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  • 1. EditorialSlimming at all costs: HerbalifeÒ-induced liver injury qFelix Stickel*Institute of Clinical Pharmacology, University of Berne, Murtenstrasse 35, CH-3010 Berne, SwitzerlandSee Articles, pages 514–520 and 521–526Complementary and alternative medicine (CAM) isexperiencing an astonishing boom due to the public’sincreasing interest in disease prophylaxis, nutrition,and improvements to health and well-being. A substan-tial contribution to this development includes nutri-tional supplements such as vitamins, antioxidants andherbals, formula diets to reduce weight, and poorlydefined preparations to ‘‘shape the body’’. Most individ-uals who use these products should be considered ‘‘cus-tomers’’ rather than ‘‘patients’’ since they have nointention to specifically treat diseases but to improvetheir health in general. The majority use herbal and foodsupplements in self medication at considerable personalexpense without prior consultation and knowledge oftheir doctors. A countrywide survey from the U.S.revealed a prevalence between 37.5% and 67% [1] anda steady rise [2] in the use of herbal medicine and nutri-tional supplements. The sales of these products are enor-mous; for example, an impressive $33 billion was spenton weight-loss products alone in 1999 [3]. One may wel-come this development since it actually reflects the pub-lic’s increased awareness of disease prevention andhealth, even if real benefits from these substances forconsumers are minor. However, several problems exist:(1) Reports about adverse reactions, particular liverinjury, have accumulated, so, these preparations arenot always as harmless as perceived [4]. (2) In most Wes-tern countries including the EU and the U.S., nutritionalsupplements and herbal CAM preparations are exemptfrom strict licensing regulations routinely imposed onsynthetic drugs or medicinal products before releasingthem onto the market. CAM preparations are handledlike food products for which no pre-marketing approvalis required. Liability remains entirely with the companyand no proof of safety, let alone efficacy, has to be pro-vided. (3) Increasingly, customers purchase herbals andnutritional supplements from largely anonymous Inter-net sources without consulting a doctor or a pharmacist.(4) Composition of most products is insufficiently char-acterized, often unlabelled, highly variable and clearbeneficial effects for the consumers do not exist. (5)Companies claim that alleged health advantages wouldonly become visible through long-term and regular usealthough this is not backed up by supporting clinical evi-dence. Therefore, the usually high costs of these prod-ucts stand in utter contrast to their unproven benefits[5,6]. (6) Often, physicians’ level of knowledge about die-tary supplements and herbals, their regulation andpotential hazards is vague and their awareness ofCAM preparations as a potential source of health dam-age is low [7]. (7) Products are often presented in a fash-ion that raises unfounded hopes and expectations whichcannot be fulfilled. It has to be emphasized that onlineinformation about the products offered constitutesadvertisements rather than serious scientific informa-tion; this distinction is often difficult to make for mostlay customers.Apart from the lack of evidence for a long-term clin-ical benefit, herbal combinations taken for weight losshave been recognized as potential causes of liver injuryin several case report series demonstrating acute hepati-tis following the intake of LipoKinetix [8], preparationscontaining ephedrin [9], and green tea extracts [10].0168-8278/$32.00 Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.jhep.2007.07.010Associate Editor: C.P. DayqThe author declared that he does not have anything to discloseregarding funding or conflict of interest with respect to this manu-script.*Tel.: +41 31 632 8715; fax: +41 31 632 4997.E-mail address: felix.stickel@ikp.unibe.chwww.elsevier.com/locate/jhepJournal of Hepatology 47 (2007) 444–446
