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 present. The IV protocol (Prescott protocol): 150 mg/kg over 60 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours. The clinician monitors serial liver enzymes (ALT peaks 72-96 hours post-ingestion), coagulation (INR is the most sensitive indicator of synthetic function and prognosis), renal function, and applies the King College Criteria for liver transplant referral (pH less than 7.30 after fluid resuscitation, OR all three: INR greater than 6.5, creatinine greater than 3.4 mg/dL, grade III-IV encephalopathy).