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Chapter 417: Drug-, Toxin-, and Total Parenteral Nutrition–Induced Liver Disease

Christopher D. Jolley; Regino P. González-Peralta; Beth A. Carter

DRUG-INDUCED INJURY

Adverse drug reactions in children are uncommon. Nevertheless, drug-induced hepatotoxicity must be promptly recognized and the offending agent discontinued. Delays in recognizing drug-induced hepatic injury may result in significant morbidity, including a need for liver transplantation or death. Comprehensive and updated online information on drug-induced liver injury caused by prescription and nonprescription drugs, herbals, and dietary supplements is available at http://www.livertox.nih.gov.

The role of the liver in the processing or biotransformation of xenobiotics (foreign substances) is discussed in Chapter 413. Mechanisms of hepatotoxicity vary, depending on the offending drug, dose, and host factors such as age, sex, nutritional status, and genetic predisposition. In general, medicinal and environmental agents known to cause liver damage have been characterized as predictable (intrinsic) or unpredictable (idiosyncratic) hepatotoxins. The patterns of liver injuries are clinically and histopathologically diverse (Table 417-1).

TABLE 417-1CLINICAL AND PATHOLOGIC FINDINGS IN DRUG-INDUCED LIVER DISEASE IN CHILDREN
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TABLE 417-1CLINICAL AND PATHOLOGIC FINDINGS IN DRUG-INDUCED LIVER DISEASE IN CHILDREN
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Biochemical Responseb
Druga AST-ALT ALP Pathologic Finding Risk Factors Clinical Characteristics
Acetaminophen 8–500× < 3× Zone 3 necrosis Dose, ↑ age, fasting Dose-dependent injury, initial nausea and vomiting; jaundice and coagulopathy if liver failure
Amiodarone 1–5× V× Steatohepatitis, phospholipidosis Dose, duration of therapy Asymptomatic elevation of ALT and AST common; cirrhosis and liver failure rare
Amoxicillin/clavulanic acid > 3× > 3× Cholestasis, hepatitis ↑ age, duration of therapy Clavulanic acid is likely cause of toxicity; most cases recover fully but rare cases of progressive ductopenia with cirrhosis reported in children
Aspirin 3–20× < 3× Nonzonal necrosis, steatosis (Reye) Dose, rheumatoid disease Dose dependent, rapid recovery if drug discontinued; ↑ risk of Reye syndrome in febrile children
Azathioprine/6-MP > 3× > 3× Cholestasis, hepatitis Transplantation Cholestasis more common with azathioprine; portal HTN and vascular injury also reported
Carbamazepine > 3× V× Hepatitis (children), granulomatosis Metabolic idiosyncrasy Hepatitis associated with drug hypersensitivity syndrome
Cyclosporine < 3× > 3× Cholestasis CYP interactions, dose Direct hyperbilirubinemia more common, mixed hepatitis/cholestasis at higher doses
Erythromycin < 3× > 3× Hepatitis/cholestasis ↑ age Anorexia, nausea, jaundice, and abdominal pain; all forms of erythromycin reported but erythromycin estolate more common in adults (1–2% develop jaundice)
Estrogens < 5× < 3× Cholestasis Dose Insidious onset of mild jaundice and pruritus; hepatic vein thrombosis, hepatic adenoma with prolonged use
Halothane 8–500× < 3× Acute hepatitis (zone 3 necrosis) ↑ age, female sex, repeated exposure Rare in children; mild ↑ ALT in 10–20% of adults; severe hepatitis and liver failure (fatal in 14–71%)
Isoniazid 8–500× < 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 sex Symptoms of hepatitis and jaundice after 6–8 weeks of therapy; cause by metabolic idiosyncrasy
Methotrexate 1–3× 1–3× Steatosis and fibrosis Obesity, ↑ dose, type 2 diabetes

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