What is the effect of Methotrexate (MTX) on the liver?

Methotrexate Effects on the Liver

Methotrexate causes hepatotoxicity ranging from transient, asymptomatic liver enzyme elevations (common) to fibrosis and cirrhosis (rare), with the risk of serious liver injury being substantially lower than historically believed when modern dosing regimens and monitoring protocols are followed. 1, 2

Spectrum of Hepatotoxicity

Acute Hepatotoxicity

• Transient liver enzyme elevations occur frequently (approximately 48.9% of patients at some point) but are usually asymptomatic and do not predict subsequent serious hepatic disease 3, 2
• Acute drug-induced hepatitis can occur but is generally reversible with dose reduction or discontinuation 1, 2
• Standard liver function tests (AST, ALT) are only 38% sensitive and 83% specific for detecting hepatic fibrosis, making them inadequate in isolation for monitoring chronic liver damage 1

Chronic Hepatotoxicity

• Fibrosis and cirrhosis can develop but generally only after prolonged use (typically two years or more) and cumulative doses exceeding 1.5 grams 2
• Recent evidence suggests that methotrexate may not directly cause progressive liver fibrosis; rather, injury previously attributed to methotrexate is likely mediated by non-alcoholic fatty liver disease (NAFLD) and other metabolic factors 4, 5
• Meta-analysis shows no statistically significant association between methotrexate dose and liver fibrosis when confounding factors are controlled 4
• The risk of cirrhosis in rheumatoid arthritis patients is rare (0.5%), though one older study in psoriasis patients showed that methotrexate-induced cirrhosis, while not typically aggressive, can rarely progress to liver failure 3, 6

Risk Factors for Hepatotoxicity

The following factors significantly increase the risk of methotrexate-induced liver damage and should be carefully assessed before initiating therapy: 1

• Greater than moderate alcohol consumption (>1 drink/day or >7 drinks/week for women; >2 drinks/day or >14 drinks/week for men) 7, 2
• Obesity (BMI ≥40 kg/m²) and metabolic syndrome 1
• Diabetes mellitus 1
• Hyperlipidemia 1
• Pre-existing chronic liver disease (hepatitis B or C, NAFLD) 2, 5
• Advanced age 8, 2
• High cumulative methotrexate doses 1, 2
• Concomitant hepatotoxic medications (NSAIDs, azathioprine, retinoids, sulfasalazine) 2

Monitoring Protocol

Baseline Assessment

• Obtain baseline liver function tests (AST, ALT, albumin, bilirubin) before initiating therapy 1, 2
• For patients with risk factors for hepatotoxicity, obtain baseline non-invasive fibrosis assessment using FIB-4 Index, FibroSure, Fibrometer, or Hepascore 1
• Baseline liver biopsy is not recommended 1
• Patients with history of excessive alcohol consumption, persistently abnormal baseline liver tests, or chronic hepatitis B or C should have pretreatment liver biopsy 2

Ongoing Monitoring

• Monitor liver function tests every 3-6 months in stable patients without abnormalities 1, 8
• Repeat testing 2-4 weeks after any dose increase 1, 8
• For patients with risk factors, perform annual gastroenterology consultation and/or vibration-controlled transient elastography 1

Response to Abnormal Results

For elevations <2× upper limit of normal (ULN):

• Continue methotrexate at current dose with close monitoring 8
• Repeat liver enzymes in 2-4 weeks 1, 8

For elevations 2-3× ULN:

• Closely monitor and repeat tests in 2-4 weeks 1
• Consider decreasing methotrexate dose 1, 8
• Assess for other hepatotoxic medications or causes (NSAIDs, alcohol, viral hepatitis) 3

For elevations ≥3× ULN (confirmed on repeat):

• Stop methotrexate immediately 1, 3, 2
• Do not wait for additional testing 3
• Repeat liver function tests within 2-4 weeks to confirm trend 3

For persistent elevation during 12-month period or decline in serum albumin below normal range:

• Consider gastroenterology consultation and/or liver biopsy 1, 2

Advanced Fibrosis Assessment

Non-Invasive Testing

• Vibration-controlled transient elastography (FibroScan) is the preferred non-invasive method for assessing liver fibrosis in patients on long-term methotrexate 1
• Magnetic resonance elastography should be used when FibroScan fails technically or in high-risk patients (BMI ≥40) 1
• If signs of stage 3 liver fibrosis are detected, consider switching to another agent or discontinuing therapy 1

Liver Biopsy Indications

• Persistent liver function test abnormalities despite dose reduction 2
• Decrease in serum albumin below normal range in well-nourished patients 1, 2
• Non-invasive testing suggesting greater than minimal fibrosis 1
• Routine liver biopsy for monitoring is no longer recommended 1, 2

Risk Mitigation Strategies

• Ensure folic acid supplementation (at least 5 mg/week, taken 1-2 days after methotrexate) to reduce hepatotoxicity 1, 8
• Address modifiable risk factors before initiating therapy (weight loss, alcohol cessation, diabetes control) 3
• Avoid concomitant hepatotoxic medications when possible 2
• Use lower doses in elderly patients and those with decreased hepatic function 2

Critical Pitfalls to Avoid

• Do not rely solely on standard liver function tests to detect fibrosis, as they have poor sensitivity for chronic liver damage 1
• Do not continue methotrexate with confirmed ALT/AST >3× ULN, as this significantly increases risk of progression to severe hepatotoxicity 3, 2
• Do not overlook NAFLD and metabolic syndrome as the primary drivers of liver injury in patients on methotrexate, rather than attributing all liver abnormalities to the drug itself 4, 5
• Alcoholism is an absolute contraindication to methotrexate therapy 7
• Methotrexate may be reinstituted at lower doses only after complete normalization of liver enzymes and addressing underlying risk factors 3