Paracetamol

Paracetamol toxicity causes acute liver injury due to ↑ levels of its toxic metabolite NAPQI due to failure of conjugation with glutathione. This can occur due to either:

Epidemiology and Risk Factors

Pathophysiology

Paracetamol is metabolised by two pathways:

  • Conjugation with glucuronide sulfates
    Normal metabolic pathway (~95% of a therapeutic dose) that produces non-toxic metabolites which are renally cleared.
  • CYP450 2E1 to NAPQI
    • Minor metabolic pathway under normal circumstances
    • Produces hepatotoxic NAPQI
    • NAPQI is conjugated with hepatic glutathione to non-toxic metabolites which are renally cleared
    • Absence of glutathione leads to accumulation of NAPQI
    • NAPQI covalently binds multiple proteins, leading to uncoupled oxidative phosphorylation and hepatic cell death

Aetiology

Risk Factors for Toxicity
↓ Hepatic Glutathione Cytochrome P450 Induction

Malnourishment:

  • Anorexia nervosa
  • Bulimia
  • Malnourishment

Antiepileptics:

  • Phenytoin
  • Carbamazepine
  • Phenobarbital

Disease:

  • HIV
  • Cystic Fibrosis

Other:

  • Rifampicin
  • Chronic ETOH

Clinical Features

Often asymptomatic in the first 24-48 hours; may then develop liver failure.

Gastrointestinal:

  • Abdominal pain
  • Nausea
  • Vomiting

Severe toxicity:

  • Coma
  • Lactic metabolic acidosis

Assessment

History:

  • Dose
  • Formulation ingested
  • Timing
    • Single ingestion
    • Staggered ingestion
    • Repeated ingestion

Exam:

Investigations

Bedside:

Laboratory:

Imaging:

Other:

Diagnostic Approach and DDx

Management

  • Activated charcoal
  • NAC
  • Liver transplant if fulminant hepatic failure

Resuscitation:

Specific therapy:

Prescottt Nomogram

  • Pharmacological
    • Activated charcoal
      Appropriate if:
      • Immediate release within 2 hours
      • Modified release within 4 hours
    • N-acetylcysteine (NAC)
      Stimulates glutathione stimulus, allowing NAPQI to be conjugated.
      • Prescott nomogram indicates when NAC therapy should be given
        • >200mg/kg or 10g in a one-off ingestion should receive NAC independent of level
        • Inaccurate in sustained-release preparations
          Empirical NAC NAC should be given in this circumstance.
      • Early administration results in significant reduction in mortality (to <1%), though even late administration may improve outcome.
      • 150mg/kg load over 15-60 minutes
      • 50mg/kg over 4 hours
      • 100mg/kg over 16 hours
      • Further doses may be indicated (usually 150mg/kg over 24 hours)
      • NAC may be ceased after 24 hours if:
        • Paracetamol concentration <10mg/L
        • ALT <50U/L
        • INR <2
        • Clinically well
  • Procedural
    • Liver transplant
      Referral indicated for:
      • SBP <80mmHg
      • Hypoglycaemia
      • Encephalopathy
      • pH <7.3 following resuscitation
      • Oliguria
      • Creatinine >200μmol/L
      • INR >4.5
      • INR >3 for 48 hours
  • Physical

If in doubt, give NAC.

Supportive care:

Disposition:

Marginal and Ineffective Therapies

Anaesthetic Considerations

Complications

Prognosis

Severe hepatic injujry has ~10% mortality.

Key Studies

References

  1. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.