Addison's disease pathophysiology: Difference between revisions

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{{Addison's disease}}
{{Addison's disease}}


{{CMG}}
{{CMG}} ; {{AE}} {{ADG}}
==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]]. When the [[adrenal glands]] do not produce enough [[cortisol]] and [[aldosterone]], it results in Addison's disease.


==Normal Physiology of Adrenal Glands==
==Normal Physiology of Adrenal Glands==
[[Image:HPA Axis Diagram (Brian M Sweis 2012).png|center|500px]]
===Hypothalamic–pituitary–adrenal axis===
*The [[paraventricular nucleus]] of the [[hypothalamus]] [[Secrete|secretes]] [[corticotropin-releasing hormone]] ([[CRH]]).
*[[Corticotropin-releasing hormone|CRH]] stimulates the anterior lobe of the [[pituitary gland]], which leads to the release of [[adrenocorticotropic hormone]] ([[Adrenocorticotropic hormone|ACTH]])
*[[ACTH]], in turn, acts on the [[adrenal cortex]], which produces [[glucocorticoid]] [[Hormone|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 gland|pituitary]] (suppression of [[Corticotropin-releasing hormone|CRH]] and [[ACTH]] production).
[[Image:HPA Axis Diagram (Brian M Sweis 2012).png|center|frame|Source: By BrianMSweis (Own work) [CC BY-SA 3.0 (<nowiki>http://creativecommons.org/licenses/by-sa/3.0</nowiki>)], via Wikimedia Commons]]


===Cortisol===
===Cortisol===
Cortisol is normally produced by the [[adrenal glands]], which are located just above the [[kidneys]]. It belongs to a class of hormones called [[glucocorticoids]], which affect almost every organ and tissue in the body. Scientists think that cortisol possibly has hundreds of effects in the body. Cortisol's most important job is to help the body respond to stress. Among its other vital tasks, cortisol;
{| class="wikitable"
 
!Harmone
* Helps maintain blood pressure and cardiovascular function
!Type of class
* Helps slow the immune system's inflammatory response
!Function
* Helps balance the effects of [[insulin]] in breaking down sugar for energy
|-
* Helps regulate the metabolism of [[proteins]], [[carbohydrates]], and [[fats]]
|[[Cortisol]]
* Helps maintain proper arousal and sense of well-being
|[[Glucocorticoids]]
 
|
Because cortisol is so vital to health, the amount of cortisol produced by the adrenals is precisely balanced. Like many other hormones, cortisol is regulated by the brain's [[hypothalamus]] and the [[pituitary gland]], a bean-sized organ at the base of the brain. First, the hypothalamus sends "releasing hormones" to the pituitary gland. The pituitary responds by secreting hormones that regulate growth, thyroid function, adrenal function, and sex hormones such as [[estrogen]] and [[testosterone]]. One of the pituitary's main functions is to secrete [[ACTH]] ([[adrenocorticotropin]]), a hormone that stimulates the adrenal glands. When the adrenals receive the pituitary's signal in the form of ACTH, they respond by producing cortisol. Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH.
* Helps maintain [[blood pressure]] and [[cardiovascular]] function
 
* Reduces [[inflammatory]] response
===Aldosterone===
* Helps balance the effects of [[insulin]] by increasing [[blood glucose]] level
Aldosterone belongs to a class of hormones called [[mineralocorticoids]], also produced by the adrenal glands. It helps maintain blood pressure and water and salt balance in the body by helping the kidney retain [[sodium]] and excrete [[potassium]]. When aldosterone production falls too low, the kidneys are not able to regulate salt and water balance, causing blood volume and blood pressure to drop.
* 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 electrolytes|fluid and electrolyte]] balance in the body by helping the [[kidney]] retain [[sodium]] and [[excrete]] [[potassium]]
|}


==Pathophysiology==
==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.
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 gland|adrenal]] [[dysgenesis]] (the [[gland]] does not form adequately during development), impaired [[steroidogenesis]] (the [[gland]] is present but is [[Biochemical|biochemically]] unable to produce [[cortisol]]) or [[Adrenal gland|adrenal]] destruction (disease processes leading to the [[gland]] being damaged).<ref name="pmid23633816">{{cite journal |vauthors=Sarkar SB, Sarkar S, Ghosh S, Bandyopadhyay S |title=Addison's disease |journal=Contemp Clin Dent |volume=3 |issue=4 |pages=484–6 |year=2012 |pmid=23633816 |pmc=3636818 |doi=10.4103/0976-237X.107450 |url=}}</ref><ref name="pmid16828409">{{cite journal |vauthors=Nieman LK, Chanco Turner ML |title=Addison's disease |journal=Clin. Dermatol. |volume=24 |issue=4 |pages=276–80 |year=2006 |pmid=16828409 |doi=10.1016/j.clindermatol.2006.04.006 |url=}}</ref><ref name="pmid13055541">{{cite journal |vauthors=SMART GA |title=Addison's disease |journal=Postgrad Med J |volume=29 |issue=330 |pages=200–7 |year=1953 |pmid=13055541 |pmc=2500363 |doi= |url=}}</ref>
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===
{| class="wikitable"
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.
!Mechanism of adrenal insufficiency
!Definition
!Pathophysiology
|-
|[[Adrenal gland|Adrenal]] [[dysgenesis]]
|Gland does not form adequately during development
|
* [[genetic mutation|Mutations]] of the ''SF1'' [[transcription factor]], [[X-linked adrenal hypoplasia congenita|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 syndrome|Triple A]] or [[Allgrove syndrome]])
* ''DAX-1'' [[mutations]] may cluster in a syndrome along 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 [[Biochemical|biochemically]] unable to produce [[cortisol]]
* To form [[cortisol]], the [[adrenal gland]] requires [[cholesterol]], which is then converted [[Biochemical|biochemically]] into [[steroid hormones]]
* Interruptions in the delivery of [[cholesterol]]
|
* [[Smith-Lemli-Opitz syndrome]] and [[abetalipoproteinemia]] <ref name="pmid21274298">{{cite journal |vauthors=Honour JW |title=Diagnosis of diseases of steroid hormone production, metabolism and action |journal=J Clin Res Pediatr Endocrinol |volume=1 |issue=5 |pages=209–26 |year=2009 |pmid=21274298 |pmc=3005746 |doi=10.4274/jcrpe.v1i5.209 |url=}}</ref>
* [[Congenital adrenal hyperplasia]] is 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]] due to a deficiency of [[steroidogenic acute regulatory protein]] [[Steroidogenic acute regulatory protein|StAR]] and [[mitochondrial DNA]] [[mutations]]
|-
|[[Adrenal gland|Adrenal]] destruction
|
*Disease processes leading to the [[gland]] being damaged
|
*[[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
*[[Adrenoleukodystrophy]] (ALD)
*[[Metastasis]] (seeding of [[cancer]] cells from elsewhere in the body)
*[[Hemorrhage]] (e.g. in [[Waterhouse-Friderichsen syndrome]] or [[antiphospholipid syndrome]])
*[[Infections]] ([[tuberculosis]], [[histoplasmosis]], [[coccidioidomycosis]])
*Deposition of abnormal [[protein]] in [[amyloidosis]]
*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]])
|}


===Impaired steroidogenesis===
==Genetics==
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.
*[[Hereditary]] factors sometimes play a key role in the development of [[autoimmune]] adrenal insufficiency.<ref name="pmid20176260">{{cite journal |vauthors=Michels AW, Eisenbarth GS |title=Immunologic endocrine disorders |journal=J. Allergy Clin. Immunol. |volume=125 |issue=2 Suppl 2 |pages=S226–37 |year=2010 |pmid=20176260 |pmc=2835296 |doi=10.1016/j.jaci.2009.09.053 |url=}}</ref>
*Common [[genetic]] conditions associated with Addison's diseases include:
**Familial [[glucocorticoid]] insufficiency (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 polyendocrine syndrome|autoimmune polyglandular failure]] might develop [[diabetes mellitus]], [[pernicious anemia]], and [[hypothyroidism]] secondary to [[antibodies]] which develop against the [[adrenal glands]].
[[Image:Renin-angiotensin-aldosterone system.png|center|frame|Source: By A. Rad (me) (Own work) [GFDL (<nowiki>http://www.gnu.org/copyleft/fdl.html</nowiki>) or CC-BY-SA-3.0 (<nowiki>http://creativecommons.org/licenses/by-sa/3.0/</nowiki>)], via Wikimedia Commons]]


===Adrenal destruction===
==Associated conditions==
[[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]]).
Addison's disease is commonly seen associated with conditions such as:<ref name="pmid7734032">{{cite journal |vauthors=Zelissen PM, Bast EJ, Croughs RJ |title=Associated autoimmunity in Addison's disease |journal=J. Autoimmun. |volume=8 |issue=1 |pages=121–30 |year=1995 |pmid=7734032 |doi=10.1006/jaut.1995.0009 |url=}}</ref>
*[[Autoimmune polyendocrine syndrome]]
*[[Autoimmune]] [[hypoparathyroidism]] resulting in [[hypocalcemia]]
*[[Vitiligo]]
*[[Premature ovarian failure]]
*[[Pernicious anemia]]
*[[Myasthenia gravis]]
*[[Candidiasis|Chronic candidiasis]]
*[[Sjögren's syndrome|Sjögren syndrome]]
*[[Chronic active hepatitis]]
*[[Diabetes mellitus type 1]]
*[[Hypothyroidism]]
*[[Hashimoto's thyroiditis|Hashimoto thyroiditis]]
*[[Graves' disease|Graves hyperthyroidism]]
*[[Adrenoleukodystrophy]]


==References==
==References==

Latest revision as of 20:05, 11 October 2017

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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. When the adrenal glands do not produce enough cortisol and aldosterone, it results in Addison's disease.

Normal Physiology of Adrenal Glands

Hypothalamic–pituitary–adrenal axis

Source: By BrianMSweis (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Cortisol

Harmone Type of class Function
Cortisol Glucocorticoids
Aldosterone Mineralocorticoids

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).[1][2][3]

Mechanism of adrenal insufficiency Definition Pathophysiology
Adrenal dysgenesis Gland does not form adequately during development
Impaired steroidogenesis
Adrenal destruction
  • Disease processes leading to the gland being damaged

Genetics

Source: By A. Rad (me) (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons

Associated conditions

Addison's disease is commonly seen associated with conditions such as:[6]

References

  1. ↑ Sarkar SB, Sarkar S, Ghosh S, Bandyopadhyay S (2012). "Addison's disease". Contemp Clin Dent. 3 (4): 484–6. doi:10.4103/0976-237X.107450. PMC 3636818. PMID 23633816.
  2. ↑ Nieman LK, Chanco Turner ML (2006). "Addison's disease". Clin. Dermatol. 24 (4): 276–80. doi:10.1016/j.clindermatol.2006.04.006. PMID 16828409.
  3. ↑ SMART GA (1953). "Addison's disease". Postgrad Med J. 29 (330): 200–7. PMC 2500363. PMID 13055541.
  4. ↑ Honour JW (2009). "Diagnosis of diseases of steroid hormone production, metabolism and action". J Clin Res Pediatr Endocrinol. 1 (5): 209–26. doi:10.4274/jcrpe.v1i5.209. PMC 3005746. PMID 21274298.
  5. ↑ Michels AW, Eisenbarth GS (2010). "Immunologic endocrine disorders". J. Allergy Clin. Immunol. 125 (2 Suppl 2): S226–37. doi:10.1016/j.jaci.2009.09.053. PMC 2835296. PMID 20176260.
  6. ↑ Zelissen PM, Bast EJ, Croughs RJ (1995). "Associated autoimmunity in Addison's disease". J. Autoimmun. 8 (1): 121–30. doi:10.1006/jaut.1995.0009. PMID 7734032.

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