Hypoaldosteronism

Excerpt

Hypoaldosteronism (HA) is a condition marked by decreased synthesis or diminished release of aldosterone (ALD) from the zona glomerulosa of the adrenal glands, or resistance to its action on target tissues. In conditions of resistance, aldosterone levels are often elevated and termed pseudo-hypoaldosteronism.

Recent advances have unraveled the mechanisms involved in the synthesis, release, and action of aldosterone on target organs. It is important first to understand these concepts to comprehend abnormalities in related diseases. The zona glomerulosa (ZG), which is the outermost layer of the adrenal cortex, is unique in possessing the key gene (CYP11B2) and enzyme (aldosterone synthase) for ALD synthesis which are absent from the other layers of the adrenal cortex. Likewise, the ZG is deficient in the machinery (CYP17 gene and related enzymes) for cortisol synthesis (see image 2).

ACTH and other neuropeptides play a less important role, while potassium (K+) and angiotensin II (Ang II) are the principal regulators of aldosterone. K+ regulates ALD independent of Ang II. The renin-angiotensin-aldosterone (RAA) axis is a feedback system that tightly regulates sodium (Na), K+, water, extracellular compartment fluid (ECF) volume, and blood pressure. A drop in perfusion will trigger the cells of the macula densa of the juxtaglomerular apparatus to secrete renin, which cleaves the hepatocyte derived protein angiotensinogen to angiotensin I (Ang I). Angiotensin-converting enzyme (ACE) in the vascular endothelium converts Ang I to Ang II, which is the most potent stimulus for aldosterone production and release.

Amiloride sensitive sodium channels are located in the distal renal tubular and collecting duct epithelial cells (ENaC). They are composed of three subunits alfa, beta, and gamma. Aldosterone mediates both genomic (ENaC gene transcription) and non-genomic (decreased ENaC degradation and hence enhanced surface expression of ENaC) effects through the mineralocorticoid receptor (MR) belonging to the family of intracellular nuclear receptors. The ENaC facilitates passive energy independent Na reabsorption. Apart from the kidneys, MR is present in the epithelia of the distal colon, sweat glands, salivary glands, airways, eyes, and nonepithelial cardiovascular and central nervous tissues.

Both cortisol and aldosterone have an equal affinity to the MR. Although cortisol levels are much higher, the 11beta HSD2 in renal tubules converts active cortisol to inactive cortisone, thereby allowing aldosterone to dominate receptor binding.