In October 2002, in the Medical Journal of Australia, there was a single case report of a 47 year old Australian woman who developed acute hepatitis and subsequently required a liver transplant.¹  It was reported that this woman had been taking a black cohosh (Cimicifuga racemosa) preparation for one week. The herbal product was never analysed to ascertain that the product did actually contain the herb black cohosh (which has been the case for the majority of reports of black cohosh suspected liver damage) and therefore causality of liver damage cannot be confirmed. The type of hepatitis that was observed in this woman was a severe immune reaction typical of an idiosyncratic immune reaction and not because of a direct toxic injury. This question as to whether black cohosh was implicated as the cause of liver failure is improbable due to the short time between the intake of the herb and transplantation.

After this first report, other authors started to implicate black cohosh as the cause of liver damage when a liver reaction was seen in a person who was taking the herb.

By 2006, there had been around 40 cases of suspected liver reactions due to black cohosh worldwide, nine of which occurred in Australia. Of the Australian cases, four were hospitalised, with two requiring liver transplantation.

TGA action

This prompted the Australian Therapeutic Goods Administration (TGA) to issue a warning of the potential liver reaction from black cohosh, as they believed there was ‘sufficient evidence of a causal association between black cohosh and serious hepatitis’.²  As a result of this, future labels of products containing black cohosh will read: ‘Warning: Black Cohosh may harm the liver in some individuals. Use under the supervision of a healthcare professional’.

The TGA, more recently established an expert advisory group to review the existing regulatory controls on black cohosh. The expert advisory group examined a total of 16 Australian reports of suspected liver damage and 11 were judged to be at least possibly related to black cohosh use, including 3 cases of liver transplantation.  “The expert group concluded that there appears to be an association between the use of black cohosh and liver damage, but it is very rare.” They state that it was not possible to identify, with any certainty, the strength of the association, or any particular vulnerable group, type of preparation, dose, duration of use or specific products.

“The expert group also determined that black cohosh is still suitable for use in complementary medicines, but recommended that the current warning statement on the medicine label be revised to better inform consumers about the risk and also to provide sufficient information to assist in the early detection of liver damage and, if detected, to seek medical attention.”

International action

The European Medicines Agency Committee on Herbal Medicinal Products (HMPC) also reviewed the evidence on Black Cohosh in a recent 2006 analysis (revised version January 2007).

The HMPC analysed all the reports of liver reactions due to black cohosh. Eight international experts formed the group dealing with hepatotoxicity. They used seven criteria to assess whether the individual cases of hepatotoxicity were related to black cohosh, including time of onset of the liver damage in relation to commencing and ceasing black cohosh; risk factors such as age (>55) alcohol consumption; concomitant drugs especially those with known hepatotoxicity; non-drug related causes including infectious hepatitis, travel to hepatitis endemic areas, underlying disease and recent infections with Cytomegalovirus (CMV), Epstein- Barr Virus (EBV) or Herpes virus; and response to re-administration of the drug. The RUCAM (Roussel UCLAF causality assessment method) was used to classify each case in question: <0 “excluded”; 1-2 “unlikely”; 3-5 “possible’; 6-8 “probable”; above 8 “highly probable”.

Overall, the reports were poorly documented. In many cases there was not even information about the time frame of treatment with black cohosh or information in relation to the onset of the liver reaction. After evaluating the information, the committee concluded: “The HMPC evaluated 42 case reports of hepatotoxicity, collected from European National Competent Authorities (34 cases) as well as literature case reports (8 cases). Of these, only 16 cases were considered sufficiently documented to allow the Committee to assess if use of Cimicifugae racemosa rhizoma (black cohosh root) could be linked to the liver injuries. As a result of the assessment, 5 cases were excluded and 7 cases were considered unlikely to be related. In the remaining 4 cases (2 autoimmune hepatitis, 1 hepatocellular liver injury and 1 fulminant hepatic failure), there was a temporal association”.³  Of these four cases, only two were classified as “probable” when rating cause and effect. These were two of the published cases.

