Hyperaldosteronism and Conn's Syndrome

A 45-year-old woman presents to her GP with persistent hypertension refractory to multiple antihypertensive medications. She complains of muscle weakness and occasional cramps. Blood tests reveal hypokalaemia and metabolic alkalosis.

Pathophysiology

Hyperaldosteronism is characterised by excessive secretion of aldosterone from the zona glomerulosa of the adrenal cortex.

• Increased aldosterone leads to increased sodium reabsorption and potassium excretion in the kidneys.
• This causes sodium and water retention, leading to increased extracellular fluid volume and hypertension.
• Potassium loss results in hypokalaemia, which can lead to muscle weakness, cramps, and potentially life-threatening cardiac arrhythmias.

Aetiology

Primary Hyperaldosteronism

• Conn's syndrome (aldosteronoma): This is the most common cause of primary hyperaldosteronism, accounting for approximately 75% of cases. It is caused by a benign, aldosterone-secreting adrenal adenoma.
• Bilateral adrenal hyperplasia: This involves excessive aldosterone secretion from both adrenal glands.
• Adrenal carcinoma: A rare malignant tumour of the adrenal gland that can secrete aldosterone.
• Glucocorticoid-remediable aldosteronism (GRA): A rare, inherited disorder caused by a chimeric gene that results in ACTH-sensitive secretion of aldosterone.

Secondary Hyperaldosteronism

• Conditions that cause decreased renal perfusion, leading to activation of the renin-angiotensin-aldosterone system (RAAS):
  • Renal artery stenosis
  • Malignant hypertension
• Other causes of RAAS activation:
  • Congestive cardiac failure
  • Hypoalbuminaemia
  • Profuse sweating
• Conditions mimicking hyperaldosteronism:
  • Gitelman syndrome (decreased NaCl reabsorption in the distal convoluted tubule)
  • Bartter syndrome (decreased NaCl reabsorption in the ascending loop of Henle)

Epidemiology & Risk Factors

• Primary hyperaldosteronism is the most common cause of secondary hypertension, accounting for 5-10% of hypertensive patients.
• Conn's syndrome is more common in women, with an age of onset between 30 and 60 years.
• Risk factors for primary hyperaldosteronism are not well-defined. However, a family history of early-onset hypertension or stroke may suggest GRA.

Clinical Features

• Often presents asymptomatically.
• Hypertension: Often resistant to conventional antihypertensive therapy.
• Hypokalaemia: Leading to:
  • Muscle weakness
  • Cramps
  • Fatigue
  • Paraesthesiae
  • Polyuria and polydipsia (due to hypokalaemia-induced nephrogenic diabetes insipidus)
• Metabolic alkalosis: Caused by increased hydrogen ion excretion in the kidneys.

Investigations

Initial Tests:

• Electrolytes: Hypokalaemia is often seen. Also possibly hypernatraemia and hypochloraemic metabolic alkalosis.
• Plasma aldosterone and renin activity: A high aldosterone-to-renin ratio is suggestive of primary hyperaldosteronism. The ratio should be measured off antihypertensives (except for alpha-blockers) and after appropriate salt loading. A ratio ≥800 is highly suggestive of primary hyperaldosteronism.
• 24-hour urinary aldosterone excretion: Can be helpful if plasma aldosterone levels are borderline elevated.
• ECG: May show signs of hypokalaemia, such as flat or inverted T waves, U waves, ST depression, and prolonged PR and QT intervals.

Confirmatory Tests:

• Imaging (CT or MRI of adrenal glands): Performed after biochemical confirmation of hyperaldosteronism to localise the cause.
• Adrenal vein sampling: This procedure involves collecting blood samples from both adrenal veins to compare aldosterone levels. It can help distinguish between unilateral adenoma and bilateral hyperplasia. A greater than 3-fold difference in aldosterone:cortisol ratios between the two sides suggests an adenoma.
• Genetic testing: Indicated for suspected GRA.

Management

The management of hyperaldosteronism depends on the underlying cause.

Conn's Syndrome (Adenoma)

• Surgical resection (laparoscopic adrenalectomy) is the definitive treatment for Conn's syndrome.
• Preoperative management:
  • Alpha-adrenergic blockade (e.g. phenoxybenzamine) is used first to control hypertension.
  • Beta-blockade can then be added to control tachycardia. 

• Postoperative:
  • Hypertension resolves in around 70% of patients after surgery.

Bilateral Adrenal Hyperplasia

• Medical therapy is the mainstay of treatment.
  • Mineralocorticoid receptor antagonists (spironolactone, eplerenone, amiloride): These drugs block the effects of aldosterone in the kidneys.
  • Other antihypertensive medications may be required to control blood pressure.

GRA

• Dexamethasone: Low-dose dexamethasone suppresses ACTH secretion, thereby decreasing aldosterone production.
• Mineralocorticoid receptor antagonists: May be used if dexamethasone alone does not adequately control blood pressure.

Adrenal Carcinoma

• Surgical resection is the primary treatment.
• Adjuvant therapy (e.g. mitotane): May be used to control tumour growth and hormone production.

Complications & Prognosis

Untreated hyperaldosteronism can lead to:

• Cardiovascular disease: Hypertension increases the risk of stroke, heart attack, and heart failure.
• Hypokalaemic complications:
  • Muscle weakness and paralysis
  • Cardiac arrhythmias (potentially life-threatening)
  • Rhabdomyolysis
  • Nephrogenic diabetes insipidus

Prognosis:

• Conn's syndrome generally has a good prognosis after surgical resection.
• Bilateral adrenal hyperplasia requires lifelong medical management to control hypertension and hypokalaemia.
• The prognosis for adrenal carcinoma depends on the stage of the tumour at diagnosis.
• GRA is usually well-controlled with dexamethasone.