The aim of therapy in Crohn's disease in childhood is to induce and to maintain a remission of disease activity so that normal growth and development of the child may occur. Enteral nutrition may now be recommended as the first-line treatment for most children with Crohn's disease. However, the evidence for remission is better for children with Crohn's disease of the small intestine rather than of the large intestine. There is evidence that amino acid feeds (elemental), whole protein (polymeric) and protein hydrolysate feeds (semi-elemental) may all be successful. Such a therapeutic approach can lead to healing of the mucosa and down-regulation of inflammation. However, in some cases surgery is required, particularly in children with growth failure and delayed puberty. Drug therapy also continues to have a role in therapy especially with severe colonic disease.

The management of patients with intestinal failure has benefited from progress in parenteral nutrition (PN), especially home-based PN. Intestinal transplantation is therefore possible and is now, in some conditions, the logical therapeutic option. Since 1985, more than 180 small-bowel grafts have been done, involving the isolated small bowel with or without the colon (38%), the liver-small bowel (46%) or several organs (16%). Two-thirds of recipients were under 20 years of age, and indications were short-bowel syndrome (64%), severe intractable diarrhoea (13%), abdominal cancer (13%) or chronic intestinal pseudo-obstruction syndrome (8%). Of the patients, 51% survived > 2 years after the graft. Patient and graft survival depends on the type of immunosuppression, i.e. cyclosporine or FK506. The results must be interpreted carefully as they represent the first experience in numerous centres using different immunosuppressive protocols, without any randomization. The results from the largest of these centres reflect the current situation more closely. Functional grafts lead to gastrointestinal autonomy (weaning of PN) while maintaining satisfactory nutritional status and normal growth in childhood. Intestinal transplantation is theoretically indicated for all patients permanently or dependent for a long time on PN. However, as PN is generally well tolerated, even for long periods, each indication for transplantation must be carefully weighed up in terms of the iatrogenic risk and quality of life. When PN has reached its limits, especially in those associated with vascular, infectious, hepatic or metabolic complications, intestinal transplantation must be undertaken. Transplantation of the small bowel alone remains the first option, as combined liver-small bowel grafting is only indicated in the case of life-threatening progressive cirrhogenic liver disease.

Pathological processes and disease entities in the upper gastrointestinal (GI) tract, specifically those of the oesophagus and the stomach in infancy, have received a disproportionately small amount of attention until recently when appreciation of their pathophysiology and concordant importance in terms of symptomatology has been highlighted. This is probably a phenomenon secondary to improved diagnostic yield from the recent technical advances in areas such as infant endoscopy and a shift in opinion regarding the pathophysiological origin of ubiquitous symptoms of infancy such as feeding disorders, colic and irritability. In addition, the apparently complex interactions of various aetiological factors such as pH-independent gastro-oesophageal reflux (GOR), cow's milk protein intolerance (CMPI), Helicobacter pylori gastritis and upper GI motor disorders have in the past 1-2 years become underlined in terms of aetiopathogenesis and have radically changed thinking regarding diagnosis and therapy of infants with apparent upper-GI-associated symptoms. The contribution to comprehension of infant upper GI disorders of inflammatory paradigms and ontogeny of the upper GI tract is also a recent area worthy of mention. The recent advances in all of these areas and their contribution to the understanding, and subsequent diagnosis and therapy, of upper GI symptoms and their explanation by way of aetiopathogenesis will be explored in this chapter.

Damage to the developing central nervous system may result in significant dysfunction in the gastrointestinal tract and is reflected in impairment in oral-motor function, rumination, gastro-oesophageal reflux, with or without aspiration, delayed gastric emptying and constipation. These problems can all potentially contribute to feeding difficulty in disabled children. Early recognition of an infant with neurological impairment that is compromising the normal feeding process is crucial. Detailed assessment of the nature of the feeding difficulties will help to predict the anticipated future nutritional needs and will allow decisions to be made about the appropriateness of input from different professionals (speech therapy, dietitians, gastroenterologists). Only when such information has been carefully assembled will rational and directed medical and surgical therapy be possible. Nutritional rehabilitation of disabled children can be associated with increased mortality and morbidity secondary to gastro-oesophageal reflux, retching, dumping syndrome or aspiration. It may also entail an increased work for care givers and increase costs of care. It is therefore necessary to document the impact of such rehabilitation on growth and quality of life for both patient and care giver.

