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Q1: Define Cushing syndrome vs Cushing disease and classify the causes (2 min)
Cushing syndrome = the clinical and biochemical state of chronic glucocorticoid excess, any cause. Cushing disease = cortisol excess caused specifically by an ACTH-secreting pituitary corticotroph adenoma (the commonest endogenous cause, ~70%).
Classification by source: exogenous (iatrogenic) = commonest overall. Endogenous ACTH-dependent (~80%): Cushing disease (pituitary, 70%), ectopic ACTH/CRH (10% — SCLC, bronchial carcinoid, pancreatic NET). Endogenous ACTH-independent (~20%): adrenal adenoma, adrenocortical carcinoma, bilateral macronodular hyperplasia, primary pigmented nodular adrenocortical disease (Carney complex).
Q2: Describe the screening algorithm (3 min)
Exclude exogenous steroid by history. Then two abnormal first-line tests of three confirm Cushing:
- 1-mg overnight dexamethasone suppression: dex 1 mg PO at 23:00; cortisol at 08:00; fail = cortisol over 50 nmol/L.
- Late-night salivary cortisol (two samples) — measures free cortisol; best for cyclic disease.
- 24-hour urine free cortisol (two collections) — integrates daily output, most specific.
Confounders: oestrogen (OCP) raises cortisol-binding globulin → false positive DST (stop 6 weeks, or use salivary/UFC). CYP3A4 inducers (rifampicin, phenytoin, carbamazepine) accelerate dex → false positive. Inhibitors (ketoconazole, ritonavir) → false negative. Pregnancy, depression, alcoholism, severe obesity → pseudo-Cushing; differentiate with dexamethasone-CRH test or midnight sleep cortisol.
Q3: How do you localise the source? (2 min)
Plasma ACTH at 08:00: over 22 pg/mL (inappropriately normal/high) = ACTH-dependent; under 10 pg/mL = ACTH-independent.
- ACTH-independent: CT adrenal (Hounsfield over 10, washout under 40% suggests carcinoma); 18-FDG PET for staging.
- ACTH-dependent: high-dose DST (over 50% suppression = pituitary), CRH stimulation (cortisol rise over 20% = pituitary), then pituitary MRI. Bilateral inferior petrosal sinus sampling is the gold standard if imaging/equivocal: petrosal-to-peripheral ACTH over 2 basally or over 3 post-CRH = pituitary; lateral gradient over 1.4 lateralises.
Q4: Treatment by subtype and complications (3 min)
- Exogenous: taper steroid; steroid-sparing immunosuppression; sick-day rules.
- Cushing disease: transsphenoidal selective adenomectomy (cure 65-90%; remission = cortisol under 50 nmol/L post-op); stereotactic radiotherapy; bilateral adrenalectomy for refractory (Nelson risk 5-10%).
- Ectopic: resect tumour; chemo/radiotherapy for SCLC; blockade.
- Adrenal adenoma: laparoscopic adrenalectomy (curative). Adrenal carcinoma: open R0 resection + mitotane (1.5 g/day titrated to plasma 14-20 mg/L, with hydrocortisone replacement) ± EDP.
Medical therapy (bridge / unresectable): metapyrapone 250 mg 4-hourly (first-line in pregnancy); ketoconazole 200-400 mg BD (LFTs); osilodrostat 2 mg BD titrate (LINC3 66% response); pasireotide (hyperglycaemia); mifepristone (cannot monitor cortisol); etomidate IV in ICU.
Complications: CV (hypertension, atherosclerosis), VTE (10-fold, give prophylaxis), diabetes, osteoporosis, infection (PJP prophylaxis), psychiatric (suicide), post-op adrenal crisis (give hydrocortisone), Nelson syndrome.
Untreated 5-year mortality up to 50%. All patients need lifelong surveillance for recurrence and HPA recovery.