Overview
Primary Hyperaldosteronism
1. Overview
Primary Hyperaldosteronism (PA) is a condition characterized by inappropriate, autonomous aldosterone secretion from the adrenal glands, which is not suppressed by sodium loading. It is the most common cause of secondary hypertension, accounting for 5-10% of all hypertension cases and up to 20% of resistant hypertension.
Key Classifications
- Bilateral Adrenal Hyperplasia (BAH): 60-70% of cases. Idiopathic. Treated medically.
- Aldosterone-Producing Adenoma (APA): "Conn's Syndrome". 30-40% of cases. Treated surgically.
- Familial Hyperaldosteronism: Rare genetic forms (Type I-IV).
- Adrenal Carcinoma: Very rare (<1%).
Why This Matters
- Cardiovascular Risk: Patients with PA have higher risk of stroke, MI, and Atrial Fibrillation than essential hypertensive patients with the same blood pressure, due to direct mineralocorticoid toxicity.
- Curable: Adrenalectomy can CURE hypertension in adenoma cases.
- Targeted Therapy: Spironolactone is specifically effective where standard antihypertensives fail.
2. Pathophysiology
┌─────────────────────────────────────────────────────────────────────────────┐
│ ALDOSTERONE PATHOPHYSIOLOGY │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ NORMAL PHYSIOLOGY (RAAS) │ │
│ │ • Low BP/Low Na+ → Renin Release (kidney) │ │
│ │ • Renin → Angiotensin I → Angiotensin II │ │
│ │ • Angiotensin II → Aldosterone Release (adrenal zona glomerulosa) │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ PRIMARY HYPERALDOSTERONISM │ │
│ │ • Autonomous Aldosterone secretion (Adenoma or Hyperplasia) │ │
│ │ • INDEPENDENT of Renin/Angiotensin control │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ KIDNEY EFFECT (Distal Tubule) │ │
│ │ • Upregulation of ENaC (Epithelial Sodium Channel) │ │
│ │ • ↑ Sodium Reabsorption → Water Retention → HYPERTENSION │ │
│ │ • ↑ Potassium Excretion → HYPOKALAEMIA │ │
│ │ • ↑ Hydrogen Ion Excretion → METABOLIC ALKALOSIS │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ FEEDBACK SUPPRESSION │ │
│ │ • High volume/High BP/High Na+ suppresses Renin │ │
│ │ • RESULT: HIGH Aldosterone + LOW Renin │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ │
└─────────────────────────────────────────────────────────────────────────────┘
Direct Cardiovascular Toxicity
Aldosterone receptors are also found in the heart and blood vessels. Excess aldosterone causes:
- Myocardial fibrosis
- Vascular inflammation
- Oxidative stress
- endothelial dysfunction This explains the disproportionate cardiovascular risk.
3. Clinical Features
History Taking
Who to Screen (Endocrine Society Guidelines):
- BP >150/100 repeatedly.
- Resistant Hypertension (>3 drugs including diuretic).
- Hypertension + Spontaneous or Diuretic-induced Hypokalaemia.
- Hypertension + Adrenal Incidentaloma.
- Hypertension + Sleep Apnea.
- Hypertension + Family History of early-onset HTN or CVA (<40y).
Physical Examination
Often unremarkable. There are NO specific features (unlike Cushing's).
- Blood Pressure: Usually elevated, may be severe.
- Neuromuscular: Weakness, muscle cramps, palpitations (if hypokalaemic).
- Edema: Usually ABSENT ("Escape phenomenon" prevents gross edema despite sodium retention).
4. Diagnosis
Diagnostic Algorithm
Step 1: Screening Test
- Aldosterone-Renin Ratio (ARR).
- Prepare: Correct hypokalemia first (low K+ suppresses aldosterone false negative). Stop diuretics (especially Spironolactone 4-6 weeks prior).
- Result: Elevated Aldosterone + Suppressed Renin = Positive Screen.
Step 2: Confirmatory Testing (if required)
- Required unless spontaneous hypokalemia + undetectable renin + PAC >20ng/dL.
