How should I evaluate and manage an adult with acute liver failure presenting with jaundice, markedly elevated transaminases, coagulopathy, and hepatic encephalopathy?

Evaluation and Management of Acute Liver Failure

Admit the patient immediately to an intensive care unit and contact a liver transplant center within the first hours of diagnosis, as the clinical window for intervention is narrow and deterioration can occur within days. 1, 2

Initial Diagnostic Evaluation

Immediate Laboratory Assessment

• Coagulation panel: Obtain prothrombin time/INR (diagnostic threshold ≥1.5) to confirm ALF 1, 2
• Arterial blood gas with lactate: Elevated lactate and metabolic acidosis (pH <7.3) are critical prognostic markers, particularly in acetaminophen toxicity 1
• Comprehensive metabolic panel: Include sodium (maintain 140-145 mmol/L to reduce cerebral edema risk), glucose (check every 2 hours for hypoglycemia), creatinine, and electrolytes 1, 2, 3
• Arterial ammonia level: Values >100-150 µmol/L predict intracranial hypertension risk 2
• Complete blood count with platelets: Assess for thrombocytopenia and anemia 2
• Acetaminophen level: Obtain in all patients regardless of history, as occult toxicity is common 1, 2
• Toxicology screen: Identify other potential drug exposures 1, 2

Etiology-Specific Testing

• Viral serologies: Anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HCV, anti-HEV to identify viral hepatitis 1, 2
• Ceruloplasmin and 24-hour urine copper: Essential in all patients ≤40 years to exclude Wilson disease 1, 2
• Autoimmune markers: ANA, ASMA, and immunoglobulin levels when autoimmune hepatitis is suspected 1, 2
• Pregnancy test: Mandatory in all women of childbearing age to identify pregnancy-related ALF 1, 2

Imaging Studies

• Doppler ultrasonography: Evaluate hepatic vasculature to exclude Budd-Chiari syndrome and assess liver size/echogenicity 1, 2
• Echocardiography: Identify cardiac dysfunction in suspected ischemic ("shock liver") hepatitis 1, 2
• Transjugular liver biopsy: Consider when etiology remains unclear after initial workup, particularly for suspected autoimmune hepatitis, as it is safer in coagulopathic patients 1, 2

Prognostic Assessment for Transplant Listing

King's College Criteria (Acetaminophen-Induced)

Poor prognosis warranting transplant listing if:

• Arterial pH <7.3 after resuscitation (single most important predictor) 1, 2
• OR all three: INR >6.5, creatinine >300 µmol/L (3.4 mg/dL), and grade 3-4 encephalopathy 1, 2

King's College Criteria (Non-Acetaminophen)

Poor prognosis warranting transplant listing if:

• INR >6.5 2
• OR any three of: Age <10 or >40 years, non-A/non-B hepatitis, drug-induced injury, jaundice >7 days before encephalopathy, INR >3.5, bilirubin >300 µmol/L (17.5 mg/dL) 2

Additional Poor Prognostic Indicators

• Factor V activity <20% (Clichy-Villejuif criteria) 2
• Vasopressor requirement: Independent predictor of mortality 2
• Grade 3-4 encephalopathy: Only ~33% short-term survival without transplant 2
• Specific etiologies: Idiosyncratic drug injury, non-hepatitis A viral infections, autoimmune hepatitis, mushroom poisoning, Wilson disease, Budd-Chiari syndrome, and indeterminate cause all carry worse prognosis 1, 3

Etiology-Specific Management

Acetaminophen Toxicity

• N-acetylcysteine (NAC): Administer immediately—140 mg/kg orally or via nasogastric tube, followed by 70 mg/kg every 4 hours for 17 doses 2, 3
• Continue NAC even if >48 hours since ingestion 2, 3
• Activated charcoal: 1 g/kg orally if presentation within 4 hours of ingestion, given just prior to NAC 2

Viral Hepatitis

• Hepatitis A and B: Supportive care only; no virus-specific treatment proven effective 1, 2
• Herpes simplex or varicella zoster: Immediate acyclovir and urgent transplant listing 1, 2
• Hepatitis B reactivation: Nucleoside analogs for patients requiring chemotherapy or immunosuppression 2

Autoimmune Hepatitis

• Corticosteroids: Prednisone 40-60 mg/day 1, 2, 3
• Liver biopsy: Consider transjugular approach to confirm diagnosis (look for severe necrosis with interface hepatitis, plasma cell infiltration, hepatocyte rosettes) 1, 2
• Simultaneous transplant listing: List even while administering corticosteroids 1, 2, 3

Wilson Disease

• Uniformly fatal without transplantation: List immediately for urgent transplant 1, 2
• Copper-lowering measures: Albumin dialysis, continuous hemofiltration, plasmapheresis, or plasma exchange to acutely lower serum copper and limit hemolysis 1, 2, 4
• Avoid penicillamine: Risk of hypersensitivity in acute setting 2

Pregnancy-Related ALF (Acute Fatty Liver/HELLP)

• Expeditious delivery: Immediate obstetrical consultation and delivery 1, 2, 3
• Recovery typically rapid: Supportive care only after delivery; transplant rarely needed 1, 2

Ischemic ("Shock Liver") Hepatitis

• Cardiovascular support: Treatment of underlying cardiac dysfunction or hypotension is primary therapy 1, 2
• Transplant seldom indicated: Focus on hemodynamic stabilization 1, 2

