Acute liver failure in the young

A child or young adult with acute hepatic dysfunction: synthetic failure (INR > 1.5 not corrected by vitamin K), aminotransferase elevation, and often hyperbilirubinemia. Without encephalopathy this is acute liver injury; with encephalopathy it becomes acute liver failure (ALF) and is a transplant-or-die emergency in hours to days. The reasoning frame is to rapidly sort by category: infectious, drug or toxin, autoimmune, vascular, and metabolic. The genetic-metabolic causes are the highest-yield missed diagnoses because several are treatable (Wilson, tyrosinemia, galactosemia, hereditary fructose intolerance, neonatal hemochromatosis) and several radically change family counseling (mitochondrial DNA depletion).

The age of the patient organizes the metabolic differential:

1. Neonate (first weeks): galactosemia, tyrosinemia type 1, neonatal hemochromatosis, mitochondrial DNA depletion (hepatocerebral), HSV, sepsis.
2. Infant / toddler: hereditary fructose intolerance (after fructose/sucrose introduction), mitochondrial DNA depletion (Alpers if epilepsy), Niemann-Pick C, Wilson is uncommon at this age.
3. Older child / adolescent: Wilson disease becomes the leading metabolic cause; autoimmune hepatitis; valproate-precipitated POLG liver failure in a child with epilepsy.

The treatable / time-sensitive items at the top of every list: acetaminophen overdose (NAC), HSV (acyclovir), Wilson (chelation or transplant), tyrosinemia (nitisinone), galactosemia (lactose elimination), hereditary fructose intolerance (fructose elimination), neonatal hemochromatosis (IVIG + exchange transfusion), and autoimmune hepatitis (steroids).

Metabolic: neonates and infants

• Classic galactosemia (GALT, AR): jaundice + hepatomegaly + coagulopathy + cataracts + E. coli sepsis after milk feeds begin. Newborn screen catches most, but the diagnosis remains treat-on-suspicion: switch to a non-lactose formula at first suspicion before the GALT result returns.
• Tyrosinemia type 1 (FAH, AR): acute liver failure picture + renal Fanconi syndrome + cabbage- or boiled-cabbage-like urine odor + hypoglycemia + coagulopathy. Succinylacetone in urine is diagnostic. Treatable with nitisinone (NTBC) + low-tyrosine, low-phenylalanine diet; HCC risk persists despite treatment.
• Hereditary fructose intolerance (ALDOB, AR): onset coincides with introduction of fructose, sucrose, or sorbitol (often around 6 months when fruit and sweetened foods begin). Hypoglycemia + vomiting + liver dysfunction after fructose-containing feeds. Lifelong fructose, sucrose, and sorbitol avoidance.
• Neonatal hemochromatosis (gestational alloimmune liver disease, GALD): alloimmune attack on fetal hepatocytes in utero. Transferrin saturation > 95% + extrahepatic siderosis on MRI or labial salivary-gland biopsy + acute liver failure at birth. Treatment: emergent IVIG + exchange transfusion, then transplant for non-responders. Recurrence ~90% in subsequent pregnancies: prevent with weekly maternal IVIG starting at 14 weeks.

Metabolic: mitochondrial

• Mitochondrial DNA depletion syndromes (POLG, MPV17, DGUOK, SUCLG1, others): the Alpers-Huttenlocher phenotype is the high-yield one. Intractable epilepsy + cognitive regression + liver failure in a child or young adult. Valproate-precipitated acute liver failure in any child with epilepsy is POLG-related until proven otherwise: this is the "do not give valproate" pediatric neurology lesson. MPV17 and DGUOK present in infancy with hepatocerebral disease.

Metabolic: older child and adolescent

• Wilson disease (ATP7B, AR): the most common metabolic cause of ALF in older child or adolescent. The Wilsonian ALF profile is distinct: low alkaline phosphatase + AST/ALT ratio > 2.2 + Coombs-negative hemolytic anemia + low ceruloplasmin + high urinary copper + Kayser-Fleischer rings on slit-lamp + extrahepatic copper deposition. The ALP-to-bilirubin ratio < 4 + AST/ALT > 2.2 has a sensitivity and specificity near 100% for Wilsonian ALF; transplant is the only intervention once ALF is established.
• Niemann-Pick disease type C (NPC1, NPC2, AR): neonatal cholestasis is often the first presentation, sometimes severe enough to be called ALF, and precedes the chronic neurodegenerative course by years. Hepatosplenomegaly + later vertical supranuclear gaze palsy.

Acquired: never miss

• Acetaminophen overdose: the most common acquired ALF in adolescents; intentional or therapeutic-misadventure. N-acetylcysteine works; the Rumack-Matthew nomogram guides treatment.
• Herpes simplex virus: neonatal disseminated HSV (skin, eye, mouth or sepsis pattern) with ALF; acyclovir empirically until cleared.
• Autoimmune hepatitis (type 1 and 2): ANA + anti-smooth-muscle (type 1) or anti-LKM1 (type 2); responsive to steroids ± azathioprine.
• Hemophagocytic lymphohistiocytosis (HLH): fever + cytopenias + splenomegaly + hyperferritinemia + hypofibrinogenemia + hypertriglyceridemia + hemophagocytosis on bone marrow. Familial HLH (PRF1, UNC13D, STX11, STXBP2) and acquired forms; treatable with HLH-2004 protocol + transplant.
• Budd-Chiari, ischemic hepatitis, sepsis-related: vascular and systemic causes; imaging and clinical context.

1. INR, PT, fibrinogen, platelets: synthetic function. INR > 1.5 unresponsive to vitamin K defines liver failure.
2. AST, ALT, ALP, GGT, total and direct bilirubin, albumin, ammonia, glucose, lactate: standard hepatic panel.
3. Acetaminophen level in every adolescent regardless of stated ingestion history; send first.
4. Ceruloplasmin + 24-hour urine copper + slit-lamp for Kayser-Fleischer rings in any patient over age 3 with unexplained ALF.
5. Urine reducing substances + urine succinylacetone: galactosemia, tyrosinemia.
6. Plasma amino acids + urine organic acids + acylcarnitine profile: metabolic screen.
7. Lactate, pyruvate, lactate-to-pyruvate ratio: mitochondrial disease.
8. Newborn screen review.
9. Ferritin + transferrin saturation + MRI of heart/pancreas (or labial salivary gland biopsy): neonatal hemochromatosis if neonate.
10. HSV PCR + viral hepatitis panel + EBV + CMV: infectious causes.
11. ANA, anti-smooth-muscle, anti-LKM1, IgG: autoimmune hepatitis.
12. Targeted gene panel or trio exome when first-line tests are unrevealing and the patient is stable enough to wait. Mitochondrial depletion panels (POLG, MPV17, DGUOK) and metabolic ALF panels are increasingly first-line.
13. Hepatology + transplant consultation the same day: King's College Criteria (Wilson-specific and general) guide listing.