Background: Adrenal incidentalomas (AI) are found in approximately 5% of the adult population. Most AIs are benign; however, small-scale studies have indicated that 2050% of patients harbouring a benign AI show biochemical evidence of mild autonomous cortisol excess (MACE), previously termed subclinical Cushings syndrome. MACE is differentiated into MACE-1 (serum cortisol after overnight suppression with 1 mg dexamethasone (1 mg-DST) 50140 nmol/l) and MACE-2 (1 mg-DST serum cortisol >140 nmol/l). MACE patients do not show clinically overt signs of Cushings, but previous series have suggested an increased risk of metabolic disease. However, large-scale data about the metabolic impact of MACE are lacking.
Methods: We included 1201 AI patients with benign adrenocortical adenoma and 1mg-DST results from the prospective multi-centre EURINE-ACT study. All patients underwent detailed clinical phenotyping and provided a 24 h urine sample. Results of mass spectrometry-based urinary steroid profiling were compared to 162 healthy controls and 56 patients with clinically overt adrenal Cushings syndrome, using a linear regression model adjusting for sex and age.
Results: MACE was found in 48% of patients (MACE-1 37%, MACE-2 11%), while 52% had non-functioning (NF) AIs. MACE was more frequent in women (NF: 64%, MACE-1: 67%; MACE-2: 77%). MACE AIs had a larger tumour diameter (median 32 mm vs 22 mm in NF) and were more often bilateral (31% vs 17% in NF). Metabolic disease burden increased with severity of cortisol excess (hypertension: NF 64%, MACE-1 67%, MACE-2 71%; type 2 diabetes: NF 18%, MACE-1 21%, MACE-2 25%). Urinary steroid profiling revealed significantly lower androgen and androgen precursor excretion and increased cortisol metabolite excretion in both MACE and Cushings; both groups also showed significantly decreased 5a-reductase activity (all P<0.001).
Conclusions: MACE is highly prevalent in AIs and carries an increased metabolic disease burden. The MACE steroid metabolome signature is highly similar to Cushings, including reduced glucocorticoid inactivation via 5a-reductase.