Utility of measurement of dexamethasone levels in the diagnostic testing for Cushing’s syndrome

Posted on June 21, 2014 by MaryO

From Day 1 of the 16th International Congress of Endocrinology and the Endocrine Society’s 96th Annual Meeting and Expo »

Chicago, IL – June 21, 2014

ST Sharma, JA Yanovski, SB Abraham, LK Nieman

Summary: Dexamethasone (dex) suppression tests (DST) are used for screening and differential diagnosis of Cushing’s syndrome (CS). The 1 mg overnight (LD) DST is used to diagnose CS, the dex-suppressed CRH stimulation (Dex-CRH) test to differentiate CS from pseudocushings (PCS) while the 8 mg overnight (HD) DST is used to differentiate Cushing’s disease (CD) from ectopic ACTH syndrome (EAS). Researchers assessed the utility of dex levels in improving the diagnostic accuracy of these tests and they found that low dex and high CBG levels can account for false positive (FP) DST and Dex-CRH test results. Use of a higher dex dose in pts with low dex levels can help decrease FP results.

Methods:

  • This is a retrospective study of patients (pts) with CS, PCS and normal volunteers (NV) who had a dex level measured as part of LDDST, HDDST or Dex-CRH test.
  • A post-dex cortisol (F) level ≥1.8 mcg/dl in the LDDST and a 15 min post-CRH F level ≥1.4 mcg/dl in the Dex-CRH test suggested CS.
  • A ≥69% suppression of F levels in HDDST indicated CD.
  • Dex levels

Results:

  • LDDST (n=77): Post-dex F was abnormal in 44 pts, 37 of these did not have CS on follow-up.
  • Proportion of pts with low dex levels was similar in those with incorrect or correct LDDST results (P=0.7).
  • Three of 5 pts with an abnormal result and low dex levels (44-117 ng/dl) had suppressed post-dex F levels after a 2 mg overnight DST. HDDST (N=56): Results were not consistent with the final diagnosis (CD or EAS) in 13 (23%) pts.
  • Of these, 5 had low dex levels (400-1220 ng/dl).
  • Proportion of pts with low dex levels was similar between those with correct and incorrect HDDST results (P=0.5).
  • HDDST in 1 pt with ACTH-dependent CS suggested EAS (28% suppression) with low dex level.
  • IPSS indicated CD.
  • After a doubled dex dose (16 mg), F levels suppressed by 76%, changing the HDDST result to CD.
  • Dex-CRH (n=139): Results were consistent with the final diagnosis in 133 pts (74 CS, 20 NV, 39 PCS).
  • Six pts with an abnormal result had dex levels
  • Of these, repeat testing with doubled dex dose (1 mg every 6 hours) in 2 pts led to higher dex levels (610, 757 ng/dl) and normal F level in one.
  • Two pts with abnormal result were on OCPs, 1 with a known high cortisol binding globulin (CBG) level.
  • None had CS on follow-up.
  • There was no correlation between dex and post-dex F levels in LDDST, 15 min post-CRH F levels in Dex-CRH test and % suppression of F post-dex in HDDST (P=NS).

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Prolactin Measure Didn’t Help Localize Pituitary Adenoma

Posted on August 10, 2013 by MaryO

By: SHERRY BOSCHERT, Clinical Endocrinology News Digital Network

SAN FRANCISCO – Measurements of prolactin levels during inferior petrosal sinus sampling did not help localize pituitary adenomas in patients with Cushing’s disease in a study of 28 patients, contradicting findings from a previous study of 28 patients.

The value of prolactin measurements in tumor localization using inferior petrosal sinus sampling (IPSS) remains unclear and needs further study in a larger, prospective study, Dr. Susmeeta T. Sharma said at the Endocrine Society’s Annual Meeting. The current and previous studies were retrospective analyses.

Although IPSS has been considered the standard test in patients with ACTH-dependent Cushing’s syndrome to differentiate between ectopic ACTH secretion and Cushing’s disease, there has been controversy about its value in localizing adenomas within the pituitary gland once a biochemical diagnosis of Cushing’s disease has been made. Various studies that used an intersinus ACTH ratio of 1.4 or greater before or after corticotropin-releasing hormone (CRH) stimulation have reported success rates as low as 50% and as high as 100% for tumor location.

A previous retrospective study of 28 patients with Cushing’s disease reported that adjusting the ACTH intersinus gradient by levels of prolactin before or after CRH stimulation, and combining the prolactin-adjusted ACTH intersinus ratio, improved pituitary adenoma localization. Magnetic resonance imaging (MRI) alone correctly localized the pituitary adenoma in 17 patients (61%), a prolactin-adjusted ACTH intersinus ratio of at least 1.4 improved the localization rate to 21 patients (75%), and combining MRI and the prolactin-adjusted ACTH intersinus ratio improved localization further to 23 patients, or 82% (Clin. Endocrinol. 2012;77:268-74).

The findings inspired the current retrospective study. The investigators looked at prolactin levels measured in stored petrosal and peripheral venous samples at baseline and at the time of peak ACTH levels after CRH stimulation for 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013. The investigators calculated prolactin-adjusted values by dividing each ACTH value by the concomitant ipsilateral prolactin value. They used an intersinus ACTH ratio of 1.4 or greater to predict tumor location.

At surgery, 26 patients had a single lateral tumor (meaning its epicenter was not in the midline), 1 patient had a central microadenoma, and 1 patient had a macroadenoma, reported Dr. Sharma of the National Institute of Child Health and Human Development, Bethesda, Md.

MRI findings accurately identified the location of 21 of the 26 lateral tumors (81%), compared with accurate localization in 18 patients using either the unadjusted ACTH intersinus ratio or the prolactin-adjusted ACTH intersinus ratio (69% for each), she said.

Incorrect tumor localization occurred with one patient using MRI alone and seven patients using either ratio. In four patients whose tumors could not be localized by MRI, the uncorrected and prolactin-adjusted ratios localized one tumor correctly and three tumors incorrectly. Only MRI correctly localized the one central microadenoma.

“We did not find any difference in localization rates by measurement of prolactin during IPSS,” she said. The small size of the study and its retrospective design invite further research in a more robust study.

Dr. Sharma reported having no financial disclosures.

From Clinical Endocrinology News

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Pituitary tumor size not definitive for Cushing’s

Posted on July 12, 2013 by MaryO

By: SHERRY BOSCHERT, Family Practice News Digital Network

SAN FRANCISCO – The size of a pituitary tumor on magnetic resonance imaging in a patient with ACTH-dependent Cushing’s syndrome can’t differentiate between etiologies, but combining that information with biochemical test results could help avoid costly and difficult inferior petrosal sinus sampling in some patients, a study of 131 cases suggests.

If MRI shows a pituitary tumor larger than 6 mm in size, the finding is 40% sensitive and 96% specific for a diagnosis of Cushing’s disease as the cause of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome, and additional information from biochemical testing may help further differentiate this from ectopic ACTH secretion, Dr. Divya Yogi-Morren and her associates reported at the Endocrine Society’s Annual Meeting.

Pituitary tumors were seen on MRI in 6 of 26 patients with ectopic ACTH secretion (23%) and 73 of 105 patients with Cushing’s disease (69%), with mean measurements of 4.5 mm in the ectopic ACTH secretion group and 8 mm in the Cushing’s disease group. All but one tumor in the ectopic ACTH secretion group were 6 mm or smaller in diameter, but one was 14 mm.

Because pituitary “incidentalomas” as large as 14 mm can be seen in patients with ectopic ACTH secretion, the presence of a pituitary tumor can’t definitively discriminate between ectopic ACTH secretion and Cushing’s disease, said Dr. Yogi-Morren, a fellow at the Cleveland Clinic.

That finding contradicts part of a 2003 consensus statement that said the presence of a focal pituitary lesion larger than 6 mm on MRI could provide a definitive diagnosis of Cushing’s disease, with no further evaluation needed in patients who have a classic clinical presentation and dynamic biochemical testing results that are compatible with a pituitary etiology (J. Clin. Endocrinol. Metab. 2003;88:5593-602). The 6-mm cutoff, said Dr. Yogi-Morren, came from an earlier study reporting that 10% of 100 normal, healthy adults had focal pituitary abnormalities on MRI ranging from 3 to 6 mm in diameter that were consistent with a diagnosis of asymptomatic pituitary adenomas (Ann. Intern. Med. 1994;120:817-20).

A traditional workup of a patient with ACTH-dependent Cushing’s syndrome might include a clinical history, biochemical testing, neuroimaging, and an inferior petrosal sinus sampling (IPSS). Biochemical testing typically includes tests for hypokalemia, measurement of cortisol and ACTH levels, a high-dose dexamethasone suppression test, and a corticotropin-releasing hormone (CRH) stimulation test. Although IPSS is the gold standard for differentiating between the two etiologies, it is expensive and technically difficult, especially in institutions that don’t regularly do the procedure, so it would be desirable to avoid IPSS if it’s not needed in a subset of patients, Dr. Yogi-Morren said.

The investigators reviewed charts from two centers (the Cleveland Clinic and the M.D. Anderson Cancer Center, Houston) for patients with ACTH-dependent Cushing’s syndrome seen during 2000-2012.

ACTH levels were significantly different between groups, averaging 162 pg/mL (range, 58-671 pg/mL) in patients with ectopic ACTH secretion, compared with a mean 71 pg/mL in patients with Cushing’s disease (range, 16-209 pg/mL), she reported. Although there was some overlap between groups in the range of ACTH levels, all patients with an ACTH level higher than 210 pg/mL had ectopic ACTH secretion.

Median serum potassium levels at baseline were 2.9 mmol/L in the ectopic ACTH secretion group and 3.8 mmol/L in the Cushing’s disease group, a significant difference. Again, there was some overlap between groups in the range of potassium levels, but all patients with a baseline potassium level lower than 2.7 mmol/L had ectopic ACTH secretion, she said.

Among patients who underwent a high-dose dexamethasone suppression test, cortisol levels decreased by less than 50% in 88% of patients with ectopic ACTH secretion and in 26% of patients with Cushing’s disease.

Most patients did not undergo a standardized, formal CRH stimulation test, so investigators extracted the ACTH response to CRH in peripheral plasma during the IPSS test. As expected, they found a significantly higher percent increase in ACTH in response to CRH during IPSS in the Cushing’s disease group, ranging up to more than a 1,000% increase. In the ectopic ACTH secretion group, 40% of patients did have an ACTH increase greater than 50%, ranging as high as a 200%-300% increase in ACTH in a couple of patients.

“Although there was some overlap in the biochemical testing, it is possible that it provides some additional proof to differentiate between ectopic ACTH secretion and Cushing’s disease,” Dr. Yogi-Morren said.

In the ectopic ACTH secretion group, the source of the secretion remained occult in seven patients. The most common identifiable cause was a bronchial carcinoid tumor, in six patients. Three patients each had small cell lung cancer, a thymic carcinoid tumor, or a pancreatic neuroendocrine tumor. One patient each had a bladder neuroendocrine tumor, ovarian endometrioid cancer, medullary thyroid cancer, or a metastatic neuroendocrine tumor from an unknown primary cancer.

The ectopic ACTH secretion group had a median age of 41 years and was 63% female. The Cushing’s disease group had a median age of 46 years and was 76% female.

Dr. Yogi-Morren reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

From Famiiy Practice News

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