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.

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.

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."

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 contains the papers presented and discussed during the Symposium on 'Portal Hypertension in the 21st Century', held in Montreal, Canada, in April 2004, and sponsored by Axcan Pharma Inc. and NicOx S.A. There are eight sections covering basic mechanisms, new drugs, prevention and current treatment of variceal bleeding, prevention of recurrent bleeding and hepatic hemodynamic monitoring.

An international faculty of authors have contributed chapters at an outstanding scientific level which will be vital reading for scientists and clinicians alike."

Therapeutic immunosuppression has very broad applications in clinical medicine, ranging from prevention and treatment of organ and bone marrow transplant rejection, management of various autoimmune disorders (e.g., rheumatoid arthritis), skin disease, and asthma. Whereas traditionally only a small repertoire of immunosuppressive agents was available for clinical use, recent discoveries have significantly increased the number of approved agents, resulting in numerous trials to further evaluate their potential. In addition, products of the biotechnology industry - monoclonal antibodies, cytokines, cytokine antagonists, and other products of genetic engineering that target key molecular pathways in disease pathogenesis - have either already made, or are on the verge of making an important impact on treatment. There is also considerable interest in the potential of cell-based therapies (particularly hematopoietic stem and dendritic cell therapy) of allo- and autoimmunity. Important recent advances in the immunotherapy of allergic diseases are also covered in this book. Gene therapy offers considerable promise for suppressing pathogenic processes in either transplantation or autoimmune disorders. The possibility of combining these important new advances to maximize benefit to the patient, and to minimize possible untoward effects (which are also given extensive coverage in this book), is one of the most exciting challenges of contemporary medicine. This volume is intended both for practising physicians and surgeons and for biomedical scientists at the graduate/postdoctoral levels, and is designed to provide the theory behind these various approaches to immunosuppression, and to provide state-of-the-art reviews of current developments in each area. Each chapter is contributed by one or more experts in the field. There was a need to bring this information together in a single volume, as much of the key recent developments have been dispersed throughout the biomedical literature, largely in specialized journals. Since, as in the past, important developments in immunosuppressive therapy in one branch of medicine (i.e. transplantation) are likely to benefit another (e.g., dermatology, rheumatology, gastroenterology), cross-disciplinary coverage of the mechanistic basis of the various therapeutic strategies in a single volume is likely to convey the potential of advances in therapy in the most coherent manner possible.

Adenomatous Polyps of the Colon: Pathobiological and Clinical Features consolidates the vast body of basic science and clinical data associated with adenomatous polyps of the colon, much of it inspired by the realization that most colorectal carcinomas seem to arise in such polyps. This book strives to evaluate these data, with particular emphasis on their implications for management of polyp-bearing subjects. Topics comprehensively explored include anatomy and histology of the normal colon; pathologic characteristics of adenomatous polyps, differential diagnosis, and grading schemes for degree of dysplasia and villosity; adenomatous polyposes; histologic and epidemiologic evidence for the malignant potential of adenomatous polyps; and detection and management, with special attention to endoscopy, endoscopic polypectomy, the malignant polyp, and post-polypectomy surveillance schedules.

It is now widely accepted that multidisciplinary collaboration and multimodality treatment approaches are important in improving the survival of patients with hepatocellular carcinoma. In this comprehensive textbook, internationally renowned experts in the field present and discuss the various strategies employed in the treatment of the disease. Up-to-date information is provided on the indications for and outcome of a range of treatment options, including surgical resection, liver transplantation, radiofrequency ablation, transarterial chemoembolization, yttrium-90 transarterial radioembolization, and systemic therapy. In addition, important background information is included on biology, pathology, staging, and imaging. This book will be particularly helpful to all professionals and trainees worldwide who have an interest in the diagnosis and treatment of hepatocellular carcinoma.

Needle biopsy of the liver is now an accepted procedure in most large hospitals, and surgeons and laparoscopists are more likely to biopsy the liver under direct vision than in the past. Consequently, increasing demands are being made on pathologists for rapid diagnosis. This full colour atlas provides a practical guide to the histopathological diagnosis of liver disorders, with particular emphasis on clinicopathological correlation and the need for the pathologist to be in full possession of all the available clinical information. Although containing over 350 colour illustrations, the book is more than just an atlas and each section includes a brief description of the main clinical and pathological features of the subject under discussion. For this second edition, many chapters have been rewritten - e.g. on viral hepatitis - and many new illustrations added. The book is intended for the practising and trainee pathologist and the clinician who performs liver biopsies, but will also be of value to postgraduates, residents and students in other branches of medicine.

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.

Primary Liver Cancer: Surveillance, Diagnosis and Treatment focuses on the many therapies rapidly evolving to assist with controlling hepatocellular carcinoma as well as emerging technologies to assist in early diagnosis as well as prevention. All chapters are written by experts in their fields and include the most up to date information for diagnosis, treatment, surveillance, epidemiology, staging, recurrence and prevention. This volume will serve as a useful resource for clinical gastroenterologists, hepatologists, oncologists, pathologists, and physicians who treat patients with chronic liver disease and hepatocellular carcinoma.

The intestine, particularly the small bowel, represents a large surface (in the adult 2 human approximately 200m ) through which the body is exposed to its environment. A vigorous substrate exchange takes place across this large surface: nutrients and xenobiotics are absorbed from the lumen into the bloodstream or the lymph, and simultaneously, the same types of substrate pass back into the lumen. The luminal surface of the intestine is lined with a "leaky" epithelium, thus the passage of the substrates, in either direction, proceeds via both transcellular and intercellular routes. Simple and carrier-mediated diffusion, active transport, pinocytosis, phagocytosis and persorption are all involved in this passage across the intestinal wall. The term "intestinal permeation" refers to the process of passage of various substances across the gut wall, either from the lumen into the blood or lymph, or in the opposite direction. "Permeability" is the condition of the gut which governs the rate of this complex two-way passage. The pharmacologist's interest in the problem of intestinal permeation is twofold: on the one hand, this process determines thebioavailability of drugs and contributes significantly to the pharmacokinetics and toxicokinetics of xeno biotics; on the other hand, the pharmacodynamic effects of many drugs are manifested in a significant alteration of the physiological process of intestinal permeation.

Because of the increasing burden of hepatitis C and fatty liver disease, there is an explosion in the prevalence of chronic liver failure and hence its complications. The onset of Hepatic Encephalopathy (HE) in these patients has a significant impact on the quality of life, morbidity and mortality. Unfortunately, the approach observed by most clinicians to this complex disorder is minimalistic. Hepatic Encephalopathy provides a comprehensive review on pathophysiology and clinically important aspects in HE. Topics in basic physiology, nitrogen metabolism, new insights into pathogenesis and brain edema are covered in great detail. The authors have made a special effort by simplifying the complex aspects of pathogenesis and diagnosis so that it can be easily understood and applied clinically. This volume also focuses on recent developments regarding diagnoses of subtle forms of HE, also known as minimal or covert HE as well as on new treatments. Hepatic Encephalopathy will be of great value to gastroenterologists, hepatologists, pathologists, medical residents, fellows, internists, and general practitioners who treat patients with hepatic encephalopathy.

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.

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.

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."

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.

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.

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.

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."

The aim of this Atlas is to present the three-dimensional arrangement of the liver structures, which should be familiar to those who diagnose and treat diseases of the liver, particularly in an era when the methods of diagnostic imaging and surgical treatment are becoming increasingly sophisticated. For this purpose a series of corrosive preparations of the blood vessels and bile ducts of the liver was made and photographed. In addition to the normal situations, many frequent and rare variations are shown. The Atlas also shows some blood vessels that have not been adequately described or are not well-known in the reference literature, but are nevertheless of great importance in performing segmental liver resections.This Atlas takes a fresh approach to the subject. The method used allows the size, three-dimensional arrangement and structure of the blood vessels and bile ducts of the liver to be preserved. The majority of photographs were taken from the direction from which surgeons see the liver during an operation. This, together with the schematic presentations complementing most of the photographs, gives a further instructional value to the work. With colour photographs and explanatory text, the Atlas forms a basic guide to orientation inside the liver parenchyma, to understanding and diagnosing certain pathological processes and to planning surgcial procedures.

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.