Methotrexate-Induced Folate Deficiency
The most likely cause of this patient's macrocytic anemia (MCV 108) is methotrexate-induced folate deficiency, which occurs because methotrexate inhibits dihydrofolate reductase, preventing the conversion of dietary folates to their biologically active tetrahydrofolate form required for DNA synthesis. 1, 2
Mechanism of Methotrexate-Induced Macrocytic Anemia
Methotrexate acts as a folate antagonist by inhibiting dihydrofolate reductase, the enzyme responsible for producing tetrahydrofolates from dietary folates 3. This mechanism directly impairs DNA synthesis and amino acid metabolism, leading to megaloblastic changes in rapidly dividing cells, particularly in the bone marrow 3, 4.
- Macrocytic anemia is a well-established toxicity of methotrexate, even at low doses used for rheumatologic conditions 5
- The elevated MCV (108 fL, with macrocytosis defined as >98-100 fL) is characteristic of folate deficiency 5
- Progressive fatigue and shortness of breath over 3 months with severe anemia (Hb 7 g/dL) and pallor are consistent with symptomatic megaloblastic anemia 1, 2
Critical Risk Factors in This Case
This 50-year-old patient has multiple risk factors that increase susceptibility to methotrexate toxicity:
- Advanced age (≥50 years) is a documented risk factor for methotrexate-induced hematologic toxicity 2, 6
- Self-restarted methotrexate without medical supervision, likely resulting in lack of folate supplementation 1, 2
- Absence of folate supplementation is the most common preventable risk factor for methotrexate toxicity 1, 2
Diagnostic Confirmation
The increase in MCV serves as an early indicator of folate deficiency and impending methotrexate toxicity before severe anemia develops 2, 4:
- Check serum folate and vitamin B12 levels to confirm folate deficiency and exclude combined deficiency 7, 8
- Obtain complete blood count with differential to assess for pancytopenia, as methotrexate can cause isolated erythroid suppression or affect all cell lines 1, 2, 4
- Review reticulocyte count to distinguish between decreased production (low reticulocyte index) versus hemolysis or blood loss 5
Important caveat: While rare, autoimmune hemolytic anemia has been reported with low-dose methotrexate in RA patients, but this typically presents with elevated reticulocytes and positive Coombs testing, not the macrocytosis seen here 9.
Immediate Management
Discontinue methotrexate immediately upon recognition of significant hematologic toxicity 1, 2:
- Administer leucovorin (folinic acid) as the antidote, which bypasses the blocked dihydrofolate reductase enzyme and is life-saving in methotrexate toxicity 1, 2
- Start folic acid supplementation (5 mg daily) for ongoing management after acute toxicity resolves 1, 2
- Monitor complete blood counts closely during recovery 2
Prevention of Future Toxicity
All patients on methotrexate must receive folate supplementation to prevent gastrointestinal, hepatic, and hematologic toxicity 1, 2:
- Standard dosing: 1 mg folic acid daily OR 5 mg weekly (except on the day of methotrexate administration) 1, 2
- Regular monitoring with complete blood counts every 3-4 months to detect early MCV elevation before severe anemia develops 2, 4
- Patient education about the critical importance of not self-adjusting methotrexate dosing and maintaining folate supplementation 1, 2
Critical pitfall: The FDA label warns that methotrexate can cause severe bone marrow suppression and that elderly patients require especially careful monitoring for early signs of hematologic toxicity 6. This patient's self-restart of leftover medication without medical supervision and likely without folate supplementation created a preventable but serious complication.