Cyclic Cortisol Production May Lead to Misdiagnosis in Cushing’s

Increased cortisol secretion may follow a cyclic pattern in patients with adrenal incidentalomas, a phenomenon that may lead to misdiagnosis, a study reports.

Since cyclic subclinical hypercortisolism may increase the risk for heart problems, researchers recommend extended follow-up with repeated tests to measure cortisol levels in these patients.

The study, “Cyclic Subclinical Hypercortisolism: A Previously Unidentified Hypersecretory Form of Adrenal Incidentalomas,” was published in the Journal of Endocrine Society.

Adrenal incidentalomas (AI) are asymptomatic masses in the adrenal glands discovered on an imaging test ordered for a problem unrelated to adrenal disease. While most of these benign tumors are considered non-functioning, meaning they do not produce steroid hormones like cortisol, up to 30% do produce and secrete steroids.

Subclinical Cushing’s syndrome is an asymptomatic condition characterized by mild cortisol excess without the specific signs of Cushing’s syndrome. The long-term exposure to excess cortisol may lead to cardiovascular problems in these patients.

While non-functioning adenomas have been linked with metabolic problems, guidelines say that if excess cortisol is ruled out after the first evaluation, patients no longer need additional follow-up.

However, cortisol secretion can be cyclic in Cushing’s syndrome, meaning that clinicians might not detect excess amounts of cortisol at first and misdiagnose patients.

In an attempt to determine whether cyclic cortisol production is also seen in patients with subclinical Cushing’s syndrome and whether these patients have a higher risk for metabolic complications, researchers in Brazil reviewed the medical records of 251 patients with AI — 186 women, median 60 years old — followed from 2006 to 2017 in a single reference center.

Cortisol levels were measured after a dexamethasone suppression test (DST). Dexamethasone is used to stop the adrenal glands from producing cortisol. In healthy patients, this treatment is expected to reduce cortisol levels, but in patients whose tumors also produce cortisol, the levels often remain elevated.

Patients were diagnosed with cyclic subclinical Cushing’s syndrome if they had at least two normal and two abnormal DST tests.

From the 251 patients, only 44 performed the test at least three times and were included in the analysis. The results showed that 20.4% of patients had a negative DST test and were considered non-functioning adenomas.

An additional 20.4% had elevated cortisol levels in all DST tests and received a diagnosis of sustained subclinical Cushing’s syndrome.

The remaining 59.2% had discordant results in their tests, with 18.3% having at least two positive and two negative test results, matching the criteria for cyclic cortisol production, and 40.9% having only one discordant test, being diagnosed as possibly cyclic subclinical Cushing’s syndrome.

Interestingly, 20 of the 44 patients had a normal cortisol response at their first evaluation. However, 11 of these patients failed to maintain normal responses in subsequent tests, with four receiving a diagnosis of cyclic subclinical Cushing’s syndrome and seven as possibly cyclic subclinical Cushing’s.

Overall, the findings suggest that patients with adrenal incidentalomas should receive extended follow-up with repeated DST tests, helping identify those with cyclic cortisol secretion.

“Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk,” the study concluded.

From https://cushingsdiseasenews.com/2019/04/11/cyclic-cortisol-production-may-lead-to-misdiagnosis-in-cushings-study-finds/

Mild Cortisol Increases Affect Cardiovascular Changes Linked to Heart Disease in Cushing’s

Increases in cortisol secretion, even if mild, induce early heart and blood vessel changes that may increase the risk for cardiovascular disease, according to Italian researchers.

The findings continue to support the role of the hormone cortisol in heart disease, and demonstrate the need for carefully monitoring cardiovascular risk in patients with high levels of the hormone, including those with Cushing’s disease.

The study, “Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas,” was published in the European Journal of Endocrinology.

While most patients with adrenal incidentalomas don’t have symptoms, nearly half have excess cortisol production. Adrenal incidentalomas are masses in the adrenal glands discovered only when a patient undergoes imaging tests for another unrelated condition.

These asymptomatic, mild cortisol-producing cases are defined as possible autonomous cortisol secretion (pACS), according to the European Society of Endocrinology Guidelines.

