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Cholestatic liver injury after glimepiride therapy
Journal of Hepatology 42 (2005) 944–946 www.elsevier.com/locate/jhep
Case report
Cholestatic liver injury after glimepiride therapy Athina Chounta1,*, Spyros Zouridakis1, Christos Ellinas1, Sotirios Tsiodras1, Christina Zoumpouli2, Stylianos Kopanakis1, Helen Giamarellou1 1
Hepatology Division, 4th Academic Department of Internal Medicine, Attikon University General Hospital, 7 Orfeos Street, Palaio Faliro, 17564 Athens, Greece 2 Laboratory of Histopathology, Attikon University General Hospital, 7 Orfeos Street, Palaio Faliro, 17564 Athens, Greece
Drug induced hepatotoxicity has been reported infrequently with sulfonylureas. For glimepiride, a secondgeneration sulfonylurea there is no report of hepatotoxicity in English literature. A patient with non-insulin-dependent diabetes mellitus who developed cholestatic liver injury soon after initiation of glimepiride therapy is presented. Complete work-up disclosed no other cause for hepatotoxicity including negative serological results for viral hepatitis. Liver biopsy was consistent with drug-induced cholestasis. The patient recovered 50 days after stopping glimepiride with no further recurrences. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Glimepiride; Hepatitis; Cholestasis 1. Introduction Glimepiride is a second-generation sulfonylurea used in the management of non-insulin-dependent diabetes mellitus (NIDDM). Recently introduced in Europe, glimepiride is prescribed regularly because of its efficacy, convenient dosing schedule, and safety. A major advantage of glimepiride is the absence of common side effects of first generation oral agents such as disulfiram-like reactions. We report a case of a patient who developed hepatotoxicity soon after the initiation of glimepiride therapy. The clinical and laboratory findings, the liver biopsy results, as well as rechallenge with glimepiride supported the etiopathogenic role of glimepiride in producing liver dysfunction in the presented case.
2. Case report A 65-year-old man with a history of hypertension, presented at the outpatient surgical clinic with jaundice, Received 22 December 2004; received in revised form 24 January 2005; accepted 7 February 2005; available online 7 April 2005 * Corresponding author. Tel.: C30 210 583 1990; fax: C30 210 532 6446. E-mail address: [email protected] (A. Chounta).
right upper quadrant abdominal pain, light stools and dark urine. NIDDM was diagnosed 2 weeks earlier and glimepiride (2 mg/d) was prescribed. At that time, the patient had normal liver function tests. His past medical history was non-significant and in addition there was no previous history of biliary tract disease, alcohol abuse, drug addiction or blood transfusions. He was receiving nifedipine and atenolol continuously for the last 14 years for his hypertension. He denied use of any non-prescription medications. He had no history of foreign travel and no family history of liver disease. His vital signs were stable with a temperature of 36.8 8C, a blood pressure of 150/85 mmHg, and a heart rate of 74 beats/min. His physical exam disclosed RUQ abdominal pain with normal bowel sounds and no rebound tenderness. The patient was admitted to our department. Results of some of the laboratory tests on admission and over the follow-up periods are shown in Table 1. His renal function and electrolytes were normal. Due to the liver abnormalities and the RQU pain abdominal ultrasonography was performed which revealed a stone in the common bile duct (CBD). An endoscopic retrograde cholangiography confirmed an 8 mm CBD stone, which was removed successfully after sphincterotomy at day 9 of admission. Soon after the patient developed fever with negative blood and urine cultures that responded successfully to the initiation of piperacillin/
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.02.011
A. Chounta et al. / Journal of Hepatology 42 (2005) 944–946
945
Table 1 Results of laboratory tests on admission and at different follow-up periods Laboratory test
Day 1
Day 9
Day 19
Day 30
Day 40
Day 42
Day 70
Total bilirubina Direct bilirubinb Alkaline phosphatasec g-GTd ALT ASTe Albuminf Hematocrit Hemoglobing INRh ESRi
6.91 6.82 403 231 141 63 4.6 43 14.9 1.0 – Admission
15.1 13.05 334 102 42 45 3.8 40.9 14.2 0.89 – ERCP
12.8 9.22 277 63 31 34 3.4 35.7 12.1 1.0 116 2nd ERCP
7.4 6.12 342 166 38 42 3.7 32.9 11.4 0.92 77 Biopsy
3.6 2.96 394 236 50 45 3.2 32.7 10.9 – – Before restart
7.1 6.8 432 390 107 112 – – – – – After restart
0.50 0.10 125 46 32 26 – 46 15.7 – – Follow-up
Normal range 13–40 mU/ml; normal range 39.0–52.0%. a Normal range 0.2–1.2 mg/dl. b Normal range 0.0–0.3 mg/dl. c Normal range 53–128 mU/ml. d Normal range 9–50 mU/ml. e Normal range 15–48 mU/ml. f Normal range 3.4–5.0 g/dl. g Normal range 13.5–18.0 g/dl. h International normalized ratio: normal 1.0. i Erythrocyte sedimentation rate: normal range 0.0–15 mm/first hour.
