Cushing's Syndrome

Cushing's syndrome describes a constellation of symptoms and signs resulting from chronic glucocorticoid excess. It is important to distinguish 'Cushing's Syndrome' (the umbrella term) from 'Cushing's Disease' (specifically a pituitary adenoma secreting ACTH). The most common cause overall is iatrogenic, due to long-term high-dose corticosteroid therapy (e.g., for asthma or rheumatoid arthritis). Endogenous causes are divided into ACTH-dependent (80%) and ACTH-independent (20%). ACTH-dependent causes include Cushing's Disease (pituitary) and ectopic ACTH secretion (most commonly from Small Cell Lung Cancer). ACTH-independent causes include adrenal adenomas and carcinomas. Excess cortisol has widespread metabolic effects, including gluconeogenesis (leading to diabetes), protein catabolism (leading to skin thinning and muscle wasting), and mineralocorticoid activity (leading to hypertension and hypokalaemia). Diagnosis is complex and involves a two-stage process: first, confirming hypercortisolism (e.g., overnight dexamethasone suppression test or 24h urinary cortisol), and second, localising the source using ACTH levels and imaging.

Cortisol is a steroid hormone produced by the zona fasciculata of the adrenal cortex under the control of ACTH. In health, the Hypothalamic-Pituitary-Adrenal (HPA) axis is regulated by negative feedback: high cortisol inhibits CRH and ACTH. In Cushing's syndrome, this feedback is lost. Excessive cortisol binds to glucocorticoid receptors, leading to skeletal muscle atrophy (via myostatin induction), skin thinning (inhibition of collagen synthesis), and hyperglycaemia (stimulation of gluconeogenesis). At high levels, cortisol also binds to mineralocorticoid receptors in the kidney, which causes sodium retention, volume expansion (hypertension), and potassium excretion (hypokalaemia). This is particularly prominent in ectopic ACTH production because the extremely high levels of cortisol overwhelm the 11β-HSD2 enzyme that normally protects the mineralocorticoid receptor.

Physical features: Central obesity with 'spindly' limbs, 'Moon face', 'Buffalo hump' (interscapular fat pad), and supraclavicular fat pads. Integumentary: Thin skin, easy bruising, and wide (usually >1cm), purple abdominal striae. Musculoskeletal: Proximal myopathy and osteoporosis (causing vertebral fractures). Cardiovascular/Metabolic: Hypertension, impaired glucose tolerance or T2DM. Psychological: Depression, insomnia, or 'steroid psychosis'. In ACTH-dependent causes, there may be hyperpigmentation (due to ACTH cross-reactivity with MSH receptors) and virilisation (hirsutism and acne) due to concurrent androgen excess.

Step 1: Confirm hypercortisolism. Options: 1. Overnight Dexamethasone Suppression Test (ODST) – failure to suppress cortisol to <50nmol/L. 2. 24-hour urinary free cortisol. 3. Late-night salivary cortisol. Step 2: Determine cause. Plasma ACTH. If ACTH is suppressed (<5pg/mL), it is ACTH-independent (look at adrenals via CT). If ACTH is high or normal, it is ACTH-dependent. Step 3: Localise ACTH source. High-dose (8mg) dexamethasone suppression test (Cushing's Disease suppresses; Ectopic ACTH does not). MRI Pituitary or CT Chest/Abdomen/Pelvis. Gold standard for pituitary vs. ectopic is Inferior Petrosal Sinus Sampling (IPSS).

Surgical: 1. Cushing's Disease: Trans-sphenoidal resection of the pituitary adenoma. 2. Adrenal tumours: Adrenalectomy (usually laparoscopic). 3. Ectopic ACTH: Treatment of the underlying malignancy (e.g., lung resection). Medical: Used pre-operatively or when surgery is not possible. Ketoconazole or Metyrapone (inhibits cortisol synthesis). Mitotane is used for adrenal carcinoma. Radiotherapy: Pituitary radiotherapy if surgery fails. Management of complications: Treat hypertension, osteoporosis (bisphosphonates), and diabetes.