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Autoimmune pancreatitis and IgG4-associated sclerosing cholangitis
Best Practice & Research Clinical Gastroenterology 23 (2009) 11–23
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Best Practice & Research Clinical Gastroenterology
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Autoimmune pancreatitis and IgG4-associated sclerosing cholangitis Isao Nishimori, MD, Associate Professor a, *, Makoto Otsuki, MD, Professor b a
Department of Gastroenterology and Hepatology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan Department of Gastroenterology and Metabolism, University of Occupational and Environmental Health, Japan, School of Medicine, 1-1 Iseigaoka, Kitakyushu 807-8555, Japan b
Keywords: autoimmune pancreatitis sclerosing cholangitis IgG4 steroid therapy pathology
Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterised by a high serum IgG4 concentration and complications that include various extrapancreatic manifestations, one of which is sclerosing cholangitis. In AIP patients, infiltration of abundant IgG4-positive plasma cells and dense fibrosis are commonly observed in the pancreas and wall of the bile duct and gallbladder. The major symptom at onset of AIP is obstructive jaundice caused by stricture of the bile duct, and this requires differential diagnosis of AIP from pancreato-biliary malignancies and primary sclerosing cholangitis (PSC). Recently, there have been reports of particular cases of sclerosing cholangitis with a high serum IgG4 level and cholangiographic and pathological findings comparable to those observed in AIP patients. Being apparently different from PSC and similar to that in AIP, sclerosing cholangitis with and without AIP shows a clinical response to steroid therapy and thus is designated as ‘IgG4-associated sclerosing cholangitis’. The pathogenesis of AIP and IgG4-associated sclerosing cholangitis remains at yet undetermined. Ó 2008 Elsevier Ltd. All rights reserved.
In 1960s, Sarles et al reported cases of idiopathic chronic pancreatitis which showed hypergammaglobulinaemia, intense fibrosis, and a marked infiltration of lymphocytes and plasma cells in pancreatic tissue. They proposed a novel clinicopathological entity of chronic inflammatory sclerosis of the pancreas, or primary inflammatory pancreatitis [1,2]. Since then, similar cases of pancreatitis have appeared in the literature, with characteristic pathological findings, [3–6] and the condition has been designated lymphoplasmacytic sclerosing pancreatitis (LPSP) [6,7]. In these case reports, an * Corresponding author. Tel.: þ81 88 880 2338. E-mail address: [email protected] (I. Nishimori). 1521-6918/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2008.11.017
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autoimmune mechanism has been implicated in the pathogenesis of pancreatitis. However, extensive efforts in both clinical and basic research settings have failed to provide evidence that autoimmunity is a causative factor of the pancreatitis, [8,9] and thus there is no general consensus regarding ‘autoimmune pancreatitis (AIP)’ as an independent disease entity. The main reason for the failure was the absence of the clinical features characteristic of AIP, so it remains obscure among idiopathic chronic pancreatitides. Interestingly, most such cases of idiopathic chronic pancreatitis reported until the early 1990s showed a mass-like lesion in the pancreas head accompanied by strictures of the distal common bile duct (CBD) [3–5] or the hilar biliary ducts, [5] which are consistent with the findings currently known as AIP-associated sclerosing cholangitis. Some cases concomitantly showed retroperitoneal fibrosis, [4,5] which has been introduced as Ormond’s disease [10]. In addition, some of these reports noted irregular narrowing of the main pancreatic duct (MPD) on endoscopic retrograde cholangio-pancreatography (ERCP) [4]. In 1992, Toki et al focused on this unique ERCP finding, and then proposed a morphological clinical entity: a ‘duct-narrowing type’ of chronic pancreatitis [11]. In 1995, this atypical form of pancreatitis was adopted in the clinical diagnostic criteria for chronic pancreatitis proposed by the Japan Pancreas Society [12]. Subsequently, Toki’s group reported that patients with ‘duct-narrowing type’ of chronic pancreatitis showed a dramatic response to steroid therapy, and then finally proposed the concept of AIP [13]. Following this report, a number of case reports of AIP have appeared in the literature [14]. This was the major breakthrough for AIP, which began to emerge as a clinically and academically important disease. In 2001, the second breakthrough came with the discovery of an increased serum IgG4 level in AIP patients, which was identified by Hamano et al as a polyclonal band in the rapidly migrating fraction of g-globulins on serum electrogram [15]. Surprisingly, the use of a cut-off value for serum IgG4 concentrations of 135 mg/dL showed extremely high sensitivity, specificity and accuracy (more than 95%) for differentiating AIP patients from normal subjects, as well as patients with ordinary chronic pancreatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or Sjo¨gren’s syndrome (SjS) [15]. Along the same lines, abundant infiltration of IgG4-positive plasma cells with marked interstitial fibrosis was reported in the affected pancreatic tissue of AIP patients [15,16]. In addition, similar inflammatory processes were found in extrapancreatic lesions associated with AIP, as described below, but were not observed in the pancreas and salivary glands of patients with ordinary pancreatitis and seropositive (positive anti-SS-A/SS-B antibody) SjS [16]. These findings supported the concept that AIP was part of a much broader spectrum of systemic diseases, in which IgG4 plays some role in the pathogenesis, designated as IgG4-related sclerosing disease [17] or IgG4-associated multifocal systemic fibrosis [18]. Subsequently, various clinical researchers started to discriminate IgG4-related sclerosing disease from other inflammatory diseases in a number of organs, e.g. the liver, leading to IgG4-associated sclerosing cholangitis versus PSC. We review herein the clinical and pathological characteristics of AIP and sclerosing cholangitis, which is the most frequently observed extrapancreatic manifestation in AIP patients. Autoimmune pancreatitis Epidemiology Because AIP is a novel disease entity, there are no epidemiological studies apart from a nationwide survey in Japan which estimated the prevalence of AIP to be 0.82 per 100,000 [19]. This survey employed diagnostic criteria for AIP proposed by the Japanese Pancreas Society (JPS) in 2002, [20] in which the characteristic findings on pancreatic imaging should be observed in more than one third of the entire pancreas (see below) [20]. In 2006, the Japanese criteria were revised to exclude the extent limit displaying the abnormal pancreatic configuration (Japanese AIP criteria 2006), [21] because it was proved that some AIP cases were excluded by this limitation. Accordingly, the prevalence of AIP is currently estimated to be much higher than previously reported. In Japan, in the nationwide survey (2002) approximately half the patients (47%) showed disease onset in their sixties, [19] which is in agreement with reports from the United States [7] and Europe [22]. AIP occurs in both genders, but it is at least twice as common in men as in women (2.85 times in the nationwide survey 2002 in Japan) [19].
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Pathogenesis Several lines of evidence support the importance of immunological mechanisms in the pathogenesis of AIP. Linkage study of the human leukocyte antigen (HLA) genes showed that AIP was significantly associated with the DRB1*0405-DQB1*0401 alleles, [23] suggesting that a specific peptide triggers the autoimmune response. In addition, the substitution of aspartic acid with other amino acid residues at position 57 of the DQB1 sequence showed a significant association with relapse of AIP [24]. Among non-HLA genes, certain types of genetic polymorphisms in the Fc-receptor-like gene 3 [25] and cytotoxic-T-lymphocyte antigen 4 [26] showed a significant association with AIP, similar to observations in systemic lupus erythematosus (SLE) or autoimmune thyroiditis [27,28]. These findings suggest that AIP patients exhibit a particular genetic background predisposing to autoimmune disorders. AIP patients have increased serum levels of IgG4 with a high sensitivity of 73–90% at a cut-off value of 135–140 mg/dL [15,29,30]. They also display abundant infiltration of IgG4-positive cells in the pancreas [15,16,31,32]. Serum IgG4 in AIP patients was reported to react with ductal epithelial cells of the pancreas, biliary system and salivary gland [33]. Circulating autoantibodies to particular molecules – such as carbonic anhydrase II and IV, [34,35] lactoferrin, [36] and pancreatic secretory trypsin inhibitor [37] – have been reported in AIP patients. However, the target antigen recognised by the serum IgG4 antibodies is not defined, and the precise role of IgG4 in the pathogenesis of AIP is still uncertain. Recently, Okazaki et al reported an increased prevalence of naturally occurring CD4þCD25high regulatory T cells (Treg) and a decreased prevalence of CD4þCD25þCD45RAþ Treg (naive Treg) in the peripheral blood of AIP patients compared to healthy subject and patients with other types of pancreatitis [38]. In the pancreas and the portal area in the liver of AIP patients, IL-4-producing CD4þ cells (Th2 cells) and naturally occurring CD4þCD25þFoxp3þ Treg were predominantly observed along with infiltration of abundant IgG4-positive cells [39]. It is well known that naturally occurring Treg produce IL-10 and tumour growth factor b (TGF-b), resulting in IgG4 class switching on B cells and fibrogenesis [40]. IgG4 was reported to possess anti-inflammatory function [41] and rheumatoid factorlike activity capable of binding to IgG Fc via its Fab portion [42]. These findings suggest that a Th2dominant immune reaction primarily occurs in AIP patients and, as a secondary inhibitory response, IgG4-positive plasma cells infiltrate into the pancreas and extrapancreatic lesions, and serum IgG4 increases together with activation of naturally occurring Treg. Hardacre et al reported that 16% of 37 AIP patients had a clinical history of asthma [43]. An increased serum IgG4 is found in certain kinds of allergic disease, such as atopic dermatitis [44]. It has been reported that a Th2-dominant immune mechanism plays a major role in the allergic process, [40,45] and in contrast many autoimmune diseases display a Th1-dominant immune reaction [45]. Taking all findings together – except for one early study which showed a significantly increased prevalence of ginterferon- (g-IFN-)producing CD4þ cells (Th1 cells) in the peripheral blood of AIP patients [36] – it seems likely that the underlying immunological mechanism of AIP consists of an allergic reaction rather than an autoimmune reaction. Pathology Almost all AIP experts the world over, including pathologists and physicians, consider LPSP as the pathological hallmark of AIP. This is characterised by periductal lymphoplasmacytic infiltration with obliterative phlebitis and storiform fibrosis [6,7,16,22,39,46]. Interestingly, the European research group has proposed an additional histological subtype of AIP [22]. They studied pancreatic tissue specimens from 53 patients with chronic pancreatitis lacking findings to suggest its etiology [22]. The most significant histological findings in these patients were periductal lymphoplasmacytic infiltration, cuff-like periductal fibrosis and venulitis, which were consistent with LPSP. These patients were further subdivided into two groups according to the presence or absence of granulocyte epithelial lesions (GELs), and the clinical pictures were analysed comparatively (Fig. 1) [22]. In the AIP/GEL(þ) group, the male-to-female ratio was almost even, and an average age of disease onset was 40.5 years. These patients more often had inflammatory bowel disease (IBD) such as Crohn’s disease and ulcerative colitis (29%), as compared to patients in the AIP/GEL() group (7%). In the AIP/GEL() group patients were predominantly male, onset ages were older (mean age 64 years)
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Fig. 1. Clinicopathological subtypes of autoimmune pancreatitis 1. Version 1.0 (2001), proposed by Whitcomb et al. [46]. 2. Seronegative means absence of serum antibodies to SS-A (Ro) and SS-B (La) AIP, autoimmune pancreatitis; GEL, granulocytic epithelial lesion; IDCP, idiopathic duct-centric chronic pancreatitis; IDDP, idiopathic duct-destructive pancreatitis; LPSP, lymphoplasmacytic sclerosing pancreatitis.
