Unveiling the Etiopathogenic Spectrum of Hypophysitis: A Narrative Review

Abstract

Hypophysitis, a rare inflammatory disorder of the pituitary gland, has seen an uptick in reported cases in recent years. Our objective is to summarize the most recent research on the etiopathogenesis, molecular mechanisms, and genetics of both primary and secondary hypophysitis. Primary autoimmune hypophysitis (PAH): During the acute phase of the disease, the pituitary gland in enlarged due to the infiltration of T and B lymphocytes. The chronic phase is characterized by progressive and irreversible pituitary atrophy. APA may play a role in the management, diagnosis, and prognosis of PAH. Specific autoantibodies such as anti-GH, anti-PIT-1, and anti-T-PIT have been found in patients with hypophysitis and hypopituitarism. A recent study suggested that a mechanism of escaping clonal deletion and mounting an immune response against self antigens can explain the unusual nature of the immune response observed in PAH patients. A cytokine array shows the presence of gamma-interferon and interleukin-17. Patients carrying mutations in the PIT1 or PROP1 genes may present PAH. Individuals carrying the HLA DQ8 haplotype are four times more likely to develop PAH. Immune checkpoint inhibitors induce hypophysitis (IIHs): IIHs is an increasingly frequent toxicity of in patients on treatment with inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1). ICIs inhibit the CTLA-4 pathway, leading to overactivation of T lymphocytes. The binding of PD-1/PD-L1 suppresses the activity of T cells, promotes the conversion of T-helpers into T-regulatory cells, and activates pro-survival signaling pathways in cancer cells. Cytokines play a crucial role in IIHs. B-cell infiltration has been observed in IIHs, suggesting that antibody-mediated pituitary injury may contribute. Genetic polymorphisms of CTLA-4 and PD-1 genes can increase the risk of IIHs. HLA alleles may also be involved in the onset of IIHs; this HLA association presents a possible alternative mechanistic hypothesis. IIHs may also be linked to a paraneoplastic syndrome triggered by ectopic expression of pituitary specific antigens. SARS-CoV-2-related hypophysitis: Recently, the literature has reported occurrences of hypophysitis associated with the SARS-CoV-2 virus; long COVID-19 may also present as infundibulo-neuro-hypophysitis. The virus enters the central nervous system because of its distinct interaction with angiotensin-converting enzyme receptors via spike proteins binding the capillary endothelium, and it directly damages the pituitary cells. The effect of SARS-CoV-2 can occur indirectly through inflammation and the release of cytokines. The exact mechanism remains ambiguous. The available data on endocrine complications associated with the SARS-CoV-2 vaccine are scant. Nonetheless, isolated cases of hypophysitis have been documented. Treatment of hypophysitis: Glucocorticoids are the cornerstone in managing primary hypophysitis, given their targeted action on inflammation. A better understanding of the etiopathogenesis and molecular mechanism of hypophysitis can lead to more effective and personalized treatment strategies.

Keywords: autoimmune; hypophysitis; immune checkpoint inhibitors.

Figure 1

Etiopathogenesis of primary autoimmune hypophysitis and IgG4-related hypophysitis. (CD: cluster of differentiation; Th: T helper cells; APA: anti-pituitary antibodies; AHA: anti-hypothalamus antibodies; ACTH: adrenocorticotropic hormone; Pit1: pituitary transcription factor 1; IL17: interleukin 17; IFN-γ: interferon-gamma; POMC: pro-opiomelanocortin; POMC: pro-opiomelanocortin; PGSF: pituitary gland specific factor; HPL: anti-chorionic somatomammotropin hormone; PC: anti-prohormone convertase; Rph3A: rabphilin-3A; IgG4: immunoglobulin G4; GH: growth hormone).

Figure 2

Etiopathogenesis of IIH (CTLA4: cytotoxic T-lymphocyte-associated protein 4; PD1: programmed cell death protein-1; PDL1: programmed death-ligand 1; ACTH: adrenocorticotropic hormone; Pit1: pituitary transcription factor 1).

Figure 3

Etiopathogenesis of SARS-CoV-2 and vaccine-related hypophysitis (ACE2: angiotensin-converting enzyme 2; IL-6: interleukin 6; TLR: tall cell receptor; INF-I: interferon I).