A clinical textbook

Hepatology 2018

Ninth Edition 2018

Foreword

Hepatology – A clinical textbook is now in its ninth edition and the editors as the book are more mature. The current edition has again been thoroughly updated to reflect the latest medical progress. Because of this annual revision process it remains an up-to-date reference for all aspects of clinical hepatology. This would not have been possible without the continuous contributions of all the authors who have dutifully revised and updated their chapters and the help of Simon Collins who checked all chapters for language and correctness.

The Editors
Stefan Mauss, Thomas Berg, Jürgen Rockstroh, Christoph Sarrazin, Heiner Wedemeyer

Preface of the first edition

Hepatology is a rapidly evolving field that will continue to grow and maintain excitement over the next few decades. Viral hepatitis is not unlike HIV 10 or 15 years ago. Today, hepatitis B viral replication can be suppressed by potent antiviral drugs, although there are risks regarding the emergence of resistance. Strategies to enhance the eradication rates of HBV infection still need to be developed. On the other hand, hepatitis C virus infection can be eradicated by treatment with pegylated interferon plus ribavirin, although the sustained virologic response rates are still suboptimal, particularly in those infected with genotype 1. Many new antiviral drugs, especially protease and polymerase inhibitors, are currently in clinical development, and the data from trials reported over the last few years provide optimism that the cure rates for patients with chronic hepatitis C will be enhanced with these new agents, and even that all-oral regimens are around the corner! In other areas of hepatology, e.g., hereditary and metabolic liver diseases, our knowledge is rapidly increasing and new therapeutic options are on the horizon.

In rapidly evolving areas such as hepatology, is the book format the right medium to gather and summarise the current knowledge? Are these books not likely to be outdated the very day they are published? This is indeed a challenge that can be convincingly overcome only by rapid internet-based publishing with regular updates. Another unmatched advantage of a web-based book is the free and unrestricted global access. Viral hepatitis and other liver diseases are a global burden and timely information is important for physicians, scientists, patients and health care officials all around the world.

The editors of this web-based book – Thomas Berg, Stefan Mauss, Jürgen Rockstroh, Christoph Sarrazin and Heiner Wedemeyer – are young, bright, and internationally renowned hepatologists who have created an excellent state-of-the-art textbook on clinical hepatology. The book is well-written and provides in-depth information without being lengthy or redundant. I am convinced that all five experts will remain very active in the field and will continue to update this book regularly as the science progresses. This e-book should rapidly become an international standard.

Stefan Zeuzem – Frankfurt, Germany, January 2009

Therapeutic options and diagnostic procedures in hepatology have quickly advanced during the last decade. In particular, the management of viral hepatitis has completely changed since the early nineties. Before nucleoside and nucleotide analogues were licensed to treat hepatitis B and before interferon α + ribavirin combination therapy were approved for the treatment of chronic hepatitis C, very few patients infected with HBV or HCV were treated successfully. The only option for most patients with end-stage liver disease or hepatocellular carcinoma was liver transplantation. And even if the patients were lucky enough to be successfully transplanted, reinfection of the transplanted organs remained major challenges. In the late eighties and early nineties discussions were held about rejecting patients with chronic hepatitis from the waiting list as posttransplant outcome was poor. Today, just 15 years later, hepatitis B represents one of the best indications for liver transplantations, as basically all reinfection can be prevented. In addition, the proportion of patients who need to be transplanted is declining − almost all HBV-infected patients can nowadays be treated successfully with complete suppression of HBV replication and some well-selected patients may even be able to clear HBsAg, the ultimate endpoint of any hepatitis B treatment.

Hepatitis C has also become a curable disease with a sustained response of 50–80% using pegylated interferons in combination with ribavirin. HCV treatment using direct HCV enzyme inhibitors has started to bear fruit (we draw your attention to the HCV chapters).