The use of oral rehydration solution (ORS) with early refeeding forms the basis of therapy for dehydration secondary to diarrhoea ORS has produced such positive results in dehydrated patients that no further scientific demonstration is needed to confirm its efficacy. This review presents several issues that remain unsettled or controversial. They include the following. 1. The mechanism of water handling by the intestine is discussed; this is more complex than initially thought, at the epithelial, cellular and molecular level. 2. The composition of ORS which has been successfully adapted for the most frequent conditions, except for severely malnourished children, is described. 3. In contrast to the strong scientific basis and obvious efficacy in rehydration of ORS, its consequences for growth, nutrition and mortality are difficult to demonstrate, unless adequate long-term nutritional support is also provided in addition to ORS. 4. Finally, discrepancies between the recommendations and the practice of oral rehydration therapy are now well documented. Analysis of the causes of these discrepancies may participate in improving public health campaigns.

Coeliac disease is the life-long intolerance to dietary gluten, usually characterized by severe damage to the small-intestinal mucosa. The widespread use of sensitive diagnostic tools, such as the serum anti-gliadin and the anti-endomysial antibodies, has shown not only that coeliac disease is one of the commonest disorders in Western countries but also that this condition is characterized by a higher degree of clinical variability than previously thought (typical, atypical and silent forms). The existence of a latent-potential coeliac disease and even a gluten-sensitive disease with immunological activation of an otherwise normal small-intestinal mucosa has recently been postulated. An increased prevalence of coeliac disease in a number of other disorders has also been reported in both children and adults. The reasons for such a wide clinical heterogeneity are still poorly understood but are likely to depend on both genetic and environmental factors. Further investigations are required to evaluate the impact of undiagnosed, clinically milder forms of coeliac disease on the well-being of the population.

This chapter primarily concerns three main categories of diarrhoeagenic Escherichia coli, enteropathogenic (EPEC), enterohaemorrhagic (EHEC) and enteroaggregative (EAEC) E. coli. They have distinctive virulence factors and vary in the enteropathies they produce. The molecular biological approach has opened up the complex way in which they interact with the intestine. EPEC and EHEC show a subversive approach to colonization in that they adapt the host cell to their requirements in the formation of the attaching effacing lesion. EAEC appear to co-opt the host defence system to produce a biofilm-like colony and currently go unrecognized in routine laboratories.

Gene expression is central to the pathogenesis of many disorders. An ability to alter the expression of genes would, if their relationship to disease processes were fully understood, constitute a new modality of treatment. This review examines the evidence that nutritional factors can regulate genes in the gastrointestinal epithelium and it discusses the physiological relevance of such alterations in gene expression. Dietary regulation of the genes expressed by the epithelium confers three fundamental advantages for mammals. It enables the epithelium to adapt to the luminal environment to digest and absorb food better; it provides the means whereby mother's milk can influence the development of the gastrointestinal tract; when the proteins expressed by the epithelium act on the immune system, it constitutes a signalling mechanism from the intestinal lumen to the body's defences. Each of these mechanisms is amenable to manipulation for therapeutic purposes.

The intractable diarrhoeas of infancy present very major problems of clinical management. However, the conceptual importance of these conditions lies in the information that they may provide about normal small-intestinal function in humans: among such infants will be found the human equivalents of the 'knock-out' mice, in which targeted gene disruption allows sometimes unexpected insight into the regulation of intestinal function. The challenge posed by the intractable diarrhoeal syndromes, of working backwards from an apparently common phenotype to probably multiple genotypes, is, however, immense. Very few of these conditions have been described at the genetic level, although the molecular basis of pathogenesis has been better explored in recent years. The two major groups of intractable diarrhoea are due to (1) primary epithelial abnormalities (which usually present within the first few days of life) and (2) immunologically mediated (which generally present after the first few weeks). The high prevalence of autoimmune enteropathy among infantile autoimmune disease, in contrast to adult autoimmunity, is intriguing and may reflect constitutive abnormality of extrathymic lymphocyte maturation. The use of potent immunosuppressive drugs and increasing expertise with parenteral nutrition are improving the outlook of these previously fatal conditions. Viewed globally, however, the pressing problem is to treat effectively the millions of infants who die from severe persistent diarrhoea and wasting, which would certainly not be considered intractable in wealthy countries.

