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A new study on liver injury caused by Chinese herbal medicines: substantial data, questionable conclusions

veröffentlicht: 2017
Verfasser: Axel Wiebrecht

The study

A recent study by Melchart and co-authors [1] analysed the incidence of liver injuries occurring in an TCM hospital in Kötzting, Germany from 1994 to 2015. Included were patients treated with Chinese herbal therapy whose liver enzyme ALT (alanine aminotransferase) at the time of admission was within the normal range. Just before discharge, the liver function was checked again. An elevation of ALT up to 5 times the upper norm was considered as an adaptive phenomenon of the liver, and a higher increase was interpreted as liver injury. The average treatment time was 19.5 days due to the duration of inpatient stay. The association of liver injury with the Chinese medicines was assessed using the internationally accepted RUCAM (or CIOMS) scale.

21,740 patient cases were evaluated. An ALT elevation above the normal range was observed in 3.93% of cases, and liver injury with an at least 5-fold ALT elevation occurred in 26 patients (0.12%). In 8 out of these 26 patients, the authors stated a "probable" association with Chinese herbs, in 16 cases a "possible" association, and in 2 cases they excluded a causality. Bupleuri Radix (chai hu) and Scutellariae Radix (huang qin) particularly stand out, as they were involved in 7 of the "probable" or "possible" cases, in 6 of which both were involved simultaneously.

In their analysis, the authors supposed a known hepatotoxicity for a number of herbs („associated with potential liver injury as evidenced from the scientific literature“) which were involved in the cases, namely Bombyx batryticatus (jiang can), Dictamni cortex (bai xian pi), Ephedrae herba (ma huang), Glycyrrhizae radix (gan cao), Polygoni multiflori caulis (shou wu teng), Polygoni multiflori radix (he shou wu), Polygoni cuspidati rhizoma (hu zhang), Psoraleae fructus (bu gu zhi), Puerariae radix (ge gen), Rhei radix et rhizoma (da huang), Sennae folium* (fan xie ye) and Toosendan fructus* (chuan lian zi).

*Name has been adjusted to the current nomenclature.

Commentary

This study provides valuable, unprecedented data for assessing the potential risk of Chinese herb-induced liver injury, characterised by the following features:

  • the prospective design
  • the high number of 21,470 included patients which allows a valid estimate of the incidence of liver injuries in non-predisposed patients within a limited period of time (19.5 days on average)
  • the prior authentication and testing for contamination of the herbs used
  • reference to European conditions by exclusion of prohibited substances, the most toxic medicinals which are uncommon in this area, and the use of excessively high doses
  • and last but not least, full transparency regarding all components of the herbal formulas and the calculation of the RUCAM scores.

This is thanks to the authors. An important signal is that relevant liver injury caused by Chinese herbs - at least under the conditions of the study - rarely occurs, and after the discontinuation of therapy, usually regresses uneventfully. However, with regard to the interpretation of the results, some comments and corrections to the study appear to be appropriate.

In evaluating the causality between certain herbs and an observed liver injury, the extent to which hepatotoxicity is already considered proven for these herbs is a key point. Known hepatotoxicity leads to an increase of 1 to 2 points in the probability of a causality concerning the RUCAM score used in the study. These points often make the difference between a "possible" and a "probable" association or if one herb or another is suspected of being the causative agent. If an assumption is made without sufficient evidence, one runs the risk of confirming prejudices and reproducing misconceptions. Frequent repetitions do not make statements more true. In addition, evidence of causality assignment can only rely on "probable" or "very probable" associations to avoid misjudgements. "Possible" associations may have a supportive role or may draw attention to certain herbs, but they can not establish evidence.

For several herbs, which were suspected of being hepatotoxic in the study, these reservations are relevant. The most striking example is Glycyrrhizae radix. This is the herb most commonly used in Chinese medicine which is contained in approximately 50% of herbal formulas. If a formula is suspected of liver toxicity, then Glycyrrhizae radix is automatically involved in about half of the cases. The same also applies to other herbs commonly used in Chinese medicine such as Atractylodis macrocephalae rhizoma or Angelica sinensis radix. Therefore, the suspicion is justified only if the involvement of a herb in liver injury is significantly higher than its average frequency of use. Reservation should be used when a particular herb is involved that commonly is prescribed together with a potentially hepatotoxic agent, because both substances are indicated for certain diseases or their effects complement each other. Here, the frequent involvement of a herb can create a wrong picture.

In a previous smaller study from the Kötzting hospital [2], Glycyrrhizae radix and Atractylodis macrocephalae rhizoma stood out significantly as ingredients of herbal formulas associated with liver enzyme elevations. The authors had described these results as possibly due to chance or to confounding factors, since these herbs had not previously been reported as hepatotoxic in the literature. In the current study, Glycyrrhizae radix and Atractylodis macrocephalae rhizoma are involved in only 2 out of 9 cases as being "probably" associated with liver injury, whereupon the inclusion criterion is not based on a 2-fold, but on a more than 5-fold elevation of ALT above upper norm. Nevertheless, a suspected hepatotoxicity for Glycyrrhizae radix in the present study is stated because this property is assumed as being established.

One contributing author repeatedly stressed a hepatotoxicity of Glycyrrhizae radix (gan cao) as having been documented in the literature [3-5] which increased the likelihood of it being associated with liver injury in the present study according to the RUCAM test by 2 points. This assessment is based on two poorly documented case reports within a single publication from Hong Kong [6]. One of these two case reports is sufficient for Teschke and co-authors [3, 5] to establish the hepatotoxicity of three herbs simultaneously, which is hard to reconcile with the laws of logic. The rationale was that the hepatotoxicity of the herbs should be apparently known, but references are not provided by either the authors of the case reports or by Teschke et al. A complete account of the ingredients used in the herbal formulas was missing, as well as the authentication of the herbs or testing for contaminants. The accepted and widely used procedure for assessing the causality of drug-related liver injury is the RUCAM (or CIOMS) test [7]. The scores cited by Teschke et al. [3] for the RUCAM tests are fiction. A recalculation resulted in a RUCAM score of 2 or 3 instead of "6 to 8" for the herbs in question, so that the causality is "unlikely" or even "possible" [8]. Thus, these case reports are not appropriate for establishing hepatotoxicity. There is no evidence of hepatotoxicity relating to Glycyrrhizae radix.

Another case is Bombyx batryticatus. Here too, without legitimacy, the authors claim hepatotoxicity as being known. In many larger case compilations of liver injury, this medicine is missing [9-19]. In the publication by B. Shaw [20], Bombyx batryticatus was present, as an ingredient of the complex formulas, in just 2 out of 40 patients with a liver reaction likely or possibly related to Chinese herbal therapy, without it being cause for suggesting a suspected hepatotoxicity. The review by Tu et al. [21] gives a detailed report on the side effects of Bombyx batryticatus, with no mention of liver toxicity. If you search for "Bombyx" and "(liver injury or hepatotoxicity)" in Pub Med, you will find 3 publications that describe a hepatoprotective property of this herb. The work by Teschke et al. [22], which in turn relies merely on the unsuitable Hong Kong case study [6], stands alone in asserting a potential hepatotoxicity.

For a valid causality assessment, clear evidence for the assumption of a "known" hepatotoxicity is required. Herbal medicines, especially those from TCM, involve a particular challenge: they are rarely used as single herbs. In multicomponent herbal formulas, it is difficult to blame a particular ingredient for the reaction. The identity of the herbs must be ensured, since mistakes or deliberate adulterations do occur. Furthermore, contamination due to impurities, undesirable substances or conventional drugs must be excluded. The way in which a herb is prepared or pre-treated, which is often done just to reduce toxicity, can also play a crucial role [9]. Therefore, one cannot unconditionally apply study results from another therapeutic system (e.g., Kampo, Ayurveda) which uses a different method of preparation, to TCM.

The conditions for evidence are fulfilled by only a few herbs. For polygoni multiflori radix (he shou wu), they are beyond doubt. It is often used as a single herb, too. Among the numerous case reports, authentication or testing for contaminants was partially carried out. For Dictamni cortex (bai xian pi), there are only a few cases of it being used as a single herb [23, 24]. However, it is striking that this herb is significantly more probable to be involved in liver injury than its frequency of use accounts for.

Other herbs with insufficiently documented evidence, which are considered potentially hepatotoxic in the study, are: Sennae folium, Polygoni cuspidati rhizoma, Polygoni multiflori caulis, Pueraria radix and Rhei radix et rhizoma. For example, with Puerariae radix: Teschke et al. [22] cited a reference dealing with two cases of hepatitis due to the juice of Puerariae lobatae radix from Korea [25]. An authentication of the preparations was not documented. The phytochemical composition of the juice cannot be equated with that of a decoction from the dried herb as it is used in the context of Chinese medicine. The RUCAM tests which were carried out, each with a high score of 10 [25], are not credible since the differential diagnosis is incomplete and the documentation of the quo ante hepatotoxicity is not sufficiently substantiated.

The updated RUCAM test assigns two points for hepatotoxicity if it is listed in the product characteristic, and one point if there is only evidence in the literature [7]. A product characteristic is missing for raw herbs. TCM finished products with a single herb as the active ingredient exist only as an exception. For the assured, albeit very rare, hepatotoxicity of Polygoni multiflori radix (he shou wu), 2 points can be applied analogously. For other herbs that are mentioned in publications, but for which there is no clear evidence, a rating with a quo-ante score of "1" is appropriate: this applies for Ephedrae herba, Toosendan fructus, Bupleuri radix and Scutellariae radix. For the remaining herbs mentioned in the study, no valid references have been documented which would justify one point.

In several cases, this approach leads to an amendment of the RUCAM assessment (Table 1). Of the 9 study cases whose association with Chinese medicine should be "probable", only 4 remain: cases 3, 12, 14 and 19.2; each with a RUCAM score of 6. This "probable" association applies to the entire herbal formula and can only be applied to a single herb if not more than one ingredient of the formula is suspected of being hepatotoxic. This is true for case no. 12, where only Toosendan fructus with a score of "1" justifies a RUCAM score of 6 for a "probable" association. The RUCAM test states that if other substances are eligible as an alternative cause, "2" points should be deducted [7]. If 2 or more herbs with a pre-existing suspicion of hepatotoxicity are involved, then, if you want to break down the causality to the individual herbs, these 2 points should be subtracted. Then, a "probable" causality can no longer be assumed for these single herbs.

 

Case no.

3

4

12

14

17

18

19(1)

19(2)

24


RUCAM score formula, acc. to publication

7

6

7

7

6

6

6

7

6

RUCAM score Rezeptur, revised

6

5

6

6

5

5

5

6

5

Association with formula

pr

po

pr

pr

po

po

po

pr

po

                   

Involvement of so-called "suspected herbs":

                 

Bupleuri Rx. (RUCAM, herb)

x(4)

x(3)

   

x(3)

x(3)

x(3)

x(4)

x(3)

Scutellariae Rx. (RUCAM, herb)

x(4)

   

x(4)

x(3)

x(3)

x(3)

x(4)

x(3)

Ephedrae Hb. (RUCAM, herb)

x(4)

         

x(3)

   

Toosendan Fr. (RUCAM, herb)

   

x(6)

x(4)

         

Table 1: Compilation of cases for which the publication, using the RUCAM score, claims a "probable" association of the liver injuries with the respective formula, and revision of the RUCAM scores (red). For the association with individual herbs, corrected RUCAM scores were also given (red). RUCAM score ≤0 = “excluded”, 1-2 = "unlikely", 3-5 = "possible" (po), 6-8 = "probable" (pr),> 8 = "highly probable". Herbs contained in the formulas which are without any suspicion of hepatotoxicity are omitted.

Bupleuri radix and Scutellariae baicalensis Radix deserve special consideration. There is an abundance of cases of hepatotoxicity in Kampo medicine for formulas containing these substances. Mostly often, both herbs are used simultaneously, e.g. in the formula sho-saiko-to. In Chinese medicine, however, liver injury due to these herbs is scarcely known [26]. Kampo herbs are not simply comparable to those of Chinese medicine. For Bupleuri radix, the species Bupleurum falcatum is used in Kampo medicine [27]. In Chinese medicine, the species B. chinense or B. scorzonerifolium are officinal [28]. In Japan, standard formulas are predominantly used as granules. Alcohol is also applied for extraction [27], which means that the composition of the extracts is not comparable to that of decoctions from Chinese medicine. As to acute toxicity testing, an ethanol extract was more toxic to the liver than an aqueous extract [29].

Within Chinese medicine, there have been only sporadic case reports with inadequate causality criteria [30, 31] in which these herbs appeared. For the first time, the present study documents several cases with formulas containing Bupleuri radix and Scutellariae radix associated with liver injury, where testing for identity and contamination was done. In the 4 cases remaining as "probable" after revision, Bupleuri radix is involved twice and Scutellariae radix three times. In case 3, where both herbs are involved, Ephedrae herba appears as an alternative causative agent, and in case 14 (without Bupleuri radix), the potential causative agent Toosendan fructus is present. A clear assignment to Bupleuri radix or Scutellariae radix is therefore not possible here. In case 19.2, only these two herbs are present with a potential quo-ante suspicion. Of particular importance here is the patient's rechallenge by a formula (19.2), which again contained both of these herbs, but only 3 other herbs (Curcumae longae rhizoma, Curcumae radix and Mori ramulus), which were given in the first formula and for which no reasonable suspicion exists. In addition, it is peculiarly striking how many cases with a “possible” causality these two herbs were involved in.

Based on this new data quality, one has to reassess the hepatotoxicity of Bupleuri radix and Scutellariae baicalensis radix. Either one herb or the other, or both herbs together, should be considered to be potentially hepatotoxic. However, a definite allocation of causality to one or the other herb does not appear to be feasible without reservation according to the current level of evidence. When using either one of these herbs, one must be prepared for the very rare possibility of an idiosyncratic (unpredictable) reaction.

