Masahiro Maruyama

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.

Type 1 Autoimmune Pancreatitis Can Transform into Chronic Pancreatitis: A Long-Term Follow-Up Study of 73 Japanese Patients

Some patients with autoimmune pancreatitis (AIP) form pancreatic stones suggestive of transformation into chronic pancreatitis (CP). The present study examined the underlying risk factors and mechanism of AIP progression to confirmed CP. We compared the clinical and laboratory parameters of subjects who progressed to confirmed CP with those of the subjucts who did not in a cohort of 73 type 1 AIP patients. A total of 16 (22%) AIP patients progressed to CP. Univariate analysis revealed that relapse was significantly more frequent in the progression group, and multivariate analysis indicated that pancreatic head swelling (OR 12.7, P = 0.023) and nonnarrowing of the main pancreatic duct in the pancreatic body (OR 12.6, P = 0.001) were significant independent risk factors for progression to CP. Kaplan-Meier testing showed that the progression rate to CP was approximately 10% at 3 years and 30% at 10 years in total AIP patients and 30% at 3 years and 60% at 10 years in subjects with both risk factors. AIP with pancreatic head swelling and a history of relapse may cause pancreatic juice stagnation and nonnarrowing of the main pancreatic duct in the pancreatic body, which can progress to advanced stage chronic pancreatitis.

Association Between Immunoglobulin G4–related Disease and Malignancy within 12 Years after Diagnosis: An Analysis after Longterm Followup

Objective. Because it is uncertain whether immunoglobulin G4–related disease (IgG4-RD) is associated with malignancy, we evaluated the incidence of cancer development in a large cohort of patients with IgG4-RD. Methods. The study enrolled 158 patients diagnosed as having IgG4-RD between 1992 and 2012. We calculated the standardized incidence ratio (SIR) and cumulative rate of malignancies in this group and searched for risk factors associated with the occurrence of tumors. Results. A total of 34 malignancies were observed in the patients with IgG4-RD over a mean followup period of 5.95 ± 4.48 years. The overall SIR of malignancies was 2.01 (95% CI 1.34–2.69). The SIR of patients who exhibited a tumor within 1 year after IgG4-RD diagnosis was 3.53 (95% CI 1.23–5.83), while that of subjects forming a malignancy in subsequent years was 1.48 (95% CI 0.99–1.98). The cumulative rate of malignancy development was significantly higher in patients with IgG4-RD within 12 years after diagnosis than in the Japanese general population. Comparable results were obtained for an autoimmune pancreatitis subgroup. The serum concentrations of several disease activity markers at diagnosis were significantly higher in patients with malignancies than in those without. Conclusion. We identified a close association between IgG4-RD and malignancy formation within 12 years after diagnosis, particularly during the first year. An active IgG4-RD state is presumed to be a strong risk factor for malignancy development.

International Consensus Diagnostic Criteria for Autoimmune Pancreatitis and Its Japanese Amendment Have Improved Diagnostic Ability over Existing Criteria

Objectives. The recent International Consensus Diagnostic Criteria (ICDC) for autoimmune pancreatitis (AIP) and its Japanese amendment developed by the Japanese Pancreas Society (JPS 2011) may have overcome the drawbacks of earlier criteria and achieved a higher diagnostic ability for AIP. The aim of the present study is to evaluate this possibility and identify the underlying causes of this change. Methods. We compared the diagnostic abilities of the ICDC and JPS 2011 with those of the Japanese diagnostic criteria 2006 (JPS 2006), Korean diagnostic criteria (Korean), Asian diagnostic criteria (Asian), and HISORt diagnostic criteria in 110 patients with AIP and 31 patients with malignant pancreatic cancer. Results. The ICDC achieved the highest diagnostic ability in terms of accuracy (95.0%), followed by JPS 2011 (92.9%), Korean (92.2%), HISORt (88.7%), Asian (87.2%), and JPS 2006 (85.1%). Nearly all criteria systems exhibited a high specificity of 100%, indicating that the enhanced diagnostic ability of the ICDC and JPS 2011 likely stemmed from increased sensitivity brought about by inclusion of diagnostic items requiring no endoscopic retrograde pancreatography. The diagnostic ability of JPS 2011 was nearly equivalent to that of the ICDC. Conclusions. The ICDC and JPS 2011 have improved diagnostic ability as compared with earlier criteria sets because of an increase in sensitivity.

Autoimmune pancreatitis can develop into chronic pancreatitis

Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into ordinary chronic pancreatitis resembling alcoholic pancreatitis over a long-term course based on several clinical findings, most notably frequent pancreatic stone formation. In this review article, we describe a series of study results to confirm our hypothesis and clarify that: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of AIP patients experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsung’s and Santorini’s ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised Japanese Clinical Diagnostic Criteria, with independent risk factors being pancreatic head swelling and non-narrowing of the pancreatic body duct.

Mechanisms of lower bile duct stricture in autoimmune pancreatitis.

Objectives We attempted to clarify the mechanism underlying lower bile duct stricture in autoimmune pancreatitis. Methods Imaging and histologic finding of the bile duct were assessed for 73 patients with autoimmune pancreatitis to clarify whether IgG4-related biliary inflammation or pancreatic head swelling is associated with lower bile duct stricture. Results Lower bile duct stricture was found in 59 (81%) patients. Pancreatic head swelling was significantly more frequent among patients with lower bile duct stricture than those patients without lower bile duct stricture (53 [90%] vs 4 [29%]; P < 0.01). Intraductal ultrasonography findings revealed lower bile duct wall thickening in 21 (95%) of the 22 patients with lower bile duct stricture, and the lower bile duct wall of the patients with pancreatic head swelling was significantly thicker than those patients without pancreatic head swelling (P = 0.028). Among the 38 patients with lower bile duct biopsies, 14 (37%) exhibited abundant IgG4-bearing plasma cell infiltration. Among the patients with lower bile duct stricture, an IgG4-related inflammation seemed to exert a dominant effect under limited conditions, including concomitant middle bile duct stricture and neither pancreatic swelling nor pancreatic duct stricture in the head region. Conclusions Both pancreatic head swelling and IgG4-related biliary inflammation affect lower bile duct stricture, which may be included in IgG4-related sclerosing cholangitis. Pancreatic head swelling affects IgG4-related biliary wall thickening.

Comparison of carbon dioxide and air insufflation use by non-expert endoscopists during endoscopic retrograde cholangiopancreatography.

Background:  Endoscopic retrograde cholangiopancreatography (ERCP) is subject to several complications that include a lengthy procedure time, technical difficulty, and active bowel movement induced by air insufflation. In ERCP carried out by non‐expert endoscopists who are prone to excessive luminal insufflation, insufflation with carbon dioxide (CO2) may provide better and safer outcomes. We aimed to assess the efficacy and safety of CO2 insufflation during ERCP by non‐expert endoscopists.

Autoimmune Pancreatitis Can Transform Into Chronic Features Similar to Advanced Chronic Pancreatitis With Functional Insufficiency Following Severe Calcification.

Objectives Because several studies for autoimmune pancreatitis (AIP) have revealed pancreatic calcification resembling that in chronic pancreatitis (CP), we sought to clarify whether AIP could transform into chronic features similar to advanced CP with severe pancreatic dysfunction. Methods Pancreatic functions of 92 AIP patients, 47 definite CP patients, and 30 healthy controls were assessed by fecal elastase-1 concentration (FEC), fasting immunoreactive insulin (IRI), and homeostatic model assessment (HOMA)-R. Results The 92 AIP patients included 17 (18%) with severe calcification (SC) and 75 without. The FEC levels in AIP and CP patients were significantly lower than that in controls. Exocrine insufficiency defined as FEC less than 200 &mgr;g/g was 39% in AIP without SC, 56% in AIP with SC, and 74% in CP. Fasting IRI and C-peptide reactivity values in CP were significantly lower than those in AIP, with no significant differences between AIP subgroups. The prevalence of endocrine insufficiency according to fasting IRI less than 5.0 &mgr;U/mL was 26% in AIP without SC, 31% in AIP with SC, and 59% in CP, respectively. HOMA-R values were significantly higher in all AIP groups than in CP. Conclusions Autoimmune pancreatitis can transform into a state of pancreatic insufficiency after calcification that is less severe than that in definite CP.

Usefulness of three-dimensional magnetic resonance cholangiopancreatography with partial maximum intensity projection for diagnosing autoimmune pancreatitis

PURPOSE To compare three-dimensional magnetic resonance cholangiopancreatography (MRCP) with/without partial maximum intensity projection (MIP) and endoscopic retrograde cholangiopancreatography (ERCP) in patients with autoimmune pancreatitis (AIP). MATERIALS AND METHODS Three-dimensional MRCP and ERCP images were retrospectively analyzed in 24 patients with AIP. We evaluated the narrowing length of the main pancreatic duct (NR-MPD), multiple skipped MPD narrowing (SK-MPD), and side branches arising from the narrowed portion of the MPD (SB-MPD) using four MRCP datasets: 5 original images (MIP5), 10 original images (MIP10), all original images (full-MIP), and a combination of these three datasets (a-MIP). The images were scored using a 3- or 5-point scale. The scores of the four MRCP datasets were statistically analyzed, and the positive rate of each finding was compared between MRCP and ERCP. RESULTS The median scores for SB-MPD on MIP5 and a-MIP were significantly higher than those on MIP10 and full-MIP. In other words, partial MIP is superior to full-MIP for visualization of detailed structures. The positive rate for SB-MPD on full-MIP was significantly lower than that on ERCP, whereas the positive rate on MIP5, MIP10, and a-MIP was not significantly different from that on ERCP. Moreover, the positive rate for NR-MPD and SK-MPD on the MRCP images was significantly higher than that on the ERCP images. CONCLUSION Partial MIP is useful for evaluating the MPD and is comparable with ERCP for diagnosing AIP.

Development to Chronic Pancreatitis

The long-term prognosis and outcomes of autoimmune pancreatitis (AIP) remain unclear. Because patients with AIP respond favorably to prednisolone (PSL) therapy in clinical, serological, imaging, and pathological settings [1–5], the disease was previously believed to be an acute condition that did not progress to an advanced stage of chronic pancreatitis. However, over the last decade, it has been revealed that some patients with AIP could progress to pancreatic stone formation, pancreatic atrophy, and/or irregular dilatation of the main pancreatic duct (MPD), which may raise new questions about whether AIP can progress to confirmed chronic pancreatitis or not.