Definition

Rare, severe multi-system disorder characterized by massive hepatocyte necrosis or profound functional impairment.
Diagnosis requires three core criteria:
- Biochemical evidence of acute liver injury.
- Hepatic-based coagulopathy unresponsive to vitamin K. Defined as prothrombin time >15 seconds or international normalized ratio >1.5 in presence of clinical encephalopathy; OR prothrombin time >20 seconds or international normalized ratio >2.0 regardless of encephalopathy.
- Absence of preexisting chronic liver disease (exceptions include acute initial presentations of Wilson disease or autoimmune hepatitis).

Pathophysiology

Hepatocyte death/injury triggers massive release of bio-active substances and toxins, initiating multiorgan failure cascade.
Factor VII possesses shortest half-life (4-6 hours) among vitamin K-dependent factors; depletes earliest, rendering international normalized ratio a dynamic, sensitive marker of synthetic inadequacy.
Cerebral edema/Intracranial hypertension: Ammonia and inflammatory cytokines induce astrocyte swelling, altering intracellular fluid shifts.
Coagulopathy: Decreased synthesis of coagulation factors, protein C, protein S, and antithrombin.
Metabolic derangement: Hypoglycemia secondary to impaired gluconeogenesis, reduced glycogen stores, and impaired hepatic insulin clearance. Lactic acidosis results from impaired tissue perfusion and decreased hepatic detoxification.

Age Category	Common Etiologies
Neonates/Infants	Galactosemia, tyrosinemia type 1, gestational alloimmune liver disease (neonatal hemochromatosis), mitochondrial hepatopathies, hemophagocytic lymphohistiocytosis, viral (herpes simplex virus, cytomegalovirus, echovirus).
Children/Adolescents	Acetaminophen toxicity, viral hepatitis (A, B, E), autoimmune hepatitis, Wilson disease, indeterminate/idiopathic (40-50% of cases).

System	Specific Signs And Symptoms
General/Hepatic	Progressive jaundice, fetor hepaticus, rapid decrease in liver size (ominous sign indicating massive necrosis), abdominal pain, vomiting.
Neurological	Hepatic encephalopathy (irritability, sleep rhythm inversion, somnolence, combative behavior, decerebrate/decorticate posturing, coma), cerebral edema, seizures.
Hematological	Bleeding diathesis (gastrointestinal hemorrhage), thrombocytopenia, aplastic anemia.
Renal/Metabolic	Hepatorenal syndrome, hypoglycemia, hypokalemia, hyponatremia, metabolic acidosis, respiratory alkalosis.
Immunological	High susceptibility to systemic infections (Staphylococcus aureus, Staphylococcus epidermidis, gram-negative organisms, fungal infections) secondary to impaired Kupffer cell and polymorphonuclear function.

Complete blood count, comprehensive metabolic panel, transaminases, fractionated bilirubin, prothrombin time, international normalized ratio.
Ammonia, lactate, blood glucose, amylase, lipase.
Blood, urine, and sputum cultures (prior to antimicrobial initiation).

Suspected Etiology	Diagnostic Investigations
Viral	Hepatitis A IgM, Hepatitis B surface antigen/core IgM, Hepatitis C antibody/PCR, Epstein-Barr virus, Cytomegalovirus, Herpes simplex virus PCR.
Metabolic	Galactose-1-phosphate uridyl transferase, urinary succinylacetone, plasma acylcarnitines, transferrin isoelectrophoresis.
Autoimmune	Antinuclear antibodies, smooth muscle antibodies, liver-kidney microsomal antibodies, serum IgG.
Toxic/Drug	Acetaminophen levels, serum toxicology screen.
Wilson Disease	Serum ceruloplasmin, 24-hour urinary copper, slit-lamp examination, Coombs-negative hemolytic anemia markers.

Etiology	Transaminases (IU/L)	Coagulopathy (INR)	Ferritin (ng/mL)
Gestational Alloimmune Liver Disease	Normal/mild increase (<100)	Significant increase	800 - 7,000
Hemophagocytic Lymphohistiocytosis	Moderate/significant increase (>1000)	Moderate/significant increase	Significant increase (>20,000)
Mitochondrial Hepatopathy	Moderate increase (100 - 500)	Moderate/significant increase	Variable
Ischemic Hepatitis	Significant increase (>1,000 - 6,000)	Moderate/significant increase	Variable

Data derived from diagnostic profiles of neonatal hepatic failure.

Predicts mortality and guides urgent liver transplantation listing.

Category	Criteria Mandating Transplantation
Acetaminophen-Induced	Arterial pH <7.30 (post-resuscitation) OR all three of: INR >6.5, creatinine >3.4 mg/dL, and Grade III/IV encephalopathy.
Non-Acetaminophen	Prothrombin time >100 seconds (INR >6.5) OR any three of: age <11 years, jaundice to encephalopathy >7 days, bilirubin >17.4 mg/dL (300 umol/L), prothrombin time >50 seconds (INR >3.5), drug toxicity etiology.

Note: In pediatric cohorts, isolated peak INR >4 demonstrates high sensitivity for mortality without transplantation.

Neurological: Maintain quiet environment, head elevation 30 degrees. Treat intracranial hypertension with 3% hypertonic saline, 20% mannitol, or transient hyperventilation. Avoid benzodiazepines.
Metabolic/Fluid: Utilize 10% dextrose-based maintenance fluids targeting euglycemia. Avoid fluid overload and Ringer's lactate (impaired hepatic lactate metabolism).
Coagulation: Administer parenteral vitamin K. Restrict fresh frozen plasma or prothrombin complex concentrates exclusively to active bleeding episodes or prior to invasive procedures (allows accurate INR monitoring). Use proton pump inhibitors for stress ulcer prophylaxis.
Infection: Initiate broad-spectrum prophylactic intravenous antibiotics and antifungals. Add acyclovir for neonates pending viral diagnostics.
Renal/Ammonia: Implement continuous renal replacement therapy for hyperammonemia (>200 umol/L) or acute kidney injury. Administer lactulose or rifaximin.

Etiology	Targeted Therapy
Acetaminophen Toxicity	Intravenous N-acetylcysteine.
Gestational Alloimmune Liver Disease	Double volume exchange transfusion combined with intravenous immunoglobulin.
Tyrosinemia Type 1	Nitisinone; dietary restriction of phenylalanine and tyrosine.
Autoimmune Hepatitis	Systemic corticosteroids.
Herpes Simplex Virus	Intravenous acyclovir.
Wilson Disease	Copper chelation (Penicillamine, Trientine).
Galactosemia	Strict lactose/galactose-free dietary formula.

Liver Assist Devices: Cell-free cleansing devices or bioartificial liver systems utilized strictly as experimental bridging therapies to remove toxins (ammonia, cytokines) while awaiting transplantation.
Orthotopic Liver Transplantation: Definitive, lifesaving therapy for irreversible failure (advanced coma, King's College criteria fulfillment). Absolute contraindications include fixed dilated pupils, systemic mitochondrial disease, and uncontrolled sepsis. Survival approaches 75% at 6 months post-transplantation.