M2 Macrophages Play Critical Roles in Progression of Inflammatory Liver Disease in Hepatitis C Virus Transgenic Mice

ABSTRACT Macrophages in liver tissue are widely defined as important inflammatory cells in chronic viral hepatitis due to their proinflammatory activity. We reported previously that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) play significant roles in causing chronic hepatitis in hepatitis C virus (HCV) transgenic mice (S. Sekiguchi et al., PLoS One 7: e51656, 2012, http://dx.doi.org/10.1371/journal.pone.0051656 ). In addition, we showed that recombinant vaccinia viruses expressing an HCV nonstructural protein (rVV-N25) could protect against the progression of chronic hepatitis by suppression of macrophage activation. Here, we focus on the role of macrophages in liver disease progression in HCV transgenic mice and examine characteristic features of macrophages following rVV-N25 treatment. The number of CD11b + F4/80 + CD11c − CD206 + (M2) macrophages in the liver of HCV transgenic mice was notably increased compared to that of age-matched control mice. These M2 macrophages in the liver produced elevated levels of IL-6 and TNF-α. rVV-N25 infection suppressed the number and activation of M2 macrophages in liver tissue. These results suggested that inflammatory cytokines produced by M2-like macrophages contribute to the induction of chronic liver inflammation in HCV transgenic mice. Moreover, the therapeutic effect of rVV-N25 might be induced by the suppression of the number and activation of hepatic macrophages. IMPORTANCE HCV causes persistent infections that can lead to chronic liver diseases, liver fibrosis, and hepatocellular carcinoma; the search for an HCV curative is the focus of ongoing research. Recently, effective anti-HCV drugs have been developed; however, vaccine development still is required for the prevention and therapy of infection by this virus. We demonstrate here that M2 macrophages are important for the pathogenesis of HCV-caused liver diseases and additionally show that M2 macrophages contribute to the therapeutic mechanism observed following rVV-N25 treatment.

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Quantitative Analysis of Aldolase A mRNA in Liver Discriminates between Hepatocellular Carcinoma and Cirrhosis

Clinical Chemistry ◽

10.1093/clinchem/46.7.901 ◽

2000 ◽

Vol 46 (7) ◽

pp. 901-906 ◽

Cited By ~ 24

Author(s):

Giuseppe Castaldo ◽

Giuseppe Calcagno ◽

Raffaella Sibillo ◽

Rosario Cuomo ◽

Gerardo Nardone ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Chronic Hepatitis ◽

Quantitative Analysis ◽

Hepatitis C ◽

Liver Tissue ◽

Liver Diseases ◽

Chronic Liver ◽

Chronic Liver Diseases ◽

Liver Biopsies ◽

Aldolase A

Abstract Background: Chronic liver diseases can progress to cirrhosis and to hepatocellular carcinoma. Timely and unequivocal recognition of the neoplastic evolution of cirrhosis is critical. To this aim, we used a noncompetitive reverse transcription-PCR procedure to analyze aldolase A mRNA in liver tissue from patients with chronic liver diseases at different stages. Methods: We studied 12 patients with hepatocellular carcinoma, 19 patients affected by chronic hepatitis C or cirrhosis, and 7 healthy controls. Aldolase A mRNA was reverse-transcribed to cDNA, which was then amplified by PCR. The amplified segments were “read” with a novel dot-blot procedure. A calibrator with the same sequence, synthesized in vitro using a T7 phage promoter, was processed at scalar dilutions in parallel to the target samples to generate a calibration curve and so quantify the target mRNA (detection limit, 0.03 amol; linearity spanning five orders of magnitude). Results: Aldolase A mRNA was ∼10-fold higher in liver biopsies from patients with hepatocellular carcinoma vs patients with chronic hepatitis C or cirrhosis, and healthy individuals. Furthermore, aldolase A mRNA concentrations were 1.2- to 21.3-fold higher in 12 liver biopsies compared with the paired surrounding cirrhotic tissue. Conclusions: The quantitative analysis of liver tissue aldolase A mRNA differentiates between nonneoplastic chronic liver diseases and hepatocellular carcinoma, which suggests that it has diagnostic potential.

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Hepatitis B Virus DNA in Liver Tissue and Risk for Hepatocarcinogenesis in Patients with Hepatitis C Virus-Related Chronic Liver Disease

Intervirology ◽

10.1159/000121363 ◽

2008 ◽

Vol 51 (1) ◽

pp. 59-68 ◽

Cited By ~ 16

Author(s):

Mikako Obika ◽

Toshiyuki Shinji ◽

Shin-ichi Fujioka ◽

Ryo Terada ◽

Hiromasa Ryuko ◽

...

Keyword(s):

Hepatitis C Virus ◽

Liver Disease ◽

Hepatitis C ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Liver Disease ◽

Liver Tissue ◽

Chronic Liver ◽

Hepatitis B Virus Dna ◽

B Virus

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Burden of Liver Diseases: A Review from Iran

Middle East Journal of Digestive Diseases ◽

10.15171/mejdd.2019.147 ◽

2019 ◽

Vol 11 (4) ◽

pp. 189-191

Author(s):

Amir Anushiravani ◽

Sadaf Ghajarieh Sepanlou

Keyword(s):

Chronic Hepatitis ◽

Liver Disease ◽

Hepatitis C ◽

Hepatitis B ◽

Fatty Liver Disease ◽

Liver Diseases ◽

Chronic Liver ◽

Chronic Liver Diseases ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

There has been an increase in the burden of liver diseases in Iran, with an increasing trend from communicable to non-communicable diseases. Almost 5400 deaths were due to chronic liver diseases in 2017. We aim to provide a concise update on the epidemiological trends of liver diseases in Iran. Estimations of deaths, disability-adjusted life years, prevalence of chronic liver diseases and cirrhosis in Iran with its common etiologies have been reported. We investigated the major causes of chronic liver diseases in Iran, we have reported our hepatology research centers, and also we have depicted the future of liver diseases in Iran. In 2017, there was a rising trend in chronic liver diseases in Iran. The most common etiologies for chronic liver disease were chronic hepatitis B, chronic hepatitis C, and non-alcoholic steatohepatitis with highest mortalities due to liver cancer and hepatitis C. The prevalence of HBV infection has decreased from 2.9% to 1.3% with effective vaccination, but new cases are still seen due to perinatal transmission. Treatment of HCV has dramatically changed with new drugs which are being produced by local pharmaceuticals at a low cost. The main obstacle in its elimination is finding patients and linkage to care. More than a third of our population have non-alcoholic fatty liver disease in which central obesity had a stronger association than weight itself. Iran has a high burden of liver diseases. The Ministry of Health has effectively controlled hepatitis B and is working towards the World Health WHO’s goals for hepatitis C by 2030. This being said, non-alcoholic fatty liver disease is becoming a major threat to our nation’s health and quality of life.

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Iron Overload andHFEGene Mutations in Czech Patients with Chronic Liver Diseases

Disease Markers ◽

10.1155/2012/790464 ◽

2012 ◽

Vol 32 (1) ◽

pp. 65-72 ◽

Cited By ~ 7

Author(s):

Marketa Dostalikova-Cimburova ◽

Karolina Kratka ◽

Jaroslav Stransky ◽

Ivana Putova ◽

Blanka Cieslarova ◽

...

Keyword(s):

Chronic Hepatitis ◽

Liver Disease ◽

Hepatitis C ◽

Hepatitis B ◽

Iron Overload ◽

Alcoholic Liver Disease ◽

Liver Diseases ◽

Gene Mutations ◽

Chronic Liver ◽

Chronic Liver Diseases

The aim of the study was to identify the prevalence ofHFEgene mutations in Czech patients with chronic liver diseases and the influence of the mutations on iron status. The presence ofHFEgene mutations (C282Y, H63D, and S65C) analyzed by the PCR-RFLP method, presence of cirrhosis, and serum iron indices were compared among 454 patients with different chronic liver diseases (51 with chronic hepatitis B, 122 with chronic hepatitis C, 218 with alcoholic liver disease, and 63 patients with hemochromatosis). Chronic liver diseases patients other than hemochromatics did not have an increased frequency ofHFEgene mutations compared to controls. Although 33.3% of patients with hepatitis B, 43% of patients with hepatitis C, and 73.2% of patients with alcoholic liver disease had elevated transferrin saturation or serum ferritin levels, the presence ofHFEgene mutations was not significantly associated with iron overload in these patients. Additionally, patients with cirrhosis did not have frequencies ofHFEmutations different from those without cirrhosis. This study emphasizes the importance, not only of C282Y, but also of the H63D homozygous genetic constellation in Czech hemochromatosis patients. Our findings show that increased iron indices are common in chronic liver diseases butHFEmutations do not play an important role in the pathogenesis of chronic hepatitis B, chronic hepatitis C, and alcoholic liver disease.

