Determinants of Plasma Methylmalonic Acid in a Large Population: Implications for Assessment of Vitamin B12 Status

Abstract Background: Methylmalonic acid (MMA) in plasma or serum is widely used for assessment of vitamin B12 status. However, data are sparse regarding factors, besides renal function, that may influence MMA concentrations. We searched for important determinants of plasma MMA in the general population. Methods: In 6946 middle-aged (47–49 years) and elderly (71–74 years) individuals from the Hordaland Homocysteine Study in Norway, we collected anthropometric measurements, lifestyle data, and plasma MMA, vitamin B12, and creatinine measurements. For 5820 individuals, we also collected dietary data. Results: Age and plasma creatinine were positively associated with plasma MMA, whereas plasma vitamin B12 was negatively associated. These variables together with sex were the strongest determinants of plasma MMA, accounting for 16% of the variation (R2 = 0.16). Addition of anthropometric measures and lifestyle and dietary factors only gave slight improvement (total R2 = 0.167). Increased plasma MMA was seen when plasma vitamin B12 was <400 pmol/L. In individuals with vitamin B12 ≥400 μmol/L (vitamin B12–replete), the 2.5th–97.5th percentile reference limits for MMA were 0.10–0.28 μmol/L (middle-aged) and 0.10–0.36 μmol/L (elderly). When plotted against creatinine (nomograms), the 97.5th percentile of MMA was similar in men and women but approximately 0.15 μmol/L higher in elderly than middle-aged individuals. Vitamin B12–replete participants had MMA upper limits approximately 0.1 μmol/L (elderly) and 0.04 μmol/L (middle-aged) below those of the unselected population at all creatinine concentrations. Conclusions: Identified determinants accounted for <17% of the overall variation in plasma MMA. The difference in MMA between middle-aged and elderly individuals is only partly explained by creatinine and vitamin B12 concentrations.

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Diagnostic Performances of Urinary Methylmalonic Acid/Creatinine Ratio in Vitamin B12 Deficiency

Journal of Clinical Medicine ◽

10.3390/jcm9082335 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2335 ◽

Cited By ~ 2

Author(s):

Sopak Supakul ◽

Floris Chabrun ◽

Steve Genebrier ◽

Maximilien N’Guyen ◽

Guillaume Valarche ◽

...

Keyword(s):

Renal Impairment ◽

Vitamin B12 ◽

Methylmalonic Acid ◽

Vitamin B12 Deficiency ◽

Plasma Homocysteine ◽

Plasma Vitamin ◽

Creatinine Ratio ◽

Normal Range ◽

B12 Deficiency ◽

High Degree

Sole measurement of plasma vitamin B12 is no longer enough to identify vitamin B12 (B12) deficiency. When plasma vitamin B12 is in the low-normal range, especially between 201 and 350 ng/L, B12 deficiency should be assessed by measurements of plasma homocysteine and/or plasma methylmalonic acid (MMA). However, these biomarkers also accumulate during renal impairment, leading to a decreased specificity for B12 deficiency. In such cases, urinary methylmalonic acid/creatinine ratio (uMMA/C) could be of interest, due to the stable urinary excretion of MMA. The objectives were to evaluate the influence of renal impairment on uMMA/C compared to plasma homocysteine and plasma methylmalonic acid, and to determine the diagnostic performances of uMMA/C in the diagnosis of B12 deficiency. We prospectively studied 127 patients with a plasma B12 between 201 and 350 ng/L. We noticed that uMMA/C was not dependent on renal function (p = 0.34), contrary to plasma homocysteine and plasma methylmalonic acid. uMMA/C showed a perspective diagnostic performance (AUC 0.71 [95% CI: 0.62–0.80]) and the threshold of 1.45 umol/mmol presented a high degree of specificity (87.9% [95% CI: 72.0–98.9]). In conclusion, uMMA/C is a promising biomarker to assess vitamin B12 status in doubtful cases, notably during renal impairment.

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Reference intervals for plasma vitamin B12 and plasma/serum methylmalonic acid in Danish children, adults and elderly

Clinica Chimica Acta ◽

10.1016/j.cca.2021.12.015 ◽

2021 ◽

Author(s):

Abildgaard Anders ◽

Knudsen Cindy Soendersoe ◽

Hoejskov Carsten Schriver ◽

Greibe Eva ◽

Parkner Tina

Keyword(s):

Vitamin B12 ◽

Methylmalonic Acid ◽

Reference Intervals ◽

Plasma Vitamin

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Relationships between plasma methylmalonic acid and ruminal succinate in cobalt-deficient and -repleted sheep

Australian Journal of Agricultural Research ◽

10.1071/ar05125 ◽

2007 ◽

Vol 58 (4) ◽

pp. 367 ◽

Cited By ~ 1

Author(s):

S. C. Wiese ◽

C. L. White ◽

I. H. Williams ◽

J. G. Allen

Keyword(s):

Vitamin B12 ◽

Methylmalonic Acid ◽

Plasma Concentrations ◽

Plasma Vitamin ◽

Normal Range ◽

Deficient Diet ◽

Wool Growth ◽

Cobalt Deficiency ◽

Vitamin B12 Supplementation ◽

Effective Degree

We measured methylmalonic acid (MMA) in plasma and succinate in the rumen during the depletion of sheep to a state of severe cobalt deficiency and repletion by various forms of supplementation. Groups of 10, cobalt-deficient weaners were allocated to one of 4 treatments: no supplement, 0.1 or 4.0 mg/day of cobalt as a solution of CoSO4.7H2O per os, or intramuscular vitamin B12. Plasma concentrations of MMA were elevated above the normal range (5 µmol/L) after 35 days on the cobalt-deficient diet, before a reduction in feed intake and while liveweights were still increasing. In all 3 supplemented groups of sheep, plasma vitamin B12 concentrations increased to normal levels within 10 days of supplementation (P < 0.001). Plasma MMA concentrations were reduced to normal levels within 10 days with vitamin B12 supplementation but took 31 days with oral cobalt supplementation (P < 0.001). Plasma MMA concentration in the unsupplemented group continued to rise and remain high for the duration of the experiment and did not show the peak and decline to levels indistinguishable from cobalt adequate levels as observed by others. Rumen succinate concentrations were elevated within 6 days of sheep being introduced to a cobalt-deficient diet and in the unsupplemented sheep remained elevated for the duration of measurement. This rise in rumen succinate was seen at a wider range of cobalt intakes than previously reported. In both oral cobalt treatments, vitamin B12 concentrations increased (P < 0.001) and succinate concentrations decreased (P < 0.001) in the rumen to normal levels within 6 days of supplementation. However, the vitamin B12 provided to the sheep by injection was not recycled to the rumen to any effective degree, as demonstrated by the persistence of high rumen succinate concentrations. The ability of the vitamin B12-supplemented sheep to maintain higher rates of wool growth than deficient sheep, while still exhibiting elevated succinate concentrations in the rumen, demonstrates that overcoming the blockage of the methylmalonyl CoA mutase pathway in the rumen is not essential for restoring metabolic pathways such as those responsible for wool growth. This work contributes to the knowledge of plasma MMA and rumen succinate as useful indicators of functional cobalt status and cobalt intake in sheep.

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Age dependency of plasma vitamin B12 status markers in Dutch children and adolescents

Pediatric Research ◽

10.1038/s41390-021-01372-2 ◽

2021 ◽

Author(s):

M. Rebecca Heiner-Fokkema ◽

Ineke J. Riphagen ◽

Nicole S. Wiersema ◽

Jelmer J. van Zanden ◽

Jenny E. Kootstra-Ros ◽

...

