Download The Thyroid Gland

The Thyroid Gland
The Thyroid Gland
Structure and development of the thyroid
What does the thyroid gland do?
Makes tri-iodothyronine (T3) and thyroxine (T4)
What do thyroid hormones do?
Important for normal development , control of
metabolic rate and thermogenesis
How is the thyroid gland controlled?
Thursday 17th February 2011
Hypothalamo-pituitary-thyroid axis. Failure of
control -hypothyroidism, hyperthyroidism
Helen Christian
Anatomy of the Thyroid
isthmus lies
anterior to
2nd-4
4th
tracheal rings
enclosed in
fascia which
anchors
thyroid to the
trachea
Unique feature of the thyroid is
requirement for iodine
1. Thyroid gland has unique structure.
2. T3 and T4 contain iodine. The only source of
iodide is dietary (veg, fish, salt).
3. The thyroid stores iodine within hormone
precursor ‘thyroglobulin’
p
y g
extracellularly.
y
profuse blood
supply and
venous
drainage
1
Cell arrangements in the thyroid
Thyroid structure
epithelial ‘follicular’ cells form follicles
the lumen is filled with ‘colloid’ – thyroglobulin precursor
colloid
T4 T3
calcitonin
Follicular cells make T4 and T3
Pendrin
I-
I-
Key structure-function features of
follicular cells
colloid
I2
TPO
Iodinated
thyroglobulin
endocytosis
T3 & T4
TPO=thyroid peroxidase
NIS=sodium iodide symporter
Electron microscopy
2
Regulation of T4 and T3 production
stimuli e.g.cold, stress
TRH neurons in the hypothalamus
Paraventricular
nucleus of
h
hypothalamus
h l
Hypothalamus
TRH
rostral
caudal
Anterior
pituitary
Inhibitory
feedback
TSH
Thyroid
T3 and T4
Target tissue effects:
• increase metabolism
• increase body
temperature
• normal growth and
development
TRβ2 knockout in mice ablates T3
negative feedback
ICC
for
TRH
T4 is metabolically inactive
inactive
Abel et al, 1999, 2001
Co-release
CART peptide
(function
unclear)
Glu-His-Pro
Type 3
Elevated basal TSH and no
inhibition of TSH by T3
TRH neurons
project to
external zone
of median
eminence
Type 1
active
The main thyroid product, T4, is not metabolically active.
T4 is converted to metabolically active T3 by Type 1
deiodinase in liver and kidney. Type 3 breaks down.
3
Thyroid Receptors (TR)
Types of deiodinase
Type 1 - provides T3 to plasma
(located liver, kidney)
Type 2 deiodinase
knockout mouse
Type 2 – provides intracellular
T3 (brain, pituitary, adipose)
Type 3 - inactivates T3 and T4
TR in the
nucleus bind
DNA and
activate
transcription,
timescale hours
Mice show cold intolerance
yet plasma T3 normal is –
local generation therefore
very important
RXR KO mouse shows RXR needed in
part for T3 repressor action
some TSH repression but not fully
Rapid ‘non-genomic’ actions of thyroid
hormones
Integrin binds T4 with
much higher
g
affinity
y
than T3 – the opposite
to nuclear receptors
Physiological effects:
Induction of
angiogenesis
B
Bone
resorption
ti
Brain development and
neuronal migration
Membrane ion pumps
Brown et al PNAS 2000
Davis et al 2008
4
What is the Basal Metabolic Rate
(BMR)?
Cellular reactions which make up BMR –
obligatory thermogenesis and T3
Sustain ventilation and circulation in minimal state,
maintain stable core body temperature
Increase ATP usage
• Protein turnover
• Ion movement across the plasma membrane, increases
production of Na+/K+ ATPase (which uses 20-45% of all
ATP)
p
• Turnover of nucleic acids and lipids
The minimum calorific requirement
needed to sustain life in a resting
individual
Therefore, the amount of energy
your body would burn if you slept
all day (24h)
A major component of total energy
expenditure whether resting or
working (60-75%)
Reduce efficiency of ATP synthesis
• Proton leak across mitochondrial inner membrane
(uncoupling)
• increases heat loss, which forces cells to burn more fuel
to maintain ATP levels for vital functions
BMR is significantly reduced in TR
knockout mice
Bile acid signalling – signal of food availability
that bridges nutrition with metabolism
Watanabe et al Nature 439 2006
Bile acids also enters circulation
Bile activates
deiodinase type 2
in brown fat
Marrif 2005
LCT= lowest critical temperature
Golozoubova et al, 2004
Bile secreted after meal to promote fat absorption
Oxygen
consumption
increases, effect
not seen in DIO2
KO mouse
5
Effects of T3 on nutrient metabolism
protein metabolism: stimulates protein
b
breakdown
kd
carbohydrate metabolism: potentiates
glycogenolysis, gluconeogenesis
lipid metabolism: stimulates cholesterol
breakdown and enhances lipolysis
Increase ATP consumption in ‘futile’ way to generate heat
Effects of T3
increases cardiac output, rate and
force
acts by increasing production of
myosin, β1 receptors, Ca2+ ATPase
'bounding pulse' in hyperthyroidism,
weak pulse in hypothyroidism
gastrointestinal tract: stimulates gut motility
increases skeletal muscle activity
potentiate beta-adrenergic sympathetic
effects in heart, adipose, skeletal muscle,
liver
Hypothyroidism
Plasma
measurements:
Low T4
High TSH
heart slowing
and slow
pulse
‘myxoedema’
Developmental effects of T3
apathy, tired
goitre
i
Normal metamorphosis
Thyroidectomised
muscle
weakness
Allen, Science 1916
weight gain
intolerance
of cold
cold hands
constipation
essential for postnatal growth of CNS
stimulates the production of myelin,
neurotransmitters, axonal growth
stimulates linear growth of bone
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Iodine deficiency
Prenatal thyroid
deficiency (cretinism)
poor neural development
stunted growth
muscle weakness
Iodine deficiency is the single most common cause of
preventable mental retardation and brain damage in the
world
treated by giving thyroid
hormone at birth
Globally, 2.2 billion people (38% of the world's population)
live in areas with iodine deficiency and its risks. Iodine
deficiency is common in desert and mountain regions.
In areas of endemic iodine deficiency food fortification is
highly successful and cheap
Iodine deficiency causes thyroid growth
Hypothalamus
TRH
Anterior
pituitary
TSH
Thyroid
Deficiency of iodine in diet causes
increased secretion of TRH and TSH
because of lack of T3/T4 feedback
Lack iodine, lack T3/T4
Hypothyroidism
Possible causes
failure of production by thyroid
thyroid, lack of iodine,
iodine
autoimmune inhibition
failure of thyroid development
failure of pituitary to produce TSH or
hypothalamus TRH
thyroid hormone resistance – inactivating
mutation of thyroid hormone receptor
failure of thyroid hormone transporters
increased thyroid
growth= goitre
7
Thyroid hormone transporters
Patients identified 2001
• absent speech, never walked, seizures, muscle
h
hypoplasia,
l i severe cognitive
iti impairment,
i
i
t unable
bl
to sit or stand unaided
• T3 high, but T4 low
2003: MCT8 identified as specific T3 transporter
•
•
•
•
MCT8 expression CNS
2005
Neuronal
localisation of
MCT8 in brain
regions critically
involved in motor
control and mental
development and
hypothalamus PVN
BUT
MCT8 KO mouse
does not show
Severe motor deficit seen in
humans
A member of the MCT family, TAT1, shown to
p
aromatic amino-acids but not T4
transport
MCT8 highly homologous to TAT1 but function
unknown
Friesema cloned MCT8 and tested for thyroid
hormone transport in Xenopus oocytes
MCT8 found to be high affinity transporter of T3>T4
Hyperthyroidism – ‘thyrotoxicosis’
restless, anxiety
eye problems
goitre
tachycardia
and rapid
pulse
lose weight
despite
normal
appetite
intolerance
of heat
hot hands
Plasma
as a
measurements:
High T4, T3
Low TSH
Graves’
disease most
common cause
i UK
in
diarrhoea
hand
tremor
8
Graves disease
Autoimmune antibodies to TSH receptor bind
and activate TSH receptor
Thyroid hormones and treatment of obesity
Overactivity of the TSH R stimulates enlargement
of thyroid gland. T4/T3 production very high
Normal
Thyroid cancers
Different types
Thyroid hormones have a long history in
the treatment of obesity
However, no longer used due to side
effects:
Increased heart weight
Tachycardia, atrial arrhythmias
Thyroid atrophy
Loss of lean body mass
Bone loss
Graves
Chernobyl and Thyroid
cancer
April 26th 1986
Tumour tissue may
comprise functional
follicles that secrete
T3/T4, ‘follicular
cancer’
Tumours can also
be ‘non-functioning’
Increased incidence thyroid cancer from 1 to
50 children per million per year in Belarus
9
Drugs affecting the Thyroid
The Thyroid Gland: key points
Structure and development of the thyroid
Thyroxine (T4) for hypothyroidism
Carbimazole prevents the thyroid
peroxidase enzyme from coupling and
iodinating the tyrosine residues on
thyroglobulin, for hyperthyroidism
Radioactive iodine can be given to
destroy thyroid tissue by local
irradiation
unique follicle structure with large
extracellular store of hormone precursor
How are thyroid hormones produced?
iodination of thyroglobulin and hydrolysis
Thyroid hormone actions
affect metabolism of virtually all cells
Disorders of thyroid function
common, hyper- and hypothyroidism
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