Definition of the concept

In 1955, Cohn described a syndrome characterized by arterial hypertension and a decrease in serum potassium levels, the development of which is associated with aldosteroma (an adenoma of the adrenal cortex that secretes aldosterone).

Primary hyperaldosteronism is more common in adults, women are more likely to get sick (ratio 3: 1) at the age of 30-40 years. Among children, the incidence of the disease in girls and boys is the same.

Causes of the disease

1. Aldosteromas (Cohn's syndrome)

2. Bilateral adrenal hyperplasia or multiple adrenal cortex adenomatosis (15%):

a) idiopathic hyperaldosteronism (overproduction of aldosterone is not suppressed);

3. Aldosterone-producing adenoma, completely suppressed by glucocorticoids.

4. Carcinoma of the adrenal cortex.

5. Extra-adrenal hyperaldosteronism

Mechanisms of the onset and development of the disease (pathogenesis)

1. Aldosteromas (Cohn's syndrome) - aldosterone-producing adrenal tumor (70% of cases of primary hyperaldosteronism). Aldosterone-producing adenoma of the adrenal cortex is usually unilateral, no more than 4 cm in size. Multiple and bilateral adenomas are extremely rare. Adrenal cancer as a cause of aldosteronism is also rare - 0.7-1.2%. In the presence of an adenoma, aldosterone biosynthesis does not depend on ACTH secretion.

2. Bilateral adrenal hyperplasia (30% of cases) or multiple adenomatosis of the adrenal cortex (15%):

a) idiopathic hyperaldosteronism (overproduction of aldosterone, not suppressed);

b) undefined hyperaldosteronism (overproduction of aldosterone, selectively suppressed);

c) hyperaldosteronism, completely suppressed by glucocorticoids.

3. Aldosterone-producing adenoma, is completely suppressed by glucocorticoids.

4. Carcinoma of the adrenal cortex.

A relatively rare cause of primary aldosteronism is a malignant tumor of the adrenal cortex.

5. Extra-adrenal hyperaldosteronism (tumor of the ovaries, intestines, thyroid gland).

Malignant tumors account for 2-6% of all cases.

The clinical picture of the disease (symptoms and syndromes)

1. Arterial hypertension. Persistent arterial hypertension is sometimes accompanied by severe headaches in the forehead. Hypertension is stable, but paroxysms are possible. Malignant hypertension is very rare.

Hypertension does not respond to orthostatic load (renin-dependent reaction), resistant to the Valsalva maneuver (blood pressure does not increase during the test, unlike other types of hypertension).

BP is corrected with spironolactone (400 mg / day for 10-15 days), as is hypokalemia.

2. "Kaliypenichesky kidney"

In almost all cases, primary aldosteronism is accompanied by hypokalemia due to excessive loss of potassium by the kidneys under the influence of aldosterone. Potassium deficiency causes the formation of a "caliopenic kidney". The epithelium of the distal renal tubules is affected, in combination with general hypokalemic alkalosis, leading to a violation of the mechanisms of oxidation and urine concentration.

In the initial stages of the disease, renal impairment may be minor.

1) Polyuria, mainly nocturnal, reaches 4 liters per day, nocturia (70% of patients). Polyuria in primary hyperaldosteronism is not suppressed by vasopressin drugs, and does not decrease with fluid intake restriction.

2) Typical hypoisostenuria - 1008-1012.

3) Transient, moderate proteinuria is possible.

4) The urine reaction is often alkaline, which increases the incidence of concomitant pyelitis and pyelonephritis.

Thirst and compensatory polydipsia develop as a reaction to polyuria. Polydipsia and polyuria at night, along with neuromuscular manifestations (weakness, paresthesias, myoplegia attacks), are mandatory components of the hypokalemic syndrome. Polydipsia has a central origin (hypokalemia stimulates the center of thirst) and reflex genesis (due to the accumulation of sodium in cells).

Edema is not typical - only in 3% of patients with concomitant kidney damage or circulatory failure. Polyuria, accumulation of sodium in cells does not contribute to fluid retention in the interstitial space.

3. Muscle damage. Muscle weakness, pseudoparalysis, periodic seizures of varying intensity, tetany is observed, overt or latent. Twitching of facial muscles, positive symptoms of Khvostek and Trusso are possible. Increased electrical potential in the rectum. Characteristic paresthesias in various muscle groups.

4. Changes in the central and peripheral nervous system

General weakness occurs in 20% of patients. Headaches are observed in 50% of patients, are intense in nature - due to increased blood pressure and hyperhydration of the brain.

5. Violation of carbohydrate metabolism.

Hypokalemia suppresses insulin secretion, promotes the development of reduced carbohydrate tolerance (60% of patients).

Diagnosis of the disease

1. Hypokalemia

Increased urinary potassium excretion (normally 30 mmol / l).

2. Hypernatremia

3. Hyperosmolarity

Specific stable hypervolemia and high plasma osmolarity. An increase in intravascular volume of 20-75% does not change with the introduction of saline or albumin.

Alkalosis is present in 50% of patients - blood pH reaches 7.60. Increased blood bicarbonate content up to 30-50 mmol / l. Alkalosis is combined with a compensatory decrease in the level of chlorine in the blood. The changes are enhanced by the use of salt, and are eliminated by spironolactone.

4. Violation of hormonal levels

The level of aldosterone in the blood is often increased at a rate of 2-16 ng / 100 ml to 50 ng / 100 ml. Blood sampling should be carried out with the patient in a horizontal position. Increased blood levels of aldosterone metabolites. Changes in the daily profile of aldosterone secretion: determination of the level of aldosterone in the blood serum at 8 am and at 12 noon. With aldosteroma, the content of aldosterone in the blood at 12 noon is lower than at 8 a.m., whereas with small- or large-nodular hyperplasia, the concentration of aldosterone during these periods hardly changes or slightly higher at 8 a.m.

Increased urinary excretion of aldosterone.

Reduced unstimulated plasma renin activity is a cardinal symptom of primary hyperaldosteronism. Renin secretion is suppressed by hypervolemia and hyperosmolarity. In healthy people, the content of renin in the blood in a horizontal position is 0.2-2.7 ng / ml / hour.

The criterion for the diagnosis of primary hyperaldosteronism syndrome is a combination of decreased plasma renin activity with hyperaldosteronemia. Differential diagnostic criterion from secondary hyperaldosteronism in renovascular hypertension, chronic renal failure, renin-forming kidney tumor, malignant arterial hypertension, when both the level of renin and aldosterone are increased.

5. Functional tests

1. Load with sodium 10 g / day for 3-5 days. In practically healthy individuals with normal regulation of aldosterone secretion, the serum potassium level will remain unchanged. With primary aldosteronism, the serum potassium content decreases to 3-3.5 mmol / l, the urinary potassium excretion increases sharply, the patient's condition worsens (severe muscle weakness, heart rhythm disturbances).

2. 3-day diet low (20 mEq / day) sodium - the level of renin remains unchanged, the level of aldosterone may even decrease.

3. Test with furosemide (lasix). Before the test, the patient should be on a diet with a normal sodium chloride content (about 6 g per day), not receive any antihypertensive drugs for a week, and not take diuretics for 3 weeks. When conducting a sample, the patient takes 80 mg of furosemide orally and is in an upright position (walking) for 3 hours. After 3 hours, blood is taken to determine the level of renin and aldosterone. In primary aldosteronism, there is a significant increase in aldosterone levels and a decrease in the concentration of renin in the blood plasma.

