Editing Hashimoto's thyroiditis (section)

== Causes ==
The causes of Hashimoto's thyroiditis are complex. Around 80% of the risk of developing an autoimmune thyroid disorder is due to [[Genetics|genetic factors]], while the remaining 20% is related to [[environmental factor]]s (such as iodine, drugs, infection, stress, radiation).<ref name="Casto-2021">{{cite journal | vauthors = Casto C, Pepe G, Li Pomi A, Corica D, Aversa T, Wasniewska M | title = Hashimoto's Thyroiditis and Graves' Disease in Genetic Syndromes in Pediatric Age | journal = Genes | volume = 12 | issue = 2 | pages = 222 | date = February 2021 | pmid = 33557156 | pmc = 7913917 | doi = 10.3390/genes12020222 | doi-access = free }}</ref>

=== Genetics ===
Thyroid autoimmunity can be [[Heredity|familial]].<ref name="Dayan96">{{cite journal | vauthors = Dayan CM, Daniels GH | title = Chronic autoimmune thyroiditis | journal = The New England Journal of Medicine | volume = 335 | issue = 2 | pages = 99–107 | date = July 1996 | pmid = 8649497 | doi = 10.1056/nejm199607113350206 }}</ref>  Many patients report a family history of autoimmune thyroiditis or [[Graves' disease]].<ref name="Singh2020"/>  The strong genetic component is borne out in studies on [[monozygotic twins]],<ref name="Mincer2022" /> with a [[Concordance (genetics)|concordance]] of 38–55%, with an even higher concordance of circulating thyroid antibodies not in relation to [[clinical presentation]] (up to 80% in monozygotic twins). Neither result was seen to a similar degree in [[dizygotic twins]], offering strong favour for high genetic [[etiology]].<ref name="Chistiakov-2005" />

The genes implicated vary in different ethnic groups<ref name="Jacobson-2008" /> and the impact of these genes on the disease differs significantly among people from different ethnic groups. A gene that has a large effect in one ethnic group's risk of developing Hashimoto's thyroiditis might have a much smaller effect in another ethnic group.<ref name="Chistiakov-2005" /> 

The incidence of autoimmune thyroid disorders is increased in people with [[chromosomal disorders]], including [[Turner syndrome|Turner]], [[Down syndrome|Down]], and [[Klinefelter syndrome]]s.<ref name="Casto-2021" />

==== HLA genes ====
The first gene [[Locus (genetics)|locus]] associated with autoimmune thyroid disease was the [[major histocompatibility complex]] (MHC) region on [[chromosome]] 6p21. It encodes [[human leukocyte antigen]]s (HLAs). Specific HLA [[Allele|alleles]] have a higher affinity to auto-antigenic thyroidal [[Peptide|peptides]] and can contribute to autoimmune thyroid disease development. Specifically, in Hashimoto's disease, aberrant expression of HLA II on [[Thyroid follicular cell|thyrocytes]] has been demonstrated. They can present thyroid autoantigens and initiate autoimmune thyroid disease.<ref name="Jacobson-2008">{{cite journal | vauthors = Jacobson EM, Huber A, Tomer Y | title = The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology | journal = Journal of Autoimmunity | volume = 30 | issue = 1–2 | pages = 58–62 | date = 2008 | pmid = 18178059 | pmc = 2244911 | doi = 10.1016/j.jaut.2007.11.010 }}</ref> Susceptibility alleles are not consistent in Hashimoto's disease. In Caucasians, various alleles are reported to be associated with the disease, including [[Death receptor 3|DR3]], [[Death receptor 5|DR5]], and [[HLA-DQ7|DQ7]].<ref>{{cite journal | vauthors = Tandon N, Zhang L, Weetman AP | title = HLA associations with Hashimoto's thyroiditis | journal = Clinical Endocrinology | volume = 34 | issue = 5 | pages = 383–386 | date = May 1991 | pmid = 1676351 | doi = 10.1111/j.1365-2265.1991.tb00309.x | s2cid = 28987581 }}</ref><ref>{{cite journal | vauthors = Bogner U, Badenhoop K, Peters H, Schmieg D, Mayr WR, Usadel KH, Schleusener H | title = HLA-DR/DQ gene variation in nongoitrous autoimmune thyroiditis at the serological and molecular level | journal = Autoimmunity | volume = 14 | issue = 2 | pages = 155–158 | date = January 1992 | pmid = 1363895 | doi = 10.3109/08916939209083135 }}</ref>

