Aristolochia, „Malignant Lie” or the Bitter Truth?

veröffentlicht: März 2017

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[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 

References:

1. Dhaenens C. Aristolochia: The malignant lie and the benign truth. J Register Chin Herbal Med 2013;10:39-41

2. Dhaenens C. Aristolochia - die bösartige Lüge und die gutartige Wahrheit. Naturheilpraxis 2016;69:65-8

3. Debelle FD, Vanherweghem JL and Nortier JL. Aristolochic acid nephropathy: a worldwide problem. Kidney Int 2008;74:158-69

4. De Broe ME. On a nephrotoxic and carcinogenic slimming regimen. Am J Kidney Dis 1999;33:1171-3

5. Wiebrecht A. Über die Aristolochia-Nephropathie. Dt Zschr Akupunktur 2000;43:187-97

6. Gökmen MR, Cosyns JP, Arlt VM, et al. The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review. Ann Intern Med 2013;158:469-77

7. Pena JM, Borras M, Ramos J and Montoliu J. Rapidly progressive interstitial renal fibrosis due to a chronic intake of a herb (Aristolochia pistolochia) infusion. Nephrol Dial Transplant 1996;11:1359-60

8. Yang L, Su T, Li XM, et al. Aristolochic acid nephropathy: variation in presentation and prognosis. Nephrol Dial Transplant 2012;27:292-8

9. Chen W, Chen Y and Li A. [The clinical and pathological manifestations of aristolochic acid nephropathy--the report of 58 cases] (Chinese). Zhonghua Yixue Zazhi 2001; 81:1101-5

10. Hagemann U, Grase R, Thiele A, et al. Probleme der Arzneimittelsicherheit: Aristolochiasäure, Münchner Med Wschr 1982;124:611-2

11. Cosyns JP, Jadoul M, Squifflet J-P, et al. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999;33:1011-7

12. Nortier JL, Martinez M-CM, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). New Engl J Med 2000;342:1686-92

13. Zlotta AR, Roumeguere T, Kuk C, et al. Select screening in a specific high-risk population of patients suggests a stage migration toward detection of non-muscle-invasive bladder cancer. Eur Urol 2011;59:1026-31

14. Lemy A, Wissing KM, Rorive S, et al. Late onset of bladder urothelial carcinoma after kidney transplantation for end-stage aristolochic acid nephropathy: a case series with 15-year follow-up. Am J Kidney Dis 2008;51:471-7

15. Hoang ML, Chen CH, Chen PC, et al. Aristolochic acid in the etiology of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev 2016;25:1600-8

16. Pfohl-Leszkowicz A. Ochratoxin A and aristolochic acid involvement in nephropathies and associated urothelial tract tumours. Arh Hig Rada Toksikol 2009;60:465-83

17. Chen CH, Dickman KG, Moriya M, et al. Aristolochic acid-associated urothelial cancer in Taiwan. Proc Natl Acad Sci U S A 2012;109:8241-6

18. Jelakovic B, Karanovic S, Vukovic-Lela I, et al. Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid. Kidney Int 2012;81:559-67

19. Dong H, Suzuki N, Torres MC, et al. Quantitative determination of aristolochic acid-derived DNA adducts in rats using 32P-postlabeling/polyacrylamide gel electrophoresis analysis. Drug Metab Dispos 2006;34:1122-7

20. Chen CH, Dickman KG, Huang CY, et al. Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes. Int J Cancer 2013;133:14-20

21. Hsieh SC, Lin IH, Tseng WL, et al. Prescription profile of potentially aristolochic acid containing Chinese herbal products: an analysis of National Heath Insurance data in Taiwan between 1997 and 2003. BioMed Central 2008;3:1-6

22. Guh JY, Chen HC, Tsai JF and Chuang LY. Herbal therapy is associated with the risk of CKD in adults not using analgesics in Taiwan. Am J Kidney Dis 2007;49:626-33

23. Lai MN, Lai JN, Chen PC, et al. Increased risks of chronic kidney disease associated with prescribed Chinese herbal products suspected to contain aristolochic acid. Nephrology 2009;14:227-34

24. Lai MN, Wang SM, Chen PC, et al. Population-based case-control study of Chinese herbal products containing aristolochic acid and urinary tract cancer risk. J Natl Cancer Inst 2010;102:179-86

25. Wang SM, Lai MN, Wei A, et al. Increased risk of urinary tract cancer in ESRD patients associated with usage of Chinese herbal products suspected of containing aristolochic acid. PLoS One 2014;9:e105218

26. Hsieh CF, Huang SL, Chen CL, et al. Non-aristolochic acid prescribed Chinese herbal medicines and the risk of mortality in patients with chronic kidney disease: results from a population-based follow-up study. BMJ Open 2014;4:e004033