Health Care Challenges in the Management of Primary Aldosteronism in Southeast Asia.

CONTEXT: While guidelines have been formulated for the management of primary aldosteronism (PA), following these recommendations may be challenging in developing countries with limited health care access. OBJECTIVE: We aimed to assess the availability and affordability of health care resources for managing PA in the Association of Southeast Asian Nations (ASEAN) region, which includes low-middle-income countries. METHODS: We instituted a questionnaire-based survey to specialists managing PA, assessing the availability and affordability of investigations and treatment. Population and income status data were taken from the national census and registries. RESULTS: Nine ASEAN country members (48 respondents) participated. While screening with aldosterone-renin ratio is performed in all countries, confirmatory testing is routinely performed in only 6 countries due to lack of facilities and local assays, and cost constraint. Assays are locally available in only 4 countries, and some centers have a test turnaround time exceeding 3 weeks. In 7 countries (combined population of 442 million), adrenal vein sampling (AVS) is not routinely performed due to insufficient radiological facilities or trained personnel, and cost constraint. Most patients have access to adrenalectomy and medications. In 6 countries, the cost of AVS and adrenalectomy combined is more than 30% of its annual gross domestic product per capita. While most patients had access to spironolactone, it was not universally affordable. CONCLUSION: Large populations currently do not have access to the health care resources required for the optimal management of PA. Greater efforts are required to improve health care access and affordability. Future guideline revisions for PA may need to consider these limitations.

Identifying KCNJ5 Mutation in Aldosterone-Producing Adenoma Patients With Baseline Characteristics Using Machine Learning Technology.

Background: Primary aldosteronism is characterized by inappropriate aldosterone production, and unilateral aldosterone-producing adenoma (uPA) is a common type of PA. KCNJ5 mutation is a protective factor in uPA; however, there is no preoperative approach to detect KCNJ5 mutation in patients with uPA. Objectives: This study aimed to provide a personalized surgical recommendation that enables more confidence in advising patients to pursue surgical treatment. Methods: We enrolled 328 patients with uPA harboring KCNJ5 mutations (n = 158) or not (n = 170) who had undergone adrenalectomy. Eighty-seven features were collected, including demographics, various blood and urine test results, and clinical comorbidities. We designed 2 versions of the prediction model: one for institutes with complete blood tests (full version), and the other for institutes that may not be equipped with comprehensive testing facilities (condensed version). Results: The results show that in the full version, the Light Gradient Boosting Machine outperformed other classifiers, achieving area under the curve and accuracy values of 0.905 and 0.864, respectively. The Light Gradient Boosting Machine also showed excellent performance in the condensed version, achieving area under the curve and accuracy values of 0.867 and 0.803, respectively. Conclusions: We simplified the preoperative diagnosis of KCNJ5 mutations successfully using machine learning. The proposed lightweight tool that requires only baseline characteristics and blood/urine test results can be widely applied and can aid personalized prediction during preoperative counseling for patients with uPA.

Functional Characteristic and Significance of Aldosterone-Producing Cell Clusters in Primary Aldosteronism and Age-Related Hypertension.

Primary aldosteronism (PA) is one of the most frequent curable forms of secondary hypertension. It can be caused by the overproduction of aldosterone in one or both adrenal glands. The most common subtypes of PA are unilateral aldosterone over-production due to aldosterone-producing adenomas (APA) or bilateral aldosterone over-production due to bilateral hyperaldosteronism (BHA). Utilizing the immunohistochemical (IHC) detection of aldosterone synthase (CYP11B2) has allowed the identification of aldosterone-producing cell clusters (APCCs) with unique focal localization positive for CYP11B2 expression in the subcapsular portion of the human adult adrenal cortex. The presence of CYP11B2 supports that synthesis of aldosterone can occur in these cell clusters and therefore might contribute to hyperaldosteronism. However, the significance of the steroidogenic properties of APCCs especially in regards to PA remains unclear. Herein, we review the available evidence on the presence of APCCs in normal adrenals and adrenal tissues adjacent to APAs, their aldosterone-stimulating somatic gene mutations, and their accumulation during the ageing process; raising the possibility that APCCs may play a role in the development of PA and age-related hypertension.

Estrogen Receptors in Nonfunctioning Pituitary Neuroendocrine Tumors: Review on Expression and Gonadotroph Functions.

