Editing Hashimoto's thyroiditis (section)

==== Low tissue tri-iodothyronine (T<sub>3</sub>) hypothesis ====
Peripheral tissue T<sub>4</sub> to T<sub>3</sub> conversion may be inadequate: Some patients on LT<sub>4</sub> monotherapy may have blood T<sub>3</sub> levels low or below the normal range,<ref name=":6" /><ref name="Taylor-2024" /> and/or may have local T<sub>3</sub> deficiency in some tissues.<ref name="Wiersinga-2014">{{cite journal |vauthors=Wiersinga WM |date=March 2014 |title=Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism |journal=Nature Reviews. Endocrinology |volume=10 |issue=3 |pages=164–174 |doi=10.1038/nrendo.2013.258 |pmid=24419358}}</ref> Although both [[Molecule|molecules]] can have biological effects, thyroxine (T<sub>4</sub>) is considered the "storage form" of thyroid hormone with much less effect, while tri-iodothyronine (T<sub>3</sub>) is considered the active form used by [[Tissue (biology)|body tissues]].<ref>{{cite journal | vauthors = Morris JC, Galton VA | title = The isolation of thyroxine (T4), the discovery of 3,5,3'-triiodothyronine (T3), and the identification of the deiodinases that generate T3 from T4: An historical review | journal = Endocrine | volume = 66 | issue = 1 | pages = 3–9 | date = October 2019 | pmid = 31256344 | doi = 10.1007/s12020-019-01990-1 }}</ref><ref name="Abdalla-2014">{{cite journal | vauthors = Abdalla SM, Bianco AC | title = Defending plasma T3 is a biological priority | journal = Clinical Endocrinology | volume = 81 | issue = 5 | pages = 633–641 | date = November 2014 | pmid = 25040645 | pmc = 4699302 | doi = 10.1111/cen.12538 }}</ref> Thus the body must convert thyroxine into tri-iodothyronine.<ref name="Abdalla-2014" /> Tri-iodothyronine is produced primarily by conversion in the [[liver]], [[kidney]], [[skeletal muscle]] and [[pituitary gland]].<ref>{{cite journal | vauthors = Danzi S, Klein I | title = Thyroid hormone and the cardiovascular system | journal = The Medical Clinics of North America | volume = 96 | issue = 2 | pages = 257–268 | date = March 2012 | pmid = 22443974 | doi = 10.1016/j.mcna.2012.01.006 | series = Thyroid Disorders and Diseases }}</ref> 

Adequate conversion requires sufficient levels of the micronutrients [[zinc]],<ref>{{cite journal | vauthors = Knezevic J, Starchl C, Tmava Berisha A, Amrein K | title = Thyroid-Gut-Axis: How Does the Microbiota Influence Thyroid Function? | journal = Nutrients | volume = 12 | issue = 6 | pages = 1769 | date = June 2020 | pmid = 32545596 | pmc = 7353203 | doi = 10.3390/nu12061769 | doi-access = free }}</ref> [[selenium]],<ref name="Winther-2020" /> [[iron]],<ref>{{Cite journal | vauthors = Ghiya R, Ahmad S |date=2019-04-30 |title=SUN-591 Severe Iron-Deficiency Anemia Leading to Hypothyroidism |journal=Journal of the Endocrine Society|volume=3 |issue=Suppl 1 |pages=SUN-591 |doi=10.1210/js.2019-SUN-591 |doi-access=free |pmc=6552785 }}</ref> and possibly [[vitamin A]].<ref>{{cite journal |vauthors=Capriello S, Stramazzo I, Bagaglini MF, Brusca N, Virili C, Centanni M |title=The relationship between thyroid disorders and vitamin A.: A narrative minireview |journal=Frontiers in Endocrinology |volume=13 |pages=968215 |date=2022-10-11 |pmid=36303869 |pmc=9592814 |doi=10.3389/fendo.2022.968215 |doi-access=free}}</ref> Conversion rates may decline with age.<ref>{{cite journal | vauthors = Strich D, Karavani G, Edri S, Gillis D | title = TSH enhancement of FT4 to FT3 conversion is age dependent | journal = European Journal of Endocrinology | volume = 175 | issue = 1 | pages = 49–54 | date = July 2016 | pmid = 27150496 | doi = 10.1530/EJE-16-0007 }}</ref> Since [[DIO2|deiodinase type 2]] is necessary for T<sub>4</sub> to T<sub>3</sub> conversion in some peripheral tissues, "patients with ''DIO2'' gene polymorphisms may have variable peripheral T<sub>3</sub> availability", leading to localised [[hypothyroidism]] in some tissues.<ref name="Groenewegen-2021" /><ref name="Klubo-Gwiezdzinska-2022" /><ref name="Winther-2020" /> The Thr92Ala ''DIO2'' polymorphism is present in 12–36% of the population.<ref name="Groenewegen-2021" />

For the latter patients, levothyroxine monotherapy may not be sufficient<ref name="Groenewegen-2021" /> and patients may have improvement on combination therapy of T<sub>4</sub> and T<sub>3</sub>.<ref name=":6" /><ref name="Winther-2020" /><ref>{{Cite journal | vauthors = Veríssimo D, Reis A, Monteiro M, Dias L |date=2020-08-21 |title=When levothyroxine is not enough- combination therapy with liothyronine |url=https://www.endocrine-abstracts.org/ea/0070/ea0070ep451 |journal=Endocrine Abstracts |language=en |publisher=Bioscientifica |volume=70 |doi=10.1530/endoabs.70.EP451|url-access=subscription }}</ref> As standard immunoassay tests can overestimate blood T<sub>4</sub> and T<sub>3</sub> levels, Ultrafiltration LC-MSMS T<sub>4</sub> and T<sub>3</sub> tests may help to identify patients who would benefit from additional T<sub>3</sub>.<ref name="Welsh-2016" />