Phil Rasmussen from Kiwiherb New Zealand Reports on Black cohosh and Alleged Liver Toxicity.
Thursday, February 5th 2009
Concerns regarding the potential liver toxicity of black cohosh first appeared following publication of two Australian case reports in 2002(1). This was followed by a second single Australian case report in 2003(2), then a further three published case reports from the U.S. over the next three years(3,4,5). Between 2002 and 2008, a total of around 42 case reports of hepatotoxicity associated with use of products containing black cohosh were made(6).
In 2006, I individually assessed each of the first six case reports, and identified a number of potentially confounding or contributory factors to most of these(7). These included failure to analyse or verify the ingredients in the products implicated, insufficient information about past or present medical history, co-medication with over-the-counter or recreational drugs, and other lifestyle factors of the patients involved. Missing data regarding the treatment duration and dose, natural course of the liver function tests and exclusion of unrelated diseases, were other shortcomings of most of these early reports.
One case for example involved a 57 year old diabetic woman who developed autoimmune hepatitis, three weeks after starting to take an unknown brand and unknown dose of black cohosh(3). While the authors attributed this to the herbal preparation, this patient was also taking the drugs labetalol, fosinopril, verapamil, metformin, aspirin and insulin. Their statement that 'none of the woman's other medications have ever been implicated as triggers for autoimmune hepatitis', is highly debatable, given the fact that a simple search of the literature at the time showed that hepatitis had been associated in at least 13 published case reports for labetalol(6,7,8), several also for verapamil(9,10,11) and metformin(12,13,14,15), and one for fosinopril(16).
Another patient from the published US case reports developed autoimmune hepatitis and required a liver transplant within months of starting to take black cohosh-containing products. While in the published case report it was stated that the patient did not drink alcohol and was not taking any other medications, during a subsequent court trial it emerged that she had regularly drank wine, took the drug ibuprofen, and had been prescribed the antiviral drug valacyclovir(19). As with the above case report, the literature search I did in 2006 located several published case reports of hepatitis associated with ibuprofen and valacyclovir use(20-23).
In none of these early cases was a rechallenge with black cohosh or the usual serological tests used to help provide more conclusive evidence of a causative link between exposure to a particular substance and adverse effects, undertaken by the clinicians involved.
Potential quality aspects of the products concerned, were also poorly considered by authors of these early case reports, and the presence of black cohosh was only conclusively established in one of these. Verification of the correct botanical species by herbal manufacturers as well as toxicologists is critical, as was highlighted by an American study in 2006. This showed that four out of 11 black cohosh products being sold on the marketplace at that time contained a cheaper Asian species of Cimicifuga rather than true Cimicifuga racemosa(24).
Diagnosis of idiosyncratic hepatotoxicity is in fact notoriously challenging, due to lack of a specific aid(25,26). In appraising suspected cases of this rare feature of drug therapy, it is essential that differential diagnoses are thoroughly considered to confidently exclude other diseases unrelated to drug-related liver injury. The fact that authors of some of the U.S. studies cite the published Australian case reports to justify their identification of black cohosh as the cause of their patient's liver problems, highlights the risk of a self-fulfilling prophecy, unless these issues are fully addressed.
Liver failure is frequently reported to occur without any identifiable cause, an issue highlighted by a study by hepatologists in Canada. This found that acute liver failure of unknown origin occurred in 27% of 81 consecutive patients admitted to their hospital between 1991 and 1999(27). These findings reinforce the fact that many cases of spontaneous liver toxicity can occur in large population groups, due to as yet unidentified viruses or other unknown causes.
Our understanding of this subject has increased recently, through publication of two further reviews into suspected black cohosh hepatotoxicity, by American and German authors(6,28).
