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Part 1 book “For the first aid USMLE step 1 2017” has contents: Excelling in the preclinical years , timeline for study, study materials, clinical vignette strategies, testing agencies, public health sciences, approaching the organ systems, public health sciences,… and other contents.
A STUDENT-TO-STUDENT GUIDE • 1,300+ frequently tested facts and mnemonics • • High-yield updates throughout with reorganized neurology chapter • • 100+ new and revised color illustrations and photos • • Student-proven exam tips and strategies • • Revised resource guide with web and mobile apps • FIRST AID FOR THE® USMLE STEP 2017 TAO LE, MD, MHS VIKAS BHUSHAN, MD Associate Clinical Professor Chief, Section of Allergy and Immunology Department of Medicine University of Louisville School of Medicine Boracay MATTHEW SOCHAT, MD KIMBERLY KALLIANOS, MD Resident, Department of Internal Medicine Temple University Hospital Resident, Department of Radiology and Biomedical Imaging University of California, San Francisco School of Medicine YASH CHAVDA, DO ANDREW ZUREICK Resident, Department of Emergency Medicine St Barnabas Hospital, Bronx University of Michigan Medical School Class of 2018 MEHBOOB KALANI, MD Resident, Department of Internal Medicine Allegheny Health Network Medical Education Consortium New York / Chicago / San Francisco / Athens / London / Madrid / Mexico City Milan / New Delhi / Singapore / Sydney / Toronto Copyright © 2017 by McGraw-Hill Education All rights reserved Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher ISBN: 978-1-25-983762-3 MHID: 1-25-983762-9 The material in this eBook also appears in the print version of this title: ISBN: 978-1-25-983763-0, MHID: 1-25-983763-7 eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark Where such designations appear in this book, they have been 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errors or omissions or for the results obtained from use of the information contained in this work Readers are encouraged to confirm the information contained herein with other sources For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration This recommendation is of particular importance in connection with new or infrequently used drugs TERMS OF USE This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work Use of this work is subject to these terms Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited Your right to use the work may be terminated if you fail to comply with these terms THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE McGraw-Hill Education and its licensors not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom McGraw-Hill Education has no responsibility for the content of any information accessed through the work Under no circumstances shall McGraw-Hill Education and/ or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise Dedication To the contributors to this and past editions, who took time to share their knowledge, insight, and humor for the benefit of students and physicians everywhere Contents Contributing Authors vii General Acknowledgments xiii Associate Authors viii How to Contribute xvii Faculty Advisors ix How to Use This Book xix Preface xi Selected USMLE Laboratory Values xx Special Acknowledgments xii First Aid Checklist for the USMLE Step ` SECTION I G U I D E TO E F F I C I E N T E X A M P R E PA R AT I O N xxii Introduction Test-Taking Strategies 20 USMLE Step 1—The Basics Clinical Vignette Strategies 21 Defining Your Goal 12 If You Think You Failed 22 Excelling in the Preclinical Years 13 Testing Agencies 22 Timeline for Study 14 References 23 Study Materials 18 ` SECTION I SUPPLEMENT ` SECTION II S P E C I A L S I T UAT I O N S 25 HIGH-YIELD GENERAL PRINCIPLES 27 How to Use the Database 28 Pathology 203 Biochemistry 31 Pharmacology 223 Immunology 91 Public Health Sciences 245 Microbiology 119 v ` SECTION III H I G H - Y I E L D O R G A N S YS T E M S 263 Approaching the Organ Systems 264 Neurology and Special Senses 459 Cardiovascular 267 Psychiatry 523 Endocrine 311 Renal 547 Gastrointestinal 343 Reproductive 579 Hematology and Oncology 385 Respiratory 625 Musculoskeletal, Skin, and Connective Tissue 423 Rapid Review 651 ` SECTION IV TO P - R AT E D R E V I E W R E S O U R C E S 671 How to Use the Database 672 Cell Biology and Histology 677 Question Banks 674 Microbiology and Immunology 677 Question Books 674 Pathology 677 Web and Mobile Apps 674 Pharmacology 678 Comprehensive 675 Physiology 679 Anatomy, Embryology, and Neuroscience 675 Abbreviations and Symbols 681 Behavioral Science 676 Image Acknowledgments 689 Biochemistry 676 About the Editors 777 ` Index vi 711 Contributing Authors MARINA BOUSHRA, MD M SCOTT MOORE, DO Resident, Department of Emergency Medicine East Carolina University/Vidant Medical Center Research Fellow Affiliated Dermatology THEODORE CRISOSTOMO-WYNNE JUN YEN NG, MD F Edward Hébert School of Medicine Class of 2017 Intern Central Queensland