Does a Normal Urine Free Cortisol Result Rule out Cushing’s Syndrome?

Endocrine Society’s 97th Annual Meeting and Expo, March 5–8, 2015 – San Diego
SAT-384:
Does a Normal Urine Free Cortisol Result Rule out Cushing’s Syndrome?
1 and 2

  • 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
  • 2National Institutes of Health, Bethesda, MD
Presentation Number: SAT-384
Date of Presentation: March 7, 2015
Abstract:Background: Urine free cortisol (UFC) has been traditionally used as one of the first steps in the diagnostic evaluation of Cushing’s syndrome (CS) (1). False positive results, especially values less than twice the upper limit of normal (ULN), can be seen in uncontrolled diabetes, obesity, depression, alcoholism, increased fluid intake, overcollection and stress. False negative results have also been reported with incomplete collection, in mild or cyclic CS and in patients with renal insufficiency (2-3). We evaluated the diagnostic accuracy of UFC and 24-hour urine 17-hydroxycorticosteroids (17OHCS) in patients with CS.Methods: Retrospective study of all CS patients evaluated at the National Institutes of Health (NIH) from 2009 to 2014. Screening tests used for CS included UFC, 17OHCS, late night salivary cortisol (LNSC), midnight serum cortisol and low dose (1mg overnight or 2-day 2mg/day) dexamethasone suppression test (DST). Values above reference range for UFC, 17OHCS and LNSC, a midnight serum cortisol ≥ 7.5 mcg/dL, and post-dexamethasone cortisol values ≥ 1.8 mcg/dL were considered abnormal. Hourly 24-hour sampling for cortisol was performed in a few cases with a mild clinical phenotype and equivocal test results. UFC was measured using liquid chromatography/tandem mass spectrometry (LC-MS/MS). 17OHCS was measured using colorimetric methodology with Porter-Silber reaction (reported as mg/g of creatinine). Mean of the first two UFC and 17OHCS values (appropriate collection by urine volume and creatinine) obtained within 30 days of initial NIH presentation were used for the purpose of this study.

Results: Seventy-two patients were diagnosed with CS (aged 18-77 years, 51 females). Of these, 51 had Cushing’s disease (CD), 10 had ectopic CS while 2 had an adrenal source of Cushing’s based on pathology. Biochemical tests including inferior petrosal sinus sampling (IPSS) suggested ectopic CS but no tumor was found (occult) in 6 patients. IPSS was indicative of a pituitary source in 2 patients with failed transsphenoidal surgery while one patient did not complete evaluation for ACTH-dependent CS. UFC results were available in all, 17OHCS in 70, LNSC in 21, midnight serum cortisol in 68 and DST results in 37 patients. UFC was falsely normal in six and only minimally elevated (< 2 x ULN) in 13 patients (normal renal function, no history of cyclicity, all had CD). Of these 19 patients, 24h 17OHCS was abnormal in all, LNSC was abnormal in 12, midnight serum cortisol was abnormal in 18 and DST was abnormal in 12 patients. Hourly 24-hour sampling for cortisol performed in 3 of these patients revealed abnormal nadir (> 7.5 mcg/dL) and mean daily serum cortisol (> 9 mcg/dL) levels.

Conclusion: UFC can be falsely normal or only minimally elevated in mild CS. Multiple collections and use of complimentary screening tests including 24-hour urine 17OHCS and LNSC can help make a diagnosis and prevent delay in treatment.

(1) Newell-Price J, et al. Cushing’s syndrome. Lancet. 2006;367(9522):1605-17.  (2) Alexandraki KI, et al. Is urinary free cortisol of value in the diagnosis of Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes. 2011;18:259–63.  (3) Kidambi S, et al. Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur J Endocrinol. 2007;157(6):725-31

Nothing to Disclose: STS, LKN

Sources of Research Support: This research was in part supported by the intramural research program of NICHD/NIH

Read the entire article at http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2015.ahpaa.9.sat-384

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