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."

Cancer is one of the major health problems of our time and liver cancer is responsible for over one million deaths per year world-wide, making it the fourth most common cause of death from cancer. Surgical resection of the tumour(s) is the treatment of choice and offers the only chance of prolonged survival. Yet the best attempts are often frustrated by either advanced or co-existent disease that renders the patient non-resectable. This book tackles the many options available to doctors and patients in an attempt to combat this desperate disease.

This volume contains the papers presented at the International Symposium on "Cirrhosis, Hyperammonemia and Hepatic Encephalopathy," held in Valencia, Spain, January 24th-27th, 1994. Liver cirrhosis and other hepatic dysfunctions such as fulminant hepatic failure and congenital defects of urea cycle enzymes can lead to hepatic encephalopathy, coma and death. Hepatic encephalopathy is one of the main causes of death in western countries. The ability to detoxify ammonia by its incorporation into urea is diminished by impaired liver function, 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. However, the molecular bases of the pathogenesis of hepatic encephalopathy and the role of hyperammonemia in this process remain unclear and several hypotheses have been proposed. To clarify the mechanisms involved in hepatic encephalopathy and hyperammonemia suitable animal models are necessary. The animal models available and the ideal features of an animal model are presented in the initial part of the book.

Hepatitis viruses research started more than fifty years ago. The names of hepatitis A and hepatitis B were introduced in 1947 when it became clear that there were two types of hepatitis that were transmitted either enterically or parenterally. It became apparent in the 1970's that there were additional hepatitis viruses distinct from hepatitis A and hepatitis B, and thus, the term non-A, non-B hepatitis was introduced. The non-A, non-B hepatitis was further divided into post-transfusion non-A, non-B hepatitis and enterically-transmitted non-A, non-B hepatitis in the 1980's. By the end of the 1980's, both post-transfusion non-A, non-B virus and enterically-transmitted non-A, non-B virus had been identified and renamed hepatitis C virus and hepatitis E virus, respectively. Hepatitis delta antigen was first recognized as an antigen associated with hepatitis B virus infection in the 1970's. In the early 1980's, a virus was isolated and named hepatitis delta virus. These five different hepatitis viruses have distinct replication pathways and are major health concerns. They have become an important topic for teaching to graduate-level and medical students.Hepatitis Viruses provides a comprehensive, up-to-date review of these viruses to readers. Each chapter is written by one of the top researchers in the field, and topics include: * the epidemiology and the natural history of infection of these viruses, * the molecular biology and the replication cycle of individual hepatitis viruses, * host-virus interactions and the pathogenesis of hepatitis viruses, * the immunology of hepatitis viruses, * the relationship between hepatitis viruses and hepatocellular carcinoma, * the viral vaccines and antiviral drugs. This book can serve as a supplemental reading material to graduate students and medical students, and to any researcher who would like to learn more about hepatitis viruses.

The past 20 years have seen a surge of research into colorectal cancer, which is a reflection of the need to improve our methods of treating patients suffering from this increasingly common form of cancer. Greater knowledge of the basic mechanisms involved in colorectal carcinogenesis is an essential prerequisite to improvements in cancer prevention. In this volume the editors have brought together an impressive list of experts to cover the epidemiology, pathophysiology, morphology and basis for new diagnostic and therapeutic approaches to early detection and prevention. This broad scientific approach provides the reader with up-to-date review of our current state of knowl edge of colorectal carcinogenesis and indicates how this information can be used to generate more research and create new opportunities for diagnosis and treatment. This is a book of knowledge and ideas, some of them still at the stage of theoretical interest, but others with practical potential for the care of patients. I recommend it to those who have a research interest in colorectal carcinogenesis, as well as to readers who wish to know just how far medical scientists have progressed in their efforts to achieve the ideal of cancer prevention."

At the Mie International Symposium held in Japan in April 1994, leading scientists reviewed recent advances in the understanding of the contractile mechanism in smooth muscle. The present volume collects the papers presented at the symposium, summarizing the latest advances in smooth muscle function and emphasizing important components of the contraction-relaxation cycle. Topics include a discussion of the smooth muscle cell membrane, with emphasis on its ion channels; the regulation of cytosolic Ca2+ levels and the relationship to force in smooth muscle; aspects of the two key regulatory enzymes involved with myosin phosphorylation-dephosphorylation; the molecular basis for pharmacomechanical coupling in smooth muscle; developments in the basic contractile mechanisms involving the crossbridge cycle of tonic and phasic muscle; the role of myosin light chains; and many others. The approach is broad and presents contemporary opinions in pharmacology, physiology, and biochemistry as they relate to smooth muscle function. The book will appeal not only to those working in these disciplines, but to vascular clinicians, obstetric-gynecological physicians, and gastroenterologists as well.

"Neuropeptides and Stress" presents a comprehensive survey by leading pioneers in the field of the knowledge and concepts implicating neuropeptides in the regulations of responses to stress. Topics covered include: recent advances on the regulation and modulation of the behavioral, endocrine, autonomic, gastrointestinal, immune and analgesic responses to stress by neuropeptides. Neuroanatomical and biological data are considered. Special emphasis is given to corticotropin-releasing factor (CRF) and opioid peptides.

Get the authoritative, up-to-date information you need on liver disease from the 7th Edition of the most trusted reference worldwide. Covering both basic science and recent clinical developments, this revised edition by Drs. Arun J. Sanyal, Thomas D. Boyer, Norah A. Terrault, and Keith D. Lindor, provides an in-depth, comprehensive look at the pathophysiology, diagnostic, and treatment information related to the liver. More than 1,100 figures and tables, many new and in full color, highlight completely updated content throughout. Expert, international authorship and comprehensive, easy-to-access information makes this edition the gold standard in the field of hepatology. Expert ConsultT eBook version included with purchase. This enhanced eBook experience allows you to search all of the text, figures, videos, and references from the book on a variety of devices. Includes new information on the rapid changes in treatment paradigms for acute liver failure, the latest treatments for primary biliary cholangitis, full coverage of the gut microbiome and its role in liver disease, the newest developments in drug-induced liver injury, and changes in hepatitis C virus treatment and hot-button concerns about access to care. New summary boxes at the end of each chapter and a newly streamlined table of contents make it easier to find and understand the information you're looking for. Hundreds of brand-new illustrations clearly present key aspects of liver disease.

Hepatitis C virus (HCV), a major causative agent of chronic liver disease, is spread throughout the world and around 170 million people are persistently infected. In this volume, world-leading experts in the field of HCV research have compiled the most recent scientific advances to provide a comprehensive and very timely overview of the various facets of HCV. The book starts with a discussion of the possible origin of HCV and its spread among the human population. The focus of the subsequent chapters is on available cell culture and in vivo models before shifting to the molecular and cellular principles underlying the viral replication cycle. These chapters are complemented by insightful descriptions of the innate and adaptive immune responses to HCV as well as the virus-associated pathogenesis. Finally, the development of antiviral therapies, which is closely linked with progress in basic research, and the implementation of those therapies into present and future daily clinical practice are highlighted.

In the spring of 1987, nearly 350 individuals gathered in a hotel in Bethesda, Maryland, just outside of Washington, D. C. , to participate in a two-day medical symposium devoted to the topic of liver diseases. A small minority of this group had been attracted by what promised to be an outstanding Continuing Medical Education course. The remainder, however, although obviously interested in the content of the symposium, had come primarily to honor a man who, over the years, had profoundly touched them, personally or professionally, for the course had been conceived as a tribute to an exceptional man of medicine, a man with remarkable scholarly and personal attributes: Hyman J. Zimmerman. Dr. Zimmerman, referred to affectionately by all as Hy, was born in 1914 in Rochester, New York, the city in which he received both his early schooling and his undergraduate education. In the late 1930s, he moved to Palo Alto to begin his medical education at Stanford University, from which he graduated cum laude in 1942, having spent an additional year acquiring a masters degree and as World War II in bacteriology. Almost immediately thereafter, he entered military service, was in progress, was assigned to duty in France. Soon after his arrival, he was made chief of an Army field hospital. A major medical problem plaguing U. S. troops at the time was viral hepatitis, which resulted in a deluge of patients admitted to his hospital.

In recent years there have been huge advances in the understanding of the genetic and molecular basis of the fibrocystic diseases. This volume provides a thorough review of fibrocyctic diseases that affect the liver. It contains in-depth discussions of the genetics, molecular biology, pathogenesis, histology, clinical presentations, complications of, treatment, and prognosis of the conditions affecting children and adults, and hence will be the gold-standard reference for these conditions. In addition, the histological features that distinguish these conditions from other potentially fibrosing hepatopathies are illustrated. Conditions with syndromic features involving the kidney or other organ systems are also reviewed. Thorough review of the clinical phenotypes, their presentations, treatment, potential complications of, and prognosis is discussed.

