Herbalife nutritional products and liver injury revisited
Authors: Louis Ignarro, David Heber, Y. Steven Henig, Ezra Bejar
Journal: Journal of Hepatology (2008)

Recently, two reports of 12 and 10 cases of idiopathic liver disease from Israel [[1]Elinav E. Pinsker G. Safadi R. Pappo O. Bromberg M. Anis E. et al.Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity.J Hepatol. 2007; 47: 514-520Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar] and Switzerland [[2]Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: 10 cases of severe hepatotoxicity associated with dietary supplements from Herbalife products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar], respectively, appeared in the same issue of this journal alleging in the articles and in an accompanying editorial that these cases were caused by the consumption of Herbalife products. In fact, the two papers [1Elinav E. Pinsker G. Safadi R. Pappo O. Bromberg M. Anis E. et al.Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity.J Hepatol. 2007; 47: 514-520Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 2Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: 10 cases of severe hepatotoxicity associated with dietary supplements from Herbalife products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar] concluded unequivocally that causation was certain in some cases. Despite the authors' strong assertion that a cause and effect relationship between Herbalife product use and liver injury exists, an objective review of the facts raises serious doubt whether such a conclusion can be drawn. In Israel [[1]Elinav E. Pinsker G. Safadi R. Pappo O. Bromberg M. Anis E. et al.Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity.J Hepatol. 2007; 47: 514-520Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar], the observed liver abnormalities resolved in eleven of the twelve cases reported. The remaining patient succumbed to complications of liver transplantation and despite the fact that this patient also had evidence of hepatitis B infection, sole attribution of the liver injury to Herbalife products was made. Another patient had stage I primary biliary cirrhosis and other patients consumed a variety of substances or had other co-morbid diseases that could have caused or contributed to the liver disease observed. In Switzerland [[2]Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: 10 cases of severe hepatotoxicity associated with dietary supplements from Herbalife products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar], a total of 10 evaluable case reports with similar characteristics were documented over seven years. Taken at face value, these few cases represent an extremely low incidence of suspected liver injury among the millions of Herbalife consumers worldwide (5.5 million consumers in 2004 alone). In 2004 more than 40,000,000 servings from 29 different products were distributed to approximately 37,000 Israeli consumers. A similar number of servings from 26 different products were distributed to approximately 80,000 Swiss consumers. In the 5 combined cases where causation was assessed as "certain" due to a reported combination of positive dechallenge and rechallenge, the case details remain unclear. As an example, 4 of these patients described between 3 and 17 different and specific Herbalife products previously consumed prior to dechallenge, and in the remaining patient no specific Herbalife product in either the reported dechallenge or rechallenge could be identified. Equally concerning is the fact that there is no mention of which of the initially reported products were subsequently consumed by any of the patients that allegedly led to the recurrence of symptoms. Even if all 4 patients consumed the exact same 3–17 products, respectively, there was no purported toxic ingredient identified by the authors in the article that was common among all 4 of these patients. It is also interesting that in one of these 4 patients, rechallenge of unspecified Herbalife product was reported to result in recurrence of symptoms, yet the patient purportedly continues to use unspecified Herbalife product(s) and remains asymptomatic. The generally accepted criteria for causality of liver diseases cited in the editorial, including dechallenge/rechallenge, were designed to consider drug-induced hepatotoxicity when a specific defined ingredient has been identified, and were not designed to consider the effects of multiple different foods, supplements, and distinct nutritional products in combination or totality. The comment made in the editorial [[3]Stickel F. Slimming at all costs: Herbalife-induced liver injury.J Hepatol. 