Addison's disease pathophysiology: Difference between revisions

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Revision as of 19:36, 14 July 2017

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. 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).

Causes	Definition	Pathophysiology
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	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).

References

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 {| class="wikitable"
-!
+!Causes
-!
+!Definition
-!
+!Pathophysiology
-!
 |-
 |Adrenal dysgenesis
-|gland has not formed adequately during development
+|Gland has not formed adequately during development
 |
 * [[genetic mutation|Mutations]] to the ''SF1'' [[transcription factor]], [[X-linked adrenal hypoplasia congenita|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 syndrome|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
@@ Line 67: / Line 65: @@
 * Of the synthesis problems, [[congenital adrenal hyperplasia]] is the most common (in various forms: [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase]], [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency|17α-hydroxylase]], [[Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency|11β-hydroxylase]], and [[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|3β-hydroxysteroid dehydrogenase]]).
 * [[Lipoid congenital adrenal hyperplasia|Lipod CAH]] is due to a deficiency of [[Steroidogenic acute regulatory protein|StAR]] and [[mitochondrial DNA]] mutations.
-|
 |-
 |Adrenal destruction
@@ Line 76: / Line 73: @@
 *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 [[infection]]s ([[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]]).
-|
 |}
-===Adrenal dysgenesis===
-All causes in this category are genetic, and generally very rare. These include [[genetic mutation|mutations]] to the ''SF1'' [[transcription factor]], [[X-linked adrenal hypoplasia congenita|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 syndrome|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: [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase]], [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency|17α-hydroxylase]], [[Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency|11β-hydroxylase]], and [[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|3β-hydroxysteroid dehydrogenase]]). [[Lipoid congenital adrenal hyperplasia|Lipod CAH]] is due to a deficiency of [[steroidogenic acute regulatory protein|StAR]] and [[mitochondrial DNA]] mutations.
-===Adrenal destruction===
-[[Autoimmunity|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 [[infection]]s ([[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]]).
 ==References==