Diffuse Toxic Goiter (Graves' Disease): Clinical Guidelines

List of Abbreviations

ALT - alanine aminotransferase

AST - aspartate aminotransferase

GD - Graves' disease

NOS - "not otherwise specified"

DTG - diffuse toxic goiter

GI - gastrointestinal tract

CT — computed tomography

MRI — magnetic resonance imaging

PTU - #propylthiouracil

RET - retrobulbar adipose tissue

RIT - radioiodine therapy

TSHR - thyrotropin receptor

RP - radiopharmaceutical (ATC: V09FX Various diagnostic radiopharmaceuticals for thyroid)

FT3 - free triiodothyronine

FT4 - free thyroxine

FNAB - fine-needle aspiration biopsy

Tg - thyroglobulin

TPO - thyroid peroxidase

TSH - thyroid-stimulating hormone

hCG - human chorionic gonadotropin

Ultrasound - ultrasound examination

EOM - extraocular muscles

TED - thyroid eye disease

TG - thyroid gland

Terms and Definitions

Hyperthyroidism is an elevated level of thyroid hormones in the blood resulting either from their increased secretion or destruction of the thyroid gland, or from excessive intake of thyroid hormone preparations.

Radioisotope diagnostics is a method of investigating human organs and body systems using radionuclide-labeled compounds approved for human administration for diagnostic purposes.

Radioiodine therapy (RIT) is a type of radiation therapy in which the radiation source is #Sodium iodide [131I] (ATC code: V09FX03).

Endocrine ophthalmopathy (EO) is an autoimmune inflammatory disease of the retrobulbar adipose tissue and extraocular muscles associated with Graves' disease.

Thyrotoxicosis is a syndrome caused by an excess of thyroid hormones in the blood and their toxic effect on various organs and tissues.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Graves' disease (GD) or Basedow's disease is a systemic autoimmune disease developing as a result of the production of antibodies against the thyrotropin receptor (TSHR-Ab), clinically manifested by thyroid involvement with the development of thyrotoxicosis syndrome combined with extrathyroidal pathology [1,4].

Hyperthyroidism is an elevated level of thyroid hormones in the blood resulting either from increased secretion or destruction of the thyroid gland, or from excessive intake of thyroid hormone preparations.

Thyrotoxicosis is a syndrome caused by an excess of thyroid hormones in the blood and their toxic effect on various organs and tissues.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

1.2.1 Diffuse Toxic Goiter (Graves' Disease)

The most common cause of hyperthyroidism (in 95% of cases) in both children and adults is Graves' disease.

A central role in the pathogenesis of Graves' disease is played by disorders in the T-cell link of immunity. The autoantigens are thyroid-stimulating hormone receptors (TSHR). Stimulation of TSHR as a result of contact with antibodies leads to increased secretion of thyroid hormones and the appearance of symptoms of hyperthyroidism, as well as stimulates the growth of the thyroid gland (TG) and the development of its vascular bed. Activation of cellular response mechanisms against this antigen, manifested in fibroblasts of the eye orbits and skin, leads to the occurrence of extrathyroidal symptoms of the disease [1].

1.2.2 Thyrotoxicosis with Ectopic Thyroid Tissue

Hydatidiform mole and choriocarcinoma belong to the group of trophoblastic diseases — rare tumors arising as a result of malignant transformation of various trophoblast elements, which is obligatorily associated with pregnancy.

The pathogenesis is based on the production of large amounts of hCG, which has TSH-like activity, which can lead to thyroid hyperstimulation and increased production of thyroid hormones.

1.2.3 Factitious Thyrotoxicosis

- drug-induced thyrotoxicosis, iatrogenic thyrotoxicosis, thyroid hormone overdose. This is a pathological condition caused by the intake of an excessive amount of thyroid hormones into the body. Among drug-induced (including iatrogenic) forms, thyrotoxicosis caused by an overdose of levothyroxine sodium** is most common in children.

1.2.4 Other Forms of Thyrotoxicosis

Thyroid-stimulating hormone hypersecretion: TSH-producing pituitary adenoma is the rarest type of hormonally active pituitary adenomas, extremely rare in children. As a rule, these are macroadenomas well visualized during pituitary MRI.

1.2.5 Thyroid Crisis or Coma

Thyrotoxic crisis. Graves' disease in rare cases is accompanied by the development of a thyrotoxic crisis. The most life-threatening complication of thyrotoxicosis is a thyrotoxic crisis, which can be caused by various reasons. The most frequent are thyroid resection against the background of uncompensated thyrotoxicosis or non-use of glucocorticoids in the pre- and postoperative periods. In addition, the causes of the crisis may be the withdrawal or inadequate administration of antithyroid therapy, infectious diseases, psychological trauma, heavy physical exertion. Understanding the pathophysiology of TC is mainly based on the analysis of precipitating factors. The latter can be divided into two categories: 1) leading to a rapid increase in the concentration of thyroid hormones; 2) reducing the body's compensatory reserves. With a sharp increase in the concentration of thyroid hormones, a temporary deficiency of plasma transport proteins (thyroxine-binding globulin (TBG), transthyretin, albumin) leads to an increase in the concentration of free forms of thyroxine (FT4) and triiodothyronine (FT3). The latter freely enter the cell. Decreased hepatic and renal clearance of thyroid hormones in systemic diseases [15], as well as increased formation of metabolically active 3,5,3'-triiodothyroacetic acid (TRIAC) are also possible mechanisms for the development of TC.

1.3 Epidemiology of the Disease or Condition

1.3.1 Diffuse Toxic Goiter (Graves' Disease)

Among adults, Graves' disease occurs in approximately 2% of women and 0.2% of men. In children, DTG is relatively rare (8:1,000,000). Girls get sick 6–8 times more often. Graves' disease occurs in childhood at any age, but its frequency increases with age, peaking in adolescents. The disease is often hereditary.

The prevalence of Graves' disease varies in different countries: from 1/10,000 in the USA to 1/100,000 in the UK and Ireland [2, 3]. In the Russian Federation, between 3,000 and 3,800 children with thyrotoxicosis (E05.0) aged 0 to 17 years are registered annually, with the number of new cases ranging from 700 to 900. The prevalence of the disease in 2024 was 7.1 in the 0–14 age group and 41.4 per 100,000 child population in the 15–17 age group; the incidence was 1.6 in the 0–14 age group and 9.9 per 100,000 child population in the 15–17 age group.

1.3.2 Thyrotoxicosis with Ectopic Thyroid Tissue

Simple hydatidiform mole (complete and partial) belongs to "precancerous" conditions of the trophoblast, occurring in 1-3 cases per 1,000 pregnancies in European countries; the incidence is higher in Asian countries, but currently there is a trend towards an increase in incidence in the European population. All these trophoblastic conditions are pathological and precede malignant neoplasms of the placenta, which is why they are often collectively grouped as "gestational trophoblastic disease." In childhood, it is extremely rare.

1.3.3 Factitious Thyrotoxicosis

The prevalence of drug-induced thyrotoxicosis (iatrogenic, drug-induced hyperthyroidism) in clinical endocrinology is unknown.

1.3.4 Other forms of thyrotoxicosis

Pituitary tumors producing isolated thyroid-stimulating hormone (TSH) are rare and account for about 0.5–3% of all pituitary adenomas. Pituitary thyrotropinomas in the majority of detected cases (82–87%) are macroadenomas.

1.3.5 Thyroid storm or coma

Thyrotoxic crisis (thyroid storm) is a rare, life-threatening complication of thyrotoxicosis. According to various statistical data, the frequency of the crisis ranges from 0.5 to 9% of severe thyrotoxicosis cases.

The severity of the crisis depends on the patient's age, the rate of increase in free thyroid hormone levels, the presence of comorbidities, and the nature of the precipitating factor.

1.4 Features of Coding the Disease or Condition

E05.0 Thyrotoxicosis with diffuse goiter

Exophthalmic or toxic goiter NOS

Graves' disease

Graves' disease

E05.3 Thyrotoxicosis with ectopic thyroid tissue

E05.4 Thyrotoxicosis, artificial

E05.5 Thyroid crisis or coma

E05.8  Other forms of thyrotoxicosis

Thyroid-stimulating hormone hypersecretion

1.5 Classification of the disease or condition

By origin, the following are distinguished:

Thyroid diseases:

• diffuse toxic goiter (Graves' disease);

• toxic adenoma (Plummer's disease);

• nodular and multinodular toxic goiter;

• autoimmune thyroiditis (thyrotoxic phase);

• subacute thyroiditis;

• radiation thyroiditis;

• iodine-induced thyrotoxicosis (Jod-Basedow phenomenon);

• familial non-autoimmune thyrotoxicosis.

Diseases of other organs:

• struma ovarii (atypically located hyperfunctioning thyroid tissue);

• TSH-producing pituitary adenoma;

• pituitary resistance to thyroid hormones;

• chorioepithelioma - a tumor secreting hCG that stimulates thyroid function.

According to pathogenetic features, the following are distinguished:

• thyrotoxicosis caused by hyperproduction of thyroid hormones - develops in Graves' disease, multinodular toxic goiter, and certain other diseases;

• destructive thyrotoxicosis - develops as a result of the destruction of thyroid follicles and the release of thyroid hormones into the bloodstream (develops in subacute, postpartum, painless ("silent"), and cytokine-induced thyroiditis).

According to the features of thyroid #sodium iodide [131I] uptake, the following are distinguished:

• Diseases occurring with increased uptake of #sodium iodide [131I]:

- Graves' disease;

- nodular toxic goiter;

- TSH-secreting pituitary adenoma;

- trophoblastic disease;

• Conditions associated with decreased uptake of #sodium iodide [131I]:

- subacute thyroiditis;

- autoimmune thyroiditis;

- exogenous intake of thyroid preparations;

- amiodarone-induced thyroiditis.

Depending on the severity of clinical manifestations and hormonal disorders, overt and subclinical thyrotoxicosis are distinguished [1].

Table 1. Classification of thyrotoxicosis by severity of clinical manifestations

1.6 Clinical presentation of the disease or condition

1.6.1 Graves' disease

The clinical presentation of Graves' disease is determined by the thyrotoxicosis syndrome resulting from excessive secretion of thyroid hormones (T4 and T3, and their free fractions): weight loss (often against the background of increased appetite), sweating, tachycardia and palpitations, inner restlessness, nervousness, hand tremor, and sometimes tremor of the entire body, general and muscular weakness, and rapid fatigability.

The classic triad of the disease: goiter, tachycardia, and exophthalmos, described by K. Basedow, occurs in approximately 50% of patients [1,2,4].

Thyrotoxicosis is characterized by:

1. Disorders of the nervous system in the psycho-emotional and motor spheres, which are often leading in the clinical picture of thyrotoxicosis in children. Not infrequently, the first manifestations of the disease in a child are behavioral changes noted by parents and peers (nervousness, emotional lability, tearfulness). Marked fatigability, sleep disturbances, sharp mood swings, and groundless outbursts of anger lead to conflicts with parents, friends, and teachers. Concentration is impaired and memory worsens—all of which lead to a decline in academic performance and social maladaptation of the child. Among motor disorders, the most characteristic are hyperkinesias of the choreiform type—involuntary, rapid, jerky movements of the fingers, head, contractions of facial muscles and limb musculature. Upon examination, the child is hyperactive, movements are rapid, sharp, sweeping, and often purposeless. Examination reveals a fine tremor of the fingers, tongue, and eyelids.

2. Impairment of the cardiovascular system function is a cardinal sign of thyrotoxicosis. The most frequent cardiac symptom of thyrotoxicosis is persistent tachycardia. Tachycardia may frequently precede other signs of the disease. Children with thyrotoxicosis often complain of palpitations, which can occur spontaneously or against the background of minimal psychological or physical exertion. Tachycardia in children with Graves' disease is constant and does not resolve during sleep. Heart sounds are usually accentuated and amplified; severe forms of the disease may be accompanied by muffled heart sounds. Quite often, children with Graves' disease exhibit non-organic functional murmurs, typically systolic murmurs at the apex, over the pulmonary artery, and at Erb's point. Graves' disease is characterized by decreased peripheral resistance and increased cardiac output. This leads to an increase in systolic pressure, a decrease in diastolic pressure, and consequently, an increase in pulse pressure. In mild and moderate cases, blood pressure may be within the normal range.

3. The appearance of ocular symptoms—thyrotoxic ophthalmopathy in patients with Graves' disease can be either a manifestation of thyrotoxicosis or a manifestation of an autoimmune process localized in the retrobulbar adipose tissue. The incidence of clinically overt endocrine ophthalmopathy (EO) in Graves' disease is 30–50%. It has been proven that the true incidence of EO in patients with Graves' disease is much higher if subclinical forms are taken into account. Extremely severe EO develops in approximately 3–5% of cases [39]. EO is more common in girls than in boys, and more frequently seen in adolescents aged 11 to 18 years. EO can be combined with other autoimmune pathologies, both endocrine and non-endocrine. In 95% of cases, EO develops against the background of Graves' disease, and in 5% of cases, against the background of autoimmune thyroiditis.

As a rule, the clinical manifestations of thyrotoxic ophthalmopathy decrease as thyrotoxicosis is compensated, and the changes are reversible.

In the case of autoimmune involvement of the retrobulbar adipose tissue and extraocular muscles, infiltrative orbitopathy or infiltrative ophthalmopathy develops. Signs of autoimmune infiltrative ophthalmopathy persist even after the symptoms of thyrotoxicosis have resolved and require a special approach to treatment. Infiltrative ophthalmopathy can also develop in the absence of signs of Graves' disease. One of the most characteristic symptoms of ophthalmopathy in children with Graves' disease is exophthalmos. Exophthalmos is generally symmetric; unilateral exophthalmos in children is extremely rare. Periorbital edema can mask the manifestations of exophthalmos. Sometimes patients complain of a feeling of pressure behind the eyeballs. Exophthalmos can be so pronounced that the eyes do not close during sleep; this symptom is called lagophthalmos. Clinical symptoms of thyrotoxic ophthalmopathy also include increased photosensitivity, tearing that worsens in the wind, conjunctival injection, quite frequently blurred vision, diplopia, and rapid eye fatigue [5,39]. Severe EO is often combined with infectious conjunctival lesions and corneal ulcerations.

The "eye" symptoms in Graves' disease are very well studied and named after the authors who first described them:

- Dalrymple's sign—wide palpebral fissures;

- Reprev-Melikhov sign—angry stare;

- Braun's sign—absence of palpebral fissure narrowing when smiling;

- Kocher's sign—inability to close eyes completely;

- Rosenbach's sign—tremor of closed eyelids;

- Graefe's sign—lag of the upper eyelid when looking down slowly;

- Stellwag's sign—rare and incomplete blinking;

- Jellinek's sign—increased pigmentation of the eyelids;

- Kraus's sign—increased eye brilliance;

- Goldzieher's sign—conjunctival hyperemia;

- Moebius's sign—convergence insufficiency;

- Geoffroy's sign—absence of forehead wrinkles when looking upward.

The severity of EO is determined independently of EO activity, reflecting the degree of functional impairment and cosmetic defects (degree of eyelid retraction, proptosis, soft tissue, extraocular muscle and corneal involvement, and degree of visual impairment). The NOSPECS classification is used to assess the severity of EO (see Appendix G2). There are 3 degrees of EO severity: mild, moderate, and severe [9]. Severe forms of EO are rare in children.

4. Among the symptoms characterizing the state of the gastrointestinal tract, patients with marked thyrotoxicosis frequently exhibit an increased appetite. However, despite the increased appetite, severe forms of thyrotoxicosis often lead to weight loss of varying degrees. Stool frequency increases to several times a day, but diarrhea is rare.

5. Regarding the urinary system, the most frequent symptom in children is polyuria, which develops as a result of increased renal blood flow and renal filtration. Polyuria and nervous system disorders often lead to the development of enuresis in the child, more commonly nocturnal and occasionally diurnal.

6. In children with thyrotoxicosis, the skin, as a rule, is warm and moist, which distinguishes it from vegetative-vascular dysfunction, which is characterized by hyperhidrosis and hypothermia restricted to the distal extremities. These features are the result of cutaneous vasodilation and increased sweating; the skin flushes easily, and a characteristic feature is a rapid, red, persistent dermographism.

7. Changes are noted in the hematopoietic system. Patients with hyperthyroidism may exhibit erythrocytosis, moderate lymphocytosis, moderate granulocytopenia, and thrombocytopenia. In some cases, microcytic hypochromic anemia develops, and in 1–3%, pernicious anemia (vitamin B12-deficiency anemia). The clearance of clotting factors in hyperthyroidism is increased, but the plasma concentration of most of them remains normal. In addition, the plasma concentration of coagulation factor VIII may decrease and the partial thromboplastin time may be prolonged, which is accompanied by hemostatic disorders such as increased bleeding time after surgical procedures and easy bruising [6].

8. A number of symptoms of Graves' disease are a manifestation of adrenal insufficiency, which occurs to varying degrees in all children with Graves' disease. General weakness, fatigue, skin pigmentation, and low diastolic blood pressure reflect glucocorticoid deficiency in Graves' disease. The increase in sympathoadrenal activity caused by hyperthyroxinemia contributes to an increase in the functional activity of the adrenal glands. At the same time, the high intensity of metabolic processes is accompanied by an accelerated metabolism of adrenal cortex hormones and cholesterol, which is the source of their formation; in prolonged and severe thyrotoxicosis, this leads to adrenal exhaustion and the development of relative hypocorticism [7].

9. Physical development and bone age in children with thyrotoxicosis are generally somewhat accelerated, but growth parameters rarely fall outside the normal range. In some cases, delayed sexual development may be observed.

10. Enlargement of the thyroid gland is a characteristic sign of diffuse toxic goiter. When examining a patient, it is necessary to keep in mind the possibility of a retrosternal location of the thyroid gland. Mild and moderate forms of Graves' disease are more often accompanied by a slight enlargement of the thyroid gland; severe forms are typically characterized by a large goiter size, although a complete parallelism between goiter size and thyrotoxicosis severity is not observed [1,2,4].

1.6.2 Thyrotoxicosis with ectopic thyroid tissue

The main clinical symptoms of complete hydatidiform mole, which are most often detected at 10–18 weeks of gestation, include: vaginal bleeding (more than 90%), discrepancy between uterine size and gestational age: uterine size greater than gestational age, bilateral theca-lutein cysts (including large ones), signs of toxemia, nausea, vomiting, dizziness, and signs of hyperthyroidism. Complications of the tumor process may develop: arterial hypertension, preeclampsia, rupture of the theca-lutein cysts, torsion of the cyst stalk, infectious complications, trophoblastic embolization with acute respiratory disorders, uterine bleeding, and disseminated intravascular coagulation (DIC) syndrome. In partial hydatidiform mole, the size of the uterus may be less than the gestational age, spotting from the genital tract in the first trimester of pregnancy and signs of spontaneous abortion may occur, and fetal heart sounds are absent. The tumor has the ability for rapid and deep invasion of the myometrium and can cause massive intraperitoneal bleeding. Pregnancy symptoms may occur: nausea, dizziness, and taste aberrations. The spectrum of other possible symptoms of the tumor process is associated with metastatic lesions of various organs and systems [41,43].

1.6.3 Factitious thyrotoxicosis

The varying sensitivity of individual systems to the action of thyroid hormones is the reason why, initially with a moderate dose increase, certain symptoms come to the foreground.

Clinical manifestations of drug-induced thyrotoxicosis:

- nervousness, irritability, emotional lability, insomnia;

- sweating;

- palpitations;

- increased fatigue, weakness;

- weight loss with normal or increased appetite;

- poor heat tolerance, fever, hyperhidrosis;

- tachycardia, arrhythmia;

- dyspnea;

- tremor, increased tendon reflexes;

- unstable stool, nausea.

