HEPATIC ENCEPHALOPATHY, HYPERAMMONEMIA, AND AMMONIA TOXICITY

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1 HEPATIC ENCEPHALOPATHY, HYPERAMMONEMIA, AND AMMONIA TOXICITY

2 ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board: NATHAN BACK, State University of New York at Buffalo IRUN R. COHEN, The Weizmann Institute of Science DAVID KRITCHEVSKY, Wistar Institute ABEL LAJTHA, JV. S. Kline Institute for Psychiatric Research RODOLFO PAOLETTI, University of Milan Recent Volumes in this Series Volume 360 ARTERIAL CHEMORECEPTORS: Cell to System Edited by Ronan G. O'Regan, Philip Nolan, Daniel S. McQueen, and David J. Paterson Volume 361 OXYGEN TRANSPORT TO TISSUE XVI Edited by Michael C. Hogan, Odile Mathieu-Costello, David C. Poole, and Peter D. Wagner Volume 362 ASPARTIC PROTEINASES: Structure, Function, Biology, and Biomedical Implications Edited by Kenji Takahashi Volume 363 NEUROCHEMISTRY IN CLINICAL APPLICATION Edited by Lily C. Tang and Steven J. Tang Volume 364 DIET AND BREAST CANCER Edited under the auspices of the American Institute for Cancer Research; Scientific Editor: Elizabeth K. Weisburger Volume 365 MECHANISMS OF LYMPHOCYTE ACTIVATION AND IMMUNE REGULATION V: Molecular Basis of Signal Transduction Edited by Sudhir Gupta, William E. Paul, Anthony DeFranco, and Roger Perlmutter Volume 366 FREE RADICALS IN DIAGNOSTIC MEDICINE: A Systems Approach to Laboratory Technology, Clinical Correlations, and Antioxidant Therapy Edited by Donald Armstrong Volume 367 CHEMISTRY OF STRUCTURE-FUNCTION RELATIONSHIPS IN CHEESE Edited by Edyth L. Malin and Michael H. Tunick Volume 368 HEPATIC ENCEPHALOPATHY, HYPERAMMONEMIA, AND AMMONIA TOXICITY Edited by Vicente Felipo and Santiago Grisolia A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher.

3 HEPATIC ENCEPHALOPATHY, HYPERAMMONEMIA, AND AMMONIA TOXICITY Edited by Vicente Felipo Santiago Grisolia Instituto de Investigaciones Citologicas de la F. I. B. Valencia, Spain SPRINGER SCIENCE+BUSINESS MEDIA, LLC

4 Library of Congress Cataloging-in-Publication Data On file Proceedings of an international symposium on Hepatic Encephalopathy, Hyperarnmonemia, and Ammonia Toxicity, held January 24-27, 1994, in Valencia, Spain ISBN ISBN (ebook) DOI / Springer Science+Business Media New York Originally published by Plenum Press New York in 1994 Softcover reprint of the hardcover 1 st edition 1994 All rights reserved 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, or otherwise, without written permission from the Publisher

5 PREFACE This volume contains the papers presented at the International Symposium on "Cirrhosis, Hyperammonemia and Hepatic Encephalopathy", held in Valencia, Spain, January 24th-27th, Liver cirrhosis and other hepatic dysfunctions such as fulminant hepatic failure and congenital defects of urea cycle enzymes can lead to hepatic encephalopathy, coma and death. Hepatic encephalopathy is one of the main causes of death in western countries. The ability to detoxify ammonia by its incorporation into urea is diminished by impaired liver function, resulting in increased ammonia levels in blood and brain. Hyperammonemia is considered one of the main factors in the mediation of hepatic encephalopathy and the classical clinical treatments are directed towards reducing blood ammonia levels. However, the molecular bases of the pathogenesis of hepatic encephalopathy and the role of hyperammonemia in this process remain unclear and several hypotheses have been proposed. To clarify the mechanisms involved in hepatic encephalopathy and hyperammonemia suitable animal models are necessary. The animal models available and the ideal features of an animal model are presented in the initial part of the book. The following section is devoted to the discussion of the effects of hepatic encephalopathy and hyperammonemia on brain metabolism, trying to clarify the mechanisms involved in these alterations. The use of in vivo magnetic resonance in these studies and the new findings provided by this technology are also induded. The interaction between astrocytes and neurons in hepatic encephalopathy and hyperammonemia and the role of cellular hydration in the control of cell metabolism and function are also described. Altered neurotransmission is an important step in the pathogenesis of hepatic encephalopathy. The effects of hyperammonemia and of hepatic encephalopathy on synaptic transmission anp on. g l u t a m a tgabaergic, e ~ ~ i ~, serotoninergic and other neurotransmitter systems are reviewed, as well as the possible role of their alterations in the pathogenesis of hepatic encephalopathy and the clinical implications of these findings. The molecular mechanism of acute ammonia toxicity, of its prevention by L-carnitine and the role of glutamate receptors in this processes is also presented. The deficiencies in methionine metabolism and S-adenosyl-L-methionine in liver cirrhosis are discussed. The following part of the book is devoted to the consideration of the diagnosis and therapy of hepatic encephalopathy. The mechanism of action of neomycin and the clinical use of carnitine are discussed. The diagnosis, course and clinical treatment of congenital deficiencies of acetylglutamate synthetase are also reviewed. The use of gene therapy and the methods of gene delivery for the treatment of congenital deficiencies of ornithine transcarbamylase and of the LDL receptor are also dealt with. The possibility of using artificial liver support for patients and recent experimental findings using hepatocyte culture bioreactors are discussed. The hepatitis C viral infection after liver transplantation is reviewed. Finally, the volume concludes with a brief treatment of the central and peripheral effects of exercise-induced hyperammonemia and the possible role of ammonia in the brain in Alzheimer's disease are discussed. v

