What is the workup and management of macrocytosis?

Workup of Macrocytosis

Begin with a complete blood count with indices, peripheral blood smear, reticulocyte count, vitamin B12, and folate levels—this initial panel identifies the cause in approximately 75% of cases. 1, 2, 3

Initial Laboratory Evaluation

Essential First-Line Tests

• CBC with indices and red cell distribution width (RDW): An elevated RDW suggests mixed microcytic and macrocytic processes, which can mask each other and produce a falsely normal MCV 1, 2
• Mean corpuscular hemoglobin (MCH): More sensitive than MCV for detecting concurrent iron deficiency—a reduced MCH despite macrocytosis indicates a mixed picture requiring iron studies 1
• Peripheral blood smear: Distinguishes megaloblastic (macro-ovalocytes, hypersegmented neutrophils present in 86% of cases) from non-megaloblastic morphology 2, 3, 4
• Reticulocyte count: Differentiates ineffective erythropoiesis (low/normal reticulocytes) from hemolysis or hemorrhage (elevated reticulocytes) 5, 1, 2
• Vitamin B12 and folate levels: Essential first-line tests, though 20.9% of B12-deficient patients present with isolated macrocytosis without anemia 2, 4

Medication and Exposure History

• Thiopurines (azathioprine, 6-mercaptopurine): Cause direct myelosuppression rather than vitamin deficiency, particularly common in inflammatory bowel disease patients 1, 2
• Methotrexate: Inhibits dihydrofolate reductase, blocking DNA synthesis 2
• Hydroxyurea: Well-established cause of drug-induced macrocytosis 2
• Alcohol use: One of the most common causes, producing non-megaloblastic macrocytosis in 36.5% of cases 2, 4

Algorithmic Approach Based on Smear Morphology

If Megaloblastic (Macro-ovalocytes, Hypersegmented Neutrophils)

• Check B12 and folate levels first 2, 3
• If both normal, measure homocysteine and methylmalonic acid: Homocysteine elevated in both B12 and folate tissue deficiency; methylmalonic acid specific for B12 deficiency with better sensitivity than serum B12 1
• In inflammatory bowel disease patients: Consider ileal involvement (>30 cm resection or active disease impairs B12 absorption), jejunal disease (folate malabsorption), or sulfasalazine use (blocks folate absorption) 2

Critical pitfall: Never give folic acid before excluding B12 deficiency—folate supplementation masks B12 depletion and can precipitate subacute combined degeneration of the spinal cord 2

If Non-Megaloblastic Morphology

With Elevated Reticulocyte Count

• Evaluate for hemolysis: Check haptoglobin, LDH, indirect bilirubin, direct antibody test (Coombs) 5, 1
• Assess for recent hemorrhage: Reticulocytes are larger cells, causing transient macrocytosis 2
• Consider peripheral blood smear for schistocytes: Critical for diagnosing microangiopathic hemolytic anemia 5

With Low/Normal Reticulocyte Count

• Thyroid function tests: Hypothyroidism decreases erythropoiesis 2, 3
• Liver function tests: Chronic liver disease of any etiology causes macrocytosis 2, 3
• Review medications: Beyond those mentioned, consider erythropoietin therapy (shifts immature reticulocytes into circulation) 2

Special Considerations for Concurrent Iron Deficiency

• In inflammatory conditions: Ferritin <100 μg/L may indicate iron deficiency (not the usual <30 μg/L threshold), and transferrin saturation <16% with ferritin 30-100 μg/L suggests hypoferritinemia 5, 1
• Check iron studies if MCH is reduced despite macrocytosis: This mixed picture requires different treatment approaches 1
• Inflammatory bowel disease patients: At particularly high risk for multiple concurrent nutritional deficiencies 5, 1

When to Pursue Bone Marrow Evaluation

Perform bone marrow biopsy when other cytopenias are present alongside macrocytosis, as diagnostic yield increases to 75% compared to 33.3% in isolated macrocytosis. 6

• Unexplained macrocytosis after initial workup: 11.6% develop primary bone marrow disorders (myelodysplastic syndrome, lymphomas, plasma cell disorders) over median follow-up of 4 years 6
• Progressive or severe macrocytosis: Particularly in elderly patients, as myelodysplastic syndrome commonly affects this population 6, 7
• Worsening cytopenias: 16.3% of patients with unexplained macrocytosis develop additional cytopenias, with median time to first cytopenia of 18 months 6

Monitoring Strategy for Unexplained Macrocytosis

• Follow CBC every 6 months: Even when initial workup is unrevealing, as 69.7% have stable disease but close monitoring is essential 6
• Reassess B12 and folate periodically: Deficiencies may develop over time even with initially normal levels 1
• Consider hematology consultation: If cause remains unclear after initial workup or concerning hematologic abnormalities develop 1
• Mean time to diagnosis of bone marrow disorder: 31.6 months in patients with unexplained macrocytosis, emphasizing need for long-term follow-up 6

Common Diagnostic Pitfalls

• Assuming normal B12/folate excludes deficiency: Tissue deficiency can exist with normal serum levels—check homocysteine and methylmalonic acid 1
• Overlooking medication effects: Particularly thiopurines in IBD patients, where macrocytosis is expected and does not indicate vitamin deficiency 1, 2
• Neglecting follow-up: Even unexplained macrocytosis requires monitoring given significant percentage developing bone marrow disorders 6
• Missing mixed deficiencies: Concurrent iron deficiency masks expected microcytosis—check RDW and MCH 1, 2