Falk Symposium – serie

The advent of molecular biology and recombinant DNA technology has changed contemporary medicine profoundly. These new scientific tools have made it possible to identify and understand pathological mechanisms at cellular, subcellular and molecular levels which has added previously unimaginable novel dimensions to the diagnosis, therapy and prevention of a rapidly increasing number of diseases of the liver and biliary system. The title of this book expresses this epochal progress in hepatology. A series of acute or chronic diseases of the liver has been chosen whose modern clinical management reflects the impact of the new scientific insight gained from molecular biology. The book, the proceedings of the 87th Falk Symposium (X International Congress of Liver Diseases: Part II of the Basel Liver Week 1995) held in Basel, Switzerland, October 19-21, 1995, first presents an overview of the molecular pathology of the chosen disease, followed by discussions of the clinical inference which this new scientific information entails for diagnosis, management and therapy.This approach is expected to ease the readers' endeavour to connect basic to clinical science and to facilitate appreciation of the enormous progress but also of the inherent limitations and emerging questions which modern molecular biology has brought to clinical medicine.

Molecular diagnosis and gene therapy are of increasing interest and importance in clinical medicine. The increasing understanding of the pathogenesis of human diseases at the molecular level opens new perspectives for their diagnosis, prevention and therapy. The first part of this book, the proceedings of Falk Symposium No. 88 'Molecular Diagnosis and Gene Therapy', held in Basel, Switzerland, October 22-23, 1995, is aimed at an in-depth understanding of the methodology of molecular diagnosis by hybridization analysis, polymerase chain reaction and others. Further, the applications and limitations of these technologies in clinical medicine for the detection of genetic, malignant and infectious diseases are reviewed. In the second part of the book, the basic strategies of gene therapy are presented, including gene transfer and targeting. Further, experimental and clinical applications of gene therapy strategies for the prevention and treatment of hepatic and other diseases are presented. Molecular diagnosis and gene therapy are clearly going to be key elements of clinical medicine after the year 2000. In this sense, the book should allow basic scientists as well as clinicians to be informed about the state-of-the-art of molecular diagnosis and gene therapy and should provide a perspective for future developments in molecular medicine.

Pregnancy is the main determinant of some liver diseases in humans: acute fatty liver of pregnancy, cholestasis of pregnancy, and acute liver failure in toxaemia of pregnancy. Pregnancy also modifies the natural history of other more common hepatobiliary diseases, such as cholesterol gallstones. Sex hormones (mainly oestrogens, progesterone and/or some of its metabolites) and prolactin are considered responsible for these pathological consequences and they also appear to be influential in the outcome of several other hepatobiliary disorders, in both sexes and all ages. Although these disorders and their hormonal interrelations have been clinically well characterized, their pathogenesis remains obscure from the biomolecular point of view. In recent years, novel approaches using new technologies have improved our understanding of hormone actions and metabolism, hormone receptors, metabolic pathways and their interrelations with closely related molecules, such as bile acids. This book, the proceedings of the 89th Falk Symposium, held in Santiago, Chile, 10-11 November, 1995, will help research scientists and clinicians to review basic and clinical aspects of these interactions, in order to stimulate biomedical research in a relevant and exciting area.

The clinical efficacy of glucocorticoids in the treatment of inflammatory bowel disease has been confirmed in a multitude of controlled monocentre and multicentre studies as well as from observations of the clinical course of the disease. Although, in the past, the treatment recommendations, dose regimen, substance selection and mode of administration were deduced principally from clinical trials, in recent years experimental research has yielded a mass of therapeutically significant new results. This seeks to optimize the clinical effects of the steroids and minimize their adverse events on a rational basis by the application of the knowledge obtained in pharmacokinetic and pharmacodynamic models, taking into account the different types of protein binding and the intrinsic activity of the various glucocorticoids. However, the transfer of this type of `disease-adapted differential glucocorticoid treatment' into a clinical context involves a critical examination of the `received' notions that have characterized steroid treatment in the past, such as strictly circadian administration or time-related dose reduction, as well as proof of the clinical superiority of the new therapeutic approaches. This book, the proceedings of a workshop on Glucocorticoid Treatment held in Strasbourg, France, identifies the current status of existing therapeutic concepts in inflammatory bowel disease, presents the pharmacokinetic and pharmacodynamic interactions in connection with the specific pharmacological properties of steroids with reference to substance differences and different modes of administration, and demonstrates their therapeutic significance.

This text presents a major group of causes of end-stage chronic liver disease. There has been great scientific interest in these disorders in recent years, so this text evaluates treatment modalities in old and even new cholestatic diseases. Since secondary malnutrition plays an important role in inducing multiorgan morbidity in these patients, nutritional and metabolic aspects need better understanding. The influence of disease and nutrition-related problems on liver transplantation as the ultimate therapy of cholestatic disorders is also of current interest.

Zinc has an important role in human physiology due to its involvement in numerous enzymatic reactions and its other functions as part of hormones and structural proteins. As a consequence a wide variety of symptoms may occur in different states of zinc deficiency. Several diseases of the digestive tract can lead to zinc deficiency and consequently to deficiency symptoms. This book, the proceedings of an International Falk Workshop held in Freiburg, Germany, on 27 October 1996, aims at a dialogue between basic researchers and gastroenterologists in order to improve the understanding of the role of zinc in disorders of the digestive tract. Based on lectures on the role of zinc in cell biology, the pathophysiology of zinc deficiency and consequently the possibilities of zinc substitution in these disorders is discussed. It is hoped that this book will initiate fruitful discussions and collaborations leading to a better knowledge of the role of this trace element in gastroenterology.

Since the last International Bile Acid Meeting in San Diego in 1994, new advances have been made in the understanding of bile acid metabolism and transport. The cytotoxic as well as the therapeutic effects of specific bile acids have been further explored and the beneficial effects of ursodeoxycholic acid in various chronic cholestatic conditions have been substantiated. Much basic and clinical research has been conducted to unravel the underlying mechanisms of action. This volume, the proceedings of Falk Symposium No. 93 (XIV International Bile Acid Meeting), held in Freiburg-im-Breisgau, Germany, October 22-24, 1996, is dedicated to both basic and clinical aspects of bile acid research related to the role of bile acids in hepatobiliary diseases.

There are many separate groups working in gut biology, and they feel that the gut is an excellent model for investigating general problems in differentiation, growth control, stem cell biology, and regeneration and adaptive responses. Part III of the Gastroenterology Symposia Freiburg 1996 (Falk Symposium No. 94), held in Freiburg, Germany, October 25-26, brought together some of these groups with a view to identifying areas which are not being utilized and need to be exploited, such as transgenic and knockout approaches, retrovirus delivery systems, and model cell/tissue systems. The main themes of this text are gastrointestinal development and differentiation, gut stem cell biology, and the control of gut growth in normal and abnormal situations. Basic research findings are related to clinical situations, and the book should appeal not only to gut cell and molecular biologists, but also to gastroenterologists interested in the potential applications of these subject areas.

Constipation and incontinence are of considerable importance to a great number of patients but many put it under taboo. Both functional disturbances comprise a wide spectrum of pathophysiological findings of neuro-muscular changes of the colon or the pelvic floor, but psychological factors may play an important role as well. In recent years much progress has been made in several disciplines which are important for the understanding and handling of constipation and incontinence. This volume, the proceedings of Falk Symposium No. 95 held in Freiburg, Germany, October 28-30, 1996, concentrates on clinically relevant and open questions rather than trying to cover the whole field in all details.

The therapeutic handling of autoimmune liver disease is limited because basic mechanistic insights into immunologically mediated pathophysiology have not yet been translated into standard pharmacological treatments. A future expansion of the incidence of autoimmune liver diseases is anticipated because of growing rates of exposure to an increased variety of xenobiotics of dietary, pharmaceutical or environmental origin. This book, the proceedings of an International Falk Workshop held in Konstanz, Germany, January 23-24, 1997, aims to share thinking among immunologists, biochemists, pharmacologists and clinicians in order to better understand the aetiology of this liver disease and its relation to extra-hepatic factors.

Most symposia on chronic inflammatory bowel disease during the last few years have focused on new aspects of aetiology and pathophysiology. However, based on such new aspects, changes in diagnosis and treatment have been developed in recent years and some others are currently under investigation. This book, the proceedings of Falk Symposium 97: Clinical Challenges in Inflammatory Bowel Diseases - Diagnosis, Prognosis and Treatment, held in Switzerland in April 1997, summarizes these changes and new developments, discusses their value and defines further new approaches. The topics include primary diagnosis, definition of different patient groups, special problems of these patients in daily life and recent therapeutic principles.

In recent years functional gastrointestinal disorders have attracted much interest. These disorders are extremely common. They are characterized by symptoms and the lack of structural lesions that can be identified with clinically available routine diagnostic tests. Several functional abnormalities are now believed to play a role in the development of the symptoms. This book summarizes the presentations at the International Falk Symposium No. 99 `Functional Dyspepsia and Irritable Bowel Syndrome: Concepts and Controversies' that took place on May 27-28, 1997. This symposium brought together clinical and basic researchers and clinicians to improve interdisciplinary communication. The meeting comprehensively covered basic and clinical aspects of these disorders, and it not only summarized the current knowledge, but also identified scientific questions that need to be addressed in the future.

This book, the proceedings of Falk Symposium 100, `Gut and the Liver', held in Freiburg, Germany, 29-31 May 1997, comprehensively reviews the physiological and pathophysiological interactions between the intestine and the liver as well as between intestinal and hepatic diseases. Apart from the basic aspects of the intestinal microflora and the immune system of the gut, gastrointestinal permeability and translocation as well as the contribution of the intestine and the intestinal bacteria to the metabolism of bile acids, amino acids and drugs are discussed. In addition, experimental as well as clinical data demonstrating the significance of gut-derived bacterial toxins for the development of liver diseases and the effect of liver diseases on gastrointestinal functions are discussed. The major aim of this book, therefore, is to highlight the interactions between gut and liver at the molecular level as well as in clinical disease.

Primary sclerosing cholangitis is a chronic disease of the intra and extrahepatic bile ducts leading to obstructions and dilatations followed by liver cirrhosis and in some cases cholangiocarcinoma. In 50% of cases primary sclerosing cholangitis is associated with inflammatory bowel disease. The cause of the disease is unknown and many questions concerning the pathogenesis still remain open. In recent years our knowledge of the natural course, the risk of cholangiocarcinoma and the possibility of medical, endoscopic and surgical treatment has increased. Ursodeoxycholic acid, endoscopic treatment and liver transplantation have become standard therapeutic procedures. This book is the proceedings of the Falk Workshop held on October 3, 1997, in Freiburg, Germany (Part II of the Liver Week Freiburg 1997), and covers the most important aspects of this disease.

This work, the proceedings of Falk Symposium No. 104 - organized in collaboration with the Society of Mucosal Immunology, and held in Saarbrucken, Germany, March 5-7 1998 - is centered around the immunological mechanisms of mucosal protection and their disturbances leading to intestinal inflammation and destruction. This is a rapidly expanding field involving knowledge of basic immunology and cell biology as well as clinical observations. The conference and this book summarize recent data in this field and suggest strategies for future research and clinical applications, and should be of interest to both basic scientists and clinicians.

Although cell turnover in normal adult liver is extremely low, hepatic tissue is notorious for its almost infinite capacity to regenerate in cases of viral, toxic or traumatic damage. Hepatocellular carcinoma is one of the most frequent malignancies worldwide and causes more than a million deaths per year. The mechanisms governing normal proliferation and malignant transformation of liver cells are of utmost interest for the understanding of regeneration and hepatocarcinogenesis and for the development of new therapeutic strategies. Therefore, the International Falk Workshop held in Halle, Germany, on January 29-30 1998, focused on the issues of normal and malignant liver cell growth. Knowledge in this area of research has expanded rapidly during recent years. This text of proceedings summarizes the latest advances both in basic science and clinical research. Stimulating discussion set the basis for the development of new strategies in diagnosis and treatment of hepatocellular carcinoma and for the manipulation of regeneration in cases of acute or chronic loss of functional liver tissue.

Containing papers from the Falk Symposium on "Innovative Concepts in Inflammatory Bowel Diseases", held in Rostock, Germany, from April 30 to May 2 1998, this volume contains papers on genetics, animal models, immunology, epithelial cells, endotoxin, diagnostic procedures, malignancy, medical therapies, and surgery, with suggestions concerning future research and clinical management of patients with inflammatory bowel diseases. Chronic inflammatory bowel diseases represent an important medical problem, since they have a devastating impact on the quality of life and require longstanding medical care. Many medical disciplines are involved in tackling the immensely complex studies on pathogenesis, clinical expression and treatment possibilities.

Ulcerative colitis and Crohn's disease remain a great therapeutic challenge to the medical community. In recent years knowledge about the pathogenesis of these diseases has progressed rapidly but the cause of the diseases remains completely unknown. It has become clear that dysregulation of the mucosal immune system is the basis for the chronic evolution of the diseases in a genetically susceptible population. Exciting new therapeutic approaches have been attempted in the last couple of years and cytokine and anti-cytokine treatments in particular seem very promising, especially in intractable disease. The format of the Falk Symposium 106 on `Advances in Inflammatory Bowel Diseases', held in Brussels, Belgium, June 18-20, 1998, was somewhat innovative as each session attempted to link the new insights into pathogenetic mechanisms with new therapeutic approaches, resulting in optimal information transfer. The classic therapeutic schemes were updated with a special focus on step-wise build-up of therapy.

Knowledge about the cell biology of the cholangiocytes and the function of the bile ducts has increased considerably. Their role in liver diseases is increasingly recognized. As a consequence, important progress has been made not only in the pathogenesis and pathophysiology but also in the diagnosis and treatment of biliary liver diseases. This book, the proceedings of the Falk Symposium 107 on "Diseases of the Liver and the Bile Ducts, New Aspects and Clinical Implications", held in Prague, Czech Republic, on 30 April - 2 May, 1998, brings together scientists and clinicians to highlight advances in molecular biology, physiology, diagnosis and therapy of diseases of the biliary system. World experts cover a broad spectrum of topics from genetic tests to endoscopy and from medical treatment to liver transplantation.

These proceedings of Falk Symposium 110 on `Intestinal Mucosa and its Diseases - Pathophysiology and Clinics' held at Titisee/Black Forest, Germany, 16-17 October 1998, comprehensively review salient clinical as well as scientific aspects - pending or settled - of the main intestinal diseases. In particular, chapters deal with infectious and neuroendocrine diarrhoeas, coeliac sprue, allergic enteropathy, intestinal lymphomas, colorectal carcinomas, and chronic inflammatory bowel diseases, in terms of clinical presentation as well as underlying mechanisms. This book therefore aims to bridge the gaps between basic science and clinics for the eventual treatment of patients afflicted with these diseases.

This volume contains the proceedings of the Falk Workshop on "Bile Acids in Hepatobiliary Disease", which took place at the Royal Society of Medicine (RSM) in London, UK, on 29-30 March 1999, and was held in association with the Section of Measurement in Medicine at the RSM. The main interest in bile acid therapy has been recently in cholestatic liver disease. The proceedings of the workshop not only discusses this, but moves on to examine its possible use in alcoholic liver disease, and moves back to re-examine its role in biliary disease. Leading world experts attempt to define its mechanism of action, and the current role of other non-surgical treatments in biliary disease. The physiology and pathogenesis of cholestatic and alcoholic liver disease and cholesterol gallstone disease is also examined.

