Thyroid Flashcards
1
Q
Hypothalamo-pituitary-thyroid axis: recall and draw the hypothalamo-pituitary-thyroid axis and its regulation
A
1) TRH (thyrotropin-releasing hormone) from the hypothalamus
2) TRH stimulating thyrotrophs of the anterior pituitary to make TSH (thyroid stimulating hormone)
3) TSH stimulates the thyroid to make T3 and T4
4) Negative feedback: thyroid hormones inhibit production TSH and TRH
- -> Iodide can also inhibit the release of thyroid hormones (Wolff-Chaikoff effect)
- -> glucocorticoids inhibit TSH -
- -> oestrogen stimulates TSH +
2
Q
Explain thyroid hormone synthesis
A
- TSH binds to TSH receptor
- Iodide Trapping using NIS (Sodium-Iodide Symporter) – secondary active transport. Sodium conc. gradient maintained via Na+ K+ ATPase
- Iodide pumped into colloid using Pendrin Pump (Iodide/chloride antiporter)
- Thyroglobulin (TG) is synthesised via transcription and translation and diffuses to colloid
- In the colloid, I- is rapidly oxidised to I* via the enzyme thyroid peroxidase (TPO) in the presence of H2O2.
- I* attaches to a tyrosine on a molecule of TG. This reaction is also catalysed using TPO in the presence of H2O2.
- If one I* is added to the TG-tyrosine, it is called a 3-mono-iodotyrosine (MIT).
- If two I* are added to the TG-tyrosine, it is called a 3,5-di-iodotyrosine (DIT).
- Coupling occurs: TPO and H2O2 combine a DIT from one TG to either an MIT or another DIT on another TG: DIT+MIT gives a T3 hormone (triiodothyronine); DIT+ DIT gives a T4 hormone (thyroxine).
- A lysozome moves towards the apical membrane.
- T3/T4-TG are taken up into the cell via endocytosis, they are now inside the lysozome.
- Inside the lysozome, proteolysis cleaves T3 and T4 from the TG.
- The T3/T4 diffuse towards the basolateral membrane and then diffuse into the blood. They are secreted to have an action all around the body
3
Q
Name and draw the structure which is the site of thyroxine synthesis
A
Thyroid follicular cell
4
Q
Thyroid hormones: explain the mechanism of action of thyroid hormones
A
Thyroid Hormones
- A healthy adult thyroid gland secretes both T4 and T3
- Tetraiodothyronine (Thyroxine, T4) is a prohormone that gets converted to the active T3
- T3 is a more active hormone
- but T4: is the main hormone product of the thyroid gland
- T4 is converted to T3 by deiodinase
- The majority of circulating T3 is NOT released by the thyroid gland itself (only 20%) but instead formed by the deiodination of T4 (80%)
- So:
- 80% - deiodination of T4
- 20% - direct thyroidal secretion
- T3 provides almost all the thyroid hormone activity in the target cells
1) Deiodinated to T3 (bioactive form) in target tissues
2) Also deiodinated in a different position to produce reverse T3 (inactive)
Mechanism A:
1) T4 enters the cell and is converted to T3 by deiodinase
2) T3 then binds to the Thyroid Hormone Receptor (THR), enters the nucleus, and stimulates transcription of a number of genes leading to protein synthesis
3) It then heterodimerises with a Retinoid X Receptor
4) This complex then binds to the Thyroid Response Element that causes a change in gene expression – that’s how it affects change in thyroid cells
OR
Mechanism B:
2) It doesn’t enter the nucleus and acts on ion channel cell surface proteins
5
Q
Explain how thyroid hormones are transported in the blood
A
Mostly bound to plasma proteins
1) thyroid-binding globulin: TBG (70-80%)
BEWARE: Thyroglobulin is not thyroid-binding globulin
2) albumin (10-15%)
3) prealbumin (aka transthyretin)
Only 0.05% T4 and 0.5% T3 unbound (bioactive components)
Latent period:
T3: ~ 12h
T4: ~ 72h
Half-lives:
T4 around 7-9 days
T3 around 2 days
6
Q
Hypothyroidism: explain the effects of thyroid hormone deficiency
A
Thyroid Gland Failure -
- Affects 5% of the population
- Female : male ratio = 4 : 1 (Much more common in females)
- Overactive : underactive = 1 : 1
Primary Hypothyroidism (Myxoedema)
- Primary thyroid failure
- Autoimmune damage to the thyroid (or operation)
- Thyroxine levels decline
- TSH levels climb
- This leads to a fall in the level of thyroxine - they may start feeling cold and tired because their basal metabolic rate starts to fall
- The pituitary will detect a fall in thyroxine and will produce loads of TSH
- This causes a slowly falling thyroxine despite a slowly rising TSH
- This is the biochemistry of primary hypothyroidism (myxoedema)
- Summary of the effects of primary hypothyroidism:
- Tongue gets thick
- Speech slows down
- Deepening of the voice
- BMR falls
- Bradycardia
- General weakness
- Depression
- Cold intolerance
- Weight gain and reduced appetite
- Constipation
- Eventual myxoedema coma
- Thyroid Function Test - High TSH and Low T3/T4
Treatment:
1) Simply replace thyroxine - usually one tablet (100 micrograms on average) daily
2) Monitor the TSH and adjust dose until TSH is normal
7
Q
Recall types of thyroid hormone replacement and their limitations.
A
Thyroid Hormone Replacement Therapy
- The usual thyroxine replacement is LEVOTHYROXINE SODIUM
- NOTE: thyroid hormones are rich in IODINE
- Very rarely, T3 is used - LIOTHYRONINE SODIUM (this has THREE iodine residues)
- When someone has primary hypothyroidism: top up with drugs
Clinical use of LEVOTHYROXINE SODIUM (synthetic thyroxine)
- AUTOIMMUNE PRIMARY HYPOTHYROIDISM (thyroid not working)
- IATROGENIC PRIMARY HYPOTHYROIDISM (e.g. post thyroidectomy or post-radioactive iodine) or autoimmune
- The tablet tends to be a one a day tablet that is taken orally
- TSH level is used as guidance for the thyroxine dose
- You want to suppress TSH into the reference range - TSH falls, when it reaches the normal range appropriate dose is established
- Remember T3 and T4 have negative feedback at the level of the hypothalamus and the pituitary so the levels of T3 and T4 tend to remain constant normally
- If you have a failing thyroid gland you will have LOW T3 + T4 and HIGH TSH
- This replacement is also used for SECONDARY HYPOTHYROIDISM(e.g. pituitary tumour, post-pituitary surgery or radiotherapy) - they can’t make TSH
-
Secondary Hypothyroidism:
- This is a problem with the pituitary
- The thyroid gland is fine
- As they don’t produce any TSH, this can NOT be used as guidance to get the right dose
- So you adjust the dose to achieve an fT4 (free T4 (free aka active not protein bound)) that is in the middle of the reference range
OVERALL
Majority of patients will take thyroxine and monitor TSH
Some, TSH isn’t high, t4 levels used as reference range
Clinical Use of Liothyronine (T3)
- MYXOEDEMA COMA
- This is a VERY RARE complication of hypothyroidism
- You give I.V. Liothyronine (T3) in this situation because the onset of action is faster than T4 (T3 much more potent and administered IV)
- Switch them to oral thyroxine replacement if possible (when they get better)
Controversy about T3
NHS England does not support prescription of T3
Deiodinase T4 is converted to T3
(explain it from a first principle pov)
Combined Thyroid Hormone Replacement (T3 + T4)
Sometimes when there is the use of both or T3 it is very difficult to give the right dose – TSH goes below because t3 is very potent
- T4 is the prohormone that is converted by deiodinase to T3
- There are some patients that don’t feel better with T4 even if their TSH is normal
- Some of these patients feel better when they are given a combination of T3 and T4
- However, T3 is very potent so it is difficult to get the dose right
- It will switch off TSH and the patients may complain of symptoms of thyrotoxicosis:
- Palpitations
- Tremor
- Anxiety
8
Q
Discuss the pharmacokinetics of thyroid replacement drugs
A
Pharmacokinetics of Thyroid Replacement Drugs
- Active orally
-
LONG half-life:
- T4 = 6 days
- T3 = 2-5 hours
- Around 99.97% of circulating T4 and 99.7% of circulating T3 is bound to PLASMA PROTEINS
- They are mainly bound to thyroxine binding globulin (TBG) (not thyroglobulin in colloid)
- Only the free, unbound thyroid hormone is available to tissues
- Plasma proteins increase in pregnancy and on prolonged treatment with oestrogens and phenothiazides
- These plasma proteins are produced in the liver so if you have liver disease or if you are severely malnourished, your TBG production will fall
- Certain drugs (e.g. phenytoin and salicylates) can compete for the protein binding sites and displace it from TBG
- There is 10 times more T4 in the plasma than T3
- Free and conjugated hormone is secreted into the bile and urine:
- T3 is cleared in hours
- T4 is cleared in about 6 days
9
Q
List the causes of hyperthyroidism
A
Hyperthyroidism has TWO common causes:
- Graves’ Disease
- Nodular Goitre (Plummer’s Disease)
- This is a benign tumour that produces thyroxine
10
Q
Grave’s disease
A
Graves’ Disease
- This is an autoimmune disease - the immune system makes a mistake
- Antibodies bind to and stimulate the TSH receptor in the thyroid
- This makes the thyroid overactive because there are loads of antibodies stimulating the TSH receptors
- This stimulation leads to the thyroid gland becoming smoothly enlarged (goitre) and you get hyperthyroidism
