What diagnostic tests are recommended for Cushing's syndrome and insulin resistance?

Diagnostic Tests for Cushing's Syndrome and Insulin Resistance

For diagnosing Cushing's syndrome, a combination of late-night salivary cortisol, 24-hour urinary free cortisol, and overnight dexamethasone suppression test should be performed, while insulin resistance evaluation requires fasting glucose, insulin levels, and HOMA-IR calculation. 1, 2, 3

Diagnostic Tests for Cushing's Syndrome

First-Line Screening Tests

• Late-night salivary cortisol (LNSC): Collect at least 2-3 samples on consecutive days; highly sensitive (95%) and specific (100%) 1, 3
• 24-hour urinary free cortisol (UFC): Collect at least 2-3 samples to account for variability; diagnostic cut-off >193 nmol/24h (>70 μg/m²); sensitivity 89%, specificity 100% 1, 3
• Overnight 1 mg dexamethasone suppression test (DST): Normal response is serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after 1 mg dexamethasone at midnight 1, 2

Determining Etiology of Cushing's Syndrome

• Morning plasma ACTH level: Essential to differentiate ACTH-dependent from ACTH-independent causes 1, 2

  • Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L): Suggests ACTH-dependent Cushing's syndrome
  • Low/undetectable ACTH: Indicates ACTH-independent Cushing's syndrome

• For ACTH-dependent cases:

  • Pituitary MRI: To detect pituitary adenoma (sensitivity 63%, specificity 92%) 2, 3
  • CRH stimulation test: ≥20% increase in cortisol from baseline supports pituitary origin 1, 3
  • Bilateral inferior petrosal sinus sampling (BIPSS): For equivocal findings; central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after stimulation indicates pituitary source 2

• For ACTH-independent cases:

  • Adrenal CT scan or MRI: To identify adrenal tumors 4

Special Considerations in Cushing's Syndrome Testing

• Consider false positives in conditions such as severe obesity, uncontrolled diabetes, depression, and alcoholism 1, 2
• Measure dexamethasone levels along with cortisol to improve test interpretability 4, 2
• In children, screen only if weight gain is inexplicable and combined with either decreased height standard deviation score or height velocity 4, 3
• Consider cyclic Cushing's syndrome in cases with inconsistent results 1

Diagnostic Tests for Insulin Resistance

First-Line Tests

• Fasting plasma glucose: Values ≥100 mg/dL indicate impaired fasting glucose 4
• Fasting insulin levels: Elevated levels suggest insulin resistance 4
• HOMA-IR (Homeostatic Model Assessment for Insulin Resistance): Calculated as (fasting insulin [μU/mL] × fasting glucose [mg/dL])/405; values >2.5 suggest insulin resistance 4

Additional Tests

• Oral glucose tolerance test (OGTT): Measures glucose and insulin levels at 0,30,60,90, and 120 minutes after 75g glucose load; delayed glucose clearance and exaggerated insulin response indicate insulin resistance 4
• Glycated hemoglobin (HbA1c): Values between 5.7-6.4% indicate prediabetes 4
• Lipid profile: Triglycerides >150 mg/dL and HDL <40 mg/dL in men or <50 mg/dL in women suggest metabolic syndrome associated with insulin resistance 4

Diagnostic Algorithm

1. Rule out exogenous glucocorticoid use as the most common cause of Cushing's syndrome 4, 2
2. For intermediate to high clinical suspicion of Cushing's syndrome, perform all three first-line screening tests (LNSC, UFC, DST) 1, 2
3. For low clinical suspicion, start with LNSC as it's easier for patient compliance 1, 2
4. If any test is abnormal, repeat 1-2 screening tests to confirm 4, 1
5. If Cushing's syndrome is confirmed, measure morning plasma ACTH level to determine etiology 1, 2
6. Simultaneously evaluate for insulin resistance with fasting glucose, insulin levels, and HOMA-IR calculation 4
7. Proceed with appropriate imaging based on ACTH results 4, 2

Common Pitfalls and Caveats

• Single measurements of UFC or LNSC may miss mild or cyclic Cushing's syndrome; multiple samples are necessary 5, 6
• Severe obesity can cause false-positive results in Cushing's syndrome testing 4, 1
• Estrogen-containing oral contraceptives can affect DST results by increasing cortisol binding globulin 4, 1
• Renal impairment (CrCl <60mL/min) or significant polyuria (>5 L/24 h) can affect UFC results; LNSC may be preferred in these cases 4
• Insulin resistance tests should be performed in the fasting state for accurate results 4