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Black Cohosh: Does It Really Cause Liver Damage?

By Kerry Bone, BSc (hons), Dip. Phyto, FNIMH, FNHAA, MCPP

In the past three years, four papers or letters have been published purporting to demonstrate a link between the use of black cohosh (Actea racemosa, also known as Cimicifuga racemosa) ingestion and subsequent liver injury.

The first publication was from Australia and described six patients with evidence of severe hepatitis linked to taking a range of herbal products.1 Two of these patients were taking black cohosh, although one also was taking other herbs, including skullcap, an herb that can be substituted by Teucrium species, a known hepatotoxic genus.2 The one case attributed to black cohosh alone (case 1) truly was dramatic. Of the cases reported, the most serious illness occurred in a 47-year-old woman taking black cohosh for menopausal symptoms. She required liver transplantation, even though, according to the publication, the patient had been taking the black cohosh for just one week. Histological examination of her liver confirmed severe hepatitis and early fibrosis. The patient did not exhibit eosinophilia and had no signs of any systemic disturbance. Serology for hepatitis A, B and C was negative, but rechallenge with the herb was not performed "for ethical reasons." The dose of black cohosh taken was not specified.

The second publication, also from Australia, described a 52-year-old woman with acute liver failure (case 2).3 She had been taking an herbal formula containing 1:1 liquid extracts prescribed by a pharmacist. Black cohosh 1:1 was 10 percent of the mixture and the daily dose of the combination was 7.5 mL twice a day. The patient underwent successful liver transplantation. Although the authors stated, "Extensive investigation excluded other recognized causes of liver failure," they provided no details of what these investigations were. Analysis was said to confirm the presence of golden seal, black cohosh and ginkgo in the herbal mixture. Other stated ingredients were ground ivy and oats seed.

The third and fourth publications detail single case reports from the U.S. One report described the development of autoimmune hepatitis, which the authors claim was triggered by the use of black cohosh (case 3).4 A 57-year-old diabetic woman presented with a two-week history of lethargy and fatigue. Her medications (all of which had been used for more than two years) included labetalol, fosinopril, verapamil, metformin, aspirin and insulin. Three weeks before presentation, the patient began taking black cohosh tablets (unknown brand or dose) for hot flashes. Drug-induced autoimmune hepatitis, attributed to the black cohosh, was diagnosed. Tests for hepatitis A, B and C were negative.

The most recent case report (case 4) was that of a 50-year-old woman suffering from acute-onset jaundice.5 The provisional diagnosis was autoimmune hepatitis, since tests for hepatitis A, B and C, cytomegalovirus and Epstein-Barr virus all were negative. In the five months prior to the onset of jaundice, the patient was taking black cohosh (500 mg daily) for menopausal symptoms and was not on any other medications. The patient underwent liver transplantation. No further details concerning the black cohosh usage by the patient (or its cessation) were provided and a rechallenge probably was not undertaken.

The phenomenon of idiosyncratic hepatic reactions to drugs is well-documented. It also appears this reaction does occur to certain herbs, e.g. chaparral (Larrea tridentata) and germander (Teucrium species). By definition, such reactions are rare and unpredictable and are not dose related.6 There are two types of idiosyncratic hepatic injury: hypersensitivity and aberrant metabolism. The former develops one to five weeks after exposure to the drug and, since it is immune-mediated and acute, also involves a systemic reaction including rash, fever and eosinophilia. The latter takes weeks to months to develop and symptoms are confined to the liver.6 Diagnosis of drug-induced idiosyncratic liver injury (DILI) is very difficult and relies largely on circumstantial evidence. Factors taken into account include a temporal association, exclusion of other possible causes, a consistent latency period to those described above, presence or absence of hypersensitivity (systemic) features, positive response to drug removal (dechallenge), positive response to rechallenge, and a positive lymphocyte stimulation test (this last factor is quite controversial). Complicating this is the fact that DILI can mimic every known human liver disease.6

There are many confounding factors that could lead to incorrect associations between ingested medications or herbs and idiosyncratic liver injury. Many viruses that cause liver disease still are to be identified7 and there are no tests for them. Even known viruses are not always tested for. For example, a Dutch study published this year found that Hep E virus was a significant cause of unexplained hepatitis.8 Occult celiac disease has been suggested as a cause of unexplained hypertransaminasemia (raised ALT and AST). Rare liver diseases might not be excluded.10,11 Hair dye was a cause of DILI in a Japanese man.12 Other environmental factors could be implicated.

The experience of a liver transplant unit which has recently been described highlights some key issues behind the history and incidence of severe acute hepatitis (fulminant hepatic failure, FHF). All adult cases of FHF presenting to the Victorian Liver Transplant Unit (Australia) from 1988 to 2002 were analyzed. Eighty patients (mostly female) were referred, at a rate of approximately one case per million population per year. Mean age was approximately 38 years. Most cases were due to acetaminophen poisoning (36 percent) or idiopathic hepatitis (34 percent).13 Only five of the 80 cases were classified as drug induced, making this causality a rare factor. The 27 cases (34 percent) of hepatitis due to unknown causes (idiopathic) is a staggering rate. These cases also are described as non-A non-B hepatitis, since patients are not positive for hepatitis A or B. In the U.S., the most common cause of FHF was in fact non-A non-B (idiopathic) hepatitis.13 (Note that this study was published in 1995, well before the dramatic rise in herbal use.) Presumably, these cases of idiopathic hepatitis could be caused by unidentified infections or environmental factors. However, the authors of the Australian study state, "The strong female predominance of cases argues against a viral cause and raises the possibility that hormonal factors are involved, or that the condition is linked to autoimmune liver diseases. There is clearly a need for large, detailed, multicenter epidemiological studies, to provide further clues to a possible etiology/ies of this syndrome."

The case reports linking black cohosh to liver injury have some serious flaws. In particular, for all cases, the presence of black cohosh in the products being consumed was not definitely established. Moreover, in most cases the name of the product and the dosage taken were not specified. Certainly for case 2, there is the assertion that black cohosh was identified in the herbal mixture, but no details of the results or how this was done are provided. The fact that two herbs in the mixture could not be identified makes any argument for the involvement of black cohosh in case 2 fundamentally flawed.

The features of case 1 are baffling. Since the problem developed after one week of taking black cohosh, this would have to be a hypersensitivity reaction if the herb truly was the cause. Yet the patient lacked any features of a hypersensitivity reaction (rash, fever, systemic reaction, eosinophilia). In fact, eosinophilia specifically was stated to be absent. Furthermore, the explant liver showed signs of early fibrosis, a phenomenon that could develop only after months of exposure to the causative agent. Clearly, on the evidence provided, one week of black cohosh is the least likely cause of this patient's liver damage.

For case 3, the authors claimed none of the drugs the patient was taking had been linked to autoimmune hepatitis. Yet a simple search revealed several cases for labetalol in which this drug might have indeed caused an idiosyncratic autoimmune hepatitis, including one overview report of 11 cases from the FDA.14,15,16

In case 4, the authors justify their identification of black cohosh as the cause of the patient's liver injury on the basis of the two flawed Australian publications. In their discussion, they attribute to black cohosh the presence of hepatotoxic alkaloids and salicylates. Such attributions are nonsensical, unsupported by the literature17 and, above all, cast doubt on the credibility and academic diligence of their overall analysis of the case.

Additional problems with the four cases include the lack of positive identification of black cohosh as the cause by either a rechallenge or a lymphocyte stimulation test. While the latter can give false negatives, if positive, it would have provided more conclusive evidence of any link to black cohosh use. But the likelihood is that most of the authors involved never actually saw what the patients were taking (as evidenced by the appalling lack of product and dosage information) and therefore would have been unable to undertake such tests.

The demographics of patients with non-A non-B (idiopathic) hepatitis closely match those of the black cohosh user (female, age 40-50). Hence, the most likely and rational explanation of the cases described is that they are idiopathic hepatitis mistakenly attributed to black cohosh because of the common use of this herb. Once one mistaken case is described in the literature - however poor its quality - others likely will follow in a process akin to a self-fulfilling prophecy. Hopefully, the regulators will not be motivated to act on such poor-quality case reports. The association of black cohosh and DILI remains unproven based on the current evidence.

References

  1. Whiting PW, Clouston A, Kerlin P. MJA 2002;177:432-35.
  2. Mills S, Bone K. The Essential Guide to Herbal Safety. Churchill Livingstone, USA, 2005: pp. 581-84.
  3. Lontos S, Jones RM, Angus PW, et al. MJA 2003;179:390-91.
  4. Cohen SM, O'Connor AM, Hart J, et al. Menopause 2004;11(5):575-577.
  5. Levitsky J, Alli TA, Wisecarver J, et al. Dig Dis Sci 2005;50(3):538-539.
  6. Lewis JH. Drug-Induced Liver Disease. In: Best Practice of Medicine 2000.
  7. Bowden DS, Moaven LD, Locarnini SA. MJA 1996;164:87-89.
  8. Waar K, Herremans MM, Vennema H, et al. J Clin Virol 2005;33(2):145-149.
  9. Bardella MT, Vecchi M, Conte D, et al. Hepatology 1999;29(3):654-657.
  10. Tordjmann T, Grimbert S, Genestie C, et al. Gastroenterol Clin Biol 1998;22(3):305-310.
  11. Gaya DR, Thorburn D, Oien KA, et al. J Clin Pathol 2003;56(11):850-853.
  12. Tokumoto Y, Horiike N, Onji M, et al. Intern Med 2003;42(11):1104-1106.
  13. Gow PJ, Jones RM, Dobson JL, et al. J Gastroenterol Hepatol 2004;19(2):154-159.
  14. Marinella MA. J Clin Hypertens 2002;4(2):120-121.
  15. Stronkhorst A, Bosma A, van Leeuwen DJ. Neth J Med 1992;40(3-4):200-202.
  16. Clark JA, Zimmerman HJ, Tanner LA. Ann Intern Med 1990;113(3):210-213.
  17. Mills S, Bone K. The Essential Guide to Herbal Safety. Churchill Livingstone, USA, 2005: pp. 269-272.

About the Author: Kerry Bone was an experienced research and industrial chemist before studying herbal medicine full-time in the U.K., where he graduated from the College of Phytotherapy and joined the National Institute of Medical Herbalists. He is a practicing herbalist; cofounder and head of Research and Development at MediHerb; and principal of the Australian College of Phytotherapy. Kerry is a regular contributor to various journals and has co-authored several books, including the Principles and Practice of Phytotherapy and The Essential Guide to Herbal Safety.

 



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Date Last Modified - Friday, 17-Oct-2008 12:10:32 PDT