What are the steps to diagnose and treat Cushing syndrome?

Cushing Syndrome Diagnosis

Begin by ruling out exogenous glucocorticoid use (oral, inhaled, topical, or injected steroids), then perform 2-3 first-line screening tests—late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), or overnight 1 mg dexamethasone suppression test (DST)—to confirm hypercortisolism before proceeding to determine the etiology. 1, 2, 3

Step 1: Rule Out Exogenous Glucocorticoids

• Exclude all forms of exogenous steroid exposure including oral medications, inhalers, topical creams, intra-articular injections, and epidural steroids, as this is the most common cause of Cushing syndrome 2, 4
• If exogenous steroids are identified, discontinue them if medically feasible before pursuing further workup 1

Step 2: Initial Screening Tests (Confirm Hypercortisolism)

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

• Late-night salivary cortisol (LNSC): Collect at least 2-3 samples (sensitivity 95%, specificity 100%); this is the easiest test for patient compliance and preferred for shift workers or those with disrupted sleep schedules 1, 3
• 24-hour urinary free cortisol (UFC): Collect 2-3 samples to account for variability (sensitivity 89%, specificity 100%) 1, 3
• Overnight 1 mg dexamethasone suppression test (DST): Normal response is serum cortisol <1.8 μg/dL at 8 AM (sensitivity 95%, specificity 80-90%); consider measuring dexamethasone levels if false-positive suspected 1, 5

For patients with low clinical suspicion, start with LNSC alone given its ease of use 2

Key Clinical Features to Look For:

• Most specific findings: Supraclavicular and temporal fat pads, proximal muscle weakness (difficulty rising from chair without using arms), wide (>1 cm) purple striae, easy bruising, facial plethora 6
• In children: Lack of height gain with concurrent weight gain is the hallmark presentation 1, 2

Common Pitfalls—Pseudo-Cushing States:

• False positives occur with severe obesity, uncontrolled diabetes (HbA1c >8%), major depression, alcoholism, pregnancy, and anorexia nervosa 2, 7
• If pseudo-Cushing is suspected, repeat testing in 3-6 months or treat the underlying condition (e.g., depression) and retest 1

Step 3: Determine Etiology (ACTH-Dependent vs. ACTH-Independent)

Once hypercortisolism is confirmed with abnormal screening tests:

• Measure morning (8 AM) plasma ACTH level 2, 3, 5:
  • Low or undetectable ACTH (<5 pg/mL): ACTH-independent (adrenal cause)—proceed to adrenal CT imaging 3, 4
  • Normal or elevated ACTH (>20 pg/mL): ACTH-dependent (pituitary or ectopic source)—proceed to pituitary MRI 3, 5

Step 4: Localize the Source

For ACTH-Dependent Cushing Syndrome:

• Pituitary MRI with gadolinium (sensitivity 63%, specificity 92%): Use thin-slice (1 mm) spoiled gradient-recalled sequences 1, 3, 5

  • If adenoma ≥10 mm visible: Presume Cushing disease (pituitary source) 2, 5
  • If MRI negative or equivocal, or lesion <6 mm: Proceed to bilateral inferior petrosal sinus sampling (BIPSS) 1, 3

• BIPSS criteria (sensitivity 100%): Central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH/desmopressin stimulation confirms pituitary source 2, 3

  • Important caveat: BIPSS should NOT be used to diagnose hypercortisolism itself, only to localize the source after hypercortisolism is confirmed 1

For ACTH-Independent Cushing Syndrome:

• Adrenal CT scan: Identifies adrenal adenoma, carcinoma, or bilateral hyperplasia 4, 8

Step 5: Treatment Approach

First-Line Treatment:

• Transsphenoidal surgery is the treatment of choice for Cushing disease (pituitary adenoma) 2, 5, 4
• Adrenalectomy for adrenal tumors 4, 6

Medical Therapy (for patients awaiting surgery, surgical failures, or inoperable cases):

• Osilodrostat (11β-hydroxylase inhibitor): Achieves UFC normalization in 86% of patients with median response time of 2 months 2, 5
• Ketoconazole or metyrapone: Alternative steroidogenesis inhibitors with ~70% response rates 2, 5, 6
• Pasireotide: FDA-approved for Cushing disease; monitor closely for hyperglycemia (nearly all patients develop worsening glycemia in first 2 weeks) and check baseline FPG, HbA1c, liver tests, ECG, and gallbladder ultrasound before initiation 9

Post-Treatment Monitoring:

• Adrenal function typically recovers within 12 months after successful treatment (80% recovery rate) 2, 5
• In children, evaluate for growth hormone deficiency at 3-6 months postoperatively and initiate replacement if needed 1, 5

Special Populations

Children:

• Refer to multidisciplinary pediatric endocrinology centers for management 1, 2, 5
• Use diagnostic cut-offs: UFC >193 nmol/24h (>70 μg/m²), midnight serum cortisol ≥50 nmol/L (≥1.8 μg/dL), or low-dose DST (0.5 mg every 6 hours for 48 hours) with cortisol ≥50 nmol/L at 48 hours 3
• Avoid routine thromboprophylaxis due to bleeding risk; reserve for selected cases 1

Genetic Syndromes:

• Consider genetic testing if family history or syndromic features present (MEN1, FIPA, DICER1, PRKAR1A) 1, 2

Cyclic Cushing Syndrome:

• Confirm active hypercortisolism phase with LNSC, DST, or UFC before proceeding to dynamic testing or BIPSS 1