Fibrocystic Diseases of the Liver will be an invaluable resource for hepatologists, gastroenterologists, nephrologists, and hepatic surgeons who care for children and adults with liver disease, as well as basic scientists in molecular genetics, hepatobiliary pathophysiology, hepatology and nephrology.

The liver is an exceptionally complex and diverse organ that functions both as an exocrine and an endocrine gland. It secretes bile, which contains many con stituents in addition to bile salts, and it synthesizes and releases many substances in response to the body's demands, including prohormones, albumin, clotting factors, glucose, fatty acids, and various lipoproteins. It has a dual blood supply providing a rich mixture of nutrients and other absorbed substances via the portal vein and oxygen-rich blood via the hepatic artery. This functional heterogeneity is accompanied by cellular heterogeneity. The liver contains many cell types including hepatic parachymal cells, Kiipffer cells, Ito cells, and endothelial cells. The most abundant cell type, the parenchymal cells, are biochemically and structurally heterogeneous. The cells in the oxygen-rich areas of the portal triad appear more dependent on oxidative metabolism, whereas those around the central vein (pericentral, perivenous, or centrolobular areas) are more dependent upon an anaerobic mechanism. Throughout this volume the latter three terms are used synonymously by various authors to indicate the five to eight layers of cells radiating from the central vein. Structural and metabolic heterogeneity of hepatic parenchymal cells has been demonstrated by a variety of approaches, including histochemical, ultra structural, and ultramicrobiochemical studies. This microheterogeneity is linked to the physiological functions of the liver and its response to injurious substances."

Both the investigation and treatment of cancer of the oesophagus are comprehensively presented in Management of Oesophageal Carcinoma. This information is otherwise not easily available in one source. The chapters are written by experts in the fields of anatomy, cancer research, radiology, and thoracic surgery and give up-to-date information on this difficult disease. All aspects are covered: anatomy, epidemiology, endoscopic and radiologic diagnosis, pathology, surgical treatment, radiotherapy, palliative and laser therapy, and the management of complications. Surgeons will be especially interested in the discussion of the recent technique of oesophagectomy without formal thoracotomy, and the use of stapling devices. This complete reference is ideal for all clinics and medical centers specializing in thoracic surgery or treatment of oesophageal carcinoma.

The transformation of a normal cell into a cancer cell is not a sudden but a slow continuous process which may take years. A systematic study of the morphological and structural changes that take place during this cellular transformation has only become possible since methods were developed to induce a high incidence of tumors in experimental animals. The growth of such tumors can be followed during all stages of their development. For several reasons, rat liver has proved to be particularly suitable. For more than thirty years it has been known that one can induce tumors in rat liver experimentally with many different substances. The azo dyes which were used originally (YOSHIDA, 1932; KINOSITA, 1937) have since been replaced by more potent carcinogens. The recently discovered nitrosamines, dimethylnitrosamine (MAGEE and BARNES, 1956), diethylnitrosamine (SCHMAHL et aI. , 1960) and N-nitrosomorpholine (DRUCKREY et aI. , 1961) should be mentioned in this context. Used in the proper dose, these carcinogens lead within a few months to the formation of multicentric hepatomas in practically 100 Ufo of the experimental animals, and are therefore a very useful tool for studies of the cytogenesis of cancer (see BUCHNER, 1961; GRUND MANN, 1961; GRUNDMANN and SIEBURG, 1962; OEHLERT and HARTJE, 1963; BAN NASCH and MULLER, 1964). The liver parenchyma as such offers a very big technical advantage because it consists of a rather homogenous cell population.

Liver-Directed Therapy for Primary and Metastatic Liver Tumors is a comprehensive examination of tumors of the liver. It provides a unique multi-modality approach to management of all types of primary and secondary liver tumors. The biology of liver cancers, state of the art radiologic imaging and novel, non-surgical interventional strategies are given. There is an in depth analysis of surgical options including transplantation, resection, interstitial ablation techniques and liver-directed chemotherapy for hepatocellular carcinoma, bile duct cancers, and colorectal and neuroendocrine liver metastases. Because of the unique and comprehensive examination of liver tumors, this work is an excellent resource for surgical, transplant and medical oncologists, surgeons, gastroenterologists, and radiologists.

In their second year in medical school, students begin to learn about the differences between "disease" and "illness." In their studies of pathology they learn to understand disease as pertubations of molecular biological events. And we clinicians can show disease to them by our scans, lay it out even on our genetic scrolls, and sometimes even point out the errant nucleotide. Disease satisfies them and us; at Yale, lectures on the gastrointestinal tract run from achalasia to proctitis. There is, alas, little mention of functional bowel disease or of the irritable or spastic colon, for that is not easy to show on hard copy. Functional bowel disease represents "illness," the response of the person to distress, to food, to the environment, and to the existential problems of living. In real life such matters are most important. Richard Cabot first found out at the Massachusetts General Hospital almost a century ago that 50% of the patients attending the outpatient clinic had "functional" complaints. The figure had grown to over 80% when the very same question was reexamined 60 years later.

More than 2 million people in Japan have chronic hepatitis C and many of them will lose their lives to liver cirrhosis or complications of hepatocellular carcinoma. Hepatitis C virus-related diseases are a serious concern both in developing countries and in Japan and the United States, where the number of patients is also in the millions. Therapeutic modalities recently developed in Japan, including interferon therapy and nutritional supportive therapy, are gaining worldwide acceptance. At this critical juncture, HCV and Related Liver Diseases presents new information on etiology, pathology, diagnosis, and therapy. Viral hepatitis was the theme of the Yamaguchi Symposium on Liver Disease, meeting in December 1998 and attended by leading hepatologists and virologists. Collected in this volume are the papers from the symposium, providing a valuable resource for hepatologists, gastroenterologists, and others working to understand and treat viral hepatitis.

In an attempt to attain the best possible delimitation of all the problems posed today by benign diseases of the esophagus, 181 authors each agreed to answer one or more of 210 questions that had been drawn up on the subject. These questions, each one deliberately limited and difficult, mostly concerned reflux esophagitis: its natural history, the means of its diagnosis, all existing treatments, and its eventual degeneration. The authors approached are today's most reputed specialists in the fields of epidemiology, gastroenterology, endoscopy, pathology, and surgery of esophageal diseases. The authors were all assigned one or more questions in their own field, none of which was simple: all did their best to synthesize in their replies their own experience on the precise point under review and included all the most useful bibliographical references on the topic. The book is thus the result of an original, individual approach to try to pinpoint the heart of a problem. The 210 answers succeed one another in logical progression according to the different diagnostic and therapeutic stages, specifying, at each step, the degree of precision sought. Consequently, the reader has at his disposal an exceptional synthesis of facts and concepts. Opening the book at random he will find at once the detail he is looking for, the professional opinion he is lacking, or the development of a question he had perhaps not yet asked himself.

This volume contains the papers presented at the Inter- national Symposium on "Cirrhosis, Hepatic Encephalopathy and Ammonium Toxicity", held in Valencia, Spain, November 27-29, 1989. Hepatic cirrhosis as well as other liver failures usual- ly lead to hepatic encephalopathy which is an important cause of death in occidental countries. However the molecular bases of the pathogenesis of hepatic encephalopathy remain unclear and several hypotheses have been proposed. Hyperammonemia is considered one of the main factors responsible for the mediation of hepatic encephalopathy. Therefore, a part of the book is devoted to the effects of hyperammonemia on cerebral function, ammonia and amino acid metabolism, brain microtobules, astrocytes and synaptic trans- mission and their possible role in the pathogenesis of hepatic encephalopathy. Carnitine has a remarkable protective effect against acute ammonium intoxication. Thus some results regarding this effect are also presented, as well as the clinical use of car- nitine. The alterations of the metabolism of ammonia and of seda- tives in liver diseases and their clinical implications are also discussed. The possible role of altered GABA-ergic neurotransmission on the pathogenesis of hepatic encephalopathy has received considerable attention recently. Results of these studies and those on benzodiazepine receptor ligands are presented as well as those on the hypothesis of the role of altered synaptic plasma membrane on the pathogenesis of hepatic encephalopathy.

We have been privileged to start our academic careers at the begin ning of the decade in which the immunological roles and hypersensitivity diseases of the gastrointestinal tract and liver have been defined. In the early 1960s IgA was reported to be the main secretory immunoglobulin, immunoblasts were shown to home to the intestinal mucosa and certain serum autoantibodies were described in patients with chronic liver disease. Shortly thereafter IgE and Australia antigen were discovered. Parallel advances in clinical investigation, in particular closed biopsy techniques, facilitated correlation of morphological changes with im munological mechanisms in disease of the gastrointestinal tract and liver. Only 10 years later, the concepts of immunity and hypersensitivity are regularly applied to the pathogenesis, diagnosis, treatment and prog nosis of many chronic diseases in these organs. In designing this book we have attempted to integrate theorectical and clinical immunology as they pertain in 1975; our ultimate aim is aptly described by Brachet as quoted by Professor Paronetto (page 319). We would like to think that this review provides a basis for the next major advances in the fields of gastrointestinal and hepatic immunology. As we see it, the outstanding problem in both sites is how to produce protective immunity without hypersensitivity."

The pathogenesis of cell death and necrosis in the liver is a central topic of research in liver disease. A molecular understanding of events and sequences leading to cellular death provides the basis for preventive and therapeutic efforts. This volume originates from a "Workshop on Experimental Liver Injury" held on November 9 and 10, 1974, in Freiburg, Germany. Recent progress in the elucidation of the mode of action includes agents inducing liver cell necrosis by a primary dis- turbance of nucleotide and nucleic acid metabolism as well as hepa- totoxins characterized by a primary attack on cellular membranes. I hope that this book will contribute to an increasing understanding of disease mechanisms. Freiburg im Breisgau Dietrich Keppler June 1975 Acknowledgments The generous support from Dr. H. Falk, Freiburg, has been a prereqUIsite for the organisation and publication of the meeting on "Pathogenesis and Mechanisms of Liver Cell Necrosis". I wish to express my sincere thanks for this sponsorship. I am indebted to those who acted as chairmen during the meeting: Professors H. Remmer (Tilbingen), M. Frimmer (Giessen), W. Gerok (Freiburg), H. Popper (New York), H. Schimassek (Heidelberg), and K. Decker (Freiburg).

Ever since the emergence of the concept of catharral jaundice by Virchow, viral hepatitis has eluded scientists as a pathogenetic enigma. A tremendous new impetus was given to hepatitis research by Baruch Blumberg's discovery of his 'Australia Antigen', now known as hepatitis B surface antigen. This led to an unheard-of outburst of research activity to elucidate the nature of the virus, its chemical and antigenic composition, its epidemiology, and pathogenetic mechanisms in the causation of liver disease. Coinciding with this period, modern medical science witnessed impressive progress in the analysis of the extraordinarily complex mechanism of immunological reactions. Immunohistochemical techniques for the detection of hepatitis B viral components are a product of this scientific progress in both areas. The application of such tech niques forms the core of this work. It represents a vast amount of work, performed during the course of several years, with meticulous application of advanced immunohisto chemical techniques, combined with histopathology and clinical-patho logical methods. This has resulted in the compilation of original results and new insights into the cellular and tissular localization of the anti genic components of the hepatitis B virus in different forms of chronic liver disease. The most outstanding results are the demonstration of the superior sensitivity of the applied immunohistochemical technique in the search for viral components in chronic hepatitis patients. and the differ ential distribution patterns of hepatitis B surface antigen in the various forms of chronic liver disease."

The literature of medicine continues to expand at a remarkable pace. The number of papers and monographs published has increased dramatically in the past five years. Nowhere has this increase been as dramatic as in the field of acute and chronic hepatitis. Why then should there be still another book? Despite the sheer volume of words published, it is still difficult to find in anyone volume a compilation of all of the most significant work. Most mono graphs have considered either chronic or acute hepatitis, not both. Few works have addressed both the clinician and the basic scientist. This book addresses both of these audiences and considers both of these diseases. It was designed to provide an authoritative but concise assessment of our changing concepts of acute and chronic hepatitis. It covers what is currently known and, based on the most convincing research, believed about these diseases. To fulfill this ambitious goal, only authors with international reputations in their fields of expertise were invited to contribute. In the evolution of our current thoughts on the pathogenesis and manage ment of acute and chronic hepatitis, our ideas have changed several times. This book presents the facts as they are known today and, in areas where all the facts are not established, presents the well-founded opinions of those considered to be authorities. The authors present established and usually confirmed data and do not deal extensively with areas of speculation or unconfirmed material."

Inflammatory dieseases of the pancreas occur with increasing incidence in western industrialized countries. This volume deals with all aspects of CHRONIC PANCREATITIS including epidemiology, etiology, morphology and pathophysiology, dia- gnostic imaging as well as conservative and operative treat- ment. Very recent data based on experimental and clinical research projects are presented. The contributions have all been written by a team of internationally well recognized authorities in the various fields involved. Topics of parti- cular interest include feed-back regulation, new aspects of conservative and interventional treatment as well as modern surgical approaches including organ-preserving procedures.