Emergent Cardiovascular Risk Factor: Homocysteine

Cindy J. Warren, MSN, RN


Prog Cardiovasc Nurs. 2002;17(1) 

In This Article

The Role of Vitamins

The three vitamins necessary to metabolize homocysteine are folic acid, vitamin B6, and vitamin B12. When homocysteine levels are elevated, a deficiency of folic acid, vitamin B12, and to a lesser extent, vitamin B6 may be indicated.[4] Folic acid can be found in citrus fruits, tomatoes, green leafy vegetables, asparagus, broccoli, yeast, lentils, beans, eggs, beef, organ meats, whole grains, and enriched cereals. Vitamin B6 is found in meat, poultry, fish, legumes, peanuts, walnuts, oats, brown rice, and whole wheat. Vitamin B12 is found only in animal products and supplements. It is abundant in organ and muscle meats, fresh shrimp and oysters, fish, milk, eggs, and cheese.[4] Dietary consumption of these vitamins should be evaluated to ensure adequacy.[4] If a patient does not consume adequate B vitamins or has risk factors that predispose to a high homocysteine level, then supplementation is recommended.[4,12]

On January 1, 1998, the Food and Drug Administration mandated that grains and cereals be fortified with folic acid.[4] At the November, 1998 American Heart Association 71st Scientific Sessions, Jacques Genest, Jr., MD, Cardiovascular Genetics Laboratory, Montreal, Canada, was one of the speakers.[18] He recommended the following regimen to reduce homocysteine levels: rule out secondary causes of high homocysteine and treat with a multivitamin containing 400 µg of folic acid. If, after 4-8 weeks of therapy, plasma homocysteine is still elevated, a daily regimen of 1-2 mg of folic acid, 1 mg of vitamin B12, and 100 mg of vitamin B6 is recommended. If his patients remain unresponsive to this regimen, he increases folic acid to 15 mg daily. Despite his own recommendations for treatment, he said the position of the American Heart Association was to recommend that people eat foods rich in B vitamins and folic acid to lower homocysteine levels, but did not recommend vitamin supplementation for therapy of hyper-homocysteinemia.[18] He named six ongoing studies, scheduled to be completed in 5 years, that will likely provide a consensus on the value of treating elevated total plasma homocysteine. Those studies are: VISP (Vitamin Intervention for Stroke Prevention), NORVIT (NORwegian study of total plasma homocysteine lowering with B-VITamins), SEARCH (Study of the Effect- iveness of Additional Reduction in Cholesterol and Homocysteine), WACS (Women Antioxidant and Cardiovascular disease Study), CHAOS-2 (Cambridge Heart Attack AntiOxidant Study), and PACIFIC (Prevention with A Combined Inhibitor and Folate in Coronary artery disease).[18] No other information is currently available about these studies.

At the University of Wisconsin, Patrick McBride, MD, MPH, and James H. Stein, MD, have created an algorithm for the management of patients with hyperhomocysteinemia.[12] They conservatively recommend measurement of Vitamin B12 levels in all patients with hyperhomocysteinemia (total plasma homocysteine of 14 µmol/L or higher). If the vitamin B12 level is low and treated, that may reverse the homocysteine elevation. After vitamin B12 deficiency has been excluded or treated, and offending medications eliminated if possible, folic acid may be started as primary therapy. They start with a folic acid supplement (400-1000 µg) and a high-potency multivitamin (without iron for men and postmenopausal women) that contains at least 400 µg of folic acid and the US recommended daily allowance of vitamin B6 and vitamin B12. They remeasure the homocysteine level 6-8 weeks after beginning treatment. If the level remains high, they increase the amount of folic acid to 2000 µg per day and repeat the homocysteine measurement in another 6-8 weeks. In patients with end-stage renal disease, or in others with high amounts of folic acid loss, up to 5000 µg per day may be needed. If folic acid supplementation is unsuccessful and the homocysteine level is ≥24 µmol/L, vitamin B6 deficiency should be considered. If high homocysteine levels persist, patient compliance should be evaluated or other possible causes should be considered. They noted that this algorithm may need to be modified when the results of prospective clinical trials become available.[12] No other treatment algorithms were found in the literature.

Some researchers have found that B vitamins, taken as a dietary supplement or consumed in fortified cereals and grains, lower homocysteine levels to the normal range.[4,19] Boushey's meta-analysis of 27 studies[19] states that the largest potential reduction of coronary artery disease mortality occurs with folic acid fortification of grains, rather than supplementation with folic acid. Most studies have shown that high homocysteine levels can be lowered by vitamin B supplementation, especially folic acid,[4,5,12,19,20,21] but it has not been proved that taking B vitamins decreases the risk of occlusive vascular disease.[4,5,19,20,22] Folic acid supplementation is considered safe.[4,5,12,19,20,21] Only when folic acid has been given in doses of 10 mg/day or greater have there been reports of exacerbation of vitamin B12 deficiency.[12]

At the Chinese University of Hong Kong, Woo et al. recruited healthy volunteers aged 40-70 who had no history of hypertension, diabetes mellitus, hyperlipidemia, or ischemic heart disease and no family history of premature atherosclerosis.[21] Seventeen of the 89 subjects with fasting total plasma homocysteine levels above the 75th percentile (mean, 9.8±2.8 µmol/L) consented to participate in a double-blind, randomized, crossover study of oral folic acid and placebo. The researchers assessed flow-mediated, endothelium-dependent dilation of the brachial artery using high-resolution ultrasound, before and after folic acid or placebo supplementation. Compared with placebo, folic acid supplementation resulted in higher serum folate levels, lower total plasma homocysteine, and significant improvement in arterial endothelium-dependent dilation. Endothelium-independent responses to nitroglycerin were unchanged. They concluded that folic acid supplementation significantly improves arterial endothelial function in adults with asymptomatic elevations of homocysteine.[21]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.