Herbs and Liver Injury

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Herbs and Liver Injury: A Clinical Perspective

Simona Rossi and Victor J. Navarro

Division of Hepatology, Einstein Medical Center Philadelphia, Philadelphia, Pennsylvania

Despite a perception that herbal and dietary supplements

are safe, devastating liver injury has been reported to

result from their use. The difculty in characterizing liver

injury attributable to herbal and dietary supplements

stems from the permissive regulatory environment, the

complexity of marketed products, and underreporting by

the patients who use them. Despite these limitations, re-

searchers, clinicians, and regulators have increasing

awareness of the need for study in this area.

Keywords: Herbal and Induced Liver Injury; Dietary Supple-ments Induced Liver Injury; Causality Assessment in Drug-

Induced Liver Injury.

Despite the perceived safety of herbal and dietarysupplements (HDS), devastating liver injury has

been reported. The goal of this review is to discuss thescope of use of HDS in the United States and theirregulation and provide a clinical approach to diagnosis ofHDS-induced liver injury (HILI).

The Scope of Use of Herbal and DietarySupplements and Epidemiology of Herbaland Dietary Supplementinduced Injury

Dietary supplements are used for many reasons,including health maintenance, management of anxiety,obesity, diabetes, rheumatologic illness, cancer, cardio-vascular disease, and pain, among others.1 Liver diseaseis also a reason for use of HDS, which is demonstrated bythe nding that 23% of patients enrolled in a long-termhepatitis C treatment trial reported use of HDS.2

The ease of access to HDS through many outletsleaves the consumer to assume that HDS are safe andtheir use is without consequences. Moreover, patients donot commonly divulge use of dietary supplements tohealth care providers because of the perceived biasagainst their use and the assumptionthat providers areuninformed about the supplements.3

Data from the National Health and Nutrition Exami-nation Survey show that 52% of respondents reportedusing a dietary supplement.4 Another survey has re-ported even higher rates of use, up to 73% in thenoninstitutionalized U.S. adult population.5 This extent ofuse translates into a large commercial enterprise, with

the most recent reliable data indicating that more than

$5 billion in commerce can be attributed to the dietarysupplement industry.6 In some Asian and African coun-tries, up to 80% of the population use herbals as theirprimary means of medical care.7

Unfortunately, there are no U.S. data on the overallincidence of HILI or injury caused by any specic prod-uct. This results from lack of information on the overalluse of HDS and not having a mandatory reportingmechanism to identify cases. Even in the few population-based studies on drug-related liver injury, injury attrib-utable to HDS was only variably reported.812

The frequency of HILI can only be described in rela-tive terms in Western studies; in prospective studiesfrom Spain, medicinal herbal preparations accounted foronly 1%2% of cases of liver injury, with antibioticsbeing among the most common class implicated.13,14 Inkeeping with their more common use, medicinal herbswere the most common cause for drug-related liverinjury in Singapore where 71% of cases (22 of 31) wereattributed to medicinal herbs, many adulterated withactive drugs.15 In Iceland, HILI has been observed withthe use of Herbalife products.16 In the United States, the

Drug Induced Liver Injury Network (DILIN) promises toprovide useful information on HILI. Preliminary data onHILI cases compiled by the DILIN provide a glimpse intothe relative frequency of liver injury attributable to di-etary supplements in the United States, compared withconventional drugs.17 Among 109 patients in whom HDSwere implicated in their liver injury, most (33%) usedproducts intended for bodybuilding, followed by prod-ucts used for weight loss (26%). Although it is not apopulation-based study per se, reports from the DILINindicate that HDS are responsiblefor an increasing pro-portion of hepatotoxicity cases.17

Regulation for Herbal and Dietary Supplements

The current regulatory environment in the UnitedStates for dietary supplements was established by

Abbreviations used in this paper:CIOMS, Council for International Orga-nizations of Medical Sciences; DILI, drug-induced liver injury; DILIN, DrugInduced Liver Injury Network; FDA, Food and Drug Administration; GTE,green tea extract; HDS, herbal and dietary supplements; HILI, HDS-induced liver injury; RUCAM, Roussel Uclaf Causality Assessment Method.

2014 by the AGA Institute1542-3565/$36.00

http://dx.doi.org/10.1016/j.cgh.2013.07.030

Clinical Gastroenterology and Hepatology 2014;12:10691076
http://dx.doi.org/10.1016/j.cgh.2013.07.030http://dx.doi.org/10.1016/j.cgh.2013.07.030


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Congress through the landmark Dietary SupplementHealth and Education Act of 1994. Through this law,manufacturers were required to attest to a productssafety, but it gives no authority to the Food and DrugAdministration (FDA) to approve HDS before marketing.It is only when a manufacturer introduces a new dieta ryingredient that a premarket safety review is conducted.18

The Final Rule for Dietary Supplement Current GoodManufacturing Practices, enacted in 2007, further aimsto ensure the safety ofmarketed products by stipulatingproduction standards.19 However, not long after the nalrule was published, instances of dietary supplementscontaminated with various compounds became apparent,and the FDA issued a warning to manufacturers.20

Routine analysis of products contents by the FDA isperformed on only a random basis.18

Diagnosis of Herbal and DietarySupplementinduced Liver Injury

The key diagnostic elements for drug-induced liverinjury (DILI), as discussed at an important ClinicalResearch Workshop, apply to HDS as well.21 Funda-mentally, the diagnosis of HILI depends rst on having asuspicion that a supplement may be accountable forinjury. The time to onset of injury can be variable withHILI because products consumed during long periods oftime must be considered, because injury could be cu-mulative, or products and their contents may changeover time.22

The clinical features should be recognized as hepa-tocellular, cholestatic, or mixed. The R ratio can becalculated at various times during the course of injury,although conventionally, it is determined at onset.23

Observing the course of liver injury after cessation ofan agent is an important component to diagnosis,because a deceleration of the enzyme abnormalities orclinical symptoms is expected (dechallenge). Improve-ment is not necessarily sine qua non for the diagnosis,because some HDS have been shown to leadtochronic,self-perpetuating injury, even after cessation.22 Finally,recrudescence of liver injury on incidental re-exposure toa suspect supplement provides compelling evidence of acausal association.

The most decisive approach to the diagnosis of HILI,after documentation of the ingestion of an agent thatprecedes injury, is exclusion of other liver diseases thatmay present similarly (Figure 1).

Causality Assessment in Herbal and Dietary

Supplementinduced Liver Injury

Causality assessment refers to the process of assem-bling evidence that may link a drug or dietary supple-ment to liver injury. Instruments for causalityassessment are based predominantly on clinical criteria,

such as patient age, alcohol use, exclusion of underlying

liver diseases, and temporal exposure to a drug. The useof a universal assessment method when assessing po-tential DILI provides for increased evaluator agreement.However, even with the use of these causality assess-ment methods, variability among evaluators remains aconcern.24 A few causality assessment methods deservemention in the context of HILI. An early causality

assessment process is the Naranjo scoring system, orAdverse Drug Reaction Probability Scale.25 The Naranjosystem has been applied in the causality assessmentprocess with natural products,26 but this has drawncriticism because ofits lack of specicity for liver-relateddrug reactions.27,28

The Roussel Uclaf Causality Assessment Method(RUCAM) was created in 1989 as the rst liver-specicinstrument and addresses many features unique todrug liver injury. It has been applied widely to HILIcases.23 The RUCAM assigns points to specic categoriesand has been validated and found to be a sensitive andrelatively specic way to support a diagnosis of DILI.29

A modication of the RUCAM, the Maria and Victorinoscale, is commonly used in determining the likelihood ofDILI.30 Unlike the RUCAM, there is no requirement for aproduct label warning to assign the highest possiblescore for previous information on an agent.

Arguably, the most comprehensive approach to cau-sality assessment, and the one that may be most adapt-able to the nuances ofHILI, is the expert opinion process,as used by the DILIN.31 The DILIN has made signicantinroads into the causality assessment process,

Figure 1.Algorithm for assessment of suspected HILI. Alk P,alkaline phosphatase; ALT, alanine aminotransferase; CMV,cytomegalovirus; EBV, EpsteinBarr virus; HSV, herpes sim-plex virus; ULN, upper limit of normal; VZV, vesicular sto-

matitis virus.

