Pathophysiology
Clinical meaning
Acetaminophen overdose is the most common cause of acute liver failure in North America. At therapeutic doses (less than 4 g/day in adults), approximately 5% of acetaminophen is metabolized by CYP2E1 to the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI), which is immediately conjugated with glutathione to a non-toxic metabolite. In overdose (greater than 150 mg/kg or 7.5 g total in adults), glutathione stores are depleted below 30% of normal, and unconjugated NAPQI binds to hepatocyte proteins, initiating mitochondrial dysfunction, oxidative stress, and centrilobular hepatic necrosis (zone III is most affected due to highest CYP2E1 concentration). The Rumack-Matthew nomogram plots serum acetaminophen level against time post-ingestion (beginning at 4 hours) to determine NAC treatment necessity: the treatment line begins at 150 mcg/mL at 4 hours (US line; Canadian/UK use 100 mcg/mL for increased safety margin). N-acetylcysteine (NAC) is the specific antidote, replenishing glutathione and providing alternative sulfhydryl groups for NAPQI conjugation. NAC is most effective when started within 8 hours of ingestion but should be administered at any time point if the level is above the treatment line or if clinical hepatotoxicity is...