Over a period of 33 years, it has become possible to successfully transplant individual intra-abdominal viscera or combinations of these organs. The consequences have been, first, new information about the metabolic interrelations that the visceral organs have in disease or health; second, the addition of several procedures to the treatment armamentarium of gastrointestinal diseases; and third, a more profound understanding of the means by which all whole organ grafts are accepted.

The parietal cells, which are responsible for the production of gastric HCl acid, are uniquely equipped for high-gradient ion transport. Adequate energy is supplied by oxidative metabolism in the mitochondria, which occupy an exceptionally high proportion of the cytoplasmic volume. Another characteristic feature is the secretory canaliculi. These are tortuous small channels lined by microvilli which penetrate all parts of the cytoplasm and which expand during stimulation of secretion. The activity of the parietal cell is controlled by receptors for acetylcholine, histamine and gastrin on the basolateral cell membrane. Stimulation of these receptors modulates the levels of protein kinases in the cell and brings about the changes from resting to stimulated structure. A key role in the production of acid is played by the gastric acid pump, also known as the H+, K(+)-ATPase, which exports hydrogen ions in 1:1 exchange for potassium ions. This protein is a member of the P-type ATP-driven ion pumps and appears to be uniquely located in the parietal cell. The gastric acid pump is found in the tubulovesicular membranes of the resting cell and moves to the membrane lining the secretory canaliculus when acid secretion is stimulated. Functional acid secretion also requires the presence of KCl pathways in the secretory membrane in order to supply the acid pump with a source of potassium ions. For each hydrogen ion secreted across the secretory membrane, one bicarbonate ion is generated in the cytoplasm and is transported across the basolateral membrane in exchange for chloride. The movement of ions across the apical membrane is followed osmotically by water, resulting in the secretion of 160 mM HCl from the parietal cell.

An important approach to the major health problem of bacterial infection in young children has been to examine bacterial toxin binding to microvillus membrane receptors, the signal transduction produced by that interaction and the mechanisms of fluid secretion in the developing intestine as a basis for toxigenic diarrhea in the infant population. These studies indicate that receptor binding and effector responses may be subjected to developmental regulation. This regulation process of toxin interaction with the developing intestine may have an enhanced or harmful effect or, under some circumstances, may have a beneficial effect and be protective to the vulnerable child. Specific mechanisms for the developmental control of receptor expression may involve the regulation of individual glycosyltransferases responsible for the addition of receptor sugar sequences to glycolipids and/or glycoproteins, presumably at the transcriptional level. Furthermore, although highly speculative at this point, the differential expression of signal transducers (e.g., guanine nucleotide-regulatory proteins or G proteins) and ion transporters (e.g., Na+,K(+)-stimulated adenosine triphosphatase, the Cl- channels, etc.) during development may also alter the neonatal host's responsiveness. Therefore, the developmental control of microvillus membrane receptors, signal transduction mechanisms, and ion transport systems in the gastro-intestinal tract may in part contribute to the altered host sensitivity in toxigenic diarrhea of infancy.

Gastric acid secretion tests have limited use in clinical practice. For practical purposes, a pH measurement on a fasting gastric aspirate will provide strong evidence of the presence or absence of achlorhydria. Tests of gastric acidity, in particular 24-h acidity studies, have provided considerable insight into normal and abnormal gastric physiology, and have largely determined the dosing regimens for the management of acid-peptic diseases. Acid tests may be simple to perform, so much so that they have been suggested as 'practicals' for student teaching (Nicol et al, 1991). However, reproducible and meaningful results require careful attention to detail, and the appropriate mathematical analysis is still subject to some debate. It is important that the presentation of the data should allow the reader to assess the response over the 24-h period, and also the range of individual responses. Despite the many years of research into gastric acid secretion, only recently have the effects of age, sex, diet, smoking and mental stress been identified. In addition, many data need to be reviewed in the light of the effects of H. pylori infection on gastrin release. H2-receptor antagonists had been studied extensively before and since their first clinical use in 1974, but surprisingly only recently have the issues of tolerance and rebound been defined. The 24-h intragastric acidity profile remains an essential study before the start of clinical trials on any new drug to be used for the treatment of acid-peptic diseases.