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demonstrating that its process for assigning causality byusing expert opinion produces higher agreement ratesand likelihood scores than the RUCAM.32 This systemhas been applied to both drugs and dietary supple-ments.33 However, in the DILINs published experiencecomparing its expert opinion approach with the RUCAM,only a smallsubset of the study sample (5%) comprised

HILI cases.32

Thus, it is unclear what impact HILI caseshad on the nding that DILINs expert opinion processproduces higher agreement rates than the RUCAM.

A causality assessment process that is specic forHILI has not been developed, although a preliminaryattempt was made by the DILIN.34 The causality as-sessments are summarized inTable 1.

The Problem of Variability, Adulteration, andContamination

The variability of HDS is well documented for some

products.3538

Because of the nature of botanical prod-ucts, which may vary over time and under differentharvest conditions, it can be assumed that all HDS aresusceptible to variability. Their ingredients may changein concentration, purity, and potency depending onconditions and location of harvest.

Although it is tempting to attribute liver injury to anadulterant, even when that agent is known to have toxicpotential, such a presumption is not valid without toxi-cologic conrmatory testing.

Hepatotoxicity Associated With Specic

Products and Ingredients

Currently there is no conventional paradigm fororganizing HDS. Categorization that is based on mar-keted use is therefore a reasonable organizationalapproach. Furthermore, marketed products for specicbenets are likely to contain similar ingredients, thus inmany cases resulting in categorization of the individualingredients contained in the marketed products.

Weight Loss Supplements

Hydroxycut. Hydroxycut comprises many differentsupplements and is most commonly marketed toincrease metabolism. The rst 2 cases of Hydroxycut-associated liver injury were initially reported in2005.39 Although the FDA ordered removal of ephedra

from original formulations of Hydroxycut and otherephedra-containing supplements, additional cases ofhepatotoxicity with Hydroxycut have been reported.40

These cases among others, including one fatality,4144

led the FDA to post a warning on the potential hepato-toxicity of Hydroxycut in 2009. The manufacturer sub-sequently withdrew many but not all Hydroxycutproducts from the market.45 The Hydroxycut experienceis illustrative of the problem with HILI; pinpointing theingredient responsible for injury is a difcult endeavor.

Herbalife. Herbalife products are marketed forvarious purposes, including weight management, energyand tness, as well as targeted nutrition.46 Hepato-toxicity associated with the use of this product line wasinitially reported in 2 separate case series, one fromIsrael47 and the other from Switzerland.48 The reportfrom Israel prompted withdrawal of a locally manufac-tured product because of concerns that either adultera-tion or contamination was the cause for injury. Anothercase series from Spain further underscores the potentialfor this product line to cause hepatotoxicity.49

Green tea. Green tea extract (GTE), derived from theleaves of Camellia sinensis, is a frequent ingredient ofHDS promoting weight loss. Although several have pro-posed cellular-protective effects of this compound

through its antioxidant properties,5052

reports ofGTEs

potential hepatotoxicity have also been published.5356

Early reports were linked to the weight loss supple-ment, Exolise. These and other cases led to the decisionto suspend the manufacturing of this supplement inSpain and France.57

Exposure has also been shown to be increased in thefasting state in both animals and humans.58,59 Thepattern of injury most commonly described with patients

Table 1. Overview of Causality Assessment Methods

RUCAM/CIOMS23 Maria and Victorino30 Naranjo25 DILIN31

Temporal relationship Yes Yes Yes Yes

Course after discontinuation Yes Yes Yes Yes

Specic to liver injury Yes Yes No Yes

Hepatitisvs Cholestatic Yes No No No

Risk factorsa Yes Yes Yes Yes

Age of patient Yes No No No

Extrahepatic manifestations No Yes No No

Placebo challenge No No Yes No

Reported toxicity history Yes Yes No Yes

Rechallenge Yes Yes Yes Yes

Dose effect No No Yes No

Interobserver correlation No No No Yes

aViral hepatitis, alcohol, biliary disease, shock liver, etc.

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taking GTE-containing products is hepatocellular, andmost patients seem to recover with cessation of use.60

In a systematic review of the available literature by theUnited States Pharmacopeia, it was concluded that althoughone should be concerned that extracts of green tea maypredispose to hepatotoxicity,a cautionary labeling statementin the monograph was not issued by this organization.61,62

Usnic acid. Usnic acid is a metabolite derived fromlichens.63 Its weight loss property was incidentallynotedas a side effect of exposed workers in the1930s.64 As amembrane uncoupler, usnic acid leads to an increase infat metabolism and desired weight loss; however, withthis effect there is a concomitant increase in oxidativestress and cellular injury.63,65

Compounds containing usnic acid have been linked tosevere hepatotoxicity includingfulminant hepatic failurerequiring liver transplantation.6670

An FDA warning on the use of Lipokinetix, an usnicacidcontaining product, was issued in 2001 as regardsits risk for liver injury and liver failure.71 Ultimately,

Lipokinetix was taken off the market, but other supple-ments containing usnic acid remain available.

Health-Promoting Herbal Supplements

Black cohosh. Cimicifuga racemosa, more commonlyknown as black cohosh, has been used to treat gyneco-logic disorders, especially menopausal symptoms. Itsactive ingredients are extracted from the root/rhizome ofthis herb.72

The majority of HILI cases with black cohosh havedescribed an extensive hepatocellular injury with

concomitant jaundice that in some cases resulted infulminant hepatic failure.7380 Subsequent to the appli-cation of the Naranjo scale to determine causality forblack cohosh hepatotoxicity, the United States Pharma-copeia determined that therewas sufcient evidence toissue a cautionary monograph.81 However, low causalityscores by using the Council for International Organiza-tions of Medical Sciences (CIOMS)/RUCAM scale appliedto many of these cases challenge the causal association ofblack cohosh with liver injury.82,83

Pyrrolizidine alkaloids. Toxicity from pyrrolizidinealkaloids has been known for many years. The plant

species most commonly associated with hepatotoxicity,Symphytum, is otherwise known as comfrey tea.84 Initialcase reports of hepatotoxicity in the form of venoocclu-sive disease originated from Afghanistan and Indiawhere these plants are commonly used to make teas.85,86

However, additional cases worldwide soon followed.8789

The mechanism by which alkaloids causeinjury centersaround their metabolism is via CYP3A.90,91 The alkaloidsare metabolized to N-oxides and conjugated dienic pyrrolesthat affect the structure and function of hepatocellularproteins. Injury can persist beyond the discontinuation ofthe ingestion of the alkaloid because of the formation ofadducts with the proteins and nucleic acids with which they

react, thus leading to chronic liver injury.92

Kava. Kava, Piper methysticum, is found in variousdietary supplements used to promote sleep and improveanxiety and menopausal symptoms. The key ingredientsare the kava pyrones.93 Since the initial reports of necro-tizing hepatitis and early cases of fulminant hepatic failure,multiple cases of variable degrees of liver injury includingdeath have been reported with kava ingestion.9499 As

a result, restrictions were placed on kava-containingproducts in many different countries as summarized bythe Natural Standard Research Collaboration.100

A recent analysis of previously reported cases of kavahepatotoxicity subjected to the CIOMS/RUCAM causalityscoring system identied that only 1 of 26 cases waslikely related to kava.101 Additional cases subject toscrutiny by using the CIOMS/RUCAM scoring systemfurther question the relationship between kava andhepatotoxicity.102 Thus far, the specic hepatotoxin inkava is unknown.

Joint Health Supplements

Flavocoxid. This supplement, distributed as Limbrel, isused to manage symptoms of osteoarthritis and is cate-gorized as a medical food, which requires a providerprescription. However, unlike FDA-regulated drugs, as amedical food, it does not need to undergo rigorous pre-marketing safety and efcacy studies.103 The mechanismof the plant-derived ingredients is proposed to be medi-ated through the inhibition of cyclooxygenase and5-lipoxygenase, which blocks the inammatory cascade.104

Initial studies identied a mild transaminase elevation, but

a recent case series reported 4 patients who developed asignicant transaminase elevation and hyperbilirubinemia.These cases were among 877 patients enrolled in theDILIN prospective study, and follow-up showed nodevelopment of chronicity. The pattern of injury was amixed hepatocellular and cholestatic pattern with a latencyperiod of 212 weeks.105 These cases of hepatic injurywere more severe than initial reports.106109

Glucosamine-based supplements. Move Free Advancedis used in the United States to help with joint discomfort.Its main ingredients are glucosamine, chondroitin, hya-luronic acid, in addition to a Uniex proprietary extract,which is composed of Chinese skullcap and black catechu.

