PRIMARY ALDOSTERONISM (PA)

Definition and Subtypes

• Primary Aldosteronism (PA): Characterized by hypertension, suppressed renin, and increased aldosterone secretion (Conn, 1955).
• Main Subtypes:
  1. Bilateral Idiopathic Hyperaldosteronism (IHA): Most common.
  2. Aldosterone-Producing Adenoma (APA): Also common.
  3. Unilateral Adrenal Hyperplasia (UAH): Rare, unilateral zona glomerulosa hyperplasia.
  4. Familial Hyperaldosteronism (FH):
     • Type I (Glucocorticoid-Remediable Aldosteronism, GRA): Autosomal dominant, suppressed by exogenous glucocorticoids.
     • Type II: Familial occurrence of APA and/or IHA.
  5. Ectopic Aldosterone Secretion (very rare, e.g., ovarian tumor).

Clinical Presentation

• Prevalence: ~5% of all hypertension cases (most common identifiable secondary HTN).
• Many Patients: Normal serum potassium (no hypokalemia).
• Hypokalemia (if present): May cause alkalosis, nocturia, polyuria, muscle cramps, palpitations, positive Chvostek/Trousseau signs.
• Suspect PA:
  • Hypertension + Hypokalemia.
  • Resistant (treatment-refractory) hypertension.
  • Hypertension + Adrenal incidentaloma.
  • Onset of hypertension <20 years old.
  • Severe hypertension.

Case-Finding and Confirmation

1. Screening Test: Morning (8–10 am) ratio of Plasma Aldosterone Concentration (PAC) to Plasma Renin Activity (PRA).
   • Avoid MR antagonists or high-dose amiloride.
   • Correct hypokalemia first to avoid false negatives.
   • PAC:PRA ratio has ~75% sensitivity/specificity.
   • Elevated ratio → proceed to confirmatory aldosterone-suppression testing (oral sodium loading, saline infusion, captopril test, or fludrocortisone test).
2. Subtyping
   • Imaging (CT) of adrenals is done, but non-diagnostic in many cases.
   • Adrenal Venous Sampling (AVS) is usually necessary if a surgical cure is desired.

Treatment Options

• Unilateral Aldosterone Excess (APA or UAH): Unilateral laparoscopic adrenalectomy → corrects hypokalemia, improves HTN (30–60% cured).
• Bilateral Idiopathic Hyperaldosteronism (IHA) or Familial Hyperaldosteronism Type I (GRA):
  • Medical therapy with Mineralocorticoid Receptor (MR) antagonist (e.g., spironolactone, eplerenone).
• Goal: Not only lower BP but also block/minimize aldosterone’s harmful cardiovascular effects.

THE BIOLOGIC ACTIONS OF ALDOSTERONE

Regulation of Aldosterone Secretion

• Stimulators:
  • Angiotensin II (RAAS)
  • Hyperkalemia
  • ACTH (minor)
• Inhibitors:
  • Atrial Natriuretic Factor (ANF)
  • Hypokalemia
• About 50–70% of aldosterone is bound (to albumin, CBG); 30–50% free.
• Half-life: ~15–20 min. Normal blood aldosterone: 0–21 ng/dL.

Classic Roles

• Regulation of ECF Volume & Potassium Homeostasis.
• Binds mineralocorticoid receptor (MR) in distal nephron → promotes Na⁺ reabsorption in exchange for K⁺/H⁺ excretion.
• Angiotensin II → negative feedback loop with ECF volume.
• MR Tissue Distribution: Highest in kidney (distal tubule), colon, hippocampus. Lower in heart, GI tract, etc.
• Mechanism: Increases expression of aldosterone-regulated kinase → modifies apical Na⁺ channels → ↑Na⁺ reabsorption → negative luminal charge → ↑K⁺ & H⁺ excretion.

Mineralocorticoid Escape

• After 3–5 days of high mineralocorticoid exposure, escape phenomenon occurs: various counterregulatory mechanisms (renal hemodynamics, ANP, etc.) limit continued volume expansion.

Nonclassic Effects

• Nongenomic Actions: Rapid cell surface receptor (likely G protein–coupled) modifies sodium-hydrogen exchange.
• Tissue Fibrosis and Injury: Aldosterone can induce collagen gene expression, TGF-β, PAI-1 → possible microangiopathy, fibrosis in heart, vessels, kidney. Imbalance between volume state & aldosterone is key.

ADRENAL VENOUS SAMPLING (AVS) FOR PRIMARY ALDOSTERONISM

Rationale

• Distinguish unilateral aldosterone-producing adenoma (APA) vs. bilateral hyperaldosteronism (IHA).
• Imaging (CT) is only ~50% accurate. AVS is gold standard for subtyping if surgical cure is pursued.

Protocol

1. Patient Preparation
   • Control BP but hold MR antagonists (spironolactone) a few weeks prior.
   • Some centers use continuous cosyntropin (ACTH) infusion to stabilize aldosterone secretion.
2. Procedure
   • Femoral vein approach → selective catheterization of both adrenal veins + a reference vein (IVC or external iliac).
   • Radiographic contrast to confirm correct catheter tip position.
   • Blood sampling for aldosterone & cortisol from each adrenal vein + reference site.
3. Interpretation
   • Cortisol levels confirm correct catheterization.
   • Compare aldosterone/cortisol ratios from each side to reference.
   • Unilateral disease: Markedly elevated ratio on one side, suppressed on contralateral.
   • Bilateral disease: Similar ratios both sides.

Complications

• ~2.5% rate in experienced centers: groin hematoma, adrenal hemorrhage, vein dissection.

RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM (RAAS) AND RENOVASCULAR HYPERTENSION

RAAS Basics

1. Renin:
   • Produced by juxtaglomerular cells in kidney.
   • Rate-limiting step converting angiotensinogen → angiotensin I.
   • Stimulated by low renal perfusion, low tubule NaCl (macula densa), sympathetic tone.
   • Suppressed by high BP, high sodium, etc.
2. Angiotensin I → II
   • Via angiotensin-converting enzyme (ACE).
   • Angiotensin II → vasoconstriction, aldosterone secretion, increased sympathetic outflow, vasopressin release, etc.
3. Aldosterone
   • Final effector in Na⁺ reabsorption, K⁺ excretion.
   • ECF volume & BP regulation.

Renovascular Hypertension

• Cause: Renal artery stenosis (atherosclerosis or fibromuscular dysplasia) → decreased perfusion → ↑renin → ↑angiotensin II → ↑aldosterone → HTN.
• Suspicion:
  • Onset <30 years or >55 years with no risk factors/family history.
  • Sudden severe or treatment-resistant HTN.
  • Unexplained atrophic kidney, rise in creatinine after ACE inhibitor, etc.
• Diagnosis:
  • Gold standard: Renal arteriography.
  • Less invasive: MR angiography, CT angiography, Duplex Doppler US.