What symptom is characteristic of primary hyperaldosteronism? Hyperaldosteronism is a disorder of the adrenal glands caused by excessive secretion of aldosterone. Familial form of hyperaldosteronism

Sometimes PHA is identified with Conn's syndrome, which is only one form of the disease - an aldosterone-producing adenoma of the adrenal cortex, first described by J.W. Conn in 1955

Prevalence. Initially, Conn's syndrome was considered a rare disease. Primary hyperaldosteronism is found in approximately 10% of patients with arterial hypertension.

Classification of primary hyperaldosteronism

PHA is subdivided into aldosterone-producing adrenal adenoma, aldosterone-producing adrenal cancer, glucocorticoid-suppressed hyperaldosteronism, and primary uniadrenal hyperplasia.

Causes of primary hyperaldosteronism

In most cases, the cause of excess mineralocorticoids in the body is overproduction of aldosterone, which can be primary or secondary and is usually manifested by arterial hypertension and hypokalemia.

The etiology of PHA is different for each of its forms. Often the cause of PGA (60-70% of cases) is an aldosterone-producing adenoma - a benign neoplasm of the zona glomerulosa of the adrenal cortex. Bilateral and multiple aldosteromas are rare (5-10%), aldosterone-producing cancer of the adrenal cortex is even rarer.

Pathogenesis. Hypernatremia entails an increase in blood osmolarity and hypersecretion of vasopressin. As a result, an increase in blood pressure is observed - a cardinal symptom of PHA. Hypokalemia and hypomagnesemia lead to neuromuscular disorders, impaired insulin secretion (usually mild or moderate), and rarely visual disturbances. Prolonged hypokalemia and metabolic alkalosis lead to the formation of a “hypokalemic kidney.”

Symptoms and signs of primary hyperaldosteronism

The overwhelming majority of patients experience a persistent increase in blood pressure with all the typical features of symptomatic hypertension. Hypertrophy and overload of the left ventricle of the heart develops. In 30-40% of patients with PHA, arterial hypertension can be of a crisis nature, and in some cases it becomes malignant. Hypokalemia manifests itself as a neuromuscular syndrome (50-75%) in the form of general muscle weakness, fatigue, weakness in the lower extremities, paresthesia, muscle pain, cramps and short-term mono- or paraplegia (20-25%). Changes in renal tubular function are accompanied by polyuria, hypoisosthenuria, nocturia, polydipsia and thirst. More than half of patients with PHA have asymptomatic impaired carbohydrate tolerance, which in approximately a quarter of patients reaches the level of mild diabetes.

If we highlight the diagnostically significant (specific) signs of primary hyperaldosteronism, they are as follows:

• moderate or severe arterial hypertension, which is often resistant to conventional treatment; disproportionate left ventricular hypertrophy is possible;
• hypokalemia is usually asymptomatic; sometimes, against the background of severe hypokalemia, patients may experience tetany, myopathy, polyuria and nocturia;
• may be combined with osteoporosis.

Aldosteroma (Conn's syndrome)

Conn's syndrome is an aldosterone-producing adrenal adenoma, benign, less than 2.5 cm in diameter and yellowish in color on section due to high cholesterol content. The adenoma has a very high concentration of the enzyme aldosterone synthetase. Recently, it was found that the cause of aldosterone-producing tumors in 40% of cases is an inactivating mutation in the potassium channel KCJN5.

Bilateral idiopathic adrenal hyperplasia (bilateral idiopathic hyperaldosteronism)

This pathological condition is the most common cause of primary hyperaldosteronism (60%), occurring in an older age group than Conn's syndrome. Adrenal hyperplasia is usually bilateral and can appear as micronodular or macronodular hyperplasia. The pathophysiological mechanism is unknown, but it is noted that aldosterone secretion responds very actively to increased levels of angiotensin II in the blood.

Adrenal carcinoma

Adrenal carcinoma is a rare disease in which the tumor most often synthesizes not only aldosterone, but also other corticosteroids (cortisol, androgens, estrogens). In this case, hypokalemia can be very pronounced and is associated with very high levels of aldosterone. The tumor is usually 4.5 cm in diameter or larger, with evidence of locally invasive growth. The combination of an adrenal tumor larger than 2.5 cm with elevated aldosterone levels is recommended to be considered a high-risk condition for adrenal carcinoma.

Glucocorticoid-suppressed hyperaldosteronism

Glucocorticoid-suppressed hyperaldosteronism is a very rare pathology of childhood, genetically determined. As a result of a genetic defect, the enzyme aldosterone synthetase is expressed in the zona fasciculata and zona glomerulosa of the adrenal glands, so the secretion of hormones from both zones is under the control of ACTH. This circumstance determines the only possible treatment with glucocorticoids. This disease is characterized by its onset in childhood, similar pathology in relatives, and increased secretion of 18-OH-cortiosol and 18-oxocortisol.

Diagnosis of primary hyperaldosteronism

After the diagnosis of primary hyperaldosteronism has been verified using a biochemical examination, topical and differential diagnosis of diseases accompanied by hyperaldosteronism begins.

Computed/magnetic resonance imaging

Using CT or MRI, nodules with a diameter of more than 5 mm can be detected in the adrenal glands. Since the frequency of detection of adrenal incidentalomas increases with age, the question often arises about the advisability of collecting venous blood for aldosterone. CT or MRI can detect the following changes in the adrenal glands:

• with bilateral adrenal hyperplasia, both adrenal glands may be enlarged or of normal size;
• with macronodular hyperplasia, nodes may be detected in the adrenal glands;
• a tumor with a diameter of more than 4 cm is not typical for Conn’s syndrome and is suspicious for carcinoma;
• It should always be borne in mind that in a patient with essential hypertension, a hormonally inactive tumor in the adrenal gland can be detected using CT/MRI, i.e. CT and MRI are methods of morphological, not functional diagnostics, therefore the results of studying the adrenal glands with these methods do not provide information about the function of the identified pathological formations.