Two cases of hepatotoxicity withuse of this supplementhave been reported recently.110 Another recent casereport described the development of hepatocellular injuryin a patient taking over-the-counter glucosamine.111

Bodybuilding Supplements

Anabolic steroids. In an effort to limit their access,anabolic steroids were classied as Class III controlledsubstances in 1991, and their control was furtherexpanded in 2004.112 Their potential hepatotoxicity wasrecognized early on with the observation of a link be-

tween anabolic androgenic steroids and jaundice and



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liver tumors.113,114 Subsequent animal studies suggestedthat anabolic steroids are capable of altering cellularmetabolism as well as exerting a proliferative effect onliver cells.115 DILI associated with anabolic steroidsencompasses cholestasis, proliferation of bile ducts,atypical hyperplasia of hepatocytes, peliosis hepatitis,hepatocellular cancer, cholangiocarcinoma, and hepatic

adenomas.116118

In a recent report, 20 male bodybuilders taking variousdietary supplements, among them a newer testosterone-containing supplement, T Bomb II, experienced hepato-cellular injury. Formal causality assessment (RUCAM)assigned a possible score.119 Another supplement pre-sumed to contain anabolic steroids that has been linked tohepatotoxicity is Superdrol. In this small case series, pa-tients developed a mixed hepatocellular and cholestaticpattern of injury, in which the cholestatic component ofthe injury took several weeks to resolve.120 On the basis ofthese and other case reports, it is reasonable to concludethat HDS used for bodybuilding and presumed to containanabolic steroids can lead to liver injury that is typicallycholestatic in nature and prolonged.

Despite the link between anabolic steroids and hep-atotoxicity, the use of these agents remains prevalent.121

Future Directions in Research

The limitations in attributing liver injury to aningredient within any given dietary supplement is thesingle greatest challenge to clinicians and researchersinterested in the eld of HILI. Even detailed chemical

analysis of products, an expensive and complexendeavor, does not necessarily identify the agentresponsible for injury. An alternative approach is to usechemical analysis to identify ingredients common toproducts implicated in injury. In this way, hypothesescould be constructed to propose culprit ingredients,which would then be subjected to formal toxicologicanalysis. Neither of these approaches precludes thepossibility of idiosyncratic injury or injury resulting froman ingredient in susceptible individuals. Identication ofgenetic susceptibilities to injury from common dietaryingredients, such as GTE or its component catechins, is

an interesting area of research that merits exploration. Abetter understanding of the epidemiology of HILI isneeded to identify the scope of the problem, the mostcommon groups affected, and to develop disease man-agement and prevention strategies. However, withoutmore accurate estimates of the overall use of HDS andmore complete reporting of adverse events, reliabledisease prevalence and incidence statistics cannot bemade. Finally, much more needs to be learned about whypeople use products and where information on their useis obtained. Such information is applicable not only toHILI, but in a broader sense it will facilitate preventativemeasures by better informing regulatory approaches to

ensure the safety of HDS.

HDS-induced Liver Injury Resources forthe Clinician

Reporting of adverse events that are thought to bedue to HDS or any drug or medical device can be done byboth patients and providers through the FDAs Med-Watch system. This can occur online (http://www.fda.

gov/Safety/MedWatch/default.htm) or through its hot-line (1-800-FDS-1088). Reports of suspected dietarysupplement toxicity are then triaged to the Center forFood Safety and Applied Nutrition, which bears the re-sponsibility to investigate reports of injury and prove aproduct unsafe.

References

1. Metcalfe A, Williams J, McChesney J, et al. Use of comple-

mentary and alternative medicine by those with a chronic dis-

ease and the general population: results of a national population

based survey. BMC Complement Altern Med 2010;10:58.

2. Seeff LB, Curto TM, Szabo G, et al. Herbal product use bypersons enrolled in the Hepatitis C Antiviral Long-Term Treat-

ment against Cirrhosis (HALT-C) Trial. Hepatology 2008;

47:605612.

3. Blendon RJ, DesRoches CM, Benson JM, et al. Americans

views on the use and regulation of dietary supplements. Arch

Intern Med 2001;161:805810.

4. Radimer K, Bindewald B, Hughes J, et al. Dietary supplement

use by US adults: data from the National Health and Nutrition

Examination Survey, 1999-2000. Am J Epidemiol 2004;

160:339349.

5. Timbo BB, Ross MOPP, McCarthy PV, et al. Dietary supple-

ments in a national survey: prevalence of use and reports of

adverse events. J Am Diet Assoc 2006;106:19661974.

6. Cavaliere C, Rea P, Lynch ME, et al. Herbal supplement sales

rise in all channels in 2009. Herbal Gram 2010;86:6265.

7. Available at: http://www.who.int/mediacentre/factsheets/fs134/

en/.htm. Accessed February 25, 2013.

8.Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced

hepatic injuries: a French population-based study. Hepatology

2002;36:451455.

9.De Valle MB, Av Klinteberg V, Alem N, et al. Drug-induced liver

injury in a Swedish University hospital out-patient hepatology

clinic. Aliment Pharmacol Ther 2006;24:11871195.

10.De Abajo FJ, Montero D, Madurga M, et al. Acute and clinically

relevant drug-induced liver injury: a population based case-

control study. Br J Clin Pharmacol 2004;58:7180.

11.Galan MV, Potts JA, Silverman AL, et al. The burden of acute

nonfulminant drug-induced hepatitis in a United States ter-

tiary referral center [corrected]. J Clin Gastroenterol 2005;

39:6467.

12.Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-

onset jaundice: how often is it caused by idiosyncratic drug-

induced liver injury in the United States? Am J Gastroenterol

2007;102:558562.

13.Andrade RJ, Lucena MI, Fernandez MC, et al. Drug-induced liver

injury: an analysis of 461 incidences submitted to the Spanish

registry over a 10 year period. Gastroenterology 2005;

129:512521.

14.Ibanez I, Perez E, Vidal X, et al. Grup dEstudi Multicentric dHe-

patotoxicitat Aguda de Barcelona (GEM-HAB): prospective

http://www.fda.gov/Safety/MedWatch/default.htmhttp://www.fda.gov/Safety/MedWatch/default.htmhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref1http://refhub.elsevier.com/S1542-3565(13)01094-X/sref1http://refhub.elsevier.com/S1542-3565(13)01094-X/sref1http://refhub.elsevier.com/S1542-3565(13)01094-X/sref1http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref3http://refhub.elsevier.com/S1542-3565(13)01094-X/sref3http://refhub.elsevier.com/S1542-3565(13)01094-X/sref3http://refhub.elsevier.com/S1542-3565(13)01094-X/sref3http://refhub.elsevier.com/S1542-3565(13)01094-X/sref3http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref5http://refhub.elsevier.com/S1542-3565(13)01094-X/sref5http://refhub.elsevier.com/S1542-3565(13)01094-X/sref5http://refhub.elsevier.com/S1542-3565(13)01094-X/sref5http://refhub.elsevier.com/S1542-3565(13)01094-X/sref6http://refhub.elsevier.com/S1542-3565(13)01094-X/sref6http://refhub.elsevier.com/S1542-3565(13)01094-X/sref6http://www.who.int/mediacentre/factsheets/fs134/en/.htmhttp://www.who.int/mediacentre/factsheets/fs134/en/.htmhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref7http://refhub.elsevier.com/S1542-3565(13)01094-X/sref7http://refhub.elsevier.com/S1542-3565(13)01094-X/sref7http://refhub.elsevier.com/S1542-3565(13)01094-X/sref7http://refhub.elsevier.com/S1542-3565(13)01094-X/sref8http://refhub.elsevier.com/S1542-3565(13)01094-X/sref8http://refhub.elsevier.com/S1542-3565(13)01094-X/sref8http://refhub.elsevier.com/S1542-3565(13)01094-X/sref8http://refhub.elsevier.com/S1542-3565(13)01094-X/sref9http://refhub.elsevier.com/S1542-3565(13)01094-X/sref9http://refhub.elsevier.com/S1542-3565(13)01094-X/sref9http://refhub.elsevier.com/S1542-3565(13)01094-X/sref9http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref12http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref11http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref10http://refhub.elsevier.com/S1542-3565(13)01094-X/sref9http://refhub.elsevier.com/S1542-3565(13)01094-X/sref9http://refhub.elsevier.com/S1542-3565(13)01094-X/sref9http://refhub.elsevier.com/S1542-3565(13)01094-X/sref9http://refhub.elsevier.com/S1542-3565(13)01094-X/sref8http://refhub.elsevier.com/S1542-3565(13)01094-X/sref8http://refhub.elsevier.com/S1542-3565(13)01094-X/sref8http://refhub.elsevier.com/S1542-3565(13)01094-X/sref8http://refhub.elsevier.com/S1542-3565(13)01094-X/sref7http://refhub.elsevier.com/S1542-3565(13)01094-X/sref7http://refhub.elsevier.com/S1542-3565(13)01094-X/sref7http://refhub.elsevier.com/S1542-3565(13)01094-X/sref7http://www.who.int/mediacentre/factsheets/fs134/en/.htmhttp://www.who.int/mediacentre/factsheets/fs134/en/.htmhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref6http://refhub.elsevier.com/S1542-3565(13)01094-X/sref6http://refhub.elsevier.com/S1542-3565(13)01094-X/sref6http://refhub.elsevier.com/S1542-3565(13)01094-X/sref5http://refhub.elsevier.com/S1542-3565(13)01094-X/sref5http://refhub.elsevier.com/S1542-3565(13)01094-X/sref5http://refhub.elsevier.com/S1542-3565(13)01094-X/sref5http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref4http://refhub.elsevier.com/S1542-3565(13)01094-X/sref3http://refhub.elsevier.com/S1542-3565(13)01094-X/sref3http://refhub.elsevier.com/S1542-3565(13)01094-X/sref3http://refhub.elsevier.com/S1542-3565(13)01094-X/sref3http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref2http://refhub.elsevier.com/S1542-3565(13)01094-X/sref1http://refhub.elsevier.com/S1542-3565(13)01094-X/sref1http://refhub.elsevier.com/S1542-3565(13)01094-X/sref1http://refhub.elsevier.com/S1542-3565(13)01094-X/sref1http://www.fda.gov/Safety/MedWatch/default.htmhttp://www.fda.gov/Safety/MedWatch/default.htm


