Slide 1The ThyroidThyroid glandThyroid hormones are made from iodine and tyrosineStep 1: thyroglobulin synthesisStep 2: Active transport of iodine from the bloodStep 3: Iodine conjugation to thyroglobulinStep 4: Colloid formationStep 5: Colloid  T4 & T3T4 critical to thyroid buffering system#1: T4/T3 binding proteins buffer serum concentration#2: Conversion of T4T3Signaling: T3 activates thyroid nuclear receptorThyroid hormone metabolismThyroid hormone functionSystemic effects of thyroid hormoneMetabolic effects are futileMetabolic effects are futileGeneral BMR increaseRegulation through HPATRH & TSH increase thyroid hormone synthesisHPA feedback controlPathophysiology: hypothyroidismIodine deficiency results is goiterPathophysiology: hyperthyroidismGraves disease: autoantibodiesTriumph of science-based medicineHormonesNotesNotes (cont)Review questionsPGY452/552: Endocrine physiology10.Thyroid hormoneA. SynthesisB. Buffering & metabolismC. Effects D. HPA regulation & feedbackE. PathophysiologyThe ThyroidFirst recognized gland & hormoneAmide hormoneMany similarities to steroidsEssential in childhood for normal growth & developmentAdults: normal metabolismKnown for pathophysiology2Thyroid gland3Follicles: follicular cells +follicular lumenFollicles: follicular cells +follicular lumenC cell(calcitonin)C cell(calcitonin)Follicular cellsFollicular cellsCapsuleCapsuleCapillaryCapillaryFollicular lumenFollicular lumenThyroid hormones are made from iodine and tyrosineT3 & T4 collectively known as “thyroid hormone”Unique biosynthetic pathwayDepends on thyroid anatomyOnly biological role for iodineFive Steps to synthesis4Tyrosine Y or TyrDIT di-iodothyronineMIT monoiodo-thyronineT3 (tri-iodothyronine)T4 (thyroxine)Follicular cell Follicular LumenECFStep 1: thyroglobulin synthesis5OHCH2CHNCOCRCONRCHHFollicular cells synthesize thyroglobulin – 5496 amino acid protein Follicular cells synthesize thyroglobulin – 5496 amino acid protein thyroglobulin has 140 tyrosines  substrate for iodinationthyroglobulin has 140 tyrosines  substrate for iodinationTransported to lumen via exocytosisTransported to lumen via exocytosisPol IIFollicular cell Follicular LumenECFStep 2: Active transport of iodine from the blood62·K+2·Na+I−3·Na+ATPATPI−I−Na/I cotransporter follicular cellNa/I cotransporter follicular cellNa/K-ATPase provides energyNa/K-ATPase provides energyIodine  lumen down concentration gradient through “Pendrin”Iodine  lumen down concentration gradient through “Pendrin”Iodine uptake: 80 μg/dayCapacity ~8 mgIodine uptake: 80 μg/dayCapacity ~8 mgPendrin (Na⁺-independent Cl−/I− transporter)Pendrin (Na⁺-independent Cl−/I− transporter)ADPStep 3: Iodine conjugation to thyroglobulin7OHCH2CHNCOCCOHOHCH2IIIOHCH2CHNCOCCOHOHCH2I−I 0ThyroglobulinThyroglobulin90% DIT90% DITThyroid peroxidase complexThyroid peroxidase complexH2O2Follicular cellFollicular Lumen“Organification”“Organification”Organification required for “Iodine Trap” High [iodine] leaving lumenOrganification required for “Iodine Trap” High [iodine] leaving lumenStep 4: Colloid formation8IIOHCH2CHNCOHSpontaneous rearrangementSpontaneous rearrangementFollicular LumenIodinated Thyroglobulin = ColloidIodinated Thyroglobulin = ColloidBetweenBetweenIIOHCH2CHNCOHIIOCH2CHNCOHOHIICH2CHNCOHWithinWithinWithinWithinColloid is the major source of stored thyroid hormone  Usually several weeks supplyColloid is the major source of stored thyroid hormone  Usually several weeks supplyFollicular cell Follicular LumenECFStep 5: Colloid  T4 & T39I−Endocytosis into follicular cellsEndocytosis into follicular cellsColloid digested by proteases to give T3 & T4Colloid digested by proteases to give T3 & T4Iodine scavenged by thyroid deiodinase & transported to lumen through Pendrin Iodine scavenged by thyroid deiodinase & transported to lumen through Pendrin T3 & T4 pass through a transporter to ECFT3 & T4 pass through a transporter to ECFDITDITMITMIT90%10%T4 critical to thyroid buffering systemThyroid gland makes >90% T4Half-lives (t1/2)●~24 hr for T3●8 days for T4BUT T3 activity >15x T4AND the available T3 concentration is much higherFree T3 ~⅓ of total free thyroid hormoneHow?1. Affinity for thyroxin binding globulin2. Conversion of T4T310OHOI II IT4OHOII IT3#1: T4/T3 binding proteins buffer serum concentrationThyroxin binding globulinMajor thyroxin binding proteinGlycoprotein (54 kD)Made in liverBinds one T4 or T325x higher affinity for T4Increases [T3]free 11T3 T410% Made 90%99.50% Bound 99.98%0.50% Free 0.02%1 Ratio free 0.36TBGTBGTBGTBGTarget#2: Conversion of T4T312Liver (kidney)TH 5ʹ/3ʹ deiodinase: T4T3oLiver & kidney oCirculatesTarget cell T4T3 Doesn’t circulateOHOI II IT4OHOII IT3TBGTBGITBGTBGOHOI II IT4OHOII IT3ITBGTBGReceptorReceptorSignaling: T3 activates thyroid nuclear receptorType II nuclear receptorHeterodimerThyroid receptor●Two forms: α & β ●Tissue-specificRetinoid X receptorTRE=Thyroid response elementRegulates transcriptionSimilar to steroidsGene expressionGene expressionTRETREPol IIH+H+Thyroid/H+ co-transporter(MCT8)Thyroid/H+ co-transporter(MCT8)RXRTRCorepressorCoactivator13Thyroid hormone metabolism14Type 2 iodothyronine deiodinase (D2)T4 → T3rT3 → T2D1D2Type 1 iodothyronine deiodinase (D1)T4 → T3 /rT3 → T2D3D1D3D1D1D2Type 3 iodothyronine deiodinase (D3)T4 → rT3T3 → T2Modified by glucuranation or sulfationModified by glucuranation or sulfationExcretedExcretedTBG-bound hormone is not metabolizedTBG-bound hormone is not metabolizedThyroid hormone functionT3•THR transcription factor is required for normal expression of genes required for metabolism, stress response and development in many tissues……especially in fetal & neonatal development15Systemic effects of thyroid hormoneEssential for growth, development, maturation during fetal development & in childrenMusculoskeletalCentral & peripheral nervous system β adrenergic response Receptor synthesisEpinephrine & norepinephrine●Endocrine system●Sympathetic nervous systemImportant for normal cardiac outputThyroid hormone levels don’t change muchExcept in pathophysiology16Metabolic effects are futile17MuscleProteinsAdipose Liver11223344LPLHSLATPATPAmino AcidsTAGTAGNEFANEFAPyruvateoxphosCitric acid