Toxic Adenoma pathophysiology: Difference between revisions

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{{CMG}} ; {{AE}} {{ADG}}
{{CMG}} ; {{AE}} {{ADG}}
==Overview==
==Overview==
[[Thyroid-stimulating hormone]] ([[TSH]]) binds to its [[receptor]] on the surface of [[Thyroid follicular cell|thyroid follicular cells]]. When [[TSH]] binds to the [[TSH receptor]], it stimulates [[adenylyl cyclase]] conversion of [[adenosine triphosphate]] ([[ATP]]) to [[cyclic adenosine monophosphate]] ([[cAMP]]). Activation of this pathway leads to [[cell growth]] and [[thyroid hormone]] secretion. When [[TSH]] concentrations are five- to tenfold higher, [[TSH]] binding to its [[receptor]] leads to its interaction with [[Gq proteins|Gq]], activating [[phospholipase C]], which in turn leads to increased intracellular [[calcium]], [[diacylglycerol]], and [[inositol phosphate]]. Activation of this pathway regulates [[iodination]] and [[thyroid hormone]] production. Alteration of the above pathway by activation of [[Germline mutation|germline]] or [[Mutations|somatic mutations]] in the [[TSH]] receptor or [[cAMP]] signal transduction system is believed to be responsible for the development of autonomous [[thyroid gland]] growth and hormonogenesis. The molecular alterations responsible for toxic adenomas include somatic gain-of-function mutations in the [[TSH receptor]] or the stimulatory [[Gs alpha subunit|Gsα subunit]]. Both result in constitutive activation of the [[CAMP|cAMP pathway]], which results in enhanced proliferation and function of [[Thyroid follicular cell|thyroid follicular cells]].
[[Thyroid-stimulating hormone]] ([[TSH]]) binds to its [[receptor]] on the surface of [[Thyroid follicular cell|thyroid follicular cells]]. When [[TSH]] binds to the [[TSH receptor]], it stimulates [[adenylyl cyclase]] conversion of [[adenosine triphosphate]] ([[ATP]]) to [[cyclic adenosine monophosphate]] ([[cAMP]]). Activation of [[cyclic adenosine monophosphate]] ([[cAMP]]) results in [[thyroid hormone]] secretion. When [[TSH]] concentrations are five- to tenfold higher, [[TSH]] binding to its [[receptor]] leads to its interaction with [[Gq proteins|Gq]], activating [[phospholipase C]], which in turn leads to increased intracellular [[calcium]], [[diacylglycerol]], and [[inositol phosphate]]. Activation of this pathway regulates [[iodination]] and [[thyroid hormone]] production. Alteration of the above pathway by activation of [[Germline mutation|germline]] or [[Mutations|somatic mutations]] in the [[TSH]] receptor or [[cAMP]] signal [[transduction]] system is believed to be responsible for the development of autonomous [[thyroid gland]] growth and hormonogenesis. The molecular alterations responsible for toxic [[adenomas]] include somatic gain-of-function [[mutations]] in the [[TSH receptor]] or the stimulatory [[Gs alpha subunit|Gsα subunit]]. Both result in constitutive activation of the [[CAMP|cAMP pathway]], which results in enhanced proliferation and function of [[Thyroid follicular cell|thyroid follicular cells]].


==Pathogenesis==
==Pathogenesis==
[[Thyroid-stimulating hormone]] ([[TSH]]) binds to its [[receptor]] on the surface of [[Thyroid follicular cell|thyroid follicular cells]]. When [[TSH]] binds to the [[TSH receptor]], it stimulates [[adenylyl cyclase]] conversion of [[adenosine triphosphate]] ([[ATP]]) to [[cyclic adenosine monophosphate]] ([[cAMP]]). Activation of this pathway leads to [[cell growth]] and [[thyroid hormone]] secretion. When [[TSH]] concentrations are five- to tenfold higher, [[TSH]] binding to its [[receptor]] leads to its interaction with [[Gq proteins|Gq]], activating [[phospholipase C]], which in turn leads to increased intracellular [[calcium]], [[diacylglycerol]], and [[inositol phosphate]]. Activation of this pathway regulates [[iodination]] and [[thyroid hormone]] production. Alteration of the above pathway by activation of [[Germline mutation|germline]] or [[Mutations|somatic mutations]] in the [[TSH]] receptor or [[cAMP]] signal transduction system is believed to be responsible for the development of autonomous [[thyroid gland]] growth and hormonogenesis. The molecular alterations responsible for toxic adenomas include somatic gain-of-function mutations in the [[TSH receptor]] or the stimulatory [[Gs alpha subunit|Gsα subunit]]. Both result in constitutive activation of the [[CAMP|cAMP pathway]], which results in enhanced proliferation and function of [[Thyroid follicular cell|thyroid follicular cells]].<ref name="pmid1320763">{{cite journal |vauthors=Dumont JE, Lamy F, Roger P, Maenhaut C |title=Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors |journal=Physiol. Rev. |volume=72 |issue=3 |pages=667–97 |year=1992 |pmid=1320763 |doi= |url=}}</ref><ref name="pmid7673398">{{cite journal |vauthors=Van Sande J, Parma J, Tonacchera M, Swillens S, Dumont J, Vassart G |title=Somatic and germline mutations of the TSH receptor gene in thyroid diseases |journal=J. Clin. Endocrinol. Metab. |volume=80 |issue=9 |pages=2577–85 |year=1995 |pmid=7673398 |doi=10.1210/jcem.80.9.7673398 |url=}}</ref><ref name="pmid8592518">{{cite journal |vauthors=Parma J, Van Sande J, Swillens S, Tonacchera M, Dumont J, Vassart G |title=Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas: identification of additional mutations activating both the cyclic adenosine 3',5'-monophosphate and inositol phosphate-Ca2+ cascades |journal=Mol. Endocrinol. |volume=9 |issue=6 |pages=725–33 |year=1995 |pmid=8592518 |doi=10.1210/mend.9.6.8592518 |url=}}</ref><ref name="pmid20926595">{{cite journal |vauthors=Hébrant A, van Staveren WC, Maenhaut C, Dumont JE, Leclère J |title=Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations |journal=Eur. J. Endocrinol. |volume=164 |issue=1 |pages=1–9 |year=2011 |pmid=20926595 |doi=10.1530/EJE-10-0775 |url=}}</ref><ref name="pmid11434721">{{cite journal |vauthors=Trülzsch B, Krohn K, Wonerow P, Chey S, Holzapfel HP, Ackermann F, Führer D, Paschke R |title=Detection of thyroid-stimulating hormone receptor and Gsalpha mutations: in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis |journal=J. Mol. Med. |volume=78 |issue=12 |pages=684–91 |year=2001 |pmid=11434721 |doi= |url=}}</ref>
[[Thyroid-stimulating hormone]] ([[TSH]]) binds to its [[receptor]] on the surface of [[Thyroid follicular cell|thyroid follicular cells]]. When [[TSH]] binds to the [[TSH receptor]], it stimulates [[adenylyl cyclase]] conversion of [[adenosine triphosphate]] ([[ATP]]) to [[cyclic adenosine monophosphate]] ([[cAMP]]). Activation of this pathway leads to [[cell growth]] and [[thyroid hormone]] secretion. When [[TSH]] concentrations are five- to tenfold higher, [[TSH]] binding to its [[receptor]] leads to its interaction with [[Gq proteins|Gq]], activating [[phospholipase C]], which in turn leads to increased intracellular [[calcium]], [[diacylglycerol]], and [[inositol phosphate]]. Activation of this pathway regulates [[iodination]] and [[thyroid hormone]] production. Alteration of the above pathway by activation of [[Germline mutation|germline]] or [[Mutations|somatic mutations]] in the [[TSH]] receptor or [[cAMP]] signal transduction system is believed to be responsible for the development of autonomous [[thyroid gland]] growth and hormonogenesis. The molecular alterations responsible for toxic adenomas include [[somatic]] gain-of-function [[mutations]] in the [[TSH receptor]] or the stimulatory [[Gs alpha subunit|Gsα subunit]]. Both result in constitutive activation of the [[CAMP|cAMP pathway]], which results in enhanced proliferation and function of [[Thyroid follicular cell|thyroid follicular cells]].<ref name="pmid1320763">{{cite journal |vauthors=Dumont JE, Lamy F, Roger P, Maenhaut C |title=Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors |journal=Physiol. Rev. |volume=72 |issue=3 |pages=667–97 |year=1992 |pmid=1320763 |doi= |url=}}</ref><ref name="pmid7673398">{{cite journal |vauthors=Van Sande J, Parma J, Tonacchera M, Swillens S, Dumont J, Vassart G |title=Somatic and germline mutations of the TSH receptor gene in thyroid diseases |journal=J. Clin. Endocrinol. Metab. |volume=80 |issue=9 |pages=2577–85 |year=1995 |pmid=7673398 |doi=10.1210/jcem.80.9.7673398 |url=}}</ref><ref name="pmid8592518">{{cite journal |vauthors=Parma J, Van Sande J, Swillens S, Tonacchera M, Dumont J, Vassart G |title=Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas: identification of additional mutations activating both the cyclic adenosine 3',5'-monophosphate and inositol phosphate-Ca2+ cascades |journal=Mol. Endocrinol. |volume=9 |issue=6 |pages=725–33 |year=1995 |pmid=8592518 |doi=10.1210/mend.9.6.8592518 |url=}}</ref><ref name="pmid20926595">{{cite journal |vauthors=Hébrant A, van Staveren WC, Maenhaut C, Dumont JE, Leclère J |title=Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations |journal=Eur. J. Endocrinol. |volume=164 |issue=1 |pages=1–9 |year=2011 |pmid=20926595 |doi=10.1530/EJE-10-0775 |url=}}</ref><ref name="pmid11434721">{{cite journal |vauthors=Trülzsch B, Krohn K, Wonerow P, Chey S, Holzapfel HP, Ackermann F, Führer D, Paschke R |title=Detection of thyroid-stimulating hormone receptor and Gsalpha mutations: in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis |journal=J. Mol. Med. |volume=78 |issue=12 |pages=684–91 |year=2001 |pmid=11434721 |doi= |url=}}</ref>


===Somatic activating GS alpha mutations===
===Somatic activating GS alpha mutations===
*Toxic adenomas represent a [[clone]] of proliferating follicular epithelial cells that grow and produce [[thyroid hormone]] autonomously.
*Toxic adenomas represent a [[clone]] of proliferating follicular [[epithelial]] cells that grow and produce [[thyroid hormone]] autonomously.
*The first [[mutations]] identified in toxic adenomas were somatic activating point [[mutations]] in [[Gs alpha subunit|Gs alpha]], which were identified after similar mutations were found in pituitary [[Somatotrophs|somatotroph]] adenomas.<ref name="pmid2116665">{{cite journal |vauthors=Lyons J, Landis CA, Harsh G, Vallar L, Grünewald K, Feichtinger H, Duh QY, Clark OH, Kawasaki E, Bourne HR |title=Two G protein oncogenes in human endocrine tumors |journal=Science |volume=249 |issue=4969 |pages=655–9 |year=1990 |pmid=2116665 |doi= |url=}}</ref><ref name="pmid8413627">{{cite journal |vauthors=Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, Dumont J, Vassart G |title=Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas |journal=Nature |volume=365 |issue=6447 |pages=649–51 |year=1993 |pmid=8413627 |doi=10.1038/365649a0 |url=}}</ref>  
*The first [[mutations]] identified in toxic adenomas were [[somatic]] activating point [[mutations]] in [[Gs alpha subunit|Gs alpha]], which were identified after similar [[mutations]] were found in [[pituitary]] [[Somatotrophs|somatotroph]] [[adenomas]].<ref name="pmid2116665">{{cite journal |vauthors=Lyons J, Landis CA, Harsh G, Vallar L, Grünewald K, Feichtinger H, Duh QY, Clark OH, Kawasaki E, Bourne HR |title=Two G protein oncogenes in human endocrine tumors |journal=Science |volume=249 |issue=4969 |pages=655–9 |year=1990 |pmid=2116665 |doi= |url=}}</ref><ref name="pmid8413627">{{cite journal |vauthors=Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, Dumont J, Vassart G |title=Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas |journal=Nature |volume=365 |issue=6447 |pages=649–51 |year=1993 |pmid=8413627 |doi=10.1038/365649a0 |url=}}</ref>  
*[[Mutations]] located at [[arginine]] 201 and [[glutamine]] 227 lead to constitutive activation of the [[G protein]], with consequent stimulation of the [[cAMP]] signaling cascade.  
*[[Mutations]] located at [[arginine]] 201 and [[glutamine]] 227 lead to constitutive activation of the [[G protein]], with consequent stimulation of the [[cAMP]] signaling cascade.  
*Gain-of-function mutations in [[Gs alpha subunit|Gsα]] impair the [[hydrolysis]] of guanine triphosphate (GTP) to guanine diphosphate (GDP), resulting in persistent activation of [[Adenylate cyclase|adenylyl cyclase]].   
*Gain-of-function [[mutations]] in [[Gs alpha subunit|Gsα]] impair the [[hydrolysis]] of guanine triphosphate (GTP) to guanine diphosphate (GDP), resulting in persistent activation of [[Adenylate cyclase|adenylyl cyclase]].   
*[[Mosaicism]] for [[Gs alpha subunit|Gsα]] mutations with onset during [[blastocyst]] development causes [[McCune-Albright syndrome]], which can also be associated with toxic adenomas in which there is a sporadic activating [[mutation]] in [[arginine]] 201.<ref name="pmid1944469">{{cite journal |vauthors=Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM |title=Activating mutations of the stimulatory G protein in the McCune-Albright syndrome |journal=N. Engl. J. Med. |volume=325 |issue=24 |pages=1688–95 |year=1991 |pmid=1944469 |doi=10.1056/NEJM199112123252403 |url=}}</ref>  
*[[Mosaicism]] for [[Gs alpha subunit|Gsα]] mutations with onset during [[blastocyst]] development causes [[McCune-Albright syndrome]], which can also be associated with toxic adenomas in which there is a sporadic activating [[mutation]] in [[arginine]] 201.<ref name="pmid1944469">{{cite journal |vauthors=Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM |title=Activating mutations of the stimulatory G protein in the McCune-Albright syndrome |journal=N. Engl. J. Med. |volume=325 |issue=24 |pages=1688–95 |year=1991 |pmid=1944469 |doi=10.1056/NEJM199112123252403 |url=}}</ref>  
*In addition to [[thyrotoxicosis]], which occurs in 33% of these patients, constitutive activation of the [[cAMP]] cascade in other tissues can cause [[polyostotic fibrous dysplasia]] (98%), cafe-au-lait skin [[hyperpigmentation]] (85%), and other endocrine gland hyperfunction, including gonadotropin-independent [[precocious puberty]] (62%), [[acromegaly]] (27%), and adrenocortical hyperfunction (6%).
*In addition to [[thyrotoxicosis]], which occurs in 33% of these patients, constitutive activation of the [[cAMP]] cascade in other tissues can cause [[polyostotic fibrous dysplasia]] (98%), [[Cafe-au-lait spots|cafe-au-lait]] skin [[hyperpigmentation]] (85%), and other [[endocrine gland]] [[hyperfunction]], including [[gonadotropin]]-independent [[precocious puberty]] (62%), [[acromegaly]] (27%), and [[adrenocortical]] hyperfunction (6%).


===Somatic activating thyroid-stimulating hormone receptor mutations===
===Somatic activating thyroid-stimulating hormone receptor mutations===
*Somatic mutations in the [[TSH receptor]] in toxic adenomas were among the first discovered naturally occurring [[G protein-coupled receptor|G protein–coupled receptor]] ([[G protein-coupled receptor|GPCR]]) mutations.<ref name="pmid16135672">{{cite journal |vauthors=Watson SG, Radford AD, Kipar A, Ibarrola P, Blackwood L |title=Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism |journal=J. Endocrinol. |volume=186 |issue=3 |pages=523–37 |year=2005 |pmid=16135672 |doi=10.1677/joe.1.06277 |url=}}</ref>   
*Somatic [[mutations]] in the [[TSH receptor]] in toxic adenomas were among the first discovered naturally occurring [[G protein-coupled receptor|G protein–coupled receptor]] ([[G protein-coupled receptor|GPCR]]) [[mutations]].<ref name="pmid16135672">{{cite journal |vauthors=Watson SG, Radford AD, Kipar A, Ibarrola P, Blackwood L |title=Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism |journal=J. Endocrinol. |volume=186 |issue=3 |pages=523–37 |year=2005 |pmid=16135672 |doi=10.1677/joe.1.06277 |url=}}</ref>   
*Somatic activating [[TSH receptor|thyroid-stimulating hormone receptor]] [[mutations]] increase basal [[cAMP]] levels, and also activate the [[phospholipase C]] cascade in a constitutive manner.  
*Somatic activating [[TSH receptor|thyroid-stimulating hormone receptor]] [[mutations]] increase basal [[cAMP]] levels, and also activate the [[phospholipase C]] cascade in a constitutive manner.  
*The prevalence of [[TSH receptor]] mutations in toxic adenomas varies widely from 8% to 80%.     
*The [[prevalence]] of [[TSH receptor]] [[mutations]] in toxic [[adenomas]] varies widely from 8% to 80%.     
*Somatic activating [[TSH receptor]] mutations are more commonly responsible in the pathogenesis of toxic adenoma than [[Gs alpha subunit|Gsα mutations]].
*Somatic activating [[TSH receptor]] [[mutations]] are more commonly responsible in the [[pathogenesis]] of toxic [[adenoma]] than [[Gs alpha subunit|Gsα mutations]].


===Germline activating thyroid-stimulating hormone receptor mutations===
===Germline activating thyroid-stimulating hormone receptor mutations===
*[[Germline mutation|Germline mutations]] that activate the [[TSH receptor]] are rare.<ref name="pmid21487943">{{cite journal |vauthors=Paschke R |title=Molecular pathogenesis of nodular goiter |journal=Langenbecks Arch Surg |volume=396 |issue=8 |pages=1127–36 |year=2011 |pmid=21487943 |doi=10.1007/s00423-011-0788-5 |url=}}</ref>
*[[Germline mutation|Germline mutations]] that activate the [[TSH receptor]] are rare.<ref name="pmid21487943">{{cite journal |vauthors=Paschke R |title=Molecular pathogenesis of nodular goiter |journal=Langenbecks Arch Surg |volume=396 |issue=8 |pages=1127–36 |year=2011 |pmid=21487943 |doi=10.1007/s00423-011-0788-5 |url=}}</ref>
*[[Germline mutation|Germline mutations]] are more commonly associated with diffuse gland involvement and present with more severe [[thyrotoxicosis]]
*[[Germline mutation|Germline mutations]] are more commonly associated with diffuse [[Glands|gland]] involvement and present with more severe [[thyrotoxicosis]].
*Affected individuals develop a toxic multinodular goiter that can have its onset from infancy to adult.
*Affected individuals develop a [[toxic multinodular goiter]] that can have its onset from [[infancy]] to adult.
*Transmission is usually [[autosomal dominant]].<ref name="pmid11507648">{{cite journal |vauthors=Derwahl M, Studer H |title=Nodular goiter and goiter nodules: Where iodine deficiency falls short of explaining the facts |journal=Exp. Clin. Endocrinol. Diabetes |volume=109 |issue=5 |pages=250–60 |year=2001 |pmid=11507648 |doi=10.1055/s-2001-16344 |url=}}</ref>  
*Transmission is usually [[autosomal dominant]].<ref name="pmid11507648">{{cite journal |vauthors=Derwahl M, Studer H |title=Nodular goiter and goiter nodules: Where iodine deficiency falls short of explaining the facts |journal=Exp. Clin. Endocrinol. Diabetes |volume=109 |issue=5 |pages=250–60 |year=2001 |pmid=11507648 |doi=10.1055/s-2001-16344 |url=}}</ref>  


===Role of Growth Factors===
===Role of Growth Factors===
Growth factors play an important role in the pathogenesis of toxic adenoma of thyroid. The following table summarizes the role of growth factors in the pathogenesis of toxic adenoma.<ref name="pmid7902304">{{cite journal |vauthors=Taton M, Lamy F, Roger PP, Dumont JE |title=General inhibition by transforming growth factor beta 1 of thyrotropin and cAMP responses in human thyroid cells in primary culture |journal=Mol. Cell. Endocrinol. |volume=95 |issue=1-2 |pages=13–21 |year=1993 |pmid=7902304 |doi= |url=}}</ref><ref name="pmid15615818">{{cite journal |vauthors=Krohn K, Führer D, Bayer Y, Eszlinger M, Brauer V, Neumann S, Paschke R |title=Molecular pathogenesis of euthyroid and toxic multinodular goiter |journal=Endocr. Rev. |volume=26 |issue=4 |pages=504–24 |year=2005 |pmid=15615818 |doi=10.1210/er.2004-0005 |url=}}</ref><ref name="pmid14737114">{{cite journal |vauthors=Eszlinger M, Krohn K, Frenzel R, Kropf S, Tönjes A, Paschke R |title=Gene expression analysis reveals evidence for inactivation of the TGF-beta signaling cascade in autonomously functioning thyroid nodules |journal=Oncogene |volume=23 |issue=3 |pages=795–804 |year=2004 |pmid=14737114 |doi=10.1038/sj.onc.1207186 |url=}}</ref><ref name="pmid1880476">{{cite journal |vauthors=Beere HM, Soden J, Tomlinson S, Bidey SP |title=Insulin-like growth factor-I production and action in porcine thyroid follicular cells in monolayer: regulation by transforming growth factor-beta |journal=J. Endocrinol. |volume=130 |issue=1 |pages=3–9 |year=1991 |pmid=1880476 |doi= |url=}}</ref><ref name="pmid3053751">{{cite journal |vauthors=Miyakawa M, Saji M, Tsushima T, Wakai K, Shizume K |title=Thyroid volume and serum thyroglobulin levels in patients with acromegaly: correlation with plasma insulin-like growth factor I levels |journal=J. Clin. Endocrinol. Metab. |volume=67 |issue=5 |pages=973–8 |year=1988 |pmid=3053751 |doi=10.1210/jcem-67-5-973 |url=}}</ref><ref name="pmid8772597">{{cite journal |vauthors=Cheung NW, Lou JC, Boyages SC |title=Growth hormone does not increase thyroid size in the absence of thyrotropin: a study in adults with hypopituitarism |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue=3 |pages=1179–83 |year=1996 |pmid=8772597 |doi=10.1210/jcem.81.3.8772597 |url=}}</ref><ref name="pmid11600550">{{cite journal |vauthors=Eszlinger M, Krohn K, Paschke R |title=Complementary DNA expression array analysis suggests a lower expression of signal transduction proteins and receptors in cold and hot thyroid nodules |journal=J. Clin. Endocrinol. Metab. |volume=86 |issue=10 |pages=4834–42 |year=2001 |pmid=11600550 |doi=10.1210/jcem.86.10.7933 |url=}}</ref><ref name="pmid1656299">{{cite journal |vauthors=Frautschy SA, Gonzalez AM, Martinez Murillo R, Carceller F, Cuevas P, Baird A |title=Expression of basic fibroblast growth factor and its receptor in the rat subfornical organ |journal=Neuroendocrinology |volume=54 |issue=1 |pages=55–61 |year=1991 |pmid=1656299 |pmc=4237606 |doi= |url=}}</ref><ref name="pmid7657804">{{cite journal |vauthors=Sato K, Yamazaki K, Shizume K, Kanaji Y, Obara T, Ohsumi K, Demura H, Yamaguchi S, Shibuya M |title=Stimulation by thyroid-stimulating hormone and Grave's immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo |journal=J. Clin. Invest. |volume=96 |issue=3 |pages=1295–302 |year=1995 |pmid=7657804 |pmc=185751 |doi=10.1172/JCI118164 |url=}}</ref>
[[Growth factors]] play an important role in the [[pathogenesis]] of toxic [[adenoma]] of [[thyroid]]. The following table summarizes the role of [[growth factors]] in the [[pathogenesis]] of toxic [[adenoma]].<ref name="pmid7902304">{{cite journal |vauthors=Taton M, Lamy F, Roger PP, Dumont JE |title=General inhibition by transforming growth factor beta 1 of thyrotropin and cAMP responses in human thyroid cells in primary culture |journal=Mol. Cell. Endocrinol. |volume=95 |issue=1-2 |pages=13–21 |year=1993 |pmid=7902304 |doi= |url=}}</ref><ref name="pmid15615818">{{cite journal |vauthors=Krohn K, Führer D, Bayer Y, Eszlinger M, Brauer V, Neumann S, Paschke R |title=Molecular pathogenesis of euthyroid and toxic multinodular goiter |journal=Endocr. Rev. |volume=26 |issue=4 |pages=504–24 |year=2005 |pmid=15615818 |doi=10.1210/er.2004-0005 |url=}}</ref><ref name="pmid14737114">{{cite journal |vauthors=Eszlinger M, Krohn K, Frenzel R, Kropf S, Tönjes A, Paschke R |title=Gene expression analysis reveals evidence for inactivation of the TGF-beta signaling cascade in autonomously functioning thyroid nodules |journal=Oncogene |volume=23 |issue=3 |pages=795–804 |year=2004 |pmid=14737114 |doi=10.1038/sj.onc.1207186 |url=}}</ref><ref name="pmid1880476">{{cite journal |vauthors=Beere HM, Soden J, Tomlinson S, Bidey SP |title=Insulin-like growth factor-I production and action in porcine thyroid follicular cells in monolayer: regulation by transforming growth factor-beta |journal=J. Endocrinol. |volume=130 |issue=1 |pages=3–9 |year=1991 |pmid=1880476 |doi= |url=}}</ref><ref name="pmid3053751">{{cite journal |vauthors=Miyakawa M, Saji M, Tsushima T, Wakai K, Shizume K |title=Thyroid volume and serum thyroglobulin levels in patients with acromegaly: correlation with plasma insulin-like growth factor I levels |journal=J. Clin. Endocrinol. Metab. |volume=67 |issue=5 |pages=973–8 |year=1988 |pmid=3053751 |doi=10.1210/jcem-67-5-973 |url=}}</ref><ref name="pmid8772597">{{cite journal |vauthors=Cheung NW, Lou JC, Boyages SC |title=Growth hormone does not increase thyroid size in the absence of thyrotropin: a study in adults with hypopituitarism |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue=3 |pages=1179–83 |year=1996 |pmid=8772597 |doi=10.1210/jcem.81.3.8772597 |url=}}</ref><ref name="pmid11600550">{{cite journal |vauthors=Eszlinger M, Krohn K, Paschke R |title=Complementary DNA expression array analysis suggests a lower expression of signal transduction proteins and receptors in cold and hot thyroid nodules |journal=J. Clin. Endocrinol. Metab. |volume=86 |issue=10 |pages=4834–42 |year=2001 |pmid=11600550 |doi=10.1210/jcem.86.10.7933 |url=}}</ref><ref name="pmid1656299">{{cite journal |vauthors=Frautschy SA, Gonzalez AM, Martinez Murillo R, Carceller F, Cuevas P, Baird A |title=Expression of basic fibroblast growth factor and its receptor in the rat subfornical organ |journal=Neuroendocrinology |volume=54 |issue=1 |pages=55–61 |year=1991 |pmid=1656299 |pmc=4237606 |doi= |url=}}</ref><ref name="pmid7657804">{{cite journal |vauthors=Sato K, Yamazaki K, Shizume K, Kanaji Y, Obara T, Ohsumi K, Demura H, Yamaguchi S, Shibuya M |title=Stimulation by thyroid-stimulating hormone and Grave's immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo |journal=J. Clin. Invest. |volume=96 |issue=3 |pages=1295–302 |year=1995 |pmid=7657804 |pmc=185751 |doi=10.1172/JCI118164 |url=}}</ref>
{| class="wikitable"
{| class="wikitable"
!Growth Factors (GF)
!Growth Factors (GF)
Line 41: Line 41:
* Blocks uptake and organification of [[iodine]]
* Blocks uptake and organification of [[iodine]]


* Inhibits [[thyroglobulin]] expression, and thyroid follicular cell proliferation
* Inhibits [[thyroglobulin]] expression, and [[thyroid]] follicular cell [[proliferation]]
|-
|-
|Insulin-like
|Insulin-like
GF-1
GF-1
|
|
* Works synergistically with [[TSH]] in thyroid growth
* Works synergistically with [[TSH]] in [[thyroid]] growth
|-
|-
|Insulin-like
|Insulin-like
Line 60: Line 60:
|
|
* [[Fibroblasts]] with the help of [[proteases]] become active [[mitogens]]
* [[Fibroblasts]] with the help of [[proteases]] become active [[mitogens]]
* Control [[TSH]] production similar to that of [[Insulin-like growth factor|IGF]] BPs and IGF-1
* Control [[TSH]] production similar to that of [[Insulin-like growth factor|IGF]] BPs and [[IGF]]-1
|-
|-
|Vascular endothelial
|Vascular endothelial
Line 68: Line 68:
* Production of [[VEGF]] receptors on [[endothelial cells]], but not follicular cells, is stimulated by [[TSH]]
* Production of [[VEGF]] receptors on [[endothelial cells]], but not follicular cells, is stimulated by [[TSH]]
* [[VEGF]] then activates the [[VEGF]] receptors on [[endothelial cells]] in a [[paracrine]] fashion
* [[VEGF]] then activates the [[VEGF]] receptors on [[endothelial cells]] in a [[paracrine]] fashion
* Responsible for thyroid cell proliferation and hypervascularity
* Responsible for [[thyroid]] cell [[proliferation]] and hypervascularity
* Iodide can inhibit TSH-induced expression of the angiogenic factors
* [[Iodide]] can inhibit [[TSH]]-induced expression of the [[angiogenic]] factors
|-
|-
|Atrial natriuretic peptide
|Atrial natriuretic peptide
|
|
* [[Atrial natriuretic peptide|ANP]] decreases the production of [[VEGF]] 
* [[Atrial natriuretic peptide|ANP]] decreases the production of [[VEGF]] 
* Mutation in ANP producing results uncontrolled VEGF production
* [[Mutations|Mutation]] in [[ANP]] producing results uncontrolled [[VEGF]] production
* Finally TSH and hyperplasia of thyroid
* Finally [[TSH]] and [[hyperplasia]] of [[thyroid]]
|}
|}


==Gross Pathology==
==Gross Pathology==
*On macroscopic examination, a solitary toxic nodule is red and surrounded by normal thyroid tissue that is functionally suppressed and is pale in color.
*On [[macroscopic]] examination, a solitary toxic [[nodule]] is red and surrounded by normal [[thyroid]] tissue that is functionally suppressed and is pale in color.


==Microscopic Pathology==
==Microscopic Pathology==
On histological examination, toxic adenomas demonstrate following findings:  
On [[histological]] examination, toxic [[adenomas]] demonstrate following findings:  
*Uniform hypertrophy and hyperplasia of the acinar cells.
*Uniform [[hypertrophy]] and [[hyperplasia]] of the [[acinar]] cells.
*Some papillary infolding
*Some [[papillary]] infolding
*Nodules can be encapsulated follicular neoplasms or adenomatous nodules without a capsule.<ref name="pmid2914297">{{cite journal |vauthors=Hedinger C, Williams ED, Sobin LH |title=The WHO histological classification of thyroid tumors: a commentary on the second edition |journal=Cancer |volume=63 |issue=5 |pages=908–11 |year=1989 |pmid=2914297 |doi= |url=}}</ref>  
*[[Nodules]] can be encapsulated follicular neoplasms or [[adenomatous]] [[nodules]] without a [[capsule]].<ref name="pmid2914297">{{cite journal |vauthors=Hedinger C, Williams ED, Sobin LH |title=The WHO histological classification of thyroid tumors: a commentary on the second edition |journal=Cancer |volume=63 |issue=5 |pages=908–11 |year=1989 |pmid=2914297 |doi= |url=}}</ref>  
*[[Hemorrhage]], [[Calcification|calcifications]], and cystic degeneration can also be demonstrated.
*[[Hemorrhage]], [[Calcification|calcifications]], and [[cystic]] degeneration can also be demonstrated.


==References==
==References==
{{reflist|2}}
{{reflist|2}}
​​
[[Category:Medicine]]
[[Category:Endocrinology]]
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Latest revision as of 00:26, 30 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Overview

Thyroid-stimulating hormone (TSH) binds to its receptor on the surface of thyroid follicular cells. When TSH binds to the TSH receptor, it stimulates adenylyl cyclase conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Activation of cyclic adenosine monophosphate (cAMP) results in thyroid hormone secretion. When TSH concentrations are five- to tenfold higher, TSH binding to its receptor leads to its interaction with Gq, activating phospholipase C, which in turn leads to increased intracellular calcium, diacylglycerol, and inositol phosphate. Activation of this pathway regulates iodination and thyroid hormone production. Alteration of the above pathway by activation of germline or somatic mutations in the TSH receptor or cAMP signal transduction system is believed to be responsible for the development of autonomous thyroid gland growth and hormonogenesis. The molecular alterations responsible for toxic adenomas include somatic gain-of-function mutations in the TSH receptor or the stimulatory Gsα subunit. Both result in constitutive activation of the cAMP pathway, which results in enhanced proliferation and function of thyroid follicular cells.

Pathogenesis

Thyroid-stimulating hormone (TSH) binds to its receptor on the surface of thyroid follicular cells. When TSH binds to the TSH receptor, it stimulates adenylyl cyclase conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Activation of this pathway leads to cell growth and thyroid hormone secretion. When TSH concentrations are five- to tenfold higher, TSH binding to its receptor leads to its interaction with Gq, activating phospholipase C, which in turn leads to increased intracellular calcium, diacylglycerol, and inositol phosphate. Activation of this pathway regulates iodination and thyroid hormone production. Alteration of the above pathway by activation of germline or somatic mutations in the TSH receptor or cAMP signal transduction system is believed to be responsible for the development of autonomous thyroid gland growth and hormonogenesis. The molecular alterations responsible for toxic adenomas include somatic gain-of-function mutations in the TSH receptor or the stimulatory Gsα subunit. Both result in constitutive activation of the cAMP pathway, which results in enhanced proliferation and function of thyroid follicular cells.[1][2][3][4][5]

Somatic activating GS alpha mutations

Somatic activating thyroid-stimulating hormone receptor mutations

Germline activating thyroid-stimulating hormone receptor mutations

Role of Growth Factors

Growth factors play an important role in the pathogenesis of toxic adenoma of thyroid. The following table summarizes the role of growth factors in the pathogenesis of toxic adenoma.[12][13][14][15][16][17][18][19][20]

Growth Factors (GF) Role of Growth Factors on TSH[21]
Transforming

GF-β1

  • Blocks uptake and organification of iodine
Insulin-like

GF-1

Insulin-like

GF–Binding proteins

  • Binds to IGF-1 and control its availability by stimulating IGF-I action
  • Mechanisms of their stimulatory effects include
    • Enhancing IGF-1 binding to its receptor and prolonging its intracellular half-life.
  • Insulin and epidermal growth factor (EGF) increase the productions of binding proteins
Fibroblast GF and

their receptors

Vascular endothelial

growth factor (VEGF)

Atrial natriuretic peptide

Gross Pathology

  • On macroscopic examination, a solitary toxic nodule is red and surrounded by normal thyroid tissue that is functionally suppressed and is pale in color.

Microscopic Pathology

On histological examination, toxic adenomas demonstrate following findings:

References

  1. ↑ Dumont JE, Lamy F, Roger P, Maenhaut C (1992). "Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors". Physiol. Rev. 72 (3): 667–97. PMID 1320763.
  2. ↑ Van Sande J, Parma J, Tonacchera M, Swillens S, Dumont J, Vassart G (1995). "Somatic and germline mutations of the TSH receptor gene in thyroid diseases". J. Clin. Endocrinol. Metab. 80 (9): 2577–85. doi:10.1210/jcem.80.9.7673398. PMID 7673398.
  3. ↑ Parma J, Van Sande J, Swillens S, Tonacchera M, Dumont J, Vassart G (1995). "Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas: identification of additional mutations activating both the cyclic adenosine 3',5'-monophosphate and inositol phosphate-Ca2+ cascades". Mol. Endocrinol. 9 (6): 725–33. doi:10.1210/mend.9.6.8592518. PMID 8592518.
  4. ↑ Hébrant A, van Staveren WC, Maenhaut C, Dumont JE, Leclère J (2011). "Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations". Eur. J. Endocrinol. 164 (1): 1–9. doi:10.1530/EJE-10-0775. PMID 20926595.
  5. ↑ Trülzsch B, Krohn K, Wonerow P, Chey S, Holzapfel HP, Ackermann F, Führer D, Paschke R (2001). "Detection of thyroid-stimulating hormone receptor and Gsalpha mutations: in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis". J. Mol. Med. 78 (12): 684–91. PMID 11434721.
  6. ↑ Lyons J, Landis CA, Harsh G, Vallar L, Grünewald K, Feichtinger H, Duh QY, Clark OH, Kawasaki E, Bourne HR (1990). "Two G protein oncogenes in human endocrine tumors". Science. 249 (4969): 655–9. PMID 2116665.
  7. ↑ Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, Dumont J, Vassart G (1993). "Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas". Nature. 365 (6447): 649–51. doi:10.1038/365649a0. PMID 8413627.
  8. ↑ Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM (1991). "Activating mutations of the stimulatory G protein in the McCune-Albright syndrome". N. Engl. J. Med. 325 (24): 1688–95. doi:10.1056/NEJM199112123252403. PMID 1944469.
  9. ↑ Watson SG, Radford AD, Kipar A, Ibarrola P, Blackwood L (2005). "Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism". J. Endocrinol. 186 (3): 523–37. doi:10.1677/joe.1.06277. PMID 16135672.
  10. ↑ Paschke R (2011). "Molecular pathogenesis of nodular goiter". Langenbecks Arch Surg. 396 (8): 1127–36. doi:10.1007/s00423-011-0788-5. PMID 21487943.
  11. ↑ Derwahl M, Studer H (2001). "Nodular goiter and goiter nodules: Where iodine deficiency falls short of explaining the facts". Exp. Clin. Endocrinol. Diabetes. 109 (5): 250–60. doi:10.1055/s-2001-16344. PMID 11507648.
  12. ↑ Taton M, Lamy F, Roger PP, Dumont JE (1993). "General inhibition by transforming growth factor beta 1 of thyrotropin and cAMP responses in human thyroid cells in primary culture". Mol. Cell. Endocrinol. 95 (1–2): 13–21. PMID 7902304.
  13. ↑ Krohn K, Führer D, Bayer Y, Eszlinger M, Brauer V, Neumann S, Paschke R (2005). "Molecular pathogenesis of euthyroid and toxic multinodular goiter". Endocr. Rev. 26 (4): 504–24. doi:10.1210/er.2004-0005. PMID 15615818.
  14. ↑ Eszlinger M, Krohn K, Frenzel R, Kropf S, Tönjes A, Paschke R (2004). "Gene expression analysis reveals evidence for inactivation of the TGF-beta signaling cascade in autonomously functioning thyroid nodules". Oncogene. 23 (3): 795–804. doi:10.1038/sj.onc.1207186. PMID 14737114.
  15. ↑ Beere HM, Soden J, Tomlinson S, Bidey SP (1991). "Insulin-like growth factor-I production and action in porcine thyroid follicular cells in monolayer: regulation by transforming growth factor-beta". J. Endocrinol. 130 (1): 3–9. PMID 1880476.
  16. ↑ Miyakawa M, Saji M, Tsushima T, Wakai K, Shizume K (1988). "Thyroid volume and serum thyroglobulin levels in patients with acromegaly: correlation with plasma insulin-like growth factor I levels". J. Clin. Endocrinol. Metab. 67 (5): 973–8. doi:10.1210/jcem-67-5-973. PMID 3053751.
  17. ↑ Cheung NW, Lou JC, Boyages SC (1996). "Growth hormone does not increase thyroid size in the absence of thyrotropin: a study in adults with hypopituitarism". J. Clin. Endocrinol. Metab. 81 (3): 1179–83. doi:10.1210/jcem.81.3.8772597. PMID 8772597.
  18. ↑ Eszlinger M, Krohn K, Paschke R (2001). "Complementary DNA expression array analysis suggests a lower expression of signal transduction proteins and receptors in cold and hot thyroid nodules". J. Clin. Endocrinol. Metab. 86 (10): 4834–42. doi:10.1210/jcem.86.10.7933. PMID 11600550.
  19. ↑ Frautschy SA, Gonzalez AM, Martinez Murillo R, Carceller F, Cuevas P, Baird A (1991). "Expression of basic fibroblast growth factor and its receptor in the rat subfornical organ". Neuroendocrinology. 54 (1): 55–61. PMC 4237606. PMID 1656299.
  20. ↑ Sato K, Yamazaki K, Shizume K, Kanaji Y, Obara T, Ohsumi K, Demura H, Yamaguchi S, Shibuya M (1995). "Stimulation by thyroid-stimulating hormone and Grave's immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo". J. Clin. Invest. 96 (3): 1295–302. doi:10.1172/JCI118164. PMC 185751. PMID 7657804.
  21. ↑ Kopp P (2001). "The TSH receptor and its role in thyroid disease". Cell. Mol. Life Sci. 58 (9): 1301–22. PMID 11577986.
  22. ↑ Hedinger C, Williams ED, Sobin LH (1989). "The WHO histological classification of thyroid tumors: a commentary on the second edition". Cancer. 63 (5): 908–11. PMID 2914297.

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