Summary Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism ...is based on statistical reference ranges of the relevant biochemical parameters and is increasingly a matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with levothyroxine. However, a substantial proportion of patients who reach biochemical treatment targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and symptoms of hypothyroidism; summarise evidence on diagnosis, long-term risk, treatment, and management; and highlight future directions for research.
Thyroid function in critically ill patients Fliers, Eric; Bianco, Antonio C; Langouche, Lies ...
The lancet. Diabetes & endocrinology,
10/2015, Letnik:
3, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Patients in the intensive care unit (ICU) typically present with decreased concentrations of plasma tri-iodothyronine, low thyroxine, and normal range or slightly decreased concentration of ...thyroid-stimulating hormone. This ensemble of changes is collectively known as non-thyroidal illness syndrome (NTIS). The extent of NTIS is associated with prognosis, but no proof exists for causality of this association. Initially, NTIS is a consequence of the acute phase response to systemic illness and macronutrient restriction, which might be beneficial. Pathogenesis of NTIS in long-term critical illness is more complex and includes suppression of hypothalamic thyrotropin-releasing hormone, accounting for persistently reduced secretion of thyroid-stimulating hormone despite low plasma thyroid hormone. In some cases distinguishing between NTIS and severe hypothyroidism, which is a rare primary cause for admission to the ICU, can be difficult. Infusion of hypothalamic-releasing factors can reactivate the thyroid axis in patients with NTIS, inducing an anabolic response. Whether this approach has a clinical benefit in terms of outcome is unknown. In this Series paper, we discuss diagnostic aspects, pathogenesis, and implications of NTIS as well as its distinction from severe, primary thyroid disorders in patients in the ICU.
The thyroid hormone (TH) plays a significant role in diverse processes related to growth, development, differentiation, and metabolism. TH signaling modulates energy expenditure through both central ...and peripheral pathways. At the cellular level, the TH exerts its effects after concerted mechanisms facilitate binding to the TH receptor. In the hypothalamus, signals from a range of metabolic pathways, including appetite, temperature, afferent stimuli via the autonomic nervous system, availability of energy substrates, hormones, and other biologically active molecules, converge to maintain plasma TH at the appropriate level to preserve energy homeostasis. At the tissue level, TH actions on metabolism are controlled by transmembrane transporters, deiodinases, and TH receptors. In the modern environment, humans are susceptible to an energy surplus, which has resulted in an obesity epidemic and, thus, understanding the contribution of the TH to cellular and organism metabolism is increasingly relevant.
The deiodinases activate or inactivate thyroid hormone, and their importance in thyroid hormone homeostasis has become increasingly clear with the availability of deiodinase-deficient animals. At the ...same time, heightened interest in the field has been generated following the discovery that the type 2 deiodinase can be an important component in both the Hedgehog signaling pathway and the G protein-coupled bile acid receptor 1-mediated (GPBAR1-mediated) signaling cascade. The discovery of these new roles for the deiodinases indicates that tissue-specific deiodination plays a much broader role than once thought, extending into the realms of developmental biology and metabolism.
Abstract
Deiodinases modify the biological activity of thyroid hormone (TH) molecules, ie, they may activate thyroxine (T4) to 3,5,3′-triiodothyronine (T3), or they may inactivate T3 to ...3,3′-diiodo-L-thyronine (T2) or T4 to reverse triiodothyronine (rT3). Although evidence of deiodination of T4 to T3 has been available since the 1950s, objective evidence of TH metabolism was not established until the 1970s. The modern paradigm considers that the deiodinases not only play a role in the homeostasis of circulating T3, but they also provide dynamic control of TH signaling: cells that express the activating type 2 deiodinase (D2) have enhanced TH signaling due to intracellular build-up of T3; the opposite is seen in cells that express type 3 deiodinase (D3), the inactivating deiodinase. D2 and D3 are expressed in metabolically relevant tissues such as brown adipose tissue, skeletal muscle and liver, and their roles have been investigated using cell, animal, and human models. During development, D2 and D3 expression customize for each tissue/organ the timing and intensity of TH signaling. In adult cells, D2 is induced by cyclic adenosine monophosphate (cAMP), and its expression is invariably associated with enhanced T3 signaling, expression of PGC1 and accelerated energy expenditure. In contrast, D3 expression is induced by hypoxia-inducible factor 1α (HIF-1a), dampening T3 signaling and the metabolic rate. The coordinated expression of these enzymes adjusts TH signaling in a time- and tissue-specific fashion, affecting metabolic pathways in health and disease states.
