Wednesday, April 18, 2012

Ingredient in herbal medicines linked to urothelial cancer

A number of researchers have looked at at an herbal ingredient called aristolochic acid, or AA. It comes from plants, including wild ginger (Asarum canadense), that have been used in Chinese medicine to treat “stomach ailments, to restore a woman’s energy after the birth of a child, to treat cough, allergy and breathing problems, and in some weight-loss formula. 

Aristolochic acids are a family of carcinogenicmutagenic, and nephrotoxic compounds commonly found in the Aristolochiaceae family of plants, including Aristolochia and Asarum, which are commonly used in Chinese herbal medicine. Aristolochic acid I is the most abundant of the aristolochic acids and is found in almost all Aristolochia species. Aristolochic acids may be a causative agent in Balkan nephropathy.

On May 31, 2000, the FDA issued a letter to health care professionals concerning the nephrotoxicity and carcinogenicity of botanical products containing aristolochic acid. During this time period, FDA also issued a letter to representatives of the dietary supplement trade associations urging that their members review their manufacturing procedures to ensure that botanical products are free of aristoclochic acid. In addition, FDA issued an import alert providing for the detention of any botanical ingredients that were either labeled as containing the plant Aristolochia or may be confused with it. These actions were the result of several factors, including:

  • In Belgium, there have been approximately 100 cases of renal disease in patients who had participated in a "slimming regimen" from 1990-1992 consisting, in part, of a weight-reducing pill containing powdered herbs. The major pathological lesion consisted of extensive renal interstitial fibrosis with atrophy and loss of tubules. At least 70 of these patients have required either dialysis or transplantation. It was concluded that one of the botanicals (Stephania tetrandra) had been inadvertently substituted with Aristolochia fangchi, a botanical known to contain aristolochic acid, because of the close similarity of the Chinese names.
  • In 1996, it was reported that aristolochic acid-related DNA adducts had been detected in renal tissue from 5 of the original Belgian patients. (Schmeiser HH et al. Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy. Cancer Res 1996;56:2025-8)
  • In August 1999, 2 new cases of interstitial fibrosis were reported from the UK in which the patients had consumed botanical preparations containing aristolochic acid. Both patients have developed end-stage renal failure; one has already been transplanted and the other is awaiting transplant. (Lord GM et al. Nephropathy caused by Chinese herbs in the UK. Lancet 1999;354:481-2)
Since this time, the following new information is available:

  • A study conducted in Belgium reported that among 39 patients with end-stage renal failure from the original Belgian cohort, who had agreed to undergo prophylactic surgery, there were 18 cases (46%) of urothelial carcinoma. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The authors concluded that "our data suggest that aristolochia toxins (aristolochic acids and also possibly other derivatives) cause renal disease and urothelial cancer."[Nortier JL et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686-92]
  • Seven cases similar to the Belgian cases were identified in France, corresponding to exposure to botanical preparations contaminated with Aristolochia fangchi from 1989-1992. In May 2000, a case of urothelial carcinoma was diagnosed in one of these patients. A second case of urothelial carcinoma is suspected and in a third patient, lymphoma on a graft was detected. (Communication from the French Medical Products Safety Agency; October 27, 2000)
  • Laboratory analyses by the FDA of certain botanical products sold in the United States have revealed the presence of aristolochic acid. These include single-ingredient products labeled as Aristolochia(sometimes called Virginia snakeroot) and botanicals that are likely to be substituted with Aristolochia (e.g.,Stephania tetrandraClematis armandii, and Akebia extract). In addition, aristolochic acid was detected in several finished products sold as dietary supplements. Warning letters and requests for recalls have been issued to the various manufacturers or distributors involved.
  • Two patients in the U.S. have been recently reported who developed end-stage renal disease in association with the use of botanical preparations containing aristolochic acid.
  • The first patient began using herbal "medicines" in 1994. She progressed to end-stage renal disease within 8 months. A renal biopsy showed extensive interstitial fibrosis with focal lymphocytic infiltration. A renal transplant was performed in 1996. Laboratory analyses of the patient's botanical products, conducted in Belgium, indicated the presence of aristolochic acid in 2 of the products that she had been using. (Meyer MM et al. Chinese herb nephropathy. Baylor Univ Med Center Proc 2000;13:334-7.
  • The second patient had consumed a botanical product called "Stephania tablets" for approximately 2 years, until 1994. She was recently diagnosed with end-stage renal disease and is awaiting a renal transplant. Laboratory analysis by the California Department of Health Services showed the botanical product to contain aristolochic acid. Although the product was labeled as containing the herb Stephania tetrandra, it is likely that Aristolochia fangchi had been substituted for it, thereby accounting for the presence of aristolochic acid in the product.