Primary Aldosteronism

Complex MONDO:0001422 Pathograph 29 Show in embeddings browser hyperaldosteronism

Primary aldosteronism is autonomous adrenocortical aldosterone production that is not suppressed by volume expansion and proceeds independently of the renin-angiotensin system. Somatic gain-of-function mutations in zona glomerulosa ion channels and pumps (KCNJ5, CACNA1D, ATP1A1, ATP2B3), and constitutive Wnt/beta-catenin signalling through CTNNB1, converge on cell depolarization, calcium entry, and transcription of aldosterone synthase (CYP11B2). The resulting mineralocorticoid receptor overactivation drives renal sodium retention, potassium and hydrogen ion wasting, and low-renin hypertension, together with cardiac, vascular, and renal inflammation and fibrosis that exceed what the blood pressure elevation alone predicts. Primary aldosteronism is the most common identifiable cause of secondary hypertension, is curable by adrenalectomy when aldosterone production lateralizes to one adrenal, and is markedly underdiagnosed.

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Mappings

ICD-10-CM

ICD10CM:E26.0 Primary hyperaldosteronism

ICD-10-CM E26.0 is titled "Primary hyperaldosteronism" and covers the same concept as this entry.

ICD-11 Foundation

icd11f:100169070 Nonfamilial primary hyperaldosteronism

Narrower, not exact: the ICD-11 Foundation term excludes the familial forms, which this entry cross-references rather than restates. The deep-research report proposed the ICD-11 stem code 5A11, but that CURIE does not resolve in the icd11f build, which keys terms by numeric identifier; it was not bound. This term was found by searching the build rather than taken from the report.

📘

Definitions

Scope of this entry

This entry curates primary aldosteronism as a single disease with one pathophysiology: renin-independent aldosterone secretion from the adrenal zona glomerulosa and the mineralocorticoid receptor overactivation that follows. The lateralization axis (aldosterone-producing adenoma, unilateral adrenal hyperplasia, bilateral idiopathic hyperaldosteronism) is modelled in has_subtypes because it determines surgical curability. The inherited forms (familial hyperaldosteronism types I-IV) are curated separately in kb/disorders/Familial_Hyperaldosteronism.yaml and kb/disorders/Familial_Hyperaldosteronism_Type_I.yaml and are deliberately not restated here; the germline channel mechanisms described there converge on the same glomerulosa depolarization and calcium entry step modelled in this entry.

OTHER

Show evidence (2 references)

PMID:40658480 SUPPORT Human Clinical

"a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands"

The guideline defines primary aldosteronism as one adrenal disorder that may involve either or both glands, which is the unified disease concept this entry curates.

PMID:15837256 SUPPORT Human Clinical

"The two major PA subtypes are unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia."

Supports treating lateralization as the principal subtype axis of a single disease rather than as separate diseases.

◆

Subtypes

Aldosterone-producing adenoma MONDO:0016505

KCNJ5 hgnc:6266 CACNA1D hgnc:1391 ATP1A1 hgnc:799 ATP2B3 hgnc:816 CTNNB1 hgnc:2514

A solitary, usually benign adrenocortical adenoma that produces aldosterone autonomously. Aldosterone secretion lateralizes to the affected gland, so the disease is potentially curable by unilateral adrenalectomy. Most adenomas carry a somatic gain-of-function driver mutation in an ion channel or pump gene, or an activating CTNNB1 mutation.

Show evidence (2 references)

PMID:24866132 SUPPORT Human Clinical

"In conclusion, recurrent somatic mutations were identified in 54% of APAs."

The largest genotyped APA series establishes that recurrent somatic driver mutations account for the majority of adenomas in this subtype.

PMID:28576687 SUPPORT Human Clinical

"Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes."

Supports surgical curability as the feature that distinguishes the lateralizing subtypes from bilateral disease.

Unilateral adrenal hyperplasia MONDO:0016504

Lateralized aldosterone excess arising from hyperplastic zona glomerulosa in one adrenal gland without a discrete adenoma. It behaves like an aldosterone-producing adenoma for management purposes: adrenal venous sampling shows lateralization and unilateral adrenalectomy is the treatment of choice.

Show evidence (1 reference)

PMID:26934393 SUPPORT Human Clinical

"We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy."

The guideline treats unilateral primary aldosteronism as a single management category defined by lateralization on adrenal venous sampling, which is what groups unilateral hyperplasia with adenoma.

Bilateral idiopathic hyperaldosteronism

Bilateral, non-lateralizing autonomous aldosterone production from both adrenal glands, historically called idiopathic hyperaldosteronism. It is not surgically curable and is managed with mineralocorticoid receptor antagonists. No MONDO term for this concept exists, so no subtype_term is bound.

Show evidence (2 references)

PMID:26934393 SUPPORT Human Clinical

"We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist."

Establishes bilateral disease as the medically managed arm of the lateralization axis.

PMID:17161262 SUPPORT Human Clinical

"Evidence of excess autonomous aldosterone secretion without such criteria led to a diagnosis of idiopathic hyperaldosteronism (IHA)."

Gives the operational definition of idiopathic (bilateral) hyperaldosteronism used in prevalence studies.

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Pathophysiology

Somatic Gain-of-Function Mutation in a Zona Glomerulosa Ion Channel or Pump

An acquired, tumour-restricted mutation in KCNJ5, CACNA1D, ATP1A1, or ATP2B3 alters ion handling in an adrenal zona glomerulosa cell. KCNJ5 mutations near the channel selectivity filter admit sodium; ATP1A1 and ATP2B3 mutations disable the sodium/potassium and calcium pumps; CACNA1D mutations shift CaV1.3 activation to less depolarized potentials.

adrenal zona glomerulosa cell CL:0002099

KCNJ5 hgnc:6266 CACNA1D hgnc:1391 ATP1A1 hgnc:799 ATP2B3 hgnc:816

zona glomerulosa UBERON:0002053

Downstream

Zona Glomerulosa Cell Depolarization and Calcium Entry Each driver class converges on depolarization or on direct enhancement of voltage-gated calcium entry.

Show evidence (2 references)

PMID:21311022 SUPPORT Human Clinical

"We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied."

Establishes the somatic ion-channel lesion as the initiating event in a substantial fraction of adenomas.

PMID:23416519 SUPPORT Human Clinical

"Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium."

Gives the functional consequence of the pump mutations that constitutes this node.

Constitutive Wnt Signalling from Stabilized Beta-Catenin

Activating CTNNB1 exon 3 substitutions in the GSK3-beta binding domain prevent beta-catenin degradation, producing constitutive Wnt pathway activity. This branch is mutually exclusive with the ion channel and pump drivers and reaches aldosterone synthesis without passing through membrane depolarization.

adrenal zona glomerulosa cell CL:0002099

CTNNB1 hgnc:2514

zona glomerulosa UBERON:0002053

Downstream

Clonal Expansion of Aldosterone-Producing Adrenocortical Cells

Autonomous CYP11B2 Expression and Aldosterone Synthesis CTNNB1-mutant adenomas retain aldosterone synthase expression and produce aldosterone.

Show evidence (1 reference)

PMID:26815163 SUPPORT In Vitro

"The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggesting activation of WNT signaling."

Establishes beta-catenin stabilization and Wnt pathway output as the molecular consequence of the CTNNB1 mutations.

Zona Glomerulosa Cell Depolarization and Calcium Entry

Aberrant sodium influx, failed sodium and calcium extrusion, or a lowered activation threshold of CaV1.3 depolarize the glomerulosa cell membrane and open voltage-gated calcium channels. Sustained cytosolic calcium elevation is the convergence point at which every common driver class meets, and is the proximate signal for aldosterone synthesis and for proliferation.

adrenal zona glomerulosa cell CL:0002099

membrane depolarization GO:0051899 ↑ INCREASED calcium ion import across the plasma membrane GO:0098703 ↑ INCREASED

zona glomerulosa UBERON:0002053

Downstream

Autonomous CYP11B2 Expression and Aldosterone Synthesis

Clonal Expansion of Aldosterone-Producing Adrenocortical Cells

Show evidence (1 reference)

PMID:23913001 SUPPORT Human Clinical

"These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa."

States that increased calcium influx is a sufficient stimulus for aldosterone production, which is the claim this convergence node makes.

Clonal Expansion of Aldosterone-Producing Adrenocortical Cells

The same driver mutations that raise intracellular calcium, and the Wnt branch, also drive proliferation, producing an aldosterone-producing adenoma or hyperplastic glomerulosa tissue. Small subcapsular aldosterone-producing cell clusters carrying the same driver mutations are present in histologically normal adrenal glands, which is why the disease is best understood as a continuum rather than an all-or-nothing tumour event.

adrenal zona glomerulosa cell CL:0002099

adrenal cortex UBERON:0001235

Downstream

Autonomous CYP11B2 Expression and Aldosterone Synthesis Expansion of the aldosterone-competent cell population raises total aldosterone synthase output.

Show evidence (2 references)

PMID:26240369 SUPPORT Human Clinical

"Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na(+)/(K+) transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent..."

Shows that aldosterone driver mutations are present in discrete expanded cell clusters within otherwise normal adrenal glands.

PMID:21311022 SUPPORT Human Clinical

"These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K+ channel selectivity in constitutive cell proliferation and hormone production."

Links the same channel lesion to constitutive proliferation as well as to hormone production.

Autonomous CYP11B2 Expression and Aldosterone Synthesis

Aldosterone synthase (CYP11B2) transcription becomes constitutive rather than being set by angiotensin II and extracellular potassium, so aldosterone synthesis proceeds irrespective of volume and renin status.

adrenal zona glomerulosa cell CL:0002099

CYP11B2 hgnc:2592

aldosterone biosynthetic process GO:0032342 ↑ INCREASED

Downstream

Renin-Independent Aldosterone Excess

Show evidence (1 reference)

PMID:26240369 SUPPORT Human Clinical

"Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue."

Identifies aldosterone synthase expression as the measured output of the aldosterone-producing lesion.

Renin-Independent Aldosterone Excess

Circulating aldosterone is inappropriately high for the prevailing sodium and volume status and is not suppressed by sodium loading. This is the biochemical definition of the disease and the single node that all upstream branches feed and all downstream consequences depend on.

Downstream

Mineralocorticoid Receptor Overactivation in the Distal Nephron

Mineralocorticoid Receptor-Driven Tissue Inflammation and Oxidative Stress

Show evidence (1 reference)

PMID:32449886 SUPPORT Human Clinical

"Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease."

States the renin-independent, non-suppressible character of aldosterone production that defines this node.

Mineralocorticoid Receptor Overactivation in the Distal Nephron

Excess aldosterone occupies the mineralocorticoid receptor in principal cells of the distal nephron and collecting duct, increasing epithelial sodium channel activity and the electrochemical driving force for potassium and hydrogen ion secretion.

renal principal cell CL:0005009

renal sodium ion absorption GO:0070294 ↑ INCREASED

kidney UBERON:0002113

Downstream

Sodium Retention and Extracellular Volume Expansion

Renal Potassium and Hydrogen Ion Wasting

Show evidence (1 reference)

PMID:32449886 SUPPORT Human Clinical

"This renin-independent aldosterone production can cause hypertension, but interactions with the mineralocorticoid receptor also cause hypokalemia and increased risk for adverse cardiovascular outcomes"

Attributes both the hypertensive and the potassium-wasting consequences to mineralocorticoid receptor interaction rather than to aldosterone concentration alone.

Sodium Retention and Extracellular Volume Expansion

Sustained distal sodium reabsorption expands extracellular fluid volume, which raises blood pressure and, by the normal negative-feedback loop, suppresses renin release from the juxtaglomerular apparatus.

renal sodium ion transport GO:0003096 ↑ INCREASED

Downstream

Suppression of Renin Release

Hypertension

Show evidence (1 reference)

PMID:26934393 SUPPORT Human Clinical

"For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions"

The aldosterone-renin ratio is the case-detection test precisely because volume expansion suppresses renin while aldosterone stays high, which is what this node asserts.

