Physiology, Thyroid Function


Article Author:
Maggie Armstrong
Numan Aziz


Article Editor:
Abbey Fingeret


Editors In Chief:
David Wood
Andrew Wilt
Mary Cataletto


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/28/2019 5:50:37 PM

Introduction

The thyroid is an endocrine gland. Its location is in the inferior, anterior neck, and it is responsible for the formation and secretion of the thyroid hormones as well as iodine homeostasis within the human body. The thyroid produces approximately 90% inactive thyroid hormone, or thyroxine (T4) and 10% active thyroid hormone, or triiodothyronine (T3). Inactive thyroid hormone is converted peripherally to either activated thyroid hormone or an alternative inactive thyroid hormone.

Development

The thyroid diverticulum first forms at the end of the fourth week of development as a solid, proliferating mass of endoderm at the foramen cecum on what will become the tongue. This mass of endoderm migrates down through the developing neck via the thyroglossal duct toward its eventual home just inferior to the cricoid cartilage. In normal development, the thyroglossal duct deteriorates by the end of the fifth week. The only remaining aspect of the thyroid’s embryonal development will be the foramen cecum at the base of the developed tongue. The isolated thyroid gland develops two distinct lobes connected by an isthmus of tissue by this time and continues to descend and reaches its final destination by the end of the seventh week of development. Cells from the ultimobranchial bodies invade the developing thyroid and form the parafollicular cells, or C cells, which will produce calcitonin. The connective tissue of the thyroid gland forms from invading neural crest cells.[1]

Organ Systems Involved

Thyroid hormone induces effects on practically all nucleated cells in the human body, generally increasing their function and metabolism

  • Cardiac output, stroke volume, and resting heart rate increase through positive chronotropic and inotropic effects. Active thyroid hormone increases myocardial intracellular calcium to increase contraction force and speed. Concomitantly, vasculature in the skin, muscle, and heart dilate resulting in decreased peripheral vascular resistance while blood volume increases through activation of the renin-angiotensin-aldosterone system.
  • Basal metabolic rate (BMR), heat production, and oxygen consumption elevate through thyroid hormone activation of mitochondrial uncoupling proteins. Glucose and fatty acid uptake, and oxidation also increase, which results in increased thermogenesis and necessitates increased heat dissipation. Heat intolerance in hyperthyroidism can be attributed to this increase in thermogenesis. Compensation for increased thermogenesis is also mediated by thyroid hormone through increases in blood flow, sweating, and ventilation.
  • Resting respiratory rate and minute ventilation undergo stimulation by active thyroid hormone, triiodothyronine (T3), to normalize arterial oxygen concentration in compensation for increased rates of oxidation. T3 also promotes oxygen delivery to the tissues by simulating erythropoietin and hemoglobin production as well as promoting folate and cobalamin absorption through the gastrointestinal tract.
  • T3 is responsible for the development of fetal growth centers and linear bone growth, endochondral ossification, and epiphyseal bone center maturation following birth. Additionally, T3 simulates adult bone remodeling and degradation of mucopolysaccharides and fibronectin in extracellular connective tissue.
  • T3 stimulates the nervous system resulting in increased wakefulness, alertness, and responsiveness to external stimuli. Thyroid hormone also stimulates the peripheral nervous system, resulting in increased peripheral reflexes and gastrointestinal tone and motility.
  • Thyroid hormone also plays a role in reproductive health and other endocrine organ function. It allows for the regulation of normal reproductive function in both men and women by regulating both the ovulatory cycle and spermatogenesis. Thyroid hormone also regulates pituitary function; growth hormone production and release are stimulated by thyroid hormone while inhibiting prolactin production and release. Additionally, renal clearance of many substances, including some medications, can be increased due to activated thyroid hormone stimulation of renal blood flow and glomerular filtration rate.[2][3]

