Thyroid 1-Phys Lec 4

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TSH

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stimulates iodine uptake, stimulates thyroid peroxidase which is responsible for the iodination and coupling of the tyrosyl residues on thyroglobulin. Principal product of the thyroid gland is T4 which acts a prohormone and is converted peripherally to t3. Thyroid hormones are tightly bound in plasma and therefore have long half lives.

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thyroid had C cells and follicular cells

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C cells - calcitonin
follicular- t3 and t4

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bllod flow

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blood flow per gram is twice that of kidney. IN goiter can be 1liter/ min. detectable as bruit in goiter.

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structure

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consists of a ring of epithelial cell surrounding a colloid of thryoglobulin which is where thryoid horomones are stored.

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Hormone structure

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two iodinated tyrosine residues that are connected by an ester linkage, T3 active, t4 and reverse t3 inactive. t4 is 90%.

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iodine trap

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iodine taken up by the follicular cells on basal side. regulated by tsh. Na-I cotransport. thyocyanate and perchlorate ions are inhibitors of the trap. Can be up to 30 times more than serum and extrme at 400. T/s ratio normally 30.

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Thyroglobulin synthesis

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Thyroglobulin is synthesized on the rough ER, glycosylated, and packaged into vesicles and extruded into the lumen of the follicle. During the process of extrusion, tyrosyl residues on thyroglobulin are idodinated and coupled to form the thyroid hormones.

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Step process of hormone formation

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1. trapping, 2. oxidation, 3. exocytosis, 4. iodination of TGB, 5. coupling of iodotyrosines 6. endocytosis of TGB, 8) release of t4 and t4, 9) deiodination of MIT and DIT, recycling of iodine

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Thyroid peroxidase

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uses H202 as an oxidizing agent to oxidize iodide to an active intermediate. This enzyme also catalyzes the iodination of tyrosyl residues on thryoglobulin. It is also catalyzed by thyroid peroxidase. this process is referred to as organification.

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Products of thyroid peroxidase

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MIT, and DIT are biologically inactive. The third step catalyzed by TP is the coupling reaction in which two DITs are coupled eventually forming T4 or DIT and MIT forming T3. Coupling occurs when DIT and MIT are part of thyroglobulin. Alanine also incorporated.

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Endocytosis and release

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TSH causes colloid droplets to be taken into cell
-psuedopods engulf colloid
-once in cell droplets fuse with lysozomes that have proteases that degrade thyroglobulin
-horomones are released from the cell and iodine from hormones later on are recycled by thyroid deiodinase

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Plasma Half lives

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thyroid hormones long lived:
t3 one day
t4 one week

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relarive biological activity

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t3 is 3-5 times more potent and t4 is a prohormone

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Compunds altering iodine uptake

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these have greater affinity for Na-I cotransport or trap. Cassava (thiocynate)

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Compounds inhibiting thyroid peroxidase

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class of drugs include the thioureas like PTU which inhibts the peripheral conversion of t4 to t3. Methimazole-blocks peroxidase but not peripheral conversion of t4 to t3

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Wolff Chaikoff effect

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iodine defecicney and excess inhibt thyroid synthesis. excess lessens response of follicle to TSH.

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Plasma Binding Proteins (thyroid)

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1) thyroxine binding protein-high affinity low abundance
2) thyroxine binding prealbumin---intermedite affinnity- abundant
3) albumin-low affinity , most abundant

99% of t3 bound, 99.9 of t4 bound,
free hormone in equilibrium
t3 mostly to albumin and TBG
t4 longer half life-TBG TBPA

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Factors affecting binding

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estrogen increases TBG production,
androgens, glucocorticoids, and liver disease decrease globulin production by the liver. TBG measured by T3 resin uptake which measure binding of radioactive T3 to a synthetic resin in an assay system that contains a sample o serum. despite TBG up can still be euthyroid.

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estrogens and glucs, adnd adrogens

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just affect serum levels or equilibrium. high binding protein then high serum levels and vice versa. Usually euthyroid. TSH low if plasma levels high.

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Hormone metabolism of thyroid horomones

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most T3 is formed peripherlly by a deiodinase; outer ring deiodinase or 5' deiodinase. Sharp increase in enzyme activity following birth.

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inner ring deiodinase or 5 monodeiodinase

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converts t4 to rT3 inactive

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production of rT3

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increases with increasing age

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mechanism of action

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thyroid hormones binf to thyroid espons elements of target genes by either diffusion or carrier mediated transport. Thyroid receptor forms a heterodimer with RXR. In absence of hormone bind to RXR1, in absence of hormone recruit repressors. when hormone is bound repressors removed and coactivators bind.

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mechanism of action continued.

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more affinty for t3(10 times). target tissue has 5'-deiodinase.

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thyroid receptor

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there is more than one form of thyroid receptor. two different genes make the receptor and each has a splice variant. Both forms are widely distributed in the tissues. One from in cardiac and muslce and another brain liver kidney. negative feedback through brain variant in pituitary and hypothalamus. All tissues respond but Spleen testes brain and pituitary do not increase oxygen consumption.