tazobactam, and netilmicin. A new ERCP, MRCP, abdominal ultrasound, and CT scan were all normal. The liver function test results remained abnormal during follow up and this initiated further laboratory work-up to exclude other causes of chronic liver disease. These included negative serology for hepatitis A, B and C viruses, EBV and CMV viruses, normal prothrombin time, normal serum a-fetoprotein levels, normal iron studies, serum protein electrophoresis, normal folate, vitamin B12, FT3, FT4 and TSH levels and normal immunological testing including anti-smooth-muscle (SMA), anti-nuclear (ANA), antiLKM, and anti-mitochondrial (AMA) antibodies. His complete blood count and the peripheral eosinophil count (0.2!103 ml) remained normal. Forty days following his initial admission, the patient was restarted on glimepiride as part of his usual regimen and the liver function tests became markedly increased again (see Table 1). A liver biopsy performed at this stage showed a histological pattern of an acute hepatitis, with striking confluent necrosis in zone 3 (Fig. 1), as well as the presence of mild portal tract inflammation, comprising of a small number of eosinophils. Mild bilirubinostasis (Fig. 2) coexisted in hepatocytes and bile sinusoids. The medication was stopped, and the enzymes returned to normal 1 month later. The case was reported to the National Medicine Organization of Greece.
large controlled international trials [1] and this together with its convenient dosing schedule has led to its widespread use [2]. Glimepiride is generally well tolerated. Adverse effects such as dizziness, headache, asthenia or nausea prompt discontinuation in a small percentage of patients [1]. The medical literature contains three reports in French, but none in English, of severe hepatotoxicity due to glimepiride [3–5]. The cases were attributed to the glimepiride use due to (a) the absence of other causes of acute hepatitis, e.g. viral pathogens, (b) the chronologic order of events regarding the close association between the introduction of glimepiride, the onset of liver function test abnormalities and their normalization shortly after the discontinuation of the drug, and (c) the absence of significant biliary disease by
3. Discussion Glimepiride belongs to the sulfonylurea class of drugs [1]. Its safety has been evaluated in over 3500 patients in
Fig. 1. Zone 3 necrosis, a common feature of acute drug-induced hepatitis.
946
A. Chounta et al. / Journal of Hepatology 42 (2005) 944–946
however, one showed hepatic necrosis [3]. Newer sulfonylureas like glibenclamide have been associated with hepatic toxicity [4] however, this is a rare phenomenon [4].
4. Conclusion
Fig. 2. Bilirubinostasis in bile canaliculi and hepatocytes.
ultrasound imaging [3–5]. One of the cases was confounded by the use of anti-epileptic drugs including benzodiazepines and alcohol consumption [4]. The association between cholestatic hepatitis and glimepiride use was confounded by the presence of choledocholithiasis in our case. This led to the unfortunate reintroduction of glimepiride that essentially confirmed the diagnosis of a glimepiride related adverse effect as the liver enzymes increased immediately. However, re-challenge with a hepatotoxic drug in case of hepatotoxicity is not advised [6]. It is possible that the concomitant biliary lithiasis might have predisposed the patient to develop hepatitis. The specific pathophysiology responsible for this adverse event remains unclear. The histologic features seen on liver biopsy samples in our case were compatible with drug-associated hepatotoxicity with cholestasis being the predominant finding. In the previously described cases, a cholestatic pattern was noted in liver biopsy as well [4,5]
In conclusion, we describe a rare case of glimepiride associated liver injury that calls for caution in the use of glimeperide. All patients receiving glimepiride should have their liver function tests periodically assessed, especially if they have any history of liver disease. Glimepiride administration must be discontinued immediately upon the onset of abnormal liver function results.
References [1] Amaryl prescribing information. Rev; August 2004. Available at http:// www.aventis-us.com/PIs/amaryl.pdf [2] Schneider J. An overview of the safety and tolerance of glimepiride. Horm Metab Res 1996;28:413–418. [3] Dusoleil A, Condat B, Sobesky R, Pelletier G, Buffet C. Glimeprimideinduced acute hepatitis. Gastroenterol Clin Biol 1999;1096–1097 [French]. [4] Sitruc V, Mohib S, Grando-Lemaire V, Ziol M, Triuchet JC. Acute cholestatic hepatitis induced by glimeprimide. Gastroenterol Clin Biol 2000;1233–1234 [French]. [5] Heurgue A, Bernard-Chabert B, Higuero T, Lucas-Croisier C, Caron J, Cadiot G. Glimepiride-induced acute cholestatic hepatitis. Ann Endocrinol 2004;65:174–175 [French]. [6] Larson A. Drugs and the liver: patterns of hepatotoxicity. Up to date in gastroenterology and hepatology. 12.: Up to Date, Inc.; 2004 p. 1 [Windows XP].
Case report
Cholestatic liver injury after glimepiride therapy Athina Chounta1,*, Spyros Zouridakis1, Christos Ellinas1, Sotirios Tsiodras1, Christina Zoumpouli2, Stylianos Kopanakis1, Helen Giamarellou1 1
Hepatology Division, 4th Academic Department of Internal Medicine, Attikon University General Hospital, 7 Orfeos Street, Palaio Faliro, 17564 Athens, Greece 2 Laboratory of Histopathology, Attikon University General Hospital, 7 Orfeos Street, Palaio Faliro, 17564 Athens, Greece
Drug induced hepatotoxicity has been reported infrequently with sulfonylureas. For glimepiride, a secondgeneration sulfonylurea there is no report of hepatotoxicity in English literature. A patient with non-insulin-dependent diabetes mellitus who developed cholestatic liver injury soon after initiation of glimepiride therapy is presented. Complete work-up disclosed no other cause for hepatotoxicity including negative serological results for viral hepatitis. Liver biopsy was consistent with drug-induced cholestasis. The patient recovered 50 days after stopping glimepiride with no further recurrences. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Glimepiride; Hepatitis; Cholestasis 1. Introduction Glimepiride is a second-generation sulfonylurea used in the management of non-insulin-dependent diabetes mellitus (NIDDM). Recently introduced in Europe, glimepiride is prescribed regularly because of its efficacy, convenient dosing schedule, and safety. A major advantage of glimepiride is the absence of common side effects of first generation oral agents such as disulfiram-like reactions. We report a case of a patient who developed hepatotoxicity soon after the initiation of glimepiride therapy. The clinical and laboratory findings, the liver biopsy results, as well as rechallenge with glimepiride supported the etiopathogenic role of glimepiride in producing liver dysfunction in the presented case.
2. Case report A 65-year-old man with a history of hypertension, presented at the outpatient surgical clinic with jaundice, Received 22 December 2004; received in revised form 24 January 2005; accepted 7 February 2005; available online 7 April 2005 * Corresponding author. Tel.: C30 210 583 1990; fax: C30 210 532 6446. E-mail address: [email protected] (A. Chounta).
right upper quadrant abdominal pain, light stools and dark urine. NIDDM was diagnosed 2 weeks earlier and glimepiride (2 mg/d) was prescribed. At that time, the patient had normal liver function tests. His past medical history was non-significant and in addition there was no previous history of biliary tract disease, alcohol abuse, drug addiction or blood transfusions. He was receiving nifedipine and atenolol continuously for the last 14 years for his hypertension. He denied use of any non-prescription medications. He had no history of foreign travel and no family history of liver disease. His vital signs were stable with a temperature of 36.8 8C, a blood pressure of 150/85 mmHg, and a heart rate of 74 beats/min. His physical exam disclosed RUQ abdominal pain with normal bowel sounds and no rebound tenderness. The patient was admitted to our department. Results of some of the laboratory tests on admission and over the follow-up periods are shown in Table 1. His renal function and electrolytes were normal. Due to the liver abnormalities and the RQU pain abdominal ultrasonography was performed which revealed a stone in the common bile duct (CBD). An endoscopic retrograde cholangiography confirmed an 8 mm CBD stone, which was removed successfully after sphincterotomy at day 9 of admission. Soon after the patient developed fever with negative blood and urine cultures that responded successfully to the initiation of piperacillin/
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.02.011
A. Chounta et al. / Journal of Hepatology 42 (2005) 944–946
945
Table 1 Results of laboratory tests on admission and at different follow-up periods Laboratory test
Day 1
Day 9
Day 19
Day 30
Day 40
Day 42
Day 70
Total bilirubina Direct bilirubinb Alkaline phosphatasec g-GTd ALT ASTe Albuminf Hematocrit Hemoglobing INRh ESRi
6.91 6.82 403 231 141 63 4.6 43 14.9 1.0 – Admission
15.1 13.05 334 102 42 45 3.8 40.9 14.2 0.89 – ERCP
12.8 9.22 277 63 31 34 3.4 35.7 12.1 1.0 116 2nd ERCP
7.4 6.12 342 166 38 42 3.7 32.9 11.4 0.92 77 Biopsy
3.6 2.96 394 236 50 45 3.2 32.7 10.9 – – Before restart
7.1 6.8 432 390 107 112 – – – – – After restart
0.50 0.10 125 46 32 26 – 46 15.7 – – Follow-up
Normal range 13–40 mU/ml; normal range 39.0–52.0%. a Normal range 0.2–1.2 mg/dl. b Normal range 0.0–0.3 mg/dl. c Normal range 53–128 mU/ml. d Normal range 9–50 mU/ml. e Normal range 15–48 mU/ml. f Normal range 3.4–5.0 g/dl. g Normal range 13.5–18.0 g/dl. h International normalized ratio: normal 1.0. i Erythrocyte sedimentation rate: normal range 0.0–15 mm/first hour.
tazobactam, and netilmicin. A new ERCP, MRCP, abdominal ultrasound, and CT scan were all normal. The liver function test results remained abnormal during follow up and this initiated further laboratory work-up to exclude other causes of chronic liver disease. These included negative serology for hepatitis A, B and C viruses, EBV and CMV viruses, normal prothrombin time, normal serum a-fetoprotein levels, normal iron studies, serum protein electrophoresis, normal folate, vitamin B12, FT3, FT4 and TSH levels and normal immunological testing including anti-smooth-muscle (SMA), anti-nuclear (ANA), antiLKM, and anti-mitochondrial (AMA) antibodies. His complete blood count and the peripheral eosinophil count (0.2!103 ml) remained normal. Forty days following his initial admission, the patient was restarted on glimepiride as part of his usual regimen and the liver function tests became markedly increased again (see Table 1). A liver biopsy performed at this stage showed a histological pattern of an acute hepatitis, with striking confluent necrosis in zone 3 (Fig. 1), as well as the presence of mild portal tract inflammation, comprising of a small number of eosinophils. Mild bilirubinostasis (Fig. 2) coexisted in hepatocytes and bile sinusoids. The medication was stopped, and the enzymes returned to normal 1 month later. The case was reported to the National Medicine Organization of Greece.
