Portal Hypertension in the 21st Century

Transcription

1 Portal Hypertension in the 21st Century

2 Portal Hypertension in the 21st Century Edited by R. J. Groszmann J. Bosch Yale University School of Medicine Hepatic Hemodynamic Laboratory New Haven, CT, Liver Unit, Hospital Clinic University of Barcelona, Spain The proceedings of a symposium sponsored by Axcan Pharma Inc. and NicOx S.A., held in Montreal, Canada, April 2-4, 2004 AXCAN PHARMA SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.

3 Library of Congress Cataloging-in-Publication Data is available. ISBN ISBN (ebook) DOI / Printed on acid-free paper All Rights Reserved 2004 Springer Science+Business Media Dordrecht Originally published by Kluwer Academic Publishers and Axcan Pharma Inc. in 2004 Softcover reprint of the hardcover 1st edition 2004 No part of the material protected by this copyright notice 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 owners.

4 Contents List of principal contributors Preface J Rodes ix xv Section I: Introductory lectures 1 Portal hypertensive syndrome: its importance and complications AT Blei 2 The vascular endothelium and nitric oxide JL Wallace 3 Endothelial-derived nitric oxide as a marker for healthy endothelium we Sessa Section II: Mechanisms of disease progression 4 Mechanisms of hepatic fibrogenesis SL Friedman 27 5 The role of hepatic stellate cells/myofibroblasts M Pinzani 37 6 Structural changes in the liver leading to cirrhosis and portal hypertension IR Wanless 47 Section III: Pathophysiology: increased resistance and increased blood flow 7 The paradox: vasoconstriction and vasodilation Y Iwakira, RJ Groszmann 57 v

5 CONTENTS 8 Nitric-oxide-mediated vasodilation and portal hypertension R Wiest 69 9 Impaired vasodilation in cirrhotic livers MR Loureiro-Silva, RJ Groszmann Enhanced release of vasoconstrictors JC Garcia-Pagan 11 Endogenous cannabinoids and circulatory dysfunction in cirrhosis W~~~J~ 89 W Section IV: Mini-symposium: Possibilities of manipulating NO biosynthesis in the treatment of portal hypertension 12 NCX-1105: a liver-specific NO donor S Fiorucci, E Antonelli, A Morelli Possibilities of manipulating NO biosynthesis in the treatment of portal hypertension: statins JG Abraldes, C Zafra, J Bosch Pathophysiological role of Akt and endothelial nitric oxide synthase in cirrhosis M Morales-Ruiz Nitric oxide synthase gene transfer JS Lee, V Shah Inhibition of nitric-oxide-mediated vasodilation (including K+ channels) R Moreau 133 Section V: Introduction to variceal bleeding 17 Esophageal varices: from appearance to rupture; natural history and prognostic indicators G D'Amico Pathophysiology of variceal bleeding A Escorsell, J Bosch Approaches to the management of pediatric portal hypertension: results of an informal survey BL Shneider 167 Section VI: Therapeutic tools 20 Therapeutic tools in portal hypertension: drugs A Albillos 175 vi

6 CONTENTS 21 Endoscopy in the management of portal hypertension GJ Monkewich, NE Marcon Transjugular intrahepatic portosystemic shunt (TIPS): current indications Z Hassoun, G Pomier-Layrargues 209 Section VII: Present therapy 23 Prevention of first variceal bleeding: drugs o Lebrec Prevention of first variceal bleeding: endoscopy M Schepke, T Sauerbruch Treatment of acute variceal bleeding: general management and prevention of infections G Garcia-Tsao Hemostatic treatments R de Franchis Prevention of recurrent portal hypertensive bleeding NO Grace 28 Cost -effectiveness of primary prophylaxis for esophageal variceal bleeding JA Talwalkar 261 Section VIII: Problems in treatment 29 The cirrhotic patient with no varices and with small varices C Merkel, M Bolognesi, A Gatta Gastric varices SK Sarin The patient who cannot receive beta-blockers TO Boyer 32 Hepatic venous pressure gradient: the facts JO Vorobioff, JG Abraldes, RJ Groszmann HemodynamiC monitoring: implications for randomized controlled trials and clinical practice U Thalheimer, 0 Samonakis, C Triantos, 0 Patch, AK Burroughs What to do with non-responders C Villanueva, C Aracil, J Balanz What else we need J Turnes, JC Garcia-Pagan, J Bosch 349 Index 361 vii

