1 LEADING ARTICLE Autoimmune related pancreatitis Gut: first published as 10.1136/gut.51.1.1 on 1 July 2002. Downloaded from K Okazaki, T Chiba ............................................................................................................................. Gut 2002;51:1–4 Since the first documented case of a particular form of (i) increased levels of serum gammaglobulin or pancreatitis with hypergammaglobulinaemia, similar IgG; cases have been reported, leading to the concept of an (ii) presence of autoantibodies; autoimmune related pancreatitis or so-called (iii) diffuse enlargement of the pancreas; “autoimmune pancreatitis”. Although it has not yet been (iv) diffusely irregular narrowing of the main pancreatic duct and occasionally stenosis of the widely accepted as a new clinical entity, the present intrapancreatic bile duct on endoscopic retro- article discusses the recent concept of autoimmune grade cholangiopancreatographic (ERCP) im- pancreatitis. ages; .......................................................................... (v) fibrotic changes with lymphocyte infiltration; (vi) no symptoms or only mild symptoms, usually SUMMARY without acute attacks of pancreatitis; Since Sarles et al reported a case of particular (vii) rare pancreatic calcification or cysts; pancreatitis with hypergammaglobulinaemia, (viii) occasional association with other auto- similar cases have been noted, which has led to immune diseases; and the concept of an autoimmune related pancreati- tis or so-called “autoimmune pancreatitis”. The (ix) effective steroid therapy. clinical characteristics are: (i) increased levels of Other nomenclatures such as “chronic inflam- serum gammaglobulin or IgG; (ii) presence of matory sclerosis of the pancreas”,1 “sclerosing autoantibodies; (iii) diffuse enlargement of the pancreatitis”,15 “pancreatitis showing the narrow- pancreas; (iv) diffusely irregular narrowing im- ing appearance of the pancreatic duct (PNPD)”,16 ages of the main pancreatic duct; (v) fibrotic and “sclerosing pancreatocholangitis”14 have also http://gut.bmj.com/ changes with lymphocyte infiltration; (vi) no or been proposed. However, cases without evidence only mild symptoms; (vii) rare pancreatic calcifi- of autoimmunity should be classified as a cation or pancreatic cysts; (viii) occasional associ- different entity from AIP,even if steroid therapy is ation with other autoimmune diseases; and (ix) effective. effective steroid therapy. In addition to various systemic autoimmune diseases, diabetes mellitus Primary and secondary AIP or bile duct lesions responsive to steroid therapy Recently, cases of primary (or isolated) AIP with- are often observed. Further studies are needed to on September 26, 2021 by guest. Protected copyright. out other autoimmune diseases have been re- clarify the pathogenesis. ported. In contrast, occasional coexistence of INTRODUCTION pancreatitis with other systemic exocrinopathy has led to the concept of “a complex syndrome”,2 Since Sarles et al observed a case of particular “dry gland syndrome”,3 or “autoimmune exocrin- pancreatitis with hypergammaglobulinaemia,1 opathy.” The most commonly associated auto- occasional coexistence of pancreatitis with other immune disease is SjS.10–13 18 In addition, PSC, autoimmune diseases such as Sjögren’s syndrome ulcerative colitis, or systemic lupus erythemato- (SjS),2 primary sclerosing cholangitis (PSC),3 or sus was sometimes observed.17 18 However, it is primary biliary cirrhosis (PBC),3 has been re- still unclear whether or not the pathogenetic ported. These findings support the hypothesis mechanism of secondary (or syndromic) AIP with that an autoimmune mechanism may be involved other autoimmune diseases is different from pri- in the pathogenesis and pathophysiology in some mary AIP.13 17 It was noted that there is a patients with pancreatitis.4–14 Recently, similar possibility of developing systemic autoimmune cases without systemic autoimmune diseases diseases in patients previously diagnosed as hav- have been reported, which has led to the concept See end of article for ing primary AIP.13 17 authors’ affiliations of an autoimmune related pancreatitis,13 so called ....................... “autoimmune pancreatitis (AIP)”.5 Although it Correspondence to: has not yet been widely accepted as a new clinical ................................................. Dr K Okazaki, Department entity, the present article discusses the recent of Gastroenterology and concept of AIP. Abbreviations: ACA-II, anticarbonic anhydrase II Endoscopic Medicine, antibody; AIP, autoimmune related pancreatitis; ALF, Kyoto University Hospital, antilactoferrin antibody; ANA, antinuclear antibody; CA-II, Shogoin-Kawaracho, DEFINITION AND CONCEPT OF AIP carbonic anhydrase-II; ERCP, endoscopic retrograde Sakyo, Kyoto, 606-8507, Although the pathogenesis and pathophysiology Japan; okak@ of AIP are still unclear, clinical aspects have been cholangiopancreatography; IL, interleukin; LF, lactoferrin; kuhp.kyoto-u.ac.jp 4–14 PBC, primary biliary cirrhosis; PNPD, pancreatitis showing reported. The characteristic findings in most the narrowing appearance of the pancreatic duct; PSC, Accepted for publication cases of AIP can be summarised as follows (table primary sclerosing cholangitis; RF, rheumatoid factor; SjS, ....................... 