Hair glucocorticoids as biomarker for endogenous Cushing's syndrome: validation in two independent cohorts

Background/Aims: The current diagnostic workup of Cushing’s syndrome (CS) requires various tests which only capture short-term cortisol exposure, whereas patients with endogenous CS generally have elevated long-term cortisol levels. Scalp hair assessment has emerged as a convenient test in capturing glucocorticoid concentrations over long periods of time. The aim of this multicenter, multinational, prospective, case-control study was to evaluate the diagnostic efficacy of scalp hair glucocorticoids in screening of endogenous CS. Methods: We assessed the diagnostic performances of hair cortisol (HairF), hair cortisone (HairE), and sum of both (sumHairF+E), as measured by state-of-the-art LC-MS/MS technique, in untreated patients with confirmed endogenous CS (n=89), and community controls (n=295) from the population-based Lifelines cohort study. Results: Both glucocorticoids were significantly elevated in CS patients when compared to controls. High diagnostic efficacy was found for HairF (area under the curve (AUC), 0.87 [95% CI, 0.83 to 0.92]), HairE (0.93 [0.89 to 0.96]) and sumHairF+E (0.92 [0.88 to 0.96]; all P<.001). Participants were accurately classified at optimal cut-off threshold in 86% of cases (81% sensitivity, 88% specificity, 94% negative predictive value (NPV)) for HairF, in 90% of cases (87% sensitivity, 90% specificity, 96% NPV) for HairE, and 87% of cases (86% sensitivity, 88% specificity, 95% NPV) for the sum. HairE was shown to be most accurate in differentiating CS patients from controls. Conclusion: Scalp hair glucocorticoids, especially hair cortisone, can be seen as a promising biomarker in screening of CS. Its convenience in collection and workup additionally makes this feasible for first-line screenin

Long-term glucocorticoid exposure and incident cardiovascular diseases - the Lifelines cohort

CONTEXT: Long-term glucocorticoid levels in scalp hair (HairGCs), including cortisol and the inactive form cortisone, represent the cumulative systemic exposure to glucocorticoids over months. HairGCs have repeatedly shown associations with cardiometabolic and immune parameters, but longitudinal data are lacking.DESIGN: We investigated 6341 hair samples of participants from the Lifelines cohort study for cortisol and cortisone levels, and associated these to incident cardiovascular diseases (CVD) during 5-7 years of follow-up. We computed the odds ratio (OR) of HairGC levels for incident CVD via logistic regression, adjusting for classical cardiovascular risk factors, and performed a sensitivity analysis in subcohorts of participants &lt;60 years and &gt;= 60 years. Also, we associated HairGC levels to immune parameters (total leukocytes and subtypes).RESULTS: Hair cortisone levels (available in n = 4701) were independently associated with incident CVD (p &lt; 0.001), particularly in younger individuals (multivariate-adjusted OR 4.21, 95% confidence interval (CI) 1.91-9.07 per point increase in 10-log cortisone concentration (pg/mg), p &lt; 0.001). All immune parameters except eosinophils were associated with hair cortisone (all multivariate-adjusted p &lt; 0.05).CONCLUSIONS: In this large, prospective cohort study, we found that long-term cortisone levels, measured in scalp hair, represent a relevant and significant predictor for future cardiovascular diseases in younger individuals. These results highlight glucocorticoid action as possible treatment target for CVD prevention, where hair glucocorticoid measurements could help identify individuals that may benefit from such treatments.</p

The Impact of Obesity and Lifestyle on the Immune System and Susceptibility to Infections Such as COVID-19

Background: COVID-19 is a global challenge to healthcare. Obesity is common in patients with COVID-19 and seems to aggravate disease prognosis. In this review we explore the link between obesity, chronic disease, life

Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain

Clinical applications of cortisol measurements in hair

Cortisol measurements in blood, saliva and urine are frequently used to examine the hypothalamus-pituitary-adrenal (HPA) axis in clinical practice and in research. However, cortisol levels are subject to variations due to acute stress, the diurnal rhythm and pulsatile secretion. Cortisol measurements in body fluids are not always a reflection of long-term cortisol exposure. The analysis of cortisol in scalp hair is a relatively novel method to measure cumulative cortisol exposure over months up to years. Over the past years, hair cortisol concentrations (HCC) have been examined in association with a large number of somatic and mental health conditions. HCC can be used to evaluate disturbances of the HPA axis, including Cushing's syndrome, and to evaluate hydrocortisone treatment. Using HCC, retrospective timelines of cortisol exposure can be created which can be of value in diagnosing cyclic hypercortisolism. HCC have also been shown to increase with psychological stressors, including major life events, as well as physical stressors, such as endurance exercise and shift work. Initial studies show that HCC may be increased in depression, but decreased in general anxiety disorder. In posttraumatic stress disorder, changes in HCC seem to be dependent on the type of traumatic experience and the time since traumatization. Increased hair cortisol is consistently linked to obesity, metabolic syndrome and cardiovascular disease. Potentially, HCC could form a future marker for cardiovascular risk stratification, as well as serve as a treatment target

Approach to the Patient: Diagnosis of Cushing Syndrome

Cushing syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing syndrome) or autonomous cortisol overproduction, whether or not ACTH-dependent (endogenous Cushing syndrome). An early diagnosis of Cushing syndrome is warranted; however, in clinical practice, it is very challenging partly because of resemblance with other common conditions (ie, pseudo-Cushing syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing syndrome. Interpretation of results can be difficult because of individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80%-85%) or ACTH-independent (15%-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of "Approach to the patient," the diagnostic workup of Cushing syndrome is discussed with answering the questions when to screen, how to screen, and how to differentiate the different causes. In this respect, the latest developments in biochemical and imaging techniques are discussed as well

T Cell Deficits and Overexpression of Hepatocyte Growth Factor in Anti-inflammatory Circulating Monocytes of Middle-Aged Patients with Bipolar Disorder Characterized by a High Prevalence of the Metabolic Syndrome

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