Advertisement

IgG4 HPB Disease

  • Jimil Shah
  • Usha Dutta
Chapter
Part of the GI Surgery Annual book series (GISA, volume 25)

Abstract

IgG4-related hepato-pancreato-biliary (IgG4 HPB) disease is a part of a multisystem disease called IgG4-related diseases (IgG4 RD). It may involve the liver, pancreas, or biliary tree in various combinations and termed as IgG4 hepatopathy, autoimmune pancreatitis type-1 (AIP-1), or IgG4 cholangiopathy, respectively. It is characterized by multi-organ fibroinflammatory condition with tumefactive lesions, dense lymphoplasmacytic infiltration, IgG4-rich plasma cells, storiform fibrosis, and elevated serum IgG4 levels. It can present with mass lesion, stricture, or features of end-organ damage. It mimics various malignancies, infectious etiologies, and vasculitis posing difficulties in diagnosis. Though the disease lacks any gold standard test for diagnosis, serum IgG4 levels, IgG4/IgG RNA ratio, and increased circulating plasmablast are helpful in diagnosing this disease. Steroid remains the main stay of therapy; however, some patients may require immunosuppressive treatment.

References

  1. 1.
    Bartholomew LG, Cain JC, Woolner LB, Utz DC, Ferris DO. Sclerosing cholangitis: its possible association with Riedel’s struma and fibrous retroperitonitis. Report of two cases. N Engl J Med. 1963;269:8–12.CrossRefGoogle Scholar
  2. 2.
    Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40:1561–8.CrossRefGoogle Scholar
  3. 3.
    Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732–8.CrossRefGoogle Scholar
  4. 4.
    Kamisawa T, Egawa N, Nakajima H. Autoimmune pancreatitis is a systemic autoimmune disease. Am J Gastroenterol. 2003;98:2811–2.CrossRefGoogle Scholar
  5. 5.
    Kanno A, Masamune A, Okazaki K, Kamisawa T, Kawa S, Nishimori I, et al. Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2011. Pancreas. 2015;44:535–9.CrossRefGoogle Scholar
  6. 6.
    Uchida K, Masamune A, Shimosegawa T, Okazaki K. Prevalence of IgG4-related disease in Japan based on nationwide survey in 2009. Int J Rheumatol. 2012;2012:358371.  https://doi.org/10.1155/2012/358371.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134:706–15.CrossRefGoogle Scholar
  8. 8.
    Huggett MT, Culver EL, Kumar M, Hurst JM, Rodriguez-Justo M, Chapman MH, et al. Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort. Am J Gastroenterol. 2014;109:1675–83.CrossRefGoogle Scholar
  9. 9.
    Umemura T, Zen Y, Hamano H, Kawa S, Nakanuma Y, Kiyosawa K. Immunoglobulin G4-hepatopathy: association of immunoglobulin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology. 2007;46:463–71.CrossRefGoogle Scholar
  10. 10.
    Tanaka A, Tazuma S, Okazaki K, Nakazawa T, Inui K, Chiba T, et al. Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis. Clin Gastroenterol Hepatol. 2017;15:920–926.e3.CrossRefGoogle Scholar
  11. 11.
    Schuurman J, Perdok GJ, Gorter AD, Aalberse RC. The inter-heavy chain disulfide bonds of IgG4 are in equilibrium with intra-chain disulfide bonds. Mol Immunol. 2001;38:1–8.CrossRefGoogle Scholar
  12. 12.
    van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martínez-Martínez P, Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317:1554–7.CrossRefGoogle Scholar
  13. 13.
    Kawa S, Ota M, Yoshizawa K, Horiuchi A, Hamano H, Ochi Y, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology. 2002;122:1264–9.CrossRefGoogle Scholar
  14. 14.
    Park DH, Kim M-H, Oh HB, Kwon O-J, Choi Y-J, Lee S-S, et al. Substitution of aspartic acid at position 57 of the DQbeta1 affects relapse of autoimmune pancreatitis. Gastroenterology. 2008;134:440–6.CrossRefGoogle Scholar
  15. 15.
    Chang M-C, Chang Y-T, Tien Y-W, Liang P-C, Jan I-S, Wei S-C, et al. T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis. Clin Chem. 2007;53:1700–5.CrossRefGoogle Scholar
  16. 16.
    Frulloni L, Lunardi C, Simone R, Dolcino M, Scattolini C, Falconi M, et al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med. 2009;361:2135–42.CrossRefGoogle Scholar