Abstract
Thyroid hormone (TH) molecules enter cells via membrane transporters and, depending on the cell type, can be activated (i.e., T4 to T3 conversion) or inactivated (i.e., T3 to ...3,3′-diiodo-l-thyronine or T4 to reverse T3 conversion). These reactions are catalyzed by the deiodinases. The biologically active hormone, T3, eventually binds to intracellular TH receptors (TRs), TRα and TRβ, and initiate TH signaling, that is, regulation of target genes and other metabolic pathways. At least three families of transmembrane transporters, MCT, OATP, and LAT, facilitate the entry of TH into cells, which follow the gradient of free hormone between the extracellular fluid and the cytoplasm. Inactivation or marked downregulation of TH transporters can dampen TH signaling. At the same time, dynamic modifications in the expression or activity of TRs and transcriptional coregulators can affect positively or negatively the intensity of TH signaling. However, the deiodinases are the element that provides greatest amplitude in dynamic control of TH signaling. Cells that express the activating deiodinase DIO2 can rapidly enhance TH signaling due to intracellular buildup of T3. In contrast, TH signaling is dampened in cells that express the inactivating deiodinase DIO3. This explains how THs can regulate pathways in development, metabolism, and growth, despite rather stable levels in the circulation. As a consequence, TH signaling is unique for each cell (tissue or organ), depending on circulating TH levels and on the exclusive blend of transporters, deiodinases, and TRs present in each cell. In this review we explore the key mechanisms underlying customization of TH signaling during development, in health and in disease states.
Cells are not passive bystanders in the process of hormonal signaling and instead can actively customize hormonal action. Thyroid hormone gains access to the intracellular environment via membrane ...transporters, and while diffusing from the plasma membrane to the nucleus, thyroid hormone signaling is modified via the action of the deiodinases. Although the type 2 deiodinase (D2) converts the prohormone T4 to the biologically active T3, the type 3 deiodinase (D3) converts it to reverse T3, an inactive metabolite. D3 also inactivates T3 to T2, terminating thyroid hormone action. Therefore, D2 confers cells with the capacity to produce extra amounts of T3 and thus enhances thyroid hormone signaling. In contrast expression of D3 results in the opposite action. The Dio2 and Dio3 genes undergo transcriptional regulation throughout embryonic development, childhood, and adult life. In addition, the D2 protein is unique in that it can be switched off and on via an ubiquitin regulated mechanism, triggered by catalysis of T4. Induction of D2 enhances local thyroid hormone signaling and energy expenditure during activation of brown adipose tissue by cold exposure or high-fat diet. On the other hand, induction of D3 in myocardium and brain during ischemia and hypoxia decreases energy expenditure as part of a homeostatic mechanism to slow down cell metabolism in the face of limited O2 supply.
Idiopathic hypogonadotropic hypogonadism (IHH) has an incidence of 1-10 cases per 100,000 births. About 60% of patients with IHH present with associated anosmia, also known as Kallmann syndrome, ...characterized by total or partial loss of olfaction. Many of the gene mutations associated with Kallmann syndrome have been mapped to KAL1 or FGFR1. However, together, these mutations account for only about 15% of Kallmann syndrome cases. More recently, mutations in PROK2 and PROKR2 have been linked to the syndrome and may account for an additional 5-10% of cases. The remaining 40% of patients with IHH have a normal sense of smell. Prior to 2003, the only gene linked to normosmic IHH was the gonadotropin-releasing hormone receptor gene. However, mutations in this receptor are believed to account for only 10% of cases. Subsequently, mutations in KISS1R, TAC3 and TACR3 were identified as causes of normosmic IHH. Certain genes, including PROK2 and FGFR1, are associated with both anosmic and normosmic IHH. Despite recent advances in the field, the genetic causes of the majority of cases of IHH remain unknown. This Review discusses genes associated with hypogonadotropic disorders and the molecular mechanisms by which mutations in these genes may result in IHH.
Summary
Triiodothyronine (T3), the active form of thyroid hormone is produced predominantly outside the thyroid parenchyma secondary to peripheral tissue deiodination of thyroxine (T4), with <20% ...being secreted directly from the thyroid. In healthy individuals, plasma T3 is regulated by the negative feedback loop of the hypothalamus–pituitary–thyroid axis and by homoeostatic changes in deiodinase expression. Therefore, with the exception of a minimal circadian rhythmicity, serum T3 levels are stable over long periods of time. Studies in rodents indicate that different levels of genetic disruption of the feedback mechanism and deiodinase system are met with increase in serum T4 and thyroid‐stimulating hormone (TSH) levels, while serum T3 levels remain stable. These findings have focused attention on serum T3 levels in patients with thyroid disease, with important clinical implications affecting therapeutic goals and choice of therapy for patients with hypothyroidism. Although monotherapy with levothyroxine is the standard of care for hypothyroidism, not all patients normalize serum T3 levels with many advocating for combination therapy with levothyroxine and liothyronine. The latter could be relevant for a significant number of patients that remain symptomatic on monotherapy with levothyroxine, despite normalization of serum TSH levels.
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