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 B12 deficiency.

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 form methionine.

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.

• Liver
• Kidney
• Milk
• Eggs
• Fish
• Cheese

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 cobalt atom.

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 psychotic.

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 cardiovascular disease.

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 effects.

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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