Normal UFC Results in ACTH-Dependent Cyclic Cushing's Syndrome with Large Urine Volume
Normal urinary free cortisol (UFC) levels in a patient with suspected ACTH-dependent cyclic Cushing's syndrome despite large urine volume (3-4L) are likely due to the cyclical nature of the condition, where periods of normal cortisol production alternate with hypercortisolism. 1, 2
Understanding Cyclic Cushing's Syndrome
- Cyclic Cushing's syndrome is characterized by repeated episodes of cortisol excess interspersed with periods of normal cortisol secretion, with cycles occurring regularly or irregularly 2
- The intercyclic phases (periods of normal cortisol) can range from days to years, making diagnosis challenging 2
- To formally diagnose cyclic Cushing's syndrome, three peaks and two troughs of cortisol production should be demonstrated 2
- Most cases (54%) originate from pituitary corticotroph adenomas, 26% from ectopic ACTH-producing tumors, and 11% from adrenal tumors 2
Impact of Large Urine Volume on UFC Results
- Large urine volumes (3-4L) can dilute cortisol concentration, potentially leading to falsely normal UFC results despite active disease 3
- The random variability in UFC can be as high as 50%, which is why multiple collections are recommended to account for intra-patient variability 3
- UFC measurements reflect overall cortisol production independent of cortisol-binding globulin changes, but can be affected by significant polyuria 3
Diagnostic Approach for Cyclic Cushing's Syndrome
- For suspected cyclic Cushing's syndrome, the Endocrine Society recommends obtaining multiple UFC measurements, late-night salivary cortisol (LNSC), and dexamethasone suppression tests (DST) 1
- At least two or three UFC collections should be obtained to evaluate variability 1
- Frequent measurements of urinary cortisol or salivary cortisol levels are a reliable and convenient screening tool for suspected cyclic Cushing's syndrome 2
- In classical cyclic Cushing's disease or in patients with unpredictable fluctuating cortisol levels, dynamic testing and localization testing should be preceded by confirmatory tests to document the active phase 1
Diagnostic Challenges in Cyclic Cushing's Syndrome
- The fluctuating clinical picture and discrepant biochemical findings make cyclic Cushing's syndrome extremely difficult to diagnose 2
- Cortisol stimulation or suppression tests may give spurious results due to spontaneous falls or rises in serum cortisol at the time of testing 2
- DST may be the preferred test for shift workers and patients with disrupted circadian rhythm due to uneven sleep schedules 1, 4
- The desmopressin test has high specificity for Cushing's disease and is less complex and expensive than the Dex-CRH test 1
Recommendations for Further Evaluation
- For suspected cyclic Cushing's syndrome with normal UFC despite clinical suspicion:
- Perform repeated UFC measurements over time to capture the cyclical pattern 1, 3
- Consider late-night salivary cortisol tests which may be easier for the patient to complete 1
- Use DST during suspected active phases of the disease 1, 5
- Consider measuring dexamethasone levels during DST to ensure adequate absorption 4
- Document the active phase before proceeding with dynamic testing and localization studies 1
Pitfalls to Avoid
- Don't rely on a single normal UFC result to rule out cyclic Cushing's syndrome 3, 2
- Be aware that the condition may be unrecognized for years since typical Cushing's features may be absent due to the intermittent and brief duration of cortisol hypersecretion 6
- Don't perform bilateral inferior petrosal sinus sampling (IPSS) to diagnose hypercortisolism, as the central-to-peripheral ACTH gradient in healthy controls and pseudo-Cushing's overlaps with Cushing's disease 1
- Consider that some cases of cyclic Cushing's syndrome may present with recurrent episodes of edema, hypokalemia, or cardiac arrhythmia rather than classic Cushing's features 6, 7