Cushing's Syndrome
Cortisol excess — diagnosis, causes and management
Cushing's syndrome results from prolonged exposure to excess glucocorticoids, most commonly due to exogenous steroid use or an endogenous cortisol-secreting tumour. It is a complex disorder with significant morbidity if untreated, including cardiovascular disease, osteoporosis, diabetes and immunosuppression.
Causes
The most common cause overall is exogenous steroid therapy (e.g. long-term prednisolone). Endogenous Cushing's is classified as ACTH-dependent (80% of cases) or ACTH-independent (20%). ACTH-dependent causes include Cushing's disease (pituitary ACTH-secreting adenoma — the most common endogenous cause, accounting for 70%) and ectopic ACTH syndrome (from small cell lung cancer, carcinoid tumours). ACTH-independent causes include adrenal adenoma and adrenal carcinoma.
Symptoms and signs
Classic features include central (truncal) obesity with thin limbs, moon face, buffalo hump (supraclavicular fat pad), facial plethora, easy bruising, wide purple striae (>1 cm), proximal muscle weakness, and poor wound healing. Metabolic consequences include hyperglycaemia/diabetes, hypertension, hypokalaemia, osteoporosis (vertebral fractures), and recurrent infections. Psychological effects — depression, anxiety, and cognitive impairment — are common and often underrecognised.
Diagnosis
First-line tests (Endocrine Society guidelines): 24-hour urinary free cortisol (UFC) — elevated on two collections; late-night salivary cortisol (midnight salivary cortisol — elevated on two collections); and 1 mg overnight dexamethasone suppression test (DST) — failure to suppress cortisol to <50 nmol/L confirms hypercortisolism. Once confirmed, measure plasma ACTH: suppressed ACTH (<5 pg/mL) indicates ACTH-independent disease; elevated ACTH (>20 pg/mL) indicates ACTH-dependent disease. MRI pituitary for suspected Cushing's disease; CT chest/abdomen/pelvis for ectopic ACTH; CT/MRI adrenal for adrenal causes.
Management
Cushing's disease: transsphenoidal surgery (TSS) is first-line — remission rate 70–90% in experienced centres. Radiotherapy or second-line surgery for persistent disease. Adrenal adenoma: unilateral adrenalectomy. Ectopic ACTH: treat the underlying tumour. Medical therapy is used to control hypercortisolism pre-operatively or if surgery is not feasible: metyrapone (11β-hydroxylase inhibitor) 250 mg–6g/day in divided doses, or ketoconazole 400–1200 mg/day. Mifepristone (glucocorticoid receptor antagonist) or osilodrostat may be used in specialist settings. Regular evaluation of cortisol levels and clinical response guides dose adjustments. Monitor for adrenal insufficiency post-operatively — hydrocortisone cover is essential. This guidance reflects current Endocrine Society and NICE recommendations.