Treatment of vitamin B12 and folate deficiencies
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Blood Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
This topic reviews the treatment of vitamin B12 and folate deficiencies, including the route and duration of therapy, monitoring, and expected hematologic and neurologic response.
Separate topic reviews discuss the clinical manifestations, diagnosis, causes, and pathophysiology of these deficiencies:
●Clinical presentation and diagnosis – (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
●Causes and pathophysiology – (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)
GENERAL PRINCIPLES OF TREATMENT
All individuals with documented vitamin B12 and/or folate deficiency should be treated, unless there is a strong reason not to do so (eg, palliative care setting or patient refusal). A number of general principles apply to both vitamin B12 and folate deficiency. These are outlined below and in a 2014 guideline on the diagnosis and treatment of vitamin B12 and folate deficiency from the British Committee for Standards in Haematology .
- Devalia V, Hamilton MS, Molloy AM, British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol 2014; 166:496.
- Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood 2008; 112:2214.
- Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med 2013; 368:149.
- Solomon LR. Oral vitamin B12 therapy: a cautionary note. Blood 2004; 103:2863.
- Sugrue A. Author's reply to Charkin. BMJ 2014; 349:g5391.
- Balcı YI, Ergin A, Karabulut A, et al. Serum vitamin B12 and folate concentrations and the effect of the Mediterranean diet on vulnerable populations. Pediatr Hematol Oncol 2014; 31:62.
- Carmel R, Mallidi PV, Vinarskiy S, et al. Hyperhomocysteinemia and cobalamin deficiency in young Asian Indians in the United States. Am J Hematol 2002; 70:107.
- Antony AC. Vegetarianism and vitamin B-12 (cobalamin) deficiency. Am J Clin Nutr 2003; 78:3.
- Centers for Disease Control and Prevention (CDC). Neurologic impairment in children associated with maternal dietary deficiency of cobalamin--Georgia, 2001. MMWR Morb Mortal Wkly Rep 2003; 52:61.
- Grattan-Smith PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord 1997; 12:39.
- Renault F, Verstichel P, Ploussard JP, Costil J. Neuropathy in two cobalamin-deficient breast-fed infants of vegetarian mothers. Muscle Nerve 1999; 22:252.
- Green R. Vitamin B12 deficiency from the perspective of a practicing hematologist. Blood 2017.
- 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; 23:279.
- Glass GB, Skeggs HR, Lee DH. Hydroxocobalamin. V. Prolonged maintenance of high vitamin B12 blood levels following a short course of hydroxocobalamin injections. Blood 1966; 27:234.
- Carmel R, Watkins D, Rosenblatt DS. Megaloblastic anemia. In: Nathan and Oski's hematology and oncology of infancy and childhood, 8th ed, Orkin SH, Fisher DE, Ginsburg D, et al (Eds), Elsevier Saunders, Philadelphia 2015. Vol 1, p.308.
- Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation. Lancet 1999; 354:740.
- Slot WB, Merkus FW, Van Deventer SJ, Tytgat GN. Normalization of plasma vitamin B12 concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients. Gastroenterology 1997; 113:430.
- Hathcock JN, Troendle GJ. Oral cobalamin for treatment of pernicious anemia? JAMA 1991; 265:96.
- Eussen SJ, de Groot LC, Clarke R, et al. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med 2005; 165:1167.
- Rajan S, Wallace JI, Brodkin KI, et al. Response of elevated methylmalonic acid to three dose levels of oral cobalamin in older adults. J Am Geriatr Soc 2002; 50:1789.
- Kuzminski AM, Del Giacco EJ, Allen RH, et al. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92:1191.
- Bolaman Z, Kadikoylu G, Yukselen V, et al. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study. Clin Ther 2003; 25:3124.
- Metaxas C, Mathis D, Jeger C, et al. Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: a randomised parallel-group trial. Swiss Med Wkly 2017; 147:w14421.
- Parry-Strong A, Langdana F, Haeusler S, et al. Sublingual vitamin B12 compared to intramuscular injection in patients with type 2 diabetes treated with metformin: a randomised trial. N Z Med J 2016; 129:67.
- Castelli MC, Friedman K, Sherry J, et al. Comparing the efficacy and tolerability of a new daily oral vitamin B12 formulation and intermittent intramuscular vitamin B12 in normalizing low cobalamin levels: a randomized, open-label, parallel-group study. Clin Ther 2011; 33:358.
- Sanz-Cuesta T, González-Escobar P, Riesgo-Fuertes R, et al. Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: a pragmatic, randomised, multicentre, non-inferiority clinical trial undertaken in the primary healthcare setting (Project OB12). BMC Public Health 2012; 12:394.
- Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005; 105:978.
- Turck D. Cow's milk and goat's milk. World Rev Nutr Diet 2013; 108:56.
- Alférez MJ, Rivas E, Díaz-Castro J, et al. Folic acid supplemented goat milk has beneficial effects on hepatic physiology, haematological status and antioxidant defence during chronic Fe repletion. J Dairy Res 2015; 82:86.
- Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci U S A 2007; 104:19995.
- Dhar M, Bellevue R, Carmel R. Pernicious anemia with neuropsychiatric dysfunction in a patient with sickle cell anemia treated with folate supplementation. N Engl J Med 2003; 348:2204.
- Vasconcelos OM, Poehm EH, McCarter RJ, et al. Potential outcome factors in subacute combined degeneration: review of observational studies. J Gen Intern Med 2006; 21:1063.
- Healton EB, Savage DG, Brust JC, et al. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 1991; 70:229.
- GENERAL PRINCIPLES OF TREATMENT
- Urgency of correction
- Route of administration
- Available therapeutic preparations
- Duration of therapy
- Need for additional testing
- Adverse effects/overdose
- VITAMIN B12
- Prevention of vitamin B12 deficiency
- Treatment of vitamin B12 deficiency
- Individuals without documented vitamin B12 deficiency
- Prevention of folate deficiency
- Treatment of folate deficiency
- Individuals without documented folate deficiency
- ASSESSING AND MONITORING RESPONSE TO TREATMENT
- Typical response
- Intensity of and duration of monitoring
- Approach to lack of response
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS