Vitamin B12

Pronunciation

Cobalamin (koh-​bal-ah-min)

Summary

Vitamin B12 is an essential water-soluble nutrient found primarily in food derived from animal sources, such as meat, eggs, dairy, and seafood (118). It can also be found in shiitake mushrooms (13), green and purple lavers (nori), and fortified cereals (118). Vitamin B12 contains cobalt compounds that can be converted to the active coenzymes, methylcobalamin and adenosylcobalamin. It is also a cofactor for methionine synthase and l-methylmalonyl-CoA mutase, which synthesize methionine from homocysteine, and convert methylmalonyl coenzyme A to succinyl coenzyme A, respectively (56). B12 is crucial for the formation of DNA and red blood cells, and proper neurological function (48). Vegans and vegetarians have an increased risk of B12 deficiency due to the dietary restriction of animal-derived foods (44). Elderly individuals and other populations with conditions of malabsorption are also at risk of deficiency (4).

Main Medical Uses

Vitamin B12 supplementation is used to prevent and treat B12 deficiency (5, 7, 45, 66, 101), as deficiencies in B12 can lead to a wide variety of related health conditions. Treatment with B12 is effective in deficiency-related conditions such as pernicious anemia (5, 20, 30), megaloblastic anemia (15), and recurrent aphthous stomatitis (112). B12 deficiencies also can lead to hyperhomocysteinemia (1, 25, 53, 75, 106). Elevated homocysteine levels can occur via methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms, which are associated with B12 deficiency (98). Some evidence supports the use of B12 to reduce homocysteine levels in individuals with MTHFR polymorphisms (70), though it may only play a secondary role to folate (12, 46, 83). Low B12 levels may be associated with an increased risk of developing age-related macular degeneration (34) and depression, particularly with older women (87). Vitamin B12 supplementation has been shown to reduce the risk of depressive relapse and symptom onset (3). B12 may also be effective in treating autism spectrum disorder (10, 42).

B12 may decrease pain in subacute herpetic neuralgia (121) and compressive neuralgia (33), as well as treat diabetic neuropathy (26, 47, 58, 62, 104, 105, 124). B12 may also improve the quality of life and decrease the use of analgesics in patients with postherpetic neuralgia (117). Research has shown that supplementation may also play a role in cognition (16, 29), fatigue (29) and growth (103). Furthermore, B12 may treat multiple sclerosis (54, 115). B12 may have some benefit in celiac’s disease (41), migraines (112), and chronic obstructive pulmonary disease (85). Hydroxocobalamin injections are used to treat suspected cyanide poisoning (23) and may assist in treating Bell’s Palsy when combined with acupuncture (116).

Dosing and Administration

Recommended Dietary Allowance (RDA) for vitamin B12 (48):

  • Ages 0-6 months 0.4 μg (adequate intake)
  • Ages 7-12 months 0.5 μg (adequate intake)
  • Ages 1-3: 0.9 μg
  • Ages 4-8: 1.2 μg
  • Ages 9-13: 1.8 μg
  • Ages 14+: 2.4 μg
  • Pregnancy: 2.6 μg
  • Lactation: 2.8 μg

B12 is found in high concentrations in cow’s liver (26-58 µg/100g), beef and lamb (1-3 µg/100g), eggs (1-2.5 µg/100g), dairy (0.3-2.4 µg/100g) and chicken (up to 1 µg/100g) (73).

For an explanation of the classes of evidence, please see the Rating Scales for Evidence-Based Decision Support.

Forms

Vitamin B12 has four main forms, including synthetic cyanocobalamin and naturally-occurring methylcobalamin, hydroxocobalamin, and adenosylcobalamin. There is currently not enough evidence to suggest differences in bioavailability, biological outcomes, or efficacy between forms. However, the use of cyanocobalamin supplementation is popular due to its inexpensive and stable nature (74). Vitamin B12 can be administered intranasally, intravenously, intramuscularly, or orally in tablet, sublingual lozenge, liquid, or capsule form.

