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Aldosterone is the principal mineralocorticoid in humans that regulates extracellular volume and electrolyte homeostasis primarily through its effects on the renal distal convoluted tubule. In this manner, aldosterone activates the mineralocorticoid receptor in principal cells of the distal nephron, resulting in increased expression of luminal epithelial sodium channels (ENaC) (). Sodium is reabsorbed via ENaC resulting in a potent electronegative luminal potential that induces the efflux of cations, namely potassium and hydrogen ions, from the principal cells. Thus, the net effect of this aldosterone action on the kidney is reabsorption of sodium (which ultimately will result in water reabsorption and intravascular volume expansion) and urinary excretion of potassium and hydrogen. In addition to these classical actions of aldosterone in the kidney, the non-classical extra-renal actions of aldosterone, particularly on cardiovascular tissues such as the endothelium and myocardium, are now increasingly recognized in human disease (,).

Aldosterone is synthesized in the zona glomerulosa of the adrenal gland cortex. Its production is restricted to this layer of the cortex because of zona-specific expression of aldosterone synthase (CYP11B2)(), which is the key enzyme for aldosterone biosynthesis (). The expression of CYP11B2 is controlled by aldosterone secretagogues. Previous immunohistochemistry studies of the adrenal gland reported that in early life, cells express CYP11B2 in a continuous mode, whereas with increasing age, expression of CYP11B2 is less continuous. Subsequently, in adults, CYP11B2-expressing cells are distributed in a diffuse manner in the subcapsular cortex among typical zona glomerulosa cells not expressing the enzyme, whereas the CYP11B2-expressing area decreases with age (,). Aldosterone secretion is primarily stimulated by angiotensin II acting on ATR1 receptors in the adrenal zona glomerulosa and by elevated plasma potassium levels.

The renin–angiotensin–aldosterone system (RAAS) is the principal regulator of aldosterone production. Renin, an enzyme produced in the juxtaglomerular apparatus of the kidney, catalyzes the conversion of angiotensinogen (an inactive precursor peptide) to angiotensin I. Angiotensin I undergoes further enzymatic conversion by angiotensin-converting enzyme (ACE) to produce angiotensin II (Ang II). Ang II acts via the adrenal angiotensin receptor ATR1 to stimulate the release of aldosterone by increasing the transcription of aldosterone synthase. The physiologic role of RAAS is to regulate sodium homeostasis and thereby intravascular plasma volume and arterial pressure. In normal physiology, renin secretion is stimulated by decreased delivery of chloride ion to the macula densa of the juxtaglomerular apparatus. This is typically the consequence of decreased systemic arterial pressure resulting in decreased renovascular pressure and glomerular filtration. Increased renin activity results in activation of the RAAS and increased synthesis of Ang II, an activator of Ca2+ influx and Ca2+/calmodulin-dependent protein kinases (CaMKs) stimulating transcription of CYP11B2 and aldosterone biosynthesis (). Ang II has many functions to counter the initial hypotensive and hypoperfusion insult: It acts as a direct arterial vasopressor and can induce vasoconstriction to address systemic hypotension.

It stimulates vasopressin (antidiuretic hormone) release to induce distal nephron water reabsorption and thus expand intravascular volume. It acts at the proximal renal tubule of the nephron to maximize proximal sodium (and therefore water) reabsorption to expand intravascular volume. It maximizes renal sodium reabsorption by stimulating adrenal aldosterone biosynthesis; aldosterone then acts at the principal cells to increase sodium reabsorption as described earlier. The net effect of these actions is a feedback loop, whereby expansion of intravascular volume increases renal perfusion and glomerular filtration and decreases renin secretion ().

Both potassium and angiotensin II can independently stimulate aldosterone secretion by increasing cytoplasmic calcium concentrations in zona glomerulosa cells, and act synergistically to amplify aldosterone production. Potassium, in addition, enhances the sensitivity of zona glomerulosa cells to angiotensin II. The calcium influx induced by potassium-mediated membrane depolarization activates intracellular signaling pathways that overlap substantially with those triggered by angiotensin II, augmenting aldosterone response to angiotensin II in hyperkalemic states. Beyond this permissive role, aldosterone secretion can also be directly stimulated by elevated serum potassium concentrations, which increase transcription of aldosterone synthase (CYP11B2) within the zona glomerulosa.

