Vol 63, No 1 (2017)

Clinical endocrinology
The respiratory explosion activity of neutrophils in blood from patients with Graves' disease manifestation
Dogadin S.A., Dudina M.A., Savchenko A.A., Mankovskiy V.A., Gvozdev I.I.


Objective. To study respiratory burst activity in neutrophilic granulocytes in the onset of Graves’ disease (GD).

Material and methods. Twenty-six females aged 18—55 years (mean age, 40.7±13.2 years), with the diagnosis of Graves’ disease verified for the first time, were enrolled in this study. Spontaneous and zymosan-induced chemiluminescence (CL) was assessed using a CL3606 36-channel analyzer for 90 min. The following parameters of the chemiluminescence curve were determined: time to attain the maximum (Tmax), the maximum intensity (Imax), and the area under the curve (S).

Results. Patients with GD and lucigenin-dependent CL of neutrophils exhibited decreased zymosan-induced CL and the increased Imax of luminol-dependent spontaneous and zymosan-induced CL of neutrophils. Association between the anti-TPO level in blood serum with Tmax (r=–0,70; р=0.036) and Imax of luminol-dependent induced CL (r=–0.72; р=0.030) was found. The maximum level of synthesis of secondary reactive oxygen species (ROS) was found to be elevated in patients with GP both at relative rest and upon antigen-induced respiratory burst.

Conclusion. In patients with GD, respiratory burst activity in neutrophils increases due to synthesis of secondary reactive oxygen species. Upon the onset of GD, already at the stage of subclinical thyrotoxicosis, the association between the indices of respiratory burst in neutrophils and thyroid hormones is lost but there emerges a relationship between the CL response and anti-TPO concentration.

Problems of Endocrinology. 2017;63(1):4-8
Research of association of the polymorphic locus rs11212617 ATM gene with the response to therapy with metformin in patients with type 2 diabetes
Bondar I.A., Shabelnikova O.Y., Sokolova E.A., Filipenko M.L.

Rationale. The genetic aspects influencing the effectiveness of metformin (MF) therapy in patients with type 2 diabetes mellitus (DMT2) have recently been intensively studied.

Objective — to study the association between the rs11212617 polymorphism in the ATM gene and response to metformin therapy in DMT2 patients in the Novosibirsk region and to conduct a metaanalysis of the previously reported data.

Material and methods. 460 DMT2 patients (97 males and 363 females) who received MF, both as a part of monotherapy and in combination with sulfonylurea (SU) drugs, were subjected to cross-sectional examination. Depending on HbA1c level, patients were divided into the following groups: patients who have attained the target HbA1c level after MF therapy (n=209) and those who did not attain the target HbA1c level although receiving the maximum dose of MF (n=251). Alleles and genotypes were determined by real-time PCR using TaqMan probes at the Institute of Chemical Biology and Fundamental Medicine (SB RAS).

Results. Frequency of the rare C allele of the rs11212617 polymorphism in the ATM gene in the examined patients was 0.41 and statistically did not differ between the subgroups who received MF monotherapy and combination therapy. Statistically significant association between the genotype of the rs11212617 polymorphism in the ATM gene and the type of response was revealed neither in the total group of patients (OR=0.94, 95% CI 0.73—1.23; p=0.67) nor in the MF monotherapy (OR=0.94, 95% CI 0.73—1.23; p=0.67) or combination therapy subgroups (OR=1.02, 95% CI 0.72—1.43; p=0.92). However, the metaanalysis results verify that the C allele is associated with attainment of the target HbAc1 level (the total OR=1.27, 95% CI 1.10—1.46; p=0.0008).

Conclusions. The rs11212617 polymorphism in the ATM gene can influence the effectiveness of MF therapy in DMT2 patients.

Problems of Endocrinology. 2017;63(1):9-16
Evaluation of the clinical safety and analytical reliability of blood glucose self-control tools "Glucocard Sigma" and "Glucocard Sigma-mini" in type 1 diabetes children.
Andrianova E.A., Ilyin A.V., Kuraeva T.L., Peterkova V.A.

Rationale. Arkray blood glucose meters have become widely used in Russia since 2013. Studies focused on their accuracy, where Arkray Glucocard II glucose meter is used as the reference monitoring system, have been published. Since insulin dose to be injected relies upon readings of a personal blood glucose meter, the system being used must comply with the clinical safety and analytical accuracy criteria for glucose meters.

Objective — to assess clinical safety and analytical accuracy of the results of studying blood glucose level measured using Glucocard Sigma and Glucocard Sigma Mini blood glucose meters.

Material and methods. Glucose level in a drop of capillary blood was studied in 48 pediatric and adolescent patients with type 1 diabetes mellitus (DMT1). The mean age of the patients was 9.4±5.6 years; average duration of the disease, 4.2±2.7 years. Parallel studies on glycaemia using the Glucocard Sigma and Glucocard Sigma Mini glucose meters being tested, as well as a BIOSEN C-line stationary biochemical analyzer system, were carried out at the Department of Diabetes Mellitus of the Institute of Pediatric Endocrinology and the Biochemical Laboratory of the Endocrinology Research Center of the Ministry of Healthcare of the Russian Federation. A total of 320 samples were examined. The hexokinase method performed on a BIOSEN C-line biochemical analyzer system was used as the reference method for measuring blood glucose level.

Results. Assessment of clinical safety demonstrated that 100% of test results belonged to zone A (will not result in patient error) and B (will not result in patient error or there will be a minor error not affecting patient’s condition). These findings fully comply with the ISO 15197-2016 standard. Investigation of the analytical accuracy of Glucocard Sigma and Glucocard Sigma Mini glucose meters (capillary blood, glucose blood level >4.2 mmol/L) compared to the results obtained using the BIOSEN C-line biochemical analyzer system showed a <5% deviation in 118 (51.3%) measurements; <10%, in 202 (87.8%) measurements; less than 15%, 222 (96.5%) measurements; and less than 20%, in 230 (100%) measurements. These results comply both with the ISO 15197-2015 criteria and stricter criteria ISO 15197-2016.

Conclusion. The high accuracy of Glucocard Sigma and Glucocard Sigma Mini glucose meters has been confirmed. The accuracy of these glucose meters complies with the State Standard GOST ISO 15197-2015 and the ISO 15197-2016 standard.

Problems of Endocrinology. 2017;63(1):17-22
Evaluation of the efficiency of using glucose monitoring devices upon unsatisfactory diabetes compensation
Kurnikova I.A., Ualihanova A.U., Morgunov L.Y., Mavlyalieva E.R., Surikova M.A.

Rationale. The key purpose of modern glucose meters is to ensure regular self-monitoring of glucose level when receiving outpatient management, provided that fair diabetes compensation is achieved. Although glucose meters are not intended for assessing the glucose level in severe metabolic disorders (ketosis, ketoacidosis), since these conditions have a negative effect on device accuracy, in actual life a patient (or a physician) can face a situation when a glucose meter is the only tool for evaluating carbohydrate metabolism disorders.

Objective. To evaluate clinical accuracy of Satellite Express PKG-03 glucose meter in measuring the glucose level in patients with type 1 and 2 diabetes mellitus (DM) receiving insulin therapy when the disease course is complicated by ketosis or ketoacidosis.

Material and methods. Capillary blood was simultaneously collected in two groups of patients receiving insulin therapy from the same drop to evaluate the glucose blood level using the Satellite Express glucose meter and a SUPER GL laboratory analyzer of glucose and lactate levels. Acid-base imbalance was the key criterion for distributing patients into groups: no disorders were detected in group 1 patients, while group 2 patients had ketosis or ketoacidosis. The results were evaluated using the Clarke error grid.

Results. Comparative analysis of blood samples collected from 77 patients showed that all deviations in glucose level indices measured using the Satellite Express glucose meter from the reference values belonged to zones A (the clinically valid values) and B (safe deviations) in patients without acid-base imbalance. In patients hospitalized for ketosis and ketoacidosis (group 2), the deviations from the reference values lay in zones A and B in 97%, while lying on the boundary between zones B and C only in 3%.

Problems of Endocrinology. 2017;63(1):23-29
The Clinical use of glimepiride in patients with type 2 diabetes mellitus, uncontrolled on combination of DPP4-inhibitors and metformin: results of ESCALATION observational study
Mkrtumyan A.M.

Background. Russian guidelines for T2DM management 2015 recommend intensification to triple combination therapy in patients not reaching glycaemia treatment targets on dual oral antidiabetic therapy for 6 months. Despite this, clinical experience shows that physicians may also switch one component of the dual therapy, or add the third component of the therapy. This study sought to assess the effect of physician-led prescription of glimepiride (GLIM) to individuals with T2DM uncontrolled by metformin (MET) and DPP-inhibitor.

Material and methods. This observational study was carried out in real clinical practice in 142 Russian clinical centers, among 1447 T2DM patients, which consume glimepiride according to medical disposal. Entry criteria included 18—80 years male and female with HbA1c≥ 7,6% и ≤10 (during 2 month) and uncontrolled carbohydrate metabolism by individualized HbA1c target level by MET(in a dose ≥1500 mg/per day) and DPP-4i for ≥3 months, which doctor prescribed glimepiride in mono- or combination therapy. Duration of observation after inclusion into research was 24 weeks.

Results. Patients were prescribed glimepiride as part of three-component therapy — GLIM+MET+DPP-4i (54.5%), two-component — GLIM+MET (34.4%), in other combinations — GLIM+other (11.1%). Mean HbA1c reduction at 24 weeks was 1.49±0.71%, and fasting blood glucose (FBG) reduction — 2.18±1.38 mmol/l. Significant changes in glycemic control in different groups of patients were not committed. Postprandial blood glucose (PPG, mmol/l) on an average decreased — 3.00±1.71, in groups GLIM+MET+DPP-4i, GLIM+MET and GLIM+other 2.98±1.63; 3.07±1.81 и 2.95±1.84. At week 24, body mass index (BMI, kg/m2 )was overall decrease by 0.36±1.99 and not significantly reduced in the GLIM+MET+DPP-4i, GLIM+MET and GLIM+other groups. Adverse events (AEs), inclusive of symptomatic hypoglycaemia, were reported in 370 patients (25.8% of all participants). In GLIM+MET+DPP-4i, GLIM+MET and GLIM+other groups frequency of symptomatic hypoglycaemia composed 13.2, 8.5 и 14.5%. Incidence of asymptomatic hypoglycaemia was reported at 8.4% of patient. In GLIM+MET+DPP-4i, GLIM+MET and GLIM+other groups it were 8.4, 7.3 и 11.9% , with maximum in GLIM+other group. There were no significant differences in the proportions of patients with hypoglycaemic episodes between other study groups. No episodes of severe hypoglycaemia or serious AEs were reported.

Conclusion. More than a half of incidences of uncontrolled T2DM by metformin and DPP-4 inhibitor combination treatment in real-life clinical practice is intensify by prescribing three-component treatment setting. Approximately, in third cases the choice of the therapeutic approach depend on switch of iDPP-IV for the GLIM. Further 11.1% composed combinations glimepiride+ iDPP-IV (DRC). Various combinations of GLI with MET and/or iDPP4 provided improvement of glycemic control, affecting of HbA1c, FPG and PPG. During the study, there was no significant difference in glycemic control between different types of the therapy. Episodes of symptomatic hypoglycemia were more frequent in the DRC group compared with the group GLY+MET. No severe hypoglycemic events and no influence for body weight were reported in research indicating the safety of GLIM at T2DM patients uncontrolled by metformin and DPP-4 inhibitor combination therapy.

Problems of Endocrinology. 2017;63(1):30-38
Case Reports
TSH-secreting pituitary adenoma: late diagnosis and effectiveness of therapy
Petrik G.G., Kosmacheva E.D., Polyakova U.I., Butaeva S.V., Rozhinskaya L.Y., Belaya Z.E.

The modern therapeutic and diagnostic algorithms allow timely detection of pituitary disorder to prescribe adequate treatment. Meanwhile, when interpreting the thyroid status, physicians need to take into account the extremely rare but the actually existing possibility of central thyrotoxicosis. The worldwide practice shows that diagnosis of this condition is rather challenging.

We report a clinical case of a TSH-secreting pituitary adenoma in a 47-year-old female who received a long-term thyrostatic therapy for thyrotoxicosis. The patient was diagnosed with Graves’ disease; however, thyrotoxicosis was actually caused by TSH-oma. The key laboratory signs of central thyrotoxicosis included the combination of episodes of normal or elevated TSH level with the high or normal free T4 level. MRI showed a pituitary macroadenoma. The clinical manifestations of thyrotoxicosis made it possible to rule out the thyroid hormone resistance syndrome. The attempted therapy with octreotide eliminated the clinical and laboratory signs of thyrotoxicosis, so the conservative method was selected as first-line therapy. The features of clinical and laboratory signs, as well as the principles of differential diagnosis and modern methods for treating TSH-secreting pituitary adenomas are discussed.

Problems of Endocrinology. 2017;63(1):39-45
Thyrotoxic hepatitis
Pikulev D.V., Klemenov A.V.

In most cases, liver pathology in hyperthyroidism is confined to asymptomatic changes in laboratory indices, while clinical signs are much rarer. Three clinical variants of liver pathology in patients with hyperthyroidism can be differentiated: drug-induced hepatitis that develop in response to administration of thyrostatic agents (mainly propylthiouracil); concomitant autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis), and hepatopathies as a direct manifestation of thyrotoxicosis (thyrotoxic hepatitis). Thyrotoxic hepatitis is a rare condition difficult to diagnose. The variety of etiological factor of liver pathology in hyperthyroidism, universal clinical symptoms, and the lack of specific histological markers make it difficult to make a correct diagnosis.

A clinical case of Graves’ disease complicated with severe thyrotoxic hepatitis, the edema-ascites syndrome and hyperbilirubinemia is reported. The patient was diagnosed with thyrotoxic hepatitis after all other reasons for liver pathology have been ruled out. The concomitant thyrogenic myocardiodystrophy, cardiomegaly and atrial fibrillation required ruling out the diagnosis of cardiogenic liver injury and made diagnosing more difficult. Normalization of the thyroid status in patients receiving mercazolyl therapy was accompanied by alleviation of clinical symptoms of hepatitis and the positive dynamics of the indices of liver function tests.

A brief review of the data on clinical variants and mechanisms of liver injury in patients with thyrotoxicosis is presented.

Problems of Endocrinology. 2017;63(1):46-50
Tikhonovich Y.V., Kolodkina A.A., Kulikova K.S., Golubkina Y.Y., Kalinchenko N.Y., Savelieva L.V., Kostik M.M., Rozhinskaya L.Y., Tiulpakov A.N.

Vitamin D plays a central role in calcium homeostasis. Impaired degradation  of 1,25-dihydroxyvitamin D due to loss-of-function mutations in CYP24A1 leads to significant hypercalcemia, hypercalciuria,  suppressed level of parathyroid hormone (PTH),  nephrocalcinosis and nephrolithiasis.  This condition has been called Idiopathic infantile hypercalcemia.

Treatment includes low calcium diet, rehydration, furosemid,  avoidance of vitamin D supplements  and sun protection.   In severe  cases   glucocorticoids, ketoconazole,  bisphosphonates  and  hemodiafiltration may be used.

Early diagnosis of the disease allows to develop an individual plan for managing these patients to prevent the formation of kidney disease, to conduct a genetic family counseling.

Here, we describe the cohort of  patients (3  children, 2 adults)  with significant hypercalcemia due to  homo- and compound heterozygous mutations in CYP24A1, describe  the main clinical and laboratory characteristics, diagnosis, principles and foundations of the management of patients with this pathology.

Problems of Endocrinology. 2017;63(1):51-57
Neuroprotective properties of incretin mimetics in brain ischemia and neurodegenerative diseases
Tyurenkov I.N., Bakulin D.A., Kurkin D.V., Volotova E.V.

Type 2 diabetes mellitus (DMT2) is a disease significantly increasing the risk of neurodegenerative disorders and stroke. The keen interest in anti-diabetic medications, which can reduce the risk of cardiovascular and neurodegenerative disorders, is caused by the substantial rise in the number of patients with DMT2 as a result of population aging.

According to the clinical trial data, incretin mimetics significantly reduce the glycosylated hemoglobin level, while moderately reducing blood pressure and adipose tissue mass in DMT2patients. When added to the conventional hypoglycemic therapy, analogues of glucagon-like peptide-1 (GLP-1) significantly decrease the risk of cardiovascular complications in DMT2 patients. The positive effect of these medications in patients with neurodegenerative diseases, both the independent and T2DM-associated ones, has been observed. Today, there are ongoing clinical trials of the effect of GLP-1 analogues in patients with Parkinson’s and Alzheimer’s disease.

The available data show that incretin mimetics exhibit neuroprotective properties due to GLP-1 receptors on neurons, microglial and endothelial cells. These receptors were found to be able to trigger the major intracellular signaling pathways that maintain cellular function and inhibit apoptosis under pathological conditions.

In this review, we summarize the results of studies focused on neuroprotective properties of drugs with the incretin-mimetic mechanism of action. The findings on their effect on a number of pathological processes in patients with neurodegenerative diseases and cerebrovascular disturbance are reported. The ability of incretin mimetics to reduce microglial activation, secretion of proinflammatory cytokines and pathological protein aggregation, as well as inhibit neuronal apoptosis, improve mitochondrial functional state, enhance expression of trophic factors and stimulate neurogenesis, is demonstrated.

Problems of Endocrinology. 2017;63(1):58-67

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