Drug-Induced Hepatotoxicity

• Discontinue all non-essential medications 2, 3
• Detailed medication history: Include prescription drugs, over-the-counter medications, herbs, and dietary supplements 2

Mushroom Poisoning

• Penicillin G and silymarin: Consider administration 2, 3
• Urgent transplant listing: Often the only lifesaving option 2, 3

Critical Care Management

Neurologic Management

• Frequent mental status assessment: Grade encephalopathy using West Haven criteria 1, 2
• Airway protection: Intubate for grade 3-4 encephalopathy (Glasgow Coma Scale <8) 2, 3
• Head elevation: Position at 30 degrees and minimize stimulation 2
• Sedation: Use propofol (favorable pharmacokinetics); avoid benzodiazepines as they worsen encephalopathy 1, 2, 3
• Seizure control: Phenytoin is first-line; add diazepam only as needed 2
• Lactulose: May reduce ammonia levels, though evidence for improved outcomes is limited 2
• Serum sodium: Maintain 140-145 mmol/L; hypertonic saline can decrease intracranial pressure 2, 3
• ICP monitoring: Transcranial Doppler is useful for non-invasive assessment; invasive devices carry 7-20% hemorrhage risk without proven mortality benefit 3

Hemodynamic Support

• Fluid resuscitation: Colloid (albumin) preferred over crystalloid; all solutions should contain dextrose 2
• Target mean arterial pressure: ≥50-60 mmHg 1, 2, 3
• Vasopressors: If fluid replacement fails, use epinephrine, norepinephrine, or dopamine; do NOT use vasopressin 2
• Pulmonary artery catheterization: Consider in hemodynamically unstable patients to guide therapy 1, 2

Coagulation Management

• Vitamin K administration: Give to all patients 2
• Fresh frozen plasma (FFP): Reserve for active bleeding or invasive procedures only; do not correct INR prophylactically as ALF exhibits "rebalanced" hemostasis 2, 3
• Platelets: Transfuse for counts <10,000/mm³ or before invasive procedures 2
• Recombinant factor VIIa: May be considered for invasive procedures 2
• Bleeding occurs in only ~10% of patients, most commonly from upper GI tract 3

Renal Support

• Avoid nephrotoxic agents: Including NSAIDs 2, 3
• Continuous renal replacement therapy (CRRT): Preferred over intermittent hemodialysis if dialysis needed 1, 2, 3
• Hepatorenal syndrome: Treat with terlipressin and albumin; use norepinephrine if terlipressin unavailable 1, 2
• Monitor citrate anticoagulation: Potential metabolic effects in ALF 2

Respiratory Support

• Oxygen therapy and mechanical ventilation: As needed for respiratory failure 1, 2
• Lung-protective ventilation: Follow critical care guidelines 2, 3
• Avoid high PEEP: Keep ≤10 cmH₂O to prevent hepatic congestion 2, 3

Metabolic Management

• Glucose monitoring: Check at least every 2 hours 2, 3
• Hypoglycemia management: Continuous glucose infusions 2
• Electrolyte supplementation: Monitor and replace phosphate, magnesium, and potassium 2

Nutritional Support

• Early enteral feeding: Initiate with moderate protein intake (~60 grams/day); avoid severe protein restriction 2
• Parenteral nutrition: If enteral feeding contraindicated, despite increased fungal infection risk 2
• Branched-chain amino acids: Not shown superior to other enteral preparations 2

Infection Prevention and Management

• Stress ulcer prophylaxis: H2 blockers (ranitidine) or proton pump inhibitors 2, 4
• Aggressive infection surveillance: Screen frequently as bacterial infections are common precipitants 1, 2
• Empiric broad-spectrum antibiotics: Initiate for worsening encephalopathy or signs of systemic inflammatory response syndrome 3

Liver Support Systems

Extracorporeal liver support systems (MARS, Prometheus) do not improve survival and should not be routinely used. 1, 2, 4

• No survival benefit: Large RCTs show no improvement in 28-day or 90-day mortality 1, 2
• Transient improvements only: May improve hepatic encephalopathy and hepatorenal syndrome temporarily without long-term benefit 2
• High-volume plasma exchange (HVPE): Has Level I evidence supporting use specifically in ALF (not ACLF), though Western guidelines recommend against routine use outside research protocols 4

Liver Transplantation

Urgent liver transplantation is indicated when prognostic indicators suggest high likelihood of death; post-transplant survival reaches 80-90% even with multiple organ failures. 1, 2, 3

• Early listing: List patients early in ALF course, particularly those meeting King's College criteria 1, 2
• Status 1 priority: ALF patients receive highest priority for deceased-donor organs 3
• Transplant survival: 80-90% post-transplant survival versus <10% without transplant in poor-prognosis patients 1, 2
• Timing is critical: Late referral may make transplantation impossible due to rapid ACLF progression 1

Critical Pitfalls to Avoid

• Delaying transplant center contact: The transplantation window is narrow; contact within first hours of diagnosis 2, 3
• Prophylactic INR correction: Do not correct coagulopathy without active bleeding; this masks disease progression 2, 3
• Using benzodiazepines: Worsens encephalopathy; use propofol instead 1, 2, 3
• Administering nephrotoxic agents: Including NSAIDs 2, 3
• Missing acetaminophen toxicity: Check level in all patients regardless of history 1, 2
• Overlooking Wilson disease: Consider in all patients ≤40 years without obvious cause 1, 2
• Delaying delivery in pregnancy-related ALF: Expeditious delivery is curative 1, 2
• Severe protein restriction: Avoid; provide ~60 grams/day 2