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Liver injury may follow the inhalation, ingestion, or parenteral administration of a number of pharmacologic and chemical agents. These include industrial toxins (e.g., carbon tetrachloride, trichloroethylene, and yellow phosphorus); the heat-stable toxic bicyclic octapeptides of certain species of Amanita and Galerina (hepatotoxic mushroom poisoning); and, more commonly, pharmacologic agents used in medical therapy. Among patients with acute liver failure, drug-induced liver injury is the cause in a majority of all cases, and liver toxicity accounts for the abandonment of many new drugs during their development. It is essential that any patient presenting with jaundice or altered biochemical liver tests be questioned carefully about exposure to chemicals used in work or at home, drugs taken by prescription or bought over the counter, and herbal or alternative medicines. Hepatotoxic drugs can injure the hepatocyte directly (e.g., via a free-radical or metabolic intermediate that causes peroxidation of membrane lipids and that results in liver cell injury). Alternatively, the drug or its metabolite can distort cell membranes or other cellular molecules, bind covalently to intracellular proteins, activate apoptotic pathways, interfere with bile salt export proteins, or block biochemical pathways or cellular integrity (Figure 305-1). Interference with bile canalicular pumps can allow endogenous bile acids, which can injure the liver, to accumulate. Such injuries, in turn, may lead to necrosis of hepatocytes; injure bile ducts, producing cholestasis; or block pathways of lipid movement, inhibit protein synthesis, or impair mitochondrial oxidation of fatty acids, resulting in lactic acidosis and intracellular triglyceride accumulation (expressed histologically as microvesicular steatosis). In some cases, drug metabolites sensitize hepatocytes to toxic cytokines, and differences between susceptible and nonsusceptible drug recipients may be attributable to polymorphisms in elaboration of competing, protective cytokines, as has been suggested for acetaminophen hepatotoxicity (see below). Immunologically mediated liver injury has been postulated to represent another mechanism of drug hepatotoxicity (see below). In addition, a role has been shown for activation of nuclear transporters, such as the constitutive androstane receptor (CAR), in the induction of drug hepatotoxicity.

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Figure 305-1
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Potential mechanisms of drug-induced liver injury. The normal hepatocyte may be affected adversely by drugs through A. disruption of intracellular calcium homeostasis that leads to the disassembly of actin fibrils at the surface of the hepatocyte, resulting in blebbing of the cell membrane, rupture, and cell lysis; B. disruption of actin filaments next to the canaliculus (the specialized portion of the cell responsible for bile excretion), leading to loss of villous processes and interruption of transport pumps such as multidrug resistance–associated protein 3 (MRP3), which, in turn, prevents the excretion of bilirubin and other organic compounds; C. covalent binding of the heme-containing cytochrome P-450 enzyme to the drug, thus creating nonfunctioning adducts; D. migration of these enzyme-drug adducts to the cell surface in vesicles to serve as target immunogens for cytolytic attack by T cells, stimulating an immune response involving cytolytic T cells and cytokines; ...

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