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Gut. 2007 July; 56(7): 1020.
PMCID: PMC1994384

Author's response

In theory, profound acid suppression can promote the development of gastric neoplasia via various pathways, including the trophic effect of hypergastrinaemia on the epithelial lining, stimulation of enterochromaffin‐like (ECL) cells leading to formation of carcinoids and neuroendocrine carcinomas, promotion of bacterial overgrowth and induction of a chronic active Helicobacter pylori pan‐gastritis pattern. Waldum et al focus on the theoretical implications of hypergastrinaemia and ECL cell stimulation, a relevant hypothesis that has often been discussed but remains speculative. Indeed, as Waldum points out, data suggest that the incidence of gastric carcinoids has been rising. This has been noted over the past 50 years, in particular since the early 1970s. This primarily correlates with the increase in gastric diagnostic procedures, firstly using x rays and later endoscopy with biopsy sampling, rather than the more recent introduction of proton pump inhibitors (PPIs).1 Nevertheless, gastric carcinoids remain rare, with an incidence of 0.1–0.2 per 100 000 population per year,2 without an obvious association with PPI use. I mentioned previously that carcinoids have never been described in long‐term PPI users, but I was mistaken. Dr Manson from the UK had reported a patient who was diagnosed with a primary gastric carcinoid after having taken 40 mg omeprazole for 4 years for reflux disease.3 Waldum refers to another case; this was, however, not a long‐term PPI user, but a patient with recurrent peptic ulcer who was diagnosed with a gastric carcinoid after intermittently having been treated with famotidine, omeprazole and lansoprazole for a total of 5 months over a 5‐year period (ie, <10% of the time).4

ECL cells may also play a role in the formation of gastric adenocarcinoma. In fact, it has been suggested that about 10% of gastric adenocarcinomas, in particular of the diffuse type, may have a neuroendocrine component.5 In the US, a rise in the incidence of the diffuse type of gastric cancer between 1973 and 2000 has been noted, from 0.3 to 1.8 per 100 000 per annum.6 It is unknown whether acid‐suppressive drugs have made any contribution to this process. As pointed out previously, data on gastric cancer formation in long‐term PPI users have not shown any increased incidence of gastric cancer (diffuse and intestinal) at all within the first 18 years after the introduction of PPI.7

In conclusion, in contrast with the statement of Waldum et al, there is, at present, no evidence that promotion of ECL cell growth is a clinically important issue in long‐term PPI users, for the formation of either gastric carcinoids or neuroendocrine adenocarcinomas. I fully agree though with the implicit proposition that monitoring of large cohorts of long‐term PPI users as well as reporting of any specific cases such as that by Dawson et al3 remains relevant, because only in that way can we eventually settle issues such as raised in this discussion.

Footnotes

Competing interests: In the past 5 years, EJK has received research funding from Altana Pharma, AstraZeneca and Janssen Pharmaceutics, and consulting fees from AstraZeneca.

References

1. Modlin I M, Kidd M, Latich I. et al Current status of gastrointestinal carcinoids. Gastroenterology 2005. 1281717–1751.1751 [PubMed]
2. Modlin I M, Lye K D, Kidd M. Carcinoid tumors of the stomach. Surg Oncol 2003. 12153–172.172 [PubMed]
3. Dawson R, Manson J M. Omeprazole in oesophageal reflux disease. Lancet 2000. 3561770–1771.1771 [PubMed]
4. Haga Y, Nakatsura T, Shibata Y. et al Human gastric carcinoid detected during long‐term antiulcer therapy of H2 receptor antagonist and proton pump inhibitor. Dig Dis Sci 1998. 43253–257.257 [PubMed]
5. Waldum H L, Aase S, Kvetnoi I. et al Neuroendocrine differentiation in human gastric carcinoma. Cancer 1998. 83435–444.444 [PubMed]
6. Henson D E, Dittus C, Younes M. et al Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973–2000: increase in the signet ring cell type. Arch Pathol Lab Med 2004. 128765–770.770 [PubMed]
7. Kuipers E J. Proton pump inhibitors and gastric neoplasia. Gut 2006. 551217–1221.1221 [PMC free article] [PubMed]

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