201223130-136

Terbinafine

Terbinane 3.3 %

terbinane 250mg
terbinane

(Drug hepatotoxicity)
(Drug induced liver Injury)
(Hepatocellular liver injury)
(Cholestatic liver injury)
(Mixed liver injury)
(Adverse Drug Reaction, ADR)

acetaminophenNSAID

Terbinane (cuta-

neous dermatophytosos) (Onychomy-

cosis) 250mg

2002 2005

10% 4,5.6

(36%)

(32%)Acetaminophen (12%)

1997 25884

(hepato-cellular) (88%)

terbinane

(cholestatic)(4%) (mixed)

0.2% ( )

(8%) 1985 1996

0.01% ( )4

3.3% 7

43503 699

Terbinane

2001 4 (April 2001) FDA (food and

drug administration) 16 terbinane

131

(severe liver damage linked toT)

terbinane

11 2

terbinane

58 terbinane

terbinane

250mg

terbinane

terbinane

RUCAM (

8 ) Naranjo ( 7 )

total bilirubin5.8 mg/dl (

terbinane

<1.2mg/dl)aspartate aminotransferase (AST)293

900

IU/L ( <37 IU/L)alanine aminotransferase

800

(ALT)773 IU/L ( <39 IU/L )alkaline

( <85 IU/L)

600

AST (IU/L)

500

ALT (IU/L)

400

AP (IU/L)

300

-GT (IU/L)

200

18

100

151

136

121

91

76

61

46

106

(palmar erythema)

31

0
16

gamma-glutamyl transpeptidase (-GT)715 IU/L

IU/L

phosphatase (AP)183 IU/L ( <145 IU/L)

700

days after stopping Terbinafine

(spider angioma)

total bilirubin
2.5 1.1 mg/
dlALT 5.3 66 IU/L-GT 188
IU/L

D-Bil (mg/dL)

2
1
155

141

127

113

99

85

0
71

ceruloplasmin

T-Bil (mg/dl)

57

anti-mitochondril antibody (AMA)

43

(ANA)anti-smooth muscle antibody (ASMA)

29

anti-CMV IgM anti-nuclear antibody

15

IgMHBsAganti-HCV anti-EBV

bilirubin concentration (mg/dL)

anti-HAV

days after stopping Terbinafine

Terbinafine
TB (total bilirubin)<1.2mg/dlCB (conjugated
bilirubin)<0.5mg/dlAST (aspartate
aminotransferase)<37 IU/LALT (alanine
aminotransferase)<39 IU/LAP (alkaline
phosphatase)<145IU/L-GT (gammaglutamyl transpeptidase)<85 IU/L

132

( ) (specically&

selectively) squalene epoxidase

) squalene

terbinane

80%
9

terbinane

20%

(canalicular)

terbinane

6,7,9-14

terbinane

(idiosyncratic) 16

(prolonged cholestasis

with disappearance of interlobular bile ducts)

14

8,9,15

Terbinane 70-80%

6,16

(oxidation)

17

(demethylation)

terbinane

( 80%)

5,6

Terbinane

terbinane

(cytochrome) P450

13

P450

24 40

5,6

7 40

4-6 7,12

Terbinane allylamine

6
Squalene

Allylamines

Squalene Epoxidease

(polymorphism)

Squalene Epoxide

INH (isoniazid)
N-acetyltransferase

Lanosterol
Azoles

(NAT-2) slow acetylators

genome-wide

Lanosterol a-m ethylase

Ergosterol
Cell Mem brane

Azoles Allyamines (eg, Terbinafine)

(
)
Azoles lanosterol-a-demethylase
(cytochrome) P450 Allylamine
Squalene epoxidase

association studies (GWAS)

(susceptibility) HLA

18,19
(specic markers)

Terbinane

133

Cases reports of terbinafine-induced liver jnjury

Reference Case

Age/Gender

Onset time

ALT(IU/L)

AP(IU/L)

T-bili.(mg/dl)

Outcome

58/F

40days

470

934

16.7

Resolved 6 months later

54/M

21 days

407

273

0.9

Resolved 6 months later

42/F

28 days

521

214

5.3

Loss of F.U.

74/F

4 weeks

333

157

10.0

Loss of F.U.

50/M

144

497

68.6

Orthotopic Liver transplantation :

success

10

53/F

1 weeks

1272

154

5.8

Resolved 6 months later

11

24/M

3.5 weeks

584

222

30.9

Resolved 100 days later

12

63/M

38 days

194

440

11.4

Resolved 11 weeks later

52/F

31 days

446

296

7.8

only T-bili. Normal

3 months later

14

10

75/F

10 days

277

375

5.6

r-GT moderate elevation by 17 months

later

15

11

48/F

4 weeks

17

12

66/M

4.5 weeks

365

105

0.8

Hypersensitivity syndrome reaction

improved after DC terbinane

Present
case

13

58/M

4 weeks

773

183

5.8

ALT: r-GT:mild elevation

5.3months later

Orthotopic Liver transplantation :

success

ALTalanine aminotransferaseAPalkaline phosphataseT-bilitotal bilirubinr-GTgamrna-glutamyl transpeptidase

Resolvedall liver tests returned to normal.

Organizations of Medical Science) RUCAM

(Roussel Uclaf Causality Assessment Method)

(compatible)

20,23,24

(suggestive)

RUCAM

(reproducibility)

ADR (consisteacy)

(reliability)

(accuracy) (objectiveness)

(reproducibility) (specicity)20,24

(several numerical scoring

RUCAM 7 (criteria)

systems)

1 (temporal relationship)2

(response after
1981 Naranjo Adverse Drug reaction

withdrawal of drug)3 (risk factors)

Probability Scale

4 (concomittent drugs)5

(simplicity)

20,21

(wide applicability) ( )

7 (rechalleng)

>8

(highly propable)6 8

20

( )

(probable)3 5 (possible)1

1992 CIOMS (Council for International

2 (unlikely) 0

134

Naranjo

1.

+1

2.

+2

-1

3.

+1

4.

+2

-1

5. ( )

-1

+2

6.

-1

+2

7.

+1

8.

+1

9.

+1

10.

+1

>=9 5-8 1-4 <= 0

RUCAM & Maria & Victorino
RUCAM criteria

Score

Maria&Victorino criteria

Score

+2 to +1

+1 to +3

+1 to 0

-3 to +3

-2 to +3

0 to +3

-3 to +3

+1 to 0

+1 to 0

0 to +3

-3 to 0

-3 to +2

-3 to +2

0 to +3

0 to +2

-2 to +3

(excluded)

2000 clinical
20,24

diagnostic scale M&V scale

( 15 )

Terbinane

Terbinane
( )

3.3%

terbinane
4-6
(baseline)

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Terbinafine Induced Liver Injury :

A Case Report and Review of Literatures
Cheng-Yu Hsu

Division of Gastroenterology, Department of Internal Medicine,

Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan

Terbinafine is widely applied and also is an effective antifungal agent. Although It was rarely found
symptomatic hepato-biliary abnormality, but severe hepatitis probably occurred in idiosyncratic individuals. One
case was reported, that he took terbinafine 250 mg daily for two weeks. The severe heptatocellular liver injury
developed four weeks after the first dose of terbinafine. The mechanism of terbinafine induced liver injury and
scales for adverse drug reaction were discussed by literature. (J Intern Med Taiwan 2012; 23: 130-136)