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Hepatitis C virus infection and chronic liver disease in children with leukemia in long-term remission

Blood ◽

10.1182/blood.v78.6.1619.1619 ◽

1991 ◽

Vol 78 (6) ◽

pp. 1619-1622 ◽

Cited By ~ 44

Author(s):

A Locasciulli ◽

G Gornati ◽

A Tagger ◽

ML Ribero ◽

D Cavalletto ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C Virus ◽

Liver Disease ◽

Hepatitis C ◽

Chronic Liver Disease ◽

Chronic Liver ◽

Enzyme Linked Immunosorbent Assay ◽

Positive Group ◽

Group A ◽

Group B

Abstract Antibody to the recently identified hepatitis C virus (HCV) was investigated in sera of 50 leukemic children who had chronic liver disease (CLD), observed for 1 to 12.6 years after therapy withdrawal. All patients were tested for anti-HCV at regular intervals: Ortho- enzyme-linked immunosorbent assay (ELISA) test was performed in all cases. Reactive sera were also tested by recombinant immunoblotting assay to define the specificity of the results obtained by ELISA. Twelve cases (24%) were persistently positive (group A), 11 (22%) were transiently anti-HCV+ positive (group B), and 27 (54%) were negative. Mean SGPT peak during follow-up was significantly higher in group A (P = .014, A v B and P less than .00001, A v C). SGPT normalized off- therapy in 1 of 12 cases (group A), 10 of 11 (group B), and 19 of 27 (group C) (P = .0004, A v B and P = .012, A v C). Accordingly, liver histology, available in 37 patients, showed signs of chronic hepatitis in all patients in group A while most patients in group B and C had less severe liver lesions. These results indicate that HCV plays a significant role in the etiology of chronic hepatitis in leukemic patients and that persistent anti-HCV activity correlates with a more severe CLD, which could jeopardize the final prognosis of children cured of leukemia.

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Hepatitis C virus infection and chronic liver disease in children with leukemia in long-term remission

Blood ◽

10.1182/blood.v78.6.1619.bloodjournal7861619 ◽

1991 ◽

Vol 78 (6) ◽

pp. 1619-1622 ◽

Cited By ~ 2

Author(s):

A Locasciulli ◽

G Gornati ◽

A Tagger ◽

ML Ribero ◽

D Cavalletto ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C Virus ◽

Liver Disease ◽

Hepatitis C ◽

Chronic Liver Disease ◽

Chronic Liver ◽

Enzyme Linked Immunosorbent Assay ◽

Positive Group ◽

Group A ◽

Group B

Antibody to the recently identified hepatitis C virus (HCV) was investigated in sera of 50 leukemic children who had chronic liver disease (CLD), observed for 1 to 12.6 years after therapy withdrawal. All patients were tested for anti-HCV at regular intervals: Ortho- enzyme-linked immunosorbent assay (ELISA) test was performed in all cases. Reactive sera were also tested by recombinant immunoblotting assay to define the specificity of the results obtained by ELISA. Twelve cases (24%) were persistently positive (group A), 11 (22%) were transiently anti-HCV+ positive (group B), and 27 (54%) were negative. Mean SGPT peak during follow-up was significantly higher in group A (P = .014, A v B and P less than .00001, A v C). SGPT normalized off- therapy in 1 of 12 cases (group A), 10 of 11 (group B), and 19 of 27 (group C) (P = .0004, A v B and P = .012, A v C). Accordingly, liver histology, available in 37 patients, showed signs of chronic hepatitis in all patients in group A while most patients in group B and C had less severe liver lesions. These results indicate that HCV plays a significant role in the etiology of chronic hepatitis in leukemic patients and that persistent anti-HCV activity correlates with a more severe CLD, which could jeopardize the final prognosis of children cured of leukemia.

