Serum adiponectin correlates with viral characteristics but not histologic features in patients with chronic hepatitis C

BACKGROUND/AIMS: Adiponectin induces insulin sensitivity and modulates inflammatory responses. We thus studied the implications of adiponectin in patients with chronic hepatitis C virus (HCV) infection inherently linked to insulin resistance. METHODS: We analyzed the association of serum adiponectin levels with clinical, virologic, and histologic findings in 95 naive Taiwanese patients with chronic hepatitis C before and after antiviral therapy. RESULTS: At baseline, 14 (15%) of the 95 patients were obese and 26 (27%) had type 2 diabetes mellitus. Fifty-seven patients were infected with HCV genotype 1 and 38 with genotype 2. Steatosis and periportal fibrosis was present in 44 (46%) and 69 (73%), respectively. In multivariate analysis, male gender, insulin resistance, high HCV load and genotype 2 were significantly associated with a lower serum adiponectin level. In contrast, intrahepatic gene expression of adiponectin receptors was higher in genotype 2 compared with genotype 1. Serum adiponectin level did not correlate with other clinical or histologic parameters. After treatment, change of steatosis also did not correlate with the change of adiponectin level (P=0.61). CONCLUSIONS: Adiponectin correlated with hepatitis C viral factors at both serum and liver tissue levels. The interactions among adiponectin, insulin resistance and chronic HCV infection merit further studies.     

Liver cell apoptosis in chronic hepatitis C correlates with histological but not biochemical activity or serum HCV-RNA levels

In hepatitis C virus (HCV) infection, mechanisms responsible for liver cell damage are still poorly understood and both necrosis and apoptosis may be operative. By using terminal deoxynucleotydil transferase-mediated d-UTP-biotin nick-end labeling (TUNEL) we have evaluated and quantified apoptosis in liver biopsy specimens from 61 patients with chronic hepatitis C. All patients had detectable apoptotic cells in the liver. Presence of increased apoptotic activity was confirmed in selected cases by electron microscopy and by DNA gel electrophoresis. The amount of liver cell apoptosis expressed as apoptotic index, ranged between 0.01% to 0.54% and showed a positive correlation with histological activity grading (P <.0005) and with the amount of infiltrating CD8-positive cells (P =. 01). Apoptosis did not correlate with transaminase levels or with HCV load and genotype. These results support the concept that immune-mediated apoptosis may play a role in the pathogenesis of chronic hepatitis C and indicate that this type of reaction may occur in the absence of significant alanine transaminase (ALT) elevation, thus explaining the lack of correlation between biochemical activity and liver histological damage.     

Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C

BACKGROUND: In chronic hepatitis C, it has been suggested that steatosis could accelerate progression of fibrosis. However, results of the few published studies are controversial. Aim: To determine the characteristics (epidemiological, biological, and histological) associated with steatosis and its relationship with liver lesions (grade of necroinflammation and stage of fibrosis) in patients with chronic hepatitis C. METHODS: From November 2000 to July 2001, untreated consecutive adults with chronic hepatitis C admitted for liver biopsy were included in this study. On the day of liver biopsy, a questionnaire for risk factors was completed prospectively, and a blood sample was obtained for laboratory analysis. RESULTS: Our study included 290 patients (143 men, 147 women). Mean body mass index (BMI) was 24 (3.8) kg/m(2). Proportions of patients with genotypes 1 and 3 were, respectively, 48% and 18%. A total of 135 patients (46.6%) had steatosis. Liver steatosis, in multivariate analysis, was associated with hepatitis C virus genotype 3, higher grade of necroinflammation, and higher BMI. There was no significant association between stage of fibrosis and liver steatosis. In multivariate analysis, high stage of fibrosis was associated with male sex, age over 50 years, high BMI, and high grade of necroinflammation. CONCLUSION: In our population of patients with chronic hepatitis C, steatosis does not seem to be an important determinant of liver fibrosis. High grade of necroinflammation is associated with a high stage of fibrosis.     

Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection

Dendritic cells (DCs) are important for the initiation of immune responses to foreign antigens. Their antigen uptake and presentation capacities enable them to prime and activate T cells. Immature DCs capture antigens; however, they must be activated to mature before serving as efficient antigen-presenting cells. The antigen-presenting capacity of DCs can be diminished during viral infection and as a consequence of tumor formation. Chronic infection with hepatitis C virus (HCV) has been shown to affect the allostimulatory function of DCs. In this study, it is demonstrated that monocyte-derived DCs from patients with chronic HCV infection do not respond to maturation stimuli. Instead, they maintain their immature phenotype, reflected by the pattern of cell surface markers and by their continued capacity to uptake antigen. Moreover, their allostimulatory abilities are impaired compared with those of mature DCs derived from healthy donors. To investigate a possible correlation between viral clearance and this DC maturation defect, patients with resolved HCV infection after a course of antiviral therapy were studied. Results demonstrate that DCs from patients who cleared HCV behaved like DCs from healthy donors: in response to maturation stimuli, they decrease antigen uptake, up-regulate expression of appropriate surface markers, and are potent stimulators of allogeneic T cells. (Blood. 2001;97:3171-3176)     

Impaired regulation of serum hepcidin during phlebotomy in patients with chronic hepatitis C

Aim: This study was conducted to determine the clinical relevance of hepcidin, a recently identified key iron regulatory hormone, in patients with chronic hepatitis C virus (C‐HCV). Methods: Serum hepcidin levels were measured in 9 C‐HCV patients by surface‐enhanced laser desorption/ionization time of flight mass spectrometry (SELDI‐TOF‐MS), and compared to those of healthy controls. Sequential changes of hepcidin were also investigated during phlebotomy. Results: Serum hepcidin and ferritin were significantly higher in C‐HCV than in controls (P = 0.0002), these two variables were strongly related to each other (r = 0.658; P < 0.01), and phlebotomy significantly decreased serum hepcidin in C‐HCV (P = 0.0007); all these results recollect the hepcidin response to iron signal. Hepcidin/ferritin ratio, an index of the appropriateness of hepcidin expression relative to iron overload, was significantly lower in C‐HCV than in controls (0.33 ± 0.41 vs. 0.73 ± 0.36, P = 0.0068). This relative impairment of hepcidin expression was not reversible after phlebotomy (P = NS). Conclusions: Although the hepcidin expression responds to iron conditions in C‐HCV, this response is relatively limited. This relative impairment of hepcidin expression may be relevant to disease progression, and thus correction of its regulation may be beneficial for these iron‐overloaded C‐HCV patients.     

重视对慢性病毒性肝炎合并肝脂肪变的研究

慢性乙型肝炎是我国最常见的慢性传染病之一,资料显示,全球至少有20亿人感染过HBV,我国HBV携带率为9.75%,约有1.2亿人感染过HBV.丙型肝炎呈全球性流行,以往文献报道我国一般人群抗HCV阳性率为3.2%,感染者约为4100万,根据中国疾病预防控制中心提供的数据,我国每年的新发丙型肝炎已从2003年的2万多人发展为2005年的近6万人.     

High molecular weight adiponectin correlates with insulin sensitivity in patients with hepatitis C genotype 3, but not genotype 1 infection

BACKGROUND: Obesity is recognized as a cofactor in hepatitis C (HCV) liver injury. Adipokines may be the link between increasing body mass index (BMI) and disease progression in HCV. Adiponectin is an anti-inflammatory adipokine that is present in serum in a range of multimeric forms that appear to have different metabolic functions. METHODS: We studied 30 male patients with untreated chronic HCV (15 each with genotypes 1 and 3) and 12 controls. The three groups were matched for age and BMI. Total adiponectin and high (HMW) and low (LMW) molecular weight adiponectin multimers were measured. The relationships between adiponectin, BMI, insulin sensitivity, and liver histology were examined. RESULTS: Genotype 3 was associated with greater hepatic steatosis and inflammation than genotype 1. Patients with genotype 1 were less insulin sensitive than genotype 3, who had similar insulin sensitivity to controls. Insulin resistance was associated with a decrease in total and HMW adiponectin in both HCV and controls, while LMW adiponectin was unchanged. When the effect of genotype was examined, this association was present with genotype 3 but not genotype 1 infection. CONCLUSIONS: These data demonstrate that the relationship between insulin resistance and adiponectin is similar in controls and patients with genotype 3 but not genotype 1 infection. The greater degree of insulin resistance in genotype 1 appears to be a genotype-specific effect.     

Liver stiffness measured by transient elastography correlates with fibrosis area in liver biopsy in patients with chronic hepatitis C

Aim: Liver stiffness (LS) measured by transient elastography (TE) has been reported to correlate with liver fibrosis, which is usually semiquantitatively assessed. In the present study, the fibrosis area was measured by image analysis software in liver biopsy specimens and its correlation with LS was assessed. Methods: LS was measured by TE in all 165 patients with chronic hepatitis C virus (HCV) infection who underwent liver biopsy consecutively in Fujita Health University Hospital from July 2004 to September 2007. Results: Fibrosis area was significantly correlated with fibrosis stage as assessed by the Metavir score (ρ = 0.733, P < 0.0001). The optimal cut‐off value of fibrosis area was 1.6% for F > or = 2, 3.1% for F > or = 3, and 3.8–6.4% for F4. LS was significantly correlated with fibrosis stage (ρ = 0.734, P < 0.0001). The optimal cut‐off value of LS was 7.1 kPa for F > or = 2, 9.6 kPa for F > or = 3 and 11.6–16.9 kPa for F4. Multiple linear regression analysis selected fibrosis area (P = 0.0002), alanine aminotransferase (ALT) (P = 0.0237), γ‐glutamyltransferase (γ‐GTP) (P = 0.0114), prothrombin time (P = 0.0114) and hyaluronic acid (P < 0.0001) as factors correlating with LS. Conclusion: The correlation between LS and liver fibrosis was confirmed by the objective measurement of fibrosis area. ALT was significantly correlated with LS, suggesting that inflammatory activity also affects LS values. Despite some limitation, LS measurement is a useful method for the diagnosis of liver fibrosis.     

Liver iron deposits in hepatitis B patients: association with severity of liver disease but not with hemochromatosis gene mutations

BACKGROUND AND AIMS: Iron deposits in the liver and abnormalities in serum iron biochemistry are frequently observed in patients with chronic liver diseases, but data for patients with hepatitis B virus (HBV) infection are scarce. Moreover, the role of HFE mutations in iron deposits in this condition remains unknown. The aim of the present study was to determine the prevalence of serum iron biochemical abnormalities and iron deposits in the liver of chronic HBV patients, and to evaluate the consequences for the activity and severity of liver disease. Additionally, we studied the role of HFE gene mutations in iron deposits. METHODS: Eighty-one male non-cirrhotic HBV patients were studied. Serum iron biochemistry, liver enzymes and C282Y/H63D mutations were investigated. Liver biopsies were scored for necroinflammatory activity (histological activity index [HAI]), fibrosis and iron deposits. RESULTS: Elevated transferrin saturation (TS) was found in 27.1% of patients and liver iron deposits in 48.7%; these deposits were mild in 68.4% and moderate in 31.6%. Patients with liver iron deposits exhibited significantly higher scores for HAI and fibrosis than those without iron deposits. HFE mutations were identified in 23.4% of patients (14 H63D heterozygotes, four H63D homozygotes, one compound mutation). No difference in the prevalence of C282Y and H63D mutations was observed between HBV patients (1.2% and 23.4%, respectively) and the general population (4.1% and 27.8%, respectively). No association was detected between HFE mutations and elevated TS or liver iron deposits. CONCLUSIONS: Elevated TS and liver iron deposits were frequent in non-cirrhotic HBV patients. Iron deposits were mainly mild and associated with higher activity and severity of liver disease, but not with HFE mutations.     

慢性丙型肝炎铁代谢的失调机制

肝脏是人体储存铁离子的主要器官,因此铁离子代谢失常与慢性肝炎密切相关。目前,慢性丙型肝炎(CHC)中铁离子过载的机制并没有完全阐明。铁调素调控非常复杂,依赖于许多变量,包括不同阶段的肝脏炎症情况、转铁蛋白参与的铁离子循环以及胞内铁离子储存等,这些因素都与引起HCV相关肝脏疾病患者中铁离子浓度的变化有关。讨论了系统铁离子稳态的调控、CHC与铁离子失调的关系及诱发CHC铁离子过载的机制。认为深入认识铁离子稳态和相关信号通路之间的关系将促进HCV相关疾病的控制与治疗。     

Clinical significance of elevated alpha-fetoprotein (AFP) in patients with chronic hepatitis C, but not hepatocellular carcinoma

BACKGROUND: Although elevated serum alpha-fetoprotein (AFP) is often seen in patients with chronic hepatitis C (CHC), its prevalence, risk factors, and clinical significance remain to be determined. AIMS: The present study assessed the frequency of, the risk factors for, and the clinical significance of elevated AFP in patients with CHC, but not hepatocellular carcinoma. METHODS: This retrospective study utilized systematic chart review and statistical analyses to investigate 357 U.S. patients with CHC from a university medical center and a regional veteran administration medical center. RESULTS: The prevalence of elevated serum AFP (i.e., >/=10.0 microg/L) was 23.0%, including 15.3% (28/183), 24.5% (25/102), and 42.0% (29/69) in patients with chronic hepatitis C and stage 0-II, III, and IV hepatic fibrosis, respectively. After adjusting for age, HCV load, and hepatic steatosis, stage III/IV fibrosis, elevated aspartate aminotransferase (AST), and prolonged prothrombin time as measured by international normalized ratio (INR) remained independently associated with elevated serum AFP in these patients. A serum AFP level of 15.0 microg/L was 22.8% sensitive and 94.5% specific for stage III/IV fibrosis. CONCLUSIONS: In patients with chronic hepatitis C, 23.0% had elevated serum AFP that is independently associated with stage III/IV hepatic fibrosis, elevated level of AST, and prolonged INR.     

Liver regeneration is not altered in patients with nonalcoholic steatohepatitis (NASH) when compared to chronic hepatitis C infection with similar grade of inflammation

Fatty infiltration is associated with an increased incidence of complications and mortality after liver resection and transplantation. The aim of this study was to document the regenerative response in patients with hepatic steatosis and mild inflammatory activity (NASH) and to identify potential levels of impaired regeneration. Ki-67 immunostaining was similar in patients with NASH (ages 44.6 ± 15 years, labeling index, 0.4 ± 0.3%) when compared to patients with chronic hepatitis C infection (ages 50.7 ± 17 years, labeling index; 0.4 ± 0.7%). The labeling index was not increased in patients with a higher level of inflammation, a higher level of fibrosis, and a higher level of fat in either study group. In conclusion, liver regeneration is not altered in patients with nonalcoholic steatohepatitis, suggesting that the delayed postoperative liver failure seen in these patients may be related to another mechanism.     

Duodenal nonheme iron content correlates with iron stores in mice,but the relationship is altered by Hfe gene knock-out

Hereditary hemochromatosis is a common iron-loading disorder found in populations of European descent. It has been proposed that mutations causing loss of function of HFE gene result in reduced iron incorporation into immature duodenal crypt cells. These cells then overexpress genes for iron absorption, leading to inappropriate cellular iron balance, a persistent iron deficiency of the duodenal mucosa, and increased iron absorption. The objective was to measure duodenal iron content in Hfe knock-out mice to test whether the mutation causes a persistent decrease in enterocyte iron concentration. In both normal and Hfe knock-out mice, duodenal nonheme iron content was found to correlate with liver iron stores (P <.001, r = 0.643 and 0.551, respectively), and this effect did not depend on dietary iron levels. However, duodenal iron content was reduced in Hfe knock-out mice for any given content of liver iron stores (P <.001).     

Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C

Hepatic iron has been described in hepatitis C virus (HCV) infection as an important cofactor of disease outcome. The mechanisms leading to hepatic iron deposits (HIDs) in HCV patients are partially understood. We investigated HIDs in the liver biopsies of a consecutive series of 242 HCV-infected patients with well-compensated liver disease. Serum ferritin was elevated in 20.7% and transferrin saturation in 19.0%, while 38.8% had stainable HIDs indicating that serum markers of systemic iron overload have low sensitivity in predicting HIDs in hepatitis C. A cut-off value of serum ferritin (350 microg/L in females and 450 microg/L in males) had good negative predictive value in excluding presence of mild-moderate HIDs (grade II-III). Hepatic iron deposits correlated by multivariate analysis with serum ferritin [odds ratio (OR) 1.008, 95% confidence interval (CI) 1.005-1.011] and albumin (OR 1.15, 95% CI 1.02-1.297). Hepatic iron deposits were more frequent in HCV-3-infected cases than in other genotypes (P = 0.027) while raised serum iron indices were more frequent in non-HCV-3 genotypes (P = 0.02). Furthermore, advanced fibrosis (F3-F4 by METAVIR) was more frequent in non-HCV-3 genotypes (P = 0.04). In HCV-3 cases there was a close association between HIDs and severe (grade II-III) steatosis (P < 0.00001). These results indicate that in well-compensated chronic hepatitis C HIDs are strongly associated with HCV-3 and viral-induced hepatic steatosis, while in the presence of other genotypes they might merely reflect a more advanced stage of liver disease and/or a systemic iron overload. Serum ferritin could identify a subgroup of patients in which the need of venesection could be excluded without liver biopsy.