than that in the AIP/GEL(þ) group, and the disease was more often complicated by sialoadenitis and retroperitoneal fibrosis. Pathologists from the Mayo Clinic also reported a similar classification of histological types of AIP [7]. They employed pancreatic tissue specimens surgically resected from 35 patients with idiopathic chronic pancreatitis, in which histological study showed periductal lymphoplasmacytic infiltration. They further subdivided these patients into two groups according to histological findings, idiopathic duct-centric chronic pancreatitis (IDCP) and LPSP. Interestingly, comparative analyses of clinical manifestations showed strong similarities between IDCP and the AIP/GEL(þ) group, as well as between the LPSP and AIP/GEL() groups (Fig. 1) [7]. Recently, the same group used the term idiopathic ductdestructive pancreatitis (IDDP) instead of IDCP, and reported that moderate to marked infiltration with those showing IDDP (n ¼ 12) [32]. In the TIGAR-O classification system for etiological risk factors associated with chronic pancreatitis, [46] AIP was subdivided to ‘isolated’ and ‘syndromic’ subgroups. In this classification system, syndromic AIP is associated with SjS, IBD and PBC. The different histological types of AIP discussed above possibly cause different spectra of complications. Thus, the panel of extrapancreatic manifestations in AIP patients as described below [47–49] also suggests that there may be two different clinicopathological types of AIP (Fig. 1). Clinical features The major symptom of AIP at onset is obstructive jaundice. From analysis of questionnaires in a nationwide survey for AIP in Japan, [19] 54.2% of 190 AIP patients, who fulfilled the Japanese diagnostic criteria proposed in 2006, [21] showed obstructive jaundice (unpublished data). In this case series abdominal pain, pyrexia, and abdominal tenderness were observed in 38.5%, 9.7%, and 19.7% of the patients, respectively. In AIP, severe abdominal pain is rare, but most patients complain of abdominal discomfort [50]. Screening blood tests show abnormal findings suggestive of obstructive jaundice. Table 1 shows results of immunological blood tests in AIP patients from the nationwide survey in Japan. [51] Antinuclear antibody and rheumatoid factor were observed in 63% and 28% of the patients, respectively. Disease-labelled antibodies such as anti-SS-A/SS-B antibodies for SjS and anti-mitochondrial antibody for PBC were scarcely observed, suggesting a clinical importance of these specific antibodies in differentially diagnosing these diseases from AIP. Increased levels of total IgG (1800 mg/dL) and IgG4 (135 mg/dL) showed relatively high sensitivities in accordance with previous reports, which showed elevated serum levels of total IgG and IgG4 in 42–70% and 73–90% of AIP patients, respectively
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Table 1 Serum autoantibody and immunoglobulin in autoimmune pancreatitis (AIP) patients. Autoantibody/immunoglobulin
Positive prevalence (n)
Anti-nuclear antibody Rheumatoid factor Anti-SS-A(Ro) antibody Anti-SS-B(La) antibody Anti-mitochondrial antibody g-globulin (2.0 g/dL) IgG (1800 mg/dL) IgA (500 mg/dL) IgM (300 mg/dL) IgG4 (135 mg/dL)
63% 28% 0% 2% 1% 46% 74% 3% 6% 83%
(179) (123) (132) (130) (96) (158) (185) (156) (156) (80)
Those patients fulfilling the revised diagnostic criteria for AIP 2006 in Japan [21] from analysis of second questionnaires in a nationwide survey for AIP in Japan [29].
[15,29,30]. However, it was recently reported that some patients with pancreatic cancer [52,53] or PSC [54,55] also showed an increased level of serum IgG4 with significant infiltration of IgG4-positive cells in the pancreas and liver, respectively. Although serum IgG4 is a sensitive marker for diagnosing AIP, it is not a gold standard for AIP. Typical cases of AIP show diffuse enlargement of the pancreas – the so-called sausage-like appearance – on computed tomography (CT), ultrasonography (US), and magnetic resonance imaging (MRI) (Fig. 2A) [13,14,30,47,50,56,57]. Dynamic CT and MRI show delayed enhancement of the swollen pancreas [56–58]. Some AIP cases show ‘a capsule-like rim’ surrounding the swollen pancreas
Fig. 2. Computed tomography and endoscopic retrograde cholangio-pancreatogram of a patient with autoimmune pancreatitis. (A) In a 64-year-old patient, contrast-enhanced computed tomography at onset revealed a diffusely swollen pancreas. (B) Endoscopic retrograde pancreatogram at onset showed diffusely irregular narrowing of the main pancreatic duct. (C) Following steroid therapy for 7 months, contrast-enhanced computed tomography at 5 years after onset in a 69-year-old patient revealed atrophic pancreas with dilated main pancreatic duct (arrows). (D) At 5 years after onset, endoscopic retrograde pancreatography showed a beaded appearance of the main pancreatic duct and stricture of the distal common bile duct.
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appearing as a low-density area on CT and a hypointense area on MRI, which is relatively specific and thus of diagnostic value for AIP [56–58]. ERCP shows diffuse narrowing of the MPD with some irregularity (Fig. 2B) [13,14,30,47,50,56]. Some atypical cases of AIP show a focal mass-like lesion in the pancreas and segmental narrowing of the MPD, which are often indistinguishable from pancreatic cancer [58–60]. In both diffuse and focal-lesion types of AIP, [18]F-fluorodeoxyglucose positron emission tomography shows a significant signal uptake, which means that this technique cannot differentiate between AIP and pancreatic cancer [61,62]. Diagnostic criteria To date, three systematic diagnostic criteria for AIP have been proposed from Japan, [21] the Mayo Clinic, [30] and Korea [63]. These criteria commonly include three major diagnostic categories: (1) findings on pancreatic imaging; (2) laboratory data; and (3) histological finding (see Table 2). As there are notable differences in these categories among three criteria, typical findings on imaging studies are essential for the diagnosis according to the Japanese and Korean criteria, but not according to the Mayo criteria. The latter emphasise the histological findings with LPSP as a gold standard for the diagnosis [30]. The critical differences between the Japanese and the other two diagnostic systems are in the use of ‘other organ involvement’ and ‘steroid responsiveness’. Employment of these factors in clinical diagnostic criteria possibly increases the risk that general physicians will employ steroid therapy in treatment of patients with pancreatic or biliary malignancy. Treatment Although the disease concept for AIP was based on the effectiveness of steroid therapy, [13] exact indications and optimal regimens of steroid therapy for AIP are still not well established. Recently, the Intractable Pancreatic Diseases Research team funded by the Japanese Ministry of Health, Labour and Welfare came up with a consensus proposal for the treatment of AIP (Fig. 3) [64]. It recommended that steroid therapy start with 30–40 mg (0.6 mg/kg body weight) of oral prednisolone per day. Following administration of the initial prednisolone dose for 2–4 weeks, the prednisolone dose will be tapered to
Table 2 Comparison of diagnostic criteria for autoimmune pancreatitis. Diagnostic factors
Japanese criteria 2006 [21] (RCIPD and JPS)
HISORt criteria 2006 [30] (Mayo Clinic)
Korean criteria 2007 [63] (KSPBD)
I. Imaging criteria
Essential Narrowing of the MPD plus enlargement of pancreas
Not essential Typical (same as JPS)
Essential Same as JPS
II. Laboratory criteria III. Histological criterion IV. Other organ involvement V. Response to steroida Definite diagnosis
g-globulin, IgG, or IgG4 Autoantibodies LPSP Not included Not included I þ II I þ III
Atypical forms: pancreatic atrophy, calcification or pancreatitis IgG4
LPSP (full spectrum) IgG4þ cells IgG4þ cells Response to steroid Pancreatic lesion Extrapancreatic lesion III (gold standard) I (typical) þ II I (atypical) þ II þ V I (atypical) þ IV (IgG4þ cells) þ V
IgG or IgG4 Autoantibodies LPSP IgG4þ cells IgG4þ cells Response to steroid Pancreatic lesion Extrapancreatic lesion I þ II I þ III I þ IV IþV
JPS, Japan Pancreas Society; RCIDP, The Research Committee on Intractable Pancreatic Diseases, Ministry of Health, Labour and Welfare of Japan; KSPBD, Korean Society of Pancreatobiliary Diseases; HISORt, histology, imaging, serology, other organ involvement, and response to steroid therapy; LPSP, lymphoplasmacytic sclerosing pancreatitis. a After negative work-up for known etiologies including cancer.
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Fig. 3. Standard regimen of steroid therapy for autoimmune pancreatitis with minor modification from the ‘consensus for a treatment of AIP’ proposed by the Intractable Pancreatic Diseases Research team funded by the Japanese Ministry of Health, Labour and Welfare [64].
a maintenance dose (5.0–7.5 mg prednisolone per day) for a total of 2–3 months. Evaluation of the disease activity in the course of steroid therapy requires biochemical blood tests such as serum gglobulin, IgG and IgG4, imaging findings, and clinical manifestations such as jaundice and abdominal discomfort [64]. The duration of maintenance therapy is still controversial. Chari recommended a total of 12 weeks of steroid therapy [65]. In our experience, however, AIP patients often show relapse of pancreatic and/or extrapancreatic manifestations within 3 years from the initiation of the steroid therapy (unpublished data), and thus the steroid therapy could possibly be maintained for at least 3 years. Relapse was reported in 6–26% of AIP patients [22,66–69]. When AIP patients relapse during or after steroid therapy, we would restart the steroid therapy, possibly with a high dose of prednisolone [70]. As a note of caution regarding steroid therapy, we avoid using steroid as a therapeutic diagnostic technique just to distinguish AIP from pancreatic or biliary malignancy. Kim et al observed that a marked improvement of pancreatic ductal narrowing by steroid administration may be a unique finding specific to AIP, and could be observed as early as 2 weeks after the initiation of steroid therapy [71]. However, pancreatic swelling in patients with pancreatic cancer, especially that developed due to upstream pancreatitis, could also be improved by steroid therapy. After administration of 30–40 mg/ day of prednisolone for 2 weeks, it takes at least an additional 1 or 2 weeks to completely quit the steroid therapy in order to avoid steroid hormone withdrawal syndrome, resulting in a delay in treating patients with pancreatic or biliary malignancy. Prior to steroid therapy, even in patients who fulfilled the minimum diagnostic criteria proposed by the Japanese group, a negative work-up of these malignancies should be attempted [30]. For this purpose, Levy et al reported the usefulness of EUSguided pancreatic biopsy by using a large-calibre (19-gauge) trucut needle [72]. The Mayo Clinic group reported that steroids should preferably not be given to patients in whom response cannot be objectively assessed: for example, patients without structural changes on imaging studies [65]. Prognosis The long-term prognosis for AIP remains as yet undefined. As the pancreatic exocrine and endocrine functions, as well as the morphological findings, are reversible after steroid therapy in most AIP cases, the prognosis for AIP seems better than that of chronic pancreatitis, which is usually followed by exocrine and endocrine pancreatic insufficiency with disease progression [69]. After steroid therapy, however, in some AIP cases both imaging and histological studies revealed morphological alterations similar to those observed in an advanced stage of ordinary pancreatitis (see Fig. 2C,D), [60,73,74] suggesting that AIP as currently diagnosed is a kind of early stage of chronic pancreatitis. Although the risk for progression to cancer in AIP is unknown, some AIP patients developed a malignancy during the follow-up period, including pancreatic cancer, probably due to its preponderance among elderly people [74–77].
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Extrapancreatic manifestations of AIP One of the prominent features of AIP is that it involves a variety of extrapancreatic diseases, including sclerosing cholangitis, [30,48,49,78–81] Mikulicz’s disease previously reported as seronegative (absence of anti-SS-A/SS-B antibody) SjS, [30,48,49,78,82] hypothyroidism, [50] hilar lymphoadenopathy, [30,48,49,78] retroperitoneal fibrosis, [30,48,49,78] interstitial pneumonia, [83] and tubulonephritis [84]. From the analysis of questionnaires obtained by the nationwide survey in Japan, [19] extrapancreatic manifestations of 191 AIP patients are shown in Fig. 4 [50]. The most frequently observed complication was sclerosing cholangitis (9.9%), followed by sialoadenitis (9.4%) and retroperitoneal fibrosis (7.3%). It is of note that this analysis excluded patients with stricture of only the distal CBD. Interstitial pneumonia and tubulonephritis were rarely seen (1%). Seropositive SjS, PSC, PBC and IBD are rarely observed in AIP patients showing histological findings of LPSP without GEL; [48] however, they have sometimes been reported in patients with idiopathic chronic pancreatitis [46,85] or the AIP subtype, which was diagnosed by the histological findings of IDCP (IDDP) or AIP/GEL(þ) (see above) [7,22].
IgG4-associated sclerosing cholangitis Imaging study Sclerosing cholangitis has been reported in 74–96% of AIP patients [49,78–81]. The analysis in the nationwide survey in Japan showed that a total of 81% of the patients (n ¼ 191) had a stricture of the bile ducts on ERCP [50] and that approximately half of the patients displayed obstructive jaundice at disease onset. Abnormalities were observed not only in the distal CBD (66%) but also in the hilar region (7.9%) and intrahepatic bile ducts (4.7%). Involvement of the gallbladder in AIP has also been reported [86,87]. AIP patients with sclerosing cholangitis show a cholangiographic appearance that is often confused with PSC, but careful observation on adequately represented cholangiography can discriminate these two types of cholangitis. Nakazawa et al reported that segmental strictures, dilation after confluent stricture, and strictures of the lower common bile duct were significantly more common in sclerosing cholangitis with AIP than PSC (Fig. 5). In contrast, band-like strictures, a beaded or pruned-tree appearance, and diverticulum-like out-pouching were indicative of PSC rather than sclerosing cholangitis with AIP [79]. Otherwise, a long-segmental and smooth-narrowing bile duct in sclerosing cholangitis with AIP is sometimes difficult to distinguish from that of cholangiocarcinoma [60,88]. Ultrasonography, CT and MRI showed wall thickening of the bile duct and gallbladder with delayed
Fig. 4. Extrapancreatic lesions in patients with autoimmune pancreatitis (AIP) from the analysis of second questionnaires obtained by a nationwide survey for AIP in Japan [51]. *Cases showing stricture of the extrapancreatic biliary system; cases showing stricture of only the distal common bile duct are excluded.
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Fig. 5. Cholangiogram of a patient (an 87-year-old male) with autoimmune pancreatitis. (A) Before steroid therapy, segmental strictures (arrows), dilation after confluent stricture, and strictures of the lower common bile duct (an arrowhead) are seen. (B) After steroid therapy, the abnormal findings observed before steroid therapy almost disappear.
enhancement as observed in the pancreas of AIP (Fig. 6) [55,80,81]. It is of note that the wall thickening of the biliary tract is seen even in the segment which shows no apparent abnormalities on cholangiography [80,89]. Pathology Histologically, dense infiltration of mononuclear cells including IgG4-positive plasma cells and massive fibrosis are observed in the wall of the biliary system in many patients with AIP [16,17,39,90–92]. Although PSC patients also show infiltration of IgG4-positive cells around the bile duct in the portal areas and the extrahepatic bile duct, the degree of the infiltration is significantly lower than that in AIP patients [90]. In both the pancreas and biliary-duct wall of AIP patients, IL-4-producing CD4þ cells (Th2 cells) and naturally occurring CD4þCD25þFoxp3þ Treg are predominantly observed as described above [39]. These findings indicate that the same mechanism plays a role in the disease process of pancreatitis and sclerosing cholangitis in AIP patients, which have been introduced as sclerosing pancreatocholangitis, [93] autoimmune pancreatocholangitis, [94] or autoimmune sclerosing cholangio-pancreatitis [95].
Fig 6. Computed tomography (CT) and magnetic resonance imaging (MRI) of a patient with autoimmune pancreatitis and sclerosing cholangitis. (A) Contrast-enhanced CT shows swelling of the pancreas head (star) and thickening of the walls of the bile duct and gallbladder (arrows). (B) T2-weighted MRI (coronary section) shows diffuse swelling of the pancreas (stars) and thickening of the walls of the bile duct and gallbladder (arrows).
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IgG4-associated sclerosing cholangitis without AIP Recently, several cases of sclerosing cholangitis with an increased serum IgG4 level but without apparent pancreatic lesion have been reported [88,95,96]. In these cases cholangiography revealed similar findings as observed in AIP patients with sclerosing cholangitis. Pathological study also showed infiltration of abundant IgG4-positive plasma cells in the bile duct wall, and thus they were designated as IgG4-related lymphoplasmacytic sclerosing cholangitis, [88] autoimmune sclerosing cholangitis, [95] or IgG4-associated cholangitis [97]. Although sclerosing cholangitis in AIP patients needs to be differentially diagnosed from cholangiocarcinoma and PSC, [79,91] in cases of sclerosing cholangitis without AIP it is especially difficult to discriminate these diseases [88,95]. Treatment and prognosis Being apparently different from PSC, IgG4-associated sclerosing cholangitis with and without AIP shows good response to the steroid therapy with the same regimen used for the pancreatic lesions in AIP patients. Improvement of the bile duct stricture diminishes obstructive jaundice, but approximately half the patients show persistent stricture of the CBD to some extent [81]. Multivariate analysis has indicated that obstructive jaundice at disease onset was a significant predictive factor for relapse of AIP and/or its extrapancreatic lesions [96]. Patients with the extrapancreatic bile duct lesion show a significantly higher relapse rate as compared to patients without it [98]. In patients with IgG4associated sclerosing cholangitis, careful observation for relapse of IgG4-related sclerosing diseases should be warranted during the course and after withdrawal of the steroid therapy. Practice points
AIP is often seen in elderly men there appear to be two clinicopathological subtypes of AIP among extrapancreatic lesions of AIP, sclerosing cholangitis is the most frequent some patients with IgG4-associated sclerosing cholangitis lack pancreatic manifestations steroid therapy is effective for AIP and IgG4-associated sclerosing cholangitis, but before therapy a work-up for possible pancreato-biliary malignancies should be negative
Research agenda the pathogenesis of AIP and IgG4-associataed sclerosing cholangitis needs to be defined prospective controlled studies are necessary to define an appropriate duration of steroid therapy in AIP and IgG4-associated sclerosing cholangitis the long-term prognosis of AIP and IgG4-associated sclerosing cholangitis need to be clarified
Conflict of interest No conflict of interest has been declared by the authors. Acknowledgement This work was supported in part by the Health and Labour Sciences Research Grant for Intractable Pancreatic Diseases. References [1] Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreasdan autonomous pancreatic disease? Am J Dig Dis 1961;6:688–98.
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[2] Sarles H, Sarles JC, Camatte R, et al. Observations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis. Gut 1965;6:545–59. [3] Nakano E, Takeda I, Kitamura K, et al. Vanishing tumor of the abdomen of in patients with Sjo¨gren’s syndrome. Am J Dig Dis 1978;23(Suppl):75S–79. [4] Renner IG, Ponto GC, Savage 3rd WT, Boswell WD. Idiopathic retroperitoneal fibrosis producing common bile duct and pancreatic duct obstruction. Gastroenterology 1980;79:348–51. [5] Laitt RD, Hubscher SG, Buckels JA, et al. Sclerosing cholangitis associated with multifocal fibrosis: a case report. Gut 1992; 33:1430–2. [6] Kawaguchi K, Koike M, Tsuruta K, et al. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol 1991;22:387–95. *[7] Notohara K, Burgart LJ, Yadav D, et al. Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases. Am J Surg Pathol 2003;27:1119–27. [8] Antal L, Kavai M, Szabo G, et al. Immunological investigations in acute and chronic human pancreatitis. Digestion 1980;20:100–5. [9] Lankisch PG, Koop H, Seelig R, Seelig HP. Antinuclear and pancreatic acinar cell antibodies in pancreatic diseases. Digestion 1981;21:65–8. [10] Dejaco C, Ferenci P, Schober E, et al. Stenosis of the common bile duct due to Ormond’s disease: case report and review of the literature. J Hepatol 1999;31:156–9. [11] Toki F, Kozu T, Oi I, Nakasato T, et al. An unusual type of chronic pancreatitis showing diffuse irregular narrowing of the entire main pancreatic duct on ERCP: a report of four cases [abstract]. Endoscopy 1992;24:640. [12] Homma T, Harada H, Koizumi M. Diagnostic criteria for chronic pancreatitis by the Japan Pancreas Society. Pancreas 1997; 15:14–5. [13] Yoshida K, Toki F, Takeuchi T, et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci 1995;40:1561–8. [14] Ito T, Nakano I, Koyanagi S, 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. *[15] Hamano H, Kawa S, Ochi Y, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet 2002;359:1403–4. [16] Kamisawa T, Funata N, Hayashi Y, et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut 2003;52:683–7. [17] Kamisawa T, Nakajima H, Egawa N, et al. IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy. Pancreatology 2006;6:132–7. [18] Tanabe T, Tsushima K, Yasuo M, et al. IgG4-associated multifocal systemic fibrosis complicating sclerosing sialadenitis, hypophysitis, and retroperitoneal fibrosis, but lacking pancreatic involvement. Intern Med 2006;45:1243–7. [19] Nishimori I, Tamakoshi A, Otsuki M, et al. Prevalence of autoimmune pancreatitis in Japan from a nationwide survey in 2002. J Gastroenterol 2007;42(Suppl 18):6–8. [20] Otsuki M. Autoimmune pancreatitis: a message from Japan. J Gastroenterol 2007;42(Suppl 18):1–5. [21] Okazaki K, Kawa S, Kamisawa T, et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal. J Gastroenterol 2006;41:626–531. *[22] Zamboni G, Lu¨ttges J, Capelli P, et al. Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens. Virchows Arch 2004;445:552–63. *[23] Kawa S, Ota M, Yoshizawa K, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology 2002;122:1264–9. [24] Park do H, Kim MH, Oh HB, et al. Substitution of aspartic acid at position 57 of the DQbeta1 affects relapse of autoimmune pancreatitis. Gastroenterology 2008;134:440–6. [25] Umemura T, Ota M, Hamano H, et al. Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients. Gut 2006;55:1367–8. [26] Umemura T, Ota M, Hamano H, et al. Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am J Gastroenterol 2008;103:588–94. [27] Kochi Y, Yamada R, Suzuki A, et al. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 2005;37:478–85. [28] Barreto M, Santos E, Ferreira R, et al. Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus. Eur J Hum Genet 2004;12:620–6. [29] Choi EK, Kim MH, Lee TY, et al. The sensitivity and specificity of serum immunoglobulin G and immunoglobulin G4 levels in the diagnosis of autoimmune chronic pancreatitis: Korean experience. Pancreas 2007;35:156–61. *[30] Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 2006;4:1010–6. [31] Kojima M, Sipos B, Klapper W, et al. Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells. Am J Surg Pathol 2007;31:521–8. [32] Zhang L, Notohara K, Levy MJ, et al. IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod Pathol 2007;20:23–8. [33] Aoki S, Nakazawa T, Ohara H, et al. Immunohistochemical study of autoimmune pancreatitis using anti-IgG4 antibody and patients’ sera. Histopathology 2005;47:147–58. [34] Kino-Ohsaki J, Nishimori I, Morita M, et al. Serum antibodies to carbonic anhydrase I and II in patients with idiopathic chronic pancreatitis and Sjo¨gren’s syndrome. Gastroenterology 1996;110:1579–86. [35] Nishimori I, Miyaji E, Morimoto K, et al. Serum antibodies to carbonic anhydrase IV in patients with autoimmune pancreatitis. Gut 2005;54:274–81. [36] Okazaki K, Uchida K, Ohana M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2type cellular immune response. Gastroenterology 2000;118:573–81. [37] Asada M, Nishio A, Uchida K, et al. Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. Pancreas 2006;33:20–6.
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[38] Miyoshi H, Uchida K, Taniguchi T, et al. Circulating naı¨ve and CD4þCD25high regulatory T cells in patients with autoimmune pancreatitis. Pancreas 2008;36:133–40. *[39] Zen Y, Fujii T, Harada K, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 2007;45:1538–46. [40] Robinson DS, Larche´ M, Durham SR. Tregs and allergic disease. J Clin Invest 2004;114:1389–97. [41] van der Neut Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 2007;317:1554–7. [42] Kawa S, Kitahara K, Hamano H, et al. A novel immunoglobulin-immunoglobulin interaction in autoimmunity. PLoS ONE 2008;3: e1637. [43] Hardacre JM, Iacobuzio-Donahue CA, Sohn TA, et al. Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis. Ann Surg 2003;237:853–8. [44] Aalberse RC, Van Milligen F, Tan KY, Stapel SO. Allergen-specific IgG4 in atopic disease. Allergy 1993;48:559–69. [45] Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 2003;8: 223–46. [46] Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682–707. [47] Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol 2006;41: 613–25. [48] Ohara H, Nakazawa T, Sano H, et al. Systemic extrapancreatic lesions associated with autoimmune pancreatitis. Pancreas 2005;31:232–7. *[49] Hamano H, Arakura N, Muraki T, et al. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol 2006;41:1197–205. [50] Kawa S, Hamano H. Clinical features of autoimmune pancreatitis. J Gastroenterol 2007;42(Suppl 18):9–14. [51] Nishimori I, Onishi S, Otsuki M. Nationwide survey for autoimmune pancreatitis in Japan. J Jpn Panc Soc 2007;22:651–6 (in Japanese with English abstract). [52] Ghazale A, Chari ST, Smyrk TC, et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol 2007;102:1646–1453. [53] Kamisawa T, Chen PY, Tu Y, et al. Pancreatic cancer with a high serum IgG4 concentration. World J Gastroenterol 2006;12: 6225–8. [54] Mendes FD, Jorgensen R, Keach J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol 2006;101:2070–5. [55] Hirano K, Kawabe T, Yamamoto N, et al. Serum IgG4 concentrations in pancreatic and biliary diseases. Clin Chim Acta 2006;367:181–4. [56] Sahani DV, Kalva SP, Farrell J, et al. Autoimmune pancreatitis: imaging features. Radiology 2004;233:345–52. [57] Irie H, Honda H, Baba S, et al. Autoimmune pancreatitis: CT and MR characteristics. AJR Am J Roentgenol 1998;170:1323–7. [58] Kamisawa T, Egawa N, Nakajima H, et al. Clinical difficulties in the differentiation of autoimmune pancreatitis and pancreatic carcinoma. Am J Gastroenterol 2003;98:2694–9. [59] Tabata M, Kitayama J, Kanemoto H, et al. Autoimmune pancreatitis presenting as a mass in the head of the pancreas: a diagnosis to differentiate from cancer. Am Surg 2003;69:363–6. [60] Nakazawa T, Ohara H, Sano H, et al. Difficulty in diagnosing autoimmune pancreatitis by imaging findings. Gastrointest Endosc 2007;65:99–108. [61] Nakamoto Y, Saga T, Ishimori T, et al. FDG-PET of autoimmune-related pancreatitis: preliminary results. Eur J Nucl Med 2000;27:1835–8. [62] Nakajo M, Jinnouchi S, Fukukura Y, et al. The efficacy of whole-body FDG-PET or PET/CT for autoimmune pancreatitis and associated extrapancreatic autoimmune lesions. Eur J Nucl Med Mol Imaging 2007;34:2088–95. [63] Ryu JK. Overview of diagnostic criteria for autoimmune pancreatitis. Korean J Panc Bilary Tract 2007;12:105–12. *[64] Ito T, Nishimori I, Inoue N, et al. Treatment for autoimmune pancreatitis: consensus on the treatment for patients with autoimmune pancreatitis in Japan. J Gastroenterol 2007;42(Suppl 18):50–8. *[65] Chari ST. Current concepts in the treatment of autoimmune pancreatitis. JOP 2007;8:1–3. [66] Wakabayashi T, Kawaura Y, Satomura Y, et al. Long-term prognosis of duct-narrowing chronic pancreatitis: strategy for steroid treatment. Pancreas 2005;30:31–9. [67] Takayama M, Hamano H, Ochi Y, et al. Recurrent attacks of autoimmune pancreatitis result in pancreatic stone formation. Am J Gastroenterol 2004;99:932–7. [68] Kim KP, Kim MH, Song MH, et al. Autoimmune chronic pancreatitis. Am J Gastroenterol 2004;99:1605–16. [69] Kamisawa T, Okamoto A, Wakabayashi T, et al. Appropriate steroid therapy for autoimmune pancreatitis based on longterm outcome. Scand J Gastroenterol 2008;43:609–13. [70] Kamisawa T, Okamoto A. Prognosis of autoimmune pancreatitis. J Gastroenterol 2007;42(Suppl 18):59–62. [71] Kim MH, Kwon S. Diagnostic criteria for autoimmune chronic pancreatitis. J Gastroenterol 2007;42(Suppl 18):42–9. [72] Levy MJ, Reddy RP, Wiersema MJ, et al. EUS-guided trucut biopsy in establishing autoimmune pancreatitis as the cause of obstructive jaundice. Gastrointest Endosc 2005;61:467–72. [73] Suda K, Nishimori I, Takase M, et al. Autoimmune pancreatitis can be classified into early and advanced stages. Pancreas 2006;33:345–50. [74] Nishino T, Toki F, Oyama H, et al. Long-term outcome of autoimmune pancreatitis after oral prednisolone therapy. Intern Med 2006;45:497–501. [75] Inoue H, Miyatani H, Sawada Y, Yoshida Y. A case of pancreas cancer with autoimmune pancreatitis. Pancreas 2006;33: 208–9. [76] Kubota K, Iida H, Fujisawa T, et al. Clinical factors predictive of spontaneous remission or relapse in cases of autoimmune pancreatitis. Gastrointest Endosc 2007;66:1142–51. [77] Fukui T, Mitsuyama T, Takaoka M, et al. Pancreatic cancer associated with autoimmune pancreatitis in remission. Intern Med 2008;47:151–5.
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[78] Kamisawa T, Egawa N, Nakajima H, et al. Extrapancreatic lesions in autoimmune pancreatitis. J Clin Gastroenterol 2005; 39:904–7. *[79] Nakazawa T, Ohara H, Sano H, et al. Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis. Gastrointest Endosc 2004;60:937–44. [80] Hirano K, Shiratori Y, Komatsu Y, et al. Involvement of the biliary system in autoimmune pancreatitis: a follow-up study. Clin Gastroenterol Hepatol 2003;1:453–64. [81] Nishino T, Toki F, Oyama H, et al. Biliary tract involvement in autoimmune pancreatitis. Pancreas 2005;30:76–82. [82] Yamamoto M, Harada S, Ohara M, et al. Clinical and pathological differences between Mikulicz’s disease and Sjo¨gren’s syndrome. Rheumatology (Oxford) 2005;44:227–34. [83] Hirano K, Kawabe T, Komatsu Y, et al. High-rate pulmonary involvement in autoimmune pancreatitis. Intern Med J 2006; 36:58–61. [84] Saeki T, Nishi S, Ito T, et al. Renal lesions in IgG4-related systemic disease. Intern Med 2007;46:1365–71. [85] Nishimori I, Morita M, Kino J, et al. Pancreatic involvement in patients with Sjo¨gren’s syndrome and primary biliary cirrhosis. Int J Pancreatol 1995;17:47–54. [86] Kamisawa T, Tu Y, Nakajima H, et al. Sclerosing cholecystitis associated with autoimmune pancreatitis. World J Gastroenterol 2006;12:3736–9. [87] Gumbs AA, Kim J, Kiehna E, et al. Autoimmune pancreatitis presenting as simultaneous masses in the pancreatic head and gallbladder. JOP 2005;6:455–9. [88] Abraham SC, Cruz-Correa M, Argani P, et al. Lymphoplasmacytic chronic cholecystitis and biliary tract disease in patients with lymphoplasmacytic sclerosing pancreatitis. Am J Surg Pathol 2003;27:441–51. [89] Hyodo N, Hyodo T. Ultrasonographic evaluation in patients with autoimmune-related pancreatitis. J Gastroenterol 2003; 38:1155–61. [90] Uehara T, Hamano H, Kawa S, et al. Distinct clinicopathological entity ‘autoimmune pancreatitis-associated sclerosing cholangitis’. Pathol Int 2005;55:405–11. [91] Deshpande V, Chicano S, Finkelberg D, et al. Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol 2006;30:1537–45. [92] Erkelens GW, Vleggaar FP, Lesterhuis W, et al. Sclerosing pancreato-cholangitis responsive to steroid therapy. Lancet 1999;354:43–4. [93] van Buuren HR, Vleggaar FP, Willemien Erkelens G, et al. Autoimmune pancreatocholangitis: a series of ten patients. Scand J Gastroenterol 2006;243(Suppl):70–8. [94] Hayashi K, Nakazawa T, Ohara H, et al. Autoimmune sclerosing cholagiopancreatitis with little pancreatic involvements by imaging findings. Hepatogastroenterology 2007;54:2146–51. [95] Hamano H, Kawa S, Uehara T, et al. Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of a spectrum of autoimmune pancreatitis? Gastrointest Endosc 2005;62:152–7. [96] Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 2008;134:706–15. [97] Bjo¨rnsson E, Chari ST, Smyrk TC, Lindor K. Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on review of the literature. Hepatology 2007;45:1547–54. [98] Hirano K, Tada M, Isayama H, et al. Long-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment. Gut 2007;56:1719–24.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
2
Autoimmune pancreatitis and IgG4-associated sclerosing cholangitis Isao Nishimori, MD, Associate Professor a, *, Makoto Otsuki, MD, Professor b a
Department of Gastroenterology and Hepatology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan Department of Gastroenterology and Metabolism, University of Occupational and Environmental Health, Japan, School of Medicine, 1-1 Iseigaoka, Kitakyushu 807-8555, Japan b
Keywords: autoimmune pancreatitis sclerosing cholangitis IgG4 steroid therapy pathology
Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterised by a high serum IgG4 concentration and complications that include various extrapancreatic manifestations, one of which is sclerosing cholangitis. In AIP patients, infiltration of abundant IgG4-positive plasma cells and dense fibrosis are commonly observed in the pancreas and wall of the bile duct and gallbladder. The major symptom at onset of AIP is obstructive jaundice caused by stricture of the bile duct, and this requires differential diagnosis of AIP from pancreato-biliary malignancies and primary sclerosing cholangitis (PSC). Recently, there have been reports of particular cases of sclerosing cholangitis with a high serum IgG4 level and cholangiographic and pathological findings comparable to those observed in AIP patients. Being apparently different from PSC and similar to that in AIP, sclerosing cholangitis with and without AIP shows a clinical response to steroid therapy and thus is designated as ‘IgG4-associated sclerosing cholangitis’. The pathogenesis of AIP and IgG4-associated sclerosing cholangitis remains at yet undetermined. Ó 2008 Elsevier Ltd. All rights reserved.
