Lower Homocysteine Concentrations Research Articles

Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?

In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements. The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians. Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency. The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.

Relationship between Serum Homocysteine Concentration and Dietary Factors in Young Japanese Women.

Homocysteine is a methionine metabolism intermediate and its increased blood levels are associated with a higher risk of noncommunicable diseases. Reportedly, blood homocysteine levels increase with inadequate folate, vitamin B6, and vitamin B12 intake; however, its relationship with dietary factors other than these three vitamins remains unknown. Thus, we investigated the relationship of homocysteine with other nutrient intake. We performed a dietary survey on 227 young women using a food record with approximate amounts for 7 consecutive days in conjunction with digital imaging. We collected early morning fasting blood samples the day after the dietary survey was completed and analyzed the serum homocysteine levels. We observed that the serum homocysteine concentrations were significantly negatively associated with soluble, insoluble, and total fiber intake. In addition, participants with high fruit and mushroom intake displayed lower serum homocysteine concentrations, suggesting dietary fiber involvement from these foods. However, we observed no serum homocysteine concentration-related association with cereals and vegetables (well-documented dietary fiber sources) or with fruits and mushrooms. In conclusion, fiber quality-related differences could thus be caused by different sources, including antioxidant components such as fruit polyphenols and mushroom antioxidant and anti-inflammatory factors.

The role of folate in the management of insulin resistance in adults : a systematic review

Insulin resistance (IR) is one of the main risk factors for type 2 diabetes. IR employs a heavy economic burden, and the prevalence rate of IR in Indonesia is high. Homeostasis model of assessment-insulin resistance (HOMA-IR) is proven to be a great clinical tool to assess IR. Nutrition intervention should be the primary focus in treating IR. Folate is proven to be effective in lowering homocysteine concentrations, which is one of the risk factors for IR. This study aimed to summarize the role of folate in the management of IR in adults.

Homocysteine, folate, and nonalcoholic fatty liver disease: a systematic review with meta-analysis and Mendelian randomization investigation

Circulating concentrations of homocysteine and folate are inconsistently associated with the risk of nonalcoholic fatty liver disease (NAFLD) in observational studies. We conducted a meta-analysis and Mendelian randomization (MR) analyses to examine these associations. We performed a meta-analysis of observational studies identified from 3 databases to evaluate the associations of serum homocysteine and folate concentrations with NAFLD from inception to 7 April 2022. We conducted MR analyses to strengthen the causal inference in these associations. Independent single-nucleotide polymorphisms without linkage disequilibrium (r2<0.01) that were strongly associated (P < 5×10-8) with serum homocysteine (n=13) and folate (n=2) concentrations were selected as instrumental variables from 2 meta-analyses of genome-wide association studies (GWASs) of 44,147 and 37,645 individuals of European ancestry, respectively. Data on NAFLD were obtained from a GWAS of 8434 NAFLD cases and 770,180 controls of European ancestry. We further included 4 liver enzymes as secondary outcomes from a GWAS of 361,194 individuals with European descent. Twenty-two observational studies comprising 30,368 participants were included in the meta-analysis. There was a positive association between serum homocysteine and NAFLD risk (n=20; OR: 1.96; 95% CI: 1.57, 2.45) and an inverse association between serum folate and NAFLD risk (n=12; OR: 0.75; 95% CI: 0.58, 0.99). In MR analysis, the ORs of NAFLD were 1.17 (95% CI: 1.01, 1.36) and 0.75 (95% CI: 0.55, 1.02) per 1-SD increment of genetically predicted circulating concentrations of homocysteine and folate, respectively. Each 1-SD increase of genetically predicted circulating homocysteine and folate conferred a change in ALT concentrations of 0.62 U/L (95% CI: 0.20, 1.04) and -0.84 U/L (95% CI: -0.14, -1.54). This study suggests a potential role of circulating homocysteine and possibly folate in NAFLD, which calls for future clinical exploration of the possibility of lowering homocysteine concentrations to prevent NAFLD. This systematic review was registered at PROSPERO as CRD42021296434.

Preoperative homocysteine modifies the association between postoperative C-reactive protein and postoperative delirium.