Hospital and Health Services MATTHEW S DELFINER SATYAJIT REDDY, MD New York Institute of Technology College of Osteopathic Medicine Class of 2017 Resident, Department of Internal Medicine Temple University Hospital ANGELA GAUTHIER VADIM ROSIN Yale School of Medicine Class of 2018 University of Michigan Medical School Class of 2017 BENJAMIN GOUGH, DO SARAH SCHIMANSKY, MB BCh BAO Resident, Department of General Surgery Christiana Care Health System Academic Foundation Doctor North Bristol NHS Trust JAN ANDRE GRAUMAN, MD, MA ZACHARY G SCHWAM, MD Family Medicine Resident, Northern Remote Stream University of Manitoba Resident, Department of Otolaryngology Icahn School of Medicine at Mount Sinai JESSICA F JOHNSTON, MSc NINO SIKHARULIDZE, MD Yale School of Medicine MD/PhD Candidate Department of Endocrinology Tbilisi State Medical University JAMES N McCOY VAISHNAVI VAIDYANATHAN Texas A&M Health Science Center Class of 2017 University of Missouri-Kansas City School of Medicine Class of 2018 IMAGE AND ILLUSTRATION TEAM RYAN W HADDEN RENATA VELAPATIÑO University of Alabama School of Medicine Class of 2017 San Martín de Porres University School of Medicine vii Associate Authors JAMES E BATES, MD JESSE D SENGILLO Resident, Department of Radiation Oncology University of Florida School of Medicine SUNY Downstate College of Medicine Class of 2018 REED GILBOW, MD WENHUI ZHOU Resident, Department of Otolaryngology–Head and Neck Surgery University of Virginia School of Medicine Tufts University School of Medicine MD/PhD Candidate RYAN KELSCH Midwestern University Chicago College of Osteopathic Medicine Class of 2017 IMAGE AND ILLUSTRATION TEAM NAKEYA KHOZEMA DEWASWALA Lokmanya Tilak Municipal Medical College Class of 2016 viii Faculty Advisors MARK A.W ANDREWS, PhD CHARLES S DELA CRUZ, MD, PhD Lake Erie College of Osteopathic Medicine at Seton Hill Greensburg, PA Assistant Professor, Department of Pulmonary and Critical Care Medicine Yale School of Medicine MARIA ANTONELLI, MD CONRAD FISCHER, MD Clinical Faculty, Division of Rheumatology Case Western Reserve University School of Medicine Associate Professor, Medicine, Physiology, and Pharmacology Touro College of Medicine HERMAN SINGH BAGGA, MD JEFFREY J GOLD, MD Urologist, Allegheny Health Network University of Pittsburgh Medical Center Associate Professor, Department of Neurology Assistant Professor, University of California, San Diego School of Medicine ADITYA BARDIA, MBBS, MPH RAYUDU GOPALAKRISHNA, PhD Attending Physician, Massachusetts General Hospital Harvard Medical School Associate Professor, Department of Cell and Neurobiology Keck School of Medicine of University of Southern California PAULETTE BERND, PhD RYAN C.W HALL, MD Professor, Department of Pathology and Cell Biology Columbia University College of Physicians and Surgeons Assistant Professor, Department of Psychiatry University of South Florida SHELDON CAMPBELL, MD, PhD LOUISE HAWLEY, PhD Associate Professor of Laboratory Medicine Yale School of Medicine Immediate Past Professor and Chair, Department of Microbiology Ross University School of Medicine BROOKS D CASH, MD MARGARET M HAYES, MD Professor of Medicine, Division of Gastroenterology University of South Alabama School of Medicine Instructor of Medicine Harvard Medical School SHIVANI VERMA CHMURA, MD JEFFREY W HOFMANN, MD, PhD Adjunct Clinical Faculty, Department of Psychiatry Stanford University School of Medicine Resident, Department of Pathology University of California, San Francisco School of Medicine PETER V CHIN-HONG, MD BRIAN C JENSEN, MD Professor, Department of Medicine University of California, San Francisco School of Medicine Assistant Professor of Medicine and Pharmacology University of North Carolina Health Care CHRISTINA E CIACCIO, MD, MSc CLARK KEBODEAUX, PharmD Assistant Professor, Departments of Pediatrics and Medicine The University of Chicago Pritzker School of Medicine Clinical Assistant Professor, Pharmacy Practice and Science University of Kentucky College of Pharmacy LINDA S COSTANZO, PhD MICHAEL R KING, MD Professor, Physiology & Biophysics Virginia Commonwealth University School of Medicine Instructor, Department of Pediatric Anesthesiology Northwestern University Feinberg School of Medicine ANTHONY L DeFRANCO, PhD KRISTINE KRAFTS, MD Professor, Department of Microbiology and Immunology University of California, San Francisco School of Medicine Assistant Professor, Department of Basic Sciences University of Minnesota School of Medicine ix GERALD LEE, MD MELANIE SCHORR, MD Assistant Professor, Department of Pediatrics University of Louisville School of Medicine Research Fellow, Department of Medicine Massachusetts General Hospital KACHIU C LEE, MD, MPH NATHAN W SKELLEY, MD Assistant Clinical Professor, Department of Dermatology Brown University, Providence, Rhode Island Assistant Professor, Department of Orthopaedic Surgery University of Missouri, The Missouri Orthopaedic Institute WARREN LEVINSON, MD, PhD SHEENA STANARD, MD, MHS