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Background and Aim: Direct-acting antiviral (DAA) therapies have been proven to be highly effective for the eradication of hepatitis C virus (HCV) without resistance-associated substitutions (RASs). However, even in cases with no detected RASs, treatment sometimes fails, suggestive of the existence of some host-related factors involved in HCV eradication by DAAs. To explore such factors, we analyzed the serum microRNAs (miRNAs) of patients who received DAA treatment., Methods: The serum miRNA expression levels of 39 patients with chronic HCV infection without any detectable RASs, who achieved sustained virological response with asunaprevir/daclatasvir or grazoprevir/elbasvir therapy, were investigated cyclopedically, using oligonucleotide microarrays. The effects of specific miRNAs on the replication of HCV were measured in the HCV genomic replicon containing Huh-7 hepatoma cells., Results: Along with the disappearance of HCV, the expression quantiles of 16 miRNAs in the asunaprevir/daclatasvir group and 18 miRNAs in the grazoprevir/elbasvir group showed a tendency to increase or decrease. Among these molecules, adjustments for multiple testing yielded a significant differential expression at a false discovery rate of less than 5% for only one molecule, hsa-miR-762. Its expression quantile increased after HCV exclusion in all patients who had achieved sustained virological response. Quantitative polymerase chain reaction analysis validated a significant increase in the serum hsa-miR-762 after disappearance of HCV. On the contrary, hsa-miR-762 was decreased in the relapse and breakthrough of HCV in DAA failures. Transfection of hsa-miR-762 into cultured HCV-infected hepatocytes significantly decreased HCV-RNA replication., Conclusion: These data suggest that hsa-miR-762 is one of the host factors participating in HCV exclusion by DAA therapy., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: We investigated the correlation between serum complement component 3 (C3) levels and metabolic and histological abnormalities in patients with chronic hepatitis C (CH-C)., Methods: Obesity and insulin resistance were estimated by calculating body mass index (BMI) and the values of the homeostasis model for assessment of insulin resistance (HOMA-IR), respectively. Severity of hepatic steatosis and fibrosis were evaluated by New Inuyama Classification and the classification proposed by Brunt and colleagues, respectively. The degree of hepatic C3 expression was examined, using an immunohistochemical procedure., Results: Serum C3 levels were significantly correlated with BMI, HOMA-IR value, and serum triglyceride levels in CH-C patients. Histological analysis revealed that serum C3 levels were significantly elevated in proportion to the severity of hepatic steatosis in such patients. The serum C3 level tended to increase as the severity of hepatic fibrosis progressed. However, the degree of C3 expression in hepatocytes was not associated with serum C3 level among those patients., Conclusions: These results suggest that the elevation of serum C3 levels may reflect obesity, insulin resistance, and/or hepatic steatosis in patients with CH-C, and that the increase in the synthesis of C3 may derive from the activation of cells other than hepatocytes in those patients., (© 2019 by the Association of Clinical Scientists, Inc.)

Background: The real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1., Methods: The rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics., Results: Overall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment., Conclusions: The EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen.

Combination therapy with ledipasvir and sofosbuvir (LDV/SOF), direct-acting antiviral agents, is highly effective against hepatitis C virus genotype 1 infection. Although LDV/SOF is safer than conventional treatment, reports have indicated that LDV/SOF was discontinued in certain cases due to severe skin disorders. A 68-year-old woman presented with a rash after starting LDV/SOF treatment. We interrupted LDV/SOF and began the oral administration of prednisolone (PSL). After the rash improved, we re-started LDV/SOF with PSL. After treatment, the rash clearly improved; we checked for a sustained virologic response 12 weeks after treatment. Steroids may therefore be an effective treatment option for controlling the side effects of LDV/SOF.

Background: Anticentromere antibodies (ACAs) have been observed in patients with autoimmune hepatitis (AIH) and hepatitis C virus (HCV)-related chronic liver disease (CLD-C) as well as those with primary biliary cirrhosis (PBC). However, little is known about the differences in immune responses to the centromere proteins among these liver diseases., Objective: By synthesizing recombinant proteins consisting of the N- and C-termini of major centromere proteins, we investigated the humoral responses against them in each disease., Results: Eight of the 754 (1%) patients with CLD-C, 14 of the 57 (25%) patients with PBC and six of the 38 (16%) patients with AIH were seropositive for ACAs. There were no significant differences in ACA titers determined by an indirect immunofluorescent method among the groups of patients with CLD-C, PBC and AIH. However, the analysis of immunoreactivities against each recombinant protein revealed that the titers of IgG-subclass autoantibodies against the C-terminus of centromere protein (CENP)-B were significantly higher in the CLD-C patients than in the AIH patients. Likewise, the titers of IgM-subclass autoantibodies against the N-terminus of CENP-A were significantly higher in the PBC group than in the CLD-C group. The ACA-positive patients who developed liver cirrhosis had significantly higher titers of the IgA-subclass autoantibodies against the C-terminus of CENP-C than those who did not., Conclusion: These findings suggest that immunoreactivities against the fragments of centromere proteins show distinct patterns among CLD-C, PBC and AIH and that the determination of immunoreactivities against the centromere proteins may be useful for the prediction of disease progression., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The role of zinc (Zn) in hepatic steatosis of patients with HCV-related chronic liver disease (CLD-C) remains uncertain, although persistent HCV infection often evokes hepatic steatosis. The primary purpose of this study was to elucidate the contribution of Zn deficiency to hepatic steatosis in patients with CLD-C. Fifty nondiabetic patients with CLD-C were enrolled. Hepatic 4-hydroxy-2-nonenal (4-HNE) expression was examined using an immunohistochemical procedure as a marker for lipid peroxidation. Serum ferritin levels were assessed for iron overload. Insulin resistance was evaluated using the values of the homeostasis model for assessment of insulin resistance (HOMA-IR). The severity of hepatic steatosis was graded on the classification system proposed by Brunt and colleagues. Serum Zn levels were inversely correlated with serum ferritin levels in the patients with CLD-C (r = -0.382, p = 0.0062). Serum ferritin levels were strongly associated with the HOMA-IR values (r = 0.476, p = 0.0005). Therefore, Zn deficiency resulted in insulin resistance through iron overload. Moreover, serum Zn levels were significantly decreased in proportion to the level of hepatic 4-HNE expression, which was enhanced as hepatic steatosis developed. Then, Zn deficiency eventually seemed to exacerbate hepatic steatosis by way of an increase in lipid peroxidation. However, the serum Zn levels were not associated with either loads of HCV-RNA or HCV genotypes. These data suggest that, in patients with CLD-C, Zn deficiency promotes insulin resistance by exacerbating iron overload in the liver and induces hepatic steatosis by facilitating lipid peroxidation.

Recent studies have elucidated a lower level of serum insulin-like growth factor-I (IGF-I) or a decrease in the IGF-I/IGF-binding protein-3 (IGFBP-3) ratio in patients with type 2 diabetes mellitus or hepatic steatosis. Persistent hepatitis C virus (HCV) infection often evokes metabolic abnormalities including hepatic steatosis and insulin resistance. We hypothesized that the relationship between the ratio of IGF-I/IGFBP-3 and the severity of hepatic steatosis or insulin resistance would be observed in patients with HCV-related chronic liver disease (CLD). On the basis of the classifications proposed by Brunt and colleagues (Am J Gastroenterol 1999; 94: 2467-2474), among the 42 enrolled patients with HCV-related CLD, 23 of them had no hepatic steatosis (grade 0), 14 had grade 1 steatosis, and 5 had grade 2 steatosis. The levels of serum IGF-I in the enrolled patients declined in proportion to the severity of hepatic steatosis, whereas serum IGFBP-3 levels did not affect its severity. Therefore, the ratio of IGF-I/IGFBP-3, which corresponds to the circulating free IGF-I status, was significantly lower in those patients with hepatic steatosis (grades 1 and 2) than in those without hepatic steatosis. Serum IGF-I levels significantly correlated with serum zinc levels (r = 0.370, P = .0266), but IGFBP-3 levels did not. However, the linear regression analysis revealed an inverse correlation between the IGF/IGFBP-3 ratio and the value of homeostasis model for assessment of insulin resistance (r =-0.411, P = .0094). These findings suggest that the decline of the circulating free IGF-I level, which derives from zinc deficiency, may contribute to hepatic steatosis and insulin resistance in patients with HCV-related CLD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The significance of antibodies to cardiolipin (anti-CL) remains uncertain in patients with chronic hepatitis C (CH-C). The main purpose of this study was to elucidate the clinical characteristics of patients with CH-C seropositive for anti-CL. The prevalence of anti-CL and clinical parameters associated with anti-CL in those patients were examined. Six of the 45 (13%) patients with CH-C had anti-CL. However, none of these six CH-C patients fulfilled the criteria for antiphospholipid syndrome. Serum triglyceride and apolipoprotein B (ApoB) levels in CH-C patients with anti-CL were significantly higher than those in CH-C patients without anti-CL. Serum triglyceride levels positively correlated with serum ApoB levels. CH-C patients with anti-CL had significantly more progressive hepatic fibrosis than those without anti-CL. The degree of 8-hydroxy 2'-deoxyguanosine (8-OHdG) expression in the liver tissue was more severe in CH-C patients with anti-CL than in those without it. However, the emergence of anti-CL in CH-C patients was independent of insulin resistance, hepatic steatosis, and iron overload. These findings suggest that the emergence of anti-CL is associated with oxidative stress and that CH-C patients seropositive for anti-CL have clinical characteristics of hypertriglyceridemia, which derives from the facilitation of ApoB synthesis, and progressive hepatic fibrosis., (© 2012 Wiley Periodicals, Inc.)

