**Hashimoto's Thyroiditis in Children and Adolescents**

Erkan Sar, Abdulbaki Karaoglu and Ediz Yeşilkaya *Gülhane Military Medical Academy Department of Pediatric Endocrinology, Ankara, Turkey* 

#### **1. Introduction**

26 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

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Hashimoto's thyroiditis (HT) is an autoimmune disease with genetic background. It is also named as autoimmune thyroiditis or chronic lymphocytic tiroiditis. Hashimoto's thyroiditis is the most common cause of thyroid diseases in children and adolescents and it is also the most common cause of acquired hypothyroidism with or without goiter. Hashimoto's thyroiditis was rst described in 1912 by Hakura Hashimoto in a series of patients with diffusely enlarged, rm thyroid glands with distinct pathologic features, classied as chronic lymphocytic thyroiditis (1). The characteristic histologic features include diffuse lymphocytic inltration, atrophic follicles, well-developed germinal centers, and brosis.

Hashimoto's thyroiditis is the most important cause of hypothyroidism in children and adolescents. In an American population with age between 11 and 18 years, five new cases were detected out of 1,000 adolescents screened every year. It is more common among girls, varying from 4:1 to 8:1 depending on the geographical region. Although the disease can be seen before three years of age, it is usually seen after six years of age and its peak ages are 10 and 11 years (2). The prevelance of Hashimoto's thyroiditis between 6-18 years old is 3% in Japan. Thirty-40% of the cases have familial history of thyroid disease. It occurs far more often in women than in men (between 10:1 and 20:1), and is most prevalent between 45 and 65 years old.

Autoimmune thyroid disease (AITD) has two clinical forms: a goitrous form more common in young age groups, in whom goiter may be the only clinical expression (3), often referred to as classical Hashimoto's disease, and an atrophic one often called atrophic thyroiditis (4). Both are characterized by circulating thyroid autoantibodies and varying degrees of thyroid dysfunction, differing only by the presence or absence of goiter.

The prognosis is not known very well, and studies reporting about long-term outcome of the disease are scarce (3,5). Thyroid function tests show variations at the time of diagnosis; mostly euthyroid or hypothyroid and rarely hyperthyroid. Hypothyroidism is thought to be a permanent sequelae of HT. Patients with overt hypothyroidism may have been recommended lifelong levothyroxine (LT4) therapy but it should be checked after puberty if LT4 therapy is still necessary or not.

#### **2. Etiology**

Hashimoto's thyroiditis is inuenced by both genetic and environmental factors (6). Family and twin studies support the evidence for genetic susceptibility (7-9). Dittmar et al. (10) have

Hashimoto's Thyroiditis in Children and Adolescents 29

deiodinases and glutathione peroxidase. Selenium influences the immune system probably by enhancing plasma glutathione peroxidase and thioredoxin reductase activity and by decreasing toxic concentrations of hydrogen peroxide and lipid hydroperoxides, resulting from thyroid hormone synthesis (19,20). A deficit of selenium results in increased intrathyroidal levels of hydrogen peroxide, which possibly increase the activity and immunogenicity of Thyroid Peroxidase (TPO) (21). Low selenium blood levels cause increased thyroid volume and thyroid hypoechogenicity, a marker for lymphocytic

Several medications may play a role in the development of HT. Interferon-α, interleukin-2, lithium, amiodarone, and highly active antiretroviral therapy are the agents most commonly

Several infections have been implicated in the pathogenesis of HT including Helicobacter pylori, Borrelia burgdorferi, Yersinia enterocolitica, Coxsackie virus, and retroviruses. Furthermore, recent studies but not all have substantiated a strong association between HT

Seasonal and geographic variations also support infection as a trigger of HT (11,23). Various mechanisms have been proposed to explain induction of autoimmunity by infection but it seems that three possibilities may be important in individuals susceptible to developing autoimmune disease: molecular mimicry (perhaps to retroviruses); polyclonal T cell activation (by an endogenous superantigen or an infecting organism); and MHC class II antigen induction (26). Although infections may promote HT, they can also be partially protective, as suggested by the hygiene hypothesis. According to this hypothesis, the immune system builds tolerance to repeated infectious exposures, and this may explain a