A re-evaluation also seems appropriate for Toosendan fructus. So far, a possible hepatotoxicity only applied in the case of overdose [32]. Now, the herb is implicated in two out of four cases with a probable association; in case 12, without any other suspected herbs included in the formula. Apparently, hepatotoxicity can also occur in the normal dose range. Unfortunately, dosages are not detailed in this study. However, if there is a dose-dependency, it may be an intrinsic hepatotoxicity that could be controlled by limiting the dosage.

For a reassessment of Ephedrae herba, the results of the study are not sufficient. This herb is involved in case 3 in which Bupleuri radix and Scutellariae radix are present, so a clear assignment is not possible. The same applies to case 7 and the first formula in case 19 (19.1), for which the association is merely "possible"; in case 20, Bupleuri radix was used simultaneously. The limited number of hepatotoxicity cases involving Ephedra herba documented in the literature must be weighed against the million-fold uses of the herb, especially in the years previous to 2004. However, with the cases from the present study, this herb shifts into the upper range of a "possible" hepatotoxicity.

Conclusion

The study contains unprecedented data quality for assessing the hepatotoxic risk of Chinese herbal medicines. However, many of the evaluations made in the publication do not hold up. The potential hepatotoxicity of Bupleuri radix or Scutellariae baicalensis radix, or of a combination of both drugs together in the context of Chinese medicine must be deemed adequately secured although a further differentiation currently is not possible. Toosendan fructus, at standard dosages, also appears to be possibly hepatotoxic even though the dosages were not explicitly reported in the respective cases of the study. The possible liver injury caused by Polygoni multiflori radix has already been confirmed, and the study provides no additional support on this. Toxicity cases involving this herb seem to be less common in Western countries than in Asia.

Overall, liver injuries caused by Chinese herbal medicine are very rare and their prognosis, if recognized early enough, is generally uneventful. For a duration of use longer than 19.5 days, as in the present study, the incidence might be higher. If liver reactions associated with Chinese herbal therapy occur, it is advisable to carry out a full differential diagnostic procedure [33] to either confirm or disprove the causality, so that the evidence regarding Chinese herbs and their actual hepatotoxic risks increases. This applies not only to the Kötzting hospital, but in every case. The Centre for Safety of Chinese Herbal Medicines, CTCA (Centrum für Therapiesicherheit in der Chinesischen Arzneitherapie) in Berlin is an appropriate address for dealing with this matter.

Literature:

  1. Melchart D, Hager S, Albrecht S, Dai J, Weidenhammer W and Teschke R. Herbal Traditional Chinese Medicine and suspected liver injury: A prospective study. World J Hepatol 2017;9:1141-1157
  2. Melchart D, Linde K, Hager S, et al. Monitoring of liver enzymes in patients treated with traditional Chinese drugs. Complement Ther Med 1999;7:208-216
  3. Teschke R, Zhang L, Long H, et al. Traditional Chinese Medicine and herbal hepatotoxicity: a tabular compilation of reported cases. Ann Hepatol 2015;14:7-19
  4. Teschke R, Wolff A, Frenzel C and Schulze J. Review article: herbal hepatotoxicity - an update on traditional Chinese medicine preparations. Aliment Pharmacol Ther 2014;40:32-50
  5. Teschke R, Larrey D, Melchart D and Danan G. Traditional Chinese Medicine (TCM) and herbal hepatotoxicity: RUCAM and the role of novel diagnostic biomarkers such as MicroRNAs. Medicines 2016;3:18
  6. Yuen MF, Tam S, Fung J, et al. Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study. Aliment Pharmacol Ther 2006;24:1179-1186
  7. Danan G, Teschke R. RUCAM in drug and herb induced liver injury: The update. Int J Mol Sci 2015;17:E14
  8. Wiebrecht A. Dubious pseudoscience – on the alleged hepatotoxicity of Chinese herbal medicines. www.ctca.de/index.php/en/news/dubious-pseudoscience-on-the-alleged-hepatotoxicity-of-chinese-herbal-medicines
  9. Teo DC, Ng PS, Tan SH, et al. Drug-induced liver injury associated with Complementary and Alternative Medicine: a review of adverse event reports in an Asian community from 2009 to 2014. BMC Complement Altern Med 2016;16:192
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  12. Chau TN, Cheung WI, Ngan T, et al. Causality assessment of herb-induced liver injury using multidisciplinary approach and Roussel Uclaf Causality Assessment Method (RUCAM). Clin Toxicol 2011;49:34-39
  13. Lee WJ, Kim HW, Lee HY and Son CG. Systematic review on herb-induced liver injury in Korea. Food Chem Toxicol 2015;84:47-54
  14. Ma X, Peng JH and Hu YY. Chinese Herbal Medicine-induced Liver Injury. J Clin Transl Hepatol 2014;2:170-175
  15. Peng XL, Li CS and Cui SZ. [Biometrical analysis on liver injury caused by traditional Chinese herbs] (Chinese). Shizhen Guoyi Guoyao 1999;10:392-393
  16. Pittler MH, Ernst E. Systematic review: hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther 2003;18:451-471
  17. Zhang P, Ye Y, Yang X and Jiao Y. Systematic review on Chinese herbal medicine induced liver injury. Evid Based Complement Alternat Med 2016;2016:3560812
  18. Zhao P, Wang C, Liu W and Wang F. Acute liver failure associated with traditional Chinese medicine: report of 30 cases from seven tertiary hospitals in China. Crit Care Med 2014;42:e296-299
  19. Wang XJ, Xu LP and Wang M. [Hepatotoxicity caused by commonly used Chinese medicinal herbs and compound preparations] (Chinese). Shoudu Yike Daxue Xuebao 2007;28:220-224
  20. Shaw BJ. Aspects of Chinese herbal medicine with relation to their hepatotoxicity. A thesis submitted to King's College London for the degree of Doctor of Philosophy. School of Biomedical and Health Sciences, King's College London & Royal Botanical Gardens, Kew, 2007
  21. Tu YD, Yu XP. [The clinical use of Bambusa textilis in lung diseases and its side effects] (Chinese). Shanghai Zhongyiyao Zazhi 2012;46:64-66
  22. Teschke R. Traditional Chinese Medicine induced liver injury. J Clin Translat Hepatol 2014;2:80-94
  23. Lee JH, Lee HY, Koh KC, et al. [Drug induced liver disease caused by ingestion of Dictamnus dasycarpus] (Korean). Korean J Gastroenterol 1998;31:251-257
  24. Jang JS, Seo EG, Han C, et al. [Four cases of toxic liver injury associated with Dictamnus dasycarpus] (Korean). Korean J Hepatol 2008;14:206-212
  25. Kim SY, Yim HJ, Ahn JH, et al. [Two cases of toxic hepatitis caused by arrowroot juice] (Korean). Korean J Hepatol 2009;15:504-509
  26. Wu SX, Sun HF, Yang XH, et al. ["Re-evaluation upon suspected event" is an approach for post-marketing clinical study: lessons from adverse drug events related to Bupleuri Radix preparations] (Chinese). Zhongguo Zhongyao Zazhi 2014;39:2983-2988
  27. Japanese Pharmacopoeia (JP XVI). English Version. 16th ed. Tokyo: Pharmaceutical and Medical Device Regulatory Science Society of Japan, 2012
  28. Chinese Pharmacopoeia Commission. Pharmacopoeia of the Peoples Republic of China (English version). Vol. I. Beijing, China: China Medical Science Press, 2015
  29. Liu YM, Liu XM and Pan RL. [Research progress on toxic effects of Radix bupleuri] (Chinese). Zhong Chengyao 2012;34:1148-1151
  30. Lee CH, Wang JD and 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
  31. Melchardt T, Magnes T, Weiss L, et al. Liver toxicity during temozolomide chemotherapy caused by Chinese herbs. BMC Complement Altern Med 2014;14:115
  32. Bensky D, Clavey S and Stöger E. Chinese Herbal Medicine. Materia Medica. 3rd ed. Seattle, WA: Eastland Press, 2004
  33. Center for Safety of Chinese Herbal Therapy (CTCA). Website: www.ctca.de. A report schedule is available there.

Dubious pseudoscience – on the alleged hepatotoxicity of Chinese herbal medicines*

veröffentlicht: Oktober 2016
Verfasser: Axel Wiebrecht

 *Slightly edited version of an article from Deutsche Zeitschrift für Akupunktur 2016;59(4): 33-35. 

Translated by Dough Chick

Abstract

In recent years, a circle of authors around the first author Rolf Teschke has written several articles in international journals on the alleged hepatotoxicity of Chinese herbal medicines. Rolf Teschke often exhibited as a critical scientist who has repeatedly demanded a careful assessment of causality in cases of suspected drug-induced liver injury by use of the CIOMS scale. However, in the case of Chinese herbal medicines all principles are forgotten. A review which claims an established hepato­toxicity by means of the CIOMS scale for 28 of 57 herbs or herbal mixtures is partly based on scienti­fically worthless case reports and insupportable causality statements. In some cases, a CIOMS test was not even conducted; nevertheless, CIOMS values were planted in those cases. But even these values do not stand up to scrutiny by any means. Moreover, the authors incorrectly assign herbs which are used exclusively in Western medicine to traditional Chinese herbal medicine. With regards to two "Kampo" medicines adulterated with the anorectic N-nitroso-fenfluramine, the hepatotoxicity is attributed to the herbal ingredients without any valid reason; although, on the basis of studies and a statement from the Japanese Ministry of Health, the chemical admixture is responsible for this.

