Thyroid gland and thyroid disorders Flashcards
Where is the thyroid gland located?
In the neck in front of the lower pharynx and upper trachea.
What is the structure of the thyroid gland?
A butterfly shape with two lateral lobes joined by a central isthmus. It is one of the largest endocrine glands in the body.
What is the chemical structure of thyroid hormones?
T3 and T4 are small molecules derived from the amino acid tyrosine with the addition of atoms of iodine.
How are thyroid hormones produced?
- 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-iodityrosine)
- Coupling of DIT with MIT or DIT to form T3 and T4 respectively within the thyroglobulin.
How are thyroid hormones stored?
T3 and T4 are stored extracellularly in the lumen of follicles as part of thyroglobulin molecules. Considerable amounts are stored, they would last several months at normal rates of secretion.
How are thyroid hormones secreted?
Thyroglobulin is endocytosed into the epithelial cells. Proteolytic cleavage of the thyroglobulin occurs to release T3 and T4 which diffuse from the epithelial cells into the circulation
How is the activity of the thyroid gland controlled?
Hypothalamus: Thyrotropin-releasing hormone (TRH)
A. pituitary: Thyroid stimulating hormone (TSH)
Negative feedback: T3 and T4
What are the metabolic effects of thyroid hormones on cells and the body as a whole?
Increase the metabolic rate of many tissues. They are generally catabolic and lead to an increase in BMR, heat production and oxygen consumption.
Stimulate glucose uptake and metabolism
Stimulate mobilisation and oxidation of fatty acids
Stimulate protein metabolism
What is a goitre?
When a thyroid gland becomes enlarged and is visible or palpable, due to overstimulation. This can accompany either hypothyroidism or hyperthyoidism, but not necessarily present in either.
What is at high risk of getting damaged during thyroid surgery?
Two nerves which lie in close proximity to the gland (the recurrent laryngeal and external branch of the superior laryngeal). These nerves innervate the larynx and are involved in speech.
What are the names of the three arteries and three veins supplying the thyroid?
Superior, middle and inferior thyroid arteries and veins
What are the two major cell types found in the thyroid gland?
Follicular and parafollicular (C-cells)
What is the name of the functional unit that follicular cells arrange themselves in?
Follicles
What separates each follicle from each other?
Connective tissue
Where are the parafollicular cells located?
In the connective tissue
Describe the structure of the follicle
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 are the three hormones that the thyroid produces?
T3 - triiodothyonine
T4 - thyroxine
calcitonin (only one produced in parafollicular cells)
What is the chemical structure of calcitonin?
Polypeptide hormone
T3 and T4 are produced in what ratio?
Approximately 1:10
The tri-peptide TRH secretion is increased by what factors?
Increased stress and fall in temperature
What is the name of the cells that produce TSH in the anterior pituitary?
Thyrotropes
What is the target cells of TSH?
Follicilar cells in the thyroid
Which type of hormone is TSH?
Glycoprotein with two non-covalently linked subunits (alpha- and beta-)
What rhythm is TSH released in?
Diurnal - higher levels during night which decrease in early hours of the morning
What are the actions of TSH?
It interacts with receptors on the surface of follicular cells and stimulates all aspects of the synthesis and secretion of T3 and T4,
It also has trophic effects on the gland which increases its vascularity, size and number of follicle cells. Which can result in an enlarged thyroid (goitre).
How is T3 and T4 transported in the blood?
They are hydrophobic and the majority are transported bound to proteins (thyronine binding globulin (TBG), pre-albumin and albumin). Only a small amount (
Which thyroid hormone (T3 of T4) has a longer half-life in blood and why?
T4 has a longer half-life (8 days vs 2 days) because it has a higher afinity for the transport proteins than T3. Therefore a greater % of T3 protein is free
What affect does oestrogen produced during pregnancy have on T3 and T4?
Oestrogen increases the synthesis of TBG during pregnancy -> decrease in free T3 and T4 in circulation (more is bound). This reduced the negative feedback of T3 and T4, so more TRH and TSH are produced and hence more T3 and T4. Overall this returns the level of free T3 and T4 in circulation, but increases the total amount of T3 and T4 in the blood
How fast to target tissues respond to T3 and T4?
In general, the response is slow and may take days/ weeks to manifest themselves
What other effects than metabolic does T3 and T4 have on tissues?
Important for normal growth and development. In part because of their effect on metabolism but also because:
- Affect bone mineralisation
- Increase the synthesis of heart muscle protein
- Important for normal development of NS (nerve cell cellular processes, hyperplasia of corticol neurons and myelination of nerve fibres)
What happens to a child if they lack thyroid hormones from birth to puberty?
Abnormal development of the NS and physical development causing mental and physical retardation (cretinism)
Why is thyroid function assessed soon after birth?
Because if a deficiency in thyroid hormones is not corrected within a few weeks of birth irreversible damage occurs
What is lack of thyroid hormones in an adult characterised by?
Poor concentration
Poor memory
Lack of initiative
List some indirect actions of T3 and T4, that are related to important interactions with other hormones and neurotransmitters
- Stimulate hormone and neurotransmitter receptor synthesis in a variety of tissues (e.g. heart muscle, GIT), which may produce an increased responsiveness of these tissues to regulatory factors
- Permissive role in the actions of hormones such as FSH and LH: ovulation fails to occur in the absence of thyroid hormones
What is the mechanism of action of T3 and T4?
Cross plasma membrane and interact with specific receptors in the nucleus,
Thought that T3 binding to hormone-binding domain produces a conformational change that umasks the DNA-binding domain. Interaction of the hormone-receptor complex with DNA (nuclear or mitochondrial) increases the rate of transcription or specific genes that are translated into proteins.
Do the receptors located in the nucleus (and possibly mitochondria) have a higher afinity for T3 or T4?
They have a 10-fold greater affinity for T3 than T4
The increase in protein synthesis that T3 and T4 create, has what effect on target cells?
- Stimulates oxidative energy metabolism to provide extra energy for protein synthesis
- It produces increased amounts of specific functional proteins leading to increased cell activity and an increased demand of energy
How is T4 converted to T3 and why?
By removal of the 5’-iodide. This is an important mechanism for controlling the amount of active hormones in cells as T3 has 10 times the activity of T4
What happens if T4 has it 3’-iodide removed?
It produces inactive reverse T3 (rT3) which can bind to thyroid hormone receptors but does not stimulate them. The has the effect of blocking T3 binding.
What is Hashimotos’ disease?
The most common form of hypothyroidism, affecting 1% of the population (mostly woman). It is an autoimmune disease that results in either the destruction of the thyroid follicles or the production of an antibody that blocks the TSH receptor on follicle cells - preventing them from responding to TSH.
How is hypothyroidism treated?
Generally treated with oral thyroxine (T4 used since has a longer half-life). The dose is adjusted depending on the patient’s signs and symptoms and TSH levels.
What is Grave’s disease?
The most common form of hyperthyroidism affecting approximately 1% of the population (mostly woman). It is an autoimmune disease in which antibodies (thyroid stimulation immunoglobulin (TSI)) are produced that stimulate the TSH receptors on follicle cells resulting in an increased production of T3 and T4
High levels of T3 and T4 in Grave’s disease result in a decrease in TSH secretion, due to negative feedback, how does that affect levels of T3 and T4?
It doesn’t affect them because the stimulus for thyroid hormone release is from TSI rather than TSH
How are patients with hyperthroidism treated?
They may be treated with carbimazole, a drug that inhibits the incorporation of iodine into thyroglobulin by inhibiting the enzyme thyroid peroxidase. This therefore prevents the coupling and iodination of tyrosine residue on thyroglobulin
What may the signs and symptoms of hypothyroidism in adults include?
Cold intolerance and reduced BMR Weight gain Tiredness and lethargy Bradycardia Neuromuscular system - weakness, muscle cramps and cerebellar ataxia (clumsiness of movement) Dry and flaky skin Alopecia (hair loss) Voice is deep and husky
What may the signs and symptoms of hyperthyroidism in adults include?
Heat intolerance, increased oxygen consumption and increased BMR
Weight loss
Physical and mental hyperactivity
Tachycardia
Intestinal hyper-mobility
Skeletal and cardiac myopathy giving rise to tiredness, weakness and breathlessness
Osteoporosis due to increased bone turnover and preferential reaborption
What three separate reactions does thyroid peroxidase catalyse?
- Oxidation of iodide to iodine (required H2O2)
- Addition of iodine - to tyrosine residue on thyroglobulin
- Coupling of MIT of DIT to generate thyroid hormones within the thyroglobulin protein
What happens to dietary iodine before it can be absorbed (primarily in the small intestine)?
Iodide is reduced to iodide
How is iodide (I-) taken up by thyroid epithelial cells?
They have a sodium-iodide symporter or “iodide trap”
What are common dietary sources of iodine (from highest to lowest daily intake of iodine)?
iodised salt grains dairy products meat vegetables eggs
90% of thyroid hormone secreted is T4, but T3 is 4 times more biologically active than T4. Where is T4 converted to T3 in the body?
