Black cohosh and liver failure

In the news...

Michael Thomsen

ABC The 7.30 Report - How safe are herbal medicines? 24 February 2010

A response from Michael Thomsen

The report described the unfortunate case of Maree Furler who suffered liver failure for which her doctor blamed the herbal medicine, black cohosh. The case was presented as news and a warning of the dangers of unregulated herbal medicines.

The fact is that this is an old case. Maree Furler was diagnosed in 2006 and her case report published in the Medical Journal of Australia (MJA) in 2008.  

The report by Dr Chow and colleagues from the South Australian Liver Transplant Unit Department of Gastroenterology and Hepatology, Flinders Medical Centre in Adelaide has been criticised for drawing the conclusion that black cohosh was responsible for her liver failure.

The causality of black cohosh was entirely dismissed by a leading German hepatologist in a letter to the editor of the MJA published in January 2009.3

The patient had been a steady drinker, and had a history of obesity for which she had received a gastric bypass operation – all of which could have contributed to her liver failure.

Furthermore, no temporal association between black cohosh and the start of liver symptoms could be established, thereby excluding a causal relationship.3

The 7.30 Report failed to mention any of this and just accepted the erroneous conclusion as fact, that the herbal medicine, black cohosh, was the cause of the liver failure. 

Is black cohosh directly hepatotoxic? No. In a rat study, 300 mg/kg/day of black cohosh did not produce any liver toxicity.  That is the equivalent of 21 g black cohosh or nearly 100 times the therapeutic dose. A 12 month study of 107 women taking black cohosh, failed to demonstrate any sign of hepatic disease, or worsening of already altered but stable liver parameters. 

Are there any, clear cut case where black cohosh definitely caused liver damage? No. 

Are there any OTC drugs which definitely cause liver damage and death every year in Australia? Yes, and that drug is paracetamol found in Panadol and other products for pain and headache.

Unlike black cohosh, the direct liver toxicity of paracetamol is well known and toxic levels of paracetamol can be detected in the blood of poisoned patients. Such direct and causal relationship has never been demonstrated in any of the cases of assumed liver toxicity of black cohosh.

Let us get things in perspective. Paracetamol use should be considered in any liver failure. Between 1989 and 2004, 42 patients were referred to the Victorian Liver Transplant Unit with paracetamol-induced acute liver failure. Two of them died.  Paracetamol is estimated to cause 20% of acute liver failures in the US.

Maree Furler says to camera that black cohosh is on the supermarket shelf next to the Panadol and the band aid and that it shouldn't be as it is dangerous. In fact, perhaps it is the Panadol which shouldn't be there!

The program muddles the investigation into black cohosh further by drawing in issues of herb-drug interactions, heavy metal contamination and the addition of pharmaceutical drugs to herbal medicines by unscrupulous manufacturers.

These issues are complex, but separate issues, which deserves proper attention. Herb-drug interactions are a cause for concern but that does not imply that herbal medicines are toxic or dangerous, but that more research is needed so that potential interactions can be avoided.

The TGA does a good job of regulating complementary medicines in Australia. Quality manufacturers test all herbal ingredients for heavy metal contamination. The contamination with pharmaceutical drugs is rare and generally related to unscrupulous manufacturers from overseas, notably China.

There is no need to tighten the regulation further. The TGA does a very good job of keeping complementary medicines safe and free of contamination with heavy metals and pharmaceutical drugs. Label claims (indications for use) by marketing companies are sometimes excessive, but generally restricted to the symptomatic relief of minor illnesses. What is needed is not more regulation, but more independent research into the efficacy of herbal medicines.

If any regulation is needed, it is the introduction of statutory registration of naturopaths or herbal medicine practitioners which will make it very easy to restrict the use of controversial herbal medicines to qualified herbal medicine practitioners. 

In the future, let us have transparency in regards to the data details of each case of suspected hepatotoxicity. Let us have all the details analysed by unbiased hepatologists. Let us not jump to conclusion about the causality of black cohosh without proof just because it makes a good story.

