- Email: [email protected]
Sertraline-Associated Cholestasis and Ductopenia Consistent with Vanishing Bile Duct Syndrome
Sertraline-Associated Cholestasis and Ductopenia Consistent with Vanishing Bile Duct Syndrome Maire A. Conrad, MD, MS1, Jiawei Cui2, and Henry C. Lin, MD1 An adolescent with depression treated with sertraline developed cholestasis and bile duct paucity, which resolved with medication discontinuation. Vanishing bile duct syndrome is an acquired destruction of interlobular bile ducts. This type of drug-induced liver injury has been associated with other medications and requires practitioners’ awareness of potential hepatotoxicity. (J Pediatr 2015;-:---).
M
ajor depressive disorder is a major public health concern with increasing impact in pediatrics. The introduction of selective serotonin reuptake inhibitors (SSRIs) has increased the prevalence of antidepressant medication use in children.1 Barriers to mental health resources have placed the responsibility of treating pediatric depression on the primary care physician. Children receiving these medications need to be monitored for side effects including sleepiness, insomnia, dizziness, headache, psychiatric changes, and gastrointestinal side effects rarely including hepatotoxicity. Vanishing bile duct syndrome (VBDS) is an acquired progressive destruction and disappearance of interlobular bile ducts causing chronic cholestasis. Associated exposures include infections, drugs, toxins, oncologic, and immunologic processes.2 Sertraline has not previously been implicated in VBDS, although it is a known cause of druginduced liver injury (DILI). We present a case of bile duct paucity in a healthy teenager with resolution of symptoms following cessation of sertraline.
Case Report A 15-year-old boy with major depressive disorder was treated with oral sertraline 75 mg daily for 6 months; he presented with 1 month of jaundice, pruritus, nausea, anorexia, and pale stools. He reported no associated rashes, fevers, hospitalizations, or other medical problems. Past medical and family histories were negative for liver disease. He denied alcohol, drug, or herbal supplement use and was not sexually active. There were no other medication exposures in the months prior to onset of symptoms. Two weeks after the onset of symptoms, laboratory studies revealed elevated total bilirubin, direct bilirubin, aspartate aminotransferase, and alanine aminotransferase, and normal international normalized ratio (Table). His white blood cell count was 6.4 103 uL with 3% eosinophils. Infectious work up was negative including hepatitis A IgM, hepatitis B surface antigen, and
DILI SSRI VBDS
Drug-induced liver injury Selective serotonin reuptake inhibitor Vanishing bile duct syndrome
hepatitis C RNA polymerase chain reaction. Abdominal ultrasound revealed a 16 cm liver span, enlarged for age, multiple gallstones without obstruction, and mildly enlarged spleen. Because of worsening nausea, pruritus, and rising bilirubin in the absence of ductal obstruction, he underwent liver biopsy. Pathology revealed preserved lobular architecture with 14-16 portal tracts notable for rare bile duct profiles, minimal lymphocytic infiltration, and marked hepatocellular and canalicular cholestasis (Figures 1 and 2; available at www.jpeds.com). Evaluation for causes of ductopenia such as Alagille syndrome were performed, including a normal echocardiogram, absence of butterfly vertebrae detected by radiograph, and an unremarkable ophthalmologic examination. Jaundice Chip resequencing array, sent to Cincinnati Children’s Hospital Medical Center to screen for the most common heritable causes of cholestatic liver disease in children, revealed heterozygous polymorphisms in JAG1 and SERPINA1, which are not pathogenic in the heterozygous state. Urine bile acids were not consistent with a bile acid synthesis defect. Markers for autoimmune hepatitis including antinuclear antibody and smooth muscle antibody were negative. Magnetic resonance cholangiopancreatogram was normal. Despite initiation of ursodiol, his cholestasis and fatigue progressed over 1 month. Total bilirubin peaked at 33.7 mg/dL with direct bilirubin 29.2 mg/dL. With rising bilirubin levels and no etiology for ductopenia established, sertraline was discontinued because of concern for moderate to severe DILI evidenced by elevated alanine aminotransferase and total bilirubin and need for hospitalization.3 Within 4 weeks of discontinuation, his total bilirubin had decreased. Four months after medication cessation, his laboratories were within normal limits (Table). Intentional rechallenge with sertraline was not attempted to avoid severe recurrence. Antidepressant therapy was initiated with fluoxetine. Hepatic tests remained normal 9 months later.