In 1960s, Sarles et al reported cases of idiopathic chronic pancreatitis which showed hypergammaglobulinaemia, intense fibrosis, and a marked infiltration of lymphocytes and plasma cells in pancreatic tissue. They proposed a novel clinicopathological entity of chronic inflammatory sclerosis of the pancreas, or primary inflammatory pancreatitis [1,2]. Since then, similar cases of pancreatitis have appeared in the literature, with characteristic pathological findings, [3–6] and the condition has been designated lymphoplasmacytic sclerosing pancreatitis (LPSP) [6,7]. In these case reports, an * Corresponding author. Tel.: þ81 88 880 2338. E-mail address: [email protected] (I. Nishimori). 1521-6918/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2008.11.017
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autoimmune mechanism has been implicated in the pathogenesis of pancreatitis. However, extensive efforts in both clinical and basic research settings have failed to provide evidence that autoimmunity is a causative factor of the pancreatitis, [8,9] and thus there is no general consensus regarding ‘autoimmune pancreatitis (AIP)’ as an independent disease entity. The main reason for the failure was the absence of the clinical features characteristic of AIP, so it remains obscure among idiopathic chronic pancreatitides. Interestingly, most such cases of idiopathic chronic pancreatitis reported until the early 1990s showed a mass-like lesion in the pancreas head accompanied by strictures of the distal common bile duct (CBD) [3–5] or the hilar biliary ducts, [5] which are consistent with the findings currently known as AIP-associated sclerosing cholangitis. Some cases concomitantly showed retroperitoneal fibrosis, [4,5] which has been introduced as Ormond’s disease [10]. In addition, some of these reports noted irregular narrowing of the main pancreatic duct (MPD) on endoscopic retrograde cholangio-pancreatography (ERCP) [4]. In 1992, Toki et al focused on this unique ERCP finding, and then proposed a morphological clinical entity: a ‘duct-narrowing type’ of chronic pancreatitis [11]. In 1995, this atypical form of pancreatitis was adopted in the clinical diagnostic criteria for chronic pancreatitis proposed by the Japan Pancreas Society [12]. Subsequently, Toki’s group reported that patients with ‘duct-narrowing type’ of chronic pancreatitis showed a dramatic response to steroid therapy, and then finally proposed the concept of AIP [13]. Following this report, a number of case reports of AIP have appeared in the literature [14]. This was the major breakthrough for AIP, which began to emerge as a clinically and academically important disease. In 2001, the second breakthrough came with the discovery of an increased serum IgG4 level in AIP patients, which was identified by Hamano et al as a polyclonal band in the rapidly migrating fraction of g-globulins on serum electrogram [15]. Surprisingly, the use of a cut-off value for serum IgG4 concentrations of 135 mg/dL showed extremely high sensitivity, specificity and accuracy (more than 95%) for differentiating AIP patients from normal subjects, as well as patients with ordinary chronic pancreatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or Sjo¨gren’s syndrome (SjS) [15]. Along the same lines, abundant infiltration of IgG4-positive plasma cells with marked interstitial fibrosis was reported in the affected pancreatic tissue of AIP patients [15,16]. In addition, similar inflammatory processes were found in extrapancreatic lesions associated with AIP, as described below, but were not observed in the pancreas and salivary glands of patients with ordinary pancreatitis and seropositive (positive anti-SS-A/SS-B antibody) SjS [16]. These findings supported the concept that AIP was part of a much broader spectrum of systemic diseases, in which IgG4 plays some role in the pathogenesis, designated as IgG4-related sclerosing disease [17] or IgG4-associated multifocal systemic fibrosis [18]. Subsequently, various clinical researchers started to discriminate IgG4-related sclerosing disease from other inflammatory diseases in a number of organs, e.g. the liver, leading to IgG4-associated sclerosing cholangitis versus PSC. We review herein the clinical and pathological characteristics of AIP and sclerosing cholangitis, which is the most frequently observed extrapancreatic manifestation in AIP patients. Autoimmune pancreatitis Epidemiology Because AIP is a novel disease entity, there are no epidemiological studies apart from a nationwide survey in Japan which estimated the prevalence of AIP to be 0.82 per 100,000 [19]. This survey employed diagnostic criteria for AIP proposed by the Japanese Pancreas Society (JPS) in 2002, [20] in which the characteristic findings on pancreatic imaging should be observed in more than one third of the entire pancreas (see below) [20]. In 2006, the Japanese criteria were revised to exclude the extent limit displaying the abnormal pancreatic configuration (Japanese AIP criteria 2006), [21] because it was proved that some AIP cases were excluded by this limitation. Accordingly, the prevalence of AIP is currently estimated to be much higher than previously reported. In Japan, in the nationwide survey (2002) approximately half the patients (47%) showed disease onset in their sixties, [19] which is in agreement with reports from the United States [7] and Europe [22]. AIP occurs in both genders, but it is at least twice as common in men as in women (2.85 times in the nationwide survey 2002 in Japan) [19].
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Pathogenesis Several lines of evidence support the importance of immunological mechanisms in the pathogenesis of AIP. Linkage study of the human leukocyte antigen (HLA) genes showed that AIP was significantly associated with the DRB1*0405-DQB1*0401 alleles, [23] suggesting that a specific peptide triggers the autoimmune response. In addition, the substitution of aspartic acid with other amino acid residues at position 57 of the DQB1 sequence showed a significant association with relapse of AIP [24]. Among non-HLA genes, certain types of genetic polymorphisms in the Fc-receptor-like gene 3 [25] and cytotoxic-T-lymphocyte antigen 4 [26] showed a significant association with AIP, similar to observations in systemic lupus erythematosus (SLE) or autoimmune thyroiditis [27,28]. These findings suggest that AIP patients exhibit a particular genetic background predisposing to autoimmune disorders. AIP patients have increased serum levels of IgG4 with a high sensitivity of 73–90% at a cut-off value of 135–140 mg/dL [15,29,30]. They also display abundant infiltration of IgG4-positive cells in the pancreas [15,16,31,32]. Serum IgG4 in AIP patients was reported to react with ductal epithelial cells of the pancreas, biliary system and salivary gland [33]. Circulating autoantibodies to particular molecules – such as carbonic anhydrase II and IV, [34,35] lactoferrin, [36] and pancreatic secretory trypsin inhibitor [37] – have been reported in AIP patients. However, the target antigen recognised by the serum IgG4 antibodies is not defined, and the precise role of IgG4 in the pathogenesis of AIP is still uncertain. Recently, Okazaki et al reported an increased prevalence of naturally occurring CD4þCD25high regulatory T cells (Treg) and a decreased prevalence of CD4þCD25þCD45RAþ Treg (naive Treg) in the peripheral blood of AIP patients compared to healthy subject and patients with other types of pancreatitis [38]. In the pancreas and the portal area in the liver of AIP patients, IL-4-producing CD4þ cells (Th2 cells) and naturally occurring CD4þCD25þFoxp3þ Treg were predominantly observed along with infiltration of abundant IgG4-positive cells [39]. It is well known that naturally occurring Treg produce IL-10 and tumour growth factor b (TGF-b), resulting in IgG4 class switching on B cells and fibrogenesis [40]. IgG4 was reported to possess anti-inflammatory function [41] and rheumatoid factorlike activity capable of binding to IgG Fc via its Fab portion [42]. These findings suggest that a Th2dominant immune reaction primarily occurs in AIP patients and, as a secondary inhibitory response, IgG4-positive plasma cells infiltrate into the pancreas and extrapancreatic lesions, and serum IgG4 increases together with activation of naturally occurring Treg. Hardacre et al reported that 16% of 37 AIP patients had a clinical history of asthma [43]. An increased serum IgG4 is found in certain kinds of allergic disease, such as atopic dermatitis [44]. It has been reported that a Th2-dominant immune mechanism plays a major role in the allergic process, [40,45] and in contrast many autoimmune diseases display a Th1-dominant immune reaction [45]. Taking all findings together – except for one early study which showed a significantly increased prevalence of ginterferon- (g-IFN-)producing CD4þ cells (Th1 cells) in the peripheral blood of AIP patients [36] – it seems likely that the underlying immunological mechanism of AIP consists of an allergic reaction rather than an autoimmune reaction. Pathology Almost all AIP experts the world over, including pathologists and physicians, consider LPSP as the pathological hallmark of AIP. This is characterised by periductal lymphoplasmacytic infiltration with obliterative phlebitis and storiform fibrosis [6,7,16,22,39,46]. Interestingly, the European research group has proposed an additional histological subtype of AIP [22]. They studied pancreatic tissue specimens from 53 patients with chronic pancreatitis lacking findings to suggest its etiology [22]. The most significant histological findings in these patients were periductal lymphoplasmacytic infiltration, cuff-like periductal fibrosis and venulitis, which were consistent with LPSP. These patients were further subdivided into two groups according to the presence or absence of granulocyte epithelial lesions (GELs), and the clinical pictures were analysed comparatively (Fig. 1) [22]. In the AIP/GEL(þ) group, the male-to-female ratio was almost even, and an average age of disease onset was 40.5 years. These patients more often had inflammatory bowel disease (IBD) such as Crohn’s disease and ulcerative colitis (29%), as compared to patients in the AIP/GEL() group (7%). In the AIP/GEL() group patients were predominantly male, onset ages were older (mean age 64 years)
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Fig. 1. Clinicopathological subtypes of autoimmune pancreatitis 1. Version 1.0 (2001), proposed by Whitcomb et al. [46]. 2. Seronegative means absence of serum antibodies to SS-A (Ro) and SS-B (La) AIP, autoimmune pancreatitis; GEL, granulocytic epithelial lesion; IDCP, idiopathic duct-centric chronic pancreatitis; IDDP, idiopathic duct-destructive pancreatitis; LPSP, lymphoplasmacytic sclerosing pancreatitis.
than that in the AIP/GEL(þ) group, and the disease was more often complicated by sialoadenitis and retroperitoneal fibrosis. Pathologists from the Mayo Clinic also reported a similar classification of histological types of AIP [7]. They employed pancreatic tissue specimens surgically resected from 35 patients with idiopathic chronic pancreatitis, in which histological study showed periductal lymphoplasmacytic infiltration. They further subdivided these patients into two groups according to histological findings, idiopathic duct-centric chronic pancreatitis (IDCP) and LPSP. Interestingly, comparative analyses of clinical manifestations showed strong similarities between IDCP and the AIP/GEL(þ) group, as well as between the LPSP and AIP/GEL() groups (Fig. 1) [7]. Recently, the same group used the term idiopathic ductdestructive pancreatitis (IDDP) instead of IDCP, and reported that moderate to marked infiltration with those showing IDDP (n ¼ 12) [32]. In the TIGAR-O classification system for etiological risk factors associated with chronic pancreatitis, [46] AIP was subdivided to ‘isolated’ and ‘syndromic’ subgroups. In this classification system, syndromic AIP is associated with SjS, IBD and PBC. The different histological types of AIP discussed above possibly cause different spectra of complications. Thus, the panel of extrapancreatic manifestations in AIP patients as described below [47–49] also suggests that there may be two different clinicopathological types of AIP (Fig. 1). Clinical features The major symptom of AIP at onset is obstructive jaundice. From analysis of questionnaires in a nationwide survey for AIP in Japan, [19] 54.2% of 190 AIP patients, who fulfilled the Japanese diagnostic criteria proposed in 2006, [21] showed obstructive jaundice (unpublished data). In this case series abdominal pain, pyrexia, and abdominal tenderness were observed in 38.5%, 9.7%, and 19.7% of the patients, respectively. In AIP, severe abdominal pain is rare, but most patients complain of abdominal discomfort [50]. Screening blood tests show abnormal findings suggestive of obstructive jaundice. Table 1 shows results of immunological blood tests in AIP patients from the nationwide survey in Japan. [51] Antinuclear antibody and rheumatoid factor were observed in 63% and 28% of the patients, respectively. Disease-labelled antibodies such as anti-SS-A/SS-B antibodies for SjS and anti-mitochondrial antibody for PBC were scarcely observed, suggesting a clinical importance of these specific antibodies in differentially diagnosing these diseases from AIP. Increased levels of total IgG (1800 mg/dL) and IgG4 (135 mg/dL) showed relatively high sensitivities in accordance with previous reports, which showed elevated serum levels of total IgG and IgG4 in 42–70% and 73–90% of AIP patients, respectively
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Table 1 Serum autoantibody and immunoglobulin in autoimmune pancreatitis (AIP) patients. Autoantibody/immunoglobulin
Positive prevalence (n)
Anti-nuclear antibody Rheumatoid factor Anti-SS-A(Ro) antibody Anti-SS-B(La) antibody Anti-mitochondrial antibody g-globulin (2.0 g/dL) IgG (1800 mg/dL) IgA (500 mg/dL) IgM (300 mg/dL) IgG4 (135 mg/dL)
63% 28% 0% 2% 1% 46% 74% 3% 6% 83%
(179) (123) (132) (130) (96) (158) (185) (156) (156) (80)
Those patients fulfilling the revised diagnostic criteria for AIP 2006 in Japan [21] from analysis of second questionnaires in a nationwide survey for AIP in Japan [29].
[15,29,30]. However, it was recently reported that some patients with pancreatic cancer [52,53] or PSC [54,55] also showed an increased level of serum IgG4 with significant infiltration of IgG4-positive cells in the pancreas and liver, respectively. Although serum IgG4 is a sensitive marker for diagnosing AIP, it is not a gold standard for AIP. Typical cases of AIP show diffuse enlargement of the pancreas – the so-called sausage-like appearance – on computed tomography (CT), ultrasonography (US), and magnetic resonance imaging (MRI) (Fig. 2A) [13,14,30,47,50,56,57]. Dynamic CT and MRI show delayed enhancement of the swollen pancreas [56–58]. Some AIP cases show ‘a capsule-like rim’ surrounding the swollen pancreas
Fig. 2. Computed tomography and endoscopic retrograde cholangio-pancreatogram of a patient with autoimmune pancreatitis. (A) In a 64-year-old patient, contrast-enhanced computed tomography at onset revealed a diffusely swollen pancreas. (B) Endoscopic retrograde pancreatogram at onset showed diffusely irregular narrowing of the main pancreatic duct. (C) Following steroid therapy for 7 months, contrast-enhanced computed tomography at 5 years after onset in a 69-year-old patient revealed atrophic pancreas with dilated main pancreatic duct (arrows). (D) At 5 years after onset, endoscopic retrograde pancreatography showed a beaded appearance of the main pancreatic duct and stricture of the distal common bile duct.
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appearing as a low-density area on CT and a hypointense area on MRI, which is relatively specific and thus of diagnostic value for AIP [56–58]. ERCP shows diffuse narrowing of the MPD with some irregularity (Fig. 2B) [13,14,30,47,50,56]. Some atypical cases of AIP show a focal mass-like lesion in the pancreas and segmental narrowing of the MPD, which are often indistinguishable from pancreatic cancer [58–60]. In both diffuse and focal-lesion types of AIP, [18]F-fluorodeoxyglucose positron emission tomography shows a significant signal uptake, which means that this technique cannot differentiate between AIP and pancreatic cancer [61,62]. Diagnostic criteria To date, three systematic diagnostic criteria for AIP have been proposed from Japan, [21] the Mayo Clinic, [30] and Korea [63]. These criteria commonly include three major diagnostic categories: (1) findings on pancreatic imaging; (2) laboratory data; and (3) histological finding (see Table 2). As there are notable differences in these categories among three criteria, typical findings on imaging studies are essential for the diagnosis according to the Japanese and Korean criteria, but not according to the Mayo criteria. The latter emphasise the histological findings with LPSP as a gold standard for the diagnosis [30]. The critical differences between the Japanese and the other two diagnostic systems are in the use of ‘other organ involvement’ and ‘steroid responsiveness’. Employment of these factors in clinical diagnostic criteria possibly increases the risk that general physicians will employ steroid therapy in treatment of patients with pancreatic or biliary malignancy. Treatment Although the disease concept for AIP was based on the effectiveness of steroid therapy, [13] exact indications and optimal regimens of steroid therapy for AIP are still not well established. Recently, the Intractable Pancreatic Diseases Research team funded by the Japanese Ministry of Health, Labour and Welfare came up with a consensus proposal for the treatment of AIP (Fig. 3) [64]. It recommended that steroid therapy start with 30–40 mg (0.6 mg/kg body weight) of oral prednisolone per day. Following administration of the initial prednisolone dose for 2–4 weeks, the prednisolone dose will be tapered to
Table 2 Comparison of diagnostic criteria for autoimmune pancreatitis. Diagnostic factors
Japanese criteria 2006 [21] (RCIPD and JPS)
HISORt criteria 2006 [30] (Mayo Clinic)
Korean criteria 2007 [63] (KSPBD)
I. Imaging criteria
Essential Narrowing of the MPD plus enlargement of pancreas
Not essential Typical (same as JPS)
Essential Same as JPS
II. Laboratory criteria III. Histological criterion IV. Other organ involvement V. Response to steroida Definite diagnosis
g-globulin, IgG, or IgG4 Autoantibodies LPSP Not included Not included I þ II I þ III
Atypical forms: pancreatic atrophy, calcification or pancreatitis IgG4
LPSP (full spectrum) IgG4þ cells IgG4þ cells Response to steroid Pancreatic lesion Extrapancreatic lesion III (gold standard) I (typical) þ II I (atypical) þ II þ V I (atypical) þ IV (IgG4þ cells) þ V
IgG or IgG4 Autoantibodies LPSP IgG4þ cells IgG4þ cells Response to steroid Pancreatic lesion Extrapancreatic lesion I þ II I þ III I þ IV IþV
JPS, Japan Pancreas Society; RCIDP, The Research Committee on Intractable Pancreatic Diseases, Ministry of Health, Labour and Welfare of Japan; KSPBD, Korean Society of Pancreatobiliary Diseases; HISORt, histology, imaging, serology, other organ involvement, and response to steroid therapy; LPSP, lymphoplasmacytic sclerosing pancreatitis. a After negative work-up for known etiologies including cancer.
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Fig. 3. Standard regimen of steroid therapy for autoimmune pancreatitis with minor modification from the ‘consensus for a treatment of AIP’ proposed by the Intractable Pancreatic Diseases Research team funded by the Japanese Ministry of Health, Labour and Welfare [64].
a maintenance dose (5.0–7.5 mg prednisolone per day) for a total of 2–3 months. Evaluation of the disease activity in the course of steroid therapy requires biochemical blood tests such as serum gglobulin, IgG and IgG4, imaging findings, and clinical manifestations such as jaundice and abdominal discomfort [64]. The duration of maintenance therapy is still controversial. Chari recommended a total of 12 weeks of steroid therapy [65]. In our experience, however, AIP patients often show relapse of pancreatic and/or extrapancreatic manifestations within 3 years from the initiation of the steroid therapy (unpublished data), and thus the steroid therapy could possibly be maintained for at least 3 years. Relapse was reported in 6–26% of AIP patients [22,66–69]. When AIP patients relapse during or after steroid therapy, we would restart the steroid therapy, possibly with a high dose of prednisolone [70]. As a note of caution regarding steroid therapy, we avoid using steroid as a therapeutic diagnostic technique just to distinguish AIP from pancreatic or biliary malignancy. Kim et al observed that a marked improvement of pancreatic ductal narrowing by steroid administration may be a unique finding specific to AIP, and could be observed as early as 2 weeks after the initiation of steroid therapy [71]. However, pancreatic swelling in patients with pancreatic cancer, especially that developed due to upstream pancreatitis, could also be improved by steroid therapy. After administration of 30–40 mg/ day of prednisolone for 2 weeks, it takes at least an additional 1 or 2 weeks to completely quit the steroid therapy in order to avoid steroid hormone withdrawal syndrome, resulting in a delay in treating patients with pancreatic or biliary malignancy. Prior to steroid therapy, even in patients who fulfilled the minimum diagnostic criteria proposed by the Japanese group, a negative work-up of these malignancies should be attempted [30]. For this purpose, Levy et al reported the usefulness of EUSguided pancreatic biopsy by using a large-calibre (19-gauge) trucut needle [72]. The Mayo Clinic group reported that steroids should preferably not be given to patients in whom response cannot be objectively assessed: for example, patients without structural changes on imaging studies [65]. Prognosis The long-term prognosis for AIP remains as yet undefined. As the pancreatic exocrine and endocrine functions, as well as the morphological findings, are reversible after steroid therapy in most AIP cases, the prognosis for AIP seems better than that of chronic pancreatitis, which is usually followed by exocrine and endocrine pancreatic insufficiency with disease progression [69]. After steroid therapy, however, in some AIP cases both imaging and histological studies revealed morphological alterations similar to those observed in an advanced stage of ordinary pancreatitis (see Fig. 2C,D), [60,73,74] suggesting that AIP as currently diagnosed is a kind of early stage of chronic pancreatitis. Although the risk for progression to cancer in AIP is unknown, some AIP patients developed a malignancy during the follow-up period, including pancreatic cancer, probably due to its preponderance among elderly people [74–77].
