OC40 - Aldosterone/cortisol ratio as a new marker for diagnosing mild autonomous cortisol secretion (MACS). Investigating the effects of mild hypercortisolism on the renin-angiotensin-aldosterone system

Background/Introduction The overnight 1 mg dexamethasone suppression test (ONDST) is currently the only method to distinguish non-functioning adrenal incidentalomas (NFAI) from those with MACS. Biomarkers for better characterization of MACS are still under investigation. In Cushing’s syndrome, cortisol excess activates renal mineralocorticoid receptors, causing sodium retention and volume expansion, which suppress aldosterone and renin levels. In MACS, with slightly elevated cortisol and urinary free cortisol (UFC), a partial suppression of the renin- angiotensin-aldosterone system (RAAS) is hypothesized. Consequently, ratios such as aldosterone/cortisol, aldosterone/UFC, and cortisol/renin may be reduced in MACS, potentially serving as useful discriminative biomarkers. Purpose To evaluate the diagnostic accuracy of the ratios of aldosterone/cortisol, renin/cortisol, and aldosterone/UFC in differentiating MACS from NFAI. Additionally, to investigate the effects of MACS on the RAAS. Methods A retrospective study was conducted on 149 patients with adrenal incidentalomas: 69 MACS and 80 NFAI, per 2023 ESE-ENSAT guidelines. Blood levels of cortisol(C), ACTH, aldosterone(A), renin(R), UFC, and related ratios (A/C, C/R, A/UFC) were measured. Comparisons were made both overall and after wash-out from interfering therapies affecting the RAAS. Results 69 MACS (mean age 69; F/M 40/29) and 80 NFAI (mean age 61 [49-70]; F/M 36/44) were initially compared without pharmacological wash-out. Aldosterone levels were significantly lower in MACS compared to NFAI (p<0.001), while cortisol levels were higher(p=0.015). Renin showed no significant difference (p=0.179). The A/C ratio was significantly lower in MACS than in NFAI (p<0.001), as was the A/UFC ratio (p<0.001). ROC analysis of the A/C ratio yielded an AUC of 0.736 (95%CI 0.655-0.817, p<0.001), with a cut-off <6.52 for MACS (sensitivity 65.2%, specificity 74.7%). This accuracy improved after wash-out (35 MACS vs 61 NFAI), reaching an AUC of 0.813 (95%CI 0.724-0.903, p<0.001), with a cutoff <6.13 for MACS diagnosis (sensitivity 74.3%, specificity 73.8%). Other ratios showed similar trends, maintaining statistical significance (p<0.001) but lower accuracy. Conclusions This pilot study suggests that the Aldosterone/Cortisol ratio could be a simple, effective biomarker to distinguish MACS from NFAI before the dexamethasone test, especially with proper wash-out. The findings also support that even mild hypercortisolism may suppress the RAAS.