Original article 1

Herbal hepatotoxicity: suspected cases assessed for

alternative causes
Rolf Teschkea, Johannes Schulzeb, Alexander Schwarzenboecka, Axel Eickhoffa
and Christian Frenzelc
Background and objectives Alternative explanations are
common in suspected drug-induced liver injury (DILI) and
account for up to 47.1% of analyzed cases. This raised the
question of whether a similar frequency may prevail in
cases of assumed herb-induced liver injury (HILI).
Methods We searched the Medline database for the
following terms: herbs, herbal drugs, herbal dietary
supplements, hepatotoxic herbs, herbal hepatotoxicity, and
herb-induced liver injury. Additional terms specifically
addressed single herbs and herbal products: black cohosh,
Greater Celandine, green tea, Herbalife products,
Hydroxycut, kava, and Pelargonium sidoides. We retrieved
23 published case series and regulatory assessments
related to hepatotoxicity by herbs and herbal dietary
supplements with alternative causes.
Results The 23 publications comprised 573 cases of
initially suspected HILI; alternative causes were evident in
278/573 cases (48.5%). Among them were hepatitis by
various viruses (9.7%), autoimmune diseases (10.4%),
nonalcoholic and alcoholic liver diseases (5.4%), liver injury
by comedication (DILI and other HILI) (43.9%), and liver
involvement in infectious diseases (4.7%). Biliary and
pancreatic diseases were frequent alternative diagnoses
(11.5%), raising therapeutic problems if specific treatment

Introduction
Patients with herb-induced liver injury (HILI) and druginduced liver injury (DILI) usually have a good prognosis,
but acute liver failure with a lethal outcome or the
requirement for a liver transplant rarely may occur [15]. As
a specific and valid diagnostic laboratory marker is lacking,
the diagnosis of HILI and DILI requires a thorough clinical
assessment and an appropriate diagnostic algorithm that
considers specific hepatotoxicity characteristics [6,7].
In case series of initially assumed DILI, alternative diagnoses
are common [822] and may account for up to 47.1% in one
study evaluating the accuracy of hepatic idiosyncratic
adverse drug reactions initially identified in 138 patients of
an English health region [10]. In this report, primary
underlying diagnoses included common bile duct stone,
ischemic hepatitis, autoimmune hepatitis, sepsis, alcoholic
liver disease, Gilberts syndrome, hepatitis because of
cytomegalovirus and Epstein Barr virus infections, steatosis,
postictal state, lymphoma, paracetamol overdose, cholangitis,
thyrotoxicosis, hepatitis C cirrhosis, and cryptogenic cirrhoc 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
0954-691X

is withheld; pre-existing liver diseases including cirrhosis

(9.7%) were additional confounding variables. Other
diagnoses were rare, but possibly relevant for the
individual patient.
Conclusion In 573 cases of initially assumed HILI, 48.5%
showed alternative causes unrelated to the initially
incriminated herb, herbal drug, or herbal dietary
supplement, calling for thorough clinical evaluations and
appropriate causality assessments in future cases of
c
suspected HILI. Eur J Gastroenterol Hepatol 00:000000
2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
European Journal of Gastroenterology & Hepatology 2013, 00:000000
Keywords: hepatotoxic herbs, herb-induced liver injury, herbal
hepatotoxicity, herbal medicine, herbs
a
Department of Internal Medicine II, Division of Gastroenterology and
Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty,
b
Institute of Industrial, Environmental and Social Medicine, Medical Faculty,
Goethe University, Frankfurt/Main and cDepartment of Medicine I, University
Medical Center, Hamburg-Eppendorf, Germany

Correspondence to Rolf Teschke, MD, Department of Internal Medicine II,

Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic
Teaching Hospital, Medical Faculty, Goethe University of Frankfurt/Main,
Leimenstrasse 20, D-63450 Hanau, Germany
Tel: + 49 6181 21859; fax: + 49 6181 2964211; e-mail: rolf.teschke@gmx.de
Received 30 November 2012 Accepted 15 February 2013

sis. In an additional 15.2% of the cases, the cause was

indeterminate, whereas in only 37.7% of the cases were the
reactions considered to be drug related [10]. In another
DILI study, 40% of the initially identified 110 patients were
eventually classified as having drug-related hepatotoxicity,
38.2% with alternative causes, 16.4% lacking a causal relation
with any drug, and 5.4% with a drug overdose problem [9].
In this study, we analyzed case series of HILI to assess
the frequency and features of alternative causes unrelated to the use of herbs, herbal drugs, and herbal dietary
supplements.

Patients and methods

Literature search

We searched the Medline database with the following

terms: herbs, herbal drugs, herbal dietary supplements,
hepatotoxic herbs, herbal hepatotoxicity, herb-induced
liver injury, black cohosh, Greater Celandine, green tea,
Herbalife products, Hydroxycut, kava, and Pelargonium sidoides
for the period from January 2001 until September 2012. For
DOI: 10.1097/MEG.0b013e3283603e89

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2 European Journal of Gastroenterology & Hepatology 2013, Vol 00 No 00

each term, we used the first 50 publications consisting of

single case reports, case series, regulatory assessments, and
review articles; on the basis of these publications, we
reviewed the lists of references, selected those publications
relevant to the aim of our study, and retrieved 141 English
language publications related to herbal hepatotoxicity.

Publication selection

Initial assessment of the 141 publications indicated that

single case reports and review articles did not address
alternative diagnoses in HILI cases. We therefore
analyzed publications with case series and regulatory
assessments. Twenty-three publications contained either
specified alternative causes as diagnoses, or at least
causality gradings of excluded, unlikely, unrelated, or
possible for the individual herb or herbal dietary
supplement, implicating alternative causes, which were
not specifically presented as diagnoses [2345]. Details
were not sufficiently documented in other publications of
HILI [4651] related to Greater Celandine [46], numerous herbs [47,49], kava [48], green tea extracts [50], and
Polygonum multiflorum [51]; these publications were therefore excluded. In the 23 publications, causality assessment for HILI cases was performed using the ad hoc
approach [52], the WHO global introspection method
(WHO method) [53], the scales of Naranjo [54] and of
the Council for International Organizations of Medical
Sciences (CIOMS) [6,7,55], the method of the DrugInduced Liver Injury Network (DILIN) [20,39], or the
Karch and Lasagna (K&L) method [56].
Table 1

Assessment approach

In all 23 case series with suspected HILI, established

diagnoses as alternative explanations were researched by
quantitative and qualitative evaluation [2345]. Diagnoses for alternative causes were reported in most
publications, occasionally with more than one specific
alternative diagnosis given [2326,3032,3545]. Four
publications presented the alternative diagnoses for only
some of their cases [2729,34]; one publication did not
provide this information [33].

Results
Initially suspected herb-induced liver injury cases with
alternative causes

All 23 publications of suspected HILI provided evidence

for alternative explanations other than the incriminated
herbal drugs or herbal dietary supplements (Table 1). In
19/23 publications, the focus was on HILI cases by a single
herb; in one publication, it was on HILI by various herbs,
and in three publications on HILI by several products of a
single manufacturer. The 23 publications presented 573
cases of initially suspected HILI (Table 1) and provided on
average 24.9 cases (range 480) per publication. In 278/573
cases (48.5%), alternative causes were evident in these
publications (Table 1), with specified diagnostic alternatives in 224/278 cases (Tables 2 and 3); for some of these
224 cases, more than one alternative diagnosis was
provided, resulting in a total of 280 diagnoses (Table 3).
In 54/278 cases, alternative causes were reported but
remained unspecified if causality for the incriminated herb
cases was graded as excluded, unlikely, unrelated, or
possible, but no alternative diagnosis provided.

Frequency of specified and unspecified alternative causes in initially suspected herb-induced liver injury cases

Herbs
Herbal drugs
Herbal supplements
Kava
Kava
Kava
Kava
Kava
Greater Celandine
Black cohosh
Herbalife products
Herbalife products
Kava
Black cohosh
Green tea
Black cohosh
Black cohosh
Kava
Hydroxycut
Black cohosh
Greater Celandine
Herbalife products
Various herbs
Greater Celandine
Pelargonium sidoides
Pelargonium sidoides
Study cohort

Initially suspected
HILI cases (n)
20
30
20
36
80
23
31
12
12
26
30
34
4
9
31
17
22
22
20
45
21
15
13
573

Cases with alternative

causes [n (%)]
8
16
10
24
46
7
20
4
4
13
11
9
3
8
18
2
10
9
3
18
12
13
10
278

(40)
(53)
(50)
(67)
(58)
(30)
(65)
(33)
(33)
(50)
(37)
(27)
(75)
(89)
(58)
(12)
(46)
(41)
(15)
(40)
(57)
(93)
(87)
(48.5)

Causality
assessment methods
Ad hoc
WHO
Ad hoc
CIOMS
WHO
Ad hoc
CIOMS
WHO
WHO
CIOMS
Naranjo
Naranjo
CIOMS
CIOMS
CIOMS
DILIN
CIOMS
CIOMS
K&L
CIOMS
CIOMS
CIOMS
CIOMS

References
BfArM [23]
Denham et al. [24]
Teschke et al. [25]
Stickel et al. [26]
Schmidt et al. [27]
BfArM [28]
EMA [29]
Elinav et al. [30]
Schoepfer et al. [31]
Teschke et al. [32]
Mahady et al. [33]
Sarma et al. [34]
Teschke and Schwarzenboeck [35]
Teschke et al. [36]
Teschke [37]
Fong et al. [38]
Teschke et al. [39]
Teschke et al. [40]
Manso et al. [41]
Chau et al. [42]
Teschke et al. [43]
Teschke et al. [44]
Teschke et al. [45]

BfArM, Bundesinstitut fur Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medicinal Products in Germany); CIOMS, Council for International
Organizations of Medical Sciences; DILIN, Drug-Induced Liver Injury Network; EMA, European Medicines Agency; HILI, herb-induced liver injury; K&L, Karch and
Lasagna.

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Herbal hepatotoxicity Teschke et al.

Analysis of specified alternative causes in initially

suspected herb-induced liver injury cases

Table 2

Hepatitis B
1/12 cases [30], 7/45 cases [42]
Hepatitis C
1/17 cases [38], 1/45 cases [42]
Hepatitis E
1/45 cases [42], 1/8 cases [31]
CMV hepatitis
1/20 cases [23], 1/26 cases [32], 1/31 cases [37]
EBV hepatitis
2/26 cases [32], 2/31 cases [37]
HSV hepatitis
1/26 cases [32], 2/4 cases [35], 1/31 cases [37]
VZV hepatitis
1/31 cases [37]
Adenovirus hepatitis
1/22 cases [40]
Giant cell hepatitis
1/10 cases [31], 1/9 cases [36]
Ischemic hepatitis
1/45 cases [42]
Mallory bodies hepatitis
1/22 cases [41]
Autoimmune hepatitis
1/20 cases [23], 1/23 cases [28], 3/31 cases [29], 3/26 cases [32],
1/4 cases [35], 4/31 cases [37], 1/22 cases [39], 1/22 cases [40],
1/13 cases [45]
LKM-positive autoimmune hepatitis
1/31 cases [37]
SMA-positive autoimmune hepatitis
1/31 cases [37]
Primary biliary cirrhosis
1/20 cases [25], 1/12 cases [30], 2/26 cases [32], 3/31 cases [37]
Overlap syndrome
2/26 cases [32], 2/31 cases [37]
Fatty liver
2/12 cases [30], 1/9 cases [36], 1/22 cases [39]
Nonalcoholic steatohepatitis
1/26 cases [32], 1/31 cases [37], 1/15 cases [44]
Nonalcoholic liver cirrhosis
1/9 cases [36]
Alcoholic liver disease
2/30 cases [24], 4/36 cases [26], 2/22 cases [39], 1/15 cases [44]
Alcoholic hepatitis: 1/31 cases [29]
Alcoholic liver cirrhosis: 1/9 cases [36]
Liver injury by comedication
DILI 6/20 cases [23], 16/30 cases [24], 9/20 cases [25], 20/36 cases [26],
20/80 cases [27], 3/23 cases [28], 2/31 cases [29], 4/26 cases [32],
3/34 cases [34], 2/9 cases [36], 8/31 cases [37], 1/22 cases [40],
2/20 cases [41], 4/45 cases [42], 3/21 cases [43], 4/15 cases [44],
8/13 cases [45]
DILI by interferon: 1/22 cases [39]
DILI by fluoxetine: 1/22 cases [39]
DILI by flupirtin: 1/22 cases [40]
DILI by roxithromycin: 1/21 cases [43]
HILI: 1/20 cases [41], 2/21 cases [43], 1/15 cases [44]
Liver abscess
1/45 cases [42]
Infection with hepatic involvement
1/9 cases [36], 8/15 cases [44], 3/13 cases [45]
Biliary diseases
Biliary disease 1/22 cases [40], 1/21 cases [43]
Biliary disease with cholecystitis: 1/21 cases [43]
Biliary tract infection, symptomatic cholecystolithiasis: 1/22 cases [40]
Cholecystolithiasis: 3/9 cases [36], 1/22 cases [40]
Cholecystitis: 1/31 cases [37], 1/45 cases [42], 1/13 cases [45]
Cholecystitis with cystic duct obstruction: 1/22 cases [40]
Cholecystitis with microcalculi in the gallbladder, choledocholithiasis
requiring endoscopic stenting, diffuse bowel inflammation: 1/21 cases [45]
Cholangitis: 1/23 cases [28], 1/31 cases [37]
Cholangitis, possibly transient choledocholithiasis: 1/13 cases [45]
Extrahepatic bile duct obstruction because of excessive hilar adenopathy:
1/21 cases [43]
Pre-existing biliary stone disease with cholecystolithiasis: 1/22 cases [40]
Pre-existing biliary stone disease: 4/21 cases [43]
Sludge in the gallbladder with cystic duct obstruction: 1/23 cases [23]

Table 2 (continued)
Pancreatitis
1/26 cases [32], 3/31 cases [37], 2/22 cases [40], 1/13 cases [45]
Pancreas carcinoma
2/45 cases [42]
Celiac disease
1/15 cases [44]
Previous gastric bypass operation
1/9 cases [36]
Cardiac hepatopathy
1/22 cases [39], 1/13 cases [45]
Hyperthyroid hepatopathy
1/26 cases [32], 1/31 case [37]
Rhabdomyolysis by statin
1/22 cases [39]
Myelodysplastic syndrome
1/31 cases [37]
Polytrauma
1/13 cases [45]
Stevens Johnson syndrome
1/31 cases [29]
Pre-existing liver diseases
2/31 cases [29], 1/26 cases [32], 1/34 cases [34], 6/9 cases [36],
1/17 cases [38], 1/22 cases [39], 1/22 cases [40], 4/15 cases [44],
2/13 cases [45]
Pre-existing liver cirrhosis
1/20 cases [23], 1/31 cases [29], 1/26 cases [32], 1/22 cases [39]
CMV, cytomegalovirus; DILI, drug-induced liver injury; EBV, Epstein-Barr virus;
HILI, herb-induced liver injury; HSV, herpes simplex virus; LKM, liver kidney
microsomes; SMA, smooth muscle antibodies; VZV, varicella zoster virus.

Of 573 cases, the CIOMS scale was applied in 275 cases

(48.0%), the WHO method in 134 cases (23.4%), the
Naranjo scale in 64 cases (11.2%), the ad hoc approach in
63 cases (11.0%), the K&L method in 20 cases (3.5%),
and the DILIN method in 20 cases (3.0%) (Table 1).
Types of alternative diagnoses

For 224 cases, a broad range of diagnoses with alternative

causation was presented for 224 cases (Table 2). They
included hepatitis by various viruses, autoimmune
diseases, nonalcoholic and alcoholic liver diseases, liver
injury by comedication (DILI and other HILI), and liver
involvement by infectious diseases. Biliary and pancreatic
diseases were frequent alternative diagnoses and may
represent a major clinical issue if specific treatment is
withheld because of misdiagnosing. Other diagnoses were
rare but of possible relevance in individual patients. Preexisting liver diseases including cirrhosis were additional
challenges in the evaluation of initially assumed HILI
cases. In 166/573 cases (29.0%), the presence of liver disease
was questionable, a temporal association was lacking, or case
data for assessment were missing (Table 4).
Frequency

The most frequent alternative cause was liver injury

because of potentially hepatotoxic comedication in 123
cases (Table 3). This is of little clinical concern as in
suspected liver injury all herbs and drugs are discontinued. With 23 cases, biliary diseases were frequent and
relevant, as were autoimmune liver diseases with 25
patients, as both conditions require specific therapies. In

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4 European Journal of Gastroenterology & Hepatology 2013, Vol 00 No 00

27 cases, underlying virus infections were identified

comprizing nine different viral pathogens; here, misdiagnosis may be fatal if corticosteroid treatment is initiated.

Discussion
This study shows possible or likely alternative diagnoses in
278/573 cases (48.5%) of suspected HILI (Table 1);
causality assessment was impeded in 165/573 patients
(29.0%) (Table 4), resulting in diagnostic problems in
Table 3

Frequency of cases with specified alternative causes

Specified alternative causes

Hepatitis B
Hepatitis C
Hepatitis E
CMV hepatitis
EBV hepatitis
HSV hepatitis
VZV hepatitis
Adenovirus hepatitis
Giant cell hepatitis
Ischemic hepatitis
Mallory bodies hepatitis
Autoimmune hepatitis
LKM-positive autoimmune hepatitis
SMA-positive autoimmune hepatitis
Primary biliary cirrhosis
Overlap syndrome
Fatty liver
Nonalcoholic steatohepatitis
Nonalcoholic liver cirrhosis
Alcoholic liver disease
Liver injury by comedication
Liver abscess
Infection with hepatic involvement
Biliary diseases
Pancreatitis
Pancreas carcinoma
Celiac disease
Previous gastric bypass operation
Cardiac hepatopathy
Hyperthyroid hepatopathy
Rhabdomyolysis by statin
Myelodysplastic syndrome
Polytrauma
Stevens Johnson syndrome
Pre-existing liver diseases
Pre-existing liver cirrhosis
Total causes

Cases (n)

Frequency (%)

8
2
2
3
4
4
1
1
2
1
1
16
1
1
7
4
4
3
1
11
123
1
12
23
7
2
1
1
2
2
1
1
1
1
22
5
280

2.9
0.7
0.7
1.1
1.4
1.4
0.4
0.4
0.7
0.4
0.4
5.7
0.4
0.4
2.5
1.4
1.4
1.1
0.4
3.9
43.9
0.4
4.3
8.2
2.5
0.7
0.4
0.4
0.7
0.7
0.4
0.4
0.4
0.4
7.9
1.8
100

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; LKM,
liver kidney microsomes; SMA, smooth muscle antibodies; VZV, varicella zoster
virus.

Table 4

77.5% of all cases. Most of the alternative diagnoses have

been supported by laboratory data reanalysis (including
serology), imaging data, and pre-existing diseases from case
histories (Tables 2 and 3). Alternatives were considered possible in some patients with potentially hepatotoxic comedications, but causality could not be ascertained
because of lack of treatment data. Problems of alternative
diagnoses are not confined to HILI cases (Tables 1 and 2),
but are also common in assumed DILI [822,57]. In 65/138
cases (47.1%) of initially assumed DILI, different diagnoses
unrelated to drugs were proven with a delay of up to 1480
days until correct diagnosis [10]. Therefore, in suspected
HILI and DILI, a thorough and timely clinical and
diagnostic assessment is mandatory.
Valid exclusion of alternatives is a prerequisite for the
diagnosis of HILI and has to be done when the caring
physician can still modify the diagnostic procedures. For
the evaluation of alternative diagnoses, diagnostic algorithms or checklists are available [6,7,55]; for causality
assessment, use of the CIOMS scale with all its strengths
and weaknesses is recommended, and results are achievable within a few minutes and do not require expert
knowledge [68,55]. This scale contains diagnostic core
elements of hepatotoxicity, is structured, quantitative,
and validated by positive re-exposure cases [8,55].
CIOMS-based assessment has shown good sensitivity
(86%), specificity (89%), positive predictive value (93%),
and negative predictive value (78%) [8]. Another possible
approach is the DILIN method, but this requires an
expert team and is more suitable for retrospective studies
when time is not a critical issue [20,39].
Other methods in use for assessing HILI cases are not
validated for hepatotoxicity and considered obsolete.
This applies to the ad hoc approach, the WHO method,
the Naranjo scale, and the K&L method [5254,5660];
in the present study of 23 publications, the CIOMS scale
was applied in 52.2%, the WHO method in 17.4%, the ad
hoc approach in 13.1%, the Naranjo scale in 8.7%, and the
K&L and DILIN method each in 4.3% (Table 1). With 60
different herbs and herbal supplements reported as
potentially hepatotoxic in 185 publications without stringent causality assessments [61], and considering abundant

