Hypoaldosteronism pathophysiology: Difference between revisions

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__NOTOC__
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{{Hypoaldosteronism}}
{{Hypoaldosteronism}}
{{CMG}}; {{AE}}
{{CMG}}; {{AE}}{{Akshun}}{{SSW}}


==Overview==
==Overview==
 
Hypoaldosteronism is defined as decreased levels of the [[hormone]] [[aldosterone]] or a [[resistance]] of the target tissue to the actions of [[aldosterone]]. Hypoaldosteronism from decreased production is seen in conditions such as congenital isolated hypoaldosteronism, [[Primary adrenal insufficiency|primary adrenal insufficiency,]] [[diabetic nephropathy]], [[critical illness]], and [[drugs]] such as [[ACE inhibitor|ACE inhibitors]], [[NSAIDs]] and [[Calcineurin inhibitor|calcineurin inhibitors]]. [[Resistance]] of the target tissue to the actions of [[aldosterone]] is seen with [[mineralocorticoid receptor]] defects (seen in [[pseudohypoaldosteronism]]) and with [[drugs]] such as [[potassium-sparing diuretics]] and [[trimethoprim]]. Hypoaldosteronism results in reduced reabsorption of [[sodium]] in the [[principal cells]] of [[Cortical collecting duct|cortical collecting tubules]] (CCT). This leads to decreased excretion of [[potassium]] ([[hyperkalemia]]) and mild non-anion gap [[metabolic acidosis]]. On gross pathology, [[adrenal glands]] may be irregularly shrunken or [[hyperplastic]].
The exact pathogenesis of [disease name] is not fully understood.
 
OR
 
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
 
OR
 
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
 
OR
 
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
 
OR
 
 
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
 
OR
 
The progression to [disease name] usually involves the [molecular pathway].
 
OR
 
The pathophysiology of [disease/malignancy] depends on the histological subtype.


==Pathophysiology==
==Pathophysiology==
===Physiology===
===Physiology===
*The [[juxtaglomerular apparatus]] of the [[macula densa]] primarily senses the [[concentration]] of [[Blood plasma|plasma]] [[sodium]] and [[perfusion pressure]].  
*The [[juxtaglomerular apparatus]] of the [[macula densa]] primarily senses the [[concentration]] of [[Blood plasma|plasma]] [[sodium]] and [[renal]] [[perfusion pressure]].<ref name="pmid12208992">{{cite journal |vauthors=Schnermann J, Levine DZ |title=Paracrine factors in tubuloglomerular feedback: adenosine, ATP, and nitric oxide |journal=Annu. Rev. Physiol. |volume=65 |issue= |pages=501–29 |year=2003 |pmid=12208992 |doi=10.1146/annurev.physiol.65.050102.085738 |url=}}</ref><ref name="pmid17280552">{{cite journal |vauthors=Castrop H |title=Mediators of tubuloglomerular feedback regulation of glomerular filtration: ATP and adenosine |journal=Acta Physiol (Oxf) |volume=189 |issue=1 |pages=3–14 |year=2007 |pmid=17280552 |doi=10.1111/j.1748-1716.2006.01610.x |url=}}</ref>
** In response to low [[plasma]] [[sodium]] concentration or decreased [[perfusion pressure]] the [[juxtaglomerular apparatus]] secretes [[renin]].  
** In response to low [[plasma]] [[sodium]] concentration or decreased [[renal]] [[perfusion pressure]], the [[juxtaglomerular apparatus]] secretes [[renin]].  
** On secretion, [[renin]] cleaves [[angiotensinogen]] (produced by [[liver]]) to [[angiotensin I]].  
** On secretion, [[renin]] cleaves [[angiotensinogen]] (produced by [[liver]]) to [[angiotensin I]].  
** [[Angiotensin-converting enzyme]] produced in the [[lungs]] further cleaves [[angiotensin I]] to [[angiotensin II]].  
** [[Angiotensin-converting enzyme]] produced in the [[lungs]] further cleaves [[angiotensin I]] to [[angiotensin II]].  
** The main site of activity for [[angiotensin II]] is [[zona glomerulosa]] of [[adrenal cortex]], where [[angiotensin II]] stimulates [[aldosterone synthase]] which converts [[deoxycorticosterone]] to [[aldosterone]].  
** The main site of activity for [[angiotensin II]] is [[zona glomerulosa]] of [[adrenal cortex]], where [[angiotensin II]] stimulates [[aldosterone synthase]] which converts [[deoxycorticosterone]] to [[aldosterone]].  


* The [[renin-angiotensin-aldosterone axis]] is a tightly controlled [[feedback mechanism]] which regulates [[sodium]] and [[blood pressure]] in our [[Human body|body]].
* The [[renin-angiotensin-aldosterone axis]] is a tightly controlled [[feedback mechanism]] which regulates [[sodium]] and [[blood pressure]] in our [[Human body|body]].<ref name="pmid1893644">{{cite journal |vauthors=Hall JE |title=Control of blood pressure by the renin-angiotensin-aldosterone system |journal=Clin Cardiol |volume=14 |issue=8 Suppl 4 |pages=IV6–21; discussion IV51–5 |year=1991 |pmid=1893644 |doi= |url=}}</ref>
**  Low [[plasma]] [[sodium]], decreased [[perfusion pressure]] and [[hyperkalemia]] stimulates [[aldosterone]] [[secretion]].
**  Low [[plasma]] [[sodium]], decreased [[perfusion pressure]] and [[hyperkalemia]] stimulates [[aldosterone]] [[secretion]].
**  [[Hypokalemia]] suppresses [[aldosterone]] [[secretion]].
**  [[Hypokalemia]] suppresses [[aldosterone]] [[secretion]].
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* [[Aldosterone]] is synthesized at a [[rate]] of approximately 100 to 150 ug/day.
* [[Aldosterone]] is synthesized at a [[rate]] of approximately 100 to 150 ug/day.


