Common Medications That Cause Macrocytosis
The most common medications that cause macrocytosis include methotrexate, azathioprine, 6-mercaptopurine, phenytoin, valproate, zidovudine, and other immunosuppressive agents. These medications can lead to macrocytosis through various mechanisms, often without causing anemia.
Mechanism-Based Classification of Medications Causing Macrocytosis
1. Medications Affecting Folate Metabolism
- Methotrexate: Inhibits dihydrofolate reductase, preventing conversion of dihydrofolic acid to tetrahydrofolic acid 1
- Sulfasalazine: Causes folate malabsorption 1
- Trimethoprim/Sulfamethoxazole (TMP/SMX): Interferes with folate metabolism
2. Immunosuppressive Medications
- Azathioprine: Causes macrocytosis through myelosuppressive activity 1
- 6-Mercaptopurine: Similar to azathioprine, induces macrocytosis through bone marrow effects 1
- Mycophenolate mofetil: Immunosuppressant that can affect cell maturation
3. Anticonvulsants
- Phenytoin: Can cause macrocytosis and megaloblastic anemia, often responding to folate therapy 2
- Valproate: Commonly causes macrocytosis in pediatric and adult populations 3
4. Antiretroviral Medications
- Zidovudine (AZT): Frequently causes macrocytosis, especially in HIV patients 3
5. Other Medications
- Hydroxyurea: Used in psoriasis and other conditions, affects DNA synthesis 1
- Leflunomide: Can contribute to macrocytosis when used with other DMARDs 4
Clinical Significance and Monitoring
Medication-induced macrocytosis may present with or without anemia. In a study of patients with macrocytosis, 35% of cases were attributed to medication use 3. Importantly, only 20% of patients with medication-induced macrocytosis had concurrent anemia 4.
Monitoring Recommendations:
- For patients on methotrexate: Regular CBC monitoring; 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; supplementation with either folic or folinic acid may be needed 1
- For patients on azathioprine or 6-mercaptopurine: Monitor CBC regularly as these can cause pancytopenia in addition to macrocytosis 5
Important Clinical Considerations
Differential Diagnosis: When macrocytosis is detected, it's important to rule out other causes including:
- Vitamin B12 deficiency
- Folate deficiency
- Alcoholism
- Liver disease
- Hypothyroidism
- Myelodysplastic syndromes 6
Persistent Unexplained Macrocytosis: Requires follow-up as approximately 11.6% of patients with unexplained macrocytosis may develop primary bone marrow disorders 7
Medication Combinations: The risk of macrocytosis increases with combination therapy, particularly when using multiple DMARDs together 4
Monitoring Frequency: For patients on high-risk medications, CBC monitoring should be performed:
- Initially: Every 2-4 weeks
- Maintenance: Every 1-3 months depending on medication stability
Recognizing medication-induced macrocytosis is important as it may be an early indicator of drug toxicity or, in some cases like methotrexate therapy, may actually correlate with treatment efficacy 4.