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Gerd: increased gastric acid secretion as a possible cause of gerdIncreased gastric acid secretion as a possible
cause of GERD
Jerry D. Gardner
Many experts maintain that gerD is caused by dysfunction of the gastroesophageal barrier and that gastric acid secretion is not the primary underlying defect. By contrast, a recent study by reimer and colleagues raises the possibility that increased gastric acid secretion is an important cause of gerD.
reimer and colleagues1 report results from treatment is stopped, the increased numbers of parietal and enterochromaffin cel s then stopping the PPi would lead to increased controlled study of healthy individuals who amplify the effects of normal physiologic symptoms of GerD, reimer et al., under- received 40 mg daily doses of the PPi eso- stimuli on gastric acid secretion. the results standably, did not measure 24 h gastric and meprazole or placebo for 8 weeks, followed esophageal pH at baseline and after with- by placebo for 4 weeks in both groups. of also support the hypothesis that the symp- 59 individuals who received esomeprazole, toms of GerD can be triggered in healthy gastric acidity and increased esophageal 26 (44%) experienced at least one episode of individuals simply by increasing gastric acid exposure. interpretation of the authors’ clinical y significant heartburn, dyspepsia findings, therefore, depends critically on or acid regurgitation during weeks 9–12, in two important studies that assessed changes contrast with nine of 59 (15%) individuals in basal and gastrin-stimulated gastric acid who received placebo. at weeks 10, 11 and esophageal barrier and that gastric acid secretion in healthy individuals before and 12 the percentage of individuals with clini- after 8 weeks of daily treatment with 40 mg cally significant heartburn, dyspepsia or defect.2 a few studies have, however, raised omeprazole, another PPi.3,4 evidence for acid regurgitation was 21–22% for the eso- the possi bility of a link between increased rebound hypersecretion of gastric acid from meprazole group and 2–7% for the placebo gastric acid secretion and GerD,2 but the these studies was not strong10 and although importance of these findings has been diffi- both studies showed a significant increase in tions at weeks 4 and 8 were significantly cult to determine and they have been largely gastrin-stimulated gastric acid output, only higher in the esomeprazole group than in ignored. although one study reported that one8 showed a signifi cant increase in basal the placebo group, although all values were basal or pentagastrin-stimulated gastric acid acid output after omeprazole treatment.
secretion in esophagitis was compar able gastric concentrations in the esomeprazole to that in unspecified medical conditions group returned to baseline after treatment without esophagitis,5 other studies have was stopped. Fasting plasma concentrations reported increased basal, peak or maximal tively (Figure 1; even though the authors of chromogranin a, an indirect measure of gastric acid secretion in patients with GerD report that 12 indivi duals were studied enterochromaffin cell mass, were signifi- compared with that in healthy individuals.6–8 for gastrin- stimulated acid output, i could cantly higher at weeks 8 and 12 in indivi- meal-stimulated gastric acid secretion and only find data for 11 individuals in Figure 2 postprandial gastric acidity were also found of their article).8 15 days after the 8-week to be significantly increased in patients with stopped, 10 individuals showed an increase and two showed a decrease in basal gastric since not al individuals experienced acid- acid output (Figure 1a), while 10 indivi- with eso meprazole resulted from rebound hyper secretion of gastric acid that occurred a decrease in gastrin-stimulated gastric after the PPi treatment was stopped.2–4 the acid output (Figure 1b). the study did not explana tion for rebound acid hyper secretion all treated individuals, might only trigger include a control group of indivi duals receiv- is that PPis cause hypergastrinemia, which clinical y rele vant symptoms in those with ing placebo. if it had, one would expect that in turn causes hyperplasia of gastric parietal pre- existing lower esophageal sphincter half of the participants, on average, would cells (which secrete acid) and also hyper- dysfunction and a predisposition to reflux. have higher gastric acid output and half an equal y likely explanation is that only a would have lower output than their corre- mediate the action of gastrin on acid secre- fraction of individuals experienced rebound sponding baseline output. in that case, the differences in gastric acid output between nature reviews | gastroenterology & hepatology volume 7 | marCH 2010 | 125
0 Macmil an Publishers Limited. Al rights reserved The author declares an association with the following company: science for Organizations. see the article online for full details of the relationship.
1. Reimer, C., søndergaard, B., Hilsted, L. & Bytzer, P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2. McColl, K. e. & Gillen, D. evidence that proton- pump inhibitor therapy induces the symptoms it is used to treat. Gastroenterology 137, 20–22 3. Gillen, D., wirz, A. A., Ardill, J. e. & McColl, K. e. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology Figure 1 | Gastric acid output measured at baseline and 15 days after stopping 8 weeks of
treatment with omeprazole in healthy individuals not infected with Helicobacter pylori. Points 4. Gillen, D., wirz, A. A. & McColl, K. e. above the diagonal line (identity line) indicate that the value after omeprazole treatment is Helicobacter pylori eradication releases higher than the corresponding baseline value and points below the identity line indicate the prolonged increased acid secretion following opposite. The magnitude of the difference between post-omeprazole and baseline values is omeprazole treatment. Gastroenterology 126, given by either the vertical or the horizontal distance between the point and the identity line. 5. Hirschowitz, B. i. A critical analysis, with a | Basal gastric acid output, 12 individuals. b | Gastrin-stimulated gastric acid output, 11
appropriate controls, of gastric acid and pepsin individuals. values were estimated from Figures 1 and 2 in Gillen et al.3 secretion in clinical esophagitis. Gastroenterology 101, 1149–1158 (1991).
6. Collen, M. J., Lewis, J. H. & Benjamin, s. B. controls would not be significant because of of treatment with either a PPi or placebo. Gastric acid hypersecretion in refractory gastroesophageal reflux disease. the small sample size (P = 0.19 and P = 0.07, the authors found that the prevalence of Gastroenterology 98, 654–661 (1990).
calculated by Fisher’s exact test, for basal clinical y relevant heartburn, dyspepsia or 7. Collen, M. J. & Johnson, D. A. Correlation and gastrin-stimulated gastric acid output acid regurgitation was significantly higher between basal acid output and daily ranitidine after stopping the PPi than after stopping dose required for therapy in Barrett’s esophagus. Dig. Dis. Sci. 37, 570–576 (1992).
that half of the individuals receiving placebo placebo. these findings raise the possibil- 8. Johansson, K. e., Ask, P., Boeryd, B., would show an increase in basal acid output ity that increased gastric acid secretion is a Fransson, s. G. & Tibbling, L. Oesophagitis, and in gastrin-stimulated acid output after signs of reflux, and gastric acid secretion in patients with symptoms of gastro-oesophageal the placebo was stopped, a sample size of Future studies should try to measure symp- reflux disease. Scand. J. Gastroenterol. 21, 40 in each group would be required to have 90% power to detect the increase in basal expand on the very important findings by 9. Gardner, J. D., sloan, s., Miner, P. B. Jr & Robinson, M. Meal-stimulated gastric acid acid output illustrated in Figure 1a with a secretion and integrated gastric acidity in signifi cance level of 0.05. similarly, a sample gastro-oesophageal reflux disease. Aliment. size of 25 in each group would be required Science for Organizations Inc., 75 DeSilva Pharmacol. Ther. 17, 945–953 (2003).
Island Drive, Mill Valley, CA 94941, USA. to have 90% power to detect the increase in 10. Hunfeld, n. G., Geus, w. P. & Kuipers, e. J. systematic review: rebound acid hypersecretion gastrin-stimulated acid output illustrated after therapy with proton pump inhibitors. in Figure 1b with a significance level of 0.05.
Aliment. Pharmacol. Ther. 25, 39–46 (2007).
the six points closest to the identity line in Figure 1a or the five points closest to the identity line in Figure 1b represent Bacterial clearance in Crohn’s
acid output that would be likely to induce disease pathogenesis
these results suggests that only a fraction of the individuals treated with the PPi in fested acid-related symptoms because they evidence from a recent study strongly implicates innate immunity in the were the only participants that developed etiology of Crohn’s disease, with particular focus on impaired secretion a suffi ciently high rebound gastric acid of cytokines and chemokines by intestinal macrophages in response hyper secretion to lead to an increase in to bacterial stimuli. these findings highlight the importance of acute inflammatory responses in the first stages of disease pathogenesis.
induced rebound gastric acid hypersecretion have lacked appropriate control groups.10 Crohn’s disease is a chronic form of iBD that affects one in 1,000 adults. owing to its characteristic inflammatory symptoms are, however, known to arise from defects in the ing gastroesophageal symptoms in healthy lying the initial manifestation of disease epithelial barrier and the mucosal immune 126 | MARCH 2010 | voluMe 7
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