K. Okita - Böcker

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.

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.

The first single-topic annual conference on hepatology in Japan was held in November 2002 to discuss therapies for viral hepatitis and the prevention of hepatocellular carcinoma (HCC). Bringing together researchers and clinicians from North America, Europe, Japan, and other parts of Asia, the conference included symposia on the hepatitis C replicon system, new antivirals that lower or prevent the incidence of HCC, and transplantation in cases of hepatitis B and C, as well as new treatment modalities for viral hepatitis and preventative measures for HCC. With the rising number of HCC cases worldwide, this collection of papers presented at the conference provides a valuable, up-to-date resource and reference for all professionals involved in the treatment and prevention of viral hepatitis and hepatocellular carcinoma.

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.

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.

The liver has an important role in nutritional homeostasis, and it is well known that liver diseases can lead to abnormalities in the nutrient metabolism and to subsequent malnutrition. Because malnutrition is particularly prevalent in patients with liver cirrhosis, proper nutritional assessment and support for cirrhotic patients is essential. This collection of research and clinical findings on nonalcoholic steatohepatitis (NASH) and nutritional therapy contains significant new findings in several fields. As NASH frequently causes liver cirrhosis, the nutritional aspects of its treatment are discussed. Other areas covered include nonalcoholic fatty liver, the role of leptin in the pathogenesis of NASH, restricted diets and exercise therapy, mammalian targets of the peptide rapamycin, and genetic factors influencing the development of NASH. This book is intended to be of particular relevance to researchers and those practicing in the field.

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.

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. The 12th symposium was held on December 9 and 10,2000, at the ANA Hotel, Ube, Japan.

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.

The rising incidence of hepatocellular cancer (HCC) is a cause for concern in all parts of the world today. Epidemiologists predict that HCC will become endemic because of the large numbers of carriers of hepatitis viruses that lead to the chronic liver diseases, which, in turn, are predisposing factors for the development of HCC. The eradication of HCC thus becomes an urgent priority. Against this background, Progress in HCC Treatment was the focus of the Yamaguchi (Japan) Symposium held in December 1998. Japanese hepatologists, unsurpassed in the diagnosis and treatment of HCC, were joined by specialists from other parts of the world to exchange the latest information about HCC treatment. Topics included percutaneous ablation of HCC, ultrasonographic screening for early detection, surgical treatment, and prevention by fibrosuppression. The papers collected in this volume provide a wealth of information on HCC for hepatologists, physicians, and others in the field.

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.

To gain a better understanding of the pathology of liver disease, the signaling system controlling hepatocyte differentiation, proliferation, and apoptosis was selected as the theme of the 12th Yamaguchi Symposium on Liver Diseases. Ten leading researchers presented their latest experimental results. Focusing on apoptosis, guest speaker Professor D.A. Brenner, USA, spoke on the regulation of tumor necrosis factor alpha and Fas ligand-induced hepatic apoptosis by nerve factor-kappa B. Other researchers covered the molecular basis for clonal deletion therapy in hepatocellular carcinoma, hepatitis C virus induction of proliferation signals, helix-loop-helix protein in liver-specific gene expression, and reconstitution of hepatic tissues using liver stem cells, among other topics of current interest. These proceedings thus serve as a useful resource for all involved in hepatology research.