Download 04 The thyroid

LCRS: Endocrinology
Usama Asif
ENDOCRINOLOGY 6:
The thyroid and the iodothyronines
Professor John Laycock ([email protected])
1. Describe the anatomy of the thyroid and the structure of the follicles
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The thyroid gland is situated in the neck over the trachea
It is essentially bilobed but has four major components
o Isthmus – the bridge between the right and left lobes of the thyroid. It is located inferior to
the cricoid cartilage
o Pyramidal lobe
o Two lobes
The cellular anatomy of the thyroid shows that the thyroid gland has follicles. These follicles are
made up of follicular cells lining the outside of the follicle, and surround the colloid – a gel-like
extracellular matrix
There are also parafollicular cells, but these do not produce any thyroid hormones (these play a
part in calcium metabolism – they produce calcitonin)
2. List the main hormones produced by the follicular and parafollicular cells of the thyroid
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The follicular cells produce two main thyroid hormones:
o Triiodothyronine (T3)
o Tetraiodothyronine (T4) – thyroxine
The parafollicular cells produce calcitonin – involved in calcium metabolism
LCRS: Endocrinology
Usama Asif
3. Describe by means of a labelled diagram the principal features of iodothyronine synthesis, storage and
release
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The above diagram shows how iodothyronines are produced
The basolateral membrane of the follicular cell is in contact with blood; the apical membrane is in
contact with the colloid of the follicle
The function of these two membranes is to transport iodide ions (I-) through them. However, they
have different proteins that do this
Iodothyronine synthesis
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When thyroid stimulating hormone from the adenohypophysis reaches the thyroid cells, it binds
to the TSH receptor
The TSH receptor is a Gs-protein coupled receptor. It activates the adenylate cyclase cascade. The
cascade has multiple effects:
o One effect is to stimulate the Na+/I- symporter to work more. This pumps in iodide and
sodium ions into the cell (along the concentration gradient). The iodide diffuses to the
apical membrane and is transported to the colloid via another different iodide transporter
(called pendrin)
o Once activated, the TSH receptor migrates to the nucleus to act as a transcription factor for
a protein called thyroglobulin
o The TSH receptor also activates an enzyme called thyroid peroxidase
o It also stimulates lysosomes to migrate to the apical membrane surface (function explored
later)
LCRS: Endocrinology
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Usama Asif
Thyroid peroxidase (TPO) is an oxidising enzyme. It uses peroxide as the oxidising agent. It has
two functions
TPO causes the liberation of the iodide ion to a more organically viable form – to atomic iodine (I)
This iodine iodinates the thyroglobulin molecule
Thyroglobulin has the amino acid tyrosine as part of its structure. These tyrosyl residues are what
are iodinated by thyroid peroxidase
The tyrosyl residues become iodinated in either one or two places: on the 3C of the cyclic ring or at
the 3C and 5C of the cyclic ring. Thus, these become either monoiodotyrosyls (MIT) or
diiodotyrosyls (DIT)
The thyroglobulin has many tyrosyl residues, thus, on iodination it has many DITs and MITs. The
enzyme TPO then couples the MIT and DITs together to form T3 and T4 residues on the
thyroglobulin molecule
Thyroglobulin is a protein and it is in abundance in the colloid, thus why the colloid is gel-like. It
is the main reserve of the iodothyronines in the follicles
The Tg-T3-T4 complexes are endocytosed by the thyroid follicular cell’s lysosomes (TSH receptor
action)
The lysosome contains enzymes that liberate the T3 and T4 from the thyroglobulin molecule
The enzymes also mop up any remaining amino acids and MIT/DITs for reuse
The hormones enter the circulation
The iodothyronines are transported in the blood mostly bound to plasma proteins
o Thyronine-binding globulin (around 70% T4 and 80% T3)
o Albumin (around 10% T4 and 15% T3)
o Prealbumin (transthyretin) (around 15% T4 and 2% T3)
LCRS: Endocrinology
Usama Asif
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Only around 0.05% T4 and 0.5% T3 are present unbound in blood – and are thus biologically active,
because with a plasma protein on them, they aren’t the right shape for their receptor – this forms a
dynamic equilibrium
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The majority of production is thyroxine
These hormones have long latent periods – they take time to take effect
o T3 = 12 hours
o T4 = 72 hours
And they have long half-lives – thus they are long acting hormones
o T3 = 2 days
o T4 = 7-9 days
Even though thyroxine is the main product of the thyroid gland, it is largely deiodinated (by the
enzyme iodothyronine iodinase) in target tissues to make T3, thus, T4 is a precursor to T3
It can also be iodinated in a different position to make a biologically inactive molecule known as
reverse T3 (rT3)
rT3 can be important in regulation, i.e. during a fasted state, there can be less active and more active
hormone
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4. Describe the physiological actions of the iodothyronines
The main actions of the iodothyronines
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Increase basal metabolic rate – in most peripheral tissues. It results in calorigenesis (apart from in
the brain, because it cannot use fat). It also results in heat production
Increase protein, carbohydrate and fat metabolism (intermediary metabolism) – therefore, the
iodothyronines are important for growth and development – both anabolic and catabolic
metabolism are influences, usually more catabolic than anabolic
o The iodothyronines play a particularly important role during foetal growth and
development. The lack of iodothyronines during foetal development and after birth results
in a condition known as cretinism if it is left untreated within the first few months of life
Potentiate some of the actions of the catecholamines e.g. tachycardia, glycogenolysis and
lipolysis etc.
Interact with other endocrine systems e.g. oestrogens
Effects on the CNS
Increase Vitamin A and retinal synthesis
o Thus, an increase in carotenes cause yellow eyes, this not jaundice
LCRS: Endocrinology
Usama Asif
5. Explain the mechanism(s) of action of the iodothyronines
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Both of the iodothyronines can bind to the thyronine receptor on target cells
Once in the cell, the iodothyronines can illicit many things:
o They can act as transcription factors to increase protein synthesis of certain proteins that
cause their function (as above) – this is their main mechanism
o They might go into the mitochondria and stimulate metabolic activity somehow
(unconfirmed), by either stimulating metabolic activity or the mitochondrion itself
o They might stimulate membrane transport mechanisms (unconfirmed)
6. Describe the control mechanisms of iodothyronine production with particular reference to the
hypothalamo-pituitary-thyroidal axis
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The hypothalamo-pituitary-thyroidal axis is the control mechanism for iodothyronine production
The hypothalamus produces thyrotrophin releasing hormone (TRH), which goes to the
adenohypophysis and stimulates the release of thyrotrophin (TSH – thyroid stimulating
hormone). Thyrotrophin goes to the thyroid and stimulates the release of the iodothyronines
However, once this is activated, if there was no other control, then the whole axis would just
continue increasing secretions linearly
The feedback mechanisms for the HPT axis involve:
o Direct negative feedback from the iodothyronines to TSH in the adenohypophysis
o Indirect negative feedback from the iodothyronines to TRH in the hypothalamus
o The thyroid is unique in its function for auto-negative feedback, from the TSH in the
adenohypophysis feeding back negatively to the TRH in the hypothalamus
Other factors that play a part in thyroid hormone control include:
o Sympathetic innervation positively feeds back to the thyroid gland
o Inorganic iodide ions negatively feed back to the thyroid gland – this is the WolffChaikoff effect
o Somatostatin from the hypothalamus has an inhibitory effect on TSH in the
adenohypophysis
o Oestrogens stimulate TSH production
o Glucocorticoids
inhibit
TSH
production
Thyrostimulin
- A recently discovered 2-unit glycoprotein
- Found in the adenohypophysis and other
tissues, including the heart, adipose tissue,
testes, ovary etc.
