Conn syndrome pathophysiology: Difference between revisions
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== Overview == | |||
== Pathophysiology == | |||
=== Basic physiology of aldosterone === | |||
* Circulating aldosterone is principally made in the zona glomerulosa of the adrenal cortex (outer layer of the cortex) by a cascade of enzyme steps leading to the conversion of cholesterol to aldosterone. Aldosterone's production is regulated at two critical enzyme steps: | |||
** (1) early in its biosynthetic pathway (the conversion of cholesterol to pregnenolone cholesterol side chain cleavage enzyme) and | |||
** (2) late (the conversion of corticosterone to aldosterone by aldosterone synthase). | |||
* A variety of factors modify aldosterone secretion--the most important are angiotensin II (AngII), the end-product of the renin-angiotensin system (RAS), and potassium. However ACTH, neural mediators and natriuretic factors also play part in the feedback mechanism. | |||
* Aldosterone's classical epithelial effect is to increase the transport of sodium across the cell in exchange for potassium and hydrogen ions. <ref name="pmid15947886">{{cite journal |vauthors=Williams GH |title=Aldosterone biosynthesis, regulation, and classical mechanism of action |journal=Heart Fail Rev |volume=10 |issue=1 |pages=7–13 |year=2005 |pmid=15947886 |doi=10.1007/s10741-005-2343-3 |url=}}</ref> | |||
=== Primary hyperaldosteronism === | |||
* Primary hyperaldosteronism (PH) features overproduction of aldosterone despite suppressed plasma renin activity (PRA). The resulting Na+ retention produces hypertension, and elevated K+ excretion may cause hypokalemia. | |||
* About one third of patients with PH have aldosterone producing adrenocortical adenoma (APA), a small subset (~2%) have unilateral hyperplasia, and most of the remainder exhibit idiopathic hyperaldosteronism (IHA, also known as bilateral adrenal hyperplasia).<ref name="pmid26252618">{{cite journal |vauthors=Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kücükköylü S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T |title=Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype |journal=Clin. Endocrinol. (Oxf) |volume=83 |issue=6 |pages=779–89 |year=2015 |pmid=26252618 |pmc=4995792 |doi=10.1111/cen.12873 |url=}}</ref> Familial forms (familial hyperaldosteronism types I, II, and III) have also been described. | |||
* Ectopic secretion of aldosterone (The ovaries and kidneys are the 2 organs described in the literature that, in the setting of neoplastic disease, can be ectopic sources of aldosterone, but this is a rare occurrence.) | |||
* Classically, hyperaldosteronism caused due to aldosterone producing adrenocortical adenomas (APA) is referred to as Conn's syndrome.<ref name="pmid17492946">{{cite journal |vauthors=Young WF |title=Primary aldosteronism: renaissance of a syndrome |journal=Clin. Endocrinol. (Oxf) |volume=66 |issue=5 |pages=607–18 |year=2007 |pmid=17492946 |doi=10.1111/j.1365-2265.2007.02775.x |url=}}</ref> | |||
=== Conn's syndrome (Aldosterone producing adrenocortical adenomas-APA) === | |||
* APAs are typically solitary, well circumscribed, and diagnosed between ages 30 and 70. | |||
* Inherited and acquired mutations in ''KCNJ5'' gene, which codes for a K ion channel has been associated ''with'' autonomous cell proliferation in the adrenal cortex. <ref name="pmid21311022">{{cite journal |vauthors=Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Åkerström G, Wang W, Carling T, Lifton RP |title=K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension |journal=Science |volume=331 |issue=6018 |pages=768–72 |year=2011 |pmid=21311022 |pmc=3371087 |doi=10.1126/science.1198785 |url=}}</ref> Two somatic mutations in the K+ channel KCNJ5 (G151R and L168R) cause ~40% of APA. <ref name="pmid262526182">{{cite journal |vauthors=Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kücükköylü S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T |title=Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype |journal=Clin. Endocrinol. (Oxf) |volume=83 |issue=6 |pages=779–89 |year=2015 |pmid=26252618 |pmc=4995792 |doi=10.1111/cen.12873 |url=}}</ref> These mutations affect K ion selectivity leading to increased Na+ conductance and membrane depolarization resulting in activation of voltage-gated Ca2+channels. Increased intracellular Ca results in release of aldosterone from the adrenal gland. | |||
__NOTOC__ | __NOTOC__ | ||
{{Conn syndrome}} | {{Conn syndrome}} | ||
==References== | ==References== | ||
{{reflist|2}} | {{reflist|2}} | ||
Revision as of 19:01, 18 May 2017
Overview
Pathophysiology
Basic physiology of aldosterone
- Circulating aldosterone is principally made in the zona glomerulosa of the adrenal cortex (outer layer of the cortex) by a cascade of enzyme steps leading to the conversion of cholesterol to aldosterone. Aldosterone's production is regulated at two critical enzyme steps:
- (1) early in its biosynthetic pathway (the conversion of cholesterol to pregnenolone cholesterol side chain cleavage enzyme) and
- (2) late (the conversion of corticosterone to aldosterone by aldosterone synthase).
- A variety of factors modify aldosterone secretion--the most important are angiotensin II (AngII), the end-product of the renin-angiotensin system (RAS), and potassium. However ACTH, neural mediators and natriuretic factors also play part in the feedback mechanism.
- Aldosterone's classical epithelial effect is to increase the transport of sodium across the cell in exchange for potassium and hydrogen ions. [1]
Primary hyperaldosteronism
- Primary hyperaldosteronism (PH) features overproduction of aldosterone despite suppressed plasma renin activity (PRA). The resulting Na+ retention produces hypertension, and elevated K+ excretion may cause hypokalemia.
- About one third of patients with PH have aldosterone producing adrenocortical adenoma (APA), a small subset (~2%) have unilateral hyperplasia, and most of the remainder exhibit idiopathic hyperaldosteronism (IHA, also known as bilateral adrenal hyperplasia).[2] Familial forms (familial hyperaldosteronism types I, II, and III) have also been described.
- Ectopic secretion of aldosterone (The ovaries and kidneys are the 2 organs described in the literature that, in the setting of neoplastic disease, can be ectopic sources of aldosterone, but this is a rare occurrence.)
- Classically, hyperaldosteronism caused due to aldosterone producing adrenocortical adenomas (APA) is referred to as Conn's syndrome.[3]
Conn's syndrome (Aldosterone producing adrenocortical adenomas-APA)
- APAs are typically solitary, well circumscribed, and diagnosed between ages 30 and 70.
- Inherited and acquired mutations in KCNJ5 gene, which codes for a K ion channel has been associated with autonomous cell proliferation in the adrenal cortex. [4] Two somatic mutations in the K+ channel KCNJ5 (G151R and L168R) cause ~40% of APA. [5] These mutations affect K ion selectivity leading to increased Na+ conductance and membrane depolarization resulting in activation of voltage-gated Ca2+channels. Increased intracellular Ca results in release of aldosterone from the adrenal gland.
References
- ↑ Williams GH (2005). "Aldosterone biosynthesis, regulation, and classical mechanism of action". Heart Fail Rev. 10 (1): 7–13. doi:10.1007/s10741-005-2343-3. PMID 15947886.
- ↑ Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kücükköylü S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T (2015). "Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype". Clin. Endocrinol. (Oxf). 83 (6): 779–89. doi:10.1111/cen.12873. PMC 4995792. PMID 26252618.
- ↑ Young WF (2007). "Primary aldosteronism: renaissance of a syndrome". Clin. Endocrinol. (Oxf). 66 (5): 607–18. doi:10.1111/j.1365-2265.2007.02775.x. PMID 17492946.
- ↑ Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Åkerström G, Wang W, Carling T, Lifton RP (2011). "K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension". Science. 331 (6018): 768–72. doi:10.1126/science.1198785. PMC 3371087. PMID 21311022.
- ↑ Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kücükköylü S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T (2015). "Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype". Clin. Endocrinol. (Oxf). 83 (6): 779–89. doi:10.1111/cen.12873. PMC 4995792. PMID 26252618.