Highlights of the 78th Annual Meeting American Thyroid ... - Thyrolink

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16 Thyroid International 2 2008at a dose one-third that needed to affect the heart, bodyweight, fasting blood glucose, insulin, free fatty acidlevels or the thyroid–pituitary axis.Jinzhao Hou, La Jolla, CA, reported preliminary resultswith MB07811, the liver-targeted thyroid hormonereceptor agonist, indicating that it is safe and welltoleratedat the doses studied, and has minimal effectson genes in extrahepatic tissues.Thyroid Hormone Receptors and CofactorsSamuel Refetoff, Chicago, IL, reviewed how he discoveredthe original patient with resistance to thyroidhormone, who had deaf-mutism, a small goiter, a highPBI, and stippled epiphyses on X-ray. Forty years later,2000 patients in 400 families have been identified, witha wide variety of mutations in the three functionalthyroid hormone receptor genes that have been characterized.In some patients, there are signs of hypothyroidismin one tissue but hyperthyroidism in another,the signs and symptoms being related to differences inrelative receptor expression in different tissues.Herbert Samuels, New York, NY, reviewed the distributionof thyroid hormone receptors and how additionalfactors are involved in thyroid hormone action. TRα-1is expressed predominantly in skeleton and brown fat,TRβ-1 is expressed widely but at low levels in the heart,and TRβ-2 is present in the pituitary, retina, hypothalamus,hippocampus, and inner ear. In the absenceof T 3 , various co-repressors interact with unligandedreceptors on DNA. However, in the presence of T 3 , theco-repressors are replaced with co-activators. Some ofthe co-activators and co-repressors produce opposingcovalent modifications on chromatin proteins, changingthe structure of chromatin around particular genes.One interesting finding is that when some thyroidhormone receptors have been totally knocked out, thephenotype produced is not as dramatic as the changethe phenotype produced by hormone deficiency.Thomas Zoeller, Amherst, MA, described the role ofthyroid hormone analogs, such as Bisphenol-A, whichantagonize TR-β mediated negative feedback in thebrain. He also described the action of other endocrinedisrupters such as PCBs, which may be selective forparticular types of receptors or tissues.Anthony Hollenberg, Boston, MA, described the selectiveexpression of a mutant of the co-repressor NCoR in thelivers of transgenic mice, which prevents its interactionwith thyroid hormone receptors. When these animalswere made hypothyroid, thyroid hormone-responsivehepatic mRNAs did not fall as much as in hypothyroidanimals bearing the normal NCoR gene. Furthermore, ineuthyroid animals expressing the mutant NCoR, severalhormone-regulated mRNAs (Cyp7A, spot 14, and DIO1)were expressed at much higher levels than in normalanimals. These in vivo data indicate that NCoR affectsthe thyroid hormone receptor function both in the presenceand absence of thyroid hormone.Several patients have been described who have relativecentral resistance to thyroid hormone but displaysome peripheral responses to their elevated circulatingthyroid hormones. Machado, DS, New York, NY, studiedmice engineered to express a thyroid hormone receptor,TRβ bearing a mutation commonly found in clinicalcases of central resistance, R429Q. Mice heterozygousfor the mutant TRβ gene had free T 3 and T 4 levels twicenormal, while the levels were four times normal inTRβ-homozygous mice. Confirming the fact that therewas central resistance, pituitary levels of TSH were2.6- and 4.5-fold higher than normal, respectively. Theheterozygotes weighed 15 % less and the homozygotes20 % less than the normal mice, and the levels of twoT 3 -responsive genes in the liver, spot 14 and 5′deiodinase,were increased. When propylthiouracil and a lowiodine diet were given to the mutants, the level of TSHbeta subunit mRNA increased more than in wild typemice. Some of the observations made in this mousemodel of central resistance have not been noted inhumans bearing this mutation, suggesting that modifiersof TRβ may act differently between species.Vijay Panicker and colleagues, Bristol, UK and Oslo andTrondheim, Norway, described the role of TSH in predictingdepression. They found that while a lower TSHdoes appear to predict anxiety in a population, subjectson T 4 therapy had a positive association between serum
American Thyroid Association – Highlights of the 78 th Annual Meeting17TSH and both anxiety and depression. This may haveimplications for treatment targets in thyroid diseaseand may explain dissatisfaction with therapy in a subgroupof patients on thyroxine.Translational Symposium:Deiodinases/SelenoproteinsP. Reed Larsen, Boston, MA, discussed the role of selenoproteinsin biology. He described how selenoproteinsincorporated in enzymes such as glutathione peroxidaseprotect DNA, RNA and proteins from oxidative damage.In addition to their involvement inactivating thyroidhormones through deiodinase enzymes, he describedtheir role in spermatogenesis. The importance of seleniumin deiodinases was emphasized by the fact thatreplacement of S by SE in Type 1 deiodinase increasedthe speed of deiodination by 100 times. The topic ofdeiodination was continued by Ronald Lechan, Boston,MA, who discussed central mechanisms for thyroidhormone regulation by deiodinases. He described howD2 mRNA was expressed by tancytes in the third ventricle.These tancytes touched neurons and blood vessels.Interestingly, tancytes also expressed the thyroidhormone transporter MCT8. Tancyte D2 is upregulatedby endotoxins, unlike in the pituitary where the effectis mediated by thyroid hormone. Finally Jack Leonard,Worcester, MA, discussed deiodinase dimerization andpointed out that full catalytic activity of D1 requiredboth appropriately fused deiodinase units.two of its substrates, I - and ClO - 4 , with different stoichiometries”explained the basis underlying the use ofperchlorate (ClO - 4 ) as a thyroid function blocker. Sheexplained how ClO - 4 is translocated first, and only whenall is translocated is I- transported by NIS. The NIS has ahigher affinity for ClO4- than for I - , with a lower Vmaxdue to 1:1 Na ion stoichiometry. She explained howClO4- transport into milk inhibits I - transport to thesuckling newborn suggesting that ClO - 4 contaminationmay be more harmful in the nursing mother. Finally,Honey Reddi, Rochester, MN, reported on “the oncogenicpotential of PAX8=PPARγ fusion proteins” (PFRP) inthyroid follicular carcinoma. She reported on possiblemodes of action and on the therapeutic potential of thePFRP fusion proteins.Reports from ATA Research Grant HoldersDouglas, Los Angeles, CA, discussed “The Phenotypeof Mononuclear Cells in Graves Ophthalmopathy”. Hedescribed the aberrant immune response in orbitalfibroblasts which uniquely produce cytokines leadingto orbital tissue remodeling. Sara Danzi, New York, NY,described her work on the project “Is there a role forthyroid hormone in congestive heart failure?” and outlinedhow a low T 3 is an indicator of heart failure. Theworking hypothesis she outlined involved the progressionto congestive cardiac failure following an acuteMI with decreased T 4 to T 3 conversion. She pointed outthat replacement with T 3 will improve cardiac functionin congestive cardiac failure. Orsolya Dohán, New York,NY, speaking on “the Na + /I - symporter (NIS) transports
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