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1 25 2 ( ) 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 Medicine, College of Korean Medicine, Woosuk University Background : A report published by the National Institute of Toxicological Research (NITR) in January 2004 about toxic hepatitis in Korea contained the result of analysis on 55 cases of severe toxic hepatitis from 7 university hospitals for 8 months. NITR claimed that the extrapolated annual frequency of severe toxic hepatitis in Korea was 1904 cases per year. They also claimed that the most frequent etiology of severe toxic hepatitis were herbal medications and similar plant preparations (61.7%), contrasted with traditional therapeutic preparations and healthy foods (29.1%). I have investigated that report to be certain of the result because it is a very important subject for public health and society in Korea. Results : The NITR report has too many problems to have faith in its results. They include the following: 1. The report uses only 55 cases to estimate annual prevalence rate of severe toxic hepatitis in Korea. 2. There was a large regional preponderancy in the NITR report (2 cases in Seoul from a population of million, 19 cases in Gwangju from a population of 1.4 million) 3. There was another preponderancy that selected much fewer cases caused by western medication (9.1%) than other reasons. 4. The NITR report used a modified scale than that officially recognized to diagnose toxic hepatitis. 5. There was a mistake using the scale to adapt the right indications. 6. They collected cases before beginning the study, although it was a prospective study. There was also not any questionnaire or other materials concerned with alcohol, drugs, or history of past liver disease. Conclusions : NITR is one of the important official arms of the government of Korea. Nevertheless, there is a severe problem in validity because of selection bias, uncertain accuracy, and insufficiency of raw materials in the report. Therefore it seems incorrect to generalize the results of the report and there is a lack of confidence in it as a national study publishing by the NITR. Key Words: toxic hepatitis, hepatotoxicity, drug-induced liver injury, herbal medicine : : : : (Tel , Fax , kmdjang@mail.woosuk.ac.kr) ( ) 1) 78

2 (519) ). 2003, ( ) , 7, 1,904, (61.7%), (29.1%), (7.3%).,,, (90.8%). ( )., AST, ALT, CB(conju gated bilirubin), AP(alkaline phosphatase), TB(total bilirubin) 2 1,3,4).,, (drug-induced liver injury),4)., (61.7%) (29.1%) (90.8%), (7.3%) 1),.,,. ( ) ) /.,,,,,. (A pilot, prospective, multi-center study) , 1904.,,,, (61.7%), (29.1%),.. Table 1. 79

3 (520) 25 3 ( ) Table 1. Abstract of the Toxic Hepatitis Report (Quoted from the Report of National Institute of Toxicological Research),,,, :,,.,,..,,.. : (modified RUCAM score). ALT, AST, total bilirubin, alkaline phosphatase 2N (N; ),,, 3, SNP(single nucleotide polymorphism) proteomics study. : , 1904.,,, (5.2% vs %) (34.5%), 36 (65.5%), (61.7%), (29.1%) ( B 1, 1 ). : (5.2/1000 ),,, (27.1/1000 ). 3. (61.7%), (29.1%), (7.3%). 4. (3.6%)

(521) 2003 2004 1 28 2),.,.. 2004 3 5),.... (1) 2003 7 11 7 (,,,,,, ) 55 Table 2.

4 (521) ),., ),.... (1) (,,,,,, ) 55 Table 2. Reported Cases of Toxic Hepatitis (Quoted from the report of National Institute of Toxicological Research) ( / ) 1000 (750/0.69) (454/2.50) (829/4.57) ( ) (570/5.15) ( ) (1,040/8.18) ( ) (550/1.90) (500/9.09) / : (coverage rate, %) = ( / ) 100 Fig 1. Regional Difference of Toxic Hepatitis Incidence (Quoted from the report of National Institute of Toxicological Research) Fig 2. Causes of Toxic Hepatitis (Quoted from the report of National Institute of Toxicological Research) 81

5 (522) 25 3 ( ) Table 3. Clinical Characteristics of Toxic Hepatitis (Quoted from the report of National Institute of Toxicological Research) Age (, mean 2SD, [range]) [29-81] Sex (men / women (%)) 19(34.5) / 36(65.5) (%) 27 (49.0) 7 (12.7), 16 (29.1) 1 (1.8) 3 (5.5) 1 (1.8) (, mean 2SD, [range]) [2-163] (, mean 2SD, [range]) [3-67] AST(IU/L, mean 2SD, [range]) [ ] ALT(IU/L, mean 2SD, [range]) [ ] ALP(IU/L, mean 2SD, [range]) [ ] TB(mg/dl, mean 2SD, [range]) [ ] RUCAM Score (, mean 2SD, [range]) [4-11] (%) 6(10.9) (%) 35(63.6) (%) 14(25.5) AST: asparate aminotransferase, ALT: alanine aminotransferase, ALP: Alkaline phosphatase, TB: total bilirubin :, :, :, :, : (Table 2). 55,. (2), (multicenter trial).. ( ) 2, ( ) 19, ( ) 10, ( ) 12 (Table 2). 6), , , % 10, ,, %. 34.5%, 1/3 1. (bias).,,,,,. (causality)., (selection bias). (internal validity). (3) 55, %. 82

6 (523) 4 ( 3, 1 ). 7 ( 4,693 ) OECD,. Estes( 2003) 7) Ibanez L(Spain 2002) 8), 9) 10), 11), 12), 13). (4).,,,,, 6 RUCAM scale(1993) M&V scale(1997) 3,4,14-18). RUCAM (Table 5) modified RUCAM 1,4,18) (Table 4). modified RUCAM RUCAM 2, 1., 3. RUCAM 7, 3-5 (possible), 6-8 (probable), 8 (high probable). modified RUCAM RUCAM 1 6, ) modified RUCAM 1 RUCAM 1, 15, 30. modified RUCAM score RUCAM, RUCAM,. 40, RUCAM,... RUCAM Danan (1993). (pharmacovigilance),.(since chronological criteria provide crucial information in pharmacovigilance, The role of the drug, as in many methods, must be ruled out by an incompatible time to onset. For some reactions, e.g. acute liver injury, when the time interval is unknown, the case report can be considered as insufficiently documented to allow any causality assessment.) Danan G, Benichou C J Clin Epidemiol 46:

7 (524) 25 3 ( ) Table 4. Scale of that Report Modified RUCAM Score (Quoted from the Report of National Institute of Toxicological Research) a b. <5, >90 >15 <5, >90 >90 +1 a ALT ULN AP(TB) ULN a. 8 50% +3 b % % +2 c % +1 d % 0 e % (, ) (, ) +1, 0 55 (, ) 55 (, ) +1, ( ) (6 )=IgM anti HAV, IgM anti HBc Ab, anti HCV Ab,,, = ;CMV,EBV,HSV ( ( ) ), ( ) +2.(.) +1, ALT 2 AP(TB) N N ; +1 ; -1 ; 0 # ; (definitive) 10, 7-9, 4-6, 1-3, 0 84

8 (525) Table 5. Assassement Scale of Original RUCAM Score(CIOMS) (Quoted from the Report of National Institute of Toxi cological Research) ( ) ( ) a b. <5, >90 >15 <5, >90 >90 +1 a ALT ULN AP(TB) ULN a. 8 50% +3 b % % +2 c % +1 d % 0 e % (, ) (, ) +1, 0 55 (, ) 55 (, ) +1, ( ) (6 )=IgM anti HAV, IgM anti HBc Ab, anti HCV Ab,,, = ;CMV,EBV,HSV ALT 2 AP(TB) N N -2 0 # ; (definitive) 9, 6-8, 3-5, 1-2, 0 85

9 (526) 25 3 ( )., ( ), RUCAM. 2) modified RUCAM 6 RUCAM 6 ( ) +2, ( ) +1, 0 (Table 5). modified RUCAM +2, +1, 0 (Table 4) ( : ),.. modified RUCAM +4,.. 3) modified RUCAM 8 RUCAM 7, 3, 9. modified RUCAM 8. +1, -1, 0... (specific) 19-22). RUCAM,. +1., 8. (5) RUCAM modified RUCAM, RUCAM ( ), modified RUCAM. 90.8% ( ) 7.2%., ( ). modified RUCAM, RUCAM. RUCAM. ( ) modified RUCAM RUCAM.,. (6), A pilot, prospective, multi-center study. 86

10 (527) , , 3,.,. RUCAM,. (7),,,,.,,,.,.,,.,., (raw data). (8).,.,,. (9) (toxic hepatitis induced by various plant preparations and healthy foods), ( ),., ( ). (drug-induced hepatitis)...,.,, p-value.., (causality). (causality assessment) (systematic procedure), (bias). (internal validity), (external validity) (scientific literature) ( 87

11 (528) 25 3 ( ) ).,, (selection bias),,. (validity),, ( ) ;10(suppl 1): (Medical Postgraduate). 2002;30(3): ,,,,,,,,, ;10(suppl 1): ( ) 7. Estes JD, Stolpman D, Olyaei A, Corless CL, Ham JM, Schwartz JM, Orloff SL. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg Aug;138(8): Ibanez L, Perez E, Vidal X, Laporte JR; Grup d Estudi Multicenteric d Hepatotoxicitat Aguda de Barcelona (GEMHAB). Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol Nov;37(5): ,,,,,, ;6(1): ,,,,,, ;63(2): ,,,,,,, :s ,,,,,,,,, ;7(suppl2):s ,,,,,, ;7(Suppl2):s Report of an international consensus meeting. Criteria of drug-induced liver disorders. J Hepatol. 1990; 11: 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 drug-induced 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: ; : ;10(suppl 1):

12 (529) : ;7(1): ,,,,. 62 :. 2001;35:

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