Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency

Arch Intern Med. 2001 Jun 25;161(12):1534-41. doi: 10.1001/archinte.161.12.1534.


Background: The prevalence of vitamin B(12) deficiency, defined as an elevated concentration of plasma methylmalonic acid (P-MMA), has been estimated to be 15% to 44% in the elderly. However, we do not know whether an increased P-MMA level actually indicates or predicts a clinical condition in need of treatment.

Participants and methods: In a follow-up study, 432 individuals not treated with vitamin B(12) were examined 1.0 to 3.9 years after initial observation of an increased P-MMA concentration (>0.28 micromol/L). The examination included laboratory tests, a structured interview to disclose symptoms, a food frequency questionnaire, and a clinical examination including a Neurological Disability Score.

Results: Variation in P-MMA levels over time was high (coefficient of variation, 34%). In only 16% of participants, P-MMA levels increased substantially, whereas 44% showed a decrease. Level of P-MMA was significantly but not strongly associated with levels of plasma cobalamins (r = -0.22, P<.001) and plasma total homocysteine (r = 0.37, P<.001). After adjustment for age and sex, we found no associations between P-MMA concentration and the total symptom score (P =.61), the total Neurological Disability Score (P =.64), or other clinical manifestations related to vitamin B(12) deficiency.

Conclusions: An increased level of P-MMA did not predict a further increase with time and clinical manifestations related to vitamin B(12) deficiency. We therefore challenge the use of an increased P-MMA concentration as the only marker for diagnosis of vitamin B(12) deficiency.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Denmark
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Methylmalonic Acid / blood*
  • Middle Aged
  • Predictive Value of Tests
  • Probability
  • Registries
  • Sensitivity and Specificity
  • Vitamin B 12 / administration & dosage
  • Vitamin B 12 Deficiency / blood*
  • Vitamin B 12 Deficiency / diagnosis*
  • Vitamin B 12 Deficiency / drug therapy


  • Biomarkers
  • Methylmalonic Acid
  • Vitamin B 12