Hepatology and Transplant Hepatology Board Review E-Book

Jawad Ahmad

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 524

Veröffentlichungsjahr: 2023

Beschreibung

Hepatology and Transplant Hepatology Board Review Hepatology and Transplant Hepatology: Board Review with Multiple Choice Questions is the only source you will need to pass the American Board of Internal Medicine (ABIM) transplant hepatology examination. Written by two highly experienced hepatologists, this indispensable study guide covers all the main topics tested on the exam: pre-transplant, perioperative, post-transplant, and transplant immunology. 261 multiple-choice questions with answers, including questions based on the authors' real-life cases, are designed to mimic the clinical scenarios you will encounter in hepatology practice. Questions testing your medical knowledge, clinical insight, and management skills are supported by brief topic overviews, key references, high-quality images, pathology slides, and cholangiograms. Throughout the book, "Pearls" and "Must-Know Facts" sections emphasize testable points that are likely to appear on the ABIM board examination. The first hepatology-specific study aid of its kind, Hepatology and Transplant Hepatology: Board Review with Multiple Choice Questions is a must-have for medical professionals preparing for the hepatology boards, as well as practicing gastroenterologists and hepatologists who want to refresh their knowledge and test their proficiency in both fundamental and advanced hepatology topics.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

Preface

Acknowledgments

Exam Blueprint

Table of Abbreviations Used and Units for Laboratory Tests

Questions and Answers

Question 1

Question 2

Question 3

Question 4

Question 5

Question 6

Question 7

Question 8

Question 9

Question 10

Question 11

Question 12

Question 13

Question 14

Question 15

Question 16

Question 17

Question 18

Question 19

Question 20

Question 21

Question 22

Question 23

Question 24

Question 25

Question 26

Question 27

Question 28

Question 29

Question 30

Question 31

Question 32

Question 33

Question 34

Question 35

Question 36

Question 37

Question 38

Question 39

Question 40

Question 41

Question 42

Question 43

Question 44

Question 45

Question 46

Question 47

Question 48

Question 49

Question 50

Question 51

Question 52

Question 53

Question 54

Question 55

Question 56

Question 57

Question 58

Question 59

Question 60

Question 61

Question 62

Question 63

Question 64

Question 65

Question 66

Question 67

Question 68

Question 69

Question 70

Question 71

Question 72

Question 73

Question 74

Question 75

Question 76

Question 77

Question 78

Question 79

Question 80

Question 81

Question 82

Question 83

Question 84

Question 85

Question 86

Question 87

Question 88

Question 89

Question 90

Question 91

Question 92

Question 93

Question 94

Question 95

Question 96

Question 97

Question 98

Question 99

Question 100

Question 101

Question 102

Question 103

Question 104

Question 105

Question 106

Question 107

Question 108

Question 109

Question 110

Question 111

Question 112

Question 113

Question 114

Question 115

Question 116

Question 117

Question 118

Question 119

Question 120

Question 121

Question 122

Question 123

Question 124

Question 125

Question 126

Question 127

Question 128

Question 129

Question 130

Question 131

Question 132

Question 133

Question 134

Question 135

Question 136

Question 137

Question 138

Question 139

Question 140

Question 141

Question 142

Question 143

Question 144

Question 145

Question 146

Question 147

Question 148

Question 149

Question 150

Question 151

Question 152

Question 153

Question 154

Question 155

Question 156

Question 157

Question 158

Question 159

Question 160

Question 161

Question 162

Question 163

Question 164

Question 165

Question 166

Question 167

Question 168

Question 169

Question 170

Question 171

Question 172

Question 173

Question 174

Question 175

Question 176

Question 177

Question 178

Question 179

Question 180

Question 181

Question 182

Question 183

Question 184

Question 185

Question 186

Question 187

Question 188

Question 189

Question 190

Questions 191–200: Immunology Questions

Question 201

Question 202

Question 203

Question 204

Question 205

Question 206

Question 207

Question 208

Question 209

Question 210

Question 211

Question 212

Question 213

Question 214

Question 215

Question 216

Question 217

Question 218

Question 219

Question 220

Question 221

Question 222

Question 223

Question 224

Questions 225–227

Questions 228–231

Question 232

Question 233

Question 234

Question 235

Question 236

Questions 237–243 (Infections and Prophylaxis)

Question 244

Questions 245 and 246

Question 247

Questions 248 and 249

Questions 250 and 251

Question 252

Question 253

Question 254

Question 255

Question 256

Question 257

Index

End User License Agreement

Guide

Cover

Table of Contents

Title Page

Copyright

Preface

Acknowledgments

All good things begin

Exam Blueprint

Table of Abbreviations Used and Units for Laboratory Tests

Begin Reading

Index

End User License Agreement

Pages

iii

iv

vii

viii

ix

xi

xii

xiii

xv

xvi

xvii

xviii

xix

xxi

xxii

xxiii

xxiv

xxv

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

25

26

27

28

29

30

31

33

34

35

36

37

39

40

41

43

44

45

46

47

48

49

50

51

52

53

55

56

57

58

59

60

61

62

63

65

66

67

68

69

71

72

73

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

101

102

103

104

105

106

107

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

171

172

173

174

175

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

195

196

197

198

199

201

202

203

204

205

207

208

209

210

211

213

214

215

216

217

218

219

221

222

223

224

225

226

227

229

230

231

232

233

234

235

236

237

239

240

241

242

243

244

245

247

249

251

252

253

255

256

257

258

259

261

262

263

264

265

266

267

269

270

271

272

273

275

276

277

279

280

281

282

283

284

285

287

288

289

290

291

292

293

295

296

297

298

299

300

301

303

304

305

306

307

309

310

311

313

314

315

316

317

319

320

321

322

323

324

325

326

327

329

330

331

332

333

334

335

336

337

338

339

341

342

343

344

345

346

347

349

350

351

353

354

355

357

358

359

361

362

363

364

365

366

367

369

370

371

372

373

375

376

377

378

379

380

381

382

383

384

385

386

387

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

429

430

431

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

541

542

543

544

545

546

547

548

549

550

551

553

554

555

557

558

559

561

562

563

564

565

Hepatology and Transplant Hepatology Board Review

Jawad Ahmad, MD, FRCP, FAASLD

Icahn School of Medicine at Mount SinaiNew York, NY, USA

Shahid M. Malik, MD

University of Pittsburgh Medical CenterPittsburgh, PA, USA

This edition first published 2023© 2023 John Wiley & Sons Ltd

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Jawad Ahmad and Shahid M. Malik to be identified as the authors of this work has been asserted in accordance with law.

Registered OfficesJohn Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USAJohn Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK

For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.

Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats.

Trademarks: Wiley and the Wiley logo are trademarks or registered trademarks of John Wiley & Sons, Inc. and/or its affiliates in the United States and other countries and may not be used without written permission. All other trademarks are the property of their respective owners. John Wiley & Sons, Inc. is not associated with any product or vendor mentioned in this book.

