Pathophysiology: NAPQI Toxicity

Normal metabolism: ~90% of acetaminophen conjugated by glucuronidation and sulfation → non-toxic. ~5% metabolized by CYP2E1 → NAPQI (N-acetyl-p-benzoquinone imine) — highly reactive toxic metabolite. NAPQI is normally conjugated by glutathione → harmless. Overdose: glutathione stores depleted → NAPQI accumulates → covalent binding to hepatocyte proteins → centrilobular necrosis (zone 3 of liver, highest CYP2E1 activity). Risk factors for increased toxicity at lower doses: chronic alcohol use (induces CYP2E1 + depletes glutathione), fasting/malnutrition (depletes glutathione), CYP2E1-inducing drugs (isoniazid, rifampin).

Clinical Stages

Stage 1 (0–24h): nausea, vomiting, malaise — minimal or no symptoms; hepatotoxicity not yet apparent. Stage 2 (24–72h): RUQ pain + elevated AST/ALT (can exceed 10,000 IU/L) + INR rising; clinical improvement of initial GI symptoms may mislead. Stage 3 (72–96h): peak hepatotoxicity — AST/ALT peak, INR >2, bilirubin rising, possible fulminant hepatic failure (encephalopathy, coagulopathy, jaundice, renal failure from hepatorenal syndrome). Stage 4 (4–14 days): recovery or death. AST/ALT very high but ASPARTATE-rich hepatocyte necrosis hallmark — AST often > ALT (unlike viral hepatitis). Renal failure: acute tubular necrosis from NAPQI direct toxicity to proximal tubules.

Rumack-Matthew Nomogram and NAC Protocol

Rumack-Matthew nomogram: plot serum acetaminophen level (drawn at ≥4h post-ingestion) against time post-ingestion on a semi-log plot. Treatment line: if level plots above the treatment line (150 mcg/mL at 4h → 37.5 mcg/mL at 12h) → treat with NAC. Below treatment line: no treatment needed. NAC (N-acetylcysteine): mechanism — replenishes glutathione stores + directly detoxifies NAPQI. Oral NAC (preferred): 140 mg/kg loading dose, then 70 mg/kg q4h × 17 doses. IV NAC (use for vomiting, pregnancy, or hepatic failure): 150 mg/kg IV over 1h, then 50 mg/kg over 4h, then 100 mg/kg over 16h. Efficacy: near-complete protection if given within 8h; still beneficial if given later (reduces mortality in established liver failure). NAC for unknown ingestion time or delayed presentation: treat empirically if level detectable.