SUPPLEMENT ARTICLE |
Liver
* Alfred I. duPont Hospital for Children, Wilmington, Delaware
Ohio State Environmental Protection Agency, Columbus, Ohio
The liver’s unique metabolism and relationship to the gastrointestinal tract make it an important target of the toxicity of drugs and xenobiotics. The developmental changes that occur in the liver’s metabolic activity from birth to adolescence contribute to the varied sensitivity to toxins seen in the pediatric population. Hepatic drug metabolism, often with an imbalance between the generation of toxic metabolites and detoxification processes, can influence the degree of hepatotoxicity. The decreased capacity of the neonatal liver to metabolize, detoxify, and excrete xenobiotics explains the prolonged action of drugs such as phenobarbital, theophyline, and phenytoin. The reduced capacity of glucuronide conjugation in the neonate not only predisposes them to physiologic jaundice but also is probably responsible for the chloramphenicol-induced gray infant syndrome. Age-related sensitivity to drugs is attributable in part to differences in metabolic activity. For example, young children are more resistant to acetaminophen hepatotoxicity when compared with adults, whereas children are more susceptible to valproic acid–induced toxicity. The resistance to acetaminophen toxicity is attributable to biochemical differences in young children. In children, sulfation predominates over glucuronidation, leading to decreased formation of toxic intermediates. In addition, infants have a greater capacity to synthesize glutathione, thereby inactivating toxic metabolites of acetaminophen more effectively. Hepatic toxicity as a result of drugs and environmental toxins presents a wide spectrum of clinical disease. Hepatitis is the most common presentation, but every major type of liver pathology can occur. Most drug reactions are attributable to idiosyncratic hepatotoxins; therefore, liver injury occurs rarely. The diagnosis of toxin-induced liver disease requires a high index of suspicion and often entails the exclusion of other causes of liver disease in children. Drug or environmental xenobiotic-induced hepatotoxicity should be considered in the setting of identified exposure or when other causes of childhood liver disease are excluded. Children who take medications that are known to be hepatotoxic, such as anticonvulsants and antineoplastic drugs, need frequent monitoring for evidence of hepatic toxicity. The treatment is often nonspecific; the most important intervention is the prompt discontinuation of the drug or removal of the environmental toxin. A specific antidote is available only for acetaminophen intoxication. In cases of severe toxicity, the patient may develop liver failure. Liver transplantation may be necessary for patients whose liver failure does not resolve.
Key Words: hepatotoxicity • xenobiotic • drug metabolism
Abbreviations: CYP, cytochrome P450 • ALT, alanine aminotransferase • AFB, aflatoxin B • ALP, alkaline phosphatase • VOD, veno-occlusive disease • PCB, polychlorinated biphenyl • PCP, pentachlorophenol • TCHQ, tetrachlorohydroquinone
Received for publication Oct 7, 2003; Accepted Oct 20, 2003.
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