| Hashimoto's thyroiditis | |
|---|---|
| Other names | Chronic lymphocytic thyroiditis, autoimmune thyroiditis, struma lymphomatosa, Hashimoto's disease |
 | |
| Amicrograph of thethyroid of someone with Hashimoto's thyroiditis | |
| Specialty | Endocrinology |
| Symptoms | Weight gain,feeling tired,constipation, joint and muscle pain, cold intolerance,dry skin,hair loss,slowed heart rate[1] |
| Complications | Thyroid lymphoma.[2] |
| Usual onset | 30–50 years old[3][4] |
| Causes | Genetic andenvironmental factors.[5] |
| Risk factors | Family history, anotherautoimmune disease[3] |
| Diagnostic method | TSH, T4,anti-thyroid autoantibodies, ultrasound[3] |
| Differential diagnosis | Graves' disease,nontoxic nodular goiter[6] |
| Treatment | Levothyroxine, surgery[3][6] |
| Frequency | 2% at some point[5] |
Hashimoto's thyroiditis, also known aschronic lymphocytic thyroiditis,Hashimoto's disease andautoimmune thyroiditis, is anautoimmune disease in which thethyroid gland is gradually destroyed.[7][1]
Early on, symptoms may not be noticed.[3] Over time, the thyroid may enlarge, forming a painlessgoiter.[3] Most people eventually develophypothyroidism with accompanyingweight gain,fatigue,constipation,hair loss, and general pains.[1] After many years the thyroid typically shrinks in size.[1] Potential complications includethyroid lymphoma.[2] Further complications of hypothyroidism can includehigh cholesterol,heart disease,heart failure,high blood pressure,myxedema, and potential problems in pregnancy.[1]
Hashimoto's thyroiditis is thought to be due to a combination ofgenetic andenvironmental factors.[5][8] Risk factors include a family history of the condition and having another autoimmune disease.[3] Diagnosis is confirmed with blood tests forTSH,Thyroxine (T4),antithyroid autoantibodies, andultrasound.[3] Other conditions that can produce similar symptoms includeGraves' disease andnontoxic nodular goiter.[6]
Hashimoto's is typically not treated unless there is hypothyroidism, or the presence of a goiter, when it may be treated withlevothyroxine.[6][3] Those affected should avoid eating large amounts ofiodine; however, sufficient iodine is required especially during pregnancy.[3] Surgery is rarely required to treat the goiter.[6]
Hashimoto's thyroiditis has a global prevalence of 7.5%, and varies greatly by region.[9] The highest rate is in Africa, and the lowest in Asia.[9] In the US white people are affected more often than black. 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.[9] It is the most common cause of hypothyroidism indeveloped countries.[10] It typically begins between the ages of 30 and 50.[3][4] Rates of the disease have increased.[9] It was first described by theJapanese physicianHakaru Hashimoto in 1912.[11] Studies in 1956 discovered that it was an autoimmune disorder.[12]
In the early stages of autoimmune thyroiditis, patients may have normal thyroid hormone levels and nogoiter or a small one.[5] Enlargement of the thyroid is due tolymphocytic infiltration andfibrosis.[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 theT cell-mediated destruction of the gland.[5]
As lymphocytic infiltration progresses, patients may exhibit signs ofhypothyroidism 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, andataxia.[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 arepericardial effusion,pleural effusion, both of which require further medical attention, andmyxedema coma, which is anendocrine 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 andmuscle pain,constipation, dry and thinning hair,heavy menstrual flow orirregular periods,depression, aslowed heart rate,problems getting pregnant,miscarriages,[17] andmyopathy.[15] Some patients in the early stage of the disease may experience symptoms ofhyperthyroidism 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 facialedema),neuropsychiatric system (forgetfulness, anxiety, depressed, fatigue, insomnia, irritability, and indifferent [sic]) andmucocutaneous 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 togenetic factors, while the remaining 20% is related toenvironmental factors (such as iodine, drugs, infection, stress, radiation).[23]
Thyroid autoimmunity can befamilial.[24] Many patients report a family history of autoimmune thyroiditis orGraves' disease.[14] The strong genetic component is borne out in studies onmonozygotic twins,[10] with aconcordance of 38–55%, with an even higher concordance of circulating thyroid antibodies not in relation toclinical presentation (up to 80% in monozygotic twins). Neither result was seen to a similar degree indizygotic twins, offering strong favour for high geneticetiology.[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 withchromosomal disorders, includingTurner,Down, andKlinefelter syndromes.[23]
The first genelocus associated with autoimmune thyroid disease was themajor histocompatibility complex (MHC) region onchromosome 6p21. It encodeshuman leukocyte antigens (HLAs). Specific HLAalleles have a higher affinity to auto-antigenic thyroidalpeptides and can contribute to autoimmune thyroid disease development. Specifically, in Hashimoto's disease, aberrant expression of HLA II onthyrocytes 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, includingDR3,DR5, andDQ7.[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-cellproliferation 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-genomelinkage 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 impairedthymic 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-mediatedcytotoxicity 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 ofIL-4 (Th2 cytokine suppressing cell-mediated autoimmunity),[34] lower secretion ofTGF-β (inhibitor ofcytokine production),[35] and mutations ofFOXP3, an essential regulatory factor for theregulatory T cells (Tregs) development.[36] Development of Hashimoto's disease was associated with mutation of the gene forTNF-α (stimulator of the IFN-γ production), causing its higher concentration.[37]
Study of healthy Danish twins divided to three groups (monozygotic and dizygotic same sex, and opposite sex twin pairs) estimated that genetic contribution to thyroid peroxidase antibodies susceptibility was 61% in males and 72% in females, and contribution to thyroglobulin antibodies susceptibility was 39% in males and 75% in females.[38]
The high female predominance in thyroid autoimmunity may be associated with the X chromosome. It contains sex and immune-related genes responsible forimmune tolerance.[39]A higher incidence of thyroid autoimmunity was reported in patients with a higher rate of X-chromosomemonosomy in peripheral white blood cells.[40] Another potential mechanism might be skewedX-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]
Both excessive and insufficientiodine 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]
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 includeceliac disease,type 1 diabetes,vitiligo,alopecia,[46]Addison disease,Sjogren's syndrome, andrheumatoid arthritis[14][47] Autoimmune thyroiditis has also been seen in patients withautoimmune polyendocrine syndromes type 1 and 2.[16]
Other environmental factors includeselenium deficiency,[8] infectious diseases such ashepatitis C,rubella, and possiblyCovid-19,[48][49][50] toxins,[5] dietary factors,[16] radiation exposure,[5] andgut dysbiosis.[51]
Thepathophysiology of autoimmune thyroiditis is not well understood.[5] However, once the disease is established, its core processes have been observed:
Hashimoto's thyroiditis is aT-lymphocyte mediatedattack on the thyroid gland.[13]T helper 1 cells triggermacrophages andcytotoxic lymphocytes to destroythyroid follicular cells, while T helper 2 cells stimulate the excessive production ofB cells andplasma cells which generateantibodies against the thyroidantigens, leading to thyroiditis.[52] The three major antibodies are:Thyroid peroxidase Antibodies (TPOAb),Thyroglobulin Antibodies (TgAb), andThyroid stimulating hormone receptor Antibodies (TRAb),[24] with TPOAb and TgAb being most commonly implicated in Hashimotos.[5] They are hypothesized to develop as a result of thyroid damage, where T-lymphocytes are sensitized to residual thyroid peroxidase and thyroglobulin, rather than as the initial cause of thyroid damage.[5] However, they may exacerbate further thyroid destruction by binding thecomplement system and triggeringapoptosis of thyroid cells.[5] TPO antibody levels may correlate with the degree oflymphocyte infiltration of the thyroid.[53][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 ofhyperthyroidism). 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 withparenchymatous 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 an 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 (includingplasma B-cells) diffusely infiltrating theparenchyma.[55] The lymphocytes are predominately T-lymphocytes with a representation of bothCD4+ andCD8+ cells.[5] The plasma cells arepolyclonal, with presentgerminal centers resembling the structure of alymph node[5] (also called secondary lymphoid follicles, not to be confused with the normally presentcolloid-filledfollicles that constitute the thyroid).[55]
