Letters to the Editors xiao yao san. However, Kampo medicine uses different plant species for the medicinals Bupleuri Radix and Angelicae Radix than Chinese medicine, namely B. falcatum and A. acutiloba or A. acutiloba var. Sugiyamae. In Table 1 of the article by Teschke et al., A. sinensis is erroneously listed as an ingredient. The reported liver injury, which may only have a ‘possible’ causality association with the formula, can neither simply be related to Chinese medicine nor to a single component of the Kampo formula. What in the article does really concern Chinese Medicine? In one case, the remedy ban tu wan (‘alopecia areata pills’) was taken. This is a combination of nine Chinese medicinal herbs. No identity check was done, no investigation on contaminants or adulteration and no standardised causality assessment. A causality assignment of the fatal liver injury to the ingredient Polygoni multiflori Radix (he shou wu) is vague. An investigation carried out in Taiwan8 found that there was an increased risk for hepatitis B patients to be hospitalised for liver injury when taking formulas containing Bupleuri Radix (chai hu). Generally, from this nonrandomised study no proof of causality can be derived. Since the two major suspicious formulas contained not only Bupleuri Radix but, among many other ingredients, also Scutellariae Radix, the results cannot be one-sidedly related to Bupleuri Radix. A causal link to Bupleuri Radix thus cannot be verified. The only conclusive association of Chinese medicine with hepatotoxicity presented in this article is the case compilation concerning Polygoni multiflori Radix (he shou wu).9 In these cases, Polygoni multiflori Radix apparently had been applied as a single herb (although reported differently by Teschke et al.), namely as an unprepared herb. The striking number of cases in which this herb has been ingested as tea, liquid or powder suggests a hepatotoxic risk, even though tests for identity and contaminants or adulteration are missing. The causality assessment has been done according to CIOMS
Letter: herbal hepatotoxicity – an update on traditional Chinese medicine preparations; authors0 reply R. Teschke*, A. Wolff†, C. Frenzel‡ & J. Schulze§ *Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt/Main, Hanau, Germany. 738
and classified as ‘probable’. In one case, there was even a re-exposure to the herbal preparation with a positive outcome. We, too, considered Polygoni multiflori Radix as potentially hepatotoxic because of the numerous cases reported in the literature. Thus, only a small part of the study applies to the practice of Chinese Medicine as executed in western countries or as taught academically in China.
ACKNOWLEDGEMENTS Declaration of personal interests: The authors indicate that they do not have conflicts of interest in this study. Declaration of funding interests: None. REFERENCES 1. Teschke R, Wolff A, Frenzel C, Schulze J. Review article: herbal hepatotoxicity – an update on traditional Chinese medicine preparations. Aliment Pharmacol Ther 2014; 40: 32–50. 2. Vaysse J, Balayssac S, Gilard V, et al. Analysis of adulterated herbal medicines and dietary supplements marketed for weight loss by DOSY 1H-NMR. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2010; 27: 903–16. 3. Ye F, Wang H, Jiang S, et al. Quality evaluation of commercial extracts of Scutellaria baicalensis. Nutr Cancer 2004; 49: 217–22. 4. Sovak M, Seligson AL, Konas M, et al. Herbal composition PCSPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst 2002; 94: 1275–81. 5. Lu WI, Lu DP. Impact of Chinese herbal medicine on American society and health care system: perspective and concern. Evid Based Complement Alternat Med 2014; 2014: 251891. 6. Bj€ ornsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant druginduced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095–101. 7. Inoue H, Yamazaki S, Shimizu M, et al. Liver injury induced by the Japanese herbal drug kamishoyosan. Gastroenterol Hepatol 2011; 7: 692–5. 8. Lee CH, Wang JD, Chen PC. Risk of liver injury associated with Chinese herbal products containing Radix Bupleuri in 639,779 patients with hepatitis B virus infection. PLoS ONE 2011; 6: e16064. 9. Jung KA, Min HJ, Yoo SS, et al. Drug-induced liver injury: twenty five cases of acute hepatitis following ingestion of Polygonum multiflorum Thunb. Gut Liver 2011; 5: 493–9.
