Herbalife revisited: Reply
Authors: Daniel Shouval, Eran Elinav
Journal: Journal of Hepatology (2008)

We read with interest the Herbalife™ response by Dr. Ignarro and co-authors to the two reports and Editorial printed in the Journal on association of Herbalife™ with hepatotoxicity. We wish to address a number of statements in their letter: We agree with the authors that the incidence of Herbalife™-associated hepatotoxicity is probably low, but not as low as they suggest. We disagree with their comment that 22 cases among 5.5 million consumers world-wide can be used as proof for a low incidence of the compound(s) associated hepatotoxicity. The cases reported by us, were identified through an ICD-9 search in all Israeli hospitals during a two year period, starting in 2004. This survey identified 12 cases which reported intake of Herbalife™ products among 33 patients diagnosed with cryptogenic liver dysfunction. The association between intake of Herbalife™ products and hepatic injury was classified as certain in 3, probable in 6 and possible in 3 patients using WHO criteria. A rough calculation of the incidence of Herbalife™ associated hepatotoxicity could recently be made, following information requested from Herbalife by the Israeli ministry of health and received in 2007. An estimated incidence of 25–30 cases per 100,000 consumers was made. This figure is only an approximation, since demographic data on the population of consumers was unavailable at time of analysis. We also disagree with the authors of the letter that the so called “low level of risk of liver disease is indistinguishable from the background incidence of idiopathic liver disease”. In our survey in all Israeli hospitals, we identified initially 12/33 hospitalized patients with liver injury of so called undetermined etiology who reported intake of Herbalife™ products. This still leaves 21/33 patients with so called idiopathic liver disease reflecting an incidence of <6 cases/million of undetermined etiology of the liver injury (after exclusion of Herbalife™ consumers). Finally it is common knowledge among hepatologists that sub-clinical, asymptomatic ALT elevation may occur in patients with occult liver disease. Our survey included only hospitalized patients, identified retrospectively through hospital records. Therefore, the number of patients who may have developed occult hepatotoxicity in association with Herbalife™ products intake may be even higher than the estimated incidence figure described above. Both the Israeli and the Swiss groups used cited, internationally-accepted criteria for determining causality. The fact that we were unable to identify yet a single agent as a potential hepatotoxic agent does not exclude causality between ingestion of the product(s) and the described liver injury. Moreover, among three Israeli patients, the cause and effect was clearly established in consumers who developed hepatic injury who discontinued treatment followed by normalization of liver function tests and then, by their own initiative restarted intake of Herbalife™ product(s) after initial resolution of the disease, resulting in a second bout of liver injury. Thus, these cases were classified as “certain.” While the described hepatotoxicity may have been the result of an idiosyncratic reaction, there are other potential explanations for the described phenomenon. These include among others, direct hepatotoxicity, immune-mediated hepatotoxicity (some patients were ANA+), interaction between several Herbalife™ ingredients, a pharmacogenetic susceptibility to one of more Herbalife™ products or contamination of one or more Herbalife™ batches by an unidentified etiologic agent or toxin. We also disagree with the statement that liver injury occurs with substantial and predictable frequency and severity in a dose-dependant fashion in such patients with suspected acute hepatotoxicity. The fact that the mechanism of Herbalife™-associated hepatotoxicity is not understood at present, does not exclude causality as often observed in DILI. Indeed, Herbalife™ submitted to the Israeli MOH a large binder with information on extensive quality control tests performed by the company and a designated lab regarding some toxic ingredients and heavy metals. However, information on specific batch numbers and analysis of products used by the patients in Israel in 2004 has not been provided so far. Therefore, it is not possible at present to link the observed cases of liver injury to specific batches or ingredients in Herbalife™ products. We also wish to draw the readers’ attention to a misquotation in the discussed letter. In our original report, we did not state that the severe liver injury in the HBsAg positive patient was the “sole” result of Herbalife™ hepatotoxicity. This patient developed massive hepatocellular necrosis with liver failure which required liver transplantation. Immuno-histochemical tests of the liver explant were negative for HBsAg and HBcAg in this patient, who consumed excessive amounts of Herbalife™ products. This observation suggests, in our opinion, possible superimposed injury in an HBV patient. Similarly, the patient with primary biliary cirrhosis (PBC) also developed an exacerbation of her liver dysfunction in association with intake of Herbalife™ products which was mainly hepatocellular, not typical for PBC. In conclusion, we support the statement in the Editorial accompanying these two papers from Israel and Switzerland that there is little doubt that one (or more) Herbalife™ products was involved directly or indirectly in the described hepatotoxicity. Although the mechanism of the presumed Herbalife™ associated hepatotoxicity has not been established yet, we have recommended and still recommend an increased awareness by the medical community and the public regarding this association until further information is available.