From the 1Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia; and 2University of Pennsylvania, Philadelphia, PA The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.10.065
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www.jpeds.com
Table. Laboratory values throughout presentation Reference ranges Total bilirubin Direct bilirubin INR ALT AST GGT
0.6-1.4 mg/dL 0.0-0.3 mg/dL 10-45 U/L 15-40 U/L 10-28 U/L
Onset of symptoms, 6 mo from exposure start
At hospitalization 2 wk after symptom onset
Prior to discontinuing sertraline, 7 mo after exposure
1 wk after discontinuation
4 wk after discontinuation
4 mo after discontinuation
8.0 4.7 1.0 238 160 -
17.6 14.5 1.19 47 47 36
33.7 29.2 1.04 62 94 56
33.5 24.9 1.1 36 61 36
12.2 5.9 1.0 110 164 341
1.5 0.2 1.1 22 21 42
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; INR, international normalized ratio.
Discussion Major depressive disorder is an increasingly common mental illness in up to 3% of children and 6% of adolescents with increased use of serotonin reuptake inhibitors.4,5 Sertraline is commonly prescribed for a variety of mental health disorders.6 Abnormalities in serum aminotransferases have been reported in 1% or less of patients on sertraline, but most are mild and do not require dose adjustment, therefore, routine monitoring has not been recommended.7 Elevated transaminases and hepatotoxicity have been rarely reported in other SSRIs as well. DILI is an idiosyncratic cause of both acute and chronic liver disease that can initially present asymptomatically and is characterized by hepatocellular, cholestatic, or mixed phenotypes. Risk factors for DILI are unclear, but HLA class II alleles may be helpful in distinguishing predisposition for the different phenotypes.8,9 The etiology of sertralineinduced liver injury is not well described, but may include dose escalation, drug interactions on the same CYP450 metabolic pathway, and previous chronic liver disease. Although sertraline may increase the risk of hepatotoxicity in chronic liver disease, a small case control study demonstrated symptomatic improvement when used as therapy for pruritus in chronic cholestatic liver disease, but laboratory evaluation was not performed.10 Adult case reports describe laboratory values indicative of hepatocellular injury in patients on sertraline with symptoms characteristic of cholestasis.11 The onset of injury typically ranges from 2-24 weeks after starting sertraline.11-14 A case report of hepatotoxicity in a woman treated with sertraline for 6 months revealed a liver biopsy with lobular hepatitis with mild prominence of eosinophils.13 The diagnosis can be confirmed by rechallenging with the inciting medication, although this is rarely performed because of safety concerns. VBDS is defined as a reduced ratio of interlobular ducts to portal tracts, usually <0.5. Other causes of bile duct paucity include Alagille syndrome, viral infections, cystic fibrosis, progressive intrahepatic cholestasis, primary sclerosing cholangitis, and familial idiopathic adulthood ductopenia. The typical presentation includes jaundice, abdominal pain, pruritus, and weight loss as well as cholestasis and elevated transaminases. VBDS is diagnosed by pathology and is consistent 2
with a known presentation of DILI.2,3 This acquired condition is associated with >30 medications, including amoxicillin, nonsteroidal anti-inflammatory drugs, steroids, erythromycin, and tricyclic antidepressants.2,15-17 However, sertraline has not been previously described in association with VBDS in adults or children. Drug-associated VBDS can cause histologic changes including inflammatory infiltrate with mononuclear cells, eosinophils, and neutrophils around bile ducts and lobular cholestasis.18,19 Over time, there is decreasing inflammation, increasing cholestasis, and progressive loss of ducts. The treatment for VBDS is discontinuation of inciting medication, but it can take months for laboratory values to normalize.12,14 There is difficulty differentiating reversible cases from progressive ones that do not achieve bile duct reproliferation and may require liver transplant.20 Because of the rising prevalence of psychiatric disorders and the increasing use of SSRIs in adolescents, it is important that practitioners be aware of this reaction. Routine laboratory monitoring has not been recommended in otherwise healthy patients because of the low likelihood of hepatotoxicity, but related symptoms or incidental findings should prompt referral to a pediatric gastroenterologist for evaluation. In addition, discussion with a child psychiatrist regarding medication management prior to abrupt sertraline discontinuation and identification of a safe alternative medication is warranted in this scenario in order to minimize adverse effects and continue treatment of the psychiatric disorder. n Submitted for publication Jan 29, 2015; last revision received Oct 7, 2015; accepted Oct 21, 2015. ire A. Conrad, MD, MS, Division of Gastroenterology, Reprint requests: Ma Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Room 7NW41, 3401 Civic Center Boulevard, Philadelphia, PA 19104. E-mail: [email protected]
References 1. Meng X, D’Arcy C, Tempier R. Long-term trend in pediatric antidepressant use, 1983-2007: a population-based study. Can J Psychiatry 2014;59: 89-97. 2. Cho HJ, Jwa HJ, Kim KS, Gang DY, Kim JY. Urosodeoxycholic acid therapy in a child with trimethoprim-sulfamethoxazole-induced
Conrad, Cui, and Lin
- 2015
3.
4. 5. 6.
7.
8.
9.
10.
vanishing bile duct syndrome. Pediatr Gastroenterol Hepatol Nutr 2013;16:273-8. Fontana RJ, Seeff LB, Andrade RJ, Bjornsson E, Day CP, Serrano J, et al. Standardization of nomenclature and causality assessment in druginduced liver injury: summary of a clinical research workshop. Hepatology 2010;52:730-42. Thapar A, Collishaw S, Pine DS, Thapar AK. Depression in adolescence. Lancet 2012;379:1056-67. Ryan ND. Treatment of depression in children and adolescents. Lancet 2005;366:933-40. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341-5. Tabak F, Gunduz F, Tahan V, Tabak O, Ozaras R. Sertraline hepatotoxicity: report of a case and review of the literature. Dig Dis Sci 2009;54: 1589-91. Andrade RJ, Lucena MI, Alonso A, Garcia-Cortes M, Garcia-Ruiz E, Benitez R, et al. HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease. Hepatology 2004;39:1603-12. Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressantinduced liver injury: a review for clinicians. Am J Psychiatry 2014;171: 404-15. Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 2007;45: 666-74.
CLINICAL AND LABORATORY OBSERVATIONS 11. Persky S, Reinus JF. Sertraline hepatotoxicity: a case report and review of the literature on selective serotonin reuptake inhibitor hepatotoxicity. Dig Dis Sci 2003;48:939-44. 12. DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother 2007;41:1201-11. 13. Suen CF, Boyapati R, Simpson I, Dev A. Acute liver injury secondary to sertraline. BMJ Case Rep 2013 Sep 26;2013. pii: bcr2013201022. http:// dx.doi.org/10.1136/bcr-2013-201022. 14. Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013;8:207-23. 15. Alam I, Ferrell LD, Bass NM. Vanishing bile duct syndrome temporally associated with ibuprofen use. Am J Gastroenterol 1996;91:1626-30. 16. King PD, Blitzer BL. Drug-induced cholestasis: pathogenesis and clinical features. Semin Liver Dis 1990;10:316-21. 17. Kullak-Ublick GA. Drug-induced cholestatic liver disease. In: Madame Curie Bioscience Database [Internet]. Austin, TX: Landes Bioscience; 2000. 18. Bhayana H, Appasani S, Thapa BR, Das A, Singh K. Lamotrigineinduced vanishing bile duct syndrome in a child. J Pediatr Gastroenterol Nutr 2012;55:e147-8. 19. Taghian M, Tran TA, Bresson-Hadni S, Menget A, Felix S, Jacquemin E. Acute vanishing bile duct syndrome after ibuprofen therapy in a child. J Pediatr 2004;145:273-6. 20. Vuppalanchi R, Chalasani N, Saxena R. Restoration of bile ducts in druginduced vanishing bile duct syndrome due to zonisamide. Am J Surg Pathol 2006;30:1619-23.
Sertraline-Associated Cholestasis and Ductopenia Consistent with Vanishing Bile Duct Syndrome
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THE JOURNAL OF PEDIATRICS
www.jpeds.com
Vol. -, No. -
Figure 1. Liver biopsy, hematoxylin and eosin (H&E) stain, 40. Representative portal tract with lack of bile ducts and cholestasis.