BackgroundHomocysteine and C-reactive protein (CRP) may serve as biomarkers of postoperative delirium. We set out to compare the role of blood concentration of homocysteine versus CRP in predicting postoperative delirium in patients.Materials and methodsIn this prospective observational cohort study, the plasma concentration of preoperative homocysteine and postoperative CRP was measured. Delirium incidence and severity within 3 days postoperatively were determined using the Confusion Assessment Method and Confusion Assessment Method-Severity algorithm.ResultsOf 143 participants [69% female, median (interquartile range, 25th–75th) age of 71 (67–76) years] who had knee or hip surgery under general anesthesia, 44 (31%) participants developed postoperative delirium. Postoperative plasma concentration of CRP was associated with postoperative delirium incidence [adjusted odds ratio (OR) per one standard deviation change in CRP: 1.51; 95% Confidence Interval (CI): 1.05, 2.16; P = 0.026], and severity [in which each one standard deviation increase in postoperative CRP was associated with a 0.47 point (95% CI: 0.18–0.76) increase in the severity of delirium, P = 0.002] after adjusting age, sex, preoperative Mini-Mental State Examination score and the days when postoperative CRP was measured. A statistically significant interaction (adjusted P = 0.044) was also observed, in which the association between postoperative plasma concentration of CRP and postoperative delirium incidence was stronger in the participants with lower preoperative plasma concentrations of homocysteine compared to those with higher preoperative levels.ConclusionPending validation studies, these data suggest that preoperative plasma concentration of homocysteine modifies the established association between postoperative plasma concentration of CRP and postoperative delirium incidence.

B vitamins and homocysteine as determinants of bone health: A literature review of human studies.

Although there are several factors related to bone diseases such as physical activity, gender (oestrogen), race/ethnicity, smoking and alcohol habits, nutrition is a modifiable risk factor that could be employed to prevent or manage the onset of bone health diseases such as osteoporosis in humans. Aside from calcium and vitamin D, B vitamins are a group of water-soluble vitamins that play a vital role in cell metabolism. In this review, current evidence on B vitamins and bone health is assessed. Clinical trials (interventions) indicate that treatment with B vitamins impact the concentrations of total plasma/serum homocysteine concentrations (tHcy); however, most studies have reported the lack of an effect of low homocysteine concentrations on bone turnover markers, bone mineral density or fracture risks. Current studies have been inconsistent in their reports on the role of B vitamins and homocysteine in bone health. More data are therefore required to show the mechanism and effect of tHcy and B vitamins on bone mineral density, bone metabolism and fracture risk.

Maternal serum concentrations of one-carbon metabolism factors modify the association between biomarkers of arsenic methylation efficiency and birth weight

BackgroundInorganic arsenic (iAs) is a ubiquitous metalloid and drinking water contaminant. Prenatal exposure is associated with birth outcomes across multiple studies. During metabolism, iAs is sequentially methylated to mono- and di-methylated arsenical species (MMAs and DMAs) to facilitate whole body clearance. Inefficient methylation (e.g., higher urinary % MMAs) is associated with increased risk of certain iAs-associated diseases. One-carbon metabolism factors influence iAs methylation, modifying toxicity in adults, and warrant further study during the prenatal period. The objective of this study was to evaluate folate, vitamin B12, and homocysteine as modifiers of the relationship between biomarkers of iAs methylation efficiency and birth outcomes.MethodsData from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort (2011–2012) with maternal urine and cord serum arsenic biomarkers and maternal serum folate, vitamin B12, and homocysteine concentrations were utilized. One-carbon metabolism factors were dichotomized using clinical cutoffs and median splits. Multivariable linear regression models were fit to evaluate associations between each biomarker and birth outcome overall and within levels of one-carbon metabolism factors. Likelihood ratio tests of full and reduced models were used to test the significance of statistical interactions on the additive scale (α = 0.10).ResultsAmong urinary biomarkers, % U-MMAs was most strongly associated with birth weight (β = − 23.09, 95% CI: − 44.54, − 1.64). Larger, more negative mean differences in birth weight were observed among infants born to women who were B12 deficient (β = − 28.69, 95% CI: − 53.97, − 3.42) or experiencing hyperhomocysteinemia (β = − 63.29, 95% CI: − 154.77, 28.19). Generally, mean differences in birth weight were attenuated among infants born to mothers with higher serum concentrations of folate and vitamin B12 (or lower serum concentrations of homocysteine). Effect modification by vitamin B12 and homocysteine was significant on the additive scale for some associations. Results for gestational age were less compelling, with an approximate one-week mean difference associated with C-tAs (β = 0.87, 95% CI: 0, 1.74), but not meaningful otherwise.ConclusionsTissue distributions of iAs and its metabolites (e.g., % MMAs) may vary according to serum concentrations of folate, vitamin B12 and homocysteine during pregnancy. This represents a potential mechanism through which maternal diet may modify the harms of prenatal exposure to iAs.

Effect of Folate and/or Vitamin B12 Supplementation between 6 to 30 Months of Age on Markers of Cardiovascular Illness at School Age: A Secondary Analysis

ObjectivesDeficiencies of vitamin B12 and folate in childhood are associated with cardiovascular risk in later life. The main objective of this analysis is to measure the effect of vitamin B12 and/or folic acid supplementation in children between 6 to 30 months of age on biochemical markers of cardiovascular risk at school age.MethodsThis is a follow-up study of a randomized, 2 × 2 factorial, double-blind, placebo-controlled trial which assessed the effect of 2 recommended daily allowances of vitamin B12 and/or folic acid supplementation for 6 months on the risk of common infections in children aged between 6 to 30 months. The follow-up study was done 6 years later. The outcomes of the current analyses were plasma concentrations of total homocysteine, leptin, high molecular weight (HMW) adiponectin, and total adiponectin. We used multivariable linear regression to measure the effect of vitamin B12, folic acid, or both during early childhood on these outcomes. We included interaction terms in the statistical models to measure whether the two vitamins modified the effect of each other.ResultsCompared to the placebo, giving both B12 and folate supplementation resulted in 1.19 μmol/L (95% confidence interval: 0.09, 2.30) lower total homocysteine concentration at 7 years of age. There was no effect of B12 and folate supplementation on any of the other biomarkers. The effect of folic acid or vitamin B12 alone did not reach statistical significance for any of the outcomes.ConclusionsVitamin B12 and folic acid supplementation in early life resulted in lower plasma homocysteine at school age. Elevated homocysteine is a risk factor for many illnesses and our findings support improving the status of these vitamins in early life.Funding SourcesThe main study and follow-up study were funded by Thrasher Research Fund and Research Council of Norway.

Association between homocysteine and obesity: A meta-analysis.

According to previous studies of obesity, we found that the association between homocysteine concentrations and obesity was reported controversially. Thus, we carried out this meta-analysis to investigate this association. We searched PubMed, The Cochrane library, and EMBASE database for studies that evaluate the relationship between homocysteine concentrations and obesity from inception to March, 2019. The quality of all included studies was assessed by the Newcastle Ottawa Scale (NOS) and the Agency for Healthcare Research Quality (AHRQ). The RevMan5.3 software and Stata12.0 software were used for conducting all data analyses. Standardized mean differences (SMD) with the corresponding 95% confidence intervals (95% CIs) were used as a measure of effect size to assess the relationship betweenhomocysteine concentrations and obesity through a meta-analysis. The level of significance was set at P<.05. A total of 14 studies were ultimately included in our meta-analysis. Meta-analysis of the 14 studies found remarkable lower homocysteine concentrations in controls than in obese patients (SMD=0.76, 95% CI=0.25-1.27, P<.01; I2 =94% and P<.01 for heterogeneity), regardless of nutritional status, dietary habit, insulin resistance (IR) status, special disease history, history of medicine taken, genetic background, and so on. Homocysteine concentrations in nonobese patients with polycystic ovarian syndrome (PCOS) were lower than obese patients with PCOS (SMD=0.48, 95% CI=0.20-0.77, P<.01; I2 =39% and P=.18 for heterogeneity). The result of our meta-analysis showed that homocysteine concentrations were significantly elevated among obese patients.

Association of antenatal vitamin B complex supplementation with neonatal vitamin B12 status: evidence from a cluster randomized controlled trial.

Evidence about the effect of maternal vitamin B12 supplementation on offspring's vitamin B12 status is limited. The present interventional study sought to evaluate the association of antenatal vitamin B complex supplementation with neonatal vitamin B12 status. In an ongoing cluster randomized controlled trial conducted in three rural counties in northwest China, pregnant women < 20weeks of gestation were randomized to three treatment groups: blank control, iron supplements, or vitamin B complex supplements. All women were administered folic acid supplements during the periconceptional period. In a sub-study, we collected cord blood samples of 331 participants from the control or vitamin B complex groups in the Xunyi county from January 2017 to December 2017. Plasma concentrations of folate, vitamin B12, and homocysteine were measured. Linear mixed models with a random intercept for cluster were used to compare biochemical indexes between groups after controlling for covariates. Compared with newborns whose mothers were in the control group, newborns of the vitamin B complex-supplemented women had significantly higher cord plasma vitamin B12 (P = 0.001) and lower homocysteine concentrations (P = 0.043). The association of antenatal vitamin B complex supplementation with cord blood vitamin B12 concentrations appeared to be more pronounced among newborns with high folate status than those with low folate status (Pinteraction = 0.060). Maternal vitamin B complex supplementation during pregnancy was associated with better neonatal vitamin B12 status in rural northwest China.

Homocysteine is associated with severity of microvasculopathy in sickle cell disease patients.

The pathophysiology of sickle cell disease (SCD) includes vasculopathy as well as anaemia. Elevated plasma homocysteine is a risk factor for vascular disease and may be associated with increased risk of vascular complications in SCD patients. In the present study, microvascular characteristics were assessed in the bulbar conjunctiva of 18 paediatric and 18 adult SCD patients, using the non-invasive technique of computer-assisted intravital microscopy. A vasculopathy severity index (SI) was computed to quantify the degree of microvasculopathy in each patient. Plasma homocysteine and several of its determinants [serum folate and vitamin B12, plasma pyridoxal-5'-phosphate (vitamin B6 status) and creatinine (kidney function)] were measured. Age was strongly correlated with microvasculopathy in the SCD patients, with the SI increasing about 0·1 unit per one-year increase in age (P<0·001). After adjusting for age, gender, B-vitamin status and creatinine, homocysteine concentration was directly correlated with severity index (P<0·05). Age and homocysteine concentration were independent predictors of microvasculopathy in SCD patients. It remains to be determined whether lowering homocysteine concentrations using appropriate B-vitamin supplements (folate and vitamins B12 and B6) - particularly if started early in life - could ameliorate microvasculopathy and its associated complications in SCD patients.

A prospective study of serum concentrations of leptin, homocysteine and insulin resistance in children with steroid-sensitive nephrotic syndrome

Aim: To measure serum leptin, homocysteine concentrations and insulin resistance in active and remission stages of children with nephrotic syndrome (NS) and to investigate their role in NS pathogenesis. Methods: A total of 70 children were included in the study, 40 patients who had been diagnosed with NS and 30 healthy patients were control. Changes in plasma concentration of the serum homocysteine, leptin, and insulin were measured and compared with the other parameters in the groups. Results: Serum leptin concentrations in active phase were lower than the remission phase (1.48 ± 0.09 ng/dl, 1.84 ± 1.64 ng/ml, p<0.05). Also, serum homocysteine concentrations in NS group during the active phase were lower than the remission phase and the control group (6.45±2.54 ng/dl, 9.35±2.99 ng/ml, 7.76± 1.97 ng/ml, p<0.05). The serum fasting insulin concentrations and homeostatic model assessment for insulin resistance (HOMA-IR) values of remission phase were significantly higher than those of active phase (p<0.05). A positive relationship was found between the homocysteine concentrations and the body mass index of the patient; whereas, a negative relationship was detected between erythrocyte sedimentation rate (ESR), and the LDL-cholesterol concentrations (p<0.05). ESR was found as the only factor associated with lower concentrations of homocysteine during the active phase (r:-0.592, p<0.05). Conclusion: In this study, we demonstrated that serum leptin and homocysteine concentrations decreased in active phase and increased in remission phase in children with NS. Insulin resistance could also develop as a result of steroid use in a short period of time in these patients.

The determinants of maternal homocysteine in pregnancy: findings from the Ottawa and Kingston Birth Cohort.

Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population. Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration. Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009. Women were recruited when presenting for prenatal care in the early second trimester. In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration. We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

Serum homocysteine and folate concentrations in early pregnancy and subsequent events of adverse pregnancy outcome: the Sichuan Homocysteine study

BackgroundHyperhomocysteinemia may be a risk factor for endothelial dysfunction. Folate and vitamin B12 regulate the homocysteine metabolic process. This study aimed to evaluate the associations between subsequent events of adverse pregnancy outcome and early variables of homocysteine, folate, and vitamin B12 in pregnant women.MethodsThis multicenter, retrospective, case–control study involved 563 pregnant women with adverse pregnancy outcome and 600 controls. Adverse pregnancy outcomes included one or more of the following events: preeclampsia, preterm birth, low birth weight, and stillbirth. The associations between subsequent events of adverse pregnancy outcome and early variables of homocysteine, folate, and vitamin B12; metabolic parameters; inflammatory markers; anthropometrics; and lifestyle habits at 11–12 weeks of gestation were analyzed using the logistic regression model.ResultsCompared to the lower quartile homocysteine concentrations, the upper quartile homocysteine concentrations were associated with preeclampsia, preterm birth and low birth weight. On the contrary, the lower quartile folate concentrations were associated with preeclampsia, preterm birth and low birth weight compared with the upper quartile folate concentrations. The incidence of adverse pregnancy outcome increased progressively from the first to fourth homocysteine quartiles but decreased progressively from the first to fourth folate quartiles. After adjusting for confounding factors, multivariate logistic regression analysis showed that besides systolic blood pressure, diastolic blood pressure, body mass index and age, homocysteine (IV vs I quartile, aOR 5.89, 95% CI 4.08–8.51, P < 0.001), folate (IV vs I quartile, aOR 0.35, 95% CI 0.25–0.50, P < 0.001), folate supplementation (yes vs no, aOR 0.55, 95% CI 0.35–0.86, P = 0.010) during early pregnancy were independently associated with subsequent events of adverse pregnancy outcome, and vitamin B12 was rejected. Of these, the homocysteine revealed the highest odds ratio in all risk variables, and folate showed the lowest odds ratio in all protective variables.ConclusionsHigher homocysteine concentration and lower folate level during early pregnancy were associated with adverse pregnancy outcome. However, no association was found between vitamin B12 and adverse pregnancy outcome. Supplementation with folate in early pregnancy may reduce adverse pregnancy outcome.

Subclinical inflammation, telomere shortening, homocysteine, vitamin B6, and mortality: the Ludwigshafen Risk and Cardiovascular Health Study

PurposeShort telomeres and B vitamin deficiencies have been proposed as risk factors for age-related diseases and mortality that interact through oxidative stress and inflammation. However, available data to support this concept are insufficient. We aimed to investigate the predictive role of B vitamins and homocysteine (HCY) for mortality in cardiovascular patients. We explored potential relationships between HCY, B vitamins, relative telomere length (RTL), and indices of inflammation.MethodsVitamin B6, HCY, interleukin-6 (IL-6), high-sensitive-C-reactive protein (hs-CRP), and RTL were measured in participants of the Ludwigshafen Risk and Cardiovascular Health Study. Death events were recorded over a median follow-up of 9.9 years.ResultsAll-cause mortality increased with higher concentrations of HCY and lower vitamin B6. Patients in the 4th quartile of HCY and vitamin B6 had hazard ratios (HR) for all-cause mortality of 2.77 (95% CI 2.28–3.37) and 0.41(95% CI 0.33–0.49), respectively, and for cardiovascular mortality of 2.78 (95% CI 2.29–3.39) and 0.40 (95% CI 0.33–0.49), respectively, compared to those in the 1st quartile. Multiple adjustments for confounders did not change these results. HCY and vitamin B6 correlated with age-corrected RTL (r = − 0.086, p < 0.001; r = 0.04, p = 0.031, respectively), IL-6 (r = 0.148, p < 0.001; r = − 0.249, p < 0.001, respectively), and hs-CRP (r = 0.101, p < 0.001; r = − 0.320, p < 0.001, respectively). Subjects with the longest telomeres had a significantly higher concentration of vitamin B6, but lower concentrations of HCY, IL-6, and hs-CRP. Multiple regression analyses identified HCY as an independent negative predictor of age-corrected RTL.ConclusionsIn conclusion, hyperhomocysteinemia and vitamin B6 deficiency are risk factors for death from any cause. Hyperhomocysteinemia and vitamin B6 deficiency correlate with increased mortality. This correlation might, at least partially, be explained by accelerated telomere shortening induced by oxidative stress and systemic inflammation in these circumstances.

