What is the management for paracetamol (acetaminophen)-induced liver injury with elevated liver enzymes and hyperbilirubinemia?

Management of Paracetamol-Induced Liver Injury with Elevated Liver Enzymes and Hyperbilirubinemia

N-acetylcysteine (NAC) should be administered immediately in all patients with acetaminophen-induced liver injury with elevated liver enzymes and hyperbilirubinemia, regardless of the time since ingestion, as it significantly reduces mortality and progression of liver failure. 1

Initial Assessment and Management

• Admit patients with acetaminophen-induced liver injury to an intensive care unit for close monitoring 1
• Contact a transplant center early in the evaluation process for potential transfer of appropriate patients 1
• Determine the precise etiology and pattern of liver injury to guide management decisions 1
• Obtain baseline laboratory tests including:
  • Liver function tests (ALT, AST, alkaline phosphatase, GGT, total and direct bilirubin) 1
  • Coagulation studies (prothrombin time/INR) 1
  • Renal function tests (creatinine, BUN) 1
  • Electrolytes, glucose, and arterial blood gases 1
  • Acetaminophen level (even if time of ingestion is remote) 1

N-acetylcysteine (NAC) Administration

• Begin NAC promptly in all patients with acetaminophen-induced liver injury, even if more than 48 hours have passed since ingestion 1
• NAC administration options:
  • Oral route: 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 doses (diluted to 5% solution) 1, 2
  • Intravenous route (if oral administration is precluded by gastrointestinal bleeding or worsening mental status): 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours 1
• For patients presenting within 4 hours of ingestion, administer activated charcoal (1 g/kg) just prior to starting NAC 1

Monitoring and Follow-up

• Repeat liver function tests, coagulation studies, and electrolytes daily if acetaminophen levels are in the potentially toxic range 2
• Monitor for signs of hepatic encephalopathy and other complications of liver failure 1
• Assess for direct vs. indirect hyperbilirubinemia:
  • When hyperbilirubinemia is due to drug-induced liver injury (DILI), the fraction of direct bilirubin is usually greater than 35% 1
  • Consider Gilbert's syndrome if unconjugated (indirect) bilirubin predominates (less than 20-30% conjugated) 1
• For patients with prolonged INR, consider vitamin K deficiency and administer parenteral vitamin K supplementation before assigning causality to liver failure 1

Special Considerations

• Risk factors for acetaminophen hepatotoxicity at therapeutic doses include:
  • Fasting for ≥1 day 3
  • Excess alcohol consumption 3
  • Repeated acetaminophen use over several days 3
  • Malnutrition 4
• Acetaminophen hepatotoxicity can occur with doses as low as 3-4 g/day in susceptible individuals 1
• Very high aminotransferases (exceeding 3,500 IU/L) are highly correlated with acetaminophen poisoning 1
• Patients with acetaminophen-induced liver injury at therapeutic doses have more severe liver injury and lower 30-day survival compared to overdose cases 3

Prognosis and Transplantation Considerations

• Independent predictors of poor outcome include:
  • Older age 3
  • Presence of King's College Hospital criteria 3
• Early contact with a transplant center is essential for appropriate patients 1
• The pattern of unconjugated vs. conjugated hyperbilirubinemia may reflect the extent of liver injury, but there is insufficient data to use this as a definitive prognostic factor 5

Common Pitfalls to Avoid

• Do not wait for acetaminophen levels before initiating NAC in patients with suspected acetaminophen-induced liver injury 1, 2
• Do not rely solely on the standard acetaminophen toxicity nomogram, as it cannot exclude possible toxicity due to multiple doses over time or altered metabolism in alcoholic or fasting patients 1
• Do not assume low or absent acetaminophen levels rule out acetaminophen poisoning, as the time of ingestion may be remote or unknown 1
• Do not withhold NAC in cases of acute liver failure where acetaminophen ingestion is possible but unconfirmed 1