Hypophysitis: An update on the novel forms, diagnosis and management of disorders of pituitary inflammation

Abstract

Hypophysitis is a heterogeneous condition that leads to inflammation of the sella and/or suprasellar region, potentially resulting in hormonal deficiencies and/or mass effects. A preponderance of hypophysitis subtypes have an underlying autoimmune aetiology. The overall incidence and prevalence of hypophysitis has dramatically increased over the past decade, mainly due to increased awareness of the condition in the medical community, improvements in imaging techniques, and a rise in the occurrence of certain forms of hypophysitis such as IgG4 hypophysitis (IgG4Hy) and immune checkpoint inhibitor induced hypophysitis (ICIHy). The clinical presentation varies from an asymptomatic condition to a fatal disease often as a result of electrolyte abnormalities due to glucocorticoid deficiency in the context of adrenal crisis from central adrenal insufficiency. Milder forms of hypophysitis are treated with replacement of deficient hormones while more acute presentations with mass effects require glucocorticoid therapy, immunosuppressive therapy or surgery. Timely diagnosis and interventions are keys to prevention of the lethal complications of this disease. In this review, we provide an update on the recent advances in the field of pituitary autoimmunity, with an emphasis on autoimmune hypophysitis and novel forms of hypophysitis such as anti-PIT1 hypophysitis, IgG4Hy and ICIHy.

Keywords: adrenal insufficiency; autoimmunity; hypophysitis; immune checkpoint inhibitors; immunotherapy; pituitary.

Figure 1:

Mechanism of immune checkpoint inhibitor-induced hypophysitis (ICIH). A: The tumor antigen is presented to T lymphocyte (TLC) by antigen presenting cell (APC), which in this scenario can be a tumor cell, through the interaction between the T-cell receptor (TCR) and the major histocompatibility complex I (MHCI). Another simultaneous interaction occurs between CD28 on the TLC and B7 on the APC which leads to the completion of TLC activation. B: Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a negative immunomodulator that is induced after the initial activation of TLC. CTLA4 binds to B7 with a higher affinity when compared to CD28, and causes inactivation of TLC. Programmed death 1 (PD1) is up-regulated in activated TLCs and, in response to the inflammatory state, various tissues express PD1 ligand 1 (PDL1) and the PD1/PDL1 interaction down-regulates TLC activation. These mechanisms act as immune checkpoints and are utilized by normal cells in the body to prevent immune-mediated destruction. But the tumor cells take advantage of these immunomodulatory pathways to evade the immune system. C: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target the immune checkpoints (CTLA4, PD1/PDL1) and inhibit their action, leading to persistent TLC activation and proliferation. This up-regulation in TLC activity caused by ICIs leads to destruction of the tumor and, as an adverse effect, also causes ICIH and other immune-related adverse events. The binding of ICI to pituitary cells elicits various immune reactions: a type II hypersensitivity reaction leading to activation of macrophages and complement pathways, a type IV hypersensitivity reaction causing cytotoxic T lymphocyte activation resulting in the release of granzyme, perforin, and cytokines, and activation of humoral immunity pathway leading to the production of anti-pituitary antibodies, all of which cause the disruption of the pituitary gland. (Courtesy of Sriram Gubbi, NIDDK, NIH)

Figure 2:

Diagrammatic representation of normal anatomy of the sellar region and the adjacent neurovascular structures (left panel) and the mass effects of hypophysitis (right panel). (Courtesy of Sriram Gubbi, NIDDK, NIH)

Figure 3:

Diagnostic evaluation and treatment of hypophysitis.

Figure 4:. Magnetic Resonance Imaging Findings in a Case of Primary Hypophysitis.

Panel A) T1-weighted image, sagittal section. Panel B) T1-weighted image, coronal section. Panel C) T1-weighted image post-gadolinium, sagittal section. Panel D) T1-weighted image post-gadolinium, coronal section. A homogeneous enlargement of the pituitary with thickening of the stalk can be seen. The mass shows intense and homogeneous enhancement post-gadolinium. With permission from ref. Prete A, Salvatori R. Hypophysitis. in: Feingold KR¹, Anawalt B², Boyce A³, Chrousos G⁴, Dungan K⁵, Grossman A⁶, Hershman JM⁷, Kaltsas G⁸, Koch C⁹, Kopp P¹⁰, Korbonits M¹¹, McLachlan R¹², Morley JE¹³, New M¹⁴, Perreault L¹⁵, Purnell J¹⁶, Rebar R¹⁷, Singer F¹⁸, Trence DL¹⁹, Vinik A²⁰, Wilson DP²¹, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. 2018 Aug 15. https://www.ncbi.nlm.nih.gov/books/NBK519842/

Figure 5:

Magnetic resonance imaging (MRI) features (T1-weighted images) of hypophysitis. White arrows: pituitary gland; Blue arrows: pituitary stalk. 1: sagittal non-contrast T1-weighted image; 2: sagittal post-contrast; 3: coronal post-contrast. A: Initial MRI of acute hypophysitis in a lady presenting at 6-weeks post-partum with severe headaches, nausea, vomiting, and lactation failure without diabetes insipidus. MRI shows an enlarged pituitary gland along with thickened stalk. The post-contrast images demonstrate a homogeneous uptake within the pituitary gland. B: Follow-up MRI 2 months after initiation of glucocorticoid therapy (prednisone 40 mg per day for 2 months followed by 20 mg per day for 3 months, then gradual taper to 5 mg per day for 6 months, and then maintenance therapy with hydrocortisone for 6 months). There is evidence of reduction in the pituitary enlargement and stalk thickening. All symptoms resolved one month after initiation of therapy. C: Follow-up MRI 17 months after the initial MRI. There is resolution of all the features of acute hypophysitis. The patient continues to be on hormone replacement and is clinically doing well. (Courtesy of Joseph G. Verbalis, Georgetown University Medical Center, Washington, DC)