What are the clinical features of paracetamol (Acetaminophen) toxicity?

Clinical Features of Paracetamol (Acetaminophen) Toxicity

Paracetamol toxicity primarily affects the liver and can progress from mild hepatic dysfunction to severe hepatotoxicity and even fatal liver failure, with clinical manifestations typically developing over several days following ingestion. 1, 2

Toxic Dose Thresholds

• Single acute ingestions of ≥150 mg/kg or ≥10 grams in adults are considered potentially toxic and require medical evaluation 1
• Repeated supratherapeutic ingestions (RSTI) totaling ≥10 grams or 200 mg/kg over 24 hours, or ≥6 grams or 150 mg/kg per day for 48 hours or longer are potentially toxic 1
• Even therapeutic doses of 4 g/day for 14 days can cause elevations of ALT >3 times normal in 31-41% of healthy adults 1
• Severe hepatotoxicity has been reported with doses as low as 3-4 grams per day in susceptible individuals 1

Clinical Course and Manifestations

• Stage 1 (0-24 hours post-ingestion):

  • Nausea, vomiting, malaise, pallor, and diaphoresis 2, 3
  • Laboratory values may be normal or show early elevation of transaminases 3

• Stage 2 (24-72 hours post-ingestion):

  • Right upper quadrant pain and tenderness 4, 3
  • Progressive elevation of liver enzymes (AST, ALT) 2, 3
  • Prolongation of prothrombin time 3
  • Oliguria and elevated creatinine may indicate renal injury 5, 3

• Stage 3 (72-96 hours post-ingestion):

  • Peak hepatotoxicity with maximum elevation of transaminases typically occurring 48-96 hours after ingestion 2, 3
  • Jaundice, coagulopathy, and hypoglycemia 3
  • Hepatic encephalopathy with asterixis and global neurological dysfunction 6
  • Acute kidney injury may develop 5, 7

• Stage 4 (4 days to 2 weeks):

  • Resolution of hepatotoxicity or progression to liver failure 2, 3
  • In severe cases, multi-organ failure, cerebral edema, and death 3

Risk Factors for Increased Toxicity

• Chronic alcohol consumption significantly increases risk of hepatotoxicity, even at therapeutic doses 1, 5
• Pre-existing liver disease 1
• Fasting or malnutrition 7
• Medications that induce cytochrome P450 2E1 enzyme system 7

Important Clinical Considerations

• Paracetamol overdose does not typically cause focal neurological deficits; if present, consider alternative causes 6
• Hepatic encephalopathy presents with asterixis and global neurological dysfunction rather than focal deficits 6
• Rhabdomyolysis may occur in patients with prolonged immobility after overdose 6
• Renal toxicity occurs in approximately 1-2% of patients with paracetamol overdose and is more common with chronic ingestion 5, 7

Laboratory Findings

• Elevated serum paracetamol levels (interpreted using the Rumack-Matthew nomogram) 2
• Elevated liver enzymes (AST, ALT) with peak levels typically 48-96 hours post-ingestion 2, 3
• Prolonged prothrombin time/INR and elevated bilirubin in severe cases 3
• Elevated creatinine and blood urea nitrogen in cases with renal involvement 5
• Metabolic acidosis in severe cases 3

Treatment Indicators

• N-acetylcysteine (NAC) treatment should be initiated for any patient with acetaminophen levels above the treatment line on the nomogram 1, 8
• NAC should be initiated for any patient with suspected acetaminophen ingestion with signs of liver injury (elevated transaminases) 1, 8
• Early treatment with NAC (within 10 hours of ingestion) is most effective in preventing hepatotoxicity 7, 8

Understanding these clinical features is essential for early recognition and appropriate management of paracetamol toxicity to prevent progression to severe hepatotoxicity and liver failure.