49046
The thyroid
- Thyroid hormone functions
- Growth and cellular development
- Rate of postanatal growth
- Functional and biochemical
maturation of foetal brain and bone
- Gene switching during development
- Regulation of mitochondrial metabolic
enzymes and membrane synthesis
- Rate of postanatal growth
- Metabolism
- Regulation of basal metabolic
rate (can control temperature)
- Movement of H2O and Na(+) across cell membrane
- Calcium and phosphorus metabolism
- Regulation of cholesterol and lipid metabolism
- Nitrogen (urea) metabolism
- Control of glucose metabolism
- Regulation of basal metabolic
rate (can control temperature)
- Growth and cellular development
- Development and strcuture
- During development the thyroid arises from a
downward growth from the floor of the pharynx
where it develops infront kf the trachea
- Bilobular strucutre in the neck
also feature parathyroid glands
- Hstology
- Thyroid follicular cells line colloid filled follicles
- Between each follicle are cells which produce
calcitonin (C cells or parafollicular cells)
- Thyroid follicular cells line colloid filled follicles
- During development the thyroid arises from a
downward growth from the floor of the pharynx
where it develops infront kf the trachea
- Hormones
- Modified dipeptitde (two
tyrosines) - requires iodine
- Source of iodine
- Milk
- Iodised salt
- Fish
- Nuclear fallout
- Radioactive iodine concentrates
in the thyroid and kills cells
- Radioactive iodine concentrates
in the thyroid and kills cells
- Milk
- Iodine metabolism: there are two main
pools of iodine in the body (the thyroid
pool and the hormone [T3 and T4] pool)
- Most of the iodine intake Is excreted in the urine
- Most of the iodine intake Is excreted in the urine
- Source of iodine
- Synthesis and storage
- Thyroid hormone (T3 abd T4) is made up from two amino
acids (Tyr) linked together - they are both iodinated
- T3 has three iodines attached
- T4 has four iodines
- Each hormone is made and stored in a large
(660,000 MW) protein molecule called thyroglobulin
- Has many tyrosine residues
- Stored in colloid
- Has many tyrosine residues
- TSH stimulates thyroid hormone synthesis -
which occurs on the thyroglobulins in the colloid
- T3 has three iodines attached
- Thyroid hormone (T3 abd T4) is made up from two amino
acids (Tyr) linked together - they are both iodinated
- Thyroid hormone structure
- T3H (active)
- O
- CH2
- CH
- HOOC
- NH2
- HOOC
- CH
- CH2
- I
- I
- O
- I
- OH
- T4 (inactive)
- OH
- I
- O
- I
- I
- CH2
- CH
- HOOC
- NH3
- HOOC
- CH
- I
- O
- I
- Thyroxine
- OH
- If the iodinated pattern
of T3 reversed (i.e. one
iodine on the bottom ring
and two on the top) =
"reverse T3" (inactive)
- Triiodothyronine
- Produced on the thyroglobulin
within the thyroid follicles
- Follicular cells line the follicles and receive
TSH on there basal membrane - there
apical membrane faces into the follicle
- The enzyme which catalyses the production of T3/4 is on
the apical membrane and is expressed in response to TSH
- The enzyme which catalyses the production of T3/4 is on
the apical membrane and is expressed in response to TSH
- Follicular cells line the follicles and receive
TSH on there basal membrane - there
apical membrane faces into the follicle
- T3H (active)
- Synthesis
- Iodine in the blood is taken
up through the basal
membrane of the follicular cell
- Via a sodium/iodine symporter protein
- Sodium is constantly being
exchanged out of the cell by a 3Na/2K
ATPase protein (also basal)
- Na(+)
- Na
cycle
- Na
cycle
- Na(+)
- Iodine then passes through the cell to apical
membrane where it passes into the follicle via a
second iodine transporter called PENDRIN
- +
- TSH -> receptor (G
protein coupled) ->
increased cAMP
- TSH -> receptor (G
protein coupled) ->
increased cAMP
- Sodium is constantly being
exchanged out of the cell by a 3Na/2K
ATPase protein (also basal)
- Via a sodium/iodine symporter protein
- Thyroglobulin is made in
the follicular cell and
packaged by the golgi
- Thyroglobulin vesicles release
thyroglobulin into the follicle lumen
- Colloid = pool of thyroglobulin
- The apical membrane enzyme THYROID
PEROXIDASE (TPO) catalyses the iodination and
coupling of tyrosine residues in the thyroglobulin
- Tyrosines can be mono-iodinated
(MIT) or di-iodinated (DIT)
- TPO then catalyses the coupling of two tyrosine residues;