  • 2. In this issue of the Journal, two case report seriesfrom Israel and Switzerland for the first time describeincidents of severe liver injury along with the intake ofa panel of different HerbalifeÒproducts [11,12]. Herba-lifeÒsells nutritional and herbal supplements for weightcontrol, improvement of nutrition, and ‘‘well-being’’,and cosmetics online or through independently operat-ing sales agents. Among the 22 cases of liver damage fol-lowing HerbalifeÒintake analyzed in the two reports,two patients developed fulminant hepatic failure requir-ing super urgent liver transplantation which saved onepatient’s life while the second died due to postoperativecomplications. Causality between the intake of Herba-lifeÒproducts and the evolution of liver injury was care-fully assessed by internationally accepted causalityscores [13,14]. In five patients, causality was labelled‘‘certain’’ by a positive re-challenge reaction and ‘‘prob-able’’ in additional 13 patients. Other potential causeswere ruled out in all patients, although one patient withpositivity for HBsAg seemingly developed hepatitis Breactivation and proceeded to fulminant liver failure.Considering the patients in whom symptoms and signsof liver injury recurred following re-administration ofHerbalifeÒproducts, there appears to be little doubtthat these products were the cause. All internationallyevaluated scoring systems regard a positive rechallengeas the strongest proof of causality [13–15]. Althoughentirely descriptive, the two papers are important andadd another, thus far unknown, candidate to the listof products that can cause liver damage.However, the two reports raise more questionsthan they answer. Although causality was testedappropriately, it remains entirely speculative whatmight have been the cause of liver damage in the22 patients. The patients took between 3 and 17 dif-ferent HerbalifeÒproducts which makes it extremelydifficult, if not impossible, to identify the crucial com-pound(s). Efforts by the authors to retrieve a detailedcomposition analysis were apparently unsuccessfulsince the company refused to provide such informa-tion. In 2006, the stock market quoted HerbalifeÒcompany as having a revenue of $ 3.1 billion; thecompany’s reluctance to provide detailed analyses oftheir products’ composition is difficult to understandconsidering what is at stake should news about asso-ciated dangers spread. However, due to this lack ofco-operation, attempts should have been made bythe investigators to analyze the ingested Herba-lifeÒproducts for toxins, microbial contamination orto screen affected individuals for possible immunoal-lergic reactions to the consumed material. While thiswas not possible in the Swiss series due to retrospec-tive data collection, at least one of the Israeli caseswas apparently followed up recently as the relapsewas noticed. However, neither the batch taken bythese patients nor those taken by the other patientswere subjected to a closer analysis, although allpatients were contacted personally. Fulminant liverfailure due to bacterial toxins was described byMahler et al. in two cases following the ingestion ofreheated pasta sauce contaminated with Bacilluscereus which produces a hepatotoxic toxin [16]. How-ever, such catastrophic incidents usually do not resultin larger series of unrelated cases.Another explanation for HerbalifeÒ-associated liverdamage could be a locally restricted contaminationwith chemicals such as softeners, preservatives, flavourenhancers, pesticides, or heavy metals either intention-ally added during the manufacturing process or con-tained in the unrefined raw products, i.e. herbextracts [17]. This possibility could explain the differ-ent patterns of liver injury found in the two serieswith predominantly cholestatic hepatitis in the Swisspatients and hepatocellular hepatitis in the Israeli sub-jects. Two unusual patterns of injury were observed inthe Swiss series – sinusoidal obstruction syndrome andgiant cell hepatitis. These two lesions are typical ofintoxication with pyrrolizidine alkaloids and intakeof Plantago ovata/Emblica officinalis (Isabgol), respec-tively, and it cannot be excluded that the consumedHerbalifeÒproducts contained either of thesecompounds. Apart from these considerations, it iswell-known