Low B12 Concentrations Research Articles

Decreased Protein Levels and Vitamin B12 Plasma Concentration in Primary Sjögren Syndrome are Associated with Peripheral Neuropathy: A Case-Control Study

Prognostic factors for peripheral nervous system (PNS) manifestations in primary Sjögren Syndrome (pSS) are essential for predicting and preventing disease-related disability. Given the established relationship between vitamin B12 deficiency and pSS, we aimed to investigate the predictive value of low B12 concentration for Sjögren's induced peripheral neuropathy (PN).

Telomere length, vitamin B12 and mortality in persons undergoing coronary angiography: the Ludwigshafen risk and cardiovascular health study.

Background: Vitamin B12 (B12) deficiency and excess are associated with increased risk of age-related-diseases and mortality. It has been suggested that high- and low-B12 concentrations link to increased mortality through accelerated genomic aging and inflammation. Evidence to support this is limited.Results: B12 was associated with all-cause-mortality, RTL and hsCRP in a non-linear fashion. The association between B12 and mortality was not independent, as it lost significance after adjustment for potential confounders. In the lowest-(LB12) and highest-(HB12) quartiles of B12 mortality was higher than in the mid-range (HR:LB12:1.23;CI95%:1.06-1.43; HR:HB12:1.24;CI95%:1.06-1.44). We divided subjects with LB12 in quartiles of their RTL. Those with the longest-telomeres had a lower mortality-rate (HR:0.57;95%CI:0.39-0.83) and lower homocysteine than those with the shortest-telomeres. Amongst subjects with HB12, those with long-telomeres also had a lower mortality than those with short-telomeres (HR:0.40;95%CI:0.27-0.59). IL-6 and hsCRP concentrations were low in HB12LT but were high in HB12ST.Methods: B12, homocysteine, telomere length (RTL), interleukin-6 (IL-6) and high-sensitive-C-reactive-protein (hsCRP) were measured in 2970 participants of the LURIC study.Conclusions: Mortality, stratified according to B12 and RTL, seems to be driven by different mechanisms. In LB12 and HB12 subjects, mortality and accelerated telomere shortening might be driven by homocysteine and inflammation, respectively.

Functional Biomarkers of Vitamin B12 Status, Diet, and Metabolic Control in Women with Phenylketonuria (P24-005-19)

ObjectivesMetabolic control in Phenylketonuria (PKU) requires a protein-restricted diet, which elevates the risk of vitamin B12 deficiency. Neurological sequelae driven by suboptimal B12 status in PKU may be overlooked due to concomitant elevations in phenylalanine and B12 monitoring techniques that lack sensitivity. The aim of this analysis was to assess the effectiveness of functional biomarkers of B12 status, methylmalonic acid (MMA) and total homocysteine (tHcy), in the early identification of B12 deficiency in PKU. MethodsDiet and blood measures (plasma amino acids, B6; serum B12, folate, MMA, tHcy) were assessed in 31 females with PKU who attended the Emory Metabolic Camp in 2012 (N = 14) or 2018 (N = 17). The prevalence of functional B12 deficiency (MMA > 378 nmol/L and B12 < 914 pg/mL) was determined, and Spearman rank correlations between dietary intake, metabolic control, and biochemical indicators of B12 status were assessed (SAS 9.4, α = 0.05). ResultsAll characteristics were similar for 2012 and 2018 participants except tHcy, which was higher among females in 2012 (P = 0.01). Median age was 20 years (IQR: 16–24) and mean BMI was 29.6 ± 8.3 kg/m2. Of the 31 participants, 13 (41.9%) were on a phenylalanine-lowering medication (Kuvan). Five females (16%) had low B12 concentrations (<230 pg/mL), and one of these five had elevated MMA. Dietary consumption of B12 was below the RDA in seven females (22.6%), five of which also had suboptimal consumption of B6 and folate. Low B12 was associated with increased MMA (r = −0.49, P = 0.01) and tHcy (r = −0.42, P = 0.02) levels. Whereas, higher serum B12 was associated with elevated plasma B6 (r = 0.86, P < 0.01), dietary compliance (r = 0.41, P = 0.03), and increased intake of B12 (r = 0.63, P < 0.01), B6 (r = 0.47, P = 0.01), folate (r = 0.46, P = 0.01), and total protein (r = 0.43, P = 0.02). ConclusionsVitamin B12 has a moderate correlation with MMA and tHcy in females with PKU. Functional B12 deficiency, however, is not prevalent in this sample. This may reflect the regular consumption of fortified medical food among the females in this sample. Monitoring MMA and tHcy, regardless of B12 levels, may still have utility in this population for the detection of early deficiency. Funding SourcesNational Center for Advancing Translational Sciences of the NIH, private donations.