Many empirical clinical trials have used complex carbohydrate as substrate in oral rehydration solutions (ORSs) instead of glucose and have shown a number of important clinical benefits. Foremost among these are reduced stool volumes, shorter duration of diarrheal illness, and lower ORS intake. The underlying mechanisms to explain this clinical advantage have not been fully established, but a number of possible factors have been proposed: (1) increased substrate availability, (2) a "kinetic advantage" for glucose absorption by glucose polymer, (3) differential handling of glucose monomer and polymer by the small intestine, (4) low osmolality, (5) a separate effect of peptides and amino acids on solute-linked sodium absorption, (6) an antisecretory moiety in rice, and (6) enhanced mucosal repair and regeneration by luminal nutrients. In this report, we assess the relative contribution of these factors using evidence from laboratory-based studies, mainly in disease-related intestinal perfusion systems in animals and humans, and the relevant clinical studies available to date. We advance the hypothesis that of all the possible mechanisms proposed to underlie the enhanced clinical efficacy of complex carbohydrate ORSs, their hypotonicity plays the dominant role. If confirmed, this concept could guide future development of glucose and complex carbohydrate-based ORSs.

The peritoneum is more than a mechanical covering that allows for the easy gliding of opposed peritoneal surfaces. The peritoneal mesothelial cells facilitate the action of powerful innate immune mechanisms. In addition, the peritoneal-associated lymphoid tissues contain unique cells that may play a crucial role in the localization of intraperitoneal infection. A clearer understanding of the molecular and cellular events underlying peritoneal functions in both the unstimulated and stimulated state will aid future treatment of peritonitis.

Several areas regarding Helicobacter pylori that need improvement or clarification in the United States include treatment of dyspepsia, physician education on disease associations with H. pylori, and evidence from U.S. studies that 7-day H. pylori eradication regimens are more effective than current regimens. Dyspepsia, a ubiquitous condition in the United States, is routinely managed on the basis of a positive H. pylori serology without other investigations. This approach has been fostered by cost-effectiveness studies of various approaches to duodenal ulcer and dyspeptic patients. Serology-directed therapy was the most cost-effective option vs. endoscopy-directed management. The option of not obtaining endoscopy had broad appeal to primary care physicians. In addition, a recent survey suggests that even gastroenterologists routinely attempt H. pylori eradication in infected patients with nonulcer dyspepsia, despite a number of negative efficacy studies. Finally, the option of not eradicating a World Health Organization-defined carcinogen in the litigious United States is unappealing to clinicians. Eradication of H. pylori in patients with dyspepsia despite more negative trials is likely to continue. There is evidence that U.S. physician awareness of the H. pylori-disease associations and the best therapies are improving rapidly, but further improvement is needed. Discrepancy of awareness of H. pylori between gastroenterologists and family physicians exists. In a recent survey, 94% and 72% of gastroenterologists regarded H. pylori as a causative agent in duodenal and gastric ulcer, respectively, vs. 68% and 68% of family physicians, and only 9% of family physicians believed there was a definite relationship between H. pylori infection and gastric cancer vs. 21% of gastroenterologists. One hundred three different H. pylori regimens were being used; 31% of family physicians and 11% of gastroenterologists used ineffective regimens or regimens of unknown effectiveness. Although 1-week proton pump inhibitor triple therapy is promising, there is skepticism that U.S. studies will yield the optimistic results that have characterized the European studies. Unlike in Europe, the U.S. standard is to use double diagnostics to prove eradication rather than just the urea breath test and to use intent-to-treat rather than assessable patient analyses. Both approaches reduce apparent eradication rates.

