-
The Lancet. Diabetes & Endocrinology Dec 2021Primary aldosteronism is a common cause of secondary hypertension associated with excess cardiovascular morbidities. Primary aldosteronism is underdiagnosed because it... (Review)
Review
Primary aldosteronism is a common cause of secondary hypertension associated with excess cardiovascular morbidities. Primary aldosteronism is underdiagnosed because it does not have a specific, easily identifiable feature and clinicians can be poorly aware of the disease. The diagnostic investigation is a multistep process of screening, confirmatory testing, and subtype differentiation of unilateral from bilateral forms for therapeutic management. Adrenal venous sampling is key for reliable subtype identification, but can be bypassed in patients with specific characteristics. For unilateral disease, surgery offers the possibility of cure, with total laparoscopic unilateral adrenalectomy being the treatment of choice. Bilateral forms are treated mainly with mineralocorticoid receptor antagonists. The goals of treatment are to normalise both blood pressure and excessive aldosterone production, and the primary aims are to reduce associated comorbidities, improve quality of life, and reduce mortality. Prompt diagnosis of primary aldosteronism and the use of targeted treatment strategies mitigate aldosterone-specific target organ damage and with appropriate patient management outcomes can be excellent. Advances in molecular histopathology challenge the traditional concept of primary aldosteronism as a binary disease, caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Somatic mutations drive autonomous aldosterone production in most adenomas. Many of these same mutations have been identified in nodular lesions adjacent to an aldosterone-producing adenoma and in patients with bilateral disease. In addition, germline mutations cause rare familial forms of aldosteronism (familial hyperaldosteronism types 1-4). Genetic testing for inherited forms in suspected cases of familial hyperaldosteronism avoids the burdensome diagnostic investigation in positive patients. In this Review, we discuss advances and future management approaches in the diagnosis of primary aldosteronism.
Topics: Adenoma; Adrenalectomy; Adrenocortical Adenoma; Aldosterone; Humans; Hyperaldosteronism; Hypertension; Quality of Life
PubMed: 34798068
DOI: 10.1016/S2213-8587(21)00210-2 -
Nature Reviews. Endocrinology Oct 2020Early diagnosis and appropriate treatment of primary aldosteronism, the most frequent cause of secondary hypertension, are crucial to prevent deleterious cardiovascular... (Review)
Review
Early diagnosis and appropriate treatment of primary aldosteronism, the most frequent cause of secondary hypertension, are crucial to prevent deleterious cardiovascular outcomes. In the past decade, the discovery of genetic abnormalities responsible for sporadic and familial forms of primary aldosteronism has improved the knowledge of the pathogenesis of this disorder. Mutations in genes encoding ion channels and pumps lead to increased cytosolic concentrations of calcium in zona glomerulosa cells, which triggers CYP11B2 expression and autonomous aldosterone production. Improved understanding of the mechanisms underlying the disease is key to improving diagnostics and to developing and implementing targeted treatments. This Review provides an update on the genetic abnormalities associated with sporadic and familial forms of primary aldosteronism, their frequency among different populations and the mechanisms explaining excessive aldosterone production and adrenal nodule development. The possible effects and uses of these findings for improving the diagnostics for primary aldosteronism are discussed. Furthermore, current treatment options of primary aldosteronism are reviewed, with particular attention to the latest studies on blood pressure and cardiovascular outcomes following medical or surgical treatment. The new perspectives regarding the use of targeted drug therapy for aldosterone-producing adenomas with specific somatic mutations are also addressed.
Topics: Adrenal Glands; Aldosterone; Animals; Humans; Hyperaldosteronism; Hypertension; Mutation
PubMed: 32724183
DOI: 10.1038/s41574-020-0382-4 -
The Journal of Clinical Endocrinology... Dec 2020New approaches are needed to address the evolution of the primary aldosteronism syndrome and to increase its recognition. Herein, we review evidence indicating that... (Review)
Review
CONTEXT
New approaches are needed to address the evolution of the primary aldosteronism syndrome and to increase its recognition. Herein, we review evidence indicating that primary aldosteronism is a prevalent syndrome that is mostly unrecognized, and present a pragmatic and pathophysiology-based approach to improve diagnosis and treatment.
METHODS
Evidence was gathered from published guidelines and studies identified from PubMed by searching for primary aldosteronism, aldosterone, renin, and hypertension. This evidence was supplemented by the authors' personal knowledge, research experience, and clinical encounters in primary aldosteronism.
INTERPRETATION OF EVIDENCE
Renin-independent aldosterone production is a prevalent phenotype that is diagnosed as primary aldosteronism when severe in magnitude, but is largely unrecognized when milder in severity. Renin-independent aldosterone production can be detected in normotensive and hypertensive individuals, and the magnitude of this biochemical phenotype parallels the magnitude of blood pressure elevation, the risk for incident hypertension and cardiovascular disease, and the likelihood and magnitude of blood pressure reduction with mineralocorticoid receptor antagonist therapy. Expansion of the indications to screen for primary aldosteronism, combined with the use of a pathophysiology-based approach that emphasizes inappropriate aldosterone production in the context of renin suppression, will substantially increase the diagnostic and therapeutic yields for primary aldosteronism.
