Autoimmune hepatitis associated with the use of black cohosh:
a case study
Stanley M. Cohen, MD, Anne M. O’Connor, MD, John Hart, MD, Nina H. Merel, MD,
and Helen S. Te, MD
Herbal remedies generate more than $1.8 billion in annual sales in the United States. Herbal
Health Initiative Study demonstrating increased risk of breast cancer and cardiovascular events
pause symptoms. We report a case of autoimmune hepatitis likely triggered by the use of black
cohosh (Actaea racemosa), an agent marketed to treat menopause symptoms. Given this case re-
port, we recommend close monitoring of women using this herbal preparation.
Key Words: Black cohosh – Actaea racemosa – Autoimmune hepatitis – Complementary and
alternative medications – Phytoestrogens.
is associated with an increased risk of breast cancer,
cardiovascular events, strokes, and pulmonary em-
boli.1Based on this data, many women have discontin-
ued or been taken off hormone therapy. Some women
have resorted to the use of phytoestrogens and other
herbal supplements. Herbal products have been associ-
ated with a wide spectrum of hepatic toxicity. We re-
port the first case of autoimmune hepatitis likely trig-
strogen and related compounds have been
used to relieve symptoms associated with
menopause. However, recent data from the
Women’s Health Initiative (WHI) have
A 57-year-old woman presented with a 2-week his-
tory of lethargy and fatigue. Her past history was sig-
nificant for diabetes, polymyositis, obstructive sleep
apnea, and hypertension. She had no history of liver
disease. Her medications (all of which had been used
for more than 2 years) included labetalol, fosinopril,
verapamil, metformin, aspirin, and insulin. She also
had been on hormone therapy with estrogen and pro-
gesterone for several years; however, this was discon-
tinued by her physician 6 months earlier based on data
from the WHI study. Three weeks before presentation,
brand or dose) for hot flashes. She had no history of
allergies. Family history revealed no liver disease or
autoimmune diseases. The woman denied using alco-
hol, tobacco, or drugs. She had no history of transfu-
sions, tattoos, recent travel, or contact with others who
were ill. A review of systems was otherwise negative.
Physical examination was completely unrevealing.
Laboratory data revealed significant elevations in
the aspartate aminotransferase (AST) and alanine ami-
count (CBC), electrolytes, albumin, and bilirubin were
normal. Liver tests 9 months earlier had been normal.
Serologies for hepatitis A, B, and C were negative. An-
tinuclear antibody titer was positive at 1:640, homoge-
neous pattern. An antinuclear antibody (ANA) titer
from 4 years earlier had been negative. Smooth muscle
sound with Dopplers was unrevealing. Liver biopsy re-
Received January 8, 2004; revised and accepted February 18, 2004
University of Chicago, Division of Gastroenterology, Liver Study Unit,
Address correspondence to: Stanley Martin Cohen, MD, Rush Univer-
sity Medical Center, Section of Hepatology, 1725 W. Harrison St., Suite
158, Chicago, IL 60612, USA. E-mail: firstname.lastname@example.org.
Menopause: The Journal of The North American Menopause Society
Vol. 11, No. 5, pp. 575-577
© 2004 The North American Menopause Society
? ? Text printed on acid-free paper.
Menopause, Vol. 11, No. 5, 2004 575
vealed piecemeal necrosis and lobular infiltrates with
extensive plasma cells and eosinophils (Fig. 2).
to black cohosh, was the clinical diagnosis. The black
cohosh was discontinued, and a tapering steroid course
was instituted. Complete resolution of symptoms oc-
curred within 2 weeks, and resolution of the abnormal
liver function tests (LFTs) occurred within 9 weeks.
after steroids were discontinued. However, at 4
months, the woman returned with a complaint of jaun-
dice and fatigue. LFTs revealed AST 1260 U/L, ALT
1694 U/L, and bilirubin 9.2 mg/dL. The woman had
rapid improvement on a second course of steroids.