Figure 2. Liver biopsy, cytokeratin 7 (CK7) stain, 40. Highlights rare ducts and aberrant positivity in hepatocytes around portal tracts. 3.e1
Conrad, Cui, and Lin
M
ajor depressive disorder is a major public health concern with increasing impact in pediatrics. The introduction of selective serotonin reuptake inhibitors (SSRIs) has increased the prevalence of antidepressant medication use in children.1 Barriers to mental health resources have placed the responsibility of treating pediatric depression on the primary care physician. Children receiving these medications need to be monitored for side effects including sleepiness, insomnia, dizziness, headache, psychiatric changes, and gastrointestinal side effects rarely including hepatotoxicity. Vanishing bile duct syndrome (VBDS) is an acquired progressive destruction and disappearance of interlobular bile ducts causing chronic cholestasis. Associated exposures include infections, drugs, toxins, oncologic, and immunologic processes.2 Sertraline has not previously been implicated in VBDS, although it is a known cause of druginduced liver injury (DILI). We present a case of bile duct paucity in a healthy teenager with resolution of symptoms following cessation of sertraline.
Case Report A 15-year-old boy with major depressive disorder was treated with oral sertraline 75 mg daily for 6 months; he presented with 1 month of jaundice, pruritus, nausea, anorexia, and pale stools. He reported no associated rashes, fevers, hospitalizations, or other medical problems. Past medical and family histories were negative for liver disease. He denied alcohol, drug, or herbal supplement use and was not sexually active. There were no other medication exposures in the months prior to onset of symptoms. Two weeks after the onset of symptoms, laboratory studies revealed elevated total bilirubin, direct bilirubin, aspartate aminotransferase, and alanine aminotransferase, and normal international normalized ratio (Table). His white blood cell count was 6.4 103 uL with 3% eosinophils. Infectious work up was negative including hepatitis A IgM, hepatitis B surface antigen, and
DILI SSRI VBDS
Drug-induced liver injury Selective serotonin reuptake inhibitor Vanishing bile duct syndrome
hepatitis C RNA polymerase chain reaction. Abdominal ultrasound revealed a 16 cm liver span, enlarged for age, multiple gallstones without obstruction, and mildly enlarged spleen. Because of worsening nausea, pruritus, and rising bilirubin in the absence of ductal obstruction, he underwent liver biopsy. Pathology revealed preserved lobular architecture with 14-16 portal tracts notable for rare bile duct profiles, minimal lymphocytic infiltration, and marked hepatocellular and canalicular cholestasis (Figures 1 and 2; available at www.jpeds.com). Evaluation for causes of ductopenia such as Alagille syndrome were performed, including a normal echocardiogram, absence of butterfly vertebrae detected by radiograph, and an unremarkable ophthalmologic examination. Jaundice Chip resequencing array, sent to Cincinnati Children’s Hospital Medical Center to screen for the most common heritable causes of cholestatic liver disease in children, revealed heterozygous polymorphisms in JAG1 and SERPINA1, which are not pathogenic in the heterozygous state. Urine bile acids were not consistent with a bile acid synthesis defect. Markers for autoimmune hepatitis including antinuclear antibody and smooth muscle antibody were negative. Magnetic resonance cholangiopancreatogram was normal. Despite initiation of ursodiol, his cholestasis and fatigue progressed over 1 month. Total bilirubin peaked at 33.7 mg/dL with direct bilirubin 29.2 mg/dL. With rising bilirubin levels and no etiology for ductopenia established, sertraline was discontinued because of concern for moderate to severe DILI evidenced by elevated alanine aminotransferase and total bilirubin and need for hospitalization.3 Within 4 weeks of discontinuation, his total bilirubin had decreased. Four months after medication cessation, his laboratories were within normal limits (Table). Intentional rechallenge with sertraline was not attempted to avoid severe recurrence. Antidepressant therapy was initiated with fluoxetine. Hepatic tests remained normal 9 months later.
