Paracetamol-Induced Liver Injury

Paracetamol induced liver injury results from the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which depletes glutathione and damages hepatocytes.

• Acute toxicity: single ingestion above 150 mg/kg or 12 g, whichever is lower, in adults (children: above 200 mg/kg; staggered doses over 8 hours or more are also treated).
• Chronic or repeated supratherapeutic ingestion: more than 4 g daily for 2 days or more (lower threshold with malnutrition, alcohol use, enzyme-inducing drugs such as rifampicin, isoniazid, phenytoin and carbamazepine, and fasting).
• It is a major cause of acute liver failure and of intentional self-poisoning.

Stage 1 (0 to 24 hours): asymptomatic, or nausea and vomiting, malaise.

• Stage 2 (24 to 72 hours): right upper quadrant pain and tenderness, rising ALT and INR.
• Stage 3 (72 to 96 hours): peak liver injury with jaundice, coagulopathy, hypoglycaemia, encephalopathy, lactic acidosis, renal failure.
• Stage 4: recovery or death.
• Differential diagnosis: other drug-induced liver injury, viral hepatitis, ischaemic hepatitis, mushroom poisoning, Budd-Chiari syndrome, heat stroke, acute fatty liver of pregnancy, Wilson disease, sepsis.
• Complications: acute liver failure, cerebral oedema, acute kidney injury, pancreatitis, metabolic acidosis, cardiovascular collapse, infection, death, and (rarely) isolated renal failure.

Time of ingestion and amount; psychiatric assessment for intentional overdose.

• Serum paracetamol level at 4 hours or later after ingestion; plot on a treatment nomogram; treat if the concentration is at or higher than the treatment threshold of 100 mg/L at 4 hours falling to 15 mg/L at 15 hours (patients with risk factors are treated at the same threshold).
• ALT, AST, bilirubin, INR, creatinine, electrolytes, lactate, venous gas, glucose, phosphate, full blood count; repeat at 12 to 24 hours.
• Co-ingestants: salicylate level, ethanol, ECG.

Supportive: airway and cardiovascular support, glucose monitoring, antiemetics (ondansetron 4 to 8 mg IV), correction of electrolytes, fluids.

Pharmacological

• Activated charcoal 50 g (1 g/kg children) orally if within 1 hour of a large ingestion with a protected airway.
• N-acetylcysteine IV (the antidote, started at once if timing is uncertain, staggered, or within 8 hours if level is high): 150 mg/kg in 200 mL of 5 percent dextrose over 1 hour, then 50 mg/kg in 500 mL over 4 hours, then 100 mg/kg in 1000 mL over 16 hours (total 300 mg/kg over 21 hours); cap weight at 110 kg.
• Oral N-acetylcysteine alternative: 140 mg/kg loading then 70 mg/kg every 4 hours for 17 doses.
• Continue the infusion beyond 21 hours (100 mg/kg over 16 hours) if the ALT is rising, INR is above 1.3, paracetamol is still detectable, or in presentation after 8 hours with liver injury.
• Anaphylactoid reaction to N-acetylcysteine: stop the infusion, give chlorphenamine 10 mg IV and salbutamol if bronchospasm, then restart at a slower rate.
• Acute liver failure: lactulose, mannitol 0.5 g/kg or hypertonic saline for cerebral oedema, vitamin K 10 mg IV, and early transplant referral.
• Transplant referral indications: arterial pH below 7.30 after fluid resuscitation, or INR above 6.5 with creatinine above 300 micromol/L and grade 3 or 4 encephalopathy, or rising lactate above 3 mmol/L.

Special groups: pregnancy (treat without delay, as treatment protects the fetus), children (dose by weight), chronic alcohol users and malnourished (treated at the same threshold, starting acetylcysteine early when the level is uncertain), unknown time of ingestion (treat).

Red flags: encephalopathy, INR above 3, creatinine rise, lactate above 3 mmol/L, hypoglycaemia, pH below 7.30.

Follow-up: psychiatric assessment before discharge, ALT and INR until normal, limit access to paracetamol packs (package size reduction), counsel on safe dose (maximum 4 g daily, 2 g daily with risk factors).