Addison's disease pathophysiology: Difference between revisions
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{{CMG}} ; {{AE}} {{ADG}} | {{CMG}} ; {{AE}} {{ADG}} | ||
==Overview== | ==Overview== | ||
The [[hypothalamus]] releases [[corticotropin-releasing hormone]] (CRH), which stimulates the [[pituitary gland]] to release [[ | 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== | ||
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*[[ACTH]], in turn, acts on the [[adrenal cortex]], which produces [[glucocorticoid]] [[Hormone|hormones]] (mainly [[cortisol]] in humans). | *[[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). | *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| | [[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=== | ||
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| | | | ||
* Maintains [[blood pressure]], [[Fluid and electrolytes|fluid and electrolyte]] balance in the body by helping the [[kidney]] retain [[sodium]] and [[excrete]] [[potassium]] | * 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 | 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> | ||
{| class="wikitable" | {| class="wikitable" | ||
! | !Mechanism of adrenal insufficiency | ||
!Definition | !Definition | ||
!Pathophysiology | !Pathophysiology | ||
|- | |- | ||
|Adrenal dysgenesis | |[[Adrenal gland|Adrenal]] [[dysgenesis]] | ||
|Gland | |Gland does not form adequately during development | ||
| | | | ||
* [[genetic mutation|Mutations]] | * [[genetic mutation|Mutations]] of the ''SF1'' [[transcription factor]], [[X-linked adrenal hypoplasia congenita|congenital adrenal hypoplasia]] (AHC) due to ''DAX-1'' [[gene]] [[mutations]] | ||
* 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 with [[glycerol kinase]] deficiency with a number of other symptoms when ''DAX-1'' is deleted together with a number of other genes | * ''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 | |Impaired [[steroidogenesis]] | ||
| | | | ||
* The gland is present but is biochemically unable to produce cortisol | * The [[gland]] is present but is [[Biochemical|biochemically]] unable to produce [[cortisol]] | ||
* To form cortisol, the adrenal gland requires [[cholesterol]], which is then converted biochemically into steroid hormones | * To form [[cortisol]], the [[adrenal gland]] requires [[cholesterol]], which is then converted [[Biochemical|biochemically]] into [[steroid hormones]] | ||
* Interruptions in the delivery of cholesterol | * Interruptions in the delivery of [[cholesterol]] | ||
| | | | ||
* [[Smith-Lemli-Opitz syndrome]] and [[abetalipoproteinemia]]. | * [[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 | * [[Lipoid congenital adrenal hyperplasia]] due to a deficiency of [[steroidogenic acute regulatory protein]] [[Steroidogenic acute regulatory protein|StAR]] and [[mitochondrial DNA]] [[mutations]] | ||
|- | |- | ||
|Adrenal destruction | |[[Adrenal gland|Adrenal]] destruction | ||
| | | | ||
*Disease processes leading to the gland being damaged | *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 | *[[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) | ||
*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]]) | *[[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]]) | |||
|} | |} | ||
==Genetics== | ==Genetics== | ||
*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> | *[[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 | *Common [[genetic]] conditions associated with Addison's diseases include: | ||
**Familial glucocorticoid insufficiency | **Familial [[glucocorticoid]] insufficiency (associated with a recessive gene pattern) | ||
**Adrenomyeloneuropathy is known to be X-linked | **[[Adrenomyeloneuropathy]] is known to be [[X-linked]] | ||
*Addison disease is associated with a variety of autoimmune conditions that have been linked to genetic factors. | *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 | *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]] | |||
==Associated conditions== | ==Associated conditions== | ||
Addison's disease is commonly seen associated with conditions such as: | 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 hypoparathyroidism resulting in hypocalcemia | *[[Autoimmune polyendocrine syndrome]] | ||
*Vitiligo | *[[Autoimmune]] [[hypoparathyroidism]] resulting in [[hypocalcemia]] | ||
*Premature ovarian failure | *[[Vitiligo]] | ||
*Pernicious anemia | *[[Premature ovarian failure]] | ||
*Myasthenia gravis | *[[Pernicious anemia]] | ||
*Chronic candidiasis | *[[Myasthenia gravis]] | ||
*Sjögren syndrome | *[[Candidiasis|Chronic candidiasis]] | ||
*Chronic active hepatitis | *[[Sjögren's syndrome|Sjögren syndrome]] | ||
*Diabetes mellitus type 1 | *[[Chronic active hepatitis]] | ||
*Hypothyroidism | *[[Diabetes mellitus type 1]] | ||
*Hashimoto thyroiditis | *[[Hypothyroidism]] | ||
*Graves hyperthyroidism | *[[Hashimoto's thyroiditis|Hashimoto thyroiditis]] | ||
*Adrenoleukodystrophy | *[[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
- 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).
.png)
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 |
|
|
Genetics
- Hereditary factors sometimes play a key role in the development of autoimmune adrenal insufficiency.[5]
- 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 polyglandular failure might develop diabetes mellitus, pernicious anemia, and hypothyroidism secondary to antibodies which develop against the adrenal glands.
Associated conditions
Addison's disease is commonly seen associated with conditions such as:[6]
- Autoimmune polyendocrine syndrome
- 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
References
- ↑ 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.
- ↑ 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.
- ↑ SMART GA (1953). "Addison's disease". Postgrad Med J. 29 (330): 200–7. PMC 2500363. PMID 13055541.
- ↑ 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.
- ↑ 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.
- ↑ 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.