Insulinlike growth factors (IGFs) express anabolic and mitogenic activity on wide variety of cells. Besides endocrine effects, IGFs have major autocrine and paracrine effects on many cellular functions. Two factors that significantly affect the extent of cellular response to IGFs include the membrane receptors for IGFs and the soluble binding proteins (BPs), which modulate the action of IGFs at the receptor level. IGFs, IGF receptors, and IGFs and their BPs (IGF-BPs) thus constitute three components of the IGF system. A role of IGFs in the transformation and proliferation of cancer cells has become increasingly evident in the past few years. Studies from several laboratories show that all three components of the IGF system may play an important role in the proliferation of colon cancers. It was recently shown that the relative expression of IGFs and IGF/BPs may critically control the metastatic potential of colon cancers. The purpose of this article is to summarize our current knowledge of the IGF system and to present support for a significant role of IGFs in the initiation and growth of colon cancers. The expression and structural aspects of IGFs, their receptors, and BPs are outlined first, followed by a discussion of the role of IGFs in gastrointestinal functions and in colon cancers.

The overrepresentation of particular HLA alleles in patients with celiac disease was first noted two decades ago. Several lines of evidence obtained during the last years strongly suggest that a particular HLA-DQ heterodimer, encoded by the DQA1*0501 and DQB1*0201 genes in cis or trans configuration, confers the primary disease susceptibility. This paper reviews the evidence behind this concept and discusses how this particular DQ molecule may be involved in the pathogenesis.

The role of liver transplantation as a treatment for end-stage liver disease occurring in alcoholic patients is controversial. Earlier predictions that survival of alcoholic patients after liver transplantation was worse than that of non-alcoholic liver graft recipients, or that few alcoholic patients with serious liver disease could meet stringent selection criteria, have proved false. As a result, in many liver transplant programmes, alcoholic liver disease constitutes one of the most common diagnoses among patients proceeding to transplantation. Survival of alcoholic patients after transplantation is similar to that in non-alcoholic patients, i.e. up to 80% or more alive at 1 year. A multidisciplinary selection process has been introduced which includes careful psychiatric assessment to try to identify those patients most likely to maintain long-term abstinence after transplantation. Using this method, approximately 45% of alcoholic patients referred for transplantation have been selected for surgery. Furthermore, the survival rate of alcoholic patients not selected for transplantation because they were considered a poor prognostic risk for sobriety was significantly less than that of alcoholic patients undergoing liver transplantation. The ethical foundations for this multidisciplinary approach are explained in this chapter. Good data on recidivism after transplantation are few. In many programmes, including ours, instances of recidivism, defined as a relapse to a pathologic pattern of alcohol use, are uncommon and occur in 10% or less of alcoholic patients selected for liver transplantation, at least in the first 3 postoperative years. This figure underestimates the incidence of consumption of small amounts of alcohol. The data are limited also by the relatively short period of follow-up in most studies published to date. Whether recidivism will become more common as more patients are followed beyond 3 years remains to be seen.

The most effective treatment for alcoholic liver disease is abstinence from alcohol and it is the only treatment for patients with alcoholic fatty liver. Although many empirical therapeutic agents have been studied in the short-term and long-term treatment of alcoholic hepatitis, results have been mainly inconclusive. To date, only corticosteroids have proved to decrease the short-term mortality rate of patients with severe forms of acute alcoholic hepatitis. Corticosteroids are not beneficial to the majority of patients with mild or moderate forms of acute alcoholic hepatitis; such patients improve with abstinence from alcohol and general supportive measures and do not need a specific short-term treatment. Most long-term trials have only showed that most patients with alcoholic liver disease were neither abstinent nor compliant, and that long-term survival was strongly correlated to abstinence from alcohol. In one study, propylthiouracil decreased the long-term mortality rate of compliant patients with severe alcoholic liver disease who reduced their alcohol intake; however, further clinical trials are needed before propylthiouracil can be recommended. In another study, colchicine decreased the long-term mortality rate of cirrhotic patients, 45% of whom had alcoholic cirrhosis. Results were highly significant, and the need for further clinical trials of colchicine in the long-term treatment of alcoholic and non-alcoholic cirrhosis is imperative. Enteral nutrition should also be studied in severely malnourished cirrhotic patients, since it was shown to decrease the short-term mortality rate of such patients in a recent study.

Many of the extrahepatic manifestations of alcoholic liver disease are not specific and can be seen in other forms of cirrhosis and with alcohol abuse. Features that are more common or more florid in patients with alcoholic liver disease have been discussed in this chapter. Alcoholic liver disease results in changes in many systems in the body and it is important that these are recognized and treated where appropriate.

In heavy drinkers with clinical evidence of liver disease, routine investigations should exclude the possibility of other chronic liver diseases of non-alcoholic aetiology requiring specific therapy--these include chronic viral hepatitis, autoimmune diseases of the liver, Wilson's disease and genetic haemochromatosis. If abnormalities in liver biochemistry persist despite abstinence, or if the diagnosis of alcoholic liver disease is in doubt, a liver biopsy should be carried out. Studies evaluating the role of liver biopsy in alcoholic liver disease suggest that without histological confirmation the diagnosis will be inaccurate in 10-20% of patients. Serum biochemistry and the currently available imaging modalities have severe limitations in determining the relative contributions of fatty liver, alcoholic hepatitis and cirrhosis to the overall picture in alcoholic liver disease. Histological examination is therefore of additional value in determining the prognosis, which is worst in patients with a combination of alcoholic hepatitis and cirrhosis. There are a number of indices available, based on clinical and laboratory information, for evaluating the short-term prognosis, but these can only be used with accuracy if the histological pattern of damage has initially been evaluated.

