Acute Hepatic Failure in Children (Pediatric Acute Liver Failure - PALF)

Definition

• Biochemical evidence of acute liver injury, PLUS
• Coagulopathy not corrected by Vitamin K with hepatic encephalopathy (HE), OR
• Severe coagulopathy (INR ≥2.0 / PT ≥20 s) regardless of HE grade

• Fischer's Mastery of Surgery 8e, p. 5659

Etiology - Age-Specific Patterns

• Hepatitis A and E (supportive care only)
• Hepatitis B (treat with nucleoside analogs)
• Wilson disease - distinctive: Coombs-negative hemolytic anemia + rapid deterioration; requires urgent transplant evaluation
• Autoimmune hepatitis - may respond to corticosteroids if caught early (avoid if multiorgan failure)
• Mushroom poisoning (Amanita phalloides) - treat with penicillin G
• Malignancy - leukemia/lymphoma (33%), metastatic disease - rare but important to exclude
• Etiology cannot be established in ~50% of pediatric cases vs. ~15% of adults
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 768
• Plum & Posner's Diagnosis and Treatment of Stupor and Coma, p. 627

Pathophysiology

Mechanism of Hepatic Injury

• Direct toxic damage (e.g., acetaminophen): massive hepatic necrosis within hours-days, insufficient time for regeneration or scar formation
• Immune-mediated destruction (e.g., viral hepatitis): slower onset over weeks; regeneration may be evident alongside ongoing injury
• Mitochondrial dysfunction (valproate, fatty liver of pregnancy, some metabolic disorders): widespread hepatocyte dysfunction without obvious cell death; diffuse microvesicular steatosis

Hepatic Encephalopathy (HE) Mechanism

• Liver failure impairs ammonia conversion to glutamine
• Excess ammonia causes astrocyte swelling and GABAergic inhibition
• NMDA receptor-mediated nitric oxide release causes cerebral vasodilation and breakdown of cerebral autoregulation
• Astrocytic aquaporin-4 water channels and systemic inflammation amplify brain edema
• Plum & Posner's, p. 629

Morphology (Pathology)

• Massive hepatic necrosis with broad regions of parenchymal loss surrounding islands of preserved/regenerating hepatocytes
• Affected livers are small and shrunken
• Toxic injuries (acetaminophen): little regeneration due to rapid course
• Viral injuries: regeneration often visible alongside necrosis
• Robbins, Cotran & Kumar, p. 768

Clinical Features

Presentation

• Jaundice, fatigue, anorexia, nausea/vomiting
• Evidence of coagulopathy: easy bruising, bleeding, prolonged PT/INR
• Hepatic encephalopathy (see grading below)
• Hepatomegaly (may be absent or liver may shrink as necrosis progresses)
• Associated features of the precipitating cause (e.g., Kayser-Fleischer rings in Wilson disease)

West Haven Criteria for HE Grading

Investigations

Initial Workup

• LFTs: AST, ALT, GGT, bilirubin (conjugated + unconjugated), albumin
• Coagulation: PT, INR (key diagnostic marker; also monitors progression)
• Metabolic: glucose (hypoglycemia is common and dangerous!), Na, K, BUN, Cr, Mg, phosphate, lactate
• Ammonia (arterial preferred for accuracy)
• CBC with differential
• Acetaminophen level (even if not suspected)

Etiology-Directed Testing

• Viral hepatitis serology (HAV IgM, HBsAg, anti-HBc IgM, HCV, HEV, HSV, EBV, CMV, adenovirus, VZV)
• Autoimmune: ANA, ASMA, anti-LKM1, serum immunoglobulins
• Wilson disease: serum ceruloplasmin, 24-hour urine copper, slit-lamp exam (Kayser-Fleischer rings), blood film for hemolysis
• Metabolic: urine/serum amino acids, organic acids, lactate:pyruvate ratio (mitochondrial disease), alpha-1-antitrypsin phenotype
• Toxicology screen
• HIV testing

Imaging

• Abdominal USS with Doppler (hepatic vasculature, Budd-Chiari)
• CT/MRI head if any focal neurological signs or encephalopathy ≥Grade 1 to exclude hemorrhage (given coagulopathy risk)
• EEG (spectral EEG useful for assessing HE grade in children)

Management

General Supportive Care

• Continuous glucose infusion (GIR 6-8 mg/kg/min; increase if needed)
• Use 10-12.5% dextrose solutions; central access needed for >12.5%
• Target normoglycemia; avoid repeated boluses (risk of rebound hypoglycemia)

• Fluid-restrict to 70-80% maintenance to reduce cerebral edema risk
• Sodium: target Na 145-155 mEq/L using hypertonic saline (2.7% or 3% NaCl) - ISPGHAN 2024 guideline
• Correct hypokalemia, hypomagnesemia, hypophosphatemia

• Continue enteral nutrition if tolerated; do not restrict protein arbitrarily
• Nasogastric feeding preferred

• Fresh frozen plasma (FFP) 10 mL/kg for active bleeding or procedures
• Platelets 15 mL/kg if thrombocytopenic bleeding
• Do NOT correct coagulopathy prophylactically (PT/INR is a prognostic marker)

Etiology-Specific Treatment

Neurological Complications

• Minimize sedatives (hepatically metabolized, cause prolonged sedation; mask grade transitions)
• Lactulose: titrate to 2-3 soft stools/day; monitor for megacolon (controversial in PALF)
• Rifaximin: adjunct for reducing ammonia
• Treat precipitating factors (infection, GI bleed, constipation)
• Intubate and secure airway at HE Grade 2 or more in PALF
• Target normocapnia (ETCO2 4-5 cmH2O), normothermia, normoglycemia

• Nursing: head elevation 30°, minimize stimulation, treat pain/fever/agitation
• Hypertonic saline (2.7-3%): 1-2 mL/kg for raised ICP prevention; 3 mL/kg bolus if Cushing response (hypertension + bradycardia + dilated pupils)
• Mannitol 0.5-1 g/kg IV bolus: effective but use cautiously if serum osmolality >320 mOsm/L or renal impairment
• Invasive ICP monitoring: consider for Grade 3-4 HE in transplant candidates (requires coagulopathy reversal before placement; 7% hemorrhagic complication rate)
• Refractory ICP: mild hypothermia (34-35°C), barbiturates, mild hyperventilation (pCO2 target 28-30 mmHg)
• Avoid corticosteroids for cerebral edema
• Continuous renal replacement therapy (CRRT) reduces ammonia and brain edema, especially with concurrent renal failure

Renal Support

• Avoid nephrotoxic drugs (neomycin, NSAIDs, aminoglycosides)
• CRRT preferred over intermittent hemodialysis in hemodynamically unstable children
• Monitor for hepatorenal syndrome (HRS) and treat per ADQI/ICA 2024 guidelines

Therapeutic Plasma Exchange (TPE)

Liver Transplantation

Indications

• Spontaneous recovery is possible
• LT carries significant morbidity + lifelong immunosuppression

• King's College Criteria (originally adult, used with modification in pediatrics)
• Progressive rise in PT/INR despite medical management
• Grade 3-4 HE
• Multi-organ failure
• Specific cause criteria (e.g., Wilson disease - almost always requires LT)

• LT listing rates for PALF have decreased (7.7% in 2020) as medical management has improved
• 1-year survival post-LT for PALF: patient survival 73%, graft survival 59% - significantly lower than LT for biliary atresia (89%/78%)
• This reflects the acuity and instability of PALF at time of transplant
• Fischer's Mastery of Surgery 8e, p. 5659

Prognosis and Outcome

• Overall mortality with modern management: ~30% (vs. 70-95% historically)
• Etiology is the strongest predictor: acetaminophen PALF has the best spontaneous recovery rate; indeterminate etiology has the worst
• A 2025 systematic review (PMID 41159810) identified recurrent PALF as a distinct phenotype with unique outcomes requiring genetic/metabolic investigation
• Autoimmune hepatitis presenting as PALF: 2024 meta-analysis (PMID 38700362) showed transplant-free survival is achievable with immunosuppression, particularly when started early

Summary Algorithm

Suspected PALF
      ↓
Confirm: Coagulopathy (INR ≥1.5 with HE, or INR ≥2.0 without HE) + No known chronic liver disease
      ↓
TRANSFER TO TRANSPLANT CENTER + ICU admission
      ↓
┌──────────────────────────────────────────────────────────────┐
│ Parallel: Etiology workup + Supportive care + LT evaluation  │
└──────────────────────────────────────────────────────────────┘
      ↓
Glucose/electrolytes/fluids → Vitamin K → Etiology-specific Rx
      ↓
Monitor HE grade (q1h neuro exams)
      ↓
HE Grade 2+? → Intubate, control ICP (hypertonic saline, mannitol, CRRT)
      ↓
Progressive deterioration? → LT listing + TPE as bridge

• ISPGHAN 2024 guidelines recommend hypertonic saline targeting Na 145-155 mEq/L for cerebral edema prevention in PALF
• 2025 meta-analysis confirms TPE improves survival as a bridge to LT or spontaneous recovery in PALF
• Recurrent PALF (2025 systematic review) is a recognized entity - warrants genetic/metabolic investigation for POLG mutations, mitochondrial disorders