This hormonal imbalance leads to

• Enhanced sodium reabsorption through amiloride-sensitive epithelial sodium channels (ENaC) in the distal nephron, resulting in extracellular volume expansion and hypertension.
• Suppressed renin activity, producing a characteristic biochemical pattern of high aldosterone and low renin.
• Renal potassium and hydrogen ion excretion, which may cause hypokalaemia and metabolic alkalosis when aldosterone excess is sustained and severe.

Genetic and Familial Causes

Familial Hyperaldosteronism Type I (FH-I)

• Also known as glucocorticoid-remediable aldosteronism (GRA).
• Caused by a chimeric gene combining the promoter of the CYP11B1 gene with the coding region of the CYP11B2 gene, rendering aldosterone synthesis responsive to ACTH.
• Hypertension can be effectively managed with low-dose glucocorticoids.

Familial Hyperaldosteronism Type II (FH-II)

• Originally a clinical descriptor for non-glucocorticoid-remediable familial cases.
• Now associated with germline mutations in CLCN2.
• Typically presents before age 20, often with mild aldosterone excess and no clear adrenal abnormalities on imaging.

Familial Hyperaldosteronism Type III (FH-III)

• Linked to germline mutations in KCNJ5, encoding an inwardly rectifying potassium channel.
• Causes early-onset and sometimes severe PA due to disrupted ion selectivity and increased calcium influx stimulating aldosterone production.

Familial Hyperaldosteronism Type IV (FH-IV)

• Associated with mutations in CACNA1H, which encodes a voltage-gated calcium channel.
• Onset typically occurs before the age of 10 and can run in families.

Familial Hyperaldosteronism with Neurological Features (PASNA or FH-V)

• Caused by mutations in CACNA1D.
• Presents with early-onset PA and may include seizures and neurodevelopmental abnormalities.

Sporadic Forms and Somatic Mutations

• Somatic mutations in genes regulating ion transport and adrenal cell growth have been found in up to 90% of APAs.
  • KCNJ5 mutations are the most common, especially in Asian populations.
  • Additional mutations have been identified in ATP1A1 (Na⁺/K⁺-ATPase α-subunit), ATP2B3 (Ca²⁺-ATPase), and CACNA1D (voltage-gated calcium channel).
• These mutations disturb ion homeostasis and promote cell depolarisation, leading to increased intracellular calcium and overproduction of aldosterone.

Aldosterone-Producing Cell Clusters (APCCs)

• Immunohistochemical studies have shown CYP11B2-positive clusters within adrenal cortices, increasing with age.
• APCCs may represent precursors to both BAH and APA and are thought to drive autonomous aldosterone production over time.

Other Pathophysiological Mechanisms

Regulatory Disruption

• Renin–angiotensin system
• Serum potassium and sodium
• ACTH In PA, these regulatory mechanisms become uncoupled. The extent of this dysregulation depends on the underlying aetiology—whether sporadic, genetic, or associated with adrenal nodular changes.

Tertiary Aldosteronism

• A proposed but controversial entity thought to arise from chronic secondary hyperaldosteronism (e.g. due to renal artery stenosis).
• Persistent stimulation leads to autonomous aldosterone secretion, even after the original trigger is removed.
• Histology may reveal mixed adrenal hyperplasia and adenomas, reflecting irreversible structural changes.

Structural Subtypes and Origins

• Unilateral Disease: Typically includes large APAs (>10 mm) or smaller aldosterone-producing micronodules.
• Bilateral Disease: Encompasses diffuse or nodular hyperplasia of both glands; often familial in origin.
• Adrenocortical Carcinomas or Ectopic Tumours: Rare causes, occasionally secreting aldosterone autonomously from non-adrenal tissue (e.g. kidney or ovary).

Autonomous Aldosterone Production

• Aldosterone secretion in PA is excessive, renin-independent, and unresponsive to usual suppressive feedback (e.g. sodium loading or volume expansion).
• Inappropriate activation of aldosterone receptors results in progressive sodium retention, hypertension, and electrolyte disturbances.

Renal Mechanisms

• Aldosterone stimulates epithelial sodium channels (ENaC) in principal cells of the distal nephron:
  • Increases sodium reabsorption and water retention.
  • Enhances excretion of potassium and hydrogen ions, resulting in:
    • Hypokalaemia (in 30–40% of cases).
    • Metabolic alkalosis if prolonged or severe.
• Factors potentiating potassium loss:
  • Elevated aldosterone levels.
  • Sufficient tubular flow rate and dietary sodium.
• A new steady state develops:
  • Sodium and potassium excretion eventually match intake.
  • Hypokalaemia may not manifest unless confounding factors (e.g. diuretics) are present.

Aldosterone Escape

• Despite sodium retention, significant oedema does not develop due to aldosterone escape:
  • Triggered by mild weight gain (~3 kg).
  • Mediated by:
    • Increased atrial natriuretic peptide (ANP).
    • Downregulation of thiazide-sensitive sodium-chloride cotransporters.
    • Pressure natriuresis.

Aldosterone-Producing Cell Clusters (APCCs)

• Microscopic foci of CYP11B2-positive cells seen increasingly with age.
• These foci secrete aldosterone independently of renin or volume status.
• APCCs may contribute to:
  • Bilateral adrenal hyperplasia (BAH).
  • Development of aldosterone-producing adenomas (APAs).
  • An age-associated form of subclinical or overt PA.

Somatic Mutations in APAs

• Found in >90% of aldosterone-producing adenomas.
• Common mutations:
  • KCNJ5: Increases sodium conductance, causes membrane depolarisation, calcium influx, and aldosterone overproduction.
    • More prevalent in women and associated with larger tumours.
  • ATP1A1 and ATP2B3: Affect Na⁺/K⁺-ATPase and Ca²⁺-ATPase, respectively.
  • CACNA1D: Encodes L-type calcium channels; associated with smaller adenomas and older age.
  • CTNNB1: Activates Wnt/β-catenin pathway; causes adrenal cell dedifferentiation.
• Functional effects:
  • Enhanced calcium signalling is a shared pathway promoting aldosterone synthase activity and cell proliferation.

Familial Hyperaldosteronism Variants

• FH-I: Caused by a chimeric CYP11B1/CYP11B2 gene; aldosterone becomes ACTH-regulated.
• FH-II–V: Linked to mutations in CLCN2, KCNJ5, CACNA1H, and CACNA1D:
  • Common mechanism involves cell membrane depolarisation and calcium influx.

Idiopathic Hyperplasia

• Seen in bilateral disease (IHA); often lacks clear anatomical nodules.
• Immunohistochemistry shows:
  • Sparse CYP11B2 expression in non-nodular areas.
  • Frequent aldosterone-producing micronodules (<10 mm) harbouring somatic mutations (e.g. CACNA1D).

Systemic Effects of Aldosterone

Cardiovascular

• Increased left ventricular mass.
• Diastolic dysfunction and myocardial fibrosis (detectable via echocardiography).
• Reduced myocardial perfusion and increased cardiovascular event rates.

Renal

• Proteinuria and impaired glomerular filtration.
• Visceral adiposity correlates with lower eGFR in PA.

Metabolic

• ~20% exhibit impaired glucose tolerance (due to hypokalaemia-induced insulin resistance).
• Serum triglycerides and total cholesterol are lower in PA than in essential hypertension.

Clinical Implications

• Aldosterone contributes to organ damage beyond blood pressure elevation.
• Cardiovascular and renal complications may be reversed following:
  • Surgical treatment (e.g. adrenalectomy for APA).
  • Pharmacologic blockade (e.g. with mineralocorticoid receptor antagonists).
• Cardiac remodelling can occur in genetically predisposed individuals (e.g. FH-I) even before the development of hypertension.

Historical Perspective

• PA was historically believed to be a rare cause of hypertension, affecting fewer than 1% of patients.
• The condition was primarily suspected in individuals with hypertension and hypokalaemia.
• Since the early 1990s, evidence has revealed that normokalaemia is far more common, and PA may be significantly underdiagnosed.
  
  

Prevalence Estimates

• Prevalence rates vary due to differences in:
  • Study design.
  • Patient selection criteria.
  • Diagnostic protocols (e.g. aldosterone-renin ratio vs suppression tests).
• Confirmed prevalence rates include:
  • 2.6% in UK primary care patients with new hypertension diagnoses.
  • 5.9% in Italian hypertensive patients overall.
    • Stratified by hypertension severity:
      • 3.9% in stage 1 hypertension.
      • 11.8% in stage 3 hypertension.
  • 8.5% in normokalaemic hypertensive referrals in Australia.
  • 12% in hypertensive volunteers in antihypertensive drug trials.
    
    

Impact of Screening Policies

• Introduction of routine aldosterone-renin ratio (ARR) screening (regardless of potassium status) markedly increased detection rates.
  • One Australian centre reported:
    • A 10-fold increase in detection of PA after ARR screening implementation.
    • A 4-fold increase in surgical treatment for APAs.
    • Only 22% of diagnosed patients had hypokalaemia.
    • Annual growth of 50–90 new PA cases.
• These findings prompted global interest, with other centres reporting PA prevalence of 3–32% depending on population and diagnostic approach.
  
  
  

Primary Aldosteronism in Resistant Hypertension

• In the United States, estimated prevalence:
  • 10–20% of patients with essential hypertension.
  • Up to 40% of patients with resistant hypertension.
• Higher risk groups include:
  • Older individuals.
  • Those with low serum potassium.
  • Patients requiring multiple antihypertensives.
    
    
    

Global Distribution

• PA occurs worldwide without clear regional predilection.
• No data suggest overrepresentation in any specific geographic area, although diagnostic practices vary.
  
  

Demographic Patterns

• Race and Ethnicity:
  • Higher prevalence suggested among African Americans and other individuals of African descent.
  • This is especially relevant for idiopathic hyperaldosteronism (IHA).
  • May relate to genetic variations in the ARMC5 gene.
• Sex:
  • APAs are more frequent in women, with a female-to-male ratio of 2:1.
  • Typical APA patient: woman aged 30–50 years.
• Age:
  • IHA is more common in men and peaks in the sixth decade of life.
  • Familial forms may present much earlier, including in adolescence or childhood.
    
    
    
    

Hypertension

• Present in almost all patients, regardless of duration or severity.
• Historically, a family history of hypertension was thought to reduce the likelihood of secondary causes. Now, due to the identification of familial hyperaldosteronism, a positive family history increases suspicion.
• May have early onset (<40 years), especially in familial subtypes (FH-I to FH-IV).
  
  

Hypokalaemia-Associated Features

• History of spontaneous hypokalaemia in the presence of hypertension is a red flag.
• Exaggerated or persistent hypokalaemia despite low or moderate doses of potassium-wasting diuretics.
• Symptoms of severe hypokalaemia:
  • Muscle cramps
  • Weakness
  • Fatigue
  • Paraesthesias
  • Palpitations
  • Nocturia and polyuria (due to nephrogenic diabetes insipidus)
    
    

Refractory or Resistant Hypertension

• Consider PA in individuals with hypertension that is:
  • Poorly controlled on ≥3 medications (including a diuretic).
  • Particularly difficult to manage despite adherence.
    
    

Demographics and Age Range

• Most patients are between 20–70 years at diagnosis.
• Familial forms can occur in children or adolescents.
• Diagnosis in elderly individuals is also possible, particularly in those with bilateral adrenal hyperplasia.
  
  

Neuropsychiatric and Non-Specific Symptoms

• Regardless of potassium levels, many patients report:
  • Lethargy
  • Mood changes (e.g. irritability, anxiety, depression)
  • Cognitive difficulties (e.g. difficulty concentrating)
  • Headaches
    
    
    

Family History Clues

• Positive family history of PA, especially with documented subtypes or young-onset hypertension.
• Family history of stroke at a young age, particularly haemorrhagic strokes, may point towards FH-I or FH-III.
  
  

Strong Risk Indicators in the Family History

• Known or suspected familial hyperaldosteronism subtypes:
  • FH-I: Glucocorticoid-remediable; may present with hypertension and stroke in young individuals.
  • FH-II: Often indistinguishable from sporadic PA.
  • FH-III (KCNJ5 mutations): Can cause early-onset hypertension with hypokalaemia.
  • FH-IV (CACNA1H mutations): Early childhood onset with low renin, normal imaging.
  • PASNA syndrome (FH-V): Presents with hypertension, seizures, and neurologic abnormalities (mutation in CACNA1D).
    
    

Clinical Suspicion Scenarios

• Low-renin hypertension without overt cause.
• Hypertension in children or young adults.
• Patients previously diagnosed with “essential hypertension” who:
  • Have a poor response to standard treatment.
  • Show low potassium or are normokalaemic but meet other suggestive criteria.

General Considerations

• Primary aldosteronism (PA) does not typically present with distinctive physical signs.
• Diagnosis requires a high index of suspicion, guided predominantly by history and biochemical findings.
• Physical examination may reveal features of hypertension or its complications, but there are no unique findings exclusive to PA.
  
  

Cardiovascular Findings

• Hypertension is almost universally present:
  • Can vary in severity; may be newly diagnosed or long-standing.
  • Rarely, PA can occur without overt hypertension.
    
    
• Signs of end-organ damage from chronic hypertension may be present:
  • Cardiac failure: Elevated jugular venous pressure, peripheral oedema (if secondary heart failure present).
  • Cerebrovascular disease: Hemiparesis or focal neurological signs due to stroke.
  • Vascular bruits: Carotid or abdominal bruits in the setting of vascular disease.
  • Hypertensive encephalopathy: Confusion, seizures, altered level of consciousness.
  • Retinopathy: Hypertensive retinal changes such as arteriovenous nicking or cotton wool spots.
    
    

Neuromuscular and Gastrointestinal Signs (Hypokalaemia-Related)

• Usually only evident in severe or prolonged hypokalaemia:
  • Generalised weakness.
  • Rare ileus (intestinal paralysis) due to profound potassium depletion.
  • Abdominal distension in extreme cases.
  • Flaccid paralysis may occur if serum potassium is critically low.

Volume Status and Oedema

• Despite expanded extracellular volume, patients with PA:
  • Do not typically have peripheral oedema.
  • This is due to the aldosterone escape phenomenon, where volume expansion leads to spontaneous natriuresis and diuresis.
  • Mediated by:
    • Atrial natriuretic peptide (ANP).
    • Possibly P2Y2 receptor-mediated inhibition of ENaC in the collecting ducts, reducing further sodium reabsorption.
• The presence of significant oedema should prompt consideration of alternative diagnoses or comorbid conditions such as:
  • Cardiac failure.
  • Renal insufficiency.
  • Nephrotic syndrome.

First-Line Tests (Screening)

• Low in ~20% of cases.
• False elevations can occur; best practice includes:
  • Avoiding fist clenching.
  • Using syringes instead of Vacutainers.
  • Processing samples promptly and separating plasma within 30 minutes.
    
    

• Most reliable initial screening test.
• Elevated ARR suggests autonomous aldosterone secretion.
• Suggested thresholds:
  • Plasma aldosterone >15 ng/dL.
  • ARR >20 (ng/dL per ng/mL/h) or >900 (pmol/L per mU/L).
• Pre-test conditions:
  • Correct hypokalaemia prior to testing.
  • Liberal salt intake.
  • Mid-morning blood collection after 2–4 hours upright.
• Withhold interfering medications:
  • Stop diuretics for 6 weeks; other agents for 2–4 weeks.
  • Alternatives during testing: verapamil SR, hydralazine, prazosin.
    
    
    

Second-Line Tests (Confirmatory)

• Most sensitive confirmatory test; requires inpatient admission.
• Criteria for positive test:
  • Aldosterone >6 ng/dL at 10:00 a.m.
  • Suppressed renin (<1 ng/mL/h).
  • 10:00 a.m. cortisol < 7:00 a.m. level.
  • Normokalaemia during test maintained by potassium supplementation.
    
    

• Outpatient or inpatient IV infusion of 2 L 0.9% saline over 4 hours.
• Supine posture preferred; seated version may improve sensitivity.
• Diagnostic thresholds:
  • Aldosterone >10 ng/dL = PA likely.
  • <5 ng/dL = PA unlikely.
    
    
    

• High sodium intake (≥200 mmol/day) for 3 days.
• 24-hour urinary aldosterone:
  • 12 μg/day = PA likely.
  • <10 μg/day = PA unlikely.
    
    

• 25–50 mg oral captopril; aldosterone and renin measured at baseline and 1–2 hours post-dose.
• Failure of aldosterone to suppress with continued low renin suggests PA.
  
  

Third-Line Tests (Subtype Classification)

• Detects large lesions, e.g., adrenal carcinomas.
• Misses small APAs (~50%) and cannot distinguish functional from non-functioning nodules.
• False positives common due to incidentalomas.
• High-resolution, contrast-enhanced CT preferred.
  
  

• Gold standard for differentiating unilateral from bilateral disease.
• Required when surgery is being considered.
• Lateralisation defined by:
  • Aldosterone-to-cortisol ratio >4:1 between dominant and non-dominant adrenal vein.
  • ACTH stimulation may enhance reliability.
• Avoid if:
  • Age <35 years.
  • Hypokalaemia, markedly raised aldosterone.
  • Unilateral lesion <2.5 cm with typical imaging features.
    
    
    

Specialised or Emerging Tests

• Targets CYP11B2-expressing adenomas.
• May be used when AVS is inconclusive or not feasible.
  
  

• Aldosterone measured before and after upright posture or angiotensin II infusion.
• Rise ≥50% suggests bilateral disease or angiotensin-responsive APA.
• Unresponsive in angiotensin-unresponsive APA or FH-I.

• Elevated in FH-I and angiotensin II-unresponsive APA.
• Normal in BAH and angiotensin II-responsive APA.
• Performed in specialised labs.

• Low-dose dexamethasone suppresses aldosterone in FH-I.
• Plasma aldosterone suppression ≥80% supports FH-I diagnosis.
  
  

• Indicated in early-onset hypertension or strong family history.
• Detects mutations in:
  • CYP11B1/CYP11B2 fusion (FH-I).
  • KCNJ5, CLCN2, CACNA1H, CACNA1D (FH-II to V).
    
    

• Elevated in aldosteronomas and FH-I.
• Not used routinely.
  
  

Laboratory Findings

• Routine labs typically show:
  • Hypokalaemia.
  • Hypernatraemia.
  • Metabolic alkalosis.
    
    
    

Histopathology (Post-Adrenalectomy)

• Aldosterone-Producing Adenomas (APAs):
  • Clear/lipid-laden zona fasciculata-like cells.
  • Often ≤3 cm.
    
    
• Idiopathic Hyperplasia (IHA):
  • Diffuse or nodular hyperplasia.
  • Resembles zona glomerulosa.
    
    
• Primary Adrenal Hyperplasia (PAH):
  • Unilateral, diffuse hyperplasia with fasciculata-like morphology.
    
    
• Adrenocortical Carcinoma (ACC):
  • Rare in PA; histology shows mitotic figures, invasion, and metastasis.

Essential Hypertension (EH)

• Clinical Features:
  • Typically no specific symptoms to distinguish from PA.
  • Most common cause of elevated blood pressure in the general population.
    
    
• Investigative Clues:
  • ARR is usually within normal limits, provided medications interfering with renin or aldosterone have been discontinued.
  • Hypokalaemia is not typical unless induced by diuretics.
  • A normal ARR after drug withdrawal essentially excludes PA.
    
    

Diuretic-Induced Hypokalaemia (e.g. Thiazides)

• Clinical Features:
  • Hypertensive patient with known thiazide use.
• Investigative Clues:
  • ARR normal after 6-week washout of the thiazide and correction of potassium levels.
  • No independent aldosterone excess.
    
    
    

Renovascular Hypertension (Renal Artery Stenosis)

• Clinical Features:
  • May be suspected in patients with known atherosclerosis or peripheral arterial disease.
  • Onset of hypertension at an older age.

• Investigative Clues:
  • ARR is often low or normal.
  • Imaging (e.g. CT angiography, Doppler ultrasound) reveals renal artery stenosis.
    
    
    

Monogenic Syndromes of Sodium Retention

• Features:
  • Often presents during childhood or adolescence.
  • Autosomal dominant inheritance.
• Investigative Findings:
  • Persistent hypertension and hypokalaemia.
  • Both renin and aldosterone are suppressed → ARR is normal.
    
    
    

• Features:
  • Genetic (childhood-onset) or acquired (e.g. excess liquorice consumption).
• Investigative Findings:
  • Suppressed renin and aldosterone.
  • Elevated urinary cortisol/cortisone ratio confirms diagnosis.
    
    

• Features:
  • Hypertension and hypokalaemia, often worsened during pregnancy.
  • Familial inheritance pattern.
• Investigative Findings:
  • Low renin and aldosterone → normal ARR.
    
    
    

Familial Hyperkalaemic Hypertension (FHHt / Gordon Syndrome)

• Features:
  • Hypertension with elevated potassium, not low.
  • Often inherited but may occur due to spontaneous mutation.
• Investigative Findings:
  • Renin suppressed; ARR may be mildly elevated.
  • High potassium levels are the key distinguishing factor.
    
    
    

 Congenital Adrenal Hyperplasia (CAH) – Hypertensive Forms

• Subtypes:
  • 11β-hydroxylase deficiency: androgen excess, virilisation.
  • 17α-hydroxylase deficiency: feminisation, delayed puberty.
• Investigative Findings:
  • Aldosterone suppressed; renin low.
  • Characteristic hormonal precursors elevated (e.g. 11-deoxycortisol, deoxycorticosterone).
  • ARR is not elevated.
    
    

Primary Glucocorticoid Resistance

• Features:
  • May include signs of androgenisation or hypertension without features of Cushing syndrome.
• Investigative Findings:
  • High ACTH and cortisol levels with no suppression after dexamethasone.
  • Low aldosterone and renin → normal ARR.
    
    
    

Ectopic ACTH Syndrome

• Features:
  • Severe Cushingoid appearance (e.g. proximal myopathy, skin thinning, bruising, diabetes).
  • Associated with occult malignancy (e.g. small cell lung cancer).
• Investigative Findings:
  • Elevated cortisol and ACTH.
  • High-dose dexamethasone fails to suppress cortisol.
  • Aldosterone and renin levels remain low → normal ARR.
    
    

Bartter Syndrome

• Presents with hypokalaemia and metabolic alkalosis.
• Distinguished from PA by elevated renin and aldosterone.
  
  
  

Adrenal Disorders

• Adrenal carcinoma or incidentaloma may co-exist with hypertension.
• Imaging and hormonal profiling help determine function.
  
  
  

Iatrogenic Causes

• Cushing syndrome from exogenous steroid use may mimic PA, but clinical history and cortisol levels guide differentiation.

General Approach

• The choice of treatment is guided by:
  • Subtype classification: unilateral (surgical candidate) vs bilateral (medical therapy).
  • Patient-specific factors: age, cardiovascular risk, renal function, reproductive status, and treatment preferences.
  • Feasibility and outcomes of adrenal venous sampling (AVS) and cross-sectional imaging.
• Core goals of management:
  • Normalise blood pressure and serum potassium levels.
  • Suppress autonomous aldosterone production.
  • Restore physiological renin activity as a marker of adequate treatment.
    
    

Surgical Management

• Unilateral aldosterone-producing lesions confirmed by AVS.
• Most common causes include:
  • Aldosterone-producing adenoma (APA).
  • Unilateral adrenal hyperplasia.
• May also be considered in rare cases of bilateral disease when one gland is clearly dominant or medical therapy is intolerable.
  
  

• Laparoscopic adrenalectomy is preferred due to reduced morbidity, shorter hospital stay, and faster recovery.
• Surgery achieves:
  • Cure of hypertension in 50–60% of appropriately selected patients.
  • Improved BP control in nearly all others.
  • Resolution of hypokalaemia in almost all cases.
• Total adrenalectomy is generally performed even if a solitary adenoma is visualised, due to the potential for adjacent functional micronodules.
  
  
  

• Spironolactone or eplerenone is used prior to surgery to:
  • Optimise volume status.
  • Control blood pressure.
  • Reduce risk of postoperative hyperkalaemia due to transient contralateral hypoaldosteronism.
• Discontinue potassium supplements and MRAs shortly before surgery.
• Correct hypokalaemia and consider reducing other antihypertensive agents preoperatively.
  
  

• IV fluids: Administer isotonic saline to mitigate hypotension during surgery.
• Electrolyte monitoring:
  • Plasma potassium twice daily for first 48 hours.
  • Daily thereafter for at least 3 days.
• Antihypertensives:
  • Tapered or discontinued postoperatively depending on blood pressure response.
  • Some patients may remain normotensive without any medication.
    
    

• Watch for transient hyperkalaemia due to suppressed renin-aldosterone axis.
• Consider repeat biochemical assessment (e.g. fludrocortisone suppression test) at 1–3 months postoperatively to detect residual PA.
• Reinitiate MRAs in patients with persistent aldosterone excess or residual hypertension.
  
  
  

Medical Management

• Bilateral adrenal hyperplasia (IHA).
• Patients not suitable for surgery or who decline surgical intervention.
• Persistent PA after unilateral adrenalectomy.
  
  
  

Therapeutic Agents

• Spironolactone:
  • First-line agent; corrects hypokalaemia and lowers BP.
  • May cause progestogenic/antiandrogenic effects (gynaecomastia, menstrual irregularities, reduced libido).
  • Start with low doses (12.5–25 mg daily) and titrate based on BP and potassium levels.
    
    
• Eplerenone:
  • More selective MRA; fewer hormonal side effects.
  • Typically requires twice-daily dosing and may be less potent.
  • Preferred in patients intolerant to spironolactone.
    
    
    
• Amiloride:
  • Potassium-sparing diuretic that blocks ENaC directly (not a steroidal MRA).
  • Useful alternative, particularly in younger patients or where MRAs are not tolerated.
    
    

• Monitor:
  • Serum potassium and renal function (eGFR, creatinine).
  • Renin levels: target is unsuppressed renin as a marker of adequate aldosterone blockade.
• Caution:
  • Avoid over-treatment to prevent volume depletion, hypotension, and hyperkalaemia.
  • Monitor closely in patients with impaired renal function.
    
    
    

Management of Familial Hyperaldosteronism

• Low-dose glucocorticoids (e.g. hydrocortisone or prednisolone) suppress ACTH and therefore reduce aldosterone production.
• Monitor for:
  • Adequate BP control.
  • Adverse effects from long-term steroid use (e.g. bone loss, growth suppression in children).
• Alternatives:
  • Amiloride or eplerenone may be preferred in children to avoid growth or hormonal disruption.
    
    

• Management mirrors that of bilateral PA.
• Severe FH-III variants (e.g. with KCNJ5 mutations) may require bilateral adrenalectomy.
• Genetic testing is advised for family screening and determining targeted treatment approaches.
  
  
  

Special Situations

• Surgery ideally deferred until after delivery.
• If necessary, second trimester is the safest window.
• High levels of progesterone during pregnancy antagonise aldosterone action, often improving symptoms.
• Prednisolone or hydrocortisone may be used in FH-I; avoid dexamethasone due to placental transfer.
  
  
  

• Consider residual disease in:
  • Incomplete resection.
  • Contralateral micronodular hyperplasia.
• Diagnostic options:
  • Repeat biochemical assessment (e.g. ARR or suppression testing).
• Management:
  • Reinstitute MRAs at adjusted doses.
    
    

• Bilateral adrenalectomy may be indicated in:
  • Refractory bilateral PA.
  • FH-III with life-threatening hypertension.
• Requires lifelong glucocorticoid and mineralocorticoid replacement.
• Reserved for extreme cases due to morbidity and long-term hormonal dependence.

• Complications of Chronic Aldosterone Excess:
  • Cardiac arrhythmias due to hypokalaemia.
  • Increased incidence of:
    • Stroke
    • Myocardial infarction
    • Heart failure
    • Osteoporosis
    • Atrial fibrillation
      
      
• Renal and Retinal Complications:
  • Hypertensive nephropathy.
  • Hypertensive retinopathy.
    
    
• Independent Aldosterone Effects:
  • Aldosterone excess may cause cardiac fibrosis and vascular remodelling, even without severe hypertension.
  • These effects contribute to a greater cardiovascular burden compared to essential hypertension.
    
    

Supporting Evidence

• Multiple cohort studies have shown that PA is associated with greater cardiovascular morbidity than essential hypertension, even when blood pressure levels are matched.
• Key risk factors for adverse outcomes in PA include:
  • Hypokalaemia
  • High plasma aldosterone concentrations (>125 pg/mL)
  • Unilateral disease
    
    

Cardiovascular Complications

• Timeframe: Long-term.
• Risk: Medium.
• Mechanism:
  • Both ischaemic and haemorrhagic strokes are more common than in essential hypertension.
  • Aldosterone-driven vascular remodelling and endothelial dysfunction contribute to cerebrovascular risk.
  • Risk is not entirely blood pressure-dependent.
  • Haemorrhagic stroke is particularly prevalent in FH-I.
    
    

• Timeframe: Long-term.
• Risk: Medium.
• Mechanism:
  • Aldosterone excess accelerates coronary atherosclerosis and induces left ventricular hypertrophy (LVH).
  • These structural changes increase myocardial oxygen demand and reduce coronary perfusion.
    
    

• Timeframe: Long-term.
• Risk: Medium.
• Mechanism:
  • Persistent hypertension leads to diastolic dysfunction and LVH.
  • Aldosterone promotes cardiac fibrosis and impairs myocardial compliance.
    
    

• Timeframe: Long-term.
• Risk: Medium.
• Mechanism:
  • Result of myocardial fibrosis, left atrial enlargement, and hypokalaemia.
  • Frequently observed in PA even in the absence of overt cardiovascular disease.
    
    

• Timeframe: Long-term.
• Risk: Medium to high.
• Mechanism:
  • One of the earliest structural cardiac effects of PA.
  • Regresses significantly following surgical or medical treatment.
    
    

Renal Complications

• Timeframe: Long-term.
• Risk: Medium.
• Mechanism:
  • Chronic aldosterone excess causes glomerular hyperfiltration, inflammation, and interstitial fibrosis.
  • Hypertension accelerates vascular nephropathy.
    
    

• Timeframe: Progressive in uncontrolled cases.
• Mechanism:
  • PA may contribute to the development or progression of chronic kidney disease (CKD).
  • Risk is higher in the presence of coexistent diabetes or vascular disease.
    
    

Metabolic and Musculoskeletal Complications

• Timeframe: Long-term.
• Mechanism:
  • Aldosterone impairs insulin sensitivity and contributes to visceral adiposity.
  • PA may coexist with or worsen diabetes, dyslipidaemia, and central obesity.
    
    

• Timeframe: Long-term.
• Mechanism:
  • Emerging evidence suggests aldosterone may promote bone resorption, potentially through renal calcium loss and secondary hyperparathyroidism.
  • Increased risk of osteopenia and fractures has been reported.
    
    

• Timeframe: Variable.
• Mechanism:
  • Secondary to hypokalaemia.
  • May present as weakness, cramps, or even paralysis in severe cases.
    
    

Complications of Medical Therapy

• Timeframe: Variable.
• Risk: Medium.
• Mechanism:
  • Occurs with use of spironolactone, eplerenone, or amiloride.
  • Higher risk in:
    • Older adults.
    • Patients with CKD, diabetes, or those on other potassium-retaining drugs.
      
      
• Prevention:
  • Regular monitoring of serum potassium and renal function.
  • Use of low initial doses and dose titration.
    
    

Complications of Surgery

• Timeframe: Short-term.
• Risk: Low (especially with laparoscopic approach).
• Examples:
  • Bleeding, infection, deep vein thrombosis, pulmonary embolism, wound hernia.
• Recovery:
  • Laparoscopic adrenalectomy is associated with shorter hospital stays, reduced morbidity, and faster return to normal activities compared to open surgery.
    
    
    
    

1. Adler GK, Williams JS, Bandi V, et al. Insulin sensitivity and insulin clearance in primary aldosteronism. J Clin Endocrinol Metab. 2010;95(8):4037–4042.
2. Azizan EA, Xu Z, Johnson C, et al. Microarray, qPCR, and Immunohistochemistry Reveal Differential Expression of CYP11B1 and CYP11B2 in Aldosterone-Producing Adenomas. J Clin Endocrinol Metab. 2012;97(5):E819–E829.
3. Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized prevalence of primary aldosteronism: a cross-sectional study. Ann Intern Med. 2020;173(1):10–20.
4. Cesari M, Rossi GP, Maiolino G, et al. Subclinical cardiac damage in primary aldosteronism: a comparison with essential hypertension. J Clin Endocrinol Metab. 2006;91(2):403–409.
5. Choi M, Scholl UI, Yue P, et al. K⁺ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331(6018):768–772.
6. Dekkers T, Prejbisz A, Kool LJS, et al. Adrenal vein sampling versus CT scan to determine the lateralisation of primary aldosteronism: an outcome-based randomised diagnostic trial. Lancet Diabetes Endocrinol. 2016;4(9):739–746.
7. Fardella CE, Mosso L, Gómez-Sánchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab. 2000;85(5):1863–1867.
8. Fernandes-Rosa FL, Daniil G, Orozco IJ, et al. A gain-of-function mutation in CLCN2 causes familial hyperaldosteronism type II. Nat Genet. 2018;50(3):355–361.
9. Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment. J Clin Endocrinol Metab. 2016;101(5):1889–1916.
10. Gumz ML, Rabinowitz L, Wingo CS. An integrated view of potassium homeostasis. N Engl J Med. 2015;373(1):60–72.
11. Hannemann A, Wallaschofski H. Prevalence of primary aldosteronism in patient cohorts and in population-based studies – a review of the current literature. Horm Metab Res. 2012;44(3):157–162.
12. Haze T, Yamamoto M, Matsuda Y, et al. Visceral adiposity is associated with renal dysfunction in patients with primary aldosteronism. Clin Endocrinol (Oxf). 2020;92(3):223–231.
13. Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11β-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism. Nature. 1992;355(6357):262–265.
14. Lombès M, Oblin ME, Gasc JM, et al. Aldosterone increases kidney expression of calcium transport proteins and bone resorption markers. J Clin Invest. 1995;95(6):2517–2525.
15. Monticone S, Burrello J, Tizzani D, et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care. J Am Coll Cardiol. 2017;69(14):1811–1820.
16. Moon MK, Kim S, Kim MJ, et al. Dyslipidemia in patients with primary aldosteronism: a case-control study. Hypertens Res. 2010;33(4):389–393.
17. Mulatero P, Monticone S, Rainey WE, Veglio F, Williams TA. Role of KCNJ5 in familial and sporadic primary aldosteronism. Nat Rev Endocrinol. 2013;9(2):104–112.
18. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centres from five continents. J Clin Endocrinol Metab. 2004;89(3):1045–1050.
19. Nanba K, Nakao K, Seki T, et al. Adrenal zonation in humans: implications of APCCs in pathogenesis of PA. J Clin Endocrinol Metab. 2013;98(8):3239–3246.
20. Nishimoto K, Seki T, Hayashi Y, et al. Immunohistochemistry-guided transcriptome analysis reveals adrenocortical zonation and a unique cell cluster in aldosterone-producing adenomas. Endocrinology. 2016;157(9):3520–3530.
21. Ohno Y, Sone M, Inagaki N, et al. Cardiovascular complications and their association with aldosterone levels in patients with primary aldosteronism. Hypertens Res. 2014;37(7):574–579.
22. Pan Y, Wu J, Wang X, et al. Adrenalectomy lowers risk of new-onset atrial fibrillation in patients with primary aldosteronism. J Clin Endocrinol Metab. 2021;106(1):e142–e152.
23. Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48(11):2293–2300.
24. Rossi GP, Bisogni V, Baccarelli A, et al. Genetic screening in familial hyperaldosteronism: implications for diagnosis and management. Hypertension. 2020;76(4):1221–1230.
25. Rossi GP, Rossi E, Funder JW. Aldosterone escape in primary aldosteronism: mechanisms and clinical implications. J Hypertens. 2013;31(5):1053–1055.
26. Rossi GP, Sechi LA, Giacchetti G, et al. Primary aldosteronism: cardiovascular, renal and metabolic implications. Trends Endocrinol Metab. 2008;19(3):88–90.
27. Scholl UI, Goh G, Stölting G, et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet. 2013;45(9):1050–1054.
28. Stowasser M, Gordon RD. Familial forms of primary aldosteronism. Horm Metab Res. 2009;41(10):737–741.
29. Stowasser M, Gordon RD. Primary aldosteronism—careful investigation is essential and rewarding. Mol Cell Endocrinol. 2004;217(1–2):33–39.
30. Sutherland DJA, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J. 1966;95(22):1109–1119.
31. Verrey F, Hummler E. ENaC regulation by aldosterone: beyond classical paradigms. Pflugers Arch. 2008;455(6):889–900.
32. Williams TA, Lenders JWM, Mulatero P, et al. Genetics of primary aldosteronism: a contemporary update. Curr Hypertens Rep. 2015;17(7):527.
33. Young WF. Diagnosis and treatment of primary aldosteronism: practical clinical perspectives. J Intern Med. 2019;285(2):126–148.
34. Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf). 2007;66(5):607–618.