Drug-induced Cholestasis

Drug-induced Cholestasis

Drugs are a common cause of cholestasis. A spectrum of drug-induced liver injury ranges from acute reversible cholestasis to chronic cholestasis with loss of bile ducts. In a large study of 1100 cases, acute cholestasis accounted for about 17% of liver-related adverse drug reactions.¹⁷ Drugs can interfere with various aspects of bile acid metabolism including uptake, transport, and secretion at the hepatocyte level.¹⁸

Drug-induced cholestasis can be categorized into acute and chronic forms (Table 2).¹⁹ The acute forms are subdivided into cholestasis without inflammation ("bland" cholestasis), cholestasis with inflammation, and cholestasis with bile duct injury. Chronic forms include a vanishing bile duct syndrome and a sclerosing cholangitis-like syndrome.

Table 2:
Drug-induced Cholestasis
Cholestasis without Hepatitis	Cholestasis with Hepatitis	Cholestasis with Bile Duct Injury	Vanishing Bile Duct Syndrome	Sclerosing Cholangitis-like
Estrogens	Chlorpromazine	Dextropropoxyphene	Chlorpromazine	Floxuridine
Anabolic steroids	Macrolide antibiotics	Flucoxacillin	Flucloxacillin and other oxypenicillins	Intralesiond scolicidal agents (2% formaldehyde, 20% hypertonic saline, absolute alcohol, silver nitrate, iodine solution)
Cyclosporine	Tricyclic antidepressants	Carmustine	Amoxicillin-clavulanic acid
Tamoxifen	Carbamazepine	Toxins: paraquat, methylenedianiline	Ampicillin
Azathioprine	Amoxicillin-clavulanate		Amitriptyline
	Oxypenicillins		Azathioprine
	NSAIDs		Barbiturates
	Azathioprine		Carbamazepine
			Chlorthiazide
			Co-trimoxazole
			Clindamycin
			Chlorpromazine
			Cimetidine
			Cyproheptadine
			Dicloxacillin
			Erythromycin esters
			Estradiol
			Flucloxacillin
			Glycyrrhizin
			Haloperidol
			Ibuprofen
			Imipramine
			D-penicillamine
			Phenytoin
			Norandrostenolone
			Prochlorperazine
			Tetracycline
			Terbinafine
			Thiabendazole
			Tiopronin
			Tolbutamide
			Methyl testosterone

Drug-induced cholestasis can be accompanied by nausea, anorexia, malaise, and pruritus.¹⁹ Symptoms can occur weeks to months after beginning treatment. Drugs that cause cholestasis with bile duct injury often are accompanied by additional clinical features such as fever, rigors, jaundice, and tender hepatomegaly mimicking acute cholangitis. Drugs that result in a vanishing bile duct syndrome may lead to progressive cholestasis with prolonged jaundice and pruritus, and occasionally cirrhosis and liver failure. The most important tool in the diagnosis of drug-induced cholestasis is a careful medical history eliciting from the patient a history of taking prescribed, over-the-counter, or alternative medications including herbs. Biliary obstruction should be excluded with an imaging study (ultrasound or computerized tomography [CT] scan) of the biliary tree. Principle treatment is withdrawal of the drug. Management of symptoms associated with cholestasis are similar to those for PBC.

Most cholestatic hepatic injury will resolve with withdrawal of the offending medication. A small subgroup of patients will develop progressive liver disease resulting in biliary cirrhosis and liver failure.

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Intrahepatic Cholestatic Liver Disease