[Clinical and immunological predictors of Graves' orbitopathy after radioiodine therapy of Graves' disease].

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-ß1 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-ß1, 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-ß1 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-ß1 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-ß1 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-ß1.

[Prevention of iodine deficiency diseases: focus on regional targeted programs].

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.

[Regional target program «Prevention of iodine deficiency diseases for 202X-202X¼].

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[Treatment of Graves' disease in patients with thyroid eye disease]. / Lechenie bolezni Greivsa pri soputstvuyushchei endokrinnoi oftal'mopatii.

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.

[Autoantibodies, immunoglobulins and cytokine profile in patients with graves' disease and Graves' orbitopathy].

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-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-13, sIL-6R, sTNFα- RI и TNFα- R2 IL-2R, TGFß1, TGF ß3, 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), TGFß1 (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<0,05) and TGFß1 (P=0,011, p≤0,05) were positively correlated with the duration of GO. The positive correlations between the serum level of sIL-6R (p=0,034, p≤0,05) and the severity of GO as well as between the serum level of sTNFα- R 1 (P=0,012, p≤0,05) and activity of GO were observed. 54% of patients had elevated concentration level of IgG4 in IgG ( >5%). CONCLUSION: High levels of soluble cytokine receptors sTNFα-R2 and sIL-2R and cytokine TGFß1 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 TGFß1 can determine the development of fibrotic changes in the orbital tissues. A decrease in the concentration of cytokine TGFß1 can indicate an unfavorable course of the disease GO.

[Radioiodine therapy for Graves' disease as a risk factor of endocrine ophthalmopathy].

In 1973 and 1976 R. Wasnich and R. Jackson described 2 cases of endocrine ophthalmopathy (EO) that occurred after external irradiation of the anterior surface of the neck due to a tumor (Hodgkin's lymphoma). Further observations showed that treatment of Graves' disease with radioactive iodine (131I) can worsen the course of EO. So, L. De Groot et al., Observing 264 patients after exposure to 131I for Graves' disease, found progression of EO in 4% of patients after the 1st course of therapy and in 12% after subsequent sessions. L. Bartalena et al. observed the appearance or significant progression of EO in 15% of 150 patients treated with 131I. At the same time, against the background of glucocorticoid therapy, only 10% of patients worsened the course of EO. Other studies have shown that the progression of EO after treatment with 131I without glucocorticoid administration was observed in 18-30% of cases. Along with this, it is believed that 131I does not affect the incidence of clinical symptoms in the orbit, and hypothyroidism that occurs after it does not lead to the progression of eye symptoms. The relationship between treatment and the onset or progression of EO is not clear. Nevertheless, there is evidence of an adverse effect of an elevated level of antibodies to the thyroid stimulating hormone receptor (TSH) in the blood serum after 1131I training for EO. This review is devoted to a review of the problem presented.

[Radioiodine therapy for Graves disease as a risk factor of endocrine ophthalmopathy].

In 1973 and 1976 2 cases of endocrine ophthalmopathy (EO) after external irradiation of the anterior surface of the neck due to a tumor (Hodgkin's lymphoma) was described. Further observations showed that treatment of Graves' disease (BG) with radioactive iodine (131I) can worsen the course of EO. So, L. De Groot et al., Observing 264 patients after exposure to 131I for BG, found progression of EO in 4% of patients after the 1st course of therapy and in 12% after subsequent sessions. Later the appearance or significant progression of EO in  patients treated with 131I has been observed. Some studies have shown that the progression of EO after treatment with 131I without glucocorticoids administration can be observed in 18-30% of cases. Along with this, there is an opinion that 131I does not affect the incidence of clinical symptoms in the orbit and that hypothyroidism that occurs after it does not lead to the progression of eye symptoms. The relationship between treatment and the onset or progression of EO is not clear. Nevertheless, there is evidence of an adverse effect of an elevated level of antibodies to the thyroid stimulating hormone receptor in the blood serum after 131I training for EO.

[C-peptide and insulin ratio in patients with juvenile dyspituitarism in varying symptomatology]. / Sootnoshenie C-peptida i insulina u bol'nykh s iunosheskim dispituitarizmom pri razlichnoi klinicheskoi simptomatike.

Altogether 24 adolescents with pubertal juvenile dyspituitarism (PJD) were investigated in the course of an oral GTT for 3 hours. The patients were divided into 3 groups: (1) with liver dysfunction and normal BP; (2) with normal liver and arterial hypertension; (3) with normal BP and normal liver function. The levels of glycemia, immunoreactive insulin, C-peptide and a molar C-peptide/insulin ratio were measured. All the examinees were characterized by basal and stimulated hyperinsulinemia against a background of a normal C-peptide value, the absence of a tendency to IRI reduction by the end of the GTT. A decrease in the C-peptide/IRI ratio was marked in the 1st group. One of the reasons of hyperinsulinemia in PJD in parallel with high insulin secretory pancreatic function can be a decrease in the metabolic clearance of liver insulin, especially noticeable in patients with hepatocyte dysfunction.

[Use of finoptin in patients with non-insulin-dependent diabetes mellitus with concomitant essential hypertension]. / Primenenie finoptina u bol'nykh insulinnezavisimym sakharnym diabetom s soputstvuiushchei gipertonicheskoi bolezn'iu.

The paper is devoted to a study of the time course of lipid metabolism, analysis of glucose tolerance, change in indices of immunoreactive insulin, glucagon and C-peptide before the start of verapamil therapy and 6 mos. after it during monotherapy with this drug. These parameters were investigated in the blood serum using biochemical methods and radioimmunoassays. A marked antihypertensive effect was achieved in patients suffering from noninsulin dependent diabetes mellitus with concomitant essential hypertension of the 2nd degree. No negative effect on the pancreatic hormone secretion was noted. Lipid transport indices were improved.

[The nature of the pancreatic hormone secretion and of the metabolic indices during the acute and chronic administration of peroral hypoglycemic preparations]. / Izuchenie kharaktera sekretsii gormonov podzheludochnoi zhelezy i nekotorykh metabolicheskikh pokazatelei pri ostrom i khronicheskom vvedenii peroral'nykh sakharoponizhaiushchikh preparatov.

A comparative study of the effect of acute and chronic administration of sulfanilureal sugar lowering drugs (glipizide and glibenclamide) on the secretion of the pancreatic hormones, indices of microcirculation, the level of triglycerides and nonesterified fatty acids was conducted. Patients with primary detected diabetes mellitus with normal body mass and obesity of I-III degrees were investigated. The principal differences in insulinotropic action of sugar lowering drugs in various groups of patients and significant differences in the mechanism of their hypoglycemic action at varying time of treatment indicate the necessity of a strictly differentiated approach to subscription of these drugs for patients with primary detected diabetes mellitus.

[Pancreatic hormone secretion in patients with newly detected diabetes mellitus]. / Izuchenie sekretsii gormonov podzheludochnoi zhelezy u bol'nykh s vpervye vyiavlennym sakharnym diabetom.

The level of pancreatic hormones was studied in 10 healthy persons and in 40 patients with diabetes mellitus detected for the first time by GTT, their body mass being normal. For assessment of immunoreactive insulin (IRI), the level of proinsulin and biological activity of serum insulin were determined, and these indices were compared with glucose and C-peptide levels. The examinees' inhomogeneity was shown; on the basis of the findings obtained 2 groups were identified. A decrease in the levels of IRI, C-peptide and biological activity of serum insulin in the 1st group indicated a possibility of type I diabetes mellitus in such patients. Hyperinsulinemia, not correlating with glucose and C-peptide, a high percentage of proinsulin and low biological activity of serum insulin were noted in the 2nd group. The study permitted a differentiated approach to assessment of patients and a choice of therapeutic tactics.

[The role of gastrin in regulating insulin and glucagon secretion in patients with diabetes mellitus]. / Rol' gastrina v reguliatsii sekretsii insulina i gliukagona u bol'nykh sakharnym diabetom.

The paper is concerned with the results of investigation of 26 donors and 85 patients with diabetes mellitus, type II, with normal body mass and obesity during GTT and a test breakfast to reveal correlation of IRI and IRG levels with the level of gastrin. Comparative analysis of indices during OGTT and food intake has shown that an increase in the levels of gastrin in patients with diabetes mellitus, type II, does not correlate with body mass and the total level of insulin, but it may correlate with a metabolically active form of insulin. During food intake the levels of gastrin rise and do not change during GTT. A rise of the level of gastrin in patients with diabetes mellitus, type II, during a test breakfast is accompanied by change in the level of insulin, its peak being lower than that during GTT. Attention was focused on a group of patients with a history of obesity in whom by the time of investigation body mass returned to normal and the level of glucose was decreased. However, gastrin and insulin levels were still high, and metabolic regulation was disturbed. Therefore, body mass normalization did not eliminate causative and pathogenetic factors of diabetes mellitus.