Major achievements for the patients do sometimes lead to significant challenges for the treating physician. Is the diagnostic work-up complete? Did I any recent development to evaluate the stage and grade of liver disease? What sensitivity is really necessary for assays to detect hepatitis viruses? When do I need to determine HBV polymerase variants, before and during treatment of hepatitis B? When can I safely stop treatment without risking a relapse? How to treat acute hepatitis B and C? When does a health care worker need a booster vaccination for hepatitis A and B? These are just some of many questions we have to ask ourselves frequently during our daily routine practice. With the increasing number of publications, guidelines and expert opinions it is getting more and more difficult to stay up-to-date and to make the best choices for the patients. That is why Hepatology – A Clinical Textbook is a very useful new tool that gives a state-of-the art update on many aspects of HAV, HBV, HCV, HDV and HEV infections. The editors are internationally-known experts in the field of viral hepatitis; all have made significant contributions to understanding the pathogenesis of virus-induced liver disease, diagnosis and treatment of hepatitis virus infections.

Hepatology – A Clinical Textbook gives a comprehensive overview on the epidemiology, virology, and natural history of all hepatitis viruses including hepatitis A, D and E. Subsequent chapters cover all major aspects of the management of hepatitis B and C including coinfections with HIV and liver transplantation. Importantly, complications of chronic liver disease such as hepatocellular carcinoma and recent developments in assessing the stage of liver disease are also covered. Finally, interesting chapters on autoimmune and metabolic non-viral liver diseases complete the book.

We are convinced that this new up-to-date book covering all clinically relevant aspects of viral hepatitis will be of use for every reader. The editors and authors must be congratulated for their efforts.

