Advertisement

IgG4-Related Diseases and the Liver

  • Kenichi HaradaEmail author
Chapter

Abstract

IgG4-related disease (IgG4-RD) is a systemic illness including autoimmune pancreatitis and IgG4-related sclerosing cholangitis (IgG4-SC). Although hepatic presentation of IgG4-RD has been reported, whether intrahepatic small bile ducts and hepatocytes are direct targets of IgG4-RD is uncertain. IgG4-RD is pathologically characterized by the numerous IgG4+ cells found in affected organs, but this IgG4 positivity is also frequently found in extrahepatic cholangiocarcinoma and is prominent, albeit rarely, in other hepatobiliary diseases including primary sclerosing cholangitis and autoimmune hepatitis. Moreover, cholangiocarcinoma arising from precedent IgG4-SC and IgG4-SC accompanying precursor lesions of cholangiocarcinoma (biliary intraepithelial neoplasia) are also reported. Diagnostic criteria for IgG-RD and IgG4-SC were recently proposed, but each individual case should be diagnosed clinicopathologically on the basis of its individual features.

Keywords

Cholangiocarcinoma IgG4-sclerosing cholangitis IgG4 hepatopathy IgG4-associated autoimmune hepatitis Primary biliary cholangitis 

References

  1. 1.
    Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22:21–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539–51.CrossRefPubMedGoogle Scholar
  4. 4.
    Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet. 2015;385:1460–71.CrossRefPubMedGoogle Scholar
  5. 5.
    Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, Okamoto A, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38:982–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Umemura T, Zen Y, Hamano H, Ichijo T, Kawa S, Nakanuma Y, Kiyosawa K. IgG4 associated autoimmune hepatitis: a differential diagnosis for classical autoimmune hepatitis. Gut. 2007;56:1471–2.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Umemura T, Zen Y, Hamano H, Joshita S, Ichijo T, Yoshizawa K, Kiyosawa K, et al. Clinical significance of immunoglobulin G4-associated autoimmune hepatitis. J Gastroenterol. 2011;46 Suppl 1:48–55.CrossRefPubMedGoogle Scholar
  8. 8.
    Umemura T, Zen Y, Hamano H, Kawa S, Nakanuma Y, Kiyosawa K. Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology. 2007;46:463–71.CrossRefPubMedGoogle Scholar
  9. 9.
    Hamano H, Kawa S, Ochi Y, Unno H, Shiba N, Wajiki M, Nakazawa K, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet. 2002;359:1403–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol. 2010;34:1812–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Nakanuma Y. A novel approach to biliary tract pathology based on similarities to pancreatic counterparts: is the biliary tract an incomplete pancreas? Pathol Int. 2010;60:419–29.CrossRefPubMedGoogle Scholar
  12. 12.
    Nonomura A, Minato H, Shimizu K, Kadoya M, Matsui O. Hepatic hilar inflammatory pseudotumor mimicking cholangiocarcinoma with cholangitis and phlebitis – a variant of primary sclerosing cholangitis? Pathol Res Pract. 1997;193:519–25; discussion 526.CrossRefPubMedGoogle Scholar
  13. 13.
    Zen Y, Fujii T, Sato Y, Masuda S, Nakanuma Y. Pathological classification of hepatic inflammatory pseudotumor with respect to IgG4-related disease. Mod Pathol. 2007;20:884–94.CrossRefPubMedGoogle Scholar
  14. 14.
    Ahn KS, Kang KJ, Kim YH, Lim TJ, Jung HR, Kang YN, Kwon JH. Inflammatory pseudotumors mimicking intrahepatic cholangiocarcinoma of the liver; IgG4-positivity and its clinical significance. J Hepatobiliary Pancreat Sci. 2012;19:405–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Hamano H, Kawa S, Uehara T, Ochi Y, Takayama M, Komatsu K, Muraki T, et al. Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of a spectrum of autoimmune pancreatitis? Gastrointest Endosc. 2005;62:152–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Nakazawa T, Ikeda Y, Kawaguchi Y, Kitagawa H, Takada H, Takeda Y, Makino I, et al. Isolated intrapancreatic IgG4-related sclerosing cholangitis. World J Gastroenterol. 2015;21:1334–43.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hayashi K, Nakazawa T, Ohara H, Ando T, Takada H, Tanaka H, Sasaki M, et al. Autoimmune sclerosing cholangiopancreatitis with little pancreatic involvements by imaging findings. Hepatogastroenterology. 2007;54:2146–51.PubMedGoogle Scholar
