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.

Chemical hepatotoxicity can be predictable or idiosyncratic. Predictable hepatotoxicity implies a high incidence of hepatic injury in exposed persons, with dose dependence. It is understandable that only a few drugs in clinical use fall into this category. These agents might damage the hepatocyte directly through alteration of membrane lipids (peroxidation) or through denaturation of proteins; such agents include carbon tetrachloride and trichloroethylene. Indirect injury can occur through interference with metabolic pathways essential for cell integrity or through distortion of cellular constituents by covalent binding of a reactive metabolite; examples include the liver injury produced by acetaminophen or by antimetabolites such as methotrexate or 6-mercaptopurine.

Idiosyncratic hepatotoxicity is uncommon and unpredictable but accounts for the majority of adverse reactions. The likelihood of injury is not dose dependent and can occur at any time during exposure to the agent. Idiosyncratic drug reactions in certain patients can reflect aberrant pathways for drug metabolism, possibly related to genetic polymorphisms, with production of toxic intermediates (isoniazid and sodium valproate can cause liver damage through this mechanism). Duration of drug use before liver injury varies (weeks to ≥1 yr) and the response to re-exposure may be delayed.

An idiosyncratic reaction can also be immunologically mediated as a result of prior sensitization (hypersensitivity); extrahepatic manifestations of hypersensitivity can include fever, rash, arthralgia, and eosinophilia. Duration of exposure before reaction is generally 1-4 wk, with prompt recurrence of injury on re-exposure. Studies indicate that arene oxides, generated through oxidative (cytochrome P450) metabolism of aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine), can initiate the pathogenesis of some hypersensitivity reactions. Arene oxides, formed in vivo, can bind to cellular macromolecules, thus perturbing cell function and possibly initiating immunologic mechanisms of liver injury.

Although the generation of chemically reactive metabolites has received great attention in the pathogenesis of hepatoxicity, increasing evidence now exists for the multifactorial nature of the process, in particular the role played by the host immune system. Activation of liver nonparenchymal Kupffer cells and infiltration by neutrophils perpetuate toxic injury by many drugs by release of reactive oxygen and nitrogen species as well as cytokines. Stellate cells can also be activated, potentially leading to hepatic fibrosis and cirrhosis.

The pathologic spectrum of drug-induced liver disease is extremely wide, is rarely specific, and can mimic other liver diseases (Table 355-1). Predictable hepatotoxins such as acetaminophen produce centrilobular necrosis of hepatocytes. Steatosis is an important feature of tetracycline (microvesicular) and ethanol (macrovesicular) toxicities. A cholestatic hepatitis can be observed, with injury caused by erythromycin estolate and chlorpromazine. Cholestasis without inflammation may be a toxic effect of estrogens and anabolic steroids. Use of oral contraceptives and androgens has also been associated with benign and malignant liver tumors. Some idiosyncratic drug reactions can produce mixed patterns of injury, with diffuse cholestasis and cell necrosis. Some herbal supplements have been associated with hepatic failure (Table 355-2). Chronic hepatitis has been associated with the use of methyldopa and nitrofurantoin.

Table 355-1 PATTERNS OF HEPATIC DRUG INJURY

Clinical manifestations can be mild and nonspecific, such as fever and malaise. Fever, rash, and arthralgia may be prominent in cases of hypersensitivity. In ill hospitalized patients, the signs and symptoms of hepatic drug toxicity may be difficult to separate from the underlying illness. The differential diagnosis should include acute and chronic viral hepatitis, biliary tract disease, septicemia, ischemic and hypoxic liver injury, malignant infiltration, and inherited metabolic liver disease.

The laboratory features of drug- or toxin-related liver disease are extremely variable. Hepatocyte damage can lead to elevations of serum aminotransferase activities and serum bilirubin levels and to impaired synthetic function as evidenced by decreased serum coagulation factors and albumin. Hyperammonemia can occur with liver failure or with selective inhibition of the urea cycle (sodium valproate). Toxicologic screening of blood and urine specimens can aid in the detecting drug or toxin exposure. Percutaneous liver biopsy may be necessary to distinguish drug injury from complications of an underlying disorder or from intercurrent infection.

Slight elevation of serum aminotransferase activities (generally <2-3 times normal) can occur during therapy with drugs, particularly anticonvulsants, capable of inducing microsomal pathways for drug metabolism. Liver biopsy reveals proliferation of smooth endoplasmic reticulum but no significant liver injury. Liver test abnormalities often resolve with continued drug therapy.

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