Plasma Folate Adequacy as Determined by Homocysteine Level^a

Abstract

The classic vitamin deficiency syndromes are the result of acute and severe enzymatic disfunction resulting from extremely low vitamin levels. In recent years, more interest has been focused on less severe deficiencies that may lead to chronic disease. One such relationship is that of folate and homocysteine (HCY). Folate is a cofactor for methionine synthetase, an enzyme that recycles HCY into methionine.' If folate levels are insufficient, HCY levels rise. Elevated HCY levels have been associated with the risks of coronary, cerebral, and peripheral vascularThe relationship between folate and HCY can be used as a sensitive measure to determine what levels of folate are necessary to avoid increased plasma HCY levels. Thus, the objective of this study was to determine the level of plasma folate adequate to prevent an elevation of plasma homocysteine.Plasma folate was measured by microbiological assay, using L . casei as the assay ~rganism.~.' Plasma HCY was measured by electrochemical detection after separation by high-performance liquid chromatography (HPLC).6.7 The population studied included 108 community-based white males (controls) and 101 patients (cases) with angiographically demonstrated coronary artery disease, with comparable demographic characteristics. The cases had angiographic evidence of at least 50% occlusion of one or more major coronary arteries. All subjects were 50 years of age or younger.Cases were found to have lower plasma folate levels than controls (p < 0.0005).The geometric mean of folate was 10.2 nmol/L for cases and 12.5 nmol/L for controls. Plasma HCY levels were significantly higher among cases than among controls (p < 0.0005). The geometric mean of HCY concentration in p n o l / L was 13.5 for cases and 11.9 for controls. Folate levels were inversely associated with HCY levels (p = 0.0001) for both case and control groups. N o difference in the shape or slope of this association was found between cases and controls; thus the groups were combined, and the mean HCY level was plotted by folate level (FIG. I ) .A threshold for low folate can be observed from the FIGURE. Plasma folate levels at the lower range of those considered to be normal in the United States (>6.8 n m~l / L )~.~ were inadequate to prevent elevations in plasma HCY levels. The World Health Organization considered plasma folate levels above 13.6 nmol/ L (6.0 ng/ml) as acceptable.1° The NHANES I1 considered plasma folate levels of less than 6.8 nmol(3.0 ng/mL) asIn the NHANES study, the median plasma

The responsiveness of plasma homocysteine to small increases in dietary folic acid: a primary care study

“…Hence, the importance of the ®ndings of this primary care study which show that the higher the initial homocysteine, the greater the folate effect, even with relatively small increases in folic acid intake. Published work also indicates that there is a decrease in the slope of the inverse relationship between homocysteine and serum folate when folate concentrations are in the upper half of the reference range (Molgaard et al, 1992;Lewis et al, 1992;Selhub et al, 1993;Jacobsen et al, 1994;Pancharuniti et al, 1994). This bimodal inverse relationship is con®rmed here, as the plasma homocysteine decrease following supplementation Homocysteine responsiveness to folate CJ Schorah et al was largely con®ned to those who were initially within the lower tertile of the serum folate range ( Table 2).…”

Folate intake, plasma folate and homocysteine status in a random Finnish population

“…In that case, the prevalence of low plasma folate in our population would increase from 1% to 10.5%. In a similar approach Lewis et al (1992) suggested a cut-off value of 15 nmol=l. Brouwer et al (1998) established a cut-off value of 10 nmol=l using also an oral methionine tolerance test and folic acid supplementation, resulting in 31% being folate deficient.…”

Assessment of three levels of folic acid on serum folate and plasma homocysteine: a randomised placebo-controlled double-blind dietary intervention trial

“…Indeed this is likely given that in the United States fortification of enriched cereal grain products had commenced 2 y prior to the publication of their study (Lawrence et al, 1999). With reference to the microbiological assay, there appears to be a clear inverse association between tHcy and plasma folate when plasma folate is less than 15 nmol=l and a less robust relationship when plasma folate exceeds this level (Lewis et al, 1992). While this appears to be the most likely explanation of the differences in response of tHcy between the study by Malinow et al (1998) and our own study, it should also be noted that participants in the Malinow study were older individuals with ischaemic heart disease while those in the Ward et al (1997) study and our own study were younger and free of clinical disease.…”

“…It is of interest that one of the potentially important clinical and public health benefits of folate, namely its association with tHcy and vascular disease, appears to require a level of serum folate (around 15 nmol=l, Lewis et al, 1992), which can be achieved with a very small amount of supplemental folic acid. This observation is relevant to national policies regarding fortification.…”