epidermal-growth-factor and Hepatitis-C--Chronic

Growth factors (GF) that participate in regeneration and apoptosis have an important role in chronic liver diseases. We analyzed serum GF concentration during antiviral treatment and correlated it with morphological liver failure in chronic hepatitis C.. The levels of GF were determined in sera by ELISA method in 0, 16, 32 and 48 wk of therapy in 40 patients treated with IFNalpha2b (9 MU sc/wk) and RBV (1.2 g/d) and in 25 healthy subjects. Blind liver biopsies were done before treatment with histological grading and staging examination.. The hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were markedly elevated prior the treatment and decreased during the therapy, although they did not reach the normal level. In non-responding (NR) patients, HGF and EGF were higher than that in responders (R), however differences were not significant. Before the treatment thrombopoietin (TPO) level was significantly lower in R than in NR (P<0.03). Platelet-derived growth factor (PDGF) concentration was lower in chronic hepatitis C than in healthy subjects and decreased during the treatment. A significant positive correlation was observed between inflammatory activity in the liver tissue and the concentration of HGF (in R: r = 0.4, in NR: r = 0.5), TPO (R: r = 0.6), and a significant negative correlation between this activity and EGF (R: r = -0.6) and PDGF (R: r = -0.5). Serum HGF concentration was higher in more advanced fibrosis (R: r = 0.5, P<0.05; NR: r = 0.4, P<0.03).. The decrease in PDGF can be an effective prognostic marker of the treatment and HCV elimination. Decreasing HGF, EGF, and PDGF can influence the inhibition of inflammatory and fibrotic processes in the liver during the antiviral treatment.

Topics: Adult; Antiviral Agents; Biomarkers; Epidermal Growth Factor; Female; Growth Substances; Hepatitis C, Chronic; Hepatocyte Growth Factor; Humans; Interferon alpha-2; Interferon-alpha; Liver; Liver Cirrhosis; Male; Middle Aged; Platelet-Derived Growth Factor; Prognosis; Recombinant Proteins; Ribavirin

In this study, we evaluated the effect of hepatitis C virus eradication using direct-acting antivirals (DAA) on the serum cytokine and growth factor profiles of chronic hepatitis C patients (CHC). Serum concentrations of 12 cytokines and 13 growth factors were measured in 56 patients with CHC before, during the DAA treatment and after sustained virological response using bead-based flow cytometry. Cytokine and growth factor levels were also measured in 15 healthy individuals. The majority of the selected cytokines and growth factors exhibited similar concentrations before, during and after successful DAA treatment, the exceptions being IL-10, EGF, HGF and VEGF. Significantly lower concentrations of IL-10, IL-13, IL-4, IL-4, IL-9, TNF- α and higher levels of Ang-2, HGF and SCF were observed in patients with CHC before and after DAA treatment compared with healthy individuals. Patients with severe fibrosis stages exhibited higher levels of Ang-2 and lower levels of EGF, PDGF-AA and VEGF. Furthermore, IL-4, IL-5 and SCF were characterized as potential biomarkers of DAA treatment using random forest. Additionally, logistic regression characterized EGF as a potential biomarker of severe CHC. Our results suggest inhibition of pro-inflammatory processes and promotion of liver regeneration in CHC patients during DAA treatment.

Topics: Antiviral Agents; Cytokines; Epidermal Growth Factor; Hepatitis C, Chronic; Humans; Vascular Endothelial Growth Factor A

To affect immune response and inflammation, the hepatitis C virus (HCV) substantially influences intercellular communication pathways that are decisive for immune cell recruitment. The present study investigates mechanisms by which HCV modulates chemokine-mediated intercellular communication from infected cells.. Chemokine expression was studied in HCV. HCV enhances expression of CXCR2 ligands in its host cell via the induction of epidermal growth factor (EGF) production. Knockdown of EGF or of the p65 subunit of the NF-κB complex results in a substantial downregulation of HCV-induced CXCR2 ligand expression, supporting the involvement of an EGF-dependent mechanism as well as activation of NF-κB. Furthermore, HCV upregulates expression of CXCR2 ligands in response to EGF stimulation via downregulation of the T-cell protein tyrosine phosphatase (TC-PTP [PTPN2]), activation of NF-κB, and enhancement of EGF-inducible signal transduction via MEK1 (MAP2K1). This results in the production of a cytokine/chemokine pattern by the HCV-infected cell that can recruit neutrophils but not monocytes.. These data reveal a novel EGF-dependent mechanism by which HCV influences chemokine-mediated intercellular communication. We propose that this mechanism contributes to modulation of the HCV-induced inflammation and the antiviral immune response.. In most cases hepatitis C virus (HCV) results in chronic infection and persistent viral replication, taking decades until development of overt disease. To achieve such a course, the respective virus must have developed mechanisms to circumvent antiviral response, to modulate the inflammatory response and to utilise the infrastructure of its host with moderate effect on its viability. The present study provides novel data indicating that HCV induces epidermal growth factor production in its host cell, enhancing epidermal growth factor-inducible expression of chemokines that bind to the CXCR2 receptor and recruit neutrophile granulocytes. Importantly, chemokines are critical mediators determining the pattern of immune cells recruited to the site of injury and thereby the local inflammatory and immunological milieu. These data strongly suggest that HCV triggers mechanisms that enable the virus to influence the inflammatory and immunological processes of its host.

Topics: Cell Communication; Cell Line; Epidermal Growth Factor; Hepacivirus; Hepatitis C, Chronic; Host Microbial Interactions; Humans; Immunity, Cellular; Inflammation; Receptors, Interleukin-8B; Signal Transduction; Up-Regulation; Virus Replication

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.

Topics: Adult; Allografts; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Disease Progression; Epidermal Growth Factor; Female; Follow-Up Studies; Genotype; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Interleukins; Lipase; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Membrane Proteins; Middle Aged; Polymorphism, Single Nucleotide; Postoperative Complications; Prognosis; Risk Factors; Tissue Donors; Transplantation, Homologous; Young Adult

Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver disease including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis C (CHC) is also a problem in patients with chronic kidney disease (CKD), particularly in those on haemodialysis. Excessive iron in the liver of CHC patients contributes to hepatic fibrosis, cirrhosis and finally HCC, while iron depletion is beneficial. In CHC patients without CKD, in HCV-infected experimental animals and in cell culture studies, serum hepcidin levels and/or cellular hepcidin expression are low and directly suppressed by HCV, radical oxygen species, growth factors and/or transcription factors. In contrast, antiviral therapy (e.g. with pegylated interferon-alpha combined with ribavirin) raises hepcidin levels and reduces iron overload in patients with CHC. Hepcidin directly inhibits HCV replication mediated by STAT3 activation. HCV circumvents hepatic innate antiviral defence by lowering hepcidin. If hepcidin is also low in CKD patients with CHC, iron supplementation should be avoided even in CKD patients with CHC treated with erythropoiesis-stimulating agents.

Topics: Adult; Animals; Antimicrobial Cationic Peptides; Antiviral Agents; Epidermal Growth Factor; Female; Hepacivirus; Hepatitis C, Chronic; Hepatocyte Growth Factor; Hepcidins; Humans; Interferon-alpha; Iron; Iron Overload; Liver Cirrhosis; Male; Middle Aged; Phlebotomy; Renal Insufficiency, Chronic; Ribavirin; Virus Replication

Epidermal growth factor (EGF) gene single-nucleotide polymorphism (SNP) is associated with an increased risk of hepatic tumors. The study aimed to elucidate the impact of EGF SNP and EGF receptor (EGFR) expression on the recurrence of hepatocellular carcinoma (HCC) after hepatectomy. To examine the impact of EGF SNP and EGFR on recurrent HCC, we retrospectively analyzed 141 HCC patients with chronic hepatitis C virus infection who underwent curative hepatectomy. The EGF *61 GG allele was present in 69 patients (48.9%), AG in 56 (39.7%) and AA in 16 (11.4%). The AA group had a significantly lower rate of intrahepatic metastasis (0% vs 16.5%, P = 0.02), lower serum EGF concentration (26.3 ± 15.9 pg/mL vs 43.4 ± 30.5 pg/mL, P = 0.02) and lower proportion of early recurrence (≤2 years; 28.6% vs 71.2%, P = 0.03) than the AG/GG group. The AA group had significantly higher recurrence-free survival than the AG/GG group (P = 0.04), but there was no significant difference in overall survival between these two groups (P = 0.97). High versus low EGFR expression analyzed by immunohistochemical staining in cancer cells was not significantly associated with overall survival (P = 0.37) or recurrence-free survival (P = 0.39). Therefore, EGF *61 AA was associated with a lower risk of recurrence after curative hepatectomy for HCC in patients with hepatitis C virus infection than other genotypes, but EGFR expression in cancer cells was not significantly associated with prognosis.

Topics: Aged; Carcinoma, Hepatocellular; Epidermal Growth Factor; ErbB Receptors; Female; Gene Frequency; Genotype; Hepacivirus; Hepatectomy; Hepatitis C, Chronic; Humans; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Polymorphism, Single Nucleotide; Retrospective Studies

The epidermal growth factor (EGF) rs4444903 A>G polymorphism has been associated with the development of liver cancer, which commonly complicates cirrhosis of viral origin; however, whether this polymorphism might be associated with fibrosis progression in chronic viral hepatitis is unknown. The present study was performed to assess the allelic and genotypic frequencies of the rs4444903 A>G polymorphism in patients with chronic hepatitis C virus HCV infection and to ascertain whether this polymorphism might be an independent predictor of the degree of fibrosis.. An RFLP-PCR technique was used to genotype 645 patients (211 with cirrhosis); 528 were referred for the diagnosis and treatment of chronic hepatitis C, and 117 were transplanted for HCV-related end stage liver disease. A group of 428 healthy subjects served as a control. All the subjects were of Caucasian ethnicity.. The EGF rs4444903 A>G polymorphism genotype frequencies in HCV chronic infected patients were as follows: A/A=227 (35.3%), A/G=328 (50.9%), and G/G=90 (14.8%). Genotype frequencies were found to differ between patients with an Ishak staging score⩽2 (A/A=117, A/G=157, G/G=34) and patients with a score>2 (A/A=110, A/G=171, G/G=56, p=0.038). A highly significant linear relationship between increasing stage scores and EGF genotype was detected in younger patients (A/A: 2.02±0.18, A/G: 2.55±0.17, G/G: 3.00±0.32, p=0.008). However, no significant association was detected between the stage score and EGF genotype in older patients (A/A: 3.79±0.19, A/G: 3.64±0.15, G/G: 3.98±0.30 p=0.579).. The EGF rs4444903 A>G polymorphism may facilitate liver fibrosis progression in Caucasian patients with chronic hepatitis C, especially in younger patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Epidermal Growth Factor; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Logistic Models; Male; Middle Aged; Polymorphism, Single Nucleotide; Young Adult

Overexpression of epidermal growth factor (EGF) in the liver induces transformation into hepatocellular carcinoma (HCC) in animal models. Polymorphisms in the EGF gene modulate EGF levels.. To evaluate the effect of EGF gene single nucleotide polymorphism and to assess its correlation with the risk of HCC in patients with chronic liver diseases.. The present study included 80 participants divided into four groups: group 1 included 20 asymptomatic healthy control volunteers, group 2 included 20 patients with chronic hepatitis C viral (HCV) infection, group 3 included 20 patients with liver cirrhosis, and group 4 included 20 patients with HCC. For all participants, the following investigations were performed: routine laboratory investigations including complete blood count, liver function tests, sero markers of hepatitis viruses HBsAg, HCV-RNA by quantitative polymerase chain reaction, and α-fetoprotein. DNA was extracted from whole blood for detection of single nucleotide polymorphism of the EGF by polymerase chain reaction, followed by restriction fragment length polymorphism.. We found a significant difference between both patients with HCC and HCV versus controls in terms of the G carrier (GG and GA; 80 vs. 40%, P<0.05). In addition, the cirrhotic and chronic hepatitis C patients with GG had three-fold and 2.3-fold odds ratio for developing HCC, respectively.. The EGF 61GG genotype might be associated with a high risk for the development of HCC in Egyptian patients with chronic liver disease.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Early Diagnosis; Electrophoresis, Agar Gel; Epidermal Growth Factor; Female; Genetic Predisposition to Disease; Genotype; Hepatitis C, Chronic; Heterozygote; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Pilot Projects; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Young Adult

Strong interest exists about the biomolecular basis of the chronic liver diseases due to viral infections. It seems to be very interesting because of their evolutive potential. In this context the study of oncogenes and oncoproteins could be interesting as prognostic factors for chronic viral diseases of the liver. In this study the authors show the results obtained about EGF and p62 expression in 39 selected patients with cirrhosis and 3 different chronic viral hepatitis (persistent, lobular, and active).

Topics: Biomarkers, Tumor; Biopsy; Chronic Disease; Epidermal Growth Factor; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Viral, Human; Hepatocytes; Humans; Liver; Liver Cirrhosis; Prognosis; Proto-Oncogene Proteins c-myc; Receptor, ErbB-2