Skip Navigation LinksHome > May 2012 - Volume 19 - Issue 3 > Hashimoto Thyroiditis: A Century Later
Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e3182534868
Review Articles

Hashimoto Thyroiditis: A Century Later

Ahmed, Rania MD; Al-Shaikh, Safa MD; Akhtar, Mohammed MD

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Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia

The authors have no funding or conflicts of interest to disclose.

Reprints: Mohammad Akhtar, MD, Department of Pathology and Laboratory Medicine (MBC 10), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia (e-mail:

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More than a century has passed since the first description of Hashimoto thyroiditis (HT) as a clinicopathologic entity. HT is an autoimmune disease in which a breakdown of immune tolerance is caused by interplay of a variety of immunologic, genetic, and environmental factors. Thyrocyte injury resulting from environmental factors results in expression of new or hidden epitopes that leads to proliferation of autoreactive T and B cells. Infiltration of thyroid by these cells results in HT. In addition to the usual type of HT, several variants such as the fibrous type and Riedal thyroiditis are also recognized. The most recently recognized variant is immunoglobulin G4+ HT, which may occur as isolated thyroid limited disease or as part of a generalized Ig4-related sclerosing disease. The relationship between HT and Riedel thyroiditis remains unclear; however, recent evidence seems to suggest that it may also be part of the spectrum of Ig4-related sclerosing disease. HT is frequently associated with papillary thyroid carcinoma and may indeed be a risk factor for developing this type of cancer. The relationship between thyroid lymphoma and HT on the other hand appears well established.

Thyroid goiter of 1 type or another has been known for centuries. Most of the goiters are associated with iodine deficiency and may be preventable by introducing sufficient iodine in the diet. Some goiters, however, are not related to iodine deficiency. One of these is Hashimoto thyroiditis (HT), an autoimmune disease of thyroid, first described by Hakaru Hashimoto (1912), a surgeon in Fokouka, Japan. His study was based on clinicopathologic evaluation of 4 women with goiters treated by partial thyroidectomy. Histologic examination of the thyroid revealed features, which were completely different from those of the usual colloid goiter. The paper included detailed description of histologic features, which included extensive lymphocytic infiltration, eosinophilic change in thyroid cells, and interstitial fibrosis. In view of the extensive lymphoid infiltration in these thyroids, Hashimoto suggested the term “struma lymphamatosa” (lymphomatous goiter) and argued that this disease is different from Grave disease and Riedel thyroiditis (RT). It took several decades for the medical community around the world to fully recognize this disease as a well-defined clinicopathologic entity. HT is now considered to be a form of autoimmune thyroid disease, which may overlap with other autoimmune thyroid conditions such as RT and Grave disease.1

HT is a common form of autoimmune thyroid disease, affecting up to 2% of general population. It is 5 to 10 times more common in women than men. The annual incidence of HT worldwide is estimated to be 0.3 to 1.5 cases per 1000 persons. The incidence, however, varies widely in different geographic locations depending on iodine content of diet and various other environmental factors. It may coexist with other autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, etc. Clinically the patient presents with variable thyroid enlargement, along with a multitude of symptoms including weight gain, paresthesia, fatigue, constipation, muscle weakness, cramps, hair loss, infertility, and a variety of psychological problems. Clinical work-up and laboratory studies reveal evidence of hypothyroidism and the presence of antithyroiglobulin and antiperoxidase antibodies.2–5

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Pathogenesis of HT has been the subject of numerous studies over the last several decades. The development of autoimmune destruction and failure of thyroid follicles is a multistep process involving several converging environmental and genetic factors. The key factor in the development of autoimmune thyroiditis is breakdown of immune tolerance, initiated by inflammatory events in the gland probably as a result of viral or bacterial infection or injury to the thyroid cells from toxins such as iodine. The injured thyroid cells may exhibit new epitopes or unmask hidden epitopes, resulting in an influx of major histocompatability complex (MHC) class II-positive antigen presenting cells, including dendritic cells and different subclasses of macrophages. These cells present thyroid-specific antigens to naive lymphocytes within the regional lymph nodes, leading to clonal expansion of autoreactive CD4+ T cells, CD8+ cytotoxic T cells, and immunoglobulin (IgG antibody)-producing B cells. These cells accumulate in the thyroid resulting in thyroiditis (Fig. 1). Initially, the production of self-reactive cells occurs in the regional lymph nodes; however, later the lymphoid tissue develops directly in the thyroid gland. The cells lining the thyroid follicles (thyrocytes), which are the target for these autoreactive lymphocytes, are progressively destroyed, ultimately leading to hypothyroidism.6

