Liver International ISSN 1478-3223

CLINICAL STUDIES

Herbal hepatotoxicity: a tabular compilation of reported cases

Rolf Teschke1*, Albrecht Wolff2, Christian Frenzel3, Johannes Schulze4 and Axel Eickhoff1
1 Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt/Main, Germany 2 Department of Internal Medicine II, Division of Gastroenterology, Hepatology and Infectious Diseases, Friedrich Schiller University Jena, Germany 3 Department of Medicine I, University Medical Center Hamburg Eppendorf, Germany 4 Ofce of the Dean, Medical Faculty of the Goethe University Frankfurt/Main, Germany

Keywords Herb-induced liver injury Herbal hepatotoxicity Herbal medicine Herbs

Correspondence Rolf Teschke, M.D., Professor of Medicine, Department of Internal Medicine II, Klinikum Hanau, Academic Teaching Hospital of the Goethe University of Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany Tel: +49-6181/21859 Fax: +49-6181/2964211 e-mail: rolf.teschke@gmx.de Received 18 May 2012 Accepted 23 July 2012 DOI:10.1111/j.1478-3231.2012.02864.x

Abstract Background: Herbal hepatotoxicity is a eld that has rapidly grown over the last few years along with increased use of herbal products worldwide. Aims: To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity. Methods: A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity. Results: A total of 185 publications were identied and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specic ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan. In many other publications, however, causality was not properly evaluated by a liver-specic and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences). Conclusions: This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future.

Research in herbal hepatotoxicity, synonymous herbinduced liver injury, is a eld that has grown rapidly over the last few years along with higher use of herbal products affecting patients worldwide. It represents compelling challenges, as recently discussed in excellent review articles (13). Issues of herbs and herbal hepatotoxicity relate to production factors, i.e. the quality of herbal products, risks of impurities and adulterants, use of the correct plant species and plant part, and to patient factors, i.e. comedication, co- or multimorbidity, alternative diagnoses and other confounding variables in cases of suspected herbal hepatotoxicity. Publications also suffer from poor quality of case data and improper causality assessment of an individual herbal product with its multiple components. It appears, therefore, that herbal hepatotoxicity as a complex disease requires a systematic compilation of all herbal products primarily
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implicated in toxic liver injury. At present, reported cases of hepatotoxicity for individual herbal products are distributed over multiple publications, lacking a systematic overview. This analysis presents case publications and regulatory spontaneous reports of herbal hepatotoxicity as tabular compilation and provides details of herbs and herbal products with their synonyms, botanical names and ingredients. The compilation also contains all references with authors that can be matched to each herbal product and to its effect on the liver.
Literature search and identication of reports

For a selective literature search, PubMed was searched using the terms herbal hepatotoxicity, herb-induced liver injury, drug hepatotoxicity and drug-induced liver

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injury. From each search, the rst 100 publications being the most recent publications were analysed for subject matter, data quality and overall suitability. Citations in retrieved publications were searched for other yet unidentied case reports. The search primarily focused on publications in English, but few reports in other languages were also considered; the evaluation based on our private archives initially included 215 publications with 26 different herbs prior to critical assessment.
Reported cases of herbal hepatotoxicity as tabular compilation

be considered in evaluating related hepatotoxicity causality. Under clinical aspects, some non-herbal but nature-related products with reported hepatotoxicity are of relevance: Artemisin as a chemical product derived from Artemisia annua and in use for malaria treatment (190); usnic acid derived from Usnea Dasypoga and used as slimming aids such as LipoKinetix and UCP-1 (191194); Himematsutake, synonym for Agaricus blazei (195); death cap, synonym for Amanita phalloides (172); vitamin A overdose (172); Aatoxins (172); glucosamine containing products (196198); and anecdotically carp juice (199).
Causality attribution

