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Abstract and Figures

Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.
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International Journal of
Molecular Sciences
Review
Hepatotoxicity by Dietary Supplements: A Tabular
Listing and Clinical Characteristics
Miren García-Cortés
1,2,
, Mercedes Robles-Díaz
1,2,
*
,
, Aida Ortega-Alonso
1
,
Inmaculada Medina-Caliz
1
and Raul J. Andrade
1,2
1
Servicio de Farmacología Clíınica and Unidad de Gestión Clínica (UGC) de Gastroenterología y Hepatología,
Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria,
Universidad de Málaga (UMA), 29010 Málaga, Spain; mirengar1@hotmail.com (M.G.-C.);
aida_ortega_alonso@hotmail.com (A.O.-A.); imcaliz@uma.es (I.M.-C.); andrade@uma.es (R.J.A.)
2
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd),
28029 Madrid, Spain
* Corresponding: mrobles@uma.es; Tel.: +34-95-213-6647
These authors contributed equally to this work.
Academic Editor: Igor P. Pogribny
Received: 22 February 2016; Accepted: 25 March 2016; Published: 9 April 2016
Abstract:
Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy.
The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed
due to the general belief of safety of these products. Reported cases of herbals and DS-induced
liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with
a description of DS associated with hepatotoxicity as well as review the phenotype and severity
of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced
liver injury and DS-induced liver injury. In this article, we describe different DS associated with
liver injury, some of them manufactured DS containing several ingredients (Herbalife
products,
Hydroxycut
, LipoKinetix
, UCP-1 and OxyELITE
) while others have a single ingredient (green
tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma
huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury
are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this
work, as they are frequently sold under the denomination of DS despite being conventional drugs.
Keywords:
dietary supplements; liver injury; hepatotoxicity; anabolic steroids; green tea; Herbalife
products; Hydroxycut; Oxyelite Pro; vitamin A; usnic acid
1. Introduction
Herbals and dietary supplements (HDS) are used to maintain or improve health. Regulation of
herbal products may vary between different countries. In the European Union, the concepts of
traditional herbal medicines and traditional plant food supplements are defined under different legal
frameworks [
1
]. The European Directive 2004/24/EC released in 2004 by the European Parliament
and by the European Council provides the guidelines for the use of herbal medicines; where an herbal
product is considered a medicinal product when presented as having properties for treating or
preventing disease in human beings or when it has a pharmacological, immunological or metabolic
action. It is the competence and responsibility of national authorities to decide, on a case-by-case
basis, whether an herbal product fulfils the definition of medicinal product. On the other hand, herbal
products marketed in the form of food supplements should comply with Directive 2002/46/EC on food
supplements and Regulation (EC) No 1924/2006 on nutrition and health claims made on foods of the
European Food Safety Authority (EFSA) (http://www.efsa.europa.eu/). An herb may be considered
Int. J. Mol. Sci. 2016, 17, 537; doi:10.3390/ijms17040537 www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2016, 17, 537 2 of 23
a medicinal product or a dietary supplement (DS) depending on medical claims of a therapeutic
indication [
2
]. In the United States (US), the Dietary Supplement Health and Education Act (DSHEA)
of 1994 remains the foundation for current regulation of herbal products that are all classified as DS or
botanicals [
3
]. Therefore, they are regulated as food products and not subjected to the same premarket
requirements for safety or efficacy.
Although the real prevalence of HDS consumption is unknown, it is estimated that more than 50%
of the US adult population uses HDS [
4
,
5
]. Besides, a recent survey made in Europe (Finland, Germany,
Romania, Italy, Spain, and the United Kingdom (UK)) estimated that 18.8% out of 2359 consumers
admitted using one or more DS, excluding herbal products [6].
However, HDS are not as safe as many people believe. These products can induce adverse
effects including liver injury. Moreover, occurrence of HDS-related liver toxicity ranges from 2% to
16% of all identified cases of hepatotoxicity included in different drug-induced liver injury (DILI)
Registries in Western countries with an increasing prevalence over time in the US [
7
10
]. Besides, the
number of illicit anabolic androgenic steroids (AAS) inducing liver injury and submitted to the DILI
Network (DILIN) in the US and to the Spanish DILI Registry has also increased in recent years [
10
,
11
].
An even higher prevalence of HDS-DILI can be found in Asian countries where there is a widespread
consumption of HDS, 73% in Korea, 71% in Singapore, and 40% in China [1214].
Unlike what happens with conventional drugs that have the Anatomical Therapeutic Chemical
(ATC) classification system, an unresolved problem is the lack of a standard nomenclature or
classification scheme for HDS. Stickel et al. classified HDS related to hepatotoxicity into two different
groups: herbal-induced liver injury and dietary supplement induced liver injury (DSILI) [
15
].
This author considers DS if consumed as an aid to improve nutritional status, to lose weight or
to treat constipation [
15
]. The DSHEA defines DS as any product intended to supplement, but not
substitute the diet. Dietary supplements may contain one or more ingredients including vitamins,
minerals, herbs, botanicals, aminoacids or extracts thereof [
3
]. Although herbals and DS sometimes
overlap, the substances considered as DS associated with liver injury are Camellia sinensis (green tea
extract), usnic acid, 1,3-Dimethylamylamine (1,3-DMAA), vitamin A, Herbalife products, Hydroxycut,
LipoKinetix, UCP-1, OxyELITE pro, and anabolic androgenic steroids [
16
,
17
]. We also include in this
list linoleic acid, ma huang and Garcinia cambogia, DS marketed for weight loss.
DSILI is challenging due to the fact that these products are not regulated in the same way as
prescription drugs are, and subsequently lack uniform criteria for manufacturing and authentication of
this products. Probably, underreporting is even higher with DS than with DILI given that consumers
and health care practitioners are not always aware of the possible adverse events of these supplements.
Moreover, as occurs with DILI, diagnosis and causality assessment of DSILI is difficult given the
absence of diagnostic tests or biomarkers, and causality assessment methods such as the Roussel
Uclaf Causality Assessment Method (RUCAM) [
18
] are not completely validated for this purpose.
