Extrapancreatic Organ Involvement Research Articles

Recent advances in diagnosis, treatment, and prognosis of IgG4-related autoimmune pancreatitis: a narrative review

Immunoglobulin G4 (IgG4)-related autoimmune pancreatitis (AIP), also known as “type 1 AIP,” is a rare, chronic, and fibroinflammatory disease manifested as obstructive jaundice and enlargement of the pancreas, usually accompanied by extra-pancreatic organ involvement. The understanding of IgG4-related AIP is gradually deepening. In this review, we summarized the basic concepts, common clinical manifestations, and new progress of the disease including diagnostic, therapeutic strategies, and prognosis mainly based on published case reports, cohort studies, meta-analyses, and guidelines in the past 5 years. Issues such as diagnostic markers, risk factors for relapse, and more effective treatment still need to be further studied.

The Clinical Phenotype of Chinese Patients With Autoimmune Pancreatitis Differs Significantly From Western Patients

AimTo characterize the clinical features of autoimmune pancreatitis (AIP) in China and compare differences between our Chinese cohort and Western cohorts.MethodsThis was a retrospective study of patients with AIP that was carried out in the China-Japan Friendship Hospital between January 2010 and April 2021. We included a total of 50 patients (46 males and 4 females) aged between 27 and 86 years who fulfilled the international Consensus Diagnostic (ICD) Criteria. For comparative purposes, we included data from seven representative Western cohorts.ResultWhen comparing Chinese and Western patients, we found that obstructive jaundice was the most frequent initial symptom (68 vs. 43%, P < 0.001). Extra-pancreatic organ involvement was more common in Chinese patients (68 vs. 30%, P < 0.001). Sclerosing cholangitis was the most frequent extrapancreatic lesion (48 vs. 24%, P = 0.001). The elevation of serum IgG4 was more obvious in our cohort (86 vs. 49%, P < 0.001). Conversely, the rates of ANA-positivity were significantly higher in Western populations (17 vs. 50%, P = 0.006). With regards to imaging, diffuse swelling was significantly more common in China (44 vs. 27%, P = 0.021). Steroid therapy was used more frequently in our Chinese patients (84 vs. 59%, P = 0.001). The steroid-response rate was also significantly higher in our Chinese patients (85 vs. 54%, P = 0.001); However, the rate of resection was higher in Western cohorts (2 vs. 31%, P < 0.001). There was no significant difference between the two populations with regards to recurrence rate (33 vs. 33%, P = 1.000).ConclusionThis study identified significant differences between Chinese and Western populations of patients with AIP. Within the Chinese population, AIP was more likely to have jaundice and extra-pancreatic organ involvement, and elevated serum IgG4 levels. Chinese patients were also showed favorable responses to treatment with glucocorticoids.

Analysis of Clinical, Serological, and Imaging Features of Autoimmune Pancreatitis and a Case-Control Study on Prognostic Factors in Response to Hormone Therapy.

Objective The paper aimed to analyze the clinical, serological, and imaging features of autoimmune pancreatitis (AIP) and the prognostic factors affecting hormone therapy. Methods A total of 106 patients with AIP enrolled in our hospital from March 2016 to August 2018 were treated with the hormone. The curative effect and recurrence were followed up. The patients were divided into relapse group (n = 42) and nonrelapse group (n = 64) according to the recurrence within 3 years after initial hormone therapy. The symptoms and signs, laboratory examination, and treatment were compared, and binary logistic regression was employed to explore the risk factors of AIP recurrence. Results Among the 106 patients included in this study, there were 78 males and 28 females, with a male-to-female ratio of 3:1. The average age of onset was 56.25 ± 8.87 years; the minimum age was 39 years; and the maximum age was 7 years. The main clinical symptoms were jaundice (67.92%), abdominal pain (48.11%), and abdominal distension (33.96%). In addition, there were symptoms of weight loss, nausea, vomiting, itching, and gray stool. Previous complications included 27.35% diabetes (29/106), 22.64% hypertension (24/106), 35.84% smoking (38/106), and 28.30% alcohol consumption (30/106). The serological characteristics were mainly the increase in serum IgG4 level; 92.45% (98/106) level was higher compared to the upper limit of normal value; the median level was 11.65 g/L; and the highest level was 35.79 g/L. A total of 88.67% (94/106) had an abnormal liver function. The results of imaging examination indicated that 58.49% (62/106) of extrapancreatic organs were involved, of which 46.22% (49/106) were the most common bile duct involvement. All the patients in the group reached a state of remission after hormone treatment. After the disease was relieved, the patients were followed up for 3 years. The recurrence rate was 39.62% (42/106), and the median time of recurrence (month) was 9 (range 2–36). The recurrence rates within 1, 2, and 3 years were 20.75%, 31.13%, and 39.62%, respectively. Among the recurrent patients, 52.38% (22/42) relapsed within 1 year, 78.57% (33/42) within 2 years, and 100.00% (42/42) within 3 years. Multivariate analysis showed that the short duration of glucocorticoid therapy and involvement of extrapancreatic organs were risk factors for relapse after glucocorticoid therapy in patients with type I AIP. Conclusion Type 1 AIP is more common in middle-aged and elderly men. The clinical symptoms of jaundice, abdominal pain, and abdominal distension are common, often accompanied by involvement of extrapancreatic organs, of which bile duct involvement is the most common. Type 1 AIP glucocorticoid treatment acceptance and disease remission are better, but the recurrence rate is higher after glucocorticoid treatment. Patients with a short time of glucocorticoid treatment and involvement of extrapancreatic organs may have a higher risk of recurrence.

