PHYSIOLOGY Thyroid, parathyroid Learning objectives hormones and calcium After reading this article you should be able to describe: homeostasis C the synthesis, secretion and regulation of thyroid hormones C the physiological effects of thyroid hormones C calcium and phosphate homeostasis Rebecca Summers C the role of the parathyroid gland Ross Macnab Abstract consist of a tyrosine molecule that is attached to a phenyl ring via The thyroid gland secretes thyroxine (T4) and triiodothyronine (T3) in an ether linkage, and have two iodine atoms on the tyrosine ring. response to thyroid-stimulating hormone release from the anterior pi- However, T4 has two iodine atoms on its phenyl ring, whereas tuitary gland. Iodine is essential for the synthesis of thyroid hormones. T3 only has one (Figure 1). T4 and T3 increase the basal metabolic rate, heat production, and help Dietary iodine is essential for production of thyroid hormones, to maintain normal growth and development. Serum calcium levels are with a recommended daily intake of 150 mg/day in adults. Foods under very tight control. The majority of calcium is found in bones. Cal- which are rich in iodine include seafood, dairy products and cium and phosphate levels are maintained by four hormones e para- some vegetables. Many countries add iodine to salt to maintain thyroid hormone (PTH), calcitonin, vitamin D and fibroblast growth adequate levels within the population’s diet. À factor 23. PTH is produced by the parathyroid glands and its secretion Iodide (I ) is actively transported into thyroid follicular cells is determined by serum calcium levels. via the sodium iodine transporter on the basolateral membrane Keywords Calcium; homeostasis; parathyroid; phosphate; thyroid; of the cell. The iodide is then oxidized in vesicles on the apical thyroxine; triiodothyronine cell membrane in a process catalysed by thyroid peroxidase. It then diffuses into the colloid and becomes covalently bound to Royal College of Anaesthetists CPD Matrix: 1A01 some of the tyrosyl residues of thyroglobulin. This forms MIT and DIT. Thyroid peroxidase then catalyses the ‘coupling’ of these residues to form T4 from two DIT residues, and T3 from one MIT and one DIT residues. Thyroid When the thyroid is stimulated to produce T3 and T4, colloid Anatomy droplets containing the thyroglobulin, are reabsorbed via pino- The thyroid is a large endocrine gland which lies anterior to the cytosis into the follicular cells. These droplets then fuse with trachea, at the level of C5 to T1. It has two lobes which are lysosomes and the thyroglobulin is hydrolysed to form T4 and connected by a central isthmus. The average weight of an adult T3. These hormones are released into the extracellular fluid and thyroid is 20 g. It receives a rich blood supply from the superior then into the circulation (Figure 2). and inferior thyroid arteries. T4 is produced solely in the thyroid gland, at a rate of 80e100 Microscopically, the gland is composed of spherical follicles, mg/day. About 20% of T3 is produced by the thyroid gland, with each of which contains a single layer of columnar cells sur- a production rate of roughly 30e40 mg/day. The rest is formed by rounded by protein-rich colloid within the lumen. Colloid con- extrathyroidal deiodination of T4 in target tissues. The liver and sists mainly of a large glycoprotein called thyroglobulin. Thyroid kidney are the main sites at which this occurs, but some T3 is hormones are synthesized and stored within the protein of produced in the majority of tissues. T3 is significantly more thyroglobulin. potent than T4. Hormones Hormone transport: T3 and T4 are relatively insoluble, therefore Hormone biosynthesis: there are two active thyroid hormones, are carried in the blood bound to serum binding proteins thyroxine (T4 or tetraiodothyronine) and 3,5,3-triiodothyronine (Table 1). These include thyroxine-binding globulin (TBG), (T3). These are produced from the biologically inactive hor- albumin, lipoproteins and transthyretin (TTR). mones, mono-iodotyrosine (MIT) and diiodothyrosine (DIT) which are found in the follicular thyroid gland in small quanti- Hormone mechanism of action: thyroid hormones enter cells ties. T3 is formed when one molecule of MIT joins with one DIT; through membrane transporter proteins before binding to their T4 is formed when two DIT molecules combine. Both T3 and T4 receptor in the nucleus. This hormone-receptor complex interacts with DNA resulting in the synthesis of new mRNA and protein. There is an increase in the number of mitochondria and meta- bolic rate increases. Rebecca Summers MB ChB FRCA is an ST6 in Anaesthesia at the North West School of Anaesthesia, UK. Conflicts of interest: none. Ross Macnab MB ChB FRCA is a Consultant Anaesthetist at Central Regulation of thyroid function Manchester University Hospitals NHS Foundation Trust, UK. The production of thyroid hormones is regulated by a negative Conflicts of interest: none. feedback loop (Figure 3). Low