Clotilde Fernández-Gutiérrez

Implication of inflammation-related cytokines in the natural history of liver cirrhosis.

Abstract: Background/Aims: Increased serum concentrations of pro‐inflammatory cytokines have been detected in patients with liver cirrhosis. However, their role in the natural history of cirrhosis and portal hypertension, in the absence of infection, and the prognostic significance of inflammation‐related cytokines have not been reported. Our objective was the analysis of the prognostic value of inflammation‐related cytokines in cirrhotic patients.

Adhesion molecules as a prognostic marker of liver cirrhosis

Objective Endothelial activation plays an active role in modifications of the circulatory status of cirrhotic patients. Soluble endothelial adhesion molecules, induced by pro-inflammatory cytokines, could be considered markers of endothelial activation. Their role in the natural history of cirrhosis and portal hypertension has not been reported. Our objective was to analyze the prognostic value of soluble adhesion molecules in cirrhotic patients. Material and methods Serum concentrations of soluble CD14, soluble receptors of tumor necrosis factor alpha and adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule 1) as well as mean blood pressure, plasma renin activity, aldosterone, vasopressin and norepinephrine concentrations were determined in 64 cirrhotic patients (Child Pugh class: A 48.4%, B 34.4%, C 17.2%), without any evidence of infection, and in 25 healthy controls. Patients were followed-up for a mean of 36.4 (range 6–60) months. Results Increased concentrations of soluble CD14, tumor necrosis factor receptors and ICAM-1 and VCAM-1 were detected in cirrhotic patients when compared with healthy controls. Tumor necrosis factor receptors and adhesion molecule concentrations were both significantly higher in advanced phases of cirrhosis (Child Pugh class C and B versus A). Fifteen patients died as a related consequence of liver cirrhosis. Multivariate analysis demonstrated that Child-Pugh score and serum levels of tumor necrosis factor receptor I and ICAM-1 were associated with mortality. Conclusions In addition to the classic factor implicated in mortality (Child-Pugh class), alterations in inflammation-related components and soluble adhesion molecules, as representatives of hemodynamic alterations, are of prognostic significance in cirrhotic patients.

Haemodynamic derangement in human immunodeficiency virus-infected patients with hepatitis C virus-related cirrhosis: the role of bacterial translocation.

Background and aims: Analysis of the influence of the effects of increased intestinal permeability on haemodynamic alterations in human immunodeficiency virus (HIV)‐infected patients with decompensated hepatitis C virus (HCV)‐related liver disease.

Prevalence of Primary Resistance of Helicobacter pylori to Clarithromycin and Levofloxacin in Southern Spain

Background: The eradication of Helicobacter pylori (HP) using clarithromycin (CLA)-based triple therapy depends on the resistance of HP to antibiotics. The Maastricht III conference recommends the implementation of locoregional surveillance programmes for primary resistance of HP to CLA. In Andalusia, there are no previous data in this respect. The aim of this study was to determine the prevalence of the primary resistance of HP to CLA and levofloxacin (LF) in southern Spain. Methods: Multicentre cross sectional study was carried out in 6 hospitals in Andalusia. Patients of both sexes numbering 401 were included (male 48%), aged 18-80 years and naïve to HP eradication. Resistance of HP to CLA (CLAr) and LF (LFr) was assessed by determining mutations by PCR: mutations of the 23S rRNA gene define CLAr and mutations of the gene gyrA define LFr. Four hundred one gastric samples were collected. CLAr was detected in 72 patients (17.9%) and LFr was detected in 56 patients (13.9%). Heteroresistance was detected for both antibiotics: CLA 37/72 (51.3%) and LF 28/56 (50%). Variability for CLAr was detected among the centres, ranging from 11.5% to 24.7% without statistical significance (p = 0.12). Female sex was related to CLAr. Conclusions: In Andalusia, there is a high rate of primary CLAr and LFr. CLA-based triple therapy should be avoided as the primary eradication regimen in this region. There is a wide variability in the rate of CLAr among centres.

