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Etifoxine-induced acute hepatitis: A case series
Clinics and Research in Hepatology and Gastroenterology (2012) 36, e85—e88
Available online at
www.sciencedirect.com
CASE REPORT
Etifoxine-induced acute hepatitis: A case series Céline Moch a, Fanny Rocher b, Pascale Lainé c, Jacqueline Lacotte d, Michel Biour e, Aurore Gouraud a, Nathalie Bernard a, Jacques Descotes a, Thierry Vial a,∗ a
Pharmacovigilance centre of Lyon, Lyon, France Pharmacovigilance centre of Nice, Nice, France c Pharmacovigilance centre of Angers, Angers, France d Pharmacovigilance centre of Caen, Caen, France e Pharmacovigilance centre of Paris Saint-Antoine, Paris, France b
Available online 23 May 2012
Summary Objective: Etifoxine is approved for the treatment of psychosomatic manifestations of anxiety. Several cases of acute hepatitis have been recently notified to the French pharmacovigilance centres. Our aim was to review all relevant cases of etifoxine hepatitis. Methods: All cases of liver disorders involving etifoxine and reported since November 1995 were extracted from the French pharmacovigilance database. Only cases with suggestive chronological events, no other drug-related or non-drug causes, and sufficient information, were included. Results: Of the 30 selected cases, 18 were retained for further analysis. The median duration of treatment before the onset of symptoms was 18 days (11 to 61 days). The results of liver tests evidenced cytolytic hepatitis in 15 cases and mixed-type hepatitis in 3. One patient also exposed to lisinopril/hydrochlorothiazide developed a fulminant hepatitis that required liver transplantation and six other patients had biological signs of severity. Except for the transplanted patient, 15 patients fully recovered within 3 months, and two clearly improved (further outcome unknown) after etifoxine withdrawal. Conclusion: One previously published case and our series confirm that etifoxine can cause acute liver injury with a possibly severe outcome. This adverse effect is not mentioned in the summary of the product characteristics. © 2012 Elsevier Masson SAS. All rights reserved.
∗
Corresponding author. 162, avenue Lacassagne, 69003, Lyon, France. Tel.: +33 4 72 11 69 97; fax: +33 4 72 11 69 85. E-mail address: [email protected] (T. Vial).
2210-7401/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2012.04.002
e86
Introduction Etifoxine chlorhydrate (Stresam® , Laboratoire Biocodex, France) is a benzoxazine derivative approved for the treatment of psychosomatic manifestations of anxiety at a daily dose of 150 to 200 mg. Although this drug has been marketed since 1979, very few data are available. Etifoxine is mostly used in France. A cross-sectional survey performed in les Bouches-du-Rhône, a southern department of France, in 2002 among teenagers showed this was one of the most frequently prescribed anxiolytic drugs in this population [1]. Known adverse effects include drowsiness and acute hypersensitivity reactions, such as urticaria and angioedema, and only one single case of acute hepatitis has been published so far [2]. A recent and convincing case of etifoxine-associated acute hepatitis reported to Lyon pharmacovigilance centre was an incentive to analyse all spontaneously reported cases retrieved in the French pharmacovigilance database (FPD).
Patients and methods Between November 1995 and September 2011, 30 reports of etifoxine-associated acute hepatitis were retrieved in the FPD. All cases were carefully reviewed and those with insufficient information, the presence of any concomitant drug known to be clearly hepatotoxic, other obvious pathological causes, or with only a slight increase in aminotransferase serum levels (< 3N) without clinical symptoms were excluded for further evaluation. The remaining cases were classified according to an international consensus report into hepatocellular, mixed or cholestatic type of liver injury on the basis of the results of liver test abnormalities [3]. Severe liver injury was defined by the presence of jaundice or both marked hyperbilirubinemia and prothrombin time below 50%. Finally, the causal relationship with drug treatment was assessed using the RUCAM score [4].
