Drug-Induced Cholestasis

Intrahepatic cholestasis, defined as arrested bile flow, mimics extrahepatic obstruction in its biochemical, clinical and morphological features. It may be due to hepatocyte lesions of which there are three types, termed canalicular, hepatocanalicular and hepatocellular, respectively; or it may be due to ductal lesions at the level of the cholangiole or portal or septal ducts. Defective bile flow due to hepatic lesions reflects abnormal modification of the ductular bile. Defective formation of canalicular bile may involve bile acid-dependent or independent flow. It appears to result most importantly from defective secretion of bile acid-dependent flow secondary to defective uptake from sinusoidal blood, defective transcellular transport and defective secretion; or from regurgitation of secreted bile via leaky tight junctions. An independent defect in bile acid-independent flow is less clear. Defective flow of bile along the canaliculus may reflect increased viscosity and impaired canalicular contractility secondary to injury of the pericanalicular microfibrillar network. Impaired flow beyond the canaliculus may result from ductal injury. Sites of lesions that contribute to cholestasis include the sinusoidal and canalicular plasma membrane, the pericanalicular network and the tight junction and, less certainly, microtubules and microfilaments and Golgi apparatus. A number of drugs that lead to cholestasis have been found to lead to injury at one or more of these sites. Other agents (α-naphthylisothiocyante, methylenedianiline, contaminated rapeseed oil, paraquat) lead to ductal injury resulting in cholestasis. Reports of inspissated casts in ductules (benoxaprofen jaundice) and injury to the major excretory tree (5-fluorouridine after hepatic artery infusion) have led to other forms of ductal cholestasis. Most instances of drug-induced cholestasis present as acute, transient illness, although important chronic forms also occur. The clinical features include the reflection of the cholestasis (pruritus, jaundice), systemic manifestations and extrahepatic organ involvement. While nearly all classes of medicinal agents include some that can lead to cholestasis, there are differences among the various categories. Phenothiazines and related antipsychotic and ‘tranquilliser’ drugs characteristically lead to cholestatic hepatic injury. The tricyclic antidepressants may lead to cholestatic or hepatocellular injury. The anticonvulsants include agents that lead to mainly hepatocellular injury with only occasional instances of cholestasis (e.g. phenytoin, carbamazepine), to characteristic, though rare, cholestasis (phenobarbitone) or to only hepatocellular injury (e.g. valproate). Some antimicrobial agents characteristically lead to mainly cholestatic injury (e.g. organic arsenicals, erythromycin esters, thiabendazole), others to hepatocellular injury. Most non-steroidal anti-inflammatory drugs tend to produce hepatocellular injury, although a few lead to cholestasis (e.g. benoxaprofen, naproxen, gold compounds) or to either cholestatic or hepatocellular injury (sulindac, phenylbutazone). C-17 alkylated anabolic and contraceptive steroids can lead to cholestasis. Ethinyloestradiol has proved to be an important experimental tool for production of cholestasis in animals. Jaundice provoked by all antithyroid drugs, except propylthiouracil, is cholestatic. Drugs used to treat cardiovascular disease that can provoke cholestasis include ajmaline, captopril, warfarin, phenindione, disopyramide, propafonone, thiazide diuretics and verapamil. Most antineoplastic drug-induced jaundice is hepatocellular. The drugs in this category that can lead to cholestasis include azathioprine, chlorozotocin, busulphan, aminoglutethimide (and 5-fluorouridine by infusion into the hepatic artery). Other drugs that can lead to cholestasis include penicillamine, dextropropoxyphene and cimetidine. Ranitidine seems more prone to cause hepatocellular injury. Non-medicinal agents of natural origin that can lead to cholestasis include the sterolike alkaloid, icterogenin, fungal alkaloids (sporidesmin, cytochalasin B), monohydroxy bile acids, (lithocholate) and bacterial toxins (e.g., endotoxin). The cholestasis induced by total parenteral nutrition (TPN) may perhaps be grouped appropriately with these agents. Other non-medicinal agents that can lead to cholestasis include methylenedianiline α-napthylisothiocyanate, trivalent manganese ion, contaminated rapeseed oil and paraquat.