Liver Disease in Pediatric Inflammatory Bowel Disease

  • Amanda Ricciuto
  • Binita M. KamathEmail author


Hepatobiliary diseases are among the most common extraintestinal manifestations of inflammatory bowel disease (IBD). These include immune-mediated liver diseases, namely, primary sclerosing cholangitis, autoimmune hepatitis, and an overlap condition between the two, termed autoimmune sclerosing cholangitis. More recently, an additional entity that likely shares an immunological basis, known as IgG4-associated cholangitis (IAC), has been defined and observed to also occur in association with IBD. A number of hepatobiliary manifestations can result from the adverse effects of medications used to treat pediatric IBD, such as methotrexate, thiopurines, and antitumor necrosis factor-α antibodies. Another category of hepatobiliary involvement is that which reflects the pathophysiology of IBD, such as cholelithiasis. Abnormal liver biochemistry is common in children with IBD. While often transient and of little consequence, such abnormalities may occasionally herald serious underlying liver disease or medication toxicity. The challenge lies in determining which patients warrant further investigation and intervention versus simple observation. This chapter strives to facilitate this task by providing an overview of and suggesting clinical approaches to various hepatobiliary conditions associated with pediatric IBD.


Hepatobiliary Liver Primary sclerosing cholangitis (PSC) Autoimmune hepatitis (AIH) Autoimmune sclerosing cholangitis (ASC) IgG4-associated cholangitis (IAC) Hepatotoxicity Cholelithiasis 


  1. 1.
    Navaneethan U, Shen B. Hepatopancreatobiliary manifestations and complications associated with inflammatory bowel disease. Inflamm Bowel Dis. 2010;16:1598–619. doi: 10.1002/ibd.21219.PubMedCrossRefGoogle Scholar
  2. 2.
    Gisbert JP, Luna M, Gonzalez-Lama Y, Pousa ID, Velasco M, Moreno-Otero R, Mate J. Liver injury in inflammatory bowel disease: long-term follow-up study of 786 patients. Inflamm Bowel Dis. 2007;13:1106–14. doi: 10.1002/ibd.20160.PubMedCrossRefGoogle Scholar
  3. 3.
    Mendes FD, Levy C, Enders FB, Loftus Jr EV, Angulo P, Lindor KD. Abnormal hepatic biochemistries in patients with inflammatory bowel disease. Am J Gastroenterol. 2007;102:344–50. doi: 10.1111/j.1572-0241.2006.00947.x.PubMedCrossRefGoogle Scholar
  4. 4.
    Yamamoto-Furusho JK, Sanchez-Osorio M, Uribe M. Prevalence and factors associated with the presence of abnormal function liver tests in patients with ulcerative colitis. Ann Hepatol. 2010;9:397–401.PubMedGoogle Scholar
  5. 5.
    Nemeth A, Ejderhamn J, Glaumann H, Strandvik B. Liver damage in juvenile inflammatory bowel disease. Liver. 1990;10:239–48.PubMedCrossRefGoogle Scholar
  6. 6.
    Pusateri AJ, Kim SC, Dotson JL, Balint JP, Potter CJ, Boyle BM, Crandall WV. Incidence, pattern, and etiology of elevated liver enzymes in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2015;60:592–7. doi: 10.1097/MPG.0000000000000672.PubMedCrossRefGoogle Scholar
  7. 7.
    Valentino PL, Feldman BM, Walters TD, Griffiths AM, Ling SC, Pullenayegum EM, Kamath BM. Abnormal liver biochemistry is common in pediatric inflammatory bowel disease: prevalence and associations. Inflamm Bowel Dis. 2015; doi: 10.1097/MIB.0000000000000558.PubMedGoogle Scholar
  8. 8.
    Hyams J, Markowitz J, Treem W, Davis P, Grancher K, Daum F. Characterization of hepatic abnormalities in children with inflammatory bowel disease. Inflamm Bowel Dis. 1995;1:27–33.PubMedGoogle Scholar
  9. 9.
    Goyal A, Hyams JS, Lerer T, et al. Liver enzyme elevations within 3 months of diagnosis of inflammatory bowel disease and likelihood of liver disease. J Pediatr Gastroenterol Nutr. 2014;59:321–3. doi: 10.1097/mpg.0000000000000409.PubMedCrossRefGoogle Scholar
  10. 10.
    Riegler G, D’Inca R, Sturniolo GC, et al. Hepatobiliary alterations in patients with inflammatory bowel disease: a multicenter study. Caprilli & Gruppo Italiano Studio Colon-Retto. Scand J Gastroenterol. 1998;33:93–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Card TR, Solaymani-Dodaran M, West J. Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study. J Hepatol. 2008;48:939–44. doi: 10.1016/j.jhep.2008.02.017.PubMedCrossRefGoogle Scholar
  12. 12.
    Deneau M, Jensen MK, Holmen J, Williams MS, Book LS, Guthery SL. Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history. Hepatology. 2013;58:1392–400. doi: 10.1002/hep.26454.PubMedCrossRefGoogle Scholar
  13. 13.
    Kaplan GG, Laupland KB, Butzner D, Urbanski SJ, Lee SS. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol. 2007;102:1042–9. doi: 10.1111/j.1572-0241.2007.01103.x.PubMedCrossRefGoogle Scholar
  14. 14.
    Feldstein AE, Perrault J, El-Youssif M, Lindor KD, Freese DK, Angulo P. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology. 2003;38:210–7. doi: 10.1053/jhep.2003.50289.PubMedCrossRefGoogle Scholar
  15. 15.
    Miloh T, Arnon R, Shneider B, Suchy F, Kerkar N. A retrospective single-center review of primary sclerosing cholangitis in children. Clin Gastroenterol Hepatol. 2009;7:239–45. doi: 10.1016/j.cgh.2008.10.019.PubMedCrossRefGoogle Scholar
  16. 16.
    Wilschanski M, Chait P, Wade JA, et al. Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis. Hepatology. 1995;22:1415–22.PubMedGoogle Scholar
  17. 17.
    Warren KW, Athanassiades S, Monge JI. Primary sclerosing cholangitis. A study of forty-two cases. Am J Surg. 1966;111:23–38.PubMedCrossRefGoogle Scholar
  18. 18.
    Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56:1181–8. doi: 10.1016/j.jhep.2011.10.025.PubMedCrossRefGoogle Scholar
  19. 19.
    Schrumpf E, Boberg KM. Epidemiology of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2001;15:553–62. doi: 10.1053/bega.2001.0204.PubMedCrossRefGoogle Scholar
  20. 20.
    Batres LA, Russo P, Mathews M, Piccoli DA, Chuang E, Ruchelli E. Primary sclerosing cholangitis in children: a histologic follow-up study. Pediatr Dev Pathol. 2005;8:568–76. doi: 10.1007/s10024-005-0020-0.PubMedCrossRefGoogle Scholar
  21. 21.
    Dotson JL, Hyams JS, Markowitz J, et al. Extraintestinal manifestations of pediatric inflammatory bowel disease and their relation to disease type and severity. J Pediatr Gastroenterol Nutr. 2010;51:140–5. doi: 10.1097/MPG.0b013e3181ca4db4.PubMedCrossRefGoogle Scholar
  22. 22.
    Jose FA, Garnett EA, Vittinghoff E, et al. Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2009;15:63–8. doi: 10.1002/ibd.20604.PubMedCrossRefGoogle Scholar
  23. 23.
    Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51:660–78. doi: 10.1002/hep.23294.PubMedCrossRefGoogle Scholar
  24. 24.
    Mells GF, Kaser A, Karlsen TH. Novel insights into autoimmune liver diseases provided by genome-wide association studies. J Autoimmun. 2013;46:41–54. doi: 10.1016/j.jaut.2013.07.004.PubMedCrossRefGoogle Scholar
  25. 25.
    Williamson KD, Chapman RW. Primary sclerosing cholangitis: a clinical update. Br Med Bull. 2015;114:53–64. doi: 10.1093/bmb/ldv019.PubMedCrossRefGoogle Scholar
  26. 26.
    Eksteen B, Grant AJ, Miles A, et al. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med. 2004;200:1511–7. doi: 10.1084/jem.20041035.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Tabibian JH, O’Hara SP, Lindor KD. Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies. Scand J Gastroenterol. 2014;49:901–8. doi: 10.3109/00365521.2014.913189.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Loftus Jr EV, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut. 2005;54:91–6. doi: 10.1136/gut.2004.046615.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Halliday JS, Djordjevic J, Lust M, Culver EL, Braden B, Travis SP, Chapman RW. A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn disease. J Crohn Colitis. 2012;6:174–81. doi: Scholar
  30. 30.
    Lundqvist K, Broome U. Differences in colonic disease activity in patients with ulcerative colitis with and without primary sclerosing cholangitis: a case control study. Dis Colon Rectum. 1997;40:451–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Schaeffer DF, Win LL, Hafezi-Bakhtiari S, Cino M, Hirschfield GM, El-Zimaity H. The phenotypic expression of inflammatory bowel disease in patients with primary sclerosing cholangitis differs in the distribution of colitis. Dig Dis Sci. 2013;58:2608–14. doi: 10.1007/s10620-013-2697-7.PubMedCrossRefGoogle Scholar
  32. 32.
    Faubion Jr WA, Loftus EV, Sandborn WJ, Freese DK, Perrault J. Pediatric “PSC-IBD”: a descriptive report of associated inflammatory bowel disease among pediatric patients with psc. J Pediatr Gastroenterol Nutr. 2001;33:296–300.PubMedCrossRefGoogle Scholar
  33. 33.
    Ordonez F, Lacaille F, Canioni D, et al. Pediatric ulcerative colitis associated with autoimmune diseases: a distinct form of inflammatory bowel disease? Inflamm Bowel Dis. 2012;18:1809–17. doi: 10.1002/ibd.22864.PubMedCrossRefGoogle Scholar
  34. 34.
    Lascurain L, Jensen MK, Guthery SL, Holmen J, Deneau M. Inflammatory bowel disease phenotype in pediatric primary sclerosing cholangitis. Inflamm Bowel Dis. 2016;22:146–50. doi: 10.1097/MIB.0000000000000586.PubMedCrossRefGoogle Scholar
  35. 35.
    Marelli L, Xirouchakis E, Kalambokis G, Cholongitas E, Hamilton MI, Burroughs AK. Does the severity of primary sclerosing cholangitis influence the clinical course of associated ulcerative colitis? Gut. 2011;60:1224–8. doi: 10.1136/gut.2010.235408.PubMedCrossRefGoogle Scholar
  36. 36.
    Cangemi JR, Wiesner RH, Beaver SJ, et al. Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology. 1989;96:790–4.PubMedCrossRefGoogle Scholar
  37. 37.
    Cholongitas E, Shusang V, Papatheodoridis GV, et al. Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl. 2008;14:138–43. doi: 10.1002/lt.21260.PubMedCrossRefGoogle Scholar
  38. 38.
    Bjornsson E, Chari S, Silveira M, Gossard A, Takahashi N, Smyrk T, Lindor K. Primary sclerosing cholangitis associated with elevated immunoglobulin G4: clinical characteristics and response to therapy. Am J Ther. 2011;18:198–205. doi: 10.1097/MJT.0b013e3181c9dac6.PubMedCrossRefGoogle Scholar
  39. 39.
    Lindor KD, Kowdley KV, Harrison ME. ACG Clinical Guideline: primary sclerosing cholangitis. Am J Gastroenterol. 2015;110:646–59. quiz 660 doi: 10.1038/ajg.2015.112.PubMedCrossRefGoogle Scholar
  40. 40.
    MacCarty RL, LaRusso NF, Wiesner RH, Ludwig J. Primary sclerosing cholangitis: findings on cholangiography and pancreatography. Radiology. 1983;149:39–44. doi: 10.1148/radiology.149.1.6412283.PubMedCrossRefGoogle Scholar
  41. 41.
    Deneau M, Adler DG, Schwartz JJ, et al. Cholangiocarcinoma in a 17-year-old boy with primary sclerosing cholangitis and inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2011;52:617–20. doi: 10.1097/MPG.0b013e3181f9a5d2.PubMedCrossRefGoogle Scholar
  42. 42.
    Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc. 2002;56:48–54.PubMedCrossRefGoogle Scholar
  43. 43.
    Ponsioen CY, Vrouenraets SM, Prawirodirdjo W, et al. Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population. Gut. 2002;51:562–6.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Bjornsson E, Olsson R, Bergquist A, et al. The natural history of small-duct primary sclerosing cholangitis. Gastroenterology. 2008;134:975–80. doi: 10.1053/j.gastro.2008.01.042.PubMedCrossRefGoogle Scholar
  45. 45.
    Tabibian JH, Lindor KD. Primary sclerosing cholangitis: a review and update on therapeutic developments. Expert Rev Gastroenterol Hepatol. 2013;7:103–14. doi: 10.1586/egh.12.80.PubMedCrossRefGoogle Scholar
  46. 46.
    Gilger MA, Gann ME, Opekun AR, Gleason Jr WA. Efficacy of ursodeoxycholic acid in the treatment of primary sclerosing cholangitis in children. J Pediatr Gastroenterol Nutr. 2000;31:136–41.PubMedCrossRefGoogle Scholar
  47. 47.
    Triantos CK, Koukias NM, Nikolopoulou VN, Burroughs AK. Meta-analysis: ursodeoxycholic acid for primary sclerosing cholangitis. Aliment Pharmacol Ther. 2011;34:901–10. doi: 10.1111/j.1365-2036.2011.04822.x.PubMedCrossRefGoogle Scholar
  48. 48.
    Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50:808–14. doi: 10.1002/hep.23082.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Cox KL, Cox KM. Oral vancomycin: treatment of primary sclerosing cholangitis in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1998;27:580–3.PubMedCrossRefGoogle Scholar
  50. 50.
    Davies YK, Cox KM, Abdullah BA, Safta A, Terry AB, Cox KL. Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic. J Pediatr Gastroenterol Nutr. 2008;47:61–7. doi: 10.1097/MPG.0b013e31816fee95.PubMedCrossRefGoogle Scholar
  51. 51.
    Tabibian JH, Weeding E, Jorgensen RA, Petz JL, Keach JC, Talwalkar JA, Lindor KD. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis – a pilot study. Aliment Pharmacol Ther. 2013;37:604–12. doi: 10.1111/apt.12232.PubMedCrossRefGoogle Scholar
  52. 52.
    Abarbanel DN, Seki SM, Davies Y, et al. Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. J Clin Immunol. 2013;33:397–406. doi: 10.1007/s10875-012-9801-1.PubMedCrossRefGoogle Scholar
  53. 53.
    Farkkila M, Karvonen AL, Nurmi H, Nuutinen H, Taavitsainen M, Pikkarainen P, Karkkainen P. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology. 2004;40:1379–86. doi: 10.1002/hep.20457.PubMedCrossRefGoogle Scholar
  54. 54.
    Silveira MG, Torok NJ, Gossard AA, Keach JC, Jorgensen RA, Petz JL, Lindor KD. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am J Gastroenterol. 2009;104:83–8. doi: 10.1038/ajg.2008.14.PubMedCrossRefGoogle Scholar
  55. 55.
    Tabibian JH, Gossard A, El-Youssef M, et al. Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis. Am J Ther. 2014; doi: 10.1097/mjt.0000000000000102.Google Scholar
  56. 56.
    Johnson GK, Saeian K, Geenen JE. Primary sclerosing cholangitis treated by endoscopic biliary dilation: review and long-term follow-up evaluation. Curr Gastroenterol Rep. 2006;8:147–55.PubMedCrossRefGoogle Scholar
  57. 57.
    Venkat VL, Ranganathan S, Sindhi R. The challenges of liver transplantation in children with primary sclerosing cholangitis. Expert Rev Gastroenterol Hepatol. 2015;9:289–94. doi: 10.1586/17474124.2015.1002085.PubMedCrossRefGoogle Scholar
  58. 58.
    Squires RH, Ng V, Romero R, Ekong U, Hardikar W, Emre S, Mazariegos GV. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2014;59:112–31. doi: 10.1097/mpg.0000000000000431.PubMedCrossRefGoogle Scholar
  59. 59.
    Miloh T, Anand R, Yin W, Vos M, Kerkar N, Alonso E, Studies of Pediatric Liver Transplantation Research Group. Pediatric liver transplantation for primary sclerosing cholangitis. Liver Transpl. 2011;17:925–33. doi: 10.1002/lt.22320.PubMedCrossRefGoogle Scholar
  60. 60.
    Venkat VL, Ranganathan S, Mazariegos GV, Sun Q, Sindhi R. Recurrence of primary sclerosing cholangitis in pediatric liver transplant recipients. Liver Transpl. 2014;20:679–86. doi: 10.1002/lt.23868.PubMedCrossRefGoogle Scholar
  61. 61.
    Jimenez-Rivera C, Ling SC, Ahmed N, et al. Incidence and characteristics of autoimmune hepatitis. Pediatrics. 2015; doi: 10.1542/peds.2015-0578.PubMedGoogle Scholar
  62. 62.
    Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, Mieli-Vergani G. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33:544–53. doi: 10.1053/jhep.2001.22131.PubMedCrossRefGoogle Scholar
  63. 63.
    Mieli-Vergani G, Vergani D. Paediatric autoimmune liver disease. Arch Dis Child. 2013;98:1012–7. doi: 10.1136/archdischild-2013-303848.PubMedCrossRefGoogle Scholar
  64. 64.
    Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children: what is different from adult AIH? Semin Liver Dis. 2009;29:297–306. doi: 10.1055/s-0029-1233529.PubMedCrossRefGoogle Scholar
  65. 65.
    Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology. 1997;25:541–7. doi: 10.1002/hep.510250308.PubMedCrossRefGoogle Scholar
  66. 66.
    Manns MP, Lohse AW, Vergani D. Autoimmune hepatitis–update 2015. J Hepatol. 2015;62:S100–11. doi: 10.1016/j.jhep.2015.03.005.PubMedCrossRefGoogle Scholar
  67. 67.
    Mieli-Vergani G, Vergani D. Autoimmune hepatitis. Nat Rev Gastroenterol Hepatol. 2011;8:320–9. doi: 10.1038/nrgastro.2011.69.PubMedCrossRefGoogle Scholar
  68. 68.
    Radhakrishnan KR, Alkhouri N, Worley S, et al. Autoimmune hepatitis in children–impact of cirrhosis at presentation on natural history and long-term outcome. Dig Liver Dis. 2010;42:724–8. doi: 10.1016/j.dld.2010.01.002.PubMedCrossRefGoogle Scholar
  69. 69.
    Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: contrasts and comparisons in children and adults – a comprehensive review. J Autoimmun. 2013;46:7–16. doi: 10.1016/j.jaut.2013.08.004.PubMedCrossRefGoogle Scholar
  70. 70.
    Manns MP, Woynarowski M, Kreisel W, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010;139:1198–206. doi: 10.1053/j.gastro.2010.06.046.PubMedCrossRefGoogle Scholar
  71. 71.
