Seiichi Hara

Short and Long-Term Outcomes of Diabetes Mellitus in Patients with Autoimmune Pancreatitis after Steroid Therapy

Background/Aims Autoimmune pancreatitis (AIP) is frequently associated with diabetes mellitus (DM). This study evaluated the effect of steroid therapy on the course of DM in AIP. Methods Glucose tolerance was examined in 69 patients with AIP. DM onset was classified as either a simultaneous onset with AIP or an exacerbation of pre-existing DM. Based on the changes in the HbA1c levels and insulin dose, the responses of DM to steroids were classified as improved, no change, or worsened. Results Thirty (46%) patients were diagnosed as having DM (simultaneous onset, n=17; pre-existing, n=13). Three months after starting the steroid treatment, the DM improved in 13 (54%) of 24 DM patients. The DM improved in 55%, had no change in 36%, and worsened in 9% of the 11 simultaneous onset DM patients, and it improved in 54%, had no change in 31%, and worsened in 15% of the 13 pre-existing DM patients. At approximately 3 years after starting the steroid treatment, the DM improved in 10 (63%) of 16 patients. The pancreatic exocrine function improved in parallel with the changes in the DM in seven patients. Conclusions Because approximately 60% of DM associated with AIP is responsive to steroids in the short- and long-terms, marked DM associated with AIP appears to be an indication for steroid therapy.

Intraductal papillary mucinous neoplasm of the pancreas and IgG4-related disease: A coincidental association

BACKGROUND/AIMS Coexistence of autoimmune pancreatitis (AIP) and pancreatic cancer, elevation of serum IgG4 levels in pancreatic cancer patients, and infiltration of IgG4-positive plasma cells in peritumorous pancreatitis have been described in a few reports. This study examined the relationship between intraductal papillary mucinous neoplasm (IPMN) of the pancreas and peritumorous IgG4-positive lymphoplasmacytic infiltrates. METHODS Serum IgG4 levels were measured in 54 patients with IPMN (median 70 years, 26 males and 28 females; 13 main duct type and 41 branch duct type). Histological findings focusing on dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis were reviewed, and immunostaining with IgG4 and IgG was performed in 23 surgically resected IPMN cases (18 main duct type and 5 branch duct type). The presence of IgG4-positive plasma cells >10/hpf and an IgG4-positive/IgG-positive plasma cell ratio >40% were considered significant. RESULTS Serum IgG4 levels were elevated in 2 (4%) IPMN patients. Significant infiltration of IgG4-positive plasma cells was detected in 4 IPMN cases (17%). The IgG4-positive/IgG-positive plasma cell ratio was >40% in all 4 cases. In one case with a markedly elevated serum IgG4 level (624 mg/dL), typical lymphoplasmacytic sclerosing pancreatitis (AIP type 1) lesions surrounded the whole IPMN. In the 3 other cases, infiltration of IgG4-positive plasma cells with fibrosis was focally detected mainly in the periductal area around the IPMN. CONCLUSIONS In a few patients with IPMNs, IgG4-positive plasma cell infiltration can occur in the peritumorous area. The association of an IPMN with AIP type 1-like changes seems to be exceptional and coincidental.

Differentiating Immunoglobulin G4-Related Sclerosing Cholangitis from Hilar Cholangiocarcinoma

Background/Aims Few studies have differentiated immunoglobulin G (IgG) 4-related sclerosing cholangitis (IgG4-SC) from hilar cholangiocarcinoma (CC). Thus, we sought to investigate useful features for differentiating IgG4-SC from hilar CC. Methods We retrospectively compared clinical, serological, imaging, and histological features of six patients with IgG4-SC and 42 patients with hilar CC. Results In patients with hilar CC, obstructive jaundice was more frequent (p<0.01), serum total bilirubin levels were significantly higher (p<0.05), serum CA19-9 levels were significantly higher (p<0.01), and serum duke pancreatic monoclonal antigen type 2 levels were frequently elevated (p<0.05). However, in patients with IgG4-SC, the serum IgG (p<0.05) and IgG4 (p<0.01) levels were significantly higher and frequently elevated. The pancreas was enlarged in all IgG4-SC patients but only in 17% of hilar CC patients (p<0.01). Salivary and/or lacrimal gland swelling was detected in only 50% of IgG4-SC patients (p<0.01). Endoscopic retrograde cholangiography revealed that the hilar or hepatic duct was completely obstructed in 83% of hilar CC patients (p<0.01). Lower bile duct stenosis, apart from hilar bile duct stenosis, was more frequent in IgG4-SC patients (p<0.01). Bile duct wall thickening in areas without stenosis was more frequent in IgG4-SC patients (p<0.01). Conclusions An integrated diagnostic approach based on clinical, serological, imaging, and histological findings is necessary to differentiate IgG4-SC from hilar CC.

Clinical Characteristics of Patients with Autoimmune Pancreatitis with or without Mikulicz's Disease and Mikulicz's Disease Alone

Background/Aims The objective of this study was to compare the clinical characteristics of patients with autoimmune pancreatitis (AIP) with or without Mikuliczs disease (MD) and with MD alone. Methods We investigated the clinical findings in 15 AIP patients with MD (group A+M), 49 AIP only patients (group A), and 14 MD only patients (group M). Results The male-female ratio was significantly higher in group A+M (73%, p<0.05) and group A (78%, p<0.01) than group M (21%). Serum immunoglobulin G (IgG) levels were significantly higher in group A+M than in group A (p<0.01) and group M (p<0.05). Serum IgG4 levels were significantly higher in group A+M than in group A (p<0.01). Other organ involvement was observed in 73% (11/15) of patients in group A+M. The number of patients with diabetes mellitus was significantly higher in group A+M (66%, p<0.01) and group A (51%, p<0.05) than in group M (7%). All of the patients responded well to steroid therapy, but the relapse rate in group A+M (33%) was significantly higher than that in group A (3%, p<0.01). Salivary gland function was impaired in all groups compared with the control group, but the degree of dysfunction was less in group A compared with group A+M and group M. Conclusions The relapse rate of AIP in MD patients was significantly higher than that of AIP in patients without MD.

Management strategies for autoimmune pancreatitis

Introduction: Autoimmune pancreatitis (AIP) is a newly developed concept for a peculiar type of pancreatitis, and at present is recognized as a pancreatic lesion reflecting IgG4-related systemic disease. It is of utmost importance to differentiate AIP from pancreatic cancer to avoid unnecessary surgery. Areas covered: The current management strategies for AIP, including its clinical features, diagnostic criteria, clinical subtypes, steroid therapy and prognosis are discussed, based on our 66 AIP cases and papers searched in PubMed from 1992 to March 2011, using the term ‘autoimmune pancreatitis’. A new clinicopathological entity, an ‘IgG4-related sclerosing disease’ is also mentioned. Expert opinion: AIP should be considered in the differential diagnosis in elderly male patients presented with obstructive jaundice and pancreatic mass. Steroids are a standard therapy for AIP, but their regimen including maintenance therapy should be evaluated in prospective trials.

Ulcerative Colitis and Immunoglobulin G4

Background/Aims Ulcerative colitis (UC) is sometimes associated with autoimmune pancreatitis (AIP). Infiltration of immunoglobulin G4 (IgG4)-positive plasma cells is sometimes detected in the colonic mucosa of AIP or UC patients. This study aimed to clarify the relation between UC and IgG4. Methods Associations with UC were reviewed in 85 AIP patients. IgG4 immunostaining was performed on biopsy specimens from the colonic mucosa of 14 AIP and 32 UC patients. Results UC was confirmed in two cases (type 1 AIP, n=1; suspected type 2 AIP, n=1). Abundant infiltration of IgG4-positive plasma cells in the colonic mucosa was detected in the case of suspected type 2 AIP with UC and two cases of type 1 AIP without colitis. Abundant infiltration of IgG4-positive plasma cells was detected in 10 UC cases (IgG4-present, 31%). Although 72% of IgG4-absent UC patients showed mild disease activity, 70% of IgG4-present patients showed moderate to severe disease activity (p<0.05). Conclusions UC is sometimes associated with AIP, but it seems that UC is not a manifestation of IgG4-related disease. Infiltration of IgG4-positive plasma cells is sometimes detectable in the colonic mucosa of UC patients and is associated with disease activity.

Importance of early diagnosis of pancreaticobiliary maljunction without biliary dilatation

AIM To clarify the strategy for early diagnosis of pancreaticobiliary maljunction (PBM) without biliary dilatation and to pathologically examine gallbladder before cancer develops. METHODS The anatomy of the union of the pancreatic and bile ducts was assessed by using endoscopic retrograde cholangiopancreatography (ERCP). Patients with a long common channel in which communication between the pancreatic and bile ducts was maintained even during sphincter contraction were diagnosed as having PBM. Of these, patients in which the maximal diameter of the bile duct was less than 10 mm were diagnosed with PBM without biliary dilatation. The process of diagnosing 54 patients with PBM without biliary dilatation was retrospectively investigated. Histopathological analysis of resected gallbladder specimens from 8 patients with PBM without biliary dilatation or cancer was conducted. RESULTS Thirty-six PBM patients without biliary dilatation were diagnosed with gallbladder cancer after showing clinical symptoms such as abdominal or back pain (n = 16) or jaundice (n = 12). Radical surgery for gallbladder cancer was only possible in 11 patients (31%) and only 4 patients (11%) survived for 5 years. Eight patients were suspected as having PBM without biliary dilatation from the finding of gallbladder wall thickening on ultrasound and the diagnosis was confirmed by ERCP and/or magnetic resonance cholangiopancreatography (MRCP). The median age of these 8 patients was younger by a decade than PBM patients with gallbladder cancer. All 8 patients underwent prophylactic cholecystectomy and bile duct cancer has not occurred. Wall thickness and mucosal height of the 8 resected gallbladders were significantly greater than controls, and hyperplastic changes, hypertrophic muscular layer, subserosal fibrosis, and adenomyomatosis were detected in 7 (88%), 5 (63%), 7 (88%) and 5 (63%) patients, respectively. Ki-67 labeling index was high and K-ras mutation was detected in 3 of 6 patients. CONCLUSION To detect PBM without biliary dilatation before onset of gallbladder cancer, we should perform MRCP for individuals showing increased gallbladder wall thickness on ultrasound.

Recent advances in autoimmune pancreatitis

It is now clear that are two histological types (Type-1 and Type-2) of autoimmune pancreatitis (AIP). The histological pattern of Type-1 AIP, or traditional AIP, is called lymphoplasmacytic sclerosing pancreatitis (LPSP). The histological pattern of Type-2 AIP is characterized by neutrophilic infiltration in the epithelium of the pancreatic duct. In general, Type-2 AIP patients are younger, may not have a male preponderance, and rarely show elevation of serum IgG4 compared with Type-1 AIP patients. Unlike Type-1 AIP patients, Type-2 AIP patients rarely have associated sclerosing diseases, but they are more likely to have acute pancreatitis and ulcerative colitis. Although Type-2 AIP is sometimes observed in the USA and Europe, most AIP cases in Japan and Korea are Type-1. The international consensus diagnostic criteria for AIP comprise 5 cardinal features, and combinations of one or more of these features provide the basis for diagnoses of both Type-1 and Type-2 AIP. Due to the fact that steroid therapy is clinically, morphologically, and serologically effective in AIP patients, it is the standard therapy for AIP. The indications for steroid therapy in AIP include symptoms such as obstructive jaundice and the presence of symptomatic extrapancreatic lesions. Oral prednisolone (0.6 mg/kg/day) is administered for 2–4 weeks and gradually tapered to a maintenance dose of 2.5–5 mg/day over a period of 2–3 months. Maintenance therapy by low-dose prednisolone is usually performed for 1–3 years to prevent relapse of AIP.

ABO blood type, long-standing diabetes, and the risk of pancreatic cancer

AIM To retrospectively study pancreatic cancer patients with respect to their ABO blood type and diabetes. METHODS Our analysis included a cohort of 1017 patients with pancreatic ductal cancer diagnosed at our hospital in Tokyo. They were divided into two groups: 114 patients with long-standing type 2 diabetes (DM group, defined as diabetes lasting for at least three years before the diagnosis of pancreatic cancer) and 903 patients without diabetes (non-DM group). Multivariate analysis was performed to identify factors that are associated with long-standing diabetes. The DM group was further divided into three subgroups according to the duration of diabetes (3-5 years, 5.1-14.9 years, and 15 years or more) and univariate analyses were performed. RESULTS Of the 883 pancreatic cancer patients with serologically assessed ABO blood type, 217 (24.6%) had blood type O. Compared with the non-DM group, the DM group had a higher frequency of blood type B [odds ratio (OR) = 2.61, 95%CI: 1.24-5.47; reference group: blood type A]. Moreover, male (OR = 3.17, 95%CI: 1.67-6.06), older than 70 years of age (OR = 2.19, 95%CI: 1.20-3.98) and presence of a family history of diabetes (OR = 6.21, 95%CI: 3.38-11.36) were associated with long-standing type 2 diabetes. The mean ages were 64.8 ± 9.2 years, 67.1 ± 9.8 years, and 71.7 ± 7.0 years in the subgroups with the duration of diabetes, 3-5 years, 5.1-14.9 years, and 15 years or more, respectively (P = 0.007). A comparison of ABO blood type distribution among the subgroups also showed a significant difference (P = 0.03). CONCLUSION The association of pancreatic cancer with blood type and duration of diabetes needs to be further examined in prospective studies.

Differences between diffuse and focal autoimmune pancreatitis

AIM To investigate differences in clinical features between diffuse- and focal-type autoimmune pancreatitis (AIP). METHODS Based on radiological findings by computed tomography and/or magnetic resonance imaging, we divided 67 AIP patients into diffuse type (D type) and focal type (F type). We further divided F type into head type (H type) and body and/or tail type (B/T type) according to the location of enlargement. Finally, we classified the 67 AIP patients into three groups: D type, H type and B/T type. We compared the three types of AIP in terms of clinical, laboratory, radiological, functional and histological findings and clinical course. RESULTS There were 34 patients with D-type, 19 with H-type and 14 with B/T-type AIP. Although obstructive jaundice was frequently detected in D-type patients (88%) and H-type patients (68%), no B/T-type patients showed jaundice as an initial symptom (P < 0.001). There were no differences in frequency of abdominal pain, but acute pancreatitis was associated more frequently in B/T-type patients (36%) than in D-type patients (3%) (P = 0.017). Serum immunoglobulin G (IgG)4 levels were significantly higher in D-type patients (median 309 mg/dL) than in B/T-type patients (133.5 mg/dL) (P = 0.042). Serum amylase levels in B/T-type patients (median: 114 IU/L) were significantly greater than in H-type patients (72 IU/L) (P = 0.049). Lymphoplasmacytic sclerosing pancreatitis (LPSP) was histologically confirmed in 6 D-type, 7 H-type and 4 B/T-type patients; idiopathic duct-centric pancreatitis was observed in no patients. Marked fibrosis and abundant infiltration of CD20-positive B lymphocytes with few IgG4-positive plasma cells were detected in 2 B/T-type patients. Steroid therapy was effective in all 50 patients (31 D type, 13 H type and 6 B/T type). Although AIP relapsed during tapering or after stopping steroids in 3 D-type and 3 H-type patients, no patients relapsed in B/T type. During follow-up, radiological features of 6 B/T-type patients were not changed and 1 B/T-type patient improved naturally. CONCLUSION Clinical features of H-type AIP were similar to those of D-type, but B/T-type differed from D and H types. B/T-type may involve diseases other than LPSP.