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MOUNT SINAI

EXPERT GUIDES

Hepatology

MOUNT SINAI EXPERT GUIDES

HepatologyEDITED BY

Jawad Ahmad MDAssociate Professor of Medicine

Division of Liver Diseases

Icahn School of Medicine at Mount Sinai

New York, NY, USA

Scott L. Friedman MDFishberg Professor of Medicine

Dean for Therapeutic Discovery

Chief, Division of Liver Diseases


New York, NY, USA

Henryk Dancygier MD, PhDProfessor of Medicine

Chair, Departments of Medicine II and IV

Sana Klinikum Offenbach, Goethe University

Frankfurt am Main, Germany;

Adjunct Professor of Medicine

Department of Medicine, Division of Liver Diseases


New York, NY, USA

This edition first published 2014 © 2014 by John Wiley & Sons, Ltd

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Library of Congress Cataloging-in-Publication DataMount Sinai expert guides. Hepatology / edited by Jawad Ahmad, Scott L. Friedman, Henryk Dancygier. p. ; cm. Hepatology Includes bibliographical references and index. ISBN 978-1-118-51734-5 (alk. paper) – ISBN 978-1-118-74251-8 (emobi) – ISBN 978-1-118-74252-5 (epub) – ISBN 978-1-118-74253-2 (epdf) – ISBN 978-1-118-74862-6 I. Ahmad, Jawad (Hepatologist), editor of compilation. II. Friedman, Scott L., editor of compilation. III. Dancygier, Henryk, editor of compilation. IV. Title: Hepatology. [DNLM: 1. Liver Diseases. 2. Liver Transplantation. WI 700] RC845 616.3’62–dc23

2013024785

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover image: iStock file File #6124416 © David Marchal Cover design by Ruth Bateson

