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Vol 65, No 5 (2019)

Clinical endocrinology
Primary hyperparathyroidism in Russia according to the registry
Mokrysheva N.G., Mirnaya S.S., Dobreva E.A., Maganeva I.S., Kovaleva E.V., Krupinova J.A., Kryukova I.V., Tevosyan L.K., Lukyanov S.V., Markina N.V., Bondar I.A., Podprugina N.G., Ignatieva I.A., Shabelnikova O.Y., Dreval A.V., Antsiferov M.B., Mel'nichenko G.A., Dedov I.I.

BACKGROUND: There are no large-scale epidemiological studies on primary hyperparathyroidism (PHPT) in Russia. The high prevalence of the disease, the high risk of disability and death in this cohort of patients requires the study of the epidemiological and clinical structure of PHPT to determine the extent of medical care.

AIM: Evaluate the frequency of PHPT detection and characterize its clinical forms in Russia using an online registry.

METHODS: The object of the study is the database of the State Register of Patients with PHPT – 1914 patients from 71 regions of the Russian Federation. New cases of the disease, as well as dynamic indicators are recorded when patients visit outpatient clinics or medical institutions. The analysis of data made at the end of December 2017 was carried out. The following parameters were evaluated: demographic and clinical indicators; indicators of phosphorus-calcium metabolism, the main forms of PHPT and its course, the primary characteristic of PHPT in hereditary syndromes and parathyroid carcinoma. Results are presented as mean and standard deviations, or medians and quartiles; descriptive statistics of qualitative attributes – absolute and relative frequencies.

RESULTS: the total number of patients with PHPT in the registry on 31 of December 2017 was 1914 cases (0.001% of the population of the Russian Federation). Identification of PHPT was 1.3 cases per 100 thousand of the population in Russia, 7.6 cases in Moscow, 6.1 cases per 100 thousand in the Moscow region. The average age of patients at the time of diagnosis was 55.6 ± 10 years. The active phase of the disease was registered in 84.6% of patients (1620/1914), most of whom had a symptomatic PHPT – 67.1% (1087/1620), and 32.9% – a asymptomatic disease (533/1620). Symptomatic disease with visceral complications was detected in 15.8% cases (172/1087), with bone complications in 48.4% (526/1087). The mixed form of the disease was detected in 35.8% of patients with manifest form (389/1087). Normocalcemic variant PHPT (nPHPT) was registered in 14.5% cases (234/1620). Sporadic PHPT occurs in 83% of cases (1592/1914). 326 patients (17%) had a suspicion for hereditary form of the disease: average age was 31.2 ± 12.3 years. A genetic analysis was conducted in 61 patients (3.2%): showed the mutation in the MEN1 gene in 2.9% of cases (55/1914) and the mutation in the CDC73 gene – in 0.3% of cases (6/1914) (HPT-JT syndrome). Parathyroid carcinoma was confirmed in 1.8% of all patients (35/1914). Surgical treatment was performed in 64.5% of patients (1234/1914). Remission was achieved in 94% of cases (1160/1234), in 6% of cases relapse after surgical treatment or persistence of PHPT was recorded.

CONCLUSION: detection of PHPT in the Russian Federation raised in comparison to 2016, which is associated with an active start of registration of patients in the regions. At this stage, it is necessary to modify the principles of registration and control, to make a platform for gathering information and calculating the necessary volumes of medical care for PHPT patients.

Problems of Endocrinology. 2019;65(5):300-310
Expression of plasma microRNA in patients with acromegaly
Lutsenko A.S., Belaya Z.E., Przhiyalkovskaya E.G., Nikitin A.G., Koshkin P.A., Lapshina A.M., Khandaeva P.M., Melnichenko G.A.

BACKGROUND: microRNA is a class of small non-coding RNA molecules involved in posttranscriptional regulation of gene expression. MicroRNAs are detectable in blood in stable concentrations, which makes them promising biomarkers for various diseases.

AIM: to assess plasma microRNA expression in patients with active acromegaly compared with healthy controls.

MATERIAL AND METHODS: single-center, case-control study: assessment of plasma microRNA in patients with acromegaly compared with healthy controls. Fasting blood samples were drawn and centrifuged at +5°С temperature and 3000 rpm for 20 minutes, then aliquoted and frozen at –80°C until further analysis. MicroRNA extraction and library preparation was done according to manufacturer’s instructions. Expression analysis was performed on NextSeq sequencer. Bioinformatic analysis using atropos (adapted deletion), STAR (aligning), FastQC (quality control), seqbuster/seqcluster/miRge2 (microRNA annotation, isomiR and new microRNA search, expression analysis). Primary endpoint of the study – differential expression of plasma microRNA in patients with acromegaly compared with healthy controls.

RESULTS: we included 12 patients with acromegaly – age 33.1 [20; 47], BMI 29.3 kg/m2 [24.0; 39.6], IGF-1 686.1 ng/mL [405.9; 1186.0] and 12 healthy subjects – age 36.2 [26; 44], BMI 26.7 kg/m2 [19.5; 42.5], IGF-1 210.4 ng/mL [89.76; 281.90]; gender ratio for both groups – 4 males, 8 females. The groups did not differ in gender (p=0.666), age (p=0.551) and BMI (p=0.378). We found decreased expression of four microRNAs in patients with acromegaly: miR-4446-3p –1.317 (p=0.001), miR-215-5p –3.040 (p=0.005), miR-342-5p –1.875 (p=0.013) and miR-191-5p –0.549 (p=0.039). However, none of these changes were statistically significant after adjustment for multiple comparisons (q >0.1).

CONCLUSION: we found four microRNAs, which could potentially be downregulated in plasma of patients with acromegaly. The result need to be validated using different measurement method with larger sample size.

Problems of Endocrinology. 2019;65(5):311-318
Clinical, genetic, and radionuclide characteristics of the focal form of congenital hyperinsulinism
Gubaeva D.N., Melikyan M.A., Ryzhkova D.V., Poyda M.D., Bairov V.G., Sukhotskaya A.A., Sokolov Y.Y., Efremenkov A.M., Mitrofanova L.B., Christesen H., Nikitina I.L.

BACKGROUND: Congenital hyperinsulinism (CHI) is a severe disease with a high risk of complications including neurological deficit. Persistent hypoglycemia in patients with focal form of CHI can not be managed with medical treatment in 96.4% of cases, what subsequently leads to surgical treatment. Currently, there is a lack of information regarding patients with focal form of CHI. This study is aimed at finding better approaches for diagnosis and treatment of patients with focal form of CHI.

AIMS: To study clinical, genetic and PET/CT findings of the focal form of CHI in Russian group of patients.

MATERIALS AND METHODS: The observational research included all patients with a histologically confirmed focal form of CHI, who were admitted to Endocrinology Research Centre during the period from January 2008 to January 2019. A statistical analysis of clinical data, genotype, and positron emission tomography (PET) with 18F-dihydroxyphenylalanine (18F-DOPA) was performed. The median follow-up was 18 months.

RESULTS: The study included 31 patients with focal CHI (14 boys, 45.2%). All patients had a neonatal presentation of the disease and demanded high levels of continuous glucose infusion to maintain euglycemia. The difference between the age of hypoglycemia presentation and the age of diagnosis ranged from 1 day to 3.9 months. In all cases, diazoxide was found to be ineffective. However, in 9 patients, it was possible to withdraw continuous glucose infusion and maintain euglycemia using octreotide in the preoperative period. A molecular genetic study allowed us to detect diverse pathogenic variants in ABCC8 and KCNJ11 genes in 30 patients. According to PET data with 18F-DOPA, the pancreatic index (PI) varied widely from 1.16 to 3.59. After partial resection of the pancreatic region with insulin hypersecretion, all patients showed complete recovery.

CONCLUSIONS: The focal form of CHI is a severe condition with high prevalence of neurological complications. For preoperative diagnosis of the morphological form of the disease, it is necessary to conduct genetic analysis and radionuclide studies. Solely evaluation of mathematical parameters in 18F-DOPA PET without taking into account the visual data and the results of genetic analysis does not allow establishing the robust diagnosis. Timely diagnosis, identification of risk factors, and prevention of complications of persistent hypoglycemia are important tasks for clinicians.

Problems of Endocrinology. 2019;65(5):319-329
Clinical features and diagnosis of secondary adrenal insufficiency followed complex treatment nonpituitary brain tumors
Yudina A.E., Pavlova M.G., Sotnikov V.M., Yudina A.E., Sych Y.P., Mazerkina N.A., Zheludkova O.G., Teryaeva N.B., Gerasimov A.N., Martynova E., Kim E.I., Berkovskaya M.A.

BACKGROUND: The most of the current studies include patients who are different by the etiology of secondary adrenal insufficiency (SAI), or investigate SAI among other late effects of the radiation therapy.

AIMS: To describe the features of SAI and to select the best method of screening SAI in adult patients followed complex treatment of nonpituitary brain tumors in childhood.

MATERIALS AND METHODS: It was the retrospective cross-sectional study. 31 patients after the complex treatment of nonpituitary brain tumors in childhood and 20 healthy volunteers were examined. Age and sex ratio were comparable between the groups. Biochemical and clinical blood tests, levels of cortisol, ACTH, DHEA-C were evaluated. The insulin tolerance test (ITT) was performed for all patients and 11 volunteers.

RESULTS: The prevalence of SAI by ITT was 45.2%. The levels of basal cortisol (BC) were significantly higher in patients without SAI in comparison with the SAI group and volunteers (505 [340; 650] vs 323 [233; 382] and 372 [263; 489] nmol / l; pSAI- without_SAI=0.001; pwihtout_SAI-healthy = 0.04). The SAI group had DHEA-C significantly lower than in other groups one (3.1 [1.8; 3.4] vs 5.1 [2.5; 6.4] and 6.8 [4.1; 8.9]; рSAI- without_SAI = 0.036; pSAI-healthy = 0.001). ROC analysis showed that BC and DHEA-S can be used as high-quality screening tests for SAI (AUC = 89.3% and 88.3%). The maximum level of cortisol (656 [608-686] vs 634 [548-677]; p = 1) and the time of its increase (45 and 60 min) did not differ during ITT in patients without SAI and volunteers. Side effects: delayed hypoglycemia occurred in 4/14 patients of the SAI group 40–90 minutes late of injection 60-80 ml of 40% glucose solution for stopping hypoglycemia in the test.

CONCLUSIONS: 45.2% of patients followed craniospinal irradiation had SAI that is characterized by a decrease in DHEA-C levels. A highly normal level of basal cortisol was observed in 45% of patients without SAI. DHEA-C and blood cortisol can be used for SAI screening.

Problems of Endocrinology. 2019;65(5):330-340
The frequency of formation of a motivated refusal to take androgenic anabolic steroids by men with recreational activity
Lykhonosov M.P., Babenko A.Y., Makarin V.A., Fedotov Y.N.

BACKGROUND: The widespread use of AAS for non-medical purposes is more than often becoming the cause of secondary hypogonadism. The study of the formation of the negative attitude towards the use of AAS among the gym visitors is quite relevant.

AIMS: To identify the frequency of the formation of a motivated refusal to continue taking androgenic anabolic steroids among men who voluntarily declared their use.

MATERIALS AND METHODS: The study included 44 men, all users of AAS. There has been estimated the effectiveness of the clinical examination: how ready they were to disclose information about the use of AAS (drugs, doses, regimens, duration) or how much they were aware of the mechanisms of action of AAS and their effects on the body. The participants were also asked to evaluate their psychological and emotional state (on the scale “Index of life satisfaction”, Hamilton’s depression, aggressiveness). The experience of our informational lectures on the topic “Risks of using AAS” prior to the selection of volunteers for research, anonymous surveys and interviews with potential participants in the clinical trial, the clinical work itself with the selected volunteers, the characteristic features of a medical history and tests that we identified were compared with clinical recommendations for hypogonadism diagnostic (domestic and foreign).

RESULTS: More than 105 gym visitors responded positively to a motivated offer (free medical consultation and laboratory tests) to participate in a clinical study. Based on the results of the individual interview, 54 men (51.4%) who indicated the use of AAS signed an informed consent. 44 volunteers (41.9%) completed all stages of the study. Among them, 32 participants (72.7%) were aware of the mechanisms of action and side effects of AAS. 21 volunteers (47.7%) filled in the scales. The index of life satisfaction was determined as high, equal to 34 [29; 38] points; the index of aggressiveness was higher than the generally accepted standard and composed 27 [25; 29] points, the level of depression corresponded to a mild depressive disorder, equal to 9 [3; 12] points. Over the use of AAS 22.7% (n = 10) of the examined noted an increase in aggressiveness, which they themselves associated with the use of steroids. The clinical symptoms of hypogonadism (decreased libido, erectile dysfunction) after the cancellation of AAS were indicated by 25% (n = 11) of the volunteers and that was one of the reasons they continued to use anabolics. 31.8% (n = 14) of the participants were ready to completely stop using the steroids.

CONCLUSIONS: Individual informational interviews aimed at providing knowledge about the negative effects of steroids on the body motivated the desire to stop using them amongst 31.8% of AAS users. The obtained data points out to a developed AAS addiction which requires the involvement of psychiatrists to get rid of it.

Problems of Endocrinology. 2019;65(5):341-350
Experimental endocrinology
Streptozocin-induced Alzheimer’s disease as an independent risk factor for the development of hyperglycemia in Wistar rats
Stavrovskaya A.V., Voronkov D.N., Shestakova E.A., Gushchina A.S., Olshansky A.S., Yamshikova N.G.

BACKGROUND: In recent years the theme of the relationship of Alzheimer’s disease (AD) and metabolic disorders has been widely discussed. Nevertheless, it remains unclear whether AD is a direct cause of carbohydrate metabolism disorders or it is the presence of classical risk factors for type 2 diabetes mellitus (DM 2), primarily obesity, that significantly increases the risk of AD.

AIM: To evaluate the separate contribution of two factors to the development of disorders of carbohydrate metabolism: (1) weight gain due to a high-calorie diet and (2) experimental-induced AD.

METHODS: Male Wistar rats were injected with streptozocin (STZ) in the lateral ventricles of the brain to induce AD or saline (sham operated animals - SO) during stereotactic operations. After 2 weeks, the animals were divided into four groups: 1) the SO group, which was assigned to the normal calorie (NCD) diet (SO NCD); 2) the SO group, which was assigned to the high-calorie diet (SO HCD); 3) the group to which the norm-calorie diet was prescribed after the administration of STZ into the lateral ventricles of the brain (STZ NCD); 4) the group to which the HCD was assigned after the administration of STZ (STZ HCD). The animals were on a diet for 3 months. Intraperitoneal glucose tolerance tests were carried out before the diet and after 3 months. At the end of the study, a morphological assessment of brain tissue, pancreas, and liver was performed.

RESULTS: 3 months after surgical interventions and the appointment of diets, the glycemic curves significantly differed in the 4 studied groups: normoglycemia persisted only in the SO + NCD group, while HCD and the STZ administration were accompanied by the development of hyperglycemia (p = 0.0001). The STZ + NСD group, which represented the isolated effect of AD, was also characterized by impaired carbohydrate metabolism. A morphological study showed that HCD leads to a more pronounced ectopic accumulation of fat in the liver and pancreas tissue than NCD. The administration of STZ, regardless of the diet, led to changes typical for the AD model – an increase in the size of the ventricles of the brain, degeneration of white matter, and the accumulation of β-amyloid in the hypothalamus.

CONCLUSIONS: The STZ-induced brain damage typical for AD led to impaired carbohydrate metabolism regardless of diet and was an independent risk factor for hyperglycemia.

Problems of Endocrinology. 2019;65(5):351-361
Case Reports
Clinical case report: history of diagnosis and clinical features of type autoimmune polyglandular syndrome 1
Troshina V.V., Romanova N.Y., Sozaeva L.S., Troshina E.A.

Autoimmune polyglandular syndrome type 1 (APS-1) is a rare disease with autosomal recessive inheritance and it caused by mutations in the autoimmune regulator (AIRE) gene. This disease has clinical polymorphism that including besides endocrinopathies other organ-specific manifestations and that complicates to diagnose of this condition on time. However, most often APS-1 has a characteristic debut and a certain stage of clinical symptom manifestation. This article describes a case report of an 18-year-old patient with confirmed APS-1, in which the course of disease was erased over a long period of life and didn’t meet of clinical criteria for the diagnosis in this syndrome. A high quality of life for such patients is possible with timely, individually selected replacement therapy with subsequent follow-up. It is important to remember the need for screening in risk groups for the formation of clinical forms of APS among the subjects presenting with a single endocrine pathology. The continuity of medical supervision by pediatric and adult endocrinological service physicians must be respected that can be traced on the example of the case from our practice.

Problems of Endocrinology. 2019;65(5):362-366
IgG4-associated disease in differential diagnosis of inflammatory orbitopathy
Grusha Y.O., Ismailova D.S., Sviridenko N.Y., Novikov P.I., Kovrigina A.M.

IgG4-associated disease (IgG4-RD) is a systemic inflammatory disease characterized by tumorlike sclerosing masses in different organs. Differential diagnosis in orbital IgG4-RD includes majority of conditions, such as thyroid eye disease (TED), sarcoidosis, granulomatosis with polyangiitis, idiopatic orbital inflammation, limphoproliferative diseases and others. A case of IgG4-RD with different organs involvement and complicated differential diagnosis is presented. This case demonstrates very uncommon manifestation of IgG4-RD, when orbital involvement was very similar with TED. Systemic process was not recognized during a long period of time and diagnosis of IgG4-RD was established only after biopsy of abnormally increased lacrimal gland. Differential diagnosis included other systemic diseases, first of all sarcoidosis, GPA, and lymphoma. Biopsy results were consistent with the gold standard of diagnosis, e. g. more than 40% of plasma cells were IgG4 positive. This case demonstrates the necessity of orbital biopsy before starting immunosuppression to avoid inappropriate treatment strategy.

Problems of Endocrinology. 2019;65(5):367-372
Current aspects of diagnosis and treatment of adult GH-deficiency
Lutsenko A.S., Nagaeva E.V., Belaya Z.E., Chukhacheva O.S., Zenkova T.S., Melnichenko G.A.

Adult growth hormone (GH) deficiency (AGHD) is a condition characterized by alterations in body composition, lipid and carbohydrate metabolism, bone mineral density and poor quality of life; however, clinical presentations of AGHD are mostly non-specific. Untreated AGHD is associated with increased cardiovascular morbidity and mortality. Stimulation tests are used for the diagnosis: insulin tolerance test, glucagon stimulation test, growth-hormone releasing hormone and arginine stimulation test. Moreover, in 2017 FDA approved the use of macimorelin (oral GH secretagogue) for the diagnosis of AGHD. In childhood GH-deficiency, apolipoprotein A-IV, CFHR4 (complement factor H-related protein 4) and PBP (platelet basic protein) were identified as potential biomarkers of the disease, however, this was not investigated in AGHD. GH treatment starts from the minimal dose, which allows minimizing the adverse effects. According to published meta-analyses, AGHD treatment generally does not lead to increased risk of malignancy and recurrence of sellar neoplasms in adult patients. Published data on GH receptor polymorphism associations with treatment efficacy remains controversial. Development of long-acting GH formulations is a currect perspective for the increase of treatment compliance.

Problems of Endocrinology. 2019;65(5):373-388
Perspectives of application of intranasally administered insulin for correction of metabolic and hormonal disorders in diabetes mellitus and metabolic syndrome
Shpakov A.O., Derkach K.V., Surkova E.V., Bespalov A.I.

In recent years, the possibility of using intranasally administered insulin to treat Alzheimer’s disease and other cognitive disorders has been widely studied. At the same time, the possibility of its use in the treatment of diabetes mellitus is practically not investigated, which is due to the insufficient study of the molecular mechanisms of its action on the hormonal and metabolic status of the organism. The review discusses literature data and the results of our own research on the role of insulin in the central regulation of energy homeostasis, as well as on the experience of using intranasally administered insulin to correct eating disorders and metabolic and hormonal dysfunctions developing under conditions of experimental diabetes mellitus and metabolic syndrome. In studies involving healthy volunteers, various effects of intranasally administered insulin were shown, including effects on cognitive function, eating behavior and weight loss, and the gender specificity of its action was found. In the course of numerous studies of intranasally administered insulin in animal models of diabetes mellitus, not only stabilization of carbohydrate homeostasis was shown, but also a positive effect in the form of restoration of the functional activity of insulin signaling pathways in the hypothalamus and other parts of the brain. We have presented and analyzed data on the systemic effects of intranasally administered insulin in rodents with experimental models of diabetes mellitus, as well as in healthy individuals.

Problems of Endocrinology. 2019;65(5):389-395

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