Michael P. Manns – Hannover, January 2009

Table of Contents

1. Hepatitis A

Sven Pischke and Heiner Wedemeyer

The virus

Epidemiology

Transmission

Clinical course

Extrahepatic manifestations

Diagnosis

Treatment and prognosis

References

2. Hepatitis B

Raphael Mohr, Christoph Boesecke and Jan-Christian Wasmuth

Introduction

Transmission

Sexual transmission

Percutaneous inoculation

Perinatal transmission

Horizontal transmission

Blood transfusion

Nosocomial infection

Organ transplantation

Postexposure prophylaxis

Natural history and clinical manifestations

Acute hepatitis

Chronic hepatitis

Prognosis and survival

Extrahepatic manifestations

References

3. Hepatitis C

Christoph Boesecke and Jan-Christian Wasmuth

Epidemiology

Transmission

Injection drug use

Blood transfusion

Organ transplantation

Sexual or household contact

Perinatal transmission

Hemodialysis

Other rare transmission routes

Needle stick injury

Clinical manifestations

Acute HCV

Chronic HCV

Extrahepatic manifestations

Natural history

Cirrhosis and hepatic decompensation

Disease progression

References

4. Hepatitis E: a relevant disease with many aspects

Sven Pischke and Heiner Wedemeyer

Introduction

Genetic characteristics of HEV

Hepatitis E diagnosis

Worldwide distribution of HEV infections

Transmission of HEV

Acute hepatitis E in immunocompetent individuals

Acute and chronic HEV infections in organ transplant recipients

Hepatitis E in patients with HIV infection or other immunological deficiencies

Extrahepatic manifestations of hepatitis E

Treatment of chronic hepatitis E

Vaccination

Conclusions and recommendations

References

5. HBV virology

Maura Dandri, Jörg Petersen

Introduction

Taxonomic classification and genotypes

HBV structure and genomic organisation

HBV structural and non-structural proteins

The HBV replication cycle

Animal models of HBV infection

References

6. HCV virology

Bernd Kupfer

History

Taxonomy and genotypes

Viral structure

Genome organisation

Genes and proteins

Viral life cycle

Adsorption and viral entry

Translation and post-translational processes

HCV RNA replication

Assembly and release

Model systems for HCV research

References

7. Prophylaxis and vaccination

Heiner Wedemeyer

Introduction

Prophylaxis of hepatitis viruses

Hepatitis A and E

Hepatitis B and D

Hepatitis C

Vaccination against HAV

Vaccination against HBV

Efficacy of vaccination against HBV

Post-exposure prophylaxis

Safety of HBV vaccines

Long-term immunogenicity of HBV vaccination

Prevention of vertical HBV transmission

Vaccination against HCV

Vaccination against HEV

References

8. Hepatitis B: diagnostic tests

Jörg Petersen

Introduction

Serological tests for HBV

Collection and transport

Hepatitis B surface antigen and antibody

Hepatitis B core antibody

Hepatitis B e antigen and antibody

Serum HBV DNA assays

HBV genotypes

Antiviral resistance testing

Future markers that are not yet in clinical practice

Assessment of liver disease

Acute HBV infection

Past HBV infection

Chronic HBV infection

Serum transaminases

Occult HBV infection

Assessment of HBV immunity

Liver biopsy and noninvasive liver transient elastography

References

9. Treatment of hepatitis B infections

Florian van Bömmel, Johannes Wiegand, Thomas Berg

Introduction

Goals of treatment

Endpoints of treatment

Indication for antiviral therapy

Treatment of acute hepatitis B

Treatment of chronic hepatitis B

How to treat

Treatment options

Interferons

Nucleoside and nucleotide analogues

Choosing the right treatment option

Prognostic factors for treatment response

Monitoring before and during antiviral therapy

Treatment duration and stopping rules

Management of HBV resistance

Treatment of HBV infection in special populations

Novel treatments for HBV infections

References

10. Hepatitis D – diagnosis and treatment

Heiner Wedemeyer

Introduction

Virology of HDV

Epidemiology of HDV

Pathogenesis of HDV

Clinical course of HDV

Acute HBV/HDV coinfection

Chronic HDV

Diagnosis of HDV

Treatment of HDV

Nucleoside and nucleotide analogues

Recombinant interferon α

Pegylated interferon α

Liver transplantation for HDV

References

11. Hepatitis C: diagnostic tests

Christian Lange and Christoph Sarrazin

Serologic assays

HCV core antigen assays

Nucleic acid testing for HCV

Qualitative assays for HCV RNA detection

Qualitative RT-PCR

Transcription-mediated amplification (TMA) of HCV RNA

Quantitative HCV RNA detection

Competitive PCR: Cobas® Amplicor™ HCV 2.0 monitor

Branched DNA hybridisation assay (Versant™ HCV RNA 1.0 quantitative assay)

Real-time PCR-based HCV RNA detection assays

Cobas® TaqMan® HCV test

RealTime HCV test

Artus hepatitis C virus QS-RGQ assay

Versant HCV 1.0 kPCR assay

Cepheid Xpert HCV Viral Load Assay and Beckman Coulter DxN Veris HCV Assay

HCV genotyping

Reverse hybridising assay (Versant® HCV Genotype 2.0 System (LiPA))

Direct sequence analysis (Trugene® HCV 5'NC genotyping kit)

Real-time PCR technology (RealTime™ HCV Genotype II assay)

Cobas® HCV genotyping test

Implications for diagnosing and managing acute and chronic hepatitis C

Diagnosing acute hepatitis C

Diagnosing chronic hepatitis C

Diagnostic tests in the management of hepatitis C therapy

References

12. Standard therapy of chronic hepatitis C virus infection

Markus Cornberg, Christoph Höner zu Siederdissen, Benjamin Maasoumy, Michael P. Manns

Preface

Goal of antiviral therapy

Therapeutic concepts and medication

Development of antiviral treatment

Treatment indication

Predictors of treatment response and pre-therapeutic assessment

Antiviral resistance

Treatment in 2018

Treatment of patients with prior DAA treatment failure

Optimisation of HCV treatment

Management of side effects and complications

Drug-drug interactions

Treatment of hepatitis C in special populations

Patients with acute hepatitis C

Patients with normal aminotransferase levels

Patients with compensated versus decompensated liver cirrhosis

Patients with hepatocellular carcinoma (HCC)

Patients after liver transplantation

Patients with chronic kidney disease

Drug use and patients on stable maintenance substitution

Patients with co-infections

Patients with hemophilia

Patients with extrahepatic manifestations

References

13. Hepatitis C: drug development and resistance

Christian Lange, Christoph Sarrazin

Introduction

HCV life cycle and treatment targets

NS3/4A protease inhibitors

Molecular biology

NS3 protease inhibitors

Resistance to NS3/4A inhibitors

NS5B polymerase inhibitors

Molecular biology

Nucleoside analogues

Non-nucleoside analogues

NS5A inhibitors

Compounds targeting viral attachment and entry

Host factors as targets for treatment

Cyclophilin B inhibitors

Nitazoxanide

Silibinin

RNA interference-based treatment strategies (miravirsen, RG-101 and TT-034)

