Herbal medicine hepatotoxicity: A new step with development of specific biomarkers
Authors: Dominique Larrey, Stéphanie Faure
Journal: Journal of Hepatology (2010)

Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetumJournal of HepatologyVol. 54Issue 4PreviewOne major cause of hepatic sinusoidal obstruction syndrome (HSOS) is the intake of pyrrolizidine alkaloid (PA)-containing products. Over 8000 PA-induced HSOS cases have been reported worldwide and at least 51 among them were suspected to be attributed to exposure to the Chinese medicine ‘Tusanqi’. PA-induced hepatotoxicity involves cytochrome P450-mediated metabolic activation of PAs to electrophilic pyrrolic metabolites which react with macromolecules, such as proteins. However, no studies have found such protein adduction in HSOS patients. Full-Text PDF Herbal medicine hepatotoxicity revisitedJournal of HepatologyVol. 56Issue 2PreviewIn the April 2011 issue of the Journal of Hepatology, an editorial discussed hepatotoxicity associated with the use of herbal preparations [1]. The focus of the article is primarily on the need to develop specific biomarkers for compounds or ingredients suspected to be associated with hepatotoxicity in order to establish clinical specificity when determining if a relationship exists between an adverse event and the consumption of these agents. We agree that identification methods are crucial to product safety and the industry continues to develop and validate identification methods for many commercialized ingredients. Full-Text PDF Open AccessReply to: “Herbal medicine hepatotoxicity revisited”Journal of HepatologyVol. 56Issue 2PreviewThe author’s letter states that the mention of some instances of herbal medicines is immaterial in the context of the article’s discussion. We do not agree with this view for the following reasons. Full-Text PDF Open Access Hepatic impairment resulting from the use of conventional drugs is widely acknowledged, but there is less awareness of the potential hepatotoxicity of alternative medicines such as herbal preparations [[1]Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar]. The increasing attraction for herbals medicines is partly explained by the return to natural products occurring along with the ecological movement in industrialized countries [[1]Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar]. It is also related to the limited efficacy or the important side effects of treatments of various chronic diseases [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. Several recent studies that focused on the use of herbal medicines in chronic hepatitis C are particularly demonstrative in Western countries [6Detkova Z. Lefebvre A. Bastide C. Peladan N. Pageaux G.P. Blanc P. et al.Herbal medicine consumption in chronic liver diseases and functional intestinal disorders. Prospective study in 526 outpatients.Gastroenterology. 2001; 120: A-228Crossref Google Scholar, 7Seeff LB, Curto TM, Szabo G, Everson GT, Bonkosky HL, Dienstag JL, et al. the HALT-C Trial Group. Herbal product use by persons enrolled in the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology;47:605–612.Google Scholar]. A prospective inquiry carried out in France, based on outpatients seen for chronic liver diseases, has revealed that there was a herbal medicine intake for at least 1 month in 30% of included patients with hepatitis C [[6]Detkova Z. Lefebvre A. Bastide C. Peladan N. Pageaux G.P. Blanc P. et al.Herbal medicine consumption in chronic liver diseases and functional intestinal disorders. Prospective study in 526 outpatients.Gastroenterology. 2001; 120: A-228Crossref Google Scholar]. Similarly, the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial conducted in the USA showed that 21% of enrolled patients had taken herbal medicines before and 23% at the time of inclusion [[7]Seeff LB, Curto TM, Szabo G, Everson GT, Bonkosky HL, Dienstag JL, et al. the HALT-C Trial Group. Herbal product use by persons enrolled in the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology;47:605–612.Google Scholar]. In both studies, the most commonly used herbal compounds were sylimarin and valerian [6Detkova Z. Lefebvre A. Bastide C. Peladan N. Pageaux G.P. Blanc P. et al.Herbal medicine consumption in chronic liver diseases and functional intestinal disorders. Prospective study in 526 outpatients.Gastroenterology. 2001; 120: A-228Crossref Google Scholar, 7Seeff LB, Curto TM, Szabo G, Everson GT, Bonkosky HL, Dienstag JL, et al. the HALT-C Trial Group. Herbal product use by persons enrolled in the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology;47:605–612.Google Scholar]. The use of herbal medicines does not require any medical prescription. Patients may find these products in various stores, some of them being specialized in herbal products but also in pharmacy stores. Furthermore, the possibility to get herbal products via the internet has markedly contributed to the increase in their sales [[4]Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar]. In several areas of the world, particularly in Asia, Africa, and central and South America, the use of herbal medicines is an important part of a traditional medicine exhibiting several advantages, in particular, easy availability and