TWIK-related acid-sensitive potassium (TASK)-1 (KCNK3), TASK-2 (KCNK5), and TASK-3 (KCNK9) channels are two-pore-domain potassium channels, also referred to as K + -selective leak channels, that are predominantly expressed in the adrenal cortex (,). These channels generate background potassium currents, maintaining a highly polarized (negative) membrane potential in adrenocortical cells under resting conditions (,). Inhibition or genetic deletion of TASK channels leads to membrane depolarization, increased intracellular calcium, and overproduction of aldosterone (,). TASK-1 and TASK-3 can form homo- or hetero-meric channels, and their inhibition (by factors such as angiotensin II or extracellular protons) depolarizes the membrane, triggering aldosterone synthesis (,). The TASK channels are members of the KCNK family and exhibit sensitivity to extracellular pH (,). These channels are crucial for setting the resting membrane potential and are inhibited by extracellular protons within the physiological range(). Kir3.4, encoded by the KCNJ5 gene, is a G protein-activated inwardly rectifying potassium channel that also contributes to maintaining the hyperpolarized state of adrenocortical cells. Mutations or dysfunction in Kir3.4 can disrupt potassium efflux, leading to depolarization and increased aldosterone production (,). Through the coordinated actions of these potassium channels, even small increases in extracellular potassium can result in a several-fold increase in aldosterone secretion. Activation of the renin–angiotensin–aldosterone system, typically occurring in response to reduced renal blood flow or sodium depletion, further augments aldosterone synthesis and secretion (,). Aldosterone’s production can be upregulated acutely following increased expression and phosphorylation of the StAR protein or more chronically due to increased expression of CYP11B2 ().

Adrenocorticotropic hormone (ACTH) is another aldosterone secretagogue, although its effect is modest and transient; ACTH is a 39-amino acid peptide, resulting from the cleavage of its proopiomelanocortin (POMC) precursor. It is produced by the anterior pituitary corticotropes, but, to a lesser degree, can be produced in the brain, adrenal medulla, skin, and placenta (). It binds to melanocortin type 2 receptor (MC2R), stimulating both cortisol and aldosterone secretion (). However, earlier and more recent data have suggested that the ACTH effect on aldosterone secretion may be more complex and underestimated (). It has been reported that increasing StAR expression, as well as activation of the PKA pathway and calcium/calmodulin-dependent protein kinase, may lead to increased aldosterone secretion (). A recent study evaluated 61 normotensive and 113 hypertensive patients with normal aldosterone suppression in a combined fludrocortisone-dexamethasone suppression test (dexamethasone was administered to eliminate any stimulatory effect of ACTH on aldosterone secretion) who had normal findings in computed tomography. All the patients underwent stimulation tests with 0.03 μg ACTH, while among them, 26 also had genetic studies. The study found that 27% of the hypertensive group exhibited increased aldosterone secretion following the test. Sequencing of the KCNJ5 gene revealed that 2 patients had two different heterozygous germline mutations. Interestingly, MR antagonist therapy was effective for blood pressure normalization (). These findings led to the hypothesis that glomerulosa cells were primed by chronic stress-induced ACTH secretion, and, hence, became more sensitive to ACTH and/or REN/angiotensin II (,). Additional modulators and mechanisms also include other substances:

Adipokines: The adipokine CTRP-1 can directly stimulate aldosterone secretion from human adrenocortical cells in vitro. Other factors or states, such as leptin, insulin, insulin resistance, and sympathetic nervous system activation, can also increase aldosterone secretion, particularly in overweight or obese individuals, partly by sensitizing adrenocortical cells to angiotensin(), Osmolarity: The adrenal gland is intrinsically osmo-sensitive. Increased osmolarity (by as little as 10 mosmol/l) strongly reduces angiotensin-stimulated aldosterone secretion, indicating that plasma salinity modulates its secretion independently of renin and angiotensin (). Magnesium (Mg2+): Mg2+ modulates aldosterone secretion by blocking K+ and Ca2+ channels in adrenal glomerulosa cells. Higher extracellular Mg2+ reduces both basal and angiotensin II-stimulated aldosterone secretion in vitro and in vivo . In humans, Mg2+ depletion augments angiotensin II-stimulated aldosterone secretion, which can be partially reversed by Mg2+ repletion () and Parathyroid Hormone (PTH): PTH can stimulate aldosterone secretion by acting directly on adrenal zona glomerulosa cells and potentiating angiotensin II effects. Conversely, aldosterone excess can induce renal calcium loss, leading to hypocalcemia and secondary hyperparathyroidism ().

Aldosterone is secreted in both ultradian and circadian rhythmic patterns. Studies using high-frequency blood sampling have shown that basal rates and the amplitude of pulsed aldosterone secretion are significantly higher in patients with primary aldosteronism than healthy controls, though pulse frequency remains unchanged. Additionally, aldosterone secretion is under circadian regulation, with increased secretion during the biological night compared to the day, independently of sleep or posture (,).

Emerging evidence has implicated aldosterone, and specifically activation of the mineralocorticoid receptor, with cardiovascular and cardiometabolic diseases (,,). The mineralocorticoid receptor is classically considered in the context of its expression in the distal nephron; however, it is now clear that this receptor is also expressed in the vasculature and heart and plays an important role in mediating cardiovascular pathophysiology. The non-classical effects of aldosterone have stemmed from dysregulated aldosterone physiology being linked to deleterious end-organ effects. Typically, this has been evidenced by inappropriately elevated levels of aldosterone in the setting of high dietary sodium intake (subclinical or clinical primary hyperaldosteronism). However, some evidence also suggests that inappropriately low levels of aldosterone on a restricted sodium diet, or in response to angiotensin II, are also associated with adverse cardiometabolic consequences (–).

Excess or inappropriate aldosterone activity has been associated with or shown to cause cardiac fibrosis, inflammation, and remodeling (–), pathologic insulin secretion and/or peripheral resistance, as well as the metabolic syndrome (,,), kidney injury (), and increased mortality (). Interventional studies in animals and humans have supported these assertions by demonstrating the prevention of these deleterious effects with the use of mineralocorticoid antagonists (,). Taken together, this evolving body of evidence points towards subclinical aldosterone excess, particularly in the milieu of excessive dietary sodium intake, as a modifiable cardio-metabolic risk factor.

The mechanisms by which this can occur are many: 1) an adrenal tumor that autonomously secretes aldosterone; 2) unilateral or bilateral hyperplasia of the zona glomerulosa that oversecretes aldosterone; 3) or germline or somatic mutations that induce aldosterone hypersecretion that is decoupled from Ang II signaling. Autonomous aldosterone excess results in continuous renal sodium reabsorption, intravascular volume expansion, hypertension and renal-vascular hyperperfusion, and consequently suppression of the RAAS. Yet, despite this physiologic suppression of the RAAS, aldosterone secretion continues unabated, resulting in a vicious cycle of hypertension and, possibly, also hypokalemia (). Patients with primary aldosteronism (PA), when compared with matched essential hypertensives, have increased left ventricular wall and carotid intima media thickness, as well as impaired diastolic pressure and endothelial function (,,). A higher incidence of atrial fibrillation, often hypokalemia-induced, coronary artery disease, and heart failure have been reported (,). PA is also associated with a higher incidence of negative cardiovascular outcomes (myocardial infarction and stroke) than essential hypertension with a similar degree of blood pressure elevation (–). Therefore, PA is considered to induce increased cardiovascular risk independent of blood pressure effects alone. The excess cardiovascular events associated with PA were previously considered reversible if treatment with mineralocorticoid antagonists was administered in time (,). However, newer data suggest that PA patients treated with MR antagonists had an approximately two-fold higher incidence of adverse cardiovascular events. Patients with PA also had a significantly higher death risk, as well as a higher incidence of atrial fibrillation and diabetes mellitus than people diagnosed with essential hypertension. The adjusted 10-year cumulative incidence difference for occurrence of cardiovascular morbidity for patients with PA and treatment with MR antagonists was reported to be 14.1 (95% CI 10.1, 18.0) excess events per 100 individuals compared to those with essential hypertension ().

Mineralocorticoid excess states () comprise a group of disorders that can be separated into those mediated by the principal mineralocorticoid, aldosterone, and those caused by non-aldosterone etiologies PA (). PA can result from autonomous secretion of aldosterone from one or both adrenal glands. In this circumstance, the PRA is suppressed (hyporeninemic hyperaldosteronism or renin-independent aldosteronism), and the plasma aldosterone to renin activity ratio is elevated. In secondary hyperaldosteronism, increased activation of the RAAS is the initiating event, resulting in excess aldosterone production (hyperreninemic hyperaldosteronism or renin-dependent aldosteronism). Therefore, secondary hyperaldosteronism can be a normal physiologic phenomenon (such as in states of systemic hypovolemia or hypoperfusion) or can manifest as a pathologic entity when activation of the RAAS is inappropriate relative to the state of the systemic vasculature. The distinction between primary and secondary causes of hyperaldosteronism is of importance, as the manifestations, as well as the subsequent testing and treatment, differ ().

PA is recognized as the most common form of secondary hypertension, with a prevalence ranging from 5% to 15% in hypertensive patients and up to 20%–30% in those with resistant hypertension (–) The five established morphological subtypes of PA include: aldosterone-producing adenoma (APA), bilateral adrenal hyperplasia (BAH), unilateral adrenal hyperplasia (UAH), glucocorticoid-remediable aldosteronism (GRA), and, rarely, adrenocortical carcinoma (,). A potential sixth subtype may involve a morphologically normal adrenal gland (without any tumor or hyperplasia) that harbors clusters of increased expression of aldosterone synthase (the aldosterone producing cell cluster)(,,). Recent advances in genetics and clinical research have dramatically enhanced our understanding of the pathogenesis of these subtypes and have raised the question of whether these entities are part of a larger spectrum of disorders that share genetic underpinnings (,). Aldosterone-producing adenoma (APA): Estimates for the proportion of PA cases due to APA vary widely, with most recent data indicating that APA accounts for approximately 27%–35% of cases (–) Bilateral adrenal hyperplasia (BAH)/Idiopathic hyperaldosteronism (IHA ): BAH is reported to account for about 60%–65% of PA cases (–) Unilateral adrenal hyperplasia (UAH): UAH is much less common, representing about 2% of cases of PA (,)

Other rare causes : Familial hyperaldosteronism and aldosterone-producing adrenocortical carcinoma each account for less than 1% of PA cases (,). There are some discrepancies in the literature, with one source reporting APA being as high as 65% and BAH as 35% (,). The majority of studies aligns with the 30–40% APA and 60–65% BAH distribution. APAs are often small tumors, usually less than 2 cm in diameter. Histopathology of APA reveals hybrid cells which have histological features of both zona glomerulosa and zona fasciculata cells. Unilateral adrenal hyperplasia (UAH), sometimes referred to as primary adrenal hyperplasia, shares many biochemical features with APA. This diagnosis is often made on evidence of unilateral production of aldosterone in the absence of a discrete radiographic mass. Similarly to APA, the hypertension and biochemical abnormalities with UAH may be cured or substantially ameliorated with unilateral adrenalectomy (,). BAH probably represents a spectrum of disorders (–). The extent of hyperaldosteronism is often milder in BAH than in APA, and consequently the severity of hypertension, hypokalemia, and suppression of PRA is often less. Adrenal carcinomas are a rare cause of PA. At the time of diagnosis, adrenal carcinomas are generally large (>4 cm) and may be producing one or multiple adrenal cortical hormones, including cortisol, aldosterone, and adrenal androgens.

In 1954, Conn first reported the clinical syndrome of hypertension, hypokalemia, and metabolic alkalosis resulting from autonomous production of aldosterone from an adrenal adenoma – a syndrome that continues to bear his name (). Previous studies reported a prevalence of PA of 1-2%, even in patients with adrenal incidentaloma and hypertension (). Since that time, numerous studies have investigated the prevalence of PA and reported rates ranging from 3% to 20% depending on the population and diagnostic approach. The prevalence is highest in patients with resistant hypertension and increases with the severity of hypertension. Improved screening, especially using the ARR, has led to greater recognition of PA, particularly among normokalemic patients who were previously missed (–). Initial studies primarily diagnosed patients with PA if they had both hypertension and spontaneous (not diuretic-induced) hypokalemia. More recent reports, however, describe hypokalemic PA in only the minority of PA cases (<40%) (), and describe an intermediate phenotype of normotensive PA with milder manifestations than the classic hypertensive PA(–). Many (up to 63%) of patients with PA may be normokalemic (,). A recent study suggested that PA was diagnosed in 12% of normotensive and normokalemic people with adrenal incidentalomas () ().

In patients with resistant hypertension, the addition of a mineralocorticoid antagonist has been associated with substantial efficacy in blood pressure lowering, suggesting that subclinical hyperaldosteronism may be more prevalent than recognized, with a range between 17 and 23% (,–). In a study involving 1616 patients with resistant hypertension, 21% (338 pts) had an ARR of > 65 with concomitant plasma aldosterone concentrations of > 416 pmol/L (15 ng/dl) (). Low renin hypertension is not always easy to differentiate from PA (). A recent study investigated 327 people with hypertension and 90 normotensive control subjects with normal adrenal imaging. Serum aldosterone, active renin levels, aldosterone/active renin ratio were measured before and after a combined sodium chloride, fludrocortisone and dexamethasone suppression test (FDST). Post-FDST values were compared to cut-offs obtained from controls. Combined results of post-FDST aldosterone levels and ARR, revealed that 28.7% of the hypertensive patients had PA ().

Recent genetic insights have significantly advanced the understanding of PA, revealing a complex landscape involving both somatic and germline mutations in genes regulating ion channels, ATPases, and signaling pathways. These discoveries have important implications for diagnosis, classification, and personalized management of PA.

Familial Hyperaldosteronism Type I (FH-I) or Glucocorticoid-Remediable Aldosteronism GRA is an autosomal dominant disorder characterized by a chimeric duplication, whereby the 5’-promotor regions of the 11β-hydroxylase gene (regulated by ACTH) is fused to the coding sequences of the aldosterone synthase gene in a recombination event (gene defect in CYP11B1/CYPB2 -coding for 11beta-hydroxylase/aldosterone synthase). The result is that the aldosterone synthase gene (CYP11B2) is under the control of the promoter for the CYP11B1 gene, typically responsible for cortisol production under the regulation of ACTH (). It leads to an ectopic expression of aldosterone synthase activity in the cortisol-producing zona fasciculata, making mineralocorticoid production regulated by corticotropin (,). The hybrid gene has been identified on chromosome 8. Under normal conditions, aldosterone secretion is mainly stimulated by hyperkalemia and angiotensin II. An increase of serum potassium of 0.1 mmol/L increases aldosterone by 35%. In familial hyperaldosteronism type 1, urinary hybrid steroids 18-oxocortisol and 18-hydroxycortisol are approximately 20-fold higher than in sporadic aldosteronomas. Intracranial aneurysms and hemorrhagic stroke are clinical features frequently associated with familial hyperaldosteronism type 1 (). The diagnosis is made by documenting dexamethasone suppression of serum aldosterone using the Liddle’s Test (dexamethasone 0.5 mg q 6h for 48h should reduce plasma aldosterone to nearly undetectable levels (below 4 ng/dl) or by genetic testing (Southern Blot or PCR) ().

Familial hyperaldosteronism type II (FH-II) is an inherited form of PA characterized by familial clustering of PA without distinctive clinical or biochemical features differentiating it from sporadic disease. FH-II is now known to be caused by germline mutations in the inwardly rectifying chloride channel gene CLCN2 , which lead to zona glomerulosa cell depolarization, increased intracellular calcium signaling, and PA. Affected individuals may present with unilateral or bilateral disease and exhibit phenotypes indistinguishable from sporadic aldosterone-producing adenomas or bilateral adrenal hyperplasia. Consequently, diagnosis relies on family history and genetic testing rather than clinical phenotype alone (,). Familial hyperaldosteronism type III (FH-III) () is associated with germline mutations in KCNJ5, a gene that encodes the inwardly-rectifying potassium channel GIRK4 () leading to an increase in aldosterone synthase expression and production of aldosterone (). This type is characterized by severe childhood-onset hypertension, hypokalemia, remarkably high aldosterone-to-renin ratio, high concentrations of hybrid steroids and with marked adrenal enlargement and diffuse hyperplasia of the zona fasciculata (,).

This discovery set off international research efforts to investigate the role of potassium channel mutations in PA. Although the prevalence of KCNJ5 germline mutations is considered to be extremely low (,,,), investigators have now reported the presence of KCNJ5 somatic mutations in 30-50% of patients with APA’s (,,–). Hence, the discovery of a rare familial form of PA has resulted in understanding that somatic potassium channel mutations may be a highly prevalent cause of PA. In general, from the reports to date, somatic mutations in KCNJ5 appear to be associated with female gender, younger age, and higher aldosterone levels; however, these descriptions may reflect a significant sample selection bias.

Normally, adrenal zona glomerulosa cells maintain a hyperpolarized resting membrane potential that is largely regulated by potassium current. Depolarization of the cell (either by angiotensin II or hyperkalemia-mediated inhibition of the potassium current) results in the opening of voltage-gated calcium channels, increased intracellular calcium signaling, and stimulation of aldosterone synthase. A gain-of-function mutation in GIRK4 results in sodium influx, cell depolarization, and increased aldosterone synthesis (–) (). In this manner, mutations in channels that regulate the resting potential of zona glomerulosa cells have been implicated in the development of hyperaldosteronism. How these mutations may result in proliferation and adenoma production is not well understood. This understanding provoked further international collaborative research, especially among European research teams, to investigate the role of other cell membrane channels involved in maintaining zona glomerulosa cell resting potential. This research has resulted in the discovery of somatic mutations in the sodium-potassium-ATPase, calcium-ATPase, and voltage-gated calcium channel all in the zona glomerulosa cell membrane in the pathogenesis of PA ().

Familial hyperaldosteronism type IV (FH IV) results from germline mutations in the T-type calcium channel subunit gene CACNA1H (). Germline mutations in CACNA1D (encoding a subunit of L-type voltage-gated calcium channel CaV1.3) are found in patients with PA sometimes associated with seizures, and other neurological abnormalities (). Additional genes, such as PDE2A and PDE3B, have been associated with bilateral PA, further expanding the spectrum of genetic etiologies() (). With continued collaborative research, it is expected the number of mutated gene products regulating the resting potential of zona glomerulosa cells implicated in the pathogenesis of PA will grow. Whether the identification of these mutations will translate to treatment modalities remains to be seen.

The histopathological discovery of aldosterone-producing cell clusters (APCCs) also referred to as aldosterone-producing micronodules (APMs), CYP11B2 expressing area and/or areas of abnormal foci of CYP11B2-expressing cells (,), sparked another leap in the understanding of PA pathogenesis. APCCs have now been identified in more than 50% of morphologically normal adrenal glands and are found with higher prevalence in older individuals (,). Recent studies reported decreased normal zona glomerulosa CYP11B2 expression and increased APCC expression with advancing age (,). Furthermore, APCCs harbor somatic mutations known to increase autonomous aldosterone secretion in APAs() (). Although studies of APCCs to date lack biochemical or clinical correlates to confirm that this histopathological phenotype of aldosterone synthase overexpression induces renin-independent aldosteronism, they raised speculation that the APCC may represent a precursor for development of APA or BAH. For example, APCCs exist even in adrenal tissue adjacent to an aldosterone-producing adenoma (), suggesting that APCCs have non-suppressible aldosterone synthase activity.

Several clinical studies to date have shown mild or “subclinical” renin-independent aldosteronism in normotensives and early stage hypertensives, and that this phenotype increases the risk for cardiometabolic and/or chronic kidney disease (,–) However, even if APCCs/APMs are increasingly recognized as a histopathological substrate for subclinical PA, supporting the link between tissue pathology and the clinical phenotype, however, direct clinical-histopathological correlation is still being established (–). Therefore, future studies that integrate APCC histopathology with biochemical testing and incident clinical outcomes are needed to better characterize whether APCCs may represent the initial pathogenesis of PA.

The clinical features of hyperaldosteronism are non-specific and variable, often resulting in or associated with hypertension. It is more important to distinguish whether hyperaldosteronism is primary or secondary, as this pathophysiologic designation dictates the likely clinical syndrome (). Renal potassium wasting can result in hypokalemia. The phenotype depends largely on the underlying cause and the degree of the aldosterone excess, as well as the presence of other co-morbidities. The classic features of moderate-to-severe hypertension, hypokalemia, and metabolic alkalosis are highly suggestive of mineralocorticoid excess (usually PA). In most cases, however, only subtle clues of hyperaldosteronism exist, such as the recent onset of refractory hypertension (defined as refractory to treatment with three classes of antihypertensives, including a diuretic) (). Hypertension is common among patients with PA. Hypertension results from inappropriately high aldosterone secretion because of plasma volume expansion and increased peripheral vascular resistance. Hypertension may be severe or refractory to standard antihypertensive therapies. However, some patients are normotensive or have minimal blood pressure elevations and, as a result, severe hypertension is not a sine qua non for this diagnosis (,,–).

Spontaneous hypokalemia in any patient with or without concurrent hypertension warrants consideration of hyperaldosteronism as an etiology. Additionally, patients that develop severe hypokalemia after institution of a potassium-wasting diuretic (such as hydrochlorothiazide or furosemide) should be investigated. It should be noted that in most PA cases serum potassium levels are normal (,). PA results in extracellular volume expansion secondary to excess sodium reabsorption. However, after the retention of several liters of isotonic saline, an escape from the renal sodium-retaining actions of aldosterone occurs in part due to the increased secretion of atrial natriuretic peptide. Therefore, peripheral edema is rarely a feature of PA if cardiac and renal function are normal. Metabolic alkalosis occurs secondary to renal distal tubule urinary hydrogen ion secretion. It is usually mild, causing no significant sequelae, and may go unnoticed. Hypomagnesemia and mild hypernatremia (likely secondary to resetting of the osmostat) can also be observed.

Rarely, patients experience neuromuscular symptoms, including paresthesias or weakness, due to the electrolyte disturbances caused by PA. Nephrogenic diabetes insipidus, caused by renal tubule antidiuretic hormone resistance due to hypokalemia, can cause nocturia and mild polyuria and polydipsia. Atrial fibrillation and cardiac arrhythmias may occur and can be life threatening.

Secondary causes of hypertension (including hyperaldosteronism) should be considered initially in all hypertensive individuals. A thorough medical history and physical examination can greatly assist the clinician in deciding which patients should be further evaluated and what tests should be performed. Although the sensitivity of testing for hyperaldosteronism increases when limited to patients with moderate-to-severe hypertension, many patients with hyperaldosteronism have mild to moderate hypertension. The recent onset of refractory or accelerated hypertension, especially in a patient known to be previously normotensive, can be a valuable clinical clue. Therefore, the clinician must remain vigilant to the possibility of hyperaldosteronism, especially in the appropriate clinical setting.

An updated Endocrine Society clinical practice guideline (2025) provides a comprehensive, evidence-based approach to the diagnosis and management of primary aldosteronism (PA), with a notable shift toward broader screening strategies (). The guideline conditionally recommends screening all individuals with hypertension for PA using the ARR, measured alongside plasma aldosterone concentration, renin (either PRA or DRC), and potassium, to enable accurate interpretation (). In addition, screening is specifically recommended for individuals with (a) hypertension and spontaneous or diuretic-induced hypokalemia (,–), (b) resistant hypertension (uncontrolled on three antihypertensives including a diuretic, or controlled on four or more), (–,–,) (c) hypertension with an adrenal incidentaloma (,,,,,), (d) hypertension and obstructive sleep apnea (OSA) (,,,), (e) a family history of early-onset hypertension or stroke (<40 years) (,,,,,–), and (f) hypertensive first-degree relatives of individuals with confirmed PA (,,,,,–)(). The guideline also advises repeat testing in cases with negative initial results but a high pre-test probability (e.g., hypokalemia, suppressed renin, or use of interfering medications), and emphasizes the need to correct hypokalemia and, when feasible, withdraw interfering agents (e.g., β-blockers, ACE inhibitors, diuretics) prior to repeat testing to avoid false negatives (). Complementing these recommendations, recent international consensus efforts, including the Primary Aldosteronism Medical Outcome (PAMO) study, emphasize that the true prevalence of PA is likely underestimated when relying solely on classical indicators such as hypokalemia (). Notably, up to 80% of individuals with biochemically confirmed PA are normokalemic at diagnosis(). Accordingly, some expert groups and national societies (e.g., Japan) now advocate for universal PA screening in all individuals with hypertension, regardless of serum potassium or adrenal imaging findings (). The PAMO consensus also underscores the importance of screening before initiation of antihypertensive therapy, as many commonly used agents (e.g., diuretics, MRAs, β-blockers) can confound ARR interpretation by altering renin and aldosterone concentrations()