A variety of questions regarding Helicobacter pylori need to be addressed by future research. Further investigations are needed on the relationship between H. pylori and gastric cancer. In particular, the mechanism of the interaction between H. pylori infection and host genetic factors and dietary factors that lead to the cancer need to be unraveled. Also, the reversibility of cancer-associated abnormalities (e.g., hypochlorhydria, atrophy, and intestinal metaplasia) by eradication of H. pylori needs to be determined. Noninvasive means of identifying H. pylori-positive subjects at high risk of developing gastric cancer are required for such subjects to be targeted for eradication therapy. Further studies are also required on the interactions between H. pylori and proton pump inhibitor therapy that might predispose to cancer. There is considerable interest in the possibility of noninvasive H. pylori testing replacing endoscopy in determining management of nonelderly patients with uncomplicated dyspepsia unassociated with nonsteroidal anti-inflammatory drugs (NSAIDs). Randomized studies comparing endoscopy vs. noninvasive H. pylori testing in this situation are required with comprehensive outcome measures. Improvement in eradication therapy is required and will depend on the development of more effective and specific antibiotics and therapeutic vaccines. Wide-scale elimination of the infection will depend on preventing its spread from person to person. Achieving this will require further knowledge of its mode of transmission, particularly in childhood, and the development of prophylactic vaccines. Further studies are required to define the role of H. pylori infection in other diseases, including predisposition to enteric infection in the developing world as a result of H. pylori-induced chronic hypochlorhydria, nonulcer dyspepsia, pernicious anemia, atherosclerosis, and NSAID-related ulcer disease. Finally, we need to know whether H. pylori infection may be beneficial in certain circumstances and whether eradicating the infection may be disadvantageous to some subjects.

Based on the findings of several epidemiological studies, it is believed that Helicobacter pylori infection is closely associated with gastric cancer. Because some abnormalities, such as severe inflammation in the gastric mucosa, impaired secretion of vitamin C, and increased gastric cell proliferation, improve after cure of the infection, anti-H. pylori therapy may reduce the incidence of gastric cancer. In Japan, the odds ratios for the development of atrophic gastritis and gastric cancer in H. pylori-positive patients are not as high as those reported in Europe and the United States. These findings suggest that factors other than H. pylori may exert a considerable influence on the development of atrophic gastritis and gastric cancer in Japan. It is not known whether atrophy and intestinal metaplasia, possible precursors of gastric cancer, are reversible. H. pylori infection is associated with a "gastritis, intestinal metaplasia, and gastric cancer sequence," but it remains obscure whether the infection is directly associated with the development of gastric cancer. We do not know which age group of patients should be given anti-H. pylori therapy for the prevention of gastric cancer. To elucidate whether the eradication of H. pylori can prevent gastric cancer, a Japanese intervention trial is now in progress.

Helicobacter pylori has been implicated in the etiology of peptic ulcer disease, chronic gastritis, gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Although significant progress has been made in treating this infection with combinations of either antimicrobial agents or antimicrobial agents plus proton pump inhibitors, these antimicrobial-based treatments continue to be suboptimal. Over the past few years it has become increasingly recognized that direct mucosal immunization can induce protection from infection at mucosal surfaces. Therefore, prevention of H. pylori infection by oral immunization is an alternative approach for the control of H. pylori disease. Using the Helicobacter felis mouse model or H. pylori mouse model, both prophylactic and therapeutic oral immunizations have been shown to be effective against H. pylori. In addition, several H. pylori proteins have been identified as potential candidate vaccines, and a phase 1 clinical trial has been completed that demonstrates the safety and tolerability of urease as a vaccine antigen. Such antigens in combination with a safe mucosal adjuvant could be used in the form of an oral vaccine administered during childhood before exposure to H. pylori to prevent infection. In addition, therapeutic immunization alone or as an adjunct to antimicrobial therapy may be capable of achieving a cure rate approaching 100%.