circulating levels of T4 and T3 ANAESTHESIA AND INTENSIVE CARE MEDICINE 18:10 522 Ó 2017 Published by Elsevier Ltd. PHYSIOLOGY Thyroid hormone formulae R O Tyrosine HO CH2 CH C OH NH2 + iodine + (2 × iodine) I I Monoiodotyrosine HO R HO R Diiodotyrosine (MIT) (DIT) I + DIT + DIT I I I I Triiodothyronine (T3) HO O R HO O R Thyroxine (T4) I I I Figure 1 Synthesis of thyroid hormones Blood Thyroid follicular epithelial cell Follicular lumen MIT DIT – MIT I I2 + TG Deiodination DIT Na+ Thyroglobulin DIT (TG) TG MIT Tyrosine Coupling MIT, DIT Thyroid peroxidase T4 T3 DIT T4 T3 TG DIT T3 T3 Release of T3 and T4 TG T4 into circulation MIT T3 T4 T4 Diffusion MIT Lysosomal digestion Pinocytosis Figure 2 ANAESTHESIA AND INTENSIVE CARE MEDICINE 18:10 523 Ó 2017 Published by Elsevier Ltd. PHYSIOLOGY Thyroid hormone transport in blood Systemic effects of thyroid hormones Binding protein T4 (% bound) T3 (% bound) Metabolic C Increase basal metabolic rate TBG 75 80 C Increase oxygen consumption in all tissues TTR 10 5 C Heat production Albumin 12 15 Lipoproteins 3 Lipid Free 0.02 0.5 C Stimulate lipolysis and b-oxidation of fatty acids Table 1 C Reduce serum cholesterol and triglycerides Carbohydrate C Stimulate gluconeogenesis and glycogenolysis by reducing insu- Feedback control of thyroid function lin sensitivity and increasing insulin metabolism C Increase absorption from gut Hypothalamus Protein thyrotrophin-releasing hormone – C Catabolism in muscle Cardiovascular + C Increase number and sensitivity of b-adrenergic receptors C Increase heart rate Anterior pituitary C Increase contractility thyroid-stimulating hormone – C Peripheral vasodilatation + Central nervous system C Cerebellar development C Nerve myelination: increase nerve conduction velocity Thyroid C Emotional stability Thyroxine and T3 Respiratory C Raised PaCO2 stimulates increased tidal volume and respiratory rate Target cells throughout the body Skeletal Increased metabolic rate C Increase growth hormone secretion and heat production Box 1 Figure 3 hypothyroidism and can be caused by disease of the hypothala- mus, pituitary or thyroid glands, or, as a result of iodine deficiency. stimulate the hypothalamus to release thyrotrophin-releasing Parathyroids hormone (TRH) which acts on the anterior pituitary, resulting in the release of thyroid-stimulating hormone (TSH). TSH stim- Anatomy ulates the thyroid to produce T4 and T3, which in turn inhibit the The parathyroid glands are bean-shaped structures which weigh release of further TRH and TSH. Thyroid function is under very around 35 mg each. There are four glands, two on each side, tight control as minimal alterations in T4 and T3 concentrations which sit on the posterior surface of the thyroid gland at the result in changes to TSH secretion. superior and inferior poles. Blood is supplied mainly via branches of the inferior thyroid arteries. Physiological effects of thyroid hormones The glands are made up of two main types of cell: Thyroid hormones affect the function of virtually every organ chief cells contain large numbers of Golgi apparatus and system in the human body (Box 1). They are essential factors in endoplasmic reticulum; they secrete parathyroid hormone the regulation of basal metabolic rate and heat production (PTH) through the stimulation of ATP production for metabolic pro- oxyphil cells are larger and fewer in number; their function cesses and the maintenance of ionic gradients. They are also vital is relatively unknown. for normal growth and development (Box 1). Excess thyroid hormone production results in hyperthyroidism Hormones and can be caused by a disease of the thyroid itself, or excess PTH is an 84 amino-acid polypeptide with a key role in the production of TSH. A deficiency of thyroid hormones results in regulation of serum calcium and phosphate levels. It has a short ANAESTHESIA AND INTENSIVE CARE MEDICINE 18:10 524 Ó 2017 Published by Elsevier Ltd. PHYSIOLOGY Serum calcium versus parathyroid hormone levels 120 100 80 60 40 Serum PTH (% of maximum) 20 0 1.001.10 1.20 1.30 1.40 1.50 Blood ionized calcium (mmol/litre) Figure 4 half-life of roughly 5 minutes. Secretion is determined by serum reduces the activity of an enzyme, 24-hydroxylase, that is ionized calcium which acts on a sensitive calcium-sensing re- responsible for the inactivation of calcitriol. ceptor (CaSR) on the surface of the cells of the parathyroid glands. Activation of this G-protein coupled receptor results in Calcium and phosphate homeostasis inhibition of PTH release and a reduction in serum calcium Over 99% of total body calcium is stored in bone. Normal serum levels. The relationship between serum ionized calcium levels calcium levels are 2.2e2.6 mmol/litre and are under very tight and PTH is an inverse sigmoidal curve (Figure 4). control. Approximately 40% of calcium within the blood is The main actions of PTH are as follows. bound to proteins, with a further 10% bound to simple molecules such as bicarbonate, citrate and phosphate.