Methylmalonic Acid Concentrations Research Articles

Genetic polymorphisms involved in folate metabolism and concentrations of methylmalonic acid and folate on plasma homocysteine and risk of coronary artery disease

Alterations in the enzymes involved in homocysteine (Hcy) metabolism or vitamin deficiency could play a role in coronary artery disease (CAD) development. This study investigated the influence of MTHFR and MTR gene polymorphisms, plasma folate and MMA on Hcy concentrations and CAD development. MMA and folate concentrations were also investigated according to the polymorphisms. Two hundred and eighty-three unrelated Caucasian individuals undergoing coronary angiography (175 with CAD and 108 non-CAD) were assessed in a case-control study. Plasma Hcy and MMA were measured by liquid chromatography/tandem mass spectrometry. Plasma folate was measured by competitive immunoassay. Dietary intake was evaluated using a nutritional questionnaire. Polymorphisms MTHFR and MTR were investigated by polymerase chain reaction (PCR) followed by enzyme digestion or allele-specific PCR. Hcy mean concentrations were higher in CAD patients compared to controls, but below statistical significance (P = 0.246). Increased MMA mean concentrations were frequently observed in the CAD group (P = 0.048). Individuals with MMA concentrations >0.5 micromol/l (vitamin B(12) deficiency) were found only in the CAD group (P = 0.004). A positive correlation between MMA and Hcy mean concentrations was observed in both groups, CAD (P = 0.001) and non-CAD (P = 0.020). MMA mean concentrations were significantly higher in patients with hyperhomocysteinemia in both groups, CAD and non-CAD (P = 0.0063 and P = 0.013, respectively). Folate mean concentration was significantly lower in carriers of the wild-type MTHFR 1298AA genotype (P = 0.010). Our results suggest a correlation between the MTHFR A1298C polymorphism and plasma folate concentration. Vitamin B(12) deficiency, reflected by increased MMA concentration, is an important risk factor for the development both of hyperhomocysteinemia and CAD.

Urinary methylmalonic acid levels in patients with acute ischemic stroke

Objectives Vitamin B-12 and folate deficiency are common, especially in people aged 55 or over, and accompanied by elevated methylmalonic acid (MMA) and homocysteine concentrations. The aims of the study were to investigate the relationship between serum vitamin B-12, homocysteine, folate, erythrocyte folate and urinary MMA in patients with ischemic stroke, and to develop a simple screening HPLC method for the measurement of urinary MMA. Design and methods Twenty-eight patients aged 55 years and over with ischemic stroke and 23 age- and sex- matched healthy controls were included in the study. Serum vitamin B-12 and folate were measured by immunoassay; serum total homocysteine and urinary MMA concentrations by HPLC. Results There was no significant difference in vitamin B-12, folate and homocysteine concentrations between the patient and control groups. Urinary MMA concentrations and erythrocyte folate levels were significantly higher in patients than controls. There was a significantly negative correlation between vitamin B-12 and MMA. Conclusions Increased urinary MMA excretion is associated with ischemic stroke and it may more robustly reflect vitamin B-12 deficiency in patients with ischemic stroke. The method used in this study is eligible for routine urinary MMA measurements.

Folate–vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency

Previous reports on pernicious anemia treatment suggested that high folic acid intake adversely influences the natural history of vitamin B-12 deficiency, which affects many elderly individuals. However, experimental investigation of this hypothesis is unethical, and the few existing observational data are inconclusive. With the use of data from the 1999–2002 National Health and Nutrition Examination Survey (NHANES), we evaluated the interaction between high serum folate and low vitamin B-12 status [ie, plasma vitamin B-12 < 148 pmol/L or methylmalonic acid (MMA) > 210 nmol/L] with respect to anemia and cognitive impairment. With subjects having both plasma folate ≤ 59 nmol/L and normal vitamin B-12 status as the referent category, odds ratios for the prevalence of anemia compared with normal hemoglobin concentration and impaired compared with unimpaired cognitive function were 2.1 (95% CI: 1.1, 3.7) and 1.7 (95% CI: 1.01, 2.9), respectively, for those with low vitamin B-12 status but normal serum folate and 4.9 (95% CI: 2.3, 10.6) and 5.0 (95% CI: 2.7, 9.5), respectively, for those with low vitamin B-12 status and plasma folate > 59 nmol/L. Among subjects with low vitamin B-12 status, mean circulating vitamin B-12 was 228 pmol/L for the normal-folate subgroup and 354 pmol/L for the high-folate subgroup. We subsequently showed increases in circulating homocysteine and MMA concentrations with increasing serum folate among NHANES participants with serum vitamin B-12 < 148 pmol/L, whereas the opposite trends occurred among subjects with serum vitamin B-12 ≥ 148 pmol/L. These interactions, which were not seen in NHANES III before fortification, imply that, in vitamin B-12 deficiency, high folate status is associated with impaired activity of the 2 vitamin B-12–dependent enzymes, methionine synthase and MMA–coenzyme A mutase.

