Chapter 355 Drug- and Toxin-Induced Liver Injury

The liver is the main site of drug metabolism and is particularly susceptible to structural and functional injury after ingestion, parenteral administration, or inhalation of chemical agents, drugs, plant derivatives (home remedies), or environmental toxins. The possibility of drug use or toxin exposure at home or in the parents’ workplace should be explored for every child with liver dysfunction. The clinical spectrum of illness can vary from asymptomatic biochemical abnormalities of liver function to fulminant failure. Liver injury may be the only clinical feature of an adverse drug reaction or may be accompanied by systemic manifestations and damage to other organs. In hospitalized patients, clinical and laboratory findings may be confused with the underlying illness.

Hepatic metabolism of drugs and toxins is mediated by a sequence of enzymatic reactions that in large part transform hydrophobic, less-soluble molecules into more nontoxic, hydrophilic compounds that can be readily excreted in urine or bile (Chapter 56). Relative liver size, liver blood flow, and extent of protein binding also influence drug metabolism. Phase 1 of the process involves enzymatic activation of the substrate to reactive intermediates containing a carboxyl, phenol, epoxide, or hydroxyl group. Mixed-function mono-oxygenase, cytochrome-c reductase, various hydrolases, and the cytochrome P450 (CYP) system are involved in this process. Nonspecific induction of these enzymatic pathways, which can occur during intercurrent viral infection, with starvation, and with administration of certain drugs such as anticonvulsants, can alter drug metabolism and increase the potential for hepatotoxicity. A single agent can be metabolized by >1 biochemical reaction. The reactive intermediates that are potentially damaging to the cell are enzymatically conjugated in phase 2 reactions with glucuronic acid, sulfate, acetate, glycine, or glutathione. Some drugs may be directly metabolized by these conjugating reactions without 1st undergoing phase 1 activation. Phase 3 is the energy-dependent excretion of drug metabolites and their conjugates by an array of membrane transporters such as the multiple drug resistant protein 1 (MDR-1).

Pathways for biotransformation are expressed early in the fetus and infant, but many phase 1 and 2 enzymes are immature, particularly in the 1st yr of life. CYP3A4 is the primary hepatic CYP expressed postnatally and metabolizes >75 commonly used therapeutic drugs and several environmental pollutants and procarcinogens. Hepatic CYP3A4 activity is poorly expressed in the fetus but increases after birth to reach 30% of adult values by 1 mo and 50% of adult values between 6 and 12 mo of age. CYP3A4 can be induced by a number of drugs, including phenytoin, phenobarbital, and rifampin. Enhanced production of toxic metabolites can overwhelm the capacity of phase 2 reactions. Conversely, numerous inhibitors of CYP3A4 from several different drug classes, such as erythromycin and cimetidine, can lead to toxic accumulations of CYP3A4 substrates. By contrast, although CYP2D6 is also developmentally regulated (maturation by 10 yr of age), its activity depends more on genetic polymorphisms than on sensitivity to inducers and inhibitors because >70 allelic variants of CYP2D6 significantly influence the metabolism of many drugs. UDP-glucuronosyltransferase 1A6, a phase 2 enzyme that glucuronidates acetaminophen, is also absent in the human fetus, increases slightly in the neonate, but does not reach adult levels until sometime after 10 yr of age. Mechanisms for the uptake and excretion of organic ions can also be deficient early in life. Impaired drug metabolism via phrase 1 and 2 reactions present in the 1st few months of life is followed by a period of enhanced metabolism of many drugs in children through 10 yr of age compared with adults.

Genetic polymorphisms in genes encoding enzymes and transporters mediating phase 1, 2, and 3 reactions can also be associated with impaired drug metabolism and an increased risk of hepatotoxicity. Some cases of idiosyncratic hepatotoxicity can occur as a result of aberrations (polymorphisms) in phase 1 drug metabolism, producing intermediates of unusual hepatotoxic potential combined with developmental, acquired, or relative inefficiency of phase 2 conjugating reactions. Children may be more or less susceptible than adults to hepatotoxic reactions; liver injury after the use of the anesthetic halothane is rare in children, and acetaminophen toxicity is less common in infants than in adolescents, whereas most cases of fatal hepatotoxicity associated with sodium valproate use have been reported in children. Excessive or prolonged therapeutic administration of acetaminophen combined with reductions in caloric or protein intake can produce hepatotoxicity in children. In this setting, acetaminophen metabolism may be impaired by reduced synthesis of sulfated and glucuronated metabolites and reduced stores of glutathione. Immaturity of hepatic drug metabolic pathways can prevent degradation of a toxic agent; under other circumstances, the same immaturity might limit the formation of toxic metabolites.

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