Liver injury is a possible consequence of ingestion of any xenobiotic, including industrial toxins, pharmacologic agents, and complementary and alternative medications (CAMs). Among patients with acute liver failure, drug-induced liver injury (DILI) is the most common cause, and evidence for hepatotoxicity detected during clinical trials for drug development is the most common reason for failure of compounds to reach approval status. DILI requires careful history taking to identify unrecognized exposure to chemicals used in work or at home, drugs taken by prescription or bought over the counter, and herbal or dietary supplement medicines. Hepatotoxic drugs can injure the hepatocyte directly, for example, via a free-radical or metabolic intermediate that causes peroxidation of membrane lipids and that results in liver cell injury. Alternatively, a drug or its metabolite may activate components of the innate or adaptive immune system, stimulate apoptotic pathways, or initiate damage to bile excretory pathways (Fig. 333-1). Interference with bile canalicular pumps can allow endogenous bile acids, which can injure the liver, to accumulate. Such secondary injury, 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 other instances, drug metabolites sensitize hepatocytes to toxic cytokines. The differences observed between susceptible and nonsusceptible drug recipients may be attributable to human leukocyte antigens (HLA) haplotypes that determine binding of drug-related haptens on the cell surface as well as to polymorphisms in elaboration of competing, protective cytokines, as has been suggested for acetaminophen hepatotoxicity (see below). Immune mechanisms may include cytotoxic lymphocytes or antibody-mediated cellular cytotoxicity. In addition, a role has been shown for activation of nuclear transporters, such as the constitutive androstane receptor (CAR) or, more recently, the pregnane X receptor (PXR), in the induction of drug hepatotoxicity.
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 P450 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; (E) activation of apoptotic pathways by tumor necrosis factor α (TNF-α) receptor or Fas (DD denotes death domain), triggering ...