Acute Liver Failure

Acute liver failure (ALF) is defined by the simultaneous presence of:

Coagulopathy — INR ≥1.5
Hepatic encephalopathy — any grade
No pre-existing liver disease (with specific exceptions)
Illness duration typically <26 weeks

The 'No Pre-Existing Disease' Rule — With Exceptions

ALF by definition occurs in a patient without underlying chronic liver disease. However, three conditions may present de novo as ALF and are recognized exceptions: Wilson disease, autoimmune hepatitis (AIH), and Budd-Chiari syndrome. These patients may have undiagnosed underlying hepatic disease that decompensates acutely and must still be evaluated for transplant.

O'Grady Classification by Time to Encephalopathy

The interval from jaundice onset to development of encephalopathy defines the subtype and carries prognostic significance.

Subtype	Time to Encephalopathy	Cerebral Edema Risk	Prognosis
Hyperacute	<7 days	Highest	Paradoxically better spontaneous survival if etiology is treated (e.g., acetaminophen)
Acute	7–28 days	Moderate	Intermediate prognosis; mixed etiologies
Subacute	21 days – 26 weeks	Lower	Worst spontaneous survival; indolent onset often delays recognition

Quick recall

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A 32-year-old woman with 3 weeks of fatigue develops jaundice and confusion. INR 3.2, bilirubin 280 μmol/L, no prior liver disease. What single feature distinguishes this as ALF rather than acute hepatitis, and what subtype is it?

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Identifying the cause of ALF is urgent — some etiologies have specific, rapidly effective treatments that can avert the need for transplantation.

Cause	Notes
Acetaminophen overdose	Most common cause in the US (~45% of ALF cases¹); dose-dependent direct hepatotoxicity via NAPQI accumulation; highly treatable with early NAC; best prognosis among ALF etiologies
Idiosyncratic drug reactions	Isoniazid, nitrofurantoin, disulfiram, herbal and dietary supplements; unpredictable; often delayed presentation after drug initiation
Viral hepatitis	HAV and HBV (acute infection or reactivation); HEV especially in pregnancy; HSV hepatitis (rare but important — rapidly fatal without acyclovir); check full viral panel
Wilson disease	Always consider in patients <45 years; presentation may include Kayser-Fleischer rings, Coombs-negative hemolytic anemia, and disproportionately low ALP relative to bilirubin; serum ceruloplasmin, 24-hour urine copper
Autoimmune hepatitis (AIH)	May present as ALF without prior diagnosis; important to identify — corticosteroid-responsive in some cases; check ANA, ASMA, IgG; liver biopsy if coagulopathy permits
Budd-Chiari syndrome	Acute hepatic vein thrombosis; associated with myeloproliferative disorders and other hypercoagulable states; evaluate with Doppler ultrasound; anticoagulation ± TIPS
Ischemic hepatitis	"Shock liver" — AST/ALT may exceed 1,000–10,000 IU/L; often follows hemodynamic instability (cardiac arrest, severe hypotension); rapid normalization with hemodynamic recovery
Pregnancy-related	HELLP syndrome and acute fatty liver of pregnancy (AFLP); typically third trimester; delivery is definitive treatment; high fetal and maternal mortality if not recognized
Indeterminate / seronegative	~15% of US ALF cases; no identifiable cause despite full workup; paradoxically carries the worst overall prognosis and highest transplant rate

Quick recall

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A 24-year-old presents after APAP overdose: arterial pH 7.26 post-resuscitation, INR 7.8, creatinine 330 μmol/L, grade III encephalopathy. Does she meet King's College Criteria for transplant listing?

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Key Laboratory Panel

Essential Labs in ALF — Order Immediately and Monitor Frequently

INR / PT — best marker of synthetic function; rising INR signals trajectory; do not correct unless active bleeding or procedure planned
Total bilirubin — marker of severity; may be disproportionately low in Wilson-related ALF
AST / ALT — may paradoxically fall as hepatocyte mass is depleted ("burning out"); falling AST/ALT with worsening coagulopathy is an ominous sign
Serum creatinine — AKI occurs in 40–70% of ALF (etiology-dependent); critical for King's College Criteria (acetaminophen subset)
Glucose — hypoglycemia is common and rapidly dangerous; check every 1–2 hours
Arterial pH and lactate — arterial pH <7.30 is a single major KCC criterion in acetaminophen ALF
Ammonia (arterial preferred) — correlates with encephalopathy grade and cerebral edema risk; monitor serially
CBC — thrombocytopenia, leukocytosis (infection); hemolytic anemia raises Wilson concern
Blood cultures — infection is a major complication and modifier of prognosis; obtain at admission and with any clinical change

Cerebral Edema

Cerebral edema with intracranial hypertension is the leading cause of death in ALF. Risk is greatest in:

Hyperacute ALF (especially acetaminophen-related)
Grade 3–4 hepatic encephalopathy
Ammonia >150–200 µmol/L
Rapid clinical deterioration

Invasive intracranial pressure (ICP) monitoring is considered in select patients at transplant centers with grade 3–4 encephalopathy, though its benefit on outcomes is debated. Non-invasive monitoring with CT head and clinical examination remains standard in most centers.

Multiorgan Failure

ALF is a systemic disease. Anticipate and monitor for:

Acute kidney injury (AKI) — common (40–70%, etiology-dependent¹); CRRT preferred over intermittent HD in hemodynamically unstable patients
Respiratory failure — aspiration pneumonia, ARDS; early intubation if airway protection is at risk
Sepsis and infection — bacterial (especially gram-negative) and fungal infections are common; impaired Kupffer cell function eliminates a major innate immune barrier
Coagulopathy with bleeding — thrombocytopenia plus factor deficiency; paradoxically, ALF patients may be in a "rebalanced" coagulation state — not simply anticoagulated
Hypoglycemia — from impaired gluconeogenesis and glycogenolysis; requires continuous glucose infusion
Hemodynamic instability — distributive shock pattern; vasopressor support often required

Quick recall

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Falling AST/ALT with worsening coagulopathy in ALF — what does this mean?

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Phase	Dose	Duration
Loading	150 mg/kg in 200 mL D5W	Over 1 hour
Phase 2	50 mg/kg in 500 mL D5W	Over 4 hours
Phase 3	100 mg/kg in 1,000 mL D5W	Over 16 hours

ALF requires ICU-level monitoring with attention to multiple simultaneous organ systems. The following table outlines the major complications and their management.

Complication	Management
Encephalopathy / Cerebral Edema	Head of bed at 30°; minimize stimulation; mannitol 0.5–1 g/kg IV bolus for signs of ICP elevation; hypertonic saline targeting Na 145–155 mEq/L (prophylactic hypernatremia); avoid hypotension; CT head for acute change; ICP monitoring in select patients at transplant centers
Hypoglycemia	Continuous IV dextrose infusion (D10W or D20W as needed); fingerstick or point-of-care glucose every 1–2 hours; goal glucose 140–180 mg/dL; maintain access for emergent bolus glucose
Coagulopathy	Do NOT correct INR prophylactically — elevated INR in ALF reflects synthetic failure but coagulation may be "rebalanced"; correct only for active bleeding or invasive procedures (FFP, cryoprecipitate for fibrinogen <100, platelets if <50K for procedures); avoid FFP for monitoring purposes as it obscures trajectory assessment
AKI / Renal Replacement	CRRT preferred over intermittent hemodialysis in hemodynamically unstable patients — gentler solute and volume shifts; avoid nephrotoxins; standard AKI supportive care; CRRT also provides modest ammonia clearance
Infection / Sepsis	Surveil cultures (blood, urine, respiratory) at least daily; maintain low threshold for empiric antibiotics given impaired innate immunity; consider prophylactic antibiotics in patients with grade 3–4 HE; treat fungal infections aggressively; avoid aminoglycosides (nephrotoxic)
Hemodynamic Instability	Vasopressors as needed — norepinephrine is first-line; vasopressin as adjunct; consider stress-dose corticosteroids (hydrocortisone 200–300 mg/day) for refractory vasodilatory shock; optimize volume status without fluid overload

Nutrition: Enteral nutrition is preferred over parenteral if tolerated. Protein restriction is no longer recommended in ALF — adequate protein intake supports hepatocyte regeneration and does not worsen encephalopathy in the ICU setting.

Acute Liver Failure

O'Grady Classification by Time to Encephalopathy

Key Laboratory Panel

Cerebral Edema

Multiorgan Failure

Interactive KCC Checklist — Acetaminophen ALF

IV Protocol (Standard ALFSG Regimen)

US Transplant Listing: Status 1A

Disease-Specific Therapies That May Avert Transplant

References