Hypothyroidism

Question 1

What type of hormones are T3 and T4

Answer 1

Amines

Question 2

Which hormones does a healthy, adult thyroid gland secrete

Answer 2

Healthy adult thyroid gland secretes both T4 and T3.
Tetraiodothyronine (Thyroxine, T4)
= a prohormone
converted by deiodinase enzyme into the more active metabolite tri-iodothyronine (T3)

Question 3

State the origins of the circulating T3

Answer 3

Circulating T3
80% from deiodination of T4
20% from direct thyroidal secretion.
T3 provides almost all the thyroid hormone activity in target cells.

Question 4

Which thyroid hormone provides almost all the biological activity in the body

Answer 4

T3 provides almost all the thyroid hormone activity in target cells.

Question 5

Revise the thyroid gland

Answer 5

§ Remember that you need to remember how to draw the HPT-Axis.

§ You have enough thyroxine in your thyroid gland for a month- recently discovered that there can be up to 3 months of iodothyronines are stored in the follicular colloid of the thyroid gland

§ In a histological sample of the thyroid you can see the white chunks in the colloid where colloid has been taken up to have the thyroxine liberated to then pass into the blood.

Question 6

What does the colloid contain

Answer 6

Thyroglobulin and stored thyroxine

Question 7

Describe the uptake of iodide into the follicular cells

Answer 7

The concentration of inorganic iodide is greater in the follicular cell than it is in the general circulation.
Also the anion has to enter against its electrical gradient, as living cells have a negative interior with respect to the exterior.
Iodide therefore has to move against an impressive electrochemical gradient.
It does this by means of the sodium-iodide symporter (NIS) in the basolateral membrane which transports two sodium ions and one iodide ions into the cell down the sodium gradient. The energy needed to drive this process is provided by the Na+/K+ ATPase pump.

Question 8

Describe thyroglobulin synthesis

Answer 8

Binding of TSH to TSHR also stimulates the transcription of genes in the nucleus that will synthesise thyroglobulin. Thyroglobulin is a large glycoprotein homodimer. Thyroglobulin is secreted into the colloid through the apical membrane

Question 9

Describe the iodination and organification reactions that form mono- and di-iodotyrosines

Answer 9

Binding of TSH to TSHR also activates TPO.
Along the apical membrane colloid border the inorganic iodide gets oxidised to a highly active, short-lived form of iodide known as ‘reactive iodine’. This iodination reaction is catalysed by TPO (Thyroidal peroxidase) in the presence of hydrogen peroxide.
In this form it immediately gets ‘organified’ by binding to positions 1 and 2 of certain tyrosyls which are incorporated into the thyroglobulin, forming the mono- and di-iodotyrosyls (MIT and DIT).

Question 10

Describe the coupling reaction

Answer 10

The thyroglobulin undergoes a configurational change, known as the coupling reaction, in which the molecule undergoes a structural realignment such that specific di-iodotyrosyls link up with either mono- or di-iodotyrosyls to form tri- and tetra-iodothyronines. This reaction is also under control of TSH.

Question 11

How many thyronines are normally formed on each thyroglobulin

Answer 11

3-4

Question 12

Where are the thyronines stored

Answer 12

In the colloid

Question 13

Describe the uptake from colloid and release into circulation

Answer 13

Binding of TSH also results in the pinocytosis of the colloid, drawing bits of it back into follicular cells. Once the iodinated thyroglobulin is back in the follicular cell cytoplasm, it is taken up by lysosomes directed towards the apical membrane, also in response to TSH. These lysosomes contain various enzymes, including proteases and deiodinases, which break down the thyroglobulin, releasing iodine, tyrosine and thyronines. The iodine and tyrosine residues of MIT and DIT can be recirculated within the cell for reuse. T3 and T4 are secreted through the basolateral membrane into the circulation by means of a transporter mechanism.

Question 14

How are the iodide ions transported into the colloid

Answer 14

They reach the apical membrane where they are transported into the colloid by the pendrin transporter
A process stimulated by TSH- an exchange with chloride ions may be part of the precise mechanism

Question 15

What are the tyrosyls incorporated into

Answer 15

Thyroglobulin. Of the total 134 tyrosyls in each thyroglobulin dimer, only 25-30 of these are actually iodinated.

Question 16

Describe the storage in the colloid

Answer 16

The follicle lumen is filled with iodinated thyroglobulin protein which forms a yellowish, thick, gel-like substance known as colloid. This acts as a reservoir of iodothyronines which are hormones of the thyroid follicular cells. Most of the thyronines synthesised in the thyroid are in the form of T4. While this is a hormone in its own right, it is also important because it can be deiodinated to T3, which is by far the more potent of the two molecules, mostly in the peripheral tissues.

Question 17

Describe the peripheral conversions of the iodothyronines.

Answer 17

T4 plays a role as a pro-hormone in addition to its direct role of a hormone itself. Numerous peripheral tissues contain deiodinases which can deiodinate T4 to the more bioactive T3 by the removal of the iodine atom at position 5’. However, a different deiodinase can deiodinate the 5’ of pro-hormone T4 to form rT3.

