home Adviсe Recommendations for the diagnosis of primary and secondary hyperaldosteronism. Primary hyperaldosteronism: symptoms and treatment. What is hyperaldosteronism

Recommendations for the diagnosis of primary and secondary hyperaldosteronism. Primary hyperaldosteronism: symptoms and treatment. What is hyperaldosteronism

Content

The pathology of the endocrine system is characterized by hypersecretion of the hormone aldosterone. In the case of the primary form of hyperaldosteronism, such a disorder is provoked by changes in the adrenal cortex. The condition causes disruption of body functions and requires differentiated diagnosis and treatment.

What is hyperaldosteronism

Aldosterone is synthesized by the zona glomerulosa of the adrenal cortex and is part of the renin-angionetsin system, which regulates blood volume and blood pressure. The function of the hormone is the excretion of potassium and magnesium ions, the absorption of sodium ions. With hyperaldosteronism, the following processes occur:

excess production of aldosterone begins;
the amount of sodium ions in the blood increases;
water is reabsorbed;
potassium and magnesium ions are excreted from the body;
hypernatremia, hypokalemia develops;
blood pressure (BP) increases.

Forms of primary aldosteronism - causes and symptoms

The pathological condition is characterized by six forms of the disease. Each has its own cause of development and symptoms. Doctors distinguish the following types of pathology in the case of primary hyperaldosteronism:

Form of the disease		Features of the disease, symptoms
Aldosterone-producing adenoma (Conn's syndrome)	Development of aldosteroma - benign adenoma	muscle weakness; sagging head symptom; polyuria (increased daily urine output).
Idiopathic hyperaldosteronism (IHA)	Hyperplasia of the adrenal cortex, having a small-nodular or large-nodular form	mental disorders; osteoporosis; numbness of the limbs; development of diabetes; muscle atrophy; weight gain; memory loss.
Primary unilateral adrenal hyperplasia	anomalies of intrauterine development of glandular tissue; hereditary predisposition; congenital insufficiency of the adrenal cortex; violation of metabolic processes; use of potent drugs.	high growth of the child, which does not correspond to age standards; excess hair; menstrual irregularities; increased blood pressure levels; amyotrophy.
Familial hyperaldosteronism Type I (glucocorticoid-suppressed hyperaldosteronism) Type II (glucocorticoid-unsuppressible hyperaldosteronism)	Hereditary pathology caused by the formation of a defective enzyme as a result of gene mutation 11b-hydroxylase, aldosterone synthetase	heart rhythm disturbance; fundus changes; development of retinopathy, angiosclerosis, hypertensive angiopathy; cardialgia.
Aldosterone-producing carcinoma	endocrine gland tumors consumption of foods with carcinogenic substances hereditary factors Excessive production of deoxycorticosterone.	violation of the water-electrolyte balance of the body; stretch marks on the skin; anemia; weight loss; indigestion.
Aldosteronectopic syndrome with extra-adrenal localization of aldosterone-producing tumors (in the thyroid gland, ovaries, intestines)	an increase in the number of cells that produce aldosterone; intoxication of the body; immunodeficiency state.	a sharp rise in blood pressure; chest pain; suffocation; dyspnea; dizziness; convulsions.

How does the disease progress?

Primary hyperaldosteronism is caused by the proliferation of adrenal cortex cells and the development of tumors. The pathogenesis of the disease is based on the influence of excess aldosterone on water and electrolyte balance. The renin-angiotensin system, which operates on a feedback principle, plays an important role in hormone secretion. The following processes occur in the body:

the reabsorption of sodium ions in the renal tubules increases;
potassium ions are actively excreted in the urine;
water retention occurs in tissues;
the production of plasma renin decreases.

As a result of hormonal imbalance in primary hyperaldosteronism:

the sensitivity of the vascular wall increases;
the secretion of antidiuretic hormone, which regulates the excretion of water by the kidneys, is disrupted;
the resistance of peripheral vessels to blood flow increases;
kalipenic nephropathy, hypernatremia, hypokalemic syndrome develop;
severe arterial hypertension appears;
Damage to target organs - kidneys, heart, blood vessels - develops.

Clinical picture

With hyperaldosteronism, three types of syndromes are distinguished. In the case of the primary form, a characteristic clinical picture is observed. There are the following symptoms of the pathological condition:

Type of syndrome	Manifestations
Neuromuscular	sensory disturbance; convulsions; spasms; muscle weakness; paralysis of limbs, neck; fast fatiguability; tingling of limbs.
Cardiovascular	increased blood pressure; arrhythmia; dizziness; heartache; tachycardia; cardialgia; headache; drop in visual acuity.
Renal	decreased concentration function of the kidneys; polyuria; polydipsia (unquenchable thirst); nocturia (predominant urination at night); nephrogenic diabetes insipidus.

Diagnostic methods

The risk group for the development of hyperaldosteronism, which has a primary form, includes patients with arterial hypertension.

Among these patients, priority diagnosis is carried out. Laboratory tests include:

	Indicators for primary hyperaldosteronism
Blood test from a vein	potassium in plasma up to 3 mmol/liter; aldosterone level is higher than normal; plasma renin activity is reduced; the amount of sodium is increased; the aldosterone/renin ratio is higher than the norm.
Saline test (to confirm the diagnosis)	Aldosterone level over 10 ng/dl
Analysis of urine	low relative density of urine; increased daily excretion of potassium ions, aldosterone; change in structure, composition.

To determine the state of the adrenal glands, instrumental research methods are used. They may find problems such as:

Treatment of hyperaldosteronism

Before choosing a treatment regimen, the patient is examined by a cardiologist, endocrinologist, ophthalmologist, and nephrologist. Treatment is prescribed after differential diagnosis of primary hyperaldosteronism. If tumors are detected, surgery is performed. Conservative therapy involves the following methods:

sodium-restricted diet;
aerobic physical activity;
weight normalization;
use of a potassium-sparing drug – Spironolactone;
use of diuretics;
use of drugs that lower blood pressure.

Drug treatment

Conservative therapy for primary hyperaldosteronism solves several problems. Drug treatment helps in preparation for surgery. The drugs compensate for potassium deficiency in the body and stabilize blood pressure. Medicines recommended for the disease:

Type of treatment		Drugs	Application
Preoperative preparation	Aldosterone antagonist, potassium-sparing diuretic	Spironolactone
	Calcium channel blockers, lower blood pressure	Nifedipine-retard
	Beta blockers, stabilize blood pressure	Metoprolol
	Saluretics, normalize potassium levels	Amiloride
Therapy for idiopathic hyperaldosteronism	Antagonists angiotensin II receptors	Losartan
	Calcium channel blockers	Amlodipine
	Potassium-sparing diuretics	Triampiren	50/kg weight, two steps
	ACE inhibitors	Captopril	25, under the tongue
	Aldosterone antagonist	Veroshpiron
Elimination of glucocorticoid-suppressed hyperaldosteronism	Corticosteroids	Dexamethasone
Elimination of glucocorticoid-suppressed hyperaldosteronism	Corticosteroids	Prednisolone	intravenous drip from 6 to 8 am

Surgical intervention

Doctors are trying to save the patient’s vital organs. In the case of primary hyperaldosteronism with a small lesion, adrenal resection is performed. Surgical treatment with unilateral organ removal - adrenalectomy - is prescribed in the case of:

aldosteroma - a hormone-producing tumor;
adrenal cancer;
reninoma - benign formation that secretes renin;
primary hyperplasia;
carcinomas.

In the case of a malignant course of arterial hypertension, the adrenal gland that produces large amounts of aldosterone is identified and removed. The choice of surgical tactics depends on the size of the tumor. In case of large dimensions of tumors, relapses of pathology, the presence of metastases, the intervention is performed using an open access method. To do this, use the following methods:

lumbotomy – extraperitoneal dissection;
thoracophrenotomy – access through the tenth intercostal space.

Minimally invasive, gentle methods of surgical intervention for primary hyperaldosteronism include laparoscopic operations. They are carried out through small incisions into which instruments and a miniature camera are inserted. Popular methods of surgical treatment:

endovideosurgical adrenalectomy;
X-ray endovascular embolization;
adrenalectomy from a mini-access.

Diet therapy

Primary aldosteronism requires proper nutrition. A diet for this pathology involves limiting sodium intake and increasing the amount of potassium supplied with food. Nutritionists give the following recommendations:

Authorized Products

(high potassium)

Are prohibited

(due to increased sodium)

baked potato

Prunes

Sun-dried tomatoes

Oranges

Seafood

Fresh berries

bell pepper

Celery

Sea kale

Canned food

Smoking

Marinades

Rye bread

Sauerkraut

Cornflakes

Green beans

Chanterelles

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Hyperaldosteronism represents excess aldosterone in the body.

