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Dig Dis 2012;30:220–223 DOI: 10.1159/000336708

Extraintestinal Manifestations of Autoimmune Pancreatitis

Tomica Milosavljevic a Mirjana Kostic-Milosavljevic b Ivan Jovanovic a

Miodrag Krstic a

a Faculty of Medicine, University of Belgrade, and b Gastroenterology and Hepatology Clinic, Clinical Centerof Serbia, Belgrade , Serbia

matory pseudotumors of the liver, breast, mediastinum, or-bit, and aorta, and it has been observed with hypophysitis and IgG4-associated prostatitis. Abundant IgG4+ plasma cells were also confirmed in Riedel thyroiditis, sclerosing mesenteritis, and inflammatory pseudotumor of the orbit and stomach. Ex trapancreatic lesions could be synchronous-ly or metachronously diagnosed with AIP, sharing the same pathological conditions, showing also a favorable result to corticosteroid therapy and distinct differentiation between IgG4-related diseases from the inherent lesions of the cor-responding organs. Copyright © 2012 S. Karger AG, Basel

The term autoimmune pancreatitis (AIP) was first used in Japan in 1995 to describe a newly recognized form of chronic pancreatitis, after the description of Yoshida and colleagues. But in 1961, Sarles first described a form of idiopathic chronic inflammatory sclerosis of the pan-creas suspected to be due to an autoimmune process. In 1975, Waldram’s group reported 2 siblings with chronic pancreatitis, sclerosis cholangitis and sicca syndrome. In 1978, Nakano and colleagues first reported that steroid could be beneficial. After the description of Toki and col-leagues of 4 patients with lymphocytic infiltration of the pancreas in 1992, in 1995, finally Yoshida’s group first described AIP [1–3] .

Key Words

Autoimmune pancreatitis � Extrapancreatic manifestations � IgG4-positive cells

Abstract

The term autoimmune pancreatitis (AIP) was first used in Ja-pan in 1995 to describe a newly recognized form of chronic pancreatitis, after the description of Yoshida and colleagues. But Sarles in 1961, first described a form of idiopathic chron-ic inflammatory sclerosis of the pancreas, suspected to be due to an autoimmune process. AIP has become a widely accepted term because clinical, serologic, histologic, and immunohistochemical findings suggest an autoimmune mechanism. Most affected patients have hypergammaglob-ulinemia and increased serum levels of IgG, particularly IgG4. Recently published International Consensus Diagnos-tic Criteria for Autoimmune Pancreatitis include Guidelines of the International Association of Pancreatology, classifying AIP into types 1 and 2, using five cardinal features of AIP, namely imaging of pancreatic parenchyma and duct, serol-ogy, other organ involvement, pancreatic histology, and an optional criterion of response to steroid therapy. Extrapan-creatic presentations can include sclerosing cholangitis, ret-roperitoneal fibrosis, sclerosing sialadenitis (Küttner tumor), lymphadenopathy, nephritis, and interstitial pneumonia. In-creased IgG4+ plasma cell infiltrate has been reported in sclerosing lesions from other organ sites, including inflam-

Prof. Dr. Tomica Milosavljevic Clinical Center of Serbia, Gastroenterology and Hepatology Clinic Dr. Koste Todorovica 2 RS–11000 Beograd (Serbia) E-Mail tommilos   @   hotmail.com

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Extraintestinal Manifestations of Autoimmune Pancreatitis

Dig Dis 2012;30:220–223 221

AIP has become a widely accepted term because clin-ical, serologic, histologic, and immunohistochemical findings suggest an autoimmune mechanism. Most af-fected patients have hypergammaglobulinemia and in-creased serum levels of IgG, particularly IgG4. Patients may also have autoantibodies directed against lactofer-rin, carbonic anhydrase II and IV, rheumatoid factor, smooth muscle antigens, and nuclear antigens [4–6] .

Many diagnostic criteria have been proposed in the past for AIP, namely the Japanese guidelines, the Korean criteria, the Asian consensus criteria, the Italian criteria, and the Mayo Clinic HISORt (Histology, Imaging, Serol-ogy, Other organ involvement, and Response to steroids) criteria [7, 8] .

The studies from the United States and Europe report-ed differences in the prevalence of other autoimmune diseases and immunological serum abnormalities, in comparison with Eastern series. Two distinct clinical and histological patterns have been recently recognized: type 1 fits the classical description of the disease as lympho-plasmacytic sclerosing pancreatitis rich in IgG4-positive cells, and type 2 is defined by granulocyte epithelial le-sion called ‘idiopathic duct-centric pancreatitis’ with few IgG4-positive cells [9, 10] .