6/8

surveillance of acute serious liver disease unrelated to infectious,

obstructive, or metabolic diseases; epidemiological and clinical

features, and exposure to drugs. J Hepatol 2002;37:592600.

15.Wai CT. Presentation of drug-induced liver injury in Singapore.

Singapore Med J 2006;47:116120.

16.Johannsson M, Ormarsdottir S, Olafsson S. Hepatotoxicity asso-

ciated with the use of herbalife. Laeknabladid 2010;96:167172.

17. Navarro VJ, Barnhart HX, Bonkovsky HL, et al. Herbal and di-

etary supplement induced hepatotoxicity in the U.S. Gastroen-

terology 2012;142:S1, S-41.

18. U.S. Food and Drug Administration. Dietary supplements. Avail-

able at:http://www.fda.gov/Food/DietarySupplements/default.htm.

Accessed February 25, 2013.

19. U.S. Food & Drug Administration. Dietary supplements guidance

documents & regulatory information. Available at: http://www.

fda.gov/food/guidanceregulation/guidancedocumentsregulatory

information/dietarysupplements/default.htm. Accessed February

25, 2013.

20. Department of Health and Human Services. Manufacturer

of dietary supplements. Available at: http://www.crnusa.org/

FDAunity/FDAManufacturerDietarySupplements121510.pdf.

Accessed February 25, 2013.

21. Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of

nomenclature and causality assessment in drug-induced liver

injury: summary of a clinical research workshop. Hepatology

2010;52:730742.

22. Teschke R, Schwarzenboeck A, Eickhoff A, et al. Clinical and

causality assessment in herbal hepatotoxicity. Expert Opin Drug

Saf 2013;12:339366.

23. Danan G, Benichou C. Causality assessment of adverse re-

actions to drugs-I: a novel method based on the conclusions of

international consensus meetings; application to drug-induced

liver injuries. J Clin Epidemiol 1993;46:13231330.

24.Arimone Y, Begaud B, Miremont-Salame G, et al. Agreement of

expert judgment in causality assessment of adverse drug re-actions. Eur J Clin Pharmacol 2005;61:169173.

25.Naranjo CA, Busto U, Sellers EM, et al. A method for estimating

the probability of adverse drug reactions. Clin Pharmacol Ther

1981;30:239245.

26.Sarma DN, Barrett ML, Chavez ML, et al. Safety of green tea

extracts: a systematic review by the US Pharmacopeia. Drug Saf

2008;6:469484.

27.Teschke R, Schmidt-Taenzer W, Wolff A. Spontaneous reports

of assumed herbal hepatotoxicity by black cohosh: is the liver-

unspecic Naranjo scale precise enough to ascertain causal-

ity? Pharmacoepidemiol Drug Saf 2011;20:567582.

28. Teschke R, Schulze J. Suspected herbal hepatotoxicity: re-

quirements for appropriate causality assessment by the USPharmacopeia. Drug Saf 2012;35:10911097.

29.Benichou C, Danan G, Flahault A. Causality assessment of

adverse reactions to drugs-II: an original model for validation of

drug causality assessment methodscase reports with positive

rechallenge. J Clin Epidemiol 1993;46:13311336.

30.Maria VA, Victorino RM. Development and validation of a clinical

scale for the diagnosis of drug induced hepatitis. Hepatology

1997;26:664669.

31.Fontana RJ, Watkins PB, Bonkovsky HL, et al. Rationale, design

and conduct of the Drug Induced Liver Injury Network pro-

spective study. Drug Saf 2009;32:5568.

32.Rockey DC, Seeff LB, Rochon J, et al. US Drug-Induced Liver

Injury Network: causality assessment in drug-induced liver injury

using a structured expert opinion processcomparison to the

Roussel-Uclaf causality assessment method. Hepatology 2010;

51:21172126.

33.Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical

features, and outcomes from a prospective study of drug

induced liver injury in the United States. Gastroenterology 2008;

135:19241934.

34.Navarro VJ, Barnhart HX, Bonkovsky HL, et al. Diagnosing

hepatotoxicity attributable to herbal & dietary supplements

(HDS): test-retest reliability of a novel causality assessment tool.

J Hepatol 2012;56:S536.

35.Harkey MR, Henderson GL, Gershwin ME, et al. Variability in

commercial Ginseng products: an analysis of 25 preparations.

Am J Clin Nutr 2002;75:600601.

36.Zhang H, Yu C, Jia JY, et al. Contents of four active components

in different commercial crude drugs and preparations of danshen

(Salvia miltiorrhiza). Acta Pharmacol Sin 2002;23:11631168.

37. Manning J, Roberts JC. Analysis of catechin content of com-

mercial green tea products. J Herb Pharmacother 2003;3:1932.

38.Garrara J, Hamrs S, Eberly LE, et al. Variations in product

choices of frequently purchased herbs: caveat emptor. Arch

Intern Med 2003;163:22902295.

39.Stevens T, Qadri A, Zein NN. Two patients with acute liver injury

associated with use of the herbal weight-loss supplement

hydroxycut. Ann Intern Med 2005;1426:477478.

40. Available at: http://fda.gov/NewsEvents/Newsroom/PressAnno

uncements/2004/ucm108379.htm . Accessed April 2, 2013.

41. Jones FJ, Andrews AH. Acute liver injury associated with the

herbal supplement Hydroxycut in a soldier deployed to Iraq. Am

J Gastroenterol 2007;102:23572358.

42.Shim M, Saab S. Severe hepatotoxicity due to hydroxycut: a

case report. Dig Dis Sci 2009;54:40608.

43. Dara L, Hewett J, Kim JK. Hydroxycut hepatotoxicity: a case

series and review of the liver toxicity from herbal weight loss

supplements. World J Gastroenterol 2008;14:69997004.44.Fong TL, Klontz KC, Canas-Coto A, et al. Hepatotoxicity due to

hydroxycut: a case series. Am J Gastroenterol 2010;

105:15611566.

45. Available at: http://www.fda.gov/oc/opacom/hottopics/hydroxy

cut/consumeradvisory.html. Accessed February 25, 2013.

46. Herbalife. Available at: http://www.herbalife.com. Accessed

February 25, 2013.

47. Elinav E, Pinsker G, Safadi R, et al. Association between con-

sumption of herbalife nutritional supplements and acute hepa-

totoxicity. J Hepatol 2007;47:514520.

48.Schoepfer AM, Engel A, Fattinger K, et al. Herbal does not mean

innocuous: ten cases of severe hepatotoxicity associated with

dietary supplements from Herbalife products. J Hepatol 2007;47:521526.

