Primary aldosteronism: a channelopathy?
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ABSTRACT:
SUBMITTER: Gomez-Sanchez CE
PROVIDER: S-EPMC3977570 | biostudies-literature | 2014 Apr
REPOSITORIES: biostudies-literature
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Primary aldosteronism: a channelopathy?
Hypertension (Dallas, Tex. : 1979) 20140113 4
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Project description:Primary aldosteronism (PA) is a common cause of secondary hypertension caused by excessive and inappropriate secretion of the hormone aldosterone from one or both adrenal glands. The prevalence of PA ranges from 10% in the general hypertensive population to 20% in resistant hypertension, yet only a small fraction of patients is diagnosed. Disease and symptom recognition, screening in indicated populations, multidisciplinary communication, and appropriate imaging and biochemical workup can identify patients who might benefit from effective and targeted treatment modalities. Effective treatments available include both surgical and medical approaches, usually dependent on the subtype of PA present. Our collective understanding of the pathophysiology of PA is expanded by recent developments in molecular biology and genetics, including understanding the specific somatic and germline mutations involved in pathogenesis. We review the pathophysiology, diagnostic workup, and treatment considerations for this disease process.
| S-EPMC7082264 | biostudies-literature
Project description:ContextPrimary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia.ObjectiveWe investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects.MethodsPatients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods.ResultsWe identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023).ConclusionsGermline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension.
| S-EPMC4454793 | biostudies-literature
Project description:The clinical characteristics and surgical prognosis of glucocorticoid-remediable aldosteronism (GRA, also known as familial hyperaldosteronism type 1, FH-I) have not been widely studied. Using data from the Taiwan Primary Aldosteronism Investigation (TAIPAI) registry retrospectively, we describe the associated clinical factors for GRA and clinical predictors of surgical outcomes among identified GRA patients. We found 79 GRA-positive (51.2 ± 13.8 years; women 39 (49.4%)) and 114 GRA-negative primary aldosteronism (PA) patients matched with age, gender, and body mass index. Lower plasma aldosterone concentrations (PACs) and aldosterone-renin ratios were found among GRA-positive individuals. Multivariable logistic regression demonstrated that a PAC ≤ 40 ng/dL could predict concealed GRA individuals (OR 0.523, p = 0.037). Low serum potassium (OR 0.285, p = 0.008), but not the presence of GRA, was associated with hypertension-remission. Of note, PRA (OR 11.645, p = 0.045) and hypokalemia (OR 0.133, p = 0.048) were associated with hypertension-remission in GRA patients. Unilateral primary aldosteronism patients harboring concomitant GRA were not associated with inferior hypertension-remission after an adrenalectomy. Low serum potassium and high PRA were positively associated with hypertension-remission in GRA patients.
| S-EPMC8698750 | biostudies-literature
Project description:Objective: Primary aldosteronism is a major cause of secondary hypertension. Its two principal forms are bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) whose differentiation is clinically pivotal. There is a major clinical need for a reliable and easily accessible diagnostic biomarker for case identification and subtyping. Circulating microRNAs were shown to be useful as minimally invasive diagnostic markers. Our aim was to determine and compare the circulating microRNA expression profiles of adenoma and hyperplasia plasma samples, and to evaluate their applicability as minimally invasive markers. Methods: One hundred and twenty-three samples from primary aldosteronism patients were included. Next-generation sequencing was performed on 30 EDTA-anticoagulated plasma samples (discovery cohort). Significantly differently expressed miRNAs were validated by real-time reverse transcription-qPCR in an independent validation cohort (93 samples). Results: We have found relative overexpression of miR-30e-5p, miR-30d-5p, miR-223-3p, and miR-7-5p in hyperplasia compared to adenoma by next-generation sequencing. Validation by qRT-PCR confirmed significant overexpression of hsa-miR-30e-5p, hsa-miR-30d-5p, and hsa-miR-7-5p in hyperplasia samples. Regarding the microRNA expressional variations, adenoma is more heterogeneous at the miRNA level compared to hyperplasia. Conclusion: Three microRNAs were significantly overexpressed in hyperplasia samples compared to adenoma samples, but their sensitivity and specificity values are not good enough for introduction to clinical practice.
| S-EPMC6828819 | biostudies-literature
Project description:Recent discoveries of somatic mutations permit the recognition of subtypes of aldosterone-producing adenomas with distinct clinical presentations and pathological features. Here we describe three women with hyperaldosteronism, two who presented in pregnancy and one who presented after menopause. Their aldosterone-producing adenomas harbored activating mutations of CTNNB1, encoding β-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR and GNRHR, encoding gonadal receptors, at levels that were more than 100 times as high as the levels in other aldosterone-producing adenomas. The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate toward their common adrenal-gonadal precursor cell type. (Funded by grants from the National Institute for Health Research Cambridge Biomedical Research Centre and others.).
| S-EPMC4612399 | biostudies-literature
Project description:ObjectiveThe burden of symptoms and treatment in patients with primary aldosteronism (PA), as well as the patients' experience of the health care is sparsely studied. The objectives of this study were to describe symptoms considered to be the most troublesome by patients with PA, and to explore health related worries and expectations following treatment.MethodsThis was an explorative qualitative study where 25 patients with PA, diagnosed between 2017 and 2019, were included; 13 patients who had undergone adrenalectomy and 12 who were receiving medical treatment. Data was collected during six group interviews and analyzed using a thematic approach.ResultsThree main themes were identified: 1) Distress of the past, where the most important issues were struggle to receive a correct diagnosis, impaired well-being and the consumption of a large number of tablets, 2) Satisfaction after receiving a correct diagnosis, both in patients with unilateral and bilateral disease, but also dissatisfaction with lack of information about the disease, and 3) Future concerns, where worries about the long-term effects of PA on health in general dominated.ConclusionsOur findings illustrate several important issues related to PA where improvements in patient care are needed, including actions aiming at shortening the long diagnostic delay, a thorough information to the patients about the disease is of great importance, and that all patients with PA, regardless of treatment, would benefit from a structured long-term follow-up.
| S-EPMC9704575 | biostudies-literature
Project description:Primary aldosteronism is the most common single cause of hypertension and is potentially curable when only one adrenal gland is the culprit. The importance of primary aldosteronism to public health derives from its high prevalence but huge under-diagnosis (estimated to be <1% of all affected individuals), despite the consequences of poor blood pressure control by conventional therapy and enhanced cardiovascular risk. This state of affairs is attributable to the fact that the tools used for diagnosis or treatment are still those that originated in the 1970-1990s. Conversely, molecular discoveries have transformed our understanding of adrenal physiology and pathology. Many molecules and processes associated with constant adrenocortical renewal and interzonal metamorphosis also feature in aldosterone-producing adenomas and aldosterone-producing micronodules. The adrenal gland has one of the most significant rates of non-silent somatic mutations, with frequent selection of those driving autonomous aldosterone production, and distinct clinical presentations and outcomes for most genotypes. The disappearance of aldosterone synthesis and cells from most of the adult human zona glomerulosa is the likely driver of the mutational success that causes aldosterone-producing adenomas, but insights into the pathways that lead to constitutive aldosterone production and cell survival may open up opportunities for novel therapies.
| S-EPMC7615304 | biostudies-literature
Project description:Introduction: Primary aldosteronism (PA) is a major cause of secondary hypertension. The two principal forms of PA are bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) whose differentiation is clinically pivotal, due to their different treatments. Adrenal venous sampling (AVS) is considered to be the gold standard for the differentiation of the two clinical entities, but it is invasive, requires great expertise and is unavailable in many centers. There would be a major clinical need for a reliable and easily accessible diagnostic biomarker. Circulating microRNA were shown to be useful as minimally invasive diagnostic markers in many diseases, but their potential applicability in PA has not yet been investigated. Aims: To determine and compare the circulating microRNA expression profiles of AVS-confirmed APA and BAH plasma samples, and to evaluate their applicability as minimally invasive markers. Methods: 81 AVS-confirmed plasma samples were included. Next-generation sequencing (NGS) was performed on 30 EDTA-anticoagulated plasma samples. Significantly differently expressed miRNAs were validated by real-time RT-qPCR on all samples. Results: We have found relative overexpression of miR-30e-5p, miR-30d-5p, miR-223-3p and miR-7-5p in BAH compared to APA by NGS. Validation of 81 samples confirmed significant overexpression (p=0.03) of miR-7-5p. Regarding the microRNA expressional variations, APA is more heterogenous at the miRNA level compared to BAH. Conclusion: miR-7-5p was significantly overexpressed in BAH samples compared to APA samples, but its sensitivity and specificity values are not good enough for introduction to the clinical practice yet.
2019-02-12 | GSE126386 | GEO
Project description:BackgroundThe interaction between hyperaldosteronism and immune dysfunction has been reported and glucocorticoid co-secretion is frequently found in primary aldosteronism (PA). The aforementioned conditions raise the possibility of the infection risk; however, clinical episodes of sepsis have not been reported in PA.MethodsUsing Taiwan's National Health Insurance Research Database between 1997 and 2009, we identified PA and aldosterone-producing adenoma (APA) matched with essential hypertension (EH) at a 1:1 ratio by propensity scores. The incidences of sepsis and mortality after the index date were evaluated, and the risk factors of outcomes were identified using adjusted Cox proportional hazards models and taking mortality as a competing risk.ResultsWe enrolled 2448 patients with PA (male, 46.08%; mean age, 48.4 years). There were 875 patients who could be ascertained as APA. Taking mortality as the competing risk, APA patients had a lower incidence of sepsis than their matched EH patients (hazard ratio (HR) 0.29; P < 0.001) after target treatments. Patients receiving adrenalectomy showed a benefit of decreasing the risk of sepsis (PA vs EH, HR 0.14, P = 0.001; APA vs EH, HR 0.16, P = 0.003), but mineralocorticoid receptor antagonist treatment may differ. Compared with matched control cohorts, patients with APA had a lower risk of all-cause mortality (PA, adjusted HR 0.84, P = 0.050; APA, adjusted HR 0.31, P < 0.001) after target treatments.ConclusionsOur study demonstrated that patients with PA/APA who underwent adrenalectomy could attenuate the risk of sepsis compared with their matched EH patients. We further found that APA patients with target treatments could decrease all-cause mortality compared with EH patients.
| S-EPMC6249889 | biostudies-literature
Project description:ContextWhether primary aldosteronism (PA) is the consequence of a monoclonal or multiclonal process is unclear.Case descriptionA 48-year-old man with severe bilateral PA refractory to medical therapy underwent unilateral adrenalectomy of the dominant adrenal. Although computed tomography showed three left-sided cortical nodules, postsurgical histopathology and genetic analysis revealed five different adrenocortical adenomas. Two zona fasciculata (ZF)-like aldosterone-producing adenomas (APAs) each harbored distinct known somatic KCNJ5 mutations (L168R and T158A). A zona glomerulosa-like APA harbored a known CACNA1D G403R somatic mutation, whereas a zona reticularis-like adenoma, which was grossly black in pigmentation with histologic characteristics more associated with cortisol-producing adenomas, expressed CYP11B2, CYP17, and DHEA-ST by immunohistochemistry (IHC) and harbored no known somatic mutations. The fifth adenoma was ZF-type, negative for CYP11B2 and CYP17 IHC, and harbored no known somatic mutations.ConclusionsThis case highlights complex intertumor heterogeneity in histology, steroidogenesis, and somatic mutations in multiple adrenocortical adenomas arising in a single patient with PA. These findings suggest that the syndrome of PA can involve heterogeneous and multiclonal functional adrenal adenomas.
| S-EPMC5470766 | biostudies-literature