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The landscape of hepatobiliary adverse reactions across 53 herbal and dietary supplements reveals immune-mediated injury as a common cause of hepatitis

  • Jieqiang Zhu
  • Minjun Chen
  • Jürgen BorlakEmail author
  • Weida TongEmail author
Organ Toxicity and Mechanisms
  • 124 Downloads

Abstract

Recent evidence suggests herbal-induced liver injury (HILI) to account for 20% of cases among the U.S. Drug-Induced-Liver-Injury-Network. To define injury patterns of HILI, we reviewed the clinical data of 413 patients exposed to 53 HDS products by considering the evidence for HILI and its grades of severity. Outstandingly, females developed HILI more rapidly (p = 0.018) and the time to recovery was significantly increased (p = 0.0153). > 90% of reported cases were severe and half of HDS products caused acute liver failure (ALF) requiring liver transplantation or resulted in fatal outcomes. Liver biopsies of 243 patients defined 13 histological features; two-thirds of products elicited immune-mediated hepatitis and included 154 Hy’s law positive cases. The histological injury patterns were confirmed among unrelated patients, while accidental re-challenges evidenced culprits as causative. Furthermore, one-fifth of patients presented elevated autoantibody titres indicative of autoimmune-like HILI, and one-third of the products were linked to chronic hepatitis and cholestatic injuries not resolving within 6 months. Lastly, INR and TBL are critical laboratory parameters to predict progression of severe HILI to ALF. Our study highlights the need for a regulatory framework to minimize the risk for HILI. Better education of the public and a physician-supervised self-medication plan will be important measures to abate risk of HILI.

Keywords

Herbal and dietary supplements HILI Immune-mediated liver injury Acute liver failure 

Notes

Funding

This work was supported by the FDA Office of Women’s Health (Grant no. 12649). This project was supported in part by an appointment to the ORISE Research Participation Program at the National Center for Toxicological Research (Grant no. 12650), U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA/Center. JB gratefully acknowledges the financial support of the U.S. Food and Drug Administration's National Center for Toxicological Research.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

204_2019_2621_MOESM1_ESM.tif (278 kb)
Supplementary Figure S1 Serum biochemistries of HILI cases after accidental re-exposure to culprit HDS products. Shown are box plots for 30 HILI cases being re-challenged with 16 culprit HDS products. A highly significant reduction in the time to onset from about 12 weeks to 6 weeks was observed when patients were re-exposed to the same hepatotoxic HDS. Likewise, the time to recovery was significantly increased after re-challenge from about 8 weeks to 15 weeks (TIFF 279 kb)
204_2019_2621_MOESM2_ESM.xlsx (34 kb)
Supplementary Table S1 Summary information on liver injury cases due to herb and dietary supplement use (XLSX 34 kb)
204_2019_2621_MOESM3_ESM.docx (20 kb)
Supplementary Table S2 Compilation of HDS products with evidence level 3-4 for HILI (DOCX 19 kb)
204_2019_2621_MOESM4_ESM.xlsx (11 kb)
Supplementary Table S3 Indications of HDS product use (XLSX 10 kb)
204_2019_2621_MOESM5_ESM.docx (23 kb)
Supplementary Table S4 List of HDS products with evidence level 1-4 for HILI that are used as Traditional Chinese Medicines (DOCX 23 kb)
204_2019_2621_MOESM6_ESM.docx (16 kb)
Supplementary Table S5 Summary information on the clinical management of immune-mediated HILI cases (DOCX 15 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Bioinformatics and Biostatistics, National Center for Toxicological ResearchU.S. Food and Drug AdministrationJeffersonUSA
  2. 2.Centre for Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany

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