- Binds to the TSH receptor
- Unknown functions
LCRS: Endocrinology
Usama Asif
ENDOCRINOLOGY 7:
General thyroid disorders
Professor Karim Meeran ([email protected])
Anatomy of the thyroid
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The thyroid gland is in the neck. It is shield shaped:
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It is a very vascular gland and therefore, the only surgical procedure that can be done is to remove
the whole gland – thyroidectomy
It is still a risky surgery, one of the risks that surgeons tell their patients is potential voice change,
because the recurrent laryngeal nerves hook around the thyroid and could be damaged during
surgery
The parathyroid gland is embedded in the thyroid gland too, and has an important role in calcium
metabolism, thus during surgery, removing these need to be avoided
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LCRS: Endocrinology
Usama Asif
Embryology of the thyroid
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The thyroid gland originates from the back of the tongue at the point of the adult foramen caecum
The cells from the tongue migrate down and form a diverticulum. This forms a thyroglossal duct,
and the cells then spread out and form the two lobes of the thyroid
In other words, the thyroglossal duct is a diverticulum from the tongue that is in the midline, it is
an outpunching of the pharynx
Around week 7, the thyroglossal duct disappears and forms the foramen caecum. The pyramidal
lobe is a remnant of the thyroglossal duct (see image) and the thyroid then develops. The
pyramidal lobe is occasional
The thyroid weighs about 20g and each lobe measures around 4x2.5x2.5cm. The right lobe is bigger
than the left
Problems with development
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The development of the thyroid can be hindered due to many things:
o Agenesis – the thyroid is completely absent
o Incomplete descent – the thyroid grows in the wrong place – can cause lingual thyroid
o Persistent thyroglossal duct/thyroglossal cyst – a segment of the vestigial thyroglossal duct
remains in the body and presents as cyst years later
LCRS: Endocrinology
Usama Asif
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Thyroxine is essential for normal brain development. Neonates with thyroxine deficiency in utero
develop irreversible brain damage if it is not remedied – they are called cretins
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All neonates are tested for a range of disorders; this heel prick test also tests for thyroid function
by measuring TSH. If any abnormalities are found, then they are given thyroxine if TSH is found to
be high
o TSH is inhibited by thyroid hormones, if levels are high, then they aren’t being inhibited!
Microanatomy of the thyroid
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The images to the right show the thyroid follicular cells
Actual size:
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DO NOT MIX UP THYROGLOBULIN and THYRONINE BINDING GLOBULIN
They are different things
TBG binds the iodothyronines in the circulation wheras thyroglobulin is in the thyroid gland
LCRS: Endocrinology
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Usama Asif
Thyroid disease affects 5% of the population and is much more common in females, but the ratio
of hyper to hypothyroidism is 1:1
1. Describe the principal clinical effects of excess circulating iodothyronines, and name the condition
described
Thyrotoxicosis/hyperthyroidism
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This is caused by too much thyroxine in the system – as a result, TSH levels fall to zero (because of
the inhibition brought about by the thyroxine)
This causes a raised basal metabolic rate, which equals a raised temperature. It also causes these
people to burn up calories and lose weight
They suffer from tachycardia – increased heart rate
Every cell in the body “speeds up”
Features of hyperthyroidism
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Myopathy
Mood swings
Feeling hot
Diarrhoea
Tremor
Tired
Palpitations
Sore eyes
Goitre
Graves’ disease
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Grave’s disease is where the whole thyroid is smoothly enlarged and the whole gland is
overactive
Graves’ is caused by the body’s own immune system – autoimmune. The body makes antibodies
that bind to and stimulate the TSH receptor in the thyroid
It causes smooth goitre and hyperthyroidism
LCRS: Endocrinology
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Usama Asif
The sore eyes are caused by other antibodies produces (along with the TSH-like antibodies) that
bind to the muscles behind the eye and cause exophthalmos
Other antibodies stimulate growth of the shins and cause pretibial myxoedema (do not mix with
hypothyroidism) or pretibial hypertrophy – this is the swelling that occurs on the shins of patients
with Graves’ (non-pitting), it is the growth of soft tissue
Treatment
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Complicated = next year
2. Describe the principal clinical effects associated with a deficiency in circulating iodothyronines, and
name the condition described
Primary hypothyroidism (myxoedema)
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This is primary hypothyroidism, which means primary thyroid failure. The follicular cells in the
thyroid are not creating any iodothyronines
It occurs as a result of autoimmune damage to the thyroid or due to an operation (removing the
thyroid)
Thyroxine levels decline and TSH levels climb. This is due to the feedback loops of the HPT axis
Features of primary hypothyroidism
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Deepening voice
Depression and tiredness
Cold intolerance – one of the body’s mechanisms of driving temperature up is by increasing basal
metabolic rate and this is done by the thyroid hormones
Weight gain and reduced appetite
Constipation
Bradycardia (low heart rate)
Eventual myxoedemal coma
LCRS: Endocrinology
Usama Asif
Treating hypothyroidism
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Treatment is essential, otherwise patients are at risk of death and they will perform poorly. Their
cholesterol will go up, increasing their risk of cardiovascular problems
Treatment is simple, just replace thyroxine and monitor the TSH – until the TSH is normal, adjust
the dose of thyroxine given
3. Understand the principles of treatment issues in the individual patient