Hypothyroidism

Question 1

What is the very famous piuitary axis diagram (draw it!!)?

Answer 1

Question 2

Describe how T3 and T4 are made in the thyroid gland

Answer 2

Thyrotropin receptors are found on the basolateral (outside) membrane. TSH binds to the thyrotropin receptors. Binding of the TSH will stimulate the iodide pump and I-enters (by Na+/I-symporters). TSH has three effects:

TSH affects the nucleus and stimulates synthesis of thyroglobulin. Thyroglobulin (precursor to T3 and T4) travels to the apical membrane.

TSH stimulates the enzyme TPO (thyroid peroxidase). TPO converts I-to I2in the presence of hydrogen peroxide (iodine is more reactive). TPO can also do the conversion reactions to T3 and T4.

TSH stimulates lysosomes- stimulates them to move to the apical membrane and stimulate uptake of clumps of colloid (including active T4 (thyroxine)) into the follicular cell and back out into the blood.

Iodination of thyroglobulin occurs in the colloid cells to create mono-iodotyrosines (MIT) or di-iodotyrosines (DIT). TPO catalyses coupling reactions of DIT and MIT to make T3 and T4.

Question 3

Describe the arrangement of the thyroid gland (colloid and follicles)

Answer 3

Thyroid cells are arranged in follicles. In the middle (the colloid) is the thyroglobulin and stored thyroxine.

Enzymes near the edges you can see white blips. They are the enzymes releasing thyroxine.

Question 4

What is myxoedema?

Answer 4

Primary hypothyroidism

Antibodies produced against the thyroid gland. The thyroxine levels fall and the TSH climbs. It is hard to notice this

Question 5

Symptoms of myxoedema

Answer 5

Deep voice

Depressed

Fatigue

Cold intolerance

Put on weight

Constipation

Bradycardia

Eventual myxoedema coma

these symptoms can easily be mixed up with the symptoms of ageing

Question 6

Relationship between T3 and T4

Answer 6

Thyroid makes T4 (thyroxine) and T3. T4 is a prohormone and is broken down by deiodonase enzyme activity into T3. T3 is more active. Most of the T3 in circulation comes from this conversion (80%) only 20% is from direct thyroidal secretion. T3 is the biologically active hormone.

Question 7

How does T3 bring about effects in a cell?

Answer 7

T3 travels to then nucleus of cells and binds to a heterodimer of TR and RXR (look in picture above). This then binds to DNA as a part of the thyroid response element (TRE)- leads to effect.

Question 8

What is thyroid hormone replacement therapy?

Answer 8

Levothyroxine sodium- thyroxine sodium (T4). Tablets to supply the thyroxine that the thyroid gland cannot make.

T4 given is converted into T3 and this producing the effect that it needs to.

Question 9

When would you have to administer levothyroxine?

Answer 9

1. Autoimmune primary hypothyroidism
2. Iatrogenic primary hypothyroidism- post thyroidectomy. If you have had your thyroid gland taken out, you cannot utilise the TSH and need the thyroxine supplied. The dosage is based on the high levels of TSH (in order to supress TSH into the normal range).
3. Secondary hypothyroidism- this is when there is a problem with TSH production in the APG. This can occur when there is a pituitary tumour. TSH is low and so is T4. You cannot use TSH as a reference point for dosage so focus on the free T4 levels in the blood and focus on getting that in the normal range.

Question 10

What is myxoedma coma?

Answer 10

Severe hypothyroidism- decreased mental stability

Myxoedema coma is rare complication. This is the only situation when you give T3 to the patient. It is more potent and works more quickly than T4. Given by an injection then switch to T4 when they are more stable

Question 11

What is combined thyroid hormone therapy?

Answer 11

Some patients might want to take T3 as well as T4. This is called combined thyroid hormone therapy. This shouldn’t really be done. Your body takes the T4 and converts it to T3 by deiodinase. Excess T3 will help to lose weight but will lead to heart arrythmias, tremors, anxiety.

T3 is biologically potent so patients that take T3 it is difficult to get the dose right. They can end up with too little TSH.

Question 12

Describe over-replacement of thyroxine

Answer 12

There will be suppressed TSH (due to feedback as you think you don’t need to make anymore thyroxine).

This will lead to reduced bone density (osteoporosis), tachycardia and atrial fibrillation, increased BMR and weight loss, tremors and nervousness.

Question 13

Half lifes of T3 and T4

Answer 13

Thyroxine has a long half-life (good if patients forget to take their tablet)- around 6 days.

T3 has a shorter half-life- around 2.5 days.

Question 14

Are both T3 and T4 orally active?

Answer 14

yes!

Question 15

T3/ T4 and carrier proteins- whats that about?

Answer 15

Many hormones are bound to carrier proteins. The free unbound hormone is active. Majority of thyroxine is bound (99.97%) so you measure the free T4 (fT4). It is bound to TBG (thyroxine binding globulin)- not be confused with thyroglobulin (found in the follicles of the thyroid gland). The same goes for T3- 99.7% is bound to plasma proteins.

Question 16

How do the levels of plasma binding protein vary with other pathologies?

Answer 16

Remember that only the free (unbound) fraction of thyroid hormone is available to the tissues

• plasma binding proteins increase in pregnancy and on prolonged treatment with oestrogens and phenothiazines
• TBG falls with malnutrition, liver disease
• certain co-administered drugs (e.g. phenytoin, salicylates) compete for protein binding sites.

Question 17

Proportions of T4 vs T3

Answer 17

There is 10 times more T4 in the plasma than T3. Free hormone is secreted in the bile and urine. T3 is cleared in hours but T4 is cleared in around 6 days.