Sclerosing cholangitis associated with autoimmune pancreatitis differs from primary sclerosing cholangitis

AIM： To clarify the characteristic features of biliary lesions in patients with autoimmune pancreatitis （AIP） and compare them with those of primary sclerosing cholangitis （PSC）.METHODS： The clinicopathological characteristics of 34 patients with sclerosing cholangitis （SC） associated with AIP were compared with those of 4 patients with PSC.RESULTS： SC with AIP occurred predominantly in elderly men. Obstructive jaundice was the most frequent initial symptom in SC with AIP. Only SC patients with AIP had elevated serum IgG4 levels, and sclerosing diseases were more frequent in these patients. SC patients with AIP responded well to steroid therapy. Segmental stenosis of the lower bile duct was observed only in SC patients with AIP, but a beaded and prunedtree appearance was detected only in PSC patients.Dense infiltration of IgG4-positive plasma cells was detected in the bile duct wall and the periportal area, as well as in the pancreas, of SC patients with AIP.CONCLUSION： SC with AIP is distinctly different from PSC. The two diseases can be discriminated based on cholangiopancreatographic findings and serum IgG4 levels.     

Sclerosing cholangitis associated with autoimmune pancreatitis

Autoimmune pancreatitis is a unique form of chronic pancreatitis characterized by irregular narrowing of the pancreatic duct, pancreatic swelling, and a favorable response to corticosteroids, in which the autoimmune mechanism is postulated in the pathogenesis. High serum immunoglobulin (Ig)G4 concentrations and various types of extrapancreatic involvement are prominent features of this disease. Sclerosing cholangitis is a major extrapancreatic lesion of autoimmune pancreatitis that has been regarded as primary sclerosing cholangitis (PSC) complicating chronic pancreatitis. Because sclerosing cholangitis associated with autoimmune pancreatitis (SC-AIP) also favorably responds to corticosteroid therapy, it should be differentiated from PSC. Useful points regarding the differentiation between SC-AIP and PSC are as follows: (i) PSC occurs in younger and SC-AIP in older individuals; (ii) obstructive jaundice is more frequently seen in SC-AIP; (iii) PSC is complicated with inflammatory bowel disease, whereas SC-AIP is complicated with so called extrapancreatic lesions of AIP; (iv) high serum IgG4 concentrations are frequently seen in SC-AIP; (v) a cholangiogram may differentiate the two conditions to some extent; (vi) abundant IgG4-bearing plasma cell infiltration is seen in SC-AIP; and (vii) steroid therapy is effective for SC-AIP. IgG4-related sclerosing cholangitis without pancreatic lesion may be a metachronous phenotype of SC-AIP, and also should be differentiated from PSC. The pathogenesis of AIP and SC-AIP remains unclear. The complement activation system of the classical pathway may be contributing in some cases.     

Sclerosing cholangitis associated with retroperitoneal fibrosis: a case of multisystem fibroinflammatory disorder

Introduction  

Retroperitoneal fibrosis is a fibroinflammatory disease of unknown etiology that can be associated with other fibroinflammatory disorders. Lately, there have been several reports showing that retroperitoneal fibrosis is a manifestation of IgG4-related sclerosing disease, which often presents as autoimmune pancreatitis.     

IgG4相关硬化性胆管炎的研究进展

免疫球蛋白G4相关硬化性胆管炎(immunoglob-ulin G4-related sclerosing cholangitis,IgG4-SC)是一种新近认识的以血清IgG4升高、慢性进行性阻塞性黄疸、弥漫性或局限性IgG4阳性浆细胞和淋巴细胞组织浸润、纤维化及闭塞性静脉炎为特征的慢性炎症性疾病,常并发自身免疫性胰腺炎(autoimmune pancreatitis,AIP),其临床、生化及影像学特征与原发性硬化性胆管炎(primary sclerosing cholangitis,PSC)或胆管癌(cholangiocarcinoma,CC)相似.类固醇激素是IgG4-SC的主要治疗手段,而肝移植是PSC唯一的有效治疗方法,CC则需外科手术治疗.因此,IgG4-SC与PSC或CC间的准确鉴别是目前面临的一个十分重要的课题.本文详尽地阐述了免疫球蛋白G4(immunoglobulin G4,IgG4)的特征和功能,IgG4-SC的诊断和治疗,IgG4-SC与AIP、PSC及CC之间关系等研究进展,为IgG4-SC的精确诊断和治疗提供了新的思路.     

Clinical clues to suspicion of IgG4-associated sclerosing cholangitis disguised as primary sclerosing cholangitis or hilar cholangiocarcinoma

Background and Aim: This study aimed to determine the clinical characteristics of immunoglobulin G4 (IgG4)‐associated sclerosing cholangitis (ISC) and provide clinical clues differentiating ISC from primary sclerosing cholangitis (PSC) or hilar cholangiocarcinoma (CCC). Methods: Sixteen patients with ISC manifesting as hilar/intrahepatic strictures were analyzed for clinical characteristics and compared with patients with PSC and hilar CCC as disease controls for histology and serum IgG4 levels. Results: Distinguished biliary imaging findings of ISC included multifocal biliary tree involvement (n = 14), concentric bile duct thickening with preserved luminal patency (n = 13), and relatively mild proximal dilatation, despite prominent bile duct thickening (n = 11). Serum IgG4 levels were elevated in 12 patients (75%), but not in any of the 25 patients with hilar CCC. Ten patients (63%) had a past or concurrent history of autoimmune pancreatitis (AIP). The significant infiltration of IgG4‐positive cells was observed with endobiliary or liver biopsy in 11 of 16 patients (69%) with ISC, but not in any patients with PSC or hilar CCC. Extrabiliary organ involvement, including sialadenitis, inflammatory pseudotumor of the liver and kidney, and retroperitoneal fibrosis, was present in seven patients. Marked improvement of biliary strictures and/or extrabiliary involvement was observed in all ISC patients after steroid therapy. Conclusions: ISC should be considered in the differential diagnosis of hilar/intrahepatic biliary strictures. Past or concurrent AIP or extrabiliary organ involvement strongly suggests the possibility of ISC. Significant infiltration of IgG4‐positive cells on endobiliary or liver biopsy specimens, and/or elevated serum IgG4 levels, highly support the diagnosis of ISC and provide the rationale for steroid therapy.     

Isolated intrapancreatic Ig G4-related sclerosing cholangitis

Immunoglobulin G4-related sclerosing cholangitis(Ig G4-SC) is frequently associated with type 1 autoimmune pancreatitis(AIP). Association with AIP can be utilized in the diagnosis of Ig G4-SC. However, some cases of Ig G4-SC are isolated from AIP, which complicates the diagnosis. Most of the reported cases of isolated Ig G4-SC displayed hilar biliary strictures, whereas isolated Ig G4-SC with intrapancreatic biliary stricture is very rare. Recently, we have encountered 5 isolated intrapancreatic Ig G4-SC cases that were not associated with AIP, three of which were pathologically investigated after surgical operation. They all were males with a mean age of 74.2 years. The pancreas was not enlarged in any of these cases. No irregular narrowing of the main pancreatic duct was found. Bile duct wall thickening in lesions without luminal stenosis was detected by abdominal computed tomography in all five cases, by endoscopic ultrasonography in two out of four cases and by intraductal ultrasonography in all three cases. In three cases, serum Ig G4 levels were within the normal limits. The mean serum Ig G4 level measured before surgery was 202.1 mg/d L(4 cases). Isolated intrapancreatic Ig G4-SC is difficult to diagnose, especially if the Ig G4 level remains normal. Thus, this type of Ig G4-SC should be suspected in addition to cholangiocarcinoma and pancreatic cancer if stenosis of intrapancreatic bile duct is present.     

Diagnosis of IgG4-related sclerosing cholangitis

IgG4-related sclerosing cholangitis(IgG4-SC)is often associated with autoimmune pancreatitis.However,the diffuse cholangiographic abnormalities observed in IgG4-SC may resemble those observed in primary sclerosing cholangitis(PSC),and the presence of segmental stenosis suggests cholangiocarcinoma(CC).IgG4-SC responds well to steroid therapy,whereas PSC is only effectively treated with liver transplantation and CC requires surgical intervention.Since IgG4-SC was first described,it has become a third distinct clinical entity of sclerosing cholangitis.The aim of this review was to introduce the diagnostic methods for IgG4-SC.IgG4-SC should be carefully diagnosed based on a combination of characteristic clinical,serological,morphological,and histopathological features after cholangiographic classification and targeting of a disease for differential diagnosis.When intrapancreatic stenosis is detected,pancreatic cancer or CC should be ruled out.If multiple intrahepatic stenoses are evident,PSC should be distinguished on the basis of cholangiographic findings and liver biopsy with IgG4 immunostaining.Associated inflammatory bowel disease is suggestive of PSC.If stenosis is demonstrated in the hepatic hilar region,CC should be discriminated by ultrasonography,intraductal ultrasonography,bile duct biopsy,and a higher cutoff serum IgG4 level of 182 mg/dL.     

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.     

