ACTH independent Cushing's syndrome: Diagnosis and etiology

Cushing´s syndrome (CS) is a heterogeneous disorder characterized by chronic exposure to cortisol excess, leading to significant metabolic and cardiovascular complications. Timely diagnosis is crucial to reduce morbidity and mortality in these patients. Approximately 20 percent of endogenous CS cases are adrenocorticotropic hormone (ACTH)-independent and arise from primary adrenal disease. This review focuses on the diagnostic work-up and etiological spectrum of ACTH-independent CS. ACTH-independent CS most frequently results from unilateral adrenal adenomas, whereas adrenocortical carcinomas represent a less common but aggressive cause. Bilateral forms include primary pigmented nodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia, which present micronodular or macronodular adrenal enlargement, respectively, often with subtle or cyclic cortisol excess and characteristic imaging patterns. Recognizing these entities and integrating hormonal data with detailed radiological findings is essential for accurate etiological diagnosis and appropriate therapeutic planning in ACTH-independent CS​​. Radiological assessment with adrenal computed tomography, complemented by magnetic resonance imaging when needed, is crucial to distinguish unilateral from bilateral disease, characterize lesion morphology, and suggest specific etiologies, using unenhanced attenuation values in Hounsfield units to differentiate lipid-rich adenomas from non-adenomatous or potentially malignant lesions.