Cushing Syndrome Workup
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Direct answer
At least two concordant screening tests are needed before anyone chases the source of cortisol excess — choose from the 1 mg overnight dexamethasone suppression test (cortisol of 1.8 μg/dL or more at 8 a.m. is abnormal), two late-night salivary cortisols, or two 24-hour urinary free cortisol collections. Once hypercortisolism is proven, plasma ACTH stratifies the disease: below 10 pg/mL means adrenal autonomy and an adrenal CT; 20 pg/mL or more means ACTH-dependent disease, of which Cushing disease (a pituitary corticotroph adenoma) causes roughly 70–80 per cent and ectopic ACTH secretion most of the rest. Pituitary MRI with a clear adenoma and concordant dynamic testing permits transsphenoidal surgery without further steps; discordant or negative imaging moves to inferior petrosal sinus sampling — a central-to-peripheral ACTH gradient of 2 or more at baseline, or 3 or more after desmopressin, confirms Cushing disease. And before all of it: ask about steroids — in India, topical combination creams, oral "joint" medicines and depot injections make exogenous Cushing the commonest form by far.
What you must remember
- Screening trio, two needed: overnight 1 mg DST (cut-off 1.8 μg/dL), late-night salivary cortisol on two separate nights, and 24-hour urinary free cortisol twice — concordance protects against the false positives of obesity, depression and alcohol (pseudo-Cushing states).
- Physiology behind the tests: cortisol's normal circadian nadir at midnight is lost earliest in Cushing — that is what the salivary test exploits; the overnight DST probes glucocorticoid feedback.
- ACTH interpretation: under 10 pg/mL — ACTH-independent (adrenal CT next); over 20 — ACTH-dependent; 10–20 — repeat, since the zone is unreliable.
- ACTH-dependent split: Cushing disease 70–80 per cent, ectopic ACTH (small cell lung, bronchial or thymic carcinoid, medullary thyroid carcinoma, phaeochromocytoma) 15–20 per cent, rare ectopic CRH.
- IPSS numbers: basal central:peripheral ACTH gradient at least 2, or at least 3 post-desmopressin, with prolactin normalisation used for failed cannulation — sensitivity above 90 per cent for Cushing disease; every IPSS is paired because ectopic tumours occasionally grade falsely positive on basal gradients alone.
- Caveat armoury: renal failure invalidates urinary free cortisol; midnight salivary sampling fails shift workers; oestrogen (oral contraceptive) raises cortisol-binding globulin and falsely elevates total cortisol — stop it or measure free fractions; cyclic Cushing secretes in waves and needs repeated testing.
- Adrenal CT reading: lipid-rich adenoma under 10 Hounsfield units on non-contrast; indeterminate nodules need washout chemistry; large heterogeneous masses raise adrenocortical carcinoma concern.
- Post-cure reality: all treated Cushing becomes adrenal-insufficient until the axis recovers — glucocorticoid replacement and education for months to years, with taper guided by morning cortisol.
Screening to localisation in one patient
A 42-year-old woman with centripetal obesity, wide violaceous striae, proximal myopathy and new hypertension and diabetes. Step one — exclude exogenous steroids: none (asked twice, including about skin creams). Step two — screen: 1 mg DST shows 8 a.m. cortisol 9.4 μg/dL; late-night salivary cortisol elevated on both nights; the diagnosis of endogenous hypercortisolism stands. Step three — ACTH: 65 pg/mL, so ACTH-dependent. Step four — MRI pituitary: a 4 mm right-sided microadenoma; consistent so far, but incidental microadenomas exist in a tenth of the population. Step five — confirm the gradient: desmopressin-stimulated testing (ACTH rise favouring corticotroph tumour) concordant; proceed to IPSS in most units for a microadenoma of this size or where any discordance exists, and here the central:peripheral gradient is 4.6 — Cushing disease. Step six — transsphenoidal selective adenomectomy, morning cortisol under 2 μg/dL the day after (biochemical cure), hydrocortisone replacement begun with sick-day rules. Had the MRI been negative, the same pathway runs through IPSS and, if the gradient was peripheral, a CT chest for the ectopic source. The examineable discipline: never image before biochemistry, never localise before ACTH, and never declare cure without postoperative hypocortisolism.
Where students slip
The classic error is diagnosing Cushing on one screening test in an obese, depressed or alcoholic patient — pseudo-Cushing disease states produce mild abnormalities in all three screens, and two concordant positives are the entry price. The second slip is CT-scanning the adrenals of an ACTH-dependent patient and "treating" the bilateral hyperplasia found — the adrenals are victims, not culprits. The third is forgetting the high-dose dexamethasone test's fall from grace: modern practice replaces it with IPSS. Indian viva additions: asking about topical steroid creams (fairness and dermatology combinations) before labelling endogenous disease, and remembering tuberculosis of the adrenal in the differential of adrenal masses — a local twist examiners expect.
Frequently asked questions
Which tests screen for Cushing syndrome, and how many are needed?
The 1 mg overnight dexamethasone suppression test, late-night salivary cortisol and 24-hour urinary free cortisol — at least two concordant abnormal results are required before proceeding.
How does plasma ACTH guide the workup?
Below about 10 pg/mL the disease is ACTH-independent (image the adrenals); 20 pg/mL or more is ACTH-dependent (pituitary MRI, then IPSS if discordant); values between warrant repetition.
What gradient on inferior petrosal sinus sampling confirms Cushing disease?
A central-to-peripheral ACTH gradient of at least 2 at baseline or at least 3 after desmopressin stimulation, from correctly catheterised sinuses.
Why has the high-dose dexamethasone test lost favour?
Its discrimination between Cushing disease and ectopic ACTH is imperfect; IPSS provides far better diagnostic performance, so dynamic suppression testing now plays only a supporting role.
What defines biochemical cure after transsphenoidal surgery?
Postoperative morning cortisol below about 2 μg/dL (5 μg/dL by some protocols) with clinical recovery — indicating remnant corticotroph suppression — followed by glucocorticoid replacement until the axis recovers.