Naoto Egawa

A new clinicopathological entity of IgG4-related autoimmune disease.

BackgroundAutoimmune pancreatitis (AIP) is occasionally associated with other autoimmune diseases.MethodsTo investigate the pathophysiology of AIP, we immunohistochemically examined the pancreas and other organs in eight patients with AIP, and in controls, using anti-CD4-T and CD8-T cell subsets, as well as IgG4 antibodies.ResultsIn AIP patients, severe or moderate infiltration of IgG4-positive plasma cells associated with CD4- or CD8-positive T lymphocytes was detected in the peripancreatic tissue (6/6), bile duct (8/8), gallbladder (8/8), portal area of the liver (3/3), gastric mucosa (5/7), colonic mucosa (2/2), salivary glands (1/2), lymph nodes (6/6), and bone marrow (2/2), as well as in the pancreas (8/8). There were few IgG4-positive plasma cells at the same sites in controls.ConclusionsThese results suggest that AIP is not simply pancreatitis but that it is a pancreatic lesion involved in IgG4-related systemic disease with extensive organ involvement. We propose a new clinicopathological entity, of a systemic IgG4-related autoimmune disease in which AIP and its associated diseases might be involved.

Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis

Background: Autoimmune pancreatitis is a unique clinical entity proposed recently, and is sometimes associated with inflammation of other organs. Aims: To examine the pathophysiology of the pancreas and other organs in patients with autoimmune pancreatitis. Patients and methods: We evaluated clinicopathological findings in six resected and one autopsied patient with autoimmune pancreatitis. The pancreas, peripancreatic tissue, bile duct, and gall bladder were examined histologically and immunohistochemically. Biopsied salivary gland and cervical lymph node of one patient were also examined. We also performed similar immunohistochemical examinations in pancreatectomy specimens from 10 patients with alcoholic chronic pancreatitis and biopsied salivary glands from five patients with Sjögren’s syndrome. Results: Stenosis of the extrahepatic bile duct was detected in all patients. Histological findings were characterised by diffuse lymphoplasmacytic infiltration with marked interstitial fibrosis and acinar atrophy, obliterated phlebitis of the pancreatic veins, and involvement of the portal vein. Immunohistochemically, diffusely infiltrating cells consisted predominantly of CD4 or CD8 positive T lymphocytes and IgG4 positive plasma cells. Similar inflammatory processes also involved the peripancreatic tissue, extrahepatic bile duct, gall bladder, and salivary gland. Lymph nodes were swollen with infiltration of IgG4 positive plasma cells. None of these findings was seen in alcoholic chronic pancreatitis or Sjögren’s syndrome. Conclusions: The development of the specific inflammations in extensive organs as well as the pancreas in patients with autoimmune pancreatitis strongly suggests a close relationship between autoimmune pancreatitis and multifocal fibrosclerosis.

Clinical difficulties in the differentiation of autoimmune pancreatitis and pancreatic carcinoma

OBJECTIVES:Autoimmune pancreatitis (AIP) is a newly described entity with characteristic clinical, histologic, and morphologic changes, in which autoimmune mechanisms are involved in pathogenesis. However, difficulties can arise in the differentiation of AIP from pancreatic carcinoma. The aims of this study were to clarify clinical and radiologic features of AIP to elucidate areas of diagnostic confusion.METHODS:Clinical, serologic, and radiologic findings were evaluated in 17 patients with AIP.RESULTS:All 17 patients were initially suspected to have pancreatic carcinoma. The patients were predominantly elderly men who frequently presented with jaundice but without features of acute pancreatitis. Elevation of serum γ-globulin and IgG along with the presence of autoantibodies were usually evident, whereas serum tumor markers were elevated in 54% of cases. Stenosis of the bile duct was detected in 94% of cases. Diffuse enlargement of the pancreas and irregular narrowing of the main pancreatic duct were radiologically characteristic; however, segmental swelling and narrowing were detected in seven and two patients, respectively. In segmental cases, neither atrophy of the distal pancreas nor marked upstream dilation of the distal main pancreatic duct was observed.Angiographic abnormalities occurred in 54% of cases. Serologic and radiologic abnormalities showed considerable improvement with steroid therapy.CONCLUSIONS:Frequent stenosis of the bile duct, elevation of serum tumor markers, segmental pancreatic enlargement or narrowing of the main pancreatic duct, and angiographic abnormalities can cause confusion in the differential diagnosis of AIP and pancreatic carcinoma.

Differentiation of autoimmune pancreatitis from pancreatic cancer by diffusion-weighted MRI.

OBJECTIVES:We sought to clarify the clinical utility of diffusion-weighted magnetic resonance imaging (DWI) for differentiating autoimmune pancreatitis (AIP) from pancreatic cancer.METHODS:Thirteen AIP patients underwent DWI before therapy, and six of them underwent DWI after steroid therapy. The extent and shape of high-intensity areas were compared with those of 40 pancreatic cancer patients. Apparent diffusion coefficient (ADC) values were calculated in the AIP area before and after steroid therapy in pancreatic cancer patients and in a normal pancreatic body.RESULTS:On DWI, AIP and pancreatic cancer were detected as high-signal intensity areas. The high-intensity areas were diffuse (n=4), solitary (n=6), and multiple (n=3) in AIP patients, but all pancreatic cancer patients showed solitary areas (P<0.001). A nodular shape was significantly more frequent in pancreatic cancer, and a longitudinal shape was more frequently found in AIP (P=0.005). ADC values were significantly lower in AIP (1.012±0.112 × 10−3u2009mm2/s) than in pancreatic cancer (1.249±0.113 × 10−3u2009mm2/s) and normal pancreas (1.491±0.162 × 10−3u2009mm2/s) (P<0.001). Receiver operating characteristic analysis yielded an optimal ADC cutoff value of 1.075 × 10−3u2009mm2/s to distinguish AIP from pancreatic cancer. After steroid therapy, high-intensity areas on DWI disappeared or were markedly decreased, and the ADC values of the reduced pancreatic lesions increased almost to the values of normal pancreas.CONCLUSIONS:DWI is useful for detecting AIP and for evaluating the effect of steroid therapy. ADC values were significantly lower in AIP than in pancreatic cancer. An ADC cutoff value may be useful for distinguishing AIP from pancreatic cancer.

Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicentre study

Background Characteristic pancreatic duct changes on endoscopic retrograde pancreatography (ERP) have been described in autoimmune pancreatitis (AIP). The performance characteristics of ERP to diagnose AIP were determined. Methods The study was done in two phases. In phase I, 21 physicians from four centres in Asia, Europe and the USA, unaware of the clinical data or diagnoses, reviewed 40 preselected ERPs of patients with AIP (n=20), chronic pancreatitis (n=10) and pancreatic cancer (n=10). Physicians noted the presence or absence of key pancreatographic features and ranked the diagnostic possibilities. For phase II, a teaching module was created based on features found most useful in the diagnosis of AIP by the four best performing physicians in phase I. After a washout period of 3u2005months, all physicians reviewed the teaching module and reanalysed the same set of ERPs, unaware of their performance in phase I. Results In phase I the sensitivity, specificity and interobserver agreement of ERP alone to diagnose AIP were 44, 92 and 0.23, respectively. The four key features of AIP identified in phase I were (i) long (>1/3 the length of the pancreatic duct) stricture; (ii) lack of upstream dilatation from the stricture (<5u2005mm); (iii) multiple strictures; and (iv) side branches arising from a strictured segment. In phase II the sensitivity (71%) of ERP significantly improved (p<0.05) without a significant decline in specificity (83%) (p>0.05); the interobserver agreement was fair (0.40). Conclusions The ability to diagnose AIP based on ERP features alone is limited but can be improved with knowledge of some key features.

Extrapancreatic lesions in autoimmune pancreatitis.

Goals: To examine extrapancreatic lesions associated with autoimmune pancreatitis. Background: Autoimmune pancreatitis is a unique clinical entity proposed recently, and is reported to occasionally be associated with other autoimmune diseases. Study: Extrapancreatic lesions were examined clinically, radiologically, and histologically in 25 patients with autoimmune pancreatitis. Results: Stenosis of the bile duct was observed in 22 patients (lower bile duct [n = 19], upper bile duct [n = 1], intrahepatic bile duct [n = 2]). Marked extrapancreatic bile duct wall thickening not associated with obvious cholangiographic abnormality was seen on ultrasound in 3 patients. Enlargement of the salivary glands and cervical lymph nodes was detected in 4 patients. Abdominal lymphadenopathy was observed in 5 of 8 patients at laparotomy. Retroperitoneal fibrosis was noted in 2 patients. Obliterative phlebitis of the pancreatic and peripancreatic veins was observed histologically in all 6 resected specimens. Marked stenosis of the portal vein and encasement of the peripancreatic arteries was observed in 4 and 8 of 14 patients who underwent abdominal angiography, respectively. Diabetes mellitus was diagnosed in 13 patients. All associated extrapancreatic lesions except diabetes mellitus improved after steroid therapy. Conclusions: Extrapancreatic lesions found to be occasionally associated with autoimmune pancreatitis were stenosis of the bile duct, enlargement of the salivary glands, abdominal or cervical lymphadenopathy, retroperitoneal fibrosis, stenosis of the peripancreatic arteries or portal vein, and diabetes mellitus. It is possible that these lesions are induced by the same inflammatory mechanisms as autoimmune pancreatitis.

Serum IgG4 concentrations and IgG4-related sclerosing disease

BACKGROUNDnBased on histological and immunohistochemical examinations of various organs of patients with autoimmune pancreatitis (AIP), a new clinicopathological entity, IgG4-related systemic disease, was proposed. This study aimed to clarify clinical utility of serum IgG4 levels in differentiating AIP from other pancreatobiliary diseases, clinical utility of serum IgG4 levels in differentiating Mikuliczs disease from other salivary gland disorders, as well as in identifying other IgG4-related diseases.nnnMETHODSnSerum IgG4 levels were measured in 468 patients.nnnRESULTSnThe median serum IgG4 level was significantly greater in AIP (301.5mg/dl) than in other pancreatobiliary diseases (p<0.01). Using the cutoff value of 119 mg/dl that was determined on the basis of this studys ROC curve data, the sensitivity and specificity to distinguish AIP from pancreatic cancer were 82.1% and 94.8%, respectively. The median serum IgG4 level was significantly greater in Mikuliczs disease (357.0mg/dl) than in other salivary gland diseases (p<0.01). Of 75 patients with elevated serum IgG4 levels, 15 had diseases other than pancreatobiliary and salivary gland diseases.nnnCONCLUSIONSnSerum IgG4 levels were useful for diagnosing AIP and Mikuliczs disease. Some diseases with serum IgG4 level elevations may be lesions of IgG4-related systemic disease without manifestations of AIP and Mikuliczs disease.

Serum IgG4-negative autoimmune pancreatitis

BackgroundAutoimmune pancreatitis (AIP) is considered to be a pancreatic lesion of IgG4-related systemic disease, but about 20% of AIP patients do not have elevated serum IgG4 levels. This study aimed to clarify the pathophysiology of AIP patients without elevated serum IgG4 levels.MethodsFifty-eight AIP patients were divided into 2 groups: those with elevated serum IgG4 levels (>135xa0mg/dl; SIgG4-positive AIP) and those without (SIgG4-negative AIP). The 2 groups’ clinical, serological, radiological, and histological findings, as well as salivary and lacrimal gland function, were compared.ResultsSerum IgG4 levels were elevated in 45 AIP patients and normal in 13 patients. In SIgG4-negative AIP patients, the female ratio tended to be high; obstructive jaundice was less likely; abdominal pain and acute pancreatitis were more likely; segmental swelling of the pancreatic body and/or tail was more common; sclerosing extrapancreatic lesions, salivary and lacrimal gland dysfunction, and abundant infiltration of IgG4-positive plasma cells in the gastric mucosa were less likely; and conservative follow-up was sometimes implemented. Histological examination of the pancreas of SIgG4-negative AIP showed lymphoplasmacytic sclerosing pancreatitis (LPSP) rather confined to the pancreas (nxa0=xa04), inadequate material (nxa0=xa02), and pancreatic fibrosis showing infiltration of lymphocytes without infiltration of IgG4-positive cells or neutrophils (nxa0=xa02).ConclusionsClinicopathological features of SIgG4-negative AIP differed from those of SIgG4-positive AIP. Some SIgG4-negative AIP cases are LPSP rather confined to the pancreas. SIgG4-negative AIP may include idiopathic duct-centric pancreatitis (IDCP) or sclerosing pancreatitis other than LPSP or IDCP, but further studies are needed to clarify this issue.

Endoscopic Retrograde Cholangiography Does Not Reliably Distinguish IgG4-Associated Cholangitis From Primary Sclerosing Cholangitis or Cholangiocarcinoma

BACKGROUND & AIMSnDistinction of immunoglobulin G4-associated cholangitis (IAC) from primary sclerosing cholangitis (PSC) or cholangiocarcinoma is challenging. We aimed to assess the performance characteristics of endoscopic retrograde cholangiography (ERC) for the diagnosis of IAC.nnnMETHODSnSeventeen physicians from centers in the United States, Japan, and the United Kingdom, unaware of clinical data, reviewed 40 preselected ERCs of patients with IAC (n = 20), PSC (n = 10), and cholangiocarcinoma (n = 10). The performance characteristics of ERC for IAC diagnosis as well as the κ statistic for intraobserver and interobserver agreement were calculated.nnnRESULTSnThe overall specificity, sensitivity, and interobserver agreement for the diagnosis of IAC were 88%, 45%, and 0.18, respectively. Reviewer origin, specialty, or years of experience had no statistically significant effect on reporting success. The overall intraobserver agreement was fair (0.74). The operating characteristics of different ERC features for the diagnosis of IAC were poor.nnnCONCLUSIONSnDespite high specificity of ERC for diagnosing IAC, sensitivity is poor, suggesting that many patients with IAC may be misdiagnosed with PSC or cholangiocarcinoma. Additional diagnostic strategies are likely to be vital in distinguishing these diseases.

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.