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Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Journal of Virology ◽

10.1128/jvi.00619-16 ◽

2016 ◽

Vol 90 (14) ◽

pp. 6387-6400 ◽

Cited By ~ 56

Author(s):

Simonetta Bandiera ◽

Sophie Pernot ◽

Hussein El Saghire ◽

Sarah C. Durand ◽

Christine Thumann ◽

...

Keyword(s):

Hepatitis C Virus ◽

Liver Disease ◽

Hepatitis C ◽

Viral Infection ◽

Chronic Liver Disease ◽

Mirna Expression ◽

Liver Tissue ◽

Chronic Liver ◽

Hcv Infection ◽

Disease Pathogenesis

ABSTRACTHepatitis C virus (HCV)-induced chronic liver disease is a leading cause of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in homeostasis within the liver, and deregulation of miRNAs has been associated with liver disease, including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here we combined a hepatocyte-like cell-based model system, high-throughput small RNA sequencing, computational analysis, and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least 2-fold, including miRNAs that were previously described to target genes associated with inflammation, fibrosis, and cancer development. Further investigation demonstrated that the miR-146a-5p level was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes, as well as in liver tissue from HCV-infected patients. Genome-wide microarray and computational analyses indicated that miR-146a-5p overexpression modulates pathways that are related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p has a positive impact on late steps of the viral replication cycle, thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease.IMPORTANCEHCV is a leading cause of chronic liver disease and cancer. However, how HCV induces liver cancer remains poorly understood. There is accumulating evidence that a viral cure does not eliminate the risk for HCC development. Thus, there is an unmet medical need to develop novel approaches to predict and prevent virus-induced HCC. miRNA expression is known to be deregulated in liver disease and cancer. Furthermore, miRNAs are essential for HCV replication, and HCV infection alters miRNA expression. However, how miRNAs contribute to HCV-driven pathogenesis remains elusive. Here we show that HCV induces miRNAs that may contribute to liver injury and carcinogenesis. The miR-146a-5p level was consistently increased in different cell-based models of HCV infection and in HCV patient-derived liver tissue. Furthermore, miR-146a-5p increased HCV infection. Collectively, our data are relevant to understanding viral pathogenesis and may open perspectives for novel biomarkers and prevention of virus-induced liver disease and HCC.

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Vitamin A deficiency in patients with hepatitis C virus-related chronic liver disease

British Journal Of Nutrition ◽

10.1017/s0007114511002145 ◽

2011 ◽

Vol 106 (11) ◽

pp. 1724-1731 ◽

Cited By ~ 31

Author(s):

W. A. F. Peres ◽

G. V. Chaves ◽

J. C. S. Gonçalves ◽

A. Ramalho ◽

H. S. M. Coelho

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C Virus ◽

Liver Disease ◽

Hepatitis C ◽

Vitamin A ◽

Nutritional Status ◽

Chronic Liver Disease ◽

Vitamin A Deficiency ◽

Chronic Liver ◽

Serum Retinol

Hepatitis C virus (HCV) infection is associated with oxidative stress and vitamin A possesses antioxidant activity. The objective of the present study was to investigate vitamin A nutritional status in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC), according to biochemical, functional and dietetic indicators correlating these findings with liver function, liver damage and death. Vitamin A nutritional status was analysed by serum retinol levels, dietetic indicators and functional indicators. A total of 140 patients with HCV-related liver disease were enrolled. Vitamin A deficiency was detected in 54·3 % of all patients, and there was a progressive drop in serum retinol levels from chronic hepatitis C patients towards cirrhosis and HCC patients. Increased total bilirubin, liver transaminases and prothrombin time, presence of hepatic encephalopathy and ascites were related to reduced serum retinol levels, and values ≤ 0·78 μmol/l of serum retinol were associated with liver-related death. A high prevalence of inadequate intake of vitamin A was observed in all stages of chronic liver disease. The functional indicator was not an adequate parameter for evaluating the vitamin A nutritional status. Therefore, serum retinol concentration is related to severity of the disease, liver complications and mortality. The effectiveness of nutritional counselling and measures of intervention in this group in improving vitamin A nutritional status should be examined further in a controlled study.

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