What causes elevated methylmalonic acid (MMA) levels?

Causes of High Methylmalonic Acid (MMA)

Vitamin B12 deficiency is the primary cause of elevated methylmalonic acid levels, as B12 is an essential cofactor for the enzyme that converts methylmalonyl-CoA to succinyl-CoA. 1

Primary Causes of Elevated MMA

1. Vitamin B12 (Cobalamin) Deficiency

• Malabsorption conditions:

  • Pernicious anemia (autoimmune condition with anti-intrinsic factor antibodies) 1
  • Bariatric surgery (particularly sleeve gastrectomy, Roux-en-Y gastric bypass) 1
  • Other gastrointestinal disorders affecting B12 absorption

• Dietary deficiency:

  • Insufficient intake of B12-rich foods (animal products, fortified foods) 1
  • Vegetarian/vegan diets without supplementation

• Medication-induced:

  • Proton pump inhibitors (long-term use)
  • Metformin
  • Nitrous oxide recreational use 1

2. Genetic Disorders

• Inborn errors of metabolism:
  • Methylmalonic acidemia (defects in methylmalonyl-CoA mutase) 1
  • Combined malonic and methylmalonic aciduria 1
  • Defects in B12 metabolism (cblA, cblB, cblC, cblD, cblF disorders) 1

3. Renal Dysfunction

• Reduced clearance of MMA in kidney disease 1

4. Other Contributing Factors

• Intestinal bacterial overgrowth:

  • Can produce methylmalonic acid 1

• Aging:

  • Increased MMA levels associated with aging process 2

• Sample collection issues:

  • Prolonged storage at ambient temperature can enhance bacterial-origin compounds 1

Clinical Significance and Interpretation

MMA serves as a functional marker of vitamin B12 status and is more sensitive than serum B12 levels alone. When B12 is deficient, methylmalonyl-CoA accumulates and is hydrolyzed to MMA 1.

Interpretation Guidelines:

• MMA is considered a confirmatory test when initial B12 test results are indeterminate 1
• MMA testing before treatment is cost-effective compared to not testing 1
• Serum MMA levels are not significantly affected by hepatic disease 3
• Everyday meals can cause an increase in urinary MMA excretion but don't significantly affect serum MMA levels 4

Diagnostic Approach

1. Initial testing: Measure total B12 (serum cobalamin) or active B12 (serum holotranscobalamin) 1

2. Follow-up testing: Consider measuring serum MMA when:

   • Initial B12 results are indeterminate (180-350 ng/L or 133-258 pmol/L for total B12; 25-70 pmol/L for active B12) 1
   • Clinical suspicion of B12 deficiency despite normal B12 levels 5

3. Optimal testing strategy: Use a combination of at least two biomarkers:

   • Holo-transcobalamin (holo-TC) and MMA
   • Serum cobalamin can replace holo-TC when measurement is unavailable 1

Important Considerations

• MMA is unsuitable as a first-line test due to cost and specialized analytical requirements 1
• Mild elevations of MMA can be secondary to intestinal bacterial metabolism 1
• When assessing B12 deficiency, it's important to measure both serum/erythrocyte folate and serum cobalamin, as supplementation with folate alone can mask B12 deficiency while allowing neurological damage to progress 1
• MMA testing should be performed on properly collected and stored samples to avoid false results 1

By understanding these various causes of elevated MMA, clinicians can better diagnose and address the underlying conditions, particularly vitamin B12 deficiency, which can lead to serious neurological and hematological complications if left untreated.