Chronic Hepatitis C Progression Research Articles

Preliminary evidence of sustained expression of angiopoietin‐2 during monocyte differentiation in chronic hepatitis C

Monocytes are essential precursors of antigen-presenting cells, such as macrophages and dendritic cells, and contribute to the pathogenesis of chronic inflammatory diseases and cancer. As Tie2-expressing monocytes (TEMs) are increased in the peripheral blood of patients with chronic hepatitis C (CHC), we aimed to examine the expression of Tie2 and angiopoietins (Ang1 and Ang2) during monocyte differentiation and maturation in CHC. The expression of Tie2, CD11b, CD80, CD83, CD86 and MHC-II was measured by flow cytometry in peripheral blood monocytes and monocytes-derived cells (Mo-DCs) from nine healthy subjects and eight CHC patients whose HCV infection was unresolved after combination therapy. Ang1 and Ang2 levels were measured in cellular supernatants by ELISA. Mo-DCs from CHC patients expressed differential patterns of maturation markers compared with controls--primarily with regard to CD80. Tie2 was downregulated during monocyte differentiation in controls and CHC patients, whereas Ang1 expression was constant. However, Ang2 levels fell significantly during the differentiation of control monocytes, in contrast with those from CHC patients in whom Ang2 expression remained stable throughout differentiation. Altered expression of the Ang/Tie2 system in monocytes and Mo-DCs from CHC patients might account for the inflammatory and angiogenic disorders that are related to CHC. An increased understanding of Ang/Tie2 system regulation might be helpful in designing strategies to prevent CHC progression.

P21/Wafl/Cipl cellular expression in chronic long-lasting hepatitis C: correlation with HCV proteins (C, NS3, NS5A), other cell-cycle related proteins and selected clinical data.

Studies indicate that proteins of hepatitis C virus (HCV) disturb expression of cell-cycle-related proteins. A disturbed cell-cycle control is a hepatocellular carcinoma (HCC) risk factor in patients with HCV-related liver damage. The present study aimed to analyse the cellular expression of p21/Wafl/Cipl (p21) in long-lasting chronic hepatitis C (CH-C), its correlation with the key oncogenic HCV proteins (C, NS3, NS5A), other cell-cycle-related proteins (PCNA, Ki-67, cyclin D1, p53) and selected clinical data. Archival liver biopsies, obtained from patients with CH-C, normal livers, and hepatocellular carcinoma (HCC) specimens were analysed by immunocytochemistry and ImmunoMax technique. In CH-C overexpression of p21 protein was demonstrated. Positive correlations of p21 protein expression in CH-C involved age of the patients, grading, and liver steatosis. Moreover, expression of p21 correlated significantly with expression of p53 protein, of D1 cyclin and Ki-67. Although Ki-67 antigen was related to p21 expression, only Ki-67 expression proved to be directly related to liver staging. Expression of the NS3 protein, which prevailed in CH-C patients, manifested correlation with p21 expression, and that of cyclin D1. In presence of preserved potential for regeneration, overexpression of p21 indicates inhibition of cell cycle in hepatocytes, which probably plays a protective role for the chronically damaged cells. Out of the three HCV proteins only NS3 seems to affect control of p21 protein expression in in vivo infection. Nevertheless, the studies indicate that neither expression of p21 protein nor that of viral NS3 protein can serve as a marker of progression of CH-C to HCC in vivo.

Factors Associated With Hepatic Fibrosis In Patients With Chronic Hepatitis C

To determine the risk factors for stage 3 and 4 fibrosis in a large cohort of U.S. patients with chronic hepatitis C (CHC). Multiple host and viral factors affect the outcomes of CHC. Further defining the pathogenic roles of these factors in CHC progression will lead to improving management of this disease. Retrospective study of a large cohort of US patients with CHC. Of the 460 patients, 331 were males and 129 were females with mean age of 48.4+/-8.0 years, and 191 (41.7%) had stage 3 and 4 fibrosis. Clinically, a multivariate analysis revealed that age of > or =60 years at presentation, the estimated duration of hepatitis C virus (HCV) infection > or =25 years, a body mass index > or =30 kg/m, and a history of diabetes mellitus were independently associated with stage 3 and 4 fibrosis, after adjusting for history of alcohol use. Laboratorially, a multivariate analysis revealed that aspartate aminotransferase (AST) > or =2 x upper limit of normal (ULN), alpha fetoprotein > or =15 microg/L, and presence of grade 2 and 3 steatosis were independently associated with stage 3 and 4 fibrosis, after adjusting for alanine aminotransferase > or =2 x upper limit of normal, AST/alanine aminotransferase ratio > or =1, HCV genotyping, transferrin saturation, and a histology activity index score > or =7. The present study indicated that elderly, longer duration of HCV infection, obesity, and history of diabetes mellitus are independent clinical parameters associated with advanced fibrosis, whereas elevated AST, alpha fetoprotein, and presence of grade 2 and 3 steatosis are independent laboratorial parameters associated with stage 3 and 4 fibrosis in patients with CHC.

Combination of Oxidative Stress and Steatosis Is a Risk Factor for Fibrosis in Alcohol-Drinking Patients With Chronic Hepatitis C

Alcohol and HCV have been shown to interact in stimulating hepatic oxidative damage. Thus, we investigated the contribution of oxidative mechanisms in the progression of chronic hepatitis C (CHC) in alcohol consumers. An increased IgG reactivity against lipid peroxidation-derived antigens was used as the marker for alcohol-induced oxidative damage in 125 CHC patients. Alcohol intake significantly increased the frequency of the subjects with elevated lipid peroxidation-related IgG. However, no association was evident between oxidative stress markers and the severity of steatosis, necroinflammation, or fibrosis. Multivariate analysis revealed that age (P= 0.014) and hepatic iron content (P= 0.034) were the only independent predictors of fibrosis in these patients. However, the risk of fibrosis in the subjects with both steatosis and oxidative stress-induced immune responses was 6- (OR 6.2, 95% CI 1.2-31.0) and 14-fold (OR 14.6, 95% CI 3.1-68.1) higher than in the subjects with steatosis alone or without steatosis, respectively. Multivariate analysis confirmed that the combination of steatosis and oxidative stress (P= 0.045) was, together with age (P= 0.021) and hepatic iron content (P= 0.027), an independent risk factor for fibrosis in CHC patients with alcohol intake. These results demonstrate that oxidative stress interacts with steatosis to promote the progression of CHC in alcohol-consuming patients.

Detection of auto-antibodies against cytochrome P4502E1 (CYP2E1) in chronic hepatitis C

Chronic hepatitis C (CHC) is often associated with auto-immune reactions. In the light of the role of alcohol in promoting CHC progression, we have investigated the possible presence of auto-reactivity against the ethanol-inducible cytochrome P4502E1 (CYP2E1) in CHC patients with and without alcohol consumption. The IgG reactivity against recombinant human CYP2E1 was evaluated by solid-phase immunoassays in 102 CHC patients with different alcohol consumption and 59 HCV-free controls. Auto-antibodies against CYP2E1 were significantly (p<0.0001) increased in CHC patients as compared to controls. Anti-CYP2E1 IgG above the 97th percentile in the controls were evident in 41 (40%) CHC patients. Competition experiments revealed that CYP2E1 recognition was not due to the cross-reactivity with CYP2D6. The detection of anti-CYP2E1 IgG was unrelated to alcohol consumption and no difference in gender, age, aminotransferase levels and virus genotype was evident among the patients with or without anti-CYP2E1 auto-antibodies. However, anti-CYP2E1 auto-reactivity was significantly (p=0.025) associated with the severity of periportal/periseptal interface hepatitis. Moreover, confocal microscopy demonstrated that anti-CYP2E1 IgG associated with CHC recognized CYP2E1 exposed on the outer side of hepatocyte plasma membranes. HCV infection favours the breaking of self-tolerance against CYP2E1 that might contribute to hepatocyte injury.

The impact of competing risks on the observed rate of chronic hepatitis C progression

In previous studies about the natural history of chronic hepatitis C (CHC), age at the time of infection correlated with the rate at which hepatic fibrosis progresses. The presence of a competing risk, namely higher mortality from natural causes, may contribute to this observation. A simulation experiment was conducted to measure the magnitude of the effect of competing risks on the observed rate of fibrosis progression of CHC. A computer-based probabilistic model was created in which fibrosis of CHC progressed from stage 0 to 4 (cirrhosis) in 20-year-old and 50-year-old male and female cohorts. The rate of fibrosis progression was randomly assigned to each simulated individual from a distribution common to all age- and sex-specific cohorts. The cohorts also experienced mortality from natural causes according to the 2000 census data. The observed median time to reach cirrhosis for the 50-year-old cohorts was 20.4 +/- 0.2 years compared with 29.7 +/- 0.2 for the 20-year-old cohorts ( P < 0.01). The median time to reach cirrhosis in men was 24.2 +/- 0.6 years compared with 25.9 +/- 0.6 in women ( P = 0.01). Overall, the observed rate of progression was slowest among young women. Similarly, accelerating mortality from natural causes, simulating the impact of comorbid conditions that shorten survival, reduced the observed time to reach cirrhosis. Even if the underlying rate of fibrosis progression in CHC was held constant, the time to reach cirrhosis will be observed to be substantially shorter in subjects with a higher competing mortality.

Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States

Background: Hepatic steatosis has been associated with chronic hepatitis C (CHC), but its prevalence, risk factors, and clinical significance remain to be determined. Aims: The present study determined the frequency of, and risk factors for hepatic steatosis and its association with activity and progression of CHC in a large cohort of U.S. patients. Methods: This is a retrospective study that utilized systematic chart review and statistical analyzes to investigate 324 U.S. patients with CHC from a university medical center and a regional VA medical center. Results: The frequency of hepatic steatosis was 66.0%. We demonstrated that not only being obese, but also overweight (i.e. body mass index ≥25 kg/m 2) was independently associated with hepatic steatosis. In our cohort of patients with CHC, hepatic steatosis, especially grade II/III steatosis, was significantly associated with elevated aspartate aminotransferase at entry, persistently elevated alanine aminotransferase, and stage III/IV fibrosis. Grade II/III steatosis, was significantly associated with a higher histology activity index as well. Multivariate analysis indicated that steatosis, especially grade II/III steatosis, was independently associated with stage III/IV fibrosis. Conclusions: Being overweight/obese serves as an independent risk factor for hepatic steatosis in U.S. patients with CHC. Steatosis accelerates activity and progression of CHC, and is independently associated with stage III/IV hepatic fibrosis in these patients.