  17. 17.
    Guarneri F, Guarneri C, Benvenga S. Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry? J Cell Mol Med. 2005;9:741–4.CrossRefGoogle Scholar
  18. 18.
    Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, et al. Th2 and regulatory immune reactions are increased in immunoglobulin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007;45:1538–46.CrossRefGoogle Scholar
  19. 19.
    Kudo-Tanaka E, Nakatsuka S, Hirano T, Kawai M, Katada Y, Matsushita M, et al. A case of Mikulicz’s disease with Th2-biased cytokine profile: possible feature discriminable from Sjögren’s syndrome. Mod Rheumatol. 2009;19:691–5.CrossRefGoogle Scholar
  20. 20.
    Kanari H, Kagami S, Kashiwakuma D, Oya Y, Furuta S, Ikeda K, et al. Role of Th2 cells in IgG4-related lacrimal gland enlargement. Int Arch Allergy Immunol. 2010;152(Suppl 1):47–53.CrossRefGoogle Scholar
  21. 21.
    Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27.CrossRefGoogle Scholar
  22. 22.
    Detlefsen S, Sipos B, Zhao J, Drewes AM, Klöppel G. Autoimmune pancreatitis: expression and cellular source of profibrotic cytokines and their receptors. Am J Surg Pathol. 2008;32:986–95.CrossRefGoogle Scholar
  23. 23.
    Hart PA, Kamisawa T, Brugge WR, Chung JB, Culver EL, Czakó L, et al. Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis. Gut. 2013;62:1771–6.CrossRefGoogle Scholar
  24. 24.
    Yada N, Kudo M, Chung H, Watanabe T. Autoimmune hepatitis and immunoglobulin G4-associated autoimmune hepatitis. Dig Dis. 2013;31:415–20.CrossRefGoogle Scholar
  25. 25.
    Culver EL, Vermeulen E, Makuch M, van Leeuwen A, Sadler R, Cargill T, et al. Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease. Ann Rheum Dis. 2015;74:944–7.CrossRefGoogle Scholar
  26. 26.
    Sah RP, Chari ST. Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr Opin Rheumatol. 2011;23:108–13.CrossRefGoogle Scholar
  27. 27.
    Boonstra K, Culver EL, de Buy Wenniger LM, van Heerde MJ, van Erpecum KJ, Poen AC, et al. Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from primary sclerosing cholangitis. Hepatology. 2014;59:1954–63.CrossRefGoogle Scholar
  28. 28.
    Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2006;101:2070–5.CrossRefGoogle Scholar
  29. 29.
    Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis. 2015;74:14–8.CrossRefGoogle Scholar
  30. 30.
    Oseini AM, Chaiteerakij R, Shire AM, Ghazale A, Kaiya J, Moser CD, et al. Utility of serum immunoglobulin G4 in distinguishing immunoglobulin G4-associated cholangitis from cholangiocarcinoma. Hepatology. 2011;54:940–8.CrossRefGoogle Scholar
  31. 31.
    Doorenspleet ME, Hubers LM, Culver EL, Maillette de Buy Wenniger LJ, Klarenbeek PL, Chapman RW, et al. Immunoglobulin G4(+) B-cell receptor clones distinguish immunoglobulin G 4-related disease from primary sclerosing cholangitis and biliary/pancreatic malignancies. Hepatology. 2016;64:501–7.CrossRefGoogle Scholar
  32. 32.
    Mattoo H, Mahajan VS, Della-Torre E, Sekigami Y, Carruthers M, Wallace ZS, et al. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol. 2014;134:679–87.CrossRefGoogle Scholar
  33. 33.
    Wallace ZS, Mattoo H, Carruthers M, Mahajan VS, Della Torre E, Lee H, et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis. 2015;74:190–5.CrossRefGoogle Scholar
  34. 34.
    Culver EL, Sadler R, Bateman AC, Makuch M, Cargill T, Ferry B, et al. Increases in IgE, eosinophils, and mast cells can be used in diagnosis and to predict relapse of IgG4-related disease. Clin Gastroenterol Hepatol. 2017;15:1444–1452.e6.CrossRefGoogle Scholar
  35. 35.
    Suzuki K, Itoh S, Nagasaka T, Ogawa H, Ota T, Naganawa S. CT findings in autoimmune pancreatitis: assessment using multiphase contrast-enhanced multisection CT. Clin Radiol. 2010;65:735–43.CrossRefGoogle Scholar
  36. 36.