Question 18

Describe the differences in metabolic activities of T4,T3 and rT3

Answer 18

While T3 is more biologically active than T4, rT3 is metabolically inactive. Under specific conditions peripheral tissues have the ability to direct the nature of the deiodination pathway depending on their environmental circumstances, either increasing or decreasing the biological activities associated with these thyroid hormones.

Question 19

Describe the differences in half-life and latency periods of the thyroid hormones

Answer 19

Latent period: delay between stimulus and response
T3: ~ 12h
T4: ~ 72h

Half lives:
T4 around 7-9 days
T3 around 2 days

Question 20

Summarise primary hypothyroidism (myxoedema)

Answer 20

Autoimmune damage to the thyroid
Thyroxine levels decline
TSH levels climb

Question 21

What are the easily predictable consequences of primary hypothyroidism

Answer 21

Tiredness and lethargy
Lack of mental agility
Feeling cold
BMR falls- lose appetite BUT gain weight- reduced utilisation of energy and so it is stored as fat

Question 22

State the key clinical features of primary hypothyroidism

Answer 22

Deepening voice
Depression and tiredness
Cold intolerance
Weight gain with reduced appetite
Constipation
Bradycardia
Eventual myxoedema coma

Ultimately, a reduced BMR- the patient slows down mentally and physically

Question 23

What are the white blobs seen around the edge of colloid in histological slides representative of

Answer 23

Enzymes releasing thyroxine into the circulation- will see more white blobs in a patient with hyperthyroidism

Question 24

Describe how the iodothyronines exert their effects

Answer 24

Thyroxine enters the target cell and is converted to T3 by deiodinase
T3 then binds to a thyroid hormone receptor in the nucleus and then heterodimerises with a retinoid X receptor
This complex then binds to a thyroid response element (specific region of DNA), which causes a change in gene expression
Will activate or inhibit a specific gene process resulting in the synthesis (or inhibition) of new protein

Question 25

Besides the well accepted genomic action of thyronine, describe the two other potential modes of action

Answer 25

Mitochondrial genomic- high-affinity binding sites for iodothyronines on the mitochondrial membrane and they influence mitochondrial metabolism directly by acting on mtDNA. Non-genomic action- Evidence that the iodothyronines can influence mitochondrial membrane transport processes directly, once bound to the membrane located binding sites.

Question 26

How do the iodothyronines enter cells

Answer 26

The free, unbound iodothyronines are able to cross the peripheral cell membranes by means of specific transporters. These include mono-carboxylate transporters 8 and 10 and organic anion transporting protein1c1 (OATP1c1).

Question 27

What do the iodothyronines do once inside their target cells

Answer 27

Cross the nuclear membrane, probably via a transporter system, and subsequently bind to specific thyronine receptors, of which there are at least 3: TRalpha1, TRbeta1, TRbeta2- restricted to hypothalamus and pituitary (involved in negative feedback)

Question 28

Describe the two potential options for thyroid hormone replacement therapy

Answer 28

Levothyroxine sodium thyroxine sodium; thyroxine; Tetraiodothyronine; T4 usually the drug of choice- will be deiodinated to bioactive T3 in peripheral tissues to exert effects Liothyronine sodium triiodothyronine; T3 - Less commonly used

Question 29

Describe the different causes of primary hypothyroidism

Answer 29

§ Autoimmune primary hypothyroidism. § Iatrogenic primary hypothyroidism – e.g. post-thyroidectomy. · Oral form and the dosage is based off the high TSH levels (aim to supress the TSH into reference ranges. post-radioactive iodine

Question 30

Describe the causes of secondary hypothyroidism

Answer 30

Secondary hypothyroidism – eg pituitary tumour, post-pituitary surgery or radiotherapy

Question 31

Summarise secondary hypothyroidism and how the treatment differs slightly to that of primary (think of how we titrate the doses in each case)

Answer 31

This is a problem with TSH production by the adenohypophysis There is no problem with the thyroid gland itself As there is no TSH production, thyroxine replacement therapy is monitored by measuring free T4 (fT4) levels and keeping it within the reference range

Question 32

How is T4 administered in secondary hypothyroidism and how do we titrate the dose

Answer 32

Oral administration. TSH low due to anterior pituitary failure, so can’t use TSH as a guide to dose. Aim for fT4 middle of reference range

Question 33

Describe what is meant by a myxoedema coma

Answer 33

Myxoedema coma - a VERY RARE complication of hypothyroidism

Question 34

In which group of patients is a myxodema coma particularly prevalent in

Answer 34

If the diagnosis of hypothyroidism is not considered for several years in a patient with primary hypothyroidism, the patient gradually worsens until they lose consciousness (no thyroxine). At this point a patient is said to have a myxoedema coma- a condition with high mortality if left untreated. Unusual (as TSH array tests are widely available)- but can still occur in elderly patients who have no relatives. Such patients who are in residential care may not be regularly reviewed, and when they become confused- they may be thought to be suffering from senile dementia. Rushed to causalty upon unconsciousness- measure TSH when suspect confusion.

