Effect Of Chronic Hepatitis C Virus Infection Research Articles

#1050 Diabetes mellitus mediates the association between chronic hepatitis C virus infection and incidence of end-stage kidney disease

Abstract Background and Aims Chronic infection with the hepatitis C virus (HCV) is known to lead to extra-hepatic complications, notably affecting the kidneys. While prior research has established a link between chronic HCV infection and chronic kidney disease (CKD), there remains ongoing debate regarding whether this association is influenced by the presence of diabetes mellitus. Method This study, part of the REVEAL-HCV project in Taiwan, investigated the relationship between chronic HCV infection and end-stage kidney disease (ESKD). Initially, 23,820 individuals aged 30-65 from Taiwan were enrolled since 1991-1992. Data included physical exams, blood tests, and questionnaires covering sociodemographics, lifestyle, and comorbidities. The cohort was linked to Taiwan's National Health Insurance Research Database, providing extensive patient data. Hepatitis C status was determined by HCV RNA testing. ESKD was identified using ICD-9-CM codes from the health database. Covariates like age, sex, lifestyle factors, comorbidities, and lab results were considered. The study emphasized accurate diagnosis of diabetes based on insurance claims with well validation. The mediation analysis was done by constructing 2 logistic regression models, with one regressing the risk of ESKD on chronic HCV infection status and the other regressing the risk of ESKD on diabetes status. The direct and indirect (mediated through the risk of diabetes) effects of chronic HCV infection on the risk of ESKD were estimated using odds ratios. Confidence intervals for direct and indirect effects were estimated using 5000 bootstrapping replicates. Results The study examined 22,800 participants, with a mean age of 46.9 years. Among them, 738 were chronically infected with HCV. These HCV-infected participants were generally older, more likely to be female, had lower education levels, and higher prevalence of diabetes, hypertension, and CKD. During the 16.8-year median follow-up, covering 319,474 person-years, 378 end-stage kidney disease (ESKD) events occurred. The incidence of ESKD was higher in HCV-infected subjects (2.6%) compared to non-HCV-infected (1.6%). The univariate and multivariate-adjusted odds ratios (ORs) and 95% confidence interval for ESKD in HCV-infected participants were 2.06 (0.90-2.08) and 1.57 (1.01-2.44), respectively. HCV infection also showed a significant association with diabetes mellitus. The multivariable-adjusted OR for diabetes in HCV-infected individuals was 1.53 (1.31-1.78). Further, the study identified a diabetes-mediated pathway linking HCV infection to ESKD. In this pathway, HCV infection increased the odds of ESKD by 0.8%. This indirect pathway mediated by diabetes accounted for 16% of the overall association between HCV infection and ESKD with statistically significant. The direct pathway, though not statistically significant, indicated a 57% increased odds of ESKD in HCV-infected individuals compared to those without HCV. Conclusion Chronic HCV infection is linked to higher incidences of diabetes and ESKD. The mechanisms are intricate, with diabetes serving as a significant mediator in the pathway from HCV infection to ESKD.

Impact of E-cadherin and its transcription regulators on assessing epithelial-mesenchymal transition in chronic hepatitis C virus infection.

Background The mechanisms of chronic hepatitis C virus (HCV)-induced liver fibrosis and hepatocarcinogenesis are still poorly recognized. Therefore, this study aimed to determine the effect of chronic HCV infection on the expression of the major regulators of epithelial-mesenchymal transition (EMT) including E-cadherin, Snail, Slug, and Twist2, in the Egyptian population. This will help to design more efficient strategies to treat HCV-associated cirrhosis and carcinoma. Methods Fifty-nine liver biopsies from patients, that were serologically proven to be HCV positive, were included in the current study. Histopathological examination was done. Grading of hepatitis activity (A) and staging of fibrosis (F) were assessed using the METAVIR Scoring System. Additionally, an immunohistochemical examination of E-cadherin, Snail, Slug, and Twist2 expression was performed. Results E-cadherin showed a significant progressive decline of its expression with increased fibrosis staging and development of hepatocellular carcinoma (HCC). In contrast, Snail and Slug expression was positively associated with the stage of fibrosis and HCC. Meanwhile, Twist2 expression was not affected by the degree of hepatitis activity, the stage of fibrosis, or by the development of HCC. Conclusions E-cadherin and its transcriptional regulators; Snail and Slug may serve as indicators for assessing the stage of fibrosis and the progression of HCC associated with HCV infection but not for assessing the degree of hepatitis activity. Therefore, the Snail family could be a promising target for designing effective preventive and therapeutic strategies for chronic HCV infection and its serious comorbidities.

Impact of E-cadherin and its transcription regulators on assessing epithelial-mesenchymal transition in chronic hepatitis C virus infection.

The mechanisms of chronic hepatitis C virus (HCV)-induced liver fibrosis and hepatocarcinogenesis are still poorly recognized. Therefore, this study aimed to determine the effect of chronic HCV infection on the expression of the major regulators of epithelial-mesenchymal transition (EMT) including E-cadherin, Snail, Slug, and Twist2, in the Egyptian population. This will help to design more efficient strategies to treat HCV-associated cirrhosis and carcinoma. Fifty-nine liver biopsies from patients, that were serologically proven to be HCV positive, were included in the current study. Histopathological examination was done. Grading of hepatitis activity (A) and staging of fibrosis (F) were assessed using the METAVIR Scoring System. Additionally, an immunohistochemical examination of E-cadherin, Snail, Slug, and Twist2 expression was performed. E-cadherin showed a significant progressive decline of its expression with increased fibrosis staging and development of hepatocellular carcinoma (HCC). In contrast, Snail and Slug expression was positively associated with the stage of fibrosis and HCC. Meanwhile, Twist2 expression was not affected by the degree of hepatitis activity, the stage of fibrosis, or by the development of HCC. E-cadherin and its transcriptional regulators; Snail and Slug may serve as indicators for assessing the stage of fibrosis and the progression of HCC associated with HCV infection but not for assessing the degree of hepatitis activity. Therefore, the Snail family could be a promising target for designing effective preventive and therapeutic strategies for chronic HCV infection and its serious comorbidities.

Impaired insulin exocytosis in chronic hepatitis C infection: contributory role of p38δ MAPK-protein kinase D-golgi complex axis.

Hepatitis C virus (HCV) infection and chronic hepatitis C (CHC) are associated with a measurable risk of insulin resistance (IR)/impaired glucose tolerance (IGT)/diabetes mellitus (DM). While loss of hepatic endocrine function contributes to liver cirrhosis in diabetic patients, onset and progression of IR/IGT to diabetes and exacerbation of incident hyperglycemia are ostensibly linked with chronic HCV infection. In this regard, the study by Chen J et al. appearing in Clinical Science (2020) (134(5) https://doi.org/10.1042/CS20190900) attempts to understand the mechanisms underlying the savaging effects of chronic HCV infection on insulin-producing pancreatic β-cells and hence diabetic onset. The study investigated the role of mitogen-activated protein kinase (MAPK) p38δ-protein kinase D (PKD)-golgi complex axis in impacting insulin exocytosis. It was inferred that an insulin secretory defect of pancreatic β-cells, owing to disrupted insulin exocytosis, to an extent explains β-cell dysfunction in HCV-infected or CHC milieu. HCV infection negatively regulates first-phase and second-phase insulin secretion by impinging on PKD-dependent insulin secretory granule fission at trans-golgi network and insulin secretory vesicle membrane fusion events. This commentary highlights the study in question, that deciphered the contribution of p38δ MAPK-PKD-golgi complex axis to β-cell dysfunction in CHC milieu. This pivotal axis proffers a formidable therapeutic opportunity for alleviation of double burden of glucose abnormalities/DM and CHC.

Hepatitis C virus direct‐acting antivirals therapy impacts on extracellular vesicles microRNAs content and on their immunomodulating properties

Hepatitis C virus (HCV) infection is known to cause major alterations in the cross-talk between hepatic and immune cells thus contributing to the liver disease pathogenesis. Extracellular vesicles have been proved to act as major players in cell-cell communication, and their cargo changes in relation to pathophysiological states. The aim of this study was to evaluate the effects of chronic HCV infection and direct-acting antivirals (DAA) on exosome-delivered microRNAs and on their ability to modulate the innate immune response. Exosomes isolated from the plasma of healthy donors and naïve, viremic HCV patients before and after DAA treatment have been compared for their microRNAs cargo by quantitative polymerase chain reaction. Functional assays with peripheral blood cells from healthy donors were performed to assess exosome-mediated immune responses. MicroRNAs associated with HCV-related immunopathogenesis which were found to be enriched in exosomes of HCV viremic patients (in particular, miR-122-5p, miR-222-3p, miR-146a, miR-150-5p, miR-30c, miR-378a-3p and miR-20a-5p) were markedly reduced by DAA therapy. This exosome-microRNA cargo modulation parallels changes in their immunomodulatory properties in ex vivo experiments. Exosomes from HCV patients inhibit NK degranulation activity and this effect correlates with miR-122-5p or miR-222-3p levels. Enrichment of immunomodulatory microRNAs in exosomes of HCV patients was correlated with their inhibitory activity on innate immune cells function. Direct-acting antivirals (DAA) treatment was observed to revert both microRNA content and functional profiles of systemic exosomes towards those of healthy donors. Exosome-associated microRNAs may provide valuable biomarkers to monitor immune response recovery.

Effects of chronic hepatitis C infection on arterial stiffness

Nonalcoholic fatty liver disease (NAFLD) is associated with increased arterial stiffness. Although chronic hepatitis C virus (HCV) infection was shown to be associated with metabolic disorder and chronic inflammation, the effects of chronic HCV infection on arterial stiffness remain unclear. This study recruited 221 patients including 32 normal controls, 72 NAFLD patients, and 117 subjects with HCV infection. Arterial stiffness was assessed by peripheral arterial stiffness index, Compliance Index (CI), and central arterial stiffness index, Stiffness Index derived from digital volume pulse by photoplethysmography. Levels of oxidative stress marker and inflammatory markers were also measured. The HCV group had significantly lower CI (4.8 ± 3.1 units vs. 3.9 ± 2.1 units vs. 3.0 ± 1.7 units; P for trend <.001) and higher Stiffness Index (7.0 ± 1.6 m/s vs. 8.3 ± 2.3 m/s vs. 8.4 ± 2.3 m/s; P for trend = .001) compared with the normal controls and NAFLD groups. Multivariate linear regression analysis showed that CI was independently correlated with systolic blood pressure (beta = −0.202, P = .013) and HCV infection (beta = −0.216, P = .036). Chronic HCV infection was independently associated with peripheral arterial stiffness. Peripheral arterial stiffness in chronic HCV infection was not associated with a marker of general inflammation (high-sensitivity C-reactive protein); however, a role for more specific markers of inflammation cannot be ruled out.

Study of microvascular complications of chronic hepatitis C virus in nondiabetic patients

ObjectiveTo study the relationship between chronic hepatitis C infection and microvascular complications in nondiabetic individuals.BackgroundSeveral extrahepatic manifestations have been reported in the natural history of hepatitis C virus (HCV) infection. Further, extrahepatic manifestation syndromes could represent the first signal of an HCV infection, as many patients show no hepatic symptoms. As known microvascular complications of diabetes include neuropathy, nephropathy and retinopathy, this study was conducted to evaluate the effect of chronic HCV infection on microvascular complications in nondiabetic patients.Subjects and methodsFifty patients with chronic hepatitis C infection were enrolled. All were subjected to full clinical assessment including routine blood tests, fasting and 2 h postprandial blood glucose, HbA1c, HCV-RNA PCR, urinary albumin concentration indicating the presence of microalbuminuria, liver biopsy and fundus examination.ResultsMicroalbuminuria was diagnosed in five patients (10%) with chronic hepatitis C, whereas 15 patients (30%) had peripheral neuropathy as diagnosed by clinical examination; no retinopathy was diagnosed in these patients. Peripheral neuropathy correlated with age, HCV viremia and stages of liver biopsy.ConclusionPatients with chronic HCV infection had a high incidence of developing microalbuminuria (10%), a very high incidence of developing peripheral neuropathy (30%) and no incidence of developing retinopathy (zero%). Age, the HCV-RNA level and liver fibrosis are prominent risk factors for the occurrence of peripheral neuropathy in chronic HCV-infected patients.

Possible Recruitment of Peripheral Blood CXCR3+CD27+CD19+B Cells to the Liver of Chronic Hepatitis C Patients

It has been suggested that hepatitis C virus (HCV) infects not only hepatocytes but also immune cells, including B cells. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkin's lymphoma. To clarify the effects of chronic HCV infection on B-cell dynamics, peripheral B cells from chronic hepatitis C patients (CHC) were characterized. We found that the frequency of CD27(+) B cells, that is memory phenotype, was significantly reduced in the peripheral blood of CHC. At the same time, the amount of IFN-gamma-inducible protein-10 (IP-10), a CXCR3 ligand, was markedly elevated in the plasma of CHC. Furthermore, the CD27(+) B-cell population was found to highly express CXCR3 in CHC, thus suggesting that the CD27(+) B-cell population was recruited from peripheral blood to the inflammatory site of the liver of CHC, where IP-10 is produced. Immunohistochemical analyses of intrahepatic lymphocytes indicated that CXCR3(+) B cells were infiltrated in the liver of CHC. Our results thus offer new insight into the role of memory B cells in the HCV pathogenesis.

874 EPIGENETIC MODULATION OF TUMOUR SUPPRESSOR GADD45 BETA EXPRESSION BY HCV LEADS TO DEFECTIVE CELL CYCLE ARREST AND MAY PLAY A ROLE IN LIVER CARCINOGENESIS

Background and Aims: Chronic hepatitis C virus (HCV) infection is a major risk factor of hepatocellular carcinoma (HCC). Sustained oxidative stress and elevated DNA damage are considered major contributors to HCC. Gadd45b is a major mediator of the cellular response to DNA damage. Our goal was to study the effect of chronic HCV infection on Gadd45b expression. Methods: Gadd45b expression were analyzed by western blotting or quantitative RT-PCR in: (a) paired non-tumoral and tumoral human liver samples from uninfected patients, and patients chronically infected with hepatitis B virus (HBV) or HCV; (b) Huh7 cell cultures harboring the HCV genotype 1b replicon and the JFH1 infectious strain; (c) liver tissues from 18 month old wild-type (wt) and transgenic mice expressing the full-length HCV open reading frame (FL-N/35). Primary hepatocytes were isolated from 7 month old mice. Promoter hypermethylation was assessed by the effect of 5-azacytidine (a DNA methyltransferase inhibitor) on Gadd45b mRNA expression. Cell cycle arrest and mitotic indices were assessed by the presence of phospho-histone H3 after UV-C irradiation. Results: Gadd45b expression was abrogated in tumoral tissue from HBV-positive or -negative patients, whereas it was found at normal levels in non-tumoral tissues. In contrast, in HCV-infected individuals, Gadd45b was absent from both tumoral and nontumoral tissues. Gadd45b expression was also reduced in Huh7 cells exhibiting HCVRNA replication (although these cells originate from a liver tumor). A 2-fold decrease in levels of Gadd45b mRNA was observed in livers of FL-N/35 mice compared to controls, whereas amounts of related Gadd family members remained unaffected. Activation of the Gadd45b promoter was inhibited in the presence of HCV, with cells isolated from FL-N/35 mice demonstrating a 2-fold reduction in promoter activity compared to wt controls. Reduced murine Gadd45b expression was associated with decreased cell cycle arrest in response to DNA damage, and both Gadd45b expression and cell cycle arrest were restored to wt levels by treatment with 5-azacytidine. Conclusions: These data demonstrate that HCV protein expression is associated with inhibition of Gadd45b expression through hypermethylation of its promoter, adversely altering the DNA damage response and potentially promoting liver carcinogenesis.

Large Intestine Histopathology of Pegylated-Interferon-Alpha Plus Ribavirin Treated Chronic Hepatitis C Patients

Large Intestine Histopathology of Pegylated-Interferon-Alpha Plus Ribavirin Treated Chronic Hepatitis C Patients

Hepatitis C Infection is Associated With Increased Coronary Artery Atherosclerosis Defined by Modified Reardon Severity Score System

The link between arteriosclerotic disease in the carotid or coronary artery and chronic hepatitis C virus (HCV) infection has been shown in some studies although other studies have produced contrary results. However, the effect of chronic HCV infection on the extension or severity of coronary artery disease (CAD) has not been determined so the aim of the present study was to determine the effect of HCV infection on the severity of CAD. The study group comprised 139 HCV seropositive and 225 HCV seronegative patients with angiographically documented CAD. A modified scoring system of Reardon et al was used. There were no significant differences between groups in terms of sex, age, hypertension, diabetes mellitus, smoking or family history. Levels of C-reactive protein and fibrinogen were significantly higher in the HCV seropositive group (p<0.001) and the Reardon severity score was higher (8.75+/-1.69 vs 6.01+/-1.80, p<0.001). After adjustment, HCV seropositivity still represented an independent predictor for severity of coronary atherosclerosis demonstrated by higher Reardon severity score with an odds ratio of 2.018 (95% confidence interval 1.575-2.579, p<0.001). HCV infection is an independent predictor for increased coronary atherosclerosis, as demonstrated by higher Reardon severity score.

Antiproliferative effect of hepatitis C virus on mitogen-stimulated peripheral blood mononuclear cells: Potential role in viral persistence in Egyptian patients

Objectives: We aimed to study the effect of hepatitis C virus (HCV) and sera of chronic HCV patients on phytohemagglutinin (PHA)-stimulated normal donor PBMCs and to study the effect of chronic HCV infection on some cytokine profile. Subjects and methods: 3H-Thymidine uptake was utilized to study effect of pelleted virus and patients sera on PBMCs proliferation in vitro. The study included 337 Egyptian chronic liver patients from Ain Shams University Hospitals and 90 healthy control subjects. The patients’ group included chronic hepatitis C (250 subjects), and other chronic liver diseases (87 subjects). All subjects’ sera were subjected to RT-PCR for HCV RNA detection, IL-4, IL-1β, and TNF-α measurement by EIA, and biochemical measurement of ALT and albumin. Results: Treatment of PHA-stimulated normal donor PBMCs with pelleted virus led to decrease (dose response) in their rate of proliferation. This was partially reversed after addition of HCV RNA positive patients’ sera. HCV RNA positive patients were significantly higher in IL-4 and ALT, and lower in IL-1β and albumin than HCV RNA negative patients. Conclusion: HCV infection suppresses early immune response. This leads to increased IL-4 Th2 cytokine.

Modifications of plasma platelet‐activating factor (PAF)‐acetylhydrolase/PAF system activity in patients with chronic hepatitis C virus infection

Hepatitis C virus (HCV) chronically infects about 200 million individuals worldwide and leads to severe liver and lymphatic diseases. HCV circulates in the serum, associated with apoB-containing lipoproteins. Platelet-activating factor (PAF), a pro-inflammatory mediator, is mainly modulated by plasma PAF-acetylhydrolase (pPAF-AH), associated with ApoB100-containing low-density lipoproteins (LDL). The aim of the study was to evaluate the potential effects of chronic HCV infection on the PAF/pPAF-AH system. HCV-RNA was detected in plasma, peripheral blood mononuclear cells (PBMC) and liver samples. Plasma PAF levels, pPAF-AH activity, ApoB100 serum titres and pPAF-AH mRNA levels in cultured macrophages were determined. Plasma PAF levels were significantly higher and pPAF-AH activity was significantly lower in HCV patients than in controls. No significant modifications of pPAF-AH mRNA in macrophages or in ApoB100 values were observed in HCV patients compared with controls. Patients who cleared HCV after antiviral treatment showed a complete restoration of pPAF-AH activity and significant decrease of PAF levels during the follow-up. No data exist about the PAF/pPAF-AH system behaviour during HCV infection. This study shows that in HCV patients modifications of pPAF-AH activity/PAF levels take place and that HCV clearance restored pPAF-AH activity. This suggests that circulating viral particles play a role in PAF/pPAF-AH system modifications and such an alteration could be involved in HCV-related damage.

Exploring the role of diet in modifying the effect of known disease determinants: application to risk factors of liver cirrhosis.

The analysis of the combined effects of nutritional factors with other putative disease determinants in log-linear or logistic models is methodologically complicated by the strong multicollinearity between nutritional factors, resulting in poor precision in estimating the parameters. Furthermore, the generally used multiplicative structure is not always the most appropriate for describing the resulting joint effect of two or more factors on the disease risk. The authors addressed such problems in a case-control study assessing the interactions between alcohol intake, chronic hepatitis C virus (HCV) infection, and nutrient intake on the risk of liver cirrhosis. During the period from November 1989 to May 1990, 282 patients admitted to the medical departments of the hospitals of the Province of L'Aquila (central Italy) were enrolled: 115 cirrhotic patients aged 24-82 years (78 of whom were males) hospitalized because of liver decompensation, and 167 control patients aged 25-84 years (100 of whom were males) admitted to the same hospitals for acute diseases unrelated to alcohol intake, infection with hepatotropic viruses, and nutrition. No dose-effect relation was found between the intake of any nutrient and the risk of cirrhosis using classical methods. The analysis of principal components showed, however, that a pattern of higher lipid but lower protein and carbohydrate intakes was significantly associated with the risk of cirrhosis. The Breslow and Storer parametric family of relative risk functions showed that a multiplicative structure was the most adequate to describe the joint effect of nutritional pattern with alcohol intake and/or chronic HCV infection, whereas an additive structure best described the joint effect of chronic HCV infection and alcohol intake. In conclusion, the analysis of principal components and the Breslow and Storer family are useful tools to explore the role of diet on disease risk when precise pathogenic knowledge is not available. As an original finding, the authors suggest that a higher lipid intake, combined with lower protein and carbohydrate intakes, modifies multiplicatively the risk of cirrhosis associated with alcohol intake and/or chronic HCV infection.