What is the initial step in the workup of a patient with macrocytic anemia?

Macrocytic Anemia Workup

The initial workup of macrocytic anemia should include a reticulocyte count, vitamin B12 level, folate level, peripheral blood smear review, liver function tests, thyroid function tests, and assessment for alcohol use. 1, 2

Algorithmic Approach to Initial Testing

Step 1: Confirm Macrocytosis and Assess Severity

• Verify MCV >100 fL on complete blood count with indices 1
• Review peripheral blood smear to confirm red cell size, shape, and color 1
• Check for concurrent cytopenias (leukopenia, thrombocytopenia) which suggest bone marrow pathology like myelodysplastic syndrome 1, 3

Step 2: Order Core Laboratory Tests

The minimum essential workup includes:

• Reticulocyte count (corrected for degree of anemia): This is the critical branching point in your diagnostic algorithm 1, 2
  • Low/normal reticulocyte count indicates impaired red cell production (vitamin deficiencies, bone marrow dysfunction, hypothyroidism) 1
  • Elevated reticulocyte count suggests hemolysis or acute blood loss as compensatory mechanisms 1, 2
• Vitamin B12 and folate levels: Megaloblastic anemia from these deficiencies is the most common cause of macrocytic anemia 1, 2, 4
• Liver function tests: Chronic liver dysfunction causes nonmegaloblastic macrocytosis 2, 4
• Thyroid function tests (TSH): Hypothyroidism is a reversible cause of macrocytic anemia 2, 5
• Red cell distribution width (RDW): Elevated RDW may indicate coexisting microcytosis and macrocytosis that neutralize each other 1

Step 3: Assess for Common Reversible Causes

• Alcohol use history: Alcoholism is one of the most common causes and can resolve spontaneously with abstinence 5, 4, 6
• Medication review: Thiopurines (azathioprine, 6-mercaptopurine), hydroxyurea, anticonvulsants, and chemotherapy agents cause drug-induced macrocytosis 1, 2

When to Pursue Extended Workup

If the initial workup is unrevealing, obtain:

• Haptoglobin, lactate dehydrogenase, and indirect bilirubin if reticulocyte count is elevated to confirm hemolysis 1, 2
• Methylmalonic acid and homocysteine if B12 deficiency is suspected but serum B12 is borderline 1
• Intrinsic factor antibodies and parietal cell antibodies to diagnose pernicious anemia if B12 deficiency is confirmed 7
• Bone marrow aspirate and biopsy with cytogenetics if myelodysplastic syndrome is suspected (especially with concurrent cytopenias or unexplained macrocytosis in elderly patients) 1, 3, 5

Critical Pitfalls to Avoid

• Don't miss coexisting deficiencies: Simultaneous microcytosis (iron deficiency) and macrocytosis (B12/folate deficiency) can result in normal MCV with elevated RDW 1
• Don't overlook medication-induced macrocytosis: Many patients on chemotherapy or immunosuppressants have benign drug-related macrocytosis that doesn't require extensive workup 1
• Don't delay hematology referral: If pancytopenia is present or the cause remains unclear after extended workup, consult hematology promptly as myelodysplastic syndrome becomes more common with aging 1, 3
• Distinguish megaloblastic from nonmegaloblastic: Peripheral smear showing hypersegmented neutrophils (>5 lobes) indicates megaloblastic anemia and narrows your differential to B12/folate deficiency or rare inherited disorders 1, 4