Update on Genetics of Primary Aldosteronism

Primary aldosteronism (PA) is the most common form of secondary hypertension, with a prevalence of 5–10% among patients with hypertension. PA is mainly classified into two subtypes: aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism. Recent developments in genetic analysis have facilitated the discovery of mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, CLCN2, and CTNNB1 in sporadic or familial forms of PA in the last decade. These findings have greatly advanced our understanding of the mechanism of excess aldosterone synthesis, particularly in APA. Most of the causative genes encode ion channels or pumps, and their mutations lead to depolarization of the cell membrane due to impairment of ion transport. Depolarization activates voltage-gated Ca2+ channels and intracellular calcium signaling and promotes the transcription of aldosterone synthase, resulting in overproduction of aldosterone. In this article, we review recent findings on the genetic and molecular mechanisms of PA.

EXPLORATION OF THE SEATED SALINE SUPPRESSION TEST FOR THE DIAGNOSIS OF PRIMARY ALDOSTERONISM IN THE CHINESE POPULATION

Objective: We prospectively investigated the accuracy of the seated saline suppression test (SSST) in 113 patients with hypertension (including 93 primary aldosteronism [PA] and 20 essential hypertension patients) in the Department of Endocrinology and Metabolism. Methods: Each patient underwent a recumbent saline suppression test (RSST) and SSST. The accuracy of the SSST for a confirmative PA diagnosis and subtype classification was evaluated and compared with the RSST. Results: The area under the receiver operating characteristic (ROC) curve of plasma aldosterone concentration (PAC) for the SSST was significantly greater than that for the RSST (0.945 ± 0.0199 vs. 0.828 ± 0.0404; P<.05). The ROC analysis showed that the optimal PAC cut-off values were 12.94 ng/dL for the SSST (sensitivity 86.02%, specificity 95%; Youden index [YI] 0.810) and 12.04 ng/dL for the RSST (sensitivity 83.15%, specificity 57%; YI 0.401). The optimal PAC cut-off value for classifying aldosterone-producing adenoma and idiopathic hyperaldosteronism was 18.12 ng/dL for the SSST (sensitivity 73.5%, specificity 79.5%). No patients experienced adverse events during the SSST. Conclusion: The SSST is safe and convenient for PA diagnosis. The accuracy of the SSST for a confirmatory diagnosis of PA was better than that of the RSST. The SSST is a reliable alternative for PA confirmation in Chinese individuals. Abbreviations: APA = aldosterone-producing adenoma; ARR = aldosterone to renin ratio; AVS = adrenal vein sampling; CT = computed tomography; EH = essential hypertension; IHA = idiopathic hyperaldosteronism; MRI = magnetic resonance imaging; PA = primary aldosteronism; PAC = plasma aldosterone concentration; PRA = plasma renin activity; ROC = receiver operating characteristic; RSST = recumbent saline suppression test; SSST = seated saline suppression test; YI = Youden index

MON-210 Role of Female Gender and Subcutaneous Fat in the Positive Association of Obesity with Idiopathic Hyperaldosteronism

Context: Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. The relationship between PA and various metabolic disorders including obesity, diabetes mellitus and dyslipidemia has been reported. On the other hand, PA consists of two main subtypes: unilateral aldosterone-producing adenoma (APA) and the bilateral idiopathic hyperaldosteronism (IHA), which have different etiologies. Recently, it was reported that the prevalence of obesity was higher in patients with IHA than those with APA, suggesting that there is a link between obesity and the etiology of IHA (Ohno Y et al. J Clin Endocrinol Metab 2018). Furthermore, it has also been reported that female patients with PA are more likely to have IHA than male patients. Objective: Our objective was to clarify the pathological role of female gender in the positive association of obesity with IHA. Because of the difference of body fat distribution between men and women, we also investigate the contribution of visceral and subcutaneous fats in the pathogenesis of IHA. Design: This retrospective observational study comprised 117 PA patients (IHA: n = 73, APA: n = 44) diagnosed by adrenal venous sampling between January 2006 and July 2019 at Jichi Medical University Hospital. We compared prevalence of obesity and metabolic parameters including visceral and subcutaneous fat areas measured by computed tomography between patients with IHA and APA by gender. We also compared visceral and subcutaneous fat areas between patients with IHA and APA by the presence of obesity, BMI ≥25 kg/m2 (the diagnosis criteria by Japan Society for the Study of Obesity). Results: In consistent with previous reports, BMI was significantly higher in patients with IHA than those with APA. However, in male patients, no difference of BMI between IHA and APA was observed. By contrast, in female patients, not only BMI but also both visceral and subcutaneous fat areas were significantly higher in IHA than in APA. Next, we investigated the contribution of visceral and subcutaneous fats in the positive association of obesity with IHA in female patients. Subcutaneous fat area but not visceral fat area was significantly higher in female obese patients with IHA. By contrast, visceral fat area but not subcutaneous fat area was significantly higher in female non-obese patients with IHA. Conclusions: These results suggest that obesity, especially subcutaneous fat accumulation, contributes to the pathogenesis of IHA in female patients.

Genetic causes of primary aldosteronism

Primary aldosteronism is characterized by at least partially autonomous production of the adrenal steroid hormone aldosterone and is the most common cause of secondary hypertension. The most frequent subforms are idiopathic hyperaldosteronism and aldosterone-producing adenoma. Rare causes include unilateral hyperplasia, adrenocortical carcinoma and Mendelian forms (familial hyperaldosteronism). Studies conducted in the last eight years have identified somatic driver mutations in a substantial portion of aldosterone-producing adenomas, including the genes KCNJ5 (encoding inwardly rectifying potassium channel GIRK4), CACNA1D (encoding a subunit of L-type voltage-gated calcium channel CaV1.3), ATP1A1 (encoding a subunit of Na+/K+-ATPase), ATP2B3 (encoding a Ca2+-ATPase), and CTNNB1 (encoding ß-catenin). In addition, aldosterone-producing cells were recently reported to form small clusters (aldosterone-producing cell clusters) beneath the adrenal capsule. Such clusters accumulate with age and appear to be more frequent in individuals with idiopathic hyperaldosteronism. The fact that they are associated with somatic mutations implicated in aldosterone-producing adenomas also suggests a precursor function for adenomas. Rare germline variants of CYP11B2 (encoding aldosterone synthase), CLCN2 (encoding voltage-gated chloride channel ClC-2), KCNJ5, CACNA1H (encoding a subunit of T-type voltage-gated calcium channel CaV3.2), and CACNA1D have been reported in different subtypes of familial hyperaldosteronism. Collectively, these studies suggest that primary aldosteronism is largely due to genetic mutations in single genes, with potential implications for diagnosis and therapy.