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Aim: Management of low skeletal muscle mass (LSM) is a very important topic as LSM affects patient mortality in liver diseases. Changes in body composition are unexplored in chronic hepatitis C virus (HCV) patients, including those with liver cirrhosis, who receive direct‐acting antiviral (DAA) therapy. Body composition measurements and liver function tests were carried out before and after DAA therapy. Methods: Blood examination, visceral fat area (VFA) and extremity skeletal muscle mass were measured using the multifrequency bioelectrical impedance analysis method: (i) at 24 weeks before DAA therapy; (ii) at the start of DAA therapy; (iii) at the end of DAA therapy; (iv) at 24 weeks after DAA therapy; and (v) at 48 weeks after DAA therapy. Results: Serum albumin (Alb) levels were significantly increased at 48 weeks post DAA therapy, especially in patients with LSM. Skeletal muscle mass index (SMI) was significantly increased after DAA therapy (at 24 weeks and 48 weeks post DAA therapy) in patients with LSM (P < 0.05). An increase in SMI was associated with an increase in body weight or a decrease in VFA. Conclusions: We continuously measured body composition in HCV‐infected patients who received DAA therapy and found that skeletal muscle mass was significantly increased, associated with an elevation of serum Alb levels and/or body weight or reduction in VFA, but only in patients who presented with LSM before DAA therapy. [ABSTRACT FROM AUTHOR]

To clarify the impact of visceral fat on chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD) and hepatitis C, we investigated the effects of lifestyle modifications on the amount of visceral fat, liver biochemistry and serum ferritin levels in patients with liver disease. Eighty-two patients (NAFLD, n = 37; hepatitis C, n = 45) were advised to adopt lifestyle modifications, including dietary changes and exercise, and these were maintained for 6 months. Bodyweight, percentage of body fat, visceral fat area (VFA) and serum alanine aminotransferase (ALT) and ferritin were measured before and after intervention. In NAFLD, the mean VFA of 134.5 cm was significantly reduced to 125.3 cm after 6 months ( P < 0.001). ALT levels improved significantly between the values measured before and after intervention ( P = 0.039). The VFA prior to intervention was 100 cm in hepatitis C patients and it was reduced significantly after 6 months to 95.6 cm ( P < 0.001). ALT levels also improved significantly in the hepatitis C patients ( P < 0.001). The serum ferritin levels also reduced in these patients. Improvements in serum ALT and ferritin levels correlated with the amount of visceral fat reduction in both groups ( P = 0.046, P = 0.008, respectively). These findings demonstrate that restriction of calorie and iron intake results in reduction of visceral fat, liver enzymes and ferritin in patients with chronic liver disease. Visceral fat may be a central target for future interventions, not only in NAFLD but also in hepatitis C. [ABSTRACT FROM AUTHOR]

Background and Aims: Liver iron accumulation in patients with chronic hepatitis C (CHC) has received increasing attention in recent years. The aim of this study was to determine the prevalence and severity of liver iron deposition in CHC, to assess its relationship with clinical, biochemical and histological characteristics, and to study its influence on the response to interferon (IFN) plus ribavirin combination therapy. Methods: We studied liver biopsy specimens from 103 hepatitis C virus (HCV) and 34 hepatitis B virus (HBV) infected patients and total iron score (TIS) was measured. Seventy patients infected with HCV genotype 1b were treated with IFN/ribavirin for 24 weeks. Results: CHC patients had a significantly higher TIS than chronic hepatitis B (CHB) patients (7.03 ± 5.34 vs 4.41 ± 4.49, P = 0.0056). TIS was significantly correlated with alcohol intake ( P = 0.0213, r = 0.290), transaminase level ( P = 0.0126, r = 0.247), platelet count ( P = 0.0002, r = −0.369), histological grading ( P = 0.0121, r = 0.248) and staging ( P = 0.0003, r = 0.356) in CHC patients. Pretreatment TIS was significantly higher in non-sustained virological responders (SVR) than in SVR to IFN/ribavirin treatment (TIS = 7.69 ± 5.76 vs 4.39 ± 3.27, P = 0.0310). Multiple regression analysis showed that TIS was the only independent variable associated with resistance to IFN/ribavirin ( P = 0.0277). Conclusions: Liver iron deposition was common in CHC compared to CHB and was associated with liver disease progression. Increased hepatic iron stores in CHC were related to resistance to IFN/ribavirin treatment. [ABSTRACT FROM AUTHOR]

