Australian case of alleged hepatotoxicity of Cimicifuga racemosa unsubstantiated A recent article by Whiting et al (1) published in the Medical Journal of Australia caused a great deal of concern in Australia and was quickly reported in the newspapers across the country under the title:
Menopause Herb Alert The article concerned six patients, which had been reviewed by a gastroenterologist between 1996 and 2001. Data were collected when the patient presented and subsequent telephone inquiry clarified any other details. The individual herbal products were not analysed for their constituents. Six patients presented with clinical, biochemical and histological evidence of severe hepatitis. One patient required urgent liver transplantation for fulminant hepatic failure after a brief use of Cimicifuga racemosa. The other five patients had used a combination of herbs and presented with jaundice, fatigue and pruritus.
Several investigators have commented that many herbal medicine adverse reports are not, in fact, caused by herbs alleged to be in the product, but resulted from substitution or contamination of the declared ingredients, intentionally or by accident, with a more toxic herb, a poisonous metal or even a pharmaceutical compound. (2,3) There is often a serious absence of any effort to establish a positive identification of the herb involved or adulterants.
The attribution of toxicity to the wrong plant also highlights problems in accurate citations of reports leading to inaccurate and scientifically inexact information being provided to patients, practitioners and regulators. (2) A significant problem is the use of common names. As mentioned by Whiting et al, Cimicifuga racemosa (black cohosh) has at least 20 different common names, which can be very confusing.
The most tragic example of such confusion is the fatal substitution of Stephania tetrandra with the toxic herb Aristolochia fangchi due to a similarity of common names of the two herbs. In terms of recording and responding to adverse events involving herbs certain key questions need to be asked by those reporting the event and more crucially by those subsequently citing the report for the information of others. No details regarding verification of the herbal products taken by the individual patients are supplied by Whiting et al. Failing to authenticate the plant compounds in the preparations, the author has lost the opportunity to establish beyond doubt that the herbs are actually the cause of the hepatotoxicity. No information about plant part used, solvent, concentration, type of manufacturing or chemical analysis is supplied. Far too often very little information is provided about the actual cases.
Although Whiting et al rules out other causes of the hepatitis, there are other factors including past medical history, use of non-injectable recreational drugs, dietary factors that may have contributed to the reported reactions. The causal connection between the intake of a Cimicifuga racemosa preparation and the severe acute hepatitis is very speculative, because viral hepatitis was not definitively excluded by additional tests. Moreover in 5-10% of patients with virus hepatitis, no increase of HBsAg is observed. The authors state that, “all the biopsies were typical of acute hepatitis such as that seen in severe viral hepatitis.
These changes are typically found in severe immunological reactions and are not the changes of direct toxic injury.” In other word, the reactions were not the result of direct toxicity of the plants, but of some, possible immunological, reaction particular to these six patients. Such a hypersensitivity is rare to very rare and not a dose dependent reaction of the individual concerned. In an attempt to explain the immunological reaction Whiting et refers to a study where diterpenoids caused hepatotoxicity in animal models.10 Cimicifuga racemosa contains triterpenoids, not diterpenoids. Studies of isolated herbal compounds injected into animals have little relevance to human therapeutic uses. Cimicifuga racemosa triterpenoids are altered by gut bacteria and would have different effects when ingested versus when injected. No pronounced signs of cholestasis (which would be expected in drug induced liver injury) were observed.
In addition, no signs of hypersensitivity reactions (e.g. on the skin of the patient) were reported which could have confirmed a generalised allergic reaction of the patient. After a five day treatment period in patient 1, early signs of fibrosis was diagnosed. This is an amazing short period for such a reaction to occur. The causal connection between the severe hepatitis and the short-term intake of black cohosh seems not to be evident.
Indeed, hepatitis for which no cause can be identified is not uncommon. The aetiology remained unclear in 17 (31%) of 55 newly diagnosed cases of hepatitis diagnosed in a population of 71.000 people in a managed care organisation in one year.7 There were no concurrent prescription medications or blood product that appeared related to the liver injury. The authors comment that this is a “background-rate of hepatitis”. Thus this single case of a doubtful correlation between hepatitis and Cimicifuga racemosa intake cannot be misused to define an increased hepatotoxic risk of Cimicifuga racemosa preparations. Without further pathological and biochemical investigation into the specific reaction, no conclusion can be made as to the exact mechanism causing the acute hepatitis.
