hepatotoxicity induced by herbal and dietary...
TRANSCRIPT
Hepatotoxicity Induced by Herbal and DietarySupplementsVictor J. Navarro, MD1 M. Isabel Lucena, MD2
1Division of Hepatology, Einstein Medical Center, Philadelphia,Pennsylvania
2Clinical Pharmacology Service, Instituto de Investigación Biomédicade Málaga (IBIMA), Hospital Universitario Virgen de la Victoria,Malaga University, Malaga, Spain
Semin Liver Dis 2014;34:172–193.
Address for correspondence Victor J. Navarro, MD, Division ofHepatology, Einstein Medical Center, 5401 Old York Road, Suite 505,Philadelphia, PA 19141 (e-mail: [email protected]).
Herbals and dietary supplements (HDS) are consumed bynearly half of the American population and represent anenormous amount of commerce in the United States andworldwide. They are used for many reasons, but mostly as ameans to improve one’s overall feeling of well-being orappearance. In addition, HDS constitute an important partof traditional medical therapies in many parts of the world.Although these substances are often assumed to be naturaland safe, there are many reports of liver injury resulting fromHDS in the literature. Moreover, some products regarded asdietary supplements from a regulatory perspective may notbe naturally occurring, as they are partly or wholly synthe-sized in the laboratory.
The value of some HDS is indisputable. Many naturallyoccurring substances have led to remarkable advances inhuman medicine. Among these include the isolation ofopioids and alkaloids from the Papaver somniferum, digitalisderived from the foxglove plant and used for its cardiaceffects, and quinine derived from cinchona bark and used
in the prevention and management of malaria. Yet, there aremany concerns that may impact the safety of HDS and meritcareful consideration. In this review, we will address hepato-toxicity, one of the most prominent manifestations of end-organ injury associated with HDS.
International Regulatory Frameworks forHerbal and Dietary Supplements
Since the topic of liver injury-induced by HDS was lastpresented in Seminars,1 no significant regulation in theUnited States has been put forth that has had a substantialimpact on the regulatory environment for HDS. The DietarySupplement Health and Education Act (DSHEA) of 19942
remains the foundation for current regulation of HDS. TheDSHEA was championed by Utah Senator Orin Hatch, whoseoriginal goal, as stated and defended in a recent speech to theSenate3 was “clarity, predictability, and a better understand-ing of what the FDA expected from industry and vice versa.
Keywords
► herbal and dietarysupplements
► hepatotoxicity► drug-induced liver
injury
Abstract Herbals and dietary supplements (HDS) can cause hepatotoxicity. Regulation of HDSvaries across the globe. In the United States, it is defined by a law that is now twodecades old. More recent regulatory approaches in Europe still do not require testing forpremarket safety. The true incidence of hepatotoxicity from HDS is unknown. Thepresentation is most often with a hepatocellular enzyme pattern, and the outcomes canbe severe, leading to transplantation in some circumstances. The diagnosis of hepato-toxicity due to HDS is made in the same way as for drugs. However, patients often mustbe coaxed into revealing a history of use. No causality assessment approach is perfectlysuited for hepatotoxicity from HDS, but the Roussel Uclaf Causality Assessment Methodis most used. Future endeavors must focus on defining epidemiology, establishing anaccepted nomenclature, and identifying culprit ingredients, predisposing host factors,and useful biomarkers for injury.
Issue Theme Drug-Induced Liver Injury;Guest Editors, Naga Chalasani, MD, andPaul H. Hayashi, MD, MPH
Copyright © 2014 by Thieme MedicalPublishers, Inc., 333 Seventh Avenue,New York, NY 10001, USA.Tel: +1(212) 584-4662.
DOI http://dx.doi.org/10.1055/s-0034-1375958.ISSN 0272-8087.
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DSHEA provides an appropriate structure that balances therisks and benefits to consumers with continued access andaffordability.” Since enactment of the DSHEA, warnings onseveral products as causes for liver injury have been issued bythe Food and Drug Administration (FDA) (►Table 1). Themostrecent FDA warnings were for products containing multipleingredients: Uprizing 2.0,4 which was found to contain unde-clared synthetic steroids, and OxyElite Pro,5 which has beenimplicated in several cases of acute liver failure, some result-ing in death or liver transplantation.
The DSHEA defines a dietary supplement as any productintended to supplement, but not substitute for diet. Dietarysupplements may contain one or more ingredients thatinclude vitamins, minerals, herbs, or other botanicals; aminoacids; or extracts thereof. The law stipulates that a product’slabel must accurately reflect its contents. Ostensibly, the actprovides the FDA with the authority to monitor the safety ofmarketed products. Unlike conventional pharmaceuticals, theDSHEA affords no assurance to the consumer as to theeffectiveness of a product, maintenance of health, mitigationof disease, or to safety before it becomes available on themarket. Subsequent legislation through the Final Rule forDietary Supplement Current Good Manufacturing Practices(2007) still does not address assurances of safety to theconsumer. Rather, this legislation only gives guidance tomanufacturers on production standards, including an attes-tation that a product is free from adulteration and contami-nation. Essentially, the safety of any marketed dietarysupplement is predicated upon a manufacturer’s commit-ment to regulatory adherence. The burden of proof that aproduct caused harm or of a manufacturer’s nonadherence toregulation rests upon the FDA.
One class of supplements, the medical foods, merit specialmention because they require the supervision of a prescribingphysician.6However, they are still regarded as dietary supple-ments and recognized as such under the DSHEA. They are notregulated with the same rigor as are drugs, having norequirement for preclinical safety testing. A recent case seriesof liver injury resulting from the medical food Flavocoxib7
showed that this type of supplement has the capacity toinduce liver injury.
Across the globe, regulation for HDS is quite varied. In theEuropean Union, regulation is based upon the TraditionalHerbals Medicine Products Directive 2004/24/EC.8 This regu-lation stipulates that products could be licensed for use
following a simplified registration procedure if there wasan acceptably long period of demonstrated safety, specifically15 years in the European Union (EU) and 30 years total, arenot used parenterally, and do not require a medical prescrip-tion. After May 1, 2011, all unlicensed herbal medicinalproducts presented as having properties for treating orpreventing disease in humans or where it has a pharmaco-logical, immunological, or metabolic action must have beeneither marketed as medicines or withdrawn from themarket.Unlike the FDA, the European Medicines Agency has thepurview of herbal medicinal products only. Products consid-ered food supplements or cosmetics are overseen by theEuropean Food Safety Authority (EFSA), the appointed au-thority in the EU.
A Committee on Herbal Medicinal Products (HMPC),9
comprised of scientific experts in the field of herbal medi-cines from various disciplines, was established within theEuropean Medicines Agency in September 2004 to develop alist of herbal substances, preparations, and combinationsthereof that are used in traditional herbalmedicinal products.The HMPC was also charged with creating a library ofmonographs containing information on composition, indica-tions and contraindications, safety, and pharmacologicalproperties for products with well-established use.10 In theUnited Kingdom (UK), the Herbal Medicines Advisory Com-mittee was established to advise on the safety, quality, andefficacy of herbal medicinal products eligible for registrationunder the EU’s regulation, as well as other unlicensed herbalproducts.11
Beyondwhat is discussed above, there are no other broadlyapplied regulatory standards for HDS. In fact, theWorld HealthOrganization (WHO) in 2001 polled 191 member states andfound that of 141 respondents, only 53 (38%) had somelegislation governing HDS use.12 The WHO has taken on thechallenge of protecting and promoting public health andsafety, globally,13 through improved regulation of herbal med-icines with the creation of the International Regulatory Coop-eration for Herbal Medicines (IRCH) in 2006.14
The Prevalence of Use and CommerceAttributable to Herbal and DietarySupplements
The earliest reliable survey in the United States regarding theuse of alternative medicine showed that 34% of those polled
Table 1 U.S. Food and Drug Administration warnings and recalls for liver injury associated with herbal and dietary supplements
Product Year Comments
Comfrey 2001 Contained pyrrolizidine alkaloids
Lipokinetix 2001 Contained phenylpropanolamine, caffeine, yohimbine, diiodothyronine,and sodium usniate
Kava Kava 2002 Caused acute liver failure, hepatitis, cirrhosis
Hydroxycut 2009 Caused acute liver failure
Uprizing 2.0 2011 Found to contain Superdrol (anabolic steroid)
OxyElite Pro 2013 Caused acute liver failure
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Hepatotoxicity Induced by Herbal and Dietary Supplements Navarro, Lucena 173
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used some form, 2.5% using herbal remedies.15 This stands inremarkable contrast to the more recent assessments whichshow that over half of the U.S. population uses supple-ments.16,17 A perusal of any local apothecary reveals themyriad supplement types and brands available to consumers.However, the most commonly used are multivitamins, andthe most common motivations for use are health improve-ment and maintenance.18 Commercially available supple-ments are often marketed with creative and descriptivelabels, and contain many ingredients blended and com-pounded into any one of several forms, including pills,capsules, powders, and elixirs.
Outside of the United States, limited statistics are availableon the prevalence of use of HDS. It is estimated that 80% of thepopulation uses herbals for medical treatment19 in Africa. InEurope, a survey published in 2009 showed great variability,both geographically and by gender. Prevalence of use among10 European countries ranged from 2% of men in Greece tonearly 66% of women in Denmark.20
The rise in use of HDS parallels an increase in commerce.Total sales of herbals and botanical dietary supplements inthe United States have risen consistently over the past 9 yearsto $5.5 billion in 2012.21 Globally, expenditures are expectedto reach $107 billion in 2017.22 Although accurate U.S. orglobal statistics on actual use of HDS are not available, one caninfer that there has been an increase based on this rising HDScommerce.
Epidemiology of Liver Injury due to Herbaland Dietary Supplements
The epidemiology of liver injury due to HDS is largelyunknown, but is likely to be strongly influenced by type ofsupplement, geography, and cultural acceptance. As statedearlier, use of HDS is an integral part of medical care in Africa.Similar commonplace use may be seen in Southeast Asia, andin Central and South America where there also is a longhistory of traditional herbal medicine.
The true prevalence and incidence of hepatotoxicity due toHDS cannot be estimated because of the unavailability of adenominator, the number of persons in a population whoconsume them. Accurate estimates based on sales are hin-dered by the many places where one can obtain HDS, such ashealth food stores, the Internet, and gymnasiums. Even in theelegant population-based prospective 2-year cohort study onthe incidence of hepatotoxicity in Iceland in which HDSaccounted for 16% of cases, the true impact of hepatotoxicityfrom natural products could not be determined.23
Information on liver injury due to HDS has come mainlyfrom published case reports or case series. However, infer-ences on its relative frequency could be made from prospec-tive drug-induced liver injury (DILI) cohorts and retrospectivedatabases that capture hepatotoxicity cases due to HDS(►Table 2). National and international DILI registries suchas U.S. Drug-Induced Liver Injury Network (DILIN), the Span-ish DILI Registry, and Spanish-Latin American DILI network(SLATINDILI) found 9%, 6%, and 8% of their liver injury caseswere due to HDS, respectively.24–26 However, in Southeast
Asia, HDS are a more prominent cause of liver injury. In aKorean collaboration among 17 hospitals, 73% of all DILI caseswere due to HDS.27 Similarly, a single-hospital study inSingapore reported 71% of liver injury cases were due toHDS. Interestingly, 9 of 31 complementary and alternativemedicines identified as causal agents in this studywere foundto contain adulterants, including pharmaceuticals such ascodeine, dexamethasone, and paracetamol.28
The prevalence of liver injury due to HDS relative tomedications has also been demonstrated in a retrospectiveanalysis of patients seen in a single Chinese gastroenterologyunit, with 40% of the recorded cases being caused by HDS.29
Interestingly, less than 2% of 313 liver injury patients seen inan Indian single center were caused by HDS. The authorsspeculated that this low frequency was due to both the morecommon use of HDS after liver injury onset and the healthsystem organization in India, which has a network of special-izedmedical centers accustomed to, and perhaps less likely toreport, the use and adverse events associated with HDS.30
The frequency of liver injury caused by nonprescriptionperformance-enhancing products possibly tainted with orfunctioning as androgenic anabolic steroids reported both inthe DILIN and the Spanish DILI registries is a growing concern.In the DILIN registry, the proportion of cases attributed toHDS increased from7% in 2004 to 2005 to 20% in 2010 to 2012and the increase occurred with bodybuilding (2–7%) as wellas other HDS (5–12%).31 Similarly, in a span of 19 years in theSpanish-DILI Registry, 80% (20/25) of the cases of liver injurydue to anabolic steroids occurred in themost recent 3 years ofthe study (unpublished data).
Among cases of liver injury due to HDS enrolled inprospective registries, 1.5 to 11% have been reported to resultin acute liver failure (ALF), underscoring the life-threateningpotential of some HDS (►Table 2). Furthermore, HDS, non-prescription medications, weight-loss treatments, and illicitsubstances were responsible for 10.6% of ALF cases, andranked second only to antimicrobials as a cause for ALF inthe U.S. Acute Liver Failure Study group during a 10-yearperiod.32
Hepatotoxicity due to HDS is believed to be underdiag-nosed. Underreporting probably occurs due to lack of aware-ness of their hepatotoxic potential and patient reluctance toreport use of HDS. Based on a 2007 national health survey,only 43.5% of consumers of HDS disclosed their use to theirprovider.33 Besides impeding a correct diagnosis in hepato-toxicity due to HDS, concomitant use of HDS can increase therisk of adverse reaction by interaction with concomitantlyused medications.
Clinical Presentation
The liver biochemistry pattern of hepatotoxicity due to HDScan be categorized as hepatocellular, cholestatic, or mixedpattern, similar to the way drug-induced injury is described.However, the hepatocellular pattern of injury seems morefrequent than with conventional medications, ranging from63 to 89% across the prospective registries (►Table 2) andreaching 93% in the ALFSG experience (vs. 77% attributable to
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Table
2Prospe
ctivean
dretrospe
ctivestud
iesof
drug
-indu
cedliver
injury.Prev
alen
cean
dph
enotyp
eof
hepatotox
icitydu
eto
herbal
anddietarysupp
lemen
ts
PROSP
ECTIVE
Span
ishDILI
Reg
istry2
5USDILIN
24SL
ATINDILI26
Korea2
7Singap
ore
28USALF
study
group32
Icelan
d23
Years
1994
–201
320
03–2
008
2012
–201
320
05–2
007
2004
–200
619
98–2
007
2010
–201
1
Type
ofReg
istry
Nationa
l(43ce
nters)
Nationa
l(5
centers)
Multina
tiona
l(9
coun
tries)
Nationa
l(17ce
nters)
Sing
lece
nter
Nationa
l(23c
enters)
Population-ba
sed
stud
y
DILIcases
861
300
116
371
3113
396
Most
freq
uent
causative
agen
tsn(%
)
Antibiotics
332(38%)
Nervo
ussystem
128(15%)
Cardiov
ascu
larsystem
98(11%
)Muscu
loskeletal
system
97(11%
)
Antibiotics
136(45.5%
)Cen
tral
nervou
ssystem
agen
ts45
(15%
)Dietary
supp
lemen
ts28
(9%)
Antibiotics
31(27%
)Muscu
lo-skeletalsystem
23(20%
)Nervo
ussystem
12(10%
)Gen
itou
rina
rysystem
andsexho
rmon
es12
(10%
)
Herba
lmed
ications
102(27.5%
)Hea
lthfood
sor
dietary
supp
lemen
ts51
(13.7%
)Med
icinal
herbsor
plan
ts35
(9.4%)
Folk
remed
ies
32(8.6%)
Chine
setrad
itiona
lCAM
17(55%
)Malay
CAM
5(16%
)AntiTB
drug
s2(6%)
Antibiotics
61(46%
)CAM,no
nprescription
med
ications,dietary
supp
lemen
ts,weigh
t-loss
trea
tmen
ts,an
dillicitsubstan
ces
14(10.6%
)Antiepile
ptic
drug
s11
(8%)
Antim
etab
olites
and
enzymeinhibitors
11(8%)
Antibiotics
36(37%
)Dietary
supplem
ents
15(16%
)Im
mun
osup
pressant
drugs
10(10%
)Psycho
trop
ic7(7%)
NSA
IDS6(6%)
HDS,
n(%
)To
talH
DS
n(%
)54
(6%)
28(9%)
9(8%)
271(73%
)22
(71%
)14
(10.6%
)15
(16%
)
Mea
nag
e(ran
ge)
42(18–
78)
4543
(27–
60)
51(18–
79)
——
—
Herbals
30(55%
)22
(78%
)5(55%
)0
CAM
4(7%)
0(2210
0%)
AAS
20(37%
)6(21%
)4(44%
)0
Patternofinjury
Hep
atocellu
lar
42(78%
)18
(63%
)8(89%
)21
1(78%
)16
(74%
)13
(93%
)7(47%
)
Cholestatic
/Mixed
12(22%
)10
(38%
)1(11%
)60
(22%
)6(26%
)1(7%)
8(53%
)
DILIwithpos
itive
autoan
tibodies
10(18%
)—
4(44%
)—
6(26%
)1(7%)
—
Rec
halleng
e5(9.2%)
—1(11%
)—
——
—
Hosp
italization
35(65%
)11
(41%
)4(44%
)25
(9%)
—14
(100
%)
3(20%
)
ALF
3(5%)
1(3.5%)
1(11%
)4(1.5%)
1(4.5%)
14(100
%)
0
Live
rtran
splant
3(5%)
1(3.5%)
02(0.7%)
1(4.5%)
7(50%
)0
Dea
th0
01(11%
)2(0.7%)
04(29%
)0
Abbrev
iation
s:ALF,a
cute
liver
failu
re;A
AS,an
abolican
droge
nicsteroids;AntiTB,
antitubercu
losis;
CAM,c
omplemen
tary
andalternativemed
icine;
HDS,
herbal
anddietarysupp
lemen
ts;D
ILI,drug
-induc
edliver
injury.
