gastrins and Hyperplasia

Proton pump inhibitors (PPIs) have a well-established safety profile. However, concerns have been raised about a potential relationship between PPI-induced hypergastrinaemia and the development of enterochromaffin-like (ECL) cell hyperplasia, neuroendocrine tumours and gastric cancer during long-term therapy.. To review the effects of long-term PPI use on serum gastrin levels and gastric histopathology.. A systematic literature search was conducted in PubMed on 21 April 2015 to identify studies reporting the effects of long-term (defined as >3 years) PPI use on gastrin levels and gastric histopathology.. A total of 16 studies (1920 patients) met the inclusion criteria. During long-term PPI therapy, mean gastrin levels rose to one to three times the upper limit of the normal range (~100 pg/mL), and an increased prevalence of ECL cell hyperplasia was observed (+7.8-52.0%). Helicobacter pylori-positive patients had a significantly increased risk of developing ECL linear/micronodular hyperplasia compared with H. pylori-negative patients [OR: 2.45 (95% CI: 1.47-4.10), P = 0.0006]; however, no evidence of neoplastic changes was found. The risk of corpus atrophy was markedly higher in H. pylori-positive patients than in H. pylori-negative patients [OR: 11.45 (95% CI: 6.25-20.99), P < 0.00001]. Not a single case of gastric adenocarcinoma was found.. Long-term PPI therapy induced moderate hypergastrinaemia in most patients and an increased prevalence of ECL cell hyperplasia. H. pylori-positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than H. pylori-negative patients. No neuroendocrine tumours or gastric cancers were found.

Topics: Drug Administration Schedule; Enterochromaffin-like Cells; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Neuroendocrine Tumors; Proton Pump Inhibitors; Risk Factors; Stomach Neoplasms

Topics: Anti-Ulcer Agents; Biomarkers, Tumor; Chromogranin A; Disease Progression; Enterochromaffin-like Cells; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Histamine Release; Humans; Hyperplasia; Metaplasia; Middle Aged; Neuroendocrine Tumors; Parietal Cells, Gastric; Stomach Neoplasms; Synaptophysin; Vesicular Transport Proteins

The most frequent conditions of hypergastrinemia in man are the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the tumour cell and reactive hypergastrinemia in type A autoimmune chronic atrophic gastritis with achlorhydria causing unrestrained gastrin release from the gastrin-producing antral G-cells. Both entities differ with respect to the pH in the gastric fluid, which is < 2 in patients with Zollinger-Ellison syndrome and neutral in type A gastritis. Other conditions with moderate hypergastrinemia as treatment with proton pump inhibitors, gastric outlet obstruction, previous vagotomy, chronic renal failure or short bowel syndrome are of minor clinical importance.

Topics: Autoimmune Diseases; Carcinoid Tumor; Diagnosis, Differential; Duodenal Neoplasms; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastrinomas are defined as gastrin producing tumors that are associated with an elevated fasting gastrin serum level, a positive gastrin secretin stimulation test and certain clinical symptoms, e.g. recurrent peptic ulcer disease and occasionally diarrhea, the so-called Zollinger-Ellison syndrome. Most gastrinomas occur in the duodenum (approx. 70%) and not in the pancreas. The duodenal gastrinomas are small, and when they occur in association with the genetic syndrome of multiple endocrine neoplasia type 1 (MEN1), they are multicentric and originate from precursor lesions. The prognosis of duodenal gastrinomas is better than that of pancreatic gastrinomas, since despite early lymph node metastasis they progress slowly to liver metastasis.

Topics: Duodenal Neoplasms; Duodenum; Gastrin-Secreting Cells; Gastrinoma; Gastrins; Humans; Hyperplasia; Multiple Endocrine Neoplasia Type 1; Pancreas; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Today, calcitonin assay is used for the diagnosis of thyroid medullary cancer in the context of nodular thyroid disease. Calcitonin is an excellent marker of thyroid medullary cancer but some hypercalcitoninemia can also be related to other diseases, such as renal failure, endocrine tumors other than thyroid medullary cancer and sometimes to C cell hyperplasia, which is a not well-defined situation. Recent studies contributed to define calcitoninemia thresholds, which guide decision and avoid excessive invasive treatment.. After a brief reminder of physiological role of calcitonin and assays, the difficulties encountered in interpreting hypercalcitoninemia and its potential causes other than thyroid medullary cancer are addressed. Recent studies, on large series, now allow a better knowledge of specificity and sensitivity of calcitonin measurement in patients with nodular thyroid disease and a well-argued management.. In the future, calcitonin dosage will be ordered even more frequently, as some authors recommend it for the diagnosis of thyroid nodule. It is up to us to know how to use this remarkable marker, by considering all possible situations of benign hypercalcitoninemia and reserving aggressive treatments for patients who really need them.

Topics: Adult; Biomarkers; Calcitonin; Carcinoma, Medullary; Diagnosis, Differential; Endocrine Gland Neoplasms; Gastrins; Humans; Hypercalcemia; Hyperplasia; Kidney Failure, Chronic; Sensitivity and Specificity; Sepsis; Thyroid Diseases; Thyroid Gland; Thyroid Neoplasms; Thyroid Nodule

Topics: Animals; Chromogranin A; Chromogranins; Enterochromaffin Cells; Gastrins; Humans; Hyperplasia; Neuroendocrine Tumors

Rabeprazole, a new benzimidazole proton pump inhibitor (PPI), is among a class of agents known to be very potent inhibitors of gastric acid secretion. PPIs inhibit hydrogen-potassium adenosine triphosphatase activity on the luminal surface of the parietal cell, effectively blocking the final common pathway for gastric acid secretion. Raising gastric pH stimulates the production of gastrin by G cells in the antrum of the stomach, which can lead to enterochromaffin-like (ECL)-cell hyperplasia. In the past, these changes have been viewed with concern, particularly in the light of studies in rats indicating that hypergastrinaemia and ECL-cell hyperplasia induce gastric carcinoid tumour formation. All available clinical data indicate that long-term PPI use does not lead to carcinoid tumour formation in humans. In fact, both serum gastrin elevation and ECL-cell hyperplasia are now generally viewed as normal physiological responses to gastric acid suppression. Serum gastrin concentrations, in particular, correlate well with gastric acid suppression, which has led to the use of gastrin response by some investigators as a surrogate marker of antisecretory effectiveness. Long-term tolerability data indicate that PPIs have a favourable side-effect profile. Data obtained from patients receiving acute or long-term maintenance rabeprazole therapy support this conclusion. Furthermore, neither animal nor human data obtained with rabeprazole suggest a significant risk for neoplastic changes secondary to hypergastrinaemia.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Anti-Ulcer Agents; Benzimidazoles; Enterochromaffin-like Cells; Enzyme Inhibitors; Gastrins; Humans; Hyperplasia; Omeprazole; Rabeprazole

The safety of proton-pump inhibitors (PPIs) for long-term use is reviewed. PPIs are being used with increasing frequency to inhibit secretion of gastric acid in order to treat acid-related disorders such as gastroesophageal reflux disease and peptic ulcer disease. Some patients may require long-term acid suppressive treatment to control the symptoms of their disease, which raises questions about the long-term safety of PPIs. A thorough literature search was conducted, and the clinical consequences of sustained hypergastrinemia induced by all antisecretory therapy, the consequences of atrophic gastritis in patients infected with Helicobacter pylori, the effects of hypochlorhydria on bacterial overgrowth and nutrient absorption, and possible interactions of PPIs with other drugs were identified as areas of concern with long-term use of PPIs. Short- and long-term studies showed that PPIs have a wide safety margin and a favorable adverse-event profile with few drug interactions. Available data support the short- and long-term safety of PPIs.

Topics: Anti-Ulcer Agents; Colonic Neoplasms; Drug Interactions; Enterochromaffin Cells; Gastric Acid; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Proton Pump Inhibitors; Stomach Neoplasms

Topics: Enterochromaffin Cells; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Secretory Rate; Silver

The enterochromaffin-like (ECL) cell of the oxyntic, acid-secreting mucosa is at present the most extensively studied endocrine cell type in the gastrointestinal tract. It is functionally related to acid secretion through paracrine release of histamine. Its ability to undergo proliferation in response to the trophic stimulus of hypergastrinemia has important implications in pathology, being involved in the development of ECL-cell carcinoid tumors of rodents treated with powerful inhibitors of acid secretion as well as in that of most human gastric carcinoids which, with rare exceptions, are composed of ECL cells. The various aspects of the ECL-cell response to hypergastrinemia in humans are discussed in this review. The trophic effect of gastrin is specific for ECL cells and its sensitivity is enhanced by the female sex and by the genetic background of the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Exposure of ECL cells to hypergastrinemia induces peculiar changes in the structure of cytoplasmic granules and triggers the phenotypic expression of a novel protein, the alpha subunit of glycoprotein hormones, absent in normal cells. The ECL-cell hyperplasia driven by hypergastrinemia may influence the hypersecretory gastric state of patients with Zollinger-Ellison syndrome (ZES) by inappropriate intramucosal secretion of histamine and may contribute to the high circulating levels of basic fibroblast growth factor (bFGF), an ECL-cell product responsible for parathyroid mitogenic effects in MEN-1 patients. However, hypergastrinemia per se cannot promote evolution of hyperplasia into carcinoid tumors, for which additional unknown factors, particularly associated with atrophic gastritis or MEN-1 syndrome, are required. ECL-cell carcinoids developing within these backgrounds have a strikingly more favorable course than their gastrin-independent counterpart. Suppression of hypergastrinemia, either by antrectomy or treatment with somatostatin analogues, may induce regression of both ECL-cell hyperplasia and gastrin-sensitive ECL-cell carcinoids.

Topics: Carcinoid Tumor; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Stomach Neoplasms; Zollinger-Ellison Syndrome

The diagnosis and management of antral gastrin-(G-) cell hyperplasia was a major topic of interest in the 1970s. Following the discovery of Helicobacter pylori in the 1980s, little attention was paid to this condition until it was shown that H. pylori infection was associated with hypergastrinaemia and that eradication of the organism returned the gastrin level to normal. Recent reports have examined the relationship between H. pylori and antral G-cell hyperplasia. H. pylori infection is present in about 50% of cases of antral G-cell hyperplasia and, importantly, eradication of the organism normalizes not only the gastrin level but also the antral G-cell count. Eradication treatment should be the therapy of choice. It is also of interest that H. pylori-negative antral G-cell hyperplasia or hyperfunction does exist. The historical aspects, the relationship between antral G-cell hyperplasia and H. pylori and recent case reports are reviewed.

Topics: Animals; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Pyloric Antrum

The gastrointestinal neuroendocrine cell proliferations are comprised of a few hyperplasias and various neoplasias. The better characterized hyperplasias include G-cell hyperplasia, either primary or secondary, enterochromaffin-like (ECL)-cell hyperplasias, generally secondary to hypergastrinemia, and EC-cell hyperplasias. The neoplasias include carcinoid tumors, demonstrating low malignancy and divided into foregut, midgut, and hindgut varieties, poorly differentiated neuroendocrine carcinomas resembling their pulmonary counterparts the "oat cell" carcinomas both in histological pattern and in their highly malignant behavior mixed endo-exocrine tumors, which in turn can be divided into composite tumors formed by a population of endocrine cells and a population of exocrine cells, and amphicrine tumors formed by a uniform population of cells with a mixture of endocrine and exocrine phenotypic traits. Although some of these mixed tumors show a degree of malignancy intermediate between the classical carcinoid and an adenocarcinoma, more information must be gathered to establish firm prognostic parameters for these relatively new entities.

Topics: Carcinoid Tumor; Enterochromaffin Cells; Gastrinoma; Gastrins; Gastrointestinal Neoplasms; Humans; Hyperplasia; Neuroendocrine Tumors

At present at least seven different endocrine cell types have been identified in the stomach. According to their relative frequency and secretion products the antral gastrin producing G cell and somatostatin producing D cell and the fundic histamine producing ECL cell are the best characterized cell types. Total endocrine cell mass is controlled by various factors from inside and outside the stomach. Density of antral G and D cells depends on the presence and absence of food, on the antral pH and on additional humoral and/or neural factors. Gastrin and not gastric pH has been identified as the most important factor regulating the density of fundic ECL cells. Adaptation of gastric endocrine cells to gastric pH and to the presence, abundance or absence of humoral and neural regulators are well known phenomena though only partially understood. Antral G cells increase and antral D cells decrease during long-term achlorhydria which as a consequence leads to hypergastrinaemia. Examples are pernicious anaemia in man and drug-induced acid suppression under experimental conditions. Interestingly, achlorhydria-induced G cell hyperplasia never progresses to gastrinomas. Fundic ECL cell density increases markedly in the presence of long-lasting hypergastrinaemia independently of gastric pH. In contrast to G cells ECL cell hyperplasia may progress to rarely occurring ECLomas. However, this depends on additional conditioning factors as the presence of severe atrophic gastritis as in pernicious anaemia or a specific genetic trait present in patients with gastrinomas associated with the MEN I syndrome.

Topics: Adaptation, Physiological; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Hormones; Humans; Hyperplasia; Stomach

Topics: Animals; Cholecystokinin; Gastrins; Gastrointestinal Hormones; Hyperplasia; Hypertrophy; Male; Pancreas; Pancreatic Juice; Rats; Rats, Inbred Strains

During the last few years the endocrine stomach has come into focus much due to the side-effects produced by powerful acid blockers. A sustained and marked inhibition of acid secretion in the rat results in hypergastrinemia, with gastrin cell hyperplasia, and a consequent hyperplasia of the ECL cells. This response of the ECL cells was predictable in view of previous observations that sustained hypergastrinemia causes ECL cell hyperplasia. While the gastrin cell hyperplasia levels off at about twice the normal cell density a few weeks after start of treatment, the ECL cells continue to proliferate for months to reach a five-fold higher density than normally. Evidence is accumulating that ECL cells proliferate through self replication. After life-long inhibition of acid production (high doses of ranitidine or omeprazole) or after extirpation of 75% of the acid-producing part of the stomach, ECL cell carcinoids develop. Endocrine cells in the gut often contain more than one putative messenger. Thus, gastrin cells in many species store GABA and peptide YY; in e.g. cat and man they store in addition a xenopsin-like peptide. Neuromedin U and pituitary adenylate cyclase activating peptide (PACAP) have recently been demonstrated in gut nerves. Their role in gut physiology remains to be identified.

Topics: Animals; Enterochromaffin Cells; gamma-Aminobutyric Acid; Gastric Acid; Gastrins; Humans; Hyperplasia; Neuropeptides; Neurosecretory Systems; Peptide YY; Peptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Stomach

Topics: Animals; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Hyperplasia; Mice; Omeprazole; Rats; Stomach

Topics: Achlorhydria; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Histamine; Humans; Hyperplasia; Pyloric Antrum; Stomach

Life-long administration (greater than or equal to 2 years) of a number of long-acting gastric acid inhibitors (including H2-receptor antagonists, omeprazole and ciprofibrate) has been associated with the development of gastric enterochromaffin-like cell (ECL cell) carcinoids in rats. It has been postulated that they are a consequence of some unique property of the longer-acting acid inhibitors. There is, however, a great deal of evidence to support the hypothesis that these gastric ECL cell carcinoids develop as a result of life-long hypergastrinaemia in rats. Several lines of investigation reported here show that gastric ECL cell hyperplasia occurs when gastrin levels are increased without the use of acid-inhibiting drugs. In rats, hypergastrinaemia developed after 4 weeks' administration of exogenous gastrin (4 micrograms/kg/h). The number of gastric ECL cells per visual field had increased to 250 compared with 180 in the controls. Long-term hypergastrinaemia, induced by partial gastric corpectomy, increased plasma gastrin levels from 200 to 800 pg/ml and the density of gastric ECL cells increased from 190 to 310 cells/visual field 10 weeks after the operation. Importantly, gastric ECL cell hyperplasia, which was produced in rats by administration of omeprazole, 14 mg/kg/day for 1 year, was fully reversible following normalization of gastrin levels. Until now, gastric ECL cell carcinoids have not been reported in studies of shorter-acting, reversible H2-receptor antagonists such as ranitidine, perhaps because the correct staining techniques (i.e. Grimelius and Sevier-Munger silver stains) have not been used.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Hyperplasia; Omeprazole; Ranitidine; Rats; Time Factors

Topics: Animals; Diagnosis, Differential; Digestive System; Duodenal Ulcer; Enterochromaffin Cells; Fluorescent Antibody Technique; Gastrins; Gastrointestinal Diseases; Gastrointestinal Hormones; Histocytochemistry; Humans; Hyperplasia; Immunologic Techniques; Intestinal Mucosa; Microscopy, Electron; Neural Crest; Regeneration; Stomach Neoplasms

The stomach is rich in endocrine cells, most of which are still unidentified with respect to the peptide hormones they produce. The endocrine cell populations in the antrum usually differ from those in the oxyntic mucosa. Gastrin cells are found in the antrum and respond readily to stimuli from the gastric lumen, such as changes in the pH and the presence of food. In order to study the functional control of the antral gastrin cell, rats were subjected to different kinds of surgery. The serum gastrin concentrations in the various experimental groups were measured 8-10 weeks after the operations. Elevated antral pH raised the serum gastrin concentration. The combination of elevated antral pH and the passage of food over the pyloric glands produced gastrin cell hyperplasia. The operation that was most effective in inducing gastrin cell hyperplasia was removal of the acid-producing part of the stomach. Interestingly, gastrin cell hyperplasia was seen also after bilateral truncal vagotomy, indicating that an intact vagal innervation is not essential for the development of gastrin cell hyperplasia. Enterochromaffin-like (ECL) cells are endocrine/paracrine cells that are numerous in the acid-producing part of the stomach in many species. In the rat, they occur predominantly in the basal half of the oxyntic mucosa and produce and store histamine. The ECL cells have an unknown function and do not seem to respond to stimuli from the gastric lumen. They are activated by circulating gastrin and by vagal excitation. Gastrin mobilises histamine from these cells and activates the histamine-forming enzyme, histidine decarboxylase. Long-term hypergastrinaemia produces diffuse ECL cell hyperplasia, whereas hypogastrinaemia (following removal of the endogenous stores of gastrin by antrectomy) reduces the ECL cell number. Portacaval shunt brings about a marked increase in the number of ECL cells through an unknown mechanism. Also neuronal stimuli are important for the trophic control of the ECL cells. Studies of unilaterally vagotomised rats showed reduced weight and thickness of the oxyntic mucosa as well as a markedly reduced number of ECL cells on the denervated side. Gastric carcinoids in man are rare tumours predominantly made up of ECL cells. The incidence of such tumours is increased in patients with hypergastrinaemia (pernicious anaemia, Zollinger-Ellison syndrome). A diffuse ECL cell hyperplasia is a common finding in such patients, which is in keeping with the know

Topics: Animals; Carcinoid Tumor; Chromaffin System; Enterochromaffin Cells; Gastrins; Humans; Hydrogen-Ion Concentration; Hyperplasia; Microscopy, Electron; Portacaval Shunt, Surgical; Rats; Stomach; Stomach Neoplasms

Topics: Duodenal Ulcer; Enterochromaffin Cells; Food; Gastric Acid; Gastric Acidity Determination; Gastrins; Humans; Hyperplasia; Vagus Nerve

Topics: Chromaffin System; Cytoplasmic Granules; Duodenal Ulcer; Enterochromaffin Cells; Gastrins; Humans; Hyperplasia; Immunologic Techniques; Pepsinogens; Pyloric Antrum; Zollinger-Ellison Syndrome

The lining of the intestinal tract is constantly renewed in a brisk but orderly fashion. Further acceleration of cell renewal is elicited by various stimuli, notably surgical shortening of the intestine and hyperphagia, which lead to prompt but persistent increases in mucosal mass. Progressive hypoplasia ensues when the small and large bowel are deprived of their normal contents, either by fasting (with or without parenteral nutrition) or by exclusion from intestinal continuity. All atrophic changes are reversed by refeeding or restoration of the normal anatomical disposition. Intestine responds to mucosal damage by regeneration from the crypts. Pancreatobiliary secretions mediate some of the tropic effects of chyme; systemic influences, both neurovascular and humoral, also play a part in the adaptive response of the gut.

Topics: Adaptation, Physiological; Adult; Animals; Cell Division; Colectomy; Colostomy; Female; Gastrins; Glucagon-Like Peptides; Humans; Hyperphagia; Hyperplasia; Hypertrophy; Ileum; Intestinal Diseases; Intestinal Mucosa; Intestines; Jejunum; Obesity; Parenteral Nutrition; Rats; Starvation

Topics: Cimetidine; Gastrectomy; Gastric Juice; Gastrins; Humans; Hyperplasia; Neoplasm Metastasis; Postoperative Complications; Pyloric Antrum; Vagotomy; Zollinger-Ellison Syndrome

Gastrin release does play a part in the cephalic phase of acid secretion in man and is the major mechanism for the gastric phase of acid secretion. The vagal control of gastrin release is most likely mediated by cholinergic and possibly non-cholinergic excitatory fibres, as well as by cholinergic inhibitory fibres. Gastric luminal control of gastrin release is by local food and possibly distension stimulation, as well as by acid inhibition. Of the various causes of hypergastrinaemia, those associated with gastrinoma, G-cell hyperfunction and retained antrum have definite pathogenetic roles. Duodenal ulcer disease is a heterogeneous goup of disorders having different pathogenetic mechanisms. Parietal cell hyperplasia and G-cell dysfunctions, consisting of modest to florid G-cell hyperfunction and hyperplasia with secondary parietal cell hyperplasia, are but some facets of abnormalities that we have been able to identify.

Topics: Gastric Juice; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Peptic Ulcer; Pyloric Antrum; Vagus Nerve; Zollinger-Ellison Syndrome

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Adolescent; Adult; Aged; Carcinoid Tumor; Child; Dehydration; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Humans; Hyperplasia; Hypokalemia; Insulin; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Precancerous Conditions; Serotonin; Somatostatin; Syndrome; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Adult; Amines; Carboxy-Lyases; Dehydration; Endocrine Glands; Fluorescent Antibody Technique; Gastrins; Glucagon; Humans; Hyperplasia; Intestinal Neoplasms; Intestinal Secretions; Intestines; Male; Multiple Endocrine Neoplasia; Neurosecretory Systems; Pancreas; Paraneoplastic Endocrine Syndromes; Peptides; Zollinger-Ellison Syndrome

Topics: Anemia, Pernicious; Calcium; Dietary Proteins; Duodenal Ulcer; Gastric Juice; Gastrins; Gastritis; Glucagon; Humans; Hyperplasia; Intestine, Small; Kidney Failure, Chronic; Pyloric Antrum; Pyloric Stenosis; Secretin; Stomach Neoplasms; Stomach Ulcer; Vagotomy; Zollinger-Ellison Syndrome

Topics: Anxiety Disorders; Aspirin; Bile Acids and Salts; Blood Group Antigens; Diet; Duodenal Ulcer; Female; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Motility; Histamine; Humans; Hyperplasia; Male; Pentagastrin; Peptic Ulcer; Radioimmunoassay; Stomach Ulcer; Vagotomy

Topics: Acetylcholine; Achlorhydria; Adenoma; Anemia, Pernicious; Atrophy; Duodenal Ulcer; Endocrine System Diseases; Gastrectomy; Gastric Juice; Gastric Mucins; Gastric Mucosa; Gastrins; Gastritis; Humans; Hyperplasia; Intrinsic Factor; Stomach Ulcer; Vagus Nerve; Zollinger-Ellison Syndrome

The classic scheme of gastric acid secretion which divided the digestive period into cephalic, gastric and antral phases has become obsolete in the last 10 years. These "phases" are now seen as concurrently acting mechanisms which depend upon one another to be fully efficient. About half of all gastrin released during a meal is dependent upon vagal stimulation of the antrum. Also, vagotomy desensitizes the acid-secreting parietal cells to the effect of all other types of stimuli.The number of parietal cells (parietal cell mass) varies greatly according to the gastric secretory activity of each individual. It is highest with duodenal ulcer and lowest with gastric ulcer.Parietal cell hyperplasia or atrophy can be induced experimentally, but the factors controlling the size of the parietal cell mass in man have not been studied.A scheme of acid secretion which incorporates recent advances is presented.

Topics: Duodenal Ulcer; Gastric Acid; Gastric Juice; Gastrins; Histamine; Humans; Hyperplasia; Male; Parietal Cells, Gastric; Pathology; Physiology; Stomach; Vagotomy; Vagus Nerve

To compare gastric acid suppression by netazepide, a gastrin/CCK2 receptor antagonist, with that by a proton pump inhibitor (PPI), and to determine if netazepide can prevent the trophic effects of PPI-induced hypergastrinaemia.. Thirty healthy subjects completed a double-blind, randomized, parallel group trial of oral netazepide and rabeprazole, alone and combined, once daily for 6 weeks. Primary end points were: basal and pentagastrin-stimulated gastric acid and 24 h circulating gastrin and chromogranin A (CgA) at baseline, start and end of treatment, gastric biopsies at baseline and end of treatment and basal and pentagastrin-stimulated gastric acid and dyspepsia questionnaire after treatment withdrawal.. All treatments similarly inhibited pentagastrin-stimulated gastric acid secretion. All treatments increased serum gastrin, but the combination and rabeprazole did so more than netazepide alone. The combination also reduced basal acid secretion. Rabeprazole increased plasma CgA, whereas netazepide and the combination reduced it. None of the biopsies showed enterochromaffin-like (ECL) cell hyperplasia. Withdrawal of treatments led neither to rebound hyperacidity nor dyspepsia.. Netazepide suppressed pentagastrin-stimulated gastric acid secretion as effectively as did rabeprazole. The reduction in basal acid secretion and greater increase in serum gastrin by the combination is consistent with more effective acid suppression. Despite our failure to show rabeprazole-induced ECL cell hyperplasia and rebound hyperacidity, the increase in plasma CgA after rabeprazole is consistent with a trophic effect on ECL cells, which netazepide prevented. Thus, netazepide is a potential treatment for the trophic effects of hypergastrinaemia and, with or without a PPI, is a potential treatment for acid-related conditions.

Topics: Adult; Aged; Benzodiazepinones; Double-Blind Method; Drug Therapy, Combination; Female; Gastric Acid; Gastric Mucosa; Gastrins; Healthy Volunteers; Humans; Hyperplasia; Male; Middle Aged; Phenylurea Compounds; Rabeprazole; Receptor, Cholecystokinin B; Stomach; Young Adult

Chromogranin A (CgA) is a neuroendocrine tumor (NET) marker. Modest CgA elevation is found in subjects with enterochromaffin-like (ECL) cell hyperplasia due to hypergastrinemia. Somatostatin analogs reduce CgA levels in patients with NET. Meals may affect serum CgA levels. The aims of the study were to investigate meal-induced CgA release and the short-term effect of octreotide on serum CgA levels. Four groups were studied: group A, seven patients with ECL cell hyperplasia secondary to use of proton pump inhibitors (PPIs); group B, six patients with gastric carcinoid type 1/ECL hyperplasia due to chronic atrophic gastritis (CAG); group C, six patients with nongastric NETs; group D, seven controls. The subjects were studied on three separate days with the use of three exposures: a test meal, pentagastrin subcutaneously (not group C), and octreotide intravenously. Serum CgA and gastrin were analyzed. A test meal induced a significant CgA increase in long-term PPI users and in healthy controls. The meal did not affect CgA levels in patients with gastric carcinoid type 1 or patients with NETs. The test meal increased gastrin levels in all groups except in those with CAG. Pentagastrin increased CgA levels in all groups tested except in those with CAG, while octreotide, reduced CgA and gastrin levels in all groups. Serum CgA should be determined in fasting individuals. A test meal may distinguish between increased CgA levels in PPI users from nongastric NET patients. Concomitant gastrin determination may help to discriminate between nongastric NETs and CAG. Intravenous octreotide rapidly reduces serum CgA.

Topics: Aged; Biomarkers, Tumor; Carcinoid Tumor; Carcinoma, Neuroendocrine; Chromogranin A; Diagnostic Techniques, Digestive System; Enterochromaffin-like Cells; Female; Gastrins; Gastrointestinal Agents; Humans; Hyperplasia; Male; Middle Aged; Octreotide; Pentagastrin; Proton Pump Inhibitors; Radioimmunoassay; Stomach Neoplasms

Prolonged gastric acid suppression leads to hypergastrinaemia, which promotes hyperplasia of the enterochromaffin-like (ECL) cells of the oxyntic mucosa. The objective was to determine the effects of 5 years of treatment with rabeprazole or omeprazole on the gastric mucosa.. Two hundred and forty-three patients received rabeprazole (20 mg or 10 mg) or omeprazole (20 mg) once daily for up to 5 years, for gastro-oesophageal reflux disease and 51% completed the whole 5 year period. Gastric biopsy specimens were taken and examined for gastritis, Helicobacter pylori infection, and ECL cell status.. H. pylori infection in the gastric corpus was more common than in the antrum, and remained constant, whereas antral H. pylori infection became less common as the study progressed. H. pylori infection was a highly significant predictor of higher gastritis scores, which were similar among the three treatment groups. ECL cell hyperplasia occurred in a minority of patients, and was associated with serum gastrin concentrations. No ECL cell dysplasia or tumours were observed. There were no significant differences among the treatment groups in gastritis or ECL cell hyperplasia grades.. This study has confirmed the link between ECL cell hyperplasia and elevated serum gastrin concentrations, but has found no evidence that this progresses to high grades of hyperplasia during 5 years of treatment with rabeprazole or omeprazole.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Anti-Ulcer Agents; Benzimidazoles; Biopsy; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastric Mucosa; Gastrins; Gastritis; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Male; Metaplasia; Middle Aged; Omeprazole; Prospective Studies; Proton Pump Inhibitors; Rabeprazole; Severity of Illness Index

The effects of H. pylori eradication on atrophic body gastritis are controversial.. To investigate the effect of triple therapy on atrophic body gastritis in H. pylori-positive patients and its effect on morpho-functional gastric parameters.. Thirty-five consecutive atrophic body gastritis patients with histological/serological evidence of H. pylori infection were treated. Before and 6 and 12 months after H. pylori eradication the patients were evaluated for fasting gastrinemia and pepsinogen I, basal and peak acid output, and detailed histological assessment including the ECL cell proliferative patterns.. Six months after treatment, 25 out of 32 patients were cured (78%). Cure of infection was associated with improvement in both basal (basal acid output mean 0.23 +/- 0.14 mmol/h vs. 1.75 +/- 0.7 mmol/h, P < 0.005) and stimulated acid secretion (peak acid output mean 3.0 +/- 1.06 mmol/h vs. 16.6 +/- 4.1 mmol/h, P=0.0017) as well as with reduction in hypergastrinemia (mean gastrin levels 444.1 +/- 110.7 pg/mL vs. 85.3. +/- 28 pg/mL; P < 0.005). In contrast, the eradication had no effect on body corporal atrophy and intestinal metaplasia, or pepsinogen I levels (mean 16.6 +/- 2.9 ng/mL vs. 14.2 +/- 2.1 ng/mL, N.S.). These results were confirmed at 12 months after eradication. A statistical inverse correlation was obtained (r=-0.3635, P < 0.05) between the corporal chronic infiltrate score and peak acid output values. A total of 53% of atrophic body gastritis patients showed a regression in severity of body ECL cell hyperplastic change.. Cure of H. pylori infection in patients with atrophic gastritis reverses some adverse effects on gastric function and ECL cell hyperplasia. H. pylori infection may be cured in atrophic body gastritis patients with partial reversion of its negative consequences on acid secretion and body ECL cell hyperplasia.

Topics: Adult; Aged; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Male; Middle Aged; Pepsinogen A; Prospective Studies; Treatment Outcome

A cross sectional study was designed to elucidate the factors influencing the argyrophil cell population in patients with gastroesophageal reflux disease treated with omeprazole (N = 201) or H2-receptor antagonists (N = 118) and in control patients (N = 215). Fasting gastrinemia and Helicobacter pylori serology were determined. Gastritis, Helicobacter pylori infection, and argyrophil cell density and hyperplasia were evaluated in gastric biopsies. The argyrophil cell density was higher in both treatment groups than in controls (P = 0.002 and P = 0.051), whereas argyrophil cell hyperplasia was similar in the three groups. According to multivariate analysis, positive Helicobacter pylori serology was an independent parameter that decreased both density and grade of hyperplasia of argyrophil cells. Female gender and hypergastrinemia were independent factors increasing argyrophil cell density and hyperplasia, whereas antisecretory therapy, age and active gastritis were not. In addition, atrophic gastritis independently increased argyrophil cell hyperplasia. The prevalence of atrophic gastritis was significantly higher in Helicobacter pylori-positive than in negative patients and lower in the patients treated long-term with omeprazole than in the other groups.

Topics: Adult; Aged; Aged, 80 and over; Anti-Ulcer Agents; Cell Count; Cross-Sectional Studies; Enterochromaffin-like Cells; Esophagitis, Peptic; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Histamine H2 Antagonists; Humans; Hyperplasia; Male; Middle Aged; Multivariate Analysis; Omeprazole; Sex Factors

Helicobacter pylori infection is common in patients with hyperplastic gastric polyps.. To study the effect of eradication of H. pylori on the clinical course of patients with hyperplastic gastric polyps.. Single-blind, randomized, controlled trial.. University-based gastroenterology outpatient clinic.. 35 patients with H. pylori infection and hyperplastic gastric polyps at least 3 mm in diameter.. Patients were randomly assigned to a treatment group (n = 17), which received a proton-pump inhibitor (omeprazole or lansoprazole), amoxicillin, and either clarithromycin or ecabet sodium, or to a control group (n = 18), which received no treatment.. Patients underwent endoscopy before enrollment and 12 to 15 months after the end of treatment. Serum gastrin levels and titers of IgG to H. pylori were measured.. In the treatment group, the polyps had disappeared by 3 to 15 months (average, 7.1 +/- 1.2 months) after the end of treatment in 12 of all 17 patients (71%) and in 12 of the 15 patients (80%) in whom H. pylori was eradicated. However, 12 to 15 months after the start of the study, no change in polyps or H. pylori status was seen in any controls (P < 0.001). Histologic findings of inflammation and activity, serum gastrin levels, and titers of IgG to H. pylori showed significant regression in the treatment group compared with the control group (P < 0.01).. Most hyperplastic polyps disappeared after eradication of H. pylori. Thus, eradication should be attempted before endoscopic removal is done in patients with hyperplastic gastric polyps and H. pylori infection.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Abietanes; Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Diterpenes; Drug Therapy, Combination; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Immunoglobulin G; Lansoprazole; Male; Middle Aged; Omeprazole; Penicillins; Polyps; Proton Pump Inhibitors; Single-Blind Method; Statistics, Nonparametric; Stomach Neoplasms

Erosive oesophagitis refractory to high dose histamine H2 receptor antagonists (definition: failure to heal fully after > or = 3 months' treatment with cimetidine 3.2 g or ranitidine 0.9 g) responds well to omeprazole 40 mg daily but frequently relapses when the patients are put back on maintenance H2 receptor antagonists at medium or even high dose (e.g. cimetidine 1.6 g and 3.2 g, respectively).. To investigate the efficacy of maintenance omeprazole 20 mg daily in refractory erosive oesophagitis.. In this open, sequential study, patients with H2 receptor antagonist-refractory oesophagitis were healed on omeprazole 40 mg daily and then put on maintenance H2 receptor antagonists (cimetidine 1.6 g or 3.2 g). Relapses were re-treated with omeprazole 40 mg; upon rehealing, patients were put on maintenance omeprazole 20 mg daily for up to 4.5 years.. Healing on omeprazole occurred in 38 out of 39 patients (97%) at 12 weeks. Only six of the 38 patients (16%) relapsed (asymptomatic in half) during subsequent maintenance treatment, whereas all had relapsed earlier on high dose H2 receptor antagonists.. Within the limits of interpretation of an open study, omeprazole 20 mg daily seems effective in maintaining prolonged remission in this group of patients with H2 receptor antagonist-refractory oesophagitis.

Topics: Adult; Aged; Biopsy; Cimetidine; Drug Administration Schedule; Drug Resistance; Enzyme Inhibitors; Esophagitis, Peptic; Esophagus; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastroscopy; Histamine H2 Antagonists; Humans; Hyperplasia; Male; Middle Aged; Omeprazole; Ranitidine; Recurrence; Treatment Outcome; Wound Healing

The pathogenesis for non-type 1/2 gastric neuroendocrine tumors (G-NETs) remains unclear. The aim of this study was to examine the clinicopathologic features of G-NETs and associated mucosal changes.. The electronic health records of patients with non-type 1/2 G-NETs were reviewed. H&E slides were reviewed for pathologic features and mucosal changes. The t test and Fisher exact test were used for statistical analysis.. In total, 33 patients were assigned to either group 1 (n = 23) or group 2 (n = 10). Group 1 included patients with a history of proton pump inhibitor (PPI) use, increased gastrin levels, or significant PPI effect (PPI/gastrin-associated). All other patients were assigned to group 2. There was no significant difference in age and sex between the 2 groups. Group 2 tumors were more likely to be larger, invade deeper, and develop metastases (P < .05). Tumors in patients with cirrhosis tended to be larger. Peritumoral mucosal changes included loss of oxyntic glands, foveolar hyperplasia, and intestinal metaplasia. Background mucosa in group 1 patients showed PPI effect and neuroendocrine hyperplasia or dysplasia.. Although PPI/gastrin-associated non-type 1/2 G-NETs were smaller and more indolent than typical type 3 G-NETs, tumors in patients with cirrhosis tended to be larger. Additionally, peritumoral mucosal changes could mimic chronic atrophic gastritis.

Topics: Gastric Mucosa; Gastrins; Humans; Hyperplasia; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

Fundectomy, shown as an alternative to restrictive techniques, causes absorption restriction and metabolic changes. This study aimed to examine the histopathological changes caused by the fundectomy as a technique applied to rats by hormones that affect stomach and obesity metabolism and its effect on weight loss.. 2randomly selected Winstar-Hannover rat groups were evaluated by measuring their pre-and postoperative weights and biochemically measuring Gastrin, Ghrelin, and Leptin levels on day 30. After sacrification, the stomachs were taken for histopathological examination.. Significant weight loss was observed in the fundectomy group in the 1stmonth postoperatively. Biochemically, Gastrin means in the fundectomy group were statistically significantly higher than in the control group. The mean Ghrelin and Leptin levels of the Fundectomy Group were statistically significantly lower (p=0.005). Immunohistochemically, Gastrin means ™at the antrum and proximal stomach parts of the Fundectomy Group were significantly higher than in the control group. As Ghrelin, a significant decrease was observed in all 3regions of the Fundectomy Group compared to the control group. Leptin results were significantly lower at the antrum and proximal stomach parts of the Fundectomy Group. Histopathologically, in the Fundectomy Group, cystic glandular hyperplasia was moderate at the proximal stomach, foveolar hyperplasia was mild at the antrum, fibrosis was moderate at the antrum and corpus, and high at the proximal stomach.. Fundectomy is an effective method in terms of weight loss. This animal experiment, conducted as a pilot study, will be an essential step in elucidating metabolic and histopathological changes.. Bariatric surgery, Fundectomy, Obesity.. La resezione del fondo gastrico, indicata come alternativa alle tecniche restrittive, provoca restrizione dell’assorbimento e alterazioni metaboliche. Questo studio mirava a esaminare i cambiamenti istopatologici causati da questo intervento eseguito su ratti ad opera di ormoni che influenzano il metabolismo dello stomaco e dell’obesità e il suo effetto sulla perdita di peso. Sono stati utilizzati 2 Gruppi di ratti Winstar-Hannover, selezionati casualmente, valutando il loro peso pre e postoperatorio e misurando biochimicamente i livelli di gastrina, grelina e leptina al giorno 30. Dopo il sacrificio, gli stomaci sono stati sottoposti ad esame istopatologico. RISULTATI: È stata osservata nel 1° mese dopo l’intervento una significativa perdita di peso nel gruppo dei resecati del fondo gastrico. Dal punto di vista biochimico, i livelli medi della Gastrina è risultato statisticamente e significativamente più elevato nel gruppo dei gastroresecati rispetto al gruppo di controllo. I livelli medi di grelina e leptina sono risultati statisticamente e significativamente più bassi (p=0,005) nel gruppo dei gastroresecati. Dal punto di vista immuno-istochimico i livelli medi della Gastrina sono risultati significativamente più elevati nelle parti dell’antro e dello stomaco prossimale nel gruppo dei gastro-resecati rispetto al gruppo di controllo. Per quanto riguarda la Grelina, è stata osservata una diminuzione significativa in tutte e 3 le regioni del gruppo della fundectomia rispetto al gruppo di controllo. I risultati della leptina sono risultati significativamente più bassi nelle parti dell’antro e dello stomaco prossimale del gruppo dei fundectomizzati. Dal punto di vista istologico nel gruppo della fundectomia, l’iperplasia ghiandolare cistica era moderata nello stomaco prossimale, l’iperplasia foveolare era lieve all’antro, la fibrosi era moderata all’antro e al corpo ed elevata nello stomaco prossimale. CONCLUSIONE: la fundectomia si è dimostrata un metodo efficace ai fini della riduzione del peso. Questo studio sperimentale sugli animali, condotto come studio pilota, potrà rappresentare un passaggio essenziale per chiarire i cambiamenti metabolici e istopatologici della resezione del fondo gastrico.

Topics: Animals; Gastrins; Ghrelin; Hyperplasia; Leptin; Obesity; Pilot Projects; Rats; Weight Loss

Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis.. Transgenic GFAP. GFAP. GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.

Topics: Animals; Carcinogenesis; Cell Differentiation; Cell Plasticity; Gastrins; Glial Fibrillary Acidic Protein; Hedgehog Proteins; Hyperplasia; Mice; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Cells; Neuroglia; Proto-Oncogene Proteins; RNA, Small Interfering

Helicobacter pylori infection in humans typically begins with colonization of the gastric antrum. The initial Th1 response occasionally coincides with an increase in gastrin secretion. Subsequently, the gastritis segues to chronic atrophic gastritis, metaplasia, dysplasia and distal gastric cancer. Despite these well characterized clinical events, the link between inflammatory cytokines and non-cardia gastric cancer remains difficult to study in mouse models. Prior studies have demonstrated that overexpression of the Hedgehog (HH) effector GLI2 induces loss of gastrin (atrophy) and antral hyperplasia. To determine the link between specific cytokines, HH signaling and pre-neoplastic changes in the gastric antrum.. Mouse lines were created to conditionally direct IL1β or IFN-γ to the antrum using the Gastrin-CreERT2 and Tet activator. Primary cilia, which transduces HH signaling, on G cells were disrupted by deleting the ciliary motor protein KIF3a. Phenotypic changes were assessed by histology and western blots. A subclone of GLUTag enteroendocrine cells selected for gastrin expression and the presence of primary cilia was treated with recombinant SHH, IL1β or IFN-γ with or without kif3a siRNA.. IFN-γ increased gastrin and induced antral hyperplasia. However, antral expression of IL1β suppressed tissue and serum gastrin, while also inducing antral hyperplasia. IFN-γ treatment of GLUTAg cells suppressed GLI2 and induced gastrin, without affecting cilia length. By contrast, IL1β treatment doubled primary cilia length, induced GLI2 and suppressed gastrin gene expression. Knocking down kif3a in GLUTAg cells mitigated SHH or IL1β suppression of gastrin.. Overexpression of IL1β in the antrum was sufficient to induce antral hyperplasia coincident with suppression of gastrin via primary cilia. ORCID: #0000-0002-6559-8184.

Topics: Animals; Antiviral Agents; Cilia; Gastrins; Helicobacter Infections; Helicobacter pylori; Hyperplasia; Interferon-gamma; Interleukin-1beta; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pyloric Antrum

Gastrin regulates gastric acid secretion, and gastrin secretion itself is regulated by the negative feedback system of gastric acidity. Autoimmune gastritis (AG) is a disease where parietal cells are destroyed, resulting in decreased acid production and an elevated serum gastrin level. We herein report 2 AG cases with marked hypergastrinemia (>5,000 pg/mL). In both cases, 24-hour gastric pH monitoring showed no time when gastric pH was <2, and immunohistochemistry revealed more than 140 gastrin-positive cells per linear millimeter at the antral mucosa. This is the first report to confirm the relationship between marked hypergastrinemia and G-cell hyperplasia with AG.

Topics: Aged; Autoimmune Diseases; Female; Gastric Mucosa; Gastrins; Gastritis; Humans; Hyperplasia; Immunohistochemistry

Enterochromaffin-like (ECL) cells in the stomach express gastrin/cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified.. We used mice with green fluorescent protein fluorescent reporter expression in ECL cells (histidine decarboxylase [Hdc]-green fluorescent protein), as well as Cck2r- and Hdc-driven Tamoxifen inducible recombinase Cre (Cck2r-CreERT2, Hdc-CreERT2) mice combined with Rosa26Sor-tdTomato (R26-tdTomato) mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment).. Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2. We show here that hypergastrinemia induces ECL cell hyperplasia that is derived primarily from CCK2R

Topics: Animals; Disease Models, Animal; Enterochromaffin-like Cells; Gastric Mucosa; Gastrins; Humans; Hyperplasia; MAP Kinase Signaling System; Mice; Receptor, Cholecystokinin B; Stem Cells

The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia.. Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas.. MEN1-associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae.

Topics: Active Transport, Cell Nucleus; Animals; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Duodenal Neoplasms; Duodenum; Gastrinoma; Gastrins; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Humans; Hyperplasia; Mice, Inbred C57BL; Mice, Knockout; Neuroglia; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis; Proto-Oncogene Proteins; Proton Pump Inhibitors; Receptor, Cholecystokinin B; Receptors, Somatostatin; Time Factors; Ubiquitination

We report a case of developing multiple adenocarcinoma foci in multiple hyperplastic polyps in a patient with Helicobacter pylori infection and hypergastrinemia during long-term proton pump inhibitor (PPI) therapy. A 57-year-old man, who was undergoing hemodialysis for chronic renal failure, underwent an upper gastrointestinal endoscopy to elucidate the cause of anemia. Atrophic gastritis with H. pylori infection and multiple adenocarcinoma foci in multiple hyperplastic polyps were found in the endoscopic and histological examinations. Enterochromaffin-like micronests and parietal cell protrusion in the background of the polyps suggested the existence of hypergastrinemia. The serum gastrin level was markedly high-10,206 pg/ml (normal range 37-172 pg/ml). The cause of this marked hypergastrinemia was not autoimmune gastritis and gastrinoma. After discontinuing PPI therapy and successful eradication of H. pylori, the serum gastrin level decreased to normal range. These findings indicate that hypergastrinemia may be caused by long-term PPI therapy in patients with H. pylori infection. This case suggests that hypergastrinemia may mediate gastric carcinogenesis in patients with H. pylori infection.

Topics: Adenocarcinoma; Cocarcinogenesis; Drug Administration Schedule; Gastrins; Gastritis, Atrophic; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Male; Middle Aged; Polyps; Proton Pump Inhibitors; Stomach Neoplasms

By whole exome sequencing, we recently identified a missense mutation (p.R703C) in the human ATP4a gene, which encodes the proton pump responsible for gastric acidification. This mutation causes an aggressive familial type I gastric neuroendocrine tumor in homozygous individuals. Affected individuals show an early onset of the disease, characterized by gastric hypoacidity, hypergastrinemia, iron-deficiency anemia, gastric intestinal metaplasia and, in one case, an associated gastric adenocarcinoma. Total gastrectomy was performed as the definitive treatment in all affected individuals. We now describe the generation and characterization of a knockin mouse model for the ATP4a(R703C) mutation to better understand the tumorigenesis process. Homozygous mice recapitulated most of the phenotypical alterations that were observed in human individuals, strongly suggesting that this mutation is the primary alteration responsible for disease development. Homozygous mice developed premalignant condition with severe hyperplasia, dysplasia and glandular metaplasia in the stomach. Interestingly, gastric acidification in homozygous mice, induced by treatment with 3% HCl acid in the drinking water, prevented (if treated from birth) or partially reverted (if treated during adulthood) the development of glandular metaplasia and dysplasia in the stomach and partially rescued the abnormal biochemical parameters. We therefore suggest that, in this model, achlorhydria contributes to tumorigenesis to a greater extent than hypergastrinemia. Furthermore, our mouse model represents a unique and novel tool for studying the pathologies associated with disturbances in gastric acid secretion.

Topics: Anemia; Animals; Disease Models, Animal; Gastric Acid; Gastrins; Gene Knock-In Techniques; H(+)-K(+)-Exchanging ATPase; Homozygote; Humans; Hydrochloric Acid; Hyperplasia; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Neuroendocrine Tumors; Phenotype; Stomach; Stomach Neoplasms

An inhibitory mechanism toward gastrin hypersecretion is significantly different between G-cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G-cell, d-cell and ECL-cell density in a case of G-cell hyperplasia. The 70-year-old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600 pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G-cells in the pyloric glands was quantified on the surgical specimens and G-cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL-cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G-cell density. Somatostatin immunoreactive cells (D-cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G-cell hyperplasia could induce ECL-cell proliferation in a paracrinal manner. In addition, relatively non-prominent endocrinological features in the G-cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL-cells in the pyloric glands.

Topics: Aged; Cell Count; Cell Proliferation; Female; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Stomach

Topics: Autoimmune Diseases; Chromogranin A; Female; Gastrectomy; Gastric Mucosa; Gastrin-Secreting Cells; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Middle Aged; Mucin-6; Neuroendocrine Tumors; Stomach; Stomach Neoplasms; Synaptophysin

Gastrin and chromogranin A (CgA) levels have been tested for the diagnosis of enterochromaffin-like cell hyperplasia (ECLH) in patients with type 1 diabetes and autoimmune atrophic gastritis but not for patients with Hashimoto's thyroiditis (HT). The aim of the study was to develop receiver operating characteristic (ROC) curves for gastrin and CgA levels and other clinical and biochemical parameters, as means for pretest probability of gastric ECLH in patients with HT.. A total of 115 patients with HT were prospectively studied for a median period of 4 (2-7) years. Gastrin, CgA, vitamin B12, anti-parietal cell antibodies, free thyroxine, thyrotropin, and neuron-specific enolase levels were measured. Their predictive values were calculated according to the histological findings for ECLH diagnosis from esophagogastroduodenoscopy-obtained biopsies.. Thirteen patients (11.3%) had ECLH. The areas under the curve for gastrin and CgA level were 0.898 (p < 0.001) and 0.853 (p < 0.001), respectively. The product sensitivity × specificity was 0.803 and 0.653 for gastrin and CgA levels >89.5 and >89.1 ng/ml, respectively. Two and 4 patients with ECLH had normal gastrin and CgA levels, respectively. The most specific combined parameters predicting ECLH were gastrin >89.5 ng/ml with concomitant low B12 levels (96.1% specificity).. Gastrin levels have high diagnostic accuracy for ECLH identification in patients with HT, and are highly specific when combined with low B12 levels. However, they should be interpreted with caution, as some patients may harbor gastric ECLH even if gastrin levels are not increased, necessitating further follow-up.

Topics: Adult; Aged; Biomarkers; Chromogranin A; Diabetes Mellitus, Type 1; Enterochromaffin-like Cells; Female; Gastrins; Hashimoto Disease; Humans; Hyperplasia; Longitudinal Studies; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Risk Factors; ROC Curve; Sensitivity and Specificity; Stomach; Stomach Diseases

We report a rare case of an ovarian mucinous cystadenoma in which there were peculiar neuroendocrine micronests composed of gastrin-immunoreactive cells. There was no clinical evidence of hypergastrinemia. The mucinous component of the neoplasm was represented by columnar cells mostly expressing a gastric phenotype with MUC5AC and claudin 18 positivity, which was consistent with the presence of interspersed gastrin cells. The tumoral stroma displayed areas of luteinization with cells intensely positive for α-inhibin, MART-1 and calretinin.

Topics: Biomarkers, Tumor; Cystadenoma, Mucinous; Female; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Middle Aged; Neuroendocrine Cells; Ovarian Neoplasms

In contrast to sessile serrated adenomas and traditional serrated adenomas which are associated with a significant cancer risk, the role of hyperplastic polyps (HP) in colorectal carcinogenesis as well as the molecular mechanisms underlying their development remain controversial and still need to be clarified. Several reports suggest that a subset of HP may represent precursor lesions of some colorectal cancers. However, biomarkers are needed to identify the subset of HP that may have a malignant potential. The hormone precursor, progastrin (PG) has been involved in colon carcinogenesis and is known to activate pro-oncogenic pathways such as the ERK or the STAT3 pathway. We therefore analyzed PG expression and the activation of these signaling factors in HP.. We retrospectively analyzed PG expression as well as the phosphorylation of ERK and STAT3 by immunohistochemistry in HP from 48 patients.. Mean percentages of epithelial cells positive for PG or phospho-ERK were respectively, 31% and 33% in HP and were significantly higher in these lesions compared to normal colon (3%, p=0.0021 and 7%, p=0.0008, respectively). We found a significant correlation between PG and phospho-ERK expression in HP with ERK activation significantly stronger in lesions with high progastrin expression (p=0.015). In contrast, STAT3 was not significantly activated in HP compared to normal colon and we did not observe a significant correlation with PG expression.. HP overexpressing PG that have the highest activation of the ERK pathway might reflect less latent lesions that might have a malignant potential.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Colonic Polyps; Extracellular Signal-Regulated MAP Kinases; Female; Gastrins; Humans; Hyperplasia; Intestinal Mucosa; Male; Middle Aged; Oncogene Proteins; Protein Precursors; Retrospective Studies; Risk Factors; Signal Transduction; STAT3 Transcription Factor

To establish a rat model mimicking human bile reflux for studying the pathological effects of chronic bile reflux.. The duodenum of Sprague-Dawley rats was transected below the opening of the common bile duct, and a gastrojejunostomy was performed at the greater curvature of the forestomach. After the rats demonstrated bile reflux for 1 year, we studied the pathological features of the glandular stomach and forestomach mucosa. We also studied the effect of bile reflux on gastrin expression in the glandular stomach mucosa by using immunohistochemistry.. Chronic bile reflux caused significant hyperplasia and expansion of gastric glands in the glandular stomach. Dysplasia and cancer formation also developed, but the incidence was significantly lower than that reported in the literature. Intestinal metaplasia and ulceration in the glandular stomach were also rare. In the forestomach, the squamous epithelium showed significant hyperplasia and keratinization along with keratin pearls and keratocysts. Intestinal metaplasia was rare and no tumorigenesis was observed. Chronic bile reflux significantly increased gastrin expression in the glandular stomach mucosa.. When simulating the physiological bile reflux pathway, chronic bile reflux caused hyperplasia and expansion of gastric glands in the glandular stomach and squamous epithelial hyperplasia and keratinization in the forestomach.

Topics: Animals; Bile Reflux; Chronic Disease; Disease Models, Animal; Duodenum; Gastric Bypass; Gastric Mucosa; Gastrins; Hyperplasia; Male; Rats; Rats, Sprague-Dawley

The thyrogastric autoimmune syndrome (TAS) was described in patients in whom the serum cross-reacted both with gastric parietal cells antigens and thyroid antigens. We report two cases illustrating the spectrum of pathogical features of TAS. The first case associates Hashimoto's thyroiditis and anemia perniciosa,and develops a gastric neuroendocrine tumor during follow up. The second case presents with a Graves' disease and an autoimmune reversible gastritis, secondary to Helicobacter pylori. Whereas type III autoimmune polyendocrinopathy is rare, TAS is frequent in our experience. Some 13% (32/240) of patients that we have prospectively followed affected with thyroiditis have also autoimmune gastritis. Helicobacter pylori is clearly implicated in 16% of autoimmune gastritis cases. Infection, malabsorption and gastritis are potentially reversible after bacterial eradication treatment. In the other 84% of gastritis patients, no histological or serological proof of Helicobacter pylori is found. Gastric autoimmunity is then irreversible, leading to gastric severe atrophy, hypochlorhydria and hypergastrinemia. Hypergastrinemia stimulates enterochromaffin cell hyperplasia, possibly progressing to neuroendocrine tumors. We propose a diagnostic approach to improve the characterization of TAS. We review the literature on the subject and discuss some interesting animal models of infectious gastric autoimmunity.

Topics: Enterochromaffin-like Cells; Gastrins; Gastritis; Humans; Hyperplasia; Neuroendocrine Tumors; Stomach Neoplasms; Thyroiditis, Autoimmune

We investigated extra-cardiac clinical symptoms and signs in the rare Jervell and Lange-Nielsen Syndrome, characterised by impaired KCNQ1 function, a gene essential for gastric acid secretion.. All Swedish Jervell and Lange-Nielsen cases with double KCNQ1 mutations (14 cases) were investigated by medical record review, an interview, and were offered laboratory testing for iron-deficiency anaemia and gastrointestinal markers.. A history of iron-deficiency anaemia in 12 of 14 patients and subjective gastrointestinal symptoms in 13 of 14 patients was revealed. Previous endoscopy in five cases had revealed no case of coeliac or inflammatory bowel disease but three cases of mucosal hyperplasia/dysplasia. Current signs of anaemia or iron substitution were present in 9 of 12 tested cases. Elevated levels of gastrin in seven of nine cases, pepsinogen in six of seven cases, and faecal calprotectin in nine of nine cases were present. A significant correlation between elevated gastrin levels and concurrent iron-deficiency and/or anaemia was revealed (p-value 0.039).. A high frequency of extra-cardiac clinical symptoms and previous medical investigations was found. We propose that the Jervell and Lange-Nielsen Syndrome phenotypically includes gastrointestinal symptoms/signs and secondary iron-deficiency anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations. The resultant elevated gastrin level is a potential risk factor for later gastrointestinal cancer. Clinical monitoring with regard to developing anaemia and hypergastrinaemia should be considered in the Jervell and Lange-Nielsen Syndrome.

Topics: Adolescent; Adult; Aged, 80 and over; Anemia, Iron-Deficiency; Biomarkers; Biopsy; Child; Child, Preschool; Female; Gastrins; Gastroscopy; Genotype; Humans; Hyperplasia; Interviews as Topic; Jervell-Lange Nielsen Syndrome; KCNQ1 Potassium Channel; Leukocyte L1 Antigen Complex; Male; Middle Aged; Mutation; Pepsinogen A; Phenotype; Stomach; Sweden

The role of primary cilia in the gastrointestinal tract has not been examined. Here we report the presence of primary cilia on gastric endocrine cells producing gastrin, ghrelin, and somatostatin (Sst), hormones regulated by food intake. During eating, cilia in the gastric antrum decreased, whereas gastric acid and circulating gastrin increased. Mice fed high-fat chow showed a delayed decrease in antral cilia, increased plasma gastrin, and gastric acidity. Mice fed high-fat chow for 3 wk showed lower cilia numbers and acid but higher gastrin levels than mice fed a standard diet, suggesting that fat affects gastric physiology. Ex vivo experiments showed that cilia in the corpus responded to acid and distension, whereas cilia in the antrum responded to food. To analyze the role of gastric cilia, we conditionally deleted the intraflagellar transport protein Ift88 (Ift88(-/fl)). In fed Ift88(-/fl) mice, gastrin levels were higher, and gastric acidity was lower. Moreover, gastrin and Sst gene expression did not change in response to food as in controls. At 8 mo, Ift88(-/fl) mice developed foveolar hyperplasia, hypergastrinemia, and hypochlorhydria associated with endocrine dysfunction. Our results show that components of food (fat) are sensed by antral cilia on endocrine cells, which modulates gastrin secretion and gastric acidity.

Topics: Animals; Cilia; Diet, High-Fat; Female; Food; Gastric Acid; Gastric Mucosa; Gastrins; Ghrelin; Hyperplasia; Male; Mice; Mice, Inbred C57BL; Pyloric Antrum; Stomach; Tumor Suppressor Proteins

Spasmolytic polypeptide/trefoil family factor 2 expressing metaplasia (SPEM) is induced by oxyntic atrophy and is known as a precancerous or paracancerous lesion. We now have sought to determine whether hepatocyte growth factor (HGF) influences the development of SPEM and oxyntic atrophy. DMP-777, a parietal cell ablating reagent, was administered to HGF activator (HGFA)-deficient mice and wild-type mice. Gastric mucosal lineage changes were analyzed in the DMP-777 treatment phase and recovery phase. Both wild-type and HGFA knockout mice showed SPEM, and there was no difference in SPEM development. However, after cessation of DMP-777, HGFA-deficient mice showed delayed recovery from SPEM compared with wild-type mice. Foveolar cell hyperplasia and the increase in proliferating cells after parietal cell loss were reduced in HGFA-deficient mice. The HGFA does not affect emergence of SPEM. However, the absence of HGFA signaling causes a delay in the recovery from SPEM to normal glandular composition. HGFA also promotes foveolar cell hyperplasia and mucosal cell proliferation in acute oxyntic injury.

Topics: Animals; Atrophy; Azetidines; Gastric Mucosa; Gastrins; Hyperplasia; Intercellular Signaling Peptides and Proteins; Male; Metaplasia; Mice; Mice, Knockout; Parietal Cells, Gastric; Peptides; Piperazines; Serine Endopeptidases

Chronic inflammation in the stomach can lead to gastric cancer. We previously reported that gastrin-deficient (Gast⁻/⁻) mice develop bacterial overgrowth, inflammatory infiltrate, increased Il-1β expression, antral hyperplasia and eventually antral tumors. Since Hedgehog (Hh) signaling is active in gastric cancers but its role in precursor lesions is poorly understood, we examined the role of inflammation and Hh signaling in antral hyperplasia. LacZ reporter mice for Sonic hedgehog (Shh), Gli1, and Gli2 expression bred onto the Gast⁻/⁻ background revealed reduced Shh and Gli1 expression in the antra compared to wild type controls (WT). Gli2 expression in the Gast⁻/⁻ corpus was unchanged. However in the hyperplastic Gast⁻/⁻ antra, Gli2 expression increased in both the mesenchyme and epithelium, whereas expression in WT mice remained exclusively mesenchymal. These observations suggested that Gli2 is differentially regulated in the hyperplastic Gast⁻/⁻ antrum versus the corpus and by a Shh ligand-independent mechanism. Moreover, the proinflammatory cytokines Il-1β and Il-11, which promote gastric epithelial proliferation, were increased in the Gast⁻/⁻ stomach along with Infγ. To test if inflammation could account for elevated epithelial Gli2 expression in the Gast⁻/⁻ antra, the human gastric cell line AGS was treated with IL-1β and was found to increase GLI2 but decrease GLI1 levels. IL-1β also repressed human GAST gene expression. Indeed, GLI2 but not GLI1 or GLI3 expression repressed gastrin luciferase reporter activity by ∼50 percent. Moreover, chromatin immunoprecipitation of GLI2 in AGS cells confirmed that GLI2 directly binds to the GAST promoter. Using a mouse model of constitutively active epithelial GLI2 expression, we found that activated GLI2 repressed Gast expression but induced Il-1β gene expression and proliferation in the gastric antrum, along with a reduction of the number of G-cells. In summary, epithelial Gli2 expression was sufficient to stimulate Il-1β expression, repress Gast gene expression and increase proliferation, leading to antral hyperplasia.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Epithelium; Female; Gastrins; Gene Expression Regulation; Hedgehog Proteins; Humans; Hyperplasia; Immunohistochemistry; Inflammation; Interleukin-1beta; Kruppel-Like Transcription Factors; Male; Mice; Mice, Knockout; Mice, Transgenic; Pyloric Antrum; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Zinc Finger Protein Gli2

Some patients with Zollinger-Ellison syndrome post curative gastrinoma resection continue to show gastric acid hypersecretion; however, the mechanism is unknown.. The aim of this study was to prospectively study acid secretion following curative gastrinoma resection and analyze factors contributing in patients with Zollinger-Ellison syndrome.. Fifty patients cured post gastrinoma resection were studied with serial assessments of acid secretory status, cure status and ECL-cell status/activity (with serial biopsies, CgA, urinary N-MIAA). Correlative analysis was performed to determine predictive factors.. Hypersecretion occurred in 31 patients (62%) and 14 had extreme-hypersecretion. There was an initial decline (3-6 months) in BAO/MAO, which then remained stable for eight years. Preoperative BAO correlated with the postoperative secretion, but not other clinical, tumoral, laboratory variables, the degree of postoperative acid suppression or type of antisecretory drug needed. Hypersecretors had greater postoperative ECL changes (P=0.005), serum CGA (P=0.009) and 24-h urinary N-MIAA (P=0.0038).. Post curative resection, gastric hypersecretion persists long term (mean 8 years) in 62% of patients and in 28% it is extreme, despite normogastrinemia. No preoperative variable except BAO correlates with postresection hypersecretion. The persistent increased ECL-cell extent post curative resection suggests prolonged hypergastrinemia can lead to changes in ECL-cells that are either irreversible in humans or sustained by unknown mechanisms not involving fasting hypergastrinemia and which can result in hypersecretion, in a proportion of which it can be extreme. Whether similar findings may occur in patients with idiopathic GERD treated for prolonged periods (>10 years) with PPIs, at present, is unknown.

Topics: Enterochromaffin Cells; Female; Follow-Up Studies; Gastric Acid; Gastrinoma; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pancreatic Neoplasms; Parietal Cells, Gastric; Postoperative Period; Prevalence; Prospective Studies; Zollinger-Ellison Syndrome

We investigated the influence of long-term diminishing of gastric acid secretion in rats by H(+)-K(+)-ATPase omeprasole on the gastrin blood level and the basal gastric acid secretion. We performed an experimental analysis of possible prophylactic drugs of structural and functional changes in gastric mucosa evoked by hypergastrinemia. It was shown that following 28 days of omeprazole injections the blood gastrin level and the output of basal acid secretion increased by 189.3% and 173.9-283.7%, respectively. It was concluded that an augmentation of the output of basal acid secretion results from the development of parietal cells hyperplasia evoked by trophic action of gastrin. We also show here that agonists of nuclear peroxisome proliferator activator receptors pioglytasone and melanin effectively prevent the changes in gastric acid secretion as an index of morphological changes.

Topics: Animals; Anti-Ulcer Agents; Drug Therapy, Combination; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Melanins; Omeprazole; Pioglitazone; Proglumide; Rats; Thiazolidinediones; Time Factors

Antiparietal cells antibodies (APC-Ab) are commonly found in patients with autoimmune Addison's disease (AAD), usually pointing to autoimmune atrophic gastritis and pernicious anemia. The autoaggression to the gastric proton pumpmay result in a long-term hypergastrinemia, which predisposes to enterochromaffin-like cell hyper/dysplasia and gastric carcinoids.. We evaluated the clinical utility of assessing serum chromogranin A levels in patients with AAD.. Serum chromogranin A, gastrin, and gastric APC-Ab levels were determined in 40 patients with AAD using commercially available kits.. Serum chromogranin A and gastrin levels were found to be elevated in 27.5 and 22.5% of patients with AAD, respectively. The Addison's patients with elevated APC-Ab had significantly higher chromogranin A and gastrin levels, as compared to individuals with normal APC-Ab (chromogranin A: 128.00+/-123.08 vs 57.68+/-36.50 ng/ml, p=0.0036; gastrin: 141.38+/-191.43 vs 49.50+/-75.36 muU/ml, p=0.003). Additionally, the patients with AAD and coexisting elevated serum APC-Ab, contrary to those with normal levels, showed a significant correlation between the chromogranin A and gastrin concentrations (r=0.52, p=0.0092 vs r=0.211, p=0.43). Serum chromogranin A appeared also significantly correlated with APC-Ab levels (r=0.431, p=0.005).. In patients with autoimmune Addison's disease hyperchromograninemia and hypergastrinemia occur with a prevalence of 27.5 and 22.5%, respectively. Addison's patients with coexisting elevated gastric APC-Ab, particularly with elevated gastrin levels, are at risk of enterochromaffin-like cells hyper/dysplasia. Serum chromogranin A assessment may complement histology for the early diagnosis of gastric carcinoid in these patients.

Topics: Addison Disease; Adult; Aged; Autoimmune Diseases; Biomarkers; Chromogranin A; Enterochromaffin-like Cells; Female; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Parietal Cells, Gastric

RegI (Regenerating islet derived-1) was originally characterized as a growth factor involved in pancreatic islet cell regeneration. It is also considered a gastrointestinal mitogen as its expression is increased during pathologies involving aberrant cell proliferation that can lead to neoplasia. However, the absolute requirement for RegI to directly stimulate gastric mucosal cell proliferation in vivo requires further investigation. We used RegI-deficient mice to determine the requirement for RegI in normal gastric mucosal development, wound healing, hyperplasia and tumourigenesis. We found that epithelial repair of acetic acid ulcers in compound mutant RegI/gastrin-deficient mice was significantly reduced compared to wild type, RegI-deficient or gastrin-deficient mice. In contrast, RegI was dispensable for normal gastric mucosal development, hyperplasia in HKbeta-deficient mice and tumourigenesis in gp130(F/F) mice. Although RegI was not required for proliferation in these pathological models, expression of multiple Reg family members were increased during gp130(F/F) tumourigenesis. Interestingly, loss of RegI in gp130(F/F) mice resulted in decreased expression of other Reg family members. Our results indicate that RegI and gastrin may synergistically regulate gastric mucosal proliferation during certain pathological settings like wound healing while gastric epithelial proliferation in other pathologies may require coordinated expression of multiple Reg genes.

Topics: Animals; Base Sequence; Cell Proliferation; Gastric Mucosa; Gastrins; Hyperplasia; Immunoblotting; Lithostathine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Sequence Alignment; Stomach Neoplasms; Stomach Ulcer; Wound Healing

While the optimal treatment for type I gastric carcinoid tumors remains controversial, there is evidence to suggest that in multifocal disease, antrectomy may not only control local disease but also may lead to enterochromaffin-like cell (ECL) hyperplasia regression compared to medical and endoscopic treatments.. A single institution retrospective review of eight consecutive patients with multifocal type I gastric carcinoid tumor patients with no evidence of metastatic disease was performed from 2005 to 2006. All of these patients underwent laparoscopic antrectomy with Billroth II reconstruction. Patients' preoperative gastrin, chromogranin A levels, and biopsy and surgical specimen slides were compared with postoperative laboratory and biopsy slides. Pathology slides were reanalyzed by a blinded pathologist from our institution for evidence of tumor and ECL hyperplasia regression.. All patients tolerated the procedure well with no reoperations or mortalities. Six of eight patient complained of mild reflux which was treated medically. One of eight had a mild wound infection which resolved with a course of cephalexin. Gastrin levels significantly decreased (98.9%) in all patients (P = 0.001). Furthermore, chromogranin A levels also significantly decreased (81.4%). Eight of eight patients showed no evidence of carcinoid tumor after surgery at mean biopsy follow-up of 17 mo (range 2-35 mo), however there was ECL hyperplasia after resection. Four of eight patients (50%) showed regression of ECL hyperplasia on postop biopsy, while the remaining four of eight showed no evidence of regression.. This is the largest case series to investigate the surgical, clinical, and histologic outcomes of laparoscopic antrectomy in type I gastric carcinoid. Our data suggest that laparoscopic antrectomy is a safe and minimally invasive approach to treat nonmetastatic type I gastric carcinoid. All patients had no evidence of gross or microscopic disease at follow-up biopsy and almost half had regression of ECL hyperplasia at follow-up suggesting that antrectomy may be sufficient to prevent tumor recurrence. However, continued regular endoscopic surveillance and medical follow-up of patients with ECL hyperplasia are recommended.

Topics: Adult; Aged; Carcinoid Tumor; Enterochromaffin-like Cells; Female; Gastrins; Humans; Hyperplasia; Laparoscopy; Male; Middle Aged; Pyloric Antrum; Retrospective Studies; Stomach Neoplasms

The orderly differentiation of cell lineages within gastric glands is regulated by a complicated interplay of local mucosal growth factors and hormones. Histamine secreted from enterochromaffin-like cells plays an important role in not only stimulated gastric acid secretion but also coordination of intramucosal growth and lineage differentiation. We have examined histidine-decarboxylase (HDC)-deficient mice, which lack endogenous histamine synthesis, to evaluate the influence of histamine on differentiation of fundic mucosal lineages and the development of metaplasia following induction of acute oxyntic atrophy. Stomachs from HDC-deficient mice and wild-type mice were evaluated at 8 wk and 12 mo of age. DMP-777 was administrated orally to 6-wk-old mice for 1 to 14 days. Sections of gastric mucosa were stained with antibodies against Mist1, intrinsic factor, H/K-ATPase, trefoil factor 2 (TFF2), chromogranin A, and Ext1 and for the cell cycle marker phospho-histone H3. HDC-deficient mice at 8 wk of age demonstrated a prominent increase in chief cells expressing Mist1 and intrinsic factor. Importantly Mist1-positive mature chief cells were present in the midgland region as well as at the bases of fundic glands, indicating a premature differentiation of chief cells. Mice dually deficient for both HDC and gastrin showed a normal distribution of chief cells in fundic glands. Treatment of HDC-deficient mice with DMP-777 led to loss of parietal cells and an accelerated and exaggerated emergence of mucous cell metaplasia with the presence of dual intrinsic factor and TFF2-expressing cells throughout the gland length, indicative of the emergence of spasmolytic polypeptide-expressing metaplasia (SPEM) from chief cells. These findings indicate that histamine, in concert with gastrin, regulates the appropriate differentiation of chief cells from mucous neck cells as they migrate toward the bases of fundic glands. Nevertheless, histamine is not required for emergence of SPEM following acute oxyntic atrophy.

Topics: Age Factors; Animals; Azetidines; Basic Helix-Loop-Helix Transcription Factors; Cell Count; Cell Differentiation; Chief Cells, Gastric; Chromogranin A; Enterochromaffin-like Cells; Enzyme Inhibitors; Gastric Fundus; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Hyperplasia; Hypertrophy; Intrinsic Factor; Metaplasia; Mice; Mice, Inbred BALB C; Mice, Knockout; Mucins; Muscle Proteins; N-Acetylglucosaminyltransferases; Parietal Cells, Gastric; Peptides; Piperazines; Trefoil Factor-2

We recently reported a critical role of NFkappaB in mediating hyperproliferative and anti-apoptotic effects of progastrin on proximal colonic crypts of transgenic mice overexpressing progastrin (Fabp-PG mice). We now report activation of beta-catenin in colonic crypts of mice in response to chronic (Fabp-PG mice) and acute (wild type FVB/N mice) progastrin stimulation. Significant increases were measured in relative levels of cellular and nuclear beta-catenin and pbeta-cat45 in proximal colonic crypts of Fabp-PG mice compared with that in wild type littermates. Distal colonic crypts were less responsive. Interestingly, beta-catenin activation was downstream of IKKalpha,beta/NFkappaB, because treatment of Fabp-PG mice with the NFkappaB essential modulator (NEMO) peptide (inhibitor of IKKalpha,beta/NFkappaB activation) significantly blocked increases in cellular/nuclear levels of total beta-catenin/pbeta-cat45/and pbeta-cat552 in proximal colons. Cellular levels of pbeta-cat33,37,41, however, increased in proximal colons in response to NEMO, probably because of a significant increase in pGSK-3betaTyr216, facilitating degradation of beta-catenin. NEMO peptide significantly blocked increases in cyclin D1 expression, thereby, abrogating hyperplasia of proximal crypts. Goblet cell hyperplasia in colonic crypts of Fabp-PG mice was abrogated by NEMO treatment, suggesting a cross-talk between the NFkappaB/beta-catenin and Notch pathways. Cellular proliferation and crypt lengths increased significantly in proximal but not distal crypts of FVB/N mice injected with 1 nM progastrin associated with a significant increase in cellular/nuclear levels of total beta-catenin and cyclin D1. Thus, intracellular signals, activated in response to acute and chronic stimulation with progastrin, were similar and specific to proximal colons. Our studies suggest a novel possibility that activation of beta-catenin, downstream to the IKKalpha,beta/NFkappaB pathway, may be integral to the hyperproliferative effects of progastrin on proximal colonic crypts.

Topics: Animals; beta Catenin; Cell Proliferation; Colon; Cyclin D1; Gastrins; Gene Expression Regulation; Goblet Cells; Homozygote; Hyperplasia; Mice; Mice, Transgenic; Models, Biological; NF-kappa B; Protein Precursors; Signal Transduction

We describe a 30-year-old man in whom upper endoscopy revealed multiple gastric carcinoids. The peripheral blood gastrin level was 2400 ng/ml (normal range, <200 ng/ml). Mucosal biopsy of the gastric body and fundus showed no atrophy; typical type A chronic atrophic gastritis was thus unlikely. Neither abdominal computed tomography nor selective angiography showed any evidence of tumor in the pancreas or at its periphery. However, the possibility of microgastrinoma could not be ruled out. We performed radioguided surgery with a somatostatin analog, diethylenetriamine pentaacetic acid-D-Phe1-octreotide labeled with (111)In (Octreo Scan). The location of the carcinoids was confirmed. Gastrinoma was ruled out. Total gastrectomy was performed, and the gastrin level decreased to the normal range. Macroscopically, 20 carcinoid tumors, measuring 30 mm in maximum diameter, were confirmed. Microscopic examination showed large numbers of endocrine cell micronests. Hyperplasia of parietal cells was observed, suggesting early-stage type A chronic atrophic gastritis. The antrum contained increased numbers of gastrin-positive cells, which probably caused the preoperative hypergastrinemia.

