IMMUNOREGULATORY IMBALANCE AND FUNCTIONAL STATE OF THE HEART IN THE PATIENTS WITH DIABETES MELLITUS TYPE 2

Diabetes mellitus type 2 is one of the most important non-infectious diseases in the modern world, being an important risk factor of cardiovascular disorders. Changes in left ventricular myocardial diastolic function are observed in diabetic patients independently from other comorbidities. Etiology of the heart failure during diabetes mellitus type 2 is multifactorial, exhibiting cellular,  molecular and metabolic aspects. However, its pathophysiological mechanisms are not completely understood. The aim of this study was to evaluate numbers of inflammatory T lymphocytes, i.e., T helper type 1 (Th1) and T helper type 17 (Th17) cells, and FoxP3+T regulatory lymphocytes, depending on the functional state of the heart assessed by two-dimensional echocardiography in patients with arterial hypertension and diabetes mellitus type 2. A total of twenty-five patients with a combination of arterial hypertension and diabetes mellitus type 2, and 14 patients with arterial hypertension without carbohydrate disturbances were recruited to a cross-ectional case-control study. All the patients underwent echocardiography with transthoracic access at the M-mode, B-mode and Doppler mode of imaging. We evaluated numbers of Th1 and Th17 lymphocytes by intracellular production of IL-17 and IFNγ by CD4+ lymphocytes, respectively. The numbers of FoxP3+T regulatory lymphocytes were estimated by expression of CD25 and FoxP3 transcription factor. A flow cytometry approach was used in both cases. We revealed some correlations between the numbers of Th17 lymphocytes, FoxP3+T regulatory lymphocytes and functional parameters of myocardium in patients with diabetes mellitus type 2, which were absent in patientswithout carbohydrate impairments. The numbers of FoxP3+T egulatory lymphocytes, Treg/Th17 lymphocyte ratio, and mean fluorescence intensity of IL-17 for Th17 cells was lower in patients with diabetes mellitus and diastolic dysfunction compared to the patients with diabetes free of diastolic dysfunction. Association of diastolic dysfunction with diabetes mellitus type 2 was accompanied by increase of IFNγ+Th1 lymphocyte numbers and concentrations of IL-10, IFNγ and TNFα in serum as compared to the patients with diastolic dysfunction in the absence of carbohydrate metabolism disturbances. The diabetic patients with diastolic dysfunction were characterized by hyperinsulinemia, hyperglycemia, higher index of insulin resistance, increase of waist circumference and visceral adiposity index when compared to the patients with diastolic dysfunction without diabetes. Visceral obesity and decrease of insulin sensitivity may be regarded as pathogenetically significant factors for the development of immune regulatory imbalance and diastolic dysfunction in the patients with diabetes mellitus type 2

Important problems in the diagnosis and treatment of autoimmune hepatitis (based on the Russian consensus 2017)

The analysis of publications devoted to the Russian Consensus on the Diagnostic and Treatment of Autoimmune Hepatitis (AIH), which was considered at the 43rd annual Scientific Session of the CNIIG From Traditions to Innovation (March 4, 2017) is carried out. The presence of clear algorithms and recommendations for the diagnosis and treatment of AIH significantly help the doctor in real clinical practice, but do not exclude a personified approach to the patient