Professor, Department of Microbiology and Immunology University of California, San Francisco School of Medicine Hospitalist State University of New York Upstate Hospital PETER MARKS, MD, PhD HOWARD M STEINMAN, PhD Center for Biologics Evaluation and Research US Food and Drug Administration Assistant Dean, Biomedical Science Education Albert Einstein College of Medicine J RYAN MARTIN, MD STEPHEN F THUNG, MD Assistant Professor of Obstetrics, Gynecology, and Reproductive Sciences Yale School of Medicine Associate Professor, Department of Obstetrics and Gynecology The Ohio State University College of Medicine DOUGLAS A MATA, MD, MPH RICHARD P USATINE, MD Brigham and Women’s Hospital Harvard Medical School Professor, Dermatology and Cutaneous Surgery University of Texas Health Science Center San Antonio VICKI PARK, PhD PRASHANT VAISHNAVA, MD Associate Professor, Pediatrics and Medical Education University of Tennessee Health Science Center Assistant Professor, Department of Medicine Mount Sinai Hospital and Icahn School of Medicine JEANNINE RAHIMIAN, MD, MBA J MATTHEW VELKEY, PhD Associate Professor, Obstetrics and Gynecology David Geffen School of Medicine at UCLA Assistant Dean, Basic Science Education Duke University School of Medicine SOROUSH RAIS-BAHRAMI, MD BRIAN WALCOTT, MD Assistant Professor, Urology and Radiology The University of Alabama at Birmingham School of Medicine Clinical Instructor, Department of Neurological Surgery University of California, San Francisco SASAN SAKIANI, MD TISHA WANG, MD Assistant Professor, Department of Medicine Case Western Reserve University School of Medicine Associate Clinical Professor, Department of Medicine David Geffen School of Medicine at UCLA ROBERT A SASSO, MD SYLVIA WASSERTHEIL-SMOLLER, PhD Professor of Clinical Medicine Ross University School of Medicine Professor Emerita, Department of Epidemiology and Population Health Albert Einstein College of Medicine JOSEPH L SCHINDLER, MD ADAM WEINSTEIN, MD Assistant Professor, Neurology and Neurosurgery Yale School of Medicine Assistant Professor, Pediatric Nephrology and Medical Education Geisel School of Medicine at Dartmouth x 370 SEC TION III Colonic polyps HISTOLOGIC TYPE GASTROINTESTINAL ` GASTROINTESTINAL—PATHOLOGY Growths of tissue within the colon A May be neoplastic or non-neoplastic Grossly characterized as flat, sessile, or pedunculated (on a stalk) on the basis of protrusion into colonic lumen Generally classified by histologic type CHARACTERISTICS Generally non-neoplastic Hamartomatous polyps Solitary lesions not have significant risk of transformation Growths of normal colonic tissue with distorted architecture Associated with Peutz-Jeghers syndrome and juvenile polyposis Mucosal polyps Small, usually < mm Look similar to normal mucosa Clinically insignificant Inflammatory pseudopolyps Result of mucosal erosion in inflammatory bowel disease Submucosal polyps May include lesions such as lipomas, leiomyomas, fibromas, and others Hyperplastic polyps Generally smaller and predominantly located in the rectosigmoid region May occasionally evolve into serrated polyps and more advanced lesions Malignant potential Adenomatous polyps Neoplastic, via chromosomal instability pathway with mutations in APC and KRAS Tubular B histology has less malignant potential than villous C (“VILLOUS histology is VILLainOUS”); tubulovillous has intermediate malignant potential Usually asymptomatic; may present with occult bleeding Serrated polyps Premalignant, via CpG hypermethylation phenotype pathway with microsatellite instability and mutations in BRAF “Saw-tooth” pattern of crypts on biopsy Up to 20% of cases of sporadic CRC A B C Polyp Polyp Cancer Polyposis syndromes Familial adenomatous polyposis Autosomal dominant mutation of APC tumor suppressor gene on chromosome 5q 2-hit hypothesis Thousands of polyps arise starting after puberty; pancolonic; always involves rectum Prophylactic colectomy or else 100% progress to CRC Gardner syndrome FAP + osseous and soft tissue tumors, congenital hypertrophy of retinal pigment epithelium, impacted/supernumerary teeth Turcot syndrome FAP/Lynch syndrome + malignant CNS tumor (eg, medulloblastoma, glioma) Turcot = Turban Peutz-Jeghers syndrome Autosomal dominant syndrome featuring numerous hamartomas throughout GI tract, along with hyperpigmented mouth, lips, hands, genitalia Associated with q risk of breast and GI cancers (eg, colorectal, stomach, small bowel, pancreatic) Juvenile polyposis syndrome Autosomal dominant syndrome in children (typically < years old) featuring numerous hamartomatous polyps in the colon, stomach, small bowel Associated with q risk of CRC GASTROINTESTINAL Lynch syndrome ` GASTROINTESTINAL—PATHOLOGY SEC TION III Previously known as hereditary nonpolyposis colorectal cancer (HNPCC) Autosomal dominant mutation of DNA mismatch repair genes with subsequent microsatellite instability ∼ 80% progress to CRC Proximal colon is always involved Associated with endometrial, ovarian, and skin