Decreased Plasma Homocysteine Research Articles

Effects of folic acid and N-acetylcysteine on plasma homocysteine levels and endothelial function in patients with coronary artery disease

Objective — Hyperhomocysteinaemia is related with premature coronary artery disease and adverse cardiac events in patients with coronary artery disease (CAD). It is assumed that hyperhomocysteinaemia causes endothelial dysfunction. In this study, the effect of folic acid and oral N-acetylcysteine (NAC) therapies on plasma homocysteine levels and endothelial function were evaluated in hyperhomocysteinaemic patients with CAD.Methods and results — 60 patients were randomized to either folic acid 5 mg or NAC 600 mg or placebo daily for eight weeks. Brachial artery endothelial functions were studied by using highresolution ultrasound and assessed by measuring endothelium-dependent dilation (EDD) and endothe-lium-independent dilation (NEDD). Folic acid and NAC therapies decreased plasma homocysteine (from 21.7 ± 8.7 jimol/l to 12.5 ± 2.5 jimol/l, P < 0.00l;from 20.9 ± 7.6 jimol/l to 15.6 ± 4.3 jimol/l, P = 0.03, respectively), and increased EDD (6.7 ± 6.1% P = 0.002,4.4 ± 2.6% P < 0.001, respectively) compared with placebo.There was no significant difference in improving EDD between the folic acid and the NAC group (6.7 ± 6.1%, 4.4 ± 2.6%, P = 0.168). In the univariate analyses there was an inverse correlation between the post-treatment homocysteine level and the percent change in EDD with folic acid therapy (r= -0.490, P = 0.028), but there was no correlation with the NAC therapy (r = 0.259, P = 0.333)Conclusions — In patients with hyperhomocysteinaemic CAD, folic acid and NAC lowered plasma homocysteine levels and improved endothelial function.The effects of both treatments in improvement of EDD were similar.

Four week supplementation with mixed fruit and vegetable juice concentrates increased protective serum antioxidants and folate and decreased plasma homocysteine in Japanese subjects.

Fruit and vegetable consumption has been inversely associated with the risk of chronic diseases including cancer and cardiovascular disease, with the beneficial effects attributed to a variety of protective antioxidants, carotenoids and phytonutrients. The objective of the present study was to determine the effect of supplementation with dehydrated concentrates from mixed fruit and vegetable juices (Juice Plus+R) on serum antioxidant and folate status, plasma homocysteine levels and markers for oxidative stress and DNA damage. Japanese subjects (n=60; age 27.8 yrs; BMI 22.1) were recruited to participate in a double-blind placebo controlled study and were randomized into 2 groups of 30, matched for sex, age, BMI and smoking status (39 males, 22 smokers; 21 females, 13 smokers). Subjects were given encapsulated supplements containing mixed fruit and vegetable juice concentrates or a matching placebo for 28 days, with blood and urine samples collected at baseline, day 14 and day 28 for analytical testing. Compared with the placebo, 28 day supplementation significantly increased the concentration of serum beta-carotene 528% (p<0.0001), lycopene 80.2% (p<0.0005), and alpha tocopherol 39.5% (p<0.0001). Serum folate increased 174.3% (p<0.0001) and correlated with a decrease in plasma homocysteine of -19.9% (p<0.03). Compared with baseline, measures of oxidative stress decreased with serum lipid peroxides declining -10.5% (p<0.02) and urine 8OHdG decreasing -21.1% (p<0.02). Evaluation of data from smokers only (n=17) after 28 days of active supplementation showed comparable changes. In the absence of dietary modification, supplementation with the fruit and vegetable juice concentrate capsules proved to be a highly bioavailable source of phytonutrients. Important antioxidants were elevated to desirable levels associated with decreased risk of disease while markers of oxidative stress were reduced, and folate status improved with a concomitant decrease in homocysteine, and these benefits occurred to a similar extent in smokers when compared to non-smokers.

Olive extract supplement decreases pain and improves daily activities in adults with osteoarthritis and decreases plasma homocysteine in those with rheumatoid arthritis

The aim of this study was to determine the effects of a polyphenolic-rich olive extract on pain, inflammation, loss of mobility, and patients' general quality of life associated with osteoarthritis (OA) and rheumatoid arthritis (RA). In this double-blind, randomized, placebo-controlled study, the efficacy of freeze-dried olive vegetation water (OVW) on subjects with a diagnosis of OA or RA was evaluated. The treatment group received 400 mg of freeze-dried OVW per day for 8 weeks. Subjects were assessed using the Health Assessment Questionnaire–Disability Index. In addition, the Disease Activity Score With 28-Joint Count was used to evaluate joint pain and inflammation, and the Profile of Moods State questionnaire for overall well-being. During the same time intervals, serum samples were taken for clinical and biochemical tests. The RA subjects in the OVW treatment group showed significant decreases in serum homocysteine levels after 8 weeks of treatment. There was no significant change in any other clinical marker, including markers of kidney and liver function, at any time during the study, suggesting that the supplement was safe. There was significant improvement by treatment group for the Health Assessment Questionnaire–Disability Index. Subjects with OA in the OVW treatment group showed significant improvement in the Disease Activity Score With 28-Joint Count index. Thus, after a relatively short treatment with OVW, subjects with OA and RA reported decreased pain and improvement in activities of daily living. In addition, subjects with RA had a statistically significant decrease in serum homocysteine. High homocysteine levels in patients with RA have been associated with higher rates of mortality from cardiovascular events.

Platelet phospholipid n−3 PUFA negatively associated with plasma homocysteine in middle-aged and geriatric hyperlipaemia patients

Studies showed that increased dietary intake of n−3 polyunsaturated fatty acids (PUFA) has a cardiovascular beneficial effect. Increased plasma phospholipid (PL) docosahexaenoic acid (22:6 n−3) is associated with decreased plasma homocysteine (Hcy). The aim of this study was to investigate the relationship between platelet PL fatty acid and plasma Hcy in middle-aged and geriatric hyperlipaemia patients (50 males, 31 females) and 65 healthy subjects (43 males, 22 females) in Hangzhou, China. Plasma Hcy demonstrated significant positive correlation with adrenic acid (22:4 n−6) ( r = 0.188 , P = 0.018 ) and negative correlation with 22:6 n−3 ( r = – 0.277 , P = 0.001 ) and the ratio of n−3/ n−6 ( r = – 0.231 , P = 0.003 ) in sex-, age- and BMI-controlled partial correlation analysis. The present results suggest that increased ratio of n−3/ n−6 PUFA in platelet PL is associated with decreased thrombotic risks such as plasma Hcy in middle-aged and geriatric hyperlipaemia patients in Hangzhou.

Fortified mineral water improves folate status and decreases plasma homocysteine concentration in pregnant women

There is no mandatory folic acid fortification of food in Finland. We investigated the effects of mineral water fortified with folic acid, vitamins B6, B12, D and calcium on serum and erythrocyte folate concentrations, serum vitamin B12 and plasma homocysteine concentrations in pregnancy. A randomized, controlled, double-blind, parallel-group intervention study. Seventy-four pregnant women were recruited from two health care units. The study began at the eleventh week with a two-week run-in period, followed by an eight-week intervention period. The diet was monitored by food records. During the intervention, subjects consumed 1000 mL/day fortified or normal mineral water. The pregnancies were monitored carefully. The folate intake was 255 microg/day in the study group and 274 microg/day in the controls. Serum folate concentrations increased in the study group by 10.3 nmol/L and decreased in the controls by 2.7 nmol/L (P<0.05) during the study. The erythrocyte folate concentrations increased in the study group by 360.9 nmol/L and in the controls by 195.6 nmol/L (P=0.004) and serum homocysteine concentrations fell by 1.1 micromol/L and by 0.3 micromol/L, respectively (P<0.05). Finnish pregnant women have low dietary folate intake. Fortified mineral water improved folate status and reduced plasma homocysteine concentrations in the pregnant subjects.

MTHFR Gene Polymorphism and Diabetic Retinopathy

Diabetic retinopathy (DR) is the leading cause of catastrophic loss of vision. Each year, DR darkens the lives of 12,000 to 24,000 diabetic patients in the United States, and more than 4,000 patients in Japan. Clinically, hyperglycemia induces proliferative changes in DR synergistically with other risk factors for vascular diseases. Methyl- enetetrahydrofolate reductase (MTHFR) is an enzyme involved in remethylation of homocysteine to methionine. A polymorphic mutation (C677T) in the MTHFR gene leads to impaired enzyme activity, resulting in hyper- homocysteinemia as an independent risk factor for macroangiopathy. Recently, more and more attention has been paid to the involvement of hyperhomocysteinemia in the progression of DR, a serious microangiopathic complication of diabetes. Clinical studies have demonstrated that MTHFR gene polymorphism can contribute to the progression of DR, especially in the patients with blood glucose poorly controlled. Furthermore, accumulating evidence suggests that homocysteine activates vascular inflammation through inflammatory cytokines, including VEGF. These data imply that the decrease in plasma homocysteine could prevent the development and progression of DR. We also propose the possibility of personalized medicine for diabetes mellitus based on a better understanding of MTHFR gene polymorphism and its ramifications, which might cast new light on diabetic retinopathy.

Folate supplementation fails to affect vascular function and carotid artery intima media thickness in cyclosporin A-treated renal transplant recipients

Cyclosporin A (CsA)-treated renal transplant recipients (RTR) exhibit relative hyperhomocystinemia and vascular dysfunction. Folate supplementation lowers homocysteine and has been shown to improve vascular function in healthy subjects and patients with coronary artery disease. The aim of this study was to assess the effects of 3 months of folate supplementation (5 mg/day) on vascular function and structure in RTR. A double-blind, placebo-controlled crossover study was conducted in 10 CsA-treated RTR. Vascular structure was measured as carotid artery intima media thickness (IMT) and function was assessed as changes in brachial artery diameter during reactive hyperemia (RH) and in response to glyceryl trinitrate (GTN). Function data were analyzed as absolute and percent change from baseline and area under the diameter/time curve. Blood samples were collected before and after supplementation and analyzed for total plasma homocysteine, folate, vitamin B12 and asymmetric dimethyl arginine (ADMA) in addition to regular measures of hemoglobin, hematocrit, mean corpuscular volume (MCV) and serum creatinine. Folate supplementation significantly increased plasma folate by 687% (p < 0.005) and decreased homocysteine by 37% (p < 0.05) with no changes (p > 0.05) in vitamin B12 or ADMA. There were no significant (p > 0.05) changes in vascular structure or function during the placebo or the folate supplementation phases; IMT; placebo pre mean +/- SD, 0.52 +/- 0.12, post 0.50 +/- 0.11; folate pre 0.55 +/- 0.17, post 0.49 +/- 0.20 mm, 5% change in brachial artery diameter (RH, placebo pre 10 +/- 8, post 6 +/- 5; folate pre 9 +/- 7, post 7 +/- 5; GTN, placebo pre 18 +/- 10, post 17 +/- 9, folate pre 16 +/- 9, post-supplementation 18 +/- 8). Three months of folate supplementation decreases plasma homocysteine but has no effect on endothelial function or carotid artery IMT in RTR.

