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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Measuring TSH Levels Could Improve Diagnosis for Cushing’s Syndrome

Posted on June 30, 2018 by MaryO

Measuring the variation in thyroid stimulating hormone blood levels between midnight and morning may be better for diagnosing Cushing’s syndrome than current approaches, a study suggests. 

The study, “TSH ratio as a novel diagnostic method for Cushing’s syndrome,” was published in the Endocrine Journal. 

Cushing’s syndrome (CS) is a condition characterized by excess cortisol in the blood, which can lead to a variety of issues, including obesity, high blood pressure, abnormal lipid levels, osteoporosis, depression, and cognitive impairments.

In some cases, patients have high cortisol levels, but lack the typical physical features of Cushing’s syndrome. These patients are considered to have subclinical Cushing’s syndrome (SCS), and are at higher risk for cardiovascular disease.

Being able to properly diagnose CS and SCS is of utmost importance for proper intervention and treatment of these patients.

Current methods of diagnosis rely on dexamethasone suppressing tests or late-night salivary and blood cortisol tests, as well as measurements of cortisol in urine. However, because cortisol is a stress-hormone, it can be elevated in cases of mental or physical stress, leading to false positive results on these tests. 

Researchers in this study examined if another hormone, called the thyroid stimulating hormone (TSH), could be used to diagnose Cushing’s syndrome with better accuracy.

TSH is a hormone that stimulates the thyroid gland and whose secretion is affected by the body’s circadian rhythm. Its highest levels in the blood are usually seen in the late evening or early morning. However, patients with CS or SCS lack this nocturnal increase in TSH levels, which could be useful as a new diagnostic approach.

The study recruited 142 patients with suspected CS and SCS, and 21 patients with depression, being treated at the Osaka University Hospital in Japan.

Patients received the ordinal screening tests for Cushing’s syndrome, along with measurements of their midnight-to-morning TSH levels.

After taking the tests, only 20 patients were diagnosed as having Cushing’s, including 12 with over (normal) Cushing’s syndrome and 10 with subclinical Cushing’s syndrome.

Patients with Cushing’s had significantly lower midnight TSH levels than non-Cushing’s patients. No differences were seen in morning levels between the groups. Of note, TSH ratio was maintained in patients with depression, suggesting TSH levels could be used to diagnose Cushing’s in patients with depression.

Researchers observed that serum TSH ratio had powerful diagnostic accuracy. Among patients identified as having Cushing’s, 90% actually had the disease. And among patients excluded for Cushing’s, 95% did not have the condition. These sensitivity and specificity rates were better than with current diagnostic approaches.

However, when considering this test, patients with a severe TSH deficiency must be taken into account.

Overall, these results suggest that the midnight-to-morning serum TSH ratio is a potential new way to diagnose both CS and SCS with a higher specificity than the current diagnostic methods

“The strength of our current survey is its prospective design and the evaluation of not only overt CS but also SCS. The limitation is the relatively small number of CS group patients, especially overt CD,” the researchers wrote.

“New prospective studies will be needed with a larger number of patients in order to further clarify the optimal TSH ratio in the diagnosis of CS,” the study concluded. 

From https://cushingsdiseasenews.com/2018/06/28/measuring-tsh-levels-may-improve-cushings-syndrome-diagnosis-study/

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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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USC’s 7 Tesla MRI scanner first to identify Cushing’s disease in US patient

Posted on March 24, 2018 by MaryO

A noninvasive 7 Tesla MRI scanner at University of Southern California is the first 7T scanner to be used on a patient with Cushing’s disease in the U.S., according to a USC news release.

When a brain tumor was found to be “MRI-negative” in a 28-year-old female patient, physicians at the USC’s Pituitary Center were unsatisfied with the results. After deciding to use the Neuroimaging and Informatics Institute’s (INI) new ultrahigh field 7 Tesla MRI scanner to localize the tumor, the patient was officially diagnosed with Cushing’s disease and researchers were finally able to [be] see the tumor that would’ve otherwise appeared hidden in a standard MRI.

Cushing’s disease is caused by a pituitary microadenoma, or very small tumor, which results in chronically elevated cortisol. Symptoms include weight gain, skin bruising and hair loss and if left untreated, the condition can be fatal.  Because of this case, USC researchers believe the 7T scanner will be able to replace the standard, and invasive, method of clinical diagnosis, according to the news release.

“It’s clear that this is the beginning of a new frontier for ultrahigh field MR technologies,” said Arthur Toga, PhD, director of the INI, in a prepared statement. “The enhanced image quality opens many doors for neuroscientists in both research and clinical settings.”

From http://www.healthimaging.com/topics/neuroimaging/uscs-7-tesla-mri-scanner-first-identify-cushings-disease-us-patient

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Repeat Checks of Cortisol Levels in Saliva May Improve Use of Metopirone as Cushing’s Treatment

Posted on February 16, 2018 by MaryO

Measuring cortisol levels in saliva multiple times a day is a convenient and useful way to determine the best course of treatment for patients with Cushing’s syndrome, a preliminary study shows.

The research, “Multiple Salivary Cortisol Measurements Are a Useful Tool to Optimize Metyrapone Treatment in Patients with Cushing’s Syndromes Treatment: Case Presentations,” appeared in the journal Frontiers of Endocrinology.

Prompt and effective treatment for hypercortisolism — the excessive amount of cortisol in the blood — is essential to lowering the risk of Cushing’s-associated conditions, including infections, cardiovascular disease, and stroke.

Steroid hormone inhibitors, such as HRA Pharma’s Metopirone (metyrapone), have been used significantly in Cushing’s syndrome patients.

These therapies not only suppress cortisol levels, but also avoid adrenal insufficiency (where not enough cortisol is produced) and restore the circadian rhythm, which is disrupted in Cushing’s patients. However, effective medical treatment requires monitoring cortisol activity throughout the day.

Salivary measurements of cortisol are a well-known method for diagnosing and predicting the risk of recurrence of Cushing’s syndrome. The method is convenient for patients and can be done in outpatient clinics. However, the medical field lacks data on whether measuring cortisol in saliva works for regulating treatment.

Researchers analyzed the effectiveness of salivary cortisol measurements for determining the best dosage and treatment timing of Cushing’s patients with Metopirone.

The study included six patients, three with cortisol-secreting masses in the adrenal glands and and three with ACTH (or adrenocorticotropin)-secreting adenomas in the pituitary glands, taking Metopirone. Investigators collected samples before and during treatment to assess morning serum cortisol and urinary free cortisol (UFC). Patients also had salivary cortisol assessments five times throughout the day.

Saliva samples were collected at 6 a.m. (wake-up time), 8 a.m. (before breakfast), noon (before lunch), 6 p.m. (before dinner), and 10 p.m. (before sleep).

Other studies have used UFC assessments to monitor treatment. However, the inability of this parameter to reflect changes in diurnal cortisol requires alternative approaches.

Results showed that although UFC was normalized in five out of six patients, multiple salivary cortisol measurements showed an impaired diurnal cortisol rhythm in these patients.

Whereas patients with cortisol-secreting adrenocortical adenoma showed elevated cortisol levels throughout the day, those with ACTH-secreting pituitary adenoma revealed increased levels mainly in the morning. This finding indicates that “the significance of elevated morning cortisol levels is different depending on the disease etiology,” the researchers wrote.

In a prospective case study to better assess the effectiveness of performing multiple salivary cortisol assessments, the research team analyzed one of the participants who had excessive cortisol production that was not controlled with four daily doses of Metoripone (a daily total of 2,250 mg).

Results revealed that cortisol levels increased before each dosage. After the patient’s treatment regimen was changed to a 2,500 mg dose divided into five daily administrations, researchers observed a significant improvement in the diurnal cortisol pattern, as well as in UFC levels.

Subsequent analysis revealed that performing multiple salivary cortisol measurements helps with a more precise assessment of excess cortisol than analyzing UFC levels, or performing a unique midnight salivary cortisol collection, the researchers said.

Although more studies are required, the results “suggest that multiple salivary cortisol measurements can be a useful tool to visualize the diurnal cortisol rhythm and to determine the dose and timing of metyrapone [Metopirone] during the treatment in patients with [Cushing’s syndrome],” the researchers wrote.

Future studies should include a larger sample size, evaluate changes over a longer term, use a standardized protocol for treatment dosing and timing, and evaluate changes in a patient’s quality of life, the investigators said.

From https://cushingsdiseasenews.com/2018/02/15/multiple-saliva-cortisol-checks-cushings-metyrapone-study/

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