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Systematic review on herb-induced liver injury in Korea
Accepted Manuscript Systematic review on herb-induced liver injury in Korea Woo-Jin Lee, Hae-Won Kim, Hyun-Yong Lee, Chang-Gue Son, Professor PII:
S0278-6915(15)00192-1
DOI:
10.1016/j.fct.2015.06.004
Reference:
FCT 8322
To appear in:
Food and Chemical Toxicology
Received Date: 30 March 2015 Revised Date:
3 June 2015
Accepted Date: 7 June 2015
Please cite this article as: Lee, W.-J., Kim, H.-W., Lee, H.-Y., Son, C.-G., Systematic review on herbinduced liver injury in Korea, Food and Chemical Toxicology (2015), doi: 10.1016/j.fct.2015.06.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Graphical Abstract
Survey for herbal list caused HILI in Korea
Database
4 international and 4 Korean electric database PubMed, five Korean electronic databases
Data extraction
Initial independent references : n = 313 Met inclusion criteria : n = 31 (Total 97 cases)
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Single herb (21)
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HILI case
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Study
87 cases (Male: 44 Female: 43)
Main herbs caused HILI
Multiple herbs (3) 10 cases (Male: 3 Female 6, Unkn. 1)
Polygoni Multiflori (39 cases), Dictamnus dasycarpus (36 cases) Ulmus davidiana var. japonica Nakai (3 cases) et al.
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Title page
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Abbreviated title: Herbal plants with potential for HILI
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Systematic review on herb-induced liver injury in Korea
Woo-Jin Leea.#, Hae-Won Kima,#, Hyun-Yong Leea,# and Chang-Gue Sonb*
a
Korean Medical College of Daejeon University, 62, Daehak-ro Dong-gu Daejeon, 301-716,
b
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Republic of Korea
Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University,
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176-9 Daeheung-ro Jung-gu Daejeon, 301-724, Republic of Korea
Three authors contributed equally to this manuscript.
*Corresponding author: Chang Gue Son, Professor Liver and Immunology Research Center, Institute of Traditional Medicine and Bioscience of Daejeon University, 22-5 Daeheung-dong Jung-gu, Daejeon 301-704, Republic of Korea Tel: +82-42-229-6723; Fax: +82-42-257-6398; E-mail: [email protected] 1
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1. Introduction
Herbal medicines have been used as a treatment for various diseases and ailments for
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thousands of years, particularly in East Asia. In recent years, the popularity of herbal remedies has begun to spread to other parts of the world; about 18% of adults in the United States adopt herbal remedies to treat illnesses (Barnes et al., 2008; Ye and He, 2010). These
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numbers are even higher in Asia, with about 40% of individuals in Korea and China using some form of herbal product (Xu and Yang, 2009, Yoo et al., 2007).
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Given the growing use of herbal remedies, many concerns have been raised regarding the safety of herbal products, as unwanted side effects, particularly hepatotoxicity, have been reported for many of these products (Ekor, 2014). Many studies have identified herbal drugs as a major cause of drug-induced liver injury (DILI), including one Chinese study, which
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found that herbal drugs were responsible for 24.2% of DILI cases (Li et al., 2007). Similar findings were also seen in Korea, with a prospective nationwide study attributing 30.7% of 371 DILI cases to herbal drugs (Suk et al., 2012). As to the overall incidence of herb-induced
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liver injury (HILI), two studies revealed an incidence of HILI of 0.71% in Korea (Oh et al., 2015) and 0.6% in Japan (Mantani et al., 2002).
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These findings have led to a heightened awareness regarding the potential hepatotoxicity of herbal drugs, but the specific herbs associated with these effects are rarely mentioned, with the causative agents often generalized as simply “herbal drugs.” Moreover, the vast majority of studies of HILI exist solely in the form of case reports, with the herbal drugs suspected or known to cause HILI rarely listed. Here, we addressed this issue by performing a systematic review of studies describing HILI in Korea. Korea has a characteristic medical milieu compared to other countries: Oriental medicine, 2
ACCEPTED MANUSCRIPT for long, has been practiced along with conventional medicine and many folk remedies are comparatively popular. This means that many Koreans are more likely to be exposed to herbal and folk remedies, which may be related to HILI (Kang et al., 2008). Therefore, Korea
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provides a suitable medical environment to investigate the list of hepatotoxic herbal drug candidates.
We surveyed case reports of HILI in Korea between 1998 and 2015, and systematically
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classified them into single- and multi-herb groups. Our study aims to produce the list of herbal products with possibilities of hepatotoxicity, and thus analyze the characteristics of
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HILI and those herbal products.
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2. Methods
2.1. Data sources and keywords
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A systematic literature survey was conducted using publicly available electronic databases. Searches were performed for all studies published before January 2015 in PubMed (http://www.ncbi.nlm.nih.gov/pubmed), along with five Korean electronic databases, RISS
(https://www.riss.net),
KISTI
(http://society.kisti.re.kr),
KMBASE
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including
(http://kmbase.medric.or.kr), KIOM OASIS (http://oasis.kiom.re.kr), and a library database
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(http://libweb.dju.ac.kr). A secondary search of all references listed in any included study was then performed to identify titles matching the inclusion criteria. Searches were performed using combinations of the following keywords: “herb,” “herbal drug,” “herbal medicine,” “liver injury,” “hepatotoxicity,” “hepatic injury,” and “drug-induced liver injury.” Article type
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was limited to clinical reports, with no limitations as to publication language (e.g., an English-language abstract). Korean terms adapted from those listed above were used for
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Korean databases.
2.2. Eligibility criteria
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Articles were screened using the following inclusion criteria: (1) human subjects, (2) studies indicating causative drugs, (3) herbal plants (no drugs of animal origin), and (4) clinical reports conducted in Korea. Articles identified using these initial criteria were read in full by the three authors, who then together determined the suitability of each article. Potentially relevant articles not meeting all of the necessary inclusion criteria (e.g., review articles, letters to the editor, animal studies) were excluded from this study. The extracted data included the authors, title of the study, year of publication, journal, name 4
ACCEPTED MANUSCRIPT of all herbal drugs associated with the study, number of patients treated with each herbal drug, and clinical data associated with HILI. HILI data included laboratory findings for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-
clinical
outcome
and
the
Council
for
International
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glutamyl transferase (GGT), total bilirubin (TB), type of HILI, treatment period for HILI, the Organizations
of
Medical
Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale (Teschke et
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al., 2014).
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2.3. Review process
Articles passing our initial filtering criteria were divided into either single- or multi-herb groups according to the composition of causative agents. Whenever possible, we identified the name of the causative herb; cases in which no definite herb could be identified were
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excluded from the study. In each case, specific laboratory findings and the type of HILI were analyzed. All cases in which the causative herb was clearly indicated were included in this study, even those in which the other information was not complete. Only cases with well-
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defined values for each parameter were included in the statistical analysis.
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2.4. Statistical analysis
Comparisons of HILI caused by either a single herb or by multiple herbs were performed using an independent student's t-test. Analysis for types of liver injury were performed using one-way analysis of variance (ANOVA) followed by Dunnett’s post hoc test. A P value ≤0.05 was considered statistically significant. All statistical analyses were performed with SPSS (version 18.0 KO for Windows; SPSS, Inc., Chicago, IL).
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3. Results
3.1. Characteristics of data
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In total, 5034 studies were identified in the initial screening, from which 31 reports met all of the necessary inclusion criteria (Figure 1). Of these 31 reports, 21 were classified into a single herb, accounting for 11 species; the remaining 10 reports were categorized as multi-
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herb formulations (Table 1). While the earliest study was published in 1998, 93.5% of the studies (29 of 31) were conducted after 2000, including 19 studies (61.3%) published after
3.2. Patient characteristics
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2009 (data not shown). The characteristics of all studies are summarized in Table 1.
From these 31 studies, we compiled a list of 97 cases of HILI, of which 47 were male
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(49.0%) and 49 were female (51.0%); the sex of one patient was not listed. Eighty-seven cases (44 males and 43 females) were caused by a single herb; the remaining 10 cases (3 males, 6 females, and 1 unknown) were caused by multi-herb formulae. The mean age of all
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patients was 50.9 ± 11.5 years (single-herb group, 50.8 ± 11.0; multi-herb group, 51.3 ± 14.0). The mean duration of herbal drug use was 52.1 ± 68.9 days (single-herb group, 45.9 ± 44.6;
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multi-herb group, 83.9 ± 132.8). The mean treatment period for HILI was 23.9 ± 15.3 days, with patients in the single-herb group treated for a significantly shorter period of time than those in the multi-herb group (20.8 ± 12.5 vs. 37.1 ± 18.6 days, respectively; P < 0.05). CIOMS/RUCAM scales were available for 70 cases (69 single-herb and 1 multi-herb cases); the mean score was 8.2 ± 1.4 for the single-herb case, with the lone multi-herb patient scoring an 8.0 (Table 1). Three patients died, one each after taking Polygoni Multiflori, Dictamnus dasycarpus, or Cudrania tricuspidata; a fourth patient received a liver transplantation after 6
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3.3. Laboratory findings and HILI types
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Average serum levels of hepatic enzymes AST and ALT were 954.0 ± 913.4 IU/L and 1007.1 ± 534.4 IU/L, respectively, about 25-fold higher than in healthy controls. The elevations of both enzymes were significantly higher in cases caused by a single herb, rather
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than multiple herbs (1157.8 ± 982.5 vs. 485.3 ± 466.8 for AST and 1082.9 ± 503.1 vs. 643.3 ± 530.4 for ALT; P < 0.05 for both). Average serum values of ALP and GGT were 306.5 ±
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257.4 IU/L (single-herb 301.3 ± 263.7, multi-herb 341.9 ± 206.6) and 191.2 ± 154.4 IU/L (single-herb 174.0 ± 129.7, multi-herb 232.9 ± 195.9), respectively. Serum bilirubin levels were 8.3 ± 10.9 mg/dL (single-herb 8.6 ± 11.3, multi-herb 6.4 ± 6.5). No significant differences were observed between the single- and multi-herb groups for ALP, GGT, or
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bilirubin (Table 1).
Eighty-three cases of HILI were further identified by the type of liver injury, consisting of 62 cases for the hepatocellular type (74.7%), 9 cases for the cholestatic type (10.8%), and 12
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cases (Table 1).
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cases for the mixed type (14.5%). Additional details were not available for the remaining 14
3.4. Identification of herbs associated with HILI Eleven species of herbal plants were identified from the 21 single-herb studies: Polygoni Multiflori (39 cases), Dictamnus dasycarpus (36 cases), Ulmus davidiana var. japonica Nakai (3 cases), Pueraria montana (2 cases), Psoralea corylifolia (1 case), intravenous wild ginseng pharmacopuncture (1 case), Aloe vera (1 case), C. tricuspidata (1 case), Smilacis Chinae Radix (1 case), Ceramium kondoi (1 case), and Corydalis speciosa max (1 case) (Table 2). Ten reports of HILI caused by multi-herb preparations were also identified, with 7
ACCEPTED MANUSCRIPT one case of HILI reported in each. Eight cases contained the name of the herbal formulae or its component; the remaining 2 cases provided the names of only one or two of the major
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herbs found in the causative compounds (Tables 3 and 4).
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4. Discussion
DILI is defined as a liver injury caused by external agents such as medications, herbs, or
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dietary supplements (Teschke et al., 2014). DILI represents an important medical issue, as it is a common cause of liver injury worldwide, accounting for 13% of acute liver failure cases in the United States alone (Ostapowicz et al., 2002). Herbal medications also play a major
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role in the onset of DILI, accounting for 9% and 11%, of patients suffering DILI in the United States and Spain, respectively (Andrade et al., 2005; Chalasani et al., 2008). These
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levels may be even higher in countries in which herbal medicines are common (Ye and He, 2010), with one Korean epidemiological study reporting 30.7% of 371 DILI cases attributable to herbal drug use (Suk et al., 2012); a similar study from China revealed that complementary and alternative medicines accounted for 19.0% of 21,789 DILI cases (Zhou et al., 2013).
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These data would result from the fact that Korea and China have used herbal plants more frequently than Western countries, in terms of Oriental medicine (Ye and He, 2010). While both the Korea and Chinese studies described above provide strong evidence of
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causality linking herbal remedies and HILI, these studies didn’t present the herbs causing this HILI. Here, we performed a systematic review of existing studies to identify which herbs
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show the high risk for HILI, along with the pattern of HILI observed in Korean populations. Generally, identifying causative agents for DILI/HILI, is difficult due to the relative rarity of these DILI/HILI cases and the complexity of the mechanism involved (Lucena et al., 2011). Most DILI./HILI-causative drugs are therefore only identified on a case-by-case basis through case reports. A systematic evaluation of HILI in Korea was therefore warranted due to the fractured nature of this information and the widespread use of these products in this population. Together, these data can provide a better understanding of the herbs most likely to 9
ACCEPTED MANUSCRIPT cause HILI, as well as identifying clinical features specific for these herbal plants. Thirty-one studies published between 1998 and 2014 were included in this systematic review, amounting to 97 cases of HILI. The sex distribution was nearly identical between
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males and females (49.0% vs. 51.0%, respectively), unlike the general features that females are more susceptible to liver injury than males (Kang et al., 2008). Patients affected by a single-herb preparation significantly outnumbered those affected by multi-herb preparations
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(89.7% vs. 10.3%, respectively; Table 1). This discrepancy may be related to how herbal remedies are sold in Korea, with multi-herb preparations generally prescribed by specialists,
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while the use of single herbs is largely unregulated. All cases of HILI by single herb (87 cases) were self-prescribed by the affected individuals, with no direct input from a physician. In contrast, patients with HILI caused by multiple herbs had been prescribed these drugs after consultation with a physician (data not shown).
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DILI/HILI is generally classified into three types, hepatocelluar, cholestatic, and mixed type, based upon well-defined pathological features. DILI/HILI is defined as a rise in either ALT or ALP levels, as calculated based upon a fold ratio of ALT over the upper limit of
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normal (ULN) relative to ALP over the ULN (Teschke et al., 2014). Hepatocellular and mixed types are considerably more common than that of the cholestatic type in DILI/HILI,
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consistent with the results described here (74.7%, 14.5%, and 10.8%, respectively) (Andrade et al., 2005). The average values of hepatic enzymes and bilirubin were elevated by about 24fold for AST, 25-fold for ALT, 2.6-fold for ALP, 3.8-fold for GGT, and 6.9-fold for total bilirubin. These increases were much more severe among cases of HILI caused by a single herb relative to those caused by multiple herbs (P < 0.05); however, patients with HILI caused by a single herb (20.8 ± 12.5) recovered in a significantly shorter period of time compared to cases caused by multiple herbs (37.1 ± 18.6, P < 0.05; Table 1). Of the 97 cases of HILI included in this study, 94 patients recovered from HILI, while 3 10
ACCEPTED MANUSCRIPT patients died (3.1%); 1 patient received a liver transplant as part of the treatment (Table 2). Two prospective studies in the United States and Korea observed 8% and 1.8% respectively for the rates of death or liver transplantation (Chalasani et al., 2008; Suk et al., 2012). No
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progression of chronic hepatotoxicity was shown in our review study, which is different from that of previous studies. A Spanish prospective study found that 5.7% of patients with DILI/HILI developed chronic liver disease (Andrade et al., 2005), while another study in the
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United States observed persistent laboratory abnormalities in 14% of patients with DILI/HILI over the course of 6 months (Chalasani et al., 2008). As expected, hepatocellular-type HILI
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showed higher clinical values relative to the cholestatic type for both AST (1130.5 ± 627.8 vs. 899.8 ± 814.9 IU/L) and ALT (1266.6 ± 451.0 vs. 637.9 ± 450.5 IU/L), but lower levels of ALP (279.7 ± 241.1 vs. 352.1 ± 307.5 IU/L) and total bilirubin (7.1 ± 9.9 vs. 14.6 ± 7.9 IU/L) (data not shown).
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HILI is categorized into intrinsic and idiosyncratic form in pathogenic classification. Unlike idiosyncratic form, intrinsic injury is dose-independent, and then pyrrolizidine alkaloids (PAs), a group of alkaloids mainly composed of pyrrolizidine, are known to mainly
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cause the intrinsic form of HILI. Unsaturated PAs are hepatotoxic, due to inducing hepatic sinusoidal obstruction syndrome (HSOS) (Teschke et al., 2014). The main PA-containing
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herb species are: Gynura segetum, Heliotroprium, Senecio, Crotalaria (Larrey and Faure, 2011). In China, 5 patients were reported to suffer HSOS after digesting Gynura segetum (Gao et al., 2012). We however supposed that any of the herbs in our study list wasn’t relevant with PA-causative HSOS because none of them was known to contain PAs. DILI/HILI generally arises as a result of idiosyncratic metabolic responses that are both doseindependent and unpredictable in their nature (Au et al., 2011). The idiosyncratic responses could be classified into two types, metabolic or immunologic, according to the result of reexposure test (Teschke et al., 2014). We reviewed the status of re-exposure tests in 97 cases 11
ACCEPTED MANUSCRIPT of HILI in our study. Six of total 97 patients had re-administrated the herbs, but unfortunately we couldn’t find the clear answer for the “positive re-exposure tests” Polygoni Multiflori and Dictamnus dasycarpus were the most frequent causative agents
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identified in this study, accounting for 39 (40.2%) and 36 (37.1%) of the 97 cases, respectively (Tables 2 and 3). The remaining herbs shown to confer HILI included 9 distinct species, with no herb associated with more than 3 cases (Table 2). According to the practices
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of traditional Oriental medicine, Polygoni Multiflori, a member of the Polygonaceae, has been used to improve blood supply and vitality (Choi et al., 2009). This herb showed
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hepatoprotective effects in an animal model of dimethylnitrosamine-induced liver cirrhosis (Huang et al., 2007). There is however a series of reports for hepatic adverse effects associated with Polygoni Multiflori (Cárdenas et al., 2007; Yuen et al., 2006). Dictamnus dasycarpus has been used to act as a detoxifying agent, able to reduce both heat and wetness.
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It is commonly prescribed to treat skin diseases, particularly eczema or psoriasis (Jang et al., 2008). However, in the United Kingdom, two women developed acute hepatitis after taking herbal preparations containing Dictamnus dasycarpus for the treatment of chronic skin
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disorders (Kane et al., 1995). The major active compounds in Polygoni Multiflori include tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG), physcion, and emodin, while Dictamnus
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dasycarpus contains dictamine (furoquinolone alkaloid), limonoids, flavonoids, and coumarins (Chang et al., 2002; Yu et al., 2011). Many of these individual compounds, including TSG, physcion, and emodin, have been shown to confer no cytotoxic effects in vitro against human liver cells (Yu et al., 2011). Dictamnus dasycarpus was shown once among 10 multiple herbal preparations with HILI in our results (Han et al., 2003), but Polygoni Multiflori was not used as a compositional herb in any of them (Table 4). On the other hand, regarding the most frequent appearance of Polygoni Multiflori as the HILI-causative herb, we should consider a typical status in Korea. There is a high chance of 12
ACCEPTED MANUSCRIPT misuse between medicinal herbs traditionally called ‘Ha-Su-Oh( Multiflori and Cynanchum Wilfordii and called ‘Yi-Yeop-Wupiso(
乌)’ for Polygoni )’ for
Cynanchum Auriculatum. Among these herbs, Polygoni Multiflori and Cynanchum Wilfordii
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have been prescribed as a compositional herb for multiple herbal formulas by Oriental medical doctors, but Cynanchum Auriculatum hasn’t been used due to the unknown fact of its safety and efficacy. Recently Korean Consumer Agency and Korean Ministry of Food and
乌)’ in many herb-containing products such as functional foods on April 2015. In
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Oh(
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Drug Safety (MFDS) announced the many misuses of Cynanchum Auriculatum for ‘Ha-Su-
fact, Food and Drug Administration (FDA) designated Cynanchum Auriculatum as one of the poisonous plants, and a animal study showed the hepatotoxicity of Cynanchum Auriculatum in China (Lu et al., 1998). Above facts suggested that HILI cases of Polygoni Multiflori could
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be caused at least partially by Cynanchum Auriculatum.
Among the herbal preparations associated with HILI in this study, only one was related to known toxic risk herbs, Aconiti Radix Lateralis and Aconiti Ciliare Tuber (Han and Hwang,
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2009). These results suggest that most cases of HILI, including Polygoni Multiflori and Dictamnus dasycarpus, may be the result of idiosyncratic reactions, as other studies
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suspected (Cárdenas et al., 2006; Jung et al., 2011). It is unclear whether any constituents of Polygoni Multiflori and Dictamnus dasycarpus are directly causative of HILI and whether any of these adverse effects are specific to a particular ethnicity such as Korea or China. The evidence-based therapies including alternative and complementary medicine are a critical issue in these days, regarding the efficacy as well as safety of them (Fung and Linn, 2015). This data will be helpful to reduce the HILI chance in Clinic and individual use. We suggest that further intensive research and scientific regulation should be acquired for the 13
ACCEPTED MANUSCRIPT safe use of herbal remedies. Our study would provide a clue of safety of herbal plants and their hepatotoxicity especially in Korea.
Our report however has limitations. Our result may
not present the whole HILI cases in Korea, as the majority of cases are unlikely to be reported
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officially. In addition, many of the original case studies failed to provide essential information necessary for inclusion in this study, resulting in <50% of the relevant studies being included in this analysis. Moreover, even though Korea is likely typical of countries in which herbal
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drug use is common, our data may not be representative of other areas.
In conclusion, this study provides firstly the list of medicinal herbs with a high risk of
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hepatotoxicity in Korea, and features of HILI. These data will serve as a useful reference
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when prescribing herbal remedies and hopefully improve the safety of herbal treatments.
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5. Conflict of interest
The authors declare that there are no conflicts of interest.
6. Acknowledgments
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R&D Project, Ministry of Health & Welfare, Republic of Korea.
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Suh JS and Lee KH. A case of acute hepatitis and acute renal failure after ingestion of complementary medication. Chonbuk Uni Med Jour. 2000; 24(2): 197–201. Suk KT, Kim DJ, Kim CH, et al. A prospective nationwide study of drug-induced liver injury in Korea. Am J Gastroenterol. 2012; 107(9): 1380–7. Teschke R, Wolff A, Frenzel C, et al. Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment. World J Hepatol 2014; 6: 17-32. Teschke R, Wolff A, Frenzel C, et al. Review article: Herbal hepatotoxicity--an update on 20
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Policy. 2009; 90(2–3): 133–9. Yang JH, Lee JY, Kim KS, et al. One case of report of acute cholestatic-hepatitis (drug induced hepatitis) after taking herbal-medicine. Korean J Med. 2001; 22(2): 251–6.
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Ye XF and He J. The bright future of Chinese herbal medicine: only after a twisty road. Contemp Clin Trials. 2010; 31(6): 508–9.
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Yoon YK, Sun TC, Jang HJ and Song WS. A clinical case of liver injury induced by Chungsim Yeonja-tang. Korean J Med. 2004; 25(3): 539–44. Yu J, Xie J, Mao XJ, et al. Hepatoxicity of major constituents and extractions of Radix
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Polygoni Multiflori and Radix Polygoni Multiflori Praeparata. J Ethnopharmacol. 2011; 137(3): 1291–9.
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Yuen MF, Tam S, Fung J, et al. Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study. Aliment Pharmacol Ther. 2006; 24(8): 1179–86. Yun SM, Lee HG, Cheon JH, et al. Case reports: two cases of acute toxic hepatitis and renal failure after ingestion of the extract of elm bark in lung cancer patients. Korean J Med. 2003; 65: 826–31. Zhou Y, Yang L, Liao Z, et al. Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21,789 patients. Eur J Gastroenterol 21
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Figure Legend
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Fig. 1. Flowchart of studies included in this analysis.
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Hepatol. 2013; 25(7): 825–9.
The English in this document has been checked by at least two professional editors, both
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native speakers of English. For a certificate, please see:
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http://www.textcheck.com/certificate/mRla3t
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Multiple herbs
Total
Number of study
21 (67.7%)
10 (32.3%)
31 (100%)
Number of participants
87 (89.7%)
10 (10.3%)
97 (100%)
Male vs Female (unknown)
44 vs 43 (0)
3 vs 6 (1)
47 vs 49 (1)
Mean number of patients
3.6 ± 7.1
1.0 ± 0.0
3.1 ± 6.5
50.8 ± 11.0
51.3 ± 14.0
50.9 ± 11.5
45.9 ± 44.6
83.9 ± 132.8
52.1 ± 68.9
Mean value for laboratory findings Serum AST (IU/L)
1157.8 ± 982.5*
485.3 ± 466.8
954.0 ± 913.4
Serum ALT (IU/L)
1082.9 ± 503.1*
643.3 ± 530.4
1007.1 ± 534.4
Serum ALP (IU/L)
301.3 ± 263.7
341.9 ± 206.6
306.5 ± 257.4
Serum GGT (IU/L)
174.0 ± 129.7
232.9 ± 195.9
191.2 ± 154.4
Serum TB (mg/dL)
8.6 ± 11.3
6.4 ± 6.5
8.3 ± 10.9
Number of known cases
79
4
83
Hepatocellular type
60 (75.9%)
2 (50.0%)
62 (74.7%)
7 (8.9%)
2 (50.0%)
9 (10.8%)
12 (15.2%)
0 (0.0%)
12 (14.5%)
Number of unknown cases CIOMS/RUCAM Scale (Number of unknown cases)
8 8.2 ± 1.4 (18)
6 8.0 ± 0.0 (9)
14 8.2 ± 1.4 (27)
20.8 ± 12.5*
37.1 ± 18.6
23.9 ± 15.3
Mean age (year)
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Mean herb used period (day)
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Mixed type
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Type of liver injury
Cholestatic type
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Items
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Single herb
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Table 1. Study Characteristics
Mean treatment period (day) #
* p < 0.05 between single herb and multiple herbs using independent t-test. # Data didn’t include patients who died or leaved the hospital early before cured.
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Table 2. Characteristic of single herb Name of herbal medicine
Drug treatment (day)
Patient
Jung KA 2011
Polygoni multiflori
48.1±50.1
25 patients (M:18,F:7) Age: 50.0±9.9
-
1,243.6 ±449.8
180.1 ±85.2
Bae SH 2010
Polygoni multiflori
30
F/ 54
665
1178
Choi YJ 2009
30
M/53
56
Polygoni multiflori -
M/47
532
Jung GA 2007
Polygoni multiflori
-
10 patients (M:7,F:3) Age: 51.0
Cho JC 1999
Polygoni multiflori
75
F/55
Jung JH 2010
Dictamnus dasycarpus
23.6±21
28 patients (M:10, F:18) Age: 53.0±11
An SY 2010
Dictamnus dasycarpus
56
F/57
Kim SH 2009
Dictamnus dasycarpus
30
M/55
15
F/78
RUCAM score
Treatment period (day) 19.9±12.2 hepatocellular 18 1 died mixed 7 1 transplantation Type of DILI
8.2±1.1
324
469
1.5
10
hepatocellular
20
47
1,064
31
26.7
7
-
7
544
256
73
36.7
9
-
13
5-fold > ULN
5-fold > ULN
-
-
-
-
hepatocellular 8 (Unknown 2)
-
1443
1779
387
151
6.7
-
cholestatic
35
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2.0±3.1
1270±694
163±37
198±157
11.3±8.3
7.0±0.8
hepatocellular 23 mixed 5
56.6±30.4
2846
479
394
301
17.6
8
cholestatic
died
1369
1660
288
156
16
-
hepatocellular
34
805
665
896
56
32.1
10
hepatocellular
40
F/49
913
1000
753
82
10
9
hepatocellular
40
M/62
975
800
415
291
29.3
9
hepatocellular
11
F/52
1060
1225
257
83
34.2
7
hepatocellular
11
-
M/48
377
303
162
42
29.2
-
cholestatic
36
150
M/62
590
761
183
-
13.2
-
cholestatic
40
16 Dictamnus dasycarpus 80
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928±645
135 Lee JH 1998
TB (mg/dL)
-
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Jang JS 2008
AST (IU/L)
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Value for laboratory findings ALT ALP γGT (IU/L) (IU/L) (IU/L)
Author year
Dictamnus dasycarpus
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Ulmus davidiana var.japonica Nakai
10
F/48
4,546
1417
79
-
0.9
-
-
-
Yun SM 2003
Ulmus davidiana var.japonica Nakai
14
M/69
906
1211
152
-
2.5
-
-
18
Suh JS 2000
Ulmus davidiana var.japonica Nakai
15
F/37
714
612
408
-
0.4
-
-
-
Kim SY 2009
Puerariae Radix
14
F/57
963
901
171
439
10.2
10
hepatocellular
12
30
F/58
646
1952
133
139
13.8
10
hepatocellular
4
Psoralea corylifolia
49
F/44
774
398
367
192
7.3
-
cholestatic
10
Aloe Vera
30
F/21
2449
Intravenous Wild Ginseng Pharmacopuncture
-
M/64
-
Cudrania tricuspidata
4
F/30
364
Ceramium kondoi
28
F/58
Smilacis Chinae Radix
30
F/51
Corydalis speciosa Max
70
M/37
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249
1.5
9
hepatocellular
28
-
1107
-
-
3
cholestatic
-
574
-
-
36.3
8
-
died
1862
441
1035
132
1.6
8
hepatocellular
-
195
706
-
-
-
-
hepatocellular
7
579
531
117
72
24.5
9
cholestatic
30
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Koh BS 2014 Kim DB 2013 Kim JH 2012 Kang HS 2009
1703
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Jo HG 2014
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Nam SW 2005 Lee JH 2014
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Kim BH 2010
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Table 3. Characteristic of multiple herb
Shin WJ 2011
Gamiyukgunja-tang
Kwon EM 2009 Yoon YK 2004 Han CW 2003
(
)
Herbal Medicine Including Coptidis Rhizoma (
ALT (IU/L)
ALP (IU/L)
γGT (IU/L)
TB (mg/dL)
448
F/58
675
1118
-
-
30
F/64
150
129
14
M/54
62
Unknown (1)
21
F/34
20
F/74
)
Herbal Medicine including Boo-ja and Cheon-o (
)
Yeoldahanso-tang plus Rheum rhabarbarum (
)
Chungsim Yeonja-tang (
)
Herbal Medicine Including Dyctamnus dasycarpus (
)
Kim MR 2002
Yugmijihwang-won
Yang JH 2001
GamiOjuck-san
Lee SH 2000
Soyangin Dokwhaljiwhang-tang
(
(
)
)
120
F/38
Type of DILI
Treatment period (day)
-
-
-
30
261
381
2
-
hepatocellular
58
108
190
393
-
1.6
-
hepatocellular
10
154
256
-
-
-
-
-
60
919
1724
380
160
1
8
cholestatic
5
80
140
768
186
Normal
-
hepatocellular
53
1644
1304
367
92
19.85
-
hepatocellular
39
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Han HY 2009
)
AST (IU/L)
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Jhun BW 2011
(
RUCAM score
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Bangpungtongsung-san
Patient
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Lee KH 2011
Value for laboratory findings
Drug treatment (day)
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Name of herbal medicine
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Author year
33
M/32
229
498
-
648
11.36
-
-
23
-
F/45
360
354
-
57
7.2
-
cholestatic
51
7
M/63
534
720
124
106
1.7
-
cholestatic
42
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)
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(
Table 4. Constituent of multiple herbs Name of medicine
Constituent
Scutellariae Radix# , 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 Fructus
)
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(
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Bangpungtongsung-san
Cyperi Rhizoma, Zingiber officinale, Zizyphi Fructus, Atractylodes macrocephala Koidzumi, Poria Sclerotium, Citrus unshiu Markovich, Pinellia ternata Breitenbach, Ginseng Radix, Perillae Folium, Inula helenium, Amomi Fructus
Gamiyukgunja-tang )
(
Herbal Medicine Including Coptidis Rhizoma
Herbal Medicine including Boo-ja and Cheon-o
Aconiti Lateralis Radix Preparata, Aconiti Kusnezoffii Tuber were indicated and others were unknown
)
(
)
Chungsimyeonja-tang (
)
Rhei Radix et Rhizoma# , Pueraria thunbergiana Bentham, Scutellariae Radix , Ligusticum tenuissimum Kitagawa, Raphani Semen, Platycodonis Radix, Cimicifuga heracleifolia, Angelicae Dahuricae Radix
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Yeoldahanso-tang plus Rheum rhabarbarum (
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)
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(
Only Coptidis Rhizoma was indicated in original article others were unknown
Nelumbinis Semen, Dioscoreae Rhizoma, Asparagus cochinchinensis Merr, Liriopis seu Ophiopogonis Tuber, Zizyphi Semen, Dimocarpus longan Loureiro, Thujae Semen, Scutellariae Radix, Raphani Semen, Polygalae Radix, Acorus tartarinowi Schott, Chrysanthemi Indici Flos
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)
Yugmijihwang-won )
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Atractylodis Rhizoma, Citrus unshiu Markovich, Magnolia officinalis Rehder et Wilson, 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 Tuber
Gamiojuck-san (
)
Soyangin Dokwhaljiwhang-tang (
Rehmanniae Radix Preparata, Cornus officinalis, Poria Sclerotium, Alismatis Rhizoma, Moutan Radicis Cortex, Saposhnikoviae Radix, Araliae Continentalis Radix (+gypsum)
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Herbs that were supposed as causative herb for DILI by the author in original article.
