Toxic Adenoma pathophysiology: Difference between revisions

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*The first mutations identified in toxic adenomas were somatic activating point mutations in Gs alpha, which were identified after similar mutations were found in pituitary 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, which were identified after similar mutations were found in pituitary 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 Gsα impair the hydrolysis of guanine triphosphate (GTP) to guanine diphosphate (GDP), resulting in persistent activation of adenylyl cyclase. *Mosaicism for 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>  
*Gain-of-function mutations in Gsα impair the hydrolysis of guanine triphosphate (GTP) to guanine diphosphate (GDP), resulting in persistent activation of adenylyl cyclase. *
*Mosaicism for 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%), café-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%), café-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 (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 (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>   
*Mutations conferring constitutive activity occur in the entire transmembrane domain, as well as in the carboxy-terminal region of the extracellular domain.
*Somatic activating thyroid-stimulating hormone receptor mutations increase basal cAMP levels, and also activate the phospholipase C (PLC) cascade in a constitutive manner.  
*All mutations increase basal cAMP levels, and a few amino acid substitutions also activate the phospholipase C (PLC) cascade in a constitutive manner.  
*The prevalence of TSH receptor mutations in toxic adenomas varies widely from 8% to 80%.     
*The reported prevalence of TSH receptor mutations in toxic adenomas varies widely but is as high as 80%.     
*Somatic activating TSH receptor mutations are more commonly responsible in the pathogenesis of toxic adenoma than Gsα mutations.
*It is well established that somatic activating TSH receptor mutations play a predominant role in the pathogenesis of autonomusly functioning thyroid nodule, while Gsα mutations are less common.
*Somatic mutations in other genes are presumably involved in the pathogenesis of the monoclonal toxic adenomas that are negative for mutations in the TSH receptor and Gsα. 
*Most of the mutated residues are located in the third cytoplasmic loop or the sixth transmembrane portion of the receptor.  


===Germline activating thyroid-stimulating hormone receptor mutations===
===Germline activating thyroid-stimulating hormone receptor mutations===
*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 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>
*Such generalized defects would not be expected to cause solitary toxic adenoma, but rather diffuse gland involvement.
*Germline mutations are more commonly associated with diffuse gland involvement and present with more severe thyrotoxicosis
*Examples of this disorder have been described as hereditary toxic thyroid hyperplasia or familial nonautoimmune hyperthyroidism.
*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 of the disorder is autosomal dominant.
*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>  
*Among the multiple families that have been investigated, each has had a different mutation in the TSH receptor.
*Mutations in the TSH receptor have also been described in children with congenital hyperthyroidism and unaffected parents, indicating a new germline mutation.
*These patients typically have a diffuse goiter and more severe thyrotoxicosis than those with hereditary nonautoimmune hyperthyroidism.
*The mutations seen in the congenital nonautoimmune thyrotoxicosis are similar to those found in toxic adenomas, whereas the mutations seen in hereditary nonautoimmune hyperthyroidism are different.<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===

Revision as of 20:47, 31 August 2017

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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

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

  • 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, which were identified after similar mutations were found in pituitary somatotroph adenomas.[6][7]
  • 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 Gsα impair the hydrolysis of guanine triphosphate (GTP) to guanine diphosphate (GDP), resulting in persistent activation of adenylyl cyclase. *
  • Mosaicism for 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.[8]
  • 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%), café-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 mutations in the TSH receptor in toxic adenomas were among the first discovered naturally occurring G protein–coupled receptor (GPCR) mutations.[9]
  • Somatic activating thyroid-stimulating hormone receptor mutations increase basal cAMP levels, and also activate the phospholipase C (PLC) cascade in a constitutive manner.
  • 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 Gsα mutations.

Germline activating thyroid-stimulating hormone receptor mutations

  • Germline mutations that activate the TSH receptor are rare.[10]
  • Germline mutations are more commonly associated with diffuse gland involvement and present with more severe thyrotoxicosis
  • Affected individuals develop a toxic multinodular goiter that can have its onset from infancy to adult.
  • Transmission is usually autosomal dominant.[11]

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

  • Counteracts the stimulatory roles of TSH and other growth factors
  • Blocks uptake and organification of iodine
  • Inhibits thyroglobulin expression, and thyroid follicular cell proliferation
Insulin-like

GF-1

  • Works synergistically with TSH in thyroid growth
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

  • Fibroblasts with the help of proteases become active mitogens
  • Control TSH production similar to that of IGF BPs and IGF-1
Vascular endothelial

growth factor (VEGF)

  • VEGF) stimulates growth of blood vessels supplying thyroid follicular cells
  • 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
  • Responsible for thyroid cell proliferation and hypervascularity
  • Iodide can inhibit TSH-induced expression of the angiogenic factors
Atrial natriuretic peptide
  • ANP decreases the production of VEGF 
  • Mutation in ANP producing results uncontrolled VEGF production
  • Finally TSH and hyperplasia of thyroid

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 demonstrates following findings:

  • Uniform hypertrophy and hyperplasia of the acinar cells.
  • Some papillary infolding
  • Nodules can be encapsulated follicular neoplasms or adenomatous nodules without a capsule.[22]
  • Hemorrhage, calcifications, and cystic degeneration can also be demonstated.

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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