Novel IFN-free, DAA-based combination therapies

Grazoprevir plus elbasvir or ruzasvir (MK-8408) plus MK-3682 or sofosbuvir

Simeprevir (NS3 inhibitor) in combination with odalasvir (NS5A inhibitor) and AL-335 (nucleoside NS5B inhibitor)

Conclusions

References

14. Management of adverse drug reactions

Martin Schaefer and Stefan Mauss

Introduction

Interferon-based therapies

Flu-like symptoms, fever, arthralgia and myalgia

Gastrointestinal disorders

Weight loss

Asthenia and fatigue

Cough and dyspnoea

Disorders of the thyroid gland

Psychiatric adverse events

Incidence and profile of psychiatric adverse events

Preemptive therapy with antidepressants

Sleep disturbances

Hematological and immunologic effects

Skin disorders and hair loss

Adverse events associated with combination therapy of pegylated interferon and ribavirin plus direct acting antiviral agents (DAAs)

Simeprevir and daclatasvir as part of interferon-based therapy

Sofosbuvir as part of interferon-based therapy or as dual therapy with ribavirin

Adherence and interferon-based therapies

Interferon-free regimens with DAAs

Conclusion

References

15. Extrahepatic manifestations of chronic HCV

Albrecht Böhlig, Karl-Philipp Puchner and Thomas Berg

Introduction

Mixed cryoglobulinaemia

Diagnosis

Clinical presentation

Malignant lymphoproliferative disorders/NHL

Aetiology and pathogenesis of LPDs in patients with HCV infection

Treatment of lymphoproliferative disorders

Mixed cryoglobulinaemia

Systemic vasculitis

Peripheral neuropathy

Further hematological manifestations

HCV-associated thrombocytopenia

HCV-related autoimmune hemolytic anaemia

HCV-related glomerulonephritis

Endocrine manifestations

Cardiovascular manifestations

Central nervous manifestations

Dermatologic and miscellaneous manifestations

References

16. Management of HBV/HIV coinfection

Stefan Mauss and Jürgen Kurt Rockstroh

Introduction

Treatment of chronic hepatitis B in HBV/HIV-coinfected patients on antiretroviral therapy

Conclusion

References

17. Management of HCV/HIV coinfection

Christoph Boesecke, Stefan Mauss, Jürgen Kurt Rockstroh

Epidemiology of HCV/HIV coinfection

Diagnosis of HCV in HIV coinfection

Natural course of HCV in HIV coinfection

Effect of HCV on HIV

Effect of ART on HCV

Treatment of HCV in HIV coinfection

Treatment of HCV for relapse or non-response

Treatment of acute HCV in HIV

Management of liver cirrhosis and liver transplantation in people with HIV/HCV coinfection

Conclusion

References

18. HBV/HCV coinfection

Raphael Mohr, Carolynne Schwarze-Zander and Jürgen Kurt Rockstroh

Epidemiology of HBV/HCV coinfection

Screening for HBV/HCV coinfection

Viral interactions between HBV and HCV

Clinical scenarios of HBV and HCV infection

Acute hepatitis by simultaneous infection of HBV and HCV

HCV superinfection

HBV superinfection

Occult HBV infection in patients with HCV infection

Chronic hepatitis in HBV/HCV coinfection

Cirrhosis

Hepatocellular carcinoma

Treatment of HBV and HCV coinfection

Conclusion

References

19. Assessment of hepatic fibrosis and steatosis

Frank Grünhage and Frank Lammert

Introduction

Mechanisms of liver fibrosis in chronic viral hepatitis

Liver biopsy – the "gold standard" for staging of liver fibrosis

Surrogate markers of liver fibrosis

Ultrasound-based elastography

Transient elastography

Acoustic radiation force imaging (ARFI) and shear wave imaging (SSI)

Other imaging techniques for the assessment of liver fibrosis

Clinical decision algorithms

Population based screening for advanced liver fibrosis

Non-alcoholic fatty liver disease

Controlled Attenuation Parameter (CAP)

