Virus-induced Chronic Liver Disease Research Articles

LI-RADS v2018 major criteria: Do hepatocellular carcinomas in non-alcoholic steatohepatitis differ from those in virus-induced chronic liver disease on MRI?

PurposeLI-RADS v2018 diagnostic system is used to diagnose hepatocellular carcinoma (HCC) in at risk patients. However, its applicability to HCC in non-alcoholic steatohepatitis (NASH) has not been specifically studied. The purpose of this study was to assess the applicability of LI-RADS v2018 diagnostic system for HCC in patients with NASH. Materials and methodsThe MRI examinations of 41 patients with HCC and NASH (NASH group) were reviewed and compared to those obtained in 41 patients with HCC and virus-induced chronic liver disease (Virus group). MRI examinations of the two groups were compared for imaging presentation, LI-RADS major criteria and LI-RADS categorization. Qualitative variables were compared using Fisher exact test and quantitative variables using Mann-Whitney U test Interreader agreement was assessed using kappa statistic. ResultsNo significant differences in qualitative and quantitative variables were observed between the two groups. Most common findings in the two groups were hyperenhancement during the arterial phase and visibility on T2-weighted images (93 % vs. 98 %, P = 0.616 and 85 % vs. 88 %, P = 1.000 for NASH group and Virus group, respectively). No differences in prevalence between the two groups were found for any major LI-RADS v2018 criterion. Interreader agreement for LI-RADS categorization was strong for the NASH group (kappa = 0.802) and moderate for the virus group (kappa = 0.720). No differences were found between the two groups for LI-RADS categories (P = 0.303). ConclusionsThe LI-RADS v2018 diagnostic algorithm can be applied in patients with NASH.

Gut microbiota dysbiosis in patients with hepatitis B virus-induced chronic liver disease covering chronic hepatitis, liver cirrhosis and hepatocellular carcinoma.

The information regarding the effect of hepatitis B virus (HBV) infection on gut microbiota and the relationship between gut microbiota dysbiosis and hepatitis B virus-induced chronic liver disease (HBVCLD) is limited. In this study, we aimed at characterizing the gut microbiota composition in the three different stages of hepatitis B virus-induced chronic liver disease patients and healthy individuals. Faecal samples and clinical data were collected from HBVCLD patients and healthy individuals. The 16S rDNA gene amplification products were sequenced. Bioinformatic analysis including alpha diversity and PICRUSt was performed. A total of 19 phyla, 43 classes, 72 orders, 126 families and 225 genera were detected. The beta-diversity showed a separate clustering of healthy controls and HBVCLD patients covering chronic hepatitis (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC); and gut microbiota of healthy controls was more consistent, whereas those of CHB, LC and HCC varied substantially. The abundance of Firmicutes was lower, and Bacteroidetes was higher in patients with CHB, LC and HCC than in healthy controls. Predicted metagenomics of microbial communities showed an increase in glycan biosynthesis and metabolism-related genes and lipid metabolism-related genes in HBVCLD than in healthy individuals. Our study suggested that HBVCLD is associated with gut dysbiosis, with characteristics including, a gain in potential bacteria and a loss in potential beneficial bacteria or genes. Further study of CHB, LC and HCC based on microbiota may provide a novel insight into the pathogenesis of HBVCLD as well as a novel treatment strategy.

Kronik viral hepatitler, karaciğer sirozu ve hepatosellüler karsinomada inflamasyon göstergesi olarak neopterin

