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Vitamin B₁₂ deficiency associated with chronic acid suppression therapy

Professor of Internal Medicine Université Louis Pasteur Strasbourg, France Clinical Specialist Department of Internal Medicine, Diabetes and Metabolic Disorders Clinique Médicale B Hôpitaux Universitaires de Strasbourg 1 Place de l'Hôpital 67 091 Strasbourg cedex, France FAX 33-3-88-11-62-62 emmanuel.andres{at}chru-strasbourg.fr

Esther Noel, MD

Assistant of Internal Medicine Université Louis Pasteur Clinical Specialist Department of Internal Medicine, Diabetes and Metabolic Disorders Hôpitaux Universitaires de Strasbourg

Meher Ben Abdelghani, MD

Assistant of Internal Medicine Université Louis Pasteur Clinical Specialist Department of Internal Medicine, Diabetes and Metabolic Disorders Hôpitaux Universitaires de Strasbourg

Published Online, September 18, 2003. www.theannals.com, DOI 10.1345/aph.1D189

Case Reports. The median age of the patients was 70 years (range 49-76); the male/female ratio was 4/2. The mean duration of the acid-suppressive drug administration (omeprazole [n = 3], ranitidine [n = 1], cimetidine [n = 1], sodium bicarbonate [n = 1]) was 7.1 years (range 5.5-9). Clinical features included peripheral neuropathy in 1 patient. Blood count abnormalities included mild anemia (hemoglobin [Hb] <10 g/dL) in 2 patients. The mean ± SD Hb level was 10.9 ± 2.4 g/dL (range 8-12.8) and the mean erythrocyte cell volume was 96 ± 8 fL (range 87-102). The mean serum B₁₂ (normal >200 pg/mL) and total homocysteine levels (normal >13 µmol/L) were 118 ± 37 pg/mL (range 70-162) and 13 ± 2.3 µmol/L (range 11-20), respectively.

All patients had normal serum folate and creatinine levels; none had antiintrinsic factor antiparietal cell antibodies. All patients had normal Schilling's test results (Dicopac test, Amersham, Birmingham, UK). No patient had a nutritional B₁₂ deficiency. One patient with anemia was successfully treated with oral crystalline cyanocobalamin 2000 µg/wk despite continuous administration of an acid-suppressive drug. Other patients had been treated with intramuscular cyanocobalamin (n = 4). In all cases, correction of the serum B₁₂ levels and blood count abnormalities occurred during the first 6 months of treatment.

Discussion. Acid-suppressive drugs represent about 4% of the etiologies in this population, and are undoubtedly the principal causative drugs (with metformin) of B₁₂ deficiency in adults.^3,5 The B₁₂ deficiency related to long-term acid suppression therapy is mild ("subtle cobalamin deficiency"),⁵ with no or only mild clinical and hematologic abnormalities.^2,3 As several authors have previously reported,^1,2 our data suggest that the principal mechanism of B₁₂ deficiency related to long-term acid suppression therapy is food-cobalamin malabsorption (FCM). This syndrome is characterized by the inability to release B₁₂ from food or its binding protein.^3,5 Thus, patients have low serum B₁₂ levels, normal Schilling's test results, and commonly hypochlorhydria.

The partial nature of this form of malabsorption produces a more slowly progressing depletion of B₁₂ than does the more complete malabsorption engendered by disruption of intrinsic factor-mediated absorption. This partial malabsorption also explains why subtle cobalamin deficiency is often associated with FCM.⁵ This mechanism of partial FCM may explain the potential efficacy of oral crystalline cyanocobalamin.^3,5 In our opinion, acid-suppressive drugs may often be continued with appropriate B₁₂ supplementation.

Physicians should always reassess patients who are taking acid-suppressive drugs for a long time for vitamin B₁₂ status because of potentially irreversible neurologic complications.

References

1. Force RW, Meeker AD, Cady PS, Culbertson VL, Force WS, Kelley CM. Increased vitamin B₁₂ requirement associated with chronic acid suppression therapy. Ann Pharmacother 2003;37: 490-3. DOI 10.1345/aph.1C037[Abstract/Free Full Text]
2. Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B₁₂ deficiency associated with histamine₂-receptor antagonists and a proton-pump inhibitor. Ann Pharmacother 2002;36: 812-6. DOI 10.1345/aph.10325[Abstract]
3. Andrès E, Goichot B, Schlienger JL. Food-cobalamin malabsorption: a usual cause of vitamin B₁₂ deficiency.Arch Intern Med 2000;160:2061-2.[Free Full Text]
4. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions.Clin Pharmacol Ther 1981;30:239-45.[Medline]
5. Andrès E, Noel E, Kaltenbach G, Perrin AE, Vinzio S, Goichot B, et al. [Vitamin B₁₂ deficiency with normal Schilling test or non-dissociation of vitamin B₁₂ and its carrier proteins in elderly patients. A study of 60 patients] French. Rev Med Interne 2003;24:218-23.[Medline]

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