Clinical Heterogeneity of Acquired Idiopathic Isolated Adrenocorticotropic Hormone Deficiency

Abstract

ObjectiveHeterogeneous clinical characteristics are observed in acquired isolated adrenocorticotropic hormone (ACTH) deficiency (IAD); however, its classification remains to be established because of its largely unknown pathophysiology. In IAD, anti-pituitary antibodies have been detected in some patients, although their significance remains unclear. Therefore, this study aimed to classify patients with IAD and to clarify the significance of anti-pituitary antibodies.Design and MethodsWe analyzed 46 consecutive patients with IAD. Serum anti-pituitary antibodies were analyzed via immunofluorescence staining using a mouse pituitary tissue. Principal component and cluster analyses were performed to classify IAD patients based on clinical characteristics and autoantibodies.ResultsImmunofluorescence analysis using the sera revealed that 58% of patients showed anti-corticotroph antibodies and 6% of patients showed anti-follicular stellate cell (FSC) antibodies. Principal component analysis demonstrated that three parameters could explain 70% of the patients. Hierarchical cluster analysis showed three clusters: Groups A and B comprised patients who were positive for anti-corticotroph antibodies, and plasma ACTH levels were extremely low. Groups A and B comprised middle-aged or elderly men and middle-aged women, respectively. Group C comprised patients who were positive for the anti-FSC antibody and elderly men; plasma ACTH levels were relatively high.ConclusionsPatients with IAD were classified into three groups based on clinical characteristics and autoantibodies. The presence of anti-corticotroph antibody suggested severe injury to corticotrophs. This new classification clearly demonstrated the heterogeneity in the pathogenesis of IAD.

Rare clinical problem — isolated ACTH deficiency associated with chronic alcohol abuse

“…Its pathogenesis is unclear; however, most cases are related to autoimmunity against corticotrophs [7], including lymphocytic hypophysitis. In a study of 46 patients with IAD, 58% showed antibodies against corticotropic cells and 6% demonstrated anti-follicular stellate cell (FSC) antibodies [8]. Recently, a case of IAD as a form of paraneoplastic syndrome has been reported [9].…”

“…We tried to establish the aetiology of IAD in our patients. Because many cases of acquired IAD are associated with autoimmune diseases, most frequently thyroid diseases [2,7,8], we excluded the thyroid and adrenal autoimmunity; however, pituitary antibodies were not available to us. Also, the pathogenic role of pituitary autoantibodies is unclear, and they are not specific for autoimmune pituitary diseases [17].…”

“…Positive pituitary antibodies were detected in the sera collected from patients with tumours of the hypothalamo-pituitary region [germinomas (33%), Rathke's cleft cysts (25%), craniopharyngiomas (17%), non-functioning pituitary tumors (13%), GH-secreting pituitary tumours (12%)] [17]. Moreover, autoimmune aetiology of IAD can be confirmed only in 70% cases, even with advanced immunological diagnostics [8].…”

Isolated ACTH deficiency following immunization with the BNT162b2 SARS-CoV-2 vaccine: a case report

“…Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare disease in which ACTH secretion is specifically impaired; it can sometimes cause emergent events due to adrenal crisis. Acquired IAD is frequently accompanied by various autoimmune diseases [ 7 , 8 ]. Furthermore, IAD has recently been focused as immune-related adverse events (irAE) due to the immune checkpoint drugs against PD1/PD-L1 antigen, additionally suggesting immune system disturbance in IAD [ 8 , 9 ].…”

“…Furthermore, IAD has recently been focused as immune-related adverse events (irAE) due to the immune checkpoint drugs against PD1/PD-L1 antigen, additionally suggesting immune system disturbance in IAD [ 8 , 9 ]. Based on these clinical findings with evidence from basic science, disturbance of specific autoimmunity system against corticotrophs is speculated to induce or develop pathogenesis of IAD [ 7 , 8 ]. However, the precise mechanisms behind the development of autoimmunity against corticotrophs remains unknown.…”