Toxic Adenoma pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
==Pathogenesis== | ==Pathogenesis== | ||
Activating 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. | Activating 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.<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=== | ||
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*Toxic multinodular goiter can be the result of one or more benign nodules becoming autonomous in a gland with many of these benign neoplasms. | *Toxic multinodular goiter can be the result of one or more benign nodules becoming autonomous in a gland with many of these benign neoplasms. | ||
*Multinodular goiters can contain monoclonal and polyclonal nodules within the same gland. | *Multinodular goiters can contain monoclonal and polyclonal nodules within the same gland. | ||
*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. | *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. | *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. | *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. | *Mutations conferring constitutive activity occur in the entire transmembrane domain, as well as in the carboxy-terminal region of the extracellular domain. | ||
*All mutations increase basal cAMP levels, and a few amino acid substitutions 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. | ||
| Line 25: | Line 25: | ||
===Germline activating thyroid-stimulating hormone receptor mutations=== | ===Germline activating thyroid-stimulating hormone receptor mutations=== | ||
*Germline mutations that activate the TSH receptor are rare. | *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. | *Such generalized defects would not be expected to cause solitary toxic adenoma, but rather diffuse gland involvement. | ||
*Examples of this disorder have been described as hereditary toxic thyroid hyperplasia or familial nonautoimmune hyperthyroidism. | *Examples of this disorder have been described as hereditary toxic thyroid hyperplasia or familial nonautoimmune hyperthyroidism. | ||
| Line 33: | Line 33: | ||
*Mutations in the TSH receptor have also been described in children with congenital hyperthyroidism and unaffected parents, indicating a new germline mutation. 65 66 67 68 69 | *Mutations in the TSH receptor have also been described in children with congenital hyperthyroidism and unaffected parents, indicating a new germline mutation. 65 66 67 68 69 | ||
*These patients typically have a diffuse goiter and more severe thyrotoxicosis than those with hereditary nonautoimmune hyperthyroidism. | *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. | *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=== | ||
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{| class="wikitable" | {| class="wikitable" | ||
!Growth Factors (GF) | !Growth Factors (GF) | ||
!Role of Growth Factors on TSH | !Role of Growth Factors on TSH<ref name="pmid11577986">{{cite journal |vauthors=Kopp P |title=The TSH receptor and its role in thyroid disease |journal=Cell. Mol. Life Sci. |volume=58 |issue=9 |pages=1301–22 |year=2001 |pmid=11577986 |doi= |url=}}</ref> | ||
|- | |- | ||
|Transforming | |Transforming | ||
| Line 84: | Line 84: | ||
* Finally TSH and hyperplasia of thyroid | * Finally TSH and hyperplasia of thyroid | ||
|} | |} | ||
==Gross Pathology== | ==Gross Pathology== | ||
*On macroscopic examination, a solitary toxic nodule is surrounded by normal thyroid tissue that is functionally suppressed. | *On macroscopic examination, a solitary toxic nodule is surrounded by normal thyroid tissue that is functionally suppressed. | ||
Revision as of 18:34, 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
Activating 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.
- Toxic multinodular goiter can be the result of one or more benign nodules becoming autonomous in a gland with many of these benign neoplasms.
- Multinodular goiters can contain monoclonal and polyclonal nodules within the same gland.
- 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]
- Mutations conferring constitutive activity occur in the entire transmembrane domain, as well as in the carboxy-terminal region of the extracellular domain.
- All mutations increase basal cAMP levels, and a few amino acid substitutions also activate the phospholipase C (PLC) cascade in a constitutive manner.
- The reported prevalence of TSH receptor mutations in toxic adenomas varies widely but is as high as 80%.
- 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 mutations that activate the TSH receptor are rare.[10]
- Such generalized defects would not be expected to cause solitary toxic adenoma, but rather diffuse gland involvement.
- 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.
- Transmission of the disorder is autosomal dominant.
- 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. 65 66 67 68 69
- 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.[11]
Role of Growth Factors
| Growth Factors (GF) | Role of Growth Factors on TSH[12] |
|---|---|
| Transforming
GF-β1 |
|
| Insulin-like
GF-1 |
|
| Insulin-like
GF–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 surrounded by normal thyroid tissue that is functionally suppressed.
Microscopic Pathology
- Histologically, toxic adenomas are encapsulated follicular neoplasms or adenomatous nodules without a capsule. 42
- Hemorrhage, calcifications, and cystic degeneration are commonly present.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Paschke R (2011). "Molecular pathogenesis of nodular goiter". Langenbecks Arch Surg. 396 (8): 1127–36. doi:10.1007/s00423-011-0788-5. PMID 21487943.
- ↑ 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.
- ↑ Kopp P (2001). "The TSH receptor and its role in thyroid disease". Cell. Mol. Life Sci. 58 (9): 1301–22. PMID 11577986.