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Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)

Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)
Author:
Terry F Davies, MD, FRCP, FACE
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Dec 2022. | This topic last updated: Jan 26, 2022.

INTRODUCTION — Chronic autoimmune thyroiditis (Hashimoto's thyroiditis) is the most common cause of hypothyroidism in iodine-sufficient areas of the world. It occurs in up to 10 percent of the population, particularly females, and its prevalence increases with age [1]. It is characterized clinically by gradual thyroid failure, with or without goiter formation, due to lymphocytic infiltration and autoimmune-mediated destruction of the thyroid gland involving apoptosis of thyroid epithelial cells [2]. Nearly all patients have high serum concentrations of antibodies against one or more thyroid antigens, along with an intense and diffuse lymphocytic infiltration of the thyroid, which includes predominantly thyroid-specific B and T cells. Follicular destruction is the characteristic pathologic hallmark of thyroiditis.

The cause of what is most commonly referred to as Hashimoto's thyroiditis is thought to be a combination of genetic susceptibility and environmental factors. The familial association with Graves' disease and the fact that Graves' disease may sometimes evolve into Hashimoto's thyroiditis (and vice versa; Graves' alternans) indicate that the two disorders are closely related pathophysiologically, albeit not functionally [3,4]. The pathogenesis and precipitating factors for Hashimoto's thyroiditis are discussed here. The diagnosis and treatment of hypothyroidism as well as the pathogenesis of Graves' disease are reviewed elsewhere.

(See "Disorders that cause hypothyroidism", section on 'Chronic autoimmune (Hashimoto's) thyroiditis'.)

(See "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Identifying the cause'.)

(See "Treatment of primary hypothyroidism in adults".)

(See "Pathogenesis of Graves' disease".)

CLINICAL PHENOTYPES — The clinical presentation of chronic autoimmune thyroiditis (Hashimoto's thyroiditis) may vary. The presentations are considered manifestations of the same disorder with differing autoimmune events leading to the clinical phenotypes. The common pathologic feature is lymphocytic infiltration (picture 1), and the common serologic feature is the presence of high serum concentrations of antibodies to thyroid peroxidase (TPO) and thyroglobulin. Serum concentrations of TPO autoantibodies are elevated in more than 90 percent of patients. The presence of thyroid antibodies correlates well with the presence of a lymphocytic infiltrate in the thyroid gland [5].

Hypothyroidism – The most common cause of hypothyroidism in iodine-sufficient areas of the world is chronic autoimmune (Hashimoto's) thyroiditis. The two major phenotypes of chronic autoimmune hypothyroidism are goitrous autoimmune thyroiditis and atrophic autoimmune thyroiditis. In those with goiter, the thyroid enlargement is usually asymptomatic; however, rare patients have thyroid pain and tenderness [6,7], particularly if there is rapid thyroid swelling, and such patients may even require surgical relief. (See "Disorders that cause hypothyroidism", section on 'Chronic autoimmune (Hashimoto's) thyroiditis' and "Treatment of nontoxic, nonobstructive goiter", section on 'Very large or growing goiters'.)

Normal thyroid function tests – Sometimes TPO antibodies are measured concomitantly with thyroid-stimulating hormone (TSH) in patients who have symptoms of hypothyroidism and/or a goiter on physical examination, and TPO antibodies are found to be elevated in patients with normal thyroid function tests. These patients have chronic autoimmune thyroiditis but do not have hypothyroidism. They are more likely to develop hypothyroidism than antibody-negative individuals [8] as the usual course of Hashimoto's thyroiditis is gradual loss of thyroid function. Among patients with this disorder who have mild (subclinical) hypothyroidism, exhibited as slight increases in TSH and the presence of thyroid antibodies, overt hypothyroidism occurs at a rate of approximately 5 percent per year [9,10]. Overt hypothyroidism, once present, is permanent in nearly all cases, except in some children and postpartum women in whom it may be transient.

Transient hyperthyroidism or hypothyroidism alternating with hyperthyroidism – While hypothyroidism is the characteristic functional abnormality, the inflammatory process early in the course may involve enough apoptosis to cause thyroid follicular disruption and thyroid hormone release, resulting in transient hyperthyroidism sometimes referred to as "Hashitoxicosis" [11]. Some of these patients may even have a transiently increased radioiodine uptake. In addition, rare patients may cycle between hypothyroidism and Graves' disease, perhaps secondary to alternating production of TSH receptor blocking and stimulating antibodies [4,12]. (See 'Antibodies to the TSH receptor' below.)

Hashimoto's thyroiditis is primarily a disease of women, with a sex ratio of approximately 7:1; it can also occur in children (see "Acquired hypothyroidism in childhood and adolescence"). Variant mild forms of Hashimoto's thyroiditis have been given names such as silent (or painless) thyroiditis and postpartum thyroiditis, both of which are transient but may be followed years later by thyroid failure. (See "Painless thyroiditis" and "Postpartum thyroiditis".)

INTRATHYROIDAL LYMPHOCYTIC INFILTRATE — The characteristic histopathological abnormalities are profuse lymphocytic infiltration, lymphoid germinal centers, and destruction of thyroid follicles (picture 1). Fibrosis and areas of follicular cell hyperplasia, presumably induced by thyroid-stimulating hormone (TSH), are also seen in patients with severe disease and the fibroblast reaction may become excessive as seen in Reidel's thyroiditis [13]. The intrathyroidal lymphocytes are both T and B lymphocytes. T cells and plasma cells may be seen between the follicular cells within a thyroid follicle, a phenomenon called "peripolesis." There has been some insight into the development of intrathyroidal germinal centers and lymph vessels suggesting the importance of local chemokines [14].

THYROID ANTIGENS — Several antibodies and antigen-specific T cells directed against thyroid antigens have been described in chronic autoimmune thyroiditis. The major antigens are:

Thyroglobulin (Tg)

Thyroid peroxidase (TPO, historically known as the "microsomal" antigen)

The thyroid-stimulating hormone (TSH) receptor

Thyroglobulin and thyroid peroxidase — Tg is synthesized by follicular cells and secreted into the lumen of the thyroid follicle, where it is stored as colloid. TPO catalyzes the iodination of tyrosine residues of Tg to form monoiodotyrosine and diiodotyrosine (figure 1) (see "Thyroid hormone synthesis and physiology"). The induction of experimental autoimmune thyroiditis in mice by immunizing with either Tg or TPO as antigen provided evidence for their potential role in the pathogenesis of Hashimoto's thyroiditis in humans [15,16]. The TG gene may be a susceptibility gene for autoimmune thyroid disease coding for Tg variants of different immunogenicity [17].

When stimulated by TSH, the thyroid follicular cells take up Tg from the colloid. The Tg is then cleaved by peptidases yielding thyroxine (T4) and triiodothyronine (T3), which are released into the extracellular fluid. Some Tg is detectable in the serum of normal subjects, and the concentration may be increased in patients with any thyroid disease.

Tg is a large glycoprotein dimer, each subunit being approximately 330 kD. Approximately 45 of its 72 tyrosine residues can be iodinated in vitro, but only a few are primary iodine acceptors in vivo. These few are located in defined amino acid sequences near the amino and carboxyl terminals of the Tg molecule. Both the extent of iodination and posttranslational modifications of Tg are probably important determinants of its immunogenicity [18].

TPO is a key enzyme in thyroid hormonogenesis. It is located on the luminal surface of the microvilli of thyroid epithelial cells. The gene for human TPO [19] codes for an enzyme that is a 107 kD glycoprotein (933 amino acids) with 10 percent carbohydrate and a membrane-spanning region close to the carboxy-terminus. TPO catalyzes both tyrosine iodination and coupling of iodotyrosyl residues to form T3 and T4. Polymorphisms in the TPO gene have been associated with TPO antibodies [20] but have not been directly associated with clinical Hashimoto's thyroiditis.

The TSH receptor — The thyroid-stimulating hormone (TSH) receptor contains 764 amino acids and is a G-protein-coupled receptor [21-23]. The first 415 amino acids define a large extracellular domain, encoded by 10 exons. The remaining 349 amino acids constitute the seven transmembrane segments, the intracytoplasmic segments between them, and the intracytoplasmic tail (figure 2). TSH binds to multiple sites in the extracellular domain [24]. Antibodies to the TSH receptor may be found in a small number of Hashimoto's patients (approximately 15 percent) and may be of the blocking or stimulating variety [25,26].

TSH receptor expression has also been detected in other tissues (eg, fibroblasts, adipocytes, cardiac muscle cells, pituitary cells, bone cells, and brain). Although the role of the receptor in many of these tissues is unclear, data suggest that TSH can modulate bone cell and adipocyte function [27,28]. The retroocular expression of the TSH receptor has been implicated in thyroid eye disease (Graves' orbitopathy) and pretibial myxedema (thyroid dermopathy). (See "Clinical features and diagnosis of thyroid eye disease" and "Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease".)

ROLE OF B CELLS — B cells from thyroid tissue of patients with Hashimoto's thyroiditis are activated, as indicated by their ability to secrete thyroid antibodies spontaneously in vitro. Thus, the thyroid gland is a major site of thyroid antibody secretion. Additional evidence for this is the decline in serum thyroid antibody concentrations that occurs after surgery and during administration of antithyroid drugs to patients with this disorder [29]. However, there is also evidence that extrathyroidal lymphoid tissues may contribute to antibody production [30].

Antibodies to Tg and TPO — Nearly all patients with Hashimoto's thyroiditis have high serum concentrations of antibodies to thyroglobulin (Tg) and thyroid peroxidase (TPO). These antibodies are also found, although usually in lower concentration, in patients with other thyroid diseases including Graves' disease and in many subjects with no clinical or biochemical evidence of thyroid dysfunction but who presumably have a mild thyroiditis (table 1). On average, up to 20 percent of all women may have such antibodies depending on the different assays reported.

Function of thyroid antibodies — Tg and TPO antibodies are polyclonal [31] and are usually immunoglobulin G1 (IgG1) or IgG3 antibodies, but may be of any subclass. The polyclonality of these autoantibodies is strong evidence that they are a secondary phenomenon to the thyroid damage inflicted initially by T cells. Their polyclonality also indicates their variable ability to fix complement (primarily IgG1 and IgG3) and their ability to pass through the placenta. However, complement-dependent antibody-mediated cytotoxicity may indeed contribute to thyroid damage in patients with Hashimoto's thyroiditis [32]. In addition, TPO antibodies may inhibit TPO enzyme activity [32,33], although the significance of such in vitro observations are in dispute [34]. This is because the importance of these actions, in comparison with T cell- and cytokine-mediated apoptosis, is most likely only minor. More important is the potential role of thyroid antibody-secreting B cells in presenting attached thyroid antigen to the T cells. (See 'The role of T cells' below.)

Antibodies to the TSH receptor — Antibodies to the thyroid-stimulating hormone (TSH) receptor bind to the leucine-rich repeat region of the extracellular domain of the receptor [35]. They may be stimulating or blocking (figure 3).

TSH receptor antibodies of the stimulating variety were first identified by their prolonged thyroid-stimulating activity when serum from patients with Graves' hyperthyroidism was injected into animals; this activity was originally called the long-acting thyroid stimulator (LATS) [36] (see "Pathogenesis of Graves' disease"). These IgG fractions of serum from these patients were found to have thyroid-stimulating actions qualitatively similar to those of TSH in many bioassays and to block binding of radiolabeled TSH to thyroid membranes; in other words, the IgG fraction contained TSH receptor antibodies that acted as TSH agonists [37].

With the use of TSH-binding competition assays, TSH receptor antibodies were detected in the serum of some patients with Hashimoto's thyroiditis [38,39]. These antibodies, which are also usually polyclonal [40], blocked the action of TSH rather than activated it.

As noted above, patients who have had both Hashimoto's thyroiditis and Graves' hyperthyroidism at different times have been described (see 'Clinical phenotypes' above); at the appropriate times, their serum contained a predominance of TSH receptor-blocking antibodies or TSH receptor-stimulating antibodies [4,12]. Studies also suggest that Hashimoto's patients may also have TSH receptor antibodies of the stimulating variety but which are unable to stimulate much thyroid hormone synthesis because of the thyroid cell destruction [25].

Both blocking and stimulating types of TSH receptor antibodies may cross the placenta and influence thyroid function. (See "Overview of thyroid disease and pregnancy", section on 'Thyroid function in the fetus' and "Evaluation and management of neonatal Graves disease".)

THE ROLE OF T CELLS — T cells in patients with Hashimoto's thyroiditis react with processed thyroid antigens and peptides derived from these antigens. These activated T cells secrete cytokines which themselves activate a variety of other immune cells. T cells have three roles in this disease [41]:

Enhancing antibody production (a Th2 type of function [see below])

Apoptotic destruction of thyroid cells by activating cytotoxic T cells (a Th1 function) (table 2)

Regulation of the local immune response via Treg cells

The Th1 CD4+ lymphocytes, when stimulated by antigen, secrete interleukin-2 (IL-2), interferon gamma, and tumor necrosis factor-beta. In contrast, Th2 cells, when stimulated by antigens, secrete IL-4 and IL-5. Both types of T cells are found in thyroid tissue of patients with Hashimoto's thyroiditis, but Th1 cells may predominate [42,43]. In one report, a T cell clone caused cytolysis of autologous thyroid cells from a patient with Hashimoto's disease [44]. This was direct evidence for the induction of thyroid epithelial cell apoptosis.

The V gene repertoire of the T cell antigen receptor — The majority of antigen receptors on the surface of T cells consist of two noncovalently linked chains (alpha and beta), each with variable (V), diversity (D), and junctional (J) regions and with common constant (C alpha and C beta) regions. The V, D, and J genes code for the site on the receptor that recognizes a human leukocyte antigen (HLA) complex, affording antigen specificity. In addition to the many V (>100) and J (>50) genes present in the genome, random nucleotide additions and deletions to the D region add immense complexity to the receptor repertoire, causing this region, referred to as the third complementarity-determining region (CDR3), to be the major locus of antigen recognition [45].

Although some patients display a restricted (oligoclonal) T cell repertoire, many different V genes coding for the T cell antigen receptor are usually present in T cells from the thyroid and peripheral blood of patients with Hashimoto's thyroiditis (figure 4) [46]. This finding suggests that many antigenic epitopes are involved in the pathogenesis of the disease by the time the patient's pathologic material is available for examination. In contrast, the number of V genes coding for T cell antigen receptors in T cells from patients with Graves' hyperthyroidism is usually much more limited. (See "Pathogenesis of Graves' disease".)

Immune regulation — The immune system exerts some of its overall control via regulatory "suppressor" cells (CD4+CD25+Foxp3+) exerting cell-cell and cytokine-mediated suppression (so-called Treg cells) [47]. Patients with Hashimoto's thyroiditis may have reduced numbers and/or inadequate function of such circulating CD4+CD25+ regulatory cells [48,49]. Immune suppression can also be exerted in a variety of other ways including the direct effects of cytokines and the influence of "anergized" T cells [50]. There is also deletion of cells by apoptosis, which contributes to antigen-specific tolerance.

POTENTIAL MECHANISMS OF THYROID INJURY — Several mechanisms have been proposed for breaking tolerance to thyroid antigens and causing Hashimoto's thyroiditis. These include the current major hypotheses for all autoimmune diseases: molecular mimicry and bystander activation, and includes the involvement of thyroid cell expression of human leukocyte antigens (HLA) and activation of thyroid cell apoptosis by a Fas ligand-Fas interaction (table 3).

Molecular mimicry — According to this proposal, Hashimoto's disease is caused by the immune response to a foreign antigen such as a virus that is structurally similar to an endogenous substance. As an example, both bacteria and humans have heat shock proteins. During the course of a bacterial infection, the host has an antibody and T cell response to the microbe's heat shock protein [51]. These antibodies and T cells may then cross-react with the host's heat shock protein. If the mimicked protein were a thyroid antigen on the thyroid, then thyroiditis could ensue. In addition, the potential for such mimicry may be related to a patient's own HLA gene repertoire and how thyroid antigens are recognized.

Bystander activation — The arrival of a thyroid cell virus or activated nonspecific lymphocytes within the thyroid may cause the local release of cytokines, which in themselves may activate resident local thyroid-specific T cells. This bystander effect hypothesis has support from studies in an animal model of insulitis [52] and a model of experimental autoimmune thyroiditis [53].

Thyroid cell expression of HLA antigens — HLA class II molecules are present on thyroid follicular cells from patients with Hashimoto's thyroiditis, but not normal subjects (picture 1). Expression of these molecules on thyroid follicular cells can be induced by interferon gamma and other cytokine and chemokine products of T cells, when the T cells are activated (eg, by a viral infection) [54]; expression can also be induced by viruses directly [55,56]. Thyroid cells expressing major histocompatibility complex (MHC) class II molecules would be able to present antigens, either foreign or self, to T cells, thereby activating the T cells. The following observations provide indirect support for this hypothesis:

Induction of MHC class II molecules on thyroid follicular cells by interferon gamma can induce autoimmune thyroiditis in susceptible mice [57].

