Why Check MMA in Macrocytic Anemia with Elevated B12
When B12 levels are elevated (>350 ng/L or >258 pmol/L), MMA testing is NOT indicated for diagnosing B12 deficiency—elevated B12 essentially rules out B12 deficiency. 1 Instead, the clinical focus should shift to investigating the underlying cause of the elevated B12 itself, as this finding is associated with serious pathology including hematologic malignancies, liver disease, and increased mortality. 2
Understanding the Paradox: Elevated B12 Does Not Cause Macrocytic Anemia
- Elevated B12 levels (>350 ng/L) make B12 deficiency unlikely according to NICE guidelines, eliminating the need for MMA testing to confirm B12 deficiency. 1
- The macrocytic anemia and elevated B12 are likely separate findings requiring distinct diagnostic pathways rather than a single unified explanation. 2
- Elevated B12 has been associated with mortality risk ratios of 1.88 to 5.9 and requires investigation for underlying pathology such as myeloproliferative disorders, liver disease, or malignancy. 2
When MMA Testing IS Appropriate (Not This Scenario)
MMA testing is specifically recommended for indeterminate B12 results where functional deficiency remains possible:
- Total B12 between 180-350 ng/L (133-258 pmol/L) 1
- Active B12 between 25-70 pmol/L 1
- MMA has 98.4% sensitivity for detecting functional B12 deficiency in patients with low-normal B12 levels 3, 4
- Up to 50% of patients with "normal" serum B12 may have metabolic deficiency detectable by elevated MMA 4, 5
The Correct Diagnostic Approach for Elevated B12 with Macrocytosis
Step 1: Investigate the Elevated B12
- Complete blood count with differential to assess for eosinophilia, dysplasia, monocytosis, or circulating blasts 2
- Comprehensive metabolic panel with liver function tests to evaluate for hepatic disease 2
- Serum tryptase measurement, as it is often elevated alongside B12 in myeloproliferative disorders, particularly those with PDGFRA fusion genes 2
- Review peripheral blood smear for evidence of hematologic abnormalities 2
Step 2: Evaluate Alternative Causes of Macrocytosis
- Folate deficiency (though elevated homocysteine would be present, not elevated MMA) 1, 4
- Alcohol use, which can cause both macrocytosis and elevated B12 independently 2
- Medications (methotrexate, anticonvulsants, hydroxyurea) 3
- Hypothyroidism 3
- Liver disease (which also explains elevated B12 from hepatocyte damage releasing stored B12) 2
- Myelodysplastic syndromes 6
Step 3: Consider Bone Marrow Evaluation if Indicated
- For suspected hematologic malignancy, bone marrow aspirate and biopsy with immunohistochemistry for CD117, CD25, tryptase, and fibrosis stains 2
- Cytogenetic and molecular testing including FISH and RT-PCR for TK fusion gene rearrangements 2
Critical Clinical Pitfalls to Avoid
- Do not confuse elevated B12 with B12 deficiency—these require completely different diagnostic algorithms. 2
- Do not order MMA when B12 is clearly elevated, as this wastes resources (MMA costs £11-80 per test) and provides no diagnostic value for B12 status. 1, 3
- Do not ignore elevated B12 as benign—it may indicate serious underlying pathology requiring urgent investigation, particularly in elderly patients or those with unexplained cytopenias. 2
- Be aware that false-normal B12 results can occur with anti-intrinsic factor antibodies in pernicious anemia, but this presents with LOW or borderline B12, not elevated levels. 5
Special Consideration: Renal Function and MMA Interpretation
- If MMA were to be checked (inappropriately in this scenario), impaired renal function (decreased eGFR) causes MMA elevation independent of B12 status, potentially overestimating B12 deficiency by 40% in patients with low-normal B12. 7
- MMA should be corrected for eGFR, especially in elderly patients, to prevent over-diagnosis. 7