Autonomous Cortisol Secretion

Autonomous cortisol secretion is cortisol production by an adrenal lesion that is not under normal ACTH control, without the typical features of Cushing syndrome. It replaces the older term subclinical Cushing syndrome.

It is found in about 20 to 50% of adrenal incidentalomas, and in about 1 to 2% of middle aged and older adults, with a higher frequency in women. It is mostly from unilateral adenoma and in some from bilateral nodular disease.

It is linked to hypertension, type 2 diabetes, obesity, dyslipidaemia, osteoporosis with vertebral fractures, cardiovascular events and higher mortality.

Pathophysiology.

The adenoma secretes cortisol independent of ACTH, causing mild chronic excess. ACTH is suppressed, which leads to atrophy of the contralateral adrenal cortex and low DHEAS.

Causes include variants affecting cyclic AMP signalling (PRKACA) and, in bilateral disease, aberrant receptors or ARMC5 variants.

• Usually no classic features (no striae, bruising or proximal myopathy).
• Hypertension, central obesity, diabetes or impaired glucose tolerance, dyslipidaemia and vertebral fractures.
• Adrenal mass found on imaging.

Red flags.

• Developing Cushingoid features, hypokalaemia or marked hypertension.
• Large mass (over 4 cm) or irregular, heterogeneous lesion (over 20 Hounsfield units on unenhanced CT) suggesting malignancy.

• Overnight 1 mg dexamethasone suppression test: cortisol over 50 nmol/L (1.8 micrograms/dL) is unsuppressed. Cortisol of 50 to 138 nmol/L indicates possible autonomous cortisol secretion, and over 138 nmol/L (5 micrograms/dL) indicates autonomous secretion.
• Confirm with low ACTH (under 10 ng/L, 2 pmol/L), low DHEAS, and raised late night salivary cortisol or urinary free cortisol if borderline.
• Exclude phaeochromocytoma (plasma metanephrines) and, if hypertensive or hypokalaemic, primary aldosteronism (aldosterone to renin ratio). Check dexamethasone level where results are doubtful.
• Adrenal CT: lesion size, density (under 10 Hounsfield units suggests a benign lipid rich adenoma) and washout. Screen for hypertension, diabetes, dyslipidaemia and vertebral fractures.

Differential diagnosis.

• Overt Cushing syndrome and Cushing disease.
• False positive dexamethasone suppression (oestrogen, enzyme inducing drugs, obesity, depression, alcohol) and pseudo-Cushing states.
• Adrenocortical carcinoma, phaeochromocytoma, aldosterone producing adenoma and metastasis.

• Treat comorbidities: blood pressure, glucose, lipids and osteoporosis (calcium, vitamin D and alendronate 70 mg weekly where indicated).
• Unilateral adrenalectomy for patients with cortisol over 138 nmol/L after dexamethasone and comorbidities that are worsening or hard to treat, particularly under 65 to 75 years. Surgery improves blood pressure, glucose and lipids in many patients.
• Conservative management with yearly review is reasonable for older, frail patients or mild biochemistry (cortisol 50 to 138 nmol/L) without comorbidity.
• Perioperative cover: hydrocortisone 100 mg intravenously at induction, then 200 mg over 24 hours, then replace (15 to 25 mg daily in two or three divided doses) until the axis recovers, tested by a morning cortisol and short tetracosactide test. Adrenal insufficiency after surgery can last for 6 to 24 months.
• Bilateral disease: consider unilateral adrenalectomy of the dominant side in selected patients, or medical therapy (metyrapone 250 mg three times daily up to 6 g daily, osilodrostat 2 mg twice daily).

Special groups. Pregnancy: adrenal surgery is deferred where possible. Older adults: balance surgical risk against a benefit that accrues slowly.

Monitoring. Yearly review of blood pressure, glucose, lipids and bone health. Repeat the dexamethasone test every 1 to 2 years if untreated, and after surgery, cortisol at 24 hours and 6 weeks.

Referral and escalation. Endocrinology and endocrine surgery team; urgent review for suspected carcinoma.