Julio Libman, Astrid M. Libman and Alberto J. Muniagurria
Primary hyperaldosteronism is designated as the clinical picture determined by the excessive production of aldosterone, the cause of which lies in the adrenal cortex itself. This is different from what occurs in secondary hyperaldosteronism, where the determining stimulus for increased aldosterone production is extraadrenal in origin.
Mineralocorticoids, whose prototype in the human species is aldosterone, are steroids produced in the glomerular zone of the adrenal cortex, whose fundamental function is the regulation of electrolyte metabolism. Aldosterone secretion is regulated by four mechanisms, of different physiological importance, namely: 1) The renin-angiotensin system; 2) serum K +; 3) ACTH and 4) prostaglandins.
1. The main one of them is constituted by the renin-angiotensin system. Juxtaglomerular cells of the kidney, the site of renin formation, probably act as baroreceptors sensitive to changes in intraluminal, arterial, and interstitial pressure gradients secondary to changes in effective plasma volume. Renin secretion is stimulated when there is a decrease in the perfusion pressure of the juxtaglomerular apparatus. The decrease in the Na + concentration of the renal tubular fluid at the level of the macula densa and the sympathetic system also stimulates the secretion of renin; thus propanolol, a -blocker drug, inhibits its secretion in the normal individual. Renin is an enzyme that, released into the circulation, acts on angiotensinogen or renin substrate, a -globulin produced in the liver, to form a decapeptide, angiotensin. This is converted by an enzyme in the lung into a biologically active octapeptide, angiotensin II, a powerful vasoconstrictor and a powerful stimulus for aldosterone secretion. The vasoconstrictor action acts immediately to raise blood pressure, and the stimulating action of aldosterone production favors Na + retention, with expansion of the extracellular volume, which in turn tends to inhibit renin secretion, the generation of angiotensin and aldosterone secretion, constituting an example of a long-loop negative feedback system. powerful vasoconstrictor and powerful stimulus for aldosterone secretion. The vasoconstrictor action acts immediately to raise blood pressure, and the stimulating action of aldosterone production favors Na + retention, with expansion of the extracellular volume, which in turn tends to inhibit renin secretion, the generation of angiotensin and aldosterone secretion, constituting an example of a long-loop negative feedback system. powerful vasoconstrictor and powerful stimulus for aldosterone secretion. The vasoconstrictor action acts immediately to raise blood pressure, and the stimulating action of aldosterone production favors Na + retention, with expansion of the extracellular volume, which in turn tends to inhibit renin secretion, the generation of angiotensin and aldosterone secretion, constituting an example of a long-loop negative feedback system.
2. The concentration of K + is an important factor in the regulation of aldosterone production, and acts directly on the adrenal cortex. Aldosterone secretion decreases during K + depletion and increases with K + overload, stimulating one of the first steps in its biosynthesis. This is an important physiological concept, since hypokalemia is a frequent finding in primary hyperaldosteronism, which under normal circumstances should, on the contrary, produce an inhibition of aldosterone secretion. Furthermore, in some cases of primary hyperaldosteronism, hypokalemia can reduce aldosterone production, making diagnosis difficult.
3. ACTH directly stimulates the synthesis and secretion of aldosterone in the human species; This effect is self-limited to a few days, perhaps because ACTH favors the transformation of glomerular zone cells into fascicular cells, incapable of forming aldosterone due to the lack of 18-hydroxysteroid dehydrogenase, an enzyme that catalyzes the final step of its synthesis.
4. Plasma aldosterone increases after intravenous administration of A series prostaglandins. These would mediate the stimulating action of hypovolemia and Na + depletion.
Aldosterone plasma concentrations tend to be higher in the morning hours, and are higher in the upright position than in the supine position. It circulates free for the most part, being loosely bound to plasma proteins by 30%. Aldosterone increases the distal tubular reabsorption of Na + and the excretion of K +, H +, Mg, and ammonia. Although not vitally important, it also influences the electrolyte concentration in salivary, sweat, and gastrointestinal secretions. As a consequence of Na + retention, there is an expansion in the volume of the extracellular fluid, with an increase in renal plasma flow and glomerular filtration. In response to these changes, renin production decreases. Following a period of several days of Na + retention and intravascular volume expansion, the secretion of atrial natriuretic hormone is stimulated and the kidney "escapes" the action of retention of Na +, persisting the excretory effect of K +. After a period of positive Na + balance, there is no more renal retention of this ion due to an appreciable decrease in its reabsorption in the proximal portion of the renal tubule, not influenced by aldosterone. Consequently, patients with primary hyperaldosteronism do not have edema, whereas persistent hypokalemia and low plasma renin activity are characteristic findings. Hypertension is associated with increased body Na + content and expansion of vascular volume. Most of the aldosterone produced is metabolized in the liver and the metabolic products are excreted by the kidney.
Symptoms and signs
Three types of primary hyperaldosteronism have been identified, two of which are the most common, comprising more than 95% of patients. The classic type, which presents the most defined characteristics, is the aldosterone-producing adenoma, constituting Conn's syndrome. The second form is idiopathic bilateral nodular hyperplasia. Glucocorticoid-correctable hyperaldosteronism is much less common than the previous two. Continued hypersecretion of aldosterone increases Na + and K + exchange in the distal tubule, with Na + retention, increased blood volume, and arterial hypertension. Headache is common. The increase in urinary K + produces hypokalemia and cellular K + depletion, causing muscle weakness and fatigue, as well as cardiac arrhythmias. Electrocardiographic signs of K + depletion, such as the appearance of prominent U waves and extrasystoles, are not uncommon. Likewise, polyuria, due to a decrease in the tubular concentration capacity and frequently associated with polydipsia, and metabolic alkalosis with production of tetany due to a decrease in ionic Ca ++ due to its greater binding to proteins are also attributable to the K + deficiency.
Hypokalemia decreases insulin secretion by the cells of the pancreas and can be the cause of diabetes or impaired glucose tolerance, which are seen in approximately 50% of patients.
The presence of hypokalemia associated with increased excretion of K in the urine should suggest the diagnosis of primary hyperaldosteronism.
The more specific tests for the diagnosis of primary hyperaldosteronism include:
Quantification of plasma renin activity (PRA), basal and stimulated. This test does not directly quantify plasma renin levels, but rather measures the rate of angiotensin formation by the action of renin present under controlled laboratory conditions. PRA is low or not detectable in primary hyperaldosteronism, even under maximal stimulus conditions, determined by acute furosemide-induced volume depletion or slower by dietary salt restriction. As a stimulus for the determination of PRA, a diet low in Na + (10 to 20 mEq per day) for 5 days is suggested, with quantification of PRA on the 6th day after maintaining the orthostatic position for 60 minutes. A rapid test can be done by administering 80 mg of furosemide orally and maintaining an upright position for 4 hours. It is important to remember that 25% of the population with essential hypertension have a decreased PRA without presenting primary hyperaldosteronism. On the other hand, the measurement of PRA allows a clear differentiation between primary and secondary hyperaldosteronism, which is accompanied by an increased production of renin.
Plasma aldosterone dose by radioimmunoassay .The availability of a radioimmunoassay to determine plasma aldosterone allowed the development of a rapid suppression test with intravenous saline. This test requires prior normalization of plasma K + levels, and should not be performed if the patient has heart failure or severe hypertension with a diastolic pressure greater than 115 mm Hg. Plasma aldosterone in normal individuals and in most hypertensive individuals, including those with secondary hyperaldosteronism, decreases rapidly after infusion of 2000 ml of normal saline over 4 hours. The test is performed with the patient resting, and the combination of the supine position and the expansion of the circulating volume should decrease the aldosterone to less than 8 ng / dl at the end of the infusion.
Urinary Aldosterone Elimination . The finding of increased aldosterone excretion in the presence of a large Na intake confirms the diagnosis of hyperaldosteronism. The excretion rate remains parallel to that of production, representing approximately 10% of it. With a diet rich in Na + (> 150 mEq per day), the excretion of aldosterone should be less than 20 ug in 24 hours. Urinary Na + should be at least 150 mEq daily during the test period.
Studies to determine the etiology of primary hyperaldosteronism.
Computed axial tomography . It allows to locate adenomas of more than 1 cm in diameter. The non-invasive nature and easy availability of this test are obvious advantages.
Catheterization of both adrenal veins and simultaneous phlebography through percutaneous transfemoral catheterization . In the presence of a unilateral adenoma, aldosterone levels on the affected side can reach up to 15,000 ng / dl. In normal individuals in the supine position, the values range between 100 and 450 ng / ml. The relationship between both adrenal veins is more important than the absolute values. Most patients with idiopathic bilateral nodular hyperplasia have bilateral augmentations with similar numbers. Venography makes it possible to locate adenomas larger than 1 cm in diameter, doing so in approximately two thirds of cases.
Adrenal scintigraphy with I131 6-iodomethyl-19-norcholesterol. After administration for 7 days of 0.5 mgs of dexamethasone every 6 hours, the existence of an asymmetric uptake is compatible with the presence of an adenoma, while bilateral uptake favors the diagnosis of hyperplasia.
When should primary hyperaldosteronism be suspected and what diagnostic steps should be taken? Primary hyperaldosteronism should be considered in the presence of arterial hypertension associated with one or more of the following manifestations: asthenia, tetany, polyuria, carbohydrate intolerance, hypokalemia, absolute or relative hyperkaliuria, eventually hypernatremia and metabolic alkalosis. The existence of a low plasma renin activity that does not respond to volume depleting stimuli, and a plasma aldosterone that is not suppressed by plasma volume expansion confirm the diagnosis.
CT combined with adrenal scintigraphy and / or catheterization of the adrenal veins with simultaneous transfemoral venography allows to differentiate an adenoma from a bilateral idiopathic nodular hyperplasia.