Vol 88, No 10 (2016)


Diabetes mellitus in the Russian Federation: Arguments and facts

Shestakova M.V., Dedov I.I.


Diabetes mellitus (DM) is a fast-spreading non-communicable disease epidemic of the 21st century. According to the Russian State Register, in 2015 a total of 4.3 million patients were registered for seeking medical advice for DM. were registered in 2015. However, the first NATION epidemiological survey aimed to actively screen type 2 DM (T2DM) in the population of Russia has shown that the true prevalence of T2DM is twice as high as the registered one, accounting for 5.4%. The proportion of previously undiagnosed T2DM was 54%. The highest prevalence of T2DM was seen in individuals older than 45 years and in those with obesity or cardiovascular diseases. The prevalence of prediabetes was 19.3%. The main cause of death in DM patients is cardiovascular diseases. Nonmedical and indirect costs are more than a quarter of the economic burden. The medical costs of treatment for patients with DM and complications are thrice higher than those in uncomplicated DM subjects.
Terapevticheskii arkhiv. 2016;88(10):4-8
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Incretin secretion and glucose metabolism in morbidly obese patients in the early and late periods after biliopancreatic diversion

Dedov I.I., Melnichenko G.A., Troshina E.A., Ershova E.V., Mazurina N.V., Ogneva N.A., Yashkov Y.I., Ilyin А.V.


Aim. To estimate the parameters of glucose metabolism and to assess the secretion of incretins in patients after biliopancreatic diversion (BPD) for morbid obesity (MO) in the early and late postoperative periods. Subjects and methods. The prospective part of the investigation included 22 patients with a body mass index of 35.8 to 68.4 kg/m2 and type 2 diabetes mellitus (T2DM). All the patients were examined before, 3 weeks and 3 months after BPD. The retrospective part covered 23 patients who were examined after BPD for MO; the postoperative period was 4.7 [2.3; 7.2] years. A control group consisted of 22 healthy, normal weight volunteers. A 75-g oral glucose tolerance test was carried out in all the groups to study the levels of glucose, immunoreactive insulin (IRI), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon at 0, 30, 60, and 120 min. Results. T2DM patients showed improvement in glucose metabolism just 3 weeks after BPD; following 3 months, they had normalized fasting blood glucose levels (5.6 [5.0; 6.0] mmol/l). During 3 months, glycated hemoglobin decreased from 7.5 [6.6; 8.5] to 5.7 [5.3; 5.9]%. In the early period following BPD, there was an increase in basal and postprandial GLP-1 levels associated with the peak IRI concentration. In the late period after BPD, the enhanced secretion of IRI and GLP-1 persisted, which was followed by a reduction in postprandial glucose levels in 4 of the 23 patients. Conclusion. T2DM remission does not depend on weight loss in the early period after BPD. In this period, the significant improvement of glucose metabolic parameters in patients with obesity and T2DM is associated with elevated GLP-1 levels. The altered incretin response is a stable effect of BPD and remains in its late period.
Terapevticheskii arkhiv. 2016;88(10):9-18
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Comparative evaluation of the intensity of reparative processes in the lower extremity soft tissues of diabetic patients receiving local negative pressure wound treatment and standard wound care

Galstyan G.R., Tokmakova A.Y., Zaitseva E.L., Doronina L.P., Voronkova I.A., Molchkov R.V.