Taking blood from the adrenal veins

This test is one of the standard procedures used to differentiate unilateral adenoma from bilateral hyperplasia. With unilateral damage to the adrenal glands, the concentration of aldosterone on the side of the tumor is significantly higher (4 times or more). In the blood samples obtained from the adrenal glands, in addition to aldosterone, the cortisol content is also examined as an indicator of the adequate position of the catheter: in the vein flowing from the adrenal gland, the level of cortisol is 3 times higher than in the peripheral blood. The study should be performed only in those clinical centers where the number of adrenal vein catheterizations per year exceeds 20. Otherwise, the failure rate of the study is 70%.

The study is indicated in the following cases:

• bilateral changes in the adrenal glands identified by CT/MRI;
• primary hyperaldosteronism at the age of over 50 years, when CT/MRI of the adrenal glands shows a single adenoma, since with age the number of adrenal incidentalomas increases sharply. In some clinical centers, in this case, it is recommended to take blood from the veins of the adrenal glands in patients over 35 years of age, since at a younger age, against the background of primary hyperaldosteronism, a unilateral adenoma is almost always functional;
• Surgical treatment of an adrenal tumor can, in principle, be performed, and the patient is not against a potential operation.

Radioisotope scanning

Iodine-labeled cholesterol testing does not have any advantage over CT/MRI.

The diagnosis of aldosteroma or adrenal hyperplasia should not be made based solely on elevated aldosterone levels. However, in primary hyperaldosteronism, renin activity is reduced; in more rare cases, threshold values ​​of 20 and 40 times are used).

On the eve of the test, it is necessary to compensate for hypokalemia. Spironolactone, eplerenone, triamterene, loop diuretics and products containing licorice should be discontinued 4 weeks before testing plasma renin activity. If it is diagnostically insignificant, and arterial hypertension can be treated with verapamil, hydralazine or α-blockers, β-blockers, central α2-agonists, NSAIDs, and ACE inhibitors should be discontinued 4 weeks before the re-test.

Daily urinary aldosterone excretion of more than 10-14 mcg (28-39 nmol) against the background of a sodium load test is considered a sign of primary hyperaldosteronism if sodium excretion exceeds 250 mmol/day. In the saline test, plasma aldosterone levels fall below 5 ng% after infusion; When aldosterone levels are more than 10 ng%, the diagnosis of primary hyperaldosteronism is highly likely.

Diagnosis of PHA, due to the low specificity of clinical symptoms, is based on laboratory and instrumental research methods. Diagnostic measures are carried out in three stages: screening, confirmation of the autonomy of aldosterone hypersecretion and topical diagnostics with a differential diagnosis of individual forms of PHA.

At the screening stage, each patient with hypertension needs to determine the serum potassium level at least twice. Patients who have one of the following symptoms should undergo a more in-depth examination: spontaneous hypokalemia; hypokalemia while taking diuretics; failure to normalize potassium levels within 4 months after discontinuation of diuretics. Detection of normal or elevated levels of plasma renin activity at the screening stage in a patient not taking diuretics and antihypertensive drugs practically excludes PHA. If plasma renin activity is reduced, the diagnosis is aided by determining the ratio of plasma aldosterone to plasma renin activity. Its value of more than 20 is considered presumptive, and more than 30 is diagnostic.

In order to confirm the autonomy of aldosterone hypersecretion, a test is carried out with intravenous drip administration of 2 liters of physiological solution for 4 hours. Maintaining the concentration of aldosterone in the blood at a level of 10 ng/dl or more confirms the diagnosis of aldosteronism. Family history and determination of aldosterone excretion play an important role in the diagnosis of hyperaldosteronism suppressed by glucocorticoids.

In the topical diagnosis of PHA, computer X-ray or MRI is used, which makes it possible to visualize aldosteromes in the form of unilateral solitary formations of low density (0-10 units) with an average diameter of 1.6-1.8 cm. With idiopathic hyperaldosteronism, the adrenal glands look normal or symmetrically enlarged, with nodes or without them.

Hormonal examination and diagnostic signs

Screening

Indications

• Resistance to antihypertensive therapy (for example, patients do not respond to a combination of three antihypertensive drugs).
• Arterial hypertension combined with hypokalemia.
• Arterial hypertension developed before the age of 40 years.
• Adrenal incidentaloma.

Method

• If the patient is not specially prepared for the test, false-positive and false-negative results can be obtained, in particular:
• there should be no restriction of table salt in the diet;
• treatment with drugs that affect the results of renin and aldosterone tests should be discontinued for the recommended period;
• It is recommended to control blood pressure with doxazosin (an α-blocker) or verapamil (a recommended calcium channel blocker).
• Aldosterone/renin ratio:
• a high coefficient value indicates primary hyperaldosteronism:
• aldosterone/plasma renin activity >750;
• aldosterone/plasma renin activity >30-50;
• the higher the coefficient value, the more likely the diagnosis of primary hyperaldosteronism;
• false negative values ​​are observed in patients with chronic renal failure due to very high renin activity.

Diagnosis-verifying tests

The main purpose of verification tests is to demonstrate the impossibility of suppressing aldosterone secretion in response to salt loading.

• Before the test, the patient must be on a regular diet, without limiting table salt;
• patients are given instructions explaining how to include increased salt content in their diet up to 200 mmol/day for 3 days;
• if necessary, you can prescribe tablets containing salt;

An aldosterone level in daily urine of less than 10 mcg virtually eliminates primary hyperaldosteronism.

Fludrocortisone suppression test:

• prescribe 100 mcg of fludrocortisone every 6 hours for 4 days;
• measure plasma aldosterone levels at baseline and on the last day of the test;
• a decrease in aldosterone levels on day 4 indicates primary hyperaldosteronism.

Differential diagnosis of primary hyperaldosteronism

Differential diagnosis of PHA is carried out with the low-renin form of hypertension, secondary hyperaldosteronism, pseudohyperaldosteronism, Liedl and Barter syndromes, some congenital disorders of steroid synthesis (deficiency of 17a-hydroxylase, 1 10-hydroxylase), cancer of the adrenal cortex.

Once the diagnosis is established, the cause of hyperaldosteronism is determined in order to select the correct treatment. The most common causes of primary hyperaldosteronism are hyperplasia of the adrenal cortex and aldosterome. Unfortunately, the presence or absence of adrenal masses does not allow us to unambiguously confirm or exclude the presence of aldosteroma. If laboratory test data indicate aldosteroma, and radiological diagnostics do not find a tumor, blood samples are taken from the adrenal veins. This complex procedure is performed in a specialized center with extensive experience in conducting such tests. With unilateral lesions, the ratio of aldosterone levels corrected for cortisol levels in different adrenal veins of 4:1 is considered diagnostically significant.