Vitamin B12 absorption and metabolism in milk-fed lambs

AIM: To quantify aspects of absorption and retention of vitamin B12 from milk in pre-ruminant lambs, and the possible effect of activation of dependent metabolic pathways (propionatesuccinate) on vitamin B12 concentrations in tissues. METHODS: In Experiment 1, two groups of eight newborn lambs each received either milk substitute alone, or milk substitute with added propionate for 4 weeks. Half of the lambs in each group received vitamin B12 injections twice weekly. Blood and liver samples were taken on Day —1 and at the end of the trial, and blood was also collected twice weekly, for measurement in plasma of vitamin B12, methylmalonic acid (MMA), and blood-binder transcobalamin II/haptocorrin. The lambs were weighed at 0, 2 and 4 weeks. In Experiment 2, 12 milk-fed newborn lambs (n=2 or 3/group) were injected I/M with 0.2, 0.4, 0.8, 1.6 or 3.2 µg vitamin B12 and a further 12 were supplemented orally with 2, 4, 8, 16 or 32 µg vitamin B12, daily for 2 weeks. Three lambs remained as untreated controls. Blood and liver samples were taken at the start and end of the trial, and blood was also collected twice weekly, for measurement of vitamin B12 and MMA concentrations in plasma. The lambs were weighed on Days 0, 7 and 14. In Experiment 3, 14 lambs from Experiment 2 were used to repeat the highest I/M and oral rates of supplementation used in Experiment 2. Blood samples were taken at frequent intervals for 24 hours, and analysed for concentrations of vitamin B12 in plasma. RESULTS: Propionate supplementation was associated with increased concentrations of vitamin B12 in plasma in lambs supplemented with vitamin B12 but not in those not supplemented (p=0.047), but had no detectable effect on concentrations of vitamin B12 in liver (Experiment 1). Lambs with concentrations of vitamin B12 in plasma and liver in the marginal reference range were able to metabolise propionate and maintain normal concentrations of MMA at a rate of intake of propionate close to that which would depress appetite. Close to 100% of the vitamin B12 administered by I/M injection appeared in plasma in the first hour but 85% was removed from the circulation within 16 hours. The maximum liver concentration was achieved at 900 nmol/kg (=1,200 µg) fresh tissue. There were no significant differences in liveweight gain (LWG) regardless of treatment. CONCLUSIONS: Lambs with concentrations of vitamin B12 in plasma and liver in the marginal reference range were able to metabolise propionate and maintain normal concentrations of MMA in plasma at a rate of absorption of propionate close to that which would depress appetite. The coefficient of absorption of oral vitamin B12 in milk-fed lambs was low (<10%), and the ability of lambs to retain the vitamin even when tissues had physiologically low concentrations was poor. CLINICAL RELEVANCE: Pre-ruminant lambs had a low requirement for vitamin B12, and even at low tissue concentrations had poor ability to absorb and retain the vitamin. However, if supplementation is required, a method that provides a modest but continual supply may be most effective in protection against deficiency.

Biochemical indicators of vitamin B 12 and folate insufficiency and cognitive decline