  18. 18.
    Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Zhang L, Clain JE, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006;4:1010–6; quiz 1934.CrossRefPubMedGoogle Scholar
  19. 19.
    Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, Topazian MD, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134:706–15.CrossRefPubMedGoogle Scholar
  20. 20.
    Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, Nakanuma Y. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007;45:1538–46.CrossRefPubMedGoogle Scholar
  21. 21.
    Akitake R, Watanabe T, Zaima C, Uza N, Ida H, Tada S, Nishida N, et al. Possible involvement of T helper type 2 responses to Toll-like receptor ligands in IgG4-related sclerosing disease. Gut. 2010;59:542–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Suzuki K, Tamaru J, Okuyama A, Kameda H, Amano K, Nagasawa H, Nishi E, et al. IgG4-positive multi-organ lymphoproliferative syndrome manifesting as chronic symmetrical sclerosing dacryo-sialadenitis with subsequent secondary portal hypertension and remarkable IgG4-linked IL-4 elevation. Rheumatology (Oxford). 2010;49:1789–91.CrossRefGoogle Scholar
  23. 23.
    Miyake K, Moriyama M, Aizawa K, Nagano S, Inoue Y, Sadanaga A, Nakashima H, et al. Peripheral CD4+ T cells showing a Th2 phenotype in a patient with Mikulicz’s disease associated with lymphadenopathy and pleural effusion. Mod Rheumatol. 2008;18:86–90.CrossRefPubMedGoogle Scholar
  24. 24.
    Koyabu M, Uchida K, Miyoshi H, Sakaguchi Y, Fukui T, Ikeda H, Takaoka M, et al. Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases. J Gastroenterol. 2010;45:732–41.CrossRefPubMedGoogle Scholar
  25. 25.
    Robinson DS, Larche M, Durham SR. Tregs and allergic disease. J Clin Invest. 2004;114:1389–97.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY. IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol. 1998;160:3555–61.PubMedGoogle Scholar
  27. 27.
    Koyabu M, Uchida K, Fukata N, Kusuda T, Ikeura T, Sakaguchi Y, Yoshida K, et al. Primary sclerosing cholangitis with elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells. J Gastroenterol. 2010;45:122–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Harada K, Shimoda S, Kimura Y, Sato Y, Ikeda H, Igarashi S, Ren XS, et al. Significance of immunoglobulin G4 (IgG4)-positive cells in extrahepatic cholangiocarcinoma: molecular mechanism of IgG4 reaction in cancer tissue. Hepatology. 2012;56:157–64.CrossRefPubMedGoogle Scholar
  29. 29.
    Kawakami H, Zen Y, Kuwatani M, Eto K, Haba S, Yamato H, Shinada K, et al. IgG4-related sclerosing cholangitis and autoimmune pancreatitis: histological assessment of biopsies from Vater’s ampulla and the bile duct. J Gastroenterol Hepatol. 2010;25:1648–55.CrossRefPubMedGoogle Scholar
  30. 30.
    Kawa S, Hamano H, Kiyosawa K. Pancreatitis. St. Louis: Elsevier; 2006.CrossRefGoogle Scholar
  31. 31.
    Hirano K, Shiratori Y, Komatsu Y, Yamamoto N, Sasahira N, Toda N, Isayama H, et al. Involvement of the biliary system in autoimmune pancreatitis: a follow-up study. Clin Gastroenterol Hepatol. 2003;1:453–64.CrossRefPubMedGoogle Scholar
  32. 32.
    Joshi D, Webster GJ. Letter: IgG4-hepatopathy and IgG4-associated autoimmune hepatitis--authors’ reply. Aliment Pharmacol Ther. 2015;41:327.CrossRefPubMedGoogle Scholar
  33. 33.
    Perricone G. Hepatic involvement in IgG4-related disease: IgG4-hepatopathy and IgG4-autoimmune hepatitis. Autoimmun Rev. 2015;14:268.CrossRefPubMedGoogle Scholar
  34. 34.
    Umemura T, Zen Y, Nakanuma Y, Kiyosawa K. Another case of autoimmune hepatitis. Hepatology. 2010;52:389–90.CrossRefPubMedGoogle Scholar
  35. 35.
    Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–38.CrossRefPubMedGoogle Scholar
  36. 36.
    Zhao XY, Rakhda MI, Wang TI, Jia JD. Immunoglobulin G4-associated de novo autoimmune hepatitis after liver transplantation for chronic hepatitis B- and C-related cirrhosis and hepatocellular carcinoma: a case report with literature review. Transplant Proc. 2013;45:824–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Chung H, Watanabe T, Kudo M, Maenishi O, Wakatsuki Y, Chiba T. Identification and characterization of IgG4-associated autoimmune hepatitis. Liver Int. 2010;30:222–31.CrossRefPubMedGoogle Scholar
  38. 38.
    Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, Bittencourt PL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–76.CrossRefPubMedGoogle Scholar
  39. 39.
    Nakanuma Y, Ohta G. Histometric and serial section observations of the intrahepatic bile ducts in primary biliary cirrhosis. Gastroenterology. 1979;76:1326–32.PubMedGoogle Scholar
  40. 40.
    Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–73.CrossRefPubMedGoogle Scholar
  41. 41.
    Harada K, Ozaki S, Gershwin ME, Nakanuma Y. Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis. Hepatology. 1997;26:1399–405.CrossRefPubMedGoogle Scholar
  42. 42.
    Gershwin ME, Mackay IR, Sturgess A, Coppel RL. Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol. 1987;138:3525–31.PubMedGoogle Scholar
  43. 43.
    Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y. HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med. 1995;181:1835–45.CrossRefPubMedGoogle Scholar
  44. 44.
    Kita H, Lian ZX, Van de Water J, He XS, Matsumura S, Kaplan M, Luketic V, et al. Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. J Exp Med. 2002;195:113–23.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Shimoda S, Ishikawa F, Kamihira T, Komori A, Niiro H, Baba E, Harada K, et al. Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory. Gastroenterology. 2006;131:606–18.CrossRefPubMedGoogle Scholar
  46. 46.
    Dienes HP, Lohse AW, Gerken G, Schirmacher P, Gallati H, Lohr HF, Buschenfelde KH M z. Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis. Virchows Arch. 1997;431:119–24.CrossRefPubMedGoogle Scholar
  47. 47.
    Harada K, Isse K, Kamihira T, Shimoda S, Nakanuma Y. Th1 cytokine-induced downregulation of PPARgamma in human biliary cells relates to cholangitis in primary biliary cirrhosis. Hepatology. 2005;41:1329–38.CrossRefPubMedGoogle Scholar
  48. 48.
    Bertoletti A, D’Elios MM, Boni C, De Carli M, Zignego AL, Durazzo M, Missale G, et al. Different cytokine profiles of intraphepatic T cells in chronic hepatitis B and hepatitis C virus infections. Gastroenterology. 1997;112:193–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Wiegand J, Neid M, Kaiser T, Wittekind C, Mossner J, Tillmann HL, Schiefke I. Coexistence of autoimmune pancreatitis and primary biliary cirrhosis in a Caucasian patient - a rare cause of cholestasis. Z Gastroenterol. 2006;44:1227–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Li A, Wang Y, Deng Z. Concurrent autoimmune pancreatitis and primary biliary cirrhosis: a rare case report and literature review. BMC Gastroenterol. 2014;14:10.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Naitoh I, Nakazawa T, Hayashi K, Miyabe K, Shimizu S, Kondo H, Yoshida M, et al. A case of IgG4-related sclerosing cholangitis overlapped with primary biliary cirrhosis. Intern Med. 2012;51:1695–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Takemoto R, Miyake Y, Harada K, Nakanuma Y, Moriya A, Ando M, Hirohata M, et al. Overlap of IgG4-related sclerosing cholangitis and primary biliary cirrhosis. Intern Med. 2014;53:1429–33.CrossRefPubMedGoogle Scholar
  53. 53.
    Harada K, Hirohara J, Ueno Y, Nakano T, Kakuda Y, Tsubouchi H, Ichida T, et al. Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis: national data from Japan. Hepatology. 2013;57:1942–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Harada K, Nakanuma Y. Prevalence and risk factors of hepatocellular carcinoma in Japanese patients with primary biliary cirrhosis. Hepatol Res. 2014;44:133–40.CrossRefPubMedGoogle Scholar
  55. 55.
    Harada K, Van de Water J, Leung PS, Coppel RL, Nakanuma Y, Gershwin ME. In situ nucleic acid hybridization of pyruvate dehydrogenase complex-E2 in primary biliary cirrhosis: pyruvate dehydrogenase complex-E2 messenger RNA is expressed in hepatocytes but not in biliary epithelium. Hepatology. 1997;25:27–32.CrossRefPubMedGoogle Scholar
  56. 56.
    Harada K, Tsuneyama K, Yasoshima M, Kanemori Y, Ohta H, Masuda S, Onai N, et al. Type1 and type2 memory T cells imbalance shown by expression of intrahepatic chemokine receptors relates to pathogenesis of primary biliary cirrhosis. Hepatol Res. 2002;24:290–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, Gu X, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009;360:2544–55.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Kawa S, Ota M, Yoshizawa K, Horiuchi A, Hamano H, Ochi Y, Nakayama K, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology. 2002;122:1264–9.CrossRefPubMedGoogle Scholar
