Conn's Syndrome (Primary Hyperaldosteronism)

1. Clinical Overview

Summary

Primary Hyperaldosteronism (PA) is the autonomous hypersecretion of aldosterone from the adrenal cortex (zona glomerulosa), leading to suppression of renin. It represents the most common cause of secondary hypertension, accounting for 5-13% of all hypertensive patients and up to 20% of those with resistant hypertension. [1,2] The classic biochemical picture combines hypertension with hypokalaemia, though up to 50% of patients are normokalaemic at presentation. [3]

The two principal aetiologies are:

1. Bilateral Adrenal Hyperplasia (idiopathic): 60% of cases
2. Unilateral Aldosterone-Producing Adenoma (APA) (Conn's Syndrome): 35% of cases [2]

Distinguishing between these is crucial as unilateral disease is surgically curable, while bilateral disease requires lifelong mineralocorticoid receptor antagonist therapy.

Key Facts

• Mechanism: Aldosterone acts on principal cells of the collecting duct, upregulating the Na+/K+ ATPase pump and ENaC channels. This causes constant sodium (and water) retention whilst excreting potassium and hydrogen ions into the urine.

• Aldosterone is Toxic: Independent of blood pressure, excess aldosterone causes end-organ damage including cardiac fibrosis (left ventricular hypertrophy), renal injury (proteinuria, CKD), and vascular remodelling (increased stroke risk). PA patients have demonstrably higher cardiovascular morbidity than essential hypertensives matched for blood pressure. [4,5]

• Screening Gap: PA remains vastly under-diagnosed. Current guidelines recommend screening in resistant hypertension (requiring ≥3 antihypertensives), hypertension with spontaneous hypokalaemia, hypertension onset less than 40 years, and all patients with adrenal incidentaloma plus hypertension. [1,2]

• Prevalence: Studies demonstrate that 5-13% of general hypertensive populations have PA, rising to 20% in resistant hypertension cohorts. [6]

Clinical Pearls

The Spironolactone Trap: Spironolactone is a mineralocorticoid receptor antagonist. If the aldosterone/renin ratio is measured whilst the patient is taking spironolactone, the result is invalid (renin rises due to receptor blockade). It must be discontinued for 4-6 weeks (switch to doxazosin/calcium channel blocker) before diagnostic testing.

Incidentalomas: 5% of healthy adults have a benign adrenal nodule. If CT imaging reveals an adrenal mass in a PA patient, you cannot assume it is the source. The "mass" might be non-functioning, whilst the "normal-appearing" gland is hyperplastic. Only Adrenal Vein Sampling (AVS) can definitively lateralise aldosterone production. [7]

Normokalaemic PA: Hypokalaemia is a late sign. Do not wait for low potassium to screen for PA in resistant hypertension – over half of PA cases are normokalaemic. [3]

Cardiovascular Risk: Patients with PA have higher rates of stroke, myocardial infarction, and atrial fibrillation compared to patients with essential hypertension of similar severity. This excess risk is driven by aldosterone-mediated vascular and cardiac fibrosis. [4,5]

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2. Epidemiology

Demographics

• Prevalence:

  • "General hypertensive population: 5-13% [6]"
  • "Resistant hypertension: 15-20% [2]"
  • "Stage 3 hypertension: up to 29% [6]"

• Age: Peak incidence 30-60 years

• Sex:

  • "Aldosterone-producing adenomas: Female > Male (ratio ~1.5:1)"
  • "Bilateral hyperplasia: Male > Female"
  • "Overall PA: approximately equal distribution [2]"

Aetiological Subtypes

Familial Hyperaldosteronism (FH)

Rare genetic forms include:

• FH Type I (Glucocorticoid-Remediable Aldosteronism): ACTH-dependent aldosterone production due to CYP11B1/CYP11B2 chimeric gene. Suppressed by dexamethasone.
• FH Type II: Familial clustering, genetic basis heterogeneous
• FH Type III: KCNJ5 germline mutations
• FH Type IV: CACNA1H mutations [8]

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3. Pathophysiology

Normal RAAS Physiology

In health, the renin-angiotensin-aldosterone system (RAAS) maintains blood pressure and electrolyte homeostasis:

1. Low BP/Low Na+ → Juxtaglomerular cells release Renin
2. Renin cleaves Angiotensinogen → Angiotensin I
3. ACE converts Angiotensin I → Angiotensin II
4. Angiotensin II stimulates zona glomerulosa → Aldosterone secretion
5. Aldosterone acts on collecting duct → Na+ retention, K+ excretion
6. Volume expansion → BP normalises → Negative feedback suppresses renin

RAAS Failure in Primary Aldosteronism

In PA, autonomous aldosterone production disrupts this negative feedback:

• Adrenal produces aldosterone independently of renin/angiotensin II
• Aldosterone → Continuous Na+ retention → Volume expansion → Hypertension
• High BP → Renin suppressed (appropriate response to volume overload)
• Result: High Aldosterone : Low Renin (hallmark of PA)

