Open access peer-reviewed chapter

Autoimmune Hashimoto’s Thyroiditis and Hypothyroidism: Novel Aspects

Written By

Ifigenia Kostoglou-Athanassiou, Lambros Athanassiou and Panagiotis Athanassiou

Submitted: November 15th, 2021 Reviewed: January 20th, 2022 Published: March 1st, 2022

DOI: 10.5772/intechopen.102785

Chapter metrics overview

55 Chapter Downloads

View Full Metrics

Abstract

Autoimmune Hashimoto’s thyroiditis is an organ specific autoimmune disorder. It affects the thyroid gland and it is characterized by the presence of antibodies to thyroid proteins, namely, thyroid peroxidase, TPOab and thyroglobulin, Tgab and thyroid tissue invasion by lymphocytes. The presence of Hashimoto’s thyroiditis may be associated with normal thyroid function or hypothyroidism. In many cases of Hashimoto’s thyroiditis with normal thyroid function may progress to subclinical hypothyroidism or overt hypothyroidism. Risk factors for the development of Hashimoto’s thyroiditis are genetic and environmental. Genetic factors are HLA-DR4, CD40, CTLA-4 and PTP-N22 and genetic factors related to thyroglobulin gene and TSH receptor gene. Environmental factors include the presence of iodine excess in the environment, infectious agents such as hepatitis C virus and the SARS-CoV-2 virus, smoking, alcohol, selenium deficiency, drugs such as amiodarone, interferon-a, highly active antiretroviral therapy and immune checkpoint inhibitors. Female sex is also a risk factor for Hashimoto’s thyroiditis. The disease runs a variable course. Presently there are experimental efforts to pause or reverse the autoimmune process which leads to Hashimoto’s thyroiditis and may progress to the destruction of the thyroid gland. Hypothyroidism is treated by the administration of thyroxine usually for life.

Keywords

  • autoimmune hashimoto’s thyroiditis
  • subclinical hypothyroidism
  • hypothyroidism
  • thyroid antibodies
  • thyroid autoantibodies
  • thyroxine

1. Introduction

Autoimmune Hashimoto’s thyroiditis is a chronic autoimmune thyroid disorder characterized by the presence of goiter in many cases, hypothyroidism in several cases and the presence of antibodies to thyroid antigens in the blood [1, 2, 3]. It is a frequent disorder and the most frequent cause of hypothyroidism.

Hashimoto in 1912 described the disease in 4 women who had surgery for goiter and in whom lymphocytic infiltration of the thyroid was observed in the thyroid biopsy [4]. In 1956 Roitt et al. discovered the presence of antithyroid antibodies in these cases [5]. Chronic autoimmune thyroiditis presents mainly with two types of clinical presentation, one presenting with goiter and another presenting with thyroid atrophy and degeneration. Silent and postpartum thyroiditis are two forms of chronic autoimmune thyroiditis.

The development of methods for the detection of antithyroid antibodies and measurement of thyroid stimulating hormone (TSH) has led to the diagnosis of cases of chronic autoimmune thyroiditis in patients with normal thyroid function, who in the course of the disease develop subclinical or clinical hypothyroidism (Figure 1).

Figure 1.

The progression of autoimmune thyroiditis.

Advertisement

2. Prevalence and incidence

Autoimmune thyroiditis affects 5–7 times more women than men, usually middle aged or older as well as younger patients and children. The prevalence of the disease differs depending on three diagnostic criteria, namely a) the presence of thyroid tissue lymphocytic infiltration b) the detection of antithyroid antibodies, and c) the presence of increased TSH levels.

Foci of thyroiditis 1–10/cm2 of thyroid tissue in biopsies were observed in 40–45% in females and 20% in males. If the diagnostic limit increases to >40/cm2 foci of thyroiditis the prevalence is lower, i.e., 5–15% in females and 1–5% in males [6, 7]. The incidence of Hashimoto thyroiditis is 1.3% in children 11–18 years. In adult women the incidence is 3.5 per 1000 per year and in men 0.8 per 1000 per year. Although in a worldwide basis the commonest cause of hypothyroidism remains iodine deficiency, in areas of adequate iodine intake the commonest cause of hypothyroidism is Hashimoto thyroiditis with a worldwide estimated annual incidence of 0.3–1.5 cases per 1000 [8, 9].

The prevalence of positive antithyroid antibodies was investigated in studies performed in Whickham in the UK and in New South Wales in Australia and was 10–13% in female and 5% in male patients [10]. Newer studies however have found a greater incidence of thyroid antibodies which was increasing with age. Vanderpump et al. [9] observed positive thyroglobulin Tgab and thyroid peroxidase TPOab antibodies 10.6 and 14.9% in the age range 18–24 years and 33.3 and 24.2% in the age range of 55–64 years in females, respectively. Mariotti et al. [11] observed 33% positive thyroid antibodies in females aged >70 years. Thyrotropin receptor blocking antibodies, which are antibodies binding and blocking the TSH receptor have been described and may contribute to the development of hypothyroidism [12].

Higher than normal TSH levels in various studies were observed as subclinical hypothyroidism, high TSH and normal T4, in 3–13.6% in female and 0.7–5.7% in male patients. Clinical hypothyroidism, high TSH and decreased T4 levels were observed in 0.5–1.9% in females and in <1% of males [10, 13, 14, 15]. Canaris et al. [16] in an observational study performed in Colorado, USA, including 25,862 people aged 18–74 years found increased TSH in 9.4% (subclinical 9% and clinical hypothyroidism 0.4%). TSH was 5.1–10 mU/L in 74% of cases and in 26% greater than 10 mU/L. TSH levels were found to increase with age, as they were increased in 4% in the first decade of life and in 21% in the last decade of life in women and in 3% in the first decade of life in male patients and 16% in the last decade in male patients.

The prevalence of chronic autoimmune thyroiditis is better described by the presence of foci of the disease in thyroid tissue and the presence of thyroid antibodies than by TSH levels, which may increase due to other reasons.

Advertisement

3. Pathogenesis

Hashimoto thyroiditis is an autoimmune disorder which may be due to an abnormal immune reaction. T lymphocytes are involved in the pathogenesis of Hashimoto’s thyroiditis [17, 18, 19, 20] and polycoclonal antibodies are produced targeting thyroid cells. The autoimmune disorder is initiated by the activation of CD4 T helper lymphocytes specific for thyroid antigens [18]. In the literature two hypotheses have been developed for the activation of these cells.

According to the first hypothesis an infection with a virus or a bacterium which has a protein similar to a thyroid protein may induce the activation of T lymphocytes specific for the thyroid, a theory known as theory of molecular mimicry [21, 22]. According to an alternative hypothesis, epithelial thyroid cells present their intracellular proteins to helper T lymphocytes. Following their activation autoreactive CD4 T lymphocytes may stimulate autoreactive B lymphocytes which produce thyroid antibodies. Activated T lymphocytes induce the concentration of cytotoxic CD8 T lymphocytes and B lymphocytes within the thyroid [19]. The direct destruction by T lymphocytes of thyroid cells is believed to be the main mechanism responsible for the development of hypothyroidism. Thyroid antibodies may also play a pathogenetic role.

Increased apoptosis may be involved in the mechanism of thyroid cells destruction in Hashimoto thyroiditis. Cytotoxic T lymphocytes destroy target cells inducing an apoptosis mechanism. Increased apoptosis via Fas-FasL [23, 24] is observed in thyroid cells which are near the infiltrating lymphocytes and this mechanism has been described as a major thyroid cell destruction mechanism in Hashimoto thyroiditis [25].

Advertisement

4. Histology

The form of chronic autoimmune thyroiditis with goiter diffuse lymphocytic and plasmacytic infiltration of the gland takes place with the formation of lymphoid follicles with germinal centers [26, 27]. The changes in the follicular epithelium vary and the most characteristic is the oxyphilic transformation of the cells, known as Hurthle or Eskanazy cells, which may be focal or diffuse with the formation of nodules [28]. The follicular epithelium may be hyperplastic with the formation of papillae or the follicles may be small and atrophic with little colloid and there is fragmentation of their cell walls. Cell nuclei may present with atypia. Histological examination may reveal lymphocytic infiltration and the diagnosis may not be certain, except if high titers of thyroid antibodies are present. In the atrophic form, the thyroid may be small with lymphocytic and plasmacytic infiltration which replace the thyroid parenchyma and fibrosis. It appears that atrophic thyroiditis may be the final stage of that with goiter.

Advertisement

5. Etiology

Various genetic, epigenetic and environmental factors predispose to the development of chronic autoimmune thyroiditis (Figure 2).

Figure 2.

Factors contributing to the development of autoimmune Hashimoto’s thyroiditis.

5.1 Genetic factors

Various genetic factors have been recognized. The genes encoding the major histocompatibility complex HLA have been implicated in the pathogenesis of Hashimoto’s thyroiditis [29]. The presence of Tyr26, Gln70, Lys71 and Arg74 in the HLA-DRβ1 molecule may cause structural changes in pocket 4 of the molecule thereby influencing binding of thyroid-derived pathogenic peptides [30] thus predisposing to the development of autoimmune thyroiditis. The presence of Tyr30 in pocket 6 of the HLA-DR molecule may also cause structural changes and predispose to the development of autoimmune thyroiditis [31]. Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) [32] and protein tyrosine phosphatase-22 (PTPN22) [33] are major negative regulators of T cell mediated immune functions. Polymorphisms of the CTLA-4 and PTPN22 genes have been linked with Hashimoto’s thyroiditis [32, 33]. However, the mechanisms through which susceptibility to thyroid autoimmunity is induced are yet unknown. The presence of A−1623 A/G single-nucleotide polymorphism at the thyroglobulin (Tg) promoter may influence binding of nuclear transcription factors such interferon regulatory factor-1 protein [34]. Increased production of interferon-γ in a viral infection may increase expression of thyroglobulin and lead to activation of T cell response thus leading to the development of thyroid autoimmunity [35]. A polymorphism in the CD40 gene has significant effects on CD40 on antigen-presenting cells, including B lymphocytes, influencing B cell proliferation, antibody secretion and generation of memory cells thus leading to thyroid autoimmunity [36].

5.2 Environmental factors

Infections and iodine are environmental factors which may predispose to the development of Hashimoto’s thyroiditis (Figure 3). Infectious agents, such hepatitis C virus, may induce autoimmunity by molecular mimicry, tissue infection or destruction [37]. An increased prevalence of antithyroid antibodies has been observed in residents in areas with iodine excess [38]. Salt iodination may induce the development of thyroid autoimmunity [39]. The presence of autoimmune thyroiditis has been associated with both iodine deficiency and iodine excess suggesting a U-shaped relationship between iodine status and thyroid autoimmunity risk in adults [40].

Figure 3.

Environmental risk factors for the development of autoimmune Hashimoto’s thyroiditis.

5.3 SARS-CoV-2 viral infection

SARS-CoV-2 is a coronavirus which has been related to the development of autoimmunity. Autoimmune thyroid disease, in the form of subacute thyroiditis, autoimmune thyroiditis and Graves’ disease have been described in patients with the Covid-19 disease [41, 42]. The development of hypothyroidism following SARS-CoV-2 infection has also been observed.

5.4 Selenium

Selenium deficiency may be related to the development of thyroid autoimmunity [43]. Smoking seems to protect from the development of autoimmune Hashimoto’s thyroiditis and hypothyroidism [44]. Smoking cessation leads to loss of protection from autoimmune Hashimoto’s thyroiditis. Medium alcohol consumption seems to protect from the development of autoimmune Hashimoto’s thyroiditis.

5.5 Estrogens

Autoimmune Hashimoto’s thyroiditis has a higher prevalence in female patients [1]. There is a sex dimorphism in the immune response [45]. Female patients have a stronger immune response. The cost is an increased susceptibility to autoimmune diseases [46]. Estrogens modulate the immune response and induce autoimmune diseases [47]. Estrogen withdrawal in menopause also modulates the immune response [48].

5.6 Drugs

Amiodarone has a high iodine content and affects thyroid function. It may induce autoimmune thyroiditis, hypothyroidism or hyperthyroidism [49, 50].

Highly active antiretroviral therapy (HAART) for the treatment of HIV patients is related to a higher incidence of subclinical hypothyroidism [51].

Interferon-α is used for the treatment of hepatitis C and is associated with the development of autoimmune thyroiditis, hypothyroidism and destructive thyroiditis [52].

Immune check point inhibitors are a major step forward in the treatment of cancer. However, their administration is related to the development of autoimmune thyroiditis and autoimmune hypophysitis [53, 54]. In the presence of autoimmune thyroiditis, the requirement for thyroxine treatment increases depicting further immune tissue destruction of the thyroid.

The prevalence of Hashimoto’s thyroiditis is increased in relatives of patients with autoimmune thyroiditis, this phenomenon is mostly apparent in first degree relatives. Brix et al. [55] investigated the genetic effect on the etiology of autoimmune thyroid disease in female Danish twins (2945 pairs, 5890 patients) and found that genetic factors affect the incidence of autoimmune thyroid disease.

Advertisement

6. Clinical presentation

The most frequent clinical findings in chronic autoimmune thyroiditis are goiter and hypothyroidism or both.

