The morphologic lesions caused by drugs and toxins may resemble those of any known type of liver disease, from benign cholestasis to malignant tumors; most produce similar lesions in exposed or susceptible individuals, but some may have more than one type of pathologic effect. For example, tetracycline and halothane generally lead to microvesicular steatosis or acute hepatocellular degeneration and necrosis, respectively. Oral contraceptives, on the other hand, have been incriminated in cholestatic reactions, sinusoidal dilatation, hepatic vein thrombosis, and in the induction of hepatocellular adenoma.

The present review is limited to cholestatic drug injuries, both acute and chronic, caused by therapeutic drugs. Herbal preparations leading to cholestasis or a cholestatic hepatitis are mentioned and some are referenced. They are discussed by Dr. Seeff, and several reviews are referenced for further reading (Larrey, 1997; Stedman, 2002; Zimmerman & Ishak, 2002). Mechanisms of hepatotoxicity are discussed by Dr. Roberts, and several reviews are referenced for additional source material (Bissell et al, 2001; Bohan and Boyer, 2002; Kaplowitz, 2002; Larrey 2002; Watkins, 2003; Zimmerman, 1999). A classification of acute and chronic drug-related cholestatic injuries is proposed in Table 1.

Acute Cholestasis
This is divisible into two broad categories: cholestasis (bile stasis) without evidence of hepatocellular injury ("pure" or "bland" cholestasis), and cholestasis accompanied by a variable degree of hepatocytic injury, such as apoptotic bodies, small foci of necrosis and less often, ballooning, with or without zone 3 necrosis (so-called cholestatic hepatitis). Drugs leading to acute cholestasis or cholestatic hepatitis are listed in Table 2. The hepatocellular injury is often localized to the zones of cholestasis, i.e., zone 3. There is accumulation of bile in the cytoplasm of liver cells, canaliculi and Kupffer cells. Portal areas show little or no inflammation in the purely cholestatic injury, or mild to moderate (but often patchy) inflammation in the cholestatic form accompanied by mild hepatocellular injury. In cases assumed to be on the basis of hypersensitivity there may be many eosinophils in the portal areas and sinusoids, particularly if the biopsy material is obtained early in the course of the illness when the patient has peripheral eosinophilia. Patchy periportal cholangiolar proliferation is sometimes associated with a neutrophilic response ("acute cholangiolitis"). Drugs that lead to the pure cholestatic reaction include the anabolic steroids (e.g., methyl testosterone, oxymetholone, fluoxymesterone) and the contraceptive steroids. Drugs that may induce cholestasis with a minimal degree of hepatocellular injury are listed in Table 2 by therapeutic category.

Intrahepatic cholestasis may be accompanied by bile duct degeneration (with little or no inflammation), or an acute cholangitis, that may be necrotizing with progressive destruction of bile ducts. The former has been reported with several hepatotoxins, such as 4,4'-diaminodiphenylmethane, paraquat and Spanish toxic oil, while the latter has been observed in patients on chlorpromazine, allopurinol, chlorpropamide and hydralazine. Bile duct necrosis is a recognized complication of transcatheter hepatic arterial embolization by gelatin powder. Infarction of the gallbladder has also been reported after hepatic artery embolization.

Chronic Cholestasis
Most cases of drug-induced cholestasis are followed by rapid biochemical and clinical improvement and recovery upon withdrawal of the medication and supportive treatment. About 1% of patients, however, continue to have abnormal liver tests for many months. These patients may eventually recover, but some will progress, with clinical and biochemical features resembling those of primary biliary cirrhosis (PBC). Unlike PBC, however, the chronic injury typically follows an overt episode of cholestasis and evolves relatively rapidly (weeks or months, instead of years). Additionally, antibodies against mitochondria are not detectable in the serum. Histologic features characterizing chronic, drug-induced intrahepatic cholestasis include bile stasis (often periportal), pseudoxanthomatous and xanthomatous transformation of hepatocytes and Kupffer cells respectively, accumulation of copper and copper-binding protein in periportal liver cells, minimal to moderate patchy chronic portal inflammation and degeneration and variable loss of bile ducts. The term "vanishing bile duct syndrome" has been used to describe cases with marked ductopenia (Desmet, 1992). There is often progressive periportal fibrosis, with or without bridging, and some cases may develop a biliary type of cirrhosis. Drugs that can lead to chronic intrahepatic cholestasis are listed in Table 3.

Bile duct sclerosis, involving the extrahepatic biliary tract (but often sparing the distal common bile duct) and intrahepatic ducts (sclerosing cholangitis-like injury), has been reported as a complication of hepatic arterial infusion with floxuridine, and after the use of formalin for the sterilization of echinococcal cysts. In the case of floxuridine the sclerosis of bile ducts has been attributed to an associated vasculopathy (both arterial and venous). In the formalin-related injury the formalin solution gains access to the bile ducts leading to a "caustic" sclerosis.

Diagnostic Considerations
A detailed drug or toxin history is essential for adequate evaluation of drug-induced or toxic liver injury. If a therapeutic drug is suspected, the history must include the dosage, route of administration, and duration of therapy of the drug in question and any other concomitantly administered drugs. Other than therapeutic drugs, self-prescribed medicines (e.g. vitamins, herbal medicines) and substance abuse should inquired about. If a toxin is under consideration, then the amount, duration, and type of exposure (ingestion, inhalation, absorption from the skin or mucous membranes) are all extremely important in the evaluation of a given case.

