Hypothalamic Thyroid Axis Flashcards
how does TRH binding cause TSH binding
TRH binds Gq. Gq –>PKC–>IP3 binds to SR to release Ca
DAG –>PKC–>P proteins make TSHalpha,beta mRNA–>TSHa,b–>TSH released to blood
what occurs with TSH binding
binds to dimeric glycoprotein alpha and beta, causes increase in Ca, Phosphoinositide, and cAMP.
what growth is increased by increased Ca, phosphoinositide, cAMP with TSH
increased thyroid: DNA, RNA, protein and phospholipids
increased thyroid: cell size, number, and follicle formation
what is increased with increased Ca, PI, cAMP with TSH?
increased: trapping I, iodination, coupling, endocytosis of colloid, proteolysis of thyroglobulin
increased: glucose oxidation, NADPH generation
for synthesis of thyroid hormone T3 and T4
what thyroid hormone is active in target tissues
T3 but T4 has longer half life
when is TSH released
in response to stress, and is sensitive to T3 and T4 levels
what is thyroglobulin
precursor to MIT and DIT
what allows iodine to enter the cell from the blood
Na/I symporters.
what allows iodine to leave the cell to enter the follicle colloid
pendrin channel
what occurs once the iodine is in the follicle
it is oxidized and conjugated onto thyroglobulin by TPO (thyroid peroxidase)
MIT and DIT or 2 DITs added to thyroglobulin
what is DIT
and MIT
diiodotyrosine and monoiodotyrosine
what occurs once iodine is conjugated
thyroglobulin with MIT and DIT are endocytosed into the thyroid follicular cell. proteolysis clips the thyrosine and thriiodothyronine off the thyroglobulin and THYRG and unused MIT and DIT are recycled
how are T3 and T4 released into the blood
Monocarboxylate transporter 8
what is tyrosine a precursor for
dopamine, NE, epinephrine, thyroid hormones
how do thyroid hormones circulate
most are bound (0.23% and 0.025% are free)
similarities of thyroid hormones
- synthesized by enzymatic pathway
- require thyroglobulin, tyrosine, inorganic iodine
- lipid soluble so have intracellular receptor
what are thyroid hormones bound to
- thyroid binding globulin (TBG)
- thyroid hormone binding pre-albumin
- albumin
how are the thyroid hormones eliminated
conjugated glucuronic acid or sulfate for elimination via liver and kidney – into urine
does thyroglobulin circulate
yes, but is only active in the thyroid follicle
what is useful to detect differentiated thyroid tumors?
thyroglobulin Ab because is produced in follicular cells
3 steps of thyroid hormone production
iodine dependent
- uptake
- incorporation
- coupling
how much iodine is used for thyroid hormones or other tissues
the majority is excreted right away into the urine.
most that is actually used is by other tissues.
only 13% is actually used for thyroid hormones.
describe iodine uptake
I2 eaten–>GI tract–>reduction (intestinal absorption–>inorganic iodine–>blood–>ACTIVE TRANSPORT BY THYROID NA/I SYMPORTER–>into the follicle via pendrin receptor–>into the colloid—>oxidation in the colloid
where is iodine incorporated on the thyroglobulin
on tyrosine residues ON the thyroglobulin
what is iodine coupling?
when MIT and DIT are coupled together by thyroid peroxidase enzyme
2DIT or 1 MIT and 1 DIT
what is reverse T3?
when the iodine is clipped off of the 5 carbon instead of the 5’ carbon (5-deiodinase)
is not active, and is usually produced elsewhere
how are T3 and T4 released
deiodinase clips T3 and T4 off TG
what enzyme assists with coupling
thyroid peroxidase
what stimulates thyroid hormones
- TSH
- thyroid stimulating immunoglobulins
- increased thyroglobulin levels (in pregnancy)
what inhibits thyroid hormones
- iodine deficiency
- deiodinase deficiency (not recycled)
- excessive I intake (suppresses thyroid) (wolff chaikoff effect)
- perchlorate;thiocyanate (inhibit Na/I symport)
- propylthiouracil (inhibits peroxidase)
- decreased TBG levels (liver disease)
- circulating T3 T4
what foods are rich in iodine
anything that is grown in salt water like seaweed, scallops, cod
how is T4 made to T3
5’ iodinase clips an iodine and makes it T3
what effects does T3 have on CNS
maturation
effects of T3 on growth
bone maturation, growth formation
effects of T3 on BMR
- increased Na/K ATPase
- increased oxygen consumption
- increased heat production
- increased BMR
effects of T3 on metabolism
- increased glucose absorption
- increased glycogenolysis
- increased gluconeogenesis
- increased lipolysis
- increased protein synthesis and degradation (net is catabolic)
effects of T3 on CV
increased CO
what occurs once T3 binds to the intranuclear receptor
the corepressor is removed and a coactivator is added, then transcription can occur
blood response to thyroid hormones
- increases glucose (gluconeo, glycogenolysis)
- increases FFA (increased lipolysis)
- decreased free AA (growth, protein synthesis)
what occurs to AA if hypothyroid?
increased free AA (because net is catabolism, increased levels in blood)
other T3/T4 functions
- growth and development (insulin, GH, IGF)
- nervous system
- hair follicles
- teeth eruption
- vitamin A production
- neurotransmitters maybe
what is goiter
can be caused by hyperthyroidism, iodine deficiency, increased TSH, or thyroid hypertrophy
what is graves disease
Ab against TSH receptors, so TSH just keeps getting released. causes high BMR and exopthalmos d/t glycosaminoglycans by TSHr positive fibroblasts.
increased ventilation, sweating, appetite, weight loss, tachycardia, increased CO, tremors, restlessness, nervousness
what can cause hyperthryoidism
- goiter
- graves disease
- toxic goiter
- thyroid cell tumors
what is toxic goiter?
acute excess of T3/T4 without stimulation from TSH due to possible toxins like thiocyanate
what does thiocyanate do
decreases iodide transport via Na/I symporter into the follicle
(may have enough, but not enough in usable form)
what can cause hypothyroidism?
- diffuse goiter
- hashimotos thyroiditis
- iodine deficiency (leads to thyroid cell destruction)
- neonate cretinism
- adult myxedema
what causes hashimotos
Ab against thyroid peroxidase enzyme and thyroglobulin, so no T3 or T4 is made.
symptoms of cretininsm
mental/physical development is slow, secondary sex characteristics don’t develop. low body temp, poor teeth, leathery/thick skin, decreased muscle tone, low BP, HR and BMR
symptoms of myxedema
mental ability is suppressed, personality changes, lethargy, obese, dry skin, hair falls out, low BP, low HR, low BMR
sx of hashimotos
lethargy, weight gain, cold intolerance, constipated, depression, bradycardia, emotional stress, irregular menstruation, memory problems
what occurs in cretinism
decreased long bone growth and the epiphyseal plate doesn’t complete
obese and puffy face
what lab findings in myxedema?
hypoglycemia, hyponatremia, hypoxemia, hypercapnea, prolonged QT and low voltage, pericardial effusion
what is seen in both hyper and hypothyroidism
goiter!
how to treat hyperthyroidism
thyroidectomy or radioactive iodine (destroys thyroid)
what is secondary hypothyroidism?
an issue with the hypothalamo-pituitary axis (no TSH) or end organ resistance (target organs don’t have thyroid receptors)
what is primary hypothyroidism
issue with thyroid itself not releasing T3, T4. will have increased TSH.
cretinism or myxedema
what is secondary hyperthyroidism
Ab to TSH receptor cause no negative feedback, or TSH is released from somewhere in the body to produce T3,T4 (negative feedback from hypothalamus doesn’t matter)
what is primary hyperthyroidism
an adenoma or carcinoma is causing the thyroid itself to release T3/T4