The most common infection in the world, Helicobacter pylori infection, is very specific, and present experience in treating infectious diseases is not applicable in general for this infection. Animal models (e.g., mouse and ferret) are thus far inadequate as reliable screening models. Old-fashioned trial-and-error treatment of infected humans is still the screening model and the gold standard in the evaluation of regimens aimed at eradication of H. pylori. A variety of studies on treatment of H. pylori infection have been performed with varying results. This pooled analysis of the following therapeutic combinations: proton pump inhibitor (PPI) plus two antibiotics or antimicrobials, quadruple therapies, and nonantibiotic regimens is an attempt to make a fair comparison of tested therapeutic strategies aimed at eradicating H. pylori. Data from treatment groups including specified drug combinations are pooled, regardless of dose or duration. Search methods are: MEDLINE 1984-1996, Digestive Disease Week 1988-1996, United European Gastroenterology Week 1992-1996, European Helicobacter pylori Study Group 1988-1996, Asia Pacific Congress 1996, H. pylori International Workshop Hong Kong 1996, and miscellaneous. Eradication rates (efficacy) are presented as intention-to-treat data (i.e., worst-case analysis). Separate subanalyses with regard to study quality, dose, and duration are performed for some groups. A general cost-efficacy analysis is performed based on pooled efficacy data. Convenience data are presented as total number of tablets, total number of intake occasions, and duration of therapy. Drugs evaluated in the analysis are bismuthdicitrate, tetracycline, amoxicillin, nitroimidazoles, macrolides, H2-receptor antagonists, PPIs, sucralfate, and sofalcone. The most effective and convenient drug combinations are the PPI-based triple therapies. No significant difference was observed between the three PPIs. The cure rate did not improve after addition of bismuth. Cost-effectiveness is closely associated with efficacy.

The goals of therapy of Helicobacter pylori are commonly viewed as either clinical (e.g., avoid further morbidity, mortality, or prevent disease from occurring) or economic (e.g., save healthcare dollars by avoiding further expenditure of resources). However, when viewed globally, these goals are not incongruent but are inexorably linked. Prevention of disease or avoidance of further morbidity and mortality by curing H. pylori infection is obviously an improved clinical outcome, but it also concurrently avoids further utilization of healthcare resources and is "cost-effective," resulting in improved economic outcome as well. The more clinically effective an H. pylori treatment is, the more economically effective it is as well. When comparing regimens, the cost-effectiveness is determined by efficacy of the regimen, not its cost. Put more simply, "The most expensive therapy is the one that doesn't work!" Therefore, the goals of the therapy are simple: avoid further morbidity, mortality, and prevent disease while minimizing further utilization of healthcare resources, thus saving money. The most clinically effective therapy is also the most cost-effective therapy. Regimens used should have demonstrated greater than 90% efficacy or effectiveness in the population being treated for H. pylori infection. The regimens should be simple and well tolerated. It is clinically and economically inappropriate to use a regimen not meeting these criteria.

Evidence-based medicine combines clinical expertise and the best available evidence from systematic research to aid decision making in patient care. Levels of evidence can be graded from I to V, with level I, the strongest, coming from large randomized controlled trials (RCTs). When a definitive RCT has not been performed, or is impracticable or inappropriate, lesser grades of evidence are used. There is level I evidence supporting the treatment of Helicobacter pylori infection in patients with duodenal or gastric ulcers. Prospective RCTs have shown that cure of the infection is associated with ultimate cure of the ulcer diathesis. Therefore, this is a "grade A" recommendation for treatment. In nonulcer dyspepsia, numerous RCTs have yielded conflicting results regarding the benefits of treatment. Although there are methodological problems with many reported studies, there is some evidence (level II at best) to support treatment--a grade B recommendation. In early gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma, the best available evidence supporting treatment of H. pylori infection is of low quality, i.e., levels III and V. Although these carry only grade C treatment recommendations, treatment is safe and carries at least some evidence of efficacy. It is therefore indicated based on the current best available evidence. No evidence exists to support treating the infection in patients receiving long-term proton pump inhibitors for gastroesophageal reflux disease or in patients with any of the nongastrointestinal conditions that have been tentatively linked to H. pylori.