From overall 185 publications, 60 different herbs, herbal drugs and herbal supplements were identied as being linked to hepatotoxicity (Table 1) (4189). Table 1 summarizes these herbs and herbal products in alphabetical order sorted by common herb names or names of herbal products, with details for synonyms, botanical names and identied chemical ingredients (Table 1). It contains original case reports and spontaneous reports, rarely also a review article or a critical commentary. References are cited by author(s) and year of publication, allowing initial information for number and time frame of publication. In the years 19761989, the annual number of publications of herbal hepatotoxicity was fairly stable and ranged from 0 to 4 per year (average 1.7). Between 1990 and 1999, the annual publication number rose to 28 (average 4.2), with a further increase between 2000 and 2009 to 214 publications/year (average 9.9). Corresponding data for 2010 and 2011 were 12 and 10 publications, respectively, with six publications in the rst 4 months of 2012. Over the past years, therefore, an increase in publications is evident. Table 1 and the details derived from the analysed publications (4189) illustrate the complexity of herbal products and the challenging facets of their toxicity. For a classical botanical description of a herb implicated in liver injury, clear denitions of plant family, subfamily, species, subspecies and variety are required. However, the complete information was rarely provided by any publication (4189), therefore data on plant identication was not further analysed (Table 1). Similarly, data of the plant part used, solvent and/or solubilizer are also lacking for most herbal products. These parameters likely cause batchto-batch, product-to-product and variety-to-variety variability in herbal products. Resulting problems can be expected to be larger for herbal supplements lacking regulatory surveillance than for herbal drugs approved by regulatory agencies. Other open questions remain with respect to impurities, plant misidentications and adulterants, which are rarely considered in the publications (4189). Consequently, quality aspects of herbs and herbal products should

A key question in herbal hepatotoxicity is the appropriate method of causality attribution for suspected cases, in addition to quality issues of herbal products. Quality challenges emerge in data acquisition, documentation and presentation, with shortcomings evident in numerous cases publications (Table 1) (4189). In varying degrees, data are inappropriate or lacking for the type of herbal product, indication and duration of intake, daily dose, appearance of rst symptoms and liver value increase, dechallenge details, risk factors, comedication, previous and concomitant general diseases and liver diseases, and exclusion of alternative diagnoses. Therefore, initial causality attribution for published cases and reported spontaneous cases may represent misclassication and/or over-reporting that needs re-evaluation on a case basis. Although poor quality of case data and confounding variables are challenging, causality was veried with a positive re-exposure for some herbs. Among these are Chaparral (21), Chinese herbal mixture (26, 28, 29), Germander (41, 45), Greater Celandine (6062), green tea (76), few Herbalife products (91, 92), Ho Shou Wu (102), Jin Bu Huan (112, 113), Kava (48), Ma Huang (147), Mistletoe (152), Senna (177), Syo Saiko To (188) and Venencapsan (185). In the absence of a re-exposure, with a sophisticated causality assessment a probable causality may be established, as shown for Ayurvedic herbs (9). Conversely, causality was unlikely for Actaea cimicifuga (79, 200), Pelargonium sidoides (201, 202) and Hypericum perforatum, synonym for St Johns Wort, because hepatotoxicity was likely caused by comedicated pegylated interferon-a (203). For causality assessment of adverse drug reactions (ADRs), different algorithms are applicable depending on whether hepatic or non-hepatic ADRs are to be evaluated (Table 2) (139, 204209). The most appropriate causality assessment method for suspected herbal hepatotoxicity is the scale of CIOMS (Council for International Organizations of Medical Sciences) in its original form (204, 205) or its update (206). The CIOMS scale is structured, quantitative, liver-specic and validated for hepatotoxicity, thus fullling all four essential criteria (Table 2). CIOMS scale-based assessment was
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Herbal hepatotoxicity: a tabular compilation

