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THYROID HORMONES

THYROID HORMONES. Prof.Dr .Arzu SEVEN. Thyroid hormone biosynthesis involves thyroglobulin and iodide metabolism. THYROİD HORMONES. 1- Concentration of iodide I n the follicular epithelial cells , against a strong electrochemical gradient

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THYROID HORMONES

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  1. THYROID HORMONES Prof.Dr.Arzu SEVEN

  2. ThyroidhormonebiosynthesisinvolvesthyroglobulinandiodidemetabolismThyroidhormonebiosynthesisinvolvesthyroglobulinandiodidemetabolism

  3. THYROİD HORMONES • 1- Concentration of iodide • Inthefollicularepithelialcells, against a strongelectrochemicalgradient • Energy-dependentprocess, linkedtoATPase –dependentNa+ - K+pump • ThyroidalI-transporter (controlledby TSH) • İodidein thyroid/iodidein serum ratioreflectstheactivity of thistransporter (25/1) • İodidetransporter is inhibitedbyperchlorateandthiocyanate

  4. 2- Oxidation of I-bythyroidperoxidase(TPO) in theperoxisometoiodine • As an oxidizingagent, TPO requires H2O2, producedby NADPH-dependentenzyme (likecytocrome c reductase). Antithyroiddrugs-thiourea-inhibit I-oxidation • 3- Iodination of tyrosine (organification) • oxidizedioidereactswithtyrosylresidues in thyroglobulin (involvesTPO) to form MIT or DIT

  5. Thyroglobulin: • Prohormone • Precursorandstorage form of T4 and T3 • Large, iodinatedandglycosylated protein • Composed of 2 subunist • Contains115 tyrosineresidues • Thyroglobulin is synthesizedin thebasalportion of thecell. It is stored in theextracellularcolloid

  6. 4- Coupling of iodotyrosyls (catalysedby TPO, inhibitedbyantithyroiddrugs )

  7. 5-Thyroglobulin(Tgb) hydrolysis stimulatedby TSH (orcAMP) inhibitedby I- • İncrease in microvilli on theapicalmembranephagocytosis + pinocytosis, bringTgbbackintothefollicularcell • Phagosomes + lysosomes phagolysosomes in whichacidproteasesandpeptidaseshydrolyseTgbinto amino acidsandiodothyronines

  8. T3 and T4 aredischargedfromthebasalportionof cellbyfacilatedprocessintoblood MIT DIT • ~ 70% of iodide in Tgbexists in inactiveprecursors (MIT, DIT) ,~ 30% in T4 and T3 Tyrosine I- deiododinase

  9. Wheniodinesuppliesaresufficient T4/T3: 7/1 • Iniodinedeficiency, T4/T3 , DIT/MIT • Dailyiodiderequirement: 150-200 µg

  10. Transport of thyroidhormones • Thyroxinebindingglobulin (TGB) 70% • Albumin25% • Thyroxinebindingprealbumin (TBPA) 5% • TBG, a glycoprotein, bindsnearlyall T4 and T3 noncovalently • TBG is produced in liver • Itssynthesis is, increasedbyestrogens,decreasedbyandrogensorglucocorticoidtherapyand in liverdisease • Phenytoinandsalicylatescompetewith T3 and T4 tobindto TBG

  11. Thesmall, unbound (free) fraction is responsibleforbiologicalactivity • Free T4 and T3 is a measure of thyroidhormonestatus, represents <1% of total T4 and T3 • T4: 8µg/dl (100nmol/L), t1/2 : 6.5 days • T3: 0,15µg/dl(2 nmol/L), t1/2 : 1.5 days

  12. 5’_deiodinationconverts T4 to T3 • Thisprocessmayoccur in thethyroidgland, in targettissuesor in otherperipheraltissues • Since T3 bindstothyroidreceptors in targetcellswith 10 timestheaffinity of T4, T3 is themetabolicallyactive form. T4 may be regarded as a prohormone

  13. About 80% of T4 is metabolizedbydeiodinationwithequalamounts of T3 or rT3 • 20% of T4 is conjugatedwithsulfateorglucuronicacidanddeactivatedbydeamidationordecarboxylation • Amongdeiodinases 1 and 2 (DI1,DI2),DI2 is particularlyimportant in controllingnuclear T3 levels.

  14. DI3 is a majormetaboliccatabolicenzyme; it catalyzesremovalof iodidefrom 3 ratherthan 5 positionto form rT3 • rT3 is biologicallyinactiveandsimilarly de_iodinatesandinactivatesT3 • rT3 is a veryweakagonist, made in relativelylargeramounts in severe chronicdisease (sickeuthroidsyndrome) in carbohydratestarvationand in thefetus • Propylthiouracilandpropranololdecrease T4T3 conversion

  15. FUNCTON • Thyroidhormonesbindtospecific,high_affinityreceptors in targetcellnucleus • Theyareacceleratorpedal of metabolism increasewholebasalmetabolic rate • Theyregulate gene expresssion , tissuedifferentiation, general development, enhance protein synthesis , cause (+) nitrogenbalance • ThyroidhormonesincreaseNa/K dependent ATP aseactivity, increasemitochondrialmetabolism • T3 andglucocorticoidsenhance GH gene transcription GH production

  16. Clinicaldisorders of thyroidfunction • Thyroiddisease is common, affectsalmost 3% of thepopulation,9 times as manywomen as men areaffected • Autoimmune in origin(mostly) • Antibodiesmayariseagainstseveralcomponents of thyroidcells, includingtheperoxidaserichmicrosomes

  17. Hypothyroidizm • Developsslowly • İt isthereforeeasilymissedclinically • Clinicalbiochemistry has an important role in diagnosis

  18. Clinalfeatures: • Lethargyandtiredness • Coldintolerance • Weightgain • Drynessandcoarsening of skin andhair • Hoarseness • Slowrelaxation of musclesandtendonreflexes • Anemia, dementia, constipation,bradycardia • Musclestiffness, carpaltunnelsyndrome, subfertilityandgalactorrhoea

  19. Highcholesterol(downregulaton of LDL receptorson liver) • Aoutoimmunedestruction of thyroidgland (Hashimoto’sdisease) • Radioiodineorsurgicaltreatment of hyperthyroidism

  20. Rarecausesinclude • Transienthypothyroidism (lithiumcarbonatetreatment) • TSH deficiency (panhypopituitarism) • Congenitaldefectssuchas blocks in T4 andT3 synthesisorendorganresistance • Severe iodinedeficiency

  21. diagnosis • Primaryhypothyroidismis failure of thethyroidglanditself, it is one of themostcommonlyencounteredendocrine problem • Elevated TSH is usuallydiagnostic • Secondaryhypothyroidismfailure of pituitarytosecrete TSH is muchlesscommon • TRH test will be included in theprotocoltoinvestigatepituitaryorhypothalamiccauses

  22. Congenitalhypothyroidism • A conditionwhich, unlesstreatedwithin 3 months of birth , results in permanentbraindamage • Hypothyroidchildrenhavedelayedskeletalmaturation, shortstatureanddelayedpuberty: delays in treatmentresult in cretinism highblood TSH is diagnostic

  23. Hyperthyroidism(thyrotoxicosis) • Overactivity of thyroidgland • Clinicalfeatures: • Weightloss,despitenormal appetite • Sweatingandheatintolerance • Fatigue • Palpitation, sinustachycardiaoratrialfibrillation • Agitationand tremor • Generalizedmuscleweakness-proximalmyopathy

  24. Anginaandheartfailure • Diarrhea • Oligomenorrheaandsubfertility • Goitre • Eyerlidretractionandlidlag

  25. causes • Gravesdisease (diffusetoxicgoitre) • Toxicmultinodulargoitre • Solitarytoxic adenoma • Thyroiditis • Exogenouslyadminstratediodineandiodinecontainingdrugs • Excessive T3 and T4 ingestion

  26. Mostcommon • Autoimmunedisease • Antibodiesto TSH receptor on thesurface of thyroidcellsappeartomimicpituitaaryhormoneaction • Regulatorycontrols of T4 synthesisandsecretionarelacking of thyroidhormones in bloodinhibit TSH secretion

  27. diagnosis • Supressed TSH (undetectable) + raisedthyroidhormoneconfirmprimaryhyperthyroidism • Free T4 assaysareroutinelyused, as first time test of thyroiddysfunction • TSH secretion is verysensitivetochanges in free T4 • Free T4 assaysareinvaluablein diagnosiswhen TBG arealtered (pregnancy, oral contraceptiveuse,nephroticsyndrome)

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