†
Department of Internal Medicine II, Division of Gastroenterology, Hepatology and Infectious Diseases, Friedrich Schiller University Jena, Jena, Germany. ‡ Department of Medicine I, University Medical Center Hamburg Eppendorf, Hamburg, Germany. § Institute of Industrial, Environmental and Social Medicine, Medical Faculty of the Goethe University Frankfurt/Main, Frankfurt, Germany. E-mail: [email protected] doi:10.1111/apt.12887 Aliment Pharmacol Ther 2014; 40: 735-740 ª 2014 John Wiley & Sons Ltd
Letters to the Editors SIRS, We appreciate the interest in our recent review article1 and the confirm of the well known problems associated with herbal traditional Chinese medicine (TCM) preparations.2 Quality aspects and constituent authentication of herbal TCM products are accepted points of safety concern.1–8 However, reports of adverse reactions that describe toxic events including potentially life threatening hepatotoxicity trigger safety concerns with the use of TCM products containing Chinese herbs.1–5 As therapeutic efficacy of herbal TCM is poorly documented due to lack of convincing controlled clinical trials,1, 3, 4, 9, 10 currently the resulting risk/benefit ratio is negative, without a general or evidence based treatment recommendation. TCM follows a philosophical background which substantially differs from western medicine,4, 10 with interesting theoretical aspects but disputable therapeutic implications. Many effective synthetic drugs such as codeine, colchicine, coumarins, digitoxin, digoxin, morphine, quinine and salicylic acid have been developed from western herbal preparations, but not from TCM products, with the exception of artemisinin and ephedrine. Traditional western herbal drugs commonly are subjected to scientific evaluation and rigour; this should also apply to the efficacy and safety of other traditional herbal medicines including TCM. The herbal TCM product composition often is poorly declared, compounds may be mislabelled or products contaminated with toxins, bacteria, heavy metals or even semisynthetic or synthetic medications like NSAIDs, corticosteroids, fibrates or statins as adulterants.4, 5, 8 There is overall agreement that herbal TCM products may be of low quality, regulatory surveillance as mandatory for regulatory approved synthetic or herbal drugs is not commonly available.1–8 This particular challenge has been recognised not only in China7 but also worldwide,1, 3–6, 8 in line with present views.2 Since TCM products are not standardised, poorly regulated or unregulated,4, 5 ingredients of TCM products may vary among the different producers despite an identical name,5 resulting in variability in herbs (including different varieties) and herbal proportions within mixtures.1–5 For other preparations, the composition of a herbal mixture is unknown.5 Another problem is collecting multiple herbs,1–5 without knowledge of their exact nature or name.5 These shortcomings may explain why even TCM providers have difficulties correctly identifying herbal ingredients and categorising Chinese herbs as traditional or nontraditional Chinese medicinal preparations.2 Aliment Pharmacol Ther 2014; 40: 735-740 ª 2014 John Wiley & Sons Ltd
Mainstream opinion suggests that the use of some herbal TCM products carries the rare risk of liver injury, as assessed by the NIH4, 5 and other hepatotoxicity experts11, 12 including our group,1, 3 despite opposing and unspecified contrary views.2 Actual literature searches will lead to multiple relevant reports,1, 3–5, 11, 12 as did our study with hundreds of liver cases in 91 reports published since 1990.3 At present, the English literature refers to 39 individual TCM herbs, 18 classifiable herbal TCM mixtures and some unclassifiable TCM herbal mixtures with reported potential hepatotoxicity.1 Causality was assessed by the liver specific scale of CIOMS (Council for International Organizations of Sciences) and re-exposure tests. However, Wiebrecht and Kalg claim that Polygonum multiflorum is the sole TCM herb with potential hepatotoxicity.2 This misconception and downplay of hepatotoxicity by other herbal TCM products is difficult to reconcile and may imply lack of expertise in clinical case assessment. TCM providers in Germany commonly are nonmedical healers or rarely general practitioners not necessarily familiar with key issues of clinical hepatology. Unfortunately, no constructive or stimulating suggestions are provided to improve the perspectives of the ancient herbal TCM philosophy,2, 13 despite contested aspects.4, 5, 10, 14 New approaches and motivated TCM experts are needed for multicenter, randomised, double blind, placebo-controlled clinical trials and observational studies into the efficiency and safety of herbal TCM treatments. The results will provide reliable risk/benefit estimates, positively assessed TCM herbs and herbal mixtures should be registered as