Aim. To study the intensity of soft tissue repair in patients with diabetic foot syndrome (DFS) during local negative pressure wound treatment versus standard wound care. Subjects and methods. The investigators estimated the clinical (wound sizes, local tissue oxygenation), histological (light microscopy), and immunohistochemical (CD31, CD68, MMP-9, and TIMP-1) markers for reparative processes in patients with DFS during vacuum therapy versus standard wound care. Forty-two patients with the neuropathic and neuroischemic (without critical ischemia) forms of DFS were examined after debridement. In the perioperative period, 21 patients received negative pressure wound therapy and 21 had standard wound care. Results. During vacuum therapy, the area and depth of wound defects decreased by 19.8±7.8 and 42.8±5.6%, respectively (p=0.002) (as compared to the baseline data). In the control group, these indicators were 17.0±19.4 and 16.6±21.6% (p=0.002). There was a significant intensification of local microhemodynamics according to transcutaneous oximetry readings in the negative pressure wound treatment group. After 9±2 days of treatment, histological examination of granulation tissue revealed a significant reduction in edema, cessation of inflammatory infiltration, and formation of mature granulation tissue in Group 1. Immunohistological examination indicated a more obvious increase in the count of macrophages (CD68 staining) and a significant increment in the number of newly formed vessels, as evidenced by anti-CD31 antibody staining. During the treatment, there was a decline of the expression of MMP-9 and an increase in that of TIMP-1, as compared to those in the control group. Conclusion. The findings are indicative of the enhanced intensity of reparative processes in patients with DFS during vacuum therapy versus standard wound care, resulting in more rapidly decreased wound sizes, increased local microhemodynamics, reduced inflammation, and accelerated wound transition from the inflammatory to the proliferative phase.
Terapevticheskii arkhiv. 2016;88(10):19-24
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Evaluation of markers for renal graft dysfunction in patients with type 1 diabetes mellitus after kidney transplantation and simultaneous pancreas-kidney transplantation

Glazunova A.M., Arutyunova M.S., Tarasov E.V., Nikankina L.V., Ilyin A.V., Shamkhalova M.S., Shestakova M.V., Moysyuk Y.G.


Aim. To study the markers of renal graft dysfunction in patients with type 1 diabetes mellitus (T1DM) after kidney transplantation (KT) and simultaneous pancreas-kidney transplantation (SPKT). Subjects and methods. The investigation enrolled 20 patients after successful SPKT and 41 patients after KT (of them 21 received continuous subcutaneous insulin infusion with an insulin doser; 20 had multiple insulin injections). The periods after KT and SPKT at patient inclusion were 8 (7; 8) and 11 (8; 18) months, respectively. A control group comprised 15 patients with T1DM without diabetic nephropathy. The patients were matched for gender, age, and T1DM duration. At a 9-month follow-up, the main biomarkers of kidney graft dysfunction were identified using the standard kits: Cystatin C (Cys C; serum; urine), NGAL, KIM-1, Podocin, Nephrin, IL-18, MMP-9 (urine), TGF-β1, VEGF-A, and Osteopontin (OPN; serum). Fasting blood was taken; a morning urinary portion was examined. Results. The posttransplantation glomerular filtration rate (GFR) in the patients corresponded to Stage C2; albuminuria did to Category A1 chronic kidney disease. Despite successful SPKT in the group of patients with T1DM, as in that of patients after isolated KT, there was a statistically significant increase in the level of kidney dysfunction markers (Cys C, NGAL, Podocin, and OPN) versus the control group regardless of the compensation for glucose metabolism. compensation. It was found that the level of Cys C was high and correlated negatively with GFR (r=–0.36; p<0.05) and positively with the level of albuminuria (r=0.40; p<0.05). There was also a direct correlation of urinary podocin concentrations with blood creatinine levels (r=0.35; p<0.05) and that of NGAL with albuminuria (r=0.35; p<0.05) in recipients after transplantation. Conclusion. The high levels of biomarkers for kidney graft dysfunction in the examinees (including subjects after SPKT) reflect the persistence of graft microstructural injuries in clinically stable function.
Terapevticheskii arkhiv. 2016;88(10):25-34
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Acute-phase serum proteins and adipocytokines in women with type 2 diabetes mellitus: Relationships with body composition and blood glucose fluctuations

Klimontov V.V., Tyan N.V., Fazullina O.N., Myakina N.E., Orlov N.B., Konenkov V.I.


Aim. To estimate the relationships between the serum concentrations of acute-phase proteins (APPs) and adipocytokines, body composition (BC), and blood glucose (BG) fluctuations in women with type 2 diabetes mellitus (T2DM). Subjects and methods. A total of 165 women with T2DM and 22 with a normal body mass index (BMI) at the age of 40 to 70 years were examined. The concentrations of high-sensitivity C-reactive protein (hs-CRP) and acid α1-glycoprotein (α1-AGP) were determined by ELISA. The levels of interleukins 6, 8, and 18 (IL-6, IL-8, IL-18), tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor type 1 (PAI-1) were measured by a multiplex analysis. Dual energy X-ray absorptiometry was used to estimate BC parameters. BG fluctuations were estimated via continuous glucose monitoring. Results. The levels of hs-CRP, α1-AGP, IL-6, IL-8, IL-18, TNF-α, and PAI-1 were significantly higher in the obese women with T2DM than those in the control group. In the diabetic normal weight women, only hs-CRP, α1-AGP, and IL-8 concentrations exceeded those in the controls. The level of hs-CRP (other than α1-AGP) correlated positively with BMI, the mass of adipose tissue, body trunk (android), and gynoid fats. A multivariate regression analysis showed that adipose tissue mass and trunk fat proportion were independent predictors of hs-CRP levels. The concentrations of IL-6, IL-8, IL-18, PAI-1, and TNF-α correlated positively with waist-to-hip ratio, but demonstrated no associations with BMI and BC. Only the serum α1-AGP level showed a positive association with mean BG and its variability parameters. Conclusion. In the women with T2DM, the serum concentrations of APPs and adipocytokines correlate differently with the mass of adipose tissue, its distribution, and BG fluctuations. The findings indicate the multifactorial genesis of chronic inflammation in these patients.
Terapevticheskii arkhiv. 2016;88(10):35-41
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Latent autoimmune diabetes of adults (LADA): The informative value of autoantibodies

Silko Y.V., Nikonova T.V., Ivanova O.N., Stepanova S.M., Shestakova M.V., Dedov I.I.


Aim. To investigate the prevalence of autoantibodies (autoAbs) associated with the development of type 1 diabetes mellitus (T1DM) in latent autoimmune diabetes of adults (LADA) in the Russian Federation. Subjects and methods. A total of 96 patients (46 women and 50 men) with LADA were examined. All the patients underwent an immunological examination including the determination of autoAbs, such as glutamic acid decarboxylase autoAbs (GADA), islet antigen-2 auto-Abs (IA-2A), islet cell cytoplasmic auto-Abs (ICA), zinc transporter 8 auto-Abs (ZnT8A), and insulin auto-Abs (IAA). Results. GADAs were found in 61.5% of the examinees. ICAs were detected in 24%, IA-2As were observed in 57.3%. AutoAbs were more frequently observed in combination than alone. IAAs were least commonly seen in 8.3% and only in combinations. ZnT8As were found in 52.1% of the examinees and they were present alone in 5.2%. Conclusion. The antibodies that are most frequently observed in LADA are GADAs, IA-2As and ZnT8As. It is insufficient to identify only GADAs, as the latter are found in only 61.5% of the patients. IA-2As and ZnT8As, which are present in 57.3% and 52.1% of the patients, respectively, should also be used in the diagnosis of LADA. ICAs are much less commonly seen and along with IAAs may be additional markers for LADA.
Terapevticheskii arkhiv. 2016;88(10):42-45
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Ovarian reserve and adipokine levels in reproductive-aged obese women

Durmanova A.K., Otarbayev N.K., Kaiyrlykyzy A., Zhangazieva K.K., Ibrayeva Z.N., Donenbayeva G.B., Zhusupova Z.T., Saidakhmetov А.S., Temirgaliyeva G.S., Salykbayeva Z.K., Tazhigulova Z.M., Yensebayeva А.M., Seksembayeva К.K., Vasilenko О.K., Timanova S., Akkozhina B.


