Hypothyroid Disorders

Question 1

What are the hormones secreted by the thyroid gland?

Answer 1

Thyroid hormones: T3 (tri-iodothyronine) T4 (tetraiodothyronine - also known as thyroxine) → main hormone released

Question 2

Explain the hypothalamus-pituitary-thyroidal axis.

Answer 2

Hypothalamus secretes TRH into the anterior pituitary This promotes TSH release from the anterior pituitary TSH stimulates T3 and T4 release from the thyroid gland Negative feedback (maintains plasma thyroid hormone concentration: T3 and T4 inhibits TSH and TRH release TSH inhibits TRH release NOTE: be able to draw diagram

Question 3

Which thyroid hormone is more active?

Answer 3

T3 is much more active than T4 T3 provides ALMOST ALL of he thyroid hormone activity inside the target cells (i.e. it can alter gene expression) T4 is not very bioactive - may have some physiological effects but not on gene expression like T3 so has less significant effects Therefore can be considered a PROHORMONE (which can be converted into T3 - more active form) NOTE: only 20% of T3 is released directly from the thyroid gland 80% of T3

Question 4

How is T4 converted to T3?

Answer 4

T4 is deiodinated to form T3 - by action of the DEIODINASE enzyme

Question 5

State some of the effects of hypothyroidism.

Answer 5

Reduced BMR – everything slows down Symptoms: Cold intolerance (respiration releases heat energy as a by-product so there is less of that) Deepening voice (increased levels of polysaccharides in the connective tissue of the vocal folds due to loss of regulation → increased fluid retention so they become swollen) Weight gain Reduced of appetite (reduced activity of the mechanisms (involving gut/brain) which make you hungry) Depression, lethargy and tiredness (maybe due to under activity of some parts of the brain which make you feel low on energy and enthusiasm and overall dampen your mood) Bradycardia Constipation (bowels slow down) Eventual myxoedema coma (brain stops functioning)

Question 5

Describe the mechanism of action of thyroxine.

Answer 5

Thyroxine (T4) enters the target cell and is then converted to T3 by deiodinase T3 then binds to a thyroid hormone receptor in the nucleus and then heterodimerises with a retinoid X receptor (i.e. receptor-hormone complex is one protein, retinoid X is another protein; two different proteins form a complex → heterodimer) This heterodimer then binds to a thyroid response element, which causes a change in gene expression (i.e. the heterodimer acts as a TF)

Question 6

What are the two main drugs that are used as thyroxine and T3 replacement?

Answer 6

T4 replacement – Levothyroxine Sodium (main) T3 replacement – Liothyronine Sodium (less commonly used) NOTE: the drugs end in sodium as the salt form of the thyroid hormone (but still have the same effect)

Question 7

What is levothyroxine sodium (synthetic T4) used to treat?

Answer 7

Primary hypothyroidism Secondary hypothyroidism

Question 9

What is primary hypothyroidism?

Answer 9

Reduced thyroid hormone production due to a problem with the thyroid gland → you can measure free T4 in the plasma and if this is abnormally low this indicates hypothyroidism

Question 10

What is another name for primary hypothyroidism?

Answer 10

Myxoedema

Question 11

Describe and explain the levels of thyroxine and TSH in someone with primary thyroid failure.

Answer 11

Thyroxine = LOW TSH = HIGH Explanation: Reduced thyroid hormone levels mean reduced negative feedback on TSH production, so TSH levels will sharply increase to try to stimulate thyroid hormone production

Question 12

State some causes of primary hypothyroidism?

Answer 12

MOST COMMON: Autoimmune disease - immune system attacking body’s own thyroid gland → thyroid gland destruction (also known as Hashimoto’s disease) IATROGENIC (caused by medical examination/treatment): Thyroidectomy - if thyroid gland is removed then obviously there is nothing in the body to produce thyroid hormones Radioactive iodine - caused destruction of the thyroid gland (often used as a treatment in HYPERthyroidism)

Question 13

How is levothyroxine sodium taken to treat primary hypothyroidism?

Answer 13

Oral administration TSH is measured and TSH levels are used as a guidance to determine the thyroxine dose The aim is to use a high enough dose to suppress TSH (by negative feedback) so that it is within the reference range

Question 14

What is secondary hypothyroidism?

Answer 14

Reduced thyroid hormone production due to a problem with the pituitary gland - lack of TSH secretion from anterior pituitary meaning that the thyroid gland is not being stimulated as much to secrete thyroid hormone NOTE: no problem with thyroid gland itself

Question 15

State some causes of secondary hypothyroidism.

Answer 15

Pituitary tumour - this could affect/damage the thryrotrophs (TSH-secreting cells) Post-pituitary surgery - this could have resulted in removal of or damage to the thryrotrophs or the pituitary gland as a whole Radiotherapy - destruction of thryrotrophs or pituitary gland as a whole

Question 16

How is levothyroxine sodium taken to treat secondary hypothyroidism?

Answer 16

Oral administration As there is no TSH production, TSH levels can’t be used as a guide to determine the dose However the dose can be determined by measuring free T4 (fT4) levels - aim is to keep fT4 within the reference range NOTE: only free T4 can be measured; most of the T4 is bound to plasma proteins so is difficult to measure

Question 17

What is the clinical use of liothyronine sodium (synthetic T3)?

Answer 17

Treatment of myxoedema coma (VERY RARE complication of hypothyroidism) You give IV liothyronine sodium because the onset of action is faster than levothyroxine sodium (already in T3 form ready for use in the target cells - no need for body to spend time converting T4 into T3)

Question 18

Why is myxoedema coma rare?

Answer 18

Because the onset of hypothyroidism is generally gradual so over time patient should realise changes and approach a doctor Therefore, hypothyroidism is usually diagnosed before a patient gets to a very advanced stage However, in rare cases, usually when the patient is alone and cannot visit the doctor themselves (usually elderly), then the hypothyroidism progresses to the myxoedema coma stage

Question 19

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

Answer 19

Some patients don’t feel better with T4 replacement alone though their TSH may be normal Maybe because giving T3 has a faster effect as it doesn’t have to be converted first Therefore, if this drug has a faster effect (i.e. faster symptomatic relief), then it makes people think that this drug is more effective that the T4 alone (no evidence for this though)

Question 20

What is the problem with giving T3 replacement (i.e. combination treatment)?

Answer 20

Difficult to get the drug dose exactly right as T3 is very potent so as even little bit too much of T3 can lead to patients complaining of symptoms of thyroid ‘toxicity’: palpitations tremor anxiety Even a little bit too much T3 leads TSH levels going below the reference range due to the negative feedback effect - also illustrates potency (combination better at suppressing TSH than T4 alone) By giving T4 only, T3 levels would be regulated by rate of enzymatic conversion of T4 to T3 - safer and can be done according to body’s needs

Question 21

What are the plasma half-lives of T3 and T4?

Answer 21

T3 (liothyronine) = 2-5 hours T4 (levothyroxine) = 6 days NOTE: both drugs are orally active (i.e. they are still active by the time they are absorbed into the bloodstream via the gut)

Question 22

What plasma protein is T3 and T4 mainly bound to?

Answer 22

Thyroxine binding globulin (TBG) NOTE: over 99% of the circulating drug is bound to plasma proteins REMEMBER: only the free (unbound) fraction of thyroid hormone is available to the tissues Hormone + Plasma protein ⇌ Protein-bound hormone (exist in equilibrium)

Question 23

What can cause an increase in the production of plasma proteins (reduces free hormone concentration)?

Answer 23

Pregnancy Prolonged treatment with oestrogen and phenothiazines (antipsychotic drug)

Question 24

What can cause a decrease in the amounts of the plasma proteins (increases free hormone concentration)?

Answer 24

Liver failure - most plasma proteins are produced by the liver) Malnutrition - 12 essential AAs must be obtained from food so lack of intake decreases the body’s ability to make protein as they don’t have the required source of AAs

Question 25

What can increase the free hormone concentration without other than a change in the plasma protein concentration?

Answer 25

Certain co-administered drugs (e.g. phenytoin, salicylates) compete with the hormone for protein binding sites Therefore, this will decrease the amount of hormone being able to bind to the plasma proteins, resulting in an increased concentration of free hormone