Set in 8.5/12 pt Frutiger Light by Toppan Best-set Premedia Limited

1 2014

http://www.wiley.com/wiley-blackwell

v

List of Contributors, ix

Series Foreword, xii

Preface, xiii

Abbreviation List, xiv

About the Companion Website, xxi

Part 1: HEPATOLOGY

1 Approach to the Patient with Abnormal Liver Tests, 3

Charissa Y. Chang

2 Approach to the Patient with Jaundice, 13

Jawad Ahmad

3 Drug-Induced Liver Injury, 23

Ponni V. Perumalswami

4 Hepatitis A and E, 32

Ponni V. Perumalswami

5 Hepatitis B and D, 41

Elizabeth A. Kula, Donna J.C. Fanelli and Douglas T. Dieterich

6 Hepatitis C: Diagnosis, Management and Treatment, 58

Alicia C. Stivala, Deepti Dronamraju and Douglas T. Dieterich

7 HIV/HCV and HIV/HBV Co-infections, 78

Marie-Louise C. Vachon, Alicia C. Stivala and Douglas T. Dieterich

8 Hepatic Abscess, 96

Lawrence U. Liu

9 Biliary Infections, 111

Gopi Patel

10 Alcoholic Hepatitis, 120

Scott L. Friedman

11 Non-Alcoholic Fatty Liver Disease, 132

Charissa Y. Chang

12 Autoimmune Hepatitis and Overlap Syndromes, 142

Joseph A. Odin

Contents

vi Contents

13 Primary Biliary Cirrhosis, 151

Nancy Bach and Joseph A. Odin

14 Primary Sclerosing Cholangitis, 160

Nancy Bach and Joseph A. Odin

15 Hereditary Hemochromatosis, 167

Jawad Ahmad

16 Wilson Disease, 176

Joseph A. Odin, Nancy Bach and Vivek Kesar

17 Alpha-1 Antitrypsin Deficiency, 187

Joseph A. Odin and Vivek Kesar

18 Portal Hypertensive Bleeding, 196

Jawad Ahmad

19 Ascites, 209

Henryk Dancygier

20 Spontaneous Bacterial Peritonitis, 227

Henryk Dancygier

21 Hepatic Encephalopathy, 235

Priya Grewal

22 Hepatorenal Syndrome, 245

Henryk Dancygier

23 Hepatopulmonary Syndrome, 255

Jawad Ahmad

24 Portopulmonary Hypertension, 263

Jawad Ahmad

25 Pregnancy-Related Liver Disease, 271

Priya Grewal

26 Acute Liver Failure, 280

Meena B. Bansal

27 Budd–Chiari Syndrome, 294

Leona Kim-Schluger

28 Portal Vein Thrombosis, 301

Leona Kim-Schluger

29 Non-Cirrhotic Portal Hypertension, 308

M. Isabel Fiel and Thomas D. Schiano

30 Liver Lesions, 317

James S. Park

31 Cystic Lesions of the Liver, 325

Abdulelah Alhawsawi, Juan P. Rocca and Marcelo E. Facciuto

Contents vii

32 Surgery in Patients with Liver Disease, 334

Jawad Ahmad

33 Nutrition in Liver Diseases, 344

James S. Park

Part 2: PEDIATRICS

34 Diagnosis and Management of Acute Liver Failure: A Pediatric Perspective, 353

Tamir Miloh

35 Liver Function Tests in Childhood, 365

Nanda Kerkar

36 Approach to Jaundice in Infancy, 374

Jaime Chu

37 Management of End-Stage Liver Disease in Children, 382

Ronen Arnon

38 Liver Transplantation: A Pediatric Perspective, 394

Nanda Kerkar

Part 3: TRANSPLANTATION

39 Evaluation of Patients for Liver Transplantation, 407

Lawrence U. Liu

40 Live Donor Transplantation Evaluation, 415

Lawrence U. Liu

41 Surgical Evaluation for Liver Transplantation, 421

Hiroshi Sogawa

42 Post-Operative Care of The Liver Transplantation Patient, 427

Alan G. Contreras Saldivar

43 Diagnostic Approach to Abnormal Liver Tests Following Liver Transplantation, 436

Charissa Y. Chang

44 Acute Rejection, 444

Costica Aloman

45 Chronic Rejection, 453

Costica Aloman

46 Primary Non-Function, 462

Eric G. Davis and Sander S. Florman

47 Ischemia Reperfusion Injury after Liver Transplantation, 469

Matthew Y. Suh and Juan P. Rocca

viii Contents

48 VascularComplicationsofLiverTransplantation,477

Eric G. Davis and Sander S. Florman

49 BiliaryComplicationsafterLiverTransplantation,486

Marie E. Le and Marcelo E. Facciuto

50 ApproachtoProphylaxisandManagementofInfectionsafterLiverTransplantation,494

Shirish Huprikar

51 MalignancyafterLiverTransplantation,504

Lawrence U. Liu

52 HepatitisCPost-LiverTransplantation,512

Thomas D. Schiano and M. Isabel Fiel

53 RecurrentDiseasePost-LiverTransplantation:AutoimmuneDiseases,HepatitisB

andNASH,521

Thomas D. Schiano

54 HealthMaintenanceafterLiverTransplantation,530

Lawrence U. Liu

Index,538

Color Plate Section Facing p.202

List of Contributors

ix

Jawad Ahmad MDAssociate Professor of Medicine



New York, NY, USA

Abdulelah Alhawsawi MDSurgical Fellow

Recanati/Miller Transplantation Institute

Mount Sinai Hospital

New York, NY, USA

Costica Aloman MDAssociate Professor of Medicine

University of Illinois

Chicago, IL, USA

Ronen Arnon MD, MHAAssociate Professor of Pediatrics and Surgery

Department of Pediatrics


New York, NY, USA

Nancy Bach MDAssistant Professor of Medicine



New York, NY, USA

Meena B. Bansal MDAssociate Professor of Medicine



New York, NY, USA

Charissa Y. Chang MDAssistant Professor of Medicine



New York, NY, USA

Jaime Chu MDAssistant Professor of Pediatrics

Division of Hepatology


New York, NY, USA

Alan G. Contreras Saldivar MDAttending Transplant Surgeon

Instructor of Surgery


Icahn School of Medicine at Mount Sinai;



New York, NY, USA

Henryk Dancygier MD, PhDProfessor of Medicine

Chair, Departments of Medicine II and IV

Sana Klinikum Offenbach, Goethe University

Frankfurt am Main, Germany;

