Adrenal Aldosterone-producing Adenoma Research Articles

Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities.

Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline mutations are found in a syndrome of primary aldosteronism, seizures, and neurologic abnormalities (PASNA) as well as in autism spectrum disorder. Using CRISPR/Cas9, we here generated mice with a Cacna1d gain-of-function mutation found in both adenomas and PASNA syndrome (Cacna1dIle772Met/+). These mice show reduced body weight and increased mortality from weaning to approximately 100 days of age. Male mice do not breed, likely due to neuromotor impairment, and the offspring of female mice die perinatally, likely due to lack of maternal care. Mice generated by in vitro fertilization showed elevated intracellular calcium in the aldosterone-producing zona glomerulosa, an elevated aldosterone/renin ratio, and persistently elevated serum aldosterone on a high-salt diet as signs of primary aldosteronism. Anesthesia with ketamine and xylazine induced tonic-clonic seizures. Neurologic abnormalities included hyperlocomotion, impaired performance in the rotarod test, impaired nest building, and slight changes in social behavior. Intracellular calcium in the zona glomerulosa, aldosterone levels, and rotarod performance responded to treatment with the calcium channel blocker isradipine, with implications for the therapy of patients with aldosterone-producing lesions and with PASNA syndrome.

FRI144 Using Single Cell Technology To Predict The Cell Of Origin Of Aldosterone-producing Adrenal Adenomas

Abstract Disclosure: K. Laycock: None. C. Cabrera: None. E. Wozniak: None. C. Mein: None. E. Azizan: None. X. Wu: None. G. Argentesi: None. E. Goodchild: None. W. Drake: None. M.J. Brown: None. Background: Aldosterone-producing adrenal adenomas (APAs) are the commonest surgically curable cause of hypertension, but individual prediction of postoperative outcome is challenging. Emerging data suggest that outcomes are influenced by APA genotype; identifying the cell of origin of APAs could facilitate a greater understanding of why certain genotypes are more/less likely to be associated with residual/recurrent autonomous aldosterone production(1, 2). Aims: 1. To develop an adult adrenal single cell atlas. 2. To identify the likely cell of origin for APAs with different mutations. Methodology: Bulk RNA sequencing from 67 APAs discovered known or novel somatic genotypes in 55, and replicated or discovered distinctive transcriptomes for each genotype. Single nuclei RNA sequencing was performed on 13 adrenals adjacent to the genotyped APAs. After aggregation of all 13 datasets, cluster analysis was undertaken to identify cell types and some of the transitions between these. Similarities were sought between the genotype-enriched transcriptomes of APAs, and the transcriptomes of individual cell clusters in adjacent adrenal. Results: A single nuclei atlas of 56,442 nuclei was developed. Clusters included each of the 3 cortical zones, aldosterone-producing micronodules, capsular cells, adrenal medulla, macrophages, T cells, stromal cells, endothelial cells and neurones. Several zona glomerulosa selective transcripts in previous laser-capture studies(3, 4) clustered separately from CYP11B2-positive cells (e.g. LGR5, GABBR2) or in distinct non-steroidogenic clusters (e.g. KIAA1210, RSPO3, PTGDS).A sub-cluster of stromal cells, positive for KIAA1210, RSPO3, CDH13 and MFAP5 (each p<10-254 cf other clusters) is likely to represent the distinctive KIAA1210+ capsular/interstitial cells on adrenal immunohistochemistry (www.proteinatlas.org). Bulk RNA sequencing of a rare CLCN2-mutant APA showed 13-30-fold higher expression of these and multiple other genes localising to the single nuclei stromal-cell cluster. Conclusion: Single nuclei sequencing documents the heterogeneity of adrenal cells, and potential for multiple different cell-types to develop into APAs. Ongoing analysis is underway to replicate the CLCN2-mutant transcriptome and identify cells-of-origins for tumours with commoner mutations. 1.Wu X et al. 11C metomidate PET-CT versus AVS for diagnosing surgically curable PA: a prospective within-patient trial. Nat Med. In press 2.Zhou J et al. Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant APAs presenting in puberty, pregnancy or menopause. Nat Genet. 2021 3.Nishimoto K et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci USA. 2015 4.Shaikh LH et al. LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal. J Clin Endocrinol Metab. 2015 Presentation: Friday, June 16, 2023

OR02-01 Somatic Mutations In The Zinc Transporter ZnT1 Cause Primary Aldosteronism

