ࡱ>  L4bjbj-- 48OOLpppppD$_"t!!!!!!!,#&!9p!pp"Npp!!rz Tz!Ю !/"0_" ;';'z!pz!$!!_";' 6:     Thyroid Physiology Thyroid Hormone Thyroxine - T4 made in thyroid, as 4 iodine groups, is a pro-hormone converted to T3 - biologically active thyroid hormone when one iodine is removed Direct thyroid secretion - only 20% of T4(T3 activation in thyroid Peripheral activation - 80% of T3 comes from T4(T3 activation in periphery 5-deiodinase - enzyme which converts T4(T3 Type 1 5-Deiodinase (D1) - primarily in liver & kidney, main supply for plasma T3 Type 2 5-Deiodinase (D2) - made in pituitary, brain, placenta, etc for local use Type 3 Deiodinase (D3) - removes inner ring I, converts T4(reverse T3, or T3(T2 Thyroid Gland Thyroid Follicle - the functional unit of the thyroid gland Epithelium - each follicle has layer of surrounding cuboidal epithelium Colloid - pools at center of each follicle, contains stored thyroid hormone Thyroid Hormone Synthesis: Iodide taken up into cuboidal epithelial cell from bloodstream thru Na-Iodide Symporter (NIS) Tyrosine is iodinated by thyroid peroxidase (TPO) to make mono and di-iodotryosines DIT/MIT molecules interact to make T4 (2 DIT) and T3 (1 DIT + 1 MIT) Thyroglobulin contains ~ 3 T4/T3s; only 1 out of 4 Tgs contain a T3 molecule; colloid is mostly Tg Thyroid Hormone Secretion: TSH from pituitary absorbed by thyroid, stimulates pseudopodia formation Pseudopodia endocytose colloid, digest contents (including Tg) Digested Tg has T4/T3 enzymatically cleaved from protein, released into circulation TSH Functions - stimulates iodide trapping (NIS), and thyroid hormone synth/excretion QUIZ: Structure - alpha subunit is common to TSH, FSH, LH, CG; beta subunit for each is different Receptor - TSH binds to G-protein coupled receptor in thyroid; ATP ( cAMP 2o messenger Clinical Analysis - can study actions of NIS in thyroid by giving radioactive iodine ( taken up in thyroid Thyroid Health Problems Dietary Iodide - intake of > 200 g/d ideal; less than 50 g/d impairs thyroid function ( TSH elevation Goiter - thyroid enlargement from elevated TSH; if >10% of population develops ( endemic goiter USA - by iodinating salt, we have virtually eradicated problem; but still troubling worldwide Cretinism - children born to mothers with endemic goiter Abnormal Development - have mental retardation, short stature, and hearing problems Problem worldwide - due to iodine deficiency Feedback Regulation of Thyroid Function TRH - thyroid releasing hormone from HT acts on pituitary to stimulate TSH synthesis and release TSH - stimulates iodide trapping (NIS), and thyroid hormone synth/excretion QUIZ: Structure - alpha subunit is common to TSH, FSH, LH, CG; beta subunit for each is different Receptor - TSH binds to G-protein coupled receptor in thyroid; ATP ( cAMP 2o messenger (phospholipase C may also be involved) Plasma Thyroid Hormone Thyroxine Binding Globulin (TBG) - binding protein for T4/T3 for plasma transport Other plasma proteins - transerythrin & albumin can also transport some T4/T3, but minor role Tg - thyroglobulin; dont confuse with TBG; Tg is precursor protein to make T4/T3 Total Thyroid Hormone - includes bound (99.9%) and free (0.1%) forms Active hormone - only the small amount of free T4/T3 Disease of Increased TBG ( causes increase in total T4/T3 to keep free form level constant Pregnancy - !TBG ( initially !T4/T3 ( feedback ( higher total secretion ( T4/T3 stabilized Hepatitis/Liver Failure - lose TBG (made here), opposite process occurs Molecular Thyroid Hormone Action Protein Receptor - T3/T4 binds to thyroid receptor (TR) proteins ( bind DNA, activate or inhibit transcription of many genes; unliganded receptors repress T3 activated genes and activate genes that are repressed by T3 Activation - proteins w/ various metabolic functions Inhibition - TRH, TSH inhibited as part of negative feedback Receptor Superfamily - TR part of a superfamily of receptors (similar to retinoids, Vit. D, steroids, etc) Dimerization - TR receptors can form heterodimers with retinoid X receptors (RXRs) Growth - T3 has some unknown regulation on growth hormone; thyroid deficient ( slowed growth Thyroid Hormone Labs Serum Thyroxine (T4) - measure free T4, not total; only free T4 has potential to be active Serum Triiodothyronine (T3) - measures free T3, but level is always constant ( not worth measuring Hyperthyroidism - has high free T4/T3 levels, but not necessarily total T4/T3 Low TSH - since there is a lot of T4/T3, feedback on TSH high ( low TSH Hypothyroidism - same idea, but opposite ( low T4/T3 ( no feedback, high TSH QUIZ: TSH Testing - the most sensitive test for thyroid function is TSH! 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