Although the first description of patients with what we now call Crohn's disease or ulcerative colitis, was published well before 1900, both disorders seem to be diseases of the 20th century. At the very start of the 21st century, it therefore seems appropriate to look back and at the same time look forward, and to assess what knowledge has been gained during the last 100 years and in what direction research and thereby clinical practice will go in the future. This book, the proceedings of Falk Symposium No. 111 held in Freiburg, Germany, on June 19th and 20th, 1999, contains contributions from experienced senior scientists on the state of the art in pathophysiology, diagnosis and treatment, together with unpublished and new findings from young researchers. Basic scientists and clinicians are thereby involved in an exchange of information which will lead to new directions for future research and clinical management of inflammatory bowel diseases.

In the last decade, some outstanding progress has been made in the field of neurogastroenterology, a term which has been introduced to account for the crucial role of the enteric, autonomic and central nervous system in the regulation of gastrointestinal functions in health and disease. These proceedings of Falk Symposium No. 112 on Neurogastroenterology - From the Basics to the Clinics, held in Freiburg, Germany, on 21-22 June 1999, reviews and discusses the fast-growing knowledge in this field in order to initiate more interdiscliplinary discussions along with new research. Contributors include basic scientists, clinicians of various specialities, morphologists, physiologists, molecular biologists, embryologists, pharmacologists, surgeons, gastroenterologists and behavioural scientists interested in the central and the autonomic nervous system in relation to the gastrointestinal tract.

The gastrointestinal tract has a number of unique features. Its extensive surface is formed by a single layer of rapidly renewing cells, the intestinal epithelial cells. These cells are in contact with a number of other cell populations, including the largest part of the immune system, and with an excessive luminal antigen load, including vast numbers of bacteria. Furthermore two more organs, namely liver and pancreas, are part of the system. The rapid renewal of the epithelial layer, the interactions of different cell types, and the balance between cell proliferation and death, have been fascinating subjects of studies in recent years. Much has been learned, and cytokines have emerged as important mediators for all these interactions and homeostatic systems. This book, the proceedings of the Falk Symposium 113 on "Cytokines and Cell Homeostasis in the Gastrointestinal Tract", held in Regensburg, Germany, 16-18 September 1999, presents the papers from this forum for basic scientists and interested clinicians to exchange ideas, to discuss concepts and to plan further studies.

In 1992, the Falk Symposium No. 70 dealt with the topic "Immunology and Liver". At that time, basic mechanisms of immunology as well as immunopathogenetic mechanisms in viral and autoimmune liver diseases were discussed. Seven years later, the Falk Symposium No. 114, held in Basel, Switzerland, October 20-21 1999 (Part I of the Basel Liver Week 1999), focused on immunology in autoimmune liver diseases. In the first section of this text, basic mechanisms of autoimmunity are presented, including the relevance of superantigens and the role of apoptosis. A further topic is the latest developments concerning animal models for autoimmune diseases. Drug- and hepatitis-virus induced immune mediated liver diseases may serve as models for nonhepatic immune mediated disorders. DNA technology has increased our knowledge of the immunogenetic background of autoimmune liver diseases. Among the cholestatic immune mediated liver diseases, significant progress has been made concerning primary biliary cirrhosis, in particular regarding the identification of mitochondrial antigens and the characterization of the immune reactions directed at them.The involvement of infectious agents in PBC as well as the definition of overlap syndromes is a particular focus for basic and clinical research in this area. Concerning the therapy of autoimmune liver diseases, corticosteroids and azathioprin remain the state of the art for autoimmune hepatitis, while bile acids have become well established in treatment of primary biliary cirrhosis as well as primary sclerosing cholangitis. New drugs in the future will include topical steroids such as budesonide and new immunosuppressive agents like mofetil/mycophenolate.

Liver cirrhosis is a major clinical problem worldwide and is associated with significant morbidity and mortality from its complications, such as liver cell insufficiency with coagulopathy and hepatic encephalopathy, portal hypertension with ascites and gastrointestinal bleeding, hepatorenal syndrome, HCC development and otehrs. This volume, the proceedings of Falk Symposium 115 held in Basel, Switzerland, October 22-24, 1999 (Part II of the Basel Liver Week 1999; XI International Congress of Liver Diseases) covers our present knowledge of the aetiologies and early stages of liver cirrhosis development. Based on this information, strategies are discussed that are aimed at the prevention, early diagnosis and therapy of chronic liver diseases, thus preventing their progression to cirrhosis and its complications, including HCC development. The main topics mentioned above are complemented by three state-of-the-art chapters on modern aspects of medicine in general and hepatology in particular as well as their perspectives beyond the year 2000: "Molecular Medicine", "New Hepatitis Viruses" and "Genetic Liver Diseases: Diagnosis and Therapy".Introductory chapters focusing on the more basic aspects of the biology of live cells as well as on the mechanisms underlying fibrogenesis, cholestasis and inflammation will be followed by a detailed discussion of the clinically most important causes of liver cirrhosis worldwide: hepatitis viruses B, C and D; toxins (alcohol, drugs and others) as well as metabolic liver diseases (haemochromatosis, Wilson disease, alpha-1-antitrypsin deficiency, porphyria cutanea tarda and protoporhyria). This book, therefore, will interest clinically oriented basic scientists as well as those in clinical practice, givng an update on many aspects of modern hepatology and its perspectives in the 21st century.

Diagnostic and interventional endoscopy has made rapid progress in the last few years of the 20th century. Several methods are still under development and need to be properly evaluated. Bile duct diseases may have a negative impact on the liver, so early diagnosis and minimal invasive treatment options are important. Liver transplantation is now established for the treatment of liver failure. Hepatic surgery may lead to problems in the bile ducts which can be treated by endoscopic intervention. A broad spectrum of indications for interventional endoscopy in hepatology exists. This book, the proceedings of Falk Symposium No. 116, held in Basel, Switzerland, October 25 1999 (Part III of the Basel Liver Week 1999), describes the state of the art and new developments in endoscopy for these treatments, and contains chapters by well-known experts from all over the world.

Chronic hepatitis has been the focus of intense scientific research for decades and considerable progress and new insights into its pathogenesis and resulting therapeutic strategies have been made. Replication of hepatitis B and C viruses and details of its life cycle in the host have been well characterized. Immunology in general and immunopathology of the liver in viral and autoimmune hepatitis have shown more specific mechanisms of host defence and new models of autoimmune aggression have been developed. The role of apoptosis in liver damage is now well appreciated and has been analyzed precisely. Essential steps of fibrogenesis as a consequence of chronic liver damage are now better understood and new strategies for its prevention have evolved. Chronic hepatitis is the leading cause of liver cell carcinoma, the molecular basis of which has been more clearly elucidated. This increasing knowledge should provide a sound basis for more effective therapy in chronic hepatitis and its life-threatening consequences.This book, the proceedings of the Falk Workshop on Chronic Hepatitis, held in Cologne, Germany, on January 27-28, 2000, brings together experts from different fields of research such as virology, immunology, pathology, cell and molecular biology, as well as clinical medicine, and discusses in depth the novel findings in basic and clinical research.

The beginning of a new millennium is an ideal opportunity to look back, to contemplate the present and to envisage what the future might have to offer. This seems particularly appropriate for the rapidly developing field of hepatology. Therefore, the aim of the Falk Symposium 117, Hepatology 2000, held in Munich on 4-6 May 2000, was to offer state-of-the-art information on the most important aspects of hepatology and to discuss the challenges of the future. The presentations were given by experts in their respective areas, providing an update and at the same time incorporating the most recent developments. These proceedings, a tour d'horizon of hepatology at the highest clinical and scientific level, is dedicated to Gustav Paumgartner who has retired from his duties as chairman of the Department of Medicine II at the University of Munich- Großhadern. The scientific organisers take this opportunity to thank their academic teacher and to honour his lifelong engagement and achievements in hepatology. This book is cordially dedicated to him.