Excess production of the hormone, seen in Cushing’s disease patients, is associated with increased mortality, mainly due to heart diseases. Patients with asymptomatic adrenal adenomas and mild cortisol secretion also have more cardiovascular events and generally die sooner than those with normal cortisol levels.

But little is known about the causes behind cardiac and vessel damage in these patients.

To shed light on this matter, a research team at Sapienza University of Rome evaluated the cardiovascular status of patients with pACS. This allowed them to study the impact of cortisol in the heart and blood vessels without the interference of other hormone and metabolic imbalances seen in Cushing’s disease.

The ERGO trial (NCT02611258) included 71 patients. All had been diagnosed with adrenal incidentalomas, 34 of which were pACS with mildly increased levels of the hormone and 37 were defined as nonfunctioning adenoma (NFA) — adrenal masses with normal hormone levels.

The two groups were very similar, with no significant differences in metabolic and cardiovascular risk factors. Adrenal lesions in the pACS group, however, were significantly bigger, which was linked to cortisol levels.

Looking at the heart morphology, researchers found that pACS patients had a significantly higher left ventricular mass index (LVMI), which is a well-established predictive measure of adverse cardiovascular events.

Further analysis revealed that LVMI scores were associated with levels of the hormone, suggesting it has an “independent effect of cortisol on cardiac function,” the researchers wrote.

Slightly more than half of pACS patients (53%) also had a thicker left ventricle, a feature that was seen only in 13.5% of NFA patients. The performance of the left ventricle during diastole (muscle relaxation) was also affected in 82.3% of pACS patients, compared to 35.1% in those with NFA.

Patients with pACS also had less flexible arteries, which may contribute to the development of vascular diseases.

The results show that “mild autonomous cortisol secretion can sustain early cardiac and vascular remodeling” in patients who appear apparently healthy, the researchers said.

“The morphological and functional cardiovascular changes observed in pACS underline the need for further studies to correctly define the long-term management of this relatively common condition,” they added.

From https://cushingsdiseasenews.com/2018/03/13/cushings-disease-increased-cortisol-affects-cardiovascular-changes-heart-disease/

Metabolomic Biomarkers in Urine of Cushing’s Syndrome Patients

Int. J. Mol. Sci. 2017, 18(2), 294; doi:10.3390/ijms18020294 (registering DOI)
Department of Food Sciences, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland
Laboratory of Environmental Chemometrics, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
Department of Endocrinology and Internal Medicine, Medical University of Gdańsk, ul. Dębinki 7, 80-211 Gdańsk, Poland
Department ofEnvironmental Analytics, Institute for Environmental and Human Health Protection, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
Author to whom correspondence should be addressed.
Academic Editor: Ting-Li (Morgan) Han
Received: 5 December 2016 / Revised: 9 January 2017 / Accepted: 19 January 2017 / Published: 29 January 2017
(This article belongs to the Section Molecular Diagnostics)
Download PDF [1853 KB, uploaded 29 January 2017]

Abstract

Cushing’s syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS.

This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs).

Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing’s syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals.

The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects.

The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis.

 

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

From http://www.mdpi.com/1422-0067/18/2/294

Adiponectin level may serve as predictor of subclinical Cushing’s syndrome

Unal AD, et al. Int J Endocrinol. 2016;doi:10.1155/2016/8519362.

 

In adults with adrenal incidentaloma, adiponectin levels may help predict the presence of subclinical Cushing’s disease, according to recent findings.

Asli Dogruk Unal, MD, of the department of endocrinology and metabolism at Memorial Atasehir Hospital in Istanbul, and colleagues analyzed data from 40 patients with adrenal incidentaloma (24 women; mean age, 61 years) and 30 metabolically healthy adults without adrenal adenomas or hyperplasia (22 women; mean age, 26 years). All patients with type 2 diabetes were newly diagnosed and not on any antidiabetic therapies; included patients were not using statin therapy for about 12 weeks.

Participants provided blood samples

Among patients with adrenal incidentaloma, eight (20%) were diagnosed with subclinical Cushing’s syndrome; median adenoma diameter in these patients was 3.05 cm. The remaining patients were classified as nonfunctional adrenal incidentaloma. Compared with patients who had nonfunctional adrenal incidentaloma, patients with subclinical Cushing’s syndrome had a higher median midnight cortisol level (9.15 µg/dL vs. 5.1 µg/dL; P = .004) and urinary free cortisol level (249 µg per 24 hours vs. 170 µg per 24 hours; P = .007).

In two group comparisons, researchers found that only adiponectin level was lower in the subclinical Cushing’s syndrome group vs. the nonfunctional adrenal incidentaloma group (P = .007); there were no observed between-group differences for age, BMI, waist circumference, insulin levels, homeostasis model assessment for insulin resistance (HOMA-IR) or lipid profiles.

Adiponectin level was negatively associated with insulin level, HOMA-IR, triglyceride level and midnight cortisol level, and was positively associated with body fat percentage, HDL and adrenocorticotropic hormone levels. In linear regression analysis, age was found to be an increasing factor, whereas sex, HOMA-IR, LDL, waist circumference and presence of subclinical Cushing’s syndrome were decreasing factors.

In evaluating the receiver operating characteristic analysis, researchers found that adiponectin level had a predictive value in determining the presence of subclinical Cushing’s syndrome (area under the curve: 0.81; 95% CI, 0.67-0.96). Sensitivity and specificity for an adiponectin value of 13 ng/mL or less in predicting the presence of subclinical Cushing’s syndrome were 87.5% and 77.4%, respectively; positive predictive value and negative predictive value were 50% and 96%, respectively.

“Presence of [subclinical Cushing’s syndrome] should be considered in case of an adiponectin level of 13 ng/mL in [adrenal incidentaloma] patients,” the researchers wrote. “Low adiponectin levels in [subclinical Cushing’s syndrome] patients may be important in treatment decision due to the known relation between adiponectin and cardiovascular events. In order to increase the evidences on this subject, further prospective follow-up studies with larger number of subjects are needed.” – by Regina Schaffer

Disclosure: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B81c38f07-b378-4ca1-806b-d5c17bea064c%7D/adiponectin-level-may-serve-as-predictor-of-subclinical-cushings-syndrome

New Diagnostic Criteria for Subclinical Hypercortisolism using Postsurgical Hypocortisolism

Clin Endocrinol (Oxf). 2016 Jun 24. doi: 10.1111/cen.13145. [Epub ahead of print]

 

Abstract

OBJECTIVE:

There is no consensus on the biochemical diagnostic criteria for subclinical hypercortisolism (SH). Using parameters related to the hypothalamic-pituitary-adrenal axis, we aimed to develop a diagnostic model of SH for predicting postsurgical hypocortisolism and metabolic complications.

DESIGN:

Prospective and cross-sectional, observational, multicentre study in Korea.

METHODS:

After exclusion of overt Cushing’s syndrome, adrenal incidentaloma (AI) patients who underwent unilateral adrenalectomy (n = 99) and AI patients (n = 843) were included. Primary outcome was defined as the presence of postsurgical hypocortisolism; secondary outcome was the presence of ≥4 complications (components of the metabolic syndrome and low bone mass). Postsurgical hypocortisolism was determined on the fifth postsurgery day using the ACTH stimulation test.

RESULTS:

Thirty-three of the 99 patients developed postsurgical hypocortisolism. Analysis of the presurgery overnight 1-mg dexamethasone suppression test (1-mg DST) showed that all patients with cortisol levels of >138 nmol/l experienced postsurgical hypocortisolism, whereas those with levels of ≤61 nmol/l did not. The models of (i) 1-mg DST >138 nmol/l or (ii) >61 nmol/l with the presence of one among low levels of ACTH and dehydroepiandrosterone-sulphate had the highest accuracy (89·9%, P < 0·001) and odds ratio [OR 111·62, 95% confidence interval (CI) 21·98-566·74, P < 0·001] for predicting postsurgical hypocortisolism. Finally, patients with the same criteria in the 843 AI patients showed the highest risk for having ≥4 complications (OR 3·51, 95% CI 1·84-6·69, P < 0·001), regardless of gender, age, body mass index and bilaterality.

CONCLUSIONS:

Our proposed model is able to accurately predict subtle cortisol excess and its chronic manifestations in AI patients.

© 2016 John Wiley & Sons Ltd.

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