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Extrapancreatic manifestations of AIP One of the prominent features of AIP is that it involves a variety of extrapancreatic diseases, including sclerosing cholangitis, [30,48,49,78–81] Mikulicz’s disease previously reported as seronegative (absence of anti-SS-A/SS-B antibody) SjS, [30,48,49,78,82] hypothyroidism, [50] hilar lymphoadenopathy, [30,48,49,78] retroperitoneal fibrosis, [30,48,49,78] interstitial pneumonia, [83] and tubulonephritis [84]. From the analysis of questionnaires obtained by the nationwide survey in Japan, [19] extrapancreatic manifestations of 191 AIP patients are shown in Fig. 4 [50]. The most frequently observed complication was sclerosing cholangitis (9.9%), followed by sialoadenitis (9.4%) and retroperitoneal fibrosis (7.3%). It is of note that this analysis excluded patients with stricture of only the distal CBD. Interstitial pneumonia and tubulonephritis were rarely seen (1%). Seropositive SjS, PSC, PBC and IBD are rarely observed in AIP patients showing histological findings of LPSP without GEL; [48] however, they have sometimes been reported in patients with idiopathic chronic pancreatitis [46,85] or the AIP subtype, which was diagnosed by the histological findings of IDCP (IDDP) or AIP/GEL(þ) (see above) [7,22].
IgG4-associated sclerosing cholangitis Imaging study Sclerosing cholangitis has been reported in 74–96% of AIP patients [49,78–81]. The analysis in the nationwide survey in Japan showed that a total of 81% of the patients (n ¼ 191) had a stricture of the bile ducts on ERCP [50] and that approximately half of the patients displayed obstructive jaundice at disease onset. Abnormalities were observed not only in the distal CBD (66%) but also in the hilar region (7.9%) and intrahepatic bile ducts (4.7%). Involvement of the gallbladder in AIP has also been reported [86,87]. AIP patients with sclerosing cholangitis show a cholangiographic appearance that is often confused with PSC, but careful observation on adequately represented cholangiography can discriminate these two types of cholangitis. Nakazawa et al reported that segmental strictures, dilation after confluent stricture, and strictures of the lower common bile duct were significantly more common in sclerosing cholangitis with AIP than PSC (Fig. 5). In contrast, band-like strictures, a beaded or pruned-tree appearance, and diverticulum-like out-pouching were indicative of PSC rather than sclerosing cholangitis with AIP [79]. Otherwise, a long-segmental and smooth-narrowing bile duct in sclerosing cholangitis with AIP is sometimes difficult to distinguish from that of cholangiocarcinoma [60,88]. Ultrasonography, CT and MRI showed wall thickening of the bile duct and gallbladder with delayed
Fig. 4. Extrapancreatic lesions in patients with autoimmune pancreatitis (AIP) from the analysis of second questionnaires obtained by a nationwide survey for AIP in Japan [51]. *Cases showing stricture of the extrapancreatic biliary system; cases showing stricture of only the distal common bile duct are excluded.
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Fig. 5. Cholangiogram of a patient (an 87-year-old male) with autoimmune pancreatitis. (A) Before steroid therapy, segmental strictures (arrows), dilation after confluent stricture, and strictures of the lower common bile duct (an arrowhead) are seen. (B) After steroid therapy, the abnormal findings observed before steroid therapy almost disappear.
enhancement as observed in the pancreas of AIP (Fig. 6) [55,80,81]. It is of note that the wall thickening of the biliary tract is seen even in the segment which shows no apparent abnormalities on cholangiography [80,89]. Pathology Histologically, dense infiltration of mononuclear cells including IgG4-positive plasma cells and massive fibrosis are observed in the wall of the biliary system in many patients with AIP [16,17,39,90–92]. Although PSC patients also show infiltration of IgG4-positive cells around the bile duct in the portal areas and the extrahepatic bile duct, the degree of the infiltration is significantly lower than that in AIP patients [90]. In both the pancreas and biliary-duct wall of AIP patients, IL-4-producing CD4þ cells (Th2 cells) and naturally occurring CD4þCD25þFoxp3þ Treg are predominantly observed as described above [39]. These findings indicate that the same mechanism plays a role in the disease process of pancreatitis and sclerosing cholangitis in AIP patients, which have been introduced as sclerosing pancreatocholangitis, [93] autoimmune pancreatocholangitis, [94] or autoimmune sclerosing cholangio-pancreatitis [95].
Fig 6. Computed tomography (CT) and magnetic resonance imaging (MRI) of a patient with autoimmune pancreatitis and sclerosing cholangitis. (A) Contrast-enhanced CT shows swelling of the pancreas head (star) and thickening of the walls of the bile duct and gallbladder (arrows). (B) T2-weighted MRI (coronary section) shows diffuse swelling of the pancreas (stars) and thickening of the walls of the bile duct and gallbladder (arrows).
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IgG4-associated sclerosing cholangitis without AIP Recently, several cases of sclerosing cholangitis with an increased serum IgG4 level but without apparent pancreatic lesion have been reported [88,95,96]. In these cases cholangiography revealed similar findings as observed in AIP patients with sclerosing cholangitis. Pathological study also showed infiltration of abundant IgG4-positive plasma cells in the bile duct wall, and thus they were designated as IgG4-related lymphoplasmacytic sclerosing cholangitis, [88] autoimmune sclerosing cholangitis, [95] or IgG4-associated cholangitis [97]. Although sclerosing cholangitis in AIP patients needs to be differentially diagnosed from cholangiocarcinoma and PSC, [79,91] in cases of sclerosing cholangitis without AIP it is especially difficult to discriminate these diseases [88,95]. Treatment and prognosis Being apparently different from PSC, IgG4-associated sclerosing cholangitis with and without AIP shows good response to the steroid therapy with the same regimen used for the pancreatic lesions in AIP patients. Improvement of the bile duct stricture diminishes obstructive jaundice, but approximately half the patients show persistent stricture of the CBD to some extent [81]. Multivariate analysis has indicated that obstructive jaundice at disease onset was a significant predictive factor for relapse of AIP and/or its extrapancreatic lesions [96]. Patients with the extrapancreatic bile duct lesion show a significantly higher relapse rate as compared to patients without it [98]. In patients with IgG4associated sclerosing cholangitis, careful observation for relapse of IgG4-related sclerosing diseases should be warranted during the course and after withdrawal of the steroid therapy. Practice points
AIP is often seen in elderly men there appear to be two clinicopathological subtypes of AIP among extrapancreatic lesions of AIP, sclerosing cholangitis is the most frequent some patients with IgG4-associated sclerosing cholangitis lack pancreatic manifestations steroid therapy is effective for AIP and IgG4-associated sclerosing cholangitis, but before therapy a work-up for possible pancreato-biliary malignancies should be negative
Research agenda the pathogenesis of AIP and IgG4-associataed sclerosing cholangitis needs to be defined prospective controlled studies are necessary to define an appropriate duration of steroid therapy in AIP and IgG4-associated sclerosing cholangitis the long-term prognosis of AIP and IgG4-associated sclerosing cholangitis need to be clarified
Conflict of interest No conflict of interest has been declared by the authors. Acknowledgement This work was supported in part by the Health and Labour Sciences Research Grant for Intractable Pancreatic Diseases. References [1] Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreasdan autonomous pancreatic disease? Am J Dig Dis 1961;6:688–98.
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[2] Sarles H, Sarles JC, Camatte R, et al. Observations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis. Gut 1965;6:545–59. [3] Nakano E, Takeda I, Kitamura K, et al. Vanishing tumor of the abdomen of in patients with Sjo¨gren’s syndrome. Am J Dig Dis 1978;23(Suppl):75S–79. [4] Renner IG, Ponto GC, Savage 3rd WT, Boswell WD. Idiopathic retroperitoneal fibrosis producing common bile duct and pancreatic duct obstruction. Gastroenterology 1980;79:348–51. [5] Laitt RD, Hubscher SG, Buckels JA, et al. Sclerosing cholangitis associated with multifocal fibrosis: a case report. Gut 1992; 33:1430–2. [6] Kawaguchi K, Koike M, Tsuruta K, et al. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol 1991;22:387–95. *[7] Notohara K, Burgart LJ, Yadav D, et al. Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases. Am J Surg Pathol 2003;27:1119–27. [8] Antal L, Kavai M, Szabo G, et al. Immunological investigations in acute and chronic human pancreatitis. Digestion 1980;20:100–5. [9] Lankisch PG, Koop H, Seelig R, Seelig HP. Antinuclear and pancreatic acinar cell antibodies in pancreatic diseases. Digestion 1981;21:65–8. [10] Dejaco C, Ferenci P, Schober E, et al. Stenosis of the common bile duct due to Ormond’s disease: case report and review of the literature. J Hepatol 1999;31:156–9. [11] Toki F, Kozu T, Oi I, Nakasato T, et al. An unusual type of chronic pancreatitis showing diffuse irregular narrowing of the entire main pancreatic duct on ERCP: a report of four cases [abstract]. Endoscopy 1992;24:640. [12] Homma T, Harada H, Koizumi M. Diagnostic criteria for chronic pancreatitis by the Japan Pancreas Society. Pancreas 1997; 15:14–5. [13] Yoshida K, Toki F, Takeuchi T, et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci 1995;40:1561–8. [14] Ito T, Nakano I, Koyanagi S, 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. *[15] Hamano H, Kawa S, Ochi Y, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet 2002;359:1403–4. [16] Kamisawa T, Funata N, Hayashi Y, et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut 2003;52:683–7. [17] Kamisawa T, Nakajima H, Egawa N, et al. IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy. Pancreatology 2006;6:132–7. [18] Tanabe T, Tsushima K, Yasuo M, et al. IgG4-associated multifocal systemic fibrosis complicating sclerosing sialadenitis, hypophysitis, and retroperitoneal fibrosis, but lacking pancreatic involvement. Intern Med 2006;45:1243–7. [19] Nishimori I, Tamakoshi A, Otsuki M, et al. Prevalence of autoimmune pancreatitis in Japan from a nationwide survey in 2002. J Gastroenterol 2007;42(Suppl 18):6–8. [20] Otsuki M. Autoimmune pancreatitis: a message from Japan. J Gastroenterol 2007;42(Suppl 18):1–5. [21] Okazaki K, Kawa S, Kamisawa T, et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal. J Gastroenterol 2006;41:626–531. *[22] Zamboni G, Lu¨ttges J, Capelli P, et al. Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens. Virchows Arch 2004;445:552–63. *[23] Kawa S, Ota M, Yoshizawa K, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology 2002;122:1264–9. [24] Park do H, Kim MH, Oh HB, et al. Substitution of aspartic acid at position 57 of the DQbeta1 affects relapse of autoimmune pancreatitis. Gastroenterology 2008;134:440–6. [25] Umemura T, Ota M, Hamano H, et al. Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients. Gut 2006;55:1367–8. [26] Umemura T, Ota M, Hamano H, et al. Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am J Gastroenterol 2008;103:588–94. [27] Kochi Y, Yamada R, Suzuki A, et al. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 2005;37:478–85. [28] Barreto M, Santos E, Ferreira R, et al. Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus. Eur J Hum Genet 2004;12:620–6. [29] Choi EK, Kim MH, Lee TY, et al. The sensitivity and specificity of serum immunoglobulin G and immunoglobulin G4 levels in the diagnosis of autoimmune chronic pancreatitis: Korean experience. Pancreas 2007;35:156–61. *[30] Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 2006;4:1010–6. [31] Kojima M, Sipos B, Klapper W, et al. Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells. Am J Surg Pathol 2007;31:521–8. [32] Zhang L, Notohara K, Levy MJ, et al. IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod Pathol 2007;20:23–8. [33] Aoki S, Nakazawa T, Ohara H, et al. Immunohistochemical study of autoimmune pancreatitis using anti-IgG4 antibody and patients’ sera. Histopathology 2005;47:147–58. [34] Kino-Ohsaki J, Nishimori I, Morita M, et al. Serum antibodies to carbonic anhydrase I and II in patients with idiopathic chronic pancreatitis and Sjo¨gren’s syndrome. Gastroenterology 1996;110:1579–86. [35] Nishimori I, Miyaji E, Morimoto K, et al. Serum antibodies to carbonic anhydrase IV in patients with autoimmune pancreatitis. Gut 2005;54:274–81. [36] Okazaki K, Uchida K, Ohana M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2type cellular immune response. Gastroenterology 2000;118:573–81. [37] Asada M, Nishio A, Uchida K, et al. Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. Pancreas 2006;33:20–6.