7 List of principal contributors J.G. ABRALOES VA Healthcare System Hepatic Hemodynamic Laboratory/111 J 950 Campbell Avenue West Haven, CT A. ALBILLOS Department of Gastroenterology Hospital Universitario Ram6n y Cajal University of Alcala Ctra. de Colmenar, km. 9, Madrid Spain A.T. BLEI Northwestern University Feinberg School of Medicine 303 E Chicago Seale Chicago, IL J.BOSCH Hepatic Hemodynamic Laboratory, Liver Unit Hospital Clinic Villaroel Barcelona Spain T.O. BOYER Liver Research Institute University of Arizona AHSC , Rm N Campbell Avenue Tucson, AZ ix

8 PORTAL HYPERTENSION IN THE 21ST CENTURY A.BURROUGHS Liver Transplantation Hepato-Biliary Medicine Royal Free Hospital Pond Street Hampstead, London NW32QG UK G. D'AMICO Department of Gastroenterology Ospedale V Cervello Via Trabucco Palmero Italy R. DE FRANCHIS University of Milan IRCCS Ospedale Maggiore Department of Internal Medicine Gastroenterology and Gastrointestinal Endoscopy Service Via Pace Milan Italy S. FlO RUCCI Department of Gastroenterology University of Peru9ia Via E dal POllO Perugia Italy S.L. FRIEDMAN Mount Sinai School of Medicine Box 1123, Room 1170 F 1425 Madison Avenue New York, NY J.C. GARCiA-PAGAN Hepatic Hemodynamic Laboratory Liver Unit Hospital Clinic Villaroel Barcelona Spain x

9 LIST OF PRINCIPAL CONTRIBUTORS G. GARCIA-TSAO Yale University School of Medicine VA Connecticut Healthcare System 333 Cedar Street, 1080 LMP New Haven, CT N.D. GRACE Tufts University Medical School Division of Gastroenterology Brigham and Womens Hospital Harvard University 75 Francis Street Boston, MA R.J. GROSZMANN VA Connecticut Healthcare System Hepatic Hemodynamic Laboratory/ 111 J 950 Campbell Avenue West Haven, CT W. JIMENEZ Laboratorio Hormonal Hospital Clinic Universitari Villaroel Barcelona Spain D. LEBREC INSERM U-481 and Service d'hepatologie Hopital Beaujon 100 Bd du General Leclerc Clichy France M.R. LOUREIRO-SILVA Yale University School of Medicine Hemodynamic Hepatic Laboratory VA Connecticut Healthcare System 111 H Campbell Avenue West Haven, CT xi

10 PORTAL HYPERTENSION IN THE 21 ST CENTURY N.E. MARCON The Center for Therapeutic Endoscopy and Endoscopic Oncology St Michaels Hospital 30 Bond Street Toronto, Ontario M5B 1 W8 CANADA C.MERKEL Department of Clinical and Experimental Medicine University of Padua Via Giustiniani, Pad ova Italy M. MORALES-RUIZ Hormonal Laboratory Hospital Clinic, IDIBAPS University of Barcelona Villaroel Barcelona Spain R. MOREAU Service hepato-gastroenterologie INSERM U-481 Hopital Beaujon Clichy France M. PINZANI Dipartimento di Medicina Interna Universita degli Studi di Firenze Viale G.B. Morgagni, Firenze Italy G. POMIER-LAYRARGUES Liver Unit, H6pital Saint-Luc Centre Hospitalier de l'universite de Montreal 264 East Rene-Levesque Blvd Montreal, Quebec H2X 1 P1 Canada xii

11 LIST OF PRINCIPAL CONTRIBUTORS J.RODES Catedrcitico de Patologia Digestiva Servicio de Gastroenterologia y Hepatologia Hospital Clinico y Provincial Casanova Barcelona Spain S.K. SARIN Department of Gastroenterology G.B. Pant Hospital 201-Academic Block New Delhi India T.SAUERBRUCH Department of Internal Medicine I University of Bonn Sigmund-Freud-Str. 25 D Bonn Germany W.C. SESSA Yale University School of Medicine Boyer Center for Molecular Medicine 295 Congress Avenue New Haven, CT V.SHAH Department of Medicine, Physiology and Tumor Biology Mayo Clinic Foundation and School of Medicine AL 2-435, GI Research Unit 200 First St SW Rochester, MN B. SHNEIDER Division of Pediatric Hepatology Mount Sinai Medical Center, Box 1656 One Gustave L. Levy Place New York, NY xiii

