What are the steps for diagnosing and treating Cushing's syndrome?

Diagnosis and Treatment of Cushing's Syndrome

The diagnosis of Cushing's syndrome requires a stepwise approach, beginning with first-line screening tests including late-night salivary cortisol, 24-hour urinary free cortisol, and overnight dexamethasone suppression test, followed by determination of ACTH levels to identify the etiology, with transsphenoidal surgery being the first-line treatment for Cushing's disease. 1, 2, 3

Diagnostic Algorithm

Step 1: Initial Screening

• Rule out exogenous glucocorticoid use as the most common cause of Cushing's syndrome before proceeding with further testing 1
• For patients with intermediate to high clinical suspicion, perform 2-3 first-line screening tests 1, 2:
  • Late-night salivary cortisol (LNSC): sensitivity 95%, specificity 100% 2, 3
  • 24-hour urinary free cortisol (UFC): 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 2
• For low clinical suspicion, start with late-night salivary cortisol as it's easier for patient compliance 1
• If any test is abnormal, repeat 1-2 screening tests to confirm the diagnosis 1, 2

Step 2: Determining Etiology

• Measure morning plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes 1, 2, 3:
  • Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L): ACTH-dependent Cushing's syndrome 2
  • Low/undetectable ACTH: ACTH-independent Cushing's syndrome 2
• For ACTH-dependent Cushing's syndrome:
  • Perform pituitary MRI to detect pituitary adenoma (sensitivity 63%, specificity 92%) 1, 3
  • For lesions ≥10 mm, Cushing's disease is presumed 1
  • Consider CRH stimulation test (≥20% increase in cortisol from baseline supports pituitary origin) 2, 3
• For equivocal findings, perform bilateral inferior petrosal sinus sampling (BIPSS) 1, 2:
  • Diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after stimulation (sensitivity 100%) 1
• For ACTH-independent Cushing's syndrome, proceed with adrenal imaging 2

Treatment Approach

Cushing's Disease (Pituitary Adenoma)

• Transsphenoidal surgery is the first-line treatment of choice 1
• Medical therapy options for patients awaiting surgery or with persistent disease after surgery 1:
  • Ketoconazole (adrenal steroidogenesis inhibitor) 1
  • Osilodrostat (achieves UFC normalization in 86% of patients) 1
  • Metyrapone (inhibits 11-beta-hydroxylation in the adrenal cortex) 4

Adrenal Causes

• Surgical removal of adrenal tumor for ACTH-independent Cushing's syndrome 5
• Bilateral adrenalectomy may be considered for patients not responsive to other treatments 5

Special Considerations

Potential Pitfalls

• Consider false positives in conditions such as 1, 2:
  • Severe obesity
  • Uncontrolled diabetes
  • Depression
  • Alcoholism
  • Pregnancy
• DST may be less useful in women taking estrogen-containing oral contraceptives 2
• Measuring dexamethasone levels along with cortisol improves test interpretability 1, 2
• Consider cyclic Cushing's syndrome in cases with inconsistent test results 2

Pediatric Considerations

• In children, lack of height gain with concurrent weight gain is the most common presentation 1, 3
• Screen children only if weight gain is inexplicable and combined with either decreased height standard deviation score or height velocity 2, 3
• Growth failure sensitively discriminates simple obesity from Cushing's syndrome in prepubertal children but is unreliable in post-pubertal children 3
• Children with Cushing's syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise 1

Genetic Considerations

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

Monitoring and Follow-up

• After treatment, monitor for signs of adrenal insufficiency, which may require glucocorticoid replacement therapy 5
• Long-term follow-up is essential as recurrence can occur, particularly in Cushing's disease 5
• Monitor for improvement in comorbidities such as hypertension, diabetes, and osteoporosis 5