Hyperaldosteronism

Hyperaldosteronism can be defined as excessive levels of aldosterone which may be independent of the renin-angiotensin axis (primary hyperaldosteronism) or due to high renin levels (secondary hyperaldosteronism).

Many decades ago the prevalence of primary aldosteronism as a cause of hypertension was thought to be very low, figures like 0.5% had been quoted.¹ However, it has subsequently emerged that these low prevalence rates were simply because the condition was not being looked for.

Following this there began a spate of almost routine investigation looking for hyperaldosteronism in patients with hypertension. This led to higher estimated rates of prevalence in the order of 5 - 10% (of all hypertensive patients).^1,2 This too has been disputed and it is most likely that primary hyperaldosteronism is prevalent in patients with resistant hypertension, but levels are lower in the general unselected hypertensive patients (more in the order of 0.1%).³

Hyperaldosteronism usually results in hypertension most commonly around 40 years of age and is more common in females.

Excessive aldosterone levels act at the distal renal tubule promoting sodium retention, which results in water retention and volume expansion with hypertension. There is also excretion of potassium resulting in hypokalaemia.

Primary hyperaldosteronism

Adrenal adenoma

• This is known as Conn's syndrome. It was first described in 1956 by Dr Jerome Conn an american endocrinologist, who discovered an aldosterone secreting adenoma in a 34 year old patient who had a long history of periodic cramps associated with occasional complete lower limb paralysis.
• Adrenal adenoma accounts for more than 80% of all cases of hyperaldosteronism.
• Adenomas are usually unilateral and solitary.

Adrenal hyperplasia

• In bilateral adrenal hyperplasia (BAH) the adrenal cells become hyperplastic resulting in excessive secretion of aldosterone. This accounts for 15% of all cases of hyperaldosteronism.
• There is also a much rarer recognised entity of unilateral adrenal hyperplasia which is treated by adrenalectomy.⁴

Glucocorticoid-remediable aldosteronism (GRA)

• Familial hyperaldosteronism was first described when it was noted by Sutherland in 1966 that a father and son both had hypertension, low plasma renin activity and increased aldosterone which responded to steroids. There are two forms: type 1 is GRA and type 2 is characterised by familial aldosterone producing adenoma or bilateral adrenal hyperplasia.⁵
• In GRA the regulatory portion of the 11 b-OH gene binds to the aldosterone synthase gene, thus ACTH release leads to stimulation of this abnormal chimera and excessive aldosterone production. This aldosterone is produced from the zona fasciculata rather than the usual site of aldosterone production, the zona glomerulosa. The pattern of inheritance of GRA is autosomal dominant.
• GRA is associated with hypertension that begins at an early age usually in the twenties, and it can be resistant to treatment. Patients with GRA can develop haemorrhagic strokes and are usually screened for cerebral aneurysms on a regular basis. This sub set of patients are usually normokalaemic until started on diuretics when they become profoundly hypokalaemic.⁵

Adrenal carcinoma

This is a rare cause of primary hyperaldosteronism but one that should not be missed. It is usually only diagnosed once an adrenal adenoma has been removed and examined histopathologically.

Classic features include

• Hypertension.
• Hypokalaemia (usually <3.5 mmol/L, although 70% of patients may be normokalaemic).
• Metabolic alkalosis.
• Sodium may be normal or at the high end of normal.

The presence of hypokalaemia and alkalosis appears to be not as common as once thought, therefore a high index of suspicion is needed.

• Patients may also have polyuria and subsequent polydipsia due to reduced ability of the kidneys to concentrate urine.
• Weakness may be present from hypokalaemia.
• Headaches and lethargy may also be present.

Renal function and renin activity and aldosterone levels should be performed whilst the patient has been off diuretics for at least 4 weeks and off beta blockers and dihydropyridine calcium channel blockers for at least two weeks. Patients should also stop steroids, potassium supplements and laxatives.

• Urea & Electrolytes - may show hypokalaemia and hypernatraemia.
• Spot renin and aldosterone levels - aldosterone levels are raised and renin should be low (if renin is high or normal it virtually excludes the diagnosis of primary hyperaldosteronism).
• ECG - may show arrhythmias from electrolyte imbalance.
• CT/MRI - These methods can be used to locate an adrenal adenoma. CT scanning has a lower specificity compared to MRI scanning but is still the first line imaging mode. Some reports suggest that CT scanning can only correctly identify 50% of adenomas - many CT scans detect adenomas which are not necessarily functioning and these may just represent areas of hyperplasia.⁶ As the treatment of adenoma and BAH differs it may be advised that patients undergo adrenal venous sampling prior to surgery.⁷
• Selective use of adrenal venous sampling - this requires expertise and allows detection of the source of the aldosterone. It is useful in cases where aldosterone/renin levels are suggestive of primary aldosteronism but imaging fails to identify an adenoma or BAH or shows micronodules bilaterally. However, this is a difficult procedure and pick up rates vary with the operator. It is also an invasive procedure. With the newer CT scanners the need for adrenal venous sampling may be reduced.
• Genetic testing is available for GRA.

Lying and standing aldosterone/renin levels

• Aldosterone is affected by upright posture and therefore samples are taken lying down and then repeated after being upright for a few hours.
• It is a good idea to check with your local centre as some will still perform salt loading and lying/standing renin/aldosterone levels.
• In general, in primary hyperaldosteronism due to hyperplasia the plasma aldosterone increases after 4 hours of standing, usually by more than 30 %. On the other hand there is usually no alteration in renin/aldosterone levels with posture in the presence of an adrenal adenoma.⁸
• These are only guidelines and thus lying/standing levels need to be interpreted with caution taking in to account the patients history and the results of imaging investigations.⁸

Salt loading and aldosterone/renin levels

• The salt loading test can be used for further confirmation of primary aldosteronism - although it is also being used less.⁸
• The patient is loaded with salt (high sodium diet and slow release sodium tablets) for two weeks before samples are taken. The salt will suppress plasma aldosterone. Aldosterone/renin, cortisol and bicarbonate levels are measured.
• Failure to suppress aldosterone confirms primary hyperaldosteronism.⁸
• In the past fludrocortisone has been used to suppress aldosterone rather than salt, this is probably only useful in research settings.
• Salt loading is being used less and less as it does not enhance the diagnosis rate and is time consuming.⁸

• The aldosterone/renin ratio can be used as a screening test for primary hyperaldosteronism.
• Patients with hypertension and hypokalaemia or resistant hypertension should be screened.
• If the ratio is >800 then patients should be investigated with further imaging to locate the source.
• Some specialist centres may also use isolated aldosterone levels to improve specificity (if aldosterone > 1000 with a raised aldosterone/renin ratio there is almost 90 % specificity).^9,10
• The sensitivity is between 75 % - 100% and specificity is also similar. In Afro-Caribbean patients the ratio combined with the absolute aldosterone level is a better screening tool as this group of patients tend to have a low renin.⁹
• However, anti-hypertensive medication can adversely affect results of the aldosterone/renin ratio e.g. false positives occur with beta blockers and false negatives occur with diuretics, ACEIs, ARBs and dihydropyridine calcium channel blockers. Alpha blockers do not appear to have an effect on the aldosterone/renin ratio.

• U &E - hypokalaemia and renal impairment may be present.
• Ultrasonography of the renal tract - may show asymmetrically sized kidneys or small kidneys.
• MAG 3 scanning or DMSA - these tests provide information about the relative function of each kidney and their blood supply. They can also give information about kidney size and obstruction.
• Renal arteriogram is the gold standard and will allow angioplasty to take place if indicated.
• Renin and aldosterone levels will be high.

Cushing's disease may also present with hypertension and hypokalaemia but both the aldosterone and renin levels are low.

Conn's syndrome

Medical management is used in the period prior to surgery - which is the definitive treatment. Medical management involves the use of aldosterone antagonist's e.g. spironolactone usually for 4 weeks. Surgical treatment involves surgical adrenalectomy, laparoscopic surgery is safe and effective and may be better than open surgery.^12,13 However, hypertension may persist after removal of the adenoma due to effects of the previous hypertension on vasculature.

More recently the use of CT guided acetic acid injections into small functioning adenomas is proving promising.^14,15 However, the data at present is only from very small numbers of patients.

Bilateral adrenal hyperplasia

The treatment is medical with aldosterone antagonists. Amiloride is a potassium sparing diuretic which may be useful as it counteracts hypokalaemia; however it lacks mineralocorticoid inhibition and is only a weak anti-hypertensive agent. This makes the use of amiloride less attractive.¹⁶

Spironolactone is a non-selective aldosterone antagonist and thus blocks not only aldosterone receptors but also testosterone receptors leading to side effects such as, gynaecomastia, menstrual problems and erectile dysfunction.

Eplerenone is a relatively new selective aldosterone antagonist and therefore does not have the same troublesome side effects as spironolactone. The role of Eplerenone in the treatment of primary hyperaldosteronism has not been clearly evaluated.

GRA

This is usually responsive to steroids and dexamethasone is used initially for 4 weeks. The steroids act back on ACTH switching off the drive to aldosterone production. However, if the patient continues to be hypertensive then the patient should be started on spironolactone.

This is the result of excessive renin in the circulation which stimulates normal adrenals to produce aldosterone.

Causes include

• Diuretics
• Congestive cardiac failure
• Hepatic failure
• Nephrotic syndrome
• Renal artery stenosis
• Malignant hypertension

Investigations and treatment should be directed towards the underlying cause.

Prognosis is good in treated patients with primary hyperaldosteronism. However up to 50 % of patients will continue to be hypertensive and require life long anti-hypertensive therapy. Risk factors for long term hypertension include older age at diagnosis.

An excessive aldosterone level has a harmful effect on cardiac function by resulting in myocardial fibrosis and this can be off set by use of aldosterone antagonists. The RALES study showed that spironolactone markedly reduced mortality in patients with congestive cardiac failure.¹⁷ It may be that spironolactone also benefits cardiac function in primary hyperaldosteronism.

Consider the following

1. Is the patients blood pressure under control? Has the treatment of their blood pressure been difficult?
2. Request U + E - is hypokalaemia present? If so consider primary hyperaldosteronism. Even if U + E normal primary hyperaldosteronism may be present (especially if blood pressure resistant to therapy).
3. If primary hyperaldosteronism is possible consider requesting renin activity - if normal or high this virtually excludes primary hyperaldosteronism.
4. If renin activity low then request aldosterone levels and referral to specialists.
5. If renin activity high and high blood pressure present consider investigating for renovascular causes of hypertension and coarctation if appropriate. Again refer to specialists for further management.