In the early stages of autoimmune thyroiditis, patients may have normal thyroid hormone levels and no goiter or a small one.^[5] Enlargement of the thyroid is due to lymphocytic infiltration and fibrosis.^[13] Early on, thyroid autoantibodies in the blood may be the only indication of Hashimoto's disease.^[5] They are thought to be the secondary products of the T cell-mediated destruction of the gland.^[5]

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.^[14][10] Extended thyroid hormone deficiency may lead to muscle fibre changes, resulting in muscle weakness, muscle pain, stiffness, and rarely, pseudohypertrophy.^[15] 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.^[1] Graves disease may occur before or after the development of autoimmune thyroiditis.^[16]

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.^[10]

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,^[17] and myopathy.^[15] 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^[10][18] (also called "destructive thyrotoxicosis").^[5] In non-medical settings, the term "flare" is used to refer to a sudden exacerbation of symptoms, whether hyper or hypo.^[19]

While most symptoms are attributed to hypothyroidism, similar symptoms are observed in Hashimoto's patients with normal thyroid hormone levels.^[20][21][13] 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)."^[22]

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).^[23]

Thyroid autoimmunity can be familial.^[24] Many patients report a family history of autoimmune thyroiditis or Graves' disease.^[14] The strong genetic component is borne out in studies on monozygotic twins,^[10] 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.^[25]

The genes implicated vary in different ethnic groups,^[26] 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.^[25]

The incidence of autoimmune thyroid disorders is increased in people with chromosomal disorders, including Turner, Down, and Klinefelter syndromes.^[23]

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.^[26] 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.^[27][28]

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.^[29] 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.^[30] CTLA-4 was confirmed as the main locus for thyroid autoantibodies.^[31]

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.^[32]

IFN-γ promotes cell-mediated cytotoxicity against thyroid mutations causing increased production of IFN-γ were associated with the severity of hypothyroidism.^[33] Severe hypothyroidism is associated with mutations leading to lower production of IL-4 (Th2 cytokine suppressing cell-mediated autoimmunity),^[34] lower secretion of TGF-β (inhibitor of cytokine production),^[35] and mutations of FOXP3, an essential regulatory factor for the regulatory T cells (Tregs) development.^[36] 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.^[37]

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.^[38]

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.^[39] A higher incidence of thyroid autoimmunity was reported in patients with a higher rate of X-chromosome monosomy in peripheral white blood cells.^[40] Another potential mechanism might be skewed X-chromosome inactivation.^[5]

In one population study, two or more births were a risk factor for developing autoimmune hypothyroidism in pre-menopausal women.^[41]

Certain medications or drugs have been associated with altering and interfering with thyroid function. There are two main mechanisms of interference:^[42]

• Altering thyroid hormone serum transfer proteins.^[42] Estrogen, tamoxifen, heroin, methadone, clofibrate, 5-fluorouracil, mitotane, and perphenazine all increase thyroid binding globulin (TBG) concentration.^[42] 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.^[42]
• Altering the extra-thyroidal metabolism of thyroid hormone. Propylthiouracil, glucocorticoids, propranolol, iodinated contrast agents, amiodarone, and clomipramine all inhibit conversion of T₄ and T₃.^[42] Phenobarbital, rifampin, phenytoin and carbamazepine all increase hepatic metabolism.^[42] Finally, cholestryamine, colestipol, aluminium hydroxide, ferrous sulphate, and sucralfate are all drugs that decrease T₄ absorption or enhance excretion.^[42]

Both excessive and insufficient iodine intake has been implicated in developing antithyroid antibodies.^[43][44] Thyroid autoantibodies are found to be more prevalent in geographical areas after increasing iodine levels.^[44] Several mechanisms by which excessive iodine may promote thyroid autoimmunity have been proposed:^[43]

• Via thyroglobulin iodination: Iodine exposure leads to higher iodination of thyroglobulin, increasing its immunogenicity^[43] by creating new iodine-containing epitopes or exposing cryptic epitopes.^[45]
• 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.^[43] Iodine also promotes thyrocyte apoptosis.^[43]
• Via immune cell behaviour: Iodine influences immune cells.^[43]

Comorbid autoimmune diseases are a risk factor for developing Hashimoto's thyroiditis, and the opposite is also true.^[3] Another thyroid disease closely associated with Hashimoto's thyroiditis is Graves' disease.^[16] Autoimmune diseases affecting other organs most commonly associated with Hashimoto's thyroiditis include celiac disease, type 1 diabetes, vitiligo, alopecia,^[46] Addison disease, Sjogren's syndrome, and rheumatoid arthritis^[14][47] Autoimmune thyroiditis has also been seen in patients with autoimmune polyendocrine syndromes type 1 and 2.^[16]

Other environmental factors include selenium deficiency,^[8] infectious diseases such as hepatitis C, rubella, and possibly COVID-19,^[48][49][50] toxins,^[5] dietary factors,^[16] radiation exposure,^[5] and gut dysbiosis.^[51]

The pathophysiology of autoimmune thyroiditis is not well understood.^[5] 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.^[13] 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.^[52] The three major antibodies are: Thyroid peroxidase Antibodies (TPOAb), Thyroglobulin Antibodies (TgAb), and Thyroid stimulating hormone receptor Antibodies (TRAb),^[24] with TPOAb and TgAb being most commonly implicated in Hashimotos.^[5] 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.^[5] However, antibodies may exacerbate further thyroid destruction by binding the complement system and triggering apoptosis of thyroid cells.^[5] TPO antibody levels may correlate with the degree of lymphocyte infiltration of the thyroid.^[53][45] 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.^[54]

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.^[55] Hypothyroidism is caused by replacement of follicular cells with parenchymatous tissue.^[52]

Partial regeneration of the thyroid tissue can occur, but this has not been observed to normalise hormonal levels.^[56][57]

Gross pathology of a thyroid with autoimmune thyroiditis may show a symmetrically enlarged thyroid.^[5] It is often paler in color, in comparison to normal thyroid tissue, which is reddish-brown.^[5]

Microscopic examination (histology) will show lymphocytes (including plasma B-cells) diffusely infiltrating the parenchyma.^[55] The lymphocytes are predominately T-lymphocytes with a representation of both CD4+ and CD8+ cells.^[5] The plasma cells are polyclonal, with present germinal centers resembling the structure of a lymph node^[5] (also called secondary lymphoid follicles, not to be confused with the normally present colloid-filled follicles that constitute the thyroid).^[55]

In late stages of the disease, the thyroid may be atrophic.^[10] Colloid-filled follicles shrink, and the cuboidal cells that usually line the follicles become Hürthle cells.^[5] Fibrous tissue may be found throughout the affected thyroid as well.^[5] Severe thyroid atrophy presents often with denser fibrotic bands of collagen that remain within the confines of the thyroid capsule.^[55]

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.^[5] A rare but serious complication is thyroid lymphoma, generally the B-cell type, non-Hodgkin lymphoma.^[24]

Physicians will often start by assessing reported symptoms and performing a thorough physical exam, including a neck exam.^[10] Patients may have a "firm, bumpy, symmetric, painless goiter", however, up to 10% of patients may have an atrophied thyroid.^[5]

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.^[5] However, seronegative (without circulating autoantibodies) thyroiditis is also possible.^[58] There may be circulating antibodies before the onset of any symptoms.^[10]

An ultrasound may be useful in detecting Hashimoto thyroiditis, especially in those with seronegative thyroiditis,^[13] or when patients have normal laboratory values but symptoms of autoimmune thyroiditis.^[47] Key features detected in the ultrasound of a person with Hashimoto's thyroiditis include "echogenicity, heterogeneity, hypervascularity, and presence of small cysts."^[13] 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.^[47]

Nuclear imaging showing thyroid uptake can also be helpful in diagnosing thyroid function, particularly differential diagnosis.^[5]

Elevated Thyroid-stimulating hormone (TSH) levels may indicate hypothyroidism (underperforming thyroid).^[47] Hypothyroidism is a common symptom and potential indication of Hashimoto's disease.^[5] 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.^[20] The elevation is usually a marked increase over the normal range.^[14] TSH is the preferred initial test of thyroid function as it has a higher sensitivity to changes in thyroid status than free T₄.^[59]

Biotin can cause this test to read "falsely low".^[20] 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,^[60] with "a variation in TSH by a mean of between 0.95 mIU/mL to 2.0 mIU/mL".^[61] Hypothyroidism is diagnosed more often in samples taken soon after waking.^[62]

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.^[5] Hashimoto's with normal levels is possible, however.

