Liver Injury with Features Mimicking Autoimmune Hepatitis following the Use of Black Cohosh.
ABSTRACT There are a growing number of cases detailing acute hepatic necrosis in patients taking black cohosh (Cimicifuga racemosa), an over-the-counter herbal supplement for management of menopausal symptoms. Our aim is to illustrate two cases of liver injury following the use of black cohosh characterized by histopathological features mimicking autoimmune hepatitis. Both patients reported black cohosh use for at least six months and had no evidence of another cause of liver disease. Their liver biopsies showed a component of centrilobular necrosis consistent with severe drug-induced liver injury. In addition, the biopsies showed characteristics of autoimmune-like liver injury with an interface hepatitis dominated by plasma cells. Although serum markers for autoimmune hepatitis were not particularly elevated, both patients responded to corticosteroids, supporting an immune-mediated component to the liver injury. Liver injury following the use of black cohosh should be included in the list of differential diagnoses for chronic hepatitis with features mimicking autoimmune hepatitis.
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ABSTRACT: Black cohosh extracts (BCE; Actaea racemosa) are being used worldwide as an alternative to hormone replacement therapy for the management of menstrual and menopausal symptoms, yet the effects of BCE on the immune system are largely unknown. Female B6C3F1/N mice were treated daily with BCE (0, 62.5, 125, 250, 500, or 1000mg/kg) for 28 days by oral gavage. Liver weights were significantly increased (26%-32%) at the 1000mg/kg dose. Dose-related increases in mean corpuscular volume and mean corpuscular hemoglobin were observed. Decreasing trends were observed in all thymic T cell populations, with the most notable dose-responsive effects on immature thymocytes. In the spleen, dose-related decreases were observed in all cell phenotypes evaluated, reaching the level of statistical significance at the 1000mg/kg BCE dose. Splenic natural killer (NK) cell numbers were significantly decreased at all BCE doses, with the exception of absolute NK numbers at the 125mg/kg dose. No effects were observed on T-dependent antibody responses of the humoral immune system, including the antibody-forming cell response to sheep erythrocytes (sRBC) and IgM antibody levels to both sRBC and keyhole limpet hemocyanin. Cytotoxic T cell (TCTL) activity was increased, as was the mixed leukocyte response in one of two studies. Anti-CD3 mediated proliferation and the delayed-type hypersensitivity response were unaffected. No effects were observed on innate immunity or on bone marrow cellularity and colony-forming units. Overall, BCE exposure in B6C3F1/N mice for 28 days at doses up to 1000mg/kg had minimal immune effects, with the exception of an increased TCTL response.Toxicology 04/2013; · 4.02 Impact Factor
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ABSTRACT: Herbal and dietary supplement use is common. Most marketed products consist of complex mixtures. Although they are perceived as safe, instances of hepatotoxicity attributable to these products underscore their potential for injury, but the exact component that is responsible for injury is difficult to discern. The lenient regulatory environment in the United States, which opens the possibility of adulteration and contamination, adds to the challenge of disease attribution. Although many different herbal and dietary supplements have been reported to cause liver injury, in the United States, products used for bodybuilding and weight loss are the most commonly implicated.Clinics in liver disease 11/2013; 17(4):715-735.
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ABSTRACT: Background Consumption of herbal supplements in the developed world remains high. Cimicifuga racemosa (C. racemosa) extract, or black cohosh, is widely used as a hormone replacing and an anti-inflammatory agent, and has been shown to cause idiosyncratic hepatitis. The mechanism of acute liver injury in those cases is unclear. To date, hepatotoxic effects of C. racemosa have been studied mostly in vitro and in animal models. Data on human tissue is extremely limited, and mostly confined to histological findings of explanted livers. Methods We evaluated clinical data and examined surgical diagnostic liver biopsy specimens obtained from two female patients, who developed acute submassive liver necrosis, following consumption of C. racemosa. Both patients presented with acute elevation of liver enzymes, cholestasis, absence of reactivity to hepatitis A, B and C antibodies, and weak non-specific positivity for autommune serological markers. Initial histological interpretation of the biopsies, with focus on hepatic parenchyma and portal tracts, was done by light microscopy, followed by special stain series and immunohistochemical studies, including Cam 5.2, AE1/AE3, reticulin, α-actin, sirius red, and PAS with diastase. Areas of prominent lymphocytic infiltration of the periportal liver plate, observed microscopically, were further evaluated by electron microscopy (EM). 4HNE adduction study, an immunofluorescent assay, was performed to detect products of the oxidative damage and their localization in the liver parenchyma. Results Oxidative damage was evident by accumulation of 4HNE protein adducts in the cytoplasm of hepatocytes, secondary lysosomes and macrophages. We hypothesize that the adducted proteins, accumulated in the liver parenchyma, serve as autoantigens, which provoke an autoimmune response, and cause migration of lymphocytes to the affected regions. The formation of immunological synapses between hepatocytes and lymphocytes, predominantly T-lymphocytes, is demonstrated by electron microscopy. The autoimmune response induces piecemeal, or troxis necrosis of hepatocytes, a well described biological phenomenon, where lymphocytes gradually remove hepatocytes in a piecemeal fashion, slowly consuming them and leaving fragments of liver cells, or nubbins of anuclear cytoplasm of liver cell, at the interface between lymphocytes and hepatocytes. Conclusion The pattern of pathological injury of liver cells in both patients, following consumption of black cohosh, is identical to troxis necrosis, seen during autoimmune hepatitis. Recognition of the possibility of the acute hepatic injury by the herbal supplement black cohosh is essential for early accurate diagnosis, and timely patient management.Experimental and Molecular Pathology 01/2014; · 2.13 Impact Factor
Hindawi Publishing Corporation
Case Reports in Medicine
Volume 2009, Article ID 918156, 8 pages
followingtheUseof Black Cohosh
Grace Guzman,1Eric R. Kallwitz,2Christina Wojewoda,3Rohini Chennuri,1Jamie Berkes,2
Thomas J. Layden,2andScott J. Cotler2
1Department of Pathology, University of Illinois, Chicago, IL 60612, USA
2Department of Medicine, University of Illinois, Chicago, IL 60612, USA
3Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
Correspondence should be addressed to Grace Guzman, email@example.com
Received 21 July 2009; Accepted 11 November 2009
Recommended by Anne M. Larson
There are a growing number of cases detailing acute hepatic necrosis in patients taking black cohosh (Cimicifuga racemosa), an
over-the-counter herbal supplement for management of menopausal symptoms. Our aim is to illustrate two cases of liver injury
following the use of black cohosh characterized by histopathological features mimicking autoimmune hepatitis. Both patients
reported black cohosh use for at least six months and had no evidence of another cause of liver disease. Their liver biopsies
showed a component of centrilobular necrosis consistent with severe drug-induced liver injury. In addition, the biopsies showed
characteristics of autoimmune-like liver injury with an interface hepatitis dominated by plasma cells. Although serum markers for
component to the liver injury. Liver injury following the use of black cohosh should be included in the list of differential diagnoses
for chronic hepatitis with features mimicking autoimmune hepatitis.
Copyright © 2009 Grace Guzman et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Black cohosh (Cimicifuga racemosa) is an herbal supplement
that is sold over-the-counter for management of menopausal
symptoms, menstrual irregularities, and arthritis. There are
now a number of manuscripts indicating liver injury from
black cohosh [1–7]. Here, we present two patients who
developed a drug-induced liver injury following the use of
black cohosh characterized by centrilobular necrosis and
histologic features mimicking autoimmune hepatitis (AIH)
who improved with corticosteroid therapy.
The case series was approved by the Institutional Review
Board at the University of Illinois at Chicago.
Case 1. A 42-year-old woman presented to her primary care
provider with a two-month history of progressive malaise,
nausea, vomiting, and dizziness. On physical examination,
she had mild icterus and no stigmata of chronic liver disease.
Her only comorbidity was hypothyroidism. Her medications
included black cohosh, which she was taking for 6 months,
and levothyroxine 0.05mg daily. She discontinued black
of liver or autoimmune disease. She denied any alcohol or
drug use. Her total bilirubin level was 3.1mg/dL (normal
0.8–1.2), alanine transaminase (ALT) 1457U/L (normal 5–
40), aspartate transaminase (AST) 696U/L (normal 10–40),
alkaline phosphatase (ALP) 94U/L (normal 30–120U/L),
and international normalized ratio (INR) 1.2 (normal 0.8–
1.2). Further laboratories showed no serological evidence
of active hepatitis A, B, or C infection. Serological titers
for acute cytomegalovirus (CMV) and Epstein Barr virus
(EBV) were negative. Antinuclear antibody (ANA) was 1 :
40 and smooth muscle antibody was modestly elevated at 1
: 80. Serum iron was 169µg/dL (normal: 50 to 170µg/dL for
women), ferritin was 642ng/dL (normal: 15–200ng/mL for
females), and hemochromatosis gene analysis was negative.
Ceruloplasmin was in the normal range.