Table 1. Compilation of herbs and herbal products with reported hepatotoxicity Search items Acacia catechu Aloe Botanical names, ingredients, references see Ayurvedic herbs Aloe perfoliata var. vera, see also Onshido Rabe et al., 2005 (4), Kanat et al., 2006 (5), Bottenberg et al., 2007 (6), Yang et al., 2010 (7) see Hydroxycut see Bai Fang Maranta aruninacea or Tacca leontopetaloides Kim et al., 2009 (8) see Distaff thistle Psoralea corylifolia, Acacia catechu, Eclipta alba or Bacopa monnieri, Vetivexia zizaniodis Teschke and Bahre, 2009 (9) Psoralea corylifolia, see also Ayurvedic herbs Nam et al., 2005 (10) see Ayurvedic herbs Angelica sinensis, Cyperus rotundus, Ligusticum wallichii, Paeonia alba, Rehmannia glutinosa, Ginseng Estes et al., 2003 (11) Dysosma pleianthum Kao et al., 1992 (12) Psoralea corylifolia Hwang et al., 2001 (13), Nam et al., 2005 (10), Cheung et al. 2010 (14) see Pro-Lean see Dai Saiko To, see Xiao Chai Hu Tang Crotalaria species Smith and Culvenor, 1981 (15) see Impila see Chaso, see green tea, see Hydroxycut, see Onshido, see X-elles Rhamnus purshianus Nadir et al., 2000 (16) see Senna see Chaso see Gotu Kola, see Pro-Lean see Saw Palmetto Larrea tridentata, Larrea divariatica Katz and Saibil, 1990 (17), Centers of Disease, 1992 (18), Smith and Desmond, 1993 (19), Alderman et al., 1994 (20), Batchelor et al., 1995 (21), Gordon et al., 1995 (22), Sheikh et al., 1997 (23), Haller et al., 2002 (24), Estes et al., 2003 (11) Camellia sinensis, Cassia tora, Lotus, Lycium barbarum, Crataegus, Chrysanthenum morifolium Ramat., N-nitroso-fenuramine Adachi et al., 2003 (25) see Greater Celandine, see Lycopodium similiaplex Unknown or up to 12 ingredients Davies et al., 1990 (26), Graham-Brown, 1992 (27), Perharic-Walton and Murray, 1992 (28), Kane et al., 1995 (29), Sanders et al., 1995 (30), Yoshida et al., 1996 (31) see Kambala tea see Oxeye Daisy see Chaso see X-elles

Amorphophallus Konjac Angelica sinensis Arrowroot Atractylis gummifera Ayurvedic herbs

Babchi Bacopa monnieri Bai Fang

Bajiaolian Boh Gol Zhee syn. Bu Ku Zi Boronia Sm. Bupleurum falcatum Bush tea Callilepis laureola Camellia sinensis Cascara sagrada Cassia angustifolia Cassia tora Centella asiatica Chamaerops humilis Chaparral syn. Creosot

Chaso

Chelidonium majus Chinese herbs

Chlorophora species Chrysanthemum leucanthemum Chrysanthenum morifolium Ramat. Citrus aurantium

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Herbal hepatotoxicity: a tabular compilation Table 1. (continued) Search items Citrus paradisum Cyrana scolymus Cola nitida Coltsfoot Comfrey Botanical names, ingredients, references

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Compositae species Corydalis species Crataegus Creosot Crotalaria species Cyperus Cyperus rotundus Da Chai Hu Tang Dai Saiko To syn. Da Chai Hu Tang

