Conn's Syndrome (Primary Hyperaldosteronism)

1. Clinical Overview

Summary

Conn's syndrome, or primary aldosteronism (PA), represents the most common cause of secondary hypertension and potentially curable form of hypertension. First described by Jerome Conn in 1955, it is characterised by autonomous aldosterone secretion from the adrenal cortex, independent of the renin-angiotensin system. The condition affects 5-10% of all hypertensive patients and over 20% of those with resistant hypertension, making it substantially more prevalent than historically recognised. [1,2]

Primary aldosteronism encompasses several subtypes, with bilateral adrenal hyperplasia (BAH, also termed idiopathic hyperaldosteronism) accounting for approximately 60-65% of cases and aldosterone-producing adenoma (APA, the classic "Conn's syndrome") comprising 30-35% of cases. Rare causes include unilateral adrenal hyperplasia, familial hyperaldosteronism (types I-IV), and aldosterone-producing adrenocortical carcinoma. [3]

The clinical importance of diagnosing PA extends beyond blood pressure control. Aldosterone excess causes cardiovascular and renal damage independent of blood pressure elevation. Patients with PA have significantly higher rates of stroke, myocardial infarction, atrial fibrillation, and heart failure compared to blood pressure-matched patients with essential hypertension. Early diagnosis and targeted treatment can reverse these risks and potentially achieve cure in cases amenable to surgery. [4,5]

Key Facts

Clinical Pearls

"Hypokalaemia Is NOT Required": Classic teaching describes hypokalaemia as a hallmark, but it occurs in only 30-50% of cases at diagnosis. The majority of PA patients are normokalaemic. Screen for PA based on hypertension severity and resistance, not potassium levels. [1]

"The ARR Is a Screening Test — Not Diagnostic": The Aldosterone-to-Renin Ratio identifies patients requiring confirmatory testing. A positive ARR requires confirmation with a suppression test before proceeding to subtype differentiation. An isolated positive ARR does not diagnose PA. [1,2]

"CT Cannot Distinguish Subtypes Reliably": Adrenal CT may show a unilateral nodule, but this can be a non-functioning incidentaloma with contralateral micro-adenoma causing PA. Adrenal vein sampling (AVS) is essential for patients > 35 years or when CT findings are equivocal, as it determines whether disease is truly unilateral (surgical) or bilateral (medical). [1,6]

"Aldosterone Excess Causes CV Damage Beyond BP": Patients with PA have 4.2x higher stroke risk, 6.5x higher MI risk, and 12.1x higher AF risk compared to essential hypertension at equivalent blood pressures. This is due to direct aldosterone-mediated cardiac fibrosis, endothelial dysfunction, and vascular inflammation. [4,5]

"Renin Target for Medical Therapy": In medically treated PA, patients whose renin remains suppressed on MRA therapy have significantly higher cardiovascular event rates. Titrating MRA dose to achieve unsuppressed renin (PRA ≥1 μg/L/h) may mitigate excess cardiovascular risk. [7]

"KCNJ5 Mutations Predict Better Surgical Outcomes": Somatic KCNJ5 mutations occur in 30-40% of APAs, more commonly in women and younger patients. These adenomas tend to be larger and associated with higher aldosterone levels but better surgical outcomes. [8]

Why This Matters Clinically

Primary aldosteronism is severely underdiagnosed. Studies suggest that systematic screening could identify PA in 5.9% of unselected hypertensive patients in primary care settings. [2] Identifying PA has three major clinical implications:

1. Cure potential: Unilateral disease (APA) can be cured with laparoscopic adrenalectomy — complete clinical success in 37% and partial success in 47%
2. Targeted therapy: Bilateral disease responds specifically to mineralocorticoid receptor antagonists
3. Cardiovascular protection: Treatment of PA reduces the excess cardiovascular risk beyond blood pressure control

