**8. Clinical manifestation**

Hashimoto's thyroiditis is one of the most common organ specic autoimmune diseases (33). Weetman (34) reported clinical HT prevalence rate at 1 in 182 or 0.55% in the US. In the UK, Tunbridge et al (35) reported an overall HT prevalence of 0.8%. However, diagnosis based fine needle aspiration biopsy study; the cytology of HT seems to be much more prevalent, at 13.4% (36). This difference may be partially explained by the fact that for diagnosing clinical HT, abnormally elevated TSH, low thyroid hormones (34,35) and the confirmatory presence of thyroid autoantibodies are usually accounted for.

The most common clinical manifestations are goiter and hypothyroidism related findings. The goiter may appear insidiously and may be small or large. In most patients, the thyroid is diffusely enlarged, firm, and nontender. In about 30% of patients, the gland is lobular and may seem to be nodular (37). Most of the affected children are clinically euthyroid and asymptomatic; some may have symptoms of pressure in the neck. Some children have clinical signs of hypothyroidism, but others who appear clinically euthyroid have laboratory evidence of hypothyroidism. A few children have manifestations suggestive of hyperthyroidism, such as nervousness, irritability, increased sweating, and hyperactivity, but results of laboratory studies are not necessarily those of hyperthyroidism (37). In one study from iodine replete area with 140 patients with HT, the most common complaint was goiter (55%). Upon admission, 18.6% of patients had complaints related to hypothyroidism (7.4% growth retardation, 4.9% weight gain and 6.3% other complaints related to hypothyroidism). Eighteen patients (11.1%) were diagnosed incidentally upon detection of

and brain development. It is important, therefore, to be aware of environmental triggers of HT and to monitor thyroid functions closely in susceptible women during pregnancy

The activation of CD4 T-lymphocytes specic for thyroid antigens is believed to be the rst step in pathogenesis. Once activated, self-reactive CD4 T cells recruit cytotoxic CD8 T cells as well as autoreactive B cells into the thyroid. T cells play a crucial role in disease pathogenesis by reacting with thyroid antigens and secreting inflammatory cytokines. Besides the others, mutations in the Tg gene and CTLA-4 are associated with HT (31,32). The three main targets of thyroid antibodies are Tg, TPO, and the TSH receptor. It is believed that these autoantibodies are secondary to thyroid follicular cell damage induced by T cells Anti-TPO antibodies have been shown to inhibit the activity of the enzyme in vitro, but direct cytotoxicity by CD8 T cells is believed to be the main mechanism of hypothyroidism in vivo. Thyroid peroxidase is the major autoantigen and autoantibodies to TPO are closely associated with disease activity. Although this has not been proven in children Anti-TSH receptor antibodies of the blocking type may contribute to hypothyroidism in a minority of adult patients with the atrophic form of autoimmune thyroiditis. Histologically, HT is characterized by diffuse lymphocytic inltration with occasional germinal centers. Thyroid follicles may be reduced in size and contain sparse colloid. Individual thyroid cells are often enlarged with oxyphilic cytoplasm. In contrast, the gland of atrophic autoimmune thyroiditis is small, with lymphocytic inltration and brous

Hashimoto's thyroiditis is one of the most common organ specic autoimmune diseases (33). Weetman (34) reported clinical HT prevalence rate at 1 in 182 or 0.55% in the US. In the UK, Tunbridge et al (35) reported an overall HT prevalence of 0.8%. However, diagnosis based fine needle aspiration biopsy study; the cytology of HT seems to be much more prevalent, at 13.4% (36). This difference may be partially explained by the fact that for diagnosing clinical HT, abnormally elevated TSH, low thyroid hormones (34,35) and the

The most common clinical manifestations are goiter and hypothyroidism related findings. The goiter may appear insidiously and may be small or large. In most patients, the thyroid is diffusely enlarged, firm, and nontender. In about 30% of patients, the gland is lobular and may seem to be nodular (37). Most of the affected children are clinically euthyroid and asymptomatic; some may have symptoms of pressure in the neck. Some children have clinical signs of hypothyroidism, but others who appear clinically euthyroid have laboratory evidence of hypothyroidism. A few children have manifestations suggestive of hyperthyroidism, such as nervousness, irritability, increased sweating, and hyperactivity, but results of laboratory studies are not necessarily those of hyperthyroidism (37). In one study from iodine replete area with 140 patients with HT, the most common complaint was goiter (55%). Upon admission, 18.6% of patients had complaints related to hypothyroidism (7.4% growth retardation, 4.9% weight gain and 6.3% other complaints related to hypothyroidism). Eighteen patients (11.1%) were diagnosed incidentally upon detection of

confirmatory presence of thyroid autoantibodies are usually accounted for.

(15,23).

**7. Pathogenesis** 

replacement of the parenchyma (5).

**8. Clinical manifestation** 

goiter during routine examination (38). Staii et al. reviewed 761 patients for which ultrasound guided thyroid fine needle aspiration biopsy were performed for nodule. The HT cohort consisted of 102 (13.4%) patients (659 out of 761 did not have cytological Hashimoto's diagnosis) for which 46 (6%) were identified as having clinical disease (i.e. diagnosed hypothyroid on thyroid hormone replacement and with cytological Hashimoto's diagnosis), 9 (1.2%) as having subclinic hypothyroidism and 47 (6.2%) as having euthyroid autoimmunity (36). Occasionally, the disorder may coexist with Graves's disease. Ophthalmopathy may occur in lymphocytic thyroiditis in the absence of Graves's disease. Hashimoto's encephalopathy is a rare condition and the estimation of incidence and prevalence is difficult. One prospective study examining cases of unexplained encephalopathy that had detectable antithyroid antibodies, estimated a prevalence of 2.1/100 000 subjects (39). Adequate information is not available about the frequency of Hashimoto's encephalopathy in children (40). The clinical picture of a relapsing and remitting encephalopathy in a female characterised by seizures, stroke-like episodes, neurological signs such as myoclonus and tremor, cognitive disturbance and hallucinations, and other psychotic symptoms is highly suggestive of Hashimoto's encephalopathy (41). Normal routine investigations, nonspecific neuroimaging and CSF findings (apart from elevated protein), and encephalopathic EEG can be supportive of the diagnosis. Thyroid hormone studies are not helpful, but may identify subclinical thyroid dysfunction (41). Detection of antithyroid (in particular anti-TPO) antibodies confirms the diagnosis. As anti-TPO antibodies are detected in as many as 10 % of the general population, (42) high titres (usually over 100-fold normal (43)) of these antibodies in conjunction with the clinical features of Hashimoto's encephalopathy are necessary before a diagnosis can be made. Thyroid antibody levels should be measured even in the setting of normal thyroid function and the diagnosis of Hashimoto encephalopathy has to be considered in patients with Down syndrome who present with rapid cognitive decline, particularly in association with myoclonus and an abnormal EEG result (44). Corticosteroid responsiveness can also support the diagnosis (45).
