**4.1.4 Laboratory findings**

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

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

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

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

in patients who develop autoimmune hypothyroidism.

auto-antibodies.

**4.1.3 Clinical picture** 

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 are related to other thyroid diseases and in normal population.

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 immunoglobulin.

#### **4.1.5 Imaging**

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 is originated from pituitary or thyroid disease.

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

Autoimmune Disorders Associated to Type 1 Diabetes Mellitus in Children and Adolescents 15

In control population the prevalence of thyroid autoimmunity ranges from 2.9% to 3.2%, while in young patients with type 1 diabetes the prevalence is higher, ranging from 19% to 23.4% (Kakleas et al., 2009). In children and adolescents with type 1 diabetes, risk factors for developing thyroid autoimmunity are quite similar to those reported in adult population, and include mainly female gender and increasing age. The role of anti-glutamic acid decarboxylase antibody persistence, age at diabetes diagnosis and duration of diabetes remains unclear. At-risk haplotypes for autoimmune thyroiditis include HLA-DQA1\*0301 (linked to DR4), DQB1\*0301 (linked to DR5) and DQB1\*0201 (linked to DR3), which is associated with autoimmune hyperthyroidism, while the HLA-DQA1\*0501 is associated with autoimmune hypothyroidism. The HLA haplotype DR3-DQB1\*0201 confers the genetic susceptibility to type 1 diabetes mellitus, autoimmune thyroiditis and autoimmune polyendocrine syndrome type II. Finally, the HLA-haplotype DQB1\*05 seems to be protective for autoimmune thyroid disease development (Kakleas et al., 2009). Other loci, i.e. VNTR and CTLA-4 may influence disease phenotype and severity (Van Driessche et al.,

A symmetric, painless goitre is usually the first presentation of autoimmune thyroid disease, while atrophic thyroid gland is observed in 10% of patients. A subclinical hypothyroidism has been reported up to 58% of patients with thyroid autoantibodies. Early recognition and treatment of hypothyroidism is important, since the decrease in basal metabolism may exert weight gain, dyslipidemia, atheroscleroticheart disease, sometimes goiter, and may negatively affect metabolic control. Hypothyroidism is confirmed by low free thyroxin and high TSH levels. Compensated hypothyroidism mean normal thyroxine levels with increased TSH. Substitutive L-thyroxin treatment exerts normalization of TSH levels and goitre regression when present. Treatment with L-thyroxin in patients with type 1 diabetes, thyroid autoantibodies and thyroid enlargement is safe and effective to reduce thyromegaly, with no effect on thyroid autoantibodies titer (Brown, 2007, Kordonouri et al, 2007, Karges et

Autoimmune thyroid disease and type 1 diabetes mellitus are sometimes associated with chronic urticaria, also in young patients, as a possible consequence of thyroid chronic inflammations. However the mechanisms underlying this association have not yet been defined, but this association emphasizes the need for a routine screening (Hyman et al., 2008). In young patients with type 1 diabetes mellitus overt hyperthyroidism is rarely encountered. It may be expression of Graves' disease or the transient hyperthyroid phase of Hashimoto's thyroiditis. Unstable metabolic control despite strict compliance, weight loss despite regular food intake, agitation, tremors, tachycardia, insomnia, heath intolerance, thyroid enlargement and characteristic eye signs are the main clinical features. Treatment is based on anti-thyroid drugs like propylthiuracil and metimazole.During acute thyrotoxicosis beta-adrenergic blockers agents are indicated. Persistent hyperthyroidism

While the association between type 1 diabetes and celiac disease and/or thyroid autoimmunity is clearly documented, particularly in young patients, few data are available about the frequency of other autoimmune diseases, like autoimmune gastritis and

requires surgery or radioiodine (Kordonouri et al, 2009).

2009).

al. 2007).

**5. Atrophic gastritis** 

**5.1 Background** 

pernicious anemia.

#### **4.1.6 Treatment**

The treatment of autoimmune thyroid follows the guidelines of congenital hypothyroidism. If the TSH level is greater than 10 μU/ml, L-thyroxin is the drug of choice. The initial dose is related on patient's age and on patient's clinical status from 25 μg/day to 100-150 μg/day. The therapy required periodic reevaluation, in particular when prominent nodules persist despite suppressive therapy, because there is a greater risk of cancer in patients with lymphocitic thyroiditis.