Molecular Pathophysiology

Recent genetic studies have identified somatic mutations in aldosterone-producing adenomas:

These mutations lead to constitutive aldosterone synthesis independent of physiological regulation. [9]

Metabolic Consequences

Hypokalaemia

Aldosterone stimulates K+ secretion via:

• ROMK channels (apical membrane of principal cells)
• Increased Na+ delivery to distal nephron (enhances electrochemical gradient for K+ secretion)

Clinical effects:

• Muscle weakness, cramps, fatigue
• Polyuria/polydipsia (nephrogenic diabetes insipidus - K+ depletion impairs ADH action)
• Cardiac arrhythmias (prolonged QT, U waves, ventricular ectopy)
• Rhabdomyolysis (severe cases)

Metabolic Alkalosis

Aldosterone promotes H+ excretion via:

• H+/K+ ATPase in intercalated cells
• Enhanced proximal tubule HCO3- reabsorption (volume contraction)

Result: Hypokalaemic metabolic alkalosis (typical finding in PA with hypokalaemia)

Can cause:

• Paraesthesias/tetany (reduced ionised calcium)
• Confusion/lethargy

Cardiovascular Fibrosis

Aldosterone promotes fibrosis in multiple organs via mineralocorticoid receptor activation:

• Cardiac: LV hypertrophy, atrial fibrosis (AF risk), diastolic dysfunction [4]
• Vascular: Arterial stiffness, endothelial dysfunction
• Renal: Glomerulosclerosis, tubulointerstitial fibrosis [5]

This explains why PA patients have excess cardiovascular morbidity beyond that explained by BP alone.

Aldosterone Escape Phenomenon

Despite continuous Na+ retention, patients with PA rarely develop oedema. Why?

After initial volume expansion:

• Atrial Natriuretic Peptide (ANP) rises
• ANP induces natriuresis ("pressure natriuresis")
• Volume stabilises at high-normal level
• Result: Hypertension without frank fluid overload

This distinguishes PA from secondary hyperaldosteronism (e.g., heart failure, cirrhosis) where oedema is common.

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4. Clinical Presentation

Symptoms

Many patients are asymptomatic - hypertension detected incidentally at screening.

When present, symptoms relate to:

Hypertension

• Headache
• Dizziness
• Visual disturbance (if severe)

Hypokalaemia (when K+ less than 3.0 mmol/L)

• Muscle: Weakness, cramps, myalgia
• Cardiac: Palpitations
• Renal: Polyuria, polydipsia, nocturia (nephrogenic DI)
• Severe: Paralysis, rhabdomyolysis

Aldosterone Excess

• Fatigue (mechanism unclear)

Risk Factors for Screening

Current Endocrine Society guidelines [1,2] recommend screening in:

1. Sustained BP > 150/100 mmHg on 3+ separate occasions
2. Resistant hypertension (BP > 140/90 on 3+ drugs including diuretic)
3. Hypertension + spontaneous hypokalaemia (K+ less than 3.5 mmol/L)
4. Hypertension + diuretic-induced hypokalaemia (K+ less than 3.0 mmol/L)
5. Hypertension + adrenal incidentaloma
6. Hypertension + sleep apnoea
7. Hypertension + first-degree relative with PA
8. Young-onset hypertension (less than 40 years)
9. Stroke at young age (less than 40 years)

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5. Clinical Examination

General Inspection

• Usually no specific signs
• Assess for features of other causes of secondary hypertension (e.g., Cushing's, phaeochromocytoma)

Blood Pressure

• Elevated (often severely - mean BP ~165/105 mmHg in diagnosed PA)
• Measure in both arms (exclude renal artery stenosis/coarctation)

Cardiovascular Examination

• Fundoscopy: Hypertensive retinopathy (silver wiring, AV nipping, flame haemorrhages, papilloedema)
• Apex beat: Displaced/sustained (LVH)
• Heart sounds: Fourth heart sound (S4) - suggests LVH
• Murmurs: Exclude aortic stenosis, coarctation

Fluid Status

• Rarely oedematous (due to aldosterone escape phenomenon)
• Presence of oedema suggests secondary hyperaldosteronism (heart failure, liver disease, nephrotic syndrome)

Neuromuscular Examination (if hypokalaemic)

• Proximal muscle weakness (hip flexion, shoulder abduction)
• Hyporeflexia (severe hypokalaemia)

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6. Investigations

Diagnostic Pathway Overview

CLINICAL SUSPICION
        ↓
SCREENING: Aldosterone/Renin Ratio (ARR)
        ↓
    Positive ARR
        ↓
CONFIRMATORY TEST
(Saline Suppression/Captopril Challenge/Fludrocortisone Suppression)
        ↓
    PA Confirmed
        ↓
SUBTYPE CLASSIFICATION
CT Adrenals + Adrenal Vein Sampling (AVS)
        ↓
    ┌─────────────┴─────────────┐
UNILATERAL              BILATERAL
    ↓                       ↓
SURGERY                 MEDICAL

Pre-Test Preparation

Medication Interference: Many antihypertensives affect ARR

Ideal preparation:

• Switch to doxazosin and/or verapamil/amlodipine
• Correct hypokalaemia (low K+ suppresses aldosterone secretion → false negative)
• Liberalise salt intake (low salt → ↑renin → false negative)

Practical reality:

• Many patients cannot safely stop all interfering medications
• Most centres accept testing on calcium channel blockers/alpha-blockers
• Interpret results with caution if patient on suboptimal regimen [10]

Screening Test: Aldosterone-Renin Ratio (ARR)

Methodology:

• Blood sample taken mid-morning (after 2 hours upright to standardise renin)
• Patient should be seated for 5-15 minutes before sampling
• Measure:
  • Plasma Aldosterone Concentration (PAC)
  • Plasma Renin Activity (PRA) or Direct Renin Concentration (DRC)

Calculation:

• ARR = Aldosterone (pmol/L) ÷ Renin (mU/L) [if using PRA]
• Or: Aldosterone (ng/dL) ÷ DRC (mU/L) [if using DRC]

Interpretation (varies by laboratory/assay):

Important: ARR threshold varies by assay and laboratory. Some centres use different units (ng/dL for aldo, ng/mL/h for PRA). Always use local reference ranges. [1,10]

Sensitivity/Specificity:

• Sensitivity: 75-95%
• Specificity: 75-85%
• Performance varies with pre-test preparation and assay [10]

Pitfalls:

• False positives: Beta-blockers, diuretics, elderly (low renin), CKD (low renin)
• False negatives: Hypokalaemia, high salt intake on testing day

Confirmatory Tests

A positive ARR requires confirmatory testing (ARR has ~20% false positive rate).

1. Saline Suppression Test (Most Common)

Protocol:

• Patient supine
• Infuse 2 litres 0.9% NaCl IV over 4 hours
• Measure aldosterone at baseline and 4 hours

Interpretation:

• Normal: Aldosterone suppresses to less than 140-165 pmol/L (less than 5 ng/dL)
• PA: Aldosterone remains > 277 pmol/L (> 10 ng/dL) → diagnostic
• Indeterminate: 140-277 pmol/L (5-10 ng/dL)

Contraindications: Severe hypertension, heart failure, CKD

2. Oral Sodium Loading Test

Protocol:

• High salt diet (> 200 mmol/day) for 3 days
• Measure 24-hour urine aldosterone on day 3

Interpretation:

• Normal: Aldosterone less than 10 mcg/24h
• PA: Aldosterone > 12 mcg/24h

Advantage: Outpatient test

3. Fludrocortisone Suppression Test

Protocol:

• Fludrocortisone 0.1 mg QDS for 4 days
• Potassium supplementation to maintain K+ > 4.0
• Measure plasma aldosterone on day 4

Interpretation:

• Normal: Aldosterone less than 140 pmol/L
• PA: Aldosterone remains elevated

Disadvantage: Complex, requires admission, rarely used

4. Captopril Challenge Test

Protocol:

• Patient seated for 1 hour
• Baseline renin and aldosterone
• Give captopril 25-50 mg PO
• Repeat renin and aldosterone at 1-2 hours

Interpretation:

• Normal: Aldosterone suppresses by > 30%
• PA: Aldosterone remains elevated or increases

Advantage: Quick, outpatient Disadvantage: Less validated than saline suppression

Subtype Classification

Once PA is confirmed, determine unilateral vs bilateral disease.

CT Adrenals

Protocol: Thin-slice (3mm) non-contrast CT of adrenals

Findings:

• Unilateral adenoma: Homogeneous, lipid-rich mass less than 2 cm
• Bilateral hyperplasia: Normal or bilateral nodularity
• Unilateral hyperplasia: Unilateral enlargement
• Carcinoma: Large (> 4 cm), heterogeneous, irregular

CRITICAL LIMITATION:

• CT alone is insufficient for surgical planning
• 20% of PA patients have non-functioning incidentalomas
• 30% of APAs are too small to detect on CT
• CT cannot reliably distinguish APA from BAH [7]

Role of CT:

• Exclude adrenal carcinoma (> 4 cm, suspicious features)
• Identify gross unilateral masses (but still require AVS for confirmation)

Adrenal Vein Sampling (AVS)

Gold Standard for lateralisation [1,2,7]

Indications:

• All PA patients being considered for surgery
• Exception: Age less than 35 years with unilateral adenoma > 1 cm on CT + markedly elevated aldosterone (can proceed directly to surgery) [1]

Protocol:

• Experienced interventional radiologist
• Fluoroscopy-guided catheterisation of both adrenal veins via femoral vein approach
• Simultaneous blood sampling from:
  • Right adrenal vein
  • Left adrenal vein
  • Inferior vena cava (IVC) below renal veins
• Measure aldosterone and cortisol from each site
• Optional: ACTH stimulation (250 mcg cosyntropin) to increase success rate

Interpretation:

Step 1: Confirm successful cannulation

• Selectivity Index (SI) = Adrenal vein cortisol / IVC cortisol
• SI > 2 (without ACTH) or > 3 (with ACTH) confirms successful cannulation
• Right adrenal vein harder to cannulate (small, drains into IVC at acute angle)

Step 2: Lateralisation

• Lateralisation Index (LI) = (Aldo/Cortisol)dominant side ÷ (Aldo/Cortisol)non-dominant side
• LI > 4 (with ACTH) or > 2 (without ACTH) → Unilateral disease → Surgery
• LI less than 4/2 → Bilateral disease → Medical therapy

Success Rate:

• Bilateral cannulation success: 70-90% (operator-dependent) [7]

Complications:

• Adrenal haemorrhage/infarction (less than 1%)
• Adrenal vein rupture (rare)

Emerging Alternative:

• PET-CT with 11C-metomidate can localise aldosterone-producing adenomas non-invasively
• Promising results but not yet standard of care [11]

Baseline Bloods

• U\u0026Es: Hypokalaemia (present in ~50%), elevated HCO3- (metabolic alkalosis)
• Magnesium: Often low (aldosterone promotes Mg2+ excretion)
• Glucose: Hypokalaemia impairs insulin secretion (mild hyperglycaemia possible)
• Renin: Suppressed
• Aldosterone: Elevated

ECG

Findings in hypokalaemia:

• U waves (most specific - small positive deflection after T wave)
• Flattened/inverted T waves
• ST depression
• Prolonged QT interval
• Ventricular ectopy

Imaging - Echocardiography

• Left ventricular hypertrophy (concentric pattern)
• Diastolic dysfunction
• Left atrial enlargement

PA patients have greater LVH than essential hypertensives with similar BP [4]

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7. Management

Management Algorithm

           CONFIRMED PA
                ↓
          CT ADRENALS
                ↓
    ┌───────────┴────────────┐
Suspicious for          Small/bilateral
carcinoma              nodules or normal
    ↓                         ↓
ONCOLOGY            ADRENAL VEIN SAMPLING
REFERRAL                     ↓
                    ┌────────┴────────┐
                UNILATERAL      BILATERAL
             (LI > 4 or > 2)    (LI less than 4 or less than 2)
                    ↓                 ↓
            LAPAROSCOPIC      MEDICAL THERAPY
            ADRENALECTOMY  (Mineralocorticoid
                ↓          Receptor Antagonist)
        Post-op assess          ↓
        biochem/BP          Lifelong MRA +
            ↓              additional agents
    ┌───────┴────────┐      as needed
CURED         IMPROVED
(BP normal,    (Improved
aldo/K+ ok)    but not cured)
    ↓              ↓
  Observe      Continue
No meds    antihypertensives

Medical Management (Bilateral Disease or Non-Surgical Candidates)

First-Line: Mineralocorticoid Receptor Antagonists (MRAs)

Spironolactone

Mechanism: Non-selective mineralocorticoid receptor antagonist (also blocks androgen and progesterone receptors)

Dosing:

• Start: 12.5-25 mg OD
• Titrate: Increase by 12.5-25 mg every 4-8 weeks
• Target: 25-100 mg OD (up to 400 mg/day in resistant cases)
• Titrate to achieve BP less than 130/80 and K+ 4.0-5.0

Monitoring:

• U\u0026Es at 1-2 weeks, then 4 weeks, then 3-monthly
• Risk of hyperkalaemia (especially with CKD, diabetes, co-prescribed ACEi/ARB)

Side Effects (dose-dependent):

• Gynaecomastia (10-20% of men at high doses)
• Breast tenderness (males and females)
• Erectile dysfunction (anti-androgen effect)
• Menstrual irregularity
• Hyperkalaemia
• GI upset

Efficacy:

• Normalises K+ in > 95%
• BP control achieved in 50-70% as monotherapy
• Often requires additional antihypertensives [12]

Eplerenone

Mechanism: Selective mineralocorticoid receptor antagonist (no anti-androgen effect)

Dosing:

• Start: 25 mg OD
• Titrate: Increase to 50 mg OD, then 50 mg BD if needed
• Maximum: 100 mg BD

Advantages:

• No gynaecomastia or sexual dysfunction
• Better tolerated in men

Disadvantages:

• Less potent than spironolactone (may require higher doses)
• Twice daily dosing
• Expensive (less widely available)
• Shorter half-life

Monitoring: Same as spironolactone

Choice:

• Spironolactone = first line (more potent, once daily, cheap)
• Eplerenone = if spironolactone not tolerated due to sexual/hormonal side effects

