Cohosh and Liver Injury
On February 9, 2006, the Australian Therapeutic Goods Administration (TGA) announced
The Therapeutic Goods Administration (TGA) recently reviewed the safety
of Black cohosh (Cimicifuga racemosa) following reports of possible
liver problems internationally and in Australia. At the time of the
review, there were 47 cases of liver reactions worldwide, including
nine Australian cases. In Australia, four patients were hospitalized,
including two who required liver transplantation. Although some reports
are confounded by multiple ingredients, by more than one medication
or by other medical conditions, there is sufficient evidence of a causal
association between Black cohosh and serious hepatitis.
However, considering the widespread use of Black cohosh, the incidence
of liver reaction appears to be very low. Following the safety review,
the TGA has decided that medicines containing Black cohosh should include
the following label statement:
Warning: Black cohosh may harm the liver in some individuals. Use under
the supervision of a healthcare professional.
New products will need to comply with the requirement from the time
of manufacture. For existing products, a phase-in period of twelve
(12) months will be given to allow sponsors adequate time to comply
with the new labelling requirements.
On July 18, 2006, the Medicines and Healthcare
Products Regulatory Agency (MHRA) in the UK issued a press release
stating that all black
cohosh products sold there should carry the following label warning:
cohosh may rarely cause liver problems. If you become unwell (yellowing
eyes/skin, nausea, vomiting, dark urine, abdominal pain,
unusual tiredness), stop taking immediately and seek medical advice.
Not suitable for patients with a previous history of liver disease.
Australian TGA's claim concerning the
number of cases of liver damage linked to black cohosh (which include
the adverse reaction reports filed with the UK MHRA and other health
authorities), only five papers or letters have been published purporting
to demonstrate a link between black cohosh (Actea racemosa) ingestion
and subsequent liver injury. It is important to closely examine these
published reports since, because of the process of peer review, these
represent the best-documented evidence of any association with liver
The first publication, from doctors at the Princess Alexandra Hospital
in Brisbane, Australia, described six patients with evidence of severe
hepatitis that was linked to taking a range of herbal products.1 Two
of these patients were taking black cohosh, although one was also taking
other herbs including skullcap, a herb which can be substituted by
Teucrium species, a known hepatotoxic genus.2 The one case attributed
to black cohosh alone (Case 1) was truly dramatic. Of the cases reported,
the most serious illness occurred in this 47-year-old woman who was
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, neither was the product.
The second publication, also from Australia, describes a 52-year-old
woman with acute liver failure (Case 2).3 She had been taking an herbal
1:1 liquid extracts prescribed by a pharmacist. Black cohosh 1:1 was ten 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 that "Extensive investigation excluded other recognised causes
of liver failure," they provided no details of what these investigations
were. Analysis by the TGA was said to confirm the presence of goldenseal, black
cohosh, and ginkgo in the herbal mixture. Other stated ingredients were ground
ivy and oats seed.
The third, fourth, and fifth publications detail single case reports from the
United States. One report describes 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 black cohosh was discontinued, and a tapering steroid
course was instituted. Complete resolution of symptoms occurred within two
weeks, and resolution of the abnormal liver function tests (LFTs) occurred
within nine weeks. Follow-up liver chemistries remained normal two months after
steroids were discontinued. However, at four months, the woman returned with
a complaint of jaundice and fatigue. LFTs revealed AST 1260 U/L, ALT 1694 U/L,
and bilirubin 9.2 mg/dL. The patient experienced rapid improvement on a second
course of steroids, and long-term azathioprine was begun. The authors claimed
that none of the patient's other medications have ever been implicated
as triggers for autoimmune hepatitis, but provided no information as to whether
these drugs were maintained or withdrawn from the patient. Rechallenge with
black cohosh was not undertaken.
The next 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
were all 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 after she
failed to respond to initial treatment and the explanted liver showed features
of acute hepatitis. No further details concerning the black cohosh usage by
the patient (or its cessation) were provided, and a rechallenge was probably
The most recently published case report (Case 5) describes a 54-year-old woman
who presented with an eight-week history of fatigue, forgetfulness, and a ten-pound
unintentional weight loss.6 Her medications included levothyroxine 100 mcg
daily and 1000 mg of black cohosh (product not specified). The patient had
been taking the black cohosh product for eight months. She had been drinking
about two glasses of wine nightly for several years. AST was 1014 U/L, and
ALT came in at 1003 U/L. Bilirubin was mildly elevated at 2.4 mg/dL. Tests
for standard infectious causes of liver disease were all negative, as were
those for other likely causes. The patient deteriorated while in hospital and
died during a liver transplant operation.
The authors attributed the cause of the liver damage to black cohosh, but also
acknowledged that it was possible that the patient had pre-existing cryptogenic
cirrhosis or marker-negative autoimmune liver disease. The biopsy was suggestive
of autoimmune hepatitis or drug-induced chronic hepatitis with autoimmune features.
This case (Case 5) was first presented as a conferenc e report in 2004.7 Unfortunately,
there are significant inconsistencies between the published and oral versions
of this case report. The conference report lists the patient's concurrent
medications as fluoxetine, propoxyphene, and acetaminophen, as well as the
black cohosh and levothyroxine mentioned in the published report. Also, the
time of black cohosh use is stated as about three months in the conference
presentation, and the patient did apparently test positive for hepatitis B
surface antibody and herpes simplex virus IgM. The patient had travelled to
Mexico seven months earlier.
