Liver damage from herbal supplements

1. REVIEW
Liver Injury Due to Herbal and
Dietary Supplements: A Review
of Individual Ingredients
Elizabeth Zheng, M.D., and Victor Navarro, M.D.
Diagnosing liver injury caused by herbal and dietary
supplements (HDS) and establishing causality is challeng-
ing. These topics are discussed and reviewed in an
accompanying article within this current publication. In
this review, we focus on dietary supplement ingredients
that have hepatotoxic potential (Table 1).
Often, it is difficult to identify the culprit ingredient
that is responsible for liver damage among a multitude
of different components within a particular supple-
ment. However, some ingredients have been associ-
ated with hepatotoxicity. We aim to review those
ingredients that have been implicated in liver injury
and, in doing so, give the practitioner a rationale to
implicate a supplement containing them as a cause for
injury.
We highlight the fact that, although these substan-
ces have been implicated in liver injury, the specific
mechanism of injury in many cases has not been fully
clarified. In fact, in rare instances of liver injury, the
underlying mechanism may be idiosyncratic, that is,
unpredictable.
SUSPECTED TOXIC INGREDIENTS IN HERBAL
AND DIETARY SUPPLEMENTS
Black Cohosh
An herbal remedy extracted from the plant Actaea race-
mosa, black cohosh’s uses vary from alleviation of meno-
pausal symptoms to malaria. The mechanism of injury is
unknown, and some reports suggest that liver injury is an
idiosyncratic reaction. However, case reports support an
immune-meditated reaction because patients presented
with high levels of autoantibodies and exhibited a clinical
response to prednisone.1
A review performed by the US
Pharmacopeia did not reveal convincingly unfavorable clin-
ical pharmacokinetic and animal toxicological data. None-
theless, it determined that black cohosh products should
be labeled with a cautionary statement.2
Ephedrine
Ephedra is a genus of plants, of which a commonly
known species is ma huang (Ephedra sinica). The active
component of ma huang is ephedrine, which is a sympa-
thomimetic alkaloid with thermogenic properties.3
Abbreviations: ALF, acute liver failure; ANA, anti-nuclear antibody; ASMA, anti–smooth muscle actin; GTE, green tea extract; HDS,
herbal and dietary supplements.
From the Department of Hepatology, Einstein Medical Center, Philadelphia, PA.
Potential conflict of interest: Nothing to report.
Received 27 October 2015; accepted 8 February 2016
View this article online at wileyonlinelibrary.com
VC 2016 by the American Association for the Study of Liver Diseases
80 | CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD

2. Traditionally used in Chinese medicine, ephedrine has
commonly been prepared in weight-loss supplements,
resulting in liver injury as suggested by case reports.4
Ephedrine has been a suspected hepatotoxic agent caus-
ing a hepatocellular pattern of injury with massive necro-
sis on histological examination.5,6
Green Tea Extract
Extracted from the plant Camellia sinensis, green tea
extract (GTE) is composed of catechins and flavanols. As
the most abundant form of catechin, epigallocatechin
gallate is thought to be the active component in GTE
and is often touted to have weight-loss benefits. Epigal-
locatechin gallate has also been found to cause signifi-
cant liver injury through mitochondrial damage and
formation of reactive oxygen species.7,8
The toxicity is
dose dependent in animal models.9
Liver injury has also
been linked to the fasting state in dogs and mice.10,11
Case reports featuring liver injury caused by GTE have
been associated with the use of multi-ingredient weight-
loss supplements.12,13
Although it is unknown whether
hepatotoxicity was due to GTE alone or a combination of
multiple ingredients, reports in patients with previous
liver injury thought secondary to GTE revealed repeated
liver injury after inadvertent re-exposure to GTE.
Garcinia Cambogia
A fruit found in Asia and Africa, G. cambogia contains
the active ingredient hydroxycitric acid, which has the
ability to inhibit the conversion of carbohydrates to fat,
as well as alter adipogenesis.14,15
This ingredient is com-
monly found in multi-ingredient weight-loss supplements
such as Hydroxycut, Exilis, and Herbalife. Several case
reports have documented liver injury after use of Hydrox-
ycut, although direct injury due to G. cambogia is diffi-
cult to assess given the multitude of ingredients within
these supplements.16
In laboratory studies, hepatotoxicity
caused by G. cambogia has been linked to hepatic fibro-
sis, inflammation, and oxidative stress.17
TABLE 1. HEPATOTOXIC INGREDIENTS
Hepatotoxic Ingredient
(species name) Common Uses
Predominant Injury
Pattern Comments
Black cohosh (Cimicifuga racemosa,
rhizome of Actaea racemosa)
Menopausal symptoms Unknown,
autoimmune features
Liver damage ranges from transient increases in liver
enzymes to acute liver failure.
Ma huang (Ephedra sinica,
Ephedra sp.)
Weight loss Hepatocellular* Autoimmune features (ANA and ASMA positive)
observed.
Green tea (Camellia sinensis) Weight loss Hepatocellular Toxicity has been found to be dose dependent and
may be increased in the fasting state.
Garcinia cambogia Weight loss Oxidative stress Associated with hepatic fibrosis and inflammation.
Kava (Piper methysticum) Sedation, anxiolytic Cholestatic* Significant cholestatic hepatitis demonstrated. Liver
damage ranged from transient elevation in liver
enzymes to ALF leading to death and transplant.
Saw palmetto Benign prostatic
hypertension
Hepatocellular Hepatotoxicity rare and self-limited. Idiosyncratic
reaction is possible.
Senna glycosides
(Cassia senna)
Constipation Hepatocellular Damage caused by an active metabolite produced
by intestinal breakdown of the ingredient. Hepato-
toxicity is self-limited and rare.
Skullcap (Scutellaria
baicalensis)
Sedation,
anti-inflammatory
Hepatocellular Injury is self-limited.
Usnic acid Weight loss Hepatocellular
and mixed*
Hepatotoxicity has led to fulminant liver failure.
Noni juice (Morinda
citrifolia)
Seasonal flu, colds, diabetes,
high blood pressure
Hepatocellular Cases of acute liver failure that required liver trans-
plant have been reported.
Abbreviations: ALF, acute liver failure; ANA, anti-nuclear antibody; ASMA, anti–smooth muscle actin.
REVIEW Liver Injury Due to HDS Zheng and Navarro
81 | CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD

3. Kava Kava
Indigent to the Hawaiian, Polynesian, and Fiji islands, Kava
root, Piper methysticum rhizoma, has traditionally been used
for anxiolytic and antidepressant purposes. Injury has led to
cholestatic hepatitis. In 1 report, of 36 patients studied, 9
patients experienced fulminant liver failure, resulting in 8 sub-
sequent liver transplantations.18
Given that marked eosino-
philic infiltrates were observed in some liver biopsies and
there was lack of dose association with liver injury, the
authors of this series speculate that the mechanism of injury
may be both immunogenic and idiosyncratic.
Saw Palmetto
Saw palmetto is used for urinary hesitancy or urgency
because of benign prostatic hypertension.19
Hepatotoxicity
caused by saw palmetto is rare and self-limited. In the few
published cases, the mechanism of injury was not reported.20
Senna Glycosides
Commonly used for constipation, sennosides are bro-
ken down to an active metabolite, rhein anthrone, which
can cause hepatocellular injury through mitochondrial
damage. Hepatotoxicity is self-limited and rare, although
a recurrence of liver injury after re-exposure has been
observed in one case, giving greater confidence in attri-
bution of injury to this ingredient.21
Skullcap
Often used as a relaxant, Scutellaria baicalensis is a
plant that belongs to the mint family. Clinical reports
have documented use of this herbal remedy for various
reasons from sedation to osteoarthritis.22
A case of hepa-
totoxicity has been documented, but injury was self-
limited after discontinuation.23
Usnic Acid
A common ingredient previously found in weight-loss
products, usnic acid has been shown to uncouple oxida-
tive phosphorylation in mitochondria, thereby increasing
thermogenesis and theoretically possessing antiobesity
properties. Despite its purported weight-loss effects,
usnic acid has been labeled as a direct hepatotoxin, lead-
ing to fulminant liver failure as documented in previously
published case reports.24,25
Noni Juice
Extracted from the Noni fruit, Morinda citrifolia, the
juice has been used for a variety of purposes from the
seasonal flu to diabetes. Cases of acute liver failure, with
one patient requiring liver transplantation, have been
reported.26,27
Despite reported cases of associated liver
injury, the true hepatotoxic potential of M. citrifolia
requires further investigation.
CONCLUSION
Liver injury caused by HDS has become increasingly
recognized by clinical investigators. Initial clinical assess-
ment depends on a careful diagnostic approach and
being aware of the array of potentially hepatotoxic ingre-
dients. We have focused on several common ingredients
that have been implicated in liver injury. Recognition of
these ingredients within HDS consumed by patients with
liver injury should heighten the clinician’s suspicion of a
causal association. In cases in which a mechanism of
injury could not be identified or even surmised from the
clinical reports, one could conjecture idiosyncrasy. How-
ever, a more confident understanding of the mechanism
of injury requires further toxicological study.
CORRESPONDENCE
Elizabeth Zheng, M.D., Hepatology, Einstein Medical Center, Philadel-
phia, PA. E-mail: zhengeli@einstein.edu
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REVIEW Liver Injury Due to HDS Zheng and Navarro
83 | CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD