Continuous reporting of new cases in Spain supports the relationship between Herbalife products and liver injury. The study identified 20 cases of liver damage associated with Herbalife product use reported to the Spanish Pharmacovigilance Centers between 2003-2010. Most patients were middle-aged women, and over half required hospitalization. While most recovered, one patient developed cirrhosis. The variety of Herbalife products consumed by patients did not reveal a commonly hepatotoxic ingredient. The ongoing reports emphasize the liver safety concerns regarding Herbalife dietary supplements.

1. ORIGINAL REPORT
Continuous reporting of new cases in Spain supports the relationship
between HerbalifeW
products and liver injury
Gloria Manso1
*, Laureano López-Rivas2
, M. Esther Salgueiro1
, Jose M. Duque2
, Francisco J. Jimeno1
,
Raúl J. Andrade3,4
and M. Isabel Lucena3,4
1
Centro de Farmacovigilancia de Asturias, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
2
Servicio de Digestivo, Hospital San Agustín, Avilés, Spain
3
Servicios de Ap Digestivo y Farmacología Clínica, Facultad de Medicina, Hospital Universitario Virgen de la Victoria, Campus
Universitario s/n, Málaga, Spain
4
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
ABSTRACT
Purpose Previous publications have linked HerbalifeW
products to hepatotoxicity. The identification of earlier cases in which the culprit
agent could not be established raised the hypothesis of a possible contamination of some specific batches of Herbalife products.
Methods We searched the Spanish Pharmacovigilance Centres’ database of adverse reactions for reports of liver injury associated with the
use of Herbalife products from 2003, when the first case was submitted, through September 2010.
Results The search resulted in 20 reports of liver damage (mean age, 49years; 16 women), with 12 patients (60%) requiring hospitaliza-
tion. Hepatocellular damage predominated, and nine (53%) of the hepatocellular cases with bilirubin values were jaundiced, fulfilling the
Hy’s law criteria, which increases the risk for serious outcomes. Two patients experienced a positive rechallenge. One patient developed cir-
rhosis, whereas all the others recovered. Causality assessment by the Karch and Lasagna modified algorithm showed a category of definite in
1 case, probable in 14, and possible in 5. Analysis of the different Herbalife products that each patient had taken did not enable us to identify
any commonly known hepatotoxic ingredient.
Conclusions Our results support the relationship between the consumption of Herbalife products and hepatotoxicity, underscore the concern
regarding the liver-related safety of this dietary supplement, and emphasize the need to establish further regulatory measures. Copyright © 2011
John Wiley & Sons, Ltd.
key words—hepatotoxicity; HerbalifeW
; herbal medicines; adverse reactions; dietary supplements
Received 16 March 2011; Revised 5 May 2011; Accepted 10 May 2011
INTRODUCTION
The first case of hepatotoxicity related to HerbalifeW
products was reported by Hoffmann et al.1
in 2005.
Later on, this case was included in a series of cases
published by Schoepfer et al.2
in the Journal of Hepa-
tology in 2007. In the same issue of this journal, an-
other series of cases, which had occurred in Israel,
was reported by Elinav et al.3
in addition to an edito-
rial on slimming products signed by Stickel.4
In
2007, our group reported the first three cases of
hepatotoxicity suspected of being induced by the
consumption of Herbalife brand products, which oc-
curred in Spain.5
The patients were all from the same
Spanish hospital and presented a similar clinical pic-
ture to those described in the Swiss2
and Israeli3
series.
An additional case,6
the sister of a case previously
described,5
was further reported. Furthermore, in
December 2008, Chao et al.7
published a case occur-
ring in Argentina, and in 2009, Stickel et al.8
reported
two new cases in Switzerland and described the isola-
tion of Bacillus subtilis in products taken by these
patients, together with the observation that toxins
released by this bacterium induced cell damage in
cultured liver cells. In the editorial of the same is-
sue of the abovementioned journal, Seeff9
reminded
us of the need for regulatory measures for these
*Correspondence to: G. Manso, Centro de Farmacovigilancia de Asturias,
Facultad de Medicina, Universidad de Oviedo, Julián Clavería 6, 33006
Oviedo, Spain. E-mail: gmanso@uniovi.es
Copyright © 2011 John Wiley & Sons, Ltd.
pharmacoepidemiology and drug safety 2011; 20: 1080–1087
Published online 12 July 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.2180

2. products. Five new cases occurring in Iceland were
also reported.10
In Spain, after the first reports, taking into account
the series published in other countries, the Spanish
Food Safety Agency (AESAN), together with the
Spanish Agency for Medicines and Health Products
(AEMPS), published a report informing consumers
of the risk of hepatotoxicity associated with Herbalife
products. The dissemination of this information facili-
tated the detection and reporting of new cases. Since
then, the Spanish Pharmacovigilance Centres have
continued to receive reports of hepatotoxicity associ-
ated with Herbalife products occurring in different
Spanish regions. These have been collected through
the Spontaneous Reporting Program of Suspected Ad-
verse Reactions and recorded in the Farmacovigilancia
Española Datos de Reacciones Adversas (FEDRA),
the database of the Spanish System of Pharmacovigi-
lance for Medicinal Products for Human Use. The
present series, although mainly retrieved by the spon-
taneous reporting system—one must take into account
the inherent limitations that are typical of a postmar-
keting database and the fact that it is not uncommon
for data submitted to be incomplete—further supports
the observations from the first series published regard-
ing the hepatotoxicity of Herbalife products and
emphasizes the need for regulatory measures for these
products.
PATIENTS AND METHODS
Using the database FEDRA, we searched for sus-
pected adverse reactions associated with Herbalife
products, registered before September 1, 2010. We
obtained a total of 23 reports that included 21 cases
of hepatobiliary disorders, according to the system
and organ classification of the MedDRA 13.0 dictio-
nary, and 2 from others: 1 case of galactorrhea and
another of nausea, vomiting, and anorexia.
From the cases of liver disorders obtained, we ex-
cluded one report of fatal outcome due to incomplete
and confuse information. This case is briefly described
in the Results section. In the remaining cases, we ana-
lyzed the following: (i) dates of reporting and beginning
and end of the adverse reaction; (ii) patient characteris-
tics: age, gender, weight, and previous diseases; (iii)
reported adverse reaction: preferred term, duration of
the treatment with Herbalife products, liver parameters,
type of liver injury,11
and outcome; (iv) other diagnos-
tic tests performed; (v) concomitant medications taken
by the patients; and (vi) algorithm of causality. To
perform the causality assessment of reported adverse
reactions, the Spanish Pharmacovigilance Centres
use the modified Karch and Lasagna algorithm,
which ascribes levels of probability of association
between drugs and adverse reactions into the following
categories: definite>probable>possible>conditional
unlikely. In addition, we studied (vii) the composition
of the Herbalife products taken by the patients, accord-
ing to the information contained on the packaging
and published by Herbalife on its website,12
and (viii)
Herbalife products taken by each patient in our series
and compared with the products taken by the patients
in previous publications.
RESULTS
Out of the 21 cases of hepatotoxicity related to
the consumption of Herbalife products, 15 were di-
rectly reported to the Pharmacovigilance Centres in
Spain, and 6 were initially collected by the Spanish
DILI (Drug-Induced Liver Injury) Registry at the
University of Málaga (Spain) and later sent to the
Pharmacovigilance Centre of Andalusia.
One of the reports referred to the case of an 18-year-
old female with anorexia nervosa, treated with ebastine,
in which one member of the family had mentioned the
occasional intake of Herbalife products by the patient.
The suspected diagnosis in this case was Whipple’s
disease with neurologic involvement, although this
diagnosis was later not confirmed. The patient evolved
to general and progressive neurological deterioration
and death. This case was not included in the analysis
that follows.
The beginning and reporting dates of the analyzed
reports are shown in Figure 1. Until April 1, 2008,
the month of publication of the joint newsletter from
AEMPS and AESAN, at least 12 cases of hepatotoxic-
ity had occurred in Spain, of which 9 were directly
reported to the Pharmacovigilance Centres and 3 to
the Spanish DILI Registry. After this date, 8 more
cases of hepatotoxicity associated with consumption
of Herbalife products occurred, which, when added
to the previous number of cases, raised the total to 20.
Descriptive terms for the reported adverse reactions
in the Pharmacovigilance Centres were “hepatitis”
in 10 cases, “liver enzymes increased” in 5, “liver
damage” in 3, “cholestasis” in 1, and “liver function
abnormal” in another (Table 1). The mean age of the
reported patients was 49years (range, 36–63 years),
female sex predominated (80%), and seven patients
weighed less than 70kg (mean 68Æ2.9 SEM). Twelve
patients (60%) required hospitalization.
The duration of treatment with Herbalife products was
highly variable, ranging from 16 days in case 13 to 3
years in cases 1 and 4 (median, 88days) (Table 1). The
new cases of herbalife-induced liver injury 1081
Copyright © 2011 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2011; 20: 1080–1087
DOI: 10.1002/pds

3. outcome was favorable in 17 patients, unknown in 2,
and in the remaining case, which was the first to be
reported in Spain, the patient developed cirrhosis
confirmed by liver biopsy. Fourteen cases reported
negative viral serology. Neither data from liver biopsy
nor values of liver parameters were available in 3
Figure 1. Cumulative distribution of the cases according to the date of diagnosis (beginning) and the date of report to the Pharmacovigilance Centres (reporting)
Table 1. Summary of the reported cases of liver injury associated with Herbalife products recorded in the Spanish Pharmacovigilance Centres’ database
Case
Age (year)/
Gender Weight (kg) Adverse reaction/s Treatment/s
Duration
treatment Hospitalization Outcome
1* 47/F 60 Hepatitis, liver cirrhosis Herbalife 3years Yes Cirrhosis
2†
49/F 65 Cholestatic hepatitis Herbalife Unknown Yes Recovered
3†
51/F Unknown Liver enzymes increased Herbalife; tibolone, 2.5mg/day;
alprazolam, u.d.
2months No Recovered
4†
57/F Unknown Liver enzymes increased Herbalife 3years No Recovered
5 45/F Unknown Liver function abnormal Herbalife 1year No Recovered
6 50/F 52 Hepatitis Herbalife 80days Yes Recovered
7 53/F 59 Liver damage Herbalife 64days Yes Recovered
8 57/F 75 Cholestatic hepatitis Herbalife 45days Yes Recovered
9 49/F 80 Liver damage Herbalife; venlafaxine, u.d.;
clonazepam, u.d.
60days Yes Recovered
10 40/F 84 Liver enzymes increased Herbalife 1year No Unknown
11 51/F 58 Cholestasis Herbalife; hidrosoluble and
liposoluble vitamins;
ethylephrine, 250mg;
acetaminophen, 1g/day
68days No Recovered
12 39/F Unknown Hepatitis Herbalife 60days Yes Recovered
13 36/F 80 Liver enzymes increased,
hypertension
Herbalife 16days No Recovered
14 42/F Unknown Liver enzymes increased Herbalife; enalapril, 20mg/day;
amoxicillin+clavulanic acid, u.
d., for 1week;{
acetaminophen,
u.d., for 1week{
300days No Recovered
15 63/M Unknown Liver damage Herbalife 510days No Recovered
16 57/M 72 Cholestatic hepatitis Herbalife; amoxicillin+clavulanic
acid, 1.5g+375mg/day for 1
week;}
nistatine, u.d., for 1
week}
40days Yes Unknown
17 44/F Unknown Hepatitis Herbalife 120days Yes Recovered
18 45/M Unknown Acute hepatitis Herbalife Unknown Yes Recovered
19 46/M 65 Hepatitis Herbalife 95days Yes Recovered
20 49/F 69 Hepatitis Herbalife, Bach Flowers 2years Yes Recovered
*Previously published in reference 1.
†
Previously published in reference 2.
{
Treatment finished 2 months before the beginning of the adverse reaction.
}
Treatment finished 1 month before the beginning of the adverse reaction.
u.d., unknown dose.
g. manso ET AL.1082
Copyright © 2011 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2011; 20: 1080–1087
DOI: 10.1002/pds

4. cases. Of the 17 remaining cases, 2 had liver biopsy
that showed hepatic necrosis. Fourteen cases indicated
hepatocellular injury, and 1 case displayed cholestatic
injury (Table 2).
Nine reports included information on alanine amino-
transferase (ALT) values at the date of diagnosis and
after the withdrawal of Herbalife products. In all of
these cases, ALT values returned to normal when Her-
balife products were withdrawn, and a positive reexpo-
sure was documented in two cases (Figure 2). Case 12
developed idiopathic hepatitis, which improved during
the course of hospitalization, when the patient had
stopped Herbalife products, and shortly after Herbalife
rechallenge, a recurrent increase of ALT values was
identified, which returned to normal after the Herbalife
products withdrawal. Case 20 also presented a positive
rechallenge. This patient developed hepatitis when tak-
ing Herbalife products together with Bach flowers, and
the temporary withdrawal of both treatments induced a
decrease in ALT values from 992 to 793U/L in 21days.
Herbalife products were eventually reintroduced, and
8 days later, ALT values increased to 1500U/L.
Cases 3, 9, 11, 14, 16, and 20 were simultaneously
receiving other treatments (Table 1). The analysis of
the causal link between the adverse reaction and the
treatments (Table 3) showed that in cases 3 and 14,
the patients improved after the withdrawal of Herbalife
products, whereas other treatments were maintained.
In cases 9, 11, and 20, Herbalife products and concom-
itant treatments were simultaneously withdrawn, and
the outcome was favorable in all instances. Moreover,
cases 14 and 16 had received amoxicillin–clavulanate
for 1 week with good tolerance and had ended the an-
tibiotic treatment at least 1 month before the diagnosis
of hepatotoxicity was made. Causality assessment by
the Karch and Lasagna algorithm yielded a definite
score for 1 case, probable in 14, and possible in 5 for
Herbalife products. Regarding the concomitant medi-
cations, 3 reached a score of possible, 3 conditional,
and 3 unlikely.
Table 2. Liver parameters and other diagnostic tests performed in the cases occurring in Spain
Case Type of liver injury* Liver parameters Other diagnostic tests or
observations
ALT
(U/L)
ALT Â ULN AST
(U/L)
ALP
(U/L)
ALP Â ULN TB
(mg/dl)
1†
Hepatic necrosis* 1340 Â 43 1284 – 9 Negative viral serology, autoimmune-like
hepatitis
2{
Hepatocellular 1890 Â 61 1140 425 Â 1.8 26 Negative viral serology
3{
Hepatocellular 505 Â 16 218 – – Negative viral serology
4{
Hepatocellular 138 Â 4.5 84 112 Â 0.5 0.6 Negative viral serology, positive smooth
muscle titers, abdominal echography:
liver fat, colescistectomy
5 Hepatocellular 954 Â 24 552 288 Â 1.2 – Alcohol consumer (250ml/day), subclinical
hypothyroidism
6 Hepatocellular 1610 Â 40 1507 244 Â 2.3 11.8
7 Hepatocellular 2513 Â 46 1831 269 Â 2 12.2 Normal abdominal echography, negative
viral serology
8 Hepatocellular 3269 Â 82 3049 158 Â 0.6 16.3 Negative viral serology
9 Hepatocellular 2244 Â 56 1810 261 Â 2.5 23.7 Alcohol consumer (unknown amount),
normal abdominal echography
10 Hepatocellular 159 Â 4.5 45 – – – Negative viral serology
11 Hepatocellular 652 Â 21 392 134 Â 1.3 –
12 Hepatocellular 1200 Â 19 394 454 Â 3.2 6.4
13 – – – – –
14 – – – – – Negative viral serology
15 – – – – – Negative viral serology, abdominal
echography: fat liver
16 Cholestatic hepatitis* 88 Â 2 84 1034 Â 4 33.3
17 Bridging hepatic necrosis* – – – – Negative viral serology, ANA>160,
autoimmune-like hepatitis
18 Hepatocellular 2654 Â 66 2049 204 Â 2 7.7 Negative viral serology
19 Hepatocellular 1922 Â 48 1246 309 Â 2.4 – Negative viral serology
20 Hepatocellular 922 Â 14 702 201 Â 1.5 6.5 Negative viral serology
*Data from liver biopsy, when it was available.
†
Previously published in reference 1.
{
Previously published in reference 2.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; TB, total bilirubin; ULN, upper limit of normality; ANA,
antinuclear antibodies.
new cases of herbalife-induced liver injury 1083
Copyright © 2011 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2011; 20: 1080–1087
DOI: 10.1002/pds

5. Table 4 shows the composition of Herbalife pro-
ducts taken by the patients, and Table 5 displays the
variety of Herbalife products taken by each of the 12
patients where this information was available. One
had just taken one Herbalife product: RoseOx (case 7),
and the other 11 had taken between two and nine
Herbalife products, including RoseOx in eight cases.
On reviewing the Herbalife products taken by the
patients who developed hepatotoxicity in previous
publications, we found that 20 out of a total of 30
Figure 2. Alanine aminotransferase (ALT) values, before and after the withdrawal of Herbalife products in patients who developed hepatotoxicity
Table 3. Causality assignment to the treatments received by the patients, according to the Karcha and Lasagna modified algorithm
Case Treatment/s Algorithm of Karch and Lasagna modified
Previous knowledge Withdrawal effect Rechallenge effect Alternative causes Probability
1 Herbalife Occasional Irreversible No No Possible
2 Herbalife Occasional Improvement No No Probable
3 Herbalife Occasional Improvement No No Probable
Tibolone, 2.5mg/day Known Drug not withdrawn, AR
improved
No Yes, more likely Unlikely
Alprazolam, u.d. Known Drug not withdrawn, AR
improved
No Yes, more likely Unlikely
4 Herbalife Occasional Improvement No No Probable
5 Herbalife Occasional Improvement No Yes, less/equally likely Possible
6 Herbalife Occasional Improvement No No Probable
7 Herbalife Occasional Improvement No No Probable
8 Herbalife Occasional Improvement No No Probable
9 Herbalife Occasional Improvement No Yes, less/equally likely Possible
Venlafaxine, u.d. Known Improvement No Yes, less/equally likely Possible
Clonazepam, u.d. Known Improvement No Yes, less/equally likely Possible
10 Herbalife Occasional Improvement No No Probable
11 Herbalife Occasional Improvement No Yes, less/equally likely Possible
Hidrosoluble and liposoluble
vitamins
Unknown Improvement No Yes, less/equally likely Conditional
Ethylephrine, 250mg Unknown Improvement No Yes, less/equally likely Conditional
Acetaminophen, 1g/day Known Improvement No Yes, less/equally likely Possible
12 Herbalife Occasional Improvement Yes, positive No Definite
13 Herbalife Occasional Improvement No No Probable
14* Herbalife Occasional Improvement No No Probable
Enalapril, 20mg Known Drug not withdrawn, AR
improved
No Yes, more likely Unlikely
15 Herbalife Occasional Improvement No No Probable
16* Herbalife Occasional Improvement No No Probable
17 Herbalife Occasional Improvement No No Probable
18 Herbalife Occasional Improvement No Without information Possible
19 Herbalife Occasional Improvement No No Probable
20 Herbalife Occasional Improvement Yes, positive Yes, less/equally likely Probable
Bach flowers Unknown Improvement No Yes, less/equally likely Conditional
*These patients also received short courses of other treatments (see Table 1).
In all cases, the temporary sequence was compatible. u.d., unknown dose.
g. manso ET AL.1084
Copyright © 2011 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2011; 20: 1080–1087
DOI: 10.1002/pds

6. had been taking RoseOx (Table 6). On the other hand,
the Formula 1 product was the most frequently
reported to have been taken in our series (Table 5).
DISCUSSION
Since the first report of Herbalife-associated hepato-
toxicity in several cases from Israel and Switzerland,
a widespread concern has extended regarding the
safety of these very popular dietary supplements. The
present series reported in Spain until September 2010
further supports the relationship between the consump-
tion of Herbalife products and hepatotoxicity. It is
clear from these data that such risk persists even after
the launching of information about the hepatotoxicity
risk to health professionals and consumers, as the
identification of new cases has steadily continued.
We understand that all cases reported were related to
Herbalife products after an exhaustive anamnesis of
prescribed and over-the-counter (OTC) drugs and
alternative therapies to either rule out or define the in-
gestion of well-known hepatotoxins such as acetamin-
ophen or amoxicillin–clavulanic acid. A relationship
between hepatotoxicity and consumption of Herbalife
products could confidently be established in this se-
ries. In all cases, there was a clear temporal relation
between liver injury and consumption of these pro-
ducts, and in the majority of them, clinical symptoms
and liver parameters improved after Herbalife products
withdrawal. Only 5 of the 20 cases analyzed referred
simultaneous treatment with drugs, and 1 case also
took an alternative therapy (Bach flowers). The
remaining 14 cases did not refer any conventional,
OTC, or alternative treatment different from Herbalife
products. Even in those patients that were simulta-
neously taking other treatments, the end of treatments
Table 4. Components included in some of the Herbalife products.
Product Components
Formule 1: protein
drink mix
Coffee, Dextrose, Vitamin D, Potassium Iodure,
Calcium pantotenate, Pantotenic acid, Pantotenic
acid, Nicotinamide, Cinc oxide,
Fructoligosacarides, Honey, Fructose, Folic acid,
Soya protein, Soya lecithin, Pectine, Manganese
carbonate, Magnesium oxide, Soya seed oil,
Vitamin E, Copper gluconate, Iron fumarate,
Parsley core, Vitamin B6, Guar gum, Vitamin B12,
Biotine, Oats, Carica papaya, Vitamin B1, Vitamin
A, Sodium selenite, Vitamin C, Carrageenin
Rose Ox Curcuma extract, Rosemary, Clove, Celulose,
Maltodextrine, Sage
Formule 2 Folic acid, Vitamin E, Vitamin B6, Biotine,
Vitamin B12, Pantotenic acid, Vitamin A, Vtamin
B1, Vitamin B2, Vitamin C
Formule 3 Soya protein, Milk serum
Aloe-vera liquid Aloe vera, Camomile tea, Medicago Sativa dried
extract, Lemon
Bran & herbs Fennel, Camomile tea, Copper, Orange blossom,
Iron, Iodine, Phosphorus, Apple vinegar, Oats,
Carica papaya, Mint, Calcium, Parsley core
Cell-U-loss Apple vinegar, Potassium, Vitamin B6, Parsley
core, Vitamin C
Fiber tablets Fiber of citrics, Ox bile, Celulose
Guaraná tablets Guaraná extract
Herbalifeline Omega 3 acids
Thermojetics Lemon, Green tea extract
Thermo complete Green tea extract, Calcium carbonate, Corn starch,
Cacao extract, Maté extract, Cafein powder,
Cinnamon powder, Parsley, Celery, Medicago
Sativa, Liquorice, Fennel, Vitamin C
Table 5. Herbalife products consumed by the patients
Herbalife product consumed Patients
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Total
Bran and herbs tablets √ √ √ √ √ 5
Cell-U-Loss √ √ √ √ √ 5
Instant drink with plant
extracts
√ 1
Guaraná tablets √ √ √ √ √ 5
Herbal aloe √ √ √ 3
Activated fiber √ 1
Formula 1 (protein drink
mix)
√ √ √ √ √ √ √ √ √ √ 10
Formula 2 √ √ √ √ 4
Formula 3 √ √ √ √ √ √ 6
Herbalifeline √ √ √ √ √ 5
RoseOx (herbal extract) √ √ √ √ √ √ √ √ √ 9
Thermo Complete, tablets √ 1
Thermojetics herbal mix (tea) √ √ √ √ √ 5
Herbalife, n.s. √ √ √ √ √ √ √ √ 8
n.s., not-specified.
new cases of herbalife-induced liver injury 1085
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DOI: 10.1002/pds

7. with Herbalife products was enough to reverse the
liver damage.
When analyzing the causative agent responsible for
the hepatotoxicity related to Herbalife products, one
of the initial hypotheses considered was that some
batches could contain a certain specific hepatotoxic
agent.2,3,8
However, the facts that, since 2005, we
have information of cases occurring in different parts
of the world and that, at least in Spain, there have been
cases reported on a continuing basis suggest an actual
presence of one or more hepatotoxic components of
the Herbalife products.
In our series, all cases, but one, in which informa-
tion about liver tests was available showed hepatocel-
lular liver injury. Furthermore, nine cases (9/17, 53%)
fulfilled Hy’s law,13
which predicts a mortality not
lower than 10%. In addition, 80% of the cases were
women. The association of high bilirubin levels, hepa-
tocellular type of damage, and female sex has been
shown to be predictive of a worst outcome.14
The only patient who developed cholestatic liver
damage was also taking amoxicillin–clavulanate. This
raises the possibility that in this particular instance,
amoxicillin–clavulanate could be responsible for the
damage15
despite the chronology pointing toward
Herbalife. Nevertheless, cases of Herbalife-induced
cholestatic-mixed damage have been previously
reported.2,3
The analysis of the components of Herbalife prod-
ucts revealed the presence of two herbals previ-
ously associated with hepatotoxicity: green tea16–19
and aloe vera.20–22
These herbals are included in the
products Thermojetics, Thermo Complete, and Aloe-
Vera liquid from Herbalife. In addition, one case of
hepatitis associated with the consumption of soy,
which is a component of Formula 1 and Formula 3,
has been published.23
However, none of these herbal
medicines is included in the composition of RoseOx,
a single product that one of our patients took. Inter-
estingly, Stickel et al.8
demonstrated the hepatotoxic
effect of B. subtilis isolated from the products Formula
1, vitamin C tablets, and Herbalife specifically person-
alized, but not from RoseOx tablets. Therefore, it
is possible that the Herbalife products contain
various hepatotoxic agents, which could work alone
or by interacting with other components. Interactions
between chemicals should always be considered as
a possibility when several active ingredients are
administrated together. For example, Formula 1 from
Herbalife contains various heavy metals and carra-
geenan. Recently, Khotimchenko et al.24
have reported
carrageenans to bind heavy metals.
It is worth noting that there seems to be a general
consensus between consumers about the efficacy of
some Herbalife products to lose weight, which hap-
pens to be particularly surprising considering the
declared components of Herbalife products, such as
vitamins, minerals, and “innocuous” herbs. Moreover,
in medical literature, considerable documentation
exists related to contamination with adulterants (i.e.,
heavy metals, microorganisms, and undeclared
ingredients) in preparations formulated with herbal
medicines and marketed through several channels.25–30
To our knowledge, quality controls were not per-
formed on any of the products used by the patients in-
cluded in our series. In Spain, Herbalife products are
registered as dietary supplements in the AESAN and
are available from several Internet pages (www.
herbalife.com and others) and from local distributors,
often also consumers of Herbalife products, who sell
these products directly to their family, friends,
acquaintances, and other members of their communi-
ties. Liver injury associated with Herbalife products
has been recently reviewed by Stickel et al.31
Accord-
ing to this publication, Israel and Switzerland have not
noticed further incidents after publication of their
corresponding series, although investigators from Ice-
land and Spain continue to see new cases. In our opin-
ion, differences in the pharmacovigilance procedures or
in the batches of Herbalife products distributed in differ-
ent countries—with not exactly the same composition or
concentration of the components—could explain this
discrepancy.
The lack of knowledge of the mechanism of action in-
volved in the production of adverse reactions associated
with drugs has never been an obstacle in implementing
measures to prevent damage. Usually, these measures
are taken on the basis of clinical observations and con-
trasted epidemiological data. However, to evaluate
Table 6. Herbalife products taken by the patients in the published cases
Reference Total of
reported
cases
Number of patients who took it
RoseOx Other
Herbalife
products
Unknown
Schoepfer et al.,
2007 [2]
10 4 5 1
Elinav et al.,
2007 [3]
12 10 2 0
Chao et al., 2008
[7]
1 0 1 0
Stickel et al.,
2009 [8]
2 1 1 0
Jóhannsson
et al., 2010 [10]
5 5 0 0
Total 30 20 9 1
Cases from this
paper
20 9 3 8
g. manso ET AL.1086
Copyright © 2011 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2011; 20: 1080–1087
DOI: 10.1002/pds

8. efficacy and safety of herbal medicines and dietary sup-
plements is extremely difficult because they are not un-
der similar control procedures as conventional drugs
are. To know the full composition, quantitative and
qualitative, to pass strict quality controls, and to demon-
strate its effectiveness in controlled conditions are basic
and necessary requirements to be met in order to assess
the risk–benefit ratio in clinical practice.32
In conclusion, our results support the relationship
between the consumption of Herbalife products and
hepatotoxicity, underscore the concern regarding
liver-related safety of these dietary supplements—
despite the component(s) responsible for the liver
damage being unknown—and emphasize the need
to establish further regulatory measures.
ACKNOWLEDGEMENTS
We wish to express our gratitude to (i) the Spanish
Pharmacovigilance System for allowing us to analyze
and publish the FEDRA data and (ii) those health
professionals whose adverse event reports were sub-
mitted to the Spanish Pharmacovigilance System.
On behalf of the Spanish Group for the Study of Drug-
Induced Liver Disease, we would like to thank the
clinical group in each case recruitment center: Hospital
Universitario Virgen de la Victoria, Málaga (coordinat-
ing center): RJ Andrade, MI Lucena, C Stephens, Y
Borraz, M García-Cortés, E Ulzurrun, M Robles-Díaz,
and I Moreno; Hospital Costa del Sol, Málaga: JM
Navarro; Xeral-Calde Hospital, Lugo: S Avila-Nasi;
Carlos Haya Hospital, Málaga: M Jiménez and R
González-Grande; Hospital Puerto Real, Cádiz: JM
Pérez-Moreno; and Hospital Infanta Cristina, Badajoz:
JL Montero.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
KEY POINTS
• Previous cases occurred in several countries have
linked HerbalifeW
products and hepatotoxicity.
• Since 2003–2010, at least 20 cases of liver injury
related to these dietary supplements occurred in
Spain. Two of them showed positive rechallenge.
• Our results underscore the concern about these
adverse reactions and emphasize the need to es-
tablish further regulatory measures.
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new cases of herbalife-induced liver injury 1087
Copyright © 2011 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2011; 20: 1080–1087
DOI: 10.1002/pds