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 difficulty 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 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, cardio1
vascular disease, and pain, among others. Liver disease is
also a reason for use of HDS, which is demonstrated by the
finding that 23% of patients enrolled in a long-term hepatitis
2
C treatment trial reported use of HDS.
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
3
supplements.
Data from the National Health and Nutrition Examination Survey show that 52% of respondents reported using
4
a dietary supplement. Another survey has re-ported even
higher rates of use, up to 73% in the noninstitutionalized
5
U.S. adult population. 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

6
supplement industry. In some Asian and African countries, up to 80% of the population use herbals as their
7
primary means of medical care.
Unfortunately, there are no U.S. data on the overall
incidence of HILI or injury caused by any specific prod-uct.
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 population-based studies on
drug-related liver injury, injury attrib-utable to HDS was
812
only variably reported.
The frequency of HILI can only be described in rela-tive
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
13,14
among the most common class implicated.
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
15
medicinal herbs, many adulterated with active drugs. In
Iceland, HILI has been observed with the use of Herbalife
16
products. 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 di-etary
supplements in the United States, compared with
17
conventional drugs. Among 109 patients in whom HDS
were implicated in their liver injury, most (33%) used
products intended for bodybuilding, followed by prod-ucts
used for weight loss (26%). Although it is not a populationbased study per se, reports from the DILIN indicate that
HDS are responsible for an increasing pro-portion of
17
hepatotoxicity cases.

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, HDS-induced
liver injury; RUCAM, Roussel Uclaf Causality Assessment Method.
2014 by the AGA Institute 15423565/$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
18
ingredient that a premarket safety review is conducted.
The Final Rule for Dietary Supplement Current Good
Manufacturing Practices, enacted in 2007, further aims to
ensure the safety of marketed products by stipulating
19
production standards. However, not long after the final
rule was published, instances of dietary supplements
contaminated with various compounds became apparent,
20
and the FDA issued a warning to manufacturers. Routine
analysis of products contents by the FDA is performed on
18
only a random basis.

Diagnosis of Herbal and Dietary

Supplementinduced Liver Injury
The key diagnostic elements for drug-induced liver
injury (DILI), as discussed at an important Clinical
21
Research Workshop, apply to HDS as well.
Fundamentally, the diagnosis of HILI depends first 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 cu-mulative, or
22
products and their contents may change over time.

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 po-tential
DILI provides for increased evaluator agreement. However,
even with the use of these causality assess-ment methods,
24
variability among evaluators remains a concern. 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
25
Probability Scale. The Naranjo system has been applied
26
in the causality assessment process with natural products,
but this has drawn
criticism because of its lack of specificity for liver-related
27,28
drug reactions.
The Roussel Uclaf Causality Assessment Method
(RUCAM) was created in 1989 as the first liver-specific
instrument and addresses many features unique to drug liver
23
injury. It has been applied widely to HILI cases. The
RUCAM assigns points to specific categories and has been
validated and found to be a sensitive and relatively specific
29
way to support a diagnosis of DILI.
A modification of the RUCAM, the Maria and Victorino
scale, is commonly used in determining the likelihood of
30
DILI. 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 adapt-able
to the nuances of HILI, is the expert opinion process, as
31
used by the DILIN. The DILIN has made significant
inroads into the causality assessment process,

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,
23
although conventionally, it is determined at onset.
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). Improve-ment is not
necessarily sine qua non for the diagnosis, because some
HDS have been shown to lead to chronic, self-perpetuating
22
injury, even after cessation. 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).

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 supple-ment
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
sim-plex virus; ULN, upper limit of normal; VZV, vesicular
sto-matitis virus.

July 2014

Herbs and Liver Injury 1071

demonstrating that its process for assigning causality by

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

The Problem of Variability, Adulteration, and

Contamination
The variability of HDS is well documented for some
3538
products.
Because of the nature of botanical prod-ucts,
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 confirmatory testing.

Hepatotoxicity Associated With Specific

Products and Ingredients

Weight Loss Supplements

Hydroxycut. Hydroxycut comprises many different
supplements and is most commonly marketed to increase
metabolism. The first 2 cases of Hydroxycut-associated liver
39
injury were initially reported in 2005. 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
40
reported.
These cases among others, including one
4144

fatality,
led the FDA to post a warning on the potential
hepato-toxicity of Hydroxycut in 2009. The manufacturer subsequently withdrew many but not all Hydroxycut products
45
from the market. The Hydroxycut experience is illustrative
of the problem with HILI; pinpointing the ingredient
responsible for injury is a difficult endeavor.
Herbalife. Herbalife products are marketed for various
purposes, including weight management, energy and fitness, as
46
well as targeted nutrition. Hepato-toxicity associated with
the use of this product line was initially reported in 2 separate
47
case series, one from Israel
and the other from
48

Switzerland. The report from Israel prompted withdrawal of

a locally manufac-tured product because of concerns that either
adultera-tion or contamination was the cause for injury.
Another case series from Spain further underscores the
49
potential for this product line to cause hepatotoxicity.
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 pro-posed
cellular-protective effects of this compound through its
5052
antioxidant properties,
reports of GTEs potential
5356

Currently there is no conventional paradigm for

organizing HDS. Categorization that is based on mar-keted
use is therefore a reasonable organizational approach.
Furthermore, marketed products for specific benefits are
likely to contain similar ingredients, thus in many cases
resulting in categorization of the individual ingredients
contained in the marketed products.

hepatotoxicity have also been published.

