Key Facts

Paracetamol overdose is the most common cause of acute liver failure and the most frequent reason for calls to the National Poisons Information Service in the UK. Timely treatment with NAC prevents hepatotoxicity in the vast majority of cases.

Epidemiology

Approximately 80,000-100,000 paracetamol overdose presentations to UK EDs annually. ~200 deaths/year from paracetamol poisoning. It is the most common cause of acute liver failure in the UK and USA. ~75% of cases are intentional self-harm; ~25% accidental (therapeutic excess in those taking regular paracetamol for pain).

Aetiology

• Intentional self-harm: Most common — often impulsive, may take multiple medications
• Therapeutic excess (supratherapeutic ingestion): Taking more than recommended dose for pain — often staggered over hours/days; particularly dangerous as nomogram cannot be used
• Accidental: Children accessing medications

Pathophysiology

Paracetamol is normally metabolised in the liver via glucuronidation and sulphation (~95%). A small proportion (~5%) is metabolised by CYP2E1 to the toxic metabolite NAPQI (N-acetyl-p-benzoquinone imine), which is normally detoxified by conjugation with glutathione. In overdose, glutathione is depleted, and NAPQI accumulates causing hepatocellular necrosis (predominantly zone 3 — centrilobular). NAC replenishes glutathione and directly detoxifies NAPQI.

Timeline of Paracetamol Toxicity

Phase 1 (0-24h): Often asymptomatic or mild nausea/vomiting; normal LFTs

Phase 2 (24-72h): Right upper quadrant pain, rising ALT and INR, oliguria

Phase 3 (72-96h): Peak hepatotoxicity — jaundice, coagulopathy, encephalopathy, renal failure, metabolic acidosis, hypoglycaemia. Multi-organ failure in severe cases.

Phase 4 (4-14 days): Recovery phase in survivors — liver regeneration

Risk Factors for Enhanced Toxicity

• Chronic alcohol use (CYP2E1 induction, glutathione depletion)
• Malnutrition, eating disorders (glutathione depletion)
• Enzyme-inducing drugs (carbamazepine, phenytoin, rifampicin)
• HIV infection

Red Flags

• Staggered overdose — cannot use nomogram; treat with NAC if >75mg/kg
• pH <7.3 after resuscitation — indicates severe toxicity (King's criteria)
• INR >3 at 48h or rising beyond 72h — progressive liver failure
• Encephalopathy — grade III/IV indicates need for transplant assessment
• Metabolic acidosis + renal failure + coagulopathy — high mortality without transplant

Bedside

• History: Time of ingestion (CRITICAL), amount taken, preparation (standard vs modified-release), co-ingestions, staggered vs acute
• Observations: Often normal initially

Bloods

• Paracetamol level: At 4 hours post-ingestion (do NOT take before 4h) — plot on treatment nomogram
• ALT: Hepatocellular injury marker — check at presentation and 12-24h
• INR/PT: Coagulation — most sensitive early marker of synthetic liver function
• Creatinine: Renal function
• ABG/VBG: pH — acidosis is a key prognostic indicator
• Venous bicarbonate: Screen for acidosis
• Blood glucose: Hypoglycaemia in severe hepatotoxicity
• Phosphate: Low = good prognosis (liver regeneration); high = poor
• Lactate: Elevated in severe toxicity

Imaging

• Liver USS: If diagnostic uncertainty or suspected chronic liver disease

Special Tests

• Paracetamol-protein adducts: Research tool — can confirm paracetamol toxicity when history unreliable
• TOXBASE: Consult for dosing guidance and nomogram interpretation

Non-pharmacological

• Activated charcoal 50g PO: If within 1 hour of ingestion and airway intact
• Do NOT induce vomiting

Pharmacological

N-Acetylcysteine (NAC) — Modified Prescott Regimen:

• Bag 1: 100mg/kg in 200mL 5% glucose over 1 hour
• Bag 2: 50mg/kg in 500mL 5% glucose over 4 hours
• Bag 3: 100mg/kg in 1000mL 5% glucose over 16 hours
• Total treatment time: 21 hours

Indications for NAC:

• Acute ingestion: Paracetamol level above treatment line on nomogram (single line at 100mg/L at 4h)
• Staggered ingestion (over >1h): NAC if ≥75mg/kg ingested — do NOT use nomogram
• Presentation >8 hours with significant ingestion: Start NAC immediately, do not wait for level
• Clinical features of hepatotoxicity at any stage

NAC anaphylactoid reaction:

• Occurs in ~15-20%, usually within first hour
• Symptoms: Flushing, urticaria, bronchospasm, nausea
• Management: Pause infusion, give chlorphenamine 10mg IV; restart at slower rate once symptoms resolve
• TRUE anaphylaxis to NAC is extremely rare

Post-NAC assessment:

• At end of NAC course: Check ALT, INR, creatinine, paracetamol level
• If ALT rising, INR >1.3, paracetamol still detectable, or clinical concern → continue NAC (bag 3 rate)

Surgical/Interventional

• Liver transplant: For fulminant hepatic failure meeting King's College Criteria
• Referral to specialist hepatology/transplant centre if: pH <7.3, INR >3 at 48h, creatinine >300, encephalopathy, hypoglycaemia

Referral Criteria

• ALT >1000 or rising steeply — hepatology/transplant centre discussion
• INR >3 at 48h or any time rising — transplant centre assessment
• Metabolic acidosis (pH <7.3 after resuscitation) — immediate transplant centre referral
• Encephalopathy — transfer to transplant centre
• ALL intentional overdoses — psychiatric assessment before discharge

• NAC within 8 hours: Hepatotoxicity prevented in >95% of cases; mortality <0.5%
• NAC at 8-24 hours: Reduces severity of hepatotoxicity but does not prevent it entirely
• Without treatment: Mortality ~5-10% overall; higher with staggered overdose
• Fulminant hepatic failure: Mortality ~50% without transplant; ~80% survival with transplant
• King's College Criteria: Identifies patients who will die without transplant with ~90% specificity
• Complete liver recovery: Liver regenerates fully in survivors within 2-4 weeks

Paracetamol Treatment Nomogram

King's College Criteria for Paracetamol-Induced Liver Failure

NAC Infusion Summary (Modified Prescott)