regulated herbal drugs. These may even be the starting point to further investigate the active herb and its active chemical constituent. western countries have gone this way long ago, starting from the philosophy of ancient traditional western herbal medicine to evidence based medicines using registered herbal drugs and synthetic chemicals. Both eastern and western cultures with their established medicines will profit from additional therapies derived from TCM as modified according to modern scientific requirements. In modern herbal TCM, there should be no place for nonherbal elements.1, 3, 4 Among these are Bai Hua She (venom of the viper Agkistrodon acutus), Jiang Can (larvae of Bombyx Batryticatus), Ling Yang Qing Fei (antelope horn), Quan Xie (polypides of the scorpion Buthus martensii) and Wu Gong (polypites of the centipede Scolopendra subspinipes mutilans). In addition, modern herbal TCM should not follow ancient TCM philosophy and theory due to unproven efficacy.4 Ancient beliefs on which herbal TCM is based include: the human body is 739
Letters to the Editors a miniature version of the larger, surrounding universe; harmony between two opposing forces, called yin and yang, supports health, and disease results from an imbalance between these forces; five elements – fire, earth, wood, metal and water – symbolically represent all phenomena, including the stages of human life, and explain the functioning of the body and how it changes during disease; Qi, a vital energy that flows through your body, performs multiple functions in maintaining health.4 Summarising these points, ancient herbal TCM is under increasing pressure to justify its claims1–10, 14 of therapeutic efficacy and lack of side effects, to standardise and categorise its products, undergo sufficient regulatory surveillance, and improve overall product quality. Therefore, new approaches are necessary for a modern herbal TCM with fascinating and encouraging perspectives. This should cover herbal products with proven therapeutic efficacy in line with the requirements of evidence based medicine, a favourable risk/benefit profile, product standardisation and regulatory surveillance, and an effective ADR reporting system to regulatory agencies. Special scrutiny should be placed on correctly labelling of ingredients and absence of toxins (aflatoxins, bacteria and heavy metals), adulterants, and mislabelled herbs. Until substantial progress is made establishing modern herbal TCM, we are obliged to minimise toxic risks associated with medical treatments including ancient herbal TCM. Risks should be identified,1, 3–10 not ignored,2, 13 and communicated on websites4, 5 and in peer reviewed English language journals.1, 3, 6–12, 14
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.1
740
REFERENCES 1. Teschke R, Wolff A, Frenzel C, Schulze J. Review article: herbal hepatotoxicity – an update on traditional Chinese medicine preparations. Aliment Pharmacol Ther 2014; 40: 32–50. 2. Wiebrecht A, Kalg A. Letter: herbal hepatotoxicity – an update on traditional Chinese Medicine preparations. Aliment Pharmacol Ther 2014; 40: 737–8. 3. Teschke R. Traditional Chinese Medicine induced liver injury. J Clin Transl Hepatol 2014; 40: 737–8. doi:10.14218/JCTH.2014. 00003 4. NIH, National Center for Complementary and Alternative Medicine (NCCAM). Traditional Chinese medicine: an introduction, 2013. Available at: http://nccam.nih.gov/health/ whatiscam/chinesemed.htm. Accessed date July 1, 2014. 5. National Institutes of Health (NIH) and LiverTox. Chinese and other Asian herbal medicines, 2014. Available at: http://livertox. nih.gov/ChineseAndOtherAsianHerbalMedicines.htm. Accessed date July 1, 2014. 6. Posadzki P, Watson L, Ernst E. Contamination and adulteration of herbal medicinal products (HMPs): an overview of systematic reviews. Eur J Clin Pharmacol 2013; 69: 295–307. 7. Zhang L, Yan J, Liu X, et al. Pharmacovigilance practice and risk control of Traditional Chinese Medicine drugs in China: current status and future perspective. J Ethnopharmacol 2012; 140: 519–25. 8. Shaw D. Toxicological risks of Chinese herbs. Planta Med 2010; 76: 2012–8. 9. Ernst E. Review article. Methodological aspects of traditional Chinese medicine (TCM). Ann Acad Med Singapore 2006; 35: 773–4. 10. Tang JL, Liu BY, Ma KW. Traditional Chinese medicine. Lancet 2008; 372: 1938–40. 11. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther 2013; 37: 3–17. 12. Abdualmjid RJ, Sergi C. Hepatotoxic botanicals – an evidencebased systematic review. J Pharm Pharmaceut Sci 2013; 16: 376– 404. Available at: www.ctca.de. Accessed date July 1, 2014. 13. Lai JN, Tang JL, Wang JD. Review article. Observational studies on evaluating the safety and adverse effects of traditional Chinese medicine. Evid Based Complement Altern Med 2013; 2013. Available at: http://dx.doi.org/10.1155/2013/697893. Accessed date July 1, 2014.
