A recent study by Melchart and co-authors (1) analysed the incidence of liver injuries occurring in the TCM hospital in Kötzting, Germany from 1994 to 2015. Included were patients treated with Chinese herbal decoctions whose liver enzyme ALT (alanine aminotransferase) at the time of admission was within the normal range. In the days before discharge, the liver function was checked again. An elevation of ALT up to five times the upper norm was considered as an adaptive phenomenon of the liver, and a higher increase was interpreted as liver injury. The average observation period 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 fivefold ALT elevation occurred in 26 patients (0.12%). In 9 cases out of these 26 patients (one case with re-exposition counted as separate case), 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 implicated in 20 and 21 cases, respectively, in 18 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.
This study provides valuable, unprecedented data for assessing the potential risk of Chinese herb-induced liver injury, characterised by the following features:
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, a clear comment and significant corrections 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 truer. 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 cannot 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 (gan cao). 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 (gan cao) 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 (bai zhu) or Angelica sinensis radix (dang gui). In a previous smaller study from the Kötzting hospital (2), Angelica sinensis radix (dang gui) was prescribed to 57% of patients with liver enzyme elevation, but also to 58% of patients without elevation.
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 the previous Kötzting study (2), Glycyrrhizae radix (gan cao) and Atractylodis macrocephalae rhizoma (bai zhu) 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. However, in the present study a suspected hepatotoxicity for Glycyrrhizae radix (gan cao) 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.  for the RUCAM tests are fictitious, the scores were not reported. 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 qualified for establishing hepatotoxicity. There is no evidence of hepatotoxicity relating to Glycyrrhizae radix (gan cao).
Another example is Bombyx batryticatus (jiang can). Here too, without legitimacy, the authors claim hepatotoxicity as being known. In many larger compilations of cases of liver injury, this medicine is missing (9-19). In the publication by Shaw (20), Bombyx batryticatus (jiang can) 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 (jiang can), 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 (fan xie ye), Polygoni cuspidati rhizoma (hu zhang), Polygoni multiflori caulis (shou wu teng), Puerariae radix (ge gen)and Rhei radix et rhizoma (da huang). For example, with Puerariae radix (ge gen): 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 (ma huang), Toosendan Fructus (chuan lian zi), Bupleuri radix (chai hu) and Scutellariae radix (huang qin). For the remaining herbs mentioned in the study, no valid references have been documented which would justify one point.
Moreover, there are many mistakes in the data transfer and build-up of the RUCAM score in the Kötzting study. A new meticulous revision of the 9 cases for which a probable association with Chinese herbs was claimed, detected - without counting the inaccurate scoring of “known” hepatotoxicity - 16 mistakes such as false additions, discrepancies between clinical data and the RUCAM calculation and apparent flaws leading to completely deviant results (Tab. 1).
This makes 16 mistakes in data transfer and calculation of the RUCAM score plus 9 systematic flaws relating to the “known” hepatotoxicity within 9 cases. Consequently, the study appears to be unreliable and in need of revision (Tab. 1). Of the 9 study cases whose association with Chinese medicine was purported to be "probable", only 2 remain: cases 14 and 19 (2), each with a RUCAM score of 6. This "probable" association applies to the entire herbal formula and cannot be applied to a single herb because more than one ingredient of the formula is suspected of being hepatotoxic. The RUCAM test states that if other substances are eligible as an alternative cause, 1 point has to be deducted (7). Then, if you want to break down the causality to the individual herbs, the score of the cases has to be reduced by 1 point, except in case 4. Hence, for a single herb a "probable" causality cannot be stated.
Bupleuri radix (chai hu) and Scutellariae radix (huang qin) deserve special consideration. There is an abundance of cases of hepatotoxicity in Kampo medicine for formulas containing these substances. Most often, both herbs are used simultaneously, e.g. in the Kampo 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 (chai hu), 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 (chai hu) and Scutellariae radix (huang qin) possibly associated with liver injury, where testing for identity and contamination was done. In the two cases remaining as "probable" after revision, Bupleuri radix (chai hu) is involved once and Scutellariae radix (huang qin) twice. In case 14 (without Bupleuri radix, chai hu), the potential causative agent Toosendan fructus (chuan lian zi) is present. A clear assignment to Scutellariae radix (huang qin) is therefore not possible. 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 (jiang huang), Curcumae radix (yu jin) and Mori ramulus (sang zhi)), which were given in the first formula, too, and for which no reasonable suspicion exists. Possibly more important, it is peculiarly striking how many cases with a “probable” or “possible” causality Bupleuri radix (chai hu) and Scutellariae radix (huang qin) were involved in.
Based on this new data quality, one has to reassess the hepatotoxicity of Bupleuri radix (chai hu) and Scutellariae radix (huang qin). 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.
Toosendan fructus (chuan lian zi) is implicated in one “probable” case after revision. So far, a possible hepatotoxicity only applied in the case of overdose (32). The present data is not sufficient for a reassessment of hepatotoxicity of this medicinal. The same applies to Ephedrae herba (ma huang). This herb is involved in case 3 and 19 (1) in which Bupleuri radix (chai hu) and Scutellariae radix (huang qin) are present, so a clear assignment is not possible. The limited number of hepatotoxicity cases involving Ephedrae herba (ma huang) documented in the literature must be weighed against the millionfold uses of the herb, especially in the years previous to 2004. However, with the cases from the present study, this herb includes the possibility of hepatotoxicity.
The study contains unprecedented data for evaluating the hepatotoxic risk of Chinese herbal medicines. However, many of the assessments made in the publication do not hold up. It is a pity that the differential diagnoses of the liver injuries were executed so incompletely that a more precise causality assessment was not achievable. So, from the documented facts, only 2 cases of liver injury can be assessed as being probably associated with Chinese decoctions. If the work-off of differential diagnoses would have been done more completely more clarity would prevail and probably some more cases would have been identified showing an association with Chinese medicine.
The potential hepatotoxicity of Bupleuri radix (chai hu) or Scutellariae radix (huang qin), or a combination of both drugs together in the context of Chinese medicine must be deemed probable although a further differentiation currently is not possible. For Toosendan fructus (chuan lian zi) and Ephedrae herba (ma huang) a definitive appraisal seems not feasible. The possible liver injury caused by Polygoni multiflori radix (he shou wu) 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 recognised 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 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.
*Slightly edited version of an article from Deutsche Zeitschrift für Akupunktur 2016;59(4): 33-35.
Translated by Dough Chick
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  for which, together with the author Danan, he has issued an update .
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 . 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 .
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 . 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:
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 . 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 . 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:
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.
A proven hepatotoxicity for gan cao would be almost sensational. Where the authors obtained this information remains unknown. Bensky, Clavey, and Stöger  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  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. , 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 . 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 . 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 , 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 .
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.  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 , 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.
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 .
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A comment by the Center for Safety of Chinese Herbal Medicine (CTCA)
(translated by Angelica Dawson)
Preliminary note: It seems that the story of Aristolochia cannot end on a light note. Actually, it should be part of the past, with medicinal drugs containing Aristolochia banned in many countries all around the world, including China and Taiwan. Alas, still a few wrong notions, or a lack of information, towards this problem keep on circulating in the world of TCM. In 2013 the Belgian Chris Dhaenens published an article relating to this issue in the Journal of the Register of Chinese Herbal Medicine. The background was that critics of phytotherapy kept on holding this story against us. An article in the Lancet Oncology referring to the occurrence of liver injury by arsenic oxide(!), cross-referenced it to the Aristolochia-story without any substantial connection. Notwithstanding his entitlement to criticize this kind of linkage, Chris Dhaenens must be criticized for his display of ignorance towards the problem and downplaying it. Due to his recent republication in German, in the journal Naturheilpraxis (Journal of Natural Healing Practice), the CTCA feels compelled to make a comment. As in this case, we have a definite answer, and the world of TCM must take a clear stand, or face the possibility of being accused of a lack of reality awareness concerning safety issues. As Naturheilpraxis only wanted to provide limited space for our comment in the journal, we had to submit a very condensed version of our article. Below you find the complete wording.
