Pathogenesis

The liver is the major organ for metabolism of many drugs. This explains its susceptibility to drug-induced injury. Drug elimination involves three phases. In phase I, drugs are metabolized by cytochrome P-450 enzymes. This process may generate toxic electrophilic chemicals or free radicals. In phase II, these metabolites or the parent drug are conjugated with glutathione or glucuronide to improve water solubility. This permits excretion of the agents from the body in bile or urine. The route of elimination is mainly determined by excretory transporters in the hepatocyte canalicular and sinusoidal membrane (phase III). Electrophilic chemicals and free radicals are potentially toxic because they can covalently bind to proteins, lipids, and deoxyribonucleic acid (DNA); cause lipid peroxidation; and deplete glutathione. Consequently, these effects may lead to hepatotoxicity in several ways, including (1) by directly causing loss of vital cell function (eg, mitochondria) and subsequent cell death; (2) by sensitizing hepatocytes to the toxic effects of the innate immune system (eg, tumor necrosis factor, Fas ligand, interferon-7);

TABLE 119-5. Drug-Induced Chronic Liver Disease

Chronic hepatitis a-Methyldopa Diclofenac Minocycline Nitrofurantoin Granulomatous hepatitis Allopurinol Diltiazem Quinidine Penicillamine Procainamide Steatohepatitis Amiodarone Nifedipine Tamoxifen Chronic cholestasis Flucloxacillin Tetracycline

Trimethoprim-sulfamethoxazole Cirrhosis Methotrexate Vitamin A Vascular disorders Azathioprine Busulfan

Cyclophosphamide Hepatic tumors Androgens Estrogens or (3) by eliciting immune hypersensitivity via hapteniza-tion. The mechanisms of delayed metabolic idiosyncratic reactions are very poorly understood and may be the result of genetic or acquired differences in drug metabolism, canalicular secretion, mitochondrial defects, cell death receptor signaling, or the response of the innate immune system. Thus, it is speculated that host-dependent mechanisms render selected individuals highly susceptible to the toxicity of normally safe drugs.

The mechanisms of hepatotoxicity explained above can result in combined hepatic or cholestatic liver disease. For example, the canalicular secretion of toxic metabolites causes bile duct injury and inflammation and induces immune responses to haptenized duct cells. Because the same toxic metabolites can also injure hepatocytes, mixed patterns of liver injury may occur (cholestatic hepatitis). Some drugs (eg, rifampicin and cyclosporin A) may also cause cholestasis without producing appreciable liver damage by inhibiting bile salt excretory proteins. Reduced function of the bile salt transporters causes bile acids and other factors that are normally excreted in the bile to accumulate in liver and serum and can lead to pruritus.

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