IMMUNE MECHANISMS IN DRUG HEPATOTOXICITY

Abstract

Idiosyncratic drug reactions involving the liver are infrequent, not dose related, unpredictable, and usually not reproducible in animals. Idiosyncratic drug reactions may arise as a consequence of metabolic idiosyncrasy, such as when a drug is metabolized through a usually minor pathway, or when immune mechanisms are involved. That disturbances in the immune system may be apparent in patients with adverse reactions following drug administration does not necessarily imply that immune mechanisms are involved in the pathogenesis of the liver damage. For example, Smith et al 44 , 45 have shown immune reactions to paracetamol in laboratory animals with paracetamol toxicity, a well-characterized direct hepatotoxic reaction. Similarly, Lindgren reported one case of granulomatous hepatitis associated with paracetamol, raising the possibility that even recognized direct hepatotoxins may be associated with immune-mediated drug reactions, which may be secondary to the toxic insult rather than the cause. 30a In many cases of immune mediated drug reactions, the liver is only one of the organs affected. There may be concomitant other organ damage, such as hemolytic anemia or a skin rash. The pattern of liver damage associated with immune-mediated drug reactions covers the spectrum of liver disease. The most common reaction is an acute hepatitis, which may range from a mild hepatitis that resolves rapidly when the offending drug is withheld to a fulminating hepatitis leading to fulminant hepatic failure and, in the absence of transplantation, death. Other hepatic manifestations of liver damage seen in patients with immune-mediated drug reactions include cholestasis , eosinophil or lymphocytic infiltration , granuloma formation, chronic hepatitis, which may make autoimmune hepatitis, and cirrhosis . Although eosinophilic infiltration of the liver is suggestive of an immune-mediated drug reaction, it is not specific. Features of immune-mediated drug reactions Previous exposure to drug Pyrexia Arthralgia Skin rash Eosinophilia Circulating immune complexes Organ nonspecific auto-antibodies Drug-related auto-antibodies Eosinophilic infiltration Granulomas Immune-mediated drug reactions may be associated with systemic evidence of immune activation, including peripheral eosinophilia, circulating immune complexes, and organ nonspecific autoantibodies. Clinically, immune-mediated drug reactions are associated with arthralgia, pyrexia and skin rashes. None of these findings is either specific or diagnostic. In rare cases, rechallenges (intentional or inadvertent) have been performed; after re-exposure to the drug, the interval to development of hepatotoxicity is shorter. Most instances of immune-mediated drug reactions are manifest as a hepatitis, with the presumed immune target being the hepatocyte; however, it has been suggested that the vanishing bile duct syndrome seen following the use of nonsteroidal anti-inflammatory drugs may also be immune mediated. 2 Although the mechanisms of such immune reactivity are unclear, immune-mediated progressive vanishing bile duct syndromes are recognized in other situations such as chronic liver allograft rejection and graft-versus-host disease . Some drugs may be associated with more than one type of immune-mediate organ damage. Therefore, minocycline 14 has been associated in one patient with the development of an acute hepatitis and drug-induced lupus ; methyldopa is associated with both hemolytic anemia and chronic, active hepatitis .