Addison's disease pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Normal Physiology of Adrenal Glands

Hypothalamic–pituitary–adrenal axis

• The paraventricular nucleus of the hypothalamus, secrete corticotropin-releasing hormone (CRH).
• It stimulates the anterior lobe of the pituitary gland. to secrete adrenocorticotropic hormone (ACTH)
• ACTH, in turn, acts on the adrenal cortex, which produces glucocorticoid hormones (mainly cortisol in humans) in response to stimulation by ACTH.
• Glucocorticoids in turn act back on the hypothalamus and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle.

Cortisol

Harmone	Type of class	Function
Cortisol	Glucocorticoids	Helps maintain blood pressure and cardiovascular function Helps slow the immune system's inflammatory response Helps balance the effects of insulin in breaking down sugar for energy Helps regulate the metabolism of proteins, carbohydrates, and fats Helps maintain proper arousal and sense of well-being
Aldosterone	Mineralocorticoids	Maintain blood pressure and water and salt 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 of the hormone cortisol and, in some cases, the hormone aldosterone. The disease is also called adrenal insufficiency, or hypocortisolism. Causes of adrenal insufficiency can be grouped by the way in which they cause the adrenals to produce insufficient cortisol. These are adrenal dysgenesis (the gland has not formed 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).

Adrenal dysgenesis	gland has not formed adequately during development	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	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). Lipod CAH is due to a deficiency of StAR and mitochondrial DNA mutations.
Adrenal destruction	disease processes leading to the gland being damaged

Adrenal dysgenesis

All causes in this category are genetic, and generally very rare. These include mutations to the SF1 transcription factor, congenital adrenal hypoplasia (AHC) due to DAX-1 gene mutations and 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

To form cortisol, the adrenal gland requires cholesterol, which is then converted biochemically into steroid hormones. Interruptions in the delivery of cholesterol include 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). Lipod CAH is due to a deficiency of StAR and mitochondrial DNA mutations.

Adrenal destruction

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. This may be isolated or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2). 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).

Symptoms	Pathophysiology
Hyperpigmentation	Stimulant effect of excess ACTH on the melanocytes to produce melanin
Dizziness with orthostasis	Volume depletion, loss of the mineralocorticoid effect of aldosterone, Loss of the permissive effect of cortisol in enhancing the vasopressor effect of the catecholamines.
Myalgias and flaccid muscle paralysis	Hyperkalemia
Amenorrhea	Combined effect of weight loss and chronic ill health or secondary to premature autoimmune ovarian failure

References