Traditional Chinese Medicine Induced Liver Injury

Traditional Chinese Medicine (TCM) is popular around the world and encompasses many different practices with particular emphasis on herbal TCM. Using the PubMed database, a literature search was undertaken to assess the extent herbal TCM products exert rare hepatotoxicity. Analysis of reported cases revealed numerous specified herbal TCM products with potential hepatotoxicity. Among these were An Shu Ling, Bai Fang, Bai Xian Pi, Ban Tu Wan, Bo He, Bo Ye Qing Niu Dan, Bofu Tsu Sho San, Boh Gol Zhee, Cang Er Zi, Chai Hu, Chaso, Chi R Yun, Chuan Lian Zi, Ci Wu Jia, Da Chai Hu Tang, Da Huang, Du Huo, Gan Cao, Ge Gen, Ho Shou Wu, Hu Bohe You, Hu Zhang, Huang Qin, Huang Yao Zi, Hwang Geun Cho, Ji Gu Cao, Ji Ji, Ji Xue Cao, Jiguja, Jin Bu Huan, Jue Ming Zi, Kamishoyosan, Kudzu, Lei Gong Teng, Long Dan Xie Gan Tang, Lu Cha, Ma Huang, Mao Guo Tian Jie Cai, Onshido, Polygonum multiflorum, Qian Li Guang, Ren Shen, Sairei To, Shan Chi, Shen Min, Shi Can, Shi Liu Pi, Shou Wu Pian, Tian Hua Fen, White flood, Wu Bei Zi, Xi Shu, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, Zhen Chu Cao, and various unclassified Chinese herbal mixtures. Causality was firmly established for a number of herbal TCM products by a positive reexposure test result, the liver specific scale of CIOMS (Council for International Organizations of Medical Sciences), or both. Otherwise, the quality of case data was mixed, especially regarding analysis of the herb ingredients because of adulteration with synthetic drugs, contamination with heavy metals, and misidentification. In addition, non-herbal TCM elements derived from Agaricus blazei, Agkistrodon, Antelope, Bombyx, Carp, Fish gallbladder, Phellinus, Scolopendra, Scorpio, and Zaocys are also known or potential hepatotoxins. For some patients, the clinical course was severe, with risks for acute liver failure, liver transplantation requirement, and lethality. In conclusion, the use of few herbal TCM products may rarely be associated with hepatotoxicity in some susceptible individuals, necessitating a stringent pretreatment evaluation of the risk/benefit ratio, based on results of multicenter, randomized, double-blind, placebo-controlled clinical trials.


Introduction
Traditional Chinese Medicine (TCM) is one of the oldest healing systems worldwide, originating in the ancient Chinese philosophy and dating back to more than 2,500 years. 1,2 In other Asian countries, TCM became popular and is called Traditional Asian Medicine (TAM) or Traditional Oriental Medicine (TOM), and Kampo Medicine in Japan. Since these practices have been adopted in other parts of the world, technically the topic should be considered to be Traditional Chinese and other Asian Medicine. However, in Western countries, the use of the popular name TCM has remained virtually unchanged without naming each individual country engaged in Traditional Medicine originating from ancient China. The basic principles of TCM are identical or vary only little between the numerous countries. Therefore, the use of TCM as the overall term is warranted and facilitates the discussions around major TCM related issues.
TCM is not a single entity but encompasses many different practices, including herbal medicine, acupuncture, moxibustion, massage, dietary therapy, and physical exercise such as shadow boxing. 1,2 TCM is a fully institutionalized part of China's health care system and is widely used within Western medicine. 2 In 2006, the TCM sector included over 200 million outpatients and around seven million inpatients, accounting for 10-20% of health care in China. 2 Although the exact number of people who use TCM in the United States is unknown, it was estimated in 1997 that some 10,000 practitioners served more than one million patients each year. 1 Despite its popularity, there has been concern about the efficacy and safety of TCM, 1-4 and other issues related to scattered and inappropriate randomized controlled clinical trials of TCM. 2,4,5 Adverse reactions by TCM have been reported, leading to systemic and organ specific health risks 2,6 including the liver. 7,8 These reactions create concern and represent a particular clinical challenge because TCM products are commonly perceived as natural and thereby erroneously as safe.
Hepatotoxicity by TCM is limited to natural products, mainly herbs, from the more than 7,000 Chinese herbal medications in use. 8 Herb induced liver injury (HILI) is not restricted to Chinese herbs but may be commonly observed in virtually all countries where herbs are consumed. 9 At present, HILI has been documented with published case reports or case series by at least 60 different herbs and herbal mixtures, including Chinese ones. In this review, a literature search was performed for cases of herbal TCM with special reference to hepatotoxic side effects and addressed the question of how to improve collection and evaluation of case data in the future in order to facilitate causality assessment.

Literature search and identification of reports
For a selective literature search from 1990 to 2013, PubMed was searched using the terms Traditional Chinese Medicine, Traditional Asian Medicine, Traditional Oriental Medicine, Traditional Chinese Medicine liver injury, Traditional Asian Medicine liver injury, Traditional Oriental Medicine liver injury, Chinese herbal hepatotoxicity, Chinese herbal liver injury, herbal hepatotoxicity, and herb induced liver injury. From each search, the first 25 publications underwent analysis for subject matter, data quality, and overall suitability. Citations in retrieved publications were searched for other yet unidentified case reports. The search was limited primarily to English-language case reports, case series, and clinical reviews. Full lengths publications in Chinese, Japanese, or other Asian languages were not considered, but their abstracts were used occasionally if provided in English.

Individual cases
The selected publications represented reports of cases with herbal TCM induced liver injury and originated from China including Hong Kong, Taiwan, Japan, Korea, Singapore, Thailand, Australia, Italy, Spain, France, the Netherlands, the United Kingdom, Iceland, Canada, the United States, and Argentina. Outside of China, only around 500 TCM herbs are commonly used, which is a small fraction of the medicinal herbs available. In China, this number is estimated to be more than 7,000 8 or around 14,000 items. 10 The present analysis includes data from a relatively low number of potentially hepatotoxic TCM products, only a few dozen herbal products and single herbs. However, non-English language publications were excluded from this review, and the information here is not an exhaustive summary of all information collected to date.
In general, evaluation of cases with suspected herbal TCM induced liver injury is challenging because numerous aspects need to be considered for a valid assessment (Table 1). [11][12][13][14][15] This includes a liver specific causality assessment, preferentially with the scale of the Council for International Organizations of Medical Sciences (CIOMS), also called the Roussel Uclaf Causality Assessment Method (RUCAM). [13][14][15] Although rarely available, most valuable for the causality evaluation is the assessment of unintentional reexposures, which requires the application of strict criteria (Table 2). 16,17 An Shu Ling A 42-year old woman from the United States took three different herbal medicines for insomnia. 18 The products were An Shu Ling (syn. Jin Bu Huan) as TCM, ''Ignatia Amara'', and ''Relaxed Wanderer''. Following a ten week treatment course, she experienced jaundice and developed acute hepatitis. A toxicology database found the synonym Jin Bu Huan listed for An Shu Ling, L-tetrahydropalmitine was identified in chemical analysis. The analogous hepatotoxic constituent to Jin Bu Huan also contains Stephania sinica and various herbs. The two other herbal medicines contained no suspected hepatotoxins. The product lot of An Shu Ling was confiscated and a public health warning was issued. No additional cases associated with the use of this particular product were reported. Although Jin Bu Huan itself was banned from importation into the United States 18 due to the known hepatotoxic risks, 7,9 a shipment of An Shu Ling reportedly cleared US customs because the respective shipping invoice contained only the Chinese botanical name. 18 See also Jin Bu Huan.

Ba Jiao Lian
After drinking infusions made with the TCM Ba Jiao Lian (Dysosma pleianthum) and consuming the recommended dose, five patients in Taiwan manifested abnormal liver function tests associated with nausea, vomiting, diarrhea, abdominal pain, thrombocytopenia, leucopenia, sensory ataxia, altered consciousness, and persistent peripheral tingling or numbness. 19 In a recent report from Taiwan, 17 cases with poisoning by Ba Jiao Lian were published. 20 Podophyllotoxin is one of the main ingredients of the Ba Jiao Lian root and is considered the toxic agent. [19][20][21] However, the increase in the aminotransferases was small, with preference for the aspartate aminotransferase (AST) over the alanine aminotransferase (ALT). 19,21 The increase of AST 19 could reflect either isolated damage of mitochondria around the hepatic central vein or some muscular damage 21 because of the associated increase of creatine phosphokinase. 19 These uncertainties do not allow for the classification of Ba Jiao Lian as a potentially hepatotoxic herb, and it is therefore not further considered within this review.

Bai Fang
A 54-year old male patient in the United States developed subtotal liver necrosis and survived following liver transplantation (LTX). 22 He used Bai Fang as a herbal TCM for an unknown time and had acute hepatitis B virus (HBV) as a cofactor. Ingredients of Bai Fang include Angelica sinensis, Cyperus rotundus, Ginseng, Ligusticum wallichii, Paeonia alba, and Rehmannia glutinosa. The possible hepatotoxic herb and its suspected ingredient remain unknown, and the causality for Bai Fang is questionable because of the concomitant acute hepatitis B. No other cases were reported.

Bai Xian Pi
In four Korean patients, the use of the herb TCM Bai Xian Pi (Dictamnus dasycarpus) was hepatotoxic, when applied as a single herb. 23 Similarly, it was hepatotoxic in three patients from the United Kingdom when it was coadministered with other herbs. [24][25][26] Overall, fourteen patients from Korea developed acute toxic hepatitis due to Dictamnus dasycarpus, 27 and two other Korean patients required a liver transplant due to acute liver failure. 28 See also Chinese herbal mixtures.  29 Its ingredients were Angelica sinensis, Chaenomeles, Codonopsis pilosula, Notopterygium, Polygonum multiflorum, Rehmannia, and Schisandra. The patient was evaluated for a liver transplant but did not meet transplantation requirements because of septicemia, leading to a lethal outcome. 29 Other hepatotoxicity cases caused by Ban Tu Wan have not been published. See also Ho Shou Wu, Polygonum multiflorum, Shen Min, and Shou Wu Pian.

Bo He
Two men, 45-years and 46-years, from Hong Kong with a chronic HBV infection took the TCM Bo He (Mentha haplocalyx) in formulas that contained 11 elements with Bo He, shown to be hepatotoxic in the Chinese literature. 30

Bofu Tsu Sho San
A 37-year old Japanese woman used the herbal TCM Bofu Tsu Sho San, a Japanese kampo medicine also called Bofu Tsu Sho San, and a diagnosis of herb induced liver injury was   Modified and derived from previous reports. 16,17 Required data for the hepatocellular type of liver injury are the ALT levels commonly just before reexposure, designed as baseline ALT or ALTb, and the ALT levels during reexposure, designed as ALTr and correlated to 2ALTb. Response to reexposure is positive, if both criteria are met: first, ALTb , 5N with N as the upper limit of normal, and second ALTr o 2ALTb. Other variations lead to negative or uninterpretable test results. For the cholestatic (± hepatocellular) type of liver injury, corresponding values of ALP are to be used rather than of ALT, but ALPb values focus on 2N rather than on 5N as for ALTb. Definitions of the hepatocellular and the cholestatic (± hepatocellular) type of liver injury are provided previously. [13][14][15][16] Abbreviations: ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; n.a., not available.

Boh Gol Zhee
Acute hepatitis was described after use of the TCM Boh Gol Zhee (syn. Bol Gol Zhee, Bu Gu Zhi, Bu Ku Zi, Sheng Bu Gu Zhi, Sheng Po Gu Zhi) in two patients from Korea 34,35 and in three patients from Hong Kong. 36 Boh Gol Zhee represents not a herbal mixture but seeds of Psoralea corylifolia, and when used at high amounts psoralens are potentially hepatotoxic. [34][35][36] Psoralens were hepatotoxic candidates in another patient who experienced severe hepatotoxicity with Indian Ayurvedic herbal products. 37 These included Bakuchi tablets that contain extracts from Psoralea corylifolia leaves with psoralens for treatment of vitiligo.

Bupleurum
See Chai Hu.

Camellia sinensis
See Lu Cha.

Chai Hu
The risk of liver injury was increased in overall 61 Taiwanese patients with HBV infections treated with some products of TCM containing Chai Hu (Bupleurum falcatum). 38 In particular, two products were involved, Xiao Chai Hu Tang with 19 patients and Long Dan Xie Gan Tang with 14 patients. In other individuals without HBV infections, various herbal TCM products containing Bupleurum may be hepatotoxic, see for instance Da Chai Hu Tang, 39 Kamishoyosan, 40 and a report referring to a herbal TCM mixture. 25 See also Long Dan Xie Gan Tang and Xiao Chai Hu Tang.

Chaso
Six Japanese patients developed hepatic injury after using Chaso, a herbal TCM that promotes weight loss. 41 This product contained Camellia sinensis (Green tea, syn. Lu Cha as TCM), the hepatotoxic Cassia tora (Senna), Crataegus, Chrysanthenum morifolium Ramat., Lotus, and Lycium barbarum. As an ingredient of the Chaso formula, Camellia sinensis extract is known to facilitate weight loss. Since the toxic property of Camellia sinensis extract was unknown in 2003 when Chaso hepatotoxicity was first described, it was not considered to be the hepatotoxic agent. 41 Outcome was favorable in all patients, with only one patient requiring LTX. Chemical product analysis showed lack of fenfluramine and heavy metals, such as copper, lead, bismuth, cadmium, stibium, stanum, mercury, and chromium, but N-nitrosofenfluramine was found. N-nitroso-fenfluramine was considered a possible but not yet proven culprit, 41 since similar cases of hepatotoxicity by various other slimming aids in the United Kingdom, 42 Hong Kong 43 and Japan 44 including the TCM herbal product Onshido, 41 were reported. An additional 21 cases of Chaso-induced hepatotoxicity were reported to health officials in Japan and not further analyzed. 41 A cautionary statement by the authors recommended further toxicological analyses to determine possible hepatotoxicity by N-nitroso-fenfluramine, which was not established toxicologically or clinically until 2003. 41 Toxicological evidence of its hepatotoxic property was not provided since 2003, and clinical evidence cannot be expected because it was removed from the market in 1997. The popular and widely used slimming aid fenfluramine was withdrawn from clinical use because of cardiac rather than hepatic complications, which remain unknown. 41 Consequently, there is little toxicological and clinical evidence available regarding the hepatotoxicity of fenfluramine or N-nitroso-fenfluramine. For more details and discussions see Lu Cha (Camellia sinensis) and Onshido.

Chi R Yun
Taiwanese patients who used the TCM Chi R Yun (Breynia officinalis) experienced hepatotoxicity. [45][46][47] There was intentional and unintentional Chi R Yun overdose in two patients 45 and acute poisonings in 19 patients. 46,47 Because of their similarities, Breynia officinalis was mistaken for another plant, the TCM Yi Yi Qui (Securinega suffruticosa). 46,47 Chinese herbal mixtures Patients of this section used an unnamed, unclassified herbal mixture of TCM. Additionally, in some of these cases, only individual herbs had been declared by name. Since the herbal mixtures have all herbs presented as ingredients, these mixtures could not be added to an existing named herbal product group. Herbal hepatotoxicity was published for a heterogeneous group of herbal mixtures of TCM, [24][25][26][48][49][50][51] primarily from the United Kingdom. [24][25][26][48][49][50] In three cases, hepatotoxicity was described following herbal TCM use, but firm details concerning the applied herbs were missing. [48][49][50] More information was provided by other reports. [24][25][26] One treatment consisted of Dictamnus dasycarpus (syn. Bai Xian Pi), Gentiana scabra, Hedyotis diffusa, Paeonia suffructicosa, Paris polyphylla, Rehmannia glutinosa, Smilax glabra, and Sophora subprostrata. 25 Another patient used Angelica sinensis, Bupleurum chinese, Dictamnus dasycarpus, Paeonia suffructiosa, Philodendron chinese, Saposhnikovia divaricata, Shisandra chinesis, Shizonepeta tenuifolia, and Tribulus terrestris. 25 A third patient with a fatal clinical course used a mixture consisting of Cocculus trilobus, Dictamnus dasycarpus, Eurysolen gracilis, Glycyrrhiza, Lophatherum, Paeonia, Potentilla, and Rehmannia glutinosa. 24 Considering these three cases from two reports, 24,25 it is possible that either Dictamnus dasycarpus or Paeonia species could be the toxic herb. 25 Four Korean patients with toxic liver injury used Dictamnus dasycarpus as a single herb. 23 In addition, analysis of a herbal remedy taken by another patient with fulminant liver failure and unsuccessful LTX confirmed the presence of Dictamnus dasycarpus. These cases support an etiological role of this herb in TCM hepatoxicity. 26 The herbal mixture of TCM used by a patient in Canada led to acute liver failure and successful LTX in the United States. 51 This mixture consisted of twelve herbs, including Alisma plantago aquatica, Artemisia capillaris, Bupleurum, Chrysanthemum morifolium, Circuma, Gardenia jasminoidis, Gentiana scabra, Glycyrrhiza, Magnolia, Paeonia, Plantago asiatica, and Saussurea lappa. The toxic culprit remains unknown.

Chinese skullcap
See Huang Qin.

Chuan Lian Zi
A 45-year old male patient with chronic HBV infection from Hong Kong was treated with the TCM Chuan Lian Zi (Melia toosendan) and experienced herbal hepatotoxicity. 30

Ci Wu Jia
Two Korean patients consumed the herbal TCM Ci Wu Jia (Acanthopanax senticosus), developed acute toxic hepatitis with acute liver failure, and required LTX. 25

Da Chai Hu Tang
In a Japanese patient, autoimmune hepatitis was triggered by the use of the TCM Da Chai Hu Tang (syn. Dai Saiko To, TJ-8), a mixture of aqueous extracts from seven plants, Bupleurum falcatum, Ginseng, Glycyrrhiza glabra, Pinellia, Scutellaria, Zingiber officinale, and Zizyphus jujuba. 39 The specific culprit remained unknown. Da Chai Hu Tang contains the same components as the potentially hepatotoxic TCM Xiao Chai Hu Tang (syn. Sho Saiko To Syo Saiko To, Syo Xiao Hu Tang, TJ-9) but in different proportions. 39,52 See also Bupleurum and Xiao Chai Hu Tang.

Da Huang
A 45-year old man from Hong Kong with chronic HBV infection used the herbal TCM Da Huang (Rhubarb, Rheum palmatum) and died from acute liver and organ failure due to herbal hepatotoxicity. 30

Dai Saiko To
See Dai Chai Hu Tang.

Dan Zhi Xiao Yao San
See Kamishoyosan.

Gan Cao
A 46-year old man from Hong Kong with a chronic HBV infection took the TCM Gan Cao (syn. Glycyrrhiza uralensis, Liquorice, Gan Cao Zhi, Shen Nong Ben Cao Jing, Zhi Gan Cao) in formulas. These contained 11 elements, and Gan Cao was the likely toxic agent for the observed hepatotoxicity. 30 Recovery was complete after discontinuation of Gan Cao.

Ge Gen
The two 57-and 58-years old women from Korea ingested juice of the herbal TCM Ge Gen (Pueraria lobata, syn. Arrowroot) and developed symptomatic toxic hepatitis. 53 Clinical symptoms and laboratory findings rapidly improved following cessation of Ge Gen and supportive care.

Ho Shou Wu
A 54-year old Korean woman consumed Polygonum multiflorum as the TCM Ho Shou Wu (syn. He Shou Wu, Shou Wu Wan, Fo Ti) and experienced toxic hepatitis. 54 Hepatotoxicity in a 33-year old woman from Hong Kong with a chronic HBV infection was assumed to be due to Ho Shou Wu as well. However, other medications also included the hepatotoxic Jue Ming Zi (Cassia obtusifolia tora, Senna) and 10 additional, unidentified herbal items. 30

Huang Qin
Nineteen Japanese patients developed liver injury after the use of the herbal TCM Huang Qin (Scutellaria baicalensis, syn. Chinese skullcap), which is a herbal mixture called Ogon in Kampo medicine of Japan. 55 Hepatotoxicity was described in four patients from the United States who used Huang Qin in a dietary supplement which also contained black catechu (Acacia catechu), glucosamine, chondroitin, and hyaluronic acid. [56][57][58] Acacia catechu was used as one of several Indian Ayurvedic herbs in a patient with severe hepatotoxicity and is thereby a possible culprit. 37 However, the herbal extract of Chinese skullcap is the more likely cause of the reported hepatotoxicity. [56][57][58] There are some hundred species of skullcap (Scutellaria), including Scutellaria lateriflora, that have potential hepatotoxic risks, but often information regarding respective species was missing. 9 Hwang Geun Cho A 37-year old Korean male patient consumed the herbal TCM Hwang Geun Cho (Corydalis speciosa) and was diagnosed with acute herbal hepatotoxicity. 59 Symptoms disappeared and laboratory values gradually returned to near normal values following cessation and supportive management.

Ji Gu Cao
A 38-year old man from Hong Kong with chronic hepatitis B took the herbal TCM Ji Guo Cao (syn. Abrus cantoniensis, Ji Gu Cao Wan) and was diagnosed with herb induced liver injury, possibly caused by contaminated hepatotoxic seeds. 30

Ji Xue Cao
Three women aged 61, 52, and 49 years from Argentina ingested the herbal TCM Ji Xue Cao (Centella asiatica, syn.Gotu Kola) and developed herbal hepatotoxicity by Centella asiatica. 60 Outcomes were favorable after discontinuation of the medication and ursodeoxycholic acid therapy.  68 However, causal attribution to Sedum aizoon was in retrospect incorrect. Sedum aizoon lacks pyrrolizidine alkaloids (PAs), and when administered to experimental animals, HSOS did not emerge. 69 This suggested that a herb containing PAs was likely responsible for the reported cases. 68 Consistent with this, in another hepatotoxicity case from Hong Kong, HSOS was initially ascribed to Sedum aizoon but was later determined to be caused by the herbal TCM Shan Chi (Gynura segetum). 69 The appearance of Sedum aizoon is similar to Gynura segetum but can be differentiated by an expert eye. 69 Comparative studies with both herbs provided clear supportive evidence for Gynura segetum as the culprit for additional cases of HSOS over Sedum aizoon. Respective studies showed in mice that the PAs containing Gynura segetum but not the PAs lacking Sedum aizoon produced experimental HSOS as assessed by liver histology. 69 In an earlier experimental study, a model of the hepatic veno-occlusive disease was established by PAs derived from a herb described erronously as Sedum aizoon, 70 which again does not contain PAs. 69,71,72 This suggested that the described experimental model 70 was due to the action of a herb containing PAs, most likely Gynura segetum, 69,71-73 rather than to PAs lacking Sedum aizoon. 71 Other authentication problems of Gynura segetum had to be resolved in relation to the TCM Mao Guo Tian Jie Cai (Heliotropium lasiocarpum), another herb that also contains PAs. 74-76 HSOS cases had been initially attributed to Gynura segetum, 74,75 but this causal attribution was in retrospect incorrect since Heliotropium lasiocarpum was determined as culprit. 76 Overall, careful analyses finally led to a clear picture of HSOS by Gynura segetum. 77,78 Taken together, there is little evidence for the hepatotoxic potential of Jing Tian San Qi. Therefore, the herbal TCM Sedum aizoon will not be further considered for hepatotoxicity.

Jue Ming Zi
A 33-year old woman from Hong Kong with a chronic HBV infection was treated with the herbal TCM Jue Ming Zi (syn. Cassia obtusifolia, Senna obtusifolia, Cao Jue Ming) and experienced liver injury. 30

Kamishoyosan
In one single Japanese woman, liver injury was reported following the use Kamishoyosan, a traditional Japanese herbal drug (Kampo medicine) and synonym to the TCM Jia Wei Xiao Yao San, Dan Zhi Xiao Yao San, or TJ-24. 40 Kamishoyosan is a herbal mixture and contains several components, including Angelica sinensis, Atractylodes racea, Bupleurum falcatum, Gardenia, Glycyrrhiza glabra, Mentha haplocalyx, Moutan, Paeonia alba, Sclerotium Poriae Cocos, and Zingiber officinale, as described in the case report 40 or as assessed by an internet search for a refined botanical description of the herbal components. Detecting the causative agents was difficult, but Scutellaria was definitively excluded. 54,79 There is some uncertainty regarding the Mentha species, declared as Mentha herb in the case report 40 and as mentha (pennyroyal) subsequently. 79 An additional internet search to further determine the Mentha species commonly used in Kamishoyosan found Mentha haplocalyx Briq or Mentha arvensis var. piperascens Malinvaud (Japanese field mint) as the most probable component.

Kudzu
Six patients from Korea consumed the herbal TCM Kudzu (Pueraria thunbergiana) and were diagnozed with acute toxic hepatitis. 27 Liquorice See Gan Cao.

Long Dan Xie Gan Tang
Overall, fourteen Taiwanese patients with HBV infection were found to be at higher risk for hepatotoxicity when treated with the TCM Long Dan Xie Gan Tang (syn. Long Dan Xie Gan Wan). 38 This herbal mixture contains Acebia, Alisma, Angelica sinensis, Bupleurum, Gardenia, Gentiana, Glycyrrhiza, Plantago, Rehmannia, and Scutellaria. A similar increase in risk was observed in another patient group treated with the TCM Xiao Chai Hu Tang, which also contains Bupleurum among other herbs. See also Bupleurum and Xiao Chai Hu Tang.

Long Dan Xie Gan Wan
See Long Dan Xie Gan Tang.

Lu Cha
Lu Cha (Camellia sinensis, green tea) is a TCM plant and one of several herbal ingredients in the two herbal mixtures Chaso Teschke R.: Traditional Chinese medicine induced liver injury and Onshido. These mixtures were marketed as weight loss aids by Chinese pharmaceutical companies and found to be hepatotoxic, as described in 2003. 41 N-nitroso-fenfluramine but not green tea was discussed as the possible but unproven hepatotoxic ingredient for these herbal mixtures. However, this case series did not prove that N-nitrosofenfluramine was the toxic agent. 41 Whether Camellia sinesis may have contributed to the observed hepatotoxicity is unclear, because information on the amounts of green tea in these two products was not provided. At least as an extract, Camellia sinensis is a potent weight loss aid with potentially hepatotoxic effects, as thoroughly discussed first in 2004 [80][81][82] and in subsequent years. 9,83-88 Therefore, hepatotoxicity of green tea as extracts was not yet clearly established in 2003 when the respective case reports were published. 41 Green tea is one of the most popular beverages, as are black tea and coffee. There is no question that the conventional use of these beverages including green tea does not harm the liver. In the past, however, weight loss aids were supplemented by green tea concentrated as extracts, and these carried the risk of liver injury. 9,[80][81][82][83][84][85][86][87][88] According to the manufacturers, the weight loss aids Chaso and Onshido contained green tea and other herbs. 41 Presumably, green tea was included as extracts to enhance weight loss, although the extract form was not specifically mentioned by the manufacturers. The producers did not mention that the synthetic adulterant N-nitroso-fenfluramine was also an ingredient in the two products. This adulterant was later identified by chemical analyses, but evidence of hepatotoxicity was not presented and evaluation by further studies was recommended. 41 The most likely candidate for the liver injury was green tea, if it was supplied in the extract form. For details see also Chaso and Onshido.

Ma Huang
Six patients originating from the United States experienced acute hepatitis associated with the use of the herbal TCM Ma Huang and its ingredients of Ephedra species. 9,22,33,89-91 Out of these six cases, one patient also coadministered kava, one also had disulfiram, and one had a chronic HBV infection. 22 Two patients developed acute liver failure, 22,90 and one of them required LTX. 22 In another patient from the United Kingdom, acute liver failure emerged and LTX was necessary. 92 Ma Huang is also one of the ingredients of Pro-Lean1, 9 a potential hepatotoxic herbal mixture. 93 For Ephedra, see also Bofu Tsu Sho San.

Mao Guo Tian Jie Cai
In four patients from Hong Kong, HSOS developed following the use of the PAs containing herbal TCM Mao Guo Tian Jie Cai (Heliotropium lasiocarpum). 76 It was initially mistaken as the PAs containing herbal TCM Gynura segetum. [73][74][75] Outcome was deleterious for one of the four patients. 76 Onshido Six Japanese patients experienced hepatic injury due to the use of the weight loss aid Onshido, a TCM herbal mixture. 41 This herbal product contained Aloe, Camellia sinensis, Crataegus, Gynostemma pentaphyllum makino, and Raphanus. Outcome was favorable in all patients except for one with a lethal clinical course. Chemical product analysis of Onshido showed lack of fenfluramine and heavy metals such as copper, lead, bismuth, cadmium, stibium, stanum, mercury, and chromium but the presence of N-nitroso-fenfluramine as a possible but ultimately unproven hepatotoxic agent. N-nitroso-fenfluramine was also considered the possible culprit in additional cases of hepatotoxicity by various other slimming aids in the United Kingdom, 42 Hong Kong, 43 including the TCM product Chaso in Japan. 41 Additional 135 Onshido-induced cases of hepatotoxicity were reported to health officials in Japan but not further analyzed. 41 The hepatotoxic properties of Camellia sinensis extracts were discovered in 2004, 9 and its role in Camellia sinensis induced hepatotoxicity was not evaluated in 2003. 41 For additional details and discussions see also Chaso and Lu Cha (Camellia sinensis).

Polygonum multiflorum
Polygonum multiflorum is a member of the family Polygonaceae, genus Fallopia. Either alone or in combination with other herbs and vitamins, it is a constituent of various potentially hepatotoxic herbal TCM products. [28][29][30]54,[94][95][96][97][98] Among these are Ban Tu Wan, 29 Ho Wu Shou, 30,54 Shen Min, 95 and Shou Wu Pian. [96][97][98][99][100][101][102][103] Occasionally, Polygonum multiflorum containing herbal TCM products such as Ho Shou Wu, Shen Min, Shou Wu Pian, and Zhi Shou Wu are considered interchangeable terms. 94 However, ingredients may vary from product to product, requiring specific and qualifying product names. The mechanism of hepatotoxicity of Polygonum multiflorum is not known and disputed, 94-96,99-101 although the injury is usually attributed to the anthraquinones such as chrysophanol, emodin, and rhein, which are major constituents in Polygonum multiflorum. 94 In a single report, however, the major compound identified in the recovered tablets was a stilbene glycoside, tetrahydroxystilbene-glucopyranoside. 94,96 LTX was necessary in three patients from Korea after using Polygonum multiflorum. 28 For details see Ban Tu Wan, Chinese herbal mixtures, Ho Wu Shou, Shen Min and Shou Wu Pian.

Rhen Shen
Six patients originating from Korea used the herbal TCM Rhen Shen (Panax ginseng, Ren Seng) and developed acute toxic hepatitis. 27

Sairei To
Two Japanese men consumed the kampo medicine Sarei To (syn. Chai Ling Tang), which is a blend of two TCMs, Xiao Chai Hu Tang and Wu Ling San Wan, and experienced herbal hepatotoxicity. 104,105 Among the Sairei To ingredients are Alisma, Atractylis, Bupleurum, Cinnamomum, Ginseng, Glycyrrhiza, Pinellia, Polyporus, Poria, Scutellaria, Zingiber, and Zizyphus. Several possible culprits are under consideration, including Pinellia ternate, 104 and other components of Sairei To. 105 Teschke R.: Traditional Chinese medicine induced liver injury

Shan Chi
In two Chinese women, 51 and 39 years old, HSOS emerged, which was induced by PAs of the herbal TCM Shan Chi Gynura segetum (syn. Ju San Qi, Ju Shan Qi, Ju Ye San Qi, San Qi Cao). 73 One of these two patients required a LTX. Other cases of HSOS by Gynura segetum were reported from China, 59,60,77,78 with a lethal outcome in one patient. 59 In a 54-year old woman with HSOS from Hong Kong, PAs derived from Gynura segetum rather than the herbal TCM Jing Tian San Qi (Sedum aizoon) devoid of PAs were the likely hepatotoxic agents. 69 Additional six cases were earlier suspected, 74,75 but in at least four cases the culprit was the PAs containing herb Heliotropium lasiocarpum rather than Gynura segetum. 76 An additional four patients experienced HSOS by Gynura segetum, one with a lethal course. 71 Correspondingly, at least 52 HSOS cases have been attributed to Gynura segetum until 2011, 69 and 116 cases until 2012. 71 The clinical features have now been clearly described, establishing Gynura segetum but not Jing Tian San Qi (Sedum aizoon) as the cause of HSOS. 69,71,72 The diagnosis was ascertained in a 54-year old female patient with HSOS by thorough investigations of the patient herself and by animal studies. 69 Her clinical diagnosis of HSOS was firmly established by meeting the modified Seattle criteria, characterized by hyperbilirubinemia, hepatomegaly, and weight gain due to fluid accumulation. Liver histology confirmed the diagnosis of HSOS. Pyrrole-protein adducts as biomarkers and pyrrole-GSH conjugates detected in her blood using the new method ultra performance liquid chromatography-mass spectrometry (UPLC-MS) analysis. Since the ingested herb was unknown, the cultivated herb from the patient's home was collected and authenticated as the TCM herb Gynura segetum. Together with the authenticated TCM herb Sedum aizoon cultivated and collected from another Chinese area, various comparative studies in animals were made. All of these studies confirmed that the observed HSOS arose from the consumption of PAs containing Gynura segetum, an erroneous substitute of the non PAs containing Sedum aizoon. 69 The blood test of pyrrole-protein adducts using UPLC-MS analysis was employed as a biological biomarker in subsequent patients. 71 Shen Min A 28-year old woman from the United States developed acute hepatitis following the use of the herbal TCM Shen Min. 95 The product label for this Shen Min product had a list of components that included plants and vitamins. Polygonum multiflorum is one of the main components of Shen Min, and the respective content was described as Shen Min 12: 1 standardized extract (Polygonum multiflorum) 450 mg per serving and as He Shou Wu powder 870 mg per serving. Polygonum multiflorum, however, was not specified here. Other declared contents of the used Shen Min product were vitamin A, vitamin B 6 , biotin, niacin, pantothenic acid, soy isoflavones, black cohosh, horse chestnut, hydrolyzed collagen, silica from plant sources, ginkgo biloba, uva ursi, Burdock, Cayenne pepper, and Piper nigrum. See also Ho Shou Wu, Polygonum multiflorum, and Shou Wu Pian.

Shou Wu Pian
As described in 1996, a 31-year old pregnant Chinese woman from Hong Kong developed acute hepatitis after consumption of the TCM Shou Wu Pian, with Polygonum multiflorum as the main component. 99 Subsequently, similar case reports related to Shou Wu Pian followed from Australia, 100 Italy, 98,101 the Netherlands (a 5-year old girl), 96 the United States, 102 Japan, 103 and Korea. 97 Shou Wu Pian is a herbal mixture with a wide variability of its ingredients, and details are rarely mentioned. 94,97,103 For example, according to the information via the internet, one of the numerous possible formula compositions could be: Achyranthes bidentata, Cuscuta chinensis, Eclipta prostrata, Ligustrum lucidum, Lonicera japonica, Morus alba, Polygonum multiflorum, Psoralea corylifolia, Rehmannia glutinosa, Rosa laevigata, Sesemum indicum, and Siegesbeckia orientalis. This composition varies substantially from the one of Shen Min, 95 which also contains Polygonum multiflorum and is discussed above. See also Ho Shou Wu, Polygonum multiflorum, and Shen Min.

Syo Saiko To
See Xiao Chai Hu Tang.

Xiao Chai Hu Tang
The treatment with the herbal TCM Xiao Chai Hu Tang (syn. Sho Saiko To, Syo Saiko To, Syo Xiao Hu Tang, TJ-9) resulted in liver injury in four Japanese patients with increased liver values prior to treatment. 107 For 19 Taiwan patients with HBV infection, treatment with Xiao Chai Hu Tang was associated with an increased risk for liver injury. 38 One additional patient from Taiwan had the same response to Xiao Chai Hu Tang following cholecystectomy. 108 Xiao Chai Hu Tang is a mixture of several herbs, including Bupleurum falcatum, Ginseng, Glycyrrhiza glabra, Pinellia tuber, Scutellaria baicalensis, Zingiber officinale, and Zizyphus jujuba. Therefore, its composition is the same as the TCM Da Chai Hu Tang (syn. Dai Saiko To, TJ-8), but in different proportions. 39,52 See also Bupleurum, Da Chai Hu Tang, and Long Dan Xie Gan Tang.

Yin Chen Hao
In seven patients from Korea, the use of the herbal TCM Yin Chen Hao (Artemisia capillaris) resulted in the development of acute toxic hepatitis. 27 One additional Korean patient did require LTX. 28 Zexie A 59-year old man from Hong Kong with chronic hepatitis B and associated HBeAg-positive liver cirrhosis was treated for cramps with a herbal TCM formula consisting of eleven different herbal elements, including the hepatotoxic Zexie (Alisma orientalis). 30 He died from complications due to a severe course of herbal hepatotoxicity.

Zhen Chu Cao
A 37-year old man from Hong Kong with a chronic hepatitis B had been taking the TCM Zhen Chu Cao (syn. Phyllanthus urinaria) and experienced herbal hepatotoxicity due to Zhen Chu Cao. 30 After cessation of the toxic herbal product, there was a full recovery.

Zhi Gan Cao
See Gan Cao.

Clinical and regulatory considerations
The present study is a very limited analysis of herbal TCM hepatotoxicity based on some hundred cases published in 91 reports. Most patients made a full recovery upon cessation of the herbal TCM product, 18-108 but some developed acute liver failure. 24,28,29,30,41,51 In these publications, individual herbs and herbal mixtures suggested to be hepatotoxic included An A good approach with some limitations for the establishment of causality for a given herb or herbal mixture in hepatotoxicity is to assess reported positive reexposure test results. They are obtained through unintentional readministration, although this is commonly observed in only a few selected cases. 16,17 In the past, this assessment has been done for 34 cases of suspected herbal hepatotoxicity, including 14 cases due to herbal TCM, 17 applying established criteria for a positive reexposure test (Table 2). Among the now assessed 25 patients of suspected herbal hepatotoxicity of TCM with reported positive reexposure test results, criteria based evaluation confirmed a positive reexposure test result in 14 cases, whereas the results were negative in four cases or uninterpretable in seven cases (Table 3). Accordingly, positive reexposure test results were obtained for Chinese herbal mixtures (cases 2 and 3), Hwang Geun Cho (case 6), Ji Xue Cao (case 7), Jin Bu Huan (cases 9 and 10), Lu Cha (cases [13][14][15], Polygonum multiflorum (case 20), Shou Wu Pian (case 21), and Xiao Chai Hu Tang (cases 23-25) ( Table 3), confirming the hepatotoxic risk of these products. 17 The liver specific CIOMS scale for causality assessment is applicable to all cases of suspected herbal TCM hepatotoxicity. 14,15,27,28,30,53,69,71,97,109,110 This scale was rarely used in the cases of the present evaluation,  although CIOMS data were provided for all 7, 25, and 27 TCM cases in three studies. 30,97,110 In the course of causality assessment, highly probable or probable causality levels were obtained for various types of TCM formulas, 30 Bai Xian Pi, 27,28 Chinese herbal mixtures, 17 Ci Wu Jia, 28 Gan Coa, 30 Ge Gen, 53 27,28 and Zexie. 30 Clinical assessment was partly difficult because data were often incomplete in many cases regarding indication for treatment, daily dose, quantitative composition of herbal mixtures, duration of treatment, exclusion of alternative causes, and clinical course.  These shortcomings are also common to cases of herb induced liver injury, which are unrelated to TCM 7,12,[14][15][16][17]111 and to drug induced liver injury. 112 Some common TCM herbs and herbal products with potential hepatotoxicity were not discussed or specifically referenced above as additional cases since they were listed without further details. 62 62 Additional lists refer to 24 cases of liver damage by Polygonum multiflorum, 113 two cases of markedly elevated liver enzymes with the herbal TCM Bo Ye Qing Niu Dan (Tinospora crispa), 114 and to a single case of liver injury with verified causality by the CIOMS scale attributed to the herbal TCM Du Huo (Angelica archangelica). 115 Problematic for human use is the possible lack of quality control and authentication of herbal products (Table 1) 12 as well as adulteration and contamination with dust, pollens, insects, rodents, parasites, microbes, fungi, mold, toxins, and pesticides. 6 For herbal TCM products, specific problems have been linked to mislabeling on the package insert 3,63 including the wrong herbs, 46,47 insufficient sample amounts, 116 adulteration with undeclared synthetic drugs, 3,6,10,62 contamination by hepatotoxic seeds 30 and heavy metals such as

Continued
Teschke R.: Traditional Chinese medicine induced liver injury arsenic, mercury, and lead. 6,116 These shortcomings are well recognized 1-12,14,116 and require efforts by manufacturers and regulatory agencies (Table 1). 117 Of additional concern is the potential hepatotoxicity of non-herbal TCM elements. 10,27,28,30,62,[118][119][120][121][122] They are commonly used in connection with herbal TCM products, 10,30 and even named as such. 10 Known or potentially hepatotoxic nonherbal TCM elements are Bai Hua She (venom of the Chinese viper Agkistrodon acutus), 30 Jiang Can (dried larvae of Bombyx Batryticatus, infected by Batrytis bassiana), 30 Ling Yang Qing Fei (antelope horn), 30 Liyu Danzhi (carp juice), 118 Quan Xie (dry polypides of the Scorpio Buthus martensii), 30 Sang Hwang (Phellinus linteus, mushroom), 27,28 Song Rong (Agaricus blazei, Himematsutake as Japanese Kampo Medicine, mushroom), 119 Wu Gong (dried polypites of the centipede Scolopendra subspinipes mutilans), 30 Wu Shao She (syn. Wu Xiao She, Sheng Wu Shao She, parts of the snake Zaocys dhumnades), 30 and Yu Dan (fish gallbladder). [120][121][122] Finally and most importantly, the use of a few TCM products caused serious hepatotoxicity in some susceptible patients resulting in a severe clinical course with  Compilation of some clinical details and laboratory values for assessment of reported positive reexposure test results in 25 cases with suspected herbal hepatotoxicity by TCM products. 24,25,48,54,57,59,60,63,64,[82][83][84][85][86]89,96,97,107 Data are derived from a previous report, which may provide additional details. 17 Unless otherwise stated, reexposure was commonly unintentional. Criteria for a positive reexposure test result were used as described in Table 2, restricted to criteria provided for the hepatocellular type of liver injury. Accordingly, essential data are the ALT levels at baseline before reexposure (ALTb) and the ALT levels during reexposure (ALTr). Response to reexposure is positive if ALTr o 2ALTb and ALTb , 5N, with N as the upper limit of the normal value. Other combinations lead to negative or uninterpretable results. Serum enzyme activities were provided in U/L or multiples of N. Details for calculation of the R value were presented previously. 17 Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotranferase; N, upper limit of normal; R, ratio; TCM, Traditional Chinese Medicine.
additional risk for acute liver failure, LTX requirement, and lethality. 22,24,[28][29][30]41,51 Between 1992 and 2008, in Seoul (Korea) alone 24 patients underwent LTX due to acute toxic hepatitis caused by herbal medicine and preparations. 28 This is unacceptable because the benefits of herbal TCM products are at present only rarely and inadequately documented. 4,5 For the sake of the consumer, a stringent evaluation of the risk/benefit ratio based on results of multicenter, randomized, double-blind, placebo-controlled clinical trials should be the primary goal. 4 The future practice of pharmacovigilance and risk control of TCM herbs and drugs in China are promising. 117

Conclusions
In a few susceptible individuals, some commonly used herbal TCM products may rarely cause hepatotoxicity with the risk of a severe clinical course with acute liver failure, the requirement for LTX, and potential lethality. This necessitates a stringent evaluation of the risk/benefit ratio for any prospective treatment with herbal TCM products, based on results of multicenter, randomized, double-blind, placebo-controlled clinical trials.

Conflict of interest
None

Author contributions
Writing the manuscript (RT).