Suppression of Renin Release

Volume expansion suppresses juxtaglomerular renin secretion. The combination of suppressed renin with unsuppressed aldosterone produces the elevated aldosterone-to-renin ratio on which screening depends, and renin that stays suppressed on treatment marks residual, undertreated mineralocorticoid receptor activation.

Downstream

Elevated aldosterone:renin ratio

Show evidence (1 reference)

PMID:29129576 SUPPORT Human Clinical

"the excess risk for cardiovascular events and mortality was limited to patients with primary aldosteronism whose renin activity remained suppressed"

Shows that persistently suppressed renin marks continued mineralocorticoid receptor activation and carries the excess risk, which is the clinical significance of this node.

Renal Potassium and Hydrogen Ion Wasting

Increased distal sodium reabsorption creates a lumen-negative potential that drives potassium and hydrogen ion secretion. Potassium wasting is graded rather than all-or-nothing, which is why most patients are normokalemic and hypokalemia marks the more severe end of the spectrum rather than being a diagnostic requirement.

renal potassium excretion GO:0036359 ↑ INCREASED

Downstream

Hypokalemia

Metabolic alkalosis

Show evidence (1 reference)

PMID:32114853 SUPPORT Human Clinical

"The widespread screening of patients with hypertension unveiled an increased prevalence of PA with normokalemic hypertension the prevailing phenotype."

Supports modelling potassium wasting as graded, with normokalemia the usual result rather than the exception.

Mineralocorticoid Receptor-Driven Tissue Inflammation and Oxidative Stress

Mineralocorticoid receptor activation in non-epithelial tissue, in the permissive setting of a high sodium intake, produces perivascular inflammation with monocyte and macrophage infiltration and induction of proinflammatory mediators in the heart and kidney. This is the arm of the disease that damages organs beyond what the blood pressure elevation alone accounts for.

infiltrating macrophage CL:0000235

inflammatory response GO:0006954 ↑ INCREASED leukocyte migration GO:0050900 ↑ INCREASED

Downstream

Myocardial and Renal Interstitial Fibrosis

Show evidence (2 references)

PMID:12384457 SUPPORT Model Organism

"However, histopathological analysis of the heart revealed severe coronary inflammatory lesions, which were characterized by monocyte/macrophage infiltration and resulted in focal ischemic and necrotic changes."

Documents the macrophage-infiltrate lesion this node describes, in an aldosterone-salt model.

PMID:12384457 SUPPORT Model Organism

"Eplerenone attenuated proinflammatory molecule expression in the rat heart and subsequent vascular and myocardial damage."

Mineralocorticoid receptor blockade attenuates the lesion, which attributes it to receptor activation rather than to the hypertension the model also produces.

Myocardial and Renal Interstitial Fibrosis

Persistent mineralocorticoid excess with adequate dietary sodium drives fibroblast activation and interstitial and perivascular collagen accumulation in the myocardium, and analogous matrix deposition in the kidney. Left ventricular hypertrophy accompanies it.

cardiac fibroblast CL:0002548

collagen fibril organization GO:0030199 ↑ INCREASED extracellular matrix organization GO:0030198 ↑ INCREASED

heart UBERON:0000948 kidney UBERON:0002113

Downstream

Left ventricular hypertrophy

Blood-Pressure-Independent Cardiovascular and Renal Injury

Show evidence (2 references)

PMID:1453111 SUPPORT Model Organism

"Thus, in the presence of enhanced sodium intake, chronic administration of ALDO or DOCA are associated with collagen accumulation in the myocardium"

Establishes mineralocorticoid excess plus sodium as sufficient for myocardial collagen accumulation.

PMID:1453111 SUPPORT Model Organism

"hypertension and left ventricular hypertrophy with all forms of mineralocorticoid excess"

Documents left ventricular hypertrophy accompanying the fibrotic response to mineralocorticoid excess.

Blood-Pressure-Independent Cardiovascular and Renal Injury

The cumulative result of mineralocorticoid-driven inflammation and fibrosis is an excess of stroke, coronary disease, atrial fibrillation, heart failure, albuminuria and glomerular filtration decline over what is seen in essential hypertension at the same blood pressure. The excess persists in patients treated with mineralocorticoid receptor antagonists whose renin stays suppressed, which is the strongest human evidence that the injury is receptor-driven and not simply haemodynamic.

Downstream

Stroke

Atrial fibrillation

Congestive heart failure

Albuminuria

Show evidence (3 references)

PMID:29129575 SUPPORT Human Clinical

"patients with primary aldosteronism had an increased risk of stroke (odds ratio [OR] 2·58, 95% CI 1·93-3·45), coronary artery disease (1·77, 1·10-2·83), atrial fibrillation (3·52, 2·06-5·99), and heart failure (2·05, 1·11-3·78)"

Quantifies the excess cardiovascular event risk relative to essential hypertension across 31 studies.

PMID:15837256 SUPPORT Human Clinical

"Patients presenting with PA experienced more cardiovascular events than did EHT patients independent of blood pressure."

States the blood-pressure-independence of the excess event rate in a blood-pressure-matched comparison.

PMID:29129576 SUPPORT Human Clinical

"The current practice of MR antagonist therapy in primary aldosteronism is associated with significantly higher risk for incident cardiometabolic events and death, independent of blood pressure control, than for patients with essential hypertension."

Shows the excess risk persisting under blood-pressure-controlled medical therapy, supporting a receptor-driven rather than purely haemodynamic mechanism.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 6

Hypertension HP:0000822

Show evidence (1 reference)

PMID:26815163 SUPPORT Human Clinical

"Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5-10% in unreferred hypertensive patients."

Establishes hypertension as the clinical context in which the disease is found and its share of hypertensive patients.

Resistant hypertension Hypertension resistant to conventional therapy HP:0430034

Show evidence (1 reference)

PMID:18539224 SUPPORT Human Clinical

"Patients with resistant hypertension (blood pressure >140/90 mm Hg despite a three drug regimen, including a diuretic) who attended our outpatient clinic were assessed for primary hyperaldosteronism."

Defines the resistant-hypertension population in which primary aldosteronism is concentrated.

Left ventricular hypertrophy HP:0001712

Show evidence (1 reference)

PMID:29129575 SUPPORT Human Clinical

"Similarly, primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17)."

Gives the pooled odds ratio for left ventricular hypertrophy against essential hypertension.

Stroke HP:0001297

Show evidence (2 references)

PMID:29129575 SUPPORT Human Clinical

Gives the pooled odds ratio for stroke.

PMID:15837256 SUPPORT Human Clinical

"A history of stroke was found in 12.9% of patients with PA and 3.4% of patients with EHT"

Gives the absolute stroke frequency against blood-pressure-matched essential hypertension.

Atrial fibrillation HP:0005110

Show evidence (1 reference)

PMID:15837256 SUPPORT Human Clinical

"A history of atrial fibrillation was diagnosed in 7.3% of patients with PA and 0.6% of patients with EHT"

Gives the atrial fibrillation frequency against blood-pressure-matched essential hypertension.

Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:29129575 SUPPORT Human Clinical

Gives the pooled odds ratio for heart failure.

Endocrine 4

Increased circulating aldosterone concentration HP:0000859

Show evidence (1 reference)

PMID:40658480 SUPPORT Human Clinical

"a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands"

The guideline identifies excess aldosterone production as the defining abnormality.

Decreased circulating renin concentration HP:0003351

Show evidence (1 reference)

PMID:40658480 SUPPORT Human Clinical

"In individuals receiving MRA therapy, we suggest monitoring renin and, in those whose hypertension remains uncontrolled and renin is suppressed, titrating the MRA to increase renin."

The guideline treats suppressed renin as the measurable marker of continued mineralocorticoid receptor activation.

Elevated aldosterone:renin ratio HP:6000318

Show evidence (1 reference)

PMID:40658480 SUPPORT Human Clinical

"We suggest that all individuals with hypertension be screened for PA by measuring aldosterone and renin and determining the aldosterone to renin ratio"

Establishes the aldosterone-to-renin ratio as the screening measurement in every hypertensive individual.

Diabetes mellitus HP:0000819

Show evidence (1 reference)

PMID:29129575 SUPPORT Human Clinical

"Similarly, primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17)."

Gives the pooled odds ratio for diabetes and metabolic syndrome.

Genitourinary 1

Albuminuria HP:0012592

Show evidence (2 references)

PMID:16772627 SUPPORT Human Clinical

"At baseline, glomerular filtration rate and albuminuria were higher in patients with primary aldosteronism than those with essential hypertension."

Documents higher albuminuria at baseline than in essential hypertension matched for hypertension severity and duration.

PMID:16772627 SUPPORT Human Clinical

"In the majority of patients in this study, primary aldosteronism was characterized by partially reversible renal dysfunction in which elevated albuminuria is a marker of a dynamic rather than structural renal defect."

Supports the reversibility qualifier in the description.

Metabolism 2

Hypokalemia HP:0002900

Show evidence (4 references)

PMID:15001583 SUPPORT Human Clinical

"Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA."

Records the historical assumption that this entry deliberately contradicts.

PMID:15001583 SUPPORT Human Clinical

"Only a small proportion of patients (between 9 and 37%) were hypokalemic."

Quantifies the minority of confirmed cases that are hypokalemic across five continents. This 9-37% range straddles the OCCASIONAL/FREQUENT boundary on its own, which is why the phenotype asserts no band.

PMID:18539224 SUPPORT Human Clinical

"Hypokalaemia was seen only in 83 patients with primary hyperaldosteronism (45.6%)."

An independent series showing fewer than half of confirmed cases were hypokalemic, the upper end of the reported range.

+ 1 more reference

Metabolic alkalosis HP:0200114

Show evidence (1 reference)

PMID:28844072 SUPPORT Human Clinical

"These disorders can lead to hypertension, hypokalemia, hypervolemia and metabolic alkalosis."

Names metabolic alkalosis directly as a consequence of the aldosterone excess in primary aldosteronism.

🧬

Genetic Associations

KCNJ5 (Most frequent somatic driver of aldosterone-producing adenoma)

Gene: KCNJ5 hgnc:6266 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:21311022 SUPPORT Human Clinical

"We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied."

The discovery study identifies recurrent somatic KCNJ5 mutations in human aldosterone-producing adenomas.

PMID:24866132 SUPPORT Human Clinical

"Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs."

Quantifies the KCNJ5 share of adenomas in an unselected multicentre cohort.

CACNA1D (Somatic gain-of-function driver of aldosterone-producing adenoma)

Gene: CACNA1D hgnc:1391 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:23913001 SUPPORT Human Clinical

"We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5."

Identifies somatic CACNA1D mutations specifically in adenomas lacking KCNJ5 mutations, establishing them as an alternative driver.

PMID:24866132 SUPPORT Human Clinical

"Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs."

Quantifies the CACNA1D share of adenomas in the unselected multicentre cohort.

ATP1A1 (Somatic driver of aldosterone-producing adenoma)

Gene: ATP1A1 hgnc:799 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23416519 SUPPORT Human Clinical

"We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively."

The discovery study identifies somatic ATP1A1 hotspot mutations in aldosterone-producing adenomas.

ATP2B3 (Somatic driver of aldosterone-producing adenoma)

Gene: ATP2B3 hgnc:816 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23416519 SUPPORT Human Clinical

"In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3."

Gives the frequency of ATP1A1 and ATP2B3 somatic mutations in a large adenoma collection.

CTNNB1 (Somatic activating driver acting through Wnt/beta-catenin rather than membrane depolarization)

Gene: CTNNB1 hgnc:2514 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:26815163 SUPPORT Human Clinical

"Somatic CTNNB1 mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D."

Establishes CTNNB1 as a driver that is mutually exclusive with the ion channel and pump drivers, which is why it is modelled as a parallel branch.

💊

Medical Actions

Laparoscopic Unilateral Adrenalectomy

Action: adrenalectomy Ontology label: Adrenalectomy NCIT:C15177

Platform: Surgery

Removal of the affected adrenal gland in disease that lateralizes on adrenal venous sampling. It is the only curative treatment. In the international PASO cohort, complete biochemical success was achieved in 94% of patients and complete clinical success, meaning normotension off all antihypertensive drugs, in 37%, with a further 47% achieving partial clinical success.

Mechanism Target:

INHIBITS Renin-Independent Aldosterone Excess — Excising the aldosterone-producing gland removes the source of autonomous aldosterone secretion.

Show evidence (1 reference)

PMID:28576687 SUPPORT Human Clinical

"Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients."

Quantifies biochemical remission of aldosterone excess after adrenalectomy, which is the direct evidence that surgery removes the mechanism.

Target Phenotypes: Hypertension HP:0000822 Hypokalemia HP:0002900

Show evidence (2 references)

PMID:26934393 SUPPORT Human Clinical

The guideline recommendation that ties laparoscopic adrenalectomy to sampling-confirmed lateralization.

PMID:28576687 SUPPORT Human Clinical

"Most patients derive clinical benefit from adrenalectomy, with younger patients and female patients more likely to have a favourable surgical outcome."

Supports the overall clinical benefit and identifies the predictors of a favourable outcome.

Mineralocorticoid Receptor Antagonist Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: spironolactone CHEBI:9241 eplerenone CHEBI:31547

Platform: Small molecule

Spironolactone or eplerenone is the disease-specific medical therapy, used for bilateral disease and for patients who are not surgical candidates. Spironolactone is preferred on cost and availability, and lowers blood pressure more than eplerenone at the doses compared in a randomized trial, at the price of antiandrogenic effects. The dose should be titrated until renin is no longer suppressed: the excess cardiovascular risk in medically treated patients is concentrated in those whose renin stays suppressed.

Mechanism Target:

INHIBITS Mineralocorticoid Receptor Overactivation in the Distal Nephron — Receptor blockade in the distal nephron reduces sodium reabsorption and potassium wasting.

Show evidence (1 reference)

PMID:21451421 SUPPORT Human Clinical

"The antihypertensive effect of spironolactone was significantly greater than that of eplerenone in hypertension associated with primary aldosteronism."

A randomized comparison establishing that mineralocorticoid receptor blockade lowers blood pressure in this disease and ranking the two agents.

INHIBITS Mineralocorticoid Receptor-Driven Tissue Inflammation and Oxidative Stress — Receptor blockade suppresses the non-epithelial inflammatory arm, shown directly in an aldosterone-salt model.

Show evidence (1 reference)

PMID:12384457 SUPPORT Model Organism

"Eplerenone attenuated proinflammatory molecule expression in the rat heart and subsequent vascular and myocardial damage."

Shows a mineralocorticoid receptor antagonist blocking the inflammatory and fibrotic tissue response to aldosterone.

Target Phenotypes: Hypertension HP:0000822 Hypokalemia HP:0002900

Show evidence (4 references)

PMID:40658480 SUPPORT Human Clinical

"We suggest the use of mineralocorticoid receptor antagonists (MRAs) over epithelial sodium-channel (ENaC) inhibitors in the medical treatment of PA."

The 2025 guideline recommendation placing mineralocorticoid receptor antagonists first among medical options.

PMID:40658480 SUPPORT Human Clinical

"We suggest the use of spironolactone over other MRAs, given its lower cost and greater availability"

Supports spironolactone as the preferred agent within the class.

PMID:29129576 SUPPORT Human Clinical

"patients who were treated with higher MR antagonist doses and had unsuppressed renin (≥1 μg/L per h) had no significant excess risk"

Supports titrating to an unsuppressed renin rather than to blood pressure alone.

+ 1 more reference

🔬

Biochemical Markers

Plasma aldosterone concentration (INCREASED)

Show evidence (1 reference)

PMID:40658480 SUPPORT Human Clinical

"excessive aldosterone production by one or both adrenal glands"

Supports elevated aldosterone as the defining biochemical abnormality.

Plasma renin (DECREASED)

Show evidence (1 reference)

PMID:29129576 SUPPORT Human Clinical

"Titration of MR antagonist therapy to raise renin might mitigate this excess risk."

Supports renin as the on-treatment biochemical target described in the note.

Serum potassium (DECREASED)

Show evidence (1 reference)

PMID:32114853 SUPPORT Human Clinical

"The widespread screening of patients with hypertension unveiled an increased prevalence of PA with normokalemic hypertension the prevailing phenotype."

Supports normokalemia as the prevailing phenotype and hypokalemia as the minority finding.

🔬

Diagnosis

Aldosterone-to-renin ratio screening

Measurement of plasma aldosterone and renin with calculation of their ratio. The 2025 Endocrine Society guideline extends this to all individuals with hypertension, replacing the earlier risk-stratified approach that reserved testing for resistant hypertension, hypokalemia, an adrenal incidentaloma, or a suggestive family history.

aldosterone-to-renin ratio measurement NCIT:C124338

Show evidence (3 references)

PMID:40658480 SUPPORT Human Clinical

"We suggest that all individuals with hypertension be screened for PA by measuring aldosterone and renin and determining the aldosterone to renin ratio"

The current recommendation for universal screening of hypertensive individuals.

PMID:26934393 SUPPORT Human Clinical

"For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions"

The earlier, risk-stratified version of the same screening recommendation, retained to document the change.

PMID:15001583 SUPPORT Human Clinical

"The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA."

Quantifies the diagnostic yield gained by ratio-based screening, which is the argument for broadening it.

Confirmatory aldosterone suppression testing

Demonstration that aldosterone is not suppressed by sodium loading or volume expansion, using an oral sodium loading, saline infusion, fludrocortisone suppression, or captopril challenge protocol. The 2025 guideline restricts confirmatory testing to intermediate-probability cases rather than requiring it of everyone who screens positive.

aldosterone suppression testing NCIT:C18020

Show evidence (2 references)

PMID:40658480 SUPPORT Human Clinical

"aldosterone suppression testing in situations when screening results indicate an intermediate probability for lateralizing PA and individualized decision making confirms a desire to pursue eligibility for surgical therapy"

States the current, narrowed indication for confirmatory testing.

PMID:32449886 SUPPORT Human Clinical

"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."

Describes the oral sodium suppression protocol as the confirmatory diagnostic, and is the study that showed how much disease ratio-first screening misses.

Adrenal venous sampling for lateralization

Bilateral catheterization of the adrenal veins to establish whether aldosterone secretion lateralizes, performed with adrenal CT before choosing between surgery and medical therapy. Its necessity in every case is genuinely contested: an outcome-based randomized trial found no difference at one year between CT-based and sampling-based management, while prevalence studies show that centres without sampling classify many more patients as bilateral.

adrenal venous sampling NCIT:C18020

Show evidence (4 references)

PMID:40658480 SUPPORT Human Clinical

"we suggest adrenal lateralization with computed tomography scanning and adrenal venous sampling prior to deciding the treatment approach"

The guideline recommendation pairing CT with adrenal venous sampling before the surgical-versus-medical decision.

PMID:17161262 SUPPORT Human Clinical

"There were more APA (62.5%) and fewer IHA cases (37.5%) at centers where AVS was available (p = 0.002); the opposite occurred where AVS was unavailable."

Shows that subtype assignment depends on whether sampling is available, which is the case for doing it.

PMID:27325147 REFUTE Human Clinical

"Treatment of primary aldosteronism based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1 year of follow-up."

The SPARTACUS trial found no one-year clinical advantage for sampling-based management, contradicting the claim that sampling is required in every case.

+ 1 more reference

Somatic tumour genotyping of resected adenoma

Sequencing of KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 in resected adenoma tissue. This is a research and prognostic assay rather than part of routine preoperative care, since the mutations are somatic and confined to the tumour.

molecular genetic analysis NCIT:C19770

Show evidence (1 reference)

PMID:24866132 SUPPORT Human Clinical

"Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to targeted treatment options."

States the prognostic and future-therapeutic rationale for genotyping, and by naming surrogate biomarkers as a goal makes clear it is not yet routine.

📊

Prevalence

Unreferred hypertensive patients

Point Prevalence 7500.0 per 100,000 (5000.0–10000.0) >1 in 1,000

Reported as 5-10% of unreferred hypertensive patients; recorded here as 5000-10000 per 100,000 of the hypertensive population, not of the general population.

Show evidence (1 reference)

PMID:26815163 SUPPORT Human Clinical

"Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5-10% in unreferred hypertensive patients."

States the 5-10% prevalence band among unreferred hypertensive patients that this record normalizes.

Newly diagnosed hypertensive patients referred to 14 Italian hypertension centres (PAPY study)

Point Prevalence 4800.0 per 100,000 >1 in 1,000 APA

4.8% of 1,125 newly diagnosed hypertensive patients with a conclusive diagnosis.

Show evidence (1 reference)

PMID:17161262 SUPPORT Human Clinical

"Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA."

The PAPY prospective cohort gives the subtype-resolved prevalence among newly diagnosed hypertensive patients.

Newly diagnosed hypertensive patients referred to 14 Italian hypertension centres (PAPY study)

Point Prevalence 6400.0 per 100,000 >1 in 1,000 BIH

6.4% of 1,125 newly diagnosed hypertensive patients with a conclusive diagnosis.

Show evidence (1 reference)

PMID:17161262 SUPPORT Human Clinical

"Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA."

Same PAPY cohort, idiopathic (bilateral) arm.

Patients with resistant hypertension attending a Greek outpatient hypertension clinic

Point Prevalence 11300.0 per 100,000 >1 in 1,000

182 of 1,616 patients with resistant hypertension, confirmed by salt suppression testing.

Show evidence (1 reference)

PMID:18539224 SUPPORT Human Clinical

"On the basis of salt suppression tests, 182 (11.3%) patients had primary hyperaldosteronism, and response to spironolactone treatment further confirmed this diagnosis."

A large single-clinic resistant-hypertension series, deliberately included alongside the higher US estimate because the authors argue the prevalence has been overstated.

US adults with treated resistant hypertension undergoing oral sodium suppression testing at 4 academic medical centres

Point Prevalence 22000.0 per 100,000 >1 in 1,000

22.0% adjusted prevalence of biochemically overt primary aldosteronism in resistant hypertension when every participant underwent confirmatory testing regardless of the aldosterone-renin ratio.

Show evidence (1 reference)

PMID:32449886 SUPPORT Human Clinical

"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%)"

Gives adjusted prevalence across normotension, stage 1, stage 2, and resistant hypertension; the final figure is the resistant-hypertension estimate recorded here.

⚖️

Clinical Burden

High

Untreated primary aldosteronism carries a two- to three-fold excess of stroke, atrial fibrillation and heart failure over essential hypertension at matched blood pressure, and an excess of albuminuria and glomerular filtration decline. The burden is compounded by the diagnostic gap: the disease is markedly underdiagnosed, so most affected people accrue that excess risk while being treated as though they had essential hypertension. It is graded HIGH rather than VARIABLE because the excess risk is present in both the surgically curable and the medically managed subtypes, with no difference between them in the pooled analysis.

Show evidence (3 references)

PMID:40658480 SUPPORT Human Clinical

"Despite effective methods for diagnosing and treating PA, it remains markedly underdiagnosed and undertreated."

Establishes the diagnostic and treatment gap that is a component of the burden assessment.

PMID:29129575 SUPPORT Human Clinical

"These results were consistent for patients with aldosterone-producing adenoma and bilateral adrenal hyperplasia, with no difference between these subgroups."

Supports grading the burden as HIGH across subtypes rather than VARIABLE, since the excess event risk did not differ between the lateralizing and bilateral forms.

PMID:32449886 SUPPORT Human Clinical

"The prevalence of primary aldosteronism is high and largely unrecognized."

Independent support for the under-recognition component of the burden.

🔬

Clinical Trials

NCT06164379

Head-to-head comparison of the non-steroidal mineralocorticoid receptor antagonist finerenone against spironolactone in hypertensive primary aldosteronism. Relevant because the entry curates MR antagonism as the medical arm of treatment without distinguishing steroidal from non-steroidal agents, and spironolactone's anti-androgenic effects are its principal tolerability limit.

Target Phenotypes: Hypertension HP:0000822

Show evidence (1 reference)

clinicaltrials:NCT06164379 SUPPORT Other

"To study the efficacy and safety of finerenone vs. spironolactone in patients with primary aldosteronism"

Registration record establishing an active comparison of MR antagonists in this disease.

NCT04007406 PHASE_II

Phase II study of DP13 in primary aldosteronism over an 8-week treatment period, evaluating efficacy, safety and tolerability.

Show evidence (1 reference)

clinicaltrials:NCT04007406 SUPPORT Other

"The purpose of the present phase II study is to determine whether DP13 displays the clinical safety and efficacy profile to support further development in patients with primary aldosteronism."

Registration record for an interventional phase II trial of a new agent in this disease.

NCT07137364 NOT_APPLICABLE

Observational study of spironolactone dosing and long-term cardiovascular outcomes in lateralized primary aldosteronism managed medically rather than surgically. Bears directly on the entry's lateralization subtypes, which are modelled because they decide surgical curability.

Target Phenotypes: Hypertension HP:0000822

Show evidence (1 reference)

clinicaltrials:NCT07137364 SUPPORT Other

"The goal of this observational study is to learn about the optimal dose of spironolactone treatment and the long-term outcomes on cardiovascular and cerebrovascular events in patients with lateralized PA who are unwilling to undergo surgery."

Registration record; the study population is lateralized disease treated medically, which the entry models as a subtype decision.

NCT06756737 NOT_APPLICABLE

Observational imaging study using 68Ga-Pentixafor and 68Ga-FAPI-04 PET/MR to subtype primary aldosteronism non-invasively and assess myocardial injury. Relevant to the entry's contested adrenal-vein-sampling material, since a non-invasive subtyping route is the alternative under investigation.

Show evidence (1 reference)

clinicaltrials:NCT06756737 SUPPORT Other

"identify primary aldosterone patients in need of adrenal surgery using non-invasive methods, while also assessing the degree of myocardial injury"

Registration record for a non-invasive subtyping approach, the alternative to adrenal vein sampling.

{ }

Source YAML

click to show

name: Primary Aldosteronism
category: Complex
creation_date: "2026-09-05T20:15:00Z"
synonyms:
- primary hyperaldosteronism
- Conn syndrome
- Conn's syndrome
- aldosteronism
- idiopathic hyperaldosteronism
description: >
  Primary aldosteronism is autonomous adrenocortical aldosterone production that
  is not suppressed by volume expansion and proceeds independently of the
  renin-angiotensin system. Somatic gain-of-function mutations in zona
  glomerulosa ion channels and pumps (KCNJ5, CACNA1D, ATP1A1, ATP2B3), and
  constitutive Wnt/beta-catenin signalling through CTNNB1, converge on cell
  depolarization, calcium entry, and transcription of aldosterone synthase
  (CYP11B2). The resulting mineralocorticoid receptor overactivation drives
  renal sodium retention, potassium and hydrogen ion wasting, and low-renin
  hypertension, together with cardiac, vascular, and renal inflammation and
  fibrosis that exceed what the blood pressure elevation alone predicts.
  Primary aldosteronism is the most common identifiable cause of secondary
  hypertension, is curable by adrenalectomy when aldosterone production
  lateralizes to one adrenal, and is markedly underdiagnosed.
disease_term:
  preferred_term: primary aldosteronism
  term:
    id: MONDO:0001422
    label: primary aldosteronism
parents:
- hyperaldosteronism
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:E26.0
      label: Primary hyperaldosteronism
    mapping_predicate: skos:exactMatch
    mapping_source: ICD10CM
    mapping_justification: >
      ICD-10-CM E26.0 is titled "Primary hyperaldosteronism" and covers the same
      concept as this entry.
  icd11f_mappings:
  - term:
      id: icd11f:100169070
      label: Nonfamilial primary hyperaldosteronism
    mapping_predicate: skos:narrowMatch
    mapping_source: ICD-11 Foundation
    mapping_justification: >
      Narrower, not exact: the ICD-11 Foundation term excludes the familial
      forms, which this entry cross-references rather than restates. The
      deep-research report proposed the ICD-11 stem code 5A11, but that CURIE
      does not resolve in the icd11f build, which keys terms by numeric
      identifier; it was not bound. This term was found by searching the build
      rather than taken from the report.
definitions:
- name: Scope of this entry
  definition_type: OTHER
  description: >
    This entry curates primary aldosteronism as a single disease with one
    pathophysiology: renin-independent aldosterone secretion from the adrenal
    zona glomerulosa and the mineralocorticoid receptor overactivation that
    follows. The lateralization axis (aldosterone-producing adenoma, unilateral
    adrenal hyperplasia, bilateral idiopathic hyperaldosteronism) is modelled in
    has_subtypes because it determines surgical curability. The inherited forms
    (familial hyperaldosteronism types I-IV) are curated separately in
    kb/disorders/Familial_Hyperaldosteronism.yaml and
    kb/disorders/Familial_Hyperaldosteronism_Type_I.yaml and are deliberately
    not restated here; the germline channel mechanisms described there converge
    on the same glomerulosa depolarization and calcium entry step modelled in
    this entry.
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands"
    explanation: The guideline defines primary aldosteronism as one adrenal disorder that may involve either or both glands, which is the unified disease concept this entry curates.
  - reference: PMID:15837256
    reference_title: Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two major PA subtypes are unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia."
    explanation: Supports treating lateralization as the principal subtype axis of a single disease rather than as separate diseases.
has_subtypes:
- name: APA
  display_name: Aldosterone-producing adenoma
  subtype_term:
    preferred_term: aldosterone-producing adenoma
    term:
      id: MONDO:0016505
      label: aldosterone-producing adrenal cortex adenoma
  description: >
    A solitary, usually benign adrenocortical adenoma that produces aldosterone
    autonomously. Aldosterone secretion lateralizes to the affected gland, so
    the disease is potentially curable by unilateral adrenalectomy. Most
    adenomas carry a somatic gain-of-function driver mutation in an ion channel
    or pump gene, or an activating CTNNB1 mutation.
  genes:
  - preferred_term: KCNJ5
    term:
      id: hgnc:6266
      label: KCNJ5
  - preferred_term: CACNA1D
    term:
      id: hgnc:1391
      label: CACNA1D
  - preferred_term: ATP1A1
    term:
      id: hgnc:799
      label: ATP1A1
  - preferred_term: ATP2B3
    term:
      id: hgnc:816
      label: ATP2B3
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  evidence:
  - reference: PMID:24866132
    reference_title: Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, recurrent somatic mutations were identified in 54% of APAs."
    explanation: The largest genotyped APA series establishes that recurrent somatic driver mutations account for the majority of adenomas in this subtype.
  - reference: PMID:28576687
    reference_title: "Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes."
    explanation: Supports surgical curability as the feature that distinguishes the lateralizing subtypes from bilateral disease.
- name: UAH
  display_name: Unilateral adrenal hyperplasia
  subtype_term:
    preferred_term: primary unilateral adrenal hyperplasia
    term:
      id: MONDO:0016504
      label: primary unilateral adrenal hyperplasia
  description: >
    Lateralized aldosterone excess arising from hyperplastic zona glomerulosa in
    one adrenal gland without a discrete adenoma. It behaves like an
    aldosterone-producing adenoma for management purposes: adrenal venous
    sampling shows lateralization and unilateral adrenalectomy is the treatment
    of choice.
  evidence:
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy."
    explanation: The guideline treats unilateral primary aldosteronism as a single management category defined by lateralization on adrenal venous sampling, which is what groups unilateral hyperplasia with adenoma.
- name: BIH
  display_name: Bilateral idiopathic hyperaldosteronism
  description: >
    Bilateral, non-lateralizing autonomous aldosterone production from both
    adrenal glands, historically called idiopathic hyperaldosteronism. It is not
    surgically curable and is managed with mineralocorticoid receptor
    antagonists. No MONDO term for this concept exists, so no subtype_term is
    bound.
  evidence:
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist."
    explanation: Establishes bilateral disease as the medically managed arm of the lateralization axis.
  - reference: PMID:17161262
    reference_title: "A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence of excess autonomous aldosterone secretion without such criteria led to a diagnosis of idiopathic hyperaldosteronism (IHA)."
    explanation: Gives the operational definition of idiopathic (bilateral) hyperaldosteronism used in prevalence studies.
clinical_burden:
  burden_level: HIGH
  rationale: >
    Untreated primary aldosteronism carries a two- to three-fold excess of
    stroke, atrial fibrillation and heart failure over essential hypertension at
    matched blood pressure, and an excess of albuminuria and glomerular
    filtration decline. The burden is compounded by the diagnostic gap: the
    disease is markedly underdiagnosed, so most affected people accrue that
    excess risk while being treated as though they had essential hypertension.
    It is graded HIGH rather than VARIABLE because the excess risk is present in
    both the surgically curable and the medically managed subtypes, with no
    difference between them in the pooled analysis.
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite effective methods for diagnosing and treating PA, it remains markedly underdiagnosed and undertreated."
    explanation: Establishes the diagnostic and treatment gap that is a component of the burden assessment.
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results were consistent for patients with aldosterone-producing adenoma and bilateral adrenal hyperplasia, with no difference between these subgroups."
    explanation: Supports grading the burden as HIGH across subtypes rather than VARIABLE, since the excess event risk did not differ between the lateralizing and bilateral forms.
  - reference: PMID:32449886
    reference_title: "The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of primary aldosteronism is high and largely unrecognized."
    explanation: Independent support for the under-recognition component of the burden.
prevalence:
- population: Unreferred hypertensive patients
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 7500.0
  rate_low: 5000.0
  rate_high: 10000.0
  rate_denominator: POPULATION
  notes: >
    Reported as 5-10% of unreferred hypertensive patients; recorded here as
    5000-10000 per 100,000 of the hypertensive population, not of the general
    population.
  evidence:
  - reference: PMID:26815163
    reference_title: Activating mutations in CTNNB1 in aldosterone producing adenomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5-10% in unreferred hypertensive patients."
    explanation: States the 5-10% prevalence band among unreferred hypertensive patients that this record normalizes.
- subtype: APA
  population: Newly diagnosed hypertensive patients referred to 14 Italian hypertension centres (PAPY study)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 4800.0
  rate_denominator: POPULATION
  notes: 4.8% of 1,125 newly diagnosed hypertensive patients with a conclusive diagnosis.
  evidence:
  - reference: PMID:17161262
    reference_title: "A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA."
    explanation: The PAPY prospective cohort gives the subtype-resolved prevalence among newly diagnosed hypertensive patients.
- subtype: BIH
  population: Newly diagnosed hypertensive patients referred to 14 Italian hypertension centres (PAPY study)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 6400.0
  rate_denominator: POPULATION
  notes: 6.4% of 1,125 newly diagnosed hypertensive patients with a conclusive diagnosis.
  evidence:
  - reference: PMID:17161262
    reference_title: "A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA."
    explanation: Same PAPY cohort, idiopathic (bilateral) arm.
- population: Patients with resistant hypertension attending a Greek outpatient hypertension clinic
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 11300.0
  rate_denominator: POPULATION
  notes: 182 of 1,616 patients with resistant hypertension, confirmed by salt suppression testing.
  evidence:
  - reference: PMID:18539224
    reference_title: "Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On the basis of salt suppression tests, 182 (11.3%) patients had primary hyperaldosteronism, and response to spironolactone treatment further confirmed this diagnosis."
    explanation: A large single-clinic resistant-hypertension series, deliberately included alongside the higher US estimate because the authors argue the prevalence has been overstated.
- population: US adults with treated resistant hypertension undergoing oral sodium suppression testing at 4 academic medical centres
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 22000.0
  rate_denominator: POPULATION
  notes: >
    22.0% adjusted prevalence of biochemically overt primary aldosteronism in
    resistant hypertension when every participant underwent confirmatory testing
    regardless of the aldosterone-renin ratio.
  evidence:
  - reference: PMID:32449886
    reference_title: "The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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%)"
    explanation: Gives adjusted prevalence across normotension, stage 1, stage 2, and resistant hypertension; the final figure is the resistant-hypertension estimate recorded here.
genetic:
- name: KCNJ5
  association: Most frequent somatic driver of aldosterone-producing adenoma
  subtype: APA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: KCNJ5
    term:
      id: hgnc:6266
      label: KCNJ5
  frequency: about 38% of aldosterone-producing adenomas in a European multicentre series
  notes: >
    Mutations in and near the selectivity filter of the Kir3.4 channel allow
    sodium conductance, depolarizing the glomerulosa cell. Germline KCNJ5
    variants cause familial hyperaldosteronism type III, curated in
    kb/disorders/Familial_Hyperaldosteronism.yaml.
  evidence:
  - reference: PMID:21311022
    reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied."
    explanation: The discovery study identifies recurrent somatic KCNJ5 mutations in human aldosterone-producing adenomas.
  - reference: PMID:24866132
    reference_title: Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs."
    explanation: Quantifies the KCNJ5 share of adenomas in an unselected multicentre cohort.
- name: CACNA1D
  association: Somatic gain-of-function driver of aldosterone-producing adenoma
  subtype: APA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: CACNA1D
    term:
      id: hgnc:1391
      label: CACNA1D
  frequency: about 9% of aldosterone-producing adenomas in a European multicentre series
  notes: >
    Substitutions in the pore-lining S6 segments of the CaV1.3 voltage-gated
    calcium channel shift activation to less depolarized potentials and, for
    Gly403 alterations, impair inactivation.
  evidence:
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5."
    explanation: Identifies somatic CACNA1D mutations specifically in adenomas lacking KCNJ5 mutations, establishing them as an alternative driver.
  - reference: PMID:24866132
    reference_title: Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs."
    explanation: Quantifies the CACNA1D share of adenomas in the unselected multicentre cohort.
- name: ATP1A1
  association: Somatic driver of aldosterone-producing adenoma
  subtype: APA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: ATP1A1
    term:
      id: hgnc:799
      label: ATP1A1
  frequency: about 5% of aldosterone-producing adenomas in a European multicentre series
  notes: >
    Hotspot mutations in the Na+/K+-ATPase alpha subunit cause loss of pump
    activity and strongly reduced potassium affinity, depolarizing the cell.
  evidence:
  - reference: PMID:23416519
    reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively."
    explanation: The discovery study identifies somatic ATP1A1 hotspot mutations in aldosterone-producing adenomas.
- name: ATP2B3
  association: Somatic driver of aldosterone-producing adenoma
  subtype: APA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: ATP2B3
    term:
      id: hgnc:816
      label: ATP2B3
  frequency: about 2% of aldosterone-producing adenomas in a European multicentre series
  notes: >
    In-frame deletions in the plasma membrane calcium ATPase disturb calcium
    extrusion and, like ATP1A1 mutations, produce inappropriate depolarization.
  evidence:
  - reference: PMID:23416519
    reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3."
    explanation: Gives the frequency of ATP1A1 and ATP2B3 somatic mutations in a large adenoma collection.
- name: CTNNB1
  association: Somatic activating driver acting through Wnt/beta-catenin rather than membrane depolarization
  subtype: APA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  frequency: about 5% of aldosterone-producing adenomas
  notes: >
    Exon 3 substitutions at the serine/threonine residues of the GSK3-beta
    binding domain stabilize beta-catenin. This is the one common driver class
    that does not act through the depolarization-calcium route.
  evidence:
  - reference: PMID:26815163
    reference_title: Activating mutations in CTNNB1 in aldosterone producing adenomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic CTNNB1 mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D."
    explanation: Establishes CTNNB1 as a driver that is mutually exclusive with the ion channel and pump drivers, which is why it is modelled as a parallel branch.
pathophysiology:
- name: Somatic Gain-of-Function Mutation in a Zona Glomerulosa Ion Channel or Pump
  description: >
    An acquired, tumour-restricted mutation in KCNJ5, CACNA1D, ATP1A1, or
    ATP2B3 alters ion handling in an adrenal zona glomerulosa cell. KCNJ5
    mutations near the channel selectivity filter admit sodium; ATP1A1 and
    ATP2B3 mutations disable the sodium/potassium and calcium pumps; CACNA1D
    mutations shift CaV1.3 activation to less depolarized potentials.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: KCNJ5
    term:
      id: hgnc:6266
      label: KCNJ5
  - preferred_term: CACNA1D
    term:
      id: hgnc:1391
      label: CACNA1D
  - preferred_term: ATP1A1
    term:
      id: hgnc:799
      label: ATP1A1
  - preferred_term: ATP2B3
    term:
      id: hgnc:816
      label: ATP2B3
  cell_types:
  - preferred_term: adrenal zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  locations:
  - preferred_term: zona glomerulosa
    term:
      id: UBERON:0002053
      label: zona glomerulosa of adrenal gland
  evidence:
  - reference: PMID:21311022
    reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied."
    explanation: Establishes the somatic ion-channel lesion as the initiating event in a substantial fraction of adenomas.
  - reference: PMID:23416519
    reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium."
    explanation: Gives the functional consequence of the pump mutations that constitutes this node.
  downstream:
  - target: Zona Glomerulosa Cell Depolarization and Calcium Entry
    causal_link_type: DIRECT
    description: Each driver class converges on depolarization or on direct enhancement of voltage-gated calcium entry.
    evidence:
    - reference: PMID:21311022
      reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both produce increased sodium (Na(+)) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca(2+)) entry, the signal for aldosterone production and cell proliferation."
      explanation: States the depolarization-to-calcium-entry step directly for the KCNJ5 driver class.
    - reference: PMID:23416519
      reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations."
      explanation: Extends the same depolarization step to the ATPase driver class in patient adenoma cells.
- name: Constitutive Wnt Signalling from Stabilized Beta-Catenin
  description: >
    Activating CTNNB1 exon 3 substitutions in the GSK3-beta binding domain
    prevent beta-catenin degradation, producing constitutive Wnt pathway
    activity. This branch is mutually exclusive with the ion channel and pump
    drivers and reaches aldosterone synthesis without passing through membrane
    depolarization.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  cell_types:
  - preferred_term: adrenal zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  locations:
  - preferred_term: zona glomerulosa
    term:
      id: UBERON:0002053
      label: zona glomerulosa of adrenal gland
  evidence:
  - reference: PMID:26815163
    reference_title: Activating mutations in CTNNB1 in aldosterone producing adenomas.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggesting activation of WNT signaling."
    explanation: Establishes beta-catenin stabilization and Wnt pathway output as the molecular consequence of the CTNNB1 mutations.
  downstream:
  - target: Clonal Expansion of Aldosterone-Producing Adrenocortical Cells
    causal_link_type: DIRECT
  - target: Autonomous CYP11B2 Expression and Aldosterone Synthesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Wnt/beta-catenin transcriptional programme acting on zona glomerulosa differentiation and steroidogenic gene expression
    description: CTNNB1-mutant adenomas retain aldosterone synthase expression and produce aldosterone.
    evidence:
    - reference: PMID:26815163
      reference_title: Activating mutations in CTNNB1 in aldosterone producing adenomas.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "By CYP11B2 mRNA expression, CYP11B2 protein expression, and direct measurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production."
      explanation: Confirms that the CTNNB1 branch reaches the same aldosterone-synthase output node.
- name: Zona Glomerulosa Cell Depolarization and Calcium Entry
  description: >
    Aberrant sodium influx, failed sodium and calcium extrusion, or a lowered
    activation threshold of CaV1.3 depolarize the glomerulosa cell membrane and
    open voltage-gated calcium channels. Sustained cytosolic calcium elevation
    is the convergence point at which every common driver class meets, and is
    the proximate signal for aldosterone synthesis and for proliferation.
  biological_scale: CELLULAR
  role: central_effector
  cell_types:
  - preferred_term: adrenal zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  locations:
  - preferred_term: zona glomerulosa
    term:
      id: UBERON:0002053
      label: zona glomerulosa of adrenal gland
  biological_processes:
  - preferred_term: membrane depolarization
    modifier: INCREASED
    term:
      id: GO:0051899
      label: membrane depolarization
  - preferred_term: calcium ion import across the plasma membrane
    modifier: INCREASED
    term:
      id: GO:0098703
      label: calcium ion import across plasma membrane
  evidence:
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa."
    explanation: States that increased calcium influx is a sufficient stimulus for aldosterone production, which is the claim this convergence node makes.
  downstream:
  - target: Autonomous CYP11B2 Expression and Aldosterone Synthesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26240369
      reference_title: Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PA-causing aldosterone-producing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression."
      explanation: States the calcium-to-CYP11B2 step explicitly as the route from altered calcium homeostasis to renin-independent aldosterone production.
  - target: Clonal Expansion of Aldosterone-Producing Adrenocortical Cells
    causal_link_type: DIRECT
- name: Clonal Expansion of Aldosterone-Producing Adrenocortical Cells
  description: >
    The same driver mutations that raise intracellular calcium, and the Wnt
    branch, also drive proliferation, producing an aldosterone-producing adenoma
    or hyperplastic glomerulosa tissue. Small subcapsular aldosterone-producing
    cell clusters carrying the same driver mutations are present in
    histologically normal adrenal glands, which is why the disease is best
    understood as a continuum rather than an all-or-nothing tumour event.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: adrenal zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  evidence:
  - reference: PMID:26240369
    reference_title: Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na(+)/(K+) transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue."
    explanation: Shows that aldosterone driver mutations are present in discrete expanded cell clusters within otherwise normal adrenal glands.
  - reference: PMID:21311022
    reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K+ channel selectivity in constitutive cell proliferation and hormone production."
    explanation: Links the same channel lesion to constitutive proliferation as well as to hormone production.
  downstream:
  - target: Autonomous CYP11B2 Expression and Aldosterone Synthesis
    causal_link_type: DIRECT
    description: Expansion of the aldosterone-competent cell population raises total aldosterone synthase output.
- name: Autonomous CYP11B2 Expression and Aldosterone Synthesis
  description: >
    Aldosterone synthase (CYP11B2) transcription becomes constitutive rather
    than being set by angiotensin II and extracellular potassium, so aldosterone
    synthesis proceeds irrespective of volume and renin status.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: adrenal zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  genes:
  - preferred_term: CYP11B2
    term:
      id: hgnc:2592
      label: CYP11B2
  biological_processes:
  - preferred_term: aldosterone biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0032342
      label: aldosterone biosynthetic process
  chemical_entities:
  - preferred_term: aldosterone
    term:
      id: CHEBI:27584
      label: aldosterone
  evidence:
  - reference: PMID:26240369
    reference_title: Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue."
    explanation: Identifies aldosterone synthase expression as the measured output of the aldosterone-producing lesion.
  downstream:
  - target: Renin-Independent Aldosterone Excess
    causal_link_type: DIRECT
- name: Renin-Independent Aldosterone Excess
  description: >
    Circulating aldosterone is inappropriately high for the prevailing sodium
    and volume status and is not suppressed by sodium loading. This is the
    biochemical definition of the disease and the single node that all upstream
    branches feed and all downstream consequences depend on.
  biological_scale: ORGANISM
  chemical_entities:
  - preferred_term: aldosterone
    term:
      id: CHEBI:27584
      label: aldosterone
  evidence:
  - reference: PMID:32449886
    reference_title: "The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease."
    explanation: States the renin-independent, non-suppressible character of aldosterone production that defines this node.
  downstream:
  - target: Mineralocorticoid Receptor Overactivation in the Distal Nephron
    causal_link_type: DIRECT
  - target: Mineralocorticoid Receptor-Driven Tissue Inflammation and Oxidative Stress
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12384457
      reference_title: Aldosterone induces a vascular inflammatory phenotype in the rat heart.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus aldosterone and salt treatment in uninephrectomized rats led to severe hypertension and the development of a vascular inflammatory phenotype in the heart, which may represent one mechanism by which aldosterone contributes to myocardial disease."
      explanation: Supports the edge from aldosterone excess to a tissue inflammatory phenotype, in an experimental system where aldosterone is the manipulated variable.
- name: Mineralocorticoid Receptor Overactivation in the Distal Nephron
  description: >
    Excess aldosterone occupies the mineralocorticoid receptor in principal
    cells of the distal nephron and collecting duct, increasing epithelial
    sodium channel activity and the electrochemical driving force for potassium
    and hydrogen ion secretion.
  biological_scale: TISSUE
  role: effector
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  cell_types:
  - preferred_term: renal principal cell
    term:
      id: CL:0005009
      label: renal principal cell
  biological_processes:
  - preferred_term: renal sodium ion absorption
    modifier: INCREASED
    term:
      id: GO:0070294
      label: renal sodium ion absorption
  chemical_entities:
  - preferred_term: aldosterone
    term:
      id: CHEBI:27584
      label: aldosterone
  evidence:
  - reference: PMID:32449886
    reference_title: "The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This renin-independent aldosterone production can cause hypertension, but interactions with the mineralocorticoid receptor also cause hypokalemia and increased risk for adverse cardiovascular outcomes"
    explanation: Attributes both the hypertensive and the potassium-wasting consequences to mineralocorticoid receptor interaction rather than to aldosterone concentration alone.
  downstream:
  - target: Sodium Retention and Extracellular Volume Expansion
    causal_link_type: DIRECT
  - target: Renal Potassium and Hydrogen Ion Wasting
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32449886
      reference_title: "The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "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."
      explanation: Shows kaliuresis and falling serum potassium tracking the severity of renin-independent aldosterone production across the blood pressure spectrum.
- name: Sodium Retention and Extracellular Volume Expansion
  description: >
    Sustained distal sodium reabsorption expands extracellular fluid volume,
    which raises blood pressure and, by the normal negative-feedback loop,
    suppresses renin release from the juxtaglomerular apparatus.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: renal sodium ion transport
    modifier: INCREASED
    term:
      id: GO:0003096
      label: renal sodium ion transport
  evidence:
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions"
    explanation: The aldosterone-renin ratio is the case-detection test precisely because volume expansion suppresses renin while aldosterone stays high, which is what this node asserts.
  downstream:
  - target: Suppression of Renin Release
    causal_link_type: DIRECT
  - target: Hypertension
    causal_link_type: DIRECT
- name: Suppression of Renin Release
  description: >
    Volume expansion suppresses juxtaglomerular renin secretion. The
    combination of suppressed renin with unsuppressed aldosterone produces the
    elevated aldosterone-to-renin ratio on which screening depends, and renin
    that stays suppressed on treatment marks residual, undertreated
    mineralocorticoid receptor activation.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:29129576
    reference_title: "Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the excess risk for cardiovascular events and mortality was limited to patients with primary aldosteronism whose renin activity remained suppressed"
    explanation: Shows that persistently suppressed renin marks continued mineralocorticoid receptor activation and carries the excess risk, which is the clinical significance of this node.
  downstream:
  - target: Elevated aldosterone:renin ratio
    causal_link_type: DIRECT
- name: Renal Potassium and Hydrogen Ion Wasting
  description: >
    Increased distal sodium reabsorption creates a lumen-negative potential that
    drives potassium and hydrogen ion secretion. Potassium wasting is graded
    rather than all-or-nothing, which is why most patients are normokalemic and
    hypokalemia marks the more severe end of the spectrum rather than being a
    diagnostic requirement.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: renal potassium excretion
    modifier: INCREASED
    term:
      id: GO:0036359
      label: renal potassium excretion
  evidence:
  - reference: PMID:32114853
    reference_title: Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension Unit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The widespread screening of patients with hypertension unveiled an increased prevalence of PA with normokalemic hypertension the prevailing phenotype."
    explanation: Supports modelling potassium wasting as graded, with normokalemia the usual result rather than the exception.
  downstream:
  - target: Hypokalemia
    causal_link_type: DIRECT
  - target: Metabolic alkalosis
    causal_link_type: DIRECT
- name: Mineralocorticoid Receptor-Driven Tissue Inflammation and Oxidative Stress
  description: >
    Mineralocorticoid receptor activation in non-epithelial tissue, in the
    permissive setting of a high sodium intake, produces perivascular
    inflammation with monocyte and macrophage infiltration and induction of
    proinflammatory mediators in the heart and kidney. This is the arm of the
    disease that damages organs beyond what the blood pressure elevation alone
    accounts for.
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Inflammatory Recruitment and Amplification"
  cell_types:
  - preferred_term: infiltrating macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: leukocyte migration
    modifier: INCREASED
    term:
      id: GO:0050900
      label: leukocyte migration
  evidence:
  - reference: PMID:12384457
    reference_title: Aldosterone induces a vascular inflammatory phenotype in the rat heart.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, histopathological analysis of the heart revealed severe coronary inflammatory lesions, which were characterized by monocyte/macrophage infiltration and resulted in focal ischemic and necrotic changes."
    explanation: Documents the macrophage-infiltrate lesion this node describes, in an aldosterone-salt model.
  - reference: PMID:12384457
    reference_title: Aldosterone induces a vascular inflammatory phenotype in the rat heart.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Eplerenone attenuated proinflammatory molecule expression in the rat heart and subsequent vascular and myocardial damage."
    explanation: Mineralocorticoid receptor blockade attenuates the lesion, which attributes it to receptor activation rather than to the hypertension the model also produces.
  downstream:
  - target: Myocardial and Renal Interstitial Fibrosis
    causal_link_type: DIRECT
- name: Myocardial and Renal Interstitial Fibrosis
  description: >
    Persistent mineralocorticoid excess with adequate dietary sodium drives
    fibroblast activation and interstitial and perivascular collagen
    accumulation in the myocardium, and analogous matrix deposition in the
    kidney. Left ventricular hypertrophy accompanies it.
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: INCREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  - preferred_term: extracellular matrix organization
    modifier: INCREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:1453111
    reference_title: Mineralocorticoid excess, dietary sodium, and myocardial fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, in the presence of enhanced sodium intake, chronic administration of ALDO or DOCA are associated with collagen accumulation in the myocardium"
    explanation: Establishes mineralocorticoid excess plus sodium as sufficient for myocardial collagen accumulation.
  - reference: PMID:1453111
    reference_title: Mineralocorticoid excess, dietary sodium, and myocardial fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "hypertension and left ventricular hypertrophy with all forms of mineralocorticoid excess"
    explanation: Documents left ventricular hypertrophy accompanying the fibrotic response to mineralocorticoid excess.
  downstream:
  - target: Left ventricular hypertrophy
    causal_link_type: DIRECT
  - target: Blood-Pressure-Independent Cardiovascular and Renal Injury
    causal_link_type: DIRECT
- name: Blood-Pressure-Independent Cardiovascular and Renal Injury
  description: >
    The cumulative result of mineralocorticoid-driven inflammation and fibrosis
    is an excess of stroke, coronary disease, atrial fibrillation, heart
    failure, albuminuria and glomerular filtration decline over what is seen in
    essential hypertension at the same blood pressure. The excess persists in
    patients treated with mineralocorticoid receptor antagonists whose renin
    stays suppressed, which is the strongest human evidence that the injury is
    receptor-driven and not simply haemodynamic.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with primary aldosteronism had an increased risk of stroke (odds ratio [OR] 2·58, 95% CI 1·93-3·45), coronary artery disease (1·77, 1·10-2·83), atrial fibrillation (3·52, 2·06-5·99), and heart failure (2·05, 1·11-3·78)"
    explanation: Quantifies the excess cardiovascular event risk relative to essential hypertension across 31 studies.
  - reference: PMID:15837256
    reference_title: Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients presenting with PA experienced more cardiovascular events than did EHT patients independent of blood pressure."
    explanation: States the blood-pressure-independence of the excess event rate in a blood-pressure-matched comparison.
  - reference: PMID:29129576
    reference_title: "Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The current practice of MR antagonist therapy in primary aldosteronism is associated with significantly higher risk for incident cardiometabolic events and death, independent of blood pressure control, than for patients with essential hypertension."
    explanation: Shows the excess risk persisting under blood-pressure-controlled medical therapy, supporting a receptor-driven rather than purely haemodynamic mechanism.
  downstream:
  - target: Stroke
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cerebrovascular remodelling and arterial stiffening
    - atrial fibrillation-related thromboembolism
  - target: Atrial fibrillation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - atrial fibrosis and left atrial structural remodelling
  - target: Congestive heart failure
    causal_link_type: DIRECT
  - target: Albuminuria
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16772627
      reference_title: Long-term renal outcomes in patients with primary aldosteronism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At baseline, glomerular filtration rate and albuminuria were higher in patients with primary aldosteronism than those with essential hypertension."
      explanation: Documents higher albuminuria in primary aldosteronism than in severity-matched essential hypertension.
phenotypes:
- category: Cardiovascular
  name: Hypertension
  description: >
    Hypertension is the near-universal presenting feature. Primary aldosteronism
    is the most common identifiable cause of secondary hypertension.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:26815163
    reference_title: Activating mutations in CTNNB1 in aldosterone producing adenomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5-10% in unreferred hypertensive patients."
    explanation: Establishes hypertension as the clinical context in which the disease is found and its share of hypertensive patients.
- category: Cardiovascular
  name: Resistant hypertension
  description: >
    Blood pressure uncontrolled on three or more antihypertensive drugs
    including a diuretic. Roughly one in ten to one in five such patients has
    primary aldosteronism, depending on how completely the cohort is tested.
  phenotype_term:
    preferred_term: Hypertension resistant to conventional therapy
    term:
      id: HP:0430034
      label: Hypertension resistant to conventional therapy
  evidence:
  - reference: PMID:18539224
    reference_title: "Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with resistant hypertension (blood pressure >140/90 mm Hg despite a three drug regimen, including a diuretic) who attended our outpatient clinic were assessed for primary hyperaldosteronism."
    explanation: Defines the resistant-hypertension population in which primary aldosteronism is concentrated.
- category: Endocrine
  name: Increased circulating aldosterone concentration
  description: >
    Aldosterone is elevated relative to renin and to volume status and is not
    suppressed by sodium loading.
  phenotype_term:
    preferred_term: Increased circulating aldosterone concentration
    term:
      id: HP:0000859
      label: Increased circulating aldosterone concentration
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands"
    explanation: The guideline identifies excess aldosterone production as the defining abnormality.
- category: Endocrine
  name: Decreased circulating renin concentration
  description: >
    Renin is suppressed by aldosterone-driven volume expansion. Renin that
    remains suppressed during mineralocorticoid receptor antagonist therapy
    marks incomplete treatment.
  phenotype_term:
    preferred_term: Decreased circulating renin concentration
    term:
      id: HP:0003351
      label: Decreased circulating renin concentration
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In individuals receiving MRA therapy, we suggest monitoring renin and, in those whose hypertension remains uncontrolled and renin is suppressed, titrating the MRA to increase renin."
    explanation: The guideline treats suppressed renin as the measurable marker of continued mineralocorticoid receptor activation.
- category: Laboratory
  name: Elevated aldosterone:renin ratio
  description: >
    The ratio of plasma aldosterone to renin is the screening test for the
    disease, because it captures the two halves of the biochemical signature at
    once.
  diagnostic: true
  phenotype_term:
    preferred_term: Elevated aldosterone:renin ratio
    term:
      id: HP:6000318
      label: Elevated aldosterone:renin ratio
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that all individuals with hypertension be screened for PA by measuring aldosterone and renin and determining the aldosterone to renin ratio"
    explanation: Establishes the aldosterone-to-renin ratio as the screening measurement in every hypertensive individual.
- category: Biochemical
  name: Hypokalemia
  description: >
    Hypokalemia is NOT required for the diagnosis and is absent in most patients.
    Historically it was treated as a prerequisite for testing, which is a
    principal reason the disease is underdiagnosed. Series that screen
    systematically find hypokalemia in roughly 9-46% of confirmed cases, and
    normokalemic hypertension is the prevailing phenotype. When hypokalemia is
    present it is a marker of severity: among hypertensive patients with
    spontaneous potassium below 2.5 mmol/L, most have primary aldosteronism.

    No frequency band is asserted. The reported range spans roughly 9-46%
    across series, which straddles the OCCASIONAL (5-29%) and FREQUENT
    (30-79%) boundary, and the spread reflects how each cohort was
    ascertained rather than sampling error: series that screen every
    hypertensive patient report far less hypokalemia than referral series do.
    Choosing either band would assert a precision the literature does not
    support.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:15001583
    reference_title: "Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA."
    explanation: Records the historical assumption that this entry deliberately contradicts.
  - reference: PMID:15001583
    reference_title: "Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only a small proportion of patients (between 9 and 37%) were hypokalemic."
    explanation: >-
      Quantifies the minority of confirmed cases that are hypokalemic across
      five continents. This 9-37% range straddles the OCCASIONAL/FREQUENT
      boundary on its own, which is why the phenotype asserts no band.
  - reference: PMID:18539224
    reference_title: "Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypokalaemia was seen only in 83 patients with primary hyperaldosteronism (45.6%)."
    explanation: An independent series showing fewer than half of confirmed cases were hypokalemic, the upper end of the reported range.
  - reference: PMID:32114853
    reference_title: Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension Unit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of PA in patients with hypokalemia was 28.1% and increased with decreasing potassium concentrations up to 88.5% of patients with spontaneous hypokalemia and potassium concentrations <2.5 mmol/L."
    explanation: Supports hypokalemia as a severity marker and a strong indication to test, even though it is not required for the diagnosis.
- category: Biochemical
  name: Metabolic alkalosis
  description: >
    Distal hydrogen ion secretion accompanying sodium reabsorption produces a
    metabolic alkalosis, classically together with hypokalemia.
  phenotype_term:
    preferred_term: Metabolic alkalosis
    term:
      id: HP:0200114
      label: Metabolic alkalosis
  evidence:
  - reference: PMID:28844072
    reference_title: Update in diagnosis and management of primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These disorders can lead to hypertension, hypokalemia, hypervolemia and metabolic alkalosis."
    explanation: Names metabolic alkalosis directly as a consequence of the aldosterone excess in primary aldosteronism.
- category: Cardiovascular
  name: Left ventricular hypertrophy
  description: >
    Left ventricular hypertrophy is more frequent in primary aldosteronism than
    in essential hypertension at comparable blood pressure.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17)."
    explanation: Gives the pooled odds ratio for left ventricular hypertrophy against essential hypertension.
- category: Neurological
  name: Stroke
  description: >
    Stroke is the target-organ complication with the largest relative excess
    over essential hypertension.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with primary aldosteronism had an increased risk of stroke (odds ratio [OR] 2·58, 95% CI 1·93-3·45), coronary artery disease (1·77, 1·10-2·83), atrial fibrillation (3·52, 2·06-5·99), and heart failure (2·05, 1·11-3·78)"
    explanation: Gives the pooled odds ratio for stroke.
  - reference: PMID:15837256
    reference_title: Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A history of stroke was found in 12.9% of patients with PA and 3.4% of patients with EHT"
    explanation: Gives the absolute stroke frequency against blood-pressure-matched essential hypertension.
- category: Cardiovascular
  name: Atrial fibrillation
  description: >
    Atrial fibrillation occurs several times more often than in essential
    hypertension and is attributed to atrial structural remodelling.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:15837256
    reference_title: Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A history of atrial fibrillation was diagnosed in 7.3% of patients with PA and 0.6% of patients with EHT"
    explanation: Gives the atrial fibrillation frequency against blood-pressure-matched essential hypertension.
- category: Cardiovascular
  name: Congestive heart failure
  description: >
    Heart failure is part of the excess cardiovascular event burden and follows
    the hypertrophic and fibrotic remodelling of the left ventricle.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with primary aldosteronism had an increased risk of stroke (odds ratio [OR] 2·58, 95% CI 1·93-3·45), coronary artery disease (1·77, 1·10-2·83), atrial fibrillation (3·52, 2·06-5·99), and heart failure (2·05, 1·11-3·78)"
    explanation: Gives the pooled odds ratio for heart failure.
- category: Renal
  name: Albuminuria
  description: >
    Albuminuria is higher than in severity-matched essential hypertension and
    falls after treatment, indicating a largely functional rather than fixed
    structural glomerular lesion in most patients.
  phenotype_term:
    preferred_term: Albuminuria
    term:
      id: HP:0012592
      label: Albuminuria
  evidence:
  - reference: PMID:16772627
    reference_title: Long-term renal outcomes in patients with primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At baseline, glomerular filtration rate and albuminuria were higher in patients with primary aldosteronism than those with essential hypertension."
    explanation: Documents higher albuminuria at baseline than in essential hypertension matched for hypertension severity and duration.
  - reference: PMID:16772627
    reference_title: Long-term renal outcomes in patients with primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the majority of patients in this study, primary aldosteronism was characterized by partially reversible renal dysfunction in which elevated albuminuria is a marker of a dynamic rather than structural renal defect."
    explanation: Supports the reversibility qualifier in the description.
- category: Metabolic
  name: Diabetes mellitus
  description: >
    Diabetes and the metabolic syndrome are modestly more frequent than in
    essential hypertension.
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17)."
    explanation: Gives the pooled odds ratio for diabetes and metabolic syndrome.
biochemical:
- name: Plasma aldosterone concentration
  presence: INCREASED
  notes: Elevated and not suppressed by sodium loading or volume expansion.
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "excessive aldosterone production by one or both adrenal glands"
    explanation: Supports elevated aldosterone as the defining biochemical abnormality.
- name: Plasma renin
  presence: DECREASED
  notes: >
    Suppressed by volume expansion. Renin is also the treatment target on
    mineralocorticoid receptor antagonist therapy: a renin that stays suppressed
    identifies undertreatment.
  evidence:
  - reference: PMID:29129576
    reference_title: "Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Titration of MR antagonist therapy to raise renin might mitigate this excess risk."
    explanation: Supports renin as the on-treatment biochemical target described in the note.
- name: Serum potassium
  presence: DECREASED
  notes: >
    Low in a minority of patients. Normokalemia is the usual presentation, so a
    normal potassium does not exclude the diagnosis.
  evidence:
  - reference: PMID:32114853
    reference_title: Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension Unit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The widespread screening of patients with hypertension unveiled an increased prevalence of PA with normokalemic hypertension the prevailing phenotype."
    explanation: Supports normokalemia as the prevailing phenotype and hypokalemia as the minority finding.
treatments:
- name: Laparoscopic Unilateral Adrenalectomy
  description: >
    Removal of the affected adrenal gland in disease that lateralizes on adrenal
    venous sampling. It is the only curative treatment. In the international
    PASO cohort, complete biochemical success was achieved in 94% of patients
    and complete clinical success, meaning normotension off all antihypertensive
    drugs, in 37%, with a further 47% achieving partial clinical success.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: adrenalectomy
    term:
      id: NCIT:C15177
      label: Adrenalectomy
  target_mechanisms:
  - target: Renin-Independent Aldosterone Excess
    treatment_effect: INHIBITS
    description: Excising the aldosterone-producing gland removes the source of autonomous aldosterone secretion.
    evidence:
    - reference: PMID:28576687
      reference_title: "Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients."
      explanation: Quantifies biochemical remission of aldosterone excess after adrenalectomy, which is the direct evidence that surgery removes the mechanism.
  target_phenotypes:
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  - preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy."
    explanation: The guideline recommendation that ties laparoscopic adrenalectomy to sampling-confirmed lateralization.
  - reference: PMID:28576687
    reference_title: "Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients derive clinical benefit from adrenalectomy, with younger patients and female patients more likely to have a favourable surgical outcome."
    explanation: Supports the overall clinical benefit and identifies the predictors of a favourable outcome.
- name: Mineralocorticoid Receptor Antagonist Therapy
  description: >
    Spironolactone or eplerenone is the disease-specific medical therapy, used
    for bilateral disease and for patients who are not surgical candidates.
    Spironolactone is preferred on cost and availability, and lowers blood
    pressure more than eplerenone at the doses compared in a randomized trial,
    at the price of antiandrogenic effects. The dose should be titrated until
    renin is no longer suppressed: the excess cardiovascular risk in medically
    treated patients is concentrated in those whose renin stays suppressed.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: spironolactone
      term:
        id: CHEBI:9241
        label: spironolactone
    - preferred_term: eplerenone
      term:
        id: CHEBI:31547
        label: eplerenone
  target_mechanisms:
  - target: Mineralocorticoid Receptor Overactivation in the Distal Nephron
    treatment_effect: INHIBITS
    description: Receptor blockade in the distal nephron reduces sodium reabsorption and potassium wasting.
    evidence:
    - reference: PMID:21451421
      reference_title: "A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The antihypertensive effect of spironolactone was significantly greater than that of eplerenone in hypertension associated with primary aldosteronism."
      explanation: A randomized comparison establishing that mineralocorticoid receptor blockade lowers blood pressure in this disease and ranking the two agents.
  - target: Mineralocorticoid Receptor-Driven Tissue Inflammation and Oxidative Stress
    treatment_effect: INHIBITS
    description: Receptor blockade suppresses the non-epithelial inflammatory arm, shown directly in an aldosterone-salt model.
    evidence:
    - reference: PMID:12384457
      reference_title: Aldosterone induces a vascular inflammatory phenotype in the rat heart.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Eplerenone attenuated proinflammatory molecule expression in the rat heart and subsequent vascular and myocardial damage."
      explanation: Shows a mineralocorticoid receptor antagonist blocking the inflammatory and fibrotic tissue response to aldosterone.
  target_phenotypes:
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  - preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest the use of mineralocorticoid receptor antagonists (MRAs) over epithelial sodium-channel (ENaC) inhibitors in the medical treatment of PA."
    explanation: The 2025 guideline recommendation placing mineralocorticoid receptor antagonists first among medical options.
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest the use of spironolactone over other MRAs, given its lower cost and greater availability"
    explanation: Supports spironolactone as the preferred agent within the class.
  - reference: PMID:29129576
    reference_title: "Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients who were treated with higher MR antagonist doses and had unsuppressed renin (≥1 μg/L per h) had no significant excess risk"
    explanation: Supports titrating to an unsuppressed renin rather than to blood pressure alone.
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist."
    explanation: Identifies the patient groups for whom this is the primary treatment.
diagnosis:
- name: Aldosterone-to-renin ratio screening
  diagnosis_term:
    preferred_term: aldosterone-to-renin ratio measurement
    term:
      id: NCIT:C124338
      label: Aldosterone to Renin Activity Ratio Measurement
  description: >
    Measurement of plasma aldosterone and renin with calculation of their ratio.
    The 2025 Endocrine Society guideline extends this to all individuals with
    hypertension, replacing the earlier risk-stratified approach that reserved
    testing for resistant hypertension, hypokalemia, an adrenal incidentaloma,
    or a suggestive family history.
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that all individuals with hypertension be screened for PA by measuring aldosterone and renin and determining the aldosterone to renin ratio"
    explanation: The current recommendation for universal screening of hypertensive individuals.
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions"
    explanation: The earlier, risk-stratified version of the same screening recommendation, retained to document the change.
  - reference: PMID:15001583
    reference_title: "Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA."
    explanation: Quantifies the diagnostic yield gained by ratio-based screening, which is the argument for broadening it.
- name: Confirmatory aldosterone suppression testing
  diagnosis_term:
    preferred_term: aldosterone suppression testing
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >
    Demonstration that aldosterone is not suppressed by sodium loading or volume
    expansion, using an oral sodium loading, saline infusion, fludrocortisone
    suppression, or captopril challenge protocol. The 2025 guideline restricts
    confirmatory testing to intermediate-probability cases rather than requiring
    it of everyone who screens positive.
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "aldosterone suppression testing in situations when screening results indicate an intermediate probability for lateralizing PA and individualized decision making confirms a desire to pursue eligibility for surgical therapy"
    explanation: States the current, narrowed indication for confirmatory testing.
  - reference: PMID:32449886
    reference_title: "The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Describes the oral sodium suppression protocol as the confirmatory diagnostic, and is the study that showed how much disease ratio-first screening misses.
- name: Adrenal venous sampling for lateralization
  diagnosis_term:
    preferred_term: adrenal venous sampling
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >
    Bilateral catheterization of the adrenal veins to establish whether
    aldosterone secretion lateralizes, performed with adrenal CT before choosing
    between surgery and medical therapy. Its necessity in every case is
    genuinely contested: an outcome-based randomized trial found no difference
    at one year between CT-based and sampling-based management, while
    prevalence studies show that centres without sampling classify many more
    patients as bilateral.
  evidence:
  - reference: PMID:40658480
    reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we suggest adrenal lateralization with computed tomography scanning and adrenal venous sampling prior to deciding the treatment approach"
    explanation: The guideline recommendation pairing CT with adrenal venous sampling before the surgical-versus-medical decision.
  - reference: PMID:17161262
    reference_title: "A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were more APA (62.5%) and fewer IHA cases (37.5%) at centers where AVS was available (p = 0.002); the opposite occurred where AVS was unavailable."
    explanation: Shows that subtype assignment depends on whether sampling is available, which is the case for doing it.
  - reference: PMID:27325147
    reference_title: "Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of primary aldosteronism based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1 year of follow-up."
    explanation: The SPARTACUS trial found no one-year clinical advantage for sampling-based management, contradicting the claim that sampling is required in every case.
  - reference: PMID:27325147
    reference_title: "Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemically, 37 (80%) of patients with CT-based adrenalectomy and 41 (89%) of those with AVS-based adrenalectomy had resolved hyperaldosteronism (p=0.25)."
    explanation: The same trial's biochemical outcomes numerically favour sampling without reaching significance, which is why the question is contested rather than settled.
- name: Somatic tumour genotyping of resected adenoma
  diagnosis_term:
    preferred_term: molecular genetic analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >
    Sequencing of KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 in resected adenoma
    tissue. This is a research and prognostic assay rather than part of routine
    preoperative care, since the mutations are somatic and confined to the
    tumour.
  evidence:
  - reference: PMID:24866132
    reference_title: Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to targeted treatment options."
    explanation: States the prognostic and future-therapeutic rationale for genotyping, and by naming surrogate biomarkers as a goal makes clear it is not yet routine.
clinical_trials:
- name: NCT06164379
  description: >
    Head-to-head comparison of the non-steroidal mineralocorticoid receptor
    antagonist finerenone against spironolactone in hypertensive primary
    aldosteronism. Relevant because the entry curates MR antagonism as the
    medical arm of treatment without distinguishing steroidal from
    non-steroidal agents, and spironolactone's anti-androgenic effects are its
    principal tolerability limit.
  target_phenotypes:
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: clinicaltrials:NCT06164379
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To study the efficacy and safety of finerenone vs. spironolactone in patients with primary aldosteronism"
    explanation: Registration record establishing an active comparison of MR antagonists in this disease.
- name: NCT04007406
  phase: PHASE_II
  description: >
    Phase II study of DP13 in primary aldosteronism over an 8-week treatment
    period, evaluating efficacy, safety and tolerability.
  evidence:
  - reference: clinicaltrials:NCT04007406
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The purpose of the present phase II study is to determine whether DP13 displays the clinical safety and efficacy profile to support further development in patients with primary aldosteronism."
    explanation: Registration record for an interventional phase II trial of a new agent in this disease.
- name: NCT07137364
  phase: NOT_APPLICABLE
  description: >
    Observational study of spironolactone dosing and long-term cardiovascular
    outcomes in lateralized primary aldosteronism managed medically rather than
    surgically. Bears directly on the entry's lateralization subtypes, which are
    modelled because they decide surgical curability.
  target_phenotypes:
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: clinicaltrials:NCT07137364
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The goal of this observational study is to learn about the optimal dose of spironolactone treatment and the long-term outcomes on cardiovascular and cerebrovascular events in patients with lateralized PA who are unwilling to undergo surgery."
    explanation: Registration record; the study population is lateralized disease treated medically, which the entry models as a subtype decision.
- name: NCT06756737
  phase: NOT_APPLICABLE
  description: >
    Observational imaging study using 68Ga-Pentixafor and 68Ga-FAPI-04 PET/MR to
    subtype primary aldosteronism non-invasively and assess myocardial injury.
    Relevant to the entry's contested adrenal-vein-sampling material, since a
    non-invasive subtyping route is the alternative under investigation.
  evidence:
  - reference: clinicaltrials:NCT06756737
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "identify primary aldosterone patients in need of adrenal surgery using non-invasive methods, while also assessing the degree of myocardial injury"
    explanation: Registration record for a non-invasive subtyping approach, the alternative to adrenal vein sampling.
  notes: >
    NCT05432167 was considered and deliberately excluded. The deep-research
    report and a PR review both list it as a primary aldosteronism trial, but
    its own registration title is "...to Evaluate CIN-107 for the Treatment of
    Patients With Uncontrolled Hypertension and Chronic Kidney Disease" and its
    summary names uncontrolled hypertension and CKD as the population. It is an
    aldosterone synthase inhibitor trial in a different indication. The
    identifier resolves cleanly, which is exactly why it needed reading rather
    than trusting.
references:
- reference: PMID:40658480
  title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
- reference: PMID:15837256
  title: Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism.
- reference: PMID:24866132
  title: Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma.
- reference: PMID:28576687
  title: "Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort."
- reference: PMID:26934393
  title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
- reference: PMID:17161262
  title: "A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients."
- reference: PMID:29129575
  title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
- reference: PMID:32449886
  title: "The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study."
- reference: PMID:26815163
  title: Activating mutations in CTNNB1 in aldosterone producing adenomas.
- reference: PMID:18539224
  title: "Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study."
- reference: PMID:21311022
  title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
- reference: PMID:23913001
  title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
- reference: PMID:23416519
  title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
- reference: PMID:26240369
  title: Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands.
- reference: PMID:12384457
  title: Aldosterone induces a vascular inflammatory phenotype in the rat heart.
- reference: PMID:29129576
  title: "Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study."
- reference: PMID:32114853
  title: Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension Unit.
- reference: PMID:1453111
  title: "Mineralocorticoid excess, dietary sodium, and myocardial fibrosis."
- reference: PMID:16772627
  title: Long-term renal outcomes in patients with primary aldosteronism.
- reference: PMID:15001583
  title: "Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents."
- reference: PMID:28844072
  title: Update in diagnosis and management of primary aldosteronism.
- reference: PMID:21451421
  title: "A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism."
- reference: PMID:27325147
  title: "Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial."
- reference: clinicaltrials:NCT06164379
  title: "A Double-blind, Randomized Controlled Study of Finerenone vs. Spironolactone in Hypertensive Patients With Primary Aldosteronism"
- reference: clinicaltrials:NCT04007406
  title: "DP13 - A Phase II Study in Patients With Primary Aldosteronism to Evaluate the Efficacy, Safety and Tolerability of DP13, Over an 8-week Treatment Period"
- reference: clinicaltrials:NCT07137364
  title: Efficacy of Spironolactone Combined With Antihypertensive Drugs in Patients With Primary Aldosteronism
- reference: clinicaltrials:NCT06756737
  title: The Application of 68Ga-Pentixafor Alongside 68Ga-FAPI-04 PET/MR for Assessing Primary Aldosteronism.
notes: >
  Entry-type decision. Curated as a single DISEASE rather than a Grouping,
  despite MONDO:0001422 having nine descendants, because every recognized form
  runs through one pathophysiology: renin-independent aldosterone secretion from
  the zona glomerulosa, mineralocorticoid receptor overactivation, and the
  renal, cardiac and vascular consequences that follow. The somatic drivers
  KCNJ5, CACNA1D, ATP1A1 and ATP2B3 converge on glomerulosa depolarization and
  calcium entry, and the germline channel defects behind familial
  hyperaldosteronism types II to IV converge on the same step. The MONDO
  descendants split along two axes that are handled without splitting the
  disease: lateralization, modelled in has_subtypes because it decides surgical
  curability, and germline cause, which is curated in
  kb/disorders/Familial_Hyperaldosteronism.yaml and
  kb/disorders/Familial_Hyperaldosteronism_Type_I.yaml. See issue #11163.

  Deliberately out of scope here. Familial hyperaldosteronism types I-IV and
  the CACNA1D-related PASNA syndrome are not restated; the two familial entries
  carry them. Aldosterone synthase inhibitors (baxdrostat, lorundrostat) are a
  real emerging drug class that acts upstream of the mineralocorticoid receptor,
  but the primary-aldosteronism-specific evidence available at curation time was
  a research letter with no fetchable abstract, so no treatment entry was
  created for them; this is a gap to fill, not a judgement that the class is
  unimportant.

  Not curated for lack of a quotable source. Hypokalemia-related neuromuscular
  symptoms (weakness, cramping, periodic paralysis) are a real part of the
  clinical picture, but no source was found that states them for primary
  aldosteronism in a quotable sentence. The obvious candidate, PMID:25430699,
  is a hypokalaemic-paralysis case whose abstract says the patient "had not
  developed primary aldosteronism", so it was rejected. The phenotype is left
  out rather than attached to an inferential quote.

  Contested content kept as such. The necessity of adrenal venous sampling in
  every surgical candidate is recorded with evidence on both sides, including a
  REFUTE item from the SPARTACUS randomized trial, rather than resolved in
  favour of the guideline. Prevalence in resistant hypertension is likewise
  recorded twice, at 11.3% from a large single-clinic series whose authors argue
  against an "epidemic" and at 22.0% from a US study that tested every
  participant regardless of the aldosterone-renin ratio; the two disagree about
  case definition, not about arithmetic.

  Curation inputs. Deep research was run with the claude_code provider
  (research/Primary_Aldosteronism-deep-research-claude_code.md; 46/46 citations
  resolved, no confabulated identifiers, four report quotes unverified and one
  off-topic identifier). Every reference cited in this entry was independently
  located in PubMed, fetched with just fetch-reference, and read before use; no
  identifier was taken from the report on trust.

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