Genome-wide association studies (GWAS) have linked specific HLA alleles to the risk for developing DILI due to several drugs. These insights have not yet led to personalized medicine approaches to risk management of DILI because the associations lack specificity. That is, although prospective genetic testing would identify most patients susceptible to DILI, it would deny treatment to many more patients who could be safely be treated with the drug.  For this and other reasons, there is intense interest in developing non-genetic biomarkers that could be useful in DILI risk management.  Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been used for over 40 years to monitor the liver safety of drugs and are sensitive measures of liver injury.  However, there are drugs that, when administered at recommended doses, are quite safe for the liver yet cause marked elevations in serum ALT and AST.  We have been exploring whether current mechanistic biomarkers can distinguish benign enzyme elevations from those that may lead to clinically important liver injury.  We have analyzed serial serum samples obtained from cohorts of healthy adult volunteers treated with different therapeutic drug regimens that can cause marked elevations in serum ALT and AST but have low or no risk for serious hepatotoxicity (acetaminophen, various heparins, and cholestyramine).  We and our collaborators have employed a variety of techniques, including transcriptomics, metabolomics and proteomics to identify biomarkers that may provide insight into the mechanisms underlying these benign and self-limited laboratory abnormalities.  These studies indicate that recurrent therapeutic doses of acetaminophen, heparins and cholestyramine cause hepatocyte death, but the mechanisms involved in cell death differ between these treatments. The reason why these treatments are safe for the liver remains unclear but several theories will be discussed.

Biomarkers for the diagnosis and management of drug-induced liver injury

246th National Meeting (2013)

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