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Proton pump inhibitors and the risk for gastric cancer: possible confounding by serum vitamin B 12
  1. Itai Gueta1,
  2. Hillel Halkin1,2,
  3. Noa Markovits1,2,
  4. Ronen Loebstein1,2
  1. 1 The Institute of Clinical Pharmacology and Toxicology, Sheba Medical Center, Tel Hashomer, Israel
  2. 2 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  1. Correspondence to Dr Itai Gueta, Sheba Medical Center, Tel Hashomer, Ramat Gan, 5262000, Israel; itai.gueta{at}

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We read with interest the article by Cheung et al 1 reporting an increased risk of gastric cancer with long-term exposure to proton pump inhibitors (PPI) following Helicobacter pylori (HP) eradication. Several recent reports and a meta-analysis have also demonstrated this association.2 3 The present study, using strict exclusion criteria, was able to adjust for the confounding effect of previous HP infection and eradication, demonstrating a PPI exposure-dependent escalating risk for non-cardia gastric cancer (NCGC) in previously infected patients. The authors suggest that the profound acid suppression by PPIs worsens the atrophic gastritis induced by HP infection, increasing the risk. We wish to address another confounder not taken into consideration in the present study as well as in the previous ones,1–3 namely vitamin B12.

B vitamins are essential for methylation reactions, DNA stability and repair, while intact gastric mucosa and acid secretion are both crucial factors in B12 absorption.4 5 Since PPIs diminish acid secretion, long-term treatment is expected to result in lower B12 levels; indeed several studies support this association.6 7 Hence, patients taking PPIs might be at increased risk for DNA damage and malignancy. Interestingly, two studies have also demonstrated an inverse association between B12 serum levels and gastric cancer. Miranti et al 8 have recently shown that patients with NCGC had lower vitamin B12 levels up to 17 years prior to diagnosis. This association was also found in an earlier European population study by Vollset et al.9 Accordingly, it is possible that patients with more severe hypochlorhydria secondary to previous HP infection and PPI use have low vitamin B12 levels, and that the latter is actually a mediator in the development of gastric malignancy. However, B12 levels are not accounted for in any of these studies.

It is of course intuitive that lower B12 levels are just another consequence of hypochlorhydria and gastric atrophy. Yet, given the intracellular role of B12 in DNA metabolism and the above-demonstrated associations, the confounding effect of B12 levels on the development of NCGC must be excluded. We believe that this variable (not documented in the present analysis) should be accounted for in future studies.

In conclusion, it is possible that the association between PPIs and NCGC is explained by a mediator consistently not included in observational studies rather than through direct causality. If this is indeed the case and a potentially treatable mediator is involved, such treatment should be considered in the recommendations regarding long-term PPI use. This is particularly true given the widespread use of PPIs for well-proven indications, and the anxiety produced by the perception of increased NCGC risk among patients and physicians alike.


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  • Contributors IG and HH raised the conception and performed the literature survey. All authors contributed to the writing of the letter. IG is the guarantor.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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