Mild autonomous cortisol secretion (MACS, or also mild autonomous cortisol excess, MACE) is a syndrome characterized by a spectrum of hypothalamic- pituitary- adrenal axis abnormalities in a patient with adrenal mass presenting without clinically overt features of Cushing’s syndrome. The diagnosis of MACS represents a challenge due to limitations of the currently used diagnostic tests, differences in the definitions, and unclear clinical implications of MACS. Multiple definitions have been proposed for diagnosis of MACS. These include dexamethasone suppression tests, 24 h urine cortisol measurements, midnight salivary and serum cortisol measurements, morning and afternoon cortisol measurements to assess cortisol secretory circadian rhythm, measurements of adrenocorticotrophic hormone (ACTH) (corticotropin), and dehydroepiandrosterone sulphate (DHEAS). The recent ESE- ENSAT guidelines on the management of adrenal incidentalomas suggested using the 1 mg overnight dexamethasone suppression test as a first step, with ‘possible’ MACS diagnosed when post- dexamethasone serum cortisol is >50 nmol/ L and ‘confirmed’ MACS if cortisol is >140 nmol/ L, in the absence of clinically overt signs of Cushing’s syndrome. Guidelines further suggest that low or suppressed plasma ACTH and DHEAS concentrations can help confirm MACS.
The reported prevalence of MACS among patients with adrenal incidentaloma ranges from 5–50%. This heterogeneity is explained, at least in part, by the different work- up protocols and variable criteria used to define MACS as well as in different inclusion criteria and probably referral bias of the reported series.
MACS very rarely progresses towards overt Cushing syndrome, however, patients with MACS present with increased prevalence of cardiovascular comorbidities, cardiovascular events, osteopaenia, osteoporosis, and fractures, as well as increased mortality. Rates of hypertension, prediabetes, or diabetes mellitus type 2, dyslipidaemia, obesity, and fractures have been reported to be higher than in controls or patients with non- functioning adrenal tumours. Limited data on the effectiveness of adrenalectomy suggests that this leads to improvement of car diovascular risk factors and decrease in fractures in patients with MACS, especially when the degree of cortisol abnormality is higher. However, identifying patients most likely to benefit is still challenging and many patients with MACS are age- advanced and have multiple comorbidities, which increases the potential risk of surgery. At present, approach to patients with MACS remains both a diagnostic and management challenge. Diagnostic criteria for MACS are summarized in Box 1, and the major areas of un certainty are summarized in Box 2.
Box1. Diagnostic criteria for MACS
Box2. Unsolved issues with subclinical Cushing’s syndrome