In some prospective studies, associations of serum vitamin B(12) and homocysteine concentrations with cognitive decline have been reported but few have examined the role of methylmalonic acid, a more specific marker of vitamin B(12) deficiency than homocysteine. The aim of the study was to determine whether serum concentrations of vitamin B(12) or selected metabolites are related to cognitive decline. A total of 516 subjects were selected in a stratified random sampling design from among Chicago Health and Aging Project participants for clinical evaluation. We used linear mixed models to examine the association of blood markers of vitamin B(12) status to change in cognitive scores over 6 years. Cognitive function was assessed every 3 years and measured as the sum of standardized scores on four tests. Probable vitamin B(12) deficiency was observed in 14.2% of the sample. Elevated serum concentrations of homocysteine were present in 19.2% of subjects, and of methylmalonic acid, in 36.4%. Higher serum methylmalonic acid concentrations were predictive of faster rates of cognitive decline (beta = -0.00016, SE = 0.0001, p = 0.004) and higher serum vitamin B(12) concentrations were associated with slower rates of cognitive decline (beta = +0.00013, SE < 0.0001, p = 0.005) in multivariable adjusted mixed models. Serum concentrations of homocysteine had no relationship to cognitive decline. Serum methylmalonic acid and vitamin B(12) concentrations may be the more important risk factors for cognitive decline when compared to serum homocysteine concentrations, particularly in older populations exposed to food fortification and possible supplements containing folic acid.

Holotranscobalamin – An Early Marker for Laboratory Diagnosis of Vitamin B12 Deficiency

Vitamin B12deficiency is widespread. Among the population groups at risk are older people, vegetarians, pregnant women and patients with renal or intestinal diseases. The neurological symptoms of vitamin B12deficiency are unspecific and can be irreversible. Early detection is therefore important. This article reviews the diagnostic performance of the different laboratory markers for vitamin B12status. Total serum vitamin B12is a relatively insensitive and unspecific biomarker of deficiency that does not reflect recent variations in cobalamin status. Holotranscobalamin (holoTC), the metabolically active portion of vitamin B12, is the earliest laboratory parameter that becomes decreased in case of a vitamin B12negative balance. Concentration of methylmalonic acid (MMA) is a functional vitamin B12marker that will increase when the vitamin B12stores are depleted. Isolated lowering of holoTC shows vitamin B12depletion (negative balance), while lowered holoTC plus elevated MMA (and homocysteine) indicates a metabolically manifested vitamin B12deficiency, although there still may be no clinical symptoms. The diagnostic use of holoTC allows the initiation of therapeutic measures before irreversible neurological damage develops. Because the clinical manifestations of vitamin B12deficiency are unspecific, people at risk should be identified and should regularly test their holoTC with or without MMA.

Subclinical vitamin B12 deficiency in pregnant women attending an antenatal clinic in Nigeria

SummaryInadequate vitamin B12 status in a pregnant woman increases the risk for adverse maternal and fetal outcomes. The use of serum vitamin B12 concentration alone to assess vitamin B12 status in pregnant women is unreliable because of the decrease in serum vitamin B12 levels in normal pregnancy. The combination of serum vitamin B12 and methylmalonic acid (MMA) concentrations may provide a better estimate of vitamin B12 status. We obtained blood samples from 98 pregnant women in the third trimester at an antenatal clinic in Jos, Nigeria. All subjects were taking iron and folate supplements. Twelve of the subjects had a serum vitamin B12 concentration <148 pmol/l and 18 subjects had a serum MMA level >271 nmol/l. Using a combination of low serum vitamin B12 and elevated MMA concentrations, eight subjects were classified as having subclinical vitamin B12 deficiency. Because of the potential harmful consequences of vitamin B12 deficiency in pregnant women, it would be advisable to add vitamin B12 supplements to the existing regimen of folate and iron supplements currently provided to pregnant women in Nigeria.

Enhanced bone metabolism in vegetarians – the role of vitamin B12 deficiency

Vitamin B12 deficiency and bone fractures are common in vegetarians. However, a direct relationship between vitamin B12 status and bone metabolism in vegetarians has not been tested sufficiently. Our study included 96 vegetarians (23 German vegans, and 54 German and 19 Indian lacto-, lacto-ovo-vegetarians) and 89 omnivores (Germans and Asian-Indian immigrants in Oman). Blood concentrations of total vitamin B12, holotranscobalamin (holoTC), 25OH-vitamin D (25(OH)D), total homocysteine (tHcy), methylmalonic acid (MMA), and the bone turnover markers (BTMs) bone alkaline phosphatase (BAP), osteocalcin (OC), pro-collagen type I N-terminal peptide (PINP) and C-terminal telopeptides of collagen I (CTx) were measured. Vegetarians from both population groups exhibited significantly higher concentrations of tHcy, MMA, folate, and BAP, but lower concentrations of holoTC and cobalamin compared with omnivores from the same population. Additionally, German vegetarians had higher circulating activities of BAP as well as higher CTx, OC, and PINP compared with their omnivorous controls. HoloTC and MMA were correlated with OC, CTx and BAP. Subjects with low vitamin B12 status (holoTC < or =35 pmol/L and MMA >271 nmol/L) had significantly lower serum concentrations of 25(OH)D, but higher tHcy and the BTMs P1NP, BAP, OC, and CTx, compared with subjects with normal vitamin B12 status. Multiple regression analysis showed that the association between BTMs and markers of vitamin B12 status was independent from the association with 25(OH)D. Approximately 12%-14% of the variation in the concentration of BTMs was explained by a regression model including holoTC, MMA and 25(OH)D. The strictness of the diet was not related to the magnitude of change in BTMs. Low vitamin B12 status is related to increased bone turnover in vegetarians which is independent from vitamin D status.

