From the Guidelines
Methotrexate rarely causes liver cirrhosis when used at standard therapeutic doses with proper monitoring, as evidenced by a 2019 study published in Gut 1. The risk of liver damage associated with methotrexate is lower than previously thought, and routine liver biopsy after prolonged use is not necessary, according to the British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults 1. Key factors that increase the risk of liver fibrosis and potential cirrhosis in patients taking methotrexate include:
- High BMI (>28 kg/m2)
- Alcohol intake (>14 drinks per week) These factors can lead to severe liver fibrosis, as identified by transient elastography, and should be screened for in patients with additional risk factors 1. To minimize liver risks, patients on methotrexate should:
- Avoid alcohol
- Maintain a healthy weight
- Take folic acid supplements, either 1 mg daily or 5 mg weekly, to reduce gastrointestinal and liver toxicity 1 Regular monitoring of liver function through blood tests every 1-3 months is essential for early detection of potential liver damage, and methotrexate should be stopped if transaminases exceed twice the upper limit of normal 1.
From the FDA Drug Label
Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population.
Methotrexate can cause liver cirrhosis, especially after prolonged use. This is supported by liver biopsy findings that show histologic changes, fibrosis, and cirrhosis in patients with sustained use of methotrexate 2.
From the Research
Methotrexate and Liver Cirrhosis
- Methotrexate has been associated with a range of liver-related adverse events, including asymptomatic transaminase elevations, fibrosis, and fatal hepatic necrosis 3.
- However, recent studies suggest that methotrexate may not be a direct cause of liver injury, and that the injury and fibrosis attributed to methotrexate may be mediated by other mechanisms, such as non-alcoholic fatty liver disease 4.
- A meta-analysis of randomized controlled trials found that methotrexate was associated with an increased risk of total adverse liver events and minor and major liver enzyme abnormalities, but not with an increased risk of liver failure, cirrhosis, or death 5.
- Another study found that the risk of liver fibrosis and cirrhosis previously attributed to methotrexate is actually caused by metabolic liver disease or other chronic liver diseases, rather than by methotrexate itself 4.
- It is recommended that patients treated with methotrexate be monitored for liver disease, particularly those with risk factors such as diabetes, obesity, and pre-existing chronic liver disease 6, 7.
Risk Factors for Liver Disease
- Diabetes, obesity, and pre-existing chronic liver disease are associated with an increased risk of liver fibrosis and cirrhosis in patients treated with methotrexate 4, 7.
- Alcohol consumption is also a risk factor for liver fibrosis in patients treated with methotrexate 7.
- Non-alcoholic fatty liver disease (NAFLD) is a significant risk factor for methotrexate hepatotoxicity, and methotrexate can worsen the course of NAFLD 6.
Monitoring and Diagnosis
- Frequent evaluation of liver fibrosis with liver biopsy is recommended during methotrexate therapy, especially in patients treated for psoriasis 7.
- Non-invasive methods, such as the FibroScan, may be useful for the assessment of liver fibrosis associated with methotrexate and require further evaluation 7.
- Pretreatment screening and long-term monitoring of methotrexate therapy are recommended for patients who have (or are at risk for) chronic liver disease 6.