Distaff thistle Eclipta alba Emblica ofcinalis Ephedra species Exilis

Fallopia multiora Foeniculum amare Fucus vesiculosus Garcinia cambogia Germander

Ginkgo biloba Ginseng Glycyrrhiza glabra Gotu Kola Greater Celandine

see X-elles see X-elles see Pro-Lean Tussilago farfara Roulet et al., 1988 (32) Symphytum ofcinale, Symphytum asperum, Symphytum uplandicum Ridker et al., 1985 (33), Weston et al., 1987 (34), Bach et al., 1989 (35), Ridker and McDermott, 1989 (36), Miskelly and Goodyer,1992 (37) see Indian herbs see Jin Bu Huan see Chaso, see Onshido see Chaparral see Bush tea, see Rattlebox see Pro-Lean see Bai Fang see Dai Saiko To Bupleurum falcatum, Pinella tuber, Zingiber ofcinale, Ginseng, Scutellaria, Zizyphus jujuba, Glycyrrhiza glabra Kaniyama et al., 1997 (38) Atractylis gummifera Georgia, 1988 (39) see Ayurvedic herbs see Isabgol Ephedra californica, Ephedra sinica, see also Ma Huang Estes et al., 2003 (11) Garcinia cambogia, Gymnema sylvestre, White kidney bean, Camellia sinensis, L-Carnitine fumarate, Calcium, Magnesium chelate, Chromium chelate, Conjugated linoleic acid, Chitosan McDonnell et al., 2009 (40) see Pro-Lean see Herbalife see Pro-Lean see Exilis, see Herbalife, see Hydroxycut Teucrium chamaedrys, Teucrium polium Larrey et al., 1992 (41), Mostefa-Kara et al., 1992 (42), Dao et al., 1993 (43), Mattei et al., 1995 (44), Laliberte and Villeneuve, 1996 (45), Starakis et al., 2006 (46) see Pro-Lean see Bai Fang, see Dai Saiko To, see Pro-Lean, see Xiao Chai Hu Tan see Dai Saiko To, see Xiao Chai Hu Tang Centella asiatica Jorge and Jorge, 2005 (47) Chelidonium majus, see also Lycopodium similiaplex Strahl et al., 1998 (48), Greving et al., 1998 (49), Benninger et al., 1999 (50), Crijns et al., 2002 (51), Hardeman et al., 2003 (52), Stickel et al., 2003 (53), BfArM, 2005 (54), Rifai et al., 2006 (55), Conti et al., 2008 (56), Moro et al., 2009 (57), Tarantino et al., 2009 (58), EMA, 2010 (59), Teschke et al., 2011, 2012 (6062)

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Teschke et al. Table 1. (continued) Search items Green tea

Herbal hepatotoxicity: a tabular compilation

Botanical names, ingredients, references Camellia sinensis Duenas Sadornil et al., 2004 (63), Garcia-Moran et al., 2004 (64), Abu el Wafa et al., 2005 (65), Gloro et al., 2005 (66), Bonkovsky, 2006 (67), Javaid and Bonkovsky, 2006 (68), Jimemez-Saenz and Martinez-Sanchez, 2006 (69), Matinez-Sierra and Rendon Unceta, 2006 (70), Molinari et al., 2006 (71), Bjornsson and Olson, 2007 (72), Frederico et al. 2007 (73), Sarma et al., 2008 (74), Liss and Lewis, 2008 (75), Mazzanti et al., 2009 (76), Verheist et al., 2009 (77), Rohde et al., 2011 (78), Teschke et al., 2011, 2012 (79,80), Teschke and Schulze, 2012 (81) Senecio longilobus, Senecio species Stillman et al., 1977 (82), Fox et al., 1978 (83) Paullinia cupana Dara et al., 2008 (84) see Exilis , see Hydroxycut see Onshido see Crataegus see Pennyroyal Heliotropium eichwaldii, Heliotropium species Mohabbat et al., 1976 (85), Datta et al. 1978 (86), Tandon et al., 2008 (87), Kakar et al., 2010 (88) Solidago gigantea, Ilex paraguariensis, Petroselinum crispum, Garcinia cambogia, Spiraea, Matricaria chamomilla, Liquiritia, Foeniculum amare, Humulus lupulus, Chromium and numerous other ingredients Hoffmann et al., 2005 (89), Duque et al., 2007 (90), Elinav et al., 2007 (91), Schoepfer et al., 2007 (92), Chao et al., 2008 (93), Manso et al., 2008 (94), Stickel et al., 2009 (95), Johansson et al., 2010 (96), Chen et al., 2010 (97), Appelhans et al., 2011 (98), Manso et al., 2011 (99), Appelhans et al., 2012 (100), Manso, 2012 (101) see Venencapsan, see Venoplant Polygonum multiorum Bae et al., 2010 (102) Camellia sinensis, Gymnema sylvestre, Amorphophallus Konjac, Paullinia cupana, Garcinia cambogia, Caffeine, a-Lipoic acid, L-Carnitine, Calcium, Potassium, Chromium Stevens et al. 2005 (103), Jones and Andrews, 2007 (104), Dara et al., 2008 (84), Shim and Saab, 2009 (105), Chen et al., 2010 (97), Fong et al., 2010 (106) see Herbalife see Herbalife, see Mate Callilepis laureola Wainwright et al., 1977 (107), Wainwright and Schonland, 1977 (108), Popat et al., 2001 (109) Compositae species Kumana et al., 1983 (110) see Kambala tea Plantago ovata, Emblica ofcinalis Fraquelli et al., 2000 (111) Lycopodium serratum, Stephania species, Corydalis species Woolf et al., 1994 (112), Horowitz et al., 1996 (113), Picciotti et al., 1998 (114) Chlorophora excelsa, Chlorophora regia Gunawan and Kaplowitz, 2004 (115)

