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Clinical Gastroenterology and Hepatology 2014;12:10691076

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, researchers, clinicians, and regulators have increasing
awareness of the need for study in this area.
Keywords: Herbal and Induced Liver Injury; Dietary Supplements Induced Liver Injury; Causality Assessment in DrugInduced Liver Injury.

espite the perceived safety of herbal and dietary


supplements (HDS), devastating liver injury has
been reported. The goal of this review is to discuss the
scope of use of HDS in the United States and their
regulation and provide a clinical approach to diagnosis of
HDS-induced liver injury (HILI).

The Scope of Use of Herbal and Dietary


Supplements and Epidemiology of Herbal
and Dietary Supplementinduced Injury
Dietary supplements are used for many reasons,
including health maintenance, management of anxiety,
obesity, diabetes, rheumatologic illness, cancer, cardiovascular disease, and pain, among others.1 Liver disease
is also a reason for use of HDS, which is demonstrated by
the nding that 23% of patients enrolled in a long-term
hepatitis C treatment trial reported use of HDS.2
The ease of access to HDS through many outlets
leaves the consumer to assume that HDS are safe and
their use is without consequences. Moreover, patients do
not commonly divulge use of dietary supplements to
health care providers because of the perceived bias
against their use and the assumption that providers are
uninformed about the supplements.3
Data from the National Health and Nutrition Examination Survey show that 52% of respondents reported
using a dietary supplement.4 Another survey has reported even higher rates of use, up to 73% in the
noninstitutionalized U.S. adult population.5 This extent of
use 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 dietary


supplement industry.6 In some Asian and African countries, up to 80% of the population use herbals as their
primary means of medical care.7
Unfortunately, there are no U.S. data on the overall
incidence of HILI or injury caused by any specic product. This results from lack of information on the overall
use of HDS and not having a mandatory reporting
mechanism to identify cases. Even in the few populationbased studies on drug-related liver injury, injury attributable to HDS was only variably reported.812
The frequency of HILI can only be described in relative terms in Western studies; in prospective studies
from Spain, medicinal herbal preparations accounted for
only 1%2% of cases of liver injury, with antibiotics
being among the most common class implicated.13,14 In
keeping with their more common use, medicinal herbs
were the most common cause for drug-related liver
injury in Singapore where 71% of cases (22 of 31) were
attributed to medicinal herbs, many adulterated with
active drugs.15 In Iceland, HILI has been observed with
the use of Herbalife products.16 In the United States, the
Drug Induced Liver Injury Network (DILIN) promises to
provide useful information on HILI. Preliminary data on
HILI cases compiled by the DILIN provide a glimpse into
the relative frequency of liver injury attributable to dietary supplements in the United States, compared with
conventional drugs.17 Among 109 patients in whom HDS
were implicated in their liver injury, most (33%) used
products intended for bodybuilding, followed by products used for weight loss (26%). Although it is not a
population-based study per se, reports from the DILIN
indicate that HDS are responsible for an increasing proportion of hepatotoxicity cases.17

Regulation for Herbal and Dietary Supplements


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

Abbreviations used in this paper: CIOMS, Council for International Organizations of Medical Sciences; DILI, drug-induced liver injury; DILIN, Drug
Induced Liver Injury Network; FDA, Food and Drug Administration; GTE,
green tea extract; HDS, herbal and dietary supplements; HILI, HDSinduced liver injury; RUCAM, Roussel Uclaf Causality Assessment Method.
2014 by the AGA Institute
1542-3565/$36.00
http://dx.doi.org/10.1016/j.cgh.2013.07.030

