What tests can be done to diagnose Cushing's syndrome in a patient with diabetes mellitus (DM)?

Diagnostic Testing for Cushing's Syndrome in Patients with Diabetes

In patients with diabetes, screen for Cushing's syndrome using late-night salivary cortisol as the first-line test, followed by confirmation with 24-hour urinary free cortisol or the overnight 1-mg dexamethasone suppression test if initial screening is abnormal. 1, 2

Initial Screening Approach

The presence of diabetes mellitus increases the clinical suspicion for Cushing's syndrome and warrants screening, particularly given that hyperglycemia is a cardinal feature of hypercortisolism. 1

For patients with diabetes, the recommended screening tests include: 1, 2, 3

• Late-night salivary cortisol (LNSC): This is the preferred initial screening test due to its high sensitivity (92-95%) and specificity (100%), ease of collection at home, and stability at room temperature. 1, 3, 4 The test detects loss of normal circadian rhythm, which is impaired in Cushing's syndrome. 1, 5

• 24-hour urinary free cortisol (UFC): This test has a diagnostic cut-off >193 nmol/24h (>70 μg/m²) with 89% sensitivity and 100% specificity. 3 It reflects integrated tissue exposure to free cortisol over 24 hours. 5

• Overnight 1-mg dexamethasone suppression test (DST): A serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after 1 mg dexamethasone given at midnight excludes Cushing's syndrome. 1, 3 This test has high sensitivity but lower specificity compared to LNSC. 1

Important Considerations in Diabetic Patients

Uncontrolled diabetes can cause false-positive results on screening tests, so it is critical to achieve satisfactory glycemic control before testing. 6 One prospective study found that screening at diabetes diagnosis (after achieving glycemic control) identified unsuspected Cushing's syndrome in 1% of newly diagnosed diabetic patients. 6

Perform at least 2-3 abnormal screening tests to confirm the diagnosis before proceeding to further evaluation, as recommended by current guidelines. 1, 2, 3

Confirmatory Testing Algorithm

Once screening tests are abnormal, proceed with the following steps: 2, 7

1. Measure morning (8-9 AM) plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes. 2, 3, 7

   • ACTH >5 ng/L indicates ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 7
   • Low or undetectable ACTH indicates ACTH-independent Cushing's syndrome (adrenal source) 7

2. For ACTH-dependent disease: Obtain pituitary MRI to detect pituitary adenoma (sensitivity 63%, specificity 92%). 2 If the adenoma is ≥10 mm, Cushing's disease is presumed. 2 For inconclusive MRI findings, bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard, with diagnostic criteria of central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after stimulation. 2, 7

3. For ACTH-independent disease: Perform adrenal CT or MRI to identify adrenal lesions. 2, 7

Critical Pitfalls to Avoid

• False positives occur with: severe obesity, uncontrolled diabetes, depression, alcoholism, pregnancy, and certain medications (CYP3A4 inducers, oral estrogens). 1, 2, 5

• Cyclic Cushing's syndrome can produce intermittent normal results, requiring periodic re-evaluation with multiple sequential LNSC measurements. 1, 5

• Do not perform LNSC in night-shift workers due to disrupted circadian rhythm. 1

• Ensure complete 24-hour urine collections when using UFC, as incomplete collections yield false-negative results. 5

• Measure dexamethasone levels along with cortisol during DST to rule out abnormal dexamethasone metabolism, which improves test interpretability. 2, 3