The size of the kidneys, renal plasma flow, glomerular filtration rate, and transport rates for various substances are increased by thyroid hormone. Non-thyroidal illness syndrome (NTIS), also known as euthyroid sick syndrome, is frequently observed in severely ill patients requiring hospitalization. NTIS is characterized by reduced levels of circulating thyroid hormone and TSH due to CNS-mediated suppression of the hypothalamic-pituitary-thyroid axis. Additionally, the peripheral metabolism of T4 to inactive rT3 is also elevated. A similar pattern is seen during prolonged fasting. The exact mechanisms of NTIS are not fully understood, but it is believed to be a physiological energy-conserving adaptation to chronic illness or starvation.

The mechanism of thyroid hormone action was previously thought to involve passive diffusion across cell membranes, but it is now known to require transport proteins. Monocarboxylate transporters MCT8 and MCT10 play a role in transporting both T4 and T3 across the plasma membrane (see Fig. 42.5 and Fig. 42.13). Mutations in MCT8 have been identified as the cause of an X-linked developmental syndrome in humans characterized by elevated T3 levels, muscle hypoplasia, and severe neurological impairment. Another transporter, OATP1C1, appears to be involved in the transport of T4 across the blood-brain barrier.

Many, but not all, actions of T3 are mediated through binding to thyroid hormone receptors (TR). The TR family belongs to the nuclear hormone receptor superfamily of transcription factors (see also). In humans, there are two thyroid hormone receptor genes, THRA and THRB, located on chromosomes 17 and 3, respectively, that encode the nuclear thyroid hormone receptors. THRA encodes TRα, which can be alternatively spliced to form two main isoforms. TRα1 is a functional TR, while the other isoform does not bind T3. THRB encodes TRβ1 and TRβ2, which are high-affinity receptors for T3. TRα1 and TRβ1 are widely expressed in various tissues. TRα1 is strongly expressed in cardiac and skeletal muscle and is the primary mediator of thyroid hormone action on the heart. In contrast, TRβ1 is mainly expressed in the brain, liver, and kidney. TRβ2 expression is restricted to the pituitary, critical areas of the hypothalamus, cochlea, and retina. T3 acting via TRβ2 is responsible for inhibiting the expression of the prepro-TRH gene in the paraventricular neurons of the hypothalamus and the β subunit TSH gene in pituitary thyrotropes. Thus, the negative feedback effects of thyroid hormone on both TRH and TSH secretion are largely mediated by TRβ2. 

The mechanisms of thyroid hormone action involve the role of MCT transporters, D2 deiodinase, and TR-RXR heterodimers (see Fig. 42.13). Unliganded TR-RXR binds to thyroid response elements in target genes and recruits co-repressors that inhibit gene transcription. Upon T3 binding, the co-repressors are released, and co-activators are recruited to the hormone-receptor complex, inducing gene transcription.
Chapter40).Kidneysize, renalplasmaflow,glomerularfiltrationrate,andtransportratesforanumberofsubstancesarealsoincreasedbythyroidhormone.
Non-thyroidal illness syndrome (NTIS), also known as euthyroid sick syndrome, occurs frequently in severely ill patients who require hospitalization. NTIS is characterized by decreased levels of both circulating thyroid hormone and TSH caused by CNS-mediated suppression of the hypothalamic-pituitary-thyroid axis. In addition, peripheral metabolism of T4 to inactive rT3 is also increased. A similar pattern is seen upon prolonged fasting. Although it remains incompletely understood, NTIS has been proposed to represent a physiological energy-sparing adaptation to chronic illness or starvation.
Mechanism of Thyroid Hormone Action
Formanyyearsitwasthoughtthatthyroidhormonesdiffusepassivelyacrosscellmembranes,butthisisnowknowntorequiretransportproteins.TheseincludethemonocarboxylatetransportersMCT8andMCT10,whicharecapableoftransportingbothT4andT3acrosstheplasmamembrane(
Fig.
42.13
Fig.42.5 ).Recently,mutationsinMCT8havebeenshowntocauseanX-linkeddevelopmentalsyndromeinhumanscharacterizedbyelevatedT3levels,musclehypoplasia,andsevereneurologicalimpairment.Anothertransporter,OATP1C1,appearstoplayaroleintransportofT4acrosstheblood-brainbarrier.
ManybutnotallT3actionsaremediatedthroughitsbindingtooneofthemembersofthethyroid hormone receptor (TR) family. TheTRfamilybelongstothenuclearhormonereceptorsuperfamilyoftranscriptionfactors(seealso ).Inhumanstherearetwothyroidhormonereceptorgenes,THRA andTHRB, locatedonchromosomes17and3,respectively,thatencodethenuclearthyroidhormonereceptors.THRAencodesTRα, whichisalternativelysplicedtoformtwomainisoforms.TRα1isabonafideTR,whereastheotherisoformdoesnotbindT3.THRBencodesTRβ1 andTRβ2, whicharehigh-affinityreceptorsforT3.ThetissuedistributionofTRα1andTRβ1iswidespread.TRα1isstronglyexpressedincardiacandskeletalmuscle.TRα1istheprimarymediatorofthyroidhormoneactionontheheart.Incontrast,TRβ1isexpressedmainlyinbrain,liver,andkidney.TRβ2expressionisrestrictedtothepituitaryandcriticalareasofthehypothalamus,aswellasthecochleaandretina.T3actingviaTRβ2isresponsibleforinhibitingexpressionoftheprepro-TRHgeneintheparaventricularneuronsofthehypothalamusandtheβ subunitTSHgeneinpituitarythyrotropes.Thusthenegative-feedbackeffectsofthyroidhormoneonbothTRHandTSHsecretionarelargelymediatedbyTRβ2.
•Fig. 42.13 Mechanismsofthyroidhormoneaction,includingtheroleofMCTtransporters,D2deiodinase,andTR-RXRheterodimers.CoA,coactivator;CoR,co-repressor;RXR,retinoidXreceptor.
Fig.42.13 ).UnligandedTR-RXRbindstothyroidresponseelementsintargetgenesandrecruitsco-repressorsthatinhibitgenetranscription.UponT3binding,theco-repressorsarereleased,andcoactivatorsarerecruitedtothehormone-receptorcomplex,inducinggenetranscription.