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1 26 2 ( ) J Korean Oriental Med 2005;26(2): 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 The proportion of herbal and folk remedy associated hepatotoxic injuries in all drug-induced liver injury was 21.0% %. 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 : : : : (063) Fax : 063) kmdjang@woosuk.ac.kr) (WHO)

2 (359) 34 (un-conventional medicine) RUCAM (Roussel Uclaf Causality Assessment Method) 3) M&V(Maria & Victorino) 2 (Causality Assessment Method) 82.9 ( ) (selection bias) RUCAM (modified RUCAM scale) (validity) (Pittler, Ernst) (positive study) (negative study) (MedRIC, (MEDLIS, ( MedRIC 45 ( ) MEDLIS MEDLIS 167 ( ) 153

3 (360) 26 2 ( ) 2 (grey literature) 50 ( ) (Stevens-Johnson ) (case report) (Table 1) Table 1. Yearly Trend of Drug-induced Liver Injury associated Herbal Drug and Folk Remedy in Korea Published Year Total number of report Case-report (asssociated Herb) Case-report (toxic mushroom & fish gallbladder) Clinical study

4 (361) (Table 2) 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 (87) (31.3%) (68.7%) ICC* (38) (27.9%) (58.5%) (41.4%) M&V (36) (21.0%) (35.2%) (58.8%) CIOMS (48) (29.4%) (50.0%) (50.0%) M&V RUCAM (84) (41.2%) (55%) ~ RUCAM (72) (30.0%) (54%) (42%) 50 * ICC : International consensus criteria meeting

5 (362) 26 2 ( ) Table. 4 Comparison of LFT between Different Research Reference Drugs Comparison of LFT score No. AST ALT AP TB Herbal medication * * Anti-tuberculosis Anti-biotics * p<0.05 Botanical remedy * Western medicine Herb Drug Table 5. Choice of Terms about Herbal Medication in Different Report Reference No. 33 Herbal medication Botanical remedy 37 Herb 38 * ICC : International consensus criteria meeting (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 (48 ) 156

6 (363) Table 7. Laboratory Data Reference Patients age(years) CAM Liver No. gender, n medications biopsy , 6,, 7-114,, * * - * * 27-58,,11, * 40 38,, 1 * 34, Fenfluramine, * * - * ,, * * - * ,, ,,,, * * - * ,, 1 * 2 /1 (520mg) 75,,, * - * ,, 1 ( ) 15,, * - * ,, 1 1/3 4,,,,,, 62,, 1 * 5, /, * / * - * ,, 1 * 1-2pack/ 5,,, * * * ,, 1 ( ) 3-4 / 2 *, * ,, 1 * * 1, * B * ,, ,,,, * * * - 50,, ,, * * * * ,, ,, ml 12,,,, * * - * ,, 1 1 1,,,,, - * ,, 1 1 1,,, * * ,, 1 1 1,,, / * * ,, 1 1 1,,,, * * * * * ,, 1 4 / 1 * - * * * ,, 1 * 7,,,, - - * - * : not recorded 157

7 (364) 26 2 ( ) 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) ,, ,, * * * * * * * * * 40 38,, * * 41 31,, * ,, ,, * ,, * * 48 48,, ,, * * ,, * * * * * 55 69,, * * * ,, * * * * * * - + * * ,, * * * * * * * 50,, * 21 * * * * * * * * 30-50,, 1 45 * * * * * * * * * * * 37-60,, ,, * * ,, * * * * 23 * ,, * * * * * * * 51 29,, * * * * * * * 52 40,, * * * * * * * 54 30,, * * 15 * 15 * : not recorded 158

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

9 (366) 26 2 ( ) ( Ulmus macrocarpa) ( Dyctamnus dasycarpus) (Rutaceae) (Cypriunus carpio) ALT, AST, AP ) 3 13) ( %) ( %) (12.6% %) (intrinsic hepatotoxin) (idiosyncrasy) ) 160

10 (367) 1983 B 37) 34-45) ) 57.9 ( ) 15.8 (selection bias) (modified RUCAM scale) 58) (validity) ( ) (herb) (botanical remedy) Pyrrolizidine alkaloids, Germander furan (furanno neolerodane diterpenoids) Chaparral NDGA(nordihydroguaiaretic acid) Cassia angustifolia(senna) -amanitin ( genus) 161

11 (368) 26 2 ( ) 32) (coincidence) (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, Pittler MH, Ernst E. Systematic review : hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther. 2003;18: 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: Danan G. Consensus meeting on: causality assessment of drug-induced liver injury. J Hepatol. 1988;7: Maria VA, Victorino RM.Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26:

12 (369) 1999;15(1): ;24(1): ;24(3): ;24(4): :186-7,559-60, :( )171-2,( )412-3, :200, ;10(suppl 1): ;10(suppl 1): ;10(suppl 1): ( ) 2004;10(suppl 1): ( ) 2004;10(suppl 1): ;10(suppl 1): (Medical Postgraduate). 2002;30(3): ; :s ;9(suppl 3):s ;10(suppl 1): (2): (1) : 2000; 6(2): (2) 2000;6(3): (3) (Artemisia capillaris) (Artemisia iwayomogi) (Artmisia annua) 2000;6(4): (4) : 2001;9(1): (5) 2001;7(2): (6) 2001;7(3): ;44: ;7(supp 3):s ;6(1):

13 (370) 26 2 ( ) ;7(suppl 2):s ;7 (suppl 2):s ;63(2): ;10(2): ;(supp l):10(3):s ;32(1): ;65(supple 3): s (2): ( Psoralea corylifolia) ;7(3): (Ho-Shou-Wu) 1999; 56(6): ;25(3): Toxic Acute Renal Failure and Hepatitis After Ingestion of Raw Fish Gall Bladder. 1990;9(1): ;28(3): ;24(2): ;31(2): ;19(5) : ;16: ;26(2):

14 (371) ;10 (suppl 3):s Kim D, Han N, Kim J, Baek J, Lee S, Kim H, Kim Y, Lee Y. Pueraria induced acute hepatitis in a chronic alcohol drinker..2001;7(suppl 2): Amanita Virosa ;28(4): (suppl.3) : s826-s ; 8(suppl 2):s ;10(suppl 1): ;25(3):

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08-ÀåÀÎ¼ö 25 2 (2004 9 ) J Korean Oriental Med 2004;25(3):78-89 A Review on the Report about Drug-induced Hepatitis published by the National Institute of Toxicological Research Jang Insoo Department of Internal