Primary Biliary Cirrhosis: From Pathogenesis to Clinical Treatment

Primary Biliary Cirrhosis:

From Pathogenesis to Clinical Treatment

Keith D. Lindor Professor of Medicine

MayoClinic 200 First Street SW

Rochester; MN 55905 USA

Edited by

E. Jenny Heathcote Professor of Medicine University of Toronto

The Toronto Hospital, Westem Division 399 Bathurst Street, Wing 4-828

Toronto, ONT M5T 2S8 Canada

RaoulPoupon Professor of Medicine

SeNice d'Hepatologie et Gastroenterologie AP - H6pital Saint-Antoine

184, rue Du Faubourg, Saint-Antoine 75571 Paris

France

The proceedings of a symposium organised by AXCAN PHARMA, held in Chicago, November 6, 1997

+ I~I

~ . . , SPRINGER SCIENCE+BUSINESS MEDIA, B.V.

Library of Congress Cataloging-in-Publication Dala

A C.I.P. Catalogue record for this book is available from the Library of Congress.

ISBN 978-94-010-6047-9 ISBN 978-94-011-4884-9 (eBook) DOI 10.1007/978-94-011-4884-9

Printecl on adclJrel! paper

All Rights Reserved © 1998 Springer Science+Business Media Dordrecht

Original1y published by K1uwer Academic Publishers in 1998 Softcover reprint of the hardcover 1 st edition 1998

No part of this publication may be reproduced or utilized in any form or by any means, electronic, mechanical,

including photocopying, recording or by any information storage and retrieval system, without written permission from the copyright owner.

Contents

Scientific Organizers vii

List of Principal Authors ix

Preface Sheila Sherlock xiii

Section I: NATURAL HISTORY AND PATHOGENESIS

Natural history and demography of primary biliary cirrhosis 0. F. W. James 3

2 Immune basis for PBC M. F. Bassendine 11

3 Isolation and cloning of anti mitochondrial antibodies R. Joplin 19

4 Significance of anti mitochondrial antibody profiles in primary biliary cirrhosis R. Klein, P. A. Berg 24

5 Chloride/bicarbonate exchange in PBC: a clue for pathogenesis? J. F. Medina, J. Prieto 35

6 Molecular considerations of primary biliary cirrhosis M. E. Gershwin, C. T. Migliaccio, J. Van de Water; R. L. Coppel 40

7 Animal models of primary biliary cirrhosis C. D. Howell, J. U, W. Chen 53

8 Fibrogenesis in PBC D. Schuppan, E. G. Hahn 64

v

CONTENTS

9 Natural history models of primary biliary cirrhosis W R. Kim, E. R. Dickson 76

Section II: MANAGEMENT OF PRIMARY BILIARY CIRRHOSIS

10 Portal hypertension in patients with primary biliary cirrhosis P. M. Huet, J. Huet, J. Deslauriers 87

11 Management of primary biliary cirrhosis: osteoporosis A. Pares 92

12 Fatigue in the primary biliary cirrhosis patient M. G. Swain 102

13 The pruritus of cholestasis: behavioral studies shed light on its pathogenesis N. V. Bergasa, E. A. Jones 108

14 Old and new immunosuppressant drugs: mechanisms and potential value J. M. Vierling 115

15 Methotrexate and colchicine in the treatment of primary biliary cirrhosis M. M. Kaplan 124

16 Corticosteroids in PBC H. R. van Buuren 130

17 Ursodeoxycholic acid treatment of primary biliary cirrhosis: potential mechanisms of action G. Paumgartner 138

18 Ursodiol and combination therapy R. L. Carithers Jr. 147

19 Primary biliary cirrhosis transplantation and recurrent disease J. Neuberger 155

20 New clinical trials in primary biliary cirrhosis: design and endpoints J. Everhart 163

Index 173

vi

Scientific Organizers

KEITH D. LlNDOR Professor of Medicine Mayo Clinic 200 First Street SW Rochester, MN 55905 USA

E. JENNY HEATHCOTE Professor of Medicine University of Toronto Chief, Division of Gastroenterology The Toronto Hospital, Western Division 399 Bathurst Street, Wing 4-828 Toronto, ONT M5T 288 Canada