Topics: Adult; Carcinoid Tumor; Gastrectomy; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Male; Parietal Cells, Gastric; Radiopharmaceuticals; Somatostatin; Stomach Neoplasms; Surgery, Computer-Assisted

We previously showed that antral gastric tumors develop in gastrin-deficient (Gas(-/-)) mice. Therefore Gas(-/-) mice were studied sequentially over 12 months to identify molecular mechanisms underlying gastric transformation. Fundic atrophy developed by 9 months in Gas(-/-) mice. Antral mucosal hyperplasia developed coincident with the focal loss of TFF1 and Muc5AC. Microarray analysis of 12 month Gas(-/-) tumors revealed an increase in follistatin, an activin/BMP antagonist. We found that elevated follistatin expression occurred in the proliferative neck zone of hyperplastic antrums, in antral tumors of Gas(-/-) mice, and also in human gastric cancers. Follistatin induced cyclin D1 and the trefoil factors TFF1 and TFF2 in a gastric cancer cell line. We concluded that antral hyperplasia in Gas(-/-) mice involves amplification of mucous cell lineages due to follistatin, suggesting its role in the development of antral gastric tumors.

Topics: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclin D1; Follistatin; Gastric Mucosa; Gastrins; Hyperplasia; Mice; Mice, Knockout; Mucins; Muscle Proteins; Peptides; Pyloric Antrum; Stomach Neoplasms; Trefoil Factor-1; Trefoil Factor-2

Helicobacter pylori infects over half the population worldwide and is a leading cause of chronic gastritis and gastric cancer. However, the mechanism by which this organism induces inflammation and carcinogenesis is not fully understood. In the present study we used insulin-gastrin (INS-GAS) transgenic mice that fully develop gastric adenocarcinoma after infection of H. pylori-related Helicobacter felis. Histological examination revealed that more than half of those mice developed invasive adenocarcinoma after 8 months of infection. These carcinomas were stained by NCC-ST-439 and HECA-452 that recognize 6-sulfated and non-sulfated sialyl Lewis X. Lymphocytic infiltration predominantly to submucosa was observed in most H. felis-infected mice, and this was associated with the formation of peripheral lymph node addressin (PNAd) on high endothelial venule (HEV)-like vessels detected by MECA-79. Time-course analysis of gene expression by using gene microarray revealed upregulation of several inflammation-associated genes including chemokines, adhesion molecules, surfactant protein D (SP-D), and CD74 in the infected stomach. Immunohistochemical analysis demonstrated that SP-D is expressed in hyperplasia and adenocarcinoma whereas CD74 is expressed in adenocarcinoma in situ and invasive carcinoma. These results as a whole indicate that H. felis induces HEV-like vessels and inflammation-associated chemokines and chemokine receptors, followed by adenocarcinoma formation.

Topics: Adenocarcinoma; Animals; Antigens, Differentiation, B-Lymphocyte; Female; Gastric Mucosa; Gastrins; Gastritis; Gene Expression Profiling; Glycosyltransferases; Helicobacter felis; Helicobacter Infections; Histocompatibility Antigens Class II; Hyperplasia; Immunohistochemistry; Insulin; Lymphocytes; Male; Mice; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Oligosaccharides; Pulmonary Surfactant-Associated Protein D; Sialyl Lewis X Antigen; Stomach; Stomach Neoplasms; Up-Regulation

The presence of neuroendocrine (NE) cells in gastric adenocarcinoma (GCa) is well documented, however, their significance is controversial. There is no evidence in the literature concerning the possible effect of these cells on the expression of TGF-alpha and EGFR, which are believed to confer growth advantage to tumor cells. 101 partial or total gastrectomy specimens from patients operated for conventional gastric adenocarcinoma were included in the study. In each case immunohistochemistry was performed on sequential tissue sections for chromogranin A (ChrA), TGF-alpha and EGFR. Samples were graded based on the number of ChrA-positive cells (0-3). TGF-alpha and EGFR expressions were evaluated according to both the intensity (0-2) and quantification of the positively stained areas (0-3). Follow-up data was available in 54 patients. Twenty-seven patients died of disease, while 27 patients were alive with a follow-up of at least 15 months. ChrA expression was detected in 54.4% of the tumor specimens. TGF-alpha was stained positively in 42.6% and EGFR in 49.5% of the cases. NE cells in GCa was related to TGF-alpha (p<0.0001) and EGFR expression (p<0.05), and TGF-alpha/EGFR coexpression (p<0.001). Among histopathologic variables, the presence of NE cells was significantly related to grade, stage and lymph node status. Although the presence of NE cells had no effect on survival, the expression of EGFR (p<0.0001) and TGF-alpha (p=0.002) were related to survival. The results of our study suggest that the presence of NE cells may have an effect on the expression of TGF-alpha and EGFR in GCa, and the autocrine mechanism between TGF-alpha and EGFR plays an important role in the prognosis of gastric carcinoma.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Chromogranin A; ErbB Receptors; Female; Follow-Up Studies; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Hyperplasia; Kaplan-Meier Estimate; Male; Middle Aged; Neurosecretory Systems; Prognosis; Retrospective Studies; Stomach Neoplasms; Transforming Growth Factor alpha

Topics: Gastric Antral Vascular Ectasia; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Hyperplasia; Laser Coagulation; Polyps; Postoperative Complications; Stomach Neoplasms; Stomach Ulcer

Major histocompatibility complex class II deficient (Aalpha0/0) mice have decreased CD4+ T cells, making them immunologically similar to patients with acquired immunodeficiency syndrome (AIDS). Both patients with AIDS and Aalpha0/0 mice have hypertrophic gastric folds. To clarify the mechanism of gastric mucosal hyperplasia, we investigated the pathophysiology and the role of the innate immunity in the stomach of Aalpha0/0 mice.. Stomachs from 1-6 month old Aalpha0/0 mice, kept under specific pathogen free conditions, were examined at 1 month intervals histologically and immunohistochemically. Gene expression of proinflammatory cytokines, Toll-like receptors (TLRs), cyclooxygenase (COX)-2, and myeloperoxidase (MPO) activity in the gastric mucosa was investigated. Serum gastrin levels and gastric acidity were measured. Bacterial culture of the stomach was performed. To clarify the roles of hypergastrinaemia in the gastric mucosa, a gastrin receptor antagonist (AG041R) was administered.. Aalpha0/0 mice had a diffusely thick corpus mucosa with infiltration of CD11b+ granulocytes and macrophages. Anti-Ki67 staining demonstrated expansion of the proliferating neck zone. Gene expression of interleukin 1beta, interferon gamma, TLR-2, TLR-4, and COX-2 were upregulated, and MPO activity was increased. Only a small amount of non-pathogenic bacteria was detected in the stomach. Serum gastrin levels and Reg-Ialpha positive cells in the gastric mucosa increased, despite normal gastric acidity. After treatment with AG041R, gastric mucosal thickness was significantly reduced.. Persistent activation of innate immunity in the stomach induced gastric mucosal hyperplasia through upregulation of gastrin synthesis in Aalpha0/0 mice, suggesting a pathophysiology similar to the gastric changes in patients with AIDS.

Topics: Acquired Immunodeficiency Syndrome; Animals; Cytokines; Gastric Mucosa; Gastrins; Genes, MHC Class II; Hydrogen-Ion Concentration; Hyperplasia; Immunity, Innate; Immunohistochemistry; Immunophenotyping; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spleen; Up-Regulation

Genes in the KCNE family encode single transmembrane domain ancillary subunits that co-assemble with voltage-gated potassium (Kv) channel alpha subunits to alter their function. KCNE2 (also known as MiRP1) is expressed in the heart, is associated with human cardiac arrhythmia, and modulates cardiac Kv alpha subunits hERG and KCNQ1 in vitro. KCNE2 and KCNQ1 are also expressed in parietal cells, leading to speculation they form a native channel complex there. Here, we disrupted the murine kcne2 gene and found that kcne2 (-/-) mice have a severe gastric phenotype with profoundly reduced parietal cell proton secretion, abnormal parietal cell morphology, achlorhydria, hypergastrinemia, and striking gastric glandular hyperplasia arising from an increase in the number of non-acid secretory cells. KCNQ1 exhibited abnormal distribution in gastric glands from kcne2 (-/-) mice, with increased expression in non-acid secretory cells. Parietal cells from kcne2 (+/-) mice exhibited normal architecture but reduced proton secretion, and kcne2 (+/-) mice were hypochlorhydric, indicating a gene-dose effect and a primary defect in gastric acid secretion. These data demonstrate that KCNE2 is essential for gastric acid secretion, the first genetic evidence that a member of the KCNE gene family is required for normal gastrointestinal function.

Topics: Achlorhydria; Animals; Cells, Cultured; Female; Gastric Acid; Gastric Mucosa; Gastrins; Gene Targeting; Hyperplasia; Hypertrophy; KCNQ1 Potassium Channel; Mice; Mice, Inbred C57BL; Mice, Knockout; Parietal Cells, Gastric; Potassium Channels, Voltage-Gated; Protein Subunits; Stomach; Up-Regulation

MTI/G-Gly mice and hGAS mice, overexpressing glycine-extended gastrin (G-Gly) and progastrin, respectively, display colonic mucosa hyperplasia, hyperproliferation, and an increased susceptibility to intestinal neoplasia. Here, we have used these transgenic mice to analyze in vivo the modulation of intracellular signaling pathways that may be responsible for the proliferative effects of gastrin precursors. The expression, activation, and localization of signaling and cell-to-cell adhesion molecules were studied using immunofluorescence and Western blot techniques on colonic tissues derived from MTI/G-Gly, hGAS, or wild-type FVB/N mice. These analyses revealed an up-regulation of Src tyrosine kinase and related signaling pathways [phosphatidyl inositol 3'-kinase (PI3K)/Akt, Janus-activated kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, and extracellular-signal regulated kinases (ERK)] in both MTI/G-Gly and hGAS mice compared with the wild-type control animals as well as an overexpression of transforming growth factor-alpha (TGF-alpha). In contrast, overexpression of the gastrin precursors did not affect the activation status of STAT1 nor the expression and the distribution of adhesion proteins (focal adhesion kinase, cadherins, and catenins). We report for the first time that the transition from a normal colonic epithelium to a hyperproliferative epithelium in MTI/G-Gly and hGAS mice may be a consequence of the up-regulation of Src, PI3K/Akt, JAK2, STAT3, ERKs, and TGF-alpha. Deregulation of cell adhesion, a late event in tumor progression, does not occur in these transgenic models.

Topics: Animals; Cell Adhesion; Cell Proliferation; Colon; DNA-Binding Proteins; Female; Gastrins; Hyperplasia; Intestinal Mucosa; Janus Kinase 2; Male; Mice; Phosphatidylinositol 3-Kinases; Protein Precursors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Signal Transduction; src-Family Kinases; STAT3 Transcription Factor; Trans-Activators; Transforming Growth Factor alpha; Up-Regulation

Increase of intramucosal transforming growth factor alpha (TGFalpha) levels in the gastric fundus leads to oxyntic atrophy and massive foveolar hyperplasia in both metallothionein (MT)-TGFalpha mice and patients with Ménétrier's disease. We have evaluated the hypothesis that increased levels of TGFalpha in the fundus induces an antral pattern of cell differentiation in fundic glands by studying Pdx1, a transcription factor whose expression normally is confined to the gastric antrum.. Induction of Pdx1 expression was evaluated in Pdx1(lacZ/+)/MT-TGFalpha bigenic mice treated with zinc. The distribution of Pdx1 in MT-TGFalpha mice and Ménétrier's disease patients was evaluated with anti-Pdx1 antibodies. Transcript levels were evaluated by quantitative polymerase chain reaction in mouse and human tissues and AGS cells.. In Pdx1(lacZ/+) mice, Pdx1 was expressed in antral mucosal cells including gastrin cells and TFF2-expressing deep glandular mucous cells. Zinc treatment for 2 to 8 weeks in Pdx1(lacZ/+)/MT-TGFalpha transgenic mice resulted in expression of Pdx1 throughout the fundus. No ectopic fundic Pdx1 expression was observed in either H. felis-infected or DMP777-treated mice. In MT-TGFalpha mice, 8 weeks of zinc treatment elicited nuclear Pdx1 staining throughout the fundic mucosa. TGFalpha treatment in AGS cells led to increases in Pdx1 and gastrin messenger RNA expression. Fundic sections from Ménétrier's disease patients showed nuclear Pdx1 staining throughout the fundic glands. Treatment of a Ménétrier's disease patient with an anti-epidermal growth factor receptor monoclonal antibody reduced fundic expression of both Pdx1 and gastrin.. Overexpression of TGFalpha in MT-TGFalpha mice and Ménétrier's disease patients elicits ectopic expression in the fundus of Pdx1, consistent with the phenotype of antralization.

Topics: Animals; Atrophy; Epithelium; Gastric Fundus; Gastrins; Gastritis, Hypertrophic; Gene Expression; Homeodomain Proteins; Hyperplasia; Mice; Mice, Transgenic; Mucins; Muscle Proteins; Parietal Cells, Gastric; Peptides; Trans-Activators; Transforming Growth Factor alpha; Trefoil Factor-2

H+/K+-ATPase beta-subunit-deficient mice (129/Sv background) display numerous pathologies in the stomach. Expression of the mutation in BALB/cCrSlc mice results in the development of an aberrant 'mucus-rich' cell population. 'Mucus-rich' cells have been described in stomachs of mice with autoimmune gastritis, a disease mediated by CD4+ T cells. Other pathological features of autoimmune gastritis are similar to those in H+/K+ beta-deficient mice and include a mononuclear cell infiltrate in the gastric mucosa, non-functional or absent parietal cells, depletion of zymogenic cells, hypergastrinaemia, and gastric unit hypertrophy caused by immature cell hyperplasia. The present study investigates further the aberrant gastric 'mucus-rich' cell lineage and analyses the mRNA expression of mucus cell products TFF1 and TFF2. 'Mucus-rich' cells stained for both acidic and neutral mucins, and with a TFF2-specific antibody. Stomachs from both models expressed decreased TFF1 mRNA and reciprocally increased TFF2 mRNA. The involvement of gastrin in regulating trefoil mRNA expression was also investigated using gastrin-deficient mice. In contrast to previous findings, gastrin did not positively regulate TFF1 mRNA expression, but there was possible augmentation of TFF2. Additionally, a clear role for inflammation was established involving both polymorphonuclear and mononuclear cells in these models, and a link was found between mucosal hypertrophy and increased interleukin-11 (IL-11) expression.

Topics: Animals; Autoimmune Diseases; Cytokines; Disease Models, Animal; Gastric Mucosa; Gastrins; Gastritis; Gene Expression Regulation; H(+)-K(+)-Exchanging ATPase; Hyperplasia; Hypertrophy; Interleukin-11; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Mucins; Muscle Proteins; Peptides; RNA, Messenger; Species Specificity; Trefoil Factor-1; Trefoil Factor-2

The role of enterochromaffin-like (ECL) cells in gastric carcinogenesis is not fully understood. Spontaneous tumours developing in hypergastrinemic female cotton rats have an adenocarcinoma phenotype, but numerous cells in the dysplastic mucosa as well as in the carcinomas are positive for neuroendocrine markers. In the present study of female cotton rats with 2 and 8 months' hypergastrinemia, the oxyntic mucosa of the stomach was examined histologically and immunolabelled for histidine decarboxylase (HDC) and pancreastatin, and hyperplastic and neoplastic ECL cells were evaluated by electron microscopy. These animals developed hyperplasia of the oxyntic mucosa in general and of the ECL cells in particular after 2 months and dysplasia and carcinomas after 8 months. The immunoreactivity of the ECL cells in the oxyntic mucosa was increased at 2 months and declined at 8 months. These histological changes were associated with progressive loss of secretory vesicles and granules in ECL cells. We suggest that ECL cells in hypergastrinemic cotton rats dedifferentiate with time and that the gastric carcinomas may develop from ECL cells.

Topics: Animals; Carcinoma; Cell Transformation, Neoplastic; Chromogranin A; Enterochromaffin-like Cells; Female; Gastrins; Histidine Decarboxylase; Hyperplasia; Pancreatic Hormones; Parietal Cells, Gastric; Rats; Sigmodontinae; Stomach Neoplasms

Long-term administration of PPI causes hyperplastic changes of the gastric parietal cells; however, the detailed mechanism remains to be clarified. We administered high-dose omeprazole to patients with Barrett's esophagus for 2 years, and investigated changes in gastric ECL (Enterochromaffin-like) cells using endoscopic biopsy specimens to clarify the etiology of hyperplasia of the parietal cells.. The subjects were 69 patients who were diagnosed as having Barrett's esophagus (39 males, 30 females). We established two groups, an omeprazole-treated group and a ranitidine-treated group. Upper digestive tract endoscopy was performed before administration, and 12 and 24 months after the start of administration. Biopsy was performed in the greater curvature of the gastric body. The ECL/parietal cell counts and the grade of hyperplasia of the gastric mucosa were determined under a microscope. In addition, the fasting serum gastrin level was measured, and statistical analysis was performed.. In the omeprazole-treated group, the ECL cell count was markedly increased 12 months after the start of administration, but was lower than the pretreatment value 24 months after the start of administration. The parietal and ECL cell counts significantly increased. Furthermore, there were no changes in mucosa thickness. The fasting serum gastrin level significantly increased. In the ranitidine-treated group, there was no increase in the ECL cell count, and the parietal cell count was decreased. There was no significant increase in mucosa thickness. The fasting serum gastrin level increased, although the rate of increase was markedly smaller than that in the omeprazole-treated group.. Not the direct pharmacological actions of PPI but hypergastrinemia-associated secondary changes may be etiologically involved in hyperplasia of the parietal cells related to long-term administration of PPI.

Topics: Anti-Ulcer Agents; Barrett Esophagus; Cell Count; Dose-Response Relationship, Drug; Enterochromaffin Cells; Female; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Omeprazole; Parietal Cells, Gastric; Proton Pump Inhibitors; Time Factors

Determining how Helicobacter pylori promotes gastric cancer and whether H pylori eradication decreases cancer risk would be helped by suitable murine models. Mice lacking the cyclin-dependent kinase inhibitor p27kip1 are susceptible to carcinogen-induced tumors. Furthermore, p27 stimulates gastric epithelial apoptosis and inhibits proliferation, expression is decreased by H pylori, and low levels are associated with a poor prognosis in gastric cancer. We therefore evaluated p27-deficient mice as a model for H pylori-associated gastric cancer.. Wild-type and p27-/- C57BL/6 mice were infected with H pylori mouse-adapted Sydney strain at 6-8 weeks of age and 6-10 mice of each type were euthanized 15, 30, 45, 60, and 75 weeks later.. Uninfected p27-/- mice developed gastric hyperplasia. H pylori-infected p27-/- mice frequently developed intestinal metaplasia (40% at 30 weeks, 67% at 45 weeks), and after 60 weeks 7 of 12 mice developed significant dysplasia and gastric cancer, recapitulating human intestinal-type gastric carcinogenesis. Wild-type mice developed intestinal metaplasia only after 75 weeks of infection; significant gastric dysplasia was observed in 1 animal (P < .05 for each comparison with p27-/- mice). No disease developed in uninfected mice. H pylori infection in p27-/- mice was associated with significantly decreased apoptosis and increased epithelial proliferation, inflammation, and H pylori density compared with infection in wild-type mice.. p27 loss and H pylori colonization cooperate to produce gastric cancer. The p27-deficient mouse affords opportunities to examine the pathogenesis of H pylori in gastric carcinogenesis and to test eradication and chemopreventive strategies.

Topics: Animals; Apoptosis; Cell Division; Cyclin-Dependent Kinase Inhibitor p27; Female; Gastrins; Gastritis; Genetic Predisposition to Disease; Helicobacter Infections; Helicobacter pylori; Hyperplasia; Male; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Stomach Neoplasms

Ghrelin, a recently discovered peptide isolated from the gastric corpus mucosa, is believed to be important in the regulation of growth hormone secretion and has been shown to increase appetite and food intake as well. It may also have other gastrointestinal and cardiac functions. Because a cell of origin for ghrelin has not been convincingly identified in the gastric mucosa thus far, we studied the immunohistochemical expression of ghrelin in proliferative lesions of the enterochromaffin-like (ECL) cells-a cell that is not only exclusively confined to the gastric corpus mucosa but is its dominant endocrine cell type as well. Formalin-fixed, paraffin embedded tissues from three cases of gastric ECL cell hyperplasia and five ECL carcinoids (three with coexisting foci of diffuse, linear, and micronodular hyperplasia) were immunohistochemically stained for ghrelin, using a commercially available antibody. The Sevier-Munger stain for ECL cells and immunohistochemical stains for chromogranin, gastrin, serotonin, somatostatin, and vesicular monoamine transporter-2 (VMAT-2) were performed on parallel sections for correlation with the ghrelin staining results. All ECL cell carcinoids and hyperplastic lesions were positive for both the Sevier-Munger and the immunohistochemical stains for chromogranin and VMAT-2. Immunoreactivity for ghrelin was seen in 4/5 ECL carcinoids, all cases of ECL cell hyperplasia, as well as in all areas with linear and micronodular hyperplasia adjacent to the ECL cell carcinoids. In each instance, such staining was confined to the Sevier-Munger, and VMAT-2 positive cells only. Our findings indicate that the ECL cells are either the ghrelin-producing cells of the gastric mucosa or acquire the capability to synthesize ghrelin during proliferative states encompassing the entire hyperplasia to neoplasia spectrum. In view of the orexigenic and other known actions of ghrelin, the functional and/or biologic significance of ghrelin production in such ECL cell proliferations needs to be investigated further.

Topics: Carcinoid Tumor; Chromogranins; Enterochromaffin-like Cells; Gastric Mucosa; Gastrins; Ghrelin; Humans; Hyperplasia; Immunohistochemistry; Membrane Glycoproteins; Membrane Transport Proteins; Peptide Hormones; Retrospective Studies; Serotonin; Somatostatin; Stomach Neoplasms; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins

Histamine plays an important role in the regulation of gastric acid secretion; however, its role in maintenance of gastric morphology remains unclear. To clarify the necessity of histamine for gastric mucosal development and maintenance, we evaluated two different kinds of mice that lacked either mast cells (one of the gastric histamine-producing cell types) or histidine decarboxylase (HDC; a histamine-synthesizing enzyme). Measurements of stomach weight, intragastric pH, mucosal histamine levels, as well as serum gastrin and albumin levels were performed in mice. Gastric mucosal appearance was examined by immunohistochemical techniques. Although gastric mucosal histamine levels in mast cell-deficient mice were half of those observed in the wild-type mice, intragastric pH, serum gastrin levels, and gastric morphology at 12 mo were unchanged compared with the wild-type mice. In contrast, HDC-deficient mice possessed no detectable gastric histamine, but did exhibit hypergastrinemia, as well as marked increases in intragastric pH and stomach weight compared with the wild-type mice. Histological analysis revealed that 9-mo-old HDC-deficient mice demonstrated hyperplasia in the oxyntic glandular base region, as well as increased numbers of parietal and enterochromaffin-like cells. These results indicate that enterochromaffin-like cell-derived histamine is potentially involved in gastric mucosal morphology regulation.

Topics: Achlorhydria; Animals; Enteroendocrine Cells; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Hyperplasia; Male; Mast Cells; Mice; Mice, Knockout; Mice, Mutant Strains; Parietal Cells, Gastric

Hypergastrinemia in patients with pernicious anemia is a major regulator contributing to enterochromaffin-cell hyperplasia and, ultimately, to gastric carcinoids.. Between 1990 and 2003, we studied 8 women and 10 men with pernicious anemia and gastric carcinoids; their mean age was 50 years. Serum gastrin levels ranged from 740 to 4,000 pg/mL (mean 1,000 pg/mL). Six patients underwent antrectomy, four total gastrectomy, and eight endoscopic resection or biopsy. During the same period, 22 patients with Zollinger-Ellison tumors and hypergastrinemia (20 men and 2 women, mean age 49 years) had no gastric carcinoids, but 1 of 7 patients with Zollinger-Ellison and multiple endocrine neoplasia (MEN1) tumors had hypergastrinemia and gastric carcinoids.. Mean followup for pernicious anemia patients was 6 years after antrectomy and 1 to 10 years after endoscopic resection or biopsy. Tumor regression was observed in one patient after antrectomy and one patient after biopsy. There were no deaths in this group in spite of lymph node metastasis in two patients. The patient with Zollinger-Ellison and MEN1 syndrome has been followed 3 years after diagnosis and 2 years after total gastrectomy.. Gastric carcinoids are indolent tumors occurring with increasing frequency in patients with pernicious anemia. Antrectomy or biopsy and observation are preferred methods of treatment. Total gastrectomy is reserved for patients with extensive tumor involvement of the gastric wall or for emergency bleeding.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Pernicious; Biopsy; Carcinoid Tumor; Female; Gastrectomy; Gastric Mucosa; Gastrinoma; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Retrospective Studies; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric Helicobacter pylori (Hp) infection in Mongolian gerbils is an established experimental model of gastric carcinogenesis resulting from the long-term Hp infection but functional aspects accompanying this Hp-induced progression from gastritis to the cancer, especially changes in gastric acid secretion, gastric blood flow (GBF) and gastrin-somatostatin link have been little studied. It is unclear whether Hp eradication therapy alters the functional and the histopathological changes in this animal model of Hp-infection. We examined the effects of intragastric (i.g.) inoculation of Mongolian gerbils with Hp strain (cagA+ vacA+, 5 x 10(6) CFU/ml) that had been isolated from a patient with gastric ulcer as compared to those induced by vehicle (saline) in gerbils with or without gastric fistula (GF) at 1.2, 4, 6, 9, 12 and 30 wks upon gastric inoculation with this bacteria. An attempt was made to evaluate the influence of anti-Hp triple therapy with omeprazole, amoxicillin and tinidazol on gastric Hp-infection and Hp-induced functional impairment of the gastric mucosa. Gastric mucosal biopsy specimens were taken for the assessment of the morphological changes and the presence of Hp infection using rapid urease test (CLO-test) and the density of Hp-colonization were assessed by counting of the number of bacterial colonies per plate. Gastric blood flow (GBF) was measured by H2-gas clearance technique and the venous blood and the gastric content were collected for the measurement of plasma gastrin levels and the gastric luminal somatostatin level by radioimmunoassay (RIA). The Hp in gastric mucosa was detected in all animals by culture and rapid urease test at various periods upon Hp inoculation. Basal gastric acid in non-infected conscious gerbils with GF reached the level of about 28 +/- 4 micromol/h and this was reduced by over 50% immediately upon the Hp-inoculation and persisted for time intervals tested up to 30 wk. Early lesions were seen 4 wks after the Hp-inoculation and consisted of chronic gastritis with thickened gastric mucosal foldings and elongated interfoveolar ridges. Edema and congestion as well as significant mucosal inflammatory infiltration with lymphoid infiltrate in lamina propria of the mucosa occurred in all infected gerbils. Adenomatous hyperplasia with cellular atypia was observed at 12 wk upon Hp-inoculation together with increased mitotic activity and numerous apoptotic bodies formation, while lamina propria was reduced leaving di

Topics: Amoxicillin; Animals; Anti-Ulcer Agents; Colony Count, Microbial; Drug Therapy, Combination; Gastric Mucosa; Gastrins; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Hyperplasia; Microcirculation; Omeprazole; Penicillins; Radioimmunoassay; Somatostatin; Stomach Ulcer; Tinidazole

Menetrier's disease is characterized by giant gastric folds with foveolar hyperplasia and cystic dilatation, hypoproteinemia, and enhanced mucus secretion. The etiology remains unresolved and an effective treatment has yet to be established. Here we show that histamine H(2)-receptor deficient mice developed gastric pathophysiological changes resembling Menetrier's disease for up to 17 months of observation. Mutant mice were found to have an increased stomach weight, enlarged gastric folds with cystic dilatation, hypergastrinemia, hypoalbuminemia, increased mucus secretion and overexpression of mucosal transforming growth factor (TGF) alpha. Both a cholecystokinin (CCK)(2)-receptor antagonist and an epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor significantly reduced the increase in stomach weight. It appears that lack or downregulation of histamine H(2)-receptors might be involved in the pathogenesis of Menetrier's disease.

Topics: Animals; Body Weight; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Hyperplasia; Hypoproteinemia; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucus; Organ Size; Phenotype; Receptors, Histamine H2; Serum Albumin; Stomach; Stomach Diseases; Syndrome

To examine the physiological role of the histamine H(2) receptor, histamine H(2) receptor-null mice were generated by homologous recombination. Histamine H(2) receptor-null mice, which developed normally and were fertile and healthy into adulthood, exhibited markedly enlarged stomachs and marked hypergastrinemia. The former was due to hyperplasia of gastric gland cells (small-sized parietal cells, enterochromaffin-like cells and mucous neck cells which were rich in mucin), but not of gastric surface mucous cells, which were not increased in number as compared with those in wild-type mice despite the marked hypergastrinemia. Basal gastric pH was slightly but significantly higher in histamine H(2) receptor-null mice. Although carbachol but not gastrin induced in vivo gastric acid production in histamine H(2) receptor-null mice, gastric pH was elevated by both muscarinic M(3) and gastrin antagonists. Thus, both gastrin and muscarinic receptors appear to be directly involved in maintaining gastric pH in histamine H(2) receptor-null mice. Interestingly, gastric glands from wild-type mice treated with an extremely high dose of subcutaneous lansoprazole (10 mg/kg body weight) for 3 months were very similar to those from histamine H(2) receptor-null mice. Except for hyperplasia of gastric surface mucous cells, the findings for gastric glands from lansoprazole-treated wild-type mice were almost identical to those from gastric glands from histamine H(2) receptor-null mice. Therefore, it is possible that the abnormal gastric glands in histamine H(2) receptor-null mice are secondary to the severe impairment of gastric acid production, induced by the histamine H(2) receptor disruption causing marked hypergastrinemia. Analyses of the central nervous system (CNS) of histamine H(2) receptor-null mice revealed these mice to be different from wild-type mice in terms of spontaneous locomotor activity and higher thresholds for electrically induced convulsions. Taken together, these results suggest that (1) gastrin receptors are functional in parietal cells in histamine H(2) receptor-null mice, (2) abnormal gastric glands in histamine H(2) receptor-null mice may be secondary to severe impairment of gastric acid production and secretion and (3) histamine H(2) receptors are functional in the central nervous system.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Blotting, Northern; Electroshock; Gastric Acid; Gastric Mucosa; Gastrins; Gene Targeting; Hydrogen-Ion Concentration; Hyperplasia; Immunohistochemistry; Lansoprazole; Mice; Omeprazole; Pain Threshold; Proton Pump Inhibitors; Receptors, Histamine H2; Seizures

Topics: Cell Division; Chronic Disease; Enterochromaffin Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Histamine; Humans; Hyperplasia; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Evidence indicates that eradication of Helicobacter pylori leads to the disappearance of hyperplastic polyps in the stomach. However, there are some exceptions. We have compared endoscopic and serologic findings of responder and non-responder cases with hyperplastic polyps to try to identify the cause(s), other than H. pylori infection, of the formation or growth of gastric hyperplastic polyps.. We retrospectively studied 33 patients whose hyperplastic polyps disappeared after eradication of H. pylori and 10 patients whose hyperplastic polyps did not disappear after eradication. The patients were examined both endoscopically and serologically before, 1-3 months after and 12-15 months after the eradication.. The responder and non-responder groups were similar with respect to age, sex, coexisting diseases, and histologic findings. The number and maximum size of polyps tended to be larger before treatment in the non-responder group than in the responder group. The serum gastrin level was higher in the non-responder group than in the responder group before, 1-3 months after and 12-15 months after the eradication (p=0.0096, p>0.2, p=0.0014). On histologic examination, similar reductions in the degree of inflammatory cell infiltration in the gastric mucosa of the antrum and body were seen in both the responder and non-responder groups. In the non-responders, the size and numbers of the polyps regressed in 5 of the 10 patients. The score of glandular atrophy in the antrum and the serum gastrin levels in the non-regressed cases was higher than those in the regressed cases at 1-3 and 12-15 months after eradication.. Persistent high gastrin levels were found in the non-responder cases with gastric hyperplastic polyps.

Topics: Adult; Aged; Anti-Bacterial Agents; Chi-Square Distribution; Drug Therapy, Combination; Endoscopy, Gastrointestinal; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Immunoglobulin G; Male; Middle Aged; Penicillins; Pepsinogen A; Polyps; Proton Pump Inhibitors; Retrospective Studies; Statistics, Nonparametric; Stomach Neoplasms

Previous reports have suggested a possible association between hyperplastic polyposis and colorectal neoplasms. Increased gastrin may be the link between these two conditions insofar as gastrin has been reported to be a growth-promoting tumoural agent. This report describes gastric polyposis, hypergastrinaemia and colorectal neoplasms in four elderly patients.. Four male patients with no family history of cancer, who were found to have multiple gastric hyperplastic polyps, hypergastrinaemia and colorectal cancers or an adenomatous polyp, were evaluated. Assessment included clinical evaluation, biochemical and haematological profiles, fasting gastrin levels, Helicobacter pylori serology, cobalamin, parietal cell antibodies, gastroscopy with biopsies of polyps and gastric mucosa, urease tests, and colonoscopy with biopsies of colorectal neoplasms. Immunohistochemistry of specimens from gastric polyps and colonic carcinomas was performed for chromogranin A, synaptophysin, Leu 7, neuron-specific enolase and gastrin.. The mean age at diagnosis of gastric polyps was 71.2 years and at removal of colorectal neoplasm was 70.0 years. In two patients, the gastric lesion was diagnosed before the colonic lesion and conversely in the two remaining patients. Gastrin was very high (1604 pg/ml; normal level, < 115 pg/ml) in one patient with pernicious anaemia, and the mean level for the other three was 324 pg/ml. H. pylori were found in two patients. Immunohistochemistry failed to identify neuroendocrine cells in the hyperplastic gastric polyps and three of the colonic carcinomas.. Occurrence of sporadic colorectal neoplastic lesion in patients with diffuse hyperplastic gastric polyposis and hypergastrinaemia may represent a new syndrome. Gastrin is not secreted by the gastric polyps or colonic carcinomas and may be related to gastric mucosal changes and H. pylori colonization. In patients with hyperplastic gastric polyposis and hypergastrinaemia, colorectal neoplasms should be ruled out.

Topics: Aged; Colorectal Neoplasms; Gastrins; Humans; Hyperplasia; Male; Polyps; Stomach Neoplasms; Syndrome

In the present study we evaluated the effects of gastric myenteric denervation using benzalkonium chloride (BAC) on the time for gastric emptying, as well as gastric secretion, and mucosal epithelial cell size and population in rats.. Wistar rats were treated with topical serosal application of BAC to the stomach. Control animals received saline. Ninety days after surgery, gastric emptying time, gastric acid secretion and serum gastrin levels were studied. Next, the animals were sacrificed and the stomachs were removed, fixed in formalin and histologically processed for histomorphometry of the height, area and volume of the glandular portion, and volume and population of mucous, chief, parietal, G- and labelled cells. BAC animals showed a significant delay in gastric emptying and an increase in gastric acid secretion and serum gastrin levels. These animals also presented a significant reduction of myenteric neuron number, hypertrophy of parietal and chief cells, hyperplasia of G cells and an increase in the gastric mucosa area.. The absence of the myenteric plexus seems to protect the stomach from the hyperplastic effects of hypergastrinemia. Gastric food stasis may act as a factor triggering morphological and functional alterations of the gastric epithelium. Although gastric food stasis is a common finding in medical practice, its physiopathological consequences are poorly understood and have not been frequently discussed in the literature.

Topics: Animals; Benzalkonium Compounds; Chief Cells, Gastric; Detergents; Gastric Acid; Gastric Acidity Determination; Gastric Emptying; Gastric Mucosa; Gastrin-Secreting Cells; Gastrins; Hyperplasia; Muscle Denervation; Muscle, Smooth; Myenteric Plexus; Organ Size; Parietal Cells, Gastric; Rats; Rats, Wistar; Stomach

Enterochromaffin-like cell hyperplasia of the gastric body mucosa occurs in hypergastrinaemic conditions such as atrophic body gastritis and Zollinger-Ellison syndrome. However, the time course of change or factors involved are not known.. To compare the rate of change of enterochromaffin-like cell proliferation in patients with atrophic body gastritis and Zollinger-Ellison syndrome.. From a consecutive series of atrophic body gastritis and Zollinger-Ellison syndrome patients, studied at the time of first diagnosis, 10 atrophic body gastritis (4 with pernicious anaemia) and 14 Zollinger-Ellison syndrome (4 with multiple endocrine neoplasia type 1) patients were followed-up for a median time of 48 months.. At entry and during follow-up patients underwent: plasma gastrin determination, endoscopic sampling of body mucosa for qualitative assessment of enterochromaffin-like cell hyperplasia pattern and degree of glandular atrophy, qualitative and morphometric analyses of body mucosa endocrine cells.. At time of diagnosis, enterochromaffin-like cell lesions were more severe in atrophic body gastritis than in Zollinger-Ellison syndrome. During follow-up, no significant variations were observed in gastrin values, enterochromaffin-like cell patterns and grade of body mucosa atrophy in atrophic body gastritis. In contrast, gastrin levels were significantly increased [median 1200 (235-2625) vs 1947 (225-5200) pg/ml; p<0.001)] as was total volume density of enterochromaffin-like cells [median 1.60 (0.53-4.06) vs 3.18 (1.35-21.13)% of mucosal epithelial component; (p<0.005)] in Zollinger-Ellison syndrome. Micronodular hyperplasia of enterochromaffin-like cells, present in only one patient at diagnosis, was observed in 8 Zollinger-Ellison syndrome patients at follow-up.. These data suggest that the progression of enterochromaffin-like cell growth in human gastric mucosa requires an increase of and/or a prolonged exposure to severe hypergastrinaemia.

