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Physiological Research Sep 2020Iodine is essential in the biosynthesis of thyroid hormones that affect metabolic processes in the organism from the prenatal state to the elderly. The immediate... (Review)
Review
Iodine is essential in the biosynthesis of thyroid hormones that affect metabolic processes in the organism from the prenatal state to the elderly. The immediate indicator of iodine intake is the concentration of iodine in urine, but the indicator of iodine intake in the longer term of several months is thyroglobulin (Tg). Tg negatively correlated with increasing intake of iodine in population that do not suffer from thyroid disease, while a more than adequate to excessive iodine intake leads to an increase in Tg. The dependence of Tg on iodine can be described by a U-shaped curve. Thyroglobulin in serum is elevated in thyroid disease mainly in hyperthyroidism (diagnosis E05 of WHO ICD-10 codes) and in goiter (diagnosis E04 of WHO ICD-10 codes). Tg values decrease below 20 microg/l after effective treatment of patients with thyroid disease. Thyroglobulin may thus be an indicator of thyroid stabilization and the success of the thyroid gland treatment.
Topics: Animals; Humans; Iodine; Thyroglobulin; Thyroid Diseases; Thyroid Gland
PubMed: 33094621
DOI: 10.33549/physiolres.934514 -
Thyroid : Official Journal of the... Aug 2021Biotin has been reported to interfere with several commonly used laboratory assays resulting in misleading values and possible erroneous diagnosis and treatment. This...
Biotin has been reported to interfere with several commonly used laboratory assays resulting in misleading values and possible erroneous diagnosis and treatment. This report describes a prospective study of possible biotin interference in thyroid-related laboratory assays, with a comparison of different commonly used assay platforms. Thirteen adult subjects (mean age 45 ± 13 years old) were administered biotin 10 mg/day for eight days. Blood specimens were collected at three time points on day 1 and on day 8 (baseline, two, and five hours after biotin ingestion). Thyrotropin (TSH), free triiodothyronine (fT3), free thyroxine (fT4), total triiodothyronine (TT3), total thyroxine (TT4), thyroxine binding globulin (TBG), and thyroglobulin (Tg) levels were analyzed with four different platforms: Abbott Architect, Roche Cobas 6000, Siemens IMMULITE 2000, and liquid chromatography with tandem mass spectrometry (LC-MS/MS). TSH, fT3, fT4, TT3, and TT4 were measured with Abbott Architect and Roche Cobas 6000. fT3, fT4, TT3, and TT4 were also measured by LC-MS/MS. Tg was measured by Siemens IMMULITE 2000. TBG was assessed with Siemens IMMULITE 2000. Significant changes in TSH, fT4, and TT3 measurements were observed after biotin exposure when the Roche Cobas 6000 platform was used. Biotin intake resulted in a falsely lower Tg level when measurements were performed with Siemens IMMULITE 2000. At the time points examined, maximal biotin interference was observed two hours after biotin exposure both on day 1 and day 8. A daily dose of 10 mg was shown to interfere with specific assays for TSH, fT4, TT3, and Tg. Physicians must be aware of the potential risk of erroneous test results in subjects taking biotin supplements. Altered test results for TSH and Tg can be particularly problematic in patients requiring careful titration of levothyroxine therapy such as those with thyroid cancer.
Topics: Adult; Aged; Biotin; Chromatography, High Pressure Liquid; False Negative Reactions; Female; Humans; Male; Mass Spectrometry; Middle Aged; Prospective Studies; Thyroglobulin; Thyroid Function Tests; Thyroid Hormones; Thyrotropin
PubMed: 34042535
DOI: 10.1089/thy.2020.0866 -
Endocrinology and Metabolism Clinics of... Sep 2017This article summarizes the main principles for the appropriate use of laboratory testing in the diagnosis and management of thyroid disorders, as well as controversies... (Review)
Review
This article summarizes the main principles for the appropriate use of laboratory testing in the diagnosis and management of thyroid disorders, as well as controversies that have arisen in association with some of these biochemical tests. To place a test in perspective, its sensitivity and accuracy should be taken into account. Ordering the correct laboratory tests facilitates the early diagnosis of a thyroid disorder and allows for timely and appropriate treatment. This article focuses on a comprehensive update regarding thyroid-stimulating hormone, thyroxine/triiodothyronine, thyroid autoantibodies, thyroglobulin, and calcitonin. Clinical uses of these biochemical tests are outlined.
Topics: Autoantibodies; Calcitonin; Diagnostic Techniques, Endocrine; Humans; Thyroglobulin; Thyroid Diseases; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine
PubMed: 28760230
DOI: 10.1016/j.ecl.2017.04.002 -
International Journal of Molecular... Nov 2022The primary functional units of the thyroid gland are follicles of various sizes comprised of a monolayer of epithelial cells (thyrocytes) surrounding an apical... (Review)
Review
The primary functional units of the thyroid gland are follicles of various sizes comprised of a monolayer of epithelial cells (thyrocytes) surrounding an apical extracellular cavity known as the follicle lumen. In the normal thyroid gland, the follicle lumen is filled with secreted protein (referred to as colloid), comprised nearly exclusively of thyroglobulin with a half-life ranging from days to weeks. At the cellular boundary of the follicle lumen, secreted thyroglobulin becomes iodinated, resulting from the coordinated activities of enzymes localized to the thyrocyte apical plasma membrane. Thyroglobulin appearance in evolution is essentially synchronous with the appearance of the follicular architecture of the vertebrate thyroid gland. Thyroglobulin is the most highly expressed thyroid gene and represents the most abundantly expressed thyroid protein. Wildtype thyroglobulin protein is a large and complex glycoprotein that folds in the endoplasmic reticulum, leading to homodimerization and export via the classical secretory pathway to the follicle lumen. However, of the hundreds of human thyroglobulin genetic variants, most exhibit increased susceptibility to misfolding with defective export from the endoplasmic reticulum, triggering hypothyroidism as well as thyroidal endoplasmic reticulum stress. The human disease of hypothyroidism with defective thyroglobulin (either homozygous, or compound heterozygous) can be experimentally modeled in thyrocyte cell culture, or in whole animals, such as mice that are readily amenable to genetic manipulation. From a combination of approaches, it can be demonstrated that in the setting of thyroglobulin misfolding, thyrocytes under chronic continuous ER stress exhibit increased susceptibility to cell death, with interesting cell biological and pathophysiological consequences.
Topics: Mice; Humans; Animals; Thyroglobulin; Hypothyroidism; Thyroid Epithelial Cells; Endoplasmic Reticulum; Proteins
PubMed: 36362390
DOI: 10.3390/ijms232113605 -
Nature Communications Jan 2022The thyroglobulin (TG) protein is essential to thyroid hormone synthesis, plays a vital role in the regulation of metabolism, development and growth and serves as...
The thyroglobulin (TG) protein is essential to thyroid hormone synthesis, plays a vital role in the regulation of metabolism, development and growth and serves as intraglandular iodine storage. Its architecture is conserved among vertebrates. Synthesis of triiodothyronine (T) and thyroxine (T) hormones depends on the conformation, iodination and post-translational modification of TG. Although structural information is available on recombinant and deglycosylated endogenous human thyroglobulin (hTG) from patients with goiters, the structure of native, fully glycosylated hTG remained unknown. Here, we present the cryo-electron microscopy structure of native and fully glycosylated hTG from healthy thyroid glands to 3.2 Å resolution. The structure provides detailed information on hormonogenic and glycosylation sites. We employ liquid chromatography-mass spectrometry (LC-MS) to validate these findings as well as other post-translational modifications and proteolytic cleavage sites. Our results offer insights into thyroid hormonogenesis of native hTG and provide a fundamental understanding of clinically relevant mutations.
Topics: Cryoelectron Microscopy; Goiter; Humans; Iodides; Iodine; Models, Molecular; Protein Conformation; Proteolysis; Thyroglobulin; Thyroid Gland; Thyroid Hormones; Thyroxine; Triiodothyronine
PubMed: 35013249
DOI: 10.1038/s41467-021-27693-8 -
Frontiers in Endocrinology 2022Thyroid hormones (THs), including T4 and T3, are produced and released by the thyroid gland under the stimulation of thyroid-stimulating hormone (TSH). The homeostasis... (Review)
Review
Thyroid hormones (THs), including T4 and T3, are produced and released by the thyroid gland under the stimulation of thyroid-stimulating hormone (TSH). The homeostasis of THs is regulated the coordination of the hypothalamic-pituitary-thyroid axis, plasma binding proteins, and local metabolism in tissues. TH synthesis and secretion in the thyrocytes-containing thyroid follicles are exquisitely regulated by an elaborate molecular network comprising enzymes, transporters, signal transduction machineries, and transcription factors. In this article, we synthesized the relevant literature, organized and dissected the complex intrathyroidal regulatory network into structures amenable to functional interpretation and systems-level modeling. Multiple intertwined feedforward and feedback motifs were identified and described, centering around the transcriptional and posttranslational regulations involved in TH synthesis and secretion, including those underpinning the Wolff-Chaikoff and Plummer effects and thyroglobulin-mediated feedback regulation. A more thorough characterization of the intrathyroidal network from a systems biology perspective, including its topology, constituent network motifs, and nonlinear quantitative properties, can help us to better understand and predict the thyroidal dynamics in response to physiological signals, therapeutic interventions, and environmental disruptions.
Topics: Feedback; Thyroglobulin; Thyroid Gland; Thyroid Hormones; Thyrotropin; Transcription Factors
PubMed: 36187113
DOI: 10.3389/fendo.2022.992883 -
Clinical Chemistry and Laboratory... Jun 2017Different imaging tools, circulating endocrine markers, and fine-needle aspiration (FNA) cytology are of great importance in the diagnosis and follow-up of different... (Review)
Review
Different imaging tools, circulating endocrine markers, and fine-needle aspiration (FNA) cytology are of great importance in the diagnosis and follow-up of different thyroid and parathyroid diseases. Sometimes, however, they are conflicting or inconclusive: interestingly, measuring endocrine markers (i.e. thyroglobulin, calcitonin, parathyroid hormone) in fluids from FNA proved to be a very useful complementary diagnostic tool in such cases. The determination of endocrine markers in fluids other than serum/plasma has been developed in the last years. Although studies have reported overall satisfactory results, a good standardization of procedures has not yet been reached, and further efforts should be made in order to better define pre-analytical, analytical, and post-analytical aspects. Here we reviewed critically the literature on the measurement of FNA endocrine markers, focusing on laboratory issues, such as preparation of the sample, choice of solution, and technical features of determination of these markers. Indeed, information for use of FNA-Tg, FNA-CT, and FNA-PTH in clinical practice was also provided.
Topics: Biopsy, Fine-Needle; Calcitonin; Clinical Chemistry Tests; Humans; Parathyroid Hormone; Thyroglobulin
PubMed: 27802177
DOI: 10.1515/cclm-2016-0543 -
Endocrine Reviews Feb 2016Thyroglobulin (Tg) is a vertebrate secretory protein synthesized in the thyrocyte endoplasmic reticulum (ER), where it acquires N-linked glycosylation and conformational... (Review)
Review
Thyroglobulin (Tg) is a vertebrate secretory protein synthesized in the thyrocyte endoplasmic reticulum (ER), where it acquires N-linked glycosylation and conformational maturation (including formation of many disulfide bonds), leading to homodimerization. Its primary functions include iodide storage and thyroid hormonogenesis. Tg consists largely of repeating domains, and many tyrosyl residues in these domains become iodinated to form monoiodo- and diiodotyrosine, whereas only a small portion of Tg structure is dedicated to hormone formation. Interestingly, evolutionary ancestors, dependent upon thyroid hormone for development, synthesize thyroid hormones without the complete Tg protein architecture. Nevertheless, in all vertebrates, Tg follows a strict pattern of region I, II-III, and the cholinesterase-like (ChEL) domain. In vertebrates, Tg first undergoes intracellular transport through the secretory pathway, which requires the assistance of thyrocyte ER chaperones and oxidoreductases, as well as coordination of distinct regions of Tg, to achieve a native conformation. Curiously, regions II-III and ChEL behave as fully independent folding units that could function as successful secretory proteins by themselves. However, the large Tg region I (bearing the primary T4-forming site) is incompetent by itself for intracellular transport, requiring the downstream regions II-III and ChEL to complete its folding. A combination of nonsense mutations, frameshift mutations, splice site mutations, and missense mutations in Tg occurs spontaneously to cause congenital hypothyroidism and thyroidal ER stress. These Tg mutants are unable to achieve a native conformation within the ER, interfering with the efficiency of Tg maturation and export to the thyroid follicle lumen for iodide storage and hormonogenesis.
Topics: Animals; Congenital Hypothyroidism; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Genetic Predisposition to Disease; Halogenation; Humans; Models, Biological; Models, Molecular; Mutation; Protein Conformation; Thyroglobulin; Thyroid Gland
PubMed: 26595189
DOI: 10.1210/er.2015-1090 -
Nature Feb 2020Thyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates. Hormone...
Thyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates. Hormone synthesis from TG occurs in the thyroid gland via the iodination and coupling of pairs of tyrosines, and is completed by TG proteolysis. Tyrosine proximity within TG is thought to enable the coupling reaction but hormonogenic tyrosines have not been clearly identified, and the lack of a three-dimensional structure of TG has prevented mechanistic understanding. Here we present the structure of full-length human thyroglobulin at a resolution of approximately 3.5 Å, determined by cryo-electron microscopy. We identified all of the hormonogenic tyrosine pairs in the structure, and verified them using site-directed mutagenesis and in vitro hormone-production assays using human TG expressed in HEK293T cells. Our analysis revealed that the proximity, flexibility and solvent exposure of the tyrosines are the key characteristics of hormonogenic sites. We transferred the reaction sites from TG to an engineered tyrosine donor-acceptor pair in the unrelated bacterial maltose-binding protein (MBP), which yielded hormone production with an efficiency comparable to that of TG. Our study provides a framework to further understand the production and regulation of thyroid hormones.
Topics: Bacterial Proteins; Cryoelectron Microscopy; HEK293 Cells; Humans; Maltose-Binding Proteins; Models, Molecular; Mutation; Reproducibility of Results; Solvents; Thyroglobulin; Thyroid Hormones; Tyrosine
PubMed: 32025030
DOI: 10.1038/s41586-020-1995-4 -
Molecular and Cellular Endocrinology Jul 2021The thyroid gland accumulates the rare dietary element iodine and incorporates it into iodinated thyroid hormones, utilising several tightly regulated reactions and... (Review)
Review
The thyroid gland accumulates the rare dietary element iodine and incorporates it into iodinated thyroid hormones, utilising several tightly regulated reactions and molecular mechanisms. Thyroid hormones are essential in vertebrates and play a central role in many biological processes, such as development, thermogenesis and growth. The control of these functions is exerted through the binding of hormones to nuclear thyroid hormone receptors that rule the transcription of numerous metabolic genes. Over the last 50 years, thyroid biology has been studied extensively at the cellular and organismal levels, revealing its multiple clinical implications, yet, a complete molecular understanding is still lacking. This includes the atomic structures of crucial pathway components that would be needed to elucidate molecular mechanisms. Here we review the currently known protein structures involved in thyroid hormone synthesis, regulation, transport, and actions. We also highlight targets for future investigations that will significantly benefit from recent advances in macromolecular structure determination by electron cryo-microscopy (cryo-EM). As an example, we demonstrate how cryo-EM was crucial to obtain the structure of the large thyroid hormone precursor protein, thyroglobulin. We discuss modern cryo-EM compared to other structure determination methods and how an integrated structural and cell biological approach will help filling the molecular knowledge gap in our understanding of thyroid hormone metabolism. Together with clinical, cellular and high-throughput 'omics' studies, atomic structures of thyroid components will provide an important framework to map disease mutations and to interpret and predict thyroid phenotypes.
Topics: Cryoelectron Microscopy; Crystallography, X-Ray; Humans; Protein Conformation; Thyroglobulin; Thyroid Gland
PubMed: 33964321
DOI: 10.1016/j.mce.2021.111309