Overview
Acute Liver Failure
1. Clinical Overview
Summary
Acute liver failure (ALF) is a rare but devastating syndrome characterised by rapid-onset hepatic dysfunction, coagulopathy (INR ≥1.5), and hepatic encephalopathy in patients without pre-existing liver disease. In the UK, paracetamol overdose is the leading cause (>50%), followed by drug-induced liver injury, viral hepatitis, and autoimmune hepatitis. Without liver transplantation, mortality approaches 80%. The King's College Criteria guide transplant listing. Management requires early transfer to a specialist liver unit, intensive care support, and N-acetylcysteine for paracetamol toxicity.
Key Facts
- Definition: Coagulopathy (INR ≥1.5) + Encephalopathy + No prior liver disease + <26 weeks illness
- Classification: Hyperacute (<7 days), Acute (7-21 days), Subacute (21-26 days)
- UK Leading Cause: Paracetamol overdose (>50%)
- Antidote: N-acetylcysteine (NAC) - even for non-paracetamol causes
- Transplant Criteria: King's College Criteria
- Survival: 60-80% with transplant; 15-20% without (if criteria met)
Clinical Pearls
"N-AC for EVERYONE": NAC improves outcomes even in non-paracetamol ALF. Give it empirically while determining aetiology.
"Encephalopathy = Liver Unit": Any ALF with encephalopathy requires immediate discussion with a liver transplant centre. Transfer early.
"Low Blood Sugar, High Suspicion": Hypoglycaemia reflects loss of hepatic gluconeogenesis. Check glucose hourly and replace with 10% dextrose.
"Cerebral Oedema Kills": The main cause of death in ALF is cerebral oedema leading to brain herniation. Watch for posturing, pupil changes, hypertension.
Why This Matters Clinically
ALF is a medical emergency with very narrow window for intervention. Early recognition, NAC administration, and transfer to a specialist liver unit are life-saving.
2. Epidemiology
Incidence
- 1-6 per million per year (UK)
- ~2000 cases/year (US)
- Accounts for 6% of liver-related deaths
Aetiology
| Cause | UK Frequency | Notes |
|---|---|---|
| Paracetamol OD | >0% | Most common in UK; often intentional |
| Drug-induced (non-paracetamol) | 10-15% | Antibiotics, NSAIDs, anti-epileptics |
| Viral hepatitis | 10% | Hep A, B, E; rare Hep C |
| Autoimmune hepatitis | 5% | Often presents as ALF |
| Wilson's disease | <5% | Young patient, Coombs-negative haemolysis |
| Ischaemic/Budd-Chiari | <5% | Hypotension, hepatic vein thrombosis |
| Pregnancy-related | <5% | AFLP, HELLP |
| Seronegative (unknown) | 15-20% | Despite full workup |
Prognosis by Aetiology
- Paracetamol: Better prognosis (spontaneous survival 50-60%)
- Non-paracetamol: Poorer prognosis (spontaneous survival 15-20%)
3. Pathophysiology
Mechanism of Liver Failure
- Massive hepatocyte necrosis → Loss of synthetic function
- Loss of clotting factors → Coagulopathy
- Loss of gluconeogenesis → Hypoglycaemia
- Loss of ammonia clearance → Encephalopathy
- Loss of lactate clearance → Lactic acidosis
Hepatic Encephalopathy Pathophysiology
- Ammonia accumulates → Crosses blood-brain barrier
- Astrocyte swelling → Cerebral oedema
- Intracranial pressure rises → Brain herniation
Multi-Organ Dysfunction
- Cardiovascular: Hyperdynamic, low SVR (sepsis-like)
- Renal: Hepatorenal syndrome, ATN
- Respiratory: ARDS, pulmonary oedema
- Coagulation: Coagulopathy but also DIC risk
- Metabolic: Hypoglycaemia, hyponatraemia, metabolic acidosis
4. Clinical Presentation
Symptoms
Signs
Hepatic Encephalopathy Grading
| Grade | Clinical Features |
|---|---|
| I | Mild confusion, altered behaviour, sleep disturbance |
| II | Drowsiness, lethargy, disorientation, asterixis |
| III | Stupor, gross confusion, incoherent, still rousable |
| IV | Coma, unresponsive to pain |
Signs of Cerebral Oedema
Non-specific initially
Fatigue, nausea, anorexia
Jaundice (may develop rapidly)
Common presentation.
Confusion, drowsiness (encephalopathy)
Common presentation.
Right upper quadrant pain (liver stretching)
Common presentation.
Bruising/bleeding (coagulopathy)
Common presentation.