Topics: Adult; Aged; Disease Progression; Enterochromaffin-like Cells; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Immunohistochemistry; Male; Middle Aged; Prospective Studies; Zollinger-Ellison Syndrome

The effect of chronic hypergastrinemia alone on gastric enterochromaffin-like (ECL) cells in humans is largely unknown because in the common chronic hypergastrinemic states (atrophic gastritis, chronic proton pump inhibitor use), it is not possible to separate the effect of hypergastrinemia and other factors, such as gastritis or atrophy. Studies of patients with sporadic Zollinger-Ellison syndrome (ZES) allow this separation.. In 106 patients with ZES, gastric biopsies were taken, and the qualitative ECL cell pattern/grade and the alpha-subunit of human chorionic gonadotropin (alpha-hCG) expression were determined.. In patients with active disease, 99% had ECL hyperplasia and abnormal alpha-hCG staining. Fifty percent had advanced changes in both of these, with 7% having dysplasia and 0% having carcinoids. Advanced ECL cell and alpha-hCG changes were most affected by the level of hypergastrinemia. For ECL cell changes, even mild hypergastrinemia had an effect. Advanced ECL change was also affected by the duration of drug treatment, cure status, and presence of atrophic gastritis, but not by sex or previous vagotomy. The alpha-hCG expression independently predicted dysplasia.. In humans, chronic hypergastrinemia alone causes advanced ECL cell change and abnormal expression of mucosal alpha-hCG. No threshold for this effect was detected, as reported by some, and in contrast to animal studies, sex and vagal tone did not play a major role. The long-term risk of developing gastric carcinoids with chronic hypergastrinemia is low in patients with sporadic gastrinomas (at least 100 times less than in patients with multiple endocrine neoplasia type 1 with ZES) for at least 15-20 years.

Topics: Adolescent; Adult; Aged; Child; Chronic Disease; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrinoma; Gastrins; Glycoprotein Hormones, alpha Subunit; Humans; Hyperplasia; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Zollinger-Ellison Syndrome

Helicobacter pylori is said to cause atrophy of the gastric corpus and enterochromaffin-like cell proliferation in gastro-oesophageal reflux disease (GERD) patients treated long-term with a proton pump inhibitor.. To determine the effect of H. pylori infection on gastritis, enterochromaffin-like cell density and hyperplasia, mucosal atrophy and serum gastrin in patients with gastric hypersecretion (basal acid output gt; 15 mmol/h) with either hypergastrinemia (Zollinger-Ellison syndrome) or normal gastrin (non-Zollinger-Ellison syndrome) before and during long-term treatment with lansoprazole.. Lansoprazole was individually titrated to reduce basal acid output to < 5 mmol/h (< 1 mmol/h in post-surgical Zollinger-Ellison syndrome). Gastric corpus biopsies were obtained every 6 months before treatment and up to 8 years later.. H. pylori was present in corpus biopsies in approximately 50%, causing active gastritis which resolved rapidly in 15 subjects after elimination of H. pylori. Patchy mild/moderate corpus atrophy was present at entry in two and at the end in four out of 60 patients, one being H. pylori-positive. Intestinal metaplasia (< 10%) was seen in six isolated biopsies (1% of total). H. pylori did not affect serum gastrin, enterochromaffin-like cell density or hyperplasia. Enterochromaffin-like cell density was twice as high in Zollinger-Ellison syndrome as in non-Zollinger-Ellison syndrome patients (241 vs. 126 cells/mm2, P < 0.001). Enterochromaffin-like cells remained normal in the non-Zollinger-Ellison syndrome hypersecretors regardless of H. pylori status.. Corpus enterochromaffin-like cell increases were related to serum gastrin elevation, but neither H. pylori nor long-term treatment with lansoprazole alone or together had any effect on enterochromaffin-like cell density or hyperplasia. Corpus acute gastritis resulted from H. pylori infection, but did not result in mucosal atrophy despite long-term proton pump inhibitor treatment and promptly resolved with loss of H. pylori.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Enterochromaffin-like Cells; Enzyme Inhibitors; Female; Gastric Acid; Gastrins; Gastritis; Helicobacter pylori; Humans; Hyperplasia; Intestinal Mucosa; Lansoprazole; Male; Metaplasia; Middle Aged; Omeprazole; Zollinger-Ellison Syndrome

The histopathology of Fibrocalculous Pancreatic Diabetes (FCPD) has been extensively studied, but there are no reports on alteration in patterns of hormone secreting cells using immunohistochemistry in islets of FCPD patients. In this study, we report on the histopathology and immunohistochemistry of islets of FCPD patients and its possible correlation with the clinical picture. Pancreatic biopsies were carried out in six patients with FCPD at the time of surgery for abdominal pain. Routine histopathology and immunohistochemistry studies were carried out with six primary antibodies namely insulin, glucagon, pancreatic polypeptide (PP), somatostatin, vasoactive intestinal peptide and gastrin. Histopathology of the pancreas showed a spectrum of changes ranging from moderate to severe atrophy, fibrosis of the parenchyma and degeneration of the ducts. Nesidioblastosis was present in three patients. Immunohistochemical studies showed a decrease in the number of islets but some patients showed evidence of hyperplasia. There was an overall decrease in the percent of insulin cells and the positivity in the islets correlated with plasma C-peptide levels and the duration of diabetes. There was no consistent relationship with glucagon with some patients showing increased and other decreased positivity. There was a marked decrease in PP and somatostatin positivity, the significance of which is not clear. The reduction, but partial preservation of insulin positivity is consistent with the ketosis resistance shown by patients with Fibrocalculous Pancreatic Diabetes.

Topics: Adolescent; Adult; Atrophy; Biopsy; Blood Glucose; Chronic Disease; Diabetes Mellitus; Female; Gastrins; Glucagon; Humans; Hyperplasia; Immunohistochemistry; Insulin; Islets of Langerhans; Male; Middle Aged; Pancreas; Pancreatic Ducts; Pancreatic Polypeptide; Pancreatitis; Vasoactive Intestinal Peptide

Serum chromogranin A (CgA), a marker of neuroendocrine neoplasia, increases during profound gastric acid inhibition, possibly reflecting the trophic effect of gastrin on the enterochromaffin-like (ECL) cells.. This study investigated the clinical value of serum CgA as a screening test for gastric fundic enterochromaffin-like (ECL) cell hyperplasia during acid-suppressive therapy.. A consecutive series of 230 dyspeptic patients referred for upper gastrointestinal endoscopy was investigated in a cross-sectional design. They were 154 patients on continuous medium-term (6 weeks to one year) or long-term (longer than one year) acid inhibition with either proton pump inhibitors (PPIs, n = 117) or histamine2-receptor antagonists (H2RAs, n = 37) for gastro-oesophageal reflux disease, and 76 nontreated subjects, with normal endoscopic findings (control group). Fasting blood samples were analysed for gastrin and CgA. Gastric biopsy specimens (oxyntic mucosa) were examined for histological evaluation of gastritis (Sydney classification) and of ECL cell hyperplasia (Solcia classification).. Serum CgA levels correlated positively with serum gastrin, following a quadratic function (r = 0.78, P < 0.0001). Elevated serum CgA values during long-term acid inhibition correlated with the presence and severity of fundic ECL cell hyperplasia. Multivariate analysis identified hypergastrinaemia (P < 0.0001), duration of acid inhibition (P < 0.0001), H. pylori infection (P = 0.008), ECL cell hyperplasia (P = 0.012), and body gland atrophy (P = 0.043) as independent predictors of elevated serum CgA. In subjects on long-term acid inhibition (n = 123), serum CgA was equally sensitive but more specific than serum gastrin for the detection of ECL cell hyperplasia (sensitivity, 91.3% for both; specificity, 73% vs. 43%, P < 0.0001).. During long-term gastric acid inhibition, serum CgA levels reflect the presence and severity of fundic ECL cell hyperplasia. Serum CgA is therefore a useful screening test for gastric ECL cell proliferative changes within this context.

Topics: Adult; Aged; Anti-Ulcer Agents; Chromogranin A; Chromogranins; Cross-Sectional Studies; Enterochromaffin-like Cells; Female; Gastric Acid; Gastric Fundus; Gastrins; Gastritis; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Male; Mass Screening; Middle Aged; Multivariate Analysis; Sensitivity and Specificity

Chromogranin A (CgA) is a sensitive marker for neuroendocrine neoplasia. Enterochromaffin-like cell hyperplasia secondary to hypergastrinemia also leads to CgA increase in blood. Treatment with inhibitors of acid secretion, atrophic gastritis and infection with Helicobacter pylori are prevalent conditions leading to hypergastrinemia. We therefore wanted to study whether concomitant determination of gastrin could increase the utility of CgA as a marker of neuroendocrine neoplasia.. CgA and gastrin concentrations were determined by radioimmunoassay methods, while pepsinogen I (used to diagnose severe atrophic gastritis) was determined by a commercial immunoenzymatic assay.. Among 100 patients with elevated CgA, we found that 29% had hypergastrinemia. Vice versa, CgA was elevated in 23 out of 26 (88.5%) in a population of patients with hypergastrinemia. By determining pepsinogen I in blood in patients with hypergastrinemia, a proportion of them was diagnosed as having severe atrophic gastritis.. We conclude that determination of gastrin in blood in patients with CgA elevation will increase the utility of CgA in the diagnosis of neuroendocrine tumors.

Topics: Biomarkers, Tumor; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Immunoenzyme Techniques; Neuroendocrine Tumors; Pepsinogen A; Radioimmunoassay; Stomach; Stomach Neoplasms

Gastrin has a growth-promoting effect on the oxyntic mucosa of the stomach but has been claimed also to affect other parts of the gastrointestinal tract and pancreas. This report describes the effects of the cholecystokinin, (CCK2) receptor antagonists YM022 and YF476 on various growth parameters in the gastrointestinal tract and pancreas of the rat. YM022 and YF476 were given subcutaneously in doses known to produce maximum and sustained CCK2 receptor blockade. The body weight was not affected. However, the oxyntic mucosal weight, thickness and protein and DNA contents were reduced by 15-20% already within 1-2 days and by about 30% after 4-8 weeks of CCK2 receptor blockade. Hence, the response of the oxyntic mucosa to CCK2 receptor blockade was in the form of hypotrophy (reduced protein content) and hypoplasia (reduced DNA content). There were no obvious effects of CCK2 receptor blockade on the intestine or pancreas (nor on liver, kidney or thyroid). The proton pump inhibitor omeprazole was used to induce hypergastrinaemia and was given with or without YM022. Omeprazole treatment for 4 weeks increased the oxyntic mucosal weight and thickness by 15-20%. YM022 prevented these effects. We conclude that while elevated circulating gastrin levels, acting on CCK2 receptors, exert a growth-promoting effect on the oxyntic mucosa (but not elsewhere), normal serum gastrin levels exert a mucosa-preserving effect.

Topics: Animals; Benzodiazepines; Benzodiazepinones; Digestive System; Drug Interactions; Gastrins; Hormone Antagonists; Hyperplasia; Hypertrophy; Male; Omeprazole; Pancreas; Parietal Cells, Gastric; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin

Hypergastrinemia occurs frequently in association with acid suppression and Helicobacter infection, but its role in the progression to gastric atrophy and gastric cancer has not been well defined.. The effects of hypergastrinemia, and possible synergy with Helicobacter felis infection, were investigated in insulin-gastrin (INS-GAS) transgenic mice.. INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but later progressed to decreased parietal cell number and hypochlorhydria. Development of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth factor alpha. At 20 months of age, INS-GAS mice showed no evidence of increased enterochromaffin-like cell number, but instead exhibited gastric metaplasia, dysplasia, carcinoma in situ, and gastric cancer with vascular invasion. Invasive gastric carcinoma was observed in 6 of 8 INS-GAS mice that were >20 months old. Helicobacter felis infection of INS-GAS mice led to accelerated (< or = 8 mo) development of intramucosal carcinoma (85%), with submucosal invasion (54%) and intravascular invasion (46%; P < or = 0.05).. These findings support the unexpected conclusion that chronic hypergastrinemia in mice can synergize with Helicobacter infection and contribute to eventual parietal cell loss and progression to gastric cancer.

Topics: Animals; Cell Count; Epidermal Growth Factor; Epithelial Cells; Gastric Acid; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Heparin; Heparin-binding EGF-like Growth Factor; Hyperplasia; Hypertrophy; Intercellular Signaling Peptides and Proteins; Metaplasia; Mice; Mice, Transgenic; Stomach Neoplasms; Transforming Growth Factor alpha

The relationship of Helicobacter felis, a bacterium observed in the stomachs of cats, to gastric disease is unclear. The objective of this study was to determine if H. felis infection alters gastric histopathology, proinflammatory cytokine expression, and secretory function and evokes a humoral immune response in cats. Five specific-pathogen-free (SPF) Helicobacter-free cats were studied before and for 1 year after oral inoculation with H. felis (ATCC 49179). Four SPF H. felis-uninfected cats served as controls. The stomachs of all five H. felis-inoculated cats became colonized, as determined by urease activity, histopathology, PCR, culture, and transmission electron microscopy of serial gastric biopsies at 0, 3, 5, 8, and 12 months. Uninoculated cats remained Helicobacter free. Lymphoid follicular hyperplasia, atrophy, and fibrosis were observed primarily in the pylorus of infected cats. Mild mononuclear inflammation was detected in both infected and uninfected cats, but was more extensive in infected cats, with pangastric inflammation, eosinophilic infiltrates, and cardia gastritis observed only in infected cats. No upregulation of antral mucosal interleukin 1alpha (IL-1alpha), IL-1beta, or tumor necrosis factor alpha was detected by reverse transcription-PCR in any cat. The gastric secretory axes, assessed by fasting plasma gastrin, antral mucosal gastrin and somatostatin immunoreactivity, and pentagastrin-stimulated gastric acid secretion, were similar in both infected and uninfected cats. Gradual seroconversion (immunoglobulin G) was observed in four of five infected cats, with enzyme-linked immunosorbent assay values reaching 4x to 12x baseline 12 months postinfection. These findings indicate that H. felis infection in cats induces lymphoid follicular hyperplasia, mild gastritis, and seroconversion, but is associated with normal gastric secretory function.

Topics: Animals; Antibodies, Bacterial; Cats; Cytokines; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Hyperplasia; Immunohistochemistry; Lymphoid Tissue; Male; Polymerase Chain Reaction; Somatostatin; Urease

The efficacy and safety of long-term acid suppression remains a subject for debate. We report data from patients with refractory reflux esophagitis who were undergoing maintenance therapy with >/=20 mg omeprazole daily for a mean period of 6.5 years (range, 1.4-11.2 years).. Patients with severe reflux esophagitis resistant to long-term therapy with H(2)-receptor antagonists and who were not eligible for surgery were evaluated at least annually for endoscopic relapse and histological changes in the gastric corpus.. In 230 patients (mean age, 63 years at entry; 36% were >/=70 years), there were 158 relapses of esophagitis during 1490 treatment years (1 per 9.4 years), with no significant difference in relapse rates between Helicobacter pylori-positive and -negative patients. All patients rehealed during continued therapy with omeprazole at the same or higher dose. The annual incidence of gastric corpus mucosal atrophy was 4.7% and 0.7% in H. pylori-positive and -negative patients, respectively, which was mainly observed in elderly patients who had moderate/severe gastritis at entry. In patients with baseline moderate/severe gastritis, the incidences were similar: 7.9% and 8.4%, respectively. Corpus intestinal metaplasia was rare, and no dysplasia or neoplasms were observed. The adverse event profile was as might be expected from this elderly group of patients.. Long-term omeprazole therapy (up to 11 years) is highly effective and safe for control of reflux esophagitis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Ulcer Agents; Barrett Esophagus; Child; Drug Resistance; Esophagitis; Female; Gastric Mucosa; Gastrins; Gastritis; Gastroesophageal Reflux; Helicobacter Infections; Humans; Hyperplasia; Male; Middle Aged; Omeprazole; Time Factors; Treatment Outcome

Gastrin has a general growth-promoting effect on gastric oxyntic mucosa, and a more pronounced one on the enterochromaffin-like (ECL) cell. Whether gastrin has a proliferative effect on the parietal cell lineage beyond the general effect is uncertain. Hypergastrinaemia was evoked in rats using pantoprazole (group II: 100 micromol kg-1, group III: 400 micromol kg-1) for 45 days. Plasma gastrin was 43 +/- 8 pmol L-1 (control), 283 +/- 54 pmol L-1 (group II) and 577 +/- 63 pmol L-1 (group III). Gastric mucosal cells were isolated and fractionated by elutriation centrifugation. Total cell number, percentage and number of ECL and parietal cells, and histamine were determined in each fraction. The number of mucosal cells increased 1.5-fold in both hypergastrinaemic groups. Enterochromaffin-like cell content was 2.6 +/- 0.5% (control), 6.0 +/- 0.6% (group II) and 9.0 +/- 0.8% (group III). Histamine concentration in oxyntic mucosal cells rose similarly. The size of the ECL cells was 8.5 +/- 0.1 microm (control), 10.8 +/- 0.2 microm (group II) and 12.1 +/- 0.2 microm (group III), and the increased size was confirmed by shifted distribution in elutriation fractions. Histamine per ECL cell increased with cell size. The number of parietal cells increased parallel to the total number of mucosal cells (1.5-fold). Parietal cell size and percentage, assessed by image analysis and distribution in elutriation fractions, were unchanged after pantoprazole dosing. Gastrin has a pronounced, concentration-dependent specific trophic effect on ECL cells and a general proliferative effect on gastric mucosa, including parietal cells.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Benzimidazoles; Cell Division; Cell Fractionation; Centrifugation; Cytoplasmic Granules; Enterochromaffin Cells; Enzyme Inhibitors; Female; Gastric Mucosa; Gastrins; Histamine; Hyperplasia; Microscopy, Electron; Omeprazole; Pantoprazole; Parietal Cells, Gastric; Rats; Rats, Sprague-Dawley; Sulfoxides

We report a case of pseudo-Zollinger-Ellison syndrome in a 17-year-old man presenting with gastrin levels exceeding 2000 pmol/l and BAO 24 mEq/hr. Histologically, apart from hypertrophic gastritis with the thickening of mucosal folds and diffuse G-cell hyperplasia, gastric mucosa was found to contain foci of pancreatic metaplasia.

Topics: Adolescent; Gastric Acidity Determination; Gastric Mucosa; Gastrin-Secreting Cells; Gastrins; Gastritis; Humans; Hyperplasia; Male; Metaplasia; Pancreas; Stomach; Zollinger-Ellison Syndrome

The peroxisome proliferator ciprofibrate induces hypergastrinemia and as a consequence, enterochromaffin-like (ECL) cell hyperplasia. The mechanism for the gastrin cell stimulation is unknown. The somatostatin analog octreotide LAR (long-acting release) was used to see if the stimulating effects of ciprofibrate could be attenuated. Female Fischer rats were dosed with ciprofibrate (50 mg/kg body weight per day) alone or combined with octreotide LAR (10 mg/30 days) for 60 days. Plasma gastrin and histamine, gastric endocrine cell densities and mRNA abundances were measured. Ciprofibrate increased gastrin mRNA abundance (P<0.05), gastrin cell number (P<0. 001) and cell area (P<0.01), and induced hypergastrinemia (P<0.001). These rats had profound ECL cell hyperplasia, confirmed by an increase in chromogranin A (CgA) and histidine decarboxylase (HDC) mRNA, density of neuroendocrine and ECL cells and plasma histamine levels (all P<0.001). Octreotide LAR did not affect ciprofibrate stimulation of gastrin cells, but all parameters of ECL cell hyperplasia were reduced (P<0.001). Octreotide LAR also significantly inhibited basal ECL cell function and growth. Ciprofibrate stimulates gastrin cell activity by a mechanism unaffected by octreotide, but octreotide does inhibit basal and gastrin-stimulated ECL cell function and growth.

Topics: Animals; Chromogranin A; Chromogranins; Clofibric Acid; Enterochromaffin Cells; Female; Fibric Acids; Gastric Mucosa; Gastrins; Gene Expression; Histamine; Histidine Decarboxylase; Hyperplasia; Immunohistochemistry; Octreotide; Peroxisome Proliferators; Rats; RNA, Messenger

Studies in gastrin-deficient mice have demonstrated critical roles for gastrin peptides in the regulation of gastric acid secretion, but the relative contributions of amidated (G-17) and glycine-extended (G17-Gly) gastrin remain unclear. We examined the effects of these 2 forms of gastrin on acid secretion in gastrin-deficient mice.. Sixty gastrin-deficient mice received infusions of saline, or 1, 6, or 14 days of amidated gastrin 17 (G-17), G17-Gly, or both G-17 and G17-Gly at 10 nmol. kg(-1). h(-1). Twenty-four gastrin-deficient mice were then infused for 14 days with 1, 2, or 5 nmol. kg(-1). h(-1) of G-17 or G-17 and G17-Gly. Acid secretion was determined 4 hours after pyloric ligation, and gastric tissue was processed for histology, immunohistochemistry, and electron microscopy.. Infusion of G-17 increased acid secretion in a dose-dependent manner with a peak at 5 nmol. kg(-1). h(-1) and a subsequent decrease in acid secretion at higher doses. Infusion of G17-Gly alone had no effect on acid secretion, but coinfusion with G-17 resulted in significantly higher levels of acid secretion at all doses examined than infusion with G-17 alone. The potentiating effect of G17-Gly on G-17-induced acid secretion was associated with increased parietal cell activation but was independent of changes in parietal and enterochromaffin-like cell number, fundic proliferation rates, and H(+),K(+)-adenine triphosphatase expression. G17-Gly also prevented the formation of vacuolar canaliculi and lipofuscin bodies in the parietal cells induced by G-17.. G17-Gly appears to synergize with G-17 to up-regulate acid secretion and prevent parietal cell degradation. These results suggest that G17-Gly plays an important role in parietal cell function.

Topics: Animals; Cell Division; Drug Synergism; Gastric Acid; Gastric Mucosa; Gastrins; H(+)-K(+)-Exchanging ATPase; Hyperplasia; Mice; Mice, Knockout; Parietal Cells, Gastric; Stomach

We describe herein the case of a 54-year-old Japanese woman in whom an inveterate peptic ulcer developed in association with pseudo-Zollinger-Ellison Syndrome (pseudo-ZES). The patient presented with weight loss and abdominal distension caused by antral and duodenal stenosis due to an inveterate peptic ulcer. Her serum gastrin level was very high; however, no evidence of a gastrinoma or carcinoid tumor was detected by preoperative examinations or surgery. A total gastrectomy and double-tract reconstruction was performed, and pathological examination revealed a gastric ulcer (UL-IV) with no histopathological evidence of a neoplasm. Immunohistochemical staining showed an obvious increase in the number of endocrine cells that were positive for chromogranin A, and marked G-cell hyperplasia was observed in the antral mucosa. Furthermore, the number of enterochromaffin-like cells was remarkably high. From the results of the immunohistochemical examination, the patient was diagnosed as having hypergastrinemia due to antral G-cell hyperplasia. Postoperatively, the patient's serum gastrin level fell rapidly to within the normal range, her nutritional status improved, and her weight increased by about 10 kg within 1 year.

Topics: Diagnosis, Differential; Female; Gastrectomy; Gastrin-Secreting Cells; Gastrinoma; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Middle Aged; Peptic Ulcer; Pyloric Antrum; Treatment Outcome; Zollinger-Ellison Syndrome

The effect of histamine on gastrin cells and enterochromaffin-like cells has not yet been clarified. We investigated the influence of pyrilamine (a histamine H1 receptor antagonist) on serum gastrin level, gastrin cells, and enterochromaffin-like cells in rats with or without 4 weeks of famotidine treatment. The rats were divided into six groups: a control group, two pyrilamine groups (2mg/kg, or 20mg/kg, p.o.), a famotidine group (20mg/kg twice/daily i.m.), and two pyrilamine + famotidine groups. The serum gastrin concentration was determined, and gastrin cells and enterochromaffin-like cells were identified by the labeled streptavidin biotin complex method and counted. Hypergastrinemia, gastrin cell hyperplasia, and enterochromaffin-like cell hyperplasia were found after 4 weeks of famotidine treatment. Four weeks of treatment with pyrilamine alone did not affect the gastrin level, gastrin cells, or enterochromaffin-like cells in the rat stomach. When combined with famotidine, pyrilamine enhanced famotidine-induced hypergastrinemia, but it did not affect gastrin cell hyperplasia, and it significantly inhibited enterochromaffin-like cell hyperplasia. These results suggest that gastrin secretion and enterochromaffin-like cell proliferation may be regulated by histamine via the H1 receptor during acid suppression.

Topics: Animals; Enterochromaffin-like Cells; Famotidine; Gastric Acid; Gastrin-Secreting Cells; Gastrins; Histamine H1 Antagonists; Hyperplasia; Immunohistochemistry; Male; Pyrilamine; Rats; Rats, Wistar

Gastrin is a peptide hormone involved in the growth of both normal and malignant gastrointestinal tissue. Recent studies suggest that the glycine-extended biosynthetic intermediates mediate many of these trophic effects, but the in vivo relevance of glycine-extended gastrin (G-Gly) has not been tested. We have generated mice (MTI/G-GLY) that overexpress progastrin truncated at glycine-72 to evaluate the trophic effects of G-Gly in an in vivo model. MTI/G-GLY mice have elevated serum and colonic mucosal levels of G-Gly compared with wild-type mice. MTI/G-GLY mice had a 43% increase in colonic mucosal thickness and a 41% increase in the percentage of goblet cells per crypt. MTI/G-GLY mice exhibited increased colonic proliferation compared with wild-type controls, with an expansion of the proliferative zone into the upper third of the colonic crypts. Continuous infusion of G-Gly into gastrin-deficient mice for two weeks also resulted in elevated G-Gly levels, a 10% increase in colonic mucosal thickness, and an 81% increase in colonic proliferation when compared with gastrin-deficient mice that received saline alone. To our knowledge, these studies demonstrate for the first time that G-Gly's contribute to colonic mucosal proliferation in vivo.

Topics: Animals; Cell Division; Colon; Gastrins; Gastrointestinal Neoplasms; Gene Expression; Glycine; Goblet Cells; Humans; Hyperplasia; Hypertrophy; Male; Mice; Mice, Transgenic; Protein Precursors; Stomach; Tumor Cells, Cultured

Rats heavily infected with Taenia taeniaeformis larvae in the liver show a remarkable increase in their stomach weight, hyperplasia, and hypergastrinemia. However, it is unknown what causes these phenomena. Hence, as a preliminary study to investigate the importance of larval parasitism in the liver, two experiments were done. In the first experiment, 14 donor rats were orally inoculated with 3,000 T. taeniaeformis eggs. In the second experiment, 136-300 of the larvae obtained from the rats were surgically implanted into the abdominal cavity of 7 recipient rats. Gastrin levels and histopathological changes in the gastric mucosa were investigated. In all, 11 donor rats showed hypergastrinemia and hyperplasia, 5 recipient rats showed gastric mucosal hyperplasia accompanied by excessive mucous cell proliferation, and 2 recipient rats showed hypergastrinemia. These results suggest that parasitism of the liver by the larvae is not essential for the development of hyperplasia and that factors from the larvae might cause these phenomena.

Topics: Animals; Gastric Mucosa; Gastrins; Hyperplasia; Larva; Liver; Male; Peritoneal Cavity; Rats; Rats, Wistar; Taenia; Taeniasis

Female inbred cotton rats develop adenocarcinomas in the oxyntic mucosa. Since a female preponderance is typical for enterochromaffin-like (ECL) cell tumors, we examined such tumors for ECL cells. Gastrin plays a decisive role in ECL cell tumorigenesis, so blood gastrin concentration and gastric mucosal pH were measured.. The stomachs from six female cotton rats (6 to 8 months old) were studied histologically, and at euthanasia, gastric mucosal pH was determined. Euthanasia was performed on 15 other female cotton rats of similar age for determination of blood gastrin values by radioimmunoassay (RIA) and gastric mucosal pH. Rats were classified macroscopically to have normal or thick oxyntic mucosa, with or without tumor.. Among the six cotton rats studied histologically, two 6-month-old rats had normal and two others had thick gastric mucosa, whereas two 8-month-old rats had thick mucosa with tumors. The ECL cells were markedly hyperplastic in all rats with thick mucosa, and ECL cells were found in the neoplastic parenchyma. All cotton rats with normal-appearing gastric mucosa had pH <2.5, whereas 14 rats with thick mucosa had pH >3.1 and hypergastrinemia.. Gastrin may play a major role in ECL cell hyperplasia and, perhaps, in adenocarcinoma genesis.

Topics: Adenocarcinoma; Animals; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Histidine Decarboxylase; Hydrogen-Ion Concentration; Hyperplasia; Immunoenzyme Techniques; Male; Radioimmunoassay; Rats; Rodent Diseases; Sigmodontinae; Stomach Neoplasms; Synaptophysin

A high-salt diet in humans and experimental animals is known to cause gastritis, has been associated with a high risk of atrophic gastritis, and is considered a gastric tumor promoter. In laboratory rodents, salt is known to cause gastritis, and when coadministered, it promotes the carcinogenic effects of known gastric carcinogens. Because Helicobacter pylori has been associated with a progression from gastritis to gastric cancer, we designed a study to determine whether excessive dietary NaCl would have an effect on colonization and gastritis in the mouse model of H. pylori infection. Seventy-two, 8-week-old female C57BL/6 mice were infected with H. pylori strain Sydney, and 36 control mice were dosed with vehicle only. One-half of the infected and control mice were fed a high-salt diet (7.5% versus 0.25%) for 2 weeks prior to dosing and throughout the entire experiment. Twelve infected and 6 control animals from the high-salt and normal diet groups were euthanized at 4, 8, and 16 weeks. At 8 and 16 weeks postinfection (WPI), the colony-forming units per gram of tissue were significantly higher (P < 0.05) in the corpus and antrum of animals in the high-salt diet group compared with those on the normal diet. Quantitative urease was significantly higher (P < 0.05) at 4 and 8 WPI in the corpus and antrum of animals on the high-salt diet when compared with controls. At 16 WPI, mice in both the normal and the high-salt diet groups developed moderate to marked atrophic gastritis of the corpus in response to H. pylori infection. However, the gastric pits of the corpus mucosa in mice on the high-salt diet were elongated and colonized by H. pylori more frequently than those in mice on the normal diet. The high-salt diet was also associated with a significant increase in proliferation in the proximal corpus and antrum and a multifocal reduction in parietal cell numbers in the proximal corpus, resulting in the elongation of gastric pits. We conclude that excessive NaCl intake enhances H. pylori colonization in mice and in humans and that chronic salt intake may exacerbate gastritis by increasing H. pylori colonization. Furthermore, elevated salt intake may potentiate H. pylori-associated carcinogenesis by inducing proliferation, pit cell hyperplasia, and glandular atrophy.

Topics: Animals; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Helicobacter pylori; Hyperplasia; Mice; Mice, Inbred C57BL; Pyloric Antrum; Sodium, Dietary; Urease

Mucolipidosis type IV (ML-IV) is an autosomal recessive lysosomal storage disease that causes severe neurologic abnormalities. The brain disease is characterized by pigmented cytoplasmic granules in neurons and accumulation of lamellated membrane structures in lysosomes. The gastrointestinal disease in ML-IV was not previously recognized. Clinical examination of 20 patients with ML-IV (age range, 2-23 years) at the National Institutes of Health showed hypergastrinemia and constitutive achlorhydria. Endoscopic biopsy specimens from the gastric fundus, body, and antrum and from the duodenum of four such patients (ages 4, 6, 7, and 22 years) were evaluated histologically and by electron microscopy. Histologically, all gastric fundus and body biopsy specimens showed parietal cells in normal numbers. However, a striking cytoplasmic vacuolization of parietal cells was seen on hematoxylin and eosin stain. Electron microscopy showed the parietal cells to be markedly distended by large lysosomes containing lamellar, concentric, and cystic membranous inclusions. Additionally, chronic atrophic gastritis and enterochromaffin-like (ECL) cell hyperplasia were observed. Foveolar and chief cells in stomach and duodenum biopsy specimens were normal. We conclude that the cytoplasmic lysosomal inclusions in gastric parietal cells is a unique histologic feature of gastric biopsy in ML-IV.

Topics: Achlorhydria; Adult; Biopsy; Child; Child, Preschool; Enterochromaffin-like Cells; Female; Gastric Fundus; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Hyperplasia; Inclusion Bodies; Lysosomes; Male; Mucolipidoses; Parietal Cells, Gastric

A follow-up of argyrophil cell hyperplasia in Helicobacter pylori-positive corpus gastritis in gastric ulcer patients during the natural course of ulcer disease.. Endoscopic biopsies (4 specimens) were obtained step-wise from the posterior wall of the corpus mucosa in 55 gastric ulcer (GU) patients. The natural course of GU was followed up in 38 patients during more than 10 years (maximum 19 years), and altogether 115 endoscopic examinations were made: 20 patients were re-examined once, 14 twice, and 4 three times. A total of 364 biopsies from 307 biopsy sites were stained by Grimelius' silver, hematoxylin-eosin, and Giemsa method for the analysis of the argyrophil endocrine cells, chronic gastritis, and H. pylori colonization, respectively, according to the Sydney System.. Of 307 biopsy sites, 153 (50%) showed some grade of ACH. Focal (linear/micronodular) hyperplasia was found in 118 (77%) of biopsy sites; it was detected in 78 (66%) cases of atrophic corpus mucosa, but was present in only 14 (12%) cases of gastritis without atrophy or in the normal mucosa. In the follow-up patients, ACH evolved in 17 and progressed in 6 cases, and a simultaneous development of atrophic corpus gastritis was found in 20 cases.. This study demonstrates that ACH evolves during the natural course of GU, alongside the development of chronic atrophic gastritis.

Topics: Adult; Aged; Antacids; Enteroendocrine Cells; Female; Follow-Up Studies; Gastrins; Gastritis; Helicobacter pylori; Humans; Hyperplasia; Male; Middle Aged; Stomach Ulcer

Topics: Anemia, Pernicious; Autoimmunity; Gastric Mucosa; Gastrins; Gastritis; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia

Beta-microseminoprotein is a 94-kDa protein present on most mucosal surfaces in the body. It is produced in mucin cells but is also found in a particular type of cells (E-cells) in the gastric antral mucosa. Most of these cells also contain gastrin. In atrophic corpus gastritis the gastrin-producing cells become hyperplastic, and the patients have hypergastrinemia. We wanted to ascertain whether there is a similar effect on the E-cells and on the concentration of beta-microseminoprotein in serum.. Antral biopsy specimens from 10 patients with atrophic corpus gastritis and 10 controls were stained immunohistochemically for beta-microseminoprotein and gastrin. beta-Microseminoprotein and gastrin were measured by radioimmunoassay in serum from 15 women with atrophic corpus gastritis and 31 healthy female blood donors.. There was a 3.5-fold increase of the number of E-cells (which also were hypertrophic) and a 2.1 times higher serum concentration of beta-microseminoprotein in the patients with atrophic corpus gastritis than in the control subjects. Gastrin was seen in 28% of the E-cells in patients with atrophic corpus gastritis, compared with 87% in normal antral mucosa. There was no correlation between the serum concentrations of beta-microseminoprotein and gastrin.. In atrophic corpus gastritis antrum E-cells undergo hyperplasia and hypertrophy, and the proportion of E-cells containing gastrin decreases. Increased amounts of beta-microseminoprotein are secreted to the blood but uncorrelated with gastrin.

Topics: Adult; Aged; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Immunohistochemistry; Male; Middle Aged; Peptides; Prostatic Secretory Proteins; Pyloric Antrum; Radioimmunoassay

The infection of parasite-naive sheep with approximately 15,000 adult Ostertagia circumcincta via abomasal cannulae resulted in marked changes in the structure and function of the abomasum. The functional changes, which have been characterised previously, included elevated abomasal pH and increased serum concentrations of pepsinogen and gastrin. Eight days after the transplant of adult worms, the abomasa of recipient animals were significantly heavier than those of controls (P < 0.001), the thickness of the fundic mucosa was greater (P < 0.01), there were fewer parietal cells (P < 0.01) and increases in the numbers of mitotic figures and mucus-producing cells. Mucous cell hyperplasia was also evident in the fundic mucosae of sheep receiving a trickle infection of infective, third-stage O. circumcincta larvae and was prominent within nodules associated with larval development. In non-nodular mucosa, there was hyperplasia of mucous cells and changes in the distribution of parietal cells. Decreases in the number of parietal cells at the gland base were offset by increases at a mid-gland level, probably due to chronic hypergastrinaemia, so that, overall, total parietal cell number was unaffected. Mucous cell hyperplasia and the diminution of parietal cell number are seen in a diverse range of disease states and may be mediated by host growth factors such as Transforming growth factor-alpha. Alternatively, the cellular and/or the secretory changes in response to the presence of adult worms are mediated by chemicals that are cytotoxic/inhibitory for parietal cells, and released by the parasites themselves.

Topics: Abomasum; Age Factors; Animals; Gastric Fundus; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Hyperplasia; Larva; Organ Size; Ostertagia; Ostertagiasis; Parietal Cells, Gastric; Pepsinogen A; Pylorus; Sheep; Sheep Diseases; Specific Pathogen-Free Organisms; Stomach Diseases

Topics: Autoimmune Diseases; Endocrine Gland Neoplasms; Gastric Mucosa; Gastrins; Gastritis; Humans; Hyperplasia; Iatrogenic Disease; Pyloric Antrum

The mechanisms causing progression of fundic gastritis and changes in argyrophil cell morphology in patients undergoing long-term treatment with proton pump inhibitors are unknown. The hypothesis of this study was that Helicobacter pylori is a risk factor for both gastritis and argyrophil cell hyperplasia.. Forty-two patients with peptic disorders resistant to H2-blockers were treated with 30-90 mg lansoprazole daily for up to 5 years. Serum gastrin levels, antral gastrin cells, fundic argyrophil cells, parameters of gastritis, and H. pylori infection were evaluated regularly.. In nonantrectomized patients, serum gastrin levels increased from a median of 76 pg/mL to 163 pg/mL within 3 months. Antral gastrin cell density increased from 175 to 267 cells/mm2 (P < 0.001), and fundic argyrophil cell density increased from 83 to 149 cells/mm2 (P < 0.001). Chronic inflammation, activity, and atrophy of the oxyntic mucosa worsened exclusively in patients with H. pylori infection. Linear and/or micronodular argyrophil cell hyperplasia was diagnosed in 2.6% of patients before lansoprazole and in 29.2% after 5 years treatment. These changes were significantly related to serum gastrin levels, H. pylori infection, chronic inflammation, and atrophy of the oxyntic mucosa.. H. pylori represents an important factor for the progression of fundic gastritis and the development of argyrophil cell hyperplasia during long-term treatment with lansoprazole.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Female; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Lansoprazole; Male; Middle Aged; Omeprazole; Proton Pump Inhibitors; Pyloric Antrum; Risk Factors

Topics: Abdominal Pain; Adult; Anemia, Pernicious; Carcinoid Tumor; Diagnosis, Differential; Female; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Hyperplasia; Precancerous Conditions; Pyloric Antrum; Stomach Neoplasms

It is not known whether plasma chromogranin analysis could be a complement to histology for detection and grading of gastric fundic mucosal endocrine cell proliferation in hypergastrinemic (type-A) atrophic gastritis.. Gastric biopsy sections (body and antrum) from 43 patients with type-A gastritis (9 with gastric carcinoid) were examined for density and micronodules of argyrophil endocrine cells. Fasting blood samples were analyzed for chromogranin A and B, gastrin, and somatostatin.. All patients with carcinoid and 17 of the 34 without carcinoid had micronodules in the gastric fundic mucosa. The median plasma chromogranin A concentration was 5.7 (3.5-40.0) nmol/l in patients with carcinoid, 4.5 (3.0-9.5) nmol/l in patients with micronodules, and 3.7 (0.8-6.0) nmol/l in patients without micronodules. Overall, chromogranin A concentrations correlated to endocrine cell densities in the fundic mucosa (r = 0.64, P < 0.001) and to gastrin concentrations (r = 0.71, P < 0.001). Plasma somatostatin and chromogranin B concentrations did not differ significantly between the groups.. In type-A gastritis, analysis of plasma chromogranin A may be a useful complement to histology in estimating the endocrine cell mass. Moreover, subclinical type-A gastritis may be a source of error when chromogranin A analysis is used in the search for neuroendocrine neoplasia.

Topics: Aged; Anemia, Pernicious; Biopsy; Carcinoid Tumor; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Male; Stomach Neoplasms

The present study was performed to examine the effect of ageing on pancreatic hyperplasia observed after proximal small bowel resection (PSBR). Young and old Wistar rats were randomly assigned to two groups, which underwent either an approximate 90% PSBR or a jejunal and ileal transection (TRC). One week after the operation, the pancreatic wet weight and the protein, DNA and RNA content of the pancreas were all significantly higher in young PSBR rats than in young TRC rats. However, no differences were seen in the old rat groups. Plasma enteroglucagon levels were elevated in both young and old PSBR rats, but the ratio of increase between the PSBR and TRC groups was significantly higher in young rats. Plasma cholecystokinin and gastrin levels did not increase after PSBR in either the young or old rats. These findings suggest that pancreatic hyperplasia observed after PSBR is attenuated by ageing, probably due to an insufficient increase in plasma enteroglucagon levels.

Topics: Aging; Amylases; Animals; Body Weight; Cholecystokinin; DNA; Eating; Gastrins; Glucagon-Like Peptides; Hyperplasia; Intestine, Small; Lipase; Male; Organ Size; Pancreas; Radioimmunoassay; Rats; Rats, Wistar; RNA; Trypsinogen

A case of MEN type I in a 64-year-old man is reported. He had undergone partial duodenectomy because of gastric ulcer and multiple duodenal polyps (gastrin secreting carcinoid). Blood examination revealed hypercalcemia, hyperPTHemia, and hyperprolactinemia. Neck US and CT showed enlargement of 4 parathyroid glands. Brain MRI revealed the microadenoma in left pituitary gland. Total parathyroidectomy with auto-transplantation in the left forearm were performed. Histological examination showed the hyperplasia of the parathyroid. Three and a half year after parathyroidectomy, there was no evidence of recurrence of gastrin secreting tumor and hyperparathyroidism, and enlargement of pituitary microadenoma. This is the first MEN type I case in Japan which have detected 3 endocrine tumors clinically with gastrin secreting duodenal carcinoid.

Topics: Adenoma; Carcinoid Tumor; Duodenal Neoplasms; Gastrins; Humans; Hyperparathyroidism; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Parathyroid Glands; Pituitary Neoplasms; Prolactin

ECL cells in the oxyntic mucosa secrete histamine and pancreastatin in response to gastrin. The present study examined gastrin-evoked ECL-cell responses over a 10-week time span in terms of individual ECL cells and unit ECL cell volume. Rats were treated with omeprazole (400 micromol/kg per day orally). The concentrations of gastrin and pancreastatin in serum and of histamine and pancreastatin in the oxyntic mucosa were measured as was the activity of the oxyntic mucosal histidine decarboxylase (HDC). The ECL cells were visualized by immunostaining of histamine and examined by electron microscopy. The total ECL cell number and volume, and the mean ECL cell diameter and volume were determined. The HDC, chromogranin A (CGA) and cholecystokinin-B (CCK-B) receptor mRNA concentrations were determined. In terms of individual ECL cells and unit ECL cell volume, the serum pancreastatin concentration, the oxyntic mucosal histamine content, HDC activity, and HDC, CGA and CCK-B receptor mRNA contents increased slowly at first and then leveled off or started to decline after 2 weeks. After 10 weeks all ECL-cell parameters (expressed per unit ECL cell volume) were back to or approaching the starting value. In conclusion, sustained hypergastrinemia first activates each individual ECL cell (with a peak after 1-2 weeks) and then causes gradual functional impairment, the activity returning towards the pre-stimulation level.

Topics: Animals; Base Sequence; Cell Size; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Enzyme Inhibitors; Gastric Mucosa; Gastrins; Histamine Release; Histidine Decarboxylase; Hyperplasia; Male; Microscopy, Electron; Omeprazole; Pancreatic Hormones; Parietal Cells, Gastric; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; RNA, Messenger; Stomach

A total of 14 gastric biopsy specimens from patients with microcarcinoidosis were analysed by immunohistochemical methods to evaluate the pattern of endocrine cell hyperplasia and dysplasia. All the patients had type A gastritis (autoimmune gastritis). Nonantral proliferations of gastric endocrine cells were classified according to Solcia et al. All 14 cases had hyperplasia and 13 (92.9%) of them, dysplasia of gastric endocrine cells; 9 (64.3%) of the 14 were found to have showed a coexisting invasive gastric carcinoid at the time of diagnosis of microcarcinoidosis. The patients with invasive carcinoids had higher degrees and more complex forms of endocrine dysplasia (precarcinoid lesions). The average size of the foci of the microcarcinoidosis in gastric biopsies was 0.14 +/- 0.09 cm in the patients without invasive carcinoid, as against to 0.5 +/- 0.24 cm in the group of patients with associated invasive carcinoid. Microcarcinoid gastric biopsies about 0.5 cm in size, are suggestive of adjacent invasive carcinoid. However, even frankly invasive ECL carcinoids seem to be clinically less dangerous than was thought until recently.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; Carcinoid Tumor; Endocrine Glands; Female; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Male; Middle Aged; Stomach; Stomach Neoplasms

In this study, we determined in vivo morphologic effects of continuous intravenous infusion of recombinant human epidermal growth factor (EGF) in adult Wistar rats. The EGF used consisted of the amino acid residues 1-48 of the human 53-amino-acid EGF molecule, purified from transfected Escherichia coli. Doses of 25, 100, or 250 micrograms/kg body weight were administered using Harvard digital syringe infusion pumps for 4 weeks. At necropsy, the submandibular salivary glands, Harderian glands, liver, kidneys (females only), and ovaries were enlarged and urinary bladders were thickened in 100- and 250-micrograms/kg rats. Numerous tissues of the 100- and 250-micrograms/kg rats contained hyperplastic epithelial cells, and selected organs also had mesenchymal cell proliferation. Epithelial proliferation was most pronounced in the trachea, nasal cavity, nasolacrimal duct, tongue, stomach, small intestine, large intestine, urinary tract, salivary gland ducts, and Harderian gland. Periportal hepatocytes were hypertrophic, correlating with increased liver weight. In addition, mesenchymal cell proliferation was evident in the gastric mucosa lamina propria and in heart valves in 100- and 250-micrograms/kg rats. Increased ovarian weight correlated with increased number and size of corpora lutea and an increased incidence of luteal cysts. Continuous systemic exposure of adult Wistar rats to high doses of EGF resulted in generalized epithelial hyperplasia and tissue-selective mesenchymal proliferation.

Topics: Amino Acid Sequence; Animals; Body Weight; Cell Count; Digestive System; Epidermal Growth Factor; Female; Gastrins; Humans; Hyperplasia; Infusions, Intravenous; Male; Molecular Sequence Data; Organ Size; Rats; Rats, Wistar; Recombinant Proteins; Respiratory System; Urogenital System

Hypergastrinemia, induced by sustained suppression of gastric acid secretion, is associated with gastric enterochromaffin-like (ECL) cell hyperplasia and carcinoid tumor formation. We examined the effect of a selective H1-histamine antagonist, terfenadine, on gastric mucosal cell proliferation to determine whether histamine might modulate ECL cell generation.. The rodent mastomys received the H2-antagonist loxtidine (2 g/l drinking water) alone or in combination with terfenadine (0.5 g/l or 35 mg/l drinking water) for 120 days. Controls received water or terfenadine alone. Serum gastrin levels and tissue histamine content were assayed by radioimmunoassays, and tissue chromogranin levels determined (Western blot analysis). In vivo cell proliferation was measured by bromodeoxyuridine (BrdU, 200 mg/kg/day, 3 days) incorporation. Gastric mucosal thickness was determined, ECL cell number was assessed, and the percentage of proliferating ECL cells quantitated. To evaluate the direct action on ECL cells we then studied the effect of terfenadine on histamine secretion and DNA synthesis (BrdU uptake) in an isolated preparation (approximately 90% pure) of ECL cells.. Loxtidine increased serum gastrin levels, mucosal thickness, tissue chromogranin levels, tissue histamine content, BrdU incorporation, ECL cell number, and proliferating ECL cells (all parameters p < 0.05). Terfenadine alone, irrespective of dosage, had no significant effect. The high dose in combination with loxtidine significantly inhibited the increase in tissue chromogranin levels, tissue histamine content, ECL cell number and proliferating ECL cells (p < 0.05), but did not alter other parameters, compared to loxtidine alone. The low does did not alter the loxtidine-induced changes. In pure isolated ECL cells, terfenadine did not alter histamine secretion either alone or in combination with gastrin (10 nM). DNA synthesis was significantly inhibited by terfenadine (IC50 10(-10) M).. Terfenadine specifically inhibited the effect of loxtidine-induced ECL cell proliferation in vivo and significantly inhibited ECL cell DNA synthesis in vitro. We postulate that histamine, through an H1 receptor, positively modulates gastric ECL cell proliferation.

Topics: Animals; Cell Division; Chromogranins; DNA; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Hyperplasia; In Vitro Techniques; Male; Muridae; Terfenadine; Triazoles

We investigated whether duodenogastric reflux (DGR) together with gastroesophageal reflux causes growth stimulation of the foregut mucosa and if additional gastric acid suppression enhances the effect of DGR. DGR was induced in rats using a split gastroenterostomy. A cardiomyotomy was performed across the gastroeophageal junction in order to enhance reflux into the esophagus. DGR rats were divided into six subgroups: DGR, DGR + truncal vagotomy, DGR + omeprazole, DGR + gastrin receptor blockade, DGR + omeprazole + gastrin receptor blockade, and DGR + gastrin. Two sham groups, one with and one without omeprazole treatment, served as controls. DGR significantly increased the weight and DNA content of the esophageal and gastric mucosa, which was further enhanced by vagotomy or omeprazole. Histology revealed foveolar hyperplasia in the stomach and esophageal mucosal hyperplasia in these groups. In addition, severe esophagitis was found in the DGR group receiving omeprazole. Omeprazole without DGR had no growth-stimulating effect on the foregut mucosa. DGR-induced growth stimulation was accompanied by hypergastrinemia. Increased growth in the stomach but not the esophagus was inhibited by gastrin receptor blockade. Gastrin administration did not result in enhancement of DGR-induced growth stimulation of the foregut mucosa. It is concluded that DGR, often present in severe reflux esophagitis, causes mucosal growth of the foregut of rats. This trophic response may explain why severe reflux esophagitis is associated with an increased risk of esophageal adenocarcinoma. DGR-induced growth stimulation of the foregut is potentiated by gastric acid suppression, suggesting that chronic antisecretory medication in gastroesophageal reflux may not always be advisable. Omeprazole + DGR caused severe esophageal damage, which may explain why antisecretory medication may fail to heal severe reflux esophagitis.

Topics: Animals; DNA; Duodenogastric Reflux; Esophagus; Gastric Acid; Gastric Acidity Determination; Gastric Mucosa; Gastrins; Hyperplasia; Male; Omeprazole; Organ Size; Rats; Rats, Sprague-Dawley; Vagotomy

The authors determined whether ileojejunal transposition (IJT) stimulates the growth of the pancreas or the nontransposed segment of small intestine, and ascertained whether this trophic effect is altered by the location of transposed gut segment.. Transposition of the ileum to the proximal small intestine stimulates a marked mucosal growth of the transposed ileal segment; the cellular mechanisms responsible for this adaptive hyperplasia are not known.. The distal quarter of the small intestine (distal ileum) was transposed into the proximal (Type I), middle (Type II), or distal (Type III) portions of the remaining small intestine. On postoperative day 28, the pancreas and scraped mucosa from the segments of transposed ileum, proximal ileum, and duodenum were obtained, weighed, and examined for DNA and protein content.. All types of IJT increased mucosal weight and DNA content of the transposed ileum. Types I and II IJT produced a significant proliferation of the pancreas and mucosa of the duodenum and proximal ileum. The magnitude of proliferative increases was greatest in Type I IJT.. Ileojejunal transposition appears to be an excellent model to examine the mechanisms by which intestinal epithelial cells proliferate in response to luminal nutrients or humoral factors.

Topics: Adaptation, Physiological; Animals; DNA; Duodenum; Gastrins; Hyperplasia; Ileum; Intestinal Mucosa; Intestine, Small; Jejunum; Male; Neurotensin; Pancreas; Proteins; Rats; Rats, Inbred F344

A rapid induction of enterochromaffinlike (ECL) cell tumours has been shown in Praomys (Mastomys) natalensis subjected to histamine2-receptor blockade. In the present study the reversibility of ECL cell proliferation induced by acid inhibition was investigated. Short-term treatment (8 weeks) with the histamine2-receptor antagonist loxtidine caused a moderate hypergastrinemia, accompanied by a minor increase in histamine contents and a 2-fold increased volume density of the endocrine cells in gastric oxyntic mucosa. Eight weeks after withdrawal of treatment the volume density of endocrine cells was normalised as were the tissue levels of histamine, indicating a total reversibility of ECL cell hyperplasia. Long-term treatment (24 weeks) caused severe changes in the endocrine cell population of the oxyntic mucosa with neoplasia (5/21), dysplasia (11/21) and nodular hyperplasia (5/21). The endocrine cell density increased twofold and tissue histamine levels fourfold. 24 weeks after cessation of treatment, the endocrine cell density had decreased to 136% of controls, while histamine concentrations were normalised. The frequency of invasive carcinoids after recovery (4/23) differed only slightly from that seen after treatment for 24 weeks (5/21). Dysplastic lesions were only seen in 1/23 and hyperplastic lesions were of less severe type after recovery. The results demonstrate that ECL cell hyperplasia and dysplasia, induced by acid inhibition, are reversible after cessation of treatment. However, ECL cell tumours did not disappear, within the given observation period. One may therefore speculate that ECL cell proliferation is no longer reversible once the neoplastic (transformed) phenotype has developed.

Topics: Animals; Carcinoid Tumor; Cell Count; Cell Division; Cell Transformation, Neoplastic; Enterochromaffin Cells; Female; Gastrins; Histamine; Histamine H2 Antagonists; Hyperplasia; Male; Muridae; Parietal Cells, Gastric; Stomach Neoplasms; Triazoles

The present study evaluated pancreatotrophic factors after massive small bowel resection. Specifically, we examined the role of enteroglucagon in compensatory pancreatic hyperplasia after proximal small bowel resection (PSBR) by using rats fed a fiber-free elemental diet or an elemental diet containing pectin. PSBR increased the net pancreatic weight as well as the protein, DNA, RNA, and amylase contents, and elevated plasma enteroglucagon levels. Pectin addition to the diet provoked a further increase in these parameters and significant positive correlations were found between the plasma enteroglucagon levels and the protein, DNA, and RNA contents of the pancreas. Plasma gastrin and CCK levels were not affected by the small bowel resection. These results indicate that enteroglucagon may exert a potent trophic effect on the pancreas after PSBR.

Topics: Adaptation, Physiological; Amylases; Animals; Cholecystokinin; DNA; Gastrins; Glucagon-Like Peptides; Hyperplasia; Intestine, Small; Male; Organ Size; Pancreas; Proteins; Rats; Rats, Wistar; RNA

Topics: Animals; Chromogranins; Cyproheptadine; Enterochromaffin Cells; Estradiol; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Histamine Release; Hyperplasia; Muridae; Neuroendocrine Tumors; Octreotide; Tamoxifen; Triazoles

The occurrence of H. pylori infection and the levels of fasting serum gastrin (SEGA) were examined in 97 patients with different morphological types of endoscopically diagnosed gastric polyps. According to the histology of the polyps the series was divided into three groups: inflammatory polyps (43 cases), polyps with foveolar hyperplasia (25 cases), and hyperplastic polyps including adenomas (29 cases). The prevalence of H. pylori infection was significantly lower in patients with hyperplastic polyps (45%) and foveolar hyperplasia (48%) than in the group with inflammatory polyps (81%). SEGA levels were higher in patients with hyperplastic polyps (mean +/- sd: 335 +/- 298 pmol/l) and foveolar hyperplasia (183 +/- 216) than in patients with inflammatory polyps (89 +/- 127). Signs of so-called "autoimmune" gastric, i.e. corpus atrophy and presence of parietal cell antibodies, were commonly found in patients with hyperplastic polyps and foveolar hyperplasia, but rarely in patients with inflammatory polyps. These results suggest that the polyps with hyperplastic changes (hyperplastic polyps and foveolar hyperplasia) are in some of the cases closely related to autoimmune gastritis. The presence of corpus atrophy, hypoacidity and various types of metaplasia, which characterizes autoimmune gastritis, could explain the low prevalence of H. pylori and the high SEGA levels found in these patients.

Topics: Adenoma; Aged; Female; Gastrins; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Male; Middle Aged; Polyps; Stomach Neoplasms

Omeprazole, a long-acting inhibitor of gastric acid secretion, is able to increase the circulating concentrations of gastrin. Daily treatment with high doses of omeprazole cause sustained hypergastrinemia. Long-standing hypergastrinemia can be expected to exert numerous effects in the body. For instance, gastrin has been proposed to promote growth in the digestive tract and pancreas. The present study is concerned with the effect of omeprazole on parathyroid glands in the chicken.. Chickens were treated with omeprazole (400 mumol/kg/day) in methylcellulose (2.5 ml/kg) for 5 or 10 weeks. Controls received vehicle. Blood calcium and serum gastrin concentrations were studied. The weight gain of the animals and of various organs (proventriculus, antrum, thyroids, parathyroids, ultimobranchial glands, and femur) were determined. The DNA content and the size of the parathyroid chief cells were also determined.. Omeprazole reduced the body weight gain while greatly increasing the weight of the proventriculus and the parathyroid glands. The weight and density of the femur were reduced. The circulating concentrations of calcium were unaffected. The DNA content of the parathyroid glands was increased, and morphometric analysis of the parathyroid chief cells showed an increased cell size. Thus, the increased parathyroid gland weight seems to reflect both hypertrophy and hyperplasia. There was a slight increase in the weight of the ultimobranchial glands (expressed per kilogram body weight). The weight of the thyroids was unaffected (expressed in relation to body weight).. The results indicate that omeprazole treatment in chickens leads not only to trophic effects in the acid-producing gastric mucosa (probably because of the ensuing hypergastrinemia), as reported earlier, but also to growth of the parathyroid glands (both hypertrophy and hyperplasia) and to bone loss without affecting blood calcium values. The mechanism behind these effects remains unknown.

Topics: Animals; Bone Density; Chickens; DNA; Gastrins; Hyperplasia; Hypertrophy; Omeprazole; Organ Size; Parathyroid Glands; Proventriculus; Thyroid Gland; Weight Gain

The effect of moderate congenital hypergastrinemia on the enterochromaffin-like (ECL) cells was investigated in Zucker rats 4 and 18 months of age by combining autoradiography after tritiated thymidine injection and selective immunocytochemistry. In both age groups the serum gastrin concentration was 200% higher in obese (fa/fa) than in lean (Fa/Fa; Fa/fa) littermates. In 4-month-old obese rats there was a 120% increase (p < 0.05) in the ECL cell labeling index and also a moderate increase in the ECL cell density (p < 0.05) compared with lean controls. In 18-month-old obese rats the hyperplasia was quantitatively more prominent, with both linear and micronodular ECL cell hyperplasia. At this stage, the ECL cell labeling indices in obese and in lean animals were similar. These data support the hypothesis that moderate hypergastrinemia initially accelerates the ECL cell proliferation rate, leading to diffuse ECL cell hyperplasia. In similar conditions, at the latter stage, linear and micronodular ECL cell hyperplasia also develop in most of the hypergastrinemic animals.

Topics: Animals; Cell Division; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Hyperplasia; Male; Rats; Rats, Zucker

Long-term treatment with omeprazole induces hyperplasia of enterochromaffin-like cells, closely related to hypergastrinemia. We studied whether proglumide, an antagonist of gastrin/CCK receptor, and enprostil, a synthetic prostaglandin E2 derivative, might inhibit this hyperplasia. Six groups of 8 rats were treated for 10 weeks: a) untreated controls; b) omeprazole 10 mumol/kg; c) proglumide 500 mg/kg; d) enprostil 30 micrograms/kg; e) association of omeprazole and proglumide; f) association of omeprazole and enprostil. Serum gastrin levels were measured at different times during treatment. After sacrifice, fundic argyrophil cells were assessed by Grimelius' staining. Serum gastrin levels and argyrophil cell density were not modified in proglumide- and enprostil-treated groups, as compared with controls. Omeprazole increased significantly these two parameters. When given with omeprazole, proglumide decreased significantly serum gastrin levels and argyrophil cell density, as compared to omeprazole alone, while enprostil did not modify significantly these two parameters. These results indicate that proglumide, but not enprostil, can counteract the omeprazole-induced argyrophil cell hyperplasia in rats.

Topics: Animals; Cell Count; Depression, Chemical; Drug Combinations; Enprostil; Enterochromaffin Cells; Female; Gastric Fundus; Gastrins; Hyperplasia; Omeprazole; Proglumide; Rats; Rats, Wistar; Reference Values

The effect of pancreaticobiliary diversion (PBD) on the colonic mucosa was studied in hamsters over 5, 10, and 24 days. Sham-operated animals served as controls. At all three time intervals, experimental animals had increased plasma cholecystokinin concentrations and decreased gastrin concentrations. Five days after PBD, there was an increase in scintigraphically measured [3H]thymidine incorporation into colonic tissue. Correspondingly, there was an increase in the [3H]thymidine DNA labeling index of goblet cells in the colonic mucosa. The total number of cells in the colonic crypt columns were significantly increased on days 5, 10 and 24. Whether this proliferative response in the colon is due to increased release of cholecystokinin, enteroglucagon, other aberrations of hormones or growth factors, or simply an increased bile load on the colonic mucosa remains to be clarified. Such further studies may reveal an alternative animal model for studies on risk factors in colonic carcinogenesis.

Topics: Animals; Autoradiography; Biliopancreatic Diversion; Cell Division; Cholecystokinin; Colon; Cricetinae; Gastrins; Hyperplasia; Intestinal Mucosa; Male; Mesocricetus; Organ Size; Thymidine; Time Factors; Tritium

A 63-year-old woman was diagnosed as autoimmune gastritis by the presence of serum antibody against alpha-subunit of gastric H+,K(+)-ATPase. The patient did not have pernicious anemia, but showed achlorhydria, marked hypergastrinemia, enterochromaffin-like cell hyperplasia and an extremely high histidine decarboxylase activity in the gastric fundic mucosa. Intragastric acidification by infusion of hydrochloric acid via a nasogastric tube induced a transient reduction of serum gastrin level and fundic mucosal histidine decarboxylase activity. A marked increase in fundic mucosal histidine decarboxylase activity as well as hypergastrinemia appears to be the pathophysiologic response to achlorhydria caused by autoimmunity against gastric H+,K(+)-ATPase.

Topics: Achlorhydria; Autoimmune Diseases; Enterochromaffin Cells; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis; Graves Disease; H(+)-K(+)-Exchanging ATPase; Histidine Decarboxylase; Humans; Hyperplasia; Middle Aged; Parietal Cells, Gastric; Polyps; Stomach Neoplasms

This study reports the effects of 4 and 5-year treatment with octreotide (200 micrograms sc bid) in the Zollinger-Ellison syndrome (ZES). No symptoms related to acid hypersecretion were observed in the four patients throughout the study, and upper GI endoscopy was normal. Basal acid output (BAO) measured 12 h after injection, was below 10 mmol h-1 in three to four patients and previous ranitidine treatment was discontinued. In the fourth case (pretreatment BAO value: 115 mmol h-1), BAO progressively decreased to 42 mmol h-1 after 5 years of octreotide treatment. At the end of the study, serum gastrin levels were 58.5% (30-68) of the pretreatment values and two patients had normal gastrin levels. Peak acid output (PAO) decreased markedly after 2, 4 and 5 years, by 68% (35-89) suggesting that octreotide had exerted an antitrophic effect on parietal cell mass. Diffuse hyperplasia of fundic argyrophil cells present in two patients before octreotide, decreased during the treatment. Mean argyrophil cell density for all patients was not significantly modified. Antral gastrin-cell density was in the normal range. No long-term side effect of octreotide treatment was observed. Although octreotide may not be considered as a substitute for benzimidazoles in the treatment of ZES, its specific properties may be of therapeutic benefit in some ZES patients.

Topics: Adult; Female; Gastric Acid; Gastric Fundus; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Octreotide; Time Factors; Zollinger-Ellison Syndrome

We determined the maximum secretion of gastric acid and the fasting serum levels of pepsinogen I and gastrin in Japanese patients with gastric hyperplastic polyps or polypoid-type early gastric carcinoma, comparing those findings with observations in control subjects. Both the maximum acid secretion and fasting levels of serum pepsinogen I were significantly lower in the patients with gastric hyperplastic polyps or polypoid-type early gastric carcinoma than in the controls. Fasting serum gastrin levels were significantly higher in the patients with gastric hyperplastic polyps than in the other two groups of subjects. These data demonstrated that the combination of hypochlorhydria, a low level of pepsinogen I, and hypergastrinemia (type-A gastritis) was common in the patients with gastric hyperplastic polyps, whereas hypochlorhydria and a low pepsinogen I without hypergastrinemia (type-B gastritis) were common in those with polypoid-type early gastric carcinoma.

Topics: Aged; Female; Gastric Acid; Gastrins; Humans; Hyperplasia; Japan; Male; Middle Aged; Pepsinogens; Polyps; Stomach Neoplasms

Gastrin is expressed in the gastric antrum and in fetal pancreatic islets but not in adult islets. We have now identified the hepatobiliary tract as another, previously unknown, potential site of gastrin gene expression. Two human gastrin simian virus 40 large tumor antigen (SV40 T antigen) fusion genes containing 1.5 kb of 5' flanking sequence and 10.5 kb that included 5.5 kb upstream, 1.5 kb downstream, and the entire transcribed region were used to generate transgenic mice. Analysis of several transgenic lines, derived from both fusion genes, revealed development of transmissible hepatobiliary tract tumors and pancreatic islet cell tumors. Analysis of each of the tumor cells demonstrates expression of SV40 T antigen but no expression of gastrin. Of the two fusion genes, only the 10.5-kb sequence induces hyperplasia of gastrin-producing cells in the antrum. Analysis of these cells demonstrates expression of SV40 T antigen and gastrin, suggesting that the 10.5-kb sequence is sufficient for gastrin cell hyperplasia in the antrum. These data raise the possibility that gastrin is transiently expressed in the hepatobiliary tract.

Topics: Adenoma, Islet Cell; Animals; Antigens, Viral, Tumor; Biliary Tract Neoplasms; Gastric Mucosa; Gastrins; Hyperplasia; Hypoglycemia; Mice; Mice, Nude; Mice, Transgenic; Pyloric Antrum; Recombinant Fusion Proteins; Simian virus 40

The histamine-producing enterochromaffin-like (ECL) cells in the oxyntic mucosa are controlled by gastrin. An acute gastrin challenge induces release and accelerated resynthesis of ECL cell histamine. Long-term stimulation with gastrin causes ECL cell hyperplasia. We set out to study whether the ECL cells respond not only to gastrin but also to cholecystokinin (CCK). A wide dose range of gastrin-14 sulfated and -17 non-sulfated and CCK-8 sulfated (CCK-8s) and non-sulfated (CCK-8) was infused intravenously to rats for 3 h. The activity of the histamine-forming enzyme was measured at termination of infusion. Gastrins and CCK-8s were equally effective in activating the enzyme, whereas sulfated CCK-8 was notably less potent than the other three peptides. Clearly, the receptor responsible for activation of the ECL cells distinguishes poorly between gastrin-17 and CCK-8s, which is in line with the characteristics of the CCK-B receptor. Moreover, neither the response to gastrin-17 nor that to CCK-8s was affected by concomitant infusion of devazepide (200 micrograms/kg/h), a selective CCK-A-receptor antagonist. One group of rats received CCK-8s continuously via a minipump. Another group of rats was subjected to pancreaticobiliary diversion (PBD), which increases the plasma CCK concentration 10- to 20-fold. The rats were killed 7 or 10 weeks later, respectively, and the stomachs were analyzed with regard to mucosal growth and ECL cell hyperplasia. HyperCCKemic rats had increased pancreatic weights but showed no signs of growth stimulation in the stomach and no ECL cell hyperplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biliopancreatic Diversion; Cholecystokinin; Enterochromaffin Cells; Gastrins; Histidine Decarboxylase; Hyperplasia; Infusions, Intravenous; Male; Parietal Cells, Gastric; Rats; Rats, Sprague-Dawley; Stomach

To assess the value of gastroscopic cancer surveillance of patients with pernicious anaemia, 56 patients were re-endoscoped and biopsied after three years. In addition, changes in the density of fundic mucosal endocrine cells were evaluated morphometrically. Two cases (3.6%) of early gastric cancer and two cases of small gastric carcinoid tumours (3.6%) were detected in addition to the five carcinoids that had been found at the initial endoscopic screening. Nodular argyrophil cell hyperplasia and morphometric density of argyrophil cells were not stable phenomena: nodular hyperplasias regressed in five patients, remained similar in six, and progressed to a small carcinoid tumour in one. Serum gastrin concentrations did not correlate well with changes in the endocrine cell density. Regular endoscopic surveillance for gastric cancer may be beneficial and realistic in young patients with pernicious anaemia while the importance of fundic endocrine cell hyperplasia and that of small gastric carcinoids need further study.

Topics: Adenocarcinoma; Adult; Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Follow-Up Studies; Gastric Fundus; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Stomach; Stomach Neoplasms

A 60-yr-old man with longstanding duodenal ulcer was found to have hyperchlorhydria, moderate fasting hypergastrinemia, and markedly exaggerated meal-stimulated gastrin release. Antral tissue specimens showed the proliferation of gastrin cells and increased gastrin content, and he was found to have Helicobacter pylori infection in the antral mucosa. His illness was diagnosed as primary gastrin cell hyperplasia with H. pylori infection. Eradication of H. pylori normalized not only gastrin hypersecretion but also gastrin cell hyperplasia. These results indicate that H. pylori infection could be one of the causes of this syndrome.

Topics: Bismuth; Drug Therapy, Combination; Duodenal Ulcer; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Male; Metronidazole; Middle Aged; Pyloric Antrum; Tetracycline

The histamine-producing enterochromaffin-like (ECL) cells in the acid-producing portion of the rat stomach responded to long-standing hypergastrinemia (omeprazole treatment daily for 8-10 weeks) with hypertrophy (and hyperplasia) and with a reduced number of granules and vesicles per unit cytoplasm. There was a reduction in the ratio of electron-dense granules versus vesicles and an increase in the profile diameter of the vesicles. Also, portacaval shunting (PCS) induced changes in the ECL cells, manifesting (i) as an increase in cell number and size, and (ii) as a reduced number of granules and vesicles per unit area. The cytoplasmic granules and vesicle profiles were enlarged, and the ratio of granules versus vesicles was reduced. The combination of PCS and long-standing hypergastrinemia (omeprazole treatment) produced a greatly enhanced ECL cell hypertrophy (and hyperplasia) and a marked reduction in the number of granules. The ratio of granules versus vesicles was markedly reduced while the profile diameters of both granules and vesicles were increased. The relative predominance of very large vesicles (vacuoles) was a prominent feature of the ECL cells in these rats.

Topics: Animals; Enterochromaffin Cells; Gastrins; Hyperplasia; Hypertrophy; Male; Microscopy, Electron; Omeprazole; Portacaval Shunt, Surgical; Rats; Rats, Sprague-Dawley; Stomach

Topics: Adenocarcinoma; Animals; Antigens, Viral, Tumor; Carcinoma; Gastrinoma; Gastrins; Genetic Engineering; Hyperplasia; Liver Neoplasms; Mice; Mice, Transgenic; Pancreatic Neoplasms; Pyloric Antrum; Stomach Neoplasms

The effect of a somatostatin analogue, SMS 201-995 (SMS), on antral gastrin cell hyperplasia (AGH) and hypergastrinemia associated with 14-day administration of the histamine H2-receptor antagonist (H2-RA) famotidine was studied in rats. When the famotidine group was compared with the control group, the antral gastrin cell (G-cell) number was significantly increased (P < 0.01) by approximately twofold, and the serum gastrin level was significantly increased (P < 0.01) by approximately sixfold. When the famotidine+SMS group was compared with the famotidine group, the G-cell number was significantly decreased (P < 0.01) by approximately 30%, and the serum gastrin level was significantly decreased (P < 0.01) by approximately 40%. These findings suggest that SMS may be useful for inhibiting AGH and hypergastrinemia induced by long-term H2-RA administration.

Topics: Animals; Enterochromaffin Cells; Famotidine; Gastric Mucosa; Gastrins; Hyperplasia; Male; Octreotide; Rats; Rats, Wistar

Hypergastrinemia has been claimed to cause first hyperplasia and then dysplasia/neoplasia of enterochromaffin-like (ECL) cells in rat stomach. The growth is thought to reflect an accelerated self replication rate of mature ECL cells. The cytokinetics and the histidine decarboxylase (HDC) activity of the ECL cells were investigated during sustained hypergastrinemia.. Hypergastrinemia was evoked by omeprazole (400 mumol.kg-1 x day-1 orally) for up to 1 year. Immunocytochemistry for histamine was used to determine the ECL cell density and combined with [H3]-thymidine autoradiography to establish the labeling index (LI), i.e., the proportion of the ECL cells that has incorporated [H3]thymidine.. The ECL cell density increased progressively for 10-20 weeks in response to the hypergastrinemia and remained at a plateau for the remainder of the study. The hyperplasia was diffuse with additional micronodules at 52 weeks. The ECL cell Ll was maximally elevated after 1-2 weeks and declined to control values after 10-20 weeks of treatment. In contrast, the HDC activity remained elevated for the duration of the study.. The ECL cell hyperplasia reflects the transiently elevated ECL cell Ll during the early phase but is not associated with an accelerated rate of mitosis during the 10-52 weeks period. Even though with time gastrin seems to loose its ability to sustain a high ECL cell Ll it retains its ability to maintain a high HDC activity.

Topics: Animals; Carcinoid Tumor; Cell Division; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Histidine Decarboxylase; Hyperplasia; Kinetics; Male; Rats; Rats, Sprague-Dawley; Stem Cells; Stomach Neoplasms

The effects of gastric fundectomy and antrectomy on the colonic mucosa were studied in hamsters over 5 and 25 days. Sham-operated animals served as controls. Basal plasma gastrin concentrations were significantly increased after fundectomy and significantly decreased after antrectomy. Five days after fundectomy, there was a significant increase in scintigraphically determined colonic tissue [3H]-thymidine uptake and [3H]-thymidine labeling index of goblet cells, both of which were reduced 5 days after antrectomy. After fundectomy, the labeling index was maximal in differentiating-proliferative cells in the midportion of the colonic crypts, whereas the labeling index of the immature proliferative cells at the base of the crypts did not differ from that in the controls. On day 25, the crypt size and the number and percentage of goblet cells in the crypts were significantly increased in fundectomized animals. The number and percentage of goblet cells in antrectomized animals were significantly reduced on day 25. It is concluded that fundectomy in the hamster induces colonic mucosal hyperplasia with goblet cell proliferation, whereas antrectomy leads to retardation of colonic goblet cell proliferation.

Topics: Achlorhydria; Animals; Cell Division; Colon; Cricetinae; Gastrectomy; Gastric Fundus; Gastrins; Hyperplasia; Intestinal Mucosa; Male; Mesocricetus; Pyloric Antrum; Time Factors

The efficacy of octreotide in the regulation of endocrine tumor secretion and symptomatology has been well documented. Its effects on neuroendocrine tumor generation and cell proliferation are less well understood. The purpose of this study was to determine if blockade of somatostatin receptors by octreotide would alter gastrin levels and influence enterochromaffin-like (ECL) cell proliferation.. The well-established gastric ECLoma model of the rodent, mastomys, was used. Animals received loxtidine (1 mg/kg/day), an irreversible H2 blocker, and subcutaneous slow release, octreotide pellet implants (150 or 300 micrograms/kg/day) or placebo pellets for a 4-month period.. Control parameters for gastric mucosal thickness, plasma gastrin level, ECL cell density, and bromodeoxyuridine-positive cells were 517 +/- 20 microns, 46.1 +/- 11.4 pmol/L, 7.4 +/- 0.9 cells/visual field, and 13.8 +/- 2.6 cells/visual field, respectively. After loxtidine-placebo treatment all values were significantly increased (p < 0.05; 883 +/- 70 microns, 192.8 +/- 10.6 pmol/L, 97 +/- 16.2 cells/visual field, and 51.7 +/- 19.2 cells/visual field, respectively). High dose octreotide significantly inhibited all parameters (668 +/- 3.5 microns, 66.2 +/- 20.5 pmol/L, 37.0 +/- 8.0 cells/visual field, and 10.9 +/- 2.2 cells/visual field; p < 0.05). Low dose octreotide failed to significantly inhibit ECL cell density mucosal thickness, or cell proliferation.. Irreversible H2 receptor blockade results in hypergastrinemia and ECL cell tumor generation. Hypergastrinemia, ECL cell hyperplasia, and cell proliferation are significantly inhibited by in vivo blockade of somatostatin receptors by administration of octreotide.

