Subclinical Cushing Syndrome

Subclinical Cushing syndrome (mild autonomous cortisol secretion) is cortisol excess from an adrenal lesion without the specific features of overt Cushing syndrome. It is found in adrenal incidentaloma workup.

Autonomous cortisol secretion is found in roughly 5 to 30% of adrenal incidentalomas, depending on the cut off used, and is more common in older women. Bilateral lesions are frequent.

It is associated with hypertension, type 2 diabetes, dyslipidaemia, central obesity, vertebral fracture and cardiovascular events. Progression to overt Cushing syndrome is uncommon.

Pathophysiology.

Autonomous adenoma cortisol secretion is not suppressed by dexamethasone, and ACTH is low, causing atrophy of the contralateral gland. The cortisol excess is small but sustained.

Cortisol excess may be only a marker, and the link to complications is not fully proven.

• Usually no specific features. Hypertension, diabetes, obesity, osteoporosis and vertebral fracture.
• Ask for easy bruising, proximal weakness, striae and plethora, which favour overt disease.

Red flags.

• Bilateral masses or a mass over 4 cm (look for carcinoma or phaeochromocytoma).
• New striae, myopathy or hypokalaemia (progression).

• 1 mg overnight dexamethasone suppression test: cortisol under 50 nmol/L (1.8 micrograms/dL) excludes autonomous secretion, 50 to 138 nmol/L (1.8 to 5.0 micrograms/dL) indicates mild autonomous cortisol secretion, and over 138 nmol/L (5.0 micrograms/dL) indicates autonomous cortisol secretion.
• ACTH morning (under 10 ng/L, 2 pmol/L, suggests ACTH-independent disease), dehydroepiandrosterone sulphate (low), and late night salivary cortisol or urinary free cortisol. Dexamethasone concentration can be checked in discordant results.
• Imaging: unenhanced CT (under 10 Hounsfield units suggests a benign lipid rich adenoma) and size. Plasma or urinary metanephrines unless the lesion is under 10 Hounsfield units. Aldosterone to renin ratio if hypertension or low potassium.
• Screen for complications: blood pressure, glucose, lipids and bone density.

Differential diagnosis.

• Overt Cushing syndrome (ACTH dependent or independent).
• Pseudo-Cushing states, drug interference with dexamethasone (carbamazepine, rifampicin, oestrogens), and non-functioning adenoma.
• Adrenal carcinoma and phaeochromocytoma.

• Treat hypertension, diabetes, dyslipidaemia and osteoporosis to usual targets.
• Consider unilateral adrenalectomy in a younger patient with progressive or severe comorbidity that may be attributed to cortisol, with the benefit weighed against surgical risk. Bilateral disease needs individual decisions (unilateral resection of the larger gland, or medical therapy).
• Cover surgery with hydrocortisone 100 mg intravenously at induction, then 200 mg over 24 hours, then taper. Replace after surgery until the axis recovers, because contralateral suppression is expected.
• Medical control in unfit patients: metyrapone 250 mg three times daily or osilodrostat 2 mg twice daily, with dose titration to cortisol; ketoconazole is an alternative with liver monitoring.
• No further imaging is needed for a homogeneous lesion under 4 cm with an unenhanced density under 10 Hounsfield units.

Special groups. Older adults and those with limited life expectancy are managed conservatively.

Monitoring. Yearly clinical review and comorbidity control, repeat dexamethasone test at 1 to 2 years, and repeat imaging if the lesion is indeterminate (at 6 to 12 months). Bone density as indicated.

Referral and escalation. Endocrinology; adrenal surgery review for patients being considered for resection or with an indeterminate or large lesion.