Addison's disease pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Overview

The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release corticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Addison's disease results when the adrenal glands do not produce enough cortisol and aldosterone.

Normal Physiology of Adrenal Glands

Hypothalamic–pituitary–adrenal axis

• The paraventricular nucleus of the hypothalamus secretes corticotropin-releasing hormone (CRH).
• CRH stimulates the anterior lobe of the pituitary gland, which leads to the release of adrenocorticotropic hormone (ACTH)
• ACTH, in turn, acts on the adrenal cortex, which produces glucocorticoid hormones (mainly cortisol in humans).
• Glucocorticoids, in addition to having physiological functions in the body, also have a negative feedback effect on the hypothalamus and pituitary (suppression of CRH and ACTH production).

Cortisol

Harmone	Type of class	Function
Cortisol	Glucocorticoids	Helps maintain blood pressure and cardiovascular function Reduces inflammatory response Helps balance the effects of insulin by increasing blood glucose level Helps regulate the metabolism of proteins, carbohydrates, and fats Helps maintain proper arousal and sense of well-being
Aldosterone	Mineralocorticoids	Maintains blood pressure, fluid and electrolyte balance in the body by helping the kidney retain sodium and excrete potassium

Pathophysiology

Addison's disease occurs when the adrenal glands do not produce enough cortisol and, in some cases, aldosterone. Adrenal insufficiency may arise due to insufficient release of cortisol from the adrenal glands. Insufficient cortisol secretion may be due to adrenal dysgenesis (the gland does not form adequately during development), impaired steroidogenesis (the gland is present but is biochemically unable to produce cortisol) or adrenal destruction (disease processes leading to the gland being damaged).

Mechanism of adrenal insufficiency	Definition	Pathophysiology
Adrenal dysgenesis	Gland does not form adequately during development	Mutations of the SF1 transcription factor, congenital adrenal hypoplasia (AHC) due to DAX-1 gene mutations Mutations of the ACTH receptor gene (or related genes, such as in the Triple A or Allgrove syndrome) DAX-1 mutations may cluster in a syndrome alongwith glycerol kinase deficiency with a number of other symptoms when DAX-1 is deleted together with a number of other genes.
Impaired steroidogenesis	The gland is present but is biochemically unable to produce cortisol To form cortisol, the adrenal gland requires cholesterol, which is then converted biochemically into steroid hormones Interruptions in the delivery of cholesterol	Smith-Lemli-Opitz syndrome and abetalipoproteinemia. Of the synthesis problems, congenital adrenal hyperplasia is the most common (in various forms: 21-hydroxylase, 17α-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase). Lipoid congenital adrenal hyperplasia is due to a deficiency of StAR and mitochondrial DNA mutations.
Adrenal destruction	Disease processes leading to the gland being damaged	Autoimmune destruction of the adrenal cortex (often due to antibodies against the enzyme 21-Hydroxylase) is a common cause of Addison's in teenagers and adults. Adrenal destruction is also a feature of adrenoleukodystrophy (ALD), and when the adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body), hemorrhage (e.g. in Waterhouse-Friderichsen syndrome or antiphospholipid syndrome), particular infections (tuberculosis, histoplasmosis, coccidioidomycosis), and deposition of abnormal protein in amyloidosis occurs. Some medications interfere with steroid synthesis enzymes (e.g. ketoconazole), while others accelerate the normal breakdown of hormones by the liver (e.g. rifampicin, phenytoin).

Genetics

• Hereditary factors sometimes play a key role in the development of autoimmune adrenal insufficiency.
• Common genetic conditions associated with addison's diseases include:
  • Familial glucocorticoid insufficiency may be associated with a recessive gene pattern.
  • Adrenomyeloneuropathy is known to be X-linked
• Addison disease is associated with a variety of autoimmune conditions that have been linked to genetic factors.
• Patients with autoimmune polyglandular failure might develop diabetes mellitus, pernicious anemia, and hypothyroidism secondary to antibodies which develop in adrenal glands.

Associated conditions

Addison's disease is commonly seen associated with conditions such as:

• Autoimmune hypoparathyroidism resulting in hypocalcemia
• Vitiligo
• Premature ovarian failure
• Pernicious anemia
• Myasthenia gravis
• Chronic candidiasis
• Sjögren syndrome
• Chronic active hepatitis
• Diabetes mellitus type 1
• Hypothyroidism
• Hashimoto thyroiditis
• Graves hyperthyroidism
• Adrenoleukodystrophy