From the Guidelines
Methotrexate-induced liver fibrosis is a significant concern, and regular monitoring of liver function is crucial to minimize the risk of liver damage, particularly in patients with risk factors such as alcohol consumption, obesity, and higher cumulative doses, as evidenced by studies 1.
Key Considerations
- Methotrexate can cause liver fibrosis with long-term use, especially in patients with risk factors such as alcohol consumption and obesity 1.
- Regular monitoring of liver function is essential, with blood tests every 1-3 months to check liver enzymes, and more comprehensive liver assessment conducted periodically 1.
- Non-invasive assessment methods like FibroScan or serum biomarkers, such as FIB-4, Fibrosure, and Hepascore, can be used to monitor for fibrosis in patients with risk factors or abnormal liver tests 1.
- Patients should limit alcohol intake, maintain a healthy weight, take folic acid supplements (typically 1-5 mg daily), and adhere to the lowest effective dose of methotrexate to minimize risk 1.
Monitoring and Management
- For patients without risk factors, monitoring for hepatotoxicity can be done every 3-6 months, with consideration of GI consultation and/or vibration-controlled transient elastography after a cumulative dose of 3.5-4.0 g 1.
- If signs of liver damage appear, methotrexate should be reduced or discontinued, and alternative medications considered 1.
- The decision to continue or discontinue methotrexate should be based on the results of non-invasive assessments and GI consultation, with consideration of the patient's individual risk factors and overall health status 1.
From the FDA Drug Label
Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1. 5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes, and advanced age. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1 to 1. 5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months.
Methotrexate-induced liver fibrosis is a potential risk, especially with prolonged use (generally two years or more) and after a total dose of at least 1.5 grams.
- Risk factors for hepatotoxicity include alcoholism, obesity, diabetes, and advanced age.
- Liver biopsy is recommended at certain intervals to monitor for fibrosis and cirrhosis.
- Mild fibrosis may not require discontinuation of the drug, but moderate fibrosis or cirrhosis typically leads to discontinuation of methotrexate 2.
From the Research
Methotrexate Induced Liver Fibrosis
- Methotrexate has long been believed to cause liver fibrosis, but recent studies suggest this may not be the case 3, 4, 5, 6, 7
- A meta-analysis and systematic review found no statistically significant association between methotrexate dose and liver fibrosis 3
- Individual studies reported fibrosis related to confounding factors such as diabetes, obesity, and pre-existing chronic liver disease, but not methotrexate exposure 3, 5, 7
- Non-invasive methods for assessing liver fibrosis, such as transient elastography and FibroTest, have provided new evidence supporting the hypothesis that methotrexate may not be a direct cause of liver injury 5, 7
Risk Factors for Liver Fibrosis
- Body mass index (BMI) >28 kg/m2 and high alcohol consumption are associated with abnormal markers of liver fibrosis 5
- Diabetes is a significant risk factor associated with liver stiffness ≥7.9 kPa 7
- Regular use of non-steroidal anti-inflammatory drugs is associated with elevated enhanced liver fibrosis (ELF) score 7
- Age and BMI are independently associated with elevated liver stiffness and ELF 7
Monitoring Guidelines for Methotrexate
- Current guidelines recommend intensive monitoring strategies for patients on long-term methotrexate therapy due to the potential risk of liver fibrosis 7
- However, the risk of liver fibrosis attributed to methotrexate itself may have been previously overestimated, and there is a need to consider modifying current monitoring guidelines 7
- The clinical focus should be on improving patients' metabolic risk factors, such as diabetes and BMI, that are independently associated with liver stiffness 7