Hair cortisol and endocannabinoid measurement in patients with adrenal incidentalomas: a case-control study.

PURPOSE: The role of endocannabinoids (ECs) in the regulation of the hypothalamic-pituitary-adrenocortical axis has already been studied; however, data are scarce in humans. The aim of our study was to analyze EC [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and cortisol (F) levels in hair samples of patients with adrenal incidentalomas (AIs) in comparison with those found in controls and assess their association with the hormone profile. METHODS: Forty-four patients with AIs [32 with non-functioning AIs (NFAIs) and 12 with possible autonomous secretion (PACS)] and 44 controls were recruited. Basal and post-1 mg overnight dexamethasone suppression test (ODST) F, adrenocorticotropic hormone, dehydroepiandrosterone sulfate, and 24-h urinary free cortisol were analyzed. After hair collection, EC and F levels were measured by liquid chromatography tandem-mass spectrometry. RESULTS: There was no difference between the groups regarding age, sex, and metabolic status. Significantly decreased hair AEA and 2-AG levels were found in patients with AIs compared to controls (p < 0.001 and p = 0.002, respectively) as well as between NFAI or PACS and controls (p < 0.001 or p = 0.002 and p = 0.038 or p = 0.02, respectively). Among the AI patients, EC levels tended to be lower in the PACS group. AEA hair levels were negatively correlated with F levels post-1 mg ODST (rs = -0.257, p = 0.033). We found no significant difference comparing hair F between the groups. CONCLUSION: Our findings suggest that hair EC measurement could be a potential biomarker in the evaluation of patients with AIs, whereas hair F analysis is not a useful diagnostic test for mild hypercortisolemia.

Hypertriglyceridemic Waist Phenotype and Its Association with Metabolic Syndrome Components, among Greek Children with Excess Body Weight.

The hypertriglyceridemic waist (HTGW) phenotype is characterized by abdominal obesity and elevated serum triglycerides. We aimed to assess the prevalence of the HTGW phenotype among children with overweight or obesity and its association with indices of insulin resistance (IR) and dyslipidemia. A total of 145 children with mean age of 10.2 years (SD = 2.31 years), 97.2% of whom with obesity, were analyzed. The HTGW phenotype was defined as WC > 90th Centers for Disease Control and Prevention (CDC) percentile and triglyceride levels of ≥100 mg/dL and ≥130 mg/dL for children 0 to 9 or >10 years of age, respectively. In total, 77.9% of the children had a waist circumference above the 90th percentile and 22.8% had elevated triglycerides. The prevalence of the HTGW phenotype in this sample was 19.3%. Patients with the HTGW phenotype had significantly lower levels of High-Density Lipoprotein (p < 0.001) and were insulin-resistant, as evident by an increased mean Triglycerides Glucose Index 8.64 (SD = 0.24) vs. 7.92 (SD = 0.41) for those without the HTGW phenotype (p < 0.001), and increased prevalence (54.5%) of Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in ≥2.5 in patients with HTGW (p = 0.045). Children with the HTGW phenotype were more likely to have increased HOMA-IR [OR 7.9 95% CI (1.94, 32.1)]. The HTGW phenotype is a low-cost and easily available index that might help to identify children with increased cardiometabolic risk.

Postoperative complications after endoscope-assisted transsphenoidal surgery for pituitary adenomas: a case series, systematic review, and meta-analysis of the literature.

PURPOSE: Endoscope-assisted transsphenoidal surgery over the last few years has led to more radical excision of pituitary adenomas (PAs) with a low complication rate. Systematic registration of complications by experienced surgical teams could help to improve this technique while ameliorating the patients' quality of life. MATERIALS AND METHODS: One hundred ten endoscopic procedures were performed in 94 patients with PAs (37 functional) by the same neurosurgical team of a tertiary center during the period 2014-2019. Post-surgical complications were analyzed and compared with data published during the last 5 years in the PubMed and Cochrane databases by performing a systematic review and meta-analysis of the literature. RESULTS: The overall complication rate in our series was 23.4%. Diabetes insipidus (DI) and intraoperative cerebrospinal fluid (CSF) leakage were the commonest complications (12.8%), followed by postoperative hypopituitarism (9.2%) and hematoma (8.5%) during the follow-up of 2.15 ± 1.4 years. Syndrome of inappropriate antidiuretic hormone secretion, meningitis, deep vein thrombosis, and hyposmia were rare (< 3%). Postoperative hypopituitarism was significantly associated with incidence of hematoma. No statistically significant association was found between PAs Hardy and Knosp scale grading or between patients' characteristics with the occurrence of postoperative complications. Our meta-analysis including nine studies found no significant differences comparing the complications of endoscopic versus microscopic surgery. CONCLUSION: The endoscopic approach is safe when performed by experienced surgical teams. CSF leakage and DI were the commonest complications in our series; however, confirmation by larger studies is required. Meta-analysis showed no statistically significant differences in complication rates comparing endoscopic versus microscopic surgery.

Nonfunctional adrenal adenomas and impaired glucose metabolism: a systematic review and meta-analysis.

PURPOSE: Evidence on nonfunctioning adrenal incidentaloma's (NFAI) associated comorbidities and in particular, glucose disorders, is unclear in contrast to adrenal tumors with mild autonomous cortisol secretion. The current systematic review and meta-analysis aimed to assess the burden of impaired glucose metabolism including diabetes mellitus type 2 (T2DM), fasting blood glucose (FBG), and fasting blood insulin (FBI) levels in patients with NFAI and 1-mg overnight dexamethasone suppression test (ODST) ≤ 1.8 µg/dl across published studies. METHODS: We searched PubMed, Cochrane, and Scopus databases for identifying studies published between 1956 and March 2021. Twenty-five studies met the selection criteria including prospective, retrospective, and case-control studies. Two reviewers independently extracted studies, participants' characteristics and outcome data in a total pooled sample of 1548 patients. RESULTS: Patients with NFAI had twofold [(odds ratio (OR) (95% confidence interval (CI)): 2.03 (1.39-2.98)] increased odds to present T2DM as well as higher FBG [weighted mean difference (WMD) (95% CI): 3.85 (1.96-5.74)] and homeostasis model assessment (HOMA) [WMD (95% CI): 0.68 (0.23-1.12)] with respect to controls. On the contrary, the WMD of FBI levels did not differ between the two groups. The incidence of T2DM in a subgroup analysis of patients with NFAI without glucose disorders at baseline was 6% [pooled incidence (95% CI): 0.06 (0.04-0.09)]. CONCLUSIONS: Patients with NFAI and 1-mg ODST ≤ 1.8 µg/dl presented higher odds of T2DM and higher levels of FBG and HOMA index than healthy controls.

The Role of Immunohistochemical Markers for the Diagnosis and Prognosis of Adrenocortical Neoplasms.

Adrenal cortical carcinoma (ACC) is a rare cancer with poor prognosis that needs to be distinguished from adrenocortical adenomas (ACAs). Although, the recently developed transcriptome analysis seems to be a reliable tool for the differential diagnosis of adrenocortical neoplasms, it is not widely available in clinical practice. We aim to evaluate histological and immunohistochemical markers for the distinction of ACCs from ACAs along with assessing their prognostic role. Clinical data were retrospectively analyzed from 37 patients; 24 archived, formalin-fixed, and paraffin-embedded ACC samples underwent histochemical analysis of reticulin and immunohistochemical analysis of p27, p53, Ki-67 markers and were compared with 13 ACA samples. Weiss and Helsinki scores were also considered. Kaplan-Meier and univariate Cox regression methods were implemented to identify prognostic effects. Altered reticulin pattern, Ki-67% labelling index and overexpression of p53 protein were found to be useful histopathological markers for distinguishing ACAs from ACCs. Among the studied markers, only pathological p53 nuclear protein expression was found to reach statistically significant association with poor survival and development of metastases, although in a small series of patients. In conclusion, altered reticulin pattern and p53/Ki-67 expression are useful markers for distinguishing ACCs from ACAs. Immunohistopathology alone cannot discriminate ACCs with different prognosis and it should be combined with morphological criteria and transcriptome analysis.

Τriglycerides-glucose (TyG) index is a sensitive marker of insulin resistance in Greek children and adolescents.

PURPOSE: To investigate the association between Triglyceride-glucose (TyG) index and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Matsuda indices in Greek obese children and adolescents, in order to assess whether it could be used as a predictor of insulin resistance. METHODS: 367 children (47.7% boys) with mean age of 9.9 ± 2.3 years, who were investigated for obesity, were included. After overnight fasting, TyG and HOMA-IR indices were calculated in all participants. In a subpopulation of 72 children Matsuda index was also calculated. RESULTS: 48.8% and 36.1% of the participants had insulin resistance according to HOMA-IR and Matsuda index respectively. TyG was significantly and positively correlated with BMI, ΗΟΜΑ-IR, lipid profile and Matsuda index. ROC curve analysis for TyG showed that the optimal cutoff value for the prediction of insulin resistance (HOMA-IR) was 7.96 with sensitivity 65% and specificity 58%. The area under the curve (AUC) was 0.65 which significantly differs from 0.5 (p < 0.001). Similarly, the optimal cutoff value of TyG index for predicting insulin resistance as evidenced by Matsuda was 7.91 with sensitivity 85% and specificity 61%. The AUC was 0.75 (p < 0.001). The odds for insulin resistance (with HOMA-IR) was 2.54 times greater for subjects with TyG higher than 7.96, while the odds for insulin resistance (with Matsuda) was 8.56 times greater for subjects with TyG more than 7.91. CONCLUSIONS: TyG index shows a positive correlation with insulin resistance among children and adolescents, however further studies are needed to clarify its predictive ability.

Reactive Vasodilation Predicts Mortality in Primary Systemic Light-Chain Amyloidosis.

Rationale: Cardiac involvement and hypotension dominate the prognosis of light-chain amyloidosis (AL). Evidence suggests that there is also peripheral vascular involvement in AL but its prognostic significance is unknown. Objective: To evaluate vascular dysfunction in patients with AL as a potential future area of intervention, we assessed the prognostic utility of flow-mediated dilatation (FMD), a marker of vascular reactivity, which is augmented under conditions of hypotension and autonomic dysfunction. Methods and Results: We prospectively evaluated 115 newly diagnosed untreated AL patients in whom FMD was measured. FMD in AL patients was significantly higher than age-, sex- and risk factors-matched controls (4.0% versus 2.32%; P=0.006) and comparable with control groups at lower cardiovascular risk (P>0.1). Amyloidosis patients presented increased plasma and exhaled markers of the NO pathway while their FMD significantly correlated with augmented sustained vasodilatation after sympathetic stimulation. Increased FMD (≥4.5%) was associated with early mortality (hazard ratio, 4.36; 95% CI, 1.41-13.5; P=0.010) and worse survival (hazard ratio, 2.11; 95% CI, 1.17-3.82; P=0.013), even after adjustment for Mayo stage, nerve involvement and low systolic blood pressure. This finding was confirmed in a temporal validation AL cohort (n=55; hazard ratio, 4.2; 95% CI, 1.45-12.3; P=0.008). FMD provided significant reclassification value over the best prognostic model (continuous Net Reclassification Index, 0.61; P=0.001). Finally, better hematologic response was associated with lower posttreatment FMD. Conclusions: FMD is relatively increased in AL and independently associated with inferior survival with substantial reclassification value. Reactive vasodilation merits further investigation as a novel risk biomarker in AL.Visual Overview: An online visual overview is available for this article.

Amyloid-ß (1-40) and Mortality in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: A Cohort Study.

Background: Amyloid-ß (1-40) (Aß40) is implicated in mechanisms related to plaque destabilization and correlates with adverse outcomes in stable coronary artery disease. Objective: To determine the prognostic and reclassification value of baseline circulating levels of Aß40 after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is widely recommended for risk stratification in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Design: Retrospective cohort study using data from 2 independent prospective cohorts, the Heidelberg study (n = 1145) and the validation multicenter international APACE (Advantageous Predictors of Acute Coronary Syndrome Evaluation) study (n = 734). Setting: Academic hospitals in 7 European countries. Participants: Patients with adjudicated NSTE-ACS followed for a median of 21.9 and 24.9 months in the Heidelberg and APACE studies, respectively. Measurements: All-cause mortality was the primary end point. Results: Amyloid-ß (1-40) was associated with mortality after multivariate adjustment for age, sex, diabetes mellitus, high-sensitivity cardiac troponin T and C-reactive protein, revascularization, and ACS type (Heidelberg cohort hazard ratio [HR] for 80th vs. 20th percentiles, 1.66 [95% CI, 1.06 to 2.61; P = 0.026]; APACE cohort HR, 1.50 [CI, 1.15 to 1.96; P = 0.003]). It was also associated with mortality after adjustment for the GRACE score (Heidelberg cohort HR for 80th vs. 20th percentiles, 1.11 [CI, 1.04 to 1.18; P = 0.001]; APACE cohort HR, 1.39 [CI, 1.02 to 1.88; P = 0.036]). Amyloid-ß (1-40) correctly reclassified risk for death over the GRACE score (net reclassification index, 33.4% and 47.1% for the Heidelberg and APACE cohorts, respectively) (P < 0.05). Limitation: At low concentrations of Aß40, dose-response associations with mortality differed between cohorts, possibly because of varying blood preparations used to measure Aß40. Conclusion: Circulating Aß40 is a predictor of mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of Aß40 as a novel biomarker in NSTE-ACS should be further explored and validated. Primary Funding Source: German Cardiac Society.

Free androgen index as a determinant of arterial stiffness in menopause: a mediation analysis.

OBJECTIVE: Associations of endogenous androgens in menopause with blood pressure (BP) and indices of arterial stiffness are reported, but directional relationships are not clear. Structural equation modeling is a contemporary statistical method, which allows assessment of such relationships and improves pathway understanding. METHODS: We recruited 411 consecutive apparently healthy postmenopausal women who underwent noninvasive vascular evaluation. This included pulse wave analysis (aortic pressures and arterial wave reflections [augmentation index]), measurement of aortic stiffness by pulse wave velocity (PWV), stiffness index (SI), and flow-mediated dilatation. A cumulative marker combining PWV and SI (combined local and aortic arterial stiffness [CAS]) was also assessed. Free androgen index (FAI) was calculated from circulating total testosterone and sex hormone-binding globulin. RESULTS: FAI was an independent determinant of systolic BP (SBP) (P = 0.032), SI (P = 0.042), and PWV (P = 0.027). Under structural equation modeling analysis, FAI was a direct predictor for PWV (beta = 0.149, P = 0.014), SI (beta = 0.154, P = 0.022), and CAS (beta = 0.193, P = 0.02), whereas SBP was a parallel mediator of androgen's vascular effects on PWV (beta = 0.280, P < 0.001) and CAS (beta = 0.248, P = 0.004), but not SI (beta = 0.024, P = 0.404). FAI-induced increase in arterial stiffness via flow-mediated dilatation was not established. FAI was not a determinant of augmentation index. CONCLUSIONS: In healthy postmenopausal women, FAI was directly associated with PWV, SI, and CAS. FAI also directly correlated with SBP, which in turn concurrently increased PWV and CAS. The directional correlations found herein, imply that endogenous androgens may be causally associated with indices of arterial stiffness both directly and indirectly. This hypothesis should be confirmed in further studies with causal design.

Free androgen index as a predictor of blood pressure progression and accelerated vascular aging in menopause.

BACKGROUND AND AIMS: We aimed to assess the prognostic value of free androgen index (FAI) and its change over time in arterial stiffness progression, endothelial function and hypertension in postmenopausal women. METHODS: Postmenopausal women (n = 180) without clinically overt cardiovascular disease or diabetes were consecutively recruited and followed for a median of 29 months. The main outcome measures were changes over time in endothelial function (FMD), reflected waves, localized and systemic (PWV) arterial stiffness and hypertension. RESULTS: Increased baseline FAI was significantly associated with new onset hypertension (OR for each SD, 2.71, 95% CI 1.14-6.41, p = 0.024), deterioration of pulse wave velocity (PWV) (0.414 m/s per SD), flow-mediated dilation (FMD) (-0.42% per SD), systolic (2.5 mmHg per SD) and pulse pressure progression (2.3 mmHg per SD, p < 0.05 for all). Baseline FAI remained an independent predictor of changes in PWV (p = 0.006), FMD (p = 0.02), peripheral pulse pressure (p = 0.028), transition to new onset hypertension (p = 0.001) and higher BP category (p = 0.012), after adjustment for age, changes in systolic blood pressure, traditional risk factors, vasoactive medication or total testosterone. Baseline FAI improved reclassification for the risk of transition into higher BP category (NRI = 47.5 ± 20.3%, p = 0.02) and abnormal PWV (NRI = 53.4 ± 23.2%, p = 0.021). Similarly, in a subgroup of patients with measured FAI at follow-up, its changes over time predicted changes in PWV, peripheral pulse pressure and hypertension status (p < 0.05 for all). CONCLUSIONS: In apparently healthy postmenopausal women, FAI could be a novel biomarker superior to total testosterone for accelerated vascular aging and hypertension status.

Hemodynamic markers and subclinical atherosclerosis in postmenopausal women with primary hyperparathyroidism.

CONTEXT: Recent evidence suggests that primary hyperparathyroidism (pHPT) is linked with hypertension and subclinical atherosclerosis. These associations have not been examined in postmenopausal women, in whom cardiovascular risk steeply rises after menopausal transition. OBJECTIVE: The objective of the study was to assess whether pHPT is associated with hemodynamic markers and subclinical atherosclerosis in postmenopausal women under a cross-sectional case-control design. METHODS: One hundred two postmenopausal women with pHPT and 102 women matched 1:1 for age and menopausal status were consecutively recruited. In all patients, flow-mediated dilatation, carotid-femoral pulse wave velocity, reflected waves, aortic blood pressures (BP), intima-media thickness, and the presence of plaques in the carotid and common femoral arteries were measured. RESULTS: Women with pHPT had higher aortic and peripheral BP (P < .05 for all), but no correlation was observed with subclinical atherosclerosis. After adjusting for possible confounders, pHPT was an independent determinant of peripheral and aortic diastolic BP (P < .05 for all). The association with systolic BP was lost after adjusting for C-reactive protein. Further adjustment for PTH and 25-hydroxyvitamin D levels revealed that PTH but not 25-hydroxyvitamin D was an independent determinant of all BP parameters. Both peripheral and aortic BP increased across PTH tertiles as compared with the control group, but this association lost significance after adjustment for C-reactive protein. CONCLUSIONS: These results suggest that pHPT may increase peripheral and aortic BP through PTH and inflammatory-mediated mechanisms. A direct impact of the disease on the arterial wall cannot be implicated despite the large number of markers of subclinical atherosclerosis measured in this study.