Keywords

Autoimmunity; Pancreatitis; Steroids

Abbreviations

ACA-II: anti-carbonic anhydrase II antibody; AIP: autoimmunerelated pancreatitis; ALF: anti-lactoferrin antibody; AMA: anti-mitochondrial antibody; ANA: anti-nuclear antibody; ASMA: antismooth muscle antibody; BT-PABA: Nbenzoyl- L-tyrosyl-para-aminobenzoic acid; CA-II: carbonic anhydrase-II; CBD: common bile duct; DM: diabetes mellitus; ELISA: enzyme-linked immunosorbent assay; ERCP: endoscopic retrograde cholangiopancreatography; FDG: F-18 fluoro-2-deoxy- D-glucose; IDDM: insulin dependent diabetes mellitus; IFN-g: interferon-g; IL-4: interleukin-4; LF: lactoferrin; LPSP: lymphoplasmacytic sclerosing pancreatitis; mAb: monoclonal antibody; MRCP: magnetic resonance cholangio-pancreatography; NIDDM: not insulin dependent diabetes mellitus; nTx: neonatally thymectomized; PBC: primary biliary cirrhosis; PBL: peripheral blood lymphocyte; PET: positron emission tomography; PNPD: pancreatitis showing the narrowing appearance of the pancreatic duct; PSC: primary sclerosing cholangitis; RA: rheumatoid arthritis; RF: rheumatoid factor; SjS: Sjögren's syndrome

Introduction

Idiopathic pancreatitis, in which obvious causes are not detected, accounts for about 30-40% of cases of chronic pancreatitis [1]. Since Sarles et al. observed the first case of pancreatitis with hypergammaglobulinemia [2], the occasional coexistence of pancreatitis with other autoimmune diseases such as Sjögren's syndrome (SjS) [3], primary sclerosing cholangitis (PSC) [4, 5] or primary biliary cirrhosis (PBC) [4] has been reported. These findings support the hypothesis that an autoimmune mechanism may be involved in the pathogenesis and pathophysiology in some patients with pancreatitis [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17], which leads us to the concept of autoimmune-related pancreatitis [15], which is called "autoimmune pancreatitis" (AIP) [8]. Recently, the concept of AIP is thought to be acceptable as a new clinical entity due to its unique clinical and histological findings. Several hundred cases of AIP have been reported in the Japanese literature [5, 8, 9, 10, 11, 12, 13, 18, 19, 20]. We encountered 30 cases of AIP in a total of 620 cases of chronic pancreatitis (5%). Males are predominant and most patients were diagnosed at middle or advanced age (mean: 58 years). In this paper, we report recent etiopathological and clinical findings based on our experience.

Definition and Concept of AIP

Although the pathogenesis and pathophysiology of AIP are still unclear, clinical aspects have been accumulated [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. The characteristic findings in the most cases of AIP [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16] can be summarized as follows: i) increased levels of serum gammaglobulin or IgG; ii) the presence of autoantibodies; iii) diffuse enlargement of the pancreas; iv) diffusely irregular narrowing of the main pancreatic duct on endoscopic retrograde cholangio-pancreatography (ERCP) images; v) fibrotic changes with lymphocyte infiltration; vi) no symptoms or only mild symptoms, usually without acute attacks of pancreatitis; vii) rare pancreatic calcification; viii) rare pancreatic cysts; ix) occasional association with other lesions such as diabetes, sclerosing cholangitis similar to primary sclerosing cholangitis (PSC), sialoadenitis, interstitial nephritis and retroperitoneal fibrosis, and x) effective steroid therapy (Table 1). Recently, “Diagnostic Criteria for Autoimmune Pancreatitis 2002” containing three criteria, pancreatic imaging, laboratory data, and histopathological findings has been proposed by the Japan Pancreas Society (Table 2) [3]. The occasional coexistence of pancreatitis with other systemic exocrinopathies, bile ductal lesions, and diabetes mellitus (DM) have led to the concept of "a complex syndrome" [4], "dry gland syndrome" [5] and "autoimmune exocrinopathy”. Other names such as "chronic inflammatory sclerosis of the pancreas", "lymphoplasmacytic sclerosing pancreatitis" (LPSP), "pancreatitis showing the narrowing appearance of the pancreatic duct" (PNPD), "pseudotumor of the pancreas", "tumefactive chronic pancreatitis", and "IgG4 related autoimmune disease" have been proposed for cases similar to AIP [18, 19]. Recently, histological findings such as LPSP are thought to be extremely similar to AIP [18].