INTERPLAY OF INFLAMMATION AND METABOLIC FACTORS IN COMORBID OBESITY AND ARTERIAL HYPERTENSION OF HIGH AND VERY HIGH RISK

Aim. Evaluation of the FoxP3+ T-regulatory lymphocytes (Treg) content in overweight and obesity in arterial hypertension (AH) patients of high and very high risk, and relation of Treg amount with the parameters of lipid and carbohydrate metabolism.Material and methods. A momentary cross sectional study was done, that included 39 patients with AH of high and very high cardiovascular risk with anthropometric signs of overweight and grade 1 obesity. For identification of Treg, intracellular expression of FoxP3 transcriptional factor was assessed. In the blood serum, high sensitive C-reactive protein (hsCRP) was measured, with leptin, adiponectin, parameters of lipid and carbohydrate metabolism.Results. By the ROC-analysis, the content of FoxP3+ Treg below 3,18% makes it to identify patients with hsCRP >3 mg/L (sensitivity — 74%; specificity — 68%). Subgroups were selected that differ by the content of FoxP3+ of T-regulatory lymphocytes (subgroup 1: patients with the level of FoxP3+ Treg <3,18%; subgroup 2: patients with FoxP3+ Treg >3,18%). In subgroup 1 patients there was direct correlation revelaed of FoxP3+ Treg-lymphocytes content and HDL cholesterol (Rs=0,564; p=0,012). Females of subgroup 1 were characterized by higher waist circumference comparing to the females of subgroup 2 (p=0,025); in males, however, there were no differences in waist circumference. In subgroup 1 male patients were characterized by lower HDL cholesterol comparing to women (p=0,005), however such difference was absent in the subgroup of patients with FoxP3+ Treg >3,18%. Among the patients of subgroup 2 the content of FoxP3+ Treg in males showed tendency to higher values comparing with females.Conclusion. In AH patients of high and very high risk, overweight and obesity grade 1, first time an association revealed of Treg lymphocytes and HDL concentration, that is related to higher rate of subclinical inflammation. Gender specifics is found for potential mechanisms of increase of FoxP3+ Treg-lymphocytes. The relations that revealed in our study underscore an opportunity to develop novel approaches to cardiometabolic risk stratification

Liver Cirrhosis as the Outcome of Non-Alcoholic Fatty Liver Disease Associated with PNPLA3 Gene RS738409 Polymorphism

Relevance: Non-alcoholic fatty liver disease is the most common liver disease worldwide. Although the disease usually has a favorable, asymptomatic course, in some cases it can occur in the form of non-alcoholic steatohepatitis, and some patients may develop cirrhosis of the liver and hepatocellular carcinoma. There are more and more foreign studies proving the relationship of genetic factors with the progression of Non-alcoholic fatty liver disease. However, information about this association in the Russian Federation remains scarce.Goal of the study: to assess the prevalence of patatinlike phospholipase domain-containing protein 3 gene variants in patients with Non-alcoholic fatty liver disease-related cirrhosis of the liver in the Russian population sample and the effect of the mutation on the course of the disease.Materials and methods: We formed three groups of patients. Group I included 30 patients with Non-alcoholic fatty liver disease-related cirrhosis of the liver. Group II included 46 patients with Non-alcoholic fatty liver disease at the non-cirrhotic stage. Group III included 25 healthy volunteers. A retrospective analysis of patient history data was performed. We analyzed the results of biochemical blood tests, coagulogram, and ultrasound examination of abdominal organs from the medical records of patients in groups I and II. Patients from groups I and II were additionally examined using hepatic shear elastometry using the aixplorer multiwave ultrasound system (SuperSonic Imagine, USA). Alleles of the patatin-like phospholipase domain-containing protein 3 gene were detected using polymerase chain reaction–restriction fragment length polymorphism.Results. During the study, we obtained statistically reliable links between Non-alcoholic fatty liver disease and the presence of a mutation in the patatin-like phospholipase domain-containing protein 3 gene (RR-2.171; 95% CI: 1.131-4.170; χ2=6.730769; p=0.00948), between liver cirrhosis and the presence of a mutation in the PNPLA3 gene (RR-4.011; 95% CI: 1.558-10.324; p=0.0003), and the relationship between the frequency of occurrence of the GG genotype of the patatin-like phospholipase domaincontaining protein 3 gene with increasing the stage of liver fibrosis in the Russian population sample.Conclusion: The patatin-like phospholipase domain-containing protein 3 gene polymorphism rs738409 is a factor in the progression of Non-alcoholic fatty liver disease to high stages of fibrosis and liver cirrhosis. Detecting of this polymorphism in patients with NAFLD in Russian population may be useful for identifying high-risk groups for disease progression

IgG4-associated sclerosing cholangitis: a diagnosis that may change the course of events (review of the literature and a clinical case)

