Hypothalamic–pituitary axis disorders - Cushing syndrome
Description
- Cushing syndrome = chronic glucocorticoid excess, any cause
- Cushing disease = pituitary corticotroph adenoma specifically
- Nelson syndrome = corticotroph adenoma enlargement + inc ACTH pigmentation after bilateral adrenalectomy
Epidemiology
- Exogenous glucocorticoid is by far the commonest cause overall
- Endogenous 2-3 per million per year
- Cushing disease: F>M ~3:1, peak 20-40y
- Ectopic ACTH: M>F, older
- Children: adrenocortical tumour commonest in infants; consider McCune-Albright
Aetiopathogenesis
ACTH-dependent (~80% of endogenous)
- Pituitary corticotroph adenoma (Cushing disease) ~70% of all endogenous
- Almost always benign microadenoma <10 mm
- *30-40% invisible on MRI* - a normal pituitary MRI does not exclude it
- Ectopic ACTH ~10% - SCLC, bronchial/thymic/pancreatic NET, medullary thyroid ca, phaeo
- Rarely ectopic CRH
ACTH-independent (~20%)
- Adrenal adenoma, adrenal carcinoma (androgen co-secretion, rapid onset, virilisation)
- Bilateral macronodular hyperplasia, PPNAD (Carney complex)
Diagnosis
Clinical - which features actually discriminate
- Discriminating (catabolic): proximal myopathy, thin skin, easy bruising, wide purple striae >1 cm, unexplained osteoporosis, facial plethora
- Non-discriminating: central obesity, hypertension, diabetes, depression, hirsutism
- Simple obesity: tall and growing normally. Cushing in a child: short with weight gain**
- Hyperpigmentation -> ACTH-dependent, usually ectopic
Step 1 - is there hypercortisolism? (any 2 abnormal)
| Test | Sens | Spec |
|---|---|---|
| Late-night salivary cortisol x2 | 90-100% | 93-100% |
| 1 mg overnight DST (<50 nmol/L = normal) | ~95% | ~80% |
| 24h urinary free cortisol x2 | 80-90% | |
| 48h low-dose (2 mg) DST | ~95% |
- Exclude first: exogenous steroid (incl. inhaled, topical, joint injection), pseudo-Cushing (alcohol, severe depression, poorly controlled diabetes), and anything raising CBG (oestrogen, pregnancy)
- Rapid CYP3A4 inducers (phenytoin, carbamazepine) give false-positive DST - measure the dexamethasone level
Step 2 - plasma ACTH
- Suppressed (<2 pmol/L) -> adrenal: CT adrenals
- Normal or high -> ACTH-dependent: pituitary MRI
Step 3 - source of ACTH
- Inferior petrosal sinus sampling is the reference standard
- Central:peripheral ACTH >=2:1 basal or >=3:1 after CRH/desmopressin -> pituitary
- High-dose (8 mg) DST: suppression favours pituitary - low accuracy, largely superseded by IPSS
- CT chest/abdomen +/- Ga-68 DOTATATE PET if ectopic suspected
Cyclical disease
- Repeat testing over time if suspicion is high and screening negative
Management
Cushing disease
- Transsphenoidal selective adenomectomy - first line
- Initial remission 75-90% (microadenoma), lower for macroadenoma
- Post-op cortisol <50 nmol/L predicts remission; recurrence 15-25% at 10 years
- Expect secondary adrenal insufficiency - replace hydrocortisone and wean over months
- Persistent/recurrent:
- Repeat TSS (50-70%)
- Stereotactic radiotherapy + interim medical therapy (years to work; hypopituitarism)
- Bilateral adrenalectomy - immediate and definitive; lifelong replacement + Nelson risk
- Pituitary-directed medical therapy: pasireotide, cabergoline (remission 20-40%)
- Pasireotide causes hyperglycaemia in most - a near-obligate side effect
Adrenal / ectopic
- Resect the lesion. Adrenocortical carcinoma: adrenalectomy +/- mitotane
- Occult ectopic source: control cortisol medically and re-image periodically
Medical control of cortisol - any cause
- Indications: pre-op optimisation, unresectable/occult disease, awaiting radiotherapy effect, acute severe hypercortisolism
- Steroidogenesis inhibitors: osilodrostat, metyrapone, ketoconazole (hepatotoxic, needs gastric acid), etomidate for crisis
- Osilodrostat/metyrapone -> precursor accumulation -> hypokalaemia, hypertension, hirsutism
- Mifepristone - GR antagonist; used for hyperglycaemia; cortisol levels become uninterpretable
- Titrate to a target cortisol - block-and-replace if oscillating
Always, in severe hypercortisolism
- PJP prophylaxis, VTE prophylaxis, K+ repletion, glycaemic and BP control, bone protection
Associations
- Ectopic ACTH: SCLC, carcinoid, medullary thyroid carcinoma, phaeochromocytoma
- MEN1, Carney complex (PPNAD), McCune-Albright, familial isolated pituitary adenoma
- Metabolic syndrome, T2DM, hypertension, dyslipidaemia
- Depression, psychosis, cognitive impairment
- Osteoporosis, avascular necrosis
Natural history & complications
- Untreated: 5-year mortality ~50%
- Cardiovascular disease is the leading cause of death - hypertension, diabetes, dyslipidaemia, adverse cardiac remodelling
- Hypercoagulable + hypofibrinolytic -> VTE risk persists into the post-operative period
- Immunosuppression -> bacterial, fungal, PJP, reactivation infection
After cure
- Glucocorticoid withdrawal syndrome - arthralgia, fatigue, mood disturbance despite adequate replacement
- HPA recovery takes 6-18 months
- Persistent excess risk: osteoporosis, cognitive deficit, obesity, psychiatric morbidity, mortality
- Rapid cortisol lowering can unmask autoimmune disease and central hypothyroidism
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