12 PORTAL HYPERTENSION IN THE 21 ST CENTURY J.A. TALWALKAR Division of Gastroenterology and Hepatology Mayo Clinic and Foundation 200 First Street SW Rochester, MN C. VILLANUEVA Servei de Patologia Digestiva Hospital de la Santa Creu I Sant Pau Avgda. Sant Antoni Ma. Claret, Barcelona Spain J.L. WALLACE Departments of Pharmacology and Therapeutics University of Calgary 3330 Hospital Drive NW Calgary, Alberta T2N 4N1 Canada I. WANLESS Department of Pathology University of Toronto Toronto General Hospital E Elizabeth Street Toronto, Ontario M5G 2C4 Canada R. WIEST Department of Internal Medicine I University Hospital Regensburg Franz-Josef-Strauss Allee Regensburg Germany xiv

13 Preface J. RODES Portal hypertension is the most important complication of a great variety of both acute and chronic liver diseases. Nevertheless, hepatic cirrhosis is the most frequent cause of portal hypertension. Gastrointestinal bleeding due to rupture of oesophageal varices is, without doubt, the most severe complication of portal hypertension. At present, great advances are being made in the pathophysiology and in the development of new therapeutic tools for controlling and preventing this severe clinical event. This book includes the papers presented and discussed during the Symposium held in Montreal, Canada, in April There are eight Sections covering basic mechanisms, new drugs, prevention and current treatment of variceal bleeding, prevention of recurrent bleeding and hepatic hemodynamic monitoring. Portal hypertension is initially caused by distortion of the hepatic circulation. This obstruction is a consequence of the obliteration of small hepatic and portal venules. Furthermore, there is an increase in arterial flow that contributes to enhance portal pressure. At present, it has been well established that, in addition to this mechanical mechanism, there are other functional factors that may be implicated in the development of portal hypertension. All these mechanisms are discussed in depth in Sections 1 to 3. Knowledge of the biology of the endothelium and the endothelial dysfunction in the sinusoids has been essential to define the humoral factors such as the impaired activity of vasodilators (nitric oxide (NO), prostaglandins, anandamide) and the increased production of vasoconstrictors (endothelin, norepinephrine, angiotensin, vasopressin, leukotrienes and thromboxane A2) which playa key role in favoring the increased intrahepatic vascular resistance in cirrhosis. In addition to these vascular factors, hepatic fibrosis is also one of the most important phenomena in producing an increase in portal pressure. Therefore, control of hepatic fibrogenesis may, in the future, be a very useful therapeutic tool in the treatment and prevention of portal hypertension. Up to now, several drugs have proven to be useful in controlling fibrogenesis in experimental animals with hepatic cirrhosis. However, these results have not yet been reproduced in human beings. In Section 4 there is a very interesting discussion regarding the therapeutic effect of new drugs in the treatment of patients with portal hypertension. Clinical studies have shown that the use of nitrates produces a reduction in xv

14 PORTAL HYPERTENSION IN THE 21 ST CENTURY portal pressure; unfortunately this therapy causes vasodilation in both the systemic arterial and venous vascular beds which, in turn, aggravates the vasodilatory syndrome in cirrhotic patients. Consequently, the ideal drug should act by decreasing intrahepatic vascular resistance without worsening the splanchnic and systemic vasodilation. The development of liver-selective NO-donors using bile acids (ursodeoxycholic acid) as a carrier is based on this idea. Preclinical studies have shown that the administration of this drug to rats with chronic liver injury impairs the development of portal hypertension, suggesting that it may provide a new therapy for this syndrome. As indicated previously, in cirrhosis there is a decreased endothelial NO production at the sinusoids, which contributes to the increase in hepatic resistance and portal hypertension. Statins may correct endothelial dysfunction in cirrhosis because it has been demonstrated that they are able to increase NO production in endothelial cells. In a recent study, performed in cirrhotic patients, the administration of a single dose of simvastatin was followed by an acute reduction in hepatic sinusoidal resistance and an increase in hepatic blood flow with no changes in portal pressure. These findings may have a potential role in the treatment of these patients. However, new studies are required to confirm these results and to determine whether the chronic administration of simvastatin may be useful in patients with portal hypertension. Other potential therapeutic agents are also discussed. Akt is the major activator of the endothelial NO-synthase enzyme and it has been shown to be reduced in cirrhotics rats. In an experimental study it was found that myr-akt gene therapy restored Akt activation and NO production in the cirrhotic liver. On the other hand, the NO synthase gene transfer and inhibition of NO-mediated vasodilation with the use of several drugs (apamin, woutmannin, L-arginine analogs and terlipressin) were able to produce an increased production of NO and, consequently, all these agents could be considered in the future as a new therapeutic tool in the treatment of portal hypertension. Section 5 is devoted to natural history of esophageal varices, portal hypertension in childhood and the pathophysiology of variceal bleeding. It is well established that, once formed, varices tend to increase in size progressively and they rupture when the variceal wall tension increases above the elastic limit of the vessels. This is directly related to the intra variceal pressure and the radius of the varix and inversely to the thickness of the variceal wall. The role of increased intravascular pressure is underscored by the finding that the hepatic venous pressure gradient (HVPG) increases above 12 mmhg for varices to bleed. Increased radius explains why large varices are at higher risk than small ones, and decreased variceal wall thickness explains the prognostic value of endoscopic red color signs. In Sections 6 to 8, the current therapy and prevention of esophageal bleeding, and hepatic hemodynamic monitoring are discussed. It is fully accepted that the use of beta-blockers is an excellent treatment for preventing the first episode of variceal bleeding and recurrent bleeding in cirrhotic patients. More recently vasodilators (nitrates, prazosin, losartan, irbesastan and endothelin receptor blockers) have been proven in both experimental xvi

