What is the initial workup for a patient presenting with macrocytosis (large red blood cells)?

Initial Workup for Macrocytosis

The initial workup for macrocytosis should include complete blood count with indices, serum vitamin B12, serum folate, liver function tests, thyroid function tests, reticulocyte count, and peripheral blood smear examination. 1, 2

Diagnostic Approach

Step 1: Laboratory Assessment

• Complete blood count (CBC) with differential and indices
• Serum vitamin B12 level
• Serum folate level
• Liver function tests (LFTs)
• Thyroid function tests (TFTs)
• Reticulocyte count
• Peripheral blood smear examination

Step 2: Peripheral Smear Evaluation

Examine the peripheral smear for:

• Megaloblastic features (macro-ovalocytes and hypersegmented neutrophils) suggesting vitamin B12 or folate deficiency
• Non-megaloblastic features suggesting other etiologies

Step 3: Additional Testing Based on Initial Results

• If peripheral smear shows megaloblastic features:

  • Check methylmalonic acid and homocysteine levels if B12 deficiency is suspected but serum B12 is borderline
  • Consider intrinsic factor antibodies and parietal cell antibodies if pernicious anemia is suspected

• If peripheral smear shows non-megaloblastic features:

  • With elevated reticulocyte count: Evaluate for hemolysis or hemorrhage
  • With normal/low reticulocyte count: Consider medication effects, alcohol use, liver disease, or myelodysplasia

Common Etiologies of Macrocytosis

1. Vitamin B12 deficiency: Indicated by serum B12 <200 pg/mL, elevated methylmalonic acid and homocysteine 1, 3
2. Folate deficiency: Indicated by serum folate <4 ng/mL and normal B12 levels 3
3. Alcoholism: Suggested by history and elevated liver enzymes 2, 4
4. Medications: Common culprits include anticonvulsants, chemotherapy agents, and antiretrovirals 2, 5
5. Liver disease: Indicated by abnormal liver function tests 4, 5
6. Hypothyroidism: Indicated by elevated TSH and low free T4 4
7. Hemolysis or hemorrhage: Indicated by elevated reticulocyte count 4
8. Myelodysplastic syndromes: Consider when other causes are excluded, especially in older patients 6, 4

When to Consider Bone Marrow Evaluation

• Persistent unexplained macrocytosis despite normal initial workup
• Presence of other cytopenias (anemia, leukopenia, thrombocytopenia)
• Suspicion of myelodysplastic syndrome or other primary bone marrow disorder

Follow-up for Unexplained Macrocytosis

• Monitor CBC every 6 months
• Approximately 11.6% of patients with unexplained macrocytosis will develop a primary bone marrow disorder within a median follow-up of 4 years 6
• The yield of bone marrow biopsy is higher in patients with macrocytosis plus anemia (75%) compared to isolated macrocytosis (33.3%) 6

Important Considerations

• MCV values >120 fL are usually caused by vitamin B12 deficiency 5
• Anisocytosis, macro-ovalocytes, and teardrop erythrocytes are most prominent in megaloblastic hematopoiesis 5
• Red Cell Distribution Width (RDW) is typically elevated in iron deficiency and may help distinguish from other causes of anemia 1
• Combined deficiencies (e.g., B12 and folate) can occur and should be considered 3

By following this systematic approach, the underlying cause of macrocytosis can be identified in the majority of patients, allowing for appropriate treatment and follow-up.