The varying sensitivity of individual systems to the action of thyroid hormones is the reason why, initially with a moderate dose increase, certain symptoms come to the foreground.

In the majority of cases, palpitations and tachycardia are among the first symptoms, which may remain the only ones for a long time. Subclinical thyrotoxicosis develops. The monosymptomatic nature of the disorder is an important sign of the early phase in the clinical picture, and this should be kept in mind to prevent the progression of the disorder if treatment is continued.

If the emerging disorders are left without due attention from the patient and physician, the clinical presentation progresses and manifests with typical symptoms of thyrotoxicosis [41,42,44].

1.6.4 Other forms of thyrotoxicosis

The clinical picture of TSH-secreting pituitary adenomas may manifest only as a hyperthyroidism syndrome similar to the manifestation of diffuse toxic goiter, making early diagnosis of the pituitary tumor difficult. With extrasellar growth, the clinical picture shows symptoms of compression of the chiasmal-sellar region: visual and oculomotor disturbances, cephalgic syndrome, etc. [41,46]. Most of the tumors described in the literature are macroadenomas with an aggressively infiltrative growth pattern that are difficult to remove radically.

1.6.5 Thyrotoxic crisis

The crisis generally develops within a few hours, less often gradually over several days. Agitation and tachycardia increase, arrhythmia appears, temperature and systolic blood pressure rise, and diastolic blood pressure decreases. With the further development of the crisis, a decrease in both systolic and diastolic blood pressure is noted, and signs of heart failure increase. Patients experience insomnia, vomiting, diarrhea, sweating, fear, nervousness, irritability, fatigue, weakness, severe headache, oliguria, facial flushing, rapid breathing, suffocation, severe motor restlessness, and chaotic movements, which are replaced by adynamia and apathy, up to a comatose state [8,41,47].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition

The diagnosis is established based on the following criteria:

1) patient complaints;

2) anamnesis data;

3) physical examination;

4) laboratory tests;

5) instrumental examinations.

2.1 Complaints and Anamnesis

2.1.1 Diffuse toxic goiter (Graves' disease)

2.1.2 Thyrotoxicosis with ectopic thyroid tissue

2.1.3 Factitious thyrotoxicosis

2.1.4 Other forms of thyrotoxicosis

2.1.5 Thyroid storm or coma

2.2 Physical Examination

2.2.1 Diffuse toxic goiter (Graves' disease)

➣ perform a visual and palpation assessment of the thyroid gland size in accordance with the WHO classification (2001):

Grade 0: goiter is not palpable, the volume of the lobes does not exceed the volume of the subject's distal phalanx.

Grade 1: goiter is palpable, exceeds the volume of the subject's distal phalanx, but is not visible with the neck in a normal position; there is no visible enlargement of the thyroid gland. This also includes nodules that do not lead to an enlargement of the thyroid gland itself.

Grade 2: goiter is clearly visible with the neck in a normal position [7].

➣ record the presence of ocular symptoms in the patient;

➣ assess the condition of the patient's skin (warm and moist), determine dermographism (pronounced persistent red);

➣ record the presence of neurological symptoms (fine tremor of fingers, tongue, and eyelids, instability in the Romberg test, "telegraph pole" sign);

➣ perform a pulse examination, measurement of blood pressure on peripheral arteries, and measurement of heart rate;

➣ anthropometric measurements (measurement of body weight, measurement of height).

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

2.2.2 Thyrotoxicosis with ectopic thyroid tissue

2.2.3 Factitious thyrotoxicosis

Physical examination findings are described in Section 1.6 "Clinical presentation of the disease or condition (group of diseases or conditions)".

2.2.4 Other forms of thyrotoxicosis

The clinical presentation of small pituitary thyrotropinomas may manifest solely as a hyperthyroidism syndrome, similar to the manifestation of Graves' disease, which makes early diagnosis of a pituitary tumor difficult.

2.2.5 Thyroid storm or coma

Physical examination findings are described in Section 1.6 "Clinical presentation of the disease or condition (group of diseases or conditions)".

2.3 Laboratory Diagnostics

2.3.1 Diffuse toxic goiter (Graves' disease)

Comments: the TSH concentration in thyrotoxicosis should be low (< 0.1 mIU/L), while serum fT4 and fT3 levels are elevated. In some patients, a decrease in TSH levels is observed without an increase in blood thyroid hormone concentrations. This condition is regarded as subclinical hyperthyroidism.

Comments: TRAb detection is found in 99-100% of patients with autoimmune thyrotoxicosis. During treatment or spontaneous remission of the disease, antibodies may decrease, disappear, or change their functional activity, acquiring blocking properties. Classical antibodies—antibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb)—are detected in 40-60% of patients with autoimmune thyrotoxicosis.

Comment: determining blood levels of TPOAb and TgAb is performed solely for the differential diagnosis of autoimmune and non-autoimmune thyrotoxicosis [1,2].

2.3.2 Thyrotoxicosis with ectopic thyroid tissue

2.3.3 Factitious thyrotoxicosis

2.3.4 Other forms of thyrotoxicosis

2.3.5 Thyroid storm or coma

2.4 Instrumental Diagnostics

2.4.1 Diffuse toxic goiter (Graves' disease)

Comments: radioisotope testing (scintigraphy) is used as a functional imaging method for the thyroid gland. Radiopharmaceuticals (RP) based on iodine and technetium isotopes are used for this purpose. An exceptional advantage of radioisotope diagnostics is the ability to obtain information on the functional activity of thyroid tissue. In Graves' disease, increased uptake and distribution of the radiopharmaceutical is observed throughout the entire thyroid gland. In functional autonomy, localized increased radiopharmaceutical uptake is noted in the actively functioning node(s) against the background of reduced radiopharmaceutical uptake in the surrounding thyroid tissue.

Comments: fine-needle aspiration biopsy is indicated for all palpable and non-palpable nodular formations; the risk of cancer is identical in solitary nodular formations and multinodular goiter.

1. Visometry;

2. Daily eye tonometry;

3. Orbital status examination (exophthalmometry, determination of eye movement range, palpebral fissure width, eyeball reposition);

4. Biomicroscopy of the eye;

5. Ophthalmoscopy;

6. Computer perimetry;

7. Magnetic resonance imaging of the orbit.

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: the activity and severity of TAO are assessed based on the analysis of examination results. The inflammatory phase of the disease involving the autoimmune process of the eye and orbital tissues determines TAO activity. The clinical activity score (CAS) developed by the European Group on Graves' Orbitopathy (EUGOGO) is used as the standard for assessing TAO activity (Appendix G1) [4,9]. A cumulative score of 3 or more on this scale corresponds to the active phase of the disease.

Comment: Endocrine orbitopathy activity should be evaluated with caution using ultrasound assessment of extraocular muscle thickness and density, and retrobulbar tissue density. This type of study does not allow assessing the state of the orbital apex, which is its important limitation.

2.4.2 Thyrotoxicosis with ectopic thyroid tissue

2.4.3 Factitious thyrotoxicosis

Comment: thyroid scintigraphy with radiopharmaceuticals reveals low uptake and its increase after TSH stimulation, which indicates complete functional rest of the thyroid gland.

Comments: electrocardiogram recording shows sinus tachycardia and rhythm disorders (atrial fibrillation, extrasystole).

2.4.4 Other forms of thyrotoxicosis

2.4.5 Thyroid storm or coma

2.5 Other Procedures

No.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Graves' disease. Medical therapy.

3.1.1 Selection of antithyroid drugs

Comments: according to American and European guidelines for the treatment of Graves' disease, #thiamazole** is the first-line antithyroid therapy in children [8,10]. In the Russian Federation, #thiamazole** is available in 5 or 10 mg tablets. The starting dose of #thiamazole** in children varies widely depending on age, as well as the severity of laboratory and clinical signs of thyrotoxicosis. The drug is taken orally after meals, without chewing, with a sufficient amount of liquid.

Comments: according to American and European guidelines for the treatment of Graves' disease, long-term therapy with #propylthiouracil in children is not performed due to hepatotoxicity. A short course of #PTU can be prescribed only if severe side effects of #thiamazole** are detected, as well as as part of preoperative preparation in cases of persistently high FT3 levels [8,10]. In the Russian Federation, #propylthiouracil is available in 50 mg tablets.

3.1.2 Dose titration during treatment, safety monitoring of antithyroid therapy

√ up to 1 year - 1.25 mg/day;

√ from 1 year to 5 years - 2.5 - 5 mg/day;

√ from 5 to 10 years - 5-10 mg/day;

√ 10 years and older - 10-30 mg/day.

In the presence of severe clinical and hormonal signs of thyrotoxicosis, a 2-fold increase in the maximum daily dose of #thiamazole** is possible [8,10].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comment: it is important to note that TSH normalization during antithyroid therapy is delayed (especially in younger children).

Comments: currently, there is no convincing data on a lower relapse rate in children when using the "titration" scheme compared to the "block-and-replace" regimen. However, American and European guidelines for the treatment of thyrotoxicosis prefer #thiamazole** monotherapy. In 10% of cases of Graves' disease in children, it proceeds with a prolonged, persistent increase in FT3 against the background of normalization or decrease in FT4. This group of patients is characterized by long-term persistent high titers of TSH receptor antibodies, a significant increase in thyroid volume, and achieving disease compensation takes significantly longer using high doses of antithyroid drugs [8,14].

Comments: patients with bronchial asthma should avoid taking beta-blockers, but if necessary, selective beta-blockers can be an alternative.

Comments: due to the delayed TSH increase during antithyroid therapy (especially in younger children and with long-standing uncompensated thyrotoxicosis) during the first 4-6 weeks of therapy, routine TSH testing is inappropriate; for #thiamazole** dose adjustment, blood serum FT4 and FT3 levels are used as a guide.

According to international consensus statements on the treatment of Graves' disease, it is inappropriate to perform routine monitoring of the complete blood count with differential leukocyte count (leukocyte formula), and determination of blood AST and ALT activity during antithyroid therapy [8,10,11]. However, in our opinion, it is rational to test these parameters during the first 2-3 months of therapy (when the child receives maximum doses of #thiamazole** and the probability of side effects is maximal).

3.1.3 Duration of antithyroid therapy

If stable remission of the disease is not achieved at least 36 months after the initiation of antithyroid therapy in a child with Graves' disease, radical treatment is recommended [8,11,16,17].

Comments: an alternative approach may be longer-term antithyroid therapy (up to 9-10 years) in situations where the use of radioiodine therapy or surgery is limited for one reason or another. In such situations, the issue of radical treatment should be re-evaluated every 6-12 months. Currently, there is a trend towards extending the duration of antithyroid therapy in children due to a higher rate of remission and minor side effects of #thiamazole** with long-term use. With long-term #thiamazole** therapy (for 9-10 years) remission of the disease is achieved 3 times more frequently compared to antithyroid therapy for 2 years, without an increase in the rate of side effects [16,17]. According to the European Thyroid Association guidelines, the optimal duration of therapy#with #thiamazole** in children should be at least 36 months, and prolonged therapy (5-10 years) may contribute to achieving remission in a larger number of children with Graves' disease [8,11].

3.1.4 Adverse effects of antithyroid therapy

The incidence of side effects from antithyroid therapy in children is 5-25%. Side effects of antithyroid drugs include minor ones (skin rash, arthralgia, myalgia, gastrointestinal disorders) and severe ones (agranulocytosis, toxic hepatitis, polyarthritis, and ANCA-associated vasculitis). The side effects of antithyroid drugs are dose-dependent (extremely rare at a daily dose of #thiamazole** of less than 10 mg) and most commonly manifest within the first 2-3 months of treatment, although they have also been described in the long-term period [17].

Comments: there are no exact data on the incidence of agranulocytosis (decrease in absolute neutrophil count below 0.5 × 10⁹/L) in children, but it is estimated to be extremely low. In adults, agranulocytosis develops in 0.1-1% of cases. The risk of developing agranulocytosis is highest during the first 100 days of antithyroid therapy and is associated with certain HLA haplotypes (HLA-B*38:02 and HLA-DRB1*08:03). To diagnose agranulocytosis, a complete (clinical) blood count with a differential white blood cell count (leukocyte formula) is necessary to assess the absolute neutrophil count. Following the discontinuation of antithyroid therapy, spontaneous normalization of hematological parameters occurs on average within 2-3 weeks (individual variability ranging from 3 to 56 days). In severe cases, colony-stimulating factors may be used.

Comments: the most severe side effect of antithyroid therapy, especially #PTU, is acute liver injury (cases of rapidly developing liver necrosis with hepatic failure have been described). #PTU should be discontinued if liver transaminase activity exceeds the upper limit of normal by 2-3 times during treatment and does not normalize within a week.

Comments: side effects of #thiamazole** therapy most often manifest as allergic reactions in the form of urticarial skin rash, less frequently as myalgia and arthralgia (incidence 1-5%). When severe allergic manifestations develop, the group of antithyroid drugs is changed, and the issue of the need for radical treatment is discussed with the child and their parents (legal representatives).