Conclusion: The authors must be presumed as exhibiting a conscious action and a tendentious attitude. The review falls far below the usual standard of the authors. Despite this, the possible hepatotoxicity of Chinese herbal medicines is an important and serious issue whose clarification is not supported by this work

Keywords: Traditional Chinese medicine, Chinese herbal medicine, Chinese herbs, hepatotoxicity, liver injury, scientific dishonesty

 

In recent years, a number of articles from a certain group of authors on the hepatotoxicity of Chinese herbal medicines have appeared in various international journals. The respective first author Rolf Teschke, has often distinguished himself as a meticulous scientist, who in approximately twenty publications, together with several co-authors, has repeatedly called for a precise determination of causality in cases of suspected drug-induced liver injury. He insists on applying the validated CIOMS (Council for International Organizations of Medical Sciences) scale [1] for which, together with the author Danan, he has issued an update [2].

Consequently, he rejected the attribution of hepatotoxicity to Cimicifuga racemosa by the US Pharma­copoeia with the reasoning that the agency had used an unsuitable scale for evaluating various case reports [3]. Similarly, he analysed 26 cases of alleged kava kava hepatotoxicity, in which the German Federal Institute for Drugs and Medical Devices (BfArM) had supposed a probable causality and used this as rationale for a ban on the drug. He and his co-authors were only able to confirm the causality as probable in one case and as possible in two other cases [4].

For several years now, Rolf Teschke, together with his co-authors, has developed a predilection for Chinese medicine, even though, according to his own statement, it doesn’t fit into his medical and scientific worldview. Since 2012, he has written at least five articles about the hepatotoxicity of alleged traditional Chinese herbal medicines, mostly with co-authors C. Frenzel, J. Schulze and A. Wolff. In doing so, the same litany of various herbal medicines and herbal combinations are called up again and again applying the "TCM" label equally to folk medicines, substances from traditional Korean medicine, Kampo medicine, some U.S. food supplements, which contain a variety of ingredients, occasionally including Chinese herbs, and sometimes even purely Western drugs. However, relating to this standard assignment he seems to have forgotten all principles of critical causality assessment. Henceforth, everything with the above-mentioned spectrum in terms of hepatotoxicity is picked up, partially due to lack of translation, using solely the contents of abstracts.

However, among these different reviews, there is one that stands out [5]. The authors claim to present "for the first time, a compressed tabular summary of all potentially hepatotoxic TCM herbs". A further table is said to contain a causality assessment applying the CIOMS scale as well as the results of positive re-exposure tests. Although the compilation hardly differs from previous articles, one might be curious about the results of the causality assessment that the critical authors will come to. The findings are summarised in the abstract of the article, which is reproduced below:

  • Abstract: Traditional Chinese Medicine (TCM) with its focus on herbal use became popular worldwide. Treatment was perceived as safe, with neglect of rare adverse reactions including liver injury. To compile worldwide cases of liver injury by herbal TCM, we undertook a selective literature search in the PubMed database and searched for the items Traditional Chinese Medicine, TCM, Traditional Asian Medicine, and Traditional Oriental Medicine, also combined with the terms herbal hepatotoxicity or herb induced liver injury. The search focused primarily on English-language case reports, case series, and clinical reviews. We identified reported hepatotoxicity cases in 77 relevant publications with 57 different herbs and herbal mixtures of TCM, which were further analysed for causality by the Council for International Organizations of Medical Sciences (CIOMS) scale, positive reexposure test results, or both. Causality was established for 28/57 different herbs or herbal mixtures, Bai Xian Pi, Bo He, Ci Wu Jia, Chuan Lian Zi, Da Huang, Gan Cao, Ge Gen, Ho Shou Wu, Huang Qin, Hwang Geun Cho, Ji Gu Cao, Ji Xue Cao, Jin Bu Huan, Jue Ming Zi, Jiguja, Kudzu, Ling Yang Qing Fei Keli, Lu Cha, Rhen Shen, Ma Huang, Shou Wu Pian, Shan Chi, Shen Min, Syo Saiko To, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, and Zhen Chu Cao. In conclusion, this compilation of liver injury cases establishes causality for 28/57 different TCM herbs and herbal mixtures, aiding diagnosis for physicians who care for patients with liver disease possibly related to herbal TCM.

Thus, for 28 out of 57 published herbal medicines or herbal combinations, causality is deemed to be justified. Surprisingly, among these are herbs which one would hardly expect, such as gan cao (Glycyrrhizae Radix) and bo he (Menthae haplocalycis Herba). Gan cao is the most commonly used herb in Chinese herbal medicine. If it has the potential for hepatotoxicity, one would expect that after the billions of times this herb has been used, a large number of case reports should exist. In Teschke et al., only one source is found, the article by Yuen and co-workers [6]. In addition, this paper also appears to be able to demonstrate the hepatotoxicity of 5 further herbs, namely chuan lian zi (Toosendan Fructus), da huang (Rhei Radix et Rhizoma), ji gu cao (Abri Herba), jue ming zi (Sennae Folium) and ze xie (Alismatis Rhizoma).

