Vitamin B12 levels

Vitamin B12 (cobalamin) is a water-soluble vitamin obtained from animal products such as red meat, dairy products and eggs. It is essential for DNA synthesis and cellular energy production.

Vitamin B12, also known as cobalamin, comprises several forms, including cyano, methyl, deoxyadenosyl and hydroxycobalamin. There are no naturally occurring bioactive forms of vitamin B12 from plant sources, and the cyano form, which is used in supplements, is found in trace amounts in foods.

Vitamin B12 is used as a cofactor for enzymes involved in the synthesis of DNA, fatty acids and myelin. Consequently, B12 deficiency can lead to hematological and neurological symptoms.

As a general rule, serum vitamin B12 is bound to proteins known as transcobalamins and most of the vitamin is transported bound to haptocorrin and other types of transcobalamins.

Clinical B12 deficiency, with hematological or neurological manifestations, is relatively uncommon. Vitamin B12 deficiency can occur on the basis of several origins:

  • Autoimmune: Pernicious anemia is an autoimmune disease in which antibodies are produced against intrinsic factor. Intrinsic factor is a glycoprotein produced by the parietal cells of the stomach and necessary for the absorption of B12 in the terminal ileum. Antibodies against intrinsic factor bind to and inhibit the effects of intrinsic factor, resulting in an inability of B12 absorption by the terminal ileum.
  • Malabsorption: The parietal cells of the stomach produce intrinsic factor; therefore, any patient with a history of gastric bypass surgery may be at risk of developing a B12 deficiency because their new dietary pathway bypasses the site of intrinsic factor production. In patients with normal intrinsic factor production, any damage to the terminal ileum, such as surgical resection due to Crohn's disease, will impair B12 absorption and lead to deficiency. Other damage to the small intestine, such as inflammation due to celiac disease or infection with the tapeworm Diphyllobothrium latum, can also lead to B12 deficiency.
  • Dietary insufficiency.

B12 is stored in excess in the liver; however, in cases where B12 cannot be absorbed over a prolonged period (e.g., dietary insufficiency, malabsorption, lack of intrinsic factor), liver stores are depleted and deficiency occurs.

Vitamin B12 is also used as a cofactor for the enzyme methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA. Determination of methylmalonic acid (MMA) and homocysteine levels are frequently tested in clinical practice for B12 deficiency. Measurement of total serum B12 levels has the limitation that it determines total circulating B12 levels, of which approximately 80% is bound to haptocorrin and is therefore not bioavailable for cellular uptake.

Vitamin B12 deficiency in active form (cobalamin) is usually caused by a deficit in dietary intake and is more frequent in women than in men. On the other hand, the genetic factor can also affect vitamin B12 levels since genetic variants have been described that can alter vitamin B12 levels by affecting the proteins involved in its absorption, cellular uptake and intracellular metabolism. It is estimated that the heritability of variations in vitamin B12 levels can reach values of up to 60%.

Currently, genetic studies on vitamin B12 status suggest that it is a multifactorial trait, in which several single nucleotide polymorphisms (SNPs) in multiple genes interact with the environment to cause altered vitamin B12 status.

From a set of literature reviews analyzing the results of genetic studies associated with vitamin B12 status in healthy individuals from populations of different ancestries, 7 associated markers have been identified. Among the genes involved in vitamin B12 levels we can find the FUT2 gene, a gene encoding a 1, 2-fucosyltransferase. This enzyme is involved in the synthesis of ABO(H) blood group antigens on the surface of blood and epithelial cells and is necessary for the presence of soluble forms of these antigens in different secretions.

The TCN2 gene, which produces the transcobalamin 2 protein, which binds to vitamin B12 for transport; the MTHFR gene, which produces an enzyme involved in homocysteine methylation and is dependent on vitamin B12; and the CLYBL gene, which produces a mitochondrial protein and is responsible for the binding of metal ions.

Number of observed variants

13.5 million variants

Number of variants analyzed in the study

7 variants

Bibliography

Surendran S., Adaikalakoteswari A., et al An update on vitamin B12-related gene polymorphisms and B12 status. Genes Nutr. 2018 Feb 6;13:2.

Velkova A., Díaz J.E.L., et al. The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation. Hum Mol Genet. 2017 Dec 15;26(24):4975-4988.

Ankar A. et Kumar A. (2021) Vitamin B12 Deficiency. StatPearls.

O’Leary F. et Samman S. Vitamin B12 in Health and Disease. Nutrients. 2010 Mar; 2(3): 299–316.

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