What is the diagnostic and treatment approach for a patient suspected of having Cushing's syndrome?

Diagnostic and Treatment Approach for Cushing's Syndrome

Initial Screening Strategy

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

Key Clinical Features to Identify

Look specifically for these high-specificity findings that distinguish true Cushing's from obesity or metabolic syndrome:

• Facial plethora, supraclavicular and temporal fat pads 3
• Wide purple striae (>1 cm), easy bruising 3, 4
• Proximal muscle weakness 4
• In children: weight gain with growth arrest 1, 5

First-Line Test Selection

Start with any combination of these three tests, performing at least 2-3 initially 1, 2:

• Late-night salivary cortisol: Sensitivity 95%, specificity 93-100%; collect 2-3 samples on different nights 6, 2
• 24-hour urinary free cortisol: Sensitivity 89%, specificity 100%; collect 2-3 samples to account for variability 6, 2, 5
• Overnight 1 mg dexamethasone suppression test: Normal suppression is cortisol <1.8 μg/dL at 8 AM; sensitivity 95%, specificity 90% 2, 5

Critical caveat: A single normal test does NOT exclude Cushing's syndrome. Studies show 92% of patients with confirmed Cushing's had at least one normal salivary cortisol, 88% had normal UFC results, and most had multiple normal tests due to episodic hypercortisolism 7. If clinical suspicion remains high despite initial normal results, repeat testing when the patient is symptomatic 7.

Ruling Out Exogenous Glucocorticoids

First, exclude exogenous glucocorticoid use—the most common cause of Cushing's syndrome 1, 3. Review all medications including topical, inhaled, and injected steroids.

Addressing False Positives (Pseudo-Cushing's)

False positives occur with severe obesity, uncontrolled diabetes, depression, and alcoholism 1. If mild hypercortisolism is detected but clinical picture is atypical, monitor for 3-6 months and treat underlying conditions (e.g., depression) before pursuing invasive testing 6. Standard tests are unreliable in pseudo-Cushing's; consider dexamethasone-CRH testing at expert centers 6.

Determining the Etiology

Step 1: Measure Morning Plasma ACTH

Once hypercortisolism is confirmed, measure morning (8 AM) plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes 1, 2, 5:

• ACTH >5 ng/L (>1.1 pmol/L): ACTH-dependent (pituitary or ectopic source) 2
• ACTH suppressed (<5 ng/L): ACTH-independent (adrenal source) 2

Step 2A: ACTH-Dependent Cushing's (Pituitary vs. Ectopic)

Perform high-quality pituitary MRI with thin slices (1 mm intervals) using spoiled gradient-recalled acquisition 6, 1, 5:

• Lesion ≥10 mm: Presume Cushing's disease (pituitary adenoma); positive predictive value 90% 1, 5
• Lesion <10 mm or negative MRI: Proceed to bilateral inferior petrosal sinus sampling (BIPSS) 1, 2

BIPSS is the gold standard for differentiating pituitary from ectopic ACTH secretion 1, 8, 4:

• Diagnostic criteria: Central-to-peripheral ACTH ratio ≥2:1 at baseline and ≥3:1 after CRH stimulation; sensitivity 100% 1
• Important: Do NOT use IPSS to diagnose hypercortisolism itself—only for localization after hypercortisolism is confirmed 6

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

Perform adrenal CT or MRI to identify adrenal lesions 2:

• Unilateral adenoma: Laparoscopic adrenalectomy 2
• Adrenal carcinoma: Open adrenalectomy with possible adjuvant therapy 2
• Bilateral hyperplasia: Medical management or unilateral adrenalectomy 2

Treatment Approach

First-Line: Surgical Resection

Surgical removal of the cortisol-producing tumor is the optimal first-line treatment for all forms of Cushing's syndrome 2, 3:

• Cushing's disease (pituitary): Transsphenoidal surgery 1, 5, 3
• Adrenal adenoma: Laparoscopic adrenalectomy 2
• Ectopic ACTH: Surgical removal when tumor is localized 2

Medical Therapy Indications

Use medical therapy for patients awaiting surgery, with persistent disease after surgery, who are not surgical candidates, or who decline surgery 1, 2:

Preferred agent: Osilodrostat (11β-hydroxylase inhibitor):

• Achieves UFC normalization in 86% of patients with median response time of 2 months 1, 5

Alternative agents:

• Ketoconazole or metyrapone: Response rate approximately 70% 1, 5
• Metyrapone inhibits 11-beta-hydroxylation, reducing cortisol production; mean terminal half-life 1.9 hours 9

Radiation Therapy and Bilateral Adrenalectomy

Reserve these for persistent disease after surgery when medical therapy is inadequate or not tolerated 1, 2. Note that cortisol normalization with radiation may take months to years 1.

Post-Treatment Monitoring

All patients in remission require 6-monthly clinical examination, 24-hour UFC, electrolytes, and morning serum cortisol for at least 2 years, followed by lifelong annual assessment 2:

• Recurrence rates: 6-40%, usually within 5 years, though late relapse can occur 2
• Adrenal function recovery: Typically within 12 months; 80% recovery rate 1, 5
• Growth hormone deficiency: Most frequent pituitary deficit post-treatment; evaluate 3-6 months postoperatively in children 2, 5
• Monitor for psychiatric and neurocognitive comorbidities long-term 2

Special Populations

Children with Cushing's syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise 1, 5. The most common presentation is lack of height gain with concurrent weight gain 1, 5.

Patients with genetic syndrome suspicion require genetic counseling and additional investigations 1.