CONCLUSIONS
The landscape of primary aldosteronism has evolved to recognize that it is a prevalent syndrome of renin-independent aldosterone production that contributes to the pathogenesis of hypertension and cardiovascular disease. Expanding screening indications and simplifying the diagnostic approach will enable implementation of targeted treatment for primary aldosteronism.
Topics: Aldosterone; Blood Pressure; Diagnostic Techniques, Endocrine; Humans; Hyperaldosteronism; Hypertension; Mass Screening; Practice Guidelines as Topic; Prevalence; Prognosis; Renin; Syndrome
PubMed: 32865201
DOI: 10.1210/clinem/dgaa606 -
Hypertension (Dallas, Tex. : 1979) May 2022Primary aldosteronism is considered the commonest cause of secondary hypertension. In affected individuals, aldosterone is produced in an at least partially autonomous... (Review)
Review
Primary aldosteronism is considered the commonest cause of secondary hypertension. In affected individuals, aldosterone is produced in an at least partially autonomous fashion in adrenal lesions (adenomas, [micro]nodules or diffuse hyperplasia). Over the past decade, next-generation sequencing studies have led to the insight that primary aldosteronism is largely a genetic disorder. Sporadic cases are due to somatic mutations, mostly in ion channels and pumps, and rare cases of familial hyperaldosteronism are caused by germline mutations in an overlapping set of genes. More than 90% of aldosterone-producing adenomas carry somatic mutations in K channel Kir3.4 (), Ca channel Ca1.3 (), alpha-1 subunit of the Na/K ATPase (), plasma membrane Ca transporting ATPase 3 (), Ca channel Ca3.2 (), Cl channel ClC-2 (), β-catenin (), and/or G-protein subunits alpha q/11 (). Mutations in some of these genes have also been identified in aldosterone-producing (micro)nodules, suggesting a disease continuum from a single cell, acquiring a somatic mutation, via a nodule to adenoma formation, and from a healthy state to subclinical to overt primary aldosteronism. Individual glands can have multiple such lesions, and they can occur on both glands in bilateral disease. Familial hyperaldosteronism, typically with early onset, is caused by germline mutations in steroid 11-beta hydroxylase/ aldosterone synthase (), , , , and .
Topics: Adenoma; Adrenal Cortex Neoplasms; Adrenocortical Adenoma; Aldosterone; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Humans; Hyperaldosteronism; Mutation; Sodium-Potassium-Exchanging ATPase; Steroid 11-beta-Hydroxylase
PubMed: 35139664
DOI: 10.1161/HYPERTENSIONAHA.121.16498 -
Journal of the American College of... Dec 2019Primary aldosteronism (PA) is a common, but frequently overlooked, cause of arterial hypertension and excess cardiovascular events, particularly atrial fibrillation. As... (Review)
Review
Primary aldosteronism (PA) is a common, but frequently overlooked, cause of arterial hypertension and excess cardiovascular events, particularly atrial fibrillation. As timely diagnosis and treatment can provide a cure of hyperaldosteronism and hypertension, even when the latter is resistant to drug treatment, strategies to screen patients for PA early with a simplified diagnostic algorithm are justified. They can be particularly beneficial in some subgroups of hypertensive patients, as those who are at highest cardiovascular risk. However, identification of the surgically curable cases of PA and achievement of optimal results require subtyping with adrenal vein sampling, which, as it is technically challenging and currently performed only in tertiary referral centers, represents the bottleneck in the work-up of PA. Measures aimed at improving the clinical use of adrenal vein sampling and at developing alternative techniques for subtyping, alongside recommendations for drug treatment, including new development in the field, and for follow-up are discussed.
Topics: Adrenal Glands; Aldosterone; Diagnosis, Differential; Humans; Hyperaldosteronism; Hypertension
PubMed: 31779795
DOI: 10.1016/j.jacc.2019.09.057 -
Circulation Aug 2018Primary aldosteronism (PA) is the most common form of secondary hypertension. In many cases, somatic mutations in ion channels and pumps within adrenal cells initiate... (Review)
Review
Primary aldosteronism (PA) is the most common form of secondary hypertension. In many cases, somatic mutations in ion channels and pumps within adrenal cells initiate the pathogenesis of PA, and this mechanism might explain why PA is so common and suggests that milder and evolving forms of PA must exist. Compared with primary hypertension, PA causes more end-organ damage and is associated with excess cardiovascular morbidity, including heart failure, stroke, nonfatal myocardial infarction, and atrial fibrillation. Screening is simple and readily available, and targeted therapy improves blood pressure control and mitigates cardiovascular morbidity. Despite these imperatives, screening rates for PA are low, and mineralocorticoid-receptor antagonists are underused for hypertension treatment. After the evidence for the prevalence of PA and its associated cardiovascular morbidity is summarized, a practical approach to PA screening, referral, and management is described. All physicians who treat hypertension should routinely screen appropriate patients for PA.
Topics: Adrenal Glands; Adrenalectomy; Aldosterone; Antihypertensive Agents; Blood Pressure; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 30359120
DOI: 10.1161/CIRCULATIONAHA.118.033597 -
JAMA Sep 2023Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone...
IMPORTANCE
Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure.
OBJECTIVE
To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h.
INTERVENTIONS
Participants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily.
MAIN OUTCOMES AND MEASURES
The primary end point was change in automated office systolic blood pressure from baseline to study week 8.
RESULTS
Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of -14.1, -13.2, -6.9, and -4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were -10.1 and -13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was -9.6 mm Hg (90% CI, -15.8 to -3.4 mm Hg; P = .01) for the 50-mg once-daily dose and -7.8 mm Hg (90% CI, -14.1 to -1.5 mm Hg; P = .04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred.
CONCLUSIONS AND RELEVANCE
Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT05001945.
Topics: Adult; Humans; Aldosterone; Cytochrome P-450 CYP11B2; Renin; Hypertension; Blood Pressure; Hypotension; Hyperaldosteronism; Mineralocorticoid Receptor Antagonists
PubMed: 37690061
DOI: 10.1001/jama.2023.16029 -
Annals of Internal Medicine Jul 2020Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease.
BACKGROUND
Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease.
OBJECTIVE
To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure.
DESIGN
Cross-sectional study.
SETTING
4 U.S. academic medical centers.
PARTICIPANTS
Participants with normotension ( = 289), stage 1 hypertension ( = 115), stage 2 hypertension ( = 203), and resistant hypertension ( = 408).
MEASUREMENTS
Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 μg/24 h.
RESULTS
Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 μg/24 h (95% CI, 5.2 to 7.7 μg/24 h) in normotension, 7.3 μg/24 h (CI, 5.6 to 8.9 μg/24 h) in stage 1 hypertension, 9.5 μg/24 h (CI, 8.2 to 10.8 μg/24 h) in stage 2 hypertension, and 14.6 μg/24 h (CI, 12.9 to 16.2 μg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism.
LIMITATION
Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics.
CONCLUSION
The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension.
PRIMARY FUNDING SOURCE
National Institutes of Health.
Topics: Adult; Aldosterone; Cross-Sectional Studies; Female; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Potassium; Prevalence; Renin; Severity of Illness Index; United States
PubMed: 32449886
DOI: 10.7326/M20-0065 -
Circulation Research Mar 2019Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic,... (Review)
Review
Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin receptor blocker), at maximal or maximally tolerated doses. Antihypertensive medication nonadherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. RHTN is a high-risk phenotype, leading to increased all-cause mortality and cardiovascular disease outcomes. Healthy lifestyle habits are associated with reduced cardiovascular risk in patients with RHTN. Aldosterone excess is common in patients with RHTN, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and an MR (mineralocorticoid receptor) antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying RHTN, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.
Topics: Aldosterone; Animals; Antihypertensive Agents; Blood Pressure; Drug Resistance; Drug Therapy, Combination; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Risk Factors; Sodium Chloride Symporter Inhibitors; Sympathetic Nervous System; Sympatholytics; Treatment Outcome; Water-Electrolyte Balance
PubMed: 30920924
DOI: 10.1161/CIRCRESAHA.118.312156 -
Journal of Internal Medicine Feb 2019Primary aldosteronism (PA), the most common form of secondary hypertension, can be either surgically cured or treated with targeted pharmacotherapy. PA is frequently... (Review)
Review
Primary aldosteronism (PA), the most common form of secondary hypertension, can be either surgically cured or treated with targeted pharmacotherapy. PA is frequently undiagnosed and untreated, leading to aldosterone-specific cardiovascular morbidity and nephrotoxicity. Thus, clinicians should perform case detection testing for PA at least once in all patients with hypertension. Confirmatory testing is indicated in most patients with positive case detection testing results. The next step is to determine whether patients with confirmed PA have a disease that can be cured with surgery or whether it should be treated medically; this step is guided by computed tomography scan of the adrenal glands and adrenal venous sampling. With appropriate surgical expertise, laparoscopic unilateral adrenalectomy is safe, efficient and curative in patients with unilateral adrenal disease. In patients who have bilateral aldosterone hypersecretion, the optimal management is a low-sodium diet and lifelong treatment with a mineralocorticoid receptor antagonist administered at a dosage to maintain a high-normal serum potassium concentration without the aid of oral potassium supplements.
Topics: Adrenalectomy; Humans; Hyperaldosteronism; Tomography, X-Ray Computed
PubMed: 30255616
DOI: 10.1111/joim.12831