Plasma vitamin B12 status and cerebral white-matter lesions

Background and objective:Elevated homocysteine has been associated with a higher prevalence of cerebral white-matter lesions and infarcts, and worse cognitive performance. This raises the question whether factors involved in homocysteine...

Bread cofortified with folic acid and vitamin B-12 improves the folate and vitamin B-12 status of healthy older people: a randomized controlled trial

BackgroundMandatory fortification of flour with folic acid has reduced the number of neural tube defects in North America. Concerns that high intakes of folic acid might mask vitamin B-12 deficiency in older persons have delayed the introduction of fortification in many European countries. Cofortification of flour with folic acid and vitamin B-12 could simultaneously improve folate and vitamin B-12 status. ObjectiveThe objective was to estimate the effect of the consumption of bread fortified with modest amounts of folic acid and vitamin B-12 on folate and vitamin B-12 status in healthy older persons living in the Netherlands, where folic acid fortification is not taking place. DesignMen and women aged 50–75 y were randomly assigned in this 12-wk double-blind, placebo-controlled trial to consume bread fortified with 138 μg folic acid and 9.6 μg vitamin B-12 daily (n = 72) or unfortified bread (n = 70). ResultsThe consumption of fortified bread increased serum folate concentrations by 45% (mean: 6.3 nmol/L; 95% CI: 4.5, 8.1 nmol/L) and serum vitamin B-12 concentrations by 49% (mean: 102 pmol/L; 95% CI: 82, 122 pmol/L) relative to the placebo group. Fortified bread increased erythrocyte folate concentrations by 22% and holotranscobalamin concentrations by 35%; it decreased homocysteine concentrations by 13% and methylmalonic acid concentrations by 10%. Consumption of fortified bread decreased the proportion of individuals with marginal serum vitamin B-12 concentrations (<133 pmol/L) from 8% at enrollment to 0% after 12 wk. ConclusionBread fortified with modest amounts of folic acid and vitamin B-12 will improve folate and vitamin B-12 status and a considerable proportion of vitamin B-12 deficiency in older people. This trial was registered at clinicaltrials.gov as NCT00353353.

In vitamin B12 deficiency, higher serum folate is associated with increased homocysteine and methylmalonic acid concentrations

In the December 11, 2007, issue of PNAS, Selhub et al. (1) suggest that the association between elevated serum folate and methylmalonic acid (MMA) concentrations in vitamin B12 deficiency resulted from disruption of MMA metabolism by folate. An alternative explanation is that the increase in both serum folate and MMA concentrations resulted from … *E-mail: epq{at}ufl.edu

Reply to Quinlivan: Postfortification, folate intake in vitamin B12 deficiency is positively related to homocysteine and methylmalonic acid

With cross-sectional data, causes and effects are difficult to distinguish, and Quinlivan suggests that high circulating concentrations of homocysteine (Hcy), methylmalonic acid (MMA), and folate observed among vitamin B12-deficient survey participants all resulted from a lack of vitamin B12 (1). However, we observed the interaction between vitamin B12 status and folate status in the … ‡E-mail: martha.morris{at}tufts.edu

Altered red cell membrane compositions related to functional vitamin B12 deficiency manifested by elevated urine methylmalonic acid concentrations in patients with schizophrenia