15 PREFACE animals and in patients with cirrhosis. To date, only organic nitrates have shown any clinical use when applied in combination with beta-blockers to increase their effectiveness at lowering portal pressure. In addition to drugs, endoscopic treatment with band ligation or intravariceal injection of glue has been widely used in these patients. At present, there is great discussion among hepatologists and endoscopists about which of these treatments should be applied in cirrhotics with portal hypertension. As a hepatologist I prefer to use drugs! In my opinion, endoscopic procedures should be used when drug therapy fails. The transjugular intrahepatic portosystemic shunt (TIPS) is one of the most recent therapeutic tools to have been introduced in the management of these patients. At present, TIPS is used as a secondline therapy for variceal bleeding when pharmacologic and endoscopic treatment fails. The usefulness of TIPS is limited by two major problems: shunt dysfunction and hepatic encephalopathy. The use of poly tetra flu oro ethylenecovered stents may be useful to prevent the former complication. The general management of patients with acute variceal bleeding consists in the correction of hypovolemia and the prevention of infections with antibiotic prophylaxis. Hemostatic treatment should aim at controlling bleeding and preventing early rebleeding. Pharmacologic therapy with vasoactive drugs (terlipressin, vasopressin associated with nitrates, somatostatin and octreotide) and endoscopic treatment (sclerotherapy and band ligation) are effective in controlling acute bleeding. The combination of drugs and endoscopic treatment is probably the best approach for the management of these patients. It seems that the adjuvant administration of recombinant activated factor VII may be useful in Child Band C variceal bleeding patients. However, although this information is very encouraging, it is evident that further confirmation is required. The prevention of recurrent bleeding in cirrhotics is mandatory, since 65-70% of patients rebleed within 6 months of the index bleed. First-line treatment consists in the administration of beta-blockers. When this pharmacologic treatment fails, band ligation is the next therapy to be used. Band ligation seems more effective when associated with beta-blockers. It is important to point out that a reduction in HVPG greater than 20% or a reduction below 12 mmhg are the best predictors of clinical efficacy for the prevention of rebleeding. When this combination therapy fails there are other therapeutic options such as surgical shunts, TIPS or liver transplantation. In these Sections there are several important clinical chapters - cirrhotic patients with no varices and with small varices, the management of gastric variceal bleeding and patients who cannot receive beta-blockers - which are, without doubt, very useful for hepatologists treating patients. At the end of the Section there is a very interesting discussion regarding the need for hepatic hemodynamic monitoring in cirrhotic patients. In this sense the most important question is: should measurement of WHVP be incorporated in clinical practice? My answer is yes, because this measurement will allow us to predict the risk for bleeding in cirrhotic patients and to know whether a vasoactive drug may be useful to prevent the first episode and the recurrence of variceal bleeding in these patients. xvii

16 PORTAL HYPERTENSION IN THE 21 ST CENTURY In finishing, I would like to congratulate all the speakers - now authors - for their outstanding scientific level in the presentation and discussion of their papers in the meeting. And last but not the least, 1 would like to express my sincere admiration to Profs. Roberto Groszmann, Jaime Bosch and Guido Tytgat for organizing this excellent meeting on portal hypertension in Montreal. xviii