Cushing's disease

Overview

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Cushing's syndrome = cortisol excess from any cause. Cushing's disease = Cushing's syndrome caused specifically by an ACTH-secreting pituitary adenoma (most common endogenous cause, ~70%). Always exclude exogenous glucocorticoids first.

Presentation

•Central obesity - moon face, buffalo hump, truncal fat with thin limbs

•Proximal myopathy - difficulty rising from chair, climbing stairs, arm weakness

•Easy bruising and thin skin - impaired collagen synthesis

•Wide purple striae (>1 cm) - abdomen, flanks, thighs

•Hypertension - mineralocorticoid-like sodium/water retention

•Hyperglycaemia/T2DM - gluconeogenesis + insulin resistance

•Oligomenorrhoea/amenorrhoea - cortisol suppresses GnRH → reduced LH/FSH

•Osteoporosis, depression, hirsutism, acne

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Most discriminating features (vs simple obesity): proximal myopathy, wide purple striae, easy bruising. Moon face and obesity alone have poor discriminatory value.

Investigations

•Stage 1 - confirm cortisol excess (≥2 abnormal tests):

•24-hour urinary free cortisol (UFC) - elevated

•Overnight low-dose dexamethasone suppression test (LDDST) - 1 mg at midnight; cortisol >50 nmol/L at 0800 = failure to suppress = abnormal

•Late-night salivary cortisol - remains elevated (loss of normal diurnal variation)

•Stage 2 - localise source:

•Plasma ACTH - elevated/inappropriately normal = ACTH-dependent (pituitary or ectopic); suppressed = ACTH-independent (adrenal)

•High-dose dexamethasone suppression test (HDDST) - 8 mg overnight; >50% fall in cortisol = pituitary source (Cushing's disease); no suppression = ectopic or adrenal

•Pituitary MRI with gadolinium - identifies adenoma; sensitivity ~60% (negative MRI does not exclude diagnosis)

•Gold standard: bilateral inferior petrosal sinus sampling (BIPSS) - CRH-stimulated; central:peripheral ACTH ratio >3 confirms pituitary source; also lateralises tumour

Complications

•Post-operative adrenal insufficiency - predictable after successful surgery; hydrocortisone replacement required until HPA axis recovers (typically 6-18 months)

•Nelson's syndrome - after bilateral adrenalectomy, loss of cortisol feedback causes pituitary adenoma to enlarge dramatically, secreting high ACTH → hyperpigmentation; managed with pituitary radiotherapy

•Cardiovascular risk (hypertension, dyslipidaemia, hypercoagulability), osteoporosis, and psychiatric features may persist post-remission

Differential diagnosis - interpreting ACTH and dexamethasone suppression

Distinguishing causes of Cushing's syndrome
FeatureCushing's disease (pituitary)Ectopic ACTHAdrenal cause
ACTHElevatedMarkedly elevatedSuppressed
Low-dose DSTNo suppressionNo suppressionNo suppression
High-dose DST>50% suppressionNo suppressionNo suppression
Key cluesMicroadenoma on MRIRapid onset, hypokalaemia, hyperpigmentation; e.g. small cell lung cancerCT adrenal identifies mass

Feature	Cushing's disease (pituitary)	Ectopic ACTH	Adrenal cause
ACTH	Elevated	Markedly elevated	Suppressed
Low-dose DST	No suppression	No suppression	No suppression
High-dose DST	>50% suppression	No suppression	No suppression
Key clues	Microadenoma on MRI	Rapid onset, hypokalaemia, hyperpigmentation; e.g. small cell lung cancer	CT adrenal identifies mass

⚠️
Non-secretory pituitary macroadenoma causes hypopituitarism (low cortisol, low TSH, amenorrhoea) by compression - not cortisol excess. It is the most common cause of hypopituitarism overall.