Gastric acid secretion is precisely regulated by neural (acetylcholine), hormonal (gastrin), and paracrine (histamine; somatostatin) mechanisms. The stimulatory effect of acetylcholine and gastrin is mediated via increase in cytosolic calcium, whereas that of histamine is mediated via activation of adenylate cyclase and generation of cAMP. Potentiation between histamine and either gastrin or acetylcholine may reflect postreceptor interaction between the distinct pathways and/or the ability of gastrin and acetylcholine to release histamine from mucosal ECL cells. The prime inhibitor of acid secretion is somatostatin. Its inhibitory paracrine effect is mediated predominantly by receptors coupled via guanine nucleotide binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H+,K(+)-ATPase, the proton pump of the parietal cell. Precise information on the mechanisms involved in gastric acid secretion and the identification of specific receptor subtypes has led to the development of potent drugs capable of inhibiting acid secretion. These include competitive antagonists that interact with stimulatory receptors (e.g. muscarinic M1-receptor antagonists and histamine H2-receptor antagonists) as well as non-competitive inhibitors of H+,K(+)-ATPase (e.g. omeprazole). The histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine and roxatidine acetate) continue as first-line therapy for peptic ulcer disease and are effective in preventing relapse. Although they are generally well tolerated, histamine H2-receptor antagonists may cause untoward CNS, cardiac and endocrine effects, as well as interfering with the absorption, metabolism and elimination of various drugs. The dominance of the histamine H2-receptor antagonists is now being challenged by omeprazole. Omeprazole reaches the parietal cell via the bloodstream, diffuses through the cytoplasm and becomes activated and trapped as a sulfenamide in the acidic canaliculus of the parietal cell. Here, it covalently binds to H+,K(+)-ATPase, the hydrogen pump of the parietal cell, thereby irreversibly blocking acid secretion in response to all modes of stimulation. The main potential drawback to its use is its extreme potency which sometimes leads to virtual anacidity, gastrin cell hyperplasia, hypergastrinaemia and, in rats, to the development of carcinoid tumours. The cholinergic receptor on the parietal cell has recently been identified as an M3 subtype and that on postganglionic intramural neurones of the submucosal plexus as an M1 subtype.(ABSTRACT TRUNCATED AT 400 WORDS)

Collagenous colitis, a disorder characterized by increased subepithelial collagen deposition associated with an inflammatory infiltrate in the lamina propria, has been reported infrequently in children. An 8-year-old girl with collagenous colitis is described who presented with chronic watery diarrhea and abdominal pain. Biopsy specimens of the colonic mucosa showed the pathological features of collagenous colitis. The patient's symptoms resolved following corticosteroid therapy. Collagenous colitis should be considered in the differential diagnosis of children with chronic diarrhea.

ECL cells are argyrophilic endocrine cells of the stomach. Their distribution is species specific, however they are consistently located in the oxyntic mucosa and, in particular, in very close contact with the adenomeres of acidopeptic glands. ECL cells store histamine and are considered a key element in the mechanisms of gastric acid secretion as controlled by gastrin stimulus. Their peculiar anatomical disposition and secretory properties strongly suggest that ECL cells exert their function by a paracrine mechanism, i.e. by releasing histamine in the extracellular spaces surrounding acid-producing parietal cells. ECL cell activity is strongly stimulated by gastrin, which, once applied as a long-standing stimulus, also exerts a potent proliferating effect. Long-lasting hypergastrinaemia has been demonstrated to elicit ECL cell proliferation in laboratory animals, inducing ECL cell hyperplasia, dysplasia and ECL cell tumours, i.e. argyrophilic gastric carcinoids. However, in experimental rodents it is believed that hypergastrinaemia is not per se a stimulus capable of inducing ECL cell transformation, a predisposing genetic background being required for tumour development in endocrine organs. In man, long-standing hypergastrinaemia exerts the same proliferative pressure on ECL cells and is associated with hyperplasia with or without dysplastic changes and carcinoid development. Clinical evidence suggests that other factors, both genetic and environmental, are required to induce ECL cell transformation and carcinoid development. For this reason human gastric argyrophilic ECL carcinoids are subdivided into three main groups depending on their clinical background: (1) gastric carcinoids in patients with chronic atrophic gastritis; (2) gastric carcinoids in patients with Zollinger-Ellison and multiple endocrine neoplasia type 1 syndrome (MEN-ZES); and (3) solitary, sporadic gastric carcinoids. The clinical assessment of carcinoid-bearing patients is strongly recommended for better diagnosis and management of patients.

The intestine is exposed to a wide variety of macromolecules. Because macromolecules are antigenic, mechanisms have evolved in the gastrointestinal tract to regulate their absorption. Macromolecular uptake can be beneficial in delivering essential factors for growth and in sampling the antigenic milieu of the gastrointestinal tract. Specific transport mechanisms exist to execute this physiological absorption. However, inappropriate and uncontrolled antigen transport may occur in disease states or as a prelude to disease states in the gastrointestinal tract. Such transport may result in immune responses that are harmful. This review examines physiological transport of macromolecules through epithelia and through M cells. It also considers uncontrolled transport and its relation to disease states. The review concludes with an examination of the interrelationship between antigen transport and an altered immune system in the establishment of gastrointestinal disease.

A case of multiple focal nodular hyperplasia (FNH) of the liver associated with noncirrhotic portal hypertension and later complicated by pulmonary arterial hypertension leading to death from right heart failure is reported. In retrospect, the portal hypertension diagnosed in early life was most likely due to a congenital hypoplasia of portal vein branches and multiple FNH, a hyperplastic response of the liver parenchyma in association with anomalies of hepatic arterial branches as found within the lesions. This case may represent a form of multiple FNH syndrome restricted to the liver, because neither extrahepatic vascular malformation nor brain tumor was identified at autopsy. The FNH lesions had considerably expanded over the years, and the severe sinusoidal congestion due to chronic right-sided heart failure with subsequent prolonged parenchymal exposure to blood-borne hepatotrophic factors is a likely explanation for both the massive enlargement of FNH lesions and the nodular regenerative hyperplasia observed in the intervening parenchyma.

The relationships between various hepatobiliary disorders and the administration of total parenteral nutrition (TPN) were reviewed and, in particular, the role of TPN in their pathogenesis was critically evaluated. Several clinical and pathological entities including steatosis, steatohepatitis, cholestasis, and cholelithiasis have been commonly linked to TPN, and instances of chronic decompensated liver disease have been reported. However, it is concluded that it is often difficult to extricate the effects of TPN on hepatobiliary function from many other hepatotoxic factors that may be operative in these patients. Thus, whereas considerable evidence exists to support a role fro carbohydrate or calorie excess in TPN solutions in the pathogenesis of steatosis, a loss of enteric stimulation and not TPN per se may be the primary factor in the development of cholestasis, biliary sludge, and gallstones. The apparent predilection of infants to TPN-related cholestasis may be based on the relative immaturity of the neonatal biliary excretory system.

Based on our experience of 420 common bile duct procedures for stone disease and a literature review, it is evident that treatment of common duct stones today is based on a wide variety of non-operative and surgical methods which are still being developed. The mode of treatment is basically related to the time of diagnosis. Methods also differ depending on the localization of calculi, on inflammatory complications of stone disease, and whether combined or isolated cholecystocholedocholithiasis is present. At the moment, traditional operative methods as well as newly developed advanced techniques have to be evaluated. Selection of patients and their appropriate surgical and non-surgical treatment is an important issue to be further developed in the next few years. Therefore, therapeutic indications and definitive therapy present a much more demanding challenge for the surgeon than in the period when only open surgery was available.

The risk of gallstone recurrence following non-surgical treatment has been overestimated in the past for two reasons: (1) diagnosis of primary gallstone dissolution was based on oral cholecystography; and (2) gallstone recurrence was expressed as a cumulative recurrence rate. Results based on better methodologies for diagnosis of gallstones (ultrasonography) and for calculation of results (life-table analysis) have indicated that gallstones recur in about 50% of patients, and that the risk of recurrence is confined mainly to the first 5 years after dissolution. Pretreatment gallstone characteristics, but not patient characteristics, are important risk factors for gallstone recurrence. Multiple stones are more likely to recur than solitary stones, a phenomenon attributable to the presence of a potent pronucleating factor in the bile of patients with multiple stones. This observation, and the finding that NSAID administration may reduce gallstone recurrence via inhibition of mucin secretion, suggests that the nucleation defect might be a key factor in the pathogenesis of recurrent gallstones. Prophylaxis with low-dose CDCA or UDCA has proven ineffective for preventing gallstone recurrence, although it may reduce it. Since the majority of recurrent gallstones are small when first seen because of regular ultrasonographic follow-up, multiple, radiolucent and in functioning gallbladders, they are amenable to bile acid retreatment, and intermittent bile acid therapy is probably a viable strategy for long-term management of cholesterol cholelithiasis.