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#
)
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(
Alismatis Rhizoma# , Rehmanniae Radix Preparata, Cornus officinalis, Dioscoreae Rhizoma, Alismatis Rhizoma, Moutan Radicis Cortex, Poria Sclerotium
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(
Dictamnus dasycarpus#, Pueraria thunbergiana Bentham, Cimicifuga heracleifolia, Tribulus terrestris L, Spirodelae Herba, Liriopis seu Ophiopogonis Tuber, Rehmanniae Radix Preparata, Glycyrrhiza uralensis Fischer
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Herbal Medicine Including Dyctamnus dasycarpus
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Fig. 1
Excluded Not relevant ( n = 4717 )
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Initial independent references from all Databases ( n = 5034)
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Duplicated articles ( n = 142 ) Not case report (n = 110 )
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Excluded ( Total 252 )
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Full-text articles with potential relevance ( n = 317 )
Met inclusion criteria ( n = 31 )
Excluded (Total 34 ) Not herbal product ( n = 17 ) Information less (n=12) No full text (n=5)
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Highlights Among 97 HILI cases (male 47, female 49, and unknown 1) involve 74.7% hepatocellular, 10.8% cholestatic-type, and 14.5% mixed-type injury.
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Total 11 single herb and 10 multi-herb preparations were found to be causative list of HILI in Korea.
The top 2 most frequent herbs causing HILI were Polygoni Multiflori (39.2%) and Dictamnus
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dasycarpus (37.1%) in Korea.
S0278-6915(15)00192-1
DOI:
10.1016/j.fct.2015.06.004
Reference:
FCT 8322
To appear in:
Food and Chemical Toxicology
Received Date: 30 March 2015 Revised Date:
3 June 2015
Accepted Date: 7 June 2015
Please cite this article as: Lee, W.-J., Kim, H.-W., Lee, H.-Y., Son, C.-G., Systematic review on herbinduced liver injury in Korea, Food and Chemical Toxicology (2015), doi: 10.1016/j.fct.2015.06.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Graphical Abstract
Survey for herbal list caused HILI in Korea
Database
4 international and 4 Korean electric database PubMed, five Korean electronic databases
Data extraction
Initial independent references : n = 313 Met inclusion criteria : n = 31 (Total 97 cases)
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Single herb (21)
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HILI case
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Study
87 cases (Male: 44 Female: 43)
Main herbs caused HILI
Multiple herbs (3) 10 cases (Male: 3 Female 6, Unkn. 1)
Polygoni Multiflori (39 cases), Dictamnus dasycarpus (36 cases) Ulmus davidiana var. japonica Nakai (3 cases) et al.
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Title page
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Abbreviated title: Herbal plants with potential for HILI
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Systematic review on herb-induced liver injury in Korea
Woo-Jin Leea.#, Hae-Won Kima,#, Hyun-Yong Leea,# and Chang-Gue Sonb*
a
Korean Medical College of Daejeon University, 62, Daehak-ro Dong-gu Daejeon, 301-716,
b
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Republic of Korea
Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University,
#
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176-9 Daeheung-ro Jung-gu Daejeon, 301-724, Republic of Korea
Three authors contributed equally to this manuscript.
*Corresponding author: Chang Gue Son, Professor Liver and Immunology Research Center, Institute of Traditional Medicine and Bioscience of Daejeon University, 22-5 Daeheung-dong Jung-gu, Daejeon 301-704, Republic of Korea Tel: +82-42-229-6723; Fax: +82-42-257-6398; E-mail: [email protected] 1
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1. Introduction
Herbal medicines have been used as a treatment for various diseases and ailments for
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thousands of years, particularly in East Asia. In recent years, the popularity of herbal remedies has begun to spread to other parts of the world; about 18% of adults in the United States adopt herbal remedies to treat illnesses (Barnes et al., 2008; Ye and He, 2010). These
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numbers are even higher in Asia, with about 40% of individuals in Korea and China using some form of herbal product (Xu and Yang, 2009, Yoo et al., 2007).
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Given the growing use of herbal remedies, many concerns have been raised regarding the safety of herbal products, as unwanted side effects, particularly hepatotoxicity, have been reported for many of these products (Ekor, 2014). Many studies have identified herbal drugs as a major cause of drug-induced liver injury (DILI), including one Chinese study, which
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found that herbal drugs were responsible for 24.2% of DILI cases (Li et al., 2007). Similar findings were also seen in Korea, with a prospective nationwide study attributing 30.7% of 371 DILI cases to herbal drugs (Suk et al., 2012). As to the overall incidence of herb-induced
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liver injury (HILI), two studies revealed an incidence of HILI of 0.71% in Korea (Oh et al., 2015) and 0.6% in Japan (Mantani et al., 2002).
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These findings have led to a heightened awareness regarding the potential hepatotoxicity of herbal drugs, but the specific herbs associated with these effects are rarely mentioned, with the causative agents often generalized as simply “herbal drugs.” Moreover, the vast majority of studies of HILI exist solely in the form of case reports, with the herbal drugs suspected or known to cause HILI rarely listed. Here, we addressed this issue by performing a systematic review of studies describing HILI in Korea. Korea has a characteristic medical milieu compared to other countries: Oriental medicine, 2
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provides a suitable medical environment to investigate the list of hepatotoxic herbal drug candidates.
We surveyed case reports of HILI in Korea between 1998 and 2015, and systematically
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classified them into single- and multi-herb groups. Our study aims to produce the list of herbal products with possibilities of hepatotoxicity, and thus analyze the characteristics of
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HILI and those herbal products.
3
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2. Methods
2.1. Data sources and keywords
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A systematic literature survey was conducted using publicly available electronic databases. Searches were performed for all studies published before January 2015 in PubMed (http://www.ncbi.nlm.nih.gov/pubmed), along with five Korean electronic databases, RISS
(https://www.riss.net),
KISTI
(http://society.kisti.re.kr),
KMBASE
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including
(http://kmbase.medric.or.kr), KIOM OASIS (http://oasis.kiom.re.kr), and a library database
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(http://libweb.dju.ac.kr). A secondary search of all references listed in any included study was then performed to identify titles matching the inclusion criteria. Searches were performed using combinations of the following keywords: “herb,” “herbal drug,” “herbal medicine,” “liver injury,” “hepatotoxicity,” “hepatic injury,” and “drug-induced liver injury.” Article type
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was limited to clinical reports, with no limitations as to publication language (e.g., an English-language abstract). Korean terms adapted from those listed above were used for
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Korean databases.
2.2. Eligibility criteria
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Articles were screened using the following inclusion criteria: (1) human subjects, (2) studies indicating causative drugs, (3) herbal plants (no drugs of animal origin), and (4) clinical reports conducted in Korea. Articles identified using these initial criteria were read in full by the three authors, who then together determined the suitability of each article. Potentially relevant articles not meeting all of the necessary inclusion criteria (e.g., review articles, letters to the editor, animal studies) were excluded from this study. The extracted data included the authors, title of the study, year of publication, journal, name 4
ACCEPTED MANUSCRIPT of all herbal drugs associated with the study, number of patients treated with each herbal drug, and clinical data associated with HILI. HILI data included laboratory findings for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-
clinical
outcome
and
the
Council
for
International
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glutamyl transferase (GGT), total bilirubin (TB), type of HILI, treatment period for HILI, the Organizations
of
Medical
Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale (Teschke et
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al., 2014).
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2.3. Review process
Articles passing our initial filtering criteria were divided into either single- or multi-herb groups according to the composition of causative agents. Whenever possible, we identified the name of the causative herb; cases in which no definite herb could be identified were
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excluded from the study. In each case, specific laboratory findings and the type of HILI were analyzed. All cases in which the causative herb was clearly indicated were included in this study, even those in which the other information was not complete. Only cases with well-
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defined values for each parameter were included in the statistical analysis.
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2.4. Statistical analysis
Comparisons of HILI caused by either a single herb or by multiple herbs were performed using an independent student's t-test. Analysis for types of liver injury were performed using one-way analysis of variance (ANOVA) followed by Dunnett’s post hoc test. A P value ≤0.05 was considered statistically significant. All statistical analyses were performed with SPSS (version 18.0 KO for Windows; SPSS, Inc., Chicago, IL).
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3. Results
3.1. Characteristics of data
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In total, 5034 studies were identified in the initial screening, from which 31 reports met all of the necessary inclusion criteria (Figure 1). Of these 31 reports, 21 were classified into a single herb, accounting for 11 species; the remaining 10 reports were categorized as multi-
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herb formulations (Table 1). While the earliest study was published in 1998, 93.5% of the studies (29 of 31) were conducted after 2000, including 19 studies (61.3%) published after
3.2. Patient characteristics
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2009 (data not shown). The characteristics of all studies are summarized in Table 1.