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DILI cases).32 This clinical presentation has prognostic im-plications, as a hepatocellular pattern has been associatedwith a more severe outcome.34,35 Indeed, need for livertransplantation is more likely in cases with liver injuryassociated with HDS.31
The spectrum of clinical features resulting from hepato-toxicity due to HDS is quite broad. Acute and chronic hepatitiswith autoimmune features, hepatic fibrosis, cirrhosis, zonalor diffuse hepatic necrosis, microvesicular steatosis, giant cellhepatitis, cholestatic hepatitis, bile duct injury, veno-occlu-sive disease, fulminant liver failure, and carcinogenesis haveall been described.36,37 The autoimmune phenotype may bemore common with injury from HDS, occurring in up to 44%of the cases in one series.26 Patients with hepatotoxicity dueto HDS tend to be younger than those with hepatotoxicityfrom conventional medications, probably because youngerpeople more commonly take certain HDS, such as “fat burn-ing,” weight-loss, and body-building agents. No informationin pediatric populations is available andmay be either under-reported across the registries or there is less use of HDS.Rechallenge, either inadvertent or voluntary, is more com-mon with HDS consumption ranging from 9 to 11% ascompared with 6% in an analysis of 520 DILI cases includedin the Spanish registry.38
Diagnosis
Making an accurate diagnosis of hepatotoxicity attributableto HDS is predicated upon the same stepwise approach as isfollowed for conventional drug-related hepatotoxicity, anddiscussed elsewhere in this issue of Seminars. At the outset,the astute clinician must recognize that hepatotoxicity neednot present with obvious signs of liver injury such as jaundiceor encephalopathy. Rather, liver injury can present in muchmore subtle ways, such as with malaise, abdominal pain, ornausea. The timing of symptoms with recently begun HDSwill suggest a potential causative link. At this earliest stage,however, the clinician must specifically ask about use of HDS,as many may not volunteer this information to their healthcare providers without prompting.15,39–41
Just as with a DILI diagnosis, making a diagnosis ofhepatotoxicity due to HDS requires that other causes, eitheralternative or pre-existing of liver injury be excluded, includ-ing anatomical, infectious, autoimmune, metabolic, ischemic,alcoholic, and inherited processes. Comprehensive serologi-cal evaluation and hepatic imaging are used in this process ofexclusion.
The respective presentation of liver injury from manypharmaceuticals has been well described in the medicalliterature. The LiverTox website houses a large number ofdrugs and descriptions of their respective hepatotoxicitypresentations.42 Such descriptions help the clinician to es-tablish the association between a hepatotoxic event and thedrug with confidence. Unfortunately, there are only a fewsituations where the phenotype of liver injury due to HDS isso typical that an association between clinical presentationand a product can be made with the same degree of confi-dence as pharmaceuticals. Anabolic steroidal com-
pounds43–46 and other products containing pyrrolidinealkaloids47–50 offer one of the few examples where the injuryphenotype is stereotypic and many times unmistakable. Onlyafter an exhaustive search for alternative explanations can adiagnosis of liver injury attributable to HDS be made withreasonable confidence.
Even in cases where a methodical evaluation has linked asupplement to an injury event, the vagaries of many naturalproducts preclude an unequivocal causal association to aparticular ingredient, or combination of ingredients. Forexample, the inclusion of an unlabeled ingredient that couldlead to harm constitutes adulteration.51 Adulterants reportedinclude substances such as pharmaceuticals, microbials,52,53
heavymetals,54–56 and unlabeled botanicals or chemicals. Notinfrequently, the adulterant leads to an enhanced desiredeffect that is in line with the products purported benefit.Sildenafil has been identified in products marketed to en-hance sexual performance.57,58 Also, herbals may be prone tovariability in regards to their ingredients and their respectiveconcentrations59–61 due to changes in growth and harvestconditions. Unlabeled botanicals may also show up in HDS.For example, in the DILIN’s experience, 40% of HDS that didnot list green tea extract (or any of its component catechins)on the label, had catechins found on careful analysis.62 Recentwork has shown that detecting the genetic sequences ofbotanicals through barcoding may be of great value to verifyingredients of HDS.63 How such technology can be used topredict or prevent end-organ injury has yet to be determined.
Causality assessment is the systematic or semiquantitativeapproach to identify an agent as a cause for end-organ injury.This is used commonly in the research setting and forpublished case reports. Formal assessments were designedwith pharmaceuticals in mind and several have been appliedto DILI.64–67 None were crafted specifically for liver injuryfrom HDS, although experience exists with severalapproaches.
The Naranjo system has68 been used for causality assess-ment with natural products.69 However, it has limited speci-ficity for hepatic reactions. The Roussel Uclaf CausalityAssessmentMethod (RUCAM)was crafted for hepatic adversereactions from pharmaceuticals,64,65,70 and has been used incases of liver injury induced by HDS quite commonly. TheRUCAM assigns points based on the clinical features of a case.However, limitations of this scale when applied to the evalu-ation of liver injury from HDS have been highlighted. Specifi-cally, an important component of the RUCAM requires anassessment of an agent’s labeled reactions, and the literaturepublished about hepatic reactions. Unfortunately, in the caseof HDS, the literature is immature and of insufficient qualityto fulfill this RUCAM component with confidence in mostcircumstances.
In another component of the RUCAM, a lower score isawarded in the setting of more than a 90-day period ofexposure prior to the onset of injury. However, the inherentvariability of botanicals means that different batches of thesame product may have different compositions. Hence, la-tency as a factor in determining the causal associationbetween an agent and liver injury must be thought of
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differently with HDS than with pharmaceuticals. Given thelack of verifiable standards in product quality and composi-tion, it is entirely possible, if not probable, that a naturalproduct may vary over time, even if marketed under the samelabel. Furthermore, causality assessment is confounded bythe fact that patients may be taking a single product withsingle or multiple ingredients, or multiple productsconcurrently.
TheMaria and Victorino Scale represents amodification ofthe RUCAM.66 Its special feature is that it incorporatesextrahepatic manifestations of disease that may hint at anautoimmune pathophysiological basis. This score seemsto perform less well in causality assessment in mostinstances of DILI71 and has not been used to any greatextent in the assessment of liver injury due to HDS orpharmaceuticals.
Finally, the expert opinion process represents the standardapproach used by the DILIN, including the adjudication ofinjury due to HDS.72 Unlike the above-mentioned scoringsystems, the expert opinion approach allows the assessors agreater degree of latitude in making their decisions oncausality. Specifically, all clinical details can be taken intoaccount in determining the attribution of liver injury to anagent. Even this approach, however, remains confounded byfactors unique to HDS as discussed above.
Given the lack of a causality assessment approach that isperfectly suited to and validated for the nuances of HDS, theDILIN attempted to craft an approach that would performmore reliably in this situation. The process, built upon theexpert opinion approach routinely used by the DILIN, putsgreater emphasis on the complexity of HDS, the experts’perception of the quality of the available literature andpersonal experience with injury due to the HDS in question.In a small test-retest reliability study, this approach per-formed with modest accuracy (weighted kappa statistic0.53, 95% confidence interval [CI] 0.20–0.86).73 Given thisperformance, a change in the DILIN’s expert opinion approachto causality assessment for HDS was not adopted. However,the challenges remain andmerit further study. Until a processthat is demonstrably more reliable for liver injury due to HDSis developed, the assessment of causality is best undertakenwith the RUCAM or expert opinion process, as has beenproposed by others.74
Hepatotoxicity due to HDS: Specific Agents,Uses, and Injury Phenotype
►Table 3 outlines the name, common usages, suggested toxicmechanism, clinical presentation, and liver histology of sev-eral HDS linked to hepatotoxicity. The salient features of achosen few that are more likely to be encountered in clinicalpractice are discussed in this section as well. The reader isreferred to other excellent reviews on hepatotoxicity due toHDS for more details on other products.75–77
As for intended uses, we emphasize that there is nowidely accepted classification schema or nomenclature forHDS, many of which are marketed as mixtures of various
ingredients, as opposed to single herbs. In fact, in theDILIN’s experience, most products that caused liver injurywere proprietary blends, not single herbs. Therefore, in arecent presentation of its data, the DILIN assigned HDS thathad been implicated in liver injury to categories based ontheir purported benefits or main marketed uses (►Table 4).This categorization takes into account that many differentingredients often are combined in a given product toachieve a desired effect. Although not a scientific schema,these categories allow clinicians, researchers, and consum-ers to group HDS for comparison purposes, and to facilitaterecognition of clinical presentations that may be commonto some HDS. For example, the products generally used forbodybuilding or muscle enhancement lead to an injurythat is characteristic, with prolonged jaundice, pruritus,minimal inflammation, and complete recovery. A funda-mental problem with any categorization scheme basedon purported uses is that some, if not most HDS aremarketed for more than one purpose, and are not mutuallyexclusive.
Ayurvedic Herbs. Traditional medical therapies are com-monly used in India for various purposes. These have beenlinked to both acute and chronic hepatitis. Contaminationwith heavy metals54,56 has been demonstrated. However,whether the contamination was the cause for injury has notbeen proven.
