The case for mild hyperhomocysteinaemia as a risk factor

The high incidence of vascular complications in severe hyperhomocysteinaemia in homozygotes for cystathionine beta-synthase deficiency has focused attention upon homocysteine as an atherogenic and thrombophilic agent. For two decades there has been accumulating evidence of mild hyperhomocysteinaemia as risk factor of vascular disease. Pooled data on hundreds of coronary, cerebrovascular and peripheral arterial disease patients show that mild hyperhomocysteinaemia was detectable in about 20-30%. In a recent meta-analysis of 27 studies up to 1994, including about 4000 patients and as many controls, it is calculated that the summary odds ratio of elevated homocysteine levels was 1.7, with 95% confidence interval (CI) 1.5-1.9, for coronary heart disease; it was 2.5, with 95% CI 2.0-3.0, for cerebro-vascular disease; and it was 6.8, with 95% CI 2.9-15.8, for peripheral vascular disease. The relevance of this newly recognized risk factor will be demonstrated by the outcome of the European Comac study on 'Hyperhomocysteinaemia and Vascular Disease', a multicentre case-control study on 800 vascular patients and 750 controls. Despite the selection for epidemiological reasons of a relatively low cut-off level as the criterion for mild hyperhomocysteinaemia in this study - the upper 20% of the distribution of control levels - the relative risk of thus-defined hyperhomocysteinaemia for arterial disease is about 2. This equals the relative risk of hypercholesterolaemia and of smoking; hypertension leads to a higher excess risk. The observed synergistic interaction between hyperhomocysteinaemia and hypertension and smoking may warrant a change in the now generally followed procedure of screening for hyperhomocysteinaemia only if conventional risk factors have not been detected in the patient. Those vascular patients with combined risk factors leading to synergism in their joint effect may profit most from homocysteine-lowering intervention.