further light on the potential mechanism of hepatotoxic-ity in these sisters. Although it cannot be established forcertain if autoimmunity or a pharmaco-genetic prepon-derance is the driving force behind these events, the reac-tive hepatitis in the two sisters suggests a commonmechanism. Dr. Manso et al. raise the possibility thatgreen tea or aloe vera ingredients, previously reportedto induce hepatotoxicity may also be the cause in theSpanish group of patients. However, these ingredientswere not taken uniformly by all the reported patientsfrom Israel and Switzerland, and therefore a detailed listof all the ingredients including the chemical compositionis required as stated in the two original reports. In Spainas well as in Israel and Switzerland, it was not possibleto establish the true incidence of hepatotoxicity amongHerbalifeTM users since the number of consumers andtheir demographic characteristics are only partiallyknown. A rough calculation suggested an incidence of25–30 cases per 100,000 HerbalifeTM products among Is-raeli consumers. We agree with the colleagues fromSpain that the true incidence may be higher since liverinjury may remain occult and asymptomatic as is wellknown by practising hepatologists. Thus, it is importantto draw the attention of the Journals readers to reportsof similar cases.

References

[1] Manso G, Lopez-Rivas L, Duque JM, Salgueiro E. Spanish reportsof hepatotoxicity associated with herbalife� products. J Hepatol2008;48:290–291.

[2] Elinav E, Pinsker G, Safadi R, Pappo O, Bromberg M, Anis E,et al. Association between consumption of Herbalife� nutri-tional supplements and acute hepatotoxicity. J Hepatol2007;47:514–520.

[3] Schoepfer AM, Engel A, Fattinger K, Marbet UA, Criblez D,Reichen J, et al. Herbal does not mean innocuous: ten cases ofsevere hepatotoxicity associated with dietary supplements fromHerbalife� products. J Hepatol 2007;47:521–526.

[4] Stickel F. Slimming at all costs: Herbalife�-induced liver injury. JHepatol 2007;47:444–446.

Daniel ShouvalEran Elinav

Hadassah-Hebrew University Medical Center,

P.O. Box 12000, Jerusalem 91120, Israel

Tel.: +972 2 6777 337; fax: +972 2 6420 338(D. Shouval)

E-mail address: shouval@cc.huji.ac.il (D. Shouval)

doi:10.1016/j.jhep.2008.05.006

Herbalife nutritional products and liver injury revisited

To the Editor:

Recently, two reports of 12 and 10 cases of idio-pathic liver disease from Israel [1] and Switzerland[2], respectively, appeared in the same issue of thisjournal alleging in the articles and in an accompanyingeditorial that these cases were caused by the consump-tion of Herbalife products. In fact, the two papers [1,2]concluded unequivocally that causation was certain insome cases. Despite the authors’ strong assertion thata cause and effect relationship between Herbalife prod-uct use and liver injury exists, an objective review ofthe facts raises serious doubt whether such a conclu-sion can be drawn. In Israel [1], the observed liverabnormalities resolved in eleven of the twelve cases re-ported. The remaining patient succumbed to complica-tions of liver transplantation and despite the fact thatthis patient also had evidence of hepatitis B infection,sole attribution of the liver injury to Herbalife productswas made. Another patient had stage I primary biliarycirrhosis and other patients consumed a variety of sub-stances or had other co-morbid diseases that couldhave caused or contributed to the liver disease ob-served. In Switzerland [2], a total of 10 evaluable case

reports with similar characteristics were documentedover seven years.

Taken at face value, these few cases represent an ex-tremely low incidence of suspected liver injury amongthe millions of Herbalife consumers worldwide (5.5 mil-lion consumers in 2004 alone). In 2004 more than40,000,000 servings from 29 different products were dis-tributed to approximately 37,000 Israeli consumers. Asimilar number of servings from 26 different productswere distributed to approximately 80,000 Swiss consum-ers. In the 5 combined cases where causation wasassessed as ‘‘certain” due to a reported combination ofpositive dechallenge and rechallenge, the case detailsremain unclear. As an example, 4 of these patientsdescribed between 3 and 17 different and specific Herba-life products previously consumed prior to dechallenge,and in the remaining patient no specific Herbalife prod-uct in either the reported dechallenge or rechallengecould be identified. Equally concerning is the fact thatthere is no mention of which of the initially reportedproducts were subsequently consumed by any of the pa-tients that allegedly led to the recurrence of symptoms.Even if all 4 patients consumed the exact same 3–17

Letters to the Editor / Journal of Hepatology 49 (2008) 288–294 291

products, respectively, there was no purported toxicingredient identified by the authors in the article thatwas common among all 4 of these patients. It is alsointeresting that in one of these 4 patients, rechallengeof unspecified Herbalife product was reported to resultin recurrence of symptoms, yet the patient purportedlycontinues to use unspecified Herbalife product(s) and re-mains asymptomatic.

The generally accepted criteria for causality of liverdiseases cited in the editorial, including dechallenge/rechallenge, were designed to consider drug-inducedhepatotoxicity when a specific defined ingredient hasbeen identified, and were not designed to considerthe effects of multiple different foods, supplements,and distinct nutritional products in combination ortotality. The comment made in the editorial [3] that‘‘there can be little doubt that these products werethe cause” is simply not supported by the facts. Inacute hepatotoxicity, liver injury typically occurs witha substantial and predictable frequency, its severity isdose-dependent, and a responsible agent can be iden-tified. In contrast, liver injury from an immune-medi-ated hypersensitivity reaction is sporadic, and clinicalsymptoms and abnormal liver biochemical tests occurin only a very small number of individuals who met-abolically convert some constituent of the productconsumed into a substance that stimulates an immunereaction [4]. While this is the generally accepted sce-nario among hepatologists, the exact cause, predispos-ing individualistic factors, and precise pathophysiologyof this rare form of liver disease remain poorlyunderstood.

Furthermore, the incidence of these cases appears tobe very low compared to the risks associated with someover-the-counter and prescription drugs on the market.A population-based survey in Atlanta, Georgia, USApublished in 2007 found that the incidence of acute li-ver failure in eight counties was 5.5 per million individ-uals, and the use or abuse of acetaminophen wasassociated with 41 percent of the cases, while a signif-icant percentage of adults had liver failure of unknownetiology [5]. As indicated in the Swiss article, the rareincidence of these events having been ten cases col-lected over seven years, makes the overall incidencesome 1.8 per million patients/year [2]. This low levelof risk of liver disease is indistinguishable from thebackground incidence of idiopathic liver disease, whereno cause can be found. In a study of 71,000 NorthAmericans in 1992, the background rate of idiopathicor cryptogenic liver disease was 24 cases per 100,000individuals compared to 14 per 100,000 attributed tocases of hepatitis B, 25 per 100,000 due to alcoholism,and 7 per 100,000 due to other viral illnesses [6]. Whilethe spectrum of liver diseases has certainly changed

since 1992 when this survey was done, the number ofidiopathic liver diseases remains a significant percent-age of all the cases.

Herbalife nutritional products are registered andnotified as foods, meal replacements, and dietary sup-plements and not as herbal medicines. There are ingre-dients such as guarana, green tea, and caffeine, whichare being used extensively in numerous food productsand are not unique to Herbalife. Herbalife conductstesting, through independent laboratories, on productbatches for heavy metals, pesticides, ochratoxin A,aflatoxins, comfrey retrosine (pyrrolizidine alkaloids;PAs), and kava kavalactones. Completed tests haveconsistently shown no detection of pesticides, kava orPAs, and traces of ochratoxins, aflatoxins, and heavymetals are below minimum threshold levels. Also, thecompany has a well-developed adverse event reportingsystem which monitors and evaluates adverse eventsglobally and has sought the involvement of outside,independent experts to evaluate its adverse eventexperience.

The core products of Herbalife provide healthy solu-tions to the worldwide epidemic of obesity. The prod-ucts are designed to deliver balanced nutrition andassist in the promotion of fitness and a healthy, activelifestyle. These products are primarily based in vegeta-ble proteins, fish oils, vitamins, and minerals for whichsafe use is very well established. Some of the com-pany’s products also contain botanical ingredients thatare well characterized and tested. These botanicals areincluded in Herbalife product at levels that are in asafe nutritional range where they have antioxidantproperties and support normal function, and are la-beled in accordance with all the applicable laws. Thecompany does not market or encourage the use ofany of its products as medicines for the treatment ofspecific diseases.

There were no undefined or unlabeled herbs in theseproducts as suggested in the articles and contrary towhat has been portrayed, the company has cooperatedfully with the ministries of health in their investigationof these cases. In fact, government officials and clini-cians investigating these cases in both countries were gi-ven access to full product formulas and ingredients.These ingredient disclosures were documented in numer-ous communiques and included full product dossiersand results of independent testing regarding productpurity and integrity.

It is also unfortunate in our view that Herbalife’sbrand name was generically linked to liver injuryrather than specific products or ingredients wheresuch an association could not be established. This ap-proach is unprecedented. Although Herbalife remainscommitted in the spirit of product stewardship to

292 Letters to the Editor / Journal of Hepatology 49 (2008) 288–294

cooperate openly and fully in the evaluation of anyadverse event potentially associated with a Herbalifeproduct, we believe that objective review of thesecases does not support a cause and effect relationshipbetween any specific Herbalife product or ingredientand liver injury.

References

[1] Elinav E, Pinsker G, Safadi R, Pappo O, Bromberg M, Anis E,et al. Association between consumption of Herbalife nutritionalsupplements and acute hepatotoxicity. J Hepatol2007;47:514–520.

[2] Schoepfer AM, Engel A, Fattinger K, Marbet UA, Criblez D,Reichen J, et al. Herbal does not mean innocuous: 10 cases ofsevere hepatotoxicity associated with dietary supplements fromHerbalife products. J Hepatol 2007;47:521–526.

[3] Stickel F. Slimming at all costs: Herbalife-induced liver injury. JHepatol 2007;47:444–446.

[4] Gunawan B, Kaplowitz N. Clinical perspectives on xenobiotic-induced hepatotoxicity. Drug Metab Rev 2004;36:301–312.

[5] Bower WA, Johns M, Margolis HS, Williams IT, Bell BP.Population-based surveillance for acute liver failure. Am JGastroenterol 2007;102:2459–2463.

[6] Walker AM, Cavanaugh RJ. The occurrence of new hepaticdisorders in a defined population. Post Marketing Surveillance1992;6:107–117.

Louis Ignarro �

David Heber �

David Geffen School of Medicine,

UCLA, 900 Veteran Avenue,

Room 12217-Warren Hall,

Los Angeles, CA 90095, USA

Y. Steven HenigEzra Bejar

Herbalife International,990 West 190th St. Torrance,

CA 90502, USA

Tel.: +1 310 410 9600; fax: +1 310 767 3314 (E. Bejar)

E-mail address: ezrab@herbalife.com (E. Bejar)

� Dr. Ignarro is a member of the Scientific Advisory Board of Herbalife

International. Dr. Ignarro’s title is for identification purposes only. The

University of California does not endorse specific products or services as

a matter of policy.� Dr. Heber is Chairman of the Nutritional and Scientific Advisory

Boards of Herbalife International. Dr. Heber’s title is for identification

purposes only. The University of California does not endorse specific

products or services as a matter of policy.

doi:10.1016/j.jhep.2008.05.005

Herbalife revisited: Reply

To the Editor:

We read with interest the HerbalifeTM response by Dr.Ignarro and co-authors to the two reports and Editorialprinted in the Journal on association of HerbalifeTM withhepatotoxicity. We wish to address a number of state-ments in their letter:

1. Incidence

We agree with the authors that the incidence of Herba-lifeTM-associated hepatotoxicity is probably low, but notas low as they suggest. We disagree with their commentthat 22 cases among 5.5 million consumers world-widecan be used as proof for a low incidence of the com-pound(s) associated hepatotoxicity. The cases reportedby us, were identified through an ICD-9 search in all Israe-li hospitals during a two year period, starting in 2004. Thissurvey identified 12 cases which reported intake of Herba-lifeTM products among 33 patients diagnosed with crypto-genic liver dysfunction. The association between intake ofHerbalifeTM products and hepatic injury was classified ascertain in 3, probable in 6 and possible in 3 patients usingWHO criteria. A rough calculation of the incidence of

HerbalifeTM associated hepatotoxicity could recently bemade, following information requested from Herbalifeby the Israeli ministry of health and received in 2007.An estimated incidence of 25–30 cases per 100,000 con-sumers was made. This figure is only an approximation,since demographic data on the population of consumerswas unavailable at time of analysis. We also disagree withthe authors of the letter that the so called ‘‘low level of riskof liver disease is indistinguishable from the backgroundincidence of idiopathic liver disease”. In our survey inall Israeli hospitals, we identified initially 12/33 hospital-ized patients with liver injury of so called undeterminedetiology who reported intake of HerbalifeTM products.This still leaves 21/33 patients with so called idiopathic li-ver disease reflecting an incidence of <6 cases/million ofundetermined etiology of the liver injury (after exclusionof HerbalifeTM consumers). Finally it is common knowl-edge among hepatologists that sub-clinical, asymptom-atic ALT elevation may occur in patients with occultliver disease. Our survey included only hospitalized pa-tients, identified retrospectively through hospital records.Therefore, the number of patients who may have devel-oped occult hepatotoxicity in association with HerbalifeTM

Letters to the Editor / Journal of Hepatology 49 (2008) 288–294 293