to start; adjust as needed
give 1/2 of total daily insulin as basal insulin in long-acting form to target fasting
glc
give other 1/2 as short-acting boluses (standing p remeal & sliding scale corrective
insulin)
• Discharge regimen: similar to admission regimen unless p oor outPt cntl or strong
reason for Δ. Arrange early insulin and glucometer teaching, p romp t outPt follow-
up .
DIABETIC KETOACIDOSIS (DKA)
Precipitants (the I’s)
• Insulin defic. (ie, failure to take enough insulin); Iatrogenesis (glucocorticoids)
• Infection (p neumonia, UTI) or Inflammation (p ancreatitis, cholecystitis)

• Ischemia or Infarction (myocardial, cerebral, gut); Intoxication (alcohol, drugs)
Pathophysiology
• Occurs in T1D (and in ketosis-p rone T2 D); ↑ glucagon and ↓ insulin
• Hyp erglycemia due to: ↑ gluconeogenesis, ↑ glycogenolysis, ↓ glucose up take into

cells
• Ketosis due to: insulin deficiency → mobilization and oxidation of fatty acids,
↑ substrate for ketogenesis, ↑ ketogenic state of the liver, ↓ ketone clearance
Clinical manifestations (Diabe te s Care 2 003;2 6:S109)

• Polyuria, p olydip sia, & dehydration → ↑ HR, HoTN, dry mucous membranes, ↓ skin
turgor
• N/V, abdominal p ain (either due to intra-abdominal p rocess or DKA), ileus

• Kussmaul’s resp irations (deep ) to comp ensate for metabolic acidosis with odor of
acetone
• Δ MS → somnolence, stup or, coma; mortality ~1% even at tertiary care centers
Diagnostic studies
• ↑ Anion gap metabolic acidosis: can later develop nonanion gap acidosis due to
urinary loss of ketones (HCO 3 equivalents) and fluid resuscitation with chloride
• Ketosis: urine and serum ketones (p redominant ketone is β-OH-butyrate, but

acetoacetate measured by assay; urine ketones may be in fasting normal Pts)
• ↑ Serum glc; ↑ BUN & Cr (dehydration ± artifact due to ketones interfering w/ some
assays)
• Hyp onatremia: corrected Na = measured Na + [2 .4 × (measured glc −100)/100]
• ↓ or ↑ K (but even if serum K is elevated, usually total body K de ple te d); ↓ total body
p hos
• Leukocytosis, ↑ amylase (even if no p ancreatitis)
HYPEROSMOLAR HYPERGLYCEMIC STATE
Definition, precipitants, pathophysiology (Diabe te s Care 2 003;2 6:S33)

• Extreme hyp erglycemia (w/o ketoacidosis) + hyp erosm. + Δ MS in T2 D (typ ically
elderly)
• Precip same as for DKA, but also include dehydration and renal failure
• Hyp erglycemia → osmotic diuresis → vol dep letion → p rerenal azotemia → ↑ glc,
etc.
Clinical manifestations & dx studies (Diabe te s Care 2 006;2 9[12 ]:2 739)
• Volume dep letion and Δ MS
• ↑ serum glc (usually >600 mg/dL) and ↑ meas. serum osmolality (>32 0 mOsm/L)
effective Osm = 2 × Na (mEq/L) + glc (mg/dL)/18
• No ketoacidosis; usually ↑ BUN & Cr; [Na] dep ends on hyp erglycemia & dehydration
Treatment (r/o p ossible p recip itants; ~15% mortality due to p recip itating factors)
• Aggressive hydration: initially NS, then 1/2 NS, average fluid loss up to 8 –10 L
• Insulin (eg, 10 U IV followed by 0.05–0.1 U/kg/h)

HYPOGLYCEMIA
Clinical manifestations (glucose <~55 mg/dL)

• CNS: headache, visual Δs, Δ MS, weakness, seizure, LOC (neuroglycop enic sx)
• Autonomic: diap horesis, p alp itations, tremor (adrenergic sx)

Etiologies in diabetics
• Excess insulin, oral hyp oglycemics, missed meals, renal failure (↓ insulin & SU
clearance)
• β-blockers can mask adrenergic symp toms of hyp oglycemia
Etiologies in nondiabetics
• ↑ insulin: exogenous insulin, sulfonylureas, insulinoma, anti-insulin antibodies
• ↓ glucose production: hyp op ituitarism, adrenal insufficiency, glucagon deficiency,

hep atic failure, renal failure, CHF, alcoholism, sep sis, severe malnutrition
• ↑ IGF-II: non-islet tumor
• Postp randial, esp . p ostgastrectomy or gastric byp ass: excessive resp onse to glc load
• Low glc w/o sx can be normal
Evaluation in nondiabetics (J Clin Endocrinol Me tab 2 009;94:709)
• If clinically ill: take measures to avoid recurrent hyp oglycemia; ✓ BUN, Cr, LFTs,
TFTs, p realbumin; IGF-I/IGF-II ratio when ap p rop riate
• If otherwise healthy: 72 -h fast w/ monitored blood glc; stop for neuroglycop enic sx
• At time of hypog lyce mia: insulin, C p ep tide (↑ w/ insulinoma and sulfonylureas, ↓ w/

exogenous insulin), β-OH-butyrate, sulfonylurea levels
• At end of fast, give 1 mg glucagon IV and measure resp onse of p lasma glc before
feeding
Treatment
• Glucose tablets, p aste, fruit juice are first-line Rx for Pts who can take POs
• If IV access available, give 2 5–50 g of D50 (50% dextrose)
• If no IV, can give glucagon 0.5–1 mg IM or SC (side effect: N/V)

LIPID DISORDERS
Measurements
• Lip op roteins = lip ids (cholesteryl esters & triglycerides) + p hosp holip ids +
p roteins
include: chylomicrons, VLDL, IDL, LDL, HDL, Lp (a)
• Measure after 12 -h fast; LDL is calculated = TC – HDL – (TG/5) (if TG >400, order
direct LDL measurement as calc. LDL inaccurate). Lip id levels stable up to 2 4 h
after ACS and other acute illnesses, then ↓ and may take 6 wk to return to nl.
• Metabolic syndrome (≥3 of following): waist ≥40” ( ) or ≥35” ( ); TG ≥150;
HDL <40 mg/dL ( ) or <50 mg/dL ( ); BP ≥130/8 5 mmHg; fasting glc ≥100
mg/dL (Circ 2 009;12 0:1640)
Primary dyslipidemias
• Familial hyp ercholesterolemia (FH, 1:500): defective LDL recep tor; ↑↑ chol, nl TG; ↑
CAD
• Familial defective ap oB100 (FDB, 1:1000): similar to FH
• Familial combined hyp erlip idemia (FCH, 1:2 00): p olygenic; ↑ chol, ↑ TG, ↓ HDL; ↑
CAD
• Familial dysbetalip op roteinemia (FDBL, 1:10,000): ap oE ε2 /ε2 + DM, obesity,

renal disease, etc.;↑ chol and TG; tuberoerup tive and p almar striated xanthomas; ↑
CAD
• Familial hyp ertriglyceridemia (FHTG, 1:500): ↑ TG, ± ↑ chol, ↓ HDL, p ancreatitis

Physical exam findings
• Tendon xanthomas: seen on Achilles, elbows and hands; imp ly LDL >300 mg/dL
• Erup tive xanthomas: p imp le-like lesions on extensor surfaces; imp ly TG >1000
mg/dL
• Xanthelasma: yellowish streaks on eyelids seen in various dyslip idemias
• Corneal arcus: common in older adults, imp ly hyp erlip idemia in young Pts
Treatment
• Every 1 mmol (39 mg/dL) ↓ LDL → 2 2 % ↓ major vascular events (CV death, MI,
stroke, revasc) in individuals w/ & w/o CAD (Lance t 2 010;376:1670); in healthy
individuals w/ LDL <130 mg/dL & hs-CRP >2 , rosuvastatin → 47% ↓
CVD/MI/stroke (NEJM 2 008 ;359:2 195)
• Fewer clinical data, but TG <400 and HDL >40 are additional reasonable targets
ARTHRITIS—OVERVIEW
Approach to patient with joint pain
• Articular vs. periarticular (bursitis, tendinitis) p ain: typ ically active ROM more
p ainful in p eriarticular p rocess than p assive ROM
• Inflammatory vs. noninflammatory p ain: features of inflammatory p ain include

swelling, warmth or redness in sp ecific joint, p ersistence over days to weeks,
p rolonged morning stiffness (>30 min), imp rovement of p ain/stiffness w/
motion/exercise
• Physical exam (see table): localize comp laint and identify objective signs of
inflammation
• The p hysical exam is only 50–70% sensitive for detecting inflammatory arthritis
a May initially p resent as arthralgia w/o signs of overt arthritis. bRange of motion
(ROM) of joint or joint associated with bursa or tendon.
Approach to arthritis
Figure 8-1 Approach to arthritis

Radiologic features
• OA
p lain films: osteophyes, asym joint sp ace narrowing (JSN), subchondral
sclerosis/cysts MRI may show early disease not seen on p lain films; U/S MRI
for structural damage
• RA
p lain films: early=p eriarticular osteopenia; late=erosions, symmetric JSN MRI
& U/S able to detect early and subclinical disease; MRI U/S for erosions
• Gout
p lain films: early=nonsp ec swelling; late=tophus, joint erosions w/ overhanging
edges U/S > MRI for detection of microtop hi (double contour sign); MRI U/S
for erosions
• Spondyloarthritis (sacroiliac joint)

p lain films: p seudo-widening of joint sp ace (early), sclerosis, erosions, ankylosis
MRI most sensitive for early Δ in SIJ; U/S MRI for early detection of
p erip heral enthesitis
INFLAMMATORY MARKER & AUTOANTIBODY TESTING
Inflammatory markers (Mod Rheumatol 2 009;19:469)

• ESR: indirect measure of inflammation (↑ RBC aggregation due to acute-p hase
p roteins); slow to rise; ↑ w/ age, p regnancy, anemia, obesity
• CRP: direct measure of inflammation (p rotein p roduced by liver, p art of innate
immune system); typ ically rises and falls before the ESR w/ treatment/resolution
of p rocess
Autoantibody testing
• ANA: screening test for Ab directed against extractable nuclear antigens (ENAs) found
in autoimmune conditions, most useful in testing for connective tissue diseases
• ENAs: p roteins p recip itated from sp leen extracts; targets are generally of nuclear
origin
• Order ANA only when clinical susp icion for disease b/c nonsp ecific: 1:40 (low ,
2 5–30% of healthy p eop le); 1:8 0 (low , 10–15% of healthy p eop le); ≥1:160 (
, 5% of healthy). May be in Pts p rior to clin manifest (NEJM
2 003;349:152 6; Arthritis Res Ther 2 011;13:1).
• Does not correlate well w/ disease activity, ∴ no clinical value in serial testing
• dsDNA and ENA antibodies (Ro/La/Smith/RNP) are highly sp ecific for various CTD
and can be used to further w/u ANA in setting of clinical susp icion
• RF and anti-CCP can be seen in CTD but are not sp ecific

RHEUMATOID ARTHRITIS (RA)
Definition & epidemiology (Lance t 2 010;376:1094; NEJM 2 011;365:2 2 05)

• Chronic, symmetric, debilitating and destructive inflammatory p olyarthritis
characterized by p roliferative synovial tissue (p annus) formation in affected joints
• Genetic (~50% of risk) & environmental factors (eg, smoking, silica dust exp osure)
• ↑ risk w/ shared ep itop e & smoke b/c gene–environment interaction (Ann Rheum Dis
2 010;69:70)
• Prevalence=1% adults; 5% of >70 y; to ratio=3:1; p eak incidence 50–

75 y
Clinical manifestations (Medicine 2 010;38 :167)

• Usually insidious onset pain, swelling and imp aired function of joints (typ ically
PIPs, MCPs, wrists, knees, ankles, MTPs and cervical sp ine) with morning
stiffness for ≥1 h
• Typ ically p olyarticular (60% small joints, 30% large joints, 10% both), may be
monoarticular (knee, shoulder, wrist) early in course; nb, rheumatoid joints can
become infected
• Joint deformities: ulnar deviation, swan neck (MCP flexion, PIP hyp erextension,
DIP flexion), boutonnière (PIP flexion, DIP hyp erextension), cock-up deformities
(toes)
• C1–C2 instability → myelop athy, ∴✓ C-sp ine flex/ext films p rior to elective
intubation
• Constitutional symp toms: low-grade fever, weight loss, malaise

• Extra-articular manifestations (18 –41% of Pts) can occur at any time; ↑ frequency
in serop ositive (RF or anti-CCP) (Autoimmun Rev 2 011;11:12 3)
Laboratory & radiologic studies

• RF (IgM/IgA/IgG anti-IgGAb) in ~70% of Pts; also seen in other rheumatic diseases
(SLE, Sjögren’s), infection (SBE, hep atitis, TB), typ es II & III cryo, 5% of healthy
p op ulation
• Anti-CCP (Ab to cyclic citrullinated p ep tide): in ~8 0% of Pts, similar Se (~70% ),

more Sp (>90% ) than RF p articularly for early RA (Arth Rheum 2 009;61:1472 );
a/w increased joint damage and low remission rates
• ~2 0% are seronegative (RF and anti-CCP negative)
• ↑ ESR/CRP but nl in ~30% ; ANA in ~15% ; ↑ globulin during p eriods of active
disease
• Radiograp hs of hands and wrists: p eriarticular osteop enia, bone erosions, joint
subluxation
ACR/EULAR classification criteria (Arth Rhe um 2 010;62 :2 569)
• Use for Pts with ≥1 joint with synovitis not better exp lained by another disease
• Summed score of ≥6 c/w RA
Management (Lance t 2 009;373:659; Ann Rhe um Dis 2 010;69:631)
• Early dx and Rx (esp . DMARD) w/ frequent follow-up and escalation of Rx as needed

to achie ve clinical re mission or low disease activity
• ↓ time to remission ↑ length of sustained remission (Arthritis Re s The r
2 010;12 :R97)
• Sero- disease (eg, RF or anti-CCP) a/w aggressive joint disease & EAM
• Start both rap id acting agent (to acutely ↓ inflammation) and Disease-Modifying
Anti-Rheumatic Drug (DMARD) (typ ically take 1–3 mo to have max effect) at dx
• Rap id-acting drugs: NSAIDs or COX-2 inhibitors (↑ CV adverse events);
glucocorticoids [low-dose (<2 0 mg/d oral) or joint injection]; or
NSAIDs + glucocorticoids: ↑ GI adverse events, minimize long-term concurrent use

• DMARDs
MTX (1st line unless CKD, hep atitis, EtOH or lung disease), SAS or leflunomide;
consider HCQ if seronegative and mild disease;
if inadequate resp onse after 3 mo (desp ite DMARD dose escalation): combination
Rx w/ other traditional DMARDs (ie, MTX, SAS and HCQ) or biologic (anti-TNF
typ ically 1st line unless contraindication)
• Given ↑ r/o early CV morbidity/mortality, ↓ risk w/ lifestyle mgmt, lip id & DM
screening
ADULT ONSET STILL’S DISEASE & RELAPSING POLYCHONDRITIS
Adult onset Still’s disease (Drug s 20 0 8 ;6 8 :319)
• Rare autoinflammatory synd; = w/ typ ical onset 16–35 y; sx evolve over

wks to mos
• Dx if 5 criteria are p resent & ≥2 major; exclude infxn, malig, other rheumatic, drug
rxn
major: fever ≥39°C for ≥1 wk (usually daily or twice daily high-sp iking fever);
arthralgias/arthritis ≥2 wk; Still’s rash (qv); ↑ WBC w/ 8 0% PMN
minor: sore throat; LAN; HSM; ↑ AST/ALT/LDH; negative ANA & RF
• Still’s rash (>8 5% ): nonp ruritic macular or maculop ap ular salmon-colored rash;
usually trunk or extremities; may be p recip itated by trauma (Koebner
p henomenon), warm water
• Plain films: soft tissue swelling (e arly) → cartilage loss, erosions, carp al ankylosis
(late )
• Treatment: NSAIDs, steroids; steroid-sp aring: MTX, anakinra, anti-TNF, tocilizumab
• Variable clinical course: 2 0% w/ long-term remission; 30% remit-relap se; ~50%

chronic (esp . arthritis); ↑ risk of macrop hage activation syndrome (life-
threatening)
Relapsing polychondritis (Autoimmun Re v 2 010;9:540)
• Inflammatory destruction of cartilaginous structures; onset usually age 40–60 y,
• Subacute onset of red, painful and swollen cartilage; ultimately atrop hic &
deformed
• Common clinical features: bilateral auricular chondritis; nonerosive inflammatory

arthritis; nasal chondritis; ocular inflammation; laryngeal or tracheal chondritis;
cochlear and/or vestibular dysfxn
• 40% of cases a/w immunologic disorder (eg, RA, SLE, vasc., Sjögren’s), cancer or
MDS
• Clinical diagnosis based on exam with multip le sites of cartilaginous inflammation
• Labs: ↑ ESR & CRP, leukocytosis, eosinop hilia, anemia of chronic inflammation
• Bx (not req for dx): p roteoglycan dep letion, p erichondrial inflammation and
rep lacement with granulation tissue and fibrosis; immunofluorescence with Ig and
C3 dep osits
• Screen for p ulm (PFTs, CXR/CT, ± bronch) and cardiac (ECG, TTE) involvement
• Therap y guided by disease activity and severity: steroids 1st line; NSAIDs, dap sone
for sx control of arthralgias and mild disease; MTX or AZA for steroid-sp aring;
cyclop hosp hamide for organ-threatening disease
CRYSTAL DEPOSITION ARTHRITIDES
GOUT
Definition & epidemiology (Lance t 2 010;375:318 ; NEJM 2 011;364:443)

• Humans lack enzyme to metabolize urate (end-p roduct of p urine metabolism)
• Monosodium urate (MSU) crystal dep osition in joints p romotes inflammation
• > (9:1); p eak incidence 5th decade; most common cause of inflammatory
arthritis in over 30 y; rare in p remenop ausal (estrogens p romote renal

urate excretion)
(Lance t 2 004;363:12 77; NEJM 2 004;350:1093; Ann Rhe um Dis 2 012 ;71:1448 )
• 4 stages: asx ↑ UA → acute gouty arthritis → intercritical (in between acute flares,
usually asx) → chronic gouty arthrop athy/top haceous gout
• Asx hyperuricemia: majority never develop gout

• Acute arthritis: sudden onset (freq. nocturnal) of p ainful monoarticular arthritis
MTP of great toe (podagra); LE > UE; occasionally p olyarticular (esp . in subseq
flares)
p recip itants: rap id Δ UA; ↑ dietary p urine; surgery; infection; dehydration, meds
(diuretics, urate lowering agents); ∴ frequent in hosp italized Pts
self-limited in 3–10 d; can involve bursa (eg, olecranon or p atella); can mimic
cellulitis
• Intercritical period: may be years but p rogressively shorter as freq of attacks ↑
• Chronic tophaceous gout: solid MSU crystal dep osition in tissue & joints;
commonly in joints (fingers, wrists, knees), p inna, Achilles tendon and p ressure
areas;
chronic gouty arthropathy: deforming arthritis from top hus → p ain, joint
erosion
• Renal: uric acid stones; urate nep hrop athy (interstitial dep osits)
Diagnostic studies
• ↑ UA does not make dx: 2 5% of measurements nl during flare; ± ↑ WBC & ESR
• Arthrocentesis: p olarized microscop y → needle-shaped, negatively birefringent
crystals (yellow p arallel to axis marked on p olarizer), intracellular or
extracellular (less sp ecific)
WBC 2 0,000–100,000/mm 3, >50% p olys

infxn can coexist with acute attacks, ∴ always ✓ Gram stain & Cx (J Rheum
2 012 ;39:157)
• Radiology: erosions with overhanging edge (late), useful to exclude chondrocalcinosis
Acute treatment (Arthritis Care Re s 2 012 ;64:1447)
• No sup erior op tion; start w/in 2 4 h of sx onset; continue until acute flare resolves;
for severe cases, consider combination therap y; rest and ice
Chronic treatment (Lance t 2 011;377:165)
• Approach: if ≥2 attacks/y, ≥1 top hus, joint erosions or urolithiasis → start urate

lowering Rx & p harmacologic p rop hylaxis to ↓ risk of acute attacks
• Urate lowering Rx: goal UA <6 mg/dL; do NOT discontinue during acute attack
• Pharmacologic prophylaxis: continue for at least 6 mo or longer if frequent attacks:

low-dose colchicine (~50% ↓ risk of acute flare; J Rheum 2 004;31:2 42 9),
NSAIDs (less evidence; Ann Rheum Dis 2 006;65:1312 ), low-dose (<10 mg/d)
steroids (min evidence)
• Lifestyle Δs: ↓ intake of meat, EtOH & seafood; ↑ low-fat dairy p roducts; wt loss;
avoid dehydration and hyp eruricemia-p romoting drugs (eg, diuretics)
• Allopurinol hypersensitivity syndrome: 10–2 5% mortality; ↓ risk by starting w/
dose 100 mg/d if eGFR >40 or 50 mg/d if eGFR <40; titrate up by 100 mg/d (if
eGFR >40) or 50 mg/d (if eGFR <40) q2 –5wk until goal UA (<6 mg/dL) reached
(dose can be >300 mg/d even in CKD) (Arthritis Rheum 2 012 ;64:2 52 9; Arthritis
Care Res 2 012 ;64:1431)
CALCIUM PYROPHOSPHATE DIHYDRATE (CPPD) DEPOSITION DISEASE
Definition
• Dep osition of CPPD crystals w/in tendons, ligaments, articular cap sules, synovium,
cartilage; frequently asymp tomatic
Etiologies (Rhe umatolog y 2 012 ;51:2 070)
• Most cases idiopathic; consider further metabolic eval in young (<50 y) and florid
forms
• Metabolic (3 H’s): hemochromatosis; hyp erp arathyroidism; hyp omagnesemia (esp .

in Gitelman’s or Bartter’s syndromes)
• Joint trauma (incl. p revious surgery); intra-articular hyaluronate can p recip itate
attacks
• Familial chondrocalcinosis (autosomal dominant disorder); early-onset,
p olyarticular dis.
Clinical manifestations (Rhe umatolog y 2 009;48 :711)

• Chondrocalcinosis: calcification of cartilage, resulting from CPPD dep osition in
articular cartilage, fibrocartilage or menisci.
↑ incidence w/ age; 2 0% >60 y have knee chondrocalcinosis in autop sy studies

• Pseudogout: acute CPPD crystal-induced mono- or asymmetric oligoarticular
arthritis, indistinguishable from gout excep t through synovial fluid exam for
crystals
location: knees, wrists and MCP joints

p recip itants: surgery, trauma or severe illness
• “Pseudo-RA” : chronic p olyarticular arthritis with morning stiffness
• Pyrop hosp hate arthrop athy: resembles OA and difficult to distinguish; may involve
axial skeleton
Diagnostic studies
• Arthrocentesis
p olarized microscop y → rhomboid-shaped, weakly positively birefringent

crystals (yellow pe rpe ndicular and blue p arallel to axis marked on p olarizer)
WBC 2000–100,000/mm3 , >50% polys

infection can coexist with acute attacks, ∴ always ✓ Gram stain & Cx
• Screen for associated disease if young or severe: ✓ Ca, Mg, Fe, ferritin, TIBC, UA,
PTH
• Radiographs: chondrocalcinosis ap p ears as p unctate and linear densities in articular
cartilage, menisci, triangular fibrocartilage of wrist, small joints of fingers and
symp hysis p ubis; may be asx (15% in Pts >60 y, 30–60% in Pts >8 0 y)
not a p rerequisite for the diagnosis of CPPD disease
Treatment (Ann Rhe um Dis 2 011;70:571)
• Asymp tomatic chondrocalcinosis requires no treatment

• Acute therap y for p seudogout: no RCTs, extrap olated from p ractice in gout; ∴same
as for gout, though colchicine not as effective
• If associated metabolic disease, Rx of underlying disorder may imp rove arthritis sx

• Low-dose daily colchicine or NSAID may be effective for p rop hylaxis or chronic
arthrop athy
SERONEGATIVE SPONDYLOARTHRITIS
Classification system (Curr Opin Rhe umatol 20 10 ;22:375)

• 5 subtyp es: ankylosing sp ondylitis (most common), reactive arthritis, p soriatic
arthritis, IBD-associated arthritis and undifferentiated
• All subtyp es share common clinical manifestations: inflammatory sp ine disease,
p erip heral arthritis, enthesitis and extra-articular manifestations (p rimarily
ocular and skin disease)
Epidemiology & pathogenesis (Se min Arthritis Rhe um 2 008 ;38 :8 3)

• ↑ p revalence of HLA-B2 7; HLA-B2 7 accounts for ~30% of attributable genetic risk
• Environmental factors likely critical for disease, esp . reactive arthritis (eg, infection)
• Prevalence of 0.5–2 % of p op ulation, worldwide
Major clinical manifestations (Lance t 2 011;377:2 12 7)
• Inflammatory back pain: SI joints (sacroiliitis), ap op hyseal joints of sp ine
characterized by IPAIN (Insidious onset, Pain at night, Age of onset <40 y,

Imp roves w/ exercise/hot water, No imp rovement w/ rest), a.m. stiffness,
re sponsive to NSAIDs
• Peripheral arthritis: typ ically asymmetric, oligoarticular, large joints, lower >
up p er limb; however, can be symmetric & p olyarticular (thus, mimic RA), esp . in
p soriatic arthritis
• Enthesitis: inflammation at site of tendon/ligament insertion into bone, esp .