Summary

References

20. Diagnosis, prognosis & therapy of hepatocellular carcinoma

Ulrich Spengler

Classification of HCC

Epidemiology

Surveillance of patients at high risk and early HCC diagnosis

Diagnosis

Stage-adapted therapy for liver cancer

Potentially curative therapy in BCLC stages 0-A

Palliative therapy in BCLC stages B and C

Prophylaxis of liver cancer

References

21. Transplant hepatology: a comprehensive update

S. Beckebaum, V. R. Cicinnati

Introduction

Timing and indications for liver transplantation

Patient evaluation

Pretransplant management issues

Waiting list monitoring of hepatitis B liver transplant candidates

Waiting list monitoring and treatment of hepatitis C liver transplant candidates

Adjunct treatment and staging of HCC transplant candidates

Liver transplantation in autoimmune hepatitis and cholestatic liver diseases

Living donor liver transplantation: indications, donor evaluation, and outcome

Perioperative complications

Long-term complications after liver transplantation

Opportunistic infections

Hepatitis E

Chronic ductopenic rejection

Calcineurin inhibitor-induced nephrotoxicity and alternative immunosuppressive protocols

Other side effects of CNI

Corticosteroid minimisation/avoidance protocols and additional strategies to reduce metabolic complications

De novo malignancies

Biliary complications

Metabolic bone disease

Recurrent diseases after liver transplantation

Pregnancy after liver transplantation

Experiences with liver transplantation in inherited metabolic liver diseases in adult patients

Outcome after liver transplantation for acute hepatic failure

Conclusion

References

22. End-stage liver disease, HIV and liver transplantation

José M. Miró, Fernando Agüero, Alejandro Forner, Christian Manzardo, Maria Londoño, Montserrat Laguno, Montserrat Tuset, Juan Ambrosioni, Anna Lligoña, Asuncion Moreno, Juan-Carlos García-Valdecasas, Antonio Rimola and the Hospital Clinic OLT in HIV Working Group

Introduction

End-stage liver disease in HIV positive patients

Magnitude of the problem and natural history

Clinical features of HIV-coinfected patients with ESLD

Prognosis after hepatic decompensation

Mortality during the evaluation process for liver transplantation

Management of complications of cirrhosis

HCV/HBV management

Antiretroviral therapy (ART)

Hepatocellular carcinoma in HIV positive patients

Evaluation process for liver transplantation in HIV positive patients

Liver transplant (LT) in HIV positive patients

Liver disease criteria

HIV criteria

Outcome of LT in HIV positive patients

Complications after LT in HIV positive patients

Infectious complications

Other complications

Pharmacokinetic interactions in the posttransplant period

Immunosuppression and rejection in HIV positive LT recipients

HCV recurrence after LT

HBV recurrence after LT

Hepatocellular carcinoma

Liver retransplantation

Conclusions

References

23. Metabolic liver diseases: haemochromatosis

Claus Niederau

Definition and classification of iron overload diseases

Type 1 HFE haemochromatosis

History

Epidemiology

Aetiology and pathogenesis

Diagnosis

Early diagnosis and screening

Complications of iron overload

Therapy

Prognosis

Juvenile hereditary haemochromatosis

Transferrin receptor 2 (TFR2)-related type 3 haemochromatosis

Type 4 haemochromatosis – Ferroportin Disease

Secondary haemochromatosis

Pathophysiology

Use of blood from patients with HFE haemochromatosis (type 1) for blood donation

References

24. NAFLD and NASH

Claus Niederau

Introduction

Prevalence

Demographics and risk factors

Pathogenesis

Human genetic factors

Microbiome

Natural history

Diagnosis

Diet, physical exercise and lifestyle recommendations

Alcohol and coffee

Pharmacological treatment

Novel pharmacological approaches

Alterations of the intestinal microbiome

Surgery for obesity

Liver transplantation (LTX) for NASH

Follow-up of NAFDL and NASH patients

References

25. Wilson's disease

Claus Niederau

Introduction

Clinical presentation

Diagnosis

Scoring system

Serum ceruloplasmin

Serum copper

Urinary copper excretion

Hepatic copper concentration

Radiolabelled copper

Liver biopsy findings

Neurology and MRI of the CNS

Genetic Studies

Treatment

Monitoring of treatment

References

26. Autoimmune liver diseases: AIH, PBC and PSC

Christian P. Strassburg

Autoimmune hepatitis (AIH)

Definition and diagnosis of autoimmune hepatitis

Epidemiology and clinical presentation

Natural history and prognosis

Who requires treatment?

