The present strategies for the management of peptic ulceration are well tolerated and clinically effective. Histamine H2-receptor antagonists can be used for mild to moderate disease, and proton pump inhibitors are of particular benefit for patients with severe peptic ulceration and the Zollinger-Ellison syndrome. However, none of these treatments provides protection against recurrent ulceration, except when taken as long-term continuous treatment. Long-term exposure to pharmacological agents raises problems of safety, particularly relating to a lack of intragastric acidity. In addition, the accelerated development of atrophic gastritis in patients receiving omeprazole requires investigation and assessment. It is unlikely that there will be any major development in the area of control of gastric acid secretion, except perhaps the introduction of specific immunization against gastrin. However, the clinical benefit of this strategy awaits assessment. The main area for development must be the introduction of convenient and effective regimens for the eradication of Helicobacter pylori infection. Existing regimens are either simpler and relatively ineffective, or too complicated for widespread application. Bearing in mind the long gestation period of any new drug, it seems likely that the only innovative drug that will be introduced for the management of peptic ulceration before the millennium will be ranitidine bismuth citrate, an antisecretory anti-H. pylori drug that will usually be used in combination with an antibiotic.

This chapter reviews the therapeutic use of octreotide in a variety of pancreatic disorders, including acute pancreatitis, in the prevention of postoperative and post-ERCP pancreatitis, in the control of postoperative pancreatic fistulae, and in chronic pancreatitis for the control of pain and of pseudocysts and ascites. The review also discusses the use of octreotide in intestinal disorders of motility, gastrointestinal bleeding, intestinal fistulae and refractory diarrhoea, including the diarrhoeas of AIDS, diabetes, short gut, chemotherapy, ileostomy and gastric surgery. The use of octreotide in neuroendocrine tumours, both for therapy and diagnostic imaging, is reviewed briefly. The paucity of adequately controlled studies in many of these situations is indicated and the potential usefulness of octreotide estimated.

A greater understanding of the various serotonin receptor subtypes has led to a clearer appreciation of the role of serotonin in gastrointestinal motility, sensation and secretion. Serotonin is definitely involved in the aetiopathogenesis of cisplatin-induced emesis and carcinoid diarrhoea. The application of serotonergic drugs in clinical therapeutics for gut disturbances is presently dominated by the use of 5-HT3 antagonists for acute chemotherapy-induced nausea and vomiting, and the use of substituted benzamides which are 5-HT4 agonists stimulating gut motor function through 5-HT4 neuronal receptors. The best-studied 5-HT4 agonist is cisapride, which has been shown to stimulate motility at several levels of the gut. Cisapride is approved for healing and maintenance treatment of reflux oesophagitis and is used in several countries for the alleviation of symptoms consistent with regional stasis, from dyspepsia to constipation. Carcinoid diarrhoea is a prototypic disease associated with deranged serotonin metabolism, and a rationale for using 5-HT3 or 5-HT4 antagonists is based on the recent appreciation of the important role of impaired gut motor function in carcinoid diarrhoea. In the future, greater understanding of the serotonin receptor subtypes and their role in gut disorders may lead to novel approaches to alleviate increased visceral perception of functional gastrointestinal disorders, to correct changes in colonic capacitance, or to alter gastrointestinal motility that contributes to diarrhoea or constipation. However, at the present time, it must be stressed that these uses are still at an experimental stage and that careful validation and proper controlled studies are still required.

There is currently a great deal of effort being aimed at achieving effective delivery of novel therapeutic drugs, such as peptides, by the oral route. Opportunities have been identified which could lead to more convenient delivery systems for this class of drug. It is likely that a polypeptide given unprotected into the gastrointestinal environment will be degraded significantly. However, it is well known that small quantities of dietary proteins can be absorbed, even though these may have little or no physiological effect. It is felt that the colon may provide an advantageous absorption site for peptides. As a consequence there has been considerable interest, not only in the development of colonic delivery systems, but also in the establishment of strategies designed to maximize peptide absorption from the colon. Traditionally, vaccine research has been concerned with producing systemic immunity by parenteral immunization. However, the gradual acceptance of the importance of IgA in protecting mucosal surfaces against infection from numerous pathogenic organisms has led to an increased interest in oral immunization. Because of the existence of the CMIS, oral immunization induces secretory immunity in both the genital and respiratory tracts. Therefore, oral immunization offers the possibility for development of easily administered vaccines that will be effective in prevention against important respiratory and genital tract infections. The recent advances in recombinant DNA technology and the development of antigen delivery systems have given rise to optimism that several new and improved oral vaccines may be available by the next millennium.