Effect of Combined Treatment With Folic Acid, Vitamin B6, and Vitamin B12 on Plasma Biomarkers of Inflammation and Endothelial Dysfunction in Women.

BackgroundThe aim of this study was to determine whether reducing plasma homocysteine concentrations with long‐term, combined treatment with folic acid, vitamin B6, and vitamin B12 alters plasma biomarkers of inflammation and endothelial dysfunction in women at increased risk of cardiovascular disease.Methods and ResultsWe conducted a blood substudy of 300 treatment‐adherent participants (150 in the active treatment group, 150 in the placebo group) in the WAFACS (Women's Antioxidant and Folic Acid Cardiovascular Study), a randomized, double‐blind, placebo‐controlled trial testing a daily combination of folic acid (2.5 mg), vitamin B6 (50 mg), vitamin B12 (1 mg), or matching placebo, in cardiovascular disease prevention among women at increased risk of cardiovascular disease. Plasma concentration of 3 biomarkers of inflammation (C‐reactive protein, interleukin‐6, and fibrinogen) and a biomarker of endothelial dysfunction (intercellular adhesion molecule 1) were measured at baseline and at the end of treatment and follow‐up. After 7.3 years of combined treatment with folic acid, vitamin B6, and vitamin B12, homocysteine concentrations were reduced by 18% in the active treatment group as compared with the placebo group (P<0.001). However, there was no difference between treatment groups in change in blood concentration from baseline to follow‐up for C‐reactive protein (P=0.77), interleukin‐6 (P=0.91), intercellular adhesion molecule 1 (P=0.38), or fibrinogen (P=0.68).ConclusionsThese findings indicate that long‐term, combined treatment with folic acid, vitamin B6, and vitamin B12 lowers homocysteine concentrations, but does not alter major biomarkers of vascular inflammation, consistent with the lack of clinical cardiovascular disease benefit in the trial.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000541.

A Meta-Analysis of Folic Acid in Combination with Anti-Hypertension Drugs in Patients with Hypertension and Hyperhomocysteinemia.

Folic acid is generally used to lower homocysteine concentrations and prevent stroke and cardiovascular disease (CVD) at present. However, the efficacy of therapies that lower homocysteine concentrations in reducing the risk of CVD and stroke remains controversial. Our objective was to do a meta-analysis of relevant randomized controlled trials (RCTs) to evaluate the efficacy of folic acid supplementation among patients with hypertension and Hyperhomocysteinemia (HT/HHcy). We included RCTs examining the effects of folic acid plus antihypertensive therapy compared to antihypertensive alone. Weighted Mean Difference (WMD) and Relative risk (RR) were used as a measure of the effect of folic acid on the outcome measures with a random effect model. Sixty-five studies including 7887 patients met all inclusion criteria. Among them, 49 trials reported significant effect of combination therapy for reducing SBP (systolic Blood Pressure) and DBP (Diastolic Blood Pressure) levels compared with antihypertensive alone (WMD = −7.85, WMD = −6.77, respectively). Meanwhile, folic acid supplementation apparently reduced the level of total homocysteine (WMD = 5.5). In addition, folic acid supplementation obviously reduced the risk of cardiovascular and cerebrovascular events (CVCE) by 12.9% compared with control groups. In terms of the stratified analyses, a bigger beneficial effect was seen in those RCTs with treatment duration of more than 12 weeks, a decrease in the concentration of total homocysteine of more than 25%, with folic acid fortification. Our findings indicated that folic acid supplementation was effective in the primary prevention of CVCE among HT/HHcy patients, as well as reducing the blood pressure and total homocysteine levels.