    Liberal R, Longhi MS, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis after liver transplantation. Clin Gastroenterol Hepatol. 2012;10:346–53. doi: 10.1016/j.cgh.2011.10.028.PubMedCrossRefGoogle Scholar
  72. 72.
    Liberal R, Zen Y, Mieli-Vergani G, Vergani D. Liver transplantation and autoimmune liver diseases. Liver Transpl. 2013;19:1065–77. doi: 10.1002/lt.23704.PubMedGoogle Scholar
  73. 73.
    Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol. 2011;54:374–85. doi: 10.1016/j.jhep.2010.09.002.PubMedCrossRefGoogle Scholar
  74. 74.
    Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–213. doi: 10.1002/hep.23584.PubMedCrossRefGoogle Scholar
  75. 75.
    European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237–67. doi: 10.1016/j.jhep.2009.04.009.CrossRefGoogle Scholar
  76. 76.
    Beuers U, Hubers LM, Doorenspleet M, et al. IgG4-associated cholangitis – a mimic of PSC. Dig Dis. 2015;33(Suppl 2):176–80. doi: 10.1159/000440830.PubMedCrossRefGoogle Scholar
  77. 77.
    Dastis SN, Latinne D, Sempoux C, Geubel AP. Ulcerative colitis associated with IgG4 cholangitis: similar features in two HLA identical siblings. J Hepatol. 2009;51:601–5. doi: 10.1016/j.jhep.2009.05.032.PubMedCrossRefGoogle Scholar
  78. 78.
    Hirano K, Kawabe T, Yamamoto N, et al. Serum IgG4 concentrations in pancreatic and biliary diseases. Clin Chim Acta. 2006;367:181–4. doi: 10.1016/j.cca.2005.11.031.PubMedCrossRefGoogle Scholar
  79. 79.
    Mendes FD, Jorgensen R, Keach J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2006;101:2070–5. doi: 10.1111/j.1572-0241.2006.00772.x.PubMedCrossRefGoogle Scholar
  80. 80.
    Zhang L, Lewis JT, Abraham SC, et al. IgG4+ plasma cell infiltrates in liver explants with primary sclerosing cholangitis. Am J Surg Pathol. 2010;34:88–94. doi: 10.1097/PAS.0b013e3181c6c09a.PubMedCrossRefGoogle Scholar
  81. 81.
    Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134:706–15. doi: 10.1053/j.gastro.2007.12.009.PubMedCrossRefGoogle Scholar
  82. 82.
    Ohara H, Okazaki K, Tsubouchi H, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepatobiliary Pancreat Sci. 2012;19:536–42. doi: 10.1007/s00534-012-0521-y.PubMedCrossRefGoogle Scholar
  83. 83.
    Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ. Risk of liver injury among methotrexate users: a meta-analysis of randomised controlled trials. Semin Arthritis Rheum. 2015;45:156–62. doi: 10.1016/j.semarthrit.2015.05.003.PubMedCrossRefGoogle Scholar
  84. 84.
    Fournier MR, Klein J, Minuk GY, Bernstein CN. Changes in liver biochemistry during methotrexate use for inflammatory bowel disease. Am J Gastroenterol. 2010;105:1620–6. doi: 10.1038/ajg.2010.21.PubMedCrossRefGoogle Scholar
  85. 85.
    Te HS, Schiano TD, Kuan SF, Hanauer SB, Conjeevaram HS, Baker AL. Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease. Am J Gastroenterol. 2000;95:3150–6. doi: 10.1111/j.1572-0241.2000.03287.x.PubMedCrossRefGoogle Scholar
  86. 86.
    Sunseri W, Hyams JS, Lerer T, et al. Retrospective cohort study of methotrexate use in the treatment of pediatric Crohn disease. Inflamm Bowel Dis. 2014;20:1341–5. doi: 10.1097/mib.0000000000000102.PubMedCrossRefGoogle Scholar
  87. 87.
    Turner D, Doveh E, Cohen A, et al. Efficacy of oral methotrexate in paediatric Crohn disease: a multicentre propensity score study. Gut. 2015;64(12):1898–904. doi: 10.1136/gutjnl-2014-307964. Epub 2014 Nov 21.
  88. 88.
    Valentino PL, Church PC, Shah PS, Beyene J, Griffiths AM, Feldman BM, Kamath BM. Hepatotoxicity caused by methotrexate therapy in children with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2014;20:47–59. doi: 10.1097/01.MIB.0000436953.88522.3e.PubMedCrossRefGoogle Scholar
  89. 89.
    Khan N, Abbas AM, Whang N, Balart LA, Bazzano LA, Kelly TN. Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: a meta-analysis of clinical trials. Inflamm Bowel Dis. 2012;18:359–67. doi: 10.1002/ibd.21820.PubMedCrossRefGoogle Scholar
  90. 90.
    Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol. 2009;60:824–37. doi: 10.1016/j.jaad.2008.11.906.PubMedCrossRefGoogle Scholar
  91. 91.
