Springer Tokyo Berlin Heidelberg New York Hong Kong London Milan Paris K. Okita (Ed.) NASH and Nutritional Therapy With 35Figures,Including 5in Color 1 3 KiwamuOkita,M.D.,Ph.D. Professor and Chairman Department ofGastroenterology and Hepatology Yamaguchi University School ofMedicine 1-1-1Minami-Kogushi,Ube,Yamaguchi 755-8505,Japan ISBN 4-431-21388-0Springer-Verlag Tokyo Berlin Heidelberg New York Library ofCongress Control Number:2004113088 This symposium was supported by funds from the Viral Hepatitis Research Foundation ofJapan. Printed on acid-free paper © Springer-Verlag Tokyo 2005 Printed in Japan This work is subject to copyright.All rights are reserved,whether the whole or part ofthe material is concerned,specifically the rights oftranslation,reprinting,reuse ofillustrations,recitation,broad- casting,reproduction on microfilms or in other ways,and storage in data banks. The use ofregistered names,trademarks,etc.in this publication does not imply,even in the absence ofa specific statement,that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability:The publisher can give no guarantee for information about drug dosage and appli- cation thereofcontained in this book.In every individual case the respective user must check its accu- racy by consulting other pharmaceutical literature. Springer is a part ofSpringer Science+Business Media springeronline.com Typesetting:SNP Best-set Typesetter Ltd.,Hong Kong Printing and binding:Shinano Inc.,Japan Preface Fatty liver disease including nonalcoholic steatohepatitis (NASH) involves the accu- mulation oftriglycerides in hepatocytes with necrosis,inflammation,and often fibro- sis with progression to cirrhosis.The two-hit model summarizes the important early metabolic events leading to hepatocellular necrosis in NASH. In these proceedings, we present various new findings and a review of NASH.The liver has an important role in nutritional homeostasis,and liver diseases lead to abnormalities in nutrient metabolism and to subsequent malnutrition,especially in patients with liver cirrho- sis.Protein-energy malnutrition (PEM) is a common finding in cirrhotic patients;it may be present in 20% of patients with well-compensated disease and in more than 60% ofpatients with severe liver insufficiency.Therefore,special attention is required in the management ofthose patients;proper nutritional assessment and support for cirrhotic patients is essential. This volume also includes new findings on the nutri- tional aspects of the treatment of liver cirrhosis,which we hope will contribute to a better understanding ofNASH and nutritional treatment. We thank Otsuka Pharmaceutical Co.Ltd.for their continuing support. Organizing Committee ofthe Yamaguchi Symposium on Liver Disease Kiwamu Okita,M.D.,Yamaguchi University,Ube Masamichi Kojiro,M.D.,Kurume University,Kurume Masao Omata,M.D.,The University ofTokyo,Tokyo Norio Hayashi,M.D.,Osaka University,Osaka Takeshi Okanoue,M.D.,Kyoto Prefectural University ofMedicine,Kyoto Secretary General Isao Sakaida,M.D.,Yamaguchi University,Ube V Table of Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V List ofParticipants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX Nonalcoholic Fatty Liver (NAFL):Overview S.H.Caldwell,A.Al-Osaimi,C.Chang,C.Davis,E.E.Hespenheide, L.Krugner-Higby,A.I.Hylton,J.C.Iezzoni,T.H.Le,R.K.Nakamoto, J.Redick,and T.Peterson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Role ofLeptin in Pathogenesis ofNASH K.Ikejima,T.Lang,S.Yamashina,N.Enomoto,Y.Takei,and N.Sato . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Zone 3Predominance ofHistopathological Features in Nonalcoholic Steatohepatitis H.Enzan,M.Toi,Y.Hayashi,T.Hamauzu,N.Kuroda,and M.Hiroi . . . 