Hashimoto's thyroiditis

{{short description|Autoimmune disease}} {{redirect|Hashimoto's disease|the encephalopathy|Hashimoto's encephalopathy}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{use dmy dates|date=April 2020}} {{infobox medical condition (new) | name = Hashimoto's thyroiditis | image = Hashimoto thyroiditis - alt -- very low mag.jpg | caption = A micrograph of the thyroid of someone with Hashimoto's thyroiditis | synonyms = Chronic lymphocytic thyroiditis, autoimmune thyroiditis, struma lymphomatosa, Hashimoto's disease | field = Endocrinology | symptoms = Weight gain, feeling tired, constipation, joint and muscle pain, cold intolerance, dry skin, hair loss, slowed heart rate<ref name="niddk2024"/> | complications = Thyroid lymphoma.<ref name=Nou2015/> | onset = 30–50 years old<ref name=NIH2014/><ref name=Hir2013/> | duration = | causes = Genetic and environmental factors.<ref name="Ramos-Levi2023" /> | risks = Family history, another autoimmune disease<ref name=NIH2014/> | diagnosis = TSH, T4, anti-thyroid autoantibodies, ultrasound<ref name=NIH2014/> | differential = Graves' disease, nontoxic nodular goiter<ref name=Ak2000/> | prevention = | treatment = Levothyroxine, surgery<ref name=NIH2014/><ref name=Ak2000/> | medication = | prognosis = | frequency = 2% at some point<ref name="Ramos-Levi2023" /> | deaths = }}

'''Hashimoto's thyroiditis''', also known as '''chronic lymphocytic thyroiditis''', '''Hashimoto's disease''' and '''autoimmune thyroiditis''', is an autoimmune disease in which the thyroid gland is gradually destroyed.<ref name="AR">{{cite web |title=Autoimmune thyroiditis |url=https://www.autoimmuneregistry.org/autoimmune-thyroiditis |access-date=15 June 2022 |website=Autoimmune Registry Inc. |archive-date=25 February 2020 |archive-url=https://web.archive.org/web/20200225140353/https://www.autoimmuneregistry.org/autoimmune-thyroiditis |url-status=live }}</ref><ref name="niddk2024">{{cite web |title=Hashimoto's Disease |url=https://www.niddk.nih.gov/health-information/endocrine-diseases/hashimotos-disease |website=National Institute of Diabetes and Digestive and Kidney Diseases |access-date=4 December 2024}}</ref>

Early on, symptoms may not be noticed.<ref name=NIH2014>{{cite web|title=Hashimoto's Disease|url=https://www.niddk.nih.gov/health-information/endocrine-diseases/hashimotos-disease?dkrd=hispt0297|website=National Institute of Diabetes and Digestive and Kidney Diseases|access-date=9 August 2016|date=May 2014|url-status=live|archive-url=https://web.archive.org/web/20160822021514/https://www.niddk.nih.gov/health-information/health-topics/endocrine/hashimotos-disease/Pages/fact-sheet.aspx|archive-date=22 August 2016}}</ref> Over time, the thyroid may enlarge, forming a painless goiter.<ref name=NIH2014/> Most people eventually develop hypothyroidism with accompanying weight gain, fatigue, constipation, hair loss, and general pain.<ref name="niddk2024"/> After many years, the thyroid typically shrinks in size.<ref name="niddk2024"/> Potential complications include thyroid lymphoma.<ref name=Nou2015>{{cite journal | vauthors = Noureldine SI, Tufano RP | title = Association of Hashimoto's thyroiditis and thyroid cancer | journal = Current Opinion in Oncology | volume = 27 | issue = 1 | pages = 21–25 | date = January 2015 | pmid = 25390557 | doi = 10.1097/cco.0000000000000150 | s2cid = 32109200 }}</ref> Further complications of hypothyroidism can include high cholesterol, heart disease, heart failure, high blood pressure, myxedema, and potential problems in pregnancy.<ref name="niddk2024"/>

<!-- Cause and diagnosis --> Hashimoto's thyroiditis is thought to develop due to a combination of genetic and environmental factors.<ref name="Ramos-Levi2023" /><ref name="Winther-2020">{{cite journal | vauthors = Winther KH, Rayman MP, Bonnema SJ, Hegedüs L | title = Selenium in thyroid disorders - essential knowledge for clinicians | journal = Nature Reviews. Endocrinology | volume = 16 | issue = 3 | pages = 165–176 | date = March 2020 | pmid = 32001830 | doi = 10.1038/s41574-019-0311-6 }}</ref> Risk factors include a family history of the condition and having another autoimmune disease.<ref name=NIH2014/> Diagnosis is confirmed with blood tests for TSH, thyroxine (T₄), antithyroid autoantibodies, and ultrasound.<ref name=NIH2014/> Other conditions that can produce similar symptoms include Graves' disease and nontoxic nodular goiter.<ref name=Ak2000>{{cite book |vauthors=Akamizu T, Amino N, Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland J, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP |date=2000 |pmid=25905412 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK285557/ |veditors=Akamizu T, Amino N |title=Endotext |publisher=MDText |url=https://www.ncbi.nlm.nih.gov/books/NBK285557/ |chapter=Hashimoto's Thyroiditis |access-date=31 January 2021 |archive-date=24 September 2020 |archive-url=https://web.archive.org/web/20200924130429/https://www.ncbi.nlm.nih.gov/books/NBK285557/ |url-status=live }}</ref>

<!-- Treatment --> Hashimoto's is typically not treated unless there is hypothyroidism or the presence of a goiter, when it may be treated with levothyroxine.<ref name=Ak2000/><ref name=NIH2014/> Those affected should avoid eating large amounts of iodine; however, sufficient iodine is required especially during pregnancy.<ref name=NIH2014/> Surgery is rarely required to treat the goiter.<ref name=Ak2000/>

<!-- Epidemiology and history --> Hashimoto's thyroiditis has a global prevalence of 7.5%, and varies greatly by region.<ref name="Hu"/> The highest rate is in Africa, and the lowest is in Asia.<ref name="Hu"/> In the US, white people are affected more often than black people. It is more common in low- to middle-income groups. Females are more susceptible, with a 17.5% rate of prevalence compared to 6% in males.<ref name="Hu"/> It is the most common cause of hypothyroidism in developed countries.<ref name="Mincer2022">{{cite book | vauthors = Mincer DL, Jialal I | chapter = Hashimoto Thyroiditis |date=2022 | title = StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK459262/ |access-date=2023-01-23 |archive-url=https://web.archive.org/web/20231004133211/https://www.ncbi.nlm.nih.gov/books/NBK459262/ |archive-date=4 October 2023 |url-status=live |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29083758}}</ref> It typically begins between the ages of 30 and 50.<ref name=NIH2014/><ref name=Hir2013>{{cite journal | vauthors = Hiromatsu Y, Satoh H, Amino N | title = Hashimoto's thyroiditis: history and future outlook | journal = Hormones | volume = 12 | issue = 1 | pages = 12–18 | date = January 2013 | pmid = 23624127 | doi = 10.1007/BF03401282 | s2cid = 38996783 }}</ref> Rates of the disease have increased.<ref name="Hu"/> It was first described by the Japanese physician Hakaru Hashimoto in 1912.<ref>{{cite book | veditors = Shoenfeld Y, Cervera R, Gershwin ME |title=Diagnostic Criteria in Autoimmune Diseases |date=2010 |publisher=Springer Science & Business Media |isbn=978-1-60327-285-8 |page=216 |url=https://books.google.com/books?id=A_vtzMxtd9AC&pg=PA216 }}</ref> Studies in 1956 discovered that it was an autoimmune disorder.<ref>{{cite journal | vauthors = Ralli M, Angeletti D, Fiore M, D'Aguanno V, Lambiase A, Artico M, de Vincentiis M, Greco A | title = Hashimoto's thyroiditis: An update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and potential malignant transformation | journal = Autoimmunity Reviews | volume = 19 | issue = 10 | article-number = 102649 | date = October 2020 | pmid = 32805423 | doi = 10.1016/j.autrev.2020.102649 }}</ref> {{TOC limit |3}}

== Signs and symptoms == thumb|Systemic manifestations of hypothyroidism

=== Signs === thumb|Depiction of a goiterIn the early stages of autoimmune thyroiditis, patients may have normal thyroid hormone levels and no goiter or a small one.<ref name="Ramos-Levi2023" /> Enlargement of the thyroid is due to lymphocytic infiltration and fibrosis.<ref name="Klubo-Gwiezdzinska-2022">{{cite journal | vauthors = Klubo-Gwiezdzinska J, Wartofsky L | title = Hashimoto thyroiditis: an evidence-based guide to etiology, diagnosis and treatment | journal = Polish Archives of Internal Medicine | volume = 132 | issue = 3 | article-number = 16222 | date = March 2022 | pmid = 35243857 | pmc = 9478900 | doi = 10.20452/pamw.16222 }}</ref> Early on, thyroid autoantibodies in the blood may be the only indication of Hashimoto's disease.<ref name="Ramos-Levi2023" /> They are thought to be the secondary products of the T cell-mediated destruction of the gland.<ref name="Ramos-Levi2023" />

As lymphocytic infiltration progresses, patients may exhibit signs of hypothyroidism in multiple bodily systems, including, but not limited to, a larger goiter, weight gain, cold intolerance, fatigue, myxedema, constipation, menstrual disturbances, pale or dry skin, and dry, brittle hair, depression, and ataxia.<ref name="Singh2020">{{Cite book |title=The Washington Manual, The Endocrinology - Subspecialty Consult |vauthors=Singh S, Clutter WE |publisher=Lippincott Williams & Wilkins |year=2020 |isbn=978-1-9751-1333-9 |edition=4th |location=Philadelphia, PA |pages=70–76 |language=English}}</ref><ref name="Mincer2022" /> Extended thyroid hormone deficiency may lead to muscle fibre changes, resulting in muscle weakness, muscle pain, stiffness, and rarely, pseudohypertrophy.<ref name="Fariduddin-2024">{{cite book | vauthors = Fariduddin MM, Haq N, Bansal N | chapter = Hypothyroid Myopathy |date=2024 | title = StatPearls | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK519513/ |access-date=2024-11-30 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30137798}}</ref> Patients with goiters who have had autoimmune thyroiditis for many years might see their goiter shrink in the later stages of the disease due to destruction of the thyroid.<ref name="niddk2024" /> Graves disease may occur before or after the development of autoimmune thyroiditis.<ref name="Weetman2021">{{Cite book |title=Werner & Ingbar's The Thyroid: A Fundamental and Clinical Text |vauthors=Weetman AP |publisher=Lippincott Williams & Wilkins |year=2021 |isbn=978-1-975112-96-7 |edition=11th |location=Philadelphia, PA |pages=531–541 |language=English}}</ref>

While rare, more serious complications of the hypothyroidism resulting from autoimmune thyroiditis are pericardial effusion, pleural effusion, both of which require further medical attention, and myxedema coma, which is an endocrine emergency.<ref name="Mincer2022" />

=== Symptoms === Many symptoms are attributed to the development of Hashimoto's thyroiditis. Symptoms can include: fatigue, weight gain, pale or puffy face, feeling cold, joint and muscle pain, constipation, dry and thinning hair, heavy menstrual flow or irregular periods, depression, a slowed heart rate, problems getting pregnant, miscarriages,<ref>{{Cite news|url=https://www.mayoclinic.org/diseases-conditions/hashimotos-disease/symptoms-causes/syc-20351855|title=Hashimoto's disease – Symptoms and causes|work=Mayo Clinic|access-date=2018-10-05|language=en|archive-date=29 October 2018|archive-url=https://web.archive.org/web/20181029084838/https://www.mayoclinic.org/diseases-conditions/hashimotos-disease/symptoms-causes/syc-20351855|url-status=live}}</ref> and myopathy.<ref name="Fariduddin-2024" /> Some patients in the early stage of the disease may experience symptoms of hyperthyroidism due to the release of thyroid hormones from intermittent thyroid destruction<ref name="Mincer2022" /><ref name="Dyrka-2024">{{cite journal | vauthors = Dyrka K, Obara-Moszyńska M, Niedziela M | title = Autoimmune thyroiditis: an update on treatment possibilities | journal = Endokrynologia Polska | volume = 75 | issue = 5 | pages = 461–472 | date = 2024 | pmid = 39475129 | doi = 10.5603/ep.100701 | doi-access = free }}</ref> (also called "destructive thyrotoxicosis").<ref name="Ramos-Levi2023" /> In non-medical settings, the term "flare" is used to refer to a sudden exacerbation of symptoms, whether hyper or hypo.<ref>{{Cite web |title=Hashimoto's Thyroiditis: Symptoms, Causes, and Treatments |url=https://www.webmd.com/women/hashimotos-thyroiditis-symptoms-causes-treatments |access-date=2025-01-08 |website=WebMD |language=en |vauthors=Dunkin MA}}</ref><!-- Hi Editors, the claim that "the term flare is used in non-medical settings" is a non-medical claim, so it does not require a MEDRS source.--> <!-- If you want to make *medical* claims about sudden exacerbations of symptoms (e.g., that they might have specific causes) you need to back that up with a MEDRS-level source. -->

While most symptoms are attributed to hypothyroidism, similar symptoms are observed in Hashimoto's patients with normal thyroid hormone levels.<ref name=":6">{{Cite book | vauthors = Jonklaas J |title=DeGroot's Endocrinology: Basic Science and Clinical Practice |year=2023 |isbn=978-0-323-69412-4 |edition=8th |pages=1234–1248 |chapter=Hypothyroidism|publisher=Elsevier Health Sciences }}</ref><ref name="Hegedüs-2022" /><ref name="Klubo-Gwiezdzinska-2022" /> According to one study, these symptoms may include lower quality of life, and issues of the "digestive system (abdominal distension, constipation and diarrhea), endocrine system (chilliness, gain weight and facial edema), neuropsychiatric system (forgetfulness, anxiety, depressed, fatigue, insomnia, irritability, and indifferent [''sic'']) and mucocutaneous system (dry skin, pruritus, and hair loss)".<ref name="Li-2024">{{cite journal | vauthors = Li J, Huang Q, Sun S, Zhou K, Wang X, Pan K, Zhang Y, Wang Y, Han Q, Si C, Li S, Fan S, Li D | title = Thyroid antibodies in Hashimoto's thyroiditis patients are positively associated with inflammation and multiple symptoms | journal = Scientific Reports | volume = 14 | issue = 1 | article-number = 27902 | date = November 2024 | pmid = 39537841 | pmc = 11561229 | doi = 10.1038/s41598-024-78938-7 | bibcode = 2024NatSR..1427902L }}</ref>

== Causes == The causes of Hashimoto's thyroiditis are complex. Around 80% of the risk of developing an autoimmune thyroid disorder is due to genetic factors, while the remaining 20% is related to environmental factors (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 | page = 222 | date = February 2021 | pmid = 33557156 | pmc = 7913917 | doi = 10.3390/genes12020222 | doi-access = free }}</ref>

=== Genetics === Thyroid autoimmunity can be 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 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, Down, and Klinefelter syndromes.<ref name="Casto-2021" />

==== HLA genes ==== The first gene locus associated with autoimmune thyroid disease was the major histocompatibility complex (MHC) region on chromosome 6p21. It encodes human leukocyte antigens (HLAs). Specific HLA alleles have a higher affinity to auto-antigenic thyroidal peptides and can contribute to autoimmune thyroid disease development. Specifically, in Hashimoto's disease, aberrant expression of HLA II on 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 DR3, DR5, and 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-regulatory gene related to autoimmune thyroid disease. CTLA-4 gene polymorphisms may contribute to the reduced inhibition of T-cell 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 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 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 ==== A study of healthy Danish twins divided into 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, 5-fluorouracil, mitotane, and perphenazine all increase thyroid binding globulin (TBG) concentration.<ref name="Surks-1995" /> Androgens, anabolic steroids such as danazol, glucocorticoids, and slow release nicotinic acid all decrease TBG concentrations. Furosemide, fenclofenac, 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 the extra-thyroidal metabolism of thyroid hormone. Propylthiouracil, glucocorticoids, propranolol, iodinated contrast agents, amiodarone, and clomipramine all inhibit conversion of T₄ and T₃.<ref name="Surks-1995" /> Phenobarbital, rifampin, phenytoin and carbamazepine all increase hepatic metabolism.<ref name="Surks-1995" /> Finally, cholestryamine, colestipol, aluminium hydroxide, ferrous sulphate, and sucralfate are all drugs that decrease T₄ absorption or enhance excretion.<ref name="Surks-1995" />

==== Iodine ==== Both excessive and insufficient 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 epitopes or exposing cryptic epitopes.<ref name="auto">{{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 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 immunocompetent cells into the thyroid gland.<ref name=":9" /> Iodine also promotes thyrocyte apoptosis.<ref name=":9" /> * Via immune cell behaviour: Iodine influences immune cells.<ref name=":9" />

==== Comorbidities ==== 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, type 1 diabetes, vitiligo, alopecia areata,<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 disease, Sjogren's disease, 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 syndromes type 1 and 2.<ref name="Weetman2021"/>

'''Psychological Stress'''

Psychological stress may impact thyroid autoimmunity by in those who are susceptible by imbalance between the Th1 and Th2 immune response. Stress causes activation of the hypothalamic-pituitary-adrenal axis ( HPA axis) which then leads to the release of stress hormones such as glucocorticoids and catecholamines. These then subsequently leads to inducing the differentiation of Th2 cells over Th1 which leads to increasing humoral immunity. This increases antibodies in the form of B cells such as anti-thyroid peroxidanse and anti-thyroglobulin which causes destruction of thyroid tissue.<ref>{{Cite journal |last=Tsatsoulis |first=Agathocles |date=November 2006 |title=The role of stress in the clinical expression of thyroid autoimmunity |journal=Annals of the New York Academy of Sciences |volume=1088 |issue=1 |pages=382–395 |doi=10.1196/annals.1366.015 |issn=0077-8923 |pmid=17192582 |bibcode=2006NYASA1088..382T }}</ref> Chronic stress continues this mechanism and has been shown to increase the incidence of Hashimoto's and other autoimmune conditions<ref>{{Cite journal |last1=Batóg |first1=Gabriela |last2=Dołoto |first2=Anna |last3=Bąk |first3=Ewelina |last4=Piątkowska-Chmiel |first4=Iwona |last5=Krawiec |first5=Paulina |last6=Pac-Kożuchowska |first6=Elżbieta |last7=Herbet |first7=Mariola |date=2023 |title=The interplay of oxidative stress and immune dysfunction in Hashimoto's thyroiditis and polycystic ovary syndrome: a comprehensive review |journal=Frontiers in Immunology |volume=14 |article-number=1211231 |doi=10.3389/fimmu.2023.1211231 |doi-access=free |issn=1664-3224 |pmc=10426741 |pmid=37588599}}</ref>.

'''Viral Infections'''

There is implication for several viral infections triggering the development of Hashimoto's thyroiditis such as Hepatitis C, Epstein-Barr, Herpes Simplex, and human parvovirus B19<ref>{{Cite journal |last1=Li |first1=Yitian |last2=Li |first2=Weiyang |date=2025 |title=Viral infection and thyroid disorders: a narrative review |journal=Frontiers in Microbiology |volume=16 |article-number=1625179 |doi=10.3389/fmicb.2025.1625179 |doi-access=free |issn=1664-302X |pmc=12202521 |pmid=40584044}}</ref>. There are several mechanisms through which viral infections can lead to disease development, including immune upregulation<ref>{{Cite journal |last1=Cuan-Baltazar |first1=Yunam |last2=Soto-Vega |first2=Elena |date=September 2020 |title=Microorganisms associated to thyroid autoimmunity |journal=Autoimmunity Reviews |volume=19 |issue=9 |article-number=102614 |doi=10.1016/j.autrev.2020.102614 |issn=1873-0183 |pmid=32663624}}</ref> and molecular mimicry<ref>{{Cite journal |last1=Li |first1=Yitian |last2=Li |first2=Weiyang |date=2025 |title=Viral infection and thyroid disorders: a narrative review |journal=Frontiers in Microbiology |volume=16 |article-number=1625179 |doi=10.3389/fmicb.2025.1625179 |doi-access=free |issn=1664-302X |pmc=12202521 |pmid=40584044}}</ref>.

'''Environmental Toxins and Pollutants'''

There are multiple environmental factors that can lead to Hashimoto's such as decreased temperature and sunlight, chemical pollutants, heavy metals and radiation.<ref>{{Cite journal |last1=Wang |first1=Jian-Peng |last2=Xie |first2=Zi-Hui |last3=Zhou |first3=Ping-Ting |last4=Liang |first4=Bing-Yu |last5=Han |first5=Ke |last6=Fu |first6=Zi-Yue |last7=Li |first7=Fen-Fen |last8=Liu |first8=Ye-Hai |last9=Pan |first9=Hai-Feng |last10=Liu |first10=Yu-Chen |date=2025-10-15 |title=Epidemiological and experimental evidence of environmental factor-related autoimmune thyroid disease: A systematic review |journal=Ecotoxicology and Environmental Safety |volume=305 |article-number=119256 |doi=10.1016/j.ecoenv.2025.119256 |issn=1090-2414 |pmid=41130066 |bibcode=2025EcoES.30519256W |doi-access=free }}</ref>

'''Other'''

Other environmental factors include selenium deficiency,<ref name="Winther-2020" /> other 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 gut dysbiosis.<ref name="Ludgate-2024" />

== Mechanism == The pathophysiology of autoimmune thyroiditis is not well-understood.<ref name="Ramos-Levi2023">{{Cite book | vauthors = Ramos-Levi AM, Marazuela M |title=DeGroot's Endocrinology, Basic Science and Clinical Practice |publisher=Elsevier |year=2023 |isbn=978-0-323694124 |edition=8th |location=Philadelphia, PA |pages=1214–1233 |language=English |chapter=Thyroiditis |ref=Ramos-Levi2023}}</ref> However, once the disease is established, its core processes have been observed:

Hashimoto's thyroiditis is a T-lymphocyte-mediated attack on the thyroid gland.<ref name="Klubo-Gwiezdzinska-2022" /> T helper 1 cells trigger macrophages and cytotoxic lymphocytes to destroy thyroid follicular cells, while T helper 2 cells stimulate the excessive production of B cells and plasma cells which generate antibodies against the thyroid antigens, leading to thyroiditis.<ref name="ref 4" /> The three major antibodies are: Thyroid peroxidase Antibodies (TPOAb), Thyroglobulin Antibodies (TgAb), and Thyroid stimulating hormone receptor Antibodies (TRAb),<ref name="Dayan96" /> with TPOAb and TgAb being most commonly implicated in Hashimotos.<ref name="Ramos-Levi2023" /> Antibodies are hypothesized to develop as a result of thyroid damage, where T-lymphocytes become sensitized to residual thyroid peroxidase and thyroglobulin, rather than as the initial cause of thyroid damage.<ref name="Ramos-Levi2023" /> However, antibodies may exacerbate further thyroid destruction by binding the complement system and triggering apoptosis of thyroid cells.<ref name="Ramos-Levi2023" /> TPO antibody levels may correlate with the degree of lymphocyte infiltration of the thyroid.<ref>{{cite journal | vauthors = Yan YR, Gao XL, Zeng J, Liu Y, Lv QG, Jiang J, Huang H, Tong NW | title = The association between thyroid autoantibodies in serum and abnormal function and structure of the thyroid | journal = The Journal of International Medical Research | volume = 43 | issue = 3 | pages = 412–423 | date = June 2015 | pmid = 25855591 | doi = 10.1177/0300060514562487 | doi-access = free }}</ref><ref name="auto"/> A meta-analysis of 26 studies found higher levels of inflammatory helper T cell 17 and lower levels of regulatory T cells in Hashimoto's patients.<ref>{{Cite journal |last1=Chen |first1=Aizhi |last2=Huang |first2=Liang |last3=Zhang |first3=Liqin |date=Jan 2023 |title=Helper T Cell 17 and Regulatory T Cell Levels in Peripheral Blood of Newly Diagnosed Patients with Autoimmune Thyroid Disease: A Meta-Analysis |url=http://www.thieme-connect.de/DOI/DOI?10.1055/a-1972-5787 |journal=Hormone and Metabolic Research |language=en |volume=55 |issue=1 |pages=40–50 |doi=10.1055/a-1972-5787 |pmid=36332627 |issn=0018-5043}}</ref>

Gross morphological changes within the thyroid are seen in the general enlargement, which is far more locally nodular and irregular than more diffuse patterns (such as that of hyperthyroidism). While the capsule is intact and the gland itself is still distinct from surrounding tissue, microscopic examination can provide a more revealing indication of the level of damage.<ref name="Maitra 2014 The Endocrine System">{{cite book |title=Robbins and Cotran Pathologic Basis of Disease |vauthors=Maitra A |date=2014 |publisher=Elsevier Health Sciences |isbn=978-0-323-29635-9 |veditors=Kumar V, Abbas AK, Aster JC |pages=1073–1140 |chapter=The Endocrine System}}</ref> Hypothyroidism is caused by replacement of follicular cells with parenchymatous tissue.<ref name="ref 4">{{cite journal | vauthors = Berghi NO | title = Immunological Mechanisms Implicated in the Pathogenesis of Chronic Urticaria and Hashimoto Thyroiditis | journal = Iranian Journal of Allergy, Asthma, and Immunology | volume = 16 | issue = 4 | pages = 358–366 | date = August 2017 | pmid = 28865416 | url = https://ijaai.tums.ac.ir/index.php/ijaai/article/view/984 | url-status = live | access-date = 3 December 2020 | archive-url = https://web.archive.org/web/20210419162834/https://ijaai.tums.ac.ir/index.php/ijaai/article/view/984 | archive-date = 19 April 2021 }}</ref>

Partial regeneration of the thyroid tissue can occur, but this has not been observed to normalise hormonal levels.<ref>{{cite journal | vauthors = Romitti M, Costagliola S | title = Progress Toward and Challenges Remaining for Thyroid Tissue Regeneration | journal = Endocrinology | volume = 164 | issue = 10 | article-number = bqad136 | date = August 2023 | pmid = 37690118 | pmc = 10516459 | doi = 10.1210/endocr/bqad136 }}</ref><ref name="Ushakov-2024">{{Cite journal | vauthors = Ushakov AV |date=September 2024 |title=Ultrasound signs of large segmental thyroid regeneration in Hashimoto's thyroiditis: a case report of two cases |url=https://aot.amegroups.com/article/view/7822/html |journal=Annals of Thyroid |volume=9 |page=5 |doi=10.21037/aot-24-17|doi-access=free }}</ref>

=== Pathology === thumb|Marked lymphocytic infiltration (purple areas) of the thyroid gland in a patient with chronic autoimmune thyroiditis thumb|High powered magnification showing lymphocytic infiltration of the thyroid gland in autoimmune thyroiditis Gross pathology of a thyroid with autoimmune thyroiditis may show a symmetrically enlarged thyroid.<ref name="Ramos-Levi2023" /> It is often paler in color, in comparison to normal thyroid tissue, which is reddish-brown.<ref name="Ramos-Levi2023" />

Microscopic examination (histology) will show lymphocytes (including plasma B-cells) diffusely infiltrating the parenchyma.<ref name="Maitra 2014 The Endocrine System" /> The lymphocytes are predominately T-lymphocytes with a representation of both CD4+ and CD8+ cells.<ref name="Ramos-Levi2023" /> The plasma cells are polyclonal, with present germinal centers resembling the structure of a lymph node<ref name="Ramos-Levi2023" /> (also called secondary lymphoid follicles, not to be confused with the normally present colloid-filled follicles that constitute the thyroid).<ref name="Maitra 2014 The Endocrine System" />

In late stages of the disease, the thyroid may be atrophic.<ref name="Mincer2022" /> Colloid-filled follicles shrink, and the cuboidal cells that usually line the follicles become Hürthle cells.<ref name="Ramos-Levi2023" /> Fibrous tissue may be found throughout the affected thyroid as well.<ref name="Ramos-Levi2023" /> Severe thyroid atrophy presents often with denser fibrotic bands of collagen that remain within the confines of the thyroid capsule.<ref name="Maitra 2014 The Endocrine System" />

Generally, pathological findings of the thyroid are related to the amount of remaining thyroid function – the more infiltration and fibrosis, the less likely a patient will have normal thyroid function.<ref name="Ramos-Levi2023" /> A rare but serious complication is thyroid lymphoma, generally the B-cell type, non-Hodgkin lymphoma.<ref name="Dayan96" />

== Diagnosis == thumb|Ultrasound imaging of the thyroid gland (right lobe longitudinal) in a person with Hashimoto thyroiditis

=== Tests === ==== Physical exam ==== Physicians will often start by assessing reported symptoms and performing a thorough physical exam, including a neck exam.<ref name="Mincer2022" /> Patients may have a "firm, bumpy, symmetric, painless goiter", however, up to 10% of patients may have an atrophied thyroid.<ref name="Ramos-Levi2023" />

==== Antithyroid antibodies tests ==== Tests for antibodies against thyroid peroxidase, thyroglobulin, and thyrotropin receptors can detect autoimmune processes against the thyroid. 90% of Hashimoto's patients have elevated levels of thyroid peroxidase antibodies.<ref name="Ramos-Levi2023" /> However, seronegative (without circulating autoantibodies) thyroiditis is also possible.<ref>{{cite journal | vauthors = Grani G, Carbotta G, Nesca A, D'Alessandri M, Vitale M, Del Sordo M, Fumarola A | title = A comprehensive score to diagnose Hashimoto's thyroiditis: a proposal | journal = Endocrine | volume = 49 | issue = 2 | pages = 361–365 | date = June 2015 | pmid = 25280964 | doi = 10.1007/s12020-014-0441-5 | s2cid = 23026213 }}</ref> There may be circulating antibodies before the onset of any symptoms.<ref name="Mincer2022" />

==== Ultrasound ==== thumb|Ultrasound imaging of the thyroid showing Hashimoto's thyroiditis An ultrasound may be useful in detecting Hashimoto thyroiditis, especially in those with seronegative thyroiditis,<ref name="Klubo-Gwiezdzinska-2022" /> or when patients have normal laboratory values but symptoms of autoimmune thyroiditis.<ref name="Niddk2021" /> Key features detected in the ultrasound of a person with Hashimoto's thyroiditis include "echogenicity, heterogeneity, hypervascularity, and presence of small cysts".<ref name="Klubo-Gwiezdzinska-2022" /> Images obtained with ultrasound can evaluate the size of the thyroid, reveal the presence of nodules, or provide clues to the diagnosis of other thyroid conditions.<ref name="Niddk2021" />

==== Nuclear medicine ==== Nuclear imaging showing thyroid uptake can also be helpful in diagnosing thyroid function, particularly differential diagnosis.<ref name="Ramos-Levi2023" />

==== TSH levels test ==== Elevated Thyroid-stimulating hormone (TSH) levels may indicate hypothyroidism (underperforming thyroid).<ref name="Niddk2021"/> Hypothyroidism is a common symptom and potential indication of Hashimoto's disease.<ref name="Ramos-Levi2023" /> As blood levels of thyroid hormones fall due to hypothyroidism, the anterior pituitary gland increases production of TSH, which stimulates increased production of thyroid hormones in the thyroid.<ref name=":6" /> The elevation is usually a marked increase over the normal range.<ref name="Singh2020"/> TSH is the preferred initial test of thyroid function as it has a higher sensitivity to changes in thyroid status than free T₄.<ref>{{Cite book | author = Royal College of Pathologists of Australasia | chapter = Thyroid stimulating hormone | chapter-url = https://www.rcpa.edu.au/Manuals/RCPA-Manual/Pathology-Tests/T/Thyroid-stimulating-hormone | title = Royal College of Pathologists of Australasia Manual }}</ref>

Biotin can cause this test to read "falsely low".<ref name=":6" /> Time of day can affect the results of this test; TSH peaks early in the morning and slumps in the late afternoon to early evening,<ref>{{cite journal | vauthors = Ikegami K, Refetoff S, Van Cauter E, Yoshimura T | title = Interconnection between circadian clocks and thyroid function | journal = Nature Reviews. Endocrinology | volume = 15 | issue = 10 | pages = 590–600 | date = October 2019 | pmid = 31406343 | pmc = 7288350 | doi = 10.1038/s41574-019-0237-z }}</ref> with "a variation in TSH by a mean of between 0.95 mIU/mL to 2.0 mIU/mL".<ref>{{cite journal | vauthors = Sheehan MT | title = Biochemical Testing of the Thyroid: TSH is the Best and, Oftentimes, Only Test Needed - A Review for Primary Care | journal = Clinical Medicine & Research | volume = 14 | issue = 2 | pages = 83–92 | date = June 2016 | pmid = 27231117 | pmc = 5321289 | doi = 10.3121/cmr.2016.1309 }}</ref> Hypothyroidism is diagnosed more often in samples taken soon after waking.<ref>{{cite journal | vauthors = Sviridonova MA, Fadeyev VV, Sych YP, Melnichenko GA | title = Clinical significance of TSH circadian variability in patients with hypothyroidism | journal = Endocrine Research | volume = 38 | issue = 1 | pages = 24–31 | date = 2013-05-01 | pmid = 22857384 | doi = 10.3109/07435800.2012.710696 }}</ref>

==== T₃ or T₄ levels test ==== These tests detect levels of two thyroid hormones: Thyroxine (T₄) and Tri-iodothyronine (T₃). Low levels of these hormones (hypothyroidism) may indicate autoimmune damage to the thyroid due to Hashimoto's, while elevated levels may indicate an attack of destructive thyrotoxicosis.<ref name="Ramos-Levi2023" /> Hashimoto's with normal levels is possible, however.

Free or total levels can be measured. Typically, Free T₄ is the preferred test for hypothyroidism,<ref name="Van Uytfanghe-2023">{{cite journal | vauthors = Van Uytfanghe K, Ehrenkranz J, Halsall D, Hoff K, Loh TP, Spencer CA, Köhrle J | title = Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status | journal = Thyroid | volume = 33 | issue = 9 | pages = 1013–1028 | date = September 2023 | pmid = 37655789 | pmc = 10517335 | doi = 10.1089/thy.2023.0169 }}</ref> as Free T₃ immunoassay tests are less reliable at detecting low levels of thyroid hormone,<ref>{{Cite book | author = Royal College of Pathologists of Australasia | chapter = Free T3 | chapter-url=https://www.rcpa.edu.au/Manuals/RCPA-Manual/Pathology-Tests/F/Free-T3 | title = Royal College of Pathologists of Australasia Manual}}</ref> and they are more susceptible to interference.<ref name="Van Uytfanghe-2023" /> Both immunoassay tests of Free T₄ and Free T₃ may overestimate concentrations, particularly at low thyroid hormone levels, which is why results are typically read in conjunction with TSH, a more sensitive measure.<ref name="Welsh-2016">{{cite journal |vauthors=Welsh KJ, Soldin SJ |date=December 2016 |title=DIAGNOSIS OF ENDOCRINE DISEASE: How reliable are free thyroid and total T3 hormone assays? |journal=European Journal of Endocrinology |volume=175 |issue=6 |pages=R255–R263 |doi=10.1530/EJE-16-0193 |pmc=5113291 |pmid=27737898}}</ref> LC-MSMS assays are rarer, but they are "highly specific, sensitive, precise, and can detect hormones found in low concentrations".<ref name="Welsh-2016" />

==== Muscle biopsy ==== Muscle biopsy is not necessary for diagnosis of myopathy due to hypothyroid muscle fibre changes, however it may reveal confirmatory features.<ref name="Fariduddin-2024" />

== Treatment == There is no cure for Hashimoto's Thyroiditis.<ref name="Ludgate-2024">{{cite journal | vauthors = Ludgate ME, Masetti G, Soares P | title = The relationship between the gut microbiota and thyroid disorders | journal = Nature Reviews. Endocrinology | volume = 20 | issue = 9 | pages = 511–525 | date = September 2024 | pmid = 38906998 | doi = 10.1038/s41574-024-01003-w }}</ref><ref name="Australia-2023">{{Cite web | author = Healthdirect Australia |date=2023-02-03 |title=Hashimoto's disease |url=https://www.healthdirect.gov.au/hashimotos-disease |access-date=2024-12-05 |website=www.healthdirect.gov.au |language=en-AU}}</ref> There is currently no known way to stop auto-immune lymphocytes infiltrating the thyroid or to stimulate regeneration of thyroid tissue.<ref name="Ramos-Levi2023" /> However, the condition can be managed.<ref name="Ludgate-2024" /><ref name="Australia-2023" /> alt=Molecular structure of Thyroxine, Levothyroxine, Levothyroxine Sodium, Tri-iodothyronine, Liothyronine, and Liothyronine Sodium.|thumb|Molecular structure of Thyroxine, Levothyroxine, Levothyroxine Sodium, Tri-iodothyronine, Liothyronine, and Liothyronine Sodium.

=== Managing hormone levels === {| class="wikitable floatright" |+Hormone Terminology ! !Endogenous !Synthetic |- !'''T₃''' |Tri-iodothyronine |Liothyronine |- !'''T₄''' |Thyroxine |Levothyroxine |} Hypothyroidism caused by Hashimoto's thyroiditis is treated with thyroid hormone replacement agents such as levothyroxine (LT₄),<ref name=":6" /> liothyronine (LT₃),<ref name="Ramos-Levi2023" /> or desiccated thyroid extract (T₄+T₃).<ref name=":7" /> In most cases, the treatment needs to be taken for the rest of the person's life.<ref name=":6" />

The standard of care is levothyroxine (LT₄) therapy, which is an oral medication identical in molecular structure to endogenous thyroxine (T₄).<ref name=":6" /> Levothyroxine sodium has a sodium salt added to increase its gastrointestinal absorption.<ref>{{Cite book | vauthors = Wiersinga WM |title=Endocrinology: Adult and Pediatric |year=2016 |edition=7th |volume=2 |pages=1540–1556}}</ref> Levothyroxine has the benefits of a long half-life<ref name="Groenewegen-2021">{{cite journal |vauthors=Groenewegen KL, Mooij CF, van Trotsenburg AS |date=2021 |title=Persisting symptoms in patients with Hashimoto's disease despite normal thyroid hormone levels: Does thyroid autoimmunity play a role? A systematic review |journal=Journal of Translational Autoimmunity |volume=4 |article-number=100101 |doi=10.1016/j.jtauto.2021.100101 |pmc=8122172 |pmid=34027377}}</ref> leading to stable thyroid hormone levels,<ref name="McAninch-2019">{{cite journal | vauthors = McAninch EA, Bianco AC | title = The Swinging Pendulum in Treatment for Hypothyroidism: From (and Toward?) Combination Therapy | language = English | journal = Frontiers in Endocrinology | volume = 10 | article-number = 446 | date = 2019-07-09 | pmid = 31354624 | pmc = 6629976 | doi = 10.3389/fendo.2019.00446 | doi-access = free }}</ref> ease of monitoring,<ref name="McAninch-2019" /> excellent safety<ref name="McAninch-2019" /><ref>{{cite book | vauthors = Brown DC | chapter = Chapter 37 - Thyroid hormones, antithyroid drugs |date=2012-01-01 | title = Clinical Pharmacology | edition = Eleventh |pages=587–595 | veditors = Bennett PN, Brown MJ, Sharma P |chapter-url=https://www.sciencedirect.com/science/article/abs/pii/B9780702040849000768 |access-date=2024-12-05 |place=Oxford |publisher=Churchill Livingstone | doi = 10.1016/B978-0-7020-4084-9.00076-8 |isbn=978-0-7020-4084-9 }}</ref> and efficacy record,<ref name="Welsh-2016" /> and usefulness in pregnancy as it can cross the fetal blood–brain barrier.<ref name="Klubo-Gwiezdzinska-2022" />

Levothyroxine dosing to normalise TSH is based on the amount of residual endogenous thyroid function and the patient's weight, particularly lean body mass.<ref name="Klubo-Gwiezdzinska-2022" /> The dose can be adjusted based upon each patient, for example, the dose may be lowered for elderly patients or patients with certain cardiac conditions, but is increased in pregnant patients.<ref name="Mincer2022" /> It is administered on a consistent schedule.<ref name=":6" /> Levothyroxine may be dosed daily or weekly, however weekly dosing may be associated with higher TSH levels, elevated thyroid hormone levels, and transient "echocardiographic changes in some patients following 2-4 h of thyroxine intake".<ref>{{cite journal | vauthors = Chiu HH, Larrazabal R, Uy AB, Jimeno C | title = Weekly Versus Daily Levothyroxine Tablet Replacement in Adults with Hypothyroidism: A Meta-Analysis | journal = Journal of the ASEAN Federation of Endocrine Societies | volume = 36 | issue = 2 | pages = 156–160 | date = 2021 | pmid = 34966199 | pmc = 8666497 | doi = 10.15605/jafes.036.02.07 }}</ref><ref>{{cite journal | vauthors = Dutta D, Jindal R, Kumar M, Mehta D, Dhall A, Sharma M | title = Efficacy and Safety of Once Weekly Thyroxine as Compared to Daily Thyroxine in Managing Primary Hypothyroidism: A Systematic Review and Meta-Analysis | language = en-US | journal = Indian Journal of Endocrinology and Metabolism | volume = 25 | issue = 2 | pages = 76–85 | date = March–April 2021 | pmid = 34660234 | pmc = 8477739 | doi = 10.4103/ijem.IJEM_789_20 | doi-access = free }}</ref>

Some patients elect combination therapy with both levothyroxine and liothyronine (which is identical in molecular structure to tri-iodothyronine) however studies of combination therapy are limited,<ref name="Ramos-Levi2023" /> and five meta-analyses/reviews "suggested no clear advantage of the combination therapy".<ref name="Klubo-Gwiezdzinska-2022" /> However, subgroup analysis found that patients who remain the most symptomatic while taking levothyroxine may benefit from therapy containing liothyronine.<ref name="Klubo-Gwiezdzinska-2022" />

There is a lack of evidence around the benefits, side effects, and long-term risks of desiccated thyroid extract. It is no longer recommended for the treatment of hypothyroidism.<ref name=":7">{{cite journal | vauthors = Riis KR, Larsen CB, Bonnema SJ | title = Potential Risks and Benefits of Desiccated Thyroid Extract for the Treatment of Hypothyroidism: A Systematic Review | journal = Thyroid | volume = 34 | issue = 6 | pages = 687–701 | date = June 2024 | pmid = 38526391 | doi = 10.1089/thy.2023.0649 | url = https://findresearcher.sdu.dk/ws/files/265931781/RiisManuscript_clean.pdf }}</ref>

==== Side Effects ==== Side effects of thyroid replacement therapy are associated with "inadequate or excessive doses".<ref name=":6" /> Symptoms to watch for include, but are not limited to, anxiety, tremor, weight loss, heat sensitivity, diarrhea, and shortness of breath. More worrisome symptoms include atrial fibrillation and bone density loss.<ref name=":6" /> Long term over-treatment is associated with increased mortality and dementia.<ref name="Hegedüs-2022" />

==== Monitoring ==== Thyroid Stimulating Hormone (TSH) is the main laboratory value for monitoring response to treatment with levothyroxine.<ref name=":4a">{{Cite web |title=Hashimoto's Thyroiditis |url=https://www.thyroid.org/hashimotos-thyroiditis/ |url-status=live |archive-url=https://web.archive.org/web/20230923182829/http://www.thyroid.org/hashimotos-thyroiditis/ |archive-date=23 September 2023 |access-date=2023-01-23 |website=American Thyroid Association |language=en-US}}</ref> When treatment is first initiated, TSH levels may be monitored as often as every 6–8 weeks.<ref name=":4a" /> Each time the dose is adjusted, TSH levels may be measured at that frequency until the correct dose is determined.<ref name=":4a" /> Once titrated to a proper dose, TSH levels will be monitored yearly.<ref name=":4a" /> The target level for TSH is the subject of debate, with factors like age, sex, individual needs and special circumstances such as pregnancy being considered.<ref name="Taylor-2024" /> Recent studies suggest that adjusting therapy based on thyroid hormone levels (T₄ and/or T₃) may be important.<ref name=":6" />

Monitoring liothyronine treatment or combination treatment can be challenging.<ref name="Taylor-2024" /><ref name="McAninch-2019" /><ref name="Elsevier-2006">{{Citation |title=Thyroid hormones |date=2006-01-01 |pages=3409–3416 | veditors = Aronson JK |url=https://www.sciencedirect.com/science/article/abs/pii/B0444510052009773 |access-date=2024-12-05 |place=Amsterdam |publisher=Elsevier |doi=10.1016/B0-44-451005-2/00977-3 |isbn=978-0-444-51005-1 |encyclopedia=Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions (Fifteenth Edition)|url-access=subscription }}</ref> Liothyronine can suppress TSH to a greater extent than levothyroxine.<ref>{{Cite journal | vauthors = Taylor P, Arooj A, Hanna S, Eligar V, Muhammad Z, Stedman M, Premawardhana L, Okosieme O, Heald A, Dayan C |date=2023-10-31 |title=Thyroid hormone profiles on non-standard thyroid hormone replacement |url=https://www.endocrine-abstracts.org/ea/0094/ea0094p128 |journal=Endocrine Abstracts |language=en |publisher=Bioscientifica |volume=94 |doi=10.1530/endoabs.94.P128|url-access=subscription }}</ref> Short-acting Liothyronine's short half-life can result in large fluctuations of free T₃<ref name="Elsevier-2006" /> over the course of 24 hours.<ref>{{cite journal | vauthors = Saravanan P, Siddique H, Simmons DJ, Greenwood R, Dayan CM | title = Twenty-four hour hormone profiles of TSH, Free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy | journal = Experimental and Clinical Endocrinology & Diabetes | volume = 115 | issue = 4 | pages = 261–267 | date = April 2007 | pmid = 17479444 | doi = 10.1055/s-2007-973071 }}</ref>

Patients may have to adjust their dosage several times over the course of the disease. Endogenous thyroid hormone levels may fluctuate, particularly early in the disease.<ref>{{cite journal | vauthors = Dunne C, De Luca F | title = Long-Term Follow-Up of a Child with Autoimmune Thyroiditis and Recurrent Hyperthyroidism in the Absence of TSH Receptor Antibodies | journal = Case Reports in Endocrinology | volume = 2014 | issue = 1 | article-number = 749576 | date = 2014 | pmid = 25114812 | pmc = 4119923 | doi = 10.1155/2014/749576 | doi-access = free }}</ref> Patients may sometimes develop hyperthyroidism, even after long-term treatment.<ref name="Ramos-Levi2023" /> This can be due to several factors, including acute attacks of destructive thyrotoxicosis (autoimmune attacks on the thyroid resulting in rises in thyroid hormone levels as thyroid hormones leak out of the damaged tissues).<ref name="Dyrka-2024" /><ref name="Ramos-Levi2023" /> This is usually followed by hypothyroidism.<ref name="Ramos-Levi2023" />

==== Reverse T₃ ==== Measuring reverse tri-iodothyronine (rT₃) is often mentioned in the lay (non-medical) press as a possible marker to inform T₄ or T₃ therapy, "however, there is currently no evidence to support this application" as of 2023.<ref name="Van Uytfanghe-2023" /> Although cited in the lay press as a possible competitor to T₃, it is unlikely that rT₃ causes hypothyroid symptoms by out-competing T₃ for thyroid hormone receptors, as it has a binding affinity 200 times weaker.<ref name="Halsall-2021" /> It is also unlikely that rT₃ causes poor T₄ to T₃ conversion; despite being demonstrated ''in vivo'' to have the potential to inhibit DIO-mediated T₄ to T₃ conversion, this is considered improbable at normal body hormone concentrations.<ref name="Halsall-2021">{{cite journal | vauthors = Halsall DJ, Oddy S | title = Clinical and laboratory aspects of 3,3',5'-triiodothyronine (reverse T3) | journal = Annals of Clinical Biochemistry | volume = 58 | issue = 1 | pages = 29–37 | date = January 2021 | pmid = 33040575 | doi = 10.1177/0004563220969150 }}</ref>

=== 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 | url = https://orca.cardiff.ac.uk/id/eprint/173187/1/Hypothyroidism.pdf }}</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 hypothesised causes are discussed in the medical literature:<ref name=":2" /><ref name="Groenewegen-2021" /><ref name="Klubo-Gwiezdzinska-2022" />

==== Low tissue tri-iodothyronine (T₃) hypothesis ==== Peripheral tissue T₄ to T₃ conversion may be inadequate: Some patients on LT₄ monotherapy may have blood T₃ levels low or below the normal range,<ref name=":6" /><ref name="Taylor-2024" /> and/or may have local T₃ 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 molecules can have biological effects, thyroxine (T₄) is considered the "storage form" of thyroid hormone with much less effect, while tri-iodothyronine (T₃) is considered the active form used by 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 triiodothyronine.<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 | page = 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 |article-number=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 |article-number=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 deiodinase type 2 is necessary for T₄ to T₃ conversion in some peripheral tissues, "patients with ''DIO2'' gene polymorphisms may have variable peripheral T₃ 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 T₄ and T₃.<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 T₄ and T₃ levels, Ultrafiltration LC-MSMS T₄ and T₃ tests may help to identify patients who would benefit from additional T₃.<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, 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, LT₄ 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 T₄ and T₃ monitoring. The monitoring of other 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 T₃ and Free T4 tests can overestimate levels, particularly at low thyroid hormone levels, hypothyroidism may be undertreated.<ref name="Welsh-2016" /> 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 lymphocytes may travel out of the thyroid to other tissue, creating symptoms and inflammation due to 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 does not prove a causality".<ref name="Groenewegen-2021" /> No treatment currently exists for Hashimoto's autoimmunity, although observed well-being 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 co-morbidities".<ref name=":2" /><ref name="Hegedüs-2022" />

=== Improving well-being === Some patients may perceive improved well-being while in thyrotoxicosis, however overtreatment has risks (known risks for levothyroxine and unknown risks for liothyronine).<ref name="Hegedüs-2022" /> One study demonstrated surgical thyroid removal may substantially improve fatigue and well-being,<ref name="Taylor-2024" /><ref name="Ramos-Levi2023" /> see Surgery considerations, below.

=== Reducing antibodies === '''Supplements'''

It is not established that reducing antithyroid antibodies in Hashimoto's has benefits.<ref name="Chaker-2022">{{cite journal | vauthors = Chaker L, Razvi S, Bensenor IM, Azizi F, Pearce EN, Peeters RP | title = Hypothyroidism | journal = Nature Reviews. Disease Primers | volume = 8 | issue = 1 | article-number = 30 | date = May 2022 | pmid = 35589725 | pmc = 6619426 | doi = 10.1038/s41572-022-00357-7 }}</ref><ref name="Klubo-Gwiezdzinska-2022" /><ref name=":0">{{cite journal | vauthors = Wichman J, Winther KH, Bonnema SJ, Hegedüs L | title = Selenium Supplementation Significantly Reduces Thyroid Autoantibody Levels in Patients with Chronic Autoimmune Thyroiditis: A Systematic Review and Meta-Analysis | journal = Thyroid | volume = 26 | issue = 12 | pages = 1681–1692 | date = December 2016 | pmid = 27702392 | doi = 10.1089/thy.2016.0256 }}</ref> A systematic review and meta-analysis of selenium trials found that while selenium reduces TPO antibodies, there was a lack of evidence of effects on "disease remission, progression, lowered levothyroxine dose or improved quality of life".<ref name="Winther-2020" /> Additionally, it's been found that selenium is the only supplement which reduced both TPOab and TgAb<ref>{{Cite journal |last1=Peng |first1=Bingcong |last2=Wang |first2=Weiwei |last3=Gu |first3=Qingling |last4=Wang |first4=Ping |last5=Teng |first5=Weiping |last6=Shan |first6=Zhongyan |date=2024 |title=Effects of different supplements on Hashimoto's thyroiditis: a systematic review and network meta-analysis |journal=Frontiers in Endocrinology |volume=15 |article-number=1445878 |doi=10.3389/fendo.2024.1445878 |doi-access=free |issn=1664-2392 |pmc=11652148 |pmid=39698034}}</ref> especially in comparison to use of myo-inositol and Vitamin D.

Selenium,<ref>{{cite journal | vauthors = Huwiler VV, Maissen-Abgottspon S, Stanga Z, Mühlebach S, Trepp R, Bally L, Bano A | title = Selenium Supplementation in Patients with Hashimoto Thyroiditis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials | journal = Thyroid | volume = 34 | issue = 3 | pages = 295–313 | date = March 2024 | pmid = 38243784 | pmc = 10951571 | doi = 10.1089/thy.2023.0556 }}</ref><ref name="Winther-2020" /> vitamin D,<ref>{{cite journal | vauthors = Jiang H, Chen X, Qian X, Shao S | title = Effects of vitamin D treatment on thyroid function and autoimmunity markers in patients with Hashimoto's thyroiditis-A meta-analysis of randomized controlled trials | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 47 | issue = 6 | pages = 767–775 | date = June 2022 | pmid = 34981556 | pmc = 9302126 | doi = 10.1111/jcpt.13605 }}</ref> and metformin<ref name="Jia-2020">{{cite journal | vauthors = Jia X, Zhai T, Zhang JA | title = Metformin reduces autoimmune antibody levels in patients with Hashimoto's thyroiditis: A systematic review and meta-analysis | journal = Autoimmunity | volume = 53 | issue = 6 | pages = 353–361 | date = September 2020 | pmid = 32741222 | doi = 10.1080/08916934.2020.1789969 }}</ref> can reduce thyroid peroxidase antibodies. There is preliminary evidence that levothyroxine,<ref>{{cite journal | vauthors = Aksoy DY, Kerimoglu U, Okur H, Canpinar H, Karaağaoğlu E, Yetgin S, Kansu E, Gedik O | title = Effects of prophylactic thyroid hormone replacement in euthyroid Hashimoto's thyroiditis | journal = Endocrine Journal | volume = 52 | issue = 3 | pages = 337–343 | date = June 2005 | pmid = 16006728 | doi = 10.1507/endocrj.52.337 | doi-access = free | hdl = 11655/15008 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Padberg S, Heller K, Usadel KH, Schumm-Draeger PM | title = One-year prophylactic treatment of euthyroid Hashimoto's thyroiditis patients with levothyroxine: is there a benefit? | journal = Thyroid | volume = 11 | issue = 3 | pages = 249–255 | date = March 2001 | pmid = 11327616 | doi = 10.1089/105072501750159651 }}</ref><ref>{{Cite journal |last1=Liu |first1=Jia |last2=Chen |first2=Zhe |last3=Liu |first3=Min |last4=Jia |first4=Yumei |last5=Yao |first5=Zhi |last6=Wang |first6=Guang |date=2019-03-11 |title=Levothyroxine Replacement Alleviates Thyroid Destruction in Hypothyroid Patients With Autoimmune Thyroiditis: Evidence From a Thyroid MRI Study |journal=Frontiers in Endocrinology |language=English |volume=10 |article-number=138 |doi=10.3389/fendo.2019.00138 |pmid=30915035 |pmc=6421258 |doi-access=free |issn=1664-2392}}</ref> {{Needs update|date=February 2025|reason=Articles are from the very early 2000s.}}aloe vera juice<ref>{{cite journal | vauthors = Metro D, Cernaro V, Papa M, Benvenga S | title = Marked improvement of thyroid function and autoimmunity by ''Aloe barbadensis'' miller juice in patients with subclinical hypothyroidism | journal = Journal of Clinical & Translational Endocrinology | volume = 11 | pages = 18–25 | date = March 2018 | pmid = 29527506 | pmc = 5842288 | doi = 10.1016/j.jcte.2018.01.003 }}</ref> and black cumin seed<ref>{{cite journal | vauthors = Osowiecka K, Myszkowska-Ryciak J | title = The Influence of Nutritional Intervention in the Treatment of Hashimoto's Thyroiditis-A Systematic Review | journal = Nutrients | volume = 15 | issue = 4 | page = 1041 | date = February 2023 | pmid = 36839399 | pmc = 9962371 | doi = 10.3390/nu15041041 | doi-access = free }}</ref> may reduce thyroid peroxidase antibodies. Metformin can reduce thyroglobulin antibodies.<ref name="Jia-2020" />

'''Diet'''

It is not established that a gluten-free diet can reduce antibodies when there is no comorbid coeliac disease.<ref name="Szczuko-2022">{{cite journal | vauthors = Szczuko M, Syrenicz A, Szymkowiak K, Przybylska A, Szczuko U, Pobłocki J, Kulpa D | title = Doubtful Justification of the Gluten-Free Diet in the Course of Hashimoto's Disease | journal = Nutrients | volume = 14 | issue = 9 | page = 1727 | date = April 2022 | pmid = 35565695 | pmc = 9101474 | doi = 10.3390/nu14091727 | doi-access = free }}</ref><ref name="Larsen-2022" /> Gluten-free diets have been shown in several studies to reduce antibodies, and in other studies to have no effect, however there were significant confounding issues in these studies, including not ruling out comorbid coeliac disease.<ref name="Szczuko-2022" /> An effective diet in managing the symptoms and overall improving the well being of patients is an anti-inflammatory plan which aims to decrease the amount of oxidative damage that exists in propagating Hashimoto's. This diet includes healthy fatty acids, selenium, anti-oxidant components such as vitamin C an E, and essential nutrients<ref>{{Cite journal |last1=Morasiewicz-Jeziorek |first1=Joanna |last2=Buczyńska |first2=Angelika |last3=Krętowski |first3=Adam Jacek |last4=Adamska |first4=Agnieszka |date=2026-01-07 |title=The Role of Immunological Challenges, Oxidative Stress, and Dietary Interventions in Managing Hashimoto's Thyroiditis: A Narrative Review |journal=Nutrition Reviews |article-number=nuaf195 |doi=10.1093/nutrit/nuaf195 |issn=1753-4887 |pmid=41498438}}</ref>.

'''Surgery'''

One study found surgical thyroid removal can substantially reduce anti-thyroid antibody levels,<ref name="Taylor-2024" /><ref name="Ramos-Levi2023" /> see Surgery considerations, below.

=== Surgery considerations === Surgery is not the initial treatment of choice for autoimmune disease, and uncomplicated Hashimoto's thyroiditis is not an indication for thyroidectomy.<ref name="Ramos-Levi2023" /> Patients generally may discuss surgery with their doctor if they are experiencing significant pressure symptoms, or cosmetic concerns, or have nodules present on ultrasound.<ref name="Ramos-Levi2023" /> One well-conducted study of patients with troublesome general symptoms and with anti-thyroperoxidase (anti-TPO) levels greater than 1000 IU/ml (normal <100 IU/ml) showed that total thyroidectomy caused the symptoms to resolve and median anti-thyroid peroxidase levels to reduce from 2232 to 152 IU/mL,<ref name="Ramos-Levi2023" /><ref name="Garber-2019">{{Cite web | vauthors = Garber M |date=2019-08-12 |title=Is there a role for surgery in treating Hashimoto's thyroiditis? |url=https://www.health.harvard.edu/blog/is-there-a-role-for-surgery-in-treating-hashimotos-thyroiditis-2019081217443 |access-date=2024-12-05 |website=Harvard Health |language=en}}</ref> but post-operative complications were higher than expected:<ref name="Taylor-2024" /> infection (4.1%), permanent hypoparathyroidism (4.1%) and recurrent laryngeal nerve injury (5.5%).<ref name=":2">{{cite journal | vauthors = Perros P, Van Der Feltz-Cornelis C, Papini E, Nagy EV, Weetman AP, Hegedüs L | title = The enigma of persistent symptoms in hypothyroid patients treated with levothyroxine: A narrative review | journal = Clinical Endocrinology | volume = 98 | issue = 4 | pages = 461–468 | date = April 2023 | pmid = 33783849 | doi = 10.1111/cen.14473 }}</ref>

=== Other === Zinc may increase free T₃ levels.<ref name="Larsen-2022" /> A small pilot study found Ashwagandha Root may increase T₃ and T4 levels, however, there's a lack of strong evidence of this benefit and Ashwagandha has a potential to cause adrenal insufficiency.<ref name="Larsen-2022" /> As of 2022, there has been only one study of low-dose naltrexone in Hashimoto's, which did not demonstrate efficacy; therefore, nothing supports its use. Removing dairy products in those without lactose intolerance is not supported.<ref name="Larsen-2022">{{cite journal | vauthors = Larsen D, Singh S, Brito M | title = Thyroid, Diet, and Alternative Approaches | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 107 | issue = 11 | pages = 2973–2981 | date = November 2022 | pmid = 35952387 | doi = 10.1210/clinem/dgac473 }}</ref> While soy isoflavones have the potential to theoretically affect T₃ and T₄ production, studies in those with sufficient iodine find no effect.<ref name="Larsen-2022" />

== Prognosis == Overt, symptomatic thyroid dysfunction is the most common complication, with about 5% of people with subclinical hypothyroidism and chronic autoimmune thyroiditis progressing to thyroid failure every year. Transient periods of thyrotoxicosis (over-activity of the thyroid) sometimes occur, and rarely the illness may progress to full hyperthyroid Graves' disease with active orbitopathy (bulging, inflamed eyes).<ref name=":1">{{Cite book | vauthors = Monaco F |title=Thyroid Diseases |date=2012 |publisher=CRC Press |isbn=978-1-4398-6839-3 |location=Hoboken |pages=77–97}}</ref>

Rare cases of fibrous autoimmune thyroiditis present with severe shortness of breath and difficulty swallowing, resembling aggressive thyroid tumors, but such symptoms always improve with surgery or corticosteroid therapy. Although primary thyroid B-cell lymphoma affects fewer than one in 1000 persons, it is more likely to affect those with long-standing autoimmune thyroiditis,<ref name=":1" /> as there is a 67- to 80-fold increased risk of developing primary thyroid lymphoma in patients with Hashimoto's thyroiditis.<ref>{{cite journal | vauthors = Noureldine SI, Tufano RP | title = Association of Hashimoto's thyroiditis and thyroid cancer | language = en-US | journal = Current Opinion in Oncology | volume = 27 | issue = 1 | pages = 21–25 | date = January 2015 | pmid = 25390557 | doi = 10.1097/CCO.0000000000000150 | s2cid = 32109200 }}</ref>

Myopathy as a result of muscle fibre changes due to thyroid hormone deficiency may take months or years of thyroid hormone treatment to resolve.<ref name="Fariduddin-2024" /><ref>{{cite journal | vauthors = Winter S, Heiling B, Eckardt N, Kloos C, Axer H | title = Hoffmann's syndrome in the differential work-up of myopathic complaints: a case report | journal = Journal of Medical Case Reports | volume = 17 | issue = 1 | article-number = 473 | date = October 2023 | pmid = 37907975 | pmc = 10617199 | doi = 10.1186/s13256-023-04184-6 | doi-access = free }}</ref>

=== Anti-thyroid antibodies === Thyroid peroxidase antibodies typically (but not always) decline in patients treated with levothyroxine,<ref name=":0" /> with decreases varying between 10% and 90% after a follow-up of 6 to 24 months.<ref name="Schmidt-2008">{{cite journal | vauthors = Schmidt M, Voell M, Rahlff I, Dietlein M, Kobe C, Faust M, Schicha H | title = Long-term follow-up of antithyroid peroxidase antibodies in patients with chronic autoimmune thyroiditis (Hashimoto's thyroiditis) treated with levothyroxine | journal = Thyroid | volume = 18 | issue = 7 | pages = 755–760 | date = July 2008 | pmid = 18631004 | doi = 10.1089/thy.2008.0008 }}</ref> <!-- This study is being cited as a secondary source for its discussion of other studies. -->One study of patients treated with levothyroxine observed that 35 out of 38 patients (92%) had declines in thyroid peroxidase antibody levels over five years, lowering by 70% on average. 6 of the 38 patients (16%) had thyroid peroxidase antibody levels return to normal.<ref name="Schmidt-2008" />

=== Children === Many children diagnosed with Hashimoto's disease will experience the same progressive course of the disease that adults do.<ref name="De Luca-2013">{{cite journal | vauthors = De Luca F, Santucci S, Corica D, Pitrolo E, Romeo M, Aversa T | title = Hashimoto's thyroiditis in childhood: presentation modes and evolution over time | journal = Italian Journal of Pediatrics | volume = 39 | issue = 1 | page = 8 | date = January 2013 | pmid = 23363471 | pmc = 3567976 | doi = 10.1186/1824-7288-39-8 | doi-access = free }}</ref> However, of children who develop anti-thyroid antibodies and hypothyroidism, up to 50% are later observed to have normal antibodies and thyroid hormone levels.<ref name="Ramos-Levi2023" /> One case of true remission has been observed in a 12-year-old girl. Her thyroid was observed via ultrasound to progress from early inflammation to severe end-stage Hashimoto's thyroiditis with hypothyroidism, and then return to "almost normal with only minimal features of inflammation" and euthyroidism.<ref>{{cite journal | vauthors = Wu G, Zou D, Cai H, Liu Y | title = Ultrasonography in the diagnosis of Hashimoto's thyroiditis | journal = Frontiers in Bioscience | volume = 21 | issue = 5 | pages = 1006–1012 | date = June 2016 | pmid = 27100487 | doi = 10.2741/4437 }}</ref>

== Epidemiology == Hashimoto's Disease is estimated to affect 2% of the world's population.<ref name="Ramos-Levi2023" /><ref name="Chistiakov-2005">{{cite journal | vauthors = Chistiakov DA | title = Immunogenetics of Hashimoto's thyroiditis | journal = Journal of Autoimmune Diseases | volume = 2 | issue = 1 | article-number = 1 | date = March 2005 | pmid = 15762980 | pmc = 555850 | doi = 10.1186/1740-2557-2-1 | doi-access = free }}</ref> About 1.0 to 1.5 in 1000 people have this disease at any time.<ref name="Maitra 2014 The Endocrine System" />

=== Sex === Anyone may develop this disease, but it occurs between 8<ref name=":6" /> and 15 times more often in women than in men. Some research suggests a connection to the role of the placenta as an explanation for the sex difference.<ref>{{cite journal | vauthors = Natri H, Garcia AR, Buetow KH, Trumble BC, Wilson MA | title = The Pregnancy Pickle: Evolved Immune Compensation Due to Pregnancy Underlies Sex Differences in Human Diseases | journal = Trends in Genetics | volume = 35 | issue = 7 | pages = 478–488 | date = July 2019 | pmid = 31200807 | pmc = 6611699 | doi = 10.1016/j.tig.2019.04.008 }}</ref> Other research suggests the difference in prevalence amongst genders is due to the effects of sex hormones.<ref name="Weetman2021"/>

=== High iodine consumption === Autoimmune thyroiditis has a higher prevalence in societies that have a higher intake of iodine in their diet, such as the United States and Japan, and among people who are genetically susceptible.<ref name="Monaco">{{cite book |title=Thyroid Diseases |vauthors=Monaco F |publisher=Taylor and Francis |year=2012 |isbn=978-1-4398-6839-3 |page=78}}</ref> It is the most common cause of hypothyroidism in areas of sufficient iodine.<ref name="Mincer2022" /> Also, the rate of lymphocytic infiltration increased in areas where the iodine intake was once low, but increased due to iodine supplementation.<ref name="Dayan96"/><ref name="Khattak-2016">{{cite journal | vauthors = Khattak RM, Ittermann T, Nauck M, Below H, Völzke H | title = Monitoring the prevalence of thyroid disorders in the adult population of Northeast Germany | journal = Population Health Metrics | volume = 14 | article-number = 39 | date = 2016 | pmid = 27833458 | pmc = 5101821 | doi = 10.1186/s12963-016-0111-3 | doi-access = free }}</ref>

Iodine deficiency disorder is combated using an increase in iodine in a person's diet. When a dramatic change occurs in a person's diet, they become more at risk of developing hypothyroidism and other thyroid disorders. Treating iodine deficiency disorder with high salt intakes should be done carefully and cautiously, as the risk for Hashimoto's may increase.<ref name="Khattak-2016" />

=== Geographic influence of dietary trends === Geography plays a large role in which regions have access to diets with low or high iodine. Iodine levels in both water and salt should be heavily monitored to protect at-risk populations from developing hypothyroidism.<ref>{{cite journal | vauthors = Katagiri R, Yuan X, Kobayashi S, Sasaki S | title = Effect of excess iodine intake on thyroid diseases in different populations: A systematic review and meta-analyses including observational studies | journal = PLOS ONE | volume = 12 | issue = 3 | article-number = e0173722 | date = 2017-03-10 | pmid = 28282437 | pmc = 5345857 | doi = 10.1371/journal.pone.0173722 | bibcode = 2017PLoSO..1273722K | doi-access = free }}</ref> Geographic trends of hypothyroidism vary across the world as different places have different ways of defining the disease and reporting cases. Populations that are spread out or defined poorly may skew data in unexpected ways.<ref name="Chistiakov-2005" />

=== North America === Hashimoto's thyroiditis may affect up to 5% of the United States' population.<ref name=":3a">{{Cite book | vauthors = Biddinger PW |title=Diagnostic Pathology and Molecular Genetics of the Thyroid: A Comprehensive Guide for Practicing Thyroid Pathology |publisher=Lippincott Williams & Wilkins |year=2020 |isbn=978-1-4963-9653-2 |edition=3rd |location=Philadelphia, PA |pages=59–72}}</ref> Hashimoto's thyroiditis disorder is thought to be the most common cause of primary hypothyroidism in North America.<ref name="Maitra 2014 The Endocrine System" />

=== Age === Hashimoto's thyroiditis can occur at any age, including children,<ref name="Monaco" /> but more commonly appears in middle age, particularly for men.<ref>{{cite web |date=16 July 2012 |title=Hashimoto's disease fact sheet |url=http://www.womenshealth.gov/publications/our-publications/fact-sheet/hashimoto-disease.html |url-status=live |archive-url=https://web.archive.org/web/20141202154021/http://www.womenshealth.gov/publications/our-publications/fact-sheet/hashimoto-disease.html |archive-date=2 December 2014 |access-date=23 November 2014 |publisher=Office on Women's Health, U.S. Department of Health and Human Services, womenshealth.gov (or girlshealth.gov)}}</ref> Incidence peaks in the fifth decade of life, but patients are usually diagnosed between age 30–50.<ref name="Niddk2021" /><ref name=":3a" /> The highest prevalence from one study was found in the elderly members of the community.<ref name="Vanderpump-2011">{{cite journal | vauthors = Vanderpump MP | title = The epidemiology of thyroid disease | journal = British Medical Bulletin | volume = 99 | issue = 1 | pages = 39–51 | date = 2011-09-01 | pmid = 21893493 | doi = 10.1093/bmb/ldr030 }}</ref> It has been shown that the prevalence of positive tests for thyroid antibodies increases with age, "with a frequency as high as 33 percent in women 70 years old or older".<ref name="Dayan96" />

=== Race === The prevalence of Hashimoto's varies geographically. The highest rate is in Africa, and the lowest in Asia.<ref name="Hu">{{cite journal | vauthors = Hu X, Chen Y, Shen Y, Tian R, Sheng Y, Que H | title = Global prevalence and epidemiological trends of Hashimoto's thyroiditis in adults: A systematic review and meta-analysis | journal = Frontiers in Public Health | volume = 10 | issue = | article-number = 1020709 | date = 2022 | pmid = 36311599 | pmc = 9608544 | doi = 10.3389/fpubh.2022.1020709 | bibcode = 2022FrPH...1020709H | doi-access = free }}</ref> In the US, the African-American population experiences it less commonly but has greater associated mortality.<ref>{{cite news | vauthors = Boyles S |title=Hypothyroidism Hikes Death Risk in Blacks |url=https://www.medpagetoday.org/endocrinology/thyroid/39357 |work=MedPage Today |date=23 May 2013 }}</ref>

=== Autoimmune diseases === Those who already have an autoimmune disease are at greater risk of developing Hashimoto's, as the diseases generally coexist with each other.<ref name="Chistiakov-2005" /> See Causes > Comorbidities, above.

=== Secular trends === The secular trends of hypothyroidism reveal how the disease has changed over time, given changes in technology and treatment options. Even though ultrasound technology and treatment options have improved, the incidence of hypothyroidism has increased according to data focused on the US and Europe. Between 1993 and 2001, the disease was found to vary between 3.9 and 4.89 per 1000 women. Between 1994 and 2001, the disease increased from 0.65 to 1.01 per 1000 men.<ref name="Vanderpump-2011" />

== History == Also known as Hashimoto's disease, Hashimoto's thyroiditis is named after Japanese physician Hakaru Hashimoto (1881−1934) of the medical school at Kyushu University,<ref>{{WhoNamedIt|doctor|1974|Hakaru Hashimoto}}</ref> who first described the symptoms of persons with ''struma lymphomatosa'', an intense infiltration of lymphocytes within the thyroid, in 1912 in the German journal called {{Lang|de|Archiv für Klinische Chirurgie}}.<ref name="Hir2013"/><ref>{{cite journal |id={{NAID|10005555208}} | vauthors = Hashimoto H |title=Zur Kenntnis der lymphomatösen Veränderung der Schilddrüse (Struma lymphomatosa) |trans-title=Knowledge of lymphomatous changes in the thyroid gland (goiter lymphomatosa) |language=de |journal=Archiv für Klinische Chirurgie |year=1912 |volume=97 |pages=219–248 }}</ref> This paper was made up of 30 pages and 5 illustrations all describing the histological changes in the thyroid tissue. Furthermore, all results in his first study were collected from four women. These results explained the pathological characteristics observed in these women especially the infiltration of lymphocyte and plasma cells as well as the formation of lymphoid follicles with germinal centers, fibrosis, degenerated thyroid epithelial cells and leukocytes in the lumen.<ref name="Hir2013"/> He described these traits to be histologically similar to those of Mikulic's disease. As mentioned above, once he discovered these traits in this new disease, he named the disease ''struma lymphomatosa.'' This disease emphasized the lymphocyte infiltration and formation of the lymphoid follicles with germinal centers, neither of which had ever been previously reported.<ref name="Hir2013"/>

Despite Hashimoto's discovery and publication, the disease was not recognized as distinct from Riedel's thyroiditis, which was a common disease at that time in Europe. Although many other articles were reported and published by other researchers, Hashimoto's struma lymphomatosa was only recognized as an early phase of Riedel's thyroiditis in the early 1900s. It was not until 1931 that the disease was recognized as a disease in its own right, when researchers Allen Graham et al. from Cleveland reported its symptoms and presentation in the same detailed manner as Hashimoto.<ref name="Hir2013"/>

In 1956, Drs. Rose and Witebsky were able to demonstrate how immunization of certain rodents with extracts of other rodents' thyroid resembled the disease that Hakaru and other researchers were trying to describe.<ref name="Hir2013"/> These doctors were also able to describe anti-thyroglobulin antibodies in blood serum samples from these same animals.<ref name="Hir2013" />

Later in the same year, researchers from the Middlesex Hospital in London conducted human experiments on patients who presented with similar symptoms. They purified anti-thyroglobulin antibody from their serum and were able to conclude that these sick patients had an immunological reaction to human thyroglobulin.<ref name="Hir2013" /> From this data, it was proposed that Hashimoto's struma could be an autoimmune disease of the thyroid gland: "Following these discoveries, the concept of organ-specific autoimmune disease was established and HT recognized as one such disease."<ref name="Hir2013" />

Following this recognition, the same researchers from Middlesex Hospital published an article in 1962 in ''The Lancet'' that included a portrait of Hakaru Hashimoto.<ref name="Hir2013"/> The disease became more well known from that moment, and Hashimoto's disease started to appear more frequently in textbooks.<ref>{{Cite web |title=Google Books Ngram Viewer |url=https://books.google.com/ngrams/graph?content=hashimoto's+disease&year_start=1800&year_end=2022&corpus=en&smoothing=0&case_insensitive=true |access-date=2024-12-01 |website=books.google.com |language=en}}</ref>

== Pregnancy ==

=== Conception === It is recommended that hypothyroidism be treated with levothyroxine before conception, to prevent adverse effects on the course of the pregnancy and the development of the child.<ref name="Klubo-Gwiezdzinska-2022" /> In IVF, embryo transfer is improved when hypothyroidism is treated.<ref name="Gaberšček-2011" />

=== Pregnancy === The Endocrine Society recommends screening in pregnant women who are considered high-risk for thyroid autoimmune disease.<ref>{{Cite web |date=26 March 2015 |title=Endocrine Experts Support Screening for Thyroid Dysfunction in Pregnant Women |url=https://www.endocrine.org/news-room/current-press-releases/endocrine-experts-support-screening-for-thyroid-dysfunction-in-pregnant-women |archive-url=https://web.archive.org/web/20151008045642/https://www.endocrine.org/news-room/current-press-releases/endocrine-experts-support-screening-for-thyroid-dysfunction-in-pregnant-women |archive-date=8 October 2015 |access-date=4 October 2015 |website=Endocrine Society}}</ref> Universal screening for thyroid diseases during pregnancy is controversial, however, one study "supports the potential benefit of universal screening".<ref name="Lepoutre-2012">{{cite journal | vauthors = Lepoutre T, Debiève F, Gruson D, Daumerie C | title = Reduction of miscarriages through universal screening and treatment of thyroid autoimmune diseases | journal = Gynecologic and Obstetric Investigation | volume = 74 | issue = 4 | pages = 265–273 | date = 2012-01-01 | pmid = 23147711 | doi = 10.1159/000343759 | s2cid = 1646888 | doi-access = }}</ref> Pregnant women may have antithyroid antibodies (5%–14% of pregnancies<ref name="Klubo-Gwiezdzinska-2022" />), poor thyroid function resulting in hypothyroidism, or both. Each is associated with risks:<ref name="Klubo-Gwiezdzinska-2022" />

==== Anti-thyroid antibodies in pregnancy ==== The presence of Thyroid peroxidase antibodies at the outset of pregnancy are associated with a greater risk to the mother of hypothyroidism and thyroid impairment in the first year after delivery.<ref>{{cite journal | vauthors = Caturegli P, De Remigis A, Rose NR | title = Hashimoto thyroiditis: clinical and diagnostic criteria | journal = Autoimmunity Reviews | volume = 13 | issue = 4–5 | pages = 391–397 | date = 2014-04-01 | pmid = 24434360 | doi = 10.1016/j.autrev.2014.01.007 | series = Diagnostic criteria in Autoimmune diseases }}</ref> The presence of antibodies is also associated with "a 2 to 4-fold increase in the risk of recurrent miscarriages, and 2 to 3-fold increased risk of preterm birth", however the reason why is unclear. Thyroid peroxidase antibodies are speculated to indicate other autoimmune processes against the placental-fetal unit.<ref name="Klubo-Gwiezdzinska-2022" /> Levothyroxine treatment in euthyroid women with thyroid autoimmunity does not significantly impact the relative risk of miscarriage and preterm delivery, or outcomes with live birth. "Therefore, no strong recommendations regarding the therapy in such scenarios could be made, but consideration on a case-by-case basis might be implemented."<ref name="Klubo-Gwiezdzinska-2022" />

==== Hypothyroidism in pregnancy ==== Women who have low thyroid function that has not been stabilized are at greater risk of complications for both parent and child. Risks to the mother include gestational hypertension including preeclampsia and eclampsia, gestational diabetes, placental abruption, and postpartum hemorrhage.<ref name="Klubo-Gwiezdzinska-2022" /> Risks to the infant include miscarriage, preterm delivery, low birth weight, neonatal respiratory distress, hydrocephalus, hypospadias, fetal death, infant intensive care unit admission, and neurodevelopmental delays (lower child IQ, language delay or global developmental delay).<ref name="Lepoutre-2012" /><ref name="Gaberšček-2011">{{cite journal | vauthors = Gaberšček S, Zaletel K | title = Thyroid physiology and autoimmunity in pregnancy and after delivery | journal = Expert Review of Clinical Immunology | volume = 7 | issue = 5 | pages = 697–706; quiz 707 | date = September 2011 | pmid = 21895480 | doi = 10.1586/eci.11.42 | doi-access = free }}</ref><ref name="Klubo-Gwiezdzinska-2022" />

Successful pregnancy outcomes are improved when hypothyroidism is treated.<ref name="Gaberšček-2011" /> Levothyroxine treatment may be considered at lower TSH levels in pregnancy than in standard treatment.<ref name="Klubo-Gwiezdzinska-2022" /> Liothyronine does not cross the fetal blood–brain barrier, so liothyronine (T₃) only or liothyronine + levothyroxine (T₃ + T₄) therapy is not indicated in pregnancy.<ref name="Klubo-Gwiezdzinska-2022" />

Close cooperation between the endocrinologist and obstetrician benefits the woman and the infant.<ref name="Lepoutre-2012" /><ref>{{cite journal | vauthors = Budenhofer BK, Ditsch N, Jeschke U, Gärtner R, Toth B | title = Thyroid (dys-)function in normal and disturbed pregnancy | journal = Archives of Gynecology and Obstetrics | volume = 287 | issue = 1 | pages = 1–7 | date = January 2013 | pmid = 23104052 | doi = 10.1007/s00404-012-2592-z | url = https://opus.bibliothek.uni-augsburg.de/opus4/frontdoor/index/index/docId/84394 | url-status = live | access-date = 16 January 2022 | s2cid = 24969196 | archive-url = https://web.archive.org/web/20220123170145/https://opus.bibliothek.uni-augsburg.de/opus4/frontdoor/index/index/docId/84394 | archive-date = 23 January 2022 }}</ref><ref>{{cite journal | vauthors = Balucan FS, Morshed SA, Davies TF | title = Thyroid autoantibodies in pregnancy: their role, regulation and clinical relevance | journal = Journal of Thyroid Research | volume = 2013 | article-number = 182472 | date = 2013 | pmid = 23691429 | pmc = 3652173 | doi = 10.1155/2013/182472 | doi-access = free }}</ref>

==== Immune changes during pregnancy ==== Hormonal changes and trophoblast expression of key immunomodulatory molecules lead to immunosuppression and fetal tolerance. The main players in the regulation of the immune response are Tregs. Both cell-mediated and humoral immune responses are attenuated, resulting in immune tolerance and suppression of autoimmunity. It has been reported that during pregnancy, levels of thyroid peroxidase and thyroglobulin antibodies decrease.<ref name="Weetman-2010" />

=== Postpartum === Thyroid peroxidase antibody testing is recommended for women who have ever been pregnant, regardless of pregnancy outcome. "[P]revious pregnancy plays a major role in the development of autoimmune overt hypothyroidism in premenopausal women, and the number of previous pregnancies should be taken into account when evaluating the risk of hypothyroidism in a young women [''sic'']."<ref name="Carlé-2014" />

Postpartum thyroiditis can occur in women with Hashimoto's.<ref name="Ramos-Levi2023" /> In healthy women, Postpartum thyroiditis can occur up to 1 year after delivery. It should be differentiated from Hashimoto's thyroiditis as it is treated differently.<ref>{{cite journal | vauthors = Lee SY, Pearce EN | title = Assessment and treatment of thyroid disorders in pregnancy and the postpartum period | journal = Nature Reviews. Endocrinology | volume = 18 | issue = 3 | pages = 158–171 | date = March 2022 | pmid = 34983968 | pmc = 9020832 | doi = 10.1038/s41574-021-00604-z }}</ref>

After giving birth, Tregs rapidly decrease, and immune responses are re-established. It may lead to the occurrence or aggravation of autoimmune thyroid disease.<ref name="Weetman-2010">{{cite journal | vauthors = Weetman AP | title = Immunity, thyroid function and pregnancy: molecular mechanisms | journal = Nature Reviews. Endocrinology | volume = 6 | issue = 6 | pages = 311–318 | date = June 2010 | pmid = 20421883 | doi = 10.1038/nrendo.2010.46 | s2cid = 9900120 }}</ref> In up to 50% of females with thyroid peroxidase antibodies in the early pregnancy, thyroid autoimmunity in the postpartum period exacerbates in the form of postpartum thyroiditis.<ref>{{cite journal | vauthors = Lazarus JH | title = The continuing saga of postpartum thyroiditis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 96 | issue = 3 | pages = 614–616 | date = March 2011 | pmid = 21378224 | doi = 10.1210/jc.2011-0091 | doi-access = free }}</ref> Higher secretion of IFN-γ and IL-4, and lower plasma cortisol concentration during pregnancy has been reported in females with postpartum thyroiditis than in healthy females. It indicates that weaker immunosuppression during pregnancy could contribute to postpartum thyroid dysfunction.<ref>{{cite journal | vauthors = Kokandi AA, Parkes AB, Premawardhana LD, John R, Lazarus JH | title = Association of postpartum thyroid dysfunction with antepartum hormonal and immunological changes | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 3 | pages = 1126–1132 | date = March 2003 | pmid = 12629095 | doi = 10.1210/jc.2002-021219 | doi-access = free }}</ref>

=== Fetal microchimerism ===

Several years after the delivery, the chimeric male cells can be detected in the maternal peripheral blood, thyroid, lung, skin, or lymph nodes. The fetal immune cells in the maternal thyroid gland may become activated and act as a trigger that initiates or exacerbates the autoimmune thyroid disease. In Hashimoto's disease patients, fetal microchimeric cells were detected in the thyroid in significantly higher numbers than in healthy females.<ref>{{cite journal | vauthors = Koopmans M, Kremer Hovinga IC, Baelde HJ, Harvey MS, de Heer E, Bruijn JA, Bajema IM | title = Chimerism occurs in thyroid, lung, skin and lymph nodes of women with sons | journal = Journal of Reproductive Immunology | volume = 78 | issue = 1 | pages = 68–75 | date = June 2008 | pmid = 18329105 | doi = 10.1016/j.jri.2008.01.002 }}</ref>

== Other animals == Hashimoto's disease is known to occur in chickens, rats, mice, dogs, and marmosets, but Graves' disease does not.<ref name="McLachlan">{{cite journal | vauthors = McLachlan SM, Alpi K, Rapoport B | title = Review and hypothesis: does Graves' disease develop in non-human great apes? | journal = Thyroid | volume = 21 | issue = 12 | pages = 1359–1366 | date = December 2011 | pmid = 22066476 | pmc = 3229821 | doi = 10.1089/thy.2011.0209 }}</ref>

== See also == * Hashimoto's encephalopathy * Myxedematous psychosis * Hashitoxicosis * Hoffmann Syndrome

== References == {{reflist}} {{commons}} {{medical condition classification and resources | DiseasesDB = 5649 | ICD10 = {{ICD10|E|06|3|e|00}} | ICD9 = {{ICD9|245.2}} | ICDO = | OMIM = 140300 | MedlinePlus = | eMedicineSubj = med | eMedicineTopic = 949 | MeshID = D050031 | SNOMED CT = 66944004 |ICD11={{ICD11|5A03.20}}|ICD10CM={{ICD10CM|E06.3}}}} {{thyroid disease}} {{autoimmune diseases}} {{authority control}}

{{DEFAULTSORT:Hashimoto's Thyroiditis}} Category:Aging-associated diseases Category:Autoimmune diseases Category:Endocrine diseases Category:Wikipedia medicine articles ready to translate Category:Wikipedia neurology articles ready to translate Category:Thyroid disease Category:Diseases named after discoverers