A Rare Association of Autoimmune Hypophysitis With Seronegative Rheumatoid Arthritis: A Case Report.

Autoimmune hypophysitis (AH) is an uncommon condition where there is inflammation of the pituitary gland which leads to hormonal imbalances. It is often associated with autoimmune diseases; however, a case is yet to be reported with an association of AH with seronegative rheumatoid arthritis (RA). We present a case of a 45-year-old female who complained of polyuria/polydipsia and rapid weight gain. An MRI of the head revealed enlargement of the pituitary gland, concerning for AH. Although she was initially treated for diabetes insipidus, she began reporting new complaints of joint pains and morning stiffness. She was clinically diagnosed with seronegative RA and improved with a trial of hydroxychloroquine. A repeat MRI showed improvement in the abnormal pituitary findings, and the patient was closely monitored with a multidisciplinary approach. Diagnosing and managing patients with AH are topics that are still being explored and researched as it is a relatively rare pathology. Consequently, we found the need to discuss the relationship of AH with seronegative RA and delve into the various diagnostic and treatment approaches.

Unique case of lymphocytic hypophysitis with normal pituitary hormone serology mimicking a non-functioning pituitary adenoma.

BACKGROUND: Lymphocytic hypophysitis is a rare autoimmune condition that usually presents during pregnancy and causes inflammation of the pituitary gland. Although the pathophysiology is not well understood, it often presents with headaches, visual disturbances, and symptoms of hypopituitarism. However, not all cases may present with hypopituitarism which can make this rare disease with an incidence of ~ 1 in 9 million much more difficult to diagnose. CASE PRESENTATION: We present a 35-year-old G4P4 woman with progressive vision loss and intermittent frontal headaches during her first trimester through 2 months postpartum. She presented with no symptoms of hypopituitarism and her hormone panel only showed elevated prolactin, possibly due to her breastfeeding. She was treated with a right pterional craniotomy with decompression of both optic nerves, partial resection of the suprasellar mass, and glucocorticoid therapy for headaches and visual disturbances. CONCLUSION: This case is notable for a presentation of lymphocytic hypophysitis without symptoms of hypopituitarism. This is important for outpatient providers to be aware of, especially those that care for pregnant patients so that unfavorable outcomes can be avoided.

Immunotherapy-Induced Hypophysitis Following Treatment With Tislelizumab in an Elderly Patient With Bladder Cancer and Prostate Cancer: A Case Report.

Immune checkpoint inhibitors represent a hopeful and emerging group of medications employed in the regulation of the immune response against cancer, displaying tremendous potential in cancer treatment. However, the administration of these drugs has been linked to the occurrence of adverse events, among which hypophysitis appears to be a prevailing complication affecting a substantial number of patients. Given the potential gravity of this condition, it is strongly recommended to actively monitor hormone levels throughout the treatment process, allowing for the prompt detection and provision of appropriate therapeutic measures. The present study showcases a case involving a 72-year-old individual afflicted with both bladder cancer and prostate cancer, who subsequently developed autoimmune hypophysitis and secondary adrenocortical insufficiency following the administration of programmed death protein 1 (PD-1) inhibitors.

Paraneoplastic autoimmune hypophysitis: a novel form of paraneoplastic endocrine syndrome.

Paraneoplastic syndromes are defined by symptoms or signs resulting from damage to organs or tissues that are remote from the site of malignant neoplasms or its metastasis. They are due to tumor secretion of functional hormones or peptides or are related to immune cross-reactivity with the host tissue. In particular, paraneoplastic endocrine syndromes are mainly caused by ectopic hormone production by the tumor such as PTHrP in humoral hypercalcemia in malignancy and ACTH in ectopic ACTH syndrome. Recently, it has been reported that a specific form of hypophysitis is caused as an immune-mediated paraneoplastic syndrome; paraneoplastic autoimmune hypophysitis, in which an ectopic pituitary antigen expression in the tumor evoked autoimmunity against pituitary-specific antigens, resulting in hypophysitis and exhibiting the injury of specific anterior pituitary cells by cytotoxic T cells. This novel clinical entity, paraneoplastic autoimmune hypophysitis consists of several conditions such as anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and immune checkpoint inhibitor-related hypophysitis with common mechanisms. These conditions can explain at least in part, the underlying mechanisms of acquired specific pituitary hormone deficiencies. In addition, it is important to apply a comprehensive discipline of onco-immuno-endocrinology to understand the pathophysiology and this approach; the expansion and application of immune-mediated paraneoplastic syndrome to endocrine diseases may give a new clue to understand pathophysiology of the autoimmunity against endocrine organs.

Glucocorticoid therapy as first-line treatment in primary hypophysitis: a systematic review and individual patient data meta-analysis.

Objectives: High-dose glucocorticoids are associated with improved recovery of deficits in primary autoimmune hypophysitis (PAH), but optimal dosing, route, and duration are unclear. Design: We reviewed literature for first-line glucocorticoid treatment in PAH until December 2021 and performed an individual patient data meta-analysis to analyze clinical, hormonal, and radiological outcomes with respect to route, dose, and duration (<6.5 vs 6.5-12 vs >12 weeks) of glucocorticoid treatment according to disease severity. Results: A total of 153 PAH patients from 83 publications were included. The median age at presentation was 41 (32.5-48) years with a female preponderance (70.3%). Visual field recovery was significantly better with i.v. (91.7%) as compared to oral (54.5%) route and high dose (100%) and very high dose (90.9%) as compared to medium dose (20%) of glucocorticoids. Corticotroph axis recovery was greater in i.v. (54.8% vs 28.1% oral, P = 0.033) route and increasing glucocorticoid dose group (0% vs 38.1% vs 57.1%), attaining statistical significance (P = 0.012) with very high-dose. A longer duration of treatment (>6.5 weeks) was associated with better corticotroph and thyrotroph recovery. The need for rescue therapy was lower with i.v. route (38% vs 17.5%, P = 0.012) and with increasing glucocorticoid doses (53.3% vs 34.3% vs 17.3%, P = 0.016). In severe disease, visual field and corticotroph axis recovery were significantly higher with i.v. route and very high-dose steroids. The adverse effects of glucocorticoids were independent of dose and duration of treatment. Conclusions: Very high-dose glucocorticoids by i.v. route and cumulative longer duration (>6.5 weeks) lead to better outcomes and could be considered as first-line treatment of severe PAH cases.

Lymphocytic hypophysitis in pregnancy complicated by intrahepatic cholestasis of pregnancy: a case report / 中华围产医学杂志

This paper reports the diagnosis and treatment of a case of lymphocytic hypophysitis in pregnancy complicated by intrahepatic cholestasis of pregnancy. The 32-year-old patient had regular menstrual cycles and conceived naturally. Around 24 weeks of gestation, she developed a headache without abnormalities in the visual field. Skin itching occurred at 32 weeks of gestation, but her headache was significantly relieved. By 33 +1 weeks of pregnancy, the patient experienced elevated total bile acid, transaminase, and hypoglycemia, leading to a diagnosis of intrahepatic cholestasis of gestation (mild). Subsequently, at 33 +6 weeks of gestation, her total bile acid increased substantially, and the disease progressed rapidly into intrahepatic cholestasis of pregnancy (severe). As a result, an emergency cesarean section was performed to terminate the pregnancy. The Apgar score of the newborn was five points at one minute and ten points at five minutes. Following the surgery, the patient showed no lactation and had symptoms such as nausea, vomiting, fatigue, and refractory hyponatremia. Blood hormone measurement showed hypopituitarism. An enhanced intracranial MRI showed pituitary enlargement and uniform enhancement. Consequently, the clinical diagnosis was lymphocytic hypophysitis. Treatment with glucocorticoids effectively alleviated the symptoms. Menstruation resumed after more than one month of delivery. The intracranial MRI in postpartum reexamination after six months of delivery revealed a disappearance of the lesion. The patient continued with oral glucocorticoid therapy.

Inhibition of IRAK1 Is an Effective Therapy for Autoimmune Hypophysitis in Mice.

Autoimmune hypophysitis (AH) is an autoimmune disease of the pituitary for which the pathogenesis is incompletely known. AH is often treated with corticosteroids; however, steroids may lead to considerable side effects. Using a mouse model of AH (experimental autoimmune hypophysitis, EAH), we show that interleukin-1 receptor-associated kinase 1 (IRAK1) is upregulated in the pituitaries of mice that developed EAH. We identified rosoxacin as a specific inhibitor for IRAK1 and found it could treat EAH. Rosoxacin treatment at an early stage (day 0-13) slightly reduced disease severity, whereas treatment at a later stage (day 14-27) significantly suppressed EAH. Further investigation indicated rosoxacin reduced production of autoantigen-specific antibodies. Rosoxacin downregulated production of cytokines and chemokines that may dampen T cell differentiation or recruitment to the pituitary. Finally, rosoxacin downregulated class II major histocompatibility complex expression on antigen-presenting cells that may lead to impaired activation of autoantigen-specific T cells. These data suggest that IRAK1 may play a pathogenic role in AH and that rosoxacin may be an effective drug for AH and other inflammatory diseases involving IRAK1 dysregulation.

Secondary autoimmune hypothalamitis with severe memory impairment 7 years after the onset of diabetes insipidus due to lymphocytic hypophysitis: a case report.

BACKGROUND: Autoimmune hypothalamitis is a very rare neuroendocrine disorder that causes central diabetes insipidus, headache, visual impairment, and sometimes cognitive impairment. Autoimmune hypothalamitis may occur in association with autoimmune hypophysitis, including lymphocytic hypophysitis, or in isolation. It is not known whether autoimmune hypothalamitis and autoimmune hypophysitis are consecutive diseases. CASE PRESENTATION: A 52-year-old woman developed autoimmune hypothalamitis 7 years after developing central diabetes insipidus due to lymphocytic hypophysitis, resulting in severe memory impairment. High-dose intravenous methylprednisolone therapy improved her cognitive function and decreased the size of the lesion. CONCLUSION: This case presented a unique clinical course, with a long period of time between the onset of autoimmune hypopituitaritis and the development of autoimmune hypothalamitis.

Hypophysitis.

OBJECTIVE: Hypophysitis is considered a rare inflammatory disease of the pituitary gland. For a long time, primary autoimmune hypophysitis has stood out as the most relevant type of hypophysitis. However, with the advent of immunotherapy for the treatment of malignancies and identification of hypophysitis as an immune-related adverse event, hypophysitis has garnered increasing interest and recognition. Therefore, awareness, early recognition, and appropriate management are becoming important as the indication for immunomodulatory therapies broaden. METHODS: In this review, we discuss the epidemiology, diagnosis, and treatment of hypophysitis with a focus on recent data and highlight subtypes of particular interest while recognizing the gaps in knowledge that remain. RESULTS: Regardless of cause, symptoms and signs of hypophysitis may be related to mass effect (headache and visual disturbance) and hormonal disruption that warrant prompt evaluation. In the vast majority of cases, a diagnosis of hypophysitis can be made presumptively in the appropriate clinical context with radiologic findings consistent with hypophysitis and after the exclusion of other causes. CONCLUSION: Although subtle differences currently exist in management and outcome expectations between primary and secondary causes of hypophysitis, universally, treatment is aimed at symptom management and hormonal replacement therapy.

The novel concept of "Onco-Immuno-Endocrinology" led to the discovery of new clinical entity "paraneoplastic autoimmune hypophysitis".

Recent advances in tumor immunology have enabled to develop immune checkpoint inhibitors and to save many patients with advanced cancer. Various endocrine diseases are caused by autoimmune mechanisms; it is important to understand that many endocrine organs are targeted by autoimmunity. In addition, some of malignant tumors ectopically produce hormones and lead to a clinically relevant ectopic hormone syndrome as an endocrine paraneoplastic syndrome. Thus, interplay between oncology, immunology, and endocrinology is important. We have defined a new clinical entity "paraneoplastic autoimmune hypophysitis" as "hypophysitis associated with autoimmunity against pituitary antigens caused by an ectopic expression of these antigens in the tumor and resulting in a breakdown of immune tolerance". To understand the pathophysiology of paraneoplastic autoimmune hypophysitis requires a fusion of the fields of oncology, immunology, and endocrinology; therefore, I propose a new concept of Onco-Immuno-Endocrinology.

IgG4-related hypophysitis: A monocentric experience from North India.

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.

Progress in Diagnosis and Treatment of Autoimmune Hypophysitis / 罕见病研究

Autoimmune hypophysitis is a rare disorder characterized by autoimmune-mediated inflammation of the pituitary, among which lymphocytic hypophysitis is the most common type that occurs mainly in young women of reproductive ages. Its common clinical manifestation includes headache, visual dysfunction, hypopituitarism and etc. Typical magnetic resonance imaging shows diffuse homogenous enlargement of the pituitary gland with gadolinium enhancement and stalk thickening. Pituitary biopsy with histopathological examination is the gold standard for the diagnosis of autoimmune hypophysitis, but it should be performed with extra care in that transsphenoidal surgery is invasive and may cause pituitary insufficiency. Closely relating to clinical manifestation of the patients and the radiological features is advised for diagnosis. Good response to glucocorticoid therapy also help confirm the diagnosis. Full course of pharmacological glucocorticoid treatment can effectively control the clinical symptoms, reduce the mass effects, and promote the resumption of pituitary functions. Surgery is usually necessary for xanthomatous and granulomatous hypophysitis. Pathophysiological mechanism, diagnostic biomarkers, and need studying further.

Recurrent autoimmune hypophysitis treated with rituximab: a case report.

BACKGROUND: Autoimmune hypophysitis is a rare condition that often results in enlargement of the pituitary gland and hypopituitarism due to inflammatory infiltration. Management of autoimmune hypophysitis can include long-term hormonal replacement and close control of the inflammatory pituitary mass. Mass-related symptoms in patients with autoimmune hypophysitis are treated with anti-inflammatory therapy, surgery, and/or radiotherapy. CASE PRESENTATION: We present a 25-year-old White man with visual field defects of the right eye, headache, and weight loss. Magnetic resonance imaging showed a sellar mass, and the patient underwent transcranial surgery. Histopathology revealed autoimmune hypophysitis with predominantly CD20 positive B-cell infiltration. Progression of visual field defects necessitated postoperatively anti-inflammatory treatment with prednisolone. Azathioprine was initiated under gradual tapering of prednisolone with stable conditions at first, but relapse followed after dose reduction. Therefore, rituximab treatment was initiated, which resulted in regression of the pituitary mass. Rituximab treatment was discontinued after 25 months. The patient has continuously been in remission for 4 years after rituximab treatment was stopped. CONCLUSION: This case illustrates that rituximab might be an effective alternative treatment in B-cell predominant autoimmune hypophysitis.

Autoimmune hypophysitis as a cause of adrenocorticotropic hormone deficiency in pulmonary arterial hypertension: a case report.

BACKGROUND: Severe pulmonary arterial hypertension (PAH) is generally treated with multiple PAH-specific vasodilators. If these agents are unsuccessful, additional treatment options are scarce, and the prognosis is poor due to right-sided heart failure. Some of these severe cases are also accompanied by endocrinological side effects. The most common side effect of prostacyclin is thyroid dysfunction, but in very few cases, adrenocorticotropic hormone (ACTH) deficiency may occur. CASE SUMMARY: A 35-year-old woman was diagnosed with hereditary PAH 2 years ago. Since her mean pulmonary arterial pressure was high, combination therapy of vasodilators, including prostacyclin, was introduced. Several months later, she was hospitalized with a persistent fever. Laboratory tests showed no findings suggestive of infection. However, hypereosinophilia and decreased secretion of ACTH and cortisol were noted, which led to the diagnosis of ACTH deficiency. A multimodal diagnostic approach, including pituitary magnetic resonance imaging and axillary lymph node biopsy, indicated that the aetiology of the ACTH deficiency was likely autoimmune hypophysitis. She was treated with hydrocortisone supplementation, which significantly relieved her condition. DISCUSSION: Endocrinological side effects in PAH patients using prostacyclin should be carefully addressed. If right-sided heart failure worsens during the administration of prostacyclin, it is essential to determine whether it is due to progression of pulmonary hypertension or endocrinological side effects. Careful diagnosis and treatment are important for managing the haemodynamics and symptoms of PAH patients given prostacyclin.

Síndrome poliuria - polidipsia de causa autoinmune en el posparto de una mujer de 27 años

La hipofisitis autoinmune es un cuadro caracterizado por la infiltración linfocítica de la hipófisis que produce deficiencia de una o más hormonas, tanto de la adenohipófisis como de la neurohipófisis. Para el diagnóstico, es necesario un alto índice de sospecha, más aún considerando la relación temporal con el embarazoo el parto. Las características clínicas e imagenológicas sugieren el diagnóstico. A pesar que el diagnóstico definitivo es por biopsia, esta no se suele realizar por los potenciales efectos adversos del procedimiento. Presentamos un caso que describe la forma de manifestación de la enfermedad y las características imagenológicas típicas en la resonancia magnética nuclear.

Autoimmune hypophysitis is a condition characterized by lymphocytic infiltration of the pituitary resulting in deficiency of one or more hormones of both the adenohypophysis and the neurohypophysis. For diagnosis, a high index of suspicion is necessary, even more so considering the temporal relationship with pregnancy or childbirth. Clinical and imaging features are suggestive of the diagnosis. Although the definitive diagnosis is by biopsy, this is not usually performed because of the potential adverse effects of the procedure. We present a case describing the form of manifestation of the disease and the typical imaging features on magnetic resonance imaging.

Lymphocytic infundibuloneurohypophysitis with positive anti-rabphilin-3A antibodies nine years post-onset of central diabetes insipidus.

Childhood-onset lymphocytic infundibuloneurohypophysitis (LINH) due to infiltration of autoimmune lymphocyte in the neurohypophysis is rarely reported. Its definitive diagnosis requires a pituitary biopsy, which is an invasive procedure. Recently, anti-rabphilin-3A antibody has been reported as a potential diagnostic marker for LINH in adults; however, only a few cases have been reported in children. Here, we present a case of childhood-onset LINH in a 10-yr-old boy identified as anti-rabphilin-3A antibody positive during chronic phase, 9 yr post-onset of central diabetes insipidus (CDI). T1-weighted magnetic resonance imaging (MRI) revealed pituitary stalk thickening and absence of posterior pituitary bright signal spot, and the hormonal responses of the adenohypophysis to GHRH, TRH, CRH, and LHRH revealed no abnormalities during the first admission. MRI at 5 mo post-onset indicated reduced stalk swelling; however, replacement treatment with intranasal desmopressin was continued to counter unimproved CDI. Additionally, GH replacement therapy was also initiated to counter its deficiency. Pituitary re-enlargement was not observed in the subsequent routine MRI, and no increase was observed in the levels of tumor markers during follow-up, which was considered clinically consistent with LINH. Our case study suggests that anti-rabphilin-3A antibody may be considered as a useful diagnostic marker for LINH in children.

Complete Resolution of the Pituitary Mass Lesion and Improvement of Pituitary Function with Corticosteroid in Autoimmune Hypophysitis: A Case Report.

BACKGROUND: Autoimmune hypophysitis is the consequence of an immune-mediated inflammation of the pituitary gland, which is rare, and most frequently occurs in females during postpartum periods. It usually responds well to corticosteroid treatment with reported resolution of the pituitary mass lesion. CASE REPORT: A 51 years male presented with a one-month history of lethargy, headache, nausea, proximal muscle weakness with intermittent flushing. He was a diabetic with metformin 500mg twice daily. No other remarkable medical history or family history of autoimmune disease. On examination, he had no neurological deficit with a normal visual field. His initial biochemical evaluation showed features of secondary hypothyroidism as evidenced by low free FT4 and suppressed TSH with normal electrolytes. The subsequent evaluation of his hormonal profile revealed panhypopituitarism. Contrast MRI of pituitary showed an enhanced homogenous mass and minimal stalk thickening with a dural tail and preserved posterior bright spot. He was managed with glucocorticoid 20 mg once daily for two weeks along with levothyroxine and testosterone replacement. After two weeks of treatment, he improved clinically. Repeat MRI imaging of the pituitary showed complete resolution of the homogenous mass. CONCLUSION: Although autoimmune hypophysitis is rare in males, a careful clinical history with necessary hormonal investigations is required for the suspicion about the inflammatory pituitary disorders This current case highlights glucocorticoid as the primary modality of treatment and the need for long-term follow-up with periodic clinical assessment.

Magnetic resonance imaging criteria of immune checkpoint inhibitor-induced hypophysitis.

Autoimmune hypophysitis is a rare complication of immune checkpoint inhibitors. Immune checkpoint inhibitors have been used for advanced stages of melanoma, renal cell carcinoma, and lung cancer. Multiple endocrinopathies, among them hypophysitis, could result as a reverse event from this therapy. MRI is the imaging modality of choice and usually demonstrates pituitary gland hypertrophy, irregular thickening of the pituitary infundibulum, and diffuse enhancement. We present a case of stage IV metastatic renal cell carcinoma complicated with hypophysitis secondary to combined nivolumab and ipilimumab therapy.