thyroid physiology Flashcards
thyroid is located
wraps around the trachea larger in females increases in size with pregnancy two large lateral lobes connected by a thin isthmus contains 4x parathyroid glands receives very high blood flow abundant nerve supply
thyroid gland structure
follicles - hollow vissicles
THs are synthesised in epithelial cells lining the follicle
follicle interior is filled with
thyroglobulin (glycoprotein)
each follicle is surrounded by
dense capillary network
thyroid hormones are derived from
tyrosine amino acid
2 thyroid hormones
thyroxine - T4
triiodothyronine - T3
thyroxine
major secretory product
low biological activity
usually transformed to T3 within target cells
need for iodine to produce thyroid hormone
thyroid hormones need large amounts of iodoine
- low levels are absorbed int the body and absorbed as iodide and need to be oxidised to iodine (thyroid peroxidase)
iodide oxidation to iodine
by thyroid peroxidase
how does the thyroid gland concentrate iodine
powerful iodide pumps
thyroglobulin precursor TGB
large protein
has lots of tyrosine residues
stores thyroid hormones as a colloid (holds 4 or 5 hormone molecules)
thyroglobulin precursor molecule is made in
follicular cells and exocytosed into the follicle lumen
steps in thyroid hormone production
- iodide trapping
- synthesis of thyroglobulin
- oxidation of iodide and iodination of tyrosine residues
- coupling of tyrosine residues
- endocytosis and digestion of colloid
iodide trapping
sodium iodide symporter
pumps 2x Na and 1x I- from plasma into the follicle cells
concentration of iodide in the follicle is 30x plasma concentration
synthesis of TGB
made on rough endoplasmic reticulum
exocytosed into the colloid where it waits for iodine
pendrin
passive transporter
iodide transported into the follicular lumen where thyroid peroxidase can oxidise the iodide
once the iodide is oxidised
once it is oxidise it can be added to the tyrosine residues present on the thyroglobulin
iodination of tyrosine molecules forms
DIT - diiodotyrosine
MIT - monoiodotyrosine
coupling of tyrosine
forms either T4 or T3
mature hormone is still attached to TGB storage molecules in the follicle lumen
DIT + DIT = T4
MIT + DIT = T3
iodine availability
TGB allows storage of large amounts of Th precursor so the body becomes independent on day to day iodine availability
secretion of thyroid hormone
when stimulated thyroglobulin is exocytossed
endocytotic vesicles fuse with lysosomes
proteases release T3 and T4 released from TGB storage molecule
thyroid hormones migrate to the basal membrane
actively transported into the circulation via monocarboxylate transporter8
thyroid hormones are transported into the circulation by
monocarboxylate transporter 8
thyroid hormone is mosty released as
T4
dominant plasma proteins binding thyroid hormones
TBG = thyroid binding globulin (main one)
transthyretin
albumin
needs to be unbound to work
to work, thyroid hormone must be
unbound
T3 half life
much shorter half life than T4
3.5 days
T4 half life
6.5 days - longer
thyroid hormones enter cells via
iodothyronine transporters
organic anion transporters
(passive, but probably involved ion exchange) OR monocarboxylate transporter (active transport - powerful scavenging)
TH receptors
10x more affinity for T3
are ubiquitous
T4 conversion to T3
deiodinase enzymes convert T4 to T3
thyroid hormone functon
thyroid hormones bind intracellular nuclear receptors, and act to regulate the activity of specific genes
control of thyroid function
hypothalamus releases thyrotropin releasing hormone TRH
acts on anterior pituitary to release thyroid stimulating hormone TSH
acts on the thyroid gland to release thyroid hormone T3 and T4
hypothalamus stops anterior pituitary production of TRH with
somatostatin
stimuli to increase thyroid function axis
cold
thyrotropin releasing hormone stimulates production of
thyroid stimulating hormone / thyrotropin / TSH
TSH binds
TSHR to increase cAMP
TSHR
TSH receptor
increases cAMP
increases thyroid activity in 3 ways
- increases hormone synthesis (increases activity of sodium iodide symporter pump and thyroglobulin production)
- increases thyroid hormone secretion (vesicular reuptake and active transport)
- increases blood flow to the thyroid
TH is main determinant of
basal metabolic rate
- influences synthesis and degradation of CHOs, fats, and proteins
- increases the sensitivity to sympathetic NS signal (increases receptors and receptor signal)
why doesn’t ATP production cause negative feedback
- (burn it off) ion gradients are expensive
TH increases the activity of pumps involved in Na/K across the plasma membrane and Ca2+ gradients between cytoplasm - uncouple ADP phosphorylation in mitochondria - TH induces uncoupling protein expression which means protons are pumped but leak back out, burning fuel but not creating ATP
both these processes produce lots of heat
CHO metabolism
T3 accelerates CHO utilisation by
- increasing glucose absorption by the GIT
- increasing glucose oxidation in liver, fat and muscle cells
- amplifies signals from other signalling hormones (e.g. insulin)
T3 acts by increasing the synthesis of specific metabolic enzymes
TH effects on lipid metabolism
optimal TH levels determine rates of lipolysis and lipogenesis in the liver
stimulates mobilisation from fat cells (increase n free fatty acids and decrease in plasma TG and cholesterol)
TH effects on nitrogen metabolism
rate of protein synthesis and degradation is Th-dependant
Th effect on temperature
- energy utilisation
- TH increases BAT theromegenesis
- THs also act indirectly by stimulating the sympathetic nervous system to mobilise Cho and fat needed to fuel the shivering response and increase circulation to skeletal muscle and adjust blood flow to skin
Th effect on cardiovascularr regulation
increase tissue blood flow
increase cardiac output (increase heart rate and contractility
Th effects on skeletal system
T3 acts synergistically with growth hormone, IGF and other growth factors to signal increased bone formation
bone maturation ie. closing of epiphysis (cartilaginous growth plates of bones)
TH effects of CNS
Th is essential for normal brain development
primary hypothyroidism
hashimotos disease
- lack of energy, problem with fatty acid mobilisation causing increase in body weight
- decreased sensory capacity, impaired memory and psychosis may occur
- poor tolerance of cold
- oedema due to accumulation of water-retaining hyaluronic acid and condition sulphate
TH deficiency in children
- short stature, bone retardation, malformed facial bone structure
- severe, irreversible mental and physical retardation (cretinism)
treatment for goitre
thyroxine tablets
most common cause of hypothyroidism
decreased dietary iodine
deiodinase deficiency
cells can’t convert T4 to T3
hypothyroidism
goitre because negative feedback loop isn’t triggered
severe selenium deificiency
deiodinases are selenoproteins - same as deiodinase deficiency
allan-herndon-dudley syndrome
MCT8 mutations - cells can’t actively take up TH
- particularly effects CNS - moderate to severe intellectual impairment, plus aphasia and ataxia
- highly limited IQ, patients may never talk or walk, may need feeding tube
hyperthyroidism
Graves’ disease
elevated metabolic rate and heat production - poor heat tolerance
increase protein degradation, severe catabolism of muscle, increase fatty acid mobilisation
exaggerated autonomic responses
goitre, high bone age, exophthalmos - oedematous fluid retention behind the eyes
autoimmune hyperthyroidism
production of thyroid stimulating immunoglobulins that bind to the TSH receptor and activate increase in TH
thyroid tumours
TH-secreting tumours are most common
treated with antithyroid drugs to decrease TH production by blocking coupling of iodine
or beta blockers
or radioiodine which concentrated in the thyroid and kill of thyroid cells