Abstract Disclosure: J. Rege: None. S. Bandulik: None. K. Nanba: None. C. Kosmann: None. A. Blinder: None. A. Plain: None. P. Vats: None. C. Kumar-Sinha: None. A.M. Lerario: None. T. Else: None. Y. Yamazaki: None. F. Satoh: None. H. Sasano: None. T.J. Giordano: None. T.A. Williams: None. M. Reincke: None. A. Turcu: None. A. Udager: None. R. Warth: None. W.E. Rainey: None. Primary aldosteronism (PA) is the most common form of endocrine hypertension and affects approximately one in 50 adults. PA is characterized by inappropriately elevated adrenal aldosterone production via renin-independent mechanisms. Aldosterone-driver somatic mutations in a G protein-coupled inwardly rectifying potassium channel (KCNJ5), Na+/K+ and Ca2+ ATPases (ATP1A1 and ATP2B3, respectively), L-type and T-type voltage-gated calcium channels (CACNA1D and CACNA1H, respectively), and chloride voltage-gated channel (CLCN2) have been found in approximately 90% of adrenal aldosterone-producing adenomas (APAs). Other causes of lateralized adrenal PA include aldosterone-producing nodules (APNs). Using next-generation sequencing, we identified recurrent in-frame deletions in SLC30A1 in four APAs and one APN (p.L51_A57del, n=3; p.L49_L55del, n=2). SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identified SLC30A1 variants are situated in close proximity to the zinc-binding site (His43 and Asp47) in transmembrane domain II and likely cause abnormal ion transport. PA cases with the unique SLC30A1 mutations showed male dominance and demonstrated increased serum aldosterone and 18-oxo-cortisol concentrations. Functional studies of the mutant SLC30A151_57del variant in a doxycycline-inducible adrenal cell system revealed pathologic Na+ influx caused by the mutant. Aberrant Na+ current led to the depolarization of the resting membrane potential, and thus to the opening of voltage-gated calcium channels. This resulted in an increase in cytosolic Ca2+ activity, which stimulated CYP11B2 mRNA expression and aldosterone production. Collectively, these data implicate the first-in-field zinc transporter mutations as a dominant driver of aldosterone excess in PA. Presentation: Thursday, June 15, 2023

Preliminary study on the ability of 68Ga-Pentixafor PET/CT to differentiate between adrenal aldosterone-producing adenoma and nonfunctional adenoma

Objective: To evaluate the ability of 68Ga-Pentixafor (nuclide ligand imaging agents for chemokine receptor 4) PET/CT to differentiate between aldosterone-producing adenoma (APA) and adrenal nonfunctional adenoma (NFA), and to assess how well this imaging method correlates with clinical features and postoperative outcomes. Methods: This was a cross-sectional study involving 73 APA and 12 NFA patients who received 68Ga-Pentixafor PET/CT imaging at Peking Union Medical College Hospital from August 2018 to October 2021. The receiver operating characteristic (ROC) curve was used to evaluate the differential value of visual analysis and the maximum standard uptake value (SUVmax) of the focus on APA and NFA. The related factors of SUVmax, and its predictive effect on postoperative outcomes were analyzed using Pearson or Spearman analysis and χ2 text. Results: 68Ga-Pentixafor PET/CT imaging was positive in 64 APA patients (sensitivity=87.7%) and negative in all 12 NFA patients (specificity=100%). The area under the ROC curve with SUVmax differentiating APA and NFA was 0.932 (P<0.001). When the SUVmax cut-off point was 6.23, the sensitivity was 80.8% and the specificity was 100%. The SUVmax correlated positively with lesion size (r=0.598) and aldosterone/renin activity ratio (r=0.313) and correlated negatively with potassium level (r=-0.286), renin activity (r=-0.240) and age of diagnosis (r=-0.273) (all P<0.05). Of the patients who underwent adrenalectomy and received more than 6 months of post-surgical follow-up, the clinical complete remission rate was higher for 68Ga-Pentixafor PET/CT imaging-positive patients than imaging-negative patients (24/39 vs. 0/4, P=0.031). Conclusions: 68Ga-Pentixafor PET/CT is effective at differentiating between APA and NFA. The SUVmax of 68Ga-Pentixafor PET/CT correlates with age at onset, lesion size, and the severity of clinical manifestations, and is able to predict postoperative outcomes.

