physiology of thyroid and the HPT axis Flashcards
HP-thyroid axis
hypothalamus (paravenricular nucleus) -> TRH release -> pituitary gland -> TSH release -> blood -> thyroid gland -> T3/T4 (aka thyroid hormone) release
how is T3/T4 transported through the body
bound to Thyroxine-binding globulins in the blood
role of thyroid hormone on bone
normal bone growth, turnover and mineralisation
role of thyroid hormone on muscle
normal muscular function and development
general role of thyroid hormone in all cells (6)
- increases basal metabolic rate
- increase O2 usage
- LDL uptake (i.e. removal of bad cholesterol from the blood)
- lipolysis
- glyolysis
- gluconeogenesis
what connects the two ‘wings’ of they thyroid gland
isthmus
how much does a normal thyroid gland weigh
15-20g
what is a large thyroid gland known as
a goitre -> may be associated with dysregulation of thyroid hormone biosynthesis
what is the pyramidal lobe of the thyroid
a normal anatomic variant representing a superior sliver of thyroid tissue arising from the thyroid isthmus - some people have a small part that sticks up
what is the thyroid gland made of (histologically)
follulcular cells surrounding colloid
what is the height of the follicular cells dependent on
activation by TSH
what is the colloid
the store of thyroid hormone in the thyroid gland - made of thyroglobulin
what are parafollicular cells and what do they do
they are cells cells situated between follicles that synthesize, store, and secrete calcitonin
what are the 2 prinicipal products of the thyroid gland
- thyroxine (T4)
- triiodo-L-thyronine (T3)
why is iodine key in diet
iodine is a key component to T3/4 formation -> the thyroid hormones are all based on the esterification of 2 tyrosine molecules which are then iodinated
T3 vs T4 iodine structure
T3 has 3 iodines per molecule;
T4 has 4 iodines per molecule
what is reverse T3
an isomer of T3 that is biologically inactive
which thyroid hormone is the most biologically active
T3
T4 is converted into T3 within cells
what is the major hormone produced by the thyroid gland
T4 - it is a store for T3
what is another name for thyroid hormone enzymes
deiodinases
what kind of proteins are deiodinases
selenoproteins -> active Se metal at the active site
what is the cofactor for the deiodinisation reaction (T4->T3)
glutathione
what are the 3 types of deiodinases and where are they expressed
- type 1 -> present in thyroid, liver, kidney;
- type 2 -> expressed everywhere;
- type 3 -> expressed in brain and placenta
which deiodinase is the major converter of T4->T3 in circulation
type 1 deiosinase
what drug is type 1 deiodinase sensitive to
propylthiouracil
examples of food that contain iodine
fish (cod, tuna etc.); seaweed; shrimp; dairy products; iodised salt
why is salt fortified with iodine in many countries
to stop iodine deficiencies which can lead to things like neonatal hypothyroidism
what does deiodinase 3 do
it inactivates T4 (by turning it into rT3) and T3 (by further metabolising it to 3,3’-diiodothyronine
how much iodine is needed to be ingested per day
150 micrograms, 200 in pregnancy
where is the majority of iodine excreted
in the urine (15% in stool)
how much iodine is used by the kidney
75 micrograms -> BUT 25 mcg is put back
what organs absorb iodine
placenta, mammary glands, colon, stomach
what are the 2 key receptors in the basolateral membrane of the thyroid follicular cell and what do they do
- N+/I- symporter -> allows iodine to enter the cell;
- TSH receptor -> TSH must bind in order for TH production to be stimulated
what cells produce TSH
thyrotrophs in the pit gland
what is the alpha subunit of TSH almost identical to
the alpha subunit of hCG, LH and FSH
what is the TSH alpha subunit thought to be responsible for
stimulation of adenylate cyclase -> needed for generation of cAMP
what determines the receptor specificity of TSH
the beta subunit -> this is unique to TSH
other than the thyroid gland, where else is are TSH receptors present and why is this clinically significant
orbital muscle cells -> can result in ophthalmological conditions like thyroid eye disease -> proptosis can occur
what kind of antibodies are seen in grave’s disease
thyroid stimulating antibodies
what kind of antibodies are seen in hashimoto’s disease
thyroid inhibiting antibodies -> less cAMP productions
what are the 6 steps of thyroid hormone biogenesis
- iodide uptake
- thyroglobulin synthesis
- hydrogen peroxide generation
- organification
- coupling
- uptake and breakdown of colloid
where is thyroglobulin secreted into after being make by follicular cells
the colloid space
what protein is essential in the secretion of iodine from the follicular cell into the colloid space
pendrin (see notes)
what do babies with congential pendrin absence present with (2)
- kidney tube dysfunction
- sensorineural hearing loss
apart from the thyroid, what other organ is pedrin present in
the kidneys
what occurs in the peroxidation step of T3/T4 synthesis (2)
- H2O2 is generated by DUOX2 (stimulated by IP3 and Ca2+)
- H2O2 reacts with iodine and prepares it for binding with the tryosyl residues
what is the organification step in T3/T4 synthesis
incorporation of iodine into thyroglobulin by Thyroid peroxidase (TPO) -> MIT/DIT residues formed
describe the coupling mechanism of T3/T4 synthesis
- 2 DIT molecules are brought together to form T4
- 1 MIT and 1 DIT are brought together to form T3
this is done by TPO -> stored in colloid
describe the uptake and breakdown of colloid in T3/T4 synthesis
- thyroglobulin with in situ T3 and T4 is taken up into follicular cells by endocytosis
- cathepsins in lysosomes breakdown thyroglobulin -> releases T3/T4
- T3/T4 pass out of the follicular cell via MCT8/10
- free MIT/DIT is diodinated by iodotyrosine dehalogenase which allows MIT/DIT to be stored
in biochemical analysis, what form or T3/T4 is measured
free T3/T4 (i.e. not protein bound)
what proteins bind to T3/T4 (when circulating in the blood -3)
- thyroid binding globulin 60-70% (more in pregnancy, hepatitis and chronic heroine use)
- transthyretin 10%
- albumin 20%
why are thyroid hormones bound to proteins when circulating (2)
- provides a pool of thyroid hormones
- increases the half life -> T4 for 8 days and T3 for 24hrs
where does the T4 -> T3 conversion usually occur
inside the target organ cells
what enzyme is responsible for T4 -> T3 conversion
3’/5’ monodeiodinase
how does T3 act to produce an effect on a cell
- enters the cell nucleus and binds to Thyroid Hormone Receptor (THR) and Retinoid X Receptor (RXR)
- these alter the transcription of certain genes (promoting or inhibiting)
- proteins promoting certain actions e.g. Na+/K+ pump, myosin heavy chains,respiratory enzymes etc. are produced
what are futile cycles
a set of biochemical reactions that concurrently run in opposite directions, consuming ATP in one of the directions e.g breaking down proteins but also building them upw
why do futile cycles occur
to expend energy and burn fat, and to increase O2 demands
how does increased fat mass result in thyroid hormone production
increased fat -> increased leptin -> stimulated HPT axis -> TH produced in an attempt to burn fat
other than T3/4 what other molecules can inhibit TSH secretion
- DA
- somatostatin
what is the direct T3/4 -ve feedback lool
- inhibition of TSH production (action of TRHR)
- inhibtion of TRH binding
what is the indirect -ve feedback loop of T3/4
reduced the sensitivity to TRHRs
when might low/normal T3 and T4 be seen but with a normal TSH
in illness