A clinical syndrome that develops as a result of excess aldosterone production, manifested by low-renin arterial hypertension in combination with hypokalemia. Its most common cause is an aldosterone-producing tumor of the adrenal gland (Conn's syndrome). Arterial hypertension, accompanied by hyperproduction of aldosterone in combination with a tumor of the adrenal cortex, was first described by Jerome Conn in 1954.

is an increase in aldosterone levels, developing as a result of activation of the renin-angiotensin-aldosterone system in various disorders of water-electrolyte metabolism, caused by an increase in renin production.

Etiology

The most common cause of primary hyperaldosteronism is a solitary aldosterone-producing adenoma. The tumor is often small in size - up to 3 cm in diameter. Malignant aldosteromas are rare.

Pathogenesis

In primary hyperaldosteronism, excess aldosterone acts on the distal nephron and promotes sodium retention and potassium loss. As a result, fluid retention in the body occurs, an increase in circulating blood volume (CBV) and arterial hypertension. An increase in blood volume leads to suppression of renin production by the kidney. Severe and prolonged hypokalemia leads to dystrophic changes in the renal tubules (calipenic kidney). In patients with primary hyperaldosteronism, in addition to the risk of developing complications caused by arterial hypertension, a complication specific to hyperaldosteronism develops - aldosterone-induced myocardial hypertrophy.

In secondary hyperaldosteronism, an increase in aldosterone production is a secondary and compensatory change in response to a decrease in renal blood flow of any origin. This occurs with stenosis of the renal artery, with impaired circulation in the systemic circle with heart failure (congestive kidney), with a decrease in blood volume during diuretic therapy and in many other conditions.

Epidemiology

Primary hyperaldosteronism is diagnosed in 1-2% of people with arterial hypertension. About 1% of incidentally detected adrenal masses are aldosteromas. Aldosteromas are detected 2 times more often in women.

Clinical manifestations

Primary hyperaldosteronism

Arterial hypertension is usually of moderate severity and is often resistant to standard antihypertensive therapy.

Complications of hypokalemia are rare: muscle weakness, cramps, paresthesia; severe hypokalemia can be complicated by dystrophic changes in the kidneys, clinically manifested by polyuria and nocturia (hypokalemic nephrogenic diabetes insipidus).

Secondary hyperaldosteronism has no specific clinical manifestations, since it is a compensatory phenomenon in many diseases and conditions, while the electrolyte changes characteristic of primary hyperaldosteronism never develop.

Diagnostics

The main indication for examining a patient for primary hyperaldosteronism is arterial hypertension in combination with hypokalemia. In some cases, the potassium level in primary hyperaldosteronism does not fall below 3.5-3.6 mmol/l. Other indications for examination are arterial hypertension resistant to conventional antihypertensive therapy and/or persons under 40 years of age. The diagnosis of primary hyperaldosteronism is based on determining the level of aldosterone and renin and calculating their ratio. Primary hyperaldosteronism is characterized by high aldosterone levels, low plasma renin activity levels and, most importantly, a high aldosterone/renin ratio.

To correctly determine the level of plasma renin activity, strict adherence to the rules of blood sampling is necessary: blood is drawn into a test tube with an anticoagulant, the plasma is separated by centrifugation. Before the test, the patient needs to discontinue ACE inhibitors, diuretics, beta blockers and calcium channel blockers for several weeks; veroshpiron (spironolactone) must be discontinued at least 6 weeks in advance.

If the aldosterone/ARP ratio exceeds the threshold level (aldosterone (ng/dl) / renin (ng/ml/hour) › 50; aldosterone (pmol/l) / renin (ng/ml/hour) › 1400; aldosterone (pg/ml ) / renin (ng/ml/hour) › 140), the patient is indicated for marching (orthostatic) test. It is based on the fact that normally in the morning after an overnight stay in a horizontal position, the level of aldosterone and plasma renin activity before moving to a vertical position is approximately 30% lower. The first blood draw to determine the level of aldosterone and plasma renin activity is carried out at 8 o'clock in the morning, in bed before getting up. After this, the patient is asked to remain in an upright position for 3-4 hours; then the blood is taken again. In primary hyperaldosteronism, which developed as a result of hypersecretion of aldosterone by an autonomous aldosterone-secreting adenoma, the level of plasma renin activity is initially reduced and does not increase after orthostatic load. In this case, the level of aldosterone is initially elevated and does not increase as normal, but rather decreases. This is explained by the fact that when the dependence of aldosterone secretion on the level of angiotensin II is lost, its production begins to obey the circadian rhythm of ACTH secretion, which is characterized by a decrease in secretion by noon.

The next stage of diagnosis is adrenal gland imaging using CT or MRI. Aldosteroma is visualized as a small space-occupying formation in one of the adrenal glands. In idiopathic primary hyperaldosteronism, the adrenal glands are unchanged or there are small nodular formations.

Treatment

For aldosteroma, adrenalectomy is indicated. For idiopathic primary hyperaldosteronism (bilateral adrenal hyperplasia), treatment is conservative: veroshpiron is prescribed (200-400 mg per day) in combination with other drugs: ACE inhibitors, calcium channel antagonists.

Forecast

After adrenalectomy for aldosteroma, blood pressure and potassium levels are normalized in 70-80% of patients.

For quotation: Korotin A.S., Posnenkova O.M., Shevchenko O.V., Genkal E.N., Kiselev A.R., Popova Yu.V. Primary hyperaldosteronism under the guise of resistant essential hypertension: a rare disease or a rare diagnosis? // RMJ. 2015. No. 15. P. 908

Introduction

Symptomatic arterial hypertension (AH) makes up a significant proportion of the causes of resistant hypertension. One of the common but rarely identified causes of symptomatic hypertension is primary hyperaldosteronism (PHA). In the clinical practice of a cardiologist, such a diagnosis is rare, despite the fact that hypertension is the most constant symptom of PHA, and such patients, as a rule, seek medical help precisely because of the increase in pressure.

PGA is a clinical syndrome caused by excessive production of aldosterone by the zona glomerulosa of the adrenal cortex. Currently, there are several forms of PHA (Table 1), among which the most common is isolated unilateral aldosterone-producing adrenal adenoma.

It was previously thought that PHA occurs in only 0.05–2% of people with hypertension. The emergence and introduction of screening into clinical practice has led to an increase in the detection of this condition, and currently about 10% of cases of resistant hypertension are associated with hyperaldosteronism. However, systematic recording of cases of PHA in clinical practice is usually not carried out. Therefore, there are no current domestic data on the prevalence of PHA.

PHA has no specific symptoms, which makes diagnosing the condition extremely difficult. The most common clinical manifestation is hypertension, which occurs in 75–98% of cases. The group where hyperaldosteronism is most likely to be detected consists of patients with the onset of hypertension at a young age, patients with severe or resistant hypertension, i.e., a contingent of a purely cardiological profile. However, in the recommendations on hypertension, little attention is paid to the problem of diagnosis and treatment of PHA. The most detailed clinical guidelines for PHA have been prepared by the International Endocrinological Society. But even in this detailed clinical manual there are no algorithms for dynamic monitoring of patients, including after surgical treatment.

In the clinical picture of PHA, in addition to hypertensive, there are also neuromuscular and dysuric syndromes. Muscle weakness, cramps, and paresthesia are observed in 38–75% of patients. About 50–70% of patients experience polyuria, polydipsia, and nocturia. According to a number of studies, only 20–70% of patients have hypokalemia, i.e. the level of potassium in the blood, the determination of which is included in the standard examination of patients with hypertension, is an insufficiently sensitive method and therefore is not suitable for screening. The main screening method is the determination of the aldosterone-renin ratio (ARR). The rules for preparing for the determination of ARS are presented in Table 2. Patients in whom PHA is suspected based on the results of the determination of ARS are recommended to perform one of four confirmatory tests (Table 3):

with sodium load;
with isotonic sodium chloride solution;
suppression test with fludrocortisone;
with captopril.

If the presence of PHA is confirmed by testing, it is necessary to determine the source of aldosterone hyperproduction. Several techniques can be used for this:

Computed tomography (CT) of the adrenal glands - allows you to determine the size and structure of the adrenal glands and identify tumors.
Magnetic resonance imaging (MRI) of the adrenal glands - allows you to determine the size and structure of the adrenal glands, but has a slightly lower spatial resolution than CT and is a more expensive method.
Comparative selective venous blood sampling is the standard test for differentiating unilateral from bilateral lesions.
Patients with the onset of hyperaldosteronism before the age of 20 years and with a family history of this disease or acute cerebrovascular accident under the age of 40 years are offered genetic testing for the glucocorticoid-dependent form of PHA.

Other previously used methods - postural stress test, iodocholesterol scintigraphy, 18-hydroxycorticosterone study - are ineffective in the differential diagnosis of PHA.

Treatment tactics depend on the morphofunctional type of the disease. For unilateral PHA - unilateral adrenal hyperplasia or aldosterone-producing adrenal adenoma - the optimal treatment option is endoscopic adrenalectomy. After surgery, 30–60% of patients experience stabilization of blood pressure without further antihypertensive therapy; in a third of patients, it is possible to reduce the number of antihypertensive drugs.

When refusing surgery and in inoperable cases, mineralocorticoid receptor antagonists should be used. Mineralocorticoid receptor antagonists are used for bilateral adrenal hyperplasia. The first-line drug is spironolactone, and if individual tolerance is poor or side effects develop, eplerenone is used. In cases of glucocorticoid-dependent PHA, minimal titrated doses of glucocorticosteroids should be used and only if steroid therapy is ineffective, mineralocorticoid receptor antagonists should be added to the treatment.

Despite the development of diagnostic techniques and the availability of clinical recommendations, identifying PHA in the daily practice of a cardiologist remains quite problematic. An illustration of diagnostic problems is the case of newly diagnosed PHA in a patient with 20 years of refractory hypertension.

Clinical case

Patient L., 61 years old, applied to a specialized cardiology clinic due to destabilization of blood pressure over the past month, severe weakness, fatigue, and decreased performance.

The patient has been aware of increased blood pressure for 20 years. She notes frequent crises with a maximum increase in blood pressure to 200 and 110 mm Hg. Art., which are accompanied by a feeling of general weakness, dizziness, heaviness in the head. About 10 years ago she suffered a hypertensive crisis, complicated by the development of acute hypertensive encephalopathy with mnestic disorders. Over the past 5 years, he has noted the appearance of shortness of breath during physical activity (climbing to the 2nd floor, walking uphill) and periodic swelling of the legs. Throughout the year, episodes of irregular heartbeat and interruptions in heart function have been disturbing. She was hospitalized once with a paroxysm of atrial fibrillation, which was recorded on an electrocardiogram (ECG). Currently, he regularly takes a combination of amlodipine and valsartan 160/10 mg/day, indapamide 1.5 mg/day, bisoprolol 2.5 mg/day, etacizin 50 mg three times a day, acetylsalicylic acid (ASA) 100 mg/day . During therapy, blood pressure is maintained at 150 and 100 mm Hg. Art., periodically troubled by interruptions in the work of the heart.

It is also known from the anamnesis that the patient suffers from urolithiasis with two episodes of stone passage.

The patient is of average build. An objective examination revealed a displacement of the left border of the heart to the midclavicular line, with an accent of the second tone above the aorta. Heart rate 72 beats/min. There is no pulse deficit. Blood pressure 150 and 100 mm Hg. Art. The patient notes frequent, excessive urination at night, not associated with excess fluid intake. Tapping on the lumbar region is painless. Other organs and systems are without features.

The general blood test revealed no abnormalities. A general urine analysis revealed a decrease in specific gravity to 1009, and microscopy of the sediment revealed a significant amount of amorphous phosphates. Other parameters are normal. A biochemical blood test determines dyslipidemia (total cholesterol - 6.5 mmol/l, triglycerides - 1.1 mmol/l, LDL - 4 mmol/l, HDL - 1.8 mmol/l). When studying blood electrolytes, Na+ - 143 mmol/l, K+ - 2.8 mmol/l, Cl- - 98.3 mmol/l.

The ECG shows sinus rhythm with a heart rate of 60 beats/min, the electrical axis of the heart is located normally, frequent, monotopic, monomorphic, ventricular extrasystoles, the T wave is smoothed, U waves in leads V1-V4 (Fig. 1).

With Holter ECG monitoring: the main rhythm is atrial fibrillation. Frequent polytopic ventricular ectopic activity was recorded in the evening and daytime hours.

Echocardiography showed the dimensions of the left ventricular cavity to be within normal limits. Slight left ventricular hypertrophy. Myocardial thickness in diastole is up to 1.2 cm. Myocardial mass index is 98 g/m2. No significant disturbances in local contractility of the left ventricle were detected. Global contractility of the left ventricle is not reduced. Left ventricular ejection fraction - 60%. The diastolic function of the left ventricle is impaired according to the relaxation type. There were no signs of circulatory decompensation in the systemic and pulmonary circulation.

Ultrasound examination of the kidneys revealed excessive mobility of the right kidney, the area of the adrenal glands was not changed.

Taking into account the refractoriness of hypertension, the patient’s complaints of severe weakness and frequent heavy urination at night, not associated with excessive fluid intake, laboratory data (hypokalemia: K+ 2.8 mmol/l), it was assumed that the patient had hyperaldosteronism.

Taking into account the recommendations for preparing for the determination of ARS, all antihypertensive drugs that could affect the results of the study were discontinued in treatment. To control blood pressure, verapamil 240 mg/day and doxazosin 4 mg/day were prescribed. After 4 weeks The patient's blood aldosterone and renin levels were examined. The result was: aldosterone - 370 pg/ml (normal: 13.0–145.0 pg/ml), renin<0,50 мкМЕ/мл (норма: 4,4–46,1 мкМЕ/мл). Выполнена МРТ надпочечников, где выявлено объемное образование в правом надпочечнике размером 1,8×1,5 см. Пациентка консультирована эндокринологом и хирургом, рекомендовано оперативное лечение. Была выполнена эндоскопическая односторонняя адреналэктомия. После операции продолжен прием соталола в дозе 40 мг 2 р./сут (в связи с пароксизмальной формой фибрилляции предсердий), АСК - 75 мг/сут, аторвастатина - 20 мг/сут. Через 1 мес. после операции выполнен суточный мониторинг АД. Выявлено повышение систолического АД в течение суток. При холтеровском мониторировании ЭКГ определяется синусовый ритм с частыми желудочковыми экстрасистолами, преимущественно в вечерние и ночные часы. К лечению добавлены валсартан 160 мг/сут и амлодипин 5 мг/сут. От приема пероральных антикоагулянтов пациентка отказалась. На фоне проводимой терапии перебои в работе сердца не беспокоят, увеличилась толерантность к физическим нагрузкам. АД стабилизировалось на уровне 130–140 и 80 мм рт. ст., показатель К+ нормализовался (К+ 5,1 ммоль/л). От повторного исследования уровня альдостерона и АРП пациентка отказалась.

Discussion

Over the past decades, the arsenal of antihypertensive drugs has expanded significantly. But despite this, most patients with hypertension fail to achieve the target blood pressure level. One of the common causes of resistant hypertension is PHA.

In 1994, the results of a large-scale study including 4429 patients were published in the USA, which assessed the prevalence of secondary forms of hypertension. The prevalence of secondary forms of hypertension was 10.2%; the most common form was hypertension associated with pathology of the kidneys and their arteries. The next most important cause of hypertension was PHA.

Similar results were obtained in the Russian multicenter study REGATA. It involved 532 patients with uncontrolled hypertension. 89.3% of patients had primary resistant hypertension, secondary hypertension - 10.7% of patients. At the same time, PHA was detected in 15.8% - the third indicator among all causes of symptomatic hypertension.

An even greater prevalence of PHA is revealed by screening determination of renin and aldosterone levels. In a study by P. Mulatero et al., which included 5 major medical centers from 5 continents, the use of APC as a screening method resulted in a 5- to 15-fold increase in the detection of PHA, depending on the center.

A study conducted in Chile also showed a high prevalence of PHA. In 10.3% of patients with essential hypertension, PGA was detected when determining ARS. Interestingly, the incidence of PHA depended on the degree of blood pressure increase. Thus, with the 1st degree of hypertension, hyperaldosteronism was detected in 1.99% of patients, and with the 2nd and 3rd degrees of hypertension - in 8.02% and 13.2% of patients, respectively.

Thus, the real prevalence of PHA in Russia, as well as throughout the world, is currently underestimated, and it may turn out to be significant, given the widespread prevalence of hypertension among the population.

At the same time, in the case of timely and reasonable adrenalectomy, according to A. M. Sawka et al., in 33% of patients with unilateral lesions it is possible to achieve target blood pressure values without taking antihypertensive drugs. Even more optimistic results were obtained during the observation of 30 patients with PHA after adrenalectomy. In 29 out of 30 patients, potassium levels returned to normal. Hypertension persisted in only 10 of 30 patients, while in 9 of them it was possible to reduce the amount of drug therapy. In a similar study published in 2012, 68 of 124 (54.8%) patients had normalized blood pressure after adrenalectomy, 43 (34.4%) were able to achieve blood pressure control with fewer medications, and only 13 (10.8%) %) of patients remained resistant to hypertension. These studies showed that with unilateral lesions, the most important predictor of a positive treatment outcome is the duration of the disease, i.e., a timely diagnosis and timely adrenalectomy are highly likely to cure hypertension, while a long duration of the disease is associated with a worse surgical outcome treatment.

In the presented clinical case, a patient with PHA was observed for a long time by a general practitioner and cardiologist at her place of residence for severe hypertension. The opinion about possible PHA arose only after the doctor drew attention to hypokalemia and symptoms of dysuria, about which the patient herself had no active complaints. After consulting an endocrinologist, the patient was referred to a surgeon who performed an adrenalectomy. The operation did not relieve the patient of hypertension, but allowed her to achieve target blood pressure values, reduce the dose of antihypertensive drugs, and significantly improve her state of health. Further monitoring of the patient was continued by a cardiologist due to the need to control blood pressure levels.

It is cardiologists who should be most focused on identifying PHA, especially in patients with hypertension of the 2nd and 3rd degree, resistant hypertension, with a combination of hypertension with hypokalemia and with a family history. If PHA is suspected, in accordance with international recommendations, screening should be carried out to determine APC.

When verifying the diagnosis of PHA, doctors face a number of difficulties. The first is the need to control blood pressure levels in a patient with severe hypertension during the period of preparation for determining ARS using a limited number of drugs, which can provoke the development of cardiovascular complications. The second is the complexity of diagnostic techniques, which require significant material costs. The third is due to the lack of technical capabilities to carry out diagnostic procedures in a medical institution. The last two situations, as well as the obvious picture of an aldosterone-producing adrenal adenoma, lead to unnecessary surgical intervention for hormonally inactive adrenal adenomas. To avoid unnecessary surgical interventions, as well as excessive material costs due to expensive studies, it is necessary to use a single algorithm for patient management at all stages of treatment. International clinical guidelines for PHA contain information based on which a doctor can suspect PHA, conduct early screening with subsequent diagnostic tests, and provide adequate treatment. There is currently no algorithm for dynamic monitoring of the patient.

Conclusion

In daily practice, physicians should be aware of PHA as a cause of resistant hypertension. The presented clinical case illustrates the insufficient use of PHA diagnostic methods in everyday practice. This leads to an incorrect diagnosis and lack of adequate treatment. Following clinical recommendations will allow you to make a timely diagnosis and carry out the necessary treatment. In the vast majority of cases, this will relieve the patient of hypertension or soften its course, which will reduce the risk of developing cardiovascular complications.

Literature

— The development team included: the Clinical Guidelines Subcommittee (CGS) of the Endocrine Society, six additional experts, one methodologist and a medical editor. The task force received no corporate funding or compensation.

— To express the quality of certain recommendations, the terms “recommended” are used for theses developed on the basis of an overwhelming majority of expert opinion (marked as 1), and “suggested” for recommendations that are not accompanied by overwhelming expert support (marked as 2). According to the criteria of evidence-based medicine, the designation OOOO is used when the level of evidence of the recommendation is low, OOOO - when the evidence is medium, OOOO - when the evidence is high, OOOO - when the evidence is absolute.

— The consensus process involved reviewing systematic reviews of issues, group meeting discussions, several conference calls, and email exchanges.

— The projects prepared by the development team were reviewed sequentially by the Endocrine Society CGS, clinical committee and council. The version approved by the CGS and CAS was posted on the Endocrine Society website for comment by members. At each stage of the review, the development team received written comments and any necessary changes included.

1. Indications for the primary diagnosis of primary hyperaldosteronism (PHA)

1.1. It is recommended to diagnose PHA in groups with a relatively high prevalence of PHA (1|ӨӨ OO):
— stage 1 arterial hypertension according to the Joint National Commission (JNC) classification — > 160-179/100-109 mm Hg; stage 2 arterial hypertension (> 80/110 mm Hg);

— 1st degree relatives of patients with PHA who have hypertension (1|Ө OOO).

1.2. For the primary detection of PHA in patients of these groups, it is recommended to determine the aldosterone-renin ratio (ARR).

2.1. In patients with positive APC, before making a differential diagnosis of forms of PHA, it is recommended to conduct one of 4 confirmatory PHA tests (1|Ө OOO).

3.1. A CT scan of the adrenal glands to determine the subtype of PHA and exclude adrenocortical cancer is recommended for all patients with PHA (1|ӨӨ OO).

3.2. If the patient is indicated for surgical treatment, then to confirm the diagnosis of PHA, it is recommended to conduct a comparative selective venous blood sampling (CVBS) by an experienced (!) specialist (1|ӨӨӨ O).

3.3. In patients with the onset of PHA before the age of 20 years and with a family history of PHA or stroke before the age of 40 years, genetic testing for glucocorticoid-dependent PHA (GDPA) is proposed (2|ӨӨ OO).

4. Treatment

4.1. Laparoscopic adrenalectomy (1|ӨӨ OO) is recommended as the optimal treatment option for unilateral PHA (aldosterone-producing adrenal adenoma (APA) and unilateral adrenal hyperplasia (UNH). In case of inoperability or refusal of surgery, treatment with mineralocorticoid receptor antagonists (MCRA) is recommended (1|ӨӨ OO).

4.2. In case of bilateral adrenal hyperplasia, it is recommended to manage patients with the use of AMCR (1|ӨӨ OO): spironolactone or, as an alternative, eplerenone (2|Ө OO) is suggested as the primary drug.

Definition and clinical significance of PHA

PHA is a collective diagnosis characterized by elevated aldosterone levels, which are relatively independent of the renin-angiotensin system and do not decrease with sodium load. Increased aldosterone levels cause cardiovascular disorders, decreased plasma renin levels, arterial hypertension, sodium retention and accelerated potassium excretion, leading to hypokalemia. Causes of PHA include adrenal adenoma, unilateral or bilateral adrenal hyperplasia, and in rare cases, hereditary GPH.

Epidemiology of PGA

Previously, most experts estimated the prevalence of PHA to be less than 1% in patients with essential hypertension, and it was also assumed that hypokalemia was an indispensable criterion for diagnosis. Accumulating evidence has led to a revision of the rates: prospective studies have demonstrated an incidence of PHA of more than 10% among patients with hypertension.

Incidence of hypokalemia in PHA

In recent studies, hypokalemia is detected in a small number of patients with PHA (9-37%). Thus, the most common and common manifestation of PHA is hypertension; hypokalemia is detected in the most severe cases. Serum potassium concentrations less than 3.5 mmol/L are detected in half of patients with APA and in 17% of patients with idiopathic hyperaldosteronism. Thus, with regard to the diagnosis of PHA, hypokalemia has low sensitivity and specificity; the value of this symptom in relation to the prognosis of the disease is also not high.

Clinical and epidemiological significance of PHA

PHA is of great pathological significance both because of its prevalence and due to the higher incidence of cardiovascular damage and mortality compared with age- and sex-randomized patients with a similar degree of blood pressure increase in essential hypertension. The possibility of improving the quality of life with adequate treatment increases the importance of timely diagnosis.

1. Indications for primary diagnosis of PHA

1.1. It is recommended to diagnose primary hyperaldosteronism in groups with a relatively high prevalence of PHA (1| ӨӨ OO):
— stage 1 arterial hypertension according to the Joint National Commission classification — > 160-179/100-109 mmHg; stage 2 arterial hypertension (> 180/110 mm Hg);
— arterial hypertension resistant to drug therapy;
- a combination of arterial hypertension and voluntary (or diuretic-induced) hypokalemia;
- combination of arterial hypertension and adrenal incidentaloma;
- a combination of hypertension and a family history of early development of arterial hypertension or acute cerebrovascular disorders before the age of 40 years;
— 1st degree relatives of patients with PHA who have hypertension (1|Ө LLC).

Detection of PHA indirectly affects the prognosis. Clinical trials have not demonstrated the effect of PHA screening on morbidity, quality of life, or mortality. It must be taken into account that the results of these clinical trials are influenced by factors that temporarily worsen the condition of patients with PHA: withdrawal of antihypertensive therapy, invasive vascular studies, adrenalectomy, in comparison with patients who have constant effective blood pressure control and angioprotection. On the other hand, the effect of reducing aldosterone levels on the effectiveness of blood pressure control and the reduction of cardiovascular and cerebrovascular complications has been convincingly proven. Until the results of prospective studies change, the recommendation remains to determine ARS for all first-degree relatives of patients with PHA who have manifestations of hypertension.

The greatest value of recommending limited screening is to reduce the risk of “missed” undiagnosed observations of PHA. Identification of patients allows for timely effective removal of a hormonally active tumor or optimization of blood pressure control with specific treatment. To a lesser extent, the positive impact of recommendation 1.1 is manifested in a reduction in the number of false-positive PGA conclusions in comparison with the “unlimited” screening group and the economic effect as a result of savings in diagnostic tools (Table 1).

1.2. For the primary detection of PHA in patients of these groups, it is recommended to determine the aldosterone-renin ratio (1|ӨӨ OO).

ARS is currently the most reliable and accessible method for screening for PHA. Despite the identified shortcomings in studies of the diagnostic value of ARS (mainly due to inadequate research design on this problem), numerous studies confirm the diagnostic superiority of ARS in comparison with separately used methods for determining the level of potassium or aldosterone (both indicators have low sensitivity), renin (low specificity).

When determining APC, as with other biochemical tests, false positive and false negative results are possible. The influence of drugs and laboratory conditions on ARS is shown in Table. 2.

ARS is regarded as a test used in primary diagnosis. If the results are questionable due to various influences (medication, non-compliance with blood sampling conditions), the study must be repeated.

Following the recommendation for defining APC has a positive impact on diagnosis not only in groups with a high frequency of PHA, defined in recommendation 1.1. In particular, the costs of performing this test for all patients with essential hypertension are considered justified. This is contradicted by the above recommendation for selective testing. However, the risk of missed PGA in some hypertensive patients must be considered. The consequences of this error include the later development of more severe and persistent hypertension as a consequence of the long-term persistence of high aldosterone levels. In addition, the duration of hypertension has been reported by a number of researchers to negatively affect the postoperative prognosis of adrenalectomy for APA.

Technical aspects required for correct implementation and interpretation of recommendation 1.2

The test conditions are presented below.

The determination of APC is most sensitive when taking blood in the morning, after the patient has been in an upright position for about 2 hours, after being in a sitting position for 5-15 minutes.

Before performing the test, the patient should not be on a salt-free diet.

In most observations, ARS can be individually interpreted by understanding the nature of the effects of long-term therapy or other possible negative influences on ARS. Elimination of all antihypertensive drugs that affect the outcome of ARS is possible in patients with moderate hypertension, but can lead to serious problems in severe hypertension. These observations recommend the use of antihypertensive drugs that have minimal effect on ARS.

Measuring the aldosterone-renin ratio: guidelines

A. Preparation for determining APC:

1. Correction of hypokalemia is necessary after measuring plasma potassium. To exclude artifacts and overestimation of the real potassium level, blood sampling must meet the following conditions:
- carried out using a syringe method;
- avoid clenching your fist;
— draw blood no earlier than 5 seconds after removing the tourniquet;
— plasma separation for at least 30 minutes after collection.

2. The patient should not limit sodium intake.

3. Discontinue medications that affect ARS levels at least 4 weeks in advance:
a) spironolactone, eplerenone, triamterene, amiloride;
b) diuretics;
c) licorice root products.

4. If the results of ARS while taking the above-mentioned drugs are not diagnostic and if hypertension is controlled with drugs with minimal effect on aldosterone levels (Table 2), discontinue for at least 2 weeks other drugs that may affect ARS levels:
a) β-blockers, central α-adrenergic agonists (clonidine, α-methyldopa), NSAIDs;
b) 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 aldosterone levels (Table 2).

6. It is necessary to have information about taking oral contraceptives (OCs) and hormone replacement therapy, since estrogen-containing drugs can lower the level of direct renin concentration (RCC), which will cause a false-positive ARS result. Do not discontinue the OC, use the plasma renin activity level (PRA), not the PCR.

B. Conditions for blood sampling:

1. Collection 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.

2. Collection in accordance with paragraph A.1, stasis and hemolysis require repeated collection.

3. Before centrifugation, keep the tube at room temperature (and not on ice, since cold conditions increase the ARP); after centrifugation, quickly freeze the plasma component.

B. Factors influencing the interpretation of results (Table 3):

1. Age > 65 years affects the decrease in renin levels, APC is artificially increased.

2. Time of day, food (salt) diet, time period of postural position.

3. Medicines.

4. Violations of blood sampling techniques.

5. Potassium level.

6. Creatinine level (renal failure leads to false-positive APC).

Reliability of the study

Despite the development of new techniques, the immunometric method for determining plasma renin activity or direct renin concentration is the preferred method. When determining ARP, factors such as taking estrogen-containing drugs should be taken into account. Carefully selected, well-matched aliquots of the human plasma pool should be used. This technique is preferable to the use of lyophilized controls provided in commercial screening kits.

Method reproducibility

Since the APC indicator is mathematically significantly dependent on the ARP, the determination of the ARP should be quite sensitive, especially when measuring the level of activity at low values - 0.2-0.3 ng/ml/h (PCR - 2 mU/l). For ARP (but not RCC), sensitivity for levels less than 1 ng/mL/h can be increased by extending the test incubation time, as suggested by Sealey and Laragh. Although most laboratories use radioimmunoassay for the determination of urine and plasma aldosterone, the level of determination standards in some cases varies unacceptably. Tandem mass spectrometry is being increasingly used and the results of studies appear to be more consistent (Table 3).

Interpretation of laboratory results

There are significant differences in the assessment of aldosterone and renin levels, which depend on the test method and units of measurement. An aldosterone level of 1 ng/dL corresponds to 27.7 pmol/L in SI. For immunometric methods, a plasma renin activity level of 1 ng/ml/h (12.8 pmol/l/min in SI units) corresponds to a direct renin concentration of approximately 8.2 mU/l (or 5.2 ng/l in traditional units ). Conversion factors were obtained at the Nichols Diagnostic Institute using two methods: automated immunochemiluminescence or radioimmunometry (Bio-Rad Renin II). Because the definition of RCC is under development, conversion factors may change.

Due to the lack of a unified approach in diagnostic protocols and methods, there is significant variability in determining the diagnostic value of APC for PHA; in different groups of researchers the indicator varies from 20 to 100 (from 68 to 338). The vast majority of research groups use an APC value in the range of 20-40 (68-135) provided that blood sampling is performed on an outpatient basis in the morning with the patient in a sitting position. In table Table 4 lists the diagnostic values of APC when used in various units of calculation for the level of concentration of aldosterone, ARP and RCC.

Some researchers believe that for a definitive diagnosis of PHA, in addition to an increased APC value, an increase in aldosterone levels (> 15 ng/dL) is mandatory as a diagnostic criterion. Other researchers believe that a formal upper limit of normal value for aldosterone should be avoided, but it should be recognized that there is an increased likelihood of a false-positive ARS result when renin levels are low. We present a study illustrating the inappropriateness of considering the formal value of the upper limit of normal for aldosterone as a strict diagnostic criterion for PHA. 36% of 74 patients diagnosed with PHA by screening had an APC > 30 (> 100) at blood draw, and aldosterone levels were< 15 нг/дл (< 416 пмоль/л). Диагноз ПГА у этих больных был подтвержден отсутствием подавления уровня альдостерона при подавляющем тесте с флудрокортизоном (ПТФ) (кортинеффом), и у 4 из 21 пациента выявлена односторонняя гиперпродукция альдостерона по данным ССВЗК, пролеченная затем хирургически . В другом исследовании уровень альдостерона 9-16 нг/дл (250-440 пмоль/л) отмечен у 16 из 37 пациентов с ПГА, подтвержденным ПТФ .

Thus, ambiguous expert opinions and contradictory literature data, the variability of laboratory parameters of aldosterone and renin levels, depending on the blood sampling technique used, laboratory characteristics, the influence of drugs, age, etc., force us to abandon strict recommendations on the diagnostic value of ARS. It is more important to outline all the relative advantages and disadvantages of the technique, factors influencing the result of ARS, while maintaining the possibility for clinicians to individually interpret the data.

2. Confirmation of the diagnosis of PHA

2.1. For patients with positive ARS, prior to differential diagnosis of PHA forms, it is recommended that one of 4 confirmatory PHA tests be performed (1/ӨӨ OO)

At the moment, experts cannot decide on the diagnostic method of choice (gold standard) for PHA. Test results are usually assessed retrospectively in small groups of patients with an initially increased likelihood of PHA based on the results of previous tests.

The flawed research design is illustrated by the following example. Giacchetti et al. provide data on 61 patients with PHA (26 of them had confirmed APA) and 157 patients with significant hypertension. The authors found that for the sodium infusion test (saline test - SST), a decrease in plasma aldosterone levels of 7 ng/dL demonstrated a sensitivity of 88% and a specificity of 100%. In the prospective PAPY study of 317 patients who underwent TGF, a sensitivity/specificity analysis showed a diagnostic value for aldosterone levels for PHA of 6.8 ng/dL. Sensitivity and specificity were low (83 and 75%, respectively); Using cortisol controls did not improve the test's accuracy.

Of the 4 research methods (oral sodium load test, TGF, fludrocortisone suppression test (Cortineff), captopril test), none can be proposed as preferable with sufficient reliability. Significant variability in data on sensitivity, specificity and reliability (reproducibility) makes it possible to choose a specific method depending on financial aspects, patient compliance, laboratory characteristics, and the preferences of specific doctors (Table 5). The use of sodium loading tests is undesirable in severe forms of hypertension and restrictive forms of heart failure. During testing, it is recommended to use antihypertensive drugs with minimal effect on the renin-angiotensin-aldosterone system (Table 2).

The use of one of the 4 confirmatory tests with a high degree of efficiency reduces the number of false-positive PGA results for the APC level, which eliminates the need for expensive complex diagnostic procedures.

Notes

For each of the four confirmatory tests, the interpretation features are described in Table. 5.

3. Differential diagnosis of forms of PHA

According to the results of CT, PHA may reveal “norm”: unilateral macroadenoma (more than 1 cm), minimal unilateral thickening of the adrenal peduncles, unilateral microadenoma (less than 1 cm), bilateral macro- or microadenomas (or a combination). To differentiate the forms of PHA, the results obtained should be analyzed in conjunction with the CVAD and, if necessary, with auxiliary tests. On CT, aldosterone-producing adenoma may appear as small hypodense nodes (usually less than 2 cm in diameter). At the same time, in idiopathic hyperaldosteronism (IHA), the adrenal glands on CT may appear either unchanged or with nodular changes. Adrenocortical carcinoma (ACC) with aldosterone overproduction is a tumor almost always more than 4 cm in diameter, and in most patients with ACC, CT scans can reveal signs suspicious for the malignant nature of the tumor.

Limitations of CT: small aldosteromas may be interpreted as IGA in the case of bilateral or multiple adrenal nodules or may not be detected due to their small size. In addition, “obvious” adrenal microadenomas may actually turn out to be areas of focal hyperplasia - a diagnostic error in this case leads to the unreasonable performance of unilateral adrenalectomy. In addition, unilateral hormonally inactive adrenal macroadenomas are quite typical for patients over 40 years of age and do not differ from APA on CT. ONG can be detected on CT in the form of an increase in the size of the adrenal gland or completely correspond to the X-ray picture of normal adrenal glands.

In one study, CT findings were consistent with aldosterone lateralization findings in CVBD in only 59 of 111 patients with surgically proven APA. At the same time, CT revealed less than 25% of aldosterae, not reaching 1 cm in diameter. In another study of 203 patients with PHA examined using CT and CVBD, an accurate CT diagnosis was established in 53% of patients. According to CT data, 42 patients (22%) gave a false negative result (although they required surgery) and 48 (25%) may have been inappropriately operated on due to a false positive result. In a recent study, the results of SIBD performed in 41 patients with PHA were consistent with CT findings in only 54% of patients. In connection with the above, performing CVAD is extremely important for proper treatment in patients potentially requiring surgical treatment. The greatest value of CT is detected in tumors larger than 2.5 cm, when indications for removal of the adrenal gland are considered due to the malignant potential of the tumor. It is advisable to use CT when navigating cannulation of the adrenal veins in CVBD.

Notes

MRI does not have an advantage over CT in assessing forms of PHA; it is more expensive and has lower spatial resolution than CT.

3.2. If surgical treatment is indicated for the patient, then comparative selective venous blood sampling by an experienced specialist is recommended to confirm the diagnosis of PHA (1|ӨӨӨ O)

Lateralization of the source of aldosterone hyperproduction is extremely important for choosing an adequate treatment method for PHA. A differential diagnosis of unilateral or bilateral adrenal lesions is necessary due to the fact that unilateral adrenalectomy for APA or ONH leads to normalization of potassium levels and improvement of the course of hypertension in all patients and to complete cure of hypertension in 30-60% of patients; with bilateral lesions of the IHA and DHHA, both unilateral and total adrenalectomy rarely improve the course of hypertension: conservative therapy is the treatment of choice. For unilateral lesions, drug therapy can be considered if the patient is inoperable or refuses surgical treatment.

Imaging methods cannot reliably detect microadenomas or reliably distinguish hormonally inactive tumors from APA, making SIBD the most accurate method for the differential diagnosis of forms of PGA. The CVAD method is expensive and invasive. In this regard, the need for its use is discussed only for patients with a proven diagnosis of PHA. The determination of APC is associated with a certain number of false-positive results, so performing confirmatory tests is necessary to perform CVID.

The sensitivity and specificity of CVID in detecting lateralization of aldosterone hyperproduction is 95 and 100% (CT - 78 and 75%, respectively). It is important to understand that CT findings of an apparent unilateral adrenal nodule can be genuinely misleading, leading to unnecessary surgery.

CVID is a standard test for differentiating unilateral lesions (APA or ONG) from bilateral lesions (IGA and GZGA). The most difficult aspect of CVAD is catheterization of the right adrenal vein (which is shorter than the left and drains directly into the inferior vena cava rather than into the renal vein), but the number of successful determinations increases rapidly with increasing experience of the angiographer.

According to a review of 47 reports, the success rate of right adrenal vein catheterization in 384 patients was 74%. With increasing experience, performance increased to 90-96%. The intraoperative rapid study of cortisol concentration significantly improves the accuracy of catheter placement and the effectiveness of the method. Some centers perform SVBD in all patients with PHA, while others selectively use this method (for example, they believe that SVBD is not indicated for patients under 40 years of age with a single unilateral adenoma obvious on CT).

In centers with experienced radiologists, the CVD complication rate is less than 2.5%. The risk of adrenal hemorrhage can be minimized when the examination is performed by an experienced technician who does not perform adrenal venography but uses a minimal amount of contrast to determine the position of the catheter tip. The risk of thromboembolism can be reduced by studying hemostasis before the procedure and using heparin as indicated after the procedure.

The use of CVAD in the differential diagnosis of forms of PHA effectively reduces the risk of unnecessary adrenalectomy based on CT data, with a relatively low risk of potential complications of the procedure.

Notes

There are three protocols for SSVZK:
— unstimulated blood sampling;
- unstimulated blood sampling in combination with cosyntropin/corticotropin-stimulated (bolus injection) blood sampling;
- corticotropin-stimulated (continuous drip infusion) blood sampling.

Simultaneous bilateral CVAD is a difficult technique to perform and is used by few investigators; Most experts prefer the use of continuous infusion of corticotropin during CVD to:
— minimize stress-induced fluctuations in aldosterone levels;
- increase the cortisol gradient between the adrenal and inferior vena cava;
— confirm the selectivity of blood sampling from the adrenal veins;
- maximize aldosterone levels from APA and avoid the non-secretory phase.

The criteria for the effectiveness of the method differ depending on the fact of stimulation with corticotropin. The difference between the concentration levels of aldosterone and cortisol on the right and left should be corrected according to the dilution effect of their concentrations by the inferior phrenic vein, which drains into the left adrenal vein; if on the right, blood sampling is performed non-selectively - due to the flow in the inferior vena cava. In such cases, the term “cortisol-corrected aldosterone level” or “cortisol-corrected aldosterone” is used. When using continuous infusion corticotropin stimulation to confirm unilateral aldosterone production, a 4:1 cortisol-corrected aldosterone ratio between the high-secreting and low-secreting side is the diagnostic value. A ratio of less than 3:1 is suggestive of a bilateral cause of aldosterone hypersecretion. When using the above diagnostic values to detect unilateral hyperproduction of aldosterone (with APA and ANG), the sensitivity of CVID is 95%, the specificity is 100%. In patients with a lateralization ratio of aldosterone production from 3: 1 to 4: 1, the diagnosis cannot be reliably judged; the results of CVBD must be correlated with clinical manifestations, CT data and auxiliary laboratory tests.

Some researchers, in the absence of corticotropin stimulation, consider an effective lateralizing indicator of unilateral hypersecretion of aldosterone to exceed a 2:1 ratio. Other authors suggest focusing on comparing the levels of cortisol and aldosterone during selective sampling with simultaneously determined indicators in peripheral blood. When the values obtained from one adrenal vein are significantly (usually at least 2.5 times) greater than those in the periphery (cubital or inferior vena cava), and in the other adrenal vein practically correspond to peripheral blood, this fact indicates suppression of secretion in the contralateral adrenal gland and is the basis for a satisfactory prognosis for hypertension after unilateral adrenalectomy.

Use of corticotropin (cosyntropin)

In the absence of stimulation with corticotropin, CVAD should be performed in the morning after the patient has been in a supine position at night. This approach helps to avoid fluctuations in aldosterone concentrations in patients with angiotensin-dependent variants of PHA, and also uses the morning high level of endogenous corticotropin, which has a stimulating effect in all variants of PHA.

Both bolus and continuous infusion stimulation with corticotropin are used. For continuous stimulation, the dose of the drug is 50 mg per hour, starting 30 minutes before the start of the catheterization procedure, and the infusion continues throughout the study. When using a bolus of corticotropin, CVAD is performed twice: before and after the administration of 250 mg of corticotropin. However, some researchers believe that the bolus technique of corticotropin administration and simultaneous blood sampling from the adrenal veins suffers from the diagnostic accuracy of SIBD, since corticotropin administered as a bolus may actually increase the overproduction of aldosterone from the adrenal gland without APA to a greater extent than with APA.

Selective catheterization

The suprarenal veins are catheterized through the femoral vein, and the position of the catheter tip is checked by carefully injecting a minimal amount of non-ionizing contrast. Blood obtained from the adrenal veins and from the periphery (to eliminate cross-talk, a peripheral sample is taken from the cubital or iliac vein) is assessed for cortisol and aldosterone concentrations. Selective sampling on the left is typically performed with the catheter tip positioned at the junction of the inferior phrenic and left adrenal veins. Difficulties in catheterization of the right adrenal vein are due to the fact that it is very short and flows into the inferior vena cava at an acute angle. Cortisol concentrations are determined to confirm the success of catheterization. The ratio of cortisol concentrations in the adrenal and peripheral veins is more than 10:1 with corticotropin infusion stimulation and more than 3:1 without the use of stimulation.

Ineffective SSVZK

In the absence of a CVD result, which is associated with inadequate catheter position and questionable lateralization relationships, the clinician can:
- repeat SVZK;
— carry out treatment for AMCR;
- undertake unilateral adrenalectomy, justified by the results of other studies (for example, CT);
— conduct additional studies (marching test, scintigraphy with iodocholesterol).

Postural load test (march test)

In case of ineffective CVAD and the presence of a unilateral adrenal tumor on CT, some experts use the march test. This test, which was developed in the 1970s, is based on the fact that the level of aldosterone in APA does not respond to the postural (during the transition from a prolonged stay in a horizontal position to a vertical) stimulating influence of the level of angiotensin II, whereas in IHA the level of aldosterone is sensitive to the slightest changes in the level of angiotensin II. In a review of 16 studies, the accuracy of the marching test was 85% in 246 patients with surgically confirmed APA. The disadvantages of the method are explained by the fact that some patients with APA are sensitive to angiotensin II, and some patients with IHA do not experience changes in aldosterone levels during the postural test. Thus, the test has only an auxiliary value (in case of ineffective CVAD and the presence of a unilateral adrenal tumor on CT).

Scintigraphy with iodocholesterol

Iodocholesterol scintigraphy - I 131 -19-iodocholesterol was used in the 1970s, and an improved version 6β-I 131 -iodomethyl-19-norcholesterol (NP-59) has been used since 1977. A study with NP-59, performed with dexamethasone suppression, shows the correspondence of hyperfunction to the tumor process in the adrenal glands. However, the sensitivity of this test is highly dependent on the size of the adenoma. Because there is little drug uptake in adenomas smaller than 1.5 cm in diameter, this technique is not useful in interpreting micronodular changes compared with high-resolution CT. In this regard, the method is ineffective in the differential diagnosis of forms of PHA and is not used by most centers.

18-Hydroxycorticosterone Study

18-hydroxycorticosterone (18-HCS) is the result of hydroxylation of corticosterone. In patients with APA, the initial morning (at 8.00) plasma 18-GCS level usually exceeds 100 ng/dL, while in patients with IHA this figure is lower than 100 ng/dL. However, the accuracy of the test is not sufficient for the differential diagnosis of forms of PHA.

Testing for familial forms of PHA

Familial hyperaldosteronism type I (FH I) (synonym - glucocorticoid-dependent hyperaldosteronism)

FH syndrome I is inherited in an autosomal dominant manner and causes less than 1% of cases of PHA. The onset of OHHA is variable and is represented by either normal blood pressure, slightly elevated aldosterone levels and suppressed renin levels, or early manifestations of hypertension resistant to antihypertensive treatment.

Some authors talk about the high probability of OHHA in childhood and adolescence with high-amplitude or persistent hypertension in combination with a family history of early onset of hypertension or stroke at a young age. In a study by Dluhy et al. At the time of diagnosis of OHHA, 50% of children (under 18 years of age) had moderate or severe hypertension (BP exceeding the 99th percentile of the norm for age and sex). Litchfield et al. report 27 genetically proven DHGAs in 376 patients. In the family history of 48% of these patients and in 18% of the patients themselves, cerebrovascular complications were noted; the average age of onset of hypertension was 32.0 ± 11.3 years. 70% of cerebrovascular complications are strokes of the hemorrhagic type with a mortality rate of 61%. The study design does not allow for assessment of the incidence rate in the population.

Genetic testing using the Southern blot method and polymerase chain reaction are sensitive methods for detecting DHGA. The use of the method avoids the need to use non-high-precision research methods: daily excretion of 18-hydroxycortisol and 18-hydroxycortisol and a suppressive test with dexamethasone. Genetic testing for PGA is performed in patients with PGA who have a family history of: 1) PGA; 2) stroke at a young age; 3) the onset of hypertension at a young age (for example, under 20 years of age).

Familial hyperaldosteronism type II (FH II)

FH II syndrome is inherited in an autosomal dominant manner and is possibly genetically heterogeneous. Unlike FH I, the level of aldosterone in FH II is not suppressed during a suppressive test with dexamethasone, and genetic testing for the GZGA mutation is negative. Families with FH II may have APA, IHA, and be clinically indistinguishable from patients with apparent sporadic PHA. Although FH II is more common than FH I (incidence is at least 7% of patients with PHA), the prevalence of the syndrome is unknown. The molecular substrate of FH II is not completely clear; several studies demonstrate an association of the syndrome with changes in the chromosomal region 7p22.

Ultimately, APA may be quite rarely detected in MEN type 1 syndrome.

4. Treatment

4.1. Endoscopic adrenalectomy (1|ӨӨ OO) is recommended as the optimal treatment option for unilateral PHA (APA and ONH). In case of inoperability or refusal of surgery, treatment with AMKR (1|ӨӨ OO) is recommended.

Unilateral endoscopic removal of the adrenal gland eliminates hypokalemia and improves the course of hypertension in almost 100% of patients with unilateral variants of PHA. Complete cure of hypertension (BP)< 140/90 мм рт.ст. на фоне антигипертензивной терапии) отмечается примерно у 50 % (от 35 до 60 %) пациентов с АПА , послеоперационная курабельность АГ увеличивается до 56-77 % при целевом АД на фоне лечения < 160/95 мм рт.ст. . На момент опубликования наших рекомендаций не получено доказательных данных о связи односторонней адреналэктомии с улучшением качества жизни, снижением заболеваемости и смертности.

Among the factors associated with the need for blood pressure correction in the postoperative period, the presence of first-degree relatives with hypertension and the preoperative use of two or more antihypertensive drugs are reliably indicated. With less certainty due to univariate analysis and use of diagnostic criterion for initial treatment of AD< 160/95 мм рт.ст. , перечисляются другие факторы, определяющие необходимость послеоперационного лечения АГ. Среди них: продолжительность гипертензии < 5 лет , высокое (по отношению к диагностической для ПГА величине) АРС перед операцией , высокий уровень суточной экскреции альдостерона , хороший терапевтический эффект спиронолактона перед операцией . Более общие причины для персистирующей АГ после адреналэктомии — сопутствующая АГ неизвестной этиологии , пожилой возраст и/или большая длительность АГ.

Compared with open adrenalectomy, the use of endoscopic techniques is associated with a reduction in hospitalization time and complications. Since CVBD is able to identify only the side of increased aldosterone synthesis, organ-preserving tactics (subtotal adrenalectomy with preservation of part of the “unchanged” adrenal gland) can lead to persistent postoperative hypertension. High postoperative aldosterone levels are detected in 10% of patients with unilateral APA and in 27% of patients with identified multinodular lesions.

For patients with a unilateral variant of PHA, in whom surgery was not performed for some reason, drug treatment is indicated. In a retrospective study of 24 patients with ARA treated with spironolactone or amiloride for 5 years, blood pressure decreased on average from 175/106 to 129/79 mmHg. . Of these, 83% received additional antihypertensive medications to achieve this result. Side effects of spironolactone included mastalgia (54%), gynecomastia (33%), muscle spasms (29%), and decreased libido (13%). For patients with unilateral PHA, adrenalectomy is more cost-effective in the long term than lifelong conservative therapy.

The recommendation to perform endoscopic adrenalectomy in patients with unilateral PHA as a treatment method of choice is of high value in terms of the effectiveness of lowering blood pressure or reducing the number and amount of antihypertensive drugs, lowering aldosterone levels and normalizing blood potassium levels. The advantages of the method are immeasurably higher than the risks of surgery and postoperative treatment.

Preoperative preparation

The main goal of preoperative preparation is normalization of blood pressure and hypokalemia. This may require administration of AMCR and delay surgical treatment.

Postoperative management

Aldosterone levels and renin activity should be measured immediately after surgery, potassium infusions and spironolactone should be discontinued, and antihypertensive therapy should be minimized or discontinued.

For postoperative infusion, isotonic saline solutions without potassium chloride are generally used, except in situations with persistent hypokalemia (< 3,0 ммоль/л). Послеоперационная гиперкалиемия может являтся следствием гипоальдостеронизма из-за хронического подавления минералкортикоидной функции контралатерального надпочечника . В редких случаях может требоваться временная терапия флудрокортизоном (кортинеффом).

Normalization of blood pressure or maximum improvement in the course of hypertension in typical cases occurs 1-6 months after unilateral adrenalectomy for APA, but the duration of this period in some patients is up to 1 year. Some researchers use a fludrocortisone suppression test 3 months after surgery to determine further postoperative prognosis and assess contralateral adrenal function.

4.2. For bilateral adrenal hyperplasia, it is recommended to manage patients using mineralcorticoid receptor antagonists (1|ӨӨ OO), spironolactone or, as an alternative, eplerenone (2|Ө OO) is suggested as the primary drug.

The bilateral version of PGA is represented by IGA, bilateral APA and GZGA. According to summary literature data, when analyzing the postoperative condition of 99 patients with IHA (unilateral or total adrenalectomy), only 19% showed an improvement in the course of hypertension. There are currently no randomized placebo-controlled studies regarding the effectiveness of drug treatment for PHA. Nevertheless, knowledge of the pathophysiological aspects of IHA and extensive clinical experience allow us to propose several pharmacological standards of treatment.

Mineralocorticoid receptor antagonists

AMCRs effectively reduce blood pressure and provide organ protection from excess mineralcorticoids, independent of hypertension.

Spironolactone

For more than forty years, it has been the drug of choice in the medical treatment of PHA. Summary data from a study of 122 patients with IHA demonstrated a reduction in systolic blood pressure by 25% and diastolic blood pressure by 22% in response to 50-400 mg of spironolactone per day for 1-96 months. In another study of 28 patients with hypertension and APC levels > 750 pmol/l (27 ng/dl)/ng/ml/h, PGA was not confirmed by a saline test; CT scans showed no evidence of an adrenal tumor; however, therapy ( 25-50 mg/day) reduced the need for antihypertensive drugs.

The occurrence of gynecomastia during treatment with spironolactone is a dose-dependent effect. Studies provide data on the presence of gynecomastia in 6.9% of patients after 6 months of treatment at a dose< 50 мг в день и у 52 % пациентов при лечении спиронолактоном в дозе >150 mg per day.

The exact incidence of menstrual disturbances in premenopausal patients treated with spironolactone is unknown. The structurally similar drug canrenone (potassium canrenoate) is characterized by fewer sexual disorders associated with the side effects of steroids. Thiazide diuretics (triamterene, amiloride), prescribed in small doses, can reduce the dose of spironolactone and thus reduce its side effects.

Eplerenone

Eplerenone is a new selective AMKR, unlike its predecessors, it is not a progesterone agonist and does not have an antiandrogenic effect, and therefore the number of adverse endocrine side effects is less than that of spironolactone. It is used in the treatment of essential hypertension in the USA and Japan and for the correction of post-infarction heart failure in the USA and many other countries. The activity of eplerenone as an AMCR is approximately 60% of that of spironolactone; the benefits of the drug are somewhat overshadowed by the high cost and temporary shortage of current clinical evidence-based studies of its effectiveness in PHA. For optimal effect, the drug is administered twice daily, which is associated with a shorter half-life than spironolactone.

Other drugs

Increased sodium reabsorption in the distal tubule of the nephron loop is the main mechanism by which aldosterone influences plasma potassium and sodium levels. Among the available sodium channel antagonists, amiloride and triamterene are considered. The effect of amiloride has been most studied in relation to PHA. Despite being less effective than spironolactone, amiloride is a well-tolerated potassium-sparing diuretic and can improve hypertension and correct hypokalemia in patients with PHA without causing steroid-related side effects. Unlike AMKR, amiloride is not an endothelial protector.

There are few studies regarding the effectiveness of calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with PHA. The antihypertensive effect of drugs in these groups does not depend on the level of aldosterone. Studies in which positive results were obtained were carried out on small groups, are methodologically weak, and do not evaluate long-term results of therapy. The development of aldosterone synthetase inhibitors is promising.

The recommendation is effective for the treatment of hypertension, hypokalemia, specific (mineralcorticoid-dependent) heart failure and nephropathy with just one drug. The value of the recommendation is reduced due to the side effects of spironolactone (gynecomastia and erectile dysfunction in men, menstrual disorders in women). Despite the high cost, in case of severe side effects of spironolactone, the more selective eplerenone is an alternative drug.

Notes

For bilateral adrenal hyperplasia, the initial dose of spironolactone is 12.5-25 mg once daily. The effective dose is titrated gradually to a maximum dose of 100 mg per day. The starting dose for eplerenone is 25 mg twice daily. For patients with stage III chronic renal failure, spironolactone and eplerenone have a higher risk of hyperkalemia; for patients with stage IV chronic renal failure, the drugs are contraindicated.

4.3. In patients with HHGA, it is recommended to use the minimum titrated dose of glucocorticoids that normalizes blood pressure and serum potassium levels. Treatment with AMKR is not preferable in this case (1|ӨӨ OOO).

Treatment of GPH is carried out with glucocorticoids with the aim of partial suppression of corticotropin. The use of synthetic glucocorticoids (dexamethasone or prednisolone), which act longer than hydrocortisone, is recommended. Ideally, the drug should be taken at night to effectively suppress the morning, physiologically elevated corticotropin levels. To assess the effectiveness of therapy and prevent overdose, it is necessary to determine ARP and aldosterone concentration. Iatrogenic Cushing's syndrome causes growth retardation in children, so the minimum dose of glucocorticoid that normalizes blood pressure and corrects hypokalemia should be used. The treatment under consideration does not always normalize blood pressure; in these observations, AMCR is prescribed. Due to the fact that children are often treated for HHGA, the effects of spironolactone associated with growth retardation and antiandrogenic effects make the use of eplerenone relevant.

Treatment of HHHA is effective in preventing the potential consequences of hyperaldosteronism, but the value of the therapeutic effect is reduced by the side effects of chronic use of glucocorticoids.

Notes

The initial dose of dexamethasone for adults is 0.125-0.25 mg daily, for prednisolone 2.5-5 mg daily. It is advisable to take the drug at night.