2Case Reports in Medicine
Figure 1: This liver biopsy from Case 1 displays chronic hepatitis
remarkable for its dense interface activity with cholangiolar prolif-
eration (1a) (×200) and sheets of plasma cells and apoptosis (1b)
Four months after her initial presentation, the liver
enzymes remained elevated with an ALT of 334U/L, AST
229U/L, and a total bilirubin of 1.4mg/dL. A liver biopsy
was performed which prompted a referral to the liver
center at the University of Illinois. The liver biopsy was
remarkable for necrosis around terminal hepatic venules,
lobular disarray, mild ballooning, apoptosis, Kupffer cell
reactivity, mild cholangiolar proliferation, and interface hep-
atitis remarkable for numerous plasma cells and eosinophils.
A repeat antismooth muscle antibody was normal at 1 : 20.
Prednisone treatment was initiated. A follow-up liver biopsy
was performed after three months. At this time, the liver
histology demonstrated chronic hepatitis with fibroinflam-
matory expansion of portal tracts by moderate plasma cell
rich interface hepatitis, rare periportal hepatocyte apoptosis,
and mild cholangiolar proliferation (Figures 1(a) and 1(b)).
The patient was started on azathioprine. Her liver enzymes
returned to normal values within five months with an ALT of
30U/L, AST of 29U/L, ALP 36U/L, and a total bilirubin of
0.9mg/dL. A repeat liver biopsy after fifteen months showed
and no other significant histopathological changes. The liver
function test values remained normal at 15 months and at 40
months following the acute episode. The clinicopathological
features of Case 1 are illustrated in Tables 1, 2, and 3.
Case 2. A 53-years-old woman presented to our liver center
for evaluation of elevated liver enzymes detected at a health
screening fair four months earlier. She had no risk factors for
viral hepatitis, no family history of liver disease, and denied
any alcohol consumption. Although she was initially asymp-
tomatic, she developed right upper quadrant abdominal
pain, fatigue, and lower extremity edema by the time of her
presentation. Her medical history was remarkable only for
irritable bowel syndrome. Her medications within the past
year included dicyclomine for abdominal cramps as needed,
an herbal supplement which contains soy protein and black
cohosh for menopausal symptoms, and occasional over the
counter nonsteroidal anti-inflammatory drugs (NSAIDs) for
pain. She discontinued these medications on the advice of
her primary care physician. Laboratories showed a total
bilirubin of 2.0mg/dL, ALT 443U/L, AST 478U/L, ALP
188U/L, and an INR of 2.0. Other notable laboratory values
included negative serological evidence of active hepatitis
A, B, and C viral infection, undetectable hepatitis C virus
RNA by PCR, iron 137µg/dL, ferritin 1527ng/mL, negative
hemochromatosis gene analysis, and nonsignificant cerulo-
plasmin level. Serological tests for antinuclear, antismooth
muscle, antiliver kidney microsomal, and antimitochon-
drial antibodies were negative. An ultrasound demonstrated
patent portal and hepatic veins and a normal appearing liver.
Her liver biopsy was remarkable for centrilobular necrosis
with moderate cholangiolar proliferation and plasma cell
rich interface and lobular hepatitis.
The patient was started on 40mg of prednisone daily.
Liver function test values improved to a total bilirubin of
1.4mg/dL, ALT of 60U/L, AST 50U/L, and ALP 153U/L
after two weeks and normalized after five weeks of therapy.
The clinicopathological features of Case 2 are illustrated in
Tables 1, 2, and 4.
3.Application of the NaranjoCausality
Score for AdverseDrugReactions
The Naranjo causality score for adverse drug reactions 
was applied to the cases described here. As shown in Table 5,
of 3 and were both categorized as “possible adverse drug
reaction”, in a scale encompassing a minimum score of zero,
or “doubtful adverse drug reaction” to a maximum score of
≥9 , or “definite adverse drug reaction.”
While the current case studies showed histopathological
features of autoimmune hepatitis, neither fulfilled a diag-
nosis of “probable AIH” or “definite AIH” based on the
Hennes simplified criteria for diagnosis of AIH . Briefly,
Case 1 had an ANA titer of up to 1 : 80 (score 2), no
available immunoglobulin titers (no score), a liver histology
compatible with AIH (score 1), and absence of viral hepatitis
(score 2), with a total score of 5. Case 2 had a score of 1-0-1-2
= 4, on a scale where a score of ≥6 was designated “probable
AIH”, and ≥7 as “definite AIH.”
Botanical dietary supplements are used commonly in the
United States and are generally perceived to be safe .