In late stages of the disease, the thyroid may beatrophic.[10] Colloid-filled follicles shrink and the cuboidal cells that usually line the follicles becomeHürthle cells.[5] Fibrous tissue may be found throughout the affected thyroid as well.[5] Severe thyroid atrophy presents often with denser fibrotic bands ofcollagen that remains within the confines of the thyroid capsule.[55]
Generally, pathological findings of the thyroid are related to the amount of existing thyroid function — the more infiltration and fibrosis, the less likely a patient will have normal thyroid function.[5] A rare but serious complication isthyroid 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 anatrophied thyroid.[5]
Tests forantibodies againstthyroid peroxidase,thyroglobulin, andthyrotropin 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]
Anultrasound 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 smallcysts."[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]
To detect if thepituitary is stimulating an underperforming thyroid to produce morethyroid hormone.Thyroid-stimulating hormone (TSH) secretion from the anterior pituitary increases in response to decreasedserum thyroid hormones. If elevated, it signifies hypothyroidism.[47] 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 highersensitivity 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]
To detect a lack of thyroid hormones (hypothyroidism), or excess of thyroid hormones (hyperthyroidism). The two thyroid hormones areThyroxine (T4) andTri-iodothyronine (T3). T4 and T3 can be measured by their total amount, or free amount. As the free amount reflects the amount available to body tissues, the most treatment-relevant measures for thyroid disorders are Free T3 and Free T4.[63] Typically, Free T4 is the preferred test for hypothyroidism,[64] as Free T3immunoassay tests are less reliable at detecting low levels of thyroid hormone,[65] and they are more susceptible to interference.[64] Free T4 levels will usually be lowered, but sometimes might be normal.[66]
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.[63]LC-MSMS assays are rarer, but they are "highly specific, sensitive, precise, and can detect hormones found in low concentrations."[63]
Musclebiopsy is not necessary for diagnosis ofmyopathy due to hypothyroidmuscle fibre changes, however it may reveal confirmatory features.[15]
There is no cure for Hashimoto's Thyroiditis.[51][67] There is currently no known way to stop auto-immunelymphocytes infiltrating the thyroid or to stimulateregeneration of thyroid tissue.[5] However, the condition can be managed.[51][67]
| Endogenous | Synthetic | |
|---|---|---|
| T3 | Tri-iodothyronine | Liothyronine |
| T4 | Thyroxine | Levothyroxine |
Hypothyroidism caused by Hashimoto's thyroiditis is treated with thyroid hormone replacement agents such aslevothyroxine (LT4),[20]liothyronine (LT3),[5] ordesiccated thyroid extract (T4+T3).[68] In most cases, the treatment needs to be taken for the rest of the person's life.[20]
The standard of care islevothyroxine (LT4) therapy, which is an oral medication identical in molecular structure toendogenous thyroxine (T4).[20] Levothyroxine sodium has asodium salt added to increase thegastrointestinal absorption of levothyroxine.[69] Levothyroxine has the benefits of a longhalf-life[70] leading to stable thyroid hormone levels,[71] ease ofmonitoring,[71] excellent safety[71][72] and efficacy record,[63] and usefulness in pregnancy as it can cross the fetalblood-brain barrier.[13]
Levothyroxine dosing to normalise TSH is based on the amount of residualendogenous thyroid function and the patient’s weight, particularlylean 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 certaincardiac 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 higherTSH levels, elevated thyroid hormone levels, and transient "echocardiographic changes in some patients following 2-4 h of thyroxine intake".[73][74]
