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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
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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
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