Mild autonomous cortisol secretion: Diagnosis

Mild autonomous cortisol secretion (MACS) is the most frequent hormonal alteration identified in patients with adrenal incidentalomas and is characterized by adrenocorticotropic hormone (ACTH)-independent cortisol hypersecretion in the absence of specific clinical features of Cushing syndrome. Growing evidence indicates that even mild degrees of cortisol excess are associated with increased cardiometabolic morbidity, including hypertension, type 2 diabetes mellitus, dyslipidemia, and obesity, as well as skeletal fragility, frailty and excess mortality. Diagnosis relies primarily on biochemical evaluation, with the 1-mg dexamethasone suppression test as the cornerstone, complemented by confirmation of ACTH independence. However, hormonal testing is subject to important limitations. Management strategies include individualized consideration of adrenalectomy, conservative treatment with target treatment of associated comorbidities, or selected use of medical therapies targeting cortisol secretion or action. Despite increasing recognition of the clinical relevance of MACS, optimal risk stratification and identification of patients most likely to benefit from surgery remain challenging, highlighting the need for validated biomarkers and well-designed prospective randomized trials. This chapter reviews current concepts in the pathophysiology and genetic background of MACS, its clinical consequences, diagnostic challenges and evolving therapeutic strategies.