Abnormal cell membrane composition and functional cobalamin (vitamin B(12)) deficiency was reported in schizophrenic individuals. We aimed to investigate the relationship between cobalamin state and cell membrane composition in patients with schizophrenia. Malondialdehyde (MDA), cholesterol, and phospholipid classes in the erythrocyte membranes of 18 schizophrenic and 20 healthy individuals of the same age and sex distribution were determined. Serum vitamin B(12), plasma total homocysteine, serum folate, and urine methylmalonic acid (uMMA) concentrations were measured in both groups. In the schizophrenic group, uMMA, membrane MDA, membrane cholesterol, membrane phosphatidylinositol concentrations were significantly higher and the membrane phosphatidylserine concentrations were lower than the control group values. In schizophrenic individuals, uMMA concentrations have a significant positive correlation with membrane MDA and a negative correlation with membrane cholesterol concentrations (P<0.05). The negative correlation of uMMA with membrane cholesterol concentrations may be a biological response to the increased membrane rigidity. Also, a free radical elevation related to the elevated uMMA concentrations in the erythrocyte membrane, might reflect the role of methylmalonic acid (MMA) in membrane damage. Our present findings suggest that, functional vitamin B(12) deficiency representing itself by MMA elevations in schizophrenic individuals could damage cell membrane.

Association between Helicobacter pylori-infection, C-reactive protein and status of B vitamins

Some investigations, but not all, found that a chronic infection with Helicobacter pylori (Hp) is associated with deficiencies in B vitamins, elevated plasma total homocysteine concentrations (tHcy) and increased plasma levels of proinflammatory acute-phase proteins. It has been suggested that these factors promote atherogenesis and therefore could mechanistically explain why people infected with Hp might have an increased risk for cardiovascular diseases (CVD). Therefore we evaluated the association between Hp-infection, concentration of C-reactive protein (CRP), and status of various B vitamins in apparently healthy subjects. In 69 subjects with proved Hp-infection and 21 healthy control subjects identified in a cross sectional study, blood samples were collected to determine serum folate, serum vitamin B12, serum methylmalonic acid (MMA), serum CRP and plasma vitamin B6 and plasma total homocysteine (tHcy). The mean concentration of CRP was significantly higher in the Hp-positive collective than in controls. Although mean concentrations of vitamin B12, B6, and MMA differed between the groups, statistical significance was missed. However, the mean concentrations of homocysteine and folic acid were nearly the same in both groups. In univariate analysis a significant impact of Hp-status was shown on cobalamin (p=0.028; eta square: 0.055), and in multivariate analysis of variance the Hp-status had an impact on vitamin B12-values (p=0.028; eta square 0.057). In this study Hp-infection shows no significant impact on status of B vitamins, but has a significant influence on CRP concentration. However, this study does not support the hypothesis that Hp-infection is related to CVD via elevated levels of tHcy.

Methylmalonic acid values in healthy Dutch children

Plasma methylmalonic acid (MMA) is a specific marker for functional cobalamin deficiency. This deficiency can give rise to non-specific but serious symptoms in childhood such as developmental delay, convulsions and failure to thrive and may even lead to irreversible neurological damage. To analyse plasma MMA concentrations in Dutch children and to evaluate possible factors influencing its concentration. A number of 186 Dutch children aged 0-19 years were analysed cross-sectionally. Blood was collected to measure MMA, total homocysteine (tHcy), cobalamin (Cbl) and serum creatinine concentrations. In addition, information about medical history, age and sex was recorded. The geometric mean (GM) plasma MMA concentration was 0.17 micromol/l (95% CI 0.07-0.42) and the GM tHcy was 6.6 micromol/l (95% CI 3.1-13.9). There is a slight positive correlation between plasma MMA and age in children >1 year (r = 0.211, P < 0.05). Plasma MMA concentrations were significantly higher in children with low Cbl concentrations. No significant difference in MMA, Cbl, tHcy or creatinine concentrations between sexes could be observed. Regression analysis showed that Cbl was the strongest determinant of plasma MMA (regression coefficient -0.414, P < 0.05). The association between MMA and Cbl is stronger at increasing age (P for trend 0.045). Plasma Cbl is the main determinant of MMA in this group of Dutch children. The strength of the association increased with increasing age.