  59. 59.
    Hart PA, Zen Y, Chari ST. Recent advances in autoimmune pancreatitis. Gastroenterology. 2015;149:39–51.CrossRefPubMedGoogle Scholar
  60. 60.
    Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52:745–58.CrossRefPubMedGoogle Scholar
  61. 61.
    Myers RP, Swain MG, Lee SS, Shaheen AA, Burak KW. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol. 2013;108:933–41.CrossRefPubMedGoogle Scholar
  62. 62.
    Imam MH, Talwalkar JA, Lindor KD. Clinical management of autoimmune biliary diseases. J Autoimmun. 2013;46:88–96.CrossRefPubMedGoogle Scholar
  63. 63.
    Takahashi T, Miura T, Nakamura J, Yamada S, Miura T, Yanagi M, Matsuda Y, et al. Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis. Hepatology. 2012;55:846–55.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Zhang L, Lewis JT, Abraham SC, Smyrk TC, Leung S, Chari ST, Poterucha JJ, et al. IgG4+ plasma cell infiltrates in liver explants with primary sclerosing cholangitis. Am J Surg Pathol. 2010;34:88–94.CrossRefPubMedGoogle Scholar
  65. 65.
    Deshpande V, Sainani NI, Chung RT, Pratt DS, Mentha G, Rubbia-Brandt L, Lauwers GY. IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material. Mod Pathol. 2009;22:1287–95.CrossRefPubMedGoogle Scholar
  66. 66.
    Raina A, Krasinskas AM, Greer JB, Lamb J, Fink E, Moser AJ, Zeh 3rd HJ, et al. Serum immunoglobulin G fraction 4 levels in pancreatic cancer: elevations not associated with autoimmune pancreatitis. Arch Pathol Lab Med. 2008;132:48–53.PubMedGoogle Scholar
  67. 67.
    Ghazale A, Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Clain JE, et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol. 2007;102:1646–53.CrossRefPubMedGoogle Scholar
  68. 68.
    Kamisawa T, Chen PY, Tu Y, Nakajima H, Egawa N, Tsuruta K, Okamoto A, et al. Pancreatic cancer with a high serum IgG4 concentration. World J Gastroenterol. 2006;12:6225–8.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Dhall D, Suriawinata AA, Tang LH, Shia J, Klimstra DS. Use of immunohistochemistry for IgG4 in the distinction of autoimmune pancreatitis from peritumoral pancreatitis. Hum Pathol. 2010;41:643–52.CrossRefPubMedGoogle Scholar
  70. 70.
    Motosugi U, Ichikawa T, Yamaguchi H, Nakazawa T, Katoh R, Itakura J, Fujii H, et al. Small invasive ductal adenocarcinoma of the pancreas associated with lymphoplasmacytic sclerosing pancreatitis. Pathol Int. 2009;59:744–7.CrossRefPubMedGoogle Scholar
  71. 71.
    Oh HC, Kim JG, Kim JW, Lee KS, Kim MK, Chi KC, Kim YS, et al. Early bile duct cancer in a background of sclerosing cholangitis and autoimmune pancreatitis. Intern Med. 2008;47:2025–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Kimura Y, Harada K, Nakanuma Y. Pathologic significance of immunoglobulin G4-positive plasma cells in extrahepatic cholangiocarcinoma. Hum Pathol. 2012;43:2149–56.CrossRefPubMedGoogle Scholar
  73. 73.
    Nouri-Aria KT, Wachholz PA, Francis JN, Jacobson MR, Walker SM, Wilcock LK, Staple SQ, et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol. 2004;172:3252–9.CrossRefPubMedGoogle Scholar
  74. 74.
    Okazaki K, Uchida K, Fukui T. Recent advances in autoimmune pancreatitis: concept, diagnosis, and pathogenesis. J Gastroenterol. 2008;43:409–18.CrossRefPubMedGoogle Scholar
  75. 75.
    Harada K, Nakanuma Y. Cholangiocarcinoma with respect to IgG4 Reaction. Int J Hepatol. 2014;2014:803876.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Resheq YJ, Quaas A, von Renteln D, Schramm C, Lohse AW, Luth S. Infiltration of peritumoural but tumour-free parenchyma with IgG4-positive plasma cells in hilar cholangiocarcinoma and pancreatic adenocarcinoma. Dig Liver Dis. 2013;45:859–65.CrossRefPubMedGoogle Scholar
  77. 77.
    Ohtani H, Ishida H, Ito Y, Yamaguchi T, Koizumi M. Autoimmune pancreatitis and biliary intraepithelial neoplasia of the common bile duct: a case with diagnostically challenging but pathogenetically significant association. Pathol Int. 2011;61:481–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  1. 1.Department of Human PathologyKanazawa University Graduate School of Medical SciencesKanazawaJapan

Personalised recommendations