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

products intake may be even higher than the estimatedincidence figure described above.

2. Causality

Both the Israeli and the Swiss groups used cited,internationally-accepted criteria for determining causal-ity. The fact that we were unable to identify yet a singleagent as a potential hepatotoxic agent does not excludecausality between ingestion of the product(s) and thedescribed liver injury. Moreover, among three Israeli pa-tients, the cause and effect was clearly established in con-sumers who developed hepatic injury who discontinuedtreatment followed by normalization of liver functiontests and then, by their own initiative restarted intakeof HerbalifeTM product(s) after initial resolution of thedisease, resulting in a second bout of liver injury. Thus,these cases were classified as ‘‘certain.” While the de-scribed hepatotoxicity may have been the result of anidiosyncratic reaction, there are other potential explana-tions for the described phenomenon. These includeamong others, direct hepatotoxicity, immune-mediatedhepatotoxicity (some patients were ANA+), interactionbetween several HerbalifeTM ingredients, a pharmacoge-netic susceptibility to one of more HerbalifeTM productsor contamination of one or more HerbalifeTM batchesby an unidentified etiologic agent or toxin. We also dis-agree with the statement that liver injury occurs withsubstantial and predictable frequency and severity in adose-dependant fashion in such patients with suspectedacute hepatotoxicity. The fact that the mechanism ofHerbalifeTM-associated hepatotoxicity is not understoodat present, does not exclude causality as often observedin DILI.

Indeed, HerbalifeTM submitted to the Israeli MOH alarge binder with information on extensive quality controltests performed by the company and a designated labregarding some toxic ingredients and heavy metals. How-ever, information on specific batch numbers and analysisof products used by the patients in Israel in 2004 has notbeen provided so far. Therefore, it is not possible at pres-

ent to link the observed cases of liver injury to specificbatches or ingredients in HerbalifeTM products.

3. Additional comments

We also wish to draw the readers’ attention to a mis-quotation in the discussed letter. In our original report,we did not state that the severe liver injury in theHBsAg positive patient was the ‘‘sole” result of Herba-lifeTM hepatotoxicity. This patient developed massivehepatocellular necrosis with liver failure which requiredliver transplantation. Immuno-histochemical tests of theliver explant were negative for HBsAg and HBcAg inthis patient, who consumed excessive amounts of Her-balifeTM products. This observation suggests, in ouropinion, possible superimposed injury in an HBV pa-tient. Similarly, the patient with primary biliary cirrho-sis (PBC) also developed an exacerbation of her liverdysfunction in association with intake of HerbalifeTM

products which was mainly hepatocellular, not typicalfor PBC.

In conclusion, we support the statement in the Edi-torial accompanying these two papers from Israel andSwitzerland that there is little doubt that one (ormore) HerbalifeTM products was involved directly orindirectly in the described hepatotoxicity. Althoughthe mechanism of the presumed HerbalifeTM associatedhepatotoxicity has not been established yet, we haverecommended and still recommend an increasedawareness by the medical community and the publicregarding this association until further information isavailable.

Daniel ShouvalEran Elinav

Liver Unit, Hadassah-Hebrew University Hospital,

Ein-Kerem, P.O. Box 12000, Jerusalem 91120, Israel

Tel.: +972 2 6777 337; fax: +972 2 6420 338E-mail address: shouval@cc.huji.ac.il

doi:10.1016/j.jhep.2008.05.010

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