Left adrenal aldosteronism coexisting with left paraaortic paraganglioma presenting as bilateral adrenal and left paraaortic tumors– comprehensive adrenal evaluation aiding perfect management: a case report

BackgroundCoexistence of a catecholamine-secreting tumor and an adrenal cortical tumor is quite rare which makes both diagnosis and management challenging. The purpose of this article is to describe the presence of this condition, share a stepwise approach for preoperative evaluation, and review the related literature.Case presentationA 44-year-old male patient had a history of hypertension and aggravating hypokalemia for years. Abdominal computed tomography incidentally found concomitant bilateral adrenal and left para-aortic tumors. Comprehensive adrenal hormone tests revealed a high aldosterone renin ratio and mildly elevated 24-h urine vanillylmandelic acid and norepinephrine levels. Subsequently, a metaiodobenzylguanidine scan showed uptake over the left para-aortic tumor, and NP-59 adrenal scintigraphy showed uptake over the left adrenal tumor. Further confirmatory tests, including captopril suppression, irbesartan suppression, and saline infusion, all confirmed the diagnosis of hyperaldosteronism. Adrenal venous sampling following 2 months of preparation with an alpha blocker demonstrated a left aldosterone-producing adrenal adenoma. Combining hormonal analysis, imaging studies, and adrenal venous sampling, the patient was diagnosed with left adrenal aldosteronoma, right adrenal nonfunctional tumor, and left para-aortic paraganglioma (PGL). Accordingly, laparoscopic left adrenalectomy and left PGL excision were performed smoothly under alpha blocker maintenance. The pathology report confirmed left adrenal cortical adenoma and left para-aortic PGL. Postoperatively, the blood pressure, biochemical tests, and adrenal hormone assays returned to normal, and related symptoms disappeared and were relatively stable during the follow-up period of two years.ConclusionsThis is the first case of left para-aortic PGL coexisting with an ipsilateral aldosterone-producing adenoma presenting as a left para-aortic tumor associated with bilateral adrenal tumors. Awareness of the rarity of this coexistence can avoid unexpected disasters during the process of evaluation and management.

Development and Validation of Hub Genes for Adrenal Aldosterone-Producing Adenoma by Integrated Bioinformatics Analysis.

ObjectiveTo develop and validate hub genes involving in the development and progression of primary aldosteronism (PA) and adrenal aldosterone-producing adenoma (APA).Materials and MethodsA total of four datasets of gene expression profiles related to APA were downloaded from GEO datasets. GSE60042 and GSE8514 were used to identify DEGs. Weighted gene co-expression network analysis (WGCNA) and protein–protein interaction (PPI) network module analysis were conducted. GO and KEGG enrichment analysis was performed. GSE10927 and GSE33371 were used for further external validation.ResultsWe identified a total of 892 DEGs from GSE60042 and 1167 DEGs from GSE8514. WGCNA analysis demonstrated that the blue module (255 genes) and turquoise module (303 genes) were significantly correlated with APA. PPI networks were then constructed. GO term enrichment analysis suggested that cellular divalent inorganic cation homeostasis, calcium ion homeostasis, collagen-containing extracellular matrix, transport vesicle and metal ion transmembrane transporter activity were the vital annotations. KEGG pathway analysis found that these genes were significantly enriched in neuroactive ligand−receptor interaction, calcium signaling pathway. Finally, we identified a total of 11 candidate genes involving in the development and progression of APA and PA. Besides, two independent datasets (GSE10927 and GSE33371) were used for external validation, and there were seven hub genes successfully verified, including C3, GRM3, AVPR1A, WFS1, PTGFR, NTSR2, and JUN.ConclusionThese newly identified genes could contribute to the understanding of potential mechanism in APA and PA and might be promising targets for the treatment of APA and PA.

Approaches to Gene Mutation Analysis Using Formalin-Fixed Paraffin-Embedded Adrenal Tumor Tissue From Patients With Primary Aldosteronism.

Aldosterone production is physiologically under the control of circulating potassium and angiotensin II as well as adrenocorticotropic hormone and other secretagogues such as serotonin. The adrenal’s capacity to produce aldosterone relies heavily on the expression of a single enzyme, aldosterone synthase (CYP11B2). This enzyme carries out the final reactions in the synthesis of aldosterone and is expressed almost solely in the adrenal zona glomerulosa. From a disease standpoint, primary aldosteronism (PA) is the most common of all adrenal disorders. PA results from renin-independent adrenal expression of CYP11B2 and production of aldosterone. The major causes of PA are adrenal aldosterone-producing adenomas (APA) and adrenal idiopathic hyperaldosteronism. Our understanding of the genetic causes of APA has significantly improved through comprehensive genetic profiling with next-generation sequencing. Whole-exome sequencing has led to the discovery of mutations in six genes that cause renin-independent aldosterone production and thus PA. To facilitate broad-based prospective and retrospective studies of APA, recent technologic advancements have allowed the determination of tumor mutation status using formalin-fixed paraffin-embedded (FFPE) tissue sections. This approach has the advantages of providing ready access to archival samples and allowing CYP11B2 immunohistochemistry-guided capture of the exact tissue responsible for inappropriate aldosterone synthesis. Herein we review the methods and approaches that facilitate the use of adrenal FFPE material for DNA capture, sequencing, and mutation determination.

Ablation versus laparoscopic adrenalectomy for the treatment of aldosterone‑producing adenoma: a meta-analysis

To assess the relative clinical efficacy and safety of ablation and laparoscopic adrenalectomy (LA) for the treatment of adrenal aldosterone-producing adenoma (APA). Pubmed, Embase, and Cochrane Library databases were searched for relevant studies, while the meta-analysis was performed with RevMan v5.3. After initially identifying 496 potentially relevant studies, five were ultimately included in the final meta-analysis. In total, these studies contained 128 patients that underwent LA and 91 patients that underwent ablation to treat APA. Clinical success rates were comparable between these two groups (OR: 0.55, P = 0.20), whereas the pooled decreases of systolic and diastolic blood pressure were significantly larger in the ablation group (P = 0.01 and 0.002, respectively). Pooled changes in the aldosterone-to-renin ratio (ARR), serum potassium levels, and medication use were similar in both groups (P = 0.62, 0.24, and 0.96, respectively). The average operative duration in the ablation group was somewhat shorter, but the difference was not significant (MD: - 57.99; P = 0.05), whereas the average blood loss and postoperative hospital stay duration of patients in the ablation group were decreased for patients in the ablation group compared to the LA group (P < 0.00001 and 0.00001, respectively). Major complication, minor complication, and hypertension crisis rates were comparable between these groups (P = 0.35, 0.69, and 0.09, respectively). Ablation offers comparable efficacy to LA when treating patients with APA, but is associated with a reduced operative duration, decreased intraoperative blood loss, and faster postoperative recovery.

Update: Selective adrenal venous sampling (AVS) - Indication, technique, and significance.

Primary aldosteronism (PA) is the most common detectable cause of secondary hypertension. The majority of patients have either an adrenal aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia (BAH) demanding different therapeutic approaches. Screening tests and imaging cannot reliably distinguish between a unilateral or bilateral PA. This review article gives an overview concerning etiology, diagnostics, and therapeutic options of PA, and reviews the indication, the technique, and relevance of selective adrenal venous sampling (AVS) in the context of the current literature and the authors' experience. AVS can verify or exclude a unilaterally dominated secretion with a high success rate. Patients with PA and a unilateral APA can be treated curatively by adrenalectomy. AVS is an established diagnostic examination for differentiation of unilateral from bilateral adrenal disease in patients with PA. · Selective adrenal venous sampling (AVS) is a safe, reliable, and minimally invasive method to detect a unilateral or bilateral adrenal adrenal gland disease.. · Verification of lateralization by AVS has direct therapeutic relevance for patients with primary aldosteronism (PA).. · AVS can be performed with low radiation exposure, without contrast medium, and with a high success rate when performed by an experienced interventional radiologist.. · Loberg C, Antoch G, Stegbauer J et al. Update: Selective adrenal venous sampling (AVS) - Indication, technique, and significance. Fortschr Röntgenstr 2021; 193: 658 - 666.

A case of Williams syndrome with suspected coexisting ectopic aldosterone-producing tumor in the liver.