Free or total levels can be measured. Typically, Free T₄ is the preferred test for hypothyroidism,^[63] as Free T₃ immunoassay tests are less reliable at detecting low levels of thyroid hormone,^[64] and they are more susceptible to interference.^[63] 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.^[65] LC-MSMS assays are rarer, but they are "highly specific, sensitive, precise, and can detect hormones found in low concentrations."^[65]

Muscle biopsy is not necessary for diagnosis of myopathy due to hypothyroid muscle fibre changes, however it may reveal confirmatory features.^[15]

There is no cure for Hashimoto's Thyroiditis.^[51][66] There is currently no known way to stop auto-immune lymphocytes infiltrating the thyroid or to stimulate regeneration of thyroid tissue.^[5] However, the condition can be managed.^[51][66]

Hypothyroidism caused by Hashimoto's thyroiditis is treated with thyroid hormone replacement agents such as levothyroxine (LT₄),^[20] liothyronine (LT₃),^[5] or desiccated thyroid extract (T₄+T₃).^[67] In most cases, the treatment needs to be taken for the rest of the person's life.^[20]

The standard of care is levothyroxine (LT₄) therapy, which is an oral medication identical in molecular structure to endogenous thyroxine (T₄).^[20] Levothyroxine sodium has a sodium salt added to increase its gastrointestinal absorption.^[68] Levothyroxine has the benefits of a long half-life^[69] leading to stable thyroid hormone levels,^[70] ease of monitoring,^[70] excellent safety^[70][71] and efficacy record,^[65] and usefulness in pregnancy as it can cross the fetal blood-brain barrier.^[13]

Levothyroxine dosing to normalise TSH is based on the amount of residual endogenous thyroid function and the patient's weight, particularly lean body mass.^[13] 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.^[10] It is administered on a consistent schedule.^[20] 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".^[72][73]

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,^[5] and five meta-analyses/reviews "suggested no clear advantage of the combination therapy."^[13] However, subgroup analysis found that patients who remain the most symptomatic while taking levothyroxine may benefit from therapy containing liothyronine.^[13]

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.^[67]

Side effects of thyroid replacement therapy are associated with "inadequate or excessive doses."^[20] 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.^[20] Long term over-treatment is associated with increased mortality and dementia.^[21]

Thyroid Stimulating Hormone (TSH) is the main laboratory value for monitoring response to treatment with levothyroxine.^[74] When treatment is first initiated, TSH levels may be monitored as often as every 6–8 weeks.^[74] Each time the dose is adjusted, TSH levels may be measured at that frequency until the correct dose is determined.^[74] Once titrated to a proper dose, TSH levels will be monitored yearly.^[74] 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.^[75] Recent studies suggest that adjusting therapy based on thyroid hormone levels (T₄ and/or T₃) may be important.^[20]

Monitoring liothyronine treatment or combination treatment can be challenging.^[75][70][76] Liothyronine can suppress TSH to a greater extent than levothyroxine.^[77] Short-acting Liothyronine's short half-life can result in large fluctuations of free T₃^[76] over the course of 24 hours.^[78]

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.^[79] Patients may sometimes develop hyperthyroidism, even after long-term treatment.^[5] 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).^[18][5] This is usually followed by hypothyroidism.^[5]

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.^[63] 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.^[80] 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.^[80]

Multiple studies have demonstrated persistent symptoms in Hashimoto's patients with normal thyroid hormone levels (euthyroid)^{[20][75][13][69]} and an estimated 10%-15% of patients treated with levothyroxine monotherapy are dissatisfied due to persistent symptoms of hypothyroidism.^[81][21] Several different hypothesised causes are discussed in the medical literature:^[82][69][13]

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,^[20][75] and/or may have local T₃ deficiency in some tissues.^[83] 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.^[84][85] Thus, the body must convert thyroxine into triiodothyronine.^[85] Tri-iodothyronine is produced primarily by conversion in the liver, kidney, skeletal muscle and pituitary gland.^[86]

Adequate conversion requires sufficient levels of the micronutrients zinc,^[87] selenium,^[8] iron,^[88] and possibly vitamin A.^[89] Conversion rates may decline with age.^[90] 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.^[69][13][8] The Thr92Ala DIO2 polymorphism is present in 12–36% of the population.^[69]

For the latter patients, levothyroxine monotherapy may not be sufficient^[69] and patients may have improvement on combination therapy of T₄ and T₃.^[20][8][91] 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.^[65]

There is ongoing debate about how to define euthyroidism and whether TSH is its best indicator.^[81] 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.^[21][75][83] As a result, LT₄ monotherapy may not result in a "truly biochemically euthyroid state."^[69] Patients may express a preference for "low normal or below normal TSH values"^[83] and/or T₄ and T₃ monitoring. The monitoring of other biomarkers that reflect the action of thyroid hormone on tissues has also been proposed.^[13][92][21]

As immunoassay Free T₃ and Free T4 tests can overestimate levels, particularly at low thyroid hormone levels, hypothyroidism may be undertreated.^[65] LC-MSMS tests may provide more reliable measures.^[65]

It is hypothesised that autoimmunity may play some role in euthyroid symptoms.^[75][93][69] 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,^[69][94] or "the inflammatory nature of [...] persistently increased circulating cytokine levels."^[75] Multiple studies find that antibodies coincide with symptoms even in euthyroid patients,^[5][69] and higher levels are associated with increased symptoms,^[20] however "the found association does not prove a causality".^[69] 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.^[13][94]

It is hypothesised that euthyroid symptoms may not be due to Hashimoto's or hypothyroidism, but some other "physical and psychosocial co-morbidities".^[82][21]

Some patients may perceive improved well-being while in thyrotoxicosis, however overtreatment has risks (known risks for levothyroxine and unknown risks for liothyronine).^[21] One study demonstrated surgical thyroid removal may substantially improve fatigue and well-being,^[75][5] see Surgery considerations, below.

It is not established that reducing antithyroid antibodies in Hashimoto's has benefits.^[93][13][95] 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".^[8]

Selenium,^[96][8] vitamin D,^[97] and metformin^[98] can reduce thyroid peroxidase antibodies. There is preliminary evidence that levothyroxine,^{[99][100][101] [needs update]}aloe vera juice^[102] and black cumin seed^[103] may reduce thyroid peroxidase antibodies. Metformin can reduce thyroglobulin antibodies.^[98] It is not established that a gluten-free diet can reduce antibodies when there is no comorbid coeliac disease.^[104][105] 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.^[104] One study found surgical thyroid removal can substantially reduce anti-thyroid antibody levels,^[75][5] see Surgery considerations, below.

Surgery is not the initial treatment of choice for autoimmune disease, and uncomplicated Hashimoto's thyroiditis is not an indication for thyroidectomy.^[5] Patients generally may discuss surgery with their doctor if they are experiencing significant pressure symptoms, or cosmetic concerns, or have nodules present on ultrasound.^[5] 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,^[5][106] but post-operative complications were higher than expected:^[75] infection (4.1%), permanent hypoparathyroidism (4.1%) and recurrent laryngeal nerve injury (5.5%).^[82]

Zinc may increase free T₃ levels.^[105] 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.^[105] 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.^[105] While soy isoflavones have the potential to theoretically affect T₃ and T₄ production, studies in those with sufficient iodine find no effect.^[105]

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).^[107]

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,^[107] as there is a 67- to 80-fold increased risk of developing primary thyroid lymphoma in patients with Hashimoto's thyroiditis.^[108]

Myopathy as a result of muscle fibre changes due to thyroid hormone deficiency may take months or years of thyroid hormone treatment to resolve.^[15][109]

Thyroid peroxidase antibodies typically (but not always) decline in patients treated with levothyroxine,^[95] with decreases varying between 10% and 90% after a follow-up of 6 to 24 months.^[110] 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.^[110]

Many children diagnosed with Hashimoto's disease will experience the same progressive course of the disease that adults do.^[111] However, of children who develop anti-thyroid antibodies and hypothyroidism, up to 50% are later observed to have normal antibodies and thyroid hormone levels.^[5] 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.^[112]

Hashimoto's Disease is estimated to affect 2% of the world's population.^[5][25] About 1.0 to 1.5 in 1000 people have this disease at any time.^[55]

Anyone may develop this disease, but it occurs between 8^[20] 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.^[113] Other research suggests the difference in prevalence amongst genders is due to the effects of sex hormones.^[16]

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.^[114] It is the most common cause of hypothyroidism in areas of sufficient iodine.^[10] Also, the rate of lymphocytic infiltration increased in areas where the iodine intake was once low, but increased due to iodine supplementation.^[24][115]

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.^[115]

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.^[116] 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.^[25]

Hashimoto's thyroiditis may affect up to 5% of the United States' population.^[117] Hashimoto's thyroiditis disorder is thought to be the most common cause of primary hypothyroidism in North America.^[55]

Hashimoto's thyroiditis can occur at any age, including children,^[114] but more commonly appears in middle age, particularly for men.^[118] Incidence peaks in the fifth decade of life, but patients are usually diagnosed between age 30–50.^[47][117] The highest prevalence from one study was found in the elderly members of the community.^[119] 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."^[24]

The prevalence of Hashimoto's varies geographically. The highest rate is in Africa, and the lowest in Asia.^[9] In the US, the African-American population experiences it less commonly but has greater associated mortality.^[120]

Those who already have an autoimmune disease are at greater risk of developing Hashimoto's, as the diseases generally coexist with each other.^[25] See Causes > Comorbidities, above.

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.^[119]

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,^[121] 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 Archiv für Klinische Chirurgie.^[4][122] 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.^[4] 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.^[4]

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.^[4]

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.^[4] These doctors were also able to describe anti-thyroglobulin antibodies in blood serum samples from these same animals.^[4]

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.^[4] 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."^[4]

Following this recognition, the same researchers from Middlesex Hospital published an article in 1962 in The Lancet that included a portrait of Hakaru Hashimoto.^[4] The disease became more well known from that moment, and Hashimoto's disease started to appear more frequently in textbooks.^[123]

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.^[13] In IVF, embryo transfer is improved when hypothyroidism is treated.^[124]

The Endocrine Society recommends screening in pregnant women who are considered high-risk for thyroid autoimmune disease.^[125] Universal screening for thyroid diseases during pregnancy is controversial, however, one study "supports the potential benefit of universal screening".^[126] Pregnant women may have antithyroid antibodies (5%–14% of pregnancies^[13]), poor thyroid function resulting in hypothyroidism, or both. Each is associated with risks:^[13]

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.^[127] 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.^[13] 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."^[13]

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.^[13] 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).^{[126][124][13]}

Successful pregnancy outcomes are improved when hypothyroidism is treated.^[124] Levothyroxine treatment may be considered at lower TSH levels in pregnancy than in standard treatment.^[13] Liothyronine does not cross the fetal blood-brain barrier, so liothyronine (T₃) only or liothyronine + levothyroxine (T₃ + T₄) therapy is not indicated in pregnancy.^[13]

Close cooperation between the endocrinologist and obstetrician benefits the woman and the infant.^{[126][128][129]}

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.^[130]

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]."^[41]

Postpartum thyroiditis can occur in women with Hashimoto's.^[5] 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.^[131]

After giving birth, Tregs rapidly decrease, and immune responses are re-established. It may lead to the occurrence or aggravation of autoimmune thyroid disease.^[130] 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.^[132] 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.^[133]

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.^[134]

Hashimoto's disease is known to occur in chickens, rats, mice, dogs, and marmosets, but Graves' disease does not.^[135]

• Hashimoto's encephalopathy
• Myxedematous psychosis
• Hashitoxicosis
• Hoffmann Syndrome