low cost [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. Over the last decades it has become apparent that herbal medicines may cause a very large spectrum of liver injury, affecting all cells present in the liver and biliary tree, and ranging from mild asymptomatic liver enzyme elevation to acute hepatitis, chronic hepatitis, cirrhosis, liver failure, acute and chronic cholangitis, macro- and micro-vesicular steatosis, and vascular lesions [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. Furthermore, herbal medicines may produce interactions with liver drug metabolizing enzymes [[2]Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar]. A representative instance is St. John’s Wort (Hypericum perforatum L.) which can modify cytochrome P450 3A isoenzyme activity and, thereby, the metabolism of several immunosuppressive agents such as cyclosporine and tacrolimus [[2]Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar]. To avoid these side effects, utilization of “natural medicine” is increasingly controlled in many countries. Marketing authorization has been given for plants considered efficient and innocuous. Indeed, in most cases, the efficiency and safety have been based more on a reputation acquired over the centuries rather than on controlled trials and toxicity studies [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. Hepatotoxicity of herbal remedies is particularly difficult to demonstrate [[8]Larrey D. Drug-induced liver diseases.J Hepatol. 2000; 32: 77-88Abstract Full Text PDF PubMed Google Scholar]. Indeed, in addition to the usual difficulties found while assessing the relationship between an adverse event and the intake of a drug largely caused by the absence of clinical specificity [[8]Larrey D. Drug-induced liver diseases.J Hepatol. 2000; 32: 77-88Abstract Full Text PDF PubMed Google Scholar], there may be difficulties with frequent auto-medication and the reputation of safety so that the patient often forgets to mention herbal medicine ingestion to the physician [4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar, 8Larrey D. Drug-induced liver diseases.J Hepatol. 2000; 32: 77-88Abstract Full Text PDF PubMed Google Scholar]. In addition, there are specific risks contributing to the hepatotoxicity of herbal remedies [[4]Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar]: misidentification of the plant, selection of a wrong part of the medicinal plant, inadequate storage modifying the native product, adulteration during processing, and mislabeling of the final product [[4]Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar]. For instance, some Asian preparations contain more than 10 different plants [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. Another instance is Herbalife® hepatotoxicity recently reported in Israel and Switzerland [9Elinav 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, 10Schoepfer 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 (146) Google Scholar]. Interestingly, it seems that the complex composition of the products marketed under this brand name in these two countries was not exactly similar [9Elinav 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, 10Schoepfer 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 (146) Google Scholar]. Another difficulty is that the real composition of the herbal preparation may remain unclear [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. A safe herbal product may be contaminated by toxic compounds leading to hepatotoxicity. This is the case with heavy metals, pesticides, herbicides, microorganisms, and even classical pharmaceutical products [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. A recent illustration is a product marketed in Scandinavian countries under the brand name Fortodol®, normally containing Curcuma longa (turmeric) as a gentle pain killer [[11]www.lakemedelsverket.se.Google Scholar]. The occurrence of several cases of liver injury led to analyze the composition of this apparently innocuous product. It turned out that it also contained nimesulide, a non-steroidal anti-inflammatory compound, well documented to cause acute liver injury [[11]www.lakemedelsverket.se.Google Scholar]. To date, around fifty medicinal preparations have been reported to be toxic to the liver [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. The degree of evidence for toxicity is as variable as is for classical pharmaceutical agents. Herbal medicines with the highest level of evidence for hepatotoxicity are plants containing pyrrolizidine alkaloids, germander (Teucrium chamaedris), Atractylis gummifera, plants containing pennyroyal oil (Mentha pulegium, Hedeoma pulegioides), great celandine (Chelidonium majus), kava–kava (Piper methysticum), and several Asian medicinal preparations [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. Other compounds for which a fair level of evidence exists for hepatotoxicity are chaparral leaf (Larrea tridentata), senna (Cassia angustifolia), hydroalcoholic extracts of green tea and Herbalife® [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar, 9Elinav 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, 10Schoepfer 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 (146) Google Scholar]. Pyrrolizidine alkaloids make up a remarkable illustration of the difficulties encountered with herbal medicine hepatotoxicity and the particular need to have biomarkers to overcome them. These alkaloids are found in more than 6000 plants worldwide [[12]Fu P.P. Xia Q.S. Lin G. Chou M.W. Pyrrolizidine alkaloids-genotoxicity, metabolism enzymes, metabolic activation, and mechanisms.Drug Metab Rev. 2004; 36: 1-55Crossref PubMed Scopus (469) Google Scholar]. The main implicated species are: Heliotroprium, Senecio, Crotalaria [[17]Larrey D. Vial T. Pawels A. Castot A. Biour M. David M. et al.Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity.Ann Intern Med. 1992; 117: 129-132Crossref PubMed Scopus (268) Google Scholar], and Symphytum (Comfrey) [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar, 12Fu P.P. Xia Q.S. Lin G. Chou M.W. Pyrrolizidine alkaloids-genotoxicity, metabolism enzymes, metabolic activation, and mechanisms.Drug Metab Rev. 2004; 36: 1-55Crossref PubMed Scopus (469) Google Scholar] but also Gynura segetum as illustrated in the report by Lin et al. in this issue of the Journal [[13]Lin G. Wang J.Y. Li N. Gao H. Ji Y. Zhang F. et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.J Hepatol. 2010; 54: 666-673Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. Pyrrolizidine poisoning is endemic in areas such as Africa and Jamaica, where toxic alkaloids are ingested as infusions, herbal teas, decoctions, or used as an enema [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. Contamination of four by plants containing pyrrolizidine alkaloids has also caused epidemic intoxications in India and Afghanistan [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. Pyrrolizidine alkaloids are also a concern for Chinese herbal medicines [[13]Lin G. Wang J.Y. Li N. Gao H. Ji Y. Zhang F. et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.J Hepatol. 2010; 54: 666-673Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. In the Journal, Lin et al. report at least 51 cases with “Tusanqi” traditional preparation [[13]Lin G. Wang J.Y. Li N. Gao H. Ji Y. Zhang F. et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.J Hepatol. 2010; 54: 666-673Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar] and stress that there are probably many more cases [[13]Lin G. Wang J.Y. Li N. Gao H. Ji Y. Zhang F. et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.J Hepatol. 2010; 54: 666-673Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. Hepatotoxicity occurs because of the misuse of G. segetum instead of non-toxic plants in the preparation. The main liver injury induced by pyrrolizidine alkaloids is veno-occlusive disease, the so-called hepatic sinusoidal obstruction syndrome (HSOS) [2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar, 14Helmy A. Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome.Aliment Pharm Ther. 2004; 23: 11-25Crossref Scopus (134) Google Scholar, 15Dai N. Yu Y.C. Ren T.H. Wu J.G. Jiang Y. Shen L.G. et al.Gynura root induces hepatic veno-occlusive disease; a case report and review of the literature.World J Gastroenterol. 2007; 13: 1628-1631Crossref PubMed Scopus (73) Google Scholar]. Pyrrolizidine alkaloids account for more than 8000 cases of HSOS worldwide and make up one of the major causes of this syndrome [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar, 14Helmy A. Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome.Aliment Pharm Ther. 2004; 23: 11-25Crossref Scopus (134) Google Scholar, 15Dai N. Yu Y.C. Ren T.H. Wu J.G. Jiang Y. Shen L.G. et al.Gynura root induces hepatic veno-occlusive disease; a case report and review of the literature.World J Gastroenterol. 2007; 13: 1628-1631Crossref PubMed Scopus (73) Google Scholar]. HSOS brings about hepatic congestion, which may lead to parenchymal necrosis. In some cases, fibrosis and even cirrhosis may develop. Different clinical subtypes have been described [4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 14Helmy A. Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome.Aliment Pharm Ther. 2004; 23: 11-25Crossref Scopus (134) Google Scholar, 15Dai N. Yu Y.C. Ren T.H. Wu J.G. Jiang Y. Shen L.G. et al.Gynura root induces hepatic veno-occlusive disease; a case report and review of the literature.World J Gastroenterol. 2007; 13: 1628-1631Crossref PubMed Scopus (73) Google Scholar]. The acute form is characterized by markedly increased serum aminotransferase activities. When lesions are extensive, hepatic failure may occur, leading to death [4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 14Helmy A. Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome.Aliment Pharm Ther. 2004; 23: 11-25Crossref Scopus (134) Google Scholar, 15Dai N. Yu Y.C. Ren T.H. Wu J.G. Jiang Y. Shen L.G. et al.Gynura root induces hepatic veno-occlusive disease; a case report and review of the literature.World J Gastroenterol. 2007; 13: 1628-1631Crossref PubMed Scopus (73) Google Scholar]. In contrast, the chronic form insidiously develops and may mimic cirrhosis. One fatal case of veno-occlusive disease has been described in a newborn infant whose mother had been exposed to a plant containing pyrrolizidine alkaloids during pregnancy [[16]Ridker P.M. Mc Dermott V. Comfrey herb tea and hepatic veno-occlusive disease.Lancet. 1989; 7: 657-658Abstract Scopus (70) Google Scholar]. Hepatotoxicity of pyrrolizidine alkaloids is reproducible and dose-related in laboratory animals [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. It has been related to the biotransformation of unsaturated alkaloids into unstable, toxic metabolites, probably pyrrolic derivatives, by cytochrome P-450 leading mainly to lesions of endothelial cells and to a lesser extent of hepatocytes [1Larrey D. Hepatotoxicity of herbal remedies.J Hepatol. 1997; 26: 47-51Abstract Full Text PDF PubMed Google Scholar, 2Stedman C. Herbal hepatotoxicity.Semin Liver Dis. 2002; 22: 195-206Crossref PubMed Scopus (205) Google Scholar, 3Stickel F. Patsenker E. Schuppan D. Herbal hepatotoxicity.J Hepatol. 2005; 43: 901-910Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 5Liu L.U. Schiano T.D. Hepatotoxicity for herbal medicines, vitamins, and natural hepatotoxins.in: Kaplowitz N. Deleve L.D. Drug-Induced liver disease. Marcel Dekker, New York, Basel2007: 733-754Google Scholar]. Up to now, however, there was no means for providing direct evidence of the direct role of pyrrolizidine alkaloids in a clinical situation. Lin et al. have reached this new step [[13]Lin G. Wang J.Y. Li N. Gao H. Ji Y. Zhang F. et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.J Hepatol. 2010; 54: 666-673Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. Indeed, they have constructed a sensitive and specific assay enabling for the detection of a reactive pyrrole–protein adduct in serum [[13]Lin G. Wang J.Y. Li N. Gao H. Ji Y. Zhang F. et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.J Hepatol. 2010; 54: 666-673Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. This assay was used to show the presence of the reactive adduct directly in the serum of a patient with HSOS related to the Tusanqi preparation made erroneously with G. segetum instead of Sedum aizoon [[13]Lin G. Wang J.Y. Li N. Gao H. Ji Y. Zhang F. et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.J Hepatol. 2010; 54: 666-673Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. In addition, an animal study further showed the good correlation of liver injury with the ingestion of G. segetum [[13]Lin G. Wang J.Y. Li N. Gao H. Ji Y. Zhang F. et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.J Hepatol. 2010; 54: 666-673Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. This is the second instance in which a biomarker provides evidence for the role of a plant in a patient with liver injury. The other example of a diagnostic biomarker but with less direct evidence is germander (T. chamaedris) which has been responsible for numerous cases of liver injury [4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 17Larrey D. Vial T. Pawels A. Castot A. Biour M. David M. et al.Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity.Ann Intern Med. 1992; 117: 129-132Crossref PubMed Scopus (268) Google Scholar]. Germander hepatotoxicity has been reproduced in mice and is dose-dependent [[4]Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar]. The chemical composition of germander comprises furan-containing neoclerodane diterpenoids. Germander components are oxidized by cytochrome P4503A into reactive metabolites [[18]Lekehal M. Pessayre D. Lereau J.M. Moulis C. Fouraste F. Hepatotoxicity of the herbal medicine germander. Metabolic activation of its furano diterpenoids by cytochrome P450 3A depletes cytoskeleton-associated protein thiols and forms plasma membrane blebs in rat hepatocytes.Hepatology. 1996; 24: 212-218Crossref PubMed Google Scholar]. These reactive metabolites deplete glutathione and cytoskeleton-associated protein thiols, form plasma membrane blebs, and cause apoptosis contributing to liver cell death [4Larrey D. Complementary and alternative medicine hepatotoxicity. Permanyer publications. Hepatotoxicity.Ed Raul J Andrade. 2007; : 125-135Google Scholar, 20Fau D. Lekehal M. Farrell G. Moreau A. Moulis C. Feldmann G. et al.Diterpenoids from germander, an herbal medicine, induce apoptosis in isolated rat hepatocytes.Gastroenterology. 1997; 113: 1334-1336Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar]. Finally, reactive metabolites could trigger hepatotoxicity through an immunoallergic reaction [[20]De Berardinis V. Moulis C. Maurice M. Beaune P. Pessayre D. Poupon D. et al.Human microsomal epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes.Mol Pharmacol. 2000; 58: 542-551PubMed Google Scholar]. Indeed, anti-microsomal epoxide hydrolase autoantibodies have been found in the sera of patients who drank germander teas for a long period of time [[20]De Berardinis V. Moulis C. Maurice M. Beaune P. Pessayre D. Poupon D. et al.Human microsomal epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes.Mol Pharmacol. 2000; 58: 542-551PubMed Google Scholar]. This serum antibody makes up a biomarker allowing for the correlation of cases of liver injury with germander ingestion. Herbal medicines are increasingly recognized as causes of liver injury. Advances in the understanding of pathogenesis are needed to improve herbal medicine safety. The development of specific biomarkers is a key step to allow more accurate diagnoses and gain crucial information on complex medicinal preparation.