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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).
Primary aldosteronism is now considered to be the most common curable form of secondary hypertension.
Investigation looking for hyperaldosteronism in patients with hypertension (regardless of potassium levels) led to higher estimated rates of prevalence in the order of 5%-10%.
However 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%-4%).
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.
- 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.
- 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.
- Much more uncommon is unilateral adrenal hyperplasia, which is treated by adrenalectomy.
- There are two forms: type 1 is glucocorticoid-remediable aldosteronism (GRA) and type 2 is characterised by inherited aldosterone-producing adenoma or inherited BAH.
- In GRA the regulatory portion of the 11b-OH gene binds to the aldosterone synthase gene; thus, adrenocorticotrophic hormone (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 subset of patients is usually normokalaemic until started on diuretics, when they become profoundly hypokalaemic.
- 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.
Hyperaldosteronism usually presents with hypokalaemia, alkalosis (elevated bicarbonate level), and plasma sodium level greater than 140 mmol/L, or a larger than expected decrease in serum potassium when using a low-dose thiazide-type diuretic. The symptoms may be non-specific, but it may rarely present with tetany, muscle weakness, nocturia, or polyuria.
Classic features include:
- 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.
Indications to screen for primary hyperaldosteronism include:
- Blood pressure >150/100 mm Hg on three consecutive measurements on different days.
- Blood pressure >140/90 mm Hg resistant to three conventional antihypertensive medications including a diuretic.
- Blood pressure <140/90 mm Hg on four or more antihypertensive medications.
- Hypertension and hypokalemia (spontaneous or diuretic-induced).
- Hypertension and adrenal incidentaloma.
- Hypertension and sleep apnoea.
- Hypertension and a family history of hypertension or stroke prior to age 40.
- Hypertension and a first-degree relative with primary aldosteronism.
The most often recommended screening test is the aldosterone-to-renin ratio (ARR). The most widely accepted definition of a positive screen is an ARR >30 ng/dL per ng/mL/h with a serum aldosterone level >15 ng/dL. The higher the aldosterone level, and the lower the plasma renin activity, the more clear the potential diagnosis.
- U&Es - 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 scans:
- These methods can be used to locate an adrenal adenoma and may also pick up hyperplasia. CT scanning has a lower specificity compared with MRI scanning but is still the first-line initial imaging mode.
- Other imaging techniques can be used - eg, CT contrast washout analysis, single-photon emission computerised tomography (SPECT) or positron emission tomography (PET)/CT.
- Selective adrenal venous sampling - is the gold standard for localising the cause of primary hyperaldosteronism.
- Genetic testing - is available for GRA.
For patients with hypertension, hypokalemia, undetectable renin activity or levels, and serum aldosterone levels that are sufficiently elevated (ie 15 or 20 ng/dL or higher), there is no need for further dynamic testing and the diagnosis can be confirmed.
When the initial screening results are less clear, dynamic confirmatory testing is required. Confirmatory tests are effectively aldosterone suppression tests:
- Oral sodium load: this involves a high-sodium diet for 3-4 days with the addition of sodium chloride tablets if needed. On the final day of the diet, a 24-hour urine specimen is collected. A 24-hour urine aldosterone excretion of >12 mcg in the setting of 24-hour urine sodium excretion of >200 mEq is diagnostic of primary aldosteronism. Values of >10 mcg/24 hrs are also strongly suggestive.
- Saline infusion test: a two-litre infusion of isotonic saline is given over four hours. Blood samples for renin, aldosterone, cortisol, and potassium are measured immediately before and after the infusion. At the end of the infusion, a serum aldosterone level >10 ng/dL is diagnostic of primary aldosteronism, a serum aldosterone level <5 ng/dL rules out primary aldosteronism, while a serum aldosterone level of 5-10 ng/dL is considered indeterminate.
- Fludrocortisone suppression test - patients receive fludrocortisone 0.1 mg every six hours for four days together with sodium and potassium supplementation. On day 4, serum cortisol is measured at 7 AM while serum aldosterone, PRA, and cortisol are measured at 10 AM with the patient in a seated position. A serum aldosterone >6 ng/dL with a PRA <1.0 ng/mL/h and a 10 AM serum cortisol less than the 7 AM value is diagnostic of primary aldosteronism.
- Captopril challenge test: 25-50 mg of captopril is given after sitting or standing for at least one hour. Serum aldosterone and PRA are measured at time zero and at one and two hours after captopril administration, with the patient remaining seated during this period. Serum aldosterone will normally be suppressed, but, in primary aldosteronism, aldosterone will remain elevated and PRA will remain suppressed.
Cross-sectional imaging is recommended to exclude the rare instance of an aldosterone-producing adrenocortical carcinoma. However, reliance on cross-sectional imaging to determine laterality is not widely recommended and can be misleading. Non-functional adrenal incidentalomas may exist and primary aldosteronism may be present in one or both adrenal glands without a visible abnormality on cross-sectional imaging.
Patients having adrenal venous sampling (AVS) have a substantially higher likelihood of attaining biochemical cure or biochemical improvement when compared to patients who had only CT-based localisation. Therefore most authorities recommend AVS for localisation for most patients with primary aldosteronism who are interested and eligible for a potential adrenalectomy. In young (<35 years) patients with a clear unilateral adenoma on imaging and severe primary aldosteronism with hypokalemia, AVS may not be necessary since the visible unilateral adenoma is almost always the causative lesion.
Differential diagnosis of hyperaldosteronism
- Primary hyperaldosteronism (adenoma, BAH, GRA, carcinoma).
- Congenital adrenal hyperplasia.
- Renal artery stenosis (RAS).
- Coarctation of the aorta.
- Fibromuscular dysplasia.
- Renin-secreting tumours.
- Congestive cardiac failure.
- Nephrotic syndrome.
- Gitelman's syndrome.
- Bartter's syndrome.
- Diuretic use.
The main diagnosis to consider is RAS, in which patients will also have hypertension and hypokalaemia. If RAS is suspected then consider the following investigations:
- U&E - hypokalaemia and renal impairment may be present.
- Ultrasonography of the renal tract - may show asymmetrically sized kidneys or small kidneys.
- Mercaptoacetyltriglycine (MAG3) or dimercaptosuccinic acid (DMSA) scans - these tests provide information about the relative function of each kidney and its 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.
After identification of a possible adrenal adenoma on CT scan or MRI, tertiary referral is required for confirmation of unilateral aldosterone excess and possible laparoscopic adrenalectomy.
The management of primary hyperaldosteronism includes:
- Dietary sodium restriction.
- Lifelong mineralocorticoid receptor antagonists for patients with bilateral primary aldosteronism as well as those with unilateral primary aldosteronism who are unable to or unwilling to undergo surgical adrenalectomy. The two most commonly used mineralocorticoid receptor antagonists are spironolactone and eplerenone.
- Surgical adrenalectomy to cure primary aldosteronism is the treatment of choice for patients with unilateral primary aldosteronism who are healthy enough to undergo the surgery. This procedure is now usually performed laparoscopically.
Medical management is used in the period prior to surgery - which is the definitive treatment. Medical management involves the use of aldosterone antagonists - eg, spironolactone.
Surgical treatment involves adrenalectomy. Laparoscopic surgery is safe and effective and may be better than open surgery. However, hypertension may persist after removal of the adenoma, due to effects of the previous hypertension on vasculature.
The treatment is medical with aldosterone antagonists:
- Spironolactone is a nonselective 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.
This is usually responsive to steroids, and dexamethasone is used initially for four 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:
- Congestive cardiac failure
- Hepatic failure
- Nephrotic syndrome
- Malignant hypertension
Investigations and treatment should be directed towards the underlying cause.
Prognosis is good in treated patients with primary hyperaldosteronism. However, patients may continue to be hypertensive and require lifelong antihypertensive 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 offset by use of aldosterone antagonists.
The Randomized Aldactone Evaluation Study (RALES) showed that spironolactone markedly reduced mortality in patients with congestive cardiac failure. It may be that spironolactone also benefits cardiac function in primary hyperaldosteronism.
Further reading and references
Mulatero P, Monticone S, Bertello C, et al; Evaluation of primary aldosteronism. Curr Opin Endocrinol Diabetes Obes. 2010 Jun17(3):188-93.
Zennaro MC, Boulkroun S, Fernandes-Rosa F; An update on novel mechanisms of primary aldosteronism. J Endocrinol. 2015 Feb224(2):R63-77. doi: 10.1530/JOE-14-0597. Epub 2014 Nov 25.
Beuschlein F; Regulation of aldosterone secretion: from physiology to disease. Eur J Endocrinol. 2013 Apr 24168(6):R85-93. doi: 10.1530/EJE-13-0263. Print 2013 Jun.
Papadopoulou-Marketou N, Vaidya A, Dluhy R, et al; Hyperaldosteronism. Endotext, August 2020.
Hypertension - not diabetic; NICE CKS, September 2020 (UK access only)
Hundemer GL, Vaidya A; Primary Aldosteronism Diagnosis and Management: A Clinical Approach. Endocrinol Metab Clin North Am. 2019 Dec48(4):681-700. doi: 10.1016/j.ecl.2019.08.002.
Ctvrtlik F, Koranda P, Tichy T; Adrenal disease: a clinical update and overview of imaging. A review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014158(1):23-34. doi: 10.5507/bp.2014.010. Epub 2014 Feb 20.
Blondin D, Quack I, Haase M, et al; Indication and technical aspects of adrenal blood sampling. Rofo. 2015 Jan187(1):19-28. doi: 10.1055/s-0034-1385081. Epub 2014 Sep 16.
Amar L, Lorthioir A, Azizi M, et al; Progress in primary aldosteronism. Mineralocorticoid antagonist treatment for aldosterone-producing adenoma. Eur J Endocrinol. 2015 Mar172(3):R125-9. doi: 10.1530/EJE-14-0585. Epub 2014 Oct 14.
Verdugo FJ, Montellano FA, Carreno JE, et al; [Mineralocorticoid receptor antagonists and therapeutic strategies of cardiovascular damage]. Rev Med Chil. 2014 Jan142(1):61-71. doi: 10.4067/S0034-98872014000100010.