Transcript Synthesis of thyroid hormones

Endo 1.08
The thyroid gland
• Gross anatomy and histology of the
thyroid gland
• Thyroid hormone synthesis
• Thyroid hormone secretion, peripheral
conversion and metabolism
• Measurement of free T4 and TSH
• Actions of thyroid hormones, hyperand hypothyroidism
20 grams
4 cm
Blood supply
Superior and inferior thyroid arteries from external
carotids and subclavian arteries respectively
Superior, middle and inferior thyroid veins
More blood per unit weight than kidney - goitre
bruit
Histology of the
thyroid gland
Thyroid hormones derived from two iodinated
tyrosine molecules
Synthesis of thyroid hormones
• Active uptake of iodide into follicular cell
• Iodide iodine - H2O 2 (catalysed by
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TPO)
Active uptake of iodine at follicular/
colloid interface
Incorporation of iodine onto tyrosine
residues of thyroglobulin
Coupling of iodinated tyrosines
Storeage of T3 and T4
Active transport of iodine (ATPase dependent) against
electrical and chemical gradient - concentration of
iodine 30-50 times that of the circulation
• Active uptake of
iodine by a sodium
iodide symporter
• Oxidation of iodide to
iodine
• Iodination of tyrosine
residues at
apical/colloid interface
to form MIT and DIT
• Uptake of
thyroglobulin into the
lumen of the follicle
Incorporation of iodine onto tyrosine residues
on the thyroglobulin molecule
4) Release of T4 and T3 into
circulation 100g T4 & 10g T3/day
3) ~ 10% T4 undergoes monodeiodination to T3 before secretion
2) Fusion of colloid droplets with
lysosomes --> hydrolysis and
release of thyroid hormones
1) Stimulated by TSH colloid
droplets with the bound thyroid
hormones are taken back into
follicular cells by pinocytosis
Daily production
of thyroid
hormone
secretion and
serum
concentrations
5’
Thyroid hormone
metabolism
5
5’
5
3’
3
Metabolism of thyroid hormones
Series of deiodinations by deiodinases
Type 1 - liver, kidney, thyroid, pituitary gland,
CNS: 5’ and 5 positions
Type 2 - brain, brown fat, placenta, pituitary
gland: 5’ position only: T4
T3 only:
intracellular concentrations of T3
Type 3 - brain, placenta: 5 position only
T4
T3
Other metabolic pathways: sulphation,
decarboxylation, conjugated with
glucuronide
Thyroxine (T4)
1&2
other
pathways
1&3
T3 S
T3
3,5,3’
rT3
3,5’,3’
TRIAC
T2
T2
Type 1 - 5’ and 5
Type 2 - 5’ only
T1
T1
thyronine
Type 3 - 5 only
Control of thyroid
hormone synthesis
and release and
feedback control
TSH Receptors
TSH
G protein linked receptor
cAMP
IP3 + DAG
Protein Ca2+ Protein
Kinase A CM Kinase C
(high concentrations)
Actions of TSH
• Active uptake of iodine*
• Stimulates other
reactions involved in
thyroid hormone
synthesis
• Stimulates the uptake of
colloid
• Induces growth of the
thyroid gland
Thyroid hormone receptors
Thyroid hormone receptors
• Type 2 receptors in nucleus - high affinity
for T3
• Dimerize with another T3 receptor
(homodimer) or retinoic acid receptor
(heterodimer)
• Dimerized receptor + other transcription
factors
gene transcription
• Membrane receptors? Ion movements
Isoforms of the thyroid hormone receptor
DBD
DBD
DBD
DBD
Dimerization of thyroid hormone receptors and
gene activation/inactivation
T3
Functions of thyroid hormones
 Stimulate metabolic rate: increasing number and
size of mitochondria, increasing enzymes in the
metabolic chain, increasing Na+/K+ ATPase activity.
Resting metabolic rate may increase 100% with
excess thyroid hormones or decrease by 50% with a
deficiency
 Positive inotropic and chronotropic effects on the
heart
 Important in growth and development particularly skeleton and nervous system
Feedback
control of
thyroid
hormone
synthesis and
secretion
Radioisotopic (technetium) scanning of the
thyroid gland - regional function of the gland
No left lobe
hyperthyroidism
hypothyroidism
Hot nodule
Cold nodule
Measuring ‘free’ T4
Phosphate
1) Add serum sample or
standard (T4 ) to latex
beads coated with Abs
2) Add T4 labelled with
alkaline phosphatase.
This will bind to any
unoccupied Ab binding
sites
3) Add a substrate that
will fluoresce when the
alkaline phosphatase
removes a phosphate
group
4) Fluorescent
intensity will be
inversely proportional
to the concentration of
T4
Assay of antibodies to the human TSH
receptors
Patients serum Add
Precipitate Count
125I-TSH
+ TSH
receptors
(bovine)
(porcine)
Circulating concentrations of TSH and pituitary
function test in normal and primary hyperthyroidism
Saggital MR scans of a) normal and b) a patient with a
craniopharyngioma causing bitemporal hemianopia and
hypopituitarism
Primary hyperthyroidism
Hypothyroidism
Grave’s disease (10)
• Autoimmune - activating AB’s to TSH
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receptor
High concentrations of circulating
thyroid hormones, low TSH
Weight loss, tachycardia, tiredness
Diffuse goitre - TSH stimulating
growth
Opthalmompathy and dermopathy
Symptoms and signs of hyperthyroidism
Hashimoto’s (1o)
• Autoimmune - AB’s destruction of
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thyroid gland
Low concentrations of thyroid hormones,
high TSH
Lethargy, intolerance to cold
Lack of growth and development
Diffuse goitre - lymphocytic infiltration
of gland + TSH stimulated growth
Symptoms and signs of hypothyroidism