Second-Line Agents

If BP not controlled on MRA alone:

• Calcium channel blockers (amlodipine, verapamil)
• Thiazide/thiazide-like diuretics (indapamide) - be cautious with K+
• ACE inhibitors/ARBs - less effective in PA (low renin state) but can be used

Third-Line: Amiloride

Mechanism: Epithelial sodium channel (ENaC) blocker (potassium-sparing diuretic)

Dosing: 5-20 mg OD

Use:

• Alternative to MRA if MRA not tolerated
• Additive to MRA in resistant cases
• Less effective than MRA as monotherapy

Surgical Management (Unilateral Disease)

Patient Selection

Criteria for surgery:

1. Confirmed PA (positive ARR + confirmatory test)
2. Lateralisation on AVS (LI > 4 or > 2)
3. Fit for surgery (anaesthetic risk acceptable)
4. Patient preference (counselled on risks/benefits)

Exceptions (can proceed without AVS):

• Age less than 35 years
• Marked biochemical abnormality
• Unilateral adenoma > 1 cm on CT
• No imaging abnormality on contralateral side [1]

Laparoscopic Adrenalectomy

Procedure:

• Transperitoneal or retroperitoneal approach
• Removal of entire adrenal gland (not just adenoma - risk of hyperplastic tissue remaining)
• Unilateral adrenalectomy (dominant side identified on AVS)

Pre-operative Preparation:

• Treat with spironolactone 25-50 mg OD for 4 weeks to:
  • Normalise potassium
  • Control BP
  • Reduce peri-operative risk
• Ensure euthyroid if concurrent thyroid disease

Post-operative Course:

• Hyperkalaemia risk (suppressed contralateral adrenal may take weeks to recover)
• Monitor U\u0026Es closely
• May need temporary fludrocortisone if transient hypoaldosteronism develops
• Glucocorticoid supplementation NOT needed (only zona glomerulosa removed, not zona fasciculata)

Outcomes After Adrenalectomy

Biochemical Cure (normalisation of K+ and ARR): 90-100%

Hypertension Outcomes [13,14]:

• Complete cure (BP normal, no medications): 30-60%
• Partial cure (improved BP, fewer medications): 30-50%
• No improvement: 10-20%

Predictors of Cure:

• Younger age
• Shorter duration of hypertension (less than 5 years)
• Fewer antihypertensives pre-operatively (≤2 drugs)
• No family history of hypertension
• Female sex (in some studies)

Why isn't everyone cured?

• Long-standing hypertension → irreversible vascular remodelling
• Concurrent essential hypertension (genetic predisposition)

Complications (less than 5%):

• Bleeding
• Splenic injury (left-sided)
• Pneumothorax
• Adrenal insufficiency (if bilateral adrenalectomy inadvertently performed)

Post-Treatment Monitoring

After Surgery

• U\u0026Es: 1 week, 4 weeks, 3 months, then annually
• ARR: 3-6 months post-op (to confirm biochemical cure)
• BP: Weekly for 1 month, then 3-monthly
• Discontinue spironolactone post-op (no longer needed)
• Taper other antihypertensives as tolerated

During Medical Therapy

• U\u0026Es: 1-2 weeks after starting/titrating, then 3-monthly
• BP: 2-weekly until stable, then 3-monthly
• Annual:
  • Cardiovascular risk assessment
  • Screen for end-organ damage (urinary ACR, ECG/echo)

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8. Complications

Cardiovascular

PA confers excess cardiovascular risk beyond BP alone [4,5]

• Left Ventricular Hypertrophy: More prevalent and severe than essential hypertension
• Diastolic Dysfunction: Aldosterone-mediated myocardial fibrosis
• Atrial Fibrillation: 7-fold increased risk vs essential HTN (atrial fibrosis) [15]
• Stroke: 2-4 fold increased risk (independent of BP)
• Myocardial Infarction: Increased risk

Mechanism: Direct mineralocorticoid receptor activation in heart/vessels → fibrosis, inflammation, oxidative stress

Renal

• Chronic Kidney Disease: Aldosterone-mediated glomerulosclerosis and tubulointerstitial fibrosis [5]
• Proteinuria/Albuminuria: Direct effect of aldosterone on podocytes
• Hyperfiltration injury: Volume expansion + hypertension

Metabolic

• Impaired Glucose Tolerance: Hypokalaemia impairs insulin secretion
• Metabolic Syndrome: Higher prevalence than essential hypertension

Hypokalaemia-Related

• Cardiac Arrhythmias: Ventricular ectopy, torsades de pointes (if severe)
• Muscle Weakness/Paralysis: Hypokalaemic periodic paralysis (rare, severe)
• Rhabdomyolysis: Severe hypokalaemia (less than 2.0 mmol/L)
• Nephrogenic Diabetes Insipidus: Polyuria, nocturia

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9. Prognosis and Outcomes

Natural History (Untreated)

• Progressive hypertension: Often severe and resistant
• Cardiovascular events: Stroke, MI, AF, heart failure
• Renal failure: Progressive CKD
• Life expectancy: Reduced if untreated

Outcomes with Treatment

Surgical (Unilateral Disease)

• Biochemical cure: > 90%
• Complete BP cure: 30-60%
• Improved BP: 90%+
• Improved CV outcomes: Regression of LVH, reduced AF risk [14]

Medical (Bilateral Disease)

• Biochemical control: 80-90% achieve K+ normalisation
• BP control: 50-70% achieve target BP with MRA ± additional agents
• CV outcomes: Improved, but less than surgical cure [16]
• Adherence critical: Lifelong therapy required

Long-Term Cardiovascular Outcomes

Post-Treatment [16,17]:

• Regression of LVH occurs over 6-12 months
• Reduced albuminuria
• Lower AF incidence
• Stroke risk normalises

Comparison:

• Surgical cure superior to medical therapy for long-term CV outcomes
• Both superior to untreated PA
• Treated PA approaches (but may not equal) essential hypertension risk

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10. Differential Diagnosis

High Aldosterone, Low Renin (Mineralocorticoid Excess)

High Aldosterone, High Renin (Secondary Hyperaldosteronism)

Normotensive Hypokalaemia

• GI losses: Vomiting, diarrhoea, laxative abuse
• Renal losses: RTA, Bartter's, Gitelman's syndromes
• Drugs: Diuretics, penicillins, amphotericin
• Other: Hypomagnesaemia

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11. Evidence and Guidelines

Key Guidelines

Landmark Trials and Studies

1. PATHWAY-2 Trial (Lancet 2015) [18]

Design: Randomised, double-blind, crossover trial

Population: 285 patients with resistant hypertension

Intervention: Spironolactone vs placebo vs doxazosin vs bisoprolol (added to baseline triple therapy)

Results:

• Spironolactone most effective: mean BP reduction -8.7 mmHg systolic vs placebo
• Superior to doxazosin (-4.0 mmHg) and bisoprolol (-4.5 mmHg)
• 58% of patients achieved BP control with spironolactone

Conclusion: Spironolactone is the most effective fourth-line agent for resistant hypertension, supporting role of mineralocorticoid excess in "essential" hypertension

2. Primary Aldosteronism Cardiovascular Outcomes (Multiple Studies)

Milliez et al. (JCEM 2005): PA patients had 4-fold higher rate of stroke and MI vs essential HTN matched for BP severity

Savard et al. (J Hypertens 2013): PA associated with 12-fold increased risk of atrial fibrillation

Monticone et al. (Circulation 2018) [4]: Treatment of PA (surgical or medical) leads to:

• Regression of LVH
• Improved diastolic function
• Reduced arterial stiffness

3. Adrenal Vein Sampling Studies

Rossi et al. (JAMA 2008): AVS changed management in 40% of cases where CT suggested unilateral disease

Williams et al. (N Engl J Med 2018): AVS-guided surgery superior outcomes vs CT-guided approach

Evidence Level Summary

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12. Special Populations

Pregnancy

Considerations:

• PA can occur in pregnancy (rare)
• Spironolactone is contraindicated (anti-androgen effect - feminisation of male foetus)
• Eplerenone also avoided

Management:

• Amiloride preferred (safer K+-sparing diuretic)
• Methyldopa, labetalol, nifedipine for BP control
• Avoid ACEi/ARBs (teratogenic)
• Consider adrenalectomy in second trimester if severe, uncontrolled

Chronic Kidney Disease

Considerations:

• CKD reduces renin (false positive ARR)
• Hyperkalaemia risk with MRA therapy

Management:

• ARR less reliable (consider confirmatory test essential)
• Start MRA at low dose (12.5 mg spironolactone)
• Monitor K+ very closely (1-2 weekly initially)
• May need to avoid MRA if eGFR less than 30 and K+ > 5.0

Elderly

Considerations:

• Low renin common (false positive ARR)
• Polypharmacy
• Lower surgical fitness

Management:

• Higher threshold for confirmatory testing
• Medical therapy often preferred
• Lower MRA doses (risk of hyperkalaemia)

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13. Patient and Layperson Explanation

What is Conn's Syndrome?

Conn's Syndrome, also called Primary Aldosteronism, is a condition where one or both of your adrenal glands (small glands that sit on top of your kidneys) produce too much of a hormone called aldosterone.

What does Aldosterone do?

Aldosterone tells your kidneys to:

• Hold onto salt and water → This increases the amount of fluid in your blood vessels, pushing your blood pressure up
• Flush out potassium → Potassium is a vital mineral for your muscles, heart, and nerves

Why does it matter?

• High blood pressure: Can lead to stroke, heart attack, and kidney damage
• Low potassium: Can cause muscle weakness, cramps, and abnormal heart rhythms
• Heart and kidney damage: Too much aldosterone damages your heart and kidneys directly, even beyond the effects of high blood pressure

How do we find it?

We do a blood test measuring aldosterone and renin (another hormone). If the ratio is abnormal, we do more tests to confirm the diagnosis.

How do we fix it?

First, we work out if the problem is coming from one gland or both glands:

If it's one gland (usually a small benign growth):

• We can remove that gland with keyhole surgery
• This often cures the problem
• Your blood pressure may return to normal, and you may not need blood pressure tablets anymore

If it's both glands:

• We give you a medicine (called spironolactone) that blocks aldosterone's effects
• This controls your blood pressure and potassium
• You'll need to take this medicine lifelong

What can I expect?

• Surgery: Most people feel much better. Blood pressure improves in almost everyone, and many are cured completely.
• Medicine: Works well to control blood pressure and potassium. You'll need regular blood tests to check your potassium level.

Will I get better?

Yes! With proper treatment:

• Blood pressure improves
• Potassium returns to normal
• Risk of stroke and heart attack reduces
• Quality of life improves

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14. Examination Focus

Common Exam Questions

1. Biochemistry Interpretation

Q: "A 45-year-old man with hypertension has K+ 2.9 mmol/L, HCO3- 32 mmol/L. Arterial blood gas shows pH 7.50, pCO2 5.2, pO2 12.5. What is the acid-base disturbance?"

A: Metabolic alkalosis (high pH, high HCO3-, appropriate respiratory compensation). In context of hypokalaemia and hypertension → think primary aldosteronism.

2. Diagnostic Pathway

Q: "Which investigation is the gold standard for lateralising aldosterone production in primary aldosteronism?"

A: Adrenal Vein Sampling (AVS). CT adrenals cannot reliably distinguish functioning from non-functioning adenomas.

3. Pharmacology

Q: "What is the most common side effect of spironolactone in men?"

A: Gynaecomastia (due to anti-androgen effect). Occurs in 10-20% at higher doses. Eplerenone is selective and avoids this.

4. Differential Diagnosis

Q: "A patient has hypertension, hypokalaemia, low aldosterone, and low renin. What is the diagnosis?"

A: Liddle's Syndrome (or Apparent Mineralocorticoid Excess). In primary aldosteronism, aldosterone is high. Low aldosterone + low renin + mineralocorticoid excess picture suggests genetic ENaC activation (Liddle's) or exogenous mineralocorticoid/cortisol excess.

5. Management

Q: "What percentage of patients are cured of hypertension after adrenalectomy for unilateral aldosterone-producing adenoma?"

A: 30-60% achieve complete cure (no medications). 90%+ have improved BP. Predictors of cure include younger age, shorter duration of hypertension, and fewer pre-operative medications.

Viva Points

Aldosterone Escape

Q: "Why don't patients with primary aldosteronism develop pitting oedema despite continuous sodium retention?"

A: Aldosterone escape phenomenon. After initial Na+ retention and volume expansion, Atrial Natriuretic Peptide (ANP) rises in response to atrial stretch. ANP induces natriuresis ("pressure natriuresis"), preventing further volume accumulation. Volume stabilises at high-normal, causing hypertension without oedema. This distinguishes primary from secondary hyperaldosteronism (where oedema is common).

Medication Interference

Q: "A patient is on spironolactone for resistant hypertension. Can you proceed with aldosterone-renin ratio testing?"

A: No. Spironolactone is a mineralocorticoid receptor antagonist. By blocking aldosterone's action, it causes a compensatory rise in renin. This will falsely normalise the ARR, causing a false negative. Spironolactone must be stopped for 4-6 weeks before testing (switch to doxazosin/calcium channel blocker in interim).

Genetics

Q: "What is the most common genetic mutation in aldosterone-producing adenomas?"

A: KCNJ5 mutations (40-50% of APAs). This gene encodes a potassium channel (GIRK4). Mutations cause loss of selectivity → Na+ influx → cellular depolarisation → Ca2+ entry → aldosterone synthesis. Other mutations (ATP1A1, ATP2B3, CACNA1D) account for ~20% of APAs.

Glucocorticoid-Remediable Aldosteronism

Q: "How do you diagnose Familial Hyperaldosteronism Type I?"

A: Also called Glucocorticoid-Remediable Aldosteronism (GRA). Suspect in young patients with family history of early stroke/PA. Caused by chimeric gene fusion (CYP11B1/CYP11B2) → aldosterone synthase under ACTH control. Diagnosis:

• Genetic testing (CYP11B1/CYP11B2 chimeric gene)
• Dexamethasone suppression test (aldosterone suppresses with dexamethasone - unlike typical PA)
• Treat with low-dose glucocorticoid (prednisolone 2.5-5 mg) to suppress ACTH

SBA Practice Question

A 38-year-old woman presents with resistant hypertension (BP 165/105 on amlodipine, ramipril, and indapamide). Blood tests show Na+ 144, K+ 3.1, HCO3- 30. Aldosterone/renin ratio is elevated. She undergoes saline suppression test. Which result confirms primary aldosteronism?

A. Aldosterone less than 100 pmol/L after saline
B. Aldosterone 150 pmol/L after saline
C. Aldosterone 300 pmol/L after saline
D. Renin suppression to undetectable
E. Rise in blood pressure during saline infusion

Answer: C. Aldosterone > 277 pmol/L (> 10 ng/dL) post-saline confirms autonomous aldosterone production (PA). Normal response is suppression to less than 140-165 pmol/L.

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15. Future Directions and Research

Emerging Diagnostics

• 11C-Metomidate PET-CT: Non-invasive imaging to localise aldosterone-producing tissue (may replace AVS in future) [11]
• Molecular profiling: Identifying KCNJ5 and other mutations in circulating DNA
• Steroid profiling: Urinary steroid metabolomics to subtype PA

Novel Therapeutics

• Non-steroidal MRAs: Finerenone (less hyperkalaemia, trials ongoing)
• Targeted therapy: Mutation-specific treatments for somatic KCNJ5/ATP1A1

Screening Strategies

• Broadening screening: Some advocate for ARR in all hypertensive patients (not just resistant) given high prevalence
• Machine learning: AI-based prediction models to identify high-risk patients

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16. References

Primary Sources

1. Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. DOI: 10.1210/jc.2015-4061

2. Adler GK, Stowasser M, Correa RR, et al. Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2025. DOI: 10.1210/clinem/dgaf284

3. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89(3):1045-1050.

4. Monticone S, D'Ascenzo F, Moretti C, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2018;6(1):41-50.

5. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol. 2018;6(1):51-59.

6. Käyser SC, Dekkers T, Groenewoud HJ, et al. Study Heterogeneity and Estimation of Prevalence of Primary Aldosteronism: A Systematic Review and Meta-Regression Analysis. J Clin Endocrinol Metab. 2016;101(7):2826-2835.

7. Rossi GP, Battistel M, Seccia TM. Subtyping of Primary Aldosteronism by Adrenal Venous Sampling. Endocr Rev. 2025. DOI: 10.1210/endrev/bnaf007

8. Zennaro MC, Boulkroun S, Fernandes-Rosa FL. Pathogenesis and treatment of primary aldosteronism. Nat Rev Endocrinol. 2020;16(10):578-589. DOI: 10.1038/s41574-020-0382-4

9. Fernandes-Rosa FL, Boulkroun S, Zennaro MC. Genetic and genomic mechanisms of primary aldosteronism. Trends Mol Med. 2020;26(9):819-832.

10. Lin CH, Lin CH, Chung MC, et al. Aldosterone-to-renin ratio (ARR) as a screening tool for primary aldosteronism (PA). J Formos Med Assoc. 2024;123(3):285-293. DOI: 10.1016/j.jfma.2023.04.019

11. Goodchild E, Wu X, Senanayake R, et al. Molecular Imaging Versus Adrenal Vein Sampling for the Detection of Surgically Curable Primary Aldosteronism: A Prospective Within-Patient Trial. Ann Intern Med. 2025. DOI: 10.7326/ANNALS-24-00761

12. Yang J, Burrello J, Goi J, et al. Outcomes after medical treatment for primary aldosteronism: an international consensus and analysis of treatment response in an international cohort. Lancet Diabetes Endocrinol. 2025;13(2):97-109. DOI: 10.1016/S2213-8587(24)00308-5

13. Williams TA, Lenders JWM, Mulatero P, et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol. 2017;5(9):689-699.

14. Vorselaars WMCM, Nell S, Postma EL, et al. Clinical Outcomes After Unilateral Adrenalectomy for Primary Aldosteronism. JAMA Surg. 2019;154(4):e185842.

15. Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension. 2013;62(2):331-336.

16. Hundemer GL, Leung AA, Kline GA, et al. Biomarkers to Guide Medical Therapy in Primary Aldosteronism. Endocr Rev. 2024;45(1):35-64. DOI: 10.1210/endrev/bnad024

17. Inoue K, Naito T, Fuji R, et al. Primary Aldosteronism and Risk of Cardiovascular Outcomes: Genome-Wide Association and Mendelian Randomization Study. J Am Heart Assoc. 2024;13(15):e034180. DOI: 10.1161/JAHA.123.034180

18. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059-2068.

19. Rossi GP, Rossi FB, Guarnieri C, et al. Clinical Management of Primary Aldosteronism: An Update. Hypertension. 2024;81(9):1809-1820. DOI: 10.1161/HYPERTENSIONAHA.124.22642

20. Farah MH, Hegazi M, Firwana M, et al. A Systematic Review Supporting the Endocrine Society Clinical Practice Guideline on Management of Primary Aldosteronism. J Clin Endocrinol Metab. 2025. DOI: 10.1210/clinem/dgaf290

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