In vitamin B 12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations

In a recent study of older participants (age >/=60 years) in the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we showed that a combination of high serum folate and low vitamin B(12) status was associated with higher prevalence of cognitive impairment and anemia than other combinations of vitamin B(12) and folate status. In the present study, we sought to determine the joint influence of serum folate and vitamin B(12) concentrations on two functional indicators of vitamin B(12) status, total homocysteine (tHcy) and methylmalonic acid (MMA), among adult participants in phase 2 of the NHANES III (1991-1994) and the NHANES 1999-2002. Exclusion of subjects who were <20 years old, were pregnant, had evidence of kidney or liver dysfunction, or reported a history of alcohol abuse or recent anemia therapy left 4,940 NHANES III participants and 5,473 NHANES 1999-2002 participants for the study. Multivariate analyses controlled for demographic factors, smoking, alcohol use, body mass index, self-reported diabetes diagnosis, and serum concentrations of creatinine and alanine aminotransferase revealed significant interactions between serum folate and serum vitamin B(12) in relation to circulating concentrations of both metabolites. In subjects with serum vitamin B(12) >148 pmol/liter (L), concentrations of both metabolites decreased significantly as serum folate increased. In subjects with lower serum vitamin B(12), however, metabolite concentrations increased as serum folate increased starting at approximately 20 nmol/L. These results suggest a worsening of vitamin B(12)'s enzymatic functions as folate status increases in people who are vitamin B(12)-deficient.

A Population Pharmacokinetic and Pharmacodynamic Evaluation of Pralatrexate in Patients with Hematologic Malignancies.

Pralatrexate is a novel antifol designed to have high affinity for the reduced folate carrier, exhibiting improved internalization over other analogues. Phase 2 and subsequent Phase 1 studies revealed that patients with lymphoma exhibited a higher incidence of mucositis, compared to that reported in patients with solid tumors. The initial Phase 2 experiences employed dose escalation on an every other week schedule (135 to 240 mg/m2 QOW) while the follow-on Phase 1 and 2 studies employed a weekly dosing schedule (30 to 45 mg/m2 weekly for 6 of 7 weeks). The maximum tolerated dose (MTD) was 30 mg/m2 weekly for 6 of 7 weeks in lymphoma patients. Preliminary population pharmacokinetic (PK) and adverse event (AE) evaluations suggested that pralatrexate exposure could be controlled with weight or body size based dosing, and that pretreatment with folic acid and vitamin B12 could abrogate the mucositis. PK and AE data from 47 patients were evaluated using NONMEM Version V level 1.1. Model building followed standard approaches. The best PK model was a three compartment linear model, fitted to the natural log-transformed concentration versus time data. Patient weight and methylmalonic acid (MMA) were found to be predictive of inter-patient PK variability, supporting weight or body surface area (BSA) based dosing. There are observations of an apparent association between MMA concentrations and PDX PK which need to be further explored. The PK model was evaluated using bootstrapping and a visual predictive check. An ordered categorical logistic regression was conducted to evaluate the relationship between pralatrexate exposure and grade of mucositis. In this evaluation, pralatrexate area under the curve (AUC) and MMA were found to be predictive of toxicity, where patients with higher MMA or AUC had a higher probability of mucositis. Individualized dosing combined with vitamin pretreatment significantly improved the toxicity profile, allowing for a shift in the dose-limiting toxicity (DLT) from mucositis to thrombocytopenia. Although the data from the present study were limited, the covariates identified in the population PK and adverse event evaluations were comparable with those identified for other anti-folate agents. MMA is a sensitive indicator of vitamin B12 deficiency and its impact on toxicity is commonly reported for this class of agents. The rationale behind the influence of MMA on clearance is less clear and may be correlated with other aspects of patient health. Pralatrexate has exhibited promising activity in patients with chemotherapy refractory peripheral T-cell lymphoma, leading now to an international multi-center Phase 2 study in peripheral T-cell lymphoma. The application of a population PK model based analysis was a critical component in the development of this agent. Model-based evaluations allowed the identification of the safest schedules and supported the need for vitamin supplementation for the safe administration. [Display omitted]

Cobalamin and folate status in infants and young children in a low-to-middle income community in India

