An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.

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Homocysteine and Cardiovascular Disease

In 1969, McCully made the clinical observation linking elevated plasma homocyst(e)ine concentrations with vascular disease.1 He reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in two children with elevated plasma homocyst(e)ine concentrations and homocystinuria. On the basis of this observation, he proposed that elevated plasma homocyst(e)ine (hyperhomocyst(e)inemia) can cause atherosclerotic vascular disease. The term “homocyst(e)ine” is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia. Subsequent investigations have confirmed McCully's hypothesis, and it has recently become clear that hyperhomocyst(e)inemia is an independent risk factor . . .

Homocysteine and atherothrombosis

Objective. —To describe the distribution of plasma homocysteine concentrations in an elderly population and to analyze the relationship between homocysteine level and intake of vitamins and serum levels of vitamins that serve as coenzymes in homocysteine metabolism. Design. —Cross-sectional analysis of homocysteine levels and vitamin blood levels and intake in elderly participants in the Framingham Study. Setting. —Population-based cohort in Framingham, Mass. Participants. —A total of 1160 adult survivors, aged 67 to 96 years, from the original Framingham Heart Study cohort. Main Outcome Measures. —Plasma homocysteine concentration correlated with plasma folate, vitamin B 12 , pyridoxal-5'-phosphate (PLP), and oral intakes of these vitamins, and the contribution of these vitamins to the prevalence of elevated homocysteine in the population. Results. —Homocysteine levels were positively correlated with age after controlling for vitamin concentrations. After controlling for age, sex, and levels of other vitamins, homocysteine exhibited a strong inverse association with plasma folate. When subjects were grouped by deciles of plasma folate, mean homocysteine was significantly higher in the lowest two folate deciles (15.6 and 13.7 μmol/L, respectively) than in the highest decile (11.0 μmol/L). Homocysteine demonstrated weaker, inverse associations with plasma vitamin B 12 and PLP. Similar inverse associations were demonstrated between homocysteine and intakes of folate and vitamin B 6 , but not vitamin B 12 . Prevalence of high homocysteine (>14 μmol/L) was 29.3% in this cohort, and was greatest among subjects with low folate status. Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Conclusions. —These results indicate a strong association between homocysteine concentration and folate, vitamin B 12 , and vitamin B 6 status, as well as age. It is possible that a substantial majority of the cases of high homocysteine in this older population can be attributed to vitamin status. ( JAMA . 1993;270:2693-2698)

Vitamin Status and Intake as Primary Determinants of Homocysteinemia in an Elderly Population

Objective. —To assess prospectively the risk of coronary heart disease associated with elevated plasma levels of homocyst(e)ine. Design. —Nested case-control study using prospectively collected blood samples. Setting. —Participants in the Physicians' Health Study. Participants. —A total of 14916 male physicians, aged 40 to 84 years, with no prior myocardial infarction (Ml) or stroke provided plasma samples at baseline and were followed up for 5 years. Samples from 271 men who subsequently developed Ml were analyzed for homocyst(e)ine levels together with paired controls, matched by age and smoking. Main Outcome Measure. —Acute Ml or death due to coronary disease. Results. —Levels of homocyst(e)ine were higher in cases than in controls (11.1±4.0 [SD] vs 10.5±2.8 nmol/mL; P =.03). The difference was attributable to an excess of high values among men who later had MIs. The relative risk for the highest 5% vs the bottom 90% of homocyst(e)ine levels was 3.1 (95% confidence interval, 1.4 to 6.9; P =.005). After additional adjustment for diabetes, hypertension, aspirin assignment, Quetelet's Index, and total/high-density lipoprotein cholesterol, this relative risk was 3.4 (95% confidence interval, 1.3 to 8.8) ( P =.01). Thirteen controls and 31 cases (11%) had values above the 95th percentile of the controls. Conclusions. —Moderately high levels of plasma homocyst(e)ine are associated with subsequent risk of Ml independent of other coronary risk factors. Because high levels can often be easily treated with vitamin supplements, homocyst(e)ine may be an independent, modifiable risk factor. ( JAMA . 1992;268:877-881)

A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians.

Article de synthese sur le metabolisme de la methionine, acide amine essentiel, chez les mammiferes. Etude du schema metabolique, de la regulation du metabolisme (mise en evidence et importance relative de chaque facteur). Etude de la transamination de la methionine, du role de la S-adenosyl-methionine, de l'oxydation de l'homocysteine et de la cystathionine. Etude du disfonctionnement du metabolisme et des consequences chez les hommes

H Refsum

Papers

Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy.