The Thyroid Gland Flashcards
Overview of thyroid function
what are the two broad classes?
What are they essential for?
Thyroid function can be divided into two broad classes: Developmental and Metabolic
Developmental – Essential for normal development, especially in CNS and bone during early life
Metabolic – Essential for normal metabolism of many body tissues, also in cardiovascular function
Overview of thyroid regulation
Names for the 3 different functioning states of thyroid?
two types of hypo/hyper throidism -> what are they?
What is congenital thyroidism? how is it avoided?
What is the thyroid hormon under thre control of?
What stimulates the release of thyrpid hormone and where is it released from?
- Euthyroid = Thyroid function in normal range
- Hypothyroid = Thyroid function below normal
- Hyperthyroid = Thyroid function is above normal
There are two types of hypo/hyper thyroidism. Primary or secondary.
Primary hypo-/hyperthyroidism is where there is a problem with the thyroid gland itself
Secondary hypo-/hyperthyroidism is where there is a problem the pituitary regulation of the thyroid gland
Congenital Hypothyroidism associated with retarded growth and learning impairment, linked to iodine deficiency. Congenital hypothyroidism can be easily avoided by monitoring iodine levels during pregnancy. Thyroid problems in an adult aren’t fatal but can make your life miserable
Insulin is in its own feedback loop, but thyroid hormone is under control of the hypothalamic-pituitary axis.
Thyroid hormone released from the thyroid gland is stimulated by its stimulating hormone released from the anterior pituitary gland, this is TSH.
Anatomy of Thyroid Gland
lobes?
Blood supply relative to kidney?
what is it supplied by and from which trunk of what artery? (inferior)
superior supply?
Has two lobes, sometimes a third pyramidal lobe. Also has a very rich blood supply, more blood per unit weight than the kidney.
Is supplied by inferior thyroid artery from thyrocervical trunk of subclavian artery and superior thyroid artery as a branch of the external carotid artery.
The functional unit of thyroid tissue is the follicle
what is a colloid? what is this surrounded by?
what cells synthesise the thyroid hormone? and where are they stored?
where do the basal membrane and apical membrane of the capillary face?
What is the c-cell? what does it secrete and why is it essential?
A follicle consists of a mass of colloid (a protein rich storage material, contains a lot of hormones available for release). The colloid is surrounded by a single layer of follicular cells.
It is these follicular cells that synthesise the thyroid hormones and release into colloid and then take them back up from colloid when there is need for release.
Between the follicles there are capillaries, with the basal membrane of follicular cells facing the capillary and apical membrane facing the colloid.
There is also an additional cell in the thyroid called the C-cell. C-cells secrete calcitonin. Calcitonin is involved in calcium regulation.
Thyroid Hormones
what are thyroid hormone derived from?
what are the two thyroid hormones? names and why are they called this?
Which one is more active? which is released more? why?
Thyroid hormones are derived from (the joining of) two iodinated tyrosine molecules.
There are two thyroid hormones, T4 and T3.
- T4 = thyroxine, has 4 iodines
- T3 = triiodothyronine, has 3 iodines
Note there is also a reverse T3, which has the iodines in the opposite arrangement. This is inactive/has no activity.
Importantly, T4 is less active than T3, i.e. T3 is more active at the thyroid receptor. However, T4 is the major form that is released into the blood, so in many ways T4 is like a prohormone, with possible conversion of T4 -> T3 that can happen in target tissue.
TH Synthesis and Release
Where does thr basolateral membrane face and the apical membrane?
How does the process begin? How is it taken up and why? What is the transporter used?
WHat is pendrin (pds) and why is it useful? what does thyroid peroxidase (TPO) do? what else is required? What is the end product (MIT and DIT?)
How do you get T3 and T4?
How is the thyroid hormone secreted? What happens to protein store and thyroglobulin? Which hormone is released more and via what? What happens to some of the iodine?
3 different forms of carrying thryoid hormones?
which thyroid hormones in blood count?
The basolateral membrane faces the blood, while the apical membrane faces the colloid. The process begins with the uptake of iodide, it is present in relatively low concentration in the plasma and it is higher in the follicular cell, so it has to be taken up against its concentration gradient.
This therefore requires a form of active transport, in this case a secondary active transport mechanism. The sodium gradient (generated by the Na+/K+ ATPase) is used to transport iodide into the follicular cell via a Na+/I- symporter (NIS).
Once the iodide is inside, it can diffuse out of the cell through the apical membrane, through an exchanger called pendrin (PDS).
o Iodide is oxidised to iodine by an enzyme thyroid peroxidase (TPO), also requires hydrogen perioxide and a large protein called thyroglobulin (synthesised in the follicular cell, is a type of protein store), which contains many tyrosine residues.