Associated Lesions (Table 3)

Patients with AIP often show bile duct lesions such as intra-pancreatic stenosis or a sclerotic appearance of the extra-pancreatic bile duct similar to PSC. Unlike PSC, biliary lesions in AIP usually improve by administering steroids, which suggests that the mechanism of the development of biliary lesions in AIP may be different from typical PSC. DM is often (43-68%) observed in AIP and the majority of patients have type II DM; some improve after steroid therapy. Although the mechanism is obscure, cytokines from T cells and macrophages suppressing the function of islet beta-cells may be down-regulated by steroids. Eleven of our 30 cases did not have any other lesions, while 19 patients with AIP had one or more associated lesions. Fifteen patients (50%) had diabetes, 8 sclerosing cholangitis (27%), 6 rheumatoid arthritis (23%), 5 sialoadenitis (17%), 3 renal dysfunction (10%), and 3 retroperitoneal fibrosis (10%). It has been noted that there is a possibility of development of other complications even in the patients diagnosed as having only pancreatitis [10].

Histopathology

Microscopic findings in AIP are consistent with lymphoplasmacytic sclerosing pancreatitis as previously reported by Kawaguchi et al. [6]: i) diffuse lymphoplasmacytic infiltration with pronounced acinar atrophy; ii) marked fibrosis of the contiguous soft tissue as well as the total pancreas similar to retroperitoneal fibrosis; iii) obliterated phlebitis in and around the pancreas involving the portal vein; iv) inflammatory wall thickness of the common bile duct (CBD) and gallbladder; and v) the minor salivary gland in the lip biopsy having inflammation similar to the pancreatic lesion or Sjögren's syndrome. In addition to these findings, in AIP, T-cells, which are usually HLA-DR+ CD4+ or HLADR+ CD8+ cells, predominantly infiltrate around the pancreatic duct over B cells (Figure 1) [10]. Although the mechanism is still unclear, the histological differences between lymphoplasmacyte and T cell dominance may suggest the different stages of the diseases.

Figure 1. Immunohistochemistry of the pancreas in autoimmune pancreatitis. Immunohistochemistry showed T-cells mainly infiltrated around the pancreatic duct (x 250). a. pan T cells (pancreatic duct); b. pan B cell (pancreatic duct); c. pan T cell (intra-pancreatic bile duct); d. pan B cell (intra-pancreatic bile duct).

Clinical Symptoms

Patients with AIP usually have no or only slight discomfort in the epigastrium or back, and symptoms related to other associated diseases [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. The clinical symptoms are different from those in the cases of acute or severe pancreatitis. In our 30 patients, 19 patients had jaundice (63%), 8 had abdominal pain (27%), and 6 had back pain (20%). Obstructive jaundice due to the stenosis of the CBD or sclerosing cholangitis is characteristic in AIP as compared to other types of pancreatitis. Steroid therapy is usually effective for stenosis of the bile duct associated with AIP and improves clinical and laboratory findings [9, 10, 11, 12, 13].