- Hyperthyroidism causes lid lag (delay in moving the eyelid as the eye moves downwards)
Typical Graves’ Patient: Clinical Features
- This patient will be really overactive and anxious and have too much energy
- There is a rapid pulse (due to the raised basal metabolic rate)
- You are warm and you keep on burning calories
- Localised pretibial myxoedema = weird growth of soft tissue in the shin causing a swelling (non-pitting)
- Exophthalmos - there is another antibody that binds to the growth factor receptors behind the eye so the muscles behind the eye grow and push the eyes forward
- The pretibial myxoedema is also caused by the binding of another antibody to receptors in the soft tissue of the shin
- So the binding of three separate antibodies to various receptors cause:
- Hyperthyroidism/Goitre
- Exophthalmos
- Pretibial Myxoedema – hypertrophy of shins DIFFERENT from oedema as it’s non-pitting
- In the past, patients with hyperthyroidism will die of heart failure
- NOTE: for some reason, exophthalmos is made worse by SMOKING
Presentation of Graves’ patients:
- Patients will come complaining of being overactive with weight loss and sweating etc.
- On palpation, the thyroid gland will feel very diffuse and it’ll be smoothly enlarged
- You can image the thyroid by giving the patient some radioactive iodine
- It will show up on the scintigram, showing that the iodine is going into the thyroid gland and the whole thyroid gland is active
11
Q
Discuss Plummer’s disease and explain how to differentiate between Graves’ and Plummer’s
A
Plummer’s Disease
- This is a toxic nodular goitre - a bit of the thyroid gland has become tumorous and is misbehaving
- This is NOT autoimmune (not caused by antibody)
- This is caused by a benign adenoma that is overactive at making thyroxine
- There is NO pretibial myxoedema
- There is NO exophthalmos
- When you examine the neck there may be a lump on one side because the tumour will just be on one part of the thyroid
Presentation of Plummer’s patients:
- You can do a technetium or iodine scan and the scan will show the iodine going into the hot tumour
- Because there is too much thyroxine coming from the tumour part of the thyroid, the pituitary will stop making TSH and the normal part of the thyroid will slowly shrink and stop making thyroxine (-> when there is increased thyroxine the thyroid will stop producing T3,T4 so it shrinks)
- This means that in the thyroid scan you will just see a hot nodule and the rest of the thyroid scan will not be seen
- On the other hand, a large, smooth thyroid gland on the scan indicates Graves’
- Sometimes patients may have a multinodular goitre which is relatively common
12
Q
Recall the clinical features and explain the diagnosis of hyperthyroidism
A
Effects of Thyroxine on the Sympathetic Nervous System
- SENSITISES beta adrenoceptors to ambient levels of adrenaline and noradrenaline
- This means that the normal levels of adrenaline and noradrenaline will have much stronger effects than they should
- So patients with hyperthyroidism will also have features of having too much adrenaline e.g. palpitations, tachycardia, tremor, sweating, diarrhoea, lid lag (effets on lag superiorous)
- The muscles that open the eye are supplied partly by the SNS (half sympathetic and half oculomotor) - so a bit of adrenaline will make you open your eyes
- Lid lag is a feature of too much adrenaline (or too much effect from normal adrenaline levels)
Summary of Hyperthyroidism Symptoms
- Weight loss despite increased appetite
- Breathlessness
- Palpitations, tachycardia
- Sweating
- Heat intolerance
- Diarrhoea
- Lid lag and other sympathetic features
13
Q
Discuss thyroid storms
A
(Thyrotoxic Crisis)
- This is a MEDICAL EMERGENCY
- It is a rare but severe complication of hyperthyroidism
- 50% mortality if untreated
- They may die of heart failure or arrhythmia
- Blood results will confirm hyperthyroidism
- Features of Thyroid Storm:
- Hyperpyrexia > 41 degress
- Accelerated tachycardia/arrhythmia
- Cardiac failure
- Delirium/frank psychosis
- Hepatocellular dysfunction, jaundice
- If someone has left their hyperthyroidism long enough and they have at least two of the above features then there is a high risk of death
- You need prompt and aggressive treatment to deal with thyroid storm
- Treatment Options:
- Surgery (thyroidectomy)
- Radioiodine
- Drugs
14
Q
Thionamides
A
Classes of Drugs used in the treatment of Hyperthyroidism
Help manage the symptoms rather than cure the pathophysiology
-
Thionamides (thiourylenes, anti-thyroid drugs)
- Propylthiouracil (PTU) (propranolol)
- Carbimazole (CBZ)
- Potassium iodide
- Radioiodine (only if post-menopausal)
- Beta-blockers
Thionamides (e.g. propylthiouracil and carbimazole)
-
Daily treatment of hyperthyroid conditions
- Graves’ (whole of the gland turned on)
- Plummer’s (one nodule turned on)
- To control hyperthyroidism before thyroidectomy because you don’t want to give a general anaesthetic to someone who is tachycardic with a labile heart rate
- Following radioactive iodine treatment - because radioactive iodine takes a while to work so you need something else to control the thyroid hormone level before the radiotherapy starts to take effect
- The main thionamides are propylthiouracil and carbimazole
Thyroid Hormone Synthesis Recap
- Iodine is taken up into the follicular cells
- Under the action of thyroperoxidase with hydrogen peroxide you get iodination of tyrosine residues in the thyroglobulin
- You then get coupling of monoiodotyrosine and diiodotyrosine to form T3 and T4
- This is taken up and then released by the cells into the circulation
Mechanism of Action of Thionamides
- Iodine is taken up into the follicular cells
- Under the action of thyroperoxidase with hydrogen peroxide you get iodination of tyrosine residues in the thyroglobulin
- You then get coupling of monoiodotyrosine and diiodotyrosine to form T3 and T4
- This is taken up and then released by the cells into the circulation
Mechanism of Action of Thionamides
- Thionamides INHIBIT THYROPEROXIDASE
- Hence they inhibit the iodination of thyroglobulin and the coupling of iodotyrosines
- The net result is a reduction in the synthesis and secretion of thyroid hormones
- The biochemical effects of inhibition with thionamides occurs in hours but it takes weeks before the clinical effects can be seen
- This is because there is a lot of STORED thyroid hormone in the lumen of the thyroid follicles
- Anti-thyroid hormones only affect the synthesis of thyroid hormones, they do not affect the stored thyroid hormone
- Because of the delayed clinical effect of the thionamides you would want to manage the symptoms in the short-term with a non-selective beta blocker
- Anti-thyroid hormones may also suppress antibody production in Graves’ disease
- It also reduces the deiodination of T4 to T3 in peripheral tissues (this is done by propylthiouracil)
Unwanted Actions of Thionamides
-
Agranulocytosis/granulocytopenia (reduction or absence of granular leukocytes)
- This is rare and reversible on withdrawal of the drug
- Patients may present with a sore throat and a cold and they should go to the GP and have a full blood count
- Sore throats and colds are very common but you don’t want to miss the cold that is caused by the patient being neutropenic
- Rashes (relatively common)
- Headaches
- Nausea
- Jaundice
- Joint Pain
Pharmacokinetics of Thionamides
- Orally active
- Carbimazole is a pro-drug which first has to be converted to methimazole to be active
- Plasma half life of 6-15 hours
- It crosses the placenta and is secreted in the milk
- Thyroid disease is common in women around reproductive age so you have to consider pregnancy
- Patients can conceive on the drug but you want to get the dose as low as possible
- High doses of thionamides in a pregnant women could cause foetal hypothyroidism
- Both drugs cross into breast milk but propylthiouracil does this LESSthan carbimazole (PTU < CBZ)
- So a breast feeding women will be put on PTU over CBZ
- It is metabolised in the liver and excreted in the urine
Follow Up
- Usually aim to stop anti-thyroid drug treatment after 18 months
- Review patient periodically including thyroid function tests for remission/relapse
- There is a 50:50 chance of relapse after stopping the medication
What is the role of beta-blockers in thyrotoxicosis?
- It takes several weeks for the anti-thyroid drugs to have clinical effects
- So in this time you want to gives something else to deal with the problems of thyrotoxicosis e.g. tremor, tachycardia, anxiety
- To deal with these symptoms you give a NON-SELECTIVE BETA-BLOCKER (e.g. propanolol)
- You want it to be non-selective so it reduces all the effects of excess stimulation of beta adrenoceptors
15
Q
Iodide treatment
A
Iodide Treatment (usually KI)
- You give a dose that is at least 30 times the average daily requirement
- Uses in combination with other drugs:
- Preparation of hyperthyroid patients for surgery
- Severe thyrotoxic crisis (thyroid storm)
- The huge dose of iodide can be used to turn the thyroid gland off
- You’d do this when you want to take effect quickly e.g. when a patient is about to go in for an operation and you want to get them under control before administration of general anaesthetic
- Mechanism of Action of KI:
- Wolff-Chaikoff Effect = the temporary reduction in thyroid hormones following ingestion of large amounts of iodine
- This is an autoregulatory phenomenon - the thyroid rejects the ingested iodide and hence prevents the gland from sucking up loads of iodine and making too much thyroid hormone
- By giving lots of KI you inhibit the iodination of thyroglobulin and the generation of hydrogen peroxide
- This has a much quicker effect than giving anti-thyroid drugs
- It is useful for pre-surgery
- It reduces the size and vascularity of the thyroid within a couple of weeks
-
Unwanted Actions
- ALLERGIC REACTION
- Rashes
- Fever
- Angioedema
- ALLERGIC REACTION
-
Pharmacokinetics
- Orally
- Given as Lugol’s Solution or Aqueous Iodine
- Maximum effect after 10 days’ continuous administration
- Radioiodine 131I - high doses
- This treats Graves’, Plummer’s and Thyroid Cancer
- This is a way of permanently switching off the thyroid without surgery
- This method relies on the fact that the thyroid gland takes up iodine to make thyroid hormone so the thyroid follicular cells take up the iodine and it accumulates in the colloid
- Technetium 99 Pertechnetate
- This is much cheaper than radioiodine
- This is used for thyroid uptake scans
- Different results of thyroid uptake scan:
- Graves’ - the entire thyroid gland is active and smoothly enlarged
- Plummer’s/Toxic Nodule - single focus of activity and the rest is supressed
- Thyroiditis - unhappy, inflamed thyroid gland where there is NO activity at all
- From the colloid it emits beta particles of radiation that destroy the follicular cells
- This is a fairly straight forward treatment though some patients may complain of a little discomfort in the neck
-
Pharmacokinetics of Radioiodine
-
Discontinue anti-thyroid drugs 7-10 days prior to radioiodine treatment
- This is so that the thyroid gland can rev up and be really active so that it sucks up a lot of radioactive iodine when it is administered and you get maximal destruction of the gland
- Administer as a single oral dose:
- Graves’ Disease = approx. 500 MBq
- Thyroid Cancer = circa 3000 MBq
- Radioactive half-life = 8 days
- Radioactivity negligible after 2 months (maximum effect 2-3 months)
-
Discontinue anti-thyroid drugs 7-10 days prior to radioiodine treatment
-
Cautions of Radioiodine
- Avoid close contact with small children for several weeks after receiving radioiodine
- Contra-indicated in pregnancy and breast feeding
- Make sure you remind the patient that they will be radioactive for a couple of months
