Determinants of plasma methylmalonic acid in a large population: Implications for assessment of vitamin B₁₂ status

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 influenceMMAconcentrations. 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 R ² = 0.167). Increased plasma MMA was seen when plasma vitamin B ₁₂ 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.