Hepatitis C Virus Subjects Research Articles

NK cells lacking FcεRIγ are associated with reduced liver damage in chronic hepatitis C virus infection.

A novel subset of human natural killer (NK) cells, which displays potent and broad antiviral responsiveness in concert with virus-specific antibodies, was recently uncovered in cytomegalovirus (CMV)+ individuals. This NK-cell subset (g-NK) was characterized by a deficiency in the expression of FcεRIγ adaptor protein and the long-lasting memory-like NK-cell phenotype, suggesting a role in chronic infections. This study investigates whether the g-NK-cell subset is associated with the magnitude of liver disease during chronic hepatitis C virus (HCV) infection. Analysis of g-NK-cell proportions and function in the PBMCs of healthy controls and chronic HCV subjects showed that chronic HCV subjects had slightly lower proportions of the g-NK-cell subset having similarly enhanced antibody-dependent cellular cytotoxicity responses compared to conventional NK cells. Notably, among CMV+ chronic HCV patients, lower levels of liver enzymes and fibrosis were found in those possessing g-NK cells. g-NK cells were predominant among the CD56(neg) NK cell population often found in chronic HCV patients, suggesting their involvement in immune response during HCV infection. For the first time, our findings indicate that the presence of the g-NK cells in CMV+ individuals is associated with amelioration of liver disease in chronic HCV infection, suggesting the beneficial roles of g-NK cells during a chronic infection.

Insulin Resistance is Associated With Significant Liver Fibrosis in Chronic Hepatitis C Patients: A Systemic Review and Meta-Analysis.

The role of insulin resistance (IR) on fibrosis progression in hepatitis C virus (HCV) patients has not been systematically evaluated. Therefore, this systemic review aimed to summarize the available epidemiologic evidence to evaluate the strength of association between IR and advanced liver fibrosis in these patients. We performed a systemic literature search in PubMed, OvidSP, and MEDLINE from January 1990 to April 2015 without language restriction using the following search terms: insulin resistance, liver fibrosis, cirrhosis, diabetes mellitus, and chronic hepatitis C. Publication bias was assessed using the Begg and Egger tests and with a visual inspection of funnel plot. All analyses were performed using Comprehensive Meta-Analysis, version 2 software. A total of 3659 participants with HCV infection from 14 studies were included in the analysis. After adjusting for publication bias, the relative risk (RR) for significant hepatic fibrosis among HCV subjects with IR was 1.63 [95% confidence interval (CI), 1.34-2.01]. Subgroup analysis by genotypes showed RR of 2.16 (95% CI, 1.52-3.06) for genotype 1; however, the association was no longer significant when we analyzed the data for HCV genotype 3; RR=1.40 (95% CI, 0.8-2.45). Our study showed significant association between IR and significant hepatic fibrosis in patients with HCV genotype 1 infection.

Virus-Specific Cellular Response in Hepatitis C Virus Infection.

Studies performed on chimpanzees and humans have revealed that strong, multispecific and sustained CD4(+) and CD8(+) T cell immune responses is a major determinant of hepatitis C virus (HCV) clearance. However, spontaneous elimination of the virus occurs in minority of infected individuals and cellular response directed against HCV antigens is not persistent in individuals with chronic infection. This review presents characteristics of the HCV-specific T cell response in patients with different clinical course of infection, including acute and chronic infection, persons who spontaneously eliminated HCV and non-infected subjects exposed to HCV. Detection of HCV-specific response, especially in non-infected subjects exposed to HCV, may be indicative of HCV prevalence in population and rate of spontaneous viral clearance. Understanding the mechanisms and role of HCV-specific cellular immune response would contribute to better understanding of HCV epidemiology, immunopathogenesis and may help to design an effective vaccine.

Hepatitis C virus-induced hepatocellular carcinoma.

Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs.

A randomized, double blind, dose escalation, first time in human study to assess the safety, tolerability, pharmacokinetics, and antiviral activity of single doses of GSK2485852 in chronically infected hepatitis C subjects

This first-time-in-human, randomized, double-blind, placebo-controlled, dose-escalation study assessed the safety, tolerability, pharmacokinetics, and antiviral activity of GSK2485852, a hepatitis C virus (HCV) NS5B inhibitor, in 27 chronically infected HCV genotype-1 subjects. Subjects received GSK2485852 70, 420, and 70 mg with a moderate fat/caloric meal. Safety, pharmacokinetics, antiviral activity, HCV genotype/phenotype, and interleukin 28B genotype were evaluated. A statistically significant reduction in HCV ribonucleic acid (RNA) was observed after a single dose of 420 mg GSK2485852 (-1.33 log10 IU/mL) compared with placebo (-0.09 log10 IU/mL) at 24 hours post-dose. Subjects receiving 70 mg GSK2485852 were exposed to concentrations above the protein-adjusted 90% effective concentration for a short time; none experienced a significant decline in HCV RNA (-0.47 log10 copies/mL). GSK2485852 was readily absorbed; however, the observed geometric mean maximum plasma concentration (Cmax ) and area under the curve (AUC) values were significantly lower than expected due to a higher-than-predicted-oral clearance. Co-administration with food reduced the AUC and Cmax of GSK2485852 by 40% and 70%, respectively. Two metabolites were detected in human blood with one having approximately 50% higher concentrations than those of the parent. GSK2485852 was well-tolerated and exhibited antiviral activity after a single 420 mg dose in HCV subjects.

Impact of IL-10 (-1082) Promoter–Single Nucleotide Polymorphism on the Outcome of Hepatitis C Virus Genotype 4 Infection

Immunoregulatory cytokines may influence the hepatitis C virus (HCV) infection outcome. This study aimed to determine the genotypic and allelic frequencies of the interleukin (IL)-10 (−1082) G/A polymorphism, and its association with chronicity or resolution of HCV genotype 4 infection in Egypt. The frequencies of different dimorphic polymorphisms based on single nucleotide substitution in chronic HCV patients (50) and resolved HCV patients (50) were: IL-10 (−1082) G/G 22 (44%) and 18 (36%), G/A 19 (38%) and 24 (48%), and A/A 9 (18%), and 8 (16%), respectively. In the sustained virologic response (SVR) (36) and spontaneously resolved subjects (14) groups, the frequencies were: IL-10 (−1082) G/G 11 (30.6%) and 7 (50%) G/A 18 (50%) and 6 (42.9%), A/A 7 (19.4%) and 1 (7.1%), respectively. An association between male gender and chronic hepatitis C outcome (P value 0.041) was found. However, no significant gender difference was found when we compared females versus males with elevated alanine transaminase (ALT) levels in the chronic HCV patient group (P value = 1).CONCLUSIONNo significant difference in the frequency of IL-10 single nucleotide polymorphism (SNP) at position 1082 was found between chronic and resolved HCV subjects.

Elevated lipogenesis and diminished cholesterol synthesis in patients with hepatitis C viral infection compared to healthy humans

Hepatitis C virus (HCV) exerts a profound influence on host lipid metabolism. It has been suggested that the synthesis of both fatty acids (FA) and cholesterol is dysregulated in HCV but this has not been directly quantified in humans. The purpose of this study was to measure lipogenesis and cholesterol synthesis using stable isotopes in patients with HCV (n = 5) and healthy control (n = 9) subjects recruited from the University of Alberta hospital. Blood samples were taken at fasting (0 and 24 hours) and after meals over the day to mimic typical food consumption and postprandial metabolism. Isolation of free cholesterol (FC), cholesteryl ester (CE), and triglyceride (TG) from plasma and very low-density lipoproteins (VLDL) was used to measure FA and cholesterol synthesis using deuterium uptake and isotope ratio mass spectrometry. FA composition was analyzed by gas chromatography. VLDL-TG levels of polyunsaturated fatty acids (PUFA), including linoleic and linolenic acid, were lower in HCV compared to control (P < 0.05 for both). Fasting hepatic lipogenesis was significantly higher in HCV (2.80 ± 0.55%) compared to control (1.19 ± 0.27%; P = 0.03). Conversely, fasting whole-body synthesis of FC (HCV 1.64 ± 0.28% versus control 8.78 ± 1.59%) and CE (HCV 0.26 ± 0.08% versus control 1.92 ± 0.25%), as well as hepatic FC synthesis (HCV 1.68 ± 0.26% versus control 8.12 ± 0.77%) was lower in HCV (P < 0.001 for all). These data provide evidence that lipogenesis is elevated while cholesterol synthesis is impaired in HCV, supporting previous findings from cellular and animal models. Low PUFA levels combined with elevated lipogenesis suggests a role for dietary PUFA supplementation in HCV patients.

Anti‐inflammatory cytokines, pro‐fibrogenic chemokines and persistence of acute HCV infection

Chemokines and cytokines play a vital role in directing and regulating immune responses to viral infections. Persistent hepatitis C virus (HCV) infection is characterized by the loss of anti-HCV cellular immune responses, while control of HCV infection is associated with maintenance of anti-HCV cellular immune responses. To determine whether plasma concentrations of 19 chemokines and cytokines controlling T-cell trafficking and function differed based on infection outcome, we compared them in at-risk subjects followed prospectively for HCV infection. Levels were compared over time in subjects who controlled HCV infection (Clearance) and subjects who developed persistent HCV infection (Persistence) at two time points during acute infection: (i) first viraemic sample (initial viraemia) and (ii) last viraemic sample in Clearance subjects and time-matched samples in Persistence subjects. At initial viraemia, increased pro-inflammatory tumour necrosis factor α (TNFα) plasma concentrations were observed in the Clearance group, while the plasma levels of anti-inflammatory interleukin (IL)-2, IL-10 and IL-13 were higher in the Persistence group. IL-13 was positively correlated with IL-2 and IL-10 at initial viraemia in the Persistence group. At the time of last viraemia, plasma levels of eotaxin, macrophage chemoattractant protein-4 (MCP-4), IL-5 and IL-10 were higher in the Persistence group and IL-10 and IL-5 levels were positively correlated. Collectively, these results suggest that the development of persistent infection is associated with an anti-inflammatory and pro-fibrogenic chemokine and cytokine profile that is evident at the onset of infection and maintained throughout acute infection.

Dendritic cell co-stimulatory and co-inhibitory markers in chronic HCV: An Egyptian study

To assess co-stimulatory and co-inhibitory markers of dendritic cells (DCs) in hepatitis C virus (HCV) infected subjects with and without uremia. Three subject groups were included in the study: group 1 involved 50 control subjects, group 2 involved 50 patients with chronic HCV infection and group 3 involved 50 HCV uremic subjects undergoing hemodialysis. CD83, CD86 and CD40 as co-stimulatory markers and PD-L1 as a co-inhibitory marker were assessed in peripheral blood mononuclear cells by real-time polymerase chain reaction. Interleukin-10 (IL-10) and hyaluronic acid (HA) levels were also assessed. All findings were correlated with disease activity, viral load and fibrogenesis. There was a significant decrease in co-stimulatory markers; CD83, CD86 and CD40 in groups 2 and 3 vs the control group. Co-stimulatory markers were significantly higher in group 3 vs group 2. There was a significant elevation in PD-L1 in both HCV groups vs the control group. PD-L1 was significantly lower in group 3 vs group 2. There was a significant elevation in IL-10 and HA levels in groups 2 and 3, where IL-10 was higher in group 3 and HA was lower in group 3 vs group 2. HA level was significantly correlated with disease activity and fibrosis grade in group 2. IL-10 was significantly correlated with fibrosis grade in group 2. There were significant negative correlations between co-stimulatory markers and viral load in groups 2 and 3, except CD83 in dialysis patients. There was a significant positive correlation between PD-L1 and viral load in both HCV groups. A significant decrease in DC co-stimulatory markers and a significant increase in a DC co-inhibitory marker were observed in HCV subjects and to a lesser extent in dialysis patients.

Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C

Accuracy of transient elastography (TE) in hepatitis B virus (HBV) infection has not been well established. We aimed to compare the performances of TE for the assessment of liver fibrosis in patients with chronic HBV or hepatitis C virus (HCV) infection. A secondary analysis was performed to assess whether or not alanine aminotransferase (ALT) levels would impact on the accuracy of TE. This cross-sectional study, carried out in a single centre, included treatment-naïve patients with compensated chronic HBV or HCV infection, consecutively admitted between 2006 and 2008 for a liver biopsy and TE measurement on the same day. A total of 202 HBV patients and 363 HCV subjects were evaluated. Overall diagnostic accuracy of TE in the HBV group was comparable to that observed in HCV patients [area under the receiver-operating characteristics (AUROCs) 0.867 ± 0.026 vs. 0.868 ± 0.019 for predicting F ≥ 2, P = 0.975; 0.902 ± 0.029 vs. 0.894 ± 0.020 for F ≥ 3, P = 0.820; and 0.935 ± 0.024 vs. 0.947 ± 0.027 for F4, P = 0.740 respectively]. TE exhibited comparable accuracies, sensitivities, specificities, predictive values and likelihood ratios in HBV and HCV groups. AUROC analysis showed no influence of ALT levels on the performance of TE in HBV individuals. ALT-specific cut-off values did not exhibit significantly higher diagnostic performances for predicting fibrosis in HBV patients with elevated ALT. In HBV patients, TE measurement accurately predicts the absence or presence of significant fibrosis, advanced fibrosis or cirrhosis and shows similar performances as compared to HCV patients. The use of TE cut-off values adjusted to ALT level did not improve performances for estimating liver fibrosis in HBV patients.

Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition

Chronic hepatitis C virus (HCV) infection is associated with altered cerebral metabolism and cognitive dysfunction. We aimed to evaluate the effect of pegylated interferon/ribavirin (PIFN/R) and HCV clearance on cerebral metabolism, and neuropsychological performance. Fifteen non-cirrhotic HCV positive subjects underwent (1)H MR spectroscopy (MRS) before, during, and after treatment with PIFN/R. The metabolites of interest namely, N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), and the control metabolite creatine (Cr), were acquired from 3 different brain regions; left basal ganglia, left frontal cortex, and left dorso-lateral pre-frontal cortex. Coinciding with this, subjects also underwent a battery of neuropsychological tests to evaluate the domains of verbal learning, memory, attention, language, executive functioning, and motor skills. Seven HCV positive controls (not receiving anti-viral therapy) underwent MRS and neuropsychological testing at two time points, 12 weeks apart, to examine for variation in cerebral metabolites over time and the practice effect of repeat neuropsychological testing. Significant reductions in basal ganglia Cho/Cr (p=0.03) and basal ganglia MI/Cr (p=0.03) were observed in sustained virological responders (SVRs, n=8), but not non-responders/relapsers (NR/R, n=6), indicative of reduced cerebral infection and/or immune activation in those who cleared virus. SVRs demonstrated significant improvements in verbal learning, memory, and visuo-spatial memory. A small but significant improvement in neurocognitive function secondary to the practice effect was seen in both HCV controls and HCV subjects during treatment. HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease.

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single- and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC(0-8 h)) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC(0-8 h) was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC(0-8 h) (p < 0.05) and 42% lower C(max) (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.

Immune response to extracellular matrix collagen in chronic hepatitis C-induced liver fibrosis

Hepatitis C virus (HCV) infection and its recurrence after orthotopic liver transplantation (OLT) are associated with the remodeling of extracellular matrix (ECM) components [particularly collagen (Col)], which leads to fibrosis. Our aim was to determine whether the development of antibodies (Abs) to self-antigen Col in HCV-infected patients correlates with the fibrosis stage and the peripheral cytokine response. Patients with chronic HCV infection, patients with HCV recurrence after OLT who had undergone a biopsy procedure, and healthy control subjects were enrolled. The HCV subjects (n = 70) were stratified as follows: (1) a non-OLT group without fibrosis (Scheuer stages 0-2), (2) a non-OLT group with fibrosis (Scheuer stages 3-4), (3) a post-OLT group without fibrosis (Scheuer stages 0-2), and (4) a post-OLT group with fibrosis (Scheuer stages 3-4). Serum samples were analyzed for Abs against Col1, Col2, Col4, Col5, and vimentin with enzyme-linked immunosorbent assays. Serum levels of cytokines were measured with multiplex bead immunoassays. The levels of Abs to Col1 were higher in the fibrosis groups versus the no-fibrosis groups and the controls for both non-OLT patients (P < 0.001) and post-OLT patients (P = 0.01). There were increased levels of Abs to Col2, Col4, Col5, and vimentin in the non-OLT fibrosis group (Col2, P = 0.0001; Col4, P = 0.122; Col5, P < 0.0001; vimentin, P = 0.36) and in the post-OLT fibrosis group (Col2, P = 0.006; Col4, P = 0.19; Col5, P < 0.0001; vimentin, P = 0.24) in comparison with the no-fibrosis groups. The non-OLT and post-OLT fibrosis groups demonstrated significantly higher T helper 2 (T(h) 2) and T helper 17 (T(h) 17) cytokine levels and lower T helper 1 cytokine levels in comparison with the no-fibrosis groups. Our results demonstrate that in HCV-infected patients, the levels of Abs to ECM Col1, Col2, and Col5 positively correlate with liver fibrosis, which is associated with a predominantly T(h) 2 and T(h) 17 cytokine profile.

C-reactive protein and chronic hepatitis C virus infection in diabetic patients

C-reactive protein (CRP) is one of the most widely used risk markers of cardiovascular disease in clinical practice. The contribution of hepatitis C virus (HCV) infection to low-grade inflammation in diabetic patients and its significance for cardiovascular risk scoring remain unclear. The aim of the study was to investigate the relationship between HCV infection and CRP levels as one of the markers of cardiovascular risk in diabetic patients. we compared patients with HCV infection and diabetes (n = 46) with HCV-negative type 1 (n = 56) or type 2 diabetic patients (n = 54), as well as HCV patients without diabetes (n = 54). CRP levels in diabetic HCV patients were lower than in type 2 diabetic patients (P <0.001), similar to those in the type 1 diabetic group (P = 0.747), and higher than in nondiabetic HCV subjects (P = 0.002). The median values were 1.07, 2.58, 0.91, and 0.45 mg/l, respectively. White blood cell count in diabetic HCV subjects was lower than in those with type 2 diabetes (P = 0.029) and similar to that found in type 1 diabetic (P = 0.064) and nondiabetic HCV patients (P = 0.279). There was difference in erythrocyte sedimentation rate between diabetic and nondiabetic HCV groups (P = 0.025); the respective medians were 10 and 5 mm/h. these findings indicate that HCV hepatitis may modulate chronic inflammatory state in diabetic patients. Moreover, these results suggest that screening for HCV should be considered prior to assessment of cardiovascular risk in diabetic patients, because the results may affect the cardiovascular risk scoring.

Reactivation of epstein–barr virus in B cells of patients with chronic hepatitis C

Hepatitis C virus (HCV) infection is associated with lymphoproliferative disorders. HCV infection of B cells is a predictive factor for lymphoproliferative disorders in patients with chronic hepatitis C, although its molecular mechanisms remain unknown. Epstein-Barr virus (EBV) is a B cell-tropic virus with the potential to cause lymphoproliferative disorders, and its reactivation is induced by several viruses and cytokines. The possibility that HCV infection triggers reactivation of EBV and induces lymphoproliferative disorders were investigated. Expression of EBV mRNAs was analyzed by RT-PCR in patients infected with HCV and control subjects, and correlations between reactivation of EBV and markers for lymphoproliferative disorders were investigated. BZLF1 mRNA, a starter molecule of reactivation, was detected in peripheral blood mononuclear cells from 12 of 52 (23%), patients infected with HCV and the frequency was higher than in healthy subjects [3 of 43 (9%), P = 0.032]. But the presence of the BZLF1 mRNA was not associated with an abnormality of markers for lymphoproliferative disorders. This study on BZLF1 mRNA expression among lymphoid cell subsets showed that reactivation of EBV was observed specifically in B cells. The BZLF1 mRNA disappeared following anti-viral therapy and remained negative after eradication of HCV in patients with a sustained viral response, while the EBER1 RNA, a marker for persistence of EBV, was detected throughout the therapy. Infection with HCV induces reactivation of EBV in B cells, but this reactivation was not associated directly with lymphoproliferative disorders triggered by HCV.

Is the hepatitis C virus epidemic over in Egypt? Incidence and risk factors of new hepatitis C virus infections

To estimate hepatitis C virus (HCV) incidence rates and identify risk factors for current HCV transmission with emphasis on the role of living with infected household family members in rural Egypt. A 4-year population-based, cohort study of seronegative villagers was conducted to identify incident HCV seroconversion cases. A risk factor questionnaire and blood samples for anti-HCV EIA-3 and HCV RNA polymerase chain reaction testing were collected at two rounds of follow-up. Incidence rates, relative risks and 95% confidence interval (CI) were calculated based on a Poisson distribution. A matched case-control analysis to explore specific behavioural predictors of infection was conducted and odds ratios were obtained by conditional logistic regression. Twenty-five participants (11 females) seroconverted in 10,578 person years of follow-up (PY), (incidence rate of 2.4/1000 PY; 95% CI: 1.6-3.5). The median age at seroconversion was 26 years [interquartile range (IQR) 19-35] among males and 20 years (IQR 13-24) among females. The only significant risk factor identified for these cases was receiving injections [adjusted odds ratio (OR(adj))=3.3; 95% CI: 1.1-9.8]. Two of the 17 viraemic seroconvertors were infected with the same strain as at least one of their family members. This study identified the important role of injections in spreading HCV infection in this rural community. National healthcare awareness and infection control programmes should be strengthened to prevent further transmission. Screening of families of infected HCV subjects should be an essential part of case management for early detection and management.

Plasma osteopontin concentration correlates with the severity of hepatic fibrosis and inflammation in HCV-infected subjects

The association between OPN level and the histological severity of hepatic fibrosis and inflammation in hepatitis C virus (HCV) induced liver fibrosis remains unknown. 120 chronic HCV-infected subjects and 75 controls were enrolled in this study. Assessment of liver histology was performed based on liver biopsy. Plasma OPN levels were determined. Significant differences were noted in the mean plasma OPN levels between subjects with extensive fibrosis and those with mild fibrosis (4.29+/-1.01 ng/ml vs. 2.15+/-0.63 ng/ml, respectively; p<0.001). Similarly, the subjects with higher histological activity index (HAI) score had elevated OPN levels than those with mild HAI score (4.41+/-1.11 ng/ml vs. 2.25+/-0.94 ng/ml, respectively; p<0.001). The correlation between the plasma OPN levels and the severity of liver fibrosis degree and HAI score were noted (r=0.945, and r=0.788, respectively both p<0.001). Logistic regression analysis showed that serum OPN was an independent risk factor contributing to extensive liver fibrosis and inflammation (p=0.0018 and p<0.001, respectively) in patients with HCV subjects. The plasma OPN level is correlated with the severity of liver fibrosis and inflammation, suggesting OPN could be used as a biomarker to evaluate the severity of liver damages in HCV subjects.

Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection

To elucidate the role of insulin resistance (IR) and serum adiponectin level in hepatocellular carcinoma (HCC) associated with chronic hepatitis C. Clinical and biochemical characteristics were collected from 165 consecutive patients with newly diagnosed HCC. Homeostasis model assessment of IR (HOMA-IR) and serum adiponectin level were investigated in 188 patients with different stages of hepatitis C virus (HCV) infection. Among HCC patients, type 2 diabetics (DM) was more prevalent in HCV subjects (35.6%, n = 59) compared to hepatitis B virus (HBV; 12.7%, n = 63) or non-HBV, non-HCV cases (7.1%, n = 28). In patients with chronic hepatitis C, HCC subjects had higher blood sugar (P < 0.001), insulin level (P = 0.003) and HOMA-IR (P = 0.018) than those with chronic hepatitis and advanced fibrosis. Age, male sex and body mass index were significantly associated with serum adiponectin level, whereas HOMA-IR was not. Based on stepwise logistic regression analysis, age (OR: 1.124, P < 0.001), serum insulin level (OR: 1.585, P < 0.001), HOMA-IR (OR: 0.495, P = 0.001), DM (OR: 11.601, P = 0.002) and male sex (OR: 3.877, P = 0.016) were independently associated with HCC. This result was similar even if the diabetic subjects were excluded for analysis. Insulin resistance measured by HOMA-IR, regardless of the presence of diabetes, is significantly associated with HCC development in patients with chronic HCV infection.

Impact of the donor risk index on the outcome of hepatitis C virus-positive liver transplant recipients

We have investigated the impact of the donor risk index (DRI) on the outcome of hepatitis C virus (HCV)-infected patients undergoing liver transplantation (LTx). Retrospective analysis was performed from the Organ Procurement and Transplantation Network database (January 1, 2000 to June, 2006). The DRI was calculated as described by Feng et al. (Am J Transplant 2006;6:783-790). Model for End-Stage Liver Disease (MELD) exceptions were excluded from the analysis. Relative risk (RR) estimates of patient and graft loss were derived from Cox regression models. The Wald test was used to test the effect of the MELD score at transplant on the HCV-DRI interaction. Of the LTx recipients (16,678), 76.1% were Caucasian, and 66.7% were male; the median age was 52 (range, 18-80 years), and the mean follow-up time was 1148 days (range, 0-2959 days). Forty-six percent (n = 7675) of LTx recipients were HCV(+). The median DRI was 1.3 (range, 0.77-4.27). Increasing DRI was associated with a statistically significant increase in the RR of graft failure and patient death for both HCV(+) and HCV(-) recipients. However, HCV(+) recipients demonstrated a significantly higher increase in the RR of patient and graft loss as a function of the DRI than HCV(-) subjects, even after adjustments for several recipient factors, including MELD. In conclusion, a synergistic interaction between donor DRI and recipient HCV status exists, such that an allograft from a high-DRI donor more adversely affects the outcome of an HCV(+) recipient than that of an HCV(-) recipient.

Expression of pro‐ and anti‐inflammatory cytokines in relation to apoptotic genes in Egyptian liver disease patients associated with HCV‐genotype‐4

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide strongly linked to hepatitis C virus (HCV) infection. However, the exact pathogenetic mechanisms are still unclear. We assessed the expression of apoptosis genes (GSK3-B, AKT-1, Bcl-2), inflammatory cytokines (TNFalpha, TNF-RI, TNF-RII, IL-6, IL-6R), anti-inflammatory IL-10, CRP and alphaFP by reverse transcription-polymerase chain reaction (RT-PCR) in 33 HCC, 25 chronic hepatitis and 16 asymptomatic HCV carrier positive for HCV subjects. Also, pooled normal liver tissues and HepG2 cells were used as controls. Hepatocellular carcinoma and liver disease (LD) showed reduced expression of GSK-3beta, TNFalpha, TNF-R I, TNF-RII, IL-10 and overexpression of IL-6R and CRP with no significant difference between the two groups. AFP was expressed in HCC only (33%). AKT, BCL2 and IL-6 showed normal, reduced and overexpression in studied patients with a significant difference between AFP, AKT overexpression (67% and 30%), BCL2 overexpression (49% and 10%) and reduced IL-6 in between HCC and LD. The morphologically normal tissues adjacent to tumors showed aberrant expression of AKT, IL-6, CRP, TNFalpha and TNFRI. A significant relation was observed between cirrhosis and GSK-3beta, AKT and IL-6 (P = 0.0018, P = 0.018, P = 0.0001; respectively). Aberrant expressions of AKT, GSK3-B, and BCL2 are common events in HCV-associated LD and HCC. AKT, GSK3-B and IL-6 are significantly associated with cirrhosis and could be used as biomarkers for both early detection and molecular target therapy for the prevention of HCC development. TNFRII, GSK3-B and s-AFP could be used as prognostic factors that can predict the clinical outcome of HCC patients.