49.Manso G, Lopez-Rivas L, Salgueiro ME, et al. Continuous

reporting of new cases in Spain supports the relationship be-

tween Herbalife products and liver injury. Pharmacoepidemiol

Drug Saf 2011;20:10801087.

50.Jimenez-Lopez JM, Cederbaum AI. Green tea polyphenol epi-

gallocatechin-3-gallate protects HepG2 cells against CYP2E1-

dependent toxicity. Free Radic Biol Med 2004;36:359370.

51. Zhong Z, Froh M, Connor HD, et al. Prevention of hepatic

ischemia: reperfusion injury by green tea extract. Am J Physiol

Gastrointest Liver Physiol 2002;283:957964.

52.Zhong Z, Froh M, Lehnert M, et al. Polyphenols from Camellia

sinensis attenuate experimental cholestasis-induced liver

http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref14http://refhub.elsevier.com/S1542-3565(13)01094-X/sref14http://refhub.elsevier.com/S1542-3565(13)01094-X/sref14http://refhub.elsevier.com/S1542-3565(13)01094-X/sref15http://refhub.elsevier.com/S1542-3565(13)01094-X/sref15http://refhub.elsevier.com/S1542-3565(13)01094-X/sref15http://refhub.elsevier.com/S1542-3565(13)01094-X/sref16http://refhub.elsevier.com/S1542-3565(13)01094-X/sref16http://refhub.elsevier.com/S1542-3565(13)01094-X/sref16http://www.fda.gov/Food/DietarySupplements/default.htmhttp://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/dietarysupplements/default.htmhttp://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/dietarysupplements/default.htmhttp://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/dietarysupplements/default.htmhttp://www.crnusa.org/FDAunity/FDAManufacturerDietarySupplements121510.pdfhttp://www.crnusa.org/FDAunity/FDAManufacturerDietarySupplements121510.pdfhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://refhub.elsevier.com/S1542-3565(13)01094-X/sref18http://refhub.elsevier.com/S1542-3565(13)01094-X/sref18http://refhub.elsevier.com/S1542-3565(13)01094-X/sref18http://refhub.elsevier.com/S1542-3565(13)01094-X/sref18http://refhub.elsevier.com/S1542-3565(13)01094-X/sref19http://refhub.elsevier.com/S1542-3565(13)01094-X/sref19http://refhub.elsevier.com/S1542-3565(13)01094-X/sref19http://refhub.elsevier.com/S1542-3565(13)01094-X/sref19http://refhub.elsevier.com/S1542-3565(13)01094-X/sref19http://refhub.elsevier.com/S1542-3565(13)01094-X/sref20http://refhub.elsevier.com/S1542-3565(13)01094-X/sref20http://refhub.elsevier.com/S1542-3565(13)01094-X/sref20http://refhub.elsevier.com/S1542-3565(13)01094-X/sref20http://refhub.elsevier.com/S1542-3565(13)01094-X/sref21http://refhub.elsevier.com/S1542-3565(13)01094-X/sref21http://refhub.elsevier.com/S1542-3565(13)01094-X/sref21http://refhub.elsevier.com/S1542-3565(13)01094-X/sref21http://refhub.elsevier.com/S1542-3565(13)01094-X/sref22http://refhub.elsevier.com/S1542-3565(13)01094-X/sref22http://refhub.elsevier.com/S1542-3565(13)01094-X/sref22http://refhub.elsevier.com/S1542-3565(13)01094-X/sref22http://refhub.elsevier.com/S1542-3565(13)01094-X/sref23http://refhub.elsevier.com/S1542-3565(13)01094-X/sref23http://refhub.elsevier.com/S1542-3565(13)01094-X/sref23http://refhub.elsevier.com/S1542-3565(13)01094-X/sref23http://refhub.elsevier.com/S1542-3565(13)01094-X/sref23http://refhub.elsevier.com/S1542-3565(13)01094-X/sref23http://refhub.elsevier.com/S1542-3565(13)01094-X/sref23http://refhub.elsevier.com/S1542-3565(13)01094-X/sref24http://refhub.elsevier.com/S1542-3565(13)01094-X/sref24http://refhub.elsevier.com/S1542-3565(13)01094-X/sref24http://refhub.elsevier.com/S1542-3565(13)01094-X/sref24http://refhub.elsevier.com/S1542-3565(13)01094-X/sref25http://refhub.elsevier.com/S1542-3565(13)01094-X/sref25http://refhub.elsevier.com/S1542-3565(13)01094-X/sref25http://refhub.elsevier.com/S1542-3565(13)01094-X/sref25http://refhub.elsevier.com/S1542-3565(13)01094-X/sref25http://refhub.elsevier.com/S1542-3565(13)01094-X/sref25http://refhub.elsevier.com/S1542-3565(13)01094-X/sref26http://refhub.elsevier.com/S1542-3565(13)01094-X/sref26http://refhub.elsevier.com/S1542-3565(13)01094-X/sref26http://refhub.elsevier.com/S1542-3565(13)01094-X/sref26http://refhub.elsevier.com/S1542-3565(13)01094-X/sref27http://refhub.elsevier.com/S1542-3565(13)01094-X/sref27http://refhub.elsevier.com/S1542-3565(13)01094-X/sref27http://refhub.elsevier.com/S1542-3565(13)01094-X/sref27http://refhub.elsevier.com/S1542-3565(13)01094-X/sref28http://refhub.elsevier.com/S1542-3565(13)01094-X/sref28http://refhub.elsevier.com/S1542-3565(13)01094-X/sref28http://refhub.elsevier.com/S1542-3565(13)01094-X/sref28http://refhub.elsevier.com/S1542-3565(13)01094-X/sref28http://refhub.elsevier.com/S1542-3565(13)01094-X/sref28http://refhub.elsevier.com/S1542-3565(13)01094-X/sref28http://refhub.elsevier.com/S1542-3565(13)01094-X/sref29http://refhub.elsevier.com/S1542-3565(13)01094-X/sref29http://refhub.elsevier.com/S1542-3565(13)01094-X/sref29http://refhub.elsevier.com/S1542-3565(13)01094-X/sref29http://refhub.elsevier.com/S1542-3565(13)01094-X/sref29http://refhub.elsevier.com/S1542-3565(13)01094-X/sref30http://refhub.elsevier.com/S1542-3565(13)01094-X/sref30http://refhub.elsevier.com/S1542-3565(13)01094-X/sref30http://refhub.elsevier.com/S1542-3565(13)01094-X/sref30http://refhub.elsevier.com/S1542-3565(13)01094-X/sref31http://refhub.elsevier.com/S1542-3565(13)01094-X/sref31http://refhub.elsevier.com/S1542-3565(13)01094-X/sref31http://refhub.elsevier.com/S1542-3565(13)01094-X/sref31http://refhub.elsevier.com/S1542-3565(13)01094-X/sref32http://refhub.elsevier.com/S1542-3565(13)01094-X/sref32http://refhub.elsevier.com/S1542-3565(13)01094-X/sref32http://refhub.elsevier.com/S1542-3565(13)01094-X/sref32http://refhub.elsevier.com/S1542-3565(13)01094-X/sref33http://refhub.elsevier.com/S1542-3565(13)01094-X/sref33http://refhub.elsevier.com/S1542-3565(13)01094-X/sref33http://refhub.elsevier.com/S1542-3565(13)01094-X/sref34http://refhub.elsevier.com/S1542-3565(13)01094-X/sref34http://refhub.elsevier.com/S1542-3565(13)01094-X/sref34http://refhub.elsevier.com/S1542-3565(13)01094-X/sref34http://refhub.elsevier.com/S1542-3565(13)01094-X/sref35http://refhub.elsevier.com/S1542-3565(13)01094-X/sref35http://refhub.elsevier.com/S1542-3565(13)01094-X/sref35http://refhub.elsevier.com/S1542-3565(13)01094-X/sref35http://fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108379.htmhttp://fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108379.htmhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref36http://refhub.elsevier.com/S1542-3565(13)01094-X/sref36http://refhub.elsevier.com/S1542-3565(13)01094-X/sref36http://refhub.elsevier.com/S1542-3565(13)01094-X/sref36http://refhub.elsevier.com/S1542-3565(13)01094-X/sref37http://refhub.elsevier.com/S1542-3565(13)01094-X/sref37http://refhub.elsevier.com/S1542-3565(13)01094-X/sref37http://refhub.elsevier.com/S1542-3565(13)01094-X/sref38http://refhub.elsevier.com/S1542-3565(13)01094-X/sref38http://refhub.elsevier.com/S1542-3565(13)01094-X/sref38http://refhub.elsevier.com/S1542-3565(13)01094-X/sref38http://refhub.elsevier.com/S1542-3565(13)01094-X/sref39http://refhub.elsevier.com/S1542-3565(13)01094-X/sref39http://refhub.elsevier.com/S1542-3565(13)01094-X/sref39http://refhub.elsevier.com/S1542-3565(13)01094-X/sref39http://www.fda.gov/oc/opacom/hottopics/hydroxycut/consumeradvisory.htmlhttp://www.fda.gov/oc/opacom/hottopics/hydroxycut/consumeradvisory.htmlhttp://www.herbalife.com/http://refhub.elsevier.com/S1542-3565(13)01094-X/sref40http://refhub.elsevier.com/S1542-3565(13)01094-X/sref40http://refhub.elsevier.com/S1542-3565(13)01094-X/sref40http://refhub.elsevier.com/S1542-3565(13)01094-X/sref40http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref43http://refhub.elsevier.com/S1542-3565(13)01094-X/sref43http://refhub.elsevier.com/S1542-3565(13)01094-X/sref43http://refhub.elsevier.com/S1542-3565(13)01094-X/sref43http://refhub.elsevier.com/S1542-3565(13)01094-X/sref44http://refhub.elsevier.com/S1542-3565(13)01094-X/sref44http://refhub.elsevier.com/S1542-3565(13)01094-X/sref44http://refhub.elsevier.com/S1542-3565(13)01094-X/sref44http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref44http://refhub.elsevier.com/S1542-3565(13)01094-X/sref44http://refhub.elsevier.com/S1542-3565(13)01094-X/sref44http://refhub.elsevier.com/S1542-3565(13)01094-X/sref44http://refhub.elsevier.com/S1542-3565(13)01094-X/sref43http://refhub.elsevier.com/S1542-3565(13)01094-X/sref43http://refhub.elsevier.com/S1542-3565(13)01094-X/sref43http://refhub.elsevier.com/S1542-3565(13)01094-X/sref43http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref42http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref41http://refhub.elsevier.com/S1542-3565(13)01094-X/sref40http://refhub.elsevier.com/S1542-3565(13)01094-X/sref40http://refhub.elsevier.com/S1542-3565(13)01094-X/sref40http://refhub.elsevier.com/S1542-3565(13)01094-X/sref40http://www.herbalife.com/http://www.fda.gov/oc/opacom/hottopics/hydroxycut/consumeradvisory.htmlhttp://www.fda.gov/oc/opacom/hottopics/hydroxycut/consumeradvisory.htmlhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref39http://refhub.elsev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65(13)01094-X/sref19http://refhub.elsevier.com/S1542-3565(13)01094-X/sref18http://refhub.elsevier.com/S1542-3565(13)01094-X/sref18http://refhub.elsevier.com/S1542-3565(13)01094-X/sref18http://refhub.elsevier.com/S1542-3565(13)01094-X/sref18http://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://refhub.elsevier.com/S1542-3565(13)01094-X/sref17http://www.crnusa.org/FDAunity/FDAManufacturerDietarySupplements121510.pdfhttp://www.crnusa.org/FDAunity/FDAManufacturerDietarySupplements121510.pdfhttp://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/dietarysupplements/default.htmhttp://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/dietarysupplements/default.htmhttp://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/dietarysupplements/default.htmhttp://www.fda.gov/Food/DietarySupplements/default.htmhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref16http://refhub.elsevier.com/S1542-3565(13)01094-X/sref16http://refhub.elsevier.com/S1542-3565(13)01094-X/sref16http://refhub.elsevier.com/S1542-3565(13)01094-X/sref15http://refhub.elsevier.com/S1542-3565(13)01094-X/sref15http://refhub.elsevier.com/S1542-3565(13)01094-X/sref15http://refhub.elsevier.com/S1542-3565(13)01094-X/sref14http://refhub.elsevier.com/S1542-3565(13)01094-X/sref14http://refhub.elsevier.com/S1542-3565(13)01094-X/sref14http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13http://refhub.elsevier.com/S1542-3565(13)01094-X/sref13