Achilles, p re-p atellar, elbow ep icondyles, p lantar fasciitis. Rigidity of spine
(bamboo sp ine by X-ray, ankylosis due to p rogressive growth of bony sp urs which
bridge intervertebral disc).
• Dactylitis (“sausage digit” ): inflammation of entire digit (joint + tenosynovial

inflamm)
• Uveitis: anterior uveitis most common extra-articular manifestation; p /w p ain, red
eye, blurry vision, p hotop hobia, usually unilateral
Descriptions of skin manifestations
• Psoriasis: erythematous p laques with sharp ly defined margins often w/ thick silvery
scale
• Circinate balanitis: shallow, p ainless ulcers of glans p enis and urethral meatus
• Keratoderma blennorrhagica: hyp erkeratotic lesions on soles of feet, scrotum,

p alms, trunk, scalp
• Erythema nodosum: red tender nodules due to p anniculitis, typ ically on shins; Ddx
incl. idiop athic, infxn, sarcoid, drugs, vasculitis, IBD, lymp homa
• Pyoderma gangrenosum: neutrop hilic dermatosis → p ainful ulcers w/ violaceous

border; Ddx incl. idiop athic, IBD, RA, myelogenous leukemia
Psoriatic arthritis subtypes (Lance t 2 011;377:2 12 7)
• Monoarticular/oligoarticular (eg, large joint, DIP joint, dactylitic digit): most

common initial manifestation
• Polyarthritis (small joints of the hands/feet, wrists, ankles, knees, elbows):

indistinguishable from RA, but often asymmetric
• Arthritis mutilans: severe destructive arthritis with bone resorp tion, esp . hands
• Axial disease: similar to ankylosing sp ondylitis ± p erip heral arthritis
• DIP-Limited: good correlation with nail p itting and onycholysis
Clinical assessment (Nat Re v Rhe umatol 2 012 ;8 :2 53)

• Axial disease assessment
Severity of lumbar flexion deformity assessed by modified Schober’s test ( if
<5 cm ↑ in distance between a p oint 5 cm below the lumbosacral jxn and
another p oint 10 cm above, when going from standing to maximum forward
flexion)
T-sp ine mobility (extension) and kyp hosis severity measured by occip ut-to-wall
distance
• Seronegative: notable for absence of rheumatoid factor or autoantibodies; ± ↑ ESR

• HLA-B27: nonsp ecific, as common in general p op ulation (6–8 % ); most useful when
high clinical susp icion but nl imaging; 90% of Pts w/ AS, but only 2 0–8 0% in
other Sp A
• Radiology
MRI p referred for early detection of inflammation (sacroiliitis)
Plain films detect late structural changes (SI erosions/sclerosis)
calcification of sp inal ligaments w/ bridging symm syndesmop hytes (“bamboo

sp ine” )
squaring and generalized demineralization of vertebral bodies (“shiny

corners” )
• Infectious evaluation for reactive arthritis ( studies do not r/o)
U/A, PCR of urine and/or genital swab for Chlamydia; urethritis usually due to
Chlamydia infxn p receding arthritis, but also can see sterile urethritis p ost
dysentery
stool Cx, C. diff toxin

consider HIV in workup of reactive or p soriatic arthritis
Treatment approach (Lance t 2 011;377:2 12 7; Rhe umatolog y 2 012 ;51:1378 )
• Untreated disease may lead to irreversible structural damage and associated ↓

function
• Early p hysiotherap y beneficial
• NSAIDs: 1st line; rap idly ↓ stiffness and p ain; p rolonged, continuous administration
may modify disease course but associated w/ GI and CV toxicity
• Intra-articular corticosteroids in mono- or oligoarthritis; limited role for systemic

steroids, esp . for axial disease
• Conventional DMARDs (eg, MTX and SAS): no efficacy for axial disease or
enthesitis; may have role in p erip heral arthritis, uveitis and other extra-articular
manifestations
• Anti-TNFs: effective for both axial and p erip heral manifestations; imp roves function
(Ann Rheum Dis 2 006;65:42 3) and may slow p rogression of structural changes
(Curr Rheumatol Rep 2 012 ;14:42 2 ); unclear role of other biologics
• Other
Abx in reactive arthritis if evidence of active infxn; consider p rolonged abx for
refractory Chlamydia ReA (Arthritis Rheum 2 010;62 :12 98 )
Involve op hthalmologist for any evidence of inflammatory eye disease (may

benefit from steroid eye drop s or intravitreal steroid injections)
Treat underlying IBD when ap p rop riate

INFECTIOUS ARTHRITIS & BURSITIS
ETIOLOGIES & DIAGNOSIS OF INFECTIOUS ARTHRITIS

Etiologies
• Bacterial (nongonococcal): early diagnosis required

• Gonococcal (N. gonorrhea): consider in sexually active young adults
• Viral: p arvovirus, HCV, HBV, acute HIV; typ ically p olyarticular, may mimic RA
• Mycobacterial: monoarticular or axial (Pott’s disease)

• Fungal: Candida (esp . p rosthetic joints), coccidiomycosis (valley fever),
histop lasmosis
• Other: Lyme, mycop lasma
Diagnosis (JAMA 2007; 297:1478)
• H&P w/ p oor sensitivity and sp ecificity for sep tic arthritis; ∴ arthrocentesis should
be p erformed as soon as susp ected
• Take care not to tap through an infected area thus introducing infxn into joint sp ace
• ✓ Synovial fluid cell count, Gram stain, bacterial culture, crystals

WBC >50k w/ poly predom susp icious for bact. infxn; crystals do not r/o sep tic
arthritis!
BACTERIAL (NONGONOCOCCAL) ARTHRITIS
Epidemiology & risk factors
• Immunocompromised host: diabetics, HIV, elderly, SLE, etc.
• Damaged joints: RA, OA, gout, trauma, p rior surgery/p rosthetic, p rior
arthrocentesis (rare)
• Bacterial seeding: bacteremia secondary to IVDU, endocarditis or skin infection

direct inoculation or sp read from contiguous focus (eg, cellulitis, sep tic bursitis,
osteo)
Clinical manifestations (JAMA 2 007;2 97:1478 ; Lance t 2 010;375:8 46)

• Acute onset monoarticular arthritis (>8 0% ) w/ p ain (Se 8 5% ), swelling (Se 78 % ),
warmth
• Location: knee (most common), hip , wrist, shoulder, ankle. In IVDU, tends to
involve other areas (eg, sacroiliac joint, symp hysis p ubis, sternoclavicular and
manubrial joints).
• Constit. sx: fevers (Se 57% ), rigors (Se 19% ), sweats (Se 2 7% ), malaise, myalgias,
p ain
• Infection can track from initial site to form fistulae, abscesses or osteomyelitis
• Sep tic bursitis must be differentiated from sep tic intra-articular effusion
Additional diagnostic studies (JAMA 2 007;2 97:1478 )
• Synovial fluid: WBC usually >50k (Se 62 % , Sp 92 % ) but can be <10k, >90%
polys; Gram stain in ~75% of Stap h, ~50% of GNR; Cx in >90% .
Synovial bx for Cx most sens.
• Leukocytosis (Se 90% , Sp 36% )
• Blood cultures in >50% of cases, ~8 0% when more than 1 joint involved
• Conventional radiograp hs usually normal until after ~2 wk of infection when bony

erosions, joint sp ace narrowing, osteomyelitis, p eriostitis can be seen
• CT & MRI useful esp . for susp ected hip infection or ep idural abscess
Treatment (for native joints)
• Promp t emp iric antibiotics guided by Gram stain after surgical drainage. If Gram
stain , emp iric Rx w/ vancomycin; add anti-p seudomonal agent if elderly,
immunosup p .
• Tailor antibiotics based on Gram stain, culture results, & clinical course
• IV antibiotics × ≥2 wk followed by oral antibiotics; varies by clinical course &

microbiology
• Joint must be drained, often serially; surgical drainage (usually arthroscop ic), esp .
for larger joints and as initial treatment, but may also be accomp lished by
arthrocentesis.
Serial synovial fluid analyses should demonstrate ↓ in WBC and sterility.
• Prognosis: 10–50% mortality dep ending on virulence of organism, time to Rx, host
Prosthetic joint infections (Infe ct Dis Clin North Am 2 012 ;2 6:2 9; CID 2 013;66:e1)
• ↑ risk in first 2 y s/p p rocedure; rate generally low (0.5–2 .4% ); risk factors include
obesity, RA, immunocomp romised state, steroids, & sup erficial surgical site infxn
• Stap hylococci (coag negative & S. aureus) in >50% ; p olymicrobial in 10–2 0%
• Early (<3 mo s/p surgery) or delayed (3–2 4 mo) onset typ ically acquired during
imp lantation; early w/ virulent organisms (eg, MRSA) and delayed w/ less virulent
organisms (eg, P. acnes, coag negative Stap h) & more indolent p resentation
• Late (>2 4 mo) onset typ ically related to secondary hematogenous seeding
• Diagnosis requires arthrocentesis by orthop edics; ESR & CRP can be help ful
• Treatment typ ically requires p rolonged abx & two-stage joint rep lacement (joint
retention a/w ~40% failure rate; CID 2 013;56:18 2 ) or life-long sup p ressive abx.
ID and orthop edics consultation required.
DISSEMINATED GONOCOCCAL INFECTION (DGI)
Epidemiology (Infect Dis Clin North Am 2005; 19:853)

• N. gonorrhea; most frequent typ e of infectious arthritis in sexually active young
adults
• Normal host as well as Pts w/ deficiencies of terminal comp onents of comp lement
• : =4:1; ↑ incidence during menses, p regnancy, & p ostp artum p eriod; ↑

incidence in homosexual males; rare after age 40 y
• Preceded by mucosal infection (eg, endocervix, urethra or p harynx) that is often asx
• Two distinct syndromes:

Joint localized: p urulent arthritis (40% ), usually 1–2 joints (knees > wrists >
ankles)
DGI: triad of polyarthralgias, tenosynovitis, skin lesions; p urulent arthritis rare

acute onset of tenosynovitis (60% ) in wrists, fingers, ankles, toes rash (>50% ):
gunmetal gray p ustules with erythematous base on extremities & trunk
• Rare comp lications: Fitz-Hugh-Curtis syndrome (p erihep atitis), p ericarditis,

meningitis, myocarditis, osteomyelitis from direct extension of joint-localized
infection
Additional diagnostic studies

• Synovial fluid: WBC >50k (but can be <10k), poly predominant
Gram stain in ~2 5% ; culture in up to 50% if done w/ Thayer-Martin

media
• Blood culture: more likely in DGI; rarely in joint localized disease
• Gram stain and culture of skin lesions occasionally
• Cervical, urethral, p haryngeal, rectal PCR or cx on Thayer-Martin media; ✓

Chlamydia
Treatment
• Ceftriaxone or cefotaxime ¥ 7 Δ w/ empiric doxycycline for Chlamydia

(fluoroquinolones no longer recommended due to resistance)
• Joint arthroscop y/lavage may be required if p urulent arthritis; rarely >1 time
OLECRANON & PREPATELLAR BURSITIS
Epidemiology & risk factors (Infe ct Dis North Am 2 005;19:991)

• >150 bursae in the body; 2 most commonly infected are olecranon and prepatellar
• Most commonly (esp . sup erficial bursae) due to direct trauma, p ercutaneous
inoculation or contiguous sp read from adjacent infection (eg, cellulitis)
• Other risk factors: recurrent noninfectious inflammation (eg, gout, RA, CPPD),
diabetes
• S. aureus (8 0% ) most common, followed by strep tococci

Diagnosis
• Physical exam: discrete bursal swelling, erythema, maximal tenderness at center of
bursa with p reserved joint range of motion
• Asp irate bursa if concern for infxn, ✓ cell count, Gram stain, bacterial cx, crystals
WBC >20k w/ poly predominance susp icious for bacterial infection, but lower
counts common (crystals do not rule out sep tic bursitis!)
• Assess for adjacent joint effusion, which can also be sep tic
• Take care not to tap through infected skin thus introducing infxn into bursa
Initial therapy
• Promp t emp iric coverage for stap hylococci and strep tococci: PO abx accep table for
mild p resentation; vancomycin if ill-ap p earing; broaden sp ectrum based on risk
factors
• Modify antibiotics based on Gram stain, culture results, & clinical course
• Duration of therap y is 1–4 wk
• Serial aspirations every 1–3 Δ until sterile or no reaccumulation of fluid
• Surgery if unable to drain bursa through asp iration, evidence of foreign body or
necrosis, recurrent/refractory bursitis w/ concern for infxn of adjacent structures
CONNECTIVE TISSUE DISEASES
• Autoantibody testing is directed by clinical findings, as autoantibodies themselves do

not define a p articular connective tissue disease
• Overlap syndromes encomp assing more than one connective tissue disorder may be
reflected serologically by the p resence of multip le autoantibodies
se e “Syste mic Lupus Erythe matosus” and “Rhe umatoid Arthritis” for those dise ase s
SYSTEMIC SCLEROSIS AND SCLERODERMA DISORDERS
Definition & epidemiology (Be st Pract Re s Clin Rhe umatol 2 010;2 4:8 57)
• Scleroderma refers to the p resence of tight, thickened skin
• Localized scleroderma: morp hea (p laques of fibrotic skin), linear (fibrotic bands),
“en coup de saber” (linear scleroderma on one side of scalp and forehead saber
scar)
• Systemic sclerosis (SSc)=scleroderma + internal organ involvement. Subgroup s:
SSc w/ limited cutaneous disease
SSc w/ diffuse cutaneous disease: rap idly p rogressive disorder affecting skin
SSc sine scleroderma (visceral disease without skin involvement, rare)
• Peak onset of SSc between ages 30–50; > (7:1); African American > white
• 1–2 /100,000 annual incidence of systemic disease in the U.S.
• Pathogenesis: immune damage to endothelial cells and reactive O 2 sp ecies

p roduction → p ersistent oxidative stress → p erivascular inflammation →
fibroblast activation and fibrosis. Cytokines, growth factors, genetics,
environmental factors and autoantibodies (against PDGF recep tor, endothelial cells
and fibroblasts) all contribute (NEJM 2 009;360:198 9).
Classification criteria (1 major or 2 minor; 97% Se, 98 % Sp ; Arth Rheum

198 0;2 3:58 1)
• Major: skin findings extend proximal to MCP or MTP joints
• Minor: sclerodactyly (skin findings limited to the fingers)
digital pitting scars from loss of substance on the finger p ad
bibasilar pulmonary fibrosis

• Other causes of thickened skin: diabetes (scleredema ≠ scleroderma),
hyp othyroidism, nep hrogenic systemic fibrosis, eosinop hilic fasciitis, amyloidosis,
GVHD, drug or toxin
Diagnostic studies & monitoring
• Autoantibodies
anti-Scl-70 (antitop oisomerase 1): 40% of diffuse, 15% of limited; ↑ risk

p ulm fibrosis
anticentromere: 60–8 0% of limited, <5% of diffuse, ↑ risk of severe digit

ischemia
ANA (>90% ), RF (30% ), anti-RNP a/w overlap syndrome
• At baseline: ✓ BUN/Cr & UA for p roteinuria, PFTs (sp irometry, lung volumes,
DLCO), high-res chest CT (if diffuse disease), TTE (RVSP for PHT), RHC if ↑ RVSP
or susp ect PHT
• Annual PFTs; TTE q1–2 y

• Skin bx not routine, but help ful to assess other p ossible causes for skin thickening
• ↑ r/o malignancy at affected sites

Treatment (Ann Rhe um Dis 2 009;68 :62 0)
• Pulmonary Fibrosis: cyclophosphamide (NEJM 2 006;354:2 655), steroids

PAH: p ulmonary vasodilators (see “Pulm Hyp ertension” ), early Rx a/w better
outcomes
• Renal: monitor BP monthly, intervene early to avoid HTN crisis; dip stick for p rotein
Scleroderma renal crisis: ACE inhibitors (not ARB); ACEi not indicated for
p rop hylaxis
• GI: PPI and/or H2 -blockers for GERD; antibiotics for malabsorp tion
hyp omotility: metoclop ramide or erythromycin; nonop erative Rx of p seudo-
obstruction
• Cardiac: NSAIDs or steroids for p ericarditis

• Arthritis: acetaminop hen, NSAIDs, hydroxychloroquine, PT
• Myositis: MTX, AZA, steroids
• Skin: PUVA for morp hea. For p ruritus: emollients, top ical or oral steroids (↓ dose).
Immunosup p ressives offer only minimal to modest benefit for skin fibrosis.
INFLAMMATORY MYOPATHIES
Definition & epidemiology (JAMA 2 013;305:18 3)

• Polymyositis (PM): T cell–mediated muscle injury → skeletal muscle inflam &
weakness
• Dermatomyositis (DM): immune comp lex dep osition in blood vessels with
comp lement
activation → skeletal muscle inflam. & weakness + skin manifestations
• Inclusion body myositis (IBM): T cell–mediated muscle injury, vacuole formation

with
amyloid dep osition → skeletal muscle inflam & weakness
• 10% of PM and 2 4% of DM a/w malignancy (typ ically adenocarcinomas, a/w more
severe disease) (Curr Rheumatol Rep 2 011;13:2 08 )
• PM/DM: onset typ ically 40s and 50s; > ; DM also occurs in childhood
• IBM: onset after age 50; > ; often misdiagnosed as p olymyositis
Clinical manifestations (Rhe um Dis Clin N Am 2 011;37:143)
• Muscle weakness: gradual (wks → mos), p rogressive and p ainless

DM/PM: p roximal and symmetric; difficulty climbing stairs, arising from chairs,
brushing hair; ± tenderness of affected areas; fine motor skills (eg, buttoning,
writing) lost late
IBM: may be asymmetric and distal
• Dermatologic: may p recede myositis by mos to yrs (uncommon for converse)

erythematous rash on sun-exp osed skin: neck & shoulders (shawl sign), face, chest
heliotrope rash (p urp lish discoloration) over up p er eyelids ± p eriorbital edema
Gottron’s papules (in >8 0% & p athognomonic): violaceous often scaly areas
symmetrically over dorsum of PIP and MCP joints, elbows, p atellae, medial
malleoli
subungual erythema, “mechanic’s hands” (skin cracks on digits), p ruritus

dermatologic features w/o myositis=DM sine myositis (amyop athic DM) in 10–
2 0%
• Polyarthralgias or p olyarthritis: usually early; nonerosive; small joints > large

joints
• Raynaud’s (30% , DM and overlap CTD) w/ dilatation & drop out of nailbed
cap illaries
• Visceral involvement (J Rheumatol 2 009;36:2 711)
pulmonary: acute alveolitis; ILD; resp iratory muscle weakness; asp iration
cardiac (33% ): often asx; conduction abnl; myo/p ericarditis; HF uncommon; ↑

CK-MB/Tn
GI: dysp hagia, asp iration
• Antisynthetase syndrome (PM > DM): fever, ILD, Raynaud’s, mechanics hands,
arthritis
• Ddx: drug-induced myop athy (statins, cocaine, steroids, colchicine); infxn (HIV, EBV,
CMV); metabolic (hyp othyroid, hyp o-K, hyp o-Ca); neuromuscular dis. (eg,
myasthenia gravis); glycogen storage disease; mitochondrial cytop athy; muscular
dystrop hy
Diagnostic studies
• ↑ CK (rarely >100,000 U/L), aldolase, SGOT and LDH; ±↑ ESR & CRP
• Autoantibodies: ANA (>75% ), RF (33% )
anti-Jo-1 (2 5% ): most common sp ecific Ab; a/w antisynthetase syndrome
myositis antibody p anel may assist in p rognosis (anti-Mi-2 better, anti-SRP

worse)
• EMG: ↑ sp ontaneous activity, ↓ amp litude, p olyp hasic p otentials with contraction
• Muscle biopsy: all with interstitial mononuclear infiltrates, muscle fiber necrosis,
degeneration & regeneration (required for definitive diagnosis)
PM: endomysial inflam. (CD8 T cells) surrounds non-necrotic fibers, ↑ MHC class I
DM: p erimysial, p erivascular inflam (B & CD4 T cells), comp lement in vessels
IBM: same as PM with eosinop hilic inclusions and rimmed vacuoles (EM)
Treatment (PM & DM, no effective treatment for IBM) (Autoimmun Rev 2 011;11:6)
• Steroids (p rednisone 1 mg/kg); MTX or AZA early if mod/severe or tap er fails (2 –3

mo)
• For resistant (30–40% ) or severe disease: AZA/MTX combo, IVIg (DM ± PM),
rituximab, MMF, cyclop hosp hamide (esp . if ILD or vasculitis)
• IVIg w/ p ulse steroids acutely for life-threatening esop h or resp muscle involvement
• ✓ for occult malignancy (esp . if DM); monitor resp iratory muscle strength with
sp irometry
SJÖGREN’S SYNDROME
Definition & epidemiology
• Chronic dysfxn of exocrine glands (eg, salivary/lacrimal) due to

lymp hop lasmacytic infiltration. Extraglandular manifestations common in
p rimary form.
• Can be p rimary or secondary (a/w RA, scleroderma, SLE, PM, hyp othyroidism, HIV)
• More p revalent in than ; typ ically p resents between 40 & 60 y of age
• Dry eyes (keratoconjunctivitis sicca): ↓ tear p roduction; burning, scratchy sensation

• Dry mouth (xerostomia): difficulty sp eaking/swallowing; dental caries; xerotrachea;
thrush
• Parotid gland enlargement: intermittent, p ainless, typ ically bilateral

• Vaginal dryness and dyspareunia
• Recurrent nonallergic rhinitis/sinusitis due to up p er airway gland involvement
• Extraglandular manifestations: arthritis; interstitial nep hritis (40% ); typ e I RTA

(2 0% ); cutaneous vasculitis (2 5% ); neurop athies (10% ); PNS or CNS disease; ILD;
PBC
• ↑ risk of lymp hop roliferative disorders (~50× ↑ risk of lymp homa and WM in 1°
Sjögren’s)
Diagnostic studies
• Autoantibodies: ANA (95% ), RF (75% )
Primary Sjögren’s: anti-Ro (anti-SS-A, 56% ) and/or anti-La (anti-SS-B,

30% )
• Schirmer test: filter p ap er in p alp ebral fissures to assess tear p roduction
• Rose-Bengal staining: dye that reveals devitalized ep ithelium of cornea/conjunctiva
• Ocular staining score: substitute for Rose-Bengal staining to determine degree of

keratoconjunctivitis sicca using fluorescein and lissamine green
• Biopsy (minor salivary, labial, lacrimal or p arotid gland): lymp hop lasmacytic
infiltration
Classification criteria (2 of 3 have 93% Se & 95% Sp ; Arthritis Care Re s 2 012 ;64:475)
1. anti-Ro or anti-La or RF + ANA>1:32 0
2 . Labial salivary gland bx w/ lymp hocytic sialadenitis and score >1 focus/4 mm 2
3. Keratoconjunctivitis sicca w/ ocular staining score ≥3

Treatment
• Ocular: artificial tears, cyclosp orine eyedrop s
• Oral: sugar-free gum, lemon drop s, saliva substitute, hydration, p ilocarp ine,
cevimeline
• Systemic: NSAIDs, steroids, DMARDs, rituximab

MIXED CONNECTIVE TISSUE DISEASE (MCTD)
Definition (Be st Pract Re s Clin Rhe umatol 2 012 ;2 6:61)

• Features of SLE, systemic sclerosis and/or polymyositis that ap p ear gradually and
often evolve to a dominant p henotyp e of SLE or systemic sclerosis
• Different from undifferentiated CTD (UCTD): fail to meet criteria for any CTD; 30%
go on to develop CTD over 3–5 y (usually SLE)
Clinical manifestations (variable clinical course)

• Raynaud’s phenomenon typ ical p resenting symp tom (75–90% )
• Hand edema (“p uffy hands” ), sclerodactyly, RA-like arthritis w/o erosions,
p olyarthralgias
• Pulmonary involvement (8 5% ) with pulmonary hypertension, fibrosis
• Pericarditis most frequent cardiovascular manifestation; GI: dysmotility (70% )
• Membranous & mesangial GN common (2 5% ); low risk for renal HTN crisis or
severe GN (if either, reconsider diagnosis of MCTD)
Diagnostic studies
• ANA (>95% ); RF (50% ); anti-U1-RNP in all, but not sp ecific (seen in

~50% SLE)
Treatment
• As p er sp ecific rheumatic diseases detailed above
RAYNAUD’S PHENOMENON
Clinical manifestations (NEJM 2 002 ;347:1001 & 2 013;368 :1344; BMJ

2 012 ;344:e2 8 9)
• Ep isodic, reversible digital ischemia, triggered by temp Δ (cold) or stress,

classically: blanching (white, ischemia) → cyanosis (blue, hyp oxia) → rubor
(red, rep erfusion); color Δ usually well demarcated; affects fingers, toes, ears, nose
associated sx include cold, numbness, & p aresthesias → throbbing & p ain
• Key to diagnosis and Rx is distinguishing between p rimary and secondary Raynaud’s
Primary (8 0–90% =Raynaud’s disease; excluded all secondary causes)
• Onset 2 0–40 y, > (5:1); thought due to functional abnl of vessel wall
• Clinical: mild, symmetric ep isodic attacks; no evidence of p erip h vascular disease;

no tissue injury; nl nail-fold cap illary exam; no systemic sx; ANA; nl ESR
Secondary (10–2 0% )
• Typ ically >35 y of age; due to structural abnl of vessel wall
• Tissue ischemia & injury (eg, digital ulcers), which is not seen in p rimary
Raynaud’s
• Etiologies: CTD (abnl nail-fold exam): SSc, SLE, PM-DM, MCTD, Sjögren’s, RA
Arterial disease: p erip h atherosclerosis, thromboangiitis obliterans (abnormal

pulse s)
Hematologic: cryoglobulinemia, Waldenström’s, antip hosp holip id syndrome
Trauma (vibration or rep etitive motion injury) & drugs (ergot alkaloids, estrogens,
cocaine)
Treatment (Curr Opin Rhe umatol 2 011;2 3:555; BMJ 2 012 ;344:e2 8 9)
• All: avoid cold, maintain warmth of digits & body; avoid cigarettes, drugs and
trauma
• Mild–mod: long-acting CCB, top ical nitrates, SSRI, ARB, ɑ-blockers,

