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

A Sidney Barritt 4th; Paul H Hayashi; Andrew A Stolz; Huiman Barnhart; Jay H Hoofnagle; Drug-Induced Liver Injury Network (DILIN)

doi:10.14309/ajg.0000000000003145

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

Am J Gastroenterol. 2024 Oct 18. doi: 10.14309/ajg.0000000000003145. Online ahead of print.

Authors

A Sidney Barritt 4th¹, Paul H Hayashi², Andrew A Stolz³, Huiman Barnhart⁴, Jay H Hoofnagle⁵; Drug-Induced Liver Injury Network (DILIN)

Affiliations

¹ Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.
² Division of Hepatology and Nutrition, Office of New Drugs, FDA, Silver Spring, Maryland, USA.
³ Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, California, USA.
⁴ Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA.
⁵ Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland, USA .

PMID: 39422332
DOI: 10.14309/ajg.0000000000003145

Abstract

Introduction: Hyman Zimmerman observed that hepatocellular (HC) drug-induced liver injury (DILI) with jaundice had a mortality rate of ≥ 10% (Hy Law). Hy Law does not specify the timing of liver tests nor the definition of HC DILI versus cholestatic or mixed (C/M) DILI. We aimed to assess the validity of Hy Law in the prospective DILI Network (DILIN) cohort.

Methods: Drugs with ≥10 confirmed DILI cases with jaundice were analyzed. Four permutations of Hy Law were applied: R ≥ 5 using initial (1) or peak (2) alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels, and the Food and Drug Administration associated criteria of alanine aminotransferase or aspartate aminotransferase ≥ 3x upper limit of normal with alkaline phosphatase ≤ 2x upper limit of normal using initial (3) or peak values (4). Mortality was death or liver transplant adjudicated to be due to DILI.

Results: Using initial R values, mortality was 11.1% for HC vs 2.0% for C/M ( P < 0.001); using peak R values, mortality was 10.3% vs 1.6% ( P < 0.001). Using Food and Drug Administration-associated definition, mortality was 7.9% vs 3.9% ( P = 0.04) using initial values and 7.9% vs 3.0% ( P = 0.01) using peak values. Using initial R values, drugs that frequently caused HC injury generally had mortality rates ≥ 10%, while drugs that typically caused C/M injury all had rates < 10%. Occasional agents that caused HC injury with jaundice were associated with low mortality.

Discussion: Initial R values were the most reliable means of identifying Hy Law cases. There were some drugs that caused HC injury with jaundice but with mortality rates < 10%. Refinement of Hy Law is warranted.