Aliment Pharmacol Ther 2014; 40: 735-740 ª 2014 John Wiley & Sons Ltd
Letter: herbal hepatotoxicity – an update on traditional Chinese medicine preparations; authors0 reply R. Teschke*, A. Wolff†, C. Frenzel‡ & J. Schulze§ *Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt/Main, Hanau, Germany. 738
and classified as ‘probable’. In one case, there was even a re-exposure to the herbal preparation with a positive outcome. We, too, considered Polygoni multiflori Radix as potentially hepatotoxic because of the numerous cases reported in the literature. Thus, only a small part of the study applies to the practice of Chinese Medicine as executed in western countries or as taught academically in China.
ACKNOWLEDGEMENTS Declaration of personal interests: The authors indicate that they do not have conflicts of interest in this study. Declaration of funding interests: None. REFERENCES 1. Teschke R, Wolff A, Frenzel C, Schulze J. Review article: herbal hepatotoxicity – an update on traditional Chinese medicine preparations. Aliment Pharmacol Ther 2014; 40: 32–50. 2. Vaysse J, Balayssac S, Gilard V, et al. Analysis of adulterated herbal medicines and dietary supplements marketed for weight loss by DOSY 1H-NMR. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2010; 27: 903–16. 3. Ye F, Wang H, Jiang S, et al. Quality evaluation of commercial extracts of Scutellaria baicalensis. Nutr Cancer 2004; 49: 217–22. 4. Sovak M, Seligson AL, Konas M, et al. Herbal composition PCSPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst 2002; 94: 1275–81. 5. Lu WI, Lu DP. Impact of Chinese herbal medicine on American society and health care system: perspective and concern. Evid Based Complement Alternat Med 2014; 2014: 251891. 6. Bj€ ornsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant druginduced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095–101. 7. Inoue H, Yamazaki S, Shimizu M, et al. Liver injury induced by the Japanese herbal drug kamishoyosan. Gastroenterol Hepatol 2011; 7: 692–5. 8. Lee CH, Wang JD, Chen PC. Risk of liver injury associated with Chinese herbal products containing Radix Bupleuri in 639,779 patients with hepatitis B virus infection. PLoS ONE 2011; 6: e16064. 9. Jung KA, Min HJ, Yoo SS, et al. Drug-induced liver injury: twenty five cases of acute hepatitis following ingestion of Polygonum multiflorum Thunb. Gut Liver 2011; 5: 493–9.