Let us take a detailed look at this abundant source [6]. It is a paper about 7 cases of liver reactions from Hong Kong. First of all, it is conspicuous that it concerns a particular clientele, namely patients with chronic hepatitis B. However, an exacerbation of hepatitis B as the cause of liver injury should be excluded by determining the number of HBV DNA copies.

Let us take case number 4 and try to apply the CIOMS scale to it. A 45-year-old patient with HBe-AG positive chronic hepatitis B had an ALT of 70 U/l, an AST of 44 U/l, an alkaline phosphatase of 102 U/l, and a GGT of 180 U/l four weeks before being hospitalised (lab-specific reference values ​​were not provided). One month later, he began taking the formula "Lingyang Qingfei" as granules. He was taking it for its cooling effect on the lungs, and pharyngeal problems. He took 6g, 3 times per day for 3 months, until the onset of jaundice. His bilirubin level was now 288μM, ALT was 414, AST was 495, alkaline phosphatase was 135, and GGT was 178. Abdominal ultrasound showed a slightly cirrhotic liver, an enlarged spleen, and ascites. The liver function ​​improved after discontinuing the Chinese herbal medicine and after 3 months, took on a static course with bilirubin at 94 (the transaminase progress was not reported). The patient was placed on the waiting list for a liver transplant.

Now on to the CIOMS scale. Since the patient suffers from chronic hepatitis B with liver cirrhosis, the applicability of this scale is dubious. If one ignores this, a hepatocellular type of liver injury is to be considered, since the cholestasis enzymes are only slightly, or not at all, elevated. The designated procedure for this purpose is detailed in the following:

  1. Firstly, the time period from medication to the onset of liver injury is to be checked for plausi­bility. This time interval just falls within a range of 90 days, which yields 2 points.
  2. The decrease in ALT must be assessed as to whether it is above or less than 50 % within 30 days. The ALT course is not documented (after 3 months, the bilirubin level is still around one third of the peak value), yielding 0 points.
  3. Significant alcohol consumption should be excluded, yielding 0 points, the patient is under 55 years old, also yielding 0 points.
  4. The concurrent medication (including the additional formula ingredients) needs to be exa­mined for a possible cause of the liver reaction with regard to its chronological course. No mention is made of these, yielding 0 points.
  5. The exclusion of other diseases must be assessed. Group 1: Hepatitis A, B, C; through hepato­biliary sonography/colour Doppler of the liver vessels/endosonography/CT/MRI identifiable causes; alcoholism; recent acute hypotension (6 causes).

Group 2: Exclusion of viral infections CMV, EBV, HEV, HSV, VZV.

By means of the exclusion criteria from the case study, which was mentioned at the begin­ning of the article, 4 diagnoses from group 1 are excluded, which yields 0 points. From group 2, only HEV infection is excluded. Here there is only one point for the exclusion of all diag­noses in this group, thus, resulting in a total of 0 points.

  1. Existing information regarding a known hepatotoxicity of the particular substance: If pub­lished, yielding 1 point. In this case, 3 "hepatotoxic" formula components were identified for which liver toxicity is allegedly established. These are cu da huang (prepared Rhei Radix et Rhizoma), gan cao (Glycyrrhizae Radix) and bo he (Menthae haplocalycis Herba). However, no references are provided. Instead of citing evidence for Mentha hapocalyx, several cases from Western literature on Pennyroyal oil (Mentha pulegium) are cited which is apparently due to the lack of documentation for bo he hepatotoxicity.

A proven hepatotoxicity for gan cao would be almost sensational. Where the authors ob­tained this information remains unknown. Bensky, Clavey, and Stöger [6] mention jaundice as a result of da huang overdose (and only then), and liver cirrhosis after long-term use; how­ever, not even the otherwise very critical monograph "Rheum palmatum L. and Rheum officinale BAILLON, radix" of the European Medicines Agency [7] mentions a hepatotoxicity. An overdose at the stated daily dose for the formula with 12 ingredients can be excluded, resulting in 0 points.

In summary, therefore, just 2 points coincide with the CIOMS scale. According to CIOMS, therefore, a causal link is "unlikely". The authors of the case study describe the link between the formula and the liver reaction as "likely", not explicitly explaining which of the three herbs identified is responsible or whether several of them are. What is not taken into account is that nothing is known about the other ingredients in the formula, the identity of the indicated drugs is not verified, and that contaminants or even deliberate adulterations were not excluded. From a scientific perspective, using the case report for the identification of hepatotoxic drugs is out of the question. The other cases are not much better, they score at most 3 points, which formally brings causality into the realm of the "possible" - albeit with all the mentioned restrictions that finally rule out evidence of causality.