Who does not require treatment?

Standard treatment strategy

Treatment of elderly patients

Alternative treatments

Budesonide

Deflazacort

Cyclosporine A

Tacrolimus

Mycophenolic acid

Cyclophosphamide

Anti-TNF α antibodies

Ursodeoxycholic acid

Overlap syndromes and treatment

Liver transplantation

Recurrence and de novo AIH after liver transplantation

Primary biliary cholangitis

Introduction

Definition and prevalence of PBC

Diagnostic principles of PBC

Therapeutic principles in PBC

Primary sclerosing cholangitis

Diagnosis of primary sclerosing cholangitis (PSC)

Differential diagnosis: sclerosing cholangitis

Association of PSC with inflammatory bowel disease

PSC as a risk factor for cancer

Medical therapy of PSC

Therapy of IBD in PSC

References

27. Alcoholic hepatitis

Claus Niederau

Health and social problems due to alcohol overconsumption

Prevention of harmful alcohol use

Classification and natural history of alcoholic liver disease

Clinical features and diagnosis of alcoholic hepatitis

Course and severity

Mechanisms of alcohol-related liver injury

Role of PNPLA3 polymorphisms and other genetic factors in the progression of alcoholic liver disease

Treatment

Abstinence from alcohol

Supportive therapy

Corticosteroids

Pentoxifylline

Comparison and combination of corticosteroids and pentoxifylline

N-acetyl cysteine

Anti-TNF-α therapy

Therapy with granulocyte colony-stimulating factor (G-CSF)

Nutritional support

Other pharmacologic treatments

Liver transplantation

Summary

References

28. Vascular liver disease

Matthias J. Bahr

Disorders of the hepatic sinusoid

Sinusoidal obstruction syndrome (Hepatic veno-occlusive disease)

Peliosis hepatis

Disorders of the hepatic artery

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

Disorders of the portal vein

Portal vein thrombosis

Idiopathic non-cirrhotic portal hypertension (INCPH)

Disorders of the hepatic veins

Budd-Chiari syndrome

References

29. Acute liver failure

Akif Altinbas, Lars P. Bechmann, Hikmet Akkiz, Guido Gerken, Ali Canbay

Introduction and definition

Epidemiology and aetiologies

Intoxication

Amanita intoxication

Viral hepatitis

Immunologic etiologies

Wilson's Disease

Vascular disorders

Pregnancy-induced liver injury

Undetermined

Molecular mechanisms and clinical presentation

Prognosis

Treatment

General management

Hepatic encephalopathy

Coagulopathy

Liver transplantation

Extracorporal liver support systems

Specific treatment options

References

Contributing authors

Fernando Agüero
Infectious Diseases Service
Hospital Clinic – IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Hikmet Akkiz
Department of Gastroenterology and Hepatology
Çukurova University
School of Medicine
Adana, Turkey

Akif Altinbas
Diskapi Yildirim Beyazit Education and Research Hospital
Gastroenterology Clinic
Ankara, Turkey

Matthias J. Bahr
Dept. of Medicine I
Sana Kliniken Lübeck
Kronsforder Allee 71-73
23560 Lübeck, Germany

Lars P. Bechmann
Department of Gastroenterology and Hepatology,
University Hospital Essen
Hufelandstr. 55
45122 Essen, Germany

Susanne Beckebaum
Department of Internal Medicine, Gastroenterology and Hepatology
St. Josef Krankenhaus
Heidbergweg 22-24
45257 Essen, Germany

Thomas Berg
Sektion Hepatologie
Klinik und Poliklinik für Gastroenterologie & Rheumatologie
Universitätsklinikum Leipzig
Liebigstr. 20
04103 Leipzig, Germany
thomas.berg@medizin.uni-leipzig.de

