Acromegaly pathophysiology: Difference between revisions

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{{Acromegaly}}
{{Acromegaly}}
{{CMG}} {{AE}}
{{CMG}}; {{AE}} {{AEL}}  


==Overview==
Acromegaly pathogenesis depends mainly on the excessive secretion of the [[growth hormone]] from the [[pituitary gland]]. [[Pituitary adenoma|Pituitary somatotroph cell adenoma]] leads to hyper-secretion of the [[growth hormone]]. [[Insulin-like growth factor|Insulin-like growth factor 1 (IGF-1)]] inhibits the secretion of [[growth hormone]] in two ways: [[IGF-1]] inhibits directly the [[Somatotrophs|somatotroph cells]] or stimulates secretion the [[somatostatin]] that inhibits the [[GH]] secretion, IGF-1 is also responsible for the acral features of the acromegaly. The  [[IGF-1]] causes the rapid increase in the [[hand]] and [[feet]] size, [[forehead]] protrusion, and [[jaw]] prominence. A [[genetic mutation]] in the alpha subunit of the [[guanine]] nucleotide stimulatory [[protein]] leads to increase synthesis of [[cAMP]] which increases the secretion of [[growth hormone]]. Acromegaly is associated with [[Multiple endocrine neoplasia type 1|multiple endocrine neoplasia 1 (MEN-1)]], [[Carney complex|Carney complex,]] [[McCune-Albright syndrome]][[Paraganglioma|, paraganglioma,]] and [[Pheochromocytoma]].


==Overview==
==Pathophysiology==
==Pathophysiology==
<ref name="pmid26873451">{{cite journal| author=Dineen R, Stewart PM, Sherlock M| title=Acromegaly. | journal=QJM | year= 2016 | volume=  | issue=  | pages=  | pmid=26873451 | doi=10.1093/qjmed/hcw004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26873451  }} </ref>.
Acromegaly is believed to be caused by [[GH|growth hormone (GH)]] secreting [[pituitary adenomas]] either [[Microadenoma of the pituitary gland|microadenomas]] or [[Macroadenoma of the pituitary gland|macroadenomas]]. The [[pituitary adenoma]] leads to hypersecretion of the [[growth hormone]] from the [[Somatotrophs|somatotroph cells]].<ref name="pmid26873451">{{cite journal| author=Dineen R, Stewart PM, Sherlock M| title=Acromegaly. | journal=QJM | year= 2016 | volume=  | issue=  | pages=  | pmid=26873451 | doi=10.1093/qjmed/hcw004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26873451  }} </ref><ref name="pmid2549426">{{cite journal| author=Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L| title=GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. | journal=Nature | year= 1989 | volume= 340 | issue= 6236 | pages= 692-6 | pmid=2549426 | doi=10.1038/340692a0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2549426  }} </ref><ref name="pmid19884662">{{cite journal| author=Melmed S| title=Acromegaly pathogenesis and treatment. | journal=J Clin Invest | year= 2009 | volume= 119 | issue= 11 | pages= 3189-202 | pmid=19884662 | doi=10.1172/JCI39375 | pmc=2769196 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19884662  }}</ref>


===Pathogenesis===
===Normal Physiology===
*The exact pathogenesis of [disease name] is not fully understood.
*Normally, the [[growth hormone]] is secreted and stored in the [[anterior pituitary gland]] particularly in the [[Somatotrophs|somatotroph cells]].  
OR
*[[Growth hormone]] secretion is affected by several factors.
*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].
**[[Growth hormone]] is stimulated by [[ghrelin]] and [[growth hormone releasing hormone]].
*[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
**[[Somatostatin]] inhibits the [[growth hormone]] secretion.
*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
*[[Insulin-like growth factor]] 1 (IGF-1) inhibits the secretion of [[growth hormone]] in two ways.
*[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
**IGF-1 inhibits directly the [[Somatotrophs|somatotroph cells]] or stimulates secretion the [[somatostatin]] that inhibits the [[GH]] secretion.  
*The progression to [disease name] usually involves the [molecular pathway].
*[[Growth hormone]] is functioning through binding to its receptor which is a [[glycoprotein]] receptor.
*The pathophysiology of [disease/malignancy] depends on the histological subtype.
*Binding of [[GH]] to its receptor stimulates [[proteins]] which start a process called signal [[transduction]] and [[transcription]].
=== Pathogenesis ===
*In [[pituitary adenomas]], a [[mutation]] in the alpha subunit of the [[Guanine|guanine nucleotide]] stimulatory [[protein]] is responsible for the excess [[growth hormone]] secretion.
*The mutation in the alpha subunit will lead to increase synthesis of [[cAMP]] which is responsible for the growth of certain cells.
*Increase synthesis of [[cAMP]] will result in the increase secretion of the [[growth hormone]].
*Signal transduction and transcription (STAT) induce production of [[IGF-1]] from [[liver]], [[bone]] and [[pituitary gland]].  
*The [[IGF-1]] is responsible for the acral features of acromegaly. [[IGF-1]] causes the rapid increase in the [[hand]] and [[feet]] size, [[forehead]] protrusion, and [[jaw]] prominence.
*The high level of [[IGF-1]] is responsible for the following pathologic processes:
**[[IGF-1]] is responsible for the [[diabetes mellitus]] which is common in 20% of patients with acromegaly. [[IGF-1]] interferes with [[insulin]] on its receptor which leads to [[insulin resistance]] and [[hyperglycemia]].
**[[IGF-1]] causes [[hypertrophy]] of the body organs like the [[heart]] ([[cardiomegaly]]) and [[tongue]] ([[macroglossia]]).


==Genetics==
==Genetics==
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
*The development of acromegaly has been associated also with microduplications on [[chromosome]] Xq26.3 which is a location for [[G protein]] coupled receptor 101 [[gene]] (GPCR101).
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
*Microduplication of the chromosome Xq26.3 will be associated with mutations of the GPCR101 protein which leads to increase of the [[growth hormone]] secretion.<ref name="pmid25470569">{{cite journal| author=Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO et al.| title=Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 25 | pages= 2363-74 | pmid=25470569 | doi=10.1056/NEJMoa1408028 | pmc=4291174 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25470569  }} </ref>
*The development of [disease name] is the result of multiple genetic mutations.
 
==Associated Conditions==
==Associated Conditions==
*Acromegaly may be associated with the following genetic diseases:<ref name="pmid27657986">{{cite journal| author=Hannah-Shmouni F, Trivellin G, Stratakis CA| title=Genetics of gigantism and acromegaly. | journal=Growth Horm IGF Res | year= 2016 | volume= 30-31 | issue=  | pages= 37-41 | pmid=27657986 | doi=10.1016/j.ghir.2016.08.002 | pmc=5154831 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27657986  }} </ref>
**Familial isolated [[pituitary adenoma]]
**[[Multiple endocrine neoplasia type 1|Multiple Endocrine Neoplasia 1 (MEN-1)]]
**[[Carney complex]]
**[[McCune-Albright syndrome]]
**[[Paraganglioma]]
**[[Pheochromocytoma]]
**[[Diabetes mellitus]]
**[[Sleep apnea]]
**[[Carpal tunnel syndrome]]
**[[Hypertension]]
**[[Osteoarthritis]]


==Gross Pathology==
== Gross pathology ==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Gross pathology of acromegaly shows [[pituitary gland]] [[adenoma]] in most of the cases. Findings include the following:
*Microprolactinomas (<10mm size) are usually found in the lateral wing of the pituitary gland. They are most often surrounded by well defined pseudocapsules composed of reticulin.
*Macroprolactinomas (>10mm size) differ substantially in size and behavior. Some cause sellar expansion while others invade the base of the skull.
*About 50% of all prolactinoma grossly invade surrounding structures.


==Microscopic Pathology==
==Microscopic pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*Pituitary microadenomas are defined as adenomas less than 10 mm in size.
*Most frequently diagnosed as a result of investigating hormonal imbalance.
*They are confined to the [[sella]] and have no scope to produce mass effect related symptoms.
<gallery>
Pituitary adenoma (1) GH production.jpg|Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.<ref name=Wikipedia1> https://en.wikipedia.org/wiki/Pituitary_adenoma#/media/File:Pituitary_adenoma_%281%29_GH_production.jpg</ref>
Image:
Pituitary adenoma (2) GH production.jpg|Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.<ref name=Wikipedia1> https://en.wikipedia.org/wiki/Pituitary_adenoma#/media/File:Pituitary_adenoma_%281%29_GH_production.jpg</ref>
</gallery>


==References==
==References==

Latest revision as of 12:14, 5 February 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Overview

Acromegaly pathogenesis depends mainly on the excessive secretion of the growth hormone from the pituitary gland. Pituitary somatotroph cell adenoma leads to hyper-secretion of the growth hormone. Insulin-like growth factor 1 (IGF-1) inhibits the secretion of growth hormone in two ways: IGF-1 inhibits directly the somatotroph cells or stimulates secretion the somatostatin that inhibits the GH secretion, IGF-1 is also responsible for the acral features of the acromegaly. The IGF-1 causes the rapid increase in the hand and feet size, forehead protrusion, and jaw prominence. A genetic mutation in the alpha subunit of the guanine nucleotide stimulatory protein leads to increase synthesis of cAMP which increases the secretion of growth hormone. Acromegaly is associated with multiple endocrine neoplasia 1 (MEN-1), Carney complex, McCune-Albright syndrome, paraganglioma, and Pheochromocytoma.

Pathophysiology

Acromegaly is believed to be caused by growth hormone (GH) secreting pituitary adenomas either microadenomas or macroadenomas. The pituitary adenoma leads to hypersecretion of the growth hormone from the somatotroph cells.[1][2][3]

Normal Physiology

Pathogenesis

Genetics

  • The development of acromegaly has been associated also with microduplications on chromosome Xq26.3 which is a location for G protein coupled receptor 101 gene (GPCR101).
  • Microduplication of the chromosome Xq26.3 will be associated with mutations of the GPCR101 protein which leads to increase of the growth hormone secretion.[4]

Associated Conditions

Gross pathology

Gross pathology of acromegaly shows pituitary gland adenoma in most of the cases. Findings include the following:

  • Microprolactinomas (<10mm size) are usually found in the lateral wing of the pituitary gland. They are most often surrounded by well defined pseudocapsules composed of reticulin.
  • Macroprolactinomas (>10mm size) differ substantially in size and behavior. Some cause sellar expansion while others invade the base of the skull.
  • About 50% of all prolactinoma grossly invade surrounding structures.

Microscopic pathology

  • Pituitary microadenomas are defined as adenomas less than 10 mm in size.
  • Most frequently diagnosed as a result of investigating hormonal imbalance.
  • They are confined to the sella and have no scope to produce mass effect related symptoms.
  • Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.[6]

    Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.[6]

  • Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.[6]

    Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.[6]

References

  1. ↑ Dineen R, Stewart PM, Sherlock M (2016). "Acromegaly". QJM. doi:10.1093/qjmed/hcw004. PMID 26873451.
  2. ↑ Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L (1989). "GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours". Nature. 340 (6236): 692–6. doi:10.1038/340692a0. PMID 2549426.
  3. ↑ Melmed S (2009). "Acromegaly pathogenesis and treatment". J Clin Invest. 119 (11): 3189–202. doi:10.1172/JCI39375. PMC 2769196. PMID 19884662.
  4. ↑ Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO; et al. (2014). "Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation". N Engl J Med. 371 (25): 2363–74. doi:10.1056/NEJMoa1408028. PMC 4291174. PMID 25470569.
  5. ↑ Hannah-Shmouni F, Trivellin G, Stratakis CA (2016). "Genetics of gigantism and acromegaly". Growth Horm IGF Res. 30-31: 37–41. doi:10.1016/j.ghir.2016.08.002. PMC 5154831. PMID 27657986.
  6. ↑ 6.0 6.1 https://en.wikipedia.org/wiki/Pituitary_adenoma#/media/File:Pituitary_adenoma_%281%29_GH_production.jpg

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