All patients with resistant hypertension, spontaneous hypokalaemia, adrenal incidentaloma, or young-onset hypertension should be screened. [1,9]

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2. Epidemiology

Prevalence by Clinical Setting

Aetiology and Subtype Distribution

Demographics

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3. Pathophysiology

Normal Aldosterone Physiology

Aldosterone is the primary mineralocorticoid synthesised in the zona glomerulosa of the adrenal cortex. Its synthesis and secretion are regulated by:

Aldosterone Actions on Distal Nephron:

1. Binds cytoplasmic mineralocorticoid receptor (MR) in principal cells of collecting duct
2. MR-aldosterone complex translocates to nucleus
3. Upregulates epithelial sodium channel (ENaC) on apical membrane
4. Upregulates Na+/K+-ATPase on basolateral membrane
5. Net effect: Sodium reabsorption, Potassium secretion, Hydrogen ion secretion

Pathophysiology of Primary Aldosteronism

Autonomous Aldosterone Secretion:

In PA, aldosterone is produced independently of the normal physiological regulators:

• Aldosterone secretion continues despite sodium loading
• Renin production is suppressed by volume expansion (negative feedback)
• The disconnect between suppressed renin and elevated aldosterone is the biochemical hallmark

Molecular Pathogenesis of Aldosterone-Producing Adenomas:

Recent advances have identified somatic mutations driving autonomous aldosterone production in APAs: [8,10]

All mutations converge on a common pathway: increased intracellular calcium → activation of calcium-dependent transcription factors → upregulation of CYP11B2 (aldosterone synthase).

Consequences of Aldosterone Excess:

Why PA Causes Excess CV Events Independent of BP:

The landmark Milliez study demonstrated that patients with PA have significantly higher cardiovascular event rates than BP-matched essential hypertensives: [4]

• Stroke: OR 4.2 (95% CI 2.0-8.6)
• Myocardial infarction: OR 6.5 (95% CI 1.5-27.4)
• Atrial fibrillation: OR 12.1 (95% CI 3.2-45.2)

This excess risk is attributed to direct aldosterone effects on the heart and vasculature, independent of blood pressure elevation.

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4. Clinical Presentation

Symptoms

Signs

Who to Screen for Primary Aldosteronism

The Endocrine Society Clinical Practice Guideline (2016) recommends screening in the following groups: [1]

[!IMPORTANT] Indications for PA Screening (Endocrine Society 2016):

1. Resistant hypertension — BP > 140/90 mmHg on ≥3 antihypertensives (including a diuretic) at optimal doses, or controlled BP requiring ≥4 drugs

2. Hypertension + hypokalaemia — Spontaneous or diuretic-induced hypokalaemia (K+ less than 3.5 mmol/L)

3. Hypertension + adrenal incidentaloma — Any adrenal mass in a hypertensive patient

4. Hypertension + obstructive sleep apnoea — Both conditions associated with aldosterone excess

5. Hypertension + family history — Early-onset hypertension or cerebrovascular accident at young age (less than 40 years) in first-degree relatives

6. First-degree relatives of PA patients — All hypertensive first-degree relatives should be screened

7. Moderate-severe hypertension — Consider screening in all patients with sustained BP > 150/100 mmHg on two occasions

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5. Clinical Examination

Systematic Examination Approach

General Inspection:

• Usually unremarkable — no specific signs of PA
• May appear well despite significant hypertension
• Cushing's features suggest cortisol co-secretion (rare)

Cardiovascular Examination:

• Blood pressure: Elevated; measure in both arms; assess for orthostatic hypotension
• JVP: Usually normal; may be elevated if heart failure
• Apex beat: May be sustained/displaced (LVH from chronic hypertension)
• Heart sounds: S4 gallop suggests LVH; murmurs of hypertensive heart disease
• Peripheral pulses: Assess for arterial disease; radiofemoral delay (coarctation differential)

Neurological Examination:

• Proximal muscle weakness: Ask to rise from squatting position without using hands
• Deep tendon reflexes: May be diminished in hypokalaemia
• Cranial nerves/focal signs: Previous stroke sequelae

Abdominal Examination:

• Usually normal
• Adrenal masses typically not palpable unless very large (consider carcinoma if palpable mass)

End-Organ Damage Assessment:

• Fundoscopy: Hypertensive retinopathy grading
• ECG: LVH criteria; AF; U waves (hypokalaemia); prolonged QT

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6. Investigations

Diagnostic Algorithm

The investigation of suspected PA follows a three-step process:

STEP 1: SCREENING
         ↓
    Positive ARR
         ↓
STEP 2: CONFIRMATORY TESTING
         ↓
    PA Confirmed
         ↓
STEP 3: SUBTYPE DIFFERENTIATION
         ↓
    Unilateral (Surgery) vs Bilateral (Medical)

Step 1: Screening — Aldosterone-to-Renin Ratio (ARR)

Pre-Test Preparation:

Medication Effects on ARR: [1,11]

Acceptable Medications During Workup:

• Verapamil (slow-release) 90-120 mg BD
• Hydralazine 10-50 mg TDS
• Prazosin 1-5 mg BD/TDS
• Doxazosin 2-8 mg daily

ARR Interpretation:

Important: A positive ARR screen requires BOTH:

1. Elevated ARR (> 30 using PRA)
2. Elevated aldosterone level (> 15 ng/dL or > 416 pmol/L)

Step 2: Confirmatory Testing

A positive ARR requires confirmation with one of the following suppression tests: [1,12]

Choosing a Confirmatory Test:

• Saline suppression test: Most commonly used; good balance of sensitivity/specificity
• Oral sodium loading: Outpatient; useful when IV access difficult
• Fludrocortisone suppression: Gold standard sensitivity; complex and requires close monitoring
• Captopril challenge: Convenient but less standardised

Step 3: Subtype Differentiation

Once PA is confirmed, differentiating unilateral (surgical) from bilateral (medical) disease is essential: [1,6]

CT Adrenals:

CT Limitations:

• Cannot distinguish functioning from non-functioning adenomas
• 25% of unilateral CT nodules are non-functioning incidentalomas with contralateral micro-adenoma causing PA
• 20% of patients with normal/bilateral CT findings have unilateral disease on AVS

Adrenal Vein Sampling (AVS): [1,6,13]

Genetic Testing for Familial Hyperaldosteronism:

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7. Management

Management Algorithm

         PRIMARY ALDOSTERONISM — CONFIRMED
                          ↓
    ┌─────────────────────────────────────┐
    │      SUBTYPE DIFFERENTIATION        │
    │  CT Adrenals + Adrenal Vein Sampling│
    └─────────────────────────────────────┘
                          ↓
         ┌────────────────┴────────────────┐
         ↓                                 ↓
   UNILATERAL DISEASE                BILATERAL DISEASE
   (Aldosterone-Producing            (Idiopathic Hyperaldo-
    Adenoma or Unilateral             steronism / BAH)
    Hyperplasia)                             
         ↓                                 ↓
    ┌─────────────────┐           ┌─────────────────────┐
    │SURGICAL OPTION  │           │ MEDICAL THERAPY     │
    │                 │           │                     │
    │Pre-operative:   │           │First-line:          │
    │• MRA therapy    │           │• Spironolactone     │
    │  4-8 weeks      │           │  12.5-25 mg initial │
    │• Correct K+     │           │  Titrate to         │
    │• Optimise BP    │           │  50-400 mg/day      │
    │• Echo if LVH    │           │                     │
    └────────┬────────┘           │Alternative:         │
             ↓                    │• Eplerenone 25-50 mg│
    ┌─────────────────┐           │  BD (selective MRA) │
    │LAPAROSCOPIC     │           │                     │
    │ADRENALECTOMY    │           │Adjunctive:          │
    │                 │           │• Amiloride 5-20 mg  │
    │• Unilateral     │           │• Additional anti-HTN│
    │  procedure      │           │  agents as needed   │
    │• 1-3 day stay   │           │                     │
    │• Low morbidity  │           │Monitoring:          │
    │                 │           │• Target: normalise  │
    └────────┬────────┘           │  K+, optimise BP    │
             ↓                    │• Consider: unsup-   │
    ┌─────────────────┐           │  pressed renin as   │
    │POST-OPERATIVE   │           │  therapeutic target │
    │MONITORING       │           └─────────────────────┘
    │                 │
    │• Check K+ (risk │
    │  of hyperkalaemia│
    │  from suppressed│
    │  contralateral)│
    │• Wean MRA       │
    │• Monitor BP     │
    │• Reassess at    │
    │  1, 3, 6, 12 mo │
    └─────────────────┘

Pre-Operative Preparation for Adrenalectomy

Surgical Treatment — Laparoscopic Adrenalectomy

Indications:

• Confirmed unilateral PA on AVS
• Age less than 35 with clear unilateral adenoma on CT (AVS may be omitted)
• Patient fit for surgery and willing to undergo procedure

Technique:

• Laparoscopic approach preferred (lateral transperitoneal or posterior retroperitoneal)
• Conversion to open rarely required (less than 2%)
• Operative time 60-120 minutes
• Hospital stay 1-3 days

Outcomes — PASO (Primary Aldosteronism Surgical Outcome) Criteria: [14]

The international PASO consensus established standardised outcome criteria:

Predictors of Better Surgical BP Outcome:

• Younger age
• Female sex
• Shorter duration of hypertension
• Lower BMI
• Fewer antihypertensive medications pre-operatively
• Absence of vascular remodelling
• KCNJ5 somatic mutation in adenoma

Medical Treatment — Mineralocorticoid Receptor Antagonists

Indications:

• Bilateral adrenal hyperplasia (BAH)
• Unilateral disease in patients unfit or unwilling for surgery
• Pre-operative optimisation
• Familial hyperaldosteronism (except GRA)

Medication Options: [1,15]

Titration Strategy:

1. Start low (spironolactone 12.5-25 mg or eplerenone 25 mg BD)
2. Increase every 4-8 weeks based on:
   • Blood pressure response
   • Potassium normalisation (target 4.0-5.0 mmol/L)
   • Renin response (target PRA > 1 ng/mL/h — may indicate adequate MR blockade)
3. Add other antihypertensives if BP not controlled at moderate MRA doses
4. Monitor for adverse effects

Monitoring:

Renin-Guided Therapy:

Emerging evidence suggests that titrating MRA therapy to achieve unsuppressed renin (PRA ≥1 μg/L/h) may reduce the excess cardiovascular risk associated with medically treated PA. Patients with persistently suppressed renin on MRA therapy have significantly higher CV event rates. [7]

Treatment of Familial Hyperaldosteronism

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8. Complications and Prognosis

Complications of Untreated or Undertreated PA

Cardiovascular Complications:

Renal Complications:

Metabolic Complications:

Neuromuscular Complications:

Treatment-Related Complications

Prognosis

Surgical Outcomes (Using PASO Criteria): [14]

Long-Term Cardiovascular Outcomes:

With appropriate treatment (surgical or medical), the excess cardiovascular risk of PA can be substantially reduced but may not be completely eliminated:

• Treatment reduces LVH and cardiac fibrosis
• Cardiovascular event rates decrease with adequate treatment
• Earlier diagnosis and treatment associated with better outcomes
• Medically treated patients with persistently suppressed renin may have residual excess risk [7]

Mortality:

The German Conn's Registry showed no excess mortality in appropriately treated PA patients compared to the general population, highlighting the importance of diagnosis and treatment. [16]

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9. Special Considerations

PA in Pregnancy

PA in Older Adults

PA with CKD

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10. Differential Diagnosis

Causes of Secondary Hypertension — Comparison with PA

Approach to Low Renin Hypertension

When renin is suppressed in a hypertensive patient, consider:

Algorithm for Differentiating Low-Renin Hypertension

         LOW RENIN HYPERTENSION
                    ↓
            Check Aldosterone Level
                    ↓
    ┌───────────────┴───────────────┐
    ↓                               ↓
 HIGH ALDOSTERONE              LOW/NORMAL ALDOSTERONE
    ↓                               ↓
 PRIMARY                   Check Potassium
 ALDOSTERONISM                  ↓
    ↓                   ┌───────┴───────┐
 ARR Screening          ↓               ↓
    ↓               HYPOKALAEMIA    NORMOKALAEMIA
 Confirm with           ↓               ↓
 Suppression Test   • Liddle syndrome   Essential HTN
    ↓               • AME               (low-renin subset)
 AVS for subtyping  • Exogenous MC
                    • CAH (11β/17α)
                        ↓
                    Genetic/drug/
                    steroid workup

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11. Imaging Interpretation

CT Adrenal Glands — Findings and Interpretation

CT Technical Considerations:

Adrenal Vein Sampling — Technical Interpretation

Confirming Successful Cannulation (Selectivity Index):

Determining Lateralisation (Lateralisation Index):

Common AVS Pitfalls:

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12. Follow-Up and Monitoring

Post-Adrenalectomy Follow-Up Protocol

Interpreting Post-Surgical Outcomes:

Medical Therapy Follow-Up Protocol

Side Effect Monitoring:

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13. Evidence and Guidelines

Key Guidelines

Key Evidence Summary

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11. Patient/Layperson Explanation

What is Conn's Syndrome?

Conn's syndrome, also called primary hyperaldosteronism (PA), is a condition where one or both adrenal glands (small glands that sit on top of your kidneys) make too much of a hormone called aldosterone.

Aldosterone normally helps control your blood pressure and potassium levels. When there is too much of it, your body holds onto too much salt and water, which raises your blood pressure. It also causes your kidneys to lose too much potassium.

Why Does It Matter?

PA is the most common treatable cause of high blood pressure. Finding and treating it can:

• Cure your high blood pressure if caused by a single adrenal gland problem (about 1 in 3 people are cured with surgery)
• Significantly improve blood pressure control with targeted medication
• Reduce your risk of heart attacks, strokes, and heart rhythm problems which are higher in people with PA compared to regular high blood pressure

What Are the Symptoms?

Most people with PA have no symptoms other than high blood pressure. Some may experience:

• High blood pressure that is hard to control with standard medications
• Low potassium levels (may cause muscle weakness, cramps, or excessive urination)
• Feeling tired or weak

How Is It Diagnosed?

1. Blood test (aldosterone and renin levels) — a screening test
2. Confirmatory test — usually salt water given through a drip to see if aldosterone stays high
3. CT scan of the adrenal glands
4. Adrenal vein sampling — a special test to determine if one or both glands are affected

What Is the Treatment?

• If one adrenal gland is affected: Keyhole surgery to remove it can often cure the condition
• If both glands are affected: Tablets that block the effects of aldosterone (called MRAs — spironolactone or eplerenone) can effectively control the condition

Key Takeaway

If you have high blood pressure that is difficult to control, ask your doctor about testing for PA. Finding it early means better treatment and lower risk of heart problems.

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12. Examination Focus

High-Yield Exam Topics

Sample Viva Questions

Q1: A 52-year-old man has resistant hypertension on four medications including a thiazide diuretic. His potassium is 3.8 mmol/L. Would you screen for primary aldosteronism?

Model Answer: Yes, I would screen for primary aldosteronism. Resistant hypertension is a key indication for PA screening regardless of potassium level. Hypokalaemia is only present in 30-50% of PA patients, so a normal potassium does not exclude the diagnosis. I would perform an aldosterone-to-renin ratio (ARR) test after appropriate preparation — stopping the thiazide for at least 4 weeks and using calcium channel blockers or alpha-blockers for BP control. If the ARR is elevated with high aldosterone and suppressed renin, I would proceed to confirmatory testing with a saline suppression test.

Q2: How does adrenal vein sampling differentiate between aldosterone-producing adenoma and bilateral adrenal hyperplasia?

Model Answer: Adrenal vein sampling (AVS) is the gold standard for subtype differentiation in PA. The procedure involves selective catheterisation of both adrenal veins and the inferior vena cava. Cortisol is measured to confirm successful cannulation — the selectivity index (adrenal vein cortisol divided by IVC cortisol) should be > 3:1 unstimulated or > 5:1 with ACTH stimulation. To determine lateralisation, we calculate the lateralisation index — the ratio of aldosterone:cortisol on the high side divided by the low side. A ratio > 4:1 indicates unilateral disease suitable for surgery. If there is no lateralisation, this suggests bilateral hyperplasia, which should be treated medically with mineralocorticoid receptor antagonists.

Q3: What are the cardiovascular risks of untreated primary aldosteronism and why do they exceed those of essential hypertension at equivalent blood pressure levels?

Model Answer: Patients with PA have significantly higher cardiovascular event rates than blood pressure-matched essential hypertensives — approximately 4-fold higher stroke risk, 6-fold higher MI risk, and 12-fold higher atrial fibrillation risk. This excess risk is due to direct aldosterone effects beyond hypertension. Aldosterone binds to mineralocorticoid receptors in the heart and vasculature, causing myocardial fibrosis, LVH disproportionate to blood pressure, endothelial dysfunction, vascular inflammation, and increased arterial stiffness. Additionally, hypokalaemia contributes to arrhythmia risk. This is why identifying and treating PA is important not just for blood pressure control but for cardiovascular protection.

Q4: Compare spironolactone and eplerenone for medical management of primary aldosteronism.

Model Answer: Both are mineralocorticoid receptor antagonists used for bilateral PA or when surgery is not appropriate. Spironolactone is the traditional first-line agent — it is inexpensive and effective, with typical doses of 25-200 mg daily. However, it has significant anti-androgen effects due to binding to androgen and progesterone receptors, causing gynaecomastia in up to 50% of men at higher doses, breast tenderness, erectile dysfunction, and menstrual irregularities in women. Eplerenone is a selective MRA with minimal anti-androgen effects but is more expensive and may require twice-daily dosing. The choice depends on patient tolerance — spironolactone is reasonable first-line with switch to eplerenone if anti-androgen side effects occur. Titration should target normalised potassium and blood pressure, with some evidence suggesting that achieving unsuppressed renin may improve cardiovascular outcomes.

Common Exam Errors

MCQ/SBA Practice Questions

Question 1 (Difficulty: Moderate)

A 45-year-old woman with treatment-resistant hypertension (on amlodipine 10mg, lisinopril 40mg, and hydrochlorothiazide 25mg) is investigated for primary aldosteronism. Her aldosterone-to-renin ratio (ARR) returns at 45 (aldosterone 450 pmol/L, renin 10 mU/L). Serum potassium is 3.8 mmol/L.

Which of the following is the most appropriate next step?

A. Proceed directly to CT adrenals
B. Start spironolactone and monitor response
C. Stop hydrochlorothiazide and repeat ARR in 4 weeks
D. Perform saline suppression test
E. Refer for adrenal vein sampling

Answer and Explanation

Answer: C

The ARR is elevated (> 30 pmol/mU or > 20 ng/dL per ng/mL/hr), but hydrochlorothiazide causes false-negative results by lowering aldosterone and raising renin. Therefore, the screening test is unreliable in this context. The thiazide should be stopped for at least 4 weeks, with blood pressure controlled using agents that minimally affect the RAAS (calcium channel blockers like amlodipine are acceptable; alpha-blockers are ideal). The ARR should then be repeated. ACE inhibitors also affect ARR (false negatives) but can be continued if necessary for BP control.

Examiner's Note: This tests understanding that medication interference must be addressed before interpreting screening results. A truly elevated ARR despite medications that should lower it would be even more suggestive of PA.

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Question 2 (Difficulty: High)

A 52-year-old man with confirmed primary aldosteronism (positive saline suppression test) undergoes adrenal vein sampling. Results are shown:

What is the lateralisation index and recommended management?

A. LI = 1.5; bilateral hyperplasia, treat with spironolactone
B. LI = 3.1; borderline, repeat AVS with ACTH stimulation
C. LI = 3.1; unilateral disease, refer for right adrenalectomy
D. LI = 4.9; unilateral disease, refer for right adrenalectomy
E. LI = 10.0; unilateral disease, refer for right adrenalectomy

Answer and Explanation

Answer: C

Calculation:

1. First, confirm successful cannulation (selectivity index = adrenal vein cortisol / IVC cortisol):

   • Right: 850/320 = 2.7 (acceptable if > 2 unstimulated)
   • Left: 680/320 = 2.1 (acceptable if > 2 unstimulated)

2. Calculate aldosterone:cortisol ratio for each side:

   • Right: 8500/850 = 10.0
   • Left: 2200/680 = 3.2

3. Lateralisation index = higher side / lower side = 10.0/3.2 = 3.1

A lateralisation index > 4:1 is the traditional threshold for clear unilateral disease. With an LI of 3.1, this is borderline. However, many centres now consider LI > 2-3 sufficient, especially with concordant imaging. The selectivity indices are borderline (ideally > 3:1 unstimulated), so repeating with ACTH stimulation (Answer B) would be reasonable. However, given the clinical context and moderately elevated LI, Answer C (proceeding to surgery) is also acceptable.

Teaching Point: AVS interpretation requires calculating both selectivity (cannulation success) and lateralisation (side identification). Thresholds vary by centre and ACTH use.

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Question 3 (Difficulty: Moderate)

A 38-year-old woman undergoes successful laparoscopic left adrenalectomy for a left-sided aldosterone-producing adenoma confirmed on AVS. Three months post-operatively, her blood pressure is 142/88 mmHg on amlodipine 5mg. Potassium is 4.2 mmol/L.

According to the PASO consensus criteria, how would you classify her outcome?

A. Complete clinical success
B. Partial clinical success
C. Absent clinical success
D. Complete biochemical success
E. Cannot be determined at 3 months

Answer and Explanation

Answer: B - Partial clinical success

PASO (Primary Aldosteronism Surgical Outcome) criteria classify outcomes as:

Clinical Success (blood pressure outcomes):

• Complete: BP less than 140/90 without antihypertensives
• Partial: Same BP on fewer drugs OR reduced BP on same/fewer drugs
• Absent: No improvement in BP or medications

Biochemical Success (aldosterone/renin normalisation):

• Complete: Correction of hypokalaemia + aldosterone-to-renin ratio normalisation
• Partial: Correction of hypokalaemia with persistent abnormal ARR
• Absent: Persistent abnormalities

This patient has potassium normalisation and BP controlled on a single low-dose agent (reduced from pre-operative medications). This represents partial clinical success - improved BP control on reduced medications, though not drug-free normalisation.

Key Statistic: The PASO study showed complete clinical success in only 37% of patients, with partial success in 47% and absent success in 16%.

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Question 4 (Difficulty: High)

A 28-year-old man presents with severe hypertension (BP 210/120 mmHg) and hypokalaemia (K+ 2.8 mmol/L). His father died of a stroke at age 35, and his paternal uncle has resistant hypertension. ARR is markedly elevated. CT shows bilateral adrenal limb thickening.

Which genetic test is most appropriate as first-line investigation?

A. Germline KCNJ5 sequencing
B. CYP11B1/CYP11B2 chimeric gene testing
C. CACNA1D mutation analysis
D. ATP1A1 mutation screening
E. MEN1 gene sequencing

Answer and Explanation

Answer: B

The clinical features suggest Familial Hyperaldosteronism Type I (FH-I), also known as Glucocorticoid-Remediable Aldosteronism (GRA):

• Young onset
• Family history of early stroke/severe hypertension
• Autosomal dominant inheritance pattern
• Bilateral adrenal hyperplasia

FH-I is caused by a chimeric gene resulting from unequal crossing-over between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase). This places aldosterone synthase under ACTH control, causing aldosterone production that is suppressible with glucocorticoids.

Testing is via long-range PCR detecting the chimeric gene. Treatment is with low-dose dexamethasone (0.125-0.25 mg nocte) to suppress ACTH-driven aldosterone production.

Other FH types:

• FH-II: Unknown genetic basis (most common)
• FH-III: KCNJ5 germline mutations (severe, often requires adrenalectomy)
• FH-IV: CACNA1H mutations

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Question 5 (Difficulty: Moderate)

Which combination of findings would most strongly support a diagnosis of primary aldosteronism rather than secondary hyperaldosteronism?

A. High aldosterone, high renin, hypokalaemia
B. High aldosterone, low renin, metabolic alkalosis
C. Low aldosterone, high renin, normal potassium
D. High aldosterone, high renin, metabolic acidosis
E. Normal aldosterone, low renin, hyperkalaemia

Answer and Explanation

Answer: B

Primary aldosteronism is characterised by autonomous aldosterone production, leading to:

• High aldosterone (autonomous production)
• Low/suppressed renin (negative feedback from sodium retention and volume expansion)
• Hypokalaemia (from renal potassium wasting)
• Metabolic alkalosis (from renal H+ loss in exchange for sodium retention)

Answer A describes secondary hyperaldosteronism (both aldosterone and renin elevated), seen in renal artery stenosis, heart failure, or diuretic use.

The combination of high aldosterone with suppressed renin is the diagnostic hallmark that distinguishes primary from secondary causes.

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Deck: MedVellum::Endocrinology::Adrenal::Primary_Aldosteronism

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Clinical Pearls for Exams

1. The "Rule of Thirds": Approximately 1/3 of PA patients have APAs, 2/3 have BAH; approximately 1/3 achieve complete cure, 1/3 partial cure, 1/3 no improvement after surgery.

2. Hypokalaemia Misconception: Most PA patients are normokalaemic. Hypokalaemia is the exception, not the rule - it's present in only 30-50%.

3. The CV Protection Imperative: PA identification isn't just about BP control - it's about recognising a condition with 4-6x higher CV risk that requires specific treatment.

4. AVS is Non-Negotiable: For patients over 35 years, even with a clear unilateral adenoma on CT, AVS is required because CT cannot reliably distinguish subtypes.

5. Medication Timing Matters: The 4-6 week washout for MRAs before ARR testing reflects spironolactone's long-acting metabolites, not just the parent drug.

6. Surgical Expectations: Patients must be counselled that complete BP normalisation occurs in only ~37% after adrenalectomy. Many will still need antihypertensives.

7. Young + Bilateral + Family History = Think Genetics: FH-I (GRA) should be considered in young patients with family history, as it's treatable with low-dose glucocorticoids.

8. Renin is the Key: Low renin distinguishes primary from secondary causes. If renin is not suppressed, look for other diagnoses or medication interference.

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13. References

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 PMID: 26934393

2. Monticone S, Burrello J, Tizzani D, et al. Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. J Am Coll Cardiol. 2017;69(14):1811-1820. doi:10.1016/j.jacc.2017.01.052 PMID: 28385310

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Last Reviewed: 2026-01-09 | MedVellum Editorial Team

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