Toxic Adenoma pathophysiology
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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
| Growth Factors (GF) | Role of Growth Factors on TSH |
|---|---|
| Transforming
GF-β1 |
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| Insulin-like
GF-1 |
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| Insulin-like
GF–Binding proteins |
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| Fibroblast GF and
their receptors |
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| Vascular endothelial
growth factor (VEGF) |
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| Atrial natriuretic peptide |
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