Conn’s Syndrome Clinical Overview

I. The "On-Call" Snapshot

• Clinical Significance in Malaysia: This is the most common cause of secondary hypertension, present in 5-10% of our hypertensive population. You must consider it in patients with resistant hypertension or young-onset hypertension to avoid the long-term consequences of a missed diagnosis.

• High-Yield Definition: A group of disorders where aldosterone production is inappropriately high, autonomous from the renin-angiotensin system, and not suppressed by sodium loading. (Source: Endocrine Society Clinical Practice Guideline, 2016).

• Clinical One-Liner: Basically, the adrenal glands are making too much aldosterone on their own, causing high blood pressure and low potassium.

II. Etiology & Risk Factors

• Etiology:

  • Bilateral Adrenal Hyperplasia (BAH) (~60%): Both adrenal glands are diffusely hyperplastic and overproduce aldosterone. This is the most common cause overall.

  • Aldosterone-Producing Adenoma (APA) (~35%): A benign tumour on one adrenal gland. This is classic "Conn's Syndrome".

  • Rare Causes (<5%): Unilateral adrenal hyperplasia, familial hyperaldosteronism, aldosterone-producing carcinoma.

• Risk Factors (These are indications for screening, not causes):

  • Resistant hypertension (uncontrolled on ≥3 antihypertensives, including a diuretic).

  • Hypertension with spontaneous or diuretic-induced hypokalemia (K+ <3.5 mmol/L).

  • Hypertension with an adrenal incidentaloma.

  • Hypertension with a family history of early-onset hypertension or stroke (<40 years).

  • All hypertensive first-degree relatives of patients with confirmed primary aldosteronism.

III. Quick Pathophysiology

Excess autonomous aldosterone acts on the distal nephron. It binds to the mineralocorticoid receptor, leading to increased activity of the epithelial sodium channel (ENaC) and the renal outer medullary potassium channel (ROMK).

1. Sodium/Water Reabsorption: ENaC activation leads to increased sodium and water retention, causing volume expansion and hypertension.

2. Potassium/Hydrogen Excretion: ROMK activation leads to increased potassium excretion (hypokalemia) and hydrogen ion excretion (metabolic alkalosis).

   This volume expansion suppresses plasma renin activity, which is the key pathophysiological hallmark.

IV. Clinical Assessment

• Red Flags & Immediate Actions:

  • Severe Hypertension (e.g., >180/110 mmHg with symptoms): Manage as per hypertensive emergency protocol.

  • Severe Hypokalemia (K+ <2.5 mmol/L or ECG changes): Alert senior, start urgent IV potassium replacement, continuous cardiac monitoring. Can precipitate arrhythmias.

  • Muscle Paralysis: A rare but classic presentation of severe hypokalemia. Requires immediate potassium correction.

• History:

  • Common (>50%): Often completely asymptomatic apart from high blood pressure readings.

  • Less Common (10-50%): Symptoms related to hypokalemia: muscle weakness, cramps, constipation, palpitations, polyuria/polydipsia (from nephrogenic DI).

  • Pertinent Negatives: Ask about features of other secondary causes: snoring/daytime sleepiness (OSA), sweating/palpitations (pheochromocytoma), weight gain/striae (Cushing's).

• Physical Examination:

  • General: The only consistent finding is hypertension. Check for signs of end-organ damage (e.g., LV heave, retinopathy).

  • Vitals: Document BP in both arms.

• Clinical Pearl: The absence of hypokalemia does not rule out primary aldosteronism. Over 50% of patients are normokalemic at diagnosis. Your suspicion should be based on the clinical context (e.g., resistant hypertension), not the potassium level.

V. Diagnostic Workflow

This is a step-wise process: Screening → Confirmation → Subtype differentiation.

• Differential Diagnosis (for Hypertension + Hypokalemia):

  • Diuretic Use:

    • Points For: Commonest cause in practice.

    • Points Against: Renin and aldosterone will both be high (secondary hyperaldosteronism).

    • How to Differentiate: Stop the diuretic and repeat electrolytes.

  • Renovascular Hypertension (Renal Artery Stenosis):

    • Points For: Resistant hypertension.

    • Points Against: Often presents with a renal bruit, flash pulmonary edema.

    • How to Differentiate: Both renin and aldosterone are high. Imaging (e.g., CT angiogram) confirms stenosis.

  • Cushing's Syndrome:

    • Points For: Hypertension, hypokalemia.

    • Points Against: Lacks the classic Cushingoid features (central obesity, striae, etc.).

    • How to Differentiate: Overnight dexamethasone suppression test.

• Investigations Plan:

  • Step 1: Screening Test - Aldosterone-Renin Ratio (ARR)

    • Preparation is CRUCIAL:

      1. Correct Hypokalemia: Potassium must be in the normal range.

      2. Medication Washout: Stop interfering drugs. Spironolactone/Eplerenone for 4 weeks. Beta-blockers, ACEi, ARBs, diuretics for 2 weeks if safe to do so. Use alternatives like Prazosin or Hydralazine for BP control.

      3. Timing: Take the blood sample in the morning, after the patient has been upright for at least 2 hours.

    • Interpretation: A high ARR (local lab cutoffs vary, but often >750 pmol/L : ng/mL/h) suggests primary aldosteronism.

  • Step 2: Confirmatory Testing

    • If ARR is positive, you must confirm aldosterone autonomy.

    • Oral Sodium Loading Test or Saline Infusion Test: In our setting, the saline infusion test is common. Involves infusing 2L of 0.9% NaCl over 4 hours. A post-infusion plasma aldosterone that is not suppressed (e.g., >140 pmol/L) confirms the diagnosis.

  • Step 3: Subtype Differentiation

    • Goal: Differentiate unilateral adenoma (surgical) from bilateral hyperplasia (medical).

    • Adrenal CT Scan: First-line imaging to look for a unilateral adenoma (>1cm).

    • Adrenal Venous Sampling (AVS): The gold standard. An interventional radiologist samples blood directly from both adrenal veins to measure aldosterone levels. This confirms if one side is producing excess aldosterone (lateralization). AVS is essential before surgery, as CT can be misleading (non-functioning incidentalomas are common).

VI. Staging & Severity Assessment

Classification is based on subtype, which dictates management.

• Aldosterone-Producing Adenoma (APA) / Unilateral Disease: Indicates a surgical candidate.

• Bilateral Adrenal Hyperplasia (BAH): Indicates medical management.

VII. Management Plan

• Immediate Stabilisation:

  • Control severe hypertension with IV agents if needed.

  • Correct severe hypokalemia with IV potassium chloride.

• Definitive Treatment (Based on Subtype):

  • For Unilateral Disease (APA):

    • First-Line: Laparoscopic Adrenalectomy. This is potentially curative. BP improves in >80% of patients and is cured in ~40-50%. Hypokalemia is cured in almost all.

    • Pre-op: Patient must be started on a Mineralocorticoid Receptor Antagonist (MRA) like Spironolactone to control BP and potassium before surgery.

  • For Bilateral Disease (BAH) or Unilateral disease in non-surgical candidates:

    • First-Line: Lifelong MRA therapy.

      • Spironolactone: Start 12.5-25mg daily, titrate up to 100mg. Effective but has anti-androgenic side effects (gynecomastia, erectile dysfunction).

      • Eplerenone: More selective, fewer side effects, but less potent and more expensive. Start 25mg BD.

    • Goal: Normalise potassium and blood pressure.

• Long-Term & Discharge Plan:

  • Post-adrenalectomy: Monitor BP and electrolytes. Many will still need some antihypertensives.

  • On MRA therapy: Monitor renal function and potassium levels, especially after dose changes or in those with CKD.

VIII. Complications

• From Disease: All complications related to long-term uncontrolled hypertension (LVH, heart failure, stroke, CKD) and hypokalemia (arrhythmias, renal cysts).

• From Management:

  • Surgery: Risks of adrenalectomy (bleeding, infection, adrenal insufficiency if contralateral gland is suppressed).

  • Spironolactone: Hyperkalemia, gynecomastia, menstrual irregularities.

  • Eplerenone: Hyperkalemia.

IX. Prognosis

• Excellent with treatment.

• Adrenalectomy for an APA offers a potential cure for hypertension and normalises cardiovascular risk.

• MRA therapy for BAH effectively controls BP and prevents complications.

X. How to Present to Your Senior

"Dr, for review please. This is Mr. Lim from clinic, a 42-year-old man referred for resistant hypertension, currently on Amlodipine, Perindopril and HCTZ. His BP today is 165/102. His initial bloods showed a potassium of 3.2 mmol/L.

My primary differential is primary aldosteronism. I have advised him on the need for further investigation and explained about stopping his current medications to prepare for an aldosterone-renin ratio test. I would like your advice on a safe bridging regimen for his BP control during the washout period."

XI. Summary & Further Reading

• Top 3 Takeaways:

  1. Screen for it: Think of primary aldosteronism in any patient with resistant, young-onset, or hypokalemic hypertension.

  2. ARR is the Key: The aldosterone-renin ratio is the crucial first screening step, but preparation is vital.

  3. Subtype Determines Treatment: Use CT and Adrenal Venous Sampling to differentiate. Adenomas get surgery; hyperplasia gets medication (MRAs).

• Key Resources:

  • Endocrine Society CPG: The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment (Note: This is the international standard).

  • UpToDate: Diagnosis of primary aldosteronism

  • Amboss: Primary hyperaldosteronism