Dietary folate, vitamin B 12 , and vitamin B 6 and the risk of Parkinson disease

Increased homocysteine levels might accelerate dopaminergic cell death in Parkinson disease (PD), through neurotoxic effects. Higher dietary intakes of folate, vitamin B12, and vitamin B6 (cofactors in homocysteine metabolism) might decrease the risk of PD through decreasing plasma homocysteine. Moreover, vitamin B6 might influence the risk of PD through antioxidant effects unrelated to homocysteine metabolism and through its role in dopamine synthesis. In the Rotterdam Study, a prospective, population-based cohort study of people aged 55 years and older, the authors evaluated the association between dietary intake of folate, vitamin B12, and vitamin B6 and the risk of incident PD among 5,289 participants who were free of dementia and parkinsonism and underwent complete dietary assessment at baseline. PD was assessed through repeated in-person examination and continuous monitoring by computer linkage to medical records. Data were analyzed using Cox proportional hazards regression analysis. After a mean follow-up of 9.7 years, the authors identified 72 participants with incident PD. Higher dietary intake of vitamin B6 was associated with a significantly decreased risk of PD (hazard ratio per SD, 0.69 [95% CI 0.50 to 0.96]; for highest vs lowest tertile, 0.46 [0.22 to 0.96]). Stratified analyses showed that this association was restricted to smokers. No association was observed for dietary folate and vitamin B(12). Dietary vitamin B6 may decrease the risk of Parkinson disease, probably through mechanisms unrelated to homocysteine metabolism.

A fibre cocktail of fenugreek, guar gum and wheat bran reduces oxidative modification of LDL induced by an atherogenic diet in rats

LDL (low-density lipoprotein) oxidation is a key trigger factor for the development of atherosclerosis. Relatively few studies exist on the impact of dietary fibre on LDL oxidation. This study was undertaken to evaluate the influence of a novel fibre mix of fenugreek seed powder, guar gum and wheat bran (Fibernat) on LDL oxidation induced by an atherogenic diet. Male Wistar albino rats were administered one of the following diets: (1) a control diet that was fibre-free (Group I); (2) an atherogenic diet containing 1.5% cholesterol and 0.1% cholic acid (Group II) or (3) an atherogenic diet supplemented with Fibernat (Group III). Peroxidative changes in low-density lipoprotein (LDL) and the oxidative susceptibility of LDL and the LDL + VLDL (very low-density lipoprotein) fraction were determined. As a corollary to the oxidative modification theory, the titer of autoantibodies to oxidised LDL (oxLDL) was determined at various time points of the study. In addition, plasma homocysteine (tHcy) and lipoprotein (Lp (a)), apolipoprotein (apoB), cholesterol, triglyceride, phospholipid and alpha-tocopherol content of LDL were determined. A decrease in malonaldehyde (MDA) content (p<0.05) and relative electrophoretic mobility (REM) of LDL was observed in the group III rats as compared to the group II rats. An increase in lag time to oxidation (p<0.01) and decrease in maximum oxidation (p<0.01) and oxidation rate (p<0.01) were observed in the LDL + VLDL fraction of group III rats. In group II rats, formation of autoantibodies to oxLDL occurred at an earlier time point and at levels greater than in the group III rats. Fibernat, had a sparing effect on LDL alpha-tocopherol, which was about 51% higher in the group III rats than in the group II rats; apo B content of LDL was reduced by 37.6% in group III rats. LDL of group III rats displayed a decrease in free and ester cholesterol (p<0.01) as compared to that of group II. A decrease in plasma homocysteine (p<0.01) and an increase in GSH (p<0.05) were also observed in group III rats when compared with that of group II. Fibernat administration appears to combat oxidative stress resulting in a trend to lower oxidative modification of LDL. In addition, the cholesterol and apo B content of LDL were reduced significantly with a sparing effect on LDL alpha-tocopherol. This novel fibre preparation could be an effective diet therapy and therefore needs further investigation.

Four week supplementation with mixed fruit and vegetable concentrates elevated protective serum antioxidants and folate and decreased plasma homocysteine

The consumption of fruits and vegetables has been shown to be inversely correlated with the incidence of cardiovascular disease (CVD) and cancer. We investigated the effect of supplementation with dehydrated juice concentrates from mixed fruits and vegetables (JuicePlus+®) on selected serum antioxidants, folate, homocysteine and oxidative stress measures. Japanese subjects (m=39; f=21; mean age = 27.8 yrs.) including 35 smokers, participated in a randomized double-blind placebo controlled 28 day study. Subjects took either capsules containing juice powders (3g daily) or matching placebo capsules. Blood samples were taken at baseline, 2 and 4 weeks. Compared with the placebo, 4 week supplementation increased the concentration of serum beta-carotene 528% (p<0.0001), lycopene 80.2% (p<0.0005), alpha tocopherol 39.5% (p<0.0001). Serum folate increased 174.3% (p<0.0001) and correlated with a decrease in plasma homocysteine of −19.9% (p<0.03). Compared with baseline, measures of oxidative stress decreased; serum lipid peroxides −10.5% (p<0.02) and urine 8OHdG −21.1% (p<0.02). Supplementation with fruit and vegetable concentrates proved to be a highly bioavailable source of phytonutrients, which elevated important antioxidants to levels associated with decreased risk of CVD and cancer while reducing markers of oxidative stress, and improved folate status with concomitant decrease in homocysteine – a risk factor for CVD. (Support provided by NSA Inc., Memphis, TN.)