cancers Colorectal cancer EPIDEMIOLOGY Most patients are > 50 years old ~ 25% have a family history RISK FACTORS Adenomatous and serrated polyps, familial cancer syndromes, IBD, tobacco use, diet of processed meat with low fiber PRESENTATION Rectosigmoid > ascending > descending Ascending—exophytic mass, iron deficiency anemia, weight loss Descending—infiltrating mass, partial obstruction, colicky pain, hematochezia Rarely, presents with S bovis (gallolyticus) bacteremia Right side bleeds; left side obstructs DIAGNOSIS Iron deficiency anemia in males (especially > 50 years old) and postmenopausal females raises suspicion Screen low-risk patients starting at age 50 with colonoscopy A ; alternatives include flexible sigmoidoscopy, fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), and CT colonography Patients with a first-degree relative who has colon cancer should be screened via colonoscopy at age 40, or starting 10 years prior to their relative’s presentation Patients with IBD have a distinct screening protocol “Apple core” lesion seen on barium enema x-ray B CEA tumor marker: good for monitoring recurrence, should not be used for screening A B Polyp 371 372 SEC TION III Molecular pathogenesis of colorectal cancer GASTROINTESTINAL ` GASTROINTESTINAL—PATHOLOGY Chromosomal instability pathway: mutations in APC cause FAP and most sporadic CRC (via adenoma-carcinoma sequence; (firing) order of events is AK-53) Microsatellite instability pathway: mutations or methylation of mismatch repair genes (eg, MLH1) cause Lynch syndrome and some sporadic CRC (via serrated polyp pathway) Overexpression of COX-2 has been linked to colorectal cancer, NSAIDs may be chemopreventive Chromosomal instability pathway Loss of APC gene Normal colon Colon at risk ↓ intercellular adhesion ↑ proliferation Loss of tumor suppressor gene(s) (p53, DCC) KRAS mutation Adenoma Unregulated intracellular signaling Carcinoma ↑ tumorigenesis Cirrhosis and portal hypertension A Cirrhosis—diffuse bridging fibrosis (via stellate cells) and regenerative nodules (red arrows in A ; white arrows shows splenomegaly) disrupt normal architecture of liver; q risk for hepatocellular carcinoma (HCC) Etiologies include alcohol (60–70% of cases in the US), nonalcoholic steatohepatitis, chronic viral hepatitis, autoimmune hepatitis, biliary disease, genetic/metabolic disorders Portal hypertension—q pressure in portal venous system Etiologies include cirrhosis (most common cause in Western countries), vascular obstruction (eg, portal vein thrombosis, BuddChiari syndrome), schistosomiasis Integumentary Jaundice Spider angiomas Palmar erythema Purpura Petechiae Effects of portal hypertension Esophageal varices ( hematemesis) Gastric varices ( melena) Caput medusae Ascites Anorectal varices Reproductive Testicular atrophy Gynecomastia Amenorrhea Neurologic Hepatic encephalopathy Asterixis (”flapping tremor”) Gastrointestinal Anorexia Nausea, vomiting Dull abdominal pain Fetor hepaticus Hematologic Thrombocytopenia Anemia Coagulation disorders Splenomegaly Renal Hepatorenal syndrome Metabolic Hyperbilirubinemia Hyponatremia Cardiovascular Cardiomyopathy Peripheral edema GASTROINTESTINAL Spontaneous bacterial peritonitis ` GASTROINTESTINAL—PATHOLOGY SEC TION III 373 Also known as 1° bacterial peritonitis Common and potentially fatal bacterial infection in patients with cirrhosis and ascites Often asymptomatic, but can cause fevers, chills, abdominal pain, ileus, or worsening encephalopathy Commonly caused by aerobic gram ⊝ organisms, especially E coli Diagnosis: Paracentesis with ascitic fluid absolute neutrophil count (ANC) > 250 cells/mm3 Serum markers of liver pathology ENZYMES RELEASED IN LIVER DAMAGE Aspartate aminotransferase and alanine aminotransferase q in most liver disease: ALT > AST q in alcoholic liver disease: AST > ALT AST > ALT in nonalcoholic liver disease suggests progression to advanced fibrosis or cirrhosis Alkaline phosphatase q in cholestasis (eg, biliary obstruction), infiltrative disorders, bone disease γ-glutamyl transpeptidase q in various liver and biliary diseases (just as ALP can), but not in bone disease; associated with alcohol use FUNCTIONAL LIVER MARKERS Bilirubin q in various liver diseases (eg, biliary obstruction, alcoholic or viral hepatitis, cirrhosis), hemolysis Albumin r in advanced liver disease (marker of liver’s biosynthetic function) Prothrombin time q in advanced liver disease (r production of clotting factors, thereby measuring the liver’s biosynthetic function) Platelets r in advanced liver disease (r thrombopoietin, liver sequestration) and portal hypertension (splenomegaly/splenic sequestration) Reye syndrome Rare, often fatal childhood hepatic encephalopathy Findings: mitochondrial abnormalities, fatty liver (microvesicular fatty change), hypoglycemia, vomiting, hepatomegaly, coma Associated with viral infection (especially VZV and influenza B) that has been treated with aspirin Mechanism: aspirin metabolites r β-oxidation