Session 10 Flashcards
Where is the thyroid gland? Why might there be risk when operating on it?
The thyroid gland is in the neck in front of the lower larynx and upper trachea. The gland is usually only visible or palpable when enlarged (then called a goitre). Two nerves lie in close proximity to the gland - the recurrent laryngeal and the external branch of the superior laryngeal. During thyroid surgery these nerves are at risk and must be avoided as they supply the larynx and are involved in speech. The thyroid is highly vascularised with three arteries supplying it and three veins draining it (superior, middle and inferior thyroid arteries and veins).
What is the structure of the thyroid gland?
The gland has a butterfly shape with two lateral lobes joined by a central isthmus. The size varies but is usually 2-3cm across and it weighs ~15-20g making it one of the largest endocrine glands in the body. Two major cell types are found in the gland, follicular cells and parafollicular (C-cells). The follicular cells are arranged in numerous functional units called follicles separated by connective tissue. The parafollicular cells are found in the connective tissue. The follicles are spherical and are lined with epithelial (follicular) cells surrounding a central space (lumen) containing colloid which is rich in the protein thyroglobulin.
What hormones are synthesise in the thyroid gland?
The thyroid gland produces 3 hormones, thyroxine (T4) and triiodothyronine (T3) produced in the follicular cells and calcitonin produced in the parafollicular cells. T3 & T4 are small molecules derived from the amino acid tyrosine with the addition of atoms of
iodine. Calcitonin is a polypeptide hormone involved in calcium metabolism
Explain the synthesis of T3 and T4
The basic steps in the synthesis of T3 & T4 in the thyroid follicles are: • Transport of iodide into the epithelial cells against a concentration gradient. • Synthesis of a tyrosine rich protein (thyroglobulin) in the epithelial cells. • Secretion (exocytosis) of thyroglobulin into the lumen of the follicle • Oxidation of iodide to produce an iodinating species. • Iodination of the side chains of tyrosine residues in thyroglobulin to form MIT (mono-iodotyrosine) and DIT (di-iodotyrosine). • Coupling of DIT with MIT or DIT to form T3 & T4 respectively within the thyroglobulin. T3 & T4 residues are produced in the ratio of ~1:10
How are hormones in the thyroid stored?
T3 & T4 are stored extracellularly in the lumen of the follicles as part of the thyroglobulin molecules. The amounts normally stored are considerable (T3 = ~0.4 µmoles, T4 = ~6 µmoles) and would last for several months at normal rates of secretion.
How are thyroid hormones secreted?
Thyroglobulin is taken into the epithelial cells from the lumen of the follicles by the process of endocytosis. Here proteolytic cleavage of the thyroglobulin occurs to release T3 & T4 and these diffuse from the epithelial cells into the circulation
What controls thyroid hormone release?
The synthesis and secretion of T3 & T4 are under the control of the hypothalamus and anterior pituitary gland. The hypothalamic factor is Thyrotropin-Releasing Hormone (TRH). This is a tri-peptide released from cells in the dorsomedial nucleus of the hypothalamus under the influence of the circulating levels of T3 & T4 (negative feedback), stress (increases release) and temperature (fall in temp increases release). The TRH travels in the hypothalamic/pituitary portal system to stimulate the secretion of Thyroid Stimulating Hormone (TSH) from the thyrotropes in the anterior pituitary. TSH travels in the blood to affect the follicular cells of the thyroid gland.
What is TSH?
Thyroid stimulating hormone. TSH is a glycoprotein hormone consisting of two non-covalently linked subunit s (α & β-subunit s). TSH is released in low-amplitude pulses following a diurnal rhythm with higher levels attained during the night and decreasing in the early hours of the morning.
What is the action of TSH?
TSH interacts with receptors on the surface of the follicle cells and stimulates all aspects of the synthesis and secretion of T3 & T4. In addition, TSH has trophic effects on the gland that result in increased vascularity, increase in size and number of the follicle cells. These
trophic effects can result in an enlarged thyroid (goitre) that may or may not be overactive.
