ABSTRACT

I. INTRODUCTION As the liver is the major site for drug metabolism, it is not surprising that drug toxicity and adverse drug reactions would incite variable functional, histological, and ultrastructural hepatic abnormalities (1-9). Up to 10% of cases associated with abnormal liver tests are found to be drug-or toxin-induced, with the incidence rising to over 40% in patients over the age of 50 (10). Drug-induced liver injury is estimated to occur in from 2 to 5% of hospitalized patients with jaundice, and is responsible for up to 15-20% of cases of intrahepatic cholestasis, 15-30% of cases of fulminant hepatic failure, and 20-50% of cases of nonviral chronic hepatitis (11-17). The type of liver cell injury may be intrinsic

244 Kanel

Table 1 Drug and Toxin-Induced Liver Cell Injury: Morphological Variants (11,19,57) Morphology Examples

Hepatocellular injury Lobular necrosis with minimal to absent in-

flammation Zonal: Perivenular (zone 3) Alpha-methyldopa, acetaminophen, mush-

rooms

Midzonal (zone 2) Beryllium, dioxane Periportal (zone 1) Allyl formate, phosphorus, ferrous salts Diffuse (confluent) Halogenated hydrocarbons, mushrooms

Lobular necrosis with inflammation Isoniazid, phenytoin Lobular confluent necrosis with inflam-Niacin, troglitazone

mation Fatty change-macrovesicular Ethanol, rifampin, corticosteroids

—microvesicular Valproate, tetracycline, nucleosides Granulomas Diazepam, ranitidine, allopurinol Mallory bodies Amiodarone, griseofulvin

Cholestatic injury Cholestasis, simple Oral contraceptives, methimazole,

cyclosporin Cholestasis with inflammation Indomethacin, tamoxifen, carbamazapine,

erythromycins, chlorpromazine, sulindac, amoxicillin clavulanic acid

Bile duct injury Inflammation by neutrophils Allopurinol, hydralazine Inflammation by lymphocytes, ductopenia Cimetidine, tolbutamide

(duct loss) Periductal fibrosis Floxuridine

Vascular injury Sinusoids

Peliosis Arsenic, phalloidin Dilatation Oral contraceptives

Veno-occlusive disease Pyrrolizidine alkaloids, cyclophosphamide Thrombosis, fibrous obliteration Ethanol, oral contraceptives Vasculitis Allopurinol, phenylbutazone

Portal fibrosis Progression to cirrhosis Methotrexate, ethanol Without progression to cirrhosis Arsenic, vitamin A

Neoplasia Benign Oral contraceptives, toxic (rapeseed) oil Malignant Aflatoxins, thorotrast

Miscellaneous Inclusions

Hepatocytes Procainamide, lead Reticuloendothelial Polyvinyl pyrrolidone, thorotrast

Pigments Lipochrome Carbamazepine, nitrofurantoin Hemosiderin Ethanol, cimetidine Radiopaque Thorotrast Anthracite (Coal miners, city dwellers) Gold Gold sodium thiomalate

Histopathology of Drug-Induced Liver Disease 245

and dose-dependent (18); the mechanism may relate either to formation of free radicals or electrophilic intermediates, or to the production of reactive oxygen species, which, like free radicals, leads to lipid peroxidation (19-21). On the other hand, liver cell damage may be idiosyncratic and dose-independent, i.e., dependent on host susceptibility, and may be either immunologically or metabolically mediated (11,22). A wide variety of hepatic histological changes have been documented as secondary to drugs and toxins (Table 1); in addition, up to 1000 drugs and toxins have been implicated in causing these histological changes (23-25). Although the morphological features are usually reversible with stoppage of the medication and toxin exposure, unfortunately, in severe (fulminant) hepatitis and certain forms of chronic hepatitis, discontinuance of the drug does not alleviate the sometimes drastic outcomes. This chapter divides drugs and toxins into the various histological features seen on biopsy.