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Clinical Practice Keywords /Parathyroid/ / Systems of life This article has been Endocrine system double-blind peer reviewed In this article... ● How T3 and T4 act to regulate cellular ● Clinical features of and ● The role of the thyroid and parathyroid in maintaining calcium

Endocrine system 3: thyroid and parathyroid glands

Key points Authors John Knight is associate professor in biomedical science; Maria Andrade is The thyroid is in the honorary associate professor in biomedical science; Zubeyde Bayram-Weston is , just below the senior lecturer in biomedical science; all at College of Human and Health Sciences, Adam’s apple, and Swansea University. contains four tiny, independently Abstract The endocrine system comprises glands and tissues that produce hormones functioning, to regulate and coordinate vital bodily functions. This article, the third in an eight-part parathyroid glands series on the endocrine system, examines the and of the thyroid and parathyroid glands, and the pathophysiology associated with some common Thyroid follicular thyroid diseases. cells secrete -rich Citation Knight J et al (2021) Endocrine system 3: thyroid and parathyroid glands. hormones, T3 and Nursing Times [online]; 117: 7, 46-50. T4, which help regulate metabolism his eight-part series on the endo- the adult thyroid varies between 15g Release of T3 and crine system opened with an and 30g, and each of the major lobes is T4 is modulated by overview of endocrine glands and around 4cm long and 2cm wide (Benvenga and Tthe role of hormones as chemical et al, 2018; Dorion, 2017). Embedded in the signals that help maintain the homeostatic posterior portion of the thyroid are four hormones balance that is essential to health; the tiny parathyroid glands, which function remaining articles each explore different independently of the thyroid (Fig 1). Hypothyroidism and major endocrine glands and tissues. The hyperthyroidism are second article in the series focused on the common thyroid hypothalamus and pituitary gland. In this The thyroid contains two major popula- disorders, often third article, we explore the anatomy and tions of endocrine cells: treatable with drugs physiology of the thyroid and parathyroid ● Follicular cells – each major lobe of the or radioactive iodine glands, as well as the pathophysiology of thyroid consists of smaller lobules that some common thyroid diseases. are composed of sac-like follicles (Fig 2). The walls of each follicle primarily produced Thyroid gland consist of cube-shaped cells. These by the thyroid works Anatomy synthesise and secrete iodine-rich antagonistically with The thyroid is a bi-lobed gland, often hormones that regulate metabolism; parathyroid described as resembling a butterfly or bow ● Parafollicular cells – these are found in to maintain tie. It is positioned in the neck, between the much smaller numbers, interspersed calcium homeostasis C5 and T1 vertebrae, just below the thyroid between the thyroid follicles, and cartilage (Adam’s apple) of the . It synthesise calcitonin, a hormone that consists of two major lobes (right and left), helps maintain calcium homeostasis. which are connected by a smaller piece of tissue called the isthmus; around half of Thyroid hormones: T3 and T4 individuals also possess an additional third The follicular cells of the thyroid produce lobe, usually triangular shaped and known two iodine-containing hormones, called as the pyramidal lobe (Fig 1). The weight of T3 and T4 (also known as thyroxine). Each

