Hypothyroidism

Question 1

Draw the hypothalamo-pituitary-thyroid axis for regulation of T3/T4 production. (4)

Answer 1

Diagram on page 14. Marks:

• Hypothalamus produces TRH acts on thryotrophs in pituitary gland
• Release of TSH acts on thyroid gland
• Release of T3/T4 to act on peripheral tissues
• Negative feedback on hypothalamus and pituitary

Question 2

What is the role of thyroxine binding globulin? (2)

Answer 2

• 99% of T3 and 99% of T4 bound to TBG in plasma
• Only free T3/T4 is available for action
• In pregnancy amount of TBG can go up
• In malnourished people/liver failure get reduced plasma TBG

Question 3

Describe how TSH stimulates T3/TR production. (5)

Answer 3

• T3/T4 is made in follicles of thyroid gland
• TSH acts on basal membrane (TSHR)
• Ref to colloid/follicular cells
• Ref to Na/I symporter and thyroglobulin release into colloid
• Thyroid peroxidase catalyses oxidation of iodine and iodination of thyroglobulin (ref to MIT/DIT)
• TPO also catalyses coupling reaction to produce T3/T4
• Endocytosis at apical membrane + release of hormones consequently

Question 4

What effect do T3/T4 have? (2)

Answer 4

• Alter gene expression
• Increase protein synthesis
• Increase BMR

Question 5

What is the mechanism of action of T3/T4? (3)

Answer 5

• T3 is the predominant active form (T4 is deiodinated to T3 in cytoplasm of target tissues)
• T4 has longer half-life
• T3 binds to thyroid receptor (a nuclear receptor)
• Heterodimerisation with RXR (retinoid X receptor)
• Bind to HRE (thyroid response elements) on DNA to alter gene expression

Question 6

State some of the clinical manifestations of hypothyroidism (primary myxoedema). (4)

Answer 6

• Reduced basal metabolic rate – everything slows down
• Cold intolerance
• Deep voice
• Weight gain
• Loss of appetite
• Depression
• Lethargy
• Speech slows down
• Bradycardia
• Constipation

Question 7

What is primary myxoedema (aka primary hypothyroidism)? (2)

Answer 7

• It is a failure to produce T3/T4 due to failure of the thyroid gland
• Commonly due to autoimmune destruction of thyroid gland
• Characterised by low T3/T4 and high TSH

Question 8

What is pituitary myxoedema (aka secondary hypothyroidism)? (2)

Answer 8

• This is actually a failure to produce sufficient TSH therefore leading to a deficit in T3/T4
• Commonly due to a pituitary tumour/post-pituitary surgery

Question 9

How can primary myxoedema be distinguished from pituitary myxoedema? (2)

Answer 9

2 marks for a contrasting statement between the two:

• In primary myxoedema sometimes can get hypertension because get high amounts of vasoconstriction (compensatory for bradycardia). In pituitary myxoedema observe hypotension.
• In primary get heart enlargement. In pituitary myxoedema have a smaller heart
• In pituitary myxoedema do not observe the scaly skin and skin is less dry
• Could mention the difference in treatment: in primary myxoedema can use TSH to monitor dose. In pituitary myxoedema need to monitor plasma free T4 because TSH levels are low

Question 10

How can hypothyroidism be treated? (2)

Answer 10

• Leveothyroxine (synthetic T4) = preferred choice
• Liothyronine sodium (T3) = less commonly used
• T4 is preferred because longer half-life therefore missing a dose is less problematic

Question 11

Describe the levels of thyroxine and TSH in someone with primary thyroid failure. (1)

Answer 11

Need to get both:
Thyroxine = LOW
TSH = HIGH

Question 12

What is the clinical use of liothyronine sodium? (2)

Answer 12

• Treatment of myxoedema coma (very rare complication of hypothyroidism)
• You give IV liothyronine sodium because the onset of action is faster than levothyroxine sodium

Question 13

What is the problem with giving T3 replacement? (2)

Answer 13

• T3 is very potent so it is difficult to get the dose right
• Overdose can lead to adverse effects (thyrotoxicosis type symptoms): palpitations, tremor, anxiety

Question 14

Describe some adverse effects of thyroid hormone over-replacement. (3)

Answer 14

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
 Nervousness

Question 15

What factors can affect production of thryoxine binding globulins? (2)

Answer 15

1 from each section:
Increased by:
- Pregnancy
- Prolonged treatment with oestrogen and phenothiazines

Decreased by:

• Malnutrition
• Liver failure