The Changing Clinical Spectrum of Hypophysitis

doi:10.1016/j.tem.2019.06.004

Trends in Endocrinology & Metabolism

Volume 30, Issue 9, September 2019, Pages 590-602

https://doi.org/10.1016/j.tem.2019.06.004 Get rights and content

Highlights

The identification of a proper clinical context and a multidisciplinary approach are crucial for an early and univocal diagnosis of hypophysitis and for an appropriate treatment.
The natural history of hypophysitis with its acute and chronic phases guides the management, treatment, and follow-up of both primary hypophysitis (PAH) and immunotherapy-induced hypophysitis (IIH).
In the acute phase of PAH, according to the multidisciplinary evaluation of the risk/benefit ratio, the glucocorticoid immunosuppressive treatment should be suggested, for the potential recovery of pituitary function and for avoiding the development of a persistent hypopituitarism and an empty sella syndrome.
The therapeutic management of IIH has to be conducted in accordance between the oncologist and the endocrinologist, to make the optimal therapeutic choice, avoiding life-threatening conditions and improving patients’ outcome.

Hypophysitis is a rare and potentially life-threatening disease, characterized by an elevated risk of complications, such as occurrence of acute central hypoadrenalism, persistent hypopituitarism, or extension of the inflammatory process to the neighboring neurological structures. In recent years, a large number of patients have been described as being affected by hypophysitis, due to the increased administration of immuno-chemotherapies. At the present time, the heterogeneous nature of hypophysitis diagnostic criteria and of the treatment protocols makes the management of affected patients difficult. We review the current data and evidence on primary and secondary hypophysitis, in order to suggest a diagnostic and therapeutic protocol that should be focused on a multidisciplinary approach, for reaching a prompt diagnosis and an appropriate and safe treatment.

Section snippets

Hypophysitis: Actual and Future Prospective

Hypophysitis is a rare inflammatory disease of the pituitary gland and represents an emerging problem, as in recent years, an increased number of affected patients has been described. However, at the moment, no consensus for early diagnosis and management has been provided. For some years, the diagnosis of hypophysitis has been conducted on the basis of the histological detection of an inflammatory infiltration in the pituitary gland. According to the histological features of the pituitary

Epidemiology of PAH and IIH

Epidemiological data of PAH and IIH are not conclusive. The reported annual incidence of PAH is estimated as one case per 9 million inhabitants [26]. Females are predominantly affected by adenohypophysitis, and middle-aged males and children by infundibulo-neurohypophysitis 27., 28..

IIH frequency ranges from 0.7% to 15% of ICI-treated patients 29., 30., 31.. This different frequency may be influenced by different factors, such as the class of ICI, the use of ICI-associated treatments, duration

Physiopathology of PAH and IIH

The immune checkpoint is the gate regulating the immune response that is involved in maintaining immunological homeostasis and preventing the onset of autoimmune disease [43]. Programmed death (PD)-1 is one of the representative immune checkpoint molecules. It is mainly expressed on the surface of effector T cells in tumor or peripheral tissue, B cells, antigen-presenting cells, and natural killer cells. PD-1 can selectively bind to PD-1 ligand (PD-L)1 (CD274) or PD-L2 (CD273) on the cellular

Diagnostic Criteria of PAH and IIH

PAH and IIH are diagnosed in most cases through clinical criteria [47], as pathological analysis of the pituitary tissue is not performed in the absence of indications for surgery. Pituitary biopsy is not routinely performed because of its invasiveness and potential risk of further deterioration of pituitary function 12., 13., and remains limited to patients with an uncertain diagnosis and in cases with an indication of neurosurgical debulking, for reducing the obvious nerve compression 12., 13.

Hormone Replacement Therapy in PAH and IIH

As summarized in Table 1 59., 60., 61., 62., hormone replacement therapy should be administered according to the hypophysitis phase. Both in the acute and chronic phases of PAH and IIH, central hypoadrenalism, diabetes insipidus, and central hypothyroidism have to be managed. As a potential life-threatening condition, central hypoadrenalism has to be promptly treated, through the oral or parental administration of hydrocortisone, according to the patient’s clinical condition [63]. Similarly, in

Immunosuppressive Therapy in PAH and IIH

Immunosuppressive therapy should be considered only during the acute phase of hypophisitis in order to inhibit the inflammatory process, to reduce the compressive effects of the enlarged pituitary gland, and to avoid the development of glandular fibrosis that may cause irreversible hypopituitarism.

Glucocorticoids are considered as a first-line option for immunosuppressive treatment. Therapeutic schemes described in the literature are based on low or high doses of glucocorticoids (prednisolone

PAH and IIH Management

PAH and IIH represent a complex scenario that requires a multidisciplinary approach for diagnosis, treatment, and follow-up. As summarized in Figure 3, PAH diagnosis should be conducted according to the clinical findings, in the appropriate clinical context. Pituitary MR images play a central role in diagnosis, through the exclusion of focal pituitary lesions. Similarly, the etiological diagnosis of hypophysitis requires a multidisciplinary management. At diagnosis, infectious disease

Concluding Remarks and Future Perspectives

The heterogeneity of hypophysitis definition and the diagnostic/therapeutic protocols makes the evaluation and management of hypophysitis difficult, resulting in increased morbidity, worse outcomes, or even death. Cases of spontaneous partial and complete recovery have been documented. Univocal diagnostic criteria, treatment protocols, and outcome definitions are required for prompt diagnosis and treatment and for appropriate management of immunotherapy, avoiding life-threatening conditions and

Acknowledgments

The authors wish to thank the Oncology Team of Istituto Dermatopatico dell’Immacolata in Rome, and Prof. Alessandro Scoppola for collaboration and the courtesy of sharing the information and images of the clinical case reported.

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Cited by (37)

Executive summary of the consensus document on hypophysitis of the Neuroendocrinology Area of Knowledge of the Spanish Society of Endocrinology and Nutrition
2023, Endocrinologia, Diabetes y Nutricion
El término hipofisitis se emplea para designar un conjunto heterogéneo de lesiones hipofisarias caracterizadas por una infiltración inflamatoria de la adenohipófisis, neurohipófisis o ambas. Aunque las hipofisitis son poco frecuentes, la forma clínica más común es la hipofisitis linfocítica, una forma de hipofisitis primaria caracterizada por infiltración linfocitaria, que afecta predominantemente a mujeres. Otras formas de hipofisitis primaria se asocian a distintas enfermedades autoinmunes. La hipofisitis puede ser también secundaria a otros trastornos, como lesiones selares y paraselares, enfermedades sistémicas, síndromes paraneoplásicos, infecciones y fármacos, entre los que destacan los inhibidores de los puntos de control inmunitarios. La evaluación diagnóstica debe incluir siempre pruebas de función hipofisaria y otras pruebas analíticas en función de la sospecha diagnóstica. La resonancia magnética hipofisaria es la prueba de elección para la valoración morfológica de la hipofisitis. Los glucocorticoides son la base del tratamiento de la mayoría de las hipofisitis sintomáticas.
The term hypophysitis is used to designate a heterogeneous group of pituitary conditions characterized by the presence of inflammatory infiltration of the adenohypophysis, neurohypophysis, or both. Although hypophysitis are rare disorders, the most common in clinical practice is lymphocytic hypophysitis, a primary hypophysitis characterized by lymphocytic infiltration, which predominantly affects women. Other forms of primary hypophysitis are associated with different autoimmune diseases. Hypophysitis can also be secondary to other disorders such as sellar and parasellar diseases, systemic diseases, paraneoplastic syndromes, infections, and drugs, including immune checkpoint inhibitors. The diagnostic evaluation should always include pituitary function tests and other analytical tests based on the suspected diagnosis. Pituitary magnetic resonance imaging is the investigation of choice for the morphological assessment of hypophysitis. Glucocorticoids are the mainstay of treatment for most symptomatic hypophysitis.
Hypophysitis
2022, Endocrine Practice
Citation Excerpt :
Therefore, comparisons of the outcomes of treatment options should be cautiously interpreted. Furthermore, stages at presentation (acute or chronic) may play a part in responding to a treatment, with chronic disease and resultant scarring thought to be less responsive to immunosuppressive regimens.2,32 At the time of presentation, patients with clinical signs and symptoms in association with radiologic findings suggestive of hypophysitis should be assessed for pituitary hormone deficits while ruling out secondary causes, as suggested in the Table.
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.
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.
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.
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 changing clinical spectrum of endocrine adverse events in cancer immunotherapy
2022, Trends in Endocrinology and Metabolism
Citation Excerpt :
Both anti-CTLA-4 and anti-PD-1 mAbs have been associated with thyroid dysfunction, hypophysitis, hypopituitarism, and insulin-dependent diabetes [42]. The epidemiological data on e-IRAEs are not conclusive because they are influenced by several factors such as study design, sample size, heterogeneity of the patient cohort, different subtypes of ICIs, and variable diagnostic criteria for endocrinopathies [21]. Most e-IRAEs can be well managed though a multidisciplinary approach between endocrinologists and oncologists that can ensure not only patient safety but also compliance with ICI treatment [21].
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several malignancies, improving patient survival and quality of life. Endocrinopathies have emerged as a clinically significant group of immune-related adverse events (IRAEs). Although the mechanism of ICI toxicities has not been clarified, inhibition of immune checkpoints reduces immune tolerance to autoantigens, resulting in the development of autoimmunity disorders. We report current evidence regarding endocrine IRAEs that may have diagnostic and therapeutic implications. Management should be focused on a multidisciplinary approach to reach a prompt diagnosis and an appropriate and safe treatment.
Pituitary Surgery
2022, The Pituitary
Pituitary tumors are the third most common tumor of the brain. Surgical removal plays a central role in management for these tumors. The primary goals of surgery are to reduce mass effects on surrounding structures and/or alleviate hormonal excess due to hypersecretion from functional tumors, while providing a definitive diagnosis using resected tissue. The transsphenoidal approach is most commonly used to remove tumors, with the transcranial approach reserved for special situations. The advent of endoscopic transsphenoidal surgery in recent years has led to excellent outcomes and improved patient comfort. Furthermore, the endoscopic approach has fostered development of techniques to remove other parasellar intracranial tumors such as craniopharyngioma and meningioma via the transnasal approach.
Drugs and Pituitary Function
2022, The Pituitary
Several medications may alter pituitary function. Although most drugs only produce transient effects on pituitary function that are not clinically significant, in some instances, persistent drug-induced pituitary dysfunction may be seen. The list of potential “culprit” drugs is large and expanding; opioids and anticytotoxic T-lymphocyte-antigen 4 (CTLA-4) antibody therapy have been found recently to have profound effects on pituitary axes. Many therapies, including antidepressants, antipsychotics, and antihistamines, can raise prolactin levels, while antiepileptics and other drugs can cause the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Increased awareness of drug effects on the pituitary should prompt early screening, or, in the presence of suggestive symptoms and/or abnormal laboratory values, prompt treatment of hypopituitarism. Familiarity with the spectrum of pituitary dysfunction attributed to acute and chronic drug therapy use is paramount for endocrinologists, oncologists, pain specialists, psychiatrists, intensivists, and internal medicine specialists.
Hypothalamitis and pituitary atrophy
2021, Handbook of Clinical Neurology
Hypothalamitis is a rare inflammatory disorder involving the hypothalamus and classified as primary, or isolated, and secondary hypothalamitis. Secondary hypothalamitis although very rare is more common than the primary one and may occur in patients affected by autoimmune diseases such as autoimmune hypophysitis, systemic autoimmune diseases, infective diseases in patients affected by immune-deficit, paraneoplastic encephalitis, or in patients treated with immune checkpoint inhibitors. In accordance with the rarity of this disease, diagnosis and management of hypothalamitis prove to be challenging. The diagnosis requires a high index of clinical suspicion. The main symptoms may be: various degrees of hypopituitarism, neuropsychiatric and behavioral disorders, and disturbances of autonomic and metabolic regulation. Magnetic resonance images play a crucial role in the diagnosis of hypothalamitis and in the exclusion of a neoplastic lesion. Therapeutic management should be oriented according to the disease etiology. In most cases, after ruling out infective hypothalamitis, the mainstay of therapy consists of immunosuppressive treatment. Great attention should be paid to hormonal replacement therapy, if partial or total hypopituitarism is present, in particular in patients affected by diabetes insipidus, central hypoadrenalism and hypothyroidism. According to the complexity of this disease, a multidisciplinary approach is strongly advocated to reach an early diagnosis and an integrated therapy.

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Trends in Endocrinology & Metabolism

OpinionThe Changing Clinical Spectrum of Hypophysitis

Highlights

Section snippets

Hypophysitis: Actual and Future Prospective

Epidemiology of PAH and IIH

Physiopathology of PAH and IIH

Diagnostic Criteria of PAH and IIH

Hormone Replacement Therapy in PAH and IIH

Immunosuppressive Therapy in PAH and IIH

PAH and IIH Management

Concluding Remarks and Future Perspectives

Acknowledgments

Endocrinol. Metab. Clin. N. Am.

World Neurosurg.

Endocr. Pract.

Am. J. Med.

Endocr. Pract.

Autoimmun. Rev.

Ann. Oncol.

Cancer Treat. Rev.

Cancer Treat. Rev.

Ann. Oncol.

J. Chem. Neuroanat.

Clin. Endocrinol.

Bull. Cancer

Ann. Endocrinol. (Paris)

Hypophysitis due to IgG4-related disease responding to treatment with azathioprine: an alternative to corticosteroid therapy

Pituitary

Update on hypophysitis and TTF-1 expressing sellar region masses

Brain Pathol.

Giant-cell granulomatous hypophysitis: a distinct clinicopathological entity

J. Neurosurg.

Idiopathic granulomatous hypophysitis: clinical and imaging features

Neuroradiology

Xanthomatous hypophysitis: a novel entity of obscure etiology

Endocr. Pathol.

Lymphocytic hypophysitis report of 3 new cases and review of the literature

Medicine

A case of granulomatous hypophysitis with hypopituitarism and minimal pituitary enlargement

J. Neurol. Neurosurg. Psych.

Lymphocytic hypophysitis: light and microscopic findings and correlation to clinical appearance

Endocrine Pathol.

A case series of atypical features of patients with biopsy-proven isolated IgG4-related hypophysitis and normal serum IgG4 levels

Pituitary.

IgG4-related disease: a reminder for practicing pathologists

Arch. Pathol. Lab. Med.

An overview of diagnosis of primary autoimmune hypophysitis in a prospective single-center experience

Neuroendocrinology

Neuro-radiological features can predict hypopituitarism in primary autoimmune hypophysitis

Pituitary

New molecular, biological, and immunological agents inducing hypophysitis

Neuroendocrinology

Xanthogranulomatous hypophysitis: a rare and often mistaken pituitary lesion

Endocrinol. Diabetes Metab. Case Rep.

Panhypopituitarism apparently caused by hypophysitis masking a rapid development of a craniopharyngioma. A case report

Acta Clin. Belg.

Pituitary and systemic autoimmunity in a case of intrasellar germinoma

Pituitary

Central hypothyroidism and hypophysitis during treatment of chronic hepatitis C with pegylated interferon alpha and ribavirin

Eur. J. Gastroenterol. Hepatol.

Lymphocytic hypophysitis associated with Behcet’s disease: a case report and review of the literature

Neuro. Endocrinol. Lett.

Sellar inflammatory mass with inflammatory bowel disease

Can. J. Gastroenterol.

Acute hypophysitis and hypopituitarism in early syphilitic meningitis in a HIV-infected patient: a case report

BMC Infect. Dis.

Brucella hypophysitis

Acta Neurol. Belg.

Primary hypophysitis and other autoimmune disorders of the sellar and suprasellar regions

Rev. Endocr. Metab. Disord.

Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma

Eur. J. Endocrinol.

Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypo- physitis: a retrospective cohort study

Clin. Cancer Res.

Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma

J. Clin. Endocrinol. Metab.

The future of immune checkpoint cancer therapy after PD-1 and CTLA-4

Immunotherapy

Opinion
The Changing Clinical Spectrum of Hypophysitis