**4.1.1 Background and genetic susceptibility**

Autoimmune thyroid diseases include many thyroid gland disorders, with different histological and clinical pictures ranging from the hypothyroidism of chronic lymphocytic thyroiditis to the hyperthyroidism of Graves' disease.

As other autoimmune diseases, **chronic lymphocytic thyroiditis** (also defined Hashimoto's thyroiditis from the physician who firstly described this condition) derives from a combination of genetic susceptibility and some environmental trigger factors (Pearce et al, 2003).

Hashimoto's thyroiditis is more frequent in females than in males (3.5 cases/1000 people/year versus 0.8 cases/1000 people/year, respectively), and global prevalence is increasing with age.

Hashimoto thyroiditis is the most common cause of acquired hypothyroidism in children and adolescents (formerly called "adolescent" or "simple" goiter), and usually presents itself during early adolescence or among schoolchildren, with or without gout, with a prevalence of 1% among schoolchildren (Lorini et al, 2003).

Susceptibility to Hashimoto's thyroiditis is determined by individual genetic background, including both major histocompatibility complex (MHC) and non-MHC genes.

Associations have been reported between Hashimoto's thyroiditis and HLA- DR3, HLA-DR4, or HLA-DR5. Furthermore, in children and adolescents paternal alleles and antibodies status have been shown to influence susceptibility to autoimmune thyroid disease. The expression of HLA-DR antigens on thyroid cells have a potential role in perpetuating the immune response, related to certain HLA-DR subtypes. As regards non-HLA susceptibility genes, several studies demonstrated the association between a polymorphism of the CTLA-4 gene and autoimmune thyroid disease (Barker, 2006).

In literature are reported linkage with loci on the X chromosome and on chromosome 20 or 14. Observations in twins are correlated with a genetic predisposition to thyroid autoimmunity. There are several cases of identical twins where one twin showed Graves' disease and the others Hashimoto's thyroiditis. It is common to find family clusters with HT and the incidence in parents or siblings of patient with HT can reach about 25% (Lorini et al., 2003).

#### **4.1.2 Pathogenesis**

There is no evidence that a clear infectious agent is responsible for autoimmune thyroiditis. However, long-term follow-up of patients with subacute thyroiditis showed a possible reaction to viral infection with signs of persistence thyroid autoimmune disease. To this purpose, hepatitis C can act as a trigger for the development of autoimmune thyroiditis through thyroid follicular cell apoptosis. Potential mechanisms of infectious triggers include cell damage with the release of auto-antigens, expression of new antigens and molecular mimicry mechanisms.

Autoimmune Disorders Associated to Type 1 Diabetes Mellitus in Children and Adolescents 13

progressively develops hypothyroidism. Spontaneous remission is frequent in adolescents

In patients with autoimmune thyroiditis high serum levels of thyroid antibodies are present, therefore their detection is mandatory. Anti-thyroglobulin antibodies have been reported in 60% of patients with diffuse goiter or hypothyroidism or both while anti-thyroid peroxidase antibodies are detectable in 95% of cases so they represent a more sensitive marker. In 20% of cases there are significant antibody titers in the absence of thyroiditis, while lower titer

Subclinical hypothyroidism means altered values of thyroid hormones in presence of a slightly or moderately elevated TSH. Many children with HT have normal level of TSH because the goiter is caused by lymphocytic infiltrations or growth-stimulating

On imaging studies, the thyroid gland shows enlargement without specific characteristics. High resolution ultrasound may show hypoechogenic micronodules (Fig. 2). Scintigraphic findings are variable; in some patients with Hashimoto's thyroiditis have thyroid gland enlarged with dysomogeneous distribution of tracer, in other cases the thyroid scan is normal but in most patients the uptake of radioiodine is decreased or increased. The perclorate washout is positive in 60% of patients. Often children and adolescents, evaluated at diagnosis, show a thyroid ultrasound picture altered. The definitive diagnosis of HT is confirmed by a biopsy of the thyroid, that confirmed the elevated titers of thyroid autoantibodies in the serum. High serum TSH concentration can be found in 30-40% of cases, associated with low serum T4, with normal or near-normal serum T3 concentration. Thyroid scan exclude thyroid dysgenesis. Elevated level of TSH clarifies if hypothyroidism

Fig. 2. Hashimoto's thyroiditis: thyroid ultrasound showing hypoechogenicity

are related to other thyroid diseases and in normal population.

is originated from pituitary or thyroid disease.