Influence of Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Interleukin 10 Genes on the Risk of Liver Cirrhosis in HIV-HCV Coinfected Patients

Objective Analysis of the contribution of genetic (single nucleotide polymorphisms (SNP) at position -238 and -308 of the tumor necrosis factor alpha (TNF-α) and -592 of the interleukin-10 (IL-10) promotor genes) and of classical factors (age, alcohol, immunodepression, antirretroviral therapy) on the risk of liver cirrhosis in human immunodeficiency (HIV)-hepatitis C (HCV) virus coinfected patients. Patients and Methods Ninety one HIV-HCV coinfected patients (50 of them with chronic hepatitis and 41 with liver cirrhosis) and 55 healthy controls were studied. Demographic, risk factors for the HIV-HCV infection, HIV-related (CD4+ T cell count, antiretroviral therapy, HIV viral load) and HCV-related (serum ALT concentration, HCV viral load, HCV genotype) characteristics and polymorphisms at position -238 and -308 of the tumor necrosis factor alfa (TNF- α) and -592 of the interleukin-10 (IL-10) promotor genes were studied. Results Evolution time of the infection was 21 years in both patients’ groups (chronic hepatitis and liver cirrhosis). The group of patients with liver cirrhosis shows a lower CD4+ T cell count at the inclusion in the study (but not at diagnosis of HIV infection), a higher percentage of individuals with previous alcohol abuse, and a higher proportion of patients with the genotype GG at position -238 of the TNF-α promotor gene; polymorphism at -592 of the IL-10 promotor gene approaches to statistical significance. Serum concentrations of profibrogenic transforming growth factor beta1 were significantly higher in healthy controls with genotype GG at -238 TNF-α promotor gene. The linear regression analysis demonstrates that the genotype GG at -238 TNF-α promotor gene was the independent factor associated to liver cirrhosis. Conclusion It is stressed the importance of immunogenetic factors (TNF-α polymorphism at -238 position), above other factors previously accepted (age, gender, alcohol, immunodepression), on the evolution to liver cirrhosis among HIV-infected patients with established chronic HCV infections.

THIS ARTICLE HAS BEEN RETRACTED: Haemodynamic derangement in human immunodeficiency virus-infected patients with hepatitis C virus-related cirrhosis: the role of bacterial translocation

Background and aims: Analysis of the influence of the effects of increased intestinal permeability on haemodynamic alterations in human immunodeficiency virus (HIV)‐infected patients with decompensated hepatitis C virus (HCV)‐related liver disease.

La valoración de RNA del virus de la hepatitis C realizada a las 12 semanas de finalizar el tratamiento predice la respuesta virológica sostenida en enfermos con coinfección por VIH y VHC

OBJECTIVE The aim of this study was to assess whether measurement of hepatitis C virus RNA (HCV-RNA) at 12 weeks post-treatment could predict sustained virological response (SVR) to antiviral therapy for chronic hepatitis C (pegylated interferon alfa-2a and ribavirin) in HIV-co-infected patients. PATIENTS AND METHODS HIV-HCV co-infected patients were included if they completed a full course of anti-HCV therapy, achieved an end-of-treatment response and complied with the week +12 and +24 post-treatment follow-up schedule for serum HCV-RNA determination (Real-time HCV (Abbott, Wiesbaden, Germany) (lower limit of detection, 12 IU/ml). RESULTS Forty out of 66 patients (61%) showed an end-of-treatment response. They were assessed in a follow-up visit at +12 and at +24 weeks post-treatment. Serum HCV-RNA was undetectable in 28 of them at +12 weeks, and 100% of these remained undetectable at 24 weeks post-treatment (the gold standard of (SVR). The positive predictive value was 100% (95% confidence interval, 98.21-100%). CONCLUSION Post-treatment follow-up to identify virological relapse could be shortened to 12 weeks, providing a new definition of sustained virological response.

THIS ARTICLE HAS BEEN RETRACTED: Haemodynamic derangement in human immunodeficiency virus-infected patients with hepatitis C virus-related cirrhosis: the role of bacterial translocation: Haemodynamic alterations in HIV/HCV cirrhotic patients

Background and aims: Analysis of the influence of the effects of increased intestinal permeability on haemodynamic alterations in human immunodeficiency virus (HIV)‐infected patients with decompensated hepatitis C virus (HCV)‐related liver disease.

OP25 Bacterial translocation and regulatory T lymphocytes in patients with liver cirrhosis

Introduction Increased prevalence of bacterial infectious diseases has been observed in cirrhotic patients, classically attributed to immunosuppression-associated liver cirrhosis. Conversely, advanced states of liver cirrhosis predispose to increased antigenic load. A possible role has been ascribed to the translocation of bacteria and endotoxins (lypopolysaccharide, LPS) from the gut. LPS increases the plasma levels of LPS-binding protein (LBP), the principal plasma protein responsible for transporting LPS to immune effector cells. High serum LBP has been proposed to identify a subset of cirrhotic patients with ascitis characterised by an activation of the immune cells to producer proinflammatory cytokines. Moreover, raised levels of circulating LBP or proinflammatory cytokines have been implicated in the endothelial activation and haemodynamic derangement observed in cirrhosis. A chronic antigenic stimulus will induce a monocyte and lymphocyte activation. Aim Intestinal permeability and bacterial translocation and their influence on T lymphocytes activation and differentiation in T reg were analysed in patients with compensated and decompensated liver cirrhosis. In particular, the regulation of T cell activation, mediated by co-stimulatory molecules, the expression of activation markers and the proportion of T CD4+ regulatory cells, as a function of bacterial translocation, were studied. Method 40 patients with liver cirrhosis, 20 of them without previous decompensation (CC) and 20 with ascetic decompensation (DC), and 20 healthy controls (HC) were studied. Bacterial translocation was analysed by serum concentrations of lypopolysacharide-binding protein (LBP). Membrane expression of co-stimulatory molecules (CD28), activation markers (CD25 and CD122) and proportion of T regulatory cells (defined as those CD4+CD25highintracellular FoxP3+) were studied by flow cytometry with specific antibodies. Values of the variables were expressed as median (interquartile range). Comparisons between variables were made by the Mann–Whitney U test. Associations between variables were analysed by the Pearsons correlation coefficient. Results Serum concentrations of LBP were significantly elevated in patients with compensated (7.7 (5.7–9.1 microg/ml) and decompensated (28.2 (10.7–40.6)) cirrhosis when compared with healthy controls (3.4 (2.7–4.2)) (p<0.001). Significantly higher concentrations of LBP were detected in those patients with higher portal hypertension. Those patients with decompensated cirrhosis shows an activation state characterised by increased percentages of CD25+ and CD122+ expression on CD4+ T cells. A decrease of CD28 expression was detected in T CD4+ lymphocytes from patients with decompensated cirrhosis (DC, 94% (89–98%); CC, 97% (92–98%); HC, 98 (96–99), DC vs HC: p=0.010). Moreover, T reg lymphocytes, expressed as a proportion of global T CD4+ cells, were significantly increased in patients with compensated and decompensated cirrhosis (DC, 14.7% (13.3–16.1%); CC, 10.3 (10.1–11.2); HC, 8.4 (7.2–8.7), p<0.001 in each case). A significant and positive correlation was detected between serum LBP concentration and percentage of CD4+ T reg (r=0.787, p<0.001). Conclusion Patients with liver cirrhosis, fundamentally those with previous decompensation, shows increased intestinal permeability and chronic systemic antigenic stimuli. As a response to those, T lymphocyte activation is detected. Probably as a mean to decrease the continuous antigenic stimuli, a diminution of co-stimulation and an expansion of suppressor populations are observed in them.