Cholecystokinin (CCK) and gastrin stimulate growth of rodent pancreas in vivo. However, it remains unclear whether these growth effects are mediated specifically by CCK-A receptors, CCK-B receptors, or both. To clarify this issue, the present study examined the effect of highly selective and biologically active CCK agonists on pancreatic growth.

Techniques for vascularized pancreas transplantation are relatively standardized, whereas those for human islet isolation and transplantation are rapidly changing and evolving. The commonest method for transplanting the vascularized pancreas is to use the entire pancreas together with a segment of donor duodenum, and to anastomose this to the recipient bladder. This technique offers the advantages of technical ease, the maximum beta-cell mass is transplanted and graft function can be monitored by measuring urinary amylase levels. Human islet isolation requires that the pancreas is dissociated, the islets purified and then transplanted to a well-vascularized location. The pancreas is dispersed by a combination of the intraductal injection of collagenase and gentle mechanical agitation, and the islets separated from contaminating exocrine tissue by density-gradient centrifugation. Once purified, the islets can be placed into tissue culture or cryopreserved. The commonest site for human islet transplantation is intraportal injection so that the islets are embolized throughout the liver. Alternatives include transplantation to the renal subcapsular space or the spleen.

During the last decade orthotopic liver transplantation has become virtually a routine procedure and most centres are reporting, in elective cases, survival rates at 1 year in excess of 90%. As experience with liver transplantation has grown, attention has focused more on refining the indications for transplantation and determining the optimal time for the procedure. In patients with fulminant hepatic failure, it may still be difficult to select those patients who require liver replacement early enough in their illness so that a suitable organ can be found and the procedure carried out before the onset of irreversible complications. Alternatives to orthotopic liver transplantation, including liver support, heterotopic transplantation, partial orthotopic liver transplantation and xenografting, are being assessed. Progress too has been made in improving indications in patients undergoing transplantation for viral hepatitis and alcoholic liver disease. Nonetheless, liver replacement remains a poor substitute for prevention of end-stage liver disease. Even with advances made in immunosuppression, there are long-term sequelae as a consequence of liver transplantation, and now more recently attention is being paid to reducing the toll of immunosuppressive drugs.

The standard procedure for orthotopic liver transplantation remains transplantation of the whole organ together with resection of the vena cava and the use of venovenous bypass. In cases of severe mismatch of the donor and recipient vena cava, the piggyback technique, if necessary with vena cava plasty, is preferable. Furthermore, in all cases where venovenous bypass cannot be performed, the piggyback or other technique preserving the vena cava should be performed. In paediatric patients, reduced/size liver transplantation may be indicated because of the shortage of small livers. In the hands of experienced surgeons, the results of reduced-size liver transplantation in paediatric patients are similar to those of whole organ transplantation. Further innovative procedures to overcome the problem of organ shortage include split-liver and living related transplantation in children. Distinct advantages of living related transplantation can be seen in a well-functioning graft, lack of preservation injury, elective operation and optimal graft-size matching. The immunological advantage that has been claimed could not be demonstrated so far, and will need to be examined in the long-term follow-up. However, there remains a distinct disadvantage for living related transplantation with regard to the surgical technique. Preoperative portal venous thrombosis should be carefully assessed, but is not a contraindication to liver transplantation if the confluence of the superior mesenteric vein and splenic vein is patent. Arterial reconstruction at the confluence of two arteries (hepatic and gastroduodenal or splenic artery) seems to be preferable to an end-to-end anastomosis because of improved inflow into the graft and a reduced risk of arterial stenosis and thrombosis. Where the common hepatic arteries are small, with reduced or reversed flow, and in patients with coeliac trunk stenosis, we recommend a direct approach to the suprarenal or infrarenal aorta. Bile duct anastomosis may preferably be performed with a side-to-side technique, to reduce early and late biliary complications.

The transplantation of gastrointestinal organs has relied on cadaver donors for its successful development. The fact that success has been achieved is largely due to the certainty with which brain death can be diagnosed, and the acceptance of these criteria as signifying actual death by doctors, in particular, intensivists. If continuing goodwill leads to further co-operative effort, cadaveric liver, pancreas and eventually, small bowel transplants, should become more frequent. At present the numbers of recipients requiring these operations are considerably less than those in need of kidneys. There are grounds for believing therefore that the pressure to subvert good ethical standards in acquiring these organs (that pressure imposed by long waiting lists and a high death rate on those waiting lists) should be avoidable. The solution to the problem of deficits in cadaveric liver and pancreatic grafts will be achieved only by better education of nurses and doctors, professionalization and expansion of co-ordinator organizations, legal reform, and cultural change. Only by such progress, achieved at medical, governmental, and societal levels can we avoid the insidious tendency to commercialism which we have witnessed with disquiet in renal transplantation.

