27th May 2025

Diagnosis

The signs and symptoms of Cushing’s syndrome are summarised in Figure 4. 

The first-line investigations are:

• FBC, U&Es and glucose: may show raised WCC, hypokalaemia, and hyperglycaemia respectively.
• 24-hour urinary cortisol: levels will be elevated to >50 mcg/24 hours. This test should not be used in those with renal failure.
• Low-dose dexamethasone suppression test: 1mg dexamethasone is given at 11pm, and plasma cortisol is measured at 8am the following morning, where levels elevated to >50 nmol/L indicate Cushing’s syndrome.
• Midnight cortisol levels: collected between 11pm and 1am, and will be elevated due to loss of normal diurnal variation in cortisol levels.
• Plasma ACTH: suppressed ACTH and high cortisol indicates an ACTH-independent cause such as adrenal adenoma. Elevated ACTH can suggest ACTH-dependent Cushing’s disease.

If plasma ACTH is detectable, there is benefit in the following tests:

• High-dose dexamethasone suppression test: 8mg dexamethasone is given at 11pm. Initial plasma cortisol is measured, and again at 8am the following morning. Suppression of cortisol <50% of baseline, indicates ACTH-dependent Cushing’s disease. High or normal cortisol, with a low ACTH suggests ACTH-independent causes such as adrenal adenoma. Whereas high-normal cortisol with a high ACTH suggests ectopic ACTH secretion.
• Inferior petrosal sinus sampling: blood is sampled peripherally and from the inferior petrosal sinus. If there is an elevated central : peripheral ACTH ratio, this indicates a pituitary cause.
• MRI pituitary gland: should be requested for suspected ACTH-dependent disease to investigate for pituitary adenoma.
• CT chest, abdomen and pelvis: to assess adrenals to identify adrenal adenoma, carcinoma or hyperplasia. It is also warranted to look for tumours that may be a source of ectopic ACTH secretion e.g. small cell lung cancer.