Background and Aims: Neopterin is a proinflammatory indicator that plays a role in cell-mediated immunity, and elevated concentrations of neopterin indicate the presence of interferon-γ in body fluids. In this study, neopterin concentrations were determined in patients with a virus-induced chronic liver disease (chronic hepatitis, liver cirrhosis, and hepatocellular cancer), inactive hepatitis B virus carriers, and in a healthy control group to assess whether neopterin can be used as a disease marker in patients with virus-induced chronic liver disease. Materials and Methods: A total of 110 subjects (42 females and 68 males, with an average age of 44±8.90 years) were included in this study. Of these patients, 33 had chronic hepatitis; 22, liver cirrhosis; 22, hepatoma; 18, inactive hepatitis B virus carriers; and 15 were included in the healthy control group. Neopterin levels were measured before and after interferon treatment in patients with chronic hepatitis. Data collected among the groups were analyzed statistically using the Mann-Whitney test, considering p < 0.05 as statistically significant. Results: Neopterin concentrations and gender showed no statistically significant correlation. Patients with cirrhosis, hepatocellular cancer, and chronic hepatitis had statistically significantly higher neopterin levels than the healthy control and healthy carrier groups. A positive correlation was observed between neopterin levels and other disease activity indicators such as aspartate transaminase, alanine transaminase, hepatitis B virus deoxyribonucleic acid, hepatitis C virus ribonucleic acid, erythrocyte sedimentation rate, and C-reactive protein levels, and their levels were also high. Although 14 patients, who were also evaluated after interferon treatment, showed good response to the treatment, no statistically significant correlation was observed between their neopterin levels and disease activity indicator levels. Conclusion: Neopterin concentrations were found to be significantly higher in patients with inflammation than in inactive hepatitis B virus carriers who had no ongoing inflammatory activity and in the healthy control group. No correlation was detected between neopterin levels and hepatitis B virus deoxyribonucleic acid and hepatitis C virus ribonucleic acid levels in patients who received interferon treatment and benefitted from it. Although neopterin levels indicate inflammatory activity in cases of chronic hepatitis, liver cirrhosis, and hepatocellular cancer, additional studies are necessary to determine its usefulness in clinical practice.

Liver Surface Nodularity Quantification from Routine CT Images as a Biomarker for Detection and Evaluation of Cirrhosis

Purpose To determine the accuracy, reproducibility, and intra- and interobserver agreement of a computer-based quantitative method to measure liver surface nodularity (LSN) from routine computed tomographic (CT) images as a biomarker for detection and evaluation of cirrhosis. Materials and Methods For this institutional review board-approved HIPAA-compliant retrospective study, adult patients with healthy livers (n = 24) or various stages of hepatitis C virus-induced chronic liver disease (n = 70) with routine nonenhanced and portal venous phase contrast agent-enhanced liver CT imaging with thick-section (5.0 mm) and thin-section (1.25-1.50 mm) axial images obtained between January 1, 2006, and March 31, 2011, were identified from the electronic medical records. A computer algorithm was developed to measure LSN and derive a score. LSN scores, splenic volume, and the ratio of left lateral segment (LLS) to total liver volume (TLV) were measured from the same multiphasic liver CT examinations. Accuracy for differentiating cirrhotic from noncirrhotic livers was assessed by area under the receiver operating characteristic curve. Intra- and interobserver agreement was assessed by intraclass correlation coefficient. Results Median LSN scores from nonenhanced thick-section CT images in cirrhotic livers (3.16; 56 livers) were significantly higher than in noncirrhotic livers (2.11; 38 livers; P < .001). LSN scores from the four CT imaging types (94 patients for each type) were very strongly correlated (range of Spearman r, 0.929-0.960). LSN scores from portal venous phase contrast-enhanced thick-section CT images had significantly higher accuracy (area under the receiver operating characteristic curve, 0.929) than splenic volume (area under the receiver operating characteristic curve, 0.835) or LLS-to-TLV ratio measurements (area under the receiver operating characteristic curve, 0.753) for differentiating cirrhotic from noncirrhotic livers (P = .038 and .003, respectively; n = 94). Intra- and interobserver agreements that used nonenhanced thick CT images were very good (intraclass correlation coefficient, 0.963 and 0.899, respectively). Conclusion Quantitative measurement of LSN on routine CT images accurately differentiated cirrhotic from noncirrhotic livers and was highly reproducible. (©) RSNA, 2016 Online supplemental material is available for this article.

Decreased Diversity of the Oral Microbiota of Patients with Hepatitis B Virus-Induced Chronic Liver Disease: A Pilot Project.

Increasing evidence suggests that altered gut microbiota is implicated in the pathogenesis of hepatitis B virus-induced chronic liver disease (HBV-CLD). However, the structure and composition of the oral microbiota of patients with HBV-CLD remains unclear. High-throughput pyrosequencing showed that decreased oral bacterial diversity was found in patients with HBV-CLD. The Firmicutes/Bacteroidetes ratio was increased significantly, which indicated that dysbiosis of the oral microbiota participated in the process of HBV-CLD development. However, the changing patterns of the oral microbiota in patients with HBV-induced liver cirrhosis (LC) were almost similar to patients with chronic hepatitis B (CHB). HBV infection resulted in an increase in potential H2S- and CH3SH-producing phylotypes such as Fusobacterium, Filifactor, Eubacterium, Parvimonas and Treponema, which might contribute to the increased oral malodor. These key oral-derived phylotypes might invade into the gut as opportunistic pathogens and contribute to altering the composition of the gut microbiota. This study provided important clues that dysbiosis of the oral microbiota might be involved in the development of HBV-CLD. Greater understanding of the relationships between the dysbiosis of oral microbiota and the development of HBV-CLD might facilitate the development of non-invasive differential diagnostic procedures and targeted treatments of HBV-CLD patients harbouring specific oral phylotypes.

Tissue factor expression on blood monocytes in patients with hepatitis C virus-induced chronic liver disease

Chronic liver disease (CLD) is a worldwide common pathology characterised by an inflammatory and fibrotic process leading to progressive evolution from chronic hepatitis to cirrhosis. Monocytes play a crucial role in the pathogenesis of inflammation and fibrosis in chronic liver diseases. Activated monocytes increase the expression of tissue factor, a key glycoprotein that participates in haemostatic and inflammatory processes. This study aims to assess the expression of tissue factor on activated peripheral blood monocytes in patients with hepatitis C virus (HCV)-induced CLD in relation to the degree of hepatic insufficiency and haemostatic imbalance. The current study included 60 patients with HCV-induced CLD, categorised after Child–Pugh into four groups: Child A, B, C and C during acute attack of haematemesis, 15 patients each, and 15 healthy subjects were included as normal controls. Immunophenotype characterization was carried out by flow cytometric analysis for identification of monocytes tissue factor expression (CD142) on activated blood monocytes population (CD11b and CD14) in different groups studied. Data demonstrated significant increase (p < 0.05) in the expression of each of CD11b, CD14 and CD142 revealing monocytes activation and increased expression of tissue factor on peripheral blood monocytes in different groups of patients especially cases during acute attack of haematemesis, compared to healthy subjects. Increased monocytes tissue factor expression in patients with HCV may play a key role in the intensification of the inflammatory and immunological processes in conjunction with activation of the coagulation mechanisms. The interaction of all these phenomena may trigger bleeding by perturbing the unstable haemostasis in frail patients with chronic liver disease.

Changes of Fecal Bifidobacterium Species in Adult Patients with Hepatitis B Virus-Induced Chronic Liver Disease

The beneficial effects of Bifidobacteria on health have been widely accepted. Patients with chronic liver disease have varying degrees of intestinal microflora imbalance with a decrease of total Bifidobacterial counts. Since different properties have been attributed to different Bifidobacterium species and there is no information available for the detailed changes in the genus Bifidobacterium in patients with chronic liver disease heretofore, it is meaningful to investigate the structure of this bacterium at the species level in these patients. The aim of this study was to characterize the composition of intestinal Bifidobacterium in patients with hepatitis B virus-induced chronic liver disease. Nested-PCR-based denaturing gradient gel electrophoresis (PCR-DGGE), clone library, and real-time quantitative PCR were performed on the fecal samples of 16 patients with chronic hepatitis B (CHB patients), 16 patients with hepatitis B virus-related cirrhosis (HBV cirrhotics), and 15 healthy subjects (Controls). Though there was no significant difference in the diversity among the three groups (P = 0.196), Bifidobacterium dentium seems to be specifically enhanced in patients as the PCR-DGGE profiles showed, which was further validated by clone library and real-time quantitative PCR. In contrast to the B. dentium, Bifidobacterium catenulatum/Bifidobacterium pseudocatenulatum were detected less frequently in the predominant profile and by quantitative PCR in HBV cirrhotics than in the controls, and the level of this species was also significantly different between these two groups (P = 0.023). Although having no quantitative difference among the three groups, Bifidobacterium longum was less commonly detected in HBV cirrhotics than in CHB patients and Controls by quantitative PCR (P = 0.011). Thus, the composition of intestinal Bifidobacterium was deeply altered in CHB and HBV cirrhotic patients with a shift from beneficial species to opportunistic pathogens. The results provide further insights into the dysbiosis of the intestinal microbiota in patients with hepatitis B virus-induced chronic liver disease and might potentially serve as guidance for the probiotics interventions of these diseases.

Expression of the chemokine IP-10 correlates with the accumulation of hepatic IFN-gamma and IL-18 mRNA in chronic hepatitis C but not in hepatitis B.