7/8

brosis in rats. Am J Physiol Gastrointest Liver Physiol 2003;

285:10041013.

53.Garcia-Moran S, Saez-Royuela F, Cento E. Acute hepatitis

associated with Camellia thea and Orthosiphon ingestion.

Gastroenterol Hepatol 2004;27:559560.

54.Gloro R, Hourmand-Ollivier I, Mosquet B, et al. Fulminant hep-

atitis during self-medication with hydroalchoholic extract of

green tea. Eur J Gastroenterol Hep 2005;17:11351137.

55.Jimenez-Saenz M, Martinez-Sanchez M. Acute hepatitis asso-

ciated with the use of green tea infusions. J Hepatol 2006;

44:616617.

56.Molinari M, Watt KD, Kruszyna T, et al. Acute liver failure

induced by green tea extracts: a case report and review of the

literature. Liver Transpl 2006;12:18921895.

57. Available at: http://apps.who.int/medicinedocs/en/d/Js4946e/1.

4html. Accessed March 24, 2013.

58. Isbruker RA, Edwards JA, Wolz E, et al. Safety studies on epi-

gallocatechin gallate (EGCG) preparations: part 2dermal,

acute and short term toxicity studies. Food Chem Toxicol 2006;

44:636650.

59.Chow HH, Hakim IA, Vining DR, et al. Effects of dosing condition

on the oral bioavailability of green tea catechins after single-

dose administration of Polyphenon E in healthy individuals.

Clin Cancer Res 2005;11:627633.

60.Garcia-Cortes M, Borraz Y, Lucena MI, et al. Liver injury induced

by natural remedies: an analysis of cases submitted to the

Spanish Liver Toxicity Registry. Rev Esp Enferm Dig 2008;

11:688695.

61. USP. Update on the USP green tea extract monograph. Avail-

able at: http://www.usp.org/usp-nf/notices/retired-compendial-

notices/update-usp-green-tea-extract-monograph . Accessed

March 26, 2013.

62.Sarma DN, Barrett ML, Chavez ML, et al. Safety of green tea

extracts: a systematic review by the US Pharmacopeia. Drug Saf

2008;31:469484.63.Guo L, Qiang S, Fang JL, et al. Review of usnic acid and Usnea

Barbata toxicity. J Environ Sc Health C Environ Carcinoq Eco-

toxicol Rev 2008;26:317338.

64. Cutting WC, Mehrtens HG, Tainter ML. Actions and uses of

dinitriophenol: promising metabolic applications. JAMA 1933;

15:193195.

65.Colman E. Dinitrophenol and obesity: an early twentieth-century

regulatory dilemma. Regul Toxicol Pharmacol 2007;48:115117.

66.Miranda EJ, McIntyre IM, Parker DR, et al. Two deaths attributed

to the use of 2,4-dinitrophenol. J Anal Toxicol 2006;30:219222.

67.Favreau JT, Ryu ML, Braunstein G, et al. Severe hepatotoxicity

associated with the dietary supplement LipoKinetrix. Ann Intern

Med 2002;136:590

595.68.Durazo FA, Lassman C, Han SB, et al. Fulminant liver failure

due to usnic acid for weight loss. Am J Gastroenterol 2004;

99:950.

69.Neff GW, Reddy RK, Durazo FA, et al. Severe hepatotoxicity

associated with the use of weight loss diet supplements

containing ma huang or usnic acid. J Hepatol 2004;41:

10611067.

70.Sanchez W, Maple JT, Burgart LJ, et al. Severe hepatotoxicity

associated with the use of a dietary supplement containing

usnic acid. Mayo Clin Proc 2006;81:541544.

71. U.S. Food and Drug Administration. Reporting serious prob-

lems to FDA. Available at: www.fda.gov/medwatch/how.htm.

Acces sed March 23, 2013.

72.Liske E. Therapeutic efcacy and safety of Cimicifuga racemosa

for gynecologic disorders. Adv Ther 1998;15:4553.

73.Vitetta L, Thomsen M, Sali A. Black cohosh and other herbal

remedies associated with acute hepatitis A. Med J Aust 2003;

21:411412.

74.Nisbet BC, OConnor RE. Black cohoshinduced hepatitis. Del

Med J 2007;79:441444.

