Total Homocysteine Concentrations Research Articles

Oral vitamin B12 supplementation in pernicious anemia: a prospective cohort study

BackgroundThe absorption of vitamin B12 is hindered in pernicious anemia (PA) owing to intrinsic factor deficiency. Traditionally, intramuscular vitamin B12 injections were the standard treatment, bypassing the impaired absorption. Although there is potential for oral vitamin B12 supplementation through passive enteral absorption, it is not commonly prescribed in PA owing to limited studies assessing its efficacy. ObjectivesWe aimed to assess the efficacy of oral vitamin B12 supplementation in PA. MethodsWe enrolled participants diagnosed with incident vitamin B12 deficiency related to PA. The diagnosis of PA was based on the presence of classical immune gastritis and of anti-intrinsic factor and/or antiparietal cell antibodies. To evaluate the vitamin B12 status, we measured total plasma vitamin B12, plasma homocysteine, and plasma methylmalonic acid (pMMA) concentration and urinary methylmalonic acid–to–creatinine ratio. Participants were treated with oral cyanocobalamin at a dosage of 1000 μg/d throughout the study duration. Clinical and biological vitamin B12 deficiency related features were prospectively and systematically assessed over the 1-y study duration. ResultsWe included 26 patients with vitamin B12 deficiency revealing PA. Following 1 mo of oral vitamin B12 supplementation, 88.5% of patients were no longer deficient in vitamin B12, with significant improvement of plasma vitamin B12 [407 (297–485) compared with 148 (116–213) pmol/L; P < 0.0001], plasma homocysteine [13.5 (10.9–29.8) compared with 18.6 (13.7–46.8) μmol/L; P < 0.0001], and pMMA [0.24 (0.16–0.38) compared with 0.56 (0.28–1.09) pmol/L; P < 0.0001] concentrations than those at baseline. The enhancement of these biological parameters persisted throughout the 12-month follow-up, with no patients showing vitamin B12 deficiency by the end of the follow-up period. The median time to reverse initial vitamin B12 deficiency abnormalities ranged from 1 mo for hemolysis to 4 mo for mucosal symptoms. ConclusionsOral supplementation with 1000 μg/d of cyanocobalamin has been shown to improve vitamin B12 deficiency in PA.

Retrospective cohort study of the MTHFR C677T/A1298C polymorphisms and human homocysteine levels in Helicobacter pylori infection

This study avalited relationship between human Methylenetetrahydrofolate reductase (MTHFR) gene (C677T(rs1801133)/A1298C(rs1801131)) variants and homocysteine levels in 168 patients who are infected with Helicobacter pylori, diagnosed to PCR analysis. PCR-RFLP methods were performed to characterize the MTHFR gene C677T/A1298C variants in DNA samples obtained from gastric biopsies this patients. An immunoenzymatically assay was used for quantitative of total homocysteine and folate levels in the plasma of the same individuals. The adopted level statistical significance was to α = 0.05. The frequency of the C677T SNP was higher in infected individuals, wherein those with the CT/TT genotype presented a three-fold higher risk of acquiring Helicobacter pylori infection. The averages of the total homocysteine concentrations were associated with the TT genotype, advanced age and the male sex, but no dependence relationship was found with Helicobacter pylori infection.

Breastfeeding and biomarkers of folate and cobalamin status in Norwegian infants: a cross-sectional study

Abstract Folate and vitamin B12 (cobalamin) are essential for growth and development. This cross-sectional study aims to describe folate and vitamin B12 status according to infant age and breastfeeding practices in Norwegian infants. Infants aged 0–12 months (n = 125) were recruited through public health clinics. We registered breastfeeding status and measured serum concentrations of folate, cobalamin, total homocysteine (tHcy), and methylmalonic acid (MMA). The associations between infant age, breastfeeding, and biomarker concentrations were estimated in regression models. The mean (SD) age was 24 (16) weeks, and 42% were exclusively breastfed, 38% were partially breastfed, and 21% were weaned. Overall, median (IQR) folate, cobalamin, tHcy, and MMA concentrations were 47 (35–66) nmol/L, 250 (178–368) pmol/L, 6.99 (5.69–9.27) µmol/L, and 0.35 (0.24–0.83) µmol/L, respectively. None of the infants were folate deficient, 15% were vitamin B12 deficient (&lt; 148 pmol/L), and 23% had low vitamin B12 status (148–221 pmol/L). Elevated tHcy (&gt; 6.5 μmol/L) and MMA (&gt; 0.26 μmol/L) were found in 62% and 69% of the infants, respectively. Compared to weaned, exclusively or partially breastfed infants were younger and had 46% higher tHcy concentrations (P &lt; 0.001), in addition to 47% and 39% lower cobalamin concentrations (P &lt; 0.001), respectively. However, the observed biomarker concentrations appeared to be independent of infant age. In conclusion, low vitamin B12 status was prevalent and appeared to be more common in the younger exclusively breastfed compared to older weaned infants. The implications of low vitamin B12 status in infancy are unknown and require further investigation.

Periconceptional Non-medical Maternal Determinants Influence the Tryptophan Metabolism: The Rotterdam Periconceptional Cohort (Predict Study).

The vital role of the maternal tryptophan (TRP) metabolism in maternal health and pregnancy is well established. However, non-medical maternal determinants influencing the TRP metabolism have been poorly investigated. We hypothesise that periconceptional maternal non-medical determinants alter the TRP metabolism, affecting both kynurenine (KP) and serotonin pathway (SP) metabolite concentrations. Therefore, we investigated the influence of non-medical maternal determinants on the TRP metabolism during the periconception period. About 1916 pregnancies were included from the Rotterdam Periconceptional Cohort between November 2010 and December 2020. Data on periconceptional non-medical maternal determinants were collected through questionnaires. Serum samples were collected at 8.5 (SD = 1.6) weeks of gestation and TRP, kynurenine (KYN), 5-hydroxytryptophan (5-HTP), 5-HT (5-hydroxytryptamine) and 5-hydroxyindole acetic acid (5-HIAA) were determined using validated liquid chromatography (tandem) mass spectrometry. Mixed models were used to determine associations between periconceptional non-medical maternal determinants and these metabolites. In total 11 periconceptional non-medical maternal determinants were identified. Protein intake was positively associated with TRP (β = .12, 95% CI = 0.07-0.17), while age, energy intake and body mass index (BMI) (β = -.24, 95% CI = -0.37 to -0.10) were negatively associated with TRP. Age, BMI and total homocysteine were associated with higher KYN, whereas non-western geographical origin was associated with lower KYN (β = -.09, 95% CI = -0.16 to -0.03). Protein intake and total homocysteine (β = .07, 95% CI = 0.03-0.11) had a positive association with 5-HTP, while a negative association was found for energy intake. A non-western geographical origin and drug use were associated with higher 5-HT, and BMI with lower 5-HT (β = -6.32, 95% CI = -10.26 to -2.38). Age was positively associated with 5-HIAA (β = .92, 95% CI = 0.29-1.56), and BMI negatively. Periconceptional non-medical maternal determinants, including age, geographical origin, drug use, energy and protein intake, BMI and total homocysteine, influence KP and SP metabolite concentrations.

Low vitamin B12 blood levels in sickle cell disease: Data from a large cohort study in Tanzania.

Sickle cell disease (SCD) is associated with high rates of undernutrition and stunting. Undernutrition in combination with chronic haemolysis may lead to deficiencies in micronutrients necessary for erythropoiesis. Here we examined selected levels of ferritin, vitamins B2 , B6 , B9 and B12 , and vitamin C that were measured in blood samples from 820 SCD patients from Tanzania with no history of hospital admission, infections or painful episodes in the previous 30 days. We studied children (0-8 years), early adolescents (9-14 years), late adolescents (15-17 years) and adults (≥18 years). Severely low levels of vitamin B12 were observed across the four age groups. Despite the lowered vitamin B12 concentrations, total homocysteine concentrations were normal across both genders in all age groups. We found no significant gender-related differences between the other measured micronutrients. In this large SCD population, spanning the whole life cycle, a low level of vitamin B12 was consistently found across both genders and all age groups. Given the pivotal role of vitamin B12 in cellular metabolism, particularly in erythropoiesis, more studies are required to unravel how to better detect clinically relevant vitamin B12 deficiency among SCD patients, and thus to identify more precisely those who need supplementation of vitamin B12 .

Vitamin B12 and Folate Status in Pregnant Females and Their Infants in Norway: Secondary Analysis from the Mommy’s Food Study

BackgroundVitamin B12 and folate are essential micronutrients important for normal infant growth and development. ObjectivesThe aims were to describe vitamin B12 and folate status in pregnant females and their infants according to commonly used status cutoffs and examine the associations between maternal status, maternal supplement use, and breastfeeding and infant status. MethodsPregnant females were recruited at 18 wk gestation in Bergen, Norway. Maternal vitamin B12 and folate status were measured at gestational weeks 18 (n = 136) and 36 (n = 116), and infant status was measured at ages 3 (n = 73) and 6 (n = 74) mo. ResultsAt gestational weeks 18 and 36, respectively, 4.4% and 2.6% of the mothers had plasma cobalamin concentrations <148 pmol/L, 0.7% and 6.9% had methylmalonic acid (MMA) concentrations >0.26 μmol/L, and 3.7% and 30% had folate concentrations <10 nmol/L. None of the females had total homocysteine (t-Hcy) concentrations >13 μmol/L or 3 combined indicator of vitamin B12 (cB12) < −0.5. At 3 and 6 mo, respectively, 4.1% and 5.4% of the infants had cobalamin concentrations <148 pmol/L, 63% and 74% had t-Hcy concentrations >6.5 μmol/L, 59% and 66% had MMA concentrations >0.26 μmol/L, and 47% and 60% had cB12 > −0.5. None of the infants had folate concentrations <10 nmol/L. Several of the vitamin B12 biomarkers in infants were associated with maternal vitamin B12 status during pregnancy. Breastfed infants had lower vitamin B12 status (as indicated by plasma cobalamin, t-Hcy, and cB12) than nonbreastfed infants at both 3 and 6 mo. Use of supplements during pregnancy was associated with better vitamin B12 status among infants at 3 and 6 mo, as indicated by infants’ cobalamin and t-Hcy concentrations. ConclusionsSubclinical vitamin B12 deficiency among infants was common and associated with maternal vitamin B12 status during pregnancy and breastfeeding. Among the mothers, an increase in biochemical folate deficiency was discovered toward the end of gestation. Further studies are needed to investigate clinical consequences.This trial was registered at clinicaltrials.gov as NCT02610959.

Reference intervals for total serum homocysteine concentration in shenzhen adults investigated with the aid of nanomaterials

Hyperhomocysteinemia is a risk factor for cardiovascular disease. Therefore, assessing the reference intervals of total serum homocysteine concentration is a critical step in the process of preventing cardiovascular disease. The primary goals of this study were to evaluate gender- and age-related differences in homocysteine concentration in the general population of Shenzhen and possible influencing factors. This retrospective study enrolled 2665 healthy subjects aged 18 to 89 years (mean age, 46.68 years). Blood samples were collected and serum indexes were detected with the aid of magnetic nanoparticles, and serum homocysteine concentration was evaluated by the circulating enzymatic method. The reference intervals (5th and 95th percentiles) of total serum homocysteine concentrations were analyzed by the Hoffmann approach. This approach has been widely used to evaluate reference intervals for various analytical parameters. There were significant differences between males and females in some anthropometric and laboratory indexes in the Shenzhen general population. Men had higher levels of creatinine, uric acid, blood urea nitrogen, and homocysteine, whereas women had higher levels of estimated glomerular filtration rate and thyroid-stimulating hormone. Further studies showed that the reference intervals of total serum homocysteine showed significant differences between males and females and among subjects of different ages. These concentrations were higher in males (mean, 12.74 μmol/L) than in females, and the reference intervals increased with age. Men aged 18 to 40 years had a higher risk of hyperhomocysteinemia than women of the same age. Age- and gender-specific reference ranges of serum homocysteine were defined.