(MIT + DIT = T3 and DIT + DIT = T4)
- Much more T4 is synthesised than T3
- Thyroglobulin is then endocytosed -> inside the follicular cell
- Thyroglobulin is then proteolytically degraded in lysosome
- Releasing; T3, T4, MITs and DITs
- T3 and T4 leave the lysosome (some T4 is
converted to T3 by cytosolic deiodinaseY) are
secreted into the highly vascular thyroid stroma
- Thyroid hormones require transport
proteins to travel in the blood
- Thyroid binding globulin (TBG) ~75%
- Transthyretin and albumin (~10 -15%)
- Thyroid binding globulin (TBG) ~75%
- -
- Excess iodine inhibits TH release
- Excess iodine inhibits TH release
- Thyroid hormones require transport
proteins to travel in the blood
- MITs and DITs are recylced
- T3 and T4 leave the lysosome (some T4 is
converted to T3 by cytosolic deiodinaseY) are
secreted into the highly vascular thyroid stroma
- Releasing; T3, T4, MITs and DITs
- Thyroglobulin is then proteolytically degraded in lysosome
- Thyroglobulin is then endocytosed -> inside the follicular cell
- Much more T4 is synthesised than T3
- TPO then catalyses the coupling of two tyrosine residues;
(MIT + DIT = T3 and DIT + DIT = T4)
- +
- TSH -> receptor (G
protein coupled) ->
increased cAMP
- TSH -> receptor (G
protein coupled) ->
increased cAMP
- Tyrosines can be mono-iodinated
(MIT) or di-iodinated (DIT)
- The apical membrane enzyme THYROID
PEROXIDASE (TPO) catalyses the iodination and
coupling of tyrosine residues in the thyroglobulin
- Colloid = pool of thyroglobulin
- +
- TSH -> receptor (G
protein coupled) ->
increased cAMP
- TSH -> receptor (G
protein coupled) ->
increased cAMP
- Thyroglobulin vesicles release
thyroglobulin into the follicle lumen
- Cell morphology
- Thyroglobulin synthesis (in preparation for TH production)
- Columnar cells with active organelles
and many apical vesicles
- Columnar cells with active organelles
and many apical vesicles
- Resting (storage)
- Small cuboidal cells - less active ER/golgi and no vesicles
- Small cuboidal cells - less active ER/golgi and no vesicles
- TSH stimulated (active)
- Columnar cells with cytoplasmic folds
collecting colloid from the follicle lumen
- many vesicles throughout the cell
- Columnar cells with cytoplasmic folds
collecting colloid from the follicle lumen
- many vesicles throughout the cell
- Thyroglobulin synthesis (in preparation for TH production)
- Iodine in the blood is taken
up through the basal
membrane of the follicular cell
- Hormone
dynamics
- Most abundant TH secreted is T4 (with comparatively little T3 and rT3)
- T4 has t1/2 of about 7days (T3 = <1day)
- Circulating T4 can be converted
into active T3 (or rT3) by peripheral
tissues (i.e. when tissues need T3)
- 5'-deiodinase catalyses this conversion
- There are three types
of human deiodinases
- Type
1
- Converts T4 to T3 in periphery
- Location: Thyroid
hormone sensitive
peripheral tissues
- Role: produce
active T3 in
peripheral tissues
- Role: produce
active T3 in
peripheral tissues
- Location: Thyroid
hormone sensitive
peripheral tissues
- Converts T4 to T3 in periphery
- Type
2
- Converts T4 to T3 in brain
- Location: in the brain
(mostly the pituitary)
- Role: negative feedback in the
pituitary (inhibit TSH release)
- Role: negative feedback in the
pituitary (inhibit TSH release)
- Location: in the brain
(mostly the pituitary)
- Converts T4 to T3 in brain
- Type
3
- Converts T3 to T4 in placenta
- Location: placenta
- Role: inactivation of T3 to
protect foetus from mother's T3
- Role: inactivation of T3 to
protect foetus from mother's T3
- Location: placenta
- Converts T3 to T4 in placenta
- Type
1
- There are three types
of human deiodinases
- 5'-deiodinase catalyses this conversion
- Circulating T4 can be converted
into active T3 (or rT3) by peripheral
tissues (i.e. when tissues need T3)
- T4 has t1/2 of about 7days (T3 = <1day)
- Most abundant TH secreted is T4 (with comparatively little T3 and rT3)
- Regulation
- Stimuli: cold stress,
exercise and pregnancy
- Deteced by hypothalamus
- Release of TRH into the portal system -> ant. pituitary
- TRH binds to its receptor (G protein coupled)
on thyrotrope -> increase in Ca(2+) from IP3
- TSH release into the blood
- TSH acts on thyroid follicular cells
-> T3/4 synthesis and secretion
- T3
and
T4
- -
- -
- -
- T3
and
T4
- TSH acts on thyroid follicular cells
-> T3/4 synthesis and secretion
- TSH release into the blood
- TRH binds to its receptor (G protein coupled)
on thyrotrope -> increase in Ca(2+) from IP3
- Release of TRH into the portal system -> ant. pituitary
- Deteced by hypothalamus
- Stimuli: cold stress,
exercise and pregnancy
- Mechanism of TH action
- T3 uptake into TH-sensitive cell
- Via membrane carrier proteins
(Na/taurochloratecotransporter,
organic anion transporter and
L-amino acid transporters)
- Binds to TH nuclear receptor
- Multiple TH receptors (alpha and beta)
- Alpha-knockout =
bradychadia and
hypothermia (main
peripheral receptor)
- Beta-knockout =
deafness (important
for development)
- Alpha-knockout =
bradychadia and
hypothermia (main
peripheral receptor)
- Bind to TH response element (TRE)
- As a heterodimer with
retinoid-X receptor (RXR)
- Without ligand binding the dimer recruits a transcriptional corepressor
- HDAC complex
- HDAC complex
- Recruits transcriptional
coactivator upon ligand
(T3) binding
- As a heterodimer with
retinoid-X receptor (RXR)
- Multiple TH receptors (alpha and beta)
- Via membrane carrier proteins
(Na/taurochloratecotransporter,
organic anion transporter and
L-amino acid transporters)
- T3 uptake into TH-sensitive cell
- Modified dipeptitde (two
tyrosines) - requires iodine
- Thyroid disorders
- TH deficiency
(Hypothyroidism)
- Causes cretinism in children
- Short stature and slow development
- Short stature and slow development
- In adults
- Gradual onset: fatigue, lethargy, reduced
mental function, cold intolerance,
accumulation of mucopolysaccharides
(e.g. in the face = myxoedema)
- Fat deposition (e.g. Central,
slubclavicular and 'buffalo hump')
- Gradual onset: fatigue, lethargy, reduced
mental function, cold intolerance,
accumulation of mucopolysaccharides
(e.g. in the face = myxoedema)
- Causes
- Most common = iodine deficiency
- Particularly in less developed countries
- Can't synthesise THs
- Enlargement of the thyroid
to compensate (goitre)
- Enlargement of the thyroid
to compensate (goitre)
- Particularly in less developed countries
- Autoimmune
(Hashimoto's) thyroiditis
- Ab's against follicular cells
- Inflammation and destruction of
the thyroid (+/- goitre or nodules)
- Inflammation and destruction of
the thyroid (+/- goitre or nodules)
- Ab's against follicular cells
- Secondary hypothyroidism - TSH deficiency
- From disruption to the pituitary (tumour, trauma, radiation)
- From disruption to the pituitary (tumour, trauma, radiation)
- Most common = iodine deficiency
- Low T4, normal TSH
- Causes cretinism in children
- TH excess
(hyperthyroidism)
- Signs and symptoms
- Nervousness, irritability, sweating, heat intolerance, weight
loss, tachycardia, tremor, exophthalmos (bulging eyes)
- Nervousness, irritability, sweating, heat intolerance, weight
loss, tachycardia, tremor, exophthalmos (bulging eyes)
- Causes
- Grave's disease
- IgG interacts with TSH
receptor -> chronic stimulation
- Classically presents as; high T4, low
TSH and exophthalmos with goiter!
- Classically presents as; high T4, low
TSH and exophthalmos with goiter!
- Treatment; with carbamizole
(inhibitor of TPO)
- Or radioactive iodine and surgery (thyroidectomy)
- Or radioactive iodine and surgery (thyroidectomy)
- IgG interacts with TSH
receptor -> chronic stimulation
- Grave's disease
- Signs and symptoms
- TH deficiency
(Hypothyroidism)
- Non-TH producing cells
- Parafollicular (C-) cells
- Found inbetween follicles
- Produce calcitonin
- Lowers blood calcium (very little effect in humans)
- Inhibits; osteoclasts, Ca(2+)
absorption in the intestines and
renal Ca(2+) reabsorption
- Inhibits; osteoclasts, Ca(2+)
absorption in the intestines and
renal Ca(2+) reabsorption
- Lowers blood calcium (very little effect in humans)
- Produce calcitonin
- Found inbetween follicles
- Parathyroid gland
- Adipocytes
- Chief cells
- Produce parathyroid hormone
- Raises blood calcium
- Promotes; bone turnover (osteoclasts), intestinal Ca(2+)
absorption and renal Ca(2+) reabsorption [opposite to calcitonin]
- Promotes; bone turnover (osteoclasts), intestinal Ca(2+)
absorption and renal Ca(2+) reabsorption [opposite to calcitonin]
- Raises blood calcium
- Produce parathyroid hormone
- Oxyphil cells
- No endocrine activity
- No endocrine activity
- Adipocytes
- Parafollicular (C-) cells
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