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


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.


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



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)


  1. Bailey RL, Gahche JJ, Lentino CV et al (2010) Dietary supplement use in the United States, 2003–2006. J Nutr 110:133025Google Scholar
  2. Bjornsson E, Talwalkar J, Treeprasertsuk S et al (2010) Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 51(6):2040–2048. CrossRefPubMedGoogle Scholar
  3. Bjornsson ES, Bergmann O, Jonasson JG, Grondal G, Gudbjornsson B, Olafsson S (2017) Drug-induced autoimmune hepatitis: response to corticosteroids and lack of relapse after cessation of steroids. Clin Gastroenterol Hepatol 15(10):1635–1636. CrossRefPubMedGoogle Scholar
  4. Burt AD, MacSween RN (1993) Bile duct proliferation–its true significance? Histopathology 23(6):599–602CrossRefGoogle Scholar
  5. Castiella A, Zapata E, Lucena MI, Andrade RJ (2014) Drug-induced autoimmune liver disease: a diagnostic dilemma of an increasingly reported disease. World J Hepatol 6(4):160–168. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chalasani N, Fontana RJ, Bonkovsky HL et al (2008) Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135(6):1924–1934.–4) CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chalasani NP, Hayashi PH, Bonkovsky HL et al (2014) ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 109(7):950–966. 967) CrossRefPubMedGoogle Scholar
  8. Chalasani N, Bonkovsky HL, Fontana R et al (2015) Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology 148(7):1340–1352.e7CrossRefGoogle Scholar
  9. Chen M, Suzuki A, Thakkar S, Yu K, Hu C, Tong W (2016) DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 21(4):648–653. CrossRefPubMedGoogle Scholar
  10. Danan G, Teschke R (2019) Roussel Uclaf causality assessment method for drug-induced liver injury: present and future. Front Pharmacol 10:853. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Devarbhavi H, Bjornsson ES (2019) RE: incidence and etiology of drug-induced liver injury in mainland China. Gastroenterology. CrossRefPubMedGoogle Scholar
  12. Ekor M (2014) The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol. 177) CrossRefPubMedPubMedCentralGoogle Scholar
  13. Frazier TH, Krueger KJ (2009) Hepatotoxic herbs: will injury mechanisms guide treatment strategies? Curr Gastroenterol Rep 11(4):317–324CrossRefGoogle Scholar
  14. Goldberg DS, Forde KA, Carbonari DM et al (2015) Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system. Gastroenterology 148(7):1353–1361.e3CrossRefGoogle Scholar
  15. Gomes ER, Demoly P (2005) Epidemiology of hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol 5(4):309–316CrossRefGoogle Scholar
  16. Kosters A, Karpen SJ (2010) The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis 30(2):186–194. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Navarro VJ, Lucena MI (2014) Hepatotoxicity induced by herbal and dietary supplements. Semin Liver Dis 34(2):172–193. CrossRefPubMedGoogle Scholar
  18. Navarro VJ, Khan I, Bjornsson E, Seeff LB, Serrano J, Hoofnagle JH (2017) Liver injury from herbal and dietary supplements. Hepatology 65(1):363–373. CrossRefPubMedGoogle Scholar
  19. Navarro V, Avula B, Khan I et al (2019) The contents of herbal and dietary supplements implicated in liver injury in the United States are frequently mislabeled. Hepatol Commun 3(6):792–794. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Philips CA, Paramaguru R, Joy AK, Antony KL, Augustine P (2018) Clinical outcomes, histopathological patterns, and chemical analysis of Ayurveda and herbal medicine associated with severe liver injury—a single-center experience from southern India. Indian J Gastroenterol 37(1):9–17. CrossRefPubMedGoogle Scholar
  21. Real M, Barnhill MS, Higley C, Rosenberg J, Lewis JH (2019) Drug-induced liver injury: highlights of the recent literature. Drug Saf 42(3):365–387. CrossRefPubMedGoogle Scholar
  22. Shen T, Liu Y, Shang J et al (2019) Incidence and etiology of drug-induced liver injury in Mainland China. Gastroenterology 156(8):2230–2241. CrossRefPubMedGoogle Scholar
  23. Stickel F, Shouval D (2015) Hepatotoxicity of herbal and dietary supplements: an update. Arch Toxicol 89(6):851–865. CrossRefPubMedGoogle Scholar
  24. Teschke R (2019) Idiosyncratic DILI: analysis of 46,266 cases assessed for causality by RUCAM and published from 2014 to early 2019. Front Pharmacol 10:730. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Teschke R, Eickhoff A (2017) Suspected liver injury and the dilemma of causality. Dig Dis Sci 62(4):1095–1098. CrossRefPubMedGoogle Scholar
  26. Trauner M, Fickert P, Stauber RE (1999) Inflammation-induced cholestasis. J Gastroenterol Hepatol 14(10):946–959CrossRefGoogle Scholar
  27. Verdonk RC, Lozano MF, van den Berg AP, Gouw AS (2016) Bile ductal injury and ductular reaction are frequent phenomena with different significance in autoimmune hepatitis. Liver Int 36(9):1362–1369. CrossRefPubMedGoogle Scholar
  28. Wlodzimirow KA, Eslami S, Abu-Hanna A, Nieuwoudt M, Chamuleau RA (2012) Systematic review: acute liver failure - one disease, more than 40 definitions. Aliment Pharmacol Ther 35(11):1245–1256. CrossRefPubMedGoogle Scholar

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

Personalised recommendations