Albrecht Böhlig
Sektion Hepatologie
Klinik und Poliklinik für Gastroenterologie & Rheumatologie
Universitätsklinikum Leipzig
Liebigstr. 20
04103 Leipzig, Germany

Florian van Bömmel
Sektion Hepatologie
Klinik und Poliklinik für Gastroenterologie & Rheumatologie
Universitätsklinikum Leipzig
Liebigstr. 20
04103 Leipzig, Germany

Christoph Boesecke
Department of Medicine I
University Hospital Bonn
Sigmund-Freud-Strasse 25
53105 Bonn, Germany

Ali Canbay
Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie
Otto-von-Guericke-Universität
Universitätsklinikum Magdeburg A.ö.R.
Leipziger Str. 44
39120 Magdeburg, Germany

Carlos Cervera
Infectious Diseases Service
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Vito R. Cicinnati
Department of Internal Medicine, Gastroenterology and Hepatology
St. Josef Krankenhaus
Heidbergweg 22-24
45257 Essen, Germany

Markus Cornberg
Dept. of Gastroenterology, Hepatology and Endocrinology
Medical School of Hannover
Carl-Neuberg-Str. 1
30625 Hannover, Germany

Maura Dandri
University Hospital Hamburg-Eppendorf
Zentrum für Innere Medizin
I. Medizinische Klinik
Labor Hepatologie und Virus Hepatitis
Martinistr. 52
20246 Hamburg, Germany

Alejandro Forner
Barcelona Clinic Liver Cancer Group
Liver Unit
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Juan-Carlos García-Valdecasas
Liver Transplant Unit, Department of Surgery
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Guido Gerken
Department of Gastroenterology, University Hospital Essen
Hufelandstr. 55
45122 Essen, Germany

PD Dr. Frank Grünhage
Chefarzt Klinik für Gastroenterologie und Onkologie
Von Werth-Straße 5
41515 Grevenbroich, Germany

Christoph Höner zu Siederdissen
Dept. of Gastroenterology, Hepatology and Endocrinology
Medical School of Hannover
Carl-Neuberg-Str. 1
30625 Hannover, Germany

Anna Hüsing
Department of Transplant Medicine
University Hospital Münster
Albert-Schweitzer-Campus 1
48149 Münster, Germany

Iyad Kabar
Department of Transplant Medicine
University Hospital Münster
Albert-Schweitzer-Campus 1
48149 Münster Germany

Bernd Kupfer
Endenicher Strasse 266
53121 Bonn, Germany

Montserrat Laguno
Infectious Diseases Service
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Frank Lammert
Medical Department II
Saarland University Hospital
Kirrbergerstr. 1
66421 Homburg, Germany

Christian Lange
J. W. Goethe-University Hospital
Medizinische Klinik 1
Theodor-Stern-Kai 7
60590 Frankfurt am Main, Germany

Anna Lligoña
Psychiatry Department
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Benjamin Maasoumy
Dept. of Gastroenterology,
Hepatology and Endocrinology
Medical School of Hannover
Carl-Neuberg-Str. 1
30625 Hannover, Germany

Michael P. Manns
Dept. of Gastroenterology, Hepatology and Endocrinology
Medical School of Hannover
Carl-Neuberg-Str. 1
30625 Hannover, Germany

Christian Manzardo
Infectious Diseases Service
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Stefan Mauss
Center for HIV and Hepatogastroenterology
Humboldtstraße 18
40237 Duesseldorf, Germany
stefan.mauss@center-duesseldorf.de

José M. Miró
Infectious Diseases Service
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Raphael Mohr
Department of Medicine I
University Hospital Bonn
Sigmund-Freud-Strasse 25
53105 Bonn, Germany

Asuncion Moreno
Infectious Diseases Service
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Claus Niederau
Katholische Kliniken Oberhausen gGmbH, St. Josef Hospital
Department of Internal Medicine
Academic Teaching Hospital of the University
Duisburg-Essen
Mülheimer Str. 83
46045 Oberhausen, Germany

