Hypothyroidism

Question 1

Draw the thyroid - hypothalamus - pituitary axis.

Answer 1

TRH, TSH, T3+T4

Question 2

What is Myxoedema?

Answer 2

Primary hypoparathyroidism

• high TSH
• low T4
• autoimmune damage to the thyroid

Question 3

What are some symptoms of primary hypothyroidism?

Answer 3

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

Question 4

How are thyroid hormones made?

Answer 4

• TSH binds to TSHR on follicular cells.
• this has multiple effects
  a) I- enters cell via NIS and then colloid via pending pump
  b) TPO moves to the colloid
  c) TG moves to the colloid
  d) reaction 1: iodination (I- -> I* + TG -> TG bound to MIT and DIT)
  e) reaction 2: coupling reaction (DIT-TG-MIT -> TG bound to T3 and T4)

(both reactions via TPO and H2O2)

e) TG-T3-T4 packaged into a lysosome and then broken down into T3 and T4
g) packaged hormones are released into bloodstream

Question 5

What are other names for T4?

Answer 5

Tetraiodothyronine, Thyroxine

Question 6

Is T3 or T4 more active?

Answer 6

• T3 is more active
• T4 is a prohormone -> converted to T4 in the cell via deiodination
• T3 provides almost all the thyroid hormone activity in target cells.

Question 7

How much of circulating T3 is due to deiodination of T4?

Answer 7

80% (other 20% was produced as T3)

Question 8

What does T3 do inside the cell?

Answer 8

It binds to TRE (thyroid response element) and alters gene expression.

(RXR (retinoid x receptor) and TR (thyroid hormone receptor) also bind to TRE to produce effects)

Question 9

What is thyroid hormone replacement therapy?

Answer 9

• Give oral thyroxine to replace the missing hormone
  other names: thyroxine sodium; thyroxine;
  Tetraiodothyronine; T4

Less commonly used: Liothyronine sodium
triiodothyronine; T3

Question 10

Clinical use of levothyroxine sodium

Answer 10

Primary hypothyroidism:

• eg autoimmune, iatrogenic - post-thyroidectomy, post-radioactive iodine
• Oral administration
• TSH used as guidance for thyroxine dose - aim to suppress TSH into the reference range

Secondary hypothyroidism:

• eg pituitary tumour, post-pituitary surgery or radiotherapy
• 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 11

Clinical use of triiodothyronine

Answer 11

Myxoedema coma - a VERY RARE complication of hypothyroidism
-> iv initially – as onset of action faster than T4, then oral when possible

=> no clinical evidence that T3 is better, but it is more expensive!

Question 12

Combined Thyroid hormone replacement

Answer 12

• Combination T4/T3 – some reported improvement in well-being
• Complicated by symptoms of ‘toxicity’ – palpitations, tremor, anxiety - often combination treatment suppresses TSH

Question 13

Pharmacokinetics of Thyroid hormone replacement therapy

Answer 13

• orally active
• long plasma half life: T3=2.5d; T4: 6d;
• majority of hormone is ppb (tbg)
• only free fraction of hormones is available to tissues

Question 14

What is the half life of T3?

Answer 14

2.5d plasma half life

Question 15

What is the half life of T4?

Answer 15

6d plasma half life

Question 16

Plasma protein binding of thyroid hormones.

Answer 16

• Approximately 99.97% of circulating T4 and 99.7% of circulating T3 are bound to plasma proteins, mainly thyroxine binding globulin (TBG)
• only free hormone is available to 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

What fraction of T3 is plasma protein bound?

Answer 17

99.7%

Question 18

What fraction of T4 is plasma protein bound?

Answer 18

99.97%

Question 19

Which hormone provides almost all the thyroid hormone activity in target cells?

Answer 19

T3

there is ic deiodination of T4

Question 20

How would you treat myxoedema coma?

Answer 20

• a very rare complication of hypothyroidism
• i.v. T3 (trio-iodothyronine)
• onset of action is faster than T4 and then given orally when possible.

Question 21

Deiodinase

Answer 21

converts T4 to T3

Question 22

which enzyme converts T4 to T3?

Answer 22

Deiodinase

Question 23

What happens in pregnancy in terms of PPB?

Answer 23

• increase in PPB proteins

- in pregnancy and on treatment with oestrogens and phenothiazines (antipsychotics)

Question 24

What happens with TBG in malnutrition and liver disease?

Answer 24

TBG falls