by reversible inhibition of mitochondrial enzymes Avoid aspirin in children, except in those with Kawasaki disease 374 SEC TION III GASTROINTESTINAL ` GASTROINTESTINAL—PATHOLOGY Alcoholic liver disease Hepatic steatosis Macrovesicular fatty change A that may be reversible with alcohol cessation Alcoholic hepatitis Requires sustained, long-term consumption Swollen and necrotic hepatocytes with neutrophilic infiltration Mallory bodies B (intracytoplasmic eosinophilic inclusions of damaged keratin filaments) Alcoholic cirrhosis Final and usually irreversible form Regenerative nodules surrounded by fibrous bands in response to chronic liver injury p portal hypertension and end-stage liver disease Sclerosis around central vein (arrows in C ) may be seen in early disease A Nonalcoholic fatty liver disease A Hepatic encephalopathy B Metabolic syndrome (insulin resistance); obesity p fatty infiltration of hepatocytes A p cellular “ballooning” and eventual necrosis May cause cirrhosis and HCC Independent of alcohol use Make a toAST with alcohol: AST > ALT (ratio usually > 2:1) C ALT > AST (Lipids) Cirrhosis p portosystemic shunts p r NH3 metabolism p neuropsychiatric dysfunction Reversible neuropsychiatric dysfunction ranging from disorientation/asterixis (mild) to difficult arousal or coma (severe) Triggers: q NH3 production and absorption (due to dietary protein, GI bleed, constipation, infection) r NH3 removal (due to renal failure, diuretics, bypassed hepatic blood flow post-TIPS) Treatment: lactulose (q NH4+ generation) and rifaximin or neomycin (r NH3 producing gut bacteria) GASTROINTESTINAL Hepatocellular carcinoma/hepatoma ` GASTROINTESTINAL—PATHOLOGY Most common 1° malignant tumor of liver in adults A Associated with HBV (+/− cirrhosis) and all other causes of cirrhosis (including HCV, alcoholic and nonalcoholic fatty liver disease, autoimmune disease, hemochromatosis, α1-antitrypsin deficiency) and specific carcinogens (eg, aflatoxin from Aspergillus) May lead to Budd-Chiari syndrome Findings: jaundice, tender hepatomegaly, ascites, polycythemia, anorexia Spreads hematogenously Diagnosis: q α-fetoprotein; ultrasound or contrast CT/MRI B , biopsy A SEC TION III 375 B Other liver tumors Cavernous hemangioma Common, benign liver tumor A ; typically occurs at age 30–50 years Biopsy contraindicated because of risk of hemorrhage A Hepatic adenoma Rare, benign liver tumor, often related to oral contraceptive or anabolic steroid use; may regress spontaneously or rupture (abdominal pain and shock) Angiosarcoma Malignant tumor of endothelial origin; associated with exposure to arsenic, vinyl chloride Metastases GI malignancies, breast and lung cancer Most common overall; metastases are rarely solitary Budd-Chiari syndrome Thrombosis or compression of hepatic veins with centrilobular congestion and necrosis p congestive liver disease (hepatomegaly, ascites, varices, abdominal pain, liver failure) Absence of JVD Associated with hypercoagulable states, polycythemia vera, postpartum state, HCC May cause nutmeg liver (mottled appearance) α1-antitrypsin Misfolded gene product protein aggregates in hepatocellular ER p cirrhosis with PAS ⊕ globules A in liver Codominant trait Often presents in young patients with liver damage and dyspnea without a history of smoking deficiency A In lungs, r α1-antitrypsin p uninhibited elastase in alveoli p r elastic tissue p panacinar emphysema 376 SEC TION III Jaundice A GASTROINTESTINAL ` GASTROINTESTINAL—PATHOLOGY Abnormal yellowing of the skin and/or sclera A due to bilirubin deposition Hyperbilirubinemia 2° to q production or r disposition (impaired hepatic uptake, conjugation, excretion) HOT Liver—common causes of increased levels of bilirubin: Hemolysis Obstruction Tumor Liver disease Unconjugated (indirect) hyperbilirubinemia Hemolytic, physiologic (newborns), Crigler-Najjar, Gilbert syndrome Conjugated (direct) hyperbilirubinemia Biliary tract obstruction: gallstones, cholangiocarcinoma, pancreatic or liver cancer, liver fluke Biliary tract disease: 1° sclerosing cholangitis 1° biliary cholangitis Excretion defect: Dubin-Johnson syndrome, Rotor syndrome Mixed (direct and indirect) hyperbilirubinemia Hepatitis, cirrhosis Physiologic neonatal jaundice At birth, immature UDP-glucuronosyltransferase p unconjugated hyperbilirubinemia p jaundice/ kernicterus (deposition of unconjugated, lipid-soluble bilirubin in the brain, particularly basal ganglia) Occurs after first 24 hours of life and usually resolves without treatment in 1–2 weeks Treatment: phototherapy (non-UV) isomerizes unconjugated bilirubin to water-soluble form GASTROINTESTINAL Hereditary hyperbilirubinemias ` GASTROINTESTINAL—PATHOLOGY SEC TION III 377 All autosomal recessive Gilbert syndrome Mildly r UDP-glucuronosyltransferase conjugation and impaired bilirubin uptake Asymptomatic or mild jaundice usually with stress, illness, or fasting q unconjugated bilirubin without overt hemolysis Bilirubin q with fasting and stress