Hepatic Encephalopathy Pathophysiology and Treatment

Experimental Biology and Medicine Hepatic Encephalopathy: Pathophysiology and Treatment, edited by

Roger F. Butterworth and Gilles Pomier Layrargues, 1989 Molecular Actions of Alcohol: Neurobiology and Metabolism,

edited by Grace Y. Sun, P. Kevin Rudeen, W. Gibson Wood, Yau Huei Wei, and Albert Y. Sun, 1989

Macromolecular Biorecognition: Principles and Methods, edited by Irwin Chaiken, Emilia Chiancone, Angelo Fontana, and Paolo Neri, 1987

Molecular Basis of Lymphokine Action, edited by David R. Webb, Carl W. Pierce, and Stanley Cohen, 1987

Biology of Copper Complexes, edited by John R. J. Sorenson, 1987 Epstein-Barr Virus and Human Disease, edited by P. H. Levine,

D. V. Ablashi, M. Nonoyama, G. R. Pearson, and R. Glaser, 1987

Methods of Protein Sequence Analysis • 1986, edited by Kenneth A. Walsh, 1987

Regulation of Immune Gene Expression, edited by Marc Feldmann and Andrew McMichael, 1986

Biological Methylation and Drug Design, edited by Ronald T. Borchardt, Cyrus R. Creveling, and Per Magne Ueland, 1986

Retroviruses and Human Pathology, edited by Robert C. Gallo, Dominique Stehelin, and Oliviero E. Varnier, 1985

Directed Drug Delivery, edited by Ronald T. Borchardt, Arnold Repta, and Valentino Stella, 1985

Immune Regulation, edited by Marc Feldmann and N. A. Mitchison, 1985

Human T Cell Clones, edited by Marc Feldmann, Jonathan R. Lamb, and James N. Woody, 1985

Inositol and Phosphoinositides, edited by John E. Bleasdale, Joseph Eichberg, and George Hauser, 1985

Growth, Cancer, and the Cell Cycle, edited by Philip Skehan and Susan J. Friedman, 1984

Ir Genes, edited by Carl W. Pierce, Susan E. Cullen, Judith A. Kapp, Belljamil1 D. Schwartz, and Donald C. Shreffler, 1983

Methods in Protein Sequence Analysis, edited by Marshall Elzinga, 1982

Inflammatory Diseases and Copper, edited by John R. J. Sorenson, 1982

Hepatic Encephalopathy

Pathophysiology and Treatment

Edited by

Roger E Butterworth, PhD

and Gilles Pomier Layrargues, MD

Hopital St. Luc, Montreal, Quebec, Canada

Humana Press • Clifton, New Jersey

Library of Congress Cataloging-in-Publication Data

Hepatic encephalopathy: pathophysiology and treatment/edited by Roger F. Butterworth, Gilles Pomier Layrargues.

p. em. - (Experimental biology and medicine) The results of a symposium, held in Val David, Quebec from Oct.

3D-Nov. 1, 1988. ISBN-13: 978-1-4612-8851-0 e-ISBN-13: 978-1-4612-4506-3 DOl: 10.1007/978-1-4612-4506-3 1. Hepatic encephalopathy-Congresses. I. Butterworth, Roger F.

II. Layrargues, Gilles Pomier. III. Series: Experimental biology and medicine (Oilton, N.J.)

[DNLM: 1. Hepatic Encephalopathy-physiopathology--<ongresses. 2. Hepatic Encephalopathy-therapy--<ongresses. WI 700 H5257 1988] RC848.H4H463 1989 616.3'62-dc20 DNLM/DLC for library of Congress 89-20039

© 1989 The Humana Press Inc.

Softcover reprint of the hardcover 1st edition 1989

Crescent Manor PO Box 2148 Oilton, New Jersey 07015

All rights of any nature reserved.

CIP

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming. recording, computer database entry, or networking. or in any manner whatsoever without written permission from the Publisher.

The results of a symposium, held in Val David, Quebec from Oct. 3D-Nov. 1, 1988.