4. Test with kapoten (captopril). In the morning, blood is taken from the patient to determine the content of aldosterone and renin in plasma. Then the patient takes 25 mg of capoten orally and for 2 hours is in sitting position, after which blood is taken from him again to determine the content of aldosterone and renin. In patients with essential hypertension, as well as in healthy people, there is a decrease in the level of aldosterone due to inhibition of the conversion of angiotensin I to angiotensin II. In patients with primary aldosteronism, the concentration of aldosterone is increased, the ratio of aldosterone / renin activity is more than 50.

5. Spironolactone test. The patient is on a diet with a normal sodium chloride content (6 g per day) and for 3 days receives aldosterone antagonist aldactone (veroshpiron) 100 mg 4 times a day. On the 4th day, the potassium content is determined in the blood serum, and an increase in its blood level by more than 1 mmol / l compared to the initial level is confirmation of the development of hypokalemia due to an excess of aldosterone. The level of aldosterone and renin in the blood remains unchanged. Arterial hypertension is eliminated.

6. Test with non-aldosterone mineralocorticoids. The patient takes 400 μg of fluorocortisol acetate for 3 days or 10 mg of deoxycorticosterone acetate for 12 hours. The level of aldosterone in the blood serum and the excretion of its metabolites in the urine during primary aldosteronism does not change, while in secondary hyperaldosteronism, it decreases significantly. In some cases, there is a slight decrease in the level of aldosterone in the blood also with aldosteroma.

7. Test with DOX. Doxa is prescribed at 10-20 mg / day for 3 days. In patients with secondary hyperaldosteronism, the level of aldosterone decreases, in patients with Cohn's syndrome - not. Glucocorticosteroid and androgen levels are normal.

8. Orthostatic test (walking for 4 hours). Unlike healthy people, aldosterone levels are paradoxically reduced.

9. Topical diagnosis of adrenal lesions. Adenomas-aldosteromas are small, in 80% of patients less than 3 cm in diameter, more often located in the left adrenal gland.

10. Computed tomography is the most informative study with high sensitivity. In 90% of patients, tumors with a diameter of 5-10 mm are detected.

11. Scanning of the adrenal glands with I-131-iodine-cholesterol against the background of inhibition of glucocorticoid function by dexamethasone (0.5 mg every 4 hours for 4 days). The asymmetry of the adrenal glands is characteristic. Sensitivity - 85%.

12. Catheterization of the adrenal veins with bilateral selective blood sampling and determination of the level of aldosterone in them. The sensitivity of the study increases after preliminary stimulation of the adenoma with synthetic ACTH - the production of aldosterone on the side of the tumor sharply increases. The sensitivity of the study is 90%.

13. X-ray contrast venography of the adrenal glands - the sensitivity of the method is 60%: the vascularization of the tumor is insignificant, the size is small.

14. Echography of the adrenal glands.

15. Suprareno-radiography in conditions of pneumoretroperitonium, combined with or without intravenous urography. The method is informative only when large tumors, often gives false negative results. The small size of the aldosteromas located inside rarely change the contours of the adrenal glands.

Differential diagnosis

1. Secondary aldosteronism (hyperreninemic hyperaldosteronism) - conditions in which the increased production of aldosterone is associated with prolonged stimulation of its secretion by angiotensin II. For secondary aldosteronism, an increase in the level of renin, angiotensin and aldosterone in blood plasma is characteristic. The activation of the renin-angiotensin system occurs due to a decrease in the effective blood volume with a simultaneous increase in the negative balance of sodium chloride. It develops in nephrotic syndrome, cirrhosis of the liver in combination with ascites, idiopathic edema, which are often found in premenopausal women, congestive heart failure, renal tubular acidosis.

2. Barter's syndrome: hyperplasia and hypertrophy of the juxtaglomerular system of the kidneys with hyperaldosteronism. The excessive loss of potassium in this syndrome is associated with changes in the ascending renal tubules and a primary defect in chloride transport. It is characterized by dwarfism, mental retardation, the presence of hypokalemic alkalosis with normal blood pressure.

3. Tumors producing renin (primary reninism), including Wilms' tumors (nephroblastoma) - secondary aldosteronism occurs with arterial hypertension. Malignant hypertension with renal and retinal vascular damage is often combined with increased renin secretion and secondary aldosteronism. The increase in renin formation is associated with the development of necrotizing renal arteriolitis. After nephrectomy, both hyperaldosteronism and hypertension disappear.

4. Long-term use of thiazide diuretics in arterial hypertension causes secondary aldosteronism. Therefore, the determination of the level of renin and aldosterone in the blood plasma should be carried out only 3 weeks or later after the discontinuation of diuretics.

5. Long-term use of contraceptives containing estrogen leads to the development of arterial hypertension, an increase in the level of renin in the blood plasma and secondary aldosteronism. An increase in renin formation is associated with the direct effect of estrogens on the liver parenchyma and an increase in the synthesis of a protein substrate - angiotensinogen.

6. Pseudomineralocorticoid hypertensive syndrome is accompanied by arterial hypertension, a decrease in the content of renin and aldosterone in the blood plasma. It develops with excessive use of glycyrlizic acid preparations (glycyram, sodium glycyrinate) contained in the rhizomes of Ural licorice or licorice naked.

7. Liddle's syndrome - hereditary disease, accompanied by increased sodium reabsorption in the renal tubules, followed by the development of arterial hypertension, a decrease in the content of potassium, renin and aldosterone in the blood.

8. Reception or excessive formation of deoxycorticosterone in the body leads to sodium retention, excessive potassium excretion and hypertension. With a congenital disorder of cortisol biosynthesis distal to 21-hydroxylase, namely, with a deficiency of 17a-hydroxylase and 11b-hydroxylase, excessive deoxycorticosterone formation occurs with the development of the corresponding clinical picture.

9. Hypertensive disease with a low renin content in blood plasma (low-root renin arterial hypertension) accounts for 20-25% of all patients suffering from this disease. The use of steroidogenesis inhibitors in hypertensive patients with low renin content led to normalization blood pressure, while in hypertensive patients with normal renin levels, such treatment was ineffective. Blood pressure normalization was observed in such patients after bilateral total adrenalectomy. It is possible that hypertension with a low renin content is a hypertensive syndrome that develops due to an excess of secretion of yet unidentified mineralocorticoids.

The adrenal cortex is responsible for the synthesis of three groups of hormones. Including the cells of this endocrine organ produce mineralocorticoids. The main representative of this class of hormones is aldosterone.

Normally, aldosterone is secreted under the control of the renin-angiotensin blood system. The hormone increases urinary potassium loss and sodium retention.

If there is too much aldosterone, hyperaldosteronism is diagnosed. This condition can be caused by both adrenal pathology and systemic disorders.

Primary hyperaldosteronism is called Connes syndrome. This disease is based on excessive secretion of the hormone in the glomerular zone of the adrenal cortex.

Connes syndrome is three times more likely to be diagnosed in women than in men. Symptoms usually appear between the ages of 30 and 40.

Causes of primary hyperaldosteronism

Conn's syndrome can develop due to various pathological processes.

An excess of mineralocorticoid secretion is caused by:

• hyperplasia of the adrenal cortex;
• aldosteroma ( benign tumor glomerular zone);
• carcinoma (malignant tumor).

About 30-40% of primary hyperaldosteronism is associated with cortical hyperplasia. Unilateral adenoma is the cause of 60% of all cases of Connes syndrome. Frequency malignant tumors is 0.7-1% in the structure of morbidity.

The symptoms of hyperaldosteronism are the same for all etiological factors. Excessive secretion of the hormone in Conn's syndrome leads to severe electrolyte disturbances. Both tumors and the hyperplastic cortex do not respond to the regulatory action of the renin-angiotensin system. Primary hyperaldosteronism has the properties of autonomy, that is, independence.

