What is the risk of hepatotoxicity associated with Amiodarone (antiarrhythmic medication) therapy?

From the Guidelines

Amiodarone carries a significant risk of liver injury, with an annual incidence of 0.6 percent, and requires regular monitoring of liver transaminase levels, as recommended by guidelines for use and monitoring 1. The risk of hepatotoxicity is dose-dependent, with higher doses and longer treatment durations increasing the likelihood of liver damage. Amiodarone-induced liver injury typically presents as asymptomatic transaminase elevations, but can progress to acute hepatitis or, rarely, cirrhosis with long-term use.

Key Considerations

• Patients taking amiodarone should have liver function tests (LFTs) performed before starting treatment, then every 6 months during therapy, as outlined in the checklist for monitoring adult patients taking amiodarone 1.
• If a patient develops transaminase elevations exceeding 3 times the upper limit of normal or shows symptoms of liver dysfunction (jaundice, abdominal pain, fatigue), the medication should be discontinued or the dose reduced, as recommended by guidelines for use and monitoring 1.
• The mechanism of amiodarone hepatotoxicity involves both direct toxicity from the drug's accumulation in hepatocytes and immune-mediated injury, and the drug's long half-life (up to 100 days) means that liver effects can persist even after discontinuation.
• Patients with pre-existing liver disease should use amiodarone cautiously, with more frequent monitoring and possibly lower doses, as recommended by the 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death 1.

Monitoring and Management

• Regular monitoring of lung, liver, and thyroid function is needed, as chronic administration of amiodarone is associated with complex drug interactions and a host of extracardiac side effects involving the thyroid, skin, and occasionally the lung and liver 1.
• As a general rule, the longer the therapy and the higher the dose of amiodarone, the greater the likelihood that adverse side effects will require discontinuation of the drug, with 10% of patients randomized to amiodarone discontinuing therapy compared to placebo 1.

From the FDA Drug Label

Elevations of blood hepatic enzyme values – alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) – are seen commonly in patients with immediately life-threatening VT/VF Approximately 54% of patients receiving amiodarone HCl injection in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of amiodarone HCl injection at a much higher loading dose concentration and much faster rate of infusion than recommended In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of amiodarone HCl injection therapy, but patients receiving amiodarone HCl injection should be monitored carefully for evidence of progressive hepatic injury

Amiodarone Liver Injury Risk: Amiodarone is associated with a risk of liver injury, including elevations in liver enzymes and, in rare cases, acute hepatocellular necrosis leading to hepatic coma and death. Patients receiving amiodarone should be monitored carefully for evidence of progressive hepatic injury. The risk of liver injury should be weighed against the potential benefit of amiodarone therapy in patients with life-threatening arrhythmias 2.

• Key Points:
  • Elevations in liver enzymes are common in patients receiving amiodarone
  • Acute hepatocellular necrosis is a rare but potentially fatal complication of amiodarone therapy
  • Patients should be monitored carefully for evidence of progressive hepatic injury
  • The risk of liver injury should be weighed against the potential benefit of amiodarone therapy in patients with life-threatening arrhythmias

From the Research

Amiodarone Liver Injury Risk

• Amiodarone is a highly effective antiarrhythmic agent, but it can cause liver injury, which is rare but potentially harmful 3.
• The risk of liver injury associated with amiodarone can be predicted by certain factors, including elevated C-reactive protein levels before amiodarone administration 4.
• Other predictors of amiodarone-induced liver injury (AILI) include the presence of cardiomyopathy, congestive hepatomegaly, increasing baseline total bilirubin, direct current cardioversion, and increasing dose of amiodarone 5.
• The severity of AILI has been found to have a linear relationship with baseline aminotransferase levels and left ventricular systolic function 5.
• Long-term treatment with amiodarone requires close supervision by the treating physician and serial screening for thyroid, liver, and pulmonary toxicity 6.
• Amiodarone has been found to have a higher risk of acute liver injuries compared to other antiarrhythmic drugs, with an adjusted Odds Ratio of 5.90 (95% CI: 1.7-20.0) 7.

Risk Factors for Amiodarone-Induced Liver Injury

• Elevated C-reactive protein levels before amiodarone administration 4
• Presence of cardiomyopathy 5
• Congestive hepatomegaly 5
• Increasing baseline total bilirubin 5
• Direct current cardioversion 5
• Increasing dose of amiodarone 5
• Inotropic support 5
• Compromised cardiac, hepatic, and hemodynamic conditions 5

Prevention and Management of Amiodarone-Induced Liver Injury

• Close monitoring of liver function when amiodarone is administered 4
• Timely stopping of suspected drug and anti-inflammatory liver therapy may reduce the occurrence of drug-induced diseases 3
• Use of alternative drugs should be considered in patients with elevated C-reactive protein levels 4
• Serial screening for thyroid, liver, and pulmonary toxicity during long-term treatment with amiodarone 6