Kendo Kiyosawa

High Serum IgG4 Concentrations in Patients with Sclerosing Pancreatitis

BACKGROUNDnSclerosing 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.nnnMETHODSnWe 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnPatients 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.

Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis

Sclerosing pancreatitis is associated with raised concentrations of IgG4. We treated 22 patients with sclerosing pancreatitis, and identified and followed-up three with concomitant hydronephrosis caused by ureteral mass, later diagnosed as retroperitoneal fibrosis. We histologically examined the ureteral and pancreatic lesions of these patients and noted abundant infiltration of IgG4-bearing plasma cells in both tissues. Treatment with corticosteroids lowered serum concentrations of IgG4. IgG4 might also have a pathological role in a systemic fibrosing process that includes pancreatic and retroperitoneal lesions.

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.)

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

BACKGROUNDnAutoimmune 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.nnnMETHODSnClinical 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.nnnOBSERVATIONSnAll 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.nnnCONCLUSIONSnThe use of IgG4 immunostaining in biopsy specimens of the bile duct may identify the presence of corticosteroid-responsive lymphoplasmacytic sclerosing cholangitis.

Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors

The interferon sensitivity determining region (ISDR) of the hepatitis C virus (HCV) and T‐helper type 1 and type 2 (Th1/Th2) ratio were analyzed along with other host and viral factors for their ability to predict the response of patients with chronic hepatitis C to pegylated interferon alpha‐2b (Peg‐IFN) and ribavirin (RBV) combination therapy. A total of 120 chronic hepatitis C patients with genotype 1 HCV and high baseline viral loads who were to undergo combination therapy scheduled for 48 weeks were enrolled. Sustained virologic response (SVR) was achieved in 54 (45%) of the 120 patients. The pretreatment factors significantly associated with SVR by logistic regression analysis were ISDR mutant [odds ratio (OR) = 86.0, P = 0.0008], Th1/Th2 ratio ≤ 15.5 (OR = 9.6, P = 0.0021), body weight 59 kg, and neutrophil count 2,300/μL. A logistic regression model to estimate SVR before combination therapy was constructed using these four factors. Patients fell into three groups when plotted according to estimated and actual SVR rates: actual SVR rate was 91% (32/35) in the high sensitivity group, 41% (15/37) in the intermediate sensitivity group, and 15% (7/48) in the low sensitivity group. Rapid or early virological responses were seen in 80% of patients with high sensitivity and who achieved SVR but were found in only 40% of patients with intermediate or low sensitivity. Null‐ and very late virological responses were quite rare in the high sensitivity group. In conclusion, a logistic regression model that includes the sequence of ISDR of the HCV, Th1/Th2 ratio, body weight, and neutrophil count can be useful for accurately predicting actual SVR rate before combination therapy. (HEPATOLOGY 2008;48:1753‐1760.)

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.

Mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis B virus infection in Japan

Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection was found in 23 (4%) of 552 newly hepatitis B surface antigen-positive patients in Japan. Because one-fourth of cases develop into fulminant hepatic failure and mortality is 100%, management of HBV reactivation in patients with resolved HBV infection should be discussed.

Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients

Autoimmune pancreatitis is characterised by irregular narrowing of the main pancreatic duct, swelling of the pancreas, histological evidence of lymphoplasmacytic inflammation, and high serum immunoglobulin G4 (IgG4) concentration.1–4 Although the human leucocyte antigen DRB1*0405-DQB1*0401 haplotype has been associated with autoimmune pancreatitis,5 the role of genetic factors has not yet been fully defined. A new family of genes called Fc receptor-like genes ( FCRL s), which have high structural homology with classical Fcγ receptor genes, has recently been identified.6,7 FCRL3 polymorphisms have been shown to be associated with various autoimmune diseases, such as rheumatoid arthritis, autoimmune thyroid disease, and systemic lupus erythematosus, in Japanese populations.8,9 These polymorphisms alter the binding affinity of nuclear factor κB and regulate FCRL3 expression. FCRL3 expression on B cells has been observed in significant amounts and …