Michael Thomsen

 

Scientific evidence dismissing the causality of black cohosh and liver failure

The following presents the scientific evidence dismissing the accusation that black cohosh is the cause of Maree Furler's liver failure, or indeed, any of the cases of liver disease and black cohosh published so far.

Chow and her colleagues state that the patient (Maree Furler) had no history of 'significant alcohol consumption', but a presumably related adverse drug reaction report available from the Therapeutic Goods Administration reveals her alcohol use was 3–4 units of alcohol per day, with 1-2 alcohol-free days per week.

The patient was also reported to not be taking any other medications, including other herbal preparations, but the use of multivitamins was disclosed, without further information on ingredients, indication, dosage and duration of use. Notably, an overdose of vitamin A can cause severe liver disease.2

The patient also had a history of obesity for which she was treated with gastric bypass surgery. It is known that gastric bypass surgery for obesity may be associated with liver disease and fibrosis.

As the histological examination of the liver six weeks after first presentation found no recognisable residual hepatocytes (lever cells), the diagnoses of alcoholic steatohepatitis, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis cannot be excluded. Without this, the specific conclusion of the liver biopsy that the 'Massive hepatocellular necrosis [was] associated with herbal medication' cannot be substantiated.2

Furthermore, discontinuation of black cohosh failed to reduce the patient's bilirubin levels, suggesting ongoing liver cell destruction by the as-yet unknown agent. Chow et al state 'Extensive investigations to exclude other causes of acute liver failure gave negative results” It is unclear whether rare liver diseases were excluded, notably herpes infection, which has been reported to cause severe herpetic hepatitis. Nor was polymerase chain reaction testing performed for hepatitis viruses.2

Finally, and very importantly, no temporal association between black cohosh and the start of liver symptoms could be established, thereby excluding a causal relationship.

There is no apparent credible evidence that black cohosh caused liver failure in the patient (Maree Furler) described by Chow et al. Her history of obesity, gastric bypass surgery and a daily alcohol consumption of 30–40 g should be considered principally in any causality assessment. In addition, idiopathic reasons, rare or unclear liver diseases, and other medications should be considered as possible causes.2

Even in patients with liver disease who consume little or no alcohol and have no exposure to other toxic agents, the cause of the disease remains unclear in up to 30%. In view of this, reliable and sufficient reporting of adverse drug reactions is a necessary precondition to any reliable assessment of causality.2

A group of medical scientists at the Department of Internal Medicine, Division of Gastroenterology and Hepatology at Goethe-University Frankfurt/Main, in Germany published a review  of the causality for black cohosh and liver toxicity published in August 2009. They assessed all 69 patients with hepatotoxicity assumed to be caused by black cohosh reported in the medical literature up until then, including the case of Maree Furler at the centre of the story on the 7.30 Report.

The German group analysed 11 cases from the literature, as well as the 36 cases initially evaluated by EMEA (European Medicines Agency), and a further 22 cases presented by USP for spontaneous reports of CADRMP (Canadian Adverse Drug Reaction Monitoring Program), TGA (including the case of Maree Furler), and MedWatch/FDA.

Applying the original CIOMS (Council for International Organizations of Medical Sciences) scale and the main-test as its updated scale, it was concluded that for 68 of 69 patients, black cohosh as the cause of the hepatotoxicity could be excluded, or deemed unlikely, unrelated, or of unassessable causality.

For only one patient causality was possible for black cohosh but also for symptomatic cholelithiasis with confounding factors of fatty liver of undefined cause. Furthermore there was scant information about the black cohosh product. The brand was unknown and could very likely have been a herbal mixture. The dose and the duration of intake of black cohosh were unknown as well. In other words, for this single person where black cohosh could not be ruled out, nothing was known about the black cohosh product this person took, for how long or at what dose and the liver toxicity could easily have been caused by gall stones and fatty liver.

In general, all 69 case reports were poorly documented. All reports suffered from confounding variables including failure to identify the black cohosh product; use of herbal mixtures with multiple ingredients in addition to black cohosh; co-medication with synthetic drugs and dietary supplements including herbal ones; missing temporal association between black cohosh use and development of liver disease; failure of re-challenge after black cohosh discontinuation; pre-existing liver diseases; insufficiently exclusion of other liver diseases; and presence of alternative liver diseases.