Topics: Animals; Bromodeoxyuridine; Cell Count; Cell Division; Enterochromaffin Cells; Female; Gastrins; Histamine H2 Antagonists; Hyperplasia; Male; Muridae; Octreotide; Stomach; Stomach Neoplasms; Triazoles

Recently, antisecretory drugs such as H2-receptor antagonists (H2-RA) or proton pump inhibitor have been used for peptic ulcer patients widely in Japan. However, there are possibilities that long term administration of H2-RA might cause changes in intragastric environment. The present study was designed to clarify the changes of surgical treatment in Japan Surgical Society training hospitals, before and after introduction of H2-RA. Serum gastrin and antral G-cell number was measured after administration of H2-RA (1 mg/kg 14 days continuous infusion) in rat. Also, acid secretion and gastrin response stimulated by adrenalin (40 ng/kg.min) were measured in duodenal ulcer patients. 1) In the view of surgical treatment, elective operation highly decreased after the introduction of H2-receptor antagonists, and showed the increase of the rate of emergency operation up to 70%. 2) Hypergastrinemia and antral G cell hyperplasia were observed after administration of H2-RA in rats. 3) Acid secretion stimulated by adrenalin which is considered as antral G cell dependent, showed a higher response in H2-RA treated cases than in those untreated. 4) Antrectomy was carried out in 43.4% of the patients treated with H2-RA versus 18.9% to the patients untreated.

Topics: Animals; Cell Count; Famotidine; Gastric Acid; Gastrins; Histamine H2 Antagonists; Humans; Hyperplasia; Interphase; Male; Peptic Ulcer; Pyloric Antrum; Rats; Rats, Wistar; Surveys and Questionnaires

The development of gastric enterochromaffin-like (ECL)-cell hyperplasia in humans may be associated with extreme hypergastrinaemia, as occurs in Zollinger-Ellison syndrome (ZES) and pernicious anaemia (type A gastritis). More recently, endocrine cell hyperplasia has been found in all forms of chronic atrophic gastritis and even in cases of focal atrophy. Serum gastrin levels, non-antral gastric endocrine (argyrophil) cell growth, and the severity and type of concomitant gastritis were monitored in 66 unoperated and 8 antrectomized patients with poorly responsive peptic ulcer or reflux oesophagitis during up to 5 years' treatment with high-dose omeprazole, 40 mg daily. A small subgroup of patients (23%) had serum gastrin concentrations of more than four times the normal upper limit. These patients also had hyperplasia of the gastric argyrophil cells. More importantly, the same subgroup of patients had high-grade (atrophic) gastritis. Micronodular hyperplasia of argyrophil cells was significantly more frequent in biopsies showing atrophic gastritis (48%) than in biopsies showing only superficial gastritis (3.6%). It is concluded that, as previously demonstrated in untreated patients with gastric ulcer, the argyrophil cell hyperplasia observed during high-dose omeprazole therapy is related to the progression of chronic atrophic gastritis rather than to serum gastrin levels.

Topics: Biopsy; Esophagitis, Peptic; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Longitudinal Studies; Omeprazole; Peptic Ulcer; Severity of Illness Index

Biopsy specimens from the oxyntic mucosa were obtained on 210 occasions from 76 patients with the Zollinger-Ellison syndrome (ZES) before and during omeprazole treatment. One-micrometer sections were examined by light microscopy, and in 5% linear hyperplasia of endocrine cells was observed. Morphometry was carried out in 91 of the specimens and showed a significant increase of the mean endocrine cell density in comparison with both young, healthy subjects and patients suffering from active peptic ulcer disease (PUD). No metaplasia, dysplasia, or neoplasia was detected in patients with ZES, and the mean mucosal thickness and parietal cell density remained normal. The parietal cells often displayed endosome-like structures, and occasionally there were lingulate cytoplasmic projections into the gland lumen. Electron microscopic morphometry was carried out in specimens from nine patients with ZES and did not show any significant differences in the parietal cells in comparison with healthy subjects.

Topics: Adolescent; Adult; Age Factors; Aged; Biopsy; Cell Count; Evaluation Studies as Topic; Female; Gastrins; Humans; Hyperplasia; Male; Microscopy, Electron; Middle Aged; Omeprazole; Parietal Cells, Gastric; Surface Properties; Zollinger-Ellison Syndrome

An infant presented with hematemesis and gastric outlet obstruction. Preoperative diagnosis of duodenal duplication cyst was based on a collaboration of radiological studies. At exploration the patient was found to have a gastric polyp that had intussuscepted into the duodenum leading to obstruction and hypergastrinemia secondary to gastric mucosa in the duodenal alkaline environment.

Topics: Gastric Outlet Obstruction; Gastrins; Hematemesis; Humans; Hyperplasia; Infant; Male; Polyps; Stomach Neoplasms

In the rat, gastric histamine is stored mainly in the enterochromaffinlike cells. Gastrin releases histamine from these cells, and long-term hypergastrinemia results in hyperplasia. The effect of sustained hypergastrinemia on histamine-depleted enterochromaffinlike cells was studied by measuring histidine decarboxylase activity and histamine concentrations and by using quantitative histology. Hypergastrinemia maintained for 6 weeks was induced by inhibition of gastric acid secretion with omeprazole (400 mumol.kg-1.day-1) given orally, and histamine synthesis was inhibited for the same length of time with alpha-fluoromethylhistidine (3 mg.kg-1.h-1) given via osmotic minipumps. In rats given omeprazole alone, the effects of the resulting hypergastrinemia on the enterochromaffinlike cells was reflected in increased histidine decarboxylase activity, increased histamine concentration, and increased number of enterochromaffinlike cells. The general trophic effects on the stomach were seen as increased stomach and oxyntic mucosal weight and increased mucosal thickness. Treatment with alpha-fluoromethylhistidine plus omeprazole markedly reduced the histidine decarboxylase activity and histamine concentration, but the weight of the stomach and oxyntic mucosa, the enterochromaffinlike cell density, and intensity of histidine decarboxylase immunostaining were increased to at least the same extent as after omeprazole alone. These observations indicate that enterochromaffinlike cell histamine is not important for a full expression of gastrin-evoked trophic effects in the stomach.

Topics: Animals; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Hyperplasia; Methylhistidines; Omeprazole; Organ Size; Rats; Rats, Inbred Strains

The oxyntic mucosa in the rat stomach is under the influence of circulating gastrin. The histamine-producing enterochromaffin-like (ECL) cells constitute the major endocrine cell population in the oxyntic mucosa. They are notably sensitive to changes in the serum gastrin concentration and respond to long-term hypergastrinemia with hyperplasia, whereas hypogastrinemia induces hypoplasia. In the present study long-term, sustained hypergastrinemia was induced by daily treatment with a high dose of the proton pump inhibitor omeprazole. After 10 weeks omeprazole-treated and control rats were antrectomized, resulting in prompt hypogastrinemia. Antrectomy was followed by a rapid reduction of the thickness of the oxyntic mucosa and a somewhat slower reduction of the ECL cell number in both omeprazole-treated and control rats. The percentage decrease in the ECL cell number with time was similar in both groups; after 2-3 weeks the ECL cell number was half of that before antrectomy in both groups. Interestingly, however, 12 weeks after antrectomy the ECL cell number in the omeprazole-pretreated rats remained elevated compared with untreated rats. The histamine concentration of the oxyntic mucosa was markedly lowered within a week after antrectomy in both omeprazole-treated and control rats. Although antrectomy induces hypogastrinemia and although atrophy develops rapidly in the oxyntic mucosa, the omeprazole-induced ECL cell hyperplasia was not completely reversed by antrectomy during the 12 weeks of examination.

Topics: Animals; Atrophy; Cell Count; Cell Survival; Gastric Mucosa; Gastrins; Hyperplasia; Male; Omeprazole; Parietal Cells, Gastric; Pyloric Antrum; Rats; Rats, Inbred Strains

The effect of pancreaticobiliary diversion (PBD) with hypercholecystokininemia on the gastric fundic mucosa was studied in the Syrian golden hamster over 5 and 24 days. Sham-operated animals served as controls. Basal plasma gastrin concentrations were significantly decreased on days 5 and 24. Five days after PBD, there was a significant increase in the scintigraphically measured [3H]-thymidine incorporation into fundic tissue. Correspondingly, there was a significant increase in the number of cells with [3H]-thymidine-labeled DNA in the proliferative zone of the fundic mucosa. The total number of cells in the gastric pits, the number of cells in the proliferative zone and the proliferation index were also significantly increased 5 days after PBD. Although the mean values of all variables were higher after PBD than in the control group on day 24, these increases were not significant. It is concluded that PBD at least transiently stimulates gastric fundic epithelial proliferation in the hamster. Whether this is an effect of hypercholecystokininemia remains to be definitely proven in further studies.

Topics: Animals; Autoradiography; Biliopancreatic Diversion; Cell Division; Cholecystokinin; Cricetinae; Gastric Fundus; Gastric Mucosa; Gastrins; Hyperplasia; Male; Mesocricetus

The effects of vaso-active intestinal peptide (VIP) on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in Wistar rats given VIP every other day for 27 weeks after oral administration of MNNG for 25 weeks. In week 52, administration of VIP caused a significant increase in the incidence of gastric cancers, but did not influence their histological appearance. VIP significantly increased the labeling indices of the antral mucosa. Our findings indicate that VIP enhances gastric carcinogenesis, and that this effect may be related to its effect in increasing cell proliferation of the antral epithelial cells.

Topics: Animals; Drug Synergism; Gastric Juice; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Vasoactive Intestinal Peptide

In rats, hypergastrinemia due to achlorhydria produced by antisecretory drugs or resection of the gastric fundus leads to enterochromaffinlike (ECL) cell hyperplasia and gastric carcinoids. In humans, achlorhydria due to pernicious anemia may also lead to ECL cell hyperplasia and multicentric gastric carcinoids in as many as 5% of cases. To examine the apparent gastrin dependence of gastric ECL carcinoids, three patients were studied (2 men aged 59 and 73 years; 1 woman aged 45 years) who had pernicious anemia, serum gastrin concentrations of greater than 1000 ng/L (greater than 1000 pg/mL), and multicentric gastric carcinoids. Antrectomy resulted in normalization of serum gastrin levels within 8 hours and disappearance of carcinoids in 6-16 weeks. In each of the three patients, a focus of microcarcinoid was found at 12-18 months. Further follow-up in each of the three patients 21-30 months after antrectomy again showed no carcinoids or ECL cell hyperplasia. It is concluded that multicentric ECL gastric carcinoids in patients with pernicious anemia and achlorhydria appear to be gastrin dependent and disappear after normalization of serum gastrin by antrectomy. Antrectomy rather than total gastrectomy may be the most appropriate treatment for this condition.

Topics: Aged; Anemia, Pernicious; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Stomach Neoplasms

In several experimental animals treatment with large doses of the proton pump inhibitor omeprazole leads to hypergastrinemia and with time to trophic effects in the acid-producing part of the stomach, most notably an increased density of the histamine-producing enterochromaffin-like (ECL) cells. The trophic effects are thought to reflect the increase in circulating gastrin. In the present study unilateral vagal denervation in the rat partly suppressed the tropic effects seen in the denervated side of the stomach but not those in the intact side after treatment with omeprazole for 10 weeks. Unilateral vagal denervation significantly reduced the proliferative stimulus of omeprazole on the ECL cells in the denervated part of the stomach. Thus, an intact vagal innervation appears to be essential for the capacity of the oxyntic mucosa, including the ECL cells, to respond to elevations in serum gastrin. We suggest that gastrin and the vagus interact to maintain trophic control of the oxyntic glands.

Topics: Animals; Denervation; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Hyperplasia; Male; Omeprazole; Rats; Rats, Inbred Strains; Vagus Nerve

Untreated celiac disease is characterized by gastrointestinal endocrine cell hyperplasia (ECH). This study investigated the constitutive nature of the ECH. Ten duodenal biopsies showing villous atrophy from adult celiacs were evaluated against ten sex- and age-matched controls. The mean number of endocrine cells per unit length of mucosa in the celiacs was compared with the control group using the Student t test. These values, respectively, were as follows: Churukian-Schenk method, 52.4 versus 29.6 (P = 0.001); Fontana-Masson, 32.5 versus 18.4 (P = 0.016); chromogranin, 33.4 versus 23.6 (P = 0.017); serotonin, 44.7 versus 26.7 (P = 0.006); somatostatin, 5.0 versus 5.4 (P = 0.631); and gastrin, 0.37 versus 0.37 (P = 1.000). There was thus ECH as shown by the first four stains with, in some areas, the endocrine cells continuously abutting against each other to form linear profiles. With respect to specific hormonal products, only serotonin showed ECH. These results suggest that the ECH in celiac disease is not a haphazard process but, instead, a selective proliferation of certain endocrine cell types.

Topics: Adult; Aged; Biopsy; Celiac Disease; Cell Division; Chromogranins; Digestive System; Duodenum; Endocrine Glands; Female; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Male; Middle Aged; Serotonin; Somatostatin

A histologic and immunohistochemical study was carried out in 23 unselected nonantral gastric carcinoids and their precursor lesions classified according to Solcia et al. None of the patients showed Zollinger-Ellison syndrome. Two variants of carcinoids showing distinctive pathologic and pathogenetic characteristics were identified on the basis of presence or absence of associated chronic atrophic gastritis type A (A-CAG). Chronic atrophic gastritis type A was found in 19 cases showing either single or multiple neoplasms, tumor extension limited to the mucosa or submucosa, consistent endocrine cell precursor changes in extratumoral mucosa, and consistent hypergastrinemia and/or G cell hyperplasia. Associated precursor lesions were only hyperplastic in all but two cases with single carcinoids whereas they were also dysplastic in all but one case with multiple carcinoids. The four tumors arising in nonatrophic mucosa were all single, more aggressive, and not associated with extratumoral endocrine cell proliferations or with signs of gastrin hypersecretion. Tumor cells were diffusely immunoreactive for chromogranin A and synaptophysin but usually negative for chromogranin B or HISL-19. Scattered serotonin cells were found in ten carcinoids. They were more frequent in infiltrating than in intramucosal tumors as were the less represented pancreatic polypeptide cells whereas the reverse was found for alpha-subunit-containing cells. These results are of relevance for tumor pathogenesis and may provide the rationale for a less aggressive therapeutic approach in the patients.

Topics: Adolescent; Adult; Aged; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastric Mucosa; Gastrins; Glycoprotein Hormones, alpha Subunit; Humans; Hyperplasia; Immunohistochemistry; Male; Membrane Proteins; Middle Aged; Neoplasms, Multiple Primary; Nerve Tissue Proteins; Pancreatic Polypeptide; Precancerous Conditions; Serotonin; Stomach Neoplasms; Synaptophysin

Gastrin is an important trophic hormone for the acid-producing part of the stomach. There is no solid evidence that gastrin is physiologically important as a trophic agent outside the stomach. The trophic effects in the stomach are manifested as an increased weight and thickness of the oxyntic mucosa and can be induced by both exogenous and endogenous gastrin--that is, in situations of long-lasting hypergastrinemia (treatment with effective antisecretagogues, partial fundectomy, or antrum exclusion). Removal of endogenous gastrin by antrectomy induces the opposite effects--that is, diminished weight and thickness of the oxyntic mucosa. Unlike all other peptide hormone-producing endocrine cells in the oxyntic mucosa, the so-called enterochromaffin-like (ECL) cells respond readily to gastrin. An acute gastrin challenge results in release of stored products from the ECL cells (such as histamine) and activation of cytoplasmic enzymes (such as histidine decarboxylase). Sustained elevation of circulating gastrin over days results in hypertrophy of the ECL cells and over weeks results in marked hyperplasia (at most a fivefold increase in the rat). The results in other species are similar but often somewhat less marked than in the rat.

Topics: Animals; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Histamine Release; Hyperplasia; Hypertrophy; Parietal Cells, Gastric; Rats

Jejunal or colonic segments are currently used as esophageal substitutes after resection of intractable peptic stenoses. The present study was carried out in order to investigate the effects of the jejunal or colonic mucosa on antral gastrin (G) cells. Colonic or jejunal patches with intact vascular supply were sutured to the pyloric antrum or the higher portion of the gastric body in 40 rats. Ten further animals were used as controls. Three to 4 months after surgery, the serum gastrin levels were weekly determined in fasted (24 h) and freely fed rats using radioimmunoassay. The pyloric antrum was then removed, and the G cell density was assessed with an immunoperoxidase method. Transposal of the colonic mucosa to the antrum increased G cell density and basal serum gastrin levels, while grafting of the jejunal mucosa did not. G cell proliferation proved to be dependent on the topographic location of the colonic patch with respect to the pyloric antrum. Serum gastrin values in freely fed rats tended to be greater in the colon-to-antrum transposition group than in the other experimental groups, but the difference was not significant. In conclusion, variations between the properties of the jejunal and colonic mucosa would include their uneven effects on antral G cells.

Topics: Animals; Cell Division; Colon; Gastrins; Hyperplasia; Intestinal Mucosa; Jejunum; Pyloric Antrum; Rats; Rats, Inbred Strains

Studies in the rat have shown that partial gastric corpectomy, in which about 75% of the acid-producing oxyntic mucosa was removed, leads to markedly reduced acid secretion and a feedback increase in the plasma gastrin levels. Ten weeks after operation, the gastric enterochromaffin (ECL)-like cell density in the remaining part of the oxyntic mucosa had increased significantly. In the present study, the effects on the gastric ECL cells of lifelong persistent hypergastrinemia induced by partial (75%) corpectomy have been investigated. Seventy-five partially corpectomized rats and 40 control rats were investigated for plasma gastrin and oxyntic mucosal changes in a 124-week study. The partially corpectomized rats showed increased plasma gastrin levels after the operation; the mean increase compared with the controls was almost 10-fold during the entire study. The remaining oxyntic mucosa of the partially corpectomized rats differed from that of control rats in two respects, showing first general hypertrophy and second a marked hyperplasia of argyrophil ECL cells. The degree and incidence of these changes increased towards the end of the study, i.e., in the aging rats. An age-related increase in ECL-cell density occurred spontaneously also in the control rats but to a lesser extent than in the partially corpectomized group. ECL-cell carcinoids were found in the oxyntic mucosa of 26 of the 75 partially corpectomized rats. The first carcinoid was found 78 weeks after the beginning of the study. Six rats with carcinoids (23%) were found before week 104 (2 years) and the remainder, 20 (77%), were discovered later. No carcinoid tumor was found in the control rats. It is concluded that lifelong hypergastrinemia induced by partial corpectomy leads to the development of ECL-cell carcinoids in the oxyntic mucosa of some rats towards the end of their life span. This observation strongly supports the hypothesis that the gastric ECL-cell carcinoids found in rats treated with antisecretory drugs are caused by long-standing hypergastrinemia developing secondary to inhibition of gastric acid secretion.

Topics: Animals; Body Weight; Carcinoid Tumor; Enterochromaffin Cells; Feedback; Female; Gastric Mucosa; Gastrins; Hyperplasia; Hypertrophy; Parietal Cells, Gastric; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Time Factors

Post-resectional hyperplasia is the phenomenon in which residual small bowel increases in size and absorptive capacity after segmental enterectomy. This experiment studied the effect of somatostatin analogue therapy on the development of two structural parameters of post-resectional hyperplasia in rats subjected to 40% proximal small bowel resection. Octreotide acetate-treated rats failed to develop increased villus height (902 +/- 50 microns) relative to saline-treated rats (1,103 +/- 98 microns). Augmentation of residual intestinal weight was also significantly impaired in analogue-treated rats (92 +/- 3 versus 118 +/- 5 mg/cm). We conclude that somatostatin analogue treatment during the early postoperative period does impair the growth of residual bowel in rats. These findings raise concern regarding the use of this drug for postoperative patients who have undergone massive small bowel resection in whom the process of post-resectional adaptation may be critical to allow sustenance with enteral nutrition.

Topics: Adaptation, Physiological; Animals; Gastrins; Hyperplasia; Jejunum; Male; Octreotide; Organ Size; Rats; Rats, Inbred F344

Topics: Animals; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Rats

Time-related changes of serum gastrin levels, gastrin cell, and enterochromaffinlike cell densities, and proliferation kinetics of these cells have been examined in rats during treatment with the substituted benzimidazole BY 308 over a period of 73 days. Serum gastrin levels increased very rapidly from 74 +/- 6 pg/mL (controls) to 438 +/- 31 pg/mL (day 1) and 727 +/- 68 pg/mL (day 4). Thereafter, a steady increase was observed until day 70 (2097 +/- 208 pg/mL). Enterochromaffinlike cell density was unchanged until day 10, but then increased progressively without reaching a plateau (144% above control on day 73). The labeling index of these cells was enhanced shortly after drug application and remained on a constant elevated level from day 14 to day 73 (about 10-fold to 12-fold above controls from day 14 to day 70). The number of gastrin cells increased rapidly within the first week and reached a plateau after 17 days (96% increase above controls). In contrast to enterochromaffinlike cells, the labeling index did not change immediately but increased on day 7 by 37% and returned beneath control values after day 28. The results suggest that in drug-induced achlorhydria, the progressive increase of enterochromaffinlike cells is explained by an enhanced mitosis, whereas other factors in addition to proliferation are responsible for the augmentation of gastrin cells.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Achlorhydria; Animals; Cell Count; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Hyperplasia; Mitotic Index; Omeprazole; Rats; Rats, Inbred Strains; Regression Analysis; Stomach; Time Factors

Neuroendocrine cell (carcinoid) tumours have been reported in the acid-secreting part of the stomach of rodents after long-term administration of a range of potent chemically diverse antisecretory agents. Although evidence shows a link between the sequence of acid suppression, hypergastrinaemia, and neuroendocrine cell hyperplasia, other factors are also thought to be involved in neoplastic transformation. Prolonged hypochlorhydria or achlorhydria resulting in bacterial colonization of the stomach may allow the generation of carcinogenic substances. Other as yet unidentified trophic factors may be involved in tumour formation. In view of the potential risks associated with these agents, there must be concern about the possible consequences in man of marked suppression of acid. It seems wise to limit the use of these more potent agents to situations in which conventional therapy has failed and to short-term treatment.

Topics: Animals; Carcinoid Tumor; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Humans; Hyperplasia; Male; Mice; Omeprazole; Rats; Stomach Neoplasms; Time Factors; Triazoles

Fundic argyrophil cells were studied for a mean period of 68.7 months (range, 11-170) in 18 patients with fundic atrophic gastritis and achlorhydria. Initially, 12 patients had hyperplasia of the argyrophil cells, the severity of which was assessed using a semiquantitative classification based on the number of argyrophil clusters per square millimeter. At the end of the study, the degree of hyperplasia was unchanged in 9 patients, had decreased in 2, and had increased in 1; no significant increase in the number of argyrophil clusters, precarcinoid changes, or carcinoid tumors were observed and the high level of gastrinemia [mean, 4.8 (range, 1.9-8.1) times the upper limit for normal) did not change significantly. Of the 6 patients with no hyperplasia at the outset of the study, 4 continued without hyperplasia and 2 presented a low-grade hyperplasia at the 20th and 130th month. Gastrinemia increased significantly in the last patient and stayed normal in the other 5. This study argues in favor of the stable appearance of fundic argyrophil cells in patients with atrophic gastritis and stable gastrinemia.

Topics: Achlorhydria; Aged; Aged, 80 and over; Anemia, Pernicious; Biopsy; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Schilling Test

Multifocal gastric carcinoid tumors occasionally develop in patients with pernicious anemia, associated with hyperplasia of endocrine cells in the atrophic and metaplastic gastric body mucosa. This constellation of findings probably requires a trophic drive from hypergastrinemia associated with antral G cell hyperplasia, a consequence of achlorhydria in these patients. We report a case in which antrectomy was performed on such a patient in order to abrogate the trophic stimulus. Antrectomy was followed by resolution of hypergastrinemia and a decrease in the size of polyps endoscopically. Nine months later, the gastric remnant was resected. Using morphometric techniques, endocrine cells in the initial antrectomy specimen (which included body mucosa at the resection line) were compared with those in the subsequently removed gastric body. Antrectomy resulted in striking decreases in number (137 versus 34/mm2; P = 0.0001) and size (93 versus 56 microns2; P = 0.0001) of endocrine cells of body mucosa. The findings suggest that antrectomy may be useful in the management of endocrine cell hyperplasia, and possibly also associated carcinoid tumors, in pernicious anemia.

Topics: Anemia, Pernicious; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Middle Aged; Pyloric Antrum; Reproducibility of Results; Stomach Neoplasms

A patient with pernicious anemia, atrophic non-antral gastritis, hypergastrinemia, and widespread hyperplasia of enterochromaffin-like cells and manifest enterochromaffin-like cell carcinoma was followed up during 39 months, including 15 months after gastric resection. In this case normalization of gastrin levels did not prevent the development of multiple gastric carcinoids in the fundic mucosa, suggesting that factors other than gastrin are of importance in the pathogenesis.

Topics: Anemia, Pernicious; Carcinoid Tumor; Follow-Up Studies; Gastrectomy; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Male; Middle Aged; Stomach Neoplasms

A patient with pernicious anemia developed severe intractable diarrhea night and day. Investigation revealed chronic atrophic gastritis and a markedly elevated level of serum gastrin. No obvious explantation for the diarrhea was found, but after antrectomy, the gastrin level returned to normal and the diarrhea subsided. Possible mechanisms for an association between diarrhea and hypergastrinemia include colonic hypermotility secondary to release of acetylcholine and inhibition of fluid and electrolyte reabsorption within the small bowel.

Topics: Anemia, Pernicious; Diarrhea; Female; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Middle Aged; Pyloric Antrum

The histamine-storing enterochromaffinlike cells, which are numerous in the oxyntic mucosa of the rat stomach, are known to proliferate in response to long-lasting hypergastrinaemia. In addition, portacaval shunting, which is not associated with elevated serum gastrin, causes an increase in enterochromaffinlike cell density. The present study shows that the combination of portacaval shunting and omeprazole-evoked, long-lasting hypergastrinemia results in enhanced enterochromaffinlike cell hyperplasia despite the fact that the hypergastrinemia was not significantly greater than in intact omeprazole-treated rats. The mechanism behind the enhanced response to gastrin of the enterochromaffinlike cells in rats with portacaval shunts is unknown. When results from untreated and omeprazole-treated rats were plotted, there was a linear correlation between the serum gastrin concentration and the enterochromaffinlike cell density in both sham-operated rats and rats with portacaval shunts. We conclude that gastrin plays a role in the development of enterochromaffinlike cell hyperplasia following omeprazole treatment in rats with portacaval shunts but that other as yet unidentified agents may also promote the response.

Topics: Animals; Chromaffin System; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Hyperplasia; Immunohistochemistry; Male; Omeprazole; Portacaval Shunt, Surgical; Rats; Rats, Inbred Strains

A total of 61 patients with frequently relapsing duodenal ulcer were examined. Of these, 18 patients were in the acute phase and 43 experienced remission. Using 1 mm2 of the mucosa, measurements were made of the counts of duodenal and pyloric G-cells (by immunomorphologic assay), of the absolute and relative counts of T and B lymphocytes, the content of IgA, IgM and IgG, histamine and serotonin (by fluorometry) in the blood, and of the concentration of uropepsin in the urine. In the stages of exacerbation and remission, the patients suffering from duodenal ulcer with hyperplasia of G-cells manifested, as compared with the analogous patients without hyperplasia, a decrease of the absolute and relative counts of T cells, especially of those of B cells, combined with a rise of the content of IgM and IgG during exacerbation, followed by its returning to normal in the phase of remission. Over one year part of the duodenal ulcer patients with hyperplasia of G-cells received preventive treatment with ranitidine, which resulted in a tendency towards the lowering of the count of pyloric G-cells and the rise of the absolute and relative counts of T cells.

Topics: Adolescent; Adult; Antibody Formation; Chromaffin System; Duodenal Ulcer; Enterochromaffin Cells; Gastrins; Humans; Hyperplasia; Immunity, Cellular; Immunoglobulins; Leukocyte Count; Middle Aged; Pylorus; Recurrence

Topics: Adenoma; Adenoma, Islet Cell; Adrenal Cortex; Female; Gastrins; Glucagon-Like Peptides; Humans; Hydrocortisone; Hyperplasia; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Parathyroid Neoplasms; Peptides; Thyroid Gland; Thyroid Hormones

Sixty patients with surgically correctable hypergastrinemia were treated between 1960 and 1988. Provocative testing was used when available to select appropriate operations. Sources of hypergastrinemia included antral G cell hyperplasia (AGCH) (17), pancreatic gastrinomas (14), duodenal gastrinomas (11), multiple gastrinomas in patients with type I multiple endocrine neoplasia (MEN I) (five), lymph node gastrinomas (four), and the source not found in nine patients. Eugastrinemia was achieved by resection in 17 of 17 patients with AGCH, nine of 11 patients with duodenal gastrinomas, three of four patients with lymph node gastrinomas, zero of 14 patients with pancreatic gastrinomas, zero of five patients with MEN I, and zero of nine patients in whom the source was not found. Hepatic metastases developed in 11 patients with pancreatic gastrinomas, two patients with MEN I, one patient with duodenal gastrinomas, and one patient with lymph node gastrinomas. One patient in whom the source of the hypergastrinemia was not found developed hepatic metastases, and seven required total gastrectomy. This experience suggests the following: (1) that patients with AGCH, duodenal gastrinomas, or lymph node gastrinomas can usually be rendered eugastrinemic by resection; (2) that patients with pancreatic gastrinomas, whether sporadic or familial (MEN I), are rarely cured by resection and frequently develop hepatic metastases; and (3) that patients in whom the source of the hypergastrinemia is not identified and removed frequently require total gastrectomy, but antroduodenectomy should be considered because it may uncover an occult duodenal microneurogastrinoma or may correct AGCH.

Topics: Biomarkers, Tumor; Duodenal Neoplasms; Eating; Female; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prognosis; Secretin; Stomach; Stomach Neoplasms

A case of Zollinger-Ellison due to hyperplasia of antral gastrin cells in a 11 year-old child is reported. Only 49 cases of this syndrome in children have been published. The diagnosis (gastrin stimulation test, immunohistochemical detection of endocrine cells and therapeutic strategy are outlined).

Topics: Child; Female; Gastrins; Humans; Hyperplasia; Pyloric Antrum; Zollinger-Ellison Syndrome

The number and density of argyrophil endocrine cells were morphometrically calculated in gastric fundal mucosal biopsy specimens taken from 64 patients with pernicious anaemia (five with gastric carcinoids, 15 with nodular argyrophil cell hyperplasia, 44 with diffuse argyrophil cell hyperplasia) and from 14 healthy controls. Similar calculations were also made on the ileal mucosa away from the tumour of 10 patients with ileal carcinoids and 10 controls. In the stomach, the argyrophil cell counts were twice as high in the patients with pernicious anaemia than in controls and the densities in the whole mucosa or in the epithelial structures were similarly three to five times higher. The cell counts in the patients showed positive correlation with the serum gastrin concentration. The patients with nodular argyrophil cell hyperplasia and gastric carcinoids formed a uniform group with the highest cell counts and serum gastrin concentrations; the difference between the groups was in the longer duration of pernicious anaemia in the patients with carcinoid tumours. On the other hand, no endocrine cell hyperplasia was seen in those with ileal carcinoids. It is concluded that fundal mucosal endocrine cells show an increase in patients with pernicious anaemia that is related to the gastrin concentration. This phenomenon may favour the development of hyperplastic endocrine cell nodules and, eventually, carcinoid tumours.

Topics: Adult; Aged; Anemia, Pernicious; Carcinoid Tumor; Cell Count; Epithelium; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Gastrointestinal Neoplasms; Humans; Hyperplasia; Intestinal Mucosa; Male; Middle Aged

To assess the functional and morphological characteristics of the gastric mucosa of patients with fundic hyperplastic polyps (FP), the determination of gastric acid secretion, serum gastrin levels, serum pepsinogen 1 (PG1) levels and histological examination were undertaken in 24 patients with FP, 34 with foveolar hyperplastic polyps (HP) and 62 controls, who had no gastric lesions. The following were the results of our investigation. 1) There were no differences between the patients with FP and the controls as to gastric acid secretion, serum gastrin levels, and serum PG1 levels. On the other hand, hypochlorhydria, hypergastrinemia and hypopepsinogenemia were common in those with HP. 2) Histological examination using gastric biopsy specimens showed almost normal gastric mucosa in patients with FP. However, severe atrophic gastritis of the fundus was common in patients with HP. 3) It was shown that there were definite differences between the patients with FP and those with HP with regard to the gastric function and morphology, although both types of gastric polyp were histologically classified as hyperplastic.

Topics: Adolescent; Adult; Female; Gastric Acid; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pepsinogens; Polyps; Stomach Neoplasms

Female rats were treated for 28 days with high doses of the gastric acid secretion inhibitors omeprazole and ranitidine. Omeprazole, which is long-acting, was given orally once daily. Ranitidine, which is short-acting, was given by continuous infusion (via osmotic minipumps, implanted subcutaneously). The aim was to produce a similar degree of acid inhibition with the two drugs. The inhibition of acid secretion over the day and night was more pronounced in the omeprazole-treated rats (maximal inhibition 100%, minimum 85%) than in those receiving ranitidine (mean 70%). In both groups, there was a great increase in plasma gastrin, somewhat greater after omeprazole than after ranitidine. The gastrin concentration in the antrum was almost doubled by both treatments and there was a moderate increase in the number of antral gastrin cells in the omeprazole-treated rats. The number of enterochromaffin-like (ECL) cells (per visual field) increased in the oxyntic mucosa to the same extent (greater than 100%) in the ranitidine- and omeprazole-treated rats. Apart from the gastrin cells in the antrum and the ECL cells in the corpus no other gastric endocrine cell type seemed to respond to treatments with antisecretagogues. We conclude that, regardless of the type of antisecretagogue used, effective and long-term suppression of gastric acid secretion results in sustained hypergastrinemia and increased number of ECL cells. Conceivably therefore, the ECL cell hyperplasia reflects the trophic effect of gastrin.

Topics: Animals; Chromaffin System; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Hyperplasia; Omeprazole; Ranitidine; Rats; Rats, Inbred Strains

Eight patients with stomach cancer are described who had also a striking glandular hyperplasia of the fundic mucosa adjacent and remote from the tumor. Five of the eight patients were young women (30 to 37 years of age). The tumors were poorly differentiated carcinomas and six of the eight patients have died of their disease. None of the patients had clinical evidence of endocrine dysfunction including the Zollinger-Ellison syndrome. Immunohistochemistry revealed cells with endocrine differentiation in five of eight tumors, and in two tumors gastrin producing cells were found. Five of seven patients showed increased numbers of antral G-cells. In two patients numerous endocrine (chromogranin-positive) cells were present in the fundic mucosa, specific products of which could not be identified with the antigens tested. No satisfactory explanation exists for this coincidence and its apparent predominance in young female patients. It may be that endocrine substances are responsible for this fundic hyperplasia and that they may also act as promotors of tumor growth.

Topics: Adult; Carcinoma; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Male; Middle Aged; Sex Factors; Stomach Neoplasms

The histamine H2-receptor antagonist SK&F 93479 induced gastric neuroendocrine (carcinoid) ECL-cell tumor formation in 6/34 male and 8/37 female rats treated for 22-24 months at 1,000 mg/kg/day po. Focal ECL-cell hyperplasia was present in 21/34 males and 15/37 females, with local infiltration through the muscularis mucosae in half these cases. No focal hyperplasias or carcinoids were present after 200 mg/kg/day po treatment. Investigative studies showed evidence for marked and sustained hypergastrinemia increasing on chronic dosing which was capable of restoring gastric acid secretion and pH to near control values. Using morphometric analysis of immunoperoxidase anti-chromogranin A stained sections, a dose-related and time-dependent neuroendocrine ECL-cell hyperplasia was correlated with the sustained elevated hypergastrinemia. A 21-month mouse oncogenicity study showed no focal neuroendocrine cell hyperplasia or carcinoid tumor induction, but a diffuse neuroendocrine cell hyperplasia and an increase in multifocal glandular hyperplasia of the oxyntic mucosa was observed in mice treated with 1,000 mg/kg SK&F 93479 po. The morphological changes observed in both rat and mouse were considered to be secondary to the hypergastrinemia resulting from the pharmacological suppression of gastric acid secretion by SK&F 93479. These changes were also observed to a more marked degree following omeprazole treatment and were only slight following oxmetidine treatment in the rat.

Topics: Animals; Carcinogens; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Hydrogen-Ion Concentration; Hyperplasia; Imidazoles; Male; Mice; Omeprazole; Pyrimidinones; Rats; Stomach Neoplasms

The number of gastrin cells (G cells) and somatostatin cells (D cells) per surface unit, and the G/D cell ratio were estimated in biopsy specimens of the antrum from normal subjects without hypergastrinemia, and from patients with hypergastrinemia not induced by gastrinoma or supra selective vagotomy. Compared with normal subjects, antral G cell density and G/D cell ratio were significantly increased in patients with hypergastrinemia. A significant correlation was found between G cell density or G/D cell ratio and the integrated gastrin output values. A quantitative estimation appears therefore possible in biopsy specimens.

Topics: Adolescent; Adult; Aged; Anemia, Pernicious; Biopsy; Female; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Somatostatin; Stomach Ulcer

In intact rats plasma gastrin levels were increased during a 20-wk treatment course with either omeprazole or ranitidine. Although plasma gastrin levels were the same during treatment, the enterochromaffinlike (ECL) cell density increased approximately linearly with time at a rate correlated to the plasma gastrin level. Antrectomy prevented the ECL cell hyperplasia seen in omeprazole-treated rats, suggesting that it was not caused by omeprazole per se. Changes in ECL cell density roughly paralleled changes in oxyntic mucosal histidine carboxylase activity and histamine concentration. Treatment with omeprazole also raised stomach weight and antral gastrin and gastrin cell density, reduced antral somatostatin cell density, but did not affect enterochromaffin cell density. Within 19 days of cessation of a 10-wk treatment course, plasma gastrin levels, oxyntic mucosal histidine decarboxylase activity, and antral gastrin and somatostatin cell densities had returned to control levels. The stomach weight was normal within 5-10 wk, antral gastrin concentration within 10 wk, and oxyntic mucosal ECL cell density and histamine concentration within 20 wk. After renewed treatment with omeprazole for 10 wk starting 10 wk after completion of the first omeprazole treatment period, changes in all parameters were of similar magnitude in animals previously treated with omeprazole and those previously treated with vehicle. The results suggest that the effects described are reversible and that gastrin cells turn over more rapidly than ECL cells.

