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Anti-Tuberculosis Drug-Induced Liver Injury in Shanghai: Validation of Hy’s Law

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Abstract

Introduction

The most reliable liver safety signal in a clinical trial is considered to be ‘Hy’s Law cases’ defined as subjects experiencing hepatocellular injury and serum bilirubin elevations with no more likely cause than study drug. However, there is little published data to support the current biochemical criteria for Hy’s Law cases or their use to estimate postmarketing risk of severe liver injury.

Objectives

The primary objective of this study was to identify and characterize Hy’s Law cases in patients treated for tuberculosis (TB). A secondary objective was to identify patient risk factors for drug-induced liver injuries.

Methods

We utilized eDISH (evaluation of Drug-Induced Serious Hepatoxicity) to retrospectively analyze data from 517 patients treated for activeTB, a regimen well known to be capable of causing severe hepatotoxicity.

Results

We identified two Hy’s Law cases, which is consistent with the treatment’s known risk of liver failure. Despite monthly monitoring, neither Hy’s Law case experienced a documented elevation in serum alanine aminotransferase exceeding 10 × upper limits of normal. Hepatoprotectant use and infection with chronic hepatitis B were associated with increased risk of liver injury.

Conclusions

Our observations support the current biochemical criteria for Hy’s Law cases and their use to estimate postmarketing risk.

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Acknowledgments

This work was supported in part by grants from the Chinese National Science and Technology Major Project (2013ZX10004903), the Shanghai Program for Outstanding Medical Academic Leader (2010 annual grant and 2012 annual grant), Shanghai Municipal Health Bureau (grant XYQ2011051) and the Clinical and Translational Science Award to the University of North Carolina (NIH grant ULTR000083).

Authorship

Xin Shen, Zheng’an Yuan and Jian Mei contributed equally to this work as first author. Paul Watkins and Fan Wu from The Hamner Institutes and the SCDC, respectively, were the two principal investigators and are equally responsible for the content of this manuscript.

Conflict of Interest

The authors (Xin Shen, Zheng’an Yuan, Jian Mei, Zurong Zhang, Juntao Guo, Zheyuan Wu, Jie Wu, Haihua Zhang, Jieping Pan, Wenming Huang, Huili Gong, Dong Yuan, Ping Xiao, Yanqin Wang, Yi Shuai, Senlin Lin, Qichao Pan, Tong Zhou, Paul B. Watkins, Fan Wu) have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Shanghai Municipal Center for Disease Control and Prevention, 1380 Zhong Shan Road (W), Shanghai, 200336, China

    Xin Shen, Zheng’an Yuan, Jian Mei, Zurong Zhang, Juntao Guo, Zheyuan Wu, Jie Wu, Dong Yuan, Ping Xiao, Yanqin Wang, Yi Shuai, Senlin Lin, Qichao Pan, Tong Zhou & Fan Wu

  2. Nanhua Hospital, Shanghai, China

    Haihua Zhang & Jieping Pan

  3. Pudong Pulmonary Hospital, Shanghai, China

    Wenming Huang & Huili Gong

  4. Gentris Corporation, Morrisville, NC, USA

    Tong Zhou

  5. The Hamner Institutes, Hamner-University of North Carolina Institute for Drug Safety Science, Six Davis Drive, PO Box 12137, Research Triangle Park, NC, 27709-2137, USA

    Paul B. Watkins

  6. Schools of Medicine, Pharmacy and Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Paul B. Watkins

Authors
  1. Xin Shen
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  2. Zheng’an Yuan
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  3. Jian Mei
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  4. Zurong Zhang
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  5. Juntao Guo
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  6. Zheyuan Wu
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  7. Jie Wu
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  8. Haihua Zhang
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  9. Jieping Pan
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  10. Wenming Huang
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  11. Huili Gong
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  12. Dong Yuan
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  13. Ping Xiao
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  14. Yanqin Wang
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  15. Yi Shuai
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  16. Senlin Lin
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  17. Qichao Pan
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  18. Tong Zhou
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  19. Paul B. Watkins
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  20. Fan Wu
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Corresponding authors

Correspondence to Paul B. Watkins or Fan Wu.

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Shen, X., Yuan, Z., Mei, J. et al. Anti-Tuberculosis Drug-Induced Liver Injury in Shanghai: Validation of Hy’s Law. Drug Saf 37, 43–51 (2014). https://doi.org/10.1007/s40264-013-0119-6

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  • DOI: https://doi.org/10.1007/s40264-013-0119-6

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