Immunoglobulin G4-associated sclerosing cholangitis (IgG4-SC) can mimic primary sclerosing cholangitis, cholangiocarcinoma, and pancreatic adenocarcinoma. Its proper diagnosis allows for an adequate therapy and an improvement of the outcomes. The article presents a short literature review with an emphasis on the challenging diagnostic and therapeutic aspects, illustrated by a clinical case. The diagnosis of IgG4-SC is based on a combination of biochemical, radiological and histological signs and symptoms, including elevated levels of serum IgG4, intra- and extrahepatic biliary strictures detected by magnetic resonance cholangiography, and multifocal IgG4-lymphoplasmic infiltrations, sclerosing fibrosis of the bile ducts, seen at morphological assessment. Glucocorticoids (GCS) are the first line agents to achieve remission in patients with IgG4-SC. Most patients respond well to the systemic GCS. However, about 20% of patients (mostly those with extensive sclerotic intra- and/or extrahepatic abnormalities and signs of advanced disease / cirrhosis) show an insufficient or no response from the beginning of the treatment. The clinical case illustrates that timely verification of the IgG4-SC diagnosis may have an important prognostic value. The case history of a 62-year old female patient confirms the difficulties of the early diagnosis of the disease: for a relatively long time, the patient had the diagnosis of primary sclerosing cholangitis. Delay with GCS prescription (the treatment was initiated only at the stage of liver cirrhosis) had led to the lack of clinical efficacy and development of complications, such as relapsing cholangitis with advanced biliary strictures. In patients with suspected primary sclerosing cholangitis, timely differential diagnosis with IgG4-SC is relevant, because early GCS administration can slow the progression of the disease

Metabolic, Inflammatory and Imaging Biomarkers in Evaluation of Coronary Arteries Anatomical Stenosis in Patients with Stable Coronary Artery Disease

Aim. To reveal the statistically significant determinants of the coronary artery (CA) stenosis ≥70% in patients with chronic stable CA disease receiving drug therapy.Material and methods. The study included 68 patients (aged 59.6±6.4 years) with stable CA disease and optimal cardioactive therapy. Coronary angiography was performed in all patients. Basic serum parameters of carbohydrate and lipid metabolism were evaluated; serum concentration of cytokines, adipokines and high sensitive C-reactive protein (hsCRP) were determined by ELISA. The epicardial adipose tissue (EAT) thickness was measured by B-mode echocardiography.Results. The patients’ classification model was created. It allowed to determine probability P for CA stenosis of 70% or more for each patient using formula Р, where L=0.89-1.09×gender+ 0.51×triglycerides–0.28×HDL+0.24×hsCRP (HDL – high density lipoproteins). If calculated P value falls into interval (0; 0.228) the patient should be classified into the group with the risk of CA stenosis ≥70%, while if calculated P value falls into interval (0.228; 1), the patient should be classified into group with CA stenosis below 70%. Even though EAT thickness was indistinguishable determinant of CA stenosis ≥70% in our study, its inclusion into the model as a fifth variable allowed to increase the model quality: area under ROC-curve (AUC) in the model without EAT thickness constituted 0.708 (p=0.009), and increased up to 0.879 (p=0.011) after EAT thickness inclusion.Conclusions. Male sex, level of triglycerides, HDL and hsCRP are statistically significant determinants of CA stenosis ≥70%. The presence of the triglycerides level in the created model underscores an important contribution of this lipid fraction, even when elevated only up to the moderate values, into modulation of the residual cardiovascular risk in patients receiving statins

Epicardial fat thickness and biomarkers of inflammation in patients with stable coronary artery disease: correlation with the severity of coronary atherosclerosis

Aim. To study the relationship between the epicardial fat thickness (EFT), biomarkers of inflammation and metabolic dysfunction in patients with coronary artery disease (CAD) and various severity of coronary atherosclerosis.Material and methods. The study consisted of 89 patients (47 men and 42 women) with stable CAD at the age of 62,2±6,5 years, who assessed the presence and severity of coronary atherosclerosis according to angiography with the calculation of the Gensini Score (GS). We conducted an ultrasonic evaluation of the EFT. We determined the content of glucose, lipid fractions, apoproteins, pro-inflammatory cytokines and adipokines, C-reactive protein by a highly sensitive method (hsCRP).Results. In the total sample of patients, the median GS index was 13,5 (3,5; 43) points, the median EFT was 4,93 (3,95; 6,0) mm, the median hsCRP was 2,1 (1,02; 3,65) mg/l. There were no correlation relationships between the GS index and the body mass index, waist circumference, EFT, hsCRP, lipid and carbohydrate metabolism in the general group of patients. In the course of linear regression analysis, an independent contribution of hsCRP >2,1 mg/l to the formation of the first two tertiles of a sample of GS values was established (0≤ GS ≤28, paired linear regression hsCRP at GS β=0,55, p=0,0221), whereas in patients with GS values from the third tertile (GS >28 points), the growth of this parameter had an independent association with an increase in the EFT (estimation of the coefficient of paired linear regression of the EFT on GS β=0,56, p=0,0015). The range of hsCRP changes did not affect the value of the β coefficient in paired linear regression models in patients with GS >28 points (n=29) and in the subgroup of patients with GS >28 and hsCRP >2,1 mg/l (n=18).Conclusion. The absence of an independent association between EFT and minor or moderate severity of atherosclerotic lesions of the coronary arteries (for GS ≤28 points) in patients with CAD, while an independent marker of GS index increase is higher than 2,1 mg/l. An independent contribution to the formation of a severe coronary atherosclerosis (with a GS value of >28 points) is equally made by thickening of EFT, and a moderately elevated level of hsCRP

Important problems in the diagnosis and treatment of primary sclerosing cholangitis (based on the Russian consensus on diagnosis and treatment autoimmune hepatitis. Moscow, 2018)

© 2019 Consilium Medikum. All rights reserved. The article is published based on the results of the Russian Consensus on the diagnosis and treatment of primary sclerosing cholangitis (PSC), discussed at the 44 th annual Scientific Session of the CNIIG "Personalized Medicine in the Era of Standards" (March 1, 2018). The aim of the review is to highlight the current issues of classification of diagnosis and treatment of patients with PSC, which causes the greatest interest of specialists. The urgency of the problem is determined by the multivariate nature of the clinical manifestations, by often asymptomatic flow, severe prognosis, complexity of diagnosis and insufficient study of PSC, the natural course of which in some cases can be considered as a function with many variables in terms of the nature and speed of progression with numerous possible clinical outcomes. In addition to progression to portal hypertension, cirrhosis and its complications, PSC can be accompanied by clinical manifestations of obstructive jaundice, bacterial cholangitis, cholangiocarcinoma and colorectal cancer. Magnetic resonance cholangiography is the main method of radial diagnostics of PSC, which allows to obtain an image of bile ducts in an un-invasive way. The use of liver biopsy is best justified when there is a suspicion of small-diameter PSC, autoimmune cross-syndrome PSC-AIG, IgG4-sclerosing cholangitis. Currently, a drug registered to treat primary sclerosing cholangitis which can significantly change the course and prognosis of the disease does not exist. There is no unified view on the effectiveness and usefulness of ursodeoxycholic acid and its dosage in PSC. Early diagnosis and determination of the phenotype of PSC is of clinical importance. It allows to determine the tactics of treatment, detection and prevention of complications

Important problems in the diagnosis and treatment of primary sclerosing cholangitis (based on the Russian consensus on diagnosis and treatment autoimmune hepatitis. Moscow, 2018)

© 2019 Consilium Medikum. All rights reserved. The article is published based on the results of the Russian Consensus on the diagnosis and treatment of primary sclerosing cholangitis (PSC), discussed at the 44 th annual Scientific Session of the CNIIG "Personalized Medicine in the Era of Standards" (March 1, 2018). The aim of the review is to highlight the current issues of classification of diagnosis and treatment of patients with PSC, which causes the greatest interest of specialists. The urgency of the problem is determined by the multivariate nature of the clinical manifestations, by often asymptomatic flow, severe prognosis, complexity of diagnosis and insufficient study of PSC, the natural course of which in some cases can be considered as a function with many variables in terms of the nature and speed of progression with numerous possible clinical outcomes. In addition to progression to portal hypertension, cirrhosis and its complications, PSC can be accompanied by clinical manifestations of obstructive jaundice, bacterial cholangitis, cholangiocarcinoma and colorectal cancer. Magnetic resonance cholangiography is the main method of radial diagnostics of PSC, which allows to obtain an image of bile ducts in an un-invasive way. The use of liver biopsy is best justified when there is a suspicion of small-diameter PSC, autoimmune cross-syndrome PSC-AIG, IgG4-sclerosing cholangitis. Currently, a drug registered to treat primary sclerosing cholangitis which can significantly change the course and prognosis of the disease does not exist. There is no unified view on the effectiveness and usefulness of ursodeoxycholic acid and its dosage in PSC. Early diagnosis and determination of the phenotype of PSC is of clinical importance. It allows to determine the tactics of treatment, detection and prevention of complications