Vitamin B12 (cobalamin) is a water-soluble vitamin, first defined in 1926 as
the extrinsic factor in liver that could cure the then-fatal pernicious anemia.
Vitamin B12 is obtained from animal protein products in the diet. In the stomach
it binds to a glycoprotein called intrinsic factor (IF), which is secreted from
the parietal cells of the gastric mucosa. The IF-B12 complex binds to specific
receptors on ileal mucosal cells and is transported to the circulation. In the
circulation, vitamin B12 binds to the plasma globulin transcobalamin II for
transport to cells, where it carries out its metabolic function, or to the
liver, where it is stored until it is needed by other tissues. Because the liver
can store 1 to 10 mg of vitamin B12, and vitamin B12 can be reabsorbed from the
bile in the enterohepatic circulation, strict vegetarians who eat little or no
animal products may only gradually (after 20 to 30 years) develop any vitamin
Vitamin B12 is an essential coenzyme for the normal function of all cells. It
affects cell growth and replication. The active coenzyme forms of vitamin B12
are 5-deoxyadenosylcobalamin and methylcobalamin. 5-deoxyadenosylcobalamin is
required for the conversion of L-methylmalonyl CoA to succinyl CoA, which is an
important reaction in the degradation of certain amino acids and carbohydrate
and lipid metabolism. Methylcobalamin aids in the synthesis of methionine by
transferring a methyl group from methylfolate (folic acid) to homocysteine to
This reaction has two important consequences. First, methionine is converted
to S-adenosyl-methionine, which is an intermediate in methylation reactions and
protein synthesis. Second, by transferring the methyl group from methylfolate,
vitamin B12 regenerates tetrahydrofolate, which is needed for DNA
synthesis. Since methylfolate is the predominant form of folate in the serum, a
deficiency of vitamin B12 leads to folate being "trapped" as
methylfolate, which results in defective DNA synthesis and ultimately
megaloblastic (pernicious) anemia.
This process provides a common basis for the development of megaloblastic
anemia from either a vitamin B12 or folic acid deficiency. The increase in
homocysteine levels and decrease in S-adenosyl-methionine levels that are also a
consequence of vitamin B12 deficiency may play a role in the neurologic symptoms
seen in pernicious anemia.
Most deficiencies of vitamin B12 seen today are not due to a dietary
deficiency but to inadequate absorption. Gastric atrophy or gastric surgery can
inhibit the secretion of IF and lead to vitamin B12 deficiency. Gastric atrophy
is a common cause of vitamin B12 deficiency in the elderly as it is a
progressive, genetically determined, age-dependent disease that occurs as a
person ages. Less common etiologies of vitamin B12 deficiency are pancreatic
disorders, which affect the secretion of pancreatic enzymes that are needed to
release vitamin B12 from salivary proteins (so that it can bind to IF), and a
congenital absence of transcobalamin II.
The best sources of vitamin B12 include the following.
Vitamin B12 is a red crystalline water-soluble substance that contains a
corrin nucleus linked to a central cobalt atom. In the coenzymatically active
forms of vitamin B12, a methyl group or a 5-deoxyadenosyl group is bound to the
Vitamin B12 is commercially available as cyanocobalamin. This is the most
stable form of the vitamin. It is formulated into tablets, softgels, and
lozenges in multivitamin form (including chewable children's multivitamins and
drops), B-complex form, or by itself.
The therapeutic uses of vitamin B12 are limited to conditions that are caused
by B12 deficiency and prophylactic treatment of B12 deficiency. The method of
treating the deficiency depends on its underlying etiology. Symptoms of vitamin
B12 deficiency caused by insufficient intake of vitamin B12 can be alleviated by
oral vitamin B12 therapy, whereas a deficiency due to malabsorption of the
vitamin must be treated parenterally.
Pernicious anemia is the most notable disease of vitamin B12 deficiency.
Pernicious anemia is caused by malabsorption of vitamin B12, most commonly due
to a lack of availability of intrinsic factor. It is characterized by pallor,
glossitis, achlorhydria, gastric mucosal atrophy, weakness, and neurologic
symptoms. Neurologic symptoms include paresthesias of the hands and feet,
unsteadiness, decreased deep-tendon reflexes, and, in later stages of disease,
confusion, loss of memory, and moodiness. Patients can become delusional and
The hematopoietic symptoms such as megaloblastic anemia usually precede
neurologic disorders. Uncomplicated pernicious anemia, which is characterized by
mild or moderate anemia without leukopenia, thrombocytopenia or neurologic
symptoms, can be treated with 1 to 10 mcg of vitamin B12 a day. It is not
pertinent that treatment be given immediately; treatment can wait until other
causes of anemia are ruled out.
Emergency treatment including vitamin B12 and folic acid supplementation as
well as blood transfusions is needed for patients who exhibit neurologic
symptoms, thrombocytopenia, leukopenia, infection, or bleeding. Elderly patients
with severe anemia may also have tissue hypoxia, cerebrovascular insufficiency,
and congestive heart failure. A typical initial treatment consists of 100 mcg of
cyanocobalamin and 1 to 5 mg of folic acid given intramuscularly. Daily
intramuscular injections of 100 mcg of cyanocobalamin and 1 to 2 mg of oral
folic acid should be continued for one to two weeks. Subjective responses to
therapy include the patient's increased sense of well-being within the first 24
hours of therapy. Disappearance of megaloblastic morphology of the bone marrow
is the first objective hematologic response. Improvement of neurologic symptoms
depend on the duration and severity of the abnormality. Full return to normal
function can occur if the abnormality was present only for a few months;
however, patients with abnormalities present for many months or years may never
have a full recovery.
Once started, vitamin B12 therapy for pernicious anemia must be continued
throughout life. Treatment consists of a monthly intramuscular injection of
cyanocobalamin. Patients should be monitored every three to six months to ensure
the effectiveness of the therapy.
Vitamin B12 therapy has been used with some success in the treatment of
children with methylmalonic aciduria.
Together with folic acid and vitamin B6, vitamin B12 has been shown to reduce
high plasma levels of homocysteine, which is an independent risk factor for
|Dosage Ranges and Duration of
The RDA for vitamin B12 is as follows.
- Neonates to 6 months.: 0.3 mcg
- Infants 6 months to 1 year: 0.5 mcg
- Children 1 to 3 years: 0.7 mcg
- Children 4 to 6 years: 1.0 mcg
- Children 7 to 10 years: 1.4 mcg
- Men age 11 years and over: 2.0 mcg
- Women age 11 years and over: 2.0 mcg
- Pregnant women: 2.2 mcg
- Lactating women: 2.6 mcg
Daily oral ingestion of up to 100 mcg of vitamin B12 has no known toxic
Parenteral cyanocobalamin given for vitamin B12 deficiency caused by
malabsorption should be given intramuscularly or by the deep subcutaneous route
but never intravenously.
In one study, 27 patients aged 15 to 54 treated with phenobarbitone (90
mg/day phenobarbital) and diphenylhydantion (300 mg/day phenytoin) regularly for
3 to 32 years had serum levels of vitamin B6 and B12 that were increased
significantly relative to controls (Dastur and Dave 1987). Increased vitamin B12
levels in serum may indicate hepatic damage from anticonvulsants and reflect an
impairment in hepatic storage capacity for the vitamin. Studies in rats suggest
that phenytoin sodium may reduce vitamin B12 uptake by certain cells, including
hematopoietic and neural cells (Latham et al. 1990). It is not known if
phenytoin depletes vitamin B12 levels.
In one study, the bioavailability of tetracycline hydrochloride was reduced
significantly by concomitant administration of vitamin B complex to healthy
subjects (Omray 1981). Patients should be cautioned to take vitamin B complex
supplements at different times from tetracycline.
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factor. Cleve Clin J Med. 1997;64:543-549.
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time, deoxyuridine suppression, 3H-methotrexate uptake and 57C0-cyanocobalamin
uptake in HL60 cells. Clin Lab Haematol. 1990;12(1):67-75.
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Newman WA, ed. Dorland's Illustrated Medical Dictionary. 28th ed.
Philadelphia, Pa: WB Saunders Co; 1994:73.
Nilsson-Ehle H. Age-related changes in cobalamin (vitamin B12) handling:
implications for therapy. Drugs Aging. 1998;12:277-292.
Omray A. Evaluation of pharmacokinetic parameters of tetracylcine
hydrochloride upon oral administration with vitamin C and vitamin B complex.
Hindustan Antibiot Bull. 1981;23(VI):33-37
Remacha AF, Cadafalch J. Cobalamin deficiency in patients infected with the
human immunodeficiency virus. Semin Hematol. 1999;36:75-87.
van Asselt DZ, van den Broek WJ, Lamers CB, et al. Free and protein-bound
cobalamin absorption in healthy middle-aged and older subjects. J Am Geriatr
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