The clinical picture of the syndrome

Primary hyperaldosteronism has three characteristic groups of symptoms.

Allocate:

• cardiovascular;
• neuromuscular;
• renal components.

Changes in the volume of circulating blood and disorders of the heart muscle are manifested by arterial hypertension, heart failure, vascular accidents (strokes, heart attacks).

Patients are worried about headaches, shortness of breath, decreased exercise tolerance, weakness, fatigue, heaviness behind the breastbone.

When blood pressure is monitored, persistent hypertension is recorded. Patients have high numbers of both systolic and diastolic pressure. Treatment of hypertension in Connes's syndrome is practically inconclusive. All modern antihypertensive drugs and their combinations cannot maintain normal blood pressure in the patient.

As a result, target organ damage develops rapidly. In the fundus, on examination, angiopathy, hemorrhages, retinal detachment can be detected. In severe cases, these changes cause blindness. The heart muscle undergoes hypertrophy. Thickening of the myocardial wall is accompanied by a violation of its oxygen supply and nutrients... Because of this, the heart becomes less resistant to stress. The left ventricular ejection fraction falls, heart failure appears.

The neuromuscular component of Connes syndrome is associated with a change in the ratio of potassium and sodium levels in the blood. Patients with primary hyperaldosteronism complain of muscle weakness, discomfort in the extremities (cold, "chills"), convulsions. Sometimes complete or partial paralysis can develop.

Kidney damage in primary hypercortisolism syndrome is explained by an excess of potassium in the urine. Patients are worried about strong thirst, dry mouth. The volume of urine per day may be higher than normal. Usually nocturnal urine output prevails over daytime.

In urine tests, low density, alkaline reaction, proteinuria (protein) are detected. Long-term primary hyperaldosteronism can cause chronic renal failure.

Examination for hyperaldosteronism syndrome

If the doctor suspects the patient's Connes syndrome, then further it is necessary to undergo a diagnostic examination.

To clarify the condition, you need:

• identify high levels of aldosterone;
• prove the primary nature of the disease;
• assess the condition of the adrenal glands (find a tumor).

It is not always easy to assess the concentration of a hormone in the blood. Aldosterone levels, even in Connes syndrome, are prone to rapid changes. The most accurate study is the analysis for the ratio of aldosterone and plasma renin. In addition, the patient is required to determine the level of potassium in the blood.

In primary hyperaldosteronism, aldosterone is above normal, potassium and renin are reduced.

Special tests have been proposed and successfully used for diagnostics. They are usually carried out in a hospital after hospitalization.

Endocrinologists conduct tests:

• with sodium chloride;
• with hypothiazide;
• with spironolactone.

Assessment of the state of the adrenal cortex is possible in different ways. Diagnosis begins with ultrasound. Further more accurate computed tomography may be required.

If the tumor is small (up to 1 cm), then angiography is considered the most informative. it is desirable to combine it with blood samples from the vessels of the adrenal glands.

Treatment of the disease

Primary hyperaldosteronism begins to be treated conservatively. The patient is prescribed spironolactone tablets. In addition, antihypertensive and cardiovascular drugs are used. Further tactics depend on the results of ultrasound and tomography. If a tumor is found in the adrenal glands, then it is mandatory surgery... After removal of the formation, it is examined under a microscope. If signs of malignancy are found, then the oncologist determines the further tactics.

In the event that there is no volumetric neoplasm in the adrenal glands, then surgery not necessary. The patient continues to receive drugs according to the scheme and regularly undergoes a follow-up examination. Endocrinologist visits are required every few months. Monitoring of blood tests is needed even more often. Medical supervision includes assessment of symptoms, measurement of blood pressure, electrocardiogram recording, blood sampling for electrolytes, aldosterone, and plasma renin. Every year, all patients with primary idiopathic hyperaldosteronism are advised to undergo an ultrasound of the adrenal glands, computed tomography or angiography. If a tumor is found in one of the control examinations, then surgical treatment is recommended. The operation is carried out after planned preparation (correction of blood composition and cardiac activity).

Connes syndrome (primary aldosteronism, Conn syndrome) is a syndrome caused by autonomous (i.e., independent of the renin-aldosterone system) hypersecretion of aldosterone in the adrenal cortex.

Causes of Connes syndrome

The most common immediate causes of its development are aldosterone-producing adrenal adenoma or bilateral adrenal hyperplasia; much less often - unilateral hyperplasia, adrenal carcinoma, or familial hyperaldosteronism (types I and II are distinguished). In persons under the age of 40, the cause of Connes's syndrome is much more often adrenal adenoma than bilateral adrenal hyperplasia.

Reasons for mineralocorticoid hypersecretion:

• Aldosterone-producing adrenal adenoma

Aldosterone-producing adenomas account for about 35-40% of cases in the structure of primary aldosteronism. Solitary benign adenomas are almost always unilateral (unilateral). In most cases, they are small (in 20-85% of observations, less than 1 cm). Outside the adenoma, focal or diffuse tissue hyperplasia may occur in the rest of the adrenal gland tissue, as well as in the contralateral adrenal gland (which complicates differential diagnosis with bilateral hyperplasia).

• Bilateral adrenal hyperplasia
• Primary unilateral adrenal hyperplasia (rare)
• Familial hyperaldosteronism (types I and II), glucocorticoid-controlled (rare)
• Adrenal carcinoma (rare)

Most of the cases of aldosteronism (increased levels of aldosterone in the blood plasma) that occur in clinical practice are secondary to increased activity of the renin-aldosterone system (in response to decreased renal perfusion, for example, with renal artery stenosis or in some chronic conditions, accompanied by the development of edema). For differential diagnosis, you can use the determination of plasma renin activity (ARP):

• with secondary aldosteronism, this indicator is increased,
• with Conn's syndrome - reduced.

Previously, the dominant point of view was the relative rarity of primary aldosteronism. However, with the wider use of the aldosterone-renin ratio (ARC) technique, which allows the detection of milder forms of this condition (usually with bilateral adrenal hyperplasia), previously existing ideas about the prevalence of Connes syndrome have changed. Currently, it is believed that primary aldosteronism is one of the most frequent (if not the most frequent) causes of symptomatic arterial hypertension. Thus, some reports indicate that the proportion of people with Connes syndrome among the general population of patients with arterial hypertension can reach 3-10%, and among patients with grade 3 arterial hypertension - up to 40%.

Conn's syndrome can be detected in any age group (the most typical age is 30-50 years), more often in women. Classic clinical laboratory symptoms of primary aldosteronism include:

• arterial hypertension;
• hypokalemia;
• excessive excretion of potassium by the kidneys;
• hypernatremia;
• metabolic alkalosis.

Let's take a closer look at some of these manifestations.

Arterial hypertension

Arterial hypertension is present in almost all patients with Connes syndrome.

Mechanisms of development of arterial hypertension

The pressor effects of an excessive amount of aldosterone are mainly associated with the development of sodium retention (this effect is realized through a complex of genomic mechanisms of aldosterone action on sodium channels of tubular epithelial cells) and hypervolemia; a certain role is also assigned to an increase in the total peripheral vascular resistance.

Arterial hypertension in persons with Connes syndrome is usually characterized by high levels of blood pressure, often as resistant, malignant (malignant hypertension). Significant left ventricular hypertrophy can be detected, often disproportionate to the severity and duration of arterial hypertension. An important role in its development is attributed to the enhancement of the processes of myocardial fibrosis due to the action of an excessive amount of aldosterone on myocardial fibroblasts. The profibrotic effects of an excessive concentration of aldosterone (realized through its non-genomic mechanisms of action on target cells) can be quite clearly represented also in the vascular wall (with an accelerated rate of progression of atherosclerotic lesions) and kidneys (with an increase in the processes of interstitial fibrosis and glomerulosclerosis).

Hypokalemia

Hypokalemia is a common but not universal manifestation of Connes syndrome. The presence and severity of hypokalemia can depend on a number of factors. So, it is almost always present and quite clearly expressed in aldosterone-producing adrenal adenoma, but may be absent in bilateral adrenal hyperplasia. Hypokalemia may also be absent or insignificant in severity in the early stages of the formation of Connes syndrome, as well as with a significant restriction of sodium intake into the body with food (for example, during the restriction of table salt when changing the lifestyle recommended to a patient with arterial hypertension).

Experts point out that potassium levels can increase (and hypokalemia can be eliminated / masked) with:

• prolonged and painful implementation of venipuncture (mechanisms may include respiratory alkalosis with hyperventilation; release of potassium from muscle depots with repeated repeated clenching of the fist; venous stasis with prolonged clamping with a tourniquet);
• hemolysis of any nature;
• the release of potassium from erythrocytes in cases of delayed centrifugation of blood and when the blood is in the cold / ice.

Diagnostics of the Connes syndrome

Stages of diagnosing Connes syndrome, establishing the type of adrenal gland lesion and choosing treatment tactics

Diagnosis of Conn's syndrome in persons with arterial hypertension consists of several stages:

1. identification of primary aldosteronism itself, for which the study of blood and urine electrolytes, screening tests (first of all, determination of the aldosterone-renin ratio) and verification tests (with sodium load, captopril, etc.);
2. determination of the type of adrenal gland lesion - uni- or bilateral (CT scan and separate study of the aldosterone content in the blood of each of the adrenal veins).

Identifying Connes's syndrome itself

The study of levels of potassium and sodium in the blood is a routine laboratory test for hypertension. Detection of hypokalemia and hypernatremia already at the initial stage of the diagnostic search suggests the presence of Conn's syndrome. Diagnosis of primary aldosteronism is not very difficult in patients with a detailed picture of Connes syndrome (first of all, with a distinct hypokalemia not associated with other causes). At the same time, during the previous two decades, there has been a frequent possibility of the presence of primary aldosteronism among persons with normokalemia. Taking this into account, it is considered necessary to conduct additional studies to exclude Connes syndrome in a fairly wide category of patients with arterial hypertension:

• at blood pressure\u003e 160/100 mm Hg. Art. (and, especially,\u003e 180/110 mm Hg and);
• with resistant arterial hypetnesia;
• in persons with hypokalemia (both spontaneous and induced by the use of a diuretic, especially if it persists after taking potassium supplements);
• with arterial hypertension in individuals with an increase in the size of the adrenal gland according to instrumental studies (adrenal incidentaloma; it has been shown, however, that only ~ 1% of all adrenal incidentalomas are the cause of primary aldosteronism).

Assessment of the excretion of electrolytes (potassium and sodium) in urine

This study occupies a rather important place in the diagnosis of the causes of hypokalemia. The study of potassium and sodium levels is carried out in urine collected within 24 hours from a patient not receiving potassium supplements and abstaining from any diuretics for at least 3-4 days. If sodium excretion exceeds 100 mmol / day (this is the level at which the degree of potassium loss can be quite clearly estimated), a level of potassium excretion\u003e 30 mmol / day indicates hyperkaliuria. Along with primary aldosteronism, an increase in potassium excretion can be due to a number of reasons.

Causes of hypokalemia associated with increased renal excretion of potassium:

1. Increased excretion of potassium by the collecting ducts of the nephron:
   1. increased sodium excretion (eg, with a diuretic)
   2. increased urine osmolarity (glucose, urea, mannitol)
2. High concentration of potassium in the collecting ducts of the nephron:
   • with an increase in intravascular blood volume (low plasma renin):
     • primary aldosteronism
     • liddle syndrome
     • taking amphotericin B
   • with a decrease in intravascular blood volume (high plasma renin levels):
     • bartter syndrome
     • giletman syndrome
     • hypomagnesemia
     • increased excretion of bicarbonate
     • secondary aldosteronism (eg, in nephrotic syndrome)

After it has been established that the cause of the patient's hypokalemia is an increase in the excretion of potassium in the urine, it is considered desirable to attempt to correct the hypokalemia. In the absence of contraindications, potassium supplements are prescribed (potassium 40-80 mmol / day), diuretics are discontinued. It may take 3 weeks to several months to restore potassium deficiency after prolonged use of diuretics. After this period, potassium supplementation is discontinued and blood potassium is repeated\u003e 3 days after withdrawal. If blood potassium levels return to normal, plasma renin and aldosterone should be reassessed.

Assessment of the aldosterone-renin ratio

This test is currently considered the main screening method in the diagnosis of Connes syndrome. Normal values \u200b\u200bof aldosterone levels during blood sampling in the supine position are 5-12 ng / dl (in SI units - 180-450 pmol / l), plasma renin activity - 1-3 ng / ml / h, aldosterone-renin ratio - up to 30 (in SI units - up to 750). It is important to note that the normal values \u200b\u200bshown are only approximate values; for each specific laboratory (and for specific laboratory kits), they may differ (a comparison is required with the indicators in healthy individuals and in individuals with essential arterial hypertension). Given this lack of standardization of the method, one can agree with the opinion that when interpreting the results of assessing the aldosterone-renin ratio "the clinician needs flexibility of judgment." Below are the main guidelines for assessing the aldosterone-renin ratio.

Recommendations for assessing the aldosterone-renin ratio

Patient preparation:

• Correction of hypokalemia if present.
• Liberalization of salt intake.
• Withdrawal for at least 4 weeks of drugs that increase the level of renin and reduce the concentration of aldosterone, which causes false results:
  • spironolactone, eplerenone, amiloride, triamterene;
  • products containing licorice.
• Cancellation for at least 2 weeks of other drugs that may affect the test result:
  • β-AB, central a2-agonists (clonidine), NSAIDs (reduce the level of renin);
  • aCE inhibitors, sartans, direct renin inhibitors, dihydropyridine calcium channel blockers (increase the level of renin, reduce the content of aldosterone).

If it is impossible to cancel these drugs in patients with grade 3 arterial hypertension, it is permissible to maintain their intake with the obligatory cancellation of spironolactone, eplerenone, triamterene and amiloride for at least 6 weeks before the study.

• Cancellation of estrogen-containing drugs.

Blood sampling conditions:

• Blood should be collected in the middle of the morning, about 2 hours after the patient wakes up and gets out of bed. Immediately before taking blood, the patient should sit for 5-15 minutes.
• It is necessary to collect blood carefully, avoiding stasis and hemolysis.
• Before centrifugation, the blood sample should be at room temperature (not on ice, which will facilitate the conversion of inactive renin to active); after centrifugation, plasma should be rapidly frozen.

Factors to Consider When Interpreting Results

• Age (people over 65 have a more age-related decrease in renin levels compared to aldosterone).
• Time of day, recent dietary regimen, body position, length of stay in that position.
• Medicines being taken.
• Specifics of taking a blood sample, including any complications that may arise.
• Blood potassium levels.
• Decreased renal function (there may be an increase in aldosterone due to hyperkalemia and a decrease in renin secretion).

Practically important is the recommendation of Kaplan N.M .:

“Recommendations for assessing the aldosterone-renin ratio should be followed as closely as possible. Further, the levels of aldosterone and plasma renin activity should be separately assessed, without calculating the ratio between them. If the plasma renin activity is clearly low (<0,5 нг/мл/ч) и уровень альдостерона плазмы явно повышен (>15 mg / dl), it is advisable to repeat this measurement again. If low values \u200b\u200bof plasma renin activity and high levels of aldosterone are confirmed, then verification tests should be carried out. "

The study of the aldosterone-renin ratio, as well as the conduct of all further studies, requires a discussion of their purpose with the patient; a diagnostic search (with the expense of time and money) should be planned taking into account the patient's willingness and desire to undergo laparoscopic adrenalectomy in the future if an adrenal adenoma is found.

Verification test - captopril sample

Plasma aldosterone levels are assessed before and 3 hours after oral administration of captopril at a dose of 1 mg / kg of body weight of the subject (in healthy people, in patients with essential and renovascular arterial hypertension, aldosterone levels are clearly reduced, but this does not happen in Conn's syndrome). A normal response is considered to be\u003e 30% reduction in aldosterone from baseline.

Connes syndrome treatment

Long-term treatment with the use of mineralocorticoid receptor antagonists (spironolactone or eplerenone), with their intolerance - amiloride; often, a combination with a thiazide diuretic can be the therapeutic approach of choice in patients:

• who cannot perform surgery;
• who do not want to fulfill it;
• in whom arterial hypertension persists after surgery;
• the diagnosis of Connes syndrome, in which it remains not fully confirmed despite the examination.

The use of antagonists of mineralocorticoid receptors in persons with Connes syndrome provides a fairly distinct decrease in blood pressure and allows regression of left ventricular hypertrophy. At the initial stages of treatment, doses of 50-100 mg / day or more of spironolactone or eplerenone may be required; subsequently, lower dosages (25-50 mg / day) are quite effective. Their combination with thiazide diuretics may allow to reduce the dose of these drugs. For long-term treatment of Connes syndrome, a selective representative of mineralocorticoid receptor antagonists eplerenone with a significantly lower frequency inherent in it than in spironolactone side effects can be considered the drug of choice.

If others are needed, the initial choice includes calcium channel blockers (eg, amlodipine), since at high doses they have some ability to block aldosterone receptors. To control arterial hypertension, other classes of antihypertensive drugs can be used as components of treatment tactics.

In individuals with adrenal carcinoma, drugs from the groups of steroidogenesis antagonists may be used.

RCHD (Republican Center for Healthcare Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical Protocols MH RK - 2017

Primary hyperaldosteronism (E26.0)

Endocrinology

general information

Short description

Approved
Joint Commission on the Quality of Medical Services
Ministry of Health of the Republic of Kazakhstan
dated August 18, 2017
Protocol No. 26

PGA- a collective diagnosis characterized by elevated level aldosterone, which is relatively autonomous from the renin-angiotensin system and does not decrease with sodium loading. An increase in aldosterone levels is the cause of cardiovascular disorders, a decrease in plasma renin levels, arterial hypertension, sodium retention, and an accelerated excretion of potassium, which leads to hypokalemia. Among the causes of PHA are adrenal adenoma, unilateral or bilateral suprarenal hyperplasia, and in rare cases, hereditary HZHA.

INTRODUCTORY PART

ICD code (s):

Date of development / revision of the protocol:2013 (revised 2017).

Abbreviations used in the protocol:

AG	-	arterial hypertension
HELL	-	arterial pressure
APA	-	aldosterone-producing adenoma
APRA	-	aldosterone-producing renin-sensitive adenoma
APF	-	angiotensin converting enzyme
ARS	-	aldosterone-renin ratio
GZGA	-	glucocorticoid-dependent hyperaldosteronism HPHA - glucocorticoid-suppressed hyperaldosteronism
IGA	-	idiopathic hyperaldosteronism
PGA	-	primary hyperaldosteronism
PGN	-	primary adrenal hyperplasia
RCC	-	direct concentration of renin
Ultrasound	-	ultrasound procedure

Protocol users: general practitioners, endocrinologists, internists, cardiologists, surgeons and vascular surgeons.

Evidence level scale:

AND	High quality meta-analysis, systematic review of RCTs, or large RCTs with very low likelihood (++) bias that can be generalized to the relevant population
IN	High quality (++) systematic review of cohort or case-control studies or high quality (++) cohort or case-control studies with very low risk of bias or RCTs with low (+) risk of bias that can be generalized to the relevant population
FROM	A cohort or case-control study or controlled trial without randomization with a low risk of bias (+), the results of which can be generalized to the relevant population, or RCTs with a very low or low risk of bias (++ or +), the results of which cannot be directly extended to the relevant population
D	Case series description or uncontrolled research or expert opinion
GPP	Best Clinical Practice

Classification

Etiopathogenetic and clinical and morphological signs of PHA (E. G. Biglieri, J. D. Baxter, modification).
· Aldosterone-producing adenoma of the adrenal cortex (APA) - aldosteroma (Conn's syndrome);
Bilateral hyperplasia or adenomatosis of the adrenal cortex:
- idiopathic hyperaldosteronism (IHA, unsuppressed hyperproduction of aldosterone);
- undefined hyperaldosteronism (selectively suppressed production of aldosterone);
- glucocorticoid-suppressed hyperaldosteronism (HPHA);
· Aldosterone-producing, glucocorticoid-suppressed adenoma;
· Carcinoma of the adrenal cortex;
· Extra-adrenal hyperaldosteronism (ovaries, intestines, thyroid gland).

Diagnostics

DIAGNOSTIC METHODS, APPROACHES AND PROCEDURES

Diagnostic criteria

Complaints and anamnesis

: headaches, increased blood pressure, muscle weakness, especially in the calf muscles, cramps, parasthesia in the legs, polyuria, nocturia, polydipsia. The onset of the disease is gradual, symptoms appear after 40 years, more often diagnosed in 3-4 decades of life.

Physical examination:
· Hypertensive, neurological and urinary syndromes.

Laboratory research:
· Determination of potassium in blood serum;
· Determination of the level of aldosterone in blood plasma;
· Determination of the aldosterone-renin ratio (ARS).
Patients with a positive APC are recommended to undergo one of 4 confirmatory PHA tests before differential diagnosis of PHA forms (A).

Tests confirming PHA

Confirming PHA test	Methodology	Interpretation	Comments
Sodium test load	Increase sodium intake\u003e 200 mmol (~ 6 g) per day for 3 days, under the control of daily sodium excretion, constant control of normokalemia while taking potassium preparations. The daily excretion of aldosterone is determined from the morning of the 3rd day of the test.	PHA is unlikely if the daily excretion of aldosterone is less than 10 mg or 27.7 nmol (excluding cases of chronic renal failure, in which the excretion of aldosterone is reduced). The diagnosis of PHA is highly probable with a daily excretion of aldosterone\u003e 12 mg (\u003e 33.3 nmod) according to the Mayo Clinic, and\u003e 14 mg (38.8 nmol) according to the Cleveland Clinic.	The test is contraindicated in severe forms of hypertension, chronic renal failure, heart failure, arrhythmias, or severe hypokalemia. Collection of daily urine is inconvenient. The diagnostic accuracy is reduced due to laboratory problems with the radioimmunoassay method (18-oxo - aldosterone glucuronide, a metabolite unstable in an acidic environment). Currently available and most preferred HPLC tandem mass spectrometry... With CRF, there may be no increased release of 18-oxogluoronide aldosterone
Saline test	Lying position 1 hour before the start of the morning (8:00 - 9:30) 4-hour intravenous infusion of 2 liters of 0.9% NaCl. Blood on rhenium, aldosterone, cortisone, potassium at the basal point and after 4 hours. Monitoring blood pressure, heart rate during the test.	PHA is unlikely with post-infusion aldosterone levels of 10 ng / dL. Gray zone between 5 and 10 ng / dL	The test is contraindicated in severe forms of hypertension, chronic renal failure, heart failure, arrhythmias or severe hypokalemia.
Captopril test	Patients receive 25-50 mg of captopril orally no earlier than one hour after the morning lifting. Blood sampling for ARP, aldosterone and cortisol is carried out before taking the drug and after 1-2 hours (all this while the patient is sitting)	Normally, captopril reduces aldosterone levels by more than 30% from baseline. In PHA, aldosterone remains elevated with low ARP. With IHA, in contrast to APA, there may be some decrease in aldosterone.	There are reports of a significant number of false negative and questionable results.

Instrumental research:

· Ultrasound of the adrenal glands (however, the sensitivity of this method is insufficient, especially in the case of small lesions less than 1.0 cm in diameter);
· CT of the adrenal glands (the accuracy of detecting tumor formations with this method reaches 95%). Allows you to determine the size of the tumor, shape, topical location, to assess the accumulation and washout of contrast (confirms or excludes adrenocortical cancer). Criteria: benign formations usually homogeneous, their density is low, the contours are clear;
· Scintigraphy with 131 I-cholesterol - criteria: aldosteroma is characterized by asymmetric accumulation of the radiopharmaceutical (in one adrenal gland), in contrast to bilateral diffuse small-nodular hyperplasia of the adrenal cortex;
· Selective catheterization of the adrenal veins and determination of the level of aldosterone and cortisol in the blood flowing from the right and left adrenal glands (blood samples are taken from both veins of the adrenal glands, as well as from the inferior vena cava). Criteria: A fivefold increase in the aldosterone / cortisol ratio is considered confirmation of the presence of an aldosteroma.

Indications for specialist consultation:
· Consultation with a cardiologist in order to select antihypertensive therapy;
· Consultation of an endocrinologist in order to choose treatment tactics;
· Consultation of a vascular surgeon for choosing a method of surgical treatment.

Diagnostic algorithm:(diagram)




APC is currently the most reliable and affordable method for PHA screening. When determining APC, as with other biochemical tests, false positive and false negative results are possible. ARS is regarded as a test used in primary diagnosis, with questionable results due to various external influences (medication, non-compliance with the conditions for blood sampling). The effect of drugs and laboratory conditions on ARS is shown in Table 2.

Table 2. Drugs with a minimal effect on the level of aldosterone, with which we can control blood pressure in the diagnosis of PHA

Drug group	International non-proprietary drug name	Mode of application	Comment
nondihydropyridine calcium blocker channels	Verapamil, prolonged form	90-120 mg. twice a day	Used alone or with others medicines from this table
vasodilator	* Hydralazine	10-12.5 mg. twice a day with dose titration to effect	It is prescribed after verapamil, as stabilizer of reflex tachycardia. Low dose administration reduces risk side effects ( headache, tremor)
Blocker a-adrenergic receptors	* Prazosin hydrochloride	0.5-1 mg two - three once a day with dose titration before effect	Control of postural hypotension!

Measurement of the aldosterone-renin ratio:
A. Preparing to identify ADR

1. Correction of hypokalemia after plasma potassium measurement is required. To exclude artifacts and overestimate the real level of potassium, blood sampling must meet the following conditions:
· Carried out by the syringe method (it is undesirable with a vacutainer);
· Avoid clenching the fist;
· Collect blood no earlier than 5 seconds after removing the turnstile;
· Separation of plasma at least 30 minutes after sampling.
2. The patient should not limit sodium intake.
3. Cancel drugs that affect the APC values \u200b\u200bat least 4 weeks before:
Spironolactone, triamterene;
Diuretics;
· Products from licorice root.
4. If the results of ARS against the background of taking the aforementioned drugs are not diagnostic, and if hypertension is controlled by drugs with a minimal effect on the level of aldosterone (see table 2) - cancel for at least 2 weeks other drugs that may affect the level of ARS :
Beta-blockers, central alpha-adrenergic agonists (clonidine, a-methyldopa), NSAIDs;
ACE inhibitors, angiotensin receptor blockers, renin inhibitors, dihydropyridine calcium channel blockers.
5. If it is necessary to control hypertension, treatment is carried out with drugs with minimal effect on the level of aldosterone (see table 2).
6. It is necessary to have information about the use of oral contraceptives (OC) and substitution hormone therapysince estrogen-containing drugs can lower the direct concentration of renin, which will cause false positive ARS. Do not cancel OK, in this case use the ATM level, not the RPC.

B. Sampling conditions:
· A fence in the morning, after the patient has been in an upright position for 2 hours, after being in a sitting position for about 5-15 minutes.
· Sampling in accordance with A. 1, stasis and hemolysis require re-sampling.
· Before centrifugation, keep the test tube at room temperature (and not on ice, since the cold regime increases APP); after centrifugation, the plasma component should be quickly frozen.

C. Factors influencing the interpretation of results:
· Age\u003e 65 years affects a decrease in the level of renin, ARS is artificially increased;
· Time of day, food (salt) diet, time period of postural position;
· Medicines;
· Violations of the method of blood sampling;
Potassium level;
Creatinine level ( renal failure leads to a false positive APC).

Differential diagnosis

Differential diagnosis and justification for additional research

Table 3. Diagnostic tests for PHA

Diagnostic test	Adrenal adenoma		Adrenal hyperplasia
	APA	APRA	IGA	PGN
Orthostatic test (determination in plasma of aldosterone after being in an upright position for 2 hours	Decrease or no change	Magnification	Magnification	Decrease or no change
18-hydrocorticosterone serum	\u003e 100 ng / dL	\u003e 100 ng / dL	< 100 нг/дл	\u003e 100 ng / dL
Excretion of 18-hydroxycortisol	\u003e 60 μg / day	< 60 мкг/сут	< 60 мкг/сут	\u003e 60 μg / day
Excretion of tetra-hydro-18-hydroxy-cortisol	\u003e 15 mcg / day	< 15 мкг/сут	< 15 мкг/сут	< 15 мкг/сут
Computed tomography of the adrenal glands	Knot on one side	Knot on one side	Bilateral hyperplasia, ± nodes	Unilateral hyperplasia, ± knots
Adrenal vein catheterization	Lateralization	Lateralization	No lateralization	No lateralization

Treatment

Preparations ( active ingredients) used in the treatment

Groups of drugs according to ATC used in treatment

Treatment (outpatient clinic)

TREATMENT TACTICS AT THE AMBULATORY LEVEL: only in the case of preoperative preparation (see the step-by-step patient management chart):
1) the appointment of an aldosterone antagonist - spironolactone at an initial dose of 50 mg 2 times a day with a further increase after 7 days to an average dose of 200 - 400 mg / day in 3-4 doses. If ineffective, the dose is increased to 600 mg / day;
2) in order to lower blood pressure until the potassium level normalizes, dihydropyridine calcium channel blockers at a dose of 30-90 mg / day can be prescribed;
3) correction of hypokalemia (potassium-sparing diuretics, potassium preparations);
4) Spironolactone is used for the treatment of IHA. In cases of erectile dysfunction in men, it can be replaced with amiloride * at a dose of 10-30 mg / day in 2 divided doses or triamterene up to 300 mg / day in 2-4 doses. These drugs normalize potassium levels, but do not lower blood pressure, and therefore it is necessary to add saluretics, calcium antagonists, ACE inhibitors and angiotensin II antagonists;
5) in the case of HPHA, dexamethasone is prescribed in individually selected doses necessary to eliminate hypokalemia, possibly in combination with antihypertensive drugs.
* apply after registration on the territory of the Republic of Kazakhstan

Non-drug treatment:
· Mode: sparing mode;
< 2 г/сут.

Drug treatment (preoperative preparation)

List of main medicines (having a 100% chance of being applied):

Drug group	International non-proprietary drug name	Indications	Evidence level
Aldosterone antagonists	spironolactone	preoperative preparation	AND
Calcium antagonists	nifedipine, amlodipine	reduction and correction of blood pressure	AND
Sodium channel blockers	triamterene amiloride	potassium level correction	FROM

List of additional medicines (less than 100% likely to be used): none.

Further management:
· Referral to a hospital for surgical treatment.

Surgical intervention: no.

· Stabilization of blood pressure;
· Normalization of potassium levels.

Treatment (hospital)

TACTICSSTATIONARY TREATMENT

Surgery (patient routing)

Non-drug treatment:
· Mode: sparing mode;
Diet: limiting table salt to< 2 г/сут.

Drug treatment:

List of essential drugs (100% likely to be used):

List of additional medicines (less than 100% likely to be used):

Further management: control of blood pressure to exclude relapses of the disease, lifelong intake of antihypertensive drugs in patients with IHA and HPHA, observation by a therapist and cardiologist.

Treatment effectiveness indicators:
· Controlled blood pressure, normalization of potassium levels in the blood.

Hospitalization

INDICATIONS FOR HOSPITALIZATION WITH INDICATION OF THE TYPE OF HOSPITALITY

Indications for planned hospitalization:

· For surgical treatment.

Indications for emergency hospitalization:
· Hypertensive crisis / stroke;
· Severe hypokalemia.

Information

Sources and Literature

1. Minutes of meetings of the Joint Commission on the Quality of Medical Services of the Ministry of Health of the Republic of Kazakhstan, 2017
   1. 1) Primary hyperaldosteronism. clinical guidelines. Endocrine Surgery No. 2 (3), 2008, pp. 6-13. 2) Clinical endocrinology. Manual / Ed. N. T. Starkova. - 3rd ed., Rev. and add. - SPb .: Peter, 2002 .-- S. 354-364. - 576 p. 3) Endocrinology. Volume 1. Diseases of the pituitary gland, thyroid gland and adrenal glands. St. Petersburg. SpetsLit., 2011.4) Endocrinology. Edited by N. Lavin. Moscow. 1999. pp. 191-204. 5) Functional and topical diagnostics in endocrinology. S. B. Shustov., Yu.Sh. Halimov., G.E. Trufanov. P. 211-216. 6) Internal illnesses... R. Harrison. Volume number 6. Moscow. 2005. p. 519-536. 7) Endocrinology according to Williams. Diseases of the adrenal cortex and endocrine arterial hypertension. Henry M. Cronenberg, Shlomo Melmed, Kenneth S. Polonsky, P. Reed Larsen. Moscow. 2010. p. 176-194. 8) Clinical guidelines "Incidentaloma of the adrenal glands (diagnosis and differential diagnosis)". Methodical recommendations for primary care physicians. Moscow, 2015.9) Case Detection, Diagnosis, and Treatment of Patients with Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline 10) John W. Funder, Robert M. Carey, Franco Mantero, M. Hassan Murad, Martin Reincke, Hirotaka Shibata , Michael Stowasser, William F. Young, Jr; The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101 (5): 1889-1916. doi: 10.1210 / jc.2015-4061 11) Parthasarathy HK, Menard J, White WB, Young WF, Williams GH, Williams B, Ruilope LM, McInnes GT, Connell JM and MacDonald TM. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. Journal of hypertension, 2011, 29 (5), 980 12) Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, Chiandussi L, Veglio F. Drug effects on aldosterone / plasma renin activity ratio in primary aldosteronism. Hypertension. 2002 Dec; 40 (6): 897-902. 13) Pechère-Bertschi A, Herpin D, Lefebvre H. SFE / SFHTA / AFCE consensus on primary aldosteronism, part 7: Medical treatment of primary aldosteronism. Ann Endocrinol (Paris). 2016 Jul; 77 (3): 226-34. doi: 10.1016 / j.ando.2016.01.010. Epub 2016 Jun 14.

Information

ORGANIZATIONAL ASPECTS OF THE PROTOCOL

List of protocol developers:

1) Danyarova Laura Bakhytzhanovna - candidate of medical sciences, endocrinologist, head of the endocrinology department of the Republican State Enterprise at the REM "Scientific Research Institute of Cardiology and Internal Diseases".
2) Raisova Aigul Muratovna - Candidate of Medical Sciences, head of the therapeutic department of the Republican State Enterprise at the REM "Scientific Research Institute of Cardiology and Internal Diseases".
3) Smagulova Gaziza Azhmagievna - Candidate of Medical Sciences, Head of the Department of Propedeutics of Internal Diseases and Clinical Pharmacology of the Republican State Enterprise at the REM "West Kazakhstan State Medical University named after M. Ospanov".

No Conflict of Interest Statement:not.

Reviewers:
Bazarbekova Rimma Bazarbekovna - Doctor of Medical Sciences, Professor, Head of the Department of Endocrinology of JSC Kazakh Medical University of Continuing Education.

Indication of the conditions for revising the protocol:revision of the protocol 5 years after its publication and from the date of its entry into force or in the presence of new methods with a level of evidence.

Attached files

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Primary hyperaldosteronism (Connes syndrome)

What is primary hyperaldosteronism (Connes syndrome) -

In 1955, Conn described a syndrome accompanied by arterial hypertension and a decrease in the level of potassium in the blood, the development of which is associated with a tumor (adenoma) of the adrenal cortex, which produces the hormone aldosterone. This pathology is called Conn's syndrome.

Primary hyperaldosteronism (Connes syndrome) - a disease characterized by an increase in the secretion of aldosterone by the adrenal glands, which manifests itself in a decrease in the activity of a specific substance - blood plasma renin - which plays an important role in the regulation of the body, arterial hypertension and a decrease in the potassium content in the blood. Later, many other cases of hyperplasia (excessive tissue proliferation and its changes) of the adrenal cortex were described with an increase in the secretion of aldosterone, and now the term "primary hyperaldosteronism" is used both to describe the Connes syndrome itself, and other pathologies accompanied by hypersecretion of aldosterone, for example, hyperplasia of the cortex adrenal glands. Currently, primary hyperaldosteronism (PHA), and in particular Connes syndrome, is the most common reason secondary arterial hypertension.

What provokes / Causes of primary hyperaldosteronism (Conn's syndrome):

At the moment, two main causes of PHA, accompanied by an increase in aldosterone secretion, have been identified:

• unilateral aldosterone-producing tumor - adenoma or Conn's syndrome (50-60% of cases);
• bilateral hyperplasia of the adrenal cortex or idiopathic hyperaldosteronism (40-50% of cases).

There are rare types of diseases and tumors that are similar in symptoms, including hereditary diseases, accompanied by an increase in the concentration of aldosterone.

Even less common are aldosterone-secreting adrenal cortex cancers or ovarian tumors.

The most common cause of PHA is Connes syndrome, with the adenoma usually not exceeding 3 cm in diameter, unilateral and renin-independent. This means that the secretion of aldosterone is independent of changes in body position. Less commonly, the adenoma may be renin-dependent (that is, the level of aldosterone increases in an upright position). Conn's syndrome occurs in 50-60% of cases.

The remaining 40-50% of cases are bilateral adrenal hyperplasia, when the level of aldosterone increases in an upright position. Less common is primary adrenal hyperplasia, in which the level of aldosterone does not depend on body position, as in a renin-independent adenoma.

Aldosterone can be secreted by tumors of extra-adrenal localization - in the kidneys or ovaries.

Symptoms of primary hyperaldosteronism (Conn's syndrome):

Complaints of patients with severe hypokalemia: fatigue, muscle weakness, muscle cramps, headaches and palpitations. Such patients may also have increased thirst: as a result, they drink a lot, and polyuria (excrete a lot of urine) due to the so-called diabetes insipidus, which developed as a result of hypokalemia and corresponding changes in the kidneys due to the influence of aldosterone on them.

Relative hypocalcemia (a decrease in the calcium content in the blood) develops with the development of a feeling of numbness in the limbs and around the mouth, muscle spasms in the area of \u200b\u200bthe hands and feet, and, to an extreme degree, laryngeal spasm with the occurrence of a feeling of suffocation and convulsions. In this case, calcium preparations are not prescribed, since the total calcium content in the blood is normal, but due to hormonal imbalance, the calcium balance in the body changes.

Long-term arterial hypertension can lead to complications from the cardiovascular and nervous systems with all the accompanying symptoms.

Diagnostics of the primary hyperaldosteronism (Conn's syndrome):

There are no specific manifestations of Connes syndrome.

When patients develop heart failure, stroke or intracranial hemorrhage due to increased blood pressure, corresponding symptoms appear.

Laboratory research

• Tests for the content of sodium, potassium and calcium in blood plasma ( biochemical analysis) may show an increase in the sodium content in the blood, the presence of hypokalemia and "alkalinization" of the blood, which is a consequence of the action of aldosterone on the kidneys. The relative decrease in blood calcium levels can also be easily detected. In almost 20% of patients, a disorder of carbohydrate metabolism (an increase in blood glucose) can be detected, although diabetes rarely develops. It should be noted that normal blood potassium does not exclude PHA. Research shows that 7 to 38% of patients with PHA have normal serum potassium levels. Hypokalemia develops when a significant amount of sodium is consumed.
• A decrease in the level of renin in the blood plasma in patients with PHA is characteristic, and this figure does not rise above certain values \u200b\u200bwith the introduction of diuretics or the transition to an upright position (which usually occurs normally). Some experts suggest that an analysis of the level of renin in blood plasma should be considered a special test for detecting PHA. However, according to some reports, a low level of renin occurs in 30% of patients with essential hypertension. Therefore, low plasma renin levels should not be considered a specific test for PHA.
• Determination of the ratio of plasma aldosterone activity (AAR) to plasma renin activity (ARP) should be considered a fairly sensitive test for PHA. Consideration should be given to possible drug interactions when testing.
• With a positive test for AAP / ARP, additional tests are carried out: determination of the level of aldosterone in the daily portion of urine, adjusted for the level of potassium in the blood serum (since these indicators affect each other).

Instrumental examination

• Computed tomography (CT) of the abdomen. It is a mandatory examination method in the case of PHA. With the established diagnosis of PHA, the purpose of CT is to determine the type of pathology and the possibility of its surgical treatment (adrenal adenoma or bilateral hyperplasia). With CT, the scope of the operation is determined.
• Scintigraphy with 131-I-cholesterol iodine is used to detect unilateral functional (hormone-secreting) adrenal mass. However, this procedure is not widespread due to the need for careful preparation of the patient, high cost, and the fact that the method rarely reveals a mass larger than 1.5 cm in diameter.
• Magnetic resonance imaging (MRI). It is not more sensitive than CT.

Other diagnostic methods

Postural test (transition from horizontal to vertical body position). Can be used in a polyclinic for primary diagnosis renin-dependent adrenal adenoma. It is rarely used now.

Due to the complexity of differentiating the diagnosis between adrenal hyperplasia and adenoma, after CT examination, the procedure for taking an analysis directly from the adrenal vein can be performed. This involves inserting a catheter into an adrenal vein through a vein in the thigh. Blood tests are taken from both veins of the adrenal glands as well as from the inferior vena cava. The level of aldosterone after maximal stimulation of ACTH is determined.

Treatment of primary hyperaldosteronism (Connes syndrome):

The main goal is to prevent the occurrence of complications due to hypokalemia and arterial hypertension.

If in Connes syndrome, hypertension is corrected using unilateral adrenalectomy, then bilateral lesions are most often treated conservatively, since the effectiveness of unilateral or bilateral adrenalectomy is only 19%. In the case of adenoma, drug therapy is also used to control blood pressure and correct hypokalemia, which reduces the risk of subsequent surgery.

The main components of therapy:

• Restricted sodium diet (< 2 г натрия в день), поддержание оптимальной массы тела, регулярные аэробные физические нагрузки.
• Treatment for hypokalemia and hypertension is potassium-sparing drugs such as spironolactone. Moreover, if hypokalemia disappears almost immediately, then it may take 4-8 weeks of therapy to reduce blood pressure. Additional prescription of potassium preparations is not required. If, despite treatment, high blood pressure remains, second-line drugs are added to therapy.
• Second-line drugs are: diuretics, drugs that lower blood pressure.

Surgery

Surgery is the main treatment for Connes syndrome. If possible, laparoscopic adrenalectomy is performed (see below).

In patients with Connes syndrome, an indicator of the effectiveness of future unilateral adrenalectomy in relation to arterial hypertension is a decrease in blood pressure in response to spironolactone in the preoperative period. Spironolactone is prescribed for at least 1-2 weeks (preferably 6 weeks) until surgical intervention in order to reduce the risk of surgery, correct hypokalemia and control blood pressure.

It should be noted that hypertension usually does not disappear immediately after surgery. Blood pressure gradually decreases over 3-6 months. Almost all patients report a decrease in blood pressure numbers after surgery. A long-term therapeutic effect is observed after unilateral adrenalectomy for Connes syndrome in an average of 69% of patients.

Which doctors should you contact if you have primary hyperaldosteronism (Conn's syndrome):

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Hypovolemia

Hypoglycemic coma

Hypogonadism

Hyperprolactinemic hypogonadism

Isolated hypogonadism (idiopathic)

Primary congenital hypogonadism (anorchism)

Primary acquired hypogonadism

Hypokalemia

Hypoparathyroidism

Hypopituitarism

Hypothyroidism

Type 0 glycogenosis (aglycogenosis)

Type I glycogenosis (Gierke's disease)

Type II glycogenosis (Pompe disease)

Type III glycogenosis (measles disease, Forbes disease, limitdextrinosis)

Type IV glycogenosis (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Type IX glycogenosis (Haga disease)

Type V glycogenosis (McArdle disease, myophosphorylase deficiency)

Type VI glycogenosis (Hers disease, hepatophosphorylase deficiency)

Type VII glycogenosis (Tarui disease, myophosphofructokinase deficiency)

Type VIII glycogenosis (Thomson's disease)

Glycogenosis type XI

Type X glycogenosis

Deficiency (insufficiency) of vanadium

Deficiency (insufficiency) of magnesium

Deficiency (deficiency) of manganese

Deficiency (deficiency) of copper

Deficiency (deficiency) of molybdenum

Chromium deficiency (deficiency)

Iron deficiency

Calcium deficiency (alimentary calcium deficiency)

Zinc deficiency (nutritional zinc deficiency)

Diabetic ketoacidotic coma

Ovarian dysfunction

Diffuse (endemic) goiter

Delayed puberty

Excess estrogen

Breast involution

Dwarfism (short stature)

Kwashiorkor

Cystic mastopathy

Xanthinuria

Lactacidemic coma

Leucinosis (maple syrup disease)

Lipidosis

Farber's lipogranulomatosis

Lipodystrophy (fatty degeneration)

Congenital generalized lipodystrophy (Saype-Lawrence syndrome)

Hypermuscular lipodystrophy

Postinjection lipodystrophy

Lipodystrophy, progressive segmental

Lipomatosis

Painful lipomatosis

Metachromatic leukodystrophy