Preface

Hepatic Encephalopathy (HE) is a neuropsychiatric disorder resul t­ing from liver failure. HE may be associated with fulminant (acute) hepatic failure or chronic liver disease with portal-systemic shunting. The latter condition is characterized neuropathologically by astro­cytic rather than neuronal changes (Alzheimer Type II astrocytosis). The former is frequently accompanied by cerebral edema.

Several hypotheses have been proposed to explain the pathogene­sis of HE. These include:

1. A toxic action of a substance (or substances) such as ammonia on brain function

2. A deficit of cerebral energy metabolism 3. Neurotransmitter changes, and, more recently 4. The role of "endogenous benzodiazepines."

This volume summarizes the results of a symposium held in Val David, Quebec from October 3D-November I, 1988, that was devoted to an evaluation of the evidence for and against the various hypothe­ses of HE. Data from studies in patients, in experimental (animal) models of HE, and in cultured cell preparations were discussed. In addition, a review of available approaches to the treatment and man­agement of HE was included. The therapeutic use of lactulose, anti­biotics, dietary treatment, and branched-chain amino acid treatments were included, as well as the results of preliminary studies of the therapeutic use of the benzodiazepine antagonist, flumazenil.

v

Roger F. Butterworth, PhD Gilles Pomier Layrargues, MD

Acknowledgments The symposium was made possible by the generous financial

assistance of:

Hoffman-La Roche Ltd. Fonds de la recherche en sante du Quebec The Medical Research Council of Canada Departement de medecine, Universite de Montreal The Canadian Liver Foundation Janssen Pharmaceutica Interfalk Canada Squibb Canada

We would like to express our gratitude to Dominique Roy for her help with the organization of the meeting and with the preparation of manuscripts as well as to other members of the Andre-Viallet Clinical Research Centre for their invaluable assistance.

Above all, we would like to thank all participants at the meeting for their invaluable input and lively criticism. Thanks to their efforts, the meeting was able to establish some degree of order in a complex area of research.

vii

Contents

v Preface

vii Acknowledgments

xv Contributors

A. Introduction 3 Hepatic Encephalopathy: The Present and the Future,

Steven Schenker

B. Pathophysiology of Hepatic Encephalopathy

The Role of Ammonia and Other Toxins

27 Ammonia in Liver and Extrahepatic Tissues: An Overview of Metabolism and Toxicity in Mammals, Arthur J. L. Cooper, James c. K. Lai, and Alan S. Gelbard

49 Neurophysiology of Ammonia Intoxication, Winfried A. Raabe

79 Effect of Portacaval Anastomosis on Ammonia Metabolism in Brain and Liver, Guylaine Girard, Jean-Franr;ois Giguere, and Roger F. Butterworth

91 Selective Inhibition of Mitochondrial Dehydrogenases by Ammonia and Fatty Acyl Coenzyme A Derivatives, James C. K. Lai, Karin Rimpel-Lamhaouar, and Arthur J. L. Cooper

ix

99 Acute Action of Ammonia on Leucine Metabolism in Isolated Astrocytes, Neurons, and Oligo Cells of Rat Brain, J. Jessy and Ch. R. K. Murthy

113 Progressive Hyperammonemia and Insulin Resistance After Portacaval Shunt in Homozygous Familial Hypercholesterolemia, Ijaz Qureshi, Marie Lambert, Emile Levy, Muriel Godard, and Jacques Letarte

127 Mesenteric Venous Stenosis Reduces Hyperammonemia in the Portacaval Shunted Rat, Kaj Johansen, Catherine Girod, Samuel S. Lee, and Didier Lebrec

135 Hyperammonemic Encephalopathy Syndrome Due to Urinary Bladder Distention and Infection, R. R. Varma, J. W. Schenck, and A. Goswami

141 Role of Toxins and Synergism in Hepatic Encephalopathy, Leslie Zieve

Cerebral Metabolism and Function in Hepatic Failure

159 Brain Energy Metabolism in Hepatic Encephalopathy, Richard A. Hawkins and Anke M. Mans

177 In Vivo NMR Spectroscopy Studies of Cerebral Metabolism in Rats After Portacaval Shunting, Susan M. Fitzpatrick, Kevin L. Behar, and Robert G. Shulman

