Causes and pathogenesis of primary hyperaldosteronism

There are following etiopathic and clinical and morphological signs of primary hyperaldosteronism (E. G. Biglieri, JD Baxter, modification).

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

Common to all forms of primary hyperaldosteronism is the low activity of renin in plasma (ARP), and different - the measure and the nature of its independence, that is, the ability to stimulate as a result of various regulatory effects. The production of aldosterone in response to stimulation or suppression is also differentiated . "Autonomy" of hypersecretion of aldosterone is most perfect in aldosteromas (Connes syndrome). A complex, heterogeneous group is the primary hyperaldosteronism in bilateral hyperplasia of the adrenal cortex, the pathogenesis of its individual variants is largely undefined.

Idiopathic hyperaldosteronism (IG) is characterized by a relative independence of the secretion of aldosterone. Thus, a significant increase in the intravascular volume (administration of 2 liters of isotonic sodium solution for 2 hours) does not reduce the level of aldosterone, and a diet with a low sodium content (10 mmol / 24 hours) and intake of active saluretics does not stimulate APP. Along with this, changes 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 the introduction of DOXA by a decrease in aldosterone secretion (unsuppressed hyperaldosteronism), but a small proportion of them retain a normal response to an indirect increase in intravascular volume, and the introduction of the drug reduces the level of aldosterone ("vague" aldosteronism). It is possible that the relative autonomy of bilateral hyperplasia, especially adenomatosis of the adrenal cortex, is the result of previous long-term 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 coming from the adrenal glands, in particular from the medulla, is not rejected. The aldosterone-stimulating factor is isolated from the blood of patients with idiopathic aldosteronism, which is presumably synthesized in the intermediate lobe of the pituitary gland, which produces a significant amount of peptide derivatives and proopiome-lanocortin-POMC. Their aldosterone-stimulating effect has been proved experimentally. PMC is also a precursor and ACTH synthesized in the anterior lobe. However, if the level of POMC in both lobes is equally stimulated by a corticotropin releasing factor, the sensitivity of the negative feedback mechanism when glucocorticoids are administered is significantly lower from the hormonal production of the middle lobe. These data, although initially and bring together ACTH and hypothetical aldosterone stimulating factor of the middle part of the pituitary gland, however, indicate different ways of their regulation. It is also known that dopamine and its agonists, which inhibit the synthesis of aldosterone, significantly suppress the hormonal production of the intermediate lobe, rather than the anterior one. Along with experimental data on the involvement of the intermediate portion of the pituitary gland in the pathogenesis of idiopathic hyperaldosteronism, there are also clinical evidence.

The existence of glucocorticoid-dependent primary hyperaldosteronism was first shown by Suter-land 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 . Absence of absolute dependence between ACTH and aldosterone secretion creates many unclear moments in the pathogenesis of this form, as it demonstrates the reality of controlling the secretion of aldosterone from ACTH. The introduction of the latter causes a rise, and the use of glucocorticoids - a decrease in the level of aldosterone in patients with glucocorticoid-dependent aldosteronism. Glucocorticone-dependent forms of aldosterone-producing adrenal adrenal cortex are also known.

The action of aldosterone in primary hyperaldosteronism is manifested by its specific effect on the transport of sodium and potassium ions. Linking to receptors located in many secretory organs and tissues (tubules of the kidneys, sweat and salivary glands, intestinal mucosa), aldosterone controls and realizes 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, enhancing the reabsorption of sodium, induces a loss of potassium, which in its pathophysiological effect overlaps the effect of reabsorbed sodium and forms a complex of metabolic disorders underlying the clinic of primary hyperaldosteronism.

The total loss of potassium with the depletion of its intracellular stores leads to universal hypokalemia, and the excretion of chlorine and the replacement of potassium within cells by sodium and hydrogen contribute to the development of intracellular acidosis and hypokalemic hypochloraemic extracellular alkalosis.

Potassium deficiency causes functional and structural disorders in organs and tissues: the distal part of the renal tubules, in the smooth and striated muscle, in the central and peripheral nervous system. The pathological effect of hypokalemia on neuromuscular excitability is exacerbated by hypomagnetism as a result of inhibition of magnesium reabsorption. Suppressing the secretion of insulin, hypokalemia reduces tolerance to carbohydrates, and affecting the epithelium of the renal tubules, makes them refractory to the effect of ADH. In this case, a number of renal functions are disrupted, and first of all their concentration capacity decreases. The delay in sodium causes hypervolemia, suppresses the production of renin and angiotensin II, increases the sensitivity of the vascular wall to various endogenous pressor factors and, ultimately, promotes the development of arterial hypertension. When primary hyperaldosteronism, caused by adenoma and hyperplasia of the adrenal cortex, the level of glucocorticoids, as a rule, does not exceed the norm even in cases when the morphological substrate of hypersecretion of aldosterone includes not only the elements of the glomerular zone, but also the bundle. A different picture in carcinomas, which are characterized by mixed intense hypercorticism, and the variability of the clinical syndrome is determined by the prevalence of certain hormones (gluco- or mineralocorticoids, androgens). Along with this, the true primary hyperaldosteronism may be due to the highly differentiated cancer of the adrenal cortex with normal production of glucocorticoids.

[1], [2], [3], [4], [5], [6]

Pathanatomy 

Morphologically, at least 6 morphological variants of hyperaldosteronism with a low level of renin are isolated:

1. with adenoma of the adrenal cortex in combination with the atrophy of the surrounding cortex;
2. with an adenoma of the adrenal cortex in combination with hyperplasia of glomerular and / or bundle and reticular zones;
3. on the basis of primary cancer of the adrenal cortex;
4. with multiple cortical adenomatosis;
5. with isolated diffuse or focal hyperplasia of the glomerular zone;
6. with knot diffuse-nodular or diffuse hyperplasia of all areas of the cortex.

Adenomas in turn - a diverse type of structure, as well as changes in the surrounding adrenal tissue. Changes in the adrenal glands of patients with non-tumorous forms of low-grade hyperaldosteronism are reduced to diffuse or diffusive-nodular hyperplasia of one, two or all of the cortical areas and / or pronounced adenomatosis, in which focal hyperplasia is accompanied by hypertrophy of cells and their nuclei, an increase in nuclear-plasma ratio, cytoplasmic cytoplasm and a decrease in the content of lipids in it. Histochemically, these cells are characterized by a 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 bundle zone, mainly from the elements of its outer parts, which form pseudo-acinar or alveolar structures. But cells in nodular formations have the same functional activity as the cells surrounding their cortex. Hyperplastic changes lead to a 2-3-fold increase in the weight of the adrenal gland and to hypersecretion of alujosterone by both adrenal glands. This is observed in more than 30% of patients with hyperaldosteronism and low ARP. The cause of such a pathology may be aldosterone stimulating factor of a pituitary origin isolated in a number of patients with primary hyperaldosteronism, although there is no solid evidence for this.