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Original article 1093

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 (9.7%) were additional confounding variables. Other
common in suspected drug-induced liver injury (DILI) and diagnoses were rare, but possibly relevant for the
account for up to 47.1% of analyzed cases. This raised the individual patient.
question of whether a similar frequency may prevail in
Conclusion In 573 cases of initially assumed HILI, 48.5%
cases of assumed herb-induced liver injury (HILI).
showed alternative causes unrelated to the initially
Methods We searched the Medline database for the incriminated herb, herbal drug, or herbal dietary
following terms: herbs, herbal drugs, herbal dietary supplement, calling for thorough clinical evaluations and
supplements, hepatotoxic herbs, herbal hepatotoxicity, and appropriate causality assessments in future cases of
herb-induced liver injury. Additional terms specifically suspected HILI. Eur J Gastroenterol Hepatol 25:1093–1098
addressed single herbs and herbal products: black cohosh, c 2013 Wolters Kluwer Health | Lippincott Williams &
Greater Celandine, green tea, Herbalife products, Wilkins.
Hydroxycut, kava, and Pelargonium sidoides. We retrieved European Journal of Gastroenterology & Hepatology 2013, 25:1093–1098
23 published case series and regulatory assessments
related to hepatotoxicity by herbs and herbal dietary Keywords: hepatotoxic herbs, herb-induced liver injury, herbal
hepatotoxicity, herbal medicine, herbs
supplements with alternative causes.
a
Department of Internal Medicine II, Division of Gastroenterology and
Results The 23 publications comprised 573 cases of Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty,
b
Institute of Industrial, Environmental and Social Medicine, Medical Faculty,
initially suspected HILI; alternative causes were evident in Goethe University, Frankfurt/Main and cDepartment of Medicine I, University
278/573 cases (48.5%). Among them were hepatitis by Medical Center, Hamburg-Eppendorf, Germany
various viruses (9.7%), autoimmune diseases (10.4%), Correspondence to Rolf Teschke, MD, Department of Internal Medicine II,
nonalcoholic and alcoholic liver diseases (5.4%), liver injury Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic
Teaching Hospital, Medical Faculty, Goethe University of Frankfurt/Main,
by comedication (DILI and other HILI) (43.9%), and liver Leimenstrasse 20, D-63450 Hanau, Germany
involvement in infectious diseases (4.7%). Biliary and Tel: + 49 6181 21859; fax: + 49 6181 2964211; e-mail: rolf.teschke@gmx.de
pancreatic diseases were frequent alternative diagnoses
Received 30 November 2012 Accepted 15 February 2013
(11.5%), raising therapeutic problems if specific treatment
is withheld; pre-existing liver diseases including cirrhosis

Introduction thyrotoxicosis, hepatitis C cirrhosis, and cryptogenic cirrho-


Patients with herb-induced liver injury (HILI) and drug- sis. In an additional 15.2% of the cases, the cause was
induced liver injury (DILI) usually have a good prognosis, indeterminate, whereas in only 37.7% of the cases were the
but acute liver failure with a lethal outcome or the reactions considered to be drug related [10]. In another
requirement for a liver transplant rarely may occur [1–5]. As DILI study, 40% of the initially identified 110 patients were
a specific and valid diagnostic laboratory marker is lacking, eventually classified as having drug-related hepatotoxicity,
the diagnosis of HILI and DILI requires a thorough clinical 38.2% with alternative causes, 16.4% lacking a causal relation
assessment and an appropriate diagnostic algorithm that with any drug, and 5.4% with a drug overdose problem [9].
considers specific hepatotoxicity characteristics [6,7].
In this study, we analyzed case series of HILI to assess
In case series of initially assumed DILI, alternative diagnoses the frequency and features of alternative causes unre-
are common [8–22] and may account for up to 47.1% in one lated to the use of herbs, herbal drugs, and herbal dietary
study evaluating the accuracy of hepatic idiosyncratic supplements.
adverse drug reactions initially identified in 138 patients of
an English health region [10]. In this report, primary Patients and methods
underlying diagnoses included common bile duct stone, Literature search
ischemic hepatitis, autoimmune hepatitis, sepsis, alcoholic We searched the Medline database with the following
liver disease, Gilbert’s syndrome, hepatitis because of terms: herbs, herbal drugs, herbal dietary supplements,
cytomegalovirus and Epstein Barr virus infections, steatosis, hepatotoxic herbs, herbal hepatotoxicity, herb-induced
postictal state, lymphoma, paracetamol overdose, cholangitis, liver injury, black cohosh, Greater Celandine, green tea,
0954-691X
c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/MEG.0b013e3283603e89

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1094 European Journal of Gastroenterology & Hepatology 2013, Vol 25 No 9

Herbalife products, Hydroxycut, kava, and Pelargonium sidoides Assessment approach


for the period from January 2001 until September 2012. For In all 23 case series with suspected HILI, established
each term, we used the first 50 publications consisting of diagnoses as alternative explanations were researched by
single case reports, case series, regulatory assessments, and quantitative and qualitative evaluation [23–45]. Diag-
review articles; on the basis of these publications, we noses for alternative causes were reported in most
reviewed the lists of references, selected those publications publications, occasionally with more than one specific
relevant to the aim of our study, and retrieved 141 English alternative diagnosis given [23–26,30–32,35–45]. Four
language publications related to herbal hepatotoxicity. publications presented the alternative diagnoses for only
some of their cases [27–29,34]; one publication did not
Publication selection provide this information [33].
Initial assessment of the 141 publications indicated that
single case reports and review articles did not address Results
alternative diagnoses in HILI cases. We therefore Initially suspected herb-induced liver injury cases with
analyzed publications with case series and regulatory alternative causes
assessments. Twenty-three publications contained either All 23 publications of suspected HILI provided evidence
specified alternative causes as diagnoses, or at least for alternative explanations other than the incriminated
causality gradings of excluded, unlikely, unrelated, or herbal drugs or herbal dietary supplements (Table 1). In
possible for the individual herb or herbal dietary 19/23 publications, the focus was on HILI cases by a single
supplement, implicating alternative causes, which were herb; in one publication, it was on HILI by various herbs,
not specifically presented as diagnoses [23–45]. Details and in three publications on HILI by several products of a
were not sufficiently documented in other publications of single manufacturer. The 23 publications presented 573
HILI [46–51] related to Greater Celandine [46], numer- cases of initially suspected HILI (Table 1) and provided on
ous herbs [47,49], kava [48], green tea extracts [50], and average 24.9 cases (range 4–80) per publication. In 278/573
Polygonum multiflorum [51]; these publications were there- cases (48.5%), alternative causes were evident in these
fore excluded. In the 23 publications, causality assess- publications (Table 1), with specified diagnostic alterna-
ment for HILI cases was performed using the ad hoc tives in 224/278 cases (Tables 2 and 3); for some of these
approach [52], the WHO global introspection method 224 cases, more than one alternative diagnosis was
(WHO method) [53], the scales of Naranjo [54] and of provided, resulting in a total of 280 diagnoses (Table 3).
the Council for International Organizations of Medical In 54/278 cases, alternative causes were reported but
Sciences (CIOMS) [6,7,55], the method of the Drug- remained unspecified if causality for the incriminated herb
Induced Liver Injury Network (DILIN) [20,39], or the cases was graded as excluded, unlikely, unrelated, or
Karch and Lasagna (K&L) method [56]. possible, but no alternative diagnosis provided.

Table 1 Frequency of specified and unspecified alternative causes in initially suspected herb-induced liver injury cases
Herbs
Herbal drugs Initially suspected Cases with alternative Causality
Herbal supplements HILI cases (n) causes [n (%)] assessment methods References

Kava 20 8 (40) Ad hoc BfArM [23]


