Letters to the Editors
3.
4.
5.
6.
tetracycline with omeprazole as a rescue therapy for eradication of Helicobacter pylori. Aliment Pharmacol Ther 2014; 40: 171–7. Malfertheiner P, Bazzoli F, Delchier JC, et al. H. pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, openlabel, non-inferiority, phase 3 trial. Lancet 2011; 377: 905–13. Liang X, Xu X, Zheng Q, et al. Efficacy of bismuth-containing quadruple therapies for clarithromycin-, metronidazole-, and fluoroquinolone-resistant Helicobacter pylori infections in a prospective study. Clin Gastroenterol Hepatol 2013; 11: 802–7. Trifan A, Girleanu I, Cojocariu C, et al. Pseudomembranous colitis associated with a triple therapy for H. pylori eradication. World J Gastroenterol 2014; 19: 7476–9. Archimandritis A, Souyioultzis S, Katsorida M, Tzivras M. Clostridium difficile colitis associated with a triple regimen,
Letter: herbal hepatotoxicity – an update on traditional Chinese medicine preparations A. Wiebrecht & A. Kalg Center for Safety of Chinese Herbal Medicine, Berlin, Germany. E-mail: [email protected] doi:10.1111/apt.12883
SIR, In our opinion, the recent article of Teschke et al.1 does not reflect the risk of hepatotoxicity caused by Chinese herbal medicine in an authentic way. Although the case reports cited in the article are well identified, most of the suspected substances do not belong to the usual practice of Chinese herbal medicine. In many of the included cases, dietary supplements from US had been used which, among various ingredients, also contained one or two Chinese medicinal herbs. The composition of those products is often obscure. In some cases, they contain additional undeclared ingredients,2–4 and the authentication of the herbal components was missing. Contrary to the practice of Chinese Medicine, which uses the medicinals frequently in prepared form, those dietary supplements may be composed of unprepared herbs. Moreover, they use Chinese medicinal herbs without considering the framework of Chinese Medicine.5 Therefore, an extrapolation of the risks from those products to Chinese medicine, in our opinion, is not legitimate. A group of dietary supplements, which are referred to in this article as potentially hepatotoxic, contain catechins from green tea extracts. Green tea is not a Chinese medicinal, but a foodstuff. Hence, the claimed risk canAliment Pharmacol Ther 2014; 40: 735-740 ª 2014 John Wiley & Sons Ltd
containing clarithromycin and metronidazole, to eradicate H. pylori. J Intern Med 1998; 243: 251–3. 7. Dore MP, Farina V, Cuccu M, et al. Twice-a-day bismuthcontaining quadruple therapy for Helicobacter pylori eradication: a randomized trial of 10 and 14 days. Helicobacter 2011; 4: 295–300. 8. Gisbert JP, Perez-Aisa A, Rodrigo L, et al. Third-line rescue therapy with bismuth-containing quadruple regimen after failure ot two tretments (with clarithromycin and levofloxacin) for H. pylori infection. Dig Dis Sci 2014; 59: 383–9. 9. Lefebvre M, Chang HJ, Morse A, et al. Adherence and barriers to H. pylori treatment in Arctic Canada. Int J Circumpolar Health 2013; 72: 10.
not be attributed to Chinese medicine. In addition, the striking frequency of liver damage by green tea extracts, which is not observed with the common intake of green tea itself, could be related to the extraction methods that differ from the traditional tea making process. Caution should be exercised, when experience gained over centuries or millennia is disregarded. Catechins are not only present in tea derived from the plant Camellia sinensis, such as in green tea, black tea, oolong tea, etc. but are also found in many foods which are not known to be hepatotoxic. Other suspected plants, namely Hovenia dulcis (Jiguja, the Korean term) and Gynura segetum (tu san qi) are not officinal Chinese medicinals. They may be used locally in some regions of Korea and China. Outside of East Asia, they are virtually unknown and do not play any role for practice of Chinese medicine. Most of the cases of potential hepatotoxicity quoted in the article are associated with Gynura segetum. The pyrrolizidine alkaloids (PA’s), which must be contained in this plant at high concentrations, are well known for their hepatotoxic potential. In many Western countries, PA’s are either completely banned or only allowed to be used within very narrow limits. Complying with these regulations, liver injuries can be definitely ruled out. Citing the case report of Bj€ornsson et al.,6 Angelica archangelica is used synonymously with the Chinese medicinal du huo (root of Angelicae pubescentis), and the reported liver injury was ascribed to Chinese Medicine. A. archangelica, however, is a western medicinal plant and different from A. pubescens. The article of Inoue et al.7 describes a liver injury observed by the intake of a Japanese Kampo medicine formula, which is similar to the Chinese formula jia wei
737
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
3.