Limit of Liability/Disclaimer of Warranty

The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging‐in‐Publication Data applied forISBN: 9781119853510 (paperback)

Cover Design: WileyCover Images: © natali_mis/Adobe Stock Photos

Preface

Like several other specialties in medicine, historically, hepatology was always an interesting field with diagnostic conundrums that required getting a good history, a whole slew of eponymous physical exam findings, interpretation of multiple blood tests, and the “easy access to the liver” to get a biopsy that you could spend many hours reviewing. And then provide the patient with supportive care and observe!

This changed in the last 30–40 years ago with advancements in our understanding of viral hepatitis that led to initially effective and then highly effective therapies and vaccines and most importantly the development of immunosuppressive drugs that allowed liver transplantation to become the definitive treatment for patients with end‐stage liver disease.

As a result, hepatology and transplant hepatology have emerged as individual disciplines, separate from gastroenterology, and this has been recognized by the American Board of Internal Medicine (ABIM) who have offered a transplant hepatology board exam since 2006.

Since taking the exam in 2006 (and then recertifying in 2016), I have been frustrated at the lack of study guides or board review material in hepatology as there are in gastroenterology (including an annual course that I co‐direct at the Icahn School of Medicine at Mount Sinai in New York). There are many seminal textbooks of liver disease, but they are not the place to turn to when studying for the board exam. Hence, the idea for this book.

The ABIM website for transplant hepatology (https://www.abim.org/Media/lo0jcigs/transplant-hepatology.pdf) gives quite a lot of information about the content of the examination. In 2021, the examination was divided into pre‐transplant (45%), peri‐operative (20%), post‐transplant (25%), transplant immunology (5%), and miscellaneous (5%) categories.

Shahid and I have tried to cover all the main topics that could make an appearance in the board examination, but in a more concise format, so it can be read at leisure or while you have a few spare minutes between seeing patients or on rounds. To keep things interesting, we have added cases that display an interesting image or teaching point and an occasional zebra.

To mimic the examination, we have assembled 257 multiple‐choice questions, but we have deliberately not divided them into chapters. All the questions involving patients are based on real cases we have seen (with some changes to protect patient confidentiality) and the images, pathology slides, cholangiograms are all original. The bulk of the actual examination is case based. We have used the most current management guidelines from the main liver societies, but as with most of medicine, there is room for individual comments. After each question, there is a brief overview of the topic and “pearls” are scattered throughout the book for points that we felt needed to be emphasized and are likely to come up on the board examination.

The fact of the matter is, the ABIM board examination is very well written (it's written by people like us!). The questions are clinically relevant and based on scenarios you will encounter in your hepatology practice. Very few of the questions are “out of left field.” There may be a handful of terms that you may not be familiar with (such as prope tolerance, Tregs, SF‐36 questionnaire), but we hope we've covered most of these terms in this text. The questions on the exam are not meant to trick you. The questions are meant to test your medical knowledge, clinical acumen, and management skills. The test writers they are not going to try to trip you up you with a technical point, for example the genetic defect for BRIC is ATP8B1 (and not ATP7B which is seen in Wilson disease).

With that being said, the boards are the boards and there will be questions that are “board answers” but are not necessarily what we do in clinical practice. Three examples that jump to mind:

Deferring treating for

autoimmune hepatitis

(

AIH

) unless the enzyme elevation is more than 2–3× upper limits of normal. Most hepatologists would end up treating in the setting of even mild enzyme elevation, assuming other parameters (serologies and biopsy) are consistent with AIH.

Obtaining a liver biopsy in a patient with hemochromatosis with a ferritin >1000 ng/mL to rule out cirrhosis. Today, most of us would obtain a noninvasive imaging study (FibroScan, Shear‐Wave Elastography, or MRE) to assess the degree of fibrosis as opposed to a liver biopsy.

The role of

ursodeoxycholic acid

(

UDCA

) in patients with

primary sclerosing cholangitis

(

PSC

). Most hepatologists are still trialing patients on a course of UDCA, but for the boards, UDCA is always the wrong choice when it comes to PSC.

When in doubt, answer the question based on guideline recommendations.

Our main objective in writing this review was to have it be the only source you will need to (comfortably) pass the transplant hepatology examination. We have included key references in case you wanted to delve deeper into a subject, but we are hopeful that everything you need for the examination will be in this book. Until now there were no MCQ/review books specifically designed for the transplant hepatology boards. There are gastroenterology board reviews with liver questions, but nothing covering the full range of topics outlined by the ABIM.

From 2016–2020, there were 265 transplant hepatology test‐takers. The past rate has consistently been over 95%. Why such a high pass rate? Well, it goes without saying that hepatologists in general are quite smart. However, the fact of the matter is to pass the examination you only need to get at least 70% of the questions correct (this will change slightly from year to year). Based on the overall high pass rates, we can surmise that test‐takers take these exams very seriously. Not surprising given the cost of the ABIM examinations (seriously, how they justify the $3000 price tag is beyond me!). The overall pass rate of the 56,420 test takers for the 19 specialty board examinations over the last 5 years is 91%. So maybe hepatologists aren't as special as we thought, or doctors make sure they get their money's worth.

Board examination questions should be clear and unambiguous. The board will avoid questions with a lead‐in containing “all of the following EXCEPT.” We also tried to avoid questions like these, but ultimately included a handful as they are a nice means of solidifying factual points and there are a couple of trick questions (to keep you on your toes). The board questions also typically lag 1–2 years from clinical practice. Therefore, although we included the new hepatocellular carcinoma (HCC) therapies in our review, these agents are unlikely to be tested on for a few years. The boards also include some “throw away” or “litmus” questions used to gauge answers for future examinations. Remember a vast majority of test‐takers should answer most examination questions correctly. The boards like to use questions where the correct answers are agreed upon by most. You, of course, will assume that every test question on your examination will be counted toward your grade.

The questions in this book are meant as a springboard to the clinical pearls which are the real “meat” of this review. We designed each “pearl” to be a potentially testable point. Therefore, in essence, this book has well over 1500 potential testable points.

The day of the examination will go by relatively quickly, but it is easy to get burned out while studying for the examination. Pacing yourself is key. Studying can be a tedious process. We've included some personal anecdotes to help break the monotony of studying. Our recommendation is to start this review about 12 weeks before your examination. We suggest doing about 25 questions a week with a concentration on learning the clinical pearls. About 10 days before the examination, I would suggest re-doing the questions to bolster your confidence.

All right, enough stalling. Let's get to studying and smash these boards!

Remember: save livers…save lives.

Jawad Ahmad

Shahid M. Malik

Acknowledgments

“The fool doth think he is wise, but the wise man knows himself to be a fool”

As You Like It

William Shakespeare

From your first day of medical school, it becomes quickly apparent that despite being the smartest kid in school, you know very little. This is especially so in the British system of medical school training where an 18 year‐old adolescent is given a short white coat and becomes a medical student, just 5 short years away from reciting the Hippocratic coat, donning a long white coat, and prefixing Dr. to their name. However, those 5 years are just the start of your medical education, the start of a journey where there is no destination but the route you take during that journey will define how wise you become.

