Clinical Chemistry 55: 2198-2206, 2009. First published October 15, 2009; 10.1373/clinchem.2009.128678
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(Clinical Chemistry. 2009;55:2198-2206.)
© 2009 American Association for Clinical Chemistry, Inc.

Evidence-based Medicine and Test Utilization

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

Anna Vogiatzoglou1,a, Abderrahim Oulhaj1, A. David Smith1, Eha Nurk2, Christian A. Drevon2, Per M. Ueland3, Stein E. Vollset4, Grethe S. Tell4 and Helga Refsum1,2

1 OPTIMA, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK; 2 Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway; 3 Section for Pharmacology, Institute of Medicine, University of Bergen and Haukeland Hospital, Norway; 4 Department of Public Health and Primary Health Care, University of Bergen, Norway.

aAddress correspondence to this author at: Department of Physiology, Anatomy & Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford OX1 3QX, UK. E-mail anna.vogiatzoglou{at}dpag.ox.ac.uk.

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.