A rare but important case of hereditary hyperaldosteronism is glucocorticoid-dependent hyperaldosteronism. It manifests itself as persistent arterial hypertension in childhood, adolescence and young adulthood, is often not accompanied by hypokalemia and can lead to early hemorrhagic strokes. Glucocorticoid-dependent hyperaldosteronism occurs due to disequilibrium crossing over between the CYP11B1 (encoding 11β-hydroxylase) and CYP11B2 (encoding 18-hydroxylase) genes. As a result, the expression of 18-hydroxylase begins to be regulated by the ACTH-dependent promoter of the CYP11B1 gene. The diagnosis of this disease can be established by the presence of hybrid metabolites in the urine - 18-oxocortisol and 18-hydroxycortisol. In addition, you can contact the International Registry for Glucocorticoid-Dependent Hyperaldosteronism for gene diagnostics. The elimination of arterial hypertension and metabolic disorders during treatment with dexamethasone also helps in making a diagnosis.

Pathogenesis of symptoms and signs

The symptom complex that develops as a result of increased levels of mineralocorticoids in the blood or increased sensitivity of target tissues to them is called hyperaldosteronism (aldosteronism, hypermineralocorticoidism). There are two forms of it:

• primary hyperaldosteronism, including endocrinopathies of the glomerular layer of the adrenal cortex;
• secondary hyperaldosteronism, complicating the course of a number of non-endocrine diseases due to stimulation of mineralocorticoid synthesis against the background of increased activity of the renin-angiotensin system.

Secondary hyperaldosteronism accompanies many diseases in which peripheral edema develops. Aldosterone secretion is stimulated in these cases by a normally functioning physiological mechanism. In patients with liver disease, hyperaldosteronism develops due to insufficient destruction of aldosterone in the liver. Secondary hyperaldosteronism also occurs in the salt-wasting form of nephropathy.

In the above diseases and conditions, hyperaldosteronism usually does not lead to arterial hypertension. However, arterial hypertension always accompanies secondary hyperaldosteronism caused by overproduction of renin in renal artery stenosis and renin-secreting tumors (Barter syndrome). The cardinal differential diagnostic laboratory criterion for primary and secondary hyperaldosteronism is the level of plasma renin, which is reduced only in the first case.

In hyperaldosteronism, potassium is excreted in the urine in increased quantities, and its content in the extracellular fluid decreases. This stimulates the release of potassium from the cells, which is accompanied by the entry of hydrogen ions into the cells, and alkalosis develops against the background of increased excretion of hydrogen ions in the urine during hyperaldosteronism. Moderate depletion of potassium reserves in the body is accompanied by impaired glucose tolerance and resistance to the biological action of ADH (vasopressin). Severe potassium deficiency inhibits the activity of baroreceptors, which sometimes manifests as orthostatic hypotension. Against the background of increased aldosterone synthesis, the production of other mineralocorticoids, aldosterone precursors, is often activated: deoxycorticosterone, corticosterone, 18-hydroxycorticosterone.

Complaints with hyperaldosteronism - weakness, fatigue, loss of endurance and nocturia - are nonspecific and caused by hypokalemia. With severe hypokalemia, accompanied by alkalosis, thirst and polyuria (with a predominance of nocturia), as well as paresthesia and Trousseau and/or Chvostek symptoms develop. Headaches are common.

Increased synthesis of mineralocorticoids does not have any characteristic physical signs. Edema noticeable to the eye rarely develops.

Elevated blood pressure is recorded in most patients.

Retinopathy is moderate, and hemorrhages in the fundus rarely appear.

The heart slightly increases in size to the left.

Since hypokalemia develops most often during treatment with diuretics, they should be discontinued 3 weeks before the potassium test. In addition, the patient's diet should not be enriched with potassium or sodium. A low-salt diet, while helping to preserve potassium reserves in the body, can mask hypokalemia.

Since modern people consume quite a lot of sodium in salt (on average 120 mmol/day), hypokalemia is usually not masked on a normal dietary regimen. And if hypokalemia is detected in a subject who does not limit himself in salt consumption or even regularly adds additional salt to his food, then the diagnosis of hyperaldosteronism is excluded without additional research. When there is no confidence that the person being examined consumes a sufficient amount of salt, it should be recommended to add up to 1 g of salt (1/5 tablespoon) to each of the main meals to his usual (without restrictions) diet. Blood electrolytes are examined on the 5th day of this dietary regimen. If hypokalemia is detected, then the plasma renin activity is examined first. When renin activity is normal or high in a patient who has not been treated with diuretics for at least more than 3 weeks, the likelihood of primary hyperaldosteronism is extremely low.

In patients with hypokalemia and low plasma renin levels, it is necessary to examine the level of aldosterone in the urine and blood, which are elevated in hyperaldosteronism.

Associated conditions, diseases and complications

Associated conditions/diseases and complications are listed below.

• Primary hyperaldosteronism (aldosteroma).
• Hemorrhagic stroke.
• Arrhythmias.
• Hypervolemia.
• Unexpected cardiac death.
• Intoxication with cardiac glycosides.
• Nephrosclerosis benign/malignant arteriolar.
• Kidney cyst.
• Nephrogenic ND.
• Diabetes.
• Periodic paralysis syndrome.
• Tetany.
• Electrolyte myopathy.
• Hypokalemia.
• Hypokalemic nephropathy.
• Alkalosis is metabolic, hypokalemic.
• Hypernatremia.
• Hypomagnesemia.
• Drug-induced electrolyte disturbances.
• Isosthenuria.

Diseases and conditions from which hyperaldosteronism is differentiated

Differential diagnosis is carried out with the following diseases/conditions.

• Adrenogenital syndrome.
• Cushing's syndrome/disease.
• Iatrogenic Cushing's syndrome.
• Secondary hyperaldosteronism.
• Intoxication with diuretics.
• Drug-induced electrolyte disturbances.
• Drug-induced arterial hypertension.
• Electrolyte disturbances.
• Hypokalemic periodic paralysis.
• Taking licorice roots/glycyrrhizic acid.
• Familial periodic paralysis.
• Renal artery stenosis.
• Barter syndrome.

