Elevated Serum Immunoglobulin G4 Levels Research Articles

Abstract 12071: Serum Immunoglobulin G4 Level is an Independent Predictor of Major Adverse Cardiovascular Events After Percutaneous Coronary Intervention over Long-Term Follow-Up

Background: Inflammatory processes contribute to the development of atherosclerosis. However, it remains unclear whether immunoglobulin G4 (IgG4)-related immuno-inflammation may affect the progression of cardiovascular disease. We therefore analyzed the relationship between serum IgG4 level and future major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI). Methods: We measured serum levels of IgG4 in 562 patients (mean age, 66.9 ± 10.3 years) who underwent coronary angiography from October 2005 to September 2008. Furthermore, a total of 108 patients who subsequently received first PCI were followed-up for a median period of 2721 days (interquartile range [IR] 1591-3183). MACE was defined as cardiac death, acute coronary syndrome, cerebral stroke, and target vessel revascularization. Results: Serum levels of IgG4 were significantly higher in patients with coronary artery disease (34.1 mg/dL, IR 18.7-58.9) than in those without (30.5 mg/dL, IR 15.8-50.3, P=0.045). Among patients who received PCI, 40 (37.0%) patients developed MACE during the follow-up period. Patients with serum IgG4 levels of median or greater (≥37.2 mg/dL) had a significantly higher risk of MACE than those with serum IgG4 levels below median (log-rank test, P=0.017). In Cox regression analysis using age, gender, estimated glomerular filtration rate (eGFR), hypertension, dyslipidemia, diabetes, smoking, and serum levels of high-sensitivity C-reactive protein (hsCRP) as covariates, serum IgG4 level was an independent predictor of MACE (hazard ratio 2.39 per 100 mg/dL increase, 95% confidence interval 1.41-4.07, P=0.001). Conclusions: Elevated serum IgG4 level at baseline significantly predicted MACE after PCI, as well as present coronary stenosis, over long-term follow-up even among patients without apparent IgG4-related disease. IgG4-related immuno-inflammation may play a certain role in the progression of coronary atherosclerosis.

Immunoglobulin G4-related pathologic features in inflammatory neuropathies.

To evaluate the pathologic significance of immunoglobulin G4 (IgG4) in patients with inflammatory peripheral neuropathy. We clinicopathologically examined 149 consecutive patients with peripheral neuropathy who had clusters of inflammatory cells with or without vasculitis in sural nerve biopsy specimens and in whom we were able to assess the serum IgG4 levels. Elevation of serum IgG4 levels and infiltration of IgG4-positive plasma cells, which are currently defined as the diagnostic criteria for IgG4-related disease, were found in 35 and 29 patients, respectively. In the 44 patients exhibiting either elevated serum IgG4 levels or IgG4-positive cell infiltration, the diagnoses prior to the examination of IgG4 in serum and pathologic samples included microscopic polyangiitis (12 patients) and eosinophilic granulomatosis with polyangiitis, or Churg-Strauss syndrome (19 patients). Thirty-four patients (77%) had findings of vasculitis as indicated by the destruction or obstruction of the vessel walls. Sixteen (36%) of these patients had fibrinoid necrosis. Axonal degeneration without evidence of demyelination was observed irrespective of the presence of vasculitis. The extent of fibrosis, assessed as the fibrotic area in the epineurium, significantly correlated with the grade of IgG4-positive cell infiltration (p < 0.01). Elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells were observed in a subgroup of patients with inflammatory neuropathy, particularly in patients diagnosed with primary systemic vasculitis, including microscopic polyangiitis. Epineurial IgG4-positive plasma cell infiltration correlated with the extent of epineurial fibrosis.

Ocular adnexal IgG4-related disease: clinical features, outcome, and factors associated with response to systemic steroids.

The aim of this study was to investigate clinical characteristics, outcome, and factors associated with response to systemic administration of steroids in patients with ocular adnexal immunoglobulin G4 (IgG4)-related disease. This was a retrospective evaluation of 11 patients with histopathologically verified ocular adnexal IgG4-related diseases at a medical center in Taiwan between January 2006 and December 2012. Clinical features and outcome, including serial change of serum IgG4 and clinical factors related to response to steroids systemically were evaluated. Seven men and four women, mean age 54.5 years and mean follow-up of 33.5 months, were evaluated. Elevated serum IgG4 levels (>135 mg/dl) were observed in ten patients (91%). Lacrimal gland involvement was noted in eight (72.7%), followed by orbit, extraocular muscles, and eyelids. Seven patients (63.6%) had bilateral ocular lesions and eight (72.7%) had extraorbital involvement. Eight of ten patients who underwent systemic steroid treatment responded well in the early phase. Recurrence developed in five patients (45%), requiring repeat steroid therapy and adjunctive treatment. Median serum levels of IgG4 reduced from 540 to 101 mg/dl in ten patients after systemic corticosteroid administration. Patients with lower serum IgG4 and IgG4:IgG ratio at diagnosis were associated with poor response (p = 0.037). Ocular adnexal IgG4-related disease predominantly involved the lacrimal glands bilaterally and was usually associated with high serum IgG4 levels and multiple organ involvement. Most patients responded well to steroid therapy, which was accompanied by a marked decrease in serum IgG4.

Unusual IgG4-related hypophysitis: one case report and analysis of clinicopathological characteristics

Background Immunoglobulin G4 (IgG4)-related disease is a recently characterized autoimmune disease entity marked by elevated serum IgG4 levels and tissue infiltration by IgG4-positive plasma cells in multiple involved organs. Hypophysitis is a rare inflammatory disorder and IgG4-related sclerosing disease involving the ituitary alone is especially rare. Imaging studies may reveal a mass lesion in the sellar area or a thickening of pituitary stalk, mimicking a pituitary tumor. Due to its rarity and non-specific appearance in radiological examination, it is a diagnostic challenge for clinicians and histopathologists to differentiate solitary IgG4-related hypophysitis from other pituitary lesions. The aim of this study is to summarize the clinicopathological features of unusual IgG4-related hypophysitis and discuss the differential diagnosis of histologically similar inflammatory lesions in pituitary. Methods The clinical manifestation of a patient with solitary IgG4-related hypophysitis was presented retrospectively. Resected mass was routinely paraffin-embedded and stained with Hematoxylin and Eosin. Dako EnVision immunohistochemical staining system was used to detect the tumor antigen expressions, including vimentin (Vim), S-100 protein (S-100), pan cytokeratin (PCK), epithelial membrane antigen (EMA), CD3, CD20, CD68, CD1a, κ-light chain, λ-light chain and progestrone receptor (PR). Results A 47-year-old male patient presented with 1-year history of mild limb weakness and hyposexuality. Laboratory examination revealed hypopituitarism with low levels of serum testosterone, cortisol, luteinizing hormone (LH) and follicle stimulating hormone (FSH), although his serum IgG4 level was high. MRI of the pituitary gland revealed a mass lesion in the sellar area with T 1 WI mild hyperintense and homogeneous enhancement after gadolinium administration. The patient underwent a transsphenoidal mass resection of the pituitary gland. Histological examination showed bland appearing spindle cell proliferation in the sclerotic background with marked infiltration of lymphocytes, plasma cells, as well as multiple foci of meningothelial-like nodules at the periphery of tissues. Immunohistochemical staining showed that the lymphocytes were positive for CD3 and CD20. Plasma cells were distinct and the number of κ and λ-light chains was the same. There were more than 30 IgG4-positive plasma cells per high power field (HPF), which accounted for greater than 40% of the IgG-positive plasma cells. The meningothelial-like nodules were positive for Vim, EMA and PR, but negative for CD68, S-100 and CD1a. A final histological diagnosis of IgG4-related hypophysitis with meningothelial reaction was made. The patient took prednisolone orally at 35 mg/d for 2 weeks, and the symptoms of limb weakness and hyposexuality showed improvement. The mass lesion of pituitary gland demonstrated a reduction in size. The prednisolone therapy was continued at a dose of 30 mg/d to prevent recurrence of IgG4-related disease. Conclusions IgG4-related hypophysitis is a rare disease of central nervous system with good response to corticosteroid treatment. Due to the relative paucity of reported cases and similarities in histological findings, it may be difficult to differentiate IgG4-related disease from other pituitary lesions with prominent inflammatory cell infiltration and stromal fibrosis. Thorough inspection under the microscopy and more importantly elevated serum IgG4 level are necessary for correct diagnosis. doi: 10.3969/j.issn.1672-6731.2014.10.012

Recurrent severe acute hepatitis caused by hypereosinophilic syndrome associated with elevated serum immunoglobulin G4 levels.

A 46-year-old male was admitted to our hospital with severe acute hepatitis, hypereosinophilia, and serum immunoglobulin G4 (IgG4) elevation. Plasma exchange was performed, and he was treated by prednisolone; however, his hepatitis recurred twice over the following twelve months. Transjuglar liver biopsy was performed at the third onset, which demonstrated extensive hepatocyte necrosis, congestion, and severe eosinophil infiltration. We diagnosed hypereosinophilic syndrome (HES)-related hepatitis. Although no cholangitis was detected by imaging and pathological diagnosis, IgG4-positive cells were detected in the liver and bone marrow. Furthermore, the elevation of serum IgG4 levels was associated with the eosinophil count and his clinical condition. After the addition of azathioprine to his treatment regimen, no reoccurrence was observed. IgG4-positive cells may have contributed to the severity and refractoriness of this recurrent acute HES-related hepatitis.

Elevated Serum Immunoglobulin G4 Levels in Patients with Graves' Disease and Their Clinical Implications

Immunoglobulin G4-related disease (IgG4-RD) is a new clinical entity that affects various organs with increased IgG4 positive plasmacytes and progressive fibrosis. While IgG4-RDs in association with Hashimoto's thyroiditis or Riedel's thyroiditis have been reported, the relationship between IgG4-RD and Graves' disease (GD) is yet unknown. To elucidate the relation of GD to IgG4-RD, serum IgG4 levels and their clinical implications in patients with GD were investigated. In this prospective study, serum IgG4 levels were measured in 109 patients with GD and classified into two groups according to the comprehensive diagnostic criteria of IgG4-RD previously established: (i) GD with elevated-IgG4 levels (≥ 135 mg/dL), and (ii) GD with nonelevated IgG4 (<135 mg/dL). Seven out of 109 patients with GD (6.4%) had elevated serum IgG4 levels [mean ± standard deviation (range): 175.0 ± 44.5 (136-266) mg/dL] and elevated ratios of IgG4/IgG [12.7 ± 4.5% (7.6%-21.2%)]. The remaining patients with GD had serum IgG4 levels and IgG4/IgG ratios of 39.6 ± 27.6 (3-132) mg/dL and 3.2 ± 2.2% (0.3%-11.5%), respectively. Ages in the elevated IgG4 group were significantly higher than those of the nonelevated IgG4 group: 54.7 ± 6.2 versus 43.4 ± 15.4 years, respectively. Ultrasound examinations revealed that the elevated IgG4 group had significantly increased hypoechogenic areas in the thyroid in comparison to the nonelevated IgG4 group (low echo scoring: 1.66 ± 0.81 vs. 0.61 ± 0.89, respectively). In the correlation analysis, TSAb (rs=0.385, n=42) titers were significantly correlated with se rum IgG4 levels, while they were not significantly different between the two groups. In the elevated IgG4 group, symptoms were controllable with a small dose of antithyroidal drug (ATD; n=4), a combination treatment with ATD and L-T4 (n=1), or L-T4 administration only one year after the first visit (n=2). A small portion of GD patients harbored elevated serum IgG4 levels. They were older, had increased hypoechoic areas in the thyroid, and appeared to be responsive or prone to be hypothyroid after ATD treatment. Thus, the present study suggests the presence of a novel subtype of GD. Measuring serum IgG4 levels may help to distinguish this new entity and provide potential therapeutic options for GD.

Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis

Immunoglobulin G4 (IgG4)-associated cholangitis (IAC) is a manifestation of the recently discovered idiopathic IgG4-related disease. The majority of patients have elevated serum IgG4 levels and/or IgG4-positive B-cell and plasma cell infiltrates in the affected tissue. We hypothesized that clonally expanded, class-switched IgG4-positive B cells and plasma cells could be causal to these poorly understood phenomena. In a prospective cohort of six consecutive IAC patients, six healthy controls, and six disease controls, we used a novel next-generation sequencing approach to screen the B-cell receptor (BCR) repertoires, in blood as well as in affected tissue, for IgG4+ clones. A full repertoire analysis of the BCR heavy chain was performed using GS-FLX/454 and customized bioinformatics algorithms (>10,000 sequences/sample; clones with a frequency ≥0.5% were considered dominant). We found that the most dominant clones within the IgG+ BCRheavy repertoire of the peripheral blood at baseline were IgG4+ only in IAC patients. In all IAC patients, but none of the controls, IgG4+ BCR clones were among the 10 most dominant BCR clones of any immunoglobulin isotype (IgA, IgD, IgM, and IgG) in blood. The BCR repertoires of the duodenal papilla comprised the same dominant IgG4+ clones as the paired peripheral blood samples. In all IAC patients, after 4 and 8 weeks of corticosteroid therapy the contribution of these IgG4+ clones to the IgG+ repertoire as well as to total BCR repertoire was marginalized, mirroring sharp declines in serum IgG4 titers and regression of clinical symptoms. The novel finding of highly abundant IgG4+ BCR clones in blood and tissue of patients with active IAC, which disappear upon corticosteroid treatment, suggests that specific B cell responses are pivotal to the pathogenesis of IAC. (HEPATOLOGY 2013 ).

Localized or Diffuse Lesions of the Submandibular Glands in Immunoglobulin G4-Related Disease in Association With Differential Organ Involvement

Objectives The purpose of this study was to assess the relationship between the sonographic characteristics of the submandibular glands and organ involvement at the initial presentation in patients with immunoglobulin G4 (IgG4)-related disease. Methods We conducted a retrospective study that included 15 patients who had bilateral swollen submandibular glands and elevated serum IgG4 levels between January 2005 and December 2010. Results In all 15 patients, sonography revealed the involvement of both sides of the submandibular glands. The sonographic appearance of each gland was classified into two types: localized tumor-forming and diffuse focal types. On the basis of this typing, all 15 patients were classified into two groups: a group with the localized tumor-forming type observed on one or both sides of the glands (n = 10) and a group with the diffuse focal type present on both sides (n = 5). All 10 patients in the former group had lesions in local exocrine organs, such as the lacrimal and parotid glands, with regional lymphadenopathy. In contrast, all 5 patients in the latter group had lesions in abdominal organs, such as autoimmune pancreatitis and sclerosing cholangitis. Conclusions The sonographic patterns of the submandibular glands in patients with IgG4-related disease can be divided into two types: localized tumor-forming and diffuse focal. The distinctive patient groups defined by the sonographic patterns in both glands were associated with differential organ involvement and thus could be used as indicators of the disease extension and specific organ involvement.

Localized or Diffuse Lesions of the Submandibular Glands in Immunoglobulin G4-Related Disease in Association With Differential Organ Involvement

The purpose of this study was to assess the relationship between the sonographic characteristics of the submandibular glands and organ involvement at the initial presentation in patients with immunoglobulin G4 (IgG4)-related disease. We conducted a retrospective study that included 15 patients who had bilateral swollen submandibular glands and elevated serum IgG4 levels between January 2005 and December 2010. In all 15 patients, sonography revealed the involvement of both sides of the submandibular glands. The sonographic appearance of each gland was classified into two types: localized tumor-forming and diffuse focal types. On the basis of this typing, all 15 patients were classified into two groups: a group with the localized tumor-forming type observed on one or both sides of the glands (n = 10) and a group with the diffuse focal type present on both sides (n = 5). All 10 patients in the former group had lesions in local exocrine organs, such as the lacrimal and parotid glands, with regional lymphadenopathy. In contrast, all 5 patients in the latter group had lesions in abdominal organs, such as autoimmune pancreatitis and sclerosing cholangitis. The sonographic patterns of the submandibular glands in patients with IgG4-related disease can be divided into two types: localized tumor-forming and diffuse focal. The distinctive patient groups defined by the sonographic patterns in both glands were associated with differential organ involvement and thus could be used as indicators of the disease extension and specific organ involvement.

IgG4-related Disease of the Head and Neck: CT and MR Imaging Manifestations

Immunoglobulin G4 (IgG4)-related disease is a recently established systemic disease that commonly involves the head and neck, including the salivary glands, lacrimal glands, orbits, thyroid gland, lymph nodes, sinonasal cavities, pituitary gland, and larynx. Although the definitive diagnosis of IgG4-related disease requires histopathologic analysis, elevated serum IgG4 levels are helpful in making the diagnosis. Because of the proposed clinical diagnostic criteria for this disease, cross-sectional imaging modalities such as computed tomography (CT) and magnetic resonance (MR) imaging play an important diagnostic role. CT and MR imaging findings of IgG4-related disease are usually nonspecific. At CT, involved organs may demonstrate enlargement or decreased attenuation; at T2-weighted MR imaging, they may have relatively low signal intensity owing to their increased cellularity and amount of fibrosis. Some pathologic entities involving the head and neck are now considered to be part of the IgG4-related disease spectrum, including idiopathic orbital inflammatory syndrome (inflammatory pseudotumor), orbital lymphoid hyperplasia, Mikulicz disease, Küttner tumor, Hashimoto thyroiditis, Riedel thyroiditis, and pituitary hypophysitis. Because involvement of multiple sites is common in IgG4-related disease, radiologists should be familiar with manifestations of this systemic process outside the head and neck, in organs such as the pancreas, bile ducts, gallbladder, kidneys, retroperitoneum, mesentery, lungs, gastrointestinal tract, and blood vessels. Moreover, IgG4-related disease usually demonstrates a dramatic response to corticosteroid therapy, and radiologists should be familiar with its clinical and imaging manifestations to avoid a delay in diagnosis or unnecessary invasive interventions.

IgG4-related Sclerosing Disease: The Great Mimicker

Purpose: A 65-year-old woman was evaluated for recurrent painless jaundice. Prior investigations included an endoscopic retrograde cholangiopancreatogram (ERCP) that showed a stricture in the distal common bile duct (CBD) with a negative cytology for malignant cells. She underwent a laparotomy during which a pancreatic head mass was found and biopsies revealed no malignancy. A palliative cholecystojejunostomy with gastroenterostomy was performed. Postoperatively the jaundice improved but she remained with epigastric pain, persistent nausea, anorexia and a 20-lb weight loss. Two weeks later she developed recurrent jaundice and a second ERCP demonstrated a hilar stricture. A presumptive diagnosis of multicentric cholangiocarcinoma was made and she was referred to hospice care. She then presented to our institution for evaluation. Serum Immunoglobulin G4 (IgG4) levels were normal. She underwent an endoscopic ultrasound (EUS) that showed no evidence of a pancreatic head mass. However, the entire pancreas was diffusely inhomogeneous and abnormal. The parenchyma presented alternating hypoechogenic and hyperechogenic areas with strands and lobulations. The outer border of the gland was lobular and the main pancreatic duct was normal. Biopsies of the pancreas showed changes consistent with chronic pancreatitis, with loss of the acinar parenchyma and residual islets and ducts seen with fibrosis and infiltration composed of mononuclear cells. Immunostain for CD138 was performed and very high numbers of plasma cells were observed infiltrating the tissue. Immunostain for IgG4 demonstrated approximately 10-15 positive cells per high power field. These findings and the patient's clinical presentation were most consistent with autoimmune pancreatitis and IgG4-related sclerosing cholangitis. The patient was started on prednisone followed by azathioprine and experienced a rapid and sustained clinical and biochemical response for several years even after stopping immunosuppressive therapy. After treatment, repeat imaging studies were performed which showed dramatic improvement in the above mentioned abnormalities. Autoimmune pancreatitis and IgG4-related sclerosing cholangitis are manifestations of IgG4-related sclerosing disease. Elevated serum IgG4 levels suggest this diagnosis but many times remain normal. Therefore a strong clinical suspicion should prompt a biopsy of the affected tissue with immunostaining with anti-IgG4 antibody. The disease responds well to immunosuppressive therapy. In the setting of suspected malignant tumors, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery and unfavorable as well as incorrect prognosis.

Association between autoimmune pancreatitis and systemic autoimmune diseases

To investigate the association between autoimmune pancreatitis (AIP) and systemic autoimmune diseases (SAIDs) by measurement of serum immunoglobulin G4 (IgG4). The serum level of IgG4 was measured in 61 patients with SAIDs of different types who had not yet participated in glucocorticosteroid treatment. Patients with an elevated IgG4 level were examined by abdominal ultrasonography (US) and, in some cases, by computer tomography (CT). Elevated serum IgG4 levels (919 ± 996 mg/L) were detected in 17 (28%) of the 61 SAID patients. 10 patients had Sjögren's syndrome (SS) (IgG4: 590 ± 232 mg/L), 2 of them in association with Hashimoto's thyroiditis, and 7 patients (IgG4: 1388 ± 985.5 mg/L) had systemic lupus erythematosus (SLE). The IgG4 level in the SLE patients and that in patients with SS were not significantly different from that in AIP patients (783 ± 522 mg/L). Abdominal US and CT did not reveal any characteristic features of AIP among the SAID patients with an elevated IgG4 level. The serum IgG4 level may be elevated in SAIDs without the presence of AIP. The determination of serum IgG4 does not seem to be suitable for the differentiation between IgG4-related diseases and SAIDs.

Measurement of IgG4 in bile: a new approach for the diagnosis of IgG4-associated cholangiopathy

Immunoglobulin G4 (IgG4)-associated cholangitis (IAC) is difficult to diagnose because on cholangiography the associated biliary tract strictures cannot be differentiated from cholangiocarcinoma or primary sclerosing cholangitis (PSC). Serum IgG4 levels show a low sensitivity and specificity and are unreliable, particularly in patients with related diseases such as PSC. As IAC takes place at the biliary epithelium, we hypothesized that IgG4 measurement in bile may have higher sensitivity compared with serum. Bile and serum samples were collected during cholangiography in 67 patients, including 23 patients with PSC, 25 with cholangiocarcinoma, 14 with choledocholithiasis, and five with IAC. IgG4 was measured in both bile and serum. Bile IgG4 levels were markedly elevated in patients with IAC compared with patients with other biliary disorders. Whereas elevated serum IgG4 levels were found both in patients with PSC and IAC, biliary IgG4 levels were only increased in patients with IAC. The study demonstrates that bile IgG4 measurement is possible and may help to distinguish IAC from other diseases.

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

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). 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. 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. 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.

IgG4 immunostaining of duodenal papillary biopsy specimens may be useful for supporting a diagnosis of autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is now considered to be part of an immunoglobulin G4 (IgG4)-related systemic fibroinflammatory disease. We evaluated whether IgG4 immunostaining of duodenal papillary biopsy specimens is useful for supporting a diagnosis of AIP. A prospective study. A tertiary academic center. We obtained 2 forceps biopsy specimens from the major duodenal papilla (MDP) of 19 symptomatic AIP patients during ERCP before steroid administration. As a control, biopsy specimens were obtained from the MDP of patients with pancreatic cancer (n = 35), cholangiocarcinoma (n = 20), ampullary cancer (n = 11), ordinary chronic pancreatitis (n = 18), and AIP in remission (n = 16) and immunohistochemically examined. Specimens were considered positive for IgG4 immunostaining if there were more than 10 IgG4-positive plasma cells per high-power field. Positive IgG4 immunostaining of the MDP was found in 10 (53%) of 19 symptomatic AIP patients, but was absent in the control groups. Among symptomatic AIP patients (n = 19), 5 (83%) of 6 AIP patients with elevated serum IgG4 levels exhibited positive IgG4 staining of the MDP, whereas 5 (38%) of 13 AIP patients with normal serum IgG4 levels showed positive IgG4 staining of the MDP. Nine of 19 symptomatic AIP patients also underwent pancreatic biopsy, and positive IgG4 immunostaining of the MDP was observed in patients with positive pancreas IgG4 staining (4/6, 67%), but not in patients with negative pancreas IgG4 staining (0/3). Small symptomatic AIP patient population. Positive IgG4 immunostaining of the MDP was an extremely specific and moderately sensitive tool for the diagnosis of AIP. IgG4 immunostaining of the MDP may be useful for supporting a diagnosis of AIP, especially when AIP is suspected clinically but serum IgG4 levels are normal or pancreatic tissue is not available.

IgG4-Related Lung Disease Presenting as a Consolidative Mass: A Case Report

Immunoglobulin G4 (IgG4)-related sclerosing disease involving the lung is a rare condition, and this is characterized by an elevated serum IgG4 level, fibrotic inflammation with numerous IgG4-positive plasma cells and a response to steroid therapy. We present here a case of pulmonary IgG4-related disease in a 75-year-old man who presented with cough and yellowish sputum for the previous 3 months. The chest images showed a consolidative mass in the right lower lobe that suggested mucinous bronchioloalveolar carcinoma. The wedge resected specimen revealed an ill-defined gray-tan, firm lesion. Microscopically, the lesion showed a diffuse lymphoplasmacytic infiltration with irregular fibrosis in the alveolar interstitium and bronchovascular bundles. There were numerous IgG4-positve plasma cells and these cells were diffusely distributed. The serum IgG4 level was elevated on the postoperative check-up (249 mg/dL). After corticosteroid therapy for 7 months, the patient’s symptoms and radiologic abnormalities were improved. (J Lung Cancer 2010;9(2):103 �� 105)

Diagnosis and management of primary sclerosing cholangitis

Diagnosis and management of primary sclerosing cholangitis

Pituitary and Stalk Lesions (Infundibulo-hypophysitis) Associated with Immunoglobulin G4-related Systemic Disease: an Emerging Clinical Entity

Inflammatory lesions of the pituitary gland are rarely encountered. Recently, the concept of immunoglobulin G4 (IgG4)-related systemic disease was proposed in Japan, and more than 20 cases have been reported as possibly associated with infundibulo-hypophysitis since 2000. We herein review such case reports in the published literature and in the abstracts of scientific meetings. Almost all cases involved middle-aged to elderly men presenting with various degrees of hypopituitarism and diabetes insipidus and demonstrating a thickened pituitary stalk and/or pituitary mass. These structures shrank remarkably in response to glucocorticoid therapy, even in a lower dose range similar to that prescribed as a replacement for adrenocortical insufficiency. Some of the anterior pituitary insufficiencies were also resolved by glucocorticoid administration. The presence of IgG4-related systemic disease and an elevated serum IgG4 level before glucocorticoid therapy were the main clues to a correct diagnosis of IgG4-related infundibulo-hypophysitis. Autoimmunity is suggested but not yet established to play a role in the pathogenesis for IgG4-related systemic disease. The fact that hypertrophic pachymeningitis and para-sinusitis accompanied some cases suggested that both sellar and parasellar structures are involved in the chronic inflammation. We therefore classify this disorder not as a variant form of primary autoimmune hypophysitis but as a secondary form of infundibulo-hypophysitis associated with IgG4-related systemic disease.

Two Cases of Pulmonary Involvement of Immunoglobulin G4 Related Autoimmune Disease

Immunoglobulin G4 (IgG4) related autoimmune diseases are characterized by high serum IgG4 concentrations, sclerosing inflammation of numerous IgG4-positive lymphoplasma cells of varying origin, and a positive response to steroid treatment. Autoimmune pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis are representative presentations of IgG4 related autoimmune disease. Herein, we describe 2 patients (40-years-old woman and 47-years-old man) diagnosed with pulmonary involvement of IgG4-related autoimmune disease. The patients were admitted for an evaluation of the lung mass or multiple lung nodules found on chest radiography. Surgical lung biopsies were performed and pathologic finding revealed lymphoplasmacytic sclerosing inflammation with numerous IgG4 positive cells. The patients had elevated serum total IgG and IgG4 levels. Treatment consisted of high dose methylpredinisolone (1 mg/kg/day) and demonstrated good responsiveness. However, one patient experienced 2 relapses while being tapered off of steroid treatment.