The diagnostic accuracy of methylmalonic acid to detect inadequate vitamin B12 status relative to 3cB12 was higher compared to that of total cobalamin and total homocysteine in a cross-sectional survey of apparently healthy U.S. adults1

ABSTRACT Background Diagnosing low vitamin B₁₂ status is important to reduce megaloblastic anemia and neurological disorders. The lack of a highly specific and sensitive clinical marker and questions about appropriate cutoffs hamper early detection. Objectives We evaluated the predictive power of 3 conventional markers for inadequate vitamin B₁₂ status (total cobalamin [B₁₂], methylmalonic acid [MMA], and total homocysteine [tHcy]) using the combined B₁₂ indicator, 3cB₁₂ (≤-0.5), as a reference. Additionally, we derived optimum cutoffs for each conventional marker and compared the prevalence to that from traditional cutoffs. Design Using National Health and Nutrition Examination Survey (NHANES) 1999–2004 data for B₁₂, MMA, and tHcy for persons ≥20 y with normal renal function, we devised a training set (1999–2002, n=7,469) to derive new optimum cutoffs and a validation set (2003–2004, n=3,641) to test them. All analyses were weighted and accounted for clustered design. Results In the training set, the area under the curve (AUC) for MMA was 0.963, followed by B₁₂ (0.944) and tHcy (0.937); it further increased with 2- and 3-marker models (0.985–0.998). In the validation set, the diagnostic accuracy (Youden's index) for the new optimum cutoffs was 0.80 for MMA >229 nmol/L and 0.69 for B₁₂ <220 pmol/L and tHcy >10.4 μmol/L. Among the traditional cutoffs, the Youden's index varied (0.30–0.79); B₁₂ <126 or <148 pmol/L and MMA >376 nmol/L had the highest specificity (>99%). The latter also had reasonable sensitivity (54.9%) and generated an apparent (2.35%) and a sensitivity/specificity-adjusted prevalence (2.48%) close to the 3cB₁₂ reference estimate (2.74%). Conclusions When using a single marker, MMA >376 nmol/L may be a useful cutoff for healthy populations with low (<5%) prevalence of inadequate vitamin B₁₂ status to minimize false positives, whereas MMA >229 nmol/L may be preferred for screening higher-risk groups to detect more cases.