- Saline Loading Test: Infuse 2L Normal Saline over 4h. Normal response: Aldosterone suppression. PA response: Failure to suppress.
- Oral Salt Loading Test: High sodium diet -> Measure urinary aldosterone.
Step 3: Subtype Classification (Localization)
- CT Adrenals: To check for masses. NOT definitive (non-functioning adenomas are common in age >40).
- Adrenal Vein Sampling (AVS): The GOLD STANDARD to distinguish unilateral adenoma vs bilateral hyperplasia.
- Essential if surgery is considered.
- Compares cortisol-corrected aldosterone from right vs left adrenal vein.
Investigating "The Washout"
Many antihypertensives affect the ARR.
- Stop: Spironolactone/Eplerenone (4-6 weeks), Beta-blockers, ACEi/ARB/Diuretics (2 weeks if possible).
- Safe to use: Alpha-blockers (Doxazosin), Calcium Channel Blockers (Verapamil), Hydralazine.
5. Management Algorithm
┌─────────────────────────────────────────────────────────────────────────────┐
│ PRIMARY HYPERALDOSTERONISM MANAGEMENT │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ CONFIRMED PA + CT SHOWING ADRENAL ABNORMALITY │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ IS PATIENT A SURGICAL CANDIDATE? │ │
│ │ • Willing to have surgery? │ │
│ │ • Fit for anesthesia? │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ YES ↓ NO │
│ ┌──────────────────────────┐ ┌────────────────────────────────┐
│ │ ADRENAL VEIN SAMPLING │ │ MEDICAL MANAGEMENT │
│ │ (Determine Laterality) │ │ (MRA Therapy) │
│ │ │ │ │
│ │ *Skip if <35y + clear │ │ • Spironolactone (12.5-50mg) │
│ │ unilateral lesion │ │ • Eplerenone (if gynecomastia) │
│ └──────────────────────────┘ │ • Amiloride (Add-on) │
│ ↓ ↓ │ │
│ ┌──────────────┐ ┌──────────────┐ │ • Monitor K+ and Creatinine │
│ │ UNILATERAL │ │ BILATERAL │—————→│ │
│ │ DISEASE │ │ DISEASE │ └────────────────────────────────┘
│ └──────────────┘ └──────────────┘
│ ↓
│ ┌─────────────────────────────────────┐
│ │ LAPAROSCOPIC ADRENALECTOMY │
│ │ • Curative for hypokalemia (100%) │
│ │ • Cures hypertension in ~50% │
│ │ • Improves hypertension in ~100% │
│ └─────────────────────────────────────┘
Surgical Management (Unilateral APA)
- Procedure: Laparoscopic Adrenalectomy.
- Outcome:
- Hypokalaemia resolves in almost 100%.
- Hypertension cured in 30-60%.
- Significant reduction in pill burden in remainder.
Medical Management (Bilateral Hyperplasia or Unfit for Surgery)
-
Mineralocorticoid Receptor Antagonists (MRA):
- Spironolactone: First line. Non-selective.
- Side effects: Gynecomastia, breast pain, menstrual irregularity (anti-androgenic).
- Eplerenone: Second line. Selective MRA.
- Fewer sexual side effects but less potent and more expensive.
- Spironolactone: First line. Non-selective.
-
Amiloride: ENaC channel blocker. Useful adjunctive if MRA not tolerated.
6. Differentiating Primary vs Secondary
| Feature | Primary Hyperaldosteronism | Secondary Hyperaldosteronism |
|---|---|---|
| Renin | Low / Suppressed | High |
| Aldosterone | High | High |
| Causes | Adenoma, Hyperplasia | Renal artery stenosis, Renin-secreting tumor, Diuretics, Heart Failure |
| BP | High | High or Normal/Low (e.g., in HF) |
7. Prognosis
- Treated: Good prognosis. Reversal of LV hypertrophy and proteinuria.
- Untreated: High morbidity from stroke, MI, atrial fibrillation, and renal failure.
- Post-Op: "Aldosterone suppression" phase may cause transient hyperkalemia post-adrenalectomy because the contralateral gland was suppressed long-term.
8. Complications
- Atrial Fibrillation: Aldosterone causes atrial fibrosis.
- Chronic Kidney Disease: Glomerular hyperfiltration followed by sclerosis.
- Stroke: Independent risk factor beyond BP elevation.
9. Special Considerations
Glucocorticoid-Remediable Aldosteronism (GRA)
- Rare, familial (Type I). Autosomal dominant.
- Chimeric gene mutation allows ACTH to drive aldosterone production.
- Treatment: Low dose Dexamethasone suppresses ACTH → cures hypertension.
- Suspect in: Family history + early onset severe HTN + intracranial aneurysm.
10. Key Clinical Pearls
Exam-Focused Points
- Hypokalaemia is NOT required: >50% of PA patients have normal potassium. Do not rule out PA just because K+ is normal.
- Screening: Aldosterone:Renin Ratio (ARR) is the test.
- Washout: Spironolactone MUST be stopped 4-6 weeks before testing. Alpha blockers (Doxazosin) are the safe bridge.
- AVS is Key: CT is often misleading (non-functioning nodules are common). You cannot remove an adrenal based on CT alone (unless <35y with textbook picture).
- Spironolactone: The drug of choice for bilateral disease. Watch for gynecomastia in men (switch to Eplerenone).
- Secondary HTN: PA is the #1 cause.
Common Exam Scenarios
- 40yo female, BP 160/100, K+ 3.2. Next step? (Renin/Aldosterone Ratio).
- Determining laterality in confirmed PA. (Adrenal Vein Sampling).
- Management of male on spironolactone with breast pain. (Switch to Eplerenone).
11. Patient Explanation
What is Primary Hyperaldosteronism?
"You have a small gland on top of your kidney (the adrenal gland) that is making too much of a salt-retaining hormone called Aldosterone.
Normally, your body strictly controls salt levels. In this condition, the gland has 'gone rogue' and keeps hoarding salt, which holds onto water, driving your blood pressure up."
Why do you need a vein sampling test?
"We know you have high hormone levels. A CT scan showed a lump on the left gland. However, lumps are very common and often innocent. We need to be 100% sure the lump is the source of the hormone before we remove the gland. The vein sampling test acts like a GPS to pinpoint exactly where the hormone is coming from."
Will surgery cure my blood pressure?
"If we find a single 'hot' gland, removing it will cure the potassium problem immediately. For blood pressure, about half of people can stop pills entirely, and the other half can reduce them significantly. However, if you've had high blood pressure for many years, considerable damage to the blood vessels may have occurred, meaning some medication might still be needed."
12. Evidence & Guidelines
Key Guidelines
| Guideline | Organization | Year | Key Points |
|---|---|---|---|
| Primary Aldosteronism | Endocrine Society | 2016 | The global standard. Algorithm for screening/AVS. |
| Hypertension Guideline | ESC / ESH | 2018 | Screen for PA in resistant HTN. |
Landmark Trials
PATHWAY-2 Study (2015):
- Investigated optimal 4th line drug for resistant hypertension.
- Result: Spironolactone was vastly superior to Doxazosin or Bisoprolol.
- Implication: Suggests undiagnosed aldosterone excess drives most resistant hypertension.
Evidence-Based Recommendations
| Recommendation | Evidence Level |
|---|---|
| Case Detection with ARR | Moderate |
| Confirmatory Testing | Moderate |
| AVS before surgery | Moderate |
| Laparoscopic Adrenalectomy | High |
| Spironolactone for bilateral | High |
13. References
- Funder JW, 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.
- Williams B, 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.
- Monticone S, et al. Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. J Am Coll Cardiol. 2017;69(14):1811-1820.
- Mulatero P, et al. Diagnosis and Treatment of Primary Aldosteronism: Practical Clinical Perspectives. J Am Coll Cardiol. 2019.