Acid secretion from gastric parietal cells is a result of a complex interaction between different stimulatory and inhibitory mediators. One of the most important mediators is gastrin, which stimulates gastric acid secretion from parietal cells mostly indirectly, by the release of histamine from enterochromaffin-like (ECL) cells. Therapy with antisecretory agents leads to hypergastrinemia, mucosal hyperplasia and increased ECL cell mass, which results in increase of gastric acid secretion capacity. This increased secretion capacity has been shown to manifest itself after antisecretory therapy withdrawal as rebound acid hypersecretion (RAH). Various studies have quantified acid hypersecretion after the cessation of therapy with H2 antagonists and proton-pump inhibitors (PPIs). While most of those studies had small patient numbers, the findings generally demonstrate that RAH after H2 antagonist therapy is of low magnitude, short duration, and has questionable clinical significance. On the contrary, acid hypersecretion after PPI therapy is more pronounced, lasts longer, and could possibly be the cause of acid-related symptoms. Potential for causing symptoms has recently been confirmed in two randomized placebo-controlled studies, and while we witness the increasing use of PPIs, RAH could become a proven cause of failure to withdraw therapy in a proportion of patients with reflux or dyspeptic symptoms.

1.
Schubert ML, Peura DA: Control of gastric acid secretion in health and disease. Gastroenterology 2008;134:1842–1860.
2.
Kidd M, Modlin IM, Tang LH: Gastrin and the enterochromaffin-like cell: an acid update. Dig Surg 1998;15:209–217.
3.
Waldum HL, Sandvik AK, Brenna E, Petersen H: Gastrin-histamine sequence in the regulation of gastric acid secretion. Gut 1991;32:698–701.
4.
Chen D, Monstein HJ, Nylander AG, Zhao CM, Sundler F, Håkanson R: Acute responses of rat stomach enterochromaffin-like cells to gastrin: secretory activation and adaptation. Gastroenterology 1994;107:18–27.
5.
Lindström E, Chen D, Norlén P, Andersson K, Håkanson R: Control of gastric acid secretion: the gastrin-ECL cell-parietal cell axis. Comp Biochem Physiol A Mol Integr Physiol 2001;128:505–514.
6.
Bakke I, Qvigstad G, Sandvik AK, Waldum HL: The CCK-2 receptor is located on the ECL cell, but not on the parietal cell. Scand J Gastroenterol 2001;36:1128–1133.
7.
Crean GP, Marshall MW, Rumsey RD: Parietal cell hyperplasia induced by the administration of pentagastrin (ICI 50,123) to rats. Gastroenterology 1969;57:147–155.
8.
Willems G, Vansteenkiste Y, Limbosch JM: Stimulating effect of gastrin on cell proliferation kinetics in canine fundic mucosa. Gastroenterology 1972;62:583–589.
9.
Waldum HL, Brenna E, Sandvik AK: Relationship of ECL cells and gastric neoplasia. Yale J Biol Med 1998;71:325–335.
10.
Bakke I, Qvigstad G, Brenna E, Sandvik AK, Waldum HL: Gastrin has a specific proliferative effect on the rat enterochromaffin-like cell, but not on the parietal cell: a study by elutriation centrifugation. Acta Physiol Scand 2000;169:29–37.
11.
Isenberg JI, Grossman MI, Maxwell V, Walsh JH: Increased sensitivity to stimulation of acid secretion by pentagastrin in duodenal ulcer. J Clin Invest 1975;55:330–337.
12.
Petersen H, Myren J: Pentagastrin dose-response in peptic ulcer disease. Scand J Gastroenterol 1975;10:705–714.
13.
Levi S, Beardshall K, Haddad G, Playford R, Ghosh P, Calam J: Campylobacter pylori and duodenal ulcers: the gastrin link. Lancet 1989;1:1167–1168.
14.
Kohn A, Annibale B, Prantera C, Giglio L, Suriano G, Delle Fave G: Reversible sustained increase of gastrin and gastric acid secretion in a subgroup of duodenal ulcer patients on long-term treatment with H2 antagonists. J Clin Gastroenterol 1991;13:284–290.
15.
Saffouri B, DuVal JW, Arimura A, Makhlouf GM: Effects of vasoactive intestinal peptide and secretin on gastrin and somatostatin secretion in the perfused rat stomach. Gastroenterology 1984;86:839.
16.
Soll AH, Berglindh T: Receptors regulating acid secretory function; in Johnson LR, Alpers DH, Christensen J, et al (eds): Physiology of the Gastrointestinal Tract. New York, Raven Press, 1994.
17.
Shulkes A, Read M: Regulation of somatostatin secretion by gastrin- and acid-dependent mechanisms. Endocrinology 1991;129:2329.
18.
Waldum HL, Lehy T, Brenna E, et al: Effect of the histamine-1 antagonist astemizole alone or with omeprazole on rat gastric mucosa. Scand J Gastroenterol 1991;26:23–35.
19.
Ryberg B, Tielemans Y, Axelson J, et al: Gastrin stimulates the self-replication rate of enterochromaffin-like cells in the rat stomach. Effects of omeprazole, ranitidine, and gastrin-17 in intact and antrectomized rats. Gastroenterology 1990;99:935–942.
20.
Larsson H, Carlsson E, Ryberg B, Fryklund J, Wallmark B: Rat parietal cell function after prolonged inhibition of gastric acid secretion. Am J Physiol 1988;254:G33–G39.
21.
Sandvik AK, Brenna E, Waldum HL: Review article: the pharmacological inhibition of gastric acid secretion – tolerance and rebound. Aliment Pharmacol Ther 1997;11:1013–1018.
22.
Waldum HL, Qvigstad G, Fossmark R, Kleveland PM, Sandvik AK: Rebound acid hypersecretion from a physiological, pathophysiological and clinical viewpoint. Scand J Gastroenterol 2010;45:389–394.
23.
Reimer C, Søndergaard B, Hilsted L, Bytzer P: Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009;137:80–87.
24.
Frislid K, Aadland E, Berstad A: Augmented postprandial gastric acid secretion due to exposure to ranitidine in healthy subjects. Scand J Gastroenterol 1986;21:119–122.
25.
Fullarton GM, McLauchlan G, Macdonald A, Crean GP, McColl KE: Rebound nocturnal hypersecretion after four weeks treatment with an H2 receptor antagonist. Gut 1989;30:449–454.
26.
Nwokolo CU, Smith JT, Sawyerr AM, Pounder RE: Rebound intragastric hyperacidity after abrupt withdrawal of histamine H2-receptor blockade. Gut 1991;32:1455–1460.
27.
Prewett EJ, Hudson M, Nwokolo CU, Sawyerr AM, Pounder RE: Nocturnal intragastric acidity during and after a period of dosing with either ranitidine or omeprazole. Gastroenterology 1991;100:873–877.
28.
El-Omar E, Banerjee S, Wirz A, Penman I, Ardill JE, McColl KE: Marked rebound acid hypersecretion after treatment with ranitidine. Am J Gastroenterol 1996;91:355–359.
29.
Lind T, Cederberg C, Forsell H, Olausson M, Olbe L: Relationship between reduction of gastric acid secretion and plasma gastrin concentration during omeprazole treatment. Scand J Gastroenterol 1988;23:1259–1266.
30.
Lamberts R, Creutzfeldt W, Stöckmann F, Jacubaschke U, Maas S, Brunner G: Long-term omeprazole treatment in man: effects on gastric endocrine cell populations. Digestion 1988;39:126–135.
31.
Klinkenberg-Knol EC, Festen HP, Jansen JB, Lamers CB, Nelis F, Snel P, Lückers A, Dekkers CP, Havu N, Meuwissen SG: Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety. Ann Intern Med 1994;121:161–167.
32.
Waldum HL, Arnestad JS, Brenna E, Eide I, Syversen U, Sandvik AK: Marked increase in gastric acid secretory capacity after omeprazole treatment. Gut 1996;39:649–653.
33.
Gillen D, Wirz AA, Ardill JE, McColl KE: Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology 1999;116:239–247.
34.
El-Omar EM, Oien K, El-Nujumi A, Gillen D, Wirz A, Dahill S, Williams C, Ardill JE, McColl KE: Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology 1997;113:15–24.
35.
Fossmark R, Johnsen G, Johanessen E, Waldum HL: Rebound acid hypersecretion after long-term inhibition of gastric acid secretion. Aliment Pharmacol Ther 2005;21:149–154.
36.
Niklasson A, Lindström L, Simrén M, Lindberg G, Björnsson E: Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebo-controlled trial. Am J Gastroenterol 2010;105:1531–1537.
37.
Haefner M: Differential diagnosis: overlap between GERB and IBS; in Duvnjak M (ed): Dyspepsia in Clinical Practice. New York, Springer, 2011.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.