Background: Population-based data on the prevalence of cobalamin and folate deficiency in India are lacking.Objective: The objective was to measure the prevalence of cobalamin and folate deficiency among children aged 6–30 mo residing in a low-to-middle income community in North India.Design: Children aged 6–30 mo (n = 2482) were identified through a community survey in a low-to-middle socioeconomic area in New Delhi, India. Non-fasting venous blood samples were collected before enrollment in another trial.Results: The median (interquartile range; IQR) cobalamin concentration in 6–11-mo-old children was substantially lower in breastfed (183; 120–263 pmol/L) than in nonbreastfed (334; 235–463 pmol/L) children. Cobalamin concentrations decreased progressively with increasing age in the nonbreastfed children. Median (IQR) plasma folate concentrations in the 6–11-mo-old group were higher in breastfed (20.3; 11.7–34.4 nmol/L) than in nonbreastfed (5.3; 3.4–7.7 nmol/L) children (P < 0.001). Folate concentrations decreased with increasing age in the breastfed children. In the nonbreastfed children, folate concentrations increased with increasing age. Low concentrations of plasma cobalamin (<150 pmol/L) were detected in 36% of breastfed and 9% of nonbreastfed children (P < 0.001). The proportions of children with plasma folate concentrations <5 nmol/L in these 2 subgroups were 6% and 33%, respectively (P < 0.001).Conclusions: In north Indian preschool children, cobalamin and folate concentrations were commonly low and were associated with elevated total homocysteine and methylmalonic acid concentrations. Because low cobalamin and folate concentrations have functional consequences, population-based measures for improving cobalamin and folate concentrations need to be seriously considered.

The Association of Gastric Cancer Risk with Plasma Folate, Cobalamin, and Methylenetetrahydrofolate Reductase Polymorphisms in the European Prospective Investigation into Cancer and Nutrition

Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first prospective study of blood folate levels and gastric cancer. Gastric cancer cases (n=247) and controls (n=631) were matched for study center, age, sex, and time of blood donation. Two common single nucleotide polymorphisms of the MTHFR gene were determined, as were plasma concentrations of folate, cobalamin (vitamin B12), total homocysteine, and methylmalonic acid (cobalamin deficiency marker) in prediagnostic plasma. Risk measures were calculated with conditional logistic regression. Although no relations were observed between plasma folate or total homocysteine concentrations and gastric cancer, we observed a trend toward lower risk of gastric cancer with increasing cobalamin concentrations (odds ratio, 0.79 per SD increase in cobalamin; P=0.01). Further analyses showed that the inverse association between cobalamin and gastric cancer was confined to cancer cases with low pepsinogen A levels (marker of severe chronic atrophic gastritis) at the time of blood sampling. The 677 C-->T MTHFR polymorphism was not associated with gastric cancer, but we observed an increased risk with the variant genotype of the 1298 A-->C polymorphism (odds ratio, 1.47 for CC versus AA; P=0.04). In conclusion, we found no evidence of a role of folate in gastric cancer etiology. However, we observed increased gastric cancer risk at low cobalamin levels that was most likely due to compromised cobalamin status in atrophic gastritis preceding gastric cancer.

Low vitamin B-12 status and risk of cognitive decline in older adults

Background: Elevated total homocysteine (tHcy) concentrations have been associated with cognitive impairment, but it is unclear whether low vitamin B-12 or folate status is responsible for cognitive decline.Objective: We examined the associations of cognitive decline with vitamin B-12 and folate status in a longitudinal cohort study performed from 1993 to 2003 in Oxford, United Kingdom.Design: Cognitive function was assessed with the Mini-Mental State Examination on ≥3 occasions during 10 y and related to serum concentrations of vitamin B-12, holotranscobalamin (holoTC), tHcy, methylmalonic acid (MMA), and folate with the use of linear mixed models in 1648 participants who provided blood in 1995.Results: Cognitive function declined abruptly at younger ages in some participants but remained intact in others until very old age. In multivariate regression analyses after adjustment for established risk factors, concentrations of holoTC (a marker of reduced vitamin B-12 status), tHcy, and MMA predicted cognitive decline, but folate did not. A doubling in holoTC concentrations (from 50 to 100 pmol/L) was associated with a 30% slower rate of cognitive decline (−0.137 to −0.083), whereas a doubling in tHcy (from 10 to 20 μmol/L) or MMA (from 0.25 to 0.50 μmol/L) was associated with >50% more rapid cognitive decline (−0.090 to −0.169) and (−0.104 to −0.169), respectively. After adjustment for all vitamin markers simultaneously, the associations of cognitive decline with holoTC and MMA remained significant.Conclusions: Low vitamin B-12 status was associated with more rapid cognitive decline. Randomized trials are required to determine the relevance of vitamin B-12 supplementation for prevention of dementia.