Long-term safety of proton pump inhibitors: risks of gastric neoplasia and infections

After Helicobacter pylori eradication was introduced and largely eliminated the need for maintenance therapy for peptic ulcer disease, gastroesophageal reflux disease (GERD) became the main indication for prolonged gastric acid inhibition. The drug effect on GERD depends on the degree of acid inhibition, thus the efficacious proton pump inhibitors are preferred. The proton pump inhibitors have few immediate side effects, the main concern being the profound hypoacidity and hypergastrinaemia they induce. In short-term, hypergastrinaemia causes rebound hyperacidity, possibly worsening GERD and reducing the efficacy of histamine H₂ blockers. In the long-term, hypergastrinaemia causes enterochromaffin-like cell hyperplasia and carcinoids. Since enterochromaffin-like cells may be important in gastric carcinogenesis, iatrogenic hypergastrinaemia may predispose to carcinoma. Gastric hypoacidity also increases gut bacterial infections, and the barrier function of acid against viral and prion infections requires further assessment.     

Sphincter of oddi manometry in patients with acute biliary pancreatitis: evidence for sphincter of oddi dysfunction in acute biliary pancreatitis

We calculated morphometrically the amount of antral gastrin-producing (G) cells and body parietal and chief cells in gastric biopsy specimens from 30 undialysed patients with chronic renal failure (CRF) and from sex- and age-matched controls. The CRF patients had raised fasting serum gastrin levels, whereas these were normal in the controls (mean, 290 ± 283 (±SD) ng/1 (n = 27) versus 33 ± 36 (n = 30)). Serum gastrin values of the patients and controls correlated positively with G-cell density (r = 0.501, n = 36, p = 0.002), as did the maximal acid output of the CRF patients with parietal cell density (r = 0.617, n = 14, p = 0.019). In CRF patients the densities of G, parietal, and chief cells were higher than those in the controls (G cells, 351 ± 151 (±SD) cells/mm², n = 21 versus 211 ± 90, n = 16, p = 0.002; parietal cells, 299 ± 94, n = 15 versus 224 ±72, n = 14, p = 0.025; chief cells, 886 ± 346, n = 15 versus 743 ± 182, n = 14, p = 0.181). The results agree with previous findings indicating that hyposecretion of gastric acid in CRF does not derive from decreased capacity for acid secretion but rather from the inhibition of acid output. Increased parietal cell density in CRF patients gives cause to suspect that the maximum acid output might even be raised, possibly depending on the permanent hypergastrinaemic state with its trophic influence on the gastric body mucosa.     

The protective effects of calcitonin gene-related peptide on gastric mucosa injury of gastric ischemia reperfusion in rats

Gastric mucosa is one of the most vulnerable tissues in human and animal. However, little is known about the effects of calcitonin gene-related peptide (CGRP) on gastric mucosa injuries induced by gastric ischemia reperfusion. The purpose of the present study was to investigate the protective effects and mechanism of CGRP on gastric mucosa injury after gastric ischemia reperfusion in rats. Thirty-six healthy Wistar rats were randomly divided into CGRP-treated, sham-operated, and control groups. Twelve rats were involved in each group. These groups were further divided into 24-h and 48-h subgroups. Gastric ischemia reperfusion injury (GI-RI) rat model was established by a 30-min celiac artery occlusion by an artery clamp, followed by 24?h or 48?h of reperfusion. CGRP (1?μg/ml) at the dose of 3?μg/kg was given intraperiloneally (IP) at the beginning of reperfusion for rats in CGRP-treated group. Saline as vehicle (3?ml/kg body weight), IP, was administered at the beginning of reperfusion for rats in control group. Sham-operated animals were subjected to an operation without GI-RI. Twenty-four hours or 48?h after operation, the samples were taken out and processed for calculating stomach mucous membrane damage index according to Guth method, detecting pathological changes of gastric mucosa tissue by light microscopy and observing the expression of gastrin (Gas) and somatostatin (SST) by immunohistochemical staining. The results showed the following: (i) gastric mucosa with diffuse edema, splinter hemorrhage and erosion, numerous endothelial cells necrosis, mucosa dissociation, and infiltration of inflammatory cells were observed in both control and CGRP-treated animals, especially in the earlier period (24?h) and then gradually healing. CGRP administration could reduce the damage of gastric mucosa. The injury index of gastric mucosa was lower in CGRP-treated group as compared with that in control group (P?<?0.01). (ii) Gas expression in gastric antrum mucosa was lower in CGRP-treated group than that in control group (P?<?0.01). SST expression in gastric antrum mucosa was higher in CGRP-treated group than that in control group (P?<?0.01). It is concluded that CGRP regulated the secretion of Gas and SST and thus alleviated the damage of gastric mucosa induced by ischemia and reperfusion. CGRP might be a potential candidate for clinical therapy on modulating gastric mucosal protection and maintaining gastric mucosal integrity after ischemia and reperfusion of the stomach.     

Bioassay and Radioimmunoassay of Plasma Gastrin in a Case of Zollinger-Ellison Syndrome

Fasting plasma gastrin levels were measured in a patient with the Zollinger-Ellison syndrome by both bioassay and radioimmunoassay. The level remained constant following total gastrectomy, but fell sharply following parathyroidectomy. Although the bioassay gave gastrin levels which were consistently 2 to 3 times higher than those obtained by radioimmunoassay, the values showed a similar trend. However, both methods gave almost identical results for the gastrin contents of antral mucosa and pancreatic tumour samples from the patient. It is suggested that biologically active gastrin-like substances not detectable by radioimmunoassay were present in the patient's plasma.     