Can the kidney pathology associated with Aristolochia in fact “hardly implicate Aristolochia” and, have the “carcinogenic properties of Aristolochia only been established in rodents”? On the other hand, Chris Dhaenens states “nobody in his right mind disputes the ban of Aristolochia”. How does that fit? These statements in the article display a surprising ignorance and an irresponsible downplaying of the problem. The following will elaborate on the author’s arguments, trying to illustrate, that hardly any phenomenon in medicine has been as clearly demonstrated as the renal toxicity and carcinogenicity of aristolochic acid, contained in relatively potent concentrations in various plants of the Aristolochia genus.
In the Nineties, a Belgium slimming clinic administered a hazardous cocktail of anorectics and other biomedical drugs, mixed with Chinese herbal medicines. When, instead of prescribed Stephaniae tetrandrae Radix (han fang ji), another herb of the Chinese Materia Medica, Aristolochiae fangchi Radix (guang fang ji) was delivered, more than 100 cases of renal injury occurred, the progredient course mostly remaining even after the medication had been discontinued; and roughly 70 percent, with due necessity of dialysis or kidney transplantation. Aristolochia nephropathy (AN) shows itself to be a separate pathological entity with the typical histological picture of interstitial fibrosis and tubular atrophy.
Chris Dhaenens quotes, that thousands of women have been treated with Aristolochia without occurrence of renal injury; hereby overlooking the vastly different individual reactions to toxins. This kind of phenomenon is also well known with metamizole - only very few of the users develop the dreaded agranulocytosis. Furthermore, the dosage, naturally, plays an important role, in the case of Aristolochia the cumulative dosage, respectively (see below).
Chris Dhaenens assigns the role of the main trigger to serotonin, one of the slimming clinic’s medical cocktail’s components, quoting an editorial from de Broe. But de Broe only writes, that the vaso-constrictive properties of serotonin might have “accelerated or potentiated” the nephrotoxic effects of aristolochic acid which he did not question. He suspects a genetic predisposition to be the cause for only some of the exposed persons developing nephropathy or urothelial cancer. Already several years ago, a dose consideration had suggested the chemical cocktail seemed to function as accelerator in the Belgian cases.
Nevertheless, it is futile to criticize the Belgian clinic’s procedure, for without any shadow of doubt, their therapy is medically unacceptable, as well as irresponsible. Anyway, due to the cumulative occurrence of renal injuries, they can “claim credit” for raising the consciousness concerning the nephrotoxicity of Aristolochia.
The effort of dragging forth the Belgian cases with their possible serotonin phenomenon is not necessary at all. Sufficiently enough existing cases of AN have occurred without any influence of serotonin. Multiple hints towards the nephrotoxicity of aristolochic acid, predominantly in animal experiments, had already been given since the fifties. Following the Belgian incidents, many cases of renal injury with the typical feature of AN were uncovered worldwide, occurring first and foremost under usage of Chinese formulae containing Aristolochiae manshuriensis Caulis (guan mu tong) or Aristolochiae fangchi Radix (guang fan ji). The corresponding publications mainly came from Great Britain, France, Taiwan, Japan, China, Hongkong, Korea, Australia, USA and Germany. Another case occurred in Spain, caused by a Western species, Aristolochia pistolochia. These cases led to Aristolochia being banned in many countries including China and Taiwan.
Chinese nephrologists started to routinely check their patients’ case histories of applied drugs in cases of chronic renal disease, especially of the type tubulo-interstitial nephropathy with unclear etiology, after they had received knowledge about the nephrotoxicity of Aristolochia. Within several years, thousands of patients with AN appeared. These facts have been totally edited out by Chris Dhaenens.
Denying and irresponsibly playing down reality, Chris Dhaenens writes, the toxicity of the Aristolochia herb is “acute and reversible”. Such a course is rather the exception - usually the opposite applies. In a Beijing clinic’s department with 58 cases of AN, 4 patients showed an acute form, 7 a so-called tubular dysfunction and 47 a chronic-progressive development. In most patients diagnosed with AN, the disease follows a relatively rapid progress despite discontinuing the Aristolochia medication – according to a Belgian compilation, 83 percent led up to end-stage renal disease within two years.
In another department of a Beijing hospital, 300 cases had accumulated over a period of 10 years. Within 3 months after discontinuing the Aristolochia medication, 13 patients showed an acute process, 10 a tubular dysfunction and 280 a chronic development. Amongst the acute cases, only one was reversible; 5 took a progressive course leading to end-stage renal disease. Within the chronic cases, 20 percent showed a partial regression; the renal failure of the other cases progressed, 44 percent quite rapidly with a decline of the glomerular filtration-rate by more than 4 ml/min per year. Most of the patients had taken Aristolochiae manshuriensis Caulis (guan mu tong), followed by Aristolochiae Radix (ging mu xiang), Aristolochiae fangchi Radix (guang fang ji), Aristolochiae debilis Caulis (tian xian teng) and Aristolochiae molissimae Herba (xun gu feng). The contents of aristolochic acid were determined by HPLC, the cumulative dosage correlating with the rapidity of progression within the chronic cases.
The statement that “carcinogenic properties of aristolochic acid could only be found in rodents” is another unbelievable misapprehension of facts. Insights from animal experiments had only been the starting point. 1981 drugs containing aristolochic acid were banned by the Deutsches Bundesgesundheitsamt (German Health-Agency), after a distinct carcinogenicity had been proven experimenting with rats.
The Belgian cases showed, more than 40 percent of patients with AN developed malignancies, especially urothelial carcinomas of the upper urinary tract, but also renal cell and bladder carcinomas[11-14]. A current study talks of stringent evidence of the involvement of aristolochic acid in a substantial percentage of renal cell carcinoma cases in Taiwan.
A substance’s property of forming DNA-adducts is considered strong evidence for its carcinogenicity. A group of Heidelberg scientists could detect DNA adducts of aristolochic acid, or its metabolite aristolactam in tissue samples of various groups of cancer patients having been treated with Aristolochia herbs. Chris Dhaenens reasons, that these findings had been questioned by another scientist. But DNA-adducts were also verified in numerous cases of cancer associated with aristolochic acid, by other independent researchers from the USA, Croatia and Taiwan[15,17,18]. DNA-adducts could be reproduced in animal-experiments after administering aristolochic acid. In fact, it could be demonstrated, that the mutations in the tumor tissue were frequently triggered in a specific part of a certain gene, the tumor-suppressor gene TP53, that is characteristic for aristolochic acid[17,20]. The mutation deactivates this gene and promotes the development of cancer.
Between 1997 and 2003, up to a third of Taiwan’s population ingested potentially Aristolochia containing medicines; likewise, its population has the highest incidence of end-stage renal disease worldwide. A screening of 199,843 patients, after eliminating confounding influential factors, showed a significantly increased risk of chronic renal disease after ingesting more than 30g mu tong or more than 60g guang fang ji .
Another Taiwanese study showed an increased risk of developing urothelial carcinoma in patients with end-stage renal disease, after having ingested mu tong corresponding with an estimated amount of more than 100mg aristolochic acid. It is very rare in medicine that such clear evidence of a substance’s carcinogenic impact can be found, without being dependent on concluding the effect on humans from animal experiments.
For sure, it is annoying, that the Aristolochia problem actually dating from a far back time in Europe, is held against us at every incongruous opportunity. Alas, publications making light of the matter, like the one of Chris Dhaenens, possibly contribute to the adversaries’ justification for opposing Chinese Medicine. Nevertheless - the Aristolochia tragedy being, or rather having been, a disaster for Chinese Medicine, in this respect is a clear exception of the rule. Chinese herbal medicine, competently practiced and with medicines administered in conforming high quality, is a safe therapy. In fact, it has been shown, that patients with a chronic renal disease in Taiwan, who had been treated with Chinese medicines without Aristolochia, manifested a lesser mortality than those without this therapy.
Centrum für Therapiesicherheit in der Chinesischen Arzneitherapie (CTCA), (Center for Safety of Chinese Herbal Medicine (CTCA)), Berlin
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