Adjunct Professor of Medicine

Department of Medicine



New York, NY, USA

Eric G. Davis MDAssistant Professor of Surgery

University of Louisville School of Medicine

Louisville, KY, USA

Douglas T. Dieterich MDProfessor of Medicine



New York, NY, USA

x List of Contributors

Deepti Dronamraju MDFellow



New York, NY, USA

Marcelo E. Facciuto MD, MPHAssociate Professor of Surgery



New York, NY, USA

Donna J.C. Fanelli CRNPDivision of Liver Diseases


New York, NY, USA

M. Isabel Fiel MDProfessor of Pathology

Department of Pathology


New York, NY, USA

Sander S. Florman MDThe Charles Miller, MD Professor of Surgery

Director, Recanati/Miller Transplantation

Institute


New York, NY, USA

Scott L. Friedman MDFishberg Professor of Medicine

Dean for Therapeutic Discovery

Chief, Division of Liver Diseases


New York, NY, USA

Priya Grewal MDAssociate Professor of Medicine



New York, NY, USA

Shirish Huprikar MDDirector, Transplant Infectious Diseases

Program

Associate Professor

Division of Infectious Diseases

Department of Medicine


New York, NY, USA

Nanda Kerkar MDProfessor of Clinical Pediatrics

Medical Director Liver and Intestinal Program

Director Hepatology Program

Children’s Hospital of Los Angeles

University of Southern California

Los Angeles, CA, USA

Vivek Kesar MDInternal Medicine Resident

Lenox Hill Medical Center

New York, NY, USA

Leona Kim-Schluger MDProfessor of Medicine



New York, NY, USA

Elizabeth A. Kula CRNPDivision of Liver Diseases


New York, NY, USA

Marie E. Le MDSurgical Fellow



New York, NY, USA

Lawrence U. Liu MDAssistant Professor of Medicine



New York, NY, USA

List of Contributors xi

Tamir Miloh MDDirector of Pediatric Liver and Liver

Transplant Program

Department of Gastroenterology and

Hepatology

Phoenix Children’s Hospital;

Associate Professor of Pediatrics

University of Arizona, College of Medicine

Phoenix, AZ;

Associate Professor in Pediatrics

Mayo Clinic

USA

Joseph A. Odin MD, PhDDirector, Autoimmune Liver Diseases

Program

Associate Professor of Medicine



New York, NY, USA

James S. Park MD, CNSCAssistant Professor of Medicine

Division of Gastroenterology

NYU School of Medicine

New York, NY, USA

Gopi Patel MD, MSAssistant Professor



New York, NY, USA

Ponni V. Perumalswami MD, MSAssistant Professor of Medicine



New York, NY, USA

Juan P. Rocca MDAssistant Professor of Surgery

Icahn School of Medicine at Mount Sinai;

Surgical Director, Live Donor Kidney Program

Associate Director, Transplant Surgery

Fellowship



New York, NY, USA

Thomas D. Schiano MDProfessor of Medicine

Medical Director, Liver Transplantation

Clinical Director, Hepatology



New York, NY, USA

Hiroshi Sogawa MD, FACSAssistant Professor of Surgery

Director, Transplant Surgery Fellowship

Program

Thomas E. Starzl Transplantation Institute

University of Pittsburgh Medical Center

Pittsburgh, PA, USA

Alicia C. Stivala NPNurse Practitioner



New York, NY, USA

Matthew Y. Suh MDSurgical Fellow



New York, NY, USA

Marie-Louise C. Vachon MD, MScFellow



New York, NY, USA

Series Foreword

xii

Now more than ever, immediacy in obtaining accurate and practical information is the coin of

the realm in providing high quality patient care. The Mount Sinai Expert Guides series addresses

this vital need by providing accurate, up-to-date guidance, written by experts in formats that

are accessible in the patient care setting: websites, smartphone apps and portable books. The

Icahn School of Medicine, which was chartered in 1963, embodies a deep tradition of pre-

eminence in clinical care and scholarship that was first shaped by the founding of the Mount

Sinai Hospital in 1855. Today, the Mount Sinai Health System, comprised of seven hospitals

anchored by the Icahn School of Medicine, is one of the largest health care systems in the United

States, and is revolutionizing medicine through its embracing of transformative technologies for

clinical diagnosis and treatment. The Mount Sinai Expert Guides series builds upon both this

historical renown and contemporary excellence. Leading experts across a range of disciplines

provide practical yet sage advice in a digestible format that is ideal for trainees, mid-level provid-

ers and practicing physicians. Few medical centers in the US could offer this type of breadth

while relying exclusively on its own physicians, yet here no compromises were required in offering

a truly unique series that is sure to become embedded within the key resources of busy provid-

ers. In producing this series, the editors and authors are fortunate to have an equally dynamic

and forward-viewing partner in Wiley Blackwell, which together ensures that health care profes-

sionals will benefit from a unique, first-class effort that will advance the care of their patients.

Scott Friedman MDSeries Editor

Dean for Therapeutic DiscoveryFishberg Professor and Chief, Division of Liver Diseases

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

Preface

xiii

The last 20 years has seen hepatology emerge as a distinct discipline, separate from gastroen-

terology, reflecting the profound advances in our understanding of the pathophysiology, diag-

nosis and management of liver diseases. Concurrently, academic centers throughout the world

now have faculty who function exclusively as hepatologists, and even in these institutions there

is often further distinction between non-transplant and transplant hepatologists, with a similar

trend emerging in pediatrics.

In recognition of these trends, international liver societies in the US (American Society for the

Study of Liver Diseases), Europe (European Association for the Study of the Liver) and Asia (Asian

Pacific Association for the Study of the Liver), seek evidence-based guidelines to standardize

management of the most common liver diseases. This expert guide is intended to address this

need for a concise and practical guide to patient management. While many textbooks provide

detailed descriptions of pathophysiology, they may not be well suited to provide practical, acces-

sible treatment options in the clinical setting where information is urgently needed and time is

short. For students and trainees, a basic understanding of epidemiology and pathogenesis of

disease entities is important, but guidance for the management of a specific clinical condition

is the real world need.

