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pharmacoepidemiology and drug safety 2011; 20: 10801087

Published online 12 July 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.2180

ORIGINAL REPORT

Continuous reporting of new cases in Spain supports the relationship between HerbalifeW products and liver injury
Gloria Manso1*, Laureano Lpez-Rivas2, M. Esther Salgueiro1, Jose M. Duque2, Francisco J. Jimeno1, Ral J. Andrade3,4 and M. Isabel Lucena3,4
Centro de Farmacovigilancia de Asturias, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain Servicio de Digestivo, Hospital San Agustn, Avils, Spain 3 Servicios de Ap Digestivo y Farmacologa Clnica, Facultad de Medicina, Hospital Universitario Virgen de la Victoria, Campus Universitario s/n, Mlaga, Spain 4 Centro de Investigacin Biomdica en Red de Enfermedades Hepticas y Digestivas (CIBERehd), Barcelona, Spain
2 1

ABSTRACT
Purpose Previous publications have linked HerbalifeW products to hepatotoxicity. The identication of earlier cases in which the culprit agent could not be established raised the hypothesis of a possible contamination of some specic 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 rst 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 hospitalization. Hepatocellular damage predominated, and nine (53%) of the hepatocellular cases with bilirubin values were jaundiced, fullling the Hys law criteria, which increases the risk for serious outcomes. Two patients experienced a positive rechallenge. One patient developed cirrhosis, whereas all the others recovered. Causality assessment by the Karch and Lasagna modied algorithm showed a category of denite 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 wordshepatotoxicity; HerbalifeW; herbal medicines; adverse reactions; dietary supplements Received 16 March 2011; Revised 5 May 2011; Accepted 10 May 2011

INTRODUCTION The rst 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 Hepatology in 2007. In the same issue of this journal, another series of cases, which had occurred in Israel, was reported by Elinav et al.3 in addition to an editorial on slimming products signed by Stickel.4 In 2007, our group reported the rst three cases of

*Correspondence to: G. Manso, Centro de Farmacovigilancia de Asturias, Facultad de Medicina, Universidad de Oviedo, Julin Clavera 6, 33006 Oviedo, Spain. E-mail: gmanso@uniovi.es

hepatotoxicity suspected of being induced by the consumption of Herbalife brand products, which occurred in Spain.5 The patients were all from the same Spanish hospital and presented a similar clinical picture 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 occurring in Argentina, and in 2009, Stickel et al.8 reported two new cases in Switzerland and described the isolation 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 issue of the abovementioned journal, Seeff 9 reminded us of the need for regulatory measures for these

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products. Five new cases occurring in Iceland were also reported.10 In Spain, after the rst 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 facilitated the detection and reporting of new cases. Since then, the Spanish Pharmacovigilance Centres have continued to receive reports of hepatotoxicity associated with Herbalife products occurring in different Spanish regions. These have been collected through the Spontaneous Reporting Program of Suspected Adverse Reactions and recorded in the Farmacovigilancia Espaola Datos de Reacciones Adversas (FEDRA), the database of the Spanish System of Pharmacovigilance for Medicinal Products for Human Use. The present series, although mainly retrieved by the spontaneous reporting systemone must take into account the inherent limitations that are typical of a postmarketing database and the fact that it is not uncommon for data submitted to be incompletefurther supports the observations from the rst series published regarding 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 suspected 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 classication of the MedDRA 13.0 dictionary, and 2 from others: 1 case of galactorrhea and another of nausea, vomiting, and anorexia. From the cases of liver disorders obtained, we excluded one report of fatal outcome due to incomplete and confuse information. This case is briey described in the Results section. In the remaining cases, we analyzed the following: (i) dates of reporting and beginning and end of the adverse reaction; (ii) patient characteristics: 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 diagnostic 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
Copyright 2011 John Wiley & Sons, Ltd.

use the modied Karch and Lasagna algorithm, which ascribes levels of probability of association between drugs and adverse reactions into the following categories: denite>probable>possible>conditional unlikely. In addition, we studied (vii) the composition of the Herbalife products taken by the patients, according 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 directly 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 Mlaga (Spain) and later sent to the Pharmacovigilance Centre of Andalusia. One of the reports referred to the case of an 18-yearold 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 Whipples disease with neurologic involvement, although this diagnosis was later not conrmed. 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 hepatotoxicity 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, 3663 years), female sex predominated (80%), and seven patients weighed less than 70kg (mean 682.9 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
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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 1* 2 3 4 5 6 7 8 9 10 11 Age (year)/ Gender 47/F 49/F 51/F 57/F 45/F 50/F 53/F 57/F 49/F 40/F 51/F Weight (kg) 60 65 Unknown Unknown Unknown 52 59 75 80 84 58 Adverse reaction/s Hepatitis, liver cirrhosis Cholestatic hepatitis Liver enzymes increased Liver enzymes increased Liver function abnormal Hepatitis Liver damage Cholestatic hepatitis Liver damage Liver enzymes increased Cholestasis Treatment/s Herbalife Herbalife Herbalife; tibolone, 2.5mg/day; alprazolam, u.d. Herbalife Herbalife Herbalife Herbalife Herbalife Herbalife; venlafaxine, u.d.; clonazepam, u.d. Herbalife Herbalife; hidrosoluble and liposoluble vitamins; ethylephrine, 250mg; acetaminophen, 1g/day Herbalife Herbalife Herbalife; enalapril, 20mg/day; amoxicillin+clavulanic acid, u. d., for 1week;{ acetaminophen, u.d., for 1week{ Herbalife Herbalife; amoxicillin+clavulanic acid, 1.5g+375mg/day for 1 week;} nistatine, u.d., for 1 week} Herbalife Herbalife Herbalife Herbalife, Bach Flowers Duration treatment 3years Unknown 2months 3years 1year 80days 64days 45days 60days 1year 68days Hospitalization Yes Yes No No No Yes Yes Yes Yes No No Outcome Cirrhosis Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Unknown Recovered

12 13 14

39/F 36/F 42/F

Unknown 80 Unknown

Hepatitis Liver enzymes increased, hypertension Liver enzymes increased

60days 16days 300days

Yes No No

Recovered Recovered Recovered

15 16

63/M 57/M

Unknown 72

Liver damage Cholestatic hepatitis

510days 40days

No Yes

Recovered Unknown

17 18 19 20
{

44/F 45/M 46/M 49/F

Unknown Unknown 65 69

Hepatitis Acute hepatitis Hepatitis Hepatitis

120days Unknown 95days 2years

Yes Yes Yes Yes

Recovered Recovered Recovered Recovered

*Previously published in reference 1. Previously published in reference 2. Treatment nished 2 months before the beginning of the adverse reaction. } Treatment nished 1 month before the beginning of the adverse reaction. u.d., unknown dose.

outcome was favorable in 17 patients, unknown in 2, and in the remaining case, which was the rst to be reported in Spain, the patient developed cirrhosis
Copyright 2011 John Wiley & Sons, Ltd.

conrmed by liver biopsy. Fourteen cases reported negative viral serology. Neither data from liver biopsy nor values of liver parameters were available in 3
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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 aminotransferase (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 Herbalife products were withdrawn, and a positive reexposure 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 identied, which returned to normal after the Herbalife products withdrawal. Case 20 also presented a positive rechallenge. This patient developed hepatitis when taking Herbalife products together with Bach owers, 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 concomitant treatments were simultaneously withdrawn, and the outcome was favorable in all instances. Moreover, cases 14 and 16 had received amoxicillinclavulanate for 1 week with good tolerance and had ended the antibiotic treatment at least 1 month before the diagnosis of hepatotoxicity was made. Causality assessment by the Karch and Lasagna algorithm yielded a denite score for 1 case, probable in 14, and possible in 5 for Herbalife products. Regarding the concomitant medications, 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* ALT (U/L) 1 2{ 3{ 4{ 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Liver parameters ALT ULN 43 61 16 4.5 24 40 46 82 56 4.5 21 19 AST (U/L) 1284 1140 218 84 552 1507 1831 3049 1810 45 392 394 84 2049 1246 702 ALP (U/L) 425 112 288 244 269 158 261 134 454 1034 204 309 201 1.8 0.5 1.2 2.3 2 0.6 2.5 1.3 3.2 ALP ULN TB (mg/dl) 9 26 0.6 11.8 12.2 16.3 23.7 6.4 33.3 7.7 6.5

Other diagnostic tests or observations

Hepatic necrosis* Hepatocellular Hepatocellular Hepatocellular Hepatocellular Hepatocellular Hepatocellular Hepatocellular Hepatocellular Hepatocellular Hepatocellular Hepatocellular Cholestatic hepatitis* Bridging hepatic necrosis* Hepatocellular Hepatocellular Hepatocellular

1340 1890 505 138 954 1610 2513 3269 2244 159 652 1200 88 2654 1922 922

Negative viral serology, autoimmune-like hepatitis Negative viral serology Negative viral serology Negative viral serology, positive smooth muscle titers, abdominal echography: liver fat, colescistectomy Alcohol consumer (250ml/day), subclinical hypothyroidism Normal abdominal echography, negative viral serology Negative viral serology Alcohol consumer (unknown amount), normal abdominal echography Negative viral serology

2 66 48 14

4 2 2.4 1.5

Negative viral serology Negative viral serology, abdominal echography: fat liver Negative viral serology, ANA>160, autoimmune-like hepatitis Negative viral serology Negative viral serology 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.

Copyright 2011 John Wiley & Sons, Ltd.

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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 modied algorithm Case Treatment/s Previous knowledge 1 2 3 Herbalife Herbalife Herbalife Tibolone, 2.5mg/day Alprazolam, u.d. 4 5 6 7 8 9 10 11 Herbalife Herbalife Herbalife Herbalife Herbalife Herbalife Venlafaxine, u.d. Clonazepam, u.d. Herbalife Herbalife Hidrosoluble and liposoluble vitamins Ethylephrine, 250mg Acetaminophen, 1g/day Herbalife Herbalife Herbalife Enalapril, 20mg Herbalife Herbalife Herbalife Herbalife Herbalife Herbalife Bach owers Occasional Occasional Occasional Known Known Occasional Occasional Occasional Occasional Occasional Occasional Known Known Occasional Occasional Unknown Unknown Known Occasional Occasional Occasional Known Occasional Occasional Occasional Occasional Occasional Occasional Unknown Algorithm of Karch and Lasagna modified Withdrawal effect Irreversible Improvement Improvement Drug not withdrawn, AR improved Drug not withdrawn, AR improved Improvement Improvement Improvement Improvement Improvement Improvement Improvement Improvement Improvement Improvement Improvement Improvement Improvement Improvement Improvement Improvement Drug not withdrawn, AR improved Improvement Improvement Improvement Improvement Improvement Improvement Improvement Rechallenge effect No No No No No No No No No No No No No No No No No No Yes, positive No No No No No No No No Yes, positive No Alternative causes No No No Yes, more likely Yes, more likely No Yes, No No No Yes, Yes, Yes, No Yes, Yes, less/equally likely Probability Possible Probable Probable Unlikely Unlikely Probable Possible Probable Probable Probable Possible Possible Possible Probable Possible Conditional Conditional Possible Definite Probable Probable Unlikely Probable Probable Probable Possible Probable Probable Conditional

less/equally likely less/equally likely less/equally likely less/equally likely less/equally likely

12 13 14* 15 16* 17 18 19 20

Yes, less/equally likely Yes, less/equally likely No No No Yes, more likely No No No Without information No Yes, less/equally likely Yes, less/equally likely

*These patients also received short courses of other treatments (see Table 1). In all cases, the temporary sequence was compatible. u.d., unknown dose.

Table 4 shows the composition of Herbalife products 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),
Copyright 2011 John Wiley & Sons, Ltd.

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
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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 rst report of Herbalife-associated hepatotoxicity 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 consumption 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 identication 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 dene the ingestion of well-known hepatotoxins such as acetaminophen or amoxicillinclavulanic acid. A relationship between hepatotoxicity and consumption of Herbalife products could condently be established in this series. In all cases, there was a clear temporal relation between liver injury and consumption of these products, 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 owers). The remaining 14 cases did not refer any conventional, OTC, or alternative treatment different from Herbalife products. Even in those patients that were simultaneously taking other treatments, the end of treatments

Table 4. Components included in some of the Herbalife products. Product Formule 1: protein drink mix Components 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 Curcuma extract, Rosemary, Clove, Celulose, Maltodextrine, Sage Folic acid, Vitamin E, Vitamin B6, Biotine, Vitamin B12, Pantotenic acid, Vitamin A, Vtamin B1, Vitamin B2, Vitamin C Soya protein, Milk serum Aloe vera, Camomile tea, Medicago Sativa dried extract, Lemon Fennel, Camomile tea, Copper, Orange blossom, Iron, Iodine, Phosphorus, Apple vinegar, Oats, Carica papaya, Mint, Calcium, Parsley core Apple vinegar, Potassium, Vitamin B6, Parsley core, Vitamin C Fiber of citrics, Ox bile, Celulose Guaran extract Omega 3 acids Lemon, Green tea extract Green tea extract, Calcium carbonate, Corn starch, Cacao extract, Mat extract, Cafein powder, Cinnamon powder, Parsley, Celery, Medicago Sativa, Liquorice, Fennel, Vitamin C

Rose Ox Formule 2 Formule 3 Aloe-vera liquid Bran & herbs Cell-U-loss Fiber tablets Guaran tablets Herbalifeline Thermojetics Thermo complete

Table 5. Herbalife products consumed by the patients Herbalife product consumed 1 Bran and herbs tablets Cell-U-Loss Instant drink with plant extracts Guaran tablets Herbal aloe Activated ber Formula 1 (protein drink mix) Formula 2 Formula 3 Herbalifeline RoseOx (herbal extract) Thermo Complete, tablets Thermojetics herbal mix (tea) Herbalife, n.s. n.s., not-specied.

Patients 2

10

11

12

13

14

15

16

17

18

19

20

Total 5 5 1 5 3 1 10 4 6 5 9 1 5 8

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Reference Total of reported cases

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Table 6. Herbalife products taken by the patients in the published cases Number of patients who took it RoseOx Other Herbalife products 5 2 1 1 0 9 3 Unknown

Schoepfer et al., 2007 [2] Elinav et al., 2007 [3] Chao et al., 2008 [7] Stickel et al., 2009 [8] Jhannsson et al., 2010 [10] Total Cases from this paper

10 12 1 2 5 30 20

4 10 0 1 5 20 9

1 0 0 0 0 1 8

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 specic 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 information about liver tests was available showed hepatocellular liver injury. Furthermore, nine cases (9/17, 53%) fullled Hys law,13 which predicts a mortality not lower than 10%. In addition, 80% of the cases were women. The association of high bilirubin levels, hepatocellular 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 amoxicillinclavulanate. This raises the possibility that in this particular instance, amoxicillinclavulanate 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 products revealed the presence of two herbals previously associated with hepatotoxicity: green tea1619 and aloe vera.2022 These herbals are included in the products Thermojetics, Thermo Complete, and AloeVera 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,
Copyright 2011 John Wiley & Sons, Ltd.

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. Interestingly, Stickel et al.8 demonstrated the hepatotoxic effect of B. subtilis isolated from the products Formula 1, vitamin C tablets, and Herbalife specically personalized, 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 carrageenan. 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 efcacy of some Herbalife products to lose weight, which happens 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.2530 To our knowledge, quality controls were not performed on any of the products used by the patients included 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 communities. Liver injury associated with Herbalife products has been recently reviewed by Stickel et al.31 According to this publication, Israel and Switzerland have not noticed further incidents after publication of their corresponding series, although investigators from Iceland and Spain continue to see new cases. In our opinion, differences in the pharmacovigilance procedures or in the batches of Herbalife products distributed in different countrieswith not exactly the same composition or concentration of the componentscould explain this discrepancy. The lack of knowledge of the mechanism of action involved 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 contrasted epidemiological data. However, to evaluate
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efcacy and safety of herbal medicines and dietary supplements is extremely difcult because they are not under similar control procedures as conventional drugs are. To know the full composition, quantitative and qualitative, to pass strict quality controls, and to demonstrate its effectiveness in controlled conditions are basic and necessary requirements to be met in order to assess the riskbenet 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 unknownand 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 submitted to the Spanish Pharmacovigilance System. On behalf of the Spanish Group for the Study of DrugInduced Liver Disease, we would like to thank the clinical group in each case recruitment center: Hospital Universitario Virgen de la Victoria, Mlaga (coordinating center): RJ Andrade, MI Lucena, C Stephens, Y Borraz, M Garca-Corts, E Ulzurrun, M Robles-Daz, and I Moreno; Hospital Costa del Sol, Mlaga: JM Navarro; Xeral-Calde Hospital, Lugo: S Avila-Nasi; Carlos Haya Hospital, Mlaga: M Jimnez and R Gonzlez-Grande; Hospital Puerto Real, Cdiz: JM Prez-Moreno; and Hospital Infanta Cristina, Badajoz: JL Montero. CONFLICT OF INTEREST The authors declare no conict of interest. KEY POINTS Previous cases occurred in several countries have linked HerbalifeW products and hepatotoxicity. Since 20032010, 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 establish further regulatory measures.

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Pharmacoepidemiology and Drug Safety, 2011; 20: 10801087 DOI: 10.1002/pds

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