As far as goiter is concerned, the thyroid is homogenously enlarged, has a semi-hard consistency and its surface is uneven. In some cases, the enlargement is uneven and it may appear as a nodule or multinodular goiter. Rarely, especially in elderly patients, it may present with fibrosis which leads to the diffuse enlargement of the thyroid with hard consistency and the differential diagnosis with malignancy should be performed. Goiter appears gradually and the gland may be enlarged. The thyroid gland is usually minimally enlarged. Generally, there are no symptoms from goiter, except for a feeling of pressure and in very rare cases pain or tenderness on palpation. Very rarely symptoms of pressure of the trachea, the esophagus or the laryngeal nerves may be observed in the case of abrupt enlargement of the thyroid, especially in the case of fibrosis, which need differential diagnosis from thyroid lymphoma or carcinoma. Lymphoma is observed in 0.1% of patients with chronic autoimmune thyroiditis and it is 80 times more frequent than expected [56].

As far as hypothyroidism is concerned, patients with positive antithyroid antibodies are euthyroid in 50-75%, 25-50% have subclinical hypothyroidism and 5–10% have clinical hypothyroidism. Patients with positive antithyroid antibodies and normal or increased TSH, T4 normal may present with hypothyroidism in the course of the disease. In the Whickham study 20 years later in a group of female patients with normal initial TSH clinical hypothyroidism was observed in 27% and those with increased initial TSH in 55% [9]. This is a finding which indicates that patients with positive thyroid antibodies and normal TSH should be followed up for the development of subclinical or clinical hypothyroidism. In clinical hypothyroidism signs and symptoms of hypothyroidism are observed and the diagnosis is easy. In subclinical hypothyroidism, however, there are no symptoms, although it has been reported that in comparison with euthyroid people there may be symptoms, such as cold intolerance, dry skin, fatigue, depression, disorders of cognition and atypical response to psychiatric intervention [57, 58, 59]. Additionally, Canaris et al. [16] comparing the symptoms of hypothyroidism to those of subclinical hypothyroidism, found that the symptoms of patients with subclinical hypothyroidism were intermediate as compared to those of clinical hypothyroidism and those of euthyroid individuals. However, symptoms of subclinical hypothyroidism may be vague and may not be sufficient for the diagnosis of subclinical hypothyroidism, which can be made only by TSH measurement.

Advertisement

7. Diagnosis

For the diagnosis of chronic autoimmune thyroiditis history, clinical presentation and laboratory findings are used.

7.1 History and clinical presentation

The presence of other members of the family with chronic autoimmune thyroiditis will be sought, as the disease may present in families. If there is goiter, the time of presentation will be sought, the size and its change in the course of time, as in thyroiditis the thyroid is gradually enlarged in the course of time. The presence of pressure symptoms will be sought in the trachea and the esophagus. The presence of symptoms of hypothyroidism will also be sought.

Palpation of the thyroid gland will be performed to identify the consistency of the gland, which may be semi-hard and its surface uneven. The findings of hypothyroidism will also be investigated. It should be noted that a rare clinical finding is encephalopathy, Hashimoto’ encephalopathy, which regresses either without treatment or by the administration of corticosteroids [60, 61].

7.2 Laboratory findings

Laboratory examination includes biochemical examinations, ultrasonography, thyroid scanning and fine needle aspiration biopsy.

Biochemical examinations: The main characteristic of chronic autoimmune thyroiditis is the presence of positive thyroid antibodies. The titer of TPOab is increased in 95% approximately and those of Tgab in 60% of the cases. Titers of thyroid antibodies are higher in the fibrotic disease than in that with goiter. In micronodular goiter the prevalence of Hashimoto’s thyroiditis is increased. Yeh et al. [62] in the presence of micronodules 1–6.5 mm identified positive thyroid antibodies in 94.7% of the cases. Increased thyroid antibodies are observed in other thyroid diseases, as well, but their prevalence is low. In chronic autoimmune thyroiditis usually both TPOab and Tgab are usually present, however, only one type may be present. Takamatsu et al. [63] in their study of 437 patients they observed both types of antibodies present in 316 patients, one type in 85 and none in the rest 36 patients.

In chronic autoimmune thyroiditis antibodies to the TSH receptor are observed. Ducornet et al. [64] in a large review of the literature found TSH-receptor binding-inhibitory immunoglobulins in 9% of patients with thyroiditis and goiter and in 21% in patients with fibrotic atrophic thyroiditis. In the same review they found thyrotropin receptor blocking antibodies in 12% of patients with thyroiditis and goiter and in 33% of patients with atrophic thyroiditis. In patients with hypothyroidism Takasu et al. [65] found thyrotropin receptor blocking antibodies in 10% of patients with thyroiditis and goiter and in 25% of those with atrophic thyroiditis. In newborns with hypothyroidism TSH-receptor binding-inhibitory immunoglobulins were observed in 0.8–38% and in the mothers of those newborns TSH-receptor-binding-inhibitory-immunoglobulins in 5% and thyrotropin receptor blocking antibodies in 4%. These antibodies differ in their action on the TSH receptor. TSH receptor binding inhibitory immunoglobulins bind the receptor, without a stimulating action and they block binding TSH to its receptor. Thyrotropin receptor blocking antibodies block the function of TSH receptor. The presence of these antibodies is important as with thyroxine administration they may disappear and hypothyroidism may regress.

Ultrasonography: The ultrasonogram may be diagnostic of chronic autoimmune thyroiditis, as it gives information on the function of the gland. It reveals increased size of the gland with diffuse hypoechoic areas in 18–77% of cases. Foci of mixed or increased echogenicity may be found in the gland parenchyma, which may be a sign of fibrosis [66, 67]. In some patients many small hypoechoic nodules may be found within the parenchyma of the gland. These nodules present lymphoid tissue or remnants of thyroid follicles and may need to be differentially diagnosed from nodular goiter.

Scanning: Scanning with radioiosotopes does not contribute to the diagnosis of chronic autoimmune thyroiditis and it is not used in everyday practice. If applied it shows nonhomogenous distribution of the radioisotope, a picture like that of multinodular goiter [68]. Radioisotope uptake may be normal or increased in thyroiditis with goiter, even if hypothyroidism is present, and is decreased in subacute thyroiditis or silent thyroiditis.

Fine needle aspiration biopsy: Fine needle aspiration biopsy is not necessary for the diagnosis of chronic autoimmune thyroiditis. It should be performed for the diagnosis of malignancy if goiter increases in size or there are nodules which may be malignant.

Nodules suspicious for malignancy are nodules in the case of a multiglandular familial syndrome, radiation in the head or neck and chest, rapid growth of the nodule, symptoms of local infiltration such as voice hoarseness, dysphagia or dyspnea and if the nodule is hard, irregular, attached to the neighboring tissues or there are enlarged lymph nodes. The possibility of malignancy in a nodule is increased in young and older ages, especially in male patients. Nys et al. [69] in 165 cases of Hashimoto thyroiditis with nodules or pseudonodules found 4% differentiated thyroid cancer and 1% non-Hodgkin’s lymphoma. Kumarasinghe and De Silva [70] in 100 patients with autoimmune thyroiditis who had fine needle aspiration biopsy found one case of a papillary and one case of Hurthle cell carcinoma (2%). According to these authors there may be some traps in the diagnosis of the cytologic examination, as in 100 aspiration biopsies the diagnosis was certain in 78 and in the rest 22 it was only suggestive of autoimmune thyroiditis. In the case of the two cancers the typical findings of malignancy were not observed. As potential traps cell atypia, the presence of inflammatory cells either in abundancy or paucity, and the absence of cell abundancy may be observed in autoimmune thyroiditis. The presence of epithelial as opposed to inflammatory cells, the presence of many cell nuclei, intense atypia may suggest malignancy even if the other findings of autoimmune thyroiditis are present. The presence of nuclear atypia as observed in oxyphil cells, in the presence of findings of autoimmune thyroiditis should not suggest the presence of a follicular neoplasm and should not lead to an unnecessary operation.

The diagnosis of chronic autoimmune thyroiditis should be sought for when other autoimmune diseases or other diseases are present, which make its diagnosis possible or probable. Chronic autoimmune thyroiditis has been observed in 70% of patients with multiple endocrine neoplasia type 2C, 50% of people with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathies, M protein and skin alterations), 50% of Turner’s syndrome, 20% of Addison’s disease, 20% of Down’s syndrome and in other diseases such as gastritis, alopecia areata and type 1 diabetes mellitus.

Advertisement

8. Silent and postpartum thyroiditis

Silent and postpartum thyroiditis are thought to be manifestations of chronic autoimmune thyroiditis.

8.1 Silent thyroiditis

Silent thyroiditis is a frequent cause of hyperthyroidism. It is called silent as it does not manifest with pain. It affects equally male and female patients. Hyperthyroidism is mild and there is no history of upper respiratory infection. Hyperthyroidism is due to thyroid hormone release in the blood due to cell lysis and regresses in 6–12 weeks or becomes transient hypothyroidism in 50% of cases which regresses in 2–12 weeks, while in approximately 5% hypothyroidism is permanent. The size of the thyroid is normal or slightly increased and there are no extrathyroidal manifestations of Graves’ disease.

Thyroid hormone levels vary depending on the stage of the disease. The most characteristic finding of silent thyroiditis is decreased 131I uptake. TPOab are detected in 60% of cases and Tgab in 25% of cases.

Treatment with antithyroid drugs is not considered necessary as hyperthyroidism is not severe and subsequently hypothyroidism ensues. Beta-blockers may be administered. It should be noted that new episodes of silent thyroiditis may be observed in the future. In long term follow up disease recurrence has been observed in 65% of cases [71].

8.2 Postpartum thyroiditis

Postpartum thyroiditis is frequent. It appears within the first year postpartum and affects 5–10% of female patients. The diagnosis of the disease may not be made as physicians are not aware of the disease and many of the symptoms are thought to be due to depression or other manifestations of the postpartum period. The diagnosis is made by the fact that there is no history of thyroid disorder prior to the pregnancy, there are positive TPoab or Tgab, there are no positive TSH receptor antibodies and there is no toxic adenoma.

In its classical presentation it presents with transient hyperthyroidism usually 6 weeks to 6 months postpartum. Hypothyroidism follows which recedes within the first year postpartum. Its classical presentation refers to 26% of the cases and may present only with hyperthyroidism (38%) or hypothyroidism [72, 73]. Hyperthyroidism is light and of short duration. Treatment is not necessary. If symptoms are present beta-blockers are administered. In the case of hypothyroidism thyroxine treatment is necessary for a period of 6 months. It should be noted that in 25% of cases hypothyroidism is permanent in 4 or more years of follow up [74, 75].

Postpartum thyroiditis is an autoimmune disease. Pregnancy is a period of immunosuppression which is followed by a period of rebound immune activation postpartum. Thus, the titer of thyroid antibodies decreases during pregnancy and may increase in the postpartum period. The highest titer of thyroid antibodies is observed 5–7 months postpartum. Kent et al. [76] studied the prevalence of thyroiditis in 748 female patients 4.5–5.5 months postpartum. They found thyroiditis in 11.5% of the patients and positive TPOab in 63.9% as opposed to 4.9% in female patients without thyroiditis. If thyroid antibodies are present during pregnancy, thyroiditis will be observed in 33–85% of patients [77, 78]. The presence of TPOab affects pregnancy outcome [79].

The most frequent cause of hypothyroidism, which in many cases is subclinical, in pregnancy is thyroid antibodies. Haddow et al. [80] studied 25,216 pregnant patients and found hypothyroidism in 0.25% with positive TPOab in 77%. The children of these patients were studied at the age 7–9 years and none had hypothyroidism, however they presented with neuropsychiatric disorders. The prevalence of hypothyroidism in pregnant patients seems to be even greater. In studies performed in Japan, Belgium and USA in pregnant patients hypothyroidism was observed in 0.3, 2.2, and 2.5% respectively [81, 82, 83]. TSH and thyroid antibody measurement should be performed in pregnant patients. TSH measurement should be performed in the first stages of pregnancy as the fetal thyroid is activated within the 12th week of the pregnancy.

Advertisement

9. Treatment

Thyroid antibody titers are not an index of thyroid function and they are not an indication for thyroxine administration, except if there is subclinical or clinical hypothyroidism.

Subclinical hypothyroidism is frequent and in 50% of the cases it is due to autoimmune Hashimoto’s thyroiditis. It may also be due to drugs, or other etiology or disorders which increase TSH levels without subclinical hypothyroidism. Initially, it should be confirmed that subclinical hypothyroidism is due to autoimmune thyroiditis. In many cases with increased TSH and positive thyroid antibodies thyroxine should be administered, even if there are no symptoms, due to the risk of progression to clinical hypothyroidism. In the Whickham study [9] 55% of female patients in a follow up period of 20 years progressed to clinical hypothyroidism. The risk is greater in female than male patients and it increases significantly after the age of 45. The frequency of progression to clinical hypothyroidism increases with higher TSH levels and with a higher titer of thyroid antibodies. Several medical colleges and physician bodies agree that subclinical hypothyroidism should be treated if thyroid antibodies are present [84, 85].

Subclinical hypothyroidism which is due to chronic autoimmune thyroiditis should be treated, as there is a risk of progression to clinical hypothyroidism and cholesterol levels are increased. Bindels et al. [15] studied 1191 subjects, aged 40–60 years, and they found subclinical hypothyroidism 1.9% in male and 7.6% in female patients, while 3 male and 3 female patients 0.5% had clinical hypothyroidism. At cholesterol levels less than 193 mg/dl the prevalence of the disease in males was 1.5% and in females 4%, at cholesterol levels 193–309 it was 2 and 8.5% and at cholesterol levels above 309 it was 1.6 and 10.3%, respectively. For an increment of TSH of 1 mU/l cholesterol levels increased in females 3.47 and in males 6.18 mg. Michalopoulou et al. [86] in patients with hypercholesterolemia and TSH in the upper normal range found that thyroxine administration decreased cholesterol levels. The measurement of thyroid hormone levels is important in patients with hypercholesterolemia and in all female patients over the age of 50 years as subclinical hypothyroidism is present in approximately 10%. Cholesterol may increase the risk of coronary artery disease and thyroxine treatment may decrease cholesterol levels and this risk. Despite that, Hak et al. [87] found that in female patients subclinical hypothyroidism is a risk factor for atherosclerosis and cardiac infarction, independently of the levels of cholesterol, HDL cholesterol and smoking. Thyroxine administration in subclinical hypothyroidism should be performed with caution as it may cause tachycardia, atrial fibrillation, and osteoporosis. Thus, thyroxine should be administered with caution especially in elderly patients.

Thyroxine can be administered in its full dose in young patients without cardiac disease. However, in patients with known cardiac disease or in patients aged over 70 years the initial thyroxine dose should be 25 μg daily and should be increased by 25 μg every 4–6 weeks. TSH measurement should be performed every 4 weeks until TSH is within normal range. During follow up thyroid hormones should be measured once a year. Thyroxine dose is approximately 1.6 μg/kg daily and it is age related. Elderly patients need 50% of the adult dose, while children need a higher dose (3.8 μg/kg). In clinical hypothyroidism thyroxine treatment should be initiated with small doses 12.5–25 μg daily and should be increased slowly at monthly intervals. In patients with severe long-standing hypothyroidism or elderly patients caution should be exercised in the initiation of treatment and when the dose is increased. Thyroxine may be administered in liquid or soft gel form. The simultaneous administration of thyroxine and liothyronine for the treatment of hypothyroidism has also been used [88], but it has not been shown to be superior to thyroxine administration. At present, experimental efforts take place to block T cell activation by thyroglobulin by the use of small molecules, such as cepharanathine, in experimentally induced autoimmune thyroiditis and thus stop the progression of the disease [89]. The administration of selenium and vitamin D may interfere with the progression of autoimmune thyroiditis.

Hypothyroidism in chronic autoimmune thyroiditis is not always permanent and there is a percentage of patients who recover and thyroxine may be withdrawn. The recovery of thyroid function is related to decreased titers of thyrotropin receptor blocking antibodies and not to TPOab and Tgab, as these titers do not respond to thyroxine administration. Recovery of thyroid function following thyroxine administration is 0.2–24% with a mean value of 10% [9, 90, 91, 92, 93]. In chronic autoimmune thyroiditis thyotropin receptor blocking antibodies are present in approximately 20% [65, 90, 92]. The regression of these antibodies with thyroxine administration does not always lead to the recovery of hypothyroidism. Thyrotropin receptor blocking antibodies decrease in 30–75% of positive patients and recovery of hypothyroidism is observed only in some of these patients [65, 92]. A practical way to test if normal thyroid function is restored is to decrease the dose of thyroxine after a year of treatment and if TSH levels remain normal to withdraw thyroxine. Following thyroxine withdrawal TSH should be measured 4–6 weeks later. If TSH levels are normal thyroxine administration should be discontinued and the patient should be followed up. Goiter size decreases with thyroxine administration in patients with chronic autoimmune thyroiditis. It is decreased by 1/3 in 50–90% of patients after a period of 6 months on thyroxine treatment.

Advertisement

10. Conclusion

In conclusion, chronic autoimmune thyroiditis or Hashimoto’s thyroiditis is a frequent endocrine disorder which affects more female than male patients. It has been observed after SARS-CoV-2 infection. It frequently causes hypothyroidism. The effects of hypothyroidism decrease quality of life. Its diagnosis is important and should be performed promptly. Thyroid hormones should be measured in female patients after the age of 50 years, in pregnant patients and in the postpartum period and in male patients with hypercholesterolemia. Treatment of hypothyroidism is performed with thyroxine. Thyroxine in the form of liquid or soft gel preparation may also be used. There are efforts to inhibit the autoimmune process in Hashimoto thyroiditis by small molecules, however these efforts have not yet been applied in clinical practice. Treatment with thyroxine is long term and usually for life.

References

  1. 1. Hiromatsu Y, Satoh H, Amino N. Hashimoto’s thyroiditis: History and future outlook. Hormones (Athens, Greece). 2013;12(1):12-18. DOI: 10.1007/bf03401282
  2. 2. Ralli M, Angeletti D, Fiore M, et al. Hashimoto’s thyroiditis: An update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and potential malignant transformation. Autoimmunity Reviews. 2020;19(10):102649. DOI: 10.1016/j.autrev.2020.102649
  3. 3. Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: Clinical and diagnostic criteria. Autoimmunity Reviews. 2014;13(4-5):391-397. DOI: 10.1016/j.autrev.2014.01.007
  4. 4. Hashimoto H. Zur kenntnis der lymphomatosen Veranderung der Sshilddruse (Struma lymphomatosa). Arch Klin Chir. 1912;97:219-248
  5. 5. Roitt IM, Campbell PN, Doniach D. The nature of the thyroid auto-antibodies present in patients with Hashimoto’s thyroiditis (lymphadenoid goitre). The Biochemical Journal. 1958;69(2):248-256. DOI: 10.1042/bj0690248
  6. 6. Williams ED, Doniach I. The post-mortem incidence of focal thyroiditis. The Journal of Pathology and Bacteriology. 1962;83:255-264. DOI: 10.1002/path.1700830127
  7. 7. Okayasu I, Hara Y, Nakamura K, Rose NR. Racial and age-related differences in incidence and severity of focal autoimmune thyroiditis. American Journal of Clinical Pathology. 1994;101(6):698-702. DOI: 10.1093/ajcp/101.6.698
  8. 8. Vanderpump MP. The epidemiology of thyroid disease. British Medical Bulletin. 2011;99:39-51. DOI: 10.1093/bmb/ldr030
  9. 9. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clinical Endocrinology. 1995;43(1):55-68. DOI: 10.1111/j.1365-2265.1995.tb01894.x
  10. 10. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: The Whickham survey. Clinical Endocrinology. 1977;7(6):481-493. DOI: 10.1111/j.1365-2265.1977.tb01340.x
  11. 11. Mariotti S, Sansoni P, Barbesino G, et al. Thyroid and other organ-specific autoantibodies in healthy centenarians. Lancet. 1992;339(8808):1506-1508. DOI: 10.1016/0140-6736(92)91265-a
  12. 12. Diana T, Krause J, Olivo PD, et al. Prevalence and clinical relevance of thyroid stimulating hormone receptor-blocking antibodies in autoimmune thyroid disease. Clinical and Experimental Immunology. 2017;189(3):304-309. DOI: 10.1111/cei.12980
  13. 13. Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P. The aging thyroid. Thyroid deficiency in the Framingham Study. Archives of Internal Medicine. 1985;145(8):1386-1388
  14. 14. Konno N, Yuri K, Taguchi H, et al. Screening for thyroid diseases in an iodine sufficient area with sensitive thyrotrophin assays, and serum thyroid autoantibody and urinary iodide determinations. Clinical Endocrinology. 1993;38(3):273-281. DOI: 10.1111/j.1365-2265.1993.tb01006.x
  15. 15. Bindels AJ, Westendorp RG, Frölich M, Seidell JC, Blokstra A, Smelt AH. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: A need for case-finding? Clinical Endocrinology. 1999;50(2):217-220. DOI: 10.1046/j.1365-2265.1999.00638.x
  16. 16. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Archives of Internal Medicine. 2000;160(4):526-534. DOI: 10.1001/archinte.160.4.526
  17. 17. Pyzik A, Grywalska E, Matyjaszek-Matuszek B, Roliński J. Immune disorders in Hashimoto’s thyroiditis: What do we know so far? Journal of Immunology Research. 2015;2015:979167. DOI: 10.1155/2015/979167
  18. 18. Cui X, Liu Y, Wang S, et al. Circulating exosomes activate dendritic cells and induce unbalanced CD4+ T cell differentiation in hashimoto thyroiditis. The Journal of Clinical Endocrinology and Metabolism. 2019;104(10):4607-4618. DOI: 10.1210/jc.2019-00273
  19. 19. del Prete GF, Maggi E, Mariotti S, et al. Cytolytic T lymphocytes with natural killer activity in thyroid infiltrate of patients with Hashimoto’s thyroiditis: Analysis at clonal level. The Journal of Clinical Endocrinology and Metabolism. 1986;62(1):52-57. DOI: 10.1210/jcem-62-1-52
  20. 20. Del Prete GF, Vercelli D, Tiri A, et al. In vivo activated cytotoxic T cells in the thyroid infiltrate of patients with Hashimoto’s thyroiditis. Clinical and Experimental Immunology. 1986;65(1):140-147
  21. 21. Benvenga S, Guarneri F. Molecular mimicry and autoimmune thyroid disease. Reviews in Endocrine & Metabolic Disorders. 2016;17(4):485-498. DOI: 10.1007/s11154-016-9363-2
  22. 22. Cuan-Baltazar Y, Soto-Vega E. Microorganisms associated to thyroid autoimmunity. Autoimmunity Reviews. 2020;19(9):102614. DOI: 10.1016/j.autrev.2020.102614
  23. 23. Abe Y. Apoptosis in the pathogenesis of autoimmune thyroid disease. Nihon Rinsho. 1999;57(8):1717-1722
  24. 24. Stassi G, Todaro M, Bucchieri F, et al. Fas/Fas ligand-driven T cell apoptosis as a consequence of ineffective thyroid immunoprivilege in Hashimoto’s thyroiditis. Journal of Immunology. 1999;162(1):263-267
  25. 25. Phelps E, Wu P, Bretz J, Baker JR Jr. Thyroid cell apoptosis. A new understanding of thyroid autoimmunity. Endocrinology and Metabolism Clinics of North America. 2000;29(2):375-388. DOI: 10.1016/s0889-8529(05)70137-7
  26. 26. Akamizu T, Amino N. Hashimoto’s thyroiditis. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext. Oregon, USA: MDText.com, Inc; 2000
  27. 27. Mohr A, Trésallet C, Monot N, et al. Tissue infiltrating LTi-like group 3 innate lymphoid cells and T follicular helper cells in Graves’ and Hashimoto’s thyroiditis. Frontiers in Immunology. 2020;11:601. DOI: 10.3389/fimmu.2020.00601
  28. 28. Müller-Höcker J. Expression of bcl-2, bax and fas in oxyphil cells of Hashimoto thyroiditis. Virchows Archiv. 2000;436(6):602-607. DOI: 10.1007/s004280000188
  29. 29. Weissel M, Höfer R, Zasmeta H, Mayr WR. HLA-DR and Hashimoto’s thyroiditis. Tissue Antigens. 1980;16(3):256-257. DOI: 10.1111/j.1399-0039.1980.tb00302.x
  30. 30. Menconi F, Monti MC, Greenberg DA, et al. Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(37):14034-14039. DOI: 10.1073/pnas.0806584105
  31. 31. Li CW, Osman R, Menconi F, Concepcion ES, Tomer Y. Flexible peptide recognition by HLA-DR triggers specific autoimmune T-cell responses in autoimmune thyroiditis and diabetes. Journal of Autoimmunity. 2017;76:1-9. DOI: 10.1016/j.jaut.2016.09.007
  32. 32. Hu Y, Xu K, Jiang L, Zhang L, Shi H, Cui D. Associations between three CTLA-4 polymorphisms and Hashimoto’s thyroiditis risk: An updated meta-analysis with trial sequential analysis. Genetic Testing and Molecular Biomarkers. 2018;22(4):224-236. DOI: 10.1089/gtmb.2017.0243
  33. 33. Xiaoheng C, Yizhou M, Bei H, et al. General and specific genetic polymorphism of cytokines-related gene in AITD. Mediators of Inflammation. 2017;2017:3916395. DOI: 10.1155/2017/3916395
  34. 34. Lahooti H, Edirimanne S, Walsh JP, Delbridge L, Hibbert EJ, Wall JR. Single nucleotide polymorphism 1623 A/G (rs180195) in the promoter of the Thyroglobulin gene is associated with autoimmune thyroid disease but not with thyroid ophthalmopathy. Clinical Ophthalmology. 2017;11:1337-1345. DOI: 10.2147/opth.s136070
  35. 35. Stefan M, Jacobson EM, Huber AK, et al. Novel variant of thyroglobulin promoter triggers thyroid autoimmunity through an epigenetic interferon alpha-modulated mechanism. The Journal of Biological Chemistry. 2011;286(36):31168-31179. DOI: 10.1074/jbc.M111.247510
  36. 36. Jacobson EM, Tomer Y. The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid autoimmunity: Back to the future. Journal of Autoimmunity. 2007;28(2-3):85-98. DOI: 10.1016/j.jaut.2007.02.006
  37. 37. Hammerstad SS, Blackard JT, Lombardi A, et al. Hepatitis C virus infection of human thyrocytes: Metabolic, hormonal, and immunological implications. The Journal of Clinical Endocrinology and Metabolism. 2020;105(4):1157-1168. DOI: 10.1210/clinem/dgz241
  38. 38. Farebrother J, Zimmermann MB, Andersson M. Excess iodine intake: Sources, assessment, and effects on thyroid function. Annals of the New York Academy of Sciences. 2019;1446(1):44-65. DOI: 10.1111/nyas.14041
  39. 39. Teti C, Panciroli M, Nazzari E, et al. Iodoprophylaxis and thyroid autoimmunity: An update. Immunologic Research. 2021;69(2):129-138. DOI: 10.1007/s12026-021-09192-6
  40. 40. Wang B, He W, Li Q , et al. U-shaped relationship between iodine status and thyroid autoimmunity risk in adults. European Journal of Endocrinology. 2019;181(3):255-266. DOI: 10.1530/eje-19-0212
  41. 41. Speer G, Somogyi P. Thyroid complications of SARS and coronavirus disease 2019 (COVID-19). Endocrine Journal. 2021;68(2):129-136. DOI: 10.1507/endocrj.EJ20-0443
  42. 42. Brancatella A, Ricci D, Viola N, Sgrò D, Santini F, Latrofa F. Subacute Thyroiditis After Sars-COV-2 Infection. The Journal of Clinical Endocrinology & Metabolism. 2020;105(7):dgaa276. DOI: 10.1210/clinem/dgaa276
  43. 43. Ventura M, Melo M, Carrilho F. Selenium and thyroid disease: From pathophysiology to treatment. International Journal of Endocrinology. 2017;2017:1297658. DOI: 10.1155/2017/1297658
  44. 44. Sawicka-Gutaj N, Gutaj P, Sowiński J, et al. Influence of cigarette smoking on thyroid gland—An update. Endokrynologia Polska. 2014;65(1):54-62. DOI: 10.5603/ep.2014.0008
  45. 45. Taneja V. Sex hormones determine immune response. Frontiers in Immunology. 2018;9:1931. DOI: 10.3389/fimmu.2018.01931
  46. 46. Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Frontiers in Immunology. 2018;9:2279. DOI: 10.3389/fimmu.2018.02279
  47. 47. Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cellular Immunology. 2015;294(2):63-69. DOI: 10.1016/j.cellimm.2015.01.018
  48. 48. Sárvári M, Kalló I, Hrabovszky E, Solymosi N, Liposits Z. Ovariectomy and subsequent treatment with estrogen receptor agonists tune the innate immune system of the hippocampus in middle-aged female rats. PLoS One. 2014;9(2):e88540. DOI: 10.1371/journal.pone.0088540
  49. 49. Trohman RG, Sharma PS, McAninch EA, Bianco AC. Amiodarone and thyroid physiology, pathophysiology, diagnosis and management. Trends in Cardiovascular Medicine. 2019;29(5):285-295. DOI: 10.1016/j.tcm.2018.09.005
  50. 50. Jabrocka-Hybel A, Bednarczuk T, Bartalena L, et al. Amiodarone and the thyroid. Endokrynologia Polska. 2015;66(2):176-186. DOI: 10.5603/ep.2015.0025
  51. 51. Madeddu G, Spanu A, Chessa F, et al. Thyroid function in human immunodeficiency virus patients treated with highly active antiretroviral therapy (HAART): A longitudinal study. Clinical Endocrinology. 2006;64(4):375-383. DOI: 10.1111/j.1365-2265.2006.02472.x
  52. 52. Prummel MF, Laurberg P. Interferon-alpha and autoimmune thyroid disease. Thyroid. 2003;13(6):547-551. DOI: 10.1089/105072503322238809
  53. 53. Ferrari SM, Fallahi P, Galetta F, Citi E, Benvenga S, Antonelli A. Thyroid disorders induced by checkpoint inhibitors. Reviews in Endocrine & Metabolic Disorders. 2018;19(4):325-333. DOI: 10.1007/s11154-018-9463-2
  54. 54. González-Rodríguez E, Rodríguez-Abreu D. Immune checkpoint inhibitors: Review and management of endocrine adverse events. The Oncologist. 2016;21(7):804-816. DOI: 10.1634/theoncologist.2015-0509
  55. 55. Brix TH, Hegedüs L. Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity. Annales d’endocrinologie. 2011;72(2):103-107. DOI: 10.1016/j.ando.2011.03.013
  56. 56. Kato I, Tajima K, Suchi T, et al. Chronic thyroiditis as a risk factor of B-cell lymphoma in the thyroid gland. Japanese Journal of Cancer Research. 1985;76(11):1085-1090
  57. 57. Haggerty JJ Jr, Garbutt JC, Evans DL, et al. Subclinical hypothyroidism: A review of neuropsychiatric aspects. International Journal of Psychiatry in Medicine. 1990;20(2):193-208. DOI: 10.2190/adly-1uu0-1a8l-hpxy
  58. 58. Haggerty JJ Jr, Stern RA, Mason GA, Marquardt M, Prange AJ Jr. Subclinical hypothyroidism: Recognition, significance, management. Clinical Neuropharmacology. 1992;15(Suppl. 1 Pt A):386a. DOI: 10.1097/00002826-199201001-00201
  59. 59. Jackson IM. The thyroid axis and depression. Thyroid. 1998;8(10):951-956. DOI: 10.1089/thy.1998.8.951
  60. 60. Mocellin R, Walterfang M, Velakoulis D. Hashimoto’s encephalopathy: Epidemiology, pathogenesis and management. CNS Drugs. 2007;21(10):799-811. DOI: 10.2165/00023210-200721100-00002
  61. 61. Churilov LP, Sobolevskaia PA, Stroev YI. Thyroid gland and brain: Enigma of Hashimoto’s encephalopathy. Best Practice & Research. Clinical Endocrinology & Metabolism. 2019;33(6):101364. DOI: 10.1016/j.beem.2019.101364
  62. 62. Yeh HC, Futterweit W, Gilbert P. Micronodulation: Ultrasonographic sign of Hashimoto thyroiditis. Journal of Ultrasound in Medicine. 1996;15(12):813-819. DOI: 10.7863/jum.1996.15.12.813