Type 1 AIP group included patients who fulfilled the HISORt criteria, as defined by the Mayo Clinic in 2006. Three groups (A, B, and C) of patients were defined ac-cording to the HISORt criteria. Group A was defined by pancreatic histology – obtained by the pathological anal-ysis of resection specimen or endoscopic ultrasonogra-phy-fine needle aspiration – showing the full spectrum of changes of lymphoplasmacytic sclerosing pancreatitis, i.e. periductal lymphoplasmacytic infiltrate with obliter-ative phlebitis and storiform fibrosis, or 6 10 IgG4-posi-tive cells per high-power field on IgG4 immunostaining together with lymphoplasmacytic infiltrate. Group B was defined by characteristic imaging (computed tomogra-phy scan or magnetic resonance imaging scan showing diffusely enlarged pancreas with delayed and ‘rim’ en-hancement, pancreatogram showing diffusely irregular pancreatic duct) and serology (elevated serum IgG4 lev-els). Group C was defined by unexplained pancreatic dis-ease, elevated serum IgG4 levels and/or other organ in-volvement (confirmed by the presence of abundant IgG4-positive cell), and resolution/marked improvement in pancreatic and/or extrapancreatic manifestations with steroid therapy. Patients with AIP had extensive IgG4+ plasma cell infiltrate in other organs, including peri-pancreatic tissue, bile duct, gallbladder, portal area of the liver, gastric mucosa, colonic mucosa, salivary glands,

lymph nodes, and bone marrow. IgG4-related systemic disease (ISD) is defined as a syndrome characterized by elevated serum IgG4 levels, prominent lymphoplasma-cytic infiltrates with increased IgG4+ plasma cells, and dense sclerosis. The fibrosis associated with ISD may damage and even partially destroy an affected organ, but the inflammatory process typically responds to cortico-steroid therapy. Although the pancreas is the most com-monly affected organ, the presence of AIP is not essential in this systemic disease [9, 10] .

Definitive/probable type 2 AIP included patients with either histologically confirmed idiopathic duct centritis AIP (‘definitive’) or unexplained pancreatic disease, sug-gestive imaging (as defined above), normal serum IgG4 levels, and response to steroids (‘probable’). Response to steroid therapy was added as a diagnostic criterion for the type 2 AIP group, by analogy with group C in the HISORt classification. AIP is frequently associated with various extrapancreatic lesions ( table 1 ). The frequency and dis-tribution of extrapancreatic lesions preceding or subse-quent to AIP are unknown. A new clinicopathologic con-cept of ISD has been proposed. It has also been proposed to extend the IgG4-related sclerosing disease complex to

Table 1. Extrapancreatic lesions in autoimmune pancreatitis

Case association Lachrymal gland inflammation (14–39%)SialadenitisHilar lymphadenopathyInterstitial pneumonitis (8–13%)Sclerosing cholangitisRetroperitoneal fibrosisRenal involvement (35%)

Renal parenchyma (30%)Perirenal, renal sinuses, renal pelvis (13%)

Possible association HypophysitisAutoimmune neurosensory hearing lossUveitisChronic thyroiditisPseudotumor (breast, lung, liver)Gastric ulcerSwelling of papilla of VaterIgG4 hepatopathyAortitisProstatitisHenoch-Schönlein purpuraAutoimmune thrombocytopenia

Modified from Kawa et al. [2].

Milosavljevic/Kostic-Milosavljevic/Jovanovic/Krstic

Dig Dis 2012;30:220–223222

another clinical entity – IgG4-positive multiorgan lym-phoproliferative syndrome, which includes inflammato-ry pseudotumors (liver, breast, lungs).

Recently published International Consensus Diagnos-tic Criteria (ICDC) for Autoimmune Pancreatitis include Guidelines of the International Association of Pancre-atology [10] , classifying AIP into types 1 and 2, using five cardinal features of AIP, namely imaging of pancreatic parenchyma and duct, serology, other organ involve-ment, pancreatic histology, and an optional criterion of response to steroid therapy. Each feature was categorized into level 1 and 2 findings depending on the diagnostic reliability. The goals of ICDC for AIP were to develop cri-teria that can be applied worldwide, taking into consid-eration marked differences in clinical practice patterns, to safely diagnose AIP and avoid misdiagnosis of pancre-atic cancer as AIP. The diagnosis can be definitive or probable, and in some cases the distinction between sub-types 1 and 2 may not be possible.

