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Anna Lee & Charles Gomersall

Updated June 2006

Mechanism of toxicity

  • hepatic glucuronide and sulphate depleted following paracetamol OD with a consequent increase in P450 catalysed oxidation. This leads to an increased production of the reactive arylating metabolite N- acetyl-p- benzoquinoneimine (NAPQI). This is usually rendered non-toxic by conjugation with glutathione; a capacity also reduced following paracetamol OD
  • NAPQI causes cellular damage by extensive arylation of cellular proteins and oxidative stress from redox cycling
  • damaged hepatocytes release factors which attract and activate hepatic macrophages resulting in cell necrosis.

Predisposing factors

  • Increased p450 activity : enzyme inducers – smoking, barbiturates, phenytoin, Isonazid, ethanol
  • Decreased glutathione stores : malnutrition – alcoholism, HIV, chronic disease

Clinical presentation

  • Toxic dose >150mg/kg ; massive overdose >1g/kg
  • Phase1 (0.5-24h)

    • minimal symptoms; metabolic acidosis in massive overdose

  • Phase2 (24-72h)

    • RUQ pain, elevation of hepatic enzymes. 25% of hepatotoxic patients have impaired renal function

  • Phase3 (72-96h)

    • marked hepatic dysfunction including hepatic encephalopathy. Death is related to hepatic failure

  • Phase4 (4-14 days)

    • resolution of hepatic dysfunction


  • gastric lavage and activated charcoal only of benefit within 4 hours of ingestion
  • N-acetylcysteine (NAC) for:
    • patients with paracetamol level above or just below treatment line
    • all patients with potentially hepatotoxic overdose (> 150 mg/kg). Treatment can be stopped if paracetamol concentration is below standard treatment line but this approach avoids potentially fatal delays in treatment
    • all paracetamol ingestions who present late (>24 hours) with either detectable serum paracetamol or elevated tansaminases

    • chronic large ingestions (>4g/day in adult, >120mg/kg/day in children) especially those who are at high risk and have elevated transaminase

    • all patients with evidence of severe toxicity or fulminant hepatic failure, regardless of time since overdose. Continue or start NAC 150mg/kg/day until recovery from encephalopathy or patient dies
    • high risk patients (eg chronic alcohol abusers, malnutrition, HIV infection) with depleted hepatic glutathione, patients on enzyme inducing drugs (eg rifampicin, anticonvulsants, alcohol): start treatment at paracetamol levels half those of the standard treatment line
    • patients unable to give a reliable history or who have taken a sequential overdose over several hours
  • protection of NAC is 100% if given within 8 hrs of ingestion

  • hypersensitivity to N-acetylcysteine is common (6-23%), but usually mild. Reduce dose to 150 mg/kg over 20 hours, give IV antihistamines and hydrocortisone
  • refer to specialist liver unit if INR > 2 at 24 hrs, 4 at 48 hrs or 6 at 72 hrs or if patient develops: hypoglycaemia, renal failure, acidosis, hypotension or encephalopathy
  • liver transplantation when patient estimated to have < 10% chance of survival without transplantation:
    • pH < 7.3 OR
    • PT > 100, creatinine > 300 mcmol/l, grade III/IV encephalopathy

Extended Relief Preparation

  • No firm data on overdose management

  • Get a level a least 4 hours post ingestion

    • If the level is over nomogram line, treat with full course of NAC

    • If the level is under nomogram line, repeat in 4 hours

      • If it is over the nomogram line, treat with full course of NAC

      • If it is still under the nomogram line, no therapy

© Anna Lee & Charles Gomersall June 2006

©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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