[[image:Renin-angiotensin-aldosterone system.png|thumb|center| 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]]
 
[[image:Renin-angiotensin-aldosterone system.png|thumb|750px|center| 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]]
 


===Pathogenesis===
===Pathogenesis===
Hypoaldosteronism is defined as decreased levels of the [[hormone]] [[aldosterone]]. Hypoaldosteronism can be due to [[adrenal insufficiency]], [[enzyme]] deficiency ([[aldosterone synthase]], [[21-hydroxylase deficiency|21 hydroxylase]], and [[11Beta Hydroxysteroid dehydrogenase|11B hydroxylase]]), renal disorders ([[chronic renal failure]] and [[diabetic nephropathy]]) and [[drugs]] inhibiting [[aldosterone]] effect ([[Non-steroidal anti-inflammatory drug|NSAID]], [[spironolactone]], and [[triamterene]]).  
*Hypoaldosteronism is defined as decreased levels of the [[hormone]] [[aldosterone]] or a resistance of the target tissue to the actions of [[aldosterone]]. Hypoaldosteronism can be due to:<ref name="pmid8015573">{{cite journal |vauthors=White PC |title=Disorders of aldosterone biosynthesis and action |journal=N. Engl. J. Med. |volume=331 |issue=4 |pages=250–8 |year=1994 |pmid=8015573 |doi=10.1056/NEJM199407283310408 |url=}}</ref>
** '''Aldosterone deficiency''': The deficiency in [[aldosterone]] can be due to congenital isolated hypoaldosteronism, [[primary adrenal insufficiency]], [[diabetic nephropathy]], [[critical illness]], and [[drugs]] such as [[ACE inhibitor|ACE inhibitors]], [[NSAIDs|NSAID]] and [[Calcineurin inhibitor|calcineurin inhibitors]].
** '''Aldosterone resistance''': In [[aldosterone]] resistance, the level of [[aldosterone]] is normal but there is decreased response of the target tissue to the actions of [[aldosterone]]. [[Aldosterone]] resistance is seen with [[mineralocorticoid receptor]] defects (seen in [[pseudohypoaldosteronism]]) and with [[drugs]] such as [[Potassium-sparing diuretic|potassium-sparing diuretics]] and [[trimethoprim]].
 
*Hypoaldosteronism results in reduced [[reabsorption]] of [[sodium]] in the [[principal cells]] of [[Cortical collecting ducts|cortical collecting tubules]] (CCT).  This leads to decreased [[excretion]] of [[potassium]] and mild non-anion gap [[metabolic acidosis]].


=== Hyporeninemic Hypoaldosteronism===
=== Hyporeninemic Hypoaldosteronism===
* Hyporeninemic hypoaldosteronism is most commonly seen in:
* Hyporeninemic hypoaldosteronism is most commonly seen in patients with mild to moderate [[renal insufficiency]] and [[Diabetic nephropathy|diabetic nephropathy:]]<ref name="pmid6758113">{{cite journal |vauthors=Weidmann P |title=[Hyporeninemic hypoaldosteronism and the differential diagnosis of hyperkalemia] |language=German |journal=Schweiz Med Wochenschr |volume=112 |issue=49 |pages=1764–74 |year=1982 |pmid=6758113 |doi= |url=}}</ref><ref name="pmid3908957">{{cite journal |vauthors=Schambelan M, Sebastian A |title=[Type IV renal tubular acidosis: pathogenetic role of aldosterone deficiency and hyperkalemia] |language=French |journal=Nephrologie |volume=6 |issue=3 |pages=135–7 |year=1985 |pmid=3908957 |doi= |url=}}</ref><ref name="pmid7446728">{{cite journal |vauthors=Arruda JA, Kurtzman NA |title=Mechanisms and classification of deranged distal urinary acidification |journal=Am. J. Physiol. |volume=239 |issue=6 |pages=F515–23 |year=1980 |pmid=7446728 |doi= |url=}}</ref>
** Patients with mild to moderate renal insufficiency. In patients with renal insufficiency, there may be atrophy of the juxtaglomerular apparatus (JGA) which leads to decreased sensing of sodium and blood pressure by the kidneys. Over time, this leads to inadequate renin production and release. There may also be decreased response of principal cells in the cortical collecting tubule to aldosterone.
** In patients of [[renal insufficiency]], [[atrophy]] of the [[juxtaglomerular apparatus]] (JGA) leads to decreased sensing of plasma [[sodium]] concentration and renal [[perfusion pressure]].
** Patients with adrenal dysfunction such as Addison's disease. Primary adrenal insufficiency or Addison's disease can be due to adrenal dysgenesis, Impaired steroidogenesis, and adrenal destruction. In these patients, the adrenal glands do not produce sufficient cortisol and aldosterone.
** With progression of the [[renal disease]] and [[atrophy]] of the [[juxtaglomerular apparatus]] (JGA) there may be inadequate [[renin]] production and release.
** Thus, in the above conditions there occurs deceased level of renin with decreased level of aldosterone.
** A decrease in [[renin]] production and release leads to decreased [[angiotensin]] production, which eventually causes hypoaldosteronism .
** [[Renal insufficiency]] may also cause decreased response of the [[principal cells]] in the [[cortical collecting tubule]] to [[aldosterone]].


===Hyperreninemic Hypoaldosteronism===
===Hyperreninemic Hypoaldosteronism===
* Hyperreninemic hypoaldosteronism also known as secondary isolated hypoaldosteronism is seen in patients with severe illness such as sepsis, malignancy, heart failure, and liver cirrhosis.<ref name="pmid6291814">{{cite journal |vauthors=Kater CE, Biglieri EG, Brust N, Chang B, Hirai J |title=Regulation of the mineralocorticoid hormones in adrenocortical disorders with adrenocorticotropin excess |journal=Clin Exp Hypertens A |volume=4 |issue=9-10 |pages=1749–58 |year=1982 |pmid=6291814 |doi= |url=}}</ref><ref name="pmid6256154">{{cite journal |vauthors=Aguilera G, Fujita K, Catt KJ |title=Mechanisms of inhibition of aldosterone secretion by adrenocorticotropin |journal=Endocrinology |volume=108 |issue=2 |pages=522–8 |year=1981 |pmid=6256154 |doi=10.1210/endo-108-2-522 |url=}}</ref><ref name="pmid1851063">{{cite journal |vauthors=Singer DR, Shirley DG, Markandu ND, Miller MA, Buckley MG, Sugden AL, Sagnella GA, MacGregor GA |title=How important are suppression of aldosterone and stimulation of atrial natriuretic peptide secretion in the natriuretic response to an acute sodium load in man? |journal=Clin. Sci. |volume=80 |issue=4 |pages=293–9 |year=1991 |pmid=1851063 |doi= |url=}}</ref>
* Hyperreninemic hypoaldosteronism also known as secondary isolated hypoaldosteronism is seen in [[patients]] with severe [[illness]] such as [[sepsis]], [[malignancy]], [[heart failure]], adrenal dysfunction and [[liver cirrhosis]].<ref name="pmid6291814">{{cite journal |vauthors=Kater CE, Biglieri EG, Brust N, Chang B, Hirai J |title=Regulation of the mineralocorticoid hormones in adrenocortical disorders with adrenocorticotropin excess |journal=Clin Exp Hypertens A |volume=4 |issue=9-10 |pages=1749–58 |year=1982 |pmid=6291814 |doi= |url=}}</ref><ref name="pmid6256154">{{cite journal |vauthors=Aguilera G, Fujita K, Catt KJ |title=Mechanisms of inhibition of aldosterone secretion by adrenocorticotropin |journal=Endocrinology |volume=108 |issue=2 |pages=522–8 |year=1981 |pmid=6256154 |doi=10.1210/endo-108-2-522 |url=}}</ref><ref name="pmid1851063">{{cite journal |vauthors=Singer DR, Shirley DG, Markandu ND, Miller MA, Buckley MG, Sugden AL, Sagnella GA, MacGregor GA |title=How important are suppression of aldosterone and stimulation of atrial natriuretic peptide secretion in the natriuretic response to an acute sodium load in man? |journal=Clin. Sci. |volume=80 |issue=4 |pages=293–9 |year=1991 |pmid=1851063 |doi= |url=}}</ref>
** During these [[Stress (medicine)|stress]] inducing conditions, there occurs increased level of ACTH and cortisol. Under normal conditions, continuous ACTH secretion for > 96 hours leads to suppression of aldosterone synthase activity.
** During these [[Stress (medicine)|stress]] inducing conditions, increased levels of [[Adrenocorticotropic hormone|ACTH]] and [[cortisol]] are seen.  
** Thus, chronically ill patients with prolonged ACTH secretion (>96 hours) have impaired aldosterone synthase activity and decreased levels of aldosterone. In response, the kidneys via its neurohormonal regulation leads to increased levels of renin and hence the term hyperreninemic hypoaldosteronism.  
** Under normal conditions, continuous [[Adrenocorticotropic hormone|ACTH]] secretion for greater than 96 hours leads to suppression of [[aldosterone synthase]] activity.
** In addition, cytokine release from chronic illness and increased levels of atrial natriuretic peptide (in patients with heart failure) also have an inhibitory effect on zona glomerulosa.
** Chronically ill patients with prolonged [[Adrenocorticotropic hormone|ACTH]] secretion (>96 hours) have impaired [[aldosterone synthase]] activity and decreased levels of [[aldosterone]].
 