#### **4.2 Graves' disease**

Graves' disease is the most important cause of thyrotoxicosis in pediatrics and affects about 0.02% in children and adolescents. Its frequency increases with age: it is rare before the four years, gradually rises, reaching a peak during adolescence, with a preponderance for female gender (Kaguelidou et al, 2009). The aim of therapy is to reduce the excessive hormone production. First, this can be done with anti-thyroid drugs, as tionamides, with side effects especially after long-term therapy. Secondly, can be used thyroidectomy; however this surgical procedure may be complicated by several problems, such as hypoparathyroidism or recurrent nerve injury. Third method, is based on the use of radioiodine, that has not been yet universally accepted in children. Initial treatment, is medication and in the second instance, surgery or radioiodine. The goal of treatment is to maintain euthyroidism for a period at least 24 month and then discontinue the medical therapy. The positive results, with pharmacological treatment alone reaches 25% of cases. In *adults* the disease control is accomplished through the use of radioactive iodine or with drug for short periods. In *children*, however, use the medication for long periods, and then radioiodine, is just as an alternative option. The average age of onset is at 11 years (from 2.5 to 19 years), with preponderance in girls and with more cases of exophthalmos, low BMI, and higher height SDS. The goal of treatment is to limit the biosynthesis of thyroid hormones and maintain euthyroidism by maintaining a check on lab tests. Adverse effects are recorded in 5-32% of cases with skin rashes, transient neutropenia and agranulocytosis. Children have more adverse effects but less severe, often reversible spontaneously or with therapy change. Alternatively, using radioiodine in patients with hyperthyroidism resistant to drug treatment of 4.5 years, there was more remission (about 25% between 2-4 years of follow up). Most side-effect of the therapy is a permanent hypothyroidism, which can be treated with replacement therapy. The problem of this method is a potential carcinogenic risk (thyroid cancer and leukaemia), that declines with age, genetic damage, and a possible damage to reproduction. Radioiodine for safety, low cost and morbidity, could be the definitive treatment of Graves' disease in older children and young adolescents, but no in children younger than 5 years old (Gruneiro-Papendich et al, 2003).

#### **4.3 Autoimmune thyroid disease and type 1 diabetes**

Autoimmune thyroid disease is frequently reported in patients with type 1 diabetes mellitus, sometimes associated with celiac disease (Ergur et al, 2010). Serological screening studies aimed to evaluate the prevalence of thyroid involvement have gained momentum in recent years (Kadiyala et al. 2010). The prevalence of thyroid autoimmunity in patients with type 1 diabetes has been reported to be two to four times more frequent than in control population.

In control population the prevalence of thyroid autoimmunity ranges from 2.9% to 3.2%, while in young patients with type 1 diabetes the prevalence is higher, ranging from 19% to 23.4% (Kakleas et al., 2009). In children and adolescents with type 1 diabetes, risk factors for developing thyroid autoimmunity are quite similar to those reported in adult population, and include mainly female gender and increasing age. The role of anti-glutamic acid decarboxylase antibody persistence, age at diabetes diagnosis and duration of diabetes remains unclear. At-risk haplotypes for autoimmune thyroiditis include HLA-DQA1\*0301 (linked to DR4), DQB1\*0301 (linked to DR5) and DQB1\*0201 (linked to DR3), which is associated with autoimmune hyperthyroidism, while the HLA-DQA1\*0501 is associated with autoimmune hypothyroidism. The HLA haplotype DR3-DQB1\*0201 confers the genetic susceptibility to type 1 diabetes mellitus, autoimmune thyroiditis and autoimmune polyendocrine syndrome type II. Finally, the HLA-haplotype DQB1\*05 seems to be protective for autoimmune thyroid disease development (Kakleas et al., 2009). Other loci, i.e. VNTR and CTLA-4 may influence disease phenotype and severity (Van Driessche et al., 2009).

A symmetric, painless goitre is usually the first presentation of autoimmune thyroid disease, while atrophic thyroid gland is observed in 10% of patients. A subclinical hypothyroidism has been reported up to 58% of patients with thyroid autoantibodies. Early recognition and treatment of hypothyroidism is important, since the decrease in basal metabolism may exert weight gain, dyslipidemia, atheroscleroticheart disease, sometimes goiter, and may negatively affect metabolic control. Hypothyroidism is confirmed by low free thyroxin and high TSH levels. Compensated hypothyroidism mean normal thyroxine levels with increased TSH. Substitutive L-thyroxin treatment exerts normalization of TSH levels and goitre regression when present. Treatment with L-thyroxin in patients with type 1 diabetes, thyroid autoantibodies and thyroid enlargement is safe and effective to reduce thyromegaly, with no effect on thyroid autoantibodies titer (Brown, 2007, Kordonouri et al, 2007, Karges et al. 2007).

Autoimmune thyroid disease and type 1 diabetes mellitus are sometimes associated with chronic urticaria, also in young patients, as a possible consequence of thyroid chronic inflammations. However the mechanisms underlying this association have not yet been defined, but this association emphasizes the need for a routine screening (Hyman et al., 2008).

In young patients with type 1 diabetes mellitus overt hyperthyroidism is rarely encountered. It may be expression of Graves' disease or the transient hyperthyroid phase of Hashimoto's thyroiditis. Unstable metabolic control despite strict compliance, weight loss despite regular food intake, agitation, tremors, tachycardia, insomnia, heath intolerance, thyroid enlargement and characteristic eye signs are the main clinical features. Treatment is based on anti-thyroid drugs like propylthiuracil and metimazole.During acute thyrotoxicosis beta-adrenergic blockers agents are indicated. Persistent hyperthyroidism requires surgery or radioiodine (Kordonouri et al, 2009).
