26 2 (2005 6 ) J Korean Oriental Med 2005;26(2):152-165 Hepatotoxic Events Associated with Herbal Medicinal Products, Folk Remedies and Food Supplements in Korea Park Haemo, Jang Insoo, Lee Sundong Dept. of Oriental Preventive Medicine, College of Oriental Medicine, Sangji University Dept. of Internal Medicine, College of Korean Medicine, Woosuk University 1) Background : The use of herbal preparations as remedies for various medical conditions has continuously increased in Korea. Large proportions of Korean patients use herbal medicinal products, folk remedies, and food supplements. However, studies on the safety of herbal products are conducted on a less than sufficient basis even in the countries like Korea where herbal medicine is being used extensively. Some of the reports on the safety of herbs were done by the doctors of western medicine but lack of knowledge and misclassification led to misunderstandings. Objectives : This study aims to review the recent evidences on hepatotoxic events associated with the use of herbal medicinal products, folk remedy, and food supplements. In the process, this review will grasp trends in this field of studies and will direct further researches into the right direction. Methods : Systematic literature searches were performed on MedRic and MEDLIS in Korea. Screening and selection of the articles and the extraction of data were performed independently by two of authors. There were no restrictions regarding the published date. In order to avoid bias, the articles written by medical doctors, not by oriental doctors were selected. 43 journals were chosen for the review. Results : Analyzing the number of journals, studies on the drug-induced liver injury were increased after the year 2000. The proportion of herbal and folk remedy associated hepatotoxic injuries in all drug-induced liver injury was 21.0% - 30.0%. But criterion for herbal medicine is rather vague and limited objective data hindered objectiveness. Few of single medicinal herbs and combination preparations were associated with hepatotoxic injuries. But because of lack of objectivity, further researches must be conducted to yield more concrete results. Conclusions : yield more concrete results. Conclusion : Incidence figures are largely unknown, and in most cases a causal attribution is not established. The challenge for the future is to systematically research this area, educate all parties involved, and minimize patient risks. Key Words: drug induced liver injury, hepatotoxicity, herbal medicine, causality assessment, systematic review : 2005 4 4 : 2005 4 24 : 2005 5 14 : (063)220-8608 Fax : 063)220-8616 e-mail : kmdjang@woosuk.ac.kr) (WHO) 65-85 1 152

(359) 34 (un-conventional medicine) RUCAM (Roussel Uclaf Causality Assessment Method) 3) M&V(Maria & Victorino) 2 (Causality Assessment Method) 82.9 ( 57.9 25.0 ) (selection bias) RUCAM (modified RUCAM scale) (validity) (Pittler, Ernst) (positive study) (negative study) (MedRIC, http:// www.medric.or.kr/) (MEDLIS, http://medlis.riss4u.net) 1990 2004 (http://omis.ik.ac.kr/default.asp) MedRIC 45 ( 500 20 ) MEDLIS MEDLIS 167 ( ) 153

(360) 26 2 (2005 6 ) 2 (grey literature) 50 ( ) (Stevens-Johnson ) 7 43 43 (case report) 18 10 4 4 6 1 50 43 90 2000 2004 14 1-2 10 8 98 (Table 1) Table 1. Yearly Trend of Drug-induced Liver Injury associated Herbal Drug and Folk Remedy in Korea Published Year 90 93 95 96 97 98 99 00 01 02 03 04 Total number of report 1 1 1 2 1 2 2 6 7 4 6 14 Case-report (asssociated Herb) 2 1 1 2 2 2 Case-report (toxic mushroom & fish gallbladder) 1 1 1 2 1 1 1 Clinical study 1 2 1 2 154