Some patients elect combination therapy with both levothyroxine andliothyronine (which is identical in molecular structure totri-iodothyronine) however studies of combination therapy are limited,[5] and fivemeta-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, long-term effects and side effects of desiccated thyroid extract. It is no longer recommended for the treatment of hypothyroidism.[68]
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 includeatrial fibrillation andbone density loss.[20] Long term over-treatment is associated with increased mortality anddementia.[21]
Thyroid Stimulating Hormone (TSH) is the laboratory value of choice for monitoring response to treatment with levothyroxine.[66] When treatment is first initiated, TSH levels may be monitored as often as a frequency of every 6–8 weeks.[66] Each time the dose is adjusted, TSH levels may be measured at that frequency until the correct dose is determined.[66] Oncetitrated to a proper dose, TSH levels will be monitored yearly.[66] 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][71][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 a number of factors including acute attacks of destructivethyrotoxicosis (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]
Measuringreverse 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.[64] Although cited in the lay press as a possible competitor to T3, it is unlikely that rT3 causes hypothyroid symptoms by out-competing T3 forthyroid 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 demonstratedin vivo to have the potential to inhibitDIO-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][70] and an estimated 10%-15% of patients treated with levothyroxine monotherapy are dissatisfied due to persistent symptoms of hypothyroidism.[81][21] Several differenthypothesised causes are discussed in themedical literature:[82][70][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 bothmolecules 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 bybody tissues.[84][85] Thus the body must convert thyroxine into tri-iodothyronine.[85] Tri-iodothyronine is produced primarily by conversion in theliver,kidney,skeletal muscle andpituitary gland.[86]
Adequate conversion requires sufficient levels of the micronutrientszinc,[87]selenium,[8]iron,[88] and possiblyvitamin A.[89] Conversion rates may decline with age.[90] Sincedeiodinase type 2 is necessary for T4 to T3 conversion in some peripheral tissues, "patients withDIO2 gene polymorphisms may have variable peripheral T3 availability", leading to localisedhypothyroidism in some tissues.[70][13][8] The Thr92AlaDIO2 polymorphism is present in 12–36% of the population.[70]
For the latter patients, levothyroxine monotherapy may not be sufficient[70] 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.[63]
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 thehypothalamic-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."[70] Patients may express a preference for "low normal or below normal TSH values"[83] and/or T4 and T3 monitoring. The monitoring of otherbiomarkers that reflect the action of thyroid hormone on tissues has also been proposed.[13][92][21]
Asimmunoassay Free T3 and Free T4 tests can overestimate levels, particularly at low thyroid hormone levels, hypothyroidism may be undertreated.[63]LC-MSMS tests may provide more reliable measures.[63]
It is hypothesised that autoimmunity may play some role in euthyroid symptoms.[75][93][70] Hypothesised mechanisms include the proposal that TPO-antibody-producinglymphocytes may travel out of the thyroid to other tissue, creating symptoms and inflammation due tocross-reaction,[70][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][70] and higher levels are associated with increased symptoms,[20] however "the foundassociation does not prove acausality".[70] No treatment currently exists for Hashimoto's autoimmunity, although observed wellbeing improvements after surgical thyroid removal are hypothesised to be due to removing the autoimmune stimulus.[13][94]
It is hypothesised that euthyroid symptoms may not be due to Hashimoto's or hypothyroidism, but some other "physical and psychosocialco-morbidities".[82][21]
Some patients may perceive improved wellbeing while inthyrotoxicosis, however overtreatment has risks (known risks forlevothyroxine and unknown risks forliothyronine).[21] One study demonstratedsurgical thyroid removal may substantially improve fatigue and wellbeing,[75][5] see Surgery considerations, below.
