This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Practice Economics Committee. Following external review, the paper was approved by the committee on May 17, 1998.

This document presents the official recommendations of the American Gastroenterological Association (AGA) on Anorectal Testing Techniques. It was approved by the Clinical Practice and Practice Economics Committee on May 17, 1998, and by the AGA Governing Board on July 24, 1998.

A combination of approaches has begun to elucidate the mechanisms of gastrointestinal development. This review describes progress over the last 20 years in understanding human gastrointestinal development, including data from both human and experimental animal studies that address molecular mechanisms. Rapid progress is being made in the identification of genes regulating gastrointestinal development. Genes directing initial formation of the endoderm as well as organ-specific patterning are beginning to be identified. Signaling pathways regulating the overall right-left asymmetry of the gastrointestinal tract and epithelial-mesenchymal interactions are being clarified. In searching for extrinsic developmental regulators, numerous candidate trophic factors have been proposed, but compelling evidence remains elusive. A critical gene that initiates pancreas development has been identified, as well as a number of genes regulating liver, stomach, and intestinal development. Mutations in genes affecting neural crest cell migration have been shown to give rise to Hirschsprung's disease. Considerable progress has been achieved in understanding specific phenomena, such as the transcription factors regulating expression of sucrase-isomaltase and fatty acid-binding protein. The challenge for the future is to integrate these data into a more complete understanding of the physiology of gastrointestinal development.

Pathological processes and diseases of the upper gastrointestinal tract have become increasingly recognized over recent years as childhood entities responsible for a variety of upper gastrointestinal symptoms previously labelled as functional or non-organic. The term 'dyspepsia' is an adult one whose definition requires clarification before use in the paediatric context, but it encompasses age-dependent symptoms such as feed-associated irritability in the infant, peri-umbilical pain in the younger child, and heart-burn, nausea, and indigestion in the older child as in adults. The possible organic conditions giving rise to such symptoms are multiple and multiorgan and include: gastro-oesophageal reflux; peptic ulcer disease; upper gastrointestinal Crohn's disease; antroduodenal motility disorders; pancreatitis; cholecystitis; cholelithiasis; biliary dyskinesia; and abdominal migraine. However, Munchausen syndrome by proxy must not be forgotten. Non-ulcer dyspepsia, it is now clear, has a basis in altered gastroduodenal motility and may be amenable to propulsion agents. In many individuals the dyspeptic symptoms of recurrent abdominal pain may be altered by psychotherapeutic intervention. Indeed there remains a proportion of children who undoubtedly have a behavioural or psychological base to their complaint. Nevertheless, with the recent increase in diagnostic yield from improved technical investigative aids available to paediatrics in the last 5-10 years, it is clear that the responsibility of the paediatrician to the child to find a cause of their symptoms is paramount. The variety of presenting features, possible causes of these symptoms, and appropriate investigation and treatment will be discussed, and management algorithms based on published literature and personal practice will be offered.

Managing patients with new-onset dyspeptic symptoms represents a real challenge in clinical decision-making. The major controversy has been over the optimal management strategy of patients with new-onset dyspeptic symptoms who do not present with alarm symptoms. Since unaided clinical diagnosis is unreliable, proposed management strategies have included empirical treatment algorithms, computer-assisted predictive score models and Helicobacter pylori-based strategies such as test-and-scope or test-and-treat algorithms. Endoscopy remains the diagnostic 'gold standard', and the management should ideally be based on endoscopic diagnosis. Because of economic constraints and increasing waiting lists, this is not possible. When precise and comprehensive guidelines have been formulated, future patients will probably be managed in primary care by a Helicobacter test-and-treat policy, leaving only empirical treatment failures for specialist evaluation.

Many functional dyspepsia treatment trials have until recently suffered from important weaknesses in study design. A major problem has been the low number of studies that have used validated outcome measures. Fortunately, progress has been made in this area. The evidence for the efficacy of antacids, H2-receptor antagonists, omeprazole, domperidone, cisapride and anti-Helicobacter therapy is reviewed. Although several of these have shown benefit, it is unclear whether this may be a result of the inclusion of patients with unrecognized gastro-oesophageal reflux disease. The data on anti-Helicobacter therapy are conflicting.

The causes of functional dyspepsia remain unclear. Research has linked other functional gastrointestinal disorders, particularly irritable bowel syndrome, to a history of physical or sexual abuse, psychosocial distress and certain psychiatric disorders. In functional dyspepsia, there is a possibility of certain psychiatric disorders, particularly alcohol abuse and eating disorders, indirectly influencing the development of functional dyspepsia-like symptoms. However, the literature on possible psychosocial correlates in functional dyspepsia is not as mature as the literature on irritable bowel syndrome. This paper critically reviews the psychosocial dimensions and implications for the psychotherapeutic treatment of functional dyspepsia.

Symptoms of functional dyspepsia, such as epigastric pain, bloating or early satiety and nausea, are non-specific and are likely to arise from different mechanisms. Current evidence suggests the presence of at least two subgroups: patients who respond to a prolonged course of acid suppression and patients who show a significant overlap of symptoms with other functional gastrointestinal disorders such as irritable bowel syndrome. An enhanced sensitivity of visceral afferent pathways with or without associated autonomic dysregulation appears to play an important role in the aetiology of symptoms in the second group. In the absence of visceral hypersensitivity, neither the slowing of gastric emptying nor the presence of chronic gastritis appears to be sufficient to cause symptoms of functional dyspepsia. The mechanisms and aetiology of visceral hypersensitivity are incompletely understood. An alteration in the interplay between vagal and spinal afferents, and the inadequate activation of antinociceptive systems in response to tissue irritation, may play a role in symptom generation.

Gastrointestinal motor abnormalities are frequent findings in patients with functional dyspepsia. However, these abnormalities are rather non-specific and seem to be restricted to a proportion of patients. Furthermore, they are not necessarily time-linked to symptom perception. The relationship of digestive motor derangements and symptoms in functional dyspepsia remains, therefore, unsettled. A variety of methodological and conceptual shortcomings characterize many of the studies investigating the relationship between gastrointestinal motility disorders and dyspeptic symptoms, and this obviously contributes to a higher level of uncertainty in the field. Recent reports suggest that gastrointestinal dysmotility is associated with perception of some dyspeptic symptoms, at least in a subset of patients. Well-conducted studies using appropriate methodology are needed to verify whether gastrointestinal motor disorders play a causal role in functional dyspepsia and whether this is of clinical relevance.

This chapter reviews the evidence for a link between functional dyspepsia and Helicobacter pylori infection from three angles. In the section on pathophysiology, we evaluate how H. pylori could theoretically produce dyspeptic symptoms: many mechanisms can be proposed. In the discussion on epidemiology, we evaluate possible associations between the occurrence of symptoms and infection. Here, many studies claiming a coincidence or chronological sequence of infection and symptoms are criticized because of their poor design. In the section on the improvement of functional dyspepsia by the treatment of H. pylori infection, the conclusion is reached that if such an effect occurs at all--which is unlikely--it is very weak. The controversy on the link between H. pylori infection and functional dyspepsia is presently ongoing. Some authors are still trying to save an elegant concept that once looked so plausible but now has the facts against it.

The main diseases associated with dyspepsia are peptic ulcer disease, gastro-oesophageal reflux disease and non-ulcer dyspepsia. Increased gastric acid secretion is a characteristic of most duodenal ulcer patients and of a small minority of non-ulcer dyspepsia and gastro-oesophageal reflux disease patients. Although acid secretion is normal in most gastro-oesophageal reflux disease patients, the condition is mainly the result of excess exposure of the distal oesophagus to acid refluxing from the stomach. Increased mucosal sensitivity to acid is involved in the aetiology of dyspeptic symptoms in the majority of patients with peptic ulcer disease and gastro-oesophageal reflux disease, and in a minority of non-ulcer dyspepsia subjects. Gastric acid, therefore, plays an important role in both the aetiology of dyspeptic diseases and in the aetiology of dyspeptic symptoms.

A wide variety of disorders affecting the upper gastrointestinal tract, as well as systemic disorders, are associated with symptoms of dyspepsia. The more important of these conditions are considered in this chapter, with particular reference to their symptom patterns on presentation. The differentiation, on clinical grounds, between these organic causes of dyspepsia and functional dyspepsia remains an important area of research. Those aspects of the history and physical examination most relevant to this distinction are also considered.

Functional dyspepsia is a chronic disorder of unknown aetiology. The lack of endoscopic abnormalities in patients with this disorder has led many physicians to believe that gastro-oesophageal reflux disease may be responsible for most symptoms. Our group has addressed this issue, by pathophysiological studies in a large cohort of Dundee patients with persistent dyspeptic symptoms. Peptic ulcer and gallstones were excluded in all patients by appropriate tests. Ambulatory pH monitoring showed oesophageal acid reflux that lay above the conventional diagnostic threshold in approximately 20% of patients. This subset was diagnosed as having gastro-oesophageal reflux disease. In the remainder, moderate or severe reflux-like symptoms were reported by approximately 44% patients, who were categorized as reflux-like functional dyspepsia. Reflux symptoms were mild or absent in 36% patients, who were categorized as non-reflux-like dyspepsia. While oesophageal pH profiles lay within the conventional normal range in both of these functional dyspepsia subgroups, patients with reflux-like functional dyspepsia had significantly greater acid exposure values, including total oesophageal acid exposure time, percentage time at a pH of less than 4.0, DeMeester scores and pain reflux event correlation. Hence patients with reflux-like functional dyspepsia have oesophageal acid exposure that lies below the diagnostic threshold for gastro-oesophageal reflux disease but exceeds that of patients with non-reflux dyspepsia. The high pain/reflux event correlation in reflux-like functional dyspepsia suggests that subthreshold oesophageal acid exposure may be associated with troublesome reflux symptoms.