  63. 63. Takamatsu J, Yoshida S, Yokozawa T, et al. Correlation of antithyroglobulin and antithyroid-peroxidase antibody profiles with clinical and ultrasound characteristics of chronic thyroiditis. Thyroid. 1998;8(12):1101-1106. DOI: 10.1089/thy.1998.8.1101
  64. 64. Ducornet B, Moisson-Meer A, Duprey J. Hypothyroidism and blocking antibodies. Annales de medecine interne (Paris). 1995;146(8):559-574
  65. 65. Takasu N, Yamada T, Takasu M, et al. Disappearance of thyrotropin-blocking antibodies and spontaneous recovery from hypothyroidism in autoimmune thyroiditis. The New England Journal of Medicine. 1992;326(8):513-518. DOI: 10.1056/nejm199202203260803
  66. 66. Nordmeyer JP, Shafeh TA, Heckmann C. Thyroid sonography in autoimmune thyroiditis. A prospective study on 123 patients. Acta Endocrinologica. 1990;122(3):391-395. DOI: 10.1530/acta.0.1220391
  67. 67. Sostre S, Reyes MM. Sonographic diagnosis and grading of Hashimoto’s thyroiditis. Journal of Endocrinological Investigation. 1991;14(2):115-121. DOI: 10.1007/bf03350281
  68. 68. Ramtoola S, Maisey MN, Clarke SE, Fogelman I. The thyroid scan in Hashimoto’s thyroiditis: The great mimic. Nuclear Medicine Communications. 1988;9(9):639-645. DOI: 10.1097/00006231-198809000-00006
  69. 69. Nys P, Merceron RE, Cordray JP, et al. Nodular or pseudo-nodular Hashimoto thyroiditis. Value of cytologic examination. La Presse médicale. 1995;24(14):675-678 Thyroïdites de hashimoto à aspect nodulaire ou pseudo-nodulaire. Intérêt de l’examen cytologique
  70. 70. Kumarasinghe MP, De Silva S. Pitfalls in cytological diagnosis of autoimmune thyroiditis. Pathology. 1999;31(1):1-7. DOI: 10.1080/003130299105430
  71. 71. Ozawa Y. Painless (silent) thyroiditis. Nihon Rinsho. 1999;57(8):1770-1774
  72. 72. Stagnaro-Green A. Postpartum thyroiditis. Best Practice & Research. Clinical Endocrinology & Metabolism. 2004;18(2):303-316. DOI: 10.1016/j.beem.2004.03.008
  73. 73. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1081-1125. DOI: 10.1089/thy.2011.0087
  74. 74. Tachi J, Amino N, Tamaki H, Aozasa M, Iwatani Y, Miyai K. Long term follow-up and HLA association in patients with postpartum hypothyroidism. The Journal of Clinical Endocrinology and Metabolism. 1988;66(3):480-484. DOI: 10.1210/jcem-66-3-480
  75. 75. Othman S, Phillips DI, Parkes AB, et al. A long-term follow-up of postpartum thyroiditis. Clinical Endocrinology. 1990;32(5):559-564. DOI: 10.1111/j.1365-2265.1990.tb00898.x
  76. 76. Kent GN, Stuckey BG, Allen JR, Lambert T, Gee V. Postpartum thyroid dysfunction: Clinical assessment and relationship to psychiatric affective morbidity. Clinical Endocrinology. 1999;51(4):429-438. DOI: 10.1046/j.1365-2265.1999.00807.x
  77. 77. Vargas MT, Briones-Urbina R, Gladman D, Papsin FR, Walfish PG. Antithyroid microsomal autoantibodies and HLA-DR5 are associated with postpartum thyroid dysfunction: Evidence supporting an autoimmune pathogenesis. The Journal of Clinical Endocrinology and Metabolism. 1988;67(2):327-333. DOI: 10.1210/jcem-67-2-327
  78. 78. Gerstein HC. How common is postpartum thyroiditis? A methodologic overview of the literature. Archives of Internal Medicine. 1990;150(7):1397-1400
  79. 79. Meena A, Nagar P. Pregnancy outcome in euthyroid women with anti-thyroid peroxidase antibodies. Journal of Obstetrics and Gynaecology of India. 2016;66(3):160-165. DOI: 10.1007/s13224-014-0657-6
  80. 80. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New England Journal of Medicine. 1999;341(8):549-555. DOI: 10.1056/nejm199908193410801
  81. 81. Kamijo K, Saito T, Sato M, et al. Transient subclinical hypothyroidism in early pregnancy. Endocrinologia Japonica. 1990;37(3):397-403. DOI: 10.1507/endocrj1954.37.397
  82. 82. Klein RZ, Haddow JE, Faix JD, et al. Prevalence of thyroid deficiency in pregnant women. Clinical Endocrinology. 1991;35(1):41-46. DOI: 10.1111/j.1365-2265.1991.tb03494.x
  83. 83. Glinoer D. Maternal thyroid function in pregnancy. Journal of Endocrinological Investigation. 1993;16(5):374-378. DOI: 10.1007/bf03348861
  84. 84. Sue LY, Leung AM. Levothyroxine for the treatment of subclinical hypothyroidism and cardiovascular disease. Frontiers in Endocrinology (Lausanne). 2020;11:591588. DOI: 10.3389/fendo.2020.591588
  85. 85. Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: A Review. Journal of the American Medical Association. 2019;322(2):153-160. DOI: 10.1001/jama.2019.9052
  86. 86. Michalopoulou G, Alevizaki M, Piperingos G, et al. High serum cholesterol levels in persons with ‘high-normal’ TSH levels: Should one extend the definition of subclinical hypothyroidism? European Journal of Endocrinology. 1998;138(2):141-145. DOI: 10.1530/eje.0.1380141
  87. 87. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam Study. Annals of Internal Medicine. 2000;132(4):270-278. DOI: 10.7326/0003-4819-132-4-200002150-00004
  88. 88. Jonklaas J, Bianco AC, Cappola AR, et al. Evidence-based use of levothyroxine/liothyronine combinations in treating hypothyroidism: A consensus document. Thyroid. 2021;31(2):156-182. DOI: 10.1089/thy.2020.0720
  89. 89. Li CW, Menconi F, Osman R, et al. Identifying a small molecule blocking antigen presentation in autoimmune thyroiditis. The Journal of Biological Chemistry. 2016;291(8):4079-4090. DOI: 10.1074/jbc.M115.694687
  90. 90. Rieu M, Richard A, Rosilio M, et al. Effects of thyroid status on thyroid autoimmunity expression in euthyroid and hypothyroid patients with Hashimoto’s thyroiditis. Clinical Endocrinology. 1994;40(4):529-535. DOI: 10.1111/j.1365-2265.1994.tb02494.x
  91. 91. Battelino T, Krzisnik C, Gottschalk ME, Zeller WP. Testing for thyroid function recovery in children and adolescents with Hashimoto thyroiditis. Annals of Clinical and Laboratory Science. 1994;24(6):489-494
  92. 92. Khoo DH, Eng PH, Ho SC, Fok AC. Differences in the levels of TSH-binding inhibitor immunoglobulins in goitrous and agoitrous autoimmune thyroiditis after twelve months of L-thyroxine therapy. Clinical Endocrinology. 1999;51(1):73-79. DOI: 10.1046/j.1365-2265.1999.00740.x
  93. 93. Comtois R, Faucher L, Laflèche L. Outcome of hypothyroidism caused by Hashimoto’s thyroiditis. Archives of Internal Medicine. 1995;155(13):1404-1408

Written By

Ifigenia Kostoglou-Athanassiou, Lambros Athanassiou and Panagiotis Athanassiou

Submitted: November 15th, 2021 Reviewed: January 20th, 2022 Published: March 1st, 2022