Drug-induced liver injury: Hy’s rule revisited

Abstract

Drug-induced liver injury is a potential complicationof many drugs. This is to be expected because the liverplays a central role in drug metabolism. Only a veryfew drugs causing drug-induced liver injury have apredictable, dose-dependent toxic mechanism of action,the most widely recognized being acetaminophen(INN, paracetamol) and, to some extent, methotrexate.When acetaminophen overdose is excluded, in mostcases drug-induced liver injuries are due to rare, unpre-dictable reactions of commonly used drugs. These un-predictable reactions are mostly either idiosyncratic orimmune-mediated, or both, but may also, in somecases, have a dose-related component. Current defini-tion of drug-induced liver injury is dependent on non-specific elevations in liver test results, in particular,increases in aminotransferase levels. Histologic mani-festations of drug-induced liver injury can mimic mostother known liver diseases, and there are no pathogno-monic histologic features of drug-induced liver injury.In most cases of drug-induced liver injury, liver biopsyfindings are “compatible with” drug-induced liver in-jury, and the histologic examination often tells moreabout the extent of the injury than the cause. Consid-eration of the course of events and the results of dechal-lenge, as well as the results of other tests, is necessaryto achieve a high diagnostic accuracy of drug-inducedliver injury. The combination of high serum amino-transferase levels and jaundice was reported by thelegendary pioneer on the study of drug-induced liverinjury Hyman Zimmerman to result in a mortality of10% to 50% for different drugs. These observationshave been named