    Takahashi N, Fletcher JG, Fidler JL, Hough DM, Kawashima A, Chari ST. Dual-phase CT of autoimmune pancreatitis: a multireader study. Am J Roentgenol. 2008;190:280–6.CrossRefGoogle Scholar
  37. 37.
    Bodily KD, Takahashi N, Fletcher JG, Fidler JL, Hough DM, Kawashima A, et al. Autoimmune pancreatitis: pancreatic and extrapancreatic imaging findings. Am J Roentgenol. 2009;192:431–7.CrossRefGoogle Scholar
  38. 38.
    Chari ST, Takahashi N, Levy MJ, Smyrk TC, Clain JE, Pearson RK, et al. A diagnostic strategy to distinguish autoimmune pancreatitis from pancreatic cancer. Clin Gastroenterol Hepatol. 2009;7:1097–103.CrossRefGoogle Scholar
  39. 39.
    Sugumar A, Levy MJ, Kamisawa T, Webster GJ, Kim MH, Enders F, et al. Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicentre study. Gut. 2011;60:666–70.CrossRefGoogle Scholar
  40. 40.
    Tokala A, Khalili K, Menezes R, Hirschfield G, Jhaveri KS. Comparative MRI analysis of morphologic patterns of bile duct disease in IgG4-related systemic disease versus primary sclerosing cholangitis. AJR Am J Roentgenol. 2014;202:536–43.CrossRefGoogle Scholar
  41. 41.
    Zhang J, Chen H, Ma Y, Xiao Y, Niu N, Lin W, et al. Characterizing IgG4-related disease with 18F-FDG PET/CT: a prospective cohort study. Eur J Nucl Med Mol Imaging. 2014;41:1624–34.CrossRefGoogle Scholar
  42. 42.
    Nakazawa T, Ohara H, Sano H, Aoki S, Kobayashi S, Okamoto T, et al. Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis. Gastrointest Endosc. 2004;60:937–44.CrossRefGoogle Scholar
  43. 43.
    Buscarini E, Lisi SD, Arcidiacono PG, Petrone MC, Fuini A, Conigliaro R, et al. Endoscopic ultrasonography findings in autoimmune pancreatitis. World J Gastroenterol. 2011;17:2080–5.CrossRefGoogle Scholar
  44. 44.
    Lisi SD, Buscarini E, Arcidiacono PG, Petrone M, Menozzi F, Testoni PA, et al. Endoscopic ultrasonography findings in autoimmune pancreatitis: be aware of the ambiguous features and look for the pivotal ones. J Pancreas. 2010;11(1):78–84.Google Scholar
  45. 45.
    Fusaroli P, Saftoiu A, Mancino MG, Caletti G, Eloubeidi MA. Techniques of image enhancement in EUS (with videos). Gastrointest Endosc. 2011;74:645–55.CrossRefGoogle Scholar
  46. 46.
    Dietrich CF, Hirche TO, Ott M, Ignee A. Real-time tissue elastography in the diagnosis of autoimmune pancreatitis. Endoscopy. 2009;41:718–20.CrossRefGoogle Scholar
  47. 47.
    Levy MJ, Reddy RP, Wiersema MJ, Smyrk TC, Clain JE, Harewood GC, et al. EUS-guided trucut biopsy in establishing autoimmune pancreatitis as the cause of obstructive jaundice. Gastrointest Endosc. 2005;61:467–72.CrossRefGoogle Scholar
  48. 48.
    Koyama R, Imamura T, Okuda C, Sakamoto N, Honjo H, Takeuchi K. Ultrasonographic imaging of bile duct lesions in autoimmune pancreatitis. Pancreas. 2008;37:259.CrossRefGoogle Scholar
  49. 49.
    Okano N, Igarashi Y, Kishimoto Y, Ito K, Sasai D. Case of immunoglobulin G4-related cholangitis accompanying autoimmune pancreatitis: diagnosis by peroral cholangioscopy and treatment by endoscopic biliary stenting. Dig Endosc. 2012;24(Suppl 1):62–6.CrossRefGoogle Scholar
  50. 50.
    Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181–92.CrossRefGoogle Scholar
  51. 51.
    Cheuk W, Chan JKC. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol. 2010;17:303–32.CrossRefGoogle Scholar
  52. 52.
    Kubota K, Kato S, Watanabe S, Fujita K, Yoneda M, Takahashi H, et al. Usefulness of endoscopic biopsy using FOXP3+ Treg up-regulation in the duodenal papilla in the differential diagnosis between autoimmune pancreatitis and pancreatic cancer. J Hepato-Biliary-Pancreat Sci. 2011;18:414–21.CrossRefGoogle Scholar
  53. 53.
    Nakazawa T, Ohara H, Sano H, Ando T, Joh T. Schematic classification of sclerosing cholangitis with autoimmune pancreatitis by cholangiography. Pancreas. 2006;32:229.CrossRefGoogle Scholar
  54. 54.
    Ohara H, Okazaki K, Tsubouchi H, Inui K, Kawa S, Kamisawa T, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepato-Biliary-Pancreat Sci. 2012;19:536–42.CrossRefGoogle Scholar