Question 35

How do we treat patients who have suffered a myxoedema coma

Answer 35

You give IV liothyronine sodium because the onset of action is faster than levothyroxine sodium Start on small doses- usually 5mcg Because in a patient who has had hypothyroidism for several years, a sudden normalisation in fT3 may cause sudden tachycardia, which could precipitate cardiac disease and ischaemia, which in turn can be fatal.

Question 36

What can T3 be used to treat and why is it used in this case

Answer 36

We can give T3 but this is less common. o This drug is called liothyronine sodium. o You would use this when you want a rapid effect – e.g. in a myxoedema coma. o This is given intravenously. Can be injected More potent Faster acting Will improve thyroid levels quickly- can then switch to oral T4 once the patient stabilises

Question 37

Describe the changes made to the dose of T3 used in patients to treat myxoedema coma

Answer 37

If no adverse events for eight hours after the first dose of T3, the dose can be safely repeated every 8 hours until the patient awakens.

Question 38

Why is it important to exclude other causes of coma

Answer 38

Since hypothyroidism is an A.I disease, it is possible that the patient will have more than one A.I disease. Therefore the patients are often treated for Addison's too, just in case they have myxoedema and Addison's- known as Schmidt's syndrome.

Question 39

Describe the controversy surrounding T3

Answer 39

Patients feel T4 linked to depression, and T3 improves their well-being However no evidence base (RCTs) that suggests that the use of T3 replacement improves the management of primary and secondary hypothyroidism- plus it's expensive- no evidence to suggest T4 does not work either Shouldn't need T3 anyway as the T4 will be converted to T3 to exert its effects.

Question 40

Summarise combined hormone replacement therapy for hypothyroidism

Answer 40

T4 = prohormone, converted by deiodinase action to T3 Combination T4/T3 – some reported improvement in well-being- but not a substantial data base to support its use Complicated by symptoms of ‘toxicity’ – palpitations, tremor, anxiety - often combination treatment suppresses TSH- hard to get dose right as T3 is more potent. TSH can decrease massively- hard to get into reference- leading to symptoms of hyperthyroidism

Question 41

Describe some adverse effects of thyroid hormone over-replacement.

Answer 41

``` Skeletal · Increased bone turnover · Reduced bone mineral density · Risk of osteoporosis Metabolic · Increased energy expenditure · Weight loss Cardiac · Tachycardia · Risk of dysrhythmia Beta-adrenergic activity · Tremor · Nervousnes ```

Question 42

What is the issue with T3 replacement

Answer 42

T3 is very potent so it is difficult to get the dose right | Too high a dose can lead to patients complaining of thyrotoxicosis type symptoms: palpitations, tremor, anxiety

Question 43

Why would you give a patient combined thyroid hormone replacement (T3+T4)?

Answer 43

Some patients don’t feel better with T4 replacement alone though their TSH may be normal

Question 44

What is the effect of thyroxine on beta adrenergic receptors

Answer 44

Sensitises beta adrenergic receptors | potentiating (better and faster) effects of adrenaline- palpitations, weight loss

Question 45

Describe the half life and administration of both drugs

Answer 45

i) active orally ii) Half-life long Levothyroxine (T4) plasma half life of 6 days Liothyronine (T3) plasma half life 2.5 days

Question 46

What plasma protein is T3 and T4 mainly bound to?

Answer 46

Thyroxine binding globulin

Question 47

What proportion of the circulating T3 and T4 are bound to plasma proteins

Answer 47

Approximately 99.97% of circulating T4 and 99.7% of circulating T3 are bound to plasma proteins, mainly thyroxine binding globulin (TBG) (NB do NOT confuse with thyroglobulin) Only the free (unbound) fraction of thyroid hormone is available to the tissues

Question 48

What can cause an increase in the production of plasma proteins

Answer 48

- plasma binding proteins increase in pregnancy and on prolonged treatment with oestrogens and phenothiazines (anti-psychotic drug)

Question 49

What can cause a decrease in the amounts of the plasma proteins?

Answer 49

o TBG falls with malnutrition, liver disease and certain drug treatments. o Certain co-administered drugs (phenytoin- anticonvulsant and salicylates- NSAIDs) compete for PPB binding site

Question 50

Describe the relative proportions of T3 and T4 and how they are excreted

Answer 50

§ There is 10x more T4 in plasma than T3. § Free/unconjugated hormone is the secreted in the bile and urine. o T3 cleared in hours. o T4 cleared in about 6 days.

Question 51

State the features seen in primary hypothyroidism

Answer 51

``` Hair- dry, brittle Lethargy, memory impairment, slow cerebration (psychosis may occur) oedema of face and eyelids thick tounge, slow speech deep coarse voice sensation of coldness diminished perspiration heart enlarged, poor heart sounds, pericardial pain 9occasionally) hypertension (frequently) skin- coarse, dry, scaling, follicular keratosis, yellowish (carotonema) pulse slow ascites weakness menorrhagia, amenorrhoea may occur late in disease reflexes, prolonged recovery hair finer, shorter loss of pubic and axillary hair ```

Question 52

What is meant by carotenemia

Answer 52

Carotenemia is a clinical condition characterized by yellow pigmentation of the skin (xanthoderma) and increased beta-carotene levels in the blood.