Figure 1
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Immune tolerance is a complex process responsible for preventing body’s immune system from attacking its own tissues. However, this system is affected by a variety of susceptibility genes that modulate the risk for developing an autoimmune reaction. The MHC encoding the human leukocyte antigens (HLA) glycoprotein, consists of a combination of genes located on chromosome 6.21. The HLA region is highly polymorphic and contains many immune response genes, which have impact on the risk of developing autoimmune thyroid disease.7,8 These include HLA-DR3, HLA-DR4, and HLA-DR5. A molecular signature of the HLA-DR pocket, determined by specific amino acids (Tyr26, Tyr30, Gln70, Lysn71), has recently been shown to confer a significant risk for development of HT.9

Polymorphism of non-MHC genes may also modulate the risk for developing autoimmune thyroiditis. Cytotoxic T–lymphocyte-associated antigen-4 (CTLA-4) is a major negative regulator of T-cell responses. Several CTLA-4 polymorphisms have been linked to autoimmune thyroid disease. Three of these variants have been found to have consistent link with HT and include: an AT-repeat microsatellite at the 3′ untranslated region of the CTLA-4 gene; an A/T single nucleotide polymorphisms (SNP) at position 49 in the signal peptide; and an A/G SNP downstream and outside of 3′ untranslated region.10–12 Functional polymorphism of the protein tyrosine phosphatase-22 (PTPN22) gene is also thought to inhibit T cells. A tryptophan/arginine substitution at codon 620 (R620W) was found to be associated with HT.13

The role of genetic factors in HT is also supported by several studies on the prevalence of HT in monozygotic as compared with dizygotic twins. The concordance rate of HT among monozygotic twins in these studies has varied form 36% to 55% among the monozygotic twins as compared with 0% to 29% among the dizygotic twins.14–16 These studies indicate a substantial inherited susceptibility with immunoregulatory genes playing an important role in predisposing and modulating the pathogenesis of HT. However, as the concordance rate among monozygotic twins is <100%, genetic factors may not be the sole determinants for the development of HT.

Environmental factors also seem to play an important role in initiating the autoimmune process. Probable environmental triggers for HT include iodine intake, bacterial and viral infections, medications, cytokine therapy, smoking, stress, and probably pregnancy. The role of dietary iodine has been defined in several epidemiological and experimental animal studies. Dietary intake of iodine appears to be the most important environmental factor responsible for triggering the autoimmune reaction in HT. Iodine is a necessary component of normal thyroid hormonogenesis. Incorporation of iodine into thyroglogulin residues leads to the formation of monoiodotyrosine and of di-iodotyrosine derivatives that subsequently undergo an oxidative coupling event resulting in the production of T3 and T4. Several studies suggest that iodination of thyroglobulin is crucial for recognition by thyroglobulin-reactive T cells. Iodine excess can affect the thyroglobulin molecule directly creating new epitopes or unmasking “hidden” epitopes. Studies have shown that highly iodinated thyroglobulin molecule is more immunogenic than the thyroglobulin of low iodine content. Indeed highly iodinated thyroglobulin may facilitate antigen uptake and processing by antigen presenting cells. Furthermore high doses of iodine are known to stimulate the function of macrophages and dendritic calls as well as increase the number of circulating T cells and enhance Ig production by B cells. Excess amount of iodine may also be rapidly oxidized by thyroid peroxidase thereby generating excess amounts of reactive intermediates such as hypoiodous acid and oxygen radicals. These oxidative species damage thyroid follicular cells membranes by oxidation of membrane lipids and proteins causing necrosis of these cells. The state of severe iodine deficiency itself leads to lowering of thyroid autoimmunity and an immune-deficient state in autoimmune prone BB-DP rats. This hampers the autoreactive T-cell generation and autoantibody production.17–20

