Fatty liver disease including nonalcoholic steatohepatitis (NASH) involves the ac- mulation of triglycerides in hepatocytes with necrosis,in?ammation,and often ?b- 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 ?ndings 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 cirr- sis. Protein-energy malnutrition (PEM) is a common ?nding in cirrhotic patients; it may be present in 20% of patients with well-compensated disease and in more than 60% of patients with severe liver insuf?ciency. Therefore,special attention is required in the management of those patients; proper nutritional assessment and support for cirrhotic patients is essential. This volume also includes new ?ndings on the nut- tional aspects of the treatment of liver cirrhosis, which we hope will contribute to a better understanding of NASH and nutritional treatment. We thank Otsuka Pharmaceutical Co. Ltd. for their continuing support. Organizing Committee of the 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 of Tokyo,Tokyo Norio Hayashi,M. D. ,Osaka University,Osaka Takeshi Okanoue,M. D. ,Kyoto Prefectural University of Medicine,Kyoto Secretary General Isao Sakaida,M. D. ,Yamaguchi University,Ube V Table of Contents Preface ...V List of Participants ...IX Nonalcoholic Fatty Liver (NAFL): Overview S. H. Caldwell,A. Al-Osaimi,C. Chang,C. Davis,E. E.

The rise in hepatocellular carcinoma (HCC) mortality rates has caused researchers to focus increased attention on liver cirrhosis, a pathological condition known to lead to HCC. If hepatic fibrosis can be controlled, it follows that the risk of HCC among patients with chronic hepatitis can be reduced. In the quest for greater understanding of liver cirrhosis, the 1999 Yamaguchi Symposium on Liver Diseases brought together leading researchers in the field. Guest speakers included Michael J.P. Arthur, on mechanisms of the progression and regression of liver fibrosis; Mark A. Zern, on novel therapeutic modalities for hepatic disease; and Jiro Fujimoto, on gene therapy to inhibit progression to liver cirrhosis. The presentations by these groundbreaking scientists are collected in this volume along with those of other leading researchers in the field of hepatology, creating a valuable source for professionals concerned with hepatic fibrogenesis and hepatocarcinogenesis.

My training started in 1971, when I joined the First Department of Medicine of Chiba University, as Dr. Kunio Okuda became chair ofthe department. To acquire training ingeneralpathology, Iapplied for the Intern MatchingProgram and started as aninternin the DepartmentofPathologyofYale University, in 1973.While Iwas achiefresident, Ispent 10months in Dr. GeraldKlatskin'sofficestudyingthe com plete set of his famous liver biopsy samples (the Klatskin Collection). In 1976, I movedtoJohnWesleyHospital, where therewasagroup from the USC (University ofSouthern California) Liver Unit, to obtain further pathology training under the guidanceofDr. Robert L. Peters. Those experiences have given me ample opportu nity to see the differences between the United States and Japan. Ofcourse, 28 years ago in downtown Los Angeles there were enormous num bers ofpatients suffering from typical alcoholic liver diseases. Now in Japan, in contrast, we have an enormous number ofpatients suffering from hepatocellular carcinoma (HCC), due in particular to hepatitis C viral infection. Last year, in the DepartmentofGastroenterology at the University ofTokyo, we had approximately 500 admissions due to HCC. Thus, we have an urgent need to prevent the develop ment ofHCC and to provide better treatment for such patients through a basic un derstanding ofvirology, clinical features, and treatment modalities. The first single-topic conference on "TherapyofViral Hepatitis and Prevention ofHepatocellular Carcinoma" was organized by the Japan Society ofHepatology (Kiwamu Okita, Director General) and was held November 14-15,2002, near Mt. Fuji. Thisbook, which is asummaryofthe meeting, helps toupdate relevantinforma tion on this vital topic. June 28, 2003 Masao Ornata, M.D."

