Modifying Hy's Law and eDISH for the modern idiosyncratic DILI era.

INTRODUCTION

Dr. Hyman Zimmerman observed that 'hepatocellular jaundice' was a prognostic biomarker of severe drug-induced liver injury (DILI). His sentinel observation eventually became known as 'Hy's Law' which the FDA currently defines as an ALT or AST greater than 3X ULN with a total bilirubin > 2X ULN in the absence of cholestasis (i.e. alkaline phosphatase > 2X ULN) and with no other more plausible cause identified. The modern idiosyncratic DILI era has introduced variables including novel drug classes, abnormal baseline liver labs and cholestatic DILI phenotypes, that pressure-test the universal applicability of the current Hy's Law definition.

AREA COVERED: We review the various studies that seek to update Hy's Law, including the use of a new R value defining hepatocellular injury in the setting of alkaline phosphatase elevations, and the latest suggestions from FDA researchers that Sankey plots and interactive eDISH plots will be modifications for the near future.

EXPERT OPINION: While the original definition and prognostic significance of Hy's Law from 2009 guidance are still employed by drug developers, several important and practical modifications have been proposed that will no doubt become adopted as FDA recommendations for assessing hepatotoxicity of drugs are updated. We are certain that Hy himself would approve.