Cushing's syndrome pathophysiology: Difference between revisions
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{{Cushing's syndrome}} | {{Cushing's syndrome}} | ||
{{CMG}} {{MMF}} | {{CMG}}; {{AE}}{{MMF}} | ||
==Overview== | ==Overview== | ||
Both the [[hypothalamus]] and the [[pituitary gland]] are part of the brain. The hypothalamus releases [[corticotropin-releasing hormone]] (CRH), which stimulates the pituitary gland to release | Both the [[hypothalamus]] and the [[pituitary gland]] are part of the brain. The [[hypothalamus]] releases [[corticotropin-releasing hormone]] (CRH), which stimulates the pituitary gland to release [[adrenocorticotropic hormone]] ([[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]]. Strictly, Cushing's syndrome refers to excess [[cortisol]] of any etiology. One of the causes of Cushing's syndrome is a [[cortisol]] secreting [[adenoma]] in the cortex of the [[adrenal gland]]. The [[adenoma]] causes cortisol levels in the blood to be very high, and negative feedback on the [[pituitary]] from the high cortisol levels causes [[ACTH]] levels to be very low. Cushing's disease refers only to [[hypercortisolism]] secondary to excess production of [[ACTH]] from a [[Corticotrophs|corticotroph]] [[pituitary adenoma]]. This causes the blood [[ACTH]] levels to be elevated along with cortisol from the [[adrenal gland]]. The ACTH levels remain high because a tumor causes the [[pituitary]] to be unresponsive to negative feedback from high [[cortisol]] levels. Cortisol can also exhibit [[mineralcorticoid|mineralocorticoid]] activity in high concentrations, worsening [[hypertension]] and leading to [[hypokalemia]] (common in ectopic ACTH secretion). | ||
==Pathophysiology== | ==Pathophysiology== | ||
=== | ===Mechanism of cortisol secretion=== | ||
Paraventricular nuclei in the hypothalamus | The secretion of cortisol is controlled by hypothalamic-pituitary axis by the following mechanism:<ref name="pmid26004339">{{cite journal |vauthors=Lacroix A, Feelders RA, Stratakis CA, Nieman LK |title=Cushing's syndrome |journal=Lancet |volume=386 |issue=9996 |pages=913–27 |year=2015 |pmid=26004339 |doi=10.1016/S0140-6736(14)61375-1 |url=}}</ref><ref name="pmid25480800">{{cite journal |vauthors=Raff H, Carroll T |title=Cushing's syndrome: from physiological principles to diagnosis and clinical care |journal=J. Physiol. (Lond.) |volume=593 |issue=3 |pages=493–506 |year=2015 |pmid=25480800 |pmc=4324701 |doi=10.1113/jphysiol.2014.282871 |url=}}</ref> | ||
*[[Paraventricular nucleus|Paraventricular nuclei]] in the [[hypothalamus]] release [[Corticotropin-releasing hormone|corticotropin releasing hormone]] (CRH). | |||
CRH is transferred to anterior pituitary via the portal veins | *[[Corticotropin-releasing hormone|CRH]] is transferred to [[anterior pituitary]] via the [[portal veins]]. | ||
*[[CRH]] stimulates the activity of [[corticotrophs]]; cells that produce [[proopiomelanocortin]] (POMC) in the [[anterior pituitary]]. | |||
CRH stimulates the activity of corticotrophs; cells that produce proopiomelanocortin (POMC) in the anterior pituitary | *[[Corticotrophs]] produce [[adrenocorticotropic hormone]] (ACTH) by the post-translational modification of [[Proopiomelanocortin|POMC]]. | ||
*[[Adrenocorticotropic hormone|ACTH]] is drained into systemic circulation via the pituitary capillaries and stimulates the [[adrenal cortex]] ([[zona fasciculata]]) to produce [[cortisol]]. | |||
Corticotrophs produce adrenocorticotropic hormone (ACTH) by the post-translational modification of | *[[Cortisol]] acts on [[hypothalamus]] and [[pituitary]] through a feedback mechanism to regulate the secretion of [[CRH]] and [[ACTH]]. | ||
ACTH is drained into systemic circulation via the pituitary capillaries and stimulates the adrenal cortex to produce cortisol | |||
Cortisol acts on hypothalamus and pituitary through a feedback mechanism to regulate the secretion of CRH and ACTH | |||
===Cushing's syndrome=== | ===Cushing's syndrome=== | ||
Cushing's syndrome is | The pathophysiology of Cushing's syndrome is linked to [[hypercortisolism]] which can develop by excess [[ACTH]] secretion or excess [[cortisol]] secretion by [[adrenal glands]]. The underlying mechanisms are usually genetic mutations or overexpression of proteins.<ref name="pmid26004339">{{cite journal |vauthors=Lacroix A, Feelders RA, Stratakis CA, Nieman LK |title=Cushing's syndrome |journal=Lancet |volume=386 |issue=9996 |pages=913–27 |year=2015 |pmid=26004339 |doi=10.1016/S0140-6736(14)61375-1 |url=}}</ref><ref name="pmid25480800">{{cite journal |vauthors=Raff H, Carroll T |title=Cushing's syndrome: from physiological principles to diagnosis and clinical care |journal=J. Physiol. (Lond.) |volume=593 |issue=3 |pages=493–506 |year=2015 |pmid=25480800 |pmc=4324701 |doi=10.1113/jphysiol.2014.282871 |url=}}</ref><ref name="pmid24423978">{{cite journal |vauthors=Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ, Hammer GD |title=Adrenocortical carcinoma |journal=Endocr. Rev. |volume=35 |issue=2 |pages=282–326 |year=2014 |pmid=24423978 |pmc=3963263 |doi=10.1210/er.2013-1029 |url=}}</ref><ref name="pmid22347350">{{cite journal |vauthors=Vyas S, Gorsi U, Bansali A, Khandelwal N |title=Anterior mediastinal mass in a patient with Cushing's syndrome |journal=Ann Thorac Med |volume=7 |issue=1 |pages=42–3 |year=2012 |pmid=22347350 |pmc=3277041 |doi=10.4103/1817-1737.91557 |url=}}</ref><ref name="urlCushing’s Syndrome due to Ectopic ACTH from Bronchial Carcinoid: A Case Report and Review">{{cite web |url=https://www.hindawi.com/journals/crie/2012/215038/ |title=Cushing’s Syndrome due to Ectopic ACTH from Bronchial Carcinoid: A Case Report and Review |format= |work= |accessdate=}}</ref> | ||
#Excess pituitary ACTH secretion | #Excess [[ACTH]] secretion | ||
#Excess secretion of cortisol by adrenal | #*The excess ACTH secretion can be due to the [[pituitary adenoma]] or ectopic (non-pituitary) [[ACTH]] secretion. [[ACTH]] stimulates the [[adrenal cortex]] to release [[cortisol]] and is not regulated by the feedback mechanism. | ||
# | #*#'''[[Pituitary adenoma]]''': Various gene mutations are involved in the development of [[pituitary adenoma]] commonly USP8, [[MEN1]], CDKIs, and CDKN1B/p27Kip1. Many proteins are also overexpressed like Brg1, HDAC2, TR4, PTTG, and [[EGFR]]. It is the most important cause of ACTH-dependent cushing's syndrome and is also called [[cushing's disease]]. It is considered that the [[Corticotrophs|corticotroph]] tumors are resistant to [[glucocorticoid]] negative feedback inhibition which results in the [[pathological]] [[adrenal]] [[cortisol]] secretion. | ||
#*#'''[[Ectopic ACTH Syndrome|Ectopic ACTH secretion]]''': The molecular defects in the [[neuroendocrine tumors]] leading to ectopic [[ACTH]] secretion from gastroenteropancreatic tumors are largely unknown. Germline menin mutations or [[RET proto-oncogene|RET oncogene]] mutations in [[MEN|multiple endocrine neoplasias]] (MEN) may be responsible. Ectopic secretion of [[ACTH]] can be seen as a manifestation of the [[paraneoplastic syndrome]] in [[Small cell lung cancer|small cell lung carcinoma]] and [[Carcinoid syndrome|carcinoid tumors]](bronchial and thymus). | |||
#Excess secretion of [[cortisol]] by adrenal gland | |||
#*Excess secretion of the cortisol by the adrenal gland is due to the [[adrenal]] causes independent of [[ACTH]] secretion. | |||
#*#'''[[Adrenocortical adenoma|Benign Adrenocortical adenoma]]''': Common defects leading to [[adrenocortical adenoma]] are mutations or activation of the [[cAMP]]-dependent or [[β-catenin]] signaling pathways and aberrant expression and function of various [[G-protein-coupled receptor|G-protein-coupled receptors]] (GPCR). | |||
#*#'''[[Adrenocortical carcinoma|Adrenal cortical carcinoma]]''' It is associated with germline [[TP53 (gene)|TP53]] mutations and [[MEN]] syndrome. | |||
#*#'''[[Bilateral adrenal hyperplasia]]''': It is associated with [[MEN1]], [[familial adenomatous polyposis]], and [[fumarate hydratase]] gene mutations. Several inactivating mutations of armadillo repeat containing 5 genes (ARMC5, chromosome 16p11.2) are also identified. | |||
===Associated Conditions=== | |||
Cushing's syndrome is associated with the following conditions:<ref name="pmid18209870">{{cite journal |vauthors=Sahdev A, Reznek RH, Evanson J, Grossman AB |title=Imaging in Cushing's syndrome |journal=Arq Bras Endocrinol Metabol |volume=51 |issue=8 |pages=1319–28 |year=2007 |pmid=18209870 |doi= |url=}}</ref> | |||
*Carney complex | |||
*McCune-Albright syndrome | |||
*Multiple Endocrine Neoplasia Type 1 (MEN 1) | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
Latest revision as of 21:35, 29 August 2017
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]
Overview
Both the hypothalamus and the pituitary gland are part of the brain. The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropic hormone (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. Strictly, Cushing's syndrome refers to excess cortisol of any etiology. One of the causes of Cushing's syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotroph pituitary adenoma. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels. Cortisol can also exhibit mineralocorticoid activity in high concentrations, worsening hypertension and leading to hypokalemia (common in ectopic ACTH secretion).
Pathophysiology
Mechanism of cortisol secretion
The secretion of cortisol is controlled by hypothalamic-pituitary axis by the following mechanism:[1][2]
- Paraventricular nuclei in the hypothalamus release corticotropin releasing hormone (CRH).
- CRH is transferred to anterior pituitary via the portal veins.
- CRH stimulates the activity of corticotrophs; cells that produce proopiomelanocortin (POMC) in the anterior pituitary.
- Corticotrophs produce adrenocorticotropic hormone (ACTH) by the post-translational modification of POMC.
- ACTH is drained into systemic circulation via the pituitary capillaries and stimulates the adrenal cortex (zona fasciculata) to produce cortisol.
- Cortisol acts on hypothalamus and pituitary through a feedback mechanism to regulate the secretion of CRH and ACTH.
Cushing's syndrome
The pathophysiology of Cushing's syndrome is linked to hypercortisolism which can develop by excess ACTH secretion or excess cortisol secretion by adrenal glands. The underlying mechanisms are usually genetic mutations or overexpression of proteins.[1][2][3][4][5]
- Excess ACTH secretion
- The excess ACTH secretion can be due to the pituitary adenoma or ectopic (non-pituitary) ACTH secretion. ACTH stimulates the adrenal cortex to release cortisol and is not regulated by the feedback mechanism.
- Pituitary adenoma: Various gene mutations are involved in the development of pituitary adenoma commonly USP8, MEN1, CDKIs, and CDKN1B/p27Kip1. Many proteins are also overexpressed like Brg1, HDAC2, TR4, PTTG, and EGFR. It is the most important cause of ACTH-dependent cushing's syndrome and is also called cushing's disease. It is considered that the corticotroph tumors are resistant to glucocorticoid negative feedback inhibition which results in the pathological adrenal cortisol secretion.
- Ectopic ACTH secretion: The molecular defects in the neuroendocrine tumors leading to ectopic ACTH secretion from gastroenteropancreatic tumors are largely unknown. Germline menin mutations or RET oncogene mutations in multiple endocrine neoplasias (MEN) may be responsible. Ectopic secretion of ACTH can be seen as a manifestation of the paraneoplastic syndrome in small cell lung carcinoma and carcinoid tumors(bronchial and thymus).
- The excess ACTH secretion can be due to the pituitary adenoma or ectopic (non-pituitary) ACTH secretion. ACTH stimulates the adrenal cortex to release cortisol and is not regulated by the feedback mechanism.
- Excess secretion of cortisol by adrenal gland
- Excess secretion of the cortisol by the adrenal gland is due to the adrenal causes independent of ACTH secretion.
- Benign Adrenocortical adenoma: Common defects leading to adrenocortical adenoma are mutations or activation of the cAMP-dependent or β-catenin signaling pathways and aberrant expression and function of various G-protein-coupled receptors (GPCR).
- Adrenal cortical carcinoma It is associated with germline TP53 mutations and MEN syndrome.
- Bilateral adrenal hyperplasia: It is associated with MEN1, familial adenomatous polyposis, and fumarate hydratase gene mutations. Several inactivating mutations of armadillo repeat containing 5 genes (ARMC5, chromosome 16p11.2) are also identified.
- Excess secretion of the cortisol by the adrenal gland is due to the adrenal causes independent of ACTH secretion.
Associated Conditions
Cushing's syndrome is associated with the following conditions:[6]
- Carney complex
- McCune-Albright syndrome
- Multiple Endocrine Neoplasia Type 1 (MEN 1)
References
- ↑ 1.0 1.1 Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015). "Cushing's syndrome". Lancet. 386 (9996): 913–27. doi:10.1016/S0140-6736(14)61375-1. PMID 26004339.
- ↑ 2.0 2.1 Raff H, Carroll T (2015). "Cushing's syndrome: from physiological principles to diagnosis and clinical care". J. Physiol. (Lond.). 593 (3): 493–506. doi:10.1113/jphysiol.2014.282871. PMC 4324701. PMID 25480800.
- ↑ Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ, Hammer GD (2014). "Adrenocortical carcinoma". Endocr. Rev. 35 (2): 282–326. doi:10.1210/er.2013-1029. PMC 3963263. PMID 24423978.
- ↑ Vyas S, Gorsi U, Bansali A, Khandelwal N (2012). "Anterior mediastinal mass in a patient with Cushing's syndrome". Ann Thorac Med. 7 (1): 42–3. doi:10.4103/1817-1737.91557. PMC 3277041. PMID 22347350.
- ↑ "Cushing's Syndrome due to Ectopic ACTH from Bronchial Carcinoid: A Case Report and Review".
- ↑ Sahdev A, Reznek RH, Evanson J, Grossman AB (2007). "Imaging in Cushing's syndrome". Arq Bras Endocrinol Metabol. 51 (8): 1319–28. PMID 18209870.