189 Effects of Hypercarbia and Portacaval Shunting on Amino Acids and High Energy Phosphates of the Rat Brain: a IH and 31p NMR Study, K. L. Behar and S. M. Fitzpatrick

201 Positron-Emission Tomography in the Study of Hepatic Encephalopathy, Alan H. Lockwood

215 The Use of Cultured Astrocytes in the Study of Hepatic Encephalopathy, Michael D. Norenberg

Contents

231 Brain Edema in Experimental Fulminant Hepatic Failure, Andres T. Blei and Peter G. Traber

245 Encephalopathy of Reye's Syndrome: Studies

xi

of the Pathogenic Process in Animal Models, M. G. Murphy, S. C. Digout, and J. F. S. Crocker

261 The Rat with Carbon Tetrachloride-Induced Cirrhosis as a Model of Hepatic Encephalopathy, Paul Martin, Maria R. Ferreira, Sergio H. Gammal, H. Chris Fromm, and E. Anthony Jones

GABA and Benzodiazepine Receptors in Hepatic Encephalopathy

273 Hepatic Encephalopathy and Benzodiazepine Receptor Ligands, E. Anthony Jones, Sergio H. Gammal, Anthony S. Basile, Kevin D. Mullen, Mark L. Bassett, Daniel F. Schafer, and Phil Skolnick

287 Detection and Characterization of Endogenous Benzodiazepine Activity in Both Animal Models and Humans with Hepatic Encephalopathy, K. D. Mullen, K. M. Szauter, K. Kaminsky, P. D. Tolentino, and A. J. McCullough

295 Isolated CNS Neurons from a Model of Hepatic Encephalopathy Exhibit Increased Sensitivity to a Benzodiazepine, Sergio H. Gammal, Anthony S. Basile, Phil Skolnick, and E. Anthony Jones

305 Studies of Central and "Peripheral-Type" Benzodiazepine Receptors in Autopsied Brain Tissue from Cirrhotic Patients with Hepatic Encephalopathy, Joel Lavoie, Gilles Pomier Layrargues, and Roger F. Butterworth

319 Ro 15-1788 Kinetics are Markedly Impaired in Cirrhotic Patients, G. Pomier Layrargues, Jean-Franfois Giguere, Joel Lavoie, Bernard Willems, and Roger F. Butterworth

xii Contents

329 Plasma GABA-like Factor in Hepatic Encephalopathy May Be Taurine, Jill E. Maddison, Dorothy K. Leong, Peter R. Dodd, and Graham A. R. Johnston

339 Diazepam Metabolism in Perfused Cultures of Adult Rat Hepatocytes, H. O. Jauregui, S. Naik, and H. Santangini

Other Neurotransmitter Systems (amines, amino acids, peptides) in Hepatic Encephalopathy

355 Hepatocerebral Dysfunction and Brain Serotonin, Finn Bengtsson, Mogens Bugge, and Anders Nobin

389 Biogenic Amines in Hepatic Encephalopathy: Evidence for Increased Serotonin Turnover in Human Brain, Marcelle Bergeron, Tomas A. Reader, Gilles Pomier Layrargues, and Roger F. Butterworth

407 Increased Serotoninergic and Noradrenergic Activity in an Experimental Model of Hepatic Encephalopathy in Rats, C. Yurdaydin, Ch. Zimmerman, Ch. Pifl, E. Singer, H. Hortnagl, and P. Ferenci

417 Excitatory Amino Acids and Hepatic Encephalopathy, Roger F. Butterworth, Joel Lavoie, Christine Peterson, Carl W. Cotman, and John C. Szerb

435 Activities of Glutamate-Related Enzymes in Autopsied Brain Tissue from Cirrhotic Patients with Hepatic Encephalopathy, Jean-Fran,ois Giguere, Anne-Marie Besnard, Joel Lavoie, Gilles Pomier Layrargues, and Roger F. Butterworth

447 Does Ammonia Exert its Neurotoxicity Through an Inhibition of Transmitter Glutamate Synthesis? John C. Szerb

455 Beta-Endorphin and Opiate Receptor Changes in Acute and Chronic Models of Hepatic Encephalopathy, M. L. Zeneroli, M. Baraldi, E. Ventura, P. Zanoli, C. Vezzelli, and A. M. Russo

