What causes elevated Mean Corpuscular Volume (MCV) when B12 and folate levels are normal?

Causes of Elevated MCV with Normal B12 and Folate

The most common causes of macrocytosis when B12 and folate are normal are medications (especially thiopurines, anticonvulsants, and chemotherapy agents), alcohol use, liver disease, and reticulocytosis from hemolysis or recent hemorrhage. 1, 2, 3

Algorithmic Diagnostic Approach

Step 1: Order Reticulocyte Count Immediately

• Reticulocyte count is the single most critical test to differentiate causes 1, 2
• Elevated reticulocytes (>2%): Suggests hemolysis or recent hemorrhage as the cause 1, 2, 4
• Normal/low reticulocytes: Points toward medications, liver disease, hypothyroidism, or bone marrow disorders 1, 2

Step 2: Comprehensive Medication Review

• Thiopurines (azathioprine, 6-mercaptopurine) cause macrocytosis through myelosuppressive activity, not vitamin deficiency 1, 2
• Anticonvulsants are a well-documented cause 1
• Chemotherapeutic agents commonly elevate MCV 1
• Drugs account for the most common cause of macrocytosis in hospitalized patients 3

Step 3: Assess for Alcohol and Liver Disease

• Alcohol use is the second most common cause after medications 3
• Alcoholism causes macrocytosis even without significant folate depletion 5
• Liver function tests should be ordered as part of initial workup 1
• In liver disease, macrocytosis is typically mild (MCV rarely >110 fL) and RBCs appear round rather than oval 4

Step 4: Check Thyroid Function

• Hypothyroidism is a recognized cause of macrocytosis 1
• Thyroid function tests should be included in the initial evaluation 1

Step 5: Evaluate for Hemolysis if Reticulocytes Elevated

• Check haptoglobin, LDH, and indirect bilirubin 1, 2
• Review peripheral blood smear for schistocytes or other morphologic abnormalities 2
• Reticulocytosis rarely causes MCV >110 fL 4

Step 6: Consider Mixed Deficiencies

• Check mean corpuscular hemoglobin (MCH) in addition to MCV 6, 2
• Low MCH despite elevated MCV suggests concurrent iron deficiency masking the full picture 6, 2
• Elevated RDW with normal or slightly elevated MCV indicates coexisting microcytosis and macrocytosis 1, 2
• Iron deficiency can normalize MCV through counterbalancing effects with B12/folate deficiency 6

Step 7: Verify True B12/Folate Sufficiency

• Measure homocysteine and methylmalonic acid if clinical suspicion remains high despite normal serum B12 6, 2
• Metabolic B12 deficiency (elevated homocysteine or methylmalonic acid with B12 <258 pmol/L) occurs in 10.6% of patients overall and 18.1% over age 80 6
• Up to 70-83% of B12-deficient patients have normal MCV, particularly with concurrent iron deficiency 6
• Methylmalonic acid is specific for B12 deficiency and remains normal in isolated folate deficiency 6, 2

Degree of MCV Elevation Provides Diagnostic Clues

• MCV >120 fL: Usually caused by B12 deficiency, even when initial levels appear normal 3
• MCV 110-120 fL: Consider megaloblastic causes, medications, or liver disease 3, 4
• MCV 100-110 fL: Most commonly medications, alcohol, or liver disease 3, 4

When to Consult Hematology

• Unexplained macrocytosis after completing the above workup 2
• Presence of other cytopenias, which increases concern for bone marrow disorders 2
• Progressive or severe macrocytosis (MCV >120 fL without clear cause) 2
• Elderly patients with persistent unexplained macrocytosis require monitoring as they may develop primary bone marrow disorders over time 2

Critical Pitfalls to Avoid

• Do not assume normal serum B12 rules out deficiency—tissue-level metabolic deficiency is frequently missed 6
• Do not overlook concurrent iron deficiency—it normalizes MCV and is extremely common in patients with B12 deficiency 6
• Do not neglect follow-up—even unexplained macrocytosis requires monitoring for development of bone marrow disorders 2
• Do not skip reticulocyte count—it is essential for distinguishing between increased production and other causes 1, 2