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

Exposure has also been shown to be increased in the

58,59
fasting state in both animals and humans.
The
pattern of injury most commonly described with patients

Table 1. Overview of Causality Assessment Methods

23

RUCAM/CIOMS
Temporal relationship
Course after discontinuation
Specific to liver injury
Hepatitis vs Cholestatic
a
Risk factors
Age of patient
Extrahepatic manifestations
Placebo challenge
Reported toxicity history
Rechallenge
Dose effect
Interobserver correlation
a

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

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

Maria and Victorino

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

30

25

Naranjo
Yes
Yes
No
No
Yes
No
No
Yes
No
Yes
Yes
No

DILIN
Yes
Yes
Yes
No
Yes
No
No
No
Yes
Yes
No
Yes

31

1072 Rossi and Navarro

taking GTE-containing products is hepatocellular, and most

60
patients seem to recover with cessation of use.
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
61,62
the monograph was not issued by this organization.
Usnic acid. Usnic acid is a metabolite derived from
63
lichens. Its weight loss property was incidentally noted as a
64
side effect of exposed workers in the1930s. 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
63,65
injury.
Compounds containing usnic acid have been linked to
severe hepatotoxicity including fulminant hepatic failure
6670
requiring liver transplantation.
An FDA warning on the use of Lipokinetix, an usnic
acidcontaining product, was issued in 2001 as regards its
71
risk for liver injury and liver failure.
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 gyneco-logic
disorders, especially menopausal symptoms. Its active
72
ingredients are extracted from the root/rhizome of this herb.

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
93
kava pyrones.
Since the initial reports of necro-tizing
hepatitis and early cases of fulminant hepatic failure, multiple
cases of variable degrees of liver injury including death have
9499
been reported with kava ingestion.
As a result,
restrictions were placed on kava-containing products in many
different countries as summarized by the Natural Standard
100
Research Collaboration.

A recent analysis of previously reported cases of kava

hepatotoxicity subjected to the CIOMS/RUCAM causality
scoring system identified that only 1 of 26 cases was likely
101
related to kava.
Additional cases subject to scrutiny by
using the CIOMS/RUCAM scoring system further question
102
the relationship between kava and hepatotoxicity.
Thus
far, the specific hepatotoxin in kava is unknown.

Joint Health Supplements

Flavocoxid. This supplement, distributed as Limbrel, is used
to manage symptoms of osteoarthritis and is cate-gorized 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 pre-marketing safety and efficacy
103
studies.
The mechanism of the plant-derived ingredients is
proposed to be medi-ated through the inhibition of
cyclooxygenase and 5-lipoxygenase, which blocks the
104

The majority of HILI cases with black cohosh have

described an extensive hepatocellular injury with
concomitant jaundice that in some cases resulted in
7380
fulminant hepatic failure.
Subsequent to the application of the Naranjo scale to determine causality for black
cohosh hepatotoxicity, the United States Pharma-copeia
determined that there was sufficient evidence to issue a
81
cautionary monograph. However, low causality scores by
using the Council for International Organiza-tions of
Medical Sciences (CIOMS)/RUCAM scale applied
to many of these cases challenge the causal association of
82,83
black cohosh with liver injury.
Pyrrolizidine alkaloids. Toxicity from pyrrolizidine alkaloids
has been known for many years. The plant species most
commonly associated with hepatotoxicity, Symphytum, is
84
otherwise known as comfrey tea.
Initial case reports of
hepatotoxicity in the form of venoocclusive disease originated from Afghanistan and India where
85,86
these plants are commonly used to make teas.
8789
However, additional cases worldwide soon followed.
The mechanism by which alkaloids cause injury centers
90,91
around their metabolism is via CYP3A.
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
92
react, thus leading to chronic liver injury.

inflammatory cascade.
Initial studies identified a mild
transaminase elevation, but a recent case series reported 4
patients who developed a significant 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

106109

more severe than initial reports.

Glucosamine-based supplements. Move Free Advanced is

used in the United States to help with joint discomfort. Its main
ingredients are glucosamine, chondroitin, hya-luronic acid, in
addition to a Uniflex proprietary extract, which is composed of
Chinese skullcap and black catechu. Two cases of
hepatotoxicity with use of this supplement have been reported
110
recently.
Another recent case report described the
development of hepatocellular injury in a patient taking over111
the-counter glucosamine.

Bodybuilding Supplements
Anabolic steroids. In an effort to limit their access, anabolic
steroids were classified as Class III controlled substances in
112

1991, and their control was further expanded in 2004.

Their
potential hepatotoxicity was recognized early on with the
observation of a link be-tween anabolic androgenic steroids
and jaundice and

July 2014

Herbs and Liver Injury 1073

113,114

liver tumors.
Subsequent animal studies suggested
that anabolic steroids are capable of altering cellular
metabolism as well as exerting a proliferative effect on liver
115
cells.
DILI associated with anabolic steroids
encompasses cholestasis, proliferation of bile ducts, atypical
hyperplasia of hepatocytes, peliosis hepatitis,
hepatocellular cancer, cholangiocarcinoma, and hepatic
116118
adenomas.
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)
119
assigned a possible score.
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
120
injury took several weeks to resolve.
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 hep121
atotoxicity, the use of these agents remains prevalent.

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 field
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. Identification
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 man-agement 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.

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 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 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.
Conflicts of interest
The authors disclose no conflicts.