Estrogen (17ß-estradiol or E2) is a crucial regulator of the synthesis and secretion of pituitary reproductive hormones luteinizing hormone, follicle-stimulating hormone, and prolactin. In this review, we summarize the role of estrogen receptors in nonfunctioning pituitary neuroendocrine tumors (NF-Pitnets), focusing on immunoexpression and gonadotroph cell proliferation and apoptosis. Gonadotroph tumors are the most common subtype of NF-Pitnets. Two major estrogen receptor (ER) isoforms expressed in the pituitary are estrogen receptor alpha (ERα) and estrogen receptor beta (ERß). Overall, estrogen actions are mostly exerted through the ERα isoform on the pituitary. The G protein-coupled estrogen receptor (GPER) located at the plasma membrane may contribute to nongenomic effects of estrogen. Nuclear immunoreactivity for ERα and ERß was highest among gonadotroph and null cell tumors. Silent corticotroph tumors are the least immunoreactive for both receptors. A significantly elevated ERα expression was observed in macroadenomas compared with microadenomas. ERα and ERß may act in opposite directions to regulate the Slug-E-cadherin pathway and to affect invasiveness of NF-Pitnets. In the cellular pathway, ERs regulate estrogen-induced proliferation and differentiation and impact several signaling pathways including the MAPK and PI3K/Akt pathway. Estrogen was the first-discovered inducer of pituitary tumor transforming gene 1 that was abundantly expressed in NF-Pitnets. ERα can be a potential biomarker for predicting tumor size and invasiveness as well as therapeutic target for NF-Pitnets. Selective estrogen receptor modulators or antiestrogen may represent as an alternative choice for the treatment of NF-Pitnets.

Prevalence and Histopathological Characteristics of KCNJ5 Mutant Aldosterone-Producing Adenomas in a Multi-Ethnic Malaysian Cohort.

Studies on excised adrenals from primary aldosteronism patients have found that somatic mutations in KCNJ5 frequently cause excess aldosterone production in the culprit aldosterone-producing adenoma (APA). KCNJ5 mutant APAs were reported to be peculiarly overrepresented among young females and in Oriental cohorts, compared to their older male, or Caucasian counterparts. These larger APAs were also reported to have similarities with the zona fasciculata (ZF) in the adrenal both from the steroid production profile and the morphology of the cell. We therefore aimed to corroborate these findings by characterizing the APAs from a multi-ethnic Malaysian cohort. The prevalence of KCNJ5 mutations was estimated through targeted DNA sequencing of KCNJ5 in 54 APAs. Confirmation of APA sample acquisition was performed by CYP11B2 immunohistochemistry (IHC) staining. The ZF steroid production profile was based on the ZF enzyme CYP17A1 IHC staining, and ZF cell morphology was based on a high cytoplasm to nucleus ratio. Seventeen (31.5%) APAs studied, harbored a KCNJ5 mutation. No female over-representation was seen in this cohort though females were found to have a higher expression of CYP11B2 than males (p = 0.009; Mann-Whitney U test). Age at adrenalectomy correlated negatively with the percentage of ZF-like cells in the APA (p = 0.01; Spearman's rho) but not with the KCNJ5 genotype. KCNJ5 mutant APAs had a high percentage of ZF-like cells (and high CYP17A1 expression) but so did the wild-type APAs. In summary, prevalence of KCNJ5 mutant APAs in this cohort was similar to other Caucasian cohorts, however, over-representation of females did not occur, which is similar to some studies in Oriental cohorts.

Brief Overview of a Decade of Genome-Wide Association Studies on Primary Hypertension.

Primary hypertension is widely believed to be a complex polygenic disorder with the manifestation influenced by the interactions of genomic and environmental factors making identification of susceptibility genes a major challenge. With major advancement in high-throughput genotyping technology, genome-wide association study (GWAS) has become a powerful tool for researchers studying genetically complex diseases. GWASs work through revealing links between DNA sequence variation and a disease or trait with biomedical importance. The human genome is a very long DNA sequence which consists of billions of nucleotides arranged in a unique way. A single base-pair change in the DNA sequence is known as a single nucleotide polymorphism (SNP). With the help of modern genotyping techniques such as chip-based genotyping arrays, thousands of SNPs can be genotyped easily. Large-scale GWASs, in which more than half a million of common SNPs are genotyped and analyzed for disease association in hundreds of thousands of cases and controls, have been broadly successful in identifying SNPs associated with heart diseases, diabetes, autoimmune diseases, and psychiatric disorders. It is however still debatable whether GWAS is the best approach for hypertension. The following is a brief overview on the outcomes of a decade of GWASs on primary hypertension.

Aldosterone-Producing Adenomas: Histopathology-Genotype Correlation and Identification of a Novel CACNA1D Mutation.

Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10-4). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%-1.9%] versus 0.4% [0.3%-0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.