It has been reported that histological activity index and piecemeal necrosis are good factors to evaluate the prognosis in patients with chronic hepatitis C (CHC). Thus, there is a need for simple and noninvasive means to assess disease activity and piecemeal necrosis in patients with CHC. In this study, we measured the serum concentrations of large splice variants of tenascin-C (cTN-C) in patients with CHC, and examined their correlation with the degree of inflammatory activity and fibrosis as evaluated in liver biopsy specimens. Methods: The serum levels of cTN-C in 150 patients with CHC and 50 healthy volunteers were measured by enzyme-linked immunosorbent. The histology of liver biopsy specimens was also evaluated following the Desmet's grading/staging system and the Ishak's classification. Liver specimens obtained by biopsy were also immunohistochemically evaluated with anti-human tenascin-C antibodies. Results: Serum cTN-C concentrations were significantly higher in CHC patients than in healthy volunteers ( P<0.0001). The levels of cTN-C showed no significant difference among the fibrosis stages as assessed by the Desmet's grading/staging system and Ishak's classification scores. However, the concentration of cTN-C was significantly correlated with the grade of activity. According to the Ishak's classification, the concentration of cTN-C was increased in proportion to the degree of piecemeal necrosis. Specific immunostaining of cTN-C was observed in limited areas of piecemeal necrosis but not in fibrotic areas. Conclusion: The measurement of serum levels of cTN-C is a useful marker of the activity of CHC, in particular of the degree of piecemeal necrosis. [ABSTRACT FROM AUTHOR]

Iron accumulation has been reported to be associated with progression of liver injury. The mechanism of iron accumulation in the liver is not known. In the present study, hepatic messenger RNA (mRNA) expression oftransferrin receptor(TfR)1,TfR2, andferroportin(FP)1was measured in patients with chronic hepatitis (CH).Eleven patients with CH-B and 43 patients with CH-C were enrolled. All patients underwent liver biopsy. Hepatic expression ofTfR1,TfR2andFP1mRNA was analyzed using a real-time polymerase chain reaction. Total hepatic iron score (THIS) was evaluated by Prussian blue staining.Serum ferritin concentration is significantly higher in CH-C than in CH-B. Values of THIS of≥5 were observed only in CH-C patients (44% of CH-C patients). The expression level ofTfR2mRNA was 10–26-fold higher than theTfR1mRNA expression level. TheTfR2andFP1mRNA expression was significantly higher in CH-C than in CH-B patients. Hepatic expression ofTfR2andFP1mRNA was well correlated with THIS.Hepatic iron accumulation is more severe in patients with CH-C. Upregulation of hepatic iron transporters may contribute to the hepatic iron accumulation in CH-C. [ABSTRACT FROM AUTHOR]

The article describes the use of 8-nitroguanine as a biomarker for evaluating the severity of hepatitis C virus-induced chronic inflammation in relation to hepatocellular carcinoma. Interferon therapy was found to decrease the accumulation of 8-nitroguanine in the liver. This suggests that interferon therapy may prevent hepatocarcinogenesis in hepatitis C virus-induced chronic inflammation.

Presents a letter to the editor about the application of bezafibrate therapy in patients with chronic hepatits C.

Background/Aims: The aim of this study is to determine the clinical relevance of hepatic producing iron regulatory hormone-hepcidin, on iron overload in patients with chronic hepatitis C (CHC). Methods: Serum hepcidin was measured in 73 CHC patients by surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS), and compared to those of healthy controls and anemia of inflammation patients, and analyzed their relationship to hepatic hepcidin mRNA expression levels and clinical, hematological, and histological findings. The sequential changes of hepcidin were investigated in 27 CHC patients treated with a 48 week-course of pegylated-interferon (PEG-IFN) plus ribavirin therapy. Results: Serum hepcidin was positively correlated with hepatic hepcidin mRNA levels, serum ferritin and the degree of hepatic iron deposition in CHC. Serum hepcidin-to-ferritin ratios were significantly lower in HCV positive patients than in HCV negative controls in both hyper- and normal-ferritinemic conditions. This relative impairment of hepcidin production was fully reversible after successful HCV eradication by PEG-IFN plus ribavirin, concomitantly with the improvement of the iron overload condition. Conclusions: The impairment of hepatic hepcidin production occurring with chronic HCV infection may enhance iron toxicity and lead to disease progression, and modulation or supplementation of hepcidin may be beneficial for these conditions in CHC. [Copyright &y& Elsevier]

Abstract: Hepatic oxidative stress occurs in chronic hepatitis C (CH-C), but little is known about its producing mechanisms and precise role in the pathogenesis of the disease. To determine the relevance of hepatic oxidatively generated DNA damage in CH-C, 8-hydroxy-2′-deoxyguanosine (8-OHdG) adducts were quantified in liver biopsy specimens by immunohistochemical staining, and its relationship with clinical, biochemical, and histological parameters, and treatment response was assessed in 40 CH-C patients. Hepatic 8-OHdG counts were significantly correlated with serum transaminase levels (r = 0.560, p = 0.0005) and histological grading activity (p = 0.0013). Remarkably, 8-OHdG levels were also significantly related to body and hepatic iron storage markers (vs serum ferritin, r = 0.565, p = 0.0004; vs hepatic total iron score, r = 0.403, p = 0.0119; vs hepatic hepcidin messenger RNA, r = 0.516, p = 0.0013). Baseline hepatic oxidative stress was more prominent in nonsustained virological responder (non-SVR) than in SVR to interferon (IFN)/ribavirin treatment (50.8 vs 32.7 cells/105 μm2, p = 0.0086). After phlebotomy, hepatic 8-OHdG levels were significantly reduced from 53.4 to 21.1 cells/105 μm2 (p = 0.0125) with concomitant reductions of serum transaminase and iron-related markers in CH-C patients. In conclusion, this study showed that hepatic oxidatively generated DNA damage frequently occurs and is strongly associated with increased iron deposition and hepatic inflammation in CH-C patients, suggesting that iron overload is an important mediator of hepatic oxidative stress and disease progression in chronic HCV infection. [Copyright &y& Elsevier]

Patients with chronic hepatitis C frequently have serum and hepatic iron overload, but the mechanism is unknown. Recently identified hepcidin, exclusively synthesized in the liver, is thought to be a key regulator for iron homeostasis and is induced by infection and inflammation. This study was conducted to determine the hepatic hepcidin expression levels in patients with various liver diseases. We investigated hepcidin mRNA levels of liver samples by real-time detection-polymerase chain reaction; 56 were hepatitis C virus (HCV) positive. 34 were hepatitis B virus (HBV) positive, and 42 were negative for HCV and HBV (3 cases of autoimmune hepatitis, 7 alcoholic liver disease, 13 primary biliary cirrhosis, 9 nonalcoholic fatty liver disease, and 10 normal liver). We analyzed the relation of hepcidin to clinical. hematological, histological, and etiological findings. Hepcidin expression levels were strongly correlated with serum ferritin (P< 0.0001) and the degree of iron deposit in liver tissues (P< 0.0001). Hepcidin was also correlated with hematological parameters (vs. hemoglobin. P= 0.0073; vs. serum iron, P= 0.0012; vs. transferrin saturation, P< 0.0001) and transaminase levels (P = 0.00 13). The hepcidin-to-ferritin ratio was significantly lower in HCV+ patients than in HBV+ patients (P= 0.0129) or control subjects (P= 0.0080). In conclusion, hepcidin expression levels in chronic liver diseases were strongly correlated with either the serum ferritin concentration or degree of iron deposits in the liver. When adjusted by either serum ferritin values or hepatic iron scores, hepcidin indices were significantly lower in HCV+ patients than in HBV+ patients, suggesting that hepcidin may play a pivotal role in the pathogenesis of iron overload in patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

Background/Aims: Nucleic acid damage by reactive nitrogen and oxygen species may contribute to inflammation-related carcinogenesis. To investigate the extent of nucleic acid damage in hepatitis C virus infection and its change after interferon treatment, we measured 8-nitroguanine and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the liver of patients with chronic hepatitis C (CHC) before and after interferon therapy. Methods: Hepatic accumulation of 8-nitroguanine and 8-OHdG was immunohistochemically evaluated in 20 CHC patients and 7 control patients with non-alcoholic fatty liver. Results: Immunoreactivities of 8-nitroguanine and 8-OHdG were strongly detected in the liver from patients with CHC, but not in control livers. 8-Nitroguanine accumulation was found not only in infiltrating inflammatory cells, but also hepatocytes particularly in the periportal area. The accumulation of 8-nitroguanine and 8-OHdG increased with inflammatory grade (8-nitroguanine; P=0.0019, 8-OHdG; P=0.0009). In the sustained virological responder group after interferon therapy, 8-nitroguanine and 8-OHdG accumulation were markedly decreased in the liver (8-nitroguanine; P=0.018, 8-OHdG; P=0.018). Conclusions: In this study, we demonstrated for the first time that 8-nitroguanine accumulated in the liver of patients with CHC. 8-Nitroguanine is a useful biomarker to evaluate the severity of HCV-induced chronic inflammation in relation to hepatocellular carcinoma. [Copyright &y& Elsevier]

Background/Aims: To elucidate the mechanisms of action of interferon (IFN) against hepatitis C virus (HCV), we studied the serum HCV dynamics of free-virions (FV) and immune-complexes (IC) in patients treated with IFN.Methods: FV and IC were separated by immunoprecipitation using anti-human immunoglobulin and quantified serially using real-time detection-polymerase chain reaction.Results: Initially [1st phase (0–24 h)], the FV decreased more rapidly compared to IC [exponential decay slope (EDS)=1.78±0.42 vs. 0.99±0.31 log10/day, P<0.001; half-life=5.65±2.02 vs. 12.5±2.83 h, P<0.0001], but at the 2nd phase (1–14 days), half-life of FV was significantly longer than that of IC (101±117 vs. 14.2±1.08 h, P<0.005). Regarding response to IFN, the decline slope was not significantly different at the 1st phase, but at the 2nd phase, the FV-HCV RNA decreased more slowly in non-responders than in sustained responders to IFN (EDS=0.05±0.02 vs. 0.34±0.19 log10/day, P<0.005; half-life=186±112 vs. 15.3±1.85 h, P<0.005).Conclusions: The presence of escape mutants from the neutralizing antibodies may be involved in resistance to IFN. Analyzes of FV- and IC-HCV dynamics are useful for predicting the IFN efficacy and understanding the mechanism of IFN action in chronic hepatitis patients. [Copyright &y& Elsevier]

Abstract: Ninety seven patients with chronic hepatitis C (CHC) and 72 with non-alcoholic fatty liver disease (NAFLD) were enrolled. Increased visceral fat area (VFA) was associated with high values of HbA1c. The variables associated with a high risk of new-onset diabetes had a VFA>101cm2 in CHC, but not in NAFLD. [Copyright &y& Elsevier]