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Journal of Immunology (Baltimore, Md. :... Jun 2021Autoimmune hypophysitis is classified as primary if its origin is idiopathic and secondary if it develops as a consequence of treatment with immune checkpoint...
Autoimmune hypophysitis is classified as primary if its origin is idiopathic and secondary if it develops as a consequence of treatment with immune checkpoint inhibitors. Expanding use of immunotherapy has been paralleled by the increasing hypophysitis prevalence. However, understanding of the immune responses driving the disease remains limited. Using a mouse model of primary hypophysitis, we have identified CD4 T lymphocytes to be the main pituitary-infiltrating immune cell population. Functional analysis showed that they display a Th17 and Th1/Th17 phenotype. To examine involvement of proinflammatory Th1, Th17, and Th1/17 subsets in hypophysitis, we have isolated RNA from the formalin-fixed paraffin-embedded pituitary specimens from 16 hypophysitis patients (three of whom had hypophysitis secondary to immune checkpoint inhibitors), 10 patients with adenoma, and 23 normal pituitaries obtained at autopsy. Transcript levels of IFN-γ, IL-17A, IL-4, IL-10, TGF-β, CD4, CD8α, and class II MHC transactivator were analyzed by the reverse transcription-quantitative PCR (RT-qPCR). Pituitary glands of patients with hypophysitis showed significantly higher IL-17A, CD4, and class II MHC transactivator mRNA levels compared with adenoma and normal pituitaries. All three secondary hypophysitis patients showed detectable IL-17A levels, but other cytokines were not detected in their pituitaries. Levels of IFN-γ, IL-4, IL-10, and TGF-β did not differ between the groups. TGF-β transcript was found in significantly fewer hypophysitis pituitaries (2 out of 16) compared with adenoma (7 out of 10) and normal pituitaries (11 out of 23). Presence of TGF-β in two hypophysitis patients was associated with significantly lower IL-17A mRNA levels compared with hypophysitis patients with no detectable TGF-β ( = 0.03).
Topics: Animals; Autoimmune Hypophysitis; Female; Mice; Mice, Inbred Strains; Th17 Cells
PubMed: 34011522
DOI: 10.4049/jimmunol.2001073 -
Endocrine Journal Apr 2020Hypophysitis, which is often accompanied by pituitary dysfunction, is classified into several subtypes based on the cause, histology, and the location of inflammation in...
Hypophysitis, which is often accompanied by pituitary dysfunction, is classified into several subtypes based on the cause, histology, and the location of inflammation in the pituitary gland. A definitive diagnosis requires pituitary biopsy, which is invasive, and the process is limited to specialized clinical settings. In this opinion paper, we review the literature associated with hypophysitis, and provide the guidelines of the Japan Endocrine Society for the diagnosis and treatment of autoimmune and IgG4-related hypophysitis.
Topics: Autoimmune Hypophysitis; Decompression, Surgical; Endocrinology; Glucocorticoids; Headache; Hormone Replacement Therapy; Humans; Hypopituitarism; Japan; Magnetic Resonance Imaging; Neurosurgical Procedures; Societies, Medical; Vision Disorders; Visual Fields
PubMed: 32037390
DOI: 10.1507/endocrj.EJ19-0569 -
ESMO Open Feb 2021Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed... (Review)
Review
Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), and have emerged as a powerful new tool for oncologists. As these immune checkpoints are crucial for immunological self-tolerance, such therapies can trigger autoimmune adverse effects. Endocrine complications are among the most common, including hypophysitis, thyroid dysfunction, diabetes mellitus and primary adrenal insufficiency, while autoimmune polyendocrine syndrome type 2 (APS-2) may also present. The aim of this article is to critically appraise the literature and present (i) the biological role and function of the main ICs, (ii) the use of ICIs in the treatment of various cancer types, (iii) the endocrine complications of cancer immunotherapy with ICIs and (iv) practical recommendations for screening and management of patients with such endocrinopathies in everyday clinical practice.
Topics: Endocrine System; Endocrine System Diseases; Humans; Hypophysitis; Immune Checkpoint Inhibitors; Immunotherapy
PubMed: 33399077
DOI: 10.1016/j.esmoop.2020.100011 -
Endocrine Aug 2021Primary autoimmune hypophysitis (PAHs) is a rare inflammatory disease of the pituitary gland. Although largely investigated, the pathogenesis of PAH is not completely...
INTRODUCTION
Primary autoimmune hypophysitis (PAHs) is a rare inflammatory disease of the pituitary gland. Although largely investigated, the pathogenesis of PAH is not completely clarified. We aimed to investigate the immune response in PAHs.
MATERIAL AND METHODS
Serum anti-pituitary and anti-hypothalamus antibodies (respectively APAs and AHAs) were investigated though an indirect immunofluorescence on monkey hypophysis and hypothalamus slides, serum cytokines though an array membrane and cell-mediated immunity though the white blood cells count.
RESULTS
Nineteen PAH cases entered the study. APA or AHA were identified in all cases. APA were detected in 13 patients (68.4%) and AHA in 13 patients (68.4%). Ten patients (52.6%) were simultaneously positive for both APA and AHA. The prevalence of APAs and AHAs was higher as compared to those observed in 50 health controls (respectively 14% p < 0.001 and 24% p = 0.004) and in 100 not-secreting pituitary adenoma (NFPAs) (respectively 22% p = 0.002 and 8% p < 0.001). Similarly, the prevalence of simultaneous positivity for APA and AHA (52.9%) was higher as compared to the those detected in patients affected by NFPAs (0%; p < 0.001) and in health controls (16% p = 0.002). No differences were identified between PAHs and controls at qualitative and quantitative analysis of serum cytokines and white blood cells count.
CONCLUSIONS
This study suggest that APA and AHA may be detected in an high percentage of PAH cases and that their simultaneous identification may be useful for the differential diagnosis between PAH and NFPAs, in an appropriate clinical context.
Topics: Autoantibodies; Autoimmune Diseases; Autoimmune Hypophysitis; Humans; Hypopituitarism; Immunity, Cellular; Pilot Projects; Pituitary Gland
PubMed: 33484410
DOI: 10.1007/s12020-021-02612-5 -
Frontiers in Endocrinology 2021Autoimmune diabetes is a rare but severe endocrine toxicity induced by immune checkpoint inhibitor (ICI) treatment. It is unclear if ICI causes selective islet toxicity...
Autoimmune diabetes is a rare but severe endocrine toxicity induced by immune checkpoint inhibitor (ICI) treatment. It is unclear if ICI causes selective islet toxicity or non-selective pancreas toxicity. We analyzed 11 patients treated with ICI who developed ICI-related autoimmune diabetes. Eight patients had lipase and/or amylase tested on the same day of diagnosis of autoimmune diabetes. Among them, 75% (6/8) had normal lipase and 100% (6/6) had normal amylase. There was no correlation between glucose level at onset and biochemical pancreatitis. We characterized the clinical features of ICI-induced autoimmune diabetes. Fifty-five percent (6/11) of patients tested positive for GAD65 autoantibodies, and 55% (6/11) developed diabetic ketoacidosis at manifestation of hyperglycemia. In all 11 patients, C-peptide levels were low in the presence of hyperglycemia. ICI-induced thyroiditis was found in 64% (7/11), of which 36% (4/11) were newly diagnosed with thyroiditis while the remaining 27% (3/11) had pre-existing hypothyroidism followed by ICI-induced thyroiditis. Additionally, 27% (3/11), developed ICI-induced hypophysitis. Thyroiditis and autoimmune diabetes coexisted in all patients with ICI-induced hypophysitis. The median time from ICI treatment to the onset of autoimmune diabetes was 11 weeks. Our data suggest that few patients had coexistent ICI-induced autoimmune diabetes and pancreatitis, suggesting ICI mainly caused selective islet toxicity.
Topics: Adult; Aged; Autoimmune Pancreatitis; Diabetes Mellitus, Type 1; Female; Humans; Immune Checkpoint Inhibitors; Male; Middle Aged; Retrospective Studies
PubMed: 33927691
DOI: 10.3389/fendo.2021.620522 -
Acta Neurochirurgica Aug 2022IgG4-related hypophysitis (IgG4-RH) is a rare chronic inflammatory condition of the pituitary gland. This study reports the presentation, management and outcomes for...
PURPOSE
IgG4-related hypophysitis (IgG4-RH) is a rare chronic inflammatory condition of the pituitary gland. This study reports the presentation, management and outcomes for patients with histologically proven IgG4-related hypophysitis.
METHODS
A prospectively maintained electronic database was searched over a 14-year period from 1 January 2007 to 31 December 2020 at a single academic centre to identify all patients with a histological diagnosis of IgG4-RH. A retrospective case note review from electronic health records was conducted for each case to extract data on their presentation, management and outcomes.
RESULTS
A total of 8 patients (5 male) with a median age of 51 years were identified. The most common presenting symptoms were headache (4/8; 50%), fatigue (3/8; 37.5%) and visual impairment (2/8; 25%). Three patients were initially treated with high-dose steroids aiming for reduction of the pituitary mass. However, ultimately all patients underwent transsphenoidal surgery. Post-operative changes included radiological reduction in pituitary mass in all patients that had imaging (7/7; 100%), improvement in vision (1/2; 50%), residual thick pituitary stalk (5/7; 71.4%), persistent anterior hypopituitarism (4/8; 50%) and panhypopopituitarism including diabetes insipidus (3/8; 37.5%).
CONCLUSIONS
IgG4-RH is an increasingly recognised entity presenting with a variety of symptoms and signs. Clinical presentation is similar to other forms of hypophysitis. It is therefore important to consider IgG4-RH as a differential and to have a low threshold for pituitary biopsy, the diagnostic gold standard. The diagnosis of IgG4-RH will guide decisions for additional workup for IgG4-related disease, multi-disciplinary team involvement and follow-up.
Topics: Autoimmune Hypophysitis; Humans; Immunoglobulin G; Male; Middle Aged; Pituitary Diseases; Pituitary Gland; Retrospective Studies
PubMed: 35532784
DOI: 10.1007/s00701-022-05231-9 -
Surgical Neurology International 2022Immunoglobulin (Ig)G4-related disease is a systemic fibroinflammatory disease characterized by dense infiltration of IgG4-positive plasma cells in the affected tissue(s)...
BACKGROUND
Immunoglobulin (Ig)G4-related disease is a systemic fibroinflammatory disease characterized by dense infiltration of IgG4-positive plasma cells in the affected tissue(s) with or without elevated plasma levels of IgG4. Hypophysitis itself is a very rare disease with reported prevalence in the operative specimens are around 0.2-0.88%. IgG4-related hypophysitis (IgG4-RH) may account for a substantial percentage of cases previously regarded as idiopathic hypophysitis.
METHODS
This study is a registry-based, retrospective, and cohort study from a tertiary care hospital in North India. The medical records and clinical data of biopsy-proven and suspected IgG4-RH patients registered were retrospectively analyzed. Treatment outcome of cases was also explored during this analysis.
RESULTS
Two thousand and six sellar area space-occupying lesions have been operated-on since 2006, among them only four patients had IgG4-RH on histopathological specimen. One case was diagnosed on clinical suspicion. Mean age of the patients was 31.8 ± 6.32 years. Most frequent presenting complaint was headaches. Extracranial manifestations were present in four patients. The most common pituitary dysfunction was cortisol deficiency. 18 F-fluorodeoxyglucose positron emission tomography (18F FDG PET) was helpful in three cases for diagnosis of hypophysitis and other organ involvement. Classical histological findings with storiform fibrosis, obliterative phlebitis seen in two cases, and IgG4-positive plasma cell infiltration were positive in four cases. Surgery was the primary modality of treatment in all four cases. Only one patient received steroids as a primary therapeutic modality.
CONCLUSION
IgG4-RH is rare. High index of suspicion is required to diagnosis the case precisely. FDG PET is helpful in diagnosing hypophysitis and extrapituitary lesions.
PubMed: 36600729
DOI: 10.25259/SNI_1013_2022 -
Archives of Pathology & Laboratory... Nov 2017IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that produces sclerotic, tumefactive masses containing dense lymphoplasmacytic... (Review)
Review
IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that produces sclerotic, tumefactive masses containing dense lymphoplasmacytic infiltrates rich in immunoglobulin (Ig) G4 plasma cells. Initially characterized as a form of autoimmune pancreatitis, the distinctive histopathology of IgG4-RD has now been described in almost every organ system. However, because the clinical manifestations of IgG4-RD are diverse and nonspecific, the disease may go unsuspected until a biopsy or resection specimen is obtained to diagnose a presumed malignancy. Pathologists thus play a key role in the diagnosis of IgG4-RD, and familiarity with its histopathologic features is essential to preventing the irreversible comorbidities associated with this treatable disease. This brief review outlines the epidemiology, clinical manifestations, and histopathology of IgG4-RD, with the aim of furthering pathologists' awareness of and ability to diagnose this disorder.
Topics: Autoimmune Diseases; Autoimmune Hypophysitis; Diagnosis, Differential; Fibrosis; Humans; Immunoglobulin G; Lymphocytes, Tumor-Infiltrating; Plasma Cells
PubMed: 29072949
DOI: 10.5858/arpa.2017-0257-RA -
Journal of Mid-life Health 2022Lymphocytic hypophysitis (LYH) is a rare inflammatory disease in which lymphoplasmacytic infiltration of the pituitary gland can potentially lead to panhypopituitarism....
Lymphocytic hypophysitis (LYH) is a rare inflammatory disease in which lymphoplasmacytic infiltration of the pituitary gland can potentially lead to panhypopituitarism. This entity was first recognized in 1962 by Goudie and Pinkerton. We report the case of a 36-year-old nonpregnant female operated for a presumed nonsecreting pituitary adenoma. On intraoperative squash cytology and histology of excision biopsy confirmed the diagnosis of LYH. Review of the literature shows that most reported cases have occurred in women during pregnancy or during postpartum period. Many were accurately diagnosed only after biopsy or at necropsy. It is suspected to be an autoimmune endocrinopathy as concomitant lymphocytic infiltration of the thyroid and pituitary glands has been noted and antipituitary antibodies have been found in some instances. Clinically and radiologically, LYH may mimic a nonsecretory pituitary adenoma. Intraoperative diagnosis may prevent unnecessary excision of potentially functioning pituitary.
PubMed: 36950203
DOI: 10.4103/jmh.jmh_32_21 -
Digestive Diseases and Sciences Sep 2022
Topics: Autoimmune Diseases; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Cholangitis; Cholangitis, Sclerosing; Diagnosis, Differential; Humans; Hypophysitis; Immunoglobulin G4-Related Disease
PubMed: 35790701
DOI: 10.1007/s10620-022-07564-y