In one study, nearly one half of persons reported use
of at least one agent to their primary provider . A
major difficulty in studying black cohosh is uncertainty
regarding the composition of the various black cohosh
compounds including phenolic derivatives and triterpene
glycosides . Phytoestrogens were postulated to play a
role in black cohosh binding to estrogen receptors, but
the presence of these compounds is controversial. In one
study, chromatographic analysis of 11 commercial black
Case Reports in Medicine3
Table 1: Current case studies: clinical features and medications.
Progressive malaise, nausea
RUQ∗∗abdominal pain, fatigue
Lower extremity edema
OTC with soy and black cohosh
GI cramps; pain
Stigmata of CLD
LFTs: Liver function tests.
RUQ: Right upper quadrant.
CLD: Chronic liver disease.
OTC: Over the counter drug.
NSAID: Nonsteroidal anti-inflammatory drug.
Table 2: Current case studies: past medical history, serological tests, and other pertinent laboratory data.
Past medical history
Viral or non-viral hepatitis
HBV surface antigen
EBV Ca IgM
EBV Ca IgG
EBV Na IgG
HCV RNA PCR
Other laboratory values
Iron (normal: 50–70µg/dL for women)
Ferritin (normal: 15–200ng/mL in women)
HFE gene analysis
cohosh products showed that three were actually Asian Actea
species . An analysis of the remaining eight products
found variability in the composition of triterpene glycosides
and phenolic constituents. More importantly, not a single
product contained a phytoestrogen. Thus, the mechanism by
which black cohosh might impact on alleviating menopausal
symptoms is not well understood. Other possibilities include
binding to yet-to-be-defined receptors or effects on the
central nervous system . Whether black cohosh is
effective in controlling vasomotor symptoms of menopause
is controversial as well. The American College of Obstetrics
and Gynecology included black cohosh as a possible remedy
for the vasomotor symptoms of menopause . A large
randomized-blinded trial of one-year duration found no
difference between black cohosh and placebo in controlling
vasomotor symptoms . Moreover, a recent review did
not recommend long-term use due to the absence of safety
There are a growing number of case reports of hep-
atotoxicity in patients taking black cohosh (Table 6) [1–
7]. Most described acute hepatic necrosis, although three
articles of them detailed a case with clinical features of
4Case Reports in Medicine
Table 3: Duration of Illness and black cohosh use, liver function tests, autoimmune markers, histology, and treatment.
Time of use to illness: 6 mo∗∗↓
Time of use to discontinuation: 6 mo∗∗↓
Time of presentation to the liver clinic∗
Duration of illness in months
Liver function tests (normal)
Total bilirubin (0.8–1.2mg/dL)
Antismooth muscle antibody
Liver biopsy findings
Portal and periportal
Infiltrate predominant type
1 : 40
1 : 80
1 : 20
Acute hepatitisChronic hepatitisBiopsy at 15mo.
Central & portal
Mixed with eosinophils
Disarray, ballooning Apoptosis
No significant abnormality
Mixed with eosinophils
autoimmune hepatitis after black cohosh use [1, 2, 5]. The
clinicopathological features of the cases in the current series
have a fascinating combination of findings. Both patients
presented with an acute hepatitis displaying prominent
centrilobular necrosis consistent with severe drug-induced
liver injury. While autoantibodies were low titer or absent,
with a plasma cell rich interface and lobular hepatitis.
In addition, both patients responded to corticosteroids,
supporting an immune mediated component to the liver
Determining the risk of black cohosh hepatotoxicity
is further complicated by variability in both dosage and
number of other botanical herbal supplements contained
in some preparations. As an example, in the case reported
by Lontos , the preparation of black cohosh included
4 other botanicals: ground ivy, golden seal, gingko, and
oat seeds. While liver injury remains unreported with the
use of the last 3 botanicals, ground ivy contains a known
hepatotoxin, pulegone. This case culminated in liver failure
despite discontinuation of the herbal supplement .
Drug interactions might further potentiate negative
outcomes resulting from hepatoxicity due to herbal supple-
like liver injury following consumption of black cohosh
(Table 6) also had concomitant intake of synthetic thyroid
hormone, levothyroxine, merits attention [2, 5]. Herbal
supplements such as venencapsan and black cohosh, and
prescription drugs specifically rosiglitazone, ritonavir, and
valproic acid, have had reported drug interactions with
levothyroxine [1, 9, 18–22].
A 2008 review by Mahady assigned all known case
reports of black cohosh-induced liver injury under the
category of “possible causality” . As earlier stated, both
cases of the current study were also assigned “possible
causality” by Naranjo scale . Although no clinical or
animal pharmacokinetic or toxicological information were
identified in the Mahady review, it led to the inclusion of a
cautionary statement on black cohosh products which was
not previously required . Despite such development, the
use of botanical dietary supplements is generally viewed
by the public as safe . Providers are encouraged to
screen patients about their consumption of botanical herbal
supplements and to assess for any evidence of liver injury
. Timely discontinuation of hepatotoxic agents and, in
significant liver injury or could even be life saving .
The validity of reported cases of liver injury due to black
cohosh illustrated in Table 6 has been disputed. Concerns
that led to this uncertainty included cases in which the
timing of liver injury occurred at a relatively short interval
following exposure to black cohosh [2, 6, 7], presence of
comorbidities such as cholelithhiasis  or concomittant use
of drugs other than black cohosh that could have potentially
Case Reports in Medicine5
Table 4: Duration of Illness and black cohosh use, liver function tests, autoimmune markers and histology.
Time of use to illness: 8 months∗
Time of use to discontinuation: 8 months∗
Time of presentation to liver clinic∗
4.5 Duration in months45
Liver function tests (normal values)
Total bilirubin (0.8–1.2mg/dL)
Anti-smooth muscle antibody
Liver biopsy findings
1 : 20
Portal and periportal
Infiltrate predominant type
Table 5: Naranjo  Causality Scale for Adverse Drug Reactions.
Question/Scoring-Yes/No/Do not know or unavailable
Are there previous conclusive reports on this reaction? 1/0/0
Did the adverse event appear after the suspected drug was
Did the adverse reaction improve when the drug was
discontinued or a specific antagonist was given? 1/0/0
Did the adverse reaction appear when the drug was
Are there alternative causes that could have caused the reaction?
Did the reaction reappear when a placebo was given? −1/1/0
Was the drug detected in any body fluid in toxic concentrations?
Was the reaction more severe when the dose was increased/
increasing, or less severe when the dose was decreased? 1/0/0
Did the patient have a similar reaction to the same or similar
drugs in any previous exposure? 1/0/0
Scoring: >9 : definite adverse drug reaction (ADR).
5–8 : probable ADR.
1–4 : possible ADR.
0 : doubtful ADR.
6Case Reports in Medicine
Table 6: Similarities and differences among current case studies and published cases of black cohosh hepatotoxicity.
Whiting Case 1∗Whiting Case 2∗Lontos∗
Current study Case 1##
study Case 2
ground ivy#, golden seal,
presence of other
presence of other
Acute hepatitis Acute hepatitis RUQ pain
Main liver biopsy
Acute hepatitisMassive liver
Case Reports in Medicine7
Table 6: Continued.
Whiting Case 1∗Whiting Case 2∗Lontos∗
Current study Case 1##
study Case 2
LF s/p d/c black
marker for AIH
validity of black
Drug use for
only 6 days
Multi drug use
7 day use;
∗Cases adapted from Table 1 Lynch ; ALF: Acute liver failure; RUQ: Right upper quadrant pain.
OLT: Orthotopic liver transplant; LF: Liver failure.
#Herbal remedies known as hepatotoxic;##Also reported by Mahady ; AIH: Autoimmune hepatitis.
8Case Reports in Medicine
triggered the adverse drug reaction [3, 4, 7], or the notion
that some of the reported cases , including Case 1 of the
current study (also reported by Mahady ), were indeed
examples of autoimmune hepatitis rather than adverse drug
reactions. Nonetheless, application of the Naranjo causality
score to these case reports found possible cause for adverse
drug reaction . Further, autoimmune hepatitis is one
of the known outcomes of drug-induced liver injury. The
immune mechanism is precipitated by a drug or a metabolite
acting as a hapten covalently binding to host cellular protein,
converting into an immunogen  and thereby eliciting an
autoimmune response. Outcomes illustrating an association
of chronic hepatitis with autoimmune features developing
following the use of the botanical supplement black cohosh
need to be emphasized.
Here we described two cases of liver injury following the
use of black cohosh characterized by chronic hepatitis with
centrilobular necrosis and an interface activity dominated
by plasma cells. While the histopathology in both cases was
compatible with autoimmune hepatitis, clinical evidence for
an autoimmune etiology was lacking. Nonetheless both cases
improved upon withdrawal of the drug and immunosup-
pressive therapy, indicating that there was at least in part a
drug-induced immunological basis to the liver injury.
The current case studies, and three other published
cases of liver injury following the use of black cohosh,
share similar histological characteristics [1, 2, 5]. Hepatic
manifestations following the use of black cohosh should
therefore be added to the list of differential diagnoses of
hepatic necrosis culminating in chronic hepatitis mimicking
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