Herbalife 3

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Herbal hepatotoxicity: suspected cases assessed foralternative causesRolf 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

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

suspected HILI. Eur J Gastroenterol Hepatol 00:000–000 �c2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

European Journal of Gastroenterology & Hepatology 2013, 00:000–000

Keywords: hepatotoxic herbs, herb-induced liver injury, herbalhepatotoxicity, herbal medicine, herbs

aDepartment of Internal Medicine II, Division of Gastroenterology andHepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty,bInstitute of Industrial, Environmental and Social Medicine, Medical Faculty,Goethe University, Frankfurt/Main and cDepartment of Medicine I, UniversityMedical Center, Hamburg-Eppendorf, Germany

Correspondence to Rolf Teschke, MD, Department of Internal Medicine II,Division of Gastroenterology and Hepatology, Klinikum Hanau, AcademicTeaching Hospital, Medical Faculty, Goethe University of Frankfurt/Main,Leimenstrasse 20, D-63450 Hanau, GermanyTel: + 49 6181 21859; fax: + 49 6181 2964211; e-mail: [email protected]

Received 30 November 2012 Accepted 15 February 2013

IntroductionPatients with herb-induced liver injury (HILI) and drug-

induced 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 [1–5]. 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 [8–22] 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, Gilbert’s syndrome, hepatitis because of

cytomegalovirus and Epstein Barr virus infections, steatosis,

postictal state, lymphoma, paracetamol overdose, cholangitis,

thyrotoxicosis, hepatitis C cirrhosis, and cryptogenic cirrho-

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 unre-

lated to the use of herbs, herbal drugs, and herbal dietary

supplements.

Patients and methodsLiterature 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 sidoidesfor the period from January 2001 until September 2012. For

Original article 1

0954-691X �c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/MEG.0b013e3283603e89

mailto:[email protected]


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 [23–45]. Details

were not sufficiently documented in other publications of

HILI [46–51] related to Greater Celandine [46], numer-

ous herbs [47,49], kava [48], green tea extracts [50], and

Polygonum multiflorum [51]; these publications were there-

fore excluded. In the 23 publications, causality assess-

ment 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 Drug-

Induced Liver Injury Network (DILIN) [20,39], or the

Karch and Lasagna (K&L) method [56].

Assessment approach

In all 23 case series with suspected HILI, established

diagnoses as alternative explanations were researched by

quantitative and qualitative evaluation [23–45]. Diag-

noses for alternative causes were reported in most

publications, occasionally with more than one specific

alternative diagnosis given [23–26,30–32,35–45]. Four

publications presented the alternative diagnoses for only

some of their cases [27–29,34]; one publication did not

provide this information [33].

ResultsInitially 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 4–80) per publication. In 278/573

cases (48.5%), alternative causes were evident in these

publications (Table 1), with specified diagnostic alterna-

tives 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.

Table 1 Frequency of specified and unspecified alternative causes in initially suspected herb-induced liver injury cases

HerbsHerbal drugsHerbal supplements

Initially suspectedHILI cases (n)

Cases with alternativecauses [n (%)]

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

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


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. Pre-

existing 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 discon-

tinued. With 23 cases, biliary diseases were frequent and

relevant, as were autoimmune liver diseases with 25

patients, as both conditions require specific therapies. In

Table 2 Analysis of specified alternative causes in initiallysuspected herb-induced liver injury cases

Hepatitis B1/12 cases [30], 7/45 cases [42]

Hepatitis C1/17 cases [38], 1/45 cases [42]

Hepatitis E1/45 cases [42], 1/8 cases [31]

CMV hepatitis1/20 cases [23], 1/26 cases [32], 1/31 cases [37]

EBV hepatitis2/26 cases [32], 2/31 cases [37]

HSV hepatitis1/26 cases [32], 2/4 cases [35], 1/31 cases [37]

VZV hepatitis1/31 cases [37]

Adenovirus hepatitis1/22 cases [40]

Giant cell hepatitis1/10 cases [31], 1/9 cases [36]

Ischemic hepatitis1/45 cases [42]

Mallory bodies hepatitis1/22 cases [41]

Autoimmune hepatitis1/20 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 hepatitis1/31 cases [37]

SMA-positive autoimmune hepatitis1/31 cases [37]

Primary biliary cirrhosis1/20 cases [25], 1/12 cases [30], 2/26 cases [32], 3/31 cases [37]