An attempt to develop a specific scale for the causality assessment of HDS-DILI was made by the
DILIN group, but it has not been validated and published [19].
In this manuscript we aimed to make a tabular listing with a detailed description of potentially
hepatotoxic DS as well as review the phenotype and severity of DSILI. Herbal products have been
described elsewhere in other chapters of this special issue. A selective literature search in the
PubMed was performed, using search term such as dietary supplements combined with the following:
drug-induced liver injury, herb-induced liver injury, hepatotoxicity, liver damage, and hepatitis.
Besides, an individual research was made for each DS related to hepatotoxicity. The search was
primarily focused on English and Spanish language case reports, case series, and clinical reviews,
published from 1984 to November 2015. All citations in these reports were searched for other yet
unidentified case reports, including cases with sufficient information published in other languages.
Int. J. Mol. Sci. 2016, 17, 537 3 of 23
2. Reported Cases of Dietary Supplements-Induced Liver Injury: A Tabular Listing
From overall publications, different DS were identified as being linked to hepatotoxicity, green
tea extracts, linoleic acid, usnic acid, vitamin A, garcinia cambogia, ma huang, 1,3-DMAA and
multi-ingredient products such as Herbalife products, Hydroxycut, LipoKinetix, Oxy ELITE Pro and
UCP-1 and anabolic steroids illicitly sold as DS for bodybuilding. Anabolic androgenic steroids can
be divided into two groups: legal AAS with a prescription from a physician for a medical condition
and new designer steroids (“underground” drugs) that are not used clinically and are entirely illegal.
Although strictly speaking none of them are DS, we have included illicit AAS in this manuscript
because many of them are sold under the description of DS despite being conventional drugs (ATC
classification system A14A anabolic steroids). Table 1 summarizes information retrieved from original
case reports and cases from DILI registries associated with the aforementioned DS.
2.1. Illiciti Androgenic Anabolic Steroids for Body Building
Anabolic androgenic steroids are synthetic derivatives of testosterone whose medical indications
are mainly male hypogonadism, breast cancer, anemia and hereditary angioneurotic edema. However,
several AAS such as stanozolol, methyltestosterone, oxandrolone, fluoxymesterone and danazol are
also used without medical supervision for performance enhancement and muscle building purposes
due to their anabolic effects, stimulating protein synthesis and positive nitrogen balance [20].
There are numerous reported cases of liver injury due to bodybuilding products, most of them
containing illicit anabolic steroids [
10
,
11
,
21
23
]. Among the most frequent AAS involved in liver injury
are stanozolol, methasterone, methylepithiostanol [
11
,
24
26
]. The number of anabolic androgenic
steroids (AAS) hepatotoxicity cases submitted to the Spanish DILI Registry has increased in recent
years. Only five AAS hepatotoxicity cases were identified during the first 15 years (1994–2009), while
the number of cases tripled to 15 over the next four years (2010–2013) resulting in a significant increase
from 1% to 8% of the total number of hepatotoxicity cases in the Spanish DILI Registry [
11
]. The reason
for this increase could be a combination of increased usage and improved clinical awareness of this
form of hepatotoxicity. Similarly, the Drug–Induced Liver Injury Network found an increase in
bodybuilding HDS cases from 2% in 2004-2005 to 8% in 2010–2012 [10].
Several patterns of injury such as focal nodular hyperplasia, hepatocellular adenoma [
27
],
hepatocellular carcinoma [
28
], peliosis hepatis [
29
,
30
], spontaneous hepatic rupture [
31
] and, specially,
cholestasis hepatitis [
11
,
24
26
,
32
36
], have been described. However, in a recent study, AAS
hepatotoxicity was associated with a distinct phenotype, characterized by considerable total bilirubin
(TB) elevations independent of type of damage, in addition to low values of transaminases and alkaline
phosphatase, compared to values in liver injury due to convencional drugs and herbs [
10
,
11
,
24
26
,
37
].
Young men (mean age 32 years), requiring hospitalisation, hepatocellular injury and jaundice
were predominating features among the AAS cases in the Spanish and SLatin DILI Registries.
Although hepatocellular injury predominates in this study, acute kidney injury developed in cholestatic
cases with pronounced jaundice [
11
]. The precise mechanism of toxicity is not clear, but the genotyping
of patients with cholestatic pattern of liver injury due to anabolic steroids suggests that these products
could induce inhibition of biliary transporter proteins such as ATP8B1/ABCB11, as ocurr in cases of
benign recurrent intrahepatic cholestasis type 1 or 2 [38].
A study performed in 2011 in Brazil, suggested that anabolic steroids could induce non-alcoholic
fatty liver disease (NAFLD). Comparing two groups of bodybuilders, one consuming AAS with
another that did not, 12.6% had criteria of NAFLD (compatible imagen on liver ultrasound, elevated
transaminases, and exclusion of overweight, insulin resistance, significant alcohol consume or other
medication that could be related with NAFLD) vs. 2.4%, respectively [
39
]. In 2015, another Brazilian
study with 182 asymptomatic young recreational AAS using bodybuilders was performed. They, all
ě
18 years old and with AAS use for
ě
6 months, presented a wide spectrum of liver injuries that
included hepatotoxicity, fatty liver, and liver neoplasm [27].
Int. J. Mol. Sci. 2016, 17, 537 4 of 23
In addition to liver injury, many other effects have been described in AAS users: cardiovascular
effects (hypertension, cardiomyopathy, left ventricular hypertrophy, dyslipidemia with potential
acceleration of aterosclerosis, myocardial ischemia, adverse effects on coagulation and platelet
aggregation, and arrhythmias); neuroendocrine effects (temporarily hypogonadism after stopping
a cycle of AAS due to the suppression of the hypothalamic-pituitary-testicular axis); and neuropsychiatric
effects (hypomanic or manic symptoms, sometimes associated with aggression and violence, although
it may be difficult to judge which of these psychiatric effects are attributable to AAS themselves, as
opposed to underlying personality or psychosocial factors surrounding AAS use) [40].
2.2. Green Tea (Camellia sinensis) Extracts
Green tea is a highly consumed and popular drink in the world used for centuries. Depending on
the processing treatment, especially the “degree of fermentation”, tea can obtain differences in
flavor, color and composition. Green tea contains methylxanthine alkaloids (caffeine, theophylline,
theobromine), the polyphenols which are considered the major bioactive molecules of tea. In the
last decade, the consumption of tea has increased for its health benefits. While green tea infusion is
widely consumed and generally safe (although some cases of liver injury after green tea infusion intake
have been reported, Table 1), green tea extracts have shown to have a hepatotoxic potential. The first
report on liver damage related to green tea extract intake was in 1999 [
41
]. Thereafter, many cases
of liver injury related to the intake of different green tea extracts have been recorded [
8
,
15
,
16
,
42
52
].
Published cases of hepatotoxicity due to green tea extracts from the US, UK and Australia until 2008
were reviewed by the US Pharmacopeia. Out of 34 evaluated cases, 27 were labelled as probably and
the remaining 7 cases as possibly induced by green tea extracts. One of these patients died, which
indicate that this kind of hepatotoxicity can have serious outcomes [
53
]. In a review performed by
Mazzantion 34 published cases and two unpublished, seven had a positive rechallenge due to green tea
extracts [
54
]. This highlight the importance of a correct hepatotoxicity diagnosis to avoid inadvertent
reexposition to the causative agent.
The physiopathology of green tea inducing liver damage is unclear but could be explained by
the (
´
)-epigallocatechin gallate or its metabolite (
´
)-epicatechin gallate which, in certain conditions
such as fasting, can induce oxidative stress and liver damage [
55
]. However, experimental studies
have also demonstrated hepatoprotective properties
in vitro
and
in vivo
[
56
58
]. Furtheremore, a recent
systematic review presents therapeutic and favorable effects of Camellia sinensis in humans, such as
reducing mortality, attenuating steatosis, and a reducing incidence of primary liver cancer [59].
The clinical presentation and liver profile of three hepatotoxicity cases induced by Camellia sinensis
extracts from the Spanish DILI Registry includes hepatocellular pattern of liver injury, jaundice with
total bilirubin higher than 10 times the upper limit of normal (
ˆ
ULN) and high level of alanine
aminotransferase (ALT) (>45
ˆ
ULN). The duration of treatment and time to onset range from 17 to
121 days and 5 to 121 days, respectively [
8
]. Five hepatotoxicity cases due to Cuur (Camellia sinensis)
reported to the Swedish Adverse Drug Reactions Advisory Committee showed a similar profile with
hepatocellular pattern of liver injury, and four with jaundice and high levels of ALT (25–95
ˆ
ULN) and
duration of treatment from 35 to 140 days [
47
]. Another case of hepatotoxicity was reported in Spain in
2004 in a woman who had taken Camilina-Arkocápsulas (Camelia sinensis) and Ortosifón Arkocápsulas
(Orthosiphon stamineus) for weigh loss for two months. Similarly, hepatocellular pattern of liver damage
with high level of ALT (2398 U/L) and TB (19.9 mg/dL) was found [
49
]. Fulminant hepatitis that
required liver transplantation has also been associated with Exolise, an 80% ethanolic dry extract
of green tea (Camellia sinensis) standardized at 25% catechins expressed as epigallocatechin gallate,
containing 5%–10% caffeine [
60
]. Five cases of liver injury due to Exolise had been reported in Spain
before this fulminant case [
50
,
61
]. In fact, Exolise was withdrawal in Spain in 2003 (Spanish Drug and
Sanitary Products Agency, AEMPS).
There are some cases of liver injury due to green tea extracts alone but in many cases the patients
also took other drugs or products with potential hepatotoxicity, such as seen in a 28-year-old woman
Int. J. Mol. Sci. 2016, 17, 537 5 of 23
taking Somalyz (usnic acid, propionyl-L-carnitine, phosphatidylcholine/phosphatidylethanolamine,
gamma-aminobutyric acid, and vitamin E) and Lipolyz (usnic acid, propionyl-L-carnitine, green tea
extract, guggulsterone Z and guggulster-one E, cyclic adenosine monophosphate and vitamin E) for
body building purposes. Liver test showed TB 4
ˆ
ULN, ALT 23
ˆ
ULN, aspartate aminotransferase
(AST) 11.6
ˆ
ULN, alkaline phosphatase (ALP) 1
ˆ
ULN and international normalized ratio (INR) 2.6.
The patient developed encephalopathy and required liver transplantation [62].
Despite the difficulty in identifying green tea extracts as the culprit in an episode of liver damage
due to comcomitant intake of other products, as well as the assumption of green tea being a safe
product, structured causality assessments have suggested causal relationships between intake of green
tea extracts and liver damage with cases of positive reexposures as mentioned above [54,63].
2.3. Linoleic Acid
Conjugated linoleic acid (CLA), a polyunsaturated omega-6 fatty acid is a DS that has been
shown to cause reduction in body fat mass. It has also been shown to stimulate immune responses,
improve insuline sensitivity, and modify lipid metabolism. Despite the benefits attributed to CLA,
three cases of drug-induced liver injury due to CLA have been reported to date, the first one in
2009 [
64
]. All patients were women and developed hepatocelular type of liver injury after taking CLA
to aid in weight loss and body fat reduction. The most severe case was a 63-year-old female who had
taken purely CLA pills during one month, and presented at admission high levels of ALT (2300 U/L),
AST (2300 U/L), TB (26 mg/dL), ALP (255 U/L) and INR 1.65. The patient developed encephalopathy
and required liver transplantation [
65
]. Out of the other two patients, one presented jaundice (TB
12.9 mg/dL) [
64
], while both presented elevated values of transaminases at onset (ALT 2101 U/L, AST
1663 U/L and ALT 1078 U/L, AST 1519 U/L, respectively) [
64
,
66
]. Both cases had complete resolution
after discontinuation of CLA.
2.4. Usnic Acid, LipoKinetix and UCP-1
Usnic acid is uniquely found in lichens, and is especially abundant in genera of lichens such
as Alectoria, Cladonia, Usnea, Lecanora, Ramalina and Evernia. Many lichens and extracts containing
usnic acid have been utilized for medicinal, perfumery, cosmetic as well as ecological applications [
67
].
The clinical properties reported are antimicrobial, anti-inflammatory, antioxidant, analgesic, antipiretic
and weight loss. The most popular indication is for weight control alone or in combination with other
herbal products. Usnic acid functions as an uncoupler of the mitochondrial respiratory chain and is
subsequently believed to stimulate fuel oxidation and increase metabolic rates, which could influence
weight loss [
68
]. However, this mechanism could also induce mitochondrial injury and hepatocyte
death, as
in vitro
studies have shown that uncoupling mitochondrial oxidative phosphorylation can
generate oxidative stress [69].
Several cases of acute liver failure (ALF) related to a combination of DS with usnic acid
alone or in combination with other products have been reported, including cases requiring liver
transplantation [
70
74
]. Hepatotoxicity has been described related to the intake of a multiingredient
preparation LipoKinetix, a product that contains norephedrine, caffeine, yohimbine, diiodothyronine,
and sodium usniate (usnic acid) [
70
,
73
,
74
]. Favreau et al. described seven cases of acute liver injury
related to LipoKinetix. Time to onset for liver injury usually occurred within the first 3 months of
consumption. Pattern of liver test results were compatible with drug-induced acute hepatocellular
necrosis. There was no evidence of allergy, such as rash or eosinophilia. One patient developed ALF.
All recovered spontaneously after discontinuing use of LipoKinetix, and results of liver tests as well as
symptoms normalized within 4 months in five patients (two patients declined to have further testing).
Three of the seven patients, including the one who developed ALF, were taking LipoKinetix alone at
the time of presentation. Of the four patients who were taking multiple supplements, two resumed
taking supplements other than LipoKinetix without further incidents. Other causes of liver injury
were excluded in all the patients [70].
Int. J. Mol. Sci. 2016, 17, 537 6 of 23
In a case series of ALF from an adult tertiary care university hospital and a Veterans Affairs
hospital in Oregon describing 20 cases of ALF, 10 were recent or active users of DS or herbs. In two of
these cases, a 25-year-old female who died and a 42-year-old male who recovered, Lipokinetix was
identified as the only cause of ALF [73].
An analysis, performed at four transplant centers, found an elevated number of acute hepatitis
or ALF due to herbal products for weight loss. Out of 12 patients with liver injury attributed to the
intake of HDS weight loss products, two cases in two 32-year-old females were due to Lipokinetix [
74
].
Hence, the US Food and Drug Administration (FDA) published a warning about LipoKinetix, and the
product was withdrawn from the US market in November 2001.
Durazo et al. reported a case of a 28-year-old woman who developed ALF and required
orthotopic liver transplantation after two weeks of intake of pure usnic acid for weight loss [
71
].
Another two cases of severe liver toxicity related to a multi-ingredient health supplement UCP-1
(BDC Nutrition, Richmond, KY, USA), a combination containing usnic acid, L-carnitine, and calcium
pyruvate, were published by Sanchez et al. in 2006. They reported acute liver injury in a wife and
husband after taking this product for bodybuilding purposes. The wife developed ALF that required
liver transplantation [
72
]. A genetic susceptibility has been suggested after the report of three sisters
with liver toxicity related to a “fat burner” DS containing usnic acid [75].
Finally, another case of hepatotoxicity requiring liver transplantation due to DS (Somalyz and
Lipolyz, Species Nutrition, Westbury, NY, USA) containing usnic acid was reported by Yellapu et al.
in 2011 [
62
]. This case, is described in the Camellia sinensis section as green tea extract is one of the
component of Lipolyz and we are unable to determine which component is responsible for liver injury
or if there is an interaction between the components that cause hepatotoxicity.
2.5. Herbalife Products
Herbalife is a company that produces different products for weight loss, DS and cosmetics.
Products manufactured in the US are exported to more than 50 countries around the world [
76
].
In 2014, the company reported net sales of $5.0 billion, a 3% increase compared to 2013 [
77
]. Up to
date, there are 11 published reports of liver injury (with a total of 57 cases) after the intake of some
of the different products offered by Herbalife, 12 cases from Switzerland [
78
,
79
], 12 from Israel [
80
],
20 from Spain [
81
83
], 1 from Argentina [
84
], 5 from Iceland [
85
], 5 from US [
10
,
86
] and two from
Venezuela [
87
]. The more frequent type of liver injury in these cases was hepatocellular, although there
were also cases with cholestatic and mixed liver injury. Among the Herbalife products hepatotoxicity
cases there were cases of acute liver failure requiring transplants and cases of chronic liver injury
including cirrhosis. The mechanism of hepatotoxicity is very difficult to identify as most of the
patients took several different Herbalife products at the same time. Some patients had elevated titers of
autoantibodies and liver biopsies with plasma cell infiltrates, suggesting that autoimmune mechanisms
could have played a role in these patients. In two cases of liver injury after intake of Herbalife products,
contaminations with Bacillus subtilis were found in the products. Hence, adulteration of products with
bacterial pathogens could explain some cases of liver injury in patients taking Herbalife products [
79
].
Other possible causes of liver injury could be contamination with other microorganisms or chemicals
during the manufacturing process or the use of unrefined products, such as herb extracts.
2.6. Hydroxycut
Hydroxycut is a DS product for weight loss and muscle building with many changes in its
formulation. Some of the ingredients have been Garcinia cambogia, Cissus quadrangularis, caffeine,
Ma Huang (ephedra) and green tea. At least, 29 cases of Hydroxicut-induced liver injury have
been reported [
10
,
74
,
86
,
88
99
]. Typically, the episodes occur after weeks of consumption and show
a hepatocellular pattern of liver damage (25/28) and high levels of transaminases. Only few cases
showed cholestasis (3/28). In five cases reported of Hydroxycut-induced hepatotoxicity, from a case
series of 130 different HDS-induced liver injury cases, the pattern of liver injury is not specified [
10
].
Int. J. Mol. Sci. 2016, 17, 537 7 of 23
Autoimmune markers can be positive for antinuclear antibodies at the time of the acute liver injury in
some patients [
92
]. In these reports, six patients developed ALF; out of them, three received a liver
transplantation. An additional patient underwent exploratory laparotomy for liver transplantation,
and was found to have intestinal infarction. The liver transplantation was aborted and the patient
died [74,92].
The formulation of Hydroxycut has changed in recent years. The earliest reported cases of
acute liver injury related to Hydroxycut were part of a case series from four transplant centers of
patients that had developed severe hepatitis after taking various supplements containing ephedra,
also called ma huang, a plant substance whose natural ingredient is ephedrine [
74
]. In 2004 the sale
of supplements containing ephedra was banned by the FDA. However, new subsequent cases of ma
huang-free Hydroxycut-associated hepatotoxicity were reported, all of whom spontaneously recovered.
In May 2009
, the FDA published a warning about Hydroxycut products related to hepatotoxicity,
resulting in that these products were withdrawn from the market [
95
]. However, after the 2009 recall,
Hydroxycut was reformulated and reintroduced on the market, and FDA confirmed that the only
ingredient left from prior formulations was caffeine [
96
]. Despite this, a new case of hepatotoxicity due
to Hydroxycut SX-7 Clean Sensory formulation was reported in 2015, with high level of transaminases
(AST 2360 UI/L, ALT 6218 UI/L), TB 8.3 mg/dL, alteration in coagulation (INR) 5.0) and renal
impairment (creatinine 1.80 mg/dL) [97].
2.7. 1,3-Dimethylamylamine (DMAA) and OxyELITE
OxyELITE Pro (OEP) is a DS containing DMAA. It is used for performance enhancement and
muscle building and for weight control as it is believed to accelerate metabolic processes. DMAA is
an ingredient in over 20 DS and has been previously implicated in acute myocardial infarction
(Jack3d) [
100
]. A case series of OEP-induced liver injury in a military population in Southern California
with two cases requiring transplants due to acute liver failure was reported in 2014 [101].
In early 2013, several reformulated (DMAA-free) versions of OEP, in which 1,3-dimethylamylamine
was replaced with aegeline, started to be sold. However, this new ingredient in OEP products
was not notified to the FDA. Roytman reported, also in 2014, another case series of eight patients
in Hawaii with acute liver injury after taking the new DMAA-free OEP formula “Super Thermo”.
Six of the patients had also taken the “old formula” for months. Two patients underwent urgent
transplantations, and one died [
102
]. Later, a deep epidemiological investigation of the events in
Hawaii was carried out. The Hawaii Department of Health identified 36 individuals with acute onset
hepatitis (including the patients from the Roytman’s case series [
102
]), using OEP (some of them
DMAA-free formulations) 60 days before liver damage onset and residence in Hawaii during the
exposure period. Fourteen patients used only OEP, while 22 subjects used OEP and another DS as
well. Hepatitis A, B and C, alternative diagnosis in hepatic imaging and history of alcoholism were
ruled out in all the patients. The medians of ALT, AST and TB peak were 1740 U/L, 1134 U/L and
9.4 mg/d/L, respectively. No more cases of ALF than those previously reported by Roytman were
found [
103
]. However, a further investigation by Teschke et al. of the cause(s) of liver disease in this
cluster of suspected OEP hepatotoxicity patients in Hawaii reached the conclusion that there was
insufficient evidence to determine OEP as the culprit in all the cases [104].
Additional cases of liver injury associated with the consumption of OEP have been reported.
One case of liver injury attributed to OEP was presented in a case series of hepatotoxicity due to
HDS from the Drug-Induced Liver Injury Network [
10
]. Another study investigating 114 reports of
adverse event submitted to the FDA from February 2012 to February 2014 in patients who ingested
OEP was performed. Out of the 114 cases, 55 developed liver disease (viral and autoimmune hepatitis,
gallbladder disease and other known causes of liver damage were excluded) [105].
Int. J. Mol. Sci. 2016, 17, 537 8 of 23
2.8. Vitamin A
Vitamin A is used to improve immune functions, night blindness, prevent and treat vitamin A
deficiency, and also for skin conditions including eczema, psoriasis, keratosis follicularis and ichthyosis.
Acute toxicity due to hypervitaminosis A, occurs when adults and children ingest >100
ˆ
and >20
ˆ
the
recommended daily allowance, respectively, for vitamin A over a period of hours or a few days [
106
].
It is a small problem compared to chronic vitamin A toxicity from the ingestion of high amounts of
vitamin A for months or years. Daily intakes of >25,000 IU for >6 years and >100,000 IU for
>6 months
are considered toxic, but there is wide inter-individual variability for the lowest intake required
to elicit toxicity [
107
109
]. Long-term use of large amounts of vitamin A might cause side effects
including fatigue, irritability, mental changes, anorexia, stomach discomfort, nausea, vomiting, mild
fever, excessive sweating, an increase risk of osteoporosis and hip fracture and many other side effects.
Hepatotoxicity due to hypervitaminosis A has been described for years and include alterations in
liver profile, cholestasis, non-cirrhotic portal hypertension, chronic hepatitis and cirrhosis [
110
113
].
Hepatotoxicity at therapeutic doses has also been described. A case of severe hepatotoxicity associated
with habitual daily ingestion of 25,000 IU of vitamin A bought as an over-the-counter DS was reported
by Kowalski [
114
]. In addition, vitamin A tolerance can be reduced in patients with regular alcohol
consumption [
115
]. Toxicity of vitamin A is belived to be a dose-dependent effect of retinoids on
hepatic stellate cells. A study by Nollevaux showed a statistically significant correlation between the
volumen density of total fibrosis and volumen density of total
α
-smooth muscle actin-immunolabelled
cells. Moreover, histology assessment together with clinical data indicated a strong correlation between
volumen density of perisinusoidal fibrosis and the daily dose of vitamin A intake [116].
We found eighteen reports with 58 cases of vitamin A containing DS related
hepatotoxicity [110,111,114,116130]
. A rare case of cholestatic liver injury without fibrosis
with pathological features of vitamin A accumulation in the liver biopsy has also been described,
however the patient was taking Herbalife products, therefore it cannot be excluded the presence of
hepatotoxicity of other components of Herbalife products together with vitamin A intoxication [
111
].
Other individual risk factors have been described such as pre-existing liver disease, co-medication
with other potentially hepatotoxic drugs, and younger age [109,131].
3. Miscellaneous
3.1. Ma Huang Extract
Ephedra, also known as ma huang, is a medicinal preparation from the plant Ephedra sinica and is
widely used as a weight-loss product by millions of people. Analysis of safety data from 50 clinical trial
revealed that ma huang are associated with many adverse event related to this product (psychiatric,
gastrointestinal, cardiovascular and cerebrovascular) [132].
Liver injury associated with ma huang has also been reported. In an analysis at four transplant
center, 10 patients with severe liver injury were associated with the intake of DS for weight loss
containing ma huang (Xenadrine, Excelerator, Metabolife 356, Thermolite, BetaLin, Thermo diet stack
and Hydroxycut) [
74
]. Hycroxycut-induced liver injury cases has been described above. Time to
onset was approximately 6 weeks or more. Liver profiles showed high level of transaminases and
coagulopathy. The patients presented hepatic encephalopathy from grade 1 to 4 and three patients
required liver transplantations, while the remaining 7 recovered without residual lesions.
3.2. Garcinia Cambogia
Garcinia cambogia is a plant-based supplement widly promoted for weight loss. It has been
implicated in hepatotoxicity in patients taking Hydroxycut, wich contains a variety of ingredients,
including Garcinia cambogia, as mentioned above. The use of Garcinia cambogia alone has also been
implicated in cases of hepatotoxicity. A 52-year-old female needed an orthotopic liver transplant
after taking Garcinia cambogia (USA Nutra Labs) 1000 mg (2 capsules/daily) during 15 days for
Int. J. Mol. Sci. 2016, 17, 537 9 of 23
weight loss [
133
]. Another case occurred in a 42-year-old female after taking pure Garcinia cambogia
during one week also for weight loss. This patient had very high trasaminases level (ALT 70 xULN
and AST 45 xULN) and coagulopathy (INR 1.3). After several days, the patient recovered and was
discharged [134]. In both cases other ethiologies of liver injury were ruled out.
4. Discussion
Dietary supplements are regulated as food and not subjected to the same pre and postmarketing
requirements for safety or efficacy as drugs do. However, published reports of DSILI are rising
in parallel with the increasing popularity of herbal and DS in western countries. DSILI has been
recognized, in some instances with cases of positive reexposure (grean tea extracts). However, the
causality assessment in hepatotoxicity has limitations as there is an absence of diagnostic biomarkers.
Furthermore, the attribution of causality is performed through an exhaustive interview with the
patient, asking for the cronology of intake of drugs and HDS, and exclusion of alternative causes.
For DS, reaching a consistent hepatotoxicity diagnosis is even more difficult as patients do not generally
perceive them as harmful and therefore do not always inform about DS intake when being interviewed
for an episode of liver damage. Furthermore, the use of DS may not always be regular. In addition,
the ingredients in DS compounds can vary considerably and are not always adequately reflected in
the product label. It is for that, some authors have analyzed some of the published reports and have
profoundly criticized these case reports, the method of causality assessment used as well as the need
for an update in regulations [
63
,
104
,
135
,
136
]. Despite the fact that some of the reported DSILI cases
could be erroneously diagnosed, the great amount of data in the literature points to an important
problem of health related to the consumption of DS.
The different forms of DSILI considered in this review can be differentiated into two groups based
on their characteristic phenotypes: AAS and the remaining DSILI cases. While AAS hepatotoxicity
typically produce high values of TB with low levels of transaminases, and no cases of ALF described
to date [
10
,
11
,
23
26
], liver injury due to the remaining DS has typically a hepatocellular pattern of
liver damage with very high transaminase levels [
8
,
47
,
49
,
64
66
,
97
,
103
] and a high number of cases
with ALF [
53
,
60
,
62
,
65
,
70
74
,
78
,
80
,
92
,
101
,
102
]. Hence, DSILI constitutes an important cause of ALF in
transplantation centers [
73
,
74
]. The clinical presentation, liver profile and outcome of DSILI (excluding
AAS) coincide with that of herbal hepatotoxicity, while idiosyncratic hepatotoxicity due to conventional
medication have a minor percentage of fatal cases and lower levels of transaminases compared to
DSILI and lower levels of bilirubin compared to AAS liver injury [10,11].
In summary, given the unproven efficacy and the high number of cases of liver injury due to DS
in addition to the severity with risk of acute liver failure and subsequent death or transplantation,
stricter regulations for commercialization and sale of these products are required by competent health
authorities. A joint effort among clinicians and health authorities in identifying new hepatotoxicity
cases and to educate the general population on the risks of DS consumption is needed.
Int. J. Mol. Sci. 2016, 17, 537 10 of 23
Table 1. Tabular compilation of dietary supplements related to liver injury.
Dietary
Supplement *
Citations Number of Cases Constituents **
Marketed
Properties
Type of Liver
Injury
Regulatory
Measures
Camellia
sinensis
(green tea)
Euforia
Exolise
Onshido
SlimQuick
X-elles
cha verde
Curr
Camilina-
Arkocápsulas
Lipolyz
García-Cortes et al., 2008 [8] 3
Powdered leaves,
hydroalcoholic and
aqueus extracts and
infusions from green
tea leaves
Weight loss Stop
hair loss
Acute
hepatocellular
injury
Hydroalcoholic
extract of camellia
Sinensis “EXOLISE”
withdrawn from
European market
Navarro et al., 2014 [10] 8
Gavilan et al., 1999 [41] 1
Pillukat et al., 2014 [42] 1
Molinari et al., 2006 [43] 1
Verhelst et al., 2009 [44] 1
Patel et al., 2013 [45] 1
Lorenzo-Almorós et al., 2015 [46] 1
Bjornsson et al., 2007 [47] 5
Abu el Wafa et al., 2005 [48] 1
Garcia-Moran et al., 2004 [49] 1
Dueñas et al., 2004 [50] 1
Thiolet et al., 2002 [51] 1
Weinstein et al., 2012 [52] 1
Sarma et al., 2008 [53] 34
Mazzanti et al., 2009 [54] 2
Gloro et al., 2005 [60] 1
Pedros et al., 2003 [61] 4
Seddik et al., 2001 [137] 1
Vial et al., 2003 [138] 1
Peyrin-Biroulet et al., 2004 [139] 1
Mathieu et al., 2005 [140] 1
Bonkovsky et al., 2006 [141] 1
Javaid et al., 2006 [142] 1
Jimemez-Saenz et al., 2006 [143] 1
Rohde et al., 2011 [144] 1
Int. J. Mol. Sci. 2016, 17, 537 11 of 23
Table 1. Cont.
Dietary
Supplement *
Citations Number of Cases Constituents **
Marketed
Properties
Type of Liver
Injury
Regulatory
Measures
Camellia
sinensis
(green tea)
Euforia
Exolise
Onshido
SlimQuick
X-elles
cha verde
Curr
Camilina-
Arkocápsulas
Lipolyz
Martinez-Sierra et al., 2006 [145] 1
Powdered leaves,
hydroalcoholic and
aqueus extracts and
infusions from green tea
leaves
Weight loss Stop
hair loss
Acute
hepatocellular
injury
Hydroalcoholic
extract of camellia
Sinensis “EXOLISE”
withdrawn from
European market
Federico et al., 2007 [146] 2
Prieto de Paula et al., 2008 [147] 1
Bergman et al., 2009 [148] 1
McDonnell et al., 2009 [149] 1
Amariles et al., 2009 [150] 1
Jiménez-Encarnacion et al., 2012 [151] 1
Gallo et al., 2013 [152] 1
Whislett et al., 2014 [153] 1
Arzenton et al., 2014 [154] 1
Fernandez et al., 2014 [155] 3
Dela Cruz et al., 2014 [156] 1
Van straelen et al., 2008 [157] 1
Linoleic acid
Ramos et al., 2009 [64] 1
Polyunsaturated
omega-6 fatty acid
Reduction in
body fat mass
Hepatocellular
Nortadas et al., 2012 [65] 1
Bilal et al., 2015 [66] 1
Usnic acid
Lipokinetix,
UCP-1 Lipolyz
Yellapu et al., 2011 [62] 1
Usnic acid
Norephedrine
(phenylpropanolamine-
PPA), caffeine,
yohimbine,
diiodothyronine,
sodium usniate
Weight loss
Hepatocellular
Acute hepatitis
FDA warning and
withdrawn from the
market
Favreau et al., 2002 [70] 7
Durazo et al., 2004 [71] 1
Sanchez et al., 2006 [72] 2
Estes et al., 2003 [73] 2
Neff et al., 2004 [74] 2
Hsu et al., 2005 [75] 3
Int. J. Mol. Sci. 2016, 17, 537 12 of 23
Table 1. Cont.
Dietary
Supplement *
Citations Number of Cases Constituents **
Marketed
Properties
Type of Liver
Injury
Regulatory
Measures
Vitamin A
Retinol
Plethoryl
Ramanathan et al., 2010 [111] 1
Becker et al., 2007 [112] 1
Croquet et al., 2000 [113] 1
Kowalski et al., 1994 [114] 1
Geubel et al., 1991 [
110
] and Nollevaux et al.,
2006 [116]
41
Muenter et al., 1971 [117] 1
Retinoids
Immunostimulant,
prevention of
night blindness,
acne
Chronic
hepatitis,
cirrhosis,
cholestasis,
non-cirrhotic
portal
hypertension
Russell et al., 1974 [118] and Jaques et al.,
1979 [119]
1
Herbert et al., 1981 [120] 1
Farris et al., 1982 [121] 1
Weber et al., 1982 [122] 1
Hatoff et al., 1982 [123] 1
Park et al., 1985 [124] 1
Inkeles et al., 1986 [125] 1
Vincent et al., 1986 [126] 1
Witzleben et al., 1984 [127] 1
Minuk et al., 1988 [128] 3
Jorens et al., 1992 [129] 1
Cheruvattath et al., 2006 [130] 1
Herbalife
combinations
Navarro et al., 2014 [10] 4
Numerous products
with changes
among countries
Weight loss
nutritional
support,
well being
Acute hepatitis,
cholestasis,
cholestatic
hepatitis,
cirrhosis, ALF
Schoepfer et al., 2007 [78] 10
Stickel et al., 2009 [79] 2
Elinav et al., 2007 [80] 12
Duque et al., 2007 [81], Manso et al.,
2008 [82] and Manso et al., 2011 [83]
20
Chao et al., 2008 [84] 1
Johansson et al., 2010 [85] 5
Int. J. Mol. Sci. 2016, 17, 537 13 of 23
Table 1. Cont.
Dietary
Supplement *
Citations Number of Cases Constituents **
Marketed
Properties
Type of Liver
Injury
Regulatory
Measures
Herbalife
combinations
Chen et al., 2010 [86]
2
Numerous products
with changes
among countries
Weight loss
nutritional
support,
well being
Acute hepatitis,
cholestasis,
cholestatic
hepatitis,
cirrhosis, ALF
Mengual-Moreno et al., 2015 [87]
2
Ramanathan et al., 2010 [111]
1
Hydroxycut
Navarro et al., 2014 [10] 5
Camellia sinensis
Ma huang (ephedra)
Gymnema sylvestre
Amorphophallus Konjac
Paullinia cupana Garcinia
cambogia Caffeine
a-Lipoic acid L-Carnitine
Calcium
Potassium
Chromium
Weight loss
Hepatocellular
pattern. Acute
hepatitis,
cholestasis, ALF,
AIH
FDA warning
Neff et al., 2004 [74] 2
Chen et al., 2010 [86] 1
Stevens et al., 2005 [88] 2
Jones et al., 2007 [89] 1
Dara et al., 2008 [90] 2
Shim et al., 2009 [91] 1
Fong et al., 2010 [92] 8
Sharma et al., 2010 [93] 1
Kaswala et al., 2014 [94] 1
Araujo et al., 2015 [97] 1
Laczek et al., 2008 [98] 3
Haimowitz et al., 2015 [99] 1
Oxy ELITE
Pro
Navarro et al., 2014 [10] 1
Multiingredient.
1,3-Dimethylamylamine
(DMAA)
Aegeline
(N-[2-hydroxy-2
(4-methoxyphenyl)
ethyl]-3-phenyl-2-
propenamide)
Weight loss
Muscle building
Acute hepatitis,
ALF
FDA warning and
withdrawn from the
market
Foley et al., 2014 [101] 7
Roytman et al., 2014 [102] 8
Johnston et al., 2015 [103] 36
Klontz et al., 2015 [105]
55 including the 36
from Johnston
Int. J. Mol. Sci. 2016, 17, 537 14 of 23
Table 1. Cont.
Dietary
Supplement *
Citations Number of Cases Constituents **
Marketed
Properties
Type of Liver
Injury
Regulatory
Measures
Illicit
androgenic
anabolic
steroids:
Celtic dragon
Episdrol
Epistane
SUS500
Uprizing 2.0
Navarro et al., 2014 [10] 45
Androstenedione
Dehidroepiandrosterone
Desoxymethyltestosterone
Maasdrol
Stanozolol
Methasterone
Methylepithiostanol
Superdrol
Body-building,
improving
fitness and
exercise
performance
Hepatocellular
hepatitis,
cholestatic
hepatitis,
hepatocellular
adenoma,
hepatocellular
carcinoma,
peliosis
hepatitis,
focal nodular
hyperplasia
Episdrol and
Epistane were
withdrawn from the
Spanish market,
Uprizing 2.0
(superdrol): FDA
warning and recall of
the product
Robles-Diaz et al., 2015 [11] 25
Singh et al., 2009 [22] 3
Timcheh-Hariri et al., 2012 [23] 20
Kafrouni et al., 2007 [24] 2
Shah et al., 2008 [25] 5
Krishnan et al., 2009 [26] 3
Schwingel et al., 2015 [27] 23
Turani et al., 1983 [28] 11
Choi et al., 2009 [29] 1
Karasawa et al., 1979 [30] 5
Patil et al., 2007 [31] 1
Agbenyefia et al., 2014 [32] 1
Hymel et al., 2013 [33] 1
Brazeau et al., 2015 [35] 1
Sánchez Osorio et al., 2008 [36] 1
Vilella et al., 2013 [37] 1
El Sherrif et al., 2013 [38] 2
Wingert et al., 2010 [158] 1
Luciano et al., 2014 [159] 1
Int. J. Mol. Sci. 2016, 17, 537 15 of 23
Table 1. Cont.
Dietary
Supplement *
Citations Number of Cases Constituents **
Marketed
Properties
Type of Liver
Injury
Regulatory
Measures
Ma huang
(ephedra)
Xenadrine,
Excelerator,
Metabolife 356
,
Thermolite,
BetaLin,
Thermo diet
stack,
Hydroxycut
Neff et al., 2004 [74]
10 (including 2
cases of Hydroxycut
with Ma Huang
reported above)
MA HUANG (ephedra) Weight loss
Hepatocellular
ALF
Garcinia
cambogia
Corey [133] 1
Garcinia cambogia
Weight loss
Hepatocellular
ALF
Melendez-Rosado [134] 1
ALF: acute liver failure. * Dietary supplements (DS) listed are single ingredient (vitamin A, Garcinia cambogia), single ingredient with examples of marketed DS containing, among
others, this single ingredient (Usnic acid: Lipokinetix, UCP-1), marketed DS with several ingredients (Hydroxycut, Herbalife combinations); ** constituents are some of the ingredients
contained in the DS in the same row. Not all the ingredients are present in each DS. The formulation of many DS has changed over the years. DS in bold correspond to single
ingredients; the remaining DS correspond to brand names.
Int. J. Mol. Sci. 2016, 17, 537 16 of 23
Acknowledgments:
This study was supported by grants of the Instituto de Salud Carlos III cofounded by Fondo
Europeo de Desarrollo Regional – FEDER (contract numbers: PI12-00620, AC-0073-2013, PI15/01440) the Agencia
Espanñola del Medicamento y Productos Sanitarios (AEMPS) and CIBERehd (funded by Instituto de Salud Carlos III).
Author Contributions:
Literature research: Miren García-Cortés, Mercedes Robles-Díaz, Aida Ortega-Alonso
and Inmaculada Medina-Caliz; manuscript preparation: Miren García-Cortés and Mercedes Robles-Díaz; table
preparation: Miren García-Cortés, Mercedes Robles-Díaz, Aida Ortega-Alonso and Inmaculada Medina-Caliz;
conclusions and review of the manuscript: Raul J. Andrade.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
AAS
anabolic androgenic steroids
AEMPS
Spanish Drug and Sanitary Products Agency
ALF
acute liver failure
ALP
alkalin phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
CLA
conjugated linoleic acid
DS
dietary supplements
DILI
drug-induced liver injury
DILIN
drug-induced liver injury network
DMAA
dimethylamylamine
DSHEA
Dietary Supplement Health and Education Act
DSILI
dietary supplements-induced liver injury
FDA
Food and Drug Administration
HDS
herbal and dietary supplements
HDS-DILI
herbal and dietary supplement-induced liver injury
INR
international normalized ratio
NAFLD
non-alcoholic fatty liver disease
OEP
OxyELITE Pro
RUCAM
Roussel Uclaf Causality Assessment Method
TB
total bilirubin
UK
United Kingdom
US
United States
ULN
upper limit of normal
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... Another information gap in the administration of phenolic compounds is the determination of the dose-response relationship as well as their potential systemic toxicology. These pharmacological data are needed to protect consumers and producers who use large amounts of phenolic compounds in their products [40]. Although further research is needed, several studies show promising results on their use in the therapeutic field [41]. ...
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