Retroperitoneal disorders associated with IgG4-related autoimmune pancreatitis

Ig G4-related autoimmune pancreatitis is frequently accompanied by relevant lesions in the genitourinary tract and retroperitoneal organs, which cause various clinical problems, ranging from non-specific back pain or bladder outlet obstruction to renal failure. The diagnosis of Ig G4-related retroperitoneal fibrosis requires a multidisciplinary approach, including serological tests, histological examination, imaging analysis, and susceptibility to steroid therapy. Radiological examinations are helpful to diagnose this condition, but surgical resection is occasionally unavoidable to exclude malignancy, particularly for patients with isolated retroperitoneal involvement. Steroid therapy is the treatment of choice for this condition, the same as for other manifestationsof Ig G4-related disease.For patients with severe ureteral obstruction,additional ureteral stenting needs to be considered prior to steroid therapy to preserve the renal function.Some papers have suggested that Ig G4-related disease can affect male reproductive organs including the prostate and testis.Ig G4-related prostatitis usually causes lower urinary tract symptoms,such as dysuria and pollakisuria.Patients sometimes state that corticosteroids given for Ig G4-related disease at other sites relieve their lower urinary tract symptoms,which leads us to suspect prostatic involvement in this condition.Because of the limited number of publications available,further studies are warranted to better characterize Ig G4-related disease in male reproductive organs.     

IgG4-related autoimmune prostatitis: two cases with or without autoimmune pancreatitis

Recently, autoimmune pancreatitis (AIP) has been reported with a variety of extra-pancreatic manifestations and infiltration of IgG4-positive cells into the affected organs. We report herein two cases with prostatitis. One was seen in a patient with typical AIP, and the other was observed without any clinical manifestation of AIP. Serum IgG4 levels were elevated in both cases. Histological examination of the prostates showed that parenchymal cells were partially or totally replaced with fibrosis and abundant infiltration of IgG4-positive cells. Significant uptake of [18F] fluorodeoxyglucose by the prostate was seen in both cases. In the case with AIP, the uptake completely disappeared after steroid therapy. The findings observed in these cases suggest that the pathological mechanism for prostatitis is similar to the mechanism previously implicated in AIP, namely IgG4-related autoimmune prostatitis.     

Three cases of bronchial asthma preceding IgG4-related autoimmune pancreatitis

Background: Autoimmune pancreatitis is characterized by diffuse swelling of the pancreas and a high serum immunoglobulin (Ig) G4 concentration. Histopathologically, dense infiltration of lymphocytes and IgG4-positive plasma cells with fibrosis are seen in the pancreas. Although allergic diseases complicating autoimmune pancreatitis have been reported, the clinical features of bronchial asthma complicated by autoimmune pancreatitis remain unclear.Case Summary: We report three cases of bronchial asthma preceding the onset of type 1 autoimmune pancreatitis by 3 months to 30 years. All three cases were males with high serum IgG, IgG4, and IgE concentrations. The radioallergosorbent tests were positive for common allergens such as mites and house dust. One case had a pulmonary manifestation that proved to be an inflammatory pseudotumor of the lung with an accumulation of IgG4-positive plasma cells. The asthma symptom was ameliorated by oral prednisolone therapy for autoimmune pancreatitis, and when the corticosteroid doses were reduced, asthma became worse in all three cases.Discussion: It is possible that atopy and increased Th2 cell activity are related to a higher coincidence of IgG4-related diseases such as type 1 autoimmune pancreatitis. Because the present cases are few in number, further studies are necessary.     

自身免疫性胰腺炎及其合并IgG4相关硬化性胆管炎的临床特征和预后比较

目的比较分析单纯自身免疫性胰腺炎(AIP)与AIP合并IgG4相关硬化性胆管炎(IgG4-SC)患者的临床特征差异、诊治和预后。方法回顾性分析2015年6月—2020年1月郑州大学第一附属医院收治的40例1型AIP患者资料,其中包括29例单纯AIP患者及11例AIP合并IgG4-SC患者,对比两组患者的临床表现、实验室检查、影像学表现、治疗及预后。正态分布的计量资料两组间比较采用t检验,非正态分布的计量资料两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用Fisher确切检验。采用Kaplan-Meier法计算患者复发率并绘制复发曲线,采用log-rank检验进行比较。结果与单纯AIP组相比,AIP合并IgG4-SC组受累器官数目更多[3.0(3.0~4.0)个vs 3.0(1.5~3.5)个,Z=-2.172,P=0.035],治疗前反应指数更高[12.0(12.0~15.0)vs 12.0(9.0~13.5),Z=-2.157,P=0.032]。AIP合并IgG4-SC组血清IgG水平为21.0(15.8~23.7)g/L,高于单纯AIP组的14.8(13.3~15.7)g/L,差异有统计学意义(Z=-2.711,P=0.004)。在中位随访时间15.8(6.5~31.3)个月内,AIP合并IgG4-SC组复发率明显高于单纯AIP组,差异有统计学意义(χ²=8.155,P=0.004)。结论AIP合并IgG4-SC组血清IgG4水平更高、受累器官更多,且更易出现复发。早期识别、诊断和治疗可降低AIP的复发率。     

Mass-forming autoimmune pancreatitis caused after resection of an IgG4-related renal pelvic lesion

A 64-year-old man was found to have a 15-mm tumor in the pancreatic tail by CT angiography 1 year after resection of a left renal pelvic tumor. Clinically, the tumor was preoperatively suspected to be autoimmune pancreatitis. However, surgical resection was performed under a diagnosis of pancreatic ductal cancer, because atypical epithelial cells were detected by endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA). Pathological examination of the tumor revealed a mass-forming autoimmune pancreatitis. Mass-forming autoimmune pancreatitis is often difficult to preoperatively differentiate from pancreatic carcinoma. Response to steroid treatment and the detection of extrapancreatic lesions may contribute to an accurate diagnosis, thereby avoiding unnecessary surgery.     

Serum IgG4-negative autoimmune pancreatitis

Background  

Autoimmune 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.     

儿童IgG4相关自身免疫性肝炎临床与病理特征分析*

目的 探讨儿童免疫球蛋白G4相关自身免疫性肝炎(IgG4-AIH)患者临床和肝组织病理学特征。方法 2014年6月～2019年6月我科收治的AIH儿童38例,符合2008年国际AIH小组(IAIHG)制定的简化诊断积分系统或1999年IAIHG制定的AIH诊断评分系统。根据肝组织IgG4阳性浆细胞浸润≥10个/高倍镜视野(HPF)诊断IgG4-AIH。采用ELISA法检测血清IgG和IgG4。常规行肝穿刺,采用免疫组织化学染色检测肝组织IgG4阳性浆细胞。结果 在38例AIH患者中,诊断IgG4-AIH患者4例,AIH患者34例;IgG4-AIH患者血清IgG和IgG4水平分别为22.6(13.2, 29.8)mg/dL和226.5(105.8,424.6)mg/dL,与AIH患者的18.9(10.4,25.3)mg/dL和209.4(96.1,401.6)mg/dL比,差异无统计学意义(P>0.05);IgG4-AIH组肝组织IgG4阳性浆细胞计数/HPF为40.2(25.4,55.7),显著高于AIH组患者;IgG4-AIH组肝组织IgG4阳性浆细胞计数与炎性反应活动分级(r=0.48)和肝纤维化分期(r=0.37)呈正相关(P<0.05);IgG4-AIH患者血清ALT恢复正常所需要的时间为(3.5±0.8)w,显著短于AIH组,血清AST恢复时间为(3.6±0.6)w,显著短于AIH组,血清碱性磷酸酶恢复时间为(4.0±1.1)w,显著短于AIH组,血清谷氨酰转肽酶恢复时间为(4.2±1.5)w,显著短于AIH组,血清IgG水平恢复正常的时间为(7.6±2.8)w,显著短于AIH组。结论 IgG4-AIH儿童具有AIH的基本特征,血清IgG4水平并不比AIH患者更高,但肝组织IgG4阳性浆细胞浸润显著多于AIH患者。另外,IgG4-AIH儿童对皮质激素治疗具有良好的应答反应,血清学指标的恢复时间也相对较短,这些特征有助于临床诊断。本组IgG4-AIH儿童例数太少,其结论有待于验证。     

Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease

Recent studies have suggested the existence of two subtypes of autoimmune pancreatitis (AIP): type 1 AIP, related to IgG4 (lymphoplasmacytic sclerosing pancreatitis); and type 2 AIP, related to a granulocytic epithelial lesion (idiopathic duct-centric chronic pancreatitis). Compared with type 2 AIP, the clinicopathological features of type 1 AIP, with increased serum IgG4/IgE levels, abundant infiltration of IgG4 + plasmacytes and lymphocytes, autoantibodies, and steroid responsiveness, are more suggestive of abnormal immunity such as allergy or autoimmunity. Moreover, patients with type 1 AIP often have extrapancreatic lesions, such as sclerosing cholangitis, sclerosing sialadenitis, or retroperitoneal fibrosis, showing pathological features similar to those of the pancreatic lesions. Based on these findings, an international concept of and diagnostic criteria for AIP have been proposed recently. Of interest, many synonyms have been proposed for the conditions of AIP and extrapancreatic lesions associated with IgG4, such as "multifocal idiopathic fibrosclerosis," "IgG4-related autoimmune disease," "IgG4-related sclerosing disease," "systemic IgG4-related plasmacytic syndrome (SIPS)," and "IgG4-related multiorgan lymphoproliferative syndrome," all of which may refer to the same conditions. Therefore, the Japanese Research Committee for "Systemic IgG4-Related Sclerosing Disease" proposed a disease concept and clinical diagnostic criteria based on the concept of multifocal fibrosclerosing disease, in 2009, in which the term "IgG4-related disease" was agreed upon as a minimal consensus to cover these conditions. Although the significance of IgG4 in the development of "IgG4-related disease" remains unclear, we have proposed a hypothesis for the development of type 1 AIP, one of the IgG4-related diseases. The concept and diagnostic criteria of "IgG4-related disease" will be changed in accordance with future studies.     

IgG4-unrelated type 1 autoimmune pancreatitis

A 50-year-old male was referred to our hospital for the evaluation of hyperproteinemia.Fluorodeoxyglucose positron emission tomography revealed high fluorodeoxyglucose uptake in the pancreas,bilateral lacrimal glands,submandibular glands,parotid glands,bilateral pulmonary hilar lymph nodes,and kidneys.Laboratory data showed an elevation of hepatobiliary enzymes,renal dysfunction,and remarkably high immunoglobulin(Ig) G levels,without elevated serum IgG4.Abdominal computed tomography revealed swelling of the pancreatic head and bilateral kidneys.Endoscopic retrograde cholangiopancreatography showed an irregular narrowing of the main pancreatic duct in the pancreatic head and stricture of the lower common bile duct.Histological examination by endoscopic ultrasonography-guided fine-needle aspiration revealed findings of lymphoplasmacytic sclerosing pancreatitis without IgG4-positive plasma cells.Abnormal laboratory values and the swelling of several organs were improved by the treatment with steroids.The patient was diagnosed as having type 1 autoimmune pancreatitis(AIP) based on the International Consensus Diagnostic Criteria.Therefore,we encountered a case of compatible type 1 AIP without elevated levels of serum IgG4 or IgG4-positive plasma cells.This case suggests that AIP phenotypes are not always associated with IgG4.     

IgG4-associated prostatitis complicating autoimmune pancreatitis

A 65-year-old man underwent transurethral resection of the prostate on a diagnosis of benign prostatic hypertrophy. Almost simultaneously, a diagnostic resection of minor salivary glands was performed. After the resections he suffered from obstructive jaundice. Laboratory examinations revealed an increase in eosinophils and an elevation of serum IgG4. Pancreaticoduodenectomy was performed because of the possibility of pancreatic cancer. The prostate, salivary glands and pancreas showed common histological characteristics, namely, infiltration of lymphocytes and plasma cells accompanying dense fibrosis. Most of the infiltrating plasma cells showed strong immunoreactivity to IgG4. This is the first case with IgG4-associated prostatitis complicating autoimmune pancreatitis.     

IgG4-related airway involvement which developed in a patient receiving corticosteroid therapy for autoimmune pancreatitis

A 66-year-old man was diagnosed with autoimmune pancreatitis in February 2009 and started 40 mg of oral prednisolone followed by a maintenance dose of 5 mg daily. The patient developed a cough in October 2010 and visited our division. He had a high serum concentration of immunoglobulin (Ig) G4 and his chest computed tomography showed airway stenosis without bilateral hilar lymphadenopathy (BHL). The bronchial biopsy specimens revealed lymphoplasmacytic infiltrations with IgG4-positive/IgG-positive plasma cells of more than 50%. Thus, we diagnosed the airway lesion with IgG4-related airway involvement. This is the first report of a patient with IgG4-related airway involvement without BHL.     

以自身免疫性胰腺炎和Mikulicz病为特征且伴有白细胞降低的IgG4相关性疾病1例报告

Ig G4相关性疾病(IgG4-related disease)是一类慢性、进行性炎症伴有纤维化的自身免疫性疾病,特征性的表现为血清IgG4水平升高,组织中大量IgG4阳性浆细胞浸润,席纹状纤维化以及闭塞性静脉炎[1-2],临床上病变几乎可以累及所有的器官和器官[3],受累器官通常表现为弥漫性的肿大。在消化系统中,唾液腺和胰腺是最常累及的器官。现将我们收治的以自身免疫性胰腺炎和Mikulicz病为特征且伴有白细胞降低的IgG4相关性疾病1例报告如下。     

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.     

IgG4-related autoimmune pancreatitis overlapping with Mikulicz’s disease and lymphadenitis:A case report

Autoimmune pancreatitis(AIP)is a form of chronic pancreatitis that is categorized as type 1 or type 2according to the clinical profile.Type 1 AIP,which predominantly presents in a few Asian countries,is a hyper-IgG4-related disease.We report a case of IgG4-related AIP overlapping with Mikulicz’s disease and lymphadenitis,which is rare and seldom reported in literature.A 63-year male from Northeast China was admitted for abdominal distension lasting for one year.He presented symmetric swelling of the parotid and submandibular glands with slight dysfunction of salivary secretion for 6 mo.He had a 2-year history of bilateral submandibular lymphadenopathy without pain.He underwent surgical excision of the right submandibular lymph node one year prior to admission.He denied any history of alcohol,tobacco,or illicit drug use.Serological examination revealed high fasting blood sugar level(8.8 mmol/L)and high level of IgG4(15.2 g/L).Anti-SSA or anti-SSB were negative.Computed tomography of the abdomen showed a diffusely enlarged pancreas with loss of lobulation.Immunohistochemical stain for IgG4 demonstrated diffuse infiltration of IgG4-positive plasma cells in labial salivary gland and lymph node biopsy specimens.The patient received a dose of 30 mg/d of prednisone for three weeks.At this three-week follow-up,the patient reported no discomfort and his swollen salivary glands,neck lymph node and pancreas had returned to normal size.The patient received a maintenance dose of 10mg/d of prednisone for 6 mo,after which his illness had not recurred.     

Clinical characteristics of immunoglobulin IgG4-related sclerosing cholangitis: Comparison of cases with and without autoimmune pancreatitis in a large cohort

BackgroundThe clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort.AimsTo clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP.MethodsWe retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP.ResultsAIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI.ConclusionsThe clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.