==== CTLA-4 genes ====
[[CTLA-4]] is the second major immune-[[Regulator gene|regulatory]] gene related to autoimmune thyroid disease. CTLA-4 gene polymorphisms may contribute to the reduced inhibition of T-cell [[Cell proliferation|proliferation]] and increase susceptibility to autoimmune response.<ref>{{cite journal | vauthors = Zaletel K, Gaberšček S | title = Hashimoto's Thyroiditis: From Genes to the Disease | journal = Current Genomics | volume = 12 | issue = 8 | pages = 576–588 | date = December 2011 | pmid = 22654557 | pmc = 3271310 | doi = 10.2174/138920211798120763 }}</ref> CTLA-4 is a major thyroid autoantibody susceptibility gene. A linkage of the CTLA-4 region to the presence of thyroid autoantibodies was demonstrated by a whole-genome [[linkage analysis]].<ref>{{cite journal | vauthors = Tomer Y, Greenberg DA, Barbesino G, Concepcion E, Davies TF | title = CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 4 | pages = 1687–1693 | date = April 2001 | pmid = 11297604 | doi = 10.1210/jcem.86.4.7372 | doi-access = free }}</ref> CTLA-4 was confirmed as the main locus for thyroid autoantibodies.<ref>{{cite journal | vauthors = Ban Y, Davies TF, Greenberg DA, Kissin A, Marder B, Murphy B, Concepcion ES, Villanueva RB, Barbesino G, Ling V, Tomer Y | title = Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease | journal = Genes and Immunity | volume = 4 | issue = 8 | pages = 586–593 | date = December 2003 | pmid = 14647199 | doi = 10.1038/sj.gene.6364018 | s2cid = 6920190 | doi-access =  }}</ref>

====PTPN22 gene====
''[[PTPN22]]'' is the most recently identified immune-regulatory gene associated with autoimmune thyroid disease. It is located on chromosome 1p13 and expressed in lymphocytes. It acts as a negative regulator of T-cell activation. [[Mutation]] in this gene is a risk factor for many autoimmune diseases. Weaker T-cell signaling may lead to impaired [[Negative selection (immunology)|thymic deletion]] of autoreactive T cells, and increased PTPN22 function may result in inhibition of regulatory T cells, which protect against autoimmunity.<ref>{{cite journal | vauthors = Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP | title = Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? | journal = FEBS Letters | volume = 585 | issue = 23 | pages = 3689–3698 | date = December 2011 | pmid = 21515266 | doi = 10.1016/j.febslet.2011.04.032 | s2cid = 21572847 | doi-access = free | bibcode = 2011FEBSL.585.3689B }}</ref>

==== Immune-related genes ====
[[IFN-γ]] promotes cell-mediated [[cytotoxicity]] against thyroid mutations causing increased production of IFN-γ were associated with the severity of hypothyroidism.<ref>{{cite journal | vauthors = Ito C, Watanabe M, Okuda N, Watanabe C, Iwatani Y | title = Association between the severity of Hashimoto's disease and the functional +874A/T polymorphism in the interferon-gamma gene | journal = Endocrine Journal | volume = 53 | issue = 4 | pages = 473–478 | date = August 2006 | pmid = 16820703 | doi = 10.1507/endocrj.k06-015 | doi-access = free }}</ref> Severe hypothyroidism is associated with mutations leading to lower production of [[Interleukin 4|IL-4]] (Th2 cytokine suppressing cell-mediated autoimmunity),<ref>{{cite journal | vauthors = Nanba T, Watanabe M, Akamizu T, Iwatani Y | title = The -590CC genotype in the IL4 gene as a strong predictive factor for the development of hypothyroidism in Hashimoto disease | journal = Clinical Chemistry | volume = 54 | issue = 3 | pages = 621–623 | date = March 2008 | pmid = 18310157 | doi = 10.1373/clinchem.2007.099739 | doi-access =  }}</ref> lower secretion of [[TGF-β]] (inhibitor of [[cytokine]] production),<ref>{{cite journal | vauthors = Yamada H, Watanabe M, Nanba T, Akamizu T, Iwatani Y | title = The +869T/C polymorphism in the transforming growth factor-beta1 gene is associated with the severity and intractability of autoimmune thyroid disease | journal = Clinical and Experimental Immunology | volume = 151 | issue = 3 | pages = 379–382 | date = March 2008 | pmid = 18190611 | pmc = 2276968 | doi = 10.1111/j.1365-2249.2007.03575.x }}</ref> and mutations of [[FOXP3]], an essential regulatory factor for the [[regulatory T cells]] (Tregs) development.<ref>{{cite journal | vauthors = Inoue N, Watanabe M, Morita M, Tomizawa R, Akamizu T, Tatsumi K, Hidaka Y, Iwatani Y | title = Association of functional polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diseases | journal = Clinical and Experimental Immunology | volume = 162 | issue = 3 | pages = 402–406 | date = December 2010 | pmid = 20942809 | pmc = 3026543 | doi = 10.1111/j.1365-2249.2010.04229.x }}</ref> Development of Hashimoto's disease was associated with mutation of the gene for [[TNF-α]] (stimulator of the IFN-γ production), causing its higher concentration.<ref>{{cite journal | vauthors = Inoue N, Watanabe M, Nanba T, Wada M, Akamizu T, Iwatani Y | title = Involvement of functional polymorphisms in the TNFA gene in the pathogenesis of autoimmune thyroid diseases and production of anti-thyrotropin receptor antibody | journal = Clinical and Experimental Immunology | volume = 156 | issue = 2 | pages = 199–204 | date = May 2009 | pmid = 19250279 | pmc = 2759465 | doi = 10.1111/j.1365-2249.2009.03884.x }}</ref>

=== Existential (endogenous environmental) ===

==== Sex ====
Study of healthy Danish twins divided to three groups (monozygotic and dizygotic same sex, and opposite sex twin pairs) estimated that genetic contribution to thyroid peroxidase antibodies susceptibility was 61% in males and 72% in females, and contribution to thyroglobulin antibodies susceptibility was 39% in males and 75% in females.<ref>{{cite journal | vauthors = Hansen PS, Brix TH, Iachine I, Kyvik KO, Hegedüs L | title = The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: a study of healthy Danish twins | journal = European Journal of Endocrinology | volume = 154 | issue = 1 | pages = 29–38 | date = January 2006 | pmid = 16381988 | doi = 10.1530/eje.1.02060 | s2cid = 25372591 | doi-access =  }}</ref>

The high female predominance in thyroid autoimmunity may be associated with the X chromosome. It contains sex and immune-related genes responsible for [[immune tolerance]].<ref>{{cite journal | vauthors = McCombe PA, Greer JM, Mackay IR | title = Sexual dimorphism in autoimmune disease | journal = Current Molecular Medicine | volume = 9 | issue = 9 | pages = 1058–1079 | date = December 2009 | pmid = 19747114 | doi = 10.2174/156652409789839116 }}</ref>
A higher incidence of thyroid autoimmunity was reported in patients with a higher rate of X-chromosome [[monosomy]] in peripheral white blood cells.<ref>{{cite journal | vauthors = Invernizzi P, Miozzo M, Selmi C, Persani L, Battezzati PM, Zuin M, Lucchi S, Meroni PL, Marasini B, Zeni S, Watnik M, Grati FR, Simoni G, Gershwin ME, Podda M | title = X chromosome monosomy: a common mechanism for autoimmune diseases | journal = Journal of Immunology | volume = 175 | issue = 1 | pages = 575–578 | date = July 2005 | pmid = 15972694 | doi = 10.4049/jimmunol.175.1.575 | s2cid = 40557667 | doi-access = free }}</ref> Another potential mechanism might be skewed [[X-chromosome inactivation]].<ref name="Ramos-Levi2023" /> 
==== Pregnancy ====
In one population study, two or more births were a risk factor for developing autoimmune hypothyroidism in pre-menopausal women.<ref name="Carlé-2014">{{cite journal | vauthors = Carlé A, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Rasmussen LB, Laurberg P | title = Development of autoimmune overt hypothyroidism is highly associated with live births and induced abortions but only in premenopausal women | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 99 | issue = 6 | pages = 2241–2249 | date = June 2014 | pmid = 24694338 | doi = 10.1210/jc.2013-4474 | doi-access = free }}</ref>

=== Environmental ===

==== Medications ====
Certain medications or drugs have been associated with altering and interfering with thyroid function. There are two main mechanisms of interference:<ref name="Surks-1995" />

* Altering thyroid hormone serum transfer proteins.<ref name="Surks-1995">{{cite journal | vauthors = Surks MI, Sievert R | title = Drugs and thyroid function | journal = The New England Journal of Medicine | volume = 333 | issue = 25 | pages = 1688–1694 | date = December 1995 | pmid = 7477223 | doi = 10.1056/NEJM199512213332507 | veditors = Wood AJ }}</ref> [[Estrogen]], [[tamoxifen]], [[heroin]], [[methadone]], [[clofibrate]], [[Fluorouracil|5-fluorouracil]], [[mitotane]], and [[perphenazine]] all increase [[thyroid binding globulin]] (TBG) concentration.<ref name="Surks-1995" /> [[Androgen]]s, [[anabolic steroid]]s such as [[danazol]], glucocorticoids, and slow release [[nicotinic acid]] all decrease TBG concentrations. [[Furosemide]], fenoflenac, [[mefenamic acid]], [[salicylates]], [[phenytoin]], [[diazepam]], [[sulphonylureas]], [[free fatty acids]], and [[heparin]] all interfere with thyroid hormone binding to TBG and/or [[transthyretin]].<ref name="Surks-1995" />
* Altering extra-thryoidal metabolism of thyroid hormone. [[Propylthiouracil]], [[Glucocorticoid|glucocorticoids]], [[propranolol]], iondinated [[Contrast agent|contrast agents]], [[Amiodarone induced thyrotoxicosis|amiodarone]], and [[clomipramine]] all inhibit conversion of T<sub>4</sub> and T<sub>3</sub>.<ref name="Surks-1995" /> [[Phenobarbital]], [[Rifampicin|rifampin]], [[phenytoin]] and [[carbamazepine]] all increase [[hepatic]] metabolism.<ref name="Surks-1995" /> Finally, [[Colestyramine|cholestryamine]], [[colestipol]], [[aluminium hydroxide]], [[ferrous sulphate]], and [[sucralfate]] are all drugs that decrease T<sub>4</sub> absorption or enhance excretion.<ref name="Surks-1995" />

==== Iodine ====
Both excessive and insufficient [[Iodine#Dietary intake|iodine intake]] has been implicated in developing antithyroid antibodies.<ref name=":9" /><ref name=":8">{{Cite book | vauthors =  Weetman AP, Kahaly GJ |title=DeGroot's Endocrinology |year=2023 |edition=8th |pages=1178-1193 |chapter=Graves Disease}}</ref> Thyroid autoantibodies are found to be more prevalent in geographical areas after increasing iodine levels.<ref name=":8" /> Several mechanisms by which excessive iodine may promote thyroid autoimmunity have been proposed:<ref name=":9" />

* Via thyroglobulin iodination: Iodine exposure leads to higher iodination of thyroglobulin, increasing its [[immunogenicity]]<ref name=":9">{{cite journal | vauthors = Rayman MP | title = Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease | journal = The Proceedings of the Nutrition Society | volume = 78 | issue = 1 | pages = 34–44 | date = February 2019 | pmid = 30208979 | doi = 10.1017/S0029665118001192 }}</ref> by creating new iodine-containing [[Epitope|epitopes]] or exposing [[cryptic epitopes]].<ref>{{cite journal | vauthors = Teti C, Panciroli M, Nazzari E, Pesce G, Mariotti S, Olivieri A, Bagnasco M | title = Iodoprophylaxis and thyroid autoimmunity: an update | journal = Immunologic Research | volume = 69 | issue = 2 | pages = 129–138 | date = April 2021 | pmid = 33914231 | pmc = 8106604 | doi = 10.1007/s12026-021-09192-6 }}</ref>
* Via [[Thyroid follicular cell|thyrocyte]] damage: Iodine exposure has been shown to increase the level of [[reactive oxygen species]]. They enhance the expression of the [[intracellular adhesion molecule]]-1 on the thyrocytes, which could attract the immuno-competent cells into the thyroid gland.<ref name=":9" /> Iodine also promotes thyrocyte [[apoptosis]].<ref name=":9" />
* Via immune cell behaviour: Iodine has an influence on immune cells.<ref name=":9" />

==== Comorbidities ====
[[Comorbidity|Comorbid]] autoimmune diseases are a risk factor for developing Hashimoto's thyroiditis, and the opposite is also true.<ref name=NIH2014/> Another thyroid disease closely associated with Hashimoto's thyroiditis is Graves' disease.<ref name="Weetman2021"/> Autoimmune diseases affecting other organs most commonly associated with Hashimoto's thyroiditis include [[celiac disease]], [[diabetes mellitus type 1|type 1 diabetes]], [[vitiligo]], [[alopecia]],<ref name="Radetti2014">{{cite book |doi=10.1159/000363162 |chapter=Clinical Aspects of Hashimoto's Thyroiditis |title=Paediatric Thyroidology |series=Endocrine Development |year=2014 | vauthors = Radetti G |volume=26 |pages=158–170 |pmid=25231451 |isbn=978-3-318-02720-4 }}</ref> [[Addison's disease|Addison disease]], [[Sjögren syndrome|Sjogren's syndrome]], and [[rheumatoid arthritis]]<ref name="Singh2020"/><ref name="Niddk2021">{{Cite web |title=Hashimoto's Disease |url=https://www.niddk.nih.gov/health-information/endocrine-diseases/hashimotos-disease |url-status=live |archive-url=https://web.archive.org/web/20211208141910/https://www.niddk.nih.gov/health-information/endocrine-diseases/hashimotos-disease |archive-date=8 December 2021 |access-date=2023-01-23 |website=National Institute of Diabetes and Digestive and Kidney Diseases |language=en-US}}</ref> Autoimmune thyroiditis has also been seen in patients with [[autoimmune polyendocrine syndrome]]s type 1 and 2.<ref name="Weetman2021"/>

==== Other ====
Other environmental factors include [[selenium deficiency]],<ref name="Winther-2020" /> infectious diseases such as [[hepatitis C]], [[rubella]], and possibly [[Covid-19]],<ref>{{cite journal | vauthors = Saranac L, Zivanovic S, Bjelakovic B, Stamenkovic H, Novak M, Kamenov B | title = Why is the thyroid so prone to autoimmune disease? | journal = Hormone Research in Paediatrics | volume = 75 | issue = 3 | pages = 157–165 | date = 2011 | pmid = 21346360 | doi = 10.1159/000324442 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lambert N, Strebel P, Orenstein W, Icenogle J, Poland GA | title = Rubella | language = English | journal = Lancet | volume = 385 | issue = 9984 | pages = 2297–2307 | date = June 2015 | pmid = 25576992 | pmc = 4514442 | doi = 10.1016/S0140-6736(14)60539-0 }}</ref><ref>{{cite journal | vauthors = Lui DT, Lee CH, Woo YC, Hung IF, Lam KS | title = Thyroid dysfunction in COVID-19 | journal = Nature Reviews. Endocrinology | volume = 20 | issue = 6 | pages = 336–348 | date = June 2024 | pmid = 38347167 | doi = 10.1038/s41574-023-00946-w }}</ref> toxins,<ref name="Ramos-Levi2023" /> dietary factors,<ref name="Weetman2021"/> radiation exposure,<ref name="Ramos-Levi2023" /> and [[dysbiosis|gut dysbiosis]].<ref name="Ludgate-2024" />