Ulcerative colitis (UC), first described in the mid-1800s, and Crohn’s disease (CD), reported much later in 1932, share many clinical manifestations. They are grouped as “inflammatory bowel disease” (IBD) but are clearly 2 distinct pathophysiological entities.1 In 10% to 15% of cases, however, the distribution between CD and UC cannot be made (indeterminate colitis). UC and CD are well-recognized autoimmune disorders and are associated with extraintestinal manifestations involving almost every organ system—the eyes, skin, joints, kidney, liver, pancreaticobiliary tract, bones, and the vascular system. A few of these manifestations reflect generalized, systemic inflammatory activity with a common pathogenic mechanism seen in the intestine and elsewhere (arthritis, erythema nodosum, pyoderma, aphthous stomatitis, iritis/uveitis). Most of the systemic complications, however, are attributable to the same autoimmune disturbance that caused the initial IBD-associated immune disturbances.1–3 In the setting of predisposing genetic susceptibility, a destructive inflammatory response directed toward self-antigens such as mucin, goblet cells, colonocytes, and other cells has been proposed as the underlying pathogenesis of IBD, particularly UC. The sharing of colonic antigens by extraintestinal organs is the suggested mechanism of extracolonic manifestations. Anticolonic mucosal antibodies that cross-react with biliary epithelium have been identified. Also recognized are a colonic epithelial protein and the lumen tropomyosin isoform 5, which are expressed not only in the colon but also in the biliary tract and other target organs of autoimmune attack in cases of IBD.4,5 There is a strong association of IBD with primary sclerosing cholangitis, an autoimmune disease associated with HLA-B8-DR3 haplotype, lymphocyte autoreactivity to biliary antigens, and high titers of autoantibody directed against a neutrophil nuclear antigen. As a vast reservoir of microorganisms, each with its own antigenic properties, there is great potential for further autoantigen cross-reactivity, or “molecular mimicry.”
A disease is considered “autoimmune” by the demonstration of autoreactive lymphocytes or autoantibodies specific to the disease.3 There may also be association with other autoimmune disorders and specific HLA haplotypes, prominent lymphocytic infiltrate of the involved organ, and response to corticosteroid therapy.
The concept of autoimmune pancreatitis (AIP) is relatively new, first considered a possible entity in 1961 by Sarles et al.6 It was only in 1995 that Yoshida et al7 coined the term autoimmune pancreatitis. However, even as recently as 2002, the existence of AIP was doubted.8 Since 2006, however, a large number of publications from the United States, Japan, Korea, and other parts of the world have defined the disease very well.9–15 According to the most recent descriptions, AIP encompasses at least 2 different subtypes. Type 1 AIP is the pancreatic manifestation of a multiorgan fibroinflammatory disease called IgG4-related disease (IgG4-RD).16 Apart from the pancreas, IgG4-RD involves the bile ducts, gall bladder, salivary glands, retroperitoneum, lymph nodes, pleura, lungs, and kidneys.17
Type 1 AIP, also called IgG4-related pancreatitis, is characterized by a fibroinflammatory process, typical histopathology in many organs, elevated serum IgG4 levels, and a marked response to steroids. Type 1 AIP clinically mimics pancreatic ductal carcinoma. Occurring more often in men over the age of 50, it presents as obstructive jaundice. Biliary involvement can include extrahepatic and intrahepatic strictures, which are diffuse, monomorphic, long-segment strictures. Histologic features in the pancreas include storiform fibrosis, periductal lymphoplasmacytic infiltrate, obliterative phlebitis, and tissue IgG4 staining (>10 cells/HPF).18–20 Although the cholangiographic findings of sclerosing cholangitis with type 1 AIP (IgG4-SC) are similar to those of primary sclerosing cholangitis seen in a large number of patients with IBD, only IgG4-SC with AIP responds to steroid therapy.21
Type 2 AIP is defined by the presence of “granulocyte epithelial lesions” in pancreatic ducts. It appears to be a pancreas-specific disease, not associated with elevated serum IgG4 levels or tissue infiltration with IgG4 levels. It affects younger patients and does not have a sex predilection. Both subtypes respond to steroid therapy.17 Existing criteria are geared toward the diagnosis of type 1AIP; type 2 AIP can be definitively diagnosed only by histology. Endoscopic ultrasound–guided core biopsy or fine needle aspiration is required; cytology alone cannot adequately make the diagnosis of AIP.
In the current issue of this journal, Park et al22 from Asan Medical Center in Korea have reported on the prevalence of UC associated with AIP and have compared the clinical and pathologic characteristics and outcomes of UC associated with AIP. The study further establishes the association of AIP with UC. Serum IgG4 levels in the “UC only” group were not available, as IgG4 was not routinely measured in typical UC cases; in a retrospective case analysis of patients from a decade ago, the current definitions and diagnostic criteria for AIP obviously did not yet exist.
The evolving scenario of AIP associated with IBD needs further study. The prevalence of IBD is many hundred times more than that of AIP with or without UC. Every case of pancreatitis in IBD is not AIP. The most frequent causes of acute pancreatitis in IBD are gallstones and alcohol, with another major cause being medications such as azathioprine, 6-MP, sulfasalazine, 5-ASA, and others.23
IBD is more prevalent in AIP than in the general population. Increased prevalence of IBD is seen in both type 1 and type 2 AIP. In a recent study from the Mayo Clinic, 4 of 71 patients (6%) had the diagnosis of IBD (5.6%; 95% CI, 1.8%-14%).20 This study observed a 10-fold increase in the frequency of IBD in patients meeting HISORt criteria for AIP over the general population. IBD has been reported even more commonly in type 2 AIP (16% to 35%), although in 1 study the prevalence was not different between the subtypes, likely because of the small number of type 2 patients in the study.24
Most organ afflictions seen in IgG4-RD are not separate diseases but various manifestations of IgG4-RD in different organs. For example, salivary gland involvement in AIP is not Sjogren sialadenitis but IgG4-related sialadenitis. Whether IBD is a manifestation of AIP or simply an associated disease is not clear. Luminal involvement in IgG4-RD16 is hard to diagnose as IgG4 infiltration is the only clue and other histologic features seen in the pancreas are absent. Although IgG4 infiltration is invariably seen in IgG4-RD, only 2 of the 4 colons in the study by Park and colleagues showed IgG4 infiltration.16,22,24 Although we have seen some cases of IgG4-related colitis (possibly a colonic manifestation of IgG4-RD), most cases of IBD in AIP appears to be a true association rather than a manifestation of AIP.
Other provocative issues regarding the relation of AIP and UC that have not yet been explored include the fact that UC occurs in 2 peaks of age groups, the young and the middle aged, and distributes equally in both sexes. Type 1 AIP has been reported more often in older men, whereas type 2 AIP is sex nonspecific and occurs more often in the young. Sclerosing cholangitis complicates CD with colonic involvement, but it is not clear whether AIP too occurs in CD with involvement of the colon.20 AIP is a relatively “new” diagnostic entity, and clearly there are many more unanswered questions pertaining to the relationship between IBD and AIP that remain to be studied.
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