What is the first biochemical abnormality in the workup for Cushing's syndrome?

First Biochemical Abnormality in Cushing's Workup

Loss of the normal circadian rhythm of cortisol secretion, detected by late-night salivary cortisol (LNSC), is typically the earliest biochemical abnormality in Cushing's syndrome and should be the preferred initial screening test. 1

Why LNSC Detects Abnormalities First

• LNSC identifies loss of the normal cortisol nadir that occurs at night, which is one of the earliest physiologic derangements in Cushing's syndrome 1
• The test has sensitivity of 95-100% and specificity of 95-100%, making it both highly sensitive and specific 1, 2
• LNSC becomes abnormal earlier than other tests in the disease course, particularly before 24-hour urinary free cortisol (UFC) and dexamethasone suppression testing 1
• In monitoring for recurrence after surgery, LNSC detects elevated cortisol levels earlier than 1-mg DST, while UFC is usually the last test to become abnormal 1

Comparison with Other Initial Tests

24-Hour Urinary Free Cortisol (UFC)

• UFC has sensitivity of 89% and specificity of 100% in pediatric populations 1
• However, UFC is usually the last test to become abnormal in patients with mild or early Cushing's syndrome 1
• In mild Cushing's syndrome, UFC may be only slightly elevated or even normal, often less than 3-fold above the upper limit of normal 1, 3
• The test requires at least 2-3 collections due to high intra-patient variability (up to 50%) 1, 2

Overnight 1-mg Dexamethasone Suppression Test (DST)

• DST has high sensitivity (>90%) but lower specificity compared to LNSC 1
• This test assesses impaired glucocorticoid feedback, which may not be the earliest abnormality 1
• DST is particularly prone to false positives from medications, estrogen use, and increased cortisol-binding globulin 1, 4

Recommended Diagnostic Approach

Initial Screening Strategy

• Perform 2-3 LNSC measurements on consecutive days as the first-line screening test 2
• If clinical suspicion is high, perform multiple tests simultaneously (LNSC, UFC, and DST) rather than sequentially 2
• Sampling saliva at usual bedtime rather than strictly at midnight can decrease false positive results 1

Important Caveats

• Do not perform LNSC in night-shift workers or patients with disrupted circadian rhythms, as the test relies on normal sleep-wake cycles 1, 4
• Multiple sequential LNSC measurements are particularly useful for cyclic Cushing's syndrome, where patients exhibit weeks to months of normal cortisol secretion interspersed with excess episodes 1
• Mass spectrometry methods have better sensitivity than immunoassay but at the expense of reduced specificity 1

When LNSC is Not Ideal

• For patients with renal impairment (CrCl <60 mL/min) or significant polyuria (>5 L/24h), LNSC is preferred over UFC 1
• For shift workers or those with disrupted sleep schedules, DST may be more appropriate than LNSC 4
• In women taking oral estrogen-containing contraceptives, DST may be less reliable and LNSC should be prioritized 2

Clinical Bottom Line

LNSC detects the earliest biochemical abnormality—loss of circadian rhythm—and should be the first test ordered in most patients with suspected Cushing's syndrome. 1, 2 The test becomes abnormal before UFC and often before DST shows impaired suppression, making it the most sensitive early marker of the disease. 1