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Fig 1. Thyroid and parathyroid glands smaller amounts present in potato , watercress, kale, green beans, cranberries, strawberries and most types of nut. Many people supplement their iodine intake with combined multivitamin and mineral preparations or iodised table . The cur- rent recommended daily intake (reference intake) of iodine for adults is 140-150µg, rising to 200µg in women who are preg- nant or breastfeeding (Bit.ly/NHSIodine; Bit.ly/BDAIodine). Around 90% of dietary iodine is rapidly absorbed in the stomach and duodenum before circulating in the blood (Leung et al, 2010). The majority of plasma iodine is taken up by the thyroid gland and any excess is eliminated efficiently by the kid- neys. The follicular cells of the thyroid are equipped with transporter in their Fig 2. Follicular and parafolicular cells of the thyroid gland cell membranes; these facilitate rapid uptake of iodine, which is then joined to a large called . This iodised thyroglobulin is stored and con- centrated in the centre of the thyroid folli- cles, where it forms the major component of a homogenous suspension called colloid (Fig 2). Thyroglobulin is rich in the , which provides the substrate for the biosynthesis of thyroid hormones T3 and T4. These thyroid hormones are com- posed of two molecules of tyrosine linked together, containing three (T3) or four (T4) atoms of iodine (Fig 3). When T3 and T4 are required, small droplets of iodised thy- roglobulin are taken back into the follicular cells from the central colloid. The thyroglob- Fig 3. Structure of tyrosine, T3 and T4 ulin is digested by intracellular to release individual molecules of T3 and T4 (Benvenga et al, 2018; Leung et al, 2010). Like all endocrine glands, the thyroid is highly vascularised and T3 and T4 are released directly into the blood. Propor- tionally, the thyroid gland releases approx- imately 80% T4 and 20% T3, although it is estimated that T3 has around four times the potency of T4 (Sargis, 2019). Both hor- mones have very low solubility in the aqueous environment of the plasma so are transported around the body bound to plasma proteins. These include: l Albumin (the most abundant plasma protein); l ; l Thyroxine-binding globulin (TBG). molecule of T3 () has and shellfish, are particularly rich sources Each of these three plasma proteins is three atoms of iodine, while each molecule of this trace mineral. Smaller amounts are synthesised by the , with TBG having of T4 (tetraiodothyronine) has four iodine also found in eggs, red meats, poultry and the highest binding affinity (Chakravarthy atoms. To ensure normal biosynthesis of dairy products, including, milk, yoghurt and Ejaz, 2020). T3 and T4 are bound to T3 and T4, it is essential to maintain an and cheeses. For vegetarians and vegans, their plasma protein vehicles but cannot adequate intake of iodine in the diet. various forms of kelp (seaweed) offer an exert any biological effects; however, small

JENNIFER N.R. SMITH JENNIFER Seafood, including most types of fish incredibly rich source of iodine, with amounts of T3 and T4 detach and, once

