Idiosyncratic Liver Injury: Challenges and Approaches

Abstract

Clinical presentations of drug-induced liver injury (DILI) cover essentially the entire spectrum of known liver diseases. However, in the last 8 years the form of liver injury that has most frequently resulted in labeling restrictions is idiosyncratic hepatocellular injury leading to acute liver failure. This rare form of DILI has a characteristic clinical presentation that includes an acute onset after uneventful treatment with drug for weeks to months. Serum alanine aminotransferase rises to very high levels and the appearance of jaundice indicates a high mortality even if the therapy is discontinued. Drugs that can cause this type of injury almost always are associated with frequent (2–15% of all treated patients) and minor serum aminotransferase elevations. These elevations are believed to reflect true liver injury, but often reverse even if drug therapy is continued. The basis for this “adaptation” is not known, as is why some patients do not adapt and develop progressive liver injury. Understanding how drugs cause severe idiosyncratic hepatocellular toxicity has been frustrated by the lack of good preclinical models. Indeed, because these events occur so rarely, the vast majority of humans are not good models. Studies of genomic DNA from affected individuals should provide important insight but not the complete answer because environmental factors almost certainly contribute to individual susceptibility. The most fruitful approach may therefore lie in focused and well-controlled phenotype/genotype studies of the rare patients who have survived this type of injury. The National Institute of Diabetes and Digestive and Kidney Diseases of The National Institutes of Health has recently sponsored a cooperative agreement (UO1) to create a Drug Induced Liver Injury Network (DILIN). DILIN consists of University of Michigan, Indiana University, University of Connecticut, University of California, San Francisco, University of North Carolina, and Duke University. This network should provide heretofore missing resources required to address the problem.