It is not established that reducingantithyroid 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 "diseaseremission, progression, lowered levothyroxine dose or improvedquality of life".[8]
Selenium,[96][8]vitamin D,[97] andmetformin[98] can reduce thyroid peroxidase antibodies. There is preliminary evidence that levothyroxine,[99][100][needs update]aloe vera juice[101] andblack cumin seed[102] may reduce thyroid peroxidase antibodies. Metformin can reduce thyroglobulin antibodies.[98] It is not established that agluten-free diet can reduce antibodies when there is no comorbidcoeliac disease.[103][104] 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 outcomorbid coeliac disease.[103]
One study foundsurgical 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 anindication forthyroidectomy.[5] Patients generally may discuss surgery with their doctor if they are experiencing significant pressure symptoms, or cosmetic concerns, or havenodules 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][105] but post-operative complications were higher than expected:[75]infection (4.1%), permanenthypoparathyroidism (4.1%) andrecurrent laryngeal nerve injury (5.5%).[82]
Zinc may increase free T3 levels.[104] A small pilot study foundAshwagandha Root may increase T3 and T4 levels, however, there's a lack of strong evidence of this benefit and Ashwagandha has a potential to causeadrenal insufficiency.[104]
As of 2022, there has been only one study of low-dosenaltrexone in Hashimoto's, which did not demonstrate efficacy, therefore nothing supports its use; Removing dairy products in those withoutlactose intolerance has not been found to be supported.[104] While soyisoflavones have the potential to theoretically affect T3 and T4 production, studies in those with sufficientiodine find no effect.[104]
Overt, symptomatic thyroid dysfunction is the most commoncomplication, with about 5% of people withsubclinical hypothyroidism and chronic autoimmune thyroiditis progressing to thyroid failure every year. Transient periods ofthyrotoxicosis (over-activity of the thyroid) sometimes occur, and rarely the illness may progress to full hyperthyroidGraves' disease with activeorbitopathy (bulging, inflamed eyes).[106]
Rare cases of fibrous autoimmune thyroiditis present with severeshortness of breath anddifficulty swallowing, resembling aggressive thyroid tumors, but such symptoms always improve with surgery orcorticosteroid therapy. Although primary thyroidB-cell lymphoma affects fewer than one in 1000 persons, it is more likely to affect those with long-standing autoimmune thyroiditis,[106] as there is a 67- to 80-fold increased risk of developing primary thyroid lymphoma in patients with Hashimoto's thyroiditis.[107]
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][108]
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.[109] 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.[109]
Many children diagnosed with Hashimoto's disease will experience the same progressive course of the disease that adults do.[110] 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 trueremission has been observed in a 12-year-old girl. Her thyroid was observed viaultrasound to progress from earlyinflammation to severe end-stage Hashimoto's thyroiditis with hypothyroidism, and then return to "almost normal with only minimal features of inflammation" and euthyroidism.[111]
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 theplacenta as an explanation for the sex difference.[112] Other research suggests the difference inprevalence amongst genders is due to the effects ofsex hormones.[16]
Autoimmune thyroiditis has a higher prevalence in societies that have a higher intake ofiodine in their diet, such as the United States and Japan, and among people who aregenetically susceptible.[113] 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][114]
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 risk for Hashimoto's may increase.[114]
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 in order to protect at-risk populations from developing hypothyroidism.[115] Geographic trends of hypothyroidism vary across the world as different places have different ways of defining 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.[116] 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,[113] but more commonly appears inmiddle age, particularly for men.[117]Incidence peaks in the fifth decade of life, but patients are usually diagnosed between age 30–50.[47][116] The highest prevalence from one study was found in the elderly members of the community.[118] 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.[119]
Those that 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.
