Refinement of Hy Law Using the Drug-Induced Liver Injury Network Database.

Area of Science:

• Hepatology
• Clinical Pharmacology
• Drug Safety

Background:

• Hyman Zimmerman's Hy Law posits ≥10% mortality for hepatocellular (HC) drug-induced liver injury (DILI) with jaundice.
• Hy Law lacks specific timing for liver tests and clear definitions for HC vs. cholestatic/mixed (C/M) DILI.
• The DILI Network (DILIN) prospective cohort provides a dataset to validate Hy Law.

Purpose of the Study:

• To assess the validity of Hy Law in the DILIN cohort.
• To compare mortality rates between hepatocellular and cholestatic/mixed DILI.
• To evaluate different permutations of Hy Law criteria.

Main Methods:

• Analysis of drugs with ≥10 confirmed DILI cases and jaundice.
• Application of four Hy Law permutations using initial or peak liver enzyme levels (R values) and FDA criteria.
• Mortality defined as death or DILI-adjudicated liver transplant.

Main Results:

• Initial R values showed higher mortality for HC DILI (11.1%) vs. C/M DILI (2.0%) (P < 0.001).
• Peak R values also demonstrated significant differences in mortality between HC and C/M DILI.
• FDA-associated criteria showed statistically significant, though smaller, mortality differences.

Conclusions:

• Initial R values are the most reliable for identifying Hy Law cases.
• Some drugs causing HC DILI with jaundice had mortality rates below 10%.
• Refinement of Hy Law is necessary for improved accuracy in DILI assessment.