1): Sjögren’s syndrome. www.gutjnl.com 2 Okazaki, Chiba Table 1 Characteristic findings of autoimmune pancreatitis • Increased levels of serum gammaglobulin or IgG • Presence of autoantibodies • Diffuse enlargement of the pancreas Gut: first published as 10.1136/gut.51.1.1 on 1 July 2002. Downloaded from • Diffusely irregular narrowing of the main pancreatic duct on ERCP images • Fibrotic changes with lymphocyte infiltration • No symptoms or only mild symptoms, usually without acute attacks of pancreatitis • Rare pancreatic calcification or pancreatic cysts • Occasional association with other autoimmune diseases • Effective steroid therapy • Association with diabetes mellitus often improved by steroid therapy ERCP, endoscopic retrograde cholangiopancreatography. EPIDEMIOLOGY OF AIP may be involved in inflammation. CD4+ T cells are further AIP is a rare disorder, although the exact prevalence is still subdivided into Th1 and Th2 cells based on profiles of cytokine unknown. More than 150 cases have been reported as AIP or production.12 Thl cells, which produce interleukin (IL)-2, PNPD in the Japanese literature.5–10 12 18 We identified 21 cases tumour necrosis factor α, and interferon γ, mediate cellular of AIP among our total of 451 patients with chronic immunity, macrophage activation, cytotoxicity, and help in B pancreatitis.13 Although our study did not show different mor- cell production of opsonising and complement fixing bidities between the sexes, males were usually predominant in antibodies.12 Japan.12 13 18 Mean age at diagnosis was more than 55 years.12 13 18 “Th1 cytokines may be essential in the induction and/or maintenance of AIP while Th2 cytokines may be “AIP is a rare disorder, although the exact prevalence involved in disease progression” is still unknown” In contrast, Th2 cells, which produce IL-4, 5, 6, and 10, pro- Diabetes mellitus was observed in about half of AIP patients mote humoral and allergic responses.12 In SjS24 and PSC,25 the ∼ (43 68%) and the majority showed type 2 diabetes major infiltrating cells in the tissue are CD4+HLA-DR+ Th1, 13 18 19 mellitus. Although the exact morbidity of primary and although CD8+ and B cells are also present. In some cases of secondary AIP is unclear, more than half of the cases were of AIP, CD4+ Th1 cells are predominant over Th2 type cells.12 12 13 18 the primary type. Therefore, similar to SjS,24 Th1 cytokines may be essential in the induction and/or maintenance of AIP while Th2 cytokines http://gut.bmj.com/ PATHOPHYSIOLOGY OF AIP may be involved in disease progression, especially local B cell Humoral immunity and target antigens activation. An animal model of AIP,using neonatally thymec- Occasional coexistence of pancreatitis with other autoimmune tomised BALB/c mice immunised with CA-II or LF and trans- diseases suggests that there may be common target antigens ferred nude mice, showed that CD4+ Th1 cells are mainly in the pancreas and other exocrine organs, such as the salivary involved in the early development of murine AIP.26 glands, biliary tract, and renal tubules. Several autoantibodies such as antinuclear antibody (ANA), antilactoferrin (LF) antibody (ALF), anticarbonic anhydrase II (CA-II) antibody ASSOCIATED DISEASES on September 26, 2021 by guest. Protected copyright. (ACA-II), and rheumatoid factor (RF) were frequently 12 13 Biliary ductal lesions detected in patients with AIP. CA-II and LF are distributed Patients with AIP often show narrowing of the common bile in the cells of several exocrine organs, including the pancreas, 12 duct, mainly in the intrapancreatic area, which may result in salivary glands, biliary duct, and distal renal tubules. The dilatation of the upper biliary tract. The sclerosing changes of high prevalence of these antibodies suggests that CA-II and LF the extrapancreatic bile duct, similar to PSC, are reported as may be candidates for the target antigens in AIP. However, it “lymphoplasmacytic sclerosing pancreatitis with was found that these autoantibodies are not necessarily 15 14 12 cholangitis”, “sclerosing pancreatocholangitis”, or an “in- specific for AIP. Although the majority of diabetic patients flammatory pseudotumour from sclerosing cholangitis”.1 In with associated