Becoming a doctor is hard. Teaching others how to practice medicine is even harder. Neither happens without the influence of many individuals – other doctors, nurses, physician extenders, fellows, coordinators, endoscopy technicians, students, and staff, but most of all patients. We go into medicine for many different reasons but earning the trust of another human being, putting their health and life in your hands, remains the integral part of your journey.

I was privileged to spend my 5 years of medical school in London at the Royal Free Hospital School of Medicine. It was there that I first developed an appreciation for liver disease through sometimes fun, sometimes intimidating, but always rewarding interaction with giants in the field of hepatology including Dame Sheila Sherlock, Professor Peter Scheuer, Professor Andrew Burroughs, and all the others who worked on the Liver Unit.

One of the most gratifying aspects of medicine is the interaction with colleagues within your specialty and in different disciplines during weekly conferences, on rounds, or just in the hallway. Throughout the last 20 plus years, there have been hundreds of individuals ranging from eminent professors to first year medical students, who I am indebted to for teaching, stimulating and continually appraising what I think I know and the decisions that I make. At the University of Pittsburgh, it was my honor to be taught by and work with Drs. Obaid Shaikh, Mordechai Rabinovitz, Adam Slivka, John Martin, and Kathy Downey. At the Icahn School of Medicine at Mount Sinai, it has been a privilege to work with some of the smartest people I know and the epitome of a multi‐disciplinary team.

I would like to acknowledge the production team at Wiley for their incredible professionalism and patience in putting this book together during an unprecedented pandemic.

I would not be here without love and stability that family brings. I have been blessed with three beautiful children, Leila, Noor, and Aryia, who remind me, that for all my mistakes, at least three times I did something right. Finally, I dedicate this book to my loving parents, Iftikhar and Gulzar, who remain the wisest people I know.

Jawad Ahmad, MD, FRCP, FAASLD

January 2022

New York, NY

All good things beginIn the name of God, the Most Beneficent, the Most Merciful

I can't help but roll my eyes when I hear doctors being described as or having developed a God complex. Any doctor who does hold him or herself in such high regard either has not worked long enough or is delusional. Medicine is the most humbling of professions. Patients remind us of that on a daily basis.

Writing a book of this breadth is also a humbling experience. Being an educator to medical trainees is a great responsibility. Please accept my apologies for any errors, oversights, or omissions.

I want to thank all those who helped educate and train me over the years, in particular, Doctors: Kevin McGrath, Adam Slivka, Rocky Schoen, Abhinav Humar, David Whitcomb, and of course Jawad. Of all my mentors, I am most appreciative to Dr. Mordechai Rabinovitz, whose passion and “love for all things liver” was one of the main reasons I pursued a career in hepatology. To this day, discussing (some may perceive it as arguing) challenging cases with the Professor (in the hallways of Montefiore Hospital) is one of the joys that keep me in academic medicine.

Thank you to all my trainees, nurses, and mid‐level providers. A special thanks to Cathy Freehling for always looking out for me. Thanks, are also due to my patients (and families) who have entrusted their health in my hands.

I want to thank my three brothers, all accomplished physicians in their own right: Salman, Shehzad, and Sajjad Malik.

I want to thank my wife Rafia for her loyalty, patience and devotion, but most of all for giving me my three most precious gifts, Safa, Summer and Ejaz.

I have been given so much, very little of which is the result of my own efforts. I am forever in debt to the unwavering support of my parents. I am blessed with the constant prayers of my Mother, Abida Malik, and the beautiful example of my Father, Dr. Maqsood A. Malik, a great cardiologist and an even better person.

Finally, I want to acknowledge the four Pennsylvania cities that have played an integral role in my medical journey: Pottsville, Erie, Philadelphia, and Pittsburgh!

Pittsburgh, PAJanuary 2022

Shahid M. Malik, MD

Exam Blueprint

The entire exam is on computer and lasts one day. It is divided into four 2‐hour sessions containing up to 60 multiple‐choice questions. Test takers are allotted up to 100 minutes of break time. Breaks can only be taken in between the 60 block sessions (not during). There is a 30‐minute optional tutorial session, an honesty pledge which is up to 10 minutes, and an optional 10‐minute survey; the total test duration could be up to 4 × 120 = 480 + 100 minutes break + 50 minutes (tutorial, pledge, and survey) = 730 minutes or up to 10.5 hours.

The blueprint below from the ABIM expands additional detail on the five broad exam content categories.

Pretransplant

108 questions

Biliary atresia

(Pediatrics)

4–5 questions

Genetic liver diseases

9–10 questions

Alpha1‐antitrypsin deficiency Cholestatic syndromes (PFIC, BRIC) Cystic fibrosis Fibrocystic diseases (caroli and choledochal cysts) Familial amyloid polyneuropathy Hereditary hemorrhagic telangiectasia Iron overload syndromes Mitochondrial defect Urea cycle defects Wilson

Autoimmune disorders

7–8 questions

Primary biliary cholangitis Autoimmune hepatitis Overlap syndromes Primary sclerosing cholangitis IgG4 cholangiopathy Sarcoidosis Celiac disease

Viral hepatitis

16–18 questions

A‐E Other viruses (EBV, CVM, HSV)

Outflow diseases

(Budd Chiari, VOD)

3–4 questions

Growth failure

(pediatrics)

4–5 questions

Portal hypertension

4–5 questions

Varices Ascites Hepatic hydrothorax SBP Encephalopathy HRS HPS PPHTN Noncirrhotic PHTN

Liver tumors

9–10 questions

HCC Hepatoblastoma Cholangiocarcinoma Hemangioendothelioma NET Benign tumors (adenoma, FNH, hemangioma)

Pretransplant

108 questions

Selection and evaluation for transplantation

21–23 questions

PELD and MELD scoring systems including exceptions Contraindications to liver transplantation Live donor selection Impact of infection, malignancy and malnutrition on outcomes Co‐morbidities including HIV

Acute liver failure

12 questions

Epidemiology Etiology Pathophysiology Assessment Prognostic indicators Treatment Indications for liver transplantation Outcomes based on age and diagnosis

Alcoholic liver disease

4–5 questions

Transfer of care

3–4 questions

DILI

3–4 questions

Perioperative

48 questions

Donor Selection

7–8 questions

Extended criteria donors Steatosis Viral infection Domino liver transplant

Surgical options, complications to graft and donor types

(including ABO blood type)

7–8 questions

Perioperative complications

14–15 questions

PNF Vascular complications Infections (bacterial, viral, fungal) HBV and HCV therapy Biliary complications Allograft rejection Metabolic complications (including neuro and nephrotoxicity)

Drug hepatotoxicity

4–5 questions

Nutritional support

4–5 questions

Living donor

2–3 questions

Small for size Donor complications Recipient complications

Donor transmission of disease

2–3 questions

Donation after cardiac death

2–3 questions

Split graft transplantation

2–3 questions

Post‐transplant

60 questions

Immune complications

9–10 questions

Rejection GVHD Alloimmune and autoimmune diseases (De novo)

Nonimmune complications

12 questions

Diabetes Renal Bone Growth and development (pediatrics) Cardiovascular complications Vascular complications

Infectious Complications

12 questions

Viral infections (CMV, EBV, HSV) Bacterial infections Fungal infections

Recurrence Disease Post Transplant

(HCV, PBC, AIH, malignancy)

7–8 questions

Post‐Transplant Malignancy

PTLD Surveillance

4–5 questions

Indications for Retransplantation

4–5 questions

Adherence

4–5 questions

QOL

4–5 questions

Transplant immunology

12 questions

Basic immunology

4–5 questions

Innate and adaptive immune system Immune response Tolerance

Mechanism of action and pharmokinetics of IS meds

4–5 questions

Cyclosporine and tacrolimus MMF and azathioprine Sirolimus and everolimus Antibody therapy Drug–drug interactions Corticosteroids

Short‐term immune and nonimmune toxicity of IS medications

2–3 questions

Miscellaneous

12 questions

Statistics

4–5 questions

Kaplan–Meier Cox proportional hazards Relative risk Odds ratio Receiver operating characteristic curves

Ethics

4–5 questions

Psychosocial evaluation Living donor transplantation Transplant tourism Clinical trial participation

Managed care and reimbursement

2–3 questions

Regulatory issues

2–3 questions

Policy implication of organ shortage regulation

Table of Abbreviations Used and Units for Laboratory Tests

Abbreviation

Units

Total bilirubin

Tbili

g/dL

Aspartate aminotransferase

AST

U/L

Alanine aminotransferase

ALT

U/L

Alkaline phosphatase

ALP

U/L

Gamma glutamyl transferase

GGT/GGTP

U/L

Albumin

g/dL

Total protein

g/dL

International normalized ratio

INR

Creatinine

Cr

mg/dL

Hepatitis B surface antigen

HBsAg

Hepatitis B surface antibody

Anti‐HBs

Hepatitis B e antigen

HBeAg

Hepatitis B e antibody

Anti‐HBe

Hepatitis B core antibody total

Anti‐HBc

Hepatitis B core antibody IgM

Anti‐HBcIgM

Hepatitis B virus

HBV

Hepatitis C virus

HCV

Hepatitis A virus

HAV

Hepatitis E virus

HEV

Hepatitis D virus

HDV

Human immunodeficiency virus

HIV

Hepatitis A antibody

Anti‐HAV

Hepatitis D antibody

Anti‐HDV

Hepatitis C antibody

Anti‐HCV

Anti‐nuclear antibody

ANA

Smooth muscle antibody

SMA

Anti‐mitochondrial antibody

AMA

Immunoglobulin

IGG

mg/dL

Alfa‐fetoprotein

AFP

ng/mL

Abbreviation

Units

Carbohydrate antigen 19‐9

CA19‐9

U/mL

Ultrasound

US

Computed tomography

CT

Magnetic resonance image

MRI

Positron emission tomography

PET

Endoscopic retrograde cholangiopancreatography

ERCP

Endoscopic ultrasound

EUS

Percutaneous transhepatic cholangiogram

PTC

Hepatocellular carcinoma

HCC

Cholangiocarcinoma

CCA

Upper limit of normal

ULN

Ursodeoxycholic acid

UDCA

Primary biliary cholangitis

PBC

Primary sclerosing cholangitis

PSC

Hemoglobin

Hb

g/dL

White blood cell count

WBC

×10

3

/μL

Platelet count

Plts

×10

3

/μL

Electrocardiogram

EKG

Chest X‐ray

CXR

Hepatopulmonary syndrome

HPS

Portopulmonary hypertension

PPHTN

Liver transplant

LT

Orthotopic liver transplant

OLT

Live donor liver transplant

LDLT

Calcineurin inhibitor

CNI

Cytomegalovirus

CMV

Epstein Barr virus

EBV

Herpes simplex virus

HSV

Polymerase chain reaction

PCR

Post‐transplant lymphoproliferative disorder

PTLD

Gastric antral vascular ectasia

GAVE

Argon plasma coagulation

APC

Trans‐jugular intra‐hepatic porto‐systemic shunt

TIPS

Balloon retrograde transvenous obliteration

BRTO

Kaposi sarcoma

KS

Human herpes virus

HHV

Mammalian (mechanistic) target of rapamycin

mTOR

Donation after cardiac/circulatory death

DCD

Abbreviation

Units

Extended criteria donor

ECD

Hepatic artery stenosis/thrombosis

HAS/HAT

Primary non‐function

PNF

Non‐alcoholic steatohepatitis

NASH

Esophagogastroduodenoscopy

EGD

Liver function tests

LFTs

Tacrolimus

Tacro/FK

ng/mL

Cyclosporine

Cyclo

ng/mL

Mycophenolate mofetil

MMF

Sirolimus/everolimus

ng/mL

Inflammatory bowel disease

IBD

Mycobacterium avium‐intracellulare

MAI

Acquired immunodeficiency syndrome

AIDS

Fluorescent in situ hybridization

FISH

Next‐generation sequencing

NGS

Neuroendocrine tumor

NET

Yttrium 90

Y90

Transarterial chemoembolization

TACE

Radiofrequency ablation

RFA

Nonsteroidal anti‐inflammatory drug

NSAID

Model for end‐stage liver disease

MELD

Pediatric model for end‐stage liver disease

PELD

Body mass index

BMI

kg/m

2

Lactate

mmol/L

Ammonia

NH3

μmol/L

Emergency room

ER

Resistive index

RI

Focal nodular hyperplasia

FNH

Nodular regenerative hyperplasia

NRH

Recurrent pyogenic cholangitis

RPC

Major histocompatibility complex

MHC

Interleukin

IL

Antigen presenting cell

APC

T cell receptor

TCR

Interferon gamma

IFN‐g

Delayed type hypersensitivity

DTH

Ferritin

ng/mL

Hemophagocytic lymphohistiocytosis

HLH

Abbreviation

Units

Acute cellular rejection

ACR

Rejection activity index

RAI

Autoimmune hepatitis

AIH

Serum ascites albumin gradient

SAAG

mg/dL

Drug‐induced liver injury

DILI

Biliary atresia

BA

Alpha‐1‐antitrypsin (deficiency)

