Screening tool accurately predicts Cushing’s syndrome in most at-risk patients

León-Justel A, et al. J Clin Endocrinol Metab. 2016;doi:10.1210/jc.2016-1673.

A scoring system based on clinical signs and a late-night salivary cortisol test accurately predicted Cushing’s syndrome in at-risk patients, with only one missed case, according to recent findings.

In a prospective, multicenter study, Antonio León-Justel, PhD, of the biochemistry department at the Hospital Universitario Virgen del Rocío in Seville, Spain, and colleagues analyzed data from 353 patients treated in endocrinology units in 13 university hospitals in Spain between 2012 and July 2013. All participants had at least two of five features compatible with Cushing’s syndrome, including obesity, hypertension, poorly controlled diabetes,hirsutism with menstrual disorders and osteoporosis; none of the included patients was referred to clinic with the suspicion of Cushing’s syndrome. All patients underwent late-night salivary cortisol and serum cortisol measurements after a low-dose (1 mg) dexamethasone test; those with discordant results were followed until December 2014 (mean follow-up time, 22.2 months).

Within the cohort, 26 (7.4%) patients were diagnosed with Cushing’s syndrome (20 adrenocorticotropic hormone-dependent; six of adrenal origin). In univariate logistic regression analysis, researchers found that muscular atrophy (OR = 15.2), followed by osteoporosis (OR = 4.6), dorsocervical fat pad (OR = 3.32), absence of obesity (OR = 0.21) and absence of type 2 diabetes (OR = 0.26), were associated with Cushing’s syndrome; late-night salivary cortisol values were also related (OR = 1.26). However, after multivariable adjustment, researchers found that muscular atrophy (OR = 9.04; 95% CI, 2.36-34.65), osteoporosis (OR = 3.62; 95% CI, 1.16-11.35) and dorsocervical fat (OR = 3.3; 95% CI, 1.52-7.17) remained as independent variables with Cushing’s syndrome.

“Obesity and type 2 diabetes displayed a negative association with [Cushing’s syndrome],” the researchers wrote. “These results might seem paradoxical a priori, but we want to stress that in our analyzed cohort, the prevalence of obesity and diabetes was exceedingly high (likely reflecting the reasons for referral to endocrinology units).”

In receiver operating characteristic (ROC) analysis, researchers determined that a cutoff value of 9.17 nmol/L for late-night salivary cortisol provided the best results, with an area under the curve of 0.893 (P < .001), a sensitivity of 88.5% and specificity of 83.2%.

Researchers developed a risk-scoring system, determining cutoff values from a ROC curve. The estimated area under the ROC curve was 0.93 (P < .001), with a sensitivity of 96.2% and specificity of 82.9%.

“Selecting this cutoff value of four, 271 of 327 subjects (83%) without [Cushing’s syndrome] were correctly identified, while only 1 of 26 [Cushing’s syndrome] cases was missed,” the researchers wrote. “Our model yielded 56 false positives.

“Although all the assessments were performed by specialists (endocrinologists) in our study, this scoring system could be easily tested in independent cohorts and different settings such as primary care or hypertension clinics,” the researchers wrote. “At the very least, our diagnostic prediction model could be used as a framework for future studies and potential improvements in diagnostic performance.” – by Regina Schaffer

Disclosure: Leon-Justel and another researcher report receiving a research grant from Novartis Oncology, Spain.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B50d3d398-c8fe-41e9-b815-87626bfe8a4b%7D/screening-tool-accurately-predicts-cushings-syndrome-in-most-at-risk-patients

Elevated late-night salivary cortisol may indicate recurrent Cushing’s disease

Carroll TB, et al. Endocr Pract. 2016;doi:10.4158/EP161380.OR.

 

Elevated late-night salivary cortisol may serve as an early biochemical marker of recurrent Cushing’s disease, and prompt intervention may result in clinical benefits for people with Cushing’s disease, according to recent study findings.

According to the researchers, late-night salivary cortisol level is more sensitive for detecting Cushing’s disease recurrence compared with urinary free cortisol or a dexamethasone suppression test.

Ty B. Carroll, MD, assistant professor at the Medical College of Wisconsin Endocrinology Center and Clinics in Menomonee Falls, and colleagues evaluated 15 patients (14 women; mean age, 49.1 years) with postsurgical recurrent Cushing’s disease (mean time to recurrence, 3.3 years) after initial remission to determine the performance of urinary free cortisol and late-night salivary cortisol measurements for detecting recurrent Cushing’s disease.

