Acute Liver Failure

Acute liver failure (ALF) is a catastrophic, potentially reversible syndrome of rapid hepatocellular dysfunction in a patient without pre-existing liver disease, defined by the triad of coagulopathy (INR ≥ 1.5), hepatic encephalopathy, and jaundice evolving within 26 weeks. It is a true medical emergency where the central killer is cerebral oedema and where early identification of transplant candidacy (King's College criteria) decides survival.

Definition & classification

ALF (older term: fulminant hepatic failure) requires all three:

1. Coagulopathy — INR ≥ 1.5 (PT prolongation).
2. Encephalopathy — any grade of altered mentation of hepatic origin.
3. Onset within 26 weeks of the first symptom, in a patient with a previously normal liver.

High-yield: Coagulopathy without encephalopathy is acute liver injury (ALI), not ALF. The presence of encephalopathy is what converts injury into "failure."

Exceptions where ALF is accepted despite "chronic" disease: Wilson disease, vertically acquired HBV, and autoimmune hepatitis presenting acutely — because they may have been clinically silent.

O'Grady (King's College) temporal classification

This time-based scheme matters because the faster the onset, the higher the risk of cerebral oedema but, paradoxically, the better the spontaneous survival (because the cause is usually paracetamol/ischaemia).

Subtype	Jaundice → encephalopathy interval	Typical cause	Cerebral oedema	Spontaneous survival
Hyperacute	< 7 days	Paracetamol, ischaemia, HAV/HEV	Very common	Best (good)
Acute	7–28 days	Acute HBV, autoimmune	Common	Intermediate
Subacute	28 days – 12 weeks (up to 26 wk)	Drug-induced (non-paracetamol), seronegative	Uncommon	Worst (poor) — often needs transplant

High-yield: Counter-intuitively, subacute ALF has the worst prognosis and least cerebral oedema, while hyperacute has the best spontaneous recovery despite the most oedema.

(Bernuau's older terms: fulminant = <2 weeks; subfulminant = 2–8 weeks.)

Etiology

Cause varies sharply by geography — a favourite exam discriminator.

Setting	Most common cause
West / USA / UK	Paracetamol (acetaminophen) overdose (~45% in USA, ~half in UK)
India & developing world	Viral hepatitis — especially Hepatitis E (HEV)
Pregnancy (India)	Hepatitis E (mortality up to 20–30%)
Young patient + haemolysis + low ALP	Wilson disease

Key causes to memorise:

• Drugs/toxins: paracetamol (dose-dependent), anti-TB drugs (isoniazid, rifampicin, pyrazinamide), halothane, valproate, Amanita phalloides (death-cap mushroom), phenytoin, ecstasy, herbal/CAM products.
• Viral: HEV (commonest in India), HAV, HBV (± HDV co/superinfection), rarely HSV/CMV/EBV (immunocompromised), VZV.
• Vascular/ischaemic: "shock liver," Budd–Chiari syndrome, ischaemic hepatitis.
• Metabolic/pregnancy: acute fatty liver of pregnancy (AFLP), HELLP syndrome.
• Miscellaneous: Wilson disease, autoimmune hepatitis, malignant infiltration (lymphoma, breast), heat stroke, sepsis.

High-yield: HEV is the commonest cause of ALF in India and the leading cause in pregnancy, whereas paracetamol is the commonest in the West. This single fact is asked repeatedly.

Mnemonic for ALF causes — "VITAMINS": Viral, Ischaemia, Toxins (paracetamol, mushroom), Autoimmune, Metabolic (Wilson, AFLP), Infiltration (malignancy), Neoplasm/Budd-Chiari, Sepsis.

Pathophysiology

Massive hepatocyte death (necrosis ± apoptosis) → loss of synthetic, metabolic and detoxifying functions.

• Coagulopathy: reduced synthesis of clotting factors (II, V, VII, IX, X) → ↑ INR. Factor V and factor VII (shortest half-life) fall earliest; Factor VIII is normal/high (made by endothelium), distinguishing ALF from DIC.
• Encephalopathy & cerebral oedema: failure to clear ammonia → astrocytes convert glutamate + ammonia to glutamine (Warburg/osmole) → astrocyte swelling → cytotoxic cerebral oedema → raised ICP → herniation. Arterial ammonia > 150–200 µmol/L strongly predicts intracranial hypertension.
• Systemic: a SIRS-like vasodilated, hyperdynamic state → functional multi-organ failure (renal, circulatory), hypoglycaemia (loss of gluconeogenesis/glycogen), lactic acidosis, and immunoparesis → sepsis.

Paracetamol mechanism: therapeutic doses are conjugated; in overdose, glucuronidation/sulphation saturate and CYP2E1 produces toxic NAPQI, which depletes glutathione and binds hepatocyte proteins → centrizonal (zone 3) necrosis. N-acetylcysteine (NAC) replenishes glutathione.

Clinical features

• Prodrome: malaise, nausea, anorexia, RUQ pain.
• Jaundice — may be modest in hyperacute paracetamol cases.
• Hepatic encephalopathy — graded below; the defining feature.
• Coagulopathy — bruising, oozing from puncture sites.
• Cerebral oedema — the leading cause of death: rising ICP, systolic hypertension + bradycardia (Cushing reflex), sluggish pupils, decerebrate posturing, abnormal brain-stem reflexes, papilloedema (late/unreliable).
• Hypoglycaemia, lactic acidosis, hyperdynamic circulation (warm peripheries, low SVR), AKI (hepatorenal/ATN), and rapid progression to sepsis.

High-yield: A small, shrinking liver with rapidly rising bilirubin and a falling transaminase (hepatocytes "burnt out") signals massive necrosis — a poor sign, not recovery.

West Haven grades of hepatic encephalopathy

Grade	Mental state	Asterixis	EEG
I	Mild confusion, euphoria, altered sleep, ↓ attention	Mild/absent	Usually normal
II	Lethargy, disorientation to time, inappropriate behaviour	Present (obvious)	Generalised slowing, triphasic waves
III	Marked confusion, somnolent but rousable, gross disorientation	Present (if cooperative)	Abnormal, triphasic waves
IV	Coma (unresponsive ± to pain)	Absent	Delta activity

High-yield: Cerebral oedema and raised ICP correlate with advanced grades (III–IV); intracranial hypertension is rare in grades I–II. Progression to grade III/IV mandates ICU and intubation for airway protection.

Diagnosis & investigation of choice

ALF is a clinical + biochemical diagnosis; investigations confirm severity and hunt the cause.

Stepwise approach: Confirm coagulopathy + encephalopathy → prove no chronic liver disease → identify aetiology (history, paracetamol level, viral & autoimmune serology, ceruloplasmin) → assess severity/prognosis (INR, lactate, ammonia, creatinine) → apply transplant criteria.

• LFTs: very high AST/ALT (often >1000, can reach 5000–10000 in paracetamol/ischaemia), rising bilirubin.
• Coagulation: PT/INR is the single most important prognostic marker and must be tracked serially. Do not routinely correct it unless bleeding/procedure, as it guides prognosis.
• Glucose (hypoglycaemia), U&E/creatinine, arterial ammonia, arterial lactate, ABG, FBC, blood cultures.
• Aetiology screen: paracetamol level + nomogram, anti-HEV IgM, IgM anti-HAV, HBsAg + IgM anti-HBc, anti-HCV, autoimmune markers (ANA, ASMA, IgG), serum ceruloplasmin + 24-h urinary copper + slit-lamp for Kayser–Fleischer rings (Wilson), pregnancy test.
• Imaging: USG Doppler of liver/portal & hepatic veins (rule out Budd–Chiari, assess liver size, malignancy).
• Investigation of choice for diagnosing aetiology when uncertain: transjugular liver biopsy (avoids coagulopathy risk of percutaneous route) — e.g. suspected malignant infiltration, autoimmune, HSV.

High-yield (Wilson disease clue): Alkaline phosphatase : total bilirubin ratio < 4 AND AST : ALT ratio > 2.2 strongly suggest Wilsonian ALF. Also: Coombs-negative haemolytic anaemia + low/normal ALP + low uric acid in a young patient.

Management — supportive ICU care + cause-specific therapy

ALF is managed in an ICU, ideally a liver transplant centre (early transfer before grade III). Care has two arms: specific antidotes and organ support / preventing complications.

Specific (cause-directed) therapy — drugs of choice

Cause	Specific treatment
Paracetamol	N-acetylcysteine (NAC) — drug of choice; give even if late/uncertain dose
Amanita (mushroom)	Penicillin G + silibinin (silymarin) ± NAC
HSV/VZV hepatitis	IV aciclovir
HBV	Nucleos(t)ide analogue — tenofovir / entecavir
AFLP / HELLP	Urgent delivery of the fetus
Wilson disease	Liver transplant (chelation too slow for ALF); plasma exchange to bridge
Autoimmune hepatitis	Corticosteroids (limited role once ALF established)
Budd–Chiari	Anticoagulation ± TIPS, transplant

High-yield: NAC improves transplant-free survival in non-paracetamol ALF too (early grades I–II), so it is given empirically in most ALF — not only paracetamol poisoning.

General organ support

• Encephalopathy/ICP: nurse head-up 30°, avoid stimulation; intubate at grade III–IV; hyperosmolar therapy with mannitol (or hypertonic saline) for raised ICP; prophylactic hypertonic saline to keep Na⁺ 145–150 mmol/L; short-term hyperventilation for surges; consider therapeutic hypothermia (32–34 °C) as a bridge. Lactulose has a limited/uncertain role in ALF (unlike chronic liver disease) and may cause bowel distension.
• Coagulopathy: correct only if active bleeding or before invasive procedure (FFP, platelets, vitamin K); otherwise preserve INR for prognostication. Stress-ulcer prophylaxis (PPI).
• Haemodynamic: fluids; noradrenaline for refractory hypotension; vasopressin/terlipressin as adjunct (caution — may raise ICP).
• Renal: continuous (not intermittent) renal replacement therapy — CRRT preferred to avoid ICP swings; also clears ammonia.
• Metabolic: treat hypoglycaemia (10% dextrose infusion), correct electrolytes/phosphate; enteral nutrition with adequate protein (do not protein-restrict).
• Infection: low threshold for broad-spectrum antibiotics ± antifungals and surveillance cultures (sepsis is a major killer and a contraindication to transplant).
• Liver support / definitive: emergency (super-urgent) liver transplantation is the only intervention proven to alter mortality once criteria are met. Plasma exchange (high-volume) improves transplant-free survival and bridges to transplant. MARS/albumin dialysis — adjunctive bridging only.

King's College Criteria (prognosis → transplant listing)

The most-tested table in this topic — identifies patients unlikely to survive without transplant.

A) Paracetamol-induced ALF — list if:

• Arterial pH < 7.3 (after fluid resuscitation), OR
• All three together: INR > 6.5 (PT > 100 s) + serum creatinine > 300 µmol/L (~3.4 mg/dL) + grade III/IV encephalopathy.
• (Adjunct: arterial lactate > 3.5 mmol/L early or > 3.0 after resuscitation.)

B) Non-paracetamol ALF — list if:

• INR > 6.5 (PT > 100 s) alone, OR
• Any three of five: age < 10 or > 40 yr; aetiology = non-A non-B hepatitis / halothane / idiosyncratic drug; jaundice → encephalopathy interval > 7 days; INR > 3.5 (PT > 50 s); bilirubin > 300 µmol/L (~17.5 mg/dL).

High-yield mnemonic (non-paracetamol "3 of 5"): "Bad Prognosis Juniors Jump In Bilirubin" — but simplest to recall the cut-offs: age <10/>40, bad aetiology, jaundice>7d, INR>3.5, bilirubin>300.

Other tools: MELD score, and for Wilsonian ALF the Clichy criteria / Nazer (King's Wilson) index. Factor V level < 20–30% is the basis of the Clichy criteria (especially HBV ALF in young patients).

Complications

• Cerebral oedema and intracranial hypertension → uncal herniation (leading cause of death).
• Sepsis and multi-organ failure (bacterial + fungal — second major killer).
• Coagulopathy and haemorrhage (GI bleed).
• Acute kidney injury / hepatorenal syndrome.
• Metabolic: profound hypoglycaemia, lactic acidosis, hypophosphataemia, hyponatraemia.
• Circulatory collapse (distributive/vasodilatory shock).
• ARDS, pancreatitis (especially paracetamol).

High-yield: The two commonest causes of death in ALF are cerebral oedema/raised ICP and sepsis/multi-organ failure.

Key differentials

Condition	Distinguishing feature
Acute-on-chronic liver failure (ACLF)	Pre-existing cirrhosis/chronic liver disease; stigmata of chronicity, splenomegaly, low platelets
Decompensated cirrhosis	Ascites, varices, prior history; slower course
Sepsis / shock liver	Transient transaminase spike that falls fast with resuscitation; hypotension precedes
Acute fatty liver of pregnancy / HELLP	3rd trimester, microvesicular steatosis, ↓ platelets, ↑ uric acid
DIC	Factor VIII low; in ALF factor VIII is normal/high
Reye syndrome	Child + aspirin + viral illness, microvesicular steatosis, no jaundice

Recently asked / exam angle

• Single best definition question: coagulopathy + encephalopathy + onset <26 weeks in a normal liver — and the distinction that coagulopathy alone (no encephalopathy) = acute liver injury, not ALF.
• Commonest cause — geography split: paracetamol (West) vs HEV (India, especially pregnancy).
• King's College Criteria — direct recall of paracetamol arm (**pH <7.3** *or* the INR>6.5 + creatinine + grade III/IV triad) and the non-paracetamol "INR>6.5 or 3 of 5."
• NAC as DOC for paracetamol and its benefit in non-paracetamol ALF.
• Wilson disease clues in young ALF: low ALP, ALP/bilirubin ratio <4, AST/ALT >2.2, Coombs-negative haemolysis, KF rings — transplant is treatment in fulminant Wilson.
• Worst prognosis subtype = subacute; most cerebral oedema = hyperacute.
• Cerebral oedema management: hypertonic saline/mannitol, target Na 145–150, CRRT over IHD, hypothermia bridge; lactulose less useful than in chronic disease.
• Factor VIII normal distinguishes ALF coagulopathy from DIC; Factor V used in Clichy criteria.

Rapid revision

1. ALF = coagulopathy (INR ≥1.5) + encephalopathy + onset <26 weeks in a previously normal liver.
2. No encephalopathy = acute liver injury, NOT ALF.
3. Commonest cause: paracetamol in West, Hepatitis E in India (and in pregnancy).
4. Hyperacute = most cerebral oedema but best survival; subacute = least oedema but worst prognosis.
5. NAC = DOC for paracetamol ALF; also helps non-paracetamol ALF in early grades.
6. INR/PT is the key prognostic and monitoring marker — don't correct it unless bleeding/procedure.
7. Cerebral oedema (raised ICP) and sepsis are the two leading causes of death.
8. King's paracetamol: pH <7.3, **or** INR>6.5 + Cr>300 µmol/L + grade III/IV encephalopathy.
9. King's non-paracetamol: INR>6.5, or 3 of 5 (age<10/>40, bad aetiology, jaundice>7d, INR>3.5, bilirubin>300).
10. Wilson ALF clue: ALP/bilirubin <4, AST/ALT >2.2, Coombs-negative haemolysis → transplant.
11. Factor VIII normal/high in ALF (low in DIC); Factor V underlies Clichy criteria.
12. Emergency liver transplant is the only definitive therapy once criteria are met; high-volume plasma exchange bridges and improves transplant-free survival.