This 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.

The study

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.

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, reasonable transparency regarding the 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, a clear comment and significant corrections appear to be appropriate.

Assessment of “known” hepatotoxicity

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.

Glycyrrhizae radix (gan cao)

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 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). 

Bombyx batryticatus (jiang can)

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.

Herbs with hints to 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.

Questionable data transfer and RUCAM scoring

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). 

• The total points of cases 17 and 24, under the given assumptions of the study, were not correctly added up. 
• The period from starting the medication to onset of liver injury in cases 19 (1) and 19 (2) falls into the interval of 5 to 90 days, giving 2 and not 1 point.
• Decrease of ALT: In case 17, the ALT dropped from 279 to 252 U/l within 5 days, this is not a decrease of 50% within 8 days, thus only 2 points. Case 18: The treatment was stopped after 7 days because of diarrhea and headache; 14 days after admission, an elevated ALT of 76 U/l was determined, 6 days later, the ALT further increased to 233 U/l; at discharge (duration of hospital stay is not stated), the ALT was 198, after 30 + x days, it was 39 U/l, whereas x is the duration of hospital stay after withdrawal of medication; this is not a decrease of ≥50% within 30 days, leading to 0 points. Case 19 (1): The ALT dropped from 249 to 123 U/l within 3 days, 3 points appear justified. Case 19 (2): The ALT decreased from 295 to 86 U/l within 9 days, so a decline of ≥50% within 8 days appears reasonable, giving 3 points.
• Exclusion of alternative causes: In the case history of case 3 and 12, it was stated: “no hepatitis serology” or hepatitis A, B and C was not documented, respectively. Nevertheless in the RUCAM calculation the exclusion of hepatitis A, B and C was scored. In case 4, serology of hepatitis C and E and an imaging procedure are missing, thus less than 5 alternative causes are ruled out. In case 19 (1) and 19 (2) “no hepatitis serology” is stated but in the RUCAM 1 point is scored (1 point is not even scheduled in the RUCAM test). In all these cases, less than 5 causes were ruled out leading to -2 points. Further discrepancies do not bear impact on the scores: In case 12 and case 17, a EBV infection was ruled out but not noted in the RUCAM calculation; instead of this, in case 17 a positive HSV test was noted (anti-HSV-IgM or -IgG) which obviously was not performed.

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)

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.

Other herbs

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.

Conclusion

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.

Literature:

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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 
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
10. Chen YF, Cai HD. [Investigation of liver damage associated with Chinese medicines] (Chinese). Yaowu Buliang Fanying Zazhi 1999;1:27-32
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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
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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
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With medicinal drugs containing Aristolochia banned in many countries all around the world, including China and Taiwan, the Aristolochia-issue should be settled by now. Alas, still a few wrong notions, or a lack of information, towards this problem keep on circulating in the world of TCM.

A comment to the article by Chris Dhaenens 2013, from 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[1].  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.

The Belgian slimming clinic

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[3]. Aristolochia nephropathy (AN) shows itself to be a separate pathological entity with the typical histological picture of interstitial fibrosis and tubular atrophy.

A problem of serotonin?

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[4].  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[5].

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[5]. 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[6]. Another case occurred in Spain, caused by a Western species, Aristolochia pistolochia[7]. 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[8]. These facts have been totally edited out by Chris Dhaenens. 

Course of Aristolochia nephropathy

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[9]. 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[6].

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[8].

The carcinogenicity of Aristolochia

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[10].

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[15].

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[16]. 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[19]. 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.

Epidemiological studies in Taiwan

Between 1997 and 2003, up to a third of Taiwan’s population ingested potentially Aristolochia containing medicines[21]; 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 [24].

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[25]. 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.

Conclusion

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[26].

Centrum für Therapiesicherheit in der Chinesischen Arzneitherapie (CTCA), 
(Center for Safety of Chinese Herbal Medicine (CTCA)), Berlin 

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