Breast milk provides inadequate amounts of vitamin B12 for predominantly breastfed Guatemalan infants.

Vitamin B12 (B12) plays in an important role in the development and function of the brain and nervous system, and adequate B12 status is especially important for the normal development of infants. In previous research conducted in Guatemala City we reported a high prevalence of B12 deficiency in lactating women and their infants 3 and 12 months of age, and low B12 concentrations in breast milk. The objective of this study was to assess predictors of serum B12 concentration in predominantly breastfed Guatemalan infants including intake of B12 from breast milk and other foods. Serum B12, breast milk and other food intakes, anthropometry, morbidity and socioeconomic status were assessed in infants 6.7±0.6 months of age (n=127, 52% female) in peri-urban Guatemala City. Twenty-four percent of infants had deficient B12 status (serum B12 concentration<148 pmol/L) and 37% had marginal B12 status (148-220 pmol/L). Serum B12 concentrations were negatively correlated with infants' consumption of energy from breast milk (r=-0.37, p=0.001), and positively correlated with their total consumption of animal source foods, especially cow's milk (r=0.40, p=0.001). Based on previously analyzed breast milk B12 concentrations in a nearby community, breast milk provided<10% of the recommended daily B12 intake for this age. We conclude that there was a high prevalence of B12 deficiency in these Guatemalan infants by 6 months of age. Serum B12 was higher in infants consuming more cow's milk and lower in those consuming more breast milk.

Micronutrient Status among Pregnant Women in Zinder, Niger and Risk Factors Associated with Deficiency.

Anemia and micronutrient (MN) deficiencies in pregnant women are associated with adverse pregnancy outcomes. In Niger, 58.6% of pregnant women are anemic; however, MN statuses are unknown. The study objectives were to estimate the prevalence of MN deficiencies among pregnant women in Zinder, Niger and explore associated risk factors. Pregnant women living in randomly selected rural villages (n = 88) were included. Capillary and venous blood samples (n = 770) were analyzed for hemoglobin (Hb) and plasma ferritin, soluble transferrin receptor (sTfR), zinc (pZn), retinol binding protein (RBP), folate and vitamin B12. C-reactive protein and alpha-1-acid glycoprotein were measured to adjust for inflammation. The prevalence of MN deficiencies in pregnant woman was high, indicative of a severe public health problem. Prevalence of iron deficiency was 20.7% and 35.7%, by ferritin (<15 µg/L) and sTfR (>8.3 mg/L), respectively. In total, 40.7% of women had low pZn (<50 µg/dL), 79.7% had marginal RBP (<1.32 µmol/L), 44.3% of women had low folate (<10 nmol/L) and 34.8% had low B12 concentrations (<148 pmol/L). Common risk factors associated with MN status included gravidity, mid-upper-arm circumference, geophagy, malaria, and result of the woman’s last pregnancy. Interventions to promote the strengthening of antenatal care, and access and adherence to nutrition and health interventions are critical among pregnant women in this population.

Vitamin B12 in obese adolescents with clinical features of insulin resistance.

Emerging evidence indicates an association between obesity, metformin use and reduced vitamin B12 status, which can have serious hematologic, neurologic and psychiatric consequences. This study aimed to examine B12 status in obese adolescents with pre-diabetes and/or clinical features of insulin resistance. Serum B12 was measured using chemiluminescence immunoassay in 103 (43 male, 60 female) obese (mean body mass index (BMI) z-score ± SD (2.36 ± 0.29)), adolescents aged 10 to 17 years, median (range) insulin sensitivity index of 1.27 (0.27 to 3.38) and 13.6% had pre-diabetes. Low B12 (<148 pmol/L) was identified in eight (7.8%) and borderline status (148 to 221 pmol/L) in an additional 25 (24.3%) adolescents. Adolescents with borderline B12 concentrations had higher BMI z-scores compared to those with normal concentrations (2.50 ± 0.22 vs. 2.32 ± 0.30, p = 0.008) or those with low B12 concentration (2.50 ± 0.22 vs. 2.27 ± 0.226, p = 0.041). In conclusion, nearly a third of obese adolescents with clinical insulin resistance had a low or borderline serum B12 status. Therefore, further investigations are warranted to explore the cause and the impact of low B12 status in obese pediatric populations.

B12 deficiency increases with age in hospitalized patients: a study on 14,904 samples.

