Can methotrexate (MTX) cause macrocytic anemia?

Methotrexate and Macrocytic Anemia

Yes, Methotrexate Can Cause Macrocytic Anemia

Methotrexate commonly causes macrocytic anemia through folate deficiency, and all patients on methotrexate should receive folate supplementation to prevent this complication. 1

Mechanism of Methotrexate-Induced Macrocytic Anemia

Methotrexate (MTX) causes macrocytic anemia through several mechanisms:

1. Inhibition of Dihydrofolate Reductase: MTX is a folate antagonist that inhibits dihydrofolate reductase, an enzyme crucial for producing the active form of folate (tetrahydrofolate) 1, 2

2. Folate Deficiency: This inhibition leads to folate deficiency, which impairs DNA synthesis and causes megaloblastic changes in rapidly dividing cells, particularly in the bone marrow 3

3. Selective Erythroid Suppression: MTX can selectively suppress the erythroid line while sparing white blood cells and platelets, resulting in isolated macrocytic anemia 3

Clinical Presentation

Patients with MTX-induced macrocytic anemia may present with:

• Elevated mean corpuscular volume (MCV)
• Normal or low reticulocyte count
• Fatigue, pallor, and other symptoms of anemia
• Normal white blood cell and platelet counts in some cases 3

Risk Factors for MTX-Induced Macrocytic Anemia

Several factors increase the risk of developing macrocytic anemia while on MTX:

• Lack of folate supplementation
• Concurrent medications that affect folate metabolism (e.g., sulfasalazine)
• Preexisting vitamin B12 deficiency
• Renal dysfunction
• Hypoalbuminemia
• Dosing errors
• Metabolic syndrome 4

Prevention and Management

Prevention

• Folate Supplementation: All patients on MTX should receive folate supplementation 1

  • For adults: 1-5 mg of folic acid daily, or 5 mg once weekly (24-72 hours after MTX dose) 1
  • For children: Similar dosing regimens can be used, with recent evidence suggesting that weekly dosing (800 mcg) may be sufficient 5

• Regular Monitoring:

  • Complete blood count with MCV
  • Liver function tests
  • Renal function tests

Management of MTX-Induced Macrocytic Anemia

1. Identify the Cause: Check folate and vitamin B12 levels to confirm the etiology

2. Treatment:

   • Discontinue or reduce MTX dose
   • Administer leucovorin (folinic acid) for severe cases
   • Increase folate supplementation
   • Address any concurrent vitamin B12 deficiency if present 4

3. Monitoring Response:

   • Follow hemoglobin levels and MCV
   • Assess clinical symptoms

Special Considerations

Concurrent Vitamin B12 Deficiency

• Test for vitamin B12 deficiency in patients with macrocytic anemia on MTX, especially those with ileal disease or resection 1
• Vitamin B12 deficiency can exacerbate MTX-induced macrocytic anemia 4

Inflammatory Bowel Disease Patients

• IBD patients on MTX are at particular risk due to potential malabsorption and increased folate utilization from mucosal inflammation 1
• The ECCO-ESPGHAN guidelines recommend oral administration of folate in patients on MTX, 5 mg once weekly 24-72 hours after MTX, or 1 mg daily for 5 days per week 1

Pregnancy Considerations

• MTX is contraindicated during pregnancy (Category X)
• Women should wait at least 3 months after discontinuation before attempting pregnancy 6
• Pregnant IBD patients should have iron and folate levels monitored regularly 1

Conclusion

Macrocytic anemia is a recognized complication of MTX therapy due to its interference with folate metabolism. Regular monitoring of complete blood counts and folate supplementation are essential preventive measures for all patients on MTX therapy.