Androgenic Anabolic Steroids. Liver injury resulting fromandrogenic anabolic steroids runs the spectrum of spaceoccupying lesions to the more typical cholestatic hepatitis.78
Many reports of products used for bodybuilding and muscleenhancement as a suspected cause for liver injury have beenpublished.45,46,79,80 Some have been proven to be taintedwith anabolic steroids.46 Most reported injuries from theseproducts is so typical that the clinical appearance of pro-tracted jaundice in young men taking these agents hasbecome pathognomonic. While the injury is typically chole-static, the most recent report of hepatotoxicity resulting fromperformance enhancers suggested that up to a third may bemore hepatocellular in nature.81
Black Cohosh. Commonly used for menopausal symptoms,this product has been named in numerous reports of attrib-utable liver injury,82–88 with at least one report of adultera-tion.89 This herb has also been reported to produce anautoimmune-type liver injury.86,87 Severe liver injury leadingto transplantation also has been reported.90–92
Chaparral. Used for various reasons (e.g., bronchitis, jointpain, weight loss), this herb derived from the creosote bushhas been associated with severe liver injury and liverfailure.93
GreenTea Extract. Commonly consumed, this agent is oftenextracted and formed into a more potent substance and isfound in many different HDS. Thought to induce oxidativeliver injury, several lines of evidence build a convincing casefor its hepatotoxic potential. Specifically, toxicity demonstrat-ed in animal studies94 and human positive rechallengecases95,96 are most compelling.
Chinese Herbal Remedies. These encompass awide range ofproducts used for various purposes, with weight loss (Ma-
Seminars in Liver Disease Vol. 34 No. 2/2014
Hepatotoxicity Induced by Herbal and Dietary Supplements Navarro, Lucena 177
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eral
da
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ia),
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rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3Com
pen
dium
ofhe
rbal
anddietarysupp
lemen
tsassociated
withliver
injury
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
Aloe
(Aloeperfoliata
var.vera
Aloe
barbad
ensis,Aloe
arbo
rescen
s)
Gastrointestina
lalim
ents
/top
ical
emollie
nt
Ove
r75
iden
tified
in-
gred
ients,
includ
ingan
-thraqu
inon
es,vitamins,
anden
zymes.The
toxic
mec
hanism
isun
know
n.
Acu
teHCda
mag
e.Fe
-malepred
ominan
ce,
mea
nag
e58
years.
Mea
ntimeto
onsetof
symptom
s3mo.
Mea
ntimeto
resolution
2mo.
Portal/lob
ular
inflam
-mationwitheo
sino
phil-
icinfiltratesan
dacidop
hilic
bodies
Positive
rech
alleng
e124
And
roge
nican
abolic
steroids
Body
build
ing
Stan
ozolol
Methy
lepitiostano
lMetha
steron
eTh
etoxicmecha
nism
isun
know
n.
Malepa
tien
ts,mea
nag
e32
y,mea
ntimeto
onset72
d.MainlyHC
damag
epresen
ting
withjaun
dice
(92%
)an
drequ
iringho
spitaliza-
tion
.Pa
tien
tswithhigh
totalb
ilirubinlevelsat
risk
ofde
veloping
acute
rena
lfailure.Cases
ofALF/OLTx.
Intrah
epaticch
olestasis,
hepa
ticstea
tosisan
d/or
pelio
sishe
patic
Live
rtumors(hep
ato-
cellu
larad
enom
aan
dcarcinom
a)
InEU
ifa“d
ietary
sup-
plem
ent”
contains
frau
dulently
substanc
esthat
aredrug
sthey
are
considered
“ille
gal
drug
s”an
dremov
edfrom
themarket
(i.e.,EP
ISTA
NEan
dEP
ISDRO
L)12
5
Atractylisgu
mmifera
(Distaffthistle,
African
remed
y)
Multipleuses:
antipy
retic,
antiem
etic,
abortifacien
t,diuretic,
chew
inggu
m
Con
tainsatractyloside
andcarbox
yatractylo-
side
.Inhibition
ofgluc
oneo
-ge
nesisthroug
hinter-
ferenc
ewithox
idative
phosph
orylation.
Totrigge
rap
optosisby
in-
ducing
mitoc
hond
rial
perm
eability.
Cases
ofhu
man
poison
-ingmainlyin
Africa,
re-
sultingin
hepa
tican
drena
lnec
rosis
Childrenmea
nag
e9y.
Symptom
sap
pea
red
few
hoursafterco
n-sumption.
Mostpa
-tien
tsde
velope
dALF.
Diffuse
hepa
ticne
crosis
126
Ayu
rved
iche
rbs:(N
otall
prod
ucts):Psoralea
cor-
ylifo
lia,A
caciacatechu,
Eclip
taalba
orBa
copa
mon
nieri,
Vetivexiazizaniod
is
Miscella
neou
spu
r-po
ses.
Trad
itiona
lrem
edyin
India.
Possible
contam
ination
withhe
avymetals
(mercu
ry,lea
d,arsenic)
Acu
tean
dch
ronic
hepa
titis
Granu
lomatou
she
pati-
tis,
cirrho
sis
54,56
Bajia
olian
(Dysosmapleian
thum
)Multipleuses:
trea
tmen
tof
snakebite,
lumbag
o,dy
smen
orrhea
Podo
phyllotoxin
Mainlyfemale,
age
rang
ingfrom
33–5
6y.
Use
ofsing
ledo
ses
rang
ingfrom
12–6
0g.
Increasesin
liver
tests
associated
with
127
Seminars in Liver Disease Vol. 34 No. 2/2014
Hepatotoxicity Induced by Herbal and Dietary Supplements Navarro, Lucena178
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ade
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eral
da
Bah
ia),
Dot
. Lib
Info
rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
thrombo
cytope
nia,
leu-
cope
nia,
sensoryataxia,
andpe
riph
eral
numbne
ss.
Blackco
hosh
(Cim
icifu
garacemosa,
Rhizom
eof
Actaea
racemosa)
Ameliorating
men
o-pa
usal
vasomotor
symptom
s
Pathop
hysiolog
ical
mec
hanism
unkn
own.
Wea
kinhibitorof
CYP
2D6
DILIw
ithau
toim
mun
efeatures.Fe
male,
mea
nag
e55
y.Symptom
sap
pea
ring
4moafter
prod
uctco
nsum
ption.
Mea
ntimeto
resolu-
tion
,12
wk.
Theliver
damag
emay
rang
efrom
tran
sien
tincreases
inliver
enzymes
toliver
necrosiswithALF.
Assoc
iatedallergic
reac-
tion
sSa
fety
warning
sby
HMPC
2010
,AEM
PS20
06,
HMPC
2009
.12
8–13
0Prec
aution
onusein
patien
tswithun
-de
rlying
liver
disorders
Boldoleaf
extracts
Boldo-do
-chile
(Peu
mus
boldus
Molina)
Forhe
patican
dga
stro-
intestinal
disorders.
Con
tainsalka
loids,
bol-
dine
flavon
oids,an
dch
enop
odium
oil.
Ascaridoleisthetoxic
ingred
ient
that
inhibits
oxidative
phosph
orylation
Mea
nag
e82
y.Th
esymptom
sap
peared
10moafterco
nsum
ption.
Theliver
damag
ewas
mainlyHC.Mea
ntime
toresolution
was
1mo.
130,13
1
Callilepsislaureola
(Impila,Z
uluremed
y)Stom
achprob
lems,
tape
worm
infestations,
coug
h,im
potenc
e
Atrac
tyloside
sco
mpeti-
tively
inhibitthetran
s-po
rtof
ADPan
dAT
P,bloc
king
mitoc
hond
rial
oxidativeph
osph
oryla-
tion
.Cy
totoxicity
seen
inHep
G2cells
byde
pletionof
glutathion
e.
Cases
ofacuteliver
and
rena
lfailure.Highmor-
talityrate,grea
terthan
90%by
5d.
Diffuse
hepa
ticne
crosis
132
Camellia
sinensis,
Green
tea
(Chá
verde)
Weigh
tloss
Catec
hins
andtheirga
l-lic
acid
esters
(Epigallo-
catech
in-3-gallate)in-
duce
oxidativestress-
liver
damag
e.
Femalepred
ominan
ceat
youn
gerag
es.Pre-
sentationmainlyas
acuteHCda
mag
e.Im
-mun
oalle
rgic
autoim
-mun
efeatures
gene
rally
absent.Laten
cyto
onset
ofsymptom
srang
ing
Inflam
matoryinfiltrates
cholestasis,
occasion
alstea
tosis,
andne
crosis.
Positive
rech
alleng
eExolise,ahy
droa
lcoh
olic
extrac
tofC
.sinen
sis,ha
sbe
enwithd
rawnby
AEM
PS95
,96,13
3 (Con
tinued)
Seminars in Liver Disease Vol. 34 No. 2/2014
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rsid
ade
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eral
da
Bah
ia),
Dot
. Lib
Info
rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
from
10dto
7mo.
Cases
ofALT/O
LTx.
Cam
phor
(Cinna
mom
umcamph
ora)
Rubefacient,muc
olytic.
Topican
doral
administration.
Cyclic
terpen
es/ribo
-some-inac
tivating
pro-
teins.
Cam
phor
ismetab
olized
intheliver.
Infantsaremoresus-
ceptible
fortoxicity
be-
caus
eof
immature
hepa
ticde
toxification
.
Acu
tehe
patitisdu
eto
accide
ntal
expo
sure
tohigh
doses.
Twocases,
both
wereinfants2–
6mo.
Timeto
onsetbe
-tw
een2–
5-d.
Resolu-
tion
afterwithd
rawal.
One
death.
Acu
tehe
patitis,
mim
ics
Reye
synd
rome.