Is it time to reevaluate methyl balance in humans?

S-Adenosylmethionine (AdoMet) is the major biological methyl donor. AdoMet's methyl group arises both from the diet (eg, methionine, choline, and betaine) and from de novo synthesis by the process of methylneogenesis. At least 50 AdoMet-dependent methylation reactions have been identified in mammals, and genomic analyses suggest that the final number will be much higher. Such methylation reactions play major roles in biosynthesis, regulation, and detoxification. Creatine synthesis is thought to account for the use of >70% of AdoMet-derived methyl groups in humans. This is not consistent with recent studies in mice, in which the phosphatidylethanolamine methyltransferase gene was deleted (PEMT-/-). Loss of this hepatic enzyme resulted in a 50% decrease in plasma homocysteine, which suggests that it accounts for a major component of whole-body AdoMet utilization. A reexamination of human creatine metabolism showed that dietary creatine can account for as much as 50% of daily creatine requirements in nonvegetarians and, therefore, that estimates of creatine synthesis need to be reduced. We suggest that creatine synthesis is responsible for a smaller proportion of AdoMet-derived methyl groups than has been suggested and that phosphatidylcholine synthesis via phosphatidylethanolamine methyltransferase is a major consumer of these methyl groups.

Differences in plasma homocysteine levels between Zucker fatty and Zucker diabetic fatty rats following 3 weeks oral administration of organic vanadium compounds

Purpose: Recently, our laboratory group has reported that rats with Type 1 diabetes have decreased plasma homocysteine and cysteine levels compared to non-diabetic controls and that organic vanadium treatment increased plasma homocysteine concentrations to non-diabetic concentrations. However, to date, no studies have been done investigating the effects of organic vanadium compounds on plasma homocysteine and its metabolites in Type 2 diabetic animal model. These studies examined the effect of organic vanadium compounds [bis(maltolato)oxovanadium(IV) and bis(ethylmaltolato)oxovanadium(IV); BMOV and BEOV] administered orally on plasma concentrations of homocysteine and its metabolites (cysteine and cysteinylglycine) in lean, Zucker fatty (ZF) and Zucker diabetic fatty (ZDF) rats. ZF rats are a model of pre-diabetic Type 2 diabetes characterized by hyperinsulinemia and normoglycemia. The ZDF rat is a model of Type 2 diabetes characterized by relative hypoinsulinemia and hyperglycemia. Methods: Zucker lean and ZF rats received BMOV in the drinking water at a dose of 0.19±0.02 mmol/kg/day. Lean and ZDF rats received BEOV by oral gavage daily at dose of 0.1 mmol/kg. The treatment period for both studies was 21 days. At termination, animals were fasted overnight (∼16 h) and blood samples were collected by cardiac puncture for determination of plasma glucose, insulin and homocysteine levels. Plasma homocysteine and its metabolites levels were determined using high-pressure liquid chromatography. Plasma glucose was determined using a Glucose Analyzer 2. Plasma insulin levels were determined by radioimmunoassay. Plasma triglycerides were determined by an enzymatic assay methodology. Results: ZF ( n = 4 ) and ZDF ( n = 1 0 ) rats had significantly lower plasma homocysteine as compared to their respective lean groups (ZF 0.78±0.1 μmol/L vs. Zucker lean 2.19±0.7 μmol/L; ZDF 1.71±0.2 μmol/L vs. Zucker lean 3.02±0.3 μmol/L; p < 0.0 5 ). BMOV treatment in ZF rats restored plasma homocysteine levels to those observed in lean untreated rats (ZF treated: 2.04±0.2 μmol/L; lean 2.19±0.7 μmol/L). There was a modest effect of BMOV treatment on plasma glucose levels in ZF rats. BEOV treatment significantly decreased the elevated plasma glucose levels in the ZDF rats (lean 7.9±0.1 mmol/L; lean+vanadium 7.7±0.2 mmol/L; ZDF 29.9±0.4 mmol/L; ZDF+vanadium 17.4±0.3 mmol/L, p < 0.0 5 ). Organic vanadium treatment reduced cysteine levels in both ZF and ZDF rats. No differences in total plasma cysteinylglycine concentrations were observed. Conclusion: Plasma homocysteine levels are significantly reduced in a pre-diabetic model of Type 2 diabetes, which was restored to lean levels upon vanadium treatment; however, this restoration of plasma homocysteine levels was not seen in ZDF Type 2 diabetic rats following vanadium treatment. In the latter case vanadium treatment may not have totally overcome the insulin resistance seen in these animals.