Relatively common, benign condition Crigler-Najjar syndrome, type I Absent UDP-glucuronosyltransferase Presents early in life; patients die within a few years Findings: jaundice, kernicterus (bilirubin deposition in brain), q unconjugated bilirubin Treatment: plasmapheresis and phototherapy Type II is less severe and responds to phenobarbital, which q liver enzyme synthesis Dubin-Johnson syndrome Conjugated hyperbilirubinemia due to defective liver excretion Grossly black liver Benign Rotor syndrome is similar, but milder in presentation without black liver Due to impaired hepatic uptake and excretion HEPATIC SINUSOID Hemoglobin Circulating bilirubin (albumin bound, unconjugated, water insoluble) Kupffer cell (macrophage) Endothelial cell Space of Disse BILIRUBIN UPTAKE Hepatocyte UDP-glucuronosyltransferase Unconjugated bilirubin CONJUGATION Conjugated bilirubin (bilirubin diglucuronide, water soluble) INTRACELLULAR TRANSPORT Bile canaliculus lumen Stasis Bile flow Hepatocyte Obstructive jaundice (downstream) 378 SEC TION III Wilson disease (hepatolenticular degeneration) A Hemochromatosis A Biliary tract disease GASTROINTESTINAL ` GASTROINTESTINAL—PATHOLOGY Autosomal recessive mutations in hepatocyte copper-transporting ATPase (ATP7B gene; chromosome 13) p r copper excretion into bile and incorporation into apoceruloplasmin p r serum ceruloplasmin Copper accumulates, especially in liver, brain, cornea, kidneys; q urine copper Presents before age 40 with liver disease (eg, hepatitis, acute liver failure, cirrhosis), neurologic disease (eg, dysarthria, dystonia, tremor, parkinsonism), psychiatric disease, Kayser-Fleischer rings (deposits in Descemet membrane of cornea) A , hemolytic anemia, renal disease (eg, Fanconi syndrome) Treatment: chelation with penicillamine or trientine, oral zinc Recessive mutations in HFE gene (C282Y > H63D, chromosome 6, associated with HLA-A3) p abnormal iron sensing and q intestinal absorption (q ferritin, q iron, r TIBC p q transferrin saturation) Iron overload can also be 2° to chronic transfusion therapy (eg, β-thalassemia major) Iron accumulates, especially in liver, pancreas, skin, heart, pituitary, joints Hemosiderin (iron) can be identified on liver MRI or biopsy with Prussian blue stain A Presents after age 40 when total body iron > 20 g; iron loss through menstruation slows progression in women Classic triad of cirrhosis, diabetes mellitus, skin pigmentation (“bronze diabetes”) Also causes restrictive cardiomyopathy (classic) or dilated cardiomyopathy (reversible), hypogonadism, arthropathy (calcium pyrophosphate deposition; especially metacarpophalangeal joints) HCC is common cause of death Treatment: repeated phlebotomy, chelation with deferasirox, deferoxamine, oral deferiprone May present with pruritus, jaundice, dark urine, light-colored stool, hepatosplenomegaly Typically with cholestatic pattern of LFTs (q conjugated bilirubin, q cholesterol, q ALP) PATHOLOGY EPIDEMIOLOGY ADDITIONAL FEATURES Primary sclerosing cholangitis Unknown cause of concentric “onion skin” bile duct fibrosis p alternating strictures and dilation with “beading” of intra- and extrahepatic bile ducts on ERCP, magnetic resonance cholangiopancreatography (MRCP) Classically in middle-aged men Associated with ulcerative with IBD colitis p-ANCA ⊕ q IgM Can lead to 2° biliary cholangitis q risk of cholangiocarcinoma and gallbladder cancer Primary biliary cholangitis Autoimmune reaction p lymphocytic infiltrate + granulomas p destruction of intralobular bile ducts Classically in middle-aged women Secondary biliary cholangitis Extrahepatic biliary obstruction Patients with known May be complicated by obstructive lesions (gallstones, ascending cholangitis p q pressure in intrahepatic ducts p injury/ fibrosis and biliary strictures, pancreatic bile stasis carcinoma) Anti-mitochondrial antibody ⊕, q IgM Associated with other autoimmune conditions (eg, Sjögren syndrome, Hashimoto thyroiditis, CREST, rheumatoid arthritis, celiac disease) GASTROINTESTINAL Gallstones (cholelithiasis) A B ` GASTROINTESTINAL—PATHOLOGY SEC TION III 379 Risk factors (4 F’s): q cholesterol and/or bilirubin, r bile salts, and Female gallbladder stasis all cause stones Fat types of stones: Fertile (pregnant) Cholesterol stones (radiolucent with 10–20% Forty opaque due to calcifications)—80% of stones Diagnose with ultrasound B Treat with elective Associated with obesity, Crohn disease, cholecystectomy if symptomatic advanced age, estrogen therapy, multiparity, Can cause fistula between gallbladder and rapid weight loss, Native American origin GI tract p air in biliary tree (pneumobilia) Pigment stones A (black = radiopaque, Ca2+ bilirubinate, hemolysis; brown = radiolucent, p passage of gallstones into intestinal tract infection) Associated with Crohn disease, p obstruction of ileocecal valve (gallstone ileus) chronic hemolysis, alcoholic cirrhosis, advanced age, biliary infections, total parenteral nutrition (TPN) Most common complication