B-Vitamin Serum Concentrations Predicting Long-Term Overall and Stroke-Free Survival after Carotid Endarterectomy

Both deficiency and, according to recent reports, excess of vitamin B12 (B12) are associated with increased mortality. Thus, it is difficult to estimate the effect of B12 on overall survival, which also depends on folate (FA) in homocysteine lowering. This study aimed to assess FA and B12 serum concentrations associated with long-term survival of vascular surgery patients by means of a prognostic index (PI). This single-center, prospective cohort study comprised 485 consecutive carotid surgery patients. B-vitamin baseline concentrations of B12 and FA were used to compute a PI for postoperative overall survival from January 2003 to January 2012 (mean observation period 102.3 months). Increasing B12 serum concentrations showed a nonlinear association with overall survival (P = .033). A B vitamin-based PI significantly predicted overall (hazard ratio [HR] per standard deviation = 1.97, confidence interval [CI] 1.37-2.82; P < .001), cardiovascular (HR = 3.03, CI 1.78-5.14; P < .001), and stroke-free survival (HR = 2.20, CI 1.22-3.98; P = .009), and revealed that the highest adverse event-free survival was predicted by high FA (16.3 ± 12.9 ng/mL) but only moderate B12 (360.3 ± 156.0 pmol/L) baseline concentrations. Prediction of increased long-term overall, cardiovascular, and stroke-free survival is based on high FA but only moderate B12 serum concentrations. Excessive B12 concentrations might harbor a potential harm and are no requisite for low homocysteine concentrations. The association between B vitamins and survival might serve either as a tool for risk stratification or, if causative, as effective therapy, if optimal dosing of B vitamins is provided and on-treatment concentrations, including homocysteine and renal functions, are closely monitored.

Betaine is as effective as folate at re-synthesizing methionine for protein synthesis during moderate methionine deficiency in piglets

Both folate and betaine (synthesized from choline) are nutrients used to methylate homocysteine to reform the amino acid methionine following donation of its methyl group; however, it is unclear whether both remethylation pathways are of equal importance during the neonatal period when remethylation rates are high. Methionine is an indispensable amino acid that is in high demand in neonates not only for protein synthesis, but is also particularly important for transmethylation reactions, such as creatine and phosphatidylcholine synthesis. The objective of this study was to determine whether supplementation with folate, betaine, or a combination of both can equally re-synthesize methionine for protein synthesis when dietary methionine is limiting. Piglets were fed a low methionine diet devoid of folate, choline, and betaine, and on day 6, piglets were supplemented with either folate, betaine, or folate+betaine (n=6 per treatment) until day 10. [1-13C]-phenylalanine oxidation was measured as an indicator of methionine availability for protein synthesis both before and after 2days of supplementation. Prior to supplementation, piglets had lower concentrations of plasma folate, betaine, and choline compared to baseline with no change in homocysteine. Post-supplementation, phenylalanine oxidation levels were 20-46% lower with any methyl donor supplementation (P=0.006) with no difference among different supplementation groups. Furthermore, both methyl donors led to similarly lower concentrations of homocysteine following supplementation (P<0.05). These data demonstrate an equal capacity for betaine and folate to remethylate methionine for protein synthesis, as indicated by lower phenylalanine oxidation.

Betaine (N,N,N-trimethylglycine) averts photochemically-induced thrombosis in pial microvessels invivo and platelet aggregation invitro.

Betaine (N,N,N-trimethylglycine) is an important food component with established health benefits through its homocysteine-lowering effects, and is used to lower total homocysteine concentration in plasma of patients with homocystinuria. It is well established that hyperhomocysteinemia is an established risk factor for cardiovascular disease and stroke. However, the possible protective effect of betaine on coagulation events invivo and invitro has thus far not been studied. Betaine was given to mice at oral doses of either 10 mg/kg (n = 6) or 40 mg/kg (n = 6) for seven consecutive days, and control mice (n = 6) received water only. The thrombotic occlusion time in photochemically induced thrombosis in pial arterioles was significantly delayed in mice pretreated with betaine at doses of 10 mg/kg (P < 0.001) and 40 mg/kg (P < 0.01). Similar effects were observed in pial venules with 10 mg/kg (P < 0.05) and 40 mg/kg (P < 0.05) betaine. Invitro, in whole blood samples collected from untreated mice (n = 3-5), betaine (0.01-1 mg/mL) significantly reversed platelet aggregation induced by adenosine diphosphate (5 µM). The number of circulating platelets and plasma concentration of fibrinogen invivo were not significantly affected by betaine pretreament compared with the control group. Lipid peroxidation (LPO) in mice pretreated with betaine was significantly reduced compared with the control group. Moreover, betaine (0.01-1 mg/mL) caused a dose-dependent and significant prolongation of PT (n = 5) and aPTT (n = 4-6). In conclusion, our data show that betaine protected against coagulation events invivo and invitro and decreased LPO in plasma.