Keyword(s):

Young Children ◽

Vitamin B12 ◽

Reference Values ◽

Methylmalonic Acid ◽

Early Recognition ◽

Vitamin B12 Deficiency ◽

Reference Intervals ◽

Cobalamin Deficiency ◽

Plasma Vitamin ◽

B12 Deficiency

Abstract Background Vitamin B12 deficiency in children may be associated with (severe) neurological manifestations, therefore recognition is important. Diagnosing vitamin B12 deficiency in children is challenging. This study aimed to investigate plasma methylmalonic acid, holotranscobalamin, and total cobalamin in children 0–18 years of age and to estimate age-dependent reference intervals. Methods Plasma vitamin B12 markers were measured in collected plasma samples of 170 children 0–18 years visiting a local primary care laboratory. All had within-reference hemoglobin and MCV values. Pediatric plasma vitamin B12 biomarkers were measured and reference values were derived thereof. Results Plasma methylmalonic acid was higher in young children, in particular between 1 and 6 months of age; total cobalamin and holotranscobalamin were highest from 0.5 to 4 years and decreased till 10 years of age. Plasma holotranscobalamin was highly correlated with plasma total cobalamin; their ratio was independent of age. Plasma methylmalonic acid was slightly more related to total cobalamin than to holotranscobalamin. A large proportion of mainly young children would be misclassified when adult references are applied. Conclusions Pediatric reference values for cobalamin markers are necessary to allow for early recognition and monitoring of children suspect of (clinical) cobalamin deficiency. Impact We analyzed three plasma vitamin B12 status markers, i.e., total cobalamin, holotranscobalamin, and methylmalonic acid, in the plasma of 170 children 0–18 years of age and were able to derive reference intervals thereof. Recognition of vitamin B12 deficiency in children is important but challenging as pediatric reference intervals for plasma vitamin B12 status markers, particularly plasma holotranscobalamin, are not well described. We think that our results may help early recognition and monitoring of children suspect of (clinical) vitamin B12 deficiency.

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Measurement of Total Vitamin B12 and Holotranscobalamin, Singly and in Combination, in Screening for Metabolic Vitamin B12 Deficiency

Clinical Chemistry ◽

10.1373/clinchem.2005.061382 ◽

2006 ◽

Vol 52 (2) ◽

pp. 278-285 ◽

Cited By ~ 93

Author(s):

Joshua W Miller ◽

Marjorie G Garrod ◽

Alan L Rockwood ◽

Mark M Kushnir ◽

Lindsay H Allen ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Vitamin B12 ◽

Methylmalonic Acid ◽

Vitamin B12 Deficiency ◽

Reference Intervals ◽

Plasma Vitamin ◽

Roc Curve Analysis ◽

Total Vitamin ◽

B12 Deficiency ◽

Elderly Cohort

Abstract Background: The standard screening test for vitamin B12 deficiency, measurement of total plasma vitamin B12, has limitations of sensitivity and specificity. Plasma vitamin B12 bound to transcobalamin (holoTC) is the fraction of total vitamin B12 available for tissue uptake and therefore has been proposed as a potentially useful alternative indicator of vitamin B12 status. Methods: We compared the diagnostic accuracy of total vitamin B12, holoTC, and a combination of both measures to screen for metabolic vitamin B12 deficiency in an elderly cohort (age ≥60 years). Plasma methylmalonic acid and homocysteine were used as indicators of vitamin B12 deficiency. Results: Low total vitamin B12 (<148 pmol/L) and low holoTC (<35 pmol/L) were observed in 6.5% and 8.0%, and increased methylmalonic acid (>350 nmol/L) and homocysteine (>13 μmol/L) were observed in 12.1% and 17.0% of the study participants. In multiple regression models, holoTC explained 5%–6% more of the observed variance in methylmalonic acid and homocysteine than did total vitamin B12 (P ≤0.004). ROC curve analysis indicated that total vitamin B12 and holoTC were essentially equivalent in their ability to discriminate persons with and without vitamin B12 deficiency. Individuals with low concentrations of both total vitamin B12 and holoTC had significantly higher concentrations of methylmalonic acid and homocysteine than did individuals with total vitamin B12 and/or holoTC within the reference intervals (P <0.001). Conclusions: HoloTC and total vitamin B12 have equal diagnostic accuracy in screening for metabolic vitamin B12 deficiency. Measurement of both holoTC and total vitamin B12 provides a better screen for vitamin B12 deficiency than either assay alone.