Topics: Animals; Cell Count; Chromaffin System; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Hyperplasia; Omeprazole; Parietal Cells, Gastric; Pyloric Antrum; Ranitidine; Rats; Rats, Inbred Strains; Time Factors

The H+,K+-ATPase inhibitor omeprazole is a highly effective gastric antisecretory agent, both in animals and man, with a long duration of action. These properties are shared by a number of recently described histamine H2-receptor antagonists. In life-long oncogenicity studies of these H2-receptor antagonists, as well as with the H+,K+-ATPase inhibitor omeprazole, gastric enterochromaffin-like cell (ECL cell) hyperplasia and carcinoids have been found. The purpose of this paper is to summarize available evidence for the "Gastrin Hypothesis" to explain the development of ECL-cell hyperplasia. The hypothesis may be outlined as follows: 1) Inhibition of gastric acid secretion leads to elevated antral pH and, secondarily, to release of gastrin from the antral gastrin cells into the blood stream. 2) Gastrin causes both general hypertrophy of the oxyntic mucosa and hyperplasia of the ECL cells in the oxyntic mucosa. That this sequence of events occurs not only with omeprazole but also with other effective gastric antisecretory agents has been verified in the rat by giving the H2-receptor antagonist ranitidine as a continuous infusion. Ranitidine caused a hypergastrinemia of a similar magnitude as that seen after omeprazole, provided that the acid secretion was inhibited to a similar degree. At similar gastrin levels, ECL-cell hyperplasia of the same magnitude developed during both ranitidine and omeprazole treatment. Antrectomy prevented the development of ECL-cell hyperplasia during omeprazole treatment, indicating that the hyperplasia was not due to the drug treatment per se, but rather to the hypergastrinemia. Both the hypergastrinemia and the ECL-cell hyperplasia were found to be reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Chromaffin System; Dogs; Enterochromaffin Cells; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Mice; Omeprazole; Ranitidine; Rats; Species Specificity

Treatment of chickens, hamsters and guinea-pigs with large doses of the long-acting antisecretory agent omeprazole for 10 weeks resulted in elevated serum gastrin levels and in increased stomach weight and mass of oxyntic mucosa. Also the antral gastrin cell density was increased. Another striking effect was the hyperplasia of the histamine-producing enterochromaffin-like (ECL) cells - a prominent endocrine cell population with unknown function-in the oxyntic mucosa. Accordingly, the gastric mucosal histamine concentration and rate of histamine formation were increased in all three species. The results suggest that marked and long-lasting suppression of acid secretion leads to elevated serum gastrin levels and diffuse ECL cell hyperplasia not only in the rat, as previously seen, but also in the chicken, hamster and guinea-pig; this hyperplasia is associated with accelerated histamine formation in all three species. The following sequence of events is suggested to occur in mammalian as well as submammalian vertebrates: suppression of acid secretion - hypergastrinaemia - ECL cell hyperplasia.

Topics: Animals; Chickens; Chromaffin System; Cricetinae; Enterochromaffin Cells; Female; Gastrins; Guinea Pigs; Histamine; Histidine Decarboxylase; Hyperplasia; Male; Pyloric Antrum; Stomach

Parasite-free, 4-month-old-calves were inoculated with Ostertagia ostertagi and/or Trichostrongylus axei, followed 6 weeks later by inoculation with increasing doses of O ostertagi for 8 weeks in the 2 groups (n = 4) of calves that had been given O ostertagi. Gastrin immunoreactivity concentration in serum was measured before and after infection and was correlated with changes in mucosal thickness. Gastrin immunoreactivity concentration in preinoculation control sera ranged from 95.2 to 287.1 pg/ml, and increased values were measured in all parasitized calves after 15 weeks. Significantly (P less than 0.05) increased serum gastrin immunoreactivity concentration compared with the preinfection value, was found in calves infected with O ostertagi or T axei, and highly significant (P less than 0.01) values were observed in calves infected with both parasites. Abomasal mucosal hyperplasia was observed in all parasitized calves; increased mucosal thickness and mucosal cross-sectional area were most prominent in calves infected with O ostertagi and T axei.

Topics: Abomasum; Animals; Cattle; Cattle Diseases; Gastric Mucosa; Gastrins; Hyperplasia; Ostertagiasis; Trichostrongyloidiasis; Trichostrongylosis

The effects of combined administration of cimetidine and tetragastrin on gastric acid secretion, the labeling index of the gastric mucosa, and the incidence of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in inbred Wistar rats. Prolonged administration of tetragastrin in depot form after treatment with N-methyl-N'-nitro-N-nitrosoguanidine resulted in a significant increase in gastric acid secretion, a significant decrease in the labeling index of the antral mucosa, and a significant decrease in the incidence of adenocarcinomas of the glandular stomach. Administration of cimetidine at 20 mg, but not 10 mg, per kg body weight with tetragastrin significantly reduced the gastric acid secretion induced by tetragastrin alone but did not influence the labeling index of the antral mucosa or the inhibitory effect of tetragastrin on gastric carcinogenesis. These findings indicate that gastric acid secretion has no influence on the development of gastric adenocarcinomas and that the inhibitory effect of tetragastrin on gastric carcinogenesis may be related to its effect in decreasing proliferation of cells in the antral mucosa.

Topics: Adenocarcinoma; Animals; Cimetidine; DNA; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tetragastrin

The role of the antrum and duodenal bulb in gastrin regulation was investigated in 60 white rats, submitted to 1) simple laparotomy, or 2) antrectomy, or 3) antrectomy with additional removal of the duodenal bulb (1.5 cm). Serum gastrin levels 3-4 months after surgery were repeatedly measured with radioimmunoassay in fasted and in freely fed rats. The duodenum was thereafter removed and its proximal third used to assess the number and cytoplasmic granule content of duodenal G-cells. Basal serum gastrin levels were significantly increased by antrectomy, but reduced by additional resection of the duodenal bulb. Antrectomy, with or without proximal duodenectomy, completely abolished the gastrin response to feeding. Duodenal G-cell density was increased following antrectomy, but the phenomenon was not further enhanced by additional removal of the duodenal bulb. No significant changes in the patterns of gastrin granule maturation were found after antrectomy and proximal duodenectomy.

Topics: Animals; Cell Count; Cell Division; Cytoplasmic Granules; Duodenum; Gastrins; Hyperplasia; Immunohistochemistry; Male; Pyloric Antrum; Radioimmunoassay; Rats

Since little is known about the pathophysiology of pyloric stenosis, we created a partial gastric outlet obstruction in 13 Wistar rats by placing a nonabsorbable ligature of defined size around the pylorus. Sham operations were performed in 10 rats. The animals from both groups were killed after four months. G-cell count and gastrin content were determined in 10 parallel strips, which were cut by razor blades mounted on a handle. Gastric size and weight as well as thickness of mucosal and muscular layers and serum gastrin concentration were also determined. Body weight of the animals with pyloric stenosis was lower and gastric weight higher than that of the controls. Furthermore, we found an enlarged G-cell area and G-cell hyperplasia, an increased surface area and thickness of the mucosal and muscular layers of the stomach, and in the majority of rats, elevated serum gastrin levels. Total G-cell count was 583,720 +/- 90,561 in the rats with pyloric stenosis and 385,775 +/- 15,820 (mean +/- SEM) in the control rats (P less than 0.04). We conclude that partial gastric outlet obstruction in rats leads to G-cell hyperplasia and that this experiment may serve as a model for pyloric stenosis in man.

Topics: Animals; Body Weight; Cell Count; Chromaffin System; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Hyperplasia; Hypertrophy; Male; Organ Size; Pyloric Stenosis; Rats; Rats, Inbred Strains; Stomach

Topics: Abomasum; Animals; Gastric Mucosa; Gastrins; Hyperplasia; Organ Size; Ostertagiasis; Sheep; Sheep Diseases; Trichostrongyloidiasis

After administration of N-methyl-N'-nitro-N-nitrosoguanidine for 15 weeks, the effects of bilateral, anterior and posterior vagotomy on the incidence, number and location of gastric adenocarcinomas, gastric acid secretion and cell proliferation of the gastric mucosa were investigated in inbred Wistar rats. Bilateral or anterior vagotomy, but not posterior vagotomy, significantly increased the incidence and number of adenocarcinomas at experimental week 52. In sham-operated control rats and rats subjected to bilateral vagotomy, there was no significant difference between the incidence or number of gastric tumors in the anterior and posterior walls. After anterior and posterior vagal denervation, however, there were significantly more gastric cancers on the denervated side than on the other. Bilateral and unilateral vagotomy resulted in significantly reduced gastric acid secretion by experimental weeks 25 and 52. Bilateral vagotomy significantly increased the labelling indices of both the fundic and antral mucosa at both times, but did not cause any significant difference between those of the anterior and posterior wall. Anterior or posterior vagotomy resulted in a significant increase in the labelling indices of both the fundic and antral mucosa on the denervated side. These findings indicate that the vagal nerve exerts a trophic action on the gastric mucosa, and that the promoting effect of vagotomy on gastric carcinogenesis may be related to its effect in increasing proliferation of cells in the antral mucosa.

Topics: Animals; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Vagotomy

Three antisera to the C-terminally extended form of gastrin or the C-terminal flanking peptide of progastrin were used in an attempt to investigate the post-translational processing of progastrin at the cellular level by light and electron microscopical immunocytochemistry. In the normal human gastric antrum, the G-cell secretory granules were found to contain both gastrin and the C-terminal progastrin determinants (progastrin 87-93, 87-95 and 93-101). Immunostaining of serial sections at the light microscopical level revealed that duodenal gastrin-containing cells also express the C-terminal progastrin determinants, as well as gastrin-34. In foetal tissue, cells containing C-terminal gastrin and the C-flanking peptide of progastrin were first seen at 8 weeks of gestation, in the duodenum. They were not found in the stomach until the 11th week. In hyperplastic G-cells and in gastrin-producing tumour cells, the level of C-terminal peptide immunoreactivity was variable and often lower than that seen in normal antrum and only minimal immunoreactivity could be detected using electron immunocytochemistry. This was interpreted as representing altered post-translational processing of progastrin in modified G-cells.

Topics: Adenoma, Islet Cell; Duodenum; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Immune Sera; Immunohistochemistry; Peptide Fragments; Protein Precursors; Pyloric Antrum; Stomach

Topics: Achlorhydria; Antacids; Carcinoid Tumor; Enterochromaffin Cells; Gastrins; Gastritis, Atrophic; Histamine H2 Antagonists; Humans; Hyperplasia; Peptic Ulcer; Risk; Somatostatin; Stomach Neoplasms; Vagotomy, Proximal Gastric

A 42-year-old man with a 26-year history of duodenal ulcer volunteered for a 24-hour intragastric pH monitoring study, at which time his fasting gastrin concentration was found to be elevated. Secretin injection decreased the serum gastrin concentration. When not on treatment his total gastrin, gastrin-17 (G-17), and gastrin-34 (G-34) response to a protein-containing breakfast was marked. Immunocytochemical staining of antral biopsies showed hyperplasia of gastrin-containing cells, more pronounced for G-17 than for G-34. Cimetidine or cimetidine plus pirenzepine increased 24-hour intragastric pH, whereas pirenzepine alone rendered the gastric contents more acidic, particularly overnight. The total serum gastrin concentrations increased after meals and were unaffected by cimetidine or pirenzepine; enprostil, however, reduced the postprandial increase in total gastrin, G-34, and G-17. After six weeks of treatment with enprostil, the number of cells containing G-17 and G-34 was reduced. The findings show that G-cell hyperplasia may occur in the presence of a normal fasting serum gastrin concentration; fasting serum gastrin concentrations may fluctuate widely over time; the food-stimulated increase in G-17 was greater than that for G-34, and is associated with more pronounced antral hyperplasia for G-17 and G-34; and enprostil blunts the postprandial increase in G-17, G-34, and total gastrin. These observations suggest that enprostil may reduce G-cell hyperplasia and hypergastrinemia.

Topics: Adult; Cimetidine; Duodenal Ulcer; Enprostil; Gastric Acid; Gastrins; Humans; Hydrogen-Ion Concentration; Hyperplasia; Male; Pirenzepine; Prostaglandins E, Synthetic; Pyloric Antrum

Prednisolone administration in guinea pigs for 20 days induces significant hypergastrinemia and duodenal G-cell hyperplasia. Hypergastrinemia and duodenal G-cell hyperplasia are less prominent following 40 days of prednisolone administration and this could be partly attributed to the duodenal D-cell increased activity, which represents an adaptive response to the alterations of gastric secretory functions induced by corticosteroids.

Topics: Animals; Duodenum; Gastrins; Guinea Pigs; Hyperplasia; Intestinal Mucosa; Male; Prednisolone; Time Factors

Three patients with juxtapyloric ulcers and hypergastrinemia are presented. Fasting and food-stimulated serum gastrin concentration (SGC) were measured in 1970, 1972 and 1973 before the primary ulcer operation (selective gastric vagotomy and Jaboulay gastroduodenostomy; SGV + GD). Fasting SGC were 105, 149 and 158 pg/ml and the postprandial concentrations were 400, greater than 800 and greater than 800 pg/ml, respectively. The pentagastrin-stimulated acid secretion was within the normal range. After SGV + GD, only a slight decrease in acid secretion was observed. The hypergastrinemia persisted unchanged or decreased slightly in 1 patient. A recurrent ulcer developed and a precise antrectomy was carried out. Postoperatively, the fasting SGC was markedly reduced and the postprandial gastrin response abolished. The resected specimens were subjected to immunocytochemical gastrin cell quantitation. The number of gastrin cells was elevated in all 3 patients and the gastrin cell topography was distorted, with cells being present both in the lower and upper thirds of the antropyloric glands.

Topics: Adult; Female; Gastric Acid; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Radioimmunoassay; Recurrence; Stomach Ulcer

The effects of combined administration of propranolol and tetragastrin on gastric acid secretion and the incidence and histological types of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in inbred Wistar rats. Prolonged administration of tetragastrin, 1 but not 0.2 mg/kg body weight in depot form after treatment with N-methyl-N'-nitro-N-nitrosoguanidine significantly reduced the incidence of adenocarcinoma of the glandular stomach. The adenocarcinomas that did develop in rats treated with the higher dose of tetragastrin had high mucin-producing activity and showed little or no typical glandular structure. A combination of propranolol (2 mg/kg) and tetragastrin (1 mg/kg) did not influence the inhibitory effect of gastrin on gastric carcinogenesis. However, concomitant administration of propranolol (2 mg/kg) and tetragastrin (0.2 mg/kg) caused a significant increase in gastric acid secretion and a reduction in the incidence of gastric carcinomas. With this treatment, the incidence of adenocarcinoma was similar to that of treatment with tetragastrin (1 mg/kg). Histological examinations showed that like the cancers in control rats, the adenocarcinomas induced in these rats were all highly differentiated.

Topics: Adenocarcinoma; Animals; Drug Synergism; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Propranolol; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tetragastrin

Hyperplasia of the parathyroid glands is a central feature of familial multiple endocrine neoplasia type 1. We used cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with this disorder. Normal plasma stimulated [3H]thymidine incorporation, on the average, to the same extent as it was stimulated in a plasma-free control culture. This contrasted with the results of the tests with plasma from patients with familial multiple endocrine neoplasia type 1, in which parathyroid mitogenic activity increased 2400 percent over the control value (P less than 0.001). Plasma from these patients also stimulated the proliferation of bovine parathyroid cells in culture, whereas plasma from normal subjects inhibited it. Parathyroid mitogenic activity in plasma from the patients with familial multiple endocrine neoplasia type 1 was greater than that in plasma from patients with various other disorders, including sporadic primary hyperparathyroidism (with adenoma, hyperplasia, or cancer of the parathyroid), sporadic primary hypergastrinemia, sporadic pituitary tumor, familial hypocalciuric hypercalcemia, and multiple endocrine neoplasia type 2 (P less than 0.05). Parathyroid mitogenic activity in the plasma of patients with familial multiple endocrine neoplasia type 1 persisted for up to four years after total parathyroidectomy. The plasma also had far more mitogenic activity in cultures of parathyroid cells than did optimal concentrations of known growth factors or of any parathyroid secretagogue. This mitogenic activity had an apparent molecular weight of 50,000 to 55,000. We conclude that primary hyperparathyroidism in familial multiple endocrine neoplasia type 1 may have a humoral cause.

Topics: Adenoma; Adult; Animals; Cattle; Cells, Cultured; Gastrins; Growth Substances; Humans; Hypercalcemia; Hyperparathyroidism; Hyperpituitarism; Hyperplasia; Multiple Endocrine Neoplasia; Parathyroid Glands; Parathyroid Neoplasms; Thymidine; Tritium

To determine if gastrin in hyperparathyroid glands is true gastrin or artifact and to determine the frequency of gastrin in parathyroid glands, 20 parathyroid glands from 11 patients with hyperparathyroidism but without MEA were extracted and analyzed for gastrin. The parathyroid glands from 4 out of 11 patients had measurable gastrin immunoreactivity (10.7 + 6 pg/mg tissue). Column separation chromatography confirmed that this was true gastrin (40% G-34; 50% G-17). Immunohistochemistry with ABC (avidin biotin complex) immunoperoxidase confirmed the presence of gastrin in cytoplasmic vesicles in scattered parathyroid cells. True gastrin does exist in some cells in some patients with hyperparathyroidism.

Topics: Adenoma; APUD Cells; Gastrins; Humans; Hyperparathyroidism; Hyperplasia; Immunoenzyme Techniques; Parathyroid Glands; Parathyroid Neoplasms; Protein Precursors; Radioimmunoassay

Clinical and experimental evidence indicates that carcinoid tumours of the stomach fundic mucosa represent another example of hormone-dependent neoplasm, gastrin being the hormone involved in tumour induction. In this context hyperplasia of fundic endocrine cells associated with chronic atrophic gastritis (CAG) and hypergastrinaemia is regarded as the most frequent preneoplastic lesion. However, the cell type involved in this hyperplasia has not been clarified. To elucidate this problem fundic endocrine cells were characterized ultrastructurally in 9 patients from which endoscopic gastric biopsies were obtained. ECL cells were the most frequent cell type in 8 cases, in 4 of which they were more numerous than all other cell types taken together. D1 cells were the most frequent type in one case while they were inconspicuous in the other cases. P cells were found with a frequency in each case intermediate between that of ECL cells and that of D1 cells. These results indicate that fundic endocrine cell hyperplasia occurring in hypergastrinaemic CAG is in most cases cytologically similar to that found in other hypergastrinemic conditions, in which the gastrin-dependent ECL cells were already found to prevail. They also explain why fundic carcinoids arising in CAG are mostly composed of ECL cells. The relation between ECL, D1 and P cells, if any, remains obscure.

Topics: Adolescent; Aged; Biopsy; Carcinoid Tumor; Chronic Disease; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis; Gastritis, Atrophic; Humans; Hyperplasia; Male; Microscopy, Electron; Middle Aged; Precancerous Conditions

Gastrin is a trophic stimulant of the acid producing gastric mucosa. Experiments have been carried out in rats, in which chronic states of either low or high serum gastrin levels were induced by surgical manipulation or drug treatment. A relationship between circulating gastrin and a trophic effect could be demonstrated in the oxyntic mucosa, but not in the pancreas and small intestine. Endocrine cells in the oxyntic mucosa (the ECL cells and A-like cells) are among the target cells for the trophic action of gastrin. The functional significance of these two cell populations is unknown. There is much experimental evidence indicating that they are under functional as well as tropic control of gastrin. The vagus nerve also exerts trophic control on the oxyntic mucosa, including the endocrine cells within it. This could be demonstrated by one-sided truncal vagotomy which caused atrophy of the mucosa and hypoplasia of endocrine cells (notably the ECL cells) on the denervated side of the stomach. Conversely, portacaval shunt greatly increased the number of ECL cells. There was no hypergastrinaemia after portacaval shunt, and no trophic effect on other cell types in the oxyntic mucosa. The factors responsible for the ECL cell proliferation after portacaval shunting remain unknown. Tumours may arise spontaneously from the ECL cells. Such neoplasias have been described in Mastomys (Praomys natalensis) and in man. ECL cell hyperplasia and neoplasia in man, but not in Mastomys, are usually associated with hypergastrinaemia either as a result of a gastrin producing tumour or as a result of achylia (sometimes associated with pernicious anaemia). It is unlikely that gastrin alone is responsible for the neoplasia, though it is quite likely that long-standing hypergastrinaemia triggers or facilitates a sequence of events that ultimately leads to tumour formation, via diffuse ECL cell hyperplasia.

Topics: Animals; Atrophy; Carcinoid Tumor; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Parietal Cells, Gastric; Portacaval Shunt, Surgical; Stomach Neoplasms; Vagus Nerve

We have investigated the gastric endocrine cells in 19 patients with the Zollinger-Ellison syndrome. Six received a long-term treatment with omeprazole, 5 one with H2 receptor antagonists and 8 had no medical treatment. Fifteen patients (79%) had hyperplasia of the endocrine cells in the oxyntic mucosa independent of treatment. The hyperplasia involved both enterochromaffin-like (ECL) and D1 cells and was positively related to the duration of disease (p less than 0.05). The duration of hypergastrinaemia was longer in the omeprazole-treated patients, but the hyperplasia was not significantly more pronounced in these patients. Gastric carcinoid tumours consisting mainly of ECL cells are rare in man and are most often seen in states of hypergastrinaemia such as chronic atrophic gastritis. It has seldomly been reported in Zollinger-Ellison patients; but now, when potent antisecretory drugs make it possible to avoid total gastrectomy, a raised incidence might result, and an increased attention to this aspect seems appropriate.

Topics: Female; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Omeprazole; Time Factors; Zollinger-Ellison Syndrome

Antral somatostatin-immunoreactive cells (D cells) were counted pre- and postoperatively in 20 patients with duodenal ulcer and in 8 patients with gastric ulcer. Counts were obtained either over a 2-yr postoperative period (duodenal ulcer patients) at intervals of 0.5, 1, and 2 yr or over a greater than or equal to 4-yr postoperative period (gastric ulcer patients) at intervals of 1-2 yr. In patients with a normal population of gastrin-immunoreactive cells (G cells), the D cells were within the normal range (mean value 0.53% in duodenal ulcer patients and 0.67% in gastric ulcer patients). High G-cell values were accompanied by high D-cell values (e.g., in gastrin-cell hyperplasia) and low G-cell values were accompanied by low D-cell values. The G-cell to D-cell ratio was 8:1 and 6.6:1 in duodenal and gastric ulcer patients, respectively. After selective proximal vagotomy and pyloroplasty, the following observations were made: the relation of number of G cells to number of D cells remained unchanged; the postoperative rise in G-cell population was accompanied by a rise in D-cell population; hypertrophy of the D cells was apparent as was postoperative hyperplasia, with a postoperative increase in D-cell size. Morphologic coupling of the gastrin-somatostatin system in the antrum is assumed. This is constant in ulcer disease both before and after vagotomy.

Topics: Adult; Cell Count; Duodenal Ulcer; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Hyperplasia; Hypertrophy; Immunoenzyme Techniques; Male; Middle Aged; Pyloric Antrum; Somatostatin; Stomach Ulcer; Vagotomy

To evaluate the responsiveness of isolated, hyperplastic antral gastrin-producing G cells to a variety of secretagogues, hyperplastic hypergastrinemia was produced in Sprague-Dawley rats by fundusectomy. Mean serum immunoreactive gastrin (IRG) concentration was elevated fivefold above controls 4 days after operation and rose steadily to an eightfold increase at 66 days. Mean antral G cell density remained at control levels for as long as 7 days, increased twofold at 14 days, then remained between twofold and threefold greater than controls for as long as 66 days after operation. Antral mucosa IRG content increased from 141 +/- 38 (control) to 262 +/- 58 ng IRG/gm mucosa (4 to 6 weeks after fundusectomy). Crude fractions of dispersed antral mucosa cells enriched in G cells from fundusectomized rats contained 6.5% +/- 1.4% G cells with 0.19 +/- 0.6 pg IRG/G cell. Corresponding preparations from nonoperated rats contained 5.1% +/- 0.5% G cells with 0.07 +/- 0.02 pg IRG/G cell. Viability averaged greater than 95% for all preparations. Gastrin secretion was monitored in cell preparations further enriched in G cells (9% to 10%) by Percoll density gradient centrifugation either in the absence (basal) or presence of bombesin (1 mumol, 1 nmol/L), carbachol (1 mmol/L), leucine (10 mmol/L), and ethylamine (10 mmol/L). The basal secretory rate of hyperplastic G cell populations averaged 250% greater than normal G cell basal rates. Hyperplastic G cell preparations had an increased IRG secretory rate in the presence of bombesin (1 mumol/L, 750%; 1 nmol/L, 191%), leucine (120%), ethylamine (236%), and carbachol (183%). These conditions failed to increase the IRG secretory rate above basal in preparations from normal antra. Viable, dispersed, hyperplastic G cells have increased IRG content and basal IRG secretory rate and are functionally responsive to a variety of secretagogues.

Topics: Animals; Centrifugation, Density Gradient; Chromaffin System; Enterochromaffin Cells; Fluorescent Antibody Technique; Gastric Fundus; Gastric Mucosa; Gastrins; Histocytochemistry; Hyperplasia; Immunoenzyme Techniques; In Vitro Techniques; Laparotomy; Male; Pyloric Antrum; Radioimmunoassay; Rats; Rats, Inbred Strains

Clinical, histological, histochemical and ultrastructural characteristics of eight cases of carcinoid tumors of the non-antral portion of the stomach are presented. Four cases with multiple polypoid lesions are accompanied by an increased level of gastrin. A normal level of gastrin was present in the other four cases with isolated tumor and a normal component of endocrine cells in the uninvolved mucosa. In the first group with multiple lesions, the histological and histochemical analysis of the endocrine cells revealed a wide range of appearances: a) "simple hyperplasia", b) "nodular hyperplasia", and c) carcinoid tumor. These aspects suggested a different pathogenesis for the carcinoid tumors of the non-antral portion of the stomach with possible therapeutical implications.

Topics: Achlorhydria; Adult; Aged; Carcinogens; Carcinoid Tumor; Chromaffin System; Enterochromaffin Cells; Female; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Precancerous Conditions; Stomach; Stomach Neoplasms

Truncal vagotomy is associated with diminished gastric acid production, gastrin cell hyperplasia, and elevated serum gastrin levels. To study the role of reduced antral luminal acidity in the production of gastrin cell proliferation, gastrin cell densities were quantitated in preparations involving exposure of the antral mucosa to a non-acid lumen at different levels of the gastrointestinal tract. Female Sprague-Dawley rats were divided into the following experimental groups: intact controls, shams, antral diverticulum on the jejunum, antral diverticulum on the ileum, and antral diverticulum on the colon. At death, 2 weeks, 2 months, and 6 months after operation, luminal pH was at least 5.8 for each group of rats with antral diverticula. No significant changes in gastrin cell numbers were observed in rats with jejunal or ileal diverticula. For those animals with colonic diverticula, gastrin cell counts were increased 55% at 2 weeks (503 +/- 23 cells per cm versus 320 +/- 13 cells per cm for shams). At 2 months gastrin cell numbers had increased further (639 +/- 54 cells per cm) in rats with antral diverticula on the colon. Gastrin cell proliferation was sustained at 6 months in this group. A factor other than reduced luminal acidity induces gastrin cell proliferation in antral mucosa exposed to colonic content. The responsible agent is not present in the small-bowel lumen. A non-acid luminal environment is not, by itself, a sufficient stimulus for gastrin cell hyperplasia.

Topics: Animals; Cell Count; Colon; Female; Gastrectomy; Gastric Mucosa; Gastrins; Histocytochemistry; Hydrogen-Ion Concentration; Hyperplasia; Ileum; Immunochemistry; Intestinal Mucosa; Intestinal Secretions; Jejunum; Mice; Pyloric Antrum; Rats; Rats, Inbred Strains; Vagotomy

A clinical, endoscopic, and histological study of 206 cases of nodular hyperplasia of Brunner's glands was carried out. Firm nodules with a reddened surface due to hyperplastic Brunner's glands were limited mainly to the first part of the duodenum and affected almost exclusively male patients. Gastric acid secretion after pentagastrin stimulation was significantly increased compared to normal. In most cases, biopsies of the nodule center revealed spreading of Brunner's glands from within the lamina propria to the surface epithelium, whereas in biopsies performed between nodules, Brunner's glands were limited to the deeper part of the mucosa. Thirty-six nodules completely removed by diathermy were composed almost entirely of Brunner's glands. The frequent association with duodenal ulcer, chronic gastric erosions, and cobblestone pattern of the gastric body mucosa, as well as the significant hypersecretory state, suggest that hyperacidity plays a role in the pathogenesis of nodular hyperplasia of Brunner's glands.

Topics: Biopsy; Body Weight; Brunner Glands; Duodenitis; Duodenoscopy; Duodenum; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male

A consecutive series of 357 endoscopic gastric biopsies was investigated after staining of histological sections with the Grimelius silver method. Argyrophil cells were classified according to the type of mucosa (fundic, antropyloric or intestinalized) in which they were located. Cases of argyrophil cell hyperplasia detectable on a qualitative basis were selected and their associations with various gastroduodenal disorders of the patients as well as with functional and pathological findings of the gastric mucosa were investigated. Hyperplasia of fundic argyrophil cells was more frequent in patients with atrophic gastritis of the fundic mucosa and a relatively well preserved antral mucosa as well as in patients with hyperplastic polyps. In contrast, it was infrequent in patients with duodenal ulcer and gastric stump. Hyperplasia of antropyloric argyrophil (non-G) cells was most frequent in patients with gastric peptic ulcer or with hyperplastic polyps as well as in those with atrophic gastritis of the fundic mucosa irrespective of the concomitant condition of antral mucosa. Hyperplasia of metaplastic argyrophil cells was more frequent in intestinal metaplasia of the antral mucosa than in that of fundic mucosa. Moreover, it was more frequent in patients with gastric cancer.

Topics: Adolescent; Adult; Aged; Biopsy; Female; Gastric Acidity Determination; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Diseases; Gastroscopy; Humans; Hyperplasia; Intestinal Mucosa; Male; Metaplasia; Middle Aged; Peptic Ulcer; Polyps; Silver; Staining and Labeling; Stomach Neoplasms

37 patients suffering from apudomas of the pancreas are reported (18 insulinomas, 6 isletcell-hyperplasias, 9 Zollinger-Ellison syndroms, 1 glucagonoma, 3 without hormone production). In preoperative localization computerized tomography and angiography were the best with 65% positive findings. Insulinomas were enucleated, all free of recidives. 50% of operated isletcell hyperplasias had a postoperative resisting hyperinsulinism. Either gastrectomy or tumour enucleation was performed in the Zollinger-Ellison syndrome. The five-years survival rate was 43%.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Child; Female; Follow-Up Studies; Gastrectomy; Gastrins; Glucagon; Humans; Hyperplasia; Insulin; Insulinoma; Islets of Langerhans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Stomach Neoplasms; Zollinger-Ellison Syndrome

Three types of endocrine cells (G cells producing gastrin-17, D cells producing somatostatin, and GER cells containing endorphine) in the mucous membrane of the stomach antrum from 14 patients with duodenal ulcer and 10 healthy persons were studied. Biopsies were fixed in a modified Bowen solution and imbedded into paraffin. The slides were stained by Grimelins' method and immunohistochemically with the use of the peroxidase-antiperoxidase method. The number of cells per 1 mm2 of the mucous membrane was counted. Patients with ulcer have shown the increased number of G and GER cells and decreased number of D cells. Besides, pronounced G cell hyperplasia with a relative decrease of GER cells and a marked decrease of Grimelins-positive cells (as compared to other patients with duodenal ulcer) were observed in 3 out of 14 ulcer patients. The authors conclude that the alteration of the balance between antagonistic hormone effects results in the hypersecretory syndrome that plays the main role in the pathogenesis of duodenal ulcer.

Topics: Adult; Cell Count; Duodenal Ulcer; Endocrine Glands; Endorphins; Gastrins; Hormones, Ectopic; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Somatostatin

Topics: Adenoma, Islet Cell; Adult; Female; Gastrins; Glucagon; Humans; Hyperplasia; Islets of Langerhans; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Serotonin; Somatostatin; Staining and Labeling; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Extensive small bowel resection produces pancreatic hyperplasia and increases plasma gastrin levels in the rat. Because gastrin is known as a trophic factor for the exocrine pancreas, we studied the effect of endogenous variations of gastrin induced by different gastric operations on the rat pancreas in both resected and transected animals. Vagotomy increased plasma gastrin level while antrectomy decreased it; pyloroplasty was without any effect. These gastric operations enhanced slightly but not significantly the pancreatic weight, its protein and DNA content. A 90% jejunoileal resection alone increased markedly these parameters while mitotic figures appeared in acinar cells. Pyloroplasty, vagotomy and antrectomy did not modify the changes induced by intestinal resection itself except the level of protein. These findings suggest that hypergastrinemia produced by intestinal resection is not responsible for pancreatic hyperplasia.

Topics: Animals; Body Weight; DNA; Gastrectomy; Gastrins; Hyperplasia; Intestine, Small; Malabsorption Syndromes; Male; Organ Size; Pancreas; Proteins; Pylorus; Rats; Rats, Inbred Strains; Short Bowel Syndrome; Vagotomy, Proximal Gastric

Topics: Adult; Aged; Duodenal Ulcer; Female; Gastric Acid; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Vagotomy, Proximal Gastric; Zollinger-Ellison Syndrome

The prevalence of hypergastrinemia was determined in 38 consecutive patients with proved primary hyperparathyroidism. Uncorrected serum calcium levels ranged from 2.6 to 4.0 mmol/L and parathyroid hormone levels from 260 to 8750 ng/L (normal less than 600 ng/L). Preoperative serum gastrin levels were grossly elevated (1000 to 4000 ng/L) in three patients (normal median 63 ng/L; range 30 to 120 ng/L). Two patients were achlorhydric. After parathyroidectomy (adenomatous hyperplasia) in the third patient, the serum gastrin level decreased from 4000 to 3000 ng/L, with a negative response to both a secretin challenge and a meal test. The latter patient was subsequently shown to have an adrenal ganglioneuroma and islet cell hyperplasia, neither containing gastrin, and at 4-year follow-up she still has no symptoms from the hypergastrinemia. Eight patients had a modest hypergastrinemia. Serum gastrin levels returned to normal in three of the four patients after parathyroidectomy. The fourth patient had rheumatoid arthritis, which can be associated with hypergastrinemia. The mean plasma gastrin level before operation (100.3 +/- 26.1 ng/L) was similar to the postoperative value (67.0 +/- 18.5 ng/L). There was no correlation between parathyroid hormone and gastrin levels nor between serum calcium and gastrin levels. The three patients with duodenal ulcers did not have elevated gastrin levels. Therefore it would appear that routine screening of patients with primary hyperparathyroidism adds little to their clinical management.

Topics: Adult; Aged; Calcium; Female; Gastrins; Humans; Hyperparathyroidism; Hyperplasia; Male; Middle Aged; Parathyroid Glands; Parathyroid Hormone; Zollinger-Ellison Syndrome

Primary gastrin cell hyperfunction of the gastric antrum as a clinical syndrome consists of basal hypergastrinemia, an exaggerated gastrin response to feeding, the absence of any ectopic source of gastrin secretion, and peptic ulcer disease. The number of G-cells were quantitated in the gastric antrum of five patients with clinically diagnosed primary G-cell hyperfunction, and the results were compared to controls with a variety of gastric diseases. Patients with the clinical diagnosis of primary G-cell hyperfunction had a significantly increased number of antral G-cells (p less than 0.05). The clinical syndrome of primary G-cell hyperplasia appears to be associated with hyperplasia of G-cells rather than with the hypersecretion of gastrin by a normal number of G-cells.

Topics: Adult; Chromaffin System; Diagnosis, Differential; Enterochromaffin Cells; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Peptic Ulcer; Pyloric Antrum; Stomach Diseases; Syndrome; Zollinger-Ellison Syndrome

A method for measurement of gastrin in human antral mucosa or in extragastric tissue has been developed and validated. Tissue gastrin was extracted by boiling followed by homogenization at neutral pH. Extractable gastrin immunoreactivity was measured by radioimmunoassay using an antiserum with equal affinity towards G-17 I, G-17 II, G-34 I and G-34 II molecular forms. Almost all extractable gastrin immunoreactivity was recovered after a single extraction and no significant interference by other peptides and/or substances present in tissue was found. The mean gastrin concentration in antral mucosa of healthy subjects was similar to that observed in duodenal ulcer patients, while patients with type A chronic atrophic gastritis or with antral gastrin cell hyperplasia had mean values significantly higher. Gastrin concentration in all specimens from gastrinoma or its metastases was above the upper limit of the range of control tissue. Measurement of tissue gastrin seems to be a valuable tool in the diagnosis of antral gastrin cell hyperplasia and Zollinger-Ellison syndrome.

Topics: Adolescent; Adult; Aged; Cholecystitis; Chronic Disease; Duodenal Ulcer; Female; Gastric Mucosa; Gastrins; Gastritis; Humans; Hyperplasia; Male; Middle Aged; Pancreatic Neoplasms; Pyloric Antrum; Zollinger-Ellison Syndrome

A 24-month-old female child experienced watery diarrhea, growth failure, and abdominal pain from age 3 months. Hypergastrinemia, hypochlorhydria, and fundic gastritis were documented. A secretin stimulation test was normal but protein meal stimulation revealed an abnormal serum gastrin response. Antral biopsies revealed G cell hyperplasia. Chronic treatment with antacids and an anticholinergic agent was unsuccessful. Spontaneous recovery occurred at age 29 months. Gastrin stimulation tests, gastric acid secretory tests, antral mucosal biopsies, and multiple basal serum gastrin levels were repeated. All were normal. Follow-up of greater than 3 years has documented a completely normal clinical and laboratory course.