This book is separated into three sections: hepatology, pediatrics and transplantation, with

each chapter organized in a standardized format. The first section of each chapter provides the

reader a bottom-line of ‘take home’ points that emphasizes the most important aspects of the

chapter. This is followed by sections on background, prevention and diagnosis. Key features

across the chapters are: easily accessible evidence-based management algorithms, with appropri-

ate laboratory and imaging tests and commonly used medications with dosages. Short reading

lists with society guidelines complete the text. Also accompanying the book is a companion

website which provides the reader with case histories and multiple choice questions for those

preparing for specialty exams. An additional multimedia resource available for purchase is an

app with highlights of each chapter for smartphone users.

We have sought to provide a comprehensive list of diseases and situations that clinicians will

confront in general hepatology and transplant hepatology practices. The pediatric and surgical

chapters have been included to ensure that adult hepatologists understand problems they are

likely to encounter in these related specialities in practice, but not as a guide specifically for

pediatricians and surgeons.

We thank the staff at Wiley Blackwell, particularly Oliver Walter and Jennifer Seward, for

ensuring such a smooth publication process. We also gratefully acknowledge the many Mount

Sinai residents and hepatology fellows for their enthusiasm, dedication to their patients and

candid feedback throughout the preparation of this text.

Finally, we are indebted to our Mount Sinai colleagues in the Divisions of Liver Diseases and

Infectious Diseases, the Departments of Pediatrics and Pathology, and in the Recanati/Miller

Transplantation Institute. The editors are fortunate to work with such superb physicians, but

what truly distinguishes our colleagues is their selfless dedication to mentoring the next genera-

tion of trainees in caring for patients with liver disease. This book reflects their exceptional

generosity as clinicians, teachers and role models.

Jawad AhmadScott L. FriedmanHenryk Dancygier

Abbreviation List

xiv

AAP AmericanAcademyofPediatrics

AASLD AmericanAssociationfortheStudyofLiverDiseases

AAT alpha-1antitrypsin

ABG Arterialbloodgas

ABW Adjustedbodyweight

ACE Angiotensin-convertingenzyme

ACR Acutecellularrejection

ADH Alcoholdehydrogenase

AD-PCLD Adultpolycysticliverdisease

ADV Adefovir

AFLP Acutefattyliverofpregnancy

AFP Alpha-fetoprotein

AH Alcoholichepatitis

AIDs Acquiredimmunodeficiencysyndrome

AIH Autoimmunehepatitis

ALA Amebicliverabscess

ALF Acuteliverfailure

ALT Alanineaminotransferase

AMA Antimitochondrialantibodies

ANA Antinuclearantibody

ANA Antinuclearautoantibodies?

anti-HAV AntibodiestothehepatitisAvirus

anti-HBc AntibodiestothehepatitisBcoreantigen

anti-HBs AntibodiestothehepatitisBsurfaceantigen

anti-LKM Anti-liverkidneymicrosomal(antibody)

