CONTEXT:Germline CACNA1H mutations have been associated with primary aldosteronism (PA). Here, we described 3 newly discovered CACNA1H variants and explored the possible pathogenic mechanisms as well as therapeutic strategies. DESIGN:Targeted next-generation sequencing of 10 PA causative genes was performed in 305 PA patients. Variants with possible clinical significance in CACNA1H were identified. Functional analysis was performed in vitro including electrophysiology, steroid hormone production, and transcriptome. Responses to mibefradil and nifedipine were evaluated. RESULTS:We described 3 heterozygous germline CACNA1H variants (E282K, V213M, and S1249R) in 4 independent cases of PA. Recurrent E282K mutation was identified in 1 patient with severe early-onset PA and 1 patient with bilateral adrenal hyperplasia (BAH). Electrophysiological analysis of mutant Cav3.2 channels revealed significant gain-of-function changes in the voltage-dependent activation and Ca2+ current properties for Cav3.2E282K, while ambiguous for Cav3.2S1249R and Cav3.2V213M. Moreover, stable expression of the 3 CACNA1H variants in H295R cells led to increased aldosterone production and upregulated expression of genes involved in steroidogenic enzymes, both basally and after K+ treatment. T-type calcium channel blocker showed more significant inhibition of aldosterone production in mutant Cav3.2 cells compared to L-type calcium channel blocker. CONCLUSIONS:Our study suggests that Cav3.2E282K is a gain-of-function mutation and T-type calcium channel blockers may be efficient in controlling aldosterone levels for PA patients carrying mutant Cav3.2.

Primary aldosteronism (PA), a major cause of secondary hypertension, is characterized by autonomous aldosterone overproduction. Although the gut microbiota is closely linked to blood pressure regulation, its role in PA remains unclear. We performed metagenomic sequencing on fecal samples from 13 patients with essential hypertension (EH), 57 with unilateral PA (UPA), and 51 with bilateral PA (BPA). Despite comparable overall microbial diversity, gut microbial compositional differences were observed among EH and PA subtypes, particularly at finer taxonomic levels. We next identified 39 microbial species that were positively associated with plasma aldosterone concentration (PAC), and 29 that were negatively associated. In the co-abundance network, Ruminococcus gnavus emerged as one of the top three central nodes and was negatively correlated with PAC. Functionally, R. gnavus efficiently degraded aldosterone and multiple natural steroid hormones in vitro, and aldosterone degradation was accompanied by the generation of 3α,5β-tetrahydroaldosterone. R. gnavus-colonized germ-free mice showed reduced fecal aldosterone levels and downregulated expression of aldosterone downstream genes in the intestine. In an aldosterone infusion model, R. gnavus similarly decreased fecal aldosterone and improved systolic blood pressure (SBP) and serum potassium. Logistic regression further revealed that the presence of R. gnavus was associated with lower odds of having a historical highest SBP ≥ 160 mmHg in patients with PA. Collectively, this study reveals different gut microbial signatures in PA and highlights the aldosterone-metabolizing capacity and blood pressure regulation of R. gnavus. These findings advance our understanding of gut microbiota-steroid hormone interactions in PA and provide a basis for exploring microbiota-based stratification and intervention strategies in steroid hormone-related conditions.

