What are the causes of macrocytosis?

Causes of Macrocytosis

The most common causes of macrocytosis include vitamin B12 deficiency, folate deficiency, alcoholism, medications, liver disease, and myelodysplastic disorders. 1

Classification of Macrocytosis

Macrocytosis is generally defined as a mean corpuscular volume (MCV) greater than 100 fL and can be divided into two main categories:

1. Megaloblastic Macrocytosis

• Vitamin B12 deficiency

  • Most common cause of megaloblastic anemia 2
  • In Crohn's disease, prevalence ranges from 5.6-38% 3
  • Risk factors include:
    • Resection of >30 cm of distal ileum 3
    • Ileal involvement in Crohn's disease with >30-60 cm affected 3

• Folate deficiency

  • Essential for nucleoprotein synthesis and normal erythropoiesis 4
  • Causes impaired thymidylate synthesis leading to defective DNA synthesis 4
  • Common in patients taking certain medications:
    • Sulfasalazine (causes folate malabsorption) 3
    • Methotrexate (inhibits dihydrofolate reductase) 3

2. Non-Megaloblastic Macrocytosis

• Medications

  • Azathioprine and 6-mercaptopurine (through myelosuppressive activity) 3
  • Zidovudine (has become a leading cause in some populations) 5

• Liver disease 1, 6

  • Typically presents with mild, uniform macrocytosis with round RBCs 6

• Alcoholism 1, 5

• Reticulocytosis 6

  • Due to hemolysis or hemorrhage
  • MCV rarely exceeds 110 fL 6

• Hypothyroidism 1, 2

• Myelodysplastic syndromes and myeloproliferative disorders 1, 7

  • Important consideration in unexplained macrocytosis
  • 11.6% of patients with unexplained macrocytosis develop primary bone marrow disorders 7

• Multiple myeloma 3

Diagnostic Features

Laboratory Findings

• Megaloblastic anemia:

  • MCV may exceed 150 fL 6
  • Peripheral smear shows macro-ovalocytes and hypersegmented neutrophils 1
  • RBCs vary considerably in size and shape 6
  • Macrocytes tend to be oval 6

• Non-megaloblastic causes:

  • Liver disease: mild macrocytosis with round RBCs 6
  • Reticulocytosis: MCV rarely exceeds 110 fL 6

Diagnostic Approach

1. Complete blood count with MCV measurement
2. Peripheral blood smear to distinguish megaloblastic from non-megaloblastic causes
3. Reticulocyte count to identify hemolysis or hemorrhage
4. Vitamin B12 and folate levels:
   • Serum folate levels below 5 ng/mL indicate deficiency 4
   • Levels below 2 ng/mL usually result in megaloblastic anemia 4
5. Liver function tests to identify liver disease
6. Thyroid function tests to rule out hypothyroidism
7. Medication review to identify drug-induced causes
8. Bone marrow biopsy when cytopenias are present or macrocytosis remains unexplained 7

Management Considerations

• For vitamin B12 deficiency:

  • In Crohn's disease with clinical deficiency: 1000 mg vitamin B12 IM every other day for a week, then monthly for life 3
  • For patients with >20 cm ileum resected: prophylactic 1000 mg vitamin B12 monthly indefinitely 3

• For folate deficiency:

  • Patients on sulfasalazine or methotrexate should receive supplementation 3
  • For methotrexate users: 5 mg folate once weekly 24-72 hours after methotrexate, or 1 mg daily for 5 days per week 3

• For unexplained macrocytosis:

  • Close follow-up with blood cell counting every 6 months 7
  • Consider bone marrow biopsy if cytopenias develop 7

Pitfalls and Caveats

• Macrocytosis can occur with Epoetin therapy due to shifting of immature (large) reticulocytes into circulation 3
• Iron overload can also be associated with macrocytosis 3
• Unexplained macrocytosis requires vigilant monitoring as 11.6% of patients may develop primary bone marrow disorders within a median follow-up of 4 years 7
• In patients with inflammatory conditions, standard cutoffs for deficiencies may not apply, and higher thresholds for diagnosis may be needed