4.
5.
6.
tetracycline with omeprazole as a rescue therapy for eradication of Helicobacter pylori. Aliment Pharmacol Ther 2014; 40: 171–7. Malfertheiner P, Bazzoli F, Delchier JC, et al. H. pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, openlabel, non-inferiority, phase 3 trial. Lancet 2011; 377: 905–13. Liang X, Xu X, Zheng Q, et al. Efficacy of bismuth-containing quadruple therapies for clarithromycin-, metronidazole-, and fluoroquinolone-resistant Helicobacter pylori infections in a prospective study. Clin Gastroenterol Hepatol 2013; 11: 802–7. Trifan A, Girleanu I, Cojocariu C, et al. Pseudomembranous colitis associated with a triple therapy for H. pylori eradication. World J Gastroenterol 2014; 19: 7476–9. Archimandritis A, Souyioultzis S, Katsorida M, Tzivras M. Clostridium difficile colitis associated with a triple regimen,
Letter: herbal hepatotoxicity – an update on traditional Chinese medicine preparations A. Wiebrecht & A. Kalg Center for Safety of Chinese Herbal Medicine, Berlin, Germany. E-mail: [email protected] doi:10.1111/apt.12883
SIR, In our opinion, the recent article of Teschke et al.1 does not reflect the risk of hepatotoxicity caused by Chinese herbal medicine in an authentic way. Although the case reports cited in the article are well identified, most of the suspected substances do not belong to the usual practice of Chinese herbal medicine. In many of the included cases, dietary supplements from US had been used which, among various ingredients, also contained one or two Chinese medicinal herbs. The composition of those products is often obscure. In some cases, they contain additional undeclared ingredients,2–4 and the authentication of the herbal components was missing. Contrary to the practice of Chinese Medicine, which uses the medicinals frequently in prepared form, those dietary supplements may be composed of unprepared herbs. Moreover, they use Chinese medicinal herbs without considering the framework of Chinese Medicine.5 Therefore, an extrapolation of the risks from those products to Chinese medicine, in our opinion, is not legitimate. A group of dietary supplements, which are referred to in this article as potentially hepatotoxic, contain catechins from green tea extracts. Green tea is not a Chinese medicinal, but a foodstuff. Hence, the claimed risk canAliment Pharmacol Ther 2014; 40: 735-740 ª 2014 John Wiley & Sons Ltd
containing clarithromycin and metronidazole, to eradicate H. pylori. J Intern Med 1998; 243: 251–3. 7. Dore MP, Farina V, Cuccu M, et al. Twice-a-day bismuthcontaining quadruple therapy for Helicobacter pylori eradication: a randomized trial of 10 and 14 days. Helicobacter 2011; 4: 295–300. 8. Gisbert JP, Perez-Aisa A, Rodrigo L, et al. Third-line rescue therapy with bismuth-containing quadruple regimen after failure ot two tretments (with clarithromycin and levofloxacin) for H. pylori infection. Dig Dis Sci 2014; 59: 383–9. 9. Lefebvre M, Chang HJ, Morse A, et al. Adherence and barriers to H. pylori treatment in Arctic Canada. Int J Circumpolar Health 2013; 72: 10.
not be attributed to Chinese medicine. In addition, the striking frequency of liver damage by green tea extracts, which is not observed with the common intake of green tea itself, could be related to the extraction methods that differ from the traditional tea making process. Caution should be exercised, when experience gained over centuries or millennia is disregarded. Catechins are not only present in tea derived from the plant Camellia sinensis, such as in green tea, black tea, oolong tea, etc. but are also found in many foods which are not known to be hepatotoxic. Other suspected plants, namely Hovenia dulcis (Jiguja, the Korean term) and Gynura segetum (tu san qi) are not officinal Chinese medicinals. They may be used locally in some regions of Korea and China. Outside of East Asia, they are virtually unknown and do not play any role for practice of Chinese medicine. Most of the cases of potential hepatotoxicity quoted in the article are associated with Gynura segetum. The pyrrolizidine alkaloids (PA’s), which must be contained in this plant at high concentrations, are well known for their hepatotoxic potential. In many Western countries, PA’s are either completely banned or only allowed to be used within very narrow limits. Complying with these regulations, liver injuries can be definitely ruled out. Citing the case report of Bj€ornsson et al.,6 Angelica archangelica is used synonymously with the Chinese medicinal du huo (root of Angelicae pubescentis), and the reported liver injury was ascribed to Chinese Medicine. A. archangelica, however, is a western medicinal plant and different from A. pubescens. The article of Inoue et al.7 describes a liver injury observed by the intake of a Japanese Kampo medicine formula, which is similar to the Chinese formula jia wei
737
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