Assessability of assumed herb-induced liver injury cases of the study group (n = 573)

Parameter
Questionable liver disease
2/31 cases [29], 3/22 cases [39], 1/13 cases [45]
Lack of temporal association
1/20 cases [23], 1/23 cases [28], 3/31 cases [29], 4/26 cases [32], 2/22 cases [39]
Unassessable or poorly assessable cases
22/41 cases [23], 21/30 cases [24], 15/20 cases [25], 31/80 cases [27], 11/31 cases [29], 1/4 cases [35],
15/32 cases [38], 4/22 cases [39], 8/22 cases [40], 8/22 cases [44], 9/13 cases [45]
Slightly increased ALT: 2/22 cases [39]
Raised g-glutamyltransferase: 2/22 cases [39]
Total

All cases (n)

Cases/study group (%)

1.1

11

1.9

149

26.0

166

29.0

ALT, alanine aminotransaminase.

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Herbal hepatotoxicity Teschke et al.

alternative diagnoses in HILI (Tables 13) [2345,57],

future HILI cases will require sound proof with valid
causality assessment and exclusion of alternative diagnoses.
Assessment of alternatives in suspected HILI may be
problematic in spontaneous case reports because of
insufficient data [23,28,29,33,34,44,45]. Evaluation requires a sophisticated approach, as undertaken by the
European Medicines Agency (EMA) in 31 EU cases of
suspected HILI by black cohosh (BC) using the CIOMS
scale [29]. This series included 11/31 unassessable cases
(35%) because of poor data quality; alternative causation
with various degrees of certainty was evident in 20/31
cases (65%) (Table 1). EMA specified likely alternative
causes in 8/31 cases (26%): autoimmune hepatitis
(n = 2), DILI (n = 2), pre-existing liver disease (n = 2),
alcoholic hepatitis (n = 1), and pre-existing liver cirrhosis
with Stevens Johnson syndrome (n = 1) [29]. These eight
cases with specific alternative diagnoses were included in
the present study (Table 2). EMA attributed 6/31 cases as
unlikely, excluded causality in five cases, and judged one
case as possible [29], although this case was also excluded
upon further evaluation [35]. Presumably, these 12 cases
were not causally related to BC [29]. Therefore,
alternative causes may be ascribed to 20/31 cases in this
EMA study of suspected BC hepatotoxicity (Table 1).
In contrast to this excellent EMA analysis [29], insufficient efforts to assess alternative causes were made in
other cases of spontaneous HILI reports [23,28,33,34].
Problems of causality assessment were evident with the ad
hoc approach [23,28], as alternative causes are not
sufficiently addressed [32,37,40]; the Naranjo scale leaves
alternative explanations as unclassified [33,34], creating
concern [35,36,39,57,60]. Alternative causes were also
overlooked using the WHO scale [44,45,58,59,62,63].
In summary, our analysis of 573 cases with initially
assumed HILI showed alternative causes unrelated to the
initially incriminated herb in 48.5% and barely assessable
cases in an additional 29.0%. These shortcomings call for
thorough clinical evaluations, valid causality assessments
including firm exclusion of alternative diagnoses, and
stringent efforts to report complete case data for future
HILI case assessment.

Acknowledgements
Conflicts of interest

There are no conflicts of interest.

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