Pancreatic and Biliary Imaging

Computed tomography (CT), magnetic resonance imaging (MRI) or ultrasonography (US) show the diffusely enlarged pancreas with its so called "sausage-like" appearance (Figure 2), and a capsule-like rim which appears to have low density on CT and to be hypo-intense on T2-weighted MR images, and shows delayed enhancement on dynamic MR imaging [20, 21]. Pancreatic calcification or pseudocyst is seldom observed. F-18 fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) shows accumulative signals in the pancreatic lesions similar to the imaging of pancreatic cancer [22]. ERCP images in the AIP patients show segmental or diffuse narrowing of the main pancreatic duct (Figure 3) [9, 10, 11, 12, 13, 14]. On the other hand, the pancreas often shows atrophic changes after steroid treatment. This may be due to the improvement of pancreatic edema with acinar atrophy. Although magnetic resonance cholangio-pancreatography (MRCP) does not adequately show the narrowing or stenosis of the pancreatic duct, it can well demonstrate images of the CBD. Patients with AIP often show stenosis of the intra-pancreatic CBD resulting in dilatation of the upper-stream and. the sclerosing stenosis of the extra-pancreatic CBD similar to primary sclerosing cholangitis (PSC) [14]. Steroid therapy in AIP is usually effective for the stenosis of CBD as well as the pancreatic duct [13, 14], while it is not very effective for classic PSC [23]. These findings suggest that the stenotic mechanism of CBD in AIP may be different from that in classic PSC.

Figure 2. Computed tomography of the pancreas. The CT image shows the diffusely enlarged pancreas with its so-called "sausage-like" appearance before treatment.

Figure 3. ERCP images of autoimmune pancreatitis and effects of steroid therapy. Both the narrowing main pancreatic duct and intra-pancreatic common bile duct improved one month after steroid therapy.

Laboratory Data (Figures 4 and 5)

Patients with AIP usually show increased pancreatic enzymes, gamma-globulin, IgG especially the IgG4 subtype [24], several autoantibodies such as antinuclear antibody (ANA), anti-lactoferrin antibody (ALF), anticarbonic anhydrase-II antibody (ACA-II), rheumatoid factor and anti-smooth muscle antibody [25]. Patients with jaundice or stenosis of the CBD show abnormal levels of serum bilirubin and hepatobiliary enzymes. In these cases, other liver diseases such as viral hepatitis, autoimmune hepatitis or PBC should be differentiated from AIP. The laboratory data of our 30 cases showed an increase in serum hepatic, biliary and pancreatic enzymes, and total bilirubin in 22 (73%), 25 (83%), 19 (63%) and 16 (53%) patients, respectively. The pancreatic exocrine function was slightly or moderately abnormal. Seventeen of our 30 patients showed hypofunction (58%) using an N-benzoyl-Ltyrosyl- para-aminobenzoic acid (BT-PABA) exocrine test. Most cases of diabetes mellitus were type II, not insulin dependent (NIDDM) but not type Ia, insulin dependent (IDDM) [26, 27]. After steroid therapy, many abnormal laboratory findings were reversible and many cases of DM were brought under control using steroid therapy [10, 11, 12, 13, 14, 26, 27].

Figure 4. Laboratory data in 30 patients with autoimmune pancreatitis. The laboratory data of our 30 cases showed the increase of serum hepatic, biliary and pancreatic enzymes, and total bilirubin in 22 (73%), 25 (83%), 19 (63%) and 16 (53%) patients, respectively. Seventeen of our 30 patients showed hypofunction (58%) by N-benzoyl-L-tyrosyl-para-aminobenzoic acid (BT-PABA) exocrine test.

Figure 5. Autoantibodies in 30 patients with autoimmune pancreatitis. Of 30 patients, ANA was detected in 75%,, ALF in 75%, ACA-II in 55%, RF in 25% and ASMA in 15%. However, AMA was absent in all cases.

Pathophysiology of AIP

Humoral Immunity and Target Antigens

The occasional coexistence of pancreatitis with other lesions suggests that there may be common target antigens in the pancreas and other exocrine organs such as the salivary gland, biliary tract and renal tubules. We identified several autoantibodies such as antinuclear antibody (ANA), anti-lactoferrin (LF) antibody (ALF), and anti-carbonic anhydrase-II (CA-II) antibody (ACA-II) by using the patient’s serum and expression vector encoding human pancreatic cDNA [25]. Lactoferrin and CA-II are distributed in the various human tissues, including the lactating breast, bronchial, salivary and gastric glands, the pancreas and renal tubules [28]. We used animal models of autoimmune pancreatitis along with sialoadenitis and cholangitis using neonatally thymectomized (nTx) mice immunized with LF or CA-II and nude mice transferred with lymphocytes prepared from nTx mice [29]. The high prevalence of these auto-antibodies in animal models suggest that CA-II and LF may be the candidates for target antigens in AIP. However, it is noted that these antibodies are not necessarily specific for AIP because ACA-II can be detected in some patients with SjS or systemic lupus erythematosus [30], and ALF in ulcerative colitis or PSC [31].

Although the majority of patients with AIP show increased levels of IgG, especially the IgG4 subtype [24], the roles of IgG4 in AIP are still unclear. The majority of cases of diabetes mellitus associated with AIP show type II diabetes, while 10% of patients with diabetes mellitus show autoimmune diabetes (type Ia) due to the presence of autoantibodies against glutamic acid decarboxylase, insulin, or tyrosine phosphatase-like protein [13]. Interestingly, anti-CA-II and anti-LF are often observed in type I diabetes.

Cellular Immunity and Effector Cells

The role of the effector cells in AIP has been poorly understood. The activated CD4+ and CD8+ T-cells bearing HLA-DR and CD45RO were elevated in the peripheral blood lymphocytes (PBLs) as well as in the pancreas in AIP as compared to other causes of pancreatitis such as alcoholic or gallstonerelated pancreatitis [10, 25]. CD4+ T-cells are further subdivided into Th1 and Th2 cells based on profiles of cytokine production, and these two T-cell populations counterregulate each other [32]. Thl cells, which produce IL- 2, tumor necrosis factor (TNF)-a and IFN-g, mediate cellular immunity, macrophage activation, cytotoxicity and facilitate B cell production of opsonizing and complementfixing antibodies. In contrast, Th2 cells, which produce IL-4, 5, 6 and 10, promote humoral and allergic responses [32]. Similar to SjS or PSC, CD4+ T-cells showing the Th1 type of immune response are predominantly involved in the development of AIP as effector cells over Th2 type CD4+ T-cells [24]. Similarly, Th1 immune response is involved in the development of pancreatitis and sialoadenitis in animal models. In some patients with AIP, HLA-DR antigens are expressed on the pancreatic duct cells as well as CD4+ T-cells [10, 31, 32]. However, there is also a possibility that CD8+ T-cells may be effector cells, because HLA-DR+CD8+ Tcells as well as CD4+ T-cells increased in PBLs and infiltrated the pancreas in patients with AIP [25].

Treatment and Prognosis

In AIP patients with mild symptoms, the usual treatment for acute pancreatitis such as fasting, protease inhibitors and antibiotics is not necessarily required. In cases of jaundice, percutaneous transhepatic or endoscopic retrograde biliary drainage is often needed, especially with the complication of bacterial infection. Steroid therapy is usually effective for bile duct and salivary lesions as well as pancreatic duct lesions [9, 10, 11, 12, 13, 14, 18]. It has been noted that some patients may spontaneously improve without any treatment [14]. Some patients associated with type II diabetes mellitus may improve after steroid therapy [13]. In the cases of bile duct lesions without response to steroid therapy, surgery is often necessary in order to differentiate them from a malignancy as well as for relieving the symptoms [14]. Twenty-one of our 30 patients were treated successfully with prednisolone, two with pancreatectomy, and four without medication. The long-term prognosis of AIP is unknown. As the clinical and laboratory findings of most cases are reversible after steroid therapy [13, 14, 28], the prognosis of AIP may depend on the severity of the complications such as other autoimmune diseases or diabetes mellitus.

Conclusion

In summary, recent studies support the concept of autoimmune pancreatitis, which appears to be a unique clinical entity. Histopathologically, AIP is similar to LPSP showing fibrosis, infiltration of lymphocytes and plasmacytes, and obliterative phlebitis in the pancreas; major lymphocytes infiltrating around the pancreatic duct are T cells. Although the pathogenesis of AIP is still unknown, several hypotheses have been proposed from the clinical and animal experimental aspects. The first step in the disease may be an antigenic alteration at the pancreatic duct or acinar cells such as an aberrant expression of HLA-DR. Although the long-term prognosis of AIP is unknown, the clinical and laboratory findings of most cases are reversible after steroid therapy.

Acknowledgments This study was supported by Grant-in-Aid for Scientific Research of the Ministry of Culture and Science of Japan 16590645

References

1. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 1995; 332:1482-90. [PMID 7739686]
2. Sarles H, Sarles JC, Camatte R, Muratore R, Gaini M, Guien C, et al. Observation on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis. Gut 1965; 6:545-59. [PMID 5857891]
3. Japan Pancreas Society. Diagnostic criteria for autoimmune pancreatitis by the Japan Pancreas Society (2002). J Jpn Pancreas Soc 2002; 17:585-7.
4. Montefusco PP, Geiss AC, Bronzo RL, Randall S, Kahn E, McKinley MJ. Sclerosing cholangitis, chronic pancreatitis, and SjS: A syndrome complex. Am J Surg 1984; 147:822-6. [PMID 6731702]
5. Epstein O, Chapman RW, Lake-Bakaar G, Foo AY, Rosalki SB, Sherlock S. The pancreas in primary biliary cirrhosis and parimary sclerosing cholangitis. Gastroenterology 1982; 83:117-82. [PMID 7129026]
6. Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata I, Fujita N. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: A variant primary sclerosing cholangitis extensively involving pancreas. Hum Pahtol 1991; 22:387-95. [PMID 2050373]
7. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001; 120:682-707. [PMID 11179244]
8. Lankisch PG, Koop H, Seelig R, Seelig HP. Antinuclear and pancreatic acinar cell antibodies in pancreatic disease. Digestion 1981; 21:65-8. [PMID 6971769]
9. Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by autoimmune abnormality. Proposal of concept of autoimmune pancreatitis. Dig Dis Sci 1995; 40:1561-8. [PMID 7628283]
10. Ohana M, Okazaki K, Hajiro K, Kobashi Y. Multiple pancreatic masses associated with autoimmunity. Am J Gastroenterol 1998; 93:99-102. [PMID 9448184]
11. Horiuchi A, Kaneko T, Yamamura N, Nagata A, Nakamura T, Akamatsu T, et al. Autoimmune chronic pancreatitis simulating pancreatic lymphoma. Am J Gastroenterol 1996; 91:2607-9. [PMID 8946997]
12. Horiuchi A, Kawa S, Akamatsu T, Aoki Y, Mukawa K, Furuya N, et al. Characteristic pancreatic duct appearance in autoimmune chronic pancreatitis: a case report and review of the Japanese literature. Am J Gastroenterol 1998; 93:260-3. [PMID 9468255]
13. Ito T, Nakano I, Koyanagi S, Miyahara T, Migita Y, Ogoshi K, et al. Autoimmune pancreatitis as a new clinical entity. Three cases of autoimmune pancreatitis with effective steroid therapy. Dig Dis Sci 1997; 42:1458-68. [PMID 9246047]
14. Uchida K, Okazaki K, Konishi Y, Ohana M, Takakuwa H, Hajiro K, Chiba T. Clinical analysis of autoimmune-related pancreatitis. Am J Gastroenterol 2000; 95:2788-94. [PMID 11051349]
15. Coll J, Navarro S, Tomas R, Elena M, Martinez E. Exocrine pancreatic function in Sjogren syndrome. Arch Intern Med 1989; 149:848-52. [PMID 2784958]
16. Sheikh SH, Shaw-Stiffel TA. The gastrointestinal manifestations of Sjögren's syndrome. Am J Gastroenterol 1995; 90:9-14. [PMID 7801957]
17. Waldram R, Kopelman H, Tsantoulas D, Williams R. Chronic pancreatitis, sclerosing cholangitis, and sicca complex in two siblings. Lancet 1975; 7906:550- 2. [PMID 47019]
18. Pearson RK, Longnecker DS, Chari ST, Smyrk TC, Okazaki K, Frulloni L, Cavallini G. Controversies in clinical pancreatology: autoimmune pancreatitis: does it exist? Pancreas 2003, 27:1-13. [PMID 12826899]
19. Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003; 38:982-4. [PMID 14614606]
20. Irie H, Honda H, Baba S, Kuroiwa T, Yoshimitsu K, Tajima T, et al. Autoimmune pancreatitis: CT and MR characteristics. AJR Am J Roentgenol 1998; 170:1323-7. [PMID 9574610]
21. Furukawa N, Muranaka T, Yasumori K, Matsubayashi R, Hayashida K, Arita Y. Autoimmune pancreatitis: radiologic findings in three histologically proven cases. J Comput Assist Tomogr 1998; 22:880-3. [PMID 9843225]
22. Nakamoto Y, Sakahara H, Higashi T, Saga T, Sato N, Okazaki K, et al. Autoimmune pancreatitis with F- 18 fluoro-2-deoxy-D-glucose PET findings. Clin Nucl Med 1999; 24:778-80. [PMID 10512104]
23. Angulo P, Lindor KD. Primary sclerosing cholangitis. Hepatology 1999; 30:325-32. [PMID 10385674]
24. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 cncentrations in patients with sclerosing pancreatitis. N Engl J Med 2001; 344:732-8. [PMID 11236777]
25. Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and Th1/Th2-type cellular immune response. Gastroenterology 2000; 118:573-81. [PMID 10702209]
26. Tanaka S, Kobayashi T, Nakanishi K, Okubo M, Murase T, Hashimoto M, Takeuchi K. Corticosteroidresponsive diabetes mellitus associated with autoimmune pancreatitis. Lancet 2000; 356:910-1. [PMID 11036899]
27. Eisenbarth GS. Type I diabetes mellitus: a chronic autoimmune disease. N Engl J Med 1986; 314:1360-8. [PMID 3517648]
28. Masson PL, Heremans JF. New data on lactoferrin, the iron-binding protein of secretion. In: Protides of Biological Fluids. Peters H, Eds. Oxford: Pergamon Press, 1968:633-8.
29. Uchida K, Okazaki K, Nishi T, Uose S, Nakase H, Ohana M, Matsushima Y, Omori K, Chiba T. Experimental immune-mediated pancreatitis in neonatally thymectomized mice immunized with carbonic anhydrase II and lactoferrin. Lab Invest 2002 ; 82:411-24. [PMID 11950899]
30. Inagaki Y, Jinno-Yoshida Y, Hamasaki Y, Ueki H. A novel autoantibody reactive with carbonic anhydrase in sera from patients with systemic erythematosus and Sjogren's syndrome. J Dermatol Sci 1991; 2:147-54. [PMID 1908698]
31. Peen E, Almer S, Bodemar G, Ryden BO, Sjolin C, Tejle K, Skogh T. Anti-lactoferrin antibodies and other types of ANCA in Crohn’s disease, ulcerative colitis, and primary schlerosing cholangitis. Gut 1993; 34:56-62. [PMID 8432453]
32. De Carli M, D'Elios MM, Zancuoghi G, Romagnani S, Del Prete G. Human Th1 and Th2 cells: functional properties, regulation of development and role in autoimmunity. Autoimmunity 1994; 18:301-8. [PMID 7858116]