Medications That Cause Macrocytosis
Multiple medications can cause macrocytosis, most commonly methotrexate, azathioprine, 6-mercaptopurine, phenytoin, valproate, zidovudine, hydroxyurea, and sulfasalazine. 1
Common Medication Causes of Macrocytosis
Folate Antagonists and Metabolism Disruptors
- Methotrexate: Inhibits dihydrofolate reductase, preventing conversion of dihydrofolic acid to tetrahydrofolic acid 1
- Sulfasalazine: Causes folate malabsorption 1
Immunosuppressants
- Azathioprine: Causes macrocytosis through myelosuppressive activity 2, 1
- 6-Mercaptopurine: Induces macrocytosis through bone marrow effects 1
Anticonvulsants
- Phenytoin: Associated with macrocytosis and megaloblastic anemia, which usually responds to folic acid therapy 3
- Valproate: Affects DNA synthesis leading to macrocytosis 1
Other Medications
- Hydroxyurea: Affects DNA synthesis in patients with psoriasis and other conditions 1
- Zidovudine: Commonly causes macrocytosis in HIV patients 1, 4
Mechanisms of Medication-Induced Macrocytosis
- Folate antagonism: Medications like methotrexate directly interfere with folate metabolism
- Bone marrow suppression: Azathioprine and 6-mercaptopurine affect bone marrow function 2, 1
- DNA synthesis disruption: Hydroxyurea and zidovudine interfere with DNA synthesis
- Folate malabsorption: Sulfasalazine reduces folate absorption 1
Clinical Considerations
Monitoring Recommendations
- For patients on methotrexate: Regular CBC monitoring and consider folate supplementation (5 mg once weekly 24-72 hours after methotrexate, or 1 mg daily for 5 days per week) 1
- For patients on sulfasalazine: Monitor for folate deficiency and consider supplementation 1
- For patients on hydroxyurea: Regular CBC monitoring 1
Important Distinctions
- Macrocytosis from medications may occur with or without anemia
- In thiopurine (azathioprine, 6-mercaptopurine) users, macrocytosis may be an early sign of bone marrow toxicity 2
- Phenytoin can cause both macrocytosis and megaloblastic anemia that typically responds to folic acid therapy 3
Pitfalls and Caveats
- Macrocytosis may be the first sign of medication toxicity before development of cytopenias 5
- Medication-induced macrocytosis must be distinguished from other causes such as vitamin B12/folate deficiency, alcoholism, liver disease, and primary bone marrow disorders 6
- Some patients on long-term azathioprine may develop severe megaloblastic anemia with pancytopenia even after years of stable therapy 7, 8
- In pediatric populations, anticonvulsants, zidovudine, and immunosuppressants account for approximately 24% of macrocytosis cases 4
When evaluating a patient with macrocytosis, always review the medication list thoroughly as drug-induced causes are among the most common etiologies, even in the absence of anemia.