3.1.5 Criteria for discontinuing antithyroid therapy

Comments: the highest risk of thyrotoxicosis relapse after discontinuation of antithyroid therapy is observed in children with high TSH receptor antibody titers (more than 4 times the upper limit of normal) and high free T4 levels (more than 50 nmol/L) at disease onset, as well as manifestation at a young age (especially under 5 years) [16,19]. Unfavorable factors also include persistently elevated free T3 during antithyroid therapy, large thyroid volume, or lack of its reduction during antithyroid therapy [19].

Comments: the probability of stable remission is higher in patients who are in immunological remission (having TSH receptor antibody levels within the reference range). If elevated TSH receptor antibody titers persist, #thiamazole** therapy may be prolonged for up to 1 year with repeat TSH receptor antibody testing or consideration of radical treatment [11].

3.2 Diffuse toxic goiter. Surgical treatment.

The absolute advantage of this treatment method is the rapid elimination of thyrotoxicosis.

Comment: subtotal thyroidectomy is currently not used due to the potential recurrence of the autoimmune process in even a small remaining thyroid remnant.

Comment: the incidence of surgical complications during thyroidectomy is higher in children than in adults; in younger children, it is higher than in older children. Younger children have a higher risk of transient hypoparathyroidism compared to adolescents or adults.

The most frequent complication of surgical treatment (10-20% of cases) is transient hypocalcemia. In the vast majority of cases, it remains asymptomatic and unnoticed unless repeated measurements of blood ionized calcium levels are performed. The probability of developing permanent hypoparathyroidism in institutions specializing in thyroid surgery after thyroidectomy (in the case of primary thyroid surgery) is less than 2%. More frequent complications include keloid scar formation (2.8% of cases) and recurrent laryngeal nerve palsy (2% of cases).

Comment: the use of neuromonitoring allows mapping of the recurrent laryngeal nerve and thereby avoids its significant damage, although studies show this does not always prevent temporary "traction" palsy. An important task of using a neuromonitor during surgery is the prevention of bilateral laryngeal palsy, which can lead to prolonged tracheal intubation and placement of a temporary tracheostomy in the postoperative period. Such a situation, even if temporary, significantly worsens the patient's condition and well-being. At the same time, it has been established that in the vast majority of cases, vocal cord palsy is not permanent and resolves without additional measures or after neurophoniatric rehabilitation.

After surgical treatment, the majority of patients develop hypothyroidism, requiring lifelong therapy with levothyroxine sodium**. In case of incomplete thyroidectomy, recurrence of thyrotoxicosis is possible, therefore prolonged follow-up is necessary.

Comments: the criterion for an adequate dose is a free calcium level not exceeding 1.2 mmol/L for 10 days; after selecting the adequate dose, calcium monitoring is carried out constantly 1 time every 2–4 weeks, and dose adjustment is performed if necessary. Additionally, calcium preparations are prescribed to ensure sufficient calcium intake into the body [8,26].

3.3 Graves' disease. Radioiodine therapy.

The advantages of this type of therapy are ease of use, good tolerability, and the absence of side effects associated with surgical treatment. #Sodium iodide [131I] therapy should be used with caution in severe ophthalmopathy and very large thyroid gland sizes.

Comment: medical treatment with antithyroid drugs is usually stopped 10 days before the administration of #sodium iodide [131I] (in cases of severe thyrotoxicosis, treatment may be stopped 3–5 days prior).

The goal of #sodium iodide [131I] therapy in Graves' disease is to achieve hypothyroidism (not euthyroidism), since #sodium iodide [131I] activity below a certain level causes low-dose irradiation of the thyroid tissue and increases the likelihood of disease recurrence [27].

1. All children are prescribed a fixed activity of #sodium iodide [131I] of 15 mCi.

2. Activity is calculated based on the size of the thyroid gland and the #sodium iodide [131I] uptake test [8,10,11,28].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: in patients with a very large goiter, there is a risk of insufficient efficacy of the performed radioiodine therapy due to limitations on the maximum dose of #sodium iodide [131I] caused by the potential development of radiation-induced complications. Therefore, in patients with a thyroid size greater than 80 cm³, surgical treatment is considered preferable.

There is no convincing data on the higher efficacy of administering a dosimetrically calculated activity of #sodium iodide [131I] in children. Provided that the administered activity of #sodium iodide [131I] is > 150 µCi per 1 g of thyroid tissue, the incidence of hypothyroidism is about 95 %. At the same time, the personalized dosimetric approach to radioiodine therapy planning aims to reduce the radiation dose received by the body in cases where a fixed dose proves excessive for a specific patient.

Comments: #Sodium iodide [131I] is excreted from the body mainly in the urine, and to a lesser extent in saliva and feces. Significant radioactivity persists in the thyroid gland for several days after treatment. Thyroid hormone levels in children begin to decrease within the first week after #sodium iodide [131I] therapy. Although some pediatric endocrinologists resume antithyroid drug treatment after #sodium iodide [131I] therapy (7–10 days later), this is rare in pediatric practice. The administration of antithyroid drugs can make it difficult to assess the patient's condition, which in such cases may be related to the use of #thiamazole** rather than #sodium iodide [131I] therapy. TSH levels may remain suppressed for a long time. Hypothyroidism usually develops 2–3 months after treatment.

Comments: Side effects of #sodium iodide [131I] therapy in children are rare, aside from the development of hypothyroidism, which is actually the goal of therapy. Less than 10 % of children complain of mild tenderness over the thyroid gland during the first week after therapy; this can be effectively managed with nonsteroidal anti-inflammatory and antirheumatic drugs. 4–10 days after #sodium iodide [131I] therapy, thyroid hormone levels may rise due to the release of previously synthesized hormones from the destroying thyroid gland; beta-blockers may be prescribed during this period [31,32].

3.4 Treatment of endocrine ophthalmopathy in children

The basis of endocrine ophthalmopathy therapy is maintaining stable euthyroidism.

Comments: for oral administration to achieve a therapeutic effect, glucocorticoids must be prescribed in a sufficiently high dose for a prolonged period of time, which is associated with frequent side effects of therapy (onset of secondary alternating strabismus, severe extraocular muscle complications) and the development of refractory forms of TED, and therefore this therapy is not used in children. Retrobulbar glucocorticoid injections have lower (no more than 40%) and short-lived efficacy [36]. Glucocorticoids should be prescribed for the treatment of active TED in children with caution, taking into account the risks of potential side effects, which requires an individualized approach.

Comments: in most cases, TED in children has a mild course with a tendency to spontaneous remission without specific treatment, against the background of achieving a stable euthyroid state. Clinical manifestations similar to those in adults with TED and moderate TED are more common in adolescence. Smoking (both active and passive) has a negative impact on the course of TED.

