Physiology, Thyroid Hormone


Article Author:
Muhammad Shahid


Article Editor:
Sandeep Sharma


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Tehmina Warsi


Updated:
3/23/2019 1:38:53 AM

Introduction

Thyroid hormones are essential for proper brain function development in infants and metabolic activity regulation in adults, as well as a wide array of effects on every organ system in the body. The main hormones produced by the thyroid gland are thyroxine (T4), 3,5,3'-triiodothyronine (T3), and reverse 3,5,3'-triiodothyronine (rT3), and they are controlled by thyroid stimulating hormone (TSH) from the anterior pituitary gland. These hormones work in synchronous harmony with their upstream modulators to maintain a proper feedback mechanism and the body's homeostasis. To maintain these activities, there is a large collection of thyroid hormones stored in the colloid of follicular cells, which are the primary cells of the thyroid hormone. When released into circulation, T3 and T4 exert their metabolic effects on multiple organs, including the heart, bone, and brain. An important mediator to thyroid hormone function is the role of iodine, which is obtained through diet. Foods rich in iodine include seafood, seaweed, and dairy products as well as iodinated salt, which is widely available throughout the United States.[1][2][3]

Cellular

Thyroid hormone function starts at the hypothalamus, where TRH is released constitutively through the hypothalamic-hypophyseal portal system to the anterior pituitary gland, which stimulates the release of TSH. TRH is released from the periventricular nucleus (PVN) of the hypothalamus, which projects its neurosecretory neurons into the hypophyseal portal circulation. TRH then binds to TRH receptors on the anterior pituitary gland, causing a signal cascade mediated by a G-protein coupled receptor. This leads to the activation of phosphoinositide-specific phospholipase C, which stimulates phosphatidylinositol 4,5-P(PIP) hydrolysis to form inositol 1,4,5-triphosphate (IP) and 1,2-diacylglycerol (DAG). These second messengers stimulate increases in intracellular calcium and activation of protein kinase C, leading to downstream gene activation and transcription of TSH. 

TSH is released into the blood, where it travels to the thyroid gland and directly binds to the thyroid-releasing hormone receptor (TSH-R) on the basolateral aspect of the thyroid follicular cell. The TSH-R is a G-protein coupled receptor, and its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP.  The increase in cAMP activates the follicular cells of the thyroid gland, including activation of the enzyme thyroid peroxidase (TPO), synthesis of thyroglobulin, and uptake of iodide from the bloodstream. 

The binding of TSH also stimulates the uptake of iodide via the sodium/iodide transporter (Na/I-transporter), allowing iodide to go against its concentration gradient into the follicular cell while also maintaining electroneutrality with the uptake a positively charged sodium ion. Once inside, the iodide molecule is transported to the apical side of the follicular cell via an iodide-chloride transporter called pendrin, to vesicles fused with the apical membrane. Within the vesicles, the iodide is oxidized and covalently bound to tyrosine residues via the enzyme thyroid peroxidase. The formation of these covalent bonds forms monoiodotyrosine residues, which are the building blocks of T3 and T4.

Thyroglobulin is a protein found in the lumen of the follicular cells that contain tyrosine amino acid residues that are essential for the production of thyroid hormone. TPO helps to couple iodine residues with the tyrosine molecules by first oxidizing iodine into iodide (I-) and covalently linking them onto the tyrosine residues, forming MIT and DIT molecules. TPO then combines MIT and DIT residues to generate T4 and T3 within the thyroglobulin molecule. T3 is made by coupling one MIT and one DIT molecule, while T4 is made by coupling two DIT molecules. When TSH stimulates its receptor, the processed thyroglobulin molecule is endocytosed within the follicular cell and is further acted on by lysosomes, releasing the T4 and T3 molecules into circulation.

Thyroid hormones T3 and T4 work in unison to maintain a proper negative feedback loop with their upstream regulators. When there is in an increase in the levels of T3 or T4, they can travel to the hypothalamus and anterior pituitary to turn off the release of TRH and TSH respectively. When levels of T3 and T4 are decreased, TRH and TSH genes are turned on to increase their production and help increase the levels of T3 and T4.[1][4]

Organ Systems Involved

Thyroid hormone affects virtually every organ system in the body, including the heart, CNS, autonomic nervous system, Bone, GI, and metabolism. When thyroid hormone binds to its intracellular receptors in mitochondria, they cause an increase in nutrient breakdown and production of ATP. The generation of ATP leads to an increased level of heat as a byproduct of its reactions, causing an increase in body temperature. Thyroid hormone also can act primarily on beta receptors on the heart, causing an increase in heart rate. In the GI tract, thyroid hormone can cause an increase in GI motility. In the brain, thyroid hormone is essential for proper neurological development; it helps in neurogenesis, neuronal migration, neuronal and glial cell differentiation, myelination, and synaptogenesis. Thyroid hormone also increases the body’s sensitivity to catecholamines, causing an increase in sympathetic tone. The effects of this hormone are magnified when there is a disease that is causing an increase or decrease in the level of the hormone. [5]

Mechanism

In the blood, thyroid hormone is predominantly transferred while bound to serum binding proteins such as thyroid-binding globulin (TBG), transthyretin, or albumin. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. They then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of certain transcription factors. This leads to the activation of certain genes in the cell type, leading to the cell-specific response T3 and T4 exert.

