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 [[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==
Activating germline or somatic mutations in the TSH receptor–cAMP signal transduction system is believed to be responsible for the development of autonomous thyroid gland growth and hormonogenesis. These could include the TSH receptor, guanine nucleotide regulatory subunits, adenylyl cyclase, and protein kinase A. Conversely, an inactivating mutation in a protein that negatively regulates the cascade—for example, cAMP phosphodiesterases—could also activate the primary pathway regulating thyrocyte growth and function.
[[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
 
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. At the same time, multinodular goiters can contain monoclonal and polyclonal nodules within the same gland. A study of 25 nodules from 9 multinodular goiters has revealed that 9 were polyclonal and 16 were monoclonal; polyclonal and monoclonal nodules were seen in 3 goiters, with 3 goiters containing only polyclonal nodules and 3 goiters containing only monoclonal nodules.  42 Human multinodular goiters have been shown to be heterogeneous in both morphology and function. In another study, 300 samples from cold and hot regions of 20 human multinodular goiters were transplanted onto nude mice and radiolabeled with  3  H-thymidine to assess proliferation and with radioactive iodine to assess function. There was no correlation between iodine uptake and size or other morphologic features of these tissues, demonstrating that autonomous growth and autonomous function can be independent.  43
 
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.  44 45  Mutations located at arginine 201 and glutamine 227 lead to constitutive activation of the G protein, with consequent stimulation of the cAMP signaling cascade. The reported prevalences of such Gs alpha gain-of-function mutations has varied widely in various series, ranging from 0% to 75% of autonomously functioning thyroid nodules; however, they are probably responsible for less than 10% of all toxic adenomas. 3 46  Another special example of Gs alpha mutation causing hyperthyroidism is the McCune-Albright syndrome, in which there is a sporadic activating mutation in arginine 201 in a mosaic distribution.  47  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%).  48 49
 
SOMATIC ACTIVATING THYROID-STIMULATING HORMONE RECEPTOR MUTATIONS
 
The only other mutations found to date in toxic adenomas have been in the TSH receptor. Most of the mutated residues are located in the third cytoplasmic loop or the sixth transmembrane portion of the receptor. Distinct TSH receptor mutations have also been found in different nodules in the same multinodular goiter.  3 46  These are the most frequent mutations identified in toxic adenomas, with reported prevalences varying from 8% to 82%. This broad range of reported prevalences may be due to the result of a number of factors. First, the various experimental methods used to detect TSH receptor mutations—direct sequencing, single-strand conformation polymorphism, and denaturing gradient gel electrophoresis—differ in their ability to detect point mutations.  46 50 51 52 53 54 55 56  For example, one group using the more sensitive denaturing gradient gel electrophoresis to identify TSH receptor mutations in 75 toxic nodules found 6 cases of TSH receptor mutations that had been missed by direct sequencing. 54 55 56  The quality of the DNA sample also contributes to this variability, because degradation of the DNA is more likely to occur with tissue embedded in paraffin  57 58  than with tissue that has been frozen.  50 51 52 53 54 55  Other factors that contribute to this broad range of reported TSH receptor mutation prevalences are distinct populations  58 59  and their dietary iodine content.  53 54 60 61  In countries with a moderate iodine deficiency, TSH receptor mutations are found in up to 80% of toxic adenomas.
 
GERMLINE ACTIVATING THYROID-STIMULATING HORMONE RECEPTOR MUTATIONS
 
Germline mutations that activate the TSH receptor are rare. 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.  62 63 64  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. Interestingly, 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.
 
Role of Growth Factors
 
TRANSFORMING GROWTH FACTOR β1
 
Transforming growth factor β1 (TGF-β1) is thought to counteract the stimulatory roles of TSH and other growth factors, blocking uptake and organification of iodine, thyroglobulin expression, and thyroid follicular cell proliferation in vitro.  70 71 72  TSH actually stimulates thyrocyte TGF-β1 expression in vitro, representing a potential mechanism for modulating its own effects. TGF-β1 alters expression of insulin-like growth factor 1(IGF-1) and IGF-binding proteins in a manner that would diminish thyrocyte proliferation (see later). Consequently, TGF-β1 appears to inhibit goitrogenesis. Microarray assessments of gene expression in autonomously functioning thyroid nodules, with or without TSH receptor mutations, compared with adjacent normal thyroid tissue, have shown patterns of expression of TGF-β1 signaling pathway elements consistent with inactivation of this physiologic inhibitory pathway. These observations have included decreased expression of TGF-β receptor type III (betaglycan), Smad 1, 3, and 4, ERK 1, and P300, as well as increased expression of inhibin, endoglin, Smad 6 and 7, and PAI-1 in autonomously functioning thyroid nodules. 73  TGF-β1 also decreases production and release of IGF-1, which itself stimulates thyroid cell growth in vitro. 74  In human thyrocyte primary cultures, TGF-β1 also increases IGF binding protein BP-3 and BP-5 production, higher levels of which have been correlated with decreased thyroid function.  75  Finally, plasmin treatment of cultured follicular cells leads to increased TGF-β1 activity in the media, implicating the plasminogen or plasminogen activator system in the activation of TGF-β1.  76  However, derangements of this system have not been associated with the development of toxic nodular goiter to date.
 
INSULIN-LIKE GROWTH FACTOR 1
 
Several studies have supported a synergistic role for IGF-1 with TSH in thyroid growth. First, goiter is seen in more than 70% of patients with acromegaly, who have high IGF-1 levels.  77 78 79  Insulin-like growth factors enhance TSH action and are required for full TSH stimulation of thyroid cell growth and function in vitro.  80 However, the need for both TSH and IGF-1 for normal follicular cell growth is supported by the observation that when hypopituitary patients lacking TSH are treated with growth hormone, there is no increase in thyroid size despite increased IGF-1. 81  IGF-1 appears to act at least partially in an autocrine fashion, as illustrated by a primary culture of follicular cells from a thyroid adenoma that did not require exogenous IGF-1 to grow. 82 Iodide also appears to modulate IGF-1. In cultured thyroid cells, an increased intracellular organified iodide concentration decreased IGF-1 mRNA transcription, protein production, and cell growth. 74 84
 
INSULIN-LIKE GROWTH FACTOR–BINDING PROTEINS
 
IGF BPs bind IGF-1 and control its availability, with some stimulating IGF-I action and others inhibiting it. Mechanisms of their stimulatory effects include enhancing IGF-1 binding to its receptor andprolonging its intracellular half-life. TSH, via the cAMP signaling cascade, decreases IGF BP production, whereas insulin and epidermal growth factor (EGF) increase it.  85  TSH inhibition of IGF BP synthesis leads to a higher level of unbound IGF-1, increasing its availability to stimulate thyroid tissue. It has also been shown that autonomously functioning thyroid nodules express less IGF BP-5 and IGF BP-6 compared with normal thyroid tissue,  73 86 consistent with their constitutively activated cAMP signaling.
 
FIBROBLAST GROWTH FACTORS AND THEIR RECEPTORS
 
Cells from multinodular goiters have increased expression of fibroblast growth factors 1 and 2 (FGF-1 and FGF-2), as well as the FGF receptor 1 (FGFR-1). FGF-1–treated rats exhibit an increase in thyroid weight by more than one third within 1 week; however, this effect does not occur in hypophysectomized rats,  87 88  who also have no increase in FGF-2, FGFR-1, IGF-1, IGF BP-2, or IGF BP-3. These responses are restored when hypophysectomized rats are treated with TSH.
 
FGFs are usually bound to an extracellular matrix and, to be active mitogens, they must be released from the extracellular matrix. Thus, processing of FGFs by proteases represents a mechanism of control similar to that of some IGF BPs and IGF-1. Another mechanism of control is that truncated forms of the FGF receptor bind to FGF and influence its availability. It is likely that TSH is needed in combination with growth factors, such as IGF and FGF, to stimulate growth of the thyroid gland and goitrogenesis.
 
ANGIOGENIC FACTORS


Vascular endothelial growth factor (VEGF) stimulates growth of blood vessels supplying thyroid follicular cells. Human thyroid follicular cells in vitro produce VEGF in response to TSH. Production of VEGF receptors on endothelial cells, but not follicular cells, is stimulated by TSH in rats in vivo. VEGF then activates the VEGF receptors on endothelial cells in a paracrine fashion, which causes cell proliferation and hypervascularity. These findings are consistent with the hypervascularity seen in the thyroid of patients with Graves’ disease. 89 90
===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 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.
*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>
*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%).


Recently, iodide has been shown to inhibit TSH-induced expression of the angiogenic factors VEGF-A, VEGF-B, and placenta-derived growth factor (PlGF) in cultured human thyroid follicles.  91  Rat thyroid follicular cells produce PlGF. In goitrogen-treated rats, TSH stimulates the binding of PlGF to the vascular endothelial growth factor receptor (VEGFR). 90  Thus, PlGF may have effects similar to those of VEGF. Furthermore, in rat models of goitrogenesis, which was induced by iodine deficiency, methimazole, and sodium perchlorate, goiter formation was inhibited by the expression of recombinant adenovirus vectors expressing truncated and inhibitory forms of VEGF receptor 1 (VEGFR-1), FGFR-1, and the receptor for angiopoietin 2, Tie2. 92  Thus, multiple growth factor axes are implicated in the formation of goiter.
===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 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%.  
*Somatic activating [[TSH receptor]] [[mutations]] are more commonly responsible in the [[pathogenesis]] of toxic [[adenoma]] than [[Gs alpha subunit|Gsα mutations]].


Thrombospondin has an inhibitory effect on angiogenesis. In vitro, human and porcine thyrocytes secrete thrombospondin, a growth inhibitor. 93 94 95  TSH decreases the production of thrombospondin. 94  Findings in the in vivo rat goiter model are consistent with this; thrombospondin levels in endothelial cells disappear within 2 weeks after treatment with methimazole and iodine depravation. 96
===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]] 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.
*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>


ENDOTHELIN-1 AND ATRIAL NATRIURETIC PEPTIDE
===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>
{| class="wikitable"
!Growth Factors (GF)
!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
GF-β1
|
* Counteracts the stimulatory roles of [[TSH]] and other [[growth factors]]


Human thyroid follicular cells make endothelin-1 (ET-1), which is a potent vasoconstrictor. ET-1 is mainly produced by the endothelial cells of the vasculature. Endothelins bind to their receptors, ETA and ETB. ETA is located on smooth muscle cells, where activation of this receptor causes vasoconstriction. ETB is located on endothelial cells, where its activation causes the release of nitric oxide, prostacyclin, and atrial natriuretic peptide (ANP). ET-1 has been shown to bind to its high-affinity receptor in cultured human thyrocytes.  97  Homozygous knockout mice lacking ET-1 are smaller than their littermates, have small thyroid glands without midline fusion, and have small thymus glands that are not descended.  98  ET-1 stimulates the proliferation of cultured human thyroid epithelial cells. This effect of ET-1 is inhibited by the calcium channel blocker verapamil.  99  In the rat goiter model, ET-1 mRNA and protein levels increased 3.5- and 5-fold, respectively, during hyperplasia.  100  In human vascular smooth muscle cells in vitro, ET-1 increases the synthesis of VEGF, the angiogenic factor that leads to hypervascularity and proliferation.  101  These results, taken together, suggest that ET-1 functions as a growth-promoting factor for human thyroid cells.
* Blocks uptake and organification of [[iodine]]


ANP is also produced by thyroid follicular cells. ANP decreases the production of VEGF in cultured endothelial cells in vitro and is thought to act as an antiangiogenic factor.  101 102  Human thyroid cells express ANP receptors, which are thought to signal via a cyclic guanosine monophosphate (cGMP) pathway.  103  TSH has been shown to decrease the number of ANP receptors in thyroid cells.  104  In cultured bovine thyroid follicles, ANP prevents TSH from stimulating iodide uptake and decreases thyroglobulin mRNA.  105  ANP also causes a retracted cell phenotype in cultured human thyrocytes via guanylyl cyclase receptors.  106  Taken together, these data suggest that ANP has an inhibitory action on thyroid hormone synthesis.
* 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 [[Insulin-like growth factor-I|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 [[Insulin-like growth factor|IGF]] BPs and [[IGF]]-1
|-
|Vascular endothelial
growth factor (VEGF)
|
* [[Vascular endothelial growth factor|VEGF]] stimulates growth of blood vessels supplying [[Thyroid follicular cell|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
|
* [[Atrial natriuretic peptide|ANP]] decreases the production of [[VEGF]] 
* [[Mutations|Mutation]] in [[ANP]] producing results uncontrolled [[VEGF]] production
* Finally [[TSH]] and [[hyperplasia]] of [[thyroid]]
|}


The molecular alterations identified in toxic adenomas include somatic gain-of-function mutations in the TSH receptor or the stimulatory Gsα subunit (see Fig. 85-1 ). Both result in constitutive activation of the cAMP pathway, which results in enhanced proliferation and function of thyroid follicular cells. 26
==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.


Somatic mutations in the stimulatory Gsα subunit, which is encoded by the GNAS1 gene, were first discovered in toxic adenomas. 27  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. 28
==Microscopic Pathology==
On [[histological]] examination, toxic [[adenomas]] demonstrate 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]].<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.


Somatic mutations in the TSH receptor in toxic adenomas were among the first discovered naturally occurring G protein–coupled receptor (GPCR) mutations.  29  During the last 2 decades, numerous gain-of-function mutations have been discovered in the TSH receptor in toxic adenomas, as well as in non-autoimmune hyperthyroidism (see later).  30 31 32 33  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%.  31 34  For example, in a study on 33 toxic adenomas from 31 patients from Belgium, 27 of 33 of adenomas were positive for a somatic gain-of-function mutation in the TSH receptor.  35  In contrast, in a Japanese study that analyzed only the part of the gene encoding the third cytoplasmic loop and the sixth transmembrane segment, only 1 of 38 toxic adenomas harbored a functionally silent mutation.  34  Differences in sampling technique and methodologic approach, as well as variations in iodine intake, may contribute to the reported differences.  36  It is now well established that somatic, constitutively activating TSH receptor mutations play a predominant role in the pathogenesis of AFTNs, 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.  37
==References==
{{reflist|2}}
​​


It has been suggested that iodine deficiency may be a predisposing factor for the development of AFTNs.  38  Based on the fact that (multi)nodular goiters develop also in iodine-sufficient regions and that there is often a hereditary predisposition,  39 40  others propose that hereditary and acquired heterogeneity among the thyrocytes play a fundamental role in the pathogenesis of thyroid nodules and that iodine deficiency only serves as a modulating factor.  41
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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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