Hideaki Hamano

High Serum IgG4 Concentrations in Patients with Sclerosing Pancreatitis

BACKGROUND Sclerosing pancreatitis is a unique form of pancreatitis that is characterized by irregular narrowing of the main pancreatic duct, lymphoplasmacytic inflammation of the pancreas, and hypergammaglobulinemia and that responds to glucocorticoid treatment. Preliminary studies suggested that serum IgG4 concentrations are elevated in this disease but not in other diseases of the pancreas or biliary tract. METHODS We measured serum IgG4 concentrations using single radial immunodiffusion and an enzyme-linked immunosorbent assay in 20 patients with sclerosing pancreatitis, 20 age- and sex-matched normal subjects, and 154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjögrens syndrome. Serum concentrations of immune complexes and the IgG4 subclass of immune complexes were determined by means of an enzyme-linked immunosorbent assay with monoclonal rheumatoid factor. RESULTS The median serum IgG4 concentration in the patients with sclerosing pancreatitis was 663 mg per deciliter (5th and 95th percentiles, 136 and 1150), as compared with 51 mg per deciliter (5th and 95th percentiles, 15 and 128) in normal subjects (P<0.001). The serum IgG4 concentrations in the other groups of patients were similar to those in the normal subjects. In patients with sclerosing pancreatitis, serum concentrations of immune complexes and the IgG4 subclass of immune complexes were significantly higher before glucocorticoid therapy than after four weeks of such therapy. Glucocorticoid therapy induced clinical remissions and significantly decreased serum concentrations of IgG4, immune complexes, and the IgG4 subclass of immune complexes. CONCLUSIONS Patients with sclerosing pancreatitis have high serum IgG4 concentrations, providing a useful means of distinguishing this disorder from other diseases of the pancreas or biliary tract.

Standard steroid treatment for autoimmune pancreatitis

Objective: To establish an appropriate steroid treatment regimen for autoimmune pancreatitis (AIP). Methods: A retrospective survey of AIP treatment was conducted in 17 centres in Japan. The main outcome measures were rate of remission and relapse. Results: Of 563 patients with AIP, 459 (82%) received steroid treatment. The remission rate of steroid-treated AIP was 98%, which was significantly higher than that of patients without steroid treatment (74%, 77/104; p<0.001). Steroid treatment was given for obstructive jaundice (60%), abdominal pain (11%), associated extrapancreatic lesions except the biliary duct (11%), and diffuse enlargement of the pancreas (10%). There was no relationship between the period necessary to achieve remission and the initial dose (30 mg/day vs 40 mg/day) of prednisolone. Maintenance steroid treatment was given in 377 (82%) of 459 steroid-treated patients, and steroid treatment was stopped in 104 patients. The relapse rate of patients with AIP on maintenance treatment was 23% (63/273), which was significantly lower than that of patients who stopped maintenance treatment (34%, 35/104; p = 0.048). From the start of steroid treatment, 56% (55/99) relapsed within 1 year and 92% (91/99) relapsed within 3 years. Of the 89 relapsed patients, 83 (93%) received steroid re-treatment, and steroid re-treatment was effective in 97% of them. Conclusions: The major indication for steroid treatment in AIP is the presence of symptoms. An initial prednisolone dose of 0.6 mg/kg/day, is recommend, which is then reduced to a maintenance dose over a period of 3–6 months. Maintenance treatment with low-dose steroid reduces but dose not eliminate relapses.

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.

Immunoglobin G4-hepatopathy: Association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis†

Autoimmune pancreatitis (AIP) is characterized by high serum immunoglobin (Ig) G4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Since liver dysfunction is frequently seen in AIP patients, we investigated hepatic histopathology and its clinical significance in patients with AIP. We examined the clinical features, histology, and immunoglobin G (IgG)4‐bearing plasma cell infiltration of liver biopsies from 17 patients with AIP and 63 patients with either autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or chronic viral hepatitis and histological changes in the 7 of 17 livers before and after glucocorticoid therapy. The liver histology of AIP was classified into 5 patterns: evident portal inflammation with or without interface hepatitis (6 cases), large bile‐duct obstructive features (8 cases), portal sclerosis (8 cases), lobular hepatitis (5 cases), and canalicular cholestasis (4 cases); some of the histological features coexisted in the same liver. The number of IgG4‐bearing plasma cells was significantly higher in AIP patients than controls (P < 0.01), and was significantly correlated with serum IgG4 concentration (P = 0.0014, r = 0.709). Glucocorticoid therapy reduced IgG4‐bearing plasma cell infiltration in the liver (P = 0.031) and ameliorated other histological findings. In conclusion, virtually all AIP liver biopsies showed evidence of various pathological changes and infiltration of IgG4‐bearing plasma cells. These features were ameliorated by steroid therapy, suggesting that the liver is concurrently affected in AIP, and that liver biopsies can provide significant information in the clinical evaluation and diagnosis of AIP. (HEPATOLOGY 2007.)

Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012

BackgroundIgG4-sclerosing cholangitis (IgG4-SC) patients have an increased level of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a good response to steroid therapy. However, it is not easy to distinguish IgG4-SC from primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma on the basis of cholangiographic findings alone because various cholangiographic features of IgG4-SC are similar to those of the above progressive or malignant diseases.MethodsThe Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare, Japan and the Japan Biliary Association have set up a working group consisting of researchers specializing in IgG4-SC, and established the new clinical diagnostic criteria of IgG4-SC 2012.ResultsThe diagnosis of IgG4-SC is based on the combination of the following 4 criteria: (1) characteristic biliary imaging findings, (2) elevation of serum IgG4 concentrations, (3) the coexistence of IgG4-related diseases except those of the biliary tract, and (4) characteristic histopathological features. Furthermore, the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm accurate diagnosis of IgG4-SC.ConclusionThese diagnostic criteria for IgG4-SC are useful in practice for general physicians and other nonspecialists.

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.

Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma : part of a spectrum of autoimmune pancreatitis?

BACKGROUND Autoimmune pancreatitis has been designated as sclerosing pancreatocholangitis, because this disease shows a high prevalence of bile-duct lesions. We present herein the clinical characteristics of unusual cases that show dominant bile-duct lesions and mimicking infiltrating hilar cholangiocarcinomas. METHODS Clinical and pathologic findings of 3 patients with immunoglobulin (Ig) G4 related sclerosing cholangitis who had no apparent pancreatic lesions comparable with autoimmune pancreatitis were analyzed. OBSERVATIONS All patients were middle-aged or elderly individuals with slightly elevated serum IgG4 concentrations and showed long-segment narrowing of the bile-duct system, mimicking infiltrating hilar cholangiocarcinoma without significant pancreatic change. The first patient was treated with a corticosteroid, resulting in amelioration of the narrowing of the bile duct. The second patient underwent surgery based on a diagnosis of cholangiocarcinoma. In the third patient, the bile-duct stricture reversed spontaneously 1 month after the drainage procedure. Pathologic findings of the bile ducts for all patients disclosed significant lymphoplasmacytic infiltration, including abundant IgG4-bearing plasma cells. CONCLUSIONS The use of IgG4 immunostaining in biopsy specimens of the bile duct may identify the presence of corticosteroid-responsive lymphoplasmacytic sclerosing cholangitis.

Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis.

PURPOSE Autoimmune pancreatitis is a unique form of chronic pancreatitis characterized by a variety of extra-pancreatic involvements which are frequently misdiagnosed as lesions of corresponding organs. The purpose of this study was to clarify the diagnostic imaging features of extra-pancreatic lesions associated with autoimmune pancreatitis. MATERIALS AND METHODS We retrospectively analyzed diagnostic images of 90 patients with autoimmune pancreatitis who underwent computer-assisted tomography, magnetic resonance imaging, and/or gallium-67 scintigraphy before steroid therapy was initiated. RESULTS AIP was frequently (92.2%) accompanied by a variety of extra-pancreatic lesions, including swelling of lachrymal and salivary gland lesions (47.5%), lung hilar lymphadenopathy (78.3%), a variety of lung lesions (51.2%), wall thickening of bile ducts (77.8%), peri-pancreatic or para-aortic lymphadenopathy (56.0%), retroperitoneal fibrosis (19.8%), a variety of renal lesions (14.4%), and mass lesions of the ligamentum teres (2.2%). Characteristic findings in CT and MRI included lymphadenopathies of the hilar, peri-pancreatic, and para-aortic regions; wall thickening of the bile duct; and soft tissue masses in the kidney, ureters, aorta, paravertebral region, ligamentum teres, and orbit. CONCLUSIONS Recognition of the diagnostic features in the images of various involved organs will assist in the diagnosis of autoimmune pancreatitis and in differential diagnoses between autoimmune pancreatitis-associated extra-pancreatic lesions and lesions due to other pathologies.

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.

High prevalence of hypothyroidism in patients with autoimmune pancreatitis.

Autoimmune pancreatitis is a unique form of chronic pancreatitis and has been correlated with various extrapancreatic lesions. To search for a correlation between autoimmune pancreatitis and thyroid lesions, we measured thyroid functions in 41 patients with autoimmune pancreatitis and in 41 patients with chronic calcifying pancreatitis and investigated the correlation between HLA antigens and hypothyroidism. We found a significant difference in the prevalence of antithyroglobulin antibody and hypothyroidism between patients with autoimmune pancreatitis and those with chronic pancreatitis (34.1 vs. 7.3%, P = 0.005, and 26.8 vs. 0%, P = 0.0005, respectively). Patients with hypothyroidism had a significantly higher frequency of antithyroglobulin antibody (63.6%) than those without hypothyroidism but showed no differences in other findings, including serum IgG4 concentration. We could find no significant association between any HLA antigens and the hypothyroid state of autoimmune pancreatitis. One quarter of the patients with autoimmune pancreatitis have hypothyroidism that may be independent of the active state of the pancreatic lesion or systemic fibrosing disorder, and thus patients suspected of having autoimmune pancreatitis should be evaluated for possible hypothyroidism.