What are the next steps for a patient with normal Urine Free Cortisol (UFC) test results?

Management of Normal Urine Free Cortisol (UFC) Results

Two normal UFC results effectively rule out Cushing's syndrome, and no further testing for hypercortisolism is needed unless clinical suspicion remains high. 1

Interpretation of Normal UFC Results

• Normal UFC results (within reference range) on two separate occasions strongly indicate absence of Cushing's syndrome, as UFC has high sensitivity for detecting hypercortisolism 1
• UFC measurements reflect overall cortisol production independent of cortisol-binding globulin changes, making it a reliable screening test 1
• The random variability in UFC can be as high as 50%, which is why at least two collections are recommended to account for intra-patient variability 1

Next Steps After Normal UFC Results

• If clinical suspicion was low and UFC is normal x2, no further testing for Cushing's syndrome is warranted 1
• If clinical symptoms persist despite normal UFC results, consider the following algorithm:

For Persistent Clinical Suspicion Despite Normal UFC:

1. Consider alternative screening tests:

   • Overnight dexamethasone suppression test (DST) - particularly useful for shift workers or those with disrupted circadian rhythms 2, 3
   • Late-night salivary cortisol (LNSC) - multiple measurements may be easier for patients to complete 1

2. Rule out factors affecting UFC interpretation:

   • Check for renal impairment (CrCl <60mL/min) which can affect UFC levels 1
   • Consider patient's body mass index (BMI), age, urinary volume, and sodium intake which can all influence UFC levels 1
   • Evaluate for significant polyuria (>5 L/24 h) which may affect UFC results 1

3. Evaluate for pseudo-Cushing's states:

   • Assess for psychiatric disorders, alcohol use disorder, polycystic ovary syndrome, and obesity which may activate the HPA axis 1
   • Consider that these conditions can cause mild hypercortisolism that may be missed by UFC testing 1

Important Caveats and Pitfalls

• Collection accuracy is crucial: Inaccurate 24-hour urine collection is a common pitfall that can lead to false-negative results 4
• Sex differences exist: Men typically have higher UFC excretion rates than women, which should be considered when interpreting results 5
• Day-to-day variability: UFC has moderate stability in the short term (correlation coefficient ~0.7), so multiple collections are important 6
• Assay methodology matters: LC-MS/MS is more specific than immunoassays for UFC measurement and less prone to interference 7
• Cyclic Cushing's syndrome: In patients with suspected cyclic hypercortisolism, normal UFC results may occur during periods of normal cortisol production 1

When to Consider Additional Testing Despite Normal UFC

• If clinical features strongly suggest Cushing's syndrome despite normal UFC results, consider:
  • Performing the combined low-dose dexamethasone-CRH test (Dex-CRH) or desmopressin test to distinguish between ACTH-dependent Cushing's syndrome and pseudo-Cushing's states 1
  • Monitoring the patient for 3-6 months to see if symptoms resolve or progress 1
  • Treating underlying conditions that might cause pseudo-Cushing's states to see if HPA axis function normalizes 1