Vitamin B12 Deficiency

Background

• Vitamin B12 (also called cobalamin) is a cofactor important for DNA synthesis and cell metabolism.
• The most common clinical effects of insufficient vitamin B12 are megaloblastic anemia and neuropsychiatric disease.
• The most common cause of severe vitamin B12 deficiency is pernicious anemia which is due to a loss of intrinsic factor from autoimmune atrophic gastritis.
• Other causes of vitamin B12 deficiency include:
  • impaired gastrointestinal absorption due to gastric food-vitamin B12 malabsorption (especially common among the elderly), bariatric (gastric bypass) surgery, or gastric or ileal resection or disease
  • common medications that interfere with vitamin B12 absorption and affect serum levels, such as long-term use of H2 receptor antagonists, or proton pump inhibitors, and metformin; in addition, abuse of nitrous oxide may lead to chemical inactivation of vitamin B12
  • inadequate intake due to a vegan or vegetarian diet or food faddism without vitamin B12 supplementation
  • premature infants and infants of vitamin-B12 deficient mothers
  • increased vitamin B12 requirements, including during growth in children and adolescence or in pregnancy
  • inherited causes of defective vitamin B12 absorption or metabolism (very rare)
• Presentations varies widely in type and severity, but vitamin B12 deficiency often presents as either or both of:
  • macrocytic anemia, with or without symptoms (such as fatigue or dyspnea)
  • neuropsychiatric findings such as paresthesias, spastic paraparesis, gait disturbance, sensory deficits, mild cognitive impairment, or dementia

Evaluation

• Diagnostic blood testing in all patients with suspected vitamin B12 deficiency should include:
  • complete blood count and smear to look for anemia and peripheral blood smear to examine for the presence of macro-ovlocytes and hypersegmented neutrophils (suggested by > 5% of neutrophils with ≥ 5 lobes or 1% with 6 lobes)
  • serum vitamin B12 level - a low level (< 148 pmol/L [200 pg/mL]) in the appropriate setting can confirm the diagnosis
  • serum folate level to rule out a combined deficiency
• When values are in the low-normal range (between 148-221 pmol/L [200-300 pg/mL]) or even in the low-normal range in a patient suspected of having vitamin B12 deficiency, consider assessing for:
  • increased methylmalonic acid and/or plasma total homocysteine levels (Weak recommendation); methylmalonic acid is preferred because it is more specific for vitamin B12 deficiency
  • decreased holotranscobalamin level, if available (rarely performed in the United States)
• If vitamin B12 deficiency is confirmed but the etiology is unclear, perform additional blood tests to help identify the underlying cause, including anti-intrinsic factor antibodies, regardless of vitamin B12 levels to test for pernicious anemia (see Pernicious Anemia for additional information).

Management

• Identify and treat the underlying cause, if possible.
• Initial treatment:
  • In principle, in all cases of clinical vitamin B12 deficiency, first administer parenteral vitamin B12 replacement therapy in full doses using either cyanocobalamin (commonly used in the United States) or hydroxocobalamin (commonly used in Europe) to assure effective, rapid replacement of the deficient vitamin B12.
  • Recommended treatment protocols vary.
    • In patients without neurologic involvement, a typical regimen is 1,000 mcg intramuscularly several times per week for 1-2 weeks.
    • In patients with neurologic involvement, a typical regimen includes 1,000 mcg intramuscularly on alternate days for up to 3 weeks or until there is no further improvement.
    • See additional initial treatment protocol options for patients with vitamin B12 with or without neurologic involvement.
• Maintenance treatment:
  • In patients without neurologic involvement:
    • In patients with nutritional vitamin B12 deficiency, consider maintenance therapy over the long term with lower dose oral cyanocobalamin (50-150 mcg/day). Consider a daily high-dose oral vitamin B12 to replace stores over 3-4 months, then ≥ 6 mcg/day.
    • In patients with food-bound vitamin B12 malabsorption, consider a lower minimum dose of daily oral cyanocobalamin (500-1,000 mcg/day) (Weak recommendation).
    • In patients with vitamin B12 malabsorption (for example, pernicious anemia or gastric [bariatric surgery]-related bypass or ileal bypass in Crohn's disease), long-term maintenance with daily oral vitamin B12 (1,000-2,000 mcg) or monthly parenteral cyanocobalamin 1,000 mcg (or hydroxocobalamin 1,000 mcg every 3 months) is required for life.
  • In patients with neurologic involvement, typical dosing is one of the following:
    • Cyanocobalamin is administered at 1,000 mcg/day intramuscularly or subcutaneously for the first week, then twice a week for the next two weeks, followed by 1,000 mcg every month for life.
    • Parenteral hydroxocobalamin 1,000 mcg is administered on alternate days until no further neurological improvement, followed by every 2 monthly injections long term.
• Following initiation of therapy, expect reticulocytosis in 5-10 days, normalization of homocysteine or methylmalonic acid levels within 1 week, normalization of mean cell volume within 8 weeks, and maximal neurologic recovery within 6 months.
• Treat iron and folate deficiencies if present.
• Treatment duration depends on the underlying cause of vitamin B12 deficiency; lifelong maintenance therapy is required if the underlying cause is either irreversible (for example pernicious anemia) or where the diet is unlikely to change (vegans/vegetarians or nonvegetarians with infrequent consumption of animal-source foods), especially in developing countries.