SummaryA 31-year-old man with Williams syndrome (WS) was referred to our hospital because of a 9-year history of hypertension, hypokalemia, and high plasma aldosterone concentration to renin activity ratio. A diagnosis of primary aldosteronism (PA) was clinically confirmed but an abdominal CT scan showed no abnormal findings in his adrenal glands. However, a 13-mm hypervascular tumor in the posterosuperior segment of the right hepatic lobe was detected. Adrenal venous sampling (AVS) subsequently revealed the presence of an extended tributary of the right adrenal vein to the liver surrounding the tumor. Segmental AVS further demonstrated a high plasma aldosterone concentration (PAC) in the right superior tributary vein draining the tumor. Laparoscopic partial hepatectomy was performed. The resected tumor histologically separated from the liver was composed of clear cells, immunohistochemically positive for aldesterone synthase (CYP11B2), and subsequently diagnosed as aldosterone-producing adrenal adenoma. After surgery, his blood pressure, serum potassium level, plasma renin activity and PAC were normalized. To the best of our knowledge, this is the first report of WS associated with PA. WS harbors a high prevalence of hypertension and therefore PA should be considered when managing the patients with WS and hypertension. In this case, the CT findings alone could not differentiate the adrenal rest tumor. Our case, therefore, highlights the usefulness of segmental AVS to distinguish adrenal tumors from hepatic adrenal rest tumors.Learning points:Williams syndrome (WS) is a rare genetic disorder, characterized by a constellation of medical and cognitive findings, with a hallmark feature of generalized arteriopathy presenting as stenoses of elastic arteries and hypertension.WS is a disease with a high frequency of hypertension but the renin-aldosterone system in WS cases has not been studied at all.If a patient with WS had hypertension and severe hypokalemia, low PRA and high ARR, the coexistence of primary aldosteronism (PA) should be considered.Adrenal rest tumors are thought to arise from aberrant adrenal tissues and are a rare cause of PA.Hepatic adrenal rest tumor (HART) should be considered in the differential diagnosis when detecting a mass in the right hepatic lobe.Segmental adrenal venous sampling could contribute to distinguish adrenal tumors from HART.

Clinical outcomes of primary aldosteronism based on lateralization index and contralateral suppression index after adrenal venous sampling in real-world practice: a retrospective cohort study

BackgroundWe investigated whether the contralateral suppression index in aldosterone-producing adrenal adenoma could be used as a diagnostic criterion when catheterization in either right or left adrenal vein fails or when a discrepancy in the adrenal vein sampling (AVS) results and imaging findings occurs in the real-world practice.MethodsWe retrospectively reviewed 48 patients who had resistant hypertension (HTN) or hypokalemia with a biochemical diagnosis of primary aldosteronism and who underwent AVS from January 2009 to June 2017 at a tertiary referral hospital. Selection index (SI), lateralization index (LI), and contralateral suppression index (CSI) were calculated based on AVS results and the final clinical outcomes were evaluated.ResultsThe catheterization of both adrenal veins was successful in 43 of 48 (89.6%) patients. The lateralization based only on LI was performed in 23 out of 43 (53.5%) patients. When CSI and LI were combined in decision making, the concordance between adrenal computed tomography scan and AVS for unilateral lesion improved from 59.3% (19/32) to 75.0% (24/32). CSI also correlated well with unilateral adrenal disease in the catheterization failure group. The final outcomes of HTN were better in the contralateral suppression group.ConclusionCSI combined with LI could be a supplementary diagnostic tool in patients with non-lateralization or catheterization failure and predict the clinical outcomes of HTN in patients with primary aldosteronism.

Effectiveness of Thermal Ablation for Aldosterone-Producing Adrenal Adenoma: A Systematic Review and Meta-Analysis of Clinical and Biochemical Parameters.

To assess the effectiveness of thermal ablation for aldosterone-producing adrenal adenoma. A systematic search of the PubMed and CINAHL databases was performed to identify studies of thermal ablation for adrenal adenomas. Random effects meta-analysis models were used to compare pre- and post-treatment values of the following outcomes: systolic blood pressure (SBP), diastolic blood pressure (DBP), use of antihypertensive medications, and biochemical parameters (plasma aldosterone levels, aldosterone-to-renin ratio, and potassium levels). The rate of hypertension (HTN) resolution and improvement were also evaluated. A total of 89 patients from 7 studies were included in the analysis. The mean postablation follow-up duration was 45.8 months. Pooled data analysis revealed a statistically significant decrease in SBP (-29.06 mm Hg; 95% confidence interval [CI],-33.93 to-24.19), DBP (-16.03 mm Hg; 95% CI,-18.33 to-13.73), and the number of antihypertensive medications used (-1.43; 95% CI,-1.97 to-0.89) after ablation. Biochemical parameters had returned to normal ranges after ablation in all studies. The cumulative rate of resolution or improvement in HTN status was 75.3%. On metaregression analysis, there was no statistically significant association between postablation blood pressure changes or serum aldosterone levels and study follow-up duration. Thermal ablation for aldosterone-producing adrenal adenoma can be effective in controlling blood pressure, reducing the need for antihypertensive medications, and normalizing hormone secretion. Further higher-quality evidence is needed to confirm these results.

Diagnostic Efficacy of CT/MR Imaging and Adrenal Vein Sampling for Localization of Aldosterone-producing Adrenal Adenomas in Primary Aldosteronism

Objective: To test the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of CT/MR imaging and adrenal vein sampling (AVS) for diagnosis of aldosterone-producing adrenal adenoma (APA).&#x0D; Material and method: Retrospective study of 14 patients with primary hyperaldosteronism (PAL) who underwent both CT/MR imaging and AVS between June 2007 and June 2012 were performed. The study included 7 male and 7 female patients. Review CT/MR findings of these cases and compared with AVS results were done.&#x0D; Results: Five of fourteen patients (35%) had unilateral adrenal nodules on CT, and one of fourteen patients (7.1%) had bilateral adrenal nodules on CT[D1]. The remaining eight patients had no significant nodules in both adrenal glands. Among 5 patients who had unilateral adrenal nodule detected from CT, 4 patients (80%) with nodule greater than 10 mm also presented with lateralization from AVS and finally pathological proven APA. The last patient with unilateral nodule showed small size less than 10 mm and had AVS results of bilateral lesion. Medical therapy was applied for this patient instead of surgical treatment. In other group (8 of 14 patients, 57.1%), there was no significant nodule from CT or MRI and AVS results indicated bilateral lesions in two patients (25%). The rest of six patients found unilateral lesion on AVS which underwent adrenalectomy and histological revealed adrenal hyperplasia of all cases. Two of six patients concluded to be primary adrenal hyperplasia (PAH) or unilateral adrenal hyperplasia (UAH), which showed clinical cure after adenalectomy. The remaining four patients who showed no improvement of hypertension after adrenalectomy concluded to be bilateral adrenal hyperplasia (BAH). The sensitivity, specificity, accuracy, PPV and NPV for detected adrenal adenoma by CT/MRI of our study were 66.67%, 87.50%, 78.57%, 80.00%, and 77.78%, respectively. The sensitivity, specificity, accuracy, PPV and NPV for detected adrenal adenoma by AVS at cut point AVS ratio at 2 were 100%, 50%, 71.43%, 60% and 100%, respectively.&#x0D; Conclusion: In patient with suspected PAL who presented with unilateral adrenal nodule at least 10 mm in size detected by CT, these patient should be referred for adrenalectomy without need to performing AVS. The differentiation of subtype in patients with PAL is most reliably achieved with AVS which may reserve for patient who had no significant adrenal nodule from CT/MRI.

Primary hyperaldosteronism presenting as recurrent polymorphic ventricular tachycardia (RCDD code: VI-2)

Primary hyperaldosteronism (PH) is a frequently overlooked cause of secondary hypertension mostly due to an aldosterone-producing adrenal adenoma. We report the case of a 48-year-old female who presented with recurrent episodes of polymorphic ventricular tachycardia before an aldosterone-producing adrenal adenoma was diagnosed. Although her past medical history was remarkable for poorly-controlled hypertension since age 30, she had never been examined for secondary causes. The patient underwent adrenalectomy resulting in stabilisation of her clinical condition, although residual hypertension remained. Causes of atypical presentation and diagnostic pitfalls are discussed. JRCD 2018; 4 (1): 26-30.

Prevalence of Somatic KCNJ5 Mutations in Thai Patients With Aldosterone-Producing Adrenal Adenomas

Somatic KCNJ5 mutations result in excess aldosterone production and are reported to be more common in Asia than elsewhere. To assess the prevalence of somatic KCNJ5 mutations in Thai patients with aldosterone-producing adrenal adenomas (APAs) in a single tertiary center, we analyzed the paraffin-embedded tissue of KCNJ5 mutations from 96 patients with sporadic APAs who underwent unilateral laparoscopic adrenalectomy at our center during 2007 to 2016. We also assessed the clinical characteristics, treatment outcomes, and biochemistry and histologic differences among patients with and without somatic KCNJ5 mutations. Of the 96 patients with APA, 67 (70%) had somatic mutations of the KCNJ5 gene: 39 patients with p.G151R, 26 patients with p.L168R, one patient with p.T158A, and one patient with p.W126R. All patients presented with hypertension. Hypokalemia was documented in 98% of patients. The hypertension cure rate at 1 year after surgery was 35%. Patients with somatic KCNJ5 mutations required more potassium supplementation and had adrenal histology compatible with zona fasciculata–like cells compared with patients without the mutations (all P < 0.05). There were no significant differences in preoperative plasma aldosterone concentration (PAC), plasma renin activity, aldosterone/renin ratio, potassium level, treatment of hypertension, tumor size, and hypertension cure rate among patients in the KCNJ5-mutant and nonmutant groups. In a multivariate analysis, a higher PAC was associated with the presence of somatic KCNJ5 mutations. In summary, the prevalence of somatic KCNJ5 mutations in patients with sporadic APAs in Thailand, an Asian country with residents of different ethnic backgrounds, is comparable to previous reports in Asia.

GSTA1 Expression Is Correlated With Aldosterone Level in KCNJ5-Mutated Adrenal Aldosterone-Producing Adenoma.

KCNJ5 mutation is a major cause of aldosterone-producing adenomas (APAs). The development of APA apart from KCNJ5 mutation is less investigated. To investigate other mechanisms affecting aldosterone secretion apart from KCNJ5. Six pairs of KCNJ5-mutated, high and low aldosterone-secreting APAs, five non-KCNJ5-mutated APAs, and four normal adrenal glands were assayed by Affymetrix GeneChip Human Transcriptome Array 2.0. A total of 113 APA samples were investigated to explore the expression of glutathione-S-transferase A1 (GSTA1). H295R cells were used to verify the function of GSTA1. GSTA1 was the top gene downregulated in high-aldosterone KCNJ5-mutated APAs. GSTA1 was also downregulated in KCNJ5-mutated APAs compared with wild-type KCNJ5 APAs. Accordingly, mutant KCNJ5 decreased GSTA1 messenger RNA and protein expression levels. GSTA1 overexpression suppressed aldosterone secretion whether in wild-type or mutant KCNJ5 H295R cells. Adding ethacrynic acid or silencing of GSTA1 increased aldosterone secretion by increasing reactive oxygen species (ROS), superoxide, H2O2 levels, and Ca2+ influx. The expression of the transcription factors NR4A1, NR4A2, and CAMK1 and intracellular Ca2+ were significantly upregulated by GSTA1 inhibition. The reduced form of NAD phosphate oxidase inhibitor or H2O2 scavenger or blocking calmodulin or calcium channels could significantly reduce aldosterone secretion in GSTA1-inhibited cells. (1) GSTA1 expression is reversely correlated with aldosterone level in KCNJ5-mutated APAs, (2) GSTA1 regulates aldosterone secretion by ROS and Ca2+ signaling, and (3) KCNJ5 mutation downregulates GSTA1 expression, and overexpression of GSTA1 reverses increased aldosterone in KCNJ5-mutated adrenal cells.

Predictors of hypertension urgency in primary aldosteronism patients during the first 24 hours after surgery.

Study about blood pressure variation in the first 24 hours post-operation is limited in patients with adrenal aldosterone-producing adenoma. We aim to evaluate the potential predictors for postoperative hypertension urgency during the first 24 hours after laparoscopic adrenalectomy in patients with aldosterone-producing adenoma. Clinical data of 177 patients with aldosterone-producing adenoma were retrospectively collected from January 2009 to December 2015 and the potential factors that may influence postoperative blood pressure during the first 24 hours after surgery were analyzed. The factors included gender, age, body mass index, preoperative maximum systolic blood pressure, number of antihypertensive medicines, preoperative spironolactone treatment, duration of hypertension, surgical method and approach, adenoma diameter, preoperative proteinuria, estimated glomerular filtration rate, serum potassium and serum aldosterone. Univariate and multivariate regression analyses were used to evaluate the relationship between the above variables and postoperative hypertension urgency. We found that the proportion of patients with a higher systolic blood pressure ≥ 160 mmHg and ≥ 180 mmHg were significantly increased post-operation (both p < 0.001). In multivariate analysis, the maximum systolic blood pressure was an independent predictor of postoperative hypertension urgency, and the cut-off point was 157 mmHg with the sensitivity of 66% and specificity of 82%. Multivariable analysis also showed that preoperative maximum systolic blood pressure and number of antihypertensive medicines were independent risk factors for higher postoperative systolic blood pressure. This study was derived from a high volume adrenal tumor center, and these data may provide a potential tool to guide preoperative counseling.

Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations.

Somatic mutations in KCNJ5 gene have been identified in patients with adrenal aldosterone-producing adenomas (APAs). We previously reported that Japanese patients with APAs had distinct characteristics from patients in Western countries; i.e. they had a high frequency of KCNJ5 mutations and exhibited a frequent association with cortisol co-secretion. Therefore, APAs among Japanese patients may have different features from those in Western countries. We added recent cases, examined 47 cases (43% male) of APAs, including clinicopathological features, KCNJ5 mutations, and the mRNA levels of several steroidogenic enzymes, and compared the results obtained to those reported in other countries. While the prevalence of KCNJ5 mutations is approximately 40% in Western countries, 37 APA cases (78.7%) showed mutations: 26 with p.G151R and 11 with p.L168R. Although a significant gender difference has been reported in the frequency of KCNJ5 mutations in Europe, we did not find any gender difference. However, the phenotypes of Japanese patients with mutations were similar to those of patients in Western countries; patients were younger and had higher plasma aldosterone levels, lower potassium levels, and higher diastolic blood pressure. Reflecting these phenotypes, APAs with mutations had higher CYP11B2 mRNA levels. However, in contrast to APAs in Western countries, Japanese APAs with mutations showed lower CYP11B1, CYP17A1, and CYP11A1 mRNA levels. These findings demonstrated that Japanese APA patients may have distinct features including a higher prevalence of KCNJ5 mutations, no gender difference in the frequency of these mutations, and characteristics similar to the zona glomerulosa.

Long-term Outcomes of Unilateral Adrenalectomy in Patients with Dominant-side Adrenal Hyperplasia

ABSTRACT Introduction Usual treatment for patients with aldosterone-producing adrenal adenoma is adrenalectomy, whereas adrenal hyperplasia is generally treated medically. Selective adrenal venous sampling (AVS) has been adopted to differentiate between adenoma and hyperplasia. A previous ratio used in our institution for the diagnosis of adenoma proved to be too low. As a result, a disproportionate number of patients with a preoperative diagnosis of adenoma were operated and subsequently found to have hyperplasia. Materials and methods This prospective study evaluated the long-term outcomes of unilateral laparoscopic adrenalectomy in the setting of lateralizing aldosterone hypersecretion caused by adrenal hyperplasia. Results Twelve patients with unilateral excess aldosterone production due to hyperplasia underwent dominant side adrenalectomy. Long-term follow-up (mean 12 years) of these patients showed that blood pressure decreased from a mean of 163.4 ± 17.5/100 to 131.5 ± 9.7/80 mm Hg (p &lt; 0.05), and the number of antihypertensive drugs decreased from 4.3 ± 0.7 to 2.2 ± 0.9 (p &lt; 0.05). Mean potassium level increased from 3.7 to 4.2 mEq/L and the plasma aldosterone level decreased from 26.5 to 10.1 ng/dL. Conclusion Dominant side adrenalectomy in patients with primary aldosteronism (PA) due to hyperplasia results in long-term clinical improvement. This procedure should be considered in selected patients with lateralization confirmed by venous sampling. How to cite this article Paran H, Elad G, Benchetrit S, Griton I, Haas I, Yaslowitz O, Shmulevsky P. Long-term Outcomes of Unilateral Adrenalectomy in Patients with Dominant-side Adrenal Hyperplasia. World J Endoc Surg 2017;9(2):37-40.

Clinical outcomes following unilateral adrenalectomy in patients with primary aldosteronism.

In approximately half of cases of primary aldosteronism (PA), the cause is a surgically-resectable unilateral aldosterone-producing adrenal adenoma. However, long-term data on surgical outcomes are sparse. We report on clinical outcomes post-adrenalectomy in a cohort of patients with PA who underwent surgery. Retrospective review of patients treated for PA in a single UK tertiary centre. Of 120 consecutive patients investigated for PA, 52 (30 male, median age 54, range 30-74) underwent unilateral complete adrenalectomy. Blood pressure, number of antihypertensive medications, and serum potassium were recorded before adrenalectomy, and after a median follow-up period of 50 months (range 7-115). Recumbent renin and aldosterone were measured, in the absence of interfering antihypertensive medication, ≥3months after surgery, to determine if PA had been biochemically cured. Overall, blood pressure improved from a median (range) 160/95 mmHg (120/80-250/150) pre-operatively to 130/80 mmHg (110/70-160/93), P < 0.0001. 24/52 patients (46.2%) had cured hypertension, with a normal blood pressure post-operatively on no medication. 26/52 (50%) had improved hypertension. 2/52 patients (3.8%) showed no improvement in blood pressure post-operatively. Median (range) serum potassium level increased from 3.2 (2.3-4.7) mmol/l pre-operatively to 4.4 mmol/l (3.3-5.3) post-operatively, P < 0.0001). Median (range) number of antihypertensive medications used fell from 3 (0-6) pre- to 1 post-operatively (range 0-4), P < 0.0001. Unilateral adrenalectomy provides excellent long-term improvements in blood pressure control, polypharmacy and hypokalaemia in patients with lateralizing PA. These data may help inform discussions with patients contemplating surgery.