What medications can cause cirrhosis?

Medications That Can Cause Cirrhosis

Methotrexate is the most well-documented medication that causes liver fibrosis and cirrhosis, particularly after prolonged use (generally two years or more) and after a total cumulative dose of at least 1.5 grams. 1

Primary Hepatotoxic Medications Leading to Cirrhosis

Methotrexate

• Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use, with chronic toxicity being potentially fatal 1
• Risk factors that enhance progression to cirrhosis include alcoholism, obesity, diabetes, and advanced age 1
• Liver biopsy is recommended at: 1) pretherapy or shortly after initiation (2-4 months), 2) total cumulative dose of 1.5 grams, and 3) after each additional 1-1.5 grams 1
• Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug 1
• In rheumatoid arthritis patients, there are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis reported among those with liver biopsies during treatment 1

Amiodarone

• Amiodarone has been frequently implicated in chronic drug-induced liver injury phenotypes including cirrhosis 2
• This antiarrhythmic medication can cause chronic liver disease that may be indistinguishable from other etiologies 2

Medications Associated with Chronic Liver Injury Patterns

Drugs Causing Liver Fibrosis Without Frank Cirrhosis

• Sulfasalazine can cause liver fibrosis, which is a precursor to cirrhosis 3
• Thiopurines (azathioprine) have been associated with nodular regenerative hyperplasia and potential progression to portal hypertension 3

Antituberculosis and Antiretroviral Agents

• Very few drugs have documented enhanced hepatotoxicity potential in existing cirrhosis, but most involve antituberculosis or antiretroviral agents used for HIV or viral hepatitis 4
• These medications can accelerate liver damage in patients with pre-existing liver disease 4

Important Clinical Considerations

Monitoring and Prevention

• Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis, particularly in rheumatoid arthritis populations treated with methotrexate 1
• Liver function tests including serum albumin should be performed periodically, but are often normal in the face of developing fibrosis or cirrhosis 1
• The reticulin stain is more sensitive for early fibrosis detection and may increase detection rates 1

Risk Assessment

• Hepatotoxicity from medications can present as chronic liver disease at the time of diagnosis, including non-alcoholic fatty liver disease patterns, vascular lesions, drug-induced autoimmune hepatitis, chronic cholestasis, and cirrhosis 2
• Drug-induced chronic liver injury phenotypes can be indistinguishable from those related to other etiologies, making diagnosis particularly challenging 2

Medications to Avoid in Established Cirrhosis

• NSAIDs should be avoided entirely in cirrhosis due to risk of hepatic complications, renal impairment, and gastrointestinal bleeding 5
• Naltrexone should be avoided due to hepatocellular injury risk 5
• Disulfiram should be avoided due to risk of hepatotoxicity in alcoholic liver disease 5
• Nephrotoxic drugs such as aminoglycosides should be avoided to preserve renal function 5

Common Pitfall

• The definition of chronicity after acute drug-induced liver injury is controversial, and un-resolving chronic outcomes can occur even after drug discontinuation, with mechanisms and risk factors being scarcely known 2
• Drug-induced hepatotoxicity may be poorly tolerated by patients with existing cirrhosis, even if the medication did not cause the original liver disease 6