3.5 Treatment of thyrotoxicosis with ectopic thyroid tissue

3.6 Treatment of artificial thyrotoxicosis: drug-induced thyrotoxicosis, iatrogenic thyrotoxicosis, thyroid hormone overdose

3.7 Treatment of other forms of thyrotoxicosis – thyroid-stimulating hormone hypersecretion

3.8 Treatment of thyrotoxic crisis

Treatment must be multi-component. By its direction of action, it can be divided as follows:

1) reduction of circulating thyroid hormone levels;

2) attenuation of the peripheral action of thyroid hormones;

3) maintenance of vital functions;

4) therapy targeting the provoking factor;

5) radical treatment of thyrotoxicosis.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: the results of the analysis of literature sources indicate the need to create psychological support programs for adolescents with chronic somatic diseases and their families, taking into account the crisis period of learning about the diagnosis, nosological affiliation of the disease, personality traits of the adolescent, including self-esteem and anxiety level, features of family interaction, family composition, and adherence to treatment. In addition, from the onset of the disease and until sustainable compensation is achieved, parents play a key role in establishing a regimen, diet, and medication intake that comply with the doctor's prescriptions. From this perspective, optimizing parent-child relationships can be a central task of a medical psychologist at the stage of achieving control over high-vital-risk diseases. Here, a medical psychologist can be useful in the context of psychological counseling for both parents and the pediatric service.

Comments: damage to the recurrent laryngeal nerve is possible in the postoperative period after thyroidectomy. In the event of symptoms of recurrent laryngeal nerve conduction impairment, the patient is indicated for neurophoniatric rehabilitation, which significantly improves voice, breathing, and swallowing after complicated surgeries in the thyroid gland projection. To achieve the maximum possible effect, neurophoniatric rehabilitation should be performed before irreversible changes occur in the laryngeal muscles, i.e., no later than two to three months after surgery.

5. Prevention and Dispensary Observation

No preventive measures have been developed.

DISPENSARY OBSERVATION OF CHILDREN WITH THYROTOXICOSIS SYNDROME.

6. Organization of Medical Care

Elective hospitalization. Inpatient / day hospital care.

Indications for elective hospitalization in a medical organization (hospital):

- thyroid dysfunction refractory to outpatient correction.

Indications for discharge from a medical organization (hospital):

- a sustained improvement in the patient's condition, allowing them to continue treatment safely in an outpatient clinic or at home.

The prognosis is determined by the presence of concomitant severe somatic pathology in the patient.

7. Additional Information

None.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

LEADERS:

Peterkova Valentina Aleksandrovna – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Scientific Director of the Institute of Pediatric Endocrinology at the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Head of the Department of Pediatric Endocrinology and Diabetology at the Institute of Higher and Continuing Professional Education of the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Russian Ministry of Health.

Bezlepkina Olga Borisovna – Doctor of Medical Sciences, Deputy Director of the Center – Director of the Institute of Pediatric Endocrinology at the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Professor of the Department of Pediatric Endocrinology and Diabetology at the Institute of Higher and Continuing Professional Education of the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

AUTHORS OF THE TEXT:

Nagaeva Elena Vitalievna – Doctor of Medical Sciences, Head of the Department of Thyroidology, Reproductive and Somatic Development at the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Shiryaeva Tatyana Yuryevna – Candidate of Medical Sciences, Associate Professor, Leading Research Fellow at the Department of Thyroidology, Somatic and Reproductive Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Okorokov Pavel Leonidovich – Candidate of Medical Sciences, Senior Research Fellow at the Department of Thyroidology, Somatic and Reproductive Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Chikulaeva Olga Aleksandrovna – Candidate of Medical Sciences, Leading Research Fellow at the Department of Thyroidology, Somatic and Reproductive Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Brovin Dmitry Nikolaevich – Candidate of Medical Sciences, Head of the Pediatric Surgery Department, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Sheremeta Marina Sergeevna – Candidate of Medical Sciences, Head of the Radionuclide Therapy Department, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Associate Professor at the Department of Endocrinology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Bessmertnaya Elena Grigorievna – Candidate of Medical Sciences, Leading Research Fellow at the Department of Diabetic Retinopathy and Ophthalmic Surgery, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Vasyukova Olga Vladimirovna - Candidate of Medical Sciences, Leading Researcher, Department of Thyroidology, Reproductive and Somatic Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Bricheva Ella Bayzetovna - Pediatric Endocrinologist, Postgraduate Student, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

EXPERTS:

Bashnina Elena Borisovna - Doctor of Medical Sciences, Professor, Department of Endocrinology named after Academician V.G. Baranov, North-Western State Medical University named after I.I. Mechnikov, Chief freelance pediatric specialist endocrinologist of the North-Western Federal District.

Galkina Galina Aleksandrovna - Doctor of Medical Sciences, Head of the Pediatric Endocrinology Department, Research Institute of Obstetrics and Pediatrics, Rostov State Medical University of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Rostov Region, Chief freelance pediatric specialist endocrinologist of the Southern Federal District.

Kiyaev Aleksey Vasilyevich - Doctor of Medical Sciences, Professor, Department of Hospital Pediatrics, Ural State Medical University of the Russian Ministry of Health, Head of the Center for Pediatric Endocrinology, Regional Children's Clinical Hospital, Chief freelance pediatric specialist endocrinologist of the Sverdlovsk Region, Chief freelance pediatric specialist endocrinologist of the Ural Federal District.

Kostrova Irina Borisovna - Head of the Pediatric Endocrinology Department, Republican Children's Clinical Hospital named after N.M. Kuraev, Chief freelance pediatric specialist endocrinologist of the Republic of Dagestan, Chief freelance pediatric specialist endocrinologist of the North Caucasian Federal District.

Kolodkina Anna Aleksandrovna - Candidate of Medical Sciences, Head of the Department of Hereditary Diseases and Early-Onset Endocrinopathies, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Malievsky Oleg Arturovich - Doctor of Medical Sciences, Professor, Department of Hospital Pediatrics, Bashkir State Medical University of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Privolzhsky Federal District.

Petryaikina Elena Efimovna - Doctor of Medical Sciences, Director of the RSSP, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of Moscow, Chief freelance pediatric specialist endocrinologist of the Central Federal District.

Svetlova Galina Nikolaevna - Candidate of Medical Sciences, Deputy Chief Physician, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Taranushenko Tatyana Evgenyevna - Doctor of Medical Sciences, Head of the Department of Pediatrics, Institute of Postgraduate Education, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Krasnoyarsk Territory, Chief freelance pediatric specialist endocrinologist of the Siberian Federal District.