** In response, the [[kidneys]] via its neurohormonal regulation leads to increased levels of [[renin]] and hence the term hyperreninemic hypoaldosteronism.  
===Postadrenalectomy Hypoaldosteronism===
** In addition, [[cytokine]] release from chronic illness or increased levels of [[atrial natriuretic peptide]] (in patients with [[heart failure]]) also have an [[inhibitory]] effect on the [[zona glomerulosa]] of [[adrenal cortex]].
Patients of Conn syndrome who are treated with spironolactone and later undergo sugery for tumor removal may develop hypoaldosteronism. In these patients there is chronic suppression of contralateral zona glomerulosa which may lead to decreased levels of aldosterone. <ref name="pmid7001091">{{cite journal |vauthors=Kawasaki T, Uezono K, Ueno M, Noda Y, Kumamoto K, Kawano Y, Ogata M, Fukiyama K, Omae T, Bartter FC |title=Influence of unilateral adrenalectomy on renin-angiotensin-aldosterone system in primary aldosteronism |journal=Jpn Heart J |volume=21 |issue=5 |pages=681–92 |year=1980 |pmid=7001091 |doi= |url=}}</ref><ref name="pmid19721021">{{cite journal |vauthors=Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Schultze Kool LJ, Hermus AR, Deinum J |title=Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism |journal=Ann. Intern. Med. |volume=151 |issue=5 |pages=329–37 |year=2009 |pmid=19721021 |doi= |url=}}</ref><ref name="pmid20420801">{{cite journal |vauthors=Huang WT, Chau T, Wu ST, Lin SH |title=Prolonged hyperkalemia following unilateral adrenalectomy for primary hyperaldosteronism |journal=Clin. Nephrol. |volume=73 |issue=5 |pages=392–7 |year=2010 |pmid=20420801 |doi= |url=}}</ref><ref name="pmid9669438">{{cite journal |vauthors=Gadallah MF, Kayyas Y, Boules F |title=Reversible suppression of the renin-aldosterone axis after unilateral adrenalectomy for adrenal adenoma |journal=Am. J. Kidney Dis. |volume=32 |issue=1 |pages=160–3 |year=1998 |pmid=9669438 |doi= |url=}}</ref><ref name="pmid4287160">{{cite journal |vauthors=Biglieri EG, Slaton PE, Silen WS, Galante M, Forsham PH |title=Postoperative studies of adrenal function in primary aldosteronism |journal=J. Clin. Endocrinol. Metab. |volume=26 |issue=5 |pages=553–8 |year=1966 |pmid=4287160 |doi=10.1210/jcem-26-5-553 |url=}}</ref><ref name="pmid3902226">{{cite journal |vauthors=Groth H, Vetter W, Stimpel M, Greminger P, Tenschert W, Klaiber E, Vetter H |title=Adrenalectomy in primary aldosteronism: a long-term follow-up study |journal=Cardiology |volume=72 Suppl 1 |issue= |pages=107–16 |year=1985 |pmid=3902226 |doi= |url=}}</ref>
* Hyperreninemic hypoaldosteronism is also seen in patients with adrenal dysfunction such as [[Addison's disease]].
** [[Primary adrenal insufficiency]] or [[Addison's disease]] can be due to [[Adrenal gland|adrenal]] [[dysgenesis]], impaired [[steroidogenesis]], and [[Adrenal Gland|adrenal]] destruction.
** In patients of [[primary adrenal insufficiency]], the [[adrenal glands]] does not produce sufficient [[cortisol]] and [[aldosterone]].
** The decrease in level of [[aldosterone]] leads to decreased [[absorption]] of [[sodium]] in the [[kidneys]] and increased retention of [[potassium]]. This in turn activates the [[juxtaglomerular apparatus]] (JGA) of the [[kidneys]], which secretes [[renin]] in an attempt to normalise [[plasma]] [[sodium]] [[concentration]] and [[perfusion pressure]]. However, due to [[Adrenal gland|adrenal]] dysfunction the [[zona glomerulosa]] of [[adrenal cortex]] is unable to produce [[aldosterone]] and presents with hyperreninemic hypoaldosteronism.


===Isolated Hypoaldosteronism===
===Isolated Hypoaldosteronism===
*In isolated hypoaldosteronism, there is selective deficiency of aldosterone with normal cortisol production. Isolated hypoaldosteronism may result from dysfunction of zona glomerulosa or aldosterone synthase deficiency.  
*In isolated hypoaldosteronism, there is selective [[deficiency]] of [[aldosterone]] with normal [[cortisol]] production. Isolated hypoaldosteronism may result from dysfunction of [[zona glomerulosa]] or [[aldosterone synthase]] deficiency. <ref name="pmid15026188">{{cite journal |vauthors=Lisurek M, Bernhardt R |title=Modulation of aldosterone and cortisol synthesis on the molecular level |journal=Mol. Cell. Endocrinol. |volume=215 |issue=1-2 |pages=149–59 |year=2004 |pmid=15026188 |doi=10.1016/j.mce.2003.11.008 |url=}}</ref>
** Aldosterone synthase is an enzyme involved in the synthesis of aldosterone. Patients with aldosterone synthase enzyme deficiency (type I and type II) results in defective conversion of deoxycorticosterone to aldosterone and subsequently abnormal levels of aldosterone.
** [[Aldosterone synthase]] is an [[enzyme]] involved in the [[synthesis]] of [[aldosterone]]. Patients with [[aldosterone synthase]] [[enzyme]] [[deficiency]] (type I and type II) results in defective conversion of [[deoxycorticosterone]] to [[aldosterone]] and subsequently abnormal levels of [[aldosterone]].
** Certain drugs such as heparin sodium and nitric oxide have a direct suppressive effect on zona glomerulosa of adrenal cortex which may lead to decrease production of aldosterone, corticosterone and androgens.
** Certain [[drugs]] such as [[heparin]] and [[nitric oxide]] have a direct suppressive effect on the [[zona glomerulosa]] of [[adrenal cortex]] which may lead to decrease production of [[aldosterone]].
 
 
 


