From the Guidelines
Methylmalonic acid (MMA) should be checked to diagnose vitamin B12 deficiency, particularly when B12 blood levels are borderline or when there's clinical suspicion despite normal B12 levels, as recommended by the most recent guideline summary from 2024 1.
Reasons for Checking MMA
- MMA levels rise in the blood and urine when B12 is insufficient because B12 is required for the enzyme that converts methylmalonyl-CoA to succinyl-CoA; without adequate B12, methylmalonyl-CoA accumulates and is converted to methylmalonic acid.
- This test is more sensitive and specific than serum B12 measurement alone, making it valuable for detecting subtle or early deficiencies.
- MMA testing is especially useful in elderly patients, those with neurological symptoms without anemia, patients with renal insufficiency (where levels may be falsely elevated), and for monitoring treatment response in B12 deficiency.
Interpretation and Treatment
- The test requires a blood or urine sample, and elevated levels (typically >0.4 μmol/L in serum) suggest B12 deficiency that may require treatment with B12 supplementation, typically 1000 mcg daily or weekly depending on severity and cause of deficiency.
- However, interpretation should consider that kidney disease can also cause elevated MMA levels independent of B12 status, as noted in the espen micronutrient guideline from 2022 1.
Diagnostic Approach
- The guideline summary from 2024 1 suggests using either total B12 (serum cobalamin) or active B12 (serum holotranscobalamin) as the initial test for suspected vitamin B12 deficiency.
- Consider a further test to measure serum MMA concentrations in people who have symptoms or signs of vitamin B12 deficiency and an indeterminate total or active B12 test result, based on very low certainty evidence 1.
From the Research
Reasons to Check Methylmalonic Acid
- Methylmalonic acid (MMA) is a useful marker for diagnosing vitamin B12 deficiency, particularly in asymptomatic high-risk patients with low-normal levels of vitamin B12 2
- Elevated MMA concentrations are more strongly associated with poor functional status and physical performance than serum B12 levels 3
- Measuring MMA is necessary for the diagnosis of metabolic vitamin B12 deficiency, as serum B12 alone is not sufficient 4
- MMA is considered the best biomarker for detecting possible vitamin B12 deficiency, and establishing reference intervals for MMA in urine can help improve diagnosis 5
- Vitamin B12 deficiency can have severe consequences, including megaloblastic anemia, nervous system involvement, and cognitive impairment, making accurate diagnosis and treatment crucial 6
Clinical Applications
- Checking MMA levels can help confirm vitamin B12 deficiency in patients with low-normal vitamin B12 levels 2
- MMA measurements can be used to assess the effectiveness of vitamin B12 treatment and monitor patients with a history of vitamin B12 deficiency 3
- MMA testing can help identify patients with metabolic vitamin B12 deficiency, who may benefit from supplementation with oral B12, preferably methylcobalamin or hydroxycobalamin 4
- Establishing optimal reference intervals for MMA excretion in urine can aid in the diagnosis of functional vitamin B12 deficiency 5
- Accurate diagnosis and treatment of vitamin B12 deficiency can help prevent severe consequences, such as cognitive impairment and psychosis 6