†
Department of Internal Medicine II, Division of Gastroenterology, Hepatology and Infectious Diseases, Friedrich Schiller University Jena, Jena, Germany. ‡ Department of Medicine I, University Medical Center Hamburg Eppendorf, Hamburg, Germany. § Institute of Industrial, Environmental and Social Medicine, Medical Faculty of the Goethe University Frankfurt/Main, Frankfurt, Germany. E-mail: [email protected] doi:10.1111/apt.12887 Aliment Pharmacol Ther 2014; 40: 735-740 ª 2014 John Wiley & Sons Ltd
Letters to the Editors SIRS, We appreciate the interest in our recent review article1 and the confirm of the well known problems associated with herbal traditional Chinese medicine (TCM) preparations.2 Quality aspects and constituent authentication of herbal TCM products are accepted points of safety concern.1–8 However, reports of adverse reactions that describe toxic events including potentially life threatening hepatotoxicity trigger safety concerns with the use of TCM products containing Chinese herbs.1–5 As therapeutic efficacy of herbal TCM is poorly documented due to lack of convincing controlled clinical trials,1, 3, 4, 9, 10 currently the resulting risk/benefit ratio is negative, without a general or evidence based treatment recommendation. TCM follows a philosophical background which substantially differs from western medicine,4, 10 with interesting theoretical aspects but disputable therapeutic implications. Many effective synthetic drugs such as codeine, colchicine, coumarins, digitoxin, digoxin, morphine, quinine and salicylic acid have been developed from western herbal preparations, but not from TCM products, with the exception of artemisinin and ephedrine. Traditional western herbal drugs commonly are subjected to scientific evaluation and rigour; this should also apply to the efficacy and safety of other traditional herbal medicines including TCM. The herbal TCM product composition often is poorly declared, compounds may be mislabelled or products contaminated with toxins, bacteria, heavy metals or even semisynthetic or synthetic medications like NSAIDs, corticosteroids, fibrates or statins as adulterants.4, 5, 8 There is overall agreement that herbal TCM products may be of low quality, regulatory surveillance as mandatory for regulatory approved synthetic or herbal drugs is not commonly available.1–8 This particular challenge has been recognised not only in China7 but also worldwide,1, 3–6, 8 in line with present views.2 Since TCM products are not standardised, poorly regulated or unregulated,4, 5 ingredients of TCM products may vary among the different producers despite an identical name,5 resulting in variability in herbs (including different varieties) and herbal proportions within mixtures.1–5 For other preparations, the composition of a herbal mixture is unknown.5 Another problem is collecting multiple herbs,1–5 without knowledge of their exact nature or name.5 These shortcomings may explain why even TCM providers have difficulties correctly identifying herbal ingredients and categorising Chinese herbs as traditional or nontraditional Chinese medicinal preparations.2 Aliment Pharmacol Ther 2014; 40: 735-740 ª 2014 John Wiley & Sons Ltd
Mainstream opinion suggests that the use of some herbal TCM products carries the rare risk of liver injury, as assessed by the NIH4, 5 and other hepatotoxicity experts11, 12 including our group,1, 3 despite opposing and unspecified contrary views.2 Actual literature searches will lead to multiple relevant reports,1, 3–5, 11, 12 as did our study with hundreds of liver cases in 91 reports published since 1990.3 At present, the English literature refers to 39 individual TCM herbs, 18 classifiable herbal TCM mixtures and some unclassifiable TCM herbal mixtures with reported potential hepatotoxicity.1 Causality was assessed by the liver specific scale of CIOMS (Council for International Organizations of Sciences) and re-exposure tests. However, Wiebrecht and Kalg claim that Polygonum multiflorum is the sole TCM herb with potential hepatotoxicity.2 This misconception and downplay of hepatotoxicity by other herbal TCM products is difficult to reconcile and may imply lack of expertise in clinical case assessment. TCM providers in Germany commonly are nonmedical healers or rarely general practitioners not necessarily familiar with key issues of clinical hepatology. Unfortunately, no constructive or stimulating suggestions are provided to improve the perspectives of the ancient herbal TCM philosophy,2, 13 despite contested aspects.4, 5, 10, 14 New approaches and motivated TCM experts are needed for multicenter, randomised, double blind, placebo-controlled clinical trials and observational studies into the efficiency and safety of herbal TCM treatments. The results will provide reliable risk/benefit estimates, positively assessed TCM herbs and herbal mixtures should be registered as regulated herbal drugs. These may even