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The Cobalamin-Binding Proteins Transcobalamin and Haptocorrin in Maternal and Cord Blood Sera at Birth

Clinical Chemistry ◽

10.1373/clinchem.2005.057810 ◽

2006 ◽

Vol 52 (2) ◽

pp. 263-269 ◽

Cited By ~ 37

Author(s):

Rima Obeid ◽

Anne L Morkbak ◽

Winfried Munz ◽

Ebba Nexo ◽

Wolfgang Herrmann

Keyword(s):

Vitamin B12 ◽

Cord Blood ◽

Methylmalonic Acid ◽

Close Correlation ◽

Maternal Blood ◽

Maternal Serum ◽

Total Serum ◽

Plasma Vitamin ◽

Blood Samples ◽

The Relationship

Abstract Background: Two proteins carry vitamin B12 in plasma. Transcobalamin (TC) carries ∼25% of total plasma vitamin B12 and is 6% to 20% saturated with cobalamin. Haptocorrin (HC) binds ∼80% of total cobalamin and is largely saturated with cobalamin. Methods: We investigated the distribution and the relationship between concentrations of cobalamin, total and holo forms of TC, and HC in blood samples from pregnant women just before delivery (n = 92) and in cord blood samples from their newborn babies. We also investigated the relationship between these proteins and concentrations of methylmalonic acid (MMA), the functional marker of vitamin B12 status. Results: Concentrations of total serum cobalamin, total HC, holoHC, and percentage of HC saturation were higher in cord blood than in the maternal blood (mean cobalamin, 268 vs 188 pmol/L; total HC, 648 vs 538 pmol/L; holoHC, 441 vs 237 pmol/L; HC saturation, 70% vs 47%). Moreover, total TC was low in cord blood, whereas both holoTC and TC saturation were higher in cord blood than in the maternal blood (mean total TC, 654 vs 1002 pmol/L; holoTC, 118 vs 53 pmol/L; TC saturation, 19.8% vs 5.4%). Higher maternal serum cobalamin was associated with higher cord blood holoTC and TC saturation (P <0.05). Gestational age was also a significant determinant of baby total TC, TC saturation, total HC, and holoHC. Conclusion: The close correlation between the amounts of holoTC present in cord blood and in maternal serum supports the importance of maternal cobalamin status for ensuring a sufficient supply to the baby.

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Diagnostic Accuracy of Holotranscobalamin, Vitamin B12, Methylmalonic Acid, and Homocysteine in Detecting B12 Deficiency in a Large, Mixed Patient Population

Disease Markers ◽

10.1155/2020/7468506 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Araceli Jarquin Campos ◽

Lorenz Risch ◽

Urs Nydegger ◽

Jacobo Wiesner ◽

Maclovia Vazquez Van Dyck ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Vitamin B12 ◽