Function

T3 is responsible for affecting many organs and tissues throughout the body, which can, in summary, is the effect of increasing metabolic rate and protein synthesis. Parafollicular cells, or C cells, are responsible for the production and secretion of calcitonin. Calcitonin opposes parathyroid hormone to decrease blood calcium levels and maintain calcium homeostasis.[4][5]

Mechanism

The thyroid gland is responsible for the production of iodothyronines, of which there are three. The primary secretory product is inactive thyroxine, or T4, which is a prohormone of triiodothyronine, or T3. T4 is converted to T3 peripherally by type 1 deiodinase in tissues with high blood flow, such as the liver and kidneys. In the brain, T4 is converted to active T3 by type 2 deiodinase produced by glial cells. The third iodothyronine is called reverse T3, or rT3. rT3 is inactive and forms by type 3 deiodinase activity on T4.

These iodothyronines are composed of thyroglobulin and iodine. Thyroglobulin is formed from amino acids in a basal to apical fashion within the thyroid cells themselves. Thyroglobulin is then secreted into the follicular lumen where it is enzymatically combined with iodine to form iodinated thyroglobulin. Endosomes containing this iodinated thyroglobulin then fuse with lysosomes which enzymatically release the thyroglobulin from the resultant thyroid hormone. The thyroid hormones are next released from the cell while the remaining thyroglobulin is deiodinated and recycled for further use.[6][7][8]

Related Testing

When testing for thyroid function, most clinicians rely on serum thyroid stimulating hormone (TSH) and serum Free T4. Thyroid-stimulating hormone is responsible for the stimulation of the thyroid to produce more iodothyronines. Therefore, levels inversely correlate with active thyroid hormone concentrations; as T3 increases, TSH decreases and vice versa. Free levels of thyroxine are measured in the serum rather than total T4 levels which would include protein bound T4 which is not available to enter tissues. Free T4, on the other hand, can be a proxy for serum T3 levels. Most often, thyroxine levels are the last to become abnormal in thyroid disorders as the upstream products, TSH and T4, maintain available T3 at their own expense.[9]

Pathophysiology

Hypothyroidism is an endocrine disorder with resultant under-production of thyroid hormone. Common symptoms of hypothyroidism include cold intolerance and weight gain, due to decreased basal metabolic rate and thermogenesis, depression, fatigue, decreased peripheral reflexes, and constipation, due to decreased stimulation of the central and peripheral nervous system. Many other consequences of hypothyroidism can manifest secondary to the lack of activated thyroid hormone on various tissues and organs of the body.[10]

Hyperthyroidism is an endocrine disorder with excess thyroid hormone production. In contrast to hypothyroidism, hyperthyroidism often causes heat intolerance, weight gain, anxiety, hyperreflexia, and diarrhea, as well as palpitations. Increased stimulation of basal metabolic rate, thermogenesis, resting heart rate, and cardiac output, and central and peripheral nervous systems result in the most common symptoms. However, a multitude of symptoms can present, including brittle hair, dry skin, and pretibial myxedema.[11] In Graves disease, an autoimmune condition where the TSH-receptor is activated by an auto-antibody, additional pathophysiology of orbitopathy can be present. The TSH-receptor antibody also activates T cells and causes fibroblast proliferation and accumulation of glycosaminoglycans in the extraocular muscles and retroocular connective tissue leading to proptosis. 

Clinical Significance

Proper thyroid function is necessary for proper development of the growing brain throughout embryologic development. Both iodine deficiency and congenital hypothyroidism, due to absence, malpositioning, underdevelopment, or failure to make thyroid hormones, can cause fetal hypothyroidism. Hypothyroidism during embryologic development may result in intellectual disability, dwarfism, deafness, and muscle hypertonia.

