EFFECT OF VITAMIN SUPPLEMENTATION
AND DIET ON HOMOCYSTEINE
Cross-sectional and experimental evidence suggests that mild hyperhomo-cysteinemia may be related to subclinical deficiencies of folate, vitamin B6, and vitamin B12-all co factors or co substrates in homocysteine metabolism (84 - 93). In a study of vitamin and tHcy levels in an elderly population, Selhub and coauthors (21) found a strong inverse correlation between tHcy and plasma folate, and weaker inverse correlations between tHcy and both cobalamin and vitamin B6 (pyridoxal-5-phosphate). The authors concluded that elevated tHcy levels could, in great part, be due to poor vitamin status, and these results have been confirmed in many other studies. Many studies have assessed the effects of vitamin supplementation on plasma tHcy. Levels in folate-deficient patients can be reduced by oral folate supplementation.
In one study, the elevated tHcy in patients with renal failure decreased after only 2 wk of folate therapy. Maximal effects may be seen after 4 to 6 wk of therapy. The lowest effective dose for folate supplementation has not yet been determined. Doses of 5 mg or 10 mg alone or 1 mg in conjunction with vitamins B12 and B6 may be effective. Ubbink and colleagues confirmed by intervention that a daily supplement of folate (1 mg), B6 (10 mg) and B12 (0.4 mg) could normalize elevated tHcy (> 16.3 Ilmol/L, n = 44) within 6 wk. Ubbink and colleagues then looked at the effect of supplementation with the individual vitamins in 100 men, aged between 20 and 73 yr, with tHcy greater than 16.3 Jlffiol/L, over 6 wk. Folate supplementation (0.65 mg/d) reduced plasma tHcy by 42% whereas a daily vitamin B'2 supplement (0.4 mg/d) lowered it by 15%. The vitamin Bs supplement (10 mg/d) had no significant effect. The combination of the three vitamins reduced circulating tHcy by 50% that was not significantly different from the reduction achieved by folate supplementation alone.
Brattstrom and coworkers noted significantly lower tHey in middle-aged and elderly subjects taking multivitamins containing doses of folic acid ranging from only 200 - 400 Ilg. Homocysteine values increase if vitamin therapy is discontinued. Ward and colleagues carried out an uncontrolled study examining the effect oflow-dose folate supplementation in healthy male subjects. Folate supple-ments were administered daily at doses increasing from 100 Ilg for 6 wk to 200 Ilg for 6 wk and then up to 400 pig for 14 wk. A dose of 200 Ilg/d appeared to be the optimum tHey-lowering dose as there was no apparent benefit of increasing the dose to 400 Ilg/d. The subjects had reported a mean dietary folate intake of 281 ± 60 Ilg/d. Their total folate intake, with the additional 200 pig supplement, therefore corresponds well with the observation by Selhub and colleagues that total intakes over 400 Ilg/d are associated with desirable tHcy in a healthy elderly US population.
When the analysis in the former study was carried out by tertiles of baseline tHey, the lowest tertile group showed no increase in red-cell folate over the 6-mo supplementation period, suggesting that their baseline folate status was optimal to begin with. Ward and associates suggests that, although there does not appear to be a threshold in the relationship between elevated tHcy and CVD risk, there may be a threshold of plasma tHey in terms of ability to respond to folate. A further randomized placebo-controlled study in healthy women aged 18 40 yr confirmed that both 250 Ilg and 500 Ilg folate/d for 4 wk decreased tHcy. Eight weeks after the end of folate supplementation, tHey had not returned to baseline. A meta-analysis of 12 studies using B-group vitamins to lower tHcy has recently been carried out.
The magnitude of tHcy reduction was related to the pretreatment tHcy and folate levels.
Folate reduced tHcy by 25% (95% CI 23 - 28%), and the effects were similar at daily doses ranging from 0.5 - 5 mg. Vitamin BI2 yielded a further tHey reduction of 5 - 6%, but vitamin Bs had no significant effect. None of these trials, assessed the effect on tHcy after methionine loading, however, which is determined by the transsulfuration pathway where vitamin Bs is a cofactor. The effectiveness of vitamins BIZ and Bs in homocysteine-lowering therapies needs further study.
Alien and associates have shown that folate supplementation will not correct hyperhomocy steinemia that is primarily the result of vitamin BIZ defi~iency, whereas Robinson and colleagues found that vitamin B6 was inversely related to risk of CVD independently of homocysteine, although this may be due to its ability to modulate the homocysteine peak after the oral methionine load test. Administration of vitamin Bs alone does not lower fasting tHcy. Dose-optimizing studies for these vitamins are also required. Woodside and colleagues have tested the hypothesis that simultaneous administration of antioxidant vitamins may potentiate the effect ofB-group vitamins on elevated tHey. An interaction between antioxidants and folate is conceivable because the latter is susceptible to inactivation by freeradical mediated oxidation, which can be prevented both in vitro and in vivo by vitamin C.
Although B-group vitamins lowered tHey by roughly 30%, the addition of antioxidant vitamins to the supplement had no effect on this. It is clear from the foregoing evidence above that B-group vitamin supplementation effectively lowers plasma homocysteine. The question therefore arises whether a dietary change in B-vitamin intake or food fortification can achieve
