Alimentary Pharmacology and Therapeutics Review article: herbal hepatotoxicity – an update on traditional Chinese medicine preparations R. Teschke*, A. Wolff†, C. Frenzel‡ & J. Schulze§ *Department of Internal Medicine II, SUMMARY Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Background Medical Faculty of the Goethe Although evidence for their therapeutic efficacy is limited, herbal traditional University Frankfurt/Main, Hanau, Chinese medicine (TCM) preparations increasingly gain popularity. In con- Germany. † trast to other herbal products, adverse effects by herbal TCM including liver Department of Internal Medicine II, toxicity were rarely reported. In recent years, more cases were published, Division of Gastroenterology, Hepatology and Infectious Diseases, providing new clinical challenges. Friedrich Schiller University Jena, Jena, Germany. Aim ‡ Department of Medicine I, University To summarise comprehensively the literature on herbal TCM hepatotoxicity Medical Center Hamburg Eppendorf, since 2011. Hamburg, Germany. §Institute of Industrial, Environmental and Social Medicine, Medical Faculty, Methods Goethe University Frankfurt/Main, PubMed was searched using key words related to TCM, the results were Frankfurt, Germany. restricted to full English-language publications and abstracts published since 2011. In addition, the database of the National Institutes of Health (NIH) and LiverTox was accessed under the topic ‘Drug record: Chinese and other Correspondence to: ’ Dr R. Teschke, Department of Internal Asian herbal medicines . Medicine II, Klinikum Hanau, Academic Teaching Hospital of the Results Goethe University of Frankfurt/Main, Since 2011, new case reports and case series provided evidence for herbal Leimenstrasse 20, D-63450 Hanau, hepatotoxicity by TCM, focusing on nine TCM herbal mixtures and four Germany. individual TCM herbs with potential health hazards. These were the TCM E-mail: [email protected] products Ban Tu Wan, Chai Hu, Du Huo, Huang Qin, Jia Wei Xia Yao San, Jiguja, Kamishoyosan, Long Dan Xie Gan Tang, Lu Cha, Polygonum multiflo- Publication data rum products, Shan Chi, ‘White flood’ containing the herbal TCM Wu Zhu Submitted 24 March 2014 Yu and Qian Ceng Ta, and Xiao Chai Hu Tang. Other developments include First decision 9 April 2014 the establishment of a new and early diagnostic serum marker for hepatotox- Resubmitted 22 April 2014 icity caused by pyrrolizidine alkaloids, assessed using ultra performance Accepted 28 April 2014 – EV Pub Online 20 May 2014 liquid chromatography mass spectrometry analysis, and new regulatory details to improve herbal TCM product quality and safety. This uncommissioned review article was subject to full peer-review. Conclusion Stringent evaluation of the risk/benefit ratio is essential to protect traditional Chinese medicines users from health hazards including liver injury. Aliment Pharmacol Ther 2014; 40: 32–50 32 ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12798 Review: herbal hepatotoxicity of traditional Chinese medicines INTRODUCTION Du Huo,12 Huang Qin,13, 14 Jia Wei Xia Yao San,11 Jig- Hepatotoxicity by herbal Traditional Chinese Medicine uja,15 Kamishoyosan,16 Long Dan Xie Gan Tang,11 Lu (TCM) is reported from many countries around the Cha,17 Polygonum multiflorum products,10, 18 Shan world, China, Hong Kong, Taiwan, Japan, Korea, Singa- Chi,19, 20 White flood21 and Xiao Chai Hu Tang.11 The pore, Thailand, Australia, Italy, Spain, France, the Neth- NIH and LiverTox provided actual information on Chi erlands, the United Kingdom, Iceland, Canada, the R Yun (Breynia officinalis), Dai Saiko To, Jin Bu Huan United States and Argentina.1, 2 In the past 3 years, new (Lycopodium serratum), Ma Huang (Ephedra sinica), Sho cases of this neglected liver disease with substantially Saiko To, Shou Wu Pian (Polygonum multiforme) and improved data presentation were published and renewed Xiao Chai Hu Tang.1 – the scientific interest.1 5 Recent approaches to verify overall causality included the application of sophisticated Cases and case series liver specific algorithms and specific criteria for positive As a case report of fulminant hepatic failure caused by reexposure tests.6 Other developments include the estab- the TCM Ban Tu Wan, a herbal mixture containing lishment of pyrrole–protein adducts in the serum as an P. multiflorum as one of its multiple plant ingredients, early diagnostic marker for pyrrolizidine alkaloid (PA) was described in 2012 for the first time in the English hepatotoxicity, assessed with a new ultra performance literature.10 In 2011, a new detailed report estimated the liquid chromatography–mass spectrometry (UPLC–MS) risk of hospitalisation for liver injury associated with the analysis.7 Actual systematic reviews highlighted the qual- use of traditional Chinese herbal products containing ity of TCM products with focus on quality control Chai Hu (Radix bupleuri), referring to 61 liver injury including contamination and adulteration.8, 9 Finally, cases in 639 779 patients with chronic hepatitis B virus future approaches of pharmacovigilance practice and risk infection.11 The first case of liver injury by the herbal control for TCM in China are encouraging.9 TCM Du Huo (Angelica archangelica) was reported in We systematically review actual developments of her- 2013,12 hepatotoxicity by the herbal TCM Huang Qin bal hepatotoxicity by TCM of the past 3 years and (Scutellaria baicalensis) was confirmed by four new cases update the list of overall herbal TCM products suspected in 2012 and 2013.13, 14 In 2011, the liver injury risk of for potential liver injury. the TCM Jia Wei Xia Yao San was quantified in refer- ence to seven new patients.11 A new case of liver injury LITERATURE SELECTION CRITERIA by the herbal TCM Jiguja (Hovenia dulcis) was reported We selectively searched the PubMed database for the in 2012 in a 3.5-year-old boy with acute liver failure terms Traditional Chinese Medicine, Traditional Chinese and a liver transplant, confirming two previous cases in Medicine liver injury, Traditional Chinese Medicine hep- adult patients.15 In 2011, a case of liver injury was atotoxicity, Chinese herbal hepatotoxicity, Chinese herbal reported following the use of Kamishoyosan, a tradi- liver injury, herbal hepatotoxicity and herb induced liver tional Japanese herbal drug (Kampo medicine), similar injury. The search was limited to English-language to and derived from the herbal TCM Jia Wei Xia Yao reports and abstracts. The publications obtained were San.16 There were 47 additional cases reported in 2013, analysed for individual herbs and herbal mixtures which were caused by the herbal TCM Lu Cha (Camel- incriminated in herb-induced liver injury (HILI) by Tra- lia sinensis, syn. Chinese green tea).17 In 2011, 25 new ditional Chinese Medicine. We in addition accessed the hepatotoxicity cases were published after consumption database of the National Institutes of Health (NIH) and of the TCM mixture Shou Wu Pian, with P. multiflo- LiverTox under the topic Drug record: Chinese and rum as the main component.18 A new case of the hepa- other Asian herbal medicines.1 We focused on actual tic sinusoidal obstruction syndrome (HSOS) by the developments within the last few years and restricted our TCM Shan Chi (Gynura segetum) was published in search from 2011 to March 15, 2014. 2011; initially, this case was erroneously ascribed to the herbal TCM Jing Tian San Qi (Sedum aizoon).19 Four NEW HEPATOTOXICITY CASES additional new cases by the TCM Shan Chi were pub- lished in 2012,20 with at least 51 cases reported until TCM products 201119 and 116 cases until 2012.20 For the first time, Since 2011, highlighted new case reports and case series hepatotoxicity was reported in 2012 due to the use of – of herbal hepatotoxicity by TCM appeared.10 21 These White flood, containing among other ingredients the related to the TCM products Ban Tu Wan,10 Chai Hu,11 herbal TCM Wu Zhu Yu (Evodia rutaecarpa) and Qian Aliment Pharmacol Ther 2014; 40: 32-50 33 ª 2014 John Wiley & Sons Ltd R. Teschke et al. Ceng Ta (Huperzia serrata).21 Finally in 2011, the liver Exemptions include well-known herbal hepatotoxic injury risk of the TCM Xiao Chai Hu Tang was quan- chemicals such as ephedrine and PAs.2, 3, 7, 22 tied in 19 new cases of liver injury.11 Since 2011, there- As hepatotoxicity by the herbal TCM Ba Jiao Lian fore, new cases focused on nine TCM herbal mixtures (Dysosma pleianthum) does not fulfil all criteria,2, 23 this – and four individual TCM herbs.10 21 herb was not further considered as hepatotoxic.2 Evi- Combining the results of a previous analysis2 with dence against a hepatotoxic potential of the herbal TCM – those of the present case analysis,10 21 this compilation Jing Tian San Qi (S. aizoon) was provided in recent provides overall 18 classifiable TCM herbal mixtures, a studies showing that in patients with the HSOS, the hep- group of unclassifiable TCM herbal mixtures, and 39 atotoxic PAs in the herbal TCM Shan Chi (G. segetum) individual TCM herbs with reported potential hepatotox- were responsible rather than the misidentified S. aizoon icity (Table 1). TCM products often are blends of a mix- lacking these alkaloids.2, 19, 20 ture of herbs, king herb and other constituents are Since 2011, 149 new cases of liver injury by a single – believed to modify toxicity or synergistically increase the TCM herb have been published in five reports,12, 15, 18 king herb effects. Such conglomeration of constituents 20 covering four herbs as TCM ingredient, namely Du makes the identification and assignment of causative Huo (A. archangelica), Jiguja (H. dulcis), P. multiflorum hepatotoxic compounds extremely difficult, whereas and Shan Chi (G. segetum) (Table 3). These four single TCM products with one single herb as constituent facili- herbs of TCM since 2011 (Table 3) compare to a total of tate causality attribution. 39 single TCM herbs with potential liver injury reported since 1990 (Table 1).2 As for herbal mixture cases Hepatotoxic herbal mixtures (Table 2), all relevant case data by these herbs are pro- For the 18 classifiable and for unclassifiable TCM herbal vided (Table 3).