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R Value-Based Criteria Outperform Alkaline Phosphatase Less than Twice Normal in Identifying Hy’s Law Cases in Clinical Trials

Amirzadegan, Jasmine, Vouffo, Edwige Chiogo, Lan, Ling, Navarro Almario, Eileen, Avigan, Mark I., Hayashi, Paul H.·2026·Drug Safety
DOI 10.1007/s40264-025-01603-z
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Abstract

Background It is unknown whether nR value [(ALT or AST/ULN) ÷ (AP/ULN)] ≥ 5 is better than alkaline phosphatase less than twice the upper limit of normal (AP Objective We aimed to compare nR value ≥ 5 and AP 2x ULN. Methods We retrospectively categorized clinical trial, DILI cases from July 2020 to April 2024 with ALT or AST ≥ 3x ULN and jaundice as meeting nR value ≥ 5, AP Results Of 1314 liver injuries across 73 drug applications, 294 (22%) were attributed to DILI; 55 had ALT or AST ≥ 3x ULN and TB > 2x ULN. We excluded three cases (Gilbert's, high baseline enzymes, hepatitis B reactivation). Of 52 remaining, 16 (31%) met nR ≥ 5, five (10%) AP Conclusion While the number of cases with the most severe DILI outcomes was small, particularly those that resulted in fatalities or ALF, nR ≥ 5 better approximated Hy's Law and was more sensitive than AP < 2x ULN in detecting fatalities and ALF.

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Crossref · 10.1007/s40264-025-01603-z

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  • In a retrospective analysis of 294 DILI cases corresponding to 73 drug applications, the FDA recently confirmed the concept developed by nR Hy's law (bilirubin ≥ 2.5 mg/dL and nR > 5) that nR ≥ 5 is a better predictor of severe outcome than ALP < 2.

    “In a retrospective analysis of 294 DILI cases corresponding to 73 drug applications, the FDA recently confirmed the concept developed by nR Hy's law (bilirubin ≥ 2.5 mg/dL and nR > 5) that nR ≥ 5 is a better predictor of severe outcome than ALP < 2 [32].”

    From DILI Differences and Similarities between the US and Europe (2026) · cites this paper as [32]

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Research works printed but not linked: 13

  1. Avigan MI. DILI and drug development: a regulatory perspective. Semin Liver Dis. 2014;34(2):215–26. https://doi.org/10.1055/s-0034-1375961. · DOI
  2. Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. 2005;42(2):481–9. https://doi.org/10.1002/hep.20800. · DOI · Paper page
  3. Fontana RJ, Hayashi PH, Gu J, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014;147(1):96-108 e4. https://doi.org/10.1053/j.gastro.2014.03.045. · DOI · Paper page
  4. Robles-Diaz M, Lucena MI, Kaplowitz N, et al. Use of Hy’s law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology. 2014;147(1):109-118 e5. https://doi.org/10.1053/j.gastro.2014.03.050. · DOI · Paper page
  5. Senior JR. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges. Drug Saf. 2014;37(Suppl 1):S9-17. https://doi.org/10.1007/s40264-014-0182-7. · DOI
  6. Barritt ASt, Hayashi PH, Stolz AA, Barnhart H, Hoofnagle JH, Drug-Induced Liver Injury N. Refinement of Hy law using the Drug-Induced Liver Injury Network database. Am J Gastroenterol. 2024. https://doi.org/10.14309/ajg.0000000000003145. · DOI
  7. Hayashi PH, Rockey DC, Fontana RJ, et al. Death and liver transplantation within 2 years of onset of drug-induced liver injury. Hepatology. 2017;66(4):1275–85. https://doi.org/10.1002/hep.29283. · DOI · Paper page
  8. Danan G, Benichou C. Causality assessment of adverse reactions to drugs–I. a novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323–30. https://doi.org/10.1016/0895-4356(93)90101-6. · DOI · Paper page
  9. Fontana RJ, Watkins PB, Bonkovsky HL, et al. Drug-induced liver injury network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009;32(1):55–68. https://doi.org/10.2165/00002018-200932010-00005. · DOI · Paper page
  10. Polson J, Lee WM, American Association for the Study of Liver D. Aasld position paper: the management of acute liver failure. Hepatology. 2005;41(5):1179–97. https://doi.org/10.1002/hep.20703. · DOI
  11. European Association for the Study of the Liver, Wendon J, et al. EASL clinical practical guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047–81. https://doi.org/10.1016/j.jhep.2016.12.003. · DOI · Paper page
  12. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48(1):169–76. https://doi.org/10.1002/hep.22322. · DOI · Paper page
  13. Chiogo Vouffo E, Lan L, Pei V, Avigan MI, Hayashi PH. Characteristics of DILI in clinical trials: initial experience of the FDA Drug-Induced Liver Team. Hepatology. 2022;76(4611):S1444–5.

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Metadata

Authors
Amirzadegan, J., Vouffo, E. C., Lan, L., Navarro Almario, E., Avigan, M. I., & Hayashi, P. H.
Venue
Drug Safety
Publisher
Springer Science and Business Media LLC
Published
2025-08-31
Volume
49
Issue
2
Pages
217-224
ISSN
  • 0114-5916
  • 1179-1942
DOI
10.1007/s40264-025-01603-z
Cited by
3
References
0
Language
en
Licence
Funders
Oak Ridge Institute for Science and Education

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