Vitamin B12 deficiency and use of acid-suppressive drugs: The association revisited

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Vitamin B12 is a water-soluble nutrient involved in several important physiologic processes. Deficiency may lead to a variety of manifestations, such as megaloblastic anemia and neurologic deficits.1 Gastric acid plays a role in vitamin B12 absorption by activating proteolytic enzymes in the stomach, such as pepsin, which free protein-bound vitamin B12 from food sources to make it available for absorption.2, 3 

Thus, medications that reduce gastric acid secretion, such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs), could theoretically alter the absorption of dietary vitamin B12 and cause mild vitamin B12 malabsorption.1 Once identified, vitamin B12 deficiency may be treated with intramuscular or high-dose oral vitamin B therapy, depending on the etiology.

PPIs are the most potent acid-suppressive medications available in both prescription and nonprescription forms. Given the widespread availability and potential for overuse of PPIs, their impact on the development of vitamin B12 deficiency could be substantial.2–5 Despite this concern, the lack of large prospective trials demonstrating a significant relationship with use of PPIs and development of vitamin B12 deficiency has led to inconsistent recommendations on management.2-5

Largest clinical trial to date

A recent trial evaluated the association of both PPIs and H2RAs use with the development of vitamin B12 deficiency in a large number of patients.5 A nested case control design was used with 25,956 cases of vitamin B12 deficiency matched to 184,199 control participants. The study evaluated patients who received at least a 2-year of supply of PPIs or H2RAs prior to their diagnosis of vitamin B12 deficiency, while controlling for a variety of medical conditions and medications known to be associated with development of vitamin B12 deficiency. 

Overall, a 65% increased risk of vitamin B12 deficiency occurred in patients who received at least a 2-year supply of PPIs, compared with nonusers (odds ratio [OR] 1.65 [95% CI, 1.58–1.73]), and a 25% increased risk for H2RAs users (OR 1.25 [95% CI, 1.17–1.34]). Higher doses (>1.5 doses/d) of PPIs and H2RAs were most strongly associated with increased risk (OR 1.95 [95% CI, 1.77–2.15]) and (OR 1.37 [95% CI, 1.23–1.52]), respectively.

Duration of use was a nonfactor; however, the highest risk appeared to be in those whose last prescription was within 1 year of diagnosis (OR 1.8 [95% CI, 1.51–2.14]), with the risk diminishing over time. Of particular interest, risk stratified by age was highest for age less than 30 years (OR 8.12 [95% CI, 3.36–19.59]) compared with age greater than 80 years (OR 1.04 [95% CI, 0.96–1.13]).

This is one of the largest trials to date evaluating the use of acid-suppressive medications and development of vitamin B12 deficiency. While there was a significant association between diagnosis of vitamin B12 deficiency with use of both PPIs and H2RAs, as with any case control trial a direct causal relationship cannot be established. Furthermore, use of nonprescription PPIs and H2RAs was not evaluated. 

Vigilance is necessary

Currently there are no recommendations to routinely screen patients for vitamin B12 deficiency based solely on use of PPIs or H2RAs. However, pharmacists should be vigilant in evaluating the indication, dose, and duration of their use and identifying patients who may be at risk for vitamin B12 deficiency based on medical history or concurrent medication use. Other patient populations that may be at risk include those who adhere to a vegan diet or older adults who are institutionalized.1,6 Likewise, though many patients receive prescription products, a significant number of patients who chronically use nonprescription acid-suppressive agents may not seek routine medical care.


  1. N Engl J Med. 2013;368:149–60
  2. Ther Adv Drug Saf. 2013;125–133
  3. Curr Opin Gastroenterol. 2012;28:615–620
  4. Expert Rev Clin Pharmacol. 2013;6(4):443–51
  5. JAMA. 2013;310(22):2435–2442
  6. Gastroenterology. 2013;108:308–28
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