Acute Liver Failure

Risk factors

• Acetaminophen overdose (intentional or unintentional/staggered)
• Drug-induced liver injury: isoniazid, valproate, amoxicillin-clavulanate, methotrexate, halogenated anesthetics, sulfa drugs
• Herbal supplements: kava, green tea extract, comfrey, ma huang
• Viral hepatitis: A, B (acute or reactivation), C (rare), E (especially pregnancy and immunocompromised), HSV, EBV, CMV
• Autoimmune hepatitis flare
• Wilson disease (presenting with acute liver failure in a young person, with Coombs-negative hemolysis and low alkaline phosphatase)
• Ischemic hepatitis ('shock liver')
• Pregnancy-related: HELLP syndrome, acute fatty liver of pregnancy
• Budd-Chiari syndrome
• Toxic mushroom (Amanita phalloides), carbon tetrachloride, ecstasy/MDMA

Pathophysiology

Massive hepatocyte necrosis or apoptosis overwhelms regenerative capacity, producing loss of synthetic (coagulation factors, albumin), metabolic (ammonia clearance, glucose, lactate), and excretory function. Resulting ammonia accumulation crosses the blood-brain barrier, causing astrocyte swelling and cerebral edema. Inflammatory and vasoplegic responses produce circulatory and respiratory failure.

Clinical presentation

Differential diagnosis

• Decompensated cirrhosis (acute-on-chronic liver failure) — Pre-existing liver disease, stigmata of chronic disease, splenomegaly, varices, ascites
• Sepsis with hepatic dysfunction — Infection source, hemodynamic instability, modest LFT elevation
• Severe alcoholic hepatitis — Heavy alcohol use, AST:ALT >2:1, hyperbilirubinemia, modest INR; Maddrey >32
• Drug-induced cholestasis vs hepatocellular injury — Pattern of LFTs (R ratio); usually does not cause encephalopathy unless severe
• Hepatic encephalopathy from precipitant in cirrhosis — GI bleed, infection, dehydration, constipation, sedatives

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[INR ≥1.5 + encephalopathy<br/>no prior liver disease<br/>illness <26 weeks] --> B[Acute liver failure]
  B --> C[ICU + transplant center transfer]
  C --> D[Identify etiology<br/>APAP, viral, AIH, Wilson,<br/>HELLP/AFLP, ischemic, mushroom]
  D --> E[Cause-directed therapy<br/>+ N-acetylcysteine for all]
  E --> F[Manage cerebral edema<br/>head up, hypertonic saline,<br/>normocarbia]
  F --> G[Apply King's College Criteria]
  G --> H{Meets criteria?}
  H -->|Yes| I[List for emergent transplant]
  H -->|No| J[Continue medical therapy<br/>reassess frequently]

Treatment

Complications

• Cerebral edema and intracranial hypertension (leading cause of death pre-transplant)
• Multiorgan failure: AKI, ARDS, circulatory collapse
• Infection and sepsis (impaired immune function)
• Severe hypoglycemia, lactic acidosis
• Coagulopathy and bleeding
• Pancreatitis (acetaminophen)

PANCE pearls

• ALF = INR ≥1.5 + any encephalopathy + no prior liver disease + <26 weeks.
• Give N-acetylcysteine to ALL ALF patients regardless of suspected cause — low risk, potential benefit.
• Do NOT correct INR with FFP unless bleeding or procedure — it is a prognostic tool and FFP delays transplant decisions.
• Wilson ALF clue: AP:bilirubin <4 and AST:ALT >2.2 (Korman ratio) — proceed straight to transplant evaluation.
• Acetaminophen toxicity may be staggered (multiple doses, especially in alcoholics or fasting) and present with very high AST/ALT but modest acute ingestion levels.

References

• AASLD 2023 — AASLD Position Paper on Acute Liver Failure (Lee et al., Hepatology 2011; updated guidance documents)
• EASL 2017 — EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure (J Hepatol 2017)
• ACG 2017 — ACG Clinical Guideline: Drug-Induced Liver Injury (Chalasani et al., Am J Gastroenterol 2014/2017 update)