From the 1Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia; and 2University of Pennsylvania, Philadelphia, PA The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.10.065
1
THE JOURNAL OF PEDIATRICS
Vol. -, No. -
www.jpeds.com
Table. Laboratory values throughout presentation Reference ranges Total bilirubin Direct bilirubin INR ALT AST GGT
0.6-1.4 mg/dL 0.0-0.3 mg/dL 10-45 U/L 15-40 U/L 10-28 U/L
Onset of symptoms, 6 mo from exposure start
At hospitalization 2 wk after symptom onset
Prior to discontinuing sertraline, 7 mo after exposure
1 wk after discontinuation
4 wk after discontinuation
4 mo after discontinuation
8.0 4.7 1.0 238 160 -
17.6 14.5 1.19 47 47 36
33.7 29.2 1.04 62 94 56
33.5 24.9 1.1 36 61 36
12.2 5.9 1.0 110 164 341
1.5 0.2 1.1 22 21 42
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; INR, international normalized ratio.
Discussion Major depressive disorder is an increasingly common mental illness in up to 3% of children and 6% of adolescents with increased use of serotonin reuptake inhibitors.4,5 Sertraline is commonly prescribed for a variety of mental health disorders.6 Abnormalities in serum aminotransferases have been reported in 1% or less of patients on sertraline, but most are mild and do not require dose adjustment, therefore, routine monitoring has not been recommended.7 Elevated transaminases and hepatotoxicity have been rarely reported in other SSRIs as well. DILI is an idiosyncratic cause of both acute and chronic liver disease that can initially present asymptomatically and is characterized by hepatocellular, cholestatic, or mixed phenotypes. Risk factors for DILI are unclear, but HLA class II alleles may be helpful in distinguishing predisposition for the different phenotypes.8,9 The etiology of sertralineinduced liver injury is not well described, but may include dose escalation, drug interactions on the same CYP450 metabolic pathway, and previous chronic liver disease. Although sertraline may increase the risk of hepatotoxicity in chronic liver disease, a small case control study demonstrated symptomatic improvement when used as therapy for pruritus in chronic cholestatic liver disease, but laboratory evaluation was not performed.10 Adult case reports describe laboratory values indicative of hepatocellular injury in patients on sertraline with symptoms characteristic of cholestasis.11 The onset of injury typically ranges from 2-24 weeks after starting sertraline.11-14 A case report of hepatotoxicity in a woman treated with sertraline for 6 months revealed a liver biopsy with lobular hepatitis with mild prominence of eosinophils.13 The diagnosis can be confirmed by rechallenging with the inciting medication, although this is rarely performed because of safety concerns. VBDS is defined as a reduced ratio of interlobular ducts to portal tracts, usually <0.5. Other causes of bile duct paucity include Alagille syndrome, viral infections, cystic fibrosis, progressive intrahepatic cholestasis, primary sclerosing cholangitis, and familial idiopathic adulthood ductopenia. The typical presentation includes jaundice, abdominal pain, pruritus, and weight loss as well as cholestasis and elevated transaminases. VBDS is diagnosed by pathology and is consistent 2
with a known presentation of DILI.2,3 This acquired condition is associated with >30 medications, including amoxicillin, nonsteroidal anti-inflammatory drugs, steroids, erythromycin, and tricyclic antidepressants.2,15-17 However, sertraline has not been previously described in association with VBDS in adults or children. Drug-associated VBDS can cause histologic changes including inflammatory infiltrate with mononuclear cells, eosinophils, and neutrophils around bile ducts and lobular cholestasis.18,19 Over time, there is decreasing inflammation, increasing cholestasis, and progressive loss of ducts. The treatment for VBDS is discontinuation of inciting medication, but it can take months for laboratory values to normalize.12,14 There is difficulty differentiating reversible cases from progressive ones that do not achieve bile duct reproliferation and may require liver transplant.20 Because of the rising prevalence of psychiatric disorders and the increasing use of SSRIs in adolescents, it is important that practitioners be aware of this reaction. Routine laboratory monitoring has not been recommended in otherwise healthy patients because of the low likelihood of hepatotoxicity, but related symptoms or incidental findings should prompt referral to a pediatric gastroenterologist for evaluation. In addition, discussion with a child psychiatrist regarding medication management prior to abrupt sertraline discontinuation and identification of a safe alternative medication is warranted in this scenario in order to minimize adverse effects and continue treatment of the psychiatric disorder. n Submitted for publication Jan 29, 2015; last revision received Oct 7, 2015; accepted Oct 21, 2015. ire A. Conrad, MD, MS, Division of Gastroenterology, Reprint requests: Ma Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Room 7NW41, 3401 Civic Center Boulevard, Philadelphia, PA 19104. E-mail: [email protected]
References 1. Meng X, D’Arcy C, Tempier R. Long-term trend in pediatric antidepressant use, 1983-2007: a population-based study. Can J Psychiatry 2014;59: 89-97. 2. Cho HJ, Jwa HJ, Kim KS, Gang DY, Kim JY. Urosodeoxycholic acid therapy in a child with trimethoprim-sulfamethoxazole-induced
Conrad, Cui, and Lin
- 2015
3.
