Spanish reports of hepatotoxicity associated with Herbalife® products
Authors: Gloria Manso, Laureano López-Rivas, José María Duque, Esther Salgueiro
Journal: Journal of Hepatology (2008)

We have read with interest the articles recently published in this journal by Elinav et al. [[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 (101) Google Scholar] and Schoepfer et al. [[2]Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar], as well as the editorial by Stickel [[3]Stickel F. Slimming at all costs: Herbalife®-induced liver injury.J Hepatol. 2007; 47: 444-446Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar], reporting and discussing two series of cases from Israel and Switzerland of hepatotoxicity associated with the consumption of Herbalife® slimming products. Stickel [[3]Stickel F. Slimming at all costs: Herbalife®-induced liver injury.J Hepatol. 2007; 47: 444-446Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] raises the question of why products which are distributed in at least 60 countries only seem to induce hepatotoxicity in two.In Spain, as perhaps in other countries, Herbalife® distributes its products through door-to-door salesmen and the internet. Some products are registered as dietetic supplements, but others are not registered at all. In 2005, three cases of hepatotoxicity (two hepatitis and one of increased liver enzymes) were reported to the Pharmacovigilance Centre of Asturias, an area in the north of Spain. Another case of increased liver enzymes was reported in 2006. All the four cases occurred in women between 47 and 57 years old, and all came from the same hospital. Three of these were published last February in a Spanish medical journal [[4]Duque J.M. Ferreiro J. Salgueiro E. Manso G. Hepatotoxicity associated with the consumption of herbal slimming products.Med Clin (Barc). 2007; 128: 238-239Crossref PubMed Google Scholar].In the two cases of hepatitis the patients were sisters. One of whom developed severe liver damage. After taking Herbalife® products for 1 year and losing 20 kg in weight, she was referred to hospital suffering from widespread pruritus, jaundice, fatigue and abdominal strain. Biochemical tests showed liver transaminases over 1000 U/l and 12 mg/dl of total bilirubin. Test antibodies to hepatitis were negative. Abdominal ultrasound showed a cholelithiasis that was surgically removed. Although she was recommended to cease taking Herbalife® products, she continued to do so for another 2 years and developed chronic liver disease with recurrent exacerbations. Liver biopsy showed acute hepatitis grade 4 on chronic liver disease stage 3. She was diagnosed as having idiopathic or toxic autoimmune hepatitis, and is currently being treated with corticosteroids. Her sister took Herbalife® products for six months and developed diarrhea, hyperbilirubinemia, jaundice and pruritus. Biochemical tests showed transaminases over 1000 U/l and 26.7 mg/dl of total bilirubin. Viral antibodies were negative. Subacute cholestatic hepatitis was diagnosed and the withdrawal of Herbalife® products was recommended. Some months later, the patient had totally recovered. The two sisters took the following Herbalife® products: formulas 1, 2, 3 and 4, RoseOx, Herbalifeline, Guaraná, Classic Aromatized Tea and Herbal Aloe.The patients in the other two cases of reported hepatotoxicity were also taking Herbalife® products over a period of 1 month in one case and 3 years in the other, and developed increased transaminases which were detected on routine analysis. After the withdrawal of Herbalife® products, the enzyme levels returned to normal.To explain the mechanism involved in the hepatotoxicity induced by Herbalife® products, Elinav et al. [[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 (101) Google Scholar] have suggested genetic susceptibility to develop an immune-mediated liver toxicity associated with one or more constituents. The family ties between the two cases of hepatitis reported in Spain and the diagnosis of autoimmune hepatitis in one case support this observation. We agree with Stickel [[3]Stickel F. Slimming at all costs: Herbalife®-induced liver injury.J Hepatol. 2007; 47: 444-446Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] when he explains that it is extremely difficult to identify the crucial compounds when consumers of Herbalife® are taking several products. Although toxic or bacteriological contamination of some batches cannot be dismissed, we believe that some components of Herbalife® products could be the hepatoxicity inducers. Firstly, as Schoepfer et al. [[2]Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar] have suggested, the green tea contained in the Classic Aromatized Tea and also in other Herbalife® products. In the last 5 years, evidence on the ability of green tea to induce liver damage has increased [5Bonkovsky H.L. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis).Ann Intern Med. 2006; 144: 68-71Crossref PubMed Scopus (181) Google Scholar, 6Jiménez-Sáenz M. Martínez-Sánchez M.C. Acute hepatitis associated with the use of green tea infusions.J Hepatol. 2006; 44: 616-617Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. In April 2003, the Spanish Agency of Medicine and Health Products withdrew the over the counter medicine Exolise® from the market. This contained an ethanolic extract of green tea, and was the cause of four cases of hepatotoxicity in Spain [[7]Pedrós C. Cereza G. García N. Laporte J.R. Hepatotoxicidad por extracto etanólico seco de Camellia sinensis.Med Clin (Barc). 