Acromegaly pathophysiology: Difference between revisions
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=== Pathogenesis === | === Pathogenesis === | ||
*It is thought that acromegaly caused by GH secreting pituitary adenomas either microadenomas or macroadenomas. The pituitary adenoma leads to hypersecretion of the growth hormone from the somatotroph cells. | *It is thought that acromegaly caused by [[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]]. | ||
*Normally, the growth hormone is secreted and stored in the anterior pituitary gland particularly in the somatotroph cells. Growth hormone secretion is affected by several factors. Growth hormone is stimulated by ghrelin and growth hormone releasing hormone. Somatostatin inhibits the growth hormone secretion.<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> | *Normally, the [[growth hormone]] is secreted and stored in the [[anterior pituitary gland]] particularly in the [[Somatotrophs|somatotroph cells]]. Growth hormone secretion is affected by several factors. Growth hormone is stimulated by [[ghrelin]] and [[growth hormone releasing hormone]]. [[Somatostatin]] inhibits the [[growth hormone]] secretion.<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> | ||
*Insulin 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. | *[[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. | ||
*Growth hormone is functioning through binding to its receptor which is a glycoprotein receptor. Binding of GH to its receptor stimulates proteins which start a process called signal transduction and transcription. Signal transduction and transcription (STAT) | *[[Growth hormone]] is functioning through binding to its receptor which is a [[glycoprotein]] receptor. Binding of [[GH]] to its receptor stimulates [[proteins]] which start a process called signal [[transduction]] and [[transcription]]. Signal transduction and transcription (STAT) induce production of [[IGF-1]] from [[liver]], [[bone]] and [[pituitary gland]].<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> | ||
*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 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: | *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 | **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). | **IGF-1 causes [[hypertrophy]] of the body organs like the [[heart]] ([[cardiomegaly]]) and [[tongue]] ([[macroglossia]]). | ||
==Genetics== | ==Genetics== | ||
*The development of acromegaly is the result of multiple genetic mutations. In pituitary adenomas, a mutation in the alpha subunit of the 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.<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> | *The development of acromegaly is the result of multiple [[genetic mutations]]. In [[pituitary adenomas]], a [[mutation]] in the alpha subunit of the 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]].<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> | ||
*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.<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 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.<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> | ||
==Associated Conditions== | ==Associated Conditions== | ||
*Patients with 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> | *Patients with 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 | **Familial isolated [[pituitary adenoma]] | ||
**Multiple Endocrine Neoplasia 1 (MEN-1) | **[[Multiple endocrine neoplasia type 1|Multiple Endocrine Neoplasia 1 (MEN-1)]] | ||
**Carney complex | **[[Carney complex]] | ||
**McCune-Albright syndrome | **[[McCune-Albright syndrome]] | ||
**Paraganglioma | **[[Paraganglioma]] | ||
**Pheochromocytoma | **[[Pheochromocytoma]] | ||
*Patients with acromegaly may be associated with the following conditions:<ref name="pmid25356808">{{cite journal| author=Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A et al.| title=Acromegaly: an endocrine society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2014 | volume= 99 | issue= 11 | pages= 3933-51 | pmid=25356808 | doi=10.1210/jc.2014-2700 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25356808 }} </ref> | *Patients with acromegaly may be associated with the following conditions:<ref name="pmid25356808">{{cite journal| author=Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A et al.| title=Acromegaly: an endocrine society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2014 | volume= 99 | issue= 11 | pages= 3933-51 | pmid=25356808 | doi=10.1210/jc.2014-2700 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25356808 }} </ref> | ||
**Diabetes mellitus | **[[Diabetes mellitus]] | ||
** | **[[Sleep apnea]] | ||
**Carpal tunnel syndrome | **[[Carpal tunnel syndrome]] | ||
**Hypertension | **[[Hypertension]] | ||
**Osteoarthritis | **[[Osteoarthritis]] | ||
==References== | ==References== | ||
Revision as of 18:45, 14 August 2017
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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
Pathophysiology
Pathogenesis
- It is thought that acromegaly caused by GH secreting pituitary adenomas either microadenomas or macroadenomas. The pituitary adenoma leads to hypersecretion of the growth hormone from the somatotroph cells.
- Normally, the growth hormone is secreted and stored in the anterior pituitary gland particularly in the somatotroph cells. Growth hormone secretion is affected by several factors. Growth hormone is stimulated by ghrelin and growth hormone releasing hormone. Somatostatin inhibits the growth hormone secretion.[1]
- 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.
- Growth hormone is functioning through binding to its receptor which is a glycoprotein receptor. Binding of GH to its receptor stimulates proteins which start a process called signal transduction and transcription. Signal transduction and transcription (STAT) induce production of IGF-1 from liver, bone and pituitary gland.[2]
- 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
- The development of acromegaly is the result of multiple genetic mutations. In pituitary adenomas, a mutation in the alpha subunit of the 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.[3]
- 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
- Patients with acromegaly may be associated with the following genetic diseases:[5]
- Patients with acromegaly may be associated with the following conditions:[6]
References
- ↑ Dineen R, Stewart PM, Sherlock M (2016). "Acromegaly". QJM. doi:10.1093/qjmed/hcw004. PMID 26873451.
- ↑ Melmed S (2009). "Acromegaly pathogenesis and treatment". J Clin Invest. 119 (11): 3189–202. doi:10.1172/JCI39375. PMC 2769196. PMID 19884662.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A; et al. (2014). "Acromegaly: an endocrine society clinical practice guideline". J Clin Endocrinol Metab. 99 (11): 3933–51. doi:10.1210/jc.2014-2700. PMID 25356808.