Thyroid follicular cells expressing MHC class II molecules can present viral peptide antigens to cloned human T cells [58].

Autologous thyroid cells can bind to cloned thyroid antigen-specific T cells in the absence of more conventional antigen-presenting cells [59].

These findings strongly support the view that infection may induce the expression of MHC class II molecules on human thyroid cells and that these cells may act as antigen-presenting cells, thereby initiating a thyroid autoimmune response. Intrathyroidal dendritic cells and B cells also may serve as antigen-presenting cells and may provide important costimulatory molecules for effective antigen presentation. The induction of Graves' disease in mice using fibroblasts expressing thyroid-stimulating hormone (TSH) receptor antigen and MHC class II molecules is further evidence for this mechanism of disease causation [60].

It should be noted that a transgenic mouse expressing thyroid cell gamma interferon has been shown to develop less, rather than more, experimental autoimmune thyroiditis [61]. The meaning of this observation is uncertain because of the potential interference in thyroid antigen expression.

Thyroid cell apoptosis — Thyroid cell death in Hashimoto's disease is the central pathological phenomenon. Normal thyroid epithelial cells express a variety of death receptors, including Fas. Activation of the Fas ligand-Fas signaling system could contribute to the follicular cell destruction characteristic of Hashimoto's thyroiditis. In autoimmune thyroiditis, thyroid follicular cells are induced to express functional Fas and also Fas ligand by cytokine stimulation from antigen-presenting cells and Th1 cells (eg, interleukin-1 [IL-1]). This may cause self-apoptosis [62]. In one study, for example, apoptosis occurred in thyroid cells from patients with Hashimoto's thyroiditis expressing Fas or normal thyroid cells in which Fas was induced by IL-1b, after the cells were exposed to other thyroid cells constitutively expressing Fas ligand [62]. Thus, any event that leads to local production of IL-1b might initiate thyroid cell induced thyroid cell apoptosis. More likely, however, the accumulated and activated T cells expressing Fas ligand may induce apoptosis of the thyrocytes directly by interacting with Fas on the cells [63]. This is an important way of mediating autoimmune cell death [64].

GENETIC SUSCEPTIBILITY — It is now clear that there is genetic susceptibility to Hashimoto's thyroiditis, and much has been learned in recent years concerning the susceptibility genes for this disorder in particular and for autoimmune thyroid disease in general [65]. Evidence for genetic susceptibility to Hashimoto's thyroiditis includes the following observations:

The disease clusters in families, sometimes alone and sometimes in combination with Graves' disease [3].

The sibling recurrence risk is >20 [66].

The concordance rate in monozygotic twins is 30 to 60 percent [67] despite random combinations of T cell receptor and antibody V genes at the time of recombination.

It occurs with increased frequency in patients with Down syndrome and Turner syndrome.

There is an association (risk ratio [RR] approximately 4 to 5), with certain human leukocyte antigen (HLA) alleles such as DR3 and an association with the presence of Arg 74 in the DR3 amino acid-binding pocket [68]. (See "Major histocompatibility complex (MHC) structure and function".)

There is linkage to certain alleles of a small number of immune-related genes including the genes for cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and CD40, T cell surface molecules involved in T cell activation [69,70].

The thyroglobulin (Tg) gene (TG) has been linked to autoimmune thyroid disease and has been suggested to code for Tg forms with different immune reactivity [17].

PRECIPITATING FACTORS — Infection, stress, sex steroids, pregnancy, iodine intake, and radiation exposure are the known possible precipitating factors for Hashimoto's thyroiditis. Fetal microchimerism within the maternal thyroid is also a possibility (table 3).

Infection — No infection is known to cause or even to be closely associated with Hashimoto's thyroiditis in humans [71], although thyroiditis can be induced in experimental animals by certain viral infections [72]. Patients with subacute granulomatous (DeQuervain's) thyroiditis (presumed to be a viral infection) and congenital rubella may have thyroid antibodies for a few months after their illnesses, and the infections could initiate expression of major histocompatibility complex (MHC) class II molecules in the thyroid gland. However, neither disorder is known to be commonly followed by chronic thyroiditis although evidence of thyroid autoimmunity may persist [73].