Effects of diabetes and insulin on betaine-homocysteineS-methyltransferase expression in rat liver

Elevation of plasma homocysteine levels has been recognized as an independent risk factor for the development of cardiovascular disease, a major complication of diabetes. Plasma homocysteine reflects a balance between its synthesis via S-adenosyl-L-methionine-dependent methylation reactions and its removal through the transmethylation and the transsulfuration pathways. Betaine-homocysteine methyltransferase (BHMT, EC 2.1.1.5) is one of the enzymes involved in the remethylation pathway. BHMT, a major zinc metalloenzyme in the liver, catalyzes the transfer of methyl groups from betaine to homocysteine to form dimethylglycine and methionine. We have previously shown that plasma homocysteine levels and the transsulfuration pathway are affected by diabetes. In the present study, we found increased BHMT activity and mRNA levels in livers from streptozotocin-diabetic rats. In the rat hepatoma cell line (H4IIE cells), glucocorticoids (triamcinolone) increased the level and rate of BHMT mRNA synthesis. In the same cell line, insulin decreased the abundance of BHMT mRNA and the rate of de novo mRNA transcription of the gene. Thus the decreased plasma homocysteine in various models of diabetes could be due to enhanced homocysteine removal brought about by a combination of increased transsulfuration of homocysteine to cysteine and increased remethylation of homocysteine to methionine by BHMT.

Effect of folic acid supplementation on mood and serotonin response in healthy males

Evidence suggests that low folate status may be detrimental to mood and associated with depleted cerebrospinal fluid levels of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT). A placebo-controlled trial was carried out to determine the effect of folic acid supplementation (100 microg for 6 weeks followed by 200 microg for a further 6 weeks) upon subjective mood (Positive and Negative Affect Schedule) and biochemical markers of mood (5-HT) in healthy males (n 23). Blood samples were obtained at baseline (week 0) and during the intervention at week 6 and week 12. Subjective mood assessments were obtained at week 0 and week 12. The results showed an increase in serum and erythrocyte folate concentrations (P=0.02 and P=0.003, respectively) and a corresponding decrease in plasma homocysteine (P=0.015) in response to the folic acid intervention. Neither subjective mood nor 5-HT levels, however, were significantly altered in response to the change in folate status. Folic acid given at physiological doses did not appear to improve the mood of healthy folate-replete individuals over a 12-week period. Further research is needed to address the effect of folic acid supplementation or of longer duration or increased dose, particularly in the face of sub-optimal folate status.