A1AT, AATD

Graft to recipient weight ratio

GRWR

Anti‐thymocyte globulin

ATG

Hepatorenal syndrome

HRS

Glomerular filtration rate

GFR

Organ procurement and transplantation network

OPTN

Progressive familial intrahepatic cholestasis

PFIC

Hepatitis B immune globulin

HBIG

Tuberculosis

TB

Ceruloplasmin

mg/dL

Nonselective beta‐blocker

NSBB

Benign intrahepatic cholestasis

BRIC

N

‐acetyl‐

L

‐cysteine

NAC

Mean corpuscular volume

MCV

FL

Triglyceride

TG

mg/dL

Direct acting anti‐virals

DAA

Hemolytic uremic syndrome

HUS

Right upper quadrant

RUQ

Intravenous drug use/abuse

IVDU/IVDA

Kilo‐pascal

kPa

Tenofovir disoproxil fumarate

TDF

Tenofovir alafenamide

TAF

Acute fatty liver of pregnancy

AFLP

Hemolysis, elevated liver tests and low platelets

HELLP

Sinusoidal obstruction syndrome

SOS

Food and drug administration

FDA

Spontaneous bacterial peritonitis

SBP

Portal hypertension

PHTN

Sodium

Na

Potassium

K

Cold ischemia/ischemic time

CIT

Warm ischemia/ischemic time

WIT

Abbreviation

Units

Antibody mediated rejection

AMR

Donor specific antibody

DSA

Hereditary hemorrhagic telangiectasia

HHT

Arterial‐vascular‐malformations

AVM

Posterior reversible encephalopathy syndrome

PRES

Portosystemic encephalopathy

PSE

Acetaminophen

APAP

Pulmonary artery systolic pressure

PASP

Small for size syndrome

SFSS

Spontaneous splenorenal shunt

SSRS

Thromboelastographic

TEG

Graft‐versus‐host disease

GVHD

Donor risk index

DRI

Questions and Answers

Question 1

A 31‐year‐old lawyer presents with a 2‐week history of pruritus and dark urine. He finally came to the emergency room when his wife noted his eyes were yellow. His symptoms started following an upper respiratory infection. Review of systems is notable for an 8‐pound weight loss. The patient recalls one prior episode of self‐remitting jaundice and pruritus 10 years prior that was attributed to an infectious hepatitis.

On physical exam, the patient has marked scleral icterus and diffuse excoriations. His abdominal exam is benign. Mentation and neurological exam are normal.

Laboratory studies:

Total bilirubin of 14.6 with a direct component of 11; AST 112, ALT 118, ALP 333, and GGT of 32; INR is 1.

An extensive acute liver workup including serologies for viral and autoimmune hepatitis are negative; ceruloplasmin is 32. An ultrasound reveals gallstones but is otherwise normal.

Symptomatic management is recommended. The patient's symptoms resolve, and labs return to normal in 10 weeks. The diagnosis is established based on genetic testing.

Question

Which of the following is FALSE regarding this disease?

Liver pathology would be mostly benign.

A cholangiogram would be normal.

Corticosteroids are the treatment of choice.

The most commonly associated genetic abnormality is in ATP8B1.

Total serum bile acids would be expected to be increased.

C is the correct answer.

Commentary – BRIC

Clinical Pearls: Benign Recurrent Intrahepatic Cholestasis (BRIC)

Recurrence of an episode of jaundice is required for the diagnosis of

benign recurrent intrahepatic cholestasis

(

BRIC

).

For the boards

gamma glutamyl transferase

(

GGT

) will be normal.

Total serum bile acids are typically markedly elevated.

BRIC is an autosomal recessive disease.

Defects are associated with ATP8B1 (caution with the gene for Wilson: ATP7B); the more severe defects in this gene are associated with

progressive familial intrahepatic cholestasis

(

PFIC

); this gene is likely also responsible for

intrahepatic cholestasis of pregnancy

(

ICP

).

Episodes usually appears after an upper respiratory infection (>50% of cases), followed by drugs (namely hormonal).

Mean duration of episodes is six months.

A total of 80% of individuals will present within the first two decades of life. The mean age of first episode is 15 years.

ATP8B1 is also expressed in pancreas and small intestine (hence, pancreatitis and diarrhea as potential clinical clues).

Treatment is supportive; rifampin,

ursodeoxycholic acid

(

UDCA

) and in extreme cases plasmapheresis.

Proposed diagnostic criteria:

At least two episodes of jaundice separated by symptom‐free interval lasting months to years

Elevated

alkaline phosphatase

(

ALP

) (typically GGT low to mildly elevated)

Severe pruritus

Liver histology relatively benign other than centrilobular cholestasis

Normal cholangiogram

Absence of other causes of cholestasis (namely drug and pregnancy)

Notes

BRIC is one of my favorite diseases. Making a diagnosis can make you look quite smart! The disproportionately low GGT is a hallmark of BRIC and should raise high suspicion. The presentation can be dramatic, but ultimately everyone is relieved when the diagnosis is established. To fulfill diagnostic criteria, a “recurrent” attack is necessary. Given the severity of the itching episodes, patients (and spouses) may describe this disorder as anything but “benign.”

Reference

Triggers of benign recurrent intrahepatic cholestasis and its pathophysiology: a review of literature. PMID: 34599573.

Question 2

Review the following liver biopsy slide.

Question

Which statement regarding this disease is FALSE?

A deficiency of the protein alpha‐1 antitrypsin within the liver leads to hepatic damage.

Mutation in the

SERPINAI

gene causes deficiency of alpha‐1 antitrypsin.

Alpha‐1 antitrypsin protects the body from neutrophil elastase.

Patient's with ZZ phenotype are at the highest risk of developing progressive liver disease.

PAS globules are not specific for alpha‐1‐antitrypsin deficiency (A‐1ATD).

A is the correct answer.

Commentary – A‐1ATD

Clinical Pearls: Alpha‐1‐Antitrypsin Deficiency (A‐1ATD)

A‐1ATD is an autosomal recessive disease.

Alpha‐1 Antitrypsin is a protease inhibitor of the proteolytic enzyme elastase.

Mutation in the

ser

ine

p

rotease

i

nhibitor

gene:

SERPINAI

gene causes deficiency of alpha‐1 antitrypsin.

Liver disease results from the accumulation within hepatocytes of unsecreted variant alpha‐1 antitrypsin protein.

Alpha‐1 antitrypsin protects the body (specifically the lung) from neutrophil elastase, an enzyme released from white cells to fight infection but can also attack normal (lung) tissue.

Pulling this all together: A‐1ATD is a genetic disease that leads to a mutation in

SERPINA1

which leads to deficiency/defective A‐1ATD. Variants of alpha‐1 accumulate in the liver and causes damage. Less alpha‐1 in the circulation leads to less destruction of neutrophil elastase. More neutrophil elastase leads to lung damage.

Carotid artery dissection and ulcerative neutrophilic panniculitis are associated manifestations.

The most clinically significant phenotype is : ZZ, followed by SZ and MZ:

Prevalence of liver disease in ZZ patients is ∼10%:

Of which half can progress to cirrhosis.

Lung disease estimated to be ∼25% in patients with ZZ phenotype.

In infants, it can present as prolonged jaundice after birth.

Intravenous alpha‐1 augmentation is given to ZZ individuals who have reduction in FEV1.

Notes

A representative slide of a patient with A‐1ATD. The Periodic acid Schiff (PAS)‐positive stain demonstrating the striking fuchsia‐colored diastase‐resistant globules within hepatocytes.

Reference

Alpha‐1 antitrypsin deficiency. PMID: 20301692.

