From the Guidelines
Methotrexate-induced liver function test (LFT) injury is a significant concern, and if suspected, the medication should be temporarily discontinued, and the patient should be closely monitored with repeated LFTs every 2-4 weeks, as recommended by the joint American Academy of Dermatology-National Psoriasis Foundation guidelines 1.
Risk Factors for Methotrexate Hepatotoxicity
The risk factors for methotrexate hepatotoxicity include:
- Obesity
- Diabetes
- Pre-existing liver disease
- Alcohol use
- Higher cumulative doses These risk factors should be carefully evaluated when considering methotrexate treatment, as they can increase the likelihood of liver injury 1.
Monitoring and Management
Regular LFT monitoring is essential during methotrexate treatment, typically every 4-8 weeks initially, then every 1-3 months with stable dosing 1.
- Folic acid supplementation (1-5 mg daily) should be used with methotrexate to reduce hepatotoxicity risk.
- Alcohol should be strictly avoided during methotrexate therapy as it significantly increases liver injury risk.
- Liver biopsy may be considered after a cumulative dose of 3.5-4 grams in patients with persistent LFT abnormalities to assess for fibrosis or cirrhosis 1.
Recommendations
The most recent guidelines recommend a noninvasive baseline liver fibrosis assessment before starting treatment with methotrexate, and annual GI/hepatology referral or vibration-controlled transient elastography, or both, should be performed if methotrexate is continued despite abnormal baseline liver fibrosis laboratory results 1. In patients with risk factors for hepatotoxicity, a more frequent monitoring schedule may be necessary, and the medication should be discontinued if significant LFT elevations occur. By carefully monitoring patients and adjusting treatment accordingly, the risk of methotrexate-induced LFT injury can be minimized, and the benefits of treatment can be maximized.
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. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function. Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving methotrexate for rheumatoid arthritis Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection
Methotrexate can cause liver injury, including elevated transaminases, fibrosis, and cirrhosis. The risk of hepatotoxicity is increased with prolonged use (more than 2 years), high cumulative doses (at least 1.5 grams), alcoholism, obesity, diabetes, and advanced age.
- Liver function tests should be performed regularly, and
- liver biopsy may be necessary in certain cases, such as preexisting liver damage or impaired hepatic function. The drug should be used with caution in patients with risk factors for hepatotoxicity, and discontinued if liver function tests are persistently abnormal or if liver biopsy shows moderate to severe changes 2.
From the Research
Methotrexate Induced LFT Injury
- Methotrexate (MTX) is a widely used drug in the management of autoimmune and dermatological diseases, but it can cause liver injury, particularly in patients with rheumatoid arthritis and psoriasis 3, 4.
- The incidence of elevated liver enzymes (LE) in patients taking MTX is relatively high, with a cumulative incidence of 31% in the first three years of treatment 3.
- Studies have shown that MTX can cause oxidative stress, inflammation, steatosis, fibrosis, and apoptosis in hepatocytes, leading to liver injury 4.
- The risk of liver injury is higher in patients with pre-existing liver disease, such as non-alcoholic fatty liver disease (NAFLD) 5.
- Monitoring of liver enzymes is essential in patients taking MTX, and adjustments to treatment may be necessary in cases of elevated LE 3, 5.
- The molecular mechanisms of MTX-induced hepatotoxicity involve the accumulation of intracellular MTX-polyglutamate (MTX-PG), which triggers oxidative stress and inflammation in hepatocytes 4.
Predictors and Surveillance of Liver Injury
- Predictors of ALT elevation in MTX-treated patients include pre-treatment elevation of ALT, cumulative MTX dose, and serial LE elevations 3, 5.
- Surveillance of liver enzymes is crucial in patients taking MTX, and handling of elevated LE should be individualized based on patient risk factors and treatment response 5.
- Studies have shown that a pre-treatment elevation of ALT is a strong predictor of early and recurrent ALT elevations during MTX therapy 5.
Comparison of Treatment Regimens
- Comparison of treatment regimens, such as triple therapy with MTX, sulfasalazine, and hydroxychloroquine, versus combination MTX and leflunomide, has shown that triple therapy may be more effective in reducing disease activity 6, 7.
- However, the safety profile of these treatment regimens is comparable, with similar rates of adverse events and treatment discontinuations 6, 7.