IgG4‐related retroperitoneal fibrosis: a newly characterized disease

Retroperitoneal fibrosis (RPF) is a rare disease characterized by chronic, nonspecific inflammatory and sclerotic or fibrotic tissue in the periaortic or periiliac retroperitoneum that encases adjacent structures. There will be a series of clinical manifestations once the proliferated fibrous tissues encase the abdominal aorta, iliac arteries and urinary duct. RPF is generally divided into two types: idiopathic retroperitoneal fibrosis (IRPF) without identified pathogenesis, making up about two‐thirds of cases, and secondary retroperitoneal fibrosis. Recent studies on Immunoglobulin G4‐related disease (IgG4‐RD) reveal that abundant infiltration of IgG4 positive plasma cells is found in biopsies on the mass of RPF of some IRPF patients, which is identified as one spectrum of IgG4‐RD and is named IgG4‐related RPF. IgG4‐related RPF is often misdiagnosed as retroperitoneal visceral malignancy and is treated with surgery. In addition, because of its good response to glucocorticoid, early detection and treatment is important. We review the definition, epidemiology, clinical features, diagnostic criteria, treatment and prognosis of IgG4‐related RPF in this article to raise awareness of this newly characterized disease.     

IgG4-related retroperitoneal fibrosis: the first reported case in a Chinese population

Immunoglobulin G4 (IgG4)-related sclerosing disease is a newly recognized clinicopathological entity characterized by lymphoplasmacytic infiltration and varying degrees of fibrosis in various organs, with abundant IgG4-positive plasma cells in tissues. Patients usually exhibit multisystem involvement and often respond well to steroid and immunosuppressive therapy. However, this disease has been rarely reported in a Chinese population. We herein report a case of IgG4-related sclerosing disease solely presenting with retroperitoneal fibrosis that was effectively treated with systemic steroid therapy. To the best of our knowledge, this is the first reported case of IgG4-related retroperitoneal fibrosis in a Chinese population.     

IgG4‐related disease

Immunoglobulin G4‐related disease (IgG4‐RD) is a regional or systemic fibro‐inflammatory disease of unknown etiology. It presents a distinctive histopathological appearance of dense lymphoplasmacytic infiltrates with abundant IgG4‐positive plasma cells, storiform fibrosis and obliterative phlebitis with the appearance of inflammatory swelling or tumefactive lesions. This new disease entity includes a wide variety of diseases such as Mikulicz disease, autoimmune pancreatitis, Riedel thyroiditis, interstitial nephritis and retroperitoneal fibrosis. Glucocorticoid therapy can resolve the clinical and pathological abnormalities and impaired organ function. IgG4‐RD was recognized internationally in 2011, and new evidence has accumulated regarding its pathogenesis, clinical features and treatment. In this review, we outline our present understanding of IgG4‐RD.     

Diagnostic procedures for IgG4-related sclerosing cholangitis

Background/purpose

IgG4-related sclerosing cholangitis (IgG4-SC) is one of several diseases associated with autoimmune pancreatitis (AIP). However, diffuse cholangraphic abnormalities seen in association with AIP may resemble those seen in primary sclerosing cholangitis (PSC), and the presence of segmental stenosis suggests cholangiocarcinoma. IgG4-SC responds well to steroid therapy, whereas in contrast, liver transplantation is the only effective therapy for PSC, and surgical intervention is also needed for cholangiocarcinoma. The aim of this review was to establish the diagnostic procedures for IgG4-SC.

Methods

A literature search was conducted, covering English-language articles dealing with IgG4-SC published between 1991 and March 2010. As clinical data on IgG4-SC are limited, the author also took into consideration his own clinical experience with the treatment of IgG4-SC over a period of more than 19 years.

Results

When intrapancreatic stenosis is detected, pancreatic cancer should be ruled out. If multiple intrahepatic stenosis is evident, PSC should be discriminated on the basis of cholangiographic findings and liver biopsy with IgG4 immunostaining. An association with inflammatory bowel disease (IBD) is suggestive of PSC. If stenosis is demonstrated in the hepatic hilar region, cholangiocarcinoma should be discriminated by US, EUS, IDUS, and bile duct biopsy.

