-
The Journal of Clinical Investigation Sep 2012Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone... (Review)
Review
Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid hormone action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform-specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function.
Topics: Adipose Tissue; Animals; Cell Membrane; Gene Expression Regulation; Humans; Mutation; Neoplasms; Organogenesis; Receptor Cross-Talk; Receptors, Thyroid Hormone; Signal Transduction; Thyroid Hormone Resistance Syndrome; Thyroid Hormones
PubMed: 22945636
DOI: 10.1172/JCI60047 -
International Journal of Molecular... Jun 2021Thyroid hormones are necessary for the normal functioning of physiological systems. Therefore, knowledge of any factor (whether genetic, environmental or intrinsic) that... (Review)
Review
Thyroid hormones are necessary for the normal functioning of physiological systems. Therefore, knowledge of any factor (whether genetic, environmental or intrinsic) that alters the levels of thyroid-stimulating hormone (TSH) and thyroid hormones is crucial. Genetic factors contribute up to 65% of interindividual variations in TSH and thyroid hormone levels, but many environmental factors can also affect thyroid function. This review discusses studies that have analyzed the impact of environmental factors on TSH and thyroid hormone levels in healthy adults. We included lifestyle factors (smoking, alcohol consumption, diet and exercise) and pollutants (chemicals and heavy metals). Many inconsistencies in the results have been observed between studies, making it difficult to draw a general conclusion about how a particular environmental factor influences TSH and thyroid hormone levels. However, lifestyle factors that showed the clearest association with TSH and thyroid hormones were smoking, body mass index (BMI) and iodine (micronutrient taken from the diet). Smoking mainly led to a decrease in TSH levels and an increase in triiodothyronine (T3) and thyroxine (T4) levels, while BMI levels were positively correlated with TSH and free T3 levels. Excess iodine led to an increase in TSH levels and a decrease in thyroid hormone levels. Among the pollutants analyzed, most studies observed a decrease in thyroid hormone levels after exposure to perchlorate. Future studies should continue to analyze the impact of environmental factors on thyroid function as they could contribute to understanding the complex background of gene-environment interactions underlying the pathology of thyroid diseases.
Topics: Animals; Biomarkers; Diet; Environment; Environmental Pollutants; Gene Expression Regulation; Gene-Environment Interaction; Genetic Background; Humans; Life Style; Thyroid Hormones; Thyrotropin
PubMed: 34204586
DOI: 10.3390/ijms22126521 -
Polish Archives of Internal Medicine Mar 2022Hashimoto thyroiditis (HT) is a common autoimmune disorder, affecting women 7-10 times more often than men, that develops because of genetic susceptibility, Xchromosome...
Hashimoto thyroiditis (HT) is a common autoimmune disorder, affecting women 7-10 times more often than men, that develops because of genetic susceptibility, Xchromosome inactivation patterns modulated by environmental factors as well as microbiome composition, and leads to an imbalance in self‑tolerance mechanisms. The consequential thyroid infiltration by lymphocytes, potentiated by antibody‑mediated autoimmune response through the antibodies against thyroid peroxidase (TPOAbs), leads to a destruction of thyrocytes. The presence of TPOAbs is associated with a 2 to 4‑fold increase in the risk of recurrent miscarriages and preterm birth in pregnant women. The clinical presentation of HT includes: (A) thyrotoxicosis, when stored thyroid hormones are released to circulation from destroyed thyroid follicles; (B) euthyroidism, when preserved thyroid tissue compensates for destroyed thyrocytes; and (C) hypothyroidism, when thyroid hormone production by the affected thyroid gland is insufficient. The management of Hashitoxicosis is based on symptoms control usually with β‑blockers, euthyroidism requires periodical thyroid stimulating hormone measurements to assess for progression to hypothyroidism, and hypothyroidism is treated with thyroid hormone replacement therapy. The dose of levothyroxine (LT4) used for treatment is based on the degree of preserved thyroid functionality and lean body mass, and usually ranges from 1.4 to 1.8 mcg/kg/day. There is insufficient evidence to recommend for or against therapy with triiodothyronine (T3), apart from in pregnancy when only levothyroxine is indicated, as T3 does not sufficiently cross fetal blood‑brain barrier. HT is associated with 1.6 times higher risk of papillary thyroid cancer and 60 times higher risk of thyroid lymphoma than in general the population.
Topics: Female; Hashimoto Disease; Humans; Hypothyroidism; Infant, Newborn; Male; Pregnancy; Premature Birth; Thyroid Hormones; Thyroxine; Triiodothyronine
PubMed: 35243857
DOI: 10.20452/pamw.16222 -
Polish Archives of Internal Medicine May 2017Anemia is a frequent, although often underestimated, clinical condition accompanying thyroid diseases. Despite the fact that anemia and thyroid dysfunction often occur... (Review)
Review
Anemia is a frequent, although often underestimated, clinical condition accompanying thyroid diseases. Despite the fact that anemia and thyroid dysfunction often occur simultaneously, the causative relationship between the disorders remains ambiguous. Thyroid hormones stimulate the proliferation of erythrocyte precursors both directly and via erythropoietin production enhancement, while iron-deficient anemia negatively influences thyroid hormone status. Thus, different forms of anemia might develop in the course of thyroid dysfunction. Normocytic anemia is the most common, while macrocytic or microcytic anemia occurs less frequently. Anemia in hypothyroidism might result from bone marrow depression, decreased erythropoietin production, comorbid diseases, or concomitant iron, vitamin B12, or folate deficiency. Altered iron metabolism and oxidative stress may contribute to anemia in hyperthyroidism. The risk of anemia in autoimmune thyroid disease (AITD) may be related to pernicious anemia and atrophic gastritis, celiac disease, autoimmune hemolytic syndrome, or rheumatic disorders. The coexistence of anemia and thyroid disease constitutes an important clinical problem. Thus, the aim of this review was to provide a comprehensive summary of data on the prevalence, potential mechanisms, and therapy of anemia in the course of thyroid diseases from the clinical and pathogenetic perspectives. Thyroid dysfunction and AITD should be considered in a differential diagnosis of treatment-resistant or refractory anemia, as well as in the case of increased red blood cell distribution width. Of note, the presence of AITD itself, independently from thyroid hormone status, might affect the hemoglobin level.
Topics: Anemia; Female; Humans; Male; Thyroid Diseases; Thyroid Hormones
PubMed: 28400547
DOI: 10.20452/pamw.3985 -
Frontiers in Endocrinology 2022The clinical availability of tissue-specific biomarkers of thyroid hormone (TH) action constitutes a "holy grail" for the field. Scientists have investigated several... (Review)
Review
The clinical availability of tissue-specific biomarkers of thyroid hormone (TH) action constitutes a "holy grail" for the field. Scientists have investigated several TH-dependent markers, including the tissue content of triiodothyronine (T3)-the active form of TH. The study of animal models and humans indicates that the T3 content varies among different tissues, mostly due to the presence of low-affinity, high-capacity cytoplasmic T3 binding proteins. Nonetheless, given that T3 levels in the plasma and tissues are in equilibrium, T3 signaling is defined by the intracellular free T3 levels. The available techniques to assess tissue T3 are invasive and not clinically applicable. However, the tracer kinetic studies revealed that serum T3 levels can accurately predict tissue T3 content and T3 signaling in most tissues, except for the brain and pituitary gland. This is true not only for normal individuals but also for patients with hypo or hyperthyroidism-but not for patients with non-thyroidal illness syndrome. Given this direct relationship between serum and tissue T3 contents and T3 signaling in most tissues, clinicians managing patients with hypothyroidism could refocus attention on monitoring serum T3 levels. Future clinical trials should aim at correlating clinical outcomes with serum T3 levels.
Topics: Animals; Humans; Thyroxine; Kinetics; Thyroid Hormones; Triiodothyronine; Thyroid Function Tests; Hypothyroidism
PubMed: 36387853
DOI: 10.3389/fendo.2022.1044691 -
Nature Reviews. Endocrinology May 2018It has been known for a long time that thyroid hormones have prominent effects on hepatic fatty acid and cholesterol synthesis and metabolism. Indeed, hypothyroidism has... (Review)
Review
It has been known for a long time that thyroid hormones have prominent effects on hepatic fatty acid and cholesterol synthesis and metabolism. Indeed, hypothyroidism has been associated with increased serum levels of triglycerides and cholesterol as well as non-alcoholic fatty liver disease (NAFLD). Advances in areas such as cell imaging, autophagy and metabolomics have generated a more detailed and comprehensive picture of thyroid-hormone-mediated regulation of hepatic lipid metabolism at the molecular level. In this Review, we describe and summarize the key features of direct thyroid hormone regulation of lipogenesis, fatty acid β-oxidation, cholesterol synthesis and the reverse cholesterol transport pathway in normal and altered thyroid hormone states. Thyroid hormone mediates these effects at the transcriptional and post-translational levels and via autophagy. Given these potentially beneficial effects on lipid metabolism, it is possible that thyroid hormone analogues and/or mimetics might be useful for the treatment of metabolic diseases involving the liver, such as hypercholesterolaemia and NAFLD.
Topics: Animals; Humans; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease; Thyroid Hormones
PubMed: 29472712
DOI: 10.1038/nrendo.2018.10 -
Pharmacology & Therapeutics May 2017Thyroid hormones (TH) are endocrine messengers essential for normal development and function of virtually every vertebrate. The hypothalamic-pituitary-thyroid axis is... (Review)
Review
Thyroid hormones (TH) are endocrine messengers essential for normal development and function of virtually every vertebrate. The hypothalamic-pituitary-thyroid axis is exquisitely modulated to maintain nearly constant TH (T4 and T3) levels in circulation. However peripheral tissues and the CNS control the intracellular availability of TH, suggesting that circulating concentrations of TH are not fully representative of what each cell type sees. Indeed, recent work in the field has identified that TH transporters, deiodinases and thyroid hormone receptor coregulators can strongly control tissue-specific sensitivity to a set amount of TH. Furthermore, the mechanism by which the thyroid hormone receptors regulate target gene expression can vary by gene, tissue and cellular context. This review will highlight novel insights into the machinery that controls the cellular response to TH, which include unique signaling cascades. These findings shed new light into the pathophysiology of human diseases caused by abnormal TH signaling.
Topics: Animals; Gene Expression Regulation; Humans; Hypothalamo-Hypophyseal System; Receptors, Thyroid Hormone; Signal Transduction; Thyroid Hormones; Thyroxine; Triiodothyronine
PubMed: 28174093
DOI: 10.1016/j.pharmthera.2017.02.012 -
Nature Reviews. Endocrinology Oct 2014Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor α (THRA) and thyroid hormone... (Review)
Review
Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) genes. Patients with mutations in THRB present with resistance to thyroid hormone β (RTHβ), which is a disorder characterized by elevated levels of thyroid hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic-pituitary-thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.
Topics: Animals; Humans; Mutation; Receptors, Thyroid Hormone; Thyroid Diseases; Thyroid Hormones
PubMed: 25135573
DOI: 10.1038/nrendo.2014.143 -
Thyroid : Official Journal of the... Aug 2020The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis... (Review)
Review
The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis of the relative distribution of the α and β subtypes of nuclear TH receptors (TRα and TRβ) showed that TRα and TRβ are responsible for cardiac and metabolic responses, respectively. Therefore, analogues with TRβ selectivity were developed, and four different compounds have been used in clinical trials: GC-1 (sobetirome), KB-2115 (eprotirome), MB07344/VK2809, and MGL-3196 (resmetirom). Each of these compounds was able to reduce low-density lipoprotein cholesterol, but a phase 3 trial with eprotirome was interrupted because of a significant increase in liver enzymes and the contemporary report of cartilage side effects in animals. As a consequence, the other projects were terminated as well. However, in recent years, TRβ agonists have raised new interest for the treatment of nonalcoholic fatty liver disease (NAFLD). After obtaining excellent results in experimental models, clinical trials have been started with MGL-3196 and VK2809, and the initial reports are encouraging. Sobetirome turned out to be effective also in experimental models of demyelinating disease. Aside TRβ agonists, TH analogues include some TH metabolites that are biologically active on their own, and their synthetic analogues. 3,5,3'-triiodothyroacetic acid has already found clinical use in the treatment of some cases of TH resistance due to TRβ mutations, and interesting results have recently been reported in patients with the Allan-Herndon-Dudley syndrome, a rare disease caused by mutations in the TH transporter MCT8. 3,5-diiodothyronine (T2) has been used with success in rat models of dyslipidemia and NAFLD, but the outcome of a clinical trial with a synthetic T2 analogue was disappointing. 3-iodothyronamine (T1AM) is the last entry in the group of active TH metabolites. Promising results have been obtained in animal models of neurological injury induced by β-amyloid or by convulsive agents, but no clinical data are available so far.
Topics: Acetates; Anilides; Animals; Central Nervous System Diseases; Clinical Trials as Topic; Diiodothyronines; Drug Design; Dyslipidemias; Humans; Liver Diseases; Male; Mice; Mutation; Non-alcoholic Fatty Liver Disease; Phenols; Pyridazines; Rats; Signal Transduction; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Thyroid Hormones; Thyronines; Triiodothyronine; Uracil
PubMed: 32098589
DOI: 10.1089/thy.2020.0071 -
Aging Cell Nov 2020Thyroid function is central in the control of physiological and pathophysiological processes. Studies in animal models and human research have determined that thyroid... (Review)
Review
Thyroid function is central in the control of physiological and pathophysiological processes. Studies in animal models and human research have determined that thyroid hormones modulate cellular processes relevant for aging and for the majority of age-related diseases. While several studies have associated mild reductions on thyroid hormone function with exceptional longevity in animals and humans, alterations in thyroid hormones are serious medical conditions associated with unhealthy aging and premature death. Moreover, both hyperthyroidism and hypothyroidism have been associated with the development of certain types of diabetes and cancers, indicating a great complexity of the molecular mechanisms controlled by thyroid hormones. In this review, we describe the latest findings in thyroid hormone research in the field of aging, diabetes, and cancer, with a special focus on hepatocellular carcinomas. While aging studies indicate that the direct modulation of thyroid hormones is not a viable strategy to promote healthy aging or longevity and the development of thyromimetics is challenging due to inefficacy and potential toxicity, we argue that interventions based on the use of modulators of thyroid hormone function might provide therapeutic benefit in certain types of diabetes and cancers.
Topics: Aging; Diabetes Mellitus; Humans; Neoplasms; Risk Factors; Thyroid Gland; Thyroid Hormones
PubMed: 33048427
DOI: 10.1111/acel.13260