- Acetaminophen overdose is the leading cause of acute liver failure in the United States due to its widespread availability and potential for hepatotoxicity in overdose.
- The toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) depletes glutathione and causes centrilobular hepatic necrosis.
- Early recognition and treatment with N-acetylcysteine can prevent progression to liver failure.
- Other causes like viral hepatitis or autoimmune hepatitis are less common in acute liver failure in this setting.
- Hence, acetaminophen overdose remains the primary etiology due to its frequency and severity.

Reference: Davidson’s Principles and Practice of Medicine, 24th Edition, Chapter: The Liver, Page 763.