**4. Clinical symptoms**

Graves' Disease is a chronic disorder characterized by periods of exacerbations and remissions, with a differentiated clinical picture, slightly different in children as compared to adults. In the pediatric population, the CNS shows higher sensitivity to the excess of thyroid hormones and lower to the circulatory system. On the physical examination, the patient presents with restless behaviour and body mass deficiency despite good appetite. The child's skin becomes smooth, warm and moist, and the goiter is the most constant symptom. The thyroid goiter is usually evenly enlarged, with parenchymal density, smooth and painless. On palpation, throbbing and tremour of the gland can be felt, caused by enhanced blood flow, well heard (when auscultated above the thyroid) as a vascular murmur, mainly in the upper poles of the gland. The heart action is markedly accelerated and does not slow down at rest. In hyperthyroidism observed in the prepubertal group the growth rate and bone age advancement are accelerated due to increased release of growth hormone. The excess of thyroid hormones in early childhood is manifested by physical overreaction and concentration disorders. This effect is associated with the particular sensitivity of the CNS to the thyroid hormones, which affect α- and β-adrenergic postsynaptic receptors and increase serotonin release. In the prepubertal Graves' group neuropsychiatric symptoms have been observed including hyperirritability, locomotor anxiety, sleep and concentration disorders, which are manifested as worse academic performance and emotional lability. Ophthalmopathy in children with Graves' Disease is generally mild in nature and ocular lesions subside along with normalization of thyroid hormone secretion. Infiltrative-hydropic exophthalmos is rare. Pretibial edema in the pediatric group has a location similar to that in adults but is different in nature: it is soft and not well separated. **Table 1** presents the effect of hyperthyroidism on the respective systems.

Graves' Disease occurs in children with other autoimmune diseases, such as type 1 diabetes, Addison's disease, albinism, systemic lupus erythematosus, miastenia gravis, juvenile idiopathic arthritis, autoimmune thrombocytopenia, Addison-Biermer anemia. The risk of the disease is increased in children with trisomy 21, Turner syndrome and DiGeorge syndrome. In diabetic children metabolic balance is difficult to achieve. The course of the disease in these patients with concomitant hyperthyroidism is labile and it is difficult to compensate for glycemia. Demand for insulin increases, mainly as a result of developing insulin resistance and fast tissue insulin metabolism. At the same time intestinal glucose absorption is increased, gluconeogenesis is enhanced and glycogen synthesis is decreased. Moreover, in the states of thyrotoxicosis the secretion of growth hormone, which is also responsible for glycemia increase is elevated. In consequence, ketone acidosis frequently develops [1, 2].


#### **Table 1.**

*Impact of hyperthyroidism on different systems.*

## **5. Diagnosis**

#### **5.1 Medical history and clinical examination**

A detailed medical history and thorough clinical examination are indispensable for proper diagnosis. Clinical diagnosis of primary hyperthyroidism is confirmed by elevated levels of circulating thyroid hormones and TSH suppression to the values close to zero. In rare cases of hyperthyroidism, such as thyreotropinoma, ectopic TSH secretion and pituitary resistance to thyroid hormones, serum TSH level is usually elevated or inadequately normal, whereas the levels of thyroid hormones (fT4 i/lub fT3) are increased. With autoimmunization in Graves' Disease, the level of anti-TSHR antibodies is elevated. High titer of these antibodies allows for the exclusion of the toxic phase of Hashimoto thyroidits (hashitoxicosis) and subacute thyroiditis. Other antithyroid antibodies (a-TPO and a-ATG) are of minor importance. Very seldom, the co-occurrence of Graves' Disease and hashitoxicosis determines a positive titer of anti-TSHR antibodies.

#### **5.2 Imaging investigations**

Imaging investigations- thyroid ultrasound - is a subsequent stage in the diagnosis of hyperthyroidism; however, it is not indispensable for the diagnosis of Graves' Disease. In autoimmune hyperactivity, the thyroid is usually enlarged, with reduced echogenicity and markedly increased blood flow in color Doppler ultrasound (CDUS) and in power Doppler examination, with moderately increased flow in non-autoimmune hyperactivity caused by active mutation in TSH-R (**Figures 9** and **10**). Currently, due to high access to anti-TSHR antibody titer assays, gland scintigraphy with I123 or Tc99 is seldom performed. It used to be widely applied to differentiate between Graves' Disease, thyrotoxic phase of chronic lymphocytic thyroiditis, subacute thyroiditis and a hormonally active nodule.