In the first review, the Dietary Supplement Information Expert Committee of the U.S. Pharmacopeia's Council of Experts reviewed safety information for black cohosh products(28). This involved a detailed analysis of information from human clinical case reports, adverse event reports, animal pharmacological and toxicological data, historical use, regulatory status, and contemporaneous extent of use. A total of 30 nonduplicate reports on the use of black cohosh products concerning liver damage were obtained from the European Medicines Agency, the Australian T.G.A., Health Canada, and the U.S. F.D.A., and evaluated according to the Naranjo causality algorithm scale. The Expert Committee selected this scale as it allows analysis of adverse event reports from different aspects: a patient's previous experience with the substance, evaluation of alternative aetiologies, temporal correlation, correlation to intake, and dechallenge/rechallenge information. Taking these factors into account, Naranjo causation is rated as 0 (doubtful or unlikely), 1 to 4 (possible), 5 to 8 (probable) and 9 to 13 (definitive or certain)(29).
Based upon their analysis of all available data from different regulatory bodies, and all 30 published case reports, the U.S. Expert Committee concluded that "all reports of liver damage were assigned possible causality, and none were probable or certain causality". Appraisal of additional clinical pharmacokinetic and animal toxicological information, also failed to reveal any unfavourable information about black cohosh.
A further review of European case reports of alleged liver toxicity by German researchers published in the January 2009 issue of Phytomedicine came to similar conclusions(6). This study cites a total of 42 case reports, but of these, a possible or probable causality was given to only four cases after an earlier assessment by the European Medicines Agency(30).
Using both clinical evaluation as well as a validated structured qualitative and quantitative causality assessment method, each of these four cases were investigated. In one of these the lack of complete data was identified, resulting in only three remaining cases being analysed. Of these cases, one patient responded favourably to steroid therapy, and the final diagnosis was autoimmune hepatitis. Liver transplantation was required in the other two patients, and a final diagnosis of herpetic hepatitis was established.
Quantitative evaluation, however, showed no causality of the severe liver disease for black cohosh in all three patients. The authors concluded that their thorough causality assessment showed that there was no evidence for a causal relationship between treatment by black cohosh and the observed liver disease in these four patients(6).
In appraising this subject, the level of usage of black cohosh is relevant. U.S. data reported that black cohosh was the eighth most popular dietary supplement in 2005(31), such usage having increased markedly since negative findings on HRT were made public in 2002(32). In view of this high level of usage, it is in fact reasonably likely that rare instances of idiosyncratic reactions could occasionally occur, just as they do to any therapeutic substance. While determining the frequency of these remains difficult, an objective appraisal comes to the conclusion that at best, they appear to be extremely rare, and certainly much less than that for widely consumed and readily available pharmaceuticals such as paracetamol(33).
Black cohosh has a long history of safe use in many countries(34-36), and is now taken by millions of women daily, primarily for the management of menopausal symptoms. The substantial amount of research undertaken to date on this herbal medicine as well as the individual constituents it contains, has not provided any evidence of hepatotoxicity until recently. Based upon the evidence to date, including these two recently published reviews by reputable sources, we continue to view these case reports of alleged liver toxicity as being either unrelated to true black cohosh ingestion and due to other unknown causes of idiopathic hepatitis, or attributable to black cohosh ingestion, but an extremely rare, idiosyncratic reaction as will be experienced by a very small number of individuals taking any medicament.
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30. EMEA. Assessment of case reports connected to herbal medicinal products containing Cimicifugae racemosae rhizome (black cohoshroot)
31. Total Sales of Herbal Supplements in United States Show SteadyGrowth.
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/articleview.asp?a=3012, Accessed 30/3/2008.
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Phil Rasmussen Phytomed Medicinal Herbs Ltd
438 Rosebank Road Avondale, Auckland New Zealand
P O Box 83-086 Edmonton, Waitakere 0652 New Zealand
Footnote from Ideal Health:
The follwing products all contain good quality Black Cohosh:
Related health information can be found here:
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Suffering from menopausal or menstrual problems? Then consider Dong Quai - the queen of female herbs
Suffering from menopausal symptoms? Femitone may help
Related articles can be found here:
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Disclaimer: The health information presented here has been written for the New Zealand health consumer. It is of a general nature and is only intended to provide a summary of the subjects covered. The information is not intended to be comprehensive or to provide medical advice to you. While all care has been taken to ensure the accuracy of the information, no responsibility or liability is accepted, and no person should act in reliance on any statement contained in the information provided. All health ailments should be treated by a qualified health professional.
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