Clinical consequences of controversies in gastric physiology

Abstract

Studies on the regulation of gastric acid secretion started more than 100 years ago at an early phase of experimental physiology. In nearly the whole last century there were disputes about the interpretation of the findings: the interaction between the three principle gastric acid secretagogues acetylcholine, gastrin and histamine, the cell producing the relevant histamine which turned out to be the ECL cell, the ability of the ECL cell to divide and thus develop into tumours, the classification of gastric carcinomas and the mechanism for Helicobacter pylori carcinogenesis. The elucidation of the central role of the ECL cell and thus its main regulator, gastrin, solve all these controversies, and gives a solid base for handling upper gastrointestinal diseases.     

Altered Gastrin Regulation in Mice Infected with Helicobacter felis

Altered gastrin expression associated with Helicobacter pylori infection may contribute to the pathogenesis of peptic ulcer disease or gastric cancer in man, but gastrin has not been investigated in a murine model of Helicobacter infection. C57BL/6 mice were inoculated with Helicobacter felis and examined after 4–21 weeks for G and D cell numbers, antral gastrin and somatostatin mRNA, and luminal pH. In H. felis-infected mice, gastrin mRNA declined at four and six weeks after infection to 57% and 23%, respectively, of uninfected control values. Concurrently, somatostatin mRNA showed no change at four weeks and a modest 25% decrease at six weeks after infection. Similar reductions were noted in G and D cell numbers, resulting in a decrease in the G/D cell ratio after mice were infected with H. felis. Infected animals also showed a loss of parietal and chief cells, and an increased gastric pH. H. felis infection in C57BL/6 mice leads to an early suppression of G cell number and gastrin mRNA. These changes precede an alteration in somatostatin cell number and mRNA and, coupled with reductions in parietal and chief cells, may contribute both to severe impairment of gastric acid output and the potential for carcinogenic processes.     

Helicobacter pylori and gut hormones

Helicobacter pylori infection has been found to decrease the expression of antral somatostatin and to increase the release of the acid-stimulating hormone gastrin. The reversal of these changes in gut hormones by the eradication of H. pylori, and in-vivo and in-vitro studies in animals either infected with H. pylori or exposed to H. pylori-related materials may support the somatostatin-gastrin link theory in the pathophysiology of H. pylori infection. The following mechanisms have been proposed to explain the H. pylori infection-associated changes in gut hormones; (1) ammonia produced by H. pylori and monochloramine, (2) effect on somatostatin receptor subtype-2, (3) action of lipopolysaccharide from H. pylori on somatostatin receptor, (4) inflammatory cells and mediators, and (5) bacterial strain diversity. H. pylori infection can alter gastric acid secretion in both directions. The elevated acid secretion in patients with duodenal ulcer is decreased by H. pylori eradication, and is accompanied by the normalization of gut hormones in patients whose H. pylori-induced gastritis is limited to the antrum with hyperacidity. Corpus gastritis and the subsequent development of mucosal atrophy induced by H. pylori result in decreased acid secretion, although the mechanism underlying H. pylori-induced atrophy in some subjects remains unclear. Hypoacidity enhances corpus atrophy and increases gastrin secretion, mediated via a physiological suppression of somatostatin release, features that are also observed in H. pylori infection. Therefore, the capacity of acid secretion and distribution of gastritis or atrophy should be taken into consideration when we discuss the affect of H. pylori on gut hormones. Received: October 1, 2001 / Accepted: November 30, 2001     

Elevated gastric acid secretion in patients with Barrett's metaplastic epithelium

Gastric acid secretion in response to a protein meal and to exogenously administered synthetic human gastrin 17-I was measured in patients with Barrett's esophagus, patients with uncomplicated gastroesophageal reflux, and normal age- and sex-matched controls. Acid secretion, both basally and in response to gastrin 17-I, was significantly greater in patients with Barrett's esophagus compared to normal individuals without reflux. Basal gastrin levels and meal-stimulated levels of the hormone were similar among all three groups. Sensitivity to gastrin, expressed as the concentration causing half-maximal acid secretion, was also similar among the study groups. It is speculated that elevated basal acid production in Barrett's esophagus may contribute to the pathogenesis of the disorder.Study supported by Smith, Kline, and French, Inc.     

Helicobacter pylori independent chronological change in gastric acid secretion in the Japanese

Background—Gastric acid secretion in Japanesesubjects decreases with aging. One of the possible causative mechanismsof this attenuated acid secretion is speculated to be aHelicobacter pylori induced chronic gastritis. Theinfection rate of this microorganism has decreased recently in Japan.
Aims—To investigate whether gastric acidsecretion has altered over the past 20 years, and if so, what theinfluence of H pylori infection might be in the Japanese population.
Subjects and methods—Gastric acid secretion, serumgastrin and pepsinogen I and II concentrations, and Hpylori infection were determined in 110 Japanese subjects inboth the 1970s and 1990s.
Results—Basal acid output as well as maximal acidoutput have greatly increased over the past 20 years, not only inindividuals with H pylori infection but also in thosewithout infection. Furthermore, subjects with H pyloriinfection tended to show decreased gastric acid secretion in comparisonwith those without infection, particularly in geriatric subjects. Therewas a positive correlation between gastric acid secretion and serumpepsinogen I concentrations.
Conclusions—In Japan, both basal andstimulated gastric acid secretion have increased over the past 20 years; some unknown factors other than the decrease in Hpylori infection may play an important role in this phenomenon.

Keywords:gastric acid; Helicobacter pylori; aging; gastrin