Question 3

A 44‐year‐old male presents to his primary care physician with complaints of bilateral joint pain in his hands. Review of systems is notable for loss of libido and erectile dysfunction. Bloodwork reveals an iron saturation of 73% and ferritin of 690.

Question

Treatment of this underlying condition would be expected to lead to improvement in all of the following EXCEPT:

Improved cardiac function

Improvement in arthropathy

Improved control of diabetes

Improvement in liver enzymes

Improvement in skin pigmentation

B is the correct answer.

Commentary – Hemochromatosis

Clinical Pearls: Hemochromatosis

Response to phlebotomy in patients with hereditary hemochromatosis:

does not reverse testicular atrophy

leads to minimal improvement in arthropathy

does not reverse established cirrhosis

does not reduce risk of HCC in patients with established cirrhosis

The second and third

metacarpophalangeal

(

MCP

) joints are the classic rheumatologic manifestation (illustrated below):

Other extrahepatic manifestations include congestive heart failure, porphyria cutanea tarda, testicular atrophy, chondrocalcinosis, impotence, and diabetes.

Question 4

Question

Which of the following regarding hepcidin is FALSE?

Hepcidin is a 25 amino acid peptide produced in the liver that downregulates iron absorption.

When hepcidin binds to ferroportin, the ferroportin is internalized and degraded.

Hereditary hemochromatosis leads to increased levels of hepcidin.

Hepcidin is expressed predominantly in hepatocytes.

HCV infection may lead to an increased iron deposition in the liver through inhibition of hepatic hepcidin transcription.

C is the correct answer.

Commentary – Iron Homeostasis

Clinical Pearls: Hepcidin, Ferroportin, and Hemochromatosis

The interaction of hepcidin with ferroportin constitutes the key control step in systemic iron homeostasis.

Hepcidin is produced predominantly in the liver and is secreted into the circulation. It binds to ferroportin which is found in macrophages and on the basolateral surface of enterocytes:

Ferroportin is a trans‐membrane protein that transports iron from the inside of a cell to the outside of the cell; it is the only known iron exporter.

When hepcidin binds to ferroportin, the ferroportin is internalized and degraded, and thus iron export is inhibited.

Hepcidin downregulates iron absorption.

Hereditary hemochromatosis

(

HH

) leads to a reduction in hepcidin which leads to an overexpression of cell membrane ferroportin and, hence, an increased excretion of iron into the circulation.

In summary: HH is a mutation in

HFE

gene which leads to: reduced hepcidin – increased ferroportin – increased iron into circulation leading to systemic iron overload.

Question 5

A 41‐year‐old male is referred to you for elevated iron studies. He has a history obesity and hypertension. He is of Irish descent. His father died at age 62 of heart failure. His mother is 78 years old and alive.

The patient feels well other than mild fatigue. Exam is relatively unremarkable other than a BMI is 34 kg/m2.

Laboratory studies:

WBC 7, Hb 16, Platelets 222; Normal renal function and electrolytes. TBili 0.8, AST 28, ALT 40, ALP 118.

Iron % saturation is 72 with a ferritin of 628 ng/mL. HFE testing: C282Y +/+.

Ultrasound is normal. Viral serologies are negative.

Question

What do you recommend now?

MRI with iron quantification

Percutaneous US‐guided liver biopsy with iron quantification

Phlebotomy

Repeat iron studies after 12 hours fast

Dietary reduction in iron and then monitor iron studies

C is the correct answer.

Commentary – Iron Studies

Clinical Pearls: Clinical Hemochromatosis

A ferritin of >1000 should prompt liver biopsy to rule out cirrhosis; on the other hand, if homozygous for C282Y and ferritin less than a 1000 – guidelines recommend against liver biopsy, i.e. go straight to phlebotomy:

Ferritin >1000 = liver biopsy is a favorite board question, although in practice most are obtaining some form of

liver stiffness measurement

(

LSM

).

Pearls' Prussian blue stain (see histology image) is used for evaluating the degree of cellular iron distribution within hepatocytes:

In secondary iron overload, iron deposition is usually mild (1–2+) and generally occurs in Kupffer cells (as opposed to hereditary hemochromatosis in which iron deposition is concentrated with hepatocytes).

As in most other forms of chronic liver disease, HCC surveillance in patients with hemochromatosis is only recommended when a patient has cirrhosis.

Cirrhosis + Hemochromatosis? This combination has the highest incidence of HCC.

Vibrio vulnificus

have been associated in HH patients who eat raw shellfish.

Dietary adjustments in iron are not necessary.

Avoid vitamin C supplementation.

With phlebotomy, you are aiming to reduce ferritin to less than 50–100.

Phlebotomy is recommended initially 1–2×/week; ferritin can be repeated after 10–12 phlebotomies.

Chelating agents (deferoxamine, deferiprone) have many side effects and are only reserved for patients who can't tolerate phlebotomy (anemia, poor venous access, etc.).

Homozygous C282Y accounts for 85% of HH (less so C282Y/H63D; C282Y/S65C)

Notes

Of all the diseases that I get consulted for, genetic hemochromatosis is the most “overly” and “mis”‐diagnosed. Remember, iron studies are commonly elevated in many forms of hepatic injury. For the boards you must be familiar with the algorithm for diagnosis. I anticipate the rule of “ferritin >1000 should prompt liver biopsy to rule out cirrhosis” will be phased out soon (with the increasing use of LSM), but until then, that is the board answer. The roles of hepcidin and ferroportin are also commonly tested.

Reference

ACG clinical guideline: hereditary hemochromatosis. PMID: 31335359.

Question 6

A 27‐year‐old first‐time pregnant female presents to her OB‐GYN with complaints of itching. She is 32 weeks pregnant.

Laboratory studies:

TBili 0.8, AST 48, ALT 63, ALP 216, GGT 23.

Total bile acids: 48 micromol/L (normal <11).

Question

All of the following should be recommended EXCEPT:

Viral serologies for HBV and HCV.

Ursodeoxycholic acid should be prescribed at 10–15 mg/kg.

Delivery should be arranged at 34 weeks, given the increased risk of fetal distress.

The patient should be advised that the recurrence rate for the condition with subsequent pregnancies is up to 70%.

Symptomatic management for pruritus can include hydroxyzine.

C is the correct answer.

Commentary – ICP

Clinical Pearls: Intrahepatic Cholestasis of Pregnancy (ICP)

The highest incidence of ICP occurs in patients of Bolivian and Chilean descents.

There appears to be a higher incidence in twin pregnancy.

ICP occurs in second and third trimester; symptoms can take up to 6 weeks to resolve postdelivery.

Mutations have been associated with several genes, but for the boards: ABCB4.

The diagnosis typically requires bile acids >10; bile acids >40 is associated with worse fetal outcomes:

preterm, meconium, bradycardia, fetal distress; fetal loss is rare.

Ratio of bile acids: cholic acid >chenodeoxycholic acid.

Delivery is recommended at 37–38 weeks.

ICP recurs 45–70% in subsequent pregnancies.

Patients can develop vit‐K deficiency from malabsorption.

As in BRIC, GGT is usually normal or low.

There is data to suggest an increased risk of ICP in women infected with HCV.

Reference

Intrahepatic cholestasis in pregnancy: review of the literature. PMID: 32384779.

Question 7

An 18‐month‐old child presents to your office with pruritus, jaundice, diarrhea, and failure to thrive.

Laboratory studies:

TBili 14 (direct 10) AST, 124, ALT 110, ALP 480, GGTP 18.

After establishing a diagnosis, you recommend partial external biliary diversion (PEBD).

Question

All of the following are true regarding PEBD EXCEPT?

PEBD is a procedure in which bile is diverted from the gallbladder through a loop of jejunum connecting the dome of the gallbladder to the skin.

The procedure interrupts the enterohepatic circulation of bile salts.

It can alleviate intractable pruritus.

It can improve liver histology, but seldom improves liver function tests.

It can preclude the need for liver transplant in up to 75% of children.

D is the correct answer.

Commentary – PFIC

Clinical Pearls: Progressive Familial Intrahepatic Cholestasis (PFIC)

PFIC is an autosomal recessive condition.

It is associated with defects in ATP8B1 (the same gene linked to BRIC).

Defects in ATP8B1 lead to an overload in bile acids in hepatocytes due to reduced bile salt secretion and increased bile salt reabsorption.

This leads to downregulation of farnesoid X receptor (FXR): a receptor related to regulation of metabolism of bile acids:

Relevant link: Obeticholic acid is an agonist against the FXR.

AT8B1 is also expressed in the membrane of cells of the small intestine, kidney, and pancreas.

Byler disease (as opposed to Byler syndrome) has been associated with extrahepatic diseases (pancreatitis, hearing loss, and diarrhea), this is classified as

PFIC1.

PFIC2 or

Byler syndrome is a mutation in ABCB11 which results in more severe hepatobiliary disease than PFIC 1:

transaminase elevation is higher than PFIC 1

higher risk of liver tumors

giant cells on histology

PFIC3:

ABCB4: high GGT and cholesterol stones (ABCB4 genetic defect is associated with ICP).

Biliary diversion procedures: partial external biliary diversion (PEBD): 70–80% of patients with PFIC respond both biochemically and histologically.

Notes

The phenotypic spectrum of ATP8B1 deficiency manifests anywhere from mild, “benign” disease (BRIC) to severe life‐threatening disease (PFIC).

Reference

Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment. PMID: 30237746.

Question 8

A 19‐year‐old female is evaluated in the neurology clinic for a progressively worsening movement disorder. Ceruloplasmin returns at 12 mg/dL. The patient is referred to you. You obtain the following tests:

Repeat ceruloplasmin 10 mg/dL

Albumin 3.7

24‐hour urine copper 88 mcg

Ophthalmology consult is negative for Kayser–Fleisher (KF) rings

Question

Which of the following do you recommend next?

Total serum copper

Liver biopsy with copper quantification

Molecular testing

EGD with small bowel biopsies for copper staining

Serum zinc

B is the correct answer.

Commentary – Copper Metabolism

Clinical Pearls: Wilson Disease and Copper Metabolism

Wilson disease is an autosomal recessive disease.

Mutation is in the ATP7B gene.

Copper is absorbed by enterocytes, mainly in the duodenum (absorption of dietary iron is also at the level of the duodenum). Copper is then transported into the circulation and associated with albumin and the amino acid histidine and then taken to the liver.

The liver secretes the copper containing protein: ceruloplasmin and excretes excess copper into bile.

Ceruloplasmin carries 90% of copper in the blood:

A ceruloplasmin of less than 20 in the right clinical scenario should prompt further investigation.

It is not uncommon to have borderline ceruloplasmin in patients with cirrhosis (i.e. 15–20).

Processes that impair biliary copper excretion can lead to increases in hepatic copper content (most notably cholestatic diseases such as PSC).

Total serum copper is usually decreased in proportion to reduced ceruloplasmin in circulation.

Nonceruloplasmin bound copper is elevated.

Nonceruloplasmin bound copper can be estimated by: total serum copper concentration minus ceruloplasmin bound copper.

Absent or reduced function of ATP7B leads to decreased hepatocellular excretion of copper into bile and results in hepatic copper accumulation.

Hepatic parenchymal copper concentration is the gold standard for the diagnosis of Wilson; >250 mcg/dry weight.

Failure to incorporate copper into ceruloplasmin is an additional consequence of the loss of functional ATP7B protein; a defect in ATP7B in essence causes a decrease in ceruloplasmin.

A 24‐hour urinary excretion of copper reflects the amount of nonceruloplasmin bound copper in circulation:

The cut off value for 24‐hour urine copper is >40 mcg.

A combination of KF rings, ceruloplasmin, and 24‐hour urine copper collection are used to arrive at a diagnosis or need for further testing (i.e. liver biopsy or molecular testing).

In Summary: Wilson disease: a defect in ATP7B – leads to a decrease in excretion of copper into bile – which then causes an increase in hepatic copper accumulation.

A defect in ATP7B also leads to a decrease in ceruloplasmin which leads to decrease in TOTAL serum copper (less is able to be bound as there is little ceruloplasmin), but an elevation in nonceruloplasmin bound copper (usually above 25) and an increase in 24‐hour urinary excretion of copper.

Reference

Wilson's disease: a comprehensive review of the molecular mechanisms. PMID: 25803104.

Question 9

A 23‐year‐old college student is brought to her local community hospital by her roommate with a rapid decline in mental status. In the emergency room, the patient's vitals are the following: temperature: 37.6, pulse 110, BP 94/48, RR 8, 95% on room air. She cannot be aroused even to deep sternal rub and is immediately intubated. Exam is notable for marked jaundice.

STAT labs are notable for a Hemoglobin of 6.

TBili 42 (unconjugated 31), AST 108, ALT 98, ALP is undetectable:

Cr 3.4

INR is 7.2

Serum ammonia level is 343 micromol/L

Question

Which of the following should be done immediately?

Trial of corticosteroids

Penicillamine‐

D

N

‐acetyl‐L‐cysteine (NAC)

Transfer to a liver transplant center

Transjugular liver biopsy

D is the correct answer.

Commentary – Wilson Disease

Clinical Pearls: Wilson Disease

Hemolysis is seen in 10% of patients with acute Wilson disease:

Coombs negative hemolytic anemia (predominantly unconjugated hyperbilirubinemia).

KF rings are present in 50% of patients:

KF rings are present in nearly 100% of neurological Wilson.

Up to 30% of patients will have psychiatric manifestations.

Uric acid is decreased because of associated renal tubular dysfunction (Fanconi's syndrome).

There is rapid progression to renal failure.

Alkaline phosphatase is typically low, sometimes undetectable; ALP/TBili ratio <4 is highly sensitive and specific for Wilson.

Extrahepatic manifestations include the following: aminoaciduria, kidney stones, osteoporosis, arthritis, cardiomyopathy, pancreatitis, hypoparathyroidism, infertility.

First degree relatives with Wilson must be screened.

Notes

Chronic Wilson is a tricky diagnosis to make. Wilson disease rarely presents in a straightforward manner and more often than not requires piecing together the results of multiple tests. Acute Wilsonian crisis on the other hand is dramatic, with some of the most striking labs in all of liver disease. Clinical clues may include the uniquely low (and sometimes undetectable) alkaline phosphatase and the marked elevation in total bilirubin, largely from hemolysis.

Reference

Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. PMID: 18798336.

Question 10

Zinc is most commonly used as maintenance therapy in patients with Wilson disease.

Question

What is the mechanism of action of zinc?

Promotes urinary excretion of copper.

Promotes copper excretion by the kidneys.

Downregulates ATP7B.

Induces enterocyte metallothionein and interferes with copper uptake from the GI tract.

It downregulates metallothionein and interferes with copper uptake from the GI tract.

D is the correct answer.

Commentary – Wilson Disease Therapy

Clinical Pearls: Treatment of Wilson Disease

D

‐penicillamine promotes urinary excretion of copper. 30% of patients develop adverse reactions including proteinuria and lupus‐like syndrome.

D

‐penicillamine should be taken without food.

Urinary copper should increase and nonceruloplasmin copper should normalize. Should not be taken while breastfeeding.

Trientene is a chelator. It promotes copper excretion by the kidneys; it can be used even in decompensated disease.

Adequacy of treatment is monitored by measuring 24‐hour urine copper excretion. Levels should run between 200 and 500.

In those with nonadherence to therapy, nonceruloplasmin bound copper is elevated, whereas overtreatment values will be low.

Zinc interferes with the uptake of copper from the GI tract. It induces enterocyte metallothionein. Metallothionein has a greater affinity for copper than zinc and binds copper and inhibits its entry into the circulation. The nonabsorbed copper is defecated.

Foods high in copper include shellfish, nuts, chocolate, mushroom, and organ meat.

Treatment of Wilson should continue in pregnant females. Mothers should not breast feed on penicillamine.

KF rings can improve on treatment.

After hepatic manifestations, neurologic symptoms are the most frequent. Dysarthria is the most frequent neurological symptoms, reported in nearly 97% of patients. Drooling is a classic symptom and is seen in nearly 70% of patients:

Risus sardonicus

(uncontrollable grinning) may be a clinical clue.

Classic imaging findings: symmetric hyperintense changes of the basal ganglia.

Neurological manifestations for the most part improve post‐LT, but severe neurological impairment may not and may contraindicate LT.

Reference

Wilson disease. PMID: 30190489.

Question 11

A 38‐year‐old female presents with jaundice and severe fatigue. Exam is notable for marked scleral icterus, asterixis, spider angiomata, parotid gland enlargement, and conjunctival pallor. A flow murmur is appreciated on cardiac exam and a bruit is audible in her right upper quadrant (RUQ).

Laboratory studies are notable for a Hb of 6, platelets of 47 TBili of 22 (unconjugated 17), AST 98, ALT 47. and ALP of 112.

A blood smear is shown below.

Question

Which of the following would NOT be consistent with this presentation?

MCV 114

GTP 740

Unconjugated bilirubin 17

Triglyceride level 92

INR 2.7

D is the correct answer.

Commentary – Cirrhosis and Anemia

Clinical Pearls: Anemia and Cirrhosis

Massive GI hemorrhage think variceal bleed or peptic ulcer.

Slow, chronic bleeding requiring intermittent transfusion, think

gastric antral vascular ectasia

(

GAVE

):

Tranexamic acid has been used for GAVE in patients who fail

argon plasma coagulation

(

APC

), but it has been associated with an increased risk of thrombotic events.

Hypersplenism is secondary to portal hypertension that can lead to a drop in all cell lines, but most notably platelets.

Aplastic anemia is characterized by pancytopenia and hypocellular bone marrow following viral hepatitis (namely HBV, HCV, EBV, parvovirus 19).

Complications of HCV therapy (namely interferon‐inducing bone marrow suppression and ribavirin‐induced hemolysis, although these are now more historical, given DAA therapy).

Alcohol, Zieve's syndrome, may also be exacerbated by folic acid and/or B12 deficiency; inadequate dietary intake or malabsorption: Hemolytic anemia (spur cells and acanthocytes displayed in smear above), hyperlipoproteinemia, jaundice, and abdominal pain. Clinical clue may be elevated TG.

Hemolytic anemia: rarely as a result of destruction secondary to

transjugular intrahepatic portosystemic shunt

(

TIPS

).

Rapidly growing vascular tumor (usually giant hemangioma), thrombocytopenia, microangiopathic hemolytic anemia, and consumptive coagulopathy. More commonly seen in infants: Kasbach–Merritt syndrome.

Acute Wilsonian crisis can present with spherocytic severe acute hemolytic anemia (Coomb's negative) with marked elevation in total bilirubin which is predominantly unconjugated.

DIC: It may be difficult to distinguish DIC from liver disease related hemostatic abnormalities. Factor VIII activity levels are generally increased or normal in liver disease, as opposed to DIC, where consumption causes decreased factor VIII levels. DIC and liver disease may coexist especially in the setting of infection and sepsis.

Iron deficiency anemia and mild elevation in LFTs? Think celiac

It is not uncommon to see elevated liver enzymes in thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome):

Calcineurin inhibitor

(

CNI

)‐induced HUS has been described posttransplant.

Liver is affected by multiple complications related to sickle cell disease:

Multiple transfusions and risk of viral hepatitis, iron overload.

Pigmented gallstones related to chronic hemolysis.

Acute sickle cell hepatitis crisis occurs in about 10% of patients. RUQ pain, low‐grade fever, and tender HM; jaundice; enzyme elevations can be as high 1000; likely related to ischemia and sinusoidal obstruction.

Sickle cell intrahepatic cholestasis due to disseminated vaso‐occlusion in the sinusoids can present with marked jaundice.

Acute hepatic sequestration defined as sudden increase in liver size associated with RUQ pain and an acute decrease in Hb >2, thrombocytopenia, jaundice, and liver failure.

Leptospirosis: Zoonotic disease usually acquired from animal urine, infected animal tissue, or contaminated water. Hawaii reports the greatest number of cases in the United States. Presents with fever, headache, conjunctival redness. May be complicated by jaundice (can be markedly elevated) and renal failure (Weil's disease). DIC is not uncommon. Most cases are self‐limiting. Severe cases will require antibiotics (doxycycline or azithromycin).

Adult‐onset Still's disease

(

AOSD

) is an inflammatory disorder characterized by quotidian (occurring daily) fevers, arthritis, and an evanescent salmon‐colored rash typically found on the trunk. It is a diagnosis of exclusion. In addition to marked serum ferritin, hematological findings such as hemolytic anemia and DIC are not uncommon. Elevated LFTs are seen in 75% of patients.

Cytopenia is related to

hemophagocytic lymphohistiocytosis

(

HLH

).

Notes