Hep
ati-
tiswithne
crosis
Con
traind
icated
inch
il-dren
unde
r2y1
34,135
Cascara
sagrad
a(Rha
mnu
spu
rshian
a,cascarabu
ckthorn,
Sa-
cred
bark)
Con
stipation
Anthracen
eglycoside
Anthraq
uino
nes/
Mea
nag
e40
y.Timeto
onsetof
symptom
svar-
iedfrom
afewda
ysto
2mo,
andtheHCda
mag
eistypical.The
liver
injury
rang
edfrom
mild
tose-
vere,bu
tusua
llyre-
solved
rapidly
with
discon
tinu
ation.
Seve
recaseswithALF
andde
-velopm
entof
ascites
andpo
rtalhy
perten
sion
have
been
described
.
Cho
lestatic
hepa
titis,
bile
drug
injury,p
ortal
inflam
mation,
intracan
alicular
bile
sta-
sis,
portal
bridging
fi-
brosis,mild
stea
tosis
126
Cassia
angu
stifo
liaan
dCa
ssia
acutifo
lia(CassiaSenn
a,Se
no-
side
s,senn
aglycosides)
Con
stipation
Senn
osides
arebrok
endo
wnby
intestinal
bac-
teriato
anactive
me-
tabolite,
rheinan
throne
(anthracen
eglycoside).
Thehe
patotoxicity
ofrheininvo
lves
im-
pairmen
tof
mitoc
hon-
drialfun
ction.
Mea
nag
eof
78y.
The
symptom
sap
peared
5moafterco
nsum
ption.
Theliver
damag
ewas
mainlyHC.Mea
ntime
toresolution
was
1mo.
Portal
andlobu
larcell
infiltration
,exten
sive
centrilobu
larne
crosis.
Can
alicular
cholestasis
Positive
rech
alleng
e95
Centella
asiatica
Wou
ndhe
alingan
dlep-
rosy,a
ndas
aps
ycho
-ph
ysical
rege
nerator
andbloo
dpu
rifier
Triterpe
noidscanpro-
duce
hepa
ticinjury
byprom
otingap
optosis
andaltering
cellmem
-bran
esprinciples.
Mainlywom
en,m
ean
age54
y.Timeto
onset
rang
ingfrom
20–6
0d.
MainlyHCpa
tternwith
autoim
mun
efeatures
(ASM
Apo
sitive
).
Cellularne
crosisan
dap
optosis(eosinop
hilic
dege
neration
),an
dlympho
plasmoc
ytic
infiltrate.
Positive
rech
alleng
e136
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Hepatotoxicity Induced by Herbal and Dietary Supplements Navarro, Lucena180
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NS
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ade
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eral
da
Bah
ia),
Dot
. Lib
Info
rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
Mea
ntimeto
resolution
2mon
ths
Cha
parral
(Larreatriden
tate,L
arrea
divaria
tica)
Greasew
oodor
creo
sote
bush
Miscella
nea:
bron
chitis,
rheu
matic
pain,weigh
tloss,stom
achpa
in,
liver
tonics
Nordihy
drog
uaiaretic
acid,isalig
nin,
which
hasestrog
enic
activity,
andco
nstitutesup
to10
%of
dryweigh
t.Itis
hepa
totoxican
dapo
-tent
inhibitorof
cyclo-
oxyg
enasepa
thways.
Assoc
iatedwithacuteto
chronicirreve
rsible
liver
damag
e(cirrhosis)with
FLF/
OLTx
Femalepred
ominan
ce,
agerang
ingfrom
25–6
0y.Timeto
onsetfrom
3–52
wk.
Resolution
time
rang
edfrom
1–17
wk.
Cho
lestatic
hepa
titis,
biliary
chan
ges,
cirrho
-sis,
massive
necrosis
Phytoe
stroge
nsmay
enha
nceeffectsof
nor-
dihy
drog
uaiaretic
acid.93
Che
lidon
ium
majus
(Chelidon
ium
majus,
Greater
celand
ine)
Dyspe
psia,irritable
bowel
synd
rome;
gall-
ston
es;ab
dominal
pain
Alkaloids/driedae
rial
partsha
rvesteddu
ring
blos
soming
MainlyHCda
mag
ewith
casesof
autoim
mun
efeatures
(ANA&ASM
Apo
sitive
).Fe
malepre-
pond
eran
ce,mea
nag
e50
y(ran
ge37
–59y).
Timeto
onset2
8–27
0d.
Resolution
isge
nerally
achieved
.Caseof
ALF
Chron
iche
patitis,
cir-
rhosis,c
holestatic
hep-
atitis,m
assive
necrosis
Positive
rech
alleng
e137
Chine
sehe
rbal
reme-
dies
andteas:
Cha
soor
Onshido
Weigh
tloss
N-nitroso-fen
fluram
ine
might
bethetoxicin-
gred
ient.D
epletesAT
P,im
pairing
mitoc
hond
rial
oxidative
phosph
orylation
MainlyWom
en.Main
age48
y(ran
ge25
–63
y).Timeto
onsetrang
e5–
40d.
MainlyHCan
dMixed
damag
e.Mea
ntimeto
resolution
45d
(ran
ge10
–180
d)Also
ALF/O
LTxan
dde
ath
Diffuse
ormassive
ne-
crosiswith
nonspe
cificinflam
ma-
tory
infiltrate.Duc
tular
prolife
ration
withbile
stasis,an
dbridging
fibrosis.
138
JinBu
Hua
n(Lycop
odiumserratum
)Se
dation
Levo
tetrah
ydropa
lma-
tine
istheac
tive
ingre-
dien
twithstructural
similarity
topy
rrolizi-
dine
alka
loids.
Mainlymales,m
eanag
e49
y.Timeto
symptom
son
setran
gesfrom
1–52
wk.
Thetimeto
resolu-
tion
rang
edfrom
2–30
wk.
Chron
iche
patitis,
portal
andpa
renc
hymal
lympho
cyticinflam
ma-
tion
,po
rtal
fibrosis,focaln
e-crosis,stea
tosis,
cholestatiche
patitis
Gan
Cao
(Glycyrrhiza
uralen
sis,
Elab
orationof
cand
ies
orsw
eets.Chron
icviral
hepatitis.
Glycyrrhizinacid/possi-
bleinhibitionof
NA/K
ATPa
se.
MainlyMale.
Mea
nag
e46
y.Mea
ntimeto
onset
2mo(ran
ge1–
4mo).
Cen
trilo
bularne
crosis
andfibrosisin
casesof
prolon
gedco
nsum
ption
139,14
0
(Con
tinued)
Seminars in Liver Disease Vol. 34 No. 2/2014
Hepatotoxicity Induced by Herbal and Dietary Supplements Navarro, Lucena 181
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NS
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AP
ES
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FB
A U
nive
rsid
ade
Fed
eral
da
Bah
ia),
Dot
. Lib
Info
rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
RadixGlycyrrhizae)
Lico
rice
Triterpe
noidsprom
ote
apop
tosis.
Other
compon
ents
in-
clud
eflavon
oids,
isofl
a-vo
noids,
coum
arins.
Mea
ntimeto
resolution
2mo.
One
patien
tde
-velope
dALF/O
LT.
Ma-Hua
ng(Eph
edra
sin-
ica,
Ephedrasp.)
Weigh
tloss
Ephe
drinesuspec
ted
toxicco
nstituen
tHCda
mag
ewithau
to-
immun
efeatures
(ANA
andASM
Apo
sitive),
mea
nag
e51
y.Mea
ntimeto
onset53
d(ran
ge21
–135
d).
Massive
necrosis(dis-
prop
ortion
ateseverity
forc
linicalpresen
tation
)po
lymorph
onuc
lear
infiltrate
97–9
9
Polygo
num
multiforum
HeSh
ouWu
(Hesho
uwu)
and
may
bean
ingred
ient
ofvariou
sprod
ucts
includ
ing
Shen
Min,Sh
ouWuPian
and
Shou
WuWan
Prem
atureha
irgreying,
dizziness,
constipa
tion
Anthraq
uino
nes
Mainlymales,m
eanag
e48
y(ran
ge24
–65y).
MainlyHCda
mag
e.Mea
ntimeto
onset30
d(ran
ge1–
180d).C
ases
ofALF/O
LTxan
dde
ath.
Inflam
matorycellinfil-
tration,
necrosis
141
Skullcap
(Scutellaria
)Se
dative
effect,an
ti-
inflam
matory.
Flavon
oids
andalky
lat-
ingag
ents/Tox
icme-
tabolites
byCYP
450.
Hep
atoc
yteap
optosis.
Mainlyfemale,
age
rang
ingfrom
28–8
5y.
Mea
ntimeto
onset:3
wk.
Acu
tehe
patitiswith
autoim
mun
efeatures
andcasesof
ALF/O
LT.
Inflam
matoryinfil-
trates,b
ridg
ingfibrosis,
cirrho
sis.
Cen
trilo
bular
andbridging
necrosis.
100
Cop
alch
i(Cou
tarealatiflora,
Hin-
tonialatifl
ora,
Strychno
spseu
doqu
ina,
Croton
ni-
veus,C
roton
pseu
doqu
ina)
Suga
r-low
eringprop
er-
ty (diabe
tes)
Furano
terpen
oids
Acu
tehe
patitispresen
t-ingwithjaun
dice.M
ale
pred
ominan
ce,mea
nag
e76
y.Timeto
onset
betw
een2–
13mo.
Res-
olutionin
2–4mo.
Cen
trilo
bularne
crosis,
lobu
larinflam
matory
infiltrate
bylympho
-cytesan
deo
sino
philic
cells.
141
Cou
marin
Melilo
t(Swee
tclov
er)
Chron
icve
nous
dis-
eases,
lymphe
dem
a
Cou
marin
(1,2
benz
o-py
rone
)an
dco
umarin
derivative
sescu
letin
(6,7-dihyd
roxyco
u-marin),scop
aron
e(6,7-
dimetho
xyco
umarin)
Mainlyfemale,
mea
nag
e45
y.MainlyHCda
mag
e.Acu
tehe
patitisan
dcasesof
ALF/O
LTx.
Hea
vyco
nsum
ersof
Chron
iche
patitis
Carcino
genicprop
er-
ties.
Metab
olism
throug
hCYP
2A6
142
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eral
da
Bah
ia),
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. Lib
Info
rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
and4-methy
lumbellifer-
one(7-hyrox
y-4-meth-
yl).Dose-
andtime-
depe
nden
the
patotoxic-
ityof
benz
opyron
es
cassia
cinn
amon
(used
forco
okiesan
dsw
eet
dishes)m
ayreac
hahigh
daily
coum
arin
intake
Echina
ceapu
rpurea
(Purpleco
neflow
er)
Immun
ostimulan
t/wou
ndhe
aling/eczema/
psoriasis
Polysaccha
rides,glyco-
proteins,caffeicacid
derivative
s(cicho
ric
acid)an
dalka
mides.In-
teractionwithcyto-
chromeP4
501A
2.
Mainlywom
en.M
ean
age60
years
Mea
ntimeto
onset29
-da
ys.Presen
tation
mainlyas
mixed
dam-
age.
Mea
ntimeto
reso-
lution
24-days.
Hep
atic
necrosis.
Echina
ceaco
uldinter-
fere
withco
rticosteroid
andmon
oclona
lanti-
body
trea
tmen
teffect.143
–145
Flavoc
oxid
(Plant-derived
biofl
avon
oids)
Arthritisor
muscu
lo-
skeletal
pain
symptom
san
ti-in
flam
matory
Con
tainsba
icalin
and
catech
ins.
Dua
linh
ibitor
ofcyclo-
oxyg
enasean
d5-lypo
x-yg
enaseen
zymes
(sug
gestedas
alterna-
tive
toNSA
ID)
Acu
teHCinjury
with
immun
oalle
rgic
man
i-festations.A
llwom
enrang
ingin
agefrom
57–
68y.
Timeto
onset
within1–
3mo;
typically
presen
tswithjaun
dice,
abdom
inal
pain,feve
r,an
drash.Re
solution
within1–
3mo.
NoALF
orch
ronicliver
injury.
Focaln
ecrosisan
din-
flam
mation,
portal
lym-
phoc
ytic
inflam
matory
infiltrate
withsomeeo
-sino
phils
andplasma
cells
Assoc
iatedto
hype
rsen
-sitivity
reac
tion
s144
German
der(Teu
crium
cham
aedrys,T
eucrium
poliu
m)
Erva
cavalhinha
inBrazil
Weigh
tloss/ton
icFu
ran-co
ntaining
diter-
peno
idsaremetab
o-lized
viaCYP
3A4to
elec
trop
hilic
metab
o-lites
that
cande
plete
cellu
larthiols,increase
Ca2
þ,and
activate
Ca2
þ -de
pend
enttran
sgluta-
minasean
den
donu
-clea
ses,
resultin
mem
bran
edisrup
tion
andap
optosis.
Mostcasesof
hepato-
toxicity
occu
rred
after2
moof
consum
ption.
Thepred
ominan
tda
m-
agewas
HC.After
with-
draw
al,symptom
sge
nerally
disapp
eared
within8wk.
How
ever,casesof
ful-
minan
the
patitis,
chroniche
patitis,
and
cirrho
siswerealso
seen
.
Acu
tean
dch
roniche
p-
atitis,c
irrhosis,fibrosis,
massive
necrosis
CYP
3A4indu
ction-me-
diated
increasedhe
rbal
toxicmetab
olite1
46
Herba
life
Nutrition
alsupp
lemen
tsWeigh
treduc
tion
/nutri-
tion
alsupp
lemen
tation
/prom
otionof
well-b
eing
Num
erou
sprod
ucts.
Unk
nowningred
ients
that
may
chan
geacross
coun
triesan
dov
erthe
years.
Possible
contam
ination
Femaleprep
onde
ranc
e,mea
nag
e46
y.Latenc
ytimeto
onsetrang
e12
–72
9d.
Theda
mag
ewas
pred
ominan
tlyHCin
somecaseswith
Acu
tean
dch
roniclob-
ular
andpo
rtal
hepati-
tis,
withmixed
lobu
lar
inflam
mation(lym
pho
-cytican
deo
sino
philic
infiltration
),
Positive
rech
alleng
e53
,101
–104
(Con
tinued)
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ES
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nive
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ade
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eral
da
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ia),
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. Lib
Info
rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
withBa
cillussubtilisan
dcereus.
autoim
mun
efeatures.
Seve
rity
rang
edfrom
mild
toseve
rehe
patic
damag
einclud
ingcir-
rhosisan
dALF
requiring
liver
tran
splantation.
fibrosis,cirrho
sis,
he-
paticne
cros
is.
Hyd
roxycu
t(com
posi-
tion
before
2009
)Weigh
tloss,
body
build
ing
Unc
ertain.P
reviou
sto
2004
mainlyEphedra
sinica
(Ma-Hua
ng).After
2004
,Ca
mellia
sinesis.
Acu
tehe
patitis.
Mea
nag
e31
y(ran
ge17
–54
y).Malean
dHCinjury
largely.Latenc
y1–
8wk.
Presen
ceof
positive
ANA&ASM
Aan
tibod
-ies.
DILIw
ithim
mun
efeatures.Evolutionto
ALF/OLTxan
dde
ath.
Hep
atitiswithmixed
in-
flam
matoryinfiltrate
andch
olestasis
FDAWarning
in20
0910
5,10
6
Isab
gol
(Plantag
oovata,
Emblica
Officina
lis,P
syllium
sedd
husks)
Con
stipation
Toxicco
nstituen
tis
unkn
own.
Female26
y.HCda
m-
age.
Resolution
within3
wk.
Acu
tehe
patitis.
Giant
cellhe
patitis.
Cen
trilo
bularan
dpe
ri-
portal
necros
is,
lympho
cyticinfiltrate,
bridgingan
dpiecem
eal
necrosis.
Positive
rech
alleng
e8
Margo
saoil
Nee
moil
(Antelaeaazad
irachta,
Azad
irachta
indica)
Hea
lthtonic,
antipy
ret-
ic,a
nti-infl
ammatory
Relatedto
unco
uplin
gof
mitoc
hond
rial
elec-
tron
tran
sport.
Femaleinfant
prep
on-
deranc
e,mea
nag
e10
mo,
rang
e(1–48
mo).
Thesymptom
sap
-pe
ared
2hafterthe
consum
ption.
Mostpa
-tien
tsreco
veredbe
-tw
een2dto
4mo.
One
patien
tdied
.
Reye
synd
rome,
microve
sicu
larstea
tosis
147
Mixed
prep
arations
Ven
encapsan
Hea
lthtonic,
dyspep
sia
Prep
ared
from
horse
chestnut
leaf,sw
eet
clov
er(cou
marin),cel-
andine
,thistlemilk,
dand
elionroot
andmil-
foil.
Horse
chestnut
leaf
(Aesculushipp
ocasta-
num),sw
eetclov
er,a
ndceland
ineare
hepa
totoxic.
Female69
ywithHC
damag
e.Timeto
onset:
6wk.Re
solution
in6wk.
Portal
inflam
mation,
microve
sicu
larstea
to-
sis,
ballo
oning,
Kupffer
cellhy
perplasia
Positive
rech
alleng
e14
8
Seminars in Liver Disease Vol. 34 No. 2/2014
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ES
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rsid
ade
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eral
da
Bah
ia),
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. Lib
Info
rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
Morinda
citrifo
lium
(Non
ijuice
)Multipleuses:
colds,
flu,
diab
etes,
anxiety,
andhigh
bloo
dpressure
Anthraq
uino
nes
Agerang
ingfrom
24–
62y.
Symptom
sap
-pe
ared
after1moof
use.
Theda
mag
ewas
HC.Mea
nresolution
timewas
2mo(ran
ge0,5–
9mo).Cases
ofALF/O
LTx.
Hep
atic
necrosis,�
eo-
sino
philicinfiltrates
149
Penn
yroy
al(M
enthapu
legium
,He-
deom
apu
lego
ides)
Abortifacien
t/insect
re-
pellant/toindu
cemen
ses
Pulego
newhich
isme-
tabolized
byCYP
450to
Men
thofuran
/Puleg
one
depletes
hepa
ticgluta-
thione
which
increa
ses
hepa
totoxicity.
Femaleprep
onde
ranc
e,mea
nag
e24
years.
Mea
ntimeto
onsetof
symptom
s24
hours.
