Rejected letter to “Gastroenterology"

 I read with interest and astonishment the editorial by Corley ¹ based upon a multinational observational study of pantoprazole treatment compared with placebo followed for about 3 years by Moayyedi et al. ². They did not find evidence of any harmful effect on the kidneys or the cardiovascular system where previous epidemiological studies have suggested increased risk of disease. This was to be expected since there were no plausible mechanisms for these side effects. However, based upon the Moayyedi study Corley also seems to conclude that there is no reason to worry about neoplasia due to long-term PPI therapy. As I see it, this reflects lack of biological, physiological and pathological knowledge, because:

1: Cancer is mainly a disease of old age reflecting years of development. Three years say nothing. Children in a Spanish family with a missense mutation in one of the proton pump genes developed ECL carcinoids in their twenties and more malignant tumor in the thirties ^{3, 4} which is in line with the latency in animal studies done in the 1980s ^{5, 6}. This Spanish family is the best model for long-term PPI treatment in man and underscores that one should be particularly reluctant to put children on PPI treatment. The tumors both in the animals and the Spanish family^{6 3-5} were due to hypergastrinemia secondary to hypoacidity. Moreover, Håkanson et al.⁷ found that long-term PPI dosing of rats induced a positive trophic effect only in the oxyntic mucosa and particularly the ECL cell. It is therefore strange that the focus during all the years with PPIs has not been on gastric cancer ⁸. Since 1990 we have published multiple studies describing ECL cell/neuroendocrine differentiation in human gastric carcinomas ^{8, 9}. I have wondered why pharmaceutical industry has not supported a study disapproving the role of the ECL cell in gastric carcinogenesis¹⁰ and thus taken away an important argument for a risk of hypergastrinemia and PPI treatment. Such a study would have been much more important with respect to cancer than the Moayyedi study. In fact, to assess cancer risk we must rely on studies on animals with a much shorter life span than man. Accordingly, Moayyedi study is without value with respect to cancer.

It is also very peculiar that Helicobacter pylori (Hp) in combination with PPI treatment is not mentioned, since it is confirmed in studies from East Asia that PPI treatment after Hp eradication increases the risk of gastric cancer ^11-13. Hp gastritis is the principal cause of gastric cancer ¹⁴, and Uemura et al. showed that Hp gastritis predisposes to gastric cancer only after having induced atrophy of the oxyntic mucosa ¹⁵. Since not only Hp oxyntic atrophic gastritis, but also autoimmune atrophic gastritis predisposes to gastric cancer ¹⁶, we have argued that Hp gastritis causes gastric cancer via hypergastrinemia ¹⁷.  Anyhow, the studies from East-Asia ^11-13 cannot be dismissed.

 2: Biological function of gastric juice.

The biological function of the highly acid gastric juice is to kill swallowed microorganism. In the study by Moayyedi ² this aspect is only sparsely covered, but it seems that there was an increased risk of enteric infections². We do not know the etiology of most of the chronic inflammatory diseases as well as degenerative disease of the central nervous system, but infectious agents could be the cause of many of these diseases. The gut is a possible entrance for infections by micro-organisms escaping destruction in the stomach as exemplified by poliomyelitis. Variant Creutzfeldt-Jacob disease in man due to intake of meat contaminated with pathogenic prion is another example of such a disease. In this context I will mention that we have described that mice given scrapie infected brain were more prone to develop disease when dosed with PPI ¹⁸. It should be recalled that many infections may cause disease after decades of latency.

 To conclude, for complications with a latency of decades the study by Moayyedi et al.²is of little value, and we must rely on biological knowledge and animal studies. The editorial by Corley lacks completely these aspects ¹. I prefer to rely more on the evolution than imperfect studies.

 Trondheim August 5^th, 2019

Helge L. Waldum

Professor of Medicine.

References

1. Corley DA. Safety and Complications of Long-Term Proton Pump Inhibitor Therapy:
   Getting Closer to the Truth. Gastroenterology 2019;157(3):604-7.2.
2. Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin. Gastroenterology 2019;157(3):682-91. e2.
3. Calvete O, Reyes J, Zuniga S, et al. Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour. Hum Mol Genet 2015; 24: 2914-22.
4. Fossmark R, Calvete O, Mjones P, et al. ECL-cell carcinoids and carcinoma in patients homozygous for an inactivating mutation in the gastric H (+) K (+) ATPase alpha subunit. Apmis 2016; 124:561-6.

5. Havu N. Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 1986;35 Suppl 1:42-55.
6. Poynter D, Selway SA, Papworth SA, et al. Changes in the gastric mucosa of the mouse associated with long lasting unsurmountable histamine H2 blockade. Gut 1986; 27: 1338-46.
7. Hakanson R, Blom H, Carlsson E, et al. Hypergastrinaemia produces trophic effects in stomach but not in pancreas and intestines. Regul Pept 1986; 13:225-33.
8. Waldum HL, Sagatun L, Mjones P. Gastrin and Gastric Cancer. Front Endocrinol (Lausanne) 2017; 8: 1.
9. Waldum HL, Fossmark R. Types of Gastric Carcinomas. Int J Mol Sci 2018; Dec 18;19(12). pii: E4109. doi: 10.3390/ijms19124109. Review.
10. Waldum HL, Sordal OF, Mjones PG. The Enterochromaffin-like [ECL] Cell-Central in Gastric Physiology and Pathology. Int J Mol Sci 2019;20. May 17;20(10). pii: E2444. doi: 10.3390/ijms20102444. Review.
11. Cheung KS, Chan EW, Wong AYS, et al. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut 2018; 67: 28-35.
12. Niikura R, Hayakawa Y, Hirata Y, et al. Long-term proton pump inhibitor use is a risk factor of gastric cancer after treatment for Helicobacter pylori: a retrospective cohort analysis. Gut 2018; 67: 1908-1910.
13. Lai SW, Lai HC, Lin CL, et al. Proton pump inhibitors and risk of gastric cancer in a case-control study. Gut 2019; 68: 765-767.
14. Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991; 325:1127-31.
15. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345: 784-9.
16. Vannella L, Lahner E, Osborn J, et al. Systematic review: gastric cancer incidence in pernicious anaemia. Aliment Pharmacol Ther 2013; 37:375-82.
17. Waldum HL, Hauso O, Sordal OF, et al. Gastrin May Mediate the Carcinogenic Effect of Helicobacter pylori Infection of the Stomach. Dig Dis Sci 2015; 60:1522-7.
18. Martinsen TC, Benestad SL, Moldal T, et al. Inhibitors of gastric acid secretion increase the risk of prion infection in mice. Scand J Gastroenterol 2011;46: 1418-22.