The use of gastric acid inhibitors for 2 or more years is strongly associated with symptomatic vitamin B12 deficiency, according to a report published online Dec. 10 in JAMA.
This association with proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2RA) was stronger than that for other conditions known to be associated with vitamin B12 deficiency, such as thyroid disease, diabetes, and atrophic gastritis, said Jameson R. Lam of the division of research, Kaiser Permanente, Oakland, Calif., and his associates.
"These findings do not recommend against acid suppression for persons with clear indications for treatment, but clinicians should exercise appropriate vigilance when prescribing these medications and use the lowest possible effective dose," the investigators said.
Previous studies of the relationship between these drugs and vitamin B12 deficiency have produced conflicting results, and there haven’t been any large population-based studies to date. Mr. Lam and his colleagues examined this issue by performing a case-control study within a large, community-based population that was ethnically diverse and had equal access to health care.
The case subjects were adults within the Kaiser Northern California health care system who had a new diagnosis of vitamin B12 deficiency between 1997 and 2011. People who had conditions known to cause vitamin B12 deficiency directly were excluded from the study.
Control subjects for each case subject were up to 10 adults who did not have vitamin B12 deficiency and who were matched for sex, area of residence, race/ethnicity, year of birth, and membership duration.
Only people who had taken PPIs or H2RAs for 2 years or more were included. This yielded 25,956 cases and 184,199 matched controls for the analysis.
In the primary analyses, a new diagnosis of vitamin B12 deficiency was more common in PPI users than in nonusers, with an odds ratio of 1.65. It also was more common in H2RA users than in nonusers, with an OR of 1.25, the investigators said (JAMA 2013;310:2435-42).
Using a higher mean daily dose of PPIs (1.5 or more PPI pills per day) was more strongly associated with vitamin B12 deficiency, with an OR of 1.95, than was a lower mean daily dose (less than 0.75 PPI pills per day), which had an OR of 1.63. This same pattern was seen with higher vs lower H2RA doses.
Similarly, vitamin B12 deficiency was more strongly associated with longer durations of PPI use than with shorter durations. However, no such trend was noted with the duration of H2RA use.
The strength of the association between vitamin B12 deficiency and PPI use diminished after the medication was discontinued. The link was strongest among current users (OR, 1.80), weaker among patients whose most recent use was 2-3 years previously (OR, 1.43), and weakest among those whose most recent use was 3 or more years previously (OR, 1.38).
The association between vitamin B12 deficiency and the use of acid inhibitors was strongest among patients younger than 30 years of age and diminished with increasing age. It also was stronger among women than among men. However, the strength of the association did not differ across racial/ethnic categories, or between patients who had a GERD diagnosis and those who did not.
The strength of the association also did not change over time; it was similar between cases diagnosed in 1997-2003, before PPIs were made available as over-the-counter medications, as among cases diagnosed afterward.
"At a minimum, the use of these medications identifies a population at higher risk of B12 deficiency, independent of additional risk factors," Dr. Lam and his associates said.
This study was supported by Kaiser Permanente. Dr. Lam reported no conflicts of interest; one of his associates reported receiving grants from Wyeth/Pfizer.