5. Clinical Examination
Systematic Approach
| System | Assessment |
|---|---|
| Neurological | GCS, pupil responses, asterixis, tone |
| Abdominal | Liver size (shrinking liver = bad), tenderness, ascites |
| Skin | Jaundice, bruising, petechiae |
| Cardiovascular | Hypotension, tachycardia |
Red Flags for Poor Prognosis
- Shrinking liver (suggests massive necrosis)
- Grade III-IV encephalopathy
- Refractory hypoglycaemia
- Rising lactate despite resuscitation
- Worsening coagulopathy despite vitamin K
6. Investigations
Bloods
| Test | Purpose | Notes |
|---|---|---|
| INR/PT | Coagulopathy assessment | Key prognostic marker |
| LFTs | ALT/AST usually >000 | May fall as liver necroses |
| Bilirubin | Rising = poor prognosis | |
| Albumin | Synthetic function | Falls |
| Ammonia | Encephalopathy risk | Often elevated |
| Lactate | Prognosis | >.5 post-resuscitation = poor |
| Glucose | Hypoglycaemia monitoring | Check hourly |
| U&E | Renal function, sodium | Watch for hepatorenal |
| ABG | pH, lactate | pH <7.3 = poor prognosis in paracetamol |
Aetiology Workup
| Test | Purpose |
|---|---|
| Paracetamol level | Even if denied |
| Viral hepatitis serology | HAV, HBV, HCV, HEV, EBV, CMV, HSV |
| Autoimmune markers | ANA, SMA, IgG |
| Caeruloplasmin/copper | Wilson's disease |
| Pregnancy test | If applicable |
| Toxicology screen | If unclear history |
Imaging
- USS liver: Liver size, hepatic veins (Budd-Chiari), nodularity
- CT head: If encephalopathy to exclude other pathology
- Doppler: Hepatic/portal vein patency
7. Management
Immediate Management
┌──────────────────────────────────────────────────────────┐
│ ACUTE LIVER FAILURE MANAGEMENT │
├──────────────────────────────────────────────────────────┤
│ 1. STABILISE │
│ - Airway protection (intubate if GCS ≤8) │
│ - IV access + fluids (avoid saline, use balanced) │
│ - Catheter + fluid balance │
│ │
│ 2. START N-ACETYLCYSTEINE │
│ - Even if not paracetamol (improves outcomes) │
│ - 150mg/kg over 1h → 50mg/kg over 4h → 100mg/kg over 16h│
│ │
│ 3. CONTACT LIVER TRANSPLANT CENTRE │
│ - EARLY! Before patient deteriorates │
│ - Transfer if grade 2+ encephalopathy │
│ │
│ 4. SUPPORTIVE CARE │
│ - 10% dextrose (prevent hypoglycaemia) │
│ - Vitamin K 10mg IV (but transfuse only if bleeding) │
│ - PPI │
│ - Lactulose for encephalopathy │
│ - Avoid sedatives │
└──────────────────────────────────────────────────────────┘
King's College Criteria (Transplant Listing)
Paracetamol-Induced:
- pH <7.3 after resuscitation OR
- All three: INR >6.5 + Creatinine >300 + Grade 3/4 encephalopathy
Non-Paracetamol:
- INR >6.5 OR
- Any three of: Age <10 or >40, Non-A Non-B hepatitis, Drug-induced, Jaundice to encephalopathy >7 days, INR >3.5, Bilirubin >300
ICU Management
- Intracranial pressure monitoring (if grade 3-4)
- Mannitol for cerebral oedema
- Renal replacement therapy (continuous preferred)
- Avoid hyperthermia
- Prophylactic antibiotics (high infection risk)
8. Complications
Neurological
- Cerebral oedema (40% of grade 4 encephalopathy)
- Brain herniation (major cause of death)
- Seizures
Systemic
- Multi-organ failure
- Sepsis (50% develop infection)
- Acute kidney injury / Hepatorenal syndrome
- Hypoglycaemia
- Coagulopathy / DIC
- GI bleeding
Post-Transplant
- Rejection
- Infection
- Biliary complications
9. Prognosis & Outcomes
Survival
- With transplant: 60-80% 1-year survival
- Without transplant (if criteria met): 15-20%
- Spontaneous survival (paracetamol): 50-60%
- Spontaneous survival (non-paracetamol): 15-20%
Prognostic Factors
| Good Prognosis | Poor Prognosis |
|---|---|
| Paracetamol aetiology | Seronegative/drug-induced |
| Hyperacute presentation | Subacute presentation |
| Young age | Age >0 |
| Early NAC | Delayed presentation |
| Lower peak INR | INR >.5 |
| pH >.3 | pH <7.3 |
10. Evidence & Guidelines
Key Guidelines
- AASLD Position Paper: Acute Liver Failure (2011, updated 2017)
- EASL Clinical Practice Guidelines: ALF (2017)
- BSG/BASL Guidance on ALF
Key Evidence
NAC in Non-Paracetamol ALF (Lee 2009)
- RCT: NAC vs placebo in non-paracetamol ALF
- Improved transplant-free survival in early encephalopathy (grade 1-2)
- No benefit in grade 3-4
King's College Criteria
- PPV for death without transplant: 70-90%
- NPV: 25-50% (some survive despite meeting criteria)
11. Patient/Layperson Explanation
What is Acute Liver Failure?
Acute liver failure is when the liver suddenly stops working properly, usually over days to weeks, in someone who previously had a healthy liver. The liver is essential for clearing toxins, making clotting factors, and regulating blood sugar.
What Causes It?
In the UK, the most common cause is paracetamol overdose. Other causes include reactions to medications, viral infections (hepatitis), and autoimmune conditions.
What Are the Symptoms?
Early symptoms are often vague:
- Feeling unwell, nausea, tiredness
- Yellowing of eyes and skin (jaundice)
- Confusion or drowsiness (a worrying sign)
How is it Treated?
- If caused by paracetamol: An antidote called N-acetylcysteine (NAC)
- Intensive care support for organs
- In severe cases: Liver transplantation may be life-saving
Prevention
- Never exceed the recommended dose of paracetamol
- Be aware of paracetamol content in combination medicines
- Avoid alcohol when taking paracetamol
12. References
Primary Guidelines
- Lee WM, et al. AASLD Position Paper: The Management of Acute Liver Failure: Update 2011. Hepatology. 2012;55(3):965-967.
- EASL. Clinical Practical Guidelines on the Management of Acute (Fulminant) Liver Failure. J Hepatol. 2017.
Key Studies
- Bernal W, et al. Acute liver failure. Lancet. 2010;376(9736):190-201. PMID: 20638564
- Lee WM, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137(3):856-864. PMID: 19524577