is cholecystitis; can also cause acute pancreatitis, ascending cholangitis RELATED PATHOLOGIES CHARACTERISTICS Biliary colic Associated with nausea/vomiting and dull RUQ pain Neurohormonal activation (eg, by CCK after a fatty meal) triggers contraction of gallbladder, forcing stone into cystic duct Labs are normal, ultrasound shows cholelithiasis Choledocholithiasis Presence of gallstone(s) in common bile duct, often leading to elevated ALP, GGT, direct bilirubin, and/or AST/ALT Cholecystitis Acute or chronic inflammation of gallbladder usually from cholelithiasis (stone at neck of gallbladder [red arrow in C ] with gallbladder wall thickening [yellow arrows]) Calculous cholecystitis: most common type; due to gallstone impaction in the cystic duct resulting in inflammation; can produce 2° infection Acalculous cholecystitis: due to gallbladder stasis, hypoperfusion, or infection (CMV); seen in critically ill patients Murphy sign: inspiratory arrest on RUQ palpation due to pain q ALP if bile duct becomes involved (eg, ascending cholangitis) Diagnose with ultrasound or cholescintigraphy (HIDA scan) Failure to visualize gallbladder on HIDA scan suggests obstruction C Porcelain gallbladder D Ascending cholangitis Calcified gallbladder due to chronic cholecystitis; usually found incidentally on imaging D Treatment: prophylactic cholecystectomy due to high rates of gallbladder cancer (mostly adenocarcinoma) Infection of biliary tree usually due to obstruction that leads to stasis/bacterial overgrowth Charcot triad of cholangitis: Jaundice Fever RUQ pain Reynolds pentad adds: Altered mental status Shock (hypotension) 380 SEC TION III Acute pancreatitis A GASTROINTESTINAL ` GASTROINTESTINAL—PATHOLOGY Autodigestion of pancreas by pancreatic enzymes ( A shows pancreas [yellow arrows] surrounded by edema [red arrows]) Causes: Idiopathic, Gallstones, Ethanol, Trauma, Steroids, Mumps, Autoimmune disease, Scorpion sting, Hypercalcemia/Hypertriglyceridemia (> 1000 mg/dL), ERCP, Drugs (eg, sulfa drugs, NRTIs, protease inhibitors) I GET SMASHED Diagnosis by of criteria: acute epigastric pain often radiating to the back, q serum amylase or lipase (more specific) to 3× upper limit of normal, or characteristic imaging findings Complications: pseudocyst B (lined by granulation tissue, not epithelium), necrosis, hemorrhage, infection, organ failure (ARDS, shock, renal failure), hypocalcemia (precipitation of Ca2+ soaps) B Chronic pancreatitis A Pancreatic adenocarcinoma A B Chronic inflammation, atrophy, calcification of the pancreas A Major causes are alcohol abuse and idiopathic Complications include pancreatic insufficiency and pseudocysts Pancreatic insufficiency may manifest with steatorrhea, fat-soluble vitamin deficiency, diabetes mellitus Amylase and lipase may or may not be elevated (almost always elevated in acute pancreatitis) Very aggressive tumor arising from pancreatic ducts (disorganized glandular structure with cellular infiltration A ); often metastatic at presentation, with average survival ~ year after diagnosis Tumors more common in pancreatic head B (p obstructive jaundice) Associated with CA 19-9 tumor marker (also CEA, less specific) Risk factors: Tobacco use Chronic pancreatitis (especially > 20 years) Diabetes Age > 50 years Jewish and African-American males Often presents with: Abdominal pain radiating to back Weight loss (due to malabsorption and anorexia) Migratory thrombophlebitis—redness and tenderness on palpation of extremities (Trousseau syndrome) Obstructive jaundice with palpable, nontender gallbladder (Courvoisier sign) Treatment: Whipple procedure, chemotherapy, radiation therapy GASTROINTESTINAL ` GASTROINTESTINAL—PHARMACOLOGY SEC TION III 381 ` GASTROINTESTINAL—PHARMACOLOGY Acid suppression therapy GRP Vagus nerve Ach G cells ECL cells Gastrin Histamine Somatostatin H2 blockers Atropine CCKB receptor M3 receptor CI– HCO3– ”alkaline tide”— ↑ blood pH after gastric acid secretion (eg, after meals, vomiting) Prostaglandins H2 receptor Gq Gs Gi HCO3 – + H+ cAMP IP3 /Ca2+ H2CO3 Gastric parietal cell CI– Carbonic anhydrase CO2+ H2O ATPase Proton pump inhibitors Antacids H2 blockers + H Cimetidine, ranitidine, famotidine, nizatidine K + Misoprostol Sucralfate, bismuth Lumen Take H2 blockers before you dine Think “table for 2” to remember H2 MECHANISM Reversible block of histamine H2-receptors p r H+ secretion by parietal cells CLINICAL USE Peptic ulcer, gastritis, mild esophageal reflux ADVERSE EFFECTS Cimetidine is a potent inhibitor of cytochrome P-450 (multiple drug interactions); it also has antiandrogenic effects (prolactin release, gynecomastia, impotence, r libido in males); can cross blood-brain barrier (confusion, dizziness, headaches) and placenta Both cimetidine and ranitidine r renal excretion of creatinine Other H2 blockers are relatively free of these effects Proton pump inhibitors Omeprazole, lansoprazole, esomeprazole, pantoprazole, dexlansoprazole MECHANISM Irreversibly inhibit H+/K+ ATPase