Immunological investigation in hepatic drug reactions

Drug-induced liver injury is increasingly recognized as a major clinical problem. Some epidemiological studies reveal that as much as 20% of cases of jaundice admitted to hospitals in an elderly population and 25% of fulminant hepatitis in intensive care units are due to drug-induced hepatitis. Although cases of liver lesions associated with drugs can be clinically severe, they represent rare events, taking into account the high number of individuals exposed to the suspected drugs. Pre-marketing clinical studies eliminate almost completely drugs that cause dose-dependent hepatotoxicity and thus, most of the cases seen nowadays are due to dose-independent reactions in susceptible subjects. The diagnosis of dose-dependent hepatic injury is straight-forward, whereas in hepatic reactions dependent on individual susceptibility, clinical diagnostic criteria are sometimes difficult to apply, particularly when the patient had been taking multiple drugs. It is usually assumed that individual susceptibility can be metabolic and or immunological in nature, but this is largely unknown for most drugs. A pathogenic role for T-cell-mediated immunological mechanisms has been proposed on the basis of experimental models, particularly halothane-induced hepatitis. Additional evidence comes from clinical studies describing T lymphocyte-specific responses to the drugs in patients with allergic drug hepatitis, in contrast with an absence of such specific responses in healthy and pathological controls, including patients taking the drug without suffering adverse reactions. In this paper we review the experience of our group in the analysis of drug specific T-cell responses in vitro in cases of drug-induced liver injury, using several methodological modifications that increase the ability to detect T lymphocyte sensitization to drugs and we discuss the possible diagnostic value of these investigations.