The pathogenesis of hepatitis C virus-induced chronic liver disease is still poorly understood. Previous studies revealed enhanced hepatic expression of the Th1 prototype cytokine IFN-gamma in individuals with chronic hepatitis C. In accordance with several animal models of experimentally induced hepatitis, a Th1 lymphocyte driven inflammatory process, which involves newly infiltrated as well as resident monocytes/macrophages, has been proposed. An involvement of the interferon-gamma-inducible chemokine IP-10, which is chemoattractive for stimulated Th1 cells and monocytes, is also suggested. Using an HBV transgenic mouse model, a reduction of hepatic infiltration and liver disease was achieved recently by administration of antibodies directed against the interferon-gamma-inducible chemokine Mig and against IP-10. In the present study, expression of IP-10 was investigated both in serum and in the liver of patients with chronic hepatitis C and hepatitis B. Patients with liver diseases of non-viral etiologies served as controls. IP-10 expression was highest in hepatitis C. In chronic hepatitis C, but not in chronic hepatitis B nor in liver disorders unrelated to viral infections, IP-10 expression was strongly correlated with the amount of transcripts for IFN-gamma and to the amount of transcripts for the constitutively expressed macrophage derived cytokine IL-18. Hepatic inflammatory activity, however, was found to be associated more closely with IFN-gamma than with IP-10 or IL-18 mRNA expression. The data support the hypothesis that IP-10 is responsible for the recruitment of Th cells and monocytes in chronic hepatitis C, and suggest that its role in chronic hepatitis B is less determining. Moreover, they deliver additional support for the view that IFN-gamma still has to be considered as a mediator that determines the outcome of inflammation, e.g., via its ability to activate IL-18 expressing cells and to initiate a delayed type hypersensitivity reaction.

Chronic seropositive polyarthritis associated with hepatitis B virus-induced chronic liver disease: a sequel of virus persistence.

Chronic seropositive polyarthritis associated with hepatitis B virus-induced chronic liver disease: a sequel of virus persistence.

Gene mutation of transforming growth factor beta1 type II receptor in hepatocellular carcinoma.

Alteration of transforming growth factor beta1 (TGF-beta1) type II receptor (RII) appears to cause unresponsiveness to TGF-beta1 in tumorigenic cells. Defect in the mononucleotide repeat sequence, i.e., poly A region of TGF-beta1RII gene has been reported to be related to replication error-positive cancer cells. We examined if there is any TGF-beta1RII mutation in a coding microsatellite in hepatocellular carcinoma (HCC). Genomic DNAs were extracted from formalin-fixed, paraffin-embedded liver tissues obtained at surgery or autopsy in 3 normal individuals and 96 patients with hepatitis C virus-induced chronic liver disease; 3 with chronic hepatitis, 20 with liver cirrhosis and 73 with HCC. The DNA was PCR-amplified at 2 segments of TGF-beta1RII: poly A region which includes the (A)10 microsatellite sequence, and poly GT region. PCR products were directly sequenced. DNA from normal and patients with chronic liver disease contained the 10 wild-type adenines but 3 cases with liver cirrhosis in whom there were only 9 adenines within poly A tract. This microdeletion of one A resulted in a frameshift and truncated a predicted length of amino acids. In HCC lesions, the same deletion was noted in 4 cases (25%) of well-differentiated type, 10 (40%) of moderately differentiated type, 18 (53%) of poorly differentiated type. None of the lesions had mutations within the GT region. Our findings indicate that one adenine deletion of poly A microsatellite tract within TGF-beta1RII is frequently detected in patients with HCC, and the mutation may cause the abrogation of the function of TGF-beta1RII gene.

Liver transplantation in virus-induced chronic liver disease

The current status of liver transplantation (OLTx) for chronic viral hepatitis is reviewed. The major issues addressed include the rate of recurrence of disease, its severity and natural history, and the potential for therapy. These issues vary markedly for each type of viral hepatitis. The development of new antiviral agents for clinical use may change the current restriction on liver transplantation for hepatitis B virus (HBV)-related liver disease such that it begins to challenge hepatitis C virus (HCV) as the principal indication for OLTx world-wide.

Virus-induced autoimmune disease: transgenic approach to mimic insulin-dependent diabetes mellitus and multiple sclerosis.

