What are the investigations for Cushing's disease?

Investigations for Cushing's Disease

The diagnostic approach for Cushing's disease requires a stepwise process including screening tests to confirm hypercortisolism, followed by tests to determine the etiology, with late-night salivary cortisol, 24-hour urinary free cortisol, and overnight dexamethasone suppression test being the recommended first-line screening tests. 1, 2, 3

Initial Screening Tests for Hypercortisolism

• Begin with 2-3 first-line screening tests for patients with intermediate to high clinical suspicion of Cushing's syndrome 3:

  • Late-night salivary cortisol (LNSC) - sensitivity 95%, specificity 100% 2
  • 24-hour urinary free cortisol (UFC) - collect at least 2-3 samples to account for variability 1, 2
  • Overnight 1 mg dexamethasone suppression test (DST) - normal response is serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM 4

• For patients with low clinical suspicion, start with LNSC as it's easier for patient compliance 3, 4

• If any test is abnormal, repeat 1-2 screening tests to confirm the diagnosis 1, 3

• Consider measuring dexamethasone levels along with cortisol to improve DST interpretability 1, 3

Common Pitfalls in Screening Tests

• False positive results can occur in conditions such as 1, 3, 4:

  • Severe obesity
  • Uncontrolled diabetes mellitus
  • Psychiatric disorders (depression)
  • Alcoholism
  • Pregnancy
  • Polycystic ovary syndrome

• DST may be less reliable in women taking estrogen-containing oral contraceptives 1, 4

• UFC may be less reliable in patients with renal impairment (CrCl <60mL/min) or significant polyuria (>5 L/24h) 1

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, 4
  • Low/undetectable ACTH: ACTH-independent Cushing's syndrome 4

• For ACTH-dependent Cushing's syndrome 1:

  • Perform pituitary MRI to detect pituitary adenoma (sensitivity 63%, specificity 92%) 2, 3
  • For lesions ≥10 mm, Cushing's disease is presumed 3
  • For lesions <6 mm or equivocal findings, proceed with bilateral inferior petrosal sinus sampling (BIPSS) 1
  • For lesions between 6-9 mm, expert opinions differ on whether BIPSS is needed 1

• For ACTH-independent Cushing's syndrome:

  • Perform adrenal CT or MRI to identify adrenal adenoma or other adrenal pathology 1

Specialized Tests

• CRH stimulation test for ACTH-dependent Cushing's syndrome (sensitivity 74-100%) 2

• BIPSS criteria for confirming pituitary source 1, 3:

  • Central-to-peripheral ACTH ratio ≥2:1 before stimulation
  • Central-to-peripheral ACTH ratio ≥3:1 after stimulation (with CRH)

• Combined low-dose dexamethasone-CRH test (Dex-CRH) or desmopressin test may help distinguish between ACTH-dependent Cushing's syndrome and pseudo-Cushing's states 1

Special Considerations

• In children and adolescents, consider screening only if weight gain is inexplicable and combined with either decreased height standard deviation score or height velocity 2, 3

• Consider cyclic Cushing's syndrome in cases with inconsistent results 4

• Multiple samples of UFC and LNSC are needed to diagnose mild Cushing's syndrome, as single normal results do not exclude the diagnosis 5

By following this systematic approach to investigating Cushing's disease, clinicians can efficiently confirm the diagnosis and determine the underlying etiology, leading to appropriate treatment decisions that will improve patient outcomes in terms of morbidity, mortality, and quality of life.