S2: Thyroid Gland Flashcards
(34 cards)
What are the 2 broad classes that thyroid function can be split into?
- Developmental
Essential for normal development especially in CNS and bone during early life - Metabolic
Essential for normal metabolism of many body tissues also CVS function
Define Euthyroid, Hypothyroid and Hyperthyroid
Euthyroid = Thyroid function in normal range Hypothyroid = Thyroid function below normal (TH deficiency) Hyperthyroid = Thyroid function is above normal (TH excess)
Anatomy of thyroid gland
- 2 lobes (L and R)
- Sometimes a third pyrimidal lobe
- Rich blood supply - has more blood per weight than the kidney
- Supplied by the inferior thyroid artery from the thyrocervical trunk of subclavian
- Superior thyroid artery as a branch of the external carotid artery
What is the functional unit of thyroid tissue?
Follicle
Structure of a follicle
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.
Follicular cells synthesise the thyroid hormones and release them into the colloid and then take them back up from the colloid when there is need for release.
Between the follicles there are capillaries with the basal membrane of follicular cells facing the capillary and the apical membrane facing the colloid.
What do C cells in the thyroid do?
C cells secrete calcitonin. Calcitonin is involved in calcium regulation but thought to be minor role.
How are thyroid hormones derived?
Thyroid hormones are derived from the joining of two iodinated tyrosine molecules.
What is T4 and T3?
They are the two types of thyroid hormones.
T4= Thyroxine, has 4 iodines T3= Triiodothyronine, has 3 iodines
There is also a reverse T3, which has the iodines in the opposite arrangement. This is inactive/has no activity.
Which is less active:
T4 or T3?
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.
What hormones stimulates TH synthesis and release?
Thyrotropin stimulating hormone (TSH)
Describe TH synthesis
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 requires secondary active transport. The sodium gradient (generates Na+/K+ ATPase) is used to transport iodide into follicular cell via Na+/I- symporter (NIS).
Once iodide is inside the cell, it can diffuse out of the cell through apical membrane into colloid through an exchanger called pendrin (PDS).
Iodide is then oxidised into iodine by an enzyme thyroid peroxidase (TPO). This also requires hydrogen peroxide and a large protein called thyroglobulin.
What thyroid peroxidase does is it oxidises iodide to iodine and then iodinates these 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).
f you combine a MIT and a DIT you get T3
If you combine a DIT and a DIT you get T4
What exchanger takes iodide into colloid?
Pendrin (PDS)
Why is needed to oxidise iodide to iodine in the colloid?
- The enzyme Thyroid peroxidase (TPO).
- Hydrogen Peroxide
- Large protein thyroglobulin (synthesised in follicular cell and it is a type of protein store which contains many tyrosine residues)
Describe TH release
There is endocytosis/pinocytosis into the follicular cell. There is then combining of the colloid droplet with lysosomes and via lysosomal enzymes there is freeing of the T3/T4 from the protein store as well as hydrolysis of thyroglobulin.
.Most of it will be T4, less will be T3. Some T4 will be converted to T3 before it is secreted.
How is some iodine recycled in the follicular cell?
Deiodinising enzymes (shown as DEHAL-1)
How do T4/T3 exist in circulation?
T4/T3 are quite lipophilic so most exist in plasma bound to the plasma protein
- 70% bound to thyroid binding globulin
- Rest bound to either albumin or transthyretin
Why is T3 important?
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 has to be free to stimulate its receptors.
There are more free T3 than T4.
Explain the metabolic regulation of thyroid hormones (TH)
Relative levels of T3, T4 and inactive forms are controlled in target tissues.
There are the family of the three iodothyronine selenodeiodinases, D1-3 (which is why the trace element selenium is essential in diet).
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.
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.
So 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 (through varying expression of the deiodinases) of way of regulating the amount of T3 actually available to bind with the receptor.
D1 can remove an iodine from the 5 and 5’ position
D2 only from the 5’ position (T4 to T3 - activating)
D3 can remove iodine from position 5 (T4 to T2 - deactivating)
How is the synthesis, release and circulating concentration of TH controlled?
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 thyroid stimulating hormone (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.
What is TSH?
Describe its receptor
Thyroid stimulating hormone (TSH).
It is a glycoprotein and its receptor is a surface transmembrane receptor. which is part of the GPCR family.
Most of the TSH receptor appear to be via the adenylate cyclase pathway
What are the various actions of TSH?
- Increase iodide uptake by increasing the sodium iodide symporter
- Stimulates other reactions involved in TH synthesis
- Stimulates uptake of colloid (back into follicular cell for release)
- Induces growth of thyroid gland (can lead to goitre)
How can iodine deficiency lead to goitre?
Less Iodine –> Less T3/T4 synthesis –> More TRH by hypothalamus and TSH released by pituitary (neg. feedback) –> Growth of thyroid gland induced
Describe Thyroid Hormones (HR) receptors
- TH receptors belong to the nuclear receptor superfamily
- Nuclear receptors are ligand activated transcription factors
- They have higher affinity for T3 and their activation requires dimerisation with another T3 receptor or retinoic acid receptor. The dimer constitutes the receptor for TH and will then do its effects.
- There are certain domains on the receptor which bind to the hormone and bind to the DNA.
What two genes encode for TH receptors?
TR alpha and TR beta