Thesecular trends of hypothyroidism reveal how the disease has changed over the course of 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, per 1000 women, the disease was found varying between 3.9 and 4.89. Between 1994 and 2001, per 1000 men, the disease increased from 0.65 to 1.01.[118]
Also known as Hashimoto's disease, Hashimoto's thyroiditis is named after Japanese physicianHakaru Hashimoto (1881−1934) of the medical school atKyushu University,[120] who first described the symptoms of persons withstruma lymphomatosa, an intense infiltration of lymphocytes within the thyroid, in 1912 in the German journal calledArchiv für Klinische Chirurgie.[4][121] Thispaper was made up of 30 pages and 5 illustrations all describing thehistological changes in the thyroid tissue. Furthermore, all results in his first study were collected from four women. These results explained thepathological characteristics observed in these women especially the infiltration oflymphocyte andplasma cells as well as the formation of lymphoid follicles withgerminal centers, fibrosis, degenerated thyroidepithelial cells andleukocytes in thelumen.[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 diseasestruma 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 Dr. Hashimoto's discovery and publication, the disease was not recognized as distinct fromReidel'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 Reidel'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 howimmunization of certain rodents with extracts of other rodents' thyroid resembled the disease Hakaru and other researchers were trying to describe.[4] These doctors were also able to describeanti-thyroglobulin antibodies in blood serum samples from these same animals.[4]
Later on in the same year, researchers from the Middlesex Hospital in London were able to perform 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 animmunological 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 inThe 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.[122]
It is recommended thathypothyroidism be treated withlevothyoxine before conception, to prevent adverse effects on the course of the pregnancy and on the development of the child.[13] InIVF,embryo transfer is improved when hypothyroidism is treated.[123]
TheEndocrine Society recommends screening in pregnant women who are considered high-risk for thyroid autoimmune disease.[124] Universal screening for thyroid diseases during pregnancy is controversial, however, one study "supports the potential benefit of universal screening".[125] Pregnant women may haveantithyroid 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 afterdelivery.[126]
The presence of antibodies is also associated with "a 2 to 4-fold increase in the risk of recurrentmiscarriages, and 2 to 3-fold increased risk ofpreterm 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 includegestational hypertension includingpreeclampsia andeclampsia,gestational diabetes,placental abruption, andpostpartum 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, andneurodevelopmental delays (lower child IQ, language delay orglobal developmental delay).[125][123][13]
Successful pregnancy outcomes are improved when hypothyroidism is treated.[123] 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 theendocrinologist andobstetrician benefits the woman and the infant.[125][127][128]
Hormonal changes andtrophoblast expression of keyimmunomodulatory molecules lead toimmunosuppression and fetal tolerance. The main players in regulation of the immune response areTregs. Bothcell-mediated andhumoral immune responses are attenuated, resulting inimmune tolerance and suppression of autoimmunity. It has been reported that during pregnancy, levels of thyroid peroxidase and thyroglobulin antibodies decrease.[129]
Thyroid peroxidase antibodies testing is recommended for women who have ever been pregnant regardless of pregnancy outcome. "[P]revious pregnancy plays a major role in development of autoimmune overt hypothyroidism inpremenopausal 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 afterdelivery and should be differentiated from Hashimoto's thyroiditis as it is treated differently.[130]
After giving birth,Tregs rapidly decrease and immune responses are re-established. It may lead to the occurrence or aggravation of autoimmune thyroid disease.[129] 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.[131] Higher secretion ofIFN-γ andIL-4, and lower plasmacortisol 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 the postpartum thyroid dysfunction.[132]
Several years after the delivery, thechimeric 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 may initiate or exaggerate the autoimmune thyroid disease. In Hashimoto's disease patients, fetalmicrochimeric cells were detected in thyroid in significantly higher numbers than in healthy females.[133]
Hashimoto's disease is known to occur inchickens,rats,mice,dogs, andmarmosets, but Graves' disease does not.[134]
Pseudoscientific claims and "rogue practitioners" pose increasing risks to patients.[135]
"We have seen practitioners who proclaim themselves to be experts in hormonal therapy without any formal training and who often promote hormonal treatments without adequate endocrine evaluations. We have seen practitioners who make astonishing promises regarding the benefits of herbal, supplemental, and other unproven therapies that they themselves sell in their offices and/or online. And we have seen what we know to be frankly harmful and even dangerous products that contain animal whole organ (most commonly thyroid and/or adrenal) extracts or hormonal injections that produce highly elevated levels of sex hormones (especially testosterone) without any concern for short-term patient safety or longterm outcomes. And we have heard anecdotal stories from patients who visited these practitioners and had no beneficial results or frankly concerning on-treatment results at a surprisingly high financial cost, even though they had been promised symptom improvement, safety, and full insurance coverage."[135]
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