Primary Aldosteronism

• 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

• 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.
  
  

• 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.
  
  

• 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.
  
  

• 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.
  
  

• 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.
  
  

• 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

• 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.
  
  

• 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.
  
  

• 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.
    
    
    
    

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