22
I. Nishimori, M. Otsuki / Best Practice & Research Clinical Gastroenterology 23 (2009) 11–23
[38] Miyoshi H, Uchida K, Taniguchi T, et al. Circulating naı¨ve and CD4þCD25high regulatory T cells in patients with autoimmune pancreatitis. Pancreas 2008;36:133–40. *[39] Zen Y, Fujii T, Harada K, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 2007;45:1538–46. [40] Robinson DS, Larche´ M, Durham SR. Tregs and allergic disease. J Clin Invest 2004;114:1389–97. [41] van der Neut Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 2007;317:1554–7. [42] Kawa S, Kitahara K, Hamano H, et al. A novel immunoglobulin-immunoglobulin interaction in autoimmunity. PLoS ONE 2008;3: e1637. [43] Hardacre JM, Iacobuzio-Donahue CA, Sohn TA, et al. Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis. Ann Surg 2003;237:853–8. [44] Aalberse RC, Van Milligen F, Tan KY, Stapel SO. Allergen-specific IgG4 in atopic disease. Allergy 1993;48:559–69. [45] Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 2003;8: 223–46. [46] Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682–707. [47] Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol 2006;41: 613–25. [48] Ohara H, Nakazawa T, Sano H, et al. Systemic extrapancreatic lesions associated with autoimmune pancreatitis. Pancreas 2005;31:232–7. *[49] Hamano H, Arakura N, Muraki T, et al. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol 2006;41:1197–205. [50] Kawa S, Hamano H. Clinical features of autoimmune pancreatitis. J Gastroenterol 2007;42(Suppl 18):9–14. [51] Nishimori I, Onishi S, Otsuki M. Nationwide survey for autoimmune pancreatitis in Japan. J Jpn Panc Soc 2007;22:651–6 (in Japanese with English abstract). [52] Ghazale A, Chari ST, Smyrk TC, et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol 2007;102:1646–1453. [53] Kamisawa T, Chen PY, Tu Y, et al. Pancreatic cancer with a high serum IgG4 concentration. World J Gastroenterol 2006;12: 6225–8. [54] Mendes FD, Jorgensen R, Keach J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol 2006;101:2070–5. [55] Hirano K, Kawabe T, Yamamoto N, et al. Serum IgG4 concentrations in pancreatic and biliary diseases. Clin Chim Acta 2006;367:181–4. [56] Sahani DV, Kalva SP, Farrell J, et al. Autoimmune pancreatitis: imaging features. Radiology 2004;233:345–52. [57] Irie H, Honda H, Baba S, et al. Autoimmune pancreatitis: CT and MR characteristics. AJR Am J Roentgenol 1998;170:1323–7. [58] Kamisawa T, Egawa N, Nakajima H, et al. Clinical difficulties in the differentiation of autoimmune pancreatitis and pancreatic carcinoma. Am J Gastroenterol 2003;98:2694–9. [59] Tabata M, Kitayama J, Kanemoto H, et al. Autoimmune pancreatitis presenting as a mass in the head of the pancreas: a diagnosis to differentiate from cancer. Am Surg 2003;69:363–6. [60] Nakazawa T, Ohara H, Sano H, et al. Difficulty in diagnosing autoimmune pancreatitis by imaging findings. Gastrointest Endosc 2007;65:99–108. [61] Nakamoto Y, Saga T, Ishimori T, et al. FDG-PET of autoimmune-related pancreatitis: preliminary results. Eur J Nucl Med 2000;27:1835–8. [62] Nakajo M, Jinnouchi S, Fukukura Y, et al. The efficacy of whole-body FDG-PET or PET/CT for autoimmune pancreatitis and associated extrapancreatic autoimmune lesions. Eur J Nucl Med Mol Imaging 2007;34:2088–95. [63] Ryu JK. Overview of diagnostic criteria for autoimmune pancreatitis. Korean J Panc Bilary Tract 2007;12:105–12. *[64] Ito T, Nishimori I, Inoue N, et al. Treatment for autoimmune pancreatitis: consensus on the treatment for patients with autoimmune pancreatitis in Japan. J Gastroenterol 2007;42(Suppl 18):50–8. *[65] Chari ST. Current concepts in the treatment of autoimmune pancreatitis. JOP 2007;8:1–3. [66] Wakabayashi T, Kawaura Y, Satomura Y, et al. Long-term prognosis of duct-narrowing chronic pancreatitis: strategy for steroid treatment. Pancreas 2005;30:31–9. [67] Takayama M, Hamano H, Ochi Y, et al. Recurrent attacks of autoimmune pancreatitis result in pancreatic stone formation. Am J Gastroenterol 2004;99:932–7. [68] Kim KP, Kim MH, Song MH, et al. Autoimmune chronic pancreatitis. Am J Gastroenterol 2004;99:1605–16. [69] Kamisawa T, Okamoto A, Wakabayashi T, et al. Appropriate steroid therapy for autoimmune pancreatitis based on longterm outcome. Scand J Gastroenterol 2008;43:609–13. [70] Kamisawa T, Okamoto A. Prognosis of autoimmune pancreatitis. J Gastroenterol 2007;42(Suppl 18):59–62. [71] Kim MH, Kwon S. Diagnostic criteria for autoimmune chronic pancreatitis. J Gastroenterol 2007;42(Suppl 18):42–9. [72] Levy MJ, Reddy RP, Wiersema MJ, et al. EUS-guided trucut biopsy in establishing autoimmune pancreatitis as the cause of obstructive jaundice. Gastrointest Endosc 2005;61:467–72. [73] Suda K, Nishimori I, Takase M, et al. Autoimmune pancreatitis can be classified into early and advanced stages. Pancreas 2006;33:345–50. [74] Nishino T, Toki F, Oyama H, et al. Long-term outcome of autoimmune pancreatitis after oral prednisolone therapy. Intern Med 2006;45:497–501. [75] Inoue H, Miyatani H, Sawada Y, Yoshida Y. A case of pancreas cancer with autoimmune pancreatitis. Pancreas 2006;33: 208–9. [76] Kubota K, Iida H, Fujisawa T, et al. Clinical factors predictive of spontaneous remission or relapse in cases of autoimmune pancreatitis. Gastrointest Endosc 2007;66:1142–51. [77] Fukui T, Mitsuyama T, Takaoka M, et al. Pancreatic cancer associated with autoimmune pancreatitis in remission. Intern Med 2008;47:151–5.
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[78] Kamisawa T, Egawa N, Nakajima H, et al. Extrapancreatic lesions in autoimmune pancreatitis. J Clin Gastroenterol 2005; 39:904–7. *[79] Nakazawa T, Ohara H, Sano H, et al. Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis. Gastrointest Endosc 2004;60:937–44. [80] Hirano K, Shiratori Y, Komatsu Y, et al. Involvement of the biliary system in autoimmune pancreatitis: a follow-up study. Clin Gastroenterol Hepatol 2003;1:453–64. [81] Nishino T, Toki F, Oyama H, et al. Biliary tract involvement in autoimmune pancreatitis. Pancreas 2005;30:76–82. [82] Yamamoto M, Harada S, Ohara M, et al. Clinical and pathological differences between Mikulicz’s disease and Sjo¨gren’s syndrome. Rheumatology (Oxford) 2005;44:227–34. [83] Hirano K, Kawabe T, Komatsu Y, et al. High-rate pulmonary involvement in autoimmune pancreatitis. Intern Med J 2006; 36:58–61. [84] Saeki T, Nishi S, Ito T, et al. Renal lesions in IgG4-related systemic disease. Intern Med 2007;46:1365–71. [85] Nishimori I, Morita M, Kino J, et al. Pancreatic involvement in patients with Sjo¨gren’s syndrome and primary biliary cirrhosis. Int J Pancreatol 1995;17:47–54. [86] Kamisawa T, Tu Y, Nakajima H, et al. Sclerosing cholecystitis associated with autoimmune pancreatitis. World J Gastroenterol 2006;12:3736–9. [87] Gumbs AA, Kim J, Kiehna E, et al. Autoimmune pancreatitis presenting as simultaneous masses in the pancreatic head and gallbladder. JOP 2005;6:455–9. [88] Abraham SC, Cruz-Correa M, Argani P, et al. Lymphoplasmacytic chronic cholecystitis and biliary tract disease in patients with lymphoplasmacytic sclerosing pancreatitis. Am J Surg Pathol 2003;27:441–51. [89] Hyodo N, Hyodo T. Ultrasonographic evaluation in patients with autoimmune-related pancreatitis. J Gastroenterol 2003; 38:1155–61. [90] Uehara T, Hamano H, Kawa S, et al. Distinct clinicopathological entity ‘autoimmune pancreatitis-associated sclerosing cholangitis’. Pathol Int 2005;55:405–11. [91] Deshpande V, Chicano S, Finkelberg D, et al. Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol 2006;30:1537–45. [92] Erkelens GW, Vleggaar FP, Lesterhuis W, et al. Sclerosing pancreato-cholangitis responsive to steroid therapy. Lancet 1999;354:43–4. [93] van Buuren HR, Vleggaar FP, Willemien Erkelens G, et al. Autoimmune pancreatocholangitis: a series of ten patients. Scand J Gastroenterol 2006;243(Suppl):70–8. [94] Hayashi K, Nakazawa T, Ohara H, et al. Autoimmune sclerosing cholagiopancreatitis with little pancreatic involvements by imaging findings. Hepatogastroenterology 2007;54:2146–51. [95] Hamano H, Kawa S, Uehara T, et al. Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of a spectrum of autoimmune pancreatitis? Gastrointest Endosc 2005;62:152–7. [96] Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 2008;134:706–15. [97] Bjo¨rnsson E, Chari ST, Smyrk TC, Lindor K. Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on review of the literature. Hepatology 2007;45:1547–54. [98] Hirano K, Tada M, Isayama H, et al. Long-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment. Gut 2007;56:1719–24.