N-3 fatty acid supplementation decreases plasma homocysteine in diabetic dyslipidemia treated with statin–fibrate combination

The aim of this study was to study the effect of adding polyunsaturated fatty acid (PUFA) n-3 or placebo (containing oleic acid) to a combined statin–fibrate treatment on plasma lipoproteins, lipoperoxidation, glucose homeostasis, total homocysteine (tHcy) and microalbuminuria (MA) in patients with diabetic dyslipidemia (DDL). Twenty-four patients, who did not fulfill the recommended target lipid values with combined hypolipidemic therapy (pravastatin 20 mg+micronized fenofibrate 200 mg daily), were supplemented with 3.6 g PUFA n-3 daily for 3 months or placebo (olive oil) for the next 3 months. The concentrations of plasma lipids, fatty acid (FA) profiles of phosphatidylcholine (PC), cholesteryl esters (CE) and triglycerides (TG), tHcy levels, concentrations of conjugated dienes (CD) in low-density lipoprotein (LDL), and MA were determined in baseline state, after the PUFA n-3 and placebo treatment period. Supplementation with PUFA n-3 led to a significant decrease in plasma tHcy (−29%, P<.01) and TG (−28%, P<.05) levels, as well as to a significant decrease in MA (−24%, P<.05). The decrease in MA correlated significantly with the increase in total PUFA n-3 ( r=−.509, P≤.05) and docosahexaenoic acid ( r=−.52, P<.01) in TG. The concentrations of CD in LDL increased significantly (+15%, P<.05). The supplementation with PUFA n-3 to the combined statin–fibrate treatment in patients with DDL decreased the TG and tHcy levels as well as MA. It could lead to decreased risk of atherothrombosis and delay of diabetic nephropathy onset and progression.

Effect of supplementation with cobalamin carried either by a milk product or a capsule in mildly cobalamin-deficient elderly Dutch persons

A high prevalence of cobalamin deficiency occurs in the elderly population, which may be treated orally or with injections. Little is known about the relative bioavailability of crystalline cobalamin added to food products. The objective was to assess the effect of supplementation with 1000 microg crystalline cobalamin, carried either by a milk product or a capsule, on cobalamin status in mildly cobalamin-deficient elderly Dutch persons. Two double-blind randomized controlled intervention studies, each covering a 12-wk supplementation period, were carried out in parallel. Mildly cobalamin-deficient elderly persons (n = 112) were separately recruited for the milk and capsule trials. Mild cobalamin deficiency was defined as a cobalamin concentration between 100 and 300 pmol/L and a plasma methylmalonic acid (MMA) concentration > or = 0.30 micromol/L. Allocation to the placebo or cobalamin carrier was carried out independently in both trials. In the fortified-milk group, the mean (+/-SD) increase in serum cobalamin was 250 +/- 96 pmol/L, the median (5th and 95th percentiles) decrease in plasma MMA was 0.19 (-0.76, -0.04) micromol/L, and the median decrease in plasma homocysteine was 4.0 (-7.3, 3.0) micromol/L. All changes were significantly different from those in the placebo milk group (P < 0.01). Likewise, in the cobalamin-capsule group, the mean increase in serum cobalamin was 281 +/- 136 pmol/L, the median decrease in plasma MMA was 0.18 (-2.95, 0.14) micromol/L, and the median decrease in plasma homocysteine was 1.8 (-10.6, 2.4) micromol/L; all changes were significantly different from those in the placebo capsule group (P < 0.01). No significant differences were observed between the fortified-milk and capsule groups (P > 0.40). Crystalline cobalamin added to milk is an effective alternative to cobalamin capsules for improving cobalamin status.

The Role of Homocysteine in Multisystem Age-Related Problems: A Systematic Review

Homocysteine is a sulfur-containing amino acid that is involved in one-carbon metabolism. Hyperhomocysteinemia is a common phenomenon among elderly people. There is growing evidence of an association between hyperhomocysteinemia and geriatric multisystem problems, including coronary artery disease, stroke, peripheral vascular disease, cognitive impairment, dementia, depression, osteoporotic fractures, and functional decline. The proposed mechanisms of the association include angiotoxicity, neurotoxicity, and inhibition of collagen cross-linking. A homocysteine-lowering strategy may prevent or slow the development of these age-related problems. Vitamin supplementation and folic acid fortification of grain foods have been shown to decrease plasma homocysteine concentrations. More research is needed to investigate whether lifelong homocysteine lowering can prevent the development of late-life morbidity.

