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Background Elevated plasma methylmalonic acid (MMA) and/or total homocysteine (tHcy), as well as low serum vitamin B12 and/or holotranscobalamin (holoTC) are indicative of vitamin B12 deficiency. Combined indicators (cB12), which pool some or all 4 markers into an index, may be a more reliable diagnostic tool to overcome inconclusive diagnoses with individual markers. Objectives We aimed to describe different cB12 score combinations and estimate the prevalence of low or transitional vitamin B12 status compared with individual markers. Design Using cross-sectional data for B12, MMA, and tHcy in persons ≥20 y participating in NHANES 1999–2004 (n  = 12,335), we examined raw and covariate-adjusted regression models to assess determinants of 3cB12 (all 3 markers) and combinations of 2cB12 (2 markers). Results 3cB12 was significantly associated with B12 (Spearman r  = 0.75), MMA (r = −0.70), and tHcy (r = −0.59). The 3cB12 reference interval (2.5th to 97.5th percentile) was -0.538 to 1.60. In covariate-adjusted models, we found no association of 3cB12 with age; adult females and users of B12 supplements had higher, while adults with advanced chronic kidney disease had lower 3cB12 levels regardless of race-Hispanic origin group (self-reported). Only 2.7% of adults had low or transitional vitamin B12 status using the proposed cB12 cutoff of ≤−0.5, while the prevalence of low (or low-normal) status depended on the selected individual marker and its cutoff: 2.2% and 13% for B12 < 148 and 148–222 pmol/L, respectively; 6.0% for MMA exceeding an age-specific cutoff (250–320 nmol/L); and 8.4% for tHcy > 13 µmol/L. The reference intervals for B12, MMA, and tHcy overlapped from the low (<−2.5) to the transitional (−2.5 to −0.5) and to the adequate (>−0.5) cB12 categories. Conclusions Vitamin B12 deficiency may be overestimated among US adults when individual, conventional markers are used. When only 2 markers are available, the combination of B12 and MMA provides results comparable to 3cB12. [ABSTRACT FROM AUTHOR]

As an endogenous inhibitor of nitric oxide production, asymmetric dimethylarginine (ADMA) is reported to be associated with coronary artery disease (CAD). We measured plasma levels of ADMA, nitrate + nitrite (NOx), total homocysteine (tHCY), and renal function in 106 people with angiographic evidence of coronary artery disease (CAD), including 46 with single vessel disease and 60 with double/triple vessel disease, and in 70 age-matched individuals without any angiography evidence of CAD. Also the levels of these parameters were evaluated according to their history of MI. Plasma tHcy and ADMA were measured by HPLC and the levels of NOx using the Griess reaction. Levels of ADMA, ACE and tHcy levels were significantly higher and NO level was significantly lower in CAD patients compared with controls but there were no significant differences among patients with or without history of MI and between patients with single compared to those with double/triple vessel disease. Additionally a negative correlation was found between ADMA-NOx ( r = −0.396, p = 0.001) and between tHcy-NOx ( r = −0.262, p = 0.027). In the entire study group, ADMA level was significantly higher in patients with creatinine clearance (CrCl) < 91 mL/min than in patients with CrCl ≥ 91 mL/min (0.60 ± 0.23 micromoles/L versus 0.49 ± 0.25 micromoles/L, p = 0.05). We suggest that there is an abnormal plasma ADMA-to-NO balance in patients with documented CAD and that this may be due at least in part to an associated reduction in renal function. [ABSTRACT FROM AUTHOR]

Background: Remethylation of homocysteine to methionine can occur through either the folate-dependent methionine synthase pathway or the betaine-dependent betaine-homocysteine methyltransferase pathway. The relevance of betaine as a determinant of fasting total homocysteine (tHcy) is not known, nor is it known how the 2 remethylation pathways are interrelated. Objective: The objectives of the study were to examine the relation between plasma betaine concentration and fasting plasma tHcy concentrations and to assess the effect of folic acid supplementation on betaine concentrations in healthy subjects. Design: A double-blind randomized trial of 6 incremental daily doses of folic acid (50-800 μg/d) or placebo was carried out in 308 Dutch men and postmenopausal women (aged 50-75 y). Fasted blood concentrations of tHcy, betaine, choline, dimethylglycine, and folate were measured at baseline and after 12 wk of vitamin supplementation. Results: Concentrations of tHcy were inversely related to the betaine concentration (r=<0.17, P < 0.01), and the association was independent of age, sex, and serum concentrations of folate, creatinine, and cobalamin. Folic acid supplementation increased betaine concentration in a dose-dependent manner (P for trend = 0.018); the maximum increase (15%) was obtained at daily doses of 400-800 μg/d. Conclusions: The plasma betaine concentration is a significant determinant of fasting tHcy concentrations in healthy humans. Folic acid supplementation increases the betaine concentration, which indicates that the 2 remethylation pathways are interrelated. [ABSTRACT FROM AUTHOR]

