MECHANISMS IN ENDOCRINOLOGY: Hypophysitis: diagnosis and treatment

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  • 1 Department of Endocrinology, Guy’s & St. Thomas’ NHS Foundation Trust, London, UK
  • 2 Department of Endocrinology, Kings College Hospital NHS Foundation Trust, London, UK
  • 3 Faculty of Life Sciences & Medicine, King’s College Hospital London, London, UK

Correspondence should be addressed to P V Carroll; Email: paul.carroll@gstt.nhs.uk

Hypophysitis is a rare condition characterised by inflammation of the pituitary gland, usually resulting in hypopituitarism and pituitary enlargement. Pituitary inflammation can occur as a primary hypophysitis (most commonly lymphocytic, granulomatous or xanthomatous disease) or as secondary hypophysitis (as a result of systemic diseases, immunotherapy or alternative sella-based pathologies). Hypophysitis can be classified using anatomical, histopathological and aetiological criteria. Non-invasive diagnosis of hypophysitis remains elusive, and the use of currently available serum anti-pituitary antibodies are limited by low sensitivity and specificity. Newer serum markers such as anti-rabphilin 3A are yet to show consistent diagnostic value and are not yet commercially available. Traditionally considered a very rare condition, the recent recognition of IgG4-related disease and hypophysitis as a consequence of use of immune modulatory therapy has resulted in increased understanding of the pathophysiology of hypophysitis. Modern imaging techniques, histological classification and immune profiling are improving the accuracy of the diagnosis of the patient with hypophysitis. The objective of this review is to bring readers up-to-date with current understanding of conditions presenting as hypophysitis, focussing on recent advances and areas for future development. We describe the presenting features, investigation and diagnostic approach of the patient with likely hypophysitis, including existing conventional techniques and those in the research/development arena. Hypophysitis usually results in acute and persistent pituitary hormone deficiency requiring long-term replacement. Management of hypophysitis includes control of the inflammatory pituitary mass using a variety of treatment strategies including surgery and medical therapy. Glucocorticoids remain the mainstay of medical treatment but other immunosuppressive agents (e.g. azathioprine, rituximab) show benefit in some cases, but there is a need for controlled studies to inform practice.

Abstract

Hypophysitis is a rare condition characterised by inflammation of the pituitary gland, usually resulting in hypopituitarism and pituitary enlargement. Pituitary inflammation can occur as a primary hypophysitis (most commonly lymphocytic, granulomatous or xanthomatous disease) or as secondary hypophysitis (as a result of systemic diseases, immunotherapy or alternative sella-based pathologies). Hypophysitis can be classified using anatomical, histopathological and aetiological criteria. Non-invasive diagnosis of hypophysitis remains elusive, and the use of currently available serum anti-pituitary antibodies are limited by low sensitivity and specificity. Newer serum markers such as anti-rabphilin 3A are yet to show consistent diagnostic value and are not yet commercially available. Traditionally considered a very rare condition, the recent recognition of IgG4-related disease and hypophysitis as a consequence of use of immune modulatory therapy has resulted in increased understanding of the pathophysiology of hypophysitis. Modern imaging techniques, histological classification and immune profiling are improving the accuracy of the diagnosis of the patient with hypophysitis. The objective of this review is to bring readers up-to-date with current understanding of conditions presenting as hypophysitis, focussing on recent advances and areas for future development. We describe the presenting features, investigation and diagnostic approach of the patient with likely hypophysitis, including existing conventional techniques and those in the research/development arena. Hypophysitis usually results in acute and persistent pituitary hormone deficiency requiring long-term replacement. Management of hypophysitis includes control of the inflammatory pituitary mass using a variety of treatment strategies including surgery and medical therapy. Glucocorticoids remain the mainstay of medical treatment but other immunosuppressive agents (e.g. azathioprine, rituximab) show benefit in some cases, but there is a need for controlled studies to inform practice.

Invited Author’s profile

Paul Carroll is the Clinical Lead for Endocrinology at Guy’s and St Thomas’ NHS Foundation Trust and Honorary Senior Lecturer at Kings College London. He qualified from Trinity College Dublinand trained in Endocrinology at St. Bartholomew’s and St. Thomas’ Hospitals in London developing particular interests in pituitary, adrenal and thyroid disease. His research interests include clinical aspects of pituitary disease and inherited endocrine conditions.

Introduction

Hypophysitis is the collective term for conditions presenting with inflammation of the pituitary gland and infundibulum. Hypophysitis can occur as a primary entity or secondary to a predisposing local sella or multi-systemic inflammatory conditions. Hypophysitis is a rare condition; however, the recent recognition of IgG4-related disease (IgG4-RD) and the introduction of immune checkpoint inhibitors, as cancer therapies with endocrine adverse effects has prompted increased interest in inflammatory disorders affecting the pituitary gland. In the existing literature, the term hypophysitis has been used to describe a number of conditions that present with either primary or secondary inflammation of the pituitary gland. There has been inconsistency in the classification and commonly overlap in using the term for both inflammatory and neoplastic processes (including Langerhan’s cell histiocytosis (LCH)). This highlights the potentially broad differential that must be considered in the patient presenting with clinical and investigative features consistent with hypophysitis. This review guides the reader through the classification systems and highlights the diagnostic strategy. Recently recognised and emerging forms of hypophysitis are discussed in detail.

Hypopituitarism related to infective conditions has been documented for over a century (1), but it is only in the last 50 years that we have been able to begin to evaluate the primary pathologies leading to hypophysitis (2). Histological description of some of the originally described case reports suggests that lymphocytic infiltration of the gland was noted as early as the beginning of the last century (1), and in the 1950s, this was identified to have an autoimmune association (3). Our understanding of hypophysitis has grown considerably in the last decade, with contributions from large case series and comprehensive review articles (4, 5, 6).

The overall prevalence of these diseases remains low and hypophysitis is still considered a rare condition. Population-based studies report an incidence of hypophysitis (all types combined) to be about 1 in 9 million (4), but this is an underestimate, particularly as IgG4-related disease and involvement of the hypophysis by systemic pathologies has increasingly been recognised. Neurosurgical centres report hypophysitis prevalence to be of <1% of sella and suprasella lesions referred for evaluation (0.24–0.88% (4, 7)).

This review summarises the current literature on the diagnosis and management of hypophysitis, with emphasis on discussion of the newer and less common clinical entities such as immune checkpoint therapy-related hypophysitis and IgG4 hypophysitis. Little is known about the optimal diagnostic approach and treatment of both primary and secondary hypophysitis and we have summarised the available literature. We have also included areas of future research and future anticipated clinical developments. The review provides guidance for the clinician investigating and managing patients presenting with hypophysitis.

Data collection

We performed a PubMed-based search of articles using the search terms hypophysitis, adenohypophysitis adenohypoph, infundibulohypophysitis, autoimmune infection IgG4 granulomatous xanthomatous autoimmune, infection, IgG4, granulomatous, xanthomatous, immune checkpoint, CTLA-4, PD1, PD-L1 and combined them with hypophysitis, hypopituitarism, pituitary. After the original search, we used filters to select articles available in English, articles with available full texts and removed duplicate articles resulting in 1074 articles. Further short-listing was done based on the relevance of the titles using filtering for mesh terms or text-words. The final search derived 271 articles. Of these, 53 articles were review articles, 169 were case reports and 49 were other journal articles.

Classification of hypophysitis

In clinical practice, the term hypophysitis is used as an umbrella encompassing the conditions that present as a result of either primary or secondary pituitary hypophysitis. A number of classification systems have evolved to categorise hypophysitis. These include using aetiology, pattern of pituitary involvement and histological findings. In many patients, histological confirmation of the pathology has not been possible. Therefore, using a solely histology-based classification mechanism has not been possible for all patients. It is conventional to classify based on aetiology (or presumed aetiology); with conditions described as either primary (affecting the hypothalamo-pituitary structures) or secondary hypophysitis. The commonest primary condition is lymphocytic hypophysitis with idiopathic granulomatous hypophysitis being less common. Secondary causes include autoimmune conditions (e.g. systemic lupus erythematosus, autoimmune polyglandular syndrome). Traditionally infiltrative conditions including LCH and sarcoidosis have been included in the hypophysitis category. Drug therapy-induced hypophysitis, especially with CTLA-4 inhibitors, is a new entity increasingly recognised by oncologists and endocrinologists.

Historically, hypophysitis has also been just classified according to the pattern of the hypothalamic, pituitary and pituitary stalk (PS) involvement. This approach is limited as it does not necessarily relate to the particular aetiology but does have implications for describing the associated pituitary hormone deficits that arise. Patients with involvement of the neurohypophysis and those with pan-hypophysitis typically present with diabetes insipidus related to ADH deficiency. Those with pure involvement of the anterior pituitary do not have diabetes insipidus but present with the consequences of anterior pituitary hormone deficiency.

Hypophysitis can also be classified using histological appearances. Biopsy is most commonly performed to distinguish between neoplastic and inflammatory conditions and ideally make a categorical diagnosis. When a successful biopsy has been achieved, this approach is useful in guiding management decision making. There is overlap in the presentation of granulomatous, lymphocytic and xanthomatous lesions and making clear distinction between these entities is not always possible. Existing reports are mostly retrospective and are limited by lack of diagnostic histopathology. The classification of primary hypophysitis and secondary predisposing factors are summarised in Tables 1 and 2.

Table 1

Classification of primary hypophysitis (adapted and modified from(91)).

(a) Based on anatomy
 Lymphocytic adenohypophysitis
 Lymphocytic infundibuloneurohypophysitis
 Lymphocytic pan-hypophysitis
(b) Based on histology
 Lymphocytic hypophysitis
 Granulomatous hypophysitis
 Xanthomatous hypophysitis
 Plasmacytic/IgG4-related hypophysitis
 Necrotising hypophysitis
 Mixed forms (lymphogranulomatous, xanthogranulomatous)
Table 2

Conditions predisposing to the development of hypophysitis.

Autoimmune conditions

• Systemic lupus erythematosus (SLE)

• Autoimmune polyglandular syndrome (APS)
Systemic inflammatory disorders

• Sarcoidosis

• Granulomatosis with polyangitis

• IgG4-disease

• Other granulomatous (Crohn’s, Takayasu’s, Castlemans’ disease)
Drug induced

• Immune checkpoint therapy (CTLA4 Ab, PD-1 Ab)

• Interferon α
Infiltrative lesions

• Langerhans cell histiocytosis

• Erdheim–Chester disease
Local tumour effect (Sellar diseases)

• Rupture of Rathke’s cleft cyst

• Germinoma
Infection

• Tuberculosis

• Syphilis

• Fungal infections

Clinical presentation of hypophysitis

Pituitary inflammation (either primary or secondary) usually results in pituitary hormone deficiency and enlargement of the pituitary gland. Inflammatory or infiltrative expansion of the pituitary gland can result in compression of the optic apparatus with resulting neuro-ophthalmic consequences. These usually include visual field defects but reduction in colour perception and visual acuity can also occur. Involvement of the cavernous sinus with ophthalmoplegia is rare but described (8). Headache is a consistently reported symptom in the patient with hypophysitis.

Endocrine manifestations include anterior pituitary hormone deficiencies, diabetes insipidus and abnormal serum prolactin (either hypo or hyperprolactinaemia (6). The pattern of endocrine dysfunction maybe influenced by the aetiology. Lymphocytic hypophysitis is considered to have a predilection to ACTH, gonadotrophin, TSH, GH deficiencies in this sequence, but isolated hormone deficiencies though rare, have been reported (4, 9). The pattern of hormone deficits may differ in IgG4-RD and immune checkpoint inhibitor-related hypophysitis. It has been suggested that hyperprolactinemia is a feature predominantly seen in the acute phase of the lymphocytic hypophysitis, and simultaneously, other symptoms of pituitary enlargement may be present (5). Involvement of PS in isolation (infundibulo-hypophysitis) and entire involvement of the pituitary gland and stalk (pan-hypophysitis) are more likely to present with diabetes insipidus (the latter including anterior pituitary hormone deficiency).

Headache with or without nausea, vomiting (>50%) and visual disturbances are common, as described in large case studies (6, 10). Cranial nerve palsies (10, 11), cavernous sinus involvement (10), intracavernous carotid artery occlusion (12), meningitis-mimic (13) and even apoplexy-mimic (11, 14) presentations have been reported. Amongst the other common non-endocrine symptoms reported in a recent German study include weight gain and features of associated autoimmune conditions (10).

The relationship to pregnancy and known existing conditions and their treatments are important to identify the aetiology of hypophysitis. A relationship with pregnancy (particularly third trimester or early post-partum) provides evidence to support a diagnosis of lymphocytic hypophysitis.

Given the possibility that hypophysitis may be secondary to a systemic condition or an infiltrative disorder, it is important to consider a broad history and examination. Conditions such as sarcoidosis or LCH might manifest with symptoms of respiratory or bone disease. Drug history may be relevant, especially when newer oncology medications are used as immune therapy. Immune checkpoint inhibitors, most commonly ipilimumab, result in hypophysitis and thyroiditis as recognised adverse effects. A large case series of 152 PS lesions reported neoplastic lesions (32%) were more common than inflammatory pathologies (20%), highlighting the relevance of a broad differential (15).

Investigation of the patient with hypophysitis

Treatment of hypophysitis

The natural history of hypophysitis is variable, and there is no strong evidence base for management recommendations. It is likely that increased understanding of the specific causal conditions and their treatment responses (e.g. IgG4-related disease, immune checkpoint inhibitor treatment) will emerge with future studies. Bellastella et al. distinguish between the acute phase of hypophysitis, which may require primary treatment; and a chronic or burnt out phase during which only treatment of hypopituitarism is needed (7). Hypopituitarism and diabetes insipidus should be treated according to conventional recommendations (30).

The main objectives of treatment are to manage pituitary hormone deficiencies and to reduce the inflammatory pituitary enlargement with associated mass-related consequences. Primary treatment of the hypophysitis falls into four categories which include: surgery, anti-inflammatory medical therapy, conservative management and radiotherapy. Historically, surgery remains the preferred method of choice (4) when there is significant mass effect. The advantages of surgery are that it provides a histological diagnosis to guide future management and excludes the diagnosis of tumour. It also reliably and quickly treats mass effects and visual impairment due to the lesion (31). In a large German cohort, surgery for hypophysitis resulted in significant resolution of symptoms such as headaches and visual disturbances (31, 32, 33). The rate of recurrence of the lesion after surgery was reported to be 11–25% (31, 32). Post-operative follow-up showed the development of pituitary insufficiencies and was particularly frequent after gross total resection compared to biopsy or partial resection.

There are limited reports of spontaneous resolution of hypophysitis. In cases without significant mass effect or headache, surveillance of hypophysitis can be used in addition to replacement of endocrine insufficiencies (31, 34).

Glucocorticoid therapy forms the cornerstone of medical management. Numerous authors have confirmed an initial good response to ‘steroid therapy’, but the overall recurrence rate has been reported to be high and highlights the limitations of this treatment (33, 35). Up to 38% patients developed relapse on steroid therapy, in a recent large cohort (31). As is expected, treatment with long-term steroids leads to increasing adverse effects and limits the use of this strategy (31). In cases with progressive or recurrent disease steroid-sparing options such as alternative immune-suppressive agents or radiotherapy have been considered. A variety of agents have been used, and experience often reported as case reports. Supplementary Table 4 (see section on supplementary data given at the end of this article) provides a brief summary of the papers reporting use of steroid-sparing therapies. The last few years have seen a rise in the use of immunosuppressive therapies for resistant lesions (36). Azathioprine is the most commonly used immune-suppressive agent at present, while in the coming years, it is likely we will see more focussed monoclonal antibody-directed therapy such as rituximab (31).

Hyperprolactinaemia affects a minority of cases in the acute phase of the pituitary inflammation (5). Some authors have reported the possibility of prolactin modulating autoimmunity and the use of dopamine agonists for inducing treatment response (37, 38). While the beneficial effect of long-term dopamine agonist treatment is still uncertain (5), the use of cabergoline/bromocriptine in hyperprolactinaemic patients is likely to provide symptomatic relief (from galactorrhoea and/or hypogonadism if present). The approach to managing the patient with suspected hypophysitis is outlined in Fig. 1.

Figure 1
Figure 1

Early assessment for treatment response with pituitary MRI. Follow with serial imaging until clear stability, maintain clinical suspicion for recurrence. Consider escalating to immunosuppression or radiotherapy if persistent symptoms or continuing mass effect despite corticosteroids ± surgery.

Citation: European Journal of Endocrinology 179, 3; 10.1530/EJE-17-0009

Specific conditions causing hypophysitis

Recent advances in the understanding of hypophysitis: imaging modalities and immunomarkers

In recent years, a novel entity called ‘Anti-Pit 1 antibody syndrome’ has been recognised (85). This presents as an acquired deficiency of growth hormone, TSH and prolactin with detectable anti-Pit 1 antibody (26). It is considered to be a cytotoxic T cell-mediated autoimmune process, but further studies are needed to establish the exact pathogenesis (86). Similarly antibody to pituitary tissue has been identified as a possible antigenic target in LH, even in patients not presenting with ACTH deficiency (87). Heaney et al. have suggested that use of HLA markers for DQ8 and DR53 could be used to identify patients suspected to have LH. There is a 23.1-fold increase in the levels of DQ8 in the patients with LH as compared to those with other pituitary lesions (88).

The use of nuclear medicine in the diagnosis of inflammatory conditions has been evolving. Recently Lee et al. used FDG PET in IgG4-related diseases. They reported that pattern of uptake and multi-organ involvement were significant predictors of IgG4-related disease (89). The use of software-based image processing technology called textural analysis has been suggested to differentiate neoplastic and non-neoplastic PS lesions with more certainty. The distribution of the grey levels in the given region of interest could be used as a guiding tool to determine, which lesions are less likely to be inflammatory and facilitate decision making (90). In clinical practice, FDG PET has become an increasingly used tool in the assessment of the patient with inflammatory pituitary conditions, often allowing diagnosis to be made by facilitating less invasive tissue biopsy in multisite disease.

Anticipated future developments

Interest in inflammatory disorders affecting the pituitary gland has increased in recent years. Recognition of IgG4-RD has prompted reconsideration of the classification of hypophysitis and clinicians are considering this diagnosis both in new prospective cases and in historic ones labelled as LH (often without biopsy). The advent of immune checkpoint inhibition has meant an increase in clinical experience with hypophysitis for endocrine physicians and provides insight into the pathophysiological mechanisms of disease. These increases in understanding will likely result in new diagnostic algorithms and more accurate classification of disease. New serological markers are likely to emerge and non-invasive diagnostics will improve. The near future will likely see more accurate diagnosis of primary and secondary hypophysitis and lead to more consistent and specific treatments for this rare group of disorders. Collaborative multi-centre prospective studies are required to define the optimal treatment approaches for the patient with hypophysitis.

Supplementary data

This is linked to the online version of the paper at https://doi.org/10.1530/EJE-17-0009.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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    Early assessment for treatment response with pituitary MRI. Follow with serial imaging until clear stability, maintain clinical suspicion for recurrence. Consider escalating to immunosuppression or radiotherapy if persistent symptoms or continuing mass effect despite corticosteroids ± surgery.