The relationship between selenium (Se) deficiency and insulin resistance has not much been established in persistent hepatitis C virus (HCV) infection, although Se deficiency is often observed in patients with liver cirrhosis. We hypothesized that the decreased serum Se levels were associated with the severity of hepatic fibrosis or insulin resistance in patients with HCV-related chronic liver disease (CLD). To test the hypothesis, 52 patients with HCV-related CLD including chronic hepatitis and liver cirrhosis were enrolled in this study. The severity of hepatic fibrosis was divided into 4 categories (F(1) through F(4)) according to the new Inuyama classification. Insulin resistance was defined by the homeostasis model for assessment of insulin resistance value. Serum Se levels significantly declined in proportion to the severity of hepatic fibrosis and were positively correlated with serum albumin (r = 0.372, P = .0065) and zinc (r = 0.403, P = .0081) concentrations. Serum Se levels were also linked to glutathione peroxidase activities in the sera of the enrolled patients (r = 0.374, P = .0148). By contrast, serum Se levels were inversely correlated with the homeostasis model for assessment of insulin resistance values (r = -0.304, P = .0338). However, serum Se levels were independent of HCV genotype and loads of HCV-RNA. These findings suggest that Se deficiency was associated with the severity of hepatic fibrosis in patients with HCV-related CLD and that Se deficiency was likely to be one of the factors contributing to insulin resistance in those patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The association between anticentromere antibody (ACA) and hepatitis C virus (HCV) infection remains unclear. We subjected eight patients with HCV-related chronic liver disease (CLD) seropositive for ACA to a battery of clinical and laboratory tests. The patient cohort was dominated by females, and four of the eight (50%) patients had a concomitant autoimmune disease. All of the patients had high titers of ACA (>or=1:320). The histological activity index scores in chronic hepatitis C (CH-C) patients with ACA were significantly higher than those in CH-C patients without antinuclear antibody (ANA) (12.8 +/- 1.8 vs. 8.3 +/- 4.5, P = 0.0372). The frequency of human leukocyte antigen (HLA) DR-8 in patients with HCV-related CLD seropositive for ACA was significantly higher than that in patients with CH-C seronegative for ANA (71 vs. 18%, P = 0.0108). These findings suggest that ACA is induced by chronic HCV infection in association with HLA DR-8, and that CH-C patients with ACA exhibit more severe hepatic fibrosis and inflammation than CH-C patients without ANA.

Aim: Albumin–bilirubin (ALBI) grade was investigated to predict prognosis of patients with cirrhosis. It was defined using the ALBI score calculated based on serum total bilirubin and albumin, which represent liver function. The diagnostic accuracy for liver fibrosis staging in patients with chronic hepatitis using the ALBI score has not been investigated well. This study aimed to evaluate the diagnostic abilities of the ALBI score for liver fibrosis staging in chronic hepatitis and cirrhosis in Japanese patients with hepatitis C virus (HCV) infection. Methods: Japanese patients with HCV infection who underwent liver biopsy examinations were enrolled in a retrospective study. Fibrosis staging and activity grading were assessed using the modified METAVIR score. The ALBI score was calculated according to the following equation: Log10 total bilirubin (μmol/L) × 0.66 + albumin (g/L) × (−0.085). Results: A total of 382 patients were enrolled in this study. The ALBI score differentiated fibrosis stage 4 from 3 and stage 3 from 2 (P < 0.05). When an ALBI score of −2.125 was adopted as a cut‐off value, the sensitivity and specificity were 73.2% and 87.1%, respectively, with a positive likelihood ratio of 5.67 to differentiate stage 4 from stages 1–3. Kaplan–Meier analysis showed that smaller ALBI scores at baseline correlated with better hepatocellular carcinoma (HCC)‐free and overall survival (P < 0.05). Conclusions: The ALBI score indicates liver fibrosis staging in Japanese patients with HCV infection. Furthermore, smaller ALBI scores predict better HCC‐free survival and overall survival. The ALBI score has the potential to expand its application from cirrhosis to chronic hepatitis. [ABSTRACT FROM AUTHOR]