Kava 30 16 (53) WHO Denham et al. [24]
Kava 20 10 (50) Ad hoc Teschke et al. [25]
Kava 36 24 (67) CIOMS Stickel et al. [26]
Kava 80 46 (58) WHO Schmidt et al. [27]
Greater Celandine 23 7 (30) Ad hoc BfArM [28]
Black cohosh 31 20 (65) CIOMS EMA [29]
Herbalife products 12 4 (33) WHO Elinav et al. [30]
Herbalife products 12 4 (33) WHO Schoepfer et al. [31]
Kava 26 13 (50) CIOMS Teschke et al. [32]
Black cohosh 30 11 (37) Naranjo Mahady et al. [33]
Green tea 34 9 (27) Naranjo Sarma et al. [34]
Black cohosh 4 3 (75) CIOMS Teschke and Schwarzenboeck [35]
Black cohosh 9 8 (89) CIOMS Teschke et al. [36]
Kava 31 18 (58) CIOMS Teschke [37]
Hydroxycut 17 2 (12) DILIN Fong et al. [38]
Black cohosh 22 10 (46) CIOMS Teschke et al. [39]
Greater Celandine 22 9 (41) CIOMS Teschke et al. [40]
Herbalife products 20 3 (15) K&L Manso et al. [41]
Various herbs 45 18 (40) CIOMS Chau et al. [42]
Greater Celandine 21 12 (57) CIOMS Teschke et al. [43]
Pelargonium sidoides 15 13 (93) CIOMS Teschke et al. [44]
Pelargonium sidoides 13 10 (87) CIOMS Teschke et al. [45]
Study cohort 573 278 (48.5)

BfArM, Bundesinstitut für 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. 1095

Table 2 Analysis of specified alternative causes in initially Table 2 (continued)