MainlyHCda
mag
e.Mea
ntimeto
resolution
1to
5-da
ys.C
ases
ofALF
andde
ath.
Subs
tantialc
entrilo
bu-
larde
gene
ration
and
massive
necrosis.
N-acetylcysteinemay
beeffectivein
theea
rly
phases
ofpo
ison
ing
147
Pipermethysticum
(kavaka
va)
anxiety/de
pressive
symptom
sKavalacton
es(kavain,
dihy
droka
vain)metab
o-lized
byCYP
2D6;
intra-
cellu
larglutathion
ede
pletion;
Immun
e-me-
diated
.Kavalacton
esinhibitcycloo
xygen
ase
pathway.
Femaleprep
onde
ranc
e,ag
erang
e21
to81
years.
Acu
tech
ole-
static
hepatitiswith
jaun
dice
and,
less
fre-
quen
tly,
HChe
patitis.
Timeto
onsetof
symp-
tomswithin2to
7mon
ths.Live
rda
mag
erang
edfrom
tran
sien
televations
ofliver
en-
zymes
toseve
rean
dFLF/
OLTxan
dde
ath.
Cho
lestatic
hepa
titis,
bile
duct
injury.
Hep
atic
necrosis.
Gen
etic
deficien
cyin
CYP
2D6may
increase
thehe
patotoxicrisk
107–
113
Pyrrolizidinealkaloids
(PA)
Herbs
rich
inPA
:Crotalaria
sp(Bushtea,
Rattleb
ox)
Heliotrop
ium
Ilexpa
ragu
ariensis
(Maté)
T’u-san-chi(Co
mpo
sitae
spp.;Ind
ianHerbs
)Seneciospp(G
roun
dsel;
Herbal
teas,de
coctions
oren
emas
Con
taminationwith
toxicwee
ds)
Pyrrolizidinealka
loids/
Toxicmetab
olites
(pyr-
rolede
riva
tive
s)that
are
injuriou
sto
sinu
soidal
endo
thelium,thus
lead
-ing
tosinu
soidal
obstruc-
tion
synd
rome[ven
o-oc
clusivedisease
(VOD)]
Theacuteform
typically
presen
tswithhe
pato-
meg
alyan
dascitesre-
flec
ting
sinu
soidal
obstruction.
Mortality
ratesof
20an
d40
%.T
hech
ronicform
ofthedis-
ease
follo
wsapro-
trac
tedco
urse
lead
ing
tocirrho
sisan
dpo
rtal
hype
rten
sion
Vascu
larlesion
s:veno
-oc
clusivedisease.
Fibrosis.
Cirrhosis.
CYP
3A4indu
cers
asph
enob
arbital,canin-
crease
toxicpy
rroles
whileCYP
3A4inhibitors
dotheop
posite.
47–5
0
(Con
tinued)
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roxy
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NS
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AP
ES
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A U
nive
rsid
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eral
da
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ia),
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. Lib
Info
rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
Arnica)
Tussilago
farfara(Colt’s
foot)
Symph
ytum
officina
le(Com
frey
)Bo
rago
officina
lis(Borag
e)
Dose-de
pend
ent
hepa
totoxin
Rhu
barb
(Rheum
palm
atum
L.,
Rheu
mofficina
le,B
aillo
n,Rhe
irad
ix)
Chron
icliver
diseases
andco
nstipa
tion
inAsian
coun
tries
Tann
insan
dan
thraqui-
none
derivatives(rhe
inan
dem
odin)
Dosede
pend
enteffect
Twomales
infected
with
HBV
,age
45years.Time
toon
setof
symptom
swithin1to
3mon
ths.
ALF/OLTxan
dde
ath.
139
Sassafras
(Sassafras
albidu
m,
Sassafrastzum
u)
Anticoa
gulan
tan
tifun-
gal,diap
horetic
Safrol
hepatotox
in.Po
-tent
inhibitorhu
man
CYP
1A2,
CYP
2A6,
and
CYP
2E1.
Hep
atic
carcinog
enesis.
Use
cautiously
inpa
-tien
tstaking
drug
sor
herbsmetab
olized
bythecytoch
romeP4
50.
150
Saw
palm
etto
Prostata
(Serreno
arepens,C
ha-
maerops
humilis,Sa
bal
Serrulata)
Alsoco
ntains
Pygeum
african
um
Benign
prostatic
hyperplasia.
Sereno
arepens
orserru-
lata
have
estrog
enican
dan
tian
drog
enic
effect.
Pygeum
african
umalso
hasan
tian
drog
enic
ef-
fect
throug
hinhibition
oftestosterone
-5-α-
redu
ctase.
MainlyHCda
mag
ewith
autoim
mun
efeatures
inmen
.Timeto
onset:2-
wk.
Resolution
in3mon
ths.
Chron
iche
patitis,
fibrosis.
151
Soyisofl
avon
esSo
yph
ytoe
stroge
ns(G
lycine
max)
Ameliorating
men
o-pa
usal
symptom
s
Mostbiolog
ically
active
isofl
avon
esin
soyprod
-uc
tsarege
nistein,
daidzein,eq
uol,an
dglycetin.Con
trov
ersial
effect
dueto
purported
estrog
enic
activity.
Mainlyfemale.
Mea
nag
e47
y(ran
ge32
–57
y).Mea
ntimeto
on-
set5m
o(ran
ge1–
12mon
ths).MainlyHC
damag
e.Mea
ntimeto
resolution
4mon
ths
(ran
ge3to
7mo).Mild
tomod
erateincreases
intran
saminases
152
Abortifacien
ts,he
art
failu
re,lep
rosy,m
alaria,
Cardiac
glycosides:the
-vetin,
peruvo
side
,Male,
66years.
Timeto
onset:10
days.HC
Cen
trilo
bularne
crosis.
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ES
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nive
rsid
ade
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eral
da
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ia),
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. Lib
Info
rmat
ion.
Cop
yrig
hted
mat
eria
l.
Table
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
Thevetia
peruvian
a(Tronc
omin,Ye
llow
Olean
der)
ring
worm
and
indigestion
.ne
riifo
lin,thevetox
inan
druvo
side/
inac
tivate
thetran
smem
brane
Naþ
/KþAT
Pase
pump.
damag
ewithhy
persen
-sitivity
(rash)
andau
to-
immun
efeatures
(ANA
andASM
Apo
sitive).
Withd
rawnin
Mexico
byCOFEPR
IS15
3
Usnic
acic
(Usnea
Dasypog
a)LipoK
inetic
Weigh
tloss
Usnic
acid/by
unco
u-plingof
oxidativeph
os-
phorylationin
theliver
MainlyHCda
mag
ein
female.
Mea
nag
e27
years(ran
ge20
to32
years).M
eantimeto
onset36
-days(ran
ge10
to84
-days).Mea
ntime
toresolution
71-days
(ran
ge28
to90
-days).
Cases
ofALF/O
LTx.
Hep
atic
necrosisan
dinflam
mation
116,11
7
Valerian
(Valeriana
officina
lis)
Seda
tive
/Insom
nia/an
xi-
ety/dige
stivedisorders
Alkylatingag
ents
Mainlyfemale.
Mea
nag
e47
years.Even
tually
positive
ANA.Symp-
tomsap
peared
approx
i-matelyin
1-wk:
mainly
jaun
dice
dark
urinean
dpa
lestoo
l.Mea
ntimeto
resolution
:8mon
ths.
TwocasesHCan
dtw
ocasesmixed
.
Mild
hepa
titis/
fibrosis/
cirrho
sis/
Tablets
containing
mixed
prep
arations
ofskullcap
orblac
kco
hosh
andvalerian
.10
0
Viscum
albu
m(M
istletoe
)Asthm
a,infertility,high
bloo
dpressure,dizzi-
ness,a
rthritis.
Mistletoe
lectinsha
vestrong
apop
tosis-indu
c-ingeffectsan
dalso
stim
ulatetheim
mun
esystem
.
Female49
years.
HC
damag
e.Re
solution
in6
wk.
Light
inflam
matory-cell
infiltration
ofpo
rtal
trac
tswithpreservation
ofliver
arch
itec
ture.
Mixed
prep
aration
containing
mothe
rwort,
kelp,w
ildlettuc
e,skull-
cap,
andmistletoe
.Po
sitive
re-cha
lleng
e.15
4
Vitam
inA
Retino
lIm
mun
ostimulan
t,pre-
ventionof
nigh
tblindn
ess.
Dose-de
pend
enttoxici-
tyof
retino
idson
hepa
tic
stellate
cells/po
rtal
myo
fibrob
lasts,
which
arethekeyeffector
cells
intheevolutionof
fi-
brosisan
dcirrho
sis.
Hep
atic
damag
ede
-pe
ndingon
thedo
sean
ddu
ration
ofexpo
-sure.M
ildelev
ations
ofserum
liver
enzymes,
cholestatiche
patitis,
non-cirrho
ticpo
rtal
hy-
perten
sion
,progressive
fibrosisan
dcirrho
sis.
