Literature Review of Traditional Chinese Medicine Herbs–Induced Liver Injury From an Oncological Perspective With RUCAM

Abstract

Traditional Chinese medicine (TCM) herbs are commonly regarded to be safe with minimal toxicities in Chinese communities. Cancer patients who are receiving Western oncology therapy often concurrently take TCM herbs for anticancer and symptom relief purposes. We performed a literature review for current evidence on TCM herb–induced liver injury from an oncological perspective. A literature search on PubMed was performed to identify publications regarding TCM herbs and concoctions with hepatoprotective or hepatotoxic properties. Lists of commonly used herbs and their causality levels were compiled. In view of the wide range of evidence available, cases assessed by the well-established RUCAM (Roussel Uclaf Causality Assessment Method) algorithm were categorized as the highest level of evidence. More than one case of TCM herb–induced liver injury was confirmed by RUCAM in the following herbs and concoctions: Lu Cha (Camellia sinensis), Bai Xian Pi (Dictamnus dasycarpus), Tu San Qi (Gynura segetum), Jin Bu Huan (Lycopodium serratum), He Shou Wu (Polygoni multiflora), Ge Gen (Pueraria lobata), Dan Lu Tong Du tablet, Shou Wu Pian, Xiao Chai Hu Tang, Xiao Yin pill, and Yang Xue Sheng Fa capsule. Finally, TCM with anticancer or symptom relief uses were discussed in detail with regard to their hepatotoxic or hepatoprotective properties.

Introduction

Multiple studies have shown that there is widespread use of traditional Chinese medicine (TCM) among Chinese patients as an adjuvant to Western medicine in cancer treatment.^1-5 Another study revealed that the self-care of Chinese cancer patients has been heavily influenced by the TCM philosophy.⁶ In addition to taking herbal medicines prescribed by Chinese medicine practitioners, it is also common for the general public to use proprietary Chinese medicine on their own or add herbs to meals and soups. A study found that over half of the Hong Kong cancer patients surveyed used at least one form of TCM. Furthermore, 60% of these patients who were receiving chemotherapy concurrently used TCM.⁷ According to a Taiwanese survey, 69% of respondents thought that TCM is mild and has no ill effects at all.⁸ TCM herbs and concoctions, like any drug, also have side effects and toxicities.

Many oncologists do not encourage the concurrent use of TCM due to the potential of having adverse interactions between Chinese and Western drugs that may lead to hepatotoxicity. There have been numerous reports of liver injury caused by TCM herbs and concoctions. However, the establishment of causality varies in these reports. A typical example of TCM-induced liver toxicity is He Shou Wu, which is a popular herb for preventing hair loss and aging. A study found that only 30.6% of literature case reports demonstrate a high probability of He Shou Wu–induced liver injury causality.⁹ The causality between TCMs and drug-induced liver injury was ascertained by various methods, such as by patient recall, clinical suspicion, exclusion, and algorithms. It is important to note the complexity and difficulty in establishing causality for TCM herbs. One difficulty is due to polypharmacy as TCM is rarely used as a single herb, and TCM may sometimes be used concomitantly with Western drugs. Another difficulty is contamination by heavy metals.¹⁰ Evidence available in case reports, case series, and reviews may not be complete. If these confounders are not excluded, misdiagnosis and overreporting may occur.

Hence, there is a need to categorize the cases in the existing literature into different evidence levels of causality. Focus should be given to hepatotoxic TCM for which clear evidence has been demonstrated by standardized causality assessment algorithms. RUCAM (Roussel Uclaf Causality Assessment Method), or its previous synonym CIOMS (Council for International Organizations of Medical Sciences), is the most commonly used causality instrument for drug-induced liver toxicity.¹¹ RUCAM is used to assess causality quantitatively, by applying numerical weighting to key features such as chronology and risk factors, and it generates an overall score to indicate the probability of causality. The RUCAM scale ranges as follows: 0, excluded; 1 to 2, unlikely; 3 to 5, possible; 6 to 8, probable; and ≥9, highly probable.¹²

Furthermore, not all TCM herbs and concoctions cause hepatotoxicity. In fact, some of them have hepatoprotective effects against drug-induced liver injury, such as chemotherapy-induced hepatotoxicity.

In this article, we present a review of the current literature to identify potentially hepatotoxic or hepatoprotective TCM that cancer patients may concurrently use with Western systemic therapies, and stratify them using causality levels to offer easier interpretation.

Methodology

Data Sources and Searches

We carried out a systematic search of the PubMed database on March 11, 2019, to identify publications of laboratory findings, case reports, case series, and review articles of TCM-induced hepatotoxicity. By using Medical Subject Headings, English articles that were associated with the terms “Chemical and Drug-Induced Liver Injury” and “Medicine, Chinese Traditional” were selectively included. Our search yielded 64 results.

Exclusion of Publications

Publications were excluded by the following criteria. Publications were excluded if

• They were unrelated to TCM-induced hepatotoxicity or hepatoprotection, or

• Access to the full article could not be obtained, or

• No specific TCM herbs or concoctions were named, or

• No significant results were directly shown with specific TCM herbs or concoctions.

As a result, 14 publications were excluded from this review.

Data Analysis

Data Extraction

Fifty publications were analyzed. Individual herbs and herbal concoctions were identified. The scientific names of each herb and its corresponding Chinese name were determined. As a single TCM herb could have different scientific names (eg, Polygoni multiflori vs Polygonum multiflorum Thunb), results were grouped according to the Chinese name of the herb. The publications were then analyzed to yield the number of clinical cases and causality.

Duplication of Data

The references of these 50 publications were carefully inspected. There were case reports, case series, and reviews referring to the same event of hepatotoxicity caused by a certain TCM herb or concoction. In particular, 3 systematic reviews were published by the same author in 3 consecutive years, and each systematic review cited cases from the previous review. Duplicated data were discarded in this review.

Exclusion of TCM Herbs or Concoctions

If the publication failed to provide any of the aforementioned data (eg, number of cases), the reference lists of the primary and review articles were scanned. If the primary source could not be accessed, the data of the individual herb or concoction were also excluded.

Levels of Causality

Hepatotoxic herbs or concoctions

In view of the wide range of clinical causality ascertainment methods in the literature, as well as the fact that laboratory findings do not directly infer clinical significance, a stratified level of causality was devised in order to provide a clearer and more clinically oriented picture.

Entries of hepatotoxic herbs or herbal concoctions found from the publications were categorized into 1 of the 4 following levels according to the following description:

Level	Context	Description
1	Nonclinical	The publication shows that certain TCM herbs/concoctions or their chemicals lead to hepatotoxicity in a laboratory setting. The experiments were conducted with animals or human cells.
2	Clinical	The publication suspected certain TCM herbs/concoctions would lead to hepatotoxicity, or associated certain TCM herbs/concoctions with hepatotoxicity. No causality was established.
3	Clinical	The publication suggested that certain TCM herbs/concoctions caused hepatotoxicity. Causality was ascertained by RUCAM in which cases were graded “possible,” or by other assessment algorithms like the positive reexposure test.
4	Clinical	The publication suggested that certain TCM herbs/concoctions caused hepatotoxicity. Clear causality was ascertained by RUCAM, in which cases were graded “probable” or higher.13

Hepatoprotective herbs or concoctions

After excluding uncommonly used hepatoprotective herbs and herbal concoctions, only nonclinical ones remained; hence, they were not graded by causality levels.

Results

Lists of herbs and concoctions that were hepatotoxic or hepatoprotective, their respective causality levels, and number of cases are compiled in Tables 1 to 5.^9,13-46

Table 1.

TCM Herbs That Were Assessed by RUCAM to Demonstrate Clear Causality of Hepatotoxicity.

中藥名	Commonly Known as	Scientific Name	Level of Causality	No. of Cases
刺五加	Ci Wu Jia	Acanthopanax senticosus 13,14	4	1
澤瀉	Ze Xie	Alisma orientalis 13-15	4	1
蘆薈	Aloe Vera	Aloe perfoliata 16	4	1
獨活	Du Huo	Angelica archangelica 13-15	4	1
茵陳蒿	Yin Chen Hao	Artemisia capillaris 14,15	4	1
綠茶	Lu Cha/Green tea/Chaso	Camellia sinensis 13-15	4	28
決明子	Jue Ming Zi	Cassia obtusifolia 13,14	4	1
珠果黄堇	Zh Guo Huang Jin, Hwang Geun Cho	Corydalis speciose 13,14,16	4	1
柘木	Zhe Mu	Cudrania tricuspidata 16	4	1
白鮮皮	Bai Xian Pi	Dictamnus dasycarpus 13,14,16	4	7
甘草	Gan Cao, Liquorice	Glycyrrhiza uralensis 13-15	4	1
土三七	Tu San Qi	Gynura segetum/Radix Gynurae Segeti13-15	4	4
枳椇子	Ji Ju Zi, Jiguja	Hovenia dulcis 13-15	4	1
金不換	Jin Bu Huan	Lycopodium serratum 13,14	4	3
川楝子	Chuan Lian Zi	Melia toosendan 13,14	4	1
薄荷	Bo He	Mentha haplocalyx 13,14	4	1
何首烏	He Shou Wu, Hoshouwu	Polygoni multiflori/Polygonum multiflorum9,13-16	4	80
葛根	Ge Gen	Pueraria lobata 13-15	4	2
大黃	Da Huang	Rheum palmatum 13,14	4	1
菝葜	Ba Qia	Smilacis Chinae Radix16	4	1

Abbreviations: TCM, traditional Chinese medicine; RUCAM, Roussel Uclaf Causality Assessment Method.

Table 5.

TCM Herbs Found to Have Hepatotoxic Properties in the Laboratory Setting.

中草藥/成藥/方劑	TCM Herb or Concoction
刺五加	Acathopanax senticosus (Rupr et Maxim) Harms33
紅豆	Adzuki bean (Phaseolus aureus Roxb)34
蛇葡萄	Ampelopsis brevipedunculata (Maxim) Trautv (Vitaceae)35
牛樟芝	Antrodia camphorata 36,37
黃花蒿	Artemisia annua L38
赤小豆	Black bean (Glycine max [L] Merr)34
綠豆	Mung bean (Phaseolus radiatus L)34
三七	Panax notoginseng 29
白芍	Radix Paeoniae Alba39
赤芍	Radix Paeoniae Rubra39
地黃	Rehmannia glutinosa 29
黑豆	Rice bean (Phaseolus calcaratus Roxb)34
丹參	Salvia miltiorhiza 40
五味子	Schisandra chinensis 41
蒼耳	Xanthium strumarium 42
二至丸: 女貞子 旱蓮草	Er-Zhi-Wan: Fructus Ligustri Lucidi, Herba Ecliptae43
桂枝茯苓丸：桂枝 茯苓 桃仁 芍藥 牡丹皮	Guizhi-Fuling-Wan: Bark of Cinnamomum cassia Presl, Carpophores of Poria cocos Wolf, Seed of Prunus persica Batsch, Root of Paeonia lactiflora Pall, Root bark of Paeonia suffruticosa44
瀉青丸: 龍膽草 當歸 川芎 梔子 大黃 羌活 防風	Shieh-Qing-Wan: Root of Angelica sinensis Diels (Umbelliferae) Root and rhizome of Gentiana scabra Bunge (Gentianaceae) Fruit of Gardenia jasminoides Ellis (Rubiaceae) Root and rhizome of Rheum palmatum L (Polygonaceae) Rhizome of Ligusticum chuanxiong Hort. (Umbelliferae) Root and rhizome of Notopterygium incisum Ting (Umibelliferae) Root of Saposhnikovia divaricata Schischk (Umbelliferae)44
四逆散：柴胡，白芍，枳實，甘草	Si Ni San: Radix bupleuri, Radix Paeoniae Alba, Fructus Aurantii Immaturus, Radix Glycyrrhizae45
四磨飲：人參，檳榔，沉香，烏藥	Syh-Mo-Yiin: Root of Panax ginseng CA Meyer (Araliaceae) Seed of Areca eateehu L (Palmae) Lignum of i Roxb. (Euphorbiaceae) Root of Lindera strychn (/i~lia Vill (Lauraceae)44
茵陳蒿湯: 茵陳,梔子,大黃	Yin Chen Hao Tang: Artemisia capillaris Thunb (Tarragon), Gardenia jasminoides Ellis (Gardenia), and Rheum officinale Baill (Rhubarb)46

Abbreviation: TCM, traditional Chinese medicine.

Table 2.

TCM Concoctions That Were Assessed by RUCAM to Demonstrate Clear Causality of Hepatotoxicity.

中成藥/方劑名稱	TCM Concoctions	Level of Causality	No. of Cases
丹鹿通督片: 丹参、鹿角膠、黄芪、延胡索、杜仲	Dan Lu Tong Du tablet: Salvia miltiorrhiza, Cervi cornus Colla, Astragalus membranaceus, Corydalis yanhusuo, Eucommia ulmoides17	4	8
首烏片：牛膝，菟絲，鱧腸，女楨，忍冬，桑白皮，何首烏，補骨脂，地黃，金櫻子，芝麻，豨薟	Shou Wu Pian: Achyranthes bidentata, Cuscuta chinensis, Eclipta prostrata, Ligustrum lucidum, Lonicera japonica, Morus alba, Polygonum multiflorum, Psoralea corylifolia, Rehmannia glutinosa, Rosa laevigata, Sesamum indicum, Siegesbeckia orientalis13,14	4	28
小柴胡湯：柴胡，人參，甘草，半夏，黃芩，薑和大棗	Syosaikoto/Xiao Chai Hu Tang: Bupleurum falcatum, Ginseng, Glycyrrhiza glabra, Pinellia tuber, Scutellaria baicalensis, Zingiber officinale, Zizyphus jujuba13,14	4	4
消銀膠囊: 地黃，芍藥，白芍，當歸，苦參，金銀花，玄參，牛蒡子，蟬蛻，黃芩，防風，大青葉，紅花	Xiao Yin pill: Rehmannia glutinosa, Paeonia suffruticosa, Paeonia lactiflora, Angelica sinensis, Sophora flavescens, Lonicera japonica, Scrophularia ningpoensis, Arctium lappa, Periostracum cicadae, Cortex dictamni, Saposhnikovia divaricata, Folium isatidis, Carthamus tinctorius17	4	6
養血生髮膠囊:熟地黃，當歸，羌活，木瓜，川芎，白芍，菟絲子，天麻，制何首烏	Yang Xue Sheng Fa capsule: Radix rehmanniae preparata, Angelica sinensis, Notopterygium incisum, Chaenomeles speciosa, Ligusticum chuanxiong, Paeonia lactiflora, Semen cuscutae, Gastrodia elata, Radix polygoni multiflori preparata17	4	9
熱多寒少湯加大黄：大黃，葛根，黃芩，細葉藁本，萊菔子，桔梗，升麻，白芷	Yeoldahanso-tang plus Rheum rhabarbarum: Rhei Radix et Rhizomaa, Pueraria thunbergiana Bentham, Scutellariae Radix, Ligusticum tenuissimum Kitagawa, Raphani Semen, Platycodonis Radix, Cimicifuga heracleifolia, Angelicae Dahuricae Radix16	4	1

Abbreviations: TCM, traditional Chinese medicine; RUCAM, Roussel Uclaf Causality Assessment Method.

Table 3.

Single Herbs With Hepatotoxic Risks.