    Bousvaros A. Use of immunomodulators and biologic therapies in children with inflammatory bowel disease. Expert Rev Clin Immunol. 2010;6:659–66. doi: 10.1586/eci.10.46.PubMedCrossRefGoogle Scholar
  92. 92.
    Gisbert JP, Gonzalez-Lama Y, Mate J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol. 2007;102:1518–27. doi: 10.1111/j.1572-0241.2007.01187.x.PubMedCrossRefGoogle Scholar
  93. 93.
    Lee MN, Kang B, Choi SY, et al. Relationship between azathioprine dosage, 6-thioguanine nucleotide levels, and therapeutic response in pediatric patients with IBD treated with azathioprine. Inflamm Bowel Dis. 2015;21:1054–62. doi: 10.1097/MIB.0000000000000347.PubMedCrossRefGoogle Scholar
  94. 94.
    Riello L, Talbotec C, Garnier-Lengline H, et al. Tolerance and efficacy of azathioprine in pediatric Crohn disease. Inflamm Bowel Dis. 2011;17:2138–43. doi: 10.1002/ibd.21612.PubMedCrossRefGoogle Scholar
  95. 95.
    Haboubi NY, Ali HH, Whitwell HL, Ackrill P. Role of endothelial cell injury in the spectrum of azathioprine-induced liver disease after renal transplant: light microscopy and ultrastructural observations. Am J Gastroenterol. 1988;83:256–61.PubMedGoogle Scholar
  96. 96.
    Dubinsky MC, Vasiliauskas EA, Singh H, et al. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology. 2003;125:298–303. doi: 10.1016/s0016-5085(03)00938-7.PubMedCrossRefGoogle Scholar
  97. 97.
    Calabrese E, Hanauer SB. Assessment of non-cirrhotic portal hypertension associated with thiopurine therapy in inflammatory bowel disease. J Crohns Colitis. 2011;5:48–53. doi: 10.1016/j.crohns.2010.08.007.PubMedCrossRefGoogle Scholar
  98. 98.
    Seiderer J, Zech CJ, Reinisch W, et al. A multicenter assessment of liver toxicity by MRI and biopsy in IBD patients on 6-thioguanine. J Hepatol. 2005;43:303–9. doi: 10.1016/j.jhep.2005.02.051.PubMedCrossRefGoogle Scholar
  99. 99.
    Musumba CO. Review article: the association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy. Aliment Pharmacol Ther. 2013;38:1025–37. doi: 10.1111/apt.12490.PubMedCrossRefGoogle Scholar
  100. 100.
    Russmann S, Zimmermann A, Krähenbühl S, Kern B, Reichen J. Veno-occlusive disease, nodular regenerative hyperplasia and hepatocellular carcinoma after azathioprine treatment in a patient with ulcerative colitis. Eur J Gastroenterol Hepatol. 2001;13:287–90.PubMedCrossRefGoogle Scholar
  101. 101.
    Khokhar OS, Lewis JH. Hepatotoxicity of agents used in the management of inflammatory bowel disease. Dig Dis. 2010;28:508–18. doi: 10.1159/000320410.PubMedCrossRefGoogle Scholar
  102. 102.
    Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Theoret Y, Seidman EG. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118:705–13.PubMedCrossRefGoogle Scholar
  103. 103.
    Konidari A, Anagnostopoulos A, Bonnett LJ, Pirmohamed M, El-Matary W. Thiopurine monitoring in children with inflammatory bowel disease: a systematic review. Br J Clin Pharmacol. 2014;78:467–76. doi: 10.1111/bcp.12365.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Connor V. Anti-TNF therapies: a comprehensive analysis of adverse effects associated with immunosuppression. Rheumatol Int. 2011;31:327–37. doi: 10.1007/s00296-009-1292-x.PubMedCrossRefGoogle Scholar
  105. 105.
    Vaz JL, Fernandes V, Nogueira F, Arnobio A, Levy RA. Infliximab-induced autoantibodies: a multicenter study. Clin Rheumatol. 2015; doi: 10.1007/s10067-015-3140-6.Google Scholar
  106. 106.
    Weiler-Normann C, Schramm C, Quaas A, et al. Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis. J Hepatol. 2013;58:529–34. doi: 10.1016/j.jhep.2012.11.010.PubMedCrossRefGoogle Scholar
  107. 107.
    Ghabril M, Bonkovsky HL, Kum C, et al. Liver injury from tumor necrosis factor-alpha antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol. 2013;11:558–564.e553. doi: 10.1016/j.cgh.2012.12.025.PubMedCrossRefGoogle Scholar
  108. 108.
    Shelton E, Chaudrey K, Sauk J, et al. New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2015;41:972–9. doi: 10.1111/apt.13159.PubMedCrossRefGoogle Scholar
  109. 109.
    Bjornsson ES, Gunnarsson BI, Grondal G, et al. Risk of drug-induced liver injury from tumor necrosis factor antagonists. Clin Gastroenterol Hepatol. 2015;13:602–8. doi: 10.1016/j.cgh.2014.07.062.PubMedCrossRefGoogle Scholar
  110. 110.
    Loras C, Gisbert JP, Minguez M, et al. Liver dysfunction related to hepatitis B and C in patients with inflammatory bowel disease treated with immunosuppressive therapy. Gut. 2010;59:1340–6. doi: 10.1136/gut.2010.208413.PubMedCrossRefGoogle Scholar
  111. 111.
    Lin MV, Blonski W, Buchner AM, Reddy KR, Lichtenstein GR. The influence of anti-TNF therapy on the course of chronic hepatitis C virus infection in patients with inflammatory bowel disease. Dig Dis Sci. 2013;58:1149–56.PubMedCrossRefGoogle Scholar
  112. 112.
    Park SH, Yang SK, Park SK, et al. Efficacy of hepatitis A vaccination and factors impacting on seroconversion in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:69–74. doi: 10.1097/01.MIB.0000437736.91712.a1.PubMedCrossRefGoogle Scholar
  113. 113.
    Boyer DL, Li BU, Fyda JN, Friedman RA. Sulfasalazine-induced hepatotoxicity in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1989;8:528–32.PubMedCrossRefGoogle Scholar
  114. 114.
    Bashir RM, Lewis JH. Hepatotoxicity of drugs used in the treatment of gastrointestinal disorders. Gastroenterol Clin North Am. 1995;24:937–67.PubMedGoogle Scholar
  115. 115.
    Jobanputra P, Amarasena R, Maggs F, et al. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: a case series from a local surveillance of serious adverse events. BMC Musculoskelet Disord. 2008;9:48. doi: 10.1186/1471-2474-9-48.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Ribe J, Benkov KJ, Thung SN, Shen SC, LeLeiko NS. Fatal massive hepatic necrosis: a probable hypersensitivity reaction to sulfasalazine. Am J Gastroenterol. 1986;81:205–8.PubMedGoogle Scholar
  117. 117.
    Namias A, Bhalotra R, Donowitz M. Reversible sulfasalazine-induced granulomatous hepatitis. J Clin Gastroenterol. 1981;3:193–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Quallich LG, Greenson J, Haftel HM, Fontana RJ. Is it Crohn disease? A severe systemic granulomatous reaction to sulfasalazine in patient with rheumatoid arthritis. BMC Gastroenterol. 2001;1:8.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Ransford RA, Langman MJ. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut. 2002;51:536–9.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Braun M, Fraser GM, Kunin M, Salamon F, Tur-Kaspa R. Mesalamine-induced granulomatous hepatitis. Am J Gastroenterol. 1999;94:1973–4. doi: 10.1111/j.1572-0241.1999.01245.x.PubMedCrossRefGoogle Scholar
  121. 121.
    Stelzer T, Kohler S, Marques Maggio E, Heuss LT. An unusual cause of febrile hepatitis. BMJ Case Rep. 2015; 2015. doi:  10.1136/bcr-2014-205857.
  122. 122.
    Stoschus B, Meybehm M, Spengler U, Scheurlen C, Sauerbruch T. Cholestasis associated with mesalazine therapy in a patient with Crohn disease. J Hepatol. 1997;26:425–8.PubMedCrossRefGoogle Scholar
  123. 123.
    Hautekeete ML, Bourgeois N, Potvin P, et al. Hypersensitivity with hepatotoxicity to mesalazine after hypersensitivity to sulfasalazine. Gastroenterology. 1992;103:1925–7.PubMedCrossRefGoogle Scholar
  124. 124.
    Deltenre P, Berson A, Marcellin P, Degott C, Biour M, Pessayre D. Mesalazine (5-aminosalicylic acid) induced chronic hepatitis. Gut. 1999;44:886–8.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Sourianarayanane A, Garg G, Smith TH, Butt MI, McCullough AJ, Shen B. Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease. J Crohns Colitis. 2013;7:e279–85. doi: 10.1016/j.crohns.2012.10.015.PubMedCrossRefGoogle Scholar
  126. 126.
    Kotlyar DS, Osterman MT, Diamond RH, et al. A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2011;9:36–41 e31. doi: 10.1016/j.cgh.2010.09.016.PubMedCrossRefGoogle Scholar
  127. 127.
    Mason M, Siegel CA. Do inflammatory bowel disease therapies cause cancer? Inflamm Bowel Dis. 2013;19:1306–21. doi: 10.1097/MIB.0b013e3182807618.PubMedCrossRefGoogle Scholar
  128. 128.
    Deepak P, Sifuentes H, Sherid M, Stobaugh D, Sadozai Y, Ehrenpreis ED. T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-alpha) inhibitors: results of the REFURBISH study. Am J Gastroenterol. 2013;108:99–105. doi: 10.1038/ajg.2012.334.PubMedCrossRefGoogle Scholar
  129. 129.
