What is the workup for a patient with suspected Cushing's (Cushing's) syndrome?

Workup for Suspected Cushing's Syndrome

Initial Screening: Rule Out Exogenous Glucocorticoids First

Before any testing, exclude exogenous glucocorticoid use (topical, oral, inhaled, or injected steroids), as this is the most common cause of Cushing's syndrome. 1, 2, 3

First-Line Screening Tests

For patients with intermediate to high clinical suspicion, perform 2-3 of the following first-line screening tests to confirm hypercortisolism: 4, 1, 2

Late-Night Salivary Cortisol (LNSC)

• Collect at least 2-3 samples on consecutive days at the patient's usual bedtime (not necessarily midnight, as cortisol nadir is entrained to sleep onset) 4
• Sensitivity: 95%, Specificity: 100% 5, 2
• This is the easiest test for patient compliance and should be the starting point for low clinical suspicion cases 1, 2
• Avoid in night-shift workers due to disrupted circadian rhythm 4
• Multiple sequential collections are particularly useful for detecting cyclic Cushing's syndrome 4

24-Hour Urinary Free Cortisol (UFC)

• Collect 2-3 samples to account for day-to-day variability 4, 2
• Diagnostic cutoff: >193 nmol/24h (>70 μg/m²) 5
• Sensitivity: 89%, Specificity: 100% 5, 2
• Average the results from multiple collections 4

Overnight 1-mg Dexamethasone Suppression Test (DST)

• Give 1 mg dexamethasone between 11 PM and midnight, measure serum cortisol at 8 AM 4
• Normal response: cortisol <1.8 μg/dL (50 nmol/L) 4, 5
• Sensitivity: 95%, Specificity: 80% 5
• Measure dexamethasone levels simultaneously with cortisol to improve interpretability and reduce false positives from malabsorption or drug interactions 4, 2
• Avoid in women taking estrogen-containing oral contraceptives (increases cortisol-binding globulin, causing false positives) 4
• False positives occur with CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort) 4

Confirmation Strategy

• If any screening test is abnormal, repeat 1-2 different screening tests to confirm the diagnosis 1, 2
• If all tests are normal, Cushing's syndrome is unlikely 2

Common Pitfalls: Pseudo-Cushing's States

Consider false positives in these conditions, which can mimic Cushing's syndrome biochemically: 1, 2

• Severe obesity
• Uncontrolled diabetes mellitus
• Depression
• Chronic alcoholism
• Pregnancy
• Polycystic ovary syndrome (PCOS)

Determining the Etiology After Confirming Hypercortisolism

Step 1: Measure Morning Plasma ACTH

Draw ACTH at 8 AM to differentiate ACTH-dependent from ACTH-independent causes: 1, 5, 2

• ACTH >5 ng/L (>1.1 pmol/L): ACTH-dependent Cushing's syndrome (pituitary adenoma or ectopic ACTH secretion) 5, 2
• ACTH low or undetectable: ACTH-independent Cushing's syndrome (adrenal tumor) 2

Step 2A: For ACTH-Dependent Cushing's (Normal/High ACTH)

Obtain pituitary MRI with gadolinium contrast: 1, 5

• Sensitivity: 63%, Specificity: 92% for detecting pituitary adenomas 1, 5
• If adenoma ≥10 mm is visualized, presume Cushing's disease 1

If MRI is negative or shows lesion <6 mm, or if results are equivocal, proceed to bilateral inferior petrosal sinus sampling (BIPSS): 1, 2

• BIPSS is the gold standard for distinguishing pituitary from ectopic ACTH secretion 1
• Diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH/desmopressin stimulation 1
• Sensitivity: 100% 1

CRH stimulation test can support pituitary origin: 5, 2

• ≥20% increase in cortisol from baseline suggests Cushing's disease 2
• Sensitivity: 74-100% 5

Step 2B: For ACTH-Independent Cushing's (Low ACTH)

Obtain adrenal CT or MRI imaging to identify adrenal adenoma, carcinoma, or bilateral hyperplasia 2, 3

Use DST as the preferred screening test in suspected adrenal Cushing's, as LNSC has lower specificity in these patients 4

Special Considerations in Pediatric Patients

In children and adolescents, screen only if weight gain is inexplicable AND combined with either: 5, 2

• Decreased height standard deviation score, OR
• Decreased height velocity

Growth failure sensitively discriminates simple obesity from Cushing's syndrome in prepubertal children but is unreliable in post-pubertal children 5

Refer pediatric cases to multidisciplinary centers with pediatric endocrinology expertise 1

Cyclic Cushing's Syndrome

If initial tests are inconsistent or equivocal, consider cyclic Cushing's syndrome: 2

• Perform multiple sequential LNSC collections over weeks to months 4
• Patients exhibit alternating periods of normal and elevated cortisol secretion 4