Nutritional Consequences of Long-term Acid Suppression; Are They Clinically Important?

David A. Johnson


Curr Opin Gastroenterol. 2016;32(2):136-140. 

In This Article

B12 Deficiency

Vitamin B12 is normally ingested in a protein-bound state. Gastric acid is necessary for releasing it from this bound state to bind to the R protein. In the duodenum, the vitamin is then split from the R protein by action of pancreatic enzymes, then bound to intrinsic factor and subsequently absorbed in the small intestine.

A number of early clinical trials revealed conflicting evidence on the role of PPI therapy in B12 absorption and the development of B12 deficiency. Data supporting an association are from small, nonrandomized retrospective studies or sporadic case reports with varying methods for measuring B12 levels.[1,2]

A large case-controlled study comparing the risk of acid suppressive medication in B12 deficiency was performed using the Kaiser Permanente database. This study identified 25 956 patients with an incident diagnosis of vitamin B12 deficiency of whom 3120 (12.0%) received two or more years' supply of PPIs, 1087 (4.2%) received two or more years' supply of histamine 2 receptor antagonists (H2RAs), and 21 749 (83.8%) received neither PPI or H2RA. Both PPIs [odds ratio (OR) 1.65, 95% confidence interval (CI) 1.58–1.73] and H2RAs (OR 1.25, 95% CI 1.17–1.34) were found to be significantly associated with an increased risk for vitamin B12 deficiency.[3] In addition, higher frequency of PPI dosing (>1.5 pills/day) (OR 1.95, 95% CI 1.77–2.15) was more strongly associated with vitamin B12 deficiency than smaller doses (<0.75 pills/day) (OR 1.63, 95% CI 1.48–1.78). The strength of the association diminished after discontinuation of therapy, suggesting that this is (if truly present) a reversible effect. When using an overall prevalence of 2.3% for individuals over 50 years of age and an OR of 1.65 predicted from this study, PPI use for more than 2 years yields a number needed to harm of 67.

Prospective studies demonstrate reduced B12 levels that are within the normal range, suggesting that the risk of deficiency may be clinically insignificant.[4,5]

These findings conflict with the results from a study comparing vitamin B12 status in 125 couples over the age of 65 in which one partner was a long-term PPI users (>3 years) and the other was not.[6] After adjusting for age, sex, Helicobacter pylori status, C-reactive protein levels, and excluding couples in which either participant used nutritional supplements, there were no differences in mean vitamin B12 levels. In addition, there were no differences seen in the concentrations of the metabolic intermediates, methylmalonate or homocysteine; this is an important finding, as it is one of the only studies to examine these intermediates, which would likely be altered in a true B12 deficiency. The most recent evidence showing no detrimental effect on B12 levels comes from the 5-year prospective trial in which patients were randomized to surgical or PPI treatment of gastroesophageal reflux disease (GERD). No changes were evident from baseline[7] (Fig. 1).

Figure 1.

Serial B12 levels: gastroesophageal reflux disease treatment (SOPRAN/LOTUS studies) [7].

Evidence Summary

Prospective trial is needed to conclude any causative effect. In addition, to date no studies have provided a longitudinal evaluation showing alterations of specific metabolic intermediates (e.g., methylmalonate and homocysteine), which can accumulate with this deficiency. Furthermore, because hypochlorhydria would only impair the release of B12 from dietary protein, absorption of oral B12 supplements should be unimpaired. Consumption of a normal diet will safeguard against clinically significant B12 deficiency when taking a PPI. The elderly and malnourished patient may be at a higher risk.