And now comes the article by Teschke and co-authors. In case 4, a CIOMS score of "6-8" has been tagged on. How did this come about? In their table, the herbs are listed under the heading "Reported causality assessment by CIOMS in cases of herbal hepatotoxicity by TCM". In the article by Yuen et al. [6], however, there is no mention of the CIOMS scale. Instead, their authors, at their own discretion, have categorised the causality as "definite" for 3 of the 7 cases, "probable" in two cases, and "possible" in a further two cases. Teschke and co-authors have obviously used these ratings un­checked in their article and added the CIOMS scores for these evaluations: for "probable" 6 to 8 (therefore, a range rather than a fixed value was given), for "highly probable" over 8, and for "possible" 3 to 5 points. With regards to another publication they proceeded in the same way.

What is the correct description for such an approach? Deception? Scientific fraud? Probably not coinci­dentally the authors have avoided mentioning under the method section how they arrived at their CIOMS scores. By this sleight of hand, they have tried to generate evidence from scientifically worthless data. On top of that, from one case report, they have simultaneously created up to three "hepatotoxic" herbs, as if the respective case report had concurrently confirmed causality for all these herbs with "known hepatotoxicity".

It is up to the reader’s imagination, what causes sometimes highly meticulous scientists to forget all their principles. Mr Teschke has already been the subject of an editorial and article in the German Journal for Acupuncture (Deutschen Zeitschrift für Akupunktur), which was about the different stan­dards for dealing with Chinese herbal medicine compared to other medicines [8, 9].

The review contains other blatant errors. We previously pointed out to the authors that Angelica archangelica is not a Chinese herb, but a herb used in Western medicine [10]. The authors however persist with their error. A search in the Chinese literature database "Chinese Academic Journals" (CAJ) found few articles of botanical content related to Angelica archangelica. In one article, it is pointed out that it is used in foods, beverages and in Kashmiri folk medicine. In an article comparing it to Chinese A. sinensis, the samples batches of A. archangelica came from Poland. In a pharmaceuti­cal context, it is featured in an article from the journal Gouwai Yiyao (Zhiwu Yao Fence) [World Notes on Plant Medicine], where an article from Finland is referenced [11]. An application in the context of Chinese medicine could not be found.

In an inauguration, Teschke and co-workers have assigned the plant Germander (Teucrium chamaedrys) as belonging to TCM. In a recent work by the first author and co-authors [12], this plant is repeatedly referred to as a "TCM herb" and they have devoted a whole section on the patho­mecha­nism of its hepatotoxicity. A search in the CAJ provided only one paper, which is a brief note on an article from the Canadian Medical Association Journal [13].

Not all errors and weaknesses in the present work can be covered here, but one point still has to be mentioned. The authors also include the "Kampo" herbal weight loss medicines Chaso and Onshido, for which 156 cases of liver toxicity occurred in Japan until they were banned. Both herbal formulas were adulterated with N-nitroso-fenfluramine (a derivative of the anorectic fenfluramine). However, the above-mentioned authors see the cause of the liver toxicity not in these adulterants, but in the herbs themselves: “(The) hepatotoxic property (of N-nitroso-fenfluramine) was not established. N-nitroso-fenfluramine therefore is merely an adulterant and not related to liver injury.” Regarding this, they refer to the paper from Adachi et al. [14] and turn their statement around to come to the opposite conclusion. Adachi et al. state: "All the herbal components labelled on these products have not been reported to be hepatotoxic. ... N-nitroso-fenfluramine is a possible hepatotoxic ingredient."

The Japanese Ministry of Health, Labour and Welfare characterised N-nitroso-fenfluramine, on the basis animal experiments as the hepatotoxic agent [15], which was also found to be an ingredient of various other weight loss remedies and resulted in liver injury, including several hundred cases of liver transplants and deaths. It must really be regarded as malicious when Mr Teschke and Co. try to put the blame on the Chinese herbs.

Conclusion

The work in hand is an affront to science and remains far below the usual standard of its authors. Since they are not freshman interns, the authors probably know what they are doing when mani­pulating data and twisting facts. They must be presumed as having a biased attitude. The work is useless for the causality assessment of hepatotoxicity of Chinese herbal medicines. Serious scientists should consider whether they provide their name as a co-author to Mr Teschke.

In spite of all criticism of scientific dishonesty, it cannot be overlooked that liver reactions are a serious issue for Chinese herbal medicine. The CTCA (Centrum für Therapiesicherheit in der Chinesischen Arzneitherapie, Center for Safety of Chinese Herbal Medicines) has recently published a newsletter which identifies herbs whose hepatotoxicity has been adequately documented and which should deserve special attention [16].

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16. Center for Safety of Chinese Herbal Medicines, http://www.ctca.de/index.php/en/information-for-professionals/liver-toxicity, 2016