    Gizard E, Ford AC, Bronowicki JP, Peyrin-Biroulet L. Systematic review: the epidemiology of the hepatobiliary manifestations in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2014;40:3–15. doi: 10.1111/apt.12794.PubMedCrossRefGoogle Scholar
  130. 130.
    Parente F, Pastore L, Bargiggia S, et al. Incidence and risk factors for gallstones in patients with inflammatory bowel disease: a large case-control study. Hepatology. 2007;45:1267–74. doi: 10.1002/hep.21537.PubMedCrossRefGoogle Scholar
  131. 131.
    Ehlin AG, Montgomery SM, Ekbom A, Pounder RE, Wakefield AJ. Prevalence of gastrointestinal diseases in two British national birth cohorts. Gut. 2003;52:1117–21.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Margalit M, Elinav H, Ilan Y, Shalit M. Liver abscess in inflammatory bowel disease: report of two cases and review of the literature. J Gastroenterol Hepatol. 2004;19:1338–42. doi: 10.1111/j.1440-1746.2004.03368.x.PubMedCrossRefGoogle Scholar
  133. 133.
    Kappelman MD, Horvath-Puho E, Sandler RS, et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut. 2011;60:937–43. doi: 10.1136/gut.2010.228585.PubMedCrossRefGoogle Scholar
  134. 134.
    Nylund CM, Goudie A, Garza JM, Crouch G, Denson LA. Venous thrombotic events in hospitalized children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2013;56:485–91. doi: 10.1097/MPG.0b013e3182801e43.PubMedCrossRefGoogle Scholar
  135. 135.
    Maconi G, Bolzacchini E, Dell’Era A, Russo U, Ardizzone S, de Franchis R. Portal vein thrombosis in inflammatory bowel diseases: a single-center case series. J Crohns Colitis. 2012;6:362–7. doi: 10.1016/j.crohns.2011.10.003.PubMedCrossRefGoogle Scholar
  136. 136.
    Kraut J, Berman JH, Gunasekaran TS, Allen R, McFadden J, Messersmith R, Pellettiere E. Hepatic vein thrombosis (Budd-Chiari syndrome) in an adolescent with ulcerative colitis. J Pediatr Gastroenterol Nutr. 1997;25:417–20.PubMedCrossRefGoogle Scholar
  137. 137.
    Rahhal RM, Pashankar DS, Bishop WP. Ulcerative colitis complicated by ischemic colitis and Budd Chiari syndrome. J Pediatr Gastroenterol Nutr. 2005;40:94–7.PubMedCrossRefGoogle Scholar
  138. 138.
    Socha P, Ryzko J, Janczyk W, Dzik E, Iwanczak B, Krzesiek E. Hepatic vein thrombosis as a complication of ulcerative colitis in a 12-year-old patient. Dig Dis Sci. 2007;52:1293–8. doi: 10.1007/s10620-006-9503-8.PubMedCrossRefGoogle Scholar
  139. 139.
    Greenstein AJ, Sachar DB, Panday AK, et al. Amyloidosis and inflammatory bowel disease. A 50-year experience with 25 patients. Medicine (Baltimore). 1992;71:261–70.CrossRefGoogle Scholar
  140. 140.
    Serra I, Oller B, Manosa M, Naves JE, Zabana Y, Cabre E, Domenech E. Systemic amyloidosis in inflammatory bowel disease: retrospective study on its prevalence, clinical presentation, and outcome. J Crohns Colitis. 2010;4:269–74. doi: 10.1016/j.crohns.2009.11.009.PubMedCrossRefGoogle Scholar
  141. 141.
    Wester AL, Vatn MH, Fausa O. Secondary amyloidosis in inflammatory bowel disease: a study of 18 patients admitted to Rikshospitalet University Hospital, Oslo, from 1962 to 1998. Inflamm Bowel Dis. 2001;7:295–300.PubMedCrossRefGoogle Scholar
  142. 142.
    Sattianayagam PT, Gillmore JD, Pinney JH, et al. Inflammatory bowel disease and systemic AA amyloidosis. Dig Dis Sci. 2013;58:1689–97. doi: 10.1007/s10620-012-2549-x.PubMedCrossRefGoogle Scholar
  143. 143.
    Tada F, Abe M, Nunoi H, et al. Ulcerative colitis complicated with primary biliary cirrhosis. Intern Med. 2011;50:2323–7. doi: 10.2169/internalmedicine.50.5919.PubMedCrossRefGoogle Scholar
  144. 144.
    Xiao WB, Liu YL. Primary biliary cirrhosis and ulcerative colitis: a case report and review of literature. World J Gastroenterol. 2003;9:878–80.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division of Gastroenterology, Hepatology and NutritionThe Hospital for Sick ChildrenTorontoCanada
  2. 2.University of TorontoTorontoCanada

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