The overwhelming majority of incidentally discovered adrenal tumours are benign adrenocortical tumours. These can be non-functioning (NFAT) or associated with autonomous cortisol secretion on a spectrum ranging from rare clinically overt adrenal Cushing’s syndrome (CS) to much more prevalent mild autonomous cortisol secretion (MACS) without signs of CS. Here I present the characteristics of a large cohort of persons with newly diagnosed benign adrenocortical tumours.

In 1305 prospectively recruited cases, almost every second person with benign adrenocortical tumours was diagnosed with MACS. Persons with MACS had rates of cardiometabolic disease similar to CS, particularly increased prevalence and severity of hypertension and type 2 diabetes.
Urine multi-steroid profiling of these persons revealed a gradual increase in glucocorticoid excretion from NFAT over MACS to CS, whilst androgen excretion decreased. Increased glucocorticoid and 11-oxygenated androgen metabolite excretion predicted clinical outcomes including hypertension, type 2 diabetes, and the presence of bilateral adrenal tumours.

A representative group of 291 persons underwent untargeted serum metabolome profiling. Prototype-based supervised machine learning identified progressive metabolic changes in MACS and CS suggestive of lipotoxicity, dysfunctional lipid β-oxidation, and oxidative stress across the spectrum of autonomous cortisol secretion.

These results show that MACS is a prevalent cardiometabolic risk condition associated with distinct changes in the steroid and untargeted metabolome. Observed changes offer the prospect of risk stratification of affected individuals.