Editing Hashimoto's thyroiditis (section)

=== Persistent Symptoms ===
Multiple studies have demonstrated persistent symptoms in Hashimoto's patients with normal thyroid hormone levels (euthyroid)<ref name=":6" /><ref name="Taylor-2024">{{cite journal | vauthors = Taylor PN, Medici MM, Hubalewska-Dydejczyk A, Boelaert K | title = Hypothyroidism | journal = Lancet | volume = 404 | issue = 10460 | pages = 1347–1364 | date = October 2024 | pmid = 39368843 | doi = 10.1016/S0140-6736(24)01614-3 }}</ref><ref name="Klubo-Gwiezdzinska-2022" /><ref name="Groenewegen-2021" /> and an estimated 10%-15% of patients treated with levothyroxine monotherapy are dissatisfied due to persistent symptoms of hypothyroidism.<ref name="Jonklaas-2019">{{cite journal | vauthors = Jonklaas J, Razvi S | title = Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers | journal = The Lancet. Diabetes & Endocrinology | volume = 7 | issue = 6 | pages = 473–483 | date = June 2019 | pmid = 30797750 | doi = 10.1016/S2213-8587(18)30371-1 }}</ref><ref name="Hegedüs-2022">{{cite journal | vauthors = Hegedüs L, Bianco AC, Jonklaas J, Pearce SH, Weetman AP, Perros P | title = Primary hypothyroidism and quality of life | journal = Nature Reviews. Endocrinology | volume = 18 | issue = 4 | pages = 230–242 | date = April 2022 | pmid = 35042968 | pmc = 8930682 | doi = 10.1038/s41574-021-00625-8 }}</ref> Several different [[Hypothesis|hypothesised]] causes are discussed in the [[medical literature]]:<ref name=":2" /><ref name="Groenewegen-2021" /><ref name="Klubo-Gwiezdzinska-2022" />

==== 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" /> 

==== Inadequate markers hypothesis ====
There is ongoing debate about how to define euthyroidism and whether TSH is its best indicator.<ref name="Jonklaas-2019" /> TSH may be useful to detect poor thyroid output and may reflect the state of thyroid hormones in the [[Hypothalamic–pituitary–thyroid axis|hypothalamic-pituitary-thyroid axis]], but not the presence of hormones in other body tissues.<ref name="Hegedüs-2022" /><ref name="Taylor-2024" /><ref name="Wiersinga-2014" /> As a result, LT<sub>4</sub> monotherapy may not result in a "truly biochemically euthyroid state."<ref name="Groenewegen-2021" /> Patients may express a preference for "low normal or below normal TSH values"<ref name="Wiersinga-2014" /> and/or T<sub>4</sub> and T<sub>3</sub> monitoring. The monitoring of other [[Biomarker (medicine)|biomarkers]] that reflect the action of thyroid hormone on tissues has also been proposed.<ref name="Klubo-Gwiezdzinska-2022" /><ref>{{cite journal | vauthors = McAninch EA, Rajan KB, Miller CH, Bianco AC | title = Systemic Thyroid Hormone Status During Levothyroxine Therapy In Hypothyroidism: A Systematic Review and Meta-Analysis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 12 | pages = 4533–4542 | date = August 2018 | pmid = 30124904 | pmc = 6226605 | doi = 10.1210/jc.2018-01361 }}</ref><ref name="Hegedüs-2022" />

As [[immunoassay]] Free T<sub>3</sub> and Free T4 tests can overestimate levels, particularly at low thyroid hormone levels, hypothyroidism may be undertreated.<ref name="Welsh-2016" /> [[Liquid chromatography–mass spectrometry|LC-MSMS]] tests may provide more reliable measures.<ref name="Welsh-2016" />

==== Extra-thyroidal effects of autoimmunity hypothesis ====
It is hypothesised that autoimmunity may play some role in euthyroid symptoms.<ref name="Taylor-2024" /><ref name="Chaker-2022" /><ref name="Groenewegen-2021" /> Hypothesised mechanisms include the proposal that TPO-antibody-producing [[Lymphocyte|lymphocytes]] may travel out of the thyroid to other tissue, creating symptoms and inflammation due to [[Cross-reactivity|cross-reaction]],<ref name="Groenewegen-2021" /><ref name="Guldvog I et al">{{cite journal | vauthors = Guldvog I, Reitsma LC, Johnsen L, Lauzike A, Gibbs C, Carlsen E, Lende TH, Narvestad JK, Omdal R, Kvaløy JT, Hoff G, Bernklev T, Søiland H | title = Thyroidectomy Versus Medical Management for Euthyroid Patients With Hashimoto Disease and Persisting Symptoms: A Randomized Trial | journal = Annals of Internal Medicine | volume = 170 | issue = 7 | pages = 453–464 | date = April 2019 | pmid = 30856652 | doi = 10.7326/M18-0284 }}</ref> or "the inflammatory nature of [...] persistently increased circulating cytokine levels."<ref name="Taylor-2024" /> Multiple studies find that antibodies coincide with symptoms even in euthyroid patients,<ref name="Ramos-Levi2023" /><ref name="Groenewegen-2021" /> and higher levels are associated with increased symptoms,<ref name=":6" /> however "the found [[Association (statistics)|association]] does not prove a [[causality]]".<ref name="Groenewegen-2021" /> No treatment currently exists for Hashimoto's autoimmunity, although observed wellbeing improvements after surgical thyroid removal are hypothesised to be due to removing the autoimmune stimulus.<ref name="Klubo-Gwiezdzinska-2022" /><ref name="Guldvog I et al" />

==== Physical and psychosocial co-morbidities hypothesis ====
It is hypothesised that euthyroid symptoms may not be due to Hashimoto's or hypothyroidism, but some other "physical and psychosocial [[Comorbidity|co-morbidities]]".<ref name=":2" /><ref name="Hegedüs-2022" />