Tobacco smoking has been a global health problem for many years. It has especially worsened since the mass production of tobacco products. Tobacco smoking provokes various diseases, including endocrine diseases, and contributes to their progression. It is now known about the role of genetic predisposition to the development of thyroid pathology and the potential role of various environmental factors in the manifestation of thyroid diseases. Along with iodine intake, tobacco smoking is a significant risk factor affecting the functional status and volume of the thyroid gland. The introduction of electronic cigarettes as an alternative to tobacco products has raised a legitimate question: what effect do they have on thyroid status? The current literature review highlights current knowledge on the effects of smoking on the thyroid, including its relationship to changes in thyroid function and the development and progression of thyroid disorders.

AIM: The purpose of this study was to analyze the characteristics of management, diagnosis and treatment of patients with vitamin D deficiency/ by endocrinologists in the regions of Russian Federation using a sociological survey.MATERIALS AND METHODS: A cross-sectional sociological uncontrolled study was carried out. To implement this work, we used an online questionnaire “Questioning doctors on vitamin D” specially developed on the basis of the Google forms platform. The study was conducted in January 2021.All the data obtained were entered into an electronic database in MS Excel. Statistical processing was performed using the IBM SPSS Statistics 25 software.RESULTS: The survey involved 707 physicians from 86 regions of the Russian Federation. Our study revealed that not all doctors strictly adhere to clinical recommendations in patient management. Issues identified include unjustifiably widespread ordering of 25(OH)D blood tests (58.5%), lack of consideration for individual patient characteristics and clinical situations in dose selection (99.2%) and prescription of active metabolite or analogs of vitamin D to correct low 25(OH)D levels in blood (14.7%). Furthermore, recommendations for improving clinical guidelines focused on the lack of illustrative material (21.1%), expanding patient information sections (20.7%), and insufficient coverage of issues arising in clinical practice (14.6%). Our study also highlighted limited capabilities of laboratory diagnostics for assessing vitamin D status in patients in Russia. The survey revealed that only 9.2% of respondents have the ability to measure 1,25(OH)2D concentrations, and only 1.4% can order tests for 24,25(OH)2D. About 8.3% of participants did not specify which tests for assessing vitamin D status are available for prescription. Technical enhancement of laboratories and the inclusion of all recommended laboratory study requirements in the compulsory health insurance system could address this.Regarding vitamin D toxicity, 25% of surveyed doctors encountered it. Main causes included self-administration of elevated doses of cholecalciferol by patients (62%) or prescribed by physicians (40%), the use of active metabolites or analogs of vitamin D (21%), incorrect dosing of cholecalciferol preparations as indicated by the manufacturer (18%), and defects in CYP24A1 (13%). Rare causes included granulomatous and lymphoproliferative diseases (11.5%).CONCLUSION: The current clinical guidelines of the Russian Association of Endocrinologists for «Vitamin D Deficiency in Adults» are generally effective and widely used by clinicians. However, they do not entirely meet the needs of specialists and require refinement in terms of improving structure and clarity of presentation, expanding illustrative material, and justifying the frequency of laboratory diagnostics. Cases of vitamin D toxicity observed in clinical practice were predominantly associated with incorrect administration of vitamin D supplements. The identified high frequency of vitamin D toxicity in real clinical practice necessitates additional attention to this issue during the update of clinical recommendations.

ЦЕЛЬ: существующие терапевтические подходы к лечению эндокринной офтальмопатии (ЭОП) основываются на неспецифической иммуносупрессии глюкокортикоидами (ГК) и лучевой терапии орбит. При этом часть пациентов остаются резистентными к лечению. Целью настоящей работы явилось исследование динамики TGF-β1 и рецепторов цитокинов: sTNFα-R1, sTNFα-R2, sIL-2R на фоне проведения иммуносупрессивной терапии высокими дозами ГК как возможных предикторов эффективности лечения. Материалы и методы: в исследование были включены 49 пациентов (98 орбит) с БГ в состоянии эутиреоза и субклинического тиреотоксикоза и ЭОП в активной фазе, не получавших ранее лечения по поводу ЭОП. Определены концентрации цитокина TGF-β1, sTNFα-RI и sTNFα-R2, sIL-2R, антител к рецептору тиреотропного гормона (рТТГ), свободных фракций тироксина (свТ4) и трийодтиронина (свТЗ), ТТГв сыворотке крови. Выполнено ультразвуковое исследование щитовидной железы (УЗИ ЩЖ), мультиспиральная компьютерная томография (МСКТ)/магнитно-резонансная томография (МРТ) орбит. Пациентам была назначена иммуносупрессивная терапия высокими дозами ГК (метилпреднизолоном) в режиме пульс-терапии, в стандартной дозировке 4500-8000 мг с учетом тяжести и активности клинических проявлений ЭОП. Обследование проводилось через 3, 6, 12 месяцев от начала лечения. РЕЗУЛЬТАТЫ: через 3 и 6 месяцев от начала введения ГК резистентными к лечению оставались более 30% пациентов. У пациентов с положительной динамикой ЭОП уровень TGF-β1 существенно не изменился. У пациентов, резистентных к лечению ГК, уровень TGF-β1 достоверно снизился по сравнению с пациентами с положительной динамикой. Уровень sTNFR1, sTNFα-R2 существенно не изменился. Достоверных отличий уровней антител к рТТГ, тиреоидных гормонов у пациентов резистентных к лечению ГК и с положительной динамикой не отмечено. ВЫВОДЫ: иммуносупрессивная терапия высокими дозами метилпреднизолона в режиме пульстерапии показала высокую эффективностью и хорошую переносимость, при этом часть пациентов остаются резистентными к лечению. Более низкие показатели цитокина TGF-β1 исходно и в процессе лечения позволяют использовать TGF-β1 в качестве биомаркера активности процесса, эффективности лечения и прогноза заболевания. Активация TGF-β1, как фактора роста фибробластов, может способствовать развитию фиброза, косоглазия и диплопии

BACKGROUND:Data on the effect of 131I on the course of Graves' orbitopathy (GO) are contradictory. A number of studies indicate a deterioration in the course of GO against the background of RAIT, in other studies such a connection has not been established. Cytokines that regulate inflammation could potentially be biomarkers for assessing GO activity and predicting the course of GO after RAIT. AIM:The purpose of this study was to evaluate the dynamics of eye symptoms and analyze immunological parameters: cytokine TGF-β1 and cytokine receptors: sTNFα-R1, sTNFα-R2, sIL-2R, sIL-6R over time after RAIT, as possible predictors of GO activation. MATERIALS AND METHODS:The study included 59 patients (118 orbits) with GD in the state of euthyroidism and subclinical hyperthyroidism and low active and inactive GO, aimed at conducting RAIT. Concentrations of cytokine TGF-β1, sTNFα-RI and sTNFα-R2, sIL-2R, sIL-6R, TSH receptor antibodies (rTSH-Ab), free thyroxine (FT4) and free triiodothyronine (FT3), -thyroid-stimulating hormone (TSH) in the blood serum were determined. Ultrasound examination of the thyroid gland, multispiral computed tomography (MSCT)/magnetic resonance imaging (MRI) of the orbits was performed. The examination was carried out 3, 6, 12 months after the RAIT. RESULTS:The deterioration of the course of the GO (1-2 points according to CAS) was noted after 3 months. (32.5%) and to a lesser degree after 6 and 12 months (13.2% and 8.45%, respectively). Dynamics were not noted, approximately, in the same number of patients (40.5%, 41.5%, 45.8%, respectively). An improvement in the course of the GO was noted after 6 and 12 months (45.3, 45.8, respectively). After 3 and 6 months, the achievement of hypothyroidism and a significant increase in the level of rTSH-Ab were noted. In the analysis of cytokines and their receptors a significant decrease in the level of TGF-β1 was noted after 3, 6 and 12 months. There was also a significant decrease in sTNF-R1 and sIL-2R at 3 and 6 months. The level of sTNFα-R2 significantly decreased 3 months after RAIT. The level of sIL-6R has not changed significantly. After 3 months in patients with positive dynamics of image intensification, the level of TGF-β1 did not significantly change compared with the level before RAIT, in patients with worsening of the course of GO or without dynamics, the level of TGF-β1 significantly decreased. After 6 months, there was the same trend, not reaching statistical significance. The IgG4 level and the IgG4/IgG ratio increased to 6 and 12 months, which corresponded to an increase in diplopia index. CONCLUSION:The main limiting factor in the conduct of RAIT is the activity of the autoimmune process in the orbits. Since patients with inactive (CAS 0-2) or low activity (CAS 3-4) GO were referred for RAIT, there was no pronounced activation of GO after RAIT. There was a slight deterioration in the course of GO by only 1-2 points according to CAS after 3 months. (32.5%) and to a lesser degree after 6 months (13.2%). In the study, it was found that the main predictors of the deterioration of the course of GO after RAIT are uncompensated hypothyroidism, a high level of rTSH-Ab and a decrease in the level of cytokine TGF-β1.

ЦЕЛЬ: существующие терапевтические подходы к лечению эндокринной офтальмопатии (ЭОП) основываются на неспецифической иммуносупрессии глюкокортикоидами (ГК) и лучевой терапии орбит. При этом часть пациентов остаются резистентными к лечению. Целью настоящей работы явилось исследование динамики TGF-β1 и рецепторов цитокинов: sTNFα-R1, sTNFα-R2, sIL-2R на фоне проведения иммуносупрессивной терапии высокими дозами ГК как возможных предикторов эффективности лечения. Материалы и методы: в исследование были включены 49 пациентов (98 орбит) с БГ в состоянии эутиреоза и субклинического тиреотоксикоза и ЭОП в активной фазе, не получавших ранее лечения по поводу ЭОП. Определены концентрации цитокина TGF-β1, sTNFα-RI и sTNFα-R2, sIL-2R, антител к рецептору тиреотропного гормона (рТТГ), свободных фракций тироксина (свТ4) и трийодтиронина (свТЗ), ТТГв сыворотке крови. Выполнено ультразвуковое исследование щитовидной железы (УЗИ ЩЖ), мультиспиральная компьютерная томография (МСКТ)/магнитно-резонансная томография (МРТ) орбит. Пациентам была назначена иммуносупрессивная терапия высокими дозами ГК (метилпреднизолоном) в режиме пульс-терапии, в стандартной дозировке 4500-8000 мг с учетом тяжести и активности клинических проявлений ЭОП. Обследование проводилось через 3, 6, 12 месяцев от начала лечения. РЕЗУЛЬТАТЫ: через 3 и 6 месяцев от начала введения ГК резистентными к лечению оставались более 30% пациентов. У пациентов с положительной динамикой ЭОП уровень TGF-β1 существенно не изменился. У пациентов, резистентных к лечению ГК, уровень TGF-β1 достоверно снизился по сравнению с пациентами с положительной динамикой. Уровень sTNFR1, sTNFα-R2 существенно не изменился. Достоверных отличий уровней антител к рТТГ, тиреоидных гормонов у пациентов резистентных к лечению ГК и с положительной динамикой не отмечено. ВЫВОДЫ: иммуносупрессивная терапия высокими дозами метилпреднизолона в режиме пульстерапии показала высокую эффективностью и хорошую переносимость, при этом часть пациентов остаются резистентными к лечению. Более низкие показатели цитокина TGF-β1 исходно и в процессе лечения позволяют использовать TGF-β1 в качестве биомаркера активности процесса, эффективности лечения и прогноза заболевания. Активация TGF-β1, как фактора роста фибробластов, может способствовать развитию фиброза, косоглазия и диплопии

The strategy for the elimination of diseases associated with iodine deficiency throughout the Russian Federation is based on the adoption of a federal law providing for the use of iodized salt as a means of mass (population) iodine prophylaxis. Chronic iodine deficiency that exists in Russia leads to dramatic consequences: the development of mental and physical retardation in children, cretinism, thyroid diseases, and infertility. Under conditions of iodine deficiency, the risk of radiation-induced thyroid cancer in children in the event of nuclear disasters increases hundreds of times. By definition, all iodine deficiency diseases (IDDs) can be prevented, while changes caused by iodine deficiency during fetal development and in early childhood are irreversible and practically defy treatment and rehabilitation. The actual average consumption of iodine by a resident of Russia is only 40-80 mcg per day, which is 3 times less than the established norm (150-250 mcg). Every year, more than 1.5 million adults and 650 thousand children with various thyroid diseases turn to medical institutions. The cause of 65% of cases of thyroid disease in adults and 95% in children is insufficient intake of iodine from the diet. At the stage of preparing the relevant legislative act, the development and implementation of regional programs for the prevention of IDD is of utmost importance. A typical draft of such a program is proposed in this article for its adaptation and use at the regional level.

Current therapeutic approaches to the treatment of endocrine ophthalmopathy (EOP) are based on nonspecific immunosuppression with glucocorticosteroids (GCs) and radiation therapy of the eye orbits. However, some patients exhibit resistance to the treatment. In a previous study, we have detected high levels of soluble cytokine receptors: sTNFα-R1, sTNFα-R2, sIL-2R, and the TGF-β1 cytokine in euthyroid patients with long-lasting non-treated EOP and Graves’ disease (GD). TGF-β1 level was significantly higher in the patients with EOP compared to healthy individuals, and increased with prolonged EOP duration, thus suggesting activation of the factors regulating immune system which promote suppression of the autoimmune process. The aim of this work was to study the dynamics of TGF-β1 and cytokine receptors: sTNFα-R1, sTNFα-R2, sIL-2R in the course of immunosuppressive therapy with high doses of GCs, as possible predictors of treatment efficacy. The study included 49 patients (98 eye orbits) with GD of euthyroid state and subclinical thyrotoxicosis, and the persons with EOP in active phase, who had not previously treatment for EOP. Concentrations of TGF-β1 cytokine, sTNFα-RI and sTNFα-R2, sIL-2R, antibodies to the thyroid-stimulating hormone receptor (rTSH), free fractions of thyroxine (fT4) and triiodothyronine (fT3), TSH in blood serum were determined in blood serum. Ultrasound examination of the thyroid gland (ultrasound of the thyroid gland), multi-layer computed tomography (MSCT)/magnetic resonance imaging (MRI) of the orbits were also performed. The patients were administered immunosuppressive therapy with high doses of HCs (methylprednisolone) in the course of pulse therapy, at a standard dosage of 4500-8000 mg, taking into account the severity and activity of the EOP clinical manifestations. The examination was carried out 3, 6, 12 months after starting the treatment. 3 and 6 months after the GC administration, more than 30% of patients remained resistant to treatment. The levels of TGF-β1 did not change significantly in the patients with positive EOP dynamics. In the patients resistant to GC treatment, the level of TGF-β1 was significantly decreased compared with patients who showed positive clinical dynamics. The level of sNFR1 and sNFaR2 did not change significantly. There were no significant differences in the levels of antibodies to rTSH, thyroid hormones in the patients resistant to GC treatment and with positive dynamics. Immunosuppressive therapy with high-dose of methylprednisolone in pulse therapy regimen showed high efficacy and good tolerability, while some patients remain resistant to treatment. Lower levels of TGF-β1 cytokine at initial time and during the treatment allow usage of TGF-β1 levels as a biomarker of the activity of the process, treatment efficiency, and prognosis of the disease. Activation of TGF-β1, a fibroblast growth factor, may contribute to the development of fibrosis, strabismus, and diplopia.

IV (XXVII) Национальный конгресс эндокринологов с международным участием «ИННОВАЦИОННЫЕ ТЕХНОЛОГИИ В ЭНДОКРИНОЛОГИИ» 22-25 сентября 2021 года АУТОАНТИТЕЛА И ЦИТОКИНОВЫЙ ПРОФИЛЬ У ПАЦИЕНТОВ С БОЛЕЗНЬЮ ГРЕЙВСА И ЭНДОКРИННОЙ ОФТАЛЬМОПАТИЕЙ Свириденко Н .Ю ., Бессмертная Е .Г ., Беловалова И

Graves' disease (GD) is an autoimmune disease that is often complicated by thyroid eye disease (TED). Clinical presentations of TED can develop simultaneously with the manifestation of GD, after the manifestation of GD amid treatment, and before the development of thyrotoxicosis. Treatment of such patients is a difficult task, because on the one hand, it is necessary to take into account the clinical picture of thyrotoxicosis, and on the other - the symptoms of eye damage. The combination of the two pathologies determines the need for simultaneous treatment of GD and TED, and the choice of a treatment method for GD will depend on the manifestations of TED. This article presents current views on the treatment of GD with concomitant TED. The choice of GD treatment method will be largely determined by the clinical manifestations of TED and will be conducted jointly by endocrinologists and ophthalmologists.

BACKGROUND : Graves' Orbitopathy (GO) — also known as Thyroid Eye Disease (TED) — is an autoimmune condition in the modern sense. It is closely associated with autoimmune thyroid diseases. Cytokine-mediated mechanisms play a critical part in immunopathogenesis of autoimmune thyroid diseases including GO. Investigating cytokine profiles as well as antibodies to tissue-specific antigens is essential for explaining GO pathogenesis and developing future therapeutic strategies. AIMS : The study examines serum levels of cytokines, autoantibodies and immunoglobulins IgG and IgG4 as mediators of autoimmune inflammation in patients with GO and Graves' Disease (GD). MATERIALS AND METHODS : The study included 52 patients (104 orbits) aged 25-70 years (mean age 48,8±12,3) in the active phase of GO and GD verified with the international diagnostic standards. These patients did not get any treatment for GO before. The control group consisted of 14 individuals (28 orbits) aged 30-68 years without known autoimmune disease. Serum levels of IgG, IgG4,TNFα, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-13, sIL-6R, sTNFα- RI и TNFα- R2 IL-2R, TGFβ1, TGF β3, antibodies to TSH-receptor, free T4, free T3 and TSH were measured. A diagnostic ultrasound exam of thyroid gland, multislice computed tomography (MSCT) / magnetic resonance imaging (MRI) of orbits were performed. RESULTS : Mean duration of GO prior to being admitted to the centre was 8,8±1,5 months (range: 1 — 48 months). According to the degree of thyrotoxicosis compensation: 24 patients were clinically euthyroid, TSH 3,3±0,7 mU/L, free T4 11,9±0,59 pmol/L, free T3 3,97±0,1 pmol/L; 28 patients were considered to have subclinical thyrotoxicosis: TSH 0,03±0,01 mU/L, free T4 14,2±1,0 pmol/L, free T3 5,77±0,49 pmol/L. Serum levels of sTNFα-R2 (p=0,041, p≤0,05), sIL-2R (p=0,020, p≤0,05), TGFβ1 (p=0,000, p≤0,001) were significantly higher in patients with GO compared to the control group. Serum levels of sTNFRα2 (p=0,038, p 5%). CONCLUSION : High levels of soluble cytokine receptors sTNFα-R2 and sIL-2R and cytokine TGFβ1 in patients with long-standing untreated GO and GD being euthyroid or having subclinical thyrotoxicosis indicate activation of regulatory T cells aimed at suppressing autoimmune processes. High concentration level of IgG4 in IgG and cytokine TGFβ1 can determine the development of fibrotic changes in the orbital tissues. A decrease in the concentration of cytokine TGFβ1 can indicate an unfavorable course of the disease GO.