What is the appropriate workup for macrocytosis?

Workup of Macrocytosis

The appropriate workup for macrocytosis should begin with a complete blood count with indices, reticulocyte count, peripheral blood smear examination, and targeted testing based on the morphologic classification and reticulocyte response. 1

Initial Evaluation

• Complete blood count (CBC) with indices

  • Mean corpuscular volume (MCV) > 100 fL confirms macrocytosis
  • Red cell distribution width (RDW)
  • Hemoglobin level to determine if anemia is present
  • Platelet and white blood cell counts to assess other cell lines

• Peripheral blood smear examination

  • Look for macro-ovalocytes and hypersegmented neutrophils (suggesting megaloblastic anemia)
  • Assess for anisocytosis, teardrop erythrocytes (prominent in megaloblastic hematopoiesis) 2
  • Presence of schistocytes (may indicate hemolysis)

• Reticulocyte count

  • Elevated: Suggests hemolysis or hemorrhage
  • Normal/low: Suggests nutritional deficiency, drug/alcohol toxicity, or bone marrow disorder

Second-Line Testing Based on Initial Findings

For Megaloblastic Pattern (macro-ovalocytes and hypersegmented neutrophils)

• Vitamin B12 level
• Serum folate level
• Methylmalonic acid and homocysteine levels (more sensitive for B12 deficiency) 2
• Intrinsic factor antibodies if B12 deficiency is confirmed

For Non-Megaloblastic Pattern

• Liver function tests

  • AST, ALT, bilirubin, albumin
  • Particularly important if alcohol abuse is suspected

• Thyroid function tests

  • TSH and free T4 to rule out hypothyroidism

• Medication review

  • Anticonvulsants, chemotherapy agents, methotrexate, azathioprine
  • HIV medications

• Alcohol use assessment

  • Detailed history of alcohol consumption
  • GGT, MCV, AST/ALT ratio > 2 may suggest alcoholic liver disease

For Unexplained Macrocytosis or Associated Cytopenias

• Bone marrow aspiration and biopsy with cytogenetic analysis
  • Particularly if myelodysplastic syndrome (MDS) is suspected
  • Higher yield when macrocytosis is accompanied by anemia (75% vs 33.3% in isolated macrocytosis) 3

Specific Testing Based on Clinical Suspicion

• If hemolysis is suspected:

  • LDH, haptoglobin, direct Coombs test
  • Bilirubin (direct and indirect)

• If bone marrow failure syndrome is suspected:

  • Paroxysmal nocturnal hemoglobinuria screening
  • Cytogenetic analysis
  • Flow cytometry

• If inflammatory bowel disease is present:

  • More frequent monitoring (every 3-6 months) 4
  • Expanded workup including haptoglobin, LDH, reticulocyte hemoglobin

Clinical Pearls and Pitfalls

• MCV values > 120 fL are usually caused by vitamin B12 deficiency 2
• The combination of low red cell count (<4.0 × 10¹²/L) or high RDW (>15.0%) with normal platelet count and volume is highly suggestive of vitamin B12 deficiency (94.4% sensitivity) 5
• Approximately 10% of patients will have unexplained macrocytosis after initial laboratory evaluation 3
• Patients with unexplained macrocytosis require close follow-up every 6 months, as 11.6% may develop a primary bone marrow disorder and 16.3% may develop worsening cytopenias 3
• The mean time to diagnosis of a bone marrow disorder in patients with unexplained macrocytosis is approximately 32 months 3
• Misdiagnosing anemia of chronic disease as iron deficiency can lead to inappropriate treatment 1

Most Common Causes of Macrocytosis

1. Medications (most common in hospitalized patients) 2
2. Alcohol abuse
3. Liver disease
4. Vitamin B12 and folate deficiencies
5. Hemolysis or hemorrhage
6. Hypothyroidism
7. Myelodysplastic syndromes and other primary bone marrow disorders

By following this systematic approach, clinicians can efficiently diagnose the underlying cause of macrocytosis and initiate appropriate treatment to address the primary condition.