Related Testing

The initial tests of choice to screen for any thyroid abnormality are a TSH and free thyroxine (free T4) test. These determine whether the abnormality arises centrally from the thyroid gland or peripherally from the pituitary. If a diagnosis of hypothyroidism is suspected, TSH levels will be abnormally increased while T4 levels will be decreased. If a diagnosis of hyperthyroidism is suspected, TSH levels will be decreased while T4 levels will be abnormally increased. Other lab tests such as TSH receptor antibodies or antibodies to thyroid peroxidase can help aid in the diagnosis of Graves disease or Hashimoto thyroiditis respectively.[6]

Clinical Significance

Graves Disease

Graves disease is the most common cause of hypothyroidism. It is an autoimmune disease caused by the production of TSH receptor antibodies that help stimulate thyroid gland growth and thyroid hormone release. Patients will have abnormally increased T4 and T3 levels and a decrease in TSH, with a positive TSH-receptor antibody test confirming the diagnosis. Patients will often present with weight loss, tachycardia, heat intolerance, palpitations, proptosis, and a diffusely enlarged thyroid gland.

Iodine Deficiency

In developing countries, the most common cause of hypothyroidism is iodine deficiency. Since iodine is essential for creating thyroid hormone, the disease manifests itself in infancy as congenital hypothyroidism. Patients will present with multiple body dysmorphisms, growth retardation, and poor brain development. Ultimately, this can be reversed with proper iodine supplementation. 

Hashimoto Thyroiditis

The most common cause of hypothyroidism in iodine-sufficient areas is Hashimoto Thyroiditis. It is most commonly caused by antibodies that form against thyroid peroxidase, which causes fibrosis and destruction of the thyroid gland. Patients will present with signs and symptoms of hypothyroidism such as constipation, bradycardia, weight gain, fatigue, hair loss, and cold intolerance.

 Other diseases relating to thyroid abnormalities include the following: 

  • Riedel Fibrosing Thyroiditis
  • Subacute Granulomatous Thyroiditis
  • Wolf-Chaikoff Effect
  • Toxic Multinodular Goiter
  • Thyroid Storm
  • Jod-Basedow Phenomenon[7][8][9]

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Physiology, Thyroid Hormone - Questions

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Which one of the following statements is not true?



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A 17-year-old woman presents with cold intolerance, weight gain, and lethargy. Her lab work reveals decreased levels of thyroid hormones. Which of the following is a precursor of thyroid hormone?



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Select the hormone not produced by the thyroid.



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Select the option that is not correct about thyroid hormones.



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What is the most common form of thyroid hormone found in the bloodstream?



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When studying T3 and T4, which statement is true?



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What is the most abundant form of thyroid hormone found in the bloodstream?



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Is the following statement true or false? Iodine is a precursor without which the thyroid gland cannot make triiodothyronine (T3) and thyroxine (T4).



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When studying triiodothyronine (T3) and thyroxine (T4), which statement is true?



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The T3 test measures:



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All of the following statements about T3 are true except:



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What is the storage protein for T3 and T4?



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Physiology, Thyroid Hormone - References

References

[Neurodevelopmental assessment of patients with congenital hypothyroidism]., Núñez A,Bedregal P,Becerra C,Grob L F,, Revista medica de Chile, 2017 Dec     [PubMed]
Subclinical Hypothyroidism - What is Responsible for its Association with Cardiovascular Disease?, Sorisky A,, European endocrinology, 2016 Aug     [PubMed]
Evaluation and Management of the Child with Thyrotoxicosis., Leung AKC,Leung AAC,, Recent patents on endocrine, metabolic & immune drug discovery, 2018 Mar 26     [PubMed]
The influence of thyroid function on the coagulation system and its clinical consequences., Elbers LPB,Fliers E,Cannegieter SC,, Journal of thrombosis and haemostasis : JTH, 2018 Apr     [PubMed]
Thyroid-disrupting chemicals and brain development: an update., Mughal BB,Fini JB,Demeneix BA,, Endocrine connections, 2018 Apr     [PubMed]
Thyrotropic hormones., Mallya M,Ogilvy-Stuart AL,, Best practice & research. Clinical endocrinology & metabolism, 2018 Jan     [PubMed]
Differentiated thyroid cancer in childhood: a literature update., Karapanou O,Tzanela M,Vlassopoulou T,Kanaka-Gantenbein C,, Hormones (Athens, Greece), 2017 Oct     [PubMed]
The Diagnosis and Management of Thyroid Nodules: A Review., Durante C,Grani G,Lamartina L,Filetti S,Mandel SJ,Cooper DS,, JAMA, 2018 Mar 6     [PubMed]
Singh S,Sandhu S, Thyroid Disease And Pregnancy 2019 Jan;     [PubMed]

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