Thyrotoxicosis with diffuse goiter (Graves' disease), nodular/multinodular goiter: clinical guidelines

List of Abbreviations

Terms and Definitions

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

Diffuse toxic goiter (Graves' disease) is an autoimmune disease that develops as a result of the production of stimulating antibodies to the thyroid-stimulating hormone receptor (TSHR-Ab).

Nodular/multinodular goiter is a disease arising from the development of functional autonomy (independent of TSH) of thyroid nodules.

Endocrine ophthalmopathy (EO) is an independent autoimmune disease closely associated with autoimmune thyroid pathology.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Graves' disease (GD, thyrotoxicosis with diffuse goiter) is an organ-specific autoimmune disease developing as a result of the production of stimulating TSHR-Abs, clinically manifested by diffuse thyroid involvement with the development of thyrotoxicosis syndrome combined with extrathyroidal pathology (EO, pretibial myxedema, acropachy).

Nodular/multinodular toxic goiter (thyrotoxicosis with nodular/multinodular goiter; NTG) is a thyroid disease clinically manifested by nodular involvement of the thyroid with the development of thyrotoxicosis syndrome due to autonomous, TSH-independent functioning of thyroid nodules.

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

Endogenous hyperthyroidism most commonly occurs as a result of Graves' disease or a thyroid nodule. GD is a form of thyrotoxicosis caused by hypersecretion of thyroid hormones under the influence of TSHR-Abs [1–4]. TSHR-Abs are predominantly of the IgG1 isotype and bind to an epitope of the extracellular domain of the TSHR [5]. TSHR interacts with the insulin-like growth factor 1 receptor (IGF-1R) on the surface of thyrocytes and orbital fibroblasts, with TSHR-Abs activating both downstream IGF-1R pathways and TSHR activation [6]. Circulating stimulating TSHR-Abs, by binding to TSHR, enhance the production of intracellular cyclic adenosine monophosphate (cAMP), which leads to the release of thyroid hormones and thyrocyte proliferation. About 30% of patients with GD have family members who also have GD or Hashimoto's thyroiditis. Twin studies have shown that 80% of susceptibility to GD is genetic [7]. Well-established associations exist between major histocompatibility complex alleles and GD, with susceptibility conferred by the HLA-DR3 and HLA-DR4 haplotypes [8]. Other susceptibility loci where the association has been replicated include cytotoxic T-lymphocyte antigen-4, protein tyrosine phosphatase non-receptor type 22, leucine zipper transcription factor-like 1, and CD40 loci [9]. Environmental factors such as cigarette smoking, stress, and pregnancy also predispose to GD [10, 11]. In regions with normal iodine intake, GD is the most frequent disease in the nosological structure of thyrotoxicosis syndrome.

In iodine-deficient areas, the most frequent cause of thyrotoxicosis is the functional autonomy of thyroid nodules [12–13]. Autonomy can be defined as the functioning of thyroid follicular cells in the absence of the main physiological stimulator, pituitary TSH. With functional autonomy, thyroid cells escape pituitary control and synthesize hormones in excessive amounts. If the production of thyroid hormones by autonomous formations exceeds physiological needs, the patient will develop thyrotoxicosis. This may occur as a result of the natural course of nodular goiter or after the intake of additional amounts of iodine from iodine supplements or iodine-containing medications. The process of functional autonomy development lasts for years and leads to clinical manifestations of thyrotoxicosis, mainly in older individuals (over 45 years of age).

In addition to the above, causes of thyrotoxicosis can include extrathyroidal factors: endogenous (struma ovarii, metastatic variant of differentiated thyroid cancer, etc.) and exogenous (levothyroxine overdose).

1.3 Epidemiology of the Disease or Condition

The most frequent causes of thyrotoxicosis are GD and nodular/multinodular toxic goiter. GD is the most common cause of thyrotoxicosis in iodine-rich geographic areas, where 20–30 cases per 100,000 population are registered annually [14]. In 2001, the prevalence of thyrotoxicosis in Russia was 18.4 cases per 100,000 population [15]. According to the American Thyroid Association (ATA), in 2011 the prevalence of thyrotoxicosis was 1.2–1.6%, overt thyrotoxicosis 0.5–0.6%, and subclinical thyrotoxicosis 0.7–1.0% [16]. GD is more common in women and has a population prevalence of 1–1.5%. Approximately 3% of women and 0.5% of men develop GD during their lifetime [17]. The peak incidence of GD occurs in patients aged 30–60 years, with an increased incidence observed among African Americans [18].

1.4 Features of Coding the Disease or Condition

E05.0 Thyrotoxicosis with diffuse goiter.

E05.1 Thyrotoxicosis with toxic single thyroid nodule.

E05.2 Thyrotoxicosis with toxic multinodular goiter.

E05.3 Thyrotoxicosis with ectopic thyroid tissue.

E05.4 Factitious thyrotoxicosis.

E05.5 Thyrotoxic crisis or coma.

E05.8 Hypersecretion of thyrotropic hormone.

1.5 Classification of the disease or condition

Table 1. Classification of goiter (WHO, 2001)

Table 2. Classification of thyrotoxicosis by severity of clinical manifestations

1.6 Clinical presentation of the disease or condition

History and symptoms.

Patients with thyrotoxicosis complain of increased excitability, emotional lability, tearfulness, anxiety, sleep disturbances, restlessness, impaired concentration, weakness, sweating, palpitations, body tremors, and weight loss. Patients frequently note thyroid enlargement, frequent stools, menstrual irregularities, and decreased potency. Very often, patients complain of muscle weakness [19]. Cardiac effects of thyrotoxicosis pose a serious danger to elderly individuals [20, 21]. Atrial fibrillation is a formidable complication of thyrotoxicosis. Atrial fibrillation develops not only in individuals with overt, but also with subclinical thyrotoxicosis, especially those with comorbid cardiovascular pathology [22, 23]. Initially, atrial fibrillation is usually paroxysmal, but with persistent thyrotoxicosis, it becomes permanent. Patients with thyrotoxicosis and atrial fibrillation have an increased risk of thromboembolic complications [24]. In long-standing thyrotoxicosis, patients may develop dilated cardiomyopathy, which causes a decrease in cardiac functional reserve and the appearance of heart failure symptoms [25, 26]. Approximately 40–50% of patients with GD develop EO, which is characterized by damage to the soft tissues of the orbit: retrobulbar fat, extraocular muscles with involvement of the optic nerve, and the accessory apparatus of the eye (eyelids, cornea, conjunctiva, lacrimal gland). Patients develop spontaneous retrobulbar pain, pain with eye movements, eyelid erythema, eyelid edema or swelling, conjunctival hyperemia, chemosis, proptosis, and restriction of extraocular muscle mobility. The most severe complications of EO are optic neuropathy, keratopathy with corneal leucoma formation, corneal perforation, ophthalmoplegia, and diplopia [27].

