Key Facts

Acute liver failure is a rare but life-threatening emergency requiring early recognition and prompt referral to a specialist liver centre. Paracetamol toxicity is the commonest cause in the UK and is eminently treatable if identified early.

Epidemiology

ALF affects ~2,000 patients per year in the UK. Paracetamol accounts for ~50% of cases. Approximately 10-15% of ALF patients require emergency liver transplantation. Mortality without transplant in severe ALF is 40-80% depending on cause.

Aetiology

• Paracetamol overdose (~50% in UK): staggered and single overdoses
• Drug-induced liver injury (DILI): antibiotics (co-amoxiclav, flucloxacillin, isoniazid), anti-epileptics, NSAIDs, herbal/supplements
• Viral hepatitis: hepatitis A, B (including reactivation), E; rare: HSV, CMV, EBV
• Autoimmune hepatitis: acute presentation
• Wilson disease: fulminant presentation (rare but important — young patients)
• Vascular: Budd-Chiari syndrome, ischaemic hepatitis (shock liver)
• Pregnancy-related: AFLP (acute fatty liver of pregnancy), HELLP syndrome
• Indeterminate: ~15-20% of cases

Pathophysiology

Massive hepatocyte necrosis overwhelms the liver's regenerative capacity. Loss of hepatic function causes: (1) coagulopathy (reduced clotting factor synthesis); (2) encephalopathy (accumulation of ammonia, inflammatory mediators, failure of hepatic metabolism); (3) metabolic derangements (hypoglycaemia, lactic acidosis); (4) immune dysfunction (susceptibility to infection — leading cause of death if survive initial phase); (5) cerebral oedema (ammonia-induced astrocyte swelling — leading cause of death in hyperacute ALF).

Progression

• Non-specific prodrome: malaise, nausea, vomiting, anorexia, abdominal pain
• Jaundice: may be absent in hyperacute (paracetamol)
• Coagulopathy: bruising, bleeding
• Encephalopathy: confusion → drowsiness → coma (West Haven grades I-IV)
• Cerebral oedema: hypertension, bradycardia, abnormal pupils (late signs — Cushing reflex)

Organ Failure

• Renal: AKI (hepatorenal syndrome, ATN, paracetamol direct toxicity)
• Cardiovascular: hypotension, high cardiac output, low SVR
• Respiratory: ARDS, pulmonary oedema
• Metabolic: hypoglycaemia, lactic acidosis, hyponatraemia
• Infection: 80% develop infection within first week (often occult — fungal infections common)

Red Flags

• INR >1.5 with encephalopathy (= ALF by definition)
• pH <7.30 after fluid resuscitation (paracetamol — King's College criterion)
• Rapidly rising INR and bilirubin
• Shrinking liver on serial examination
• Grade III-IV encephalopathy (GCS <8)
• Renal failure requiring dialysis

Bedside

• GCS/West Haven encephalopathy grade: serial assessment
• Blood glucose: frequent monitoring (risk of hypoglycaemia)
• ABG/VBG: pH, lactate (prognostic)

Bloods

• LFTs: very high ALT/AST (often >1000 in paracetamol, ischaemic); bilirubin
• INR/PT: key prognostic marker — rising INR indicates worsening
• U&Es, creatinine: AKI monitoring
• FBC: coagulopathy assessment
• Ammonia: correlates with encephalopathy severity (>150 μmol/L = high cerebral oedema risk)
• Lactate: prognostic (>3.5 mmol/L at 4 hours post-paracetamol = severe)
• Paracetamol level: within 4-16 hours of ingestion; staggered overdoses may have low/undetectable levels despite severe toxicity
• Aetiology screen: hepatitis A/B/C/E serology, autoantibodies (ANA, SMA), immunoglobulins, caeruloplasmin (Wilson), HSV/CMV/EBV PCR, drug screen, pregnancy test
• Phosphate: paradoxically low phosphate in paracetamol ALF suggests liver regeneration (good prognostic sign)

Imaging

• USS abdomen with Doppler: hepatic vein patency (Budd-Chiari), liver size, ascites
• CT head: if encephalopathy worsening (exclude intracranial pathology; cerebral oedema may not be visible on CT until late)

Special Tests

• King's College Criteria: determine transplant listing urgency
• Intracranial pressure monitoring: in selected grade III-IV encephalopathy patients (specialist centres only)
• Liver biopsy: rarely performed in ALF (coagulopathy risk); may be done transjugularly if diagnosis uncertain

Non-pharmacological

• Contact liver transplant centre EARLY — do NOT wait for encephalopathy to develop
• ICU admission: all patients with ALF and encephalopathy
• Head elevation 30°: reduce intracranial pressure
• Avoid unnecessary stimulation: grade III-IV encephalopathy
• Blood glucose monitoring: hourly; treat hypoglycaemia with 10% dextrose infusion

Pharmacological

• Paracetamol ALF:
  • N-acetylcysteine (NAC): IV protocol — 150 mg/kg over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours; continue until INR improving
  • NAC also beneficial in non-paracetamol ALF (improves transplant-free survival — Lee et al., Gastroenterology 2009)
• Cerebral oedema: mannitol 0.5-1 g/kg IV (if ICP rising), hypertonic saline (target Na 145-150 mmol/L), avoid hyperthermia
• Coagulopathy: do NOT correct INR unless active bleeding or pre-procedure (INR is a prognostic marker — correcting it obscures assessment)
• Infection: low threshold for broad-spectrum antibiotics + antifungals; surveillance cultures
• Renal support: CVVHDF if AKI
• Specific treatments: penicillamine/trientine for Wilson disease; antivirals for HBV reactivation; delivery for AFLP/HELLP

Surgical/Interventional

• Emergency liver transplantation: life-saving for those meeting King's College Criteria; 1-year post-transplant survival ~80%
• Super-urgent transplant listing: UK criteria (different from King's) — prioritises patients who will die imminently without transplant

Referral Criteria

• Contact specialist liver centre immediately for all suspected ALF
• Transfer criteria: INR >2, encephalopathy of any grade, pH <7.30, renal failure, hypoglycaemia
• Do NOT delay transfer waiting for deterioration

Paracetamol ALF: overall survival ~60-70% (better than non-paracetamol); with transplant ~80% 1-year survival. Non-paracetamol ALF: survival ~40% without transplant. Hyperacute ALF (e.g. paracetamol) has paradoxically better prognosis than subacute ALF (which has higher encephalopathy risk and lower spontaneous recovery rate). King's College Criteria: positive predictive value ~90% for death without transplant. Spontaneous recovery occurs in ~40-50% of paracetamol ALF and ~20% of non-paracetamol ALF.

King's College Criteria

Paracetamol ALF:

• pH <7.30 after resuscitation (irrespective of encephalopathy grade)
• OR ALL three of: grade III-IV encephalopathy + INR >6.5 + creatinine >300 μmol/L

Non-Paracetamol ALF:

• INR >6.5 (irrespective of encephalopathy grade)
• OR ANY three of: age <10 or >40 + unfavourable aetiology (DILI, seronegative, Wilson) + jaundice >7 days before encephalopathy + INR >3.5 + bilirubin >300 μmol/L

West Haven Encephalopathy Grading