Background to Drug-Induced Idiosyncratic
The phenomenon of idiosyncratic hepatic reactions to drugs is well-documented.
It also appears that 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.8 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.8 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.8
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 are still to be identified,9 and there are
no tests for them. Tests are not always done for even known viruses. For example,
a Dutch study published this year found that Hep E virus was a significant
cause of unexplained hepatitis.10 Occult celiac disease has been suggested
as a cause of unexplained raised alanine aminotransferase (ALT)and aspartate
aminotrasferase (AST) levels.11 Rare liver diseases may not be excluded.12,13
Hair dye was a cause of DILI in a Japanese man.14 Other environmental factors
could be implicated.
Confusion with Idiopathic Hepatitis?
The experience of a liver transplant unit, which has been recently 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 about
38 years. Most cases were due to acetaminophen poisoning (36%) or idiopathic
hepatitis (34%).15 Only five of the 80 cases were classified as drug-induced,
making this causality a rare factor. Other main causes included hepatitis
A (three cases), hepatitis B (eight cases), and Wilson's disease (six
cases). The 27 cases (34%) of hepatitis due to unknown causes (idiopathic)
is a staggering rate. These cases are also described as non-A non-B hepatitis,
since patients are not positive for hepatitis A or B. In the USA, one study
found that the most common cause of FHF was non-A non-B (idiopathic) hepatitis.16
(Note that this US study was published in 1995, well before the dramatic
rise in herbal use in that country.) Presumably unidentified infections or
environmental factors could cause these cases of idiopathic hepatitis. However,
the authors of the Australian study state the following:
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 demographics of idiopathic hepatitis (female, late 30s to early
50s) and black cohosh use strongly overlap. Hence, there is a distinct
possibility that some patients who develop idiopathic hepatitis might
also be coincidentally taking black cohosh. The herb could then be
mistakenly attributed as the cause.
Analysis of the Published Case Reports
The published 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 the TGA identified black cohosh 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
The issue of the botanical authenticity of black cohosh products in the US
has been highlighted by a recent publication.17 Of 11 black cohosh products
tested, three were found to be from the wrong species (Asian species of Actea),
and one was a mixture of both black cohosh and an Asian Actea species. For
the seven products containing only authentic black cohosh, there was significant
product-to-product variability in phytochemical constituents.
The features of Case 1 are baffling. Since the problem reportedly developed
after one week of taking black cohosh, this would have to be a hypersensitivity
reaction if the herb was truly the cause. Yet the patient lacked any features
of a hypersensitivity reaction (rash, fever, systemic reaction, eosinophilia).
In fact, eosinophilia was specifically stated to be absent. Furthermore, the
explant liver showed signs of early fibrosis, a phenomenon that could only
develop after months of exposure to the causative agent. Clearly, on the evidence
provided, one week of black cohosh is the least likely cause of the patient's
For Case 3, the authors claimed that none of the drugs the patient was taking
have been linked to autoimmune hepatitis. Yet a simple search revealed several
cases for labetalol, where this drug may have indeed caused an idiosyncratic
autoimmune hepatitis, including one overview report of 11 cases from the US
FDA.18-20 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 Australian
publications. In their discussion, they attribute to black cohosh the presence
of hepatotoxic alkaloids and salicylates. Such attributions are nonsensical,
are unsupported by the literature,21 and above all cast doubt on the credibility
and diligence of their overall analysis of the case.
Additional problems with the five cases include the lack of positive identification
of black cohosh as the true 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.
By Case 5, the literature evidence of an association between black cohosh and
liver damage was considered to be so strong by the authors that they confidently
identified black cohosh as the causative agent. This was despite their admission
that other causes were possible. Furthermore, the inconsistencies already noted
in the reporting of this case (conference report versus published article)
create a great deal of uncertainty over the link to black cohosh. In particular,
the cocktail of medications and alcohol that the patient was taking (according
to the conference report) could well explain the hepatotoxic effect.22
Analysis of All Current Case Reports
As mentioned earlier, in addition to the published reports, there are around
40 to 50 case reports of liver reactions to black cohosh that have been recorded
by various government health authorities around the world. The European Medicines
Agency Committee on Herbal Medicinal Products (HMPC) recently analyzed these
cases, together with the published cases. Based on their evaluations, the
HMPC concluded the following:22
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 racemosae
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.
Of these four cases, only two were
rated as "probable" using
the Roussel UCLAF Causality Assessment Method (RUCAM). Not surprisingly,
these were two of the published cases (already described in this column
article as Cases 3 and 4). As previously outlined, there are several
flaws in these two case reports, not the least of which was the failure
to identify black cohosh in the products used.
The demographics of patients with non-A non-B (idiopathic) hepatitis closely
match those of the black cohosh user. Hence, the most likely and rational
explanation of some 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,
it is likely that others will follow in a process akin to a self-fulfilling
prophecy. Separate or confounding issues are the common adulteration of black
cohosh products with Asian species of Actea and the coadministration of many
drugs known to cause liver damage. Hopefully, the regulators will not be
motivated to act on such poor-quality case reports. The association of black
cohosh and DILI remains unproven on the current evidence.
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