suspected herb-induced liver injury cases
Pancreatitis
Hepatitis B 1/26 cases [32], 3/31 cases [37], 2/22 cases [40], 1/13 cases [45]
1/12 cases [30], 7/45 cases [42] Pancreas carcinoma
Hepatitis C 2/45 cases [42]
1/17 cases [38], 1/45 cases [42] Celiac disease
Hepatitis E 1/15 cases [44]
1/45 cases [42], 1/8 cases [31] Previous gastric bypass operation
CMV hepatitis 1/9 cases [36]
1/20 cases [23], 1/26 cases [32], 1/31 cases [37] Cardiac hepatopathy
EBV hepatitis 1/22 cases [39], 1/13 cases [45]
2/26 cases [32], 2/31 cases [37] Hyperthyroid hepatopathy
HSV hepatitis 1/26 cases [32], 1/31 case [37]
1/26 cases [32], 2/4 cases [35], 1/31 cases [37] Rhabdomyolysis by statin
VZV hepatitis 1/22 cases [39]
1/31 cases [37] Myelodysplastic syndrome
Adenovirus hepatitis 1/31 cases [37]
1/22 cases [40] Polytrauma
Giant cell hepatitis 1/13 cases [45]
1/10 cases [31], 1/9 cases [36] Stevens Johnson syndrome
Ischemic hepatitis 1/31 cases [29]
1/45 cases [42] Pre-existing liver diseases
Mallory bodies hepatitis 2/31 cases [29], 1/26 cases [32], 1/34 cases [34], 6/9 cases [36],
1/22 cases [41] 1/17 cases [38], 1/22 cases [39], 1/22 cases [40], 4/15 cases [44],
Autoimmune hepatitis 2/13 cases [45]
1/20 cases [23], 1/23 cases [28], 3/31 cases [29], 3/26 cases [32], Pre-existing liver cirrhosis
1/4 cases [35], 4/31 cases [37], 1/22 cases [39], 1/22 cases [40], 1/20 cases [23], 1/31 cases [29], 1/26 cases [32], 1/22 cases [39]
1/13 cases [45]
LKM-positive autoimmune hepatitis CMV, cytomegalovirus; DILI, drug-induced liver injury; EBV, Epstein-Barr virus;
1/31 cases [37] HILI, herb-induced liver injury; HSV, herpes simplex virus; LKM, liver kidney
SMA-positive autoimmune hepatitis microsomes; SMA, smooth muscle antibodies; VZV, varicella zoster virus.
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 Of 573 cases, the CIOMS scale was applied in 275 cases
2/26 cases [32], 2/31 cases [37]
Fatty liver (48.0%), the WHO method in 134 cases (23.4%), the
2/12 cases [30], 1/9 cases [36], 1/22 cases [39] Naranjo scale in 64 cases (11.2%), the ad hoc approach in
Nonalcoholic steatohepatitis 63 cases (11.0%), the K&L method in 20 cases (3.5%),
1/26 cases [32], 1/31 cases [37], 1/15 cases [44]
Nonalcoholic liver cirrhosis and the DILIN method in 20 cases (3.0%) (Table 1).
1/9 cases [36]
Alcoholic liver disease
2/30 cases [24], 4/36 cases [26], 2/22 cases [39], 1/15 cases [44] Types of alternative diagnoses
Alcoholic hepatitis: 1/31 cases [29] For 224 cases, a broad range of diagnoses with alternative
Alcoholic liver cirrhosis: 1/9 cases [36]
Liver injury by comedication causation was presented for 224 cases (Table 2). They
DILI 6/20 cases [23], 16/30 cases [24], 9/20 cases [25], 20/36 cases [26], included hepatitis by various viruses, autoimmune
20/80 cases [27], 3/23 cases [28], 2/31 cases [29], 4/26 cases [32], diseases, nonalcoholic and alcoholic liver diseases, liver
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], injury by comedication (DILI and other HILI), and liver
8/13 cases [45] involvement by infectious diseases. Biliary and pancreatic
DILI by interferon: 1/22 cases [39]
DILI by fluoxetine: 1/22 cases [39]
diseases were frequent alternative diagnoses and may
DILI by flupirtin: 1/22 cases [40] represent a major clinical issue if specific treatment is
DILI by roxithromycin: 1/21 cases [43] withheld because of misdiagnosing. Other diagnoses were
HILI: 1/20 cases [41], 2/21 cases [43], 1/15 cases [44]
Liver abscess
rare but of possible relevance in individual patients. Pre-
1/45 cases [42] existing liver diseases including cirrhosis were additional
Infection with hepatic involvement challenges in the evaluation of initially assumed HILI
1/9 cases [36], 8/15 cases [44], 3/13 cases [45]
Biliary diseases
cases. In 166/573 cases (29.0%), the presence of liver disease
Biliary disease 1/22 cases [40], 1/21 cases [43] was questionable, a temporal association was lacking, or case
Biliary disease with cholecystitis: 1/21 cases [43] data for assessment were missing (Table 4).
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]
Frequency
Cholecystitis with cystic duct obstruction: 1/22 cases [40]
Cholecystitis with microcalculi in the gallbladder, choledocholithiasis The most frequent alternative cause was liver injury
requiring endoscopic stenting, diffuse bowel inflammation: 1/21 cases [45] because of potentially hepatotoxic comedication in 123
Cholangitis: 1/23 cases [28], 1/31 cases [37]
Cholangitis, possibly transient choledocholithiasis: 1/13 cases [45]
cases (Table 3). This is of little clinical concern as in
Extrahepatic bile duct obstruction because of excessive hilar adenopathy: suspected liver injury all herbs and drugs are discon-
1/21 cases [43] tinued. With 23 cases, biliary diseases were frequent and
Pre-existing biliary stone disease with cholecystolithiasis: 1/22 cases [40]
Pre-existing biliary stone disease: 4/21 cases [43] relevant, as were autoimmune liver diseases with 25
Sludge in the gallbladder with cystic duct obstruction: 1/23 cases [23] patients, as both conditions require specific therapies. In

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1096 European Journal of Gastroenterology & Hepatology 2013, Vol 25 No 9

27 cases, underlying virus infections were identified 77.5% of all cases. Most of the alternative diagnoses have
comprizing nine different viral pathogens; here, misdiag- been supported by laboratory data reanalysis (including
nosis may be fatal if corticosteroid treatment is initiated. serology), imaging data, and pre-existing diseases from case
histories (Tables 2 and 3). Alternatives were consi-
Discussion dered possible in some patients with potentially hepato-
This study shows possible or likely alternative diagnoses in toxic comedications, but causality could not be ascertained
278/573 cases (48.5%) of suspected HILI (Table 1); because of lack of treatment data. Problems of alternative
causality assessment was impeded in 165/573 patients diagnoses are not confined to HILI cases (Tables 1 and 2),
(29.0%) (Table 4), resulting in diagnostic problems in but are also common in assumed DILI [8–22,57]. In 65/138
cases (47.1%) of initially assumed DILI, different diagnoses
unrelated to drugs were proven with a delay of up to 1480
Table 3 Frequency of cases with specified alternative causes days until correct diagnosis [10]. Therefore, in suspected
Specified alternative causes Cases (n) Frequency (%) HILI and DILI, a thorough and timely clinical and
Hepatitis B 8 2.9 diagnostic assessment is mandatory.
Hepatitis C 2 0.7
Hepatitis E 2 0.7 Valid exclusion of alternatives is a prerequisite for the
CMV hepatitis 3 1.1
EBV hepatitis 4 1.4
diagnosis of HILI and has to be done when the caring
HSV hepatitis 4 1.4 physician can still modify the diagnostic procedures. For
VZV hepatitis 1 0.4 the evaluation of alternative diagnoses, diagnostic algo-
Adenovirus hepatitis 1 0.4
Giant cell hepatitis 2 0.7 rithms or checklists are available [6,7,55]; for causality
Ischemic hepatitis 1 0.4 assessment, use of the CIOMS scale with all its strengths
Mallory bodies hepatitis 1 0.4
Autoimmune hepatitis 16 5.7
and weaknesses is recommended, and results are achiev-
LKM-positive autoimmune hepatitis 1 0.4 able within a few minutes and do not require expert
SMA-positive autoimmune hepatitis 1 0.4 knowledge [6–8,55]. This scale contains diagnostic core
Primary biliary cirrhosis 7 2.5
Overlap syndrome 4 1.4 elements of hepatotoxicity, is structured, quantitative,
Fatty liver 4 1.4 and validated by positive re-exposure cases [8,55].
Nonalcoholic steatohepatitis 3 1.1 CIOMS-based assessment has shown good sensitivity
Nonalcoholic liver cirrhosis 1 0.4
Alcoholic liver disease 11 3.9 (86%), specificity (89%), positive predictive value (93%),
Liver injury by comedication 123 43.9 and negative predictive value (78%) [8]. Another possible
Liver abscess 1 0.4
Infection with hepatic involvement 12 4.3
approach is the DILIN method, but this requires an
Biliary diseases 23 8.2 expert team and is more suitable for retrospective studies
Pancreatitis 7 2.5 when time is not a critical issue [20,39].
Pancreas carcinoma 2 0.7
Celiac disease 1 0.4 Other methods in use for assessing HILI cases are not
Previous gastric bypass operation 1 0.4 validated for hepatotoxicity and considered obsolete.
Cardiac hepatopathy 2 0.7
Hyperthyroid hepatopathy 2 0.7 This applies to the ad hoc approach, the WHO method,
Rhabdomyolysis by statin 1 0.4 the Naranjo scale, and the K&L method [52–54,56–60];
Myelodysplastic syndrome 1 0.4
Polytrauma 1 0.4
in the present study of 23 publications, the CIOMS scale
Stevens Johnson syndrome 1 0.4 was applied in 52.2%, the WHO method in 17.4%, the ad
Pre-existing liver diseases 22 7.9 hoc approach in 13.1%, the Naranjo scale in 8.7%, and the
Pre-existing liver cirrhosis 5 1.8
Total causes 280 100 K&L and DILIN method each in 4.3% (Table 1). With 60
different herbs and herbal supplements reported as
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; LKM,
liver kidney microsomes; SMA, smooth muscle antibodies; VZV, varicella zoster
potentially hepatotoxic in 185 publications without strin-
virus. gent causality assessments [61], and considering abundant

Table 4 Assessability of assumed herb-induced liver injury cases of the study group (n = 573)
Parameter All cases (n) Cases/study group (%)

Questionable liver disease 6 1.1


2/31 cases [29], 3/22 cases [39], 1/13 cases [45]
Lack of temporal association 11 1.9
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 149 26.0
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 166 29.0

ALT, alanine aminotransaminase.

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Herbal hepatotoxicity Teschke et al. 1097

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23 BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn. Federal
There are no conflicts of interest. Institute for Drugs and Medicinal Products in Germany). Rejection of drug
risks, step II. As related to: Kava-Kava (Piper methysticum)-containing,
and kavain-containing drugs, including homeopathic preparations with a
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