If a portion of the thyroglossal duct fails to obliterate during the fifth week of development, an enclosed thyroglossal cyst or a thyroglossal sinus, which opens to the skin, may form. Alternatively, a portion of the developing thyroid gland may detach at any point along its descent forming hormone-producing ectopic thyroid tissue. Most commonly, this occurs at the superior pole of the thyroid gland, forming the pyramidal lobe, which may be considered a normal anatomic variant and is present in up to half of adults.[12][13][14]


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Physiology, Thyroid Function - Questions

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A 28-year-old presents with increasing anxiety, weight loss despite a normal appetite, and palpitations. Which laboratory test would provide the most clinical utility?



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A 34-year-old woman presents with decreased heat tolerance and weight loss. Which of the following is the pathophysiological mechanism of her presentation?



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A 33-year-old female presents complaining of increased fatigue and weight gain; she also notes cold intolerance and constipation over the last several months. Which of the following would be the best screening test for her condition?



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Physiology, Thyroid Function - References

References

Coste AH,Shermetaro C, Cyst, Branchial Cleft null. 2018 Jan     [PubMed]
Choi JH,Cho JH,Kim JH,Yoo EG,Kim GH,Yoo HW, Variable Clinical Characteristics and Molecular Spectrum of Patients with Syndromes of Reduced Sensitivity to Thyroid Hormone: Genetic Defects in the THRB and SLC16A2 Genes. Hormone research in paediatrics. 2018 Nov 29     [PubMed]
Yasoda A, [Secondary osteoporosis. Hyperthyroidism.] Clinical calcium. 2018     [PubMed]
Duran İD,Gülçelik NE,Bulut B,Balcı Z,Berker D,Güler S, Differences in Calcium Metabolism and Thyroid Physiology After Sleeve Gastrectomy and Roux-En-Y Gastric Bypass. Obesity surgery. 2018 Nov 21     [PubMed]
Maradonna F,Carnevali O, Lipid Metabolism Alteration by Endocrine Disruptors in Animal Models: An Overview. Frontiers in endocrinology. 2018     [PubMed]
Khakisahneh S,Zhang XY,Nouri Z,Hao SY,Chi QS,Wang DH, Thyroid hormones mediate metabolic rate and oxidative, anti-oxidative balance at different temperatures in Mongolian gerbils (Meriones unguiculatus). Comparative biochemistry and physiology. Toxicology     [PubMed]
Cioffi F,Gentile A,Silvestri E,Goglia F,Lombardi A, Effect of Iodothyronines on Thermogenesis: Focus on Brown Adipose Tissue. Frontiers in endocrinology. 2018     [PubMed]
Benvenga S,Guarneri F, Thyroid hormone binding motifs and iodination pattern of thyroglobulin. Frontiers in bioscience (Landmark edition). 2019 Jan 1     [PubMed]
Wang D,Yu S,Ma C,Li H,Qiu L,Cheng X,Guo X,Yin Y,Li D,Wang Z,Hu Y,Lu S,Yang G,Liu H, Reference intervals for thyroid-stimulating hormone, free thyroxine, and free triiodothyronine in elderly Chinese persons. Clinical chemistry and laboratory medicine. 2018 Nov 29     [PubMed]
Merson J, Hypothyroidism. JAAPA : official journal of the American Academy of Physician Assistants. 2018 Dec     [PubMed]
Davis JR,Dackiw AP,Holt SA,Nwariaku FE,Oltmann SC, Rapid Relief: Thyroidectomy is a Quicker Cure than Radioactive Iodine Ablation (RAI) in Patients with Hyperthyroidism. World journal of surgery. 2018 Nov 27     [PubMed]
Adams J, On Goître and Cretinism. The London medical and physical journal. 1815 Jun     [PubMed]
Eshkoli T,Wainstock T,Sheiner E,Beharier O,Fraenkel M,Walfisch A, Maternal Hypothyroidism during Pregnancy and the Risk of Pediatric Endocrine Morbidity in the Offspring. American journal of perinatology. 2018 Nov 26     [PubMed]
Ayandipo OO,Afuwape OO,Soneye OY, Incidence of pyramidal thyroid lobe in the university college hospital Ibadan. Nigerian journal of clinical practice. 2018 Nov     [PubMed]

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