Epidemiology,clinical presentation,diagnosis and treatment of autoimmune pancreatitis: A retrospective analysis of 53 patients

BackgroundMost of the data about epidemiology, clinical presentation and treatment of autoimmune pancreatitis (AIP) is based on case series or small study groups. We therefore analyzed all cases of AIP treated at our clinic retrospectively.MethodsWe searched our clinical database for the diagnosis pancreatitis between January 2007 and June 2014, selected patients with AIP and entered all relevant information in a database for statistical analysis.ResultsIn total 53 patients with AIP were treated at our institution, 62% with type 1 and 23% with type 2 AIP. Gender distribution was male/female 3.1:1 for type 1 and 1:1.2 for type 2 AIP. The median age was 63.0 and 32.5 years for type 1 and type 2 AIP, respectively. The most common symptom is abdominal pain particular in patients with type 2 AIP whereas jaundice was only apparent in patients with type 1 AIP. The international diagnostic criteria seem to facilitate diagnosis of AIP as unnecessary pancreatic surgery in patients with AIP decreases. In 62.6% of the patients therapy was indicated and 84.8% showed a response to initial therapy with steroids. Recurring disease occurred in 28.3% of the cases but only 3.8% suffered a second relapse. Permanent maintenance therapy with steroids or additional therapy with immunomodulatory drugs is successful in recurring disease.ConclusionOur data further corroborate previous findings on epidemiology, clinical presentation and treatment of AIP. AIP is a well manageable autoimmune disease in most patients. Better biopsy techniques and simplified diagnostic criteria might further alleviate diagnosis of AIP.     

TLR4信号传导通路与胰腺炎

胰腺炎的发病机制长期以来一直是基础和临床研究的一个重要课题,然而至今尚不完全明确.研究证实TLRs(Toll-like receptors)家族成员中TLR4可与G-菌内毒素脂多糖(lipopolysaccharide,LPS)结合,通过NF-κB信号通路激发多种炎症因子的合成进而参与多种器官疾病的发病过程.在鼠类模型和临床研究中已经显示TLR4信号通路在急性胰腺炎(acute pancreatitis,AP)的发病过程中起着重要的作用;上调TLR4信号通路可诱导致炎细胞因子大量释放参与重症急性胰腺炎(severe acute pancreatitis,SAP)病程中多器官功能障碍综合征的形成.因此,进一步明确TLR4信号通路在胰腺炎发病机制的作用,有可能通过阻断TLR4信号通路使胰腺炎获得疗效.     

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.     

Lymphoplasmacytic sclerosing pancreatitis forming a localized mass: a variant form of autoimmune pancreatitis

Background To elucidate the correlation of autoimmune pancreatitis (AIP) and mass-forming pancreatitis, in which a localized mass is formed in the pancreas. Methods Nine cases of mass-forming pancreatitis were divided into two groups, one consisting of cases that met the histological diagnostic criteria for AIP by the Japan Pancreas Society (JPS) and the other consisting of cases which did not. Histological findings, immunohistological findings, and pancreatograms were compared between these groups. Results Six cases met the histological criteria of JPS (group A) and the other three did not (group B). In the mass-forming portion in group A, the wall of the pancreatic duct showed marked thickening. However, the epithelium was well preserved, and dilatation of the branch ducts or protein plugs were rarely observed. All cases showed marked obliterative phlebitis. The IgG4 labeling index (LI) was 25% or more in all but one case. In the portion other than the mass, the lobular structure was well preserved and the IgG4 LI was less than 10%. The pancreatogram showed localized stenosis or obstruction at the site of the mass associated with a normal-appearing main pancreatic duct in the remaining portion. In group B, histological findings typical of chronic pancreatitis with dilated branch ducts and protein plugs were observed. Obliterative phlebitis was not confirmed. The IgG4 LI in the mass-forming portion was low (2.3%–11.1%). Conclusions There exists a subgroup of AIP showing localized mass formation and stenosis or obstruction of the main pancreatic duct with prominent obliterative phlebitis associated with a normal ductal segment.     

Autoimmune Pancreatitis: Updated Concepts of a Challenging Diagnosis

Autoimmune pancreatitis is a benign process characterized by inflammation and fibrosis. It is now known that cases of “autoimmune pancreatitis” actually consist of two distinct pathologic entities. Type 1 autoimmune pancreatitis is a manifestation of a systemic process, immunoglobulin G subclass 4 (IgG4)-related disease. IgG4-related disease can affect virtually every organ system in the body. Type 1 affects older patients and is characterized by an elevated serum IgG4 level and sites of extrapancreatic disease. Type 2 autoimmune pancreatitis is a disease process confined to the pancreas. It affects younger patients and is associated with inflammatory bowel disease. Type 2 is not associated with elevated IgG4 levels or extrapancreatic disease. Both subtypes can mimic malignancy, particularly pancreatic cancer. Awareness of the clinical and imaging features of the subtypes of autoimmune pancreatitis is important to avoid an incorrect diagnosis of malignancy.     

Clinical and pathological differences between serum immunoglobulin G4-positive and -negative type 1 autoimmune pancreatitis

AIM: To identify clinical and pathological differences between serum immunoglobulin G4 (IgG4)-positive (SIP) and IgG4-negative (SIN) type 1 autoimmune pancreatitis (AIP) in South Korea. METHODS: AIP was diagnosed by the international consensus diagnostic criteria. The medical records and pathology were retrospectively reviewed and IgG4-positive cells were counted in a high power field (HPF). Type I AIP was defined as a high serum level of IgG4or histological finding. SIN type 1 AIP was defined as a histological evidence of type 1 AIP and a normal serum IgG4 level. The clinical and pathological findings were compared between the two groups. The analysis was performed using Student’s t test, Fischer’s exact test and Mann-Whitney’s U test. A P value of < 0.05 was considered statistically significant. As repeated com- parison was made, P values of less than 5% (P < 0.05) were considered significant. RESULTS: Twenty five patients with definite type 1 AIP (19 histologically and six serologically diagnosed cases) were enrolled. The mean tissue IgG4 concentrations were significantly higher in SIP than SIN group (40 cells per HPF vs 18 cells per HPF, P = 0.02). Among eight SIN patients, the tissue IgG4 concentrations were less than 15 cells per HPF in most of cases, except one. The sensitivity of serum IgG4 was 68% (17 SIP and eight SIN AIP). Other organ involvement was more frequent- ly associated with SIP than SIN AIP (59% vs 26%, P = 0.016). However, the relapse rate and diffuse swelling of the pancreas were not associated with serum IgG4 level. The concentrations of IgG4-positive cells per HPF were higher in SIP than SIN AIP (40 vs 18, P = 0.02). CONCLUSION: The sensitivity of serum IgG4 was 68% in type 1 AIP. High serum IgG4 level was associated with other organ involvement and tissue IgG4 concentration but did not affect the relapse rate in type 1 AIP.     

An autopsy case of acute pancreatitis with a high serum IgG4 complicated by amyloidosis and rheumatoid arthritis

We report an autopsy case of acute pancreatitis with a high serum IgG4 concentration complicated by systemic amyloid A amyloidosis and rheumatoid arthritis (RA). The patient was a 42-year-old Japanese female with a 22-year history of rheumatoid arthritis. She was diagnosed with myasthenia gravis when she was 31-year old. At the onset of pancreatitis, the patient was anti-nudear antibody-positive, and had high serum gamma globulin and IgG4 levels. Dexamethasone and conventional therapy induced clinical remission and significantly decreased the serum IgG4 and gamma globulin. However, despite the decreased disease parameters, the patient developed a bleeding pseudocyst and died of cardiac failure. In the autopsy examination, it was determined that pancreatitis was probably caused by ischemia due to vascular obstruction caused by amyloid deposition in the pancreas. Even though acute pancreatitis is a rare complication in RA patients, we speculate that an autoimmune pancreatitis-related mechanism and ischemia due to vascular obstruction by amyloid deposition might be attributable to a single source that leads to acute pancreatitis in our particular case.     

Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease

Autoimmune pancreatitis (AIP) is a peculiar type of pancreatitis of presumed autoimmune etiology. Many new clinical aspects of AIP have been clarified during the past 10 years, and AIP has become a distinct entity recognized worldwide. However, its precise pathogenesis or pathophysiology remains unclear. As AIP dramatically responds to steroid therapy, accurate diagnosis of AIP is necessary to avoid unnecessary surgery. Characteristic dense lymphoplasmacytic infiltration and fibrosis in the pancreas may prove to be the gold standard for diagnosis of AIP. However, since it is difficult to obtain sufficient pancreatic tissue, AIP should be diagnosed currently based on the characteristic radiological findings (irregular narrowing of the main pancreatic duct and enlargement of the pancreas) in combination with serological findings (elevation of serum γ-globulin, IgG, or IgG4, along with the presence of autoantibodies), clinical findings (elderly male preponderance, fluctuating obstructive jaundice without pain, occasional extrapancreatic lesions, and favorable response to steroid therapy), and histopathological findings (dense infiltration of IgG4-positive plasma cells and T lymphocytes with fibrosis and obliterative phlebitis in various organs). It is apparent that elevation of serum IgG4 levels and infiltration of abundant IgG4-positive plasma cells into various organs are rather specific to AIP patients. We propose a new clinicopathological entity, “IgG4-related sclerosing disease”, and suggest that AIP is a pancreatic lesion reflecting this systemic disease.     

A new clinicopathological entity of IgG4-related autoimmune disease

Background Autoimmune pancreatitis (AIP) is occasionally associated with other autoimmune diseases.Methods To 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.Results In 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.Conclusions These 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.     

Sclerosing cholecystitis associated with autoimmune pancreatitis

AIM: To evaluate the histopathological and radiological findings of the gallbladder in patients with autoimmune pancreatitis (AIP). METHODS: The radiological findings of the gallbladder of 19 AIP patients were retrospectively reviewed. Resected gallbladders of 8 AIP patients were examined histologically and were immunostained with anti- IgG4 antibody. Controls consisted of gallbladders resected for symptomatic gallstones (n = 10) and those removed during pancreatoduodenectomy for pancreatic carcinoma (n = 10), as well as extrahepatic bile ducts and pancreases removed by pancreatoduodenectomy for pancreatic carcinoma (n = 10). RESULTS: Thickening of the gallbladder wall was detected by ultrasound and/or computed tomography in 10 patients with AIP (3 severe and 7 moderate); in these patients severe stenosis of the extrahepatic bile duct was also noted. Histologically, thickening of the gallbladder was detected in 6 of 8 (75%) patients with AIP; 4 cases had transmural lymphoplasmacytic infiltration with fibrosis, and 2 cases had mucosal-based lymphoplasmacytic infiltration. Considerable transmural thickening of the extrahepatic bile duct wall with dense fibrosis and diffuse lymphoplasmacytic infiltration was detected in 7 patients. Immunohistochemically, severe or moderate infiltration of IgG4-positive plasma cells was detected in the gallbladder, bile duct, and pancreas of all 8 patients, but was not detected in controls. CONCLUSION: Gallbladder wall thickening with fibrosis and abundant infiltration of IgG4-positive plasma cells is frequently detected in patients with AIR We propose the use of a new term, sclerosing cholecystitis, for these cases that are induced by the same mechanism as sclerosing pancreatitis or sclerosing cholangitis in AIR     

Does IgG4 level at the time of diagnosis correlate with disease outcome in IgG4-Related disease?

Background/Objectives: Serum IgG4 level is used as a diagnostic criterion for immunoglobulin G4-related disease (IgG4-RD) but whether it predicts disease progression is unclear. Aim of the study was to investigate if serum IgG4 level at the time of diagnosis correlates with disease outcome.

Pancreatic cancer with a high serum IgG4 concentration

INTRODUCTION Autoimmune pancreatitis is a unique for m of pancreatitis, histopathologically characterized by dense lymphoplasmacytic infiltration and fibrosis of the pancreas with obliterative phlebitis[1,2]. Patients with this disease usually have a swollen pancreas with delayed enhancement on computed tomography (CT), irregular narrowing of the main pancreatic duct on endoscopic retrograde pancreatography, and a favorable response to steroid therapy[1-4]. Autoimmune pancreatitis has bee…     

Autoimmune pancreatitis metachronously associated with retroperitoneal fibrosis with IgG4-positive plasma cell infiltration

Retroperitoneal fibrosis is an uncommon disorder characterized by the formation of a dense plaque of fibrous tissue in the retroperitoneum, and its etiology remains unknown. Autoimmune pancreatitis is a rare type of chronic pancreatitis characterized by fibrosis with abundant infiltration of IgG4-positive plasma cells and lymphocytes and obliterative phlebitis in the pancreas. We present a case of autoimmune pancreatitis that developed 10 mo after the occurrence of retroperitoneal fibrosis. Histological findings of the resected retroperitoneal mass were marked periureteral fibrosis with abundant infiltration of IgG4-positive plasma cells and lymphocytes and obliterative phlebitis. These findings suggest a common pathophysiological mechanism for retroperitoneal fibrosis and autoimmune pancreatitis in this case. Some cases of retroperitoneal fibrosis might be a retroperitoneal lesion of IgG4-related sclerosing disease.     

Infiltration of peritumoural but tumour-free parenchyma with IgG4-positive plasma cells in hilar cholangiocarcinoma and pancreatic adenocarcinoma

Background

Recently, new guidelines for diagnosing IgG4-associated cholangitis have been published devaluing the diagnostic significance of IgG4-positive plasma cells and steroid trials. We sought to evaluate the utility of IgG4-positive plasma cells in discriminating IgG4-associated cholangitis from hilar cholangiocarcinoma and autoimmune pancreatitis from pancreatic adenocarcinoma under conditions when malignancy is likely to be missed.

Methods

Resection specimens obtained from patients with hilar cholangiocarcinoma, pancreatic adenocarcinoma or hepatocellular carcinoma were re-evaluated for IgG4-positivity. Histological analysis focussed on peritumoural but tumour-free sections. Perioperative biochemical and clinical data were reviewed.

Results

Nineteen patients with hilar cholangiocarcinoma and 29 patients with pancreatic adenocarcinoma were eligible for histological re-evaluation. Six of 19 (32%) patients with hilar cholangiocarcinoma and 5 of 29 (17%) patients with pancreatic adenocarcinoma were IgG4-positive (≥20 IgG4-positive plasma cells per high power field). Patients with IgG4-positive hilar cholangiocarcinoma showed significantly higher levels of serum total bilirubin (3.6 mg/dl vs. 1.8 mg/dl; P < 0.05) and serum alanine-aminotransferase (median 343 U/l vs. 63 U/l, P < 0.05) compared to IgG4-negative patients with hilar cholangiocarcinoma.

Conclusions

IgG4-positive plasma cells are of limited utility especially in distinguishing hilar cholangiocarcinoma from IgG4-associated cholangitis even when combined with clinical parameters and may be misleading under conditions when malignancy is missed.     

Relationship between autoimmune pancreatitis and pancreatic cancer: A single-center experience

ObjectivesOrdinary chronic pancreatitis (CP), such as alcoholic CP, is well established to have the increased risk for pancreatic cancer (PaC), nevertheless an association between autoimmune pancreatitis (AIP) and PaC is still unknown. The aims of this study are to examine the frequency of patients who developed PaC during follow-up after being diagnosed with type 1 AIP and to compare the incidence rate of PaC between patients with type 1 AIP and CP.MethodsSixty-three patients with type 1 AIP and 41 patients with CP were enrolled. We examined development of PaC during follow-up from their clinical records.ResultsThe mean follow-up period was 62.4 months in AIP group and 49.2 months in CP group. The occurrence of PaC was observed in 3 patients with AIP during the mean follow-up period of 94.7 months (range, 31–186), whereas a single CP patient developed PaC 38 months after CP diagnosis. The incident rate of PaC during follow-up was comparable between the 2 groups [4.8% (3/63) in type 1 AIP group vs. 2.4% (1/41) in CP group]. In all of 3 AIP patients who developed accompanying PaC, the clinical remission of AIP was achieved with maintenance steroid therapy, when tumors were discovered. In the histological examination of one surgical patient with PaC, lymphoplasmacytic infiltration in storiform fibrosis with abundant IgG4-positive cell infiltration was observed around the PaC area.ConclusionsSimilar to patients with ordinary CP, surveillance for development of PaC is needed at regular interval during follow-up in AIP patients.     

Determination of the duration of glucocorticoid therapy in type 1 autoimmune pancreatitis: A systematic review and meta-analysis

BackgroundThe indications for maintenance glucocorticoid therapy (MGT) and its duration after initial remission of type 1 autoimmune pancreatitis (AIP) remain controversial. In contrast to the Japanese treatment protocol, the Mayo protocol does not recommend MGT after initial remission. This study aimed to evaluate the relapse rate in patients with type 1 AIP according to the duration of glucocorticoid therapy.MethodsWe conducted a systematic literature review up until November 30, 2020, and identified 40 studies reporting AIP relapse rates. The pooled relapse rates were compared between groups according to the protocol and duration of glucocorticoids (routine vs. no MGT; glucocorticoids ≤6 months vs. 6–12 months vs. 12–36 months vs. ≥ 36 months). The pooled rates of adverse events related to glucocorticoids were also evaluated.ResultsMeta-analysis indicated calculated pooled relapse rates of 46.6% (95% confidence interval (CI), 38.9–54.3%) with glucocorticoids for ≤ 6 months, 44.3% (95% CI, 38.8–49.8%) for 6–12 months, 34.1% (95% CI, 28.6–39.7%) for 12–36 months, and 27.0% (95% CI, 23.4–30.6%) for ≥ 36 months. The rate of relapse was also significantly lower in patients with routine-use protocol of MGT (31.2%; 95% CI, 27.5–34.8%) than in patients with no MGT protocol (44.1%; 95% CI, 35.8–52.4%). Adverse events were comparable between groups.ConclusionsThe rate of relapse tended to decrease with extended durations of glucocorticoid therapy up to 36 months. Clinicians may decide the duration of glucocorticoids according to patient condition, including comorbidities and risk of relapse.     

Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases

Chronic pancreatitis lesions usually embrace both intraduct papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC). Patients at genetically-determined high risk of PDAC often harbor IPMN and/or chronic pancreatitis, suggesting IPMN, chronic pancreatitis and PDAC may share pathogenetic mechanisms. Chronic autoimmune pancreatitis (AIP) may also herald PDAC. Concurrent IPMN and AIP have been reported in few patients. Here we describe two patients with IPMN who developed type-1 AIP fulfilling the Honolulu and Boston diagnostic criteria. AIP diffusively affected the whole pancreas, as well as peripancreatic lymph nodes and the gallbladder. Previous pancreatic resection of focal IPMN did not show features of AIP. One of the patients carried a CFTR class-I mutation. Of notice, serum IgG4 levels gradually decreased to normal values after IPMN excision. Common risk factors to IPMN and AIP may facilitate its coincidental generation.     

Mass‐forming type 1 autoimmune pancreatitis mimicking pancreatic cancer

We reported three cases of mass‐forming type 1 autoimmune pancreatitis (AIP) that were preoperatively suspected to be pancreatic cancer, and reviewed their clinicopathological features. Radiological findings in the patients revealed hypoattenuating masses in the early phase or a stricture of the main pancreatic duct with upstream dilatation, which was consistent with the diagnosis of pancreatic cancer. Histopathologically, the lesions were well demarcated and met all diagnostic criteria for immunoglobulin G4 (IgG4)‐related AIP, including the presence of periductal lymphoplasmacytic infiltration, obliterative phlebitis, storiform fibrosis and abundant IgG4‐positive plasma cells. However, the adjacent uninvolved pancreatic duct and lobular structures were well preserved. And in all patients, none or some of the aforementioned characteristics were observed. We suggest that some cases of focal AIP may progress to more severe grades and exhibit mass formation, although remaining localized. These focal cases of AIP are difficult to distinguish from pancreatic cancer. To our knowledge, this report is the first to present a histopathological comparison of mass‐forming AIP with the adjacent uninvolved pancreatic tissues.