be the starting point to further investigate the active herb and its active chemical constituent. western countries have gone this way long ago, starting from the philosophy of ancient traditional western herbal medicine to evidence based medicines using registered herbal drugs and synthetic chemicals. Both eastern and western cultures with their established medicines will profit from additional therapies derived from TCM as modified according to modern scientific requirements. In modern herbal TCM, there should be no place for nonherbal elements.1, 3, 4 Among these are Bai Hua She (venom of the viper Agkistrodon acutus), Jiang Can (larvae of Bombyx Batryticatus), Ling Yang Qing Fei (antelope horn), Quan Xie (polypides of the scorpion Buthus martensii) and Wu Gong (polypites of the centipede Scolopendra subspinipes mutilans). In addition, modern herbal TCM should not follow ancient TCM philosophy and theory due to unproven efficacy.4 Ancient beliefs on which herbal TCM is based include: the human body is 739
Letters to the Editors a miniature version of the larger, surrounding universe; harmony between two opposing forces, called yin and yang, supports health, and disease results from an imbalance between these forces; five elements – fire, earth, wood, metal and water – symbolically represent all phenomena, including the stages of human life, and explain the functioning of the body and how it changes during disease; Qi, a vital energy that flows through your body, performs multiple functions in maintaining health.4 Summarising these points, ancient herbal TCM is under increasing pressure to justify its claims1–10, 14 of therapeutic efficacy and lack of side effects, to standardise and categorise its products, undergo sufficient regulatory surveillance, and improve overall product quality. Therefore, new approaches are necessary for a modern herbal TCM with fascinating and encouraging perspectives. This should cover herbal products with proven therapeutic efficacy in line with the requirements of evidence based medicine, a favourable risk/benefit profile, product standardisation and regulatory surveillance, and an effective ADR reporting system to regulatory agencies. Special scrutiny should be placed on correctly labelling of ingredients and absence of toxins (aflatoxins, bacteria and heavy metals), adulterants, and mislabelled herbs. Until substantial progress is made establishing modern herbal TCM, we are obliged to minimise toxic risks associated with medical treatments including ancient herbal TCM. Risks should be identified,1, 3–10 not ignored,2, 13 and communicated on websites4, 5 and in peer reviewed English language journals.1, 3, 6–12, 14
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.1
740
REFERENCES 1. Teschke R, Wolff A, Frenzel C, Schulze J. Review article: herbal hepatotoxicity – an update on traditional Chinese medicine preparations. Aliment Pharmacol Ther 2014; 40: 32–50. 2. Wiebrecht A, Kalg A. Letter: herbal hepatotoxicity – an update on traditional Chinese Medicine preparations. Aliment Pharmacol Ther 2014; 40: 737–8. 3. Teschke R. Traditional Chinese Medicine induced liver injury. J Clin Transl Hepatol 2014; 40: 737–8. doi:10.14218/JCTH.2014. 00003 4. NIH, National Center for Complementary and Alternative Medicine (NCCAM). Traditional Chinese medicine: an introduction, 2013. Available at: http://nccam.nih.gov/health/ whatiscam/chinesemed.htm. Accessed date July 1, 2014. 5. National Institutes of Health (NIH) and LiverTox. Chinese and other Asian herbal medicines, 2014. Available at: http://livertox. nih.gov/ChineseAndOtherAsianHerbalMedicines.htm. Accessed date July 1, 2014. 6. Posadzki P, Watson L, Ernst E. Contamination and adulteration of herbal medicinal products (HMPs): an overview of systematic reviews. Eur J Clin Pharmacol 2013; 69: 295–307. 7. Zhang L, Yan J, Liu X, et al. Pharmacovigilance practice and risk control of Traditional Chinese Medicine drugs in China: current status and future perspective. J Ethnopharmacol 2012; 140: 519–25. 8. Shaw D. Toxicological risks of Chinese herbs. Planta Med 2010; 76: 2012–8. 9. Ernst E. Review article. Methodological aspects of traditional Chinese medicine (TCM). Ann Acad Med Singapore 2006; 35: 773–4. 10. Tang JL, Liu BY, Ma KW. Traditional Chinese medicine. Lancet 2008; 372: 1938–40. 11. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther 2013; 37: 3–17. 12. Abdualmjid RJ, Sergi C. Hepatotoxic botanicals – an evidencebased systematic review. J Pharm Pharmaceut Sci 2013; 16: 376– 404. Available at: www.ctca.de. Accessed date July 1, 2014. 13. Lai JN, Tang JL, Wang JD. Review article. Observational studies on evaluating the safety and adverse effects of traditional Chinese medicine. Evid Based Complement Altern Med 2013; 2013. Available at: http://dx.doi.org/10.1155/2013/697893. Accessed date July 1, 2014.
Aliment Pharmacol Ther 2014; 40: 735-740 ª 2014 John Wiley & Sons Ltd
