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Thyroxine-binding globulin (TBG) is the major binding protein that is synthesized in the liver. It binds one molecule of T4 or T3, which are secreted by the liver. Around 70% of circulating T4 and T3 are bound to proteins. Only about 0.03% of circulating T4 and T3 is bound to TBG, while 10% to 15% of total plasma T4 and 0.3% of total plasma T3 are bound to transthyretin (TTR), another specific thyroid-binding protein. The free state of T3, which is biologically active, is bound to albumin (15% to 20%), while 3% is bound to lipoproteins. Alterations in circulating thyroid hormones feedback on the pituitary gland, decreasing TSH secretion primarily by repressing TSHβ subunit gene expression. The pituitary gland expresses the high-affinity D2, which converts T4 to T3 inside the cells. Therefore, feedback in thyrotropes, mediated by intracellular T3, represents an integrated measure of circulating free T4 and T3. TSH secretion and plasma concentrations of thyroid hormones are relatively constant due to small diurnal variation. Only small nocturnal increases in secretion of TSH and release of T4 occur. Thyroid hormones also provide feedback on hypothalamic thyroid-releasing hormone (TRH)-secreting neurons. In these neurons, T3 inhibits the expression of the prepro-TRH gene.

Iodide itself causes autoregulation of thyroid gland function. At relatively low levels of iodide intake, the rate of thyroid hormone synthesis is directly related to the availability of iodide. However, if iodide intake exceeds 2mg/day, the intraglandular concentration of iodide reaches a level that paradoxically suppresses TPO activity, blocking hormone biosynthesis. This phenomenon is known as the Wolff-Chaikoff effect. Adaptation to high iodide intake normally occurs by reducing the expression of NIS, which causes the intrathyroidal iodide level to fall. TPO activity then returns to normal, and thyroid hormone synthesis resumes within days to weeks. In unusual instances, failure of NIS to downregulate leads to prolonged inhibition of hormone synthesis by iodide and resultant hypothyroidism. The temporary reduction in hormone synthesis by excess iodide has also been used therapeutically in hyperthyroidism.

The activity of the thyroid can be assessed by radioactive iodine uptake (RAIU) due to its ability to trap and incorporate iodine into thyroglobulin (called organification). In this test, a tracer dose of 123I is administered, and RAIU is measured by placing a gamma detector on the neck at 4 to 6 hours and at 24 hours. In the United States, where the diet is relatively rich in iodine, RAIU is typically around 15% after 6 hours and 25% after 24 hours.

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Transport and Metabolism tissues in addition to exerting negative feedback on the pituitary and hypothalamus. The major binding protein is thyroxine-binding globulin (TBG), which is synthesized Secreted T4 and T3 circulate in the bloodstream almost in the liver and binds one molecule of T4 or T3. About 70% entirely bound to proteins. Normally only about 0.03% of circulating T4 and T3 is bound to TBG; 10% to 15% of total plasma T4 and 0.3% of total plasma T3 exist in is bound to another specific thyroid-binding protein called the free state (
Fig. 42.8 ). Free T3 is biologically active and transthyretin (TTR). Albumin binds 15% to 20%, and mediates the effects of thyroid hormone on peripheral 3% is bound to lipoproteins. Ordinarily only alterations in ).CirculatingthyroidhormonesfeedbackonthepituitaryglandtodecreaseTSHsecretion,primarilybyrepressingTSHβ subunitgeneexpression.Thepituitaryglandexpressesthehigh-affinityD2,whichconvertsT4enteringthesecellstoT3.ThusfeedbackinthyrotropesmediatedbyintracellularT3representsanintegratedmeasureofcirculatingfreeT4andT3(see ).BecausethediurnalvariationinTSHsecretionissmall,thyroidhormonesecretionandplasmaconcentrationsarerelativelyconstant.OnlysmallnocturnalincreasesinsecretionofTSHandreleaseofT4occur.Thyroidhormonesalsofeedbackonhypothalamicthyroid-releasinghormone(TRH)secretingneurons.Intheseneurons,T3inhibitsexpressionoftheprepro-TRHgene.
Autoregulationofthyroidglandfunctioniscausedbyiodideitself,whichhasabiphasicaction.Atrelativelylowlevelsofiodideintake,therateofthyroidhormonesynthesisisdirectlyrelatedtotheavailabilityofiodide.However,iftheintakeofiodideexceeds2mg/day,theintraglandularconcentrationofiodidereachesalevelthatparadoxicallysuppressesTPOactivity,blockinghormonebiosynthesis.ThisphenomenonisknownastheWolff-Chaikoff effect. AdaptationtohighiodideintakenormallyoccursbyreducingexpressionofNIS,whichcausestheintrathyroidaliodideleveltofall.TPOactivitythenreturnstonormal,andthyroidhormonesynthesisresumeswithindaystoweeks.Inunusualinstances,failureofNIStodownregulateleadstoprolongedinhibitionofhormonesynthesisbyiodideandresultanthypothyroidism.Thetemporaryreductioninhormonesynthesisbyexcessiodidehasalsobeenusedtherapeuticallyinhyperthyroidism.
Becauseofitsabilitytotrap andincorporateiodineintothyroglobulin(calledorganification),theactivityofthethyroidcanbeassessedbyradioactive iodine uptake (RAIU). Inthistestatracerdoseof123IisadministeredandRAIUismeasuredbyplacingagammadetectorontheneckat4to6hoursandat24hours.IntheUnitedStates,wherethedietisrelativelyrichiniodine,RAIUistypicallyaround15%after6hoursand25%after24hours(