Liver and kidneys
Thyroid hormones effect virtually every cell in the body. What are their two main interconnected responses?
- Effect on cellular differentiation and development
2. Effects on metabolic pathways
TSH is a glycoprotein hormone composed of 2 non-covalently bound subunite (alpha- and beta-). In which hormones if the same alpha-subunit also present?
FSH and LH (gonadotrophic hormones)
What does TSH stimulate?
- iodide uptake
- Iodide oxidation -> iodine
- Thyroglobulin synthesis
- Thyroglobulin iodination
- Colloid pinocytosis into cell
- Proteolysis of thyroglobulin
- Cell metabolism and growth
Where is the TSH receptor located on follicular cells?
Plasma membrane
How do thyroid hormones increase the BMR and heat production?
In most tissues (exceptions: brain, spleen and testis), thyroid hormones stimulate the metabolic rate by:
- Increasing the size and number of mitochondria
- Stimulating the synthesis of enzymes in the respiratory chain
How do thyroid hormones stimulate metabolic pathways?
Catabolic pathways are generally stimulated more than anabolic.
- Lipid metabolism: stimulates lipolysis and beta-oxidation
- Carbohydrate metabolism: stimulate insulin-dependent entry of glucose into cells and increase gluconeogenesis and glycogenolysis
What are the sympathomimetic effects of thyroid hormones?
Increases target cell response to catecholamines by increasing receptor number on target cells
What are tissue-specific effects of thyroid hormones on the cardiovascular system?
Increases the heart’s response to catecholamines, therefore:
- Increases cardiac output (increased HR and contraction force)
- Increases peripheral vasodilation to carry extra heat to the body surface
What are tissue-specific effects of thyroid hormones on the nervous system?
Essential for both development and adult function:
1. Increases myelination of nerves and development of neurons
Thyroid hormone receptors are members of a large family of nuclear receptors. How do they function as hormone-activated transcription factors?
- Thyroid hormone receptors bind DNA in the absence of hormone, usually leading to transcription repression
- Hormone binding is associated with a conformational change in the receptor that causes it to function as a transcriptional activator
What can be causes of hypothyroidism?
Failure of the thyroid gland TSH or TRH deficiency Inadequate dietary supply of iodine Radiactive iodine Autoimmune disease Post surgery Congenital Anti-thyroid drugs
What are signs and symptoms associated with cretinism/ hypothyroidism in infants?
dwarfed stature mental deficiency poor bone development slow pulse muscle weakness GI disturbances
What can be the causes of hyperthyroidism?
Autoimmune Grave's disease toxic multinodular goitre solitary toxic adenoma Excessive T4 (or T3) therapy Drugs - amiodarone Thyroid carcinoma Ectopic thyroid tissue
What are general symptoms of hyperthyroidism?
Weight loss
Irritability
Heat intolerance, sweating, warm vasodilated hands
Tachycardia (noticeable heart beat) often irregular
Fatigue, weakness
Increased bowel movements - increased apetitie
Possible tremour of outstretched hands
Hyper-reflexive
Breathlessness
Loss of libido
Sweating and tremor
What is thyroid scintigraphy?
A nuclear medicine procedure that produces a visual display of functional thyroid tissue based on the selective uptake of various radionuclides by thyroid tissue
Why is the use of Technetium-99m (^99mTc) used for isotope scanning of the thyroid?
It is the most commonly used medical isotope because:
1. Biological half-life of approximately 1 day, therefore radiation exposure low
A 45 year old woman presents to her GP with malaise, lethargy and recent weight gain of 5kg over two months. Investigations show low total plasma T4 and high TSH. What is the most likely cause of the elevated TSH concentration?
Reduced negative feedback from circulating T4 on the anterior pituitary gland (increasing TSH secretion) and hypothalamus (increasing TRH secretion). TRH stimulates secretion of TSH and TSH should stimulate secretion of thyroid hormones
A 42 year old woman with Grave’s disease has a two month history of weight loss. She feels hot and flushed all the time and has occasional palpitations. She has not changed her diet in the past year. Which substance would you expect to be below the reference range in the patient’s blood?
TSH - thyroid stimulating hormone due to increased negative feedback of the thyroid hormones T3 and T4 on the anterior pituitary gland
What is thyroglobulin?
The protein scaffold in colloid on which T3 and T4 are initially formed
What causes Grave’s disease?
It is an autoimmune disease in which antibodies called thyroid stimulating immunoglobulins (TSI) are produced that stimulate the TSH receptors on follicle cells resulting in an increased production and release of T3 and T4