How is T3 and T4 transported around the body?
T3 & T4 are hydrophobic molecules and are transported in the blood bound to proteins (thyroxine binding globulin, pre-albumin and albumin). Only a small amount (<1%) of T3 & T4 is free in solution and it is this free hormone that is biologically active. T3 has a slightly lower affinity for the transport proteins than T4 and hence a greater percentage is free and its half-life in the circulation is therefore shorter (2 days compared to 8 days for T4).
How can oestrogen affect T3 and T4 levels in the blood?
Oestrogens increase the synthesis of TBG during pregnancy and this produces a fall in the amount of T3 & T4 in the circulation as more is bound. The fall in free T3 &T4 removes the inhibitory feedback on the pituitary and hypothalamus. More TRH and TSH are produced and the thyroid gland secretes more T3 & T4. As a result the amount of free T3 & T4 returns to normal but the total amount in the blood is increased.
How long generally do target tissues take to respond to T3 and T4?
In general, the response of target tissues occurs slowly and may take day’s/weeks to manifest themselves.
What are the major physiological actions of T3 and T4?
T3 & T4 increase the metabolic rate of many tissues, stimulate glucose uptake and metabolism, stimulate mobilisation and oxidation of fatty acids and stimulate protein metabolism. Their metabolic effects are generally catabolic and lead to an increase in BMR, heat production and increased oxygen consumption. T3 & T4 are important for normal growth and development. Their effects on physical growth are in part related to their metabolic effects on tissues but they do also have specific effects on certain tissues. Thus, they directly affect bone mineralisation an important component of physical growth and increase the synthesis of heart muscle protein. The central nervous system is particularly sensitive to T3 & T4 especially during development as they are required for the development of the cellular processes of nerve cells, hyperplasia of cortical neurons and myelination of nerve fibres. In the absence of thyroid hormones from birth to puberty the child remains mentally and physically retarded (cretinism). If the deficiency is not corrected within a few weeks of birth irreversible damage occurs. All newborn have their thyroid function assessed soon after birth. In the adult lack of thyroid hormones is characterised by poor concentration, poor memory and lack of initiative. Some of the actions of T3 & T4 are indirect and are related to important interactions with other hormones and neurotransmitters. T3 & T4 stimulate hormone and neurotransmitter receptor synthesis in a variety of tissues (e.g. heart muscle, GI tract) and this may produce an increased responsiveness of these tissues to regulatory factors. In heart muscle this produces tachycardia and in the GI tract leads to increased motility. T3 & T4 have a permissive role in the actions of hormones such as FSH and LH and ovulation fails to occur in the absence of thyroid hormones.
What is the mechanism of action of T3 and T4?
T3 & T4 cross the plasma membrane of target cells and interact with specific high affinity receptors located in the nucleus and possibly mitochondria. The receptors are proteins and they have a 10-fold greater affinity for T3 than T4. The receptors have a number of domains. Binding of T3 to the hormone-binding domain is thought to produce a conformational change in the receptor that unmasks the DNA-binding domain. Interaction of the hormone-receptor complex with DNA (nuclear or mitochondrial) increases the rate of transcription of specific genes that are then translated into protein. The increased rate of protein synthesis stimulates oxidative energy metabolism in the target cells to provide the extra energy required for protein synthesis. In addition, protein synthesis produces increased amounts of specific functional proteins leading to increased cell activity and an increased demand for energy.
Can T3 and T4 be converted to each other?
T4 can be converted to T3 in tissues by removal of the 5′-iodide. This is an important mechanism for regulating the amount of active hormone in cells as T3 has 10 times the activity of T4. Removal of the 3′-iodide produces inactive reverse T3 (rT3). rT3 can bind to thyroid hormone receptors without stimulating them, but it blocks the effect of T3.
