How to manage macrocytosis in a patient with Crohn's disease who is on methotrexate (MTX) and folic acid (FA)?

Management of Macrocytosis in Crohn's Disease Patients on Methotrexate and Folic Acid

Continue the current methotrexate and folic acid regimen, but immediately check vitamin B12 levels and red blood cell folate to determine the cause of macrocytosis before making any treatment changes. 1, 2

Immediate Diagnostic Workup

The presence of macrocytosis in this clinical context requires systematic evaluation to distinguish between multiple potential etiologies:

• Measure both serum vitamin B12 and red blood cell folate levels simultaneously to identify the underlying cause, as both deficiencies can present with macrocytosis and must be excluded before adjusting therapy 1, 2
• Check complete blood count with differential to assess for myelosuppression, as methotrexate can cause macrocytosis through direct myelosuppressive effects independent of folate status 1
• Obtain liver enzymes since methotrexate requires regular hepatic monitoring and hepatotoxicity can influence drug metabolism 1

Critical caveat: If B12 deficiency is identified, treat it immediately before increasing folic acid supplementation, as folate can mask the hematologic manifestations of B12 deficiency while allowing irreversible neurological damage to progress 2

Understanding Macrocytosis Causes in This Population

Multiple mechanisms can cause macrocytosis in Crohn's disease patients on methotrexate:

• Methotrexate-induced macrocytosis occurs through inhibition of dihydrofolate reductase, blocking conversion of dihydrofolic acid to tetrahydrofolic acid, which is required for DNA synthesis 1
• Crohn's disease itself causes folate deficiency through malabsorption (particularly with ileal involvement), low dietary intake, and excess folate utilization from chronic mucosal inflammation 1
• Vitamin B12 deficiency is common in Crohn's disease (22.3% prevalence in one Spanish cohort) due to ileal disease or resection 1
• Azathioprine or 6-mercaptopurine (if previously used) can cause persistent macrocytosis through myelosuppressive activity, and in rare cases may indicate myelodysplastic syndrome 1, 3

Optimizing Folic Acid Supplementation

The current folic acid regimen should be verified against guideline-recommended dosing:

• For patients on methotrexate, the standard recommendation is 5 mg folic acid once weekly given 24-72 hours after the methotrexate dose, OR 1 mg daily for 5 days per week 1, 2
• If the patient is taking less than this, increase to guideline-recommended dosing 1
• Daily folic acid supplementation is recommended by British Society of Gastroenterology to reduce gastrointestinal and liver toxicity from methotrexate, with options of 5 mg weekly (1-2 days after methotrexate) or 1 mg daily 1

Recent pediatric evidence suggests that weekly 800 mcg folic acid may be sufficient to maintain normal folate levels without adverse symptoms, though this has not been validated in adults and lower than standard recommendations 4

Assessing Methotrexate Route and Dosing

Subcutaneous methotrexate has superior bioavailability compared to oral administration:

• Oral methotrexate bioavailability averages only 73% of subcutaneous administration and is highly variable between patients 5
• Concomitant folic acid does not significantly affect methotrexate bioavailability (relative bioavailability 0.77 for oral with folic acid vs 0.73 without) 5
• If the patient is on oral methotrexate and macrocytosis persists despite adequate folic acid, consider switching to subcutaneous administration at 15 mg/m² (maximum 25 mg) weekly 1

Management Algorithm Based on Test Results

If B12 is low:

• Treat B12 deficiency immediately with appropriate replacement therapy before adjusting folic acid 2
• Continue methotrexate with optimized folic acid supplementation 1

If red blood cell folate is low despite current supplementation:

• Increase folic acid to 5 mg daily (higher than standard maintenance dosing) for 4 months to replete body stores 2
• Consider switching methotrexate from oral to subcutaneous route if currently oral 1, 5
• Reassess folate levels in 3 months 2

If both B12 and folate are normal:

• The macrocytosis is likely a direct effect of methotrexate on DNA synthesis, which is expected and generally benign 1
• Continue current therapy with regular monitoring of complete blood count and liver enzymes 1
• Monitor for signs of myelosuppression (thrombocytopenia, leukopenia) which would require dose reduction or drug discontinuation 1

If macrocytosis is severe or progressive despite normal vitamin levels:

• Consider bone marrow biopsy to exclude myelodysplastic syndrome, particularly if the patient has prior azathioprine exposure, as this is an under-reported complication that progresses to acute myeloid leukemia in one-third of cases 3

Ongoing Monitoring Requirements

• Monitor complete blood count and liver enzymes frequently while on methotrexate therapy 1
• Recheck folate status within 3 months after any supplementation adjustment to verify normalization 2
• In patients with active Crohn's disease, test for folate deficiency regularly as inflammation increases folate utilization 1