Stress — The second case of hyperthyroidism described by Parry in 1825 was a 21-year-old woman whose symptoms began four months after she had been thrown accidentally down the stairs in a wheelchair. Subsequently, stress of various types has been linked to Graves' hyperthyroidism. The proposed mechanisms include induction of immune suppression by non-antigen-specific mechanisms, perhaps due to the effects of cortisol or corticotropin-releasing hormone on immune cells, followed by immune hyperactivity leading to autoimmune thyroid disease [74]. Such a mechanism might be operative in postpartum thyroiditis, which occurs three to nine months after delivery (see "Postpartum thyroiditis"). However, there is currently no evidence linking emotional or psychologic stress to Hashimoto's thyroiditis most probably because of the long natural history of the disease requiring a large part of the gland to be damaged before thyroid function is compromised. Any major stress may have occurred many years earlier.

Sex — More females than males have Hashimoto's thyroiditis, suggesting a role for sex steroids. However, older women may be more likely to have Hashimoto's thyroiditis than younger women, suggesting that the presence or absence of estrogen may not be the important factor. Yet, in chickens, androgens protect against thyroiditis induced by immunization with thyroglobulin (Tg) [75].

A more likely explanation for the female predominance is a role for the X chromosome. Firstly, there is skewed X chromosome inactivation, which was found in 34 percent of female twins with autoimmune thyroid disease and only 11 percent of controls [76,77], and so it is possible that the self-antigens on the inactivated X chromosome might not be expressed sufficiently to allow tolerance. Secondly, the FOXP3 gene has been associated with autoimmune thyroid disease [78]. The FOXP3 gene is on the X chromosome and commits naïve T cells to become Treg cells, but the association is not strong and not seen in any of the Graves' disease genome-wide association studies (GWAS).

Pregnancy — Pregnant individuals must generate tolerance for their fetus. During pregnancy, there is a marked increase in CD4+CD25+ regulatory T cells which lead to diminished function of both T cells and B cells [79], and the rebound from this immunosuppression is thought to contribute to the development of postpartum Hashimoto's thyroiditis. Pregnancy-associated immune changes are associated with a shift to Th2 T cells and a shift in cytokine profiles [80].

A variety of local factors at the immune cell-trophoblast interface are also known to be important modulators of immune function in pregnancy. The trophoblast cells, located in the placenta and subject to maternal immune surveillance, serve as physical barriers between mother and fetus, and they have been shown to express several immune-modulating molecules, such as human leukocyte antigen-G (HLA-G), Fas ligand, and indoleamine 2,3-dioxygenase as well as secreting a variety of cytokines. HLA-G is one of the members of the MHC class I family and is known to inhibit natural killer function and dendritic cell maturation. Fas ligand interacts with Fas antigen and induces apoptotic cell death of fetal antigen-reactive maternal lymphocytes. Indoleamine 2,3-dioxygenase, which catalyzes tryptophane in lymphocytes, has proven to be critical in the maintenance of allogeneic pregnancy in the mouse. Other than these local modulators, progesterone produced by the placenta affects cytokine profiles across the whole maternal immune system [81,82]. Approximately 20 percent of patients with postpartum thyroiditis go on to develop classical Hashimoto's disease in later years [83].

Iodine intake — Mild iodine deficiency is associated with a lower prevalence of Hashimoto's disease and hypothyroidism, while excessive intake is associated with a higher prevalence. As an example, in China, autoimmune thyroiditis was found in 0.3 percent of those with mildly deficient iodine intake and 1.3 percent of those with excessive iodine intake [84]. Similarly, high iodine-containing drugs, such as amiodarone, often precipitate autoimmune thyroiditis, although a variety of mechanisms have been suggested. (See "Amiodarone and thyroid dysfunction".)

Radiation exposure — Environmental radiation exposure may increase the possibility of developing markers of autoimmune thyroid disease, although the evidence for this and developing autoimmune hypothyroidism are conflicting [85-90].

Following the tragic Chernobyl nuclear accident, the exposed children developed a high frequency of thyroid autoantibodies [91]. In addition, 12 to 15 years after the Chernobyl accident, thyroid peroxidase (TPO) antibodies were elevated with a dose-response relationship in a cohort of radiation-exposed individuals [89]. In the same cohort, a small increase in subclinical hypothyroidism related to the level of radiation exposure was found [92]. However, the risk of subclinical hypothyroidism was less when TPO antibodies were present. In another study in the Chernobyl region comparing people with high and low exposure levels, the prevalence of TPO antibodies increased and then abated without evidence of appreciable levels of hypothyroidism [93].

