Clinical Considerations of Drug-Induced Hepatotoxicity

Abstract

Drug-induced liver injury (DILI) is an important cause of liver dysfunction and the most common cause of acute liver failure (ALF) ( Weiler et al., 2015 ). It is the leading reason for aborted drug development and drug withdrawal from the market ( Navarro and Senior, 2006 ; Senior, 2007 ). Increasingly, herbal and dietary supplements are being recognized as a substantial cause of liver injury ( Chalasani et al., 2015 ). DILI is classified as cholestatic, hepatocellular, or mixed based on the R -value, which is calculated from the relative elevations of alanine aminotransferase (ALT) and alkaline phosphatase. The clinical presentation can mimic all forms of acute and chronic hepatobiliary diseases. DILI is usually a diagnosis of exclusion and, although several offending agents have a characteristic signature pattern of injury, some drugs cause different patterns of injury in different individuals. Age and gender appear to influence the pattern of injury, with patients older than 60 more likely to develop a cholestatic pattern of injury and women more prone to develop the hepatocellular phenotype or ALF ( Hussaini and Farrington, 2014 ; Lucena et al ., 2009 ). An ALT level of > 3 × ULN (upper limit of normal) is a sensitive signal for liver toxicity. An ALT elevation of > 8–10 × ULN or an ALT level of > 3 × ULN accompanied by a bilirubin level of > 2 × ULN are more specific predictors of the risk of ALF. An observation by the late Hyman Zimmerman, colloquially known as Hy's law, states that drug-induced hepatitis accompanied by a bilirubin level > 3 × ULN, in the absence of biliary obstruction and Gilbert's syndrome, is associated with a mortality of approximately 10%. Some drugs cause elevations in serum aminotransferases but rarely, if ever, cause jaundice ( Singhal et al ., 2014 ; Harrill et al ., 2012 ). Treatment options for DILI are limited. Therefore, emphasis is placed on prevention and recognition of DILI early in the course of treatment. When feasible, the offending agent should be stopped. In cases of suspected acetaminophen or sodium valproate overdose, N -acetylcysteine or IV carnitine, respectively, should be administered.