REVERSED PHASE HPLC DETERMINATION OF TOTAL HOMOCYSTEINE, CYSTEINE, CYSTEINYL GLYCINE, GLUTATHIONE IN PLASMA OF EPILEPTIC PATIENTS

The fast and accurate reversed-phase HPLC method was predicated on qualitative and quantitative estimation of the total concentrations of the essential thiols in the plasma of adults volunteers compared with epileptic patients, which is l-cysteine (Cys) total homocysteine (tHys), cysteinyl glycine (Cys-Gly), glutathione (GSH) and cysteamine (Cstm), respectively. The plasma samples of (50) epileptic patients were classified into three groups; the non-anti-epileptic drug consisted of 20 patients (12 male, eight female) who were mainly diagnosed with idiopathic generalized epilepsy. The mean age was 34 ± 13 (range 19–48) years. The second group consisted of 30 patients receiving two types of anti-epileptic drugs, 18 patients (12 male and six female) receiving Carbamazepine, and 12 patients (7 males and five female) receiving phenytoin. The mean age of the patients was 32 ± 11 Compared with 31 healthy volunteers (20 male and 11 female). The mean age of the controls was 31 ± 9 (range 26–49 years). The mean duration of treatment of patients receiving the anti-epileptic drug was six months). All measurement was done using pre-column derivatization with bromobimane, and the derivative of each standard mixture were baseline separated on C18-DB (50 x 4.6 mm ID) column, 3μm particle size. The regression coefficients for the separated and standard deviation SD within-run ranged from 0.09 to 8.40 μmol/L, and between-run ranged from 0.15to 9.16 μmol/L; the analytical procedure gave good linearity in the range between 1.25 to 20 µmole/ l, the detection limit was 0.1 µmole /L for all the thiol groups. Analytical recovery was 96.9–107.4 %; the mean concentration of plasma cysteine and total homocysteine was slightly higher in males than females; it was 221± 75 for adult males and 190± 44 μmol/L for adult females, while t-homocysteine was (10.55 ±2.45 vs. 9.79 ± 1.88 μmol/L, the results observed that the value of cysteine and homocysteine were significantly higher in epileptic patients using Carbamazepine and phenytoin than in healthy volunteers. Mean values for glutathione were lower, while cysteinyl glycine showed no significant difference in healthy and epileptic patients and no sex- and age-dependent.

Serum 5-Methyltetrahydrofolate Status Is Associated with One-Carbon Metabolism-Related Metabolite Concentrations and Enzyme Activity Indicators in Young Women.

Maintaining optimal one-carbon metabolism (OCM) is essential for health and pregnancy. In this cross-sectional study, folate status was assessed based on 5-methyltetrahydrofolate (5-MTHF) levels, and the association between 5-MTHF and OCM-related metabolites was investigated in 227 female Japanese university students aged 18-25 years. The participants were divided into high and low 5-MTHF groups based on their folate status. Serum samples of the participants were collected while they were fasting, and 18 OCM-related metabolites were measured using stable-isotope dilution liquid chromatography-electrospray tandem mass spectrometry. The association between serum 5-MTHF and OCM-related metabolite concentrations was assessed using Spearman's rank correlation coefficient. Serum 5-MTHF concentrations were negatively correlated with total homocysteine (tHcy) concentrations and positively correlated with S-adenosylmethionine (SAM) and total cysteine (tCys) concentrations. Serum 5-MTHF concentrations demonstrated a stronger negative correlation with tHcy/tCys than with tHcy alone. The negative correlation between betaine and tHcy concentrations was stronger in the low 5-MTHF group than in the high 5-MTHF group. The 5-MTHF status could be linked to Hcy flux into the transsulfuration pathway via SAM. Therefore, the tHcy/tCys ratio may be a more sensitive indicator of the 5-MTHF status than tHcy alone. Furthermore, a low 5-MTHF status can enhance Hcy metabolism via betaine.

Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant – a case report

BackgroundSeverely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The use of Anabolic androgenic steroid (AAS) is under-reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels.Case ReportWe present a case of a man in his 40s with a large left middle cerebral artery (MCA) territory ischaemic stroke and combined multifocal, extracranial venous, and arterial thrombosis. His past medical history was significant for Crohn’s disease and covert use of AAS. A young stroke screen was negative except for a severely elevated total homocysteine concentration, folate and B12 deficiencies. Further tests revealed he was homozygous for the methylenetetrahydrofolate reductase enzyme thermolabile variant (MTHFR c.667 C > T). The etiology of this stroke was a hypercoagulable state induced by raised plasma homocysteine. Raised homocysteine in this case was likely multifactorial and related to chronic AAS use in combination with the homozygous MTHFR c.677 C > T thermolabile variant, folate deficiency and, vitamin B12 deficiency.ConclusionIn summary, hyperhomocysteinemia is an important potential cause of ischaemic stroke and may result from genetic, dietary, and social factors. Anabolic androgenic steroid use is an important risk factor for clinicians to consider, particularly in cases of young stroke with elevated serum homocysteine. Testing for MFTHR variants in stroke patients with raised homocysteine may be useful to guide secondary stroke prevention through adequate vitamin supplementation. Further studies looking into primary and secondary stroke prevention in the high-risk MTHFR variant cohort are necessary.

Homocysteine in chronic kidney disease: Clinical diagnostic aspects

Chronic kidney disease (CKD) is one of the most common pathologies worldwide. With CKD, cardiovascular risk increases and mortality rises. The article presents the role of homocysteine as a laboratory marker of renal failure and the development of cardiovascular disease. Homocysteine is a thiol-containing amino acid, which is an intermediate product of methionine metabolism, which is metabolized in two ways: due to the transfer of the sulfate group, which occurs in the presence of vitamin B 6, or remethylation, which occurs in the presence of vitamin B 12 and folic acid. Normally, in an adult, the concentration of total homocysteine in blood plasma does not exceed 15 μmol/L. It has been shown that with CKD, hyperhomocysteinemia is observed at the initial stages and its frequency increases at the pre- and dialysis stages of the disease. Hyperhomocysteinemia provokes endothelial dysfunction, accelerates systemic atherosclerosis, increases the risk of atherothrombotic complications. Evaluation of plasma homocysteine levels may be useful in stratifying nephrocardio- and cerebrovascular risk in CKD.

Morphological and Functional Remodeling of the Ischemic Heart Correlates with Homocysteine Levels.

Homocysteine (Hcy) is involved in various methylation processes, and its plasma level is increased in cardiac ischemia. Thus, we hypothesized that levels of homocysteine correlate with the morphological and functional remodeling of ischemic hearts. Thus, we aimed to measure the Hcy levels in the plasma and pericardial fluid (PF) and correlate them with morphological and functional changes in the ischemic hearts of humans. Concentration of total homocysteine (tHcy) and cardiac troponin-I (cTn-I) of plasma and PF were measured in patients undergoing coronary artery bypass graft (CABG) surgery (n = 14). Left-ventricular (LV) end-diastolic diameter (LVED), LV end-systolic diameter (LVES), right atrial, left atrial (LA) area, thickness of interventricular septum (IVS) and posterior wall, LV ejection fraction (LVEF), and right ventricular outflow tract end-diastolic area (RVOT EDA) of CABG and non-cardiac patients (NCP; n = 10) were determined by echocardiography, and LV mass was calculated (cLVM). Positive correlations were found between Hcy levels of plasma and PF, tHcy levels and LVED, LVES and LA, and an inverse correlation was found between tHcy levels and LVEF. cLVM, IVS, and RVOT EDA were higher in CABG with elevated tHcy (>12 µM/L) compared to NCP. In addition, we found a higher cTn-I level in the PF compared to the plasma of CABG patients (0.08 ± 0.02 vs. 0.01 ± 0.003 ng/mL, p < 0.001), which was ~10 fold higher than the normal level. We propose that homocysteine is an important cardiac biomarker and may have an important role in the development of cardiac remodeling and dysfunction in chronic myocardial ischemia in humans.

Potential Antioxidative Activity of Homocysteine in Erythrocytes under Oxidative Stress.

