Hypothyroidism Flashcards
Draw the hypothalamo-pituitary-thyroid axis for T3 / T4, you can just outline it here, but draw it in real life
- Hypothalamus secretes TRH
- TRH is a releasing factor that stimulates TSH secretion from the anterior pituitary
- TSH secretion stimulates T3 / T4 in the thyroid gland
- T3 / T4 secreted from the thyroid gland has negative feedback at the anterior pituitary and at the hypothalamus
Outline the process of T3 / T4 synthesis
- TSH binds TSH receptor on apical surface of follicular cell which facilitates iodide transport
- Iodide then travels down via sodium iodide transporter
- I- then enters the colloid via pendrin channels on the basolateral membrane of the follicular cells
- I- oxidised to iodine
- TSH receptor activation also activates thyroglobulin (TG) synthesis
- TPO in the presence of H2O2 uses iodine to iodinate tyrosine residues on thyroglobulin - forming monoiodotyrosine (MIT) and diiodotyrosine (DIT)
- TPO in the presence of H2O2 couples MIT + DIT, DIT + DIT to form T3 and T4
- T3 / 4 re-enter follicular cells where lysosomes break down the iodinated TG proteins into just iodinated tyrosine residues = T3 AND T4
1) What is stored in the colloid?
2) What stimulates release of one of the components stored in the colloid?
1)
- Thyroglobulin
- Thyroxine
2)
- TSH activates an enzyme tht stimulates the release of stored thyroxine from the colloid
1) What is primary hypothyroidism (and how and where)?
2) What response is seen in the other parts of the hypothalamo-pituitary-thyroid axis in response to this?
1)
- Autoimmune damage to the thyroid
- Fall in thyroxine
2)
- Rise in TSH as pituitary detects fall in thyroxine and attempts to compensate
1) Suggest some signs / symptoms of primary hypothyroidism?
2) What to look for in a thyroid function test for primary hypothyroidism?
1)
- Depression and tiredness
- Bradycardia
- Weight gain with reduced appetite
- Constipation
- Deepening voice
- Heart enlargement
- EVENTUAL MYXOEDEMA COMA - brain stops functioning due to lack of thyroxine
2)
- ↓ T3/T4, ↑ TSH (pituitary compensation)
1) Which is the active form T3 or T4? How does action occcur in target tissue?
2) What avenues do circulating T3 come from?
1)
- T3
- T4 is the prohormone
- T4 is deiodinated to T3 by deiodinases at tissues
2)
- Mostly from direct T4 deiodination
- Little from direct thyroid secretion
Outline the process for thyroid hormone mechanism of action
- Thyroxine (T4) enters the cell and is converted to T3 by deiodinase
- T3 moves to nucleus and binds a thyroid hormone receptor
- Here, the T3 / Thyroid hormone receptor complex heterodimerises with a Retinoid X Receptor
- This whole complex then binds the thyroid hormone response element (a small section of DNA) → thereby causing the alteration in gene expression
3 types of thyroid hormone replacement therapy?
- Levothyroxine sodium = T4 replacement
- Liothyronine sodium = T3 replacement
- Combined Thyroid Hormone Replacement
1) Method of levothyroxine administration?
2) 2 types of hypothyroidism that levothryoxine sodium is used to treat and describe their aetiologies
3) How to monitor dose requirement in both cases?
1) Daily, oral
2)
- Primary hypothyroidism (thyroid gland failure)
- Autoimmune
- Iatrogenic (post-thyroidectomy or post radioactive iodine)
- Secondary hypothyroidism (pituitary problem)
3)
- Primary hypothyroidism treatment monitoring
* Since there is low T3 / T4 and thus high TSH due to low negative feedback, you want to administer levothyroxine sodium until TSH is suppressed within the reference range - indicating a healthy amount of T3 / T4 having negative feedback - Secondary hypothyroidism treatment monitoring
- No TSH produced in this due to pituitary issue so can’t use this as a guide
- Get free T4 (fT4) within the reference range instead - this is the marker used instead
1) When would you use liothyronine clinically?
2) How to follow up?
1)
- In myxoedema coma - when the hypothyroidism is very severe
- I.v. liothyronine as this is medical emergency so needs urgent action
- Action of liothyronine (T3 replacement) is faster than levothyroxine sodium (T4 replacement)
2)
- Follow up with oral thyroxine replacement
List the 4 main areas of adverse effects of thyroid hormone over-replacement and expand on them (thyrotoxicosis signs and symptoms)
- Skeletal
* ↑ Bone turnover so less bone mineral density and osteoporosis - Cardiac
- Tachycardia
- Dysrhythmia (particularly atrial fibrillation)
- Increased beta-adrenergic sensitivity
- Tremor
- Nervousness
- Metabolism
- Increased energy expenditure
- Weight loss
1) When is combined thyroid hormone replacement therapy used?
2) 2 weaknesses with this therapy?
1)
- Some patients don’t feel better with T4, even if TSH within reference range - given this therapy now
2)
- T3 is v. potent so difficult to get the dose right
- Some symptoms of thyrotoxicosis may occur:
- Palpitations
- Anxiety
- Tremor
1) In what form are circulating T3 / T4 found?
2) How are the hormones cleared?
3) Circulating t 1/2 of T3 / T4?
1)
- Free, unbound → bioactive
- Plasma protein bound (conjugated hormone) - bound to thyroid binding globulin
2)
- Both free + conjugated hormones are secreted in the bile and urine
3)
- T3: 2-5 hours
- T4: 6 days
In what cases do plasma protein (e.g. TBG) production…
1) Increase?
2) Fall?
3) What do phenytoin & salicylates do with regards TBG and T3 / T4?
1)
- Pregnancy
Prolonged treatment with…
- Oestrogens
- Phenothiazides
2)
- Liver disease - as the proteins are synthesised here
- Malnourishment
3)
- Compete for the protein binding site T3 / T4, displacing T3 / T4 from TBG, leaving more bioactive unconjugated hormone
