List of Abbreviations
WHO – World Health Organization
DNG — diffuse non-toxic (euthyroid) goiter
ID – iodine deficiency
IDD – iodine deficiency disorders
MTG – multinodular toxic goiter
TSH – thyroid-stimulating hormone
FT4 – free thyroxine
FT3 – free triiodothyronine
FNAB – fine-needle aspiration biopsy – thyroid puncture (under ultrasound guidance)
NG – nodular or multinodular goiter
US – ultrasound examination
NTG – nodular toxic goiter
FA – functional autonomy
TG – thyroid gland
I – iodine
Terms and Definitions
Iodine deficiency disorders – pathological conditions caused by iodine deficiency, which can be prevented by providing the population with the necessary amount of iodine.
Nontoxic goiter – a disease characterized by diffuse or nodular enlargement of the thyroid gland without impaired function.
Diffuse nontoxic (euthyroid) goiter — enlargement of the thyroid gland without impaired function, determined by palpation or ultrasound.
Sporadic goiter – diffuse enlargement of the thyroid gland usually caused by congenital (genetic) or acquired defects in thyroid hormone synthesis.
Endemic goiter – enlargement of the thyroid gland caused by iodine deficiency in a portion of the population living in a particular region.
Nodular or multinodular goiter – a collective clinical concept that unites all palpable focal formations in the thyroid gland that have various morphological characteristics.
Nodular or multinodular colloid goiter – a thyroid disease resulting from focal proliferation of thyrocytes and colloid accumulation.
Nodular or multinodular toxic goiter – a condition in which persistent pathological hyperproduction of thyroid hormones is caused by the formation of autonomously functioning thyrocytes in the thyroid gland.
Functional autonomy of the thyroid gland – iodine uptake and thyroxine production by thyrocytes independent of the influence of pituitary thyroid-stimulating hormone.
Iodine deficiency – iodine intake below the recommended daily requirement of the body in mcg for each age group (90 mcg in children and 150 mcg in adults).
Iodized salt – table salt containing a fixed amount of iodine salts (potassium iodate), used for mass prophylaxis of iodine deficiency disorders.
Cretinism – an extreme degree of mental and physical retardation associated with a lack of thyroid hormones in the intrauterine period.
Cluster analysis – a mathematical procedure that allows grouping objects into specific classes, or clusters, based on the similarity of quantitative values of several features characteristic of each object (e.g., a subject) of any set. The main purpose of cluster analysis is to divide a set of studied objects and features into homogeneous groups or clusters in a corresponding sense.
Neonatal screening for hypothyroidism – a system for early detection of thyroid insufficiency in newborns.
Thyrotoxicosis – a clinical syndrome caused by a prolonged excess of thyroid hormones in the body and their toxic effect on various organs and tissues. The thyrotoxicosis syndrome develops both in diseases of the thyroid gland and in diseases of other organs and pathological conditions.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Iodine deficiency disorders – a term combining conditions and disorders caused by iodine deficiency (WHO, 2007).
IDDs combine not only thyroid pathology that developed as a result of iodine deficiency, but also pathological conditions caused by thyroid hormone deficiency. The spectrum of IDDs is presented in Table 1.
Table 1. Spectrum of iodine deficiency pathology (WHO, 2001)
Intrauterine period | Abortions Stillbirth Congenital anomalies Increased perinatal mortality Increased infant mortality Neurological cretinism (mental retardation, deaf-mutism, strabismus) Myxedematous cretinism (mental retardation, hypothyroidism, dwarfism) Psychomotor disorders |
|---|---|
Neonates | Neonatal hypothyroidism |
Children and adolescents | Impairment of mental and physical development |
Adults | Goiter and its complications Iodine-induced thyrotoxicosis |
All ages | Goiter Hypothyroidism Cognitive impairment Increased radioactive iodine uptake in nuclear disasters |
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
I is an essential structural component of thyroid hormones, which in turn ensure the full development and functioning of the human body. The main natural sources of I for humans are plant and animal products, drinking water, and air. The daily requirement for this element is:
90 mcg — for children under 5 years old;
120 mcg — for children from 5 to 12 years old;
150 mcg — for children from 12 years old and adults;
250 mcg — for pregnant and lactating women.
A lack of I in the soil leads to a decrease in the content of this trace element in food products produced in this area, and the people consuming them suffer from iodine deficiency [1, 2]. I deficiency has numerous negative consequences regarding the development and formation of the human body. It is known that insufficient I intake during intrauterine development and early childhood poses the greatest danger. Changes caused by ID during these periods of life manifest as irreversible defects in the intellectual and physical development of children. Table 2 reflects the role of I as a substrate for the production of thyroid hormones, which play a key role in the formation of the central nervous system [3, 4].
Table 2. The role of thyroid hormones in the formation of the central nervous system.
Step | Gestational age | CNS | Thyroid hormones |
|---|---|---|---|
I | Up to 12-15 weeks | formation of the main brain structures | maternal |
II | 15-40 weeks | formation of the central nervous system, neuronal maturation, myelination, synaptogenesis | maternal and fetal |
III | postnatal period | myelination of the central nervous system, formation of the cerebellum, dentate gyrus | neonatal |
However, the entire spectrum of iodine deficiency pathology is broad and ranges from reproductive disorders to specific thyroid diseases, including functional autonomy and iodine-induced thyrotoxicosis as one of the most severe manifestations of IDDs in regions with varying levels of dietary I deficiency [5].
In the early stages of goiter development (in children, adolescents, and young adults), compensatory hypertrophy of thyrocytes occurs. Undoubtedly, all adaptation reactions are stimulated and controlled by TSH. However, as shown in many studies, TSH levels do not increase in DNG. In the course of a number of in vivo and in vitro studies, new data were obtained on the autoregulation of the thyroid gland by I and autocrine growth factors. According to modern concepts, an increase in TSH production or increased sensitivity of thyrocytes to it is of only secondary importance in the pathogenesis of iodine-deficiency goiter. The main role in this is assigned to autocrine growth factors, such as insulin-like growth factor type 1, epidermal growth factor, and fibroblast growth factor, which exert a powerful stimulating effect on thyrocytes under conditions of reduced I content in the thyroid gland [6]. It was experimentally shown that the addition of potassium iodide** to a thyrocyte culture resulted in a decrease in TSH-induced cAMP (cyclic adenosine monophosphate) mediated by mRNA expression of insulin-like growth factor type 1, with its complete cessation at a significantly increased dose of potassium iodide**. It is well known that I itself is not only a substrate for the synthesis of thyroid hormones, but also regulates the growth and function of the thyroid gland. Thyrocyte proliferation is inversely dependent on intrathyroidal I content. High doses of I inhibit its uptake, organification, synthesis and secretion of thyroid hormones, and glucose and amino acid uptake. Entering the thyrocyte, I interacts not only with tyrosyl residues in thyroglobulin, but also with lipids. The compounds formed as a result (iodolactones and iodoaldehydes) serve as the main physiological blockers of autocrine growth factor production. Many different iodolactones have been identified in the human thyroid gland, which are formed through the interaction of membrane polyunsaturated fatty acids (arachidonic, docosahexaenoic, etc.) with I in the presence of lactoperoxidase and hydrogen peroxide.
Under conditions of chronic iodine deficiency, there is a decrease in the formation of iodolipids—substances that inhibit the proliferative effects of autocrine growth factors (insulin-like growth factor 1, fibroblast growth factor, epidermal growth factor) [7]. In addition, insufficient I content leads to an increased sensitivity of these autocrine growth factors to the growth-promoting effects of TSH, a decrease in the production of transforming growth factor-beta, which normally acts as a proliferation inhibitor, and activation of angiogenesis. All this leads to enlargement of the thyroid gland and the formation of iodine-deficient goiter. In general, the development of diffuse non-toxic goiter may also depend on many other factors that are not yet fully understood. In addition to iodine deficiency, other causes related to the development of goiter include smoking, the use of certain medications, and environmental factors. Sex, age, and genetic predisposition also matter. In endemic goiter, genetic predisposition can only manifest in the presence of a corresponding external factor—environmental I deficiency [8].
1.3 Epidemiology of the Disease or Condition
According to WHO data, more than 2 billion people live under conditions of I deficiency, and nearly 700 million of them have been diagnosed with endemic goiter. There are no territories in the Russian Federation where the population is not at risk of iodine deficiency disorders. It is considered that an area is free of ID if the median urinary I concentration in the population exceeds 100 µg/L. The average I intake by the Russian population is much lower than recommended, amounting to 40–80 µg per day. In endemic regions, the prevalence of goiter in prepubertal children exceeds 5% [9]. The prevalence of diffuse endemic goiter in various regions of Russia ranges from 5.2 to 70%, with a national average of 31% [10, 11, 12, 13, 14]. Diffuse non-toxic goiter predominantly occurs in children, adolescents, and young adults. In more than 50% of cases, it develops before the age of 20, with goiter developing 2–3 times more frequently in women than in men. As a rule, the risk of developing diffuse non-toxic goiter increases manifold during periods when an increased demand for I (childhood, puberty, pregnancy, breastfeeding) is not adequately met [15].
The use of iodinated salt is capable of eliminating iodine deficiency in many cases [16]. To assess the severity of ID and the success of prevention programs, clearly planned, representative population-based studies are required. Criteria for assessing the severity of ID and methods of epidemiological studies are presented in the supplementary information.
1.4 Features of Coding the Disease or Condition
E01.0 Iodine-deficiency related diffuse (endemic) goiter
E01.1 Iodine-deficiency related multinodular (endemic) goiter
E01.2 Iodine-deficiency related (endemic) goiter, unspecified
E01.8 Other iodine-deficiency related thyroid disorders and allied conditions
E02 Subclinical iodine-deficiency-induced hypothyroidism
E04.0 Nontoxic diffuse goiter
E04.1 Nontoxic single nodular goiter
E04.2 Nontoxic multinodular goiter
E04.8 Other specified forms of nontoxic goiter
E04.9 Nontoxic goiter, unspecified
E05.1 Thyrotoxicosis with toxic single nodular goiter
E05.2 Thyrotoxicosis with toxic multinodular goiter
E07.9 Thyroid disorder, unspecified
D34 Benign neoplasm of thyroid gland
1.5 Classification of the disease or condition
Dietary I deficiency leads to the development of the following thyroid disorders:
Diffuse nontoxic goiter
Nodular/multinodular nontoxic goiter
Thyrotoxicosis due to decompensation of thyroid functional autonomy
Subclinical iodine-deficiency hypothyroidism
1.6 Clinical presentation of the disease or condition
Clinical symptoms may be either absent or manifest as a cosmetic defect or tracheal and esophageal compression syndrome, depending on the degree of thyroid volume enlargement. In large retrosternal goiter, neck deformity may be observed, and sometimes, due to compression syndrome, engorgement of the neck veins. Palpation may reveal nodular formations, sometimes slightly tender due to overstretching of the thyroid capsule.
2. Diagnostics, medical indications and contraindications for diagnostic methods
Diagnostic criteria for diffuse goiter: based on pathognomonic data:
anamnestic data,
physical examination,
laboratory tests,
instrumental examination.
Diagnostic criteria for nodular/multinodular goiter: based on pathognomonic data:
anamnestic data,
physical examination,
laboratory tests,
instrumental examination.
2.1 Complaints and Anamnesis
2.1.1 Diffuse goiter / nodular and multinodular goiter
Small non-toxic goiter is usually asymptomatic. As a rule, goiter is an incidental finding. In the vast majority of cases under conditions of mild and moderate ID, a slight enlargement of the thyroid gland is detected only upon targeted examination. Under conditions of severe ID, goiter can reach giant proportions. When taking a medical history, it is recommended to evaluate local signs (voice changes, dysphagia, etc.), clinical signs of thyroid dysfunction, history of prior thyroid interventions, family history including the presence of thyroid cancer and medullary cancer in relatives, prior head and neck radiation, and living in conditions of ID. Furthermore, nodular goiter may subsequently develop against the background of diffuse non-toxic goiter, and thyroid functional autonomy may form, which serves as one of the main causes of thyrotoxicosis in iodine-deficient regions.
2.2 Physical Examination
2.2.1 Diffuse goiter
To assess the degree of thyroid enlargement by palpation, the WHO (2001) recommends the following classification [17]:
Grade 0 (zero) — no goiter (the volume of each lobe does not exceed the volume of the examinee's thumb distal phalanx);
Grade 1 — goiter is palpable but not visible with the neck in a normal position. This also includes nodular formations that do not cause enlargement of the gland itself;
Grade 2 — goiter is clearly visible with the neck in a normal position.
It is important to note that thyroid sizes determined by palpation do not always match the true sizes, for example, due to anatomical features of the neck structure, low position of the thyroid gland itself, or retrosternal goiter. If palpation results lead to the conclusion that the thyroid gland is enlarged or that nodular formations are present, the patient is indicated for a thyroid ultrasound.
2.2.2 Nodular/multinodular goiter
Palpation may reveal thyroid enlargement. The classification of goiter sizes (WHO, 2001) is presented above. If palpation results lead to the conclusion that the thyroid size is increased or nodular formations are present, the patient is indicated for a thyroid ultrasound.
2.3 Laboratory Diagnostics
2.3.1 Diffuse goiter
Blood TSH testing is recommended for patients with diffuse goiter to assess the functional state of the thyroid gland [21, 22, 23, 24].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
If TSH is elevated, it is recommended to: test serum free T4 levels, determine serum anti-thyroperoxidase antibodies and anti-thyroglobulin antibodies for the differential diagnosis of hypothyroidism [21, 22, 23, 24].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
If TSH is decreased, it is recommended to: test serum free T4 levels, blood free T3 levels, and determine blood TSH receptor antibodies for the differential diagnosis of thyrotoxicosis [21, 22, 23, 24].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
Comments: Hypothyroidism due to iodine deficiency is characteristic of regions with severe I deficiency (intake less than 20 µg/day). In regions with mild and moderate I deficiency, hypothyroidism caused by iodine deficiency does not occur.
2.3.2 Nodular/multinodular goiter
Blood TSH testing is recommended for patients with nodular goiter to assess the functional state of the thyroid gland [21, 22, 23, 24].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
If TSH is decreased, it is recommended to: test serum free T4 levels, blood free T3 levels, and determine blood TSH receptor antibodies for the differential diagnosis of thyrotoxicosis [21, 22, 23, 24].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
Blood calcitonin testing is recommended to rule out medullary cancer in nodular non-toxic goiter [25, 26, 27].
GCR ALEL 2Grade of Recommendations A. Level of Evidence 2.
Blood thyroglobulin testing during initial diagnosis of nodular goiter is not recommended [28, 29].
GCR CLEL 4Grade of Recommendations C. Level of Evidence 4.
2.4 Instrumental Diagnostics
2.4.1 Diffuse goiter
A patient with suspected diffuse goiter is recommended an ultrasound examination of the thyroid gland and neck lymph nodes to confirm the presence of diffuse goiter [30, 31, 32]. During ultrasound, thyroid volume is calculated taking into account the width (W), length (L), and thickness (T) of each lobe and an ellipsoid correction coefficient using the following formula:
V thyroid = [(W right * L right * T right) + (W left * L left * T left)] * 0.479
GCR ALEL 2Grade of Recommendations A. Level of Evidence 2.
Comments: In adults, diffuse goiter is diagnosed if the thyroid volume according to ultrasound exceeds 18 mL in women and 25 mL in men.
To assess goiter in children, palpation data or standards adopted for epidemiological studies are generally used, where thyroid volume is compared with the child's body surface area (see table 9).
Ultrasound examination of the thyroid gland is not recommended as a screening test [18].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
2.4.2 Nodular/multinodular goiter
Ultrasound examination of the thyroid gland and neck lymph nodes is recommended for patients with suspected nodular goiter to confirm or rule out the presence of diffuse and/or nodular goiter [19, 20, 30, 31, 33]. During the ultrasound, the thyroid volume is calculated taking into account the width (W), length (L), and thickness (T) of each lobe and an ellipsoid correction factor using the following formula:
V thyroid = [(W R * L R * T R) + (W L * L L * T L)] * 0.479
GCR ALEL 2Grade of Recommendations A. Level of Evidence 2.
It is recommended to describe nodular formations by their location, contours, dimensions, structure, echogenicity, and vascularization, which should be reflected in the ultrasound report protocol [19, 20, 33, 34].
GCR ALEL 2Grade of Recommendations A. Level of Evidence 2.
Currently, the EU-TIRADS (European Thyroid Association thyroid image reporting and data system) classification is recommended for describing nodules [35, 36, 37, 38, 39, 40].
GCP ALeE 1Grade of Recommendation A. Level of Evidence 1.
Comments: The EU-TIRADS classification is used to determine further management tactics for patients diagnosed with thyroid nodules.
EU-TIRADS classification:
EU-TIRADS 1 – no nodules (no risk of malignancy);
EU-TIRADS 2 – malignancy risk ≈ 0%, FNA is not indicated (except for therapeutic FNA);
EU-TIRADS 3 – malignancy risk 2–4%, FNA is indicated for nodules > 20 mm;
EU-TIRADS 4 – malignancy risk 6–17%, FNA is indicated for nodules > 15 mm;
EU-TIRADS 5 – malignancy risk 26–87%, FNA is indicated for nodules > 10 mm; for nodules < 10 mm, FNA or active surveillance is an option.
Comments: Initially, the EU-TIRADS classification was developed for adults; however, given similar ultrasound features, it can also be used in children.
It is recommended to perform ultrasound-guided fine-needle aspiration biopsy (FNAB) in the presence of suspicious thyroid nodules, followed by cytological examination of the thyroid tissue smear [20, 37, 38, 41, 42].
GCP BLeE 2Grade of Recommendation B. Level of Evidence 2.
FNAB of nodules measuring 1 cm or less is not recommended if ultrasound findings are not suspicious and there is no high risk of aggressive forms of thyroid cancer based on medical history [19, 20, 31, 41, 42].
GCP CLeE 3Grade of Recommendation C. Level of Evidence 3.
Due to the lack of statistical data on the risk of malignancy, ultrasound-guided fine-needle aspiration biopsy (FNAB) of all nodules larger than 1 cm is recommended in children [43, 44], followed by cytological examination of the thyroid tissue smear.
GCR CLEL 4Grade of Recommendations C. Level of Evidence 4.
To determine the management tactics for patients with nodular goiter, it is recommended to use the six standard conclusion categories of the modern international Bethesda System for Reporting Thyroid Cytopathology (2009; revised 2017, 2023) (Table 3) [41, 42].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
Table 3. Recommended diagnostic categories and management recommendations according to the Bethesda System (2023)
Diagnostic categories | Management in adults | Management in children |
|---|---|---|
I – Nondiagnostic | Repeat FNAB | Repeat FNAB |
II – Benign | Observation | Observation |
III – Atypia of undetermined significance | Repeat FNAB / molecular genetic testing / hemithyroidectomy or observation | Repeat FNAB or surgical treatment |
IV – Follicular neoplasm | Molecular genetic testing / hemithyroidectomy | Surgical resection |
V – Suspicious for malignancy | Molecular genetic testing / hemithyroidectomy or thyroidectomy | Surgical resection |
VI – Malignant | Hemithyroidectomy or thyroidectomy | Surgical resection |
Comments: Conclusions containing only a descriptive part, as well as conclusions without a specific cytological diagnosis ("no atypical cells found", "no evidence of malignancy", etc.), are regarded as uninformative. In these situations, it is necessary to have the prepared cytological slides reviewed by another independent pathologist or repeat FNAB at a specialized medical institution.
Comments: The cytological report must include one of the diagnostic categories, which will allow the clinician to establish a clinical diagnosis and determine the optimal management strategy for each individual patient.
Comments: The Bethesda classification is also convenient for use in pediatric practice. However, a higher risk of thyroid cancer in the presence of a nodule changes the approach to the "benign" category (Table 4) [42].
Table 4. Comparison of malignancy risk according to the Bethesda classification in adults and children by categories II and IV (2023 revision).
Diagnostic categories | Oncological risk adults, % mean (ranges) | Oncological risk children, % mean (ranges) |
|---|---|---|
II – Benign | 4 (2-7) | 6 (0-27) |
It is recommended to perform a repeat ultrasound-guided thyroid FNAB and cytological examination of the tissue smear [43, 44, 45] in children with Bethesda category II if the nodule volume increases by more than 50% or by 20% in two out of three dimensions, and suspicious ultrasound features according to EU-TIRADS appear.
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
2.5 Other Procedures
2.5.1 Diffuse goiter
Spiral computed tomography of the neck and magnetic resonance imaging of the neck are recommended for giant goiter and/or substernal goiter to rule out compression syndrome, as well as in the presence of thyroid malignancy when regional metastases are suspected [21, 31, 46].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
2.5.2 Nodular/multinodular goiter
Thyroid scintigraphy is recommended for patients with nodular/multinodular goiter when thyroid functional autonomy is suspected. It is usually performed when TSH levels are in the lower quartile [47, 48, 49, 50, 51, 52].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
Comments: Sodium pertechnetate [99mTc] is most commonly used for thyroid scintigraphy, with an administered activity of 185–370 MBq (5–10 mCi) intravenously; #123I-sodium iodide [I-123] – administered activity of 7–15 MBq (200–400 μCi) orally [96]. Sodium pertechnetate [99mTc] has a short half-life (6 hours), which significantly reduces the radiation dose. In functional autonomy, the isotope accumulates in the actively functioning node, while the surrounding thyroid tissue is in a suppressed state. In some cases, autonomy may be diffuse due to the dissemination of autonomously functioning areas throughout the thyroid gland.
It is recommended to perform thyroid scintigraphy in early childhood when ectopic thyroid or thyroid aplasia is suspected [53, 54, 55].
GCP CLeE 4Grade of Recommendation C. Level of Evidence 4.
Spiral computed tomography of the neck and magnetic resonance imaging of the neck are recommended for diagnosing substernal goiter, clarifying the position of the goiter relative to surrounding tissues, and determining tracheal and esophageal displacement or compression [21, 31, 46, 56].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Diffuse goiter
3.1.1 Conservative treatment
As a first-line treatment, potassium iodide** at a dose of 100 mcg per day is recommended for children, potassium iodide** at a dose of 200 mcg per day is recommended for individuals under 40 years of age [57, 58, 59], and 250 mcg per day for pregnant and breastfeeding women [64, 65, 66, 67, 68].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
Comments: The goal of treatment for diffuse nontoxic goiter is to normalize or reduce thyroid volume. It should be kept in mind that even with adequate iodine intake, the thyroid volume naturally increases somewhat during pregnancy.
Currently, there are three options for conservative therapy of diffuse nontoxic goiter:
potassium iodide** monotherapy;
levothyroxine sodium** therapy;
combination therapy with potassium iodide** and levothyroxine sodium**.
The main advantages of potassium iodide** monotherapy are its etiotropic nature (iodine-deficiency goiter is practically the only disease in endocrinology where etiotropic therapy is feasible), safety, no need for dose titration, and no need for frequent hormone testing.
Levothyroxine sodium** therapy or combination therapy is preferred in cases of large thyroid volume or lack of response to potassium iodide** monotherapy. The dose of the drug should be adjusted so that the TSH level is reduced to the lower limit of the normal range. However, choosing this treatment strategy carries the risk of drug-induced thyrotoxicosis and requires dose titration, which necessitates frequent testing.
The duration of therapy is 6–12 months; thereafter, once the treatment goal is achieved, the use of iodinated salt in the diet is mandatory.
If before pregnancy a woman was receiving combination therapy (levothyroxine sodium** + potassium iodide**) for diffuse nontoxic (endemic) goiter, it is recommended to continue it under the control of TSH (thyroid-stimulating hormone (TSH) blood level test) [66, 69, 70, 71].
GCR BLEL 2Grade of Recommendations B. Level of Evidence 2.
Patients with diffuse nontoxic goiter are recommended active surveillance with annual determination of TSH levels and thyroid ultrasound once every 12 months [60, 61, 62, 63].
GCR CLEL 3Grade of Recommendations C. Level of Evidence 3.
3.1.2 Surgical treatment
Thyroidectomy for diffuse nontoxic goiter is recommended in cases of giant size and/or compression symptoms of surrounding organs [72, 73].
GCR CLEL 4Grade of Recommendations C. Level of Evidence 4.
Hemithyroidectomy is recommended in children if the size of the nodular formation is greater than 3 cm and corresponds to Bethesda category II (due to the reduced diagnostic value of FNA in large nodules) and of any size for Bethesda category IV (due to the high risk of malignancy) [44, 45].
GCR CLEL 4Grade of Recommendations C. Level of Evidence 4.
Comments: For large diffuse nontoxic or diffuse multinodular goiter and high surgical risks, radioiodine therapy with the administration of #thyrotropin alfa may be recommended. Treatment of nontoxic goiter with radioactive iodine has been introduced in some European countries as an alternative to surgery
Treatment with the radioactive nuclide sodium iodide [131I] #causes a reduction of up to 50% in thyroid volume [74, ]. Additional single administration of recombinant human thyrotropin increases the efficacy of radioiodine treatment for compressive forms of nontoxic goiter. #Thyrotropin alfa not only increases radioiodine uptake by the thyroid gland, but also enhances the effect of radioiodide therapy. Doses of #thyrotropin alfa depend on the thyroid volume, patient age, severity of neck organ compression; according to a meta-analysis of available literature sources, the variability ranges from 0.005 to 0.45 mg/mL, administered as a single intramuscular injection. The safest doses of recombinant TSH in terms of transient side effects and hypothyroidism development range from 0.005 to 0.1 mg.
Radioiodine therapy with sodium iodide [131I] #is prescribed 24 hours after the injection, with the administered activity ranging from 300 to 1100 MBq based on thyroid volume, 131I thyroid uptake, and the half-life of 131I
All patients are prescribed a low-iodine diet 2 weeks prior to diagnostic and therapeutic procedures using radioactive iodine
3.2 Nodular/multinodular goiter
3.2.1 Conservative Treatment
There are no methods of conservative treatment for nodular nontoxic goiter.
3.2.2 Surgical treatment
Surgical treatment of nodular goiter is recommended for: [20, 31, 45, 48, 77]
malignant thyroid tumors or suspicion thereof based on FNA results;
retrosternal nodular or multinodular goiter causing local compression syndrome;
nodular/multinodular toxic goiter (if radioiodine therapy is not feasible);
cosmetic defect impairing quality of life.
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
Comments: If surgery is chosen as the treatment method for nodular/multinodular toxic goiter, patients with overt thyrotoxicosis must achieve euthyroidism on antithyroid drug therapy. The surgery of choice for multinodular toxic goiter is thyroidectomy. The surgery of choice for nodular toxic goiter is hemithyroidectomy of the affected thyroid lobe.
Following inadequately sized surgeries for nodular/multinodular toxic goiter, the treatment method of choice for thyrotoxicosis is radioiodine therapy.
3.2.3 Other types of treatment
Adult patients with nodular/multinodular toxic goiter are recommended to undergo radioiodine therapy [48, 78, 79].
GCR ALEL 2Grade of Recommendations A. Level of Evidence 2.
Comments: Prolonged conservative treatment with antithyroid drugs is advisable only when radical treatment is impossible (advanced age, severe comorbidities). Pretreatment with antithyroid drugs prior to iodine-131 radioiodine therapy (sodium iodide [131I] preparation) for nodular/multinodular toxic goiter should be discussed for patients at high risk of complications due to exacerbated thyrotoxicosis, including elderly patients and those with cardiovascular diseases or severe thyrotoxicosis. Relatively high doses of 131 I (350-450 Gy) are used to treat nodular/multinodular toxic goiter because it is absorbed only by autonomous areas and the incidence of hypothyroidism is significantly lower than in Graves' disease therapy. The goal of treatment is the destruction of autonomously functioning tissue with the restoration of euthyroidism. Patient follow-up after radioiodine therapy involves determining FT4 and TSH every 1-2 months. If thyrotoxicosis persists for 6 months after treatment, a repeat course of radioiodine therapy is recommended.
In children, due to the risk of mutagenic effects on the surrounding thyroid tissue, as well as the more frequent detection of carcinoma in an autonomous nodule, hemithyroidectomy or thyroidectomy is recommended for nodular/multinodular toxic goiter [45, 80, 81].
GCR CLEL 4Grade of Recommendations C. Level of Evidence 4.
Comments: Resection may be delayed in cases of benign FNA results and the absence of thyrotoxicosis.
Radioiodine therapy for toxic nodular goiter with benign FNA results (Bethesda II) is possible in cases of high surgical risk, or refusal of surgery by parents and the child (who has reached 15 years of age with informed consent, upon completion of puberty: deceleration of growth, decrease in mitotic activity and basal metabolic rate).
Percutaneous #ethanol** injections are recommended in adult patients for cystic thyroid nodules and nodules with a large fluid component causing a neck cosmetic defect, as well as for small nodular toxic goiter, if FNA results completely rule out a neoplastic process [82, 83].
GCR CLEL 4Grade of Recommendations C. Level of Evidence 4.
Comments: Solid formations are injected with 95% #ethanol** at a dose of 0.5-1 mL per milliliter of nodule volume. Cystic formations are injected with 3-5 mL of #ethanol** after fluid aspiration. Injections are performed 1-2 times a week. Treatment, depending on the size of the formation, usually ends after 3-4 injections.
Ethanol** injections are not recommended: for solid "cold" formations, for nodular toxic goiter with a nodular volume greater than 5 cm3, or for multinodular toxic goiter [82, 83].
GCR CLEL 4Grade of Recommendations C. Level of Evidence 4.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
No specific rehabilitation measures have been developed for these patients.
5. Prevention and Dispensary Observation
Achievement of optimal iodine intake is recommended for the population:
90 mcg/day at age 0-59 months, 120 mcg/day at age 6-12 years,
150 mcg/day for adolescents and adults, and 250 mcg/day for pregnant and lactating women [16, 17, 85, 86, 87].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
In certain risk groups (pregnancy, breastfeeding, children under 2 years of age), individual and group iodine prophylaxis is recommended [16, 17, 85, 86, 88].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
Comments: Prophylaxis in specific high-risk groups for iodine deficiency disorders is carried out by taking pharmacological agents containing a physiological dose of potassium iodide**.
Comments: Universal salt iodization is recommended by WHO as a universal, highly effective method of mass iodine prophylaxis. Universal salt iodization means that virtually all salt for human consumption (i.e., sold in stores and used in the food industry) should be iodized. To achieve optimal iodine intake (150 mcg/day for adults), WHO and the International Council for Control of Iodine Deficiency Disorders recommend adding an average of 20-40 mg of iodine per 1 kg of salt. In the Russian Federation, a resolution by the Chief Sanitary Doctor recommends adding an average of 40 +/- 15 mg of iodine per kg of salt. Potassium iodate is recommended as the iodizing additive. The use of iodized salt can eliminate iodine deficiency in many cases.
In patients with nodular colloid goiter in the absence of thyroid dysfunction, cosmetic defect, and compression syndrome, active surveillance is recommended: thyroid ultrasound, blood TSH level test every 6–12 months [19, 20, 31].
GCR CLEL 5Grade of Recommendations C. Level of Evidence 5.
6. Organization of Medical Care
Elective hospitalization. Inpatient care.
Indications for elective hospitalization in a medical organization (inpatient facility):
preparation for surgical intervention.
Indications for discharging a patient from a medical organization:
stable improvement in the patient's condition, allowing them to continue treatment safely in an outpatient clinic or at home.
7. Additional Information
7.1 Epidemiological assessment of iodine deficiency disorders
Table 5 summarizes all epidemiological criteria used to varying degrees to assess the severity of iodine deficiency. To judge the initial severity of iodine deficiency, at least two parameters must be available.
Table 5. Epidemiological criteria for assessing the severity of iodine deficiency disorders.
Criteria | Absence of iodine deficiency | Severity of iodine deficiency | ||
|---|---|---|---|---|
Mild | Mean | Severe | ||
Median urinary iodine concentration, mcg/L | >100 | 50-99 | 20-49 | <20 |
Frequency of TSH > 5 mIU/L in neonatal screening, % | <3 | 3.0-19,9 | 20.0-39,9 | >40.0 |
Goiter prevalence in schoolchildren, % | <5 | 5.0-19,9 | 20.0-29,9 | >30,0 |
Thyroglobulin median in children, ng/mL | <10 | 10.0-19,9 | 20.0-39.9 | >40,0 |
If the region is already implementing iodine prophylaxis measures, evaluating urinary iodine excretion every 5 years and tracking the proportion of households using iodized salt is sufficient to assess their effectiveness [96].
7.1.1 Neonatal TSH concentration testing
It is recommended to determine neonatal TSH concentration to assess the severity of iodine deficiency disorders (IDD). Neonatal TSH concentration is proposed as an indicator of iodine deficiency in the population. An adequate iodine supply in the population is indicated by the proportion of newborns below 3% with a neonatal TSH level above 5 mIU/L.
TSH concentration is an indicator for detecting congenital hypothyroidism, but its validity as an IDD criterion in older age groups is controversial. Elevated TSH may be caused by thyroid diseases, certain medications, etc. Furthermore, TSH levels in adults from endemic regions may be lower than in iodine-sufficient ones due to the development of autonomously functioning thyroid tissue [92–94].
7.1.2 Median urinary iodine concentration testing
Currently, urinary iodine excretion is considered the main epidemiological indicator characterizing iodine status in a given region. This parameter is highly sensitive and responds rapidly to changes in iodine intake; therefore, it is crucial not only for assessing the epidemiological situation but also for monitoring iodine deficiency disorder prevention programs.
Eighty to ninety percent of dietary iodine is excreted in the urine. The iodine concentration in a single-void urine sample correlates well with 24-hour urinary iodine and reflects immediate iodine intake at the time of testing. Because an individual's urinary iodine level varies both daily and throughout the day, these measurements can only be used to assess the iodine status of a population as a whole. This method is suitable exclusively for epidemiological studies. Due to the highly skewed distribution of urinary iodine levels across samples, using the median rather than the mean is preferable.
Criteria for assessing population iodine intake based on median urinary iodine concentration are presented in Table 6.1 and Table 6.2
Table 6.1 Criteria for assessing population iodine intake based on median urinary iodine concentration in school-age children.
Median urinary iodine concentration (µg/L) | Iodine intake | Epidemiological situation in the region |
|---|---|---|
< 20 | Insufficient | Severe iodine deficiency |
20-49 | Insufficient | Moderate iodine deficiency |
50-99 | Insufficient | Mild iodine deficiency |
100-199 | Adequate | Normal iodine sufficiency |
200-299 | Exceeds normal | Risk of iodine-induced thyrotoxicosis |
>300 | Excessive | Risk of adverse health consequences (iodine-induced hypothyroidism, autoimmune thyroid diseases) |
Table 6.2 Criteria for assessing population iodine intake based on median urinary iodine concentration in pregnant women.
Median urinary iodine concentration (µg/L) | Iodine intake |
|---|---|
<150 | Insufficient |
150 – 249 | Adequate |
250 –299 | Exceeds normal |
>500 | Excessive |
Selecting a representative group to assess population iodine intake is achieved through cluster sampling. School-based surveys are the most effective and practically justified approach. When planning and preparing the study based on a list of all schools in the region, 30 clusters are determined using a specific sampling method. At least 30 urine samples are analyzed in each cluster. For countries with large populations or multiple distinct ecological zones, several independent surveys are conducted. Conducting a representative 30-cluster survey is costly and labor-intensive; therefore, monitoring IDD prevention programs can be adequately performed by examining control areas that initially exhibited severe or moderate iodine deficiency. At least 3 schools are randomized in each control area. At least 30 urine and salt samples used by students' households are tested in each selected school. Against the background of preventive measures, such studies in control areas are conducted once every 2 years.
Tables 7 and 8 summarize the main methods of epidemiological studies and the population groups most appropriate for such research.
Table 7. Main methods of epidemiological studies.
(main principle: "30 clusters + at least 30 urine samples from each cluster") 1. Cluster surveys proportional to population size - school-based surveys - household surveys 2. Alternative methods (e.g., baseline screening in schools of regions lacking any IDD data; for geographically heterogeneous regions, etc.) |
|---|
Table 8. Main target groups for epidemiological studies.
School-age children (8–10 years) – main group Newborns (provided primary iodine screening has already been performed in the region) |
|---|
7.2 Determination of goiter prevalence in the population
Changes in thyroid volume are generally related to the level of iodine intake; however, alterations in thyroid volume in response to altered iodine consumption occur over several months or even years. The degree of thyroid enlargement is influenced by the severity of iodine deficiency, duration of living in iodine-deficient conditions, preventive measures, sex, age, etc.
Thus, goiter prevalence is currently virtually obsolete as a criterion for assessing iodine status. This is primarily because the main emphasis has shifted to monitoring universal salt iodization programs. Goiter prevalence serves as an indirect indicator of iodine intake and the severity of iodine deficiency, changing quite a long time after iodine intake normalizes. Furthermore, universally accepted ultrasound-based standards for children's thyroid volume are currently lacking. Determining the frequency of goiter in a population holds some value for assessing the severity of iodine deficiency prior to initiating preventive measures. In this case, assessing goiter frequency in children aged 8–10 years is most appropriate. Measuring thyroid volume in children under 8 presents certain technical challenges, while in older children, thyroid enlargement may be due to the onset of puberty. To assess the degree of thyroid enlargement by palpation, the WHO classification is recommended (see section 2.2). The sensitivity and specificity of palpation for assessing goiter grade are rather low. Therefore, for precise determination of thyroid dimensions and volume within an epidemiological study, performing an ultrasound with volume calculation is recommended (see section 2.4). A child's thyroid volume depends on their physical development stage; therefore, the child's height and weight are measured prior to the scan, and body surface area is calculated using a special scale or formula. In children, thyroid volume is compared against normative values (depending on body surface area, Table 9).
Table 9. Normative values of thyroid volume in children for epidemiological studies (upper limit of normal – 97th percentile) (WHO, 1997) [95].
Body surface area (m2) | 0,8 | 0,9 | 1,0 | 1,1 | 1,2 | 1,3 | 1,4 | 1,5 | 1,6 | 1,7 |
|---|---|---|---|---|---|---|---|---|---|---|
Boys | 4,7 | 5,3 | 6,0 | 7,0 | 8,0 | 9,3 | 10,7 | 12,2 | 14,0 | 15,8 |
Girls | 4,8 | 5,9 | 7,1 | 8,3 | 9,5 | 10,7 | 11,9 | 13,1 | 14,3 | 15,6 |
The upper limits of normal thyroid volume presented in the table are based on data from children living in iodine-sufficient regions. Universally accepted standards for children's thyroid volume do not currently exist, causing certain discrepancies in result interpretation. WHO recommends using the adopted normative values of thyroid volume exclusively for epidemiological studies. These standards are not applied in clinical practice, where the assessment of goiter in children is performed via palpation.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Level of evidence | Grade of Recommendation |
|---|---|---|---|
1. | Thyroid ultrasound performed | 2 | A |
2. | Blood thyroid-stimulating hormone assay performed | 5 | C |
3. | Fine-needle aspiration biopsy (FNAB) of the thyroid under ultrasound guidance performed when indicated | 2 | B |
4. | Blood calcitonin assay performed in the presence of thyroid nodules | 2 | A |
5. | Cytological examination of thyroid tissue smears with evaluation of nodular aspiration biopsy samples using the six categories of the Bethesda system performed | 5 | C |
6. | Spiral computed tomography / magnetic resonance imaging of the neck performed when compression syndrome is suspected | 5 | C |
7. | Thyroid scintigraphy performed when functional autonomy of the thyroid is suspected | 5 | C |
8. | Conservative therapy for diffuse goiter prescribed when indicated:
| 5 | C |
9. | Hemithyroidectomy or thyroidectomy performed when indicated | 5 | C |
References
Show references
Hetzel B. Iodine deficiency disorders (idd) and their eradication. Lancet. 1983; 322(8359):1126-1129. doi: 10.1016/s0140-6736(83)90636-0
Zimmermann M.B., Jooste P.L., Pandav C.S. Iodine-deficiency disorders. Lancet. 2008; 372(9645):1251-1262. doi: 10.1016/s0140-6736(08)61005-3
Taranushenko T.E. Iodine deficiency disorders in children. Doctoral dissertation. 1999.
Kovalenko T.V. Zdorov'e i razvitie detey, rozhdennykh v usloviyakh zobnoy endemii. Doktorskaya dissertatsiya. 2000.
Platonova N.M. Iodine deficiency: current state of the problem. Clinical and Experimental Thyroidology. 2015; 11(1):12-21.
Hintze G., Koebberling J. Treatment of iodine deficiency goiter with iodine, levothyroxine or a combination of both. Thyroidology. 1992; 4:37-40.
Gartner R., Dugrillon A., Bechtner G. Evidence that iodolactones are the mediators of growth inhibition by iodine on the thyroid. Acta Med Austriaca. 1996; 23(1–2):47–51.
Troshina E.A. Diffuse euthyroid goiter. Treatment algorithms and prevention with iodine preparations. Lecture. Problems of Endocrinology. 2014; 60(5):49-56.
Shapkina L.A. Zobnaya endemiya v Primorskom krae: kliniko-epidemiologicheskie i ekologicheskie aspekty. Kandidatskaya dissertatsiya. 2005.
Malievsky O.A. Difuznyy netoksicheskiy zob u detey v Respublike Bashkortostan: rasprostranennost', struktura, lechenie profilaktika. Doktorskaya dissertatsiya. 2001.
Kichikova Zh.D. Kliniko-morfologicheskie osobennosti endemicheskogo zoba u zhiteley Kalmykii. Kandidatskaya dissertatsiya. 2002.
Svinarev M.Yu. Endemicheskiy zob i nekotorye pokazateli antitireoidnogo autoinmuniteta (po materialam obsledovaniya detey Khvalynskogo rayona Saratovskoy oblasti). Kandidatskaya dissertatsiya. 1995.
Troshina E.A., Platonova N.M., Panfilova E.A., Panfilov K.O. Analytical review of the results of monitoring the main epidemiological characteristics of iodine deficiency disorders in the population of the Russian Federation for the period 2009-2015. Problems of Endocrinology. 2018; 64(1):21-37. doi: 10.14341/probl9308
Shapkina L.A. Zobnaya endemiya v Primorskom krae: kliniko-epidemiologicheskie i ekologicheskie aspekty. Kandidatskaya dissertatsiya. 2005.
Walker S.P., Wachs T.D., Gardner J.M., et al. International Child Development Steering Group. Child development: risk factors for adverse outcomes in developing countries. Lancet 2007; 369: 145–57.
Assessment of iodine deficiency disorders and monitoring their elimination: a guide for programme managers / WHO, United Nations Children’s Fund, International Council for the Control of Iodine Deficiency Disorders. – 3 rd ed. – Geneva, 2007. – Р. 1-97.
WHO, UNICEF and ICCIDD. Assessment of Iodine Deficiency Disorders and monitoring their elimination. Geneva: WHO, WHO/Euro/NUT, 2001.
Tan G.H., Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med. 1997; 126:226–231.
Uppal A., White M.G., Nagar S., et al. Benign and malignant thyroid incidentalomas are rare in routine clinical practice: A Review of 97,908 Imaging Studies. Cancer Epidemiol Biomarkers Prev. 2015; 24(9):1327–1331. doi: 10.1158/1055-9965.EPI-15-0292
Gharib H., Papini E., Paschke R., et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. Endocr Pract. 2010; 16:468–475.
Walsh J.P. Managing thyroid disease in general practice. Medical Journal of Australia. 2016; 205:179.
Troshina E.A. Goiter. - M.: Medical Information Agency, 2012.
Braverman L. Iodine and the Thyroid: 33 Years of Study. Thyroid. 1994; 4(3): 351-356. doi: 10.1089/thy.1994.4.351
Eastman C. Screening for thyroid disease and iodine deficiency. Pathology. 2012; 44:153–9
Costante G., Meringolo D., Durante C., et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 2007; 92:450–455.
Chambon G, Alovisetti C, Idoux-Louche C, et al. The use of preoperative routine measurement of basal serum thyrocalcitonin in candidates for thyroidectomy due to nodular thyroid disorders: results from 2733 consecutive patients. J Clin Endocrinol Metab. 2011; 96:75–81.
Elisei R., Bottici V., Luchetti F., et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab. 2004; 89:63–168.
Rink T., Dembowski W., Schroth H.J., Klinger K. Stellenwert. Impact of serum thyroglobulin concentration in the diagnosis of benign and malignant thyroid diseases. Nuklearmedizin. 2000;39(5):133‐138.
Gray J.L., Singh G., Uttley L., Balasubramanian S.P. Routine thyroglobulin, neck ultrasound and physical examination in the routine follow up of patients with differentiated thyroid cancer-Where is the evidence? Endocrine. 2018; 62(1):26–33. doi: 10.1007/s12020-018-1720-3
Guth S., Theune U., Aberle J., Galach A., Bamberger C. M. Very high prevalence of thyroid nodules detected by high frequency (13MHz) ultrasound examination. Eur J Clin Invest. 2009; 39:699–706.
Haugen B.R., Alexander E.K., Doherty G.M., et al. American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-147.
Zimmermann M., Saad A., Hess S., Torresani T., Chaouki N. Thyroid ultrasound compared with World Health Organization 1960 and 1994 palpation criteria for determination of goiter prevalence in regions of mild and severe iodine deficiency. Eur J Endocrinol. 2000;143(6):727‐731. doi:10.1530/eje.0.1430727
Horvath E, Majlis S, Rossi R et al. An ultrasonogram reporting system for thyroid nodules stratifying cancer risk for clinical management. J Clin Endocrinol Metab. 2009; 94(5):1748-51. doi:10.1210/jc.2008-1724
Kwak J.Y., Han K.H., Yoon J.H. et al. Thyroid imaging reporting and data system for US features of nodules: a step in establishing better stratification of cancer risk. Radiology. 2011; 260(3):892-9. doi: 10.1148/radiol.11110206
Russ G., Bonnema S.J., Erdogan M.F., Durante C., Ngu R., Leenhardt L. European Thyroid Association Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules in Adults: The EU-TIRADS. Eur Thyroid J. 2017; 6:225–237. doi: 10.1159/000478927
Russ G., Leboulleux S., Leenhardt L., Hegedüs L. Thyroid incidentalomas: epidemiology, risk stratification with ultrasound and workup. Eur Thyroid J. 2014; 3:154–163.
Bonavita J.A., Mayo J., Babb J., Bennett G., Oweity T., Macari M., Yee J. Pattern recognition of benign nodules at ultrasound of the thyroid: which nodules can be left alone? AJR Am J Roentgeno.l 2009; 193:207–213.
Brito J.P., Gionfriddo M.R., Al Nofal A., Boehmer K.R., et al. The accuracy of thyroid nodule ultrasound to predict thyroid cancer: systematic review and meta-analysis. J Clin Endocrinol Metab. 2014; 99:1253–1263.
Na D.G., Baek J.H., Sung J.Y., et al. Thyroid imaging reporting and data system risk stratification of thyroid nodules: categorization based on solidity and echogenicity. Thyroid. 2016; 26:562–572.
Wei X., Li Y., Zhang S., Gao M. Meta-analysis of thyroid imaging reporting and data system in the ultrasonographic diagnosis of 10,437 thyroid nodules. Head Neck. 2016; 38:309–315.
Cibas E.S., Ali S.Z. The Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2009; 19(11):1159-65. doi: 10.1089/thy.2009.0274
Ali SZ, VanderLaan PA. The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes, 3rd ed. Springer: New York, NY, USA; 2023.
Pediatric Thyroidology. Edited by Gabor Szinnai; Translated from English, edited by Peterkova V.A. - M.: GEOTAR-Media, 2016.
Brovin D., Peterkova V., Anikiev A., et al. The Value of Cytological, Histological and US Examination to Determine of Management Children with Nodular Goiter. Horm Res Paediatr. 2018; 90(1):88.
Lebbink, Chantal & Links, Thera & Czarniecka, Agnieszka & Dias, Renuka & Elisei, Rossella & Izatt, Louise & Krude, Heiko & Lorenz, Kerstin & Luster, Markus & Newbold, Kate & Piccardo, Arnoldo & Sorinho-Simoes, Manuel & Takano, Toru & Trotsenburg, A. S. Paul & Verburg, Frederik & Santen, Hanneke M. (2022). 2022 ETA Guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma. European thyroid journal. 11. 10.1530/ETJ-22-0146. P.16-18
Hoffman M.R., Meadows S.E., Langlois J.P. Clinical inquiries. What is the best approach to goiter for euthyroid patients? J Fam Pract. 2007; 56:479-480.
Schroeder P.R., Ladenson P.W. Toxic Nodular Goiter. Clinical Management of Thyroid Disease. 2009:203-219. doi: 10.1016/B978-1-4160-4745-2.00014-6
Bahn R.S., Burch H.B., Cooper D.S., et al. Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011; 21.
Weetman A.P. Radioiodine treatment for benign thyroid diseases. Clinical Endocrinology. 2007;66(6);757-764.
Hoermann R. Treatment Regimens in Toxic and Diffuse Goiters in Iodine Deficiency. Comprehensive Handbook of Iodine. 2009; 9:789-800. doi: 10.1016/B978-0-12-374135-6.00081
Toft A.D. Subclinical Hyperthyroidism. New England Journal of Medicine. 2001; 345(7):512-516. doi: 10.1056/NEJMcp010145
Ianni F., Perotti G., Prete A., et al. Thyroid scintigraphy: an old tool is still the gold standard for an effective diagnosis of autonomously functioning thyroid nodules. J Endocrinol Invest. 2013;36(4):233-6. doi: 10.3275/8471
Dutta D., Kumar M., Thukral A., et al. Medical management of thyroid ectopia: report of three cases. J Clin Res Pediatr Endocrinol. 2013; 5(3):212–215. doi: 10.4274/Jcrpe.1103
Tunkel D.E., Domenech E.E. Radioisotope scanning of the thyroid gland prior to thyroglossal duct cyst excision. Arch Otolaryngol Head Neck Surg. 1998; 124:597–599.
Sood A., Sood V., Sharma D.R., Seam R.K., Kumar R. Thyroid scintigraphy in detecting dual ectopic thyroid: a review. Eur J Nucl Med Mol Imaging. 2008; 35:843–846.
Medeiros-Neto G. Multinodular Goiter. 2016 [online] Ncbi.nlm.nih.gov. Available at: <https://www.ncbi.nlm.nih.gov/books/NBK285569/> [Accessed 20 May 2020].
Grussendorf M., Reiners C., Paschke R., Wegscheider K., on behalf of the LISA investigators. Reduction of thyroid nodule volume by levothyroxine and iodine alone and in combination: a randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2011; 96:2786–95.
Wilders-Truschnig M.M., Warnkross H., Leb G. The effect of treatment with levothyroxine or iodine on thyroid size and thyroid growth stimulating immunoglobulins in endemic goiter patients. Clin. Endocrinol. (Oxf.). 1993; 39(3):281-286.
Fadeev V.V. Modern principles of treatment of euthyroid goiter. Difficult Patient, 2010.
Ghaznavi S., Lithgow K., Agrawal V., Paschke R. Nontoxic Goiter. Encyclopedia Of Endocrine Diseases. 2018; 524-528. doi: 10.1016/b978-0-12-801238-3.96012-4
DeMaeyer E.M., Lowenstein F.W., Thilly C.W. and World Health Organization. The control of endemic goiter. 1979.
Szabolcs I., Podoba J., Feldkamp J., Dohan O., Farkas I., Sajgo M., Takats K.I., Goth M., Kovacs L., Kressinszky K., et al. Comparative screening for thyroid disorders in old age in areas of iodine deficiency, long-term iodine prophylaxis and abundant iodine intake. Clin Endocrinol. 1997; 47:87-92.
Kouame P., Koffi M., Ake O., Nama-Diarra A.J., Chaventre A. Management strategies for endemic goiter in developing countries. Med Trop (Mars). 1999;59(4):401‐410.
Troshina E.A. Modern standards regulating the use of potassium iodide in pregnant and breastfeeding women. Gynecology. 2013; 15(4):48-52.
Melnichenko G.A., Fadeev V.V., Dedov I.I. Thyroid diseases during pregnancy (diagnosis, treatment, prevention). A guide for physicians. - M.: 2003.
Alexander E.K., Pearce E.N., Brent G.A., et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017; 27(3). doi:10.1089/thy.2016.0457
Pearce E.N., Lazarus J.H., Moreno-Reyes R., Zimmermann M.B. Consequences of iodine deficiency and excess in pregnant women: an overview of current knowns and unknowns. Am J Clin Nutr. 2016; 104:918S-23S.
Andersson M., De Benoist B., Delange F., Zupan J. Prevention and control of iodine deficiency in pregnant and lactating women and in children less than 2 years old: conclusions and recommendations of the technical consultation. Public Health Nutr. 2007; 10:1606-1611
Van den Boogard E., Vissenberg R., Land J.A., et al. Significance of subclinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011; 17:605-619.
Hintze G., Köbberling, J. Treatment of iodine deficiency goiter with iodine, levothyroxine or a combination of both. Thyroidology Clinical and Experimental. 1992;4(1):37-40.
Haddow J.E., Palomaki G.E., Allan W.C., et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New Engl J Med. 1999; 341:49-555.
Liu Q., Djuricin G., Prinz R.A. Total thyroidectomy for benign thyroid disease. Surgery. 1998; 123:2-7.
Bellantone R., Lombardi C.P., Bossola M., et al Total thyroidectomy for management of benign thyroid disease: review of 526 cases. World J Surg. 2002; 26:1468-1471.
Le Moli R., Wesche M.F., Tiel-Van Buul MM, Wiersinga W.M. Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goitre. Clin Endocrinol. 1999; 50:783–9.
Silva MN, Rubió IG, Romão R, Gebrin EM, Buchpiguel C, Tomimori E, Camargo R, Cardia MS, Medeiros-Neto G. Administration of a single dose of recombinant human thyrotrophin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres. Clin Endocrinol (Oxf). 2004 Mar;60(3):300-308.
76 Huo Y, Xie J, Chen S, Wang H, Ma C. Recombinant human thyrotropin (rhTSH)-aided radioiodine treatment for non-toxic multinodular goitre. Cochrane Database Syst Rev. 2021 Dec 28;12(12):CD010622. doi: 10.1002/14651858.CD010622.pub2. PMID: 34961921; PMCID: PMC8712889. New source Removing source Sorensen J.R., Watt T., Cramon P., Dossing H., Hegedus L., Bonnema S.J., Godballe C. Quality of life after thyroidectomy in patients with nontoxic nodular goiter: A prospective cohort study. Head Neck. 2017; 39(11):2232-2240.
Erdogan M.F., Küçük N.O., Anil C., et al. Effect of radioiodine therapy on thyroid nodule size and function in patients with toxic adenomas. Nucl Med Commun. 2004; 25:1083–1087.
Rokni H., Sadeghi R., Moossavi Z., Treglia G., Zakavi S.R. Efficacy of different protocols of radioiodine therapy for treatment of toxic nodular goiter: systematic review and meta-analysis of the literature. Int J Endocrinol Metab. 2014; 12(2):e14424. doi:10.5812/ijem.14424
Niedziela M., Breborowicz D., Trejster E., Korman E. Hot nodules in children and adolescents in western Poland from 1996 to 2000: clinical analysis of 31 patients. J Pediatr Endocrinol Metab. 2002; 15:823–830.
Schwab K.O., Pfarr N., van der Werf-Grohmann N., Pohl M., Radecke J., Musholt T., Pohlenz J. Autonomous thyroid adenoma: only an adulthood disease? J Pediatr. 2009; 154:931–933.
Percutaneous intranodular ethanol injection Goletti O., Monzani F., Lenziardi M., et al. Cold thyroid nodules: a new application of percutaneous ethanol injection treatment. J Clin Ultrasound. 1994; 22:175-178.
Monzani F., Lippi F., Goletti O., et al. Percutaneous aspiration and ethanol sclerotherapy for thyroid cysts. J Clin Endocrinol Metab. 1994; 78:800-802.
World Health Organization, UNICEF, International Council for Control of Iodine Deficiency Disorders. Assessment of iodine deficiency disorders and monitoring their elimination: a guide for programme managers. 3rd ed. Geneva: World Health Organization; 2007.
WHO. Iodine and health. Eliminating iodine deficiency disorders safely through salt iodization. Geneva: WHO publ. 1994:1-7.
Haldimann M., Alt A., Blanc A., Blondeau K. Iodine content of food groups. J Food Comp Anal. 2005; 18:461–71.
Pearce E.N., Lazarus J.H., Moreno-Reyes R., Zimmermann M.B. Consequences of iodine deficiency and excess in pregnant women: an overview of current knowns and unknowns. Am J Clin Nutr. 2016; 104:918S-23S.
Nikiforov Y.E., Ohori N.P., Hodak S.P., et al. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. J Clin Endocrinol Metab. 2011; 96:3390–3397.
Nikiforov Y.E., Carty S.E., Chiosea S.I., Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer. 2014; 120:3627–3634.
Alexander E.K., Schorr M., Klopper J., et al. Multicenter clinical experience with the Afirma gene expression classifier. J Clin Endocrinol Metab. 2014; 99:119–125.
Verkaik-Kloosterman J. Neonatal heel prick screening TSH concentration in the Netherlands as indicator of iodine status. Nutr J. 2021;20(1):63. doi: 10.1186/s12937-021-00722-4.
González Martínez S, Prieto García B, Escudero Gomis AI, Delgado Álvarez E, Menéndez Torre EL. Neonatal TSH as a marker of iodine nutrition status. Effect of maternal ioduria and thyroid function on neonatal TSH. An Pediatr (Engl Ed). 2022; S2341-2879(22)00210-1. doi: 10.1016/j.anpede.2022.09.008.
Nazeri P, Mirmiran P, Kabir A, Azizi F. Neonatal thyrotropin concentration and iodine nutrition status of mothers: a systematic review and meta-analysis. Am J Clin Nutr. 2016;104(6):1628-1638. doi: 10.3945/ajcn.116.131953.
Zimmermann M.B., S. Hess Y., Molinari L. et al. New reference values for thyroid volume by ultrasound in iodine-sufficient schoolchildren: a World Health Organization/Nutrition for Health and Development Iodine J. Clinical Nutrition. 2004;79(2): 231-237.
UNICEF; Global Iodine Network. Guidelines for monitoring salt iodization programmes and assessing iodine status of populations (Russian-language version) // Clinical and Experimental Thyroidology. – 2018. – Vol. 14. – No. 2. – P. 100–112. doi: 10.14341/ket9734
Radionuclide diagnostics for practical physicians / Ed. by Yu.B. Lishmanov, V.I. Chernov. – Tomsk: STT, 2004. – 394 p. ISBN 5-93629-166-9. - 398 pages
Appendix A1. Working Group Composition
Abdulkhabirova F.M., Candidate of Medical Sciences, Head of the Laboratory of Cytology and Cytogenetics, Department of Fundamental Pathomorphology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Bezlepkina O.B. – Doctor of Medical Sciences, Professor, Deputy Director - Director of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Brovin D.N. – Candidate of Medical Sciences, Head of the Pediatric Surgical Department, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Vadina T.A. – Candidate of Medical Sciences, Pediatric Endocrinologist, Researcher at the Department of Epidemiology of Endocrinopathies, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Makolina N.P. - Head of the Department of Coordination, Analysis, and Statistics of the Coordination Council of the National Medical Research Center for Endocrinology, Endocrinologist at the Department of Therapeutic Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Melnichenko G.A. – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director for Research, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Nagaeva E.V. – Candidate of Medical Sciences, Associate Professor, Head of the Pediatric Department of Thyroidology, Reproductive and Somatic Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Nikankina L.V. – Candidate of Medical Sciences, Head of the Clinical Diagnostic Laboratory, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Peterkova V.A. – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Scientific Director of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Russian Ministry of Health.
Platonova N.M. – Doctor of Medical Sciences, Professor, Head of the Department of Therapeutic Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Rybakova A.A. – Endocrinologist at the Department of Therapeutic Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Soldatova T.V. – Candidate of Medical Sciences, Head of the Ultrasound Diagnostics Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Troshina E.A. - Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director – Director of the Institute of Clinical Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
Shiryaeva T.Yu. – Candidate of Medical Sciences, Associate Professor, Leading Researcher at the Pediatric Department of Thyroidology, Reproductive and Somatic Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.
None of the working group members had a conflict of interest during the development of these clinical guidelines, namely a personal interest in obtaining, personally or through a company representative, material gain or other advantage that would or could affect the proper performance of their professional duties.
Appendix A2. Methodology for Developing Clinical Guidelines
The guidelines presented herein are based on a systematic literature review performed by the group members. All articles published up to 2019 were submitted for review. The group experts reviewed these data and selected articles with the highest level of evidence.
Target audience for these clinical guidelines:
Endocrinologists;
Pediatric endocrinologists;
General practitioners;
General practitioners (family physicians);
Oncologists;
Ultrasound diagnostics physicians;
Surgeons.
Appendix 1. Levels of Evidence (LE) scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Appendix 2. Scale for grading levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods,
including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions).
LoE | Definitions |
|---|---|
1 | Systematic review of randomized controlled trials with meta-analysis |
2 | Individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Appendix 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The guideline update mechanism provides for their systematic review—at least once every three years or upon the emergence of new information on the management tactics of patients with this disease. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The submitted proposals must take into account the results of a comprehensive assessment of medicinal products and medical devices, as well as the results of clinical approbation.
Appendix A3. Reference Materials
Order of the Russian Ministry of Health No. 893n dated August 31, 2021 "On approval of the standard of medical care for adults with diseases and conditions associated with iodine deficiency"
Order of the Russian Ministry of Health No. 104n dated March 13, 2023 "On approval of the Procedure for providing medical care to the adult population in the profile 'endocrinology'"
Order of the Russian Ministry of Health No. 908n dated November 12, 2012 "On approval of the Procedure for providing medical care in the profile 'pediatric endocrinology'"
Appendix B. Physician Action Algorithms
1. Physician's action algorithm "Diffuse Goiter"
Appendix C. Patient Information
Goiter is defined as an enlargement of the thyroid gland of more than 18 ml in women and more than 25 ml in men. "Diffuse goiter" means that the enlargement occurs evenly across all parts of the thyroid gland. Iodine deficiency is the most common cause. The Russian Federation is an iodine-deficient region, with the prevalence of diffuse endemic goiter averaging 31% nationwide. In most cases, goiter is asymptomatic. If thyroid enlargement is suspected based on palpation results, it is necessary to determine the thyroid volume using ultrasound. If thyroid enlargement is confirmed, thyroid function must be evaluated. The first-line test is TSH determination. The first step in the treatment of diffuse euthyroid goiter is the prescription of iodine preparations. If iodine therapy is ineffective, combination therapy is indicated. Normalization of the thyroid volume occurs within 1.5–2.0 years of treatment. To prevent disease recurrence, regular dietary consumption of iodinated salt is recommended.
Nodular formations in the thyroid gland that are not palpable and/or do not exceed 1 cm in diameter have no clinical significance and generally do not require an active diagnostic workup. Palpable and/or >1 cm nodular formations necessitate fine-needle aspiration biopsy of the thyroid gland. The vast majority of thyroid nodules are small nodular colloid goiters with varying degrees of proliferation, for which active surveillance is indicated in most cases.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not required.