Clinical Review

Vitamin B12 Deficiency

Clinician Reviews. 2010 August;20(8):16, 18, 19

References

1. Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007;147(6):386-399.

2. Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of metformin in non–insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(9): 550-554.

3. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203.

4. Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab. 2009;11(4):338-342.

5. Berchtold B, Bolli P, Arbenz U, Keiser G. Disturbance of intestinal absorption following metformin therapy (observations on the mode of action of biguanides) [in German]. Diabetologia. 1969; 5(6):405-412.

6. Tomkin GH, Hadden DR, Weaver JA, Montgomery DA. Vitamin B12 status of patients on long-term metformin therapy. BMJ. 1971;2(5763):685-687.

7. Office of Dietary Supplements, NIH. Dietary supplement fact sheet: vitamin B12 (2010). http://ods.od.nih.gov/factsheets/VitaminB12_pf.asp. Accessed July 23, 2010.

8. US Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 22 (2010). www.ars.usda.gov/Services/docs.htm?docid=8964. Accessed July 23, 2010.

9. Dali-Youcef N, Andrès E. An update on cobalamin deficiency in adults. QJM. 2009;102(1):17-28.

10. Bauman WA, Shaw S, Jayatilleke E, et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000;23(9):1227-1231.

11. Hermann LS, Nilsson B, Wettre S. Vitamin B12 status of patients treated with metformin: a cross-sectional cohort study. Br J Diabetes Vasc Dis. 2004;4(6):401-406.

12. Caspary WF, Zavada I, Reimold W, et al. Alteration of bile acid metabolism and vitamin B12 absorption in diabetics on biguanides. Diabetologia. 1977;13(3):187-193.

13. Andrès E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004;171(3):251-259.

14. Andrès E, Noel E, Goichot B. Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002;162:2251-2252.

15. Ting RZ, Szeto CC, Chan MH, et al. Risk factors of vitamin B12 deficiency in patients receiving metformin. Arch Intern Med. 2006;166(18):1975-1979.

16. de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010; 340:c2181.

17. Acharya U, Gau JT, Horvath W, et al. Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature. J Hematol Oncol. 2008;1:26-30.

18. Lin HY, Chung CY, Chang CS, et al. Hyperhomocysteinemia, deep vein thrombosis and vitamin B12 deficiency in a metformin-treated diabetic patient. J Formos Med Assoc. 2007;106(9):774-778.

19. Cook JS. Evaluation and management of hematologic disorders. In: Buttaro TM, Trybulski J, Bailey PP, Sandberg-Cook J. Primary Care: A Collaborative Practice. 3rd ed. St. Louis, MO: Mosby Elsevier; 2008:1191-1193.

20. Centers for Disease Control and Prevention. Vitamin B12 deficiency: detection and diagnosis. www.cdc.gov/ncbddd/b12/detection.html. Accessed July 23, 2010.

21. Varughese GJ, Scarpello JH. Metformin and vitamin B12 deficiency: the role of H2 receptor antagonists and proton pump inhibitors. Age Aging. 2007;36(1):110-111.

22. Hornung N, Ellingsen T, Stengaard-Pedersen K, Poulsen JH. Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement. J Rheumatol. 2004;31 (12):2374-2381.

23. Graham MV. Hematologic problems. In: Uphold CR, Graham MV. Clinical Guidelines in Family Practice. 4th ed. Gainesville, FL: Barmarrae Books, Inc; 2003:929-932.

24. Jameson M, Roberts S, Anderson NE, Thompson P. Nitrous oxide–induced vitamin B12 deficiency. J Clin Neurosci. 1999;6(2):164-166.

25. Graells J, Ojeda RM, Muniesa C, et al. Glossitis with linear lesions: an early sign of vitamin B12 deficiency. J Am Acad Dermatol. 2009;60(3):498-500.

26. Liu KW, Dai LK, Jean W. Metformin-related vitamin B12 deficiency. Age Ageing. 2006;35(2): 200-201.

27. Bernard MA, Nakonezny PA, Kashner TM. The effect of vitamin B12 deficiency on older veterans and its relationship to health. J Am Geriatr Soc. 1998;46(10):1199-1206.

28. Hoffbrand AV. Megaloblastic anemias. In Fauci AS, Braunwald E, Dennis L, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill; 2008:643-651.

29. Oh RC, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003;67(5):979-986.

30. Filioussi K, Bonovas S, Katsaros T. Should we screen diabetic patients using biguanides for megablastic anaemia? Aust Fam Physician. 2003;32 (5):383-384.

31. Bessman D. Erythropoiesis during recovery from macrocytic anemia: macrocytes, normocytes, and microcytes. Blood. 1977;50(6):995-1000.

32. Ward PC. Modern approaches to the investigation of vitamin B12 deficiency. Clin Lab Med. 2002;22(2):435-445.

33. Stabler SP. Screening the older population for cobalamin (vitamin B12) deficiency. J Am Geriatr Soc. 1995;43(11):1290-1297.

34. Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency: an update. Haematologia. 2006;91(11):1506-1512.

35. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med. 1994;96(3):239-246.

36. American Association for Clinical Chemistry. Lab Tests Online: Vitamin B12 and folate deficiency. www.labtestsonline.org/understanding/conditions/vitaminb12-4.html. Accessed July 23, 2010.

37. Butler CC, Vidal-Alaball J, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials. Fam Pract. 2006;23 (3):279-285.

Assessment of the mental status of a patient with B12 deficiency may reveal irritability, depressed mood, altered mental functioning, and even psychosis.^28,29

Laboratory Work-up
If findings from the history and physical examination in the patient taking metformin suggest vitamin B12 deficiency, prompt laboratory assessment for the presence of macrocytic anemia, a common consequence of cobalamin deficiency, is needed.^17,30 If this condition is present, further laboratory assessment to differentiate between folic acid and B12 deficiency is critical, as the associated neurologic symptoms can be irreversible without timely treatment.

Assessment for anemias is achieved with the complete blood count (CBC); a mean corpuscular volume (MCV) exceeding 110 fL may be present in patients with macrocytic anemia.^17,31 The serum folate value may be decreased in the presence of vitamin B12 deficiency or folic acid deficiency.¹⁶

Serum concentrations of vitamin B12 should be measured by an optimized assay to evaluate circulating B12 levels. Although laboratory value norms for B12 lack uniformity,^20,32 the lower limit of normal serum B12 has been defined as 150 pmol/L (203 pg/mL) when the patient has clinical signs and symptoms; when two or more readings yield such results; or in conjunction with a total serum homocysteine level exceeding 0.4 mcmol/L.^9,13,20,33

Serum methylmalonic acid (MMA) and total homocysteine (HCY) are more sensitive diagnostic tests that can be used to detect mild or early B12 deficiency. Because these substances depend on B12 as a cofactor in their metabolism, their values will be elevated in the presence of cobalamin deficiency; an elevated MMA concentration is very specific for cobalamin deficiency.^14,34 Patients should also be evaluated for renal disease or dehydration, which are both associated with elevations in MMA levels. Serum HCY levels can be elevated in patients with either folate or B12 vitamin deficiency, but the increase is usually greater in the latter case.^20,35

Intrinsic factor deficiency can also lead to vitamin B12 deficiency. Diagnostic tests to investigate for this condition include intrinsic factor–binding antibody, intrinsic factor–blocking antibody, and parietal cell antibody tests.^15,17,20,36

Treatment/Follow-up
For many years, the standard of treatment for vitamin B12 deficiency in adults has been intramuscular injections of 1,000 mcg/d of cyanocobalamin for one to two weeks, followed by one to two injections weekly for two weeks to one month, then monthly injections thereafter until the deficiency is fully resolved.^13,23,30

In recent years, oral cyanocobalamin has been found to be an effective treatment for the hematologic symptoms associated with macrocytic anemia.³⁷ A daily B12 supplement of 1,000 to 2,000 mcg/d should be taken for one month, followed by a daily maintenance dose of as much as 1,000 mcg/d.^13,28 Cyanocobalamin is also available in a nasal gel.³³

Researchers have also demonstrated that daily use of supplemental calcium can reverse the effects of B12 malabsorption associated with metformin therapy, without interfering with metformin’s therapeutic (hypoglycemic) effects.¹⁰ Alternatively, cessation of the drug has been found to reverse B12 deficiency in a matter of weeks.⁶

Reassessment of laboratory values is recommended every two to three months to evaluate the effectiveness of the chosen treatment plan.²⁹

Patient Education
Patients with metformin-associated vitamin B12 deficiency need dietary counseling, including information about B12–rich food sources (as shown in Table 1). In patients who do not require cyanocobalamin injections, vitamin B12 supplementation will be essential. Patients who do elect intramuscular cyanocobalamin must be taught injection techniques.

If continued use of metformin is deemed necessary, the patient may be advised to take supplemental calcium to help reverse the medication’s effects on B12 levels.¹⁰ Lastly, cessation of metformin has been demonstrated to reverse B12 deficiency quickly.⁶

Patients who continue the metformin regimen may benefit from a referral to a dietitian or pharmacist who is also a diabetes educator. In addition to reinforcing diabetes self-management skills, this clinician can increase the patient’s awareness of the potential effects of metformin along with strategies (appropriate diet and supplementation) to counter the associated adverse effects.

Conclusion
Decreased levels of vitamin B12 have been reported in 10% to 30% of patients who take metformin for treatment of type 2 diabetes, but no consensus exists regarding routine monitoring of B12 levels in these patients. Considering concerns regarding elevated homocysteine concentrations that occur with cobalamin deficiency (ie, the increased risk for cardiovascular disease, particularly in patients with diabetes¹⁶), the call for annual laboratory testing for B12³⁰ appears reasonable. The efficacy of preventive screening to identify “this preventable deficiency”¹⁶ must be demonstrated, however.

Until then, the astute clinician must watch for signs and symptoms of B12 deficiency in diabetic patients who take metformin, with timely diagnosis and appropriate treatment when clinical suspicion is confirmed through laboratory testing.