Jörg Petersen
Liver Unit IFI Institute for Interdisciplinary Medicine
Asklepios Klinik St George Hamburg
Lohmühlenstr. 5
20099 Hamburg, Germany

Sven Pischke
Department of Medicine I
University Medical Centre Hamburg-Eppendorf (UKE)
Martinistrasse 52
20246 Hamburg, Germany

Kerstin Port
Dept. of Gastroenterology, Hepatology and Endocrinology
Medical School of Hannover
Carl-Neuberg-Str. 1
30625 Hannover, Germany

Karl-Philipp Puchner
Charité, Campus Virchow-Klinikum,
Universitätsmedizin
Medizinische Klinik m. S. Hepatologie und Gastroenterologie
Augustenburger Platz 1
13353 Berlin, Germany

Antonio Rimola
Liver Transplant Unit – CIBEREHD
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

J. K. Rockstroh
Department of Medicine I
University Hospital Bonn
Sigmund-Freud-Strasse 25
53105 Bonn, Germany
rockstroh@uni-bonn.de

Christoph Sarrazin
Medizinische Klinik II
St. Josefs-Hospital Wiesbaden GmbH
Beethovenstr. 20
65189 Wiesbaden, Germany
CSarrazin@joho.de

Martin Schäfer
Department of Psychiatry
and Psychotherapy
Kliniken Essen-Mitte
Ev. Huyssenstift
Henricistraße 92
45136 Essen, Germany

Carolynne Schwarze-Zander
Department of Medicine I
University Hospital Bonn
Sigmund-Freud-Strasse 25
53105 Bonn, Germany

Philipp Solbach
Dept. of Gastroenterology, Hepatology and Endocrinology
Medical School of Hannover
Carl-Neuberg-Str. 1
30625 Hannover, Germany

Ulrich Spengler
Department of Internal Medicine 1
University Hospitals of Bonn University
Sigmund-Freud-Strasse 25
53105 Bonn, Germany

Christian P. Strassburg
Department of Medicine I
University Hospital Bonn
Sigmund-Freud-Strasse 25
53105 Bonn, Germany

Montserrat Tuset
Pharmacy Department
Hospital Clínic − IDIBAPS
University of Barcelona
Villarroel, 170
08036 Barcelona, Spain

Jan-Christian Wasmuth
Department of Medicine I
University Hospital Bonn
Sigmund-Freud-Strasse 25
53105 Bonn, Germany

Heiner Wedemeyer
Dept. of Gastroenterology, Hepatology and Endocrinology
Medical School of Hannover
Carl-Neuberg-Str. 1
30625 Hannover, Germany
wedemeyer.heiner@mh-hannover.de

Johannes Wiegand
Sektion Hepatologie
Klinik und Poliklinik für Gastroenterologie & Rheumatologie
Universitätsklinikum Leipzig
Liebigstr. 20
04103 Leipzig, Germany

Stefan Zeuzem
J. W. Goethe-University Hospital
Medizinische Klinik 1
Theodor-Stern-Kai 7
60590 Frankfurt am Main, Germany

Hepatology 2018

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The Editors

Stefan Mauss
Thomas Berg
Juergen Rockstroh
Christoph Sarrazin
Heiner Wedemeyer

English language and style

Simon Collins

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Schaafkopp.de

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Gilead has supported the realisation of Hepatology 2018 with an amount of € 15,000.

AbbVie has supported the realisation of Hepatology 2018 with an amount of € 3,000.

MSD has supported the realisation of Hepatology 2018 with an amount of € 2,500.

Intercept has supported the realisation of Hepatology 2018 with an amount of € 2,000.

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Disclaimer

Hepatology is an ever-changing field. The editors and authors of Hepatology − A Clinical Textbook have made every effort to provide information that is accurate and complete as of the date of publication. However, in view of the rapid changes occurring in medical science, as well as the possibility of human error, this book may contain technical inaccuracies, typographical or other errors. Readers are advised to check the product information currently provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the treating physician who relies on experience and knowledge about the patient to determine dosages and the best treatment for the patient. The information contained herein is provided “as is” and without warranty of any kind. The editors disclaim responsibility for any errors or omissions or for results obtained from the use of information contained herein.

© 2018 by Mauss, et al.