2003; 121: 598-599PubMed Google Scholar] and nine in France [[8]Vial T. Bernard G. Lewden B. Dumortier J. Descotes J. Hépatite aiguë imputable à l'Exolise®(Camellia sinensis).Gastroenterol Clin Biol. 2003; 27: 1166-1167PubMed Google Scholar]. In none of the Herbalife® products containing green tea is the type of extract or the amount of active substances specified. On the other hand, several authors [9Rabe C. Musch A. Schirmacher P. Kruis W. Hoffmann R. Acute hepatitis induced by an aloe vera preparation: a case report.World J Gastroenterol. 2005; 11: 303-304Crossref PubMed Scopus (67) Google Scholar, 10Kanat O. Ozet A. Ataergin S. Aloe vera-induced acute toxic hepatitis in a healthy young man.Eur J Inter Med. 2006; 17: 589Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 11Bottenberg M.M. Wall G.C. Harvey R.L. Habib S. Oral aloe vera-induced hepatitis.Ann Pharmacother. 2007; 41: 1740-1743Crossref PubMed Scopus (76) Google Scholar] have reported cases of acute hepatitis associated with the consumption of Aloe vera tablets or capsules. Aloe vera is the main component of the drink Herbal Aloe sold by Herbalife®.We do not believe that the hepatotoxicity of the Herbalife® products is confined to three countries alone. The lower use in some areas, the underreporting of adverse reactions, and the lower ability to detect or report information in the international scientific media could be the reasons for explaining this lack of information from other countries. For some time, Latin American and Spanish health professionals have been discussing the safety of Herbalife® products and similar compounds on internet forums.Schoepfer et al. [[2]Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar] and Stickel [[3]Stickel F. Slimming at all costs: Herbalife®-induced liver injury.J Hepatol. 2007; 47: 444-446Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] consider that the hepatotoxicity associated with Herbalife® products does not seem to be a threat to public health and have suggested an incidence lower than that of the non-steroidal anti-inflammatory drugs. In our opinion, the evaluation of this safety problem is impossible because we have no precise consumption data nor isolated active substances of established efficacy. Perhaps the hepatotoxicity we are speaking about is of low incidence and affects patients with genetic susceptibility or other risk factors. However, the growing consumption of products promoted as "natural", without defined composition, quality control and demonstrated activity and safety is a real health problem that should be kept under control. Today we are speaking only about the products of the Herbalife® brand, but tomorrow we may be speaking about other products or other brands. We have read with interest the articles recently published in this journal by Elinav et al. [[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 (101) Google Scholar] and Schoepfer et al. [[2]Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar], as well as the editorial by Stickel [[3]Stickel F. Slimming at all costs: Herbalife®-induced liver injury.J Hepatol. 2007; 47: 444-446Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar], reporting and discussing two series of cases from Israel and Switzerland of hepatotoxicity associated with the consumption of Herbalife® slimming products. Stickel [[3]Stickel F. Slimming at all costs: Herbalife®-induced liver injury.J Hepatol. 2007; 47: 444-446Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] raises the question of why products which are distributed in at least 60 countries only seem to induce hepatotoxicity in two. In Spain, as perhaps in other countries, Herbalife® distributes its products through door-to-door salesmen and the internet. Some products are registered as dietetic supplements, but others are not registered at all. In 2005, three cases of hepatotoxicity (two hepatitis and one of increased liver enzymes) were reported to the Pharmacovigilance Centre of Asturias, an area in the north of Spain. Another case of increased liver enzymes was reported in 2006. All the four cases occurred in women between 47 and 57 years old, and all came from the same hospital. Three of these were published last February in a Spanish medical journal [[4]Duque J.M. Ferreiro J. Salgueiro E. Manso G. Hepatotoxicity associated with the consumption of herbal slimming products.Med Clin (Barc). 2007; 128: 238-239Crossref PubMed Google Scholar]. In the two cases of hepatitis the patients were sisters. One of whom developed severe liver damage. After taking Herbalife® products for 1 year and losing 20 kg in weight, she was referred to hospital suffering from widespread pruritus, jaundice, fatigue and abdominal strain. Biochemical tests showed liver transaminases over 1000 U/l and 12 mg/dl of total bilirubin. Test antibodies to hepatitis were negative. Abdominal ultrasound showed a cholelithiasis that was surgically removed. Although she was recommended to cease taking Herbalife® products, she continued to do so for another 2 years and developed chronic liver disease with recurrent exacerbations. Liver biopsy showed acute hepatitis grade 4 on chronic liver disease stage 3. She was diagnosed as having idiopathic or toxic autoimmune hepatitis, and is currently being treated with corticosteroids. Her sister took Herbalife® products for six months and developed diarrhea, hyperbilirubinemia, jaundice and pruritus. Biochemical tests showed transaminases over 1000 U/l and 26.7 mg/dl of