Many environmental pollutants, such as polyaromatic hydrocarbons, perfluorinated chemicals, phthalates, and bisphenol A, have been shown to be toxic to thyroid cells and promote the onset of HT (15). These chemicals are widely used in various industrial and consumer products and may specifically have thyroid-disrupting properties (28,29). Polyaromatic hydrocarbons, including polychlorinated biphenyls and polyhalogenated biphenyls, are organic compounds produced from coal and found in air and water, and they can possibly trigger thyroiditis. Polyhalogenated biphenyls are commonly used compounds in products including adhesives, lubricants, and flame retardants, while polychlorinated biphenyls are found in plasticizers. A high prevalence of hypothyroidism was observed in individuals exposed to polyhalogenated biphenyls with an associated elevation in antimicrosomal antibodies and anti-Tg antibodies (30). In view of the evidence that many of these chemicals can interfere with thyroid function, there is a growing concern about their effects on neurological development during embryonic life (15,29). Exposure during pregnancy, for example, which itself is a risk factor for HT, can have hazardous effects on the developing fetus in which normal thyroid hormone levels are crucial for normal growth

lower prevalence of thyroid antibodies in those of lower socioeconomic class (27).

infiltration (22).

**5. Medication** 

**6. Infections** 

and HCV (24,25).

**6.1 Environmental toxins** 

associated with thyroid dysfunction (23).

shown the increased familial risk especially for the first-degree relatives and females. In particular, children and siblings of patients with Hashimoto's thyroiditis had a 32-fold and 21-fold increased risk, respectively, for developing immunthyroiditis. In comparison, the risk for developing Graves' disease has been enhanced 7-fold in both children and siblings (10). The high prevalence of AITD in rst degree, foremost female, and relatives of patients with AITD demonstrates the importance of family history for developing AITD. This genetic susceptibility shows necessity of familial regular screening.

Candidate gene analysis, whole-genome linkage screening, genome-wide association studies, and whole-genome sequencing are the major technologies that have advanced this eld, leading to the identication of at least seven genes whose variants have been associated with AITD (11). Using these techniques, 6 AITD susceptibility genes have been identied and conrmed, HLA-DR, CD40, CTLA-4, PTPN22, Thyroglobulin (Tg) and TSH receptor. The AITD susceptibility genes identied so far can be divided into two broad groups: immune modulating genes and thyroid specic genes. The rst group includes the HLA-DR, CD40, CTLA-4, and PTPN22 genes, while the second group includes the Tg and TSH reseptor genes (12). In our previous study, we have studied an association of three polymorphic markers of CTLA-4 gene, namely, C(-318)T, A49G, and (AT)n dinucleotide repeat, which is known the relation with Graves' disease and we reported that A49G polymorphism may increase the susceptibility for Hashimoto's thyroiditis (13).

It is clear that additional genes contribute to the genetic susceptibility to AITD, as well as to the different phenotypes of AITD, disease severity, and, possibly, response to therapy but HLA-DR and Tg genes have stronger relation with HT than the others (14).

Several environmental and non-genetic triggers have been implicated in the etiology of HT. These include smoking, stress, iodine excess, medications, bacterial, and viral infections, irradiation, pollutants, and pregnancy. The mechanisms by which certain environmental agents induce thyroid disease could involve interference with thyroid function, direct toxic effects on thyrocytes, or immune stimulation, as well as other effects. It is often difficult to directly link an environmental exposure with thyroid autoimmunity, as disease may be associated with a combination of factors and can manifest over a long period of time. When an environmental exposure triggers HT in individuals with pre-existing thyroid autoantibodies, this may indicate gene-environment interaction, as the presence of thyroid antibodies is usually a surrogate marker of genetic susceptibility (15).
