Allergic hepatitis: a drug-mediated organ-specific immune reaction

Idiosyncratic toxicity (i.e. adverse reactions to drugs that occur only in certain individuals) is a major concern in drug toxicity and drug development. This type of adverse reaction may appear during the clinical use of a drug, cannot easily be explained in terms of an exaggerated pharmacological side-effect of the compound, and is very difficult to anticipate from the preclinical studies. Hepatic idiosyncratic reactions fall within two categories: those that are the consequence of an unusual metabolism of the drug (metabolic idiosyncrasy) and those resulting from an immune-mediated cell injury to hepatocytes which have been in contact with the drug previously (allergic hepatitis). In the former case, the toxicity is dose-dependent, while in the latter, toxicity may appear after several asymptomatic administrations of the compound (sensitization period). The mechanisms that trigger the immune response have not yet been precisely defined. Current understanding of how drug allergy arises is based largely on the hapten hypothesis. Most drugs are not chemically reactive but can be activated metabolically to reactive species which, after binding to cellular macromolecules, become immunogenic and can elicit an effective immune response. Presentation of drug-protein adducts by professional cells to TH lymphocytes, and/or a direct association between the drug and MHC proteins of hepatocytes could be involved in the activation of the immune system. As a consequence of this, drug-directed antibodies and/or T-lymphocytes able to recognize drug-derived haptens arise which are responsible for the clinical manifestations of the hepatitis. Drug-directed antibodies can be detected in sera of allergic patients by solid-phase immunoassays. Sensitized T-lymphocytes can be shown by hapten-induced cell proliferation experiments and by the early expression of CD69 antigen.