Drug-related acute and chronic hepatitis

The number of therapeutic drugs known to produce hepatic damage increases each year and pre-drug-release testing for potential to damage the liver is an important aspect of new drug evaluation (Klatskin, 1975; Zimmerman, 1978). It is becoming increasingly apparent that many widely used and presumably safe agents can cause significant liver damage. Furthermore, the prognosis in a patient with clinically apparent drug-induced hepatitis is much poorer than for acute viral hepatitis. The major contribution of therapeutic drugs to the syndrome of fulminant hepatic failure is established. Even more recently it has been recognized that drug reactions may be important in the production of a chronic active hepatitis-like illness and postnecrotic cirrhosis (Goldstein, Lam and Mistilis, 1973; Maddrey and Boitnott, 1977). There has been much new information concerning the incidence and epidemiology of drug reactions and advances in the understanding of the mechanisms by which drugs damage the liver (Mitchell et al, 1976). New areas of research emphasizing host factors which alter susceptibility to drug-induced liver injury and drug-drug interactions to produce injury are being developed. In this article the author shall discuss acute and chronic drug-induced hepatitis and outline mechanisms by which injury may occur. The clinical features and hepatic syndromes produced by four widely employed therapeutic agents - isoniazid, halothane, methyldopa and diphenylhydantoin - demonstrate a spectrum both of liver injury and of presumed mechanisms of injury. These four agents have all been introduced into clinical therapeutics in the past 40 years and account for a significant number of identified serious drug-induced liver injuries. Each of the four has a rather distinct natural history of liver damage and patterns of injury. All four can produce mild hepatic injury characterized by minimal often asymptomatic increases in aminotransferases, but each can produce more severe, even fatal liver disease.