large controlled international trials [1] and this together with its convenient dosing schedule has led to its widespread use [2]. Glimepiride is generally well tolerated. Adverse effects such as dizziness, headache, asthenia or nausea prompt discontinuation in a small percentage of patients [1]. The medical literature contains three reports in French, but none in English, of severe hepatotoxicity due to glimepiride [3–5]. The cases were attributed to the glimepiride use due to (a) the absence of other causes of acute hepatitis, e.g. viral pathogens, (b) the chronologic order of events regarding the close association between the introduction of glimepiride, the onset of liver function test abnormalities and their normalization shortly after the discontinuation of the drug, and (c) the absence of significant biliary disease by
3. Discussion Glimepiride belongs to the sulfonylurea class of drugs [1]. Its safety has been evaluated in over 3500 patients in
Fig. 1. Zone 3 necrosis, a common feature of acute drug-induced hepatitis.
946
A. Chounta et al. / Journal of Hepatology 42 (2005) 944–946
however, one showed hepatic necrosis [3]. Newer sulfonylureas like glibenclamide have been associated with hepatic toxicity [4] however, this is a rare phenomenon [4].
4. Conclusion
Fig. 2. Bilirubinostasis in bile canaliculi and hepatocytes.
ultrasound imaging [3–5]. One of the cases was confounded by the use of anti-epileptic drugs including benzodiazepines and alcohol consumption [4]. The association between cholestatic hepatitis and glimepiride use was confounded by the presence of choledocholithiasis in our case. This led to the unfortunate reintroduction of glimepiride that essentially confirmed the diagnosis of a glimepiride related adverse effect as the liver enzymes increased immediately. However, re-challenge with a hepatotoxic drug in case of hepatotoxicity is not advised [6]. It is possible that the concomitant biliary lithiasis might have predisposed the patient to develop hepatitis. The specific pathophysiology responsible for this adverse event remains unclear. The histologic features seen on liver biopsy samples in our case were compatible with drug-associated hepatotoxicity with cholestasis being the predominant finding. In the previously described cases, a cholestatic pattern was noted in liver biopsy as well [4,5]
In conclusion, we describe a rare case of glimepiride associated liver injury that calls for caution in the use of glimeperide. All patients receiving glimepiride should have their liver function tests periodically assessed, especially if they have any history of liver disease. Glimepiride administration must be discontinued immediately upon the onset of abnormal liver function results.
References [1] Amaryl prescribing information. Rev; August 2004. Available at http:// www.aventis-us.com/PIs/amaryl.pdf [2] Schneider J. An overview of the safety and tolerance of glimepiride. Horm Metab Res 1996;28:413–418. [3] Dusoleil A, Condat B, Sobesky R, Pelletier G, Buffet C. Glimeprimideinduced acute hepatitis. Gastroenterol Clin Biol 1999;1096–1097 [French]. [4] Sitruc V, Mohib S, Grando-Lemaire V, Ziol M, Triuchet JC. Acute cholestatic hepatitis induced by glimeprimide. Gastroenterol Clin Biol 2000;1233–1234 [French]. [5] Heurgue A, Bernard-Chabert B, Higuero T, Lucas-Croisier C, Caron J, Cadiot G. Glimepiride-induced acute cholestatic hepatitis. Ann Endocrinol 2004;65:174–175 [French]. [6] Larson A. Drugs and the liver: patterns of hepatotoxicity. Up to date in gastroenterology and hepatology. 12.: Up to Date, Inc.; 2004 p. 1 [Windows XP].