Conclusion

For diagnosis of IgG4-SC, coexistence of AIP is the most useful finding. However, the most important consideration for clinicians is to be aware of IgG4-SC when encountering patients with obstructive jaundice.     

IgG4‐related disease and lymphocyte‐variant hypereosinophilic syndrome: A comparative case series

Chronic lymphocytic leukaemia (CLL) is a chronic B‐cell lympho‐proliferative disorder in which lymphomatous transformations occur in 5%‐15% of patients. Histologically these cases resemble diffuse large B‐cell lymphoma, or Richter's transformation, in over 80% of cases. Rare cases of transformation to Hodgkin lymphoma (HL) have been reported in the literature with an estimated prevalence of 0.4%. We report a case of a 67‐year‐old female with CLL treated with the novel Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib, who subsequently presented with intractable fevers. Bone marrow trephine, and lymph node biopsy revealed classical HL with negative immuno‐histochemistry for Btk in HL cells, on a backdrop of CLL. The patient commenced treatment with Adriamycin, Vinblastine and Dacarbazine (AVD), which resulted in an excellent response. Hodgkin transformation of CLL is rare with a single retrospective study of 4121 CLL patients reporting only 18 cases. Btk expression in HL cells is recently recognised in classical HL; however, the majority of HLs are Btk negative. Given that Btk inhibitors have recently been shown to induce genomic instability in B cells, in the context of their widespread use, such emerging cases are increasingly relevant.     

Medical mirroring: granulomatosis with polyangiitis (formerly Wegener's) mimicking immunoglobulin‐G4 related disease

Granulomatosis with polyangiitis (GPA; formerly Wegener's) can present with clinical and histopathological features similar to those of immunoglobulin‐G4 related disease (IgG4‐RD), a recently described fibro‐inflammatory condition. The ability of these two distinct entities to mimic each other closely creates significant pitfalls in diagnosis. We present a unique case in which GPA presented as a peri‐aortic fibrotic mass in the retroperitoneum. The patient's other clinical features also overlapped with classic IgG4‐RD disease manifestations, but the histopathology in two organs and the serological data confirmed the diagnosis of GPA. Rigorous histopathological review remains the gold standard for the diagnosis of GPA and the distinction of this entity from IgG4‐RD and other mimickers.     

肺吸虫特异性IgG4快速检测方法的建立与应用

目的创建简易、快速、准确的肺吸虫病免疫诊断方法。方法用卫氏并殖吸虫成虫粗提液为抗原,以胶体金标记抗人IgG4单抗为检测探针,采用自行设计的垂直流渗滤装置,创建快速检测人血清肺吸虫特异性IgG4方法(P-IgG4-DIGFA),平行检测IgG作比较分析;以经典ELISA为对照,评价其诊断价值,应用P-IgG4-DIGFA检测有效治疗后病人血清,评价其疗效考核价值。结果P-IgG4-DIGFA检测人血清中肺吸虫特异性IgG4的敏感性和特异性分别为95.2%(40/42)、100%(50/50),与血吸虫病患者血清的交叉反应率仅为2%(1/50),未发现与华支睾吸虫病有交叉反应。P-IgG4-DIGFA的敏感性和特异性略高于经典ELISA,差异无统计学意义(χ2=0.25,P>0.05);应用P-IgG4-DIGFA检测有效治疗后3个月、6个月和12个月病人血清特异性IgG4,阴转率分别为0%、16.7%(1/6)和100%。结论金标渗滤法快速检测肺吸虫特异性IgG4,不仅操作简便、快速,而且敏感性高、特异性强,适用于临床检验和现场查病,对治疗后1年病人具有疗效考核价值,有待进一步开发应用。     

循环抗原和特异性IgG4对脑囊尾蚴病诊断和疗效评估价值比较

目的比较循环抗原（circulating antigen, CAg ）和特异性IgG4在脑囊尾蚴病诊断和生存状态、 疗效评估中的价值。方法依据CT和MRI的影像表现将68例脑囊尾蚴病患者分为活虫期、变性死亡早期、变 性死亡后期及钙化期四个病期组,检测各病期患者血清中囊虫CAg和IgG4;分别对38例活虫期患者治疗前 ,治疗中,治疗后血清中CAg和特异性IgG4进行检测和比较分析。结果不同病期患者血清CAg阳性率、IgG4 阳性率差异均有显著意义。38例活虫期患者血清CAg、IgG4阳性率分别为100%和98%,随疗程进展,CAg、 IgG4阳性率逐渐降低,不同疗程间CAg阳性率差别有显著性意义,而IgG4阳性率差异无统计学意义。结论 CAg和特异性IgG4能较客观地反映人体内脑囊尾蚴的生存状态,可作为早期诊断指标,两者的特异性及敏 感性无显著差异;对远期疗效评估可以优先选用CAg。     