Recent advances have been made in the treatment of chronic viral hepatitis, mainly with recombinant interferon (IFN) alpha. However, the present treatment of chronic viral hepatitis is not entirely satisfactory because the efficacy is inconstant and/or incomplete. In chronic hepatitis B IFN-alpha induces a sustained interruption of hepatitis B virus (HBV) replication, with a HBeAg to anti-HBe seroconversion in about 30% of patients. Patients most likely to respond are those with no immunosuppression, HBV infection acquired during adulthood or active liver disease with low HBV replication. Responders usually show a significant decrease in serum HBV DNA levels during the first 2 months of therapy, followed by a significant increase in the level of aminotransferases. New nucleoside analogues might be useful in combination with IFN-alpha in the treatment of those who do not respond to IFN therapy. In chronic hepatitis B-D, the rate of sustained response to IFN-alpha therapy is low. To be effective, IFN-alpha must be used at a high dosage (9-10 mega units) with a long duration (1 year). In chronic hepatitis C, IFN-alpha at a dosage of 3 mega units over 6 months, induces a sustained response in about 20% of patients. A higher dosage of IFN (5-10 mega units) and a longer duration of treatment increases the rate of sustained response but is associated with poor tolerance. Non-responders to a first course of IFN do not respond to a second course of treatment. In patients who respond but relapse after treatment, the rate of sustained response after a second course of IFN needs to be assessed. Ribavirin, which has a significant antiviral effect on hepatitis C virus, might be useful in combination with IFN-alpha. At the dosage (3-6 mega units) usually used, IFN-alpha is relatively well tolerated. In about 10% of the patients therapy is interrupted, mainly because of severe fatigue, thyroid dysfunction or depression.

Targeted delivery of 5-aminosalicylic acid to the small intestine and colon by controlled-release or azo-bonded compounds potentially offers treatment for ileal Crohn's disease as well as ulcerative colitis. The pharmacokinetics of sulphasalazine and aminosalicylate derivatives have been discussed and potential modes of action reviewed. These include actions on epithelial cell-surface receptors, cellular events and barrier function. Evidence for an influence of salicylates on circulating and tissue inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides, eicosanoids, cytokines and reactive oxygen metabolites. The precise mechanism remains unknown, but a pluripotential mode of action is an advantage when influencing the network of events that constitutes chronic inflammation. Controlled clinical trials of salicylates in ulcerative colitis and Crohn's disease have been reviewed. Their main role remains as maintenance therapy for ulcerative colitis, but relatively high doses of controlled-release preparations benefit patients with ileal Crohn's disease, following resection, or those who have recently relapsed. Finally, issues of clinical relevance have been addressed, including the choice of salicylate and safety, indications for initiating therapy, dose and duration of treatment, role in managing refractory colitis and future developments.

Ca2+ is a critical second messenger in virtually all cell types, including the various epithelial cell types within the digestive system. When measured in cell populations, Ca2+ signals usually appear as a single transient or prolonged elevation. In individual epithelial cells, signaling patterns often vary from cell to cell and may contain more complex features such as Ca2+ oscillations. Subcellular Ca2+ signals show a further level of complexity, such as Ca2+ waves, and may relate to the polarized structure and function of epithelial cells. The approaches to detect cytosolic Ca2+ signals, the patterns and mechanisms of Ca2+ signaling, and the role of such signals in regulating the function of polarized epithelium within the gastrointestinal tract, pancreas, and liver are reviewed in this report.

Approximately 50% of patients with functional dyspepsia have Helicobacter pylori infection; it remains controversial whether this infection causes chronic symptoms, but rigorously conducted therapeutic trials should establish whether H. pylori plays a role in functional dyspepsia. The aim here was to determine whether the trials published over the past 10 years were methodologically adequate to establish a role for this infection in functional dyspepsia.