Cross-sectional pictorial review of IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is an autoimmune disorder characterized by the infiltration of one or more organs with IgG4-positive plasma cells resulting in inflammatory lesions and fibrosis. Although the pancreas is the most commonly affected organ, involvement of extrapancreatic organs is an increasingly recognized manifestation of the disease. Patients may be asymptomatic and serum IgG4 concentrations may be elevated or normal. Treatment consists of glucocorticosteroid treatment, with excellent response. A definitive diagnosis requires histopathology with imaging playing a key role in avoiding treatment delays. This pictorial review will focus on the most current knowledge regarding IgG4-RD including its common and less common manifestations and the roles of multidetector CT, MRI and ultrasound in the diagnosis and management of suspected IgG4-RD. Knowledge of the varied imaging findings of this multi systemic disease is essential for radiologists to avoid misdiagnosis and assist with timely and effective treatment.

Diagnosis of autoimmune pancreatitis with computed tomography

Objective To investigate the computed tomography (CT) features of autoimmune pancreatitis (AIP). Methods The CT imaging data of 33 patients with AIP confirmed by pathology and/or steroid therapy were retrospectively analyzed. Image analysis including the shape of pancreas, density of lesion, contrast enhancement, the changes of pancreatic duct and biliary duct, peripancreatic appearances and adjacent organ involvement. T test was performed for statistical analysis. Results Among 33 patients with AIP, 23 cases (70%) with pancreatic parenchyma diffuse enlargement, eight cases (24%) with partial enlargement and two cases (6%) with normal pancreas. The lesions appeared hypoattenuating or isoattenuating on plain CT scan. After contrast-enhanced scan, the average CT values of lesions were (75.7±17.0) Hu at arterial phase, which was lower than that of venous phase (90.7±12.0) Hu, and the difference was statistically significant (t=3.378, P=0.002). The lesions demonstrated as progressive enhancement at venous phase. Among 33 patients, the main pancreatic duct was visible in six patients (18%). Sixteen patients (48%) presented with intrahepatic and extrahepatic biliary tract dilatation caused by intrapancreatic common bile duct stenosis. Thickened envelope-like structure around the lesions, presenting as capsule sign was seen in 14 patients (42%). Extra-pancreatic organ involvement was found in seven patients including three cases of kidney involvement. After treated with steroid, seven patients repeated CT which showed different degrees of improvement. Conclusion The main CT findings of AIP are diffuse and partial enlargement of pancreas with progressive enhancement at venous phase, envelope-like structure around pancreas, and stenosis of intrapancreatic common bile duct, which are important in the diagnosis and differential diagnosis of AIP. Key words: Pancreatitis; Autoimmune diseases; Tomography, X-ray computed

Diagnosis and treatment of autoimmune pancreatitis

Diagnosis and treatment of autoimmune pancreatitis

Autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) is a rare, distinct and increasingly recognized form of pancreatitis which has autoimmune features. The international consensus diagnostic criteria (ICDC) for AIP recently described two subtypes; type 1[lymphoplasmacytic sclerosing pancreatitis (LPSP)] and type 2 [idiopathic duct-centric pancreatitis (IDCP) or AIP with granulocytic epithelial lesion (GEL)]. Type 1 is the more common form of the disease worldwide and current understanding suggests that it is a pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). In contrast, type 2 AIP is a pancreas-specific disease not associated with IgG4 and mostly without the overt extra-pancreatic organ involvement seen in type 1. The pathogenesis of AIP is not completely understood and its clinical presentation is non-specific. It shares overlapping features with more sinister pathologies such as cancer of the pancreas, which continues to pose a diagnostic challenge for clinicians. The diagnostic criteria requires a variable combination of histopathological, imaging and serological features in the presence of typical extrapancreatic lesions and a predictable response to steroids.

Human cationic trypsinogen but not serine peptidase inhibitor, Kazal type 1 variants increase the risk of type 1 autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) is a distinct disease entity. Whether the genes involved in pancreatic acinar cell injury, cationic trypsinogen gene (protease, serine, 1 [trypsin 1] [PRSS1]) and the pancreatic secretory trypsin inhibitor gene (serine peptidase inhibitor, Kazal type 1 [SPINK1]), are associated with AIP remains to be explored. Genetic analyses of PRSS1 variants (exon 2 and 3) and SPINK1 variants (exon 1, 2, and 3) including the intronic areas in 118 patients with AIP and 200 control subjects were performed by direct DNA sequencing. Clinical features including imaging, histology, serology, response to steroid, and extra-pancreatic organ involvement in AIP patients with and without variants were compared. A total of 19 PRSS1 variants and one SPINK1 variant were identified in 20 (16.9%) out of 118 AIP patients. They included one K92N, nine R116C, seven T137M, one C139S, and one C139F of PRSS1 and one 2(IVS3 + 2) of SPINK1. No PRSS1 or SPINK1 variant was identified in the control group. Patients with PRSS1 variants had an increased risk of AIP with odds ratio 22.37 (95% confidence interval: 2.96-168.8, P = 0.003) and higher frequency of serum IgG4 above 280 mg/dL. Using immunosuppressive agent and PRSS1 variant were predictors of less disease relapse in univariate analysis. Presence of PRSS1 variants was the only negative predictor for disease relapse in multivariate analysis. We found a significantly higher frequency of PRSS1 variants in AIP patients than in geographically and ethnically matched control subjects. PRSS1 variants are associated with less disease relapse in AIP.

Unusual Multiorgan Immunoglobulin G4 (IgG4) Inflammation: Autoimmune Pancreatitis, Mikulicz Syndrome, and IgG4 Mastitis

Autoimmune pancreatitis (AIP) type 1 is commonly associated with simultaneous involvement of extrapancreatic organs. Sclerosing cholangitis, sialadenitis, retroperitoneal fibrosis, Sjögren syndrome, and other extrapancreatic lesions are often observed concurrently with AIP. High levels of immunoglobulin G4 (IgG4) in the blood serum and affected tissues are typical of this diagnostic entity. We describe a case report of a 58-year-old female with findings of AIP (according to Asian criteria), IgG4-positive mastitis, and histologically verified Mikulicz syndrome. The effect of corticoid therapy supported the diagnosis of AIP and simultaneously led to the eradication of recurrent mastitis. To the best of our knowledge, this is the first reported case of concurrent findings of AIP and IgG4 mastitis. Our case report supports the concept of systemic IgG4 syndrome with multisystem involvement. Timely diagnosis and appropriate therapy can be effective in a high percentage of patients.

Clinical features and relapse rates after surgery in type 1 autoimmune pancreatitis differ from type 2: A study of 114 surgically treated European patients

BackgroundAt the recent consensus conference on autoimmune pancreatitis (AIP) in Honolulu, we presented preliminary data from our study of surgically treated AIP patients. Our data strongly supported the separation of AIP into type 1 and type 2. Our study is based on a total of 114 surgically treated European AIP patients. Our aims were to elucidate serum IgG4 elevation, other organ involvement, relapse of disease, steroid treatment and diabetes after surgery in 114 surgically treated European AIP patients. Methods88 pancreaticoduodenectomies, 22 left-sided resections and 4 total pancreatectomies were examined. All cases were graded for granulocytic epithelial lesions, IgG4-positive cells, storiform fibrosis, phlebitis and eosinophilic granulocytes. Follow-up data were obtained from 102/114 patients, mean follow-up was 5.3 years. ResultsHistologically, 63 (55.3%) of the 114 patients fulfilled the criteria of type 1 AIP, while 51 (44.7%) patients fulfilled the criteria of type 2 AIP. Type 1 AIP patients were older and more often males than type 2 AIP patients. Elevation of serum IgG4, involvement of extrapancreatic organs, disease relapse, systemic steroid treatment and diabetes after surgery were noted more often in type 1 AIP, while inflammatory bowel disease (IBD) was observed mainly in type 2 AIP. ConclusionsHistological typing of AIP is clinically important because type 1 AIP is part of the IgG4-related disease and type 2 AIP is associated with IBD. Our data also show that relapse of disease and steroid treatment after surgery occur more frequently in type 1 than in type 2 AIP.

Distinguishing Autoimmune Pancreatitis From Pancreaticobiliary Cancers

A review of the literature to identify current modalities for the diagnosis of autoimmune pancreatitis (AIP) with the objective of establishing a strategy to distinguish it from pancreaticobiliary cancers. Pancreatic and biliary manifestations of AIP mimic pancreaticobiliary cancers. Misdiagnosis of AIP can result in major surgery for a steroid-responsive disease. A review of the literature was performed to identify recent advances in the diagnosis of AIP and evaluate outcomes with various diagnostic strategies to minimize operative intervention for an autoimmune disease. Diagnostic criteria for AIP are based on histology, imaging, serology, extrapancreatic organ involvement, and response to steroid therapy. The most commonly involved extrapancreatic sites are bile duct, kidney, and retroperitoneum. The Mayo Clinic diagnostic strategy utilizes core biopsy of the pancreas and the Japanese strategy depends on a characteristic pancreatogram. The rate of operative intervention was similar with both strategies and none of the patients with cancer received steroid therapy. Immunoglobulin G subtype 4 (IgG4)-associated cholangitis mimics cholangiocarcinoma and presence of more than 10 IgG4-positive plasma cells/high power field on endoscopic biopsy of the bile duct was diagnostic for AIP in 88% patients. Biliary complications and early relapse are common after surgical resection and immunomodulatory drugs can maintain long-term remission. Criteria based on histology, imaging, endoscopy, serology, extrapancreatic organ involvement, and response to steroid therapy improve the diagnostic yield for AIP. Application of diagnostic and therapeutic protocols by a multidisciplinary team will optimize outcomes with a decline in the rate of operative intervention for AIP, a steroid-responsive disease with propensity for relapse.

Autoimmune Pancreatitis Accompanied by Tubulointerstitial Nephritis

Autoimmune pancreatitis (AIP) is type of chronic pancreatitis characterized by an autoimmune inflammatory process. IgG4-positive plasma cells can be found in both the pancreas and at extrapancreatic sites of involvement. A 60-year-old man presented with abdominal discomfort. Computed tomography revealed enlargement of the pancreas and kidneys as well as low-attenuated lesions in both kidneys. MRCP showed narrowing of the distal common bile duct and the proximal pancreatic duct. The serum IgG level was elevated, but IgG4 was normal. Histologic examination revealed lymphoplasma infiltration in the renal tubulointerstitium associated with fibrosis along with many IgG4-positive plasma cells, thereby confirming the diagnosis of tubulointerstitial nephritis-associated AIP. The abnormalities in the clinical, laboratory, and radiological findings improved after oral steroid treatment. This is a case of autoimmune pancreatitis accompanied by tubulointerstitial nephritis diagnosed by renal biopsy. Clinicians should suspect the possibility of extrapancreatic organ involvement in autoimmune pancreatitis, especially when abnormalities in other organs are suggested. Proper examinations must be performed. (Korean J Med 2012;83:775-780)

IgG4-Associated Cholecystitis: Another Clue in the Diagnosis of Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) is the pancreatic manifestation of IgG4-associated systemic disease (ISD). Criteria for diagnosis of AIP include recognition of extra-pancreatic organ involvement. Because the diagnosis of AIP can be challenging, even for experts, it is important for clinicians to recognize other target organ damage in this disease. Typical gallbladder findings in AIP have been increasingly recognized. Because cholecystectomy is common in the community, the availability of previous tissue from the gallbladder can provide an important supportive clue in the diagnosis of AIP. The objective of this review is to examine the literature on common gallbladder pathology findings in AIP, and discuss their clinical utility. Gallbladder involvement in AIP seems to be common. Transmural lymphoplasmacytic inflammatory infiltrates, extramural inflammatory nodules, the presence of tissue eosinophilia, phlebitis, and increased tissue IgG4 are all seen more frequently in the gallbladders of patients with AIP. These findings are not 100% specific, because some can be seen in primary sclerosing cholangitis and pancreatic adenocarcinoma. Cholecystectomy for the purpose of diagnosing AIP is not recommended. However, if gallbladder specimens from a previous cholecystectomy are available, an expert review of gallbladder slides with IgG4 immunostaining may help to provide additional criteria for diagnosis of autoimmune pancreatitis.

Probiotic Agent Saccharomyces boulardii Reduces the Incidence of Lung Injury in Acute Necrotizing Pancreatitis Induced Rats

Acute necrotizing pancreatitis is a severe acute inflammatory disease of the pancreas that can lead to extrapancreatic organ involvement. Supervening lung injury is an important clinical entity determining the prognosis of the patient. Probiotics are dietary supplements known to reduce or alter inflammation and inflammatory cytokines. In the present study, we hypothesize that probiotics may reduce lung injury by reducing bacterial translocation, which results in reduced infection, inflammation, and generation of proinflammatory cytokines in an experimental model of acute necrotizing pancreatitis. Pancreatitis was induced by concomitant intravenous infusion of cerulein and glycodeoxycholic acid infusion into the biliopancreatic duct. Saccharomyces boulardii was used as the probiotic agent. Rats were divided into three groups: sham, pancreatitis-saline, which received saline via gavage at 6 and 24 h following the pancreatitis, pancreatitis-probiotics, which received probiotics via gavage method at 6 and 24 h following the pancreatitis. The rats were sacrificed at 48 h, venous blood, mesenteric lymph node, pancreatic and lung tissue samples were obtained for analysis. Serum pancreatic amylase, lactate dehydrogenase, secretory phospholipase A(2), and IL-6 were found to be increased in pancreatitis-saline group compared with the other groups (P < 0.05). Histological analyses revealed that edema, inflammation, and vacuolization as well as polymorphonuclear leukocyte infiltration in the lung tissue was significantly reduced in the probiotic treated group. Bacterial translocation was significantly reduced in the probiotic treated group compared with the other groups (P < 0.05). These results suggest that Saccharomyces boulardii reduce the bacterial translocation. As a result of this, reduced proinflammatory cytokines and systemic inflammatory response was observed, which may be the reason underlying reduced lung injury in acute necrotizing pancreatitis.

Substitution of Aspartic Acid at Position 57 of the DQβ1 Affects Relapse of Autoimmune Pancreatitis

Although autoimmune pancreatitis (AIP) responds well to corticosteroid therapy, relapse during maintenance corticosteroid therapy or after the withdrawal of corticosteroid treatment is not uncommon. To date, the factors related to relapse of AIP have not been fully explored. To determine the clinical and genetic predictors relating to the relapse of AIP, we evaluated clinical factors, HLA polymorphisms, and the amino acid sequences in 40 patients with AIP. At a median follow-up period of 40 months (range, 12-67 months), relapse developed in 13 of 40 patients with AIP (33%), in whom complete remission was achieved with oral corticosteroid therapy. Among demographics, clinical characteristics in the initial diagnosis of AIP, we could not find any clinical predictor for relapse of AIP; however, in amino acid sequence analysis for relapse of AIP, the substitution of aspartic acid to nonaspartic acid at residue 57 of DQbeta1 showed a significant association with relapse of AIP (nonrelapse group, 29.6%; relapse group, 100%; P = .00003; odds ratio, 3.38; 95% confidence interval, 1.9-6.0). There was a significant difference in the timing of relapse of AIP, according to density of the nonaspartic acid residue at DQbeta1 57 (nonaspartic acid homozygosity: mean +/- SD, 6.7 +/- 4.2 months; nonaspartic acid heterozygosity: mean +/- SD, 33 +/- 11 months; P < .001). Substitution of aspartic acid to nonaspartic acid at DQbeta1 57 appears to represent a key genetic factor for relapse of AIP (ClinicalTrials.gov number, NCT00444444).

Immunoglobulin G4 associated cholangitis: Description of an emerging clinical entity based on review of the literature

During the last decade, patients with steroid responsive sclerosing cholangitis have been described in a number of case reports and a few cases series. These patients meet diagnostic criteria for primary sclerosing cholangitis (PSC) but seem to have a better prognosis and are often, but not always, associated with autoimmune pancreatitis (AIP). Unlike biliary strictures in PSC, most PSC-like biliary strictures seen in association with AIP respond well to steroids and some have been shown to resolve after immunosuppressive treatment during prolonged follow-up. In addition, steroid-responsive dominant bile duct lesions, sometimes mimicking infiltrating hilar cholangiocarcinoma, without pancreatic abnormalities have also been reported. Here we review the literature on this emerging clinical entity and suggest that this condition of steroid responsive biliary strictures be named Immunoglobulin G4 (IgG4) Associated Cholangitis (IAC). We performed an electronic database search of MEDLINE for case reports and case series of sclerosing cholangitis with pancreatitis and/or pancreatic mass (1960–July 2006). Articles were limited to English and these case reports and cases series were reviewed and all references on the combination of sclerosing cholangitis and pancreatitis as well as IgG4 positive cholangitis without pancreatic involvement not identified by our original search were obtained. Terminology and Definition