The first case⁴ was a 57 year old multimorbid woman, who developed autoimmune hepatitis three weeks after first commencing black cohosh (brand and dose unknown). The patient stopped taking black cohosh and was treated with steroids and azathioprine and she recovered. According to the draft recommendations of the Scientific Advisory Panel Subgroups on Hepatotoxicity (2004), this case would be classified as idiosyncratic liver necrosis. The patient went on to have liver transplantation, but unfortunately died due to uncontrollable haemorrhage. This case was reported twice in the literature in different publications, two years apart, but to some extent the information in both reports seems contradictory. The causal relationship to black cohosh was first assessed as unclassifiable as there was incomplete and contradictory information provided concerning the reaction. When the case was published the following time, more information on therapy and investigations, although to some extent contradictory, was included. The pathology suggested drug and/or toxin-related liver failure and the authors assessed the causality as “probably” drug-induced. Of importance to note, is that the patient was taking fluoxetine, paracetamol and propoxyphene, which when taken concomitantly with contraindicated alcohol (patient drank two glasses wine per day) have a known interaction which may lead to significant hepatotoxic effects and therefore contribute to liver failure.

In the second case of autoimmune hepatitis,⁵ the connection between black cohosh and liver damage was considered possible because the onset of the reaction was related to the herb exposure. The dose was 500mg/day, which is 12 fold the suggested dose of the Commission E Monograph. Other causes of hepatitis were excluded. The patient went on to have a liver transplant. This patient was also taking valaciclovir (valtrex) 1000mg, ½ daily for over two years and ibuprofen in amounts causing anaemia, due to bleeding from a gastric ulcer. Valtrex can cause very rare irreversible increases in liver function tests, and there have been single cases of liver damage from ibuprophen reported. However, the gastroenterologist did not consider these factors responsible for the liver failure. The patient later went on to admit in court that she drank 1-2 glasses of wine on Fridays, Saturdays and Sundays, whereas in the published cases no alcohol use was recorded and therefore modified the data. The committee noted that this was close to the amount associated with risk of hepatotoxicity from chronic alcohol use (more than 7 units per week for women). The committee would have assigned this case as a possible link between black cohosh and liver damage, but because the expert gastroenterologist appeared before an American court, the HMPC preferred to keep the “probable” cause of black cohosh to the liver damage. The case was assessed as an overdose.

The report examined 15 clinical studies (controlled clinical trials and post-marketing studies from 1983-2005) and overall no case of significant liver dysfunction was reported. It was noted that long-term safety of black cohosh was not studied.

While the report overall demonstrated that there were only two cases where black cohosh was possibly related to liver damage the HMPC wanted to draw the attention of the public to the potential serious liver reaction that may occur in patients using products containing black cohosh. They offer the following:

Advice to patients:

• Patients should stop taking Cimicifugae racemosae rhizoma (black cohosh root) and consult their doctor immediately if they develop signs and symptoms suggestive of liver injury (tiredness, loss of appetite, yellowing of the skin and eyes or severe upper stomach pain with nausea and vomiting or dark urine).
• Patients using herbal medicinal products should tell their doctor about it.

Advice to healthcare professionals:

• Healthcare professionals are encouraged to ask patients about use of products containing Cimicifugae racemosae rhizoma (black cohosh root).
• Suspected hepatic reactions should be reported to the national adverse reaction reporting schemes.

Important considerations

Several key factors need to be considered when looking at the evidence suggesting black cohosh as a cause of liver damage.