Chugunov Igor Sergeevich - Candidate of Medical Sciences, Head of the Pediatric Department of Endocrine System Tumors, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Shapkina Lyubov Aleksandrovna - Doctor of Medical Sciences, Professor, Institute of Therapy and Instrumental Diagnostics, Pacific State Medical University of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Far Eastern Federal District.

Conflict of interest: the authors of the clinical guidelines declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Pediatric endocrinologists;

2. Pediatricians;

3. General practitioners (family physicians).

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Current instructions for medicinal products mentioned in the clinical guidelines are available at http://grls.rosminzdrav.ru

2. Order of the Ministry of Health of the Russian Federation No. 583n dated October 29, 2024 'On approval of the Procedure for the provision of medical care in the profile of "pediatric endocrinology".'

Thyroid volume in women should not exceed 18 ml, and in men, 25 ml. Currently, there are no universally accepted standards for assessing thyroid volume in children using ultrasound data, which causes certain discrepancies in interpreting the results. In accordance with WHO recommendations (1997), it is proposed to take into account the child's body surface area (m²), however, the developed thyroid volume standards were used predominantly in epidemiological studies (Appendix A3. Table 1). Methods for diagnosing goiter in children by comparing the thyroid volume obtained during ultrasound examination with body weight and age-specific standards are known ("Methodology for ultrasound examination of the thyroid and parathyroid glands in adults and children", Methodological recommendations for ultrasound diagnostics physicians dated 26.11.2019) (Appendix A3. Tables 2, 3). Thus, in pediatric and adolescent practice, the interpretation of volume magnitude is performed by the clinician. In clinical practice in children, thyroid volumetry in Graves' disease is of greatest interest primarily from the standpoint of dynamic volume assessment during follow-up and treatment. The echogenicity of the gland is medium, the echostructure is usually diffusely homogeneous, and blood supply is enhanced. In the presence of nodular/multinodular goiter, formations in the thyroid gland are detected.

A3.1 Normative values of thyroid volume in children for epidemiological studies (upper limit of normal values - 97th percentile, WHO, 1997)

A3.2 Total thyroid volume in infants with a body weight under 5 kg

A3.3 Total thyroid volume in children older than 6 months and with a body weight over 5 kg

Appendix B. Physician Action Algorithms

Algorithm for the diagnosis and management of a patient with Graves' disease in childhood [41]

Appendix C. Patient Information

Patient information leaflet.

What is the thyroid gland and what are thyroid hormones, and what are they needed for?

The thyroid gland is an endocrine organ located on the anterior surface of the neck, shaped like a butterfly. Despite its small size, it plays an important role in the proper functioning of the entire body. The hormones it produces (thyroxine and triiodothyronine) regulate numerous processes in the human body. The proper production of these hormones is controlled by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland, a small gland located at the base of the brain.

What is thyrotoxicosis?

Thyrotoxicosis is a condition of the body caused by an excessive content of thyroid hormones in the blood and their toxic effect on various organs and tissues; it is also referred to as "thyroid hormone poisoning".

What are the clinical manifestations of thyrotoxicosis?

Regardless of the cause of thyrotoxicosis, it is characterized by the following clinical manifestations:

• a feeling of tightness in the neck area;

• palpitations and heart rhythm disturbances;

• high blood pressure;

• increased sweating and sensations of elevated body temperature;

• tremor of the hands;

• nervousness, anxiety, and sleep problems (insomnia);

• weight loss;

• frequent bowel movements, sometimes with diarrhea;

• in girls, menstruation becomes irregular or stops.

"Eye" manifestations may also be observed:

• swelling and redness around the eyes;

• profuse lacrimation;

• irritation and increased sensitivity to light;

• exophthalmos;

• diplopia.

What are the causes of thyrotoxicosis?

The most common causes include:

• Diffuse toxic goiter (Graves' disease);

• Thyroid neoplasms (nodules);

• Thyroid inflammation (thyroiditis);

• Certain medications.

How is thyrotoxicosis diagnosed?

First, it is necessary to assess the patient's complaints, measure the heart rate and blood pressure, examine the neck area, evaluate its size, and check for «eye signs». This makes it possible to suspect thyrotoxicosis. Next, blood levels of thyroid hormones must be checked. In thyrotoxicosis, these levels are elevated.

How is thyrotoxicosis treated?

Thyrotoxicosis is treated using specialized medications that lower blood thyroid hormone levels. Treatment with these drugs must continue for at least 3 years under the supervision of a pediatric endocrinologist. If such treatment proves ineffective, thyroid surgery or radioactive iodine therapy may be performed.

What can be done to prevent the development of thyrotoxicosis?

There are no specific methods for preventing thyrotoxicosis.

Which doctor should I consult if I suspect thyrotoxicosis in my child?

Thyrotoxicosis is treated by pediatric endocrinologists, but you can start by visiting a pediatrician or general practitioner (family doctor).

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Clinical Activity Score (CAS) for endocrine ophthalmopathy

Russian title: Clinical Activity Score (CAS) for endocrine ophthalmopathy.

Original title: Clinical Activity Score (CAS).

Source: Dedov I.I., Melnichenko G.A., Belovalova I.M. et al. Federal clinical guidelines for the diagnosis and treatment of endocrine ophthalmopathy in autoimmune thyroid pathology; Moscow; 2014, p. 17.

Type: rating scale.

Purpose: evaluation of clinical symptoms to assess the activity grade of thyroid eye disease (TED).

Content (template) and interpretation key:

For initial CAS, items 1-7 are evaluated:

1. spontaneous retrobulbar pain;

2. pain on attempted eye movement;

3. eyelid erythema;

4. conjunctival injection;

5. eyelid edema;

6. chemosis;

7. swelling and redness of the plica semilunaris and caruncle.

   For patients during follow-up, additional signs are evaluated:

8. Increase in exophthalmos by more than 2 mm over the past 2 months.

9. Decrease in eye mobility by more than 8° in any direction over the past 2 months.

10. Decrease in visual acuity by more than 0.1 over the past 2 months.

Notes: TED is considered inactive if 1 - 2 points are present, and active if 3 or more points are present (CAS > 3/7-10).

APPENDIX G2. NOSPECS classification for severity assessment of endocrine ophthalmopathy

Russian title: severity grading (NOSPECS) of endocrine ophthalmopathy.

Original title: NOSPECS.

Source: Dedov I.I., Melnichenko G.A., Belovalova I.M. et al. Federal clinical guidelines for the diagnosis and treatment of endocrine ophthalmopathy in autoimmune thyroid pathology; Moscow; 2014, p. 17.

Type: rating scale.

Purpose: evaluation of clinical symptoms to assess the severity of thyroid eye disease.

Content (template) and interpretation key:

Each letter in the name corresponds to a specific class of eye involvement: