Primary aldosteronism

Notes

Definition & classification

Primary aldosteronism is a condition caused by an excess of the adrenal hormone aldosterone independent of the renin-angiotensin-aldosterone axis.

It is increasingly being recognised as a common cause of secondary hypertension. Today prevalence is thought to be in the region 15 % of patients with hypertension.

Physiology

Under normal conditions aldosterone release is primarily controlled by the renin-angiotensin system.

1. Renin

Renin, a proteolytic enzyme, is released by granular cells of the juxtaglomerular apparatus in response to:

  • Renal artery hypotension 
  • Sympathetic stimulation
  • Reduced sodium levels in the distal tubal

In the blood renin cleaves angiotensinogen into angiotensin I.

2. Angiotensin

Angiotensin-converting enzyme (ACE), found primarily in the vascular endothelium of the lungs, cleaves angiotensin I to give angiotensin II.

Angiotensin II has multiple functions:

  • Stimulates adrenal cortex to release aldosterone
  • Causes vasoconstriction
  • Increases sodium reabsorption
  • Stimulates the release of anti-diuretic hormone (ADH)
  • Increases sympathetic permissiveness

3. Aldosterone

Aldosterone is a mineralocorticoid released from the zona glomerulosa of the adrenal cortex. It is released in response to:

  • Angiotensin II (primary stimulus)
  • ACTH
  • Potassium levels

Its primary action is to increase the number of epithelial sodium channels in the distal tubule. 

This results in sodium and water reabsorption and potassium excretion.

Aldosterone escape

Despite the implied water and sodium retention, oedema is not a feature of primary aldosteronism. This is due to ‘aldosterone escape’. 

This is a spontaneous diuresis that occurs in response to the water and sodium retention caused by raised aldosterone.

Aldosterone escape is not fully understood. Atrial natriuretic peptide, pressure natriuresis and changes to reabsorption in the distal tubule are thought to contribute to its mechanism.

Aetiology

In the vast majority of cases primary aldosteronism is caused by adrenal adenomas or adrenal hyperplasia.

Adrenal adenoma

This was previously termed Conn’s syndrome, a term that is now more generally used in an interchangeable manner with primary aldosteronism.

Once thought to be the most common cause of primary aldosteronism, it is implicated in around 30% of cases

Idiopathic adrenal hyperplasia

Now thought to be the most common cause of primary aldosteronism, adrenal hyperplasia is implicated in around 70% of cases.

It is normally bilateral (bilateral adrenal hyperplasia, BAH) but in rare cases is unilateral.

Other (rare)

Familial hyperaldosteronism:

  • Type 1: Glucocorticoid-remediable aldosteronism
  • Type 2: Poorly understood, likely most common familial cause, appears to be due to an inherited adrenal adenoma or idiopathic adrenal hyperplasia.
  • Type 3: Mutations in KCNJ5 gene

Adrenal carcinoma is a rare cause.

Clinical features

Frequently asymptomatic, clinical features of primary aldosteronism are those of hypokalaemia (30%) and hypertension.

Hypokalaemia

Hypokalaemia may present with non-specific signs and symptoms. They include fatigue, muscle weakness and constipation.

Patients may develop hypokalaemia induced diabetes insipidus - manifesting with polyuria and polydipsia. 

Hypertension

Long-standing hypertension may result in end-organ damage:

  • CKD
  • Heart failure
  • Hypertensive retinopathy
  • Abdominal aortic aneurysms

Investigations

Hypertension, hypokalaemia and metabolic alkalosis are the classical findings.

Blood pressure

Primary aldosteronism is now thought to be a significant cause of secondary hypertension

Suspicion should be higher in younger patients and those with treatment-resistant hypertension.

Serum Potassium

Low serum levels are present in around 30% of patients. Urinary potassium may demonstrate inappropriate potassium loss in the setting of hypokalaemia.

In hypokalaemic patients, ECG's can show ST depression, T wave inversion and U waves.

Blood gas

Increased urinary hydrogen excretion, multifactorial, due to hypokalaemia and direct effects of aldosterone on intercalated cells may result in a metabolic alkalosis.

Diagnosis

Diagnosis of primary aldosteronism requires a multi-tier testing approach.

1. Screening

The aldosterone:renin ratio (ARR) is used as a screen in those with suspected primary aldosteronism.

It compares serum levels of aldosterone and renin. A raised ratio should prompt further investigation.

2. Diagnostic

Those with a raised ARR require confirmatory testing. A number of tests are available: 

  • Serum aldosterone levels
  • 24-hr urinary aldosterone excretion
  • Salt loading test

3. Identifying the cause

Once the diagnosis of primary aldosteronism is confirmed the exact aetiology must be identified. This can require complex testing often involving:

  • Adrenal CT
  • Adrenal vein sampling

In those with a positive family history genetic testing should be considered.

Management

Management of primary aldosteronism involves both surgical and medical modalities.

Management of primary aldosteronism

Adrenal adenoma

Medical management is used as a bridge to surgery. Aldosterone antagonists (e.g. spironolactone) may be given.

Surgical excision is the definitive therapy. Adrenalectomy, either laparoscopic or open, is the operation of choice.

Idiopathic adrenal hyperplasia

Disease tends to be milder than that caused by adrenal adenomas.

Medical management is frequently used:

  • Aldosterone antagonists: Spironolactone, Eplerenone (newer, unlike spironolactone does not cause gynaecomastia).
  • ENaC inhibitor: Amiloride, a potassium-sparing diuretic, may be used if aldosterone antagonists are not tolerated.

Other antihypertensives may be added. In cases of unilateral adrenal hyperplasia, adrenalectomy may be used.

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