AP Alkalinephosphatase

AR Acuterejection

ARDS Acuterespiratorydistresssyndrome

ARF Acuterenalfailure

ART Antiretroviraltherapy

ARV Antiretroviral

ASMA Anti-smoothmuscleantibody

AST Aspartateaminotransferase

AUDIT AlcoholUsersDisordersIndentificationTest

BCLC BarcelonaClinicLiverCancerStagingSystem

BCS Budd–Chiarisyndrome

BMI Bodymassindex

BOC Boceprevir

BRTO Balloonretrogradetransvenousobliteration

Abbreviation List xv

CBC Completebloodcount

CDC CentresforDiseaseControlandPrevention

cEVR Completeearlyvirologicalresponse

CHB ChronichepatitisB

CHF Congestiveheartfailure

CK Creatinekinase

CKD Chronickidneydisease

CMV Cytomegalovirus

CNI Calcineurininhibitors

CNS Centralnervoussystem

CO Cardiacoutput

COPD Chronicobstructivepulmonarydisease

CR Chronicrejection

CRP C-reactiveprotein

CSF Cerebrospinalfluid

CT Computedtomography

CTP Child-Pugh-TurcottiScore

CVP Centralvenouspressure

CVVH Continuousveno-venoushemofiltration

CVVHD Continuousveno-venoushemodialysis

DAA Directactingantiviralagent

DDLT Deceaseddonorlivertransplant

DGF Delayedgraftfunction

DHHS DepartmentofHealthandHumanServices

DIC Disseminatedintravascularcoagulation

DILI Drug-inducedliverinjury

DVR Delayedvirologicalresponse

EBV Epstein-Barrvirus

ECG Electrocardiogram

EEG Electroencephalogram

eEVR Extendedearlyvirologicalresponse

EGD Esophagogastroduodenoscopy

EHBA Extrahepaticbiliaryatresia

ELISA Enzyme-linkedimmunosorbentassay

ERC Endoscopicretrogradecholangiography

EOT Endoftreatment

ERCP Endoscopicretrogradecholangiopancreatography

eRVR Extendedrapidvirologicalresponse

ESLD End-stageliverdisease

ESR Erythrocytesedimentationrate

ESRD End-stagerenaldisease

ETV Entecavir

EUS Endoscopicultrasound

EV Esophagealvarices

EVR Earlyvirologicalresponse

xvi Abbreviation List

FDA FoodandDrugAdministration

FEV1 Forcedexpiratoryvolumeinonesecond

FHF Fulminanthepaticfailure

FNA Fineneedleaspiration

FNH Focalnodularhyperplasia

FVC Forcedvitalcapacity

GABA Gamma-aminobutyricacid

GFR Glomerularfiltrationrate

GGT Gammaglutamyltranspeptidase

GI Gastrointestinal

GIB Gastrointestinalbleeding

HAART Highlyactiveantiretroviraltherapy

HAT Hepaticarterythrombosis

HBcAbIgG HepatitisBcoreantibodyimmunoglobulinG

HBcAbIgM HepatitisBcoreantibodyimmunoglobulinM

HBIg HepatitisBimmuneglobulin

HBsAb HepatitisBsurfaceantibody

HBsAg HepatitisBsurfaceantigen

HBV HepatitisBvirus

HCC Hepatocellularcarcinoma

HCT Hematocrit

HCV HepatitisCvirus

HDL Highdensitylipoprotein

HE Hepaticencephalopathy

HELLP Hemolyticanemia,ElevatedLiverenzymesandLowPlateletcount

HEV HepatitisEvirus

HFE Hemochromatosis

HG Hyperemesisgravidarum

HH Hereditaryhemochromatosis

HHT Hereditaryhemorrhagictelangiectasia

HIC Hepaticironconcentration

HIDA Hepatobiliaryimmunodiaceticacid(scan)

HII Hepaticironindex

HIV Humanimmunodeficiencyvirus

HLA Humanleukocyteantigen

HLH Hemophagocyticlymphohistiocystosis

HOMA Homeostasismodelassessment

HPS Hepatopulmonarysyndrome

HRS Hepatorenalsyndrome

HSV Herpessimplexvirus

HVPG Hepaticvenouspressuregradient

IAIHG InternationalAutoimmuneHepatitisGroup

IBD Inflammatoryboweldisease

IBW Idealbodyweight

ICH Intracranialhypertension

Abbreviation List xvii

ICP Intrahepaticcholestasisofpregnancy

ICU Intensivecareunit

IDUs Intravenousdrugusers

IEF Isoelectricfocusing

IFN Interferon

IgG ImmunoglobulinG

IgM ImmunoglobulinM

IHA Indirecthemagglutination

INR Internationalnormalizedratio

IPVDs Intrapulmonaryvascularabnormalitiesordilatations

IRI Ischemiareperfusioninjury

ISC Incompleteseptalcirrhosis

IV Intravenous

IVC Inferiorvenacava

IVIG Intravenousimmunoglobulin

KF Kayser–Fleischer(rings)

LCHAD Long-chain3-hydroxyacylcoenzymeAdehydrogenase

LCT Long-chaintriglycerides

LDH Lactatedehydrogenase

LDLT Livedonorlivertransplantation

LFT Liverfunctiontests

LKM-1 Liverkidneymicrosomaltype1

LKM-3 Liverkidneymicrosomaltypes3

LLOD Lowerlimitofdetection

LLOQ Lowerlimitofquantification

LPS Lipopolysaccharide

LR Likelihoodratio

LT Livertransplantation

LV Leftventricle

LVP Largevolumeparacentesis

LVRS Lungvolumereductionsurgery

MAP Meanarterialpressure

MARS MolecularAdsorbentRecirculatingSystem

MCT Medium-chaintriglycerides

MCV Meancellvolume

MDR Multi-drugresistant

MELD Modelforendstageliverdisease(score)