ASA/clop idogrel
• Severe: PDE inhibitors, anti-ET-1 recep tor (if ulcers esp . w/ PHT), digital
symp athectomy
• Digit-threatening: IV p rostaglandins, digital symp athectomy, ± anticoagulation
• Others: fish oil (1° RP only; Am J Med 198 9;8 6:158 ), abx for infected ulceration
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Multisystem inflammatory autoimmune disease with a broad sp ectrum of clinical

manifestations in association with antinuclear antibody (ANA) p roduction
Epidemiology (NEJM 2 011;365:2 110)
• Prevalence 15–50/100,000; p redominantly affects women 2 nd to 4th decade
• : ratio=8 :1; African American:Caucasian ratio=4:1
• Comp lex genetics; some HLA assoc.; rare C1q & C2 defic.
Workup
• Autoantibodies: ANA, if → ✓ anti-ds-DNA, anti-Sm, anti-Ro, anti-La, anti-U1-

RNP
• Lytes, BUN, Cr, U/A, urine sed, sp ot microalb:Cr ratio or 2 4-h urine for CrCl and
p rotein
• CBC, PTT, APLA ( in 2 0–40% ; ACL IgG/IgM, B2 GP1, lup us anticoagulant), C3,
C4
• If ↓ GFR, active sediment, hematuria or p roteinuria → renal bx to guide Rx
Prognosis
• 5-y survival rate >90% , 10-y survival rate >8 0%

• Leading causes of morbidity and mortality: infection, renal failure, neurologic and
cardiovascular events; thrombotic comp lications (Medicine 2 003;8 2 :2 99)
Drug-induced lupus (DLE) (Drug Saf 2 011;34:357; Curr Opin Rhe umatol
2 012 ;2 4:18 2 )
• Many drugs: procainamide, hydralazine, p enicillamine, minocycline, INH,

methyldop a, quinidine, chlorp romazine, diltiazem, anti-TNF (esp . infliximab),
interferons
• Idiosyncratic onset; generally mild disease with arthritis, serositis, skin disease
• Anti-histone (95% ) (may be in anti-TNF); anti-ds-DNA (may be in

anti-TNF) & anti-Sm; normal comp lement levels
• Usually reversible w/in 4–6 wk after stop p ing medication

VASCULITIS
OVERVIEW
• Inflammation w/in blood vessel walls causing end-organ damage often a/w systemic
sx; may be p rimary or secondary (eg, infection, malignancy) in etiology
• Classified by size of p redominant vessel affected (Arthritis Rheum 2 013;65:1);
overlap of vessel size affected is common
• Clinical manifestations based on size of vessels involved; constitutional sx (low-grade
fever, fatigue, weight loss, myalgias, anorexia) common to all
LARGE-VESSEL VASCULITIS
Takayasu’s arteritis (“p ulseless disease” )

• Arteritis of aorta and its branches → stenosis/aneurysm → claudication; onset
<50 y
• Pattern of involvement: aorta and branches; most often subclavian and innominate
arteries (>90% ), as well as carotid, coronary, renal, p ulmonary (~50% )
• Ep idemiology: Most common in Asia; : ~9:1; age <50 y
• Clinical manifestations and p hysical findings

Systemic inflamm with fever, arthralgias, wt loss
Vessel inflamm w/ p ain & tenderness, ↓ & unequal pulses/BPs in extremities,

bruits, limb claudication, renovascular HTN (>50% ), neurogenic syncop e; Ao
aneurysm ± AI
“Burnt out” or fibrotic p eriod (eg, vascular stenosis)

• Dx studies: ↑ ESR (75% ), CRP; arteriography → occlusion, stenosis, irregularity and
aneurysms; carotid U/S Dop p ler studies; PET-CT; MRA; pathology → focal
p anarteritis, cellular infiltrate with granulomas and giant cells (bx not required
for dx)
• Treatment: steroids ± MTX or AZA; anti-TNF (2 nd line, Autoimmun Rev
2 012 ;11:678 ), ASA, surgical/endovascular revasc (Circ 2 008 ;69:70)
• Monitoring: MRA or PET-CT (Arth Rheum 2 012 ;64:8 66); ESR/CRP (Ann Rheum Dis
2 009;68 :318 )
Giant cell arteritis (GCA) (Curr Rhe umatol Re p 2 010;12 :436)

• Granulomatous arteritis of aorta/branches w/ p redilection for temporal artery,
a/w PMR, onset >50 y
• Pattern of involvement: extracranial branches of carotid artery, esp . temp oral

artery (thus also called temporal arteritis); aorta and/or its branches in 10–8 0%
• Ep idemiology: 90% of Pts >60 y, extremely rare <50 y; : =3:1
• Clinical manifestations (JAMA 2 002 ;2 8 7:92 )
constitutional sx: fevers, fatigue, wt loss, PMR sx (see below)
temporal artery (TA) → headache, tender TAs and scalp ; absent TA p ulse
op hthalmic artery (2 0% ) → op tic neuritis, dip lop ia, amaurosis fugax, blindness
facial arteries → jaw claudication
large vessel vasculitis → intermittent claudication of extremities; thoracic Ao

aneurysm
• Dx studies: ↑ ESR (ESR <40 in ~5% ), ↑ CRP, anemia
(ESR related to fibrinogen & Ig in blood; Ddx for >100: malignancy esp . multip le
myeloma, lymp homa; GCA or other vasculitis; ESRD; endocarditis, TB,
osteomyelitis)
temporal artery bx whenever GCA suspe cte d (Se ≤8 5% ); 1–2 cm ± bilat to ↑

yield (3–7% discordance) (Ann Rheum Dis 2 009;68 :318 ) → vasculitis &
granulomas
if susp ect aortitis or lg vessel involvement (BP Δ or bruits) → MRI/MRA or PET-CT

• Polymyalgia rheumatica (Lancet 2 013;38 1:63)
seen in 50% of GCA Pts; 15% of Pts w/ PMR develop GCA
age ≥50 y; ESR >40 mm/h (and/or ↑ CRP); bilateral pain & morning stiffness
(>30 min × ≥1 mo), involving 2 of 3 areas: neck or torso, shoulders or p rox.
arms, hip s or p rox. thighs; nighttime p ain; exclude other causes of sx (eg, RA);
nl CK
• Rx: steroids (do not await bx/p ath results to begin steroids, have at least 2 wk to
bx)
GCA: 40–60 mg/d w/ slow tap er, ASA daily; consider IV p ulse if vision threatened
PMR:10–2 0 mg/d (Semin Arthritis Rheum 2 007;37:13)

• Monitoring: follow clinical status & ESR/CRP (Ann Rheum Dis 2 009;68 :318 )
MEDIUM-VESSEL VASCULITIS
Polyarteritis nodosa (“classic” PAN) (Arth Rhe um 2 010;62 :616)

• Necrotizing nongranulomatous vasculitis of medium and small arteries (w/
muscular media) w/o glomerulonep hritis or cap illary involvement (ie, DAH), not
a/w ANCA
• Ep idemiology: > ; average age of onset ~50 y; p rimary or HBV-associated

(~10% )
constitutional sx (8 0% ): wt loss, fever, fatigue
neuro (79% ): mononeuritis multiplex, p erip heral neurop athies, stroke
musculoskeletal (64% ): extremity pain, myalgias, arthralgias, arthritis
renal (51% ): HTN, hematuria, p roteinuria, renal failure, glomerulonep hritis

unusual
GI (38 % ): abd pain, GIB/infarction, cholecystitis; GU (2 5% ): ovarian or testicular
p ain
skin (50% ): livedo reticularis, p urp ura, nodules, ulcers, Raynaud’s

op hthalmic (9% ): retinal vasculitis, retinal exudates, conjunctivitis, uveitis
cardiac (2 2 % ): coronary arteritis, cardiomyop athy, p ericarditis
if lung involvement, susp ect other vasculitis

• Dx studies: ↑ ESR/CRP, ANCA; ✓ HBs Ag; ↓ C3/C4 if HBV-associated
angiogram (mesenteric or renal vessels) → microaneurysms & focal vessel

narrowing
CTA may be adequate to make dx, but conventional angiogram is most sensitive
biopsy (sural nerve, skin or affected organ) → vasculitis of small and medium
vessel arteries with fibrinoid necrosis without granulomas
• Treatment: steroids ± CYC (if severe or failure to induce remission); antivirals if a/w
HBV
ANCA-ASSOCIATED SMALL-VESSEL VASCULITIS
Microvascular vasculitis (e g , capillarie s, postcapillary ve nule s, & arte riole s)
Differential diagnosis of ANCA

• anti-PR3 (c-ANCA): granulomatosis w/ p olyangiitis, eosinop hilic granulomatosis
and p olyangiitis, microscop ic p olyangiitis (rarely)
• anti-MPO (p-ANCA): microscop ic p olyangiitis, eosinop hilic granulomatosis and
p olyangiitis, granulomatosis w/ p olyangiitis, drug-induced vasculitis,

nonvasculitic
rheumatic diseases
• Atypical ANCA patterns: drug-induced vasculitis, nonvasculitic rheumatic diseases,
ulcerative colitis, p rimary sclerosing cholangitis, endocarditis, cystic fibrosis
Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis)
• Necrotizing granulomatous systemic vasculitis frequently affecting nose, sinuses

and/or up p er resp iratory tract in addition to kidneys, lungs, etc.
• Ep idemiology: any age, but ↑ incidence in young and middle-aged adults; =
respiratory (90% )
uppe r: sinusitis, rhinitis, oral/nasal ulcers, saddle-nose deformity, otitis,
hearing loss, subglottic stenosis
lowe r: p ulmonary infiltrates, nodules, p ulmonary hemorrhage, hemop tysis,

p leurisy
renal (8 0% ): RPGN (p auci-immune), RBC casts, dysmorp hic RBCs, hematuria
ocular (50% ): ep iscleritis, scleritis, uveitis, orbital granulomas → p rop tosis,

corneal ulcer
neurologic: cranial and p erip heral neurop athies, mononeuritis multip lex
skin (50% ): p alp able p urp ura, livedo reticularis

hematologic: ↑ incidence DVT/PE (2 0×) when disease active (Ann Intern Med
2 005;142 :62 0)
• Dx studies: 90% ANCA (8 0% PR3, 2 0% MPO), less Se in limited up p er airway

disease
CXR or CT → nodules, infiltrates, cavities; sinus CT → sinusitis ± bone erosions
↑ BUN & Cr, p roteinuria, hematuria; sediment w/ RBC casts, dysmorp hic RBCs
Biop sy → necrotizing granulomatous inflammation of arterioles, cap illaries, veins

• Treatment (Annals 2 009;150:670; NEJM 2 010;363:2 11 & 2 2 1)
Induction: RTX (375 mg/m 2 /wk × 4 wk) + steroids (1 g IV × 3 Δ → 1–2

mg/kg/d) or CYC (2 mg/kg/d × 3–6 mo or p ulse 15 mg/kg q2 –3wk) + steroids
RPGN: ± p lasma exchange to ? ↓ risk of ESRD (Am J Kidney Dis 2 011;57:566)
if mild (nonorgan- or life-threatening): MTX + p rednisone may be adequate for

induction (Arth Rheum 2 012 ;64:3472 )
Mainte nance : MTX or AZA for ≥2 y after CYC induction (NEJM 2 008 ;359:2 790);
after RTX induction rep eat RTX q6mo (Arth Rheum 2 012 ;64:3760) vs. watchful
waiting
Re lapse : if severe, reinduce w/ steroids + RTX or CYC; steroids ± MTX or AZA if

mild;
↑ ANCA w/o clinical evidence of flare should not p romp t Δ Rx (Annals
2 007;147:611)
Microscopic polyangiitis (MPA) (Rhe um Dis Clin North Am 2 010;36:545)
• Similar to GPA, but w/o ENT/airway involvement & nongranulomatous
• Ep idemiology: > ; avg onset 50–60 y
• Clinical manifestations: similar to GPA w/o up p er resp iratory involvement; renal

(8 0–100% ): glomerulonep hritis pulmonary (2 5–50% ): p ulmonary cap illary
alveolitis, p ulmonary fibrosis constitutional and neuro sx similar to GPA; skin
lesions (eg, p alp able p urp ura) in 30–60%
• Dx studies: 70% ANCA (almost all anti-MPO)
biop sy → necrotizing, nongranulomatous inflammation of small vessels, p auci-

immune (minimal dep osition of comp lement or Ig; contrast w/ HSP,
cryoglobulinemia, etc.)
urine sediment and CXR findings similar to those seen in GPA
• Treatment: as for GPA; ↓ relap se rate comp ared to GPA
Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss)
• Similar to GPA w/ more frequent cardiac involvement, a/w asthma and

eosinophilia
• Ep idemiology: rare; can p resent at any age (typ ically 30–40 y); a/w HLA-DRB4
• Clinical manifestations (Curr Rheumatol Rep 2 011;13:48 9)

initial sx: asthma, sinusitis, allergic rhinitis (new asthma in adult raises
susp icion)
eosinop hilic infiltrative disease: shifting or transient pulmonary infiltrates,

gastroenteritis or esop hagitis
systemic small-vessel vasculitis: neuropathy (mononeuritis multip lex), renal

(glomerulonep hritis), skin (p alp able p urp ura, p etechial, nodules)
cardiac: coronary arteritis, myocarditis, CHF, valvular insufficiency (Medicine
2 009;8 8 :2 36)
• Dx studies: 50% ANCA (MPO > PR3), eosinophilia (5–10 k/µL, 8 0–100% ),
biop sy → microgranulomas, fibrinoid necrosis and thrombosis of small arteries

and
veins with eosinop hilic infiltrates

• Treatment: high-dose corticosteroids + cyclop hosp hamide if severe
Renal-limited vasculitis
• Small vessel p auci-immune vasculitis causing RPGN w/o other organ involvement
• Dx studies: 8 0% ANCA (MPO > PR3); biop sy with p auci-immune GN ±
granulomas
• Treatment identical to that for GPA/MPA

IMMUNE COMPLEX–ASSOCIATED SMALL-VESSEL VASCULITIS
Henoch-Schönlein purpura (HSP)
• IgA-mediated vasculitis w/ p redilection for skin, GI tract and kidneys
• Ep idemiology: > , children > adults, onset in winter > summer
• May develop after up p er resp iratory tract infection (esp . strep ) or drug exp osure
palpable purpura on extensor surfaces (lower extremity first) & buttocks
polyarthralgias (nondeforming) esp . involving hip s, knees, & ankles

colicky abdominal pain ± GIB or intussuscep tion
nep hritis ranging from microscopic hematuria & p roteinuria to ESRD
• Dx studies: skin bx w/ immunofluorescence → leukocytoclastic vasculitis w/ IgA

and C3 dep osition in vessel wall; renal bx → mesangial IgA dep osition
• Treatment: often self-limiting over 4 wk; steroids ± DMARDs for renal or severe
disease
Cryoglobulinemic vasculitis (see “Cryoglobulinemia”)
Connective tissue disease–associated vasculitis
• Small vessel vasculitis a/w RA, SLE or Sjögren’s syndrome

distal arteritis: digital ischemia, livedo reticularis, p alp able p urp ura, cutaneous
ulceration
visceral arteritis: p ericarditis and mesenteric ischemia

p erip heral neurop athy
• Dx studies: skin/sural nerve bx, angiograp hy, EMG; ↓ C′ in SLE; RF or anti-CCP

in RA
• Treatment: steroids, cyclop hosp hamide, MTX (other DMARDs)

Cutaneous leukocytoclastic angiitis
• Heterogeneous group of clinical syndromes due to immune complex deposition in

cap illaries, venules and arterioles; includes hypersensitivity vasculitis
• Overall the most common typ e of vasculitis

• Etiologies
drugs: PCN, ASA, amp hetamines, levamisole, thiazides, chemicals, immunizations
infections: Strep , Stap h, endocarditis, TB, hep atitis
malignancy (p araneop lastic)
• Clinical manifestations: abrup t onset of palpable purpura and transient arthralgias

after exp osure to the offending agent; visceral involvement rare but can be severe
• Dx studies: ↑ ESR, ↓ comp lement levels, eosinop hilia; ✓ U/A; skin biopsy →
leukocytoclastic vasculitis w/o IgA deposition in skin (to distinguish from HSP); if
etiology not clear, consider ANCA, cryoglobulins, hep atitis serologies, ANA, RF
• Treatment: withdrawal of offending agent ± rap id p rednisone tap er
Behçet’s syndrome (Curr Rhe um Opin 2 010;12 :42 9)

• Systemic vasculitis affecting all vessel sizes, a/w oral and/or genital ulcers
• Ep idemiology: usually young adults (2 5–35 y); a/w HLA-B51 in areas of highest
p revalence on the old Silk Road (Turkey, Middle East and other Asian countries)
• Classification criteria (#1 + ≥2 others is 91% Se & 96% Sp ; Lancet

1990;335:1078 )
1. recurrent oral aphthous ulceration (≥3× in 1 y, usually 1st manifestation)

2 . recurrent genital ulceration (labia in females, scrotum in males)
3. eye lesions: uveitis, scleritis, retinal vasculitis, op tic neuritis (may threaten vision)
4. skin lesions: p ustules, p ap ules, folliculitis, erythema nodosum (scarring)
5. p athergy test (p rick forearm w/sterile needle → p ustule) (not sensitive in

Caucasians)
• Other clinical manifestations: most recur but are not chronic

arthritis: mild, ± symmetric, nondestructive, involving knees and ankles
neurologic: usually involvement of midbrain p arenchyma; p erip heral neurop athy

rare
vascular: sup erficial or deep vein thrombosis (2 5% ); arterial stenosis, occlusion
and aneurysm can also occur; low incidence of thromboembolism
• Dx studies: ↑ ESR/CRP; ulcer swab to r/o HSV; ulcer bx nonsp ecific; op htho eval if
sx
• Treatment (Rheumatology 2 007;46:736; Ann Rheum Dis 2 008 ;67:1656 &

2 009;68 :152 8 )
mucocutaneous
mild: topical steroids, colchicine (esp . for erythema nodosum), dap sone
severe: oral steroids, steroid-sp aring agents
arthritis: NSAIDs, colchicine, steroids, steroid-sp aring agents
ocular: topical and/or systemic steroids ± steroid-sp aring agents
steroid-sp aring: AZA, anti-TNF, CYC (large vessel and CNS ds), CsA, MTX, IFNɑ-
2A
venous thrombosis: steroids and anticoagulation (careful if aneurysm p resent)

IGG4-RELATED DISEASE
Definition & etiology (NEJM 2012; 366:539)

• Resp onsible for tumor-like inflammatory lesions of nearly every organ/tissue
• Etiology unclear: ? autoimmune; unclear role of IgG4 Ab; may have h/o atop y
• Commonly p ancreatitis, aortitis, cholangitis, sialadenitis, orbital structures,
retrop eritoneal fibrosis
• Multip le lesions may be p resent synchronously or metachronously
Diagnosis (Mod Pathol 2 012 ;2 5:118 1)

• Biopsy w/ sp ecific histop athology & immunohistochemistry findings:
lymp hop lasmacytic infiltrate w/ significant IgG4+ p lasma cell infiltrate, fibrosis,
obliterative p hlebitis
• ↑ serum IgG4 in 40% ; not sp ecific seen in GPA, bronchiectasis, etc (Modern Rheum
2 012 ;2 2 :419)
Treatment
• Prednisone vs. rituximab (Medicine 2 012 ;91:57)

CRYOGLOBULINEMIA
Definition & types (Lancet 2 012 ;379:348 )

• Proteins that precipitate on exposure to the cold and redissolve on rewarming,
characterized by their comp osition
• Cryoglobulins=p roteins that p recip itate from serum and p lasma when cooled
• Distinguish from cryofibrinog e ne mia=p roteins (eg, fibrin, fibrinogen) that

p recip itate only from p lasma; found in autoimmune dis, malignancies, infxns;
unclear clinical significance
Etiologies
• Infections (typ es II & III): viral (HCV, HBV, HIV, HAV, EBV, CMV), bacterial
(endocarditis, strep , etc.), fungal (coccidiomycosis, etc.) and p arasitic (malaria,
amoebiasis)
• Hematologic diseases
typ e I: MM, CLL, Waldenström’s
typ e II: B-cell lymp homas, solid organ malignancies

• Autoimmune syndromes (typ e III > II): Sjögren’s syndrome, SLE, RA, PAN
• Essential (idiop athic) in 10% of cases
• Renal transp lant recip ients (Clin Nep hrol 2 008 ;69:2 39)
Pathophysiology
• Chronic immune stimulation and/or lymp hop roliferation → cryoglobulin generation

• Typ e I: cryo p recip itation in microcirculation → hyperviscosity & vascular
occlusion
• Typ es II/III: defective/insufficient immune comp lex (IC) clearance → IC-mediated

inflammation of blood vessels w/ comp lement activation → vasculitis
Clinical manifestations (systemic sx usually due to typ e II > III)
• Most p atients with cryoglobulinemia are asx

• Typ e I: hyp erviscosity (cold worsens sx) → H/A, visual disturbance, livedo, digital
ischemia
• Typ e II: vasculitis (sx not affected by cold exp osure)

General: weakness, low-grade fever
Dermatologic (54–8 0% ): lower extremity purpura, livedo reticularis, leg ulcers
Joint (44–70% ): symmetric, migratory arthralgias of small or medium joints
Renal (50% ): glomerulonephritis (p roteinuria, hematuria, ARF, HTN, edema)
Neurologic (17–60% ): peripheral neuropathy (p olyneurop athy > mononeuritis

multip lex)
Hematologic: anemia, thrombocytop enia, ↑ risk of B-cell lymp homa

GI (5% ): abdominal p ain, hep atosp lenomegaly, abnormal LFTs
Diagnostic studies
• ✓ Cryoglobulins; must keep blood warmed to 37°C at all times en route to lab; early
cooling causes false cryoglobulin, loss of RF and ↓↓ comp lement
• Cryocrit is quantification of cryop rotein, does not always correlate w/ disease

activity
• False ↑ in WBC or p lt on automated CBC, due to cryop recip itation
• Typ e I: ✓ serum viscosity, symp tomatic if ≥4.0 centip oise; comp lement levels
normal
• Typ e II: ↓ C4 levels, variable C3 levels, ↑ ESR, rheumatoid factor (RF)
✓ HCV, HBV, & HIV serologies in all Pts w/ mixed cryoglobulinemia
Bx of affected tissue: hyaline thrombi; vasculitis w/ mixed inflammatory infiltrates of

small vessels; leukocytoclastic vasculitis in p urp uric lesions
Treatment (Autoimmun Rev 2 011;10:444; Arth Rheum 2 012 ;64:604; Blood

2 012 ;119:5996)
• Treat underlying disorder:
Lymp hop roliferative disease: chemotherap y and/or radiation

HCV: antivirals ± immunosup p ression for severe disease
Connective tissue-related disease: DMARD/steroids ± rituximab
• Typ e I: Plasma exchange if hyp erviscosity
• Typ e II: NSAIDs for control of mild symp toms for Pts w/ normal renal function
Rituximab or cyclop hosp hamide for major organ involvement
Plasmap heresis or p lasma exchange in severe, life-threatening disease

AMYLOIDOSIS
The dep osition of misfolded and insoluble fibrous p roteins in normal organs and
tissues.
Diagnostic studies
• If susp ect AL → ✓ SIEP & UIEP (↑ Se vs. SPEP & UPEP) & free light chains, ± BM bx
• If susp ect renal involvement ✓ U/A (p roteinuria)
• If susp ect cardiac involvement: ✓ ECG (↓ voltage, conduction abnl), echo

(biventricular thickening with “granular sp arkling” ap p earance; ↑ wall w/o ↑ volt
75% Se, 95% Sp ), MRI
• Biop sy (abdominal SC fat p ad, rectal or affected tissue) → ap p le-green birefringence

on Congo red stain; fat p ad bx Se 60–8 5% , Sp 90–100%
• Genetic testing for hereditary forms

Treatment
• AL: ? high-dose melp halan → auto HSCT if limited organ dysfxn (NEJM
2 007;357:108 3); o/w low-dose melp halan + dexamethasone; novel agents (eg,
bortezomib, lenalidomide, thalidomide) being evaluated (J Hematol Oncol
2 011;4:47)
• AA: Rx underlying disease; colchicine for FMF esp . to p revent p rogressive renal
disease (NEJM 2 007;356:2 3); ep rodisate p romising for renal disease (NEJM
2 007;356:2 349)
• For hereditary amyloidoses in which amyloid p recursor p rotein is p roduced by the
liver (eg, TTR), liver transp lantation may p revent further dep osition
• Cardiac involv.: diuretics; avoid dig & CCB; avoid vasodilators; ? ICD for 1°
p revention
• Heart, kidney and liver Tx may be considered in those w/ advanced disease

Prognosis
• AL amyloid: median survival ~12 –18 mo; if cardiac involvement, median survival
~6 mo
• AA amyloid: median survival ~11 y (NEJM 2 007;356:2 361)
CHANGE IN MENTAL STATUS
Definitions (description of patient & timing is most helpful)
• Unresponsive: imp lies ↓ arousal or ability to follow commands, sp ecify w/ exam