Currently, the standard immunosuppressive regimen in organ transplantation is centred around cyclosporin. However, despite the use of this drug, rejection is not uncommon and it is associated with significant side-effects. Novel drugs and regimens have been developed to combat allograft rejection. Although FK506 has a similar mode of action and toxicity profile to cyclosporin, results, particularly in the rescue situation, have been encouraging. Sodium brequinar and rapamycin inhibit lymphocyte proliferation and may be most effective when used in combination with cyclosporin. Mycophenolate mofetil has been used in the treatment of psoriasis for many years; it is safe and will perhaps be useful in second-line therapy in patients unable to tolerate cyclosporin. The specific drugs highlighted in this chapter, although successful to differing degrees in preventing immunological rejection of allografts, have wide-ranging toxic effects on other organs in the body. Future use of these drugs is likely to utilize lower doses, supplemented by specific monoclonal antibody therapy, which can target diverse arms of the immune response. Large clinical trials using monoclonal antibodies against the T-cell receptor, the IL-2 receptor, CD4 T cells and specific adhesion molecules such as ICAM-1 are eagerly awaited. The number of new drugs and their mechanism of action, together with the widening spectrum of monoclonal antibodies available, will ensure that the next decade will be an exciting and hopefully profitable period in transplantation medicine. It is hoped that the introduction and assessment of these new agents will be rather more systematic and objective than that of their antecedents.

This chapter presents some methods for the assessment of transplant benefits, using the example of liver transplantation. An independent assessment of the benefits of medical technology is especially important for evaluation of the balance between the costs and benefits involved. To enable comparison with other health-care facilities, benefits are defined in terms of a combination of life-years gained and quality of life. The number of life-years gained can be calculated by comparing the survival expected with and without transplantation. Survival with transplantation is estimated on the basis of observed survival, acknowledging that the probability of survival may have changed over time, owing to changes in therapy and selection criteria. To estimate survival without transplantation, several techniques are available. Prognostic models, correcting for stage of disease, are often used. Pitfalls in the use of these models are discussed. The number of life-years gained can be corrected for quality of life by weighing survival with and without transplantation with an index representing quality of life. A method for the calculation of such an index is given. Finally, some cost estimates are presented and the results are discussed.

Epidemiological and experimental evidence have shown that nicotine has harmful effects on the gastric mucosa. The mechanisms by which cigarette smoking or nicotine adversely affect the gastric mucosa have not been fully elucidated. In this report, clinical and experimental data are reviewed. The effects of nicotine from smoking on gastric aggressive or defensive factors are discussed. Nicotine potentiates gastric aggressive factors and attenuates defensive factors; it also increases acid and pepsin secretions, gastric motility, duodenogastric reflux of bile salts, the risk of Helicobacter pylori infection, levels of free radicals, and platelet-activating factor, endothelin generation, and vasopressin secretion. Additionally, nicotine impairs the therapeutic effect of H2-receptor antagonists and decreases prostaglandin synthesis, gastric mucosal blood flow, mucus secretion, and epidermal growth factor secretion. Although many of the studies provide conflicting results, the bulk of the evidence supports the hypothesis that nicotine is harmful to the gastric mucosa.

There is a great deal of evidence for genetic predisposition to alcoholism; considerably less is known regarding predisposition to alcoholic liver disease. The specific genes involved in either disorder are not well understood, although the enzymes of alcohol metabolism appear to play some role. It will be interesting to determine whether genetic factors that alter the expression of these enzymes, in addition to altering the kinetics of the enzymes, could modify responses to drinking. Work in the next few years will include determination of which responses to alcohol are indeed genetically influenced in twin studies, testing additional candidate genes for alcohol-related traits in populations and families, as well as the application of genomic mapping methodologies to alcoholic pedigrees. The latter strategy will be integrated into the larger number of studies that will grow from the Human Genome Project. Animal studies with selectively bred lines of rodents that differ in voluntary alcohol consumption will lead the way to define the neuronal and behavioral substrates responsible for differences in alcohol-drinking behavior. The use of the quantitative trait locus (QTL) mapping approach in F2 intercross between two inbred strains of rodents with opposite alcohol-response characteristics and in recombinant inbred strains derived from F2 intercross already has and will continue to help identify chromosomal locations of genes relevant to voluntary alcohol consumption. Perhaps in the future selective breeding of rodents and QTL mapping strategies can also be used to determine the biology and genetics of alcohol-induced liver injury.

When normal people ingest 90 mEq/day of K+ in their diet, they absorb about 90% of intake (81 mEq) and excrete an equivalent amount of K+ in the urine. Normal fecal K+ excretion averages about 9 mEq/day. The vast majority of intestinal K+ absorption occurs in the small intestine; the contribution of the normal colon to net K+ absorption and secretion is trivial. K+ is absorbed or secreted mainly by passive mechanisms; the rectum and perhaps the sigmoid colon have the capacity to actively secrete K+, but the quantitative and physiological significance of this active secretion is uncertain. Hyperaldosteronism increases fecal K+ excretion by about 3 mEq/day in people with otherwise normal intestinal tracts. Cation exchange resin by mouth can increase fecal K+ excretion to 40 mEq/day. The absorptive mechanisms of K+ are not disturbed by diarrhea per se, but fecal K+ losses are increased in diarrheal diseases by unabsorbed anions (which obligate K+), by electrochemical gradients secondary to active chloride secretion, and probably by secondary hyperaldosteronism. In diarrhea, total body K+ can be reduced by two mechanisms: loss of muscle mass because of malnutrition and reduced net absorption of K+; only the latter causes hypokalemia. Balance studies in patients with diarrhea are exceedingly rare, but available data emphasize an important role for dietary K+ intake, renal K+ excretion, and fecal K+ losses in determining whether or not a patient develops hypokalemia. The paradoxical negative K+ balance induced by ureterosigmoid anastomosis is described. The concept that fecal K+ excretion is markedly elevated in patients with uremia as an intestinal adaptation to prevent hyperkalemia is analyzed; we conclude that the data do not convincingly show the existence of a major intestinal adaptive response to chronic renal failure.

Although physiological stimuli in the healthy gastrointestinal tract are generally not associated with conscious perception, chronic abdominal discomfort and pain are the most common symptoms resulting in patient visits with gastroenterologists. Symptoms may be associated with inflammatory conditions of the gut or occur in the form of so-called functional disorders. The majority of patients with functional disorders appear to primarily have inappropriate perception of physiological events and altered reflex responses in different gut regions. Recent breakthroughs in the neurophysiology of somatic and visceral sensation are providing a series of plausible mechanisms to explain the development of chronic hyperalgesia within the human gastrointestinal tract. A central concept to all these mechanisms is the development of hyperexcitability of neurons in the dorsal horn, which can develop either in response to peripheral tissue irritation or in response to descending influences originating in the brainstem. Taking clinical characteristics and the concept of central hyperexcitability into account, a model is proposed by which abdominal pain from chronic inflammatory conditions of the gut and functional bowel disorders such as noncardiac chest pain, nonulcer dyspepsia, and irritable bowel syndrome could develop by multiple mechanisms either alone or in combination.

The genetic background of autoimmune diseases becomes more and more evident. Immunogenetics comprises the analysis of genes and their products located at the region 6p21 on the short arm of chromosome 6, which is also known as the major histocompatibility complex (MHC). MHC class I and II genes are highly polymorphic. The complement genes C2, C4A, C4B, and BF, which are also polymorphic, became known as MHC class III genes. In autoimmune hepatitis type 1, there is a dual association for white persons with either HLA-A1-B8-DR3 or HLA-DR4. In patients from Japan, autoimmune hepatitis type 1 is predominantly associated with HLA-DR4. This dual association is confirmed at the DNA level. Whereas only limited data are available for autoimmune hepatitis type 2, the association of primary biliary cirrhosis with HLA-DR8 is based on several studies. Primary sclerosing cholangitis is associated with HLA-B8-DR3 and -DR52a. This association was confirmed at the DNA level because of a significant increase of the DRB3*0101 allele. For DRB3*0101-negative individuals, a second association with DRB5*0101 (= DR2) was described. Further analysis of the hypervariable region of the HLA class II molecule indicates that lysine at position 71 is crucial for autoimmune hepatitis type 1 in white persons, whereas position 13 is important for people from Japan. In contrast, leucine at position 35 is important for patients with primary biliary cirrhosis, whereas leucine at position 38 is an important risk factor for primary sclerosing cholangitis. The MHC class III allele C4A-QO is significantly increased in autoimmune hepatitis type 1 and 2 and in primary biliary cirrhosis. Advances in immunogenetics will certainly increase our knowledge of the etiology and pathogenesis of immune-mediated liver diseases, which hopefully will lead to more specific therapeutic interventions.

After decades of therapeutic stasis, treatment advances are occurring in inflammatory bowel disease. Recognition that mesalazine was the active moiety of sulphasalazine has led to a number of new methods of delivering mesalazine without sulphapyridine, with improved toxicity ratios. Current attempts to deliver topical steroids directly to the large bowel have yet to be established as therapeutically effective. Immunosuppressive treatment has been used for many years but recent evidence has firmly established its value and cyclosporin has recently been added to the therapeutic armamentarium. Increasing understanding of the basic processes of inflammation has yielded targets for anti-inflammatory treatments aimed both at the processes of immune activation and of attraction by chemotaxis of neutrophils from the circulation to the lamina propria. Some of these novel treatments, which will be assessed in forthcoming years, involve large molecular weight bioengineered peptides and antibodies that are likely to be expensive and difficult to administer. Other treatment, e.g. 5-lipoxygenase or thromboxane synthesis inhibitors or platelet-activating factor antagonists, are conventional lower molecular weight compounds that are easier to produce and are orally active. It is predicted that 5-lipoxygenase inhibitors will be the next therapeutic advance in inflammatory bowel disease. Such a prediction may founder if blanket suppression of multiple inflammatory mechanisms, rather than targeted actions, is required in inflammation.