MHE Minimalhepaticencephalopathy

MI Myocardialinfarction

MICU Medicalintensivecareunit

MMR Measlesmumpsrubella

MPAP Meanpulmonaryarterypressure

MRA Magneticresonanceangiogram

MRCP Magneticresonancecholangiopancreatography

MRI Magneticresonanceimaging

xviii Abbreviation List

MSM Menwhohavesexwithmen

MTCT Mother-to-childtransmission

NAC N-acetylcysteine

NAFLD Non-alcoholicfattyliverdisease

NASH Non-alcoholicsteatohepatitis

NASPGHAN TheNorthAmericanSocietyforPediatricGastroenterology,Hepatologyand

Nutrition

NCA N-acetylcysteine

NCPH Non-cirrhoticportalhypertension

99TcMAA Technetiumlabeledmacro-aggregatedalbumin

NG Nasogastric

NR Nullresponse

NRH Nodularregenerativehyperplasia

NRTIs Nucleosidereversetranscriptaseinhibitors

NSAIDs Non-steroidalanti-inflammatorydrugs

OCP Oralcontraceptivepill

OLT Orthotopiclivertransplant

OPV Obliterativeportalvenopathy

PALF PediatricAcuteLiverFailure(studygroup)

P-ANCA Perinuclear-stainingantineutrophilcytoplasmicantibody

PAP Pulmonaryarterypressure

PAS PeriodacidSchiff

PASP Pulmonaryarterysystolicpressure

PBC Primarybiliarycirrhosis

PBS Primarybiliarysclerosis

PCLD Polycysticliverdisease

PCP Primarycareprovider

PCR Polymerasechainreaction

PCWP Pulmonarycapillarywedgepressure

PDH Pyruvatedehydrogenase

PEG-IFN Pegylatedinterferon

PELD Pediatricend-stageliverdisease

PEM Proteinenergymalnutrition

PFIC Progressivefamilialintrahepaticcholestasis

PFT Pulmonaryfunctiontests

PHT Portalhypertension

PHTN Pulmonaryhypertension

PI Proteaseinhibitor

PKD Polycystickidneydisease

PMN Polymorphonuclearleukocytes

PNF Primarynon-function

PO Peroram

POD Post-operativeday

PPHTN Portopulmonaryhypertension

Abbreviation List xix

PPI Proton-pumpinhibitor

PR Partialnon-response

PREP-C PsychosocialReadinessEvaluationandPreparationforHepatitisC

PSC Primarysclerosingcholangitis

PSE Portalsystemicencephalopathy

PT Prothrombintime

PTC Percutaneoustranshepaticcholangiography

PTLD Post-transplantlymphoproliferativedisorder

PTT Partialthromboplastintime

PVR Pulmonaryvascularresistance

PVS Peritoneovenousshunt

PVT Portalveinthrombosis

RAI Rejectionactivityindex

RBV Ribavarin

RCT Randomizedcontrolledtrial

RDA Recommendeddailyallowance

RES Reticuloendothelialsystem

RFA Radiofrequencyablation

RGT Response-guidedtherapy

ROS Reactiveoxygenspecies

RUQ Rightupperquadrant

RVR Rapidvirologicalresponse

SAAG Serum-ascitesalbumingradient

SBP Spontaneousbacterialperitonitis

SC Subcutaneous

SFSS Smallforsizesyndrome

SGA Subjectiveglobalassessment

SICU Surgicalintensivecareunit

SIRS Systemicinflammatoryresponsesyndrome

SLA/LP Solubleliverantigen/liverpancreas

SLE Systemiclupuserythematosus

SMA Smoothmuscleantibody

SNP Singlenucleotidepolymorphism

STD Sexuallytransmitteddisease

SVR Sustainedvirologicalresponse

TACE Transarterialchemoembolization

TDF Tenofovirdisoproxilfumarate

TIBC Totalironbindingcapacity

TIPS Transjugularintrahepaticportosystemicshunting

TNF Tumournecrosisfactor

TPGS D-alpha-tocopheryl-polyethylene-glycol-succinate

TPN Totalparenteralnutrition

TSB Totalserumbilirubin

xx Abbreviation List

TSH Thyroid-stimulatinghormone

TTG Transglutaminaseantibody

TVR Telaprevir

UCSF UniversityofCaliforniaSanFrancisco

UD Undetected

UDCA Ursodeoxycholicacid

UGT Uridine-diphosphoglucuronateglucuronosyltransferase

ULN Upperlimitofnormal

UNOS UnitedNetworkforOrganSharing

UTI Urinarytractinfection

VLDL Verylowdensitylipoprotein

VZV Varicella-zostervirus

WBC Whitebloodcells

WCC Whitecellcount

WD Wilsondisease

WHO WorldHealthOrganization

About the Companion Website

xxi

This series is accompanied by a companion website:

www.mountsinaiexpertguides.com

The website includes:

• Video clips

• Case studies

• ICD codes

• Interactive MCQs

• Patient advice

http://www.mountsinaiexpertguides.com

PART 1

HEPATOLOGY

Approach to the Patient with Abnormal Liver TestsCharissa Y. ChangDivision of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA

CHAPTER 1

OVERALL BOTTOM LINE• A detailed medical history is the single most important step in the evaluation of a patient

with abnormal liver tests.• Evaluation of liver enzyme elevation can be categorized into hepatocellular injury, cholestatic

injury, or mixed injury based on patterns of relative elevation of different liver enzymes.• Serum chemistries which are used to diagnose liver disease can be divided into laboratories

which evaluate liver function (INR, albumin), those which primarily evaluate integrity of hepatocytes (AST, ALT) and those which predominantly assess abnormalities of bile ducts and bile flow (bilirubin, AP, GGT).