Transgenic technology has been used by virologists for two main purposes. One has been to evaluate cell-specific expression and function in vivo of specific viral proteins. Of the many such studies performed, one prominent example is the work of Levine and colleagues (MARKS et al. 1989) on the expression of SV40 T antigen that resulted in choroid plexus papillomas; these experiments led to identification of p53 bound to T antigen. As another example, Nerenberg et al. (1987) used transgenic expression of the TAT protein of HTLV-1 to establish the oncogenic potential of TAT. Lastly, Nelson and colleagues (unpublished data) probed expression of the immediate early 72 KDa protein of human cytomegalo- virus and located this early regulatory protein in the islets of Langerhans, smooth muscle wall of large arteries, retina and salivary gland. All of these studies were similar in that the authentic promoter of the particular viral gene being expressed was employed. The second major avenue followed by virologists utilizing transgenic technology has been to create animal models of viral pathogenesis. Examples of this application are described in separate chapters of this volume and include, first, the isolation and expression of the gene encoding the human poliovirus receptor in mice by Ren and Racaniello (1992), REN ET AL. (1990), and independently by Horie et al. (1994) and KOIKE et al. (1991), allowing study of the virus’ tropism, pathogenesis of the disease it causes, and design of new protective vaccines. Second, CHISARI et al. (1987,1989) utilized the albumin promoter to express hepatitis B virus surface antigen in the liver to study virus-induced chronic liver disease, hepatocellular carcinoma, and the role of the immune system in either clearing virus of causing immunopathology. The third example is that of TOGGAS et al. (1994) who used an astrocyte-specific promoter to express HIV-1 gp120 in transgenic mice. The brain lesions of these mice closely mimic those of AIDS neuropathology in humans including neuronal injury, microglia activation and gliosis.KeywordsMyelin Basic ProteinViral ChallengeChoroid Plexus PapillomaLymphocytic ChoriomeningitisLymphocytic Choriomeningitis VirusThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Southern-blot analysis and simultaneous In Situ detection of hepatitis B virus-associated DNA and antigens in patients with end-stage liver disease

To gain new insights into the pathogenesis of hepatitis B virus-induced chronic liver disease, we have used nonisotopic in situ detection methods for the simultaneous analysis of hepatitis B virus DNA and antigens at the single-cell level. Paraffin-embedded liver specimens from 23 cirrhotic patients (12 HBsAg positive and 11 HBsAg negative) who underwent liver transplantation were evaluated by in situ hybridization with a digoxigenin-labeled DNA probe and digoxigenin detection system and by immunohistochemistry with an enhanced biotin-streptavidin technique. DNAs extracted from liver and serum specimens were analyzed by Southern- and slot-blot hybridization, respectively. Using the in situ techniques, we detected hepatitis B virus-specific DNA and antigens in 11 of 12 HBsAg-positive patients and in none of the 11 HBsAg-negative individuals. Replicative intermediates of hepatitis B virus DNA were detected by Southern-blot analysis in the same 11 HBsAg-positive patients, 6 of whom had no serological markers of hepatitis B virus replication. Therefore a good correlation was found between the results obtained by the in situ and Southern-blot hybridization analyses of tissue specimens. However, a lack of correlation was found between serum- and tissue-associated markers of viral replication. In addition, the simultaneous in situ detection analyses revealed that some hepatocytes containing high levels of viral DNA were devoid of detectable HBcAg, suggesting a mechanism by which the virus may escape immunological surveillance.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-actin antibodies of IgM and IgG class in chronic liver diseases detected by fluorometric immunoassay.

Using a sensitive fluoroimmunoassay, anti-actin antibodies (AA) of the IgM and IgG classes were measured in 240 patients with various chronic liver diseases and in 211 patients with non-hepatic autoimmune muscle, heart, malignant and inflammatory bowel diseases. Thirty-two out of 40 patients (80%) with autoimmune chronic active hepatitis (CAH) had AA only of the IgG class (geom. mean X = 1.78, SEM +/- 0.07) and only three patients (8%) had both IgG and IgM AA, the latter in lower titres. In patients with primary biliary cirrhosis (PBC) and AMA-positive cholestatic CAH, AA of both IgM and IgG classes were equally represented (60% IgG and 64% IgM AA in PBC, 73% IgG and 51% IgM AA in cholestatic CAH) but the titres were very low (geom. mean IgG AA in PBC 1.035, SEM +/- 0.03, in cholestatic CAH 1.18, SEM +/- 0.02). In contrast to autoimmune (lupoid) CAH, AA were rare in HBsAg positive CAH (9/43, 21%) and only present in low titres. However, in six out of 21 patients with anti-HBs and anti-HBc-positive chronic active hepatitis, high AA of IgG class were found, suggesting the autoimmune type of liver disease. In NANB virus-induced chronic liver disease after blood transfusion, AA were only occasionally found (IgG antibodies 1/19, IgM antibodies 3/19) and none were found in the eight patients with sporadic NANB hepatitis. They were also rare in 30 patients with alcoholic liver disease (3/30, 10%).(ABSTRACT TRUNCATED AT 250 WORDS)