Clinical Considerations of Drug-Induced Hepatotoxicity

Drug-induced liver injury (DILI) is an important cause of liver injury and the most common cause of acute liver failure (ALF). It is the leading reason for aborted drug development and drug withdrawal from the market. Increasingly, herbal and dietary supplements are being recognized as substantial causes of DILI. The clinical presentation of DILI can mimic all forms of acute and chronic hepatobiliary diseases. DILI is mainly 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 (ALP). An observation by the late Hyman Zimmerman, colloquially known as Hy’s law, states that drug-induced hepatitis accompanied by a jaundice (bilirubin level>3 × ULN), is associated with a high mortality, approximating 10%. DILI is a diagnosis of exclusion. While several offending agents have a characteristic signature, many drugs can present with multiple different patterns of injury, making the diagnosis of DILI challenging. Age and gender appear to influence the pattern of injury, with older patients more likely to develop a cholestatic pattern of injury and women more prone to the hepatocellular phenotype of DILI and ALF. Treatment options for DILI are limited. Therefore, emphasis is placed on prevention and early recognition of DILI. Drug discontinuation and monitoring (de-challenge) with resolution of liver injury is both diagnostic and therapeutic. Rechallenge is dangerous and should be avoided. In cases of suspected acetaminophen overdose, N-acetylcysteine should be administered.