Nursing Times [online] July 2021 / Vol 117 Issue 7 47 www.nursingtimes.net Copyright EMAP Publishing 2021 This article is not for distribution except for journal club use Clinical Practice Systems of life free, are able to exert their effects. The hypothalamus continually monitors production of that bind to Free T3 and T4 cross into their target the concentration of T3 and T4 circulating the follicular components of the thyroid cells and bind to thyroid hormone recep- in the plasma. When levels of T3 and T4 gland, which are progressively destroyed by tors (THRs) located in the cell nucleus. decrease, the hypothalamus synthesises the patient’s own . The con- Both hormones can bind to THRs, but T3 and releases thyrotropin-releasing hor- dition is associated with varying degrees of binds with a much greater affinity than T4. mone (TRH). TRH is a small that of the thyroid, while loss of Many of the target cells have enzymes, binds to receptors in the , follicular cells results in reduced called , which rapidly remove initiating the secretion of thyroid stimu- of T3 and T4, and a reduced metabolic rate an atom of iodine from the T4 molecules, lating hormone (TSH). TSH (another pep- (Machala et al, 2019). thereby generating greater amounts of the tide hormone) circulates in the blood before Blood tests usually reveal significantly more-potent T3 (Shahid et al, 2020). binding to its complementary receptors on elevated levels of TSH in patients with the follicular cells of the thyroid gland, Hashimoto’s (Chaker et al, Biological effects of T3 and T4 which then release T3 and T4 (Fig 4). 2017). This is because the low circulating Virtually all human cells and tissues have The HPT axis is fine-tuned via continual levels of T3 and T4 are detected by the THRs and can respond to free T3 and T4, . Increased levels of T3 hypothalamus, which releases TRH, initi- which play an essential role in regulating and T4 circulating in the plasma are ating the release of TSH from the anterior cellular metabolism. detected by the hypothalamus, reducing pituitary. Ageing is often linked to an To release the energy needed to drive the the secretion of TRH. This reduces the increase in circulating autoantibodies that biochemical processes necessary to sustain release of TSH by the anterior pituitary react with the follicular cells of the thyroid life, cells need to use simple -derived gland, thereby reducing the release of T3 gland (Calsolaro et al, 2019); this may par- molecules, such as sugars and fats. The pri- and T4 secretion (Chiasera, 2013). Tight tially explain the reduction in basal meta- mary – and preferred – energy source for homeostatic regulation of the HPT axis bolic rate usually observed in old age. most human cells is , a monosaccha- usually ensures a relatively stable meta- Although the recommended daily ride sugar. In cells, glucose is metabolised in bolic rate but thyroid disorders, which can intake for iodine is low, many people are the cytoplasm using specialised organelles upset homeostasis are common; these are deficient in the mineral. In some parts of called mitochondria. These contain respira- explored below. the UK, and more often in landlocked tory enzymes, which progressively release regions of Africa and Asia, access to energy from the chemical bonds present in Hypothyroidism iodine-rich marine food sources is limited. glucose molecules, and use this to synthe- Hypothyroidism is the term for an under- This can result in chronic iodine defi- sise the energy storage molecule, adenosine active thyroid gland and is characterised ciency, which may cause hypothyroidism. triphosphate (ATP). This process occurs by a deficiency in levels of circulating T3 Prolonged is often most efficiently in the presence of oxygen and T4. Hypothyroidism is the most associated with a pronounced swelling of (aerobic cellular respiration), with each common thyroid disorder; UK incidence is the thyroid gland, known as a ; this molecule of glucose (under normal condi- around 2%, increasing to 5% in people can be disfiguring and visibly stretch the tions) typically yielding around 29-32 mole- >60 years, with women five to 10 times at the front of the neck. Worryingly, cules of ATP (Flurkey, 2010). more likely to be affected compared with despite initiatives to improve iodine As a by-product of cellular metabolism, men (National Institute for Health and intake, iodine deficiency is thought to heat is also generated; this is dissipated Care Excellence (NICE), 2019). affect around 2 billion of the world’s popu- through the body via circulating blood and The most common form of hypothy- lation (Li and Eastman, 2012). other bodily fluids. This heat generation is roidism is primary hypothyroidism. In Insufficient iodine intake during preg- called and is vital to help areas where the diet is not deficient in nancy can lead to congenital iodine defi- maintain the body’s core temperature at iodine, the major form of primary hypothy- ciency syndrome (also known as cre- around 370C, the optimal temperature for roidism is an called tinism). Iodine is essential for the central the functioning of most human enzymes. Hashimoto’s thyroiditis (Chaker et al, 2017). to develop normally, and The rate at which food-derived mole- The precise cause of this disease remains deficiency is associated with varying cules, such as fats, proteins and glucose, unclear, but it is associated with the degrees of brain damage. This can result in are metabolised to release energy is largely governed by T3 and T4 levels. In addition to Fig 4. Hypothalamic-pituitary-thyroid axis regulating metabolism, T3 and T4 also influence a variety of other physiological Hypothalamus processes, including heart and respiratory function, muscle strength, neural func- Thyrotropin-releasing hormone (TRH) tion and the level of in the Pituitary blood (Sargis 2019, VanPutte et al 2017). Negative Thyroid stimulating hormone (TSH) feedback Hypothalamic-pituitary-thyroid axis Thyroid The release of T3 and T4 by the thyroid is modulated by hormones produced by the Thyroid hormone T4 hypothalamus and pituitary gland; this regulatory mechanism is referred to as Thyroid hormone T3 the hypothalamic-pituitary-thyroid axis Increased metabolism (HPT axis).

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Table 1. of hypothyroidism and hyperthyroidism

