Search

Background: Altered bacterial translocation is associated with changes in hepatic function and the progression from compensated to decompensated cirrhosis. Child-Turcotte-Pugh (CTP) score is an essential indicator of liver severity. Thus, we aimed to study differences in the blood microbiome together with metabolome profile between HCV-infected patients with CTP class B (CTP-B, significant functional compromise) and patients with CTP class A (CTP-A, well-compensated cirrhosis)., Methods: We conducted a cross-sectional study in patients with advanced HCV-related cirrhosis (n = 88) stratified by CTP-B and CTP-A. Bacterial 16S rRNA sequencing was sequenced by MiSeq Illumina technology and non-targeted metabolomics was performed by GC-MS and LC-MS ESI+ and ESI- to complement the analysis., Results: Patients with CTP-B had lower levels of richness (Chao1), and alpha diversity (Shannon and Simpson indexes) at phylum level than patients with CTP-A. Likewise, we observed significant differences in beta diversity between groups at phylum, class, and order levels, showing lower diversity in patients with CTP-B. Higher relative abundance of Proteobacteria (p = 0.012), Alphaproteobacteria (p = 0.005), Sphingomonadales (p = 0.012) and Sphingomonadaceae (p = 0.016) were significantly associated with CTP-B. The phylum Proteobacteria was positively correlated with ethanolamine and oleic acid (p = 0.005 and p = 0.004, respectively) and negatively with p-cresol (p = 0.006). In addition, the order Sphingomonadales and the family Sphingomonadaceae was also negatively correlated with p-cresol (p = 0.001 and p = 0.001)., Conclusions: Blood microbial diversity was significantly decreased in patients with CTP-B, who presented an enrichment of Proteobacteria, Alphaproteobacteria, Sphingomonadales and Sphingomonadaceae compared to patients with CTP-A., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests. The funding sources played no role in the study's design, collection, analysis, interpretation of the data, or manuscript writing., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Achieving sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) reduces all-cause mortality. However, the mechanisms and risk factors for liver fibrosis and portal hypertension post-SVR remain incompletely understood. In the gut-liver axis, mucosa-associated microbiota (MAM) substantially influence immune and metabolic functions, displaying spatial heterogeneity at the anatomical intestinal site. We analyzed MAM composition and function to isolate the locoregional MAM involved in chronic liver disease progression in HCV post-SVR patients., Methods: We collected MAM samples from three intestinal sites (terminal ileum, ascending colon, and sigmoid colon) via brushing during colonoscopy in 23 HCV post-SVR patients and 25 individuals without liver disease (controls). The 16S rRNA of bacterial DNA in specimens collected with a brush and in feces was sequenced. The molecular expression of intestinal tissues and hepatic tissues were evaluated by quantitative real-time PCR., Results: In the post-SVR group, the microbial β-diversity of MAM, especially in the ascending colon, differed from the control group and was associated with liver fibrosis progression. In PICRUSt analysis, MAM in the ascending colon in the liver cirrhosis (LC) group showed compromised functions associated with the intestinal barrier and bile acid production, and FGF19 expression was markedly decreased in the terminal ileum biopsy tissue in the LC group. At the genus level, six short-chain fatty acid (SCFA)-producing bacterial genera, Blautia , Alistipes , Roseburia , Agathobaculum , Dorea , and Pseudoflavonifractor were reduced in the ascending colon of post-SVR LC patients., Conclusion: In patients of HCV post-SVR, we identified the association between the degree of liver fibrosis and dysbiosis of mucosa-associated SCFA-producing bacterial genera that may be related to intestinal barrier and bile acid production in the ascending colon., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Midori, Nosaka, Hiramatsu, Akazawa, Tanaka, Takahashi, Naito, Matsuda, Ohtani and Nakamoto.)