Since the discovery of superoxide dismutase more than three decades ago, there has been rapid growth in the knowledge of oxidative stress and disease. This volume containing the proceedings of the 13th Yamaguchi Symposium on Liver Disease includes discussion of the direct cellular effects of hepatitis C virus (HCV) proteins on hepatocytes and reviews evidence that oxidative stress caused primarily by the HCV core protein plays a key role in disease pathogenesis. Also included are chapters on new aspects of oxidative stress and liver disease such as carbon monoxide as a regulator of liver microcirculation, hepatic iron accumulation and the incidence of hepatocellular carcinoma, and oxidative stress in the absence of inflammation in hepatocarcinogenesis. This collection of papers from the Yamaguchi Symposium creates a valuable reference resource for physicians and hepatologists.

Cellular therapy with liver stem cells and their progeny, including bone marrow cells, is a promising new approach that will contribute significantly to the treatment of liver diseases. The existence of the liver stem cell had long been debated, but it is now generally accepted that the liver contains cells with stem-like properties and that these cells can be activated to proliferate and differentiate into mature hepatocytes under certain conditions. There is also a substantial body of evidence to suggest that oval cells are involved in liver regeneration as they differentiate into hepatocytes and biliary cells. This book is a collection of work on stem cell and liver regeneration, initially delivered at the 14th Yamaguchi (Japan) Symposium on Liver Disease. Its nine chapters present the most recent data about basic and clinical research in hepatology in Japan and other countries, providing a valuable resource for researchers and practitioners alike.

Since 1998, the Japanese Society of Hepatology has campaigned to fight hepatocellu lar carcinoma (HCC). Because the mortality rate for this disease has reached more than 30 per 100,000 population, the organizing committee chose HCC as the main topic of the 1999 Yamaguchi Symposium on Liver Diseases. Regarding hepatocar cinogenesis, we know that HCC often develops secondary to liver cirrhosis; thus liver cirrhosis must be recognized as a prevalent pathological condition leading to HCC. If we can control liver fibrosis, we can reduce the risk for HCC among patients with chronic hepatitis. To achieve this goal, we must know more about hepatic fibrosis. Professor Michael J. P. Arthur is familiar as a leading scientist in this field. We were fortunate that he accepted our invitation to speak. His lecture titled "Mechanisms of the Progression and Regression of Liver Fibrosis" provided important advice for developing antifibrotic agents. We also invited Professor Mark A. Zern, who has been studying hepatic fibrosis for some time. In the symposium he talked about novel approaches, including gene therapy, to treat acute and chronic hepatic diseases in the 21st century. In addition to the informative talks by those guests from abroad, the lecture by Dr. J. Fujimoto was very impressive. He revealed that gene therapy using hepatocyte growth factor (HGF) could inhibit progression to liver cirrhosis in rats repeatedly injected with dimethylnitrosamine (DMN). Dr. Fujimoto has already pub lished his finding that administration of HGF reduced hepatocarcinogenesis in rats."

Since the 1st Yamaguchi Symposium on Liver Diseases in 1989, this series of symposia has provided opportunities for exchanges of information on the topic between leading Japanese hepatologists and internationally renowned scientists. Somewhat unusually for meetings held in Japan, the official language of the symposium is English. The pro ceedings of these symposia are published under the title Frontiers in Hepatology and distributed worldwide. The 12th symposium was held on December 9 and 10,2000, at the ANA Hotel, Ube, Japan. The theme selected by the Organizing Committee was "Growth, Proliferation, and Apoptosis in Hepatocytes;' each of which is important in the understanding of the pathophysiology of intractable liver disease. Nine Japanese hepatologists were invited to give presentations, as was leading u.S. researcher Professor D.A. Brenner, recently elected editor-in-chief of the journal Gastroenterology. The reports given at the two-day meeting were valuable in furthering our under standing of the complicated signaling system involved in hepatocyte differentiation, proliferation, and apoptosis. Progress in this field is rapid, and another symposium on the same theme will be held in the near future. We believe that these proceedings are useful in summarizing current information on this important topic. The Organizing Committee would like to express special thanks to all participants and to the Viral Hepatitis Research Foundation of Japan for its continuing financial support."