Results Of the 30 cases identified in the FPD, 18 met the criteria defined above and were considered to be probably druginduced. The main characteristics of these 18 cases are summarized on Table 1. There were 16 women and two men with a mean age of 48.3 ± 17 years. The median daily dose of etifoxine (n = 13) was 150 mg/day and the median treatment duration before the onset of clinical or biological symptoms was 18 days (11 to 61 days). In three cases (patients 4, 9, 11), etifoxine was discontinued more than 4 days after the first suggestive symptoms of hepatitis with a range of 5 to 15 days. Twelve patients experienced clinical symptoms, such as asthenia, abdominal pain, pruritus and jaundice, and none presented signs suggestive of hypersensitivity, such as fever, cutaneous eruption or hypereosinophilia. Results of liver tests evidenced a hepatocellular pattern of liver injury in 15 patients and a mixed-type in three. Overall, seven patients (39%) had biological signs of severe liver injury at presentation (patients 4, 7, 9, 13, 14, 15, 17). Interestingly, two of the three patients who continued etifoxine for more than 4 days after the onset of symptoms experienced
C. Moch et al. severe liver injury among whom the patient who developed fulminant hepatitis later on. Other common pathological causes were excluded in the majority of patients. Serological tests were negative for hepatitis viruses A and B in 16 patients, and hepatitis virus C in 15 patients (not available in two). Hepatitis C serology was found positive in one patient with a history of hepatitis C. Several patients were also negative for cytomegalovirus (n = 7), Epstein Barr virus (n = 5), Herpes simplex virus (n = 3), human immunodeficiency virus (n = 3) and hepatitis E (n = 2). Patients 1 and 4 were positive for antinuclear antibodies (1/320 and 1/640), but negative for specific liver autoantibodies. No data was available on the outcome of this autoantibodies. Two additional patients were negative for both antinuclear antibodies and specific liver autoantibodies. Abdominal ultrasound examination performed in 11 patients was normal in 10 and evidenced only a mild liver steatosis in 1. Three patients had a percutaneous liver biopsy, which was not interpretable in one case of fulminant hepatitis. In one patient (case 9), the histological examination evidenced hepatocellular necrosis with inflammatory lesions and a predominance of eosinophils in an otherwise normal liver without fibrosis. In the other patient (case 7) with a history of hepatitis C, there was significant mutilating fibrosis and nodular-type cirrhosis, but the presence of portal inflammatory lesions with eosinophilia was considered to be suggestive of a drug-related cause. Several patients were treated with other drugs that can also be suspected on the basis of chronological events because they were also discontinued before liver tests improved (Table 1). However, none of these potentially suspected drugs were known to be hepatotoxic, except for alverine. Fifteen patients fully recovered within 3 months and two other clearly improved (further outcome unknown) after etifoxine discontinuation. The last patient (case 4), who had been treated with etifoxine during 16 days and lisinopril/hydrochlorothiazide for 13 months, developed fulminant hepatitis, which required liver transplantation 6 weeks after the onset of symptoms. The RUCAM score determined for each patient ranged from 5 (possible) to 11 (highly probable) with a mean score of 7.17 ± 1.74.
Discussion This case series strongly suggests that etifoxine can cause acute hepatitis with a predominant hepatocellular pattern of biological abnormalities, occurring within one month of treatment in 89% of cases. Severe liver injury was observed in 39% of patients of whom one developed fulminant hepatic failure, and two of the three patients who continued etifoxine treatment after the onset of first symptoms developed severe hepatitis. The causal relationship with etifoxine treatment is supported by the exclusion of other common causes of hepatitis, such as viral hepatitis or biliary tract abnormalities in most patients, and improvement or complete recovery after etifoxine discontinuation in all, but one patient who required liver transplantation. Finally, concomitantly administered drugs were not clearly associated with hepatotoxicity, except for alverine, which has been involved in rare cases of acute hepatitis [5,6].