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Pathologic examination of the resected specimen (thyroidectomy, lobectomy) reveals diffuse and symmetrical enlargement of the gland, although in some cases 1 lobe is larger than the other, and in others the thyroid has a distinctly nodular appearance. The consistency is firm, but not stony hard and there is no extension of the process beyond the confines of the gland. The cut surface is friable, vaguely or distinctly nodular, and yellowish-gray without evidence of necrosis and calcification.21

Microscopically, the 2 main abnormalities are lymphocytic infiltration of the stroma and oxyphilic change of the follicular epithelium (Figs. 2 and 3). The lymphoid tissue is distributed within and around the lobules, and it invariably exhibits large follicles with prominent germinal centers. The lymphocytes are predominantly T cells, intermixed with B cells. Variable numbers of other inflammatory cells including plasma cells, histiocytes, and scattered intrafollicular multinucleated giant cells may also be present. The lymphocytic and plasmacytic population is polyclonal by immunohistochemical and gene rearrangement techniques.21–23

Figure 2
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Figure 3
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The thyroid follicles are variably atrophic, however, the lining cells may show focal features consistent with regenerative hyperplasia. Many of the follicles are lined by large cells with abundant granular and eosinophilic cytoplasm (Hürthle cells). The nuclei of these cells may show enlargement and moderate pleomorphism. The granularity of the cytoplasm of these cells correlates with presence of large numbers of mitochondria noted on ultrastructural examination.21

The connective tissue in HT is usually scanty, with slight or moderate thickening of the interlobular septa. In the fibrous variant of this disease, which comprises about 12% of all cases, fibrosis is more extensive, usually involving ≥30% of the thyroid. The intervening thyroid tissue usually reveals lymphocytic infiltration, usually without prominent Hürthle cell change, but may show squamous metaplasia (Fig. 4). Clinically, this variant is characterized by a very firm goiter (often with sudden enlargement), severe pressure symptoms, and physical signs suggestive of cancer, and markedly elevated antibody titer to thyroglobulin.21,24,25

Figure 4
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Fibrous atrophy variant of HT is morphologically similar to the fibrous variant, but presents clinically with an extremely small thyroid (1 to 6 g), which on histologic examination is characterized by abundant fibrosis with marked diffuse atrophy of thyroid tissue containing lymphoplasmacytic infiltrate. Some observers are of the view that this variant actually may represent an advanced stage in the course of fibrous variant of HT.

HT typically exhibits a diffuse appearance both grossly and microscopically. In some cases, however, a distinct nodularity is evident. The epithelial component of the nodules manifests features of nodular hyperplasia. This could be interpreted as the combination of HT and nodular hyperplasia, although the possibility that the 2 abnormalities are pathogenetically related cannot be excluded. For such lesions the term nodular HT has been suggested.21

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Another recently recognized variant of HT is the IgG4-related thyroiditis. This type of thyroiditis may be part of a generalized IgG4-related sclerosing disease (IgG4RSD) or as organ-limited autoimmune thyroiditis. IgG4-related sclerosing disease usually presents as autoimmune pancreatic disease, but may also involve several other body sites, singly or in combination with other locations including, salivary gland, orbit, thyroid, hepatobiliary tract, mediastinum, retroperitoneum, kidney, aorta, and the lung.26,27 The morphologic features of IgG4RSD include lymphoplasmacytic infiltration, lymphoid follicle formation, sclerosing fibrosis, and obliterative phlebitis along with atrophy of parenchymal cells. Immunostaining reveals increased IgG4+ plasma cells with IgG4/IgG ratio>40%. The natural history is characterized by development of multiple sites of involvement with time, sometimes after many years. Common laboratory findings include raised serum globulin IgG, IgG4, and IgE.26–27

IgG4 is the least common of the 4 subclasses of IgG, namely IgG1, IgG3, IgG3, and IgG4, respectively. These subclasses show >95% homology in amino acid sequences of the constant domains of their heavy chains. The 4 subclasses, however, have different amino acid sequences in their respective hinge regions. These differences play an important role in triggering further effector functions such as complement activation and FC receptor binding. For example, as compared with the other subclasses of IgG, IgG4 exhibits negligible binding of C1q protein complex and is unable to activate the classic complement pathway.28

IgG4 thyroiditis is characterized by presence of intense lymphoplasmacytic infiltrate within the thyroid with large numbers of IgG4+ plasma cells representing at least 30% to 40% of the total numbers of IgG+ plasma cells (Figs. 5 and 6). IgG4 thyroiditis was first described by Li Y et al29 in an immunohistochemical study of 13 cases of thyroiditis for the presence of IgG4+ plasma cells. Using a 30% cut-off level for IgG/IgG4 ratio and the presence of at least 20 IgG+ plasma cells per high power field, 5 of the 13 cases were designated as IgG4 thyroiditis. The morphologic features in these 2 groups were somewhat different. In the IgG4+ cases, the lympoplasmacytic infiltrate was more exuberant and there was more parenchymal damage and prominent sclerotic fibrosis. These observations were confirmed and further expanded in a follow-up study by the same group, comprising 70 cases of thyroiditis, 19 (27%) of which were categorized as IgG4+ thyroiditis. Furthermore, in this study significant differences in the clinical, serological, and sonographic characteristics of the IgG4+ and IgG4 types of thyroiditis were noted. For example, male patients were more likely to have IgG4+ thyroiditis, although female preponderance was still detected. Patients with IgG4+ thyroiditis were also more likely to have hypothyroidism, than those with IgG4 thyroiditis. Similarly, preoperative serum titers of thyroid antibodies (TGAb and TPOAb) were significantly higher in the IgG4+ group than in IgG4 patients. As expected serum IgG4 concentration was significantly elevated in patients with IgG4+ thyroiditis. Sonographic examination also revealed differences in these 2 groups of patients. In cases of IgG4+ thyroiditis diffuse low echogenicity was seen, compared with coarse nodular echogenicity often seen in IgG4 thyroiditis.30

Figure 5
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In 1883, Bernhard Riedel first recognized the disease. He published a description of 2 cases in 1896 and of a third case in 1897. Riedel used the term eisenharte struma to describe the stone-hard consistency of the thyroid gland and its fixation to adjacent structures.31 He noted the presence of chronic inflammation with fibrosis and the absence of malignancy on microscopic examination. The disease, however, is extremely rare and no large series have been published. In a review of 57,000 thyroidectomies performed at the Mayo Clinic between 1920 and 1984, 37 cases of RT were identified, with an estimated incidence of 1.06 cases per 100,000 outpatients.32 In another study at Cleveland Clinic, 6 cases of RT were identified over a 40-year period.33 The rarity of RT has precluded detailed studies on the etiology, pathogenesis, and treatment of this disease.31,34

RT is generally not considered to be related to HT despite the existence of isolated instances in which the 2 diseases coexist.35 RT may superficially resemble fibrous variant of HT. However, the fibrosis in fibrous variant of HT is different from that seen in RT. In HT the fibrosis is of dense hyaline type and is confined to thyroid. In contrast, the fibrosis in RT is active proliferative type and extends beyond the thyroid, causing adhesions and compression of the neighboring structures.21 Steroid therapy has been effective in some cases, but most patients need surgical intervention to relieve the compression symptoms and to rule out the presence of carcinoma. The resection may be quite difficult because no plane of cleavage exists.