Participants were identified as having Cushing’s disease between 2008 and 2013; there was no standard for follow-up, but after remission confirmation participants were followed at least every 6 months after surgery for 2 years and then annually thereafter. Late-night salivary cortisol was the primary biochemical test to screen for recurrence, and follow-up tests with a dexamethasone suppression test, urinary free cortisol or other tests were performed if late-night salivary results were abnormal or if suspicion of recurrence was high.

Of the cohort, 80% had normal urinary free cortisol (< 45 µg/24 hours) at recurrence. Primary transphenoidal adenoma resection was performed in all participants. Evidence of pituitary adenoma on MRI at the time of recurrence was present in seven of 12 participants with normal urinary free cortisol and two of three participants with abnormal urinary free cortisol. Normal renal function was present in all participants, and 14 underwent testing with late-night salivary cortisol, dexamethasone suppression test and urinary free cortisol.

Of participants with normal urinary free cortisol at recurrence, nine had an abnormal dexamethasone suppression test (cortisol 1.8 µg/dL), and all had at least one elevated late-night salivary cortisol measurement (> 4.3 nmol/L). Mean late-night salivary cortisol was 10.2 nmol/L, and mean urinary free cortisol was 19.9 µg/24 hours.

Therapy for recurrent Cushing’s disease was administered in 11 of the 12 participants with abnormal urinary free cortisol. Adrenocorticotropic hormone (ACTH)-staining pituitary adenoma was confirmed in three participants who underwent repeat transphenoidal adenoma resection. Pharmacotherapy was administered to seven participants with normal urinary free cortisol, and two additional participants underwent bilateral adrenalectomy.

Abnormal dexamethasone suppression test was found in two participants with elevated urinary free cortisol at the time of recurrence, and two participants had confirmed abnormal late-night salivary cortisol. All three participants with elevated urinary free cortisol at the time of recurrence underwent therapy.

“This study has shown potential clinical benefit of either surgical or medical therapy in recurrent [Cushing’s disease] patients with elevations of [late-night salivary cortisol] and normal [urinary free cortisol],” the researchers wrote. “We believe that the outcomes observed in this retrospective case series suggest that the risk/benefit ratio of early treatment needs to undergo a more rigorous prospective evaluation utilizing [late-night salivary cortisol] elevation as an early biochemical marker of recurrent [Cushing’s disease].” – by Amber Cox

Disclosure: Carroll reports being a consultant for Corcept Therapeutics. Please see the full study for a list of all other authors’ relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B9ea4e4ed-6428-49b8-9b2a-11462cb21349%7D/elevated-late-night-salivary-cortisol-may-indicate-recurrent-cushings-disease

VIDEO: Cushing’s syndrome still difficult to diagnose

endo2016

 

In this video exclusive, Hershel Raff, PhD, professor of medicine, surgery and physiology at the Medical College of Wisconsin and scientific director and clinical research supervisor at Aurora St. Luke’s Medical Center, discusses his presentation on the laboratory diagnosis of Cushing’s syndrome.

According to Raff, Cushing’s syndrome is the most enigmatic disease in endocrinology and one of the most difficult to diagnose.

The use of late-night salivary cortisol for diagnosis has recently become popular although the test has been around for many decades. Patients can send samples by mail to have their cortisol measured in a laboratory to determine whether they have Cushing’s. According to Raff, the test is about 95% accurate in making a diagnosis.

View video at http://www.healio.com/endocrinology/adrenal/news/online/%7B5545e9a6-7475-454a-94d5-3994ac8beec5%7D/video-cushings-syndrome-still-difficult-to-diagnose

Urinary free cortisol measurement most accurate first-line test for Cushing’s syndrome diagnosis

ufc

 

Ceccato F, et al. J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2015-2507.

Measuring 24-hour urinary free cortisol with liquid chromatography-mass spectrometry is the most accurate first-line diagnostic tool for diagnosing Cushing’s syndrome in adults, according to research published in The Journal of Clinical Endocrinology & Metabolism.

Filippo Ceccato, MD, of the University Hospital of Padova, Italy, and colleagues analyzed data from 137 adults from 2012 to 2014 (108 women; mean age, 41 years) with clinical conditions suggestive of hypercortisolism. Within the cohort, 38 had a confirmed diagnosis of Cushing’s syndrome (27 women); 99 did not have the diagnosis. In all patients, researchers measured 24-hour urinary free cortisol with liquid chromatography-tandem mass spectrometry (LC-MS/MS), late-night salivary cortisol with a radio-immunometric method and serum cortisol with a 1-mg dexamethasone suppression test. Researchers performed all three tests on patients within 2 weeks to avoid fluctuations in cortisol production.

Researchers found that using LC-MS/MS to measure urinary free cortisol revealed both a combined higher positive ratio (10.7) and a lower negative likelihood ratio (0.03) among the three first-line tests.

For the 1-mg dexamethasone suppression test, researchers found a cutoff of 138 nmol/L revealed the best specificity (97%), whereas the 50 nmol/L cutoff confirmed the best sensitivity (100%). For the late-night salivary cortisol test, researchers found a cutoff of 14.46 provided a sensitivity of 84% and specificity of 89%. For urinary free cortisol, a cutoff of 170 nmol during 24 hours provided a sensitivity of 97% and specificity of 91%.

After using a receiver operating characteristic (ROC)-contrast analysis to compare the power of each test alone and combined with one another, the urinary free cortisol assay was at least as good as all the other possible combinations, according to researchers.

“This result is rather surprising because some authors have recently advocated replacing [the urinary free cortisol] assay with other tests,” the researchers wrote. “Our findings go against such a hypothesis, probably because we used LC-MS/MS in our routine clinical practice for all patients, meaning that high [urinary free cortisol] concentrations pointed to a high likelihood of [Cushing’s syndrome].”

Researchers also observed higher urinary free cortisol levels in men with Cushing’s syndrome, as well as greater cortisol suppression in the 1-mg dexamethasone suppression test in women, but noted that sex did not affect the diagnostic accuracy of tests.

“Choosing between valid tests for ruling out [Cushing’s syndrome] in high-risk populations requires an understanding of their diagnostic performance in different clinical settings,” the researchers wrote. “We recommend measuring [urinary free cortisol] with LC-MS/MS as the first-line screening test for the diagnosis of [Cushing’s syndrome], and then confirming hypercortisolism with the 1-mg [dexamethasone suppression test] or late-night salivary cortisol assay.” – by Regina Schaffer

Disclosure: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B1851a57b-4e76-4c5d-ad7e-ef217c2a2336%7D/urinary-free-cortisol-measurement-most-accurate-first-line-test-for-cushings-syndrome-diagnosis

Does a normal urine free cortisol result rule out Cushing’s syndrome?

ENDO_2015

 

March 07, 2015

SAT 379-412-Cushing’s Syndrome

Does a normal urine free cortisol result rule out Cushing’s syndrome?

ST Sharma, LK Nieman

Summary: Researchers conducted this study to assess the diagnostic accuarcy of urine free cortisol (UFC) and 24-hour urine 17-hydroxycorticosteroids (170HCS) in patients with Cushing’s syndrome, concluding that in patients with mild CS, UFC can be falsely normal or only minimally elevated. Further, they found that to help in making a diagnosis and prevent treatment delays, clinicians may consider incorporating multiple collections and use of complimentary screening tests including 24-hour urine 17OHCS and late night salivary cortisol (LNSC) testing.

Methods:

  • For this retrospective study, researchers included all CS patients evaluated at the National Institutes of Health (NIH) from 2009 to 2014.
  • The screening tests used for CS included UFC, 17OHCS, midnight serum cortisol and low dose (1 mg overnight or 2-day 2 mg/day) dexamethasone suppression test (DST).
  • They defined abnormal as 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.
  • Hourly 24-hour sampling for cortisol was performed in a few cases with a mild clinical phenotype and equivocal test results.
  • Researchers measured UFC using liquid chromatography/tandem mass spectrometry (LC-MS/MS), and 17OHCS was measured using colorimetric methodology with Porter-Silber reaction (reported as mg/g of creatinine).
  • For this study, they used the mean of the first two UFC and 17OHCS values (appropriate collection by urine volume and creatinine) obtained within 30 days of initial NIH presentation.

Results:

  • In all, 72 patients were diagnosed with CS (aged 18-77 years, 51 females), 51 of whom had CD, 10 had ectopic CS, and 2 had an adrenal source of Cushing’s based on pathology.
  • Biochemical tests such as inferior petrosal sinus sampling (IPSS) suggested ectopic CS, but no tumor was found (occult) in 6 patients.
  • In 2 patients with failed transsphenoidal surgery, IPSS was indicative of a pituitary source, and one patient did not complete evaluation for ACTH-dependent CS.
  • UFC results were available in all patients, 17OHCS in 70, LNSC in 21, midnight serum cortisol in 68, and DST results in 37 patients.
  • UFC was falsely normal in 6 patients and only minimally elevated (<2 x ULN) in 13 patients (normal renal function, no history of cyclicity, all had CD); of these 19 patients, 24-hour 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.

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ5BA369FDE9DE4CED82CB6A7CD5BFD1BE/42581/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ENDO2015&nonus=0

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