Cobalamin deficiency is responsible for hematological, neurological, neurocognitive, and neuropsychiatric impairments and is a risk factor for cardiovascular diseases, particularly in the elderly people. In order to determine B12 status in old inpatients, a total number of 14,904 hospitalized patients in whom B12 measurements were performed in five hospitals in the Paris metropolitan area were included from January 1, 2011 to December 31, 2011. The aims of the study were to determine whether age had an impact on B12 and folate deficiencies and to evaluate correlations between B12 and biological parameters-folate, hemoglobin, mean cell volume, homocystein (tHcy)-and age. Patients were aged 70.3±19.5 years. Low B12 concentration (<200ng/L) was observed in 4.6% of cases, 24.2% had middle B12 concentration (200-350ng/L), 12.6% were functional B12 deficient (B12 < 350 ng/L associated to high tHcy level, tHcy > 17 µmol/L), 20.4% had low folate concentration (folate < 4 µg/L), 10.6% were functional folate deficient (folate < 4 µg/L associated to tHcy > 17 µmol/L), and 4.7% of patients were both functional B12 and folate deficient. The B12 or folate deficient patients had lower mean cell volume level than nondeficient patients. Increase in mean cell volume and tHcy concentrations with age and decrease in B12, folate, and hemoglobin levels with age were observed. Frequency of functional B12 deficiency was 9.6% in patients aged 30-60 years and 14.2% in patients over 90 years. Frequency of functional folate deficiency was 9.5% in 30-60 years and 12.1% in >90 years. In inpatients, functional B12 deficiency and functional folate deficiency increase with age and are not associated with anemia or macrocytosis. False vitamin B deficiencies are frequent.

Competitive chemiluminescent enzyme immunoassay for vitamin B12 analysis in human milk

Recent discoveries of matrix interferences by haptocorrin (HC) in human milk and serum show that past analyses of vitamin B12 in samples with high HC content might have been inaccurate (Lildballe et al., 2009; Carmel & Agrawal, 2012). We evaluated two competitive enzyme-binding immunoassays for serum/plasma (IMMULITE and SimulTRAC-SNB) for B12 analysis in human milk. B12-recovery rates (United States Environmental Protection Agency, 2007) were determined to be 78.9±9.1% with IMMULITE and 225±108% (range 116–553%) using SimulTRAC-SNB, most likely due to the presence of excess HC. HC-interferences were not observed with the IMMULITE assay, rendering previously reported mandatory HC-removal (Lildballe et al., 2009) unnecessary. Linearity continued at low B12-concentrations (24–193pM; r2>0.985). Milk B12 concentrations from Bangladeshi women (72–959pM) were significantly lower than those from California (154–933pM; p<0.0001) showing IMMULITE’s robustness against the complex milk matrix and its ability to measure low milk B12 concentrations.

Association between vitamin B12-containing supplement consumption and prevalence of biochemically defined B12 deficiency in adults in NHANES III (Third National Health and Nutrition Examination Survey)

To explore the association between vitamin B(12) (B(12))-containing supplement use, low B(12) concentrations and biochemically defined B(12) deficiency in US adults. A cross-sectional study with adjustment for survey design. Prevalence ratios for two age groups (18-50 and >50 years) were estimated using unconditional logistic models. Outcome measures included prevalence of low serum B(12) concentration (<148 pmol/l) and biochemical B(12) deficiency (serum B(12)< 148 pmol/l with concomitant homocysteine > 10 mumol/l). A population survey of health and nutritional measures. Subjects were non-institutionalized adults, aged 18 years and older, who participated in Phase 2 of NHANES III (Third National Health and Nutrition Examination Survey). Low B(12) concentrations were less prevalent among persons consuming B(12)-containing supplements (P = 0.001) with an adjusted prevalence ratio of 0.6 (95 % CI 0.3, 1.0). Biochemical B(12) deficiency showed a similar trend (P = 0.0002), with an adjusted prevalence ratio of 0.3 (95 % CI 0.1, 0.8). Prevalence ratios were similar in adults >50 years of age, although the prevalence of low B(12) and biochemical deficiency was proportionally higher. Consumption of B(12)-containing supplements was associated with at least 50 % lower prevalence of both low serum B(12) and biochemical B12 deficiency in a nationally representative sample of US adults, suggesting increased consumption of B(12) from supplements or from fortified foods may reduce the prevalence of B(12) deficiency. Additionally, the current Recommended Daily Allowance for B(12) of 2.4 microg may be insufficient for those aged >50 years.

Moderately low vitamin B12 does not compromise transmethylation in adults on a free diet: implications for assessment of vitamin B12 status.

