What is the approach to diagnosing and treating Cushing's syndrome?

Approach to Cushing's Syndrome

Diagnostic Algorithm

Begin with 2-3 first-line screening tests to confirm hypercortisolism: late-night salivary cortisol (sensitivity 95%, specificity 100%), 24-hour urinary free cortisol (sensitivity 89%, specificity 100%), and overnight 1 mg dexamethasone suppression test (sensitivity 95%, specificity 80%). 1, 2

Step 1: Initial Screening for Hypercortisolism

Rule out exogenous glucocorticoid use first, as this is the most common cause of Cushing's syndrome. 2, 3

For patients with intermediate to high clinical suspicion, perform multiple screening tests simultaneously rather than sequentially: 1, 2

• Late-night salivary cortisol: Collect at 11 PM-midnight; abnormal if elevated above laboratory reference range (sensitivity 95%, specificity 100%) 1
• 24-hour urinary free cortisol: Collect 2-3 samples to account for day-to-day variability; abnormal if >3 times upper limit of normal (sensitivity 89%, specificity 100%) 1, 4
• Overnight 1 mg dexamethasone suppression test: Give 1 mg dexamethasone at 11 PM, measure serum cortisol at 8 AM; abnormal if cortisol ≥1.8 μg/dL (sensitivity 95%, specificity 80%) 1, 4

If any test is abnormal, repeat 1-2 screening tests to confirm the diagnosis. 2 False positives occur in severe obesity, uncontrolled diabetes, depression, alcoholism, and pregnancy—consider these conditions before proceeding. 2

Step 2: Determine ACTH-Dependent vs ACTH-Independent

Measure morning (8-9 AM) plasma ACTH level once hypercortisolism is confirmed: 1, 2

• ACTH <5 pg/mL (low/undetectable): ACTH-independent Cushing's syndrome (adrenal cause) 1
• ACTH ≥20 pg/mL (normal or elevated): ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 1
• ACTH 5-20 pg/mL: Equivocal; repeat testing or proceed with imaging 2

Step 3A: For ACTH-Independent (Adrenal) Cushing's

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

• Unilateral adenoma: Typically <4 cm, homogeneous, low attenuation on CT
• Adrenal carcinoma: Usually >4 cm, heterogeneous, irregular margins, local invasion
• Bilateral adrenal hyperplasia: Consider genetic syndromes (primary pigmented nodular adrenal disease, McCune-Albright syndrome) 2

Step 3B: For ACTH-Dependent Cushing's

Perform pituitary MRI with gadolinium enhancement as the initial localization test (sensitivity 63%, specificity 92%): 1, 2, 4

• Lesion ≥10 mm: Cushing's disease is presumed; proceed to transsphenoidal surgery 2, 4
• Lesion 6-9 mm or no visible lesion: Proceed to bilateral inferior petrosal sinus sampling (BIPSS) 1

BIPSS is indicated when pituitary imaging is negative or equivocal (sensitivity 100% for distinguishing pituitary from ectopic sources): 1, 2

• Central-to-peripheral ACTH ratio ≥2:1 baseline or ≥3:1 after CRH stimulation: Confirms pituitary source (Cushing's disease) 2
• Ratio <2:1 baseline and <3:1 after stimulation: Suggests ectopic ACTH source; obtain chest/abdominal CT and consider octreotide scan 2

Treatment Algorithm

First-Line Treatment: Surgery

Transsphenoidal surgery is the treatment of choice for Cushing's disease (pituitary adenoma), with immediate remission rates of 70-90% for microadenomas. 2, 4

Unilateral adrenalectomy for adrenal adenoma or bilateral adrenalectomy for bilateral disease in ACTH-independent cases. 3

Medical Therapy Indications

Medical therapy is appropriate for: 2, 4

• Preoperative preparation in severe hypercortisolism
• Persistent disease after surgery
• Patients awaiting definitive treatment (surgery or radiation)
• Patients who are not surgical candidates

Osilodrostat (11β-hydroxylase inhibitor) achieves urinary free cortisol normalization in 86% of patients with median time to response of 2 months. 2, 4

Ketoconazole or metyrapone are alternative adrenal steroidogenesis inhibitors with response rates of approximately 70%. 4, 5 Metyrapone reduces cortisol production by inhibiting 11β-hydroxylation in the adrenal cortex; monitor for acute adrenal insufficiency (nausea, vomiting, hypotension). 5

Radiation Therapy

Consider radiation therapy for persistent disease after surgery when medical therapy is inadequate or not tolerated, though cortisol normalization may take months to years. 6

Bilateral Adrenalectomy

Reserve bilateral adrenalectomy as last resort for patients with persistent ACTH-dependent Cushing's syndrome refractory to surgery, medical therapy, and radiation. This requires lifelong glucocorticoid and mineralocorticoid replacement. 3

Post-Treatment Monitoring

After successful treatment, adrenal function typically recovers within 12 months (80% recovery rate). 4 Provide glucocorticoid replacement during the recovery period, starting with hydrocortisone 15-25 mg daily in divided doses. 6

Monitor for hypopituitarism including growth hormone deficiency (evaluate 3-6 months postoperatively in children, prevalence 20%). 4

Special Populations

Children and Adolescents

Screen children only if weight gain is inexplicable AND combined with decreased height velocity or decreased height standard deviation score. 1 Lack of height gain with concurrent weight gain is the most common presentation in children. 2

Pediatric diagnostic cut-offs: 1

• Urinary free cortisol >193 nmol/24h (>70 μg/m²): Sensitivity 89%, specificity 100%
• Sleeping midnight serum cortisol ≥50 nmol/L (≥1.8 μg/dL): Sensitivity 100%
• Low-dose dexamethasone suppression test (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: Sensitivity 95%

Refer all children with Cushing's syndrome to multidisciplinary centers with pediatric endocrinology expertise. 2, 4

Patients with Cirrhosis

Patients with cirrhosis may have impaired response to metyrapone due to altered hepatic metabolism; consider alternative medical therapies. 5

Common Pitfalls

Avoid single screening test reliance—false positives occur frequently; always confirm with 2-3 tests. 1, 2

Do not assume microadenoma on MRI equals Cushing's disease—10% of normal population has incidental pituitary microadenomas; biochemical confirmation is essential. 7

Measure dexamethasone levels along with cortisol in dexamethasone suppression tests to improve interpretability and identify malabsorption or rapid metabolism. 2

Consider cyclical Cushing's syndrome if initial screening is negative but clinical suspicion remains high; repeat testing during symptomatic periods or measure scalp hair cortisol for long-term exposure assessment. 8