Hyperhomocysteinemia and arteriovenous fistula thrombosis in hemodialysis patients

To date, the relationship between vascular access (VA) failure and plasma total homocysteine level has been investigated only in mixed dialysis populations (ie, patients with a native arteriovenous [AV] fistula or arterial graft), whereas almost no data exist for hemodialysis patients with a native AV fistula. In this prospective cohort study, we examined the relationship between plasma total homocysteine level and the methylenetetrahydrofolate reductase (MTHFR) gene and VA-related incident morbidity in a cohort of 205 hemodialysis patients, all with a native AV fistula. During follow-up, 78 patients experienced 1 or more VA thrombotic episodes. Patients with incident VA thrombosis had a significantly greater plasma total homocysteine level compared with patients without this event (P = 0.046). In Kaplan-Meier survival analysis, the hazard ratio for VA thrombosis increased in parallel with homocysteine level, such that patients in the third homocysteine level tertile had a relative risk for this outcome 1.72 times (95% CI, 1.21 to 2.24) greater than in those in the first tertile (log-rank test, 6.81; P = 0.009). In a multiple Cox regression model, plasma total homocysteine level was confirmed to be an independent predictor of AV fistula outcome. Plasma total homocysteine level was significantly greater (P < 0.001) in patients with the TT genotype of the MTHFR gene than in those with the CT or CC genotype. VA thrombosis in dialysis patients is associated with hyperhomocysteinemia. Intervention studies are needed to clarify whether decreasing plasma homocysteine concentrations may prevent VA failure in hemodialysis patients.

Beta blocker effects on plasma homocysteine levels in patients with hypertension

Recent studies have shown that hyperhomocysteinemia might play a role in the pathogenesis of hypertension. The effects of antihypertensive agents on plasma homocysteine levels have not been tested extensively. We investigated the effects of beta-blocker therapy on homocysteine levels in patients with hypertension. In the study, 120 patients with newly diagnosed hypertension were enrolled. All patients received metoprolol succinate 100 mg/day initially. If blood pressure was above normal on the 15th day of follow-up, the metoprolol dosage was doubled. Before initiation of the antihypertensive medication and after the fourth month of treatment, homocysteine levels were measured. Of the 120 patients enrolled, 39 could not complete the study. Homocysteine levels decreased significantly by the end of the fourth month when compared with basal values (13.5 ± 4.5 μmol/l versus 12.4 ± 4.9 μmol/l; P = 0.001). There was no relation between homocysteine level and blood pressure control. There was a significant decrease in homocysteine levels in the women treated in this study ( P = 0.001); however, this effect was absent in men ( P = 0.185). We demonstrate that metoprolol succinate treatment significantly decreases plasma homocysteine levels in patients with hypertension, especially in women.

A folate-rich diet is as effective as folic acid from supplements in decreasing plasma homocysteine concentrations

Background & Aims: At least 500 mug of folic acid are required daily to treat hyperhomocysteinemia. To reach this amount by dietary changes alone may be difficult because food has a low folic acid content and bioavailability. No studies have compared the effects of similar amounts of additional folate derived from a combination of folate-rich and fortified foods or folic acid from supplements on plasma total homocysteine (tHcy) concentrations, which was the aim of this study. Methods: Twenty male patients with hyperhomocysteinemia and coronary artery disease were included in a randomized, crossover intervention trial. Patients were treated daily with a combination of foods containing approximately 500 mug of folate or with one 500 mug capsule of synthetic folic acid over two five-week periods separated by a five-week wash-out period. Results: Plasma folate increased markedly (p<0.001) and plasma tHcy decreased (p<0.001) with both therapies. Folate-rich foods decreased tHcy by 8.6% (95% CI: -15.9 to -1.2) and synthetic folic acid capsules by 8% (95% CI: -13.3 to -2.7). Conclusions: This study shows, for the first time in the literature, that a folate-rich diet is as effective as folic acid capsules in decreasing plasma tHcy concentrations and adds further support to the recommendation of those diets to prevent cardiovascular disease.