Toxic multinodular goiter pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
- The progression to Toxic multinodular goiter usually involves the somatic gain-of-function mutations in the TSH receptor in autonomously functioning thyroid nodules.
Pathophysiology
Thyroid physiology:
- The tissue of the thyroid gland is composed mostly of thyroid follicles
- The follicles are made up of a central cavity filled with a sticky fluid called colloid. Surrounded by a wall of epithelial follicle cells, the colloid is the center of thyroid hormone production, and that production is dependent on the hormones’ essential and unique component: iodine.
- Thyroid is endocrine gland which synthase and secretes thyroid hormones in bloodstream directly.
- It is regulated by hypothalamus and pituitary gland.
- Thyroid hormones are of two biochemical structures. , triiodothyronine (T3), which is true and potent form and its pro-hormone, thyroxine (T4) majorly is secretory form later converted to T3 in peripheral tissues by deiodinase enzyme.
- Thyroid hormones has negative feedback on thyroid receptors located on hypothalamus and pituitary gland.
- Thyroid hormones majorly effects every part of body and maintains metabolic rate by acting on thyroid receptors which are nuclear receptors mediating gene expression.
- Functional unit of thyroid gland is thyroid follicles, which are aliened in continuous circular form forming hallow cavity between them called thyroid cavity. On basal side of thyroid follicle is connective tissue containing blood vessels for transport of thyroid hormone and blood cells and iodine. Apical side of thyroid follicle faces toward thyroid cavity where it has TPO enzymes located, which help in conversion of iodide to iodine. Iodine is organified to tyrosine residue of thyroglobin, which is synthesized and stored in thyroid follicle cavity. It forms mono-idodo or di-iodo thyroglobin and then they combine to form tri-iodo or trata-iodo thyroglobin. On demand of body thyroglobin goes in proteolysis and release T3,T4 in blood stream across thyroid follicle.
- At high magnification the cell surface lining the follicle is rich in microvilli that project into the follicular lumen where the colloid is secreted; hormones are secreted into the blood at the opposite basal cell pole adjoining the rich capillary net.
- TSH is heterodimeric cystine-knot glycoproteins consisting a unique β-subunit, which provides biological specificity to TSH receptor and secreted by the basophilic thyrotropes in anteroir pitutary gland.
- TSH receptor (TSH-R) which is found on basolateral surface of thyroid follecular cells, belongs to a rhodopsin/β-adrenergic receptor family in the seven-transmembrane domain, GPCR superfamily.[1]
- TSH-R is composed of 764 amino acids, plays important role in thyroid gland function and growth.[2]
- TSHR gene is found on chromosome 14q31[3]
- TSHR can be found on other parts of body such as lymphocytes, adipocytes, retroocular fibroblasts, neuronal cells, and astrocytes[4]
- TSH-R dependent interleukin-2 activation of cytotoxic lymphocytes has been associated with pathogenesis of many autoimmune thyroid disease.[5]
- It leads to activation of cAMP and formation of PIP2 and Ca ++.
- Iodide uptake, TPO, and TG synthesis occurs via the TSH-induced cAMP signal
- TSH-induced PIP2 cascade is playing role in iodide eflux, hydrogen peroxide generation, and iodination[6]
- TSH-R is divided in two parts. extracellular long hydrophillic end followed small cytoplasmic by seven loops of hydrophobic end which has a phosphrylantion site.
- Deletion of the signal peptide in the TSHR prevents its in situ processing and glycosylation.[7]
Pathogenesis
- The progression to Toxic multinodular goiter usually involves the somatic gain-of-function mutations in the TSH receptor.
- More than 30 different activating mutations causing nonautoimmune hyperthyroidism have been found which includes mutation in toxic nodule and multi nodular toxic goiter.
- he “Two-State” Model of TSH-R explains that there are two stages of TSH-R, [8]
- A: “closed” (inactive) TSHR conformation
- B: “opened” (unliganded) TSHR conformation.
- C: “opened” (hormone-activated) TSHR conformation.
- Activating mutations in the TSH-R genes may lead to increase of basal and TSH-induced activation of cAMP or inositol phosphate (IP) cascades which keep TSH-R[9] in opened unliganded or hormone-activated state. it is called somatic gain-of-function mutations.[10]
Genetics
- [Disease name] is transmitted in [mode of genetic transmission] pattern.
- Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
- The development of [disease name] is the result of multiple genetic mutations.
Associated Conditions
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ Kohn LD, Shimura H, Shimura Y, Hidaka A, Giuliani C, Napolitano G; et al. (1995). "The thyrotropin receptor". Vitam Horm. 50: 287–384. PMID 7709602.
- ↑ Graves PN, Davies TF (2000). "New insights into the thyroid-stimulating hormone receptor. The major antigen of Graves' disease". Endocrinol Metab Clin North Am. 29 (2): 267–86, vi. PMID 10874529.
- ↑ Rousseau-Merck MF, Misrahi M, Loosfelt H, Atger M, Milgrom E, Berger R (1990). "Assignment of the human thyroid stimulating hormone receptor (TSHR) gene to chromosome 14q31". Genomics. 8 (2): 233–6. PMID 2249847.
- ↑ Paschke R, Geenen V (1995). "Messenger RNA expression for a TSH receptor variant in the thymus of a two-year-old child". J Mol Med (Berl). 73 (11): 577–80. PMID 8751142.
- ↑ Abe E, Marians RC, Yu W, Wu XB, Ando T, Li Y; et al. (2003). "TSH is a negative regulator of skeletal remodeling". Cell. 115 (2): 151–62. PMID 14567913.
- ↑ Giuliani C, Cerrone D, Harii N, Thornton M, Kohn LD, Dagia NM; et al. (2012). "A TSHr-LH/CGr chimera that measures functional TSAb in Graves' disease". J Clin Endocrinol Metab. 97 (7): E1106–15. doi:10.1210/jc.2011-2893. PMID 22496495.
- ↑ Akamizu T, Kosugi S, Kohn LD (1990). "Thyrotropin receptor processing and interaction with thyrotropin". Biochem Biophys Res Commun. 169 (3): 947–52. PMID 2114112.
- ↑ Duprez L, Parma J, Costagliola S, Hermans J, Van Sande J, Dumont JE; et al. (1997). "Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain". FEBS Lett. 409 (3): 469–74. PMID 9224711.
- ↑ Tonacchera M, Van Sande J, Cetani F, Swillens S, Schvartz C, Winiszewski P; et al. (1996). "Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia". J Clin Endocrinol Metab. 81 (2): 547–54. doi:10.1210/jcem.81.2.8636266. PMID 8636266.
- ↑ Kleinau G, Neumann S, Grüters A, Krude H, Biebermann H (2013). "Novel insights on thyroid-stimulating hormone receptor signal transduction". Endocr Rev. 34 (5): 691–724. doi:10.1210/er.2012-1072. PMC 3785642. PMID 23645907.