1070 Rossi and Navarro

Congress through the landmark Dietary Supplement


Health and Education Act of 1994. Through this law,
manufacturers were required to attest to a products
safety, but it gives no authority to the Food and Drug
Administration (FDA) to approve HDS before marketing.
It is only when a manufacturer introduces a new dietary
ingredient that a premarket safety review is conducted.18
The Final Rule for Dietary Supplement Current Good
Manufacturing Practices, enacted in 2007, further aims
to ensure the safety of marketed products by stipulating
production standards.19 However, not long after the nal
rule was published, instances of dietary supplements
contaminated with various compounds became apparent,
and the FDA issued a warning to manufacturers.20
Routine analysis of products contents by the FDA is
performed on only a random basis.18

Diagnosis of Herbal and Dietary


Supplementinduced Liver Injury
The key diagnostic elements for drug-induced liver
injury (DILI), as discussed at an important Clinical
Research Workshop, apply to HDS as well.21 Fundamentally, the diagnosis of HILI depends rst on having a
suspicion that a supplement may be accountable for
injury. The time to onset of injury can be variable with
HILI because products consumed during long periods of
time must be considered, because injury could be cumulative, or products and their contents may change
over time.22
The clinical features should be recognized as hepatocellular, cholestatic, or mixed. The R ratio can be
calculated at various times during the course of injury,
although conventionally, it is determined at onset.23
Observing the course of liver injury after cessation of
an agent is an important component to diagnosis,
because a deceleration of the enzyme abnormalities or
clinical symptoms is expected (dechallenge). Improvement is not necessarily sine qua non for the diagnosis,
because some HDS have been shown to lead to chronic,
self-perpetuating injury, even after cessation.22 Finally,
recrudescence of liver injury on incidental re-exposure to
a suspect supplement provides compelling evidence of a
causal association.
The most decisive approach to the diagnosis of HILI,
after documentation of the ingestion of an agent that
precedes injury, is exclusion of other liver diseases that
may present similarly (Figure 1).

Clinical Gastroenterology and Hepatology Vol. 12, No. 7

liver diseases, and temporal exposure to a drug. The use


of a universal assessment method when assessing potential DILI provides for increased evaluator agreement.
However, even with the use of these causality assessment methods, variability among evaluators remains a
concern.24 A few causality assessment methods deserve
mention in the context of HILI. An early causality
assessment process is the Naranjo scoring system, or
Adverse Drug Reaction Probability Scale.25 The Naranjo
system has been applied in the causality assessment
process with natural products,26 but this has drawn
criticism because of its lack of specicity for liver-related
drug reactions.27,28
The Roussel Uclaf Causality Assessment Method
(RUCAM) was created in 1989 as the rst liver-specic
instrument and addresses many features unique to
drug liver injury. It has been applied widely to HILI
cases.23 The RUCAM assigns points to specic categories
and has been validated and found to be a sensitive and
relatively specic way to support a diagnosis of DILI.29
A modication of the RUCAM, the Maria and Victorino
scale, is commonly used in determining the likelihood of
DILI.30 Unlike the RUCAM, there is no requirement for a
product label warning to assign the highest possible
score for previous information on an agent.
Arguably, the most comprehensive approach to causality assessment, and the one that may be most adaptable to the nuances of HILI, is the expert opinion process,
as used by the DILIN.31 The DILIN has made signicant
inroads into the causality assessment process,

Causality Assessment in Herbal and Dietary


Supplementinduced Liver Injury
Causality assessment refers to the process of assembling evidence that may link a drug or dietary supplement to liver injury. Instruments for causality
assessment are based predominantly on clinical criteria,
such as patient age, alcohol use, exclusion of underlying

Figure 1. Algorithm for assessment of suspected HILI. Alk P,


alkaline phosphatase; ALT, alanine aminotransferase; CMV,
cytomegalovirus; EBV, EpsteinBarr virus; HSV, herpes simplex virus; ULN, upper limit of normal; VZV, vesicular stomatitis virus.

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Herbs and Liver Injury 1071

demonstrating that its process for assigning causality by


using expert opinion produces higher agreement rates
and likelihood scores than the RUCAM.32 This system
has been applied to both drugs and dietary supplements.33 However, in the DILINs published experience
comparing its expert opinion approach with the RUCAM,
only a small subset of the study sample (5%) comprised
HILI cases.32 Thus, it is unclear what impact HILI cases
had on the nding that DILINs expert opinion process
produces higher agreement rates than the RUCAM.
A causality assessment process that is specic for
HILI has not been developed, although a preliminary
attempt was made by the DILIN.34 The causality assessments are summarized in Table 1.

The Problem of Variability, Adulteration, and


Contamination
The variability of HDS is well documented for some
products.3538 Because of the nature of botanical products, which may vary over time and under different
harvest conditions, it can be assumed that all HDS are
susceptible to variability. Their ingredients may change
in concentration, purity, and potency depending on
conditions and location of harvest.
Although it is tempting to attribute liver injury to an
adulterant, even when that agent is known to have toxic
potential, such a presumption is not valid without toxicologic conrmatory testing.

Hepatotoxicity Associated With Specic


Products and Ingredients
Currently there is no conventional paradigm for
organizing HDS. Categorization that is based on marketed use is therefore a reasonable organizational
approach. Furthermore, marketed products for specic
benets are likely to contain similar ingredients, thus in
many cases resulting in categorization of the individual
ingredients contained in the marketed products.

Weight Loss Supplements


Hydroxycut. Hydroxycut comprises many different
supplements and is most commonly marketed to
increase metabolism. The rst 2 cases of Hydroxycutassociated liver injury were initially reported in
2005.39 Although the FDA ordered removal of ephedra
from original formulations of Hydroxycut and other
ephedra-containing supplements, additional cases of
hepatotoxicity with Hydroxycut have been reported.40
These cases among others, including one fatality,4144
led the FDA to post a warning on the potential hepatotoxicity of Hydroxycut in 2009. The manufacturer subsequently withdrew many but not all Hydroxycut
products from the market.45 The Hydroxycut experience
is illustrative of the problem with HILI; pinpointing the
ingredient responsible for injury is a difcult endeavor.
Herbalife. Herbalife products are marketed for
various purposes, including weight management, energy
and tness, as well as targeted nutrition.46 Hepatotoxicity associated with the use of this product line was
initially reported in 2 separate case series, one from
Israel47 and the other from Switzerland.48 The report
from Israel prompted withdrawal of a locally manufactured product because of concerns that either adulteration or contamination was the cause for injury. Another
case series from Spain further underscores the potential
for this product line to cause hepatotoxicity.49
Green tea. Green tea extract (GTE), derived from the
leaves of Camellia sinensis, is a frequent ingredient of
HDS promoting weight loss. Although several have proposed cellular-protective effects of this compound
through its antioxidant properties,5052 reports of GTEs
potential hepatotoxicity have also been published.5356
Early reports were linked to the weight loss supplement, Exolise. These and other cases led to the decision
to suspend the manufacturing of this supplement in
Spain and France.57
Exposure has also been shown to be increased in the
fasting state in both animals and humans.58,59 The
pattern of injury most commonly described with patients

Table 1. Overview of Causality Assessment Methods

Temporal relationship
Course after discontinuation
Specic to liver injury
Hepatitis vs Cholestatic
Risk factorsa
Age of patient
Extrahepatic manifestations
Placebo challenge
Reported toxicity history
Rechallenge
Dose effect
Interobserver correlation

RUCAM/CIOMS23

Maria and Victorino30

Naranjo25

DILIN31

Yes
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
No
No

Yes
Yes
Yes
No
Yes
No
Yes
No
Yes
Yes
No
No

Yes
Yes
No
No
Yes
No
No
Yes
No
Yes
Yes
No

Yes
Yes
Yes
No
Yes
No
No
No
Yes
Yes
No
Yes

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

1072 Rossi and Navarro

taking GTE-containing products is hepatocellular, and


most patients seem to recover with cessation of use.60
In a systematic review of the available literature by the
United States Pharmacopeia, it was concluded that although
one should be concerned that extracts of green tea may
predispose to hepatotoxicity, a cautionary labeling statement
in the monograph was not issued by this organization.61,62
Usnic acid. Usnic acid is a metabolite derived from
lichens.63 Its weight loss property was incidentally noted
as a side effect of exposed workers in the1930s.64 As a
membrane uncoupler, usnic acid leads to an increase in
fat metabolism and desired weight loss; however, with
this effect there is a concomitant increase in oxidative
stress and cellular injury.63,65
Compounds containing usnic acid have been linked to
severe hepatotoxicity including fulminant hepatic failure
requiring liver transplantation.6670
An FDA warning on the use of Lipokinetix, an usnic
acidcontaining product, was issued in 2001 as regards
its risk for liver injury and liver failure.71 Ultimately,
Lipokinetix was taken off the market, but other supplements containing usnic acid remain available.

Health-Promoting Herbal Supplements


Black cohosh. Cimicifuga racemosa, more commonly
known as black cohosh, has been used to treat gynecologic disorders, especially menopausal symptoms. Its
active ingredients are extracted from the root/rhizome of
this herb.72
The majority of HILI cases with black cohosh have
described an extensive hepatocellular injury with
concomitant jaundice that in some cases resulted in
fulminant hepatic failure.7380 Subsequent to the application of the Naranjo scale to determine causality for
black cohosh hepatotoxicity, the United States Pharmacopeia determined that there was sufcient evidence to
issue a cautionary monograph.81 However, low causality
scores by using the Council for International Organizations of Medical Sciences (CIOMS)/RUCAM scale applied
to many of these cases challenge the causal association of
black cohosh with liver injury.82,83
Pyrrolizidine alkaloids. Toxicity from pyrrolizidine
alkaloids has been known for many years. The plant
species most commonly associated with hepatotoxicity,
Symphytum, is otherwise known as comfrey tea.84 Initial
case reports of hepatotoxicity in the form of venoocclusive disease originated from Afghanistan and India
where these plants are commonly used to make teas.85,86
However, additional cases worldwide soon followed.8789
The mechanism by which alkaloids cause injury centers
around their metabolism is via CYP3A.90,91 The alkaloids
are metabolized to N-oxides and conjugated dienic pyrroles
that affect the structure and function of hepatocellular
proteins. Injury can persist beyond the discontinuation of
the ingestion of the alkaloid because of the formation of
adducts with the proteins and nucleic acids with which they
react, thus leading to chronic liver injury.92

Clinical Gastroenterology and Hepatology Vol. 12, No. 7


Kava. Kava, Piper methysticum, is found in various
dietary supplements used to promote sleep and improve
anxiety and menopausal symptoms. The key ingredients
are the kava pyrones.93 Since the initial reports of necrotizing hepatitis and early cases of fulminant hepatic failure,
multiple cases of variable degrees of liver injury including
death have been reported with kava ingestion.9499 As
a result, restrictions were placed on kava-containing
products in many different countries as summarized by
the Natural Standard Research Collaboration.100
A recent analysis of previously reported cases of kava
hepatotoxicity subjected to the CIOMS/RUCAM causality
scoring system identied that only 1 of 26 cases was
likely related to kava.101 Additional cases subject to
scrutiny by using the CIOMS/RUCAM scoring system
further question the relationship between kava and
hepatotoxicity.102 Thus far, the specic hepatotoxin in
kava is unknown.