• The differential diagnosis of abnormal liver tests is broad and includes infectious (viral hepatitis), metabolic (NAFLD, Wilson disease, hemochromatosis, alpha-1 antitrypsin deficiency), toxin- and drug-induced (alcohol, herbal products), immunologic (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, overlap syndromes), infiltrative, vascular and neoplastic diseases.

• Non-hepatic causes of elevated liver enzymes, such as congestive hepatopathy, shock liver, muscle diseases, thyroid disorders, celiac disease, or adrenal insufficiency must be excluded.

Section 1: BackgroundDefinition of disease

Mount Sinai Expert Guides: Hepatology, First Edition. Edited by Jawad Ahmad, Scott L. Friedman,

and Henryk Dancygier.

© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

Companion website: www.mountsinaiexpertguides.com

3

Tests which are used to assess for liver injury and liver function

Normal function Significance of abnormal value

Tests of liver injury:

ALT, formerly SGOT Catalyzes transfer of amino groups of alanine

Elevated in:• Hepatocellular injury

AST, formerly SGPT Catalyzes transfer of amino groups of L-aspartic acid

Elevated in:• Hepatocellular injury• Myocyte injury (rhabdomyolysis,

exercise, myocardial infarction)

(Continued)

4 Part 1: Hepatology

Normal function Significance of abnormal value

AP Enzyme found on canalicular membrane of hepatocytes, function unknown. Also found in bone, small intestine, placenta

Elevated in:• Cholestatic liver disease of various

etiology (biliary obstruction, biliary injury, drug induced)

• Infiltrative diseases of the liver (sarcoidosis, amyloidosis)

• Neoplastic diseases of the liver• Congestive hepatopathy• Bone disorders, normal bone

growth, pregnancy

GGT Found in cell membranes of many tissues (liver, kidney, pancreas, spleen)

Sensitive but non-specific indicator of hepatobiliary injury. An elevated GGT is not specific for alcohol use. Clinical utility is in differentiating origin of AP elevation (GGT elevated in liver disease, normal in bone disease)

Tests of liver function:

Total bilirubin Normal breakdown product of heme

Elevated in biliary obstruction, disorders of bilirubin metabolism, hepatitis, cirrhosis and acute liver failure

Indirect bilirubin Unconjugated form of bilirubin which is insoluble in plasma and converted to excretable conjugated form by hepatocytes

Elevated in:• Increased heme breakdown (i.e.

hemolysis)• Inherited disorders of bilirubin

metabolism (Gilbert’s disease)

Direct bilirubin Conjugated form of bilirubin which is excreted by hepatocytes across canalicular membrane into bile

Elevated in:• Obstruction of bile ducts• Impaired hepatocyte function

(chronic liver disease, cirrhosis, liver failure)

• Genetic syndromes (Rotor syndrome, Dubin–Johnson syndrome)

PT Measurement of clotting time

Elevated in disease states causing impaired liver function and decreased hepatic production of clotting proteins (cirrhosis, acute liver failure)

Albumin Protein synthesized by hepatocytes

Decreased in hepatocellular dysfunction/chronic liver disease

• ALT and AST are enzymes found in hepatocytes. High serum levels reflect hepatocellular injury.

AST is found in other cells including in the heart, skeletal muscle, brain and other organs. In

contrast, ALT is found mostly in liver which makes it a more specific marker of liver injury

compared with AST. Revised upper limits of ALT have been proposed (30 IU/L for men and

19 IU/L for women) after excluding individuals with probable NASH and hepatitis C from the

“normal” population used to determine range limits.

Approach to the Patient with Abnormal Liver Tests 5

• Normal ALT serum levels have a high negative predictive value (>90%) in excluding a clinically

significant liver disease.

• GGT is present in decreasing quantities in the kidneys, liver, pancreas and intestine. It is a

sensitive indicator of hepatobiliary disease, but lacks specificity. GGT levels are increased in

cholestatic liver diseases, NAFLD, space-occupying liver lesions and venous hepatic congestion.

GGT may be induced by many drugs and alcohol.

• GGT is not a marker of alcoholic liver disease.➤ Decreasing enzyme activities during abstinence from alcohol are diagnostically more

helpful than the presence of an elevated GGT per se.

• Normal GGT levels have a high negative predictive value (>90%) in excluding hepatobiliary

disease.

• An isolated elevation of GGT should not lead to an exhaustive work-up for liver disease.