中藥名	Commonly Known as	Scientific Name	Level of Causality	No. of Case
雞骨草	Ji Gu Cao	Abrus cantoniensis 13-15	3	1
刺五加	Ci Wu Jia	Acanthopanax senticosus 14	3	1
刺五加	Ci Wu Jia	Acanthopanax senticosus 13-15	2	2
七日暈	Qi Ri Yun, Chi R Yun	Breynia officinalis 13,14,24	3	19
七日暈	Qi Ri Yun, Chi R Yun	Breynia officinalis 14,15	2	2
綠茶	Lu Cha/Green tea/Chaso	Camellia sinensis 13,14	3	12
綠茶	Lu Cha/Green tea/Chaso	Camellia sinensis 14	2	121
綠茶	Lu Cha/Green tea/Chaso	Camellia sinensis 18	1	—
積雪草	Ji Xue Cao, Gotu kola	Centella asiatica 14	3	1
積雪草	Ji Xue Cao, Gotu kola	Centella asiatica 15	2	2
鯇魚膽	Carp gallbladder	Ctenopharyngodon idella 25	3	1
白鮮皮	Bai Xian Pi	Dictamnus dasycarpus 16	3	32
白鮮皮	Bai Xian Pi	Dictamnus dasycarpus 14,15	2	20
麻黃	Ma Huang	Ephedra sinica 14	3	1
麻黃	Ma Huang	Ephedra sinica 14,15	2	6
麻黃	Ma Huang	Ephedra species 18	1	—
土三七	Tu San Qi	Gynura segetum/Radix Gynurae Segeti14	3	2
土三七	Tu San Qi	Gynura segetum/Radix Gynurae Segeti14,17,19	2	171
枳椇子	Ji Ju Zi, Jiguja	Hovenia dulcis 14	3	1
枳椇子	Ji Ju Zi, Jiguja	Hovenia dulcis 14	2	1
金不換	Jin Bu Huan	Lycopodium serratum 14	3	1
金不換	Jin Bu Huan	Lycopodium serratum 14,15	2	10
人參	Ren Shen, Ginseng	Intravenous Wild Ginseng Pharmacopuncture16	3	1
人參	Ren Shen, Ginseng	Panax ginseng 13-15	2	6
何首烏	He Shou Wu, Hoshouwu	Polygoni multiflori/Polygonum multiflorum9,16	3	147
何首烏	He Shou Wu, Hoshouwu	Polygoni multiflori/Polygonum multiflorum13,15,17,21	2	516
何首烏	He Shou Wu, Hoshouwu	Polygoni multiflori/Polygonum multiflorum9,19,21-23	1	—
葉下珠	Ye XiaZhu	Phyllanthus urinaria 13-15	3	1
黃芩	Huang Qin	Scutellaria baicalensis 13,14	3	1
黃芩	Huang Qin	Scutellaria baicalensis 13-15	2	22
血見愁	Xue Jian Chou	Teucrium viscidum 26	3	1
翼枝榆	Yi Zhi Yu	Ulmus davidiana var japonica Nakai16	3	3
附子	Fu Zi	Aconitum carmichaeli 17	2	13
當歸	Dang Gui	Angelica sinensis 13,15	2
茵陳蒿	Yin Chen Hao	Artemisia capillaris 14,15	2	7
柴胡	Chai Hu	Bupleurum falcatum 13-15	2	28
決明子	Jue Ming Zi	Cassia obtusifolia 15,17	2	18
喜樹	Xi Shu	Camptotheca acuminata 13-15	2	—
及己	Ji Ji	Chloranthus serratus 13-15	2	—
珠果黄堇	Zh Guo Huang Jin,Hwang Geun Cho	Corydalis speciosa 15	2	—
延胡索	Yan Hu Suo	Corydalis yanhusuo 17	2	36
延胡索	Yan Hu Suo	Corydalis yanhusuo 18	1	—
瞿麥	Qu Mai	Dianthus superbus 20	2	1
常山	Chang Shan	Dichroa root 20	2	1
常山	Chang Shan	Dichroa febrifuga Lour13	1	—
五倍子	Wu Bei Zi	Galla chinensis 13-15	2	—
毛果天芥菜	Mao Guo Tian Jie Cai	Heliotropium lasiocarpum 13-15	2	4
紫草科植物	—	Heliotropium 18	1	—
益母草	Yi Mu Cao	Leonuri japonici 20	2	1
川楝子	Chuan Lian Zi	Melia toosendan fruit15,20	2	1
薄荷	Hu Bo He You	Mentha pulegium 13-15	2	—
石榴皮	Shi Liu Pi	Pericarpium granati 13-15	2	—
虎杖	Hu Zhang	Polygonum cuspidatum 13-15	2	—
破故紙	Po Gu Zhi, Bol Gol Zhee	Psoralea corylifolia 13-17	2	44
葛屬植物	Kudzu	Pueraria thunbergiana 13-15	2	6
大黃	Da Huang	Rheum officinale/Rheum palmatum15,17	2	24
丹蔘	Dan Shen	Salvia miltiorrhiza root20	2	1
天花粉	Tian Hua Fen	Trichosanthes kirilowii 13-15	2	—
合歡皮	He Huan Pi	Albizia julibrissin 13	1	—
艾葉	Ai Ye	Artemisia argyi 13	1	—
蒼朮苷	Cang Zhu Gan	Atractylis gummifera 18	1	—
小米辣	Xiao Mi La, Tobasco pepper	Capsicum frutescens 18	1	—
杜仲	Du Zhung	Cortex eucommiae 27	1	—
豬屎豆	Zhu Shi Dou	Crotalaria 18	1	—
莪朮	E Zhu	Curcuma phaeocaulis 27	1	—
黃藥子	Huang Yao Zi	Dioscorea bulbifera L13,27	1	—
八角蓮	Ba Jiao Lian	Dysosma versipellis 27	1	—
吳茱萸	Wu Zhu Yu	Evodia rutaecarpa 27	1	—
苦楝子	Ku Lian Zi	Melia azedarach 13	1	—
石花	Shi Hua	Parmelia saxatilis 18	1	—
商陸	Shang Lu	Phytolacca acinosa Roxb13	1	—
苦參	Ku Shen	Radix sophora 27	1	—
重樓皂苷	Chong Lou Zao Gan	Rhizoma Paridis saponins30	1	—
肉豆蔻	Rou Dou Kou	Semen myristicae 27	1	—
千里光	Qian Li Guang	Senecio scandens 13,18,27	1	—
番瀉葉	Fan Xie Ye	Sennae folium 27	1	—
雷公藤	Lei Gong Teng	Tripterygium wilfordii 13,28,29	1	—
蒼耳子	Cang Er Zi	Xanthium sibiricum/Xanthium strumarium L fruits13,31	1	—
生姜	Sheng Jiang	Zingiber officinale Roscoe27	1	—

Table 4.

Herb Concoctions With Hepatotoxic Risks.

中成藥/方劑	TCM Concoctions	Level of Causality	No. of Cases
丹鹿通督片: 丹参、鹿角膠、黄芪、延胡索、杜仲	Dan-lu-tong-du tablet: Salvia miltiorrhiza, Cervi cornus Colla, Astragalus membranaceus, Corydalis yanhusuo, Eucommia ulmoides17	3	1
首烏片：牛膝，菟絲，鱧腸，女楨，忍冬，桑白皮，何首烏，補骨脂，地黃，金櫻子，芝麻，豨薟	Shou Wu Pian: Achyranthes bidentata, Cuscuta chinensis, Eclipta prostrata, Ligustrum lucidum, Lonicera japonica, Morus alba, Polygonum multiflorum, Psoralea corylifolia, Rehmannia glutinosa, Rosa laevigata, Sesemum indicum, Siegesbeckia orientalis14	3	1
首烏片：牛膝，菟絲，鱧腸，女楨，忍冬，桑白皮，何首烏，補骨脂，地黃，金櫻子，芝麻，豨薟	Shou Wu Pian: Achyranthes bidentata, Cuscuta chinensis, Eclipta prostrata, Ligustrum lucidum, Lonicera japonica, Morus alba, Polygonum multiflorum, Psoralea corylifolia, Rehmannia glutinosa, Rosa laevigata, Sesamum indicum, Siegesbeckia orientalis14,15	2	17
防風通聖散：黃芩, 滑石, 甘草, 石膏, 桔梗, 防風, 川芎, 當歸, 白芍, 大黃,麻黃, 薄荷, 連翹, 芒硝, 荊芥, 白朮, 梔子	Bangpungtongsung-san: Scutellariae Radixa, Talcum, Glycyrrhiza uralensis Fischer, gypsum, Platycodonis Radix, Saposhnikoviae Radix, Cnidii Rhizoma, Angelicae Gigantis Radix, Paeoniae Radix, Rhei Rhizoma, Ephedrae Herba, Menthae Herba, Forsythia suspensa Vahl, Natrii Sulfas, Schizonepetae Spica, Atractylodes macrocephala Koidzumi, Gardeniae Fructus16	3	1
漢方防風通聖散：當歸，蒼朮，蛇床子，梔子，麻黃，連翹，甘草，石膏，防風，薄荷，牡丹，桔梗，大黃，荊芥，黃芩和姜; 滑石粉和硫酸鈉。	Bofu Tsu Sho San: Angelica, Atractylis, Cnidium, Gardenia, Ephedra, Forsythia, Glycyrrhhiza, Gypsum fibrosum, Ledebouriella, Mentha, Paeonia, Platycodon, Rheum, Schizonepeta, Scutellaria and Zingiber; Kadinum (talcum powder), and sodium sulfuricum13-15	2	1
加味五積散： 蒼朮, 陳皮, 厚朴, 桔梗, 枳殼, 當歸, 茯苓, 半夏, 川芎, 白芷, 肉桂, 桃仁, 紅花, 秦艽, 五加皮, 甘草, 生薑 東亞鉗蠍, 蜈蚣, 馬錢子, 白屈菜, 延胡索, 黃芩, 黃連, 蘆根, 草烏	Gamiojuck-san: Atractylodis Rhizoma, Citrus unshiu Markovich, Magnolia officinalis, Platycodonis Radix, Aurantii Fructus Immaturus, Zingiber officinale, Angelicae Gigantis Radix, Poria Sclerotium, Pinellia ternata Breitenbach, Cnidium officinale Makino, Angelicae Dahuricae Radix, Cinnamomi Ramulus, Persicae Semen, Carthami Flos, Gentianae Macrophyllae Radix, Acanth opanacis Cortex, Glycyrrhiza uralensis Fischer, Zingiber officinale, Buthus martensii Karsch, Scolopendra, Strychni Semen, Chelidonii Herba, Corydalis Tuber, Scutellariae Radix, Coptidis Rhizoma, Phragmitis Rhizoma, Aconiti Kusnezoffii Tuber16	3	1
加味六君子湯: 香附, 生姜, 大棗, 白朮, 茯苓, 陳皮, 半夏, 人参根, 紫蘇葉, 土木香, 砂仁	Gamiyukgunja-tang: Cyperi Rhizoma, Zingiber officinale, Zizyphi Fructus, Atractylodes macroephala Koidzumi, Poria Sclerotium, Citrus unshiu Markovich, Pinellia ternata Breitenbach, Ginseng Radix, Perillae Folium, Inula helenium, Amomi Fructus16	3	1
附子草烏加減方：附子 草烏	Herbal Medicine including Boo-ja and Cheon-o: Aconiti Lateralis Radix Preparata, Aconiti Kusnezoffii Tuber were indicated and others were unknown16	3	1
黄蓮加減方： 黃蓮	Herbal Medicine Including Coptidis Rhizoma: only Coptidis Rhizoma was indicated in original article; others were unknown16	3	1
白鮮加減方：白鮮, 葛根, 升麻, 蒺藜, 浮萍, 麥冬, 地黃, 甘草	Herbal medicine including Dyctamnus dasycarpus: Dictamnus dasycarpusa, Pueraria thunbergiana Bentham, Cimicifuga heracleifolia, Tribulus terrestris L, Spirodelae Herba, Liriopis seu Ophiopogonis Tuber, Rehmanniae Radix Preparata, Glycyrrhiza uralensis Fischer16	3	1
少陽人獨活地黄湯:山茱萸，茯苓，澤瀉，牡丹皮，防風，東北土當歸（+石膏）	Soyangin Dokwhaljiwhang-tang: Rehmanniae Radix Preparata, Cornus officinalis, Poria Sclerotium, Alismatis Rhizoma, Moutan Radicis Cortex, Saposhnikoviae Radix, Araliae Continentalis Radix (+gypsum)16	3	1
六味地黄元：澤瀉，地黃，山茱萸，山藥，麥冬，澤瀉，牡丹皮，茯苓	Yugmijihwang-won: Alismatis Rhizomaa, Rehmanniae Radix Preparata, Cornus officinalis, Dioscoreae Rhizoma, Alismatis Rhizoma, Moutan Radicis Cortex, Poria Sclerotium16	3	1
大柴胡湯： 柴胡，人參，甘草，半夏，黃芩，薑和棗樹	Da Chai Hu Tang: Bupleurum falcatum, Ginseng, Glycyrrhiza glabra, Pinellia, Scutellaria, Zingiber officinale, and Zizyphus jujuba13-15	2	1
複方青黛丸: 白芷,板藍根,神曲，丹參,土茯苓	Fufangqingdaiyuan: Angelica dahurica, Isatis indigotica (Indigo naturalis), Massa medicata fermentata (yeast), Salvia milthiorrhiza, Smilax glabra13,14	2	1
漢方加味逍遥散：當歸，白朮，柴胡，梔子，甘草，薄荷，牡丹皮，白芍，菌核和姜	Kamishoyosan: Angelica sinensis, Atractylodes racea, Bupleurum falcatum, Gardenia, Glycyrrhiza glabra, Mentha haplocalyx, Moutan, Paeonia alba, Sclerotium Poriae Cocos, and Zingiber officinale13-15	2	1
龍丹瀉肝湯：木通，澤瀉，當歸，柴胡，梔子，龍膽，甘草，車前子，熟地黃和黃芩	Long Dan Xie Gan Tang: Acebia, Alisma, Angelica sinensis, Bupleurum, Gardenia, Gentiana, Glycyrrhiza, Plantago, Rehmannia, and Scutellaria13-15	2	17
小柴胡湯：柴胡，人參，甘草，半夏，黃芩，薑和大棗	Syosaikoto/Xiao Chai Hu Tang: Bupleurum falcatum, Ginseng, Glycyrrhiza glabra, Pinellia tuber, Scutellaria baicalensis, Zingiber officinale, Zizyphus jujuba14,15	2	20
小柴胡湯: 柴胡，人參，甘草，半夏，黃芩，薑和大棗	Syosaikoto/Xiao Chai Hu Tang: Bupleurum falcatum, Ginseng, Glycyrrhiza glabra, Pinellia tuber, Scutellaria baicalensis, Zingiber officinale, Zizyphus jujuba23	1	—
桃紅四物湯: 桃仁，紅花，熟幹地黃，當歸，赤芍，川芎	Tao-hong-si-wu decoction: Semen Persicae, Flos Carthami, Radix Rehmanniae, Radix Angelicae Sinensis, Radix Paeoniae Rubra, Rhizoma Chuanxiong32	1	—

We found 20, 17, 34, and 27 individual herbs that were graded level 4, 3, 2, and 1 for their causality toward liver injury, respectively. For herbal concoctions, we found 6, 10, 7, and 2 concoctions that were graded level 4, 3, 2, and 1, respectively. There were in total 21 herbs or concoctions that were hepatoprotective in laboratory settings. Using RUCAM, clear causality (level 4) was established in 194 cases of TCM-induced liver toxicity.

Discussion

TCM for Symptom Relief and Body Enhancement

He Shou Wu (何首烏, Polygoni multiflori) is traditionally used for treating premature whitening of hair, dizziness, and insomnia due to the insufficiency of essence and blood.⁴⁷ This makes He Shou Wu a popular choice among cancer patients to counter the side effects of chemotherapy such as alopecia. According to our results, there were 80 cases reaching level 4 (clearly established causality), 147 cases reaching level 3 (possible causality), and 516 cases attaining level 2 (clinical suspicion). Furthermore, when He Shou Wu was coadministered with other drugs as herbal concoctions, there were 37 cases that reached level 4. Therefore, there was clear evidence that He Shou Wu could cause liver injury.

In TCM, Chuan Lian Zi (川楝子, Melia toosendan) is used for relieving pain,⁴⁸ and it is often used by cancer patients for pain control and to “relieve liver Qi congestion,” which is common among breast and liver cancer patients according to TCM theory. However, Chuan Lian Zi is known to have a slightly toxic property.⁴⁹ Our search results in a case (level 4) of Chuan Lian Zi–induced liver injury.

Ren Shen (人參, Panax ginseng) has gained popularity in recent years. The annual world ginseng production was estimated to be 80 080 tons, and its global consumption has risen steadily over the years. Ginseng is being marketed as a natural health food and various forms are available.⁵⁰ Cancer patients take Ren Shen prepared in the form of tea, capsules, or as an ingredient in soup in the hope of increasing their “inner resistance.”⁶ Ren Shen could be used for restoring Qi. It can treat severe vomiting, fatigue, diarrhea, shortness of breath, fatigue, feeble pulse, extreme weakness after severe disease, or prolonged illness.⁴⁷ During chemotherapy, patients might experience the above symptoms and may use this herb. Our review found a case of possible (level 3) hepatotoxicity caused by intravenous wild ginseng pharmacopuncture and 6 cases of suspected liver injury (level 2) caused by Ren Shen. Hence, further research should be done to confirm the causality of liver injury caused by this popular herb.

San Qi (三七, Panax notoginseng) is a herb used to arrest bleeding and remove blood stasis in TCM. It is also known to be helpful in reducing swelling and relieving pain.⁴⁸ Hence, this herb might be used to reduce the pain caused by the tumor. According to laboratory findings, it was suggested that it has hepatoprotective effects. Unfortunately, another similarly named herb named Tu San Qi (土三七), or Radix Gynurae Segeti, has been proven to induce hepatic sinusoidal obstruction syndrome/veno-occlusive disease.⁵¹ Contrary to the hepatoprotective San Qi, Tu San Qi led to 4 cases of liver injury (level 4). Hence, caution must be taken to avoid misidentification.

Chai Hu (柴胡, Bupleurum falcatum) is an important component in Xiao Chai Hu Tang (小柴胡湯; XCHT). XCHT is a commonly used concoction to treat Shaoyang disease with symptoms such as chills and fever, nausea and dizziness, restlessness, fullness, discomfort at the chest, and dry throat.⁴⁸ Cancer patients may experience neutropenic fever, and XCHT is a common folk remedy that might be taken. Our results found that there were 4 cases of XCHT reaching level 4, while Chai Hu had 28 cases reaching level 2. On the other hand, Si Ni San, a concoction containing Chai Hu, is used to treat chronic hepatitis.⁴⁸ Si Ni San was found to be hepatoprotective in laboratory settings. We hypothesize that this could be due to the interaction between different herbs in concoctions. When herbs containing hepatotoxic constituents are boiled with other herbs, it is possible that new compounds that are nonhepatotoxic are formed.

Another herb that showed conflicting results was Yin Chen Hao (茵陳蒿, Artemisia capillaris). Our literature search found that this herb causes liver injury, with 1 case of level 4 and 7 cases of level 2. On the contrary, Yin Chen Hao is used to treat jaundice in TCM. Oncology patients may take this herb to reduce jaundice. A concoction that uses Yin Chen Hao as a major herb, named Yin Chen Hao Tang (茵陳蒿湯), is also used for treating jaundice and diseases such as acute infectious icterohepatitis, acute cholecystitis, cholelithiasis, and leptospirosis in TCM. Our literature search found that laboratory findings suggesting Yin Chen Hao Tang has hepatoprotective properties. We postulate that as TCM herbs are rarely prescribed as a single herb, the other herbs that are prescribed concurrently may mitigate the hepatotoxic effects of Yin Chen Hao. Thus, in the form of a concoction, Yin Chen Hao Tang demonstrates hepatoprotective properties.

Wu Wei Zi (五味子, Schisandra chinensis) is found to be hepatoprotective in our literature search. It is also known to be effective in lowering transaminase levels in those suffering from chronic hepatitis.⁴⁸ Hence, this herb may be taken by cancer patients to reduce the liver toxicity of systemic therapies and improve their liver function.

Bai Shao (白芍, Radix Paeoniae Alba) is known to nourish the liver and treat diarrhea, dysentery, and pain.⁴⁸ This herb may be taken by cancer patients in hopes of improving their liver function. The results of our review echoed with its TCM use, as it was found to have hepatoprotective properties in the laboratory setting.

TCM With Anticancer Properties

Bai Xian Pi (白鮮皮, Dictamus dasycarpus) has been found to contain chemical constituents with cytotoxic properties.⁵² One study showed the inhibitory effect of one of its chemical constituents on human breast cancer cells. Thus, it may be prescribed by TCM practitioners to patients for anticancer purposes.⁵³ However, our review found that Bai Xian Pi could cause hepatotoxicity, which could probably be explained by its cytotoxic properties. We found 7 and 32 cases that reached level 4 and 3, respectively.

An interesting finding was Camellia sinensis (綠茶), commonly known as green tea, had 28 cases reaching level 4. In contrast, previous research has shown that green tea extract has antioxidant and antihepatotoxic properties.⁵⁴ Green tea was also reported to have anticancer properties. A review suggested green tea has anti–breast cancer activity by adjusting cell signaling pathways.⁵⁵ Its seeds were also found to have inhibitory effects on human ovarian cancer cells.⁵⁶ An extract also showed inhibitory effects on the growth of colorectal cancer cells.⁵⁷ We hypothesize that while there are certain chemical constituents that may be beneficial to health, green tea may also contain hepatotoxic constituents and may lead to liver injury when taken in large quantities.

Huang Yao Zi (黃藥子, Dioscorea bulbifera L) is traditionally used to treat goiter, hyperthyroidism, and tumors,⁴⁸ and it could be prescribed to patients with thyroid cancer. However, it is known that overdose or long-term usage could lead to liver damage.⁵⁸ Surprisingly, no clinical cases of related hepatotoxicity were found in our literature search, only laboratory findings showed the potential of liver injury caused by this herb. This could be explained by the decreasing popularity and cautious use of this herb in clinical TCM practice nowadays.

Our review found 1 case of Huang Qin (黃芩Scutellaria baicalnsis) that reached level 3 and 22 cases of level 2. This potentially hepatotoxic herb has been found to have anticancer properties, its chemical constituents were found to be cytotoxic to a broad range of human cancer cells, including brain tumor,⁵⁹ prostate cancer,⁶⁰ head and neck squamous cell carcinoma,⁶¹ acute lymphocytic leukemia, lymphoma, and myeloma cell lines.⁶²

Topoisomerase inhibitors, like irinotecan and topotecan, are a type of chemotherapeutic agents that were derived from camptothecin from the bark of Camptotheca acuminata (Xishu, 喜樹). This TCM herb was found to reach level 2 of hepatotoxicity causality.

Causality Assessment

As demonstrated in the tables above, there are varying levels of evidence in the current literature. However, the clinical and histopathological features of herb-induced liver toxicity may mimic any liver injury histopathological model,⁶³ and expert judgement could be limited by subjectivity. Hence, a widely accepted and standardized algorithm is needed to confirm causality. RUCAM is a quantitative scale that has been used worldwide,^17,64-66 allowing results to be comparable across countries. When compared with other general causality assessment algorithms like the Naranjo scale, it is more liver-specific and more relevant.¹² Among liver-oriented methods, RUCAM was found to be superior. Clinical Diagnostic Scale showed poorer discriminative power, whereas the Digestive Disease Week-Japan scale included an in vitro drug lymphocyte stimulation test evaluation criterion, which was not widely accessible.⁶⁷ RUCAM also addresses other alternative causes of liver injury like concomitant drug use. Therefore, RUCAM is by far the most preferred algorithm used in the field.

Future Implications

First of all, we should note the presence of different types of evidence in the literature. Without following established causality algorithms, problems like comedication and poor data quality may affect the establishment of causality; hence, it is unjustifiable to ascertain the causal relationship immediately. Furthermore, contaminants during production and processing may lead to liver injury. Hence, clear-cut causality is often difficult to achieve. Our review presented the stratification of causality of the current literature. RUCAM is an important tool that should be applied to all future cases to determine causality accurately. Further studies are needed to confirm the causality of herb-induced liver injury with RUCAM in order to clarify the hepatotoxicity of herbs that are suspected in the literature. The use of RUCAM should be encouraged among physicians to aid diagnosis, and RUCAM should be employed before publication of cases and inclusion in databases.

In Chinese communities, there is a common misconception that TCM is free of side effects and toxicities. Our review highlights the importance to evaluate the potential hepatotoxicity of TCM. We suggest that there is a fundamental need for raising the awareness of this issue among Chinese communities. Cancer patients should consult TCM practitioners before using TCM, instead of taking TCM without professional advice.

Also, TCM can have hepatoprotective effects. However, proving the hepatoprotective effects of a herb clinically can be challenging, and the therapeutic benefit of TCM is often questioned. TCM herbs are rarely used alone, as each patient receives a personally tailored concoction. Hence, the effectiveness of TCM is difficult to be proven in the Western-dominated setting based on a medical system that treats the same disease with the same drug on different patients.

In practice, oncologists are often uncertain of the efficacy and safety of TCM and therefore urge patients not to take any TCM during systemic treatment. TCM has been practiced for over 2000 years, and its ideologies and effectiveness have been deeply rooted and accepted in Chinese communities. A survey done in Hong Kong found that over two thirds of all interviewed Chinese cancer patients believed that integrated TCM and Western medicine was effective in treating cancer.⁷ Hence, Chinese cancer patients are keen to use TCM. The total rejection by some oncologists may prompt patients to hide the truth. The aforementioned survey found that among patients who were concurrently receiving Western medicine treatment and TCM, nearly two thirds of them did not inform their physicians. This is not only harmful to the doctor-patient relationship but also unhelpful in monitoring and treating the patient.

Recent research has shown that certain TCM when used in combination with Western medicine can be beneficial. It was found that some TCM could act as effective chemosensitizers and radiosensitizers, and could be helpful in palliative care.⁶⁸ We have learnt from history that some modern anticancer drugs were derived from plants. The Pacific Yew, the Madagascar Periwinkle, and the Chinese happy tree have yielded valuable chemicals for chemotherapy. If TCM was excluded from treating cancer patients, the advancement of cancer therapy may be hindered. More research is needed to clarify the hepatotoxicity and hepatoprotectiveness of different TCM herbs and concoctions. This is crucial to aid TCM practitioners and Western medicine doctors in making clinical decisions, as well as paving the way for TCM and Western medicine integration in treating cancer.

Conclusion

This literature review compiled a list of hepatotoxic and hepatoprotective TCM herbs and concoctions, and highlighted some that are highly likely to be used by cancer patients as they either have anticancer properties or symptom relief purposes. They were then stratified according to their levels of causality, to provide a clearer and more clinically relevant picture of the current evidence. More stringent research with the use of RUCAM is needed to confirm the causality of herb-induced liver injury before publication and inclusion in databases. Cancer patients should note the potential hepatotoxic effects of TCM herbs and should not assume the absence of side effects of TCM herbs. More collaboration between TCM and Western medicine should be encouraged to establish effective and safe screening of drug-herb interaction.