•Somatic mutations in genes involved in Ca2+ homeostasis cause 60% of sporadic APAs.•KCNJ5-mutated APAs are composed mainly of zona fasciculata-like cells.•ATPase and CACNA1D-mutated APAs are ...composed mainly of zona glomerulosa-like cells.•Nodules with high CYP11B2 expression are small and composed mainly of ZG-like cells.
Adrenal glands removed for unilateral primary aldosteronism (PA) display marked histological heterogeneity. Recently reported somatic mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D can partially account for these differences. In this study we aimed at combining phenotypic and genotypic characteristics, integrating genetic and immunohistochemistry correlates in sporadic PA. Seventy-one adrenal glands have been included in the study and analyzed for mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. Histological examination and immunohistochemical staining for CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) were performed on aldosterone-producing adenomas (APAs) and adjacent adrenal cortex. In our cohort, the final histopathological diagnosis was multinodular hyperplasia in 22.5% of the patients and single nodule in 77.5%. Forty-five percent of the removed adrenals displayed extra-APA CYP11B2-positive cell nests (B2-CN). Among adrenal vein sampling parameters the suppression of contralateral adrenal was more frequent and the lateralization index was higher in the subgroup of patients without extra-APA B2-CN compared to the subgroup with extra-APA B2-CN. KCNJ5-mutated APAs were composed mainly of zona fasciculata-like cells with high expression of CYP11B1, while ATP1A1, ATP2B3 and CACNA1D-mutated APAs presented more frequently a zona-glomerulosa-like phenotype with high expression of CYP11B2. We observed a significant inverse correlation between CYP11B2 expression and the size of the nodules and, if CYP11B2 expression was corrected for tumor volume, a significant correlation with plasma aldosterone and aldosterone to renin ratio. Our findings indicate that combination of genotyping and immunohistochemistry improves the final histopathological diagnosis between single nodule and multinodular hyperplasia of the assessed adrenals.
The available data on the natural history of pheochromocytomas and paragangliomas after radical surgery are heterogeneous and discordant. The aim of our retrospective multicenter study was to find ...predictors of recurrence in patients with pheochromocytomas and sympathetic paragangliomas submitted to radical surgery in Piedmont (a region in northwest Italy). We collected data from 242 patients diagnosed between 1990 and 2016. Forty-two patients (17.4%) had disease recurrence. Multivariate analysis showed that genetic mutation (HR = 3.62; 95% CI 1.44-9.13; p = 0.006), younger age (HR = 0.97; 95% CI 0.95-0.99; p = 0.031) and larger tumor size (HR = 1.01; 95% CI 1.00-1.02; p = 0.015) were independently associated with a higher recurrence risk of pheochromocytoma and paraganglioma; in pheochromocytomas, genetic mutation (HR = 3.4; 95% CI 1.00-11.48; p = 0.049), younger age (HR = 0.97; 95% CI 0.94-0.99; p = 0.02), higher tumor size (HR = 1.01; 95% CI 1.00-1.03; p = 0.043) and PASS value (HR = 1.16; 95% CI 1.03-1.3; p = 0.011) were associated with recurrence. Moreover, tumor size was the only predictor of metastatic pheochromocytoma and paraganglioma (HR = 4.6; 95% CI 1.4-15.0; p = 0.012); tumor size (HR = 3.93; 95% CI 1.2-16.4; p = 0.026) and PASS value (HR = 1.27; 95% CI 1.06-1.53; p = 0.007) were predictors of metastatic pheochromocytoma. In conclusion, our findings suggest that the recurrence of pheochromocytoma and sympathetic paraganglioma develops more frequently in younger subjects, patients with a family history of chromaffin tissue neoplasms, mutations in susceptibility genes, larger tumors and higher values of PASS. We recommend genetic testing in all patients with PPGL and strict follow-up at least on an annual basis.