According to a recent report from the Japanese Ministry of Health and Welfare, the mortality rate for hepatocellular carcinoma (HCC) is more than 30 per 100000 pop ulation. In addition, epidemiologists predictan increase in this figure by the year 2015, because of the rather high incidence of chronic liver diseases caused by HCY. The same situation has been observed in other Asian countries. It seems that HCC is likely to be an endemic disease, because of the higher preva lence of chronic hepatitis and liver cirrhosis caused by HBV, HCV, and/or aflatoxins in Asian and African countries. We also note that an interesting paper appeared in a recent issue of the New England Journal of Medicine describing the increase in younger HCC patients in the United States as compared with past decades. At present, silent hepatitis C infection is now smoldering in 4 million mostly unsuspecting Americans. Those carriers will be candidates for chronic liver disease, which is a pre disposing factor for the development of HCC. In Europe there are an estimated 5 million carriers. Accordingly, it is important to do all we can to reduce the prevalence of HCC not only in African and Asian countries, but also in the United States and Europe. With this perspective, last year the Japanese Society for Hepatology, in cooperation with the Ministry of Health and Welfare, initiated a national campaign to fight HCC."

Cellular therapy with liver stem cells and their progeny, including bone marrow cells, is a promising new approach that will contribute significantly to the treatment of liver diseases. The existence of the liver stem cell had long been debated, but it is now generally accepted that the liver contains cells with stem-like properties and that these cells can be activated to proliferate and differentiate into mature hepatocytes under certain conditions. There is also a substantial body of evidence to suggest that oval cells are involved in liver regeneration as they differentiate into hepatocytes and biliary cells. This book is a collection of work on stem cell and liver regeneration, initially delivered at the 14th Yamaguchi (Japan) Symposium on Liver Disease. Its nine chapters present the most recent data about basic and clinical research in hepatology in Japan and other countries, providing a valuable resource for researchers and practitioners alike.

My training started in 1971, when I joined the First Department of Medicine of Chiba University, as Dr. Kunio Okuda became chair ofthe department. To acquire training ingeneralpathology, Iapplied for the Intern MatchingProgram and started as aninternin the DepartmentofPathologyofYale University, in 1973.While Iwas achiefresident, Ispent 10months in Dr. GeraldKlatskin'sofficestudyingthe com plete set of his famous liver biopsy samples (the Klatskin Collection). In 1976, I movedtoJohnWesleyHospital, where therewasagroup from the USC (University ofSouthern California) Liver Unit, to obtain further pathology training under the guidanceofDr. Robert L. Peters. Those experiences have given me ample opportu nity to see the differences between the United States and Japan. Ofcourse, 28 years ago in downtown Los Angeles there were enormous num bers ofpatients suffering from typical alcoholic liver diseases. Now in Japan, in contrast, we have an enormous number ofpatients suffering from hepatocellular carcinoma (HCC), due in particular to hepatitis C viral infection. Last year, in the DepartmentofGastroenterology at the University ofTokyo, we had approximately 500 admissions due to HCC. Thus, we have an urgent need to prevent the develop ment ofHCC and to provide better treatment for such patients through a basic un derstanding ofvirology, clinical features, and treatment modalities. The first single-topic conference on "TherapyofViral Hepatitis and Prevention ofHepatocellular Carcinoma" was organized by the Japan Society ofHepatology (Kiwamu Okita, Director General) and was held November 14-15,2002, near Mt. Fuji. Thisbook, which is asummaryofthe meeting, helps toupdate relevantinforma tion on this vital topic. June 28, 2003 Masao Ornata, M.D."

Since the discovery of superoxide dismutase more than three decades ago, there has been rapid growth in the knowledge of oxidative stress and disease. This volume containing the proceedings of the 13th Yamaguchi Symposium on Liver Disease includes discussion of the direct cellular effects of hepatitis C virus (HCV) proteins on hepatocytes and reviews evidence that oxidative stress caused primarily by the HCV core protein plays a key role in disease pathogenesis. Also included are chapters on new aspects of oxidative stress and liver disease such as carbon monoxide as a regulator of liver microcirculation, hepatic iron accumulation and the incidence of hepatocellular carcinoma, and oxidative stress in the absence of inflammation in hepatocarcinogenesis. This collection of papers from the Yamaguchi Symposium creates a valuable reference resource for physicians and hepatologists.