• Delirium (aka acute confusional state or encep halop athy): acute change in attention
and consciousness with fluctuations. May include sleep –wake dysregulation,
autonomic changes, abnormal sensory p ercep tion and changes in affect as
additional features.
• Dementia: imp aired cognition, often incl. memory. Usually chronic & p rogressive,
eventually encomp assing more anatomical & functional p arts of the nervous
system.
Initial evaluation
• History (witness & background crucial): time course, p revious illnesses including
dementia or p sych; head trauma; meds, drug/alcohol use; infection/immune status
• General physical exam: vital sig ns, signs of trauma, asterixis, stigmata of liver
disease, embolic p henomena, signs of drug use, nuchal rigidity (may be p resent in
meningitis or SAH, but do not te st if p ossible trauma/cervical sp ine fracture)
• Neurologic exam (most meaningful off sedatives/p aralytics): look for focality or s/s
of ↑ ICP (eg, HA, vomiting, p ap illedema, unilateral dilated p up il, ↑ BP)
Initial treatment
• Resuscitation, control airway, monitor vital signs, fingerstick glucose, IV access

• Immobilization of C-sp ine if concern for cervical trauma
• Thiamine (100 mg IV) prior to de xtrose to p revent exacerb. of Wernicke’s

encep halop athy
• Dextrose (50 g IV p ush)
• Naloxone 0.01 mg/kg if op iates susp ected; sup p ortive care imp ortant in nearly all
tox cases
• If concern for ↑ ICP ± herniation: ↑ head of bed; osmotherap y w/ mannitol or
hyp ertonic saline; ↑ ventilation; dexamethasone for tumor edema; c/s neurosurgery
(? decomp ress)
Diagnostic studies (Continuum 2011; 17:967)
• Labs: CBC, electrolytes, BUN/Cr, LFTs, NH 3, tox screen, TSH, B 12 , ABG, U/A, ECG
• Imaging: head CT, consider MRI; radiograp hs to r/o C-sp ine fracture; CXR
• Lumbar p uncture to r/o meningitis, SAH or noninfectious inflammation (eg,

autoimmune)
• EEG to evaluate for nonconvulsive seizures, toxic/metabolic encep halop athy
Further treatment of delirium (Annals 2011; 154:746)
• Treat underlying acute illness, eliminate p recip itating factors, p rovide sup p ortive
care
• Address sensory & cognitive imp airments, increase familiarity
• Decrease/p revent infection/restraints if p ossible, remove lines/catheters if

unnecessary
• Promote good sleep : reduce noise & night-time interventions; selective med if
necessary
• Meds: consider antip sychotics, avoid benzos excep t for alcohol withdrawal or
seizures
ANOXIC BRAIN INJURY
Prevalence (NEJM 2012; 367:1912)
• Pts with at least 5 min of cerebral hyp oxia at risk
• 1.5 million cardiac arrests p er year in U.S.; for inPt arrest, ~2 0% survival, ~70%
of Pts who survive will have a good long-term neurologic outcome
Initial evaluation (Circulation 2010:S768)

• Neuro exam: arousal/verbal, eyes & other cranial nerves, motor resp onse to p ain
• Imaging: usually not informative w/in first day after arrest, but should be done
p rior to initiating hyp othermia if p atient found down or has had head trauma
Induced hypothermia (Circulation 2008; 118:2452 & 2013; 127:244)
• Indications: comatose (eg, no meaningful resp onse to verbal stimuli) <6 h following
cardiac arrest (not isolated resp . arrest). Fully studied only in VT/VF, but consider
after asystole or PEA arrest or 6–12 h after cardiac arrest.
• Exclusion: p regnancy, CV instability desp ite p ressors/assist devices, other cause of
coma, p ersistent ↓ O 2
• Relative contraindications: major head trauma, coagulop athy/bleeding, major

surgery <14 d, systemic infection/sep sis
• Method: target temp 32 –34°C × 2 4 h (from time of initiation of cooling). Can use
cold saline infusions; ice p acks to the head, neck and torso; cooling blankets;
cooling vest or endovascular catheter if available. Goal to achieve target temp <6
h. Start rewarming 2 4 h after cooling is initiated (rewarm no faster than 0.5°C p er
h).
• Comp lications
cardiac dysrhythmias (bradycardia most common): if signif dysrhythmia or

hemodynamic instability, d/c cooling and rewarm p atient
coagulop athy: Pts can receive fibrinolytics, GP IIb/IIIa inhibitors, etc., and still
undergo cooling. ✓ PT and PTT.
infection: ✓ surveillance blood cultures during cooling
hyp erglycemia during cooling, hyp oglycemia w/ rewarming; stop insulin if glc
<2 00 mg/dL
hyp okalemia during cooling, hyp erkalemia w/ rewarming; keep K 4–5 mEq/L
Ongoing evaluation
• Neuro exam: daily focus on coma exam. No exam finding is reliable <2 4 h or on
sedation. Pt needs to be off sedation for an adequate time to evaluate (dep ends on
doses used, duration of Rx, metabolic p rocesses in the individual Pt).
• Labs: daily CBC, PT/PTT, electrolytes. Serum neuron-sp ecific enolase (NSE) on days
1–3
• Imaging: noncontrast CT 2 4 h after arrest; if unrevealing, consider MRI around days

3–5
• EEG: consider in all to exclude seizures or myoclonus; greatest risk during

rewarming
• Somatosensory evoked p otentials (SSEP): help ful for p rediction of p oor outcome if
cortical resp onses are absent bilaterally; p erform 48 h after arrest (72 h if cooled)
Prognosis (Neuro 2006; 67:203; NEJM 2009; 361:605)

• Prior to cooling era, uniformly p oor p rognosis could be p redicted at 72 h only in
Pts who have absent p up illary and corneal reflexes, and no motor resp onse to
p ain; or with absent SSEPs at 48 h. With cooling, it is less clear if the p rior
measures are as reliable.
• Otherwise, p rognosis requires multifactorial ap p roach considering exam, age,
comorbid diseases, ancillary data (NSE, EEG, SSEP; imaging is less reliable for
p oor outcome)
• When in doubt, err on the side of giving more time (esp . in younger Pts and induced
hyp othermia Pts)
SEIZURES
Definitions (NEJM 2003; 349:1257; Epilepsia 2010; 51:676)
• Seizure = abnormal, p aroxysmal, excessive discharge of CNS neurons; occurs in 5–

10% of the p op ulation; can range clinically from dramatic to subtle
• Epilepsy = recurrent unp rovoked seizures; 0.5–1.0% of p op ulation
• Generalized seizures (involves brain diffusely)

Tonic-clonic (grand mal): tonic p hase (10–2 0 sec) with contraction of muscles
(causing exp iratory moan, cyanosis, p ooling of secretions, tongue biting) →
clonic p hase (~30 sec) with intermittent relaxing and tensing of muscles
Abse nce (p etit mal): transient lap se of consciousness w/o loss of p ostural tone,
usu p edi
Myoclonic (infantile sp asms & juvenile myoclonic ep ilep sy): sudden, brief
contraction
• Focal (partial) seizures (involves discrete brain area, imp lies a structural lesion)
Simple (w/o Δ MS) vs. comple x (w/ Δ MS): motor, sensory and/or autonomic
Focal with se condary g e ne ralization: starts focal, becomes generalized

Differential diagnosis
• Syncope (Lance t Ne urol 2 006;5:171)
• Nonepileptic seizure (NES, aka “p sychogenic” ): may see side-to-side head turning,
asymmetric large-amp litude limb movements, diffuse shaking w/o LOC, and
crying or talking during event
• Other: metabolic disorders (eg, alcoholic blackouts, hyp oglycemia), migraine, TIA,
transient global amnesia, narcolep sy (catap lexy), nonep ilep tic myoclonus, tics,
asterixis
Etiologies (varies strongly by age)
• Alcohol withdrawal, illicit drugs, meds (eg, β-lactams, bup rop ion, tramadol,
metronidazole, mep eridine, CsA, antidep ., clozap ine can lower seizure threshold)
• Brain tumor or p enetrating trauma
• Cerebrovascular disease, including subdural hematomas, hyp ertensive

encep halop athy
• Degenerative disorders of the CNS (eg, Alzheimer’s)
• Electrolyte (hyp onatremia) & other metabolic (eg, uremia, liver failure,
hyp oglycemia)
• Idiop athic (in ~60% )
• Aura (sec to mins): p remonition with p aresthesias, focal motor contractions,
abnormal smells/tastes, fear, dep ersonalization, déjà vu, autonomic changes,
automatisms
• Ictal period (sec to mins): tonic and/or clonic movements of head, eyes, trunk or
extrem.
• Postictal period (mins to h): slowly resolving p eriod of confusion, disorientation,

and lethargy. May be accomp anied by focal neurologic deficits (Todd’s p aralysis).
• Status epilepticus: continuous tonic-clonic seizure ≥30 min or rep eated seizures w/o
resolution of p ostictal encep halop athy. Comp lications include neuronal death,
rhabdomyolysis and lactic acidosis.
• Nonconvulsive status epilepticus: alteration of awareness (ranging from confusion

to coma) w/o motor manifestations of seizure. Dx with EEG.
Clinical evaluation
• Seizure: p atient usually w/o recollection, must talk to witnesses
unusual behavior before seizure (ie, an aura)

typ e & p attern of abnl movements, incl. head turning & eye deviation (gaze
p reference usually away from seizure focus)
loss of resp onsiveness

• HPI: recent illnesses/fevers, head trauma, sleep dep rivation, medication comp liance
• PMH: p rior seizures or FHx, p rior meningitis/encep halitis, p rior stroke or head
trauma
• Medications, alcohol and illicit drug use

• General p hysical exam should include the skin, looking for neuroectodermal
disorders (eg, neurofibromatosis, tuberous sclerosis) that are a/w seizures
• Neurologic exam should look for focal abnormalities → underlying structural
abnormality
Diagnostic studies (Neurology 2007; 69:1996)

• Laboratory: full electrolytes, BUN, Cr, glc, LFTs, tox screen, medication levels
• EEG: during seizure can cap ture rep etitive rhythmic activity (generalized seizures
will typ ically have abnl EEG; p artial may not); interictal EEG normal in 50% of
Pts w/ ep ilep sy, and interictal ep ilep tiform activity (sp ikes or sharp waves) seen
in only 2 5% of Pts w/ ep ilep sy but up to 2 % of normal p op ulation; sleep
dep rivation and rep eated studies ↑ dx yield of EEG; video monitoring may help w/
nonep ilep tic seizures
• MRI to r/o structural abnormalities; ↑ Se w/ fine coronal imaging of frontal &

temp oral lobes
• LP (if no sp ace-occup ying lesion on imaging): if susp ect meningitis (eg, fever, ↑
WBC, nuchal rigidity) or encep halitis and in all HIV Pts
Treatment (Lancet 2006; 367:1087 & 2007; 369:1000, 1016; NEJM 2008; 359:166)
• Treat any underlying causes, including CNS infections, intoxication, withdrawal, etc.
• Antiep ilep tic drug (AED) therap y is usually reserved for Pts w/ underlying structural
abnormality or an idiop athic seizure plus (i) status ep ilep ticus on p resentation, (ii)
focal neurologic exam, (iii) p ostictal Todd’s p aralysis or (iv) abnormal EEG
• After 1st unp rovoked sz, if EEG and MRI nl → 65% sz-free at 5 y (Lance t Ne urol
2 006;5:317)
• For Pts w/ infrequent seizures, early (vs. delayed) intervention w/ AED ↑ time to
seizure recurrence, but has no effect on long-term seizure-free status (Lance t
2 005;365:2 007)
• AED choice dep endent on typ e of seizure, side effects, cost, mechanism of elimination
(if hep atic or renal insufficiency), teratogenesis and drug interactions
• Introduce gradually, monitor carefully
• May consider withdrawal if seizure-free (typ ically for at least 1 y) and normal EEG
• Individual state laws mandate seizure-free duration before being allowed to drive
Status epilepticus (consult neurology)
• Place Pt in semip rone p osition to ↓ risk of asp iration

• Oral airway or, if p rolonged, endotracheal intubation
• IV access, start normal saline infusion
• STAT labs including glc, Na, Ca, serum & urine toxicology screen, anticonvulsant
levels
• Thiamine (100 mg IV) prior to dextrose to p revent Wernicke’s encep halop athy
• Dextrose (50 g IV p ush)

ALCOHOL WITHDRAWAL
Pathophysiology
• Alcohol is a CNS dep ressant
• Chronic use → insensitivity to inhibitory neurotransmitter g-aminobutyric acid

(GABA)
• Abrup t alcohol cessation → CNS overactivity

• Minor withdrawal sx (6–48 h after last drink): mild anxiety, tremulousness, HA
• Withdrawal seizures: typ ically w/in 48 h after last drink; if unRx’d, 1⁄3 →
delirium tremens
• Alcoholic hallucinosis: isolated hallucinations (typ ically visual) 12 –48 h after last
drink
• Delirium tremens (DT): disorientation, agitation, hallucinations, ↑ HR & BP, fever,

diap horesis; begins 48 –96 h after last drink, lasts 5–7 d
• Consider other dx: CNS infxn or bleed, sz, drug O/D, coingestions, acute liver
failure, GIB
Clinical Institute Withdrawal Assessment scale for alcohol (CIWA-Ar)

• Assign p oints for each of the 10 criteria; each criteria is scored 0–7 excep t
orientation which is scored 0–4; add p oints to calculate score
• Benzodiazepines (BDZ)
Drug: diazep am (long-acting w/ active metab; ↓ risk of recurrent withdrawal),

lorazep am (short half-life), chlordiazep oxide, oxazep am (no active metab; good
if cirrhosis)
Route: start IV, transition to PO
Dosing: typ ically start w/ diazep am 10–15 mg IV q10–15min (or lorazep am 2 –4

mg IV q15–2 0min) until ap p rop riate sedation achieved, then titrate to CIWA-Ar
scale, evaluating q1h until score <8 × 8 h, then q2 h × 8 h, and if stable, then
q4h (JAMA 1994;2 72 :519)
• If refractory to BDZ p rn, consider BDZ gtt, p henobarbital or p rop ofol (& intubation)
• Avoid halop eridol (↓ seizure threshold) or βB/central ɑ2 -agonists (mask sx)
• Mechanical restraints as needed until chemical sedation achieved
• Volume resuscitation as needed; thiamine the n glc to p revent We rnicke ’s

e nce phalopathy (ataxia, op hthalmop legia, short-term memory loss); rep lete K,
Mg, PO 4
• Prop hylaxis: if min sx or asx (ie, CIWA score <8 ) but p rolonged heavy EtOH con-
sump tion or h/o withdrawal seizures or DTs → chlordiazep oxide 2 5–100 mg
(based on severity of EtOH use) q6h × 2 4 h, then 2 5–50 mg q6h × 2 d
STROKE
ISCHEMIC STROKE
Etiologies
• Embolic (~75% ): artery → artery, cardioembolic, p aradoxical (NEJM

2 007;357:2 2 62 ), cryp togenic
• Thrombotic (~2 5% ): large vessel (atherosclerosis) vs. small vessel (“lacunar,”

lip ohyalinosis of small arteries, often related to HTN, hyp erlip idemia, & DM)
• Other: dissection, vasculitis, vasosp asm, p rothrombotic states, hyp op erfusion,
genetic
Clinical Manifestations
• Timing: embolic → sudden onset; thrombotic → stuttering course
Transient ischemic attack (TIA)
• Sudden deficit due to cerebral ischemia; no stroke on imaging; sx resolve <2 4 h

(most <1 h)
• Ddx: seizure, migraine, hyp oglycemia, amyloid sp ells, TGA, anxiety
• Risk of subsequent stroke p er ABCD 2 : Age ≥60 y (+1); BP ≥140/90 (+1); Clin
features: unilat. weak. (+2 ), sp eech imp air. w/o weakness (+1); Duration ≥60
(+2 ) or 10–59 min (+1); DM (+1)
risk of stroke at 48 h: low risk (0–3) = 1.0% ; moderate (4–5) = 4.1% ; high (6–7)
= 8 .1%
Physical exam
• General: assess for arrhythmias, murmurs, carotid & subclavian bruits, p erip heral
emboli
• Neurologic exam, NIH stroke scale

(http ://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.p df)
Acute workup (w/in 8 h for anterior and w/in 24 h for posterior circulation)
• Electrolytes, Cr (relevant for contrast); glc, CBC, coags (see exclusion criteria for
lysis)
• Cardiac biomarkers, 12 -lead ECG, tox screen

• STAT CT to r/o ICH p rior to lysis (Se MRI, faster, more widely available)
early signs: hyp erdense artery, loss of gray-white differentiation, edema, insular
ribbon
CT can be nl in first hrs after sx onset, not Se for small strokes & brainstem
strokes
obtain CT-angio head & neck or CT p erfusion if endovascular intervention
indicated
Workup to assess for etiology/modifiable risk factors
• Cardiac: Holter to assess for arrhythmias; echo to assess for thrombus or vegetation,
w/ bubble study to assess for PFO/atrial sep tal aneurysm if susp ected embolic
stroke
• Vessel imaging: carotid U/S and Dop p ler (if no vessel imaging obtained in acute
eval)
• Labs: lip ids, HbA1c, TSH, homocysteine, Lp (a), hyp ercoag w/u (if <65 y or
cryp togenic stroke; ideally drawn before starting anticoag), ESR/CRP, blood cx if
s/s systemic infection
• MRI help ful if dx of stroke unclear (esp . p ost circ) or to define stroke subtyp e, age,
exact size
DWI bright/ADC dark = earliest finding in acute ischemia (~ w/in mins, up to

days)
T2-FLAIR: hyp erintense w/in hrs, p ersists for wks; PWI differentiates irreversibly
infarcted core vs. viable p enumbra; T1 fat-sat (neck vessels) if susp icious for
dissection
Acute treatment of ischemic stroke (NEJM 2011; 364:2138; Stroke 2013; 44:870)
• Thrombolysis (IV): tPA 0.9 mg/kg (max 90 mg), w/ 10% as bolus over 1 min, rest
over 1 h
consider if onset w/in 4.5 h, ICH, contraindic. (incl. current/p rior ICH; head
trauma or stroke w/in 3 mo; intracranial neop lasm, AVM or aneurysm; recent
intracranial/intrasp inal surgery; active internal bleeding; noncomp ressible
arterial p uncture; ↑ BP; multilobar infarct; p lt <100k, INR >1.7, on Xa inhib,
PTT >40, glc <50)
0–3 h: 12 % absolute ↑ in good neuro outcome (min/no disability), 5.8 % absolute

↑ in ICH, trend toward 4% absolute ↓ mortality
3–4.5 h: 7.2 % absolute ↑ in good neuro outcome, 1.8 % absolute ↑ in ICH,

mortality benefit (nb, trial excluded p atients with p revious strokes + DM)
tenectep lase 0.2 5 mg/kg IV bolus p romising (NEJM 2 012 ;366:1099)
• Endovascular (eg, intra-arterial lysis, thrombectomy): w/o p roven benefit over

thrombolysis IV alone (NEJM 2 013;368 :8 93, 904, 914); thus still exp erimental, ?
consider for major vascular occlusions (distal ICA, p rox MCA, esp basilar given
high mortality or disability untreated)
• BP: lower to <18 5/110 to consider lysis; if lyse keep <18 0/105 × 2 4 h (consider
labetalol or nicardip ine), o/w p ermissive HTN unless >2 2 0/12 0 or sx; if sx HoTN
consider vasop ressors
• Initiate ASA w/in 2 4–48 h; avoid anticoagulation w/in 2 4 h of lysis; see below for
long-term Rx
• Cerebral edema → herniation: often occurs 1–5 d p ost large MCA or cerebellar
strokes, ↑ risk in young. Temp orize: elevate HOB >30°; mannitol ± 2 3% NaCl.
Hemicraniectomy ↓ mortality (Lance t Ne urol 2 007, 6:2 15). Neurosurgery consult
in select MCA and all large cerebellar strokes.
Secondary stroke prevention (NEJM 2012; 366:1914)
• Antiplatelet therapy: different agents likely have similar efficacy
ASA ↓ death & rep eat stroke; equal to warfarin in nonembolic stroke (NEJM
2 001;345:1444)
ASA + dipyrimadole: sup to ASA (Lance t 2 006;367:1665), but bid dosing, HA →
↓ comp liance
clopidogrel: marginally sup to ASA, slightly ↑ ICH (Lance t 1996:348 :132 9)
cilostazol: sup erior to ASA, less bleeding (Lance t Ne urol 2 010;9:959)

clop idogrel + ASA not more effective than ASA alone and ↑ ICH (Lance t
2 004;364:331)
• Anticoagulation (AC): not routinely indicated
Indications: cardiac/p aradoxical emboli (excep t bacterial endocarditis); long

segment extradural dissections; hyp ercoag state; bridge to CEA in sx carotid
stenosis w/ongoing TIAs.
INR goal 2 –3 for warfarin. Consider LMWH in Pts w/malignancy.
Hold off on AC in large strokes for ~2 –4 wk given risk of hemorrhagic

conversion.
• Long-term SBP target 12 0–139 mmHg ( JAMA 2 011;306:2 137)
• Statin: ↓ recurrent stroke w/ atorvastatin 8 0 mg, LDL goal <70 (NEJM

2 006;355:549)
• Fluoxetine: ? imp roved motor recovery after 3 mo (Lance t Ne urol 2 011;10:12 3)
• Carotid revascularization
CEA (if surgical morbidity & mortality ≤6% ) indicated for:
sx ste nosis 70–99% (benefit ↑ for males, >75 y, ≤2 wk from stroke) → 65%
↓ RR of rep eat stroke, slight benefit for 50–69% stenosis (NEJM
1991;32 5:445; Lance t 2 004;363:915)
asx ste nosis 70–90% , <79 y: 50% ↓ RR of rep eat stroke (Lance t
2 004;363:1491 & 2 010;376:1074)
stenting: comp ared w/ CEA, p erip rocedural risk of stroke ↑ (esp . in elderly) & MI
↓ (although many asx), subsequent rates of stroke similar (NEJM 2 010;363:11;
Lance t 2 010;376:1062 )
Patent foramen ovale (PFO; in ~27% of population) (NEJM 2005; 353:2361)
• ↑ stroke risk: ≥4 mm sep aration, R→L shunting at rest, ↑ sep tal mobility, atrial
sep tal aneurysm
• If PFO & stroke/TIA: no benefit of warfarin over ASA (Circ 2 002 ;105:2 62 5), but
consider if at high risk for or has DVT/PE. No sig benefit shown for PFO closure so
far, albeit studies small & w/ favorable trends (NEJM 2 012 ;366:991; 2 013:108 3 &
1092 ).
INTRACRANIAL HEMORRHAGE (ICH)
Classification by location
• Hemorrhagic strokes: intrap arenchymal hemorrhage (IPH) & subarachnoid

hemorrhage (SAH)
• Other ICH: ep idural hematoma (EDH) & subdural hematoma (SDH)
Etiologies
• AVM, aneurysm, cerebral venous sinus thrombosis → IPH or SAH
• HTN (basal ganglia, cerebellum, brainstem), cerebral amyloid (lobar), tumor (esp .
w/ melanoma, renal cell CA, chorio-CA, thyroid CA) → IPH
• Trauma → all locations (nb, IPH or SAH caused by trauma technically not a stroke)
Clinical manifestations (Lancet Neurol 2005; 4:662; BMJ 2010; 341:c5204)
• ↓ consciousness, N/V, HA, p rogressive focal neurologic deficits

• SAH: thunderclap HA, onset w/ exertion; nuchal p ain/rigidity; LOC. EDH: initial
lucid interval.
Workup
• STAT CT brain, angio (CT-A or conventional) if susp icious for vascular source
• LP to ✓ for xanthochromia if no evidence of ICH on CT and susp icious for SAH
• Coags (PT, PTT, INR)

Management
• Reverse coagulop athies w/ vit K & FFP, goal INR <1.4. Plt goal >100k; no clear
evidence for p lt transfusion if on ASA but may consider with exp anding ICH;
DDAVP if uremic.
• HOB elevation to 30–45°; strict BP control w/ arterial line, use nicardip ine or
labetalol gtt, goal SBP <160, for aneurysmal SAH <140, unless risk for
hyp op erfusion b/c of crit carotid stenosis
• SAH: surgical clip p ing vs. endovascular coiling (dep ending on location,
comorbidities) of aneurysm/AVM; nimodip ine to ↓ risk of vasosp asm (monitor w/
TCDs), seizure Pp x
• Surgical evacuation: any EDH; SDH if >1 cm or rap id exp ansion; IPH: consider in
younger Pts w/ ICH, data controversial, p otential benefit in sup erficial IPH (Lance t
2 005, 365:38 7)
• Venous sinus thrombosis: start anticoagulation, manage ↑ ICP and seizures as needed
WEAKNESS & NEUROMUSCULAR DYSFUNCTION
PERIPHERAL NEUROPATHIES
Etiologies
• Mononeuropathy (one nerve): entrap ment, comp ression, trauma, DM, Lyme.
Commonly seen: median n. (carp al tunnel syndrome); ulnar n. (at elbow or

wrist); common p eroneal n. (at knee with habitual leg crossing); lateral
femoral cutaneous n. (at inguinal ligament).
• Mononeuropathy multiplex (axonal loss of multip le, sep arate, noncontiguous
nerves):
vasculitides, sarcoid, DM, Lyme, Sjögren, hereditary neurop athy with p ressure
p alsies
• Small fiber neuropathy: (unmyelinated or thinly myelinated nerves): idiop athic,
DM, CTD, alcohol, sarcoid, thyroid dysfxn, B 12 defic, p arap roteinemia, p araneo,
celiac, hered.
• Polyneuropathy (multip le symmetric nerves, generally length dep endent)
De mye linating
acute: acute inflammatory demyelinating p olyneurop athy (AIDP) = Guillain-

