Abstract
BACKGROUND: Adrenal incidentalomas (AI) are frequently associated with mild autonomous cortisol excess (MACE). The 1mg-dexamethasone suppression test (1mg-DST) differentiates MACE into MACE-1 (possible MACE; post-Dex cortisol 50-138 nmol/L) and MACE-2 (definitive MACE; post-Dex cortisol >138 nmol/L). MACE patients do not show clinically overt signs of hypercortisolism but are thought to carry a higher metabolic risk than nonfunctioning (NF) AIs. However, large-scale data about the metabolic impact of MACE are lacking. METHODS: We included 1208 patients with benign AIs and 1mg-DST results prospectively recruited as part of the ENSAT EURINE-ACT study. Clinical information and 24-h urines were available for all patients. Results of mass spectrometry-based urinary steroid profiling were compared to 162 healthy controls and 56 patients with overt adrenal Cushing’s syndrome (CUSH), using a sex- and age-adjusted linear regression model. RESULTS: MACE was found in 48% of adrenal incidentaloma patients (MACE-1 37%, MACE-2 11%), predominantly affecting women (NF 64%, MACE-1 67%, MACE-2 77%). MACE patients were significantly older than those with NF (p<0.001). MACE AIs were larger (median 32mm vs. 22mm in NF) and more often bilateral (31% vs. 17% in NF). The presence and grade of MACE were significantly linked to metabolic risk as assessed by prevalence of hypertension (NF 64%, MACE-1 75%, MACE-2 78%), type 2 diabetes (NF 20%, MACE-1 27%, MACE-2 30%), use of lipid-lowering medications (NF 40%, MACE-1 54%, MACE-2 52%), and osteopenia/osteoporosis (NF 37%, MACE-1 50%, MACE-2 56%) (all p<0.01 by Fisher’s exact test). Patients with MACE and type 2 diabetes more frequently required insulin treatment (31% vs. 15% in NF; p<0.01), and those with hypertension more often needed ≥3 medications (42% vs. 35% in NF; p<0.01). Urinary steroid metabolome analysis of MACE urines revealed a profile characterized by decreased androgen metabolites and increased glucocorticoid metabolites, resembling the profile of CUSH patients, with the latter also showing significantly increased mineralocorticoid precursor excretion (corticosterone and 11- deoxycorticosterone metabolites) (all p<0.001 vs. controls). CONCLUSIONS: MACE is highly prevalent in AIs and associated with an increased burden of metabolic co-morbidities. In addition, the similarities between the MACE and CUSH steroid metabolomes suggests that MACE is both a highly relevant clinical and biochemical entity.