From these 31 studies, we compiled a list of 97 cases of HILI, of which 47 were male
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(49.0%) and 49 were female (51.0%); the sex of one patient was not listed. Eighty-seven cases (44 males and 43 females) were caused by a single herb; the remaining 10 cases (3 males, 6 females, and 1 unknown) were caused by multi-herb formulae. The mean age of all
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patients was 50.9 ± 11.5 years (single-herb group, 50.8 ± 11.0; multi-herb group, 51.3 ± 14.0). The mean duration of herbal drug use was 52.1 ± 68.9 days (single-herb group, 45.9 ± 44.6;
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multi-herb group, 83.9 ± 132.8). The mean treatment period for HILI was 23.9 ± 15.3 days, with patients in the single-herb group treated for a significantly shorter period of time than those in the multi-herb group (20.8 ± 12.5 vs. 37.1 ± 18.6 days, respectively; P < 0.05). CIOMS/RUCAM scales were available for 70 cases (69 single-herb and 1 multi-herb cases); the mean score was 8.2 ± 1.4 for the single-herb case, with the lone multi-herb patient scoring an 8.0 (Table 1). Three patients died, one each after taking Polygoni Multiflori, Dictamnus dasycarpus, or Cudrania tricuspidata; a fourth patient received a liver transplantation after 6
ACCEPTED MANUSCRIPT taking Polygoni Multiflori (Table 2).
3.3. Laboratory findings and HILI types
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Average serum levels of hepatic enzymes AST and ALT were 954.0 ± 913.4 IU/L and 1007.1 ± 534.4 IU/L, respectively, about 25-fold higher than in healthy controls. The elevations of both enzymes were significantly higher in cases caused by a single herb, rather
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than multiple herbs (1157.8 ± 982.5 vs. 485.3 ± 466.8 for AST and 1082.9 ± 503.1 vs. 643.3 ± 530.4 for ALT; P < 0.05 for both). Average serum values of ALP and GGT were 306.5 ±
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257.4 IU/L (single-herb 301.3 ± 263.7, multi-herb 341.9 ± 206.6) and 191.2 ± 154.4 IU/L (single-herb 174.0 ± 129.7, multi-herb 232.9 ± 195.9), respectively. Serum bilirubin levels were 8.3 ± 10.9 mg/dL (single-herb 8.6 ± 11.3, multi-herb 6.4 ± 6.5). No significant differences were observed between the single- and multi-herb groups for ALP, GGT, or
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bilirubin (Table 1).
Eighty-three cases of HILI were further identified by the type of liver injury, consisting of 62 cases for the hepatocellular type (74.7%), 9 cases for the cholestatic type (10.8%), and 12
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cases (Table 1).
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cases for the mixed type (14.5%). Additional details were not available for the remaining 14
3.4. Identification of herbs associated with HILI Eleven species of herbal plants were identified from the 21 single-herb studies: Polygoni Multiflori (39 cases), Dictamnus dasycarpus (36 cases), Ulmus davidiana var. japonica Nakai (3 cases), Pueraria montana (2 cases), Psoralea corylifolia (1 case), intravenous wild ginseng pharmacopuncture (1 case), Aloe vera (1 case), C. tricuspidata (1 case), Smilacis Chinae Radix (1 case), Ceramium kondoi (1 case), and Corydalis speciosa max (1 case) (Table 2). Ten reports of HILI caused by multi-herb preparations were also identified, with 7
ACCEPTED MANUSCRIPT one case of HILI reported in each. Eight cases contained the name of the herbal formulae or its component; the remaining 2 cases provided the names of only one or two of the major
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herbs found in the causative compounds (Tables 3 and 4).
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4. Discussion
DILI is defined as a liver injury caused by external agents such as medications, herbs, or
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dietary supplements (Teschke et al., 2014). DILI represents an important medical issue, as it is a common cause of liver injury worldwide, accounting for 13% of acute liver failure cases in the United States alone (Ostapowicz et al., 2002). Herbal medications also play a major
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role in the onset of DILI, accounting for 9% and 11%, of patients suffering DILI in the United States and Spain, respectively (Andrade et al., 2005; Chalasani et al., 2008). These
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levels may be even higher in countries in which herbal medicines are common (Ye and He, 2010), with one Korean epidemiological study reporting 30.7% of 371 DILI cases attributable to herbal drug use (Suk et al., 2012); a similar study from China revealed that complementary and alternative medicines accounted for 19.0% of 21,789 DILI cases (Zhou et al., 2013).
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These data would result from the fact that Korea and China have used herbal plants more frequently than Western countries, in terms of Oriental medicine (Ye and He, 2010). While both the Korea and Chinese studies described above provide strong evidence of
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causality linking herbal remedies and HILI, these studies didn’t present the herbs causing this HILI. Here, we performed a systematic review of existing studies to identify which herbs
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show the high risk for HILI, along with the pattern of HILI observed in Korean populations. Generally, identifying causative agents for DILI/HILI, is difficult due to the relative rarity of these DILI/HILI cases and the complexity of the mechanism involved (Lucena et al., 2011). Most DILI./HILI-causative drugs are therefore only identified on a case-by-case basis through case reports. A systematic evaluation of HILI in Korea was therefore warranted due to the fractured nature of this information and the widespread use of these products in this population. Together, these data can provide a better understanding of the herbs most likely to 9
ACCEPTED MANUSCRIPT cause HILI, as well as identifying clinical features specific for these herbal plants. Thirty-one studies published between 1998 and 2014 were included in this systematic review, amounting to 97 cases of HILI. The sex distribution was nearly identical between
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males and females (49.0% vs. 51.0%, respectively), unlike the general features that females are more susceptible to liver injury than males (Kang et al., 2008). Patients affected by a single-herb preparation significantly outnumbered those affected by multi-herb preparations
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(89.7% vs. 10.3%, respectively; Table 1). This discrepancy may be related to how herbal remedies are sold in Korea, with multi-herb preparations generally prescribed by specialists,
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while the use of single herbs is largely unregulated. All cases of HILI by single herb (87 cases) were self-prescribed by the affected individuals, with no direct input from a physician. In contrast, patients with HILI caused by multiple herbs had been prescribed these drugs after consultation with a physician (data not shown).
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DILI/HILI is generally classified into three types, hepatocelluar, cholestatic, and mixed type, based upon well-defined pathological features. DILI/HILI is defined as a rise in either ALT or ALP levels, as calculated based upon a fold ratio of ALT over the upper limit of
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normal (ULN) relative to ALP over the ULN (Teschke et al., 2014). Hepatocellular and mixed types are considerably more common than that of the cholestatic type in DILI/HILI,
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consistent with the results described here (74.7%, 14.5%, and 10.8%, respectively) (Andrade et al., 2005). The average values of hepatic enzymes and bilirubin were elevated by about 24fold for AST, 25-fold for ALT, 2.6-fold for ALP, 3.8-fold for GGT, and 6.9-fold for total bilirubin. These increases were much more severe among cases of HILI caused by a single herb relative to those caused by multiple herbs (P < 0.05); however, patients with HILI caused by a single herb (20.8 ± 12.5) recovered in a significantly shorter period of time compared to cases caused by multiple herbs (37.1 ± 18.6, P < 0.05; Table 1). Of the 97 cases of HILI included in this study, 94 patients recovered from HILI, while 3 10
ACCEPTED MANUSCRIPT patients died (3.1%); 1 patient received a liver transplant as part of the treatment (Table 2). Two prospective studies in the United States and Korea observed 8% and 1.8% respectively for the rates of death or liver transplantation (Chalasani et al., 2008; Suk et al., 2012). No
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progression of chronic hepatotoxicity was shown in our review study, which is different from that of previous studies. A Spanish prospective study found that 5.7% of patients with DILI/HILI developed chronic liver disease (Andrade et al., 2005), while another study in the
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United States observed persistent laboratory abnormalities in 14% of patients with DILI/HILI over the course of 6 months (Chalasani et al., 2008). As expected, hepatocellular-type HILI
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showed higher clinical values relative to the cholestatic type for both AST (1130.5 ± 627.8 vs. 899.8 ± 814.9 IU/L) and ALT (1266.6 ± 451.0 vs. 637.9 ± 450.5 IU/L), but lower levels of ALP (279.7 ± 241.1 vs. 352.1 ± 307.5 IU/L) and total bilirubin (7.1 ± 9.9 vs. 14.6 ± 7.9 IU/L) (data not shown).
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HILI is categorized into intrinsic and idiosyncratic form in pathogenic classification. Unlike idiosyncratic form, intrinsic injury is dose-independent, and then pyrrolizidine alkaloids (PAs), a group of alkaloids mainly composed of pyrrolizidine, are known to mainly
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cause the intrinsic form of HILI. Unsaturated PAs are hepatotoxic, due to inducing hepatic sinusoidal obstruction syndrome (HSOS) (Teschke et al., 2014). The main PA-containing
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herb species are: Gynura segetum, Heliotroprium, Senecio, Crotalaria (Larrey and Faure, 2011). In China, 5 patients were reported to suffer HSOS after digesting Gynura segetum (Gao et al., 2012). We however supposed that any of the herbs in our study list wasn’t relevant with PA-causative HSOS because none of them was known to contain PAs. DILI/HILI generally arises as a result of idiosyncratic metabolic responses that are both doseindependent and unpredictable in their nature (Au et al., 2011). The idiosyncratic responses could be classified into two types, metabolic or immunologic, according to the result of reexposure test (Teschke et al., 2014). We reviewed the status of re-exposure tests in 97 cases 11
ACCEPTED MANUSCRIPT of HILI in our study. Six of total 97 patients had re-administrated the herbs, but unfortunately we couldn’t find the clear answer for the “positive re-exposure tests” Polygoni Multiflori and Dictamnus dasycarpus were the most frequent causative agents
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identified in this study, accounting for 39 (40.2%) and 36 (37.1%) of the 97 cases, respectively (Tables 2 and 3). The remaining herbs shown to confer HILI included 9 distinct species, with no herb associated with more than 3 cases (Table 2). According to the practices
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of traditional Oriental medicine, Polygoni Multiflori, a member of the Polygonaceae, has been used to improve blood supply and vitality (Choi et al., 2009). This herb showed
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hepatoprotective effects in an animal model of dimethylnitrosamine-induced liver cirrhosis (Huang et al., 2007). There is however a series of reports for hepatic adverse effects associated with Polygoni Multiflori (Cárdenas et al., 2007; Yuen et al., 2006). Dictamnus dasycarpus has been used to act as a detoxifying agent, able to reduce both heat and wetness.
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It is commonly prescribed to treat skin diseases, particularly eczema or psoriasis (Jang et al., 2008). However, in the United Kingdom, two women developed acute hepatitis after taking herbal preparations containing Dictamnus dasycarpus for the treatment of chronic skin
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disorders (Kane et al., 1995). The major active compounds in Polygoni Multiflori include tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG), physcion, and emodin, while Dictamnus
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dasycarpus contains dictamine (furoquinolone alkaloid), limonoids, flavonoids, and coumarins (Chang et al., 2002; Yu et al., 2011). Many of these individual compounds, including TSG, physcion, and emodin, have been shown to confer no cytotoxic effects in vitro against human liver cells (Yu et al., 2011). Dictamnus dasycarpus was shown once among 10 multiple herbal preparations with HILI in our results (Han et al., 2003), but Polygoni Multiflori was not used as a compositional herb in any of them (Table 4). On the other hand, regarding the most frequent appearance of Polygoni Multiflori as the HILI-causative herb, we should consider a typical status in Korea. There is a high chance of 12
ACCEPTED MANUSCRIPT misuse between medicinal herbs traditionally called ‘Ha-Su-Oh( Multiflori and Cynanchum Wilfordii and called ‘Yi-Yeop-Wupiso(
乌)’ for Polygoni )’ for
Cynanchum Auriculatum. Among these herbs, Polygoni Multiflori and Cynanchum Wilfordii
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have been prescribed as a compositional herb for multiple herbal formulas by Oriental medical doctors, but Cynanchum Auriculatum hasn’t been used due to the unknown fact of its safety and efficacy. Recently Korean Consumer Agency and Korean Ministry of Food and
乌)’ in many herb-containing products such as functional foods on April 2015. In
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Oh(
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Drug Safety (MFDS) announced the many misuses of Cynanchum Auriculatum for ‘Ha-Su-
fact, Food and Drug Administration (FDA) designated Cynanchum Auriculatum as one of the poisonous plants, and a animal study showed the hepatotoxicity of Cynanchum Auriculatum in China (Lu et al., 1998). Above facts suggested that HILI cases of Polygoni Multiflori could
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be caused at least partially by Cynanchum Auriculatum.
Among the herbal preparations associated with HILI in this study, only one was related to known toxic risk herbs, Aconiti Radix Lateralis and Aconiti Ciliare Tuber (Han and Hwang,
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2009). These results suggest that most cases of HILI, including Polygoni Multiflori and Dictamnus dasycarpus, may be the result of idiosyncratic reactions, as other studies
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suspected (Cárdenas et al., 2006; Jung et al., 2011). It is unclear whether any constituents of Polygoni Multiflori and Dictamnus dasycarpus are directly causative of HILI and whether any of these adverse effects are specific to a particular ethnicity such as Korea or China. The evidence-based therapies including alternative and complementary medicine are a critical issue in these days, regarding the efficacy as well as safety of them (Fung and Linn, 2015). This data will be helpful to reduce the HILI chance in Clinic and individual use. We suggest that further intensive research and scientific regulation should be acquired for the 13
ACCEPTED MANUSCRIPT safe use of herbal remedies. Our study would provide a clue of safety of herbal plants and their hepatotoxicity especially in Korea.
Our report however has limitations. Our result may
not present the whole HILI cases in Korea, as the majority of cases are unlikely to be reported
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officially. In addition, many of the original case studies failed to provide essential information necessary for inclusion in this study, resulting in <50% of the relevant studies being included in this analysis. Moreover, even though Korea is likely typical of countries in which herbal
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drug use is common, our data may not be representative of other areas.
In conclusion, this study provides firstly the list of medicinal herbs with a high risk of
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hepatotoxicity in Korea, and features of HILI. These data will serve as a useful reference
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when prescribing herbal remedies and hopefully improve the safety of herbal treatments.
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5. Conflict of interest
The authors declare that there are no conflicts of interest.
6. Acknowledgments
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ACCEPTED MANUSCRIPT This study was supported by a grant (HI12C1920-010014) from the Oriental Medicine
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R&D Project, Ministry of Health & Welfare, Republic of Korea.
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Figure Legend
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Fig. 1. Flowchart of studies included in this analysis.
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Hepatol. 2013; 25(7): 825–9.
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Multiple herbs
Total
Number of study
21 (67.7%)
10 (32.3%)
31 (100%)
Number of participants
87 (89.7%)
10 (10.3%)
97 (100%)
Male vs Female (unknown)
44 vs 43 (0)
3 vs 6 (1)
47 vs 49 (1)
Mean number of patients
3.6 ± 7.1
1.0 ± 0.0
3.1 ± 6.5
50.8 ± 11.0
51.3 ± 14.0
50.9 ± 11.5
45.9 ± 44.6
83.9 ± 132.8
52.1 ± 68.9
Mean value for laboratory findings Serum AST (IU/L)
1157.8 ± 982.5*
485.3 ± 466.8
954.0 ± 913.4
Serum ALT (IU/L)
1082.9 ± 503.1*
643.3 ± 530.4
1007.1 ± 534.4
Serum ALP (IU/L)
301.3 ± 263.7
341.9 ± 206.6
306.5 ± 257.4
Serum GGT (IU/L)
174.0 ± 129.7
232.9 ± 195.9
191.2 ± 154.4
Serum TB (mg/dL)
8.6 ± 11.3
6.4 ± 6.5
8.3 ± 10.9
Number of known cases
79
4
83
Hepatocellular type
60 (75.9%)
2 (50.0%)
62 (74.7%)
7 (8.9%)
2 (50.0%)
9 (10.8%)
12 (15.2%)
0 (0.0%)
12 (14.5%)
Number of unknown cases CIOMS/RUCAM Scale (Number of unknown cases)
8 8.2 ± 1.4 (18)
6 8.0 ± 0.0 (9)
14 8.2 ± 1.4 (27)
20.8 ± 12.5*
37.1 ± 18.6
23.9 ± 15.3
Mean age (year)
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Mean herb used period (day)
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Mixed type
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Type of liver injury
Cholestatic type
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Items
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Single herb
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Table 1. Study Characteristics
Mean treatment period (day) #
* p < 0.05 between single herb and multiple herbs using independent t-test. # Data didn’t include patients who died or leaved the hospital early before cured.
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Table 2. Characteristic of single herb Name of herbal medicine
Drug treatment (day)
Patient
Jung KA 2011
Polygoni multiflori
48.1±50.1
25 patients (M:18,F:7) Age: 50.0±9.9
-
1,243.6 ±449.8
180.1 ±85.2
Bae SH 2010
Polygoni multiflori
30
F/ 54
665
1178
Choi YJ 2009
30
M/53
56
Polygoni multiflori -
M/47
532
Jung GA 2007
Polygoni multiflori
-
10 patients (M:7,F:3) Age: 51.0
Cho JC 1999
Polygoni multiflori
75
F/55
Jung JH 2010
Dictamnus dasycarpus
23.6±21
28 patients (M:10, F:18) Age: 53.0±11
An SY 2010
Dictamnus dasycarpus
56
F/57
Kim SH 2009
Dictamnus dasycarpus
30
M/55
15
F/78
RUCAM score
Treatment period (day) 19.9±12.2 hepatocellular 18 1 died mixed 7 1 transplantation Type of DILI
8.2±1.1
324
469
1.5
10
hepatocellular
20
47
1,064
31
26.7
7
-
7
544
256
73
36.7
9
-
13
5-fold > ULN
5-fold > ULN
-
-
-
-
hepatocellular 8 (Unknown 2)
-
1443
1779
387
151
6.7
-
cholestatic
35
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2.0±3.1
1270±694
163±37
198±157
11.3±8.3
7.0±0.8
hepatocellular 23 mixed 5
56.6±30.4
2846
479
394
301
17.6
8
cholestatic
died
1369
1660
288
156
16
-
hepatocellular
34
805
665
896
56
32.1
10
hepatocellular
40
F/49
913
1000
753
82
10
9
hepatocellular
40
M/62
975
800
415
291
29.3
9
hepatocellular
11
F/52
1060
1225
257
83
34.2
7
hepatocellular
11
-
M/48
377
303
162
42
29.2
-
cholestatic
36
150
M/62
590
761
183
-
13.2
-
cholestatic
40
16 Dictamnus dasycarpus 80
EP
928±645
135 Lee JH 1998
TB (mg/dL)
-
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Jang JS 2008
AST (IU/L)
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Value for laboratory findings ALT ALP γGT (IU/L) (IU/L) (IU/L)
Author year
Dictamnus dasycarpus
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Ulmus davidiana var.japonica Nakai
10
F/48
4,546
1417
79
-
0.9
-
-
-
Yun SM 2003
Ulmus davidiana var.japonica Nakai
14
M/69
906
1211
152
-
2.5
-
-
18
Suh JS 2000
Ulmus davidiana var.japonica Nakai
15
F/37
714
612
408
-
0.4
-
-
-
Kim SY 2009
Puerariae Radix
14
F/57
963
901
171
439
10.2
10
hepatocellular
12
30
F/58
646
1952
133
139
13.8
10
hepatocellular
4
Psoralea corylifolia
49
F/44
774
398
367
192
7.3
-
cholestatic
10
Aloe Vera
30
F/21
2449
Intravenous Wild Ginseng Pharmacopuncture
-
M/64
-
Cudrania tricuspidata
4
F/30
364
Ceramium kondoi
28
F/58
Smilacis Chinae Radix
30
F/51
Corydalis speciosa Max
70
M/37
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M AN U 709
249
1.5
9
hepatocellular
28
-
1107
-
-
3
cholestatic
-
574
-
-
36.3
8
-
died
1862
441
1035
132
1.6
8
hepatocellular
-
195
706
-
-
-
-
hepatocellular
7
579
531
117
72
24.5
9
cholestatic
30
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Koh BS 2014 Kim DB 2013 Kim JH 2012 Kang HS 2009
1703
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Jo HG 2014
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Nam SW 2005 Lee JH 2014
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Kim BH 2010
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Table 3. Characteristic of multiple herb
Shin WJ 2011
Gamiyukgunja-tang
Kwon EM 2009 Yoon YK 2004 Han CW 2003
(
)
Herbal Medicine Including Coptidis Rhizoma (
ALT (IU/L)
ALP (IU/L)
γGT (IU/L)
TB (mg/dL)
448
F/58
675
1118
-
-
30
F/64
150
129
14
M/54
62
Unknown (1)
21
F/34
20
F/74
)
Herbal Medicine including Boo-ja and Cheon-o (
)
Yeoldahanso-tang plus Rheum rhabarbarum (
)
Chungsim Yeonja-tang (
)
Herbal Medicine Including Dyctamnus dasycarpus (
)
Kim MR 2002
Yugmijihwang-won
Yang JH 2001
GamiOjuck-san
Lee SH 2000
Soyangin Dokwhaljiwhang-tang
(
(
)
)
120
F/38
Type of DILI
Treatment period (day)
-
-
-
30
261
381
2
-
hepatocellular
58
108
190
393
-
1.6
-
hepatocellular
10
154
256
-
-
-
-
-
60
919
1724
380
160
1
8
cholestatic
5
80
140
768
186
Normal
-
hepatocellular
53
1644
1304
367
92
19.85
-
hepatocellular
39
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Han HY 2009
)
AST (IU/L)
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Jhun BW 2011
(
RUCAM score
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Bangpungtongsung-san
Patient
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Lee KH 2011
Value for laboratory findings
Drug treatment (day)
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Name of herbal medicine
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Author year
33
M/32
229
498
-
648
11.36
-
-
23
-
F/45
360
354
-
57
7.2
-
cholestatic
51
7
M/63
534
720
124
106
1.7
-
cholestatic
42
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)
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(
Table 4. Constituent of multiple herbs Name of medicine
Constituent
Scutellariae Radix# , 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 Fructus
)
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(
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Bangpungtongsung-san
Cyperi Rhizoma, Zingiber officinale, Zizyphi Fructus, Atractylodes macrocephala Koidzumi, Poria Sclerotium, Citrus unshiu Markovich, Pinellia ternata Breitenbach, Ginseng Radix, Perillae Folium, Inula helenium, Amomi Fructus
Gamiyukgunja-tang )
(
Herbal Medicine Including Coptidis Rhizoma
Herbal Medicine including Boo-ja and Cheon-o
Aconiti Lateralis Radix Preparata, Aconiti Kusnezoffii Tuber were indicated and others were unknown
)
(
)
Chungsimyeonja-tang (
)
Rhei Radix et Rhizoma# , Pueraria thunbergiana Bentham, Scutellariae Radix , Ligusticum tenuissimum Kitagawa, Raphani Semen, Platycodonis Radix, Cimicifuga heracleifolia, Angelicae Dahuricae Radix
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Yeoldahanso-tang plus Rheum rhabarbarum (
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)
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(
Only Coptidis Rhizoma was indicated in original article others were unknown
Nelumbinis Semen, Dioscoreae Rhizoma, Asparagus cochinchinensis Merr, Liriopis seu Ophiopogonis Tuber, Zizyphi Semen, Dimocarpus longan Loureiro, Thujae Semen, Scutellariae Radix, Raphani Semen, Polygalae Radix, Acorus tartarinowi Schott, Chrysanthemi Indici Flos
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)
Yugmijihwang-won )
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Atractylodis Rhizoma, Citrus unshiu Markovich, Magnolia officinalis Rehder et Wilson, 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 Tuber
Gamiojuck-san (
)
Soyangin Dokwhaljiwhang-tang (
Rehmanniae Radix Preparata, Cornus officinalis, Poria Sclerotium, Alismatis Rhizoma, Moutan Radicis Cortex, Saposhnikoviae Radix, Araliae Continentalis Radix (+gypsum)
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Herbs that were supposed as causative herb for DILI by the author in original article.
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#
)
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(
Alismatis Rhizoma# , Rehmanniae Radix Preparata, Cornus officinalis, Dioscoreae Rhizoma, Alismatis Rhizoma, Moutan Radicis Cortex, Poria Sclerotium
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(
Dictamnus dasycarpus#, Pueraria thunbergiana Bentham, Cimicifuga heracleifolia, Tribulus terrestris L, Spirodelae Herba, Liriopis seu Ophiopogonis Tuber, Rehmanniae Radix Preparata, Glycyrrhiza uralensis Fischer
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Herbal Medicine Including Dyctamnus dasycarpus
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Fig. 1
Excluded Not relevant ( n = 4717 )
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Initial independent references from all Databases ( n = 5034)
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Duplicated articles ( n = 142 ) Not case report (n = 110 )
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Excluded ( Total 252 )
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Full-text articles with potential relevance ( n = 317 )
Met inclusion criteria ( n = 31 )
Excluded (Total 34 ) Not herbal product ( n = 17 ) Information less (n=12) No full text (n=5)
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Highlights Among 97 HILI cases (male 47, female 49, and unknown 1) involve 74.7% hepatocellular, 10.8% cholestatic-type, and 14.5% mixed-type injury.
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Total 11 single herb and 10 multi-herb preparations were found to be causative list of HILI in Korea.
The top 2 most frequent herbs causing HILI were Polygoni Multiflori (39.2%) and Dictamnus
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dasycarpus (37.1%) in Korea.