• Liver AP is a sensitive indicator of cholestasis of various etiologies, but AP does not discriminate

between intra- and extrahepatic cholestasis. Elevation in 5′nucleotidase, GGT and liver isoen-

zyme fractionation of AP can be used to confirm hepatic origin of AP.

• Mild elevations of serum AP levels may be found in viral hepatitis, drug induced, granuloma-

tous and neoplastic liver disease.

• Bilirubin is formed from breakdown of heme. It is carried bound to albumin to hepatocytes

where UGT1A1 (bilirubin-UDP-glucuronosyltransferase) conjugates bilirubin. The conjugated

bilirubin is then exported through a transporter into bile canaliculi and excreted through bile

ducts. Transport of bilirubin through the canalicular membrane into the canaliculus is the rate

limiting step (“bottle neck”) of bilirubin excretion. Causes of hyperbilirubinemia include excess

heme breakdown, disorders of conjugation and bilirubin transport, hepatocellular damage and

obstruction of bile ducts.

• Increases in conjugated bilirubin are highly specific for hepatobiliary disease.

Disease classification

Enzyme patterns of liver injury

Enzyme pattern ALT:AP ratioa

Hepatocellular ≥5Cholestatic ≤2Mixed >2 to <5

a All enzymes expressed as multiples of ULN

EtiologySee “Definition of disease.”

Pathology/pathogenesisSee “Definition of disease.”

Section 2: Prevention

Not applicable for this topic.

6 Part 1: Hepatology

Section 3: Diagnosis

BOTTOM LINE/CLINICAL PEARLS• A detailed history is the key to the correct interpretation of abnormal liver tests. History

taking should include information including alcohol use, recent use of acetaminophen, herbal products or other medications, and risk factors for viral hepatitis transmission.

• Physical examination should include assessment for jaundice and encephalopathy which can indicate acute liver failure in a patient with no prior history of underlying liver disease. Stigmata of cirrhosis (spider angiomata, ascites, muscle wasting, Dupuytren’s contracture, splenomegaly) should be noted on physical examination.

• Elevated INR and bilirubin in a patient with encephalopathy and no underlying liver disease indicates acute liver failure and should prompt consideration of referral to a transplant center.

• Further laboratory investigations and imaging to diagnose the cause of elevated liver tests should be driven by clinical history and the pattern of liver test elevation (see Table: Enzyme patterns of liver injury and algorithms shown in Algorithm 1.1 and Algorithm 1.2).

• Viral and metabolic causes (i.e. hemochromatosis and Wilson disease) can be diagnosed with

confirmatory laboratory tests. However, alcoholic liver disease, NASH and DILI rely on careful

history taking and clinical diagnosis. Herbal preparations can be overlooked as a cause of

hepatotoxicity unless an accurate history is obtained. Causes of elevated tests that are unique

to pregnancy are discussed at the end of the chapter and in a separate chapter.

Hepatocellular/mixed elevation of liver tests• The diagnostic approach to aminotransferase or mixed aminotransferase/cholestatic liver test

elevation is shown in Algorithm 1.1 and selection of testing is largely driven by the clinical

presentation and the degree of AST and ALT elevation. Aminotransferase elevation above 10

times the ULN reflects severe acute injury and is observed in shock liver, toxic- or drug-induced

injury, acetaminophen toxicity, and acute viral hepatitis A, B (± D) and E. A detailed history

eliciting recent toxin or drug exposure, or a recent period of hypotension is important in

making the diagnosis. An acetaminophen level may be helpful for confirmation of suspected

acetaminophen injury.

• Acute liver injury in the setting of suspected recent viral hepatitis exposure (hepatitis B, C and

A) should prompt specific testing (HBV core IgM, HBV DNA, HCV RNA, hepatitis A IgM) due

to absence of antibodies in the window phase of acute infection. Failure to send the proper

tests can result in a missed or delayed diagnosis.

• Lesser degrees (up to 5 × ULN) of aminotransferase elevation can be caused by chronic

viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, Wilson disease, hemochromatosis,

Budd–Chiari syndrome, and infiltrative diseases. Serologic testing is available for autoimmune

hepatitis, Wilson disease, hemochromatosis and alpha-1 antitrypsin deficiency whereas

diagnosis of alcoholic hepatitis, NASH and drug-induced liver injury relies on careful history

taking.

• Alcoholic hepatitis often causes elevations of AST and ALT in a 2:1 ratio. This is because

patients with alcoholic liver disease are deficient in pyridoxal 5′-phosphate, which is required

for synthesis of ALT more so than AST. Additional features of alcoholic hepatitis include leu-

kocytosis, fever and jaundice.

• NASH, the most common cause of abnormal liver tests in the developed world, is diagnosed

after excluding other causes of elevated liver tests and after taking a history to exclude excess

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