Clinical features Hypothyroidism Hyperthyroidism Metabolism Decreased, with tendency for weight gain; Increased, with tendency for weight loss; increased difficulty losing weight; decreased body body temperature; heat intolerance; increased temperature; cold intolerance; cold hands and feet; appetite shivering; fatigue and lethargy Central nervous system Depression; poor memory; sluggish speech; slow Overstimulation; agitation; poor concentration; reflexes anxiety; insomnia; nervous tics; mood swings; tremors Dry, scaly skin; decreased sweating, thickened Increased sweating; thinning skin; flushed skin; fine, dystrophic nails, coarse hair, on scalp and brittle hair; thin, soft nails; itchiness and skin rashes eyelids, puffy face Cardiovascular system Reduced heart rate, increased cholesterol Tachycardia; arrhythmias; systolic hypertension Reduced fertility, decreased , heavy and Irregular/light periods; amenorrhea prolonged periods, miscarriage Miscellaneous , goitre, muscle , hoarse voice, Increased bowel movements; nausea; exophthalmos pain (bulging eyes) impaired neurocognitive development, Unintended weight gain and a reduced hypothyroidism: an increased secretion of speech and hearing deficits, and muscular core temperature are the classic symptoms T3 and T4 raises the metabolic rate, which and gait problems. Many affected individ- of hypothyroidism, and necessitate a full often results in marked weight loss. As uals may also display: impaired growth; thyroid function evaluation. Fortunately, food molecules are metabolised more rap- dry, thickened skin; poor/sparse hair treatment for the most common forms of idly, there is greater thermogenesis, raising growth; and gastrointestinal problems hypothyroidism is usually fairly straight- the body’s core temperature and leading to (Toloza et al, 2020). forward and relies on taking levothy- heat intolerance and increased sweating. roxine. This drug is a synthetic form of T4 Other common clinical features of hyper- Secondary and tertiary hypothyroidism and is usually taken once a day in tablet thyroidism are summarised in Table 1. Occasionally, reduced levels of T3 and T4 form (Bit.ly/NHSLevothyroxine). For adult One of the most dramatic clinical fea- are found when the thyroid gland is patients beginning treat- tures of Graves’ disease is an accumulation healthy and receiving a steady supply of ment, it is advisable to monitor the level of of inflamed, fibrous, fatty tissue behind iodine. This can occur due to abnormali- TSH every three months until it has stabi- the eyes, which can cause a prominent ties affecting the anterior pituitary gland, lised to within the normal reference range, bulging of the eyes, called exophthalmus. such as tumours, which reduce the syn- and then once yearly (NICE, 2019). In severe cases, this may result in progres- thesis and release of TSH. Without ade- sive eyelid retraction and compressive quate TSH stimulation, the follicular cells Hyperthyroidism optic neuropathy, which may affect vision. of the thyroid gland release less T3 and T4, Hyperthyroidism is the term for an overac- This collection of clinical features and metabolic rate falls; this is referred to tive thyroid, with consistently elevated affecting the eyes is known as Graves’ oph- as secondary hypothyroidism (Beck- secretion of T3 and T4. The most common thalmopathy and affects around 50% of Peccoz et al, 2017). form of hyperthyroidism is an autoim- people with the disease to varying degrees Even more rarely, damage to the hypo- mune disorder called Graves’ disease; in (Al-Sharif and Alsuhaibani, 2017). The per- , potentially due to head trauma or the UK this affects around 2% of women ceived disfigurement caused by pro- surgery, may reduce or stop the release of and 0.2% of men (NICE, 2019). nounced exophthalmos can cause emo- TRH. This will prevent the release of TSH Graves’ disease is characterised by the tional distress and impaired psychosocial from the anterior pituitary and lead to production of autoantibodies that bind to health. This has led to various surgical reductions in T3 and T4; this is known as the same receptors as TSH. These autoanti- interventions aimed at removing excess tertiary hypothyroidism (Chaker et al, 2017). bodies act as TSH mimics, increasing the tissue behind the eye (orbital decompres- release of T3 and T4 beyond their normal sion), which are largely shown to be safe Clinical features of hypothyroidism physiological concentrations. Although and effective at improving cosmetic appear- Unsurprisingly, a reduced metabolic rate the exact causes are poorly understood, the ance (Al-Sharif and Alsuhaibani, 2017). means people with hypothyroidism often major risk factors are being female (true for Transient or mild hyperthyroidism can gain significant weight. As less energy is most autoimmune diseases) and a family be treated using the drug , being released from food, with no decrease history of autoimmune disease (Campi and which inhibits the addition of iodine to in food intake there is a calorific surplus Salvi, 2018). The disease can usually be con- tyrosine residues in the thyroid, thereby and increased fat deposition. Patients with firmed by the detection of TSH-receptor reducing the release of T3 and T4. However, hypothyroidism also generate substan- autoantibodies in the plasma. in most adults with hyperthyroidism, radi- tially less heat through thermogenesis and oactive iodine (radioiodine) therapy is rec- often complain of feeling cold all the time; Clinical features of hyperthyroidism ommended as a first-line treatment; this other common symptoms of hypothy- In many ways, the primary symptoms of provides accurate and targeted therapy as roidism are highlighted in Table 1. hyperthyroidism are the opposite of the follicular portions of the thyroid gland