Focaln
ecrosis,
sinu
soi-
dallesions,ch
olestasis,
inflam
matoryinfiltrate
(rou
ndcells,macro-
phag
es),an
dac
tivation
andprolife
ration
ofstellate
cells.Cirrhosis
Live
rtoxicity
rarely
oc-
curs,ifdo
se<50
,000
IU/day)118
,119
(Con
tinued)
Seminars in Liver Disease Vol. 34 No. 2/2014
Hepatotoxicity Induced by Herbal and Dietary Supplements Navarro, Lucena 187
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Huang, ephedra)97–99 and sedation (Skullcap, Scutellaria)100
the most often seen. The spectrum of toxicities is wide andincludes acute injury with necrosis, to chronic liver diseasewith cirrhosis.
Herbalife Nutritional Supplements. Many agents fall underthis product-line that are used for many reasons. Some havebeen implicated in liver injury that is suspected to be frombacterial contamination.53 Several other series have de-scribed injury attributable to Herbalife products.101–103How-ever, a more recent analysis of cases contributed from severalcountries showed a potential connection between an Herbal-ife product and liver injury in 16 of 20 cases in which therewas sufficient information to perform the RUCAM. It shouldbe noted that many more cases were available for inspection,but with insufficient data to determine causality.104
Hydroxycut. As in the case of Herbalife, there are manyproducts under this product line label. Theyare used formanyreasons, but primarily for weight loss. Case series105,106 ofliver injury led to some Hydroxycut products being removedfrom the market.
Kava. This product has been used as a sedative. Severalcases of severe liver injury resulting from Kava have beenreported.107–112 Warnings about the use of Kava have beenpublished in the United States and several other countries,and it has been the subject of careful safety reviews.113
Pyrrolizidine Alkaloids. Found in comfrey tea, pyrrolizidinealkaloids induce injury to the sinusoidal epithelium, leadingto a Budd-Chiari type picture, with hepatomegaly and ascites.The phenotype is so typical as to be pathognomonic, if inconsistent temporal proximity to ingestion of pyrrolizidinealkaloids.
Usnic Acid. Used as an ingredient in weight-loss products,this product is known to uncouple membrane potential andthus induce oxidative stress and cell injury.114 Liver injurycases, including some resulting in liver transplantation, led toremoval of some usnic acid containing products from themarket.115–117
Vitamin A. Known for its dose-dependent hepatotoxicity,the spectrum of injury can range from mild liver test eleva-tions with steatosis, to necrosis.118,119 Injury usually occursafter exceeding 50,000 IU per day.
Prevention
Given the current regulatory milieu, the most effective pre-vention of liver injury due to HDS is awareness amongconsumers and providers that they have the capacity to causehepatotoxicity. In addition, health care providers must keepin mind that symptoms associated with liver injury may beprotean.
An assessment of whether current regulation is adequateto protect the consumer from injury due to HDS is in order.Preclinical testing would give better assurance of safety.Verification of contents prior to and after marketing wouldgive confidence that product labels accurately reflect con-tents. On a global scale, the WHO’s effort to harmonizeregulation and safety standards for herbal medicines shouldserve as a common platform.13Ta
ble
3(Con
tinue
d)
Herbals&
dietary
supplemen
ts(Botan
ical
names)
Commonuse
Susp
ectedtoxic
ingredient/
mec
han
-ism
toxicity
Phen
otype
Live
rhistology
Commen
ts
Wou
ldSa
caca
(Crotoncajucara
Benth)
Drago
n’sBloo
d(Ama-
zonia,
Brazil)
Obesity,
Hyp
erch
olesterolemia
Diterpe
noids(sim
ilarto
Teuc
rium
cham
aedrys)
aremetab
olized
via
CYP
3A4to
elec
trop
hilic
metab
olites
that
can
depletecellu
larthiols,
increase
Ca2
þ,an
dac
ti-
vate
Ca2
þ-dep
ende
nttran
sglutaminasean
den
donu
cleases,resultin
apop
tosis.
Acu
tean
dch
roniche
p-atitis.Cases
ofALF/
OLTx.
155
Abbrev
iation
s:AEM
PS,Sp
anishMed
icines
Agen
cyan
dSa
nitary
Prod
ucts;AIH,au
toim
mun
ehe
patitis;
ALF,acute
liver
failu
re;A
NA,an
tinu
clea
rau
toan
tibod
ies;
ASM
A,an
tism
oothmuscu
laran
tibod
ies;
Cho
l,ch
olestaticda
mag
e;COFEPR
IS,T
heFede
ralC
ommission
fortheProtec
tion
agains
tSa
nitary
Riskin
Mexico;
CPM
H,C
ommitteeon
HerbalMed
icinalProd
ucts;d
,days;DILI,drug
-indu
cedliver
injury;E
MA,E
urop
ean
Med
icines
Agen
cy;H
C,he
patocellu
larliver
injury;mo,
mon
ths;
NSA
ID,n
onsteroidal
anti-in
flam
matorydrug
s;OLTx,
orthop
ticliver
tran
splant;w
k,wee
ks.
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Conclusions and Future Directions
The premise that HDS are safe must be challenged, as there isample evidence to the contrary. Achieving a culture of safetyin the HDS industry will emerge only after the mountingevidence for injury from several HDS is recognized and a newagenda for research and regulation is developed. Such anagenda must take into account the varying regulatory ap-proaches to HDS across the globe, as well as the varying usesas therapeutic agents, performance and appearance en-hancers, and as agents to promote well-being.
One of the most pressing needs is for the development of astandard and consistently applied nomenclature for HDS,recognized by all stakeholders, including clinicians, research-ers, regulators, andmanufacturers. Given the ease of access toHDS, the nomenclature system must be relevant and under-standable to the consumer. With a standard system of cate-gorizing HDS, associating injury phenotypes with producttypes becomes more feasible.
There is also a need to attain a more complete under-standing of the epidemiology of liver injury attributable toHDS. Despite numerous reports in the literature, the impactof drug- and dietary supplement-induced hepatotoxicityon public health is unclear, as there are no accurateestimates of the incidence or prevalence of injury. Thisbaseline information ensures that the appropriate resour-ces can be allocated to research, and that regulation isproposed to protect what may be a large segment of thepopulation.
Analysis of product labels reveals their complexity andmultiplicity of ingredients. In fact, in the DILIN’s experience, areviewof listed ingredients revealed that there aremore than20 ingredients in most HDS implicated in liver injury (un-published data). Identifying the actual ingredient responsiblefor injury would require a painstaking analytical approach tosingle out each constituent and perform formal toxicologicalanalysis. A more feasible approach, as the DILIN plans, is to
amass products implicated in liver injury and conduct afrequency analysis for commonly occurring ingredients, orcombinations of ingredients. In this way, ingredients can beselected as possibly the cause for injury and subjected toformal toxicology testing.
As it is not required for HDS to undergo preclinical (in vitroand animal) and human clinical testing, such analyses prior tomarketing typically are absent. Rather, less rigorous assess-ments of safety are used to support a product’s entry into themarket. Hence, product variability, unpredictable pharmaco-kinetics, interaction among ingredients within a given prod-uct, and the effect of HDS on prescribed medications areimportant concerns. A better understanding of these issueswould require detailed and complex chemical analysis fol-lowed by formal clinical pharmacology and toxicity testing. Tomake certain that the findings of such analyses led to saferproducts, findings would have to be coupled with newregulation which establishes product standards that arethen enforced by oversight bodies.
It is likely that voluntary reporting of adverse events fromuse of HDS is infrequent given the consumer’s presumption ofsafety as well as reluctance to divulge use of HDS to physi-cians. Hence, measures to promote postmarketing pharma-covigilance are needed. LiverTox,42 an authoritativecompendium of marketed drugs and their associated liverinjuries, will continue to be developed as a resource for liverinjury due to HDS. Health care providers must also make useof a voluntary reporting mechanism for suspected cases ofhepatotoxicity due to HDS. In the United States and abroad,the FDA’s MEDWATCH system (http://www.fda.gov/Safety/MedWatch/default.htm) is a valuable tool.
As is the case with several drugs,120,121 a genetic basis forinjury attributable to some HDS can reasonably be hypothe-sized. For example, liver injury due to bodybuilding prod-ucts,45,46,78 shown in some reported cases to be tainted withundeclared steroids, leads to a characteristic clinical presen-tation with prolonged jaundice, initially with hepatocellularinjury in some cases,81 but with evolution to a bland chole-stasis, and complete recovery, almost exclusively in youngmen. Although some of the reproducibility of the injurypattern may result from the demographic of use, commonlybeing young men, it is also possible that a common geneticmutation or polymorphism in a bile salt transporter mayexplain such a characteristic picture of injury.
Finally, even with stringent regulation, scrupulous adher-ence, and vigilant oversight, injury from HDS will occur as itdoes with conventional medications. Therefore, biomarkerdevelopment to predict liver injury or predict it at an earlystage should be pursued. Biomarkers for liver injury attribut-able to HDS have been detected with alkaloids and german-der,122,123 providing rationale for additional research in thisarea.
AcknowledgmentThe authors wish to acknowledge Maricruz Vega, MPH, forher expertise in editing and preparing the manuscript.
Table 4 The DILIN scheme for categorization of HDS implicatedin liver injury
Main marketed purpose for use
Bodybuilding/Muscle Enhancement
Weight Loss
Depression
Sexual Performance
Gastrointestinal Distress
Immune Support
Bone/Joint Support
Chinese Herbs
Miscellaneous
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