Objective: Develop a consensus for the nomenclature and definition of adrenal histopathologic features in unilateral primary aldosteronism (PA). Context: Unilateral PA is the most common surgically treated form of hypertension. Morphologic examination combined with CYP11B2 (aldosterone synthase) immunostaining reveals diverse histopathologic features of lesions in the resected adrenals. Patients and Methods: Surgically removed adrenals (n = 37) from 90 patients operated from 2015 to 2018 in Munich, Germany, were selected to represent the broad histologic spectrum of unilateral PA. Five pathologists (Group 1 from Germany, Italy, and Japan) evaluated the histopathology of hematoxylin-eosin (HE) and CYP11B2 immunostained sections, and a consensus was established to define the identifiable features. The consensus was subsequently used by 6 additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, United Kingdom, United States) for the assessment of all adrenals with disagreement for histopathologic diagnoses among group 1 pathologists. Results: Consensus was achieved to define histopathologic features associated with PA. Use of CYP11B2 immunostaining resulted in a change of the original HE morphology-driven diagnosis in 5 (14%) of 37 cases. Using the consensus criteria, group 2 pathologists agreed for the evaluation of 11 of the 12 cases of disagreement among group 1 pathologists. Conclusion: The HISTALDO (histopathology of primary aldosteronism) consensus is useful to standardize nomenclature and achieve consistency among pathologists for the histopathologic diagnosis of unilateral PA. CYP11B2 immunohistochemistry should be incorporated into the routine clinical diagnostic workup to localize the likely source of aldosterone production.

Extra-cellular vesicles (EVs) are bilayer membrane structures enriched with proteins, nucleic acids and other active molecules and have been implicated in many physiological and pathological processes over the past decade. Recently, evidence suggests EVs to play a more dichotomic role in the regulation of the immune system, whereby an immune response may be enhanced or supressed by EVs depending on their cell of origin and its functional state. EVs derived from antigen (Ag)-presenting cells for instance, have been involved in both innate and acquired (or adaptive) immune responses, as Ag carriers or presenters, or as vehicles for delivering active signalling molecules. On the other hand, tumor and stem cell derived EVs have been identified to exert an inhibitory effect on immune responses by carrying immuno-modulatory effectors, such as transcriptional factors, non-coding RNA (Species) and cytokines. In addition, stem cell-derived EVs have also been reported to impair dendritic cell maturation and to regulate the activation, differentiation and proliferation of B cells. They have been shown to control natural killer cell activity and to suppress the innate immune response. Studies reporting the role of EVs on T lymphocyte modulation are controversial. Discrepancy in literature may be due to stem cell culture conditions, methods of EV purification, EV molecular content and functional state of both parental and target cells. However, mesenchymal stem cell-derived EVs were shown to play a more suppressive role by shifting T cells from an activated to a T regulatory phenotype. In this review we will discuss how stem cell-derived EVs may contribute towards the modulation of the immune response. Collectively, stem cell-derived EVs mainly exhibit an inhibitory effect on the immune system.

Primary aldosteronism is the most frequent form of secondary hypertension but is still markedly underdiagnosed. In 2008, the Endocrine Society released guidelines for primary aldosteronism diagnosis and management; current indications are that they are not being widely followed. To investigate the level of knowledge and application of the guidelines in a large representative cohort of general practitioners (GPs) in Italy and Germany. The study was carried out by web questionnaire on hypertension and primary aldosteronism management with 500 GPs (250 in Italy and 250 in Germany), stratified by geographical area and city size. The mean number of patients seen was 1747 (Germany) and 1388 (Italy). Of these, 18% were diagnosed as hypertensive in Italy and 25% in Germany. Renin and aldosterone measurements were ordered by 7% of GPs in Italy and 8% in Germany. GPs in Italy considered 8% of patients eligible for aldosterone and renin measurements compared with 13% of GPs in Germany. In Italy, primary aldosteronism prevalence was 1% among hypertensive patients; 36% of the GPs reported no primary aldosteronism patients under their care or diagnosed previously. In Germany, the prevalence of primary aldosteronism was 2% among hypertensive patients; 19% of GPs had no primary aldosteronism patients. In Germany and in Italy, primary aldosteronism is not widely recognized by GPs; Endocrine Society guidelines for primary aldosteronism diagnosis are not well known or applied, resulting in marked underdiagnosis of the disease.

Aldosterone-producing adenomas (APAs) cause a sporadic form of primary aldosteronism and somatic mutations in the KCNJ5 gene, which encodes the G-protein–activated inward rectifier K ⁺ channel 4, GIRK4, account for ≈40% of APAs. Additional somatic APA mutations were identified recently in 2 other genes, ATP1A1 and ATP2B3 , encoding Na ⁺ /K ⁺ -ATPase 1 and Ca ²⁺ -ATPase 3, respectively, at a combined prevalence of 6.8%. We have screened 112 APAs for mutations in known hotspots for genetic alterations associated with primary aldosteronism. Somatic mutations in ATP1A1 , ATP2B3 , and KCNJ5 were present in 6.3%, 0.9%, and 39.3% of APAs, respectively, and included 2 novel mutations (Na ⁺ /K ⁺ -ATPase p.Gly99Arg and GIRK4 p.Trp126Arg). CYP11B2 gene expression was higher in APAs harboring ATP1A1 and ATP2B3 mutations compared with those without these or KCNJ5 mutations. Overexpression of Na ⁺ /K ⁺ -ATPase p.Gly99Arg and GIRK4 p.Trp126Arg in HAC15 adrenal cells resulted in upregulation of CYP11B2 gene expression and its transcriptional regulator NR4A2. Structural modeling of the Na ⁺ /K ⁺ -ATPase showed that the Gly99Arg substitution most likely interferes with the gateway to the ion binding pocket. In vitro functional assays demonstrated that Gly99Arg displays severely impaired ATPase activity, a reduced apparent affinity for Na ⁺ activation of phosphorylation and K ⁺ inhibition of phosphorylation that indicate decreased Na ⁺ and K ⁺ binding, respectively. Moreover, whole cell patch-clamp studies established that overexpression of Na ⁺ /K ⁺ -ATPase Gly99Arg causes membrane voltage depolarization. In conclusion, somatic mutations are common in APAs that result in an increase in CYP11B2 gene expression and may account for the dysregulated aldosterone production in a subset of patients with sporadic primary aldosteronism.

Primary aldosteronism (PA) was considered a rare disorder almost always associated with hypokalemia. The widespread screening of patients with hypertension unveiled an increased prevalence of PA with normokalemic hypertension the prevailing phenotype. Many studies have reported the prevalence of hypokalemia in patients with PA; conversely, the prevalence of PA in patients with hypokalemia is unknown. In this retrospective observational study, we define the prevalence of hypokalemia in referred patients with hypertension and the prevalence of PA in patients with hypokalemia and hypertension. Hypokalemia was present in 15.8% of 5100 patients with hypertension, whereas 76.9% were normokalemic, and 7.3% hyperkalemic. The prevalence of PA in patients with hypokalemia was 28.1% and increased with decreasing potassium concentrations up to 88.5% of patients with spontaneous hypokalemia and potassium concentrations <2.5 mmol/L. A multivariate regression analysis demonstrated the association of hypokalemia with the occurrence of cardiovascular events independent of PA diagnosis. An association of PA with the occurrence of cardiovascular events and target organ damage independent of hypokalemia was also demonstrated. In conclusion, our results confirm that PA is a frequent cause of secondary hypertension in patients with hypokalemia, and the presence of hypertension and spontaneous hypokalemia are strong indications for PA diagnosis. Finally, we show that PA and hypokalemia are associated with an increased risk of cardiovascular events.