Cryptococcus species is still a very common opportunistic infection in AIDS patients. However, it is increasingly responsible for disease in otherwise immunocompromised individuals, such as transplant recipients and the heterogeneous group of patients with underlying immunologic diseases, hematologic disorders and organ failure syndromes. Clinical presentation, prognosis, and outcomes are difficult to define given these varied host groups, and tailoring treatments to fit the necessities of each patient is likewise challenging. Our patient was on treatment with steroids and direct-acting antiviral agents (DAAs) for a chronic HCV-related hepatitis, worsened by cryoglobulinemia, membranoproliferative glomerulonephritis and a lowgrade B cells lymphoma. We report a case of systemic cryptococcal infection in an immunosenescent, HIV-negative patient.

Despite the emergence of new direct-acting antivirals, hepatitis C virus (HCV) chronic infection and its consequent fibrosis and hepatocarcinoma remain a significant burden for public health, thus requiring an effective preventive vaccine. Our group previously showed that a subunit vaccine based on recombinant soluble E2 (sE2) can induce broadly neutralizing antibodies. To improve the immunogenicity of sE2, we designed and produced a fusion protein (sE2-ferritin) comprising sE2 and a ferritin unit in Drosophila S2 cells, which self-assembled into a nanoparticle with sE2 displayed on the surface. The sE2 moiety on the sE2-ferritin nanoparticle not only had nearly natural conformation but also had better affinities than the unfused sE2 to neutralizing antibodies, receptor, and patient serum. Mouse immunization studies showed that sE2-ferritin was more potent than sE2 in inducing anti-HCV broadly neutralizing antibodies. Our results demonstrate that sE2-ferritin is a vaccine candidate superior to previously developed sE2, providing a new possibility for controlling HCV., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Proton pump inhibitors (PPI), a class of drugs commonly used, are known to be associated with changes in the intestinal microbiota. Published studies were done in heterogeneous cohorts which could hamper conclusions drawn as effects of diseases were not taken into consideration. We aimed to elucidate differences in the intestinal microbiota being associated to the use of PPI in a cohort study of patients with chronic hepatitis C. Material and Methods: The 16S rDNA gene was analyzed in stool samples of patients with and without PPI use. Patients with concomitant medication influencing the microbiota were excluded. Results were compared with the clinical course of hepatitis C patients with decompensated liver cirrhosis. Results: No differences in alpha diversity could be observed, while the microbial community structure differed significantly, especially in patients with liver cirrhosis. The relative abundance of Streptococcus spp ., Enterobacter spp . and Haemophilus spp . was significantly increased in patients with PPI use irrespectively of the stage of liver disease. Finally, in patients with decompensated liver cirrhosis due to chronic HCV infection only in these using PPI bacterial phylotypes were isolated. Conclusions: PPI use was associated with significant alterations in the microbial community in patients with chronic hepatitis C, which were even pronounced in patients with liver cirrhosis. In patients with decompensated liver cirrhosis due to chronic HCV infection, the use of PPI may promote infections either directly or indirectly through changes in the microbial community structure. Future studies should further investigate long-term impact on the microbiota and the clinical outcome.

Objective: The study retrospectively analyzed the effects of hepatic iron depletion on the therapy of chronic hepatitis C patients., Materials: A total of 195 patients from Hamad General Hospital were studied retrospectively. Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), and g-glutamyl transferase (GGT) tests were implemented; descriptive analysis and mean testing were performed to analyze the data., Results: It has been observed that ferritin increases with HCV, displaying R-value =0.450 and p -value=0.182. Levels of ALT (P-value=0.812) and GGT ( P -value=0.723) may increase slightly with the treatment. Chronic hepatitis C patients develop iron deficiency that can be marked by evaluating various iron markers in the body., Conclusion: The study identified that iron markers may decrease markedly among HCV patients; yet, researches consider the occurrence as support to management modality to improve response, delivered towards the treatment., (© 2019 by the Association of Clinical Scientists, Inc.)

