What are the diagnostic steps and treatment options for Cushing's syndrome?

Diagnosis of Cushing's Syndrome

Exclude Exogenous Glucocorticoid Use First

Before any biochemical testing, thoroughly review all glucocorticoid exposure including oral medications, injections, inhalers, topical preparations, and supplements, as failure to exclude iatrogenic Cushing's syndrome leads to unnecessary testing without patient benefit 1.

Initial Screening Tests for Hypercortisolism

Test Selection Based on Clinical Suspicion

For patients with intermediate to high clinical suspicion, perform 2-3 first-line screening tests simultaneously: late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), and overnight 1 mg dexamethasone suppression test (DST) 2, 3, 1.

• For low clinical suspicion, start with LNSC alone as it offers easier patient compliance 1
• If any screening test is abnormal, repeat 1-2 screening tests to confirm hypercortisolism before proceeding 3, 1
• If all tests are normal, Cushing's syndrome is unlikely unless clinical suspicion remains very high 3

Late-Night Salivary Cortisol (LNSC)

• Collect at least 2-3 samples on consecutive days at the patient's usual bedtime (typically 11 PM-midnight), not strictly at midnight 3
• Sensitivity: 95%, Specificity: 93-100% (highest among first-line tests) 2, 3
• Absolute contraindication: Do NOT use in night-shift workers or anyone with disrupted sleep-wake cycles 3
• Avoid topical hydrocortisone contamination, particularly when mass spectrometry is used 3
• Multiple sequential measurements are particularly useful for detecting cyclic Cushing's syndrome 3

24-Hour Urinary Free Cortisol (UFC)

• Collect at least 2-3 samples to account for variability 3
• Sensitivity: 89%, Specificity: 100% 2, 3
• Measures overall cortisol production 3

Overnight 1 mg Dexamethasone Suppression Test (DST)

• Administer 1 mg dexamethasone at midnight, measure serum cortisol at 8 AM 3
• Normal response: cortisol <1.8 μg/dL (50 nmol/L) 3
• Sensitivity: 95%, Specificity: 80% 2
• Measure dexamethasone levels along with cortisol to improve test interpretability 3, 1
• Less useful in women taking estrogen-containing oral contraceptives 3

Pitfalls and False Positives

Consider pseudo-Cushing's states that can cause false-positive results 3, 1:

• Severe obesity
• Uncontrolled diabetes
• Depression
• Alcoholism
• Pregnancy

Determining the Etiology of Hypercortisolism

Step 1: Measure Morning Plasma ACTH

Once hypercortisolism is confirmed, measure morning plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes 2, 3, 1.

• Normal or elevated ACTH (>5 ng/L or >1.1 pmol/L): ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 3
• Low or undetectable ACTH: ACTH-independent Cushing's syndrome (adrenal source) 3

Step 2: For ACTH-Dependent Cases

Pituitary MRI with Gadolinium Enhancement

• Perform first for all ACTH-dependent cases 2, 1
• Sensitivity: 63%, Specificity: 92% 2, 1
• For lesions ≥10 mm, Cushing's disease is presumed 1

Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

Perform BIPSS if pituitary MRI is negative or equivocal, or if imaging and biochemical findings are discordant 2, 1.

• Diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after CRH stimulation 1
• Sensitivity: 100% for distinguishing pituitary from ectopic ACTH sources 2, 1
• Considered the gold standard for establishing the origin of ACTH secretion 4

CRH Stimulation Test

• A ≥20% increase in cortisol from baseline during CRH testing supports pituitary origin 3

Step 3: For ACTH-Independent Cases

• Proceed directly with adrenal imaging (CT or MRI) to identify adrenal adenoma, carcinoma, or bilateral hyperplasia 1

Special Considerations for Children and Adolescents

Screen children only if weight gain is inexplicable AND combined with either decreased height standard deviation score or decreased height velocity 2, 1.

• Lack of height gain with concurrent weight gain is the most common presentation in children 4, 1
• Diagnostic cut-offs for children 2:
  • UFC >193 nmol/24 h (>70 μg/m²): 89% sensitivity, 100% specificity
  • Sleeping midnight serum cortisol ≥50 nmol/L (≥1.8 μg/dL): 100% sensitivity
  • Low-dose DST (0.5 mg every 6 hours for 48 hours, or 30 μg/kg/day for patients <40 kg) with cortisol ≥50 nmol/L at 48 hours: 95% sensitivity
• Refer children with confirmed Cushing's syndrome to multidisciplinary centers with pediatric endocrinology expertise 1
• Consider genetic screening if family history or other signs suggest genetic syndromes (MEN1, RET, AIP, PRKAR1A, CDKN1B, DICER1, SDHx, CABLES1) 4

Diagnostic Algorithm Summary

1. Exclude exogenous glucocorticoids (all forms) 1
2. Perform 2-3 screening tests (LNSC, UFC, DST) based on clinical suspicion 2, 3, 1
3. If abnormal, repeat 1-2 tests to confirm 3, 1
4. Measure morning plasma ACTH to determine ACTH-dependent vs. ACTH-independent 2, 3, 1
5. For ACTH-dependent: Pituitary MRI → BIPSS if needed 2, 1
6. For ACTH-independent: Adrenal imaging 1

Critical Pitfalls to Avoid

• Never perform biochemical testing without first excluding exogenous glucocorticoid use 1
• Do not use LNSC in night-shift workers or those with disrupted sleep cycles 3
• Consider cyclic Cushing's syndrome if results are inconsistent—perform extended monitoring with multiple periodic LNSC measurements 3
• Always measure dexamethasone levels with DST to improve interpretability 3, 1
• Do not assume pituitary source without BIPSS if MRI is negative or shows only microadenoma (<6 mm), as ectopic ACTH can occur even when pretest probability seems low 4