The development of functional autonomy, predominantly in elderly individuals, determines the clinical features of this disease. The clinical picture is usually dominated by cardiovascular and psychiatric disorders: apathy, depression, loss of appetite, weakness, palpitations, cardiac rhythm disturbances, and symptoms of circulatory insufficiency [28–30]. Concomitant cardiovascular diseases, digestive tract pathology, and neurological disorders mask the underlying cause of the disease.

Unlike functional autonomy of thyroid nodules, which is characterized by a long, multi-year history of nodular/multinodular goiter, GD typically has a short history: symptoms develop and progress rapidly and in most cases bring the patient to a physician within 6–12 months from the onset of the disease.

Physical examination.

External manifestations: patients appear anxious, restless, and fidgety. The skin is warm and moist. Depigmented areas (vitiligo) are sometimes observed on certain parts of the skin. Hair is thin and brittle, and nails are soft, ridged, and brittle. In some cases, dermopathy or pretibial myxedema is observed.

Palpation of the thyroid gland: in Graves' disease, the thyroid gland is diffusely enlarged in 80% of cases, of moderate consistency, painless, and mobile. When a stethoscope is applied to it, a systolic bruit can be auscultated, which is caused by a significant increase in the organ's blood supply. In nodular/multinodular goiter, focal lesions are palpable within the thyroid gland.

Cardiovascular system: examination reveals tachycardia, widened pulse pressure, systolic murmur, systolic hypertension, and atrial fibrillation. Although all these changes are present in the majority of patients with thyrotoxicosis, atrial fibrillation takes precedence in terms of clinical significance, developing in 5–15% of patients. This percentage is higher among elderly patients and those with pre-existing organic heart disease. Coronary artery disease, hypertension, and heart valve defects can cause rhythm disturbances on their own; in such cases, thyrotoxicosis merely accelerates this process. There is a direct correlation between atrial fibrillation and the severity and duration of the disease. At the onset of the disease, atrial fibrillation is paroxysmal in nature, but as thyrotoxicosis progresses, it can become permanent. With effective treatment of thyrotoxicosis, sinus rhythm is most often restored after euthyroidism is achieved. In patients with pre-existing heart disease or a longer duration of atrial fibrillation, sinus rhythm is restored much less frequently. Atrial flutter is relatively rare (1.2–2.3%), extrasystoles occur in 5–7% of cases, and paroxysmal tachycardia in 0.2–3.3% of cases. Sinus bradycardia is rare and may be associated with congenital changes or exhaustion of the sinus node function and the development of sick sinus syndrome.

Atrial fibrillation can cause vascular thromboembolism, especially cerebral thromboembolism, which requires anticoagulant therapy [31, 32]. In elderly patients, thyrotoxicosis may coexist with coronary artery disease (CAD) [33]. An increase in heart rate (HR) and myocardial oxygen demand can unmask latent angina pectoris and lead to decompensation of heart failure. Cardiovascular involvement in thyrotoxicosis determines the severity and prognosis of the disease. Moreover, the state of the cardiovascular system after the elimination of thyrotoxicosis will determine the quality of life and working capacity of the "recovered" individual. It is known that in thyrotoxicosis, even at rest, the myocardium develops hyperfunction, thereby supplying the body with increased oxygen demands. On the other hand, during physical exertion or in a critical situation, the myocardium must sharply increase its work, i.e., use its functional reserve. The body's adaptation to increased demands in thyrotoxicosis depends precisely on the functional reserve of the heart. In patients with thyrotoxicosis, the functional reserve of the heart is significantly reduced, but upon achieving euthyroidism, it increases without reaching the baseline level, which under certain conditions may determine the subsequent development of heart failure.

Gastrointestinal tract: despite an increased appetite, thyrotoxicosis is characterized by progressive weight loss. Rarely, against the background of uncompensated thyrotoxicosis, weight may increase, while patients show elevated levels of immunoreactive insulin with normal C-peptide levels.

Musculoskeletal system: disorders manifest as progressive weakness, proximal muscle atrophy, tremor of small muscle groups throughout the body ("telegraph pole" sign), the development of periodic transitory paralyses and paresis, decreased myoglobin content, and an increased risk of fractures [34, 35].

Central nervous system: increased reflex conduction velocity and tremor of the fingers of outstretched hands (Marie's sign) are noted.

Ocular symptoms associated with thyrotoxicosis:

• Graefe's sign – lagging of the upper eyelid behind the upper limbus when looking down (due to hypertonus of the levator palpebrae superioris muscle);

• Kocher's sign – lagging of^{+0} the upper eyelid behind the upper limbus when looking up, with the upper eyelid moving upward faster than the eyeball;

• Dalrymple's sign – widening of the palpebral fissure with the appearance of a white strip between the upper limbus and the upper eyelid margin (lid retraction);

• Stellwag's sign – infrequent blinking of the eyelids combined with widening of the palpebral fissure. Normally, healthy people blink 3 times per minute.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing diffuse toxic goiter based on pathognomonic findings:

1. anamnestic data

2. physical examination

3. laboratory tests

4. instrumental examination.

Criteria for diagnosing nodular/multinodular goiter based on pathognomonic findings:

1. anamnestic data

2. physical examination

3. laboratory tests

4. instrumental examination.

2.1 Complaints and Anamnesis

(section 1.6) regarding increased excitability, emotional lability, tearfulness, anxiety, sleep disturbances, fidgety behavior, impaired concentration, weakness, sweating, palpitations, shortness of breath, heart rhythm disorders, body tremors, weight loss, thyroid enlargement, frequent stools, menstrual irregularities, decreased libido, muscle weakness, and exophthalmos. In Graves' disease, the medical history is short. In toxic nodular goiter / toxic multinodular goiter, there is a long-standing history of nodular goiter spanning many years.

2.2 Physical Examination

(section 1.6) Thyroid enlargement, tachycardia, atrial fibrillation or flutter, hand and body tremors, exophthalmos, lid retraction, strabismus, pretibial myxedema.

2.3 Laboratory Diagnostics

2.3.1. Laboratory diagnostic tests in Graves' disease

Comments. Blood thyroid-stimulating hormone (TSH) testing has the highest sensitivity and specificity of any single blood test used when thyrotoxicosis is suspected and should be used as the initial screening test. In thyrotoxicosis, the thyroid-stimulating hormone (TSH) level should be low (<0.1 mIU/L).

Comments. In overt thyrotoxicosis, an elevated level of blood fT4 and/or fT3 is detected. In subclinical thyrotoxicosis, serum levels of fT4 and fT3 are within the normal range. There may be cases where only serum fT3 is elevated while fT4 is normal and TSH is low. Such laboratory findings are termed "T3 thyrotoxicosis".

Comments. TSH receptor antibodies are specific biomarkers for Graves' disease. A meta-analysis of 21 studies showed that the sensitivity and specificity of serum TSH receptor antibody concentration measured using second- and third-generation binding assays were 97% and 98%, respectively [41]. During treatment or spontaneous remission of the disease, antibody levels may decrease or disappear. Furthermore, determining blood TSH receptor antibody levels is a highly sensitive prognostic biomarker for extrathyroidal manifestations of Graves' disease [42–45], as well as a useful prognostic indicator of fetal or neonatal hyperthyroidism [46].

Comments. Anti-TG and anti-TPO antibodies are detected in 40-60% of patients with Graves' disease and in approximately 80-90% of patients with autoimmune thyroiditis. In inflammatory and destructive processes of the thyroid gland of non-autoimmune origin, antibodies may be present, but their levels are usually low.

2.3.2. Laboratory diagnostic tests for toxic nodular/multinodular goiter.

Comments. TSH receptor antibodies are specific biomarkers of GD [40, 41, 47]. Measurement of blood TSH receptor antibody levels is performed as part of the differential diagnosis of STG and MTMG from GD.

2.4 Instrumental Diagnostics

2.4.1. Instrumental diagnostic investigations in Graves' disease.

Comments. Ultrasound is a convenient, non-invasive, rapid, and effective diagnostic method for patients with GD [48]. Ultrasound is used to evaluate thyroid volume and echostructure. Normally, thyroid volume should not exceed 18 ml in women and 25 ml in men, with medium echogenicity and homogeneous structure. Thyroid echogenicity in GD is decreased, and the echostructure is usually homogeneous. To assess thyroid blood flow, duplex ultrasound of thyroid vessels is performed. In GD, hypervascularity is observed [49–52].

Comments. CT, MSCT, and MRI help diagnose retrosternal goiter, clarify the relationship of the goiter to surrounding tissues, and detect displacement or compression of the trachea and esophagus. Barium swallow fluoroscopy is significantly less informative in this regard.

Comments. An important indication for thyroid scintigraphy is the differential diagnosis between thyroid hyperfunction in GD and conditions presenting with destructive thyrotoxicosis (autoimmune thyroiditis, subacute thyroiditis, amiodarone-induced thyrotoxicosis type 2). Unlike sodium pertechnetate [99mTc], which enters cells via the sodium-iodide symporter, #technetium [99mTc] sestamibi crosses the thyrocyte membrane via passive diffusion and accumulates in mitochondria; this rules out the effect of amiodarone**-induced iodine blockade on imaging and helps identify thyroid tissue destruction [55].

2.4.2. Instrumental diagnostic investigations in toxic adenoma / toxic multinodular goiter.

Comments. During ultrasound, thyroid volume and echostructure as well as the presence of nodular lesions are evaluated. The ultrasound report (covered in separate guidelines) should include descriptions of the location and size of thyroid lesions and lymph nodes, considering their sonographic characteristics.

Comments. Based on the uptake and distribution of the technetium isotope—Sodium pertechnetate [99mTc] and #Technetium [99mTc] sestamibi (185–370 MBq)—one can evaluate the functional activity of the thyroid gland, the pattern of its involvement (diffuse or nodular), the volume of residual tissue after resection or thyroidectomy, and the presence of ectopic tissue [52-56]. In functional autonomy, the actively functioning nodule(s) accumulate the isotope, while surrounding thyroid tissue is suppressed. In some cases, autonomy may be diffuse due to dissemination of autonomously functioning areas throughout the thyroid gland. In GD, diffusely increased uptake throughout the entire thyroid gland is observed.

Comments. CT, MSCT, and MRI help diagnose retrosternal goiter, clarify the relationship of the goiter to surrounding tissues, and detect displacement or compression of the trachea and esophagus. Barium swallow fluoroscopy is significantly less informative in this regard.

Fine-needle aspiration biopsy and cytological examination of thyroid tissue specimens are performed when thyroid nodules are present, as discussed in separate guidelines. If a thyroid nodule is detected in a patient with GD, it should be evaluated and managed in accordance with guidelines for euthyroid nodular goiter.

2.5 Other Procedures

Given the potential for comorbidities, the high risk of thyrotoxicosis complications, the need to assess and modify cardiovascular risk factors affecting treatment strategy, and to ensure the safe use of antithyroid medications in patients with thyrotoxicosis, additional evaluation is required when planning treatment.

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

Section introduction. Currently, there are three treatment modalities for thyrotoxicosis associated with diffuse/toxic nodular goiter:

• medical therapy;

• surgical treatment;

• RAI – radioiodine therapy with sodium iodide [131I]

3.1. Treatment of Graves' disease.

3.1.1. Medical treatment. [Appendix A3]

Medical therapy is prescribed to achieve euthyroidism prior to surgery or a course of RAI, as well as in selected patient groups as a definitive long-term (12–24 months) treatment course, which in some cases leads to sustained remission [14, 65–66]. Essential prerequisites for planning long-term antithyroid drug therapy include patient adherence to medical recommendations (compliance) and access to qualified endocrinology care.

Treatment goal: resolution of clinical symptoms of thyrotoxicosis, sustained normalization of thyroid hormones and TSH levels. Treatment of thyrotoxicosis caused by thyroid hormone hyperproduction begins with antithyroid drugs.

Non-pharmacological management. Until euthyroidism is achieved, physical exertion and iodine intake should be limited, and smoking cessation is advised.

Comments. Antithyroid drugs include sulfur-containing imidazole derivatives (thiamazole**) and propylthiouracil (propylthiouracil) [62, 64]. These drugs suppress the action of TPO, inhibit iodine oxidation, thyroglobulin iodination, and the condensation of iodotyrosines, thereby reducing thyroid hormone synthesis. In addition, propylthiouracil impairs the conversion of T4 to T3. The blood elimination half-life of thiamazole** is 4–6 hours, and that of propylthiouracil is 1–2 hours. The duration of action of thiamazole** exceeds 24 hours, while that of propylthiouracil is 12–24 hours. Thiamazole** is the drug of choice for all patients scheduled for conservative treatment of GD.

Comments. Agranulocytosis is a rare (0.06%) but formidable complication of antithyroid drug therapy [58, 59, 68, 72]; isolated thrombocytopenia occurs extremely rarely. Antithyroid drugs should be discontinued pending blood test results. If neutropenia (absolute neutrophil count <1.5×10⁹/L) or agranulocytosis (absolute neutrophil count <0.5×10⁹/L) is detected, antithyroid drug therapy must not be resumed. Hospitalization is indicated. Previously prescribed medications that cause neutropenia (metamizole sodium, paracetamol, co-trimoxazole, nitrofuran derivatives, etc.) should be discontinued. Empiric intravenous therapy with systemic antibacterial drugs is indicated. The use of colony-stimulating factors (CSFs), such as filgrastim**, is possible (desirable, but not mandatory) until an absolute neutrophil count of 1.5×10⁹/L is achieved. A complete blood count should be monitored daily. Consultation with a hematologist is indicated as needed. After normalization of the neutrophil count and stabilization of the condition, surgical treatment or RAI is performed.

Other extremely rare severe adverse effects include acute hepatic necrosis, cholestatic hepatitis, lupus-like syndrome, and vasculitis, which may be associated with antineutrophil cytoplasmic antibodies [50, 61, 67, 70, 71, 73].

Routine periodic complete blood counts during antithyroid therapy are not indicated [67]. Mild leukopenic reactions occur frequently, but they are almost always transient.

Thiamazole** is initially prescribed in doses of 20–30–40 mg (in 2 divided doses), and propylthiouracil in doses of 200–300–400 mg (in 3–4 divided doses), depending on the severity of thyrotoxicosis, respectively. With such therapy, normalization of FT4 and FT3 levels is achieved after 3–4 weeks. The TSH level may remain below normal for up to 4 months despite normal or even decreased blood thyroid hormone concentrations; therefore, its measurement is of little value in managing the patient during the first months of treatment.

Following the normalization of FT4 and FT3 levels, the dose of antithyroid drugs is tapered.

Comments. Serum free T4 (FT4) and free T3 (FT3) levels should be monitored, as FT4 levels may normalize despite a persistent elevation of FT3. Serum TSH levels may remain suppressed for several months following the initiation of therapy; therefore, measuring thyroid-stimulating hormone (TSH) in the blood to monitor treatment efficacy is not advisable.

It must be kept in mind that rapidly reducing the dose of thiamazole** to 5 mg at the beginning of treatment often leads to decompensation of thyrotoxicosis. Once thyroid hormone levels normalize, it is possible to switch to one of two antithyroid therapy regimens [74]: The "block-and-replace" regimen involves monotherapy with a relatively low dose of an antithyroid drug (7.5–10 mg of thiamazole**) with monthly serum free thyroxine (FT4) and blood free triiodothyronine (FT3) assays. The advantage of this regimen is the administration of a relatively low dose of the drug, while the relative disadvantage is less reliable blockade of the thyroid gland, necessitating frequent dose adjustments (titration regimen). The "block-and-replace" regimen involves administering a higher dose of the antithyroid drug (thiamazole**, 10–15–20 mg/day) while simultaneously prescribing #levothyroxine sodium** at 25–50 mcg/day, starting from the time FT4 normalizes or slightly later [53, 112].

The likelihood of achieving sustained remission is the same whether using the "block-and-replace" regimen or antithyroid drug monotherapy [74, 75].

Comments. Beta-blockers: propranolol** (20-40 mg every 6 hours) or longer-acting beta-blockers (atenolol**/#bisoprolol** 2.5-5 mg once daily) are prescribed to control adrenergic symptoms such as palpitations and tremor, especially in the early stages prior to the onset of action of antithyroid drugs [53,77]. High doses of propranolol** (40 mg 4 times a day) inhibit the peripheral conversion of thyroxine to triiodothyronine.

Comments. It should be borne in mind that TSH receptor antibodies may remain elevated due to the potential presence of thyroid-blocking TSH receptor antibodies [80, 81].

Long-term conservative therapy is generally inappropriate for certain groups of patients (where a combination of several factors is significant: substantial enlargement of the thyroid gland (over 40 mL), a long history of thyrotoxicosis (over 2 years), including the persistence or relapse of thyrotoxicosis after a 1–2-year course of antithyroid therapy, severe complications of thyrotoxicosis (atrial fibrillation, heart failure), a history of agranulocytosis, and the inability to frequently monitor thyroid function and endocrinologist visits—every 1–2 months at the start of treatment—including due to low patient adherence).

The rate of persistent thyrotoxicosis following the discontinuation of antithyroid drugs and/or its late relapses is 70% or higher. If thyrotoxicosis recurs in a patient with GD after the cessation of antithyroid therapy, the option of radioiodine therapy or thyroidectomy must be considered [82, 83].

3.1.2. Sodium iodide [131I] therapy (radioiodine therapy)

RAI is an effective, safe, and cost-effective treatment method for patients with various forms of toxic goiter [84]. The goals of RAI are to eliminate thyrotoxicosis by destroying hyperfunctioning thyroid tissue and to achieve a sustained hypothyroid state.

Radioiodine therapy (RIT) for Graves' disease is indicated in cases of thyrotoxicosis relapse following properly administered conservative treatment (continuous antithyroid drug therapy with confirmed euthyroidism for 12–18 months), contraindications or intolerance to antithyroid drugs (leukopenia, allergic reactions), lack of conditions for conservative treatment and patient monitoring, inadequate surgical volume, and as initial treatment for Graves' disease [85].

RIT is implemented through a set of interrelated technological processes. RIT includes the following technologies: preliminary evaluation, radionuclide diagnostics with intravenous administration of radiopharmaceuticals for diagnosing thyroid diseases, preparation of radiopharmaceuticals, RIT with oral administration of radiopharmaceuticals, and dosimetric support technology (dosimetric planning of RIT, monitoring of actual patient radiation doses during RIT, radiation safety monitoring of patients, and radiation safety monitoring of personnel and RIT department facilities) [85]. RIT can only be performed in specialized centers capable of ensuring radiation and environmental safety for patients, staff, and the environment.

Comments. Fetuses exposed to RIT after the 10th–11th week of gestation may be born without a thyroid gland and also have a higher risk of intellectual disability [90]. Currently, there is no evidence of the impact of therapy on fertility, the rate of spontaneous abortion, stillbirth, or congenital developmental defects in offspring in the long term [91].

Comments. If the patient remains thyrotoxic, monitoring should be continued at 4–6-week intervals.

Comments. Hypothyroidism can develop within 4 weeks (hypothyroidism is noted in 40% of patients by the 8th week and in more than 80% by the 16th week) [95]. The incidence of hypothyroidism one year after RIT is 5–50% and positively correlates with the dose of sodium iodide [131I]. Thereafter, the annual incidence of achieving hypothyroidism is 3–5% and shows little correlation with the sodium iodide [131I] dose [96]. Even when using low doses of sodium iodide [131I], which is associated with an increased rate of disease persistence and relapse, the development of hypothyroidism cannot be ruled out [97]. Transient hypothyroidism develops early after RIT (approximately 4–6 weeks), is rare, and is followed by either complete recovery of thyroid function or a relapse of thyrotoxicosis [98].

The principle of the lowest effective dose is important in sodium iodide [131I] therapy, but this is often difficult to achieve when trying to balance rapid relief of thyrotoxicosis with delayed onset of hypothyroidism. Therefore, many specialists abandon precise calculations of sodium iodide [131I] doses and instead use fixed doses (185, 370, or 555 MBq) based on clinical parameters such as thyroid size [99]. Since TSH levels may remain suppressed for a month or longer, this parameter should be interpreted with caution and only in conjunction with fT4 and fT3 levels; it should not be used in isolation to decide on initiating levothyroxine sodium** therapy. When initiating levothyroxine sodium** therapy, its dose should be titrated using fT4 level assessments. The required dose may be lower than the standard replacement dose. Manifest hypothyroidism should be avoided, particularly in patients with the active phase of Graves' ophthalmopathy. Once an euthyroid state is achieved, lifelong evaluation of thyroid function is recommended at least annually, as well as if symptoms of hypothyroidism or thyrotoxicosis develop.

Comments. Patients with a persistently suppressed TSH level combined with normal free T4 and T3 fractions may not require immediate retreatment with RIT, but they need closer monitoring for potential relapse or development of hypothyroidism. Symptoms of thyrotoxicosis must be controlled prior to RIT. The patient should receive adequate doses of antithyroid drugs until fT4 and fT3 concentrations normalize. Preliminary therapy is necessary because radiation thyroiditis can exacerbate thyrotoxicosis symptoms due to the release of previously synthesized thyroid hormones into the bloodstream. [100]. Prior intake of antithyroid drugs does not suppress the uptake of sodium iodide [131I] into the thyroid gland and does not reduce the efficacy of RIT, provided that antithyroid drugs are discontinued one week before and one week after the procedure. RIT [101]. In subclinical thyrotoxicosis, RIT can be performed without prescribing antithyroid drugs. Patients at high risk for complications due to exacerbated thyrotoxicosis—including elderly individuals, those with cardiovascular disease, or severe thyrotoxicosis—should receive beta-blockers and antithyroid drugs prior to sodium iodide [131I] therapy and until euthyroidism is achieved [102, 103]. If beta-blockers were used prior to RIT, they should be discontinued once free T4 and T3 fractions normalize. 

Comments. Adverse effects of RIT may include thyroid pain, swelling, and sialadenitis [105]. There is no evidence of an increased incidence of thyroid cancer or overall cancer mortality following sodium iodide [131I] therapy. In the treatment of Graves' disease, a reduction in mortality is observed compared to untreated patients [106].

3.1.3. Surgical treatment of Graves' disease

Surgical treatment is a radical method and is indicated when conservative therapy is inadvisable (see criteria above), upon relapse of thyrotoxicosis after a course of antithyroid therapy, patient preference, or a large goiter with compression symptoms.

Comments. Near-total/subtotal thyroid resection and total thyroidectomy differ slightly in technique, but not functionally—both operations result in hypothyroidism. To minimize the risk of complications (hypoparathyroidism, laryngeal nerve palsy, wound infection), surgery should be performed by a qualified surgeon skilled in thyroidectomy techniques [110, 111].

Comments: prescribe 8 mg #Iodine+[Potassium iodide+Glycerol]** as 5–7 drops (0.25–0.35 ml) with water for 10 days before surgery [112, 113, 53].

Following thyroidectomy, blood ionized calcium and parathyroid hormone levels should be measured, and additional calcium, vitamin D, and vitamin D analog supplements prescribed if necessary. Antithyroid drug therapy must be discontinued. #Levothyroxine sodium** preparations are prescribed immediately at a full replacement dose based on approximately 1.7 mcg/kg of the patient's body weight [113]. Blood thyroid-stimulating hormone (TSH) levels should be evaluated 6–8 weeks after surgery.

3.2. Management of Graves' Disease During Pregnancy and the Postpartum Period.

3.2.1. Pregnancy planning in Graves' disease

Pregnancy planning should be deferred until euthyroidism is achieved and confirmed twice within two months on a stable therapeutic regimen. Women should be informed about: (1) the increased risk of congenital defects caused by antithyroid drugs; (2) the possibility of discontinuing antithyroid drugs within 6–10 weeks of pregnancy; (3) the preference for propylthiouracil before/during the first trimester of pregnancy; (4) the use of thiamazole** starting from the 16th week of pregnancy; (5) the contraindication of the "block and replace" regimen. Pregnancy should be delayed for 6 months after radioiodine therapy (RIT), and contraception is recommended during this period. Thyroidectomy is indicated in cases of contraindications to or refusal of antithyroid drugs/RIT. After surgery, euthyroidism must be confirmed prior to conception [53, 114–118].

3.2.2. Pregnancy and Graves' disease

During pregnancy, a woman's requirement for thyroid hormones increases by 30–50%, which is why changes in thyroid function occur as early as the first weeks of pregnancy [119, 120]. The increased production of thyroid hormones results from the influence of specific factors leading to hyperstimulation of the thyroid gland. Gestational hyperthyroidism develops in 2% of pregnant women as a result of the stimulating effect of human chorionic gonadotropin [119, 120, 121].

Comments. The differential diagnosis between Graves' disease and gestational hyperthyroidism is based on detecting TSH receptor antibodies, the presence of thyroid-associated ophthalmopathy, and thyroid ultrasound data; detecting TPO antibodies does not allow for this. Thyroid scintigraphy is strictly contraindicated (see above) [123].

Comments. Antithyroid drugs are the treatment of choice for thyrotoxicosis during pregnancy. The goal of antithyroid drug therapy is to alleviate maternal thyrotoxicosis symptoms without inducing fetal hypothyroidism [138]. This is achieved by selecting doses of antithyroid drugs that maintain a moderately elevated fT4 level without striving to normalize TSH.

Comments. The initial daily dose of antithyroid drugs depends on the severity of thyrotoxicosis: #thiamazole** 5–15 mg, propylthiouracil 50–200 mg. Embryopathy associated with thiamazole** occurs in 2–4% of children, particularly during the 6th–10th weeks of pregnancy. The prevalence of congenital defects is similar with propylthiouracil, but the spectrum of defects is less severe; therefore, propylthiouracil is the drug of choice in the first trimester. In the second and third trimesters, propylthiouracil should be replaced with thiamazole** (due to a higher risk of hepatotoxicity) [132–135, 138].

Propranolol** 10–40 mg 3–4 times daily may be used; however, long-term treatment should be avoided, as beta-blockers can cause intrauterine growth restriction, fetal bradycardia, and neonatal hypoglycemia [139].

Comments. The risk of spontaneous abortion is high in the first trimester, and the risk of preterm birth in the third trimester [53, 118]. Following thyroidectomy or near-total thyroid resection, levothyroxine sodium** replacement therapy is prescribed at 2.3 mcg/kg [53, 119, 113].

Comments. If sodium iodide [131I] therapy was inadvertently administered to a pregnant woman, she must be informed about the radiation risks, including the risk of fetal thyroid destruction if sodium iodide [131I] was taken after the 12th week of pregnancy. Recommendations for or against terminating a pregnancy during which a woman received sodium iodide [131I] are absent.

Comments. Only 5% of patients with negative TSH receptor antibodies experience a relapse of thyrotoxicosis within 8 weeks after discontinuing antithyroid drugs [144, 145]. Therefore, discontinuing antithyroid drugs is feasible in the first trimester, provided there is mandatory monitoring of serum free thyroxine (fT4) and blood thyroid-stimulating hormone (TSH) levels every 2 weeks. If the pregnant woman remains euthyroid, thyroid function is monitored every 4 weeks during the second/third trimesters.

Comments. TSH receptor antibodies freely cross the placental barrier and can cause transient thyrotoxicosis in the fetus and newborn [123, 124]. In women with elevated TSH receptor antibody levels (>3-fold increase), a fetal ultrasound is necessary to detect signs of thyroid dysfunction, which include growth restriction, edema, goiter, and heart failure. If TSH receptor antibodies are not detected in the woman, the risk of fetal or neonatal thyroid dysfunction is very low.

3.2.3. Postpartum period and Graves' disease

Comments. Small amounts of antithyroid drugs pass into breast milk; therefore, low doses of propylthiouracil (<250 mg) and #thiamazole** (<20 mg) are considered safe for both mother and child. Antithyroid drugs should be taken after breastfeeding and in divided doses [53, 119, 138].

3.3. Management of Graves' Disease in Patients with Graves' Ophthalmopathy.

Introduction. Prolonged uncompensated thyrotoxicosis is an established risk factor for severe TED, which dictates the need to correct thyrotoxicosis as soon as possible [146]. The choice of treatment for thyrotoxicosis in patients with TED remains a relevant issue [147, 148]. Treatment of Graves' disease always begins with the correction of thyrotoxicosis using antithyroid drugs. Currently, there is no convincing evidence regarding the impact of the dose or regimen of antithyroid drugs (monotherapy or block-and-replace therapy with subsequent levothyroxine sodium**) on the course of TED, but in individual cases where it is difficult to achieve stable euthyroidism, the block-and-replace regimen may have an advantage as it allows maintaining the euthyroid state for a long time without resorting to dose titration [149, 150]. Antithyroid therapy does not directly affect the course of TED, but may have a positive indirect effect through the achievement of euthyroidism. According to a number of studies, RAI therapy causes the progression of TED or its development de novo [151], especially in smokers, patients with a history of TED or recently diagnosed TED [151], those with delayed correction of hypothyroidism after RAI [152, 153], and those with high levels of TSH receptor antibodies [154]. In patients at risk, the administration of low-dose oral glucocorticoids [155] on the 3rd day after RAI is effective, according to the results of two randomized controlled trials [156, 157] and two meta-analyses [158, 159]. Prophylactic administration of oral glucocorticoids is not required in patients without TED or in patients with inactive TED if other risk factors for RAI-associated TED are absent [160, 161].

In patients with mild, inactive TED, the choice of treatment for thyrotoxicosis is made independently of TED due to the low risk of TED progression [162]. If RAI is the method of choice, prophylactic administration of oral glucocorticoids is not indicated in the absence of other risk factors for TED progression [163, 164]. TED rehabilitation surgery may be required to eliminate cosmetic and functional defects.

In patients with mild, active TED, the choice of treatment for thyrotoxicosis does not depend on TED and is carried out according to established criteria [2]. If RAI is the method of choice, prophylactic administration of oral glucocorticoids is indicated [164].

In patients with moderate-to-severe, inactive TED, the choice of treatment for thyrotoxicosis does not depend on TED. If RAI is the method of choice, prophylactic administration of oral glucocorticoids is not required in the absence of other risk factors for TED reactivation [164].

In patients with moderate-to-severe, active TED, rapid normalization of thyroid function and sustained maintenance of euthyroidism are prioritized [164]. Thyroidectomy is the preferred method of radical treatment [164, 165]. Urgent TED therapy is recommended.

3.4. Treatment of subclinical thyrotoxicosis.

Subclinical hyperthyroidism (SH) is associated with an increased risk of CHD mortality, atrial fibrillation, heart failure, fractures, and increased mortality in patients with serum TSH levels <0.1 mIU/L [166–170]. In addition, in the presence of TSH receptor antibodies, which indicate Graves' disease (GD), the rate of progression of SH to overt hyperthyroidism is up to 30% over the next 3 years [170]. Therefore, despite the lack of randomized trials, treatment is indicated for patients over 65 years of age with a persistently maintained TSH level of <0.1 mIU/L to potentially avoid these serious adverse events and the risk of progression to overt hyperthyroidism. Treatment may also be considered in patients older than 65 years with a TSH level of 0.1–0.39 mIU/L due to an increased risk of atrial fibrillation, and may be appropriate in younger (<65 years) patients with TSH <0.1 mIU/L due to the risk of progression, especially in the presence of risk factors or comorbidities.

3.5. Treatment of thyroid storm.

Thyroid storm (TS) is a life-threatening condition. With a mortality rate estimated at 10%, TS requires prompt diagnosis and emergency treatment [172, 173]. This condition manifests as a sharp increase in the severity of thyrotoxicosis symptoms, hyperthermia, impaired consciousness, heart failure, diarrhea, and jaundice. Diagnostic criteria for TS in patients with severe GD include fever, tachycardia, arrhythmia, congestive heart failure, agitation, delirium, psychosis, stupor, coma, nausea, vomiting, diarrhea, and hepatic failure [174]. Nationwide studies in Japan have revealed high morbidity and mortality rates from this disease and subsequently proposed multimodal treatment (a comprehensive approach to therapy), including thiamazole** or #propylthiouracil (40 mg or 400 mg every 8 h, respectively), systemic glucocorticoids (#methylprednisolone** 50 mg intravenously), beta-blockers (propranolol** 40 mg every 6 h), and intensive care unit monitoring [175]. The most common cause of death from TS was multiple organ failure, followed by cardiac and respiratory failure, arrhythmia, disseminated intravascular coagulation, gastrointestinal perforation, hypoxic encephalopathy, and sepsis [176].

3.6. Treatment of toxic nodular/multinodular goiter (TNG/TMNG).

Patients with TNG/TMNG are indicated for radioactive iodine therapy (RAIT) or thyroidectomy after preparation with antithyroid drugs. Long-term treatment with antithyroid drugs is advisable only in cases where radical treatment is not feasible (advanced age, severe comorbidities).

Comments. When deciding on treatment, several clinical and demographic factors as well as patient preferences should be taken into account. After diagnosis, the attending physician and the patient should discuss each treatment option, including benefits, expected recovery rate, and side effects. Indications for RAIT include older patient age, comorbid conditions, prior thyroid surgery, and small goiter size [178]. Indications for surgical treatment include symptoms of neck organ compression, large goiter size (>80 cm³), and retrosternal goiter [179, 180].

Preliminary treatment with thiamazole** prior to RAIT in TNG/TMNG should be discussed for patients at increased risk of complications due to exacerbated thyrotoxicosis, including elderly patients and those with cardiovascular diseases or severe thyrotoxicosis [181].

Comments. If antithyroid drugs are used in preparation for RAI in patients with toxic nodular goiter/toxic multinodular goiter (TNG/TMNG), normalization or elevation of TSH levels should be avoided to prevent the direct effect of RAI on the perinodular and contralateral normal thyroid tissue, which increases the risk of hypothyroidism [183, 184].

Comments. Higher activities (350-450 Gy) are used to treat TNG/TMNG because sodium iodide [131I] is taken up only by autonomous areas and the incidence of hypothyroidism is significantly lower than after RAI for Graves' disease [185, 186]. The goal of autonomy treatment may be the destruction of autonomously functioning tissue with the restoration of euthyroidism, although achieving hypothyroidism in this situation also provides more reliable insurance against recurrence of thyrotoxicosis.

Comments. RAI of TNG/TMNG leads to the restoration of euthyroidism in approximately 55% of patients at 3 months and 80% of patients at 6 months [187, 188]. Goiter volume decreases by approximately 40% within 24 months [189]. The risk of persistent or recurrent thyrotoxicosis varies from 0 to 30%, depending on baseline data [188].

Comments. In refractory cases of persistent thyrotoxicosis caused by TNG/TMNG, surgical intervention may be considered after RAI [190, 191]. In some patients with persistent thyrotoxicosis after RAI, the administration of antithyroid drugs followed by the assessment of serum free thyroxine (fT4) and blood thyroid-stimulating hormone (TSH) levels allows controlling thyrotoxicosis until RAI becomes effective.

Comments. The surgery of choice for TMNG is thyroidectomy [191-193]. Resection of the affected thyroid lobe may be considered for TNG [194]. Following thyroidectomy for TMNG, blood ionized calcium levels should be tested, and based on the results, calcium and vitamin D supplements and their analogs should be additionally prescribed. Following thyroidectomy for TMNG, replacement therapy with #levothyroxine sodium** should be initiated at a dose appropriate for the patient's weight (1.7 mcg/kg) [53, 113, 119]. TSH should be determined every 2 months until it stabilizes, and annually thereafter. Following surgery for TNG, TSH and fT4 levels should be determined in 4-6 weeks, and if TSH levels are persistently elevated, therapy with levothyroxine sodium** preparations should be initiated.

Comments. Following hemithyroidectomy for TNG, testing total or ionized blood calcium levels is not required. Thyroid hormone replacement is required in approximately 15-20% of patients after hemithyroidectomy [191, 193, 196]. TSH levels may remain in the high-normal range for 3-6 months after hemithyroidectomy, so continued monitoring of an asymptomatic patient for 4-6 months after surgery is advisable, as normal thyroid function may recover.

Comments. Persistent or recurrent thyrotoxicosis after surgery indicates inadequate surgical intervention. Since reoperation on the thyroid gland is associated with a significantly increased risk of hypoparathyroidism and recurrent nerve injury, sodium iodide [131I] therapy is the treatment of choice for thyrotoxicosis [197].

Comments. Antithyroid drugs do not induce remission in patients with TNG/TMNG. Therefore, discontinuing treatment leads to a recurrence of thyrotoxicosis. However, long-term (lifelong) antithyroid drug therapy may be the best choice for certain individuals with limited life expectancy and contraindications to surgery or RAI [198]. The required dose of thiamazole** to restore the euthyroid state in patients with TNG/TMNG is usually (5-10 mg/day).

Treatment of subclinical thyrotoxicosis and thyroid storm in patients with TNG/TMNG is described in sections 3.5, 3.6.

3.7. Other treatment.

Until euthyroidism is achieved, physical activity and iodine intake should be limited, and smoking should be discontinued. Patients with symptoms of thyroid-associated ophthalmopathy (TAO) are referred for a consultation with an ophthalmologist. Patients with thyroid cardiomyopathy and cardiac arrhythmias must be monitored by a cardiologist. Untreated thyrotoxicosis, lack of compensation during ongoing treatment, or non-compliance with medical recommendations increases the risk of arrhythmias, circulatory failure, and thromboembolic complications.

3.8. Rare forms of thyrotoxicosis [199]

E05.3 Thyrotoxicosis with ectopic thyroid tissue: thyrotoxicosis syndrome in trophoblastic tumors, struma ovarii, hydatidiform mole, choriocarcinoma (chorioepithelioma).

Hydatidiform mole (develops during pregnancy and is characterized by edema of all or part of the chorionic villi, trophoblastic hyperplasia) and chorioepithelioma (a malignant tumor originating from trophoblast cells) secrete large amounts of human chorionic gonadotropin (hCG). hCG, similar to TSH, stimulates thyroid thyrocytes, causing the development of thyrotoxicosis. Crucial for diagnosis are: the presence of uterine bleeding, association with pregnancy and childbirth, characteristic ultrasound signs of the ovaries, and high serum and urine hCG titers.

Struma ovarii – a benign tumor (teratoma) that is histologically similar to the thyroid gland and produces thyroid hormones, causing thyrotoxicosis. The diagnosis is generally established based on medical history, pelvic ultrasound data, and increased radiopharmaceutical uptake in the pelvis on whole-body scanning. Malignant struma ovarii most commonly presents with the picture of papillary carcinoma.

E05.4 Thyrotoxicosis due to medication: factitial thyrotoxicosis, iatrogenic thyrotoxicosis, thyroid hormone overdose – a pathological condition caused by the intake of excessive amounts of thyroid hormones into the body. The diagnosis of iatrogenic thyrotoxicosis is straightforward if the drugs taken by the patient are known. The absence of a goiter and a history of thyroidectomy also indicate factitial thyrotoxicosis. Thyroid scintigraphy reveals low radiopharmaceutical uptake. Ultrasound shows normal, reduced, or absent thyroid dimensions following thyroidectomy.

E05.8 Other thyrotoxicosis: TSH-producing pituitary adenoma: elevated levels of TSH, TSH α-subunit. Diagnosis of a TSH-secreting pituitary adenoma is based on a combination of high levels of TSH and thyroid hormones, decreased levels of FT3 and FT4 during the administration of somatostatin and long-acting analogues, and visualization of a macroadenoma or microadenoma on pituitary MRI. Differential diagnosis with thyroid hormone resistance syndrome (mutations in the thyroid hormone receptor beta-isoform gene). Treatment is surgical.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Patients with thyrotoxicosis must be under active follow-up by an endocrinologist. Timely initiated adequate treatment promotes faster restoration of the euthyroid state and prevents the development of complications. Until euthyroidism is achieved, physical activity and iodine intake should be restricted, and smoking should be discontinued.

5. Prevention and Dispensary Observation

Primary prevention is not performed. Screening is not cost-effective.

Infection is suspected among the environmental factors provoking autoimmune thyrotoxicosis, but this remains unproven. Another factor is stress. There are cases of rapid development of thyrotoxicosis after severe emotional shocks. For example, a high frequency of this disease is known among concentration camp prisoners and during wartime. In patients with functional autonomy of the thyroid gland, the development of thyrotoxicosis can be triggered by excessive iodine intake or the administration of iodine-containing drugs.

Follow-up plan. All patients with clinical and laboratory signs of thyrotoxicosis must be referred to an endocrinologist for differential diagnosis of various forms of thyrotoxicosis and determination of treatment tactics. Subsequently, the patient may be monitored by a general practitioner (family doctor) with consultation from an endocrinologist when necessary. Patients with symptoms of thyroid-associated ophthalmopathy (TAO) are referred to an ophthalmologist. During the examination, it is important to determine the severity and activity of TAO and to address the issue of emergency or planned hospitalization in specialized centers. Urgent referral for hospitalization is required for patients with unexplained deterioration of visual acuity, changes in color vision intensity, unexpected globe dislocation (proptosis), visible corneal clouding, lagophthalmos, or optic disc edema. Patients with thyroid cardiopathy or cardiac arrhythmias must be monitored by a cardiologist or therapist.