2007; 47: 444-446Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar] that "there can be little doubt that these products were the cause" is simply not supported by the facts. In acute hepatotoxicity, liver injury typically occurs with a substantial and predictable frequency, its severity is dose-dependent, and a responsible agent can be identified. In contrast, liver injury from an immune-mediated hypersensitivity reaction is sporadic, and clinical symptoms and abnormal liver biochemical tests occur in only a very small number of individuals who metabolically convert some constituent of the product consumed into a substance that stimulates an immune reaction [[4]Gunawan B. Kaplowitz N. Clinical perspectives on xenobiotic-induced hepatotoxicity.Drug Metab Rev. 2004; 36: 301-312Crossref PubMed Scopus (95) Google Scholar]. While this is the generally accepted scenario among hepatologists, the exact cause, predisposing individualistic factors, and precise pathophysiology of this rare form of liver disease remain poorly understood. Furthermore, the incidence of these cases appears to be very low compared to the risks associated with some over-the-counter and prescription drugs on the market. A population-based survey in Atlanta, Georgia, USA published in 2007 found that the incidence of acute liver failure in eight counties was 5.5 per million individuals, and the use or abuse of acetaminophen was associated with 41 percent of the cases, while a significant percentage of adults had liver failure of unknown etiology [[5]Bower W.A. Johns M. Margolis H.S. Williams I.T. Bell B.P. Population-based surveillance for acute liver failure.Am J Gastroenterol. 2007; 102: 2459-2463Crossref PubMed Scopus (222) Google Scholar]. As indicated in the Swiss article, the rare incidence of these events having been ten cases collected over seven years, makes the overall incidence some 1.8 per million patients/year [[2]Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: 10 cases of severe hepatotoxicity associated with dietary supplements from Herbalife products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar]. This low level of risk of liver disease is indistinguishable from the background incidence of idiopathic liver disease, where no cause can be found. In a study of 71,000 North Americans in 1992, the background rate of idiopathic or cryptogenic liver disease was 24 cases per 100,000 individuals compared to 14 per 100,000 attributed to cases of hepatitis B, 25 per 100,000 due to alcoholism, and 7 per 100,000 due to other viral illnesses [[6]Walker A.M. Cavanaugh R.J. The occurrence of new hepatic disorders in a defined population.Post Marketing Surveillance. 1992; 6: 107-117Google Scholar]. While the spectrum of liver diseases has certainly changed since 1992 when this survey was done, the number of idiopathic liver diseases remains a significant percentage of all the cases. Herbalife nutritional products are registered and notified as foods, meal replacements, and dietary supplements and not as herbal medicines. There are ingredients such as guarana, green tea, and caffeine, which are being used extensively in numerous food products and are not unique to Herbalife. Herbalife conducts testing, through independent laboratories, on product batches for heavy metals, pesticides, ochratoxin A, aflatoxins, comfrey retrosine (pyrrolizidine alkaloids; PAs), and kava kavalactones. Completed tests have consistently shown no detection of pesticides, kava or PAs, and traces of ochratoxins, aflatoxins, and heavy metals are below minimum threshold levels. Also, the company has a well-developed adverse event reporting system which monitors and evaluates adverse events globally and has sought the involvement of outside, independent experts to evaluate its adverse event experience. The core products of Herbalife provide healthy solutions to the worldwide epidemic of obesity. The products are designed to deliver balanced nutrition and assist in the promotion of fitness and a healthy, active lifestyle. These products are primarily based in vegetable proteins, fish oils, vitamins, and minerals for which safe use is very well established. Some of the company's products also contain botanical ingredients that are well characterized and tested. These botanicals are included in Herbalife product at levels that are in a safe nutritional range where they have antioxidant properties and support normal function, and are labeled in accordance with all the applicable laws. The company does not market or encourage the use of any of its products as medicines for the treatment of specific diseases. There were no undefined or unlabeled herbs in these products as suggested in the articles and contrary to what has been portrayed, the company has cooperated fully with the ministries of health in their investigation of these cases. In fact, government officials and clinicians investigating these cases in both countries were given access to full product formulas and ingredients. These ingredient disclosures were documented in numerous communiqués and included full product dossiers and results of independent testing regarding product purity and integrity. It is also unfortunate in our view that Herbalife's brand name was generically linked to liver injury rather than specific products or ingredients where such an association could not be established. This approach is unprecedented. Although Herbalife remains committed in the spirit of product stewardship to cooperate openly and fully in the evaluation of any adverse event potentially associated with a Herbalife product, we believe that objective review of these cases does not support a cause and effect relationship between any specific Herbalife product or ingredient and liver injury.