in stomach parietal cells CLINICAL USE Peptic ulcer, gastritis, esophageal reflux, Zollinger-Ellison syndrome, component of therapy for H pylori, stress ulcer prophylaxis ADVERSE EFFECTS q risk of C difficile infection, pneumonia r serum Mg2+ with long-term use 382 SEC TION III Antacid use GASTROINTESTINAL ` GASTROINTESTINAL—PHARMACOLOGY Can affect absorption, bioavailability, or urinary excretion of other drugs by altering gastric and urinary pH or by delaying gastric emptying All can cause hypokalemia Overuse can also cause the following problems Aluminum hydroxide Constipation and hypophosphatemia; proximal muscle weakness, osteodystrophy, seizures Aluminimum amount of feces Calcium carbonate Hypercalcemia (milk-alkali syndrome), rebound acid q Can chelate and r effectiveness of other drugs (eg, tetracycline) Magnesium hydroxide Diarrhea, hyporeflexia, hypotension, cardiac arrest Mg2+ = Must go to the bathroom Bismuth, sucralfate MECHANISM Bind to ulcer base, providing physical protection and allowing HCO3 – secretion to reestablish pH gradient in the mucous layer Require acidic environment; usually not given with PPIs/H2 blockers CLINICAL USE q ulcer healing, travelers’ diarrhea Misoprostol MECHANISM A PGE1 analog q production and secretion of gastric mucous barrier, r acid production CLINICAL USE Prevention of NSAID-induced peptic ulcers (NSAIDs block PGE1 production) Also used off-label for induction of labor (ripens cervix) ADVERSE EFFECTS Diarrhea Contraindicated in women of childbearing potential (abortifacient) Octreotide MECHANISM Long-acting somatostatin analog; inhibits secretion of various splanchnic vasodilatory hormones CLINICAL USE Acute variceal bleeds, acromegaly, VIPoma, carcinoid tumors ADVERSE EFFECTS Nausea, cramps, steatorrhea q risk of cholelithiasis due to CCK inhibition Sulfasalazine MECHANISM A combination of sulfapyridine (antibacterial) and 5-aminosalicylic acid (anti-inflammatory) Activated by colonic bacteria CLINICAL USE Ulcerative colitis, Crohn disease (colitis component) ADVERSE EFFECTS Malaise, nausea, sulfonamide toxicity, reversible oligospermia Loperamide MECHANISM Agonist at μ-opioid receptors; slows gut motility Poor CNS penetration (low addictive potential) CLINICAL USE Diarrhea ADVERSE EFFECTS Constipation, nausea GASTROINTESTINAL ` GASTROINTESTINAL—PHARMACOLOGY SEC TION III 383 Ondansetron MECHANISM 5-HT3 antagonist; r vagal stimulation Powerful central-acting antiemetic CLINICAL USE Control vomiting postoperatively and in patients undergoing cancer chemotherapy ADVERSE EFFECTS Headache, constipation, QT interval prolongation, serotonin syndrome Metoclopramide MECHANISM D2 receptor antagonist q resting tone, contractility, LES tone, motility, promotes gastric emptying Does not influence colon transport time CLINICAL USE Diabetic and postsurgery gastroparesis, antiemetic, persistent GERD ADVERSE EFFECTS q parkinsonian effects, tardive dyskinesia Restlessness, drowsiness, fatigue, depression, diarrhea Drug interaction with digoxin and diabetic agents Contraindicated in patients with small bowel obstruction or Parkinson disease (due to D2-receptor blockade) Orlistat MECHANISM Inhibits gastric and pancreatic lipase p r breakdown and absorption of dietary fats CLINICAL USE Weight loss ADVERSE EFFECTS Steatorrhea, r absorption of fat-soluble vitamins Laxatives Indicated for constipation or patients on opiates requiring a bowel regimen Bulk-forming laxatives Psyllium, methylcellulose MECHANISM Soluble fibers; draw water into gut lumen, forming a viscous liquid that promotes peristalsis ADVERSE EFFECTS Bloating Osmotic laxatives Magnesium hydroxide, magnesium citrate, polyethylene glycol, lactulose MECHANISM Provide osmotic load to draw water into GI lumen Lactulose also treats hepatic encephalopathy because gut flora degrade it into metabolites (lactic acid, acetic acid) that promote nitrogen excretion as NH4+ ADVERSE EFFECTS Diarrhea, dehydration; may be abused by bulimics Stimulants Senna MECHANISM Enteric nerve stimulation p colonic contraction ADVERSE EFFECTS Diarrhea, melanosis coli Emollients Docusate MECHANISM Osmotic draw into lumen p q water absorption by stool ADVERSE EFFECTS Diarrhea Aprepitant MECHANISM Substance P antagonist Blocks NK1 receptors in brain CLINICAL USE Antiemetic for chemotherapy-induced nausea and vomiting 384 ` NOTES SEC TION III GASTROINTESTINAL ... L E Passing Rates for the 2 014 –2 015 USMLE Step 1. 2 2 014 2 015 No Tested % Passing No Tested % Passing 19 ,582 96% 20, 213 96% 812 68% 898 68% 20,394 95% 21, 111 94% 2, 810 93% 3 ,18 5 93% 36 69% 37... your First Aid study with case-based reviews (eg, First Aid Cases for the USMLE Step 1) , flash cards (eg, First Aid Flash Facts), and practice questions (eg, the USMLE- Rx Step Qmax) Read the chapter... email us at: firstaidteam@yahoo.com Contributions submitted by May 15 , 2 017 , receive priority consideration for the 2 018 edition of First Aid for the USMLE Step We thank you for taking the time to