Causes and pathogenesis of primary hyperaldosteronism

The following etiopathogenetic and clinical-morphological signs of primary hyperaldosteronism are distinguished (E. G. Biglieri, J.D. Baxter, modification).

1. Aldosterone-producing adenoma of the adrenal cortex - aldosteroma (Conn's syndrome).
2. Bilateral hyperplasia or adenomatosis of the adrenal cortex.
   • Idiopathic hyperaldosteronism (unsuppressed overproduction of aldosterone).
   • Unspecified hyperaldosteronism (selectively suppressed aldosterone production).
   • Glucocorticoid-suppressed hyperaldosteronism.
3. Aldosterone-producing, glucocorticoid-suppressed adenoma.
4. Adrenal cortex carcinoma.
5. Extra-adrenal hyperaldosteronism (ovaries, intestines, thyroid gland).

Common to all forms of primary hyperaldosteronism is low plasma renin activity (PRA), and different are the extent and nature of its independence, i.e. the ability to be stimulated as a result of various regulatory effects. The production of aldosterone in response to stimulation or suppression is also differentiated. The "autonomy" of aldosterone hypersecretion is most perfect in aldosteromas (Conn's syndrome). Primary hyperaldosteronism in bilateral adrenal cortex hyperplasia is a complex, heterogeneous group; the pathogenesis of its individual variants has not been clarified in many respects.

Idiopathic hyperaldosteronism (IH) is characterized by relative independence of aldosterone secretion. Thus, a significant increase in intravascular volume (administration of 2 l of isotonic sodium solution for 2 hours) does not reduce the aldosterone level, and a low-sodium diet (10 mmol/24 hours) and the use of active saluretics do not stimulate ARP. Along with this, a change in body position and orthostatic load (4-hour walking), as well as direct effects on the adrenal glands with ACTH, potassium and, especially, angiotensin II increase the secretion of aldosterone, and in some cases, ARP. Most patients with idiopathic hyperaldosteronism do not respond to DOXA administration by reducing aldosterone secretion (unsuppressed hyperaldosteronism), but a small proportion of them retain a normal response to an indirect increase in intravascular volume, and administration of the drug reduces the aldosterone level ("indefinite" aldosteronism). It is possible that the relative autonomy of bilateral hyperplasia, especially adrenal cortex adenomatosis, is the result of previous prolonged stimulation. Hence the validity of such a concept as "secondary-primary" hyperaldosteronism. There are a number of hypotheses regarding the source of stimulation. The influence emanating from the adrenal glands themselves, in particular from the medulla, is not ruled out. It is reported about the isolation from the blood of patients with idiopathic aldosteronism of aldosterone-stimulating factor, which is supposedly synthesized in the intermediate lobe of the pituitary gland, which produces a significant amount of peptide derivatives and proopiomelanocortin - POMC. Their aldosterone-stimulating effect has been proven experimentally. POMC is also a precursor of ACTH synthesized in the anterior lobe. However, if the level of POMC in both lobes is equally stimulated by corticotropin-releasing factor, then the sensitivity of the negative feedback mechanism when administering glucocorticoids is significantly lower on the part of hormonal production of the middle lobe. Although these data initially bring ACTH and the hypothetical aldosterone-stimulating factor of the middle lobe of the pituitary gland closer together, they indicate different pathways of their regulation. It is also known that dopamine and its agonists, which inhibit aldosterone synthesis, suppress hormonal production of the intermediate lobe much more actively than that of the anterior lobe. Along with experimental data on the involvement of the intermediate lobe of the pituitary gland in the pathogenesis of idiopathic hyperaldosteronism, there is also clinical evidence.

The existence of glucocorticoid-dependent primary hyperaldosteronism was first demonstrated by Suterland et al. in 1966. This rare form of bilateral adrenal cortex hyperplasia, which has all the main clinical and biochemical features of primary hyperaldosteronism, including low ARP, occurs predominantly in men, is often hereditary, sometimes traced in three generations and transmitted as an autosomal dominant trait. The absence of an absolute relationship between ACTH and aldosterone secretion creates many unclear points in the pathogenesis of this form, since it demonstrates the reality of control of aldosterone secretion by ACTH. The introduction of the latter causes an increase, and the use of glucocorticoids - a decrease in the aldosterone level in patients with glucocorticoid-dependent aldosteronism. Glucocorticoid-independent forms of aldosterone-producing adenomas of the adrenal cortex are also known.

The action of aldosterone in primary hyperaldosteronism is manifested by its specific influence on the transport of sodium and potassium ions. By binding to receptors located in many secretory organs and tissues (renal tubules, sweat and salivary glands, intestinal mucosa), aldosterone controls and implements the cation exchange mechanism. In this case, the level of secretion and excretion of potassium is determined and limited by the volume of reabsorbed sodium. Hyperproduction of aldosterone, increasing sodium reabsorption, induces potassium loss, which in its pathophysiological effect overlaps the effect of reabsorbed sodium and forms a complex of metabolic disorders underlying the clinical picture of primary hyperaldosteronism.

The general loss of potassium with the depletion of its intracellular reserves leads to universal hypokalemia, and the excretion of chlorine and the replacement of potassium inside cells with sodium and hydrogen contribute to the development of intracellular acidosis and hypokalemic, hypochloremic extracellular alkalosis.

Potassium deficiency causes functional and structural disorders in organs and tissues: the distal renal tubules, smooth and striated muscles, and the central and peripheral nervous system. The pathological effect of hypokalemia on neuromuscular excitability is aggravated by hypomagnesemia due to inhibition of magnesium reabsorption. By suppressing insulin secretion, hypokalemia reduces carbohydrate tolerance, and by affecting the epithelium of the renal tubules, makes them refractory to the effects of ADH. In this case, a number of renal functions are impaired, primarily their concentrating ability is reduced. Sodium retention causes hypervolemia, suppresses the production of renin and angiotensin II, increases the sensitivity of the vascular wall to various endogenous pressor factors, and ultimately contributes to the development of arterial hypertension. In primary hyperaldosteronism caused by both adenoma and hyperplasia of the adrenal cortex, the level of glucocorticoids, as a rule, does not exceed the norm even in cases where the morphological substrate of aldosterone hypersecretion includes not only elements of the glomerular zone, but also the fascicular zone. A different picture is observed in carcinomas, which are characterized by mixed intense hypercorticism, and the variability of the clinical syndrome is determined by the predominance of certain hormones (gluco- or mineralocorticoids, androgens). Along with this, true primary hyperaldosteronism can be caused by highly differentiated cancer of the adrenal cortex with normal production of glucocorticoids.

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Pathological anatomy

Morphologically, at least 6 morphological variants of hyperaldosteronism with low renin levels are distinguished:

1. with adenoma of the adrenal cortex in combination with atrophy of the surrounding cortex;
2. with adenoma of the adrenal cortex in combination with hyperplasia of elements of the glomerular and/or fascicular and reticular zones;
3. due to primary adrenal cortex cancer;
4. with multiple adenomatosis of the cortex;
5. with isolated diffuse or focal hyperplasia of the glomerular zone;
6. with nodular diffuse-nodular or diffuse hyperplasia of all zones of the cortex.

Adenomas, in turn, have a variety of structures, as do changes in the surrounding adrenal tissue. Changes in the adrenal glands of patients with non-neoplastic forms of low-renin hyperaldosteronism are reduced to diffuse or diffuse-nodular hyperplasia of one, two or all zones of the cortex and/or to pronounced phenomena of adenomatosis, in which focal hyperplasia is accompanied by hypertrophy of cells and their nuclei, an increase in the nuclear-plasma ratio, increased oxyphilia of the cytoplasm and a decrease in the lipid content in it. Histochemically, these cells are characterized by high activity of steroidogenesis enzymes and a decrease in the content of cytoplasmic lipids mainly due to cholesterol esters. Nodular formations are formed most often in the fascicular zone, mainly from elements of its outer parts, which form pseudoacinar or alveolar structures. But the cells in the nodular formations have the same functional activity as the cells of the surrounding cortex. Hyperplastic changes lead to a 2-3-fold increase in the adrenal mass and hypersecretion of allyosterone by both adrenal glands. This is observed in more than 30% of patients with hyperaldosteronism and low ARP. The cause of such pathology may be the aldosterone-stimulating factor of pituitary origin isolated in a number of patients with primary hyperaldosteronism, although there is no firm evidence of this.