Thyroid Gland Flashcards
Give a brief overview of thyroid function.
It has developmental functions:
- essential for normal development, especially the CNS and bone
It also has metabolic functions:
- essential for normal metabolism of many body tissues
What are the functions of the different cells in the thyroid?
Follicular cells synthesise and secrete thyroid hormone.
The colloid is where TH is stored, after being synthesised by the activity of follicular cells.
C-cells secrete calcitonin.
Thyroid hormones are derived from two iodinated tyrosine molecules.
Describe two thyroid hormones learnt.
T4: major form released to blood, less active (prohormone)
T3: active form, converted in target cells
What are the steps to TH synthesis?
1) There is the active uptake of I- across the basolateral membrane, against the concentration and electrical gradient. This is done by the Na/I symporter, and stimulated by TSH.
2) Iodide efflux (by diffusion) then occurs across the apical membrane via an exchanger known as pendrin (PDS)
3) At the extracellular apical membrane, iodide is oxidised to iodine and covalently bound to tyrosine residues within thyroglobulin (TG) macromolecules. This requires thyroid peroxidase (TPO) and H2O2.
4) Tyrosine residues may be iodinated in one (mono-iodotyrosine, MIT) or two (DIT) positions. The coupling of iodotyrosine residues (catalysed by TPO) produces T4 (DIT-DIT) and a smaller amount of T3 (DIT-MIT).
What are the steps to TH release?
1) Under the influence of TSH, colloid droplets consisting of thyroid hormones within the thyroglobulin molecules are taken back up into the follicular cells by pinocytosis.
2) The fusion of the colloid droplets with the lysosomes causes hydrolysis of thyroglobulin and the release of T3 and T4.
3) About 10% of T4 undergoes mono-deiodination to T3 before it is secreted. The released iodide is reutilised. Several-fold more iodide is reused than is taken from the blood each day, but in states of iodide excess, there is a loss from the thyroid.
4) Approximately 100 μg is secreted per day (90% T4 and 10% T3). Secretion probably relies on the membrane transporter.h
How do thyroid hormones circulate?
Over 99% of thyroid hormones are bound to plasma proteins.
These are mainly thyroid-binding globulin (~70%), transthyretin (10-20%) and albumin (10-20%).
How do thyroid hormones act on target tissues?
They do this via TH receptors (TRs). TRs belong to the nuclear receptor superfamily. They are ligand-activated transcription factors. They have a high affinity for T3.
Activation requires dimerisation with another TR or a retinoid X receptor (RXR).
TRs are encoded by two genes: TR α and TR β.
Describe the metabolic regulation of THs.
The relative levels of T3, T4 and the inactive forms are controlled in large tissues. This is done by enzymes called selenodeiodinases, abbreviated to D1-3. These three enzymes used selenium as their trace element, so it is essential in the diet.
They could:
activate by converting T4 to T3 (D2)
inactivate by converting T3 to T2 (D3)
inactivate by converting T4 to rT3 (D3).
They regulate the amount of T3 actually available to bind with the receptor.
List some functions of TH in the body.
It increases metabolic rate:
affects number and size of mitochondria, enzymes in the metabolic chain, Na/K ATPase activity, etc.
has positive inotropic and chronotropic effects on the heart
synergises with the sympathetic nervous system
It is involved in energy metabolism:
partially antagonises insulin signalling
gluconeogenesis, lipolysis
It also affects growth and development.
Describe how TH moves across the membrane.
It was previously thought that TH simply diffused across the cell membrane to work. However, it has recently been discovered that there are in fact TH transporters that are required to allow TH across the membrane.
An example of such a transporter would be MCT8.
MCT8 was discovered to underlie an X-linked condition called Allan-Herndon-Dudley Syndrome, which is associated with psychomotor retardation.
Describe the role of the hypothalamic-pituitary-thyroid axis.
Negative feedback control of thyroid hormone synthesis and secretion occurs via the hypothalamo-pituitary axis.
Hypothalamic neurosecretory cells release thyrotropin-releasing hormone (TRH) into the portal capillaries. The TRH stimulates thyrotrophs of the anterior pituitary to secrete thyroid-stimulating hormone (TSH).
As the levels of T4 and T3 rise, the release of the stimulating hormones from both the hypothalamus and the anterior pituitary are turned down.
Describe congenital hypothyroidism.
Congenital hypothyroidism (CH) is inadequate thyroid hormone production in newborn infants. It can occur because of an anatomic defect in the gland, an inborn error of thyroid metabolism, or iodine deficiency.
Once, it was the commonest cause of intellectual disability.
Now, it is easily preventable with a simple neonatal heel prick. We would then test for TSH levels. There could be possible congenital hypothyroidism if the levels of TSH are high.
Describe the TSH receptor and its actions.
It is a member of the G-protein coupled receptor family. Most of its main important effects are done through Adenylate Cyclase (αGs and the cAMP-PKA cascade).
This leads to iodide uptake, the transcription of NIS (Na+/I- symporter), TG and TPO, etc.
What are the actions of TSH?
increases iodine uptake
stimulates other reactions involved in TH synthesis (eg. TPO)
stimulates the uptake of colloid
induces growth of the thyroid gland (which can lead to goitre)
Define hypo- and hyperthyroidism.
HYPERTHYROIDISM occurs when there is TH excess.
primary: when there is a problem with the thyroid gland itself
secondary: when there is a problem with pituitary regulation
HYPOTHYROIDISM occurs when there is TH deficiency.
Describe Grave’s Disease.
It is the most common cause of primary hyperthyroidism.
It is an autoimmune disease characterised by high levels of circulating TH and low levels of TSH.
This is because antibodies are developed to the TSH receptor. These then work as pharmacological agonists, so we end up with unregulated overproduction of TH.
Some of the symptoms are weight loss (due to the increased metabolism), tachycardia, fatigue, diffuse goitre (due to TSH receptor stimulation) and ophthalmopathy (an inflammatory disorder of the orbit and periorbital tissues).
Describe Hashimoto’s Disease.
It is a cause of hypothyroidism.
It is, effectively, an autoimmune disease against the thyroid gland. It is characterised by low levels of circulating TH and high levels of TSH.
In this situation, whatever antibodies are produced end up causing thyroid destruction and dysfunction.
Some of the symptoms are lethargy, weight gain, intolerance to cold, lack of growth and development and diffuse goitre.
