Diagnosis and Treatment of Cushing Syndrome
The diagnosis of Cushing syndrome requires a stepwise approach starting with screening tests to confirm hypercortisolism, followed by determining its etiology through ACTH measurement and appropriate imaging studies.
Initial Diagnostic Approach
Screening for Hypercortisolism
- First, rule out exogenous glucocorticoid use (oral, injections, inhalers, topical) as this is the most common cause of Cushing syndrome 1, 2
- For patients with intermediate to high clinical suspicion, perform 2-3 first-line screening tests 1, 2:
- Late-night salivary cortisol (LNSC) - collect at least 2 tests on consecutive days (sensitivity 95%, specificity 100%) 2, 3
- 24-hour urinary free cortisol (UFC) - collect 2-3 samples (sensitivity 89%, specificity 100%) 2, 3
- Overnight 1 mg dexamethasone suppression test (DST) - normal response is serum cortisol <1.8 μg/dL at 8 AM (sensitivity 95%, specificity 80%) 2, 3
- For low clinical suspicion, start with LNSC as it's easier for patient compliance 1, 2
Interpreting Screening Results
- If any test is abnormal, repeat 1-2 screening tests to confirm 1
- If all tests are normal, Cushing syndrome is unlikely 1
- Consider false positives in conditions such as severe obesity, uncontrolled diabetes, depression, alcoholism, and pregnancy 2, 3
- For repeatedly equivocal results, consider cyclic Cushing syndrome or re-evaluate after several months 1, 4
Determining Etiology
ACTH Measurement
- Measure morning plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes 1, 2:
ACTH-Independent Cushing Syndrome
ACTH-Dependent Cushing Syndrome
- Perform pituitary MRI to detect pituitary adenoma (sensitivity 63%, specificity 92%) 1, 3, 5
- For pituitary lesions ≥10 mm, Cushing disease is presumed 1
- For lesions <6 mm or no visible lesion, perform bilateral inferior petrosal sinus sampling (BIPSS) 1
- For lesions 6-9 mm, consider CRH stimulation test or BIPSS 1
- BIPSS criteria: central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after stimulation (sensitivity 100%) 5
- If BIPSS is negative for central source, perform whole-body CT to locate ectopic ACTH source 1, 6
Treatment Approach
Surgical Management
- First-line treatment for Cushing syndrome is surgical removal of the causative tumor 6
- For Cushing disease (pituitary adenoma), transsphenoidal surgery is the treatment of choice 1
- For adrenal causes, adrenalectomy is recommended 6
- For ectopic ACTH syndrome, surgical removal of the source tumor is indicated 6
Medical Management
- For patients awaiting surgery or with persistent disease after surgery, medical therapy may be used 1:
- Ketoconazole (400-1200 mg/day) - inhibits adrenal steroidogenesis, achieves UFC normalization in approximately 65% of patients 1
- Osilodrostat (2-7 mg/day) - FDA approved for patients with Cushing disease when surgery is not an option or has not been curative, achieves UFC normalization in 86% of patients 1
- Metyrapone - reduces cortisol production by inhibiting 11-beta-hydroxylation in the adrenal cortex 7
Special Considerations
- In children, lack of height gain with concurrent weight gain is the most common presentation 1
- Children with Cushing syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise 1
- If genetic syndrome is suspected, genetic counseling and additional investigations are necessary 1
Common Pitfalls and Caveats
- DST may be less reliable in women taking estrogen-containing oral contraceptives 2
- Measuring dexamethasone levels along with cortisol improves DST interpretability 2
- Pseudo-Cushing states (severe obesity, depression, alcoholism) can cause false-positive results 2, 8
- Cyclic Cushing syndrome may lead to inconsistent test results 2, 8
- No single test is perfect; multiple tests are often needed for accurate diagnosis 8, 9