What is the differential diagnosis (ddx) for a patient presenting with macrocytic anemia?

Differential Diagnosis of Macrocytic Anemia

Macrocytic anemia (MCV >100 fL) is primarily divided into megaloblastic causes (vitamin B12 and folate deficiency) and non-megaloblastic causes (alcoholism, liver disease, hypothyroidism, medications, and myelodysplastic syndrome), with vitamin B12 deficiency being the most common megaloblastic cause. 1

Classification Framework

Macrocytic anemia should be systematically categorized based on reticulocyte count and peripheral blood smear findings:

Low or Normal Reticulocyte Count (Production Defect)

Megaloblastic Causes:

• Vitamin B12 deficiency (most common megaloblastic cause, defined as <150 pmol/L or <203 ng/L) 1, 2
• Folate deficiency (serum folate <10 nmol/L or RBC folate <305 nmol/L) 1
• Medications impairing DNA synthesis: hydroxyurea, methotrexate, azathioprine, phenytoin 3, 1, 4

Non-Megaloblastic Causes:

• Alcoholism (most common non-megaloblastic cause) 5, 6
• Liver disease/dysfunction 5, 6, 7
• Hypothyroidism 3, 1, 6
• Myelodysplastic syndrome (MDS) - particularly important in elderly patients with concurrent leukopenia and/or thrombocytopenia 3, 1, 7
• Bone marrow infiltration by malignancy (prostate, breast cancer) 1
• Pure red cell aplasia 1
• Aplastic anemia 3

Elevated Reticulocyte Count (Destruction/Loss)

• Hemolysis 3, 4, 6
• Recent hemorrhage/acute blood loss 3, 4, 6

Critical Diagnostic Pitfalls

Mixed deficiency states can mask each other: Iron deficiency coexisting with B12/folate deficiency may result in a normal MCV, as microcytosis and macrocytosis neutralize each other. An elevated red cell distribution width (RDW) is the key clue to identify this scenario. 1, 4

Inflammatory conditions complicate interpretation: In patients with inflammation, ferritin may be falsely elevated (up to 100 μg/L) despite concurrent iron deficiency. Check transferrin saturation and RDW in these cases. 1, 4

Essential Diagnostic Algorithm

Initial laboratory workup must include:

1. Reticulocyte count - differentiates regenerative (elevated) from non-regenerative (low/normal) causes 1, 4

2. Peripheral blood smear - neutrophil hypersegmentation is highly sensitive and specific for megaloblastic anemia 6

3. Vitamin B12 level - if borderline, confirm with methylmalonic acid (>271 nmol/L confirms deficiency) 1

4. Serum and RBC folate levels 1

5. TSH and free T4 - to exclude hypothyroidism 1

6. Liver function tests 5, 6

7. RDW - to identify coexisting iron deficiency 1, 4

8. CRP and creatinine - assess for inflammatory anemia or renal failure 1

When to pursue bone marrow evaluation: If MDS is suspected, particularly in elderly patients presenting with unexplained cytopenias (anemia with leukopenia and/or thrombocytopenia), bone marrow aspirate and biopsy with cytogenetic analysis is required. Refer to hematology if the cause remains unclear after extensive evaluation. 3, 1, 7

Less Common Causes to Consider

• Thiamine-responsive megaloblastic anemia syndrome 1
• Paroxysmal nocturnal hemoglobinuria (PNH) - consider diagnostic workup if clinical suspicion exists, as small PNH clones can accompany MDS 3
• Autoimmune disorders 3
• Chronic infections 3
• Renal failure 3

Special Population Considerations

Patients with inflammatory bowel disease require frequent evaluation of B12 and folate, especially with extensive small intestine resection, extensive ileal disease, or ileal-anal pouch. 1

Cancer patients receiving chemotherapy commonly develop macrocytic anemia from myelosuppressive effects or specific agents like hydroxyurea. 3