(Lorini et al, 2003).

immunoglobulin.

**4.1.5 Imaging** 

**4.1.4 Laboratory findings** 

Drugs containing iodine or supplementary dietary iodine can trigger an autoimmune thyroiditis in subjects at risk, although the mechanism is still unknown. Accumulation of iodine in animal models leads to iodination of thyroglobulin which triggers an immune reaction because T-cell-reactive peptides can be more antigenic when iodinated. Moreover dietary supplementation of iodine in the population of iodine-deficient regions such as the use of drugs rich in iodine (i.e. amiodarone) induce cases of thyroiditis, and a significant increase in lymphocytic infiltration by thyroid-specific auto-antibodies. Furthermore, patients treated with cytokines such as IL-1 or -interferon can trigger an autoimmune thyroiditis, which is more frequent in patients with pre-existing positivity for anti-thyroid auto-antibodies.

Hashimoto's thyroiditis is an organ-specific autoimmune disease, characterized histologically by a lymphocytic infiltration of the thyroid gland, initially characterized by hyperplasia and subsequently by infiltration of lymphocytes and plasma cells between follicles, then resulting in a follicle atrophy. Lymphocytic infiltration is composed of B lymphocytes, about 30%, and T-lymphocytes, about 60%, including CD4+ helper and CD 8+ suppressor. Autoimmune thyroiditis is characterized by thyroid cell apoptosis leading to follicular destruction, rather than thyroid stimulation and cellular hyperplasia. Thyroid gland is infiltrated by B- and T-lymphocytes, the later are capable of destroying thyroid cells, which express Fas, via apoptosis and release several cytokines that increase the damage. The process is exacerbated by the action of auto-antibodies directed against several thyroid antigens, like thyroid peroxidase antibodies (TPO-Abs), detectable in 90% of patients with Hashimoto's thyroiditis, previously considered non-pathogenic, but now their role has been shown. They inhibit enzyme activity and stimulate cytotoxicity by natural killer. Anti-thyroglobulin antibodies (TgA) are detectable in a small percentage of patients, while high levels of thyrotropin receptor-blocking antibodies are often present, particularly in patients who develop autoimmune hypothyroidism.

#### **4.1.3 Clinical picture**

Hashimoto's thyroiditis is the most common cause of acquired hypothyroidism in the pediatric population, occurring in about 1% of children and adolescents. Goiter is the hallmark of this autoimmune disease, and often may appear either insidiously or variable in size, however is usually enlarged with accentuation of the normal lobular architecture. Occasionally goiter gives the sensation of local pressure or causes difficulty in swallowing. Hashimoto's thyroiditis is more frequent in girls than in boys (four to seven times), with onset at 3 years but often sharply to 6 years with a peak incidence during adolescence.

The most common clinical symptoms are related to hypothyroidism, and include deceleration in the rate of growth, although some children are apparently asymptomatic, and show abnormal values in laboratory tests only. A few children complain clinical signs and symptoms of thyroid hyperfunction, such as nervousness, irritability, agitation, hot intolerance, weight loss. Eventually patient with Hashimoto's thyroiditis can show ophthalmopathy in absence of Graves' disease. The most frequent symptom in Hashimoto's thyroiditis is goiter, followed by menstrual disorders, short stature, and nervousness in girls, while constipation and exophthalmos are more frequently reported in boys. Other signs are hot and cold intolerance, weight loss or weight gain and sweating. The clinical course of Hashimoto's thyroiditis is quite variable. In fact, the goiter may reduce or disappear, or persist unchanged for years, while the patient remains euthyroid or progressively develops hypothyroidism. Spontaneous remission is frequent in adolescents (Lorini et al, 2003).