(361) 99 99 43 (Table 2) 18 10 4 4 6 1 6 Table 3 (proportion) Table 2. Classification by Paper Contents Paper Contents Number of Paper Case-report 18 Review of liver damage caused by herbal medicines or folk remedies 10 Medical review papers on drug-induced liver damage 4 Clinical research papers on herb-induced liver damage 6 Review paper of Causality assesment method 4 Epidemiological study report 1 Total 43 Table 3. Proportion of Hepatotoxic Events associated with Herbal Medicinal Pproducts in Different Hospital Reference No. 1989.1 31 68 33 1999 99 1996.4 (87) (31.3%) (68.7%) 2149 34 2001 1998.1 31 65 46 111 ICC* 2001.3(38) (27.9%) (58.5%) (41.4%) 111 35 2001 36 2002 37 2004 1998.3 25 42 70 119 M&V 2001.2 (36) (21.0%) (35.2%) (58.8%) 429 1997.4 23 39 39 CIOMS 78 2001.3 (48) (29.4%) (50.0%) (50.0%) M&V 78 1996.1 27 37 68 RUCAM 2002.12 (84) (41.2%) (55%) 68 68 1998.3 ~ 15 27 21 38 2004 50 RUCAM 2004.3 (72) (30.0%) (54%) (42%) 50 * ICC : International consensus criteria meeting 1989 155

(362) 26 2 (2005 6 ) Table. 4 Comparison of LFT between Different Research Reference Drugs Comparison of LFT score No. AST ALT AP TB Herbal medication 516.9 478.5* 645.4 514.4* 6.8 6.5 33 Anti-tuberculosis 252.9 359.9 308.2 408.2 1.8 2.5 Anti-biotics 166.6 206.2 363.9 437.5 1.4 2.7 36 37 * p<0.05 Botanical remedy 603.0 202.6 273.8 122.5 7.4 2.5* Western medicine 449.1 126.4 131.2 19.4 2.8 1.2 Herb 1028.1 796.0 162.0 76.0 8.8 8.0 Drug 747.3 973.3 218.4 132.8 5.9 7.0 Table 5. Choice of Terms about Herbal Medication in Different Report Reference No. 33 Herbal medication 34 35 36 Botanical remedy 37 Herb 38 * ICC : International consensus criteria meeting 1989 21.0-30.0 31.3-58.5 (Causality assessment method) RUCAM, M&V M&V RUCAM 3 Table 4 AST, ALT, AP, TB (Botanical Remedy) 33) Herb 37) 6 5 herbal medication, botanical remedy, herb 18 6 18 (48 ) 156

(363) Table 7. Laboratory Data Reference Patients age(years) CAM Liver No. gender, n medications biopsy 39 25-58, 6,, 7-114,, * * - * * 27-58,,11, * 40 38,, 1 * 34, Fenfluramine, * * - * - 41 31,, 1 3 21 * * - * - 42 44,, 1 1 1 77,,,, * * - * - 43 55,, 1 * 2 /1 (520mg) 75,,, * - * - 47 37,, 1 ( ) 15,, * - * - 48 48,, 1 1/3 4,,,,,, 62,, 1 * 5, 1-2 5 /, 10 40 * + - 1 4-5 / * - * - 53 55,, 1 * 1-2pack/ 5,,, * * * - 55 69,, 1 ( ) 3-4 / 2 *, * - 56 11,, 1 * * 1, * B * - 44 45 39,, 1 11 10,,,, * * * - 50,, 1 2-3 8,, * * * * - 30-50,, 10 10 37-60,, 3 15-30ml 12,,,, * * - * - 46 29,, 1 1 1,,,,, - * - 49 32,, 1 1 1,,, * * - 50 39,, 1 1 1,,, 3 3-4 / * * - 51 29,, 1 1 1,,,, * * * * * - 52 40,, 1 4 / 1 * - * * * - 54 30,, 1 * 7,,,, - - * - * : not recorded 157

(364) 26 2 (2005 6 ) Table 6. Clinical Data of Hepatotoxic Events associated with Herbal Medicinal Products Patients age(years), Liver parameters Serologies Imaging Reference No. gender, n AST ALT T.bilirubin AP Cb -GT Anti-HAV Anit-HCV HBsAg HBsAb Ultrasono (U/L) (U/L) (mg/dl) (U/L) (mg/dl) 39 25-58,, 6 80-110- 0.4-35.8 189-27-58,, 11 1476 2620 593 * * * * * * * * * 40 38,, 1 538 996 19.5 183 9.1 75 - - - + * * 41 31,, 1 580 171 5.1 159 3.8 103 - - - + 45 * 45 42 44,, 1 774 398 7.3 367 4.2 192 - - - - 6 133 43 55,, 1 1443 1779 6.7 387 151 - - - - 35 * 35 47 37,, 1 714 612 0.4 408 * - - + 3 * 48 48,, 1 377 303 29.2 162 19.8 42 - - - - 36 120 62,, 1 590 761 13.0 180 8.2 * - - - + 40 * 40 53 55,, 1 1205 1519 7.1 252 * 202 - - - - * * * * 55 69,, 1 906 1211 144 151 * * - - - + * 18 18 56 11,, 1 1505 1511 * * * * * * - + * * 4 44 39,, 1 2660 2980 21.2 172 39 * * * * * * * 50,, 1 1401 1732 1.4 * 21 * * * * * * * * 30-50,, 1 45 * 62-1500 0.8-7.8 * * * * * * * * * * 37-60,, 3 46 29,, 1 310 1203 2.98 111 1.8 * - - - + 24 * 24 49 32,, 1 35 774 0.6 * * - - - * * 23 * 23 50 39,, 1 1373 1731 6.1 * * - - - * * * * * 51 29,, 1 310 1203 3.0 * * - - - * * * * * 52 40,, 1 1997 1013 29.4 * * * - - - - * * * * 54 30,, 1 4390 5940 3.4 79 * - - - * 15 * 15 * : not recorded 158

(365) ( ) 10 (27 ) 25-69 1 (17 ) 6 (6 ) 1 (2 ) 2 (2 ) 8 (21 ) 10 (27 ) 5 2 18 Table 7 ALT, AST, AP(alkaline phosphatase), TB(total bilirubin) 3 45 23-160 (Table 7) fenfluramine Fenfluramine 40) 74 34) ( Psoralea corylifolia) (Leguminosae) 1 (8-12g) 10 ( Polygoni multiflorum) (Polygonaceae) 31 2 (But ) 159

(366) 26 2 (2005 6 ) ( Ulmus macrocarpa) 1 3 1 ( Dyctamnus dasycarpus) (Rutaceae) 2 1 10 3 (Cypriunus carpio) 6 10 12 ALT, AST, AP 3 2 13) 3 13) (56.4-67.6%) (19.8-23.0%) (12.6% - 20.5%) (intrinsic hepatotoxin) (idiosyncrasy) 2 20 3 13) 160

(367) 1983 B 37) 34-45) 2000 98 99 2003 12 57) 57.9 ( ) 15.8 (selection bias) (modified RUCAM scale) 58) (validity) 31.3 58.5 (41.4-68.7 ) (herb) (botanical remedy) Pyrrolizidine alkaloids, Germander furan (furanno neolerodane diterpenoids) Chaparral NDGA(nordihydroguaiaretic acid) Cassia angustifolia(senna) -amanitin ( genus) 161

(368) 26 2 (2005 6 ) 32) (coincidence) 18 1 4 2 8 1 17 (8-12g) 10 (rechallenge) 1 43) (proportion) Reference 1. Anonymous program profile : International liaison brings global vision to OAM. complementary and alternative medicine at the NIH, 3 : 3, 1996. 2. Pittler MH, Ernst E. Systematic review : hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther. 2003;18:451-71. 3. Danan G, Benichou C. Causality assessment of adverse reactions to drugs-i. A novel method based on the conclusions of international consensus meetings; application to druginduced liver injuries. J Clin Epidemiol. 1993;46:1323-1330. 4. Danan G. Consensus meeting on: causality assessment of drug-induced liver injury. J Hepatol. 1988;7:132-136. 5. Maria VA, Victorino RM.Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26:664-669. 6. 162

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