75.Lontos S, Jones RM, Angus PW, et al. Acute liver failure asso-

ciated with the use of herbal preparations containing black

cohosh. Med J Aust 2003;179:390391.

76.Whiting PW, Clouston A, Kerlin P. Black cohosh and other

herbal remedies associated with acute hepatitis. Med J Aust

2002;21:440443.

77.Levitsky J, Alli TA, Wisecarver J, et al. Fulminant liver failure

associated with the use of black cohosh. Dig Dis Sci 2005;

50:538539.

78. Lynch CR, Folkers ME, Hutson WR. Fulminant hepatic failure

associated with the use of black cohosh: a case report. Liver

Transpl 2006;12:989992.

79. Joy D, Joy J, Duane P. Black cohosh: a cause of abnormal

postmenopausal liver function tests. Climacteric 2008;11:8488.

80.Vannacci A, Lapi F, Gallo E, et al. A case of hepatitis associated

with long-term use of Cimicifuga racemosa. Altern Ther Health

Med 2009;15:6263.

81.Mahady GB, Low Dog T, Barrett ML, et al. United States phar-

macopeia of the black cohosh case reports of hepatotoxicity.

Menopause 2008;15:628638.

82.Teschke R, Schwarzenboweck A. Suspected hepatotoxicity by

Cimiscifuga racemosa rhizoma (black cohash root): critical

analysis and structures causality assessment. Phytomedicine

2009;16:7284.

83. Teschke R. Black cohosh and suspected hepatotoxicity: in-

consistencies, confounding variables, and prospective use of a

diagnostic causalty algorithma critical review. Menopause

2010;17:426440.84.Smith LW, Culvenor CCJ. Plant sources of hepatotoxic pyrroli-

zidine alkaloids. J Nat Prod 1981;44:129152.

85.Mohabbat O, Srivastava RN, Younos MS, et al. An outbreak of

hepatic veno-occlusive disease in North-Western Afghanistan.

Lancet 1976;2:271276.

86. Tandon BN, Tandon RK, Tandon HD, et al. An epidemic of

veno-occlusive disease in Central India. Lancet 1976;2:

271272.

87. Weston CFM, Cooper BY, Davies JE, et al. Veno-occlusive

disease of the liver secondary to ingestion of comfrey. Br Med J

1987;295:183.

88.Bras G, Jeliffe DB, Stuart KL. Veno-occlusive disease of the liver

with non-portal type of cirrhosis occurring in Jamaica. AMA ArchPathol 1954;57:285300.

89.Stillman AE, Huxtable RJ, Consroe P, et al. Hepatic veno-

occlusive disease due to pyrrolizidine (Senecio) poisoning in

Arizona. Gastroenterology 1977;73:349352.

90.Huan JY, Miranda DR, Buhler PR, et al. Species differenced in

the hepatic microsomal enzyme metabolism of the pyrrolizidine

alkaloids. Toxicol Lett 1998;99:127137.

91.Prakash AS, Pereira TN, Reilly P, et al. Pyrrolizidine alkaloids in

human diet. Mutat Res 1999;443:5367.

92.Chojkier M. Hepatic sinusoidal-obstruction syndrome: toxicity of

pyrrolizidine alkaloids. J Hepatol 2003;3:437446.

93. Singh YN. Kava: an overview. J Ethnopharmoacol 1992;37:

13

45.

http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref46http://refhub.elsevier.com/S1542-3565(13)01094-X/sref46http://refhub.elsevier.com/S1542-3565(13)01094-X/sref46http://refhub.elsevier.com/S1542-3565(13)01094-X/sref46http://refhub.elsevier.com/S1542-3565(13)01094-X/sref47http://refhub.elsevier.com/S1542-3565(13)01094-X/sref47http://refhub.elsevier.com/S1542-3565(13)01094-X/sref47http://refhub.elsevier.com/S1542-3565(13)01094-X/sref47http://refhub.elsevier.com/S1542-3565(13)01094-X/sref48http://refhub.elsevier.com/S1542-3565(13)01094-X/sref48http://refhub.elsevier.com/S1542-3565(13)01094-X/sref48http://refhub.elsevier.com/S1542-3565(13)01094-X/sref48http://refhub.elsevier.com/S1542-3565(13)01094-X/sref49http://refhub.elsevier.com/S1542-3565(13)01094-X/sref49http://refhub.elsevier.com/S1542-3565(13)01094-X/sref49http://refhub.elsevier.com/S1542-3565(13)01094-X/sref49http://apps.who.int/medicinedocs/en/d/Js4946e/1.4htmlhttp://apps.who.int/medicinedocs/en/d/Js4946e/1.4htmlhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://www.usp.org/usp-nf/notices/retired-compendial-notices/update-usp-green-tea-extract-monographhttp://www.usp.org/usp-nf/notices/retired-compendial-notices/update-usp-green-tea-extract-monographhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref53http://refhub.elsevier.com/S1542-3565(13)01094-X/sref53http://refhub.elsevier.com/S1542-3565(13)01094-X/sref53http://refhub.elsevier.com/S1542-3565(13)01094-X/sref53http://refhub.elsevier.com/S1542-3565(13)01094-X/sref54http://refhub.elsevier.com/S1542-3565(13)01094-X/sref54http://refhub.elsevier.com/S1542-3565(13)01094-X/sref54http://refhub.elsevier.com/S1542-3565(13)01094-X/sref54http://refhub.elsevier.com/S1542-3565(13)01094-X/sref55http://refhub.elsevier.com/S1542-3565(13)01094-X/sref55http://refhub.elsevier.com/S1542-3565(13)01094-X/sref55http://refhub.elsevier.com/S1542-3565(13)01094-X/sref55http://refhub.elsevier.com/S1542-3565(13)01094-X/sref56http://refhub.elsevier.com/S1542-3565(13)01094-X/sref56http://refhub.elsevier.com/S1542-3565(13)01094-X/sref56http://refhub.elsevier.com/S1542-3565(13)01094-X/sref57http://refhub.elsevier.com/S1542-3565(13)01094-X/sref57http://refhub.elsevier.com/S1542-3565(13)01094-X/sref57http://refhub.elsevier.com/S1542-3565(13)01094-X/sref58http://refhub.elsevier.com/S1542-3565(13)01094-X/sref58http://refhub.elsevier.com/S1542-3565(13)01094-X/sref58http://refhub.elsevier.com/S1542-3565(13)01094-X/sref58http://refhub.elsevier.com/S1542-3565(13)01094-X/sref59http://refhub.elsevier.com/S1542-3565(13)01094-X/sref59http://refhub.elsevier.com/S1542-3565(13)01094-X/sref59http://refhub.elsevier.com/S1542-3565(13)01094-X/sref60http://refhub.elsevier.com/S1542-3565(13)01094-X/sref60http://refhub.elsevier.com/S1542-3565(13)01094-X/sref60http://refhub.elsevier.com/S1542-3565(13)01094-X/sref60http://refhub.elsevier.com/S1542-3565(13)01094-X/sref60http://refhub.elsevier.com/S1542-3565(13)01094-X/sref61http://refhub.elsevier.com/S1542-3565(13)01094-X/sref61http://refhub.elsevier.com/S1542-3565(13)01094-X/sref61http://refhub.elsevier.com/S1542-3565(13)01094-X/sref61http://www.fda.gov/medwatch/how.htmhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref62http://refhub.elsevier.com/S1542-3565(13)01094-X/sref62http://refhub.elsevier.com/S1542-3565(13)01094-X/sref62http://refhub.elsevier.com/S1542-3565(13)01094-X/sref62http://refhub.elsevier.com/S1542-3565(13)01094-X/sref62http://refhub.elsevier.com/S1542-3565(13)01094-X/sref63http://refhub.elsevier.com/S1542-3565(13)01094-X/sref63http://refhub.elsevier.com/S1542-3565(13)01094-X/sref63http://refhub.elsevier.com/S1542-3565(13)01094-X/sref63http://refhub.elsevier.com/S1542-3565(13)01094-X/sref64http://refhub.elsevier.com/S1542-3565(13)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ef56http://refhub.elsevier.com/S1542-3565(13)01094-X/sref56http://refhub.elsevier.com/S1542-3565(13)01094-X/sref56http://refhub.elsevier.com/S1542-3565(13)01094-X/sref55http://refhub.elsevier.com/S1542-3565(13)01094-X/sref55http://refhub.elsevier.com/S1542-3565(13)01094-X/sref55http://refhub.elsevier.com/S1542-3565(13)01094-X/sref55http://refhub.elsevier.com/S1542-3565(13)01094-X/sref54http://refhub.elsevier.com/S1542-3565(13)01094-X/sref54http://refhub.elsevier.com/S1542-3565(13)01094-X/sref54http://refhub.elsevier.com/S1542-3565(13)01094-X/sref54http://refhub.elsevier.com/S1542-3565(13)01094-X/sref53http://refhub.elsevier.com/S1542-3565(13)01094-X/sref53http://refhub.elsevier.com/S1542-3565(13)01094-X/sref53http://refhub.elsevier.com/S1542-3565(13)01094-X/sref53http://www.usp.org/usp-nf/notices/retired-compendial-notices/update-usp-green-tea-extract-monographhttp://www.usp.org/usp-nf/notices/retired-compendial-notices/update-usp-green-tea-extract-monographhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref52http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref51http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://refhub.elsevier.com/S1542-3565(13)01094-X/sref50http://apps.who.int/medicinedocs/en/d/Js4946e/1.4htmlhttp://apps.who.int/medicinedocs/en/d/Js4946e/1.4htmlhttp://refhub.elsevier.com/S1542-3565(13)01094-X/sref49http://refhub.elsevier.com/S1542-3565(13)01094-X/sref49http://refhub.elsevier.com/S1542-3565(13)01094-X/sref49http://refhub.elsevier.com/S1542-3565(13)01094-X/sref49http://refhub.elsevier.com/S1542-3565(13)01094-X/sref48http://refhub.elsevier.com/S1542-3565(13)01094-X/sref48http://refhub.elsevier.com/S1542-3565(13)01094-X/sref48http://refhub.elsevier.com/S1542-3565(13)01094-X/sref48http://refhub.elsevier.com/S1542-3565(13)01094-X/sref47http://refhub.elsevier.com/S1542-3565(13)01094-X/sref47http://refhub.elsevier.com/S1542-3565(13)01094-X/sref47http://refhub.elsevier.com/S1542-3565(13)01094-X/sref47http://refhub.elsevier.com/S1542-3565(13)01094-X/sref46http://refhub.elsevier.com/S1542-3565(13)01094-X/sref46http://refhub.elsevier.com/S1542-3565(13)01094-X/sref46http://refhub.elsevier.com/S1542-3565(13)01094-X/sref46http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45http://refhub.elsevier.com/S1542-3565(13)01094-X/sref45