Background: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate and homocysteine metabolism. The common MTHFR 677C→T polymorphism decreases the enzyme's activity. Objective: The objective of the study was to assess the effect of the polymorphism on the relations among folate intake, plasma folate concentration, and total plasma homocysteine (tHcy) concentration. Design: The design was a cross-sectional analysis in a random sample (n = 2051) of a Dutch cohort (aged 20-65 y). Results: At a low folate intake (166 μg/d), folate concentrations differed significantly among the genotypes (7.1, 6.2, and 5.4 nmol/L for the CC, CT, and TT genotypes, respectively; P for all comparisons < 0.05). At a high folate intake (250 μg/d), folate concentrations in CT and CC subjects did not differ significantly (8.3 and 8.6 nmol/L, respectively, but were significantly higher (P = 0.2) than those in TT subjects (7.3 nmol/L; P = 0.04). At a low folate concentration (4.6 nmol/L), TT subjects had a significantly higher (P = 0.0001) tHcy concentration than did CC and CT subjects (20.3 compared with 15.0 and 14.1 μmol/L, respectively), whereas at a high folate concentration (11.9 nmol/L), the tHcy concentration did not differ significantly between genotypes (P > 0.2; < 13.1 for all genotypes). The relation between folate intake and tHcy concentration had a pattern similar to that of the relation between plasma folate and tHcy concentrations. Conclusions: At any folate intake level, TT subjects have lower plasma folate concentrations than do CT and CC subjects. Yet, at high plasma folate concentrations, tHcy concentrations in TT subjects are as low as those in CT and CC subjects. [ABSTRACT FROM AUTHOR]

Background: The serum total homocysteine concentration (tHcy), an indicator of folate status and a possible risk factor for vascular disease, is elevated with impaired renal function and poor vitamin B-12 status, which are common in the elderly. Objective: Our objective was to determine the association between tHcy, folate intake, alcohol consumption, and other lifestyle factors in elderly persons. Design: This cross-sectional study used linear regression to model changes in tHcy. Subjects were 278 men and women aged 66-94 y studied in 1993. Results: Total folate intake was negatively associated with tHcy in models adjusted for age, sex, serum creatinine, and serum albumin. We found an interaction between food folate intake and supplement use. Food folate intake had an inverse dose-response relation with tHcy that was limited to nonusers of supplements. Predicted tHcy was 1.5 μmol/L lower in users of supplements containing folate and vitamin B-12 than in nonusers and was independent of food folate intake. We found a positive dose-response relation of coffee and tea intake with tHcy, a positive association for alcohol intake of ≥60 drinks/mo compared with low intake, and an interaction of alcohol use with folate intake and supplement use. Compared with alcohol users, nonusers had higher predicted tHcy and a lower inverse dose-response relation of food folate intake with tHcy. Conclusions: The inverse association between folate intake and tHcy was strongest among nonusers of supplements and among alcohol drinkers. Identifying modifiable factors related to tHcy, a possible risk factor for vascular disease, is especially important in elderly persons. [ABSTRACT FROM AUTHOR]

Background: Total homocysteine (tHcy) measured in serum or plasma is a marker of folate status and a risk factor for cardiovascular disease. Objective: Our objective was to investigate associations between tHcy and complications and adverse outcomes of pregnancy. Design: Plasma tHcy values measured in 1992-1993 in 5883 women aged 40-42 y were compared with outcomes and complications of 14492 pregnancies in the same women that were reported to the Medical Birth Registry of Norway from 1967 to 1996. Results: When we compared the upper with the lower quartile of plasma tHcy, the adjusted risk for preeclampsia was 32% higher [odds ratio (OR): 1.32; 95% CI: 0.98, 1.77; P for trend = 0.02], that for prematurity was 38% higher (OR: 1.38; 95% CI: 1.09, 1.75; P for trend = 0.005), and that for very low birth weight was 101% higher (OR: 2.01; 95% CI: 1.23, 3.27; P for trend = 0.003). These associations were stronger during the years closest to the tHcy determination (1980-1996), when there was also a significant relation between tHcy concentration and stillbirth (OR: 2.03; 95% CI: 0.98, 4.21; P for trend = 0.02). Neural tube defects and clubfoot had significant associations with plasma tHcy. Placental abruption had no relation with tHcy quartile, but the adjusted OR when tHcy concentrations > 15 µmol/L were compared with lower values was 3.13 (95% CI: 1.63, 6.03; P = 0.001). Conclusion: Elevated tHcy concentration is associated with common pregnancy complications and adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]