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Am Fam Physician. 2000;61(4):1183-1184

Effective strategies in preventing cardiovascular disease include smoking cessation and reductions in cholesterol levels and blood pressure. Recent epidemiologic studies have shown that moderately elevated plasma homocysteine levels are highly prevalent in the general population and are associated with an increased risk of fatal and nonfatal cardiovascular disease, independent of classic cardiovascular risk factors.

Eikelboom and associates reviewed the medical literature for epidemiologic studies on cardiovascular disease and homocysteine levels, including a Medline database search for articles published between January 1965 and January 1999. Homocysteine is an amino acid produced during catabolism of the essential amino acid methionine. Metabolism of homocysteine requires an adequate supply of folic acid. Deficiency of folic acid, or vitamin B6 or vitamin B12 cofactors can lead to excess homocysteine levels. Severe hyperhomocysteinemia associated with homocysteinuria can be caused by several rare inherited disorders that are associated with extreme elevations of plasma homocysteine levels and premature atherothrombotic disease.

Measurement of plasma homocysteine levels is best performed in patients during the fasting state. Higher fasting homocysteine values are classified as mild and moderate hyperhomocysteinemia (16 to 100 μmol per L) and severe hyperhomocysteinemia (greater than 100 μmol per L). The relation between plasma homocysteine levels and the risk of cardiovascular disease seems to be gradual and linear, as opposed to a sudden increase in risk of vascular disease above a certain plasma homocysteine level.

Mild and moderate homocysteinemia may be caused by a variety of factors (see the accompanying table); the most common causes are deficiencies of folic acid, vitamin B6 and vitamin B12. The atherogenesis associated with hyperhomocysteinemia is caused by endothelial dysfunction and injury followed by platelet aggregation and thrombus formation. Multiple studies of surrogate measures of cardiac events (that include the anatomic extent of carotid, coronary and peripheral vascular disease, and aortic atherosclerotic disease) demonstrate an association with plasma homocysteine levels. Prospective cohort studies that evaluated the association between hyperhomocysteinemia and vascular risk are slightly less conclusive. Studies of the association between dietary intake and blood levels of folate, vitamin B6 and vitamin B12 show positive and dose-dependent associations with the risk of cardiovascular disease.

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Therapy to decrease homocysteine levels includes folic acid taken alone or in combination with vitamins B6 and B12, even in patients who are not frankly vitamin deficient. Folic acid in a dosage of 0.5 to 5 mg per day is associated with an approximate 25 percent reduction in basal plasma homocysteine levels. The addition of vitamin B12 was associated with an additional 7 percent reduction in homocysteine levels. The addition of vitamin B6 did not provide further benefit. A minimal dosage of 0.4 mg per day of folic acid offers maximal efficacy in decreasing plasma homocysteine levels. A higher dosage does not appear to be more effective (except perhaps in patients who have renal failure), and a dosage below 0.1 mg per day seems to be inadequate. Because of varied patient response, the dosage may need to be individualized. A possible side effect of folic acid therapy is progressive neurologic damage in patients who have subclinical vitamin B12 deficiency. In these patients, folic acid therapy masks the hematologic manifestations of the deficiency. This side effect is avoided by screening patients for vitamin B12 deficiency before folic acid therapy is initiated or by supplementing folic acid with vitamin B12 at a dosage of 400 to 1,000 μg per day. The major potential side effect of vitamin B6 therapy is sensory neuropathy, which is associated with patients who are undergoing long-term vitamin B6 therapy and taking doses exceeding 400 mg per day. This side effect rarely occurs with the low doses of 25 to 50 mg per day used to treat patients who have mild or moderate elevated total plasma homocysteine levels.

The authors conclude that epidemiologic studies support a strong, dose-dependent, positive association between moderately increased plasma homocysteine levels and the risk of cardiovascular disease. This association appears to be independent of other known risk factors, although the evidence of an elevated plasma homocysteine level as an independent risk factor for atherothrombotic vascular disease is consistently supported by prospective cohort studies. Reduction of elevated plasma homocysteine levels has yet to be demonstrated as efficacious in reducing the risk of cardiovascular disease. Further studies are necessary to determine whether multivitamin therapy to decrease total homocysteine levels will result in a reduction in the risk of cardiovascular disease.

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