Characteristics of etifoxine-induced acute hepatitis. Clinical symptoms
Type of injury
Liver testsb
Severity criteriac
Outcome
RUCAM scored
No No
Cytolytic Mixed
No No
Recovery Recovery
8 7
Yes
Mixed
ALAT: 5 N ALAT: 18 N PAL: 5 N ALAT: 6 N
No
Improvement
5
Yes No Yes Yes
Cytolytic Cytolytic Cytolytic Cytolytic
Yes No No Yes
Transplantation Recovery Recovery Improvement
5 5 NA 7
15 30
Yes Yes
Cytolytic Cytolytic
No Yes
Recovery Recovery
6 8
15
16
Yes
Cytolytic
No
Recovery
11
43
25
15
No
Cytolytic
ALAT: 22 N ALAT: 18 N ALAT: 17 N ALAT: 9 N TB:10 N NA ALAT: 43 N PAL 2.5 N TB: 19 N ALAT: 5 N PAL: N ALAT: 77 N
No
Recovery
8
F F
36 45
61 15
61 18
Yes Yes
Cytolytic Mixed
No Yes
Recovery Recovery
6 6
14
F
69
21
21
Yes
Cytolytic
Yes
Recovery
10
15
F
42
61
60
Yes
Cytolytic
Yes
Recovery
7
16
M
60
22
24
Alverine, Simeticone, Esomeprazole, Cefpodoxime Fluticasone
No
Cytolytic
17
F
50
18
17
St John’s wort (hypericum perforatum)
Yes
18
F
26
12
12
No
Case number
Sex
Age
Treatment duration (days)
Onset of symptoms (days)
1 2
M F
20 37
20 16
18 16
3
F
44
23
26
4 5 6 7
F F F F
42 76 43 75
16 11 NA 24
11 11 NA 24
8 9
F F
74 32
17 45
10
F
56
11
F
12 13
Other suspected drugsa
Escitalopram, Alprazolam
Furosemide, Amiloride
Hawthorne, Valerian Bromazepam
ALAT:38 N ALAT: 15 N PAL: 4 N ALAT: 44 N PAL: 4 N ALAT: 20 N PAL: N
No
Recovery
8
Cytolytic
ALAT: 22 N PAL: 2 N ALAT: 40 N
Yes
Recovery
6
Cytolytic
ALAT: 44 N
No
Recovery
9
e87
ALAT: alanine aminotransferase; TB: total bilirubin; PAL: alkaline phosphatase; NA: not available. a Drugs started less than 3 months before the onset of hepatitis. b Results are given as multiples of the upper limit of normal value. c Severe liver injury was defined by the presence of jaundice, or marked hyperbilirubinemia and prothrombin time below 50%. d RUCAM score: ≤ 0 (relationship with the drug excluded); 1—2 (unlikely), 3—5 (possible), 6—8 (probable), > 8 (highly probable) [4].
Etifoxine hepatitis
Table 1
e88 To our knowledge, only one published case report described the occurrence of severe acute icteric cytolytic hepatitis after 11 days of etifoxine treatment in a 76year-old woman [2]. Complete recovery was noted after etifoxine withdrawal, while the other drugs were continued. In similitude with our cases, no clinical or biological signs of hypersensitivity were reported in this patient, supporting an idiosyncratic rather than immune-allergic reaction. This potentially severe adverse effect of etifoxine is not mentioned in the summary of the product characteristics. It should be weighed against the limited efficacy of etifoxine. Based on the above, etifoxine treatment should be avoided, or patients warned of this rare, but potentially severe adverse effect.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors thank all pharmacovigilance centres that contributed to the recording and analysis of these cases.
C. Moch et al.
References [1] Mancini J, Thirion X, Masut A, Saillard C, Pradel V, Romain F, et al. Anxiolytics, hypnotics, and antidepressants dispensed to adolescents in a French region in 2002. Pharmacoepidemiol Drug Saf 2006;15:494—503. [2] Mennecier D, Rimlinger H, Gidenne S, Moulin O, Marzars H, Thiolet C, et al. Etifoxine chlorhydrateinduced acute hepatitis. Gastroenterol Clin Biol 2003;27: 1050—1. [3] Bénichou C. Standardization of definitions and criteria of causality assessment of adverse drug reactions. Druginduced liver disorders: report of an international consensus meeting. Int J Clin Pharmacol Ther Toxicol 1990;28: 317—22. [4] 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: 1323—30. [5] Arhan M, Koklu S, Koksal AS, Yolcu OF, Koruk S, Koruk I, et al. Alverine citrate induced acute hepatitis. World J Gastroenterol 2004;10:2303—4. [6] Han JY, Lee JW, Kim JM, Joo K, Chon U, Lee JI, et al. A case report of alverine-citrate-induced acute hepatitis. Korean J Hepatol 2010;16:75—8.
Available online at
www.sciencedirect.com
CASE REPORT
Etifoxine-induced acute hepatitis: A case series Céline Moch a, Fanny Rocher b, Pascale Lainé c, Jacqueline Lacotte d, Michel Biour e, Aurore Gouraud a, Nathalie Bernard a, Jacques Descotes a, Thierry Vial a,∗ a
Pharmacovigilance centre of Lyon, Lyon, France Pharmacovigilance centre of Nice, Nice, France c Pharmacovigilance centre of Angers, Angers, France d Pharmacovigilance centre of Caen, Caen, France e Pharmacovigilance centre of Paris Saint-Antoine, Paris, France b
Available online 23 May 2012
Summary Objective: Etifoxine is approved for the treatment of psychosomatic manifestations of anxiety. Several cases of acute hepatitis have been recently notified to the French pharmacovigilance centres. Our aim was to review all relevant cases of etifoxine hepatitis. Methods: All cases of liver disorders involving etifoxine and reported since November 1995 were extracted from the French pharmacovigilance database. Only cases with suggestive chronological events, no other drug-related or non-drug causes, and sufficient information, were included. Results: Of the 30 selected cases, 18 were retained for further analysis. The median duration of treatment before the onset of symptoms was 18 days (11 to 61 days). The results of liver tests evidenced cytolytic hepatitis in 15 cases and mixed-type hepatitis in 3. One patient also exposed to lisinopril/hydrochlorothiazide developed a fulminant hepatitis that required liver transplantation and six other patients had biological signs of severity. Except for the transplanted patient, 15 patients fully recovered within 3 months, and two clearly improved (further outcome unknown) after etifoxine withdrawal. Conclusion: One previously published case and our series confirm that etifoxine can cause acute liver injury with a possibly severe outcome. This adverse effect is not mentioned in the summary of the product characteristics. © 2012 Elsevier Masson SAS. All rights reserved.
∗
Corresponding author. 162, avenue Lacassagne, 69003, Lyon, France. Tel.: +33 4 72 11 69 97; fax: +33 4 72 11 69 85. E-mail address: [email protected] (T. Vial).
2210-7401/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2012.04.002
e86
Introduction Etifoxine chlorhydrate (Stresam® , Laboratoire Biocodex, France) is a benzoxazine derivative approved for the treatment of psychosomatic manifestations of anxiety at a daily dose of 150 to 200 mg. Although this drug has been marketed since 1979, very few data are available. Etifoxine is mostly used in France. A cross-sectional survey performed in les Bouches-du-Rhône, a southern department of France, in 2002 among teenagers showed this was one of the most frequently prescribed anxiolytic drugs in this population [1]. Known adverse effects include drowsiness and acute hypersensitivity reactions, such as urticaria and angioedema, and only one single case of acute hepatitis has been published so far [2]. A recent and convincing case of etifoxine-associated acute hepatitis reported to Lyon pharmacovigilance centre was an incentive to analyse all spontaneously reported cases retrieved in the French pharmacovigilance database (FPD).
Patients and methods Between November 1995 and September 2011, 30 reports of etifoxine-associated acute hepatitis were retrieved in the FPD. All cases were carefully reviewed and those with insufficient information, the presence of any concomitant drug known to be clearly hepatotoxic, other obvious pathological causes, or with only a slight increase in aminotransferase serum levels (< 3N) without clinical symptoms were excluded for further evaluation. The remaining cases were classified according to an international consensus report into hepatocellular, mixed or cholestatic type of liver injury on the basis of the results of liver test abnormalities [3]. Severe liver injury was defined by the presence of jaundice or both marked hyperbilirubinemia and prothrombin time below 50%. Finally, the causal relationship with drug treatment was assessed using the RUCAM score [4].
Results Of the 30 cases identified in the FPD, 18 met the criteria defined above and were considered to be probably druginduced. The main characteristics of these 18 cases are summarized on Table 1. There were 16 women and two men with a mean age of 48.3 ± 17 years. The median daily dose of etifoxine (n = 13) was 150 mg/day and the median treatment duration before the onset of clinical or biological symptoms was 18 days (11 to 61 days). In three cases (patients 4, 9, 11), etifoxine was discontinued more than 4 days after the first suggestive symptoms of hepatitis with a range of 5 to 15 days. Twelve patients experienced clinical symptoms, such as asthenia, abdominal pain, pruritus and jaundice, and none presented signs suggestive of hypersensitivity, such as fever, cutaneous eruption or hypereosinophilia. Results of liver tests evidenced a hepatocellular pattern of liver injury in 15 patients and a mixed-type in three. Overall, seven patients (39%) had biological signs of severe liver injury at presentation (patients 4, 7, 9, 13, 14, 15, 17). Interestingly, two of the three patients who continued etifoxine for more than 4 days after the onset of symptoms experienced
C. Moch et al. severe liver injury among whom the patient who developed fulminant hepatitis later on. Other common pathological causes were excluded in the majority of patients. Serological tests were negative for hepatitis viruses A and B in 16 patients, and hepatitis virus C in 15 patients (not available in two). Hepatitis C serology was found positive in one patient with a history of hepatitis C. Several patients were also negative for cytomegalovirus (n = 7), Epstein Barr virus (n = 5), Herpes simplex virus (n = 3), human immunodeficiency virus (n = 3) and hepatitis E (n = 2). Patients 1 and 4 were positive for antinuclear antibodies (1/320 and 1/640), but negative for specific liver autoantibodies. No data was available on the outcome of this autoantibodies. Two additional patients were negative for both antinuclear antibodies and specific liver autoantibodies. Abdominal ultrasound examination performed in 11 patients was normal in 10 and evidenced only a mild liver steatosis in 1. Three patients had a percutaneous liver biopsy, which was not interpretable in one case of fulminant hepatitis. In one patient (case 9), the histological examination evidenced hepatocellular necrosis with inflammatory lesions and a predominance of eosinophils in an otherwise normal liver without fibrosis. In the other patient (case 7) with a history of hepatitis C, there was significant mutilating fibrosis and nodular-type cirrhosis, but the presence of portal inflammatory lesions with eosinophilia was considered to be suggestive of a drug-related cause. Several patients were treated with other drugs that can also be suspected on the basis of chronological events because they were also discontinued before liver tests improved (Table 1). However, none of these potentially suspected drugs were known to be hepatotoxic, except for alverine. Fifteen patients fully recovered within 3 months and two other clearly improved (further outcome unknown) after etifoxine discontinuation. The last patient (case 4), who had been treated with etifoxine during 16 days and lisinopril/hydrochlorothiazide for 13 months, developed fulminant hepatitis, which required liver transplantation 6 weeks after the onset of symptoms. The RUCAM score determined for each patient ranged from 5 (possible) to 11 (highly probable) with a mean score of 7.17 ± 1.74.
Discussion This case series strongly suggests that etifoxine can cause acute hepatitis with a predominant hepatocellular pattern of biological abnormalities, occurring within one month of treatment in 89% of cases. Severe liver injury was observed in 39% of patients of whom one developed fulminant hepatic failure, and two of the three patients who continued etifoxine treatment after the onset of first symptoms developed severe hepatitis. The causal relationship with etifoxine treatment is supported by the exclusion of other common causes of hepatitis, such as viral hepatitis or biliary tract abnormalities in most patients, and improvement or complete recovery after etifoxine discontinuation in all, but one patient who required liver transplantation. Finally, concomitantly administered drugs were not clearly associated with hepatotoxicity, except for alverine, which has been involved in rare cases of acute hepatitis [5,6].
Characteristics of etifoxine-induced acute hepatitis. Clinical symptoms
Type of injury
Liver testsb
Severity criteriac
Outcome
RUCAM scored
No No
Cytolytic Mixed
No No
Recovery Recovery
8 7
Yes
Mixed
ALAT: 5 N ALAT: 18 N PAL: 5 N ALAT: 6 N
No
Improvement
5
Yes No Yes Yes
Cytolytic Cytolytic Cytolytic Cytolytic
Yes No No Yes
Transplantation Recovery Recovery Improvement
5 5 NA 7
15 30
Yes Yes
Cytolytic Cytolytic
No Yes
Recovery Recovery
6 8
15
16
Yes
Cytolytic
No
Recovery
11
43
25
15
No
Cytolytic
ALAT: 22 N ALAT: 18 N ALAT: 17 N ALAT: 9 N TB:10 N NA ALAT: 43 N PAL 2.5 N TB: 19 N ALAT: 5 N PAL: N ALAT: 77 N
No
Recovery
8
F F
36 45
61 15
61 18
Yes Yes
Cytolytic Mixed
No Yes
Recovery Recovery
6 6
14
F
69
21
21
Yes
Cytolytic
Yes
Recovery
10
15
F
42
61
60
Yes
Cytolytic
Yes
Recovery
7
16
M
60
22
24
Alverine, Simeticone, Esomeprazole, Cefpodoxime Fluticasone
No
Cytolytic
17
F
50
18
17
St John’s wort (hypericum perforatum)
Yes
18
F
26
12
12
No
Case number
Sex
Age
Treatment duration (days)
Onset of symptoms (days)
1 2
M F
20 37
20 16
18 16
3
F
44
23
26
4 5 6 7
F F F F
42 76 43 75
16 11 NA 24
11 11 NA 24
8 9
F F
74 32
17 45
10
F
56
11
F
12 13
Other suspected drugsa
Escitalopram, Alprazolam
Furosemide, Amiloride
Hawthorne, Valerian Bromazepam
ALAT:38 N ALAT: 15 N PAL: 4 N ALAT: 44 N PAL: 4 N ALAT: 20 N PAL: N
No
Recovery
8
Cytolytic
ALAT: 22 N PAL: 2 N ALAT: 40 N
Yes
Recovery
6
Cytolytic
ALAT: 44 N
No
Recovery
9
e87
ALAT: alanine aminotransferase; TB: total bilirubin; PAL: alkaline phosphatase; NA: not available. a Drugs started less than 3 months before the onset of hepatitis. b Results are given as multiples of the upper limit of normal value. c Severe liver injury was defined by the presence of jaundice, or marked hyperbilirubinemia and prothrombin time below 50%. d RUCAM score: ≤ 0 (relationship with the drug excluded); 1—2 (unlikely), 3—5 (possible), 6—8 (probable), > 8 (highly probable) [4].
Etifoxine hepatitis
Table 1
e88 To our knowledge, only one published case report described the occurrence of severe acute icteric cytolytic hepatitis after 11 days of etifoxine treatment in a 76year-old woman [2]. Complete recovery was noted after etifoxine withdrawal, while the other drugs were continued. In similitude with our cases, no clinical or biological signs of hypersensitivity were reported in this patient, supporting an idiosyncratic rather than immune-allergic reaction. This potentially severe adverse effect of etifoxine is not mentioned in the summary of the product characteristics. It should be weighed against the limited efficacy of etifoxine. Based on the above, etifoxine treatment should be avoided, or patients warned of this rare, but potentially severe adverse effect.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors thank all pharmacovigilance centres that contributed to the recording and analysis of these cases.
C. Moch et al.
References [1] Mancini J, Thirion X, Masut A, Saillard C, Pradel V, Romain F, et al. Anxiolytics, hypnotics, and antidepressants dispensed to adolescents in a French region in 2002. Pharmacoepidemiol Drug Saf 2006;15:494—503. [2] Mennecier D, Rimlinger H, Gidenne S, Moulin O, Marzars H, Thiolet C, et al. Etifoxine chlorhydrateinduced acute hepatitis. Gastroenterol Clin Biol 2003;27: 1050—1. [3] Bénichou C. Standardization of definitions and criteria of causality assessment of adverse drug reactions. Druginduced liver disorders: report of an international consensus meeting. Int J Clin Pharmacol Ther Toxicol 1990;28: 317—22. [4] 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: 1323—30. [5] Arhan M, Koklu S, Koksal AS, Yolcu OF, Koruk S, Koruk I, et al. Alverine citrate induced acute hepatitis. World J Gastroenterol 2004;10:2303—4. [6] Han JY, Lee JW, Kim JM, Joo K, Chon U, Lee JI, et al. A case report of alverine-citrate-induced acute hepatitis. Korean J Hepatol 2010;16:75—8.