Toxic Adenoma pathophysiology: Difference between revisions

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==Overview==
==Overview==
==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.
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.


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 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.
*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.
*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. 
*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.


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
===GERMLINE ACTIVATING THYROID-STIMULATING HORMONE RECEPTOR MUTATIONS===
 
*Germline mutations that activate the TSH receptor are rare.
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
*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.  
SOMATIC ACTIVATING THYROID-STIMULATING HORMONE RECEPTOR MUTATIONS
*Affected individuals develop a toxic multinodular goiter that can have its onset from infancy to adult.
 
*Transmission of the disorder is autosomal dominant.  
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.
*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   
GERMLINE ACTIVATING THYROID-STIMULATING HORMONE RECEPTOR MUTATIONS
*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.
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
Role of Growth Factors
Line 54: Line 69:
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.
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.


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


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


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
 
 
 


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
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

Revision as of 16:07, 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.

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.
  • 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.
  • 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.
  • 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.
  • 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.

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

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.

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

ENDOTHELIN-1 AND ATRIAL NATRIURETIC PEPTIDE

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.

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.




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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