hypothyroid disorders

Question 1

what does a healthy adult thyroid gland secrete?

Answer 1

both T4 and T3

Question 2

what is T4?

Answer 2

Tetraiodothyronine (Thyroxine, T4)
= a prohormone
converted by deiodinase enzyme into the more active metabolite tri-iodothyronine (T3)

Question 3

where does the circulating T3 come from?

Answer 3

Circulating T3
80% from deiodination of T4
20% from direct thyroidal secretion.

Question 4

Is T4 or T3 more active?

Answer 4

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

Question 5

what does T3 bind to?

Answer 5

it binds to the TRE (thyroid response element in the DNA) along with the RXR (retinoid x receptor) and TR (thyroid hormone receptor)
this leads to altered gene expression

Question 6

what is used in thyroid hormone replacement therapy?

Answer 6

Levothyroxine sodium
thyroxine sodium; thyroxine;
Tetraiodothyronine; T4
usually the drug of choice

Liothyronine sodium
triiodothyronine; T3
- Less commonly used

Question 7

what is primary hypothyroidism

what would you administer and check for?

Answer 7

Primary hypothyroidism eg autoimmune, iatrogenic - post-thyroidectomy, post-radioactive iodine
– autoimmune damage to the thyroid. 
o Thyroxine (T4) levels low, TSH levels hig

LEVOTHYROXINE (synthetic thyroxine)
Oral administration

TSH used as guidance for thyroxine dose  - aim to suppress TSH into the reference range

Question 8

draw the system for how TRH, TSH and thyroxine works

Answer 8

see slide

Question 9

what is secondary hypothyroidism?

what would you administer and check for?

Answer 9

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

Oral administration of T4

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 10

what is myxoedema coma?

Answer 10

Myxoedema coma - a VERY RARE complication of hypothyroidism

Question 11

how should the LIOTHYRONINE (synthetic trio-iodothyronine) be administered?

Answer 11

iv initially – as onset of action faster than T4

then oral when possible

Question 12

what are the pros of T4 intake than T3?

Answer 12

active orally

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

Question 13

what type of thyroid hormone can the body use?

Answer 13

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

- 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 14

what happens inside the colloid?

Answer 14

Inside the colloid – [1] Iodide ions in the presence of TPO and H2O2, are converted to a reactive iodine form. [2] I* then iodinates one (MIT) or two (DIT) positions on TG to create mono-iodotyrosines (MIT) or di-iodotyrosines (DIT) – Both are forms of TG. [3] TPO and H2O2 then catalyse a coupling reaction to create tri-iodothyronines (T3) or tetra-iodothyronines (T4) – Again, forms of TG. [4] Lysosomes then uptake clumps of colloid which is broken down to liberate T3 and T4 à moves to the blood.

Question 15

symptoms of primary hypothyroidism

Answer 15

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

Question 16

When would you use levothyroxine?

Answer 16

We use this in 3 scenarios:
§ 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.
§ Secondary hypothyroidism – e.g. pituitary tumour.
· Oral form BUT TSH is low due to adenohypophysial failure so you can’t use it as a guide so you aim to move the fT4 to the middle of reference range.

Question 17

what happens in Thyroid Hormone Over-replacement ?

Answer 17

Adverse effects of thyroid hormone over-replacement are:
§ Skeletal – increased bone turnover, reduction in bone density (osteoporosis).
§ Cardiac – tachycardia, risk of dysrhythmia and atrial fibrillation.
§ Metabolism – increased energy expenditure, weight loss.
§ Increased beta-adrenergic sensitivity – tremor, nervousnes

Question 18

thyroid hormone mechanism of action

Answer 18

thyroxine enters the target cell and is converted to T3 by deiodinase
T3 then moves to the nucleus and binds to the thyroid hormone receptor.
It then heterodimerises with a retinoid X receptor
this complex then binds to the thyroid response element that causes a change in gene expression

Question 19

hypothyroidism symptoms

Answer 19

cold intolerance 
fatigue 
weight gain 
bradycardia
depression 
constipation 
deepening of voice

Question 20

production of thyroid hormone

Answer 20

Inside the colloid –
[1] Iodide ions in the presence of TPO (thyroperoxidase) and H2O2 (hydrogen peroxidase), are converted to a reactive iodine form.
[2] I* then iodinates one (MIT) or two (DIT) positions on TG (thyroglobulin) to create mono-iodotyrosines (MIT) or di-iodotyrosines (DIT) – Both are forms of TG.
[3] TPO and H2O2 then catalyse a coupling reaction to create tri-iodothyronines (T3) or tetra-iodothyronines (T4) – Again, forms of TG.
[4] Lysosomes then uptake clumps of colloid which is broken down to liberate T3 and T4 à moves to the blood.

Question 21

define primary hypothyroidism

Answer 21

Primary hypothyroidism (myxoedema) – autoimmune damage to the thyroid.

Question 22

Adverse effects of thyroid hormone over-replacement are:

Answer 22

§ Skeletal – increased bone turnover, reduction in bone density (osteoporosis).
§ Cardiac – tachycardia, risk of dysrhythmia and atrial fibrillation.
§ Metabolism – increased energy expenditure, weight loss.
§ Increased beta-adrenergic sensitivity – tremor, nervousness