50 Genetic Background ofJapanese Patients with Nonalcoholic Steatohepatitis (NASH) T.Saibara,C.Namikawa,Z.Shu-Ping,M.Rui-Hong,Y.Nozaki, Y.Nemoto,M.Ono,N.Akisawa,S.Iwasaki,M.Hiroi,H.Enzan,and S.Onishi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Predictors ofNonalcoholic Steatohepatitis in Japanese Patients: Thioredoxin and NASH T.Okanoue,N.Yamauchi,M.Furutani,A.Hirohama,Y.Sumida,and T.Nakashima . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Clinical Features ofPatients with Nonalcoholic Fatty Liver Disease E.Hashimoto,H.Kaneda,Y.Yoshioka,M.Taniai,K.Tokushige,and K.Shiratori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Pathogenesis and Significance ofRestricted Diet and Exercise Therapy in Nonalcoholic Steatohepatitis (NASH) T.Ueno,T.Nakamura,N.Sasaki,Y.Morita,E.Nagata,and M.Sata . . . 84 VII VIII Table ofContents Mammalian Target ofRapamycin (mTOR) K.Yonezawa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Effect ofOral Supplementation with Branched-Chain Amino Acids on Albumin Concentration in the Early Stage ofCirrhosis S.Nishiguchi,D.Habu,and S.Shiomi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Nutritional Therapy in Patients with Liver Cirrhosis M.Tsuchiya,I.Sakaida,M.Okamoto,and K.Okita . . . . . . . . . . . . . . . . . 108 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 List of Participants Caldwell,Stephen H. Division ofGastroenterology and Hepatology University ofVirginia Health System Virginia,USA Enzan,Hideaki First Department ofPathology,Kochi Medical School Kochi,Japan Hashimoto,Etsuko Institute ofGastroenterology Tokyo Women’s Medical University,Tokyo,Japan Hayashi,Norio Department ofMolecular Therapeutics Osaka University Graduate School ofMedicine Osaka,Japan Hino,Keisuke Department ofLaboratory Sciences,Faculty ofHealth Sciences,Yamaguchi University School ofMedicine Yamaguchi,Japan Ichida,Takafumi Third Department ofInternal Medicine,Niigata University Niigata,Japan Ikejima,Kenichi Department ofGastroenterology Juntendo University School ofMedicine,Tokyo,Japan Kodama,Takahiro Department ofInternal Medicine/Gastroenterology Yamaguchi Central Hospital,Yamaguchi,Japan Kojiro,Masamichi First Department ofPathology Kurume University School ofMedicine,Fukuoka,Japan Nakanishi,Toshio Department ofRadiology,School ofMedicine Hiroshima University,Hiroshima,Japan Nishiguchi,Shuhei Department ofHepatology,Graduate School ofMedicine Osaka City University,Osaka,Japan Okanoue,Takeshi Third Department ofInternal Medicine Kyoto Prefectural University ofMedicine,Kyoto,Japan IX X List ofParticipants Okita,Kiwamu Department ofGastroenterology and Hepatology Yamaguchi University School ofMedicine Yamaguchi,Japan Omata,Masao Department ofGastroenterology Graduate School ofMedicine,The University ofTokyo Tokyo,Japan Onishi,Saburo Department ofInternal Medicine,Kochi Medical School Kochi,Japan Saibara,Toshiji Department ofInternal Medicine,Kochi Medical School Kochi,Japan Sakaida,Isao Department ofGastroenterology and Hepatology Yamaguchi University School ofMedicine Yamaguchi,Japan Sata,Michio Second Department ofMedicine Kurume University School ofMedicine,Kurume,Japan Tanikawa,Kyuichi International Institute for Liver Research,Fukuoka,Japan Terai,Shuji Department ofGastroenterology and Hepatology Yamaguchi University School ofMedicine Yamaguchi,Japan Tokushige,Katsutoshi Institute ofGastroenterology Tokyo Women’s Medical University,Tokyo,Japan Tsuchiya,Masako Department ofGastroenterology and Hepatology Yamaguchi University School ofMedicine Yamaguchi,Japan Ueno,Takato Research Center for Innovative Cancer Therapy Kurume University School ofMedicine,Kurume,Japan Yonezawa,Kazuyoshi Biosignal Research Center,Kobe University,Kobe,Japan