The report by Whiting et al also lists “common herbal remedies suspected of being hepatotoxic”. The majority of the herbs listed are in fact uncommon or not used at all in Australia. Larrea mexicana and Chelidonium majus are not commonly used in retail products (but there is a good case for restricting the use of these two herbs to qualified herbal medicine practitioners). Symphytum officinale is restricted and only use externally. Germander (Teucrium spp.), white chameleon and Jin Bu Huan and the dosages of sassafras and pennyroyal oil, are restricted. Only senna (Cassia angustifolia), Valeriana officinalis, mistletoe (Viscum album) and skullcap (Scutellaria lateriflora) are commonly used herbs in Australia.
Reference number 13 in the article by Whiting et al (Miskelly FG, Goodyer LI. Postgrad Med J 1992; 68: 935) is listed as proof of hepatotoxicity of a mixture of valerian (Valeriana officinalis) and skullcap (Scutellaria lateriflora), however the herbal medicine product involved contained mainly comfrey (Symphytum officinale) with lesser amounts of seven other herbs and without further chemical investigation into this specific product, no conclusion can be made as to which of the herbs caused the hepatotoxicity, or, in fact, if it was due to an adulterant or contamination. Skullcap (Scutellaria lateriflora), has in the past been found to be substituted with the hepatotoxic herb germander (Teucrium chamaedrys). (4,5) The case involving senna (Cassia angustifolia) concerned a woman who took ten times the recommended dose. Her liver function test returned to normal after discontinuing the senna. (6)
There is a large body of clinical evidence and research accumulated about Cimicifuga racemosa and there has not been any suggestion to date that this herb is hepatotoxic. Indeed a German manufacturer has sold more than 350 million daily dosages of Cimicifuga racemosa preparations worldwide since the pharmacovigilance system was introduced and no comparable cases has been reported until now. An Ames test (Salmonella microsomal assay) showed no in vitro evidence of mutagenic potential of an extract of black cohsh8 and no chemical or organ toxicities were observed in Wistar rats given up to 5,000 mg of a Cimicifuga racemosa extract granulate/kg for 26 weeks. (9) While it is absolutely essential to examine and document adverse reactions to herbal medicines, let us not apply double standards.
There are many over-the-counter pharmaceutical drugs, such as paracetamo l, which are directly hepatotoxic. Applying a risk-benefit analysis to Cimicifuga racemosa, it must be concluded that it is a safe and effective herb for menopausal complaints such as hot flushes and emotional symptoms. In a review of eight human studies on the effectiveness of an extract of Cimicifuga racemosa on alleviating menopausal symptoms the authors concluded that Cimicifuga racemosa appears to be a safe, effective alternative to oestrogen replacement therapy for those patients in whom oestrogen replacement therapy is either refused or contraindicated. (11)
Reference List 1. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust 2002;177:440-3.
2. Corrigan D. Adverse Reports – some first principles. The European PhytoJournal 2001;1.
3. Fugh-Berman A. Herb-drug interactions. Lancet 2000;355:134-8.
4. MacGregor FB, Abernethy VE, Dahabra S, Cobden I, Hayes PC. Hepatotoxicity of herbal remedies. BMJ 1989;299:1156-7.
5. Therapeutic Goods Administration of Australia. Action taken by the TGA in relation to Skullcap. 2000.
6. D’Arcy PF. Adverse reactions and interactions with herbal medicines. Part 1. Adverse reactions. Adverse Drug React Toxicol Rev 1991;10:189-208.
7. Walker AM CR. The occurence of new heaptic disorders in a defined population. Post Marketing Surveillance 1992;1:107-11.
8. Liske E. Therapeutic efficacy and safety of Cimicifuga racemosa for gynecologic disorders. Adv Ther 1998;15:45-53.
9. Six-month oral toxicity study with Remifemin granulate in rats followed by an eight-week recovery period. Korn, W. D. 91. Hannover, Germany, International Bioresearch.
10. Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002;22:195-206.
11. Lieberman S. A review of the effectiveness of Cimicifuga racemosa (black cohosh) for the symptoms of menopause. J Womens Health 1998;7 :525-9.