Conservative treatment of Graves' disease is carried out for 12–18 months. The main condition is the restoration of the euthyroid state and normalization of FT3, FT4, and TSH levels. The patient is indicated for FT3 and FT4 testing in the first 2–3 months. Then, the TSH level is determined. After TSH normalizes, it is sufficient to test only its level. Before discontinuing conservative treatment, blood levels of thyrotropin receptor antibodies (TRAb) are determined. In case of thyrotoxicosis relapse, the issue of radical treatment is addressed. Patients with functional autonomy (toxic forms of nodular goiter) after normalization of FT3 and FT4 levels are referred for radioiodine therapy (RIT) or surgery.

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

1) decompensation of thyrotoxicosis (planned hospitalization);

2) complicated forms of thyrotoxicosis: atrial fibrillation, heart failure, thromboembolic complications, adrenal insufficiency, toxic hepatitis, dystrophic changes in parenchymatous organs, psychosis, cachexia, etc. (emergency hospitalization);

3) Thyrotoxic crisis (emergency hospitalization);

4) decompensation of thyrotoxicosis complicated by TAO (planned, emergency).

Criteria for patient discharge from a medical organization.

Persistent improvement in the patient's condition, with no further need for inpatient stay.

7. Additional Information

In untreated thyrotoxicosis, failure of thyroid hormones to normalize during ongoing treatment, or non-compliance with doctor's recommendations, the risk of arrhythmias, circulatory failure, and thromboembolic complications increases.

Criteria for Evaluating the Quality of Medical Care

Table 3. Criteria for assessing the quality of medical care for adults with thyrotoxicosis with diffuse goiter (Graves' disease), nodular/multinodular goiter

References

Appendix A1. Working Group Composition

LEADERS:

Dedov I.I., MD, PhD, Professor, Academician of the RAS, Moscow, President of the Russian Association of Endocrinologists.

Mokrysheva N.G., MD, PhD, Professor, Corresponding Member of the RAS, Moscow, member of the Russian Association of Endocrinologists.

Melnichenko G.A., MD, PhD, Professor, Academician of the RAS, Moscow, Vice-President of the Russian Association of Endocrinologists.

Working Group:

1. Troshina E.A. – Corresponding Member of the RAS, Professor, MD, PhD, member of the Public Organization "Russian Association of Endocrinologists".

2. Sviridenko N.Yu. – Professor, MD, PhD, member of the Public Organization "Russian Association of Endocrinologists".

3. Platonova N.M. – MD, PhD, member of the Public Organization "Russian Association of Endocrinologists"

4. Belovalova I.M. – Cand. Med. Sci., member of the Public Organization "Russian Association of Endocrinologists".

5. Sheremeta M.S. – Cand. Med. Sci., member of the Public Organization "Russian Association of Endocrinologists".

6. Bessmertnaya E.G. – Cand. Med. Sci., member of the Public Organization "Russian Association of Endocrinologists".

7. Yanovskaya E.A. – Cand. Med. Sci., member of the Public Organization "Russian Association of Endocrinologists".

8. Aleksandrov Yu.K. – MD, PhD, member of the Association of Endocrine Surgeons, member of the Council of the Association of Endocrine Surgeons.

9. Yasyuchenya V.S. – Endocrinologist, member of the Public Organization "Russian Association of Endocrinologists".

10. Syrtsova E.I. – Endocrinologist, member of the Public Organization "Russian Association of Endocrinologists".

Conflict of interest:

None of the members of the working group had a conflict of interest during the development of these clinical guidelines, specifically a personal interest in receiving, personally or through a company representative, material gain or other advantage that influences or may influence the proper performance of their professional duties and other obligations, including those related to the development and review of clinical guidelines, due to a contradiction between the personal interest of the aforementioned individuals and the interests of patients.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. endocrinologist;

2. general practitioner (family physician);

3. ophthalmologist;

4. internist;

5. cardiologist;

6. radiologist;

7. radiation oncologist;

8. ultrasound diagnostics physician;

9. surgeon.

Table 1. Levels of Evidence (LoE) grading scale 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 rehabilitative interventions)

Table 3. Scale for assessing the 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 3 years, as well as upon the emergence of new evidence-based medicine data on 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

Order of the Russian Ministry of Health dated February 28, 2019, No. 103n "On approval of the procedure and timeframe for the development of clinical guidelines, their revision, the standard form of clinical guidelines, and requirements for their structure, composition, and the scientific validity of the information included in the clinical guidelines"

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

The thyroid gland produces two hormones: T4 and very small amounts of T3. These hormones are delivered via the bloodstream to every cell and control the function of these cells. If for any reason there is an excess of hormones, thyrotoxicosis develops.

The most typical symptoms of thyrotoxicosis include: weight loss, rapid pulse with an unpleasant sensation of palpitations, muscle weakness, and fatigue. Thyrotoxicosis is dangerous due to severe complications, primarily affecting the heart. If left untreated for a long time, dystrophic changes develop in the heart muscle, manifesting as rhythm disturbances (atrial fibrillation or flutter), and subsequently heart failure. In addition, persistent changes develop in the central nervous system, bones, liver, and other organs; against this background, reproductive system function is impaired.

There are three treatment methods for thyrotoxicosis: conservative medical therapy with antithyroid drugs, surgical treatment, and radioactive iodine therapy (Iodine-131-containing agents). If a patient is prescribed a course of antithyroid therapy, they must take medications regularly and undergo hormone testing. The patient must immediately stop taking the medications and consult a physician if symptoms occur that may be associated with agranulocytosis or liver damage: itchy rash, jaundice (yellowing of the skin), acholic stools or dark urine, arthralgia, abdominal pain, nausea, fever, or pharyngitis. The probability of sustained remission, i.e., recovery, is significantly lower in smokers. Therefore, they must quit smoking.

Until thyroid hormone levels return to normal, physical activity must be significantly restricted. Patients with severe thyrotoxicosis often need hospitalization in an endocrinology department. After thyroid hormone levels normalize, physical activity can be gradually increased; however, excessively intense exertion should still be avoided. Evidence regarding whether changing time zones and climates can affect the course of the disease is currently lacking. Overdose of antithyroid drugs can lead to drug-induced hypothyroidism. Its symptoms include drowsiness, memory impairment, fluid retention and edema, sluggish bowel function, depression, and often thyroid enlargement. With regular monitoring of thyroid hormone levels (monthly at the beginning of treatment), the drug dose can be adjusted in a timely manner.

Pregnancy must not be planned during antithyroid therapy — such pregnancy carries an increased risk, and its management requires high expertise from an endocrinologist. For men taking antithyroid drugs, this therapy is not a contraindication to conceiving a child.

The choice of thyrotoxicosis treatment method should not be left entirely to the physician — the patient must also participate in this process. The physician and the patient should weigh all the pros and cons of a particular treatment method and its consequences. After surgical removal of the thyroid gland or RAI, hypothyroidism develops, which requires regular replacement therapy, while patients' quality of life is not impaired. Hypothyroidism is not a complication, but in most cases, the goal of treatment.

In untreated thyrotoxicosis, lack of compensation during treatment, or non-compliance with medical recommendations, the risk of arrhythmias, circulatory failure, and thromboembolic complications increases.

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

Not applicable