The interval of time from the beginning of drug therapy or exposure to a toxin to the development of symptoms or signs heralding the onset of the injury ("latent period") must be estimated. In some instances, it is possible to pinpoint the onset by the occurrence of a symptom complex, such as a "flu-like" syndrome, various gastrointestinal complaints, or fever followed by a rash while the patient is taking a drug. On the other hand, such symptoms and signs may be difficult to unravel from those of the underlying disease, in which case reliance must be placed on the subsequent appearance of jaundice or abnormal results of liver tests. When determined, the "latent period" should fall within the previously accepted range of time for injury from a particular drug, for example, a few days after a second or multiple exposures to halothane, one to four weeks for injury associated with chlorpromazine or phenytoin, to anywhere from five weeks to a year for a drug such as isoniazid. In patients with chronic liver disease (chronic hepatitis, cirrhosis) on long term drug therapy the onset of the illness may be difficult if not impossible to determine.

Causality assessment of drug-induced injuries, pioneered by Irey (1976) many years ago, has generated several studies more recently, with "clinical diagnostic scales" (Lucena et al, 2001, Aithal et al, 2002) which will not be discussed in this presentation.

Without question, the most important aspect of the investigation of a possible drug-induced or toxic injury is to rule out other causes of liver disease by careful assessment of all the clinical, morphologic, radiologic, biochemical and serologic findings.

The possibility of a drug or toxic insult superimposed on another, pre-existing liver disease, also should be considered (Schenker et al, 1999). Examples include the occurrence of necrosis of acinar zone 3 from acetaminophen overdose in a patient with alcoholic steatohepatitis, or the development of a hepatotoxic insult in alcoholics on antituberculous therapy.

Use of the offending drug must be immediately discontinued if clinicopathologic correlation establishes with reasonable certainty that a drug is a possible or probable cause of a hepatic injury. More often than not, this is followed by prompt clinical and biochemical improvement, providing further presumptive evidence of a drug etiology. Ultimate proof of a cause-and-effect relationship requires rechallenge with the suspected drug; today, rechallenge is conducted only when need for the drug clearly exceeds the risk. Other, less risky and more sensitive methods of diagnosis will be increasingly utilized in the future. It is well known that acquired and genetic factors influence individual susceptibility to drug hepatotoxicity. Important directions for the future include prospective studies of the incidence of hepatic adverse drug reactions, finding specific markers that augment or replace causality assessment, and further elucidating the role of the genetic and environmental factors that contribute to individual susceptibility (Larrey, 2002). Pharmacogenomics (inheritance and the drug response) is reviewed recently by Evans et al (2003) and Weinshilboum (2003).

References

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Table 2. Drug Induced Cholestasis

Antimicrobials: Erythromycin; Quinolones; Ciprofloxacin (Ofloxacin, Norfloxacin); Ketoconazole; Itraconazole; Terbinafine; Troleandomycin; Amoxicillin-clavulanate; Semisynthetic penicillins (Cloxacillin, Floxacillin, Oxacillin, Dicloxacillin, Flucloxacillin); Novobiocin; Thiabendazole; Clindamycin; Trimethoprim-sulfamethoxazole; Rifampicin; Dapsone; Nitrofurantoin. Neuroleptics: Phenothiazines (Chlorpromazine, Prochlorperazine, Haloperidol); Tricyclic antidepressants (Imipramine, Amitriptyline, Trazodone); Benzodiazepines (Chlordiazepoxide, Flurazepam). Anti-inflammatory: Sulindac; Diclofenac; Piroxicam; Indomethacin; Ibuprofen; Naproxen; Gold salts; Diflunisal; Phenylbutazone. Anticonvulsants: Phenytoin; Carbamazepine. Cardiovascular: Ajmaline; Captopril; Warfarin; Acenocoumarol; Chlorthalidone; Disopyramide; Aprindine; Diltiazem. Hypolipidemics: Lovastatin, Simvastatin; Atorvastatin; Pravastatin. Anti-Cancer Drugs: Azathioprine; 6-Mercaptopurine. Hypoglycemics: Carbutamide; Metahexamide; Chlorpropamide; Tolbutamide; Tolazamide; Rosiglitazone, Pioglitazone; Metformin. Steroids/Steroid Inhibitors: C-17 alkylated anabolic steroids; Contraceptive steroids; Tamoxifen; Danazol; Aminoglutethimide; Anti-thyroid: Carbimazole; Methimazole; Thiouracil. Miscellaneous: Total Parenteral Nutrition; Cimetidine; Ranitidine; Infliximab; Ticlopidine; Flutamide; Famotidine; Riluzole. Herbal Preparations: Kombucha tea; Apiol; Greater celandine; Pennyroyal; Cascara sagrada; Psoralea-corylifolia; "Soju" remedy; Ecstasy

TABLE 3. DRUGS INCRIMINATED IN CHRONIC CHOLESTASIS

Acetaminophen Imipramine Ajmaline and related drugs Itraconazole Amitriptyline Methyltestosterone Ampicillin Norandrostenolone Barbiturates Penicillamine Carbamazepine Phenytoin Carbutamide Prochlorperazine Chlorpromazine Sulpiride Cimetidine Thiabendazole Ciprofloxacin Ticlopidine Cyamemazine Tiopronin Cyproheptadine Tolbutamide Erythromycin Total parenteral nutrition Glycyrrhizin Troleandomycin Haloperidol Xenalamine (Xenazoic acid) Ibuprofen