Factors associated with hepatic fibrosis in patients with chronic hepatitis C: a retrospective study of a large cohort of U.S. patients.

GOALS: To determine the risk factors for stage 3 and 4 fibrosis in a large cohort of U.S. patients with chronic hepatitis C (CHC). BACKGROUND: 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. STUDY: Retrospective study of a large cohort of US patients with CHC. RESULTS: 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. CONCLUSIONS: 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.

In-vivo effects and mechanisms of celecoxib-reduced growth of cyclooxygenase-2 (COX-2)-expressing versus COX-2-deleted human HCC xenografts in nude mice.

We previously reported that celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, suppresses growth of human hepatocellular carcinoma (HCC) cells through both COX-2 dependence and independence. Recently, we established COX-2-deleted human HCC cells, C2D-HuH7, and C2D-HuH7-bearing nude mice. Using this novel model, we examined the pharmacological effects and mechanisms of celecoxib on in-vivo growth of HCC xenografts in relation to COX-2 expression. After treatment with celecoxib, the mice bearing HuH7 or C2D-HuH7 xenografts were assessed for the pharmacological effects and mechanisms of celecoxib on HCC xenograft growth in relation to COX-2 expression. Celecoxib resulted in an effective and comparable growth reduction of both COX-2-expressing and COX-2-deleted HuH7 xenografts in association with decreased Ki-67 expression. These results demonstrated celecoxib's COX-2-independent in-vivo anti-HCC effects. Celecoxib increased peroxisome proliferator-activated receptor gamma predominantly in HuH7 xenografts, indicating its COX-2 dependency. Celecoxib reduced p-Rb and DP1/E2F1 complex predominantly via upregulated p21/CDK4 complex in HuH7 xenograft, but p27/CDK4 complex in C2D-HuH7 xenografts. The effects of celecoxib on phosphatase and tensin homolog deleted on chromosome ten/PI3K/Akt signaling were COX-2 independent, but its effects on extracellular-regulated kinase signaling seemed COX-2 dependent. In addition, the effects of celecoxib on AC-H3, AC-H4, and histone deacetylase 2 could be both COX-2 dependent and independent. In conclusion, celecoxib suppresses growth of HuH7 xenografts regardless of COX-2 expression, which may be mediated through different signaling.

Clinical presentation of chronic hepatitis C in patients with end-stage renal disease and on hemodialysis versus those with normal renal function.

BACKGROUND: The natural history of chronic hepatitis C (CHC) remains to be defined in patients with end-stage renal disease (ESRD). AIMS: To determine the clinical presentation of CHC and the factors associated with stage III-IV fibrosis in patients with CHC and ESRD. METHODS: The study included patients with CHC and ESRD (n = 91) or normal renal function (NRF, n = 159). Both groups were matched for mean age, gender, history of alcohol use, and estimated duration of hepatitis C virus (HCV) infection. RESULTS: Presentation of CHC and ESRD was independently associated with non-Caucasian ethnicity (OR = 3.24, p= 0.0003), a history of diabetes mellitus (DM, OR = 7.911, p < 0.0001), and lower frequencies of being obese (OR = 0.457, p= 0.035), of having hepatic steatosis (OR = 0.372, p= 0.003), and stage III-IV fibrosis (OR = 0.403, p= 0.016). After adjusting for serum levels of alpha-fetoprotein (AFP) and HCV RNA, CHC, and ESRD were independently associated with lower frequencies of elevated alanine aminotransferase (ALT, OR = 0.175, p= 0.02) and aspartate aminotransferase (AST, OR = 0.169, p= 0.04), but higher frequencies of AST/ALT ratio >1 (OR = 7.173, p= 0.002) and hypoalbuminemia (OR = 9.567, p= 0.0007). Compared to patients with NRF and stage III-IV fibrosis, those with ESRD and stage III-IV fibrosis had a significantly higher frequency of a history of DM (OR = 8.014, p= 0.0031) and lower frequency of elevated AST (OR = 0.054, p= 0.004), which were independent of the frequencies of lower levels of ALT and albumin, and AST/ALT ratio >1. In patients with CHC and ESRD, the presence of stage III-IV fibrosis was significantly associated with hepatic steatosis (OR = 4.523, p= 0.012) and thrombocytopenia (OR = 4.884, p= 0.044), which were independent of the frequencies of a history of DM, splenomegaly, and a higher level of AST. CONCLUSIONS: CHC and ESRD are independently associated with a higher frequency of a history of DM, but lower frequencies of being obese, and having hepatic steatosis, stage III-IV fibrosis, and elevated transaminases. In patients with CHC and ESRD, stage III-IV fibrosis is not associated with a history of DM, but is independently associated with hepatic steatosis and thrombocytopenia.