Is methylmalonic acid the optimal test to confirm a suspected vitamin B12 deficiency in a patient heterozygous for an MTHFR variant?

Is MMA the Best Test for Suspected B12 Deficiency with MTHFR Heterozygous?

No, MMA is not the best initial test—start with serum B12 (total or active), then use MMA only if results are indeterminate (180-350 pg/mL for total B12 or 25-70 pmol/L for active B12). 1 MTHFR heterozygous status does not change this testing algorithm, as MTHFR variants affect folate metabolism, not B12 absorption or utilization. 2

Initial Testing Strategy

Begin with either total serum B12 or active B12 (holotranscobalamin) as your first-line test. 1, 2

• Total B12 costs approximately £2 with rapid turnaround in local laboratories 1
• Active B12 measures the biologically active form available for cellular use and is more accurate, but costs £18 per test with longer processing times 1, 2

Interpretation of Initial B12 Results

For Total B12: 1

• <180 pg/mL (133 pmol/L): Confirmed deficiency—proceed directly to treatment
• 180-350 pg/mL (133-258 pmol/L): Indeterminate—measure MMA to confirm functional deficiency
• >350 pg/mL (258 pmol/L): Deficiency unlikely, but consider MMA if high clinical suspicion

For Active B12: 1, 2

• <25 pmol/L: Confirmed deficiency—proceed to treatment
• 25-70 pmol/L: Indeterminate—measure MMA
• >70 pmol/L: Deficiency unlikely

When to Use MMA Testing

MMA should be measured only when initial B12 results fall in the indeterminate range, not as a first-line test. 1 This approach is cost-effective at £3,946 per quality-adjusted life year. 1

Why MMA is Not First-Line

• Cost: £11-80 per test versus £2 for total B12 1
• Processing delays: Requires specialized equipment and often external laboratory analysis 1
• Not cost-effective as screening: Using MMA first-line wastes resources 1, 2

MMA Diagnostic Performance

MMA has 98.4% sensitivity for detecting B12 deficiency and is more specific than homocysteine for B12 deficiency. 2 MMA >271 nmol/L confirms functional B12 deficiency. 2 Importantly, MMA detects an additional 5-10% of patients with functional B12 deficiency who have low-normal serum B12 levels. 2, 3

MTHFR Heterozygous: Does It Matter?

MTHFR heterozygous status does not alter the B12 testing algorithm. MTHFR variants affect the folate pathway (specifically the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate), not B12 absorption or metabolism directly. 2

Key Distinction

• Elevated homocysteine + normal MMA = folate deficiency or MTHFR dysfunction 2
• Elevated homocysteine + elevated MMA = B12 deficiency 2

This pattern helps differentiate whether symptoms relate to B12 or folate/MTHFR issues. If you suspect both pathways are affected, measure both MMA and homocysteine simultaneously when B12 is indeterminate. 2, 4

Critical Pitfalls to Avoid

Never rely solely on serum B12 to rule out deficiency, especially in patients >60 years. 2 Standard serum B12 testing misses functional deficiency in up to 50% of cases—the Framingham Study found that while 12% had low serum B12, an additional 50% had elevated MMA indicating metabolic deficiency despite "normal" serum levels. 2, 3

Both MMA and homocysteine can be falsely elevated in: 2

• Hypothyroidism
• Renal insufficiency
• Hypovolemia

Interpret cautiously in these conditions.

Never administer folic acid before treating B12 deficiency—it may mask anemia while allowing irreversible neurological damage to progress. 2

Practical Algorithm

1. Measure total B12 or active B12 first 1, 5
2. If <180 pg/mL (total) or <25 pmol/L (active): Diagnose deficiency and treat 1
3. If 180-350 pg/mL (total) or 25-70 pmol/L (active): Measure MMA 1, 5
   • MMA >271 nmol/L confirms functional deficiency 2
4. If >350 pg/mL (total) or >70 pmol/L (active) but high clinical suspicion: Consider MMA anyway 2, 5
5. Consider measuring homocysteine simultaneously with MMA to differentiate B12 from folate/MTHFR issues 2
   • Homocysteine >15 µmol/L supports tissue deficiency 2
   • Target <10 µmol/L for optimal cardiovascular outcomes 2

Cost-Effectiveness Considerations

The 2024 NICE guideline performed cost-utility analysis showing MMA testing before treatment is most cost-effective when used after indeterminate B12 results, not as universal screening. 1 The model assumed patients would return for correct diagnosis if initially missed, potentially overestimating savings due to uncertainty in multiple parameters including MMA accuracy, prevalence of elevated MMA, and quality of life variations. 1