Lower reference limits for vitamin B12 are often defined solely in relation to haematological criteria. This may be misleading and there is evidence indicating that biochemical anomalies should also be considered. In 50 patients we measured creatine, as the major product of B12-mediated remethylation, to see if this helps the definition of the B12 reference interval and to investigate the possible effect of low B12 on essential transmethylation. Vitamin B12 values were grouped into six fractiles covering the range 50-500 ng/L; the corresponding creatine results were assessed by analysis of variance giving F = 0.94 and a significance of 0.466. Although no correlation between B12 and creatine was found, and therefore no obvious effect on transmethylation of low B12 concentration, this must be interpreted with respect to methionine availability. Other factors indicate that biochemical perturbations should be taken into account when defining vitamin B12 reference intervals.

Neural-tube defects are associated with low concentrations of cobalamin (vitamin B12) in amniotic fluid

While folate supplementation reduces the risk of recurrent neural-tube defects (NTD), both folate and cobalamin deficiencies may be independent risk-factors for neural-tube defects. Folate-dependence and impaired remethylation of homocysteine are implicated as mechanisms for NTD. There are few references reported for folate, cobalamin, homocysteine and methionine in the fetal compartment. This case-controlled pilot study of amniotic fluid (AF) samples derived from 16 NTD pregnancies and 64 age-matched controls quantities total homocysteine (tHcy), total cysteine (tCys), folate, cobalamin (B12), and methionine. Only decreased AF B12 concentrations were found (150 pg/ml versus 540 pg/ml, P < 0.02). Since cobalamin, folate and homocysteine participate in the remethylation of homocysteine, via methyl transfer from 5-methyltetrahydrofolate to B12, to methionine, we compared ratios of these methionine synthase (EC 2.1.1.13)-related intermediates. The ratio of B12/folate for NTD versus controls was 48 (34-90) versus 126 (123-182), P < 0.001. The ratio of methionine/(folate x tHcy) was 1.4 (1.2-2.2) versus 2.7 (2.4-3.3), P < 0.001. We conclude that AF from pregnancies with NTD have lower B12 concentrations, and that ratios of product to substrate(s) of homocysteine remethylation suggest impaired methionine synthase in the fetal compartment through the early second trimester.

Neural‐tube defects are associated with low concentrations of cobalamin (vitamin B12) in amniotic fluid

While folate supplementation reduces the risk of recurrent neural-tube defects (NTD), both folate and cobalamin deficiencies may be independent risk-factors for neural-tube defects. Folate-dependence and impaired remethylation of homocysteine are implicated as mechanisms for NTD. There are few references reported for folate, cobalamin, homocysteine and methionine in the fetal compartment. This case-controlled pilot study of amniotic fluid (AF) samples derived from 16 NTD pregnancies and 64 age-matched controls quantitates total homocysteine (tHcy), total cysteine (tCys), folate, cobalamin (B12), and methionine. Only decreased AF B12 concentrations were found (150 pg/ml versus 540 pg/ml, P<0·02). Since cobalamin, folate and homocysteine participate in the remethylation of homocysteine, via methyl transfer from 5-methyltetrahydrofolate to B12, to methionine, we compared ratios of these methionine synthase (EC 2.1.1.13) -related intermediates. The ratio of B12/folate for NTD versus controls was 48 (34–90) versus 126 (123–182), P<0·001. The ratio of methionine/(folate×tHcy) was 1·4 (1·2–2·2) versus 2·7 (2·4–3·3), P<0·001. We conclude that AF from pregnancies with NTD have lower B12 concentrations, and that ratios of product to substrate(s) of homocysteine remethylation suggest impaired methionine synthase in the fetal compartment through the early second trimester. © 1998 John Wiley & Sons, Ltd.

Chemiluminescence receptor assay for measuring vitamin B12 in serum evaluated

We evaluated a chemiluminescence receptor assay for vitamin B12 in serum (Magic Lite; Ciba Corning Diagnostics), in which an acridinium ester label is used with magnetic particle separation. Within- and between-batch precisions were generally acceptable, except at low analyte concentrations. The reference range determined from 104 elective preoperative patients was 120-610 pmol/L, compared with 150-590 pmol/L for our in-house radioligand-binding assay. Magic Lite discriminated between normal and abnormal results as effectively as the in-house method when local reference ranges were applied. Magic Lite demonstrated a negative bias at low analyte concentrations and was unable to detect any vitamin B12 in two B12-deficient patients. Assay accuracy--judged from analytical recovery and comparisons with the in-house method and two other radioassay kits (Quantaphase, Bio-Rad Labs., and Immophase, Ciba Corning Diagnostics)--was poor at low B12 concentrations when the manufacturer's recommended two-point calibration was used. This problem was partially corrected by using a full set of calibrators.