Extrapancreatic presentations can include sclerosing cholangitis, retroperitoneal fibrosis, sclerosing sialadeni-tis (Küttner tumor), lymphadenopathy, nephritis, and in-terstitial pneumonia ( tables 2, 3 ). Increased IgG4+ plasma cell infiltrate has been reported in sclerosing lesions from other organ sites, including inflammatory pseudotumors of liver, breast, mediastinum, orbit, and aorta, and it has been observed with hypophysitis and IgG4-associated prostatitis. Abundant IgG4+ plasma cells were also con-firmed in Riedel thyroiditis, sclerosing mesenteritis, and inflammatory pseudotumor of the orbit and stomach.

The biliary tract is the most commonly involved ex-trapancreatic site in ISD with AIP. Several case series have described the association between AIP and biliary stric-tures. The overall rate of extrahepatic bile duct involve-ment in AIP is 71–100%. Although serum IgG4 elevation is characteristic of IAC, it is not a pathognomonic find-ing. The specificity and positive predictive value of ele-vated serum IgG4 levels for IAC are unknown.

Liver dysfunction is frequently observed in patients with AIP. It can be due either to extrahepatic obstructive lesions or to inflammatory liver injury. Another aspect of liver involvement in ISD is hepatic inflammatory pseu-dotumor. Gallbladders are frequently affected in AIP; they are characterized by a diffuse, acalculous inflamma-tion.

Salivary and lacrimal glands are frequently involved in ISD. Küttner tumor is a chronic, sclerosing sialadenitis that presents with asymmetric, firm swelling of the sub-mandibular glands. Mikulicz disease is an idiopathic, bi-lateral, painless, and symmetric swelling of the lacrimal,

parotid, and submandibular glands. Microscopically, tis-sues show marked lymphoplasmacytic infiltration, with lymphoid follicles surrounding solid epithelial nests (epi-myoepithelial islands), stromal fibrosis, acinar atrophy and destruction, and lymphoepithelial lesions.

Renal lesions in ISD usually present as tubulointersti-tial nephritis. Clinically, patients can present with renal insufficiency, vasculitis, or a ‘renal mass’. Retroperitone-al fibrosis is a disease characterized by the proliferation of fibrous tissue in the retroperitoneum (specifically, marked lymphoplasmacytic infiltrations encompassed by a dense fibrosis). The lesions show active and chronic

Table 2. S ubtypes of AIP and other organ involvement

Type 1 Type 2

Other organ involvement Unrelated to other organ involvementSclerosing cholangitisSclerosing sialadenitisRetroperitoneal fibrosisOthers

IBD – rare IBD – oftenSteroids: responsive Steroids: responsiveRelapse: high rate Relapse: rare

M odified from Kawa et al. [2].

Table 3. O ther organ involvement

Level 1 Histology of extrapancreatic organs, any three of the following:� Marked lymphoplasma infiltration with fibrosis and without

granulocytic infiltration� Storiform fibrosis� Obliterative phlebitis� Abundant (>10 cells/hpf) IgG4-positive cellsTypical radiological evidence, at least one of the following:� Segmental/multiple proximal (hilar/intrahepatic) or proximal

and distal bile duct strictures� Retroperitoneal fibrosis

Level 2 Histology of extrapancreatic organs, including endoscopicbiopsies of bile duct – both of the following:� Marked lymphoplasma infiltration without granulocytic

infiltration� Abundant (>10 cells/hpf) IgG4-positive cellsPhysical or radiological evidence, at least one of the following:� Symmetrically enlarged salivary/lachrymal glands� Radiological evidence of renal involvement described in

association with AIP

Extraintestinal Manifestations of Autoimmune Pancreatitis

Dig Dis 2012;30:220–223 223

inflammatory infiltration and sclerosis, and lymphoid follicles with germinal centers are also present.

Pulmonary involvement in ISD can present as inter-stitial pneumonia or as an inflammatory pseudotumor. Concomitant lymphadenopathy is common in ISD.

Recognition of the diagnostic features on the images of various involved organs will assist in the diagnosis of AIP and in differential diagnoses between AIP-associat-ed extrapancreatic lesions and lesions due to other pa-thologies.

Extrapancreatic lesions could be synchronously or metachronously diagnosed with AIP, sharing the same

pathological conditions, showing also a favorable re-sponse to corticosteroid therapy and distinct differentia-tion between IgG4-related diseases from the inherent le-sions of the corresponding organs.

Acknowledgement

The article was partly supported by The Ministry of Science, Education and Technology of Serbia, No. 41004.

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