Groundsel syn. Senecio Guarana Gymnema sylvestre Gynostemma pentaphyllum makino Hawthorn Hedeoma pulegoides Heliotropium

Herbalife

Horse chestnut Ho Shou Wu Hydroxycut

Humulus lupulus Ilex paraguariensis Impila

Indian herbs Iroko Isabgol Jin Bu Huan Kambala tea syn. Iroko

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Herbal hepatotoxicity: a tabular compilation Table 1. (continued) Search items Kava Botanical names, ingredients, references Piper methysticum Strahl et al., 1998 (48), Brauer et al., 2001 (116), Escher et al., 2001 (117), Kraft et al., 2001 (118), Russmann et al., 2001 (119), Sa et al., 2001 (120), BfArM, 2002 (121), Bujanda et al., 2002 (122), Denham et al., 2002 (123), Weise et al., 2002 (124), Teschke, 2002 (125), Estes et al., 2003 (11), Gow et al., 2003 (126), Humberston et al., 2003 (127), Russmann et al., 2003 (128), Schulze et al., 2003 (129), Stickel et al., 2003 (130), Teschke, 2003 (131), Teschke et al., 2003 (132), Schmidt et al., 2005 (133), WHO, 2007 (134), Teschke et al., 2008 (135,136), Christl et al., 2009 (137), Teschke and Wolff, 2009, 2011 (138,139), Teschke, 2010 (140,141), Teschke and Schulze (2010) 142), Teschke and Lebot, 2011 (143), Rowe and Ramzan, 2012 (144), Teschke et al., 2012 (145,146) see Chaparral see Chaparral see Oxeye Daisy see Bai Fang see Herbalife see Chaso see Chaso see Jin Bu Huan, see Lycopodium similiaplex, see Wolfs foot clubmass Lycopodium serratum, Chelidonium majus Conti et al., 2008 (56) Ephedra species, see also Pro-Lean Nadir et al., 1996 (147), Borum, 2001 (148), Estes et al., 2003 (11) see Arrowroot Ilex paraguariensis McGee et al., 1976 (149) see Herbalife see Pennyroyal Viscum album Harvey and Colin-Jones, 1981 (150), Hyde, 1981 (151), Colin-Jones and Harvey, 1982 (152), Farnsworth and Loub, 1982 (153), Stirpe, 1983 (154) see Red Yeast Rice see Noni see Oleander Morinda citrifolium Millonig et al., 2005 (155), Stadlbauer et al., 2005 (156), Yuce et al., 2006 (157), Lopez-Cepero Andrada et al., 2007 (158), Stadlbauer et al., 2008 (159), Yu et al., 2011 (160) Nerium oleander Altan et al., 2009 (161) Aloe, Crataegus, Camellia sinensis, Gynostemma pentaphyllum makino, Raphanus, N-nitroso-fenuramine Adachi et al., 2003 (25) Leucanthemum vulgare, Chrysanthemum leucanthemum Mokhobo, 1976 (162) see Bai Fang see Guarana, see Hydroxycut, see Pro-Lean Mentha pulegium, Hedeoma pulegoides Vallance, 1955 (163), Sullivan et al., 1979 (164), Anderson et al., 1996 (165), Bakerink et al., 1996 (166)

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Larrea divariatica Larrea tridentata Leucanthemum vulgare Ligusticum wallichii Liquiritia Lotus Lycium barbarum Lycopodium serratum Lycopodium similiaplex Ma Huang

Maranta aruninacea Mate Matricaria chamomilla Mentha pulegium Mistletoe

Monascus purpureus Morinda citrifolium Nerium oleander Noni

Oleander Onshido

Oxeye Daisy Paeonia alba Paullinia cupana Pennyroyal

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Teschke et al. Table 1. (continued) Search items Petroselinum crispum Petroselinum sativum Pinellia tuber Piper methysticum Phaseolus vulgaris Plantago ovata Polygonum multiorum Pro-Lean

Herbal hepatotoxicity: a tabular compilation

Botanical names, ingredients, references see Herbalife see X-elles see Dai Saiko To, see Xiao Chai Hu Tang see Kava see Exilis see Isabgol see Ho Shou Wu, see Shen Min, see Shou Wu Pian Ma Huang, Paullinia cupana, Cola nitida, Centella asiatica, Salix alba,Ginkgo biloba, Fucus vesiculosus, Boronia Sm., Ginseng, Fallopia multiora, Cyperus, Bee pollen, Caffeine, L-Tyrosine, Chromium, Vanadium, Magnesiumsalicylat, Folsaure, Vitamin B12 and various other ingredients Joshi et al., 2007 (167) see Ayurvedic herbs, see Babchi, see Boh Gol Zhee see Bush tea, see Comfrey, see Groundsel, see Heliotropium species, see Indian herbs, see Mate, see Rattlebox see Onshido Crotalaria species Tandon et al., 1976 (168,169) Monascus purpureus Roselle et al., 2008 (170) see Bai Fang see Cascara sagrada see Pro-Lean Sassafras albidum Larrey, 1997 (171), Zimmerman, 1999 (172) Serenoa serpens, Chamaerops humilis Lapi et al., 2010 (173) see Dai Saiko To, see Skullcap, see Xiao Chai Hu Tang MacGregor et al., 1989 (174), Caldwell et al., 1994 (175), Hullar et al., 1999 (176), Estes et al., 2003 (11) see Stonecrop see Groundsel Cassia angustifolia Beuers et al., 1991 (177), Seybold et al., 2004 (178), Vanderperren et al., 2005 (179) see Saw Palmetto Polygonum multiorum Cardenas et al., 2006 (180) Polygonum multiorum Panis et al., 2005 (181), Jung et al., 2011 (182) Stephania sinica Haller et al., 2002 (24) Scutellaria lateriora, Scutellaria species MacGregor et al., 1989 (174), Caldwell et al., 1994 (175), Hullar et al., 1999 (176), Estes et al., 2003 (11) see Herbalife see Herbalife see Shu Ling see Jin Bu Huan Sedum aizoon Wu et al., 2008 (183) see Comfrey see Xiao Chai Hu Tang see Arrowroot see Germander

Psoralea corylifolia Pyrrolizidine alkaloids

Raphanus Rattlebox syn. Crotalaria Red Yeast Rice Rehmannia glutinosa Rhamnus purshianus Salix alba Sassafras Saw Palmetto Scutellaria species

Sedum aizoon Senecio Senna

Serenoa serpens Shen Min Shou Wu Pian Shu Ling Skullcap

Solidago gigantea Spiraea Stephania sinica Stephania species Stonecrop Symphytum Syo Saiko To Tacca leontopetaloides Teucrium

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Herbal hepatotoxicity: a tabular compilation Table 1. (continued) Search items Tussilago farfara Valerian Valeriana ofcinalis Venencapsan Botanical names, ingredients, references see Coltsfoot Valeriana ofcinalis MacGregor et al., 1989 (174), Mennecier et al., 1999 (184) see Valerian Aesculus hippocastanum, Chelidonium majus, Melilotus ofcinalis, Milfoil, Silybum Adans., Taraxacum ofcinale De Smet et al., 1996 (185) Aesculus hippocastanum Takegoshi et al., 1986 (186) see Ayurvedic herbs see Mistletoe Lycopodium serratum Woolf et al., 1994 (112), Horowitz et al., 1996 (113), Conti et al., 2008 (56) Petroselinum sativum, Citrus aurantium, Citrus paradisum, Cyrana scolymus, Camellia sinensis Mathieu et al., 2005 (187) Bupleurum falcatum, Pinellia tuber, Zingiber ofcinale, Ginseng, Scutellaria, Zizyphus jujuba, Glycyrrhiza glabra Itoh et al., 1995 (188), Hsu et al., 2005 (189) see Dai Saiko To, see Xiao Chai Hu Tang see Dai Saiko To, see Xiao Chai Hu Tang

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Venoplant Vetivexia zizaniodis Viscum album Wolfs foot clubmass X-elles

Xiao Chai Hu Tang syn. Syo Xiao Hu Tang

Zingiber ofcinale Zizyphus jujuba

Data are retrieved from a selective literature search for selective reports of herbs and herbal products with hepatotoxicity. In numerous cases, causality was proposed, but not necessarily established and open for discussion. Regarding Herbalife, referenced reports mentioned few different products with numerous poorly dened ingredients and not yet established single culprit(s).

Table 2. Qualifying items of causality assessment methods Qualifying items Application Hepatic ADRs Non-hepatic ADRs Specic criteria Structured Quantitative Liver-specic Hepatotoxicity-validated CIOMS scale + + + + + Naranjo scale + + + WHO scale + + Ad hoc approach +

Compilation of details as discussed previously (7981,139) and derived from reports of the scale of CIOMS (Council for International Organizations of Medical Sciences) referring to both the original scale (204,205) and its update (206), the Naranjo scale (207), the WHO scale (208) and the ad hoc approach (209). The symbol + denotes that the specic criterion is fullled, and the symbol shows lack of this particular criterion. Abbreviation for ADRs: adverse drug reactions.

associated with a good validation regarding sensitivity (86%), specicity (89%), positive predictive value (93%) and negative predictive value (78%) (205). Validation for hepatotoxicity was accomplished with hepatotoxicity cases reporting positive re-exposure results (205). Other published methods are the Naranjo scale (207), the WHO global introspection method (208) as the WHO scale in short (139), and the ad hoc

approach (209). None of these methods (139, 207209) is liver-specic and validated for hepatotoxicity (Table 2), and their use for herbal hepatotoxicity assessment has been discouraged (139). Consequently, published causality may be invalid for cases assessed by the Naranjo scale, the WHO scale or the ad hoc approach. Analysing publications of herbal hepatotoxicity (4189), causality assessment was performed mostly with the ad hoc approach, and as shown with some examples rarely with the WHO scale (54, 92, 96, 134), the Naranjo scale (57, 74, 75) or the CIOMS scale (9, 5862, 76, 95, 96, 135, 140). At present, therefore, standard causality assessments of published HILI cases are far from adequate. A discussion of hepatotoxicity attributable to herbs is inextricably linked to the topic of drug-induced liver injury, because there is great overlap in the clinical presentation, spectrum of disease and causality assessment using the CIOMS scale in liver injury cases by herbs and drugs (2). Strengths and weaknesses of the CIOMS scale have been discussed in detail recently (81, 139, 210). Of note, the CIOMS scale takes into account even atypical chronology with +1 point for challenge period of <5 days or >90 days, whereas the period of 590 days renders +2 points (204206). The CIOMS scale is also well adapted for cases in which some data are missing, but under these conditions, the usual points cannot be
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provided because questions of other important diagnoses remained unanswered. It therefore appears reasonable to use the CIOMS scale as the method of choice for assessing causality in suspected cases of herbal hepatotoxicity.
Study limitations

Some publications may have escaped the literature search, resulting in selective retrival and incomplete listing of herbs, herbal drugs, herbal supplements, botanical names, ingredients and references (Table 1). Although 60 different herbal products with hepatotoxicity have been identied from the literature, thorough causality assessment was lacking in the majority of cases. Therefore, some relevant data may not have been published and not been used for causality assessment. Most herbal products are derived from one herb, which by itself consists of dozens of individual chemicals; each of these may be hepatotoxic. The situation is even more complex in herbal mixtures or with additional chemicals as non-herbal ingredients, which also have to be evaluated.
Requirement for novel approaches

New strategies are needed for assessment of herbal hepatotoxicity in upcoming cases. The reporting physician should provide all data relevant for a sophisticated causality assessment and allow for exclusion of alternative diagnoses (206). The use of the CIOMS scale or its update is strongly recommended, because it details item by item that should be presented for reasons of transparency. This will provide a sound basis for independent evaluation of the report when submitted to regulatory agencies and editors.
Conclusions

The tabular compilation presents cases of herbal hepatotoxicity reported in the literature to provide an overview for physicians suspecting liver injury in their patients with liver diseases. New approaches to improve case data quality and causality assessment in future cases are outlined.
Acknowledgement

The authors declare that they have no conict of interest.

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