  55. 55.
    Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Zhang L, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006;4:1010–1016; quiz 934.CrossRefGoogle Scholar
  56. 56.
    Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40:352–8.CrossRefGoogle Scholar
  57. 57.
    Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, et al. International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol. 2015;67:1688–99.CrossRefGoogle Scholar
  58. 58.
    Hirano K, Tada M, Isayama H, Yagioka H, Sasaki T, Kogure H, et al. Long-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment. Gut. 2007;56:1719–24.CrossRefGoogle Scholar
  59. 59.
    Shimizu Y, Yamamoto M, Naishiro Y, Sudoh G, Ishigami K, Yajima H, et al. Necessity of early intervention for IgG4-related disease-delayed treatment induces fibrosis progression. Rheumatology (Oxford). 2013;52:679–83.CrossRefGoogle Scholar
  60. 60.
    Kamisawa T, Okazaki K, Kawa S, Ito T, Inui K, Irie H, et al. Amendment of the Japanese consensus guidelines for autoimmune pancreatitis, 2013 III. Treatment and prognosis of autoimmune pancreatitis. J Gastroenterol. 2014;49:961–70.CrossRefGoogle Scholar
  61. 61.
    Ebbo M, Daniel L, Pavic M, Sève P, Hamidou M, Andres E, et al. IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry. Medicine (Baltimore). 2012;91:49–56.CrossRefGoogle Scholar
  62. 62.
    Bosco JJ, Suan D, Varikatt W, Lin MW. Extra-pancreatic manifestations of IgG4-related systemic disease: a single-centre experience of treatment with combined immunosuppression. Intern Med J. 2013;43:417–23.CrossRefGoogle Scholar
  63. 63.
    Buechter M, Klein CG, Kloeters C, Schlaak JF, Canbay A, Gerken G, et al. Tacrolimus as a reasonable alternative in a patient with steroid-dependent and thiopurine-refractory autoimmune pancreatitis with IgG4-associated cholangitis. Z Gastroenterol. 2014;52:564–8.CrossRefGoogle Scholar
  64. 64.
    Carruthers MN, Topazian MD, Khosroshahi A, Witzig TE, Wallace ZS, Hart PA, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis. 2015;74:1171–7.CrossRefGoogle Scholar
  65. 65.
    Hart PA, Topazian MD, Witzig TE, Clain JE, Gleeson FC, Klebig RR, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. Gut. 2013;62:1607–15.CrossRefGoogle Scholar
  66. 66.
    Yoo JJ, Park JJ, Kang EH, Lee EB, Song YW, Go HJ, et al. Risk factors for the recurrence of IgG4-related Sclerosing disease without autoimmune pancreatitis. J Clin Rheumatol. 2011;17:392–4.CrossRefGoogle Scholar
  67. 67.
    Mattoo H, Della-Torre E, Mahajan VS, Stone JH, Pillai S. Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy. Allergy. 2014;69:399–402.CrossRefGoogle Scholar
  68. 68.
    Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, Nakanuma Y. Th2 and regulatory immune reactions are increased in immunoglobulin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007;45:1538–46.CrossRefGoogle Scholar
  69. 69.
    Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23:57–66.CrossRefGoogle Scholar
  70. 70.
    Deshpande V. IgG4-related disease of the gastrointestinal tract: a 21st century chameleon. Arch Pathol Lab Med. 2015;139:742–9.CrossRefGoogle Scholar
  71. 71.
    Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol. 2004;28:1193–203.CrossRefGoogle Scholar
  72. 72.
    Ohara H, Okazaki K, Tsubouchi H, Inui K, Kawa S, Kamisawa T, Research Committee of IgG4-related Diseases, Research Committee of Intractable Diseases of Liver and Biliary Tract, Ministry of Health, Labor and Welfare, Japan, Japan Biliary Association, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepatobiliary Pancreat Sci. 2012;19:536–42.CrossRefGoogle Scholar

Copyright information

© Indian Association of Surgical Gastroenterology 2019

Authors and Affiliations

  • Jimil Shah
    • 1
  • Usha Dutta
    • 1
  1. 1.Department of GastroenterologyP.G.I.M.E.RChandigarhIndia

Personalised recommendations