total bilirubin. Viral antibodies were negative. Subacute cholestatic hepatitis was diagnosed and the withdrawal of Herbalife® products was recommended. Some months later, the patient had totally recovered. The two sisters took the following Herbalife® products: formulas 1, 2, 3 and 4, RoseOx, Herbalifeline, Guaraná, Classic Aromatized Tea and Herbal Aloe. The patients in the other two cases of reported hepatotoxicity were also taking Herbalife® products over a period of 1 month in one case and 3 years in the other, and developed increased transaminases which were detected on routine analysis. After the withdrawal of Herbalife® products, the enzyme levels returned to normal. To explain the mechanism involved in the hepatotoxicity induced by Herbalife® products, Elinav et al. [[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 (101) Google Scholar] have suggested genetic susceptibility to develop an immune-mediated liver toxicity associated with one or more constituents. The family ties between the two cases of hepatitis reported in Spain and the diagnosis of autoimmune hepatitis in one case support this observation. We agree with Stickel [[3]Stickel F. Slimming at all costs: Herbalife®-induced liver injury.J Hepatol. 2007; 47: 444-446Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] when he explains that it is extremely difficult to identify the crucial compounds when consumers of Herbalife® are taking several products. Although toxic or bacteriological contamination of some batches cannot be dismissed, we believe that some components of Herbalife® products could be the hepatoxicity inducers. Firstly, as Schoepfer et al. [[2]Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar] have suggested, the green tea contained in the Classic Aromatized Tea and also in other Herbalife® products. In the last 5 years, evidence on the ability of green tea to induce liver damage has increased [5Bonkovsky H.L. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis).Ann Intern Med. 2006; 144: 68-71Crossref PubMed Scopus (181) Google Scholar, 6Jiménez-Sáenz M. Martínez-Sánchez M.C. Acute hepatitis associated with the use of green tea infusions.J Hepatol. 2006; 44: 616-617Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. In April 2003, the Spanish Agency of Medicine and Health Products withdrew the over the counter medicine Exolise® from the market. This contained an ethanolic extract of green tea, and was the cause of four cases of hepatotoxicity in Spain [[7]Pedrós C. Cereza G. García N. Laporte J.R. Hepatotoxicidad por extracto etanólico seco de Camellia sinensis.Med Clin (Barc). 2003; 121: 598-599PubMed Google Scholar] and nine in France [[8]Vial T. Bernard G. Lewden B. Dumortier J. Descotes J. Hépatite aiguë imputable à l'Exolise®(Camellia sinensis).Gastroenterol Clin Biol. 2003; 27: 1166-1167PubMed Google Scholar]. In none of the Herbalife® products containing green tea is the type of extract or the amount of active substances specified. On the other hand, several authors [9Rabe C. Musch A. Schirmacher P. Kruis W. Hoffmann R. Acute hepatitis induced by an aloe vera preparation: a case report.World J Gastroenterol. 2005; 11: 303-304Crossref PubMed Scopus (67) Google Scholar, 10Kanat O. Ozet A. Ataergin S. Aloe vera-induced acute toxic hepatitis in a healthy young man.Eur J Inter Med. 2006; 17: 589Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 11Bottenberg M.M. Wall G.C. Harvey R.L. Habib S. Oral aloe vera-induced hepatitis.Ann Pharmacother. 2007; 41: 1740-1743Crossref PubMed Scopus (76) Google Scholar] have reported cases of acute hepatitis associated with the consumption of Aloe vera tablets or capsules. Aloe vera is the main component of the drink Herbal Aloe sold by Herbalife®. We do not believe that the hepatotoxicity of the Herbalife® products is confined to three countries alone. The lower use in some areas, the underreporting of adverse reactions, and the lower ability to detect or report information in the international scientific media could be the reasons for explaining this lack of information from other countries. For some time, Latin American and Spanish health professionals have been discussing the safety of Herbalife® products and similar compounds on internet forums. Schoepfer et al. [[2]Schoepfer A.M. Engel A. Fattinger K. Marbet U.A. Criblez D. Reichen J. et al.Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products.J Hepatol. 2007; 47: 521-526Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar] and Stickel [[3]Stickel F. Slimming at all costs: Herbalife®-induced liver injury.J Hepatol. 2007; 47: 444-446Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] consider that the hepatotoxicity associated with Herbalife® products does not seem to be a threat to public health and have suggested an incidence lower than that of the non-steroidal anti-inflammatory drugs. In our opinion, the evaluation of this safety problem is impossible because we have no precise consumption data nor isolated active substances of established efficacy. Perhaps the hepatotoxicity we are speaking about is of low incidence and affects patients with genetic susceptibility or other risk factors. However, the growing consumption of products promoted as "natural", without defined composition, quality control and demonstrated activity and safety is a real health problem that should be kept under control. Today we are speaking only about the products of the Herbalife® brand, but tomorrow we may be speaking about other products or other brands.