Patient Population ◽

Roc Analysis ◽

Operating Characteristic ◽

Methylmalonic Acid ◽

Area Under The Curve ◽

First Line ◽

B12 Deficiency ◽

The Difference

Four biomarkers are commonly employed to diagnose B12 deficiency: vitamin B12 (B12), holotranscobalamin (HoloTC), methylmalonic acid (MMA), and homocysteine (Hcy). 4cB12, a combined index of the B12 status, has been suggested to improve the recognition of B12 deficiency. We aimed to evaluate the four different markers for detecting B12 deficiency, as determined by 4cB12. Within a large, mixed patient population, 11,833 samples had concurrent measurements of B12, HoloTC, MMA, and Hcy. 4cB12 was calculated according to the methods described by Fedosov. Diagnostic cutoffs as well as diagnostic accuracy for the detection of B12 deficiency were assessed with receiver operating characteristic (ROC) analysis. The median age was 56 years, and women accounted for 58.8% of the samples. Overall, the area under the curve (AUC) for the detection of subclinical B12 deficiency was highest for HoloTC (0.92), followed by MMA (0.91), B12 (0.9) and Hcy (0.78). The difference between HoloTC and B12 was driven by a significantly higher AUC for HoloTC (0.93) than for B12 (0.89), MMA (0.91), and Hcy in women 50 years and older (0.79; p<0.05 for all). In the detection of subclinical B12 deficiency, there were no significant differences in the AUCs of HoloTC, B12, and MMA among men and women <50 years. In conclusion, in women<50 years and in men, HoloTC, MMA, or Hcy do not appear superior to B12 for the detection of B12 deficiency. For women 50 years and older, HoloTC seems to be the preferred first-line marker for the detection of subclinical B12 deficiency.

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Comparison of periodontal status between middle-aged human and the Macaca fascicularis

10.21203/rs.3.rs-21470/v1 ◽

2020 ◽

Author(s):

Lin bingpeng ◽

Zhong Mei ◽

Gao Hongbin ◽

Zhou Zijun ◽

Ser Hooi-leng ◽

...

Keyword(s):

Bone Loss ◽

Dietary Factors ◽

Rrna Gene ◽

Disease Phenotype ◽

Middle Aged ◽

Microbial Composition ◽

Periodontal Status ◽

Inflammatory Status ◽

Dental Anatomy ◽

The Difference

Abstract Background Having an adverse impact on systemic health, periodontitis is an inflammatory disease which is characterized by the loss of integrity in tooth-supporting tissues. Middle-aged human (MAH) have been reported to have a higher incidence of periodontitis and a greater extent of bone loss. Although middle-aged monkey (MAM) shares similar dental anatomy and physiology with humans, it is still unclear whether they both display same disease phenotype or not, given that literature comparing the periodontal status between MAH and MAM is limited. CBCT examination and histological analysis were performed to characterize the periodontal condition, while 16 s rRNA sequencing was carried out to evaluate the possible mechanism that may explain the difference between these two primates. Results The present study revealed a more severe disease phenotype in MAH than in MAM, along with significantly higher levels of alveolar bone loss accompanied with increased blood vessels and inflammatory cells infiltration. High-throughput gene sequencing based on 16S rRNA gene demonstrated that the diversity of salivary microorganisms in MAH was lower than that of MAM. In addition, at the phylum level, the relative abundance of Proteobacteria in the MAH was higher than MAM, while Bacteroidetes showed a totally opposite trend. At the genus level, the relative abundances of Alloprevotell, Aggregatibacter, Haemophilus, Gemella and Porphyromonas in the MAH group were significantly less than that of the MAM group. One of the possible factor that may explains for this observation would be the dietary factors, affecting the oral microbial composition and diversity, and subsequently contributing to the alterations of periodontal status. Conclusions Altogether, these results demonstrated a potential link that may explain for the difference in inflammatory status in the oral cavity of MAH and MAM – the oral microbiota, prompting further investigation to explore specific roles of these bacterial population in the maintenance of oral health.

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Cardiorespiratory fitness is positively associated with both healthy and western dietary pattern in Iranian middle-aged

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000685 ◽

2020 ◽

pp. 1-10

Author(s):

Hossein Shahinfar ◽

Farhang Djafari ◽

Nadia Babaei ◽

Samira Davarzani ◽

Mojdeh Ebaditabar ◽

...