4. 5. 6.
7.
8.
9.
10.
vanishing bile duct syndrome. Pediatr Gastroenterol Hepatol Nutr 2013;16:273-8. Fontana RJ, Seeff LB, Andrade RJ, Bjornsson E, Day CP, Serrano J, et al. Standardization of nomenclature and causality assessment in druginduced liver injury: summary of a clinical research workshop. Hepatology 2010;52:730-42. Thapar A, Collishaw S, Pine DS, Thapar AK. Depression in adolescence. Lancet 2012;379:1056-67. Ryan ND. Treatment of depression in children and adolescents. Lancet 2005;366:933-40. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341-5. Tabak F, Gunduz F, Tahan V, Tabak O, Ozaras R. Sertraline hepatotoxicity: report of a case and review of the literature. Dig Dis Sci 2009;54: 1589-91. Andrade RJ, Lucena MI, Alonso A, Garcia-Cortes M, Garcia-Ruiz E, Benitez R, et al. HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease. Hepatology 2004;39:1603-12. Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressantinduced liver injury: a review for clinicians. Am J Psychiatry 2014;171: 404-15. Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 2007;45: 666-74.
CLINICAL AND LABORATORY OBSERVATIONS 11. Persky S, Reinus JF. Sertraline hepatotoxicity: a case report and review of the literature on selective serotonin reuptake inhibitor hepatotoxicity. Dig Dis Sci 2003;48:939-44. 12. DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother 2007;41:1201-11. 13. Suen CF, Boyapati R, Simpson I, Dev A. Acute liver injury secondary to sertraline. BMJ Case Rep 2013 Sep 26;2013. pii: bcr2013201022. http:// dx.doi.org/10.1136/bcr-2013-201022. 14. Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013;8:207-23. 15. Alam I, Ferrell LD, Bass NM. Vanishing bile duct syndrome temporally associated with ibuprofen use. Am J Gastroenterol 1996;91:1626-30. 16. King PD, Blitzer BL. Drug-induced cholestasis: pathogenesis and clinical features. Semin Liver Dis 1990;10:316-21. 17. Kullak-Ublick GA. Drug-induced cholestatic liver disease. In: Madame Curie Bioscience Database [Internet]. Austin, TX: Landes Bioscience; 2000. 18. Bhayana H, Appasani S, Thapa BR, Das A, Singh K. Lamotrigineinduced vanishing bile duct syndrome in a child. J Pediatr Gastroenterol Nutr 2012;55:e147-8. 19. Taghian M, Tran TA, Bresson-Hadni S, Menget A, Felix S, Jacquemin E. Acute vanishing bile duct syndrome after ibuprofen therapy in a child. J Pediatr 2004;145:273-6. 20. Vuppalanchi R, Chalasani N, Saxena R. Restoration of bile ducts in druginduced vanishing bile duct syndrome due to zonisamide. Am J Surg Pathol 2006;30:1619-23.
Sertraline-Associated Cholestasis and Ductopenia Consistent with Vanishing Bile Duct Syndrome
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THE JOURNAL OF PEDIATRICS
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Vol. -, No. -
Figure 1. Liver biopsy, hematoxylin and eosin (H&E) stain, 40. Representative portal tract with lack of bile ducts and cholestasis.
Figure 2. Liver biopsy, cytokeratin 7 (CK7) stain, 40. Highlights rare ducts and aberrant positivity in hepatocytes around portal tracts. 3.e1
Conrad, Cui, and Lin