Hypoaldosteronism pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR

[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Hypoaldosteronism is defined as decreased levels of the hormone aldosterone (Normal range: 1-21 ng/dL). Hypoaldosteronism from decreased aldosterone synthesis can be due to :

• Adrenal Insufficiency: Primary or secondary
• Enzyme deficiency: Aldosterone synthase, 21 hydroxylase, and 11B hydroxylase
• Renal disorders: Chronic renal failure and diabetic nephropathy
• Drugs inhibiting aldosterone effect: NSAID, spironolactone, and triamterene

Adrenal insufficiency

Hypoaldosteronism from primary adrenal insufficiency or Addison's disease occurs when the adrenal glands do not produce sufficient cortisol and aldosterone. The cause of adrenal insufficiency can be:

• Adrenal dysgenesis: In adrenal dysgenesis the adrenal gland is not formed adequately during development. It can be due to
  • Mutations to the SF1 transcription factor, congenital adrenal hypoplasia (AHC) due to DAX-1 gene mutations
  • Mutations to the ACTH receptor gene (or related genes, such as in the Triple A or Allgrove syndrome)
  • DAX-1 mutations may cluster in a syndrome with glycerol kinase deficiency with a number of other symptoms when DAX-1 is deleted together with a number of other genes.

• Impaired steroidogenesis: In impaired steroidogenesis the adrenal gland is present but is biochemically unable to produce mineralocorticoid and glucocorticoid. It can be due to
  • Defect in cholesterol synthesis seen in conditions such as Smith-Lemli-Opitz syndrome and abetalipoproteinemia
  • Enzyme deficiencies such as 21-hydroxylase, 17α-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase
• Adrenal destruction: Disease processes leading to destruction of adrenal gland. It can be due to:
  • Autoimmune destruction of the adrenal cortex
  • Adrenoleukodystrophy (ALD)
  • Metastasis to adrenal glands
  • Hemorrhage as seen in Waterhouse-Friderichsen syndrome and antiphospholipid syndrome
  • Infections such as tuberculosis, histoplasmosis, and coccidioidomycosis
  • Amyloidosis

Secondary adrenal insufficiency

Hypoaldosteronism from secondary adrenal insufficiency is seen with hypothalamic disorders, panhypopituitarism, enzymatic defect in ACTH production, and high dose corticosteroid for > 4 weeks

Isolated Hypoaldosteronism

In isolated hypoaldosteronism, there is selective deficiency of aldosterone with normal cortisol production. Isolated hypoaldosteronism may result from dysfunction of zona glomerulosa or enzyme deficiencies. Enzyme deficiency such as aldosterone synthase results from mutation in genes encoding for aldosterone synthase.

Secondary Isolated Hypoaldosteronism

Hyperreninemic hypoaldosteronism is seen in patients with severe illness such as sepsis, malignancy, heart failure, and liver cirrhosis. During these stress inducing conditions, there occurs increased level of ACTH and cortisol. Under normal conditions, continuous ACTH secretion for > 96 hours leads to suppression of aldosterone synthase activity. Thus, chronically ill patients with prolonged ACTH secretion (>96 hours) have impaired aldosterone synthase activity and decreased levels of aldosterone. In response, the kidneys via its neurohormonal regulation leads to increased levels of renin and hence the term hyperreninemic hypoaldosteronism. In addition, cytokine release from chronic illness and increased levels of atrial natriuretic peptide (in patients with heart failure) also have an inhibitory effect on zona glomerulosa.

Pathophysiology

Pathogenesis

• The exact pathogenesis of [disease name] is not fully understood.

OR

• It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
• [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
• Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
• [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
• The progression to [disease name] usually involves the [molecular pathway].
• The pathophysiology of [disease/malignancy] depends on the histological subtype.

Genetics

• Gene involved in the pathogenesis of hypoaldosteronism include mutation in CYP11B2 gene, which is located on chromosome 8q24.
• Mutation in CYP11B2 gene is transmitted in autosomal recessive pattern.
• The CYP11B2 gene encodes for the enzyme aldosterone synthase (previously known as corticosterone methyloxidase).
• Aldosterone synthase catalyses the conversion of 11 Deoxycorticosterone to aldosterone

11 Deoxycorticosterone

Corticosterone

18 Hydroxycorticosterone

Aldosterone

• Mutations in CYP11B2 can lead to:
  • Type 1 aldosterone synthase deficiency: Patients have normal to decreased levels of 18-hydroxycorticosterone and undetectable levels of aldosterone.
  • Type 2 aldosterone synthase deficiency: Patients have increased levels of 18-hydroxycorticosterone and normal to decreased levels of aldosterone.
• Aldosterone synthase is a member of the cytochrome P450 family of enzymes.

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].