===Postadrenalectomy Hypoaldosteronism===
Postadrenalectomy hypoaldosteronism is seen in patients with [[Conn syndrome pathophysiology|Conn syndrome]] who undergo [[surgery]] for [[tumor]] removal:<ref name="pmid7001091">{{cite journal |vauthors=Kawasaki T, Uezono K, Ueno M, Noda Y, Kumamoto K, Kawano Y, Ogata M, Fukiyama K, Omae T, Bartter FC |title=Influence of unilateral adrenalectomy on renin-angiotensin-aldosterone system in primary aldosteronism |journal=Jpn Heart J |volume=21 |issue=5 |pages=681–92 |year=1980 |pmid=7001091 |doi= |url=}}</ref><ref name="pmid19721021">{{cite journal |vauthors=Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Schultze Kool LJ, Hermus AR, Deinum J |title=Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism |journal=Ann. Intern. Med. |volume=151 |issue=5 |pages=329–37 |year=2009 |pmid=19721021 |doi= |url=}}</ref><ref name="pmid20420801">{{cite journal |vauthors=Huang WT, Chau T, Wu ST, Lin SH |title=Prolonged hyperkalemia following unilateral adrenalectomy for primary hyperaldosteronism |journal=Clin. Nephrol. |volume=73 |issue=5 |pages=392–7 |year=2010 |pmid=20420801 |doi= |url=}}</ref><ref name="pmid9669438">{{cite journal |vauthors=Gadallah MF, Kayyas Y, Boules F |title=Reversible suppression of the renin-aldosterone axis after unilateral adrenalectomy for adrenal adenoma |journal=Am. J. Kidney Dis. |volume=32 |issue=1 |pages=160–3 |year=1998 |pmid=9669438 |doi= |url=}}</ref><ref name="pmid4287160">{{cite journal |vauthors=Biglieri EG, Slaton PE, Silen WS, Galante M, Forsham PH |title=Postoperative studies of adrenal function in primary aldosteronism |journal=J. Clin. Endocrinol. Metab. |volume=26 |issue=5 |pages=553–8 |year=1966 |pmid=4287160 |doi=10.1210/jcem-26-5-553 |url=}}</ref><ref name="pmid3902226">{{cite journal |vauthors=Groth H, Vetter W, Stimpel M, Greminger P, Tenschert W, Klaiber E, Vetter H |title=Adrenalectomy in primary aldosteronism: a long-term follow-up study |journal=Cardiology |volume=72 Suppl 1 |issue= |pages=107–16 |year=1985 |pmid=3902226 |doi= |url=}}</ref><ref name="pmid25604311">{{cite journal |vauthors=Yorke E, Stafford S, Holmes D, Sheth S, Melck A |title=Aldosterone deficiency after unilateral adrenalectomy for Conn's syndrome: a case report and literature review |journal=Int J Surg Case Rep |volume=7C |issue= |pages=141–4 |year=2015 |pmid=25604311 |pmc=4336421 |doi=10.1016/j.ijscr.2015.01.013 |url=}}</ref>
* [[Conn syndrome pathophysiology|Conn syndrome]] is most often unilateral and leads to excessive production of [[aldosterone]] from the affected [[adrenal gland]].
* Excessive production of [[aldosterone]] causes [[hypertension]] and suppression of [[renin angiotensin aldosterone system]] ([[RAAS]]).
* Patients with [[Conn syndrome pathophysiology|Conn syndrome]] who are treated with [[spironolactone]] and later undergo [[surgery]] for [[tumor]] removal may develop hypoaldosteronism.
* Patients with [[Conn syndrome pathophysiology|Conn syndrome]] have increased levels of [[aldosterone]] and decreased [[plasma renin activity]] (from suppressed [[RAAS]]) which leads to chronic suppression of contralateral [[zona glomerulosa]].
* On surgical removal of aldosterone producing [[tumor]], there is sudden decline in circulating [[aldosterone]] which leads to hypoaldosteronism.


===Mineralocorticoid Resistance===
===Mineralocorticoid Resistance===
Mineralocorticoid resistance is characterized by a decrease in response to the hormone aldosterone. In mineralocorticoid resistance the level of aldosterone may be normal or above normal. It is due to this reason it is also known as pseudohypoaldosteronism. Mineralocorticoid resistance can be further categorized into:<ref name="pmid13545877">{{cite journal |vauthors=CHEEK DB, PERRY JW |title=A salt wasting syndrome in infancy |journal=Arch. Dis. Child. |volume=33 |issue=169 |pages=252–6 |year=1958 |pmid=13545877 |pmc=2012226 |doi= |url=}}</ref><ref name="pmid11498583">{{cite journal |vauthors=Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP |title=Human hypertension caused by mutations in WNK kinases |journal=Science |volume=293 |issue=5532 |pages=1107–12 |year=2001 |pmid=11498583 |doi=10.1126/science.1062844 |url=}}</ref>
[[Mineralocorticoid]] resistance is characterized by a decrease in response to the hormone [[aldosterone]]. In [[mineralocorticoid]] resistance the level of [[aldosterone]] may be normal or supranormal. It is due to this reason [[mineralocorticoid]] resistance is also known as [[pseudohypoaldosteronism]]. [[Mineralocorticoid]] resistance can be further categorized into:<ref name="pmid13545877">{{cite journal |vauthors=CHEEK DB, PERRY JW |title=A salt wasting syndrome in infancy |journal=Arch. Dis. Child. |volume=33 |issue=169 |pages=252–6 |year=1958 |pmid=13545877 |pmc=2012226 |doi= |url=}}</ref><ref name="pmid11498583">{{cite journal |vauthors=Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP |title=Human hypertension caused by mutations in WNK kinases |journal=Science |volume=293 |issue=5532 |pages=1107–12 |year=2001 |pmid=11498583 |doi=10.1126/science.1062844 |url=}}</ref><ref name="pmid23453970">{{cite journal |vauthors=Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S, Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S |title=Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension |journal=Cell Rep |volume=3 |issue=3 |pages=858–68 |year=2013 |pmid=23453970 |doi=10.1016/j.celrep.2013.02.024 |url=}}</ref>
* Pseudohypoaldosteronism type I: The decrease in response to aldosterone is due to heterozygous or homogenous inactivating mutations in the mineralocorticoid receptor. These patients are also resistant to mineralocorticoid therapy.
* '''Pseudohypoaldosteronism Type I''':  
* Pseudohypoaldosteronism Type II: This is an extremely rare disorder. It is speculated that these patients have mutations in the genes encoding proteins of the serine threonine kinase. Pseudohypoaldosteronism type II is also known as Gordon’s syndrome.
** The decrease in response to [[aldosterone]] is due to heterozygous or homozygous inactivating [[mutations]] in the [[mineralocorticoid receptor]]. These patients are also resistant to [[mineralocorticoid]] therapy.
* Pseudohypoaldosteronism type III: This condition presents with transient mineralocorticoid resistance. Pseudohypoaldosteronism type III is seen in patients with underlying renal conditions with decreased GFR. The exact cause is unknown but is thought to be related to increased levels of TGF-β.
* '''Pseudohypoaldosteronism Type II''':  
** This is an extremely rare disorder. It is speculated that these patients have [[mutations]] in the [[genes]] encoding proteins of the serine threonine [[kinase]] family (WKNK1 or WNK4 kinases). Pseudohypoaldosteronism Type II  is characterized by low or low-normal [[plasma renin activity]] and [[aldosterone]] concentrations, leading to [[hyperkalemia]] and [[metabolic acidosis]] with normal [[renal]] function. Pseudohypoaldosteronism type II is also known as [[Gordon syndrome|Gordon’s syndrome]].
* '''Pseudohypoaldosteronism Type III''':  
** This condition presents with [[transient]] [[mineralocorticoid]] resistance. Pseudohypoaldosteronism type III is seen in patients with underlying [[renal]] conditions with decreased [[glomerular filtration rate]]. The exact cause is unknown but is thought to be related to increased levels of [[TGF beta|TGF]]-β.


==Pathophysiology==
==Genetics==
*[[Genes]] involved in the [[pathogenesis]] of hypoaldosteronism include [[mutation]] in [[CYP11B2]] gene and NR3C2 gene.<ref name="pmid1594605">{{cite journal |vauthors=Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC |title=Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue=11 |pages=4996–5000 |year=1992 |pmid=1594605 |pmc=49215 |doi= |url=}}</ref><ref name="pmid9814506">{{cite journal |vauthors=Portrat-Doyen S, Tourniaire J, Richard O, Mulatero P, Aupetit-Faisant B, Curnow KM, Pascoe L, Morel Y |title=Isolated aldosterone synthase deficiency caused by simultaneous E198D and V386A mutations in the CYP11B2 gene |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue=11 |pages=4156–61 |year=1998 |pmid=9814506 |doi=10.1210/jcem.83.11.5258 |url=}}</ref><ref name="pmid15134805">{{cite journal |vauthors=White PC |title=Aldosterone synthase deficiency and related disorders |journal=Mol. Cell. Endocrinol. |volume=217 |issue=1-2 |pages=81–7 |year=2004 |pmid=15134805 |doi=10.1016/j.mce.2003.10.013 |url=}}</ref>
*'''CYP11B2 gene''' is located on chromosome 8q24.
**[[Mutation]] in [[CYP11B2]] gene is transmitted in [[autosomal recessive]] pattern.
**The [[CYP11B2]] gene encodes for the [[enzyme]] [[aldosterone synthase]] (previously known as corticosterone methyloxidase).
**[[Aldosterone synthase]] catalyses the conversion of [[11-deoxycorticosterone]] to [[aldosterone]]. The following flowchart depicts the various steps carried out by the [[enzyme]] [[aldosterone synthase]]:


===Pathogenesis===
*The exact pathogenesis of [disease name] is not fully understood.
OR
*It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
*[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
*[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
*The progression to [disease name] usually involves the [molecular pathway].
*The pathophysiology of [disease/malignancy] depends on the histological subtype.
==Genetics==
*Gene involved in the pathogenesis of hypoaldosteronism include mutation in CYP11B2 gene, which is located on chromosome 8q24.
*Mutation in CYP11B2 gene is transmitted in autosomal recessive pattern.
*The CYP11B2 gene encodes for the enzyme aldosterone synthase (previously known as corticosterone methyloxidase).
*Aldosterone synthase catalyses the conversion of 11 Deoxycorticosterone to aldosterone


{{Family tree/start}}
{{Family tree/start}}
{{Family tree | | | | A01 | | | |A01= 11 Deoxycorticosterone}}
{{Family tree | | | | A01 | | | |A01= [[11 Deoxycorticosterone]]}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | B01 | | | |B01= Corticosterone}}
{{Family tree | | | | B01 | | | |B01= [[Corticosterone]]}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | C01 | | | |C01= 18 Hydroxycorticosterone}}
{{Family tree | | | | C01 | | | |C01= [[18 Hydroxycorticosterone]]}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | D01 | | | |D01= Aldosterone}}
{{Family tree | | | | D01 | | | |D01= [[Aldosterone]]}}
{{Family tree/end}}
{{Family tree/end}}


*Mutations in CYP11B2 can lead to:
 
**Type 1 aldosterone synthase deficiency: Patients have normal to decreased levels of 18-hydroxycorticosterone and undetectable levels of aldosterone.
*Mutations in [[CYP11B2]] can lead to:
**Type 2 aldosterone synthase deficiency: Patients have increased levels of 18-hydroxycorticosterone and normal to decreased levels of aldosterone.
**Type 1 [[aldosterone synthase]] deficiency: Patients have normal to decreased levels of 18-hydroxycorticosterone and undetectable levels of [[aldosterone]].
*Aldosterone synthase is a member of the cytochrome P450 family of enzymes.
**Type 2 [[aldosterone synthase]] deficiency: Patients have increased levels of 18-hydroxycorticosterone and normal to decreased levels of [[aldosterone]].
**[[Aldosterone synthase]] is a member of the [[cytochrome P450]] family of [[enzymes]].
 
*The other gene associated with hypoaldosteronism is '''NR3C2 gene.'''
**NR3C2 [[gene]] is located on [[chromosome]] 4q31.1-31.2; which is the long (q) arm of [[chromosome 4]] at position 31.1-31.2
**NR3C2 [[gene]] encodes for [[mineralocorticoid receptor]].
**[[Mutation]] in NR3C2 [[gene]] can be transmitted in [[autosomal recessive]] or [[autosomal dominant]] pattern.
**[[Mutated]] NR3C2 [[gene]] leads to defective [[mineralocorticoid receptor]] and presents with [[resistance]] to the actions of [[aldosterone]].


==Associated Conditions==
==Associated Conditions==
*[[Sickle-cell disease|Sickle cell disease]]
*[[Analgesic nephropathy]]
*Lead nephropathy
*[[Chronic pyelonephritis]]
*[[Obstructive nephropathy]]
*[[Diabetes]] and [[renal insufficiency]]
*[[Nonsteroidal anti-inflammatory drugs]]
*[[Calcineurin inhibitor|Calcineurin inhibitors]]
*[[Vitiligo]]
*[[Premature ovarian failure]]
*[[Pernicious anemia]]
*[[Myasthenia gravis]]
*[[Candidiasis|Chronic candidiasis]]
*[[Sjögren's syndrome|Sjögren syndrome]]
*[[Chronic active hepatitis]]
*[[Hypothyroidism]]
*[[Graves' disease|Graves hyperthyroidism]]
*[[Adrenoleukodystrophy]]


==Gross Pathology==
==Gross Pathology==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*On [[gross pathology]], [[adrenal glands]] in hypoaldosteronism can either be:
**Irregularly shrunken, or
**[[Hyperplastic]]
[[image:Adrenal glands.jpg|400px|center|Image courtesy: PathologyOutlines.com]]


==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*On [[microscopic]] [[histopathological]] analysis, [[adrenal gland]] can be divided into [[adrenal cortex]] and [[adrenal medulla]].
*[[Adrenal cortex]] can be further categorized into:
**[[Zona glomerulosa]] (produces [[aldosterone]])
**[[Zona fasciculata]] (produces [[cortisol]])
**[[Zona reticularis]] (produces [[androgens]])
[[image:Adrenal glands normal histology.jpg|400px|center|Image courtesy: PathologyOutlines.com]]


==References==
==References==
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[[Category:Disease]]
[[Category:Endocrinology]]
[[Category:Nephrology]]
[[Category:Emergency medicine]]
[[Category:Medicine]]
[[Category:Up-To-Date]]

Latest revision as of 14:07, 31 July 2018

Hypoaldosteronism Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]Sargun Singh Walia M.B.B.S.[3]

Overview

Hypoaldosteronism is defined as decreased levels of the hormone aldosterone or a resistance of the target tissue to the actions of aldosterone. Hypoaldosteronism from decreased production is seen in conditions such as congenital isolated hypoaldosteronism, primary adrenal insufficiency, diabetic nephropathy, critical illness, and drugs such as ACE inhibitors, NSAIDs and calcineurin inhibitors. Resistance of the target tissue to the actions of aldosterone is seen with mineralocorticoid receptor defects (seen in pseudohypoaldosteronism) and with drugs such as potassium-sparing diuretics and trimethoprim. Hypoaldosteronism results in reduced reabsorption of sodium in the principal cells of cortical collecting tubules (CCT). This leads to decreased excretion of potassium (hyperkalemia) and mild non-anion gap metabolic acidosis. On gross pathology, adrenal glands may be irregularly shrunken or hyperplastic.

Pathophysiology

Physiology


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


Pathogenesis

Hyporeninemic Hypoaldosteronism

Hyperreninemic Hypoaldosteronism

Isolated Hypoaldosteronism

Postadrenalectomy Hypoaldosteronism

Postadrenalectomy hypoaldosteronism is seen in patients with Conn syndrome who undergo surgery for tumor removal:[12][13][14][15][16][17][18]

Mineralocorticoid Resistance

Mineralocorticoid resistance is characterized by a decrease in response to the hormone aldosterone. In mineralocorticoid resistance the level of aldosterone may be normal or supranormal. It is due to this reason mineralocorticoid resistance is also known as pseudohypoaldosteronism. Mineralocorticoid resistance can be further categorized into:[19][20][21]

Genetics


 
 
 
11 Deoxycorticosterone
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Corticosterone
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 Hydroxycorticosterone
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aldosterone
 
 
 


Associated Conditions

Gross Pathology

Image courtesy: PathologyOutlines.com
Image courtesy: PathologyOutlines.com

Microscopic Pathology

Image courtesy: PathologyOutlines.com
Image courtesy: PathologyOutlines.com

References

  1. ↑ Schnermann J, Levine DZ (2003). "Paracrine factors in tubuloglomerular feedback: adenosine, ATP, and nitric oxide". Annu. Rev. Physiol. 65: 501–29. doi:10.1146/annurev.physiol.65.050102.085738. PMID 12208992.
  2. ↑ Castrop H (2007). "Mediators of tubuloglomerular feedback regulation of glomerular filtration: ATP and adenosine". Acta Physiol (Oxf). 189 (1): 3–14. doi:10.1111/j.1748-1716.2006.01610.x. PMID 17280552.
  3. ↑ Hall JE (1991). "Control of blood pressure by the renin-angiotensin-aldosterone system". Clin Cardiol. 14 (8 Suppl 4): IV6–21, discussion IV51–5. PMID 1893644.
  4. ↑ White PC (1994). "Disorders of aldosterone biosynthesis and action". N. Engl. J. Med. 331 (4): 250–8. doi:10.1056/NEJM199407283310408. PMID 8015573.
  5. ↑ Weidmann P (1982). "[Hyporeninemic hypoaldosteronism and the differential diagnosis of hyperkalemia]". Schweiz Med Wochenschr (in German). 112 (49): 1764–74. PMID 6758113.
  6. ↑ Schambelan M, Sebastian A (1985). "[Type IV renal tubular acidosis: pathogenetic role of aldosterone deficiency and hyperkalemia]". Nephrologie (in French). 6 (3): 135–7. PMID 3908957.
  7. ↑ Arruda JA, Kurtzman NA (1980). "Mechanisms and classification of deranged distal urinary acidification". Am. J. Physiol. 239 (6): F515–23. PMID 7446728.
  8. ↑ Kater CE, Biglieri EG, Brust N, Chang B, Hirai J (1982). "Regulation of the mineralocorticoid hormones in adrenocortical disorders with adrenocorticotropin excess". Clin Exp Hypertens A. 4 (9–10): 1749–58. PMID 6291814.
  9. ↑ Aguilera G, Fujita K, Catt KJ (1981). "Mechanisms of inhibition of aldosterone secretion by adrenocorticotropin". Endocrinology. 108 (2): 522–8. doi:10.1210/endo-108-2-522. PMID 6256154.
  10. ↑ Singer DR, Shirley DG, Markandu ND, Miller MA, Buckley MG, Sugden AL, Sagnella GA, MacGregor GA (1991). "How important are suppression of aldosterone and stimulation of atrial natriuretic peptide secretion in the natriuretic response to an acute sodium load in man?". Clin. Sci. 80 (4): 293–9. PMID 1851063.
  11. ↑ Lisurek M, Bernhardt R (2004). "Modulation of aldosterone and cortisol synthesis on the molecular level". Mol. Cell. Endocrinol. 215 (1–2): 149–59. doi:10.1016/j.mce.2003.11.008. PMID 15026188.
  12. ↑ Kawasaki T, Uezono K, Ueno M, Noda Y, Kumamoto K, Kawano Y, Ogata M, Fukiyama K, Omae T, Bartter FC (1980). "Influence of unilateral adrenalectomy on renin-angiotensin-aldosterone system in primary aldosteronism". Jpn Heart J. 21 (5): 681–92. PMID 7001091.
  13. ↑ Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Schultze Kool LJ, Hermus AR, Deinum J (2009). "Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism". Ann. Intern. Med. 151 (5): 329–37. PMID 19721021.
  14. ↑ Huang WT, Chau T, Wu ST, Lin SH (2010). "Prolonged hyperkalemia following unilateral adrenalectomy for primary hyperaldosteronism". Clin. Nephrol. 73 (5): 392–7. PMID 20420801.
  15. ↑ Gadallah MF, Kayyas Y, Boules F (1998). "Reversible suppression of the renin-aldosterone axis after unilateral adrenalectomy for adrenal adenoma". Am. J. Kidney Dis. 32 (1): 160–3. PMID 9669438.
  16. ↑ Biglieri EG, Slaton PE, Silen WS, Galante M, Forsham PH (1966). "Postoperative studies of adrenal function in primary aldosteronism". J. Clin. Endocrinol. Metab. 26 (5): 553–8. doi:10.1210/jcem-26-5-553. PMID 4287160.
  17. ↑ Groth H, Vetter W, Stimpel M, Greminger P, Tenschert W, Klaiber E, Vetter H (1985). "Adrenalectomy in primary aldosteronism: a long-term follow-up study". Cardiology. 72 Suppl 1: 107–16. PMID 3902226.
  18. ↑ Yorke E, Stafford S, Holmes D, Sheth S, Melck A (2015). "Aldosterone deficiency after unilateral adrenalectomy for Conn's syndrome: a case report and literature review". Int J Surg Case Rep. 7C: 141–4. doi:10.1016/j.ijscr.2015.01.013. PMC 4336421. PMID 25604311.
  19. ↑ CHEEK DB, PERRY JW (1958). "A salt wasting syndrome in infancy". Arch. Dis. Child. 33 (169): 252–6. PMC 2012226. PMID 13545877.
  20. ↑ Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP (2001). "Human hypertension caused by mutations in WNK kinases". Science. 293 (5532): 1107–12. doi:10.1126/science.1062844. PMID 11498583.
  21. ↑ Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S, Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S (2013). "Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension". Cell Rep. 3 (3): 858–68. doi:10.1016/j.celrep.2013.02.024. PMID 23453970.
  22. ↑ Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC (1992). "Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency". Proc. Natl. Acad. Sci. U.S.A. 89 (11): 4996–5000. PMC 49215. PMID 1594605.
  23. ↑ Portrat-Doyen S, Tourniaire J, Richard O, Mulatero P, Aupetit-Faisant B, Curnow KM, Pascoe L, Morel Y (1998). "Isolated aldosterone synthase deficiency caused by simultaneous E198D and V386A mutations in the CYP11B2 gene". J. Clin. Endocrinol. Metab. 83 (11): 4156–61. doi:10.1210/jcem.83.11.5258. PMID 9814506.
  24. ↑ White PC (2004). "Aldosterone synthase deficiency and related disorders". Mol. Cell. Endocrinol. 217 (1–2): 81–7. doi:10.1016/j.mce.2003.10.013. PMID 15134805.

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