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are so effective at taking up and concen- effect of calcitonin is to reduce the References trating iodine. I-131 is an that emits plasma–calcium concentration; this is Al-Sharif E, Alsuhaibani AH (2017) Fat-removal orbital decompression for thyroid associated gamma radiation; this damages and kills achieved by two main mechanisms: orbitopathy: the right procedure for the right patient. the follicular cells, leading to a significant ● Inhibition of activity – Saudi Journal of Ophthalmology; 31: 3, 156–161. reduction in the secretion of T3 and T4. is a dynamic tissue continually built up Bazydlo LAL, Needham M (2014) Calcium, Radioiodine therapy is not used in women by cells called (bone- magnesium, and phosphate. Laboratory Medicine; 45: 1, e44–e50. who are pregnant or breastfeeding or in forming cells) and broken down by cells Beck-Peccoz P et al (2017) Central male or female patients planning for a called (VanPutte et al, 2017). hypothyroidism: a neglected thyroid disorder. in the next 4-6 months. These two groups of cells usually work Nature Reviews: ; 13: 10, 588–598. Benvenga S (2018) Thyroid gland: anatomy and Surgical removal of the thyroid (thyro- at similar rates to maintain bone physiology. Encyclopedia of Endocrine Diseases; 4, dectomy) is recommended when thyroid density. The skeleton acts as a calcium 382-390. malignancy is suspected or there is signifi- reservoir, storing around 99% of the British Thyroid Foundation (2019) Your Guide to cant enlargement of the thyroid tissues and total calcium present in the body. By Treatment of an Overactive or Enlarged Thyroid Gland with Radioactive Iodine. BTF risk of tissue compression. 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There are usually four, each 3-5mm Li M, Eastman CJ (2012) The changing epidemiology of iodine deficiency. Nature Reviews: ● Acting as a cofactor for multiple in diameter, which tend to be oval-to-round Endocrinology; 8: 7, 434-440. enzymes; in shape and weigh around 35mg (Benvenga Machala E et al (2019) Hashimoto’s thyroiditis. ● Haemostasis and blood coagulation. et al, 2018; Dorion, 2017). Each parathyroid World Scientific News; 128: 2, 302-314. National Institute for Health and Care Excellence It is essential that calcium is always gland contains a population of cells called (2019) : Assessment and freely available and is dissolved in the chief cells, which synthesise parathyroid Management. NICE. blood and other bodily fluids at the correct hormone (PTH or parathormone). Sargis RM (2019) How your thyroid works: concentration. 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C-cells) are scattered between the follicles tion. As well as stimulating calcium release CLINICAL of the thyroid gland in relatively small from the skeletal reservoir, PTH further SERIES Endocrine system numbers and make up only around 0.1% of increases plasma–calcium by enhancing Part 1: Overview of the endocrine system the total thyroid cells (Benvenga et al, tubular calcium re-absorption in the kid- and hormones May 2018). Although the parafollicular cells are neys (Summers and Macnab, 2017). Part 2: Hypothalamus and pituitary gland Jun an intrinsic part of the thyroid gland, their Part 3: Thyroid and parathyroid glands Jul activity is not regulated by the HPT axis; Conclusion Part 4: Adrenal glands Aug instead, they act independently, continu- This article has examined the anatomy and Part 5: Pineal and glands Sep ally monitoring plasma–calcium concen- physiology of the thyroid and parathyroid Part 6: Pancreas, stomach, liver, small tration. When plasma calcium rises (for glands, and outlined hypothyroidism and intestine Oct example, after eating calcium-rich dairy hyperthyroidism. Part 4 of this series will Part 7: and testes, food, such as cheese) these cells release the explore the adrenal glands and the diverse (pregnancy) Nov Part 8: Kidneys, heart and skin Dec peptide hormone calcitonin. The major roles they play in human physiology. NT

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