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

Visceral obesity and cardiometabolic risk: features of hormonal and immune regulation

The issue of the prognostic value of obesity in the development of cardiovascular diseases still remains open. Different input of visceral and subcutaneous adipose tissue in the formation of cardiometabolic risk is highlighted in many research works. A range of epidemiological studies provides data confirming relation of the visceral adiposity with abnormal metabolic profile and increased cardiovascular risk, while subcutaneous adipose tissue is attributed with relative protective properties. Pathophysiological mechanisms mediating interconnection of visceral adiposity with the development of atherosclerosis remain studied incompletely. It was stated that sex hormones, estrogens and androgens, participate in the redistribution of adipose tissue, sustenance of energy homeostasis, influence on the secretion of adipokines and immune regulation of adipose tissue. Meanwhile cells of immune system, including cells of the adaptive immunity, widely presented in adipose tissue contribute to the development of the local subclinical inflammation and influence on the features of cardiometabolic effects of adipose tissue. The review discusses possible mechanisms, by which abovementioned relationships are executed and cardiovascular risk in obesity is realized

ADEMETHIONINE IN THERAPY OF NON-ALCOHOLIC FATTY LIVER DISEASE

The article describes the current views on the pathogenesis of nonalcoholic fatty liver disease and a short overview of possible methods of therapy. The main mechanisms of antioxidant action of ademetionine in the treatment of NAFLD and the analysis of the evidence base of its effectiveness are discussed. We present clinical cases of a positive impact of ademetionine in NAFLD patients

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

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

Risk of Cirrhosis in Patients with Non-alcoholic Fatty Liver Disease and Previous Viral Hepatitis B

Previous viral hepatitis B increases the risk of cirrhosis in various chronic liver diseases.Aim. Assessment of association between previous hepatitis B and the severity of liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD).Materials and methods. A single-centre cross-sectional trial included 110 HBsAg- and anti-HCV-negative patients with confirmed NAFLD (median (IQR) age 60 (53-66) years). Obesity, type 2 diabetes and dyslipidemia were in 78 (70.9%), 64 (58.2%) and 77 (70%) individuals, respectively. To confirm previous and occult hepatitis B virus (HBV) infection, blood of all participants was examined for anti-HBc (IgG) and HBV DNA. Liver biopsy was performed in 35 patients (31.8%), other patients had transient elastography with steatometry and/or a serum FibroMax™ assay (FibroTest+SteatoTest+NashTest).Results. In 85 patients, liver fibrosis was scored F0-F2 with METAVIR, 25 persons had severe fibrosis (F4 in 23, F3 in 2). Patients with severe fibrosis were significantly older than persons with F0-F2 and had more frequent type 2 diabetes. Anti-HBc was detected in 10 of 25 (40%) patients with F3-F4 and in 7 of 85 (8.2%) persons with F0-F2 (p <0.001). None of anti-HBc-positive individuals had HBV DNA in blood. Presence of anti-HBc was the major factor directly associated with severe liver fibrosis (OR 7.339; 95% CI 2.189-24.604; p = 0.001).Conclusion. Anti-HBc-positive patients with NAFLD have a much higher risk of severe liver fibrosis compared to patients without previous viral hepatitis B

Drugs-induced liver injury associated with non-steroidal anti-inflammatory drugs: a case report and clinical insights

Aim: To raise the awareness of general practitioners with special characteristics of the clinical manifestations of the drug-induced liver injury (DILI), which can manifest with various signs, symptoms and types of morphological injury, from asymptomatic increase in transaminases and liver steatosis to chronic hepatitis with advanced fibrosis. Key points: NSAID is one of the most commonly prescribed groups of agents worldwide. Most of them have low risk of liver toxicity. However, prolonged uncontrolled intake of NSAID by patients without proper medical follow-up and monitoring may lead to serious liver injury, illustrated by the clinical case presented. The case manifested as an extremely rare liver injury in the form of chronic hepatitis with advanced fibrosis that developed after prolonged NSAID use. Conclusion: DILI usually occur as idiosyncratic (non-predictable) reactions. This is an exclusion diagnosis requiring comprehensive medical knowledge and awareness on potential drug-induced liver toxicity, including that associated with drug interactions. To minimize potential risk of liver toxicity induced by NSAID, it is recommended to take them in the lowest effective dose and for a minimally required period. A thorough assessment of a patient's past history, monitoring of clinical chemistry parameters, and clinical judgment of the physician remain to be decisive for prevention, timely diagnosis, and treatment of DILI

Pruritus in chronic cholestatic liver diseases

Pruritus can be a prominent symptom  in patients with chronic liver disorders, especially those  with cholestasis,  and  substantially  affects  quality  of life. Management of pruritus  in cholestatic  liver diseases  remains  a  complicated   medical  problem. The review article deals with pathophysiological mechanisms of pruritus in cholestatic liver diseases, in particular, with the role of bile acids, endogenous opioids, serotonin, and histamine. There is new data on the key pathophysiological elements, such as neuronal activation lysophosphatidic acid and autotaxin, an enzyme that produces lysophosphatidic acid and whose serum activity is associated with the intensity of pruritus. Pathophysiology-based management approaches include administration of anionic exchange resin cholestyramine, ursodeoxycholic acid, rifampicin agonists, an opioid antagonist naltrexone and a  serotonin-reuptake inhibitor sertraline. These agents are recommended for the use as a stepped treatment algorithm. Patients who do not respond to these therapies can become candidates for albumin dialysis, plasmapheresis, ultraviolet B phototherapy, or need some other individualized approaches. New knowledge on the pathophysiology of pruritus may potentially result in the development of new agents for cholestatic pruritus

Cholestasis syndrome in a comorbid patient: diagnostic difficulties

The purpose of the review article is to demonstrate generalized ideas on the classification and diagnosis of cholestasis syndrome of various etiologies, to consider the possibility of using laboratory and instrumental research methods in real clinical practice in a comorbid patient. The main provisions. According to the mechanism of development, cholestasis is conditionally divided into intrahepatic and extrahepatic, as well as a mixed type. Extrahepatic cholestasis develops with mechanical obstruction of the main extrahepatic or main intrahepatic ducts. Intrahepatic cholestasis as a result of a number of diseases, such as acute viral hepatitis, primary biliary cholangitis, drug damage to the liver, amyloidosis of the liver. In real clinical practice, a combination of several etiological factors leading to the development of cholestasis is possible in a comorbid patient. A clinical observation is given when, in a patient with gallstone disease, melanoma and ulcerative colitis, after excluding a number of possible causes of cholestasis, autoimmune cross syndrome, autoimmune hepatitis and primary sclerosing cholangitis (PSC), was diagnosed, which allowed the initiation of immunosuppressive therapy with 48 mg corticosteroid (per day) and the preparation of ursodeoxycholic acid (UDCA) exhol at a dose of 1500 mg per day. Regardless of the cause of intrahepatic cholestasis, UDCA remains the drug for the treatment of first-line cholestatic lesions. Conclusion. Only a consistent methodological approach, taking into account all the possible causes of cholestasis, can lead to a correct diagnosis and timely adequate treatment in each case