that a single drug/substance can producedifferent patterns of hepatic damage. So, should fur-ther cases of HerbalifeÒhepatotoxicity be detected,clinicians and researchers are urged to retrieve thebatch(es) that were consumed by their patients to per-form detailed screenings for microbes, their toxins,and chemicals.It remains speculative why cases of HerbalifeÒhepatotoxicity were only noticed in Switzerland andIsrael, although HerbalifeÒproducts are sold in atleast 60 countries all over the world. Based on expe-riences with adverse drug reactions due to syntheticdrugs, simple probability should have led to addi-tional incidents of HerbalifeÒ-associated hepatotoxic-ity. Isolated series of drug-induced liver damage arehighly suggestive of either significant underreportingin other countries with a more widespread consump-tion, or indicate the specific distribution of ‘‘spoiled’’or contaminated batches. However, as the Swissauthors rightly state, the ‘‘threat to the publichealth’’ from HerbalifeÒproducts is minor andshould not be exaggerated when compared with inci-dence rates of adverse hepatic reactions of otherover-the-counter pharmaceuticals such as non-steroi-dal anti-inflammatory drugs [18].The two series emphasize the need for caution regard-ing poorly labelled herbal weight, loss products withquestionable benefits and, considering the principle‘‘first, do no harm’’, clearly shift the risk-benefit ratioagainst their use.F. Stickel / Journal of Hepatology 47 (2007) 444–446 445
  • 3. References[1] Kessler RC, Davis RB, Foster DF, Van Rompay MI, Walters EE,Wilkey SA, et al. Long-term trends in the use of complementaryand alternative medical therapies in the United States. Ann InternMed 2001;135:262–268.[2] Tindle HA, Davis RB, Phillips RS, Eisenberg DM. Trends in useof complementary and alternative medicine by US adults: 1997–2002. Altern Ther Health Med 2005;11:42–49.[3] Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS,Koplan JP. The spread of the obesity epidemic in the UnitedStates, 1991–1998. JAMA 1999;282:1519–1522.[4] Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. JHepatol 2005;43:901–910.[5] Bjelakovic G, Nagorni A, Nikolova D, Simonetti RG, BjelakovicM, Gluud C. Meta-analysis: antioxidant supplements for primaryand secondary prevention of colorectal adenoma. Aliment Phar-macol Ther 2006;24:281–291.[6] Stickel F, Schuppan D. Herbal medicines in the treatment of liverdiseases. Dig Liv Dis 2007;39:293–304.[7] Ashar BH, Rice TN, Sisson SD. Physician‘s understanding of theregulation of dietary supplements. Arch Intern Med2007;167:966–969.[8] Favreau JT, Ryu ML, Braunstein G, Orshansky G, Park SS, CoodyGL, et al. Severe hepatotoxicity associated with the dietarysupplement LipoKinetix. Ann Intern Med 2002;136:590–595.[9] Stevens T, Qadri A, Zein NN. Two patients with acute liver injuryassociated with use of the herbal weight-loss supplementHydroxycut. Ann Intern Med 2005;142:477–478.[10] Bjornsson E, Olsson R. Serious adverse liver reactions associatedwith herbal weight-loss supplements. J Hepatol 2007;47:295–297.[11] ElinavE, PinskerG, SafadiR,PappoO, BrombergM,AnisE, et al.Association between consumption of HerbalifeÒnutritional sup-plements and acute hepatotoxicity. J Hepatol 2007;47:514–520.[12] 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 fromHerbalifeÒproducts. J Hepatol 2007;47:521–526.[13] Benichou C, Uclaf R. Criteria of drug-induced liver disorders:report of an international consensus meeting. J Hepatol1990;11:272–276.[14] http://www.who-umc.org/DynPage,aspx?id=22682.[15] Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, De laCuesta FS. Comparison of two clinical scales for causalityassessment in hepatotoxicity. Hepatology 2001;33:123–130.[16] Mahler H, Pasi A, Kramer JM, Schulte P, Scoging AC, Ba¨r W,et al. Fulminant liver failure in association with the emetic toxinof Bacillus cereus. N Engl J Med 1997;336:1142–1148.[17] De Smet PA. Herbal remedies. N Engl J Med 2002;347:2046–2056.[18] Bjornsson E, Olsson R. Outcome and prognostic markers insevere drug-induced liver disease. Hepatology 2005;42:481–489.446 F. Stickel / Journal of Hepatology 47 (2007) 444–446