6 In summary, the book is an updating of the knowledge on some important aspects of the causes, mechanisms and clinical treatments of hepatic encephalopathy, on the effects of hyperammonemia and of the mechanism of ammonia toxicity. We would like to express our gratitude to all participants for their written contributions and for their enlightened and fruitful discussion, as well as to Forpax S.L. for help in preparing the camera-ready version of the chapters. We also acknowledge with deep gratitude, the financial support of Sigma-Tau Laboratories, Ministerio de Educacion y Ciencia, Ministerio de Sanidad y Consumo y Conselleria de Educacion de la Generalitat Valenciana and the Fundacion Valenciana de Estudios Avanzados which provided both the facilities for organizing the Symposium and for the sessions. Vicente Felipo Santiago Grisolia vi

7 CONTENTS Animal Models of Hepatic Encephalopathy and Hyperammonemia K. D. Mullen, S. Birgisson, R. C. Gacad and H. Conjeevaram Brain Metabolism in Encephalopathy Caused by Hyperammonemia R. A. Hawkins and A. M. Mans In Vivo Brain Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) in Hepatic Encephalopathy R. A. F. M. Chamuleau, B. A. P. M. Vogels, D. K. Bosman and W. M. M. 1. Bovee Role of the Cellular Hydration State for Cellular Function: Physiological and Pathophysiological Aspects D. Haussinger and W. Gerok Astrocyte-Neuron Interactions in Hyperammonemia and Hepatic Encephalopathy Albrecht and L. Faff Spinal Seizures in Ammonia Intoxication W. Raabe 55 Molecular Mechanism of Acute Ammonia Toxicity and of its Prevention by L-Carnitine V. Felipo, E. Kosenko, M. D. Miflana, G. Marcaida and S. Grisolia Portal-Systemic Encephalopathy: a Disorder of Multiple Neurotransmitter Systems R. F. Butterworth The GABA Hypothesis: State of the Art E. A. Jones, Yurdaydin, C. and Basile, A. S. Neuropharmacologic Modulation of Hepatic Encephalopathy: Experimental and Clinical Data P. Ferenci, A. Herneth, A. Piisp6k and P. Steindl vii

8 S-Adenosyl-L-Methionine Synthetase and Methionine Metabolism Deficiencies in Cirrhosis J. M. Mato, L. Alvarez, P. Ortiz, 1. Mingorance, C. Duran and M. Pajares Diagnosis and Therapy of Hepatic Encephalopathy A. Mas, J. M. Salmeron and 1. Rodes Neomycin Reduces the Intestinal Production of Ammonia from Glutamine R. A. Hawkins, J. Jessy, A. M. Mans, A. Chedid and M. R. DeJoseph N-Acetylglutamate Synthetase (NAGS) Deficiency J. P. Colombo Ornithine Transcarbamylase Deficiency: A Model for Gene Therapy M. A. Morsy and C. T. Caskey Retroviral Gene Transfer for LDL Receptor Deficiency into Primary Hepatocytes C. Pages, M. Andreoletti, M. Bennoun, D. Franco, P. Briand and A. Weber The Carnitine System: Recent Aspects N. Siliprandi, R. Venerando and V. Tassani Use of Hepatocyte Cultures for Liver Support Bioreactors J. C. Gerlach Hepatitis C Viral infection after Orthotopic Liver Transplantation J. Berenguer, M. Prieto, J. Mir, J. Cordoba and M. Rayon Exercise-Induced Hyperammonemia: Skeletal Muscle Ammonia Metabolism and the Peripheral and Central Effects T. E. Graham Possible Role of Ammonia in the Brain in Dementia of Alzheimer Type S. Hoyer Contributors Index viii

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