Clinical and Pathologic Findings in Drug-Induced Liver Disease in Children

Drug*Biochemical ResponsePathologic FindingRisk FactorsClinical Characteristics
Acetaminophen8–500×<3×Zone 3 necrosisDose, ↑ age, fastingDose-dependent injury, initial nausea and vomiting; jaundice and coagulopathy if liver failure
Amiodarone1–5×Steatohepatitis, phospholipidosisDose, duration of therapyAsymptomatic elevation of ALT and AST common; cirrhosis and liver failure rare
Amoxicillin/ clavulanic acid>3×>3×Cholestasis, hepatitis↑ age, duration of therapyClavulanic acid is likely cause of toxicity; most cases recover fully but rare cases of progressive ductopenia with cirrhosis reported in children
Aspirin3–20×<3×Nonzonal necrosis, steatosis (Reye)Dose, rheumatoid diseaseDose dependent, rapid recovery if drug discontinued; ↑ risk of Reye syndrome in febrile children
Azathioprine/6-MP>3×>3×Cholestasis, hepatitisTransplantationCholestasis more common with azathioprine; portal HTN and vascular injury also reported
Carbamazepine>3×Hepatitis (children), granulomatosisMetabolic idiosyncrasyHepatitis associated with drug hypersensitivity syndrome
Cyclosporine<3×>3×CholestasisCYP interactions, doseDirect hyperbilirubinemia more common, mixed hepatitis/cholestasis at higher doses
Erythromycin<3×>3×Hepatitis/cholestasis↑ ageAnorexia, nausea, jaundice, and abdominal pain; all forms of erythromycin reported but erythromycin estolate more common in adults (1%–2% develop jaundice)
Estrogens<5×<3×CholestasisDoseInsidious onset of mild jaundice and pruritus; hepatic vein thrombosis, hepatic adenoma with prolonged use
Halothane8–500×<3×Acute hepatitis (zone 3 necrosis)↑ age, female gender, repeated exposureRae in children; mild ↑ ALT in 10%–20% of adults; severe hepatitis and liver failure (fatal in 14%–71%)
Isoniazid8–500×<3×Acute hepatitis↑ age, dose?More common in adults; mild ↑ ALT in 7%–17% of children; use of CYP inducers may increase toxicity risk
Ketoconazole>3×Zone 3 necrosis↑ age, female genderSymptoms of hepatitis and jaundice after 6–8 wk of therapy; caused by metabolic idiosyncrasy
Methotrexate1–3×1–3×Steatosis and fibrosisObesity, ↑ dose, type 2 diabetesRisk of fibrosis with normal ALT; surveillance liver biopsy after high cumulative dose
Minocycline>3×<3×Hepatocellular necrosisUse >6 mo, female genderSLE-like syndrome or chronic hepatitis with autoimmune features; monitoring of liver function needed
Pemoline>3×HepatocellularImmunoallergic idiosyncrasyAsymptomatic elevation of serum aminotransferases to acute liver failure; several children have required liver transplantation
Phenobarbital>3×Acute hepatitisImmunoallergic idiosyncrasyHepatitis rare, usually part of a multisystem drug hypersensitivity; also at risk of hepatitis from phenytoin and carbamazepine
Phenytoin>3–8×<3×Focal necrosis, granulomasPharmacogenetic idiosyncrasyHepatitis associated with drug hypersensitivity syndrome
Propylthiouracil>3×HepatocellularFemale genderSymptoms of hepatitis and moderate elevation of ALT/AST within 2–3 mo of starting treatment
Sulfonamides>3×Hepatocellular, granulomas, cholestasisImmunoallergic idiosyncrasyHepatotoxicity associated with a systemic drug hypersensitivity reaction; TMT-SMX in children and sulfasalazine in adolescents
Valproic acid8–20×<3×Steatosis, hepatocellular↓ age, multiple anticonvulsantsDose-dependent asymptomatic ↑ ALT in 11% of patients; rare severe toxicity resembles Reye syndrome and is frequently fatal in children
  • 6-MP indicates 6-mercaptopurine; SLE, systemic lupus erythematosus; TMT-SMX, trimethoprim-sulfamethoxazole.

  • * Drugs most commonly reported to cause hepatotoxicity in children.

  • Expressed as times (×) upper limit of normal.