Barré
subacute: meds (p aclitaxel), p araneop lastic
chronic: idiop athic, DM, CIDP, hyp othyroidism, toxins, p arap roteinemia,
hereditary
Axonal
acute: acute motor axonal neurop athy (AMAN), p orp hyria, vasculitis, uremia
subacute: DM, meds (cisp latin, p aclitaxel, vincristine, INH, ddI), EtOH, sep sis,
p araneo.
chronic: DM, uremia, lead, arsenic, HIV, p arap roteinemia, B 12 defic
• Weakness, fasciculations, numbness, dysesthesias (burning/tingling), allodynia
• ± Autonomic dysfxn (orthostasis, bowel/bladder retention/incontinence, imp otence)

• Dep ressed or absent DTRs (may be normal in small fiber neurop athy)
Diagnostic studies
• Distal symmetric p olyneurop athy: start w/ HbA1C or glc tolerance test, B 12 , SPEP
+ SIEP
• EMG & NCS (often no change in first 10–14 d or in small fiber neurop athy)
• Electrolytes, BUN/Cr, CBC, TSH, LFTs, ANA, anti-Ro, anti-La, ESR, HIV, Cu, Lyme
titers, genetic testing and heavy metal screening as indicated by clinical history
and exam
• Autonomic testing/skin bx (small fiber), nerve bx (mononeurop athy multip lex)
• MRI if p ossible radiculop athy or p lexop athy (after EMG)
Treatment of neuropathic pain

• Pharmacologic: p regabalin, gabap entin, TCAs (nortrip tyline, amitrip tyline), SSRIs
(duloxetine, venlafaxine), tramadol, top ical analgesics (lidocaine, cap saicin),
op iates
• Nonp harmacologic: transcutaneous electrical nerve stimulation (TENS)

GUILLAIN-BARRÉ SYNDROME (GBS)
• Acute inflammatory demyelinating p olyneurop athy (AIDP)
• Incidence 1–2 p er 100,000; most common acute/subacute p aralysis

• Precip itants in 60% : viral illness (CMV, EBV, HIV), URI (Mycoplasma),
gastroenteritis (Campylobacte r), Lyme, immunizations (no p roven risk w/ current),
surgery
• Distal sensory dysesthesias and numbness often first symp toms, back p ain also
common
• Ascending symmetric p aralysis over hours to days; p lateau in 1–3 wk

• Hyp oactive then absent reflexes
• Resp failure requiring mech vent occurs in 30% ; autonomic instability &
arrhythmias in 50%
• Fisher variant: op hthalmop legia, ataxia, areflexia; associated with anti-GQ1b

antibodies
Diagnostic studies (results may be normal in first several days)
• LP: albuminocytologic dissociation = ↑ p rotein w/o p leocytosis (<10 WBCs) seen in

up to 50% of Pts in 1st wk, 75% by 3rd wk of symp toms
• EMG & NCS: ↓ nerve conduction velocity, conduction block, p rolonged F wave
latency
• FVC & NIF: to assess for risk of resp iratory failure (cannot rely on Pa O 2 or S a O 2 )
Treatment
• Plasma exchange (Coch Data Syst Re v 2 002 ;2 :CD001798 ) or IVIg of equal efficacy
and no additional benefit with both (Ne uro 2 012 ;78 :1009), steroids not beneficial
• Sup p ortive care with monitoring in ICU setting if rap id p rogression or resp . failure
• Watch for autonomic dysfunction: labile BP, dysrhythmias (telemetry)
• Most recover near baseline; axonal variant (~5% ) with incomp lete recovery; 3–5%
mortality
MYASTHENIA GRAVIS
• Autoimmune disorder with Ab directed against acetylcholine recep tor (AChR) in NMJ
• Prevalence: 1 in 7500; affects all ages, p eak incidence 2 0s–30s (women), 60s–70s
(men)
• Fluctuating weakness w/ fatig ability (worse w/ rep etitive use, relieved by rest)
• Cranial muscles involved early → ocular (p tosis, dip lop ia) in 50% ; bulbar
(difficulty
chewing, dysarthria, dysp hagia) in 15% . Often later p rogresses to generalized
weakness.
• Limb weakness p roximal > distal; DTRs p reserved; minimal/no atrop hy
• Exacerbations triggered by stressors such as URI, surgery, p regnancy or

p ostp artum, meds (eg, aminoglycosides, p rocainamide, p henytoin); p rednisone
can worse n acutely
• Myasthenic crisis = exacerbation → need for resp iratory assistance

• Cholinergic crisis = weakness due to ove rtre atme nt with anticholinesterase
medications; may have excessive salivation, abdominal cramp ing and diarrhea;
rare at normal doses
Diagnostic studies
• Bedside: p tosis at baseline or after >30 sec of sustained up gaze, imp roved with ice
p ack over eyes for 2 –5 min, Se 77% , Sp 98 %
• Neostigmine test: temp orary ↑ strength; false & occur; p remedicate w/

atrop ine
• EMG: ↓ resp onse with rep etitive nerve stimulation (vs. ↑ resp onse in Lambert-Eaton)
• Anti-AChR Ab: Se 8 0% , 50% if ocular disease only; Sp >90% ; muscle sp ecific

recep tor tyrosine kinase (MuSK) Ab account for most AchR Ab cases
• CT or MRI of thorax to evaluate thymus (65% hyp erp lasia, 10% thymoma)
Treatment
• Thymectomy if thymoma; may lead to imp rovement in up to 8 5% Pts w/o thymoma
• Cholinesterase inhibitors (eg, p yridostigmine) are most rap id acting (benefit in 30–
60 min)
• Immunosup p ression: p rednisone (benefit in wks) ± azathiop rine, cyclop hosp hamide
(benefit in 6–12 mo)
• Myasthenic crisis: treat p recip itant
consider d/c anticholinesterase if susp ect cholinergic crisis
immunosup p ression with glucocorticoids (in monitored setting as risk for initial
worsening)
IVIg or p lasmap heresis of equal efficacy (Ann Ne urol 2 010;68 :797)
ICU if rap id or severe (follow FVC, NIF)

MYOPATHIES
Etiologies
• Hereditary: Duchenne, Becker, limb-girdle, myotonic, metabolic, mitochondrial
• Endocrine: hyp othyroidism, hyp erp arathyroidism, Cushing syndrome

• Toxic: statins, fibrates, glucocorticoids (incl. critical illness myop athy), zidovudine,
alcohol, cocaine, antimalarials, colchicine, p enicillamine
• Infectious: HIV, HTLV-1, trichinosis, toxop lasmosis
• Inflammatory (see “Rheumatology” ): p olymyositis, dermatomyositis, inclusion body
myositis
• Progressive or ep isodic weakness (not fatigue)
• Weakness most often symmetric, p roximal > distal (stairs, rising from sitting, etc.)
• ± Myalgias (though not p rominent or frequent), cramp s, myotonia (imp aired
relaxation)
• May develop either p seudohyp ertrop hy (dystrop hies) or mild muscle atrop hy
• Assoc. organ dysfxn: cardiac (arrhythmia, CHF), p ulmonary (ILD), dysmorp hic
features
Diagnostic studies
• CK, aldolase, LDH, electrolytes, ALT/AST, PTH, TSH, ESR, HIV
• Autoantibodies (anti-Jo1, antisynthetase, anti-Mi-2 , anti-SRP, ANA, RF)
• EMG/NCS: low-amp litude, p olyp hasic units with early recruitment, ± fibrillation
p otentials
• Muscle biop sy, molecular genetic testing (where indicated)

HEADACHE
Primary headache syndromes (International Headache Society Classification)
• Tension-type: constant p ressure, freq bilateral; a/w myofascial sensitivity in neck or

head
Triggers: stress, sleep dep rivation, dehydration, hunger
Treatment: OTC analgesics (NSAIDs, acetaminop hen; risk of med overuse HA!) for
ep isodic; TCAs for chronic
• Cluster HA and trigeminal autonomic cep halgias (TACs)
Characterized by unilateral rhinorrhea, red/tearing eye, miosis/p tosis, lid edema,

sweating, differentiated by timing
Cluste r: > , unilateral eye p ain, attacks 15 min–3 h, worsened by EtOH.

Pp x: CCB (verap amil). Rx: high-flow O 2 , sumatrip tan IN/SC, lidocaine IN.
Paroxysmal he micrania: similar to cluster, but > , attacks 2 –45 min. Rx:
indomethacin.
He micrania continua: > , icep ick-like p ain lasting >3 mo. Rx: indomethacin.
Short-lasting unilate ral ne uralg iform HA w/ conjunctival inje ction and te aring
(SUNCT): > , excruciating, stabbing, electrical p ain, 5 sec–6 min, up to
2 00×/d. Rx: lamotrigine, gabap entin, top iramate.
• Migraine: se e be low
Secondary causes of headaches

• Traumatic: p ostconcussion, SAH, SDH, p ostcraniotomy
• ↑ ICP: mass (tumor, abscess, vascular malformations, ICH), hydrocep halus,

idiop athic intracranial hyp ertension (p seudotumor cerebri), altitude associated
cerebral edema
• ↓ ICP: p ost-LP headache, CSF leak/dural tear, overshunting
• Vascular causes: stroke (esp . p osterior circ), dissection, vasculitis (incl. temp oral
arteritis), reversible cerebral vasoconstriction syndrome (RCVS), ICH, venous sinus
thrombosis
• Meningeal irritation: meningitis, SAH
• Trigeminal neuralgia
• Extracranial: sinusitis, TMJ syndrome, glaucoma
• Systemic causes: hyp oxia, hyp ercap nia, dialysis HA, HTN, hyp oglycemia, ↓TSH
• Medication overuse (analgesics), withdrawal (caffeine, op ioids, estrogen)
Clinical evaluation ( JAMA 2006; 296:1274)
• History: onset (sudden vs. gradual), quality, severity, location, duration, triggers,
alleviating factors, p ositional comp onent, hormonal triggers (menstruation),
p receding trauma, associated sx (visual Δs, “floaters,” N/V, p hotop hobia, focal
neurologic sx)
• Medications (analgesics), substance abuse (op ioids, caffeine)

• General and neurologic exam (fundoscop ic exam, visual fields)
• Warning signs (should prompt neuroimaging)
e xplosive onse t (vasc); “worst HA of my life ” (SAH, RCVS); me ning ismus (SAH,
infxn)
positional: lying > standing (↑ ICP); N/V (↑ ICP; migraines)
visual sx: dip lop ia, blurring, ↓ acuity (GCA, glaucoma, ↑ ICP); e ye pain
(glaucoma, cluster)
abnl ne uro e xam (struct. lesion, p oss. in migraine); ↓ consciousne ss (± fever):
infxn, ICH
ag e >50 y; immunosuppre ssion (CNS infections, PRES)
• LP if susp icious for SAH (✓ for xanthochromia), p seudotumor (✓op ening p ress);
image first!
MIGRAINE
Epidemiology: affects 15% of women and 6% of men; onset usually by 30 y

Definition & clinical manifestations (Lancet 2004; 363:381; JAMA 2006; 296:1274)
• H/o ≥5 attacks lasting 4–72 h and with (a) N/V or p hotop hobia & p honop hobia,
and (b) ≥2 of following: unilat., p ulsating, mod–severe intensity, aggravated by
routine activity
• Migraine w/o aura (64% ): most common, p reviously called “common” migraine
• Typ ical aura w/ migraine (18 % ): visual aura (scotomata with jagged/colored edge)
p recedes HA, can also be reversible sensory or sp eech symp toms, <1 h
• Comp licated: accomp anied by stereotyp ical neurologic deficit that may last hrs (DDx
includes stroke : in migraine onset is rather gradual, sx sp read over mins)
• Precip itants: stress, hunger, foods (cheese, chocolate) and food additives (MSG),
fatigue, alcohol, menstruation, exercise

• Eliminate p recip itants
• Prop hylaxis: TCA, βB, CCB, valp roic acid, top iramate ( JAMA 2 004;2 91:965),
gabap entin
• Abortive therap y: ASA, acetaminop hen, caffeine, high-dose NSAIDs
metoclop ramide IV, p rochlorp erazine IM or IV, valp roate IV, steroids
5-HT1 agonists (“trip tans” ): most sp ecific therap y, contraindicated if comp licated
migraine, CAD, p rior stroke. Trip tan + NSAID stronger than either alone
( JAMA 2 007;2 97:1443)
ergotamine, dihydroergotamine: use with caution in Pts w/ CAD

BACK AND SPINAL CORD DISEASE
Differential diagnosis of back pain
• Musculoskeletal: musculoligamentous “strain” (exp erienced by up to 8 0% of

p op ulation at some time), OA, RA, sp ondylolisthesis, vertebral fx, inflammatory
sp ondyloarthritis (ankylosing sp ondylitis, reactive, p soriatic), myofascial p ain
syndrome
• Spinal cord (myelop athy)/nerve root (radiculop athy):

Degenerative/traumatic: disc herniation, sp ondylosis, vertebral fx and subluxation
Neop lastic: lung, breast, p rostate, RCC, thyroid, colon, multip le myeloma,
lymp homa
Infectious (also see ID section): osteomyelitis, ep idural abscess, zoster, Lyme,
CMV, HIV
• Referred pain from visceral disease: (quality of p ain can be imp ortant to
distinguish)
GI: PUD, cholelithiasis, p ancreatitis, p ancreatic cancer
GU: p yelonep hritis, nep hrolithiasis, uterine or ovarian cancer, salp ingitis
Vascular: aortic dissection, leaking aortic aneurysm

Initial evaluation
• History: location, radiation, trauma, wt loss, cancer hx, fever,

immunocomp romised, neurologic symp toms, saddle anesthesia, incontinence,
urinary retention, IV drug use
• General physical exam: local tenderness, ROM, signs of infection or malignancy,
signs of radiculop athy (exp erienced as sharp /lancinating p ain radiating into
limb):
Sp urling sign (radicular p ain w/ downward force to extended & ip silaterally

rotated head): 30% Se, 93% Sp
straight leg raise (radicular p ain at 30–70°): ip silateral: 92 % Se, 2 8 % Sp ;

crossed (contralateral leg raised): 2 8 % Se, 90% Sp
• Neurologic exam: full motor (including sp hincter tone), sensory (including p erineal
region) and reflexes including anal (S4) and cremasteric (L2 )
• Laboratory (dep ending on susp icion): CBC, ESR, Ca, PO 4, AФ, CSF
• Neuroimaging: low yield if nonradiating p ain, high false rate (incidental

sp ondylosis) dep ending on susp icion: X-rays, CT or CT myelograp hy, MRI, bone
scan
• EMG/NCS: may be useful to distinguish root/p lexop athies from p erip heral
neurop athies
SPINAL CORD COMPRESSION
• Acute: flaccid p arap aresis and absent reflexes (“sp inal shock” )
• Subacute–chronic: sp astic p arap aresis and hyp eractive reflexes

• Posterior column dysfunction in legs (loss of vibratory sense or p rop riocep tion)
• Sensory loss below level of lesion
• Bilateral p rominent Babinski resp onses ± ankle clonus
Evaluation & treatment

• Emp iric sp ine immobilization (collar, board) for all trauma p atients
• STAT MRI (at and above clinical sp inal level, p re- and p ostgadolinium) or CT
myelogram
• Emergent neurosurgical and/or neurology consultation

• Urgent radiation therap y ± surgery for comp ression if due to metastatic disease
• High-dose steroids dep ending on cause:

Tumor: dexamethasone 16 mg/d IV (usually 4 mg q6h) with slow tap er over wks
Trauma: methylp rednisolone 30 mg/kg IV over 15 min then 5.4 mg/kg/h × 2 4 h

(if started w/in 3 h of injury) or × 48 h (if started 3–8 h after injury) ( JAMA
1997;2 77:1597)
NERVE ROOT COMPRESSION
• Radicular p ain aggravated by activity (esp . bending, straining, coughing), relieved

by lying
• Sciatica = radicular p ain radiating from buttocks down lateral asp ect of leg, often
to knee or lateral calf ± numbness and p aresthesias radiating to lateral foot
Treatment of nerve root compression
• Conservative: avoid bending/lifting; NSAIDs; Rx neurop athic p ain (see “Perip heral
Neurop athies” ); p hysical therap y
• Sp inal ep idural steroid injections (ESI): limited short-term relief of refractory
radicular p ain
• Surgery: cord comp ression or cauda equina syndrome; p rogressive motor

dysfunction; bowel/bladder dysfunction; failure to resp ond to conservative Rx
(NEJM 2 007;356:2 2 45)
SURGICAL ISSUES
ABDOMINAL PAIN
Figure 10-1 Etiologies of abdominal p ain based on location
Initial evaluation
• History: onset of p ain, location, exacerbating/relieving factors
• Assoc. sx: fevers/chills, N/V, Δ in bowel habits (diarrhea/constip ation, stool diam.
or color, hematochezia, melena), jaundice, Δ in urine color, Δ in wt, menstrual hx
in women
• PMHx: p revious incisions or abdominal surgeries; Ob/Gyn hx
• Exam: VS; general p osture of Pt; comp rehensive abdominal exam sp ecifically
looking for signs of p eritonitis, which include rebound tenderness and involuntary
guarding, abdominal wall rigidity, p ain w/ p ercussion/minimal p alp ation;
p resence of hernias; rectal/p elvic
• Labs: CBC, electrolytes, LFTs, amylase/lip ase, p regnancy test
• Imaging: dep ends on susp ected etiology, may include RUQ U/S for biliary/hep atic
disease, KUB for intestinal obstruction, CT for p ancreatitis or intestinal disease.
Do not delay resucitation or surgical consultation for ill Pt while waiting for
imaging.
ACUTE ABDOMEN
Definition
• Acute onset abdominal p ain that p ortends need for urgent surgery
Etiologies
• Perforated viscous → p eritonitis (p erforated ulcer, comp licated diverticulitis,
trauma)
• Intrap eritoneal bleed
• Bowel obstruction (adhesions from p revious surgeries, malignancies, hernias)
• Mimics: severe p ancreatitis can resemble p eritonitis; renal colic causes severe
abdominal p ain but not abdominal rigidity
Initial evaluation
• H&P as above
• Labs as above p lus: PT/INR, PTT, typ e & screen
• Imaging: KUB (up right) or if stable, CT abomen/p elvis w/ IV contrast (IV/PO if

susp ect obstruction)
Initial management
• Immediate surgical consultation for susp ected acute abdomen
• NPO, start IV fluids (NS or LR)

• Broad sp ectrum abx if p erforation susp ected
EXTREMITY EMERGENCIES
Acute limb ischemia (see “Perip heral Artery Disease” for details)
• Definition: sudden ↓ in p erfusion causing threat to limb viability
• Evaluation: detailed vascular exam; CT angiograp hy or arteriograp hy

• Initial management: anticoag for embolism/thrombosis; immediate surgical
consultation
Compartment syndrome (Clin Orthop Relat Res 2010; 468:940)

• Definition: ↑ intracomp artmental p ressure w/ comp ressive closure of venules → ↑
hydrostatic force resulting in further increases in comp artment p ressure
• Etiologies: orthop edic (fracture), vascular (ischemia-rep erfusion), iatrogenic (eg,
vascular injury in anticoagulated Pt), soft tissue injury (eg, p rolonged limb
comp ression)
• Clinical manifestations: p ain esp . on p assive movement, swollen/tense

comp artment, p araesthesia, p allor, p ulselessness, p aralysis (late)
• Evaluation: ✓ comp artment p ressures (needle manometry), ICP >30 or difference
between diastolic p ressure and ICP of >10–30 is diagnostic
• Treatment: fasciotomy
SURGICAL TUBES, DRAINS, WOUNDS
Tracheostomy (Otolaryngol Head Neck Surg 2013; 148:6)

• Inserted either p ercutaneously or surgically
• Monitor for secretions and suction frequently

• Typ ically a cuffed tube, which creates a tight seal to facilitate ventilation throught
tube
• Sp eaking valve (eg, Passy-Muir): 1-way valve that allows inhalation through tube,
but exhalation around tube through vocal cords (nb, cuff should not be inflated)
• 1st routine tube change for p ercutaneously p laced tubes should be ~10 d p ostop ,
whereas surgically p laced tubes can be changed >5 d p ostop and should be
overseen by exp erienced p ersonnel
• Accidental dislodgement of tube:
intubate from above (if airway/vent necessary & anatomically p ossible)

w/in 7 d of p lacement: emergent surgical consultation
>7 d after p lacement: rep lace with a similar size tube or smaller
Chest tubes (Eur J Cardiothorac Surg 2011; 40:291)

• Inserted for PTX, chest trauma or after thoracic surgery for drainage of air/ fluid
from thoracic cavity. Tubes range from small 10-Fr catheters p laced for
sp ontaneous PTX to large bore tubes (2 8 –32 Fr) p laced after p ulmonary
resections.
• Connected to 3-chamber chest drainage system:
1st: collection chamber for p leural fluid
2 nd: water seal chamber used to allow air to exit p leural sp ace on exhalation and
p revent air from entering on inhalation
3rd: suction control chamber which regulates suction transmitted to p leural sp ace
• Monitor for oup ut and p resence of air leak (indicated by bubbling in wate r se al
chambe r)
• Removal determined by overall daily outp uts and p resence of air leak
• If accidentally removed or dislodged so not functional, tube should be comp letely

removed and an occlusive dressing (eg, 4 × 4 covered w/ Tegederm or silk tap e)
should be p laced rapidly over site. CXR STAT; new tube should be p laced if
p ersistent PTX.
Gastrostomy/jejunostomy tubes (Paediatr Child Health 2011; 16:281)
• Placed for tube feedings, hydration and delivery of medications
• Securely anchor to skin to p revent inadvertent removal

• Surrounding skin should be kep t dry to p revent breakdown
• Should not be removed for ≥6–8 wk to allow establishment of mature

gastrocutaneous tract
• Obstructed tubes can be cleared by flushing with agents such as carbonated water,
meat tenderizer, p ancreatic enzymes. ↓ obstruction by flushing before & after meds
and flushing q4–6h when receiving continuous feeds.
• If becomes inadvertently removed a foley catheter of similar size or smaller should

be p laced in the tract imme diate ly to p revent stoma from closing. Tube then
rep laced and confirmed via fluoro study w/ gastrograffin.
Suture/staple removal
• Should be done in consultation w/ surgical team
• Timing of removal dep ends on location of wound: wait 3–4 d before removal from
face, 6 d for scalp , 7 d for chest, abdomen & arms, 10 d for back & legs, 14 d for
hands
• Should not be re move d if the re is e vide nce of wound se paration during re moval!
• After removal, wound should be reap p roximated w/ steri-strip s
MAXIMIZING A SURGICAL CONSULT
• For ill Pt, call surgical consult early, do not wait for labs & imaging results
• If p otential surgical emergency, make Pt NPO, start IVF, ✓ coags, typ e & screen
• Have ap p rop riate-level MD who knows & has examined Pt call consult
OB/GYN ISSUES
VAGINAL BLEEDING
Abnormal ble e ding from lowe r (vulva, vag ina, ce rvix) or uppe r g e nital tract (ute rus)
Etiologies
• Premenop ausal
Not p regnant: menses, dysfunctional uterine bleeding (menorrhagia), leiomyoma,
p olyp , trauma, cervical dysp lasia/cancer (rare), endometrial
hyp erp lasia/cancer (rare)
Pregnant
1st trimester: threatened abortion, sp ont. abortion (missed, incomp lete or
comp lete), ectop ic p regnancy, molar p regnancy (p artial or comp lete
hydatidiform mole)
2 nd or 3rd trimester: p reterm labor, p lacenta p revia, p lacental abrup tion

• Postmenop ausal: atrop hy, p olyp , leiomyoma, endometrial hyp erp lasia/cancer,
cervical dysp lasia/cancer
History & exam

• Age, menop ausal status, gestational age if p reg.; volume & duration of current
bleeding
• If p remenop ausal: menstrual hx including age of onset, interval between & duration
of menses, any assoc. sx and LMP to assess timing of menstrual cycle
• Past Ob/Gyn hx (any structural abnl, STD and contracep tion)
• Health maint. (Pap smear, HPV screening); domestic violence; anticoag or antip lt
meds
• General p hysical & abdominal exam (incl. tenderness, masses)
• Pelvic exam: external (quantity of bleeding seen on vulva, any lesions, any trauma);
also, w/ assistance from Ob/Gyn, sp eculum exam (quantity of bleeding; cervical os
op en or close and if op en, dilation; any p olyp s) & bimanual exam (uterine size
and tenderness, adnexal mass and tenderness)
Laboratory evaluation & imaging
• Urine (rap id test) & serum p regnancy test (bhCG); Hct/hemoglobin
• Pelvic U/S: visualize intrauterine p reg to r/o ectop ic; if p reg., intrauterine not seen,
& bHCG > discrim. zone → concern for ectop ic; if bHCG < discrim. zone →
follow bHCG; nl p lacental p osition to r/o p lacenta p revia and likely severe
abrup tion
• Ectopic pre g nancy is life -thre ate ning diag nosis, ∴ must rule out if Pt pre g nant
VAGINAL DISCHARGE
Fluid or mucus from vag ina, ce rvix or ute rus
Etiologies
• Infectious: bacterial vaginosis, candida vulvovaginitis, trichomoniasis

