Clinical meaning
Acute liver failure (ALF) is defined as severe hepatic dysfunction (INR ≥1.5 and hepatic encephalopathy) in a patient without pre-existing liver disease, with illness duration <26 weeks. The most common cause in the US is acetaminophen (APAP) overdose (46%), followed by idiosyncratic drug reactions (11%), hepatitis B (7%), and autoimmune hepatitis. In APAP toxicity, therapeutic doses are metabolized primarily by glucuronidation and sulfation (95%); a small fraction (5%) is oxidized by CYP2E1 to the toxic metabolite NAPQI (N-acetyl-p-benzoquinone imine). NAPQI is normally detoxified by glutathione conjugation. In overdose (>150 mg/kg or >7.5 g in adults), glutathione stores are depleted (below 30% of normal), and excess NAPQI binds covalently to hepatocyte mitochondrial proteins, causing mitochondrial dysfunction, oxidative stress, and massive hepatocellular necrosis (zone 3 centrilobular pattern — highest CYP2E1 concentration). N-acetylcysteine (NAC) is the antidote: it replenishes glutathione stores, provides alternative sulfhydryl groups for NAPQI detoxification, enhances sulfate conjugation, and has anti-inflammatory/antioxidant effects. The Rumack-Matthew nomogram guides NAC treatment decisions for timed acute ingestions. ALF causes multi-organ dysfunction: coagulopathy (impaired synthesis of clotting factors II, V, VII, IX, X — INR is the best prognostic marker), cerebral edema (ammonia-induced astrocyte swelling, may cause brain herniation), hepatorenal syndrome, hypoglycemia (depleted hepatic glycogen, impaired gluconeogenesis), and SIRS/sepsis (impaired Kupffer cell function and complement synthesis).