What is the diagnosis and treatment for a patient suspected of having Cushing syndrome?

Cushing Syndrome: Diagnosis and Treatment

Diagnostic Approach

For patients with suspected Cushing syndrome, first rule out exogenous glucocorticoid use, then perform 2-3 first-line screening tests including late-night salivary cortisol, 24-hour urinary free cortisol, and overnight 1 mg dexamethasone suppression test to confirm hypercortisolism. 1

Initial Screening Tests

• Late-night salivary cortisol (LNSC) is the preferred initial test for low clinical suspicion due to ease of patient compliance, with sensitivity of 95% and specificity of 93-100% 1, 2

  • Collect 2-3 samples at the patient's usual bedtime on consecutive days 2
  • Critical contraindication: Do NOT use in night-shift workers or anyone with disrupted sleep-wake cycles 2
  • Avoid topical hydrocortisone contamination which can cause false positives 2

• 24-hour urinary free cortisol (UFC) measures overall cortisol production with sensitivity of 89-95% and specificity of 98-100% 1, 2

  • Collect 2-3 samples to account for day-to-day variability 1, 3

• Overnight 1 mg dexamethasone suppression test (DST) has sensitivity of 95% and specificity of 90% 3

  • Normal response: serum cortisol <1.8 μg/dL at 8 AM after 1 mg dexamethasone at midnight 1, 2
  • Measuring dexamethasone levels alongside cortisol improves test interpretability 1, 2
  • Less reliable in women taking estrogen-containing oral contraceptives 2

Confirming the Diagnosis

• If any screening test is abnormal, repeat 1-2 screening tests to confirm the diagnosis 1, 2
• Consider false positives in severe obesity, uncontrolled diabetes, depression, alcoholism, and pregnancy 1, 2
• If results are inconsistent across multiple tests, consider cyclic Cushing syndrome and perform extended monitoring with periodic sequential measurements 2

Determining Etiology

ACTH-Dependent vs ACTH-Independent

• Measure morning plasma ACTH level to differentiate causes 1, 3, 2
  • Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L): ACTH-dependent Cushing syndrome (pituitary or ectopic source) 2
  • Low/undetectable ACTH: ACTH-independent Cushing syndrome (adrenal source) 2

For ACTH-Dependent Disease

• Perform pituitary MRI with sensitivity of 63% and specificity of 92% 1, 3

  • Lesions ≥10 mm: Cushing disease is presumed; bilateral inferior petrosal sinus sampling (IPSS) is NOT necessary 4, 1, 3
  • Lesions <6 mm: IPSS is required 4
  • Lesions 6-9 mm: Majority of experts recommend IPSS to confirm diagnosis 4

• Bilateral inferior petrosal sinus sampling (BIPSS) when MRI is negative, equivocal, or shows lesions <6 mm 1, 2

  • Diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after CRH stimulation 1, 2
  • Sensitivity of 100% for localizing to pituitary gland 1
  • Not reliable for tumor lateralization within the pituitary 4

• If suspicion is high for ectopic ACTH syndrome (particularly in males with very high UFC and/or profound hypokalemia), perform neck-to-pelvis thin-slice CT scan 4

For ACTH-Independent Disease

• Proceed with adrenal imaging (CT or MRI) to identify adrenal adenoma, carcinoma, or bilateral hyperplasia 2

Treatment Approach

First-Line Treatment

Transsphenoidal surgery is the treatment of choice for Cushing disease (pituitary adenoma). 1, 3, 5

• Surgical resection of the tumor is optimal for all forms of Cushing syndrome 5, 6
• Adrenal function typically recovers within 12 months after successful treatment, with an 80% recovery rate 1, 3

Medical Therapy

Medical therapy is indicated for patients awaiting surgery, with persistent disease after surgery, or when surgery is not feasible 1, 3

• Osilodrostat (11β-hydroxylase inhibitor) achieves UFC normalization in 86% of patients with median time to response of 2 months 1, 3

• Ketoconazole or metyrapone are alternative adrenal steroidogenesis inhibitors with response rates of approximately 70% 1, 3, 6

Additional Treatment Options

• Radiation therapy can be considered for persistent disease after surgery when medical therapy is inadequate or not tolerated, though cortisol normalization may take months to years 1

• Bilateral adrenalectomy is reserved for patients not responsive to surgery and medication 5

Critical Comorbidity Management

Thromboprophylaxis

• Venous thromboembolic event (VTE) risk is 10-fold higher in CS patients versus those with nonfunctioning adenomas 4
• VTE risk persists in the first few months after surgery; at 30 days post-adrenalectomy, VTE risk is 3.4-4.75% 4
• Extended thromboprophylaxis to 30 days postoperatively decreases VTE incidence 4
• Biochemical remission with short-term medical therapy does not immediately reverse hypercoagulability risk 4

Special Populations

Children

• Lack of height gain with concurrent weight gain is the most common presentation in children 1
• Children with Cushing syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise 1, 3
• Evaluate for growth hormone deficiency 3-6 months postoperatively, with prevalence of 20% 3
• Screen children only if weight gain is inexplicable and combined with either decreased height standard deviation score or height velocity 2

Genetic Syndromes

• If genetic syndrome is suspected, genetic counseling and additional investigations are necessary 1