• Noninfectious: p hysiologic (in p reg. or non-p reg.), rup ture of membranes, foreign-
body rxn
Initial evaluation
• Age, LMP, gestational age if p reg. or menop ausal status
• Discharge quantity, color, consistency, odor, assoc. sx (itchiness, redness, abd/p elvic
p ain)
• Past gyn hx incl STD and contracep tion usage (condoms ↓ STD risk)
• Tamp on or condom use as risk factors for retained foreign body

• Pelvic exam: external (quantity & quality of discharge on vulva, any lesions);
sp eculum (discharge, ap p earance of cervix), bimanual (cervical motion tenderness)
• Laboratory: p H of discharge; microscop y (saline & KOH wet mounts); urine

p regnancy test
Treatment
• Bacterial vaginosis: oral or vaginal metronidazole or clindamycin

• Candida vulvovaginitis: oral or top ical antimycotic medications
• Trichomoniasis: oral metronidazole

ADNEXAL MASS IN NON-PREGNANT WOMAN
Mass arising from ovary, fallopian tube or surrounding conne ctive tissue
Etiologies
• Ovarian: functional (follicular and corp us luteum) or hemorrhagic cyst,

endometriomas, ovarian torsion, tubo-ovarian abscess, benign & malignant
ovarian tumors
• Fallop ian tube: p aratubal cyst, hydrosalp inx, ovarian torsion, tubo-ovarian abscess
Initial evaluation
• LMP / menop ausal status; associated sx of abd/p elvic p ain, FHx of gyn cancers
• Abd exam (distension, tenderness, masses); bimanual (uterine or adnexal masses)
• Preg. test if p remenop ausal (if , then mass likely p regnancy); CA-12 5 if
p ostmenop ausal
• Pelvic U/S (even if mass first identified on CT as U/S is best modality); U/S
ap p earance of mass most imp ortant factor used to determine risk of malignancy
OPHTHALMIC ISSUES
ACUTE VISUAL CHANGES
Description & common etiologies of other visual changes
• Fluctuation in vision (ie, blurry): med-induced refractive error (eg, systemic

steroids, chemotherap y), hyp erglycemia, dry eye (common)
• Double vision (diplopia): fixed double vision w/ op hthalmop legia from orbital
p rocess or cranial nerve p alsy. Transient “dip lop ia” due to fatigue or sedation.
• Visual field defect: bilateral (homonymous → contral. CNS lesion; bitemp oral →
p ituitary, glaucoma or toxic/nutritional); unilateral (ip silat. orbital, retinal or
op tic nerve p rob)
• Floaters: vitreous detachment (common, benign); retinal detachment (uncommon,

“flashing lights,” unilateral visual field defect); hemorrhage; intraocular
lymp homa
RED EYE
OTHER DIAGNOSES
Optic nerve disorders
• Ischemic optic neuropathy: p /w acute unilat. visual loss, altitudinal field defect
ante rior: a/w GCA; non-arteritic a/w HTN, hyp erchol., DM, thrombop hilia
poste rior (very rare): seen after severe blood loss; hyp otension during surgery
• Optic neuritis: often p /w unilat. central scotoma, p ain with EOM,↑ visual loss over
days; a/w demyelinating disease (eg, MS), also seen w/ sarcoidosis & CTD
Ocular motor palsies
• CN III palsy: EOM restricted in all directions excep t laterally (eye is “down & out” );
a/w p tosis & mydriasis; seen w/ uncal herniation, aneurysm of p ost com art.,
GCA, HTN, DM
• CN IV palsy: up ward deviation & lack of dep ression on adduction; congenital 4th (no
dip lop ia); a/w trauma, p ost fossa tumor (vertical dip lop ia, better with head tilt)
• CN VI palsy: failure of abduction (eye is “turned in” ), horizontal dip lop ia worse at
distance than near, worse w/ gaze to affected side; a/w ↑ ICP, HTN, diabetes,
trauma
Other Dx
• Orbital cellulitis: p /w fever, p rop tosis, ↓ EOM, sinusitis; requires e me rg e nt abx &
re fe rral to ophtho; differentiate from p resep tal cellulitis by p resence of p ain w/ eye
movement, p rop tosis, p up il reaction abnl, op hthalmop legia, ± visual changes
• SJS/TEN/facial burn/acute GVHD: conjunctival/lid/cornea involvement → may

lead to corneal p erforation, p ermanent vision loss; e me rg ophtho consult
INITIAL EVALUATION
• Ocular p resentation: onset (sudden or p rogressive) & duration of sx; unilateral vs.
bilateral; p ain; p hotop hobia; discharge; Δ in near (eg, book) or far (eg, TV across
room) vision
• Pre-existing ocular conditions, eye meds (incl any Ds), recent h/o ocular surgery
• Ocular exam: vision (✓with Pt’s correction [glasses/contacts]) w/ each eye;
p up illary exam; EOM; confrontation visual fields (imp ortant if susp ect CNS
p roblem)
• Overall status: VS, immunocomp romised, s/s of infxn, h/o malignancy, CNS issues,
Δ in meds, CBC, coags
ICU MEDICATIONS
Figure 11-1 ACLS pulmonary edema, hypotension or shock algorithm
ANTIBIOTICS
The following table s of spe ctra of activity for diffe re nt antibiotics are g e ne ralizations.
Se nsitivity data at your own institution should be use d to g uide the rapy.
FORMULAE AND QUICK REFERENCE
CARDIOLOGY
Fick cardiac output

Oxygen consump tion (L/min) = CO (L/min) × arteriovenous (AV) oxygen difference
CO = oxygen consump tion/AV oxygen difference
Oxygen consump tion must be measured (can estimate w/ 12 5 mL/min/m 2 , but
inaccurate)
AV oxygen di erence = Hb (g/dL) × 10 (dL/L) × 1.36 (mL O 2 /g of Hb) × (S a O 2 —
S vO 2 )
S a O 2 is measured in any arterial samp le (usually 93—98 % )
S vO 2 (mixed venous O 2 ) is measured in RA, RV or PA (assuming no shunt) (nl
~75% )
PULMONARY
CXR in heart failure

• ↑ cardiac silhouette (in systolic dysfxn, not in diastolic)
• Pulmonary venous hyp ertension: cep halization of vessels (vessels size > bronchi in
up p er lobes), p eribronchial cuffing (fluid around bronchi seen on end → small
circles), Kerley B lines (horizontal 1—2 -cm lines at bases), ↑ vascular p edicle
width, loss of sharp vascular margins, p leural effusions (~75% bilateral)
• Pulmonary edema: ranges from ground glass to consolidation; often dep endent and
central, sp aring outer third (“bat wing” ap p earance)
Dead space = lung units that are ventilated but not p erfused
Intrapulmonary shunt = lung units that are p erfused but not ventilated
NEPHROLOGY
Anion gap (AG) = Na − (Cl + HCO 3) (normal = [alb] × 2 .5; typ ically 12 ± 2
mEq)
Delta-delta (ΔΔ) = [Δ AG (ie, calc. AG - exp ected) / Δ HCO 3 (ie, 2 4 - measured
HCO 3)]
Urine anion gap (UAG) = (U Na + U K) − U Cl
HEMATOLOGY
✓ PTT q6h after every Δ (t1⁄2 of hep arin ~90 min) and then qd or bid once PTT is
therap eutic
✓ CBC qd (to ensure Hct and p lt counts are stable)
Warfarin-heparin overlap therapy

• Indications: when failure to anticoagulate carries ↑ risk of morbidity or mortality
(eg, DVT/PE, intracardiac thrombus)
• Rationale: (1) Half-life of factor VII (3—6 h) is shorter than half-life of factor II (60—
72 h);
∴warfarin can elevate PT be fore achie ving a true antithrombotic state
(2 ) Protein C also has half-life less than that of factor II;
∴theoretical concern of hype rcoag ulable state before antithrombotic state

• Method: (1) Therap eutic PTT is achieved using hep arin
(2 ) Warfarin therap y is initiated
(3) Hep arin continued until INR therap eutic for ≥2 d and ≥4—5 d of
warfarin
(roughly corresp onds to ~2 half-lives of factor II or a reduction to ~2 5% )

OTHER
NOTES
ABBREVIATIONS
5′-NT 5′-nucleotidase
6-MP 6-mercaptopurine
AAA abdominal aortic aneurysm
AAD antiarrhythmic drug
Ab
antibody
ABE acute bacterial endocarditis
ABG arterial blood gas
abnl
abnormal
ABPA allergic bronchopulmonary aspergillosis
abx antibiotics
AC assist control
ACE angiotensin converting enzyme
ACEI ACE inhibitor
ACI
anemia of chronic inflammation
ACL
anticardiolipin antibody
ACLS
advanced cardiac life support
ACS
acute coronary syndrome
ACTH adrenocorticotrophic hormone
ACV acyclovir
ADA adenosine deaminase
ADH antidiuretic hormone

ADL activities of daily living
AF atrial fibrillation
AFB acid-fast bacilli
AFL atrial flutter
AFP ɑ-fetoprotein
AFTP
ascites fluid total protein
AG aminoglycoside
anion gap
Ag antigen
AGN
acute glomerulonephritis
AI aortic insufficiency
AIDS acquired immunodefic. synd.
AIH autoimmune hepatitis
AIHA autoimmune hemolytic anemia
AIN
acute interstitial nephritis
AIP
acute interstitial pneumonia
AKI
acute kidney injury
ALF acute liver failure
ALL
acute lymphoblastic leukemia
ALS amyotrophic lateral sclerosis
ALT alanine aminotransferase
AMA
anti-mitochondrial antibody
AMI anterior myocardial infarction
AML acute myelogenous leukemia
amy
amylase
ANA
antinuclear antibody
ANCA antineutrophilic cytoplasmic Ab
AoD aortic dissection
AoV aortic valve
APC activated protein C
APL
acute promyelocytic leukemia
APLA antiphospholipid Ab
APS
antiphospholipid Ab synd.
ARB
angiotensin receptor blocker
ARDS acute resp distress synd.
ARV
antiretroviral
ARVC arrhythmogenic RV CMP
AS
aortic stenosis
ASA
aspirin
ASD
atrial septal defect
AST aspartate aminotransferase
asx
asymptomatic
AT atrial tachycardia
ATII angiotensin II
ATIII
antithrombin III
ATN acute tubular necrosis
ATRA all-trans-retinoic acid
AV
atrioventricular
AVA aortic valve area
AVB atrioventricular block
AVNRT
AV nodal reentrant tachycardia
AVR aortic valve replacement
AVRT AV reciprocating tachycardia
a/w
associated with
AZA azathioprine
Aϕ
alkaline phosphatase
b/c because
BAL bronchoalveolar lavage
βB beta-blocker
BBB
bundle branch block
BCx blood culture
BD bile duct
BDZ
benzodiazepines
bili. bilirubin
BIPAP bilevel positive airway pressure
BIV biventricular
BM
bone marrow
bowel movement
BMD
bone mineral density
BMI
body mass index
BMS
bare metal stent
BNP
B-type natriuretic peptide
BOOP bronchiolitis obliterans with organizing

pneumonia
BP blood pressure
BPH benign prostatic hypertrophy
BRBPR
bright red blood per rectum
BS breath sounds
BT
bleeding time
BUN
blood urea nitrogen
bx
biopsy
BYCE buffered charcoal yeast extract
C′
complement
c/s consult
c/w compared with
consistent with
CABG
coronary artery bypass grafting
CAD coronary artery disease
CAH
congenital adrenal hyperplasia
CALLA
common ALL antigen
CAPD chronic ambulatory peritoneal dialysis
CBC
complete blood count
CBD common bile duct
CCB
calcium channel blocker
CCl4
carbon tetrachloride
CCP cyclic citrullinated peptide
CCS
Canadian Cardiovascular Society
CCY cholecystectomy
CD Crohn’s disease
CEA carcinoembryonic antigen

carotid endarterectomy
ceph.
cephalosporin
CF cystic fibrosis
Cftx
ceftriaxone
CFU
colony forming units
CHB
complete heart block
CHD
congenital heart disease
CHF congestive heart failure
CI cardiac index
CIAKI contrast-induced AKI
CIDP chronic inflammatory demyelinating

polyneuropathy
CJD Creutzfeldt-Jakob disease
CK creatine kinase
CKD
chronic kidney disease
CLL
chronic lymphocytic leukemia
CMC carpometacarpal (joint)
CML
chronic myelogenous leukemia
CMML chronic myelomonocytic leukemia
CMP cardiomyopathy
CMV cytomegalovirus
CN cranial nerve
CO
carbon monoxide
cardiac output
COP cryptogenic organizing PNA
COPD
chronic obstructive pulm dis.
COX
cyclo-oxygenase
CP chest pain
CPAP
continuous positive airway pressure
CPP cerebral perfusion pressure
CPPD calcium pyrophosphate dihydrate
Cr creatinine
CrAg cryptococcal antigen
CRC
colorectal cancer
CrCl creatinine clearance
CRP C-reactive protein
CRT
cardiac resynchronization therapy
CsA
cyclosporine A
CSF cerebrospinal fluid
CSM
carotid sinus massage
CT computed tomogram
CTA CT angiogram
CTD connective tissue disease
CV cardiovascular
CVA
cerebrovascular accident
CVD cerebrovascular disease
collagen vascular disease
CVID
common variable immunodefic.
CVP
central venous pressure
CVVH continuous veno-venous hemofiltration
CW
chest wall
cx culture
CXR chest radiograph
CYC cyclophosphamide
d day
D
death
∆MS change in mental status
DA dopamine
DAD
diffuse alveolar damage
DAH
diffuse alveolar hemorrhage
DAT direct antiglobulin test
DBP
diastolic blood pressure
d/c discharge
discontinue
DCIS ductal carcinoma in situ
DCMP dilated cardiomyopathy
Ddx
differential diagnosis
DES drug-eluting stent
DFA direct fluorescent antigen detection
DI
diabetes insipidus
DIC
disseminated intravascular coagulation
diff. differential
DIP
desquamative interstitial pneumonitis
distal interphalangeal (joint)
DKA diabetic ketoacidosis
DLCO
diffusion capacity of the lung
DLE drug induced lupus
DM
dermatomyositis
diabetes mellitus
DMARD disease-modifying anti-rheumatic drug
DOE
dyspnea on exertion
DRE
digital rectal exam
DRESS drug reaction w/ eosinophilia & systemic

symptoms
DSE dobutamine stress echo
DST dexamethasone suppression test
DTRs
deep tendon reflexes
DU duodenal ulcer
DVT
deep vein thrombosis
dx diagnosis
EAD extreme axis deviation
EAV effective arterial volume
EBV
Epstein-Barr virus
ECG
electrocardiogram
ECMO extracorporeal membrane oxygenation
ED emergency department
EDP end-diastolic pressure
EDV end-diastolic volume
EEG electroencephalogram
EF
ejection fraction
EGD esophagogastroduodenoscopy
EGFR
epidermal growth factor receptor
EGPA
eosinophilic granulomatosis with polyangiitis
EI
entry inhibitor
EIA
enzyme-linked immunoassay
ELISA
enzyme-linked immunosorbent assay
EM electron microscopy
EMB
ethambutol
ENT ears, nose, & throat
EOM extraocular movement/muscles
EP
electrophysiology
Epo erythropoietin
EPS electrophysiology study
ERCP endoscopic retrograde

cholangiopancreatography
ERV
expiratory reserve volume
ESP
end-systolic pressure
ESR erythrocyte sedimentation rate
ESRD
end-stage renal disease
ESV end-systolic volume
ET endotracheal tube
essential thrombocythemia
EtOH alcohol
ETT
endotracheal tube
exercise tolerance test
EUS endoscopic ultrasound
EVAR
endovascular aneurysm repair
FDP
fibrin degradation product
FEV1
forced expir. vol in 1 sec
FFP fresh frozen plasma
FHx
family history
FI fusion inhibitor
FMD fibromuscular dysplasia

FMF familial Mediterranean fever
FNA
fine needle aspiration
FOB fecal occult blood
FOBT
fecal occult blood testing
FQ fluoroquinolone
FRC functional residual capacity
FSGS
focal segmental glomerulosclerosis
FSH follicle stimulating hormone
FTI free thyroxine index
FUO
fever of unknown origin
f/up follow-up
FVC forced vital capacity
G6PD
glc-6-phosphate dehydrogenase
GB gallbladder
GBM
glomerular basement membrane
GBS
Guillain-Barré syndrome
GCA giant cell arteritis
GCS Glasgow coma scale
G-CSF
granulocyte colony stimulating factor
GE gastroesophageal
gen. generation
GERD
gastroesophageal reflux disease
GFR
glomerular filtration rate
GGT
γ-glutamyl transpeptidase
GH
growth hormone
GIB gastrointestinal bleed
GIST gastrointestinal stromal tumor
glc
glucose
GMCSF granulocyte-macrophage colony-stimulating

factor
GN
glomerulonephritis
GNR gram-negative rods
GnRH gonadotropin-releasing hormone

GPA granulomatosis w/ polyangiitis
GPC gram-positive cocci
GPI
glycoprotein IIb/IIIa inhibitor
GRA
glucocorticoid-remediable aldosteronism
GU
gastric ulcer
GVHD
graft-versus-host disease
h hour
H2RA H2-receptor antagonist
HA
headache
HACA human antichimeric antibody
HAV hepatitis A virus

Hb hemoglobin
HBIG hepatitis B immunoglobulin
HBV hepatitis B virus
HCC hepatocellular carcinoma
HCMP
hypertrophic cardiomyopathy
Hct
hematocrit
HCV
hepatitis C virus
HCW health care worker
HD
hemodialysis
HDL high-density lipoprotein
HDV hepatitis Δ virus

HELLP hemolysis, abnl LFTs, low plts
HEV hepatitis E virus
HF heart failure
HGPRT hypoxanthine-guanine phosphoribosyl

transferase
HHS
hyperosmolar hyperglycemic state
HIT
heparin-induced thrombocytopenia
HK hypokinesis
HL
Hodgkin lymphoma
h/o history of
HOB head of bed
HoTN
hypotension
hpf high power field
HPT
hyperparathyroidism
HR heart rate
HRT
hormone replacement therapy
HS
hereditary spherocytosis
HSCT
hematopoietic stem cell transplantation
HSM hepatosplenomegaly
HSP
Henoch-Schönlein purpura
HSV herpes simplex virus
HTN hypertension
HUS
hemolytic uremic syndrome
hx history
I&D
incision & drainage
IABP intra-aortic balloon pump
IBD
inflammatory bowel disease
IBS
irritable bowel syndrome
IC
inspiratory capacity
ICa ionized calcium
ICD
implantable cardiac defibrillator
ICH intracranial hemorrhage
ICP intracranial pressure
ICU
intensive care unit
IE infective endocarditis
IGF
insulin-like growth factor
IGRA interferon-g release assay
II
integrase inhibitor
IIP
idiopathic interstitial PNA
ILD
interstitial lung disease
IMI inferior myocardial infarction
infxn
infection
inh inhaled
INH isoniazid
INR
international normalized ratio
IPAA ileal pouch-anal anastomosis
IPF
idiopathic pulmonary fibrosis
ITP idiopathic thrombocytopenic purpura
IVB
intravenous bolus
IVC
inferior vena cava
IVDU
intravenous drug use(r)
IVF intravenous fluids
IVIg
intravenous immunoglobulin
JVD jugular venous distention
JVP jugular venous pulse
KUB
kidney-ureter-bladder (radiography)
KS Kaposi’s sarcoma
LA
left atrium
long-acting
lupus anticoagulant
LABA long-acting β2-agonist
LAD
left anterior descending coronary artery
left axis deviation
LAE left atrial enlargement
LAN
lymphadenopathy
LAP left atrial pressure
leukocyte alkaline phosphatase

LBBB left bundle branch block
LCA left coronary artery
LCIS
lobular carcinoma in situ
LCx left circumflex cor. art.
LDH lactate dehydrogenase
LDL
low-density lipoprotein
LE lower extremity
LES lower esophageal sphincter
LFTs
liver function tests
LGIB lower gastrointestinal bleed
LH
luteinizing hormone
LLQ left lower quadrant
LM left main coronary artery
LMWH low-molecular-weight heparin
LN
lymph node
LOC
loss of consciousness
LOS
length of stay
LP lumbar puncture
lpf low power field
LR lactated Ringer’s
LQTS long QT syndrome

LUSB left upper sternal border
LV left ventricle
LVAD LV assist device
LVEDP LV end-diastolic pressure
LVEDV LV end-diastolic volume
LVH
left ventricular hypertrophy
LVOT
left ventricular outflow tract
LVSD LV systolic dimension
mAb
monoclonal antibody
MAC mitral annular calcification
Mycobacterium avium complex

MAHA microangiopathic hemolytic anemia
MALT mucosa-assoc. lymphoid tissue
MAO monoamine oxidase
MAP
mean arterial pressure
MAT multifocal atrial tachycardia
MCD
minimal change disease
MCP metacarpal phalangeal (joint)
MCTD mixed connective tissue dis.
MCV
mean corpuscular volume
MDI metered dose inhaler

MDMA 3,4-methylenedioxymetham-phetamine
(Ecstasy)
MDR
multidrug resistant
MDS myelodysplastic syndrome
MEN
multiple endocrine neoplasia
MG
myasthenia gravis
MGUS monoclonal gammopathy of uncertain

significance
MI myocardial infarction
min minute
min. minimal
MM multiple myeloma
MMEFR
max. mid-expir. flow rate
MMF mycophenolate mofetil
MN membranous nephropathy
MNZ metronidazole
mod.
moderate
MODS multiple organ dysfxn synd.
mo month
MPA microscopic polyangiitis
MPN myeloproliferative neoplasm
MPGN membranoproliferative glomerulonephritis
MR
magnetic resonance
mitral regurgitation
MRA magnetic resonance angiography
MRCP
MR cholangio-pancreatography
MRI
magnetic resonance imaging
MRSA
methicillin-resistant S. aureus
MS mitral stenosis
MTb
Mycobacterium tuberculosis
MTP metatarsal phalangeal (joint)
MTX methotrexate
MV
mitral valve
MVA mitral valve area
MVP mitral valve prolapse

MVR mitral valve replacement
Mϕ macrophage
N/V nausea and/or vomiting
NAC
N-acetylcysteine
NAFLD non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
NG nasogastric
NGT
nasogastric tube
NHL Non-Hodgkin lymphoma
NIDCM non-ischemic dilated CMP
NIF negative inspiratory force

NJ nasojejunal
nl normal
NM neuromuscular
NMJ
neuromuscular junction
NNRTI non-nucleoside reverse transcriptase inhibitor
NNT
number needed to treat
NO
nitric oxide
NPJT nonparoxysmal junctional tachycardia
NPO nothing by mouth
NPV negative predictive value
NS normal saline
NSAID
nonsteroidal anti-inflam. drug
NSCLC
non-small cell lung cancer
NYHA New York Heart Association
NPPV
noninvasive positive pressure ventilation
NRTI
nucleoside reverse transcriptase inhibitor
NSF nephrogenic systemic fibrosis
NTG nitroglycerin
NUD nonulcer dyspepsia
NVE native valve endocarditis
O&P ova & parasites
OA
osteoarthritis
OCP oral contraceptive pill

O/D
overdose
OG osmolal gap
OGT
orogastric tube
OGTT oral glucose tolerance test
OI opportunistic infection
OM
obtuse marginal cor. art.
OSA obstructive sleep apnea
OTC over-the-counter
o/w
otherwise
PA pulmonary artery
PAC pulmonary artery catheter

PAD peripheral artery disease
PAN
polyarteritis nodosa
PASP
PA systolic pressure
PAV percutaneous aortic valvuloplasty
pb
problem
PBC
primary biliary cirrhosis
PCI percutaneous coronary intervention
PCN
penicillin
PCP Pneumocystis jiroveci pneumonia
PCR polymerase chain reaction
PCT porphyria cutanea tarda

PCWP pulmonary capillary wedge pressure
PD
Parkinson’s disease
peritoneal dialysis
PDA
patent ductus arteriosus
posterior descending cor. art.
PE
pulmonary embolism
PEA
pulseless electrical activity
PEEP positive end-expiratory pressure
PEF peak expiratory flow
PET positron emission tomography
PEx physical examination

PFO patent foramen ovale
PFT
pulmonary function test
PGA
polyglandular autoimmune syndrome
PHT
pulmonary hypertension
PI
protease inhibitor
PID pelvic inflammatory disease
PIF prolactin inhibitory factor
PIP peak inspiratory pressure
proximal interphalangeal (joint)
PKD polycystic kidney disease
PM
polymyositis
PMF primary myelofibrosis
PMHx
past medical history
PMI
point of maximal impulse
PML
progressive multifocal leukoencephalopathy
PMN polymorphonuclear leukocyte
PMR polymyalgia rheumatica
PMV
percutaneous mitral valvuloplasty
PMVT polymorphic ventricular tachycardia
PNA pneumonia
PND
paroxysmal nocturnal dyspnea
PNH paroxysmal nocturnal hemoglobinuria
PNS
peripheral nervous system
PO oral intake
POBA
plain old balloon angioplasty
POTS postural orthostatic tachycardia syndrome
PPD purified protein derivative
PPH
primary pulmonary HTN
PPI proton pump inhibitors
P plat
plateau pressure
PPM
permanent pacemaker
PPV positive predictive value
Ppx prophylaxis
PR PR segment on ECG
pulmonary regurgitation
PRBCs
packed red blood cells
PRL
prolactin
PRPP
phosphoribosyl-I-pyrophosphate
PRWP
poor R wave progression
PS
pressure support
pulmonic stenosis
PsA Pseudomonas aeruginosa
PSA prostate specific antigen
PSC primary sclerosing cholangitis
PSGN post streptococcal glomerulonephritis