Long-term azathioprine was begun.
Herbal remedies generate more than $1.8 billion in
and alternative medication, and 67% have used such
these agents are exempt from proof of efficacy and
poorly standardized. Other obstacles include differ-
ences in composition of the products, variation in tech-
niques of extracting the herbs, and a general lack of
randomized, placebo-controlled studies.
to,7,8have previously been shown to cause or trigger
the development of autoimmune hepatitis. Outcomes
including complete resolution after cessation of the of-
fending agent, complete resolution after a short course
of steroids, and long-term disease requiring prolonged
immunosuppression (such as that demonstrated in the
current case) have been reported.
Black cohosh (known as Actaea racemosa or Cimi-
cifuga racemosa), the 14thbest-selling herbal product
in the United States, is reported to improve symptoms
of menopause. It was initially used as an anti-
inflammatory, analgesic, and antipyretic agent. It was
used in Europe in the early 19thcentury to treat endo-
metriosis, amenorrhea, dysmenorrhea, and threatened
abortions. The pharmacologically active ingredients
are extracted from the roots and rhizomes. The most
commonly used preparation is Remifemin.
The exact mechanism of action of black cohosh is
unknown. Although marketed as a phytoestrogen,
Conflicting data exist on black cohosh’s ability to bind
cohosh in alleviating symptoms of menopause. Of four
randomized, controlled trials,11,12,15,16three demon-
strated short-term benefits in treating hot flashes and
other menopause symptoms. The trials were limited by
small sample sizes and short follow-up. Rigorous ran-
domized, controlled trials evaluating efficacy are still
lacking. Despite the uncertainty, the American College
Side effects of black cohosh are reported to be mild
and rare. Stomach discomfort occurs in up to 7% of
users. Hepatic side effects are difficult to characterize.
Several cases seem to have been simultaneously re-
FIG. 1. Graph showing significant elevations in the aspartate amino-
transferase (AST) and alanine aminotransferase (ALT) levels, with only
a mildly elevated alkaline phosphatase.
eosinophils. Lobular infiltrates were also present (hematoxylin-eosin,
COHEN ET AL
Menopause, Vol. 11, No. 5, 2004
ported to different regulatory agencies. The reports are Download full-text
often anecdotal in nature. In addition, several people
were taking multiple herbal products simulta-
able solely to black cohosh include one case of acute
liver failure, two cases of “hepatitis” (no further clari-
We report the first case of autoimmune hepatitis
likely induced by the use of black cohosh. In the ab-
sence of a rechallenge trial (which would be definitive,
but unethical), several lines of evidence support black
cohosh as the causative agent. First, the International
Autoimmune Hepatitis Group diagnostic score20was
18, indicating “definite” autoimmune hepatitis. Sec-
ond, the correct temporal relationship occurred be-
tween exposure to the agent and the development of
disease. Third, the woman developed a strongly posi-
tive ANA. Fourth, a liver biopsy revealed features of
both autoimmune (piecemeal necrosis with plasma
titis. And finally, a rapid initial response to steroid
therapy was observed. Other possible etiologies of the
autoimmune hepatitis seem unlikely. Given the low
overall incidence of this disease in the general popula-
and a lack of other autoimmune conditions, coinciden-
of the woman’s other medications have ever been im-
plicated as triggers for autoimmune hepatitis, and all
had been present for more than 2 years. In addition,
withdrawal of estrogen and progesterone has never
been associated with the development of autoimmune
The use of herbal products is ubiquitous in the
United States. Although considered “natural,” these
agents are not without possible adverse effects. People
are often reluctant to disclose their use, and physicians
are often lacking in their inquiries into the use of these
agents. Given the results of the WHI, the use of herbal
remedies for menopause symptoms may potentially in-
crease. The present case provides evidence that black
cohosh may be associated with the development of sig-
mune hepatitis should be considered when liver dys-
function or systemic symptoms develop in people
taking black cohosh.
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