The severity and range of histological liver lesions caused by alcohol abuse varies considerably; these lesions are not specific for alcoholic damage, and diagnosis of alcoholic liver disease depends on obtaining an adequate history of prolonged alcohol abuse and on excluding other known causes of liver disease. The clinical features of alcoholic liver disease vary greatly and they have been classified into various syndromes. However, the syndromes overlap, the histological features underlying them also overlap and they represent part of a wide clinical spectrum. Alcoholic fatty liver occurs more in younger patients and has a much better prognosis than alcoholic hepatitis or alcoholic cirrhosis, but the previous view that alcoholic fatty liver is an innocuous lesion can no longer be maintained. Alcoholic hepatitis and alcoholic cirrhosis cause more severe syndromes and more florid clinical features, and mortality is related to features of liver failure and variceal bleeding. Abstinence is the only means of ensuring the best possible survival.

Until the 1960s, liver disease of the alcoholic patient was attributed exclusively to dietary deficiencies. Since then, however, our understanding of the impact of alcoholism on nutritional status has undergone a progressive evolution. Alcohol, because of its high energy content, was at first perceived to act exclusively as 'empty calories' displacing other nutrients in the diet, and causing primary malnutrition through decreased intake of essential nutrients. With improvement in the overall nutrition of the population, the role of primary malnutrition waned and secondary malnutrition was emphasized as a result of a better understanding of maldigestion and malabsorption caused by chronic alcohol consumption and various diseases associated with chronic alcoholism. At the same time, the concept of the direct toxicity of alcohol came to the forefront as an explanation for the widespread cellular injury. Some of the hepatotoxicity was found to result from the metabolic disturbances associated with the oxidation of ethanol via the liver alcohol dehydrogenase (ADH) pathway and the redox changes produced by the generated NADH, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone contributes to the exacerbation of the ethanol-induced lesions in zone 3. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450IIE1 (CYP2E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by CYP2E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, 'over the counter' analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation and decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes glutathione depletion, free-radical mediated toxicity and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis: both in vivo and in vitro (in cultured myofibroblasts and lipocytes), ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding of the pathogenesis of alcoholic liver disease may eventually improve therapy with drugs and nutrients.

Although mortality from alcoholic liver disease has declined in some Western countries in recent years, elsewhere it is increasing and overall it remains a major health problem. Deaths are predominantly seen in patients with alcoholic hepatitis or cirrhosis, and when they occur in patients with fatty liver are usually unrelated to liver disease. Progression to cirrhosis is correlated with the severity of fatty liver and particularly with the presence of alcoholic hepatitis. Mortality from cirrhosis is strongly correlated with per capita alcohol consumption. The decline in cirrhosis mortality rates seen recently is related in part to decreases in per capita consumption, but probably also to the growth of self-help organizations which facilitate abstinence from alcohol. Recent studies suggest there is not an invariable dose-response relationship between alcohol intake and the severity of liver disease and that alcohol has a permissive effect which allows other aetiological factors to operate. Factors that influence susceptibility to alcoholic liver disease include gender (women develop alcoholic cirrhosis more readily than men), concomitant hepatitis C infection and possibly hepatitis B infection. It is uncertain whether HLA status or immune mechanisms are implicated. The systematic use of screening tests for hazardous consumption combined with early intervention therapies offers a good prospect of reducing morbidity and mortality from alcoholic liver disease.

Over 60 studies have addressed the hypothesis that the risk of colorectal cancer is increased following cholecystectomy; these studies have yielded inconsistent findings. The aim of the present study was to quantitatively summarize the results from the collective studies.

It is not widely appreciated that nonsteroidal anti-inflammatory drugs (NSAIDs) may cause damage distal to the duodenum. We reviewed the adverse effects of NSAIDs on the large and small intestine, the clinical implications and pathogenesis.

Considerable progress has been made in the last decade in developing vaccines against the enteric infections of greatest public health importance. A quadrivalent rotavirus vaccine consisting of rhesus rotavirus vaccine (which contains serotype 3 neutralization antigen) and three reassortant viruses (rhesus virus expressing neutralization antigens of serotypes 1, 2 or 4) is undergoing placebo-controlled field trials of efficacy in the USA and in two developing countries. Two new vaccines against typhoid fever (oral Ty21a and parenteral Vi polysaccharide) have been licensed in many countries. Even newer generations of typhoid vaccines are undergoing clinical testing, including new attenuated S. typhi strains and Vi polysaccharide-carrier protein conjugate vaccines. Two inactivated oral cholera vaccines, consisting of inactivated V. cholerae O1 bacteria alone or in combination with purified B subunit of cholera toxin, each conferred 50-53% protection over 3 years in a field trial in Bangladesh where subjects were immunized with a three-dose regimen. In extensive clinical trials in adults and children in less-developed countries, an engineered live oral cholera vaccine, strain CVD 103-HgR, has been shown to be well tolerated and highly immunogenic following administration of just a single oral dose; a large-scale field trial in 70,000 subjects is underway to investigate the efficacy of this vaccine. Several candidate vaccines against Shigella and enterotoxigenic Escherichia coli are in clinical trials. Accumulating knowledge on pathogenesis of enteric infections and advances in mucosal and cellular immunology, coupled with the application of modern biotechnology, have resulted in a plethora of vaccine candidates. It is expected that in future years efforts will be directed to construct vaccines against other enteric pathogens.