CIRRHOSIS, HYPERAMMONEMIA, AND HEPATIC ENCEPHALOPATHY

Transcription

1 CIRRHOSIS, HYPERAMMONEMIA, AND HEPATIC ENCEPHALOPATHY

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 LAITHA. N. S. Kline Institute for Psychiatric Research RODOLFO PAOLETTI. University of Milan Recent Volumes in this Series Volume 338 CHEMISTRY AND BIOLOGY OF PTERIDINES AND FOLATES Edited by June E. Ayling. M. Gopal Nair. and Charles M. Baugh Volume 339 NOVEL APPROACHES TO SELECTIVE TREATMENTS OF HUMAN SOLID TUMORS: Laboratory and Clinical Correlation Edited by Y oucef M. Rustum Volume 340 THE DESIGN OF SYNTHETIC INHIBITORS OF THROMBIN Edited by G. Claeson. M. F. Scully. Vijay V. Kallar. and J. Deadman Volume 341 CIRRHOSIS. HYPERAMMONEMIA. AND HEPATIC ENCEPHALOPATHY Edited by Santiago GrisoUa and Vicente Felipo Volume 342 CORONA VIRUSES: Molecular Biology and Virus-Host Interactions Edited by Hubert Laude and Jean-Fran~ois Vautherot Volume 343 CURRENT DIRECTIONS IN INSULIN-LIKE GROWTH FACTOR RESEARCH Edited by Derek LeRoith and Mohan K. Raizada Volume 344 MECHANISMS OF PLATELET ACTIVATION AND CONTROL Edited by Kalwant S. Authi. Steve P. Watson. and Vijay V. Kallar Volume 345 OXYGEN TRANSPORT TO TISSUE XV Edited by Peter Vaupel. Rolf Zander. and Duane F. Bruley Volume 346 INTERACTIVE PHENOMENA IN THE CARDIAC SYSTEM Edited by Samuel Sideman and Rafael Beyer 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 CIRRHOSIS, HYPERAMMONEMIA, AND HEPATIC ENCEPHALOPATHY Edited by Santiago Grisona and Vicente F elipo Instituto de Investigaciones Citologicas Valencia, Spain SPRINGER SCIENCE+ BUSINESS MEDIA,!le

4 Ltbrary of Congress Catalogtng-tn-Publtcatton Data Ctrrhosls, Hyperammonemla, and Hepatlc Encephalopathy I edlted by Santlago Grlsolia and Vlcente Fellpo. p. cm. -- (Advances In experimental medlclne and blology v. 341) Includes blbllographlcal references and Index. ISBN l ISBN (ebook) DOI / Llver--Clrrhosls--Congresses. 2. A onla--metabollc detoxlcatlon--congresses. 3. Urea--MetabollsN--Congresses. 4. Hepatlc encephalopathy--congresses. 1. Grlso11a, Santlago, II. Fellpo, Vlcente. III. Serles. RC848.C5C5S 1993 S1S.3'S2--dc CIP Proceedings of an International Summer Course on Cirrhosis, Hyperammonemia, and Hepatic Encephalopathy, held August 10-14, 1992, in EI Escorial, Spain ISBN Springer Science+Business Media New York Softcover reprint of the hardcover Ist edition 1993 Originally published by Plenum Press in 1993 Ali 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 in the International Summer Course on "Cirrhosis, Hyperammonemia and Hepatic Encephalopathy," which was one of the prestigious Summer Course, of the Complutense University of Madrid held in EI Escorial, Spain, during August 10-14, Liver cirrhosis is one of the main causes of death in western countries. In addition there is a series of liver dysfunctions including fulminant hepatic failure, Reye's syndrome and congenital defects of urea cycle enzymes that could lead to hepatic encephalopathy, coma and death. As a consequence of impaired liver function, the ability to detoxify ammonia by its incorporation into urea is diminshed, 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. A part of the book is therefore devoted to the study of certain aspects of ammonia metabolism such as the regulation of the urea cycle, the main mechanism of ammonia detoxification in mammals, which is located mainly in the liver. The metabolism of ammonia in other tissues, including brain, is also presented, as well as the effects of hyperammonemia on brain metabolism and function and on brain microtubules. The control of cerebral protein breakdown is reviewed. The classical and some recently proposed clinical treatments as well as nutritional considerations in the management of patients with liver failure are also discussed. Altered neurotransmission is a key step in the pathogenesis of hepatic encephalopathy. Some recent results on the effects of hyperammonemia and hepatic encephalopathy on synaptic transmission and on GABAergic and glutamatergic neurotransmission are presented and their possible roles in the pathogenesis of hepatic encephalopathy are discussed. Glutamatergic neurotransmission is altered in hyperammonemia and hepatic encephalopathy and it has been recently proposed that acute ammonia toxicity is mediated by glutamate, which, under certain conditions, can be a potent neurotoxic for neurons containing glutamate receptors. The last part of the book is devoted to the study of the mechanisms that control the release of glutamate, the properties of the NMDA receptors, which mediate glutamate toxicity, as well as the mechanism of the protective effect of gangliosides against glutamate toxicity. In summary, the book presents an update of the knowledge on certain crucial aspects of the causes and mechanisms of hepatic encephalopathy. We would like to express our gratitude to all the participants in the Course for their written contributions and for their enlightened and fruitful discussion and to Forpax for help v

6 in preparing the camera-ready version of the chapters. Also the Complutense University of Madrid for providing the fmancial support and the facilities for the Course and to its personnel at EI Escorial for the excellent assistance and organization that allowed the fruitful development of the Course in a warm and pleasant atmosphere. Santiago Grisolla Vicente Felipo vi

7 CONTENTS Control of Urea Synthesis and Ammonia Detoxification S. Grisolia, M.-D. Mifiana, E. Grau, and V. Felipo Brain Metabolism in Hepatic Encephalopathy and Hyperammonemia R.A Hawkins and AM. Mans 13 Ammonia Metabolism in Mammals: Interorgan Relationship AJ.L. Cooper Clinical Manifestations and Therapy of Hepatic Encephalopathy J. Rodes 39 Nutritional Considerations in Patients with Hepatic Failure A Sastre Gallego, E. Morej6n Bootello, and P. Carda Abella Do Benzodiazepine Ligands Contribute to Hepatic Encephalopathy? 57 E.A Jones, AS. Basile, C. Yurdaydin, and P. Skolnich Effects of Hyperammonemia on Neuronal Function: NH4 +, IPSP and Cr-Extrusion W. Raabe Activation of NMDA Receptor Mediates the Toxicity of Ammonia and the Effects of Ammonia on the Microtubule-Associated Protein MAP V. Felipo, E. Grau, M.-D. Mifiana, and S. Grisolia Modulation of the Exocytotic Release of Neurotransmitter Glutamate by Protein Kinase C J. Sanchez-Prieto, I. Herrero, and M.T. Miras-Portugal Controls of Cerebral Protein Breakdown A Lajtha Two Different Families of NMDA Receptors in Mammalian Brain: Physiological Function and Role in Neuronal Development and Degeneration E.K. Michaelis vii

8 Glanglioside GMI and its Semisynthetic Lysogangliosides Reduce Glutamate Neurotoxicity by a Novel Mechanism E. Costa, D. Armstrong, A. Guidotti, A. Kharmalov, L. Kiedrowski, and J.T. Wroblewski Contributors 143 Index viii