Norikazu Arakura

Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis

BackgroundAutoimmune pancreatitis is a unique form of chronic pancreatitis characterized by high serum IgG4 concentrations and abundant IgG4-bearing plasma cell infiltration in the pancreatic lesion, and it has been reported to be associated with a variety of extrapancreatic lesions, leading us to postulate the concept of a systemic inflammatory disease. To confirm this, we clarified the exact distribution of these extrapancreatic lesions and provide a panoramic view of them.MethodsThe frequency, distribution, clinical characteristics, and pathology of five extrapancreatic lesions were determined in 64 patients with autoimmune pancreatitis by examining clinical and laboratory findings.ResultsThe most frequent extrapancreatic lesion was hilar lymphadenopathy (80.4%), followed by extrapancreatic bile duct lesions (73.9%), lachrymal and salivary gland lesions (39.1%), hypothyroidism (22.2%), and retroperitoneal fibrosis (12.5%). No patients had all five types of lesions. Patients with hilar lymphadenopathy or lachrymal and salivary gland lesions were found to have significantly higher IgG4 levels than those without (P = 0.0042 and 0.0227, respectively). Patients with three lesions were found to have significantly higher IgG4 levels than those with no lesion, suggesting that patients with multiple extrapancreatic lesions have active disease. Similar to pancreatic lesions, extrapancreatic lesions have a characteristic histological finding of abundant IgG4-bearing plasma cell infiltration, and they respond favorably to corticosteroid therapy.ConclusionsAutoimmune pancreatitis was recognized as a systemic inflammatory disease. Furthermore, recognition of these characteristic findings will aid in the correct diagnosis of this disease.

Recurrent attacks of autoimmune pancreatitis result in pancreatic stone formation.

OBJECTIVES:Autoimmune pancreatitis has been characterized by irregular narrowing of the main pancreatic duct and sonolucent swelling of the parenchyma, both of which are due to lymphoplasmacytic inflammation at the active stage of the disease, and by the absence of pancreatic stone formation. The aim of the present study was to confirm or deny whether or not this disease is progressive with recurrent attacks, resulting in pancreatic stone formation like ordinary chronic pancreatitis.METHODS:Forty-two patients, 36 of whom were treated with prednisolone, were followed up for periods longer than 12 months (median follow-up period: 54.5 months, range: 13–111 months) by regular interview and examination of their medical records for laboratory tests and image tests.RESULTS:Eleven patients (26.2%) who were treated with prednisolone showed recurrent attacks during median follow-up periods of 22 months. Eight patients (19%) showed the formation of pancreatic stones during the follow-up periods. Because 6 of 11 patients (54.5%) who suffered relapse showed pancreatic stone formation, it is significantly associated with relapse in comparison with nonrelapse (p = 0.0019).CONCLUSIONS:Contrary to previous reports, we observed both relapse and pancreatic stone formation in some patients with autoimmune pancreatitis, which suggests that autoimmune pancreatitis has the potential to be a progressive disease with pancreatic stones.

Autoimmune pancreatitis and complement activation system.

Objectives: Autoimmune pancreatitis is characterized by increased serum level of IgG4, but its pathogenesis has not been fully elucidated. Because this disease is occasionally associated with decreased levels of complements, we sought to clarify which complement activation system was operating in its active state. Methods: We measured serum levels of complements, mannose-binding lectin, and circulating immune complex in patients with autoimmune pancreatitis, patients with chronic pancreatitis, and healthy controls. Results: We found high serum circulating immune complex values, which decreased significantly after corticosteroid therapy. In patients with autoimmune pancreatitis, elevated levels of circulating immune complex, as determined by C1q assay, were significantly associated with increased serum levels of IgG1 and decreased levels of C4, as well as with a tendency toward decreased levels of C3. There were no significant differences in the serum levels of mannose-binding lectin or in the frequency of a mutant allele of mannose-binding lectin between patients with autoimmune pancreatitis and those with chronic calcifying pancreatitis. Furthermore, corticosteroid therapy had no effect on the level of mannose-binding lectin. Conclusions: Autoimmune pancreatitis exhibits a high serum circulating immune complex values in its active state, which links to a complement activation system with a classic pathway rather than the mannose-binding lectin pathway or alternative pathways.

Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients.

OBJECTIVES:Autoimmune pancreatitis (AIP) is characterized by high serum IgG4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Although the HLA DRB1*0405-DQB1*0401 haplotype and Fc receptor-like 3 polymorphisms have been associated with AIP, the role of other genetic factors is largely unknown. As cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with several autoimmune diseases, we sought to determine if CTLA4 polymorphisms and serum sCTLA4 levels were associated with AIP as well.METHODS:Five CTLA4 polymorphisms, located at −1722, −658, and −318 in the promoter, +49 in exon 1, and +6230 in the 3′ untranslated region, were genotyped in 59 patients with AIP and 102 healthy subjects. Serum sCTLA4 levels were also determined in cohorts of 52 patients and 32 controls.RESULTS:Compared with healthy subjects, we found a significant increase in the +6230 G/G genotype (64% vs 42%, odds ratio [OR] 2.48, P = 0.011) in AIP patients. Haplotype 2, which had the +6230A, was associated with AIP resistance (OR 0.49, P = 0.011). The +49A/A and +6230A/A genotypes were associated with an enhanced risk of relapse (OR 5.45, P = 0.038 and OR 12.66, P = 0.022). Additionally, median serum sCTLA4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL, P < 0.001). The +6230 G/A polymorphism did not influence sCTLA4 levels in AIP patients.CONCLUSIONS:Our findings suggest that AIP is associated with a genetic polymorphism in CTLA4 and is positively correlated with serum sCTLA4 levels.

Differentiation of autoimmune pancreatitis from suspected pancreatic cancer by fluorine-18 fluorodeoxyglucose positron emission tomography

BackgroundFluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been widely used for the diagnosis of pancreatic cancer. Because autoimmune pancreatitis is easily misdiagnosed as pancreatic cancer and can be tested for by FDG-PET analysis based on the presence of suspected pancreatic cancer, we attempted to clarify the differences in FDG-PET findings between the two conditions.MethodsWe compared FDG-PET findings between 15 patients with autoimmune pancreatitis and 26 patients with pancreatic cancer. The findings were evaluated visually or semiquantitatively using the maximum standardized uptake value and the accumulation pattern of FDG.ResultsFDG uptake was found in all 15 patients with autoimmune pancreatitis, whereas it was found in 19 of 26 patients (73.1%) with pancreatic cancer. An accumulation pattern characterized by nodular shapes was significantly more frequent in pancreatic cancer, whereas a longitudinal shape indicated autoimmune pancreatitis. Heterogeneous accumulation was found in almost all cases of autoimmune pancreatitis, whereas homogeneous accumulation was found in pancreatic cancer. Significantly more cases of pancreatic cancer showed solitary localization, whereas multiple localization in the pancreas favored the presence of autoimmune pancreatitis. FDG uptake by the hilar lymph node was significantly more frequent in autoimmune pancreatitis than in pancreatic cancer, and uptake by the lachrymal gland, salivary gland, biliary duct, retroperitoneal space, and prostate were seen only in autoimmune pancreatitis.ConclusionsFDG-PET is a useful tool for differentiating autoimmune pancreatitis from suspected pancreatic cancer, if the accumulation pattern and extrapancreatic involvement are considered. IgG4 measurement and other current image tests can further confirm the diagnosis.

A Novel Immunoglobulin-Immunoglobulin Interaction in Autoimmunity

Well over six decades since its first description, the Rheumatoid Factor (RF)—autoantibodies recognizing Fc (constant) portion of IgG through their own Fab (antigen binding variable segments)—is believed to have come of age. Autoimmune pancreatitis is a unique form of pancreatitis, biologically characterized by an elevated serum IgG4 concentration. Given the fact that IgG4 myeloma proteins can act as RF, we initially hypothesized that IgG4 in autoimmune pancreatitis might do likewise, hence potentially contributing to disease pathogenesis. Indeed Western blotting clearly showed that IgG4 binds to IgG1 κ, IgG2 κ, IgG3 κ myeloma proteins, as well as to IgG Fc, in line with a typical RF activity. Further experiments however unraveled the unexpected fact that unlike hitherto known RF, IgG4 does not engage IgG Fc through its Fab, but its very own Fc. These data therefore collectively describe a Novel RF (NRF) in autoimmune pancreatitis. In the future, the relevance of NRF, beyond autoimmune pancreatitis, in both diagnosis/prognosis as well as pathophysiology of autoimmune and other systemic diseases where IgG4s role seems paramount, needs to be systematically assessed.

Clinical features of a new disease concept, IgG4-related thyroiditis

Objectives: Immunoglobulin (Ig)G4-related disease is a recently proposed systemic disorder that includes autoimmune pancreatitis (AIP), Mikulicz’s disease, and various other organ lesions. In the present retrospective study, we examined whether thyroid lesions should also be included in IgG4-related disease (Ig4-RD) under the new term IgG4-related thyroiditis. Method: We enrolled 114 patients with Ig4-RD, including 92 patients with AIP, 15 patients with Mikulicz’s disease, and seven patients with IgG4-related cholangitis, and analysed clinical findings, function, serum values of activity markers, computed tomography (CT) images, and histology of the thyroid gland. Results: Among the 22 patients (19%) in our cohort who were found to have hypothyroidism [thyroid stimulating hormone (TSH) > 4 mIU/L], 11 patients had clinical hypothyroidism [free thyroxine (FT4) < 1 ng/dL] and 11 patients had subclinical hypothyroidism (FT4 ≥ 1 ng/dL). Serum concentrations of IgG, IgG4, circulating immune complex (CIC), and β2-microglobulin (β2-MG) were significantly higher in the hypothyroidism group compared with the remaining 92 euthyroid patients, and serum C3 concentration was significantly lower. After prednisolone treatment, TSH values had decreased significantly (p = 0.005) in this group and FT4 values had increased significantly (p = 0.047). CT images showed that the thyroid glands of patients with clinical hypothyroidism had a significantly greater volume than those of the euthyroid and other groups. Pathological analysis of one resected thyroid gland disclosed a focused lesion with infiltration of lymphocytes and IgG4-bearing plasma cells and loss of thyroid follicles. Conclusions: Thyroid lesions associated with hypothyroidism can be considered as a new disease termed IgG4-related thyroiditis. Awareness of this condition should lead to appropriate corticosteroid treatment that may prevent progression to a fibrous state.

Long-Term Follow-Up of Autoimmune Pancreatitis: Characteristics of Chronic Disease and Recurrence

Autoimmune pancreatitis is a unique disease, characterized by lymphoplasmacytic inflammation in the acute stages. However, the active clinical features are unlikely to persist for long periods. Through long-term follow-up, we investigated the disease course in 51 patients with autoimmune pancreatitis. We found recurrence in 21 (41%) patients and pancreatic stone formation in 9 (18%) patients. Pancreatic stone formation was significantly more frequent in the recurrence group (7/21, 33%), compared with the nonrecurrence group (2/30, 7%). Moreover, we found high serum immunoglobulin G4 concentrations in 13 of 175 (7.4%) patients with ordinary chronic pancreatitis. This suggested that pancreatic stone formation is closely associated with recurrence and that autoimmune pancreatitis might transform into ordinary chronic pancreatitis after several recurrences. We found that the immune complex level, with a cutoff value of 10 microg/dL, served as a good predictor of recurrence, with high sensitivity (61.9%), specificity (70.0%), and efficacy (66.7%). We also confirmed that HLA and cytotoxic T-lymphocyte antigen-4 polymorphisms were useful predictors for AIP recurrence.

Efficacy of preoperative endoscopic nasobiliary drainage for hilar cholangiocarcinoma

BACKGROUND/PURPOSE Although percutaneous transhepatic biliary drainage has previously been recommended as a primary preoperative step, endoscopic nasobiliary drainage (ENBD) is prevalent as an alternative procedure. Few reports assess the efficacy and safety of ENBD in a substantial patient cohort. METHODS Of 116 patients with hilar cholangiocarcinoma who underwent surgery, 62 (43 men and 19 women, median age 69 years) underwent preoperative ENBD. After classification of lesions according to Bismuth-Corlette (B-C) criteria, we evaluated efficacy and safety with respect to B-C type. RESULTS Patients were classified as B-C types I (n = 5), II (n = 21), IIIa (n = 23), IIIb (n = 5), and IV (n = 8). Preoperative single ENBD was effective in 46/62 patients (74%) including 5/5 (100%) B-C type I, 20/21 (94%) type II, 16/23 (70%) type IIIa, 4/5 (80%) type IIIb, and 1/8 (13%) type IV. Sixteen cases (26%) required additional drainages with ENBD or endoscopic biliary stenting (EBS) in 8/16 (50%), and with PTBD in 8/16 (50%). Mild acute pancreatitis (n = 1, 2%), segmental cholangitis (n = 2, 3%), and acute cholangitis with catheter obstruction (n = 7, 11%) occurred with ENBD. CONCLUSIONS Preoperative single ENBD in the future remnant lobe is effective treatment for B-C type I-III hilar cholangiocarcinoma. Preoperative ENBD was rarely complicated with segmental cholangitis.

The Utility of Serum IgG4 Concentrations as a Biomarker

IgG4-related disease is a new disease entity involving IgG4 in its clinical presentation and having 6 characteristic features: (1) systemic involvement; (2) solitary or multiple lesions showing diffuse or localized swelling, masses, nodules, and/or wall thickening on imaging; (3) high serum IgG4 concentration >135 mg/dL; (4) abundant infiltration of lymphoplasmacytes and IgG4-bearing plasma cells; (5) a positive response to corticosteroid therapy; and (6) complications of other IgG4-related diseases. To date, most IgG4-related diseases have been recognized as extrapancreatic lesions of autoimmune pancreatitis. This paper will discuss the utility of IgG4 as a biomarker of IgG4-related diseases, including in the diagnosis of autoimmune pancreatitis and its differentiation from pancreatic cancer, in the prediction of relapse, in the long-term follow-up of patients with autoimmune pancreatitis and normal or elevated IgG4 concentrations, and in patients with autoimmune pancreatitis and extrapancreatic lesions, as well as the role of IgG4 in the pathogenesis of IgG4-related disease.