8/8

94.Strahl S, Ehret V, Dahm HH, et al. Necrotizing hepatitis after

taking herbal medication. Dtsch Med Wschr 1998;123:

14101414.

95. Eschar M, Sesmeules J. Hepatitis associated with Kava, an

herbal remedy for anxiety. BMJ 2001;322:139.

96. Bujanda L, Palacios A, Silvarino R, et al. Kava-induced acute

icteric hepatitis. Gastroenterol Hepatol 2002;6:434435.

97.Stickel F, Baumuller HM, Seitz K, et al. Hepatitis induced by

Kava (Piper methysticum rhizorna). J Hepatol 2003;39:6267.

98.Kraft M, Spahn TW, Menzel J, et al. Fulminant liver failure after

administration of the herbal antidepressant Kava-Kava. Dtsch

Med Wochenschr 2001;126:970972.

99.Thomsen M, Vitetta L, Schmidt M, et al. Fatal fulminant hepatic

failure induced by a natural therapy containing kava. Med J Aust

2004;180:198199.

100. Ulbricht C, Basch E, Boon H, et al. Safety review of kava (Piper

methysticum) by the Natural Standard Research Collaboration.

Expert Opin Drug Saf 2005;4:779794.

101. Teschke R, Schwarzenboeck A, Hennermann KH. Kava hepa-

totoxicity: a clinical survey and critical analysis of 26 suspected

cases. Eur J Gastroenterol Hepatol 2008;20:11821193.

102. Teschke R, Wolff A. Kava hepatotoxicity: regulatory data se-

lection and causality assessment. Dig Liver Dis 2009;41:

891901.

103. U.S. Food and Drug Administration. Guidance for industry:

frequently asked questions about medicalfoods.SilverSpring, MD:

U.S.Departmentof Health andHuman Services, 2007.Available at:

http://www.fda.gov/food/guidanceregulation/guidancedocuments

regulatoryinformation/medicalfoods/ucm054048.htm . Accessed

January 2, 2012.

104. Altavilla D, Squadrito F, Bitto A, et al. Flavocoxid, a dual inhibitor

of cyclooxygenase and 5-lipoxygenase, blunts pro-inammatory

phenotype activation in endotoxin-stimulated macrophages.

Br J Pharmacol 2009;157:14101418.

105. Chalasani N, Vuppalanchi R, Navarro VJ, et al. Acute liver injurydue to Flavocoxid (limbrel), a medical food for osteoarthritis: a

case series. Ann Intern Med 2013;156:857860.

106. Morgan SL, Baggott JE, Moreland L, et al. The safety of a-

vocoxid, a medical food, in the dietary management of knee

osteoarthritis. J Med Food 2009;12:11431148.

107. Levy RM, Khokhlov A, Kopenkin S, et al. Efcacy and safety of

avocoxid, a novel therapeutic, compared with naproxen: a

randomized multicenter controlled trial in subjects with osteo-

arthritis of the knee. Adv Ther 2010;27:731742.

108. Pillai L, Burnett BP, Levy RM, et al. GOAL: multicenter, open-

label, post-marketing study of avocoxid, a novel dual

pathway inhibitor anti-inammatory agent of botanical origin.

Curr Med Res Opin 2010;26:1055

1063.

109. Primus Pharmaceuticals. Limbrel product information. Scotts-

dale, AZ: Primus Pharmaceuticals, 2011. Available at: www.

limbrel.com/downloads/limbrel_pi. Accessed February 25,

2013.

110. Linnebur SA, Rapacchietta OC, Vejar M, et al. Hepatotoxicity

associated with Chinese skullcap contained in Move Free

Advanced dietary supplement: two case reports and review of

the literature. Pharmacotherapy 2010;30: 750:258e262e.

111. Ebrahim V, Albeldawi M, Chiang DJ. Acute liver injury associated

with glucosamine dietary supplement. BMJ Case Rep 2012,

http://dx.doi.org/10.1136/bcr-2012-007665 .

112. US Department of Justice, Drug Enforcement Administration

(DEA). Rules 2005: implementation of the Anabolic Steroid

Control Act of 2004. Available at: http://www.deadiversion.

usdoj.gov/fed_regs/rules/2005/fr1216/htm . Accessed February

25, 2013.

113.Ishak KG. Hepatic lesions caused by anabolic and contraceptive

steroids. Semin Liver Dis 1981;1:116128.

114.Haupt HA, Rovere GD. Anabolic steroids: a review of the liter-

ature. Am J Sports Med 1984;12:469484.

115.Boada LD, Zumbado M, Torres S, et al. Evaluation of acute and

chronic hepatotoxic effects exerted by anabolic-androgenic ste-roid stanozolol in adult male rats. Arch Toxicol 1999;73:465472.

116.Marin NM, Dayyeh BK, Chung RT. Anabolic steroid abuse

causing recurrent hepatic adenomas and hemorrhage. World J

Gastroenterol 2008;14:45734575.

117. Elsharkawy AM, McPherson S, Masson S, et al. Cholestasis

secondary to anabolic steroid use in young men. BMJ 2012;34:

4e468.

118.Turani H, Levi J, Levin D, et al. Hepatic lesions in patients on

anabolic therapy. Isr J Med Sci 1983;19:332337.

119.Timchec-Hariri A, Balali-Mood M, Aryan E, et al. Toxic hepatitis

in a group of 20 male body-builders taking dietary supplements.

Food Chem Toxicol 2012;50:38263832.

120. Singh V, Rudraraju M, Carey E, et al. Severe hepatotoxicitycaused by a Methasteron-containing performance-enhancing

supplement. J Clin Gastroenterol 2009;43:287.

121.DesJardins M. Supplement use in the adolescent athlete. Curr

Sports Med Rep 2002;1:369373.

Reprint requestsAddress requests for reprints to: Simona Rossi, MD, Division of Hepatology,Einstein Medical Center Philadelphia, Klein Professional Building Suite 505,5401 Old York Road, Philadelphia, Pennsylvania 19141. e-mail: [email protected]; fax: (215) 456-8058.

Conicts of interest

The authors disclose no conicts.

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