RT has long been linked to a generalized fibroinflammatory process termed “multifocal fibrosclerosis.” Approximately one third of patients with RT develop fibrosing disorders in other organs including sclerosing cholangitis; retroperitoneal or mediastinal fibrosis; or fibrosis of the lung, parotid, or lachrymal glands. Little has been written about multifocal fibrosclerosis beyond case reports and small case series and its pathogenesis has remained obscure. However, the emerging knowledge and understanding regarding Ig4RSD has led to the realization that these 2 disease entities may indeed be the same. Both have a tendency to involve the biliary system, retroperitoneum, salivary and lachrymal glands, and retrobulbar space and are histologically characterized by sclerosing fibrosis and lymphoplasmacytic infiltration. Furthermore, recent immunohistochemical demonstration of abundant IgG4+ plasma cells in RT has provided additional support for linkage between RT and Ig4SRD.31,34

It seems that thyroid may be affected by Ig4-related disease in 2 different ways. In 1 type of thyroid involvement, the disease remains limited to thyroid and is characterized by lymphoplasmacytic infiltrate with abundant IgG4+ plasma cells. In these cases the clinical and morphologic features fall within the spectrum of HT. In the second setting, the thyroid involvement has clinical and pathologic features of RT. In some of these cases there may be evidence of a systemic disease with synchronous or metachronous involvement of other organ systems by Ig4RSD.36

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HT is frequently encountered in thyroids resected for a neoplastic process. The most frequent association is noted between papillary carcinoma of thyroid (PTC) and HT. Studies to date reveal that 11% to 36% of patients with PTC may have coexistent HT. The relationship between HT and papillary thyroid carcinoma was first proposed by Dailey et al in 1955.37 Since this initial description, the association between the 2 diseases has been highly debated in the literature. The coexistence of PTC with HT may merely represent a chance occurrence of 2 relatively common diseases or may be indicative of a cause and effect relationship, or at least a predisposing factor. Although several recent studies seem to favor the concept of increased risk of PTC in patients with HT, particularly in women, the precise nature of the relationship between HT and PTC remains to be determined.38–42

A possible link between PTC and HT may be provided by solid cell nests (SCN) of the thyroid (Fig. 7). SCN are remnants of ultimobranchial body and have been found in normal thyroid but are encountered at higher frequency in association with PTC and HT.43–45 These nests are composed of multipotent cells, which may give rise to follicular cells and C cells. Morphologically, many of the nests are composed of cells with irregular nuclear contours, thus mimicking papillary thyroid carcinoma. These cells are p63 and bcl-2 positive and may actually represent a pool of stem cells of thyroid. It has been suggested that at least a subset of PTC may be derived from SCN.44 This view is supported by a recent demonstration of identical BRAF V600E mutation in the SCN and in the adjacent PTC.46 Cells derived from SCN may also represent incompletely developed thyroid tissue predisposed to autoimmune reaction resulting in HT. Thus, it seems that both HT and PTC may be initiated by the same population of embryonic stem cell remnants and may thus be etiologically related.

Figure 7
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Non-Hodgkin lymphoma is another malignant neoplasm that has been described in patients with HT. Thyroid lymphomas constitute only 3% of all non-Hodgkin lymphomas and approximately 5% of all thyroid neoplasms and manifest a 4 to 1 female predominance.47 Preexisting HT is the only known risk factor for primary thyroid lymphoma, and is present in about one half of patients. Among patients with HT, the risk of thyroid lymphoma is at least 60 times higher than in patients without. Markedly increased incidence of primary thyroid lymphomas in patients with HT strongly suggests a pathogenetic link between this autoimmune disorder and thyroid malignant lymphoma.48–51 Most of the thyroid lymphomas in patients with HT are of B cell type, but may, on rare occasion, present a T-cell phenotype.47 A relatively rapid growth in size of the thyroid gland should lead one to consider lymphoma of the thyroid or anaplastic thyroid cancer as a diagnosis.

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A century after the original description of the disease, HT continues to be a subject of considerable interest as concepts regarding its etiology and pathogenesis continue to evolve. HT is an autoimmune disease with predisposition determined by genetic and environmental factors. A subset of cases of HT may belong to the recently described entity of IgG4-related diseases. Patients with HT are at risk for development of malignant lymphoma and possibly papillary thyroid carcinoma.

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thyroiditis; Hashimoto; autoimmune; carcinoma; lymphoma; IgG4

© 2012 Lippincott Williams & Wilkins, Inc.


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