Possible participation of IgG4 in the activation of complement in IgG4-related disease with hypocomplementemia

Objective: To investigate which IgG subclasses contribute to the activation of the complement pathway in IgG4-related disease (IgG4RD) patients with hypocomplementemia.

Methods: Sera of IgG4RD patients were analyzed for the binding ability of IgG subclasses to complement component 1q (C1q). Polyethylene glycol (PEG) precipitates containing immune complexes (ICs) in sera of IgG4RD patients were analyzed for IgG subclass composition by Western blotting. PEG precipitates containing ICs (PEG-ICs) in sera of patients were also analyzed for their ability to consume complement in normal human serum (NHS) using a total complement hemolytic (CH50) assay and a commercial kit to measure the complement capacity of all three individual complement pathways.

Results: The C1q binding assay revealed high serum levels of C1q-binding IgG4 in IgG4RD patients with hypocomplementemia. ICs in PEG precipitates were formed with IgG4 in IgG4RD patients, regardless of the presence or absence of hypocomplementemia. We observed a marked reduction of CH50 and reduced complement activity in the classical complement pathway as well as the mannan-binding lectin complement pathway in NHS incubated with PEG-IC isolated from IgG4RD patients with hypocomplementemia.

Conclusion: Our results suggest that IgG4 may participate in the activation of complement in IgG4RD patients with hypocomplementemia.     

IgG4-related sclerosing cholangitis and autoimmune pancreatitis: histological assessment of biopsies from Vater's ampulla and the bile duct

Background and Aim: Autoimmune pancreatitis is commonly associated with immunoglobulin (Ig) G4‐related sclerosing cholangitis (IgG4‐SC). The discrimination between IgG4‐SC and pancreatobiliary malignancies or primary sclerosing cholangitis (PSC) is now an important issue. The present study was carried out to examine the usefulness of endoscopic biopsies from Vater's ampulla and the bile duct to diagnose IgG4‐SC. Methods: The present study included 29 IgG4‐SC patients (26 with both pancreatitis and cholangitis, and 3 with cholangitis only), 6 PSC patients, and 27 pancreatobiliary carcinoma patients. All patients underwent endoscopic biopsies from Vater's ampulla and the common bile duct. Biopsied specimens were histologically examined using immunostaining for IgG4. Results: For the ampullary and bile duct biopsies, the IgG4‐SC samples had a significantly greater number of IgG4‐positive plasma cells than the PSC or pancreatobiliary carcinoma specimens. In addition, bile duct biopsies from five patients (17%) with IgG4‐SC showed diffuse inflammatory cell infiltration with irregular fibrosis corresponding to the histological features of lymphoplasmacytic sclerosing pancreatocholangitis. Based on the threshold of 10 IgG4‐positive plasma cells per high power field, the diagnostic rates of the ampullar and bile duct biopsies were both 52% (15/29 cases). Twenty‐one patients (72%) had more than 10 IgG4‐positive plasma cells in at least one biopsy. The bile duct biopsy was significantly valuable for IgG4‐SC patients with swelling of the pancreatic head. Conclusion: The present study suggested that ampullar and bile duct biopsies are useful for diagnosing IgG4‐SC.     

自身免疫性胰腺炎合并硬化性胆管炎

自身免疫性胰腺炎(AIP)的病理特异性表现为胰腺存在大量的IgG4阳性的浆细胞浸润和组织纤维化,这种病理表现也常见于大部分AIP患者的胆管系统,即AIP合并硬化性胆管炎(SC)。AIP合并SC往往以阻塞性黄疸为首发症状,其血IgG4明显升高。AIP合并SC的胆管造影与原发性硬化性胆管炎(PSC)极为相似,但AIP合并SC对皮质激素治疗往往有效,其预后较PSC好。