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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 -
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 -
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 -
Journal of Hypertension Oct 2020: Autonomous aldosterone overproduction represents the underlying condition of 5-10% of patients with arterial hypertension and carries a significant burden of mortality...
Genetics, prevalence, screening and confirmation of primary aldosteronism: a position statement and consensus of the Working Group on Endocrine Hypertension of The European Society of Hypertension.
: Autonomous aldosterone overproduction represents the underlying condition of 5-10% of patients with arterial hypertension and carries a significant burden of mortality and morbidity. The diagnostic algorithm for primary aldosteronism is sequentially based on hormonal tests (screening and confirmation tests), followed by lateralization studies (adrenal CT scanning and adrenal venous sampling) to distinguish between unilateral and bilateral disease. Despite the recommendations of the Endocrine Society guideline, primary aldosteronism is largely underdiagnosed and undertreated with high between-centre heterogeneity. Experts from the European Society of Hypertension have critically reviewed the available literature and prepared a consensus document constituting two articles to summarize current knowledge on the epidemiology, diagnosis, treatment, and complications of primary aldosteronism.
Topics: Aldosterone; Consensus; Humans; Hyperaldosteronism; Hypertension; Prevalence
PubMed: 32890264
DOI: 10.1097/HJH.0000000000002510 -
Frontiers in Endocrinology 2021Obstructive sleep apnea (OSA) is regarded as an independent risk factor for hypertension. The possible mechanism includes oxidative stress, endothelial injury,... (Review)
Review
Obstructive sleep apnea (OSA) is regarded as an independent risk factor for hypertension. The possible mechanism includes oxidative stress, endothelial injury, sympathetic excitement, renin-angiotensin-aldosterone system activation, etc. Clinical studies have found that there is a high coexistence of OSA and primary aldosteronism in patients with hypertension and that elevated aldosterone levels are independently associated with OSA severity in resistant hypertension. The underlying mechanism is that aldosterone excess can exacerbate OSA through increasing overnight fluid shift and affecting the mass and function of upper airway muscles during the sleep period. Thus, a bidirectional influence between OSA and aldosterone exists and contributes to hypertension in OSA patients, especially resistant hypertension.
Topics: Aldosterone; Continuous Positive Airway Pressure; Humans; Hyperaldosteronism; Hypertension; Sleep Apnea, Obstructive
PubMed: 35095768
DOI: 10.3389/fendo.2021.801689 -
Current Opinion in Endocrinology,... Jun 2022Renin-independent aldosterone production from one or both affected adrenal(s), a condition known as primary aldosteronism (PA), is a common cause of secondary... (Review)
Review
PURPOSE OF REVIEW
Renin-independent aldosterone production from one or both affected adrenal(s), a condition known as primary aldosteronism (PA), is a common cause of secondary hypertension. In this review, we aimed to summarize recent findings regarding pathophysiology of bilateral forms of PA, including sporadic bilateral hyperaldosteronism (BHA) and rare familial hyperaldosteronism.
RECENT FINDINGS
The presence of subcapsular aldosterone synthase (CYP11B2)-expressing aldosterone-producing micronodules, also called aldosterone-producing cell clusters, appears to be a common histologic feature of adrenals with sporadic BHA. Aldosterone-producing micronodules frequently harbor aldosterone-driver somatic mutations. Other potential factors leading to sporadic BHA include rare disease-predisposing germline variants, circulating angiotensin II type 1 receptor autoantibodies, and paracrine activation of aldosterone production by adrenal mast cells. The application of whole exome sequencing has also identified new genes that cause inherited familial forms of PA.
SUMMARY
Research over the past 10 years has significantly improved our understanding of the molecular pathogenesis of bilateral PA. Based on the improved understanding of BHA, future studies should have the ability to develop more personalized treatment options and advanced diagnostic tools for patients with PA.
Topics: Adrenal Glands; Aldosterone; Cytochrome P-450 CYP11B2; Humans; Hyperaldosteronism
PubMed: 35621175
DOI: 10.1097/MED.0000000000000729 -
The Journal of Clinical Endocrinology... Jul 2020The clinical spectrum and knowledge of the molecular mechanisms underlying primary aldosteronism (PA), the most frequent form of endocrine hypertension, has evolved over... (Review)
Review
CONTEXT
The clinical spectrum and knowledge of the molecular mechanisms underlying primary aldosteronism (PA), the most frequent form of endocrine hypertension, has evolved over recent years. In accordance with the Endocrine Society guidelines and in light of the growing evidence showing adverse cardiovascular outcomes, it is expected that a progressively wider population of patients affected by hypertension will be screened for PA, including the elderly.
EVIDENCE ACQUISITION
A systematic search of PubMed was undertaken for studies related to the renin-angiotensin-aldosterone system (RAAS), PA, and adrenal histopathology in the elderly population.
EVIDENCE SYNTHESIS
Several studies showed an age-dependent decrease in the activity of RAAS, together with a progressive decrease of the aldosterone response to sodium intake, particularly after the sixth decade of life. The positive correlation between age and serum aldosterone during liberal sodium intake over serum aldosterone during sodium restriction is paralleled by histological changes in adrenal aldosterone synthase (CYP11B2) expression patterns. Immunohistochemical studies showed a progressive loss of the continuous expression of CYP11B2 in the adrenal zona glomerulosa with aging and a concomitant increase of aldosterone-producing cell clusters, which might be responsible for relatively autonomous aldosterone production. Additionally, following PA confirmation and subtype diagnosis, older age is correlated with a lower benefit after adrenalectomy for unilateral PA.
CONCLUSIONS
Accumulating evidence suggests that RAAS physiology and regulation show age-related changes. Further studies may investigate to what extent these variations might affect the diagnostic workup of patients affected by PA.
Topics: Adrenal Glands; Age Factors; Aged; Aging; Aldosterone; Humans; Hyperaldosteronism
PubMed: 32303754
DOI: 10.1210/clinem/dgaa206