In a population-based study of 4299 subjects, 160 had an occupational exposure to ionizing radiation [88]. Nearly 60 percent of the subjects worked in a nuclear power plant, while the rest were either medical or laboratory workers. Ten percent of the female subjects with radiation exposure met criteria for autoimmune thyroid disease (anti-TPO antibodies greater than 200 international units/mL and hypoechogenicity on ultrasound) compared with 3.4 percent of those without an exposure. Subjects with greater than five years of exposure to ionizing radiation were at particularly high risk.

However, in the long-term follow-up of atomic bomb survivors, no dose-response relationship was found for autoimmune thyroid disease, the strongest evidence so far that no association exists [85]. Similarly, the long-term follow-up of people exposed by the releases from the Hanford nuclear facility found no increase in autoimmune thyroid disease and hypothyroidism [86].

Fetal microchimerism — Fetal cells have been identified within maternal thyroid glands in patients with autoimmune thyroid. Such cells may initiate graft versus host reactions within the thyroid gland and play a significant role in the development of Hashimoto's thyroiditis [35,94-97]. To date, however, this remains hypothetical.

SUMMARY

General principles – Hashimoto's thyroiditis is characterized clinically by gradual thyroid failure, with or without goiter formation, due primarily to autoimmune-mediated destruction of the thyroid gland involving apoptosis of thyroid epithelial cells. (See 'Introduction' above.)

Clinical phenotypes – The two major phenotypes of chronic autoimmune hypothyroidism are goitrous autoimmune thyroiditis and atrophic autoimmune thyroiditis, with the common pathologic feature being lymphocytic infiltration and follicular destruction (picture 1) and the common serologic feature being the presence of high serum concentrations of antibodies to thyroid peroxidase (TPO) and thyroglobulin (Tg) (table 1). (See 'Clinical phenotypes' above.)

Sometimes TPO antibodies are measured concomitantly with thyroid-stimulating hormone (TSH) in patients who have symptoms of hypothyroidism and/or a goiter on physical examination, and TPO antibodies are found to be elevated in patients with normal thyroid function tests. These patients have chronic autoimmune thyroiditis but do not have hypothyroidism. They are more likely to develop hypothyroidism than antibody-negative individuals. Overt hypothyroidism, once present, is permanent in nearly all cases, except in some children and postpartum women in whom it is may be transient. (See 'Clinical phenotypes' above.)

Role of B and T cells – B cells from thyroid tissue of patients with Hashimoto's thyroiditis are activated, as indicated by their ability to secrete thyroid antibodies spontaneously in vitro. T cells in patients with Hashimoto's thyroiditis react with processed thyroid antigens and peptides derived from these antigens. These activated T cells secrete cytokines that in turn activate a variety of other immune cells. T cells have three major roles in this disease: a role in antibody production (a Th2 type of function), a role in the apoptotic destruction of thyroid cells by activating cytotoxic T cells (a Th1 function), and a role in immunoregulation (Treg cells) (table 2). (See 'Role of B cells' above and 'The role of T cells' above.)

Mechanisms of thyroid injury – Several mechanisms have been proposed for the pathogenesis of Hashimoto's thyroiditis. These include molecular mimicry and bystander activation including the involvement of thyroid cell expression of human leukocyte antigens (HLAs) and activation of thyroid cell apoptosis by a Fas ligand-Fas interaction (table 3). (See 'Potential mechanisms of thyroid injury' above.)

Genetics and environment – The cause of Hashimoto's thyroiditis is thought to be a combination of genetic susceptibility and environmental factors.

Genetic susceptibility – Evidence for genetic susceptibility to Hashimoto's thyroiditis includes familial clustering, association with certain HLA alleles (eg, DR3), and linkage to certain alleles of immune-related genes (eg, cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], CD40, T cell surface molecules involved in T cell activation).

Precipitating factors – Infection, stress, sex steroids, pregnancy, iodine intake, and radiation exposure are the known possible precipitating factors for Hashimoto's thyroiditis. Fetal microchimerism within the maternal thyroid is also a possibility (table 3). (See 'Precipitating factors' above.)

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Topic 7854 Version 10.0

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