ContextChronic hypoxia induces complex metabolic and endocrine adaptations. High-altitude (HA) exposure is a physiological model of hypoxia.ObjectiveTo further investigate the endocrine and metabolic ...responses to extreme HA.MethodsWe studied nine male elite climbers at sea level and at 5200 m after climbing Mt. Everest.ResultsAfter 7 weeks at HA, body weight was reduced (P<0.05); regarding endocrine variables we observed: a) an increase of 2-h mean GH concentration (P<0.05) as well as of total IGF-I and IGF binding protein-3 levels (P<0.05 for both); b) a prolactin increase (P<0.05) coupled with testosterone decrease (P<0.01) and progesterone increase (P<0.05) without any change in estradiol levels: c) no change in cortisol, ACTH, and dehydroepiandrosterone sulfate (DHEAS) levels; d) an increase in free thyroxine (P<0.05) and free tri-iodothyronine (T3) decrease (P<0.05) but no change in TSH levels; e) a plasma glucose decrease (P<0.05) without any change in insulin levels; f) an increase in mean free fatty acid levels (P<0.05); g) despite body weight loss, leptin levels showed non-significant trend toward decrease, while ghrelin levels did not change at all.ConclusionsThe results of the present study in a unique experimental human model of maximal exposure to altitude and physical exercise demonstrate that extreme HA and strenuous physical exercise are coupled with specific endocrine adaptations. These include increased activity of the GH/IGF-I axis and a low T3 syndrome but no change in ghrelin and leptin that was expected taking into account body weight decrease. These findings would contribute to better understanding human endocrine and metabolic physiology in hypoxic conditions.
ObjectiveIn most cases of primary aldosteronism (PA), an adrenal aldosterone-secreting tumor cannot be reasonably proven, so these patients undergo medical treatment. Controversial data exist about ...the evolution of PA after medical therapy: long-term treatment with mineralocorticoid antagonists has been reported to normalize aldosterone levels but other authors failed to find remission of mineralocorticoid hypersecretion. Thus, we planned to retest aldosterone secretion in patients with medically treated PA diagnosed at least 3 years before.DesignRetrospective, cross-sectional study.MethodsThe same workup for PA as at diagnosis (basal aldosterone to renin activity ratio (ARR) and aldosterone suppression test) was performed after stopping interfering drugs and low-salt diet, in 34 subjects with PA diagnosed between 3 and 15 years earlier, by case finding from subgroups of hypertensive patients at high risk for PA. Criteria for persistence of PA were the same as at diagnosis (ARR (pg/ml per ng per ml per h) >400, aldosterone >150 pg/ml basally, and >100 pg/ml after saline infusion) or less restrictive.ResultsPA was not confirmed in 26 (76%) of the patients and also not in 20 (59%) using the least restrictive criteria suggested by international guidelines. Unconfirmed PA was positively associated with female sex, higher potassium levels, longer duration of hypertension, and follow-up, but not with adrenal mass, aldosterone levels at diagnosis, and treatment with mineralocorticoid antagonists.ConclusionsThis study suggests that mineralocorticoid hyperfunction in patients with PA after medical treatment may decline spontaneously. Higher potassium concentration and duration of treatment seem to increase the probability of this event.
OBJECTIVES:To assess the prevalence of primary aldosteronism and its association with cardiometabolic complications in patients with resistant and refractory hypertension.
METHODS:One hundred and ten ...consecutive patients with true resistant hypertension insufficient blood pressure control despite appropriate lifestyle measures and treatment with at least three classes of antihypertensive medication, including a diuretic and without previous cardiovascular events were screened for secondary hypertension. Refractory hypertension was diagnosed in case of uncontrolled blood pressure despite the use of at least five antihypertensive drugs.
RESULTS:Primary aldosteronism was diagnosed in 32 cases (29.1%). The multivariate analysis showed that primary aldosteronism is a strong factor positively associated with left ventricular hypertrophy odds ratio (OR) = 12.98, 95% confidence interval (CI) 3.82–60.88; P < 0.001, microalbuminuria (OR = 3.67, 95% CI 1.44–9.78; P = 0.007), carotid intima–media thickness at least 0.9 mm (OR = 2.69, 95% CI 1.02–7.82; P = 0.037), aortic ectasia (OR = 4.08, 95% CI 1,18–15.04; P = 0.027) and atrial fibrillation (OR 8.80, 95% CI 1.53–73.98; P = 0.022). Moreover, primary aldosteronism was independently associated with the presence of at least one (OR = 8.60, 95% CI 1.73–69.88; P = 0.018) and at least two types of organ damage (OR = 3.08, 95% CI 1.19–8.24; P = 0.022). Thirteen patients (11.8%) were affected by refractory hypertension. This group was characterized by significantly higher values of carotid intima–media thickness, higher rate of aldosterone-producing adenoma and atrial fibrillation, compared with the other individuals with resistant hypertension.
CONCLUSION:The current study indicates that primary aldosteronism is a frequent cause of secondary hypertension and cardiovascular complications among patients with resistant and refractory hypertension, suggesting a crucial role of aldosterone in the pathogenesis of severe hypertensive phenotypes and cardiovascular 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-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.
Purpose
Standard treatment for chronic hypoparathyroidism is represented by long-life per os supplementation of calcium and vitamin D. Since 90s, exogenous PTH is also available, but a not negligible ...number of patients experience a poor control. Starting from the experience with pumps in diabetes, it has been hypothesized that the infusion of PTH through pump might result in a better disease control. The aim of this systematic review is to summarize the published data about continuous subcutaneous PTH infusion in chronic hypoPTH patients and achieve conclusions for clinical practice.
Methods
A comprehensive computer literature search of the PubMed/MEDLINE, Embase, and Scopus databases was conducted by two authors independently (last search on November 30, 2022). All findings were summarized and critically discussed.
Results
We included 14 of the 103 retrieved articles, 2 RCTs, 8 case reports, and 4 case series, published between 2008 and 2022. Of the total 40 patients, 17 were adults, and 23 pediatric. The etiology was postsurgical in 50% of cases and genetic in the other 50%. All had a failure of standard care and a rapid improvement of clinical and biochemical parameters on PTH pump therapy, without severe adverse events.
Conclusions
Based on literature, pump PTH infusion may represent an effective, safe, and feasible option for patients with chronic hypoparathyroidism refractory to standard therapy. From a clinical perspective, careful patient selection, a skilled healthcare team, the assessment of the local setting and the collaboration with pump suppliers are essential.
Context:
Adrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary ...aldosteronism (PA). AVS protocols are not standardized and vary widely between centers.
Objective:
The objective of the study was to retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA.
Setting:
The study was carried out in eight different referral centers in Italy, Germany, and Japan.
Patients:
From 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses.
Results:
Overall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared with basal procedures (90% vs 77%). The CL ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P = .02 and P = .01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters, and patients with CL suppression underwent a significantly larger reduction in the aldosterone levels after adrenalectomy.
Conclusions:
For patients with lateralizing indices of greater than 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.
Introduzione. Il D-chiro-inositolo (DCI) è un mediatore dell’azione insulinica e ha dimostrato di migliorare i parametri metabolici delle donne con diabete gestazionale (GDM). L’obiettivo di questo ...studio è valutare l’impatto della supplementazione di DCI sul controllo metabolico e gli esiti materni e fetali delle donne affette da GDM.
Pazienti e metodi. È stata valutata retrospettivamente una coorte di 20 donne affette da GDM, trattate con dieta standard e, in metà dei casi, supplementate con DCI. Sono stati valutati e confrontati nei due gruppi (DCI vs controllo) vari parametri (compenso glicemico, dose insulinica totale, parametri biometrici materni e fetali).
Risultati. Il gruppo DCI ha mostrato una tendenza a una minor dose insulinica giornaliera, a glicemie postprandiali più basse e un minor peso al parto, mentre i feti del gruppo DCI avevano una minor circonferenza addominale e un minor peso alla nascita. A causa della bassa numerosità, le differenze riscontrate non sono risultate statisticamente significative.
Conclusioni. La supplementazione di DCI nel GDM è sicura e sembra migliorare, in associazione a terapia standard, i parametri metabolici materni, oltre che esercitare un ruolo favorevole sullo sviluppo fetale.
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