What is the diagnostic workup for Cushing's syndrome?

From the Guidelines

The workup for Cushing's syndrome should begin with screening tests, including 24-hour urinary free cortisol measurement, late-night salivary cortisol testing, and the overnight 1mg dexamethasone suppression test, as these tests have high sensitivity and specificity for detecting excess cortisol, as shown in a recent study 1. The initial screening tests are crucial in detecting excess cortisol, and at least two abnormal tests are recommended for diagnosis.

Screening Tests

• 24-hour urinary free cortisol measurement: this test measures the amount of cortisol excreted in the urine over a 24-hour period, with a sensitivity of 89% and specificity of 100% 1.
• Late-night salivary cortisol testing: this test measures the level of cortisol in the saliva at night, with a sensitivity of 95% and specificity of 100% 1.
• Overnight 1mg dexamethasone suppression test: this test measures the level of cortisol in the blood after taking a dose of dexamethasone, with a sensitivity of 95% and specificity of 80% 1. Once hypercortisolism is confirmed, ACTH levels should be measured to differentiate ACTH-dependent (pituitary or ectopic source) from ACTH-independent (adrenal) causes, with a cut-off value of 29 ng/l (6.4 pmol/l) having a 70% sensitivity and 100% specificity for diagnosing Cushing disease 1.

Confirmatory Tests

• ACTH levels: this test measures the level of adrenocorticotropic hormone (ACTH) in the blood, which helps to differentiate between ACTH-dependent and ACTH-independent causes.
• CRH stimulation test: this test measures the response of cortisol to corticotropin-releasing hormone (CRH) stimulation, with a sensitivity of 74-100% 1. For ACTH-dependent disease, an 8mg dexamethasone suppression test and CRH stimulation test can help distinguish between pituitary and ectopic sources, with a central-to-peripheral ACTH ratio of ≥3:1 after CRH or desmopressin stimulation confirming a pituitary source of ACTH excess 1.

Localization Studies

• Pituitary MRI: this test uses magnetic resonance imaging (MRI) to visualize the pituitary gland and detect any tumors or abnormalities.
• Chest/abdominal CT: this test uses computed tomography (CT) to visualize the chest and abdominal cavities and detect any tumors or abnormalities.
• Adrenal CT/MRI: this test uses CT or MRI to visualize the adrenal glands and detect any tumors or abnormalities. Bilateral inferior petrosal sinus sampling (BIPSS) may be necessary when imaging is inconclusive in ACTH-dependent cases, with a central-to-peripheral ACTH ratio of ≥2:1 before CRH or desmopressin and ≥3:1 after CRH or desmopressin stimulation confirming a central source of ACTH excess 1. This systematic approach is essential because Cushing's syndrome presents with nonspecific symptoms like central obesity, facial rounding, hypertension, and glucose intolerance that overlap with common conditions, making accurate diagnosis challenging but crucial for appropriate treatment.

From the Research

Diagnostic Approach for Cushing's Syndrome

The diagnostic workup for Cushing's syndrome involves a stepwise process that includes screening and confirming the diagnosis, as well as establishing the etiology of the syndrome 2.

Screening Tests

The tests currently used to confirm the diagnosis of Cushing's syndrome include:

• Urinary free cortisol measurements
• The dexamethasone suppression test
• Late-night salivary cortisol or midnight serum cortisol measurements 2, 3 These tests are used to assess excess total endogenous cortisol secretion, loss of the normal feedback of the hypothalamo-pituitary-adrenal axis, and disturbance of the normal circadian rhythm of cortisol secretion 3.

Establishing Etiology

After confirming the diagnosis of Cushing's syndrome, measurement of ACTH can help distinguish between ACTH-dependent and non-ACTH dependent causes of hypercortisolism 4, 2, 5.

• Adrenal imaging provides clues for the etiology of non-ACTH dependent forms
• Differentiation between the ACTH-dependent forms that involve pituitary corticotroph adenomas and ectopic ACTH sources is more complex and includes:
  • Pituitary MRI imaging
  • The high dose dexamethasone suppression test
  • The CRH test
  • Bilateral inferior petrosal sinus sampling
  • Imaging modalities to detect ectopic ACTH secreting lesions 2, 5

Diagnostic Workup

The investigation of Cushing's syndrome should start with careful history taking and clinical examination, and exogenous steroid usage must be excluded 5.

• The recommended first-line tests include midnight salivary cortisol and/or the 1 mg overnight or low-dose dexamethasone suppression tests
• The next step is to differentiate adrenocorticotrophin (ACTH)-dependent from ACTH-independent Cushing's syndrome by measuring ACTH
• Imaging should include MR scanning of the pituitary, and CT scanning of the chest and abdomen to look for an ectopic source 5