Acetaminophen toxicity

Background

• Most common cause of acute liver failure in the United States and UK
• Found in >600 OTC and prescription products (Tylenol, Percocet, Vicodin, NyQuil, etc.)
• Therapeutic dose: 10-15 mg/kg per dose (max 4g/day in adults; 2g/day in chronic alcoholics)
• Toxic dose: >150 mg/kg (single ingestion) or > 7.5 g total in adults
• Mechanism:
  • Normal metabolism: 90% glucuronidation/sulfation → nontoxic → renally excreted
  • ~5% oxidized by CYP2E1 → NAPQI (toxic metabolite) → detoxified by glutathione
  • In overdose: glucuronidation/sulfation saturated → excess NAPQI production → glutathione depletion → hepatocellular necrosis
• N-acetylcysteine (NAC) is a glutathione precursor and is nearly 100% effective when given within 8 hours of ingestion

Risk Factors for Enhanced Toxicity

• Chronic alcohol use (CYP2E1 induction + depleted glutathione stores)
• Fasting / malnutrition (depleted glutathione)
• CYP2E1 inducers: isoniazid, phenobarbital, carbamazepine, rifampin
• Lower threshold for treatment in these patients

Clinical Features

Four Stages of Toxicity

• Stage 1 (0-24h): Often asymptomatic or nonspecific (nausea, vomiting, anorexia, diaphoresis)
• Stage 2 (24-72h): RUQ pain, elevated transaminases, rising INR; may appear to improve clinically
• Stage 3 (72-96h): Peak hepatotoxicity — markedly elevated AST/ALT (can exceed 10,000), coagulopathy, jaundice, acute kidney injury, hepatic encephalopathy
  • Fulminant hepatic failure: cerebral edema, DIC, multi-organ failure, death
• Stage 4 (4-14 days): Recovery phase in survivors (hepatocytes regenerate)

Chronic/Repeated Supratherapeutic Ingestion

• More common than acute overdose in clinical practice
• Presents with hepatotoxicity without early Stage 1 symptoms
• Rumack-Matthew nomogram does NOT apply
• Treat based on APAP level + ALT elevation

Differential Diagnosis

• Viral hepatitis
• Alcoholic hepatitis
• Other drug-induced hepatitis
• Ischemic hepatitis (shock liver)
• Wilson disease (acute presentation)
• Amanita phalloides (mushroom) poisoning
• Salicylate toxicity
• Other ingestions causing liver failure

Evaluation

• Serum APAP level: draw at 4 hours post-ingestion (or immediately if >4 hours)
  • Plot on Rumack-Matthew nomogram at time since ingestion
  • Treatment line: starts at 150 mcg/mL at 4 hours (US uses this; original line at 200)
  • Below treatment line = low risk; above = treat with NAC
• AST/ALT: may be normal initially; any elevation warrants NAC
• INR/PT: coagulopathy = hepatic failure; INR is the best prognostic marker
• BMP: creatinine (renal injury occurs in ~25% of severe cases), bicarbonate, glucose
• Lipase, bilirubin, CBC
• Salicylate level (coingestion screening)
• Lactate: elevated lactate = poor prognosis
• VBG/ABG: pH <7.30 after resuscitation = poor prognosis

King's College Criteria (Liver Transplant Referral)

• Acetaminophen-induced ALF:
  • pH <7.30 after adequate fluid resuscitation (regardless of grade of encephalopathy) OR
  • All three: INR >6.5, creatinine >3.4 mg/dL, and Grade III-IV hepatic encephalopathy
• Consider early transfer to a liver transplant center

Management

GI Decontamination

• Activated charcoal 1 g/kg (max 50g) if within 1-2 hours of ingestion and patient is alert with protected airway
• May benefit up to 4 hours post-ingestion
• Do NOT delay NAC for charcoal

N-Acetylcysteine (NAC) — The Antidote

• Give NAC if:
  • APAP level above treatment line on Rumack-Matthew nomogram
  • Time of ingestion unknown and APAP level detectable
  • Elevated transaminases with history of APAP ingestion
  • Ingestion of > 150 mg/kg and level will not be available within 8 hours
  • Any doubt → give NAC (minimal side effects, potentially life-saving)

IV NAC Protocol (21-hour Protocol — Preferred)

• Loading dose: 150 mg/kg IV in 200 mL D5W over 60 minutes (or 15 minutes if used to be over 15 min)
• Second infusion: 50 mg/kg IV in 500 mL D5W over 4 hours
• Third infusion: 100 mg/kg IV in 1000 mL D5W over 16 hours
• Total: 300 mg/kg over 21 hours
• Anaphylactoid reactions (flushing, urticaria, bronchospasm) most common during loading dose
  • Slow or pause infusion; treat with antihistamines/bronchodilators; do not stop NAC permanently

Oral NAC Protocol (72-hour)

• Loading dose: 140 mg/kg PO
• Maintenance: 70 mg/kg PO every 4 hours × 17 additional doses
• Total: 1,330 mg/kg over 72 hours
• Mixed with cola or juice to improve palatability
• If patient vomits within 1 hour of dose, repeat the dose

Two-Bag Modified Prescott Protocol

• Some centers use a simplified 2-bag protocol: 200 mg/kg IV over 4 hours then 100 mg/kg IV over 16 hours
• Lower rate of anaphylactoid reactions

When to Stop NAC

• APAP level undetectable, AST/ALT normalizing/improving, INR ≤1.3, clinically well
• If AST/ALT still elevated or INR elevated: continue NAC beyond standard protocol

Fulminant Hepatic Failure

• Continue IV NAC indefinitely (has benefit even in established liver failure)
• Contact liver transplant center early
• Manage: coagulopathy (FFP only if active bleeding), cerebral edema (elevate HOB, hypertonic saline, mannitol), hypoglycemia, infection, electrolyte imbalances

Disposition

• Admit if NAC initiated, elevated transaminases, or altered mental status
• ICU for evidence of liver failure (coagulopathy, encephalopathy, acidosis, renal failure)
• Consider discharge if:
  • APAP level below treatment line at ≥4 hours post-ingestion
  • Normal AST/ALT, INR, creatinine
  • 4-6 hour observation complete
  • Psychiatric evaluation for intentional ingestions
• Poison control: 1-800-222-1222

See Also

• Toxicology
• Acute liver failure
• Salicylate toxicity
• Hepatic encephalopathy

References

• Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359(3):285-292. PMID 18635433
• Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002;40(1):3-20. PMID 11990202
• Chun LJ, et al. Acetaminophen hepatotoxicity and acute liver failure. J Clin Gastroenterol. 2009;43(4):342-349. PMID 19169150