Hyperhomocysteinemia: An Independent Risk Factor for Vascular Disease

BACKGROUND: Hyperhomocysteinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine beta-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of this association and its independence of other risk factors for cardiovascular disease are uncertain. We studied the extent to which the association could be explained by heterozygous cystathionine beta-synthase deficiency. METHODS: We first established a diagnostic criterion for hyperhomocysteinemia by comparing peak serum levels of homocysteine after a standard methionine-loading test in 25 obligate heterozygotes with respect to cystathionine beta-synthase deficiency (whose children were known to be homozygous for homocystinuria due to this enzyme defect) with the levels in 27 unrelated age- and sex-matched normal subjects. A level of 24.0 mumol per liter or more was 92 percent sensitive and 100 percent specific in distinguishing the two groups. The peak serum homocysteine levels in these normal subjects were then compared with those in 123 patients whose vascular disease had been diagnosed before they were 55 years of age. RESULTS: Hyperhomocysteinemia was detected in 16 of 38 patients with cerebrovascular disease (42 percent), 7 of 25 with peripheral vascular disease (28 percent), and 18 of 60 with coronary vascular disease (30 percent), but in none of the 27 normal subjects. After adjustment for the effects of conventional risk factors, the lower 95 percent confidence limit for the odds ratio for vascular disease among the patients with hyperhomocysteinemia, as compared with the normal subjects, was 3.2. The geometric-mean peak serum homocysteine level was 1.33 times higher in the patients with vascular disease than in the normal subjects (P = 0.002). The presence of cystathionine beta-synthase deficiency was confirmed in 18 of 23 patients with vascular disease who had hyperhomocysteinemia. CONCLUSIONS: Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency.