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Chapter 422. Drug, Toxin, and TPN Liver Disease

Drug-Induced Liver Injury

Adverse drug reactions in children are uncommon. Nevertheless, drug-induced hepatotoxicity, when it occurs, must be promptly recognized, and the offending agent discontinued, although cessation does not always result in rapid recovery. Delays in recognizing hepatic injury may significantly contribute to morbidity, resulting in a need for liver transplantation or in death.1-5

The role of the liver in the processing or biotransformation of xenobiotics (foreign substances) is discussed in Chapter 418. Mechanisms of hepatoxicity vary, as they depend on the drug, dosage, and patient factors such as age, gender, nutrition, and genetic predisposition. In general, medicinal and environmental agents known to cause hepatotoxicity have been characterized as predictable (intrinsic) or unpredictable (idiosyncratic) hepatotoxins. The patterns of liver injuries are clinically and histopathologically diverse (Table 422-1).

Table 422-1. Clinical and Pathologic Findings in Drug-Induced Liver Disease in Children
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Table 422-1. Clinical and Pathologic Findings in Drug-Induced Liver Disease in Children
Drug*Biochemical Response†Pathologic FindingRisk FactorsClinical Characteristics
AST-ALTALP
Acetaminophen8–500×<3×Zone 3 necrosisDose, ↑ age, fastingDose-dependent injury, initial nausea and vomiting; jaundice and coagulopathy if liver failure
Amiodarone1–5×V×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×V×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 buy 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 exposureRare 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×V×Zone 3 necrosis↑ age, female genderSymptoms of hepatitis and jaundice after 6–8 wk of therapy; cause 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
Minocydine>3×<3×Hepatocellular ...

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