There have been new reports of suspected hepatoxicity since the publication of this review, however, the case reports are again poorly documented and some have subsequently been shown to have been already included in the first 69 cases. All cases have already been deemed unlikely to have any causality with black cohosh. One patient admitted that she had been taking an herbal formula that she believed contained black cohosh. The herbal formula was not sent for analysis, so there is no data about the constituent ingredients or any potential contamination. Interestingly, ALT (a liver enzyme) values dropped strikingly despite continued herbal use. Another was confounded by the use of herbal mixtures, long de-challenge period over several years, and unexplained increase in liver test after treatment with methyl-prednisolone and azathioprine suggesting underlying viral hepatitis. A third patient received concurrent treatment with irbesartan, simvastatin and levothyroxine. Nine of the remaining 12 cases were spontaneous reports, lacking further information and structured, hepatotoxicity specific causality assessment. In total, neither of the 13 cases are likely to confirm a causality for black cohosh.

References

  1. Chow ECY, Teo M, Ring JA, Chen JW. Liver failure associated with the use of black cohosh for menopausal symptoms. Med J Aust 2008;188:420–2.
  2. Naser B, Liske E Liver failure associated with the use of black cohosh for menopausal symptoms MJA 2009; 190 (2): 99-100
  3. Teschke R. Liver failure associated with the use of black cohosh formenopausal symptoms. Med J Aust 2009;190:99–100
  4. Mazzanti G, Di Sotto A, Franchitto A, Mastrangelo S, Pezzella M, Vitalone A, Mammola CL.Effects of Cimicifuga racemosa extract on liver morphology and hepatic function indices.Phytomedicine. 2008 Apr 21.
  5. Firenzuoli et al Black Cohosh Hepatic Safety: Follow-up of 107 Patients Consuming a Special Cimicifuga racemosa rhizome Herbal Extract and Review of Literature eCAM 2008 1-7
  6. Lubel JS, Cheng RKY, Angus PW, Gow PJ. Fulminant hepatic failure due to accidental paracetamol overdose [abstract]. J Gastroenterol Hepatol 2004; 19: A254
  7. Holt AW Acute liver failure Critical Care and Resuscitation 1999; 1: 25-38
  8. Australian Government Department of Health and Ageing Therapeutic Goods Administration. Public case detail for case number 220336, recorded as reported to the Adverse Drug Reactions Unit, 25 July 2006
  9. Ong JP, Elariny H, Collantes R, et al. Predictors of non-alcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg 2005; 15: 310-315.
  10. Teschke R, Bahre R, Genthner A, Fuchs J, Schmidt-Taenzer W, Wolff A.Suspected black cohosh hepatotoxicity--challenges and pitfalls of causality assessment.Maturitas. 2009 Aug 20;63(4):302-14
  11. Teschke R, Bahre R, Genthner A, Fuchs J, Schmidt-Taenzer W, Wolff A.Reply to: Suspected black cohosh hepatotoxicity--challenges and pitfalls of causality assessment.Maturitas 64 (2009) 141–142

 

Links

 

Media report

ABC The 7.30 Report - How safe are herbal medicines? 24 February 2010

 

Journal references

Pubmed - Suspected black cohosh hepatotoxicity - Challenges and pitfalls of causality assessment

Elsevier (Science Direct and Maturitas subscribers, but Maturitas visitors can view abstract)

Maturitas (for registered users)

 

Commentary

Pharmacy News - CAM Safety Regime on trial

 

One of the interviewees, Professor Roger Byard, Forensic Pathologist, University of Adelaide, had previously appeared on the ABC's Radio National Breakfast

Listen to the podcast: Roger Byard, Professor of Pathology at the University of Adelaide on Radio National Breakfast 9 February 2010

Read the relevant journal article: Roger W. Byard, A Review of the Potential Forensic Significance of Traditional Herbal Medicines