Homocysteine and vascular disease

A mong Australians with vascular disease aged up to 65 years the standard genetic and environmental risk factors explain only about 50% of the occurrence and extent of the disease. I Clearly, other factors contribute, and recent interest has focused on a possible role for increased circulating levels of homocysteine. Homocysteine occupies a pivotal position in the metabolism of the essential sulfur-containing amino acid and methyl donor methionine (Figure). There is abundant methionine in the high protein diets usually consumed in developed countries, in which vascular disease is also common. The link between homocysteine and vascular disease was established in the early 1960s with the discovery of the inborn error of metabolism homocystinuria. This uncommon disorder, with a prevalence of about 1 in 60000 of the New South Wales population, is due to a recessively inherited deficiency of the enzyme cystathionine l3-synthase, which mediates the conversion of homocysteine to cystathionine (the first step in the trans-sulfuration pathway) and the urinary excretion of sulfur." Patients with this disorder have very high levels of circulating homocysteine (usually> 200 umol/L of "free" homocysteine), the equivalent of over 400 urnol/L of free plus protein-bound homocysteine. High levels of homocysteine produce endothelial damage, smooth muscle cell proliferation and thrombogenesis, and there is increasing evidence that even modest homocysteine elevation may impair endothelial function and nitric oxidemediated vasodilatation.v' Untreated, 50% of patients with homocystinuria will have a vascular event before the age of 30 years." The question then arose as to whether mildly elevated levels of circulating homocysteine, now often written as homocyst(e)ine to include all free-plus-bound moieties, could contribute to the pathogenesis of vascular disease." The association between modest homocysteine elevation and coronary artery disease identified in initial studies-? has now been substantiated and extended in a large number of publications to include cerebrovascular and peripheral vascular disease. In a meta-analysis, Boushey et al estimated that a 5I-Lmol/L increase in total (free and bound) homocysteine (normal range, 5-15 umol/L) conferred the same increase in coronary risk as an increase of 0.5 mmol/L of total cholesterol," and the most recent cross-sectional? and prospective'? studies confirm these strong associations. Furthermore, homocysteine levels are significantly increased in patients with chronic renal failure, among whom there is about a 20-fold unexplained increase in cardiovascular risk. ll , 12 What, then, are the causes of mild homocyst(e)ine elevation (hyperhomocysteinaemia)? In a diet containing adequate amounts of protein about 50% of homocysteine formed is remethylated back to methionine in steps which require folate and vitamin BI 22 as well as the enzyme 5,10methylenetetrahydrofolate reductase (MTHFR). More is