The primary objective of this prospective cohort study was to assess changes in energy metabolism and body composition following unilateral adrenalectomy in patients with unilateral primary aldosteronism (UPA). Patients with UPA undergoing adrenalectomy were enrolled and underwent standardized evaluations before surgery and at a 3-month postoperative follow-up. 24-h energy metabolism and body composition were measured using whole-room indirect calorimetry and dual-energy X-ray absorptiometry (DXA), respectively. At 3 months after surgery, mean 24-h energy expenditure decreased from 1923.67 ± 378.85 to 1851.71 ± 353.90 kcal/day (P = 0.0063). Carbohydrate oxidation declined from 136.87 ± 29.75 to 122.53 ± 33.37 g/day (P = 0.013), whereas protein oxidation increased from 62.82 ± 17.51 to 70.09 ± 14.55 g/day (P < 0.001). Postoperative body composition showed a reduction in lean mass (44.70 ± 10.31 to 43.54 ± 10.44 kg; P < 0.001), an increase in fat mass (20.45 ± 6.76 to 21.15 ± 6.41 kg; P = 0.026), and a rise in body fat percentage (29.96 ± 5.36% to 31.36 ± 5.04%; P < 0.001). Body weight did not change significantly (p = 0.25). Concurrently, insulin sensitivity indices also changed, with a lower Matsuda index (P = 0.0010) and Quantitative Insulin Sensitivity Check Index (QUICKI) (P = 0.0098), and higher Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (P = 0.015). Unilateral adrenalectomy in patients with UPA is associated with a shift in postoperative metabolic phenotype, characterized by altered energy metabolism, body composition as well as insulin sensitivity. These findings underscore the need for individualized postoperative metabolic monitoring in this population.

Waardenburg syndrome (WS) is a complex genetic disorder primarily characterized by auditory and pigmentary abnormalities, resulting from neural crest cell migration disorders. We reported 2 genetically confirmed SOX10-mutant WS cases illustrating critical management principles. Both patients underwent early auditory intervention (case 1: cochlear implantation at age 3; case 2: hearing aids from age 2), resulting in preserved age-appropriate language acquisition. Each case manifested delayed puberty with biochemical evidence of hypogonadotropic hypogonadism, necessitating gonadotropin therapy to potentiate virilization and preserve fertility. Multidisciplinary care and emerging therapeutic approaches offer hope for better management. Further studies are warranted to improve the diagnosis, treatment, and quality of life of patients with WS.

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with poor survival and limited treatment options. To comprehensively characterize its molecular landscape and identify clinically relevant subtypes, we performed an integrated genomic analysis - including whole-exome sequencing, RNA sequencing, and copy number variation profiling - on 61 Chinese patients with ACC. We identified recurrent mutations in TP53 (25%), CTNNB1 (15%), ZNRF3 (10%), and MEN1 (8%). Unsupervised clustering of transcriptomic data revealed four distinct molecular subtypes: cortisol-driven (CD, 14%), immune-suppressed (IS, 40%), cell cycle-altered (CCA, 22%), and immunomodulatory (IM, 24%). The CD subtype exhibited steroidogenic pathway activation; the IS subtype showed T cell receptor downregulation and the worst disease-free survival; the CCA subtype was marked by chromosomal instability and cell cycle gene overexpression; and the IM subtype displayed enriched immune signaling and favorable outcomes. Copy number analysis further uncovered focal amplifications (e.g. TERT, CDK4) and HLA-II deletions. This study establishes a novel molecular classification of ACC, providing a framework for subtype-specific therapeutic strategies, such as CDK4/6 inhibition for CCA and immunotherapy for IM tumors, while highlighting the clinical challenges of immune-cold IS tumors.

CONTEXT:The ubiquitin-specific protease 8 (USP8) gene mutations are the most common driver changes in Cushing disease (CD). However, few studies have investigated the association between USP8 mutation and recurrence, and the results have been inconclusive. OBJECTIVE:To identify the predictors of recurrence and evaluate the prognostic role of USP8 mutation. METHODS:One hundred and seven patients with pathologically confirmed corticotroph adenomas were included. Somatic USP8 mutations were identified using Sanger sequencing. Recurrence predictors were estimated using multivariate Cox models, followed by receiver operating characteristic curves and Kaplan-Meier analysis. RESULTS:Thirteen patients (12.6%) experienced recurrence, with a mean follow-up period of 65 months after surgery. The recurrence rate was significantly higher in USP8-mutated tumors than in USP8 wildtype tumors (26.5% vs 5.8%; P = .009). Multivariate Cox models revealed that USP8 mutation, high postsurgical morning serum cortisol (MSC), and high 1-mg dexamethasone suppression test (DST) were associated with an increased 5-year recurrence risk. Furthermore, Kaplan-Meier survival analysis showed that patients with USP8 mutation, combined with either high postsurgical MSC (>2.5 μg/dL) or high 1-mg DST (>0.78 μg/dL), were more prone to recurrence (log-rank P < .001). The negative predictive values were 98% and 100%, while the positive predictive values improved from 33% to 55% and from 47% to 86%, respectively. CONCLUSION:Our study corroborates USP8 mutational status in combination with postsurgical MSC or 1-mg DST as independent predictors of long-term remission, highlighting their potential role in stratifying patients at risk for suboptimal outcomes.

Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy with limited therapeutic options and a substantial risk of postoperative recurrence. Mitotane remains the only US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved agent specifically for ACC. Its antitumor activity involves disruption of cholesterol trafficking, inhibition of steroidogenic enzymes, and mitochondrial dysfunction, leading to selective cytotoxicity in adrenocortical cells. Current evidence indicates that maintaining therapeutic plasma concentrations between 14–20 mg/L is critical for clinical benefit, underscoring the importance of therapeutic drug monitoring. Mitotane is used in both adjuvant and advanced disease settings; however, its highly variable pharmacokinetics, broad endocrine disruptions, and frequent gastrointestinal and neurological toxicities require individualized dosing strategies and comprehensive supportive care. This review summarizes recent advances in the understanding of mitotane’s molecular mechanisms, pharmacogenetic determinants, clinical efficacy, and adverse-effect profile, with an emphasis on laboratory monitoring and practical considerations for optimizing treatment in ACC.

Context:Adrenocortical carcinoma (ACC) is rare and have high rates of recurrence and mortality. The role of adjuvant radiation therapy (RT) in localized ACC was controversial. Methods:We conducted a retrospective study in our center between 2015 and 2021 to evaluate the efficacy and safety of adjuvant RT in localized ACC. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to estimate the independent risk factors. Adverse events associated with RT were documented according to the toxicity criteria of the radiation therapy oncology group (RTOG) and the common terminology criteria for adverse events (CTCAE v5.0). Results:Of 105 patients with localized ACC, 46 (43.8%) received adjuvant RT after surgery. The median radiation dose was 45.0Gy (range:30.0-50.4) and median follow up time was 36.5 (IQR: 19.7-51.8) months. In comparison to the no adjuvant RT group, patients with adjuvant RT had better 3-year OS (87.9% vs 79.5%, P=0.039), especially for patients with ENSAT I/II stage (P=0.004). Adjuvant RT also improved the median DFS time from 16.5months (95%CI, 12.0-20.9) to 34.6months (95%CI, 16.1-53.0). Toxicity of RT was generally mild and moderate with six grade 3 events. Conclusions:Postoperative adjuvant RT significantly improved OS and DFS compared with the use of surgery alone in resected ACC patients. Although this retrospective study on RT in localized ACC indicates that RT is effective in ACC, its findings need to be prospectively confirmed.

Rationale: NPC1 is a protein localized on the lysosome membrane regulating intracellular cholesterol transportation and maintaining normal lysosome function. GWAS studies have found that NPC1 variants in T2D was a pancreatic islet expression quantitative trait locus, suggesting a potential role of NPC1 in T2D islet pathophysiology. Methods: Two-week-old Npc1-/- mice and wild type littermates were employed to examine pancreatic β cell morphology and functional changes induced by loss of Npc1. Single cell RNA sequencing was conducted on primary islets. Npc1-/- Min6 cell line was generated using CRISPR/Cas9 gene editing. Seahorse XF24 was used to analyze primary islet and Min6 cell mitochondria respiration. Ultra-high-resolution cell imaging with Lattice SIM2 and electron microscope imaging were used to observe mitochondria and lysosome in primary islet β and Min6 cells. Mitophagy Dye and mt-Keima were used to measure β cell mitophagy. Results: In Npc1-/- mice, we found that β cell survival and pancreatic β cell mass expansion as well as islet glucose induced insulin secretion in 2-week-old mice were reduced. Npc1 loss retarded postnatal β cell differentiation and growth as well as impaired mitochondria oxidative phosphorylation (OXPHOS) function to increase mitochondrial superoxide production, which might be attributed to impaired autophagy flux particularly mitochondria autophagy (mitophagy) induced by dysfunctional lysosome in Npc1 null β cells. Conclusion: Our study revealed that NPC1 played an important role in maintaining normal lysosome function and mitochondria turnover, which ensured establishment of sufficient mitochondria OXPHOS for islet β cells differentiation and maturation.

OBJECTIVE:Mineralocorticoid receptor antagonists are the recommended medical therapy for bilateral primary aldosteronism (BPA). Patients with BPA have higher risk of cardiocerebrovascular disease (CCVD) than those with essential hypertension. There is no consensus on the criteria to assess the effectiveness of medical therapy for BPA. This study aimed to investigate the incidence of and risk factors for CCVD after medical therapy of BPA. METHODS:We conducted a retrospective cohort study including 240 patients with BPA treated with mineralocorticoid receptor antagonists. The posttreatment plasma renin activity (PRA) was defined as unsuppressed (PRA, ≥1 ng/mL/h); otherwise, it was defined as suppressed. We analyzed the association of posttreatment PRA status with CCVD outcomes. RESULTS:Of patients with BPA, 7.1% (17/240) developed CCVD at a median follow-up of 5.0 (range, 2.96-7.66) years. Moreover, 57.1% of patients had a PRA of ≥1 ng/mL/h after treatment. Patients with a PRA of <1 ng/mL/h had a higher incidence of CCVD (12.6% vs 2.9%, P < .05) and were at higher risk than those with a PRA of ≥1 ng/mL/h (hazard ratio, 4.50 [95% CI, 1.47-13.83; P < .05]; adjusted hazard ratio, 3.98 [95% CI, 1.22-13.02; P < .05]). CONCLUSION:Patients with BPA who receive pharmacologic treatment have a high incidence of CCVD. PRA may be an indicator that mineralocorticoids are being adequately antagonized.

Context Cushing syndrome (CS) is a severe endocrine disease characterized by excessive secretion of cortisol with multiple metabolic disorders. While gut microbial dysbiosis plays a vital role in metabolic disorders, the role of gut microbiota in CS remains unclear.Objective The objective of this work is to examine the alteration of gut microbiota in patients with CS.Methods We performed shotgun metagenomic sequencing of fecal samples from 78 patients with CS and 78 healthy controls matched for age and body mass index. Furthermore, we verify the cortisol degradation capacity of Ruminococcus gnavus in vitro and identify the potential metabolite by LC-MC/MS.Results We observed significant differences in microbial composition between CS and controls in both sexes, with CS showing reduced Bacteroidetes (Bacteroides vulgatus) and elevated Firmicutes (Erysipelotrichaceae_bacterium_6_1_45) and Proteobacteria (Enterobacter cloacae). Despite distinct causes of hypercortisolism in ACTH-dependent and ACTH-independent CS, we found no significant differences in metabolic profiles or gut microbiota between the 2 subgroups. Furthermore, we identified a group of gut species, including R. gnavus, that were positively correlated with cortisol levels in CS. These bacteria were found to harbor cortisol-degrading desAB genes and were consistently enriched in CS. Moreover, we demonstrated the efficient capacity of R. gnavus to degrade cortisol to 11-oxygenated androgens in vitro.Conclusion This study provides evidence of gut microbial dysbiosis in patients with CS and identifies a group of CS-enriched bacteria capable of degrading cortisol. These findings highlight the potential role of gut microbiota in regulating host steroid hormone levels, and consequently host health.

BackgroundAdrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with limited therapeutic options. Treating advanced ACC with mitotane, the cornerstone therapy, remains challenging, thus underscoring the significance to predict mitotane response prior to treatment and seek other effective therapeutic strategies.ObjectiveWe aimed to determine the efficacy of mitotane via an in vitro assay using patient-derived ACC cells (PDCs), identify molecular biomarkers associated with mitotane response and preliminarily explore potential agents for ACC.MethodsIn vitro mitotane sensitivity testing was performed in 17 PDCs and high-throughput screening against 40 compounds was conducted in 8 PDCs. Genetic features were evaluated in 9 samples using exomic and transcriptomic sequencing.ResultsPDCs exhibited variable sensitivity to mitotane treatment. The median cell viability inhibition rate was 48.4% (IQR: 39.3-59.3%) and -1.2% (IQR: -26.4-22.1%) in responders (n=8) and non-responders (n=9), respectively. Median IC50 and AUC were remarkably lower in responders (IC50: 53.4 µM vs 74.7 µM, P<0.0001; AUC: 158.0 vs 213.5, P<0.0001). Genomic analysis revealed CTNNB1 somatic alterations were only found in responders (3/5) while ZNRF3 alterations only in non-responders (3/4). Transcriptomic profiling found pathways associated with lipid metabolism were upregulated in responder tumors whilst CYP27A1 and ABCA1 expression were positively correlated to in vitro mitotane sensitivity. Furthermore, pharmacologic analysis identified that compounds including disulfiram, niclosamide and bortezomib exhibited efficacy against PDCs.ConclusionACC PDCs could be useful for testing drug response, drug repurposing and guiding personalized therapies. Our results suggested response to mitotane might be associated with the dependency on lipid metabolism. CYP27A1 and ABCA1 expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.

ContextThe prevalence of unilateral primary aldosteronism (UPA) with cortisol co-secretion varies geographically.ObjectiveTo investigate the prevalence and clinical characteristics of UPA with cortisol co-secretion in a Chinese population.DesignRetrospective cohort study.MethodsWe recruited 580 patients with UPA who underwent cosyntropin stimulation test (CST) after the 1-mg dexamethasone suppression test (DST) and retrospectively analyzed the clinical characteristics and postoperative outcomes of UPA with and without cortisol co-secretion.ResultsUPA with cortisol co-secretion (1 mg DST>1.8 ug/dL) was identified in 65 of 580 (11.2%) patients. These patients were characterized by older age, longer duration of hypertension, higher concentration of plasma aldosterone and midnight cortisol, lower adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS), larger tumor diameter, and more history of diabetes mellitus. Cortisol and aldosterone levels were higher and DHEAS level was lower in UPA with cortisol co-secretion at 0–120 min after CST. Among 342 UPA patients with KCNJ5 gene sequencing and follow-up results, the complete clinical success rate was lower in UPA with cortisol co-secretion (33.3% vs. 56.4%, P<0.05); the complete biochemical success rate and KCNJ5 mutation did not differ between the two groups. Age, tumor size, and ACTH were independent predictors of UPA with cortisol co-secretion. Sex, BMI, duration of hypertension, KCNJ5 mutation, and cortisol co-secretion were independent predictors for complete clinical success in UPA after surgery.ConclusionsUPA with cortisol co-secretion is not uncommon in China, but the clinical features were distinctly different from those without co-secretion. Cortisol co-secretion is an independent risk factor for incomplete clinical success after surgery in UPA.

CONTEXT:Preoperative inflammatory markers, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR), have recently been proposed as prognostic markers in different tumors. However, their predictive values in patients with pheochromocytomas and paragangliomas (PPGLs) are uncertain. OBJECTIVE:This study aimed to investigate the prognostic significance of inflammatory biomarkers in PPGL patients. METHODS:Data from 1247 consecutive PPGL patients between 2002 and 2020 were evaluated. The preoperative inflammatory markers were evaluated. The prognostic roles were identified by X-tile software, Kaplan-Meier curves, and Cox regression models. RESULTS:A total of 728 patients were included in the analysis, with a median follow-up of 63 months (IQR, 31-111 months); 31 individuals died, 28 patients developed metastases, and 12 patients developed recurrence. Our study showed that deaths were observed significantly more frequently in patients with high NLR(≥3.5) and high PLR (≥217.4) than those with low NLR (<3.5) (P = .003) and low PLR (<217.4) (P = .005). Elevated NLR (≥3.5) and elevated PLR (≥217.4) was significantly associated with decreased overall survival (OS) (P = .005), and elevated PLR (≥238.3) was significantly associated with decreased metastasis-free survival (MFS) (P = .021). Cox models illustrated that NLR and PLR were independent prognostic factors for OS, and PLR was an independent prognostic factor for MFS. CONCLUSION:Both elevated NLR and PLR are associated with poor prognosis in PPGLs. They are convenient predictive markers that could be used in daily clinical practice.

Context:Adrenal incidentaloma (AI) is commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion is the most common functional disorder detected in AI. Objective:To delineate the association between radiological characteristics of benign adrenocortical tumors and hypothalamus-pituitary-adrenal (HPA) axis. Methods:In the study, 494 patients diagnosed with benign unilateral adrenocortical tumors were included. Mild autonomous cortisol secretion (MACS) was diagnosed when cortisol after 1mg-dexamethasone suppression test (1-mg DST) was in the range of 1.8-5ug/dl. Non-functional adrenocortical tumor (NFAT) was diagnosed as cortisol following 1-mg DST less than 1.8ug/dL. We performed Logistics regression and causal mediation analyses, looking for associations between radiological characteristics and the HPA axis. Results:Of 494 patients, 352 (71.3%) with NFAT and 142 (28.7%) with MACS were included. Patients with MACS had a higher tumor diameter, thinner contralateral adrenal gland, and lower plasma ACTH and serum DHEAS than those with NFAT. ACTH (OR 0.978, 0.962-0.993) and tumor diameter (OR 1.857, 95%CI, 1.357-2.540) were independent factors associated with decreased serum DHEAS (all P<0.05). ACTH was also associated with decreased contralateral adrenal diameter significantly (OR 0.973, 95%CI, 0.957-0.988, P=0.001). Causal mediation analysis showed ACTH mediated the effect significantly for the association between 1-mg DST results and DHEAS level (Pmediation<0.001, proportion=22.3%). Meanwhile, we found ACTH mediated 39.7% of the effects of 1-mg DST on contralateral adrenal diameter (Pmediation=0.012). Conclusions:Patients with MACS had thinner contralateral adrenal glands and disturbed HPA axes compared with NFAT. ACTH may partially be involved in mediating the mild autonomous cortisol secretion to DHEAS and the contralateral adrenal gland.

IntroductionPheochromocytomas and paragangliomas (PCC/PGL) are rare neuroendocrine tumors and can secrete catecholamine. Previous studies have found that SDHB immunohistochemistry (IHC) can predict SDHB germline gene mutation, and SDHB mutation is closely associated with tumor progression and metastasis. This study aimed to clarify the potential effect of SDHB IHC as a predictive marker for tumor progression in PCC/PGL patients. MethodsWe included PCC/PGL patients diagnosed in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from 2002 to 2014 for retrospective analysis and discovered that SDHB (-) staining patients had poorer prognoses. Then we examined SDHB protein expression by IHC on all tumors in the prospective series, which was composed of patients from 2015 to 2020 in our center. ResultsIn the retrospective series, the median follow-up was 167 months, and during follow-up, 14.4% (38/264) patients developed metastasis or recurrence, and 8.0% (22/274) patients died. Retrospective analysis revealed that 66.7% (6/9) of participants in the SDHB (-) group and 15.7% (40/255) of those in the SDHB (+) group developed progressive tumors (OR: 10.75, 95% CI: 2.72-52.60, P=0.001), and SDHB (-) was independently associated with poor outcomes after adjusting by other clinicopathological parameters (OR: 11.68, 95% CI: 2.58-64.45, P=0.002). SDHB (-) patients had shorter disease-free survival (DFS) and overall survival (OS) (P<0.001) and SDHB (-) was significantly associated with shorter median DFS (HR: 6.89, 95% CI: 2.41-19.70, P<0.001) in multivariate cox proportional hazard analysis. In the prospective series, the median follow-up was 28 months, 4.7% (10/213) patients developed metastasis or recurrence, and 0.5% (1/217) patient died. For the prospective analysis, 18.8% (3/16) of participants in the SDHB (-) group had progressive tumors compared with 3.6% (7/197) in the SDHB (+) group (RR: 5.28, 95% CI: 1.51-18.47, P=0.009), statistical significance remained (RR: 3.35, 95% CI: 1.20-9.38, P=0.021) after adjusting for other clinicopathological factors. ConclusionsOur findings demonstrated patients with SDHB (-) tumors had a higher possibility of poor outcomes, and SDHB IHC can be regarded as an independent biomarker of prognosis in PCC/PGL.

Objective:To investigate the clinical profile of primary bilateral macronodular adrenal hyperplasia(PBMAH) and sex difference.Methods:One hundred and forty cases of PBMAH were recruited in our center from 2014, and all patients were evaluated for hormone secretion, adrenal imaging, and metabolic parameters.Results:Overt Cushing′s syndrome accounted for 76.4% of PBMAH cohort and 47.9% were female. The overt group had higher serum cortisol and 24 h urinary free cortisol levels, lower adrenocorticotropic hormone, higher serum cortisol after low-dose dexamethasone suppression tests, larger total adrenal size, and a higher percentage of obesity, hypertension, diabetes mellitus, and hypokalemia than the subclinical group(all P<0.05). When compared with the male group, the female group had smaller adrenal size( P<0.001), lower HbA 1C( P=0.003), higher total cholesterol( P=0.005), and lower density lipoprotein-cholesterol levels( P=0.035). Further, 24 h urinary free cortisol in the male group was found to be positively correlated with diastolic blood pressure, fasting glucose, 2 h postprandial glucose after oral glucose tolerance test(OGTT), and HbA 1C after adjusted for age, body mass index, and onset duration, and was negatively correlated with body mass index and potassium levels. While 24 h urinary free cortisol in the female group was positively correlated only with diastolic blood pressure, fasting glucose, and 2 h postprandial glucose after OGTT(all P<0.05). During follow-up, 80.0% of patients achieved remission after unilateral adrenalectomy, with a recurrence rate of 17.9%. Conclusion:PBMAH related metabolic disorder is more pronounced in overt Cushing′s syndrome and males. Unilateral adrenalectomy as an effective treatment can benefit the majority of patients.

Background:Idiopathic hyperaldosteronism (IHA) is one of the most common types of primary aldosteronism (PA), an important cause of hypertension. Although high dietary sodium is a major risk factor for hypertension, there is no consensus on the recommended dietary sodium intake for IHA. Objective:This study investigated the effect of a low-sodium diet on hemodynamic variables and relevant disease biomarkers in IHA patients, with the aim of providing a useful reference for clinical treatment. Methods:Fifty IHA patients were evenly randomized into two groups and provided, after a 7-day run-in period (100 mmol/d sodium), either a low-sodium diet (50 mmol/d sodium) or a normal sodium diet (100 mmol/d sodium) for an additional 7 days. After the 14-day intervention (conducted without potassium supplementation), changes in blood pressure (BP) and serum potassium were evaluated in both groups. Results:After the dietary intervention, the low sodium group exhibited, compared to the normal sodium group, decreased BP (SBP: 121.8 ± 12.8 vs. 129.9 ± 12.1 mmHg, p < 0.05; DBP: 82.6 ± 7.6 vs. 86.4 ± 8.2 mmHg, p < 0.05; MAP: 95.7 ± 8.8 vs. 100.9 ± 8.4 mmHg, p < 0.05) and increased serum potassium levels (3.38 ± 0.33 vs. 3.07 ± 0.27 mmol/L, p < 0.001). The low sodium group showed also better control of both BP and serum potassium: BP <140/90 mmHg in 70.0% of total patients (76.0% vs. 64.0%, in the low and normal sodium groups, respectively; p > 0.05), BP <130/85 mmHg in 38.0% of total patients (56.0% vs. 20.0%, p < 0.05), BP <120/80 mmHg in 28.0% of total patients (44.0% vs. 12.0%, p < 0.05); serum potassium ≥3.5 mmol/L in 22.0% of total patients (32.0% vs. 12.0% in the low and normal sodium groups, respectively; p = 0.088). There were differences between the controlled BP group (<120/80 mmHg) and the non-controlled BP group (≥120/80 mmHg) in gender, BP at baseline, and type of diet (low vs. normal sodium). Female gender and low-sodium diet were protective factors for BP control. Conclusions:A low-sodium diet is effective in lowering BP and elevating serum potassium in IHA patients. Female patients on a low-sodium diet are more likely to achieve BP control (<120/80 mmHg). We advocate a dietary sodium intake of 50 mmol/d for IHA patients. Clinical trial registration:https://clinicaltrials.gov, Identifier NCT05649631.

Objective Unilateral primary aldosteronism (PA) includes aldosterone-producing adenoma (APA), unilateral adrenal hyperplasia, and unilateral multiple nodules. The correlation of multiple nodules, especially genotypic and pathological characteristics, remains unknown. KCNJ5 mutation accounts for 60–80% of unilateral PA, so we aimed to explore the correlation of KCNJ5 somatic mutation and CYP11B1/CYP11B2 staining in multiple nodules in unilateral PA. Design and Methods A total of 56 microdissected nodules from 24 patients with unilateral PA were included. We assessed somatic KCNJ5 mutations, immunohistochemistry for aldosterone synthase (CYP11B2)/cortisol synthase (CYP11B1), and histological cellular composition of nodules together with adjacent adrenal cortical statements. Results KCNJ5 mutations were identified in 17 (17/56, 30.4%) nodules from 11 adrenals (11/24, 45.8%). All KCNJ5-mutant nodules were positive for CYP11B2 staining, 6 cases (6/11) had only one KCNJ5-mutant nodular, and the other 5 cases (5/11) had more than one KCNJ5-mutant nodules. Three cases (3/11) had different KCNJ5 mutations in individual nodules. Compared with KCNJ5-positive adrenals, the cortices adjacent to the nodules in KCNJ5-negative adrenals showed significant proliferation (p = 0.004). CYP11B2/CYP11B1 expression patterns revealed great heterogeneity in intensity and range both in KCNJ5-mutant nodules and KCNJ5-WT ones. Conclusion There is great heterogeneity among nodules from patients with unilateral PA. Countable nodules could be considered as multiple APAs, featuring somatic KCNJ5 mutation, positive CYP11B2 staining, and lack of adjacent cortical proliferation in unilateral multiple nodules.

Objective To explore the prevalence and clinical significance of newly diagnosed diabetes mellitus (DM) in patients with primary aldosteronism (PA). Investigating the risk factors for cardiocerebrovascular disease (CCVD) will guide strategies for reducing CCVD in patients with PA. Methods We retrospectively included 729 PA patients without DM and conducted oral glucose tolerance tests. Results We found that 15.0% of PA patients had newly diagnosed DM. The DM prevalence increased with elevated aldosterone levels [OR = 3.20 (1.77, 5.78), P value < 0.001]. The rate of CCVD in newly diagnosed diabetic PA patients was higher than that in nondiabetic PA patients at diagnosis (11.9% vs. 5.0%, P = 0.005). Furthermore, multivariate logistic analysis revealed that HT duration [1.055 (1.002,1.111), P = 0.041] and newly diagnosed DM [2.600 (1.072,6.303), P = 0.034] were significantly associated with CCVD in PA patients. Conclusion The prevalence of newly diagnosed DM in PA patients was higher than that in the general population. Aldosterone level was an independent risk factor for DM not for CCVD. CCVD was correlated with longer HT duration and newly diagnosed DM. Therefore, it is crucial to screen DM at the diagnosis in PA patients.