What thyroid peroxidase does is it OXIDISES iodide -> iodine then IODINATES -> tyrosine residues, by covalently binding iodine to them, if it iodinates them in one place you get mono-iodotyrosine (MIT), if in two you get di-iodotyrosine (DIT).
- If you combine a MIT and a DIT you get T3
- If you combine a DIT and a DIT you get T4
Secretion of Thyroid Hormone
- Endocytosis/pinocytosis into the follicular cell.
- Combining of colloid droplet with lysosomes and via lysosomal enzymes freeing of the T3/T4 units from the protein store + hydrolysis of thyroglobulin.
- Most of it will be T4, less will be T3. Some T4 will be converted to T3 before it is secreted.
- Some iodine is recycled in the cell by deiodinising enzymes // DEHAL-1. - The T3 (about 10%) T4 (about 90%) are then released into the circulation via transporters.
Circulating Thyroid Hormones – T4/T3 are quite lipophilic so most exist in plasma bound to the plasma protein thyroid-binding globulin (around 70%).
Some is also bound to transthyretin (10-20%) and albumin (10-20%).
So, most of circulating hormone is as T4. But with regards to actual hormone action, T3 is more important and it is the free thyroid hormone that counts as it must be free to stimulate its receptors.
Metabolic Regulation of Thyroid Hormones
how are relative levels of t3, t4 and inactive form controlled in target tissues? (name the molecules and what they do)
what is the thyroid receptor? hence how does thyroid hormone interact with this?
How can D2 help have more binding?
positions where iodine can be removed and what enzyme
Which one inactivates the horomone?
Relative levels of T3, T4 and inactive forms are controlled in target tissues. There are the family of the three iodothyronine selenodeiodinases, D1-3.
These enzymes de-iodinate the thyroid hormones in various ways, they have the option of converting T4 to T3 (more active form) or converting T3 to an inactive form.
o You can increase level of T3 by converting T4 -> T3 or you can decrease level of T3 by T3 -> an/its inactive form.
The thyroid hormone receptor is a nuclear receptor, in the nucleus of the cell, meaning the thyroid hormones need to enter the cell, it does this via specific thyroid hormone transporters.
T3 that enters the cell can bind to its nuclear receptor, or if you want to upregulate T4 that enters the cell can be converted by D2 into the more active T3 which itself can then bind to its nuclear receptor, thus increasing T3 binding to its receptor.
So, the deiodinases have shown to be important tissue-specific
Done through varying expression of the deiodinases in order to regulate the amount of T3 actually available to bind with the receptor.
o D1 can remove an iodine from the 5 and 5’ position
o D2 only from the 5’ position
o D3 can remove iodine from position 5
d3 inactivate hormone
How is the synthesis, release and circulating concentration of TH controlled?
What is the feedback loop? from where?
What releases TRH and into where? What does TRH do and where? what does this new released molecule do?
How does the negative feedback loop take place?
What can influence release of TRH?
There is negative feedback control of thyroid synthesis and secretion, via the hypothalamo-pituitary axis.
Hypothalamic neurosecretory cells release thyrotrophin-releasing hormone (TRH) into portal capillaries (capillaries between hypothalamus and pituitary).
TRH stimulates thyrotrophs of the anterior pituitary to secrete TSH.
TRH stimulates pituitary, TSH release from pituitary stimulates thyroid gland to release T3/T4.
Levels of T3/T4 rise, these rising levels have a negative feedback effect and shut down synthesis and secretion of TRH and TSH.
Factors such as cold and stress can also influence release of TRH by acting on the hypothalamus.
The TSH Receptor
What is TSH so where is it? What type of receptor is it?
What intracellular pathway does TSH involve?
WHat are the various actions of TSH? (4)
what is goitre? how does prolonged iodine defiency lead to this?
The TSH is a glycoprotein and its receptor are a surface transmembrane receptor. The TSH receptor is a member of the GPCR family of receptors.
There are various intracellular pathways associate with GPCR, with regards to the TSH receptor most of its effects appear to be via the adenylate cyclase pathway.
There are various actions of TSH, these include:
o Increase iodide uptake by increasing sodium-iodide symporter
o Stimulates other reactions involved in TH synthesis (e.g. TPO)
o Stimulates uptake of colloid -> back into follicular cell for release.
o Induces growth of thyroid gland, which can lead to goitre -> prolonged iodine deficiency can lead to goitre because there will not be enough T3/T4 synthesis, meaning no more –ve feedback, so there will be increased release of TSH by pituitary and TRH by hypothalamus.
How do thyroid hormones act on their target tissues and what are their actions?*
what type of receptor is the thyroid receptor?
What do they have high affinity to and what do they require?
Wich 2 genes encode thryoid hormone receptors?
Where do they bind? How can splicing effect this? (domains)
What happens when there is an absence of lgand?
Thyroid hormone receptors belong to the nuclear receptor superfamily. Nuclear receptors are ligand-activated transcription factors.
They have a higher affinity for T3 and their activation requires dimerisation with another T3 receptor or retinioic acid receptor. The dimer constitutes the receptor for TH and will then do its effects.
TH receptors are encoded by two genes: TR alpha and TR beta
There are certain domains on the receptor which bind to the hormone and bind to the DNA. They bind to the/its hormone response element on the DNA.
o Note there are several ways of splicing the original transcript to give the receptor molecules shown below.
The receptor can and does bind in the absence of the ligand, but in this case the combination of cofactors present results in a suppressive effect, i.e. transcription is repressed.
Conversely when the ligand binds (T3) in this case, the combination of the receptor and cofactors present results in an activating effect, i.e. transcription is activated.
Recently Discovered TH Transporters
How has the theory of free diffusion of thyroid into cell been changed?
What transporter is required?
what is allan herndon dudley syndrome?
As stated earlier, the TH must cross the cell membrane in order to access the nuclear receptor. It was previously thought they were so lipophilic they could just freely diffuse across the membrane. But we now know that transporters are required, e.g. MCT8.
MCT8 -> Mutations in gene discovered to underlie an X-linked condition, Allan-Herndon-Dudley syndrome, which is associated with psychomotor retardation.
Summary:
You can regulate TH in multiple ways, levels can be increased via selective activation of the D1-D3 diodinases, allowing to up/down regulate TH in a tissue specific manner.
There is also a variety of membrane channels for TH which regulate entry into cell. Finally, there is nuclear receptor.
Functions of TH
3 functions
- Increased metabolic rate -> number and size of mitochondria, enzymes in metabolic chain, Na+/K+ ATPase activity
- Has a positive inotropic (contractility) and chronotropic (rate) effects on heart
- Role in growth and development
Hypo- and hyperthyroidism
what do we need to consider when we think of hypo-thalamic pituitary axis?
What is primary hyperthyroidism? how does it work? how does this relate to iodine defiency?
What is secondary hyperthyroidism? What could potentially cause this? what is a good indication of secondary hyperthyoridism?
Because we have the hypo-thalamic pituitary axis, it means there are various components that have to be considered when things are going wrong.
Primary hyperthyroidism would mean the thyroid gland itself is over producing TH. This would negatively feedback onto the hypothalamus and pituitary gland leading to a decrease in TRH and TSH.
In primary hypothyroidism e.g. due to iodine deficiency, the thyroid gland isn’t producing enough TH, means there is an absence of negative feedback so TSH and TRH release is up-regulated, and levels increase.
Secondary hyperthyroidism may be caused by a tumour for example in the pituitary gland effecting the thyrotrophs. There would be increased synthesis and secretion of TSH so levels will increase. Hence so T3 and T4 will increase. There will still be the negative feedback, but everything now is working at a higher level.
o So high TSH and T3/T4 would indicate secondary
Grave’s Disease: Primary Hyperthyroidism
what kind of disease is it? levels of TH and TSH?
Symtoms?
What is the pathology due to? Why does tsh levels fall?
Is an autoimmune disease, because it is primary hyperthyroidism there will be high circulating levels of TH and low TSH.
Symptoms include weight loss, tachycardia and fatigue. There also tends to be a diffuse goitre and opthalmopathy.
The pathology is due to stimulating auto-antibodies. Normally the TSH receptor binds TSH and TH synthesis and secretion is stimulated in the normal way. There is then also negative feedback on levels of TSH.
What occurs is that auto-antibodies get generated by the body and these binds to the TSH receptor as agonists. This results in the receptor being permanently activated/overactivated.
The high levels of T3/T4 will negatively feedback on TSH decreasing its levels, but T3/T4 will continue to be released as the problem is with the antibodies stimulating the TSH receptor.
Hashimoto’s: Primary Hypothyroidism
type of disease?
levels of th and tsh? why?
Is another autoimmune disease, but this time characterised by low circulating TH but high TSH.
Symptoms would reflect a lack of TH activity and include lethargy and an intolerance to cold, lack of growth and development and diffuse goitre.
Autoimmune disease – attack on thyroid gland – cellular loss – loss of thyroid gland output – classic signs of endocrine condition – low circulating levels of hormone the gland is producing and high levels of stimulating hormone – low level of thyroid hormone and high levels of thyrotropin
