Night Cortisol Levels for Diagnosing Cushing’s Syndrome Less Accurate in Clinical Practice

Posted on August 5, 2018 by MaryO

Salivary cortisol levels can be used to diagnose Cushing’s syndrome with relatively high reliability, but each test center should establish its own measurement limits depending on the exact method used for the test, a study from Turkey shows.

Researchers, however, caution that late-night salivary cortisol measurements in clinical practice is likely to be less accurate than that seen in controlled studies, and some patients might require additional tests for a correct diagnosis.

The study, “Diagnostic value of the late-night salivary cortisol in the diagnosis of clinical and subclinical Cushing’s syndrome: results of a single-center 7-year experience,” was published in the Journal of Investigative Medicine

In healthy individuals, the levels of cortisol — a steroid hormone secreted by the adrenal glands — go through changes over a 24-hour period, with the lowest levels normally detected at night.

But this circadian rhythm is disrupted in certain diseases such as Cushing’s syndrome, where night cortisol levels can be used as a diagnostic tool.

Among the tests that can be used to detect these levels are late-night serum cortisol (LNSeC) and late-night salivary cortisol (LNSaC) tests. Since it uses saliva samples, LNSaC is more practical and does not require hospitalization, so it is often recommended for the diagnosis of Cushing’s syndrome.

So far, though, there has been no consensus regarding cutoff values and the sensitivity of the test.

Mustafa Kemal Balci, MD, and his team at the Akdeniz University in Turkey aimed to evaluate the diagnostic use of LNSaC in patients with clinical Cushing’s syndrome and in those with subclinical Cushing’s syndrome — people with excess cortisol but without signs of the disease.

The study involved 58 patients with clinical Cushing’s syndrome (CCS), 53 with subclinical Cushing’s syndrome (SCS), and 213 patients without Cushing’s syndrome who were used as controls.

Saliva and serum cortisol levels were measured in all patients, and statistical tests were used to study differences in these levels among the three groups of patients.

In CSC patients, the median cortisol levels were 0.724 micrograms per deciliter of blood (µg/dL), which dropped to 0.398 and 0.18 in patients with subclinical disease and controls.

The optimal cutoff point to distinguish patients with clinical Cushing’s was set at 0.288 µg/dL, where 89.6% of patients identified as positive actually have the disease (sensitivity), and 81.6% of patients deemed as negative were without the disease (specificity).

With a lower cutoff point — 0.273 µg/dL — researchers were also able to identify patients with subclinical disease with high sensitivity and specificity.

While the test showed high sensitivity and specificity values for clinical Cushing’s syndrome, its diagnostic performance was lower than expected in daily clinical practice, researchers said.

“The diagnostic performance of late-night salivary cortisol in patients with subclinical Cushing’s syndrome was close to its diagnostic performance in patients with clinical Cushing’s syndrome,” researchers wrote.

However, regarding the application of this test in other centers, they emphasize that “each center should determine its own cut-off value based on the method adopted for late-night salivary cortisol measurement, and apply that cut-off value in the diagnosis of Cushing’s syndrome.”

From https://cushingsdiseasenews.com/2018/07/31/late-night-salivary-cortisol-levels-questioned-diagnosis-cushings-syndrome/

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Medical therapy ‘reasonable option’ vs. surgery in Cushing’s disease

Posted on July 19, 2018 by MaryO

In a large percentage of patients with Cushing’s disease, medical therapy effectively induces cortisol normalization, suggesting the choice may serve as a useful first-line treatment vs. surgery for some, according to findings from a systematic review and meta-analysis published in Pituitary.

Cushing’s syndrome is generally approached by removal of the adrenocorticotropic hormone (ACTH)-producing tumor in ectopic disease and by adrenalectomy in ACTH-independent disease, Leonie H. A. Broersen, MD, of the department of medicine at Leiden University Medical Centre in Leiden, Netherlands, wrote in the study background. However, medical therapy can be used to control cortisol secretion preoperatively and as a “bridge” until control of hypercortisolism is achieved by radiotherapy, whereas use of medical therapy as a first-line treatment is increasing, they noted.

“Medical treatment is a reasonable treatment option for Cushing’s disease patients in case of a contraindication for surgery, a recurrence, or in patients choosing not to have surgery,” Broersen told Endocrine Today. “In case of side effects or no treatment effect, an alternate medical therapy or combination therapy can be considered.”

Broersen and colleagues analyzed data from 35 studies with 1,520 patients reporting on six medical therapies for Cushing’s disease, including studies assessing pasireotide (n = 2; Signifor LAR, Novartis), mitotane (n = 5; Lysodren, Bristol-Myers Squibb), cabergoline (n = 3), ketoconazole (n = 8), metyrapone (n = 5; Metopirone, HRA Pharma), mifepristone (n = 2; Korlym, Corcept Therapeutics) and multiple medical agents (n = 10), all published between 1971 and 2017. Studies included 11 single-arm trials, two randomized controlled trials with two treatment arms, and 22 cohort studies. In 28 studies, normalization of cortisol was measured by urinary free cortisol, midnight salivary cortisol or a low-dose dexamethasone test, with 25 studies reporting on clinical improvement and three studies reporting on quality of life.