Adverse Effects

Vitamin B12 does not currently have an assigned upper limit (UL). Adverse effects from B12 intake and supplementation are atypical (48). Intramuscular, intravenous, and oral supplementation in diabetic peripheral neuropathy is safe and is not associated with adverse effects (24, 122). Doses of 1000 μg orally and intramuscularly over three months are well tolerated in B12-deficient patients (17) and considered safe for patients with GI disorders (5). Oral cyanocobalamin has been shown to be safe at doses of 1000μg for 18 months (72). Intravenous administration of hydroxocobalamin at doses ranging from 2.5 to 10 grams over 30 minutes was reported to produce reddening of the skin (the color of hydroxocobalamin), pustular/papular rash, headaches, erythema at the injection site, decrease in lymphocyte percentage, nausea, pruritus, chest discomfort, dysphagia, and increased blood pressure in some volunteers (111).

Associated Interactions and Depletions

Pharmacokinetics

Absorption and distribution

The oral bioavailability of vitamin B12 is low. The stomach, pancreas, ileum, and intrinsic factor produced by the stomach are involved in the digestion and active absorption of orally-ingested vitamin B12. Even with a dysfunctional GI system, however, small amounts of free-form B12 from supplements can be absorbed by passive diffusion. Supplemental B12 is not bound to proteins as it would be when found in food. While the total absorption increases with higher intake, relative absorption decreases. For example, 50% of a 1 μg dose may be absorbed, 20% of a 5 μg dose, 5% of a 25 μg dose, and as little as 1% may be absorbed in doses of 500 μg. However, these amounts are often sufficient to meet the RDA for vitamin B12 (84).

After oral ingestion, stomach acid and pepsin uncouple vitamin B12 bound to proteins in food thus allowing B12 to bind to R proteins produced by the salivary glands and gastric mucosa. Supplements containing vitamin B12 are more readily available to bind with R proteins and can be more easily uptaken in the gastrointestinal mucosa as the B12 is not bound to food proteins (84). As vitamin B12 bound to R proteins enters the small intestine, B12 is released from the R proteins that make contact with pancreatic proteases, allowing free B12 to bind with intrinsic factor or to undergo diffusion in the gastrointestinal mucosa if ingested in concentrations that are higher than typically found from food sources (84). This allows B12 to bind with receptors in the mucosa of the ileum and move to enterocytes. After a few hours, B12 may circulate through the blood after binding with transcobalamin I, II or III. Most B12 is bound to transcobalamin I but transcobalamin II is primarily responsible for its deposition in most tissues (48).

Metabolism

After transport into peripheral tissue cells, vitamin B12 is disassociated from transcobalamin II by lysosomes in the cytosol. All forms of vitamin B12 are reduced in the cytosol to its core inactive cobalamin form. Free cytosolic cobalamin can be converted to the active cofactor, methylcobalamin, with the addition of a methyl group derived from 5-MTHF or SAMe (84). Methionine synthase may then use methylcobalamin as an active cofactor to reduce homocysteine and produce methionine, tetrahydrofolate, and subsequently, purines and pyrimidines used in RNA and DNA synthesis (97). The use of vitamin B12 in practice is closely tied to folate and vitamin B6, especially in lowering homocysteine levels (55, 60).

The core cobalamin can also enter the mitochondria to combine with adenosyl derived from ATP molecules to form the active cofactor, adenosylcobalamin. The adenosylcobalamin may then be used by methylmalonyl CoA mutase to convert methylmalonyl CoA to Succinyl CoA, which enters the Krebs cycle (84).

Excretion

The liver acquires 50% of the circulating vitamin B12 with an estimated storage capacity of 2-3 mg, which decreases the likelihood of deficiency. Vitamin B12 can be used in bile and reabsorbed in the presence of intrinsic factor. Vitamin B12 is primarily excreted in the stool, though if it reaches blood saturation, it may be excreted in the urine (48). Between 1.4-5.1 μg are lost each day in healthy and elderly individuals (28).

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