Aim. To investigate the relationship of the ovarian reserve to the levels of adipokines and sex hormones in reproductive-aged women with abdominal obesity. Subjects and methods. A total of 157 women aged 18 to 45 years with a body mass index (BMI) of more than 30 kg/m2 were examined (a study group). A control group consisted of 93 women aged 18—45 years with a BMI of less than 25 kg/m2. Anthropometric and carbohydrate and lipid metabolic parameters and the levels of sex hormones, anti-Müllerian hormone, resistin, and adiponectin were investigated. Results. The mean age of the participants with a BMI of more than 30 kg/m2 was 33.1±6.1 years and that of those with a BMI of less than 25—30 kg/m2 was 32.8±6.2 years. No statistically significant differences were found in age, ethnicity, and marital status between the participants of both groups; however, there was a statistically significant difference in education levels — 76.3% of the women with a BMI of less than 25 kg/m2 (p<0.0001) had higher education. The obese patients were found to have a statistically significant increase in the levels of insulin, HOMA-IR, glucose, total cholesterol, low-density lipoproteins, thyrotrophic hormone, testosterone, and resistin and a decrease in those of high-density lipoproteins, adiponectin, and anti-Müllerian hormone. Comparative analysis made in the obese patients revealed that there was a statistically significant correlation of anti-Müllerian hormone values and hormonal status with the levels of follicle-stimulating hormone (p=0.0026) and resistin (p=0.0323). Conclusion. The ovarian reserve decreases and the processes of reproductive system aging accelerate in reproductive-aged women with abdominal obesity in the presence of insulin resistance and hyperinsulinemia.
Terapevticheskii arkhiv. 2016;88(10):46-50
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Prevalence of metabolic syndrome in 25—45-year-old Novosibirsk dwellers

Voevoda M.I., Kovalkova N.A., Ragino Y.I., Travnikova N.Y., Denisova D.V.


Aim. To study the prevalence of metabolic syndrome (MS) and its components in a 25—45-year-old Novosibirsk population. Subjects and methods. The Novosibirsk Research Institute of Internal and Preventive Medicine conducted a cross-sectional population-based survey in one of the typical districts of Novosibirsk in 2013—2015. The survey covered 346 men and 408 women. The criteria of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP-ATP III, 2001), the International Diabetes Federation (IDF, 2005), the Joint Interim Statement (JIS, 2009), and the All-Russian Research Society of Cardiologists (ARRSC, 2009) were used to detect MS. According to the ARRSC criteria, MS was recorded if a waist circumference (WC) was >80 cm for women and >94 cm for men in conjunction with 2 of the following criteria: a blood pressure ≥130/85 mm Hg, triglycerides (TG) ≥1.7 mmol/l, high-density lipoprotein (HDL) cholesterol <1.0 mmol/l for men and <1.2 mmol/l for women, low-density lipoprotein (LDL) cholesterol >3.0 mmol/l, and plasma glucose level ≥6.1 mmol/l. Results. According to the 2009 ARRSC criteria, the prevalence of abdominal obesity, hypertension, hypertriglyceridemia, HDL hypocholestrolemia, LDL hypercholesterolemia, and high plasma glucose level was 42.6, 33.5, 17.5, 24.3, 64.8, and 29%, respectively. The prevalence of MS in 25—45-year-old Novosibirsk people was 17% (19.9% in men and 14.5% in women) according to the 2001 NCEP-ATP III, 27% (29.5% in men and 24.5% in women) according to the 2005 IDF criteria, 30% (35.8% in men and 25% in women) according to the 2009 JIS criteria, and 29.3% (33.2% in men and 26% in women) according to the 2009 ARRSC criteria, this was higher among men than women. There was an increase in the prevalence of MS with age. Conclusion. The highest prevalence of MS was 30 and 29.3% when using the 2009 JIS and the 2009 ARRSC criteria, respectively. Whatever the criterion was used, MS was more frequently recorded in men than women,
Terapevticheskii arkhiv. 2016;88(10):51-56
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CDC73 mutations in young patients with primary hyperparathyroidism: A description of two clinical cases

Mamedova E.O., Mokrysheva N.G., Pigarova E.A., Przhiyalkovskaya E.G., Voronkova I.A., Vasilyev E.V., Petrov V.M., Gorbunova V.A., Rozhinskaya L.Y., Belaya Z.E., Tyulpakov A.N.


The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific — Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.
Terapevticheskii arkhiv. 2016;88(10):57-62
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Clinical guidelines for the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (Part 2)

Chazova I.E., Martynyuk T.V.


The paper gives current approaches to treating chronic thromboembolic pulmonary hypertension (CTEPH) from the document «Federal Guidelines for the Diagnosis and Treatment of CTEPH» approved at the Third Russian Congress on Pulmonary Hypertension on December 11, 2015. The guidelines had been elaborated to optimize the treatment of patients with CTEPH on the basis of an analysis of the data of the present-day registries and multicenter randomized clinical trials, national and international guidelines and consensus documents, and documents published in recent years. CTEPH is a unique form of pulmonary hypertension since it is potentially curable by surgical treatment. The paper presents indications for and contraindications to pulmonary thromboendartectomy; preparation for surgery; operating room facilities; the specific features of postoperative management and possible complications; and long-term results. In terms of therapy, in addition to non-pharmacological measures, the authors discuss maintenance and specific treatment options for CTEPH, balloon pulmonary angioplasty, and lung/heart-lung transplantation. In conclusion, they propose a management algorithm in patients with CTEPH and requirements for its problem to the center of experts.
Terapevticheskii arkhiv. 2016;88(10):63-73
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The canonical Wnt/β-catenin pathway: From the history of its discovery to clinical application

Grebennikova T.A., Belaya Z.E., Rozhinskaya L.Y., Melnichenko G.A.


The Wnt/β signaling pathway (Wnt-SP) is a phylogenetically ancient mechanism that regulates development and maintains tissue homeostasis through the control of cell proliferation, differentiation, migration, and apoptosis. The accurate regulation of the canonical Wnt/β-catenin signaling pathway (Wnt-SP) is critical for embryogenesis and postnatal development; and impaired signal transduction at one of its stages leads to various diseases, including organ malformations, cancers, metabolic and neurodegenerative disorders. The literature review discusses the biological role of the canonical Wnt-SP in the development of the skeleton and in the remodeling of bone tissue. The Wnt signal transmission changes observed during genetic mutations cause various human skeletal diseases. Understanding the functional mechanism involved in the development of bone abnormality could open new horizons in the treatment of osteoporosis, by affecting the Wnt-SP. The design of antibodies to sclerostin, a Wnt-SP inhibitor, is most promising now. The paper summarizes the studies that have investigated the canonical Wnt-SP and designed drugs to treat osteoporosis.
Terapevticheskii arkhiv. 2016;88(10):74-81
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Diabetes mellitus and the central nervous system

Surkova E.V.


The review considers the current views on the central nervous system (CNS) in diabetes mellitus (DM). It discusses an attitude towards the term «diabetic encephalopathy». The data of investigations of cognitive functions in types 1 and 2 DM and the brain structural imaging results obtained using up-to-date technologies are considered. The results of studies of the factors that induce cerebral changes in DM and their associated cognitive impairments are given. There is evidence that hyperglycemia has a more considerable impact on the above processes than hypoglycemia; other possible factors, apart from blood glucose control, are set out. The current views on the function of insulin in the CNS and the relationship of central insulin resistance to Alzheimer’s disease are outlined. There are current data on intranasal insulin application that is still exploratory, but, as might be judged from the findings, may by a promising method for the treatment and prevention of cognitive decline in both patients with DM and those without this condition.
Terapevticheskii arkhiv. 2016;88(10):82-86
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MiRNAs in the diagnosis of cardiovascular diseases associated with type 2 diabetes mellitus and obesity

Shvangiradze T.A., Bondarenko I.Z., Troshina E.A., Shestakova M.V.


Worldwide, the number of patients with type 2 diabetes mellitus (T2DM), obesity, and cardiovascular diseases (CVD) continues to increase steadily. Despite long-term studies of obesity and concomitant diseases, the molecular genetic bases for the development of these pathological conditions have remained the subject of numerous investigations so far. Recent investigations point to the involvement of miRNAs as dynamic modifiers of the pathogenesis of various pathological conditions, including obesity, T2DM, and CVD. MicroRNAs are involved in various biological processes underlying the development of CVDs, including endothelial dysfunction, cell adhesion, and atherosclerotic plaque formation and rupture. Some of them are considered as potential sensitive diagnostic markers of coronary heart disease and acute myocardial infarction. Approximately 1,000 microRNAs are found in the human body. It has been determined that miRNAs regulate 30% of all human genes. Among them there are about 50 circulating miRNAs presumably associated with cardiovascular diseases. This review provides recent data on the participation of some miRNAs in various pathological and physiological states associated with CVD in DM and obesity. An extended and exact understanding of the function of miRNAs in the gene regulatory networks associated with cardiovascular risk in obesity will be able to reveal new mechanisms for the progression of disease, to predict its development, and to elaborate innovative therapeutic strategies.
Terapevticheskii arkhiv. 2016;88(10):87-92
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Obesity in metabolic syndrome, as well as kidney dysfunction

Sadulaeva I.A., Vasyuk Y.A., Trofimenko O.S., Yushchuk E.N., Ivanova S.V., Shupenina E.Y., Nesterova E.A.


The presence of metabolic syndrome (MS) in a patient allows him to be assigned to a group at high risk for atherosclerosis, cardiovascular events, coronary heart disease, and type 2 diabetes mellitus. In addition, MS negatively affects not only the heart and vessels, but also kidney function, which leads to chronic kidney disease (CKD). MS is pathogenetically associated with CKD and is an independent prognostic factor of the development of the latter, namely, the involvement of the kidney frequently determines prognosis and quality of life in these patients. The paper gives a modern view on the concept of MS and CKD and considers its main diagnostic criteria, etiology, and pathogenesis. The study of the relationships between MS and CKD may suggest that the high prevalence of kidney dysfunction in the general population is largely determined by metabolic nephropathies, including obesity-related nephropathy. The identification of risk factors and poor prognostic markers in this category of patients seems to be extremely important for the early diagnosis of the disease and their timely elimination is one of the main approaches to the comprehensive prevention of CKD in these patients.
Terapevticheskii arkhiv. 2016;88(10):93-98
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Nutrition in obesity: Target criteria and monitoring of weight loss

Samorodskaya I.V., Bolotova E.V.


The review paper gives in details the current clinical guidelines for evaluation of the impact of nutrition on the correction of increased body mass index (BMI) and obesity, an overview of the efficacy of specific commercial diets, target criteria for weight loss, and monitoring the status of a patient who participates in a weight loss program. The current clinical guidelines suggest that today there is no optimal diet in terms of its impact on the correction of overweight and further maintenance of the weight loss achieved. There is a need for both the improvement of the professional capacity of healthcare workers in advising patients about nutrition and the population’s awareness about the principles of a healthy diet. The complex nature of the problem requires that a medical community should interact closely with politicians to make a legislative decision on a number of issues relating to healthy eating.
Terapevticheskii arkhiv. 2016;88(10):99-104
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Chronic hepatitis C virus infection: An internist’s opinion (Part 1)

Zubkin M.L., Chervinko V.I., Ovchinnikov Y.V., Kryukov E.V., Kotenko O.N.


Hepatitis C virus (HCV) infection results in not only chronic hepatitis and subsequent complications as liver cirrhosis and hepatocellular carcinoma, but also in a significant number of other diseases, the so-called extrahepatic manifestations of chronic HCV infection. This is because of viral hepatotropicity and lymphotropicity. The most striking example of the course of chronic HCV infection, in which the infectious and inflammatory processes are concurrent with autoimmune disorders and carcinogenesis, is mixed cryoglobulinemia and B-cell non-Hodgkin’s lymphoma. The pathogenesis of these diseases is based on the clonal expansion of B cells, which occurs under their prolonged stimulation with the virus or viral proteins. Part 1 of this review is devoted to the analysis of a correlation of chronic HCV infection with lymphoproliferative and autoimmune disorders, as well as its association with kidney injury.
Terapevticheskii arkhiv. 2016;88(10):105-113
pages 105-113 views

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