Can methotrexate (MTX) cause elevated Alanine Transaminase (ALT) levels, and is an ALT level of 60 considered concerning?

Methotrexate and Elevated ALT Levels

Yes, methotrexate can cause elevated ALT levels, and an ALT of 60 is concerning enough to warrant monitoring but does not require immediate discontinuation of the medication. 1

Methotrexate-Induced Liver Enzyme Elevations

• Methotrexate is a recognized hepatotoxin that can cause both acute elevations in liver enzymes (transaminitis) and chronic hepatotoxicity (fibrosis and cirrhosis) 1
• Approximately 48.9% of patients on methotrexate will experience ALT/AST elevations above the upper limit of normal (ULN) during treatment 1
• More significant elevations (>2× ULN) occur in approximately 16.8% of patients after a mean of 3.3 years on methotrexate 1
• Pre-treatment elevation of ALT is the strongest predictor for developing ALT elevations during therapy (odds ratio = 6.8) 2

Interpretation of ALT = 60

• An ALT of 60 is typically less than 2 times the upper limit of normal (ULN) for most laboratory reference ranges 1
• According to guidelines, ALT elevations less than 2× ULN require monitoring but not immediate discontinuation of methotrexate 1
• For ALT elevations less than 2× ULN, the recommendation is to repeat liver function tests in 2-4 weeks while continuing methotrexate 3
• Most transaminase elevations with methotrexate are transient and reversible without requiring dose adjustment 4, 2

Management Algorithm for Elevated ALT on Methotrexate

1. For ALT less than 2× ULN (like ALT = 60):

   • Continue methotrexate at current dose 1
   • Repeat liver function tests in 2-4 weeks 1, 3
   • Ensure patient is taking folic acid supplementation (at least 5 mg weekly) 1
   • Assess for other contributing factors (alcohol, medications, obesity) 1, 3

2. For ALT 2-3× ULN:

   • Consider dose reduction of methotrexate 1
   • Repeat liver function tests in 2-4 weeks 1
   • Consider gastroenterology consultation 1

3. For ALT >3× ULN:

   • Stop methotrexate immediately 1
   • Repeat liver function tests until normalization 1
   • Consider diagnostic procedures if ALT/AST remains elevated after discontinuation 1
   • Methotrexate may be reinstituted at a lower dose after normalization 1

Monitoring Recommendations

• When starting methotrexate or increasing the dose, ALT (with or without AST), creatinine, and CBC should be performed every 1-1.5 months until a stable dose is reached 1
• After reaching a stable dose, monitoring should continue every 1-3 months 1, 3
• More frequent monitoring is recommended for patients with risk factors for hepatotoxicity (obesity, diabetes, alcohol consumption, advanced age) 1, 3
• Folic acid supplementation (at least 5 mg weekly) significantly reduces the risk of hepatotoxicity and should be prescribed to all patients on methotrexate 1

Important Caveats

• Serious methotrexate-induced liver fibrosis and cirrhosis are rare with modern dosing regimens, especially when combined with folic acid supplementation 4
• ALT elevations may be transiently higher if blood tests are performed within 2 days after methotrexate administration 1
• Recurrent ALT elevations occur in approximately 70% of patients who continue methotrexate treatment, regardless of interventions like dose reduction 2
• Only about 3% of patients need to permanently discontinue methotrexate due to persistent liver enzyme elevations 2
• Certain medications (NSAIDs, antibiotics) and acute illness can increase methotrexate toxicity and should be considered when evaluating liver enzyme elevations 5