The Thyroid Gland

Question 1

What do follicular cells and c cells secrete?

Answer 1

Follicular cells synthesize and secrete TH

C-cells secrete calcitonin (not considered here)

Question 2

What are thyroid hormones derived from?

Answer 2

Thyroid hormones are derived from two iodinated tyrosine molecules
Thyroid hormones:
T4: major form released to blood, less active (prohormone)
T3: active form, converted in target cells

Question 3

How is TH synthesised and released?

Answer 3

All of these steps are stimulated by thyrotropin (aka thyroid-stimulating hormone; TSH)
The process begins with the uptake of iodine ions from the ECF
Taken up in a process of secondary active transport coupled to the sodium electrochemical gradient (generated by the K/Na ATPase pump) through the basal surface
There is another transporter on the apical surface where iodide then is passed out into the colloid
The colloid contains the thyroglobulin molecules which contains multiple tyrosine residues
So the iodide is oxidised to iodine and covalently bound to tyrosine residues
This requires an enzyme called thyroid peroxidase and hydrogen peroxide
Portions of these are endocytosed back into the follicular cell where the thyroglobulin is cleaved to release either T4 or T3
Finally, the hormone is exported into the circulation through another transporter

Question 4

What are the TH synthesis steps?

Answer 4

1. Active uptake of I- across basolateral membrane, against concentration and electrical gradient, by Na/I symporter (NIS). Stimulated by TSH.
   
   2. Iodide efflux (diffusion) across apical membrane via exchanger known as pendrin (PDS).
   3. At extracellular apical membrane iodide is oxidized to iodine and covalently bound to tyrosine residues within the thyroglobulin (TG) macromolecule. Requires thyroid peroxidase (TPO) and H2O2.
   4. Tyrosine residues may be iodinated in one (mono-iodotyrosine, MIT) or two (DIT) positions. Coupling of iodotyrosine residues (catalysed by TPO) produces T4 (DIT-DIT) and a smaller amount of T3 (MIT-DIT).

Question 5

What are the TH release steps?

Answer 5

5. 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.
   
   6. Fusion of colloid droplets with lysosomes causes hydrolysis of thyroglobulin and release of T3 and T4.
   7. About 10% of T4 undergoes mono- deiodination to T3 before it is secreted. The released iodide is reutilized. Several-fold more iodide is reused than is taken from the blood each day but in states of iodide excess, there is loss from the thyroid.
   8. Approximately 100 μg TH secreted per day (90% T4 and about 10% T3). Secretion probably relies on membrane transporter

Question 6

How do thyroid hormones circulate?

Answer 6

Circulating thyroid hormones (how do thyroid hormones circulate)
Over 99% bound to plasma protein
Mainly thyroid-binding globulin (~70%), also transthyretin (10-20%), albumin (10-20%)

Question 7

What is the thyroid hormone’s action on target tissues?

Answer 7

TH receptors (TRs) belong to the nuclear receptor superfamily
-Ligand-activated transcription factors
High affinity for T3
-Activation requires dimerization with another TR or retinoid X receptor (RXR)
-TRs encoded by two genes: TR alpha and TR beta

Question 8

What are the thyroid hormones receptors like?

Answer 8

The two genes each come in two isoforms; TRb1 and 2 and TRa1 and 2
The seconds splice variant of the alpha doesn’t seem to show binding or transcriptional activity
With nuclear receptor you get three main domains;
At the N terminal end you have the domain where various other co-regulatory factors bind
You have a DNA binding domain in the middle which binds to the promoter regions of DNA called the thyroid response element
The hormone recognition domain responsible for dimerising and binding

Question 9

What happens during the metabolic regulation of THs?

Answer 9

Relative levels of T3, T4 and inactive forms controlled in target tissues
Three iodothyronine selenodeiodinases, D1, 2 and 3 (so trace element selenium is essential in diet)
These enzymes can interconvert between T4 and biologically active T3 or convert them to their inactive forms
D-2 increases T3 levels while D-3 decreases them
Tissue-specific expression
Regulate the amount of T3 actually available to bind with receptor
T2, rT3: inactive metabolites of T3/T4

Question 10

What are recently discovered TH transporters? (what disorders do they cause?)

Answer 10

TH previously thought free to diffuse across cell membrane
In fact transporters are required, some recently identified, e.g., MCT8, OATP1C1
MCT8 (found in neurons): mutations in gene discovered to underlie an X-linked condition, Allan–Herndon–Dudley syndrome, which is associated with psychomotor retardation

Question 11

What are the functions of TH?

Answer 11

Increase metabolic rate:
-Number and size of mitochondria, enzymes in metabolic chain, Na/K ATPase activity
-Positive inotropic and chronotropic effects on heart
-Synergizes with sympathetic nervous system
Energy metabolism:
-Partially antagonizes insulin signalling
-Gluconeogenesis, lipolysis
Growth and development

Question 12

How does the hypothalamic-pituitary-thyroid axis affect TH?

Answer 12

Negative feedback control of thyroid hormones synthesis and secretions via the hypothalamic-pituitary axis
Hypothalamic neurosecretory cells release thyrotrophin-releasing hormone (TRH) into the portal capillaries
TRH stimulates thyrotrophs of anterior pituitary to secrete thyroid stimulating hormone (TSH)

Question 13

How do negative feedback control TH synthesis and secretion?

Answer 13

Lack of inhibition in physiology is usually the equivalent of excitation
TRH from the hypothalamus stimulates TSH secretion from the anterior pituitary which stimulates the thyroid gland to produce T4 and T3
The hypothalamus and anterior pituitary have receptors for thyroid hormones
As the thyroid hormones binding exerts an inhibitory effect
So the firing rate slows down at each point to a set point
The low temperature increases hypothalamic output of TRH, as does stress

Question 14

How do TSH receptors work?

Answer 14

The receptor or TSH is a G-protein coupled receptor
Most of the actions here are mediated by the adenylate cyclase pathway with an increase of cAMP activating PKA consequently many other actions (including iodide uptake)
In general, it stimulates the growth of the thyroid gland

Question 15

What are TSH actions?

Answer 15

Increases iodine uptake
Stimulates other reactions involved in TH synthesis (e.g., TPO)
Stimulates uptake of colloid
Induces growth of thyroid gland 
(which can lead to goitre)

Question 16

What are hypo and hyperthyroidism?

Answer 16

Euthyroid: normal thyroid function
Hyperthyroidism: TH excess
-Primary: problem is thyroid gland itself
-Secondary: problem is pituitary regulation
Hypothyroidism: TH deficiency

Question 17

How can you diagnose a person by measuring the TH and TSH status?

Answer 17

The diagnosis usually involves a test for TSH
If a person had primary hypothyroidism would have low levels of T4 and T3 so consequently the TRH concentration would be increased so TSH concentration are increased
In primary hyperthyroidism it’s the opposite so low TSH
In secondary hyperthyroidism such as a pituitary adenoma which secretes TSH which would stimulate the thyroid gland to produce T4 and T3 so TRH will be low but TSH will be high

Question 18

What is Grave’s disease?

Answer 18

Autoimmune- autoantibodies to the TSH receptor
These autoantibodies bind to and activate the TSH receptor stimulating thyroid synthesis but the negative feedback lowers TSH
High circulating TH, low TSH
Weight loss, tachycardia, fatigue
Diffuse goitre (general swelling of the neck) due to TSH receptor stimulation
Ophthalmopathy

Question 19

What is Hashimoto’s syndrome?

Answer 19

Autoimmune:
Antibodies destroy the thyroid tissue 
Bradycardia 
Low circulating TH, high TSH
Lethargy, intolerance to cold
Lack of growth and development (in juvenile patients)
Diffuse goitre