Keyword(s):

Cardiorespiratory Fitness ◽

Dietary Patterns ◽

Dietary Pattern ◽

Principal Component ◽

Total Sample ◽

Linear Regression Models ◽

Middle Aged ◽

Anthropometric Measures ◽

Western Dietary Pattern ◽

Healthy Dietary Pattern

Abstract. Background: The association between dietary patterns and cardiorespiratory fitness (CRF) is not well established. Objective: We sought to investigate association between a posteriori dietary pattern and CRF in middle-aged adults. Design: Adults (n = 276), aged 20–74 years, who were residents of Tehran, Iran were recruited. Diet was assessed by using a validated 168-item semi-quantitative food frequency questionnaire. Principal component analysis was used to derive dietary patterns. Socio-economic status, anthropometric measures, body composition, and blood pressure were recorded. CRF was assessed by using a graded exercise treadmill test. Analysis of variance and linear regression models were used to discern the association between dietary patterns and CRF. Results: Higher scores of the healthy dietary pattern had no association with VO2max (p = 0.13 ). After controlling for potential confounders, VO2max was positively associated across tertiles of healthy dietary patterns (p < 0.001). Higher adherence to the “mixed” dietary pattern was inversely related to VO2max (p < 0.01). After adjusting for confounders, the significant association disappeared (p = 0.14). Higher scores of the “Western” dietary pattern was not associated with VO2max (p = 0.06). However, after controlling for potential confounders, VO2max was positively associated with the “Western” dietary pattern (p = 0.01). A positive linear association between the “healthy” dietary pattern and CRF for the total sample (R2 = 0.02; p < 0.01) were presented. Conclusions: Overall, our findings suggest that higher adherence to a “healthy” and “Western” dietary pattern was positively associated with CRF. However, further studies are required to examine and clarify the causal relationship between dietary patterns and CRF.

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Correlations between Coffee Consumption and Metabolic Phenotypes, Plasma Folate, and Vitamin B12: NHANES 2003 to 2006

Nutrients ◽

10.3390/nu13041348 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1348

Author(s):

Pratibha V. Nerurkar ◽

Krupa Gandhi ◽

John J. Chen

Keyword(s):

Vitamin B12 ◽

Dietary Intervention ◽

Low Cost ◽

Coffee Consumption ◽

Normal Weight ◽

Dietary Factors ◽

Cross Sectional ◽

Metabolic Phenotypes ◽

Plasma Folate ◽

Prospective Longitudinal

Metabolic syndrome (MetS) is prevalent not only among the overweight and obese but also normal weight individuals, and the phenotype is referred to as a metabolically unhealthy phenotype (MUHP). Besides normal weight individuals, overweight/obese individuals are also protected from MetS, and the phenotype is known as a metabolically healthy phenotype (MHP). Epidemiological studies indicate that coffee and micronutrients such as plasma folate or vitamin B12 (vit. B12) are inversely associated with MetS. However, correlations among coffee consumption metabolic phenotypes, plasma folate, and vit. B12 remain unknown. Our objective was to investigate the correlation between coffee consumption, metabolic phenotypes, plasma folate, and vit. B12 as well as to understand associations between plasma folate, vit. B12, and metabolic phenotypes. Associations among coffee consumption metabolic phenotypes, plasma folate, and vit. B12 were assessed in a cross-sectional study of 2201 participants, 18 years or older, from 2003–2004 and 2005–2006 National Health and Nutrition Examination Surveys (NHANES). MUHP was classified as having > three metabolic abnormalities. Coffee consumption was not associated with metabolic phenotypes, but negatively correlated with several metabolic variables, including BMI (p < 0.001). Plasma folate was positively associated with MUHP (p < 0.004), while vit. B12 was inversely associated with MUHP (p < 0.035). Our results suggest the potential protective impact of coffee on individual components of MetS and indicate a positive correlation between coffee consumption and MUHP among overweight individuals. Identifying possible dietary factors may provide practical and low-cost dietary intervention targets, specifically for early intervention. Larger and randomized intervention studies and prospective longitudinal studies are required to further evaluate these associations.

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