Search

Background: Primary aldosteronism (PA) is the leading cause of curable endocrine hypertension, which is associated with a higher risk of cardiovascular and metabolic insults compared to essential hypertension. Aldosterone-producing adenoma (APA) is a major cause of PA, which can be treated with adrenalectomy. Somatic mutations are the main pathogenesis of aldosterone overproduction in APA, of which KCNJ5 somatic mutations are most common, especially in Asian countries. This article aimed to review the literature on the impacts of KCNJ5 somatic mutations on systemic organ damage. Evidence acquisition: PubMed literature research using keywords combination, including "aldosterone-producing adenoma," "somatic mutations," "KCNJ5," "organ damage," "cardiovascular," "diastolic function," "metabolic syndrome," "autonomous cortisol secretion," etc. Results: APA patients with KCNJ5 somatic mutations are generally younger, female, have higher aldosterone levels, lower potassium levels, larger tumor size, and higher hypertension cure rate after adrenalectomy. This review focuses on the cardiovascular andmetabolic aspects of KCNJ5 somaticmutations in APA patients, including left ventricular remodeling and diastolic function, abdominal aortic thickness and calcification, arterial stiffness, metabolic syndrome, abdominal adipose tissue, and correlation with autonomous cortisol secretion. Furthermore, we discuss modalities to differentiate the types of mutations before surgery. Conclusion: KCNJ5 somatic mutations in patients with APA had higher left ventricular mass (LVM), more impaired diastolic function, thicker aortic wall, lower incidence of metabolic syndrome, and possibly a lower incidence of concurrent autonomous cortisol secretion, but better improvement in LVM, diastolic function, arterial stiffness, and aortic wall thickness after adrenalectomy compared to patients without KCNJ5 mutations. [ABSTRACT FROM AUTHOR]

Introduction: The specificity of cortisol after 1 mg dexamethasone (cortisolDST) ≥50 nmol/L as a criterion for mild autonomous cortisol secretion (MACS) is approximately 85% in patients with adrenal incidentalomas (AI). The aim was to study the associations of cortisolDST to age, BMI, and renal function. Methods: We studied 1,129 patients with AI examined from 2005 to 2015 at Skåne University Hospital and Helsingborg Hospital. The covariates studied were gender, age, BMI, estimated glomerular filtration rate (eGFR), treatment with inhalation steroids, size of the AI, and size of the smallest AI in patients with bilateral AI (set to 0 in unilateral AI). We used machine learning models to uncover potential nonlinear associations. They were trained to fit the data and examined using feature importance analysis and partial dependence plots. Partial dependence plots show the marginal effect on cortisolDST of a covariate averaging over other covariates. Results: CortisolDST was strongly associated with the size of the AI and weakly associated with age, BMI, and eGFR according to the feature importance analysis. The partial dependence plots indicated relatively linear relationships for cortisolDST to age (positively) and eGFR (negatively). The association between cortisolDST and BMI was nonlinear. At BMI below 30 kg/m2 , cortisolDST was negatively associated with BMI, but it was unchanged at higher BMI levels. Using linear regression, we found that cortisolDST increased by 11% (95% CI, 7%–14%) for each 10-year increase in age. In patients with a BMI below 30 kg/m2 , cortisolDST increased by 23% (95% CI, 16%–31%) for each 5 kg/m2 decrease in BMI. We found no association at BMI levels above 30 kg/m2 . CortisolDST increased by 9% (95% CI, 6%–11%) for each 10 ml/min/1.73m2 decrease in eGFR. Conclusions: CortisolDST is positively associated with age, negatively with BMI if below 30 kg/m2 , and negatively with eGFR. These associations should be considered before diagnosing MACS. [ABSTRACT FROM AUTHOR]

IntroductionThe specificity of cortisol after 1 mg dexamethasone (cortisolDST) ≥50 nmol/L as a criterion for mild autonomous cortisol secretion (MACS) is approximately 85% in patients with adrenal incidentalomas (AI). The aim was to study the associations of cortisolDST to age, BMI, and renal function.MethodsWe studied 1,129 patients with AI examined from 2005 to 2015 at Skåne University Hospital and Helsingborg Hospital. The covariates studied were gender, age, BMI, estimated glomerular filtration rate (eGFR), treatment with inhalation steroids, size of the AI, and size of the smallest AI in patients with bilateral AI (set to 0 in unilateral AI). We used machine learning models to uncover potential nonlinear associations. They were trained to fit the data and examined using feature importance analysis and partial dependence plots. Partial dependence plots show the marginal effect on cortisolDST of a covariate averaging over other covariates.ResultsCortisolDST was strongly associated with the size of the AI and weakly associated with age, BMI, and eGFR according to the feature importance analysis. The partial dependence plots indicated relatively linear relationships for cortisolDST to age (positively) and eGFR (negatively). The association between cortisolDST and BMI was nonlinear. At BMI below 30 kg/m2, cortisolDST was negatively associated with BMI, but it was unchanged at higher BMI levels. Using linear regression, we found that cortisolDST increased by 11% (95% CI, 7%–14%) for each 10-year increase in age. In patients with a BMI below 30 kg/m2, cortisolDST increased by 23% (95% CI, 16%–31%) for each 5 kg/m2 decrease in BMI. We found no association at BMI levels above 30 kg/m2. CortisolDST increased by 9% (95% CI, 6%–11%) for each 10 ml/min/1.73m2 decrease in eGFR.ConclusionsCortisolDST is positively associated with age, negatively with BMI if below 30 kg/m2, and negatively with eGFR. These associations should be considered before diagnosing MACS.

Background: Non-classical multiple aldosterone-producing micronodules/nodules (mAPM/mAPN) could be the pathogenesis of primary aldosteronism (PA). The co-existence of mAPM with adenomas harboring somatic mutations has not previously been reported. Methods: We presented a PA patient with bilateral mAPM and concomitant autonomous cortisol secretion (ACS). Results: A 46-year-old Taiwanese woman presented with hypertension, hypokalemia, and bilateral adrenal adenomas. A 1 mg low-dose dexamethasone suppression test showed elevated morning serum cortisol. An adrenal vein sampling (AVS) suggested a left-sided lateralization of hyperaldosteronism. A right partial adrenalectomy and a left total adrenalectomy were performed. The patient showed biochemical and hypertension remission after the operation. This patient had bilateral mAPM with concomitant ACS, a right histopathologically classical PA adenoma, and a left non-classical PA adenoma. The right adrenal adenoma showed CYP11B1-negative and CYP11B2-positive staining and harbored the KCNJ5 -L168R mutation. The left adrenal adenoma showed CYP11B1-positive and CYP11B2-negative staining and harbored the PRKACA- L206R mutation. Conclusion: In a PA patient with concomitant ACS, bilateral APM could coexist with both histopathologically classical and non-classical PA adenomas, each with different somatic mutations. The presence of ACS could lead to the misinterpretation of AVS results. [ABSTRACT FROM AUTHOR]

BackgroundNon-classical multiple aldosterone-producing micronodules/nodules (mAPM/mAPN) could be the pathogenesis of primary aldosteronism (PA). The co-existence of mAPM with adenomas harboring somatic mutations has not previously been reported.MethodsWe presented a PA patient with bilateral mAPM and concomitant autonomous cortisol secretion (ACS).ResultsA 46-year-old Taiwanese woman presented with hypertension, hypokalemia, and bilateral adrenal adenomas. A 1 mg low-dose dexamethasone suppression test showed elevated morning serum cortisol. An adrenal vein sampling (AVS) suggested a left-sided lateralization of hyperaldosteronism. A right partial adrenalectomy and a left total adrenalectomy were performed. The patient showed biochemical and hypertension remission after the operation. This patient had bilateral mAPM with concomitant ACS, a right histopathologically classical PA adenoma, and a left non-classical PA adenoma. The right adrenal adenoma showed CYP11B1-negative and CYP11B2-positive staining and harbored the KCNJ5-L168R mutation. The left adrenal adenoma showed CYP11B1-positive and CYP11B2-negative staining and harbored the PRKACA-L206R mutation.ConclusionIn a PA patient with concomitant ACS, bilateral APM could coexist with both histopathologically classical and non-classical PA adenomas, each with different somatic mutations. The presence of ACS could lead to the misinterpretation of AVS results.

Objective: To study the differences in the cardiometabolic profile between patients with non-functioning adrenal incidentalomas (NFAI) and incidentalomas with autonomous cortisol secretion (ACS). Methods: A total of 149 patients with adrenal incidentalomas were retrospectively evaluated and followed-up for a mean time of 34.6 months at Departments of Endocrinology and Metabolic Diseases Units of four tertiary Spanish hospitals. Patients were grouped as NFAI or ACS adenomas based on two cutoffs in the dexamethasone suppression test (DST): 3.0 µg/dl (NFAIDST3 or ACSDST3) and 1.8 µg/dl (ACSDST1.8 and NFAIDST1.8). Results: The mean age of both groups was 62.0 (10.31) and was similar in ACS and NFAI. The prevalence of diabetes, high blood pressure, cardiovascular, and cerebrovascular disease was higher in ACS than in NFAI, but differences only reached statistical significance for cerebrovascular disease using the 3.0 µg/dl cutoff (15.8% vs 2.3%, p = 0.01) and for diabetes using the 1.8 µg/dl cutoff (38.0% vs 22.0%, p = 0.04). No differences were found in the prevalence of dyslipidemia. The prevalence of obesity was lower in patients with ACS than in NFAI 26.3% vs 39.2%, p = 0.18 (NFAIDST3 vs ACSDST3) and 32.1% vs 40.6%, p = 0.56 (ACSDST1.8 vs NFAIDST1.8), but the differences did not reach statistical significance. Maximum adenoma diameter (R-squared = 0.15, p < 0.001) and cerebrovascular disease (OR = 1.59, p = 0.04) were the only parameters that could be predicted by the DST. The DST was an inadequate predictor of clinical (systolic and diastolic blood pressure, body mass index), hormonal (DHEAS, ACTH, UFC, and basal serum cortisol), biochemical (glucose, cholesterol, LDL, HDL, and triglycerides), and other radiological (laterality, lipid content) parameters. Throughout the follow-up, patients did not develop overt Cushing's Syndrome; three NFAIDST3 developed ACSDST3, eight NFAIDST1.8 developed ACSDST1.8, and one NFAIDST1.8 progressed to ACSDST3. In both groups (NFAI and ACS) the metabolic profile remained stable. Conclusions: Our data suggest higher prevalence of diabetes and cerebrovascular disease in ACS patients compared with NFAI. However, probably because of the small sample size, the differences only reached statistical significance using the cutoffs of 1.8 µg/dl for diabetes and 3.0 µg/dl for cerebrovascular disease. Patients with ACS and NFAI rarely progress to more aggressive forms of hypercortisolism, and the metabolic profile usually remains stable during the follow-up. [ABSTRACT FROM AUTHOR]

In the vast majority of cases adrenal incidentalomas (AI) are benign adrenocortical adenomas. They are present in up to 10% of the population over 70 years, with incidence increasing with age. Mild cortisol excess (MCE) in the context of AI is defined as autonomous cortisol secretion (ACS) in the absence of the classical clinical features of Cushing's syndrome. MCE has been reported in up to at least one third of patients with AI. Numerous studies have shown that MCE in AI is associated with increased cardiovascular events and mortality, likely to be consequent upon both hemodynamic changes and inflammatory pathways, and a worse metabolic phenotype characterized by: pancreatic β-cell dysfunction, insulin resistance, visceral obesity and dyslipidemia. There is currently no level 3 evidence from large intervention randomized controlled trials to guide management of MCE in AI, and there is a lack of predictive tools to allow stratification to intervention of only those patients who would benefit in terms of improved metabolic and cardiovascular end-points. Here, we describe the mal-effects of cortisol on cardiovascular and metabolic tissues and discuss management strategies based on current largely observational data., Competing Interests: Conflicts of Interest: J Newell-Price has research and consultancy (paid to the University of Sheffield) from HRA Pharma and Novartis. The other authors have no conflicts of interest to declare., (2020 Gland Surgery. All rights reserved.)