Homocysteine in Health and Disease

Is an elevated plasma homocysteine level bad for you? Homocystinuria, the consequence of a severely elevated plasma homocysteine level of genetic origin, was first described in 1962 (1, 2). Patients with homocystinuria frequently experience thromboembolic events. Thirty years ago, McCully (3) noted that several different metabolic defects were characterized by two common factors: homocystinuria and premature thromboembolic disease. This implied that the elevated plasma levels of homocysteine, rather than any other metabolite, was the cause. With this information, McCully and Wilson evolved the homocysteine theory of arteriosclerosis (4), from which it has been suggested that a moderately elevated plasma homocysteine level may be a cardiovascular risk factor in the general population. As with plasma cholesterol levels, homocysteine levels may be determined by both genetic and nutritional factors. Genetic causes are mostly defects in the enzymes that control homocysteine metabolism, whereas nutritional causes are deficiencies of folate, vitamin B12, or vitamin B6, all of which affect homocysteine metabolism. Vitamin B6 is a co-factor for the irreversible degradation of homocysteine, and vitamin B12 and folate are both required for the remethylation of homocysteine to methionine. Subsequent ecological, cross-sectional, casecontrol, nested casecontrol, and cohort studies by and large indicate an association between elevated plasma homocysteine level and cardiovascular disease (5-8). However, Danesh and Lewington's meta-analysis (8) indicates that the more rigorous the epidemiologic methods, the weaker the association. It has been suggested that an elevated plasma homocysteine level merely indicates lower socioeconomic status and poor nutrition, or that it may be the result of cardiovascular disease rather than the cause. Although the association between genetic hyperhomocysteinemia and vascular disease would clearly indicate that the elevated homocysteine level precedes the disease, these issues have not been definitively resolved. In this issue, Kark and colleagues (9) address some of these questions. In a community cohort study of 1788 middle-aged and elderly residents of Jerusalem, they recorded 405 deaths over a decade. Overall, the mortality hazard ratio was 2.0 (95% CI, 1.3 to 3.0) when the highest and lowest fifths of the homocysteine distributions were compared. The difference was greater in men than in women. Ten percent of deaths were attributable to homocysteine levels exceeding 14 mmol/L. The association applied to both total and cardiovascular mortality. It also persisted after adjustment for self-appraised health, serum creatinine concentration, and albumin level (a marker of poor health status). The association was strongest in the first 5 years of follow-up. Thus, this study suggests that an elevated plasma homocysteine level is associated with both cardiovascular and total mortality and that the elevation precedes the disease. These findings support a recent report from the Framingham Study (10) indicating that nonfasting plasma total homocysteine levels relate to both all-cause and cardiovascular disease mortality in elderly participants. It is helpful to place these reports in the context of other published epidemiologic studies. Of 22 studies included in Danesh and Lewington's meta-analysis (8), 20 showed a significant or almost significant association between increasing plasma homocysteine level and risk for coronary heart disease. The higher risks found in the studies with less rigorous design suggest that part of the increased risk may be due to design biases. On the other hand, allowance for regression dilution bias, which was not made in these studies, would increase the association with risk. It is also not clear whether the two negative nested casecontrol studies reflect truth or some other factor, such as variable conditions of blood sampling and storage. Eikelboom and colleagues (11), whose report also appears in this issue, provide a careful and methodical review of the epidemiologic evidence relating homocysteine to cardiovascular disease. Unlike Danesh and Lewington, these authors think that the heterogeneity of available studies makes formal meta-analysis problematic. These authors also conclude that although the association between homocysteine and cardiovascular disease is consistent, strong, and biologically plausible, the data from prospective studies are weaker, with some conflicting results. Thus, causality has not been proven beyond reasonable doubt. Do we need reference ranges for plasma homocysteine levels? The answer has to be yes. First, plasma homocysteine is a very sensitive marker of folate and vitamin B12 status; plasma homocysteine levels are inversely related to plasma levels of these substances. The increase in homocysteine level occurs long before classic deficiency of folate and vitamin B12 is evident. Second, an elevated plasma homocysteine level, as already indicated, is a risk marker, although it is not proven to be a causal risk factor. Third, data from the European Concerted Action Project suggest that an elevated plasma homocysteine level interacts with conventional risk factors to further increase vascular disease risk (12). Thus, it may be particularly important for a person with a high homocysteine level to avoid smoking and to be particularly careful about control of hypertension and hyperlipidemia. In this issue, Selhub and colleagues (13) have added to their many important studies of relations among nutrition, homocysteine, and cardiovascular risk. They used data from the Third National Health and Nutrition Examination Survey to establish reference ranges for total plasma homocysteine levels. Using a nationally representative sample of 3563 men and 4523 women 12 years of age or older, they define reference ranges for total homocysteine level among persons who are folate and vitamin B12 replete and have normal creatinine concentrations. Given the unique nature of the database, it would have been helpful to also have tables of the 5th, 10th, 20th, 50th, 80th, 90th, and 95th percentiles of homocysteine broken down by age and sex for all participants, not just for those who were folate and vitamin B12 replete. This would provide a picture of the current situation in a U.S. population, as well as reference ranges for an idealized, nutritionally replete group. Selhub and colleagues' data on attributable risk and population attributable risk for increased homocysteine levels are of considerable interest. The attributable risk figures indicate that most people with an inadequate level of serum folate or vitamin B12 have high homocysteine levels. The population attributable risk figures suggest that most of the hyperhomocysteinemia at the population level is attributable to inadequate folate status because this occurs far more frequently than low vitamin B12 status. However, these data depend critically on the definition of low folate and vitamin B12 status. It seems that low vitamin B12 status was defined in an elderly Framingham population, and this definition may not be relevant to the much younger population surveyed in the Third National Health and Nutrition Examination Survey. Thus, the population attributable risk data must be interpreted with some caution. For the practicing physician, the critical questions are whether homocysteine levels should be measured as part of risk assessment and whether folate or vitamin B12 should be prescribed for persons with high homocysteine levels. Certainly, measurement of plasma homocysteine will refine risk prediction, given its interaction with conventional risk factors. Answers about prescribing folic acid or vitamin B12 must wait for the results of randomized, controlled trials (14). To date, seven such trials are being initiated or are under way (15). In the meantime, it may be reasonable to suggest folic acid supplementation in dosages of 0.4 to 1.0 mg/d for high-risk persons with elevated plasma homocysteine levels and to encourage the eating of plenty of fruit and vegetables for the rest of us, just as our parents always told us.