Contents

C. Treatment of Hepatic Encephalopathy

Update of Existing Therapeutic Approaches

469 Treatment of Hepatic Encephalopathy. New Perspectives on Old Ideas, Gilles Pomier Layrargues, Jean-Fran~ois Giguere, Joel Lavoie, and Roger F. Butterworth

483 Treatment of Hepatic Encephalopathy with Lactulose and Antibiotics, Fredrick L. Weber, Jr.

509 Nutritional Therapy of Portal-Systemic Encephalopathy: The Branched-Chain Amino Acid Story, Harold O. Conn and Ljusk Siw Eriksson

xiii

529 Nutrition, Diet, and Hepatic Encephalopathy, Misael Uribe

549 Partial Portal Decompression: Initial Clinical Experience with Small-Stoma Portacaval Shunt, Kaj Johansen

Potential Therapeutic Use of Benzodiazepine Antagonists

565 Benzodiazepine-Antagonist (Ro 15-1788) Flumazenil, Anexate®, Pharmacokinetics, and Therapeutic Applications, R. Meier and K. Gyr

585 Effects of the Benzodiazepine Antagonist Flumazenil in Hepatic Encephalopathy in Man, Georg Bansky and Peter J. Meier .

597 Treatment of Hepatic Encephalopathy with the Benzodiazepine Antagonist Flumazenil, Peter Ferenci and Georg Grimm

613 Index

Contributors GEORG BANSKY • Division of Clinical Phnrmacology, Department

of Medicine, University Hospital, Zurich, Switzerland M. BARALDI • Clinica Medica III e Cattedra di Farmacognosia, Univer­

sita' di Modena, Modena, Italy ANTHONY S. BASILE • Laboratory of Neuroscience, NIDDK, National

Institutes of Health, Bethesda, MD MARK L. BASSETT • Liver Diseases Section, NIDDK, National Institutes

of Health, Bethesda, MD KEVIN L. BEHAR • Department of Molecular Biophysics and Biochemistry,

Yale University, New Haven, CT FINN BENGTSSON • Department of Clinical Phnrmacology, Laboratory

for Experimental Brain Research, Lund University Hospital, Lund, Sweden

MARCELLE BERGERON· Laboratory of Neurochemistry, Andre-Viallet Clinical Research Centre, Hapital St-Luc (University of Montreal), Montreal, Quebec, Canada

ANNE-MARIE BESNARD • Laboratory of Neurochemistry, Andre-Viallet Clinical Research Centre, Hapital St-Luc (University of Montreai), Montreal, Quebec, Canada

ANDRES T. BLEI • Department of Medicine, Lakeside VA Medical Center and Northwestern University, Chicago, IL

MOGENS BUGGE • Department of Surgery, Lund University Hospital, Lund, Sweden

ROGER F. BUTTERWORTH • Laboratory of Neurochemistry, Andre-Viallet Clinical Research Centre, Hapital St-Luc (University of Montreai), Montreal, Quebec, Canada

HAROLD O. CONN • VA Medical Center West Haven, Yale University School of Medicine, New Haven, CT

ARTHUR J. L. COOPER • Departments of Biochemistry and Neurology, Cornell University Medical College, New York, NY

CARL W. COTMAN • Department of Psychobiology, University of Cali­fornia at Irvine, CA

xv

xvi Contributors

J. F. S. CROCKER • Department of Pediatrics, Izaak Walton Killam Hospital for Children, Halifax, Nova Scotia, Canada

S. C. DIGOUT • Department of Pediatrics, Izaak Walton Killam Hospital for Children, Halifax, Nova Scotia, Canada

PETER R. DODD • Department of Pharmacology, University of Sydney, N. S. W., Australia

LJUSK SIW ERIKSSON • Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden

PETER FERENCI • 1st Department of Gastroenterology, University of Vienna, Austria

MARIA R. FERREIRA • Liver Diseases Section, NIDDK, National Insti­tutes of Health, Bethesda, MD

SUSAN M. FITZPATRICK • Department of Molecular Biophysics and Bio­chemistry, Yale University, New Haven, CT

H. CHRIS FROMM • Liver Diseases Section, NIDDK, National Institutes of Health, Bethesda, MD

SERGIO H. GAMMAL • Liver Diseases Section, NIDDK, National Institutes of Health, Bethesda, MD

ALAN S. GEL BARD • Biophysics Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY

JEAN-FRAN<;OIS GIGUERE • Laboratory of Neurochemistry, Andre-Viallet Clinical Research Centre, Hapital St-Luc (University of Montreal), Montreal, Quebec, Canada

GUYLAINE GIRARD • Laboratory of Neurochemistry, Andre-Viallet Clini­cal Research Centre, Hapital St-Luc (University of Montreal), Montreal, Quebec, Canada

CATHERINE GIROD • Unite de Recherches de Physiopathologie Hepa­tique (INSERM U-24), Hapital Beaujon, France

MURIEL GODARD • Pediatric Research Center, Sainte-Justine Hospital (University of Montreal), Montreal, Quebec, Canada

A. Gosw ANI • Medical College of Wisconsin, Milwaukee, WI GEORG GRIMM • 1st Department of Medicine, University of Vienna,

Austria K. GYR • Department of Internal Medicine, Division of Gastro­

enterology, Kantonsspital Liestal, University of Basel, Switzerland RICHARD A. HAWKINS· Department of Physiology and Biophysics, Uni­

versity of Health Sciences, The Chicago Medical School, North Chicago,IL

H. HORTNAGL • University of Vienna, Austria

Contributors xvii

H. O. JAUREGUI • Department of Pathology, Rhode Island Hospital, Provi­dence, RI

J. JESSY • Department of Physiology and Biophysics, University of Health Sciences, Chicago Medical School, North Chicago, IL

KAJ JOHANSEN • Department of Surgery, Harborview Medical Center, University of Washington, School of Medicine, Seattle, WA

GRAHAM A. R. JOHNSTON • Department of Pharmacology, University of Sydney, N. S. W., Australia

E. ANTHONY JONES • Liver Diseases Section, NIDDK, National Institutes of Health, Bethesda, MD

K. KAMINSKY • Cleveland Metropolitan General Hospital, Case Western Reserve University, Cleveland, OH

JAMES C. K. LAI • Departments of Biochemistry and Neurology, Cornell University Medical College, New York, NY

MARIE LAMBERT. Pediatric Research Center, Sainte-Justine Hospital (University of Montreal), Montreal, Quebec, Canada

JOEL LAVOIE • Laboratory of Neurochemistry, Andre-Viallet Clinical Research Centre, H6pital St-Luc (University of Montreal), Montreal, Quebec, Canada

DIDIER LEBREC • Unite de Recherches de Physiopathologie Hepatique (INSERM U-24), H6pital Beaujon, France

SAMUEL S. LEE • Unite de Recherches de Physiopathologie Hepatique (INSERM U-24), H6pital Beaujon, France

DOROTHYK. LEONG· Department of Pharmacology, University of Sydney, N . S. W., Australia

JACQUES LETARTE • Pediatric Research Center, Sainte-Justine Hospital (University of Montreal), Montreal, Quebec, Canada

EMILE LEVY • Pediatric Research Center, Sainte-Justine Hospital (Uni­versity of Montreal), Montreal, Quebec, Canada

ALAN H. LOCKWOOD· Department of Neurology and Positron Diag­nostic and Research Center, University of Texas Health Science Center, Houston, TX

JILL E. MADDISON • Department of Veterinary Clinical Sciences, Uni­versity of Sydney, N. S. W., Australia

ANKE M. MANS • Department of Physiology and Biophysics, Uni­versity of Health Sciences, The Chicago Medical School, North Chicago,IL

PAUL MARTIN • Liver Diseases Section, NIDDK, National Institutes of Health, Bethesda, MD

xviii Contributors

A. J. MCCULLOUGH • Cleveland Metropolitan General Hospital, Case Western Reserve University, Cleveland, OH

PETER J. MEIER • Division of Clinical Pharmacology, Department of Medicine, University Hospital, Zurich, Switzerland

R. MEIER • Department of Internal Medicine, Division of Gastro­enterology, Kantonsspital Liestal, University of Basel, Liestal, Switzerland

KEVIN D. MULLEN • Cleveland Metropolitan General Hospital, Case Western Reserve University, Cleveland, OH

M. G. MURPHY • Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada

CH. R. K. MURTHY • School of Life Sciences, University of Hyderabad, Hyderabad, India

S. NAIK • Department of Pathology, Rhode Island Hospital, Providence, RI ANDERS NOBIN • Department of Surgery, Lund University Hosptial,

Lund, Sweden MICHAEL D. NORENBERG • Department of Pathology, V A Medical

Center and University of Miami, School of Medicine/Jackson Memorial Hospital, Miami, FL

CHRISTINE PETERSON· Department of Psychobiology, University of Cali­fornia at Irvine, CA

CH. PIFL • University of Vienna, Austria GILLES POMIER LA YRARGUES • Hepatology Unit, Andre-Viallet Clinical

Research Centre, H6pital St-Luc (University of Montreal), Montreal, Quebec, Canada

IJAZ QuRESHI • Pediatric Research Center, Sainte-Justine Hosptial (Uni­versity of Montreal), Montreal, Quebec, Canada

WINFRIED A. RAABE • Department of Neurology, V A Medical Center and University of Minnesota, Minneapolis, MN

TOMAS A. READER • Centre de recherche en sciences neurologiques (CRSN), University of Montreal, Montreal, Quebec, Canada

A. M. Russo • Clinica Medica III e Cattedra di Farmacoligia, Un ivers ita , di Modena, Modena,Italy

KARIN RIMPEL-LAMHAOUAR • Departments of Biochemistry and Neu­rology, Cornell University Medical College, New York, NY

H. SANT ANGINI • Department of Pathology, Rhode Island Hospital, Providence, RI

J. W. ScHENCK • Medical College of Wisconsin, Milwaukee, WI

Contributors xix

STEVEN SCHENKER • Department of Gastroenterology and Nutrition, University of Texas Health Science Center, and Audie L. Murphy Memorial Veterans Hospital, San Antonio, TX

ROBERT G. SHULMAN • Department of Molecular Biophysics and Bio­chemistry, Yale University, New Haven, CT

E. SINGER • University of Vienna, Austria PHIL SKOLNICK • Laboratory of Neuroscience, NlDDK, National Insti­

tutes of Health, Bethesda, MD K. M. SZAUTER • Cleveland Metropolitan General Hospital, Case

Western Reserve University, Cleveland, OH JOHN C. SZERB • Department of Physiology and Biophysics, Dalhousie

University, Halifax, Nova Scotia, Canada P. D. TOLENTINO • Cleveland Metropolitan General Hospital, Case

Western Reserve University, Cleveland, OH PETER G. TRABER • Ann Arbor V A Medical Center and University

of Michigan, Ann Arbor, MI MrSAEL URIBE • Liver Unit, National Institute of Nutrition, Mexico R. R. VARMA • Hepatology Unit, Division of Gastroenterology, Medical

College of Wisconsin, Milwaukee, WI E. VENTURA • Clinica Medica III e Cattedra di Farmacoligia, Universita' di

Modena, Modena, Italy C. VEZZELLI • Clinica Medica III e Cattedra di Farmacoligia, Universita'di

Modena, Modena, Italy FREDRICK L. WEBER, JR. • Case Western Reserve University School of Medi­

cine, V A Medical Center, Cleveland, OH BERNARD WILLEMS • Hepatology Unit, Andre-Viallet Clinical Research

Centre, H6pital St-Luc (University of Montreal), Montreal, Quebec, Canada

C. YURDAYDIN • University of Vienna, Austria P. ZANOLI • Clinica Medica III e Cattedra di Farmacognosia, Universita' di

Modena, Modena, Italy M. L. ZENEROLI • Clinica Medica III e Cattedra di Farmacoligia, Universita'

di Modena, Modena, I taZy LESLIE ZIEVE • V A and Hennepin County Medical Centers, University

of Minnesota, Minneapolis, MN CH. ZIMMERMAN • University of Vienna, Austria