Across studies, medical treatment was effective in normalizing cortisol levels in Cushing’s disease in 35.7% (cabergoline) to 81.8% (mitotane) of patients, according to the researchers. In seven studies reporting data separately for medical therapy as primary (n = 4) or secondary therapy (n = 5), researchers found medication as primary therapy normalized cortisol levels in 58.1% of patients (95% CI, 49.7-66.2), similar to the effect of medication as a secondary therapy (57.8%; 95% CI, 41.3-73.6). In studies in which at least 80% of patients with Cushing’s disease were pretreated with medication before surgery, researchers observed a preoperative normalization of cortisol levels in 32.3% of patients (95% CI, 20-45.8). Patients using medical monotherapy experienced a lower percentage of cortisol normalization vs. patients using multiple agents (49.4% vs. 65.7%), according to researchers, with normalization rates higher among patients with concurrent or previous radiotherapy.

Across studies, 39.9% of patients experienced mild adverse effects, and 15.2% experienced severe adverse effects.

“Importantly, medical agents for hypercortisolism can cause severe side effects, leading to therapy adjustment or withdrawal in 4.8% (cabergoline) to 28.4% (mitotane) of patients,” the researchers wrote. “These results suggest that medical therapy can be considered a reasonable treatment alternative to the first-choice surgical treatment when regarding treatment effectiveness and side effects.” – by Regina Schaffer

For more information: Leonie H. A. Broersen, MD, can be reached at l.h.aA.broersen@lumc.nl.

Disclosure: The authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B294187ce-3f5e-4d3f-b02e-5023515c3b0b%7D/medical-therapy-reasonable-option-vs-surgery-in-cushings-disease

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Late-night Salivary Cortisol a Poor Approach for Detecting Cushing’s in Obese Patients

Posted on March 30, 2018 by MaryO

Assessment of late-night salivary cortisol (LNSC) levels is a poor diagnostic tool for detecting Cushing’s disease in obese patients, a new study from Germany shows.

The test demonstrated a particularly poor sensitivity in obese people, meaning it will often suggest a patient has Cushing’s disease when that is not the case — called a false-positive.

The study, “Specificity of late‑night salivary cortisol measured by automated electrochemiluminescence immunoassay for Cushing’s disease in an obese population,” appeared in the Journal of Endocrinological Investigation.

Although excessive weight gain is a common symptom of Cushing’s disease, existing indications advise clinicians to test for Cushing’s in obese people only if the disease is clinically suspected.

The utility of measuring LNSC for Cushing’s disease screening is well established. However, differences in assays, sample collection methods, and controls have led to a great variability in the proposed reference ranges and cut-off values. Also, according to the Endocrine Society, the influence of gender, age, and co-existing medical conditions on LNSC concentrations is still unclear.

Regarding obesity, data on the specificity of assessing late-night salivary cortisol levels is contradictory, as some studies found no differences while others reported lower specificity compared to healthy individuals.

An additional factor complicating LNSC measures in obese people is the prevalence of type 2 diabetes mellitus (T2DM), which may also lead to elevated cortisol levels.

Research showed a high rate of false-positive LNSC measurements in obese patients with poorly controlled type 2 diabetes. Also, in patients with recently diagnosed diabetes, investigators found that LNSC had very low specificity — the proportion of patients with Cushing’s who test positive — and a poor predictive value.

Recent reports showed a high diagnostic accuracy using automated electrochemiluminescent assays (ECLIA) in patients with Cushing’s disease. These methods use special labels conjugated to antibodies that produce light when they bind to a specific target.

The research team used an ECLIA assay to test the specificity of LNSC in obese patients both with and without diabetes. The investigators also intended to establish a reference range and cut-off value for this diagnostic approach.

Adults who requested weight loss treatment were included in the study, including 34 patients with a confirmed diagnosis of Cushing’s and 83 obese people, defined as having a body mass index (BMI) of at least 35 kg/m2. Forty healthy individuals were also analyzed.

Eight out of the 34 Cushing’s patients had a BMI within the obese range, which correlates with an overlap in patients awaiting bariatric surgery for weight loss, the investigators observed.

All subjects underwent LNSC assessment at 11 p.m. Results revealed significant differences in mean LNSC values — 19.9 nmol/L in Cushing’s disease patients, 10.9 nmol/L in obese subjects, and 4.7 nmol/L in those of normal weight.

Compared to healthy and obese participants, measuring LNSC in Cushing’s disease patients had a maximum sensitivity of 67.6% and a specificity of 85.4%. This was lower than prior data from obese patients with two features of Cushing’s disease.

The cut-off value for detecting Cushing’s was 12.3 nmol/L, which is in line with other studies “and underlines the importance of an evaluation with an obese cohort vs. [Cushing’s disease],” the investigators wrote.

Results did not show an association between BMI, type 2 diabetes, and LNSC for all groups.

“In our obese cohort, we found that LNSC assayed by ECLIA had a low specificity in the diagnosis of [Cushing’s disease],” the researchers wrote. “However, the clear advantage of LNSC over other tests is the simple and stress-free sampling method.”

From https://cushingsdiseasenews.com/2018/03/29/nighttime-salivary-cortisol-poor-approach-detect-cushings-disease-obese-patients/

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Late-night salivary cortisol often fluctuates widely in Cushing’s disease

Posted on January 18, 2018 by MaryO

Among patients with new, persistent or recurrent Cushing’s disease, researchers observed cortisol levels that fluctuated widely over 6 months, with measurements falling into the normal range more than 50% of the time for a few patients, according to findings from a prospective study.

“Cortisol levels, as represented by late-night salivary cortisol, in Cushing’s disease patients without variable symptoms fluctuate much more widely than many endocrinologists may realize,” Laurence Kennedy, MD, FRCP, chairman of the department of endocrinology, diabetes and metabolism at the Cleveland Clinic, told Endocrine Today. “In patients with recurrent or persistent Cushing’s disease, the late-night salivary cortisol can be normal much more frequently than has been appreciated.”

Kennedy and colleagues analyzed late-night salivary samples (between 11 p.m. and midnight) from 16 patients with confirmed Cushing’s disease for up to 42 consecutive nights between January and June 2014 (age range, 27-62 years). Researchers defined normal late-night salivary cortisol as between 29 ng/dL and 101 ng/dL.

Within the cohort, eight patients had a new diagnosis of Cushing’s disease and underwent transsphenoidal surgery; eight patients had recurrent or persistent Cushing’s disease.

Researchers observed at least three peaks and two troughs in 12 of the 16 patients, and late-night salivary cortisol levels were in the normal range on at least one occasion in 14 patients (all patients with recurrent/persistent disease and six of eight patients with new disease). Only two of the 16 patients exhibited fluctuations that were deemed cyclical, according to researchers, with the interval between peaks approximately 4 days, they noted.

In five of the eight patients with recurrent or persistent disease, the lowest late-night salivary cortisol measurement was at or below the limit of detection on the assay and approximately 1 in 3 measurements were in the normal range, researchers found. Four patients had normal measurements more than 50% of the time.

Additionally, six of the patients with recurrent or persistent disease had measurements in the normal range on two consecutive nights on at least one occasion, two patients had six such measurements in a row, and one had 31 consecutive normal levels, according to researchers.

In six patients with newly diagnosed Cushing’s disease with at least one normal late-night salivary cortisol measurement, the maximum levels ranged from 1.55 to 15.5 times the upper limit of normal.

“First, widely fluctuant cortisol levels in patients with Cushing disease do not appear to be associated with fluctuating symptoms, at least in our patient population,” Kennedy said. “Second, you need to be careful drawing conclusions on the efficacy of potential medical treatments for Cushing’s disease based on only one or two late-night salivary cortisol levels, given the extreme variation that occurs in the untreated patient. Third, diagnosing recurrent or persistent Cushing’s disease can be challenging at the best of times, and, though it is felt that late-night salivary cortisol may be the best test for early diagnosis, it may require more than the suggested two, three or four tests on successive nights to make the diagnosis.”

Kennedy said better tests for diagnosing Cushing’s disease are needed, adding that investigating the potential utility of salivary cortisone could be useful. – by Regina Schaffer

For more information:

Lawrence Kennedy, MD, can be reached at Cleveland Clinic, Department of Endocrinology, Diabetes and Metabolism, 9500 Euclid Ave., Cleveland, OH 44195; email: kennedl4@ccf.org.

Disclosures: The authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7Bf9721377-6a2a-401c-a16d-2d4624233b63%7D/late-night-salivary-cortisol-often-fluctuates-widely-in-cushings-disease

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Who’s at Risk for Cushing’s?

Posted on August 16, 2016 by MaryO

by Kristen Monaco
Contributing Writer, MedPage Today

Researchers have developed a new method to assess specific populations for Cushing’s syndrome, based on results from a multicenter study.

The prospective cohort study evaluated at-risk patients for Cushing’s syndrome to create a novel type of scoring system in order to better predict the development of disease, stated lead author Antonio León-Justel, PhD,of the Seville Institute of Biomedicine in Spain, and colleagues.

Cushing’s syndrome is identified by an excess of cortisol and/or glucocorticoids in the blood, which can result in myriad negative health outcomes, including an increased risk of death and morbidity, according to the study in The Journal of Clinical Endocrinology & Metabolism.

Because Cushing’s syndrome (CS) is complex and difficult to diagnose, there is a necessity for new methods to assess at-risk populations in order to mitigate the rising prevalence of the disorder, the authors noted.

“The diagnosis of CS might pose a considerable challenge even for experienced endocrinologists since there are no pathognomonic symptoms or signs of CS and most of the symptoms and signs of CS are common in the general population including obesity, hypertension, bone loss, and diabetes,” the senior author, Alfonso Leal Cerro, MD, toldMedPage Today via email. “Routine screening for CS remains impractical due to the estimated low prevalence of the disease. However this prevalence might be higher in at-risk populations.”

The authors screened a total of 353 at-risk patients from 13 different hospitals across Spain between January 2012 and July 2013 to measure cortisol variability from saliva samples.

At-risk populations, which the authors note have a higher prevalence of Cushing’s syndrome, included individuals with type 2 diabetes, hypertension, and osteoporosis.

The patients screened in the study were each identified as having at least two of the risk factors for Cushing’s syndrome: high blood pressure (defined as taking two or more drugs and having a systolic blood pressure over 140 mmHg and/or a diastolic blood pressure over 90 mmHg), obesity (body mass index >30), uncontrolled diabetes (HbA1c>7.0%), osteoporosis (T-score ≥ -2.5 SD), and virilization syndrome (hirsutism) with menstrual disorders.

The researchers used clinical and biochemical methods of assessment. Clinical methods included inspection of physical characteristics, such as muscle atrophy, purple striae, and/or facial plethora. Biochemical methods included collecting saliva and blood samples from participants to test cortisol levels using a chemiluminescence method. Each individual was identified as either negative for hypercortisolism (late-night salivary cortisol [LNSC] ≤ 7.5 nmol/L and dexamethasone suppression test [DST] ≤ 50 nmol/L) or positive for hypercortisolism (LNSC > 7.5 nmol/L and DST > 50 nmol/L).

Univariate testing indicated the following significant characteristics to be positively correlated with the development of Cushing’s syndrome:

  • Muscular atrophy (15.2, CI 95% 4.48-51.25);
  • Osteoporosis (4.60, 1.66-12.75); and
  • Dorsocervical fat pad (3.32, 1.48-7.5).

A logistic regression analysis of LNSC values also showed significant correlation between Cushing’s syndrome and the following top three characteristics:

  • Muscular atrophy (9.04, CI 95% 2.36-34.65);
  • Osteoporosis (3.62, CI 95% 1.16-11.35); and
  • Dorsocervical fat pad (3.3, CI 95% 1.52-7.17).

Roberto Salvatori, MD, professor and medical director of the Johns Hopkins Pituitary Center, who was not involved with the study, commented to MedPage Today in an email: “Any endocrinologist would proceed with careful Cushing biochemical evaluation in the presence of the clinical features (muscular atrophy, osteoporosis, and dorsocervical fat pad) that are well known to be associated with hypercortisolism. Of notice, the odds ratio is further increased by an abnormal late-night salivary cortisol, which is already a screening test for hypercortisolism.”

The researchers used their results to develop an equation to determine the level of risk a patient has for developing Cushing’s syndrome, taking into account factors for osteoporosis, dorsocervical fat pads, muscular atrophy, and LNSC levels.

Although the study was able to develop a comprehensive risk model for the syndrome, when tested against the prevalence for Cushing’s syndrome in the subject group, the equation generated a total of 56 false-positive and 25 true-positive results. Overall, the researchers wrote, 83% of patients were accurately classified as belonging to the at-risk population when using the equation.

Because the newly developed equation for identifying at-risk individuals involved factors that are relatively easy to test for, the authors noted that clinical application is broad and cost-effective in a primary care setting.

“We would like to test the scoring system in different clinical settings such as primary care or hypertension clinics,” Leal Cerro said. “Primary care would be a particularly interesting setting since it might significantly decrease the time to diagnosis, something critical to avoid an excessive exposure to glucocorticoid excess and consequent deleterious effects.”

Salvatori said that while the study was a good start at shedding light on some of the unknowns about Cushing’s syndrome, more research is required. “The real question in my mind is when does a non-endocrinologist need to suspect Cushing in a general medicine, orthopedic, or other clinic? When the internal medicine residents ask me about guidelines for ‘who to screen for hypercortisolism in my clinic,’ I am unable to provide an evidence-based answer.”

The study was funded by a grant from Novartis Oncology, Spain.

León-Justel and Leal Cerro disclosed financial relationships with Novartis Oncology, Spain.

  • Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 08.15.2016

From http://www.medpagetoday.com/endocrinology/generalendocrinology/59688

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