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Vol 66, No 2 (2020)

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Clinical endocrinology
The role of non-coding RNAs in the pathogenesis of multiple endocrine neoplasia syndrome type 1
Mamedova E.O., Dimitrova D.A., Belaya Z.E., Melnichenko G.A.

Changes in the expression of non-coding ribonucleic acids (ncRNAs) takes part in the formation of various tumors. Multiple endocrine neoplasia syndrome type 1 (MEN1) is a rare autosomal dominant disease caused by mutations of the MEN1 gene encoding the Menin protein. Syndrome is characterized by the occurrence of parathyroid tumors, gastroenteropancreatic neuroendocrine tumors, pituitary adenoma, as well as other endocrine and non-endocrine tumors. The mechanisms for the formation of MEN1-related tumors due to mutations in the MEN1 gene are not . In the absence of mutations of the MEN1 gene in patients with phenotypically similar features, this condition is regarded as a phenocopy of this syndrome. The cause of the combination of several MEN-1-related tumors in these patients remains unknown. The possible cause is that changes in the expression of ncRNAs affect the regulation of signaling pathways in which Menin participates and may contribute to the development of MEN-1-related tumors. The identification of even a small number of agents interacting with Menin makes a significant contribution to the improvement of knowledge about its pathophysiological influence and ways of developing tumors within the MEN-1 syndrome and its phenocopies.

Problems of Endocrinology. 2020;66(2):4-12
About connection of clinical manifestations of glomerulonephritis with features of the thyroid status of patients
Karzakova L.M., Avtonomova O.I., Kudryashov S.I., Ukhterova N.D., Komelyagina N.А.

BACKGROUND: There are four clinical variants of glomerulonephritis (GN) - urinary (latent), hypertensive, nephrotic and mixed. It was found that the features of clinical manifestations of GN that determine its clinical variant do not depend on the etiology, pathogenesis and morphological form of the disease. Taking into account the obtained data on the association of nephrotic syndrome with hypofunction of the thyroid gland, we suggested, that the formation of clinical variants of GN may be influenced by the features of the thyroid status of patients.

AIM: Study the relationship of variants of clinical manifestations of GN with indicants of thyroid status.

MATERIALS AND METHODS: The study included patients with primary GN who received in-treatment in the nephrology unit of a general hospital. Patients were selected into 4 groups depending on the clinical variant of GN (urinary, nephrotic, hypertensive and mixed variants). When selecting patients, we achieved comparability of groups by age, gender, morphological variants and duration of the disease. In addition to the generally accepted methods of research, patients were performed: 1) assessment of the thyroid status (thyroid-stimulating hormone (TSH), free thyroxine (free T4), free triiodothyronine (free T3), antibodies to thyroperoxidase (anti-TPO), (free T3+free T4)/TSH, free T4/free T3, free T4/TSH); 2) determination of levels of interleukin - IL-1β, IL-4 and IL-10 in blood serum; 3) ultrasound (US) examination of the thyroid gland. The obtained data were compared with those of healthy people.

RESULTS: The group of patients with the nephrotic variant of GN in 50% of cases showed a decrease of the level of free Т4 with the increase of TSH level, 26.7% showed a moderate increase of TSH at unchanged concentrations of free Т4 and free T3. In patients with the urinary variant of GN, the thyroid status did not differ from that in healthy patients, and the cytokine profile was characterized by a simultaneous increase in the content of the proinflammatory cytokine IL-1β and the anti-inflammatory cytokine IL-10. The group of patients with the hypertonic variant of GN in 82% of cases showed an isolated increase in TSH content. In the group of patients with a mixed variant of GN, changes in thyroid indices were predominant, combined with a large variability in the level of IL-1β production.

CONCLUSIONS: The results of the study indicate the influence of the functional state of the pituitary-thyroid system on the formation of different clinical variants of GN, which depends mainly on the level of production of the anti-inflammatory cytokine IL-10.

Problems of Endocrinology. 2020;66(2):13-23
IGG4-related diseases in endocrinology
Rumyantsev P.O., Kozlov I.G., Kolpakova E.A., Chukhacheva O.S., Korenev S.V., Goncharov A.G., Ulanova E.U.

Immunoglobulin-G4-related disease (IgG4-RD) is a chronic immunomediated pathology of different organs of local or systemic nature, which has been established as a separate clinical entity in the early 2000s and is characterized by storiform fibroid inflammation of the affected tissues, their increase, and elevated serum immunoglobulin-G4 (IgG4) levels. The most common manifestations of the disease are major salivary and lacrimal gland enlargement, lymphadenopathy and type 1 autoimmune pancreatitis (AIP1), however, other organs may be also involved (the thyroid, eyes, meninges, heart, lungs, kidneys, aorta, upper airways, mesentery, etc.).

The effectiveness of treatment of IgG4-RD, as well as other pathological conditions, is also determined by the timely diagnosis. However, the latter is complicated due to the variety of clinical manifestations and rather variable diagnostic criteria. It is necessary to constantly update the evidence-based knowledge and diagnostic algorithms within this pathology in order to overcome the difficulties, and involve immunologists, endocrinologists, pathologists and specialists in other spheres.

This review provides information about the etiology, pathogenesis, and current methods of diagnosis and treatment of IgG4-related diseases, as well as examples of some manifestations of IgG4-RD that an endocrinologist may face in practice.

Problems of Endocrinology. 2020;66(2):24-32
The activity of NAD- and NAD(P)-dependent dehydrogenases in lymphocytes of peripheral blood in Graves’ disease
Dudina M.A., Savchenko A., Dogadin S.A., Gvozdev I.I.

BACKGROUND: The regulatory effect of thyroid hormones on the metabolism of the immune system cells (activation of oxidative processes, separation of oxidative phosphorylation and increased protein synthesis) depends on their number. Changes in the activity of intracellular enzymes in Graves’ disease (GD) can determine the mechanisms of maintaining autoimmune inflammation in relapse of the disease. The exact role of NAD(P)-dependent dehydrogenases in the development and maintenance of immune response in GD is still poorly investigated.

AIMS: To study the activity of NAD(P)-dependent dehydrogenases in lymphocytes of peripheral blood in patients with manifestation and relapse of GD to clarify the mechanisms of development and progression of the autoimmune process.

METHODS: A single-center, cohort, prospective, continuous, observational, open-label, controlled trial was conducted to evaluate the lymphocytes NAD(P)-dependent activity in 151 women with GD and hyperthyroidism, mean age 40.7±13.2, 52 (37.14%), who were on follow-up at the endocrinology center of Krasnoyarsk Regional clinical hospital from 2016 to 2019. The NAD(P)-dependent dehydrogenases activity measured using biochemiluminescence method.

RESULTS: In patients with newly diagnosed of GD, relative to the control values and levels detected in relapse group we observe the increase of G6PDH and decrease of NADH-LDH. In GD relapse group compare to the control range in blood lymphocytes decreases the activity of LDH and NAD(P)-ICDH. In patients with newly diagnosed GD, two positive сorrelation were found: between fT3 level and MDG activity (r=0.90, p=0.037), and between fT4 level and NAD(P)-ICDH activity (r=0.82, p=0.007). In patients with relapse of GD positive relationships between the concentration of TSH and the activity of LDH (r=0.73, p=0.039), and MDH (r=0.93, p=0.002), as well as in a pair of fT4 and NADGDH (r=0.70, p=0.036) were revealed.

CONCLUSION: The established differences in the activity of NAD(P)-dependent dehydrogenases in peripheral blood lymphocytes in patients with manifestation and relapse of GD can reflect in the first case the response of immune cells to a functional-regulatory signal with the development of hyperthyroidism, and in the second case, adaptive changes with the progression of autoimmune process.

Problems of Endocrinology. 2020;66(2):33-41
Bones & Adipose tissues diseases
Alexithymia and its relation with eating disorders and obesity
Berkovskaya M.A., Tarasenko A.A., Fadeev V.V., Gurova O.Y.

This manuscript provides a review of current literature on the relationship between overweight and alexithymia as a psychological factor associated with obesity, as well as the role of alexithymia in the development of various abnormalities and eating disorders (ED). Obesity is a multifactorial disease, and lifestyle characteristics are the most important pathogenetic links on its development, as well as a complex of genetic, epigenetic, biological and psychological factors that cause accumulation of excessive fat and prevent effective reduction and retention of body weight. One possible reason for the increased prevalence of obesity in adults is poor emotional management, which can affect healthy eating behavior and lifestyle.

It was found that overweight and obese people have a high prevalence of alexithymia, and also the study shows its prognostic role in the development of ED. Alexithymia is a factor that not only predisposes to weight gain, but is also a significant predictor of inefficiency and premature termination of programs for the treatment of obesity and ED. Timely diagnosis and correction of alexithymic syndrome can help in developing the effective treatment strategies for obese patients.

Problems of Endocrinology. 2020;66(2):42-48
Carbohidrates metabolism disturbancies
Specific features of the use of alogliptin in various groups of patients with type 2 diabetes mellitus: additional results of the ENTIRE study
Shestakova M.V., Shestakova E.A., Kachko V.A.

BACKGROUND: Since the obtaining of data on the effect of Alogliptin towards the lipid profile, body weight and blood pressure (BP) of patients, the additional analysis of the results of the ENTIRE study, completed in the Russian Federation in 2018, was conducted.

AIMS: Assess the dynamics of HbA1c, body weight, fats indices, blood pressure (BP), and characterize the profile of the patient who received the maximum clinical benefit on treatment of Alogliptin therapy in the ENTIRE study.

MATERIALS AND METHODS: A prospective non-interventional observational study that included patients aged 18 years and older with first-onset type 2 diabetes mellitus (T2DM) or patients with T2DM who did not achieve their glycemic targets during the previous therapy.

RESULTS: A decrease in glycated hemoglobin (HbA1c) by more than 0.5% was detected in 73.5% of patients. The most significant absolute decrease of HbA1c was noticed in patients with initially higher values. Younger patients with a shorter duration of T2DM showed the more often compensation of carbohydrate metabolism. The average loss of weight was -2.6±4.2 kg. 76.6% of patients showed the loss of weight. The most significant decrease in body weight was noticed in patients with a large initial body mass index and a shorter duration of the disease. 74.7% of patients showed a decrease of the level of low-density lipoproteins (LDL). The most significant absolute decrease in LDL was noticed in patients with initially higher values and more often in younger people with a shorter duration of T2DM. The average decrease in systolic blood pressure (BP) was 5.9±0.3 mm Hg; the average decrease in diastolic blood pressure (BP) was 2.7±0.2 mm Hg. 59% of patients showed decrease of blood pressure during the group analyzing. The most frequent BP reduction was observed in younger patients with shorter duration of T2DM. At the same time, a more significant absolute decrease in blood pressure was noticed in patients with initially higher indicators, and an increase, on the contrary, was observed in patients with initially lower indicators.

CONCLUSIONS: The intensification of Alogliptin therapy allowed to achieve the compensation of carbohydrate metabolism, moderate decrease of body weight, blood pressure and LDL indices within the majority of patients with T2DM. The most frequent achievement of HbA1c targets was noticed in young patients with a shorter duration of T2DM.

Problems of Endocrinology. 2020;66(2):49-60
Searching for additional markers of impaired iron metabolism in diabetes mellitus
Musina N.N., Saprina T.V., Prokhorenko T.S., Zima A.P.

BACKGROUND: It is known that metabolic disorders in diabetes mellitus have a regulating effect on ferrokinetics, and therefore diabetes mellitus is often accompanied by various disorders of iron metabolism, both anemia and secondary iron overload. The main problem is timely and accurate differential diagnosis between anemia of chronic diseases and iron deficiency anemia. It is necessary to establish reliable laboratory markers of anemia of chronic diseases in order to solve this problem, as well as to understand what metabolic disorders can lead to the occurrence and aggravate the course of this type of anemia.

AIMS: To study the frequency of occurrence of violations of ferrokinetics in patients with diabetes mellitus, as well as to establish clinical and biochemical correlations that are significant in the differential diagnosis of various disorders of iron metabolism: iron deficiency anemia, anemia of chronic diseases and dysmetabolic iron overload syndrome in diabetes mellitus.

MATERIALS AND METHODS: The research design a single-stage observational single-center research. The research was conducted on the basis of the endocrinological clinic of the Federal State Budgetary Educational Institution of Higher Education Siberian State Medical University in Tomsk. The research included 76 patients with type 1 and type 2 diabetes mellitus. We conducted an assessment of all patients as follows: anthropometric data assessment; glycated hemoglobin study; creatinine level study with the calculation of glomerular filtration rate (GFR) using the CKD-EPI formula. We also evaluated the number of erythrocytes, reticulocytes, the hemoglobin concentration, haematocrit level and biochemical parameters of iron metabolism: serum iron and ferritin concentrations; the concentration of hepsidin and non-specific markers of inflammation: erythrocyte sedimentation rate (ESR) and highly sensitive C-reactive protein (CRP).

RESULTS: 20 people (26.3%) of the 76 patients included in the study, had type 1 diabetes mellitus and 56 people (73.3%) had type 2 diabetes mellitus. The parameters of ferrokinetics did not significantly differ in patients with type 1 and type 2 diabetes mellitus, while in the group of patients with 20 patients (26.3%) from the 76 ones included into the research had type 1 diabetes mellitus and 56 (73.3%) from them had type 2 diabetes mellitus. The parameters of ferrokinetics did not significantly differ in patients with type 1 and type 2 diabetes mellitus, while in the group of patients with type 2 diabetes mellitus, the levels of CRP (p=0.034) and blood leukocytes (p=0.020) were significantly higher than in patients with type 1 diabetes mellitus. Both in the main group of patients with impaired carbohydrate metabolism, and in patients with type 2 diabetes mellitus, anemia of chronic diseases prevailed in the structure of the anemia syndrome. After dividing the main group of patients into groups by type of anemia syndrome: absence of anemia, anemia of chronic diseases and iron deficiency anemia, a comparative analysis of the average values of markers of inflammation and the level of hepsidin in these groups was performed. It was found that in patients with anemia of chronic diseases, the level of hepsidin is significantly higher than in patients without anemic syndrome (p=0.033). Paired correlation analysis showed a positive correlation of ESR with microalbuminuria (r=0.515; P<0.0001), creatinine level (r=0.467; P<0.0001) and negative — with GFR (r= -0.436; P<0.0001) and iron in serum (r=-0.276; p=0.017). As the result of ROC analysis the most informative in the diagnosis of anemia of chronic disease were: ferritin — sensitivity 78%, specificity 52% with a diagnostic threshold of 75.5 ng/ml (area under the curve 0,695; p=0.006); ESR — sensitivity 67%, specificity 64% with a diagnostic threshold of 15.5 mm/HR (area under the curve of 0.750 in; p=0.040) and the CRP — sensitivity 67%, specificity 64% with a diagnostic threshold of 5.2 ng/ml (area under the curve 0,646; р<0.0001).

CONCLUSION: Thus, the studied markers of inflammation — ESR and CRP, as well as hepsidin in combination with the classic diagnostic parameter — ferritin, demonstrated high value in the diagnosis of anemia of chronic diseases and can be included in the modified algorithm for differential diagnosis of anemia syndrome in patients with diabetes mellitus.

Problems of Endocrinology. 2020;66(2):61-70
Pediatric Endocrinology
Evaluation of body composition, resting metabolic rate and frequency of metabolic disorders in adolescents with Klinefelter syndrome
Bespalyuk D.A., Okorokov P.L., Chugunov I.S.

BACKGROUND: Kleinfelter syndrome (KS) is a common genetic disease characterized by hypergonadotropic hypogonadism. The high risk of developing of metabolic disorders in patients with KS is be explained by the presence of androgen deficiency, which leads to a decrease in the amount of lean soft mass and an increase of the adipose tissue content. The basal metabolic rate (BMR) is determined by the amount of lean soft mass, and its reduction can contribute to weight gain and the progression of metabolic disorders in KS.

AIM: Body composition, assessment of basal metabolism and metabolic profile in adolescents with KS.

MATERIALS AND METHODS: The study included 28 adolescents with KS, comparable in age and stage of sexual maturation. All patients were divided into two groups depending on the presence of clinical laboratory signs of hypogonadism. Patients passed through the evaluation of metabolic profile, bioelectrical impedance analysis for the body composition and chamber-based indirect calorimetry for the evaluation of BMR.

RESULTS: Normal indicants of body composition were determined in 20 (71.4%) adolescents, excess of adipose mass – in 6 (21.4%) patients, and deficit of adipose mass – in 7.2% of cases. Among 6 patients with excess of adipose mass, three were obese or overweight, while the rest had normal SDS body mass index (BMI). 64.3% of adolescents showed normal indicants of energy exchange at rest, 6 (21.4%) – a decrease of BMR, 4 (14.3%) - an increase of BMR. A comparative analysis of patient groups did not reveal statistically significant differences in BMR adjusted to a lean soft mass (OO/TM) (p=0.36). Insulin resistance was detected in 11 patients (39.3%), and the incidence of dyslipidemia was 3.6%. The groups did not significantly differ in terms of glycemia levels in the fasted state and lipid profile indicants.

CONCLUSION: Most adolescents with KS have normal indicants of body composition and basal metabolism, as well as a low frequency of metabolic disorders, regardless of the level of total testosterone in blood. In some patients with normal SDS BMI, excess of adipose mass is detected. The lack of correlation between the level of testosterone and the intensity of BMR may indicate a slight effect of androgen deficiency on energy exchange at rest in adolescents with KS.

Problems of Endocrinology. 2020;66(2):71-78
A clinical case of aromatase excess syndrome associated with 15Q21.2 duplication
Kasyanova Y.V., Chernyak I.Y., Voronina I.K., Kalinchenko N.Y.

Aromatase excess syndrome (SIA) is a rare autosomal dominant disease caused by increased extraglandular conversion of androgens to estrogens. SIA is characterizedby early gonadotropin-independent hyperestrogenemia, causing pre-pubertal gynecomastia in boys and premature isosexual development in girls. Adults patients have short stature, due to the early closure of epiphyses because of hyperestrogenemia. Women usually have macromastia, endometrial hyperplastic processes and the late onset of menopause. In men, there is a moderate decrease of gonadotropins, leading to secondary hypogonadism. SIA in children can be suspected on a combination of the clinical picture of an excess of estrogens, increased levels of estrogens with low levels of gonadotropins after the exclusion of an estrogen-producing tumor. The frequency of occurrence of SIA is unknown, due to the rarity of the disease and the complexity of its molecular and genetic verification. In this article, we describe a clinical case of a 10-year-old patient with a late diagnosis of aromatase overactivity syndrome caused by a 15q21.2 microduplication of the CYP19A1 gene, and conduct a brief review of the literature.

Problems of Endocrinology. 2020;66(2):79-84
Reproductive Endocrinology
Comparative morphofunctional analysis of the state of fetoplacental complex in diabetes mellitus (literature review)
Grigoryan O.R., Absatarova Y.S., Mikheev R.K., Andreeva E.N.

This article reviews the literature on placental morphofunctional changes in placenta of patients with type 1 and type 2 diabetes mellitus and gestational diabetes mellitus. The detailed analysis of features of pathogenesis of various abnormalities of the fetoplacental complex depending on the type of diabetes, its influence on the formation of the placental vascular bed. The analysis of mechanisms of development of placenta formation disorders, pathologies of placental vascular bed, the role of hyperglycemia and hyperinsulinemia in villous maturation, placental weight gain, perinatal outcomes. The discussed anomalies have a significant impact on the fetoplacental complex, acting as epigenetic factors, forming the environment for the fetus, which may later affect the health of the unborn child. They lead to adverse perinatal outcomes, including high infant morbidity and mortality.

Literature search was performed in Russian (eLibrary, and international (PubMed, Cochrane Library) databases in Russian and English languages. The free access to the full text of the articles was in priority. The selection of sources was prioritized for the period from 2016 to 2020. However, due to the lack of knowledge of the chosen topic, the selection of sources was dated from 2001.

Problems of Endocrinology. 2020;66(2):85-92

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