Key Facts

Cushing syndrome has multiple causes requiring systematic biochemical confirmation and localisation. Untreated cortisol excess significantly increases cardiovascular risk and mortality. Transsphenoidal surgery is first-line for Cushing disease.

Epidemiology

Endogenous Cushing syndrome: incidence ~2-3 per million/year. Cushing disease: F:M 3:1. Ectopic ACTH: M > F (SCLC, carcinoid). Iatrogenic Cushing: very common with chronic steroid use.

Aetiology

ACTH-dependent (80%): Cushing disease (pituitary adenoma — 70%), ectopic ACTH secretion (SCLC, bronchial carcinoid, thymic carcinoid, phaeochromocytoma — 15%). ACTH-independent (20%): adrenal adenoma (~10%), adrenal carcinoma (~5%), bilateral adrenal hyperplasia (BMAH, PPNAD), exogenous steroids.

Pathophysiology

Chronic cortisol excess affects virtually every organ system: metabolic syndrome (insulin resistance, central adiposity, dyslipidaemia), protein catabolism (proximal myopathy, skin thinning, striae, osteoporosis), immune suppression, psychiatric effects (depression, psychosis), mineralocorticoid effects (hypertension, hypokalaemia in ectopic ACTH).

Classic Features

• Central (truncal) obesity: redistribution of fat to trunk, face (moon face), dorsocervical (buffalo hump), supraclavicular fat pads
• Purple striae: >1 cm wide; abdomen, thighs, breasts (NOT simple stretch marks)
• Proximal myopathy: difficulty rising from chair, climbing stairs
• Easy bruising: thin fragile skin
• Facial plethora: reddened round face
• Hirsutism, acne: androgen excess (adrenal)

Metabolic

• Hypertension (~80%), diabetes/impaired glucose tolerance (~50%), dyslipidaemia
• Osteoporosis, pathological fractures (vertebral)

Psychiatric

• Depression (~50-70%), anxiety, insomnia, irritability, psychosis (~10%)
• Cognitive impairment

Other

• Menstrual irregularity, reduced libido, erectile dysfunction
• Recurrent infections (immunosuppression)
• Poor wound healing

Features Suggesting Ectopic ACTH

• Hypokalaemia (prominent mineralocorticoid effect)
• Rapid onset
• Hyperpigmentation (very high ACTH)
• Weight loss (underlying malignancy)

Red Flags

• Severe hypokalaemia + rapid-onset Cushing features → ectopic ACTH (SCLC)
• Adrenal mass + virilisation → adrenal carcinoma
• Children: growth arrest + weight gain → consider Cushing

Step 1: Confirm Cortisol Excess (≥2 Abnormal Tests)

• 24-hour urinary free cortisol (UFC): ×2 (raised — >3× ULN highly suggestive)
• Overnight dexamethasone suppression test (ONDST): 1mg dexamethasone at 11pm → 9am cortisol; failure to suppress (<50 nmol/L) = positive
• Late-night salivary cortisol: ×2 (elevated — loss of normal diurnal variation)

Step 2: Determine ACTH Dependence

• Plasma ACTH (9am): high/normal → ACTH-dependent (pituitary or ectopic); suppressed (<1.1 pmol/L) → ACTH-independent (adrenal)

Step 3: Localise Source

ACTH-dependent:

• Pituitary MRI: microadenoma visible in ~60% of Cushing disease
• High-dose dexamethasone suppression test: 2mg QDS × 48 hours; cortisol suppression >50% suggests pituitary (not ectopic)
• CRH test: ACTH/cortisol rise suggests pituitary origin
• Inferior petrosal sinus sampling (IPSS): gold standard to distinguish pituitary from ectopic; central:peripheral ACTH ratio >2:1 (>3:1 after CRH) = pituitary

ACTH-independent:

• Adrenal CT/MRI: adenoma, carcinoma, bilateral hyperplasia

Other

• U&Es (hypokalaemia), glucose/HbA1c, lipids, DEXA (osteoporosis)
• If ectopic suspected: CT chest/abdomen (SCLC, carcinoid), octreotide scan

Exogenous Cushing

• Taper corticosteroids gradually (do NOT stop abruptly — adrenal crisis risk)
• Use steroid-sparing agents where possible

Cushing Disease (Pituitary)

• First-line: transsphenoidal pituitary surgery (TSS); cure rate ~65-90% for microadenomas
• Second-line: repeat surgery, pituitary radiotherapy (conventional or stereotactic)
• Medical: metyrapone 250mg-6g/day (11β-hydroxylase inhibitor), ketoconazole 200-1200mg/day (steroidogenesis inhibitor), osilodrostat (11β-hydroxylase inhibitor — NICE), pasireotide (somatostatin analogue — reduces ACTH)
• Bilateral adrenalectomy: last resort; cures hypercortisolism but requires lifelong replacement; risk of Nelson syndrome (pituitary tumour growth → hyperpigmentation)

Adrenal Tumour

• Adrenalectomy: laparoscopic for adenoma; open for carcinoma
• Adrenal carcinoma: mitotane ± chemotherapy (EDP-mitotane)

Ectopic ACTH

• Treat underlying tumour (surgery, chemotherapy)
• Medical cortisol control: metyrapone, ketoconazole
• Bilateral adrenalectomy if source not resectable

Perioperative

• Hydrocortisone replacement post-operatively (adrenal suppression from chronic cortisol excess; may take 6-18 months for HPA axis recovery)
• DEXA scan and treat osteoporosis
• Cardiovascular risk factor management

Referral Criteria

• Endocrinology: all suspected Cushing syndrome
• Neurosurgery: Cushing disease
• Endocrine/adrenal surgery: adrenal tumours
• Oncology: ectopic ACTH

Untreated Cushing syndrome: significantly increased mortality (cardiovascular, infection). 5-year mortality ~50% without treatment. With successful treatment: mortality normalises over years but cardiovascular risk remains elevated. Cushing disease: ~65-90% cure after first TSS; ~25% recurrence at 10 years. Adrenal adenoma: excellent prognosis after adrenalectomy. Adrenal carcinoma: poor prognosis (5-year survival ~35-50%). Ectopic ACTH: depends on underlying tumour.

Cushing Syndrome — Diagnostic Algorithm

Cushing Syndrome vs Cushing Disease