This article reviews current concepts on the pathogenesis and treatment of alcoholic liver disease. It has been known that the hepatotoxicity of ethanol results from alcohol dehydrogenase-mediated excessive generation of hepatic nicotinamide adenine dinucleotide, reduced form, and acetaldehyde. It is now recognized that acetaldehyde is also produced by an accessory (but inducible) microsomal pathway that additionally generates oxygen radicals and activates many xenobiotics to toxic metabolites, thereby explaining the increased vulnerability of heavy drinkers to industrial solvents, anesthetics, commonly used drugs, over-the-counter medications, and carcinogens. The contribution of gastric alcohol dehydrogenase to the first-pass metabolism of ethanol and alcohol-drug interactions is discussed. Roles for hepatitis C, cytokines, sex, genetics, and age are now emerging. Alcohol also alters the degradation of key nutrients, thereby promoting deficiencies as well as toxic interactions with vitamin A and beta carotene. Conversely, nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine. Other "supernutrients" include polyunsaturated lecithin, shown to correct the alcohol-induced hepatic phosphatidylcholine depletion and to prevent alcoholic cirrhosis in nonhuman primates. Thus, a better understanding of the pathology induced by ethanol is now generating improved prospects for therapy.

There has been much progress in our understanding of molecular mechanisms in the pathogenesis of inherited metabolic disorders. In addition, powerful new molecular techniques have made possible phenotypic alterations by delivery of foreign genes to target cells. As a result, concepts and methods that would have been considered purely science fiction 10 years ago can now be found in human clinical trials engaged in the treatment of these disorders. In this review, we have attempted to provide an introduction and survey of the topic of gene therapy, with specific examples of laboratory and clinical achievements to date, and highlights on potentials for applications in digestive diseases.

The consequences of IBD during childhood and adolescence may be devastating in terms of loss of growth potential, particularly if there has been a clinical course of frequent relapses resulting in inadequate nutrition and associated with repeated courses of steroid treatment. There is to date, however, a paucity of data recording final adult heights in such patients. The anticipation of relapse should become easier with increasing awareness of the importance of parameters of growth and pubertal development. Early and intensive nutritional support, and the use of steroid-sparing agents should help reduce the frequency and severity of any height deficit. The performance and timing of surgery must take into account the child's status in terms of height velocity and pubertal development. The importance of inducing the remission before the onset of puberty is stressed and this remission should be sustained at all costs during the pubertal years so that valuable height is not lost as a consequence of a missed pubertal growth spurt. Thus, increasing awareness of the issues of growth and development in these patients should improve the accuracy of initial diagnosis and early recognition of relapse, such that these children are ensured the best possible provision for achieving their full height potential.

Crohn's disease and ulcerative colitis are important disorders in childhood which may present in a similar way to adult life, but the major paediatric dimension is impairment of growth and development which may occur in both disorders. Whilst the diagnosis of ulcerative colitis is usually quite quick by virtue of the pressing nature of the chief symptoms, bloody diarrhoea, the diagnosis of Crohn's disease may be significantly delayed in children as the symptoms are frequently less obvious and may not, at first, be gastrointestinal. Modern diagnosis is based upon a combination of endoscopy and radiology. Of particular importance is endoscopic biopsy which enables a definite histological diagnosis to be made. Early referral to diagnostic centres is particularly important in childhood.

The term chronic inflammatory bowel disease is usually applied to the idiopathic varieties ulcerative colitis and Crohn's disease but actually encompasses a wide range of colonic inflammatory conditions, which in children includes indeterminate colitis, microscopic colitis, allergic colitis and Behçet's enterocolitis. The pathologist's opinion is considered the final arbiter in the diagnosis of inflammatory bowel disease but classification may be hampered by the considerable histological overlap between the various types of colitis. Accurate diagnosis, particularly in biopsy specimens, thus depends on clinical and radiological input as well as on appropriately selected and adequately prepared material. This chapter discusses in detail the morphological appearances of ulcerative colitis and Crohn's disease with particular emphasis on diagnosis by mucosal biopsy and differential diagnosis in the paediatric age group. The recent demonstration of ulceration-associated cell lineage and trefoil peptide expression in inflammatory bowel disease is also discussed.

Colitis is an important cause of abdominal pain and diarrhoea and is the main cause of blood and mucus in the stool. The inflammation can be due to infectious or to non-infectious causes, most commonly ulcerative colitis and Crohn's disease. However, a wide variety of rarer causes of colitis also present in childhood. These include colitis or enterocolitis secondary to Hirschsprung's disease and metabolic disorders (which include Hermansky-Pudlak syndrome, glycogen storage disease type 1b and pellagra). Primary inflammation of the colon is seen in microscopic and collagenous colitis, ulcerating enterocolitis of infancy, allergic colitis and autoimmune enteropathy. The histological pattern of each of these diseases has a characteristic picture and separates them from each other from ulcerative colitis and Crohn's disease. The pathophysiology of these rare forms of colitis in childhood is not clear; but in the future they may give us an insight into the pathogenesis of large bowel inflammation, particularly when the colitis occurs secondary to an established disease.