• Most importantly: in many of the cases, the presence of black cohosh has not been definitely established (i.e. the product was not tested to show that it actually contained the herb black cohosh).
• In most cases the name and dosage of products have not been specified.
• In some reports, the products used contained multiple ingredients; the patient was taking more than one medication, or was suffering from other medical conditions.
• Among the herbal medicine industry, there have been reported cases of intentional or accidental substitution of herbs with other plants or by contamination of a more toxic plant, or toxin (mould, toxins of heavy metals, pharmaceuticals).
• There are at least 20 common names of black cohosh making the likelihood of mistaken substitution of this herb for another herb a possibility.
• No information regarding plant part used, extraction medium, the amount of the herb taken or method of extraction has been listed in the reports.
• Hepatitis for which no cause can be identified is not uncommon and cannot be excluded.
• Overall there is a very low incidence of reported suspected liver damage considering the widespread use of black cohosh.
• There is a potential for misinformation when an author who is not herbally qualified attempts to explain a possible reaction. For example, in the first Australian case, the authors attempt to explain the immunological reaction by referring to an animal model study in which the hepatotoxicity (liver toxicity) reaction is triggered by a plant compound called diterpenoids.
  • Black cohosh in fact contains triterpenoids, not diterpenoids.
  • Furthermore there is a difference in how a plant compound works when it has been injected (as in an animal experiment) compared to when it has been eaten and broken down by the bacteria in our gut into sometimes quite different compounds.
• There is an ongoing study of black cohosh and menopause at the Columbia University, New York City, which is investigating liver function tests in subjects every 2-3 months.⁶
• While the implications of possible hepatotoxicty are serious, the failure to authenticate the plant compounds in the implicated preparations cannot establish black cohosh as the cause of the hepatotoxicity.⁷

Summary

While acute liver failure has been suspected with Cimicifuga racemosa, it is extremely rare and somewhat unpredictable.

Further Australian Case

Another Australian case was a 52 year old woman who experienced acute liver failure after 3 months of a liquid extract mixture of black cohosh, goldenseal (Hydrastis canadensis), Ginkgo biloba, ground ivy (Nepeta hederacea), oat seed (Avena sativa). In this case there was extensive investigation that excluded other causes of liver failure. The TGA analysis of the extracts revealed no undeclared pharmaceutical drug and confirmed the presence of the herbs. The authors commented that it was not possible to determine the individual ingredient or mixture of ingredients that resulted in liver failure. Liver failure progressed despite cessation of the herbal therapy and transplant was required, suggesting a process of irreversible liver injury had been initiated before treatment was ceased. One of the herbs, ground ivy, contains pulegone, a known hepatotoxin (compound that can cause liver toxicity), however in concentrations significantly less than in pennyroyal, where pulegone-induced hepatotoxicity has been reported. In this case the WHO classification of causality of adverse reactions was “possible”.⁸

References

1. Whiting, PW. Clouston A. & Kerlin P. 2002 ‘Black Cohosh and other herbal remedies associated with acute hepatitis’ MJA 177 pp432-435.

2. http://www.tga.gov.au/cm/0705blkcohosh.htm

3. http://www.emea.europa.eu/pdfs/human/hmpc/26925806en.pdf

4. Cohen, SM: Hepatitis Associated with Black Cohosh Bethesda Maryland Nov. 22, 2004. Workshop on the safety of Black Cohosh in Clinical Studies = Cohen, SM. et al 2004 Menopause11 (5): 575-577

5. Levitsky et al 2005, Digestive Diseases and Sciences 50 (3) pp 538-539

6. Hudson, T. 2006. ‘Black Cohosh Update: Does it work? Is it Hepatotoxic?’ Altern & Compl med 12 (3) pp 132-135

7. Vitetta, L. Thomsen, M & Sali, A. 2003. ‘Black Cohosh and other herbal remedies associated with acute hepatitis’ Letters to the Editor, MJA 178 pp 411-4127. . 

8. Lontos, S. Jones, RM. Angus, PW.et al. 2003 ‘Acute liver failure associated with the use of herbal preparations containing black cohosh’ MJA letter to ed. 179 pp 390-391.

Content updated October 24, 2007