Overlap syndrome2/26 cases [32], 2/31 cases [37]

Fatty liver2/12 cases [30], 1/9 cases [36], 1/22 cases [39]

Nonalcoholic steatohepatitis1/26 cases [32], 1/31 cases [37], 1/15 cases [44]

Nonalcoholic liver cirrhosis1/9 cases [36]

Alcoholic liver disease2/30 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 comedicationDILI 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 abscess1/45 cases [42]

Infection with hepatic involvement1/9 cases [36], 8/15 cases [44], 3/13 cases [45]

Biliary diseasesBiliary 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, choledocholithiasisrequiring 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)

Pancreatitis1/26 cases [32], 3/31 cases [37], 2/22 cases [40], 1/13 cases [45]

Pancreas carcinoma2/45 cases [42]

Celiac disease1/15 cases [44]

Previous gastric bypass operation1/9 cases [36]

Cardiac hepatopathy1/22 cases [39], 1/13 cases [45]

Hyperthyroid hepatopathy1/26 cases [32], 1/31 case [37]

Rhabdomyolysis by statin1/22 cases [39]

Myelodysplastic syndrome1/31 cases [37]

Polytrauma1/13 cases [45]

Stevens Johnson syndrome1/31 cases [29]

Pre-existing liver diseases2/31 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 cirrhosis1/20 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 kidneymicrosomes; SMA, smooth muscle antibodies; VZV, varicella zoster virus.

Herbal hepatotoxicity Teschke et al. 3


27 cases, underlying virus infections were identified

comprizing nine different viral pathogens; here, misdiag-

nosis may be fatal if corticosteroid treatment is initiated.

DiscussionThis 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

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 consi-

dered possible in some patients with potentially hepato-

toxic 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 [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

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 algo-

rithms 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 achiev-

able within a few minutes and do not require expert

knowledge [6–8,55]. 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 [52–54,56–60];

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 strin-

gent causality assessments [61], and considering abundant

Table 3 Frequency of cases with specified alternative causes

Specified alternative causes Cases (n) Frequency (%)

Hepatitis B 8 2.9Hepatitis C 2 0.7Hepatitis E 2 0.7CMV hepatitis 3 1.1EBV hepatitis 4 1.4HSV hepatitis 4 1.4VZV hepatitis 1 0.4Adenovirus hepatitis 1 0.4Giant cell hepatitis 2 0.7Ischemic hepatitis 1 0.4Mallory bodies hepatitis 1 0.4Autoimmune hepatitis 16 5.7LKM-positive autoimmune hepatitis 1 0.4SMA-positive autoimmune hepatitis 1 0.4Primary biliary cirrhosis 7 2.5Overlap syndrome 4 1.4Fatty liver 4 1.4Nonalcoholic steatohepatitis 3 1.1Nonalcoholic liver cirrhosis 1 0.4Alcoholic liver disease 11 3.9Liver injury by comedication 123 43.9Liver abscess 1 0.4Infection with hepatic involvement 12 4.3Biliary diseases 23 8.2Pancreatitis 7 2.5Pancreas carcinoma 2 0.7Celiac disease 1 0.4Previous gastric bypass operation 1 0.4Cardiac hepatopathy 2 0.7Hyperthyroid hepatopathy 2 0.7Rhabdomyolysis by statin 1 0.4Myelodysplastic syndrome 1 0.4Polytrauma 1 0.4Stevens Johnson syndrome 1 0.4Pre-existing liver diseases 22 7.9Pre-existing liver cirrhosis 5 1.8Total causes 280 100

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

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 disease2/31 cases [29], 3/22 cases [39], 1/13 cases [45]

6 1.1

Lack of temporal association1/20 cases [23], 1/23 cases [28], 3/31 cases [29], 4/26 cases [32], 2/22 cases [39]

11 1.9

Unassessable or poorly assessable cases22/41 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]

149 26.0

Total 166 29.0

ALT, alanine aminotransaminase.



alternative diagnoses in HILI (Tables 1–3) [23–45,57],

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 re-

quires 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], insuffi-

cient 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.

AcknowledgementsConflicts of interest

There are no conflicts of interest.

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http://www.bfarm.de/cae/servlet/contentblob/1014620/publicationFile/66198/schoellkraut-anhoerung_050505.pdf



http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2010/02/WC500074167.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2010/02/WC500074167.pdf

http://who-umc.org/Graphics/24734.pdf

Herbalife 3

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