Topics: Achlorhydria; Biopsy; Chromaffin System; Diarrhea, Infantile; Enterochromaffin Cells; Female; Follow-Up Studies; Gastrins; Humans; Hyperplasia; Infant; Pyloric Antrum; Time Factors

A proximal 50 p. 100 resection of the small bowel was performed in six dogs while six control animals underwent a simple intestinal transsection and reanastomosis. The pre- and postoperative serum gastrin levels were measured in both groups before and after a standard test meal. The stomach was resected in both groups 6 to 8 weeks after the operation. A morphometric method using specific antigastrin and antisomatostatin antibodies was used to estimate the density and the total number of antral gastrin and somatostatin cells. No variation in basal serum gastrin was found after surgery. A 50 p. 100, though not significant, increase in the postprandial gastrin response was observed after intestinal resection whereas a significant (P less than 0.01) 50 p. 100 increase in the gastrin cell density was found in the antral mucosa of these dogs. At the same time, a remarkable hyperplasia of the antral somatostatin cell population was observed in the animals submitted to small bowel resection.

Topics: Animals; Dogs; Gastrins; Hyperplasia; Intestine, Small; Postoperative Period; Pyloric Antrum; Somatostatin

The present study includes a histopathological and immunohistochemical study of 4 cases of diffuse hyperplasia of gastric argyrophil cells. The mode of proliferation of these cells and the production of hormone by these cells have been documented. The distribution of microacinar nests composed of argyrophil cells was thought to be related to chronic gastritis in which there are atrophy of mucosa and intestinal metaplasia. In the case in which these nests were found only in the corpus ventriculi, there was intestinal metaplasia throughout the stomach. On the other hand, in the case in which these nests appeared only in the pyloric area, atrophy of the mucosa with mild intestinal metaplasia was observed only in the pyloric area. The microacinar nests composed of argyrophil cells were distributed in the deep mucosa at the basal portion of the glands in the area with intestinal metaplasia. Serial sections revealed a sprout composed of argyrophil cells budding from the gland with intestinal metaplastic changes. The sprout buds out from the growth zone of glands with intestinal metaplasia and then becomes isolated and gives rise to reactive hyperplasia. The peptide hormone contained in these cells differs according to the mucosal environments. Cells containing gastrin were observed in the pyloric area, but not in the corpus ventriculi where there was marked intestinal metaplasia. The cells in this area were assumed to contain other hormones.

Topics: Adenocarcinoma; Adult; Chromaffin System; Enterochromaffin Cells; Female; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Immunoenzyme Techniques; Male; Middle Aged; Somatostatin; Stomach Neoplasms

We performed acid secretory and histomorphometric studies in rats treated intragastrically with a regimen of 100 micrograms/kg or 5 micrograms/kg of 16,16-dimethyl prostaglandin E2, or of saline every 8 h for 21 days. All animals given the high-dose treatment developed a macroscopically visible enlargement of the ridge at the corpus-forestomach border, due to an increase in connective tissue and epithelial cell layer. Mucosal thickness was significantly increased in all parts of the stomach, the duodenum, and the proximal colon, but most markedly in the gastric antrum (+115%), where it was accompanied by a higher mitotic rate and hyperplasia of surface and foveolar mucous cells. Within the oxyntic area (corpus), high-dose prostaglandin treatment led to an increase in the number of surface and foveolar mucous cells and chief cells. In contrast, both the number of parietal cells and maximal acid output were not influenced. It is unlikely that the hyperplasia of gastric mucosa is mediated by gastrin since gastrin has no trophic effects on the rat antrum and disproportionally increases the parietal cell number of the oxyntic gastric glands.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Antacids; Female; Gastric Acid; Gastric Acidity Determination; Gastric Mucosa; Gastrins; Hyperplasia; Intestinal Mucosa; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Time Factors

Topics: Animals; Cell Count; Chronic Disease; Colon; Duodenum; Esophagus; Female; Gastric Mucosa; Gastrins; Hyperplasia; Intestinal Mucosa; Intestine, Small; Intestines; Mast Cells; Organ Size; Rats; Splenomegaly; Stomach; Taeniasis

Topics: Acromegaly; Adenocarcinoma; Adolescent; Adult; Chromaffin System; Enterochromaffin Cells; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Stomach Neoplasms; Stomach Ulcer

Topics: Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Peptic Ulcer; Pyloric Antrum; Stomach Diseases; Zollinger-Ellison Syndrome

The effects of truncal vagotomy on the functional and morphological changes produced by duodenogastric reflux have been studied in the dog. Duodenogastric reflux caused progressive damage to gastric mucosa, hypersecretion of acid to pentagastrin, and a hypergastrinemic response to a standard meal. Truncal vagotomy barely altered the mucosal changes produced by reflux, but it did prevent antral gland hyperplasia and reduced the acid and gastrin secretory responses. These findings are clinically reassuring in that vagotomy effectively prevented the hypersecretory state produced by duodenogastric reflux.

Topics: Animals; Dogs; Duodenal Diseases; Gastric Acid; Gastric Mucosa; Gastrins; Gastroesophageal Reflux; Histamine; Hyperplasia; Pentagastrin; Vagotomy

Topics: Adult; Aged; Diagnosis, Differential; Female; Gastric Acidity Determination; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Stomach Diseases; Zollinger-Ellison Syndrome

Development of the cestode parasite Taenia taeniaeformis in the liver of rats results in gross hyperplastic changes in the stomach and small intestine. In this study we investigated the mechanism by which these lesions are induced. Acutely infected rats were joined surgically to syngeneic noninfected partners in parabiosis. When hyperplastic gastropathy developed in those rats with heavy hepatic infections with cestodes, it also occurred in the uninfected partners of the parabiotic pairs. Gastric changes were usually more severe in the uninfected partner. Duodenal mastocytosis developed in both partners, even when parasite burdens were light in the infected rats. intact chronically infected rats with hyperplastic gastropathy developed markedly elevated serum levels of the hormone, gastrin (approximately 30-fold greater than normal). When rats were antrectomized 24-48 h after infection, gastric hyperplasia still developed, but hypergastrinemia was prevented or was of only moderate degree. There was no correlation between serum gastrin levels and the degree of gastrointestinal change in the intact rats, but hypergastrinemia never developed in infected animals which did not show hyperplasia in the stomach or intestine. When infected rats were bled serially over the first 100 days of infection, hypergastrinemia developed abruptly between 50 and 60 days after infection. These results suggest that the alterations in serum gastrin levels were secondary to the development of hyperplastic changes in the gastrointestinal tract of infected rats. The primary stimuli for both the hyperplasia and the hypergastrinemia remain unknown.

Topics: Animals; Gastrins; Hyperplasia; Parabiosis; Rats; Stomach Diseases; Taeniasis

Tissue and serum immunoreactive gastrin (IRG) concentrations were measured by radioimmunoassay, and antral G cell density was studied by immunofluorescence in seven non-operative and ten vagotomized (one month postoperatively) rats. In the non-operative rats, tissue IRG concentration was overwhelmingly high in the antrum, especially in the distal antrum, and much less in the small intestine, in which it tended to be lower toward the distal part. There were no significant differences between the vagotomized and non-operative rats in antral G cell density, antral tissue IRG concentration, total IRG content of the anterior antrum and serum IRG level, although significantly increased wet weight of the specimen, which was considered a result of the operation, was observed in vagotomized rats. The presence of G cell hyperplasia after vagotomy cannot be confirmed from our one-month postoperative observations in rats.

Topics: Animals; Gastrins; Hyperplasia; Intestine, Small; Rats; Stomach; Vagotomy

Topics: Adult; Diagnosis, Differential; Female; Gastrins; Humans; Hyperplasia; Peptic Ulcer; Pyloric Antrum; Zollinger-Ellison Syndrome

In a series of chronic experiments on 30 rats subjected to nephrectomy, use was made of the present-day morphological and quantitative histochemical techniques to study the activity of oxidation-reduction enzymes, hydrolases and PAS-reaction in cellular elements of the mucous membrane of the fundal and antral parts of the stomach. It was found that in the early stages of experimental renal insufficiency, all the main cells of the glands manifested marked hyperplasia. These alterations seem likely to be adaptive in nature and are caused by the stimulatory action of the increased amounts of nitrous residue in the gastric lumen of such animals. The authors discuss the origin of gastric pathology in experimental animals and make clinical and experimental correlations.

Topics: Animals; Female; Gastric Juice; Gastric Mucosa; Gastrins; Hyperplasia; Kidney Failure, Chronic; Male; Oxidoreductases; Periodic Acid-Schiff Reaction; Rats

A density study of the antral gastrin-producing cells has been performed, before and after eight weeks of treatment with a histamine H2-receptor antagonist (cimetidine 1 g per day), in a series of 38 patients suffering from chronic duodenal ulcer. The treatment produced a significant increase in numerical density and a decrease in mean cell volume. The volume density of the cells was unchanged, suggesting that the elevated serum-gastrin during treatment may be the result of gastrin-cell hyperplasia, without change in the total gastrin-cell volume. The authors suggest that G-cell hyperplasia demonstrated during cimetidine treatment may be a factor of importance with regard to the rapid recurrence of many ulcers after discontinuation of the treatment.

Topics: Adult; Aged; Cell Division; Cimetidine; Duodenal Ulcer; Female; Gastric Juice; Gastrins; Humans; Hyperplasia; Immunoenzyme Techniques; Male; Middle Aged; Pyloric Antrum

The total number of gastrin (G) cells in the stomach was determined by using a histologic counting method and planimetry in ulcerous and nonulcerous patients. The preoperative basal and postprandial serum gastrin values and the gastrin cell mass in the gastrectomy specimen could be compared in 16 surgical patients. There was a significant correlation between the integrated gastrin response to feeding and the total gastrin cell number in the stomach. No correlation was found between the basal serum gastrin level and the total gastrin cell count. A total gastrin cell number higher than 50 million was found in the stomach of three duodenal ulcer patients with preoperative postprandial hypergastrinemia as well as in one patient with normal serum gastrin values. Gastrin cell counts between 6 and 42 million were found in control stomachs and in patients with gastric ulcer. Preoperative feeding tests could be useful to select patients with an elevated antral G cell number.

Topics: Cell Count; Duodenal Ulcer; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Pyloric Antrum; Recurrence; Stomach Ulcer; Vagotomy

Topics: Animals; Cell Count; Dogs; Gastrins; Hydrogen-Ion Concentration; Hyperplasia; Pyloric Antrum; Vagotomy

The role of human pancreatic-polypeptide in endocrine tumours of the pancreas is reviewed. Pancreatic-polypeptide may be involved in 3 different ways: 1. In cases with pure PP producing tumours. 2. In mixed endocrine tumours containing PP cells. 3. In cases with PP cell hyperplasia in normal pancreatic tissue associated with endocrine pancreatic tumours as VIP-omas, insulinomas, and glucagonomas. PP does not seem to serve as a general marker for endocrine tumours of the pancreas, but PP determinations are useful in patients wbith watery diarrhoea syndromes, because such syndromes may be associated with tumours that contain PP cells. Large molecular forms of PP occur in plasma from patients with endocrine tumours and high PP concentrations, but may also be found in other groups of patients. It is suggested that an atropin-suppression test could be of diagnostic value in revealing patients with increased serum concentrations of PP from other causes than vagal stimulation of normal PP cells.

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Dehydration; Gastrins; Glucagon; Humans; Hyperplasia; Molecular Weight; Pancreas; Pancreatic Neoplasms; Pancreatic Polypeptide; Syndrome; Zollinger-Ellison Syndrome

Highly selective vagotomy was performed on five dogs. Postoperatively, gastrin cell (G cell) hyperplasia occurred in all dogs. Mean preoperative G cell numbers increased from 350 to 530/cm mucosal length (p less than 0.02). Antral tissue gastrin also increased by 100 per cent (6.7 x 10(6) to 13.7 x 10(6) pg/gm tissue, p less than 0.05). Basal and stimulated serum gastrin were unchanged following highly selective vagotomy. The cause for G cell hyperplasia is not clear, but is probably multifactorial.

Topics: Animals; Biopsy; Cell Count; Dogs; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Hyperplasia; Methods; Pyloric Antrum; Vagotomy

Topics: Cytoplasm; Cytoplasmic Granules; Gastrins; Humans; Hyperplasia; Islets of Langerhans; Organoids

Topics: Adolescent; Animals; Gastrectomy; Gastric Juice; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Peptic Ulcer; Pyloric Antrum; Vagotomy; Zollinger-Ellison Syndrome

Relative chief and parietal cell volume densities were estimated morphometrically in the remnant mucosa of 98 male patients ("series"), operated on for duodenal ulcer by the Billroth II, and in the body mucosa of 55 subjects, age and sex matched, from a random series of a Finnish population ("controls"). The relative volumes of chief and parietal cells were significantly lower in the series than in the controls. The mean chief cell: parietal cell ratio was significantly higher in the series than in the controls. In the controls the ratio decreased with increasing loss of normal tubules. However, no such decrease was discernable in the series, owing to wide scatter of the individual ratios. High ratios (greater than or equal 2.0) were found in 17 cases of the series and in one of the controls. These 17 patients with high ratios had a significantly higher mean length of the foveoles and a significantly lower mean score of the round cell infiltration than the operated patients with lower ratios.

Topics: Adult; Atrophy; Cell Count; Cell Survival; Duodenal Ulcer; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Mitosis

Topics: Animals; DNA; Duodenum; Gastrins; Hyperplasia; Intestinal Mucosa; Intestine, Small; Kidney; Male; Organ Size; Parenteral Nutrition; Pentagastrin; Proteins; Rats; Stomach

Gastrin release was studied in 5 hypergastrinemic patients, both during calcium infusion and EDTA infusion. In each patient, gastrin decreased in conjunction with the fall in plasma calcium, and increased during calcium infusion. Plasma gastrin and calcium levels were strongly correlated.

Topics: Achlorhydria; Adolescent; Adult; Calcium; Edetic Acid; Female; Gastrins; Humans; Hyperplasia; Infusions, Parenteral; Male; Middle Aged; Pyloric Antrum; Secretory Rate; Zollinger-Ellison Syndrome

Topics: Chemical Phenomena; Chemistry; Duodenal Ulcer; Gastrins; Humans; Hyperplasia; Immunologic Techniques; Pyloric Antrum; Radioimmunoassay; Secretin; Zollinger-Ellison Syndrome

In a patient with a duodenal ulcer, with acid hypersecretion and moderately disturbed gastrin secretion tests, immunocytochemical examination of the vagotomy-antrectomy specimen revealed a pyloric microgastrinoma (clinically silent and apparently benign) and focal antropyloric gastrinosis. These localised lesions represent a new variant of abnormalities affecting the gastrin cells in the context of hypersecretory duodenal ulcers.

Topics: Adenoma; Carcinoid Tumor; Duodenal Ulcer; Gastric Juice; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Pylorus; Stomach Neoplasms

Estimates of the G cell population were made in 24 resected human pyloric antra from counts of cells in multiple samples and from measurements of antral size. Measurements had been made previously in 20 subjects of acid output (basal and after pentagastrin) and in 10 subjects of plasma gastrin (basal and after insulin + bicarbonate). G cells were most dense near the pylorus, but their circumferential distribution was even. The G cell populations ranged from 8 to 15 (mean 10) million in four control patients and from 3 to 43 (mean 18) million in 15 patients with duodenal ulcer. Those with recurrent ulcer after vagotomy had either a low G cell count and incomplete vagotomy, or a high G cell count and apparently complete denervation. Two patients with hypergastrinaemia and duodenal ulcer had moderate (29 X 10(6)) or marked (56 X 10(6)) excesses of G cells. 'G cell hyperplasia' may represent the extreme end of the normal range of G cell numbers in the antrum, and can be assessed by semi-quantitative grading of G cell hyperplasia in antral biopsies. There were significant direct correlations between antral area and G cell density, between peak acid output and G cell population, and between basal plasma gastrin and G cell density (but not population). We suggest that, in patients with duodenal ulcer, acid and gastrin secretion are interrelated and that both are related to the masses of parietal cells and of G cells.

Topics: Cell Count; Duodenal Ulcer; Gastric Juice; Gastrins; Humans; Hyperplasia; Pyloric Antrum

Suspension of magnesium and aluminum hydroxide (30--60 mEq/24h) or a comparable volme of water was orally administered by gastric intubation to two groups of 20 male Wistar rats each over 60 days. The antacid treatment led to a significant increase in the height (0.464 +/- 0.02 mm v. 0.318 +/- 0.06) and in the volume (472 +/- 32 mm3v.328 +/- 45) of the fundic mucosa of the stomach, in the average count of parietal cells per unit area of the mucosa (32.37 +/- 1.8 v. 22.3 +/- 1.6), and in the total parietal cell population of the stomach (53.6 +/- 3.5 x 10(6) v. 43.2 +/- 3.7 x 10(6)). Furthermore fasting serum gastrin concentration was significantly higher in the antacid treated rats (81.2 +/- 7.4 pg/ml) than in control animals (56.9 +/- 6.9 pg/ml).

Topics: Animals; Antacids; Cell Count; Gastric Mucosa; Gastrins; Hyperplasia; Male; Rats

A case of recurrent duodenal ulcer, basal gastric hypersection, and hypergastrinemia of antral origin is presented. The diagnosis was suggested preoperatively by stimulation tests with secretin and food. Billroth II antrectomy led to normalization of serum gastrin within half an hour. The gastrin content of the antral mucosa was not increased, neither was antral G-cell hyperplasia demonstrable. Postoperatively the basal gastric acid output and fasting serum gastrin levels were normal, without a postprandial increase in serum gastrin concentrations. The case does not support the existence of a specific disease called antral G-cell hyperplasia.

Topics: Adult; Duodenal Ulcer; Gastrectomy; Gastric Juice; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Pyloric Antrum; Recurrence; Secretory Rate

The pathogenesis of peptic ulceration cannot be explained by an abnormal capacity to secrete acid, for ulcers develop in patients who secrete acid normally. Duodenal and gastric ulcers have a common cause. The location of an ulcer in each individual is primarily determined by his capacity to secrete acid at that time. There is a difference between the mechanisms which heal an ulcer and cure a patient of his disease. Procedures that reduce an individual's capacity to secrete acid, heal an ulcer by moving the focus of the ulcerogenic forces to a more proximal site. It is necessary to remove an antral factor if in addition the patient is to be cured of his disease. It is postulated that this antral factor is the gastrin (G17) which is released in abnormal amounts into gastric juice in patients with ulcers and with gastrinomas. The abnormal amount of G17 in gastric juice may be responsible for releasing abnormal amounts of G34 into the circulation from the duodenum and from gastrinomas. The abnormal release of gastrin develops as a result of an impaired response to duodenal acidification manifest in part by an impaired release of secretin. It is postulated that the abnormal stimulation of antral gastrin release may on occasions give rise to antral G-cell hyperplasia, and that the abnormal secretion of gastrin into gastric juice may on occasions give rise to gastrinomas. These abnormalities may cause ulcers by producing an uncontrolled secretion of acid and an abnormal exposure to bile.

Topics: Duodenum; Gastric Juice; Gastrins; Hormones, Ectopic; Humans; Hyperplasia; Paraneoplastic Endocrine Syndromes; Peptic Ulcer; Pyloric Antrum; Stomach Neoplasms; Vagotomy

Topics: Gastrins; Glucagon; Growth Hormone-Releasing Hormone; Humans; Hyperplasia; Insulin; Islets of Langerhans; Pancreatic Neoplasms; Peptides

The number of distribution and the numbers of G cells in the antropyloric region of the rabbit stomach were mapped employing immunoperoxidase localization and morphometric quantitation and compared to similar analyses in hypercalcemic rabbits bearing the VX2 carcinoma. In normal animals, G cells were confined to the lower third of the antropyloric mucosa, where they were randomyly distributed within the mucosal glands. In contrast, tumor-bearing animals showed an extension of these cells into the middle third of the antropyloric mucosa. The absolute counts of G cells in control rabbits were 5.3 +/- 0.78 (mean +/- SE) per unit area, while those in hypercalcemic tumor-bearing rabbits were 11.9 +/- 0.46, a statistically significant increase. It is concluded that rabbits bearing VX2 carcinoma have G-cell hyperplasia.

Topics: Animals; Carcinoma; Cell Count; Female; Gastric Mucosa; Gastrins; Hypercalcemia; Hyperplasia; Immunoenzyme Techniques; Neoplasms, Experimental; Pyloric Antrum; Rabbits

The relatives of 25 index patients with primary parathyroid hyperplasia were tested for hypercalcemia. At least 13 of these patients had one or more first degree relatives with hypercalcemia. Two familial syndromes each with autosomal dominant transmission were recognized. Two index patients were part of large kindreds categorized as having familial hypocalciuric hypercalcemia (FHH). Manifestations of multiple endocrine neoplasia type I were present in the kindreds of at least four other index patients (FMEN I). In seven other kindreds there were too few affected members to allow definitive classification. Differences between manifestations of FHH and FMEN I were described. Among offspring of affected persons in kindreds with FHH, as distinct from FMEN I, the prevalence of hypercalcemia approached the theoretic maximum of 50 per cent during the first two decades. In FHH, nephrolithiasis and peptic disease were unusual; moderate hypercalcemia occurred without hypercalciuria; and subtotal parathyroidectomy did not abolish hypercalcemia. Concentrations of peptide hormones other than parathyroid hormone (PTH) were normal in those with FHH; in FMEN I high concentrations of glucagon in plasma were found in five of six patients tested, and high concentrations of gastrin were found in three of 12 patients. Hypergastrinemia generally accompanied obvious peptic disease. Distinction of the two conditions is important since patients with FHH may not benefit from subtotal parathyroidectomy, but they generally have a better clinical prognosis than do patients with FMEN I.

Topics: Adolescent; Adult; Aged; Calcium; Child; Female; Gastrins; Glucagon; Humans; Hypercalcemia; Hyperplasia; Male; Middle Aged; Neoplasms, Multiple Primary; Parathyroid Glands; Parathyroid Hormone; Parathyroid Neoplasms; Pedigree; Prolactin

The morphology of the parathyroids in rats with hypergastrinemia, induced by antral exclusion, was compared with that of glands from untreated rats and animals from which the main source of gastrin- 17 was excluded (antral resection). Fourteen weeks after induction of hypergastrinemia the volume of the parathyroids was significantly increased owing to hyperplasia of the parenchymal cells. Removal of the antral gastrin-producing capacity of the same duration was not accompanied by any significant changes in the parathyroids. These findings suggest that hypergastrinemia could be a stimulus for the development of hyperplasia of the parathyroids, and that it may be an etiological factor in the production of hyperparathyroidism.

Topics: Animals; Body Weight; Calcium; Cell Count; Gastrins; Hyperparathyroidism; Hyperplasia; Male; Organ Size; Parathyroid Glands; Pyloric Antrum; Rats

A patient in whom Cushing syndrome had been diagnosed at the age of 23 was found 14 years later to have subclinical diabetes mellitus, subcutaneous calcified fat tissue necroses, and hypergastrinemia suggesting Zollinger-Ellison syndrome. Histopathologic investigation revealed pancreatic adenomatosis of the glucagon producing A2-cells with accompanying B-cell hyperplasia, and hyperplasia of the adrenal cortex. The origin of the increased serum gastrin concentration in this patient is not yet known. The significance of A2-cell proliferation in Zollinger-Ellison syndrome and and in multiple endocrine adenomatosis is discussed.

Topics: Adipose Tissue; Adrenal Cortex; Adrenal Glands; Adult; Calcinosis; Cholecystectomy; Cushing Syndrome; Diabetes Complications; Gastrins; Glucagon; Humans; Hyperplasia; Islets of Langerhans; Male; Multiple Endocrine Neoplasia; Necrosis; Obesity; Pancreas; Zollinger-Ellison Syndrome

A patient is described with recurrent peptic ulceration, evidence of hypersecretion of gastric acid and excess circulating gastrin. The preoperative differentiation between extragastric "gastrinoma" and G-cell hyperplasia of the pyloric antrum as a source for the hypergastrinaemia can be made by immunofluorescent staining of an antral biopsy for "gastrin cells", and by measuring the response of the gastric antrum to an amino acid meal or secretion infusion stimulus. The site of excessive gastrin production determines the nature of the surgery required. A classification of recurrent peptic ulceration types is suggested.

Topics: Amino Acids; Diagnosis, Differential; Gastrectomy; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Zollinger-Ellison Syndrome

Mucosal biopsies from multiple sites in the stomachs of 21 patients with pernicious anaemia have been examined. The histological changes almost always involved the entire gastric mucosa, including that of the pyloric antrum. Metaplastic changes were almost universal and consisted of intestinal metaplasia in the body and antrum and pyloric metaplasia in the body. The severity of the pyloric metaplasia was such as to make the distinction between body and antrum on biopsy impossible. No relationship was found between serum gastrin activity and the histological appearances of the gastric antrum or body.

Topics: Adult; Aged; Anemia, Pernicious; Antibodies; Atrophy; Female; Gastric Mucosa; Gastrins; Gastritis; Humans; Hyperplasia; Intrinsic Factor; Male; Metaplasia; Middle Aged; Pyloric Antrum

Current concepts on the pathophysiology of gastric hypersecretion in duodenal ulcer disease have been presented and the role of vagal nerves and gastrointestinal hormones particularly gastrin has been discussed. Duodenal ulcer patients form a heterogenous group with regard to the gastric acid and pepsin secretion and gastrin release. They may differ from healthy subjects by several wall defined defects including an increased mass of parietal and peptic cells, increased capacity to secrete acid and pepsin, increased vagal drive to the parietal cells, hyperreactivity of antrum, decreased effectiveness of antral and duodenal autoregulatory mechanisms, defective release of secretin, increased gastric emptying and defective removal of gastric acid load from the duodenum. Very little is known what proportion of duodenal ulcer patients suffer from various pathologic disturbences and what are the mechanisms underlying these changes.

Topics: Animals; Duodenal Ulcer; Gastric Juice; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Humans; Hyperplasia; Pyloric Antrum; Rats; Vagus Nerve

Topics: Animals; Gastrins; Hyperplasia; Intestinal Diseases; Intestine, Small; Liver; Liver Diseases; Male; Organ Size; Rats

Topics: Animals; Cortisone; Dogs; Gastric Mucosa; Gastrins; Hyperplasia

The consequences of exposure of the intact stomach to intestinal contents were examined in six dogs. Diversion of duodenal contents through the stomach lead to the following changes: histologic gastritis in both antrum and corpus, increase in resting and postprandial serum gastrin levels, increased parietal cell density in four of six animals, and enhanced maximal acid secretory capacity in three of six animals. No significant changes were seen in insulin-stimulated acid secretion, insulin-stimulated pepsin secretion, antral gastrin levels, or G cell numbers. We conclude that chronic exposure of the intact stomach to duodenal contents results in gastritis and an amplified gastrin response to food. Parietal cell numbers and maximal acid secretory capacity are increased in some animals.

Topics: Animals; Bile; Dogs; Duodenum; Female; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Hyperplasia; Pepsin A

Foregut endocrine polypeptide-secreting APUD cells (Amine-Precursor-Uptake and Decarboxylation), in their embryologic migration from neural crest to foregut may become "arrested" in the mesoderm or in other ectopic locations. They may become hyperplastic, adenomatous or malignant. Eight illustrative patients are reported. One patient had "pancreatic hyperparathyroidism" with hypercalcemic crises, pancreatic apudocarcinoma, normal parathyroids, biologically active parathormone, but inert immunochemically to the usual parathyroid antisera. Two had gastrin-secreting malignancies in the mesoderm. Remission after excision, but eventual recurrence of the syndrome due to islet cell hyperplasia required total gastrectomy. One patient had a gastric corpus apudocarcinoma found prospectively with hypergastrinemia which required excision of the tumor. One patient had acromegaly with hypergastrinemia and antral gastrinosis treated by pituitary irradiation, One patient had the antral or intermediary type of the Zollinger-Ellison syndrome with moderate hypergastrinemia, duodenal ulcer and antral gastrinosis, treated by vagotomy and antrectomy. One patient had hyperparathyroidism with antral gastrinosis, treated by parathyroidectomy. One patient had malignant Zollinger-Ellison syndrome and developed associated thyroid parafollicular cell hyperplasia and parathyroid chief cell hyperplasia, treated by total gastrectomy and multiple endocrine excisions. These investigative observations demonstrate ectopic loci and associated hyperplasias which support the concept of migration and bizarre potentiality of polypeptide-secreting cells of the foregut.

Topics: Adenoma; Adult; Aged; Amines; Child; Decarboxylation; Endocrine System Diseases; Endoderm; Female; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasms; Pancreatic Neoplasms; Parathyroid Diseases; Parathyroid Hormone; Peptides; Stomach Neoplasms; Zollinger-Ellison Syndrome

Rats surgically prepared with the antrum transposed onto the colon were compared with suitable control rats, to investigate whether chronic antral stimulation modifies gastrin cell and other endocrine cell populations. Gastrin cell and argyrophil cell density per unit area were studied in antrum using a quantitative method after staining by immunofluorescence and Grimelius argyrophily, respectively. Both gastrin cells and argyrophil cells increased significantly in density per unit area after antrocolic transposition (P smaller than 0.001). The augmentation of gastrin cells per glandular tube (78%) was also significant (P smaller than 0.001). Electron-microscopic observations confirmed these results. On the other hand, in each group, the topographic distribution of the two categories of cells was different, and the number of gastrin cells was statistically greater than that of the argyrophil cells. Thus, it appeared evident that gastrin cells were not argyrophilic. Several hypotheses to explain the mechanism of this hyperplasia of endocrine cells are discussed. It is concluded that the increase in the gastrin cell density could be one possible explanation for the hypergastrinemia observed in the antrocolic transposition model.

Topics: Animals; Cell Count; Colon; Feedback; Fluorescent Antibody Technique; Gastric Juice; Gastric Mucosa; Gastrins; Hyperplasia; Immune Sera; Male; Microscopy, Electron; Pyloric Antrum; Rabbits; Rats; Silver

Topics: Anemia, Pernicious; Bicarbonates; Duodenal Ulcer; Endocrine System Diseases; Esophagitis, Peptic; Esophagus; Gastric Juice; Gastrins; Humans; Hyperplasia; Intestines; Kidney Failure, Chronic; Pancreas; Pheochromocytoma; Pyloric Antrum; Stomach; Stomach Neoplasms; Stomach Ulcer; Vagotomy; Zollinger-Ellison Syndrome

Topics: Animals; Gastrins; Hyperplasia; Intestine, Small; Mice; Mice, Obese; Secretin

Topics: Animals; Cattle; Duodenal Ulcer; Fasting; Fluorescent Antibody Technique; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Meat; Peptic Ulcer; Pyloric Antrum; Radioimmunoassay; Recurrence; Tissue Extracts

Topics: Duodenal Ulcer; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Pyloric Antrum; Syndrome; Zollinger-Ellison Syndrome

Topics: Gastric Acidity Determination; Gastrins; Humans; Hyperplasia; Precancerous Conditions; Pyloric Antrum; Stomach; Stomach Neoplasms; Stomach Ulcer

Topics: Biopsy; Duodenal Ulcer; Gastric Juice; Gastrins; Humans; Hyperplasia; Meat; Peptic Ulcer; Postoperative Complications; Pyloric Antrum; Radioimmunoassay; Recurrence; Tissue Extracts; Zollinger-Ellison Syndrome

Topics: Gastrins; Humans; Hyperplasia; Peptic Ulcer; Pyloric Antrum; Radioimmunoassay; Recurrence; Stomach Ulcer; Terminology as Topic; Zollinger-Ellison Syndrome

Topics: Child; Duodenal Neoplasms; Duodenum; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Hyperplasia; Male; Microscopy, Electron; Pancreas; Pylorus; Serotonin; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Achlorhydria; Diagnosis, Differential; Duodenal Ulcer; Fasting; Gastrectomy; Gastrins; Humans; Hyperplasia; Malabsorption Syndromes; Male; Middle Aged; Pancreatic Neoplasms; Peptic Ulcer; Stomach Diseases; Zollinger-Ellison Syndrome

Topics: Animals; Dogs; Gastric Juice; Gastrins; Hyperplasia; Metabolic Diseases; Molecular Weight; Pyloric Antrum; Radioimmunoassay; Secretin

Topics: Cholecystokinin; Diarrhea; Gastric Juice; Gastrins; Humans; Hyperplasia; Pancreatic Diseases; Peptides; Stomach

Although histochemical, immunohistochemical, and electron microscopic methods have led to the identification of a large variety of endocrine cells in the upper gastrointestinal mucosa, no conventional light microscopic technique capable of the simultaneous identification of these cells has been reported. Such a staining method would be of considerable value to the pathologist as the malfunction of the endocrine cells of the gut, which produce numerous digestive hormones and biogenic amines, is closely related to a number of clinical conditions afflicting man. In this work, after testing three different polychrome staining methods, it has been concluded that a slightly modified Herlant's tetrachrome in tissues fixed in Zenker-formol is the procedure of choice. This method allows the distinction of several different cell types in the upper gastrointestinal mucosa of man and dog and permits the easy identification of the gastrin-producing cells on a routine basis. This identification has been confirmed in the case of two patients with gastrin cell hyperplasia, seen by both light and electron microscopy. Herlant's tetrachrome has proven valuable in the screening of human as well as experimental gastrointestinal tissues and it has been found to be very suitable for recognizing gastrin-producing cell hyperplasias. The usefulness of this method is expected to increase with the establishment of further correlations between the light and electron microscopy of the endocrine cells of the gut.

Topics: Adenocarcinoma; Animals; Chromates; Dogs; Duodenal Ulcer; Duodenum; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Intestinal Mucosa; Methods; Microscopy, Electron; Peptic Ulcer; Staining and Labeling; Stomach Neoplasms

Topics: Adenoma, Islet Cell; Duodenal Neoplasms; Follow-Up Studies; Gastrectomy; Gastric Acidity Determination; Gastrins; Humans; Hyperplasia; Lymph Node Excision; Lymphatic Metastasis; Male; Methods; Pancreatic Neoplasms; Vagotomy; Zollinger-Ellison Syndrome

Some patients with the Zollinger-Ellison syndrome appear to have hypergastrinaemia and hyperplasia of the antral G cells but no tumour. This subgroup has been classified as Zollinger-Ellison syndrome type 1. We have treated such a patient by vagotomy and antrectomy, the fasting plasma gastrin and acid secretion subsequently returning to normal.A 17-year-old male had a four-year history of duodenal ulcer. Gastric secretion tests showed acid hypersecretion. Fasting plasma gastrin was 8350 pg/ml (normal 50-170 pg/ml). At laparotomy duodenal ulceration was confirmed but no pancreatic or other tumours were found. Truncal vagotomy and antrectomy was performed with distal pancreatectomy. Immunofluorescent staining showed hyperplasia of G cells in the resected antrum but a normal pancreas and duodenum. Six months after operation he was symptom free and acid secretion was reduced by 92%. The fasting plasma gastrin at two months was <50 pg/ml. These findings suggest that type 1 Zollinger-Ellison syndrome may be a clinical entity.

Topics: Adolescent; Duodenal Ulcer; Fluorescent Antibody Technique; Gastric Juice; Gastrins; Humans; Hyperplasia; Islets of Langerhans; Male; Microscopy, Electron; Pancreas; Pyloric Antrum; Vagotomy; Zollinger-Ellison Syndrome

Topics: Duodenal Ulcer; Gastrins; Humans; Hyperplasia; Meat; Peptic Ulcer; Pyloric Antrum; Recurrence

Topics: Biological Assay; Diagnosis, Differential; Gastrectomy; Gastrins; Humans; Hyperplasia; Methods; Peptic Ulcer; Postoperative Care; Zollinger-Ellison Syndrome

Topics: Epithelial Cells; Gastric Mucins; Gastric Mucosa; Gastrins; Glycoproteins; Histocytochemistry; Humans; Hyperplasia; Microscopy, Electron; Pepsinogens; Staining and Labeling; Stomach; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adult; Calcium; Duodenal Ulcer; Gastric Juice; Gastrins; Humans; Hypercalcemia; Hyperparathyroidism; Hyperplasia; Male; Neoplasm Metastasis; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adult; Aged; Biopsy; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Microscopy, Electron; Middle Aged; Pedigree; Pituitary Neoplasms; Prospective Studies; Pyloric Antrum; Thyroid Neoplasms; Zollinger-Ellison Syndrome

Topics: Adrenal Gland Diseases; Endocrine System Diseases; Erythrocytes; Female; Gastrins; Gynecomastia; Hormones, Ectopic; Humans; Hypercalcemia; Hyperplasia; Hyperthyroidism; Hypoglycemia; Male; Malignant Carcinoid Syndrome; Metabolic Diseases; Neoplasms; Neurologic Manifestations; Polycythemia; Prognosis; Puberty, Precocious; Vasopressins

Topics: Adolescent; Duodenal Ulcer; Gastrectomy; Gastric Juice; Gastrins; Humans; Hyperplasia; Male; Pylorus; Vagotomy; Zollinger-Ellison Syndrome

Topics: Duodenal Ulcer; Gastrectomy; Gastrins; Humans; Hyperplasia; Islets of Langerhans; Male; Middle Aged; Pancreatectomy; Pancreatic Diseases; Vagotomy; Zollinger-Ellison Syndrome

Topics: Adenoma; Animals; Biopsy; Cell Count; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Hyperparathyroidism; Hyperplasia; Microscopy; Microscopy, Electron; Parathyroid Neoplasms; Peptides; Pylorus; Rabbits; Television; Thyroid Diseases

Examination of human gastric biopsies by an indirect immunofluorescence technique using antihuman gastrin confirms the variability in distribution and number of gastrin-secreting (G) cells (Solcia, Vassallo, and Capella, 1969) observed by morphological, cytochemical, and electron microscopical studies. In cases with presumed secondary hypersecretion a profound degree of G-cell hyperplasia is observed. Immunofluorescence with. antigastrin can provide valuable information on the state of the G cells in different physiological states, particularly if used in conjunction with other cytochemical techniques.

Topics: Adult; Animals; Biopsy; Female; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Rabbits

Topics: Animals; Gastric Fistula; Gastric Juice; Gastric Mucosa; Gastrins; Histamine; Hyperplasia; Male; Rats; Secretory Rate

Topics: Adenocarcinoma; Adenoma; Aortography; Diagnosis, Differential; Diarrhea; Gastrectomy; Gastric Juice; Gastrins; Gastrointestinal Hemorrhage; Gastrointestinal Motility; Humans; Hyperplasia; Intestine, Small; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Adult; Diagnosis, Differential; Gastrectomy; Gastric Acidity Determination; Gastric Juice; Gastrins; Humans; Hyperplasia; Male; Stomach Neoplasms; Zollinger-Ellison Syndrome