Homocysteine is an amino acid containing a free sulfhydryl group, making it probably contribute to the antioxidative capacity in the body. We recently found that plasma total homocysteine (total-Hcy) concentration increased with time when whole blood samples were kept at room temperature. The present study was to elucidate how increased plasma total-Hcy is produced and explore the potential physiological role of homocysteine. Erythrocytes and leukocytes were separated and incubated in vitro; the amount of total-Hcy released by these two kinds of cells was then determined by HPLC-MS. The effects of homocysteine and methionine on reactive oxygen species (ROS) production, osmotic fragility, and methemoglobin formation in erythrocytes under oxidative stress were studied. The reducing activities of homocysteine and methionine were tested by ferryl hemoglobin (Hb) decay assay. As a result, it was discovered that erythrocytes metabolized methionine to homocysteine, which was then oxidized within the cells and released to the plasma. Homocysteine and its precursor methionine could significantly decrease Rosup-induced ROS production in erythrocytes and inhibit Rosup-induced erythrocyte's osmotic fragility increase and methemoglobin formation. Homocysteine (but not methionine) was demonstrated to enhance ferryl Hb reduction. In conclusion, erythrocytes metabolize methionine to homocysteine, which contributes to the antioxidative capability under oxidative stress and might be a supplementary protective factor for erythrocytes against ROS damage.

Protective Effects of L-Arginine on Mitochondria of Rat Epididymis in Hyperhomocysteinemia Induced by Prolonged Methionine Load

INTRODUCTION: The study of markers of oxidative stress, metabolites of nitric oxide (II) (NOx) and the balance of carnitine fractions in mitochondria of rat epididymis, permits to evaluate the protective role of L-arginine in experimental hyperhomocysteinemia.&#x0D; AIM: To study the influence of L-arginine on the parameters of energy metabolism, level of NO metabolites, oxidative modification of proteins and balance of carnitine fractions in mitochondria of the head and tail of rat epididymis in hyperhomocysteinemia.&#x0D; MATERIALS AND METHODS: In animals of group 1 (n = 8), severe hyperhomocysteinemia (HHcy) was modeled by administration of methionine suspension at a dose of 1.5 g/kg twice daily for 21 days with addition of 1% methionine in drinking water; group 2 rats (n = 8) received suspension base without methionine; animals of group 3 (n = 8) were daily administered L-arginine solution at a dose of 500 mg/kg intragastrically against the background methionine load from day 11 to day 21; group 4 animals (n = 8) were administered L-arginine solution of at a dose of 500 mg/kg for 10 days; group 5 (n = 8) served as a control for group 4 and received drinking water intragastrically. Concentrations of total homocysteine and NOx were determined in serum. In the mitochondrial fraction of the homogenate of epididymis tissues, the level of oxidatively modified proteins (OMP), the concentration of NOx, lactate and carnitine fractions, the activity of lactate dehydrogenase (LDH), superoxide dismutase (SOD), H+-ATPase, succinate dehydrogenase (SDH) were evaluated.&#x0D; RESULTS: HHcy was accompanied by reduction of the level of NOx in blood serum and mitochondria of epididymis head tissues. In mitochondria of tissues of head and tail of epididymis, a marked reduction of all fractions of carnitine, activity of LDH, H+-ATPase, SDH, increase in the activity of SOD and in the level of OMP were observed. With modeled HHcy, L-arginine reduced the extent of hyperhomocysteinemia, prevented reduction of NOx level in the blood serum and epididymis head and reduced the content of OMP of the epididymis mitochondria.&#x0D; CONCLUSION: L-arginine introduced in combination with methionine, reduces the extent of severity of hyperhomocysteinemia. The positive effect of L-arginine on increase in the concentration of NOx metabolites in blood serum and mitochondria of epididymis in conditions of methionine load was also confirmed. L-arginine exhibits antioxidant properties, reducing the severity of oxidative stress induced by hyperhomocysteinemia. Differences in the adaptive response to oxidative stress of the mitochondria of the head and tail of epididymis were demonstrated.

Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial

BackgroundBetaine is an “alternate” methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been used for more than 30 years in pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) and cobalamin C (cblC) deficiencies to lower the hyperhomocysteinemia, although little is known about the optimal therapeutic dosage and its pharmacokinetic in these patients.AimsWe compared 2 betaine doses (100 mg/kg/day vs. 250 mg/kg/day) in children affected by pnrCBS or cblC deficiencies. We also measured the pharmacokinetics parameters after a single dose of betaine (100 or 250 mg/kg) in these patients.MethodsWe conducted a prospective, randomized, crossover clinical trial with blinded evaluation. The primary outcome was the equivalence of total plasma homocysteine (tHcy) concentrations upon one-month oral treatment with betaine at 100 versus 250 mg/kg/day.ResultsEleven patients completed the study (5 pnrCBS and 6 cblC). tHcy concentrations were equivalent after a one-month treatment period for the two betaine dosages. Multivariate analysis showed a significant effect of betaine dose on methionine (Met) (p = 0.01) and S-adenosylmethionine (SAM) concentrations (p = 0.006).ConclusionsOur analysis shows that there is no overt benefit to increasing betaine dosage higher than 100 mg/kg/day to lower tHcy concentrations in pnrCBS and cblC deficiencies. However, increasing betaine up to 250 mg/kg/d could benefit cblC patients through the increase of methionine and SAM concentrations, as low Met and SAM concentrations are involved in the pathophysiology of this disease. In contrast, in pnrCBS deficiency, betaine doses higher than 100 mg/kg/day could be harmful to these patients with pre-existing hypermethioninemia.Trial registration: Clinical Trials, NCT02404337. Registered 23 May 2015—prospectively registered, https://clinicaltrials.gov.

Does Risk of Hyperhomocysteinemia Depend on Thiol-Disulfide Exchange Reactions of Albumin and Homocysteine?

Significance: Increased plasma concentrations of total homocysteine (tHcy; mild-moderate hyperhomocysteinemia: 15-50 μM tHcy) are considered an independent risk factor for the onset/progression of various diseases, but it is not known about how the increase in tHcy causes pathological conditions. Recent Advances: Reduced homocysteine (HSH ∼1% of tHcy) is presumed to be toxic, unlike homocystine (∼9%) and mixed disulfide between homocysteine and albumin (HSS-ALB; homocysteine [Hcy]-albumin mixed disulfide, ∼90%). This and other notions make it difficult to explain the pathogenicity of Hcy because: (i) lowering tHcy does not improve pathological outcomes; (ii) damage due to HSH usually emerges at supraphysiological doses; and (iii) it is not known why tiny increments in plasma concentrations of HSH can be pathological. Critical Issues: Albumin may have a role in Hcy toxicity, because HSS-ALB could release toxic HSH via thiol-disulfide (SH/SS) exchange reactions in cells. Similarly, thiol-disulfide exchange processes of reduced albumin (albumin with free SH group of Cys34 [HS-ALB]) or N-homocysteinylated albumin are plausible alternatives for initiating Hcy pathological events. Adverse effects of albumin and other data reviewed here suggest the hypothesis of a role of albumin in Hcy toxicity. Future Directions: HSS-ALB might be involved in disruption of the antioxidant/oxidant balance in critical tissues (brain, liver, kidney). Since homocysteine-albumin mixed disulfide is a possible intermediate of thiol-disulfide exchange reactions, we suggest that homocysteinylated albumin could be a new pathological factor, and that studies on the redox role of albumin and mixed disulfide production via thiol-disulfide exchange reactions could offer new therapeutic insights for reducing Hcy toxicity.

Consumption of a light meal affects serum concentrations of one-carbon metabolites and B-vitamins. A clinical intervention study.

