Long-term gastric acid suppression associated with vitamin B12 deficiency

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1. Long-term gastric acid suppression greater than 2 years was associated with vitamin B12 deficiency. 

2. The strongest association was among those less than 30 years of age (with a decreasing association with increasing age), women, and those with higher frequency dosing. 

Evidence Rating Level: 3 (Average)       

Study Rundown: Gastric acid production is needed for proper absorption of vitamin B12 and therefore the use of proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) may lead to malabsorption of this essential vitamin.  A nested, case-control trial was performed among patients with a diagnosis of vitamin B12 deficiency and exposure to PPIs or H­2RAs. A greater than 2 years of PPI use at any dosage was associated with increased risk of vitamin B12 deficiency with an increase in association with duration of use and with maximum dosage (>1.50 pills/day) compared to nonusers.  Furthermore, the association was stronger in those younger than 30 (decreased with increasing age) and among women.  The association did diminish with discontinuation of use.  In those taking H2RAs, similar results were seen, however, only among users of >0.75 pills/day. Duration of H2RA was not associated with increases in vitamin B12 deficiency.

The study does not account for short-term use of these medications which may be associated with vitamin B12 deficiency as well.  Furthermore, the way the mean daily dose was calculated fails to account for compliance and/or over the counter using of these drugs.  The strengths of this study are the large cohort and the use of electronic records with up to 15 years of exposure data.  In conclusion, the results of this study suggest that those taking PPIs or H2RAs might be at a higher risk of vitamin B12 deficiency regardless of confounding factors, and physicians should take this into account when managing these patients.

Click to read the study in JAMA

Relevant Reading: An update on cobalamin deficiency in adults

In-Depth [nested, case-control study]: This study included 25,956 cases of vitamin B12 deficiency and 184,199 controls.   Acid inhibitor use for more than 2 years was higher among the cases, with 12% using PPIs and 4.2% using H2RAs compared to 7.2% using PPIs and 3.2% using H2RAs among the controls.  Vitamin B12 deficiency was associated with a 2 or more years supply of PPIs (OR, 1.65 [95% CI, 1.58-1.73]) or H2RAs (OR, 1.25 [95% CI, 1.17-1.34]) compared to nonusers.  Among PPI users, the highest dosage (>1.5 pills/day) was strongly associated with vitamin B12 deficiency (OR, 1.95 [95% CI, 1.77-2.15]) with decreasing association with lower dosages (<0.75 pills/day OR, 1.63 [95% CI, 1.48-1.78] and 0.75 -1.50 pills/day OR 1.55, [95% CI 1.46-1.64]). With increasing duration of use, there was a significant increase in association among PPI users (P <0.001) but not among H2RA users (P = 0.40).  The strongest association with vitamin B12 deficiency was among those younger than 30 years of age using PPIs for 2 or more years (OR, 8.12 [ 95% CI, 2.26 – 19.56]), decreasing with increasing age.

By Camellia Banerjee and Brittany Hasty

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