Systematic Review of the Cause of Drug-Induced Liver Injuries in Korean Literature

윤영주¹, 신병철², 이명수³, 조성일⁴, 박재현⁵, 이혜정⁶

1경희대학교 동서의학대학원 동서의학과, ²부산대학교 한의학전문대학원 한방재활의학과,

3한국한의학연구원 의료연구부, ⁴서울대학교 보건대학원 및 보건환경연구소,

5원광대학교 한의과대학 한방신경정신과, ⁶경희대학교 한의과대학 침구경락과학연구센터

Original Article

Systematic Review of the Cause of Drug-Induced Liver Injuries in Korean Literature

Young-Ju Yun¹, Byung-Cheul Shin², Myeong-Soo Lee³, Sung-Il Cho⁴, Jae-Hyeon Park⁵, Hye-Jung Lee⁶

1Dept. of East-West Medicine, Graduate School of East-West Medical Science, Kyunghee University

2Dept. of Oriental Rehabilitation Medicine, School of Oriental Medicine, Pusan National University

3Dept. of Medical Research, Korea Institute of Oriental Medicine

4Seoul National University School of Public Health and Institute for Health and Environment

5Dept. of Neuropsychiatry, College of Oriental Medicine, Wonkwang University

6Acupuncture & Meridian Science Research Center, College of Oriental Medicine, Kyunghee University Background: The safety of herbal products is an important issue in Korea. It is more complicated because of the concomitant use of conventional western drugs and herbal medicine, including prescribed medicine, folk herbs and food supplements. Although both western and traditional Korean medical doctors have studied on the safety of HMP, their results did not show relevant or consistent conclusions because of the poor quality of studies, including bias.

Objectives: The aim of this study was to review the studies in Korea related to drug induced liver injury (DILI) systematically. We tried to estimate the proportion of causative materials of DILI and evaluate the clinical difference of DILIs from different materials.

Methods: Systematic searches were performed on MedRIC and MEDLIS in Korea. The extraction of data as well as selective screening of the studies was carried out independently by two of the authors. There were no restrictions on the types of publication, including grey literature.

Results: Twenty-one articles were included. Of them only 7 adapted prospective design and only 6 were published in peer-reviewed journals. The proportion of conventional drugs associated with hepatotoxic injuries in all DILI ranged from 15.8% to 83.3% and that of herbal medicine was from 28.9% to 44.7%. However, the criteria for herbal medicine were not clearly defined and concomitant medications were not fully investigated in most studies. There were limited objective data in the clinical differences of liver injuries from different materials and their results were conflicting.

Conclusions: The causality assessments regarding DILI of herbal medicine were not performed properly and causative materials were misclassified in most of the studies published in Korea. These make the safety issue still ambiguous because of the limitations and lack of objectivity of the studies. More rigorous studies are required for clearly addressing these conflicting issues with cooperative investigation between traditional Korean and western medicine.

Key Words : drug-induced liver injury, hepatotoxicity, herbal medicine, causality assessment, systematic review

접수：2008년 9월 17일 채택：2009년 1월 2일

교신저자：이혜정(Hye-Jung Lee)

(130-701) 서울 동대문구 회기동 1번지 경희대학교 침구경락과학연구센터 Tel：+82-2-961-0975, Fax：+82-2-963-2175, E-mail：[email protected]

서 론

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RUCAM

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29) ,

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연구방법

(http://kmbase.medric.or.kr),

(MEDLIS, http://medlis.riss4u.net), (http://www.nanet.go.kr)

. DB

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, , , ,

.

1990 1 2008 5

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27 ( 12 ,

4 , 2 , 9 )

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6 ( 3 ,

2 , 1

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, 4 , 1 , 9

) (Fig. 1).

, . 1. Study design:

? - ? ?

2. Study populations: ,

? - ?,

? 3. Comparability of subjects:

-

? 4. Exposure or Intervention:

, , , -

?,

, ?,

? 5. Outcome measurement:

, -

?,

?,

?

AHRQ(Agency for Healthcare Research and Quality)

30) (Observational Study)

4 ,

. 2

,

Publications indentified (n=27)

Studies included in this review (n=21)

Further evaluation of the causative materials of DILI (n=15) -DILI for acute hepatitis (n=10, Table 1) -DILI for bile congestion (n=2, Table 2) -DILI for fulminant liver failure (n=3, Table 2)

Publications excluded after screening (n=6)

Reason: Studies were duplicated publication

Publications excluded for further evaluation (n=6)

-Study only including Western drug (n=1) -Studies only including Herbal medicine (n=2) -Duplicated studies from same institution and

research period (n=3)

Fig. 1.

.

결 과

21 7 ,

4 , 1 , 9

(Table 1-3). (grey literature)

12 , 9 , 3

, (peer

reviewed journal) 6 .

1999 1 , 2001 3 , 2002 3 , 2003 2 , 2004 2 , 2005 4 , 2006

3 , 2007 3 1999

2001

, .

3

18 , 3 .

3 ,

.

First author (year) Reference

Publication Research Institution (number involved)

Observatio n period (month)

Patients Number of DILI

Cause of DILI n (%)

Study design

Target population

(n)

Exclusion criteria specified

Assessment method of cause of

DILI

Standard of Western DILI

Drugs Herbal Medicine

nutritional supplement or folk medicine(including

herbal medicine) Joo (1999)

4)

Journal of university

UH (single)

1989.01- 1996.04 (88)

99 68 (68.7%) (DD)

not classified

31 (31.3%) Retro hepatitis patients (2,149)

HD excuded Patients use above 2 drugs excluded

Self estabilished standard

None

Chun (2002) 5)

Paper in journal

UH (single)

1997.04- 2001.03 (48)

78 39 (50.0%) (DD)

23 (29.5%)

39 (50%) (KS)

Retro acute liver injury (150)

previous HD patients excluded

RUCAM (compare with M&V)

RUCAM 3 items (ALT,ALP, TB) Ahn

(2002) 6)

governmen t report

UH (single)

1998.03- 2002.10 (56)

209 111 (53.1%)

not classified

98 (46.9%) (specified in some cases)

Pros acute liver injury (751)

patients with HD included

modified RUCAM RUCAM 3 items

Kim (2003) 7)

governmen t report

UH (7)

2003.03- 2003.10 (8)

76 12 (15.8%) (DNS)

34 (44.7%)

63 (82.9%) (KS) (unknown : 1)

Pros toxic hepatitis (76)

not report modified RUCAM RUCAM 5 items (ALT, AST, ALP, TB, DB) (no DB data) Kim

(2004) 8)

Paper in journal paper

UH (single)

1996.01.01 -2002.12.3 1 (84)

68 36 (55%) (DNS)

not classified

27 (42%) (KS)

(complex use: 5 (3%))

Retro acute toxic liver injury (68)

Patients with chronic HD, alcoholic hepatitis excluded

RUCAM self estabilished standard

Lee (2005) 9)

abstract only

UH (single)

2002.01- 2005.03 (39)

99 16 (16.2%) (DD)

43 (43.4%)

79 (79.8%) (KS)

(complex use: 4 (4%))

Retro drug induced hepatitis (99)

not report modified RUCAM None

Seo (2006) 10)

Paper in journal

UH (single)

1998.3-200 4.3 (61)

48 20 (42%) (DNS)

17 (35%) 28 (58%) (KS)

Retro toxic hepatitis (48)

not report RUCAM (above 4 points)

None

Kim (2006) 11)

governmen t report

UH (17)

2005.05- 2006.09 (17)

314 88 (28.0%)

92 (29.3%)

192 (61.2%) (complex use: 26, other:

8)

Pros toxic hepatitis (314)

not report RUCAM RUCAM 5

items (no DB data) Shin

(2007) 12)

Master dissertation

UH (single)

1995.01- 2005.12 (132)

109 26 (23.9%) (DNS)

41 (37.6%)

78 (71.6%) (KS)

(complex use: 3, other: 2)

Retro toxic hepatitis-in patients only (628)

patients with HD included

M&V RUCAM 3

items

Lee (2007) 13)

abstract only

UH (single)

1997.01- 2006.12 (120)

163 33 (20.2%)

66 (40.5%)

130 (79.8%) Retro DILI

(163)

not report Self estabilished standard

None

UH: University Hospital; DILI: Drug Induced Liver Injury; DNS: drugs and numbers specified; DD: Drugs described; KS: kinds specified; HD: Hepatic Disease;

RUCAM: Roussel Uclaf Causality Assessment Method; Retro: retrospective; Pros: prospective

Table 1.

2 , 4 ,

2 , 2 , 3

, , , , ,

1

.

7 , (

) 14 .

,

13 , 8 ( 3 ,

2 , 3 ) ,

.

6 ,

7 . 8

.

3 18

1989 CIOMS

(Council for International Organizations of Medical Sciences) = ICC(International consensus criteria

meeting) ³¹⁾ 5 (AST, ALT, ALP,

TB, DB) 5 , 3 (ALT, ALP, TB)

4 , 2 ,

7 .

( )

RUCAM 4 ( 1

), M&V 2 ,

RUCAM M&V

First author (year) Reference

Publication Research Institution (number involved)

Observation period (month)

Patients Number of DILI

Cause of DILI n (%)

Study design

Target population

(n)

Exclusion criteria specified

Assessmen t method of cause of

DILI

Standard of BCLI, FLF Western

Drugs

Herbal Medicine

nutritional supplement or

folk medicine(inclu

ding herbal medicine) Cho

(2001) 14)

Paper in journal

UH (single)

1990-1997 (84)

52 33 (63.5%) (DNS)

15 (28.9%) 19 (36.5%) (KS)

Retro Liver cell BCLI diagnosed by biopsy (62)

HD included Self estabilishe d standard

Standard of liver cell BCLI (histological diagnosis)

Shin (2002) 15)

Abstract only

UH (single)

1999.11- 2002.02 (27)

24 20 (83.3%) (DNS)

not classified 4 (16.7%) Pros BCLI without bile duct obstruction (31)

Viral HD, drinker, bile problem excluded

Self estabilishe d standard

non

Shin (2004) 16)

Paper in journal

UH (single)

1992.01- 2003.06 (138)

25 13 (52%) (DD)

not classified 12 (48%) Retro FLF (60)

HD history excluded

Drug use before DILI

FLF with hepatic encepalopathy Heo

(2006) 17)

Paper in journal

UH (single)

1999.01.01- 2004.12.31 (72)

35 (*)

21 (60%) (DNS)

not classified 14(*) (40%) (KS)

Retro FLF

(114)

HD history excluded

Drug use before DILI

hepatic encepalopathy occurred within 8 weeks from the onset of liver disease Park

(2007) 18)

Abstract only

UH (single)

2004-2006(?) (36)

33 9 (27.3%) not classified 24 (72.2%) Pros FLF (101)

Chronic HD with norman liver function included

non hepatic

encepalopathy occurred within 8 weeks from the onset of liver disease and INR>1.5 UH: University Hospital; DILI: Drug Induced Liver Injury; DNS: drugs and numbers specified; DD: Drugs described; KS: kinds specified; HD: Hepatic Disease; BCLI: Bile Conjugation Liver Injury; FLF: Fulminant Liver Failure; INR: International normalized ratio; Retro: retrospective; Pros: prospective

*modified from the original article(Original article classified mushroom into other causes, while other articles in this study classified mushroom into folk medicine. So we modified the number following reclassification)

Table 2.

4 , modified RUCAM(=phytoscale)

3 , ( 3

) 6 ,

2 .

16 ICC ³¹⁾

( , , )

12 , 4 .

1 , 2 ,

18 . 1

20 (

) 11 , 9

. 2

19 (

, ) 11

8 .

, 21

10 (Table 1)

. 3

3 6 (Table 3)

.

5 (Table 2) (Fig.1).

10

65.3±40.85 ( 8 - 132 )

, ( ) 1,263

.

1.53±0.93( / ) , 0.79 /

, 3.73 / .

9 ,

62.5% (659/1,054) ,

49.5% 72.9%

.

8 61.2%(582/950) ( 15.2%-

First author (year) Reference

Publication Research Institution (number involved)

Observat ion period

Patients Number of DILI

Cause of DILI n (%)

Study design Target population (n)

Exclusion criteria specified

Assessment method of cause of DILI

Standard of DILI

Reason for exclusion Western

Drugs Herbal Medicine

nutritional supplement or

folk medicine(inclu

ding herbal medicine) Ahn

(2001) 19)

Abstract only

UH (single)

1998.03- 2001.02

119 70 (58.8%)

25 (21.0%) 49 (41.2%) Prospective Acute hepatitis (439)

Not report M&V non Included in ref 3)

Seo (2001) 20)

Abstract only

UH (single)

1998.01- 2001.03

111 46 (41.4%)

31 (27.9%) 65 (58.6%) Retrospective DILI (111)

HD included

Not report ICC standard

Included in ref 10)

Lee (2003) 21)

Abstract only

UH (single)

1998.05- 2002.12

99 not included

not classified

59 (other HD: 40)

Retrospective Acute liver injury (induced by herbs or nutritional supplement) (99)

HD included

RUCAM (compare with M&V)

RUCAM 5 items

Study for herbs only

Lee (2005) 22)

Journal of university

UH (single)

1998.05- 2002.12

121 not included

not classified

68 (other HD: 53)

Retrospective Acute liver injury (induced by herbs, ect) (121)

HD included

RUCAM (compare with M&V)

RUCAM 5 items

Study for herbs only

Kim (2005) 23)

Report UH

(17)

2005.05- 2005.10

110 22 (27.8%)

26 (33.0%) 88 (72.2%) Prospective Toxic liver injury (110)

Not report RUCAM non Included in ref 8)

Seo (2005) 24)

Journal of university

UH (single)

2002.01- 2005.12

40 40 not

included

not included Retrospective DILI induced by western drug (40)

Not report RUCAM (compare with M&V)

RUCAM 3 items

Study for western drug

only UH: University Hospital; DILI: Drug Induced Liver Injury; HD: Hepatic Disease; Retro: retrospective; Pros: prospective

Table 3.

81.6%), 21.4%(10.5%-41.3%),

17.4%(6%-59.6%) .

, ,

, .

,

15 (Table 1, 2)

(proportion) .

38.1%(545/1432) 15.8%, 83.3%

. ,

, 61.9%(16.7

%-84.2%) .

15.8% ⁷⁾ , 16.2% ⁹⁾ ,

modified RUCAM .

1

52%-83.3% .

27.3%

18)

.

Classifications Ingredient name Case number(*)

항결핵제 isoniazid, rifampicin, pyrazinamide, ethionamide, p-aminosalicylic acid 71 항생제 cefiprin, cefoxitin, cefotetal, cefamandol, cefazoline, cefalexin, cefaclo, ofloxacin,

enoxacin, amoxacillin+clavulanate, micronomycin, tobramycin 69

NSAID, 소염제 loxoprofen, aspirin, ibuprofen, fhenoprofen acetaminophen 57

항진균제 ketoconazole, itraconazole, ciclopirox 12

혈압강하제 nimodipine, nifedipine irbesartan, propranolol, captopril, amlodipine, verapamil 4

마취제 halothane,enflurane, sevoflurane 3

천식약 aminophylline,theophylline 3

진해거담제 thenothiola, carboxymethylcysteine 2

피부과 약 Not reported in detail 1

항갑상선제 propylthiouracil, methimazole 4

마약성진통제 solumedrol 1

수면제 zolpidem, diazepam, diltiazem 2

항경련제 phenytoin, gabapentin, carbamazepin, phenobarbital 6

면역억제제 azathioprine, prednisolone 2

항히스타민제 terfenadine 1

항불안제 Not reported in detail 1

호르몬제 estrogen, progesterone, oxymetholone 3

항응고제, 항혈전제 ticlopidine, heparine 11

항말라리아제 Not reported in detail 1

혈당강하제 glibenclamide 1

체중감소제 Not reported in detail 3

위궤양치료제 ranitidine, cisapride, misoprostol, roxatidine, rebamipide, 7

항암제 Not reported in detail 1

(*원저에서 종류별로 숫자가 명시된 것은 숫자를 표시했으나 숫자 없이 종류만 나열된 연구는 1로 계산하여, 합계가 정확하지 않다. 병용 시에는 해당약물 모두에 중복 표시했다.)

Table 4.

, ¹³⁾ 1997

-2001 2002 -2006 5

5 4.9% 29.4

% .

15 , ,

, ( ), ,

, ,

.

,

‘ ’ .

, 8

‘ ’ 37.1%(

28.9%- 44.7%) .

‘ ’ 58.2%(49.4

-78.9%) . 8 , ‘

’,

1:1:1

Name of folk medicine and nutritional supplement Case number(*)

인진쑥 17

오가피 7

홍삼 9

허깨나무 5

느릅나무 3

상황버섯 6

동물의 간 1

어성초 1

영지버섯 1

녹즙, 케일즙, 신선초 1

흑염소 1

사슴피 1

옻닭 1

소태나무 1

누에 1

백년초 1

중국 다이어트 음식 1

환약 5

칡뿌리 2

호박소주, 개소주 2

잉어, 붕어즙 3

풀뿌리 1

갓버섯 4

돌미나리 5

민들레 1

뽕잎 1

산초나무 1

키토산 2

무화유음료 1

사슴엑기스 3

스쿠알렌 1

미슬토 1

(*원저에서 종류별로 숫자가 명시된 것은 숫자를 표시했으나 숫자 없이 종류만 나열된 연구는 1로 계산하여, 합계가 정확하지 않다. 병용 시에는 해당약물 모두에 중복 표시했다.)

Table 5.

. ‘ ’ ‘ ’

4 , 3-4%

. 4 ‘ ’ ‘ ’

. (

, )

11 . ,

(Table 4). 10

4,5,14)

, ,

7,8) .

32)

.

8 ,

, , , , ,

(Table 5).

고 찰

‘ ’, ‘ ’

DILI(Drug Induced Liver Injury,

) . ‘

’ ‘ ’

LFT(Liver Function Test)

. ¹⁾ ALT DB

2N( 2 ) , ²⁾

AST, ALP, TB 2N

31) .

ALT ALP ‘ ’, ‘

’, ‘ ’ ,

, RUCAM .

15.8%-83.3% , , ,

16.7%-84.2%

.

, herb

. 10

461 medicinal herb (western herb)

9 (2%) ³³⁾ .

2 , 2006 29 TCM(Tra-

ditional Chinese Medicine)

11 (37.9%) , 1

34) . 2007 31 TCM 17

(55%) ,

31 9 ,

35) .

1999-2007 8

36-43)

11.8%-46.67% . ,

, , 53.33%-88.2%

.

,

,

, .

.

, .

, 21 ( 7 ,

4 , 1 , 9 )

2007 2 , 1

9 ,

. ,

detection bias .

, 1999 1995 1999

23.0%, 12.0%, 27.5%,

17.9%, 28.5% ⁴⁴⁾ .

2002 1998.3-2002.10 27.83

% ⁶⁾ . 1999

( 1989.1-1996.4)

4.6% ⁴⁾ , 2002

( 1997.4-2001.3) 52%

5), (

2005.11-2006.10, 2 )

8.28% ⁴⁵⁾ .

,

.

7) 7

1,000

4.0 46.2

.

,

(high index of suspicion)

. (

1995.1- 2005.12)

628

109 ¹²⁾ .

(

) .

, (modified RUCAM)

2

. 2002

6) 53.1%

2003 ⁷⁾ 15.8%

. 2002 ,

, 2003 7

.

,

selection bias .

LFT ,

,

1.4% ⁴⁶⁾ . 50%

.

.

,

. ,

. 15

(Table 1,2)

7 . 4

, 4

.

1 .

(

, )

. 8

,

. , ,

1 ¹¹⁾ 1 ¹²⁾

,

.

, ,

( )

,

, 2006 ¹¹⁾

.

. ,

.

2 ^14,15) 63.5,

83.3% /

.

52% ¹⁶⁾ , 60%(

) ¹⁷⁾

.

18)

27.3%, 72.7%

.

,

. B

,

.

.

6 ,

7

. 8

. ,

2,5,8,15)

.

,

. ,

. 1987 Roussel Uclaf

. CIOMS(Council for International Organizations of Medical Sciences)

RUCAM ,

RUCAM CIMOS .

3

. M&V

,

RUCAM M&V

. RUCAM

47) .

.

48) “RUCAM

” .

RUCAM M&V

. RUCAM

modified RUCAM(=phytoscale)

6,27)

. RUCAM

, ‘

90 ,

30 ’ ‘

90

, 30

’ ,

.

30

.

‘ ’

( ) +1

.

, RUCAM

, LFT

.

CIOMS(1989 ICC )

5 (AST, ALT,

ALP, TB, DB) 5

DB

, 3 (ALT, ALP, TB) 4

, CIOMS ,

. AST, ALT, ALP, TB,

DB 2N

, CIOMS ALT DB

2N , AST, ALP,

TB (

) 2N

.

13,20-22)

.

21,22)

, ,

,

99 121 .

. 2001

39 46

20) , 39

120 2007

33 ¹³⁾ . 2001

41.4%, ‘ ’ 27.9% , 2007

20.2%, ‘ ’ 40.5% .

,

.

6) 23.6%(177/751) ‘

’ ,

104 , 3 , 1 ,

2 . RUCAM

.

.

.

4 ,

,

.

.

. 76

7)

2

. -

.

. 61.2%

(15.2-81.6%), 21.4% (10.5-41.3%)

17.4%(6-59.6%) .

4,5) , ⁸⁾

.

73.8% ⁶⁾

.

.

,

.

27) .

5 ,

, TB

4,5) .

. 2N

,

.

5N

, RUCAM

5N

8) . LFT

,

.

. ,

. ,

. ,

, .

,

. ,

.

, .

결 론

, ( , )

15.8%-83.3%,

, ,

16.7%-84.2%

.

, .

,

.

, ,

, (

) ,

.

.

.

, ,

,

.

참고문헌

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Influence of taking medicine for a period of time on the liver function and improvement of the developmental disordered children. Korean J Orient Physiol Pathol. 2006; 20(2):494-7.

3. Pittler MH, Ernst E. Systematic Review : hrpatotoxic events associated with herbal medicinal products.

Aliment Pharmacol Ther. 2003;18:451-71.

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