Vitamin Deficiencies

Hyperhomocysteinemia is also caused by B vitamin deficiencies. Deficiencies of folate and vitamin B12 lead to impaired remethylation of homocysteine causing mild, moderate, or severe elevations in plasma homocysteine, depending on the severity of the deficiency, as well as coexistence of genetic or other factors that interfere with homocysteine metabolism (see below). Because riboflavin is required for the synthesis of flavin adenine dinucleotide (FAD), and because FAD serves as a cofactor for MTHFR, ribo-flavin deficiency can also affect homocysteine remethylation, and thus contribute to elevations in plasma homocysteine. Vitamin B6 deficiency leads to impairment of homocysteine catabolism and thus also causes hyperhomocysteinemia. However, the nature of hyperhomocysteinemia caused by vitamin B6 deficiency differs from that caused by folate and vitamin B12 deficiencies: In vitamin B6 deficiency, fasting blood levels of homocysteine are usually not elevated or only slightly elevated. Only after a protein meal or after consumption of an oral methionine load (see below), does plasma homocysteine become abnormally elevated in vitamin B6-deficient patients. In contrast, plasma homocysteine levels tend to be elevated regardless of prandial state in patients with folate or vitamin B12 deficiency. The basis for these different manifestations is likely due to differential effects of the vitamin deficiencies on intracellular SAM levels and consequent disruption of the allosteric control of homocysteine metabolism.

Recently, there has been growing interest in the concept of nutritional genomics. This refers to genetic variability among individuals and its effect on nutritional requirements. A prime example of this concept is a common polymorphism in MTHFR (677C!T) in which an alanine is replaced by valine at codon 222 in the primary sequence of the enzyme. Individuals with the homozygous variant (677TT) of this gene (10-15% of the general population; lower in blacks, higher in Latinos and in some parts of Europe, e.g., Southern Italy) have an enzyme that is thermolabile, with reduced affinity for its substrate (methylenetetrahydrofolate) and its cofactor (FAD). Consequently, 677TT individuals require a higher intake of folate and riboflavin to maintain optimal enzyme activity than those with the wild-type isoform of the enzyme (677CC). This is reflected by the fact that blood homocysteine levels are higher in people with the 677TT isoform than in those with the 677CC isoform, but only when overall folate and/or riboflavin status is low. When overall folate and riboflavin status is high, no difference in homocysteine levels is observed between the isoforms.

The clinical and public health importance of the MTHFR polymorphism is that women with the 677TT isoform are at increased risk of having a child with a neural tube defect (e.g., spina bifida, sp. anencephaly). This risk can be reduced by folic acid supplements, an observation that underlies the decision by the US government to mandate folic acid fortification of grain products as of January, 1998. This program has been highly successful, having reduced the prevalence of folate deficiency from over 20% to about 1%, the prevalence of hyperhomocysteinemia by about 50%, and the incidence of neural tube defects by at least 20%. The success of the folic acid fortification program in the US

spawned similar programs in several countries in the Americas, including Canada, Chile, and Costa Rica. Folic acid fortification has also been initiated in Hungary and Israel, but other European countries, most notably the UK, have been slow to adopt this intervention strategy. This is due to concerns about the feasibility of fortification, a hesitancy to impose manditory fortification on the population, lingering concerns over masking B12 deficiency, and the possibility of other unrecognized health consequences associated with excess folic acid intake.

Other polymorphisms in MTHFR and other enzymes involved in homocysteine metabolism (e.g., methionine synthase, methionine synthase reductase (EC 1.16.1.8), cystathionine ^-synthase) have been identified and their overall influence on homocysteine metabolism, B vitamin requirements, and disease risk have been and continue to be evaluated.

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