RAOUL POUPON Professor of Hepatology and Gastroenterology Department of Pathology AP - Hopital Saint -Antoine 184, rue Du Faubourg 75571 Paris France

vii

List of Principal Authors

M. F. BASSENDINE Uver Unit Freeman Hospital Newcastle upon Tyne NE77DN UK

N.V.BERGASA Division of Gastroenterology & Uver Disease Beth Israel Medical Center First Avenue at 16th Street New York NY 10003 USA

R. L. CARITHERS Jr. Hepatology Section University of Washington 1959 NE Pacific Street Seattle WA 98195-0004 USA

E. R. DICKSON Division of Gastroenterology and Hepatology Mayo Clinic r-N19) 200 First Street SW Rochester MN 55905 USA

J.EVERHART Epidemiology and Clinical Trials Branch Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AN-12J 45 Center Dr MSC 6600 Bethesda MD 20892-6600 USA

ix

LIST OF PRINCIPAL AUTHORS

M. E. GERSHWIN University of california at Davis Division of Rheumatology, Allergy and Clinical Immunology One Shields Avenue, TB 192, School of Medicine Davis CA 95616-8660 USA

C. D. HOWELL Hepatology Section The University of Maryland School of Medicine 22 S Green St Room N3W 130 Baltimore MD 21201-1595 USA

P.-M. HUET Hepatology Research Group CHUM Clinical Research Center Sainl-Luc Pavilion 164 Rene-Levesque Blvd. E. Montreal QC H2X 1P1 Canada

O. F. W. JAMES School of Clinical Medical Sciences University of Newcastle Senior Consultant Physician Uver Unit Freeman Hospital Newcastle upon Tyne NE24HH UK

R. JOPLIN Uver Research Laboratories University Hospital The Queen Elizabeth Hospital Birmingham B152TH UK

M. M. KAPLAN Tufts University School of Medicine Gastroenterology Division New England Medical Center 750 Washington Street, Box 233 Boston MA02111 USA

x

LIST OF PRINCIPAL AUTHORS

R. KLEIN Department of Internal Medicine University of TLibingen Otfried MOiler Str. 10 72076 TLibingen Germany

J.NEUBERGER The Liver Unit and Hepatobiliary Unit The Queen Elizabeth Hospital Birmingham B152TN UK

A.PARES Liver Unit Hospital Clinic i Provincial Calle Villarroel 170 08036 Barcelona Spain

G. PAUMGARTNER Department of Medicine II Klinikum Grosshadern Marchioninistrasse 15 D-81377 Munich Germany

J. PRIETO Department of Medicine and Liver Unit CHnica Universitaria de Navarra Avenida Pio XII. 36 E-31008 Pamplona Spain

D.SCHUPPAN Department of Medicine I (Gastroenterology & Hepatology) University of Erlangen-NOrnberg Krankenhausstr. 12 D-91054 Erlangen Germany

M. G. SWAIN Liver Unit. Gastroenterology Research Group Health Sciences Center University of Calgary 3330 Hospital Drive NW Calgary AB T2N 4N1 Canada

xi

LIST OF PRINCIPAL AUTHORS

H. R. VAN BUUREN Department of Hepatogastroenterology and Intemal Medicine University Hospital Rotterdam Dr Molewaterplein 40 3015 GD Rotterdam The Netherlands

J. M. VIERLING Center for Uver Diseases and Transplantation 8635 West Third Street, Site 590W Los Angeles CA 90048 USA

xii

Preface

The condition of prolonged obstructive jaundice with patent bile ducts was first described in 1851 by Addison and Gull of Guy's Hospital, London. The term primary biliary cirrhosis (PBC) was defined in 1950 by Ahrens and colleagues of the Rockefeller Institute, New York. The condition was considered rare but this changed in 1965 with the discovery of a definitive diagnostic serum mitochondrial antibody test and the recognition that a raised serum alkaline phosphatase value, often discovered incidentally, could be a diagnostic pointer. If the diagnosis is made earlier, the end stages are rarely reached as death is replaced by liver transplantation.

On November 6th 1997, in Chicago, an International Faculty discussed in depth the clinical features, pathogenesis and treatment of PBC, no longer considered a rare disease. The course of PBC is long, but some 18 years after the discovery of a positive mitochondrial antibody test in a symptom­free patient with normal serum biochemistry, 83% will have developed abnormal tests and 76% will be symptomatic. Identification of those who will progress rapidly is difficult. The serum antimitochondrial profile may be useful but this is a very specialist technique. Mathematical prognostic models are useful in therapeutic trials and in the selection and timing of patients for liver transplantation but have limited value in individual patients. An increasing serum bilirubin level remains the most important indicator of rapid progression. Its value however can be negated by the use of ursodeoxycholic acid which has a bilirubin-lowering effect.

PBC is generally considered to be an autoimmune disease. The sufferer is believed to be genetically predisposed. There is a weak association with MHC class II allele HLA DR8. The link is however not nearly so close as that found with autoimmune chronic active hepatitis.

The part played by mitochondrial antibodies (AMA) in pathogenesis remains controversial. The mitochondrial antigen responsible for the AMA is the pyruvate dehydrogenase complex (PDC). In PBC, aberrant expression of the E2 component of PDC has been shown on bile duct epithelium, possibly rendering bile ducts susceptible to immune-mediated damage. Alternatively, the disease may have an infectious etiology as there is cross­reactivity between AMA and sub-cellular constituents of Gram-positive and

xiii

PRIMARY BILIARY CIRRHOSIS

Gram-negative organisms. The AMA found in PBC may be primarily directed against enterobacterial antigens resulting from intestinal infection.

The immunological lesion is mediated by CD4 T-cells secreting T-helper cytokines (IL-2, IFNy, TNFoc/IJ). Later, as the bile ducts disappear, fibrosis and cirrhosis develop. Cholestasis is enhanced by decreased levels of biliary transport proteins secondary to the biliary obstruction and to endotoxaemia.

Therapy can be directed against any of these injurious processes. Immunological manipulations have been many. Corticosteroids block CD4 lymphocytes but bone thinning prevents their long-term use. Azathioprine, chlorambucil, D-penicillamine and cyclosporin have been tested and gen­erally found wanting, usually because of side-effects or failure to prove benefit in long-term placebo-controlled clinical trials. It is also difficult to justify the continued use, over many years, of drugs which have potential toxicity. Drug failures may also be related to the stage of the disease. It is clearly not possible to reverse cirrhotic nodules and fibrosis or the interfer­ence with hepatobiliary transport.

Colchicine, which has anti-inflammatory and anti-fibrotic actions, failed to provide conclusive benefit. Methotrexate may benefit some patients in the early stages of PBC but pneumonitis and hematological complications can develop. Ursodeoxycholic acid (UDCA; ursodiol) is currently the most effective medical therapy for PBC. Biochemical tests improve, progression of portal hypertension is reduced and time to death or liver transplantation is prolonged. However, histological changes in the liver progress and effects on lethargy and pruritus are variable. UDCA should be given to all symp­tomatic patients. The role in pre- and asymptomatic sufferers is not clear. The mechanism of action of UDCA is complex. The bile acid pool becomes more hydrophilic and less detergent so acting as a protectant of the luminal membrane of the interlobular bile ducts. U DCA stimulates the biliary excre­tion of endogenous hydrophobic (toxic) bile acids, perhaps by stimulating vesicular exocytosis by which transport carrier proteins are targeted to the canalicular membrane. Finally, UDCA may reduce the immune attack of cytotoxic T -cells by decreasing H LA 1 expression on bile ducts.

Combinations of drugs may have greater benefit than mono therapy. UDCA plus methotrexate or corticosteroids is being assessed. Triple therapy with prednisolone, azathioprine and UDCA are under trial and results are awaited.

Fibrosis accompanies bile ductular proliferation and is responsible for the end picture of cirrhosis. Fibrosis is unaffected by immunomodulation or UDCA and holds the key to reversibility. This has led to therapy with such drugs as colchicine, silimarin and pentoxifylIin, which are largely ineffective. Better anti-fibrotic agents are awaited.

Complications such as ascites and portal hypertension need to be treated. Bone thinning may be reduced by etidronate and fluoride. Opiate antagonists are being used to control pruritus.

Hepatic transplantation performed before the terminal stages offers a five­year survival exceeding 85%. There is increasing evidence of recurrence in the graft. Granulomatous cholangitis develops in the livers of patients having a transplant for PBC but not where the operation is done for other indic-

xiv

PREFACE

ations. Short- and medium-term significance of the recurrence is probably little but longer follow-up is necessary.

The conference demonstrated the advantages of attracting international experts from various disciplines, clinical, immunological, biochemical, genetic and histopathological, to focus down on one disease. PBC, however, has something for everyone. It provides examples of model situations which can be applied to all of hepatology and indeed to all of general medicine.

Sheila Sherlock Department of Surgery Royal Free Hospital London

xv