Clinical Significance

Homocysteine (HCY) circulates mostly in its oxidized form. Total homocysteine (tHCY) represents the sum of all the HCY species found in serum or plasma (free plus protein bound). Homocysteine is metabolized to either cysteine or methionine. In the vitamin B6 trans-sulphuration pathway, homocysteine is irreversibly catabolized to cysteine. A major part of homocysteine is remethylated to methionine, mainly by the folate and cobalamin dependent enzyme methionine synthase. Homocysteine accumulates and is excreted into blood when these reactions are impaired. Severely elevated concentrates of total homocysteine are found in subjects with homocystinuria, a rare genetic disorder of the enzymes involved in the metabolism of homocysteine. Patients with homocystinuria exhibit mental retardation, early arteriosclerosis and arterial and venous thromboembolism. Other less severe genetic defects which lead to moderately elevated levels of total homocysteine are also found.

Epidemiological studies have investigated the relationship between elevated homocysteine levels and cardiovascular disease (CVD). The risk associated with a 5 μmol/L increase in total homocysteine was the same as that associated with 0.5 mmol/L (20 mg/dL) increase in cholesterol. Peripheral arterial disease also showed a strong association.

Hyperhomocysteinemia, an elevated level of homocysteine, can be associated with an increased risk of CVD. There have also been many published reports of prospective studies, with mixed results, on the relationship between hyperhomocysteinemia and risk of CVD in men and women who were initially healthy. End points were based on a cardiovascular event such as acute myocardial infarction, stroke, CAD, or mortality. Post-menopausal women who developed cardiovascular events had significantly higher baseline homocysteine levels. Those with levels in the highest quartile had a two-fold increase in risk of any cardiovascular event. Elevated levels of homocysteine are independently associated with increased rates of all-cause and CVD mortality.

Patients with chronic renal disease experience an excess morbidity and mortality due to arteriosclerotic CVD. Elevated concentration of homocysteine is a frequently observed finding in the blood of these patients. Although such patients lack some of the vitamins involved in the metabolism of homocysteine, the elevated HCY levels are mainly due to impaired HCY removal from the blood by the kidneys.