Both Helicobacter pylori ( H. pylori ) infection and liver diseases, including nonalcoholic fatty liver disease (NAFLD), viral hepatitis, and hepatocellular carcinoma (HCC), have high prevalences worldwide, and the relationship between H. pylori infection and liver disease has been discussed for many years. Although positive correlations between H. pylori and NAFLD have been identified in some clinical and experimental studies, negative correlations have also been obtained in high-quality clinical studies. Associations between H. pylori and the pathogenesis of chronic viral hepatitis, mainly disease progression with fibrosis, have also been suggested in some clinical studies. Concerning HCC, a possible role for H. pylori in hepatocarcinogenesis has been identified since H. pylori genes have frequently been detected in resected HCC specimens. However, no study has revealed the direct involvement of H. pylori in promoting the development of HCC. Although findings regarding the correlations between H. pylori and liver disease pathogenesis have been accumulating, the existing data do not completely lead to an unequivocal conclusion. Further high-quality clinical and experimental analyses are necessary to evaluate the efficacy of H. pylori eradication in ameliorating the histopathological changes observed in each liver disease., Competing Interests: Conflict-of-interest statement: No author has any relevant conflicts of interest.

Current interest in HCV therapy with direct acting antivirals is focused on shortening treatment length. We managed two cirrhotics who achieved virological cure after 4 weeks of ombitasvir/paritaprevir/ritonavir, dasabuvir, ribavirin treatment. Analysis to identify potential predictive factors for a successful outcome with a shorter treatment course was conducted.

Background and Study Aims: Occult hepatitis B infection (OBI) is known to be mostly prevalent in chronic hepatitis C (CHC) patients and OBI reactivation might be life-threatening in patients undergoing interferon (IFN)-free direct acting antiviral (DAA) therapy. As previous studies have revealed a relationship between OBI and non-response to IFN-based antiviral therapy, the aim of the current study was to determine if there was a higher prevalence of OBI in IFN non-responders than responders., Patients and Methods: This retrospective cross-sectional study was conducted in CHC patients who had previously received IFN-based antiviral therapy. Serum samples of 100 HBsAg negative CHC patients were tested for HBV DNA, anti-HBc IgG, anti-HBs, ALT and AST. The presence of OBI was compared between 50 IFN responders and 50 IFN non-responders. Patients with a history of previous HBV infection, patients with evidence of cirrhosis and patients who had received IFN therapy within the last one year were excluded from the study., Results: Anti-HBc IgG positivity was determined in 53% of the patients. HBV DNA positivity, indicating OBI was determined in 1 (1%) patient. This patient was anti-HBc IgG positive, anti-HBs negative, ALT and AST levels were normal. The HBV DNA and anti-HBc IgG positivity rates were higher in the non-responder group than in the responder group, but the difference was not statistically significant (p = 0.31 and p = 0.07 respectively)., Conclusion: According to the results of this study, the prevalence of OBI is lower than expected amongst CHC patients in Turkey and it may not be necessary to apply routine screening to IFN non-responders for OBI infection before DAA therapy. However, there is a need for multicentre studies with larger patient series., (Copyright © 2018 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The importance of the intestinal microbiota for the onset and clinical course of many diseases, including liver diseases like non-alcoholic steatohepatitis and cirrhosis, is increasingly recognized. However, the role of intestinal microbiota in chronic hepatitis C virus (HCV) infection remains unclear., Methods: In a cross-sectional approach, the intestinal microbiota of 95 patients chronically infected with HCV (n=57 without cirrhosis [NO-CIR]; n=38 with cirrhosis [CIR]) and 50 healthy controls (HC) without documented liver diseases was analysed., Results: Alpha diversity, measured by number of phylotypes (S) and Shannon diversity index (H'), decreased significantly from HC to NO-CIR to CIR. S and H' correlated negatively with liver elastography. Analysis of similarities revealed highly statistically significant differences in the microbial communities between HC, NO-CIR and CIR (R=.090; P<1.0×10 -6 ). Stratifying for HCV genotypes even increased the differences. In addition, we observed distinct patterns in the relative abundance of genera being either positive or negative correlated with diseases status., Conclusions: This study shows that not only the stage of liver disease but also HCV infection is associated with a reduced alpha diversity and different microbial community patterns. These differences might be caused by direct interactions between HCV and the microbiota or indirect interactions facilitated by the immune system., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients., Methods: Patients who had failed PegIFNα/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFNα/RBV. Eight patients in the Phase 1 group received short-term (≤14 days) simeprevir. Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFNα-2a/RBV for 12 weeks followed by PegIFNα-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determine total treatment duration in Phase 2/3 prior relapsers or breakthrough) or 36 weeks fixed (Phase 2/3 group non-responders and Phase 1 group). The primary endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12)., Results: Phase 2/3 group: SVR12 rate was 69.6% (87/125) overall; 92.7% (51/55), 60.0% (6/10), 64.3% (18/28), and 36.7% (11/30) in patients with prior relapse, viral breakthrough, partial response, or null response, respectively. SVR12 rates were similar for patients with HCV GT1a (66.0% [33/50]) and GT1b infection (72.0% [54/75]) and among HCV GT1a-infected patients with/without a baseline Q80K polymorphism (66.7% [8/12] and 65.8% [25/38], respectively). The majority of RGT-eligible patients (prior viral relapse or breakthrough) met RGT criteria (89.2% [58/65]); of these, 89.7% (52/58) achieved SVR12. Overall, 16.0% (20/125) of patients experienced on-treatment failure and 14.4% (18/125) experienced post-treatment failure (15 relapses, 3 missing data). Phase 1 group (simeprevir-naïve and -experienced patients combined): SVR12 rate was 37.5% (6/16). Safety and tolerability findings were comparable to those of the feeder studies., Conclusions: The majority of RGT-eligible patients met criteria for shortening treatment to 24 weeks in total. Simeprevir 150 mg QD with PegIFNα-2a/RBV led to a high SVR rate among prior relapsers with HCV GT1 infection. No new safety signals were noted., Trial Registration: NCT01323244 . (date of registration: March 24, 2011).

Background:  The development of direct-acting antivirals in recent years has dramatically enhanced rates of viral eradication to >90% in patients with chronic hepatitis C virus (HCV) infection. To determine true treatment efficacy and define the most appropriate retreatment, it is important to distinguish virologic relapse from reinfection when patients in whom HCV is eradicated during treatment become infected with a new HCV strain after treatment., Methods:  We investigated the prevalence of late recurrent viremia (patients with sustained virologic response 12 weeks after the end of treatment but detectable HCV RNA at follow-up week 24) and used refined phylogenetic analysis of multiple HCV genes to distinguish virologic relapse from reinfection., Results:  Across 11 phase 3 clinical trials of ledipasvir-sofosbuvir (SOF) and SOF, only 12 of 3004 patients had detectable HCV RNA following sustained virologic response 12 weeks after the end of treatment. Of these 12 patients with late recurrent viremia, 11 had the same HCV genotype/subtype at baseline and at recurrence. Phylogenetic analysis demonstrated that 58% (7 of 12) of these patients were successfully treated with the SOF-based regimen, with HCV eradication achieved, but became reinfected with a different HCV strain after treatment. The remaining 5 patients with late recurrent viremia had virologic relapse in which the HCV present at baseline persisted in the liver or another compartment and reemerged in the blood 24 weeks after treatment., Conclusions:  The incidence of late recurrent viremia was low. Distinguishing reinfection from virologic relapse has implications for determining true treatment efficiency and selecting optimal retreatment strategies., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

BACKGROUND Haemophilus species are the most common microbiota in humans. The aim of this paper was to investigate Haemophilus spp., mainly H. parainfluenzae prevalence, in the upper respiratory tract of chronic hepatitis C (CHC-positive) patients with or without therapy using pegylated interferon alfa and ribavirin. MATERIAL AND METHODS We collected 462 samples from 54 healthy people and 100 CHC-positive patients at various stages: before (group A), during (group B), and after (group C) antiviral therapy. Identification of bacterial isolates including biotypes and antimicrobials susceptibility was accomplished by means of standard microbiological methods. RESULTS In 70.4% of healthy people (control group) and in 27.0% of CHC-positive patients, the presence of haemophili, mainly H. parainfluenzae was observed, and those differences were statistically significant (p<0.0001). Statistically significant differences in Haemophilus spp. colonization were also observed among healthy people and CHC-positive patients from group A (p=0.0012) and from B or C groups (p<0.0001). Resistance to ampicillin in beta-lactamase-positive isolates and multidrug resistance (MDR) of H. parainfluenzae was detected mainly in group A. CONCLUSIONS The obtained data suggest that chronic hepatitis C, together with antiviral therapy, may influence the respiratory tract microbiota composition as found using haemophili, mainly H. parainfluenzae.

Background: Microbial translocation (MT) contributes to immune activation during HIV and HCV infections. We investigated the kinetics of MT markers during anti-HCV and anti-HIV treatments, and if baseline plasma levels of lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) could predict anti-HCV treatment outcome., Methods: Plasma from 78 HIV-infected patients was evaluated for LPS, LBP and sCD14. The patients starting anti-HCV treatment (with ongoing antiretroviral (ART) treatment) were categorized into sustained viral responders (SVR; n = 21) or non-responders (NR; n = 15) based on treatment outcome. ART starting subjects--were categorized into chronically HCV-infected (CH; n = 24) and mono-infected (HIV; n = 18), based on the HCV infection status. Samples were collected before start (at baseline) of pegylated-interferon-alpha/ribavirin (peg-IFN/RBV) or antiretroviral-therapy and two years after treatment start (at follow up). χ2-test, non-parametric statistics and logistic regression were applied to determine the associations with treatment response and changes of the soluble markers., Results: Plasma levels of LPS and sCD14 were elevated in all subjects before antiviral-treatment but remained unchanged at follow-up. Elevated levels of LBP were present in patients with HIV and HIV/HCV co-infection and were reduced by ART. Additionally, higher levels of LBP were present at baseline in NR vs. SVR. Higher levels of LBP at baseline were associated with non-response to peg-IFN/RBV treatment in both bivariate (OR: 0.19 95% CI: 0.06-0.31, p = 0.004) and multivariate analysis (OR: 1.43, 95% CI: 1.1-1.86, p = 0.07)., Conclusion: In HIV/HCV co-infected patients high baseline LBP levels are associated with non-response to peg-IFN/RBV therapy. Plasma LBP (decreased by ART) may be a more relevant MT marker than LPS and sCD14.

Lung cancer and pulmonary tuberculosis (TB) are highly prevalent and representing major public health issues. They share common risk factors and clinical manifestations. It is also suggested that TB predicts raised lung cancer risk likely related to chronic inflammation in the lungs. However, it does not seem to influence the clinical course of lung cancer provided that it is properly treated. We present a case report of a 57-year old male with concurrent TB and lung cancer. He was diagnosed with positive sputum smear for acid fast bacilli (AFB) and subsequent culture of Mycobacterium tuberculosis. Besides, his comorbid conditions were chronic hepatitis C virus (HCV) infection and peripheral artery disease (PAD). Later while on anti-tuberculous treatment (ATT) squamous cell lung cancer (SCC) was confirmed with computed tomography (CT) guided biopsy. Due to poor general condition the patient was not fit for either surgery or radical chemo- and radiotherapy. He was transferred to hospice for palliative therapy. We want to emphasize that both TB and lung cancer should be actively sought for in patients with either disorder. In addition, there is no doubt that these patients with lung cancer and with good response to TB treatment should be promptly considered for appropriate anticancer therapy.

Aim: : Although numerous animal studies suggest that probiotic therapy has beneficial effects in various liver diseases, the evidence for beneficial effects in human liver disease is controversial. This study was carried out to investigate the efficacy of probiotic therapy in alleviating small intestinal bacterial overgrowth (SIBO) and permeability in chronic liver disease., Methods: Fifty-three patients with chronic liver disease were randomized to either probiotic therapy or placebo. Six bacterial species were used: Bifidobacterium bifidum, Bifidobacterium lactis, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus rhamnosus, and Streptococcus thermophilus. After 4 weeks, changes in the composition of fecal bacteria, SIBO, intestinal permeability, and clinical symptoms were examined., Results: Three of the six probiotic species, B. lactis, L. rhamnosus, and L. acidophilus, increased in the feces of the probiotic therapy group (P<0.001), whereas there was no change in fecal microbiota in the placebo group. SIