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.
Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and ...have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.
Thyroid hormone (TH) has actions in every tissue of the body and is essential for normal development, as well as having important actions in the adult. The earliest markers of TH action that were ...identified and monitored clinically, even before TH could be measured in serum, included oxygen consumption, basal metabolic rate, serum cholesterol, and deep tendon reflex time. Cellular, rodent, amphibian, zebrafish, and human models have been used to study TH action.
Early studies of the mechanism of TH action focused on saturable-specific triiodothyronine (T3) nuclear binding and direct actions of T3 that altered protein expression. Additional effects of TH were recognized on mitochondria, stimulation of ion transport, especially the sodium potassium ATPase, augmentation of adrenergic signaling, role as a neurotransmitter, and direct plasma membrane effects. The cloning of the thyroid hormone receptor (THR) genes in 1986 and report of the THR crystal structure in 1995 produced rapid progress in understanding the mechanism of TH nuclear action, as well as the development of modified THR ligands. These findings revealed nuances of TH signaling, including the role of nuclear receptor coactivators and corepressors, repression of positively stimulated genes by the unliganded receptor, THR isoform-specific actions of TRα (THRA) and TRβ (THRB), and THR binding DNA as a heterodimer with retinoid-x-receptor (RXR) for genes positively regulated by TH. The identification of genetic disorders of TH transport and signaling, especially Resistance to Thyroid Hormone (RTH) and monocarboxylate transporter 8 (
) defects, has been highly informative with respect to the mechanism of TH action.
The impact of THR isoform, post-translational modifications, receptor cofactors, DNA response element, and selective TH tissue uptake, on TH action, have clinical implications for diagnosing and treating thyroid disease. Additionally, these findings have led to the development of novel TH and TH analogue therapies for metabolic, neurological, and cardiovascular diseases.
Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2011, ...significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid disease in women during pregnancy, preconception, and the postpartum period.
The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. The guideline task force had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members.
The revised guidelines for the management of thyroid disease in pregnancy include recommendations regarding the interpretation of thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy, thyrotoxicosis in pregnancy, thyroid nodules and cancer in pregnant women, fetal and neonatal considerations, thyroid disease and lactation, screening for thyroid dysfunction in pregnancy, and directions for future research.
We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid disease in pregnant and postpartum women. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with these disorders.
Thyroid hormone (TH) is essential for normal brain development and may also promote recovery and neuronal regeneration after brain injury. TH acts predominantly through the nuclear receptors, TH ...receptor alpha (THRA) and beta (THRB). Additional factors that impact TH action in the brain include metabolism, activation of thyroxine (T4) to triiodothyronine (T3) by the enzyme 5′-deiodinase Type 2 (Dio2), inactivation by the enzyme 5-deiodinase Type 3 (Dio3) to reverse T3 (rT3), which occurs in glial cells, and uptake by the Mct8 transporter in neurons. Traumatic brain injury (TBI) is associated with inflammation, metabolic alterations and neural death. In clinical studies, central hypothyroidism, due to hypothalamic and pituitary dysfunction, has been found in some individuals after brain injury. TH has been shown, in animal models, to be protective for the damage incurred from brain injury and may have a role to limit injury and promote recovery. Although clinical trials have not yet been reported, findings from in vitro and in vivo models inform potential treatment strategies utilizing TH for protection and promotion of recovery after brain injury.
Approach to the Patient With a Suppressed TSH Praw, Stephanie Smooke; Brent, Gregory A
The journal of clinical endocrinology and metabolism,
01/2023, Letnik:
108, Številka:
2
Journal Article
Recenzirano
Subclinical hyperthyroidism (SCH) is a laboratory diagnosis defined by a serum thyrotropin (TSH) concentration below the reference range (< 0.4 mU/L in most assays), and a free thyroxine (FT4) and ...3,5,3'-triiodothyronine levels (FT3) in the reference range. Many patients diagnosed with SCH will be clinically euthyroid while others may present with manifestations characteristic of thyroid hormone excess, such as tachycardia, tremor, intolerance to heat, bone density loss, or weight loss. In addition to the laboratory abnormalities, patient factors such as age, symptoms, and underlying heart and bone disease are used to stratify patients for the risk of adverse outcomes and determine the appropriate treatment. Evaluation should include repeat thyroid function tests to document persistent TSH suppression, investigation of the underlying cause, as well as evaluation of the patient's risk of adverse outcomes in the setting of a subnormal TSH. Persistent SCH has been associated with an increased risk of a range of adverse events, including cardiovascular events such as atrial fibrillation and heart failure, bone loss and fracture, and in some studies, cognitive decline. Despite the consistent association of these adverse events with SCH, prospective studies showing improved outcomes with treatment remain limited. Management options include observation without active therapy, radioactive iodine ablation of the thyroid, antithyroid medication, thyroid surgery, or radiofrequency ablation, as appropriate for the patient and clinical setting. The choice of therapy should be guided by the underlying etiology of disease, patient factors, and the risks and benefits of each treatment option.
Expression of the sodium iodide symporter (NIS) is required for efficient iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, β-emitting radioactive ...iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioiodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of iodide uptake is required to target tumors with radioiodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioiodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioiodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS.
Environmental exposures, ranging from perchlorate in rocket fuel to polychlorinated biphenols, have been shown to influence thyroid function. Although most of these agents are associated with reduced ...thyroid hormone levels or impaired thyroid hormone action, a number of environmental exposures confer an increased risk of autoimmune thyroid disease.
Factors that increase autoimmune thyroid disease risk include radiation exposure, both from nuclear fallout and medical radiation, increased iodine intake, as well as several contaminants in the environment that influence the thyroid. Although approximately 70% of the risk for developing autoimmune thyroid disease is attributable to genetic background, environmental triggers are thought to play a role in the development of autoimmune thyroid disease in susceptible individuals.
Understanding the association of environmental agents with thyroid dysfunction can be utilized to reduce the risk to populations. Knowledge of the specific factors that trigger autoimmune thyroid disease and their mode of action, however, may also inform risk reduction in the individual patient. These factors are especially relevant for those at increased risk of autoimmune thyroid disease based on family history.
Advanced differentiated thyroid cancer that is resistant to radioactive iodine therapy may become responsive with a unique treatment combination of chloroquine and vorinostat. This treatment was ...demonstrated in cellular and animal models of thyroid cancer to inhibit endocytosis of the plasma membrane-bound iodine transporter, NIS, and restore iodine uptake. See related article by Read et al., p. 1352.
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