Joint Health Supplements


Flavocoxid. This supplement, distributed as Limbrel, is
used to manage symptoms of osteoarthritis and is categorized as a medical food, which requires a provider
prescription. However, unlike FDA-regulated drugs, as a
medical food, it does not need to undergo rigorous premarketing safety and efcacy studies.103 The mechanism
of the plant-derived ingredients is proposed to be mediated through the inhibition of cyclooxygenase and
5-lipoxygenase, which blocks the inammatory cascade.104
Initial studies identied a mild transaminase elevation, but
a recent case series reported 4 patients who developed a
signicant transaminase elevation and hyperbilirubinemia.
These cases were among 877 patients enrolled in the
DILIN prospective study, and follow-up showed no
development of chronicity. The pattern of injury was a
mixed hepatocellular and cholestatic pattern with a latency
period of 212 weeks.105 These cases of hepatic injury
were more severe than initial reports.106109
Glucosamine-based supplements. Move Free Advanced
is used in the United States to help with joint discomfort.
Its main ingredients are glucosamine, chondroitin, hyaluronic acid, in addition to a Uniex proprietary extract,
which is composed of Chinese skullcap and black catechu.
Two cases of hepatotoxicity with use of this supplement
have been reported recently.110 Another recent case
report described the development of hepatocellular injury
in 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 controlled
substances in 1991, and their control was further
expanded in 2004.112 Their potential hepatotoxicity was
recognized early on with the observation of a link between anabolic androgenic steroids and jaundice and

July 2014

liver tumors.113,114 Subsequent animal studies suggested


that anabolic steroids are capable of altering cellular
metabolism as well as exerting a proliferative effect on
liver cells.115 DILI associated with anabolic steroids
encompasses 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 various
dietary supplements, among them a newer testosteronecontaining supplement, T Bomb II, experienced hepatocellular injury. Formal causality assessment (RUCAM)
assigned a possible score.119 Another supplement presumed to contain anabolic steroids that has been linked to
hepatotoxicity is Superdrol. In this small case series, patients developed a mixed hepatocellular and cholestatic
pattern of injury, in which the cholestatic component of
the injury took several weeks to resolve.120 On the basis of
these and other case reports, it is reasonable to conclude
that HDS used for bodybuilding and presumed to contain
anabolic steroids can lead to liver injury that is typically
cholestatic in nature and prolonged.
Despite the link between anabolic steroids and hepatotoxicity, the use of these agents remains prevalent.121

Future Directions in Research


The limitations in attributing liver injury to an
ingredient within any given dietary supplement is the
single greatest challenge to clinicians and researchers
interested in the eld of HILI. Even detailed chemical
analysis of products, an expensive and complex
endeavor, does not necessarily identify the agent
responsible for injury. An alternative approach is to use
chemical analysis to identify ingredients common to
products implicated in injury. In this way, hypotheses
could be constructed to propose culprit ingredients,
which would then be subjected to formal toxicologic
analysis. Neither of these approaches precludes the
possibility of idiosyncratic injury or injury resulting from
an ingredient in susceptible individuals. Identication of
genetic susceptibilities to injury from common dietary
ingredients, such as GTE or its component catechins, is
an interesting area of research that merits exploration. A
better understanding of the epidemiology of HILI is
needed to identify the scope of the problem, the most
common groups affected, and to develop disease management and prevention strategies. However, without
more accurate estimates of the overall use of HDS and
more complete reporting of adverse events, reliable
disease prevalence and incidence statistics cannot be
made. Finally, much more needs to be learned about why
people use products and where information on their use
is obtained. Such information is applicable not only to
HILI, but in a broader sense it will facilitate preventative
measures by better informing regulatory approaches to
ensure the safety of HDS.

Herbs and Liver Injury 1073

HDS-induced Liver Injury Resources for


the Clinician
Reporting of adverse events that are thought to be
due to HDS or any drug or medical device can be done by
both patients and providers through the FDAs MedWatch system. This can occur online (http://www.fda.
gov/Safety/MedWatch/default.htm) or through its hotline (1-800-FDS-1088). Reports of suspected dietary
supplement toxicity are then triaged to the Center for
Food Safety and Applied Nutrition, which bears the responsibility to investigate reports of injury and prove a
product unsafe.

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Reprint requests
Address 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: rossisim@
einstein.edu; fax: (215) 456-8058.
Conicts of interest
The authors disclose no conicts.