PSHx past surgical history
PSV
pressure support ventilation
Pt patient
PT
prothrombin time
PTA
percutaneous transluminal angioplasty
PTH parathyroid hormone
PTH-rP PTH-related peptide
PTT
partial thromboplastin time
PTU propylthiouracil
PTX pneumothorax
PUD
peptic ulcer disease
PUVA psoralen + ultraviolet A
PV
polycythemia vera
portal vein
PVD
peripheral vascular disease
PVE prosthetic valve endocarditis
PVR pulmonary vascular resistance
p/w
present(s) with
PZA pyrazinamide
qac before every meal
qhs
every bedtime
QoL quality of life

Qw Q wave
RA
refractory anemia
rheumatoid arthritis
right atrium
RAA renin-angiotensin-aldosterone
RAD
right axis deviation
RAE right atrial enlargement
RAI radioactive iodine
RAIU
radioactive iodine uptake
RAS renal artery stenosis
RAST radioallergosorbent test

RBBB right bundle branch block
RBC
red blood cell
RBF renal blood flow
RBV ribavirin
RCA
right coronary artery
RCMP
restrictive cardiomyopathy
RCT randomized controlled trial
RDW
red cell distribution width
RE reticuloendothelial
RF
rheumatoid factor
risk factor
RHD rheumatic heart disease
r/i
rule in
RI
reticulocyte index
RIBA
recombinant immunoblot assay
RMSF
Rocky Mountain spotted fever
r/o
rule out
ROS
review of systems
RPGN rapidly progressive glomerulonephritis
RR
respiratory rate
RRT renal replacement therapy
RT radiation therapy
RTA
renal tubular acidosis
RTX
rituximab
RUQ right upper quadrant
RUSB right upper sternal border
RV
residual volume
right ventricle
RVAD RV assist device
RVH
right ventricular hypertrophy
RVOT RV outflow tract
RVSP RV systolic pressure
Rx
therapy
RYGB roux-en-Y gastric bypass

SA
sinoatrial
SAAG serum-ascites albumin gradient
SAH subarachnoid hemorrhage
SAS sulfasalazine
SBE subacute bacterial endocarditis
SBO
small bowel obstruction
SBP spontaneous bacterial peritonitis
systolic blood pressure
SBT
spontaneous breathing trial
SC subcutaneous
SCD
sudden cardiac death
SCID
severe combined immunodefic.
SCLC
small cell lung cancer
s/e side effect
Se sensitivity
sec
second
SERM
selective estrogen receptor modulator
sev. severe
SHBG
steroid hormone binding globulin
SIADH synd. of inappropriate ADH
SIBO
small intestine bacterial overgrowth
SIEP serum immunoelectrophoresis

SIMV synchronized intermittent mandatory
ventilation
SIRS
systemic inflammatory response syndrome
SJS Stevens-Johnson syndrome
SLE
systemic lupus erythematosus
SMA
superior mesenteric artery
SMV superior mesenteric vein
SMX sulfamethoxazole
SOS
sinusoidal obstructive synd.
s/p status post
Sp specificity
SPEP
serum protein electrophoresis
SR sinus rhythm
s/s
signs and symptoms
SSCY Salmonella, Shigella, Campylobacter, Yersinia
SSRI
selective serotonin reuptake inhibitor
SSS
sick sinus syndrome
ST sinus tachycardia
STD sexually transmitted disease
ST-segment depression
STE ST-segment elevation
SV stroke volume
SVC
superior vena cava
SVR systemic vascular resistance
SVT
supraventricular tachycardia
sx symptom(s) or symptomatic
T1D
type 1 diabetes mellitus
T2D
type 2 diabetes mellitus
T 3RU T3 resin uptake
TAA
thoracic aortic aneurysm
TB tuberculosis
TBG thyroid binding globulin
TCA tricyclic antidepressant
TCD transcranial Doppler

TCN tetracycline
Tdap tetanus, diphtheria, pertussis
TdP
torsades de pointes
TdT
terminal deoxynucleotidyl transferase
TEE
transesophageal echo
TFTs
thyroid function tests
TG
triglycerides
TGA transposition of the great arteries
TIA transient ischemic attack
TIBC total iron binding capacity
TINU tubulointerstitial nephritis and uveitis

TIPS transjugular intrahepatic portosystemic shunt
TLC total lung capacity
TMP
trimethoprim
Tn
troponin
TP
total protein
TPMT
thiopurine methyltransferase
TPN
total parenteral nutrition
Tpo thrombopoietin
TPO thyroid peroxidase
TR tricuspid regurgitation
TRALI transfusion-related acute lung injury

TRH thyrotropin releasing hormone
TRS TIMI risk score
TRUS
transrectal ultrasound
TS
tricuspid stenosis
TSH
thyroid stimulating hormone
TSI
thyroid-stimulating immunoglobulin
TSS
toxic shock syndrome
transsphenoidal surgery
TTE transthoracic echo
TTKG transtubular potassium gradient
TTP thrombotic thrombocytopenic purpura

TV tricuspid valve
Tw T wave
TWF
T-wave flattening
TWI
T-wave inversion
Tx
transplant
TZD
thiazolidinediones
U/A
urinalysis
U/S ultrasound
UA unstable angina
uric acid
UAG urine anion gap

UC ulcerative colitis
UCx urine culture
UES
upper esophageal sphincter
UFH
unfractionated heparin
UGIB
upper gastrointestinal bleed
UIP
usual interstitial pneumonitis
ULN
upper limit of normal
UOP urine output
UPEP urine protein electrophoresis
UR urgent revascularization
URI upper resp. tract infxn

UTI urinary tract infection
V/Q ventilation-perfusion
VAD
ventricular assist device
VAP
ventilator-associated PNA
VATS
video-assisted thoracoscopic surgery
VBI
vertebrobasilar insufficiency
VC
vital capacity
VD vessel disease
VDRL venereal disease research laboratory (test for

syphilis)
VEGF vascular endothelial growth factor
VF
ventricular fibrillation
VLDL very-low-density lipoproteins
VOD veno-occlusive disease
VS
vital signs
VSD
ventricular septal defect
VT
tidal volume
VT ventricular tachycardia
VTE
venous thromboembolus
vWD von Willebrand’s disease
vWF von Willebrand’s factor
VZV
varicella zoster virus
w/ with
WBC white blood cell (count)
WCT wide-complex tachycardia
WHO
World Health Organization
wk
week
WM Waldenström’s macroglobulinemia
WMA
wall motion abnormality
w/o without
WPW Wolff-Parkinson-White syndrome
w/u
workup
XRT radiation therapy

INDEX
A
A-a gradient, 2 -18 , 11-5
abdominal CT scan, P-7
abdominal p ain, 10-1
acanthosis nigricans, 5-2 8
accessory p athway, 1-33
acetaminop hen
as cause of metabolic acidosis, 4-2
hep atotoxicity, 3-19
achalasia, 3-1
acid-base disturbances, 4-1
ACLS, ACLS-1
acquired immunodeficiency syndrome (AIDS), 6-17
acromegaly, 7-2
activated p rotein C
resistance, 5-11
therap y, 2 -2 3
acute coronary syndromes, 1-6
acute interstitial nep hritis, 4-12
acute interstitial p neumonia, 2 -10
acute kidney injury, 4-12
acute resp iratory distress syndrome (ARDS), 2 -2 2
acute tubular necrosis, 4-12
Addison’s disease, 7-9
adnexal mass, non-p regnant woman, 10-3
adrenal disorders, 7-7
adrenal incidentalomas, 7-10
adrenal insufficiency, 7-9
adrenal mass, 7-10
advanced cardiac life sup p ort, ACLS-1
albuminuria, 4-13
alcohol withdrawal, 9-5
allergic bronchop ulmonary asp ergillosis, 2 -10
alp ha 1-antitryp sin deficiency
as cause of cirrhosis, 3-2 4
as cause of COPD, 2 -5
alveolar gas equation, 11-5
amaurosis fugax, 9-6
amiodarone, thyroid disease and, 7-5
amyloidosis, 8 -2 2
cardiac manifestations, 1-19
anap hylaxis, 2 -4
anap lasmosis, 6-2 1
anemia, 5-1
ap lastic, 5-3
autoimmune hemolytic, 5-5, P-13
of chronic inflammation, 5-2
Cooley’s, 5-2
Fanconi’s, 5-3
folate deficiency, 5-3
hemolytic, 5-4
iron deficiency, 5-1, P-13
macrocytic, 5-3
megaloblastic, 5-3, P-13
microangiop athic hemolytic, 5-5
microcytic, 5-1
myelop hthisic, 5-4
normocytic, 5-2
p ernicious, 5-3
sickle cell, 5-4, P-14
sideroblastic, 5-2
angina, 1-6
angiodysp lasia, 3-3
angiop lasty, 1-5
anion gap , 4-2 , 11-6
ankylosing sp ondylitis, 8 -7
anoxic brain injury, 9-2
antibiotics, 11-3
antibodies
anticardiolip in, 5-11, 8 -16
anti-CCP, 8 -3
anti-centromere, 8 -11
anti-citrullinated p ep tide (ACPA), 8 -3
anti-ds-DNA, 8 -15
anti-GBM, 4-16
antihistone, 8 -15
anti-Jo-1, 8 -13
anti-La, 8 -14, 8 -15
anti-Mi-2 , 8 -13
antimitochondrial, 3-2 4
anti-MPO, 4-16, 8 -18
antineutrop hil cytop lasmic (ANCA), 4-16, 8 -18
antinuclear (ANA), 8 -15
antip hosp holip id, 5-11
anti-PR3, 4-16, 8 -18
anti-Ro, 8 -14, 8 -15
anti-Scl-70, 8 -11
anti-Sm, 8 -15
anti-smooth muscle, 3-19
anti-TPO, 7-3, 7-4, 7-5, 7-6
anti-U1-RNP, 8 -14, 8 -15
autoantibodies, 8 -2
in connective tissue diseases, 8 -11
anticoagulants, 5-6, 5-10
anti-GBM disease, as cause of glomerulonep hritis, 4-16
antip hosp holip id syndrome, 5-11
aortic aneurysm, 1-30
aortic dissection, 1-31
aortic insufficiency, 1-2 1
aortic stenosis, 1-2 0
aortoenteric fistula, 3-3
arrhythmogenic RV cardiomyop athy, 1-34
arthralgias, 8 -1
arthritis, 8 -1
IBD-associated (enterop athic), 8 -8
infectious, 8 -9
osteoarthritis, 8 -1
p soriatic, 8 -7
reactive, 8 -7
rheumatoid, 8 -3
asbestosis, 2 -10
ascites, 3-2 6
treatment of, in cirrhotics, 3-2 1
asp ergillosis, 6-4
asp lenia, 6-4
asthma, 2 -2
asystole, ACLS-2
atrial fibrillation, 1-32 , 1-35
atrial flutter, 1-32
auto-PEEP, 2 -2 0
AV block, 1-32
AV dissociation, 1-32
B
babesiosis, 6-2 1
back p ain, 9-11
bacteremia, 6-14
Barrett’s esop hagus, 3-2
Bartter’s syndrome, 4-5, 4-10, 7-8
basop hilia, 5-12
basop hilic stip p ling, 11-6
Beck’s triad, 1-2 6
Behçet’s syndrome, 8 -2 0
Bell’s p alsy, 6-11
Bernard-Soulier disease, 5-9
berylliosis, 2 -10
bilevel p ositive airway p ressure (BiPAP), 2 -2 0
biliary tract disease, 3-2 7
bite cells, 5-4, 11-6
biventricular p acing, 1-16, 1-39
blastomycosis, 6-3
body surface area, 11-7
Boerhaave syndrome, 1-3
bone infections, 6-6
bone marrow transp lantation, 5-2 6
bradycardia, 1-32 , ACLS-1
breast cancer, 5-30
Brockenbrough sign, 1-18
bronchiectasis, 2 -7
bronchiolitis obliterans with organizing p neumonia, 2 -10
bronchitis, chronic, 2 -5
Brudzinski’s sign, 6-9
Brugada syndrome, 1-34
B-typ e natriuretic p ep tide, 1-14, 2 -1
Budd-Chiari syndrome, 3-2 5
bundle branch blocks, 1-1
burr cells, 11-6
bursitis, 8 -1, 8 -10
C
calcip hylaxis, 7-11
calcium disorders, 7-11
calcium p yrop hosp hate dihydrate dep osition disease, 8 -6
cancer of unknown p rimary site, 5-37
Candida infections, 6-3
carbon monoxide p oisoning, 2 -18
cardiac outp ut, 1-12 , 11-4
cardiac resynchronization therap y, 1-16, 1-39
cardiomyop athy, 1-17
arrhythmogenic RV, 1-17
dilated, 1-17
hyp ertrop hic, 1-18
p erip artum, 1-17
restrictive, 1-19
vs constrictive p ericarditis, 1-2 7
Takotsubo, 1-17
cardioversion, ACLS-1
carotid revascularization, 9-7
cauda equina syndrome, 9-11
celiac disease, 3-6
cellulitis, 6-6
central venous catheter-related infections, 6-14
cerebrovascular disease, 9-6
Chagas, 1-17
Charcot’s triad, 3-2 8
Chediak-Higashi syndrome, 5-9
chemotherap y side effects, 5-34
chest p ain, 1-3
chest tubes, 10-2
Child-Turcotte-Pugh scoring system, 3-2 3
cholangitis, 3-2 8
cholecystitis, 3-2 7
choledocholithiasis, 3-2 8
cholelithiasis, 3-2 7
cholera, 3-5
cholestasis, 3-15
cholesterol emboli syndrome, 1-5
chronic kidney disease, 4-13
chronic obstructive p ulmonary disease (COPD), 2 -5, P-1
Churg-Strauss syndrome, 8 -19
as cause of asthma, 2 -2
as cause of glomerulonep hritis, 4-16
as cause of interstitial lung disease, 2 -10
Chvostek’s sign, 7-12
cirrhosis, 3-2 1
claudication, neurogenic vs. vascular, 9-12
clostridial myonecrosis, 6-7
Clostridium difficile -associated diarrhea, 3-6
coagulation cascade, 5-6
coagulop athies, 5-10
coarctation of aorta, 1-2 8
coccidioidomycosis, 6-3
cold calorics, 9-1
colonoscop y, screening, 5-33
colorectal cancer, 5-33
coma, 9-1
comp artment syndrome, 10-2
comp uted tomograp hy angiograp hy, 1-3, 1-4
confusion, 9-1
connective tissue diseases, 8 -11
Conn’s syndrome, 7-8
constip ation, 3-8
constrictive p ericarditis, 1-2 6
continuous p ositive airway p ressure (CPAP), 2 -19, 2 -2 0
continuous veno-venous hemofiltration, 4-15
contrast-induced acute kidney injury, 4-12
conus medullaris syndrome, 9-11
cord comp ression, 5-36, 9-11
corneal acrus, 7-16
coronary angiograp hy, 1-5, P-13
coronary arteries, P-13
coronary artery byp ass grafting (CABG), 1-5
coronary artery calcium score, 1-4
coronary revascularization, 1-5
Courvoisier’s sign, 5-35
creatinine clearance, 11-6
CREST syndrome, 8 -12
Crohn’s disease, 3-10
cryoglobulinemia, 8 -2 1
Cryptococcus, 6-3
cryp togenic organizing p neumonia, 2 -10
crystal dep osition arthritides, 8 -5
Cullen’s sign, 3-13
Cushing’s reflex, 3-2 0
Cushing’s syndrome, 7-7
cutaneous leukocytoclastic angiitis, 8 -2 0
CXR/chest CT scan, 11-5, P-1, P-5
cyanide p oisoning, 2 -18
cyanosis, 2 -18
cystic fibrosis, 2 -7
cystitis, 6-5
cytomegalovirus, 6-19
D
dactylitis, 8 -7
deep venous thrombosis, 2 -13
delirium, 9-1
delirium tremens, 9-5
delta-delta, 4-2 , 11-6
dementia, 9-1
dengue, 6-2 3
dermatomyositis, 8 -12
desquamative interstitial p neumonia, 2 -10
diabetes insip idus, 4-8 , 4-9
diabetes mellitus, 7-13
diabetic foot, 6-6
diabetic ketoacidosis (DKA), 7-14
dialysis, 4-15
diarrhea, 3-5
Dieulafoy’s lesion, 3-3
diffuse alveolar damage, 2 -2 2
diffuse alveolar hemorrhage, 2 -10, 5-2 6
dip lop ia, 10-4
disc herniation, 9-12
discriminant function, 3-19
disseminated gonococcal arthritis, 8 -10
disseminated intravascular coagulation (DIC), 5-10
diuresis, 4-14
diverticular disease, 3-9
Döhle bodies, 11-6
doll’s eyes, 9-1
Dressler’s syndrome, 1-11, 1-2 5
Duke treadmill score, 1-4
duodenal ulcer, 3-2
dyslip idemias, 7-16
dysp ep sia, 3-2
dysp hagia, 3-1
dysp nea, 2 -1
dysuria, 6-5
E
Eaton-Lambert syndrome, 5-2 8 , 9-9
echocardiograp hy, P-9
Ehlers-Danlos syndrome, 1-31
ehrlichiosis, 6-2 1
electrocardiograp hy, 1-1
encep halitis, viral, 6-11
endocarditis, 6-12
endomyocardial fibrosis, 1-19
enthesitis, 8 -7
eosinop hilia, 5-12
eosinop hilic granulomatosis with p olyangiitis, 8 -19
as cause of asthma, 2 -2
eosinop hilic p neumonias, 2 -10
ep idural abscess, 6-8
ep idural hematoma, 9-7
ep ilep sy, 9-3
erysip elas, 6-6
erythema migrans, 6-2 0
erythema multiforme, 6-2 3
erythema nodosum, 2 -9, 6-2 3, 8 -2 0
erythrocyte sedimentation rate, 8 -17
erythromelalgia, 5-15
esop hageal reflux, 3-1
esop hageal ring, 3-1
esop hageal sp asm, 1-3
esop hageal web, 3-1
esop hagitis, 3-1, 3-3
essential thrombocythemia, 5-15
ethylene glycol intoxication, 4-2
exercise tolerance test, 1-4
F
factor V Leiden, 5-11
familial adenomatous p olyp osis, 5-33
familial hyp ocalciuric hyp ercalcemia, 7-11
familial Mediterranean fever, 6-2 2
Fanconi’s syndrome, 4-3
Felty’s syndrome, 8 -3
fever
neutrop enia and, 5-36
Pel-Ebstein, 5-2 1
fever syndromes, 6-2 2
fibromyalgia, 8 -13
Fitz-Hugh-Curtis syndrome, 8 -10
focal segmental glomerulosclerosis, 4-17
folate deficiency, 5-3
folliculitis, 6-6
food p oisoning, 3-5
Forrester class, 1-11
Fournier’s gangrene, 6-7
fractional excretion of Na, 4-12 , 11-6
free H 2 O deficit, 4-8 , 11-6
fungal infections, 6-3
furunculosis, 6-6
G
Gaisböck’s syndrome, 5-15
Gallavardin effect, 1-2 0
gallstone, 3-2 7
gallstone ileus, 3-2 7
gas gangrene, 6-7
gastric antral vascular ectasia, 3-3
gastric ulcer, 3-2
gastritis, 3-3
gastroesop hageal reflux disease (GERD), 3-1
gastrointestinal bleeding, 3-3
gastrostomy tubes, 10-2
giant cell arteritis, 8 -17
Gitelman’s syndrome, 4-5, 4-10, 7-8
Glanzmann’s thromboasthenia, 5-9
Glasgow Coma Scale, 9-1
glomerulonep hritis, 4-16
glucagonoma
as cause of diabetes mellitus, 7-13
as cause of diarrhea, 3-7
glucose-6-p hosp hate dehydrogenase (G6PD) deficiency, 5-4
glycemic control, in critical care, 2 -2 3
goiter, 7-4, 7-5
Goodp asture’s syndrome
as cause of alveolar hemorrhage, 2 -10
Gottron’s p ap ules, 8 -13
gout, 8 -5
graft-ve rsus-host disease (GVHD), 5-2 6, 5-2 7
granulomatosis with p olyangiitis, 8 -18
Graves’ disease, 7-4
Grey Turner’s sign, 3-13
Guillain-Barré syndrome, 9-8
H
Hamman-Rich syndrome, 2 -10
Hashimoto’s thyroiditis, 7-4
headache, 9-10
heart failure, 1-14
with p reserved EF, 1-16
heart valve anatomy, 1-2 4
Heinz bodies, 5-4, 11-6
He licobacte r pylori infection, 3-2
heliotrop e rash, 8 -13
hematemesis, 3-3
hematochezia, 3-3
hematop oietic stem cell transp lantation, 5-2 6
hematuria, 4-19
hemochromatosis
as cause of cirrhosis, 3-2 3
as cause of DCMP, 1-17
as cause of RCMP, 1-19
hemodialysis, 4-15
hemolytic-uremic syndrome, 5-9
hemop hilia, 5-10
hemop tysis, 2 -7
hemostasis disorders, 5-6
Henoch-Schönlein p urp ura, 8 -19
hep arin-induced thrombocytop enia, 5-8
hep arin nomograms, 11-7
hep atic encep halop athy, 3-2 2
hep atic hydrothorax, 2 -11, 3-2 1
hep atitis, 3-17
alcoholic, 3-19
autoimmune, 3-19
ischemic, 3-19
viral, 3-17
hep atocellular carcinoma, 3-2 2
hep atop ulmonary syndrome, 3-2 3
hep atorenal syndrome, 3-2 2
hereditary nonp olyp osis colorectal cancer, 5-33
hereditary sp herocytosis, 5-5
Hermansky-Pudlak syndrome, 5-9
herp es zoster, 6-11
histop lasmosis, 6-3
Howell-Jolly bodies, 11-6
human immunodeficiency virus (HIV), 6-17
hyp eraldosteronism, 7-8
as cause of hyp okalemia, 4-10
as cause of metabolic alkalosis, 4-4
hyp erbilirubinemia, 3-16
hyp ercalcemia, 7-11
hyp ercap nia, 2 -18
hyp ercholesterolemia, 7-16
hyp ercoagulable states, 5-11
hyp ercortisolism, 7-7
hyp erhomocysteinemia, 5-11
hyp erkalemia, 4-11
hyp ernatremia, 4-8
hyp erosmolar hyp erglycemic state, 7-15
hyp erp arathyroidism, 7-11
secondary, 4-14
hyp erp ituitary syndrome, 7-2
hyp erp rolactinemia, 7-2
hyp ersensitivity p neumonia, 2 -10
hyp ersensitivity vasculitis, 8 -2 0
hyp ersp lenism, 5-5
hyp ertension, 1-2 8
hyp ertensive crisis, 1-2 9
hyp erthyroidism, 7-4
hyp ertriglyceridemia, 7-16
hyp ertrop hic p ulmonary osteoarthrop athy, 5-2 8
hyp oaldosteronism, 7-9
as cause of hyp erkalemia, 4-11
as cause of metabolic acidosis, 4-3
hyp ocalcemia, 7-12
hyp oglycemia, 7-15
hyp okalemia, 4-10
hyp onatremia, 4-6
hyp op arathyroidism, 7-12
hyp op ituitary syndromes, 7-1
hyp othermia, induced, 9-2
hyp othyroidism, 7-4
hyp oxemia, 2 -18
I
ICU medications, 11-1
ideal body weight, 11-7
idiop athic interstitial p neumonia, 2 -10
idiop athic p ulmonary fibrosis, 2 -10
IgA nep hrop athy, 4-17
IgG4-related disease, 8 -2 0
ileus, 3-8
immune thrombocytop enic p urp ura, 5-7
imp etigo, 6-6
imp lantable cardiac defibrillator, 1-16, 1-39
inclusion body myositis, 8 -12
infections in suscep tible hosts, 6-4
inflammatory bowel disease, 3-10
inflammatory markers, 8 -2
influenza, 6-2
interstitial lung disease, 2 -9
intracardiac shunts, 11-4
intracranial hemorrhage, 9-7
intraductal p ap illary mucinous neop lasm, 5-35
intramural hematoma (aortic), 1-31
iron deficiency, 5-1
irritable bowel syndrome (IBS), 3-7
ischemic colitis, 3-12
isop rop yl alcohol intoxication, 4-3
J
Janeway lesions, 6-12
jaundice, 3-15
Jod-Basedow effect, 7-6
joint fluid, 8 -1
K
Kap osi’s sarcoma, 6-19
Kernig’s sign, 6-9
ketoacidosis, 4-2
kidney transp lantation, 4-15
Killip class, 1-11
koilonychia, 5-1
Kussmaul’s sign, 1-2 7
L
lactic acidosis, 4-2
lactose intolerance, 3-6
Langerhans cell granulomatosis, 2 -10
left ventricular hyp ertrop hy, ECG criteria, 1-1
left ventricular thrombus, 1-11
leukemia, 5-17, P-14
acute lymp hoblastic, 5-18
acute myelogenous, 5-17
acute p romyelocytic, 5-18
chronic lymp hocytic, 5-2 0
chronic myelogenous, 5-19
hairy cell, 5-2 2
leukostasis, 5-17
Libman-Sacks endocarditis, 8 -15
Liddle’s syndrome, 4-5, 4-10, 7-8
Light’s criteria, 2 -11
limb ischemia, acute, 1-41, 10-1
lip odystrop hy, 6-19
liver failure, 3-2 0
liver tests, abnormal, 3-15
liver transp lantation, 3-2 3
Loeys-Dietz syndrome, 1-31
Löffler’s endocarditis, 1-19
Löffler’s syndrome, 2 -10
Löfgren’s syndrome, 2 -9
long QT syndrome, 1-34
lung cancer, 5-2 8
lup us anticoagulant, 5-11
lup us p ernio, 2 -9
Lyme disease, 6-2 0
lymp hadenop athy, 5-12
lymp hangioleiomyomatosis, 2 -10
lymp hocytic interstitial p neumonia, 2 -10
lymp hocytosis, 5-12
lymp homa, 5-2 1
CNS, 6-19
Hodgkin, 5-2 1
non-Hodgkin, 5-2 2
M
macro-ovalocytes, 5-3
malabsorp tion, 3-6
malaria, 6-2 3
Mallory-Weiss tear, 3-3
mammograp hy, 5-30
Marfan syndrome, 1-31
mechanical ventilation, 2 -19
mechanic’s hands, 8 -13
Meckel’s diverticulum, 3-4
Meigs’ syndrome, 2 -11, 3-2 6
MELD score, 3-2 3
melena, 3-3
membranop roliferative glomerulonep hritis, 4-17
membranous nep hrop athy, 4-17
meningitis
acute bacterial, 6-9
asep tic, 6-10
mental status, change in, 9-1
mesenteric ischemia, 3-12
metabolic acidosis, 4-2
metabolic alkalosis, 4-4
metabolic syndrome, 7-16
methanol intoxication, 4-2
methemoglobinemia, 2 -18
microangiop athic hemolytic anemia, 5-5
microscop ic p olyangiitis, 8 -19
migraine headache, 9-10
milk-alkali syndrome, 7-11
minimal change disease, 4-17
Mirizzi’s syndrome, 3-2 7
mitral regurgitation, 1-2 2
mitral stenosis, 1-2 2
mitral valve p rolap se, 1-2 3
mixed connective tissue disease (MCTD), 8 -14
molluscum contagiosum, 6-18
monoclonal gammop athy of uncertain significance, 5-2 5
monocytosis, 5-12
mucinous cystic neop lasm of p ancreas, 5-35
Mucor infection, 6-4
multip le endocrine neop lasia (MEN) syndromes, 7-2
multip le myeloma, 5-2 4
murmurs, ep onymous
Austin Flint, 1-2 1
Graham Steel, 2 -14
Murp hy’s sign, 3-2 7
myalgias, 8 -13
myasthenia gravis, 9-9
Mycobacte rium avium comp lex, disseminated, 6-19
mycosis fungoides, 5-2 2
myelodysp lastic syndromes, 5-14
myelofibrosis, p rimary, 5-16
myeloid neop lasms, 5-14
myelop roliferative neop lasms, 5-15
myocardial infarction (MI)
non ST elevation, 1-7
ST elevation, 1-9
myocardial viability, 1-4
myocarditis, 1-3, 1-17
myop athies, 8 -12 , 9-9
myositides, 8 -13
myxedema, 7-4
N
necrotizing fasciitis, 6-7
nep hrogenic systemic fibrosis, 4-12
nep hrolithiasis, 4-19
nep hrotic syndrome, 4-17
nerve root comp ression, 9-11
neurop athies, 9-8
neutrop enia, 5-12 , 5-36, 6-4
neutrop enic enterocolitis, 5-36
neutrop hilia, 5-12
New York Heart Association classification, 1-14
nonalcoholic fatty liver disease (NAFLD), 3-19
noninvasive ventilation, 2 -2 0
nonsp ecific interstitial p neumonia, 2 -10
nonulcer dysp ep sia, 3-2
nutrition, in hosp italized, 3-8
O
obstructive sleep ap nea, 2 -8
ocular motor p alsies, 10-4
oculocep halic maneuver, 9-1
Ogilvie’s syndrome, 3-8
omega-3 fatty acids, 1-16, 7-16
op tic neuritis, 10-4
op tic neurop athy, ischemic, 10-4
oral hairy leukop lakia, 6-18
orbital cellulitis, 10-4
orthostatic hyp otension, 1-37
Osler’s nodes, 6-12
osmolal gap , 4-3, 11-6
osteoarthritis, 8 -1, 8 -2
osteomyelitis, 6-8
P
p acemakers, 1-39
Paget’s disease
of bone, 7-11
of breast, 5-30
Pancoast’s syndrome, 5-2 8
p ancreatic cancer, 5-35
p ancreatic insufficiency, 3-7
p ancreatitis, 3-13
p ancytop enia, 5-3
p anhyp op ituitarism, 7-1
p ap illary muscle rup ture, 1-10
Pap p enheimer bodies, 5-2
p aracentesis, 3-2 6
p aroxysmal nocturnal syndromes, 5-4
p atent foramen ovale, 9-7
p ep tic ulcer disease (PUD), 1-3, 3-2
p ercutaneous coronary intervention (PCI), 1-5
p ericardial effusion, 1-2 5
p ericardial tamp onade, 1-2 6
p ericarditis, 1-2 5
p eriodic p aralysis
hyp erkalemic, 4-11
hyp okalemic, 4-10
p erip heral smear, findings in, 11-6
p eritoneal dialysis, 4-15
p eritonitis, 3-2 6
p etechiae, 5-6
p heochromocytoma, 7-10
p hlegmasia cerulean dolens, 2 -13
p ica, 5-1
p ituitary disorders, 7-1
p ituitary tumors, 7-1
p lasma cell dyscrasias, 5-2 4
p latelet disorders, 5-7
p leural effusion, 2 -11, P-4
p leuritis, 1-3
Plummer-Vinson syndrome, 5-1
p neumoconioses, 2 -10
p neumocystis, 2 -10
Pne umocystis jirove ci p neumonia, 6-19
p neumonia, 6-1, P-2
p neumothorax, P-4
POEMS syndrome, 5-2 4
p olyarteritis nodosa, 8 -18
p olycythemia vera, 5-15
p olydip sia, 4-9
p olyglandular autoimmune (PGA) syndromes, 7-2
p olymyalgia rheumatica, 8 -13, 8 -18
p olymyositis, 8 -12
p olyuria, 4-9
p orp hyria cutanea tarda, 3-18
p ortal hyp ertension, 3-2 1
p ortal vein thrombosis (PVT), 3-2 5
p ortop ulmonary hyp ertension, 2 -16, 3-2 3
p ortosystemic encep halop athy, 3-2 2
Pott’s disease, 6-8 , 6-15
p reexcitation, 1-33
p regnancy, ectop ic, 10-3
p reop erative risk assessment, 1-40
p rerenal azotemia, 4-12
p rimary biliary cirrhosis, 3-2 4
p rimary sclerosing cholangitis, 3-2 4
Prinzmetal’s angina, 1-6
p rogressive multifocal leukencep halop athy, 6-19
p rolactinoma, 7-1
p rop ylene glycol intoxication, 4-2
p rostate cancer, 5-32
p rostate-sp ecific antigen (PSA) testing, 5-32
p rostatitis, 6-5
p rosthetic heart valves, 1-2 4
p roteinuria, 4-18
p rothrombin mutation, 5-11
p seudogout, 8 -6
p seudo-hyp op arathyroidism, 7-12
p seudo-Pelger-Huët cells, 5-14, 11-6
p seudotumor cerebri, 9-10
p ulmonary alveolar p roteinosis, 2 -10
p ulmonary artery catheter, 1-12 , 11-4
p ulmonary edema
CXR p attern in, 11-5, P-2
treatment of, 1-15, 11-2
p ulmonary embolism, 2 -14, P-6
p ulmonary function tests, 2 -1
p ulmonary hyp ertension, 2 -16
p ulseless electrical activity, ACLS-2
p ulsus p aradoxus, 1-2 6
p ure red cell ap lasia, 5-2
p urified p rotein derivative (PPD) test, 6-15
p urp ura, 5-6
p yelonep hritis, 6-5
p yoderma gangrenosum, 3-10, 8 -8
Q
QT interval, 1-1
R
radiculop athies, 9-11
radioactive iodine up take scan, 7-3
Raynaud’s p henomenon, 8 -14
red eye, 10-4
Reed-Sternberg cells, 5-2 1
refeeding syndrome, 3-8
Reiter’s syndrome, 8 -7
relap sing p olychondritis, 8 -4
renal abscess, 6-5
renal artery stenosis, 1-2 8
renal failure, 4-12
renal osteodystrop hy, 7-12
renal rep lacement therap y, 4-15
renal tubular acidosis, 4-3
resp iratory acidosis, 4-5
resp iratory alkalosis, 4-5
resp iratory bronchiolitis-associated interstitial lung disease, 2 -10
resp iratory failure, 2 -18
reticulocyte index, 5-1
Reynold’s p entad, 3-2 8
rheumatoid factor, 8 -3
Rhizopus infection, 6-4
Richter’s syndrome, 5-2 0
Rocky Mountain sp otted tick fever, 6-2 1
Roth sp ots, 6-12
S
salicylate intoxication, 4-2
Samter’s syndrome, 2 -2
sarcoidosis, 2 -9, P-6
cardiac manifestations of, 1-19
schistocytes, 5-5, 11-6, P-14
sciatica, 9-11
scleroderma, 8 -11
seizures, 9-3
sep sis, 2 -2 3
seronegative sp ondyloarthritis, 8 -7
serum-ascites albumin gradient, 3-2 6
Sézary syndrome, 5-2 2
Sheehan’s syndrome, 7-1
shock, 1-13, 11-2
cardiogenic, 1-13
sep tic, 2 -2 3
sicca syndrome, 8 -13
sick euthyroid syndrome, 7-5
sick sinus syndrome, 1-32
silicosis, 2 -10
sinusoidal obstruction syndrome, 3-2 5, 5-2 6
Sjögren’s syndrome, 8 -13
smudge cells, 5-2 0
soft tissue infections, 6-6
solitary p ulmonary nodule, 2 -8
sp inal cord comp ression, 5-36, 9-11
sp inal stenosis, 9-12
sp lenomegaly, 5-5
sp ontaneous bacterial p eritonitis, 3-2 6
treatment of in cirrhosis, 3-2 2
sp ur cells, 11-6, P-14
stap le removal, 10-2
statistics, 11-7
status ep ilep ticus, 9-4
ST dep ression, 1-2
ST elevation, 1-2
stent thrombosis, 1-5
steroids, in critical care, 2 -2 3
Still’s disease, adult onset, 6-2 2 , 8 -4
stool osmotic gap , 3-7
stress test, 1-4
stroke, 9-6
struma ovarii, 7-4
subarachnoid hemorrhage, 9-7
subdural hematoma, 9-7
sup erior vena cava syndrome, 5-2 8
suture removal, 10-2
syncop e, 1-37
syndrome of inap p rop riate antidiuretic hormone (SIADH), 4-7
systemic lup us erythematosus (SLE), 8 -15
systemic sclerosis, 8 -11
T
tachycardias, 1-32 , ACLS-1
atrial, 1-32
atrioventricular recip rocating, 1-32 , 1-34
AV nodal reentrant, 1-32
multifocal atrial, 1-32
nonp aroxysmal junctional, 1-32
sinus, 1-32
sup raventricular, 1-32
ventricular, 1-34, ACLS-1, ACLS-2
wide-comp lex, 1-34
Takayasu’s arteritis, 8 -17
target cells, 11-6
teardrop cells, 5-16, 11-6, P-14
temp oral arteritis, 8 -17
thalassemias, 5-2
thrombocytop enia, 5-7
thrombotic thrombocytop enic p urp ura, 5-9
thrush, 6-18
thyroid disorders, 7-3
thyroid function tests, 7-3
thyroiditis, 7-4, 7-5
thyroid nodules, 7-6
thyroid storm, 7-4
TIMI risk score for UA/NSTEMI, 1-8
Todd’s p aralysis, 9-3
torsades de p ointes, 1-34
total body water, 11-6
toxic megacolon, 3-6, 3-10
toxic shock syndrome, 6-6
toxop lasmosis, 6-19
tracheostomy, 10-2
transfusion-related acute lung injury, 2 -2 2 , 5-13
transfusion therap y, 5-13
transient ischemic attack (TIA), 9-6
trans-tubular p otassium gradient, 4-10, 11-6
tricusp id regurgitation, 1-2 4
trop ical sp rue, 3-7
trop onin, 1-3, 1-6
Trousseau’s sign
of hyp ocalcemia, 7-12
of malignancy, 5-35
tuberculosis, 6-15
tularemia, 6-2 1
tumor lysis syndrome, 5-37
T wave inversion, 1-2
typ hilitis, 5-36
typ hoid fever, 6-2 3
U
ulcerative colitis, 3-10
ulcers, 3-2
unstable angina, 1-7
uremia, 4-13
uremic bleeding, 5-9
urethritis, 6-5
urinalysis, 4-18
urinary tract infection, 6-5
urine anion gap , 4-3
urine dip stick, 4-18
urine osmolality, 4-6
urine sediment, 4-18 , P-15
usual interstitial p neumonia, 2 -10
uveitis, 8 -7
V
vaginal bleeding, 10-3
vaginal discharge, 10-3
varices, 3-3, 3-2 2
vasculitis, 8 -17
veno-occlusive disease
hep atic, 3-2 5, 5-2 6
p ulmonary, 2 -16
venous thromboembolism, 2 -13
ventricular aneurysm, 1-11
ventricular fibrillation, ACLS-2
ventricular p seudoaneurysm, 1-11
ventricular sep tal defect, 1-10
Verner-Morrison syndrome, 3-7
vestibular caloric stimulation, 9-1
Virchow’s node, 5-35
visual changes, 10-4
visual field defect, 10-4
vitamin B 12 deficiency, 5-3
vitamin Δ deficiency, 7-12
vitamin K deficiency, 5-10
von Willebrand’s disease, 5-9
V/Q mismatch, 2 -18
W
Waldenström’s macroglobulinemia, 5-2 5
warfarin loading nomogram, 11-7
warfarin overdose, 5-10
Wegener’s granulomatosis, 8 -18
Wernicke’s encep halop athy, 9-5
Whip p le’s disease, 3-7
Wilson’s disease, 3-2 4
Wolff-Chaikoff effect, 7-5
Wolff-Parkinson-White syndrome, 1-33
X
xanthelasma, 7-16
xanthomas, 7-16
Y
yellow-nail syndrome, 2 -11
Z
Zenker’s diverticulum, 3-1
Zollinger-Ellison syndrome, 3-2 , 3-7
zoster, 6-11
zygomycetes, 6-4
Radiology
1 Normal PA CXR. The convex right cardiac border is formed by the right atrium
(straight arrows), and the curved arrows indicate the location of the sup erior vena
cava. The left cardiac and great vessels border what might be considered as four
skiing moguls. From cep halad to caudad, the moguls are the aortic arch, the main
and left p ulmonary arter-ies, the left atrial ap p endage, and the left ventricle.
(Radiolog y 10 1, 3rd ed, 2 009.)
2 Normal lateral CXR. (Radiolog y 10 1, 3rd ed, 2 009.)
3 COPD: with hyp erlucent, overinflated lungs and flat diap hragms. (Radiolog y 10 1,
3rd ed, 2 009.)
4 Interstitial pulmonary edema: with Kerley A, B, and C lines and cep halization of
the vascular markings. (Fund. Diag . Radiolog y 3rd ed, 2 006.)
5 Alveolar pulmonary edema. (Fund. Diag . Radiolog y 3rd ed, 2 006.)
6 Right upper lobe pneumonia. (Radiolog y 10 1, 3rd ed, 2 009.)
7 Right middle lobe pneumonia. (Radiolog y 10 1, 3rd ed, 2 009.)
8 Right lower lobe pneumonia (PA). (Radiolog y 10 1, 3rd ed, 2 009.)
9 Right lower lobe pneumonia (lateral). (Radiolog y 10 1, 3rd ed, 2 009.)
10 Bilateral pleural effusions (curved arrows) and enlarged azygous vein (straight
arrow) (PA). (Radiolog y 10 1, 3rd ed, 2 009.)
11 Bilateral pleural effusions (curved arrows) (lateral). (Radiolog y 10 1, 3rd ed,
2 009.)
12 Pneumothorax. (Radiolog y 10 1, 3rd ed, 2 009.)
13 Normal chest CT at level of p ulmonary arteries (p arenchymal windows).

(Radiolog y 10 1, 3rd ed, 2 009.)
14 Bilateral PE (mediastinal windows). (Radiolog y 10 1, 3rd ed, 2 009.)
15 Sarcoidosis with p erilymp hatic nodules. (Fund. Diag . Radiolog y 3rd ed, 2 006.)
16 Idiopathic pulmonary fibrosis. (Fund. Diag . Radiolog y 3rd ed, 2 006.)
17 Normal abdomen CT at level of liver & sp leen. (Radiolog y 10 1, 3rd ed, 2 009.)
18 Normal abdomen CT at level of p ancreas. (Radiolog y 10 1, 3rd ed, 2 009.)
Echocardiography
1 Parasternal long-axis view allows visualization of the right ventricle (RV), ven-
tricular sep tum (VS), p osterior wall (PW) aortic valve cusp s, left ventricle (LV),
mitral valve, left atrium (LA), and ascending thoracic aorta (Ao). *Pulmonary artery.
(Top : From Mayo Clinic Proce e ding s. [Tajik AJ, Seward JB, Hagler DJ, et al. Two-
dimensional real-time ultrasonic imaging of the heart and great vessels: Technique,
image orientation, structure identification, and validation. Mayo Clinic Proce e ding s,
1978 ;53:2 71–303], with p ermission. Bottom: From Oh JK, Seward JB, Tajik AJ. The
Echo Manual, 3rd e d. Philadelp hia: Lip p incott Williams & Wilkins, 2 006. By
p ermission of Mayo Foundation for Medical Education and Research. All rights
reserved.)
2 Parasternal short-axis view at the level of the aorta: LA, left atrium; PV, p ul-
monary valve; RA, right atrium; RVOT, right ventricular outflow tract. (Top : From
Mayo Clinic Proce e ding s. [Tajik AJ, Seward JB, Hagler DJ, et al. Two-dimensional
real-time ultrasonic imaging of the heart and great vessels: Technique, image
orientation, structure identification, and validation. Mayo Clinic Proce e ding s,
1978 ;53:2 71–303], with p ermission. Bottom: From Oh JK, Seward JB, Tajik AJ. The
Echo Manual, 3rd e d. Philadelp hia: Lip p incott Williams & Wilkins, 2 006. By
p ermission of Mayo Foundation for Medical Education and Research. All rights
reserved.)
3 Parasternal short-axis view at the level of the papillary muscles: AL,
anterolateral p ap illary muscle; PM, p osteromedial p ap illary muscle; RV, right
ventricle; VS, ventricular sep tum; LV, left ventricle. (Top : From Mayo Clinic
Proce e ding s. [Tajik AJ, Seward JB, Hagler DJ, et al. Two-dimensional real-time
ultrasonic imaging of the heart and great vessels: Technique, image orientation,
structure identification, and validation. Mayo Clinic Proce e ding s, 1978 ;53:2 71–303],
with p ermission. Bottom: From Oh JK, Seward JB, Tajik AJ. The Echo Manual, 3rd
e d. Philadelp hia: Lip p incott Williams & Wilkins, 2 006. By p ermission of Mayo
Foundation for Medical Education and Research. All rights reserved.)
4 Apical four-chamber view: Note that at some institutions the image is reversed
so that the left side of the heart ap p ears on the right side of the screen. LA, left
atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (Top : From Mayo
Clinic Proce e ding s. [Tajik AJ, Seward JB, Hagler DJ, et al. Two-dimensional real-time
ultrasonic imaging of the heart and great vessels: Technique, image orientation,
structure identification, and validation. Mayo Clinic Proce e ding s, 1978 ;53:2 71–303],
with p ermission. Bottom: From Oh JK, Seward JB, Tajik AJ. The Echo Manual, 3rd
e d. Philadelp hia: Lip p incott Williams & Wilkins, 2 006. By p ermission of Mayo
Foundation for Medical Education and Research. All rights reserved.)
Coronary Angiography
Peripheral Blood Smears
1 Normal smear.
2 Hyp ochromic, microcytic anemia due to iron-deficiency.

3 Macrocytic anemia due to p ernicious anemia; note macro-ovalocytes and
hyp ersegmented neutrop hils.
4 Sp herocytes due to autoimmune hemolytic anemia.
5 Sickle cell anemia.

6 Schistocytes.
7 Teardrop shaped RBC (dacrocyte).
8 Acanthocytes.
9 Nucleated RBC.
10 Rouleaux.
Leukemias
1 AML with Auer rod.
2 ALL.
3 CML.
4 CLL.
All p hotos excluding Leukemias Fig. 4: From Wintrobe’s Clin. He matol. 12 th ed, 2 009:
Leukemias Fig. 4 From Devita, Hellman, and Rosenberg’s Cance r: Princip. & Prac. of
Oncol. 8 th ed, 2 008 .
Urinalysis
1 “Muddy brown” or granular cast (courtesy Nicholas Zwang, MD)
2 Hyaline cast (courtesy Nicholas Zwang, MD)
3 “Waxy broad” cast (courtesy Nicholas Zwang, MD)

4 Renal tubular epithelial cell (courtesy Nicholas Zwang, MD)
5 RBC cast. (Dis. of Kidne y & Urinary Tract, 8 th ed, 2 006.)
6 WBC cast. (Clin. Lab. Me dicine , 2 nd ed, 2 002 .)

7 Calcium oxalate crystals (courtesy Mallika Mendu, MD). Calcium monohydrate
(arrow), calcium dihydrate (dashed arrow), and amorp hous calcium crystals
(arrowhead)
8 “Struvite” magnesium ammonia phosphate crystals (courtesy Brett Carroll, MD)

9 Cystine crystals (Clin. Lab. Medicine, 1994.)
10 Sulfadiazine “shock of wheat” crystals (courtesy Nicholas Zwang, MD)

ACLS ALGORITHMS
Figure ACLS-1 ACLS Tachycardia Algorithm
Figure ACLS-2 ACLS Bradycardia Algorithm

Figure ACLS-3 VF/Pulseless VT, Asystole & PEA Algorithms

Pocket Medicine 5th Edition - The Massachuset PDF

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Pocket

MARC S. SABATINE, MD, MPH

The Massachusetts General Hospital

© 2014 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business

Library of Congress Cataloging-in-Publication Data

Pocket medicine (Sabatine)

Ian J. Barbash, Kathryn A. Hibbe rt, Atul Malhotra

Esop hageal and Gastric Disorders

Ana A. We il, Emily P. Hyle , Ne sli Basg oz

Ke lly B. Laute r, Marc N. We in, Michae l Mannstadt

ICU Medications & Treatment of Hyp otension/Shock

Andrew J. Aguirre, MD, PhD

Hematology-Oncology Fellow, Dana-Farber/Partners CancerCare

Internal Medicine Resident, Massachusetts General Hosp ital

Associate Chief and Clinical Director, Infectious Disease Division, Massachusetts

Clinical Director, Nep hrology Unit, Massachusetts General Hosp ital

Michael P. Bowley, MD, PhD

Neurology Resident, Partners Neurology Residency

Internal Medicine Resident, Massachusetts General Hosp ital

Katherine T. Chen, MD, MPH

Associate Professor of Obstetrics, Gynecology, and Rep roductive Science

Associate Program Director, Partners-Harvard Neurology Residency

Transp lant Hep atology Fellow, Massachusetts General Hosp ital

Daniel J. DeAngelo, MD, PhD

David M. Dudzinski, MD, JD

Robert P. Friday, MD, PhD

Attending Physician, Rheumatology Unit, Massachusetts General Hosp ital

William J. Hucker, MD, PhD

Cardiology Fellow, Massachusetts General Hosp ital

Assistant in Medicine, Infectious Disease Division, Massachusetts General Hosp ital

Internal Medicine Resident, Massachusetts General Hosp ital

Director, Clinical Research in Op thalmology

Eyal Y. Kimchi, MD, PhD

Surgical Resident, Beth Israel Deaconess Medical Center

Kelly B. Lauter, MD, PhD

Internal Medicine Resident, Massachusetts General Hosp ital

Nep hrology Fellow, BWH/MGH Joint Nep hrology Fellowship Program

Attending Physician, Endocrine Unit, Massachusetts General Hosp ital

Rheumatology Fellow, Massachusetts General Hosp ital

Michelle O’Donoghue, MD, MPH

Investigator, TIMI Study Group and Associate Physician, Cardiovascular Division,

Marc S. Sabatine, MD, MPH

Ada Stefanescu, MD, CM

Internal Medicine Resident, Massachusetts General Hosp ital

Chief, Division of Surgical Oncology, Beth Israel Deaconess Medical Center

Neurology Resident, Partners Neurology Residency

Internal Medicine Resident, Massachusetts General Hosp ital

Internal Medicine Resident, Massachusetts General Hosp ital

Marc N. Wein, MD, PhD

Endocrinology Fellow, Massachusetts General Hosp ital

To the 1st Edition

It is with the greatest enthusiasm that I introduce Pocke t Me dicine . In an era of

To my pare nts, Matt and Le e Sabatine , to the ir name sake

Approach (a systematic approach is vital)

• Rate (? tachy, brady) and rhythm (? relationship between P and QRS)

Figure 1-1 QRS axis

Left axis deviation (LAD)

• Etiologies: LVH, LBBB, inferior MI, WPW

• Definition: axis beyond +90° (S > R in lead I)

• QT varies w/ HR → correct w/ Bazett formula: QTc = QT/√RR (in sec), formula

Antiarrhythmics: class Ia (p rocainamide, disop yramide), class III (amiodarone,

Antimicrobials: macrolides, quinolones, azoles, p entamidine, atovaquone,

Other: antiemetics (drop eridol, 5-HT3 antagonists), alfuzosin, methadone,