{"id":3006,"date":"2019-06-10T15:35:58","date_gmt":"2019-06-10T15:35:58","guid":{"rendered":"http:\/\/ibshypo.com\/?page_id=3006"},"modified":"2021-12-26T13:14:53","modified_gmt":"2021-12-26T13:14:53","slug":"where-is-the-t3-coming-from","status":"publish","type":"page","link":"https:\/\/ibshypo.com\/index.php\/where-is-the-t3-coming-from\/","title":{"rendered":"Where is the T3 Coming From?"},"content":{"rendered":"\n<p class=\"has-light-green-cyan-background-color has-background\"><strong>Where is the T3 Coming From? &#8211; The most important question in thyroidology.<\/strong><\/p>\n\n\n\n<p class=\"has-very-light-gray-background-color has-background\">We measure TSH, fT3 and fT4 in the blood.  Blood is the &#8216;intermediate space&#8217;, it conveys hormones from the primary space (thyroid or tablets) to the active space (the receptors in the cell nucleus).  Thyroid status is determined by T3 saturation at the receptors.  The current view is that we can&#8217;t know tissue T3 levels because we can&#8217;t directly measure them.  This approach fails to address important issues: &#8211;<\/p>\n\n\n\n<ul><li><strong>Many patients are hypothyroid with normal blood hormone levels<\/strong><\/li><li><strong>Restoring normal blood hormone levels is not sufficient to cure all cases of hypothyroidism. <\/strong> <\/li><\/ul>\n\n\n\n<hr class=\"wp-block-separator\"\/>\n\n\n\n<p class=\"has-light-green-cyan-background-color has-background\">We know about &#8216;T3&#8217; and other molecules because particle physicists detect and measure atomic particles.  Endocrinology must adopt similar initiatives in order to understand what happens to thyroid hormones within tissues.<\/p>\n\n\n\n<p class=\"has-very-light-gray-background-color has-background\">We can&#8217;t directly measure intracellular T3 levels, but we can use our understanding of thyroidology to interpret TFTs in a way that gives an indication of tissue hormone levels.  We must look at <strong>where the T3 is coming from<\/strong> and to do so we need to understand deiodinases, specifically T4 to T3 conversion.  For a detailed understanding refer to &#8216;Metabolism of Thyroid Hormone&#8217; in <a rel=\"noreferrer noopener\" aria-label=\"Thyroid Disease Manager (opens in a new tab)\" href=\"http:\/\/ibshypo.com\/index.php\/thyroid-disease-manager\/\" target=\"_blank\">Thyroid Disease Manager<\/a> (register for free) and the content of <a rel=\"noreferrer noopener\" aria-label=\"Bianco Lab (opens in a new tab)\" href=\"http:\/\/ibshypo.com\/index.php\/bianco-lab-deiodinase\/\" target=\"_blank\">Bianco Lab,<\/a> both of which are listed under <a rel=\"noreferrer noopener\" aria-label=\"Resources (opens in a new tab)\" href=\"http:\/\/ibshypo.com\/index.php\/resources-2\/\" target=\"_blank\">Resources<\/a>.  For simplicity, we  concentrate on T4 to T3 conversion.<\/p>\n\n\n\n<p class=\"has-very-light-gray-background-color has-background\">T3 comes from various sources: &#8211;<\/p>\n\n\n\n<ul><li>The Thyroid &#8211; Secretes T3 and converts T4 to T3<\/li><li>From Tablets &#8211; T3 in Liothyronine and natural desiccated thyroid (NDT)<\/li><li>Peripheral tissues &#8211; Type-1 deiodinase<\/li><li>Peripheral tissues &#8211; Type-2 deiodinase<\/li><\/ul>\n\n\n\n<hr class=\"wp-block-separator\"\/>\n\n\n\n<h3>Deiodinases<\/h3>\n\n\n\n<p class=\"has-very-light-gray-background-color has-background\">There are three deiodinases, Type-1, Type-2 and Type-3 referred to as D1, D2 and D3.  (See this helpful <a rel=\"noreferrer noopener\" aria-label=\"diagram from thyroidmanager (opens in a new tab)\" href=\"https:\/\/www.thyroidmanager.org\/wp-content\/uploads\/2017\/01\/figure2.jpg\" target=\"_blank\">diagram from thyroidmanager)<\/a><\/p>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter\"><a href=\"https:\/\/www.thyroidmanager.org\/wp-content\/uploads\/2017\/01\/figure2.jpg\" target=\"_blank\" rel=\"noreferrer noopener\"><img loading=\"lazy\" width=\"859\" height=\"691\" src=\"http:\/\/ibshypo.com\/wp-content\/uploads\/2019\/09\/image-3.png\" alt=\"\" class=\"wp-image-3611\" srcset=\"https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/09\/image-3.png 859w, https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/09\/image-3-300x241.png 300w, https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/09\/image-3-768x618.png 768w\" sizes=\"(max-width: 859px) 100vw, 859px\" \/><\/a><figcaption> <br><strong>7. TRADEMARK AND COPYRIGHT INFORMATION<\/strong> ENDOCRINE  EDUCATION, INC., THYROID DISEASE MANAGER, AND THYROIDMANAGER  are  trademarks of ENDOCRINE EDUCATION, INC. The information available   through the website is the property of ENDOCRINE EDUCATION, INC. and is   protected by copyright. Information received through the site may be   displayed, reformatted and printed for your personal, non-commercial use   only. You agree not to reproduce, retransmit, distribute, disseminate,   sell, publish, broadcast or circulate the information received through   the website to anyone without permission from ENDOCRINE EDUCATION,  INC.  Any copy made of information obtained through the site must  include the  copyright notice. <\/figcaption><\/figure><\/div>\n\n\n\n<hr class=\"wp-block-separator\"\/>\n\n\n\n<ul><li><strong>D1<\/strong> converts T4 -> T3, T4 -> rT3 usually in equimolar amounts.  D1 is expressed in the liver, kidneys and thyroid.  D1 is localized in the plasma membrane of the cell and provides plasma T3, it also mitigates the effects of thyrotoxicity by converting half the T4 to rT3.  D1 activity increases in hyperthyroidism and reduces in hypothyroidism.<\/li><li><strong>D2<\/strong> converts T4 -> T3.  It is expressed in the pituitary, brain, brown fat (BAT), skeletal muscle and the heart.  D2 is localized in the  endoplasmic reticulum, close to the cell nucleus.  D2 is responsible for local T3 levels, it is also the major source of circulating T3.  Peripheral D2 activity decreases in hyperthyroidism and increases in hypothyroidism &#8211; the opposite of D1 and D3.<\/li><li><strong>D3<\/strong> converts T4 -> rT3, T3 -> T2.  It is expressed in the brain, placenta and foetal tissues.  D3 activity increases in hyperthyroidism and decreases in hypothyroidism.  D3 prevents excess T3 levels.<\/li><\/ul>\n\n\n\n<p class=\"has-very-light-gray-background-color has-background\">The deiodinases respond in complex ways to thyroid hormones and other influences to maintain local and circulating T3 levels.  For example, D2 activity in brown adipose tissue increases dramatically  during cold exposure.  D2 activity in peripheral tissues decreases as T4 levels rise but the <a rel=\"noreferrer noopener\" aria-label=\"hypothalamus (opens in a new tab)\" href=\"https:\/\/www.jci.org\/articles\/view\/77588\" target=\"_blank\">hypothalamus<\/a> and pituitary are unique in that their D2 activity does not vary in this manner.  This makes sense, the hypothalamus and pituitary measure circulating fT3 and fT4 levels.  Deiodinase in other tissues responds to circulating hormone levels and local requirements.<\/p>\n\n\n\n<h3>Which T3 Matters?<\/h3>\n\n\n\n<p class=\"has-very-light-gray-background-color has-background\">Tissues such as the brain and skeletal muscle rely on D2 activity to regulate local T3 levels.  <\/p>\n\n\n\n<p class=\"has-very-light-gray-background-color has-background\">Most T3 comes from peripheral deiodinase of T4 with D2 being the major source.  D2 activity increases as thyroid hormone levels fall.  In hypothyroid scenarios the rate of T4 to T3 conversion increases, as we saw in McDermott&#8217;s <a rel=\"noreferrer noopener\" aria-label=\"Figure 1 (opens in a new tab)\" href=\"https:\/\/www.researchgate.net\/publication\/40042239_In_the_clinic_Hypothyroidism\" target=\"_blank\">Figure 1<\/a>.  This maintains not only circulating T3 levels but also crucially local T3 levels in tissues such as the brain which are highly dependent upon D2 activity.<\/p>\n\n\n\n<p class=\"has-light-green-cyan-background-color has-background\">The diagram below shows how deiodinases control local and circulating T3 levels.  Larger fonts indicate preferred substrates, i.e. which hormone the enzyme prefers to work on.  D1 and D3 takes place near the cell membrane whereas D2 is located close to the cell nucleus.  If you find the detail a bit too much, just look at the D2 enzyme.  D2 activity increases as thyroid hormone levels fall thus maintaining stable T3 levels &#8211; at least until T4 levels have fallen too low.<\/p>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter\"><img loading=\"lazy\" width=\"904\" height=\"922\" src=\"http:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/deiodinase-diagram-1.png\" alt=\"\" class=\"wp-image-3261\" srcset=\"https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/deiodinase-diagram-1.png 904w, https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/deiodinase-diagram-1-294x300.png 294w, https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/deiodinase-diagram-1-768x783.png 768w, https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/deiodinase-diagram-1-60x60.png 60w\" sizes=\"(max-width: 904px) 100vw, 904px\" \/><\/figure><\/div>\n\n\n\n<p class=\"has-very-light-gray-background-color has-background\"><strong>D2 is especially important in the brain<\/strong>.  <a rel=\"noreferrer noopener\" aria-label=\"In mice 80% of brain T3 comes from D2 converting T4 to T3 (opens in a new tab)\" href=\"https:\/\/doi.org\/10.1210\/endo-110-2-367\" target=\"_blank\">In rats up 80% of cerebral cortex T3 comes from D2 converting T4 to T3<\/a>.<\/p>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter\"><img loading=\"lazy\" width=\"753\" height=\"640\" src=\"http:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/brain-t4-t3-1.png\" alt=\"\" class=\"wp-image-3189\" srcset=\"https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/brain-t4-t3-1.png 753w, https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/brain-t4-t3-1-300x255.png 300w\" sizes=\"(max-width: 753px) 100vw, 753px\" \/><\/figure><\/div>\n\n\n\n<p class=\"has-light-green-cyan-background-color has-background\">Consider what happens if D2 activity is reduced and sufficient levothyroxine \/ liothyronine prescribed to restore normal serum levels.  The reduced D2 activity reduces T3 levels within the brain causing a form of brain hypothyroidism that cannot be detected by blood tests.  Restoring normal brain T3 levels requires supra-physiological blood T3 levels.<\/p>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter\"><img loading=\"lazy\" width=\"753\" height=\"640\" src=\"http:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/brain-t4-t3-D2-2.png\" alt=\"\" class=\"wp-image-3199\" srcset=\"https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/brain-t4-t3-D2-2.png 753w, https:\/\/ibshypo.com\/wp-content\/uploads\/2019\/06\/brain-t4-t3-D2-2-300x255.png 300w\" sizes=\"(max-width: 753px) 100vw, 753px\" \/><\/figure><\/div>\n\n\n\n<p class=\"has-very-light-gray-background-color has-background\">We have seen that &#8216;D2T3&#8217; is rather special now let&#8217;s see why <a href=\"http:\/\/ibshypo.com\/index.php\/type-2-deiodinase-d2-is-crucial\/\">Type-2 Deiodinase (D2) is Crucial<\/a>.<\/p>\n\n\n\n<p><br><\/p>\n\n\n\n<hr class=\"wp-block-separator\"\/>\n","protected":false},"excerpt":{"rendered":"<p>Where is the T3 Coming From? &#8211; The most important question in thyroidology. We measure TSH, fT3 and fT4 in the blood. Blood is the &#8216;intermediate space&#8217;, it conveys hormones from the primary space (thyroid or tablets) to the active space (the receptors in the cell nucleus). Thyroid status is determined by T3 saturation at [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"_links":{"self":[{"href":"https:\/\/ibshypo.com\/index.php\/wp-json\/wp\/v2\/pages\/3006"}],"collection":[{"href":"https:\/\/ibshypo.com\/index.php\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/ibshypo.com\/index.php\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/ibshypo.com\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/ibshypo.com\/index.php\/wp-json\/wp\/v2\/comments?post=3006"}],"version-history":[{"count":252,"href":"https:\/\/ibshypo.com\/index.php\/wp-json\/wp\/v2\/pages\/3006\/revisions"}],"predecessor-version":[{"id":6386,"href":"https:\/\/ibshypo.com\/index.php\/wp-json\/wp\/v2\/pages\/3006\/revisions\/6386"}],"wp:attachment":[{"href":"https:\/\/ibshypo.com\/index.php\/wp-json\/wp\/v2\/media?parent=3006"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}