Primary aldosteronism, also known as primary hyperaldosteronism or Conn syndrome, occurs when there is excessive aldosterone production in the body that is not regulated by the renin-angiotensin-aldosterone system (RAAS).
🏃♀️ Physiology
The RAAS is a vital system in the regulation of blood pressure, fluid balance and electrolyte homeostasis.
Let’s recap the RAAS and then look specifically at the function of aldosterone:
- A stimulus triggers the release of renin from the juxtaglomerular cells of the kidney. The stimulus may be low blood pressure and renal hypoperfusion, hyponatraemia or increased sympathetic tone due to stimulation of B1 adrenoreceptors.
- Renin then converts angiotensinogen (produced in the liver) → angiotensin I.
- Angiotensin converting enzyme (ACE) is found abundantly in the lungs and stimulates the conversion of angiotensin I → angiotensin II.
- Angiotensin II binds to the AT1 and AT2 receptors found in vascular smooth muscle. This then activates downstream signalling for phosphorylation of myosin which then causes vasoconstriction. Angiotensin II also binds to receptors in the zona glomerulosa of the adrenal cortex which then results in the release of aldosterone.
So what does aldosterone do?
Aldosterone binds to the mineralocorticoid receptor in the principal cells in the distal convoluted tubule and collecting duct. This results in increased expression of the following channels:
- Na+/K+-ATPase - this is expressed on the basolateral membrane to allow for sodium reabsorption into the systemic circulation and potassium secretion into the tubule cells.
- H+-ATPase - this is expressed on the apical membrane to allow for excretion of hydrogen ions into the urine to maintain acid-base balance.
- ENaC - the ENaC is expressed on the apical surface to allow for reabsorption of sodium from the tubular lumen back into the principal cell (it may then pass into the systemic circulation via the Na+/K+-ATPase).
- ROMK (renal outer medullary K+ channel) - this is expressed on the apical membrane to facilitate potassium excretion into the urine.
The ultimate outcome of expression of these channels is sodium reabsorption as well as potassium and hydrogen ion excretion. The increase in sodium retention results in fluid retention and an increased blood pressure. The potassium and hydrogen ion excretion prevent acidaemia and hyperkalaemia.
Pathophysiology
Primary aldosteronism results in excessive adolsterone release that is not responsive to RAAS regulation. As aldosterone leads to sodium reabsorption, excessive reabsorption leads to hypernatraemia and hypertension (due to osmotic reabsorption of fluid as well). The excessive loss of potassium and hydrogen ions leads to hypokalaemia and metabolic alkalosis (in severe, prolonged cases).
The causes of primary aldosteronism are most commonly:
- Aldosterone-producing adenoma (30% of cases)
- Bilateral idiopathic adrenal hyperplasia (60% of cases)
Less commonly it may be due to:
- Unilateral adrenal hyperplasia
- Aldosterone-secreting carcinomas of the adrenal cortex
- Familial hyperaldosteronism
- Type I - due to mutations in a hybrid gene of 11-ß-hydroxylase and aldosterone synthase. The outcome is an aldosterone release that is regulated by ACTH. Therefore it is responsive to glucocorticoids (glucocorticoid-remediable).
- Type II - due to germ-line mutations of the CLCN2 gene.
- Type III - due to germ-line mutations of the KCNJ5 gene (a potassium channel).
- Type IV - due to germ-line mutations of the CACNA1H gene (a calcium channel).
- Ectopic aldosterone production - which may occur in some ovarian or renal tumours.
Type I is glucocorticoid-remediable while types II-IV are non-glucocorticoid-remediable.
😷 Presentation
- Hypertension - any degree of severity and duration
- Polyuria and polydipsia
- Mood disturbances - such as depression, anxiety, irritability.
- Difficulty concentrating
- Absence of oedema - despite fluid retention. This is known as aldosterone escape. Aldosterone escape occurs due to 2 proposed mechanisms. The first one is the increased secretion of atrial natriuretic peptide (ANP) which results in increased natriuresis. The second mechanism is known as pressure natriuresis which is increased renal perfusion pressure which leads to decreased reabsorption of sodium in the renal tubules and thus increased excretion of the sodium. These mechanisms result in oedema not being a prominent manifestation of primary hyperaldosteronism.
- Hypokalaemia features:
- Fatigue
- Muscle weakness
- Cramping
- Headaches
- Palpitations
- Paraesthesia - secondary to severe metabolic alkalosis.
- Constipation
🔍 Investigations
🥇 First-line investigations:
- Serum potassium - normal or decreased (only low in 20% of patients).
- Aldosterone/renin ratio - this is the most reliable available screening test. It should be markedly elevated as the aldosterone is released independently from renin release.
🏆 Definitive confirmatory tests:
- Fludrocortisone suppression test - fludrocortisone is a synthetic mineralocorticoid used to replace endogenous aldosterone. Normally it should suppress endogenous aldosterone production. A positive test is if plasma aldosterone is not suppressed to <6ng/dL.
- Saline infusion testing - an alternative method to fludrocortisone suppression testing. Saline infusion should suppress aldosterone as the body normally tries to excrete the sodium. Primary aldosteronism is probable in patients with an aldosterone level >10ng/dL.
- Oral salt loading test - another alternative. A high sodium intake is adhered for 3 days. On the last day a 24-hour urine aldosterone is taken. A diagnosis is likely if the 24-hour urinary aldosterone level >12mcg/day.
Other investigations may include:
- Genetic testing
- Adrenal CT - to look for adrenal adenoma
- Adrenal venous sampling - during this procedure, a catheter is passed into the adrenal veins. Blood samples are then taken from the veins on both sides to measure aldosterone and cortisol. By comparing hormone levels from each side, we can determine whether it is unilateral or bilateral adrenal disease.
🧰 Management
General principles of treatment include reducing blood pressure and limiting end-organ damage.
The management can be divided into unilateral adrenal disease or bilateral adrenal disease.
This includes issues such as an adrenal adenoma, adrenal carcinoma, unilateral adrenal hyperplasia. For these circumstances, we prefer surgical removal of the adrenal gland:
- Laparoscopic unilateral adrenalectomy
Prior to surgery, we need to correct hypokalaemia.
After surgery it is important to monitor for hyperkalaemia. Patients will also need to be regularly monitored for their aldosterone/renin ratio and blood pressure in outpatient clinics.
If surgery is contra-indicated in unilateral disease then an aldosterone receptor antagonist may be used (such as spirinolactone or eplirenone).
Bilateral adrenal disease or contra-indications for surgery require medical management through antagonism of the aldosterone receptors.
- Aldosterone receptor antagonist (such as spirinolactone or eplirenone)
For familial hyperaldosteronism type I we may also use glucorticoids such as dexamethasone. This works by suppressing ACTH which suppresses hybrid gene expression and subsequently lowers aldosterone levels. This is why it is referred to as glucocorticoid-remediable.
🔍 It can be diagnosed with an increase in plasma aldosterone concentration coupled with an increase in plasma renin concentration. Therefore the aldosterone/renin ratio remains normal (or less elevated).
🔍 It can be diagnosed with presence of elevated plasma aldosterone concentration and elevated plasma renin concentration (therefore the aldosterone/renin concentration might not be elevated).
Secondary aldosteronism occurs due to RAAS mediated secretion of aldosterone. This differs from primary aldosteronism which is independent of the RAAS as the adrenals secrete aldosterone independently.
Causes relate to renal hypoperfusion or obstruction as well as oedematous disorders, such as:
- Renal artery stenosis
- Renin-secreting tumours
- CKD
- Advanced CHF
- Fibromuscular dysplasia
- Cirrhosis
- Diuretics (as hyperkalaemia stimulate aldosterone secretion)
- Laxative abuse
🔍 We should see elevated plasma aldosterone concentration and elevated plasma renin concentration too (hence the aldosterone/renin ratio may be normal).
Pseudohyperaldosteronism is a syndrome characterised by hypokalaemia, metabolic alkalosis and decreased renin levels in the absence of elevated aldosterone levels.
It may occur due to enzyme deficiencies, enzymatic inhibition, channelopathies, or constitutive activation of the mineralocorticoid receptor. This may be seen in:
- Congenital adrenal hyperplasia - leads to enzyme deficiencies which results in underproduction of aldosterone.
- Exogenous mineralocorticoid administration
- Cushing syndrome
- Liddle syndrome
🔍 Investigations
- Hypokalaemia
- Plasma aldosterone concentration - decreased.
- Plasma renin concentration - decreased.
