MACS: mild by definition, challenging by nature

Mild autonomous cortisol secretion (MACS) is the most frequent form of cortisol excess in patients with adrenal incidentalomas. Although it lacks the classical phenotype of overt Cushing’s syndrome, MACS is increasingly recognized as a clinically relevant condition associated with multisystem complications rather than a benign biochemical finding. This narrative review summarizes current evidence on the pathophysiology, clinical manifestations, diagnostic limitations, and management of MACS, with particular focus on cardiometabolic, skeletal, muscular, neuropsychiatric, frailty-related, reproductive, and emerging microbiome-related consequences. Chronic exposure to low-grade cortisol excess is being recognized as a factor associated with hypertension, disorders of glucose metabolism, dyslipidemia, increased cardiovascular risk, metabolic dysfunction-associated steatotic liver disease, skeletal fragility, impaired muscle function, frailty, sleep and circadian disturbances, cognitive and mood alterations, hypogonadism, and possible changes in gut microbiota. The 1 mg overnight dexamethasone suppression test remains the cornerstone of diagnosis, but its interpretation is limited by assay variability, medication interference, comorbidities, and imperfect reflection of long-term tissue glucocorticoid exposure. Emerging approaches, including steroid profiling, hair cortisol/cortisone, salivary cortisone, inflammatory indices, metabolomic tools, and exploratory biomarkers related to microbial metabolites, may improve risk stratification in the future but remain investigational. Management should be individualized. Adrenalectomy may benefit selected patients with unilateral disease and clinically relevant cortisol-related comorbidities, whereas evidence supporting pharmacological therapy remains limited. MACS should be regarded as a heterogeneous multisystem condition requiring structured clinical assessment and individualized management. Prospective studies are needed to define clinically meaningful endpoints, refine diagnostic thresholds, and identify patients most likely to benefit from intervention.