The overall impression gained from the experience of the Departments of Paediatric Gastroenterology and Surgery attached to St Bartholomew's Hospital are the enormous benefits that surgery has to confer on the large percentage of children with both Crohn's disease and idiopathic proctocolitis who require it. The surgical procedures described in this chapter have been accompanied by a remarkably low complication rate, dispelling the impression that morbidity in such cases would be high. This must in large measure be due to the fact that the children who come to surgery are in as good a state of nutrition as can be achieved by means of the various forms of enteral and parenteral feeding now available. Anxiety about healing of anastomoses and the development of fistulas after surgery for example, has not been a feature of the surgical care of these patients. The principal benefit of surgery has been a clear demonstration of an improvement in growth velocity in both Crohn's disease and idiopathic proctocolitis patients provided always that surgery is correctly timed. It is the author's experience that maximum benefit is achieved if the bulk of the diseased bowel can be removed. Plainly relief of symptoms such as abdominal pain and diarrhoea has also been rewarding. In many instances second procedures such as restorative proctectomy in idiopathic proctocolitis can be timed to fit in with educational commitments. In Crohn's disease the likelihood of recurrence in adult life is high but these patients are in a fit state to cope with further therapy including surgery should the need arise. From the management point of view the close cooperation between physicians and surgeons at all stages has been crucial, firstly to achieve smooth preparation prior to surgery and satisfactory after care. But of even more importance in the assessment of Crohn's disease is the presence of all clinicians involved in the case in the operating theatre so that the surgical options are fully assessed. This united approach avoids any unnecessary anxiety when, as inevitably happens, recurrence of symptoms due to relapse occurs. The involvement of patients of whatever age, and parents in all the decision making processes from the time of diagnosis has been vital. Early discussion about stomas involving members of the Stomatherapy Department has been invaluable. One final important aspect of the management of these patients is the seamless hand-over of care to an adult combined medical and surgical clinic at an appropriate time, usually at the age of 17 years.(ABSTRACT TRUNCATED AT 400 WORDS)

In the absence of a definitive cure for Crohn's disease and ulcerative colitis, the aim of therapy must be to induce and maintain clinical remission at acceptable cost to the patient in terms of adverse effects. Despite the differences in their pathogenesis, the first-line treatments for Crohn's disease and ulcerative colitis are still based upon combinations of amino-salicylic acid derivatives and corticosteroids, although the use of enteral nutrition regimes is becoming increasingly widespread in Crohn's disease. In this chapter we attempt to provide reasonably didactic guidance for the management of most cases of chronic inflammatory bowel disease. However, we have tried to go beyond this brief, motivated by the recent explosion in knowledge of inflammatory mechanisms, to suggest a rational approach to the choice of newer and less well tested therapeutic approaches in the affected child who is not responding effectively. The relative failure of cyclosporine therapy in Crohn's disease has been particularly disappointing in view of its ideal theoretical suitability. However, the encouraging early reports of treatment with anti-CD4 and anti-TNF alpha monoclonals suggest that the shift from broad spectrum immunomodulation to the targeting of critical components of the inflammatory cascade may yet field important dividends.

Flexible endoscopy, performed after oral bowel preparation and under moderate intravenous sedation, proves to be well tolerated, safe and highly effective in the diagnosis and management of children with IBD. At St Bartholomew's Hospital it is performed as the investigation of first choice, on the basis that it supplies colour documentation, histopathological and (where relevant) bacteriological evidence, which achieves certain confirmation or exclusion in almost every case and in the shortest possible time. Biopsies must always be taken, as mucosa of normal appearance can show either microscopic ulcerative colitis or Crohn's disease. When there are the characteristic 'aphthoid' ulcers, visual diagnosis of Crohn's disease is reasonably certain, particularly in early-stage disease, although amoebic and other infective causes of colitis can give misleadingly similar appearances. The endoscopist can usually inspect (and almost always biopsy) the terminal ileum, and can expect many children to show the prominent 'nodular lymphoid hyperplasia' which is essentially a normal finding-though sometimes misdiagnosed radiologically as being Crohn's deformity. However, it is important that radiological assessment by barium follow-through complements colonoscopy in view of the not infrequent cases of intestinal Crohn's disease in children where the proximal small intestine is involved, even if the colon and terminal ileum are spared.