Treatment of primary hyperaldosteronism

Treatment of PHA should take into account the etiology of the syndrome and include the correction of hypertension and metabolic disorders. In order to normalize potassium homeostasis, aldosterone antagonists - spironolactone or eplerenone - are prescribed.

Adrenal aldosteroma and primary adrenal hyperplasia can be successfully treated with surgery. For idiopathic hyperaldosteronism, continued conservative therapy is indicated; if it is ineffective, subtotal adrenalectomy can be performed. Patients with glucocorticoid-suppressed aldosteronism are prescribed dexamethasone in an individually adjusted dose.

Conservative treatment of primary hyperaldosteronism, regardless of etiology, consists primarily of prescribing a low-salt diet (containing less than 80 mEq of sodium). This reduces urinary potassium loss by reducing the amount of sodium exchanged for potassium in the distal tubules of the kidneys. In addition, such a diet helps lower blood pressure, since it reduces intravascular volume.

Diet therapy is complemented by treatment with spironolactone, a competitive mineralocorticoid receptor antagonist. After achieving a therapeutic effect, the dose of spironolactone is reduced to a maintenance dose of 100 mg/day. The expected increase in blood potassium levels under spironolactone therapy is 1.5 mmol/L. Side effects of spironolactone occur in 20% of patients in the form of gastrointestinal disorders and general weakness.

Along with or instead of spironolactone, potassium-sparing diuretics can be used, which block sodium channels in the distal renal tubules. The initial dose of amiloride is 10 mg per day, if necessary, it is increased by 10 mg/day to a maximum of 40 mg/day. The hypotensive effect is more pronounced with aldosterome.

When surgical treatment is indicated for hyperaldosteronism syndrome (apdosteroma, adrenal carcinoma, primary hyperaldosteronism, etc.), then preoperative preparation consists of normalizing potassium and blood pressure, which may require conservative therapy (diet and medications) for hyperaldosteronism syndrome for up to 1-3 months. This treatment prevents the development of postoperative hypoaldosteronism, since against its background the renin-angiotensin system and, accordingly, the glomerular layer of the unaffected adrenal gland are activated. Plasma potassium levels are regularly monitored during surgery, as the function of the remaining adrenal gland is sometimes so suppressed that massive steroid replacement therapy may be required. To prevent rebound mineralocorticoid deficiency after surgical removal of the affected tissue, hydrocortisone is infused during surgery at a rate of 10 mg/h. After surgery, glucocorticoids are prescribed, the dose of which is gradually reduced until completely eliminated over 2-6 weeks.

Some patients, despite preoperative preparation, develop hypoaldosteronism after surgery, the symptoms of which are usually eliminated with adequate (without restrictions) salt and fluid intake. If dietary treatment does not correct hypoaldosteronism, mineralocorticoid replacement therapy is indicated.

Surgery

Laparoscopic adrenalectomy is currently the treatment of choice for aldosterone-secreting adenoma and is associated with a significantly lower complication rate than open surgery. Arterial hypertension disappears in 70% of cases, but if it remains, it turns out to be more manageable with antihypertensive medications. Normalization of blood pressure after surgery occurs in 50% of patients during the first month and in 70% after a year.

Surgical treatment is not indicated for patients with idiopathic hyperaldosteronism, since even bilateral removal of the adrenal glands does not eliminate arterial hypertension.

Prognosis of primary hyperaldosteronism

In patients with idiopathic hyperaldosteronism, complete recovery is not observed; patients require constant therapy with aldosterone antagonists.

Primary hyperaldosteronism should be understood as a clinical syndrome based on increased secretion of aldosterone, which is the result of a tumor or hyperplastic process in the adrenal glands. A characteristic feature of this pathology is primary damage to the adrenal cortex.

Causes

Depending on the cause, it is customary to distinguish the following variants of primary hyperaldosteronism:

• idiopathic;
• ACTH-dependent;
• unilateral hyperplasia of the adrenal cortex;
• syndrome of ectopic aldosterone production.

Aldosteroma is a solitary tumor of the adrenal cortex that secretes aldosterone. This is the most common reason for the primary increase in this hormone in the body. In 80% of cases, the tumor loses contact with and autonomously produces hormones. And only in 20% of cases sensitivity to angiotensin 2 remains.

In rare cases, aldosterone-producing tumors are located in other organs (for example, in the thyroid gland or ovaries in women).

In the idiopathic variant of the disease, a person has bilateral hyperplasia of the adrenal cortex. At the same time, the functional dependence of these cells on angiotensin 2 remains.

The ACTH-dependent variant of the disease is extremely rare and is inherited. It is characterized by a pronounced therapeutic effect after the use of corticosteroids.

Development mechanisms

Normally, the most significant regulators of aldosterone secretion are the renin-angiotensin system and the potassium-sodium pump. In primary hyperaldosteronism, such regulation is impossible or insufficient. A large amount of aldosterone accumulates in the body, which has a negative effect on the organs:

• heart and blood vessels (promotes diastolic overload and dilatation of the left atrium, as well as the development of fibrosis in the heart muscle);
• kidneys (damage to the inner surface of the renal tubules due to a lack of potassium in the blood leads to inflammatory infiltration and sclerotic changes in the interstitium).

The action of this hormone causes an increase in the reabsorption of sodium in the nephron tubules, an increase in its concentration in the blood and, accordingly, a decrease in the potassium content in it (as a result of increased secretion). This leads to an increase in plasma osmotic pressure and an increase in intravascular blood volume (sodium draws water onto itself). Also, a large amount of sodium in the blood sensitizes the vascular wall to the action of catecholamines. The result of such pathophysiological changes is an increase in blood pressure.

Clinical manifestations

Primary hyperaldosteronism can have a different course, the severity of which varies from asymptomatic to obvious with a characteristic clinical picture. The main signs of this disease are:

• arrhythmia (usually);
• frequent;
• muscle weakness;
• burning sensation, tingling sensation in various parts of the body;
• convulsions;
• impaired renal function (thirst, increased amount of daily urine, frequent urination at night).

A relatively constant sign of primary hyperaldosteronism is arterial hypertension. It often has a severe course with resistance to most antihypertensive drugs. Moreover, the higher the concentration of aldosterone in the blood serum, the higher the blood pressure numbers. However, in some patients the course of the disease is mild and can be easily corrected with small doses of medications.

Diagnostics

The diagnosis of “primary hyperaldosteronism” is based on clinical data and the results of laboratory and instrumental examinations. First of all, the following persons are subject to examination:

• with malignant resistant hypertension;
• with early onset of the disease;
• burdened family history;
• a combination of high blood pressure and hypokalemia.

During the examination, in addition to standard general clinical examinations, such patients are prescribed:

• determination of the level of aldosterone and renin in the blood;
• calculation of aldosterone-renin ratio;
• functional tests.

Currently, the most accessible and reliable screening method is the determination of the aldosterone-renin ratio. To reduce the possibility of obtaining false results during testing, certain conditions must be observed:

• 2 weeks before the proposed study, it is recommended to stop taking all medications that can affect the result (aldosterone antagonists, diuretics, β-blockers, α-adrenergic agonists, angiotensin receptor and renin blockers, ACE inhibitors);
• on the eve of blood sampling, correction of electrolyte disorders is carried out;
• During the 3 days before the study, salt intake is not limited.

The interpretation of the results is carried out individually, taking into account all possible external influences and long-term. If after the study a positive result is obtained, then proceed to one of the confirmatory tests:

• with a sodium load (increase salt intake to more than 6 g per day; on the third day, aldosterone excretion is determined, if it is more than 12-14 mg, then the diagnosis is highly likely);
• saline solution (carried out 4 hours after a slow intravenous infusion of 0.9% sodium chloride solution with a volume of about 2 liters; the diagnosis is confirmed when the concentration of aldosterone in the blood is more than 10 ng/dl);
• captopril (blood sampling is carried out an hour after taking captopril; normally the level of aldosterone is reduced by 30%; with primary hyperaldosteronism it remains elevated with a low ratio to renin);
• fludrocortisone (the drug is taken every 6 hours in combination with potassium supplements and sodium chloride infusion; a study is performed on the fourth day; the test is considered positive if the aldosterone level is more than 6 ng/dl).

Instrumental diagnostic methods make it possible to visualize the adrenal glands and identify the pathological process in them. For this purpose:

• ultrasound examination (a safe and informative method that allows you to identify adenomas measuring 1-2 cm);
• computed tomography and (have greater sensitivity and make it possible to examine the organ in more detail);
• scintigraphy (based on the ability of gland tissue to accumulate radiopharmaceuticals);
• (helps to distinguish the tumor process from hyperplasia).

Treatment

The management of patients with primary hyperaldosteronism depends on its cause.

• The main treatment method for adrenal adenoma is its surgical removal along with the affected adrenal gland. At the stage of preparation for surgery, such patients are recommended to have therapeutic nutrition (potassium-rich foods), the water-electrolyte balance is corrected, and drug treatment with aldosterone antagonists or calcium channel blockers is prescribed.
• For idiopathic aldosteronism, lifelong therapy with aldosterone antagonists in minimally effective doses is prescribed. However, resistant hypertension with a high risk of complications is considered an indication for unilateral adrenalectomy.
• The ACTH-dependent variant of the disease responds well to treatment with dexamethasone.

Which doctor should I contact?

If hyperaldosteronism is suspected, you should consult an endocrinologist. Depending on the cause of the pathology, treatment by a surgeon or oncologist, as well as consultation with a neurologist and cardiologist, may be required.

Hyperaldosteronism is a pathology of the adrenal cortex, characterized by excessive production of the mineralocorticoid hormone - aldosterone. Previously, the disease was considered rare; now it occurs in every tenth patient with arterial hypertension.

Classification of the disease

Hyperaldosteronism can be primary or secondary. Primary, in turn, is divided into:

• Adrenal cortex adenoma;
• Adrenal cortex carcinoma;
• Glucocorticoid suppressed hyperaldosteronism;
• Primary adrenal hyperplasia.

Each of these conditions is characterized by increased production of aldosterone, and in some cases, several steroid hormones.

Primary hyperaldosteronism

The pathogenesis and symptoms of primary and secondary hyperaldosteronism are different, therefore there is a separation of their symptoms and causes.

Causes

The most common causes of aldosteronism are:

• Adrenal cortical adenoma is a benign neoplasm that produces excess amounts of aldosterone. In 75% of cases, it is the adenoma that causes primary aldosteronism.
• In 20% of cases the disease is caused by bilateral aldosteromas.
• Only in 5% of cases the disease develops as a result of carcinoma of the adrenal cortex.

In medicine, a hereditary cause is also identified, which leads to a family disease with excessive production of aldosterone. And if in one family member the pathology can be caused by a neoplasm of any nature, then in the rest it is simply transmitted in the form of a syndrome. Hereditary transmission occurs through autosomal dominant inheritance.

Symptoms

The main symptoms of hyperaldosteronism are manifested in the cardiovascular and autonomic nervous systems. This is chronic stable arterial hypertension, overload of the left ventricular myocardium, sometimes hypertension reaches crises.

Other symptoms of the disease:

• Lethargy, fatigue;
• Muscle weakness;
• Convulsions;
• Numbness of the limbs;

• Twitching in muscles;
• Headache;
• Thirst and polyuria;
• Feeling of numbness in the limbs;
• Decreased visual concentration.

Arterial hypertension, which develops against the background of the disease, also exhibits its own symptoms, expressed in migraines, stress on the heart, and hypokalemia. Every fourth patient develops a prediabetic state. Possible combination with osteoporosis.

Conn's syndrome

Doctors call primary hyperaldosteronism Conn's syndrome in cases where excessive concentrations of aldosterone are produced by an adrenal adenoma.

This is a benign neoplasm, reaching a maximum diameter of 25 mm, filled with cholesterol and therefore has a yellowish color. There is also a high content of aldosterone synthetase inside the adenoma.

Idiopathic hyperplasia

Bilateral idiopathic hyperaldosteronism occurs in half of cases in patients over the age of 45 years and is more common than adrenal adenoma.

Essentially, hyperplasia is an increase in the cells of the adrenal cortex, while the volume of the cortex increases. Hyperplasia, more than other types of primary hyperaldosteronism, is a hereditary pathology.

Carcinoma is a malignant formation that synthesizes not only estrogen, cortisol, and androgens. Severe hypokalemia is noted.

The neoplasm reaches 45 mm in diameter and shows signs of growth. When neoplasms of unknown etiology are detected, with a diameter of more than 25 mm, it is customary to consider the patient’s condition as a syndrome of increased risk of carcinoma formation.

Secondary form of the disease

Secondary hyperaldosteronism is a separate diagnosis, although it occurs against the background of existing diseases of the human internal organ systems.

Reasons for development

Secondary hyperaldosteronism is associated with the following pathologies:

• Reactivity, which manifests itself during pregnancy, with excess potassium in food, with loss of sodium from the body during diets, diarrhea, long-term drug treatment with diuretics, and large blood loss.
• With tumors or vascular stenosis, organic secondary hyperaldosteronism is noted.
• Disturbance of metabolic processes with the participation of aldosterone, which is observed in chronic pathologies of the kidneys and adrenal glands, heart failure.
• Long-term treatment with hormonal drugs based on estrogen, as well as during menopause, accompanied by hormonal imbalance.

The fundamental difference from primary hyperaldosteronism is that primary entails an electrolyte imbalance, while secondary hyperaldosteronism is a natural reaction to the reactivity of the renin-angiotensin-aldosterone complex.

Symptoms

Secondary hyperaldosteronism does not show its own symptoms, since it is a compensatory pathology. Therefore, its symptoms manifest themselves precisely in those diseases or conditions against which it manifests itself. Unlike the primary form, the secondary form is not accompanied by disturbances in water-salt balance, high blood pressure and cardiac pathologies.

The only symptom that can be associated with a secondary form of aldosteronism is swelling. Sodium accumulation and fluid accumulation lead to excess aldosterone secretion, but sodium accumulation is caused by concomitant diseases.

Diagnostic methods

Diagnosis of primary or secondary hyperaldosteronism can only be done using a biochemical blood test. When excess aldosterone is identified, they move on to diagnosing diseases that accompany or cause excessive secretion of aldosterone.

CT and MRI

Computed tomography and magnetic resonance imaging can detect tumors from five millimeters in diameter. Using computer diagnostics, the following pathologies can be diagnosed:

• An increase in the size of the adrenal glands indicates bilateral hyperplasia, or unilateral if the size of only one adrenal gland is changed.
• The presence of nodes in the adrenal cortex can be regarded as macronodular hyperplasia.
• If tumors larger than 30 mm are detected, especially in the body of the adrenal gland, carcinoma is suspected.
• Detection of a hormonally inactive tumor may indicate essential hypertension.

It should be understood that computer diagnostic methods examine morphological changes, not functional ones, therefore additional methods are always required that can clarify the suspected diagnosis.

Primary hyperaldosteronism (PHA, Conn's syndrome) is a collective concept that includes pathological conditions that are similar in clinical and biochemical characteristics and differ in pathogenesis. The basis of this syndrome is the excessive production of the hormone aldosterone, which is produced by the adrenal cortex, autonomous or partially autonomous from the renin-angiotensin system.

General information

For the first time, a benign unilateral adenoma of the adrenal cortex, which was accompanied by high arterial hypertension, neuromuscular and renal disorders, manifested against the background of hyperaldosteronuria, was described in 1955 by the American Jerome Conn. He noted that removal of the adenoma led to the recovery of the 34-year-old patient, and called the identified disease primary aldosteronism.

In Russia, primary aldosteronism was described in 1963 by S.M. Gerasimov, and in 1966 by P.P. Gerasimenko.

In 1955, Foley, studying the causes of intracranial hypertension, suggested that the disturbance of water and electrolyte balance observed with this hypertension is caused by hormonal disorders. The connection between hypertension and hormonal changes was confirmed by studies by R. D. Gordone (1995), M. Greer (1964) and M. B. A. Oldstone (1966), but the cause-and-effect relationship between these disorders was not finally identified.

Research conducted in 1979 by R. M. Carey et al. on the regulation of aldosterone by the renin-angiotensin-aldosterone system and the role of dopaminergic mechanisms in this regulation showed that aldosterone production is controlled by these mechanisms.

Thanks to experimental studies on rats conducted in 1985 by K. Atarachi et al., it was found that atrial natriuretic peptide inhibits the secretion of aldosterone by the adrenal glands and does not affect the levels of renin, angiotensin II, ACTH and potassium.

Research data obtained in 1987 -2006 suggest that hypothalamic structures influence hyperplasia of the zona glomerulosa of the adrenal cortex and hypersecretion of aldosterone.

In 2006, a number of authors (V. Perrauclin and others) revealed that vasopressin-containing cells are present in aldosterone-producing tumors. Researchers suggest the presence of V1a receptors in these tumors, which control the secretion of aldosterone.

Primary hyperaldosteronism is the cause of hypertension in 0.5–4% of cases of the total number of patients with hypertension, and among hypertension of endocrine origin, Conn’s syndrome is detected in 1–8% of patients.

The incidence of primary hyperaldosteronism among patients with arterial hypertension is 1-2%.

1% of incidentally detected adrenal tumors are aldosteromas.

Aldosteromas are 2 times less common in men than in women, and are extremely rarely observed in children.

Bilateral idiopathic adrenal hyperplasia as the cause of primary hyperaldosteronism is detected in most cases in men. Moreover, the development of this form of primary hyperaldosteronism is usually observed at a later age than aldosteromas.

Primary hyperaldosteronism is usually observed in adults.

The ratio of women to men aged 30-40 years is 3:1, and in girls and boys the incidence of the disease is the same.

Forms

The most common is the classification of primary hyperaldosteronism according to nosological principle. In accordance with this classification, the following are distinguished:

• Aldosterone-producing adenoma (APA), which was described by Jerome Conn and called Conn's syndrome. It is detected in 30–50% of cases of the total disease.
• Idiopathic hyperaldosteronism (IHA) or bilateral small- or large-nodular hyperplasia of the zona glomerulosa, which is observed in 45 - 65% of patients.
• Primary unilateral adrenal hyperplasia, which occurs in approximately 2% of patients.
• Familial hyperaldosteronism type I (glucocorticoid-suppressed), which occurs in less than 2% of cases.
• Familial hyperaldosteronism type II (glucocorticoid-unsuppressible), which accounts for less than 2% of all cases of the disease.
• Aldosterone-producing carcinoma, detected in approximately 1% of patients.
• Aldosteronectopic syndrome occurs with aldosterone-producing tumors located in the thyroid gland, ovary or intestines.

Reasons for development

The cause of primary hyperaldosteronism is excessive secretion of aldosterone, the main mineralocorticosteroid hormone of the human adrenal cortex. This hormone promotes the transition of fluid and sodium from the vascular bed to the tissues by enhancing the tubular reabsorption of sodium cations, chlorine anions and water and the tubular excretion of potassium cations. As a result of the action of mineralocorticoids, circulating blood volume increases and systemic blood pressure increases.

1. Conn's syndrome develops as a result of the formation of an aldosteroma, a benign adenoma that secretes aldosterone, in the adrenal glands. Multiple (solitary) aldosteromas are detected in 80 - 85% of patients. In most cases, aldosteroma is unilateral, and only in 6 - 15% of cases do bilateral adenomas form. The size of the tumor in 80% of cases does not exceed 3 mm and weighs about 6–8 grams. If the aldosteroma increases in volume, there is an increase in its malignancy (95% of tumors exceeding 30 mm are malignant, and 87% of tumors of smaller size are benign). In most cases, adrenal aldosteroma consists primarily of cells of the zona glomerulosa, but in 20% of patients the tumor consists primarily of cells of the zona fasciculata. Damage to the left adrenal gland is observed 2–3 times more often, since anatomical conditions predispose to this (compression of the vein in the “aorto-mesenteric forceps”).
2. Idiopathic hyperaldosteronism is presumably the last stage in the development of low-renin arterial hypertension. The development of this form of the disease is caused by bilateral small- or large-nodular hyperplasia of the adrenal cortex. The zona glomerulosa of hyperplastic adrenal glands produces excess amounts of aldosterone, as a result of which the patient develops arterial hypertension and hypokalemia, and plasma renin levels decrease. The fundamental difference between this form of the disease is the preservation of sensitivity to the stimulating influence of angiotensin II in the hyperplastic zona glomerulosa. The formation of aldosterone in this form of Conn's syndrome is controlled by adrenocorticotropic hormone.
3. In rare cases, the cause of primary hyperaldosteronism is adrenal carcinoma, which is formed during the growth of an adenoma and is accompanied by increased excretion of 17-ketosteroids in the urine.
4. Sometimes the cause of the disease is genetically determined glucocorticoid-sensitive aldosteronism, which is characterized by increased sensitivity of the zona glomerulosa of the adrenal cortex to adrenocorticotropic hormone and suppression of hypersecretion of aldosterone by glucocorticoids (dexamethasone). The disease is caused by an unequal exchange of sections of homologous chromatids during meiosis of the 11b-hydroxylase and aldosterone synthetase genes located on chromosome 8, resulting in the formation of a defective enzyme.
5. In some cases, aldosterone levels increase due to the secretion of this hormone by extra-adrenal tumors.

Pathogenesis

Primary hyperaldosteronism develops as a result of excessive secretion of aldosterone and its specific effect on the transport of sodium and potassium ions.

Aldosterone controls the cation exchange mechanism through communication with receptors located in the kidney tubules, intestinal mucosa, sweat and salivary glands.

The level of potassium secretion and excretion depends on the amount of sodium reabsorbed.

With hypersecretion of aldosterone, sodium reabsorption is enhanced, resulting in induced potassium loss. In this case, the pathophysiological effect of potassium loss overrides the effect of reabsorbed sodium. Thus, a complex of metabolic disorders characteristic of primary hyperaldosteronism is formed.

A decrease in potassium levels and depletion of its intracellular reserves causes universal hypokalemia.

Potassium in cells is replaced by sodium and hydrogen, which, in combination with the excretion of chlorine, provoke the development of:

• intracellular acidosis, in which there is a decrease in pH less than 7.35;
• hypokalemic and hypochloremic extracellular alkalosis, in which there is an increase in pH above 7.45.

With potassium deficiency in organs and tissues (distal renal tubules, smooth and striated muscles, central and peripheral nervous system), functional and structural disorders occur. Neuromuscular irritability is aggravated by hypomagnesemia, which develops with a decrease in magnesium reabsorption.

In addition, hypokalemia:

• suppresses insulin secretion, so patients have reduced tolerance to carbohydrates;
• affects the epithelium of the renal tubules, so the renal tubules are exposed to antidiuretic hormone.

As a result of these changes in the functioning of the body, a number of renal functions are disrupted - the concentrating ability of the kidneys decreases, hypervolemia develops, and the production of renin and angiotensin II is suppressed. These factors help to increase the sensitivity of the vascular wall to a variety of internal pressor factors, which provokes the development of arterial hypertension. In addition, interstitial inflammation with an immune component and interstitial sclerosis develop, so a long course of primary hyperaldosteronism contributes to the development of secondary nephrogenic arterial hypertension.

The level of glucocorticoids in primary hyperaldosteronism caused by adenoma or hyperplasia of the adrenal cortex in most cases does not exceed the norm.

In carcinoma, the clinical picture is complemented by impaired secretion of certain hormones (gluco- or mineralocorticoids, androgens).

The pathogenesis of the familial form of primary hyperaldosteronism is also associated with hypersecretion of aldosterone, but these disorders are caused by mutations in the genes responsible for encoding adrenocorticotropic hormone (ACTH) and aldosterone synthetase.

Normally, the expression of the 11b-hydroxylase gene occurs under the influence of adrenocorticotropic hormone, and the aldosterone synthetase gene occurs under the influence of potassium ions and angiotensin-P. When mutation (unequal exchange during the process of meiosis of sections of homologous chromatids of the 11b-hydroxylase and aldosterone synthetase genes, localized on chromosome 8), a defective gene is formed, including the 5ACTH-sensitive regulatory region of the 11b-hydroxylase gene and a 3′-nucleotide sequence that encodes the synthesis of the enzyme aldosterone synthetase . As a result, the zona fasciculata of the adrenal cortex, whose activity is regulated by ACTH, begins to produce aldosterone, as well as 18-oxocortisol, 18-hydroxycortisol from 11-deoxycortisol in large quantities.

Symptoms

Conn's syndrome is accompanied by cardiovascular, renal and neuromuscular syndromes.

Cardiovascular syndrome includes arterial hypertension, which may be accompanied by headaches, dizziness, cardialgia and heart rhythm disturbances. Arterial hypertension (AH) can be malignant, resistant to traditional antihypertensive therapy, or correctable even with small doses of antihypertensive drugs. In half of the cases, hypertension is of a crisis nature.

The daily profile of hypertension demonstrates an insufficient decrease in blood pressure at night, and if the circadian rhythm of aldosterone secretion is disturbed at this time, an excessive increase in blood pressure is observed.

With idiopathic hyperaldosteronism, the degree of nocturnal decrease in blood pressure is close to normal.

Sodium and water retention in patients with primary hyperaldosteronism also causes hypertensive angiopathy, angiosclerosis and retinopathy in 50% of cases.

Neuromuscular and renal syndromes manifest themselves depending on the severity of hypokalemia. Neuromuscular syndrome is characterized by:

• attacks of muscle weakness (observed in 73% of patients);
• convulsions and paralysis affecting mainly the legs, neck and fingers, which last from several hours to a day and are characterized by a sudden onset and end.

Paresthesia is observed in 24% of patients.

As a result of hypokalemia and intracellular acidosis in the cells of the renal tubules, dystrophic changes occur in the tubular apparatus of the kidneys, which provoke the development of kaliopenic nephropathy. Renal syndrome is characterized by:

• decreased concentration function of the kidneys;
• polyuria (increased daily diuresis, detected in 72% of patients);
• (increased urination at night);
• (extreme thirst, which is observed in 46% of patients).

In severe cases, nephrogenic diabetes insipidus may develop.

Primary hyperaldosteronism can be monosymptomatic - in addition to elevated blood pressure, patients may not show any other symptoms, and potassium levels may not differ from normal.

With aldosterone-producing adenoma, myoplegic episodes and muscle weakness are observed more often than with idiopathic hyperaldosteronism.

Hypertension in the familial form of hyperaldosteronism manifests itself at an early age.

Diagnostics

Diagnosis primarily involves identifying Conn's syndrome among individuals with arterial hypertension. The selection criteria are:

• The presence of clinical symptoms of the disease.
• Blood plasma test data to determine potassium levels. The presence of persistent hypokalemia, in which the potassium content in plasma does not exceed 3.0 mmol/l. It is detected in the vast majority of cases with primary aldosteronism, but normokalemia is observed in 10% of cases.
• ECG data that can detect metabolic changes. With hypokalemia, a decrease in the ST segment, inversion of the T wave is observed, the QT interval is prolonged, a pathological U wave and conduction disturbances are detected. Changes detected on the ECG do not always correspond to the true concentration of potassium in the plasma.
• The presence of urinary syndrome (a complex of various disorders of urination and changes in the composition and structure of urine).

To identify the connection between hyperaldosteronemia and electrolyte disturbances, a test with veroshpiron is used (veroshpiron is prescribed 4 times a day, 100 mg for 3 days, with at least 6 g of salt included in the daily diet). A potassium level increased by more than 1 mmol/l on the 4th day is a sign of aldosterone overproduction.

To differentiate various forms of hyperaldosteronism and determine their etiology, the following is carried out:

• a thorough study of the functional state of the RAAS system (renin-angiotensin-aldosterone system);
• CT and MRI, which allow us to analyze the structural state of the adrenal glands;
• hormonal examination to determine the level of activity of the identified changes.

When studying the RAAS system, stress tests are carried out aimed at stimulating or suppressing the activity of the RAAS system. Since the secretion of aldosterone and the level of renin activity in the blood plasma are influenced by a number of exogenous factors, 10-14 days before the study, drug therapy that could affect the result of the study is excluded.

Low plasma renin activity is stimulated by walking for an hour, a hyposodium diet, and diuretics. With unstimulated plasma renin activity in patients, aldosteroma or idiopathic adrenal hyperplasia is assumed, since with secondary aldosteronism this activity is subject to significant stimulation.

Tests to suppress excess aldosterone secretion include a high-sodium diet, deoxycorticosterone acetate, and intravenous isotonic saline. When performing these tests, aldosterone secretion does not change in the presence of aldosterone, which autonomously produces aldosterone, and with adrenal hyperplasia, suppression of aldosterone secretion is observed.

Selective adrenal venography is also used as the most informative x-ray method.

To identify the familial form of hyperaldosteronism, genomic typing is used using the PCR method. In familial hyperaldosteronism type I (glucocorticoid-suppressed), trial treatment with dexamethasone (prednisolone) to eliminate signs of the disease is of diagnostic value.

Treatment

Treatment of primary hyperaldosteronism depends on the form of the disease. Non-drug treatment includes limiting the use of table salt (less than 2 grams per day) and a gentle regimen.

Treatment of aldosteroma and aldosterone-producing carcinoma involves the use of a radical method - subtotal or total resection of the affected adrenal gland.

For 1-3 months before surgery, patients are prescribed:

• Aldosterone antagonists - the diuretic spironolactone (initial dose is 50 mg 2 times a day, and subsequently it is increased to an average dose of 200-400 mg/day 3-4 times a day).
• Dihydropyridine calcium channel blockers, which help lower blood pressure until potassium levels normalize.
• Saluretics, which are prescribed after normalization of potassium levels to lower blood pressure (hydrochlorothiazide, furosemide, amiloride). It is also possible to prescribe ACE inhibitors, angiotensin II receptor antagonists, and calcium antagonists.

For idiopathic hyperaldosteronism, conservative therapy with spironolactone is justified, which, when erectile dysfunction occurs in men, is replaced with amiloride or triamterene (these drugs help normalize potassium levels, but do not reduce blood pressure, so it is necessary to add saluretics, etc.).

For glucocorticoid-suppressed hyperaldosteronism, dexamethasone is prescribed (the dose is selected individually).

In the event of a hypertensive crisis, Conn's syndrome requires emergency care in accordance with the general rules for its treatment.

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