The transfer of one-carbon units between molecules in metabolic pathways is essential for maintaining cellular homeostasis, but little is known about whether the circulating concentrations of metabolites involved in the one-carbon metabolism are affected by the prandial status. Epidemiological studies do not always consistently use fasting or non-fasting blood samples or may lack information on the prandial status of the study participants. Therefore, the main aim of the present study was to investigate the effects of a light breakfast on serum concentrations of selected metabolites and B-vitamins related to the one-carbon metabolism; i.e. the methionine-homocysteine cycle, the folate cycle, the choline oxidation pathway and the transsulfuration pathway. Sixty-three healthy adults (thirty-six women) with BMI ≥ 27 kg/m2 were included in the study. Blood was collected in the fasting state and 60 and 120 min after intake of a standardised breakfast consisting of white bread, margarine, white cheese, strawberry jam and orange juice (2218 kJ). The meal contained low amounts of choline, betaine, serine and vitamins B2, B3, B6, B9 and B12. Serum concentrations of total homocysteine, total cysteine, flavin mononucleotide, nicotinamide and pyridoxal 5'-phosphate were significantly decreased, and concentrations of choline, betaine, dimethylglycine, sarcosine, cystathionine and folate were significantly increased following breakfast intake (P < 0·05). Our findings demonstrate that the intake of a light breakfast with low nutrient content affected serum concentrations of several metabolites and B-vitamins related to the one-carbon metabolism.

Vitamin B12 and/or folic acid supplementation on linear growth; a 6 years follow-up study of a randomised controlled trial in early childhood in North India.

Folate and vitamin B12 are essential for growth. Our objective was to estimate their long-term effects on linear growth in North Indian children. This is a follow-up study of a factorial designed, double-blind, randomized placebo-controlled trial in 1,000 young children. Starting at 6-30 months of age, we gave folic acid (∼2 RDAs), vitamin B12 (∼2 RDAs), both vitamins, or a placebo daily for six months. Six years after the end of supplementation, we measured height in 791 children. We used the plasma concentrations of cobalamin, folate, and total homocysteine to estimate vitamin status. The effect of the interventions, the association between height-for-age z-scores (HAZ) and baseline vitamin status, and the interactions between supplementation and baseline status were estimated in multiple regression models. Mean (SD) age at follow-up was 7.4 (0.7) years (range 6 to 9 years). There was a small, non-significant effect of vitamin B12 on linear growth and no effect of folic acid. We observed a subgroup-effect of vitamin B12 supplementation in those with plasma cobalamin concentration < 200 pmol/L (P interaction = 0.01). The effect of vitamin B12 supplementation in this group was 0.34 HAZ (95% CI: 0.11-0.58). We found an association between cobalamin status and HAZ in children not given vitamin B12 (P interaction = 0.001). In this group, each doubling of the cobalamin concentration was associated with 0.26 (95% CI: 0.15 to 0.38) higher HAZ. Suboptimal B12 status in early childhood seemingly limits linear growth in North Indian Children.

Association of Vitamin B&lt;sub&gt;12&lt;/sub&gt; Status with Biochemical Parameters among the Adult Population (30 - 50 Years) of Vallabh Vidyanagar, Anand, Gujarat

Vitamin B12 deficiency is known to be very common amongst the vegan population and can cause hyperhomocysteinemia due to various hematologic and neuropsychiatric disorders. Vitamin B12 deficiency is a global epidemic caused by malabsorption and inadequate consumption. Vitamin B12 deficiency has the greatest impact on the blood and nervous system. Elevated Methylmalonic Acid (MMA) and/or total homocysteine levels are sensitive indications of vitamin B12 deficiency and have been linked to clinical problems. Hematological parameters like erythrocyte count, hemoglobin concentration or hematocrit, Mean Cell Volume (MCV), blood values such as plasma B12 and the metabolite MMA are only a few examples. A total of 398 subjects, aged 30-50 years were selected from Vallabh Vidyanagar, Anand, Gujarat. Fourty two percent of the subjects were suffering from vitamin B12 deficiency. The subjects were screened for their vitamin B12 status and several biochemical parameters like homocysteine, iron, hemoglobin, total RBC, PCV, MCV, MCH, MCHC and RDW. Total RBC, MCV, MCH, MCHC levels, and homocysteine concentration of the subjects were found to be significantly (P ? 0.05) associated with the vitamin B12 status of the subjects. A positive and significant (P ? 0.05) relationship was observed between serum vitamin B12 and iron levels (r = 0.127, P ? 0.05) of the subjects. In conclusion, vitamin B12 status was significantly associated with total RBC, MCV, MCH, MCHC levels and homocysteine concentration

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.