Acute liver failure: recognising the emergency and transferring immediately

What acute liver failure is

Acute liver failure (ALF) is one of the most time-compressed emergencies in medicine — a healthy liver can fail completely within days, and the progression from jaundice to coma to death can be measured in hours once cerebral oedema establishes. The definition, per AASLD 2023 and EASL 2017, is:

Acute liver injury producing INR ≥1.5 AND hepatic encephalopathy of any grade, in a patient without pre-existing chronic liver disease, within 26 weeks of jaundice or first liver-injury symptom.

Without liver transplantation, mortality is 60–80%. With transplantation at an expert centre, one-year survival approaches 70%. The GP role is to recognise the syndrome before encephalopathy becomes irreversible, call for ambulance transfer, call the Poisons Information Centre (13 11 26) if paracetamol is involved, and start IV N-acetylcysteine (NAC) if indicated — before the patient deteriorates.

ALF subtypes by time course

The O’Grady classification by jaundice-to-encephalopathy interval carries important prognostic implications:

Subtype	Interval	Typical cause	Cerebral oedema	Transplant-free survival
Hyperacute	<7 days	Paracetamol, ischaemia, HAV, HSV	Very high	Relatively good
Acute	8–28 days	HBV, HEV, autoimmune	Intermediate	Poor
Subacute	29 days–12 weeks	DILI, autoimmune, indeterminate	Lower	Worst

Hyperacute ALF (paracetamol) paradoxically has the best transplant-free survival because rapid hepatocyte regeneration is possible when the toxic insult is removed early.

A. Core clinical — the AU general-practice framework

Australian aetiology

• Paracetamol (~40–50%) — the leading cause in Australia, United Kingdom, and United States
  • Accidental staggered ingestion more common than single deliberate overdose — chronic pain, dental pain, viral illness with stacked paracetamol-containing products; patients often do not realise they have exceeded safe limits
  • Risk-modifying factors that increase hepatotoxicity at lower doses: chronic alcohol use (CYP2E1 induction), malnutrition or prolonged fasting (glutathione depletion), concurrent CYP-inducing medications (isoniazid, rifampicin, carbamazepine, phenytoin)
• Idiosyncratic drug-induced liver injury (DILI) (~10–15%) — augmentin (amoxicillin-clavulanate), flucloxacillin, isoniazid, anti-epileptics, herbal preparations (kava, comfrey, black cohosh, Chinese herbal “cocktails”), nitrofurantoin; any temporal association between a new medication and liver injury warrants assessment
• Viral hepatitis (~10–12%) — HBV reactivation (rituximab, chemotherapy), acute HBV, HAV (unvaccinated), HEV (rising in Australia; imported and locally acquired; particularly severe in pregnancy), HSV (often anicteric; markedly elevated transaminases; pregnancy and immunocompromise)
• Autoimmune hepatitis (~5%) — acute presentation without prior diagnosis
• Vascular — Budd-Chiari syndrome, ischaemic hepatitis (“shock liver”)
• Metabolic — Wilson’s disease (young patient, Coombs-negative haemolytic anaemia, low ALP:bilirubin ratio), acute fatty liver of pregnancy (AFLP), HELLP syndrome
• Amanita phalloides (“death cap” mushroom) — foraging history; GI prodrome 6–24 hours, then a deceptive “honeymoon period” of apparent clinical improvement 1–3 days, followed by fulminant liver failure; well-documented cluster in Canberra region
• Indeterminate (~10%)

Staggered paracetamol thresholds

For staggered ingestion (no discrete single-ingestion time zero), Poisons Information guidance identifies the following as hepatotoxicity risk thresholds requiring NAC consideration:

• More than 10 g or 200 mg/kg over 24 hours
• More than 12 g or 300 mg/kg over 48 hours
• More than 150 mg/kg per day for 2 or more consecutive days

Lower thresholds apply when risk-modifiers are present (see above). Call 13 11 26 for case-specific guidance — the Poisons Information Centre is available 24 hours per day, 7 days per week.

Clinical presentation

Jaundice + altered mental status + coagulopathy = acute liver failure until proven otherwise.

• Progressive jaundice (may develop rapidly in hyperacute cases)
• Hepatic encephalopathy — asterixis (flapping tremor), confusion, agitation, drowsiness; a subtle change from baseline is sufficient for the ALF diagnosis
• Coagulopathy — spontaneous bruising, mucosal bleeding, prolonged bleeding from venepuncture sites
• Hypoglycaemia — depleted hepatic glycogen stores; may be profound and recurrent
• Right upper quadrant tenderness or hepatomegaly (or diminishing liver size in fulminant cases)
• Ascites — more prominent in subacute presentations

Critical sign: ammonia >150 µmol/L predicts cerebral oedema and intracranial hypertension — particularly relevant in hyperacute paracetamol-induced ALF with grade III–IV encephalopathy.

B. Immediate GP assessment and transfer

The immediate flowsheet

In any patient with jaundice plus confusion or coagulopathy:

1. Call 000 — Category 1 ambulance transfer to the nearest liver transplant centre ED; simultaneously call the transplant centre hepatology fellow or liver unit on-call to pre-alert them
2. Blood sugar level — check immediately; if hypoglycaemic, administer IV 10% dextrose (not 50% dextrose bolus) and plan continuous infusion
3. IV access × 2 and collect bloods: FBC, UEC, LFT, INR/PT, fibrinogen, blood glucose, ammonia, paracetamol level (a 4-hour post-ingestion level AND a repeat 4 hours later), ABG, lactate, lipase, urine β-hCG (women of reproductive age), blood cultures
4. IV N-acetylcysteine — start if any paracetamol toxicity is plausible (see below); do not wait for results
5. Nil oral intake — aspiration risk from encephalopathy; IV fluids only
6. GCS and neurological baseline — document GCS score; any deterioration is an emergency

N-acetylcysteine (NAC)

Start IV NAC without delay if any of the following apply:

• Paracetamol level above the Rumack-Matthew nomogram treatment line (for acute single-ingestion)
• Staggered paracetamol ingestion meeting toxicity thresholds (regardless of current level)
• Delayed presentation (>24 hours after ingestion) — levels may have cleared but hepatotoxicity is established
• INR rising and/or transaminases >1,000 U/L with no other clear cause
• Paracetamol is among the possible ingested substances and clinical presentation is consistent

Lee Gastroenterology 2009 demonstrated improved transplant-free survival for NAC in non-paracetamol ALF with grade I–II encephalopathy as well — widening the indication beyond paracetamol-confirmed cases. The risk of NAC is anaphylactoid reaction in approximately 15%; manage by temporarily stopping the infusion, treating urticaria/bronchospasm, and restarting at a slower rate once settled. The benefit in paracetamol toxicity is substantial.

Standard IV NAC regimen: 150 mg/kg in 200 mL 5% dextrose over 60 minutes (loading dose), followed by 50 mg/kg in 500 mL over 4 hours, followed by 100 mg/kg in 1,000 mL over 16 hours. Consult the Poisons Information Centre (13 11 26) or eTG for precise dosing.

King’s College Criteria — when to list for transplant

The King’s College Criteria (O’Grady Gastroenterology 1989) identify patients unlikely to survive without transplantation:

Paracetamol ALF:

• Arterial pH <7.3 after resuscitation (regardless of encephalopathy grade), OR
• All three of: creatinine >300 µmol/L + PT >100 seconds + grade III–IV encephalopathy

Non-paracetamol ALF:

• INR >6.5 (regardless of encephalopathy grade), OR
• Any three of five: age <10 or >40 years; aetiology of non-A non-B hepatitis or idiosyncratic DILI; jaundice-to-encephalopathy interval >7 days; INR >3.5; bilirubin >300 µmol/L

Contact the transplant centre before these thresholds are fully met — early referral is essential for timely listing and organ procurement.

Do not correct the INR prophylactically

The INR is the primary monitoring tool for ALF progression and the key metric in King’s College Criteria. Fresh frozen plasma (FFP) should only be given for active bleeding or before an invasive procedure — not to correct the INR in a stable patient. Prophylactic FFP normalises the INR, obscures disease trajectory, and prevents accurate assessment of listing criteria. This is a firm AASLD 2023 and EASL 2017 recommendation.

C. Specialist management overview

High-volume plasma exchange (HVPE)

Larsen J Hepatol 2016 demonstrated that high-volume plasma exchange (8–12 litres of plasma daily for 3 days) in patients with ALF reduced systemic inflammatory response and improved transplant-free survival compared with standard medical therapy. This intervention is not universally available but is offered at several Australian transplant centres for patients meeting criteria. Contact the transplant unit to discuss suitability.

Liver transplantation

Liver transplantation offers approximately 70% one-year survival for ALF with transplantation, compared with 20–40% for non-paracetamol ALF without transplant. Contraindications to transplantation (assessed by the multidisciplinary transplant team) include uncontrolled extrahepatic infection, severe hypoxic ischaemia, sustained intracranial hypertension, and multi-organ failure beyond the point of liver recovery.

Specific antidotes and additional therapies

• HSV hepatitis — IV acyclovir empirically in any pregnant patient or immunocompromised patient with ALF and markedly elevated transaminases; HSV can cause anicteric or minimally jaundiced ALF with AST/ALT in the thousands
• Amanita phalloides — IV penicillin G (high-dose, binds amatoxin), silibinin (silymarin, not readily PBS-listed in Australia), early aggressive supportive care; liver transplantation is required in severe cases
• Autoimmune hepatitis ALF — corticosteroids may be considered by the specialist team in early-stage autoimmune ALF before encephalopathy is advanced; the decision is nuanced and specialist-directed
• Wilson’s disease — D-penicillamine or trientine, supportive care, urgent transplant evaluation; the combination of haemolytic anaemia, low ALP, and ALF in a young patient is the key diagnostic cluster

D. Australian operations

Liver transplant referral

Contact the hepatology fellow or liver transplant coordinator on-call at the nearest Australian liver transplant programme:

• Austin Health, Heidelberg VIC — Victoria’s primary liver transplant programme
• Royal Prince Alfred Hospital, Sydney NSW — major national programme
• Liverpool Hospital, Sydney NSW — additional NSW site
• Princess Alexandra Hospital, Brisbane QLD — Queensland programme
• Sir Charles Gairdner Hospital, Perth WA — Western Australia programme

Early referral — before King’s College Criteria are fully met — allows the transplant team time to assess the patient, obtain cross-matching, and list before irreversible deterioration occurs.

MBS items relevant to ALF workup

• MBS 65070 — serum paracetamol level (Authority for suspected toxicity)
• MBS 66500 — INR/prothrombin time
• MBS 73529 — ammonia
• MBS 56507/56807 — CT abdomen for vascular aetiology (Budd-Chiari, hepatic artery thrombosis)
• MBS 55036/55054 — liver ultrasound with Doppler
• MBS 23/36/44 — emergency consultation items appropriate to the level of complexity

PBS

• IV N-acetylcysteine — PBS Authority item for paracetamol toxicity in hospitals; the prescribing clinician (usually emergency department) completes the form; GPs should not delay transfer to arrange PBS access — NAC is available in hospital
• Rifaximin — PBS Authority for hepatic encephalopathy
• IV acyclovir — PBS-listed for HSV; administer empirically in qualifying patients without awaiting serology results

Notifiable diseases

The following hepatitis diagnoses are notifiable in all Australian states and territories: hepatitis A, hepatitis B, hepatitis C, hepatitis E. Notify the relevant state public health unit when a new viral hepatitis aetiology is confirmed. Death from ALF is reportable to the coroner when cause of death is uncertain or death is unexpected.

Poisons Information Centre

The Australian Poisons Information Centre (13 11 26) is the primary clinical resource for all paracetamol dosing queries — including staggered ingestion, co-ingestion with alcohol or interacting medicines, and delayed presentations. Available 24 hours per day, 7 days per week. Call before calculating NAC eligibility independently from the nomogram in any non-standard presentation.

E. Special populations

Pregnancy — AFLP, HELLP, and HSV

Three distinct pregnancy-associated ALF presentations require urgent specialist involvement:

• Acute fatty liver of pregnancy (AFLP) — third trimester; microvesicular steatosis; DIC; hypoglycaemia; fetal distress; management is immediate delivery once the diagnosis is made or strongly suspected, followed by supportive care; the liver recovers post-partum in most cases
• HELLP syndrome — haemolysis, elevated liver enzymes, low platelets; also third trimester and post-partum; management is delivery; hepatic haematoma and rupture are life-threatening complications
• HSV hepatitis in pregnancy — often anicteric; AST/ALT markedly elevated (>1,000 U/L); prodrome of fever, malaise, and mucocutaneous lesions may be absent; empirical IV acyclovir should be started immediately when HSV ALF is suspected in any pregnant patient — do not wait for HSV serology or PCR

Amanita phalloides (death cap mushroom) poisoning

Amanita phalloides is the most dangerous wild mushroom in Australia; most poisonings occur in migrant communities foraging for familiar-looking mushrooms. The amatoxin (α-amanitin) mechanism involves deceptive latency:

1. Latent period — no symptoms for 6–24 hours after ingestion (toxin absorbed silently)
2. GI phase — abdominal pain, vomiting, diarrhoea for 12–24 hours
3. Apparent recovery (“honeymoon period”) — 1–3 days of seeming improvement; extremely dangerous because patients and clinicians may be falsely reassured
4. Hepatorenal failure — days 3–7; fulminant liver failure, AKI, DIC

Any patient reporting ingestion of wild mushrooms who presents with GI illness should be referred to hospital immediately. Call Poisons Information (13 11 26).

Wilson’s disease

Wilson’s disease (autosomal-recessive copper accumulation) can present as acute liver failure in children and young adults. The diagnostic cluster: young age + Coombs-negative haemolytic anaemia + ALF + low ALP despite severe liver injury + Kayser-Fleischer rings (not always present acutely). Low ALP in the context of jaundice and liver failure is highly suggestive of Wilson’s. Ceruloplasmin is often low but can be falsely normal in acute inflammation. Urgent liver transplant evaluation is required in Wilson’s ALF — medical chelation alone is insufficient.

Suicidality after deliberate paracetamol overdose

Deliberate paracetamol overdose requires concurrent mental health assessment alongside the medical emergency. Engage the hospital psychiatric liaison team early. The period of medical treatment — when the patient is physically recovering — is high-risk for further impulsive acts. Any patient who presents after deliberate self-harm should have a formal psychiatric risk assessment before discharge from any level of care, regardless of the medical outcome of the overdose.

When to escalate

• Jaundice + any confusion, agitation, or altered consciousness → call 000; this is acute liver failure until proven otherwise; do not treat empirically and review in 24 hours
• Progressive jaundice + rising INR in any patient, even without encephalopathy → same-day emergency referral; ALF can deteriorate from early encephalopathy to coma within hours
• Staggered paracetamol ingestion above thresholds → call Poisons Information 13 11 26 and start IV NAC; transfer to hospital
• Any known or suspected Amanita phalloides ingestion → emergency hospital transfer immediately; the GI phase and honeymoon period precede liver failure by days
• Pregnant patient with markedly elevated transaminases + fever → empirical IV acyclovir for HSV; emergency obstetric and hepatology involvement
• Acute hepatitis B or E in an unwell patient → monitor closely for encephalopathy and coagulopathy; early transfer if either develops
• Post-overdose psychiatric risk → psychiatric liaison assessment before discharge, regardless of medical trajectory

What this article is and is not

This article provides a general-practice recognition and emergency management framework for acute liver failure in Australia, drawing on AASLD 2023 Practice Guidance, EASL 2017 Clinical Practice Guidelines, King’s College Criteria (O’Grady 1989), Lee Gastroenterology 2009 on NAC in non-paracetamol ALF, Larsen J Hepatol 2016 on high-volume plasma exchange, Therapeutic Guidelines (eTG), and RACGP. All definitive treatment decisions — transplant listing, IVIg dosing, plasma exchange, antidote selection — are made by the specialist transplant hepatology and intensive care team. Nothing in this article constitutes clinical advice for any individual patient.

For paracetamol dosing advice: call Poisons Information Centre 13 11 26 (24/7). For acute emergency: call 000.

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Sources cited

1. AASLD 2023 Practice Guidance — Acute liver failure (Shingina et al. Hepatology 2023)
2. EASL 2017 — Clinical Practice Guidelines on the management of Acute (Fulminant) Liver Failure
3. O’Grady JG et al. — King’s College Criteria for liver transplantation in ALF. Gastroenterology 1989;97:439
4. Lee WM et al. — Intravenous N-acetylcysteine improves transplant-free survival in non-acetaminophen ALF. Gastroenterology 2009;137:856
5. Larsen FS et al. — High-volume plasma exchange in patients with ALF. J Hepatol 2016;64:69
6. Lee WM — Acetaminophen-related acute liver failure in the United States. Hepatology 2004;40:6
7. Australian Poisons Information Centre — 13 11 26
8. eTG complete — Acute liver failure
9. RACGP — Liver disease in general practice
10. GESA — Hepatology guidance and position statements