Measurement of Homocyst(e)ine in the Prediction of Arteriosclerosis

Homocyst(e)ine [H(e)], the sum of homocysteine, homocystine, and the homocysteine-cysteine mixed disulfide, free and protein-bound, has been shown to be associated in retrospective case control studies, and in one prospective study, with vascular disease, including coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease. Elevated levels of homocyst(e)ine severe enough to cause homocystinuria are seen in severe nutritional deficiencies of vitamin B12, folic acid and vitamin B6. Rare genetic disorders of vitamin B12 synthesis of 5′-10′-methylene tetrahydrofolate reductase, or the pyridoxal phosphate-dependent enzyme cystathionine β-synthase may cause severe hyperhomocyst(e)inemia and homocystinuria. The clinical manifestation of these disorders are mental retardation, neurological disorders, and widespread thromboembolic phenomena. The measurement of H(e) is currently performed using high-pressure liquid chromatography with fluorescence detection. Other methods, especially mass spectroscopy, are also used. Internal standards using increasing concentrations of homocystine and acetylcysteine and several external standards are used to ensure accuracy of the assay. Milder elevations of H(e) have recently been associated with vascular disease, in both men and women. The strength of this association appears to be stronger for peripheral and cerebrovascular disease than for CAD. Nevertheless, several case control studies in Europe, Canada, and the United States have shown that H(e) levels are elevated in CAD patients compared with controls, and H(e) levels are independent of the conventional cardiovascular risk factors (age, gender, lipid and lipoprotein cholesterol levels, hypertension, or cigarette smoking). One prospective study, the Physiciansʹ Health Study, has shown that H(e) levels are slightly but significantly higher in CAD cases vs controls in a population of US physicians. Because CAD is a major public health issue, new biochemical markers for the disease are of potential interest. Low-dose folic acid, vitamin B6 or both are used to reduce elevated H(e) levels in affected individuals. Resistant cases may be treated with betaine. It remained to be determined in large, prospective studies, whether H(e) is an important cardiovascular risk factor and whether treatment of an elevated H(e) level will lead to a decrease in cardiovascular events and mortality.