Clinicopathological differentiation between sclerosing cholangitis with autoimmune pancreatitis and primary sclerosing cholangitis

Background The present study was undertaken to identify the clinicopathological differences between sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) and primary sclerosing cholangitis (PSC). Methods We retrospectively compared the clinical, cholangiographic, and liver biopsy findings between 24 cases of PSC and 24 cases of SC-AIP. Results Patient age at the time of diagnosis was significantly lower in the PSC group than in the SC-AIP group. The peripheral blood eosinophil count was significantly higher in the PSC group than in the SC-AIP group, but the serum IgG4 level was significantly higher in the SC-AIP group. Cholangiography revealed band-like strictures, beaded appearance, and pruned-tree appearance significantly more frequently in PSC, whereas segmental strictures and strictures of the distal third of the common bile duct were significantly more common in SC-AIP. Liver biopsy revealed fibrous obliterative cholangitis only in the PSC specimens. No advanced fibrous change corresponding to Ludwig's stages 3 and 4 was observed in any of the SC-AIP specimens. IgG4-positive plasma cell infiltration of the liver was significantly more severe in SC-AIP than in PSC. Subsequent cholangiography showed no improvement in any of the PSC cases, but all SC-AIP patients responded to steroid therapy, and improvement in the strictures was observed cholangiographically. Conclusions Based on the differences between the patients' ages and blood chemistry, cholangiographic, and liver biopsy findings, SC-AIP should be differentiated from PSC.     

Controversies in the management of primary sclerosing cholangitis

Primary sclerosing cholangitis(PSC) remains a rare but significant disease, which affects mainly young males in association with inflammatory bowel disease. There have been few advances in the understanding of the pathogenesis of the condition and no therapeutics with proven mortality benefit aside from liver transplantation. There remain areas of controversy in the management of PSC which include the differentiation from other cholangiopathies, in particular immunoglobulin G4 related sclerosing cholangitis, the management of dominant biliary strictures, and the role of ursodeoxycholic acid. In addition, the timing of liver transplantation in PSC remains difficult to predict with standard liver severity scores. In this review, we address these controversies and highlight the latest evidence base in the management of PSC.     

Autoimmune cholangitis and cholangiocarcinoma

Autoimmune cholangitis, immunoglobulin G4‐associated cholangitis (IAC), is a part of multiorgan IgG4‐related systemic disease, which was recognized as a new clinicopathological entity in recent years. IAC is defined as a biliary stricture that responds to steroid therapy, frequently is associated with other fibrosing conditions, especially autoimmune pancreatitis and is characterized by elevation of IgG4 in serum and infiltration of IgG4 positive plasma cells in bile ducts. Since IAC shares a number of clinical, biochemical, and imaging features with cholangiocarcinoma (CCA), it is often misdiagnosed as CCA, and unnecessary surgery was performed. In this compact review, we clarify the disease of IAC, summarize criteria for diagnosis of IAC, discuss the role of CA 19‐9, and provide key information to differentiate diagnosis of IAC from CCA. IAC should be highly suspected in unexplained biliary stricture associated with increased IgG4 (in serum especially in bile) and other organ involvement (kidney, retroperitoneum etc. especially pancreas in which there are abundant IgG4‐positive plasmocytes infiltration). Correct diagnosis of IAC will avoid unnecessary surgery because IAC responds well to steroid therapy. In a word, increased IgG4 levels, other organ involvement and response to steroids are keys to distinguishing IAC from CCA.     

A case of primary sclerosing cholangitis mimicking chronic pancreatitis

Summary A case of a 37 year old male is presented, who died from primary sclerosing cholangitis (PSC) with characteristic radiological picture and laboratory data suggesting chronic pancreatitis (CP).     

免疫球蛋白G4相关性胆管炎诊断和治疗进展

一、概述1995年,日本学者报道了一种以血清免疫球蛋白(Immunoglobulin,IG) G4水平升高和IgG4阳性淋巴-浆细胞的组织浸润为特征的纤维炎症性疾病,即自身免疫性胰腺炎(autoimmune pancreatitis,AIP)[1].现已认识到AIP是一世界性疾病.其特征性表现包括胰腺肿大或肿块(可能类似于恶性肿瘤)、血清IgG4水平升高、组织淋巴-浆细胞浸润和激素治疗有效[2].     

First case of IgG4-related sclerosing cholangitis associated with autoimmune hemolytic anemia

To our knowledge, patients with immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) associated with autoimmune hemolytic anemia (AIHA) have not been reported previously. Many patients with IgG4-SC have autoimmune pancreatitis (AIP) and respond to steroid treatment. However, isolated cases of IgG4-SC are difficult to diagnose. We describe our experience with a patient who had IgG4-SC without AIP in whom the presence of AIHA led to diagnosis. The patient was a 73-year-old man who was being treated for dementia. Liver dysfunction was diagnosed on blood tests at another hospital. Imaging studies suggested the presence of carcinoma of the hepatic hilus and primary sclerosing cholangitis, but a rapidly progressing anemia developed simultaneously. After the diagnosis of AIHA, steroid treatment was begun, and the biliary stricture improved. IgG4-SC without AIP was thus diagnosed.     

自身免疫性胰腺炎81例临床特征分析

目的 总结我国自身免疫性胰腺炎(AIP)患者的临床特征.方法 分析上海长海医院2005年2月至2012年5月诊断为AIP的81例患者临床资料.结果 81例AIP患者中男女比例7.1∶1,平均年龄(57±12)岁.51.9％ (42/81)患者以梗阻性黄疸为首发症状.影像学显示胰腺局灶型占位45例,弥漫型肿大35例,胰腺假性囊肿为主要表现1例;72.8％ (59/81)伴有胆管受累,11.1％(5/45)伴有主胰管扩张.PET-CT表现为全胰腺(11例)或胰头颈部(2例)代谢增高,5例伴有胰腺外显著高代谢区.血清IgG4阳性率94.6％(53/56),CA19-9阳性率54.4％(37/68),ss-DNA抗体阳性率14.3％ (4/28),抗核抗体阳性率10.7％(3/28),ds-DNA抗体阳性率7.1％(2/28).20例手术标本行HE染色和IgG4免疫组化染色,均符合淋巴浆细胞硬化性胰腺炎表现.结论 我国AIP以1型为主,结合临床症状,胰腺外表现、影像学和(或)核医学、血清学、细胞学和(或)组织学等检查可有效提高AIP的正确诊断率.     

IgG4-related sclerosing disease

Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prosrate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AlP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4- related sclerosing diseases. This disease includes AlP, sclerosing cholangitis, cholecystitis, sialadenitis, retro-peritoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AlP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunos-taining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.     

Autoimmune pancreatitis

The purpose of this review is to provide a concise view of the existing knowledge of autoimmune pancreatitis (AIP) for practicing clinicians. AIP is a rare disease whose recognition and understanding are evolving. It is a type of chronic pancreatitis that often presents as obstructive jaundice, has a distinctive histology, and is exquisitely sensitive to steroid therapy. This form of chronic pancreatitis has a unique clinical, biochemical, and radiological profile. The term "AIP" encompasses two subtypes: types 1 and 2. Type 1 AIP is the pancreatic manifestation of a systemic fibro-inflammatory disease called immunoglobulin G4-associated systemic diseases. Type 2 AIP has been shown to be associated with inflammatory bowel disease. Existing criteria are geared towards the diagnosis of type 1 AIP. At present, pancreatic histology is a requirement for the definitive diagnosis of type 2 AIP. AIP can mimic most other pancreatic diseases in its presentation, but in clinical practice, it often has to be differentiated from pancreatic cancer. There are established criteria and algorithms not only to diagnose AIP, but also to differentiate it from pancreatic cancer. The utility of these algorithms and the approach to management are discussed here.     

Characteristic Findings of Endoscopic Retrograde Cholangiopancreatography in Autoimmune Pancreatitis

Background/Aims

Diffuse or segmental irregular narrowing of the main pancreatic duct (MPD), as observed by endoscopic retrograde cholangiopancreatography (ERCP), is a characteristic feature of autoimmune pancreatitis (AIP).

Methods

ERCP findings were retrospectively examined in 40 patients with AIP in whom irregular narrowing of the MPD was detected near the orifice. The MPD opening sign was defined as the MPD within 1.5 cm from the orifice being maintained. The distal common bile duct (CBD) sign was defined as the distal CBD within 1.5 cm from the orifice being maintained. Endoscopic findings of a swollen major papilla and histological findings of specimens obtained from the major papilla were examined in 26 and 21 patients, respectively.

Results

The MPD opening sign was detected in 26 of the 40 patients (65%). The distal CBD sign was detected in 25 of the 32 patients (78%), which showed stenosis of the lower bile duct. The patients who showed the MPD opening sign frequently showed the distal CBD sign (p=0.018). Lymphoplasmacytic infiltration, but not dense fibrosis, was histologically detected in biopsy specimens obtained from the major papilla.

Conclusions

On ERCP, the MPD and CBD adjacent to the major papilla are frequently maintained in patients with AIP involving the pancreatic head. These signs are useful for diagnosing AIP on ERCP.     

自身免疫性硬化性胆管炎:新概念与新证据

硬化性胆管炎根据其病因及发病机制不同可分为原发性硬化性胆管炎(PSC)和继发性硬化性胆管炎,其中PSC的发病可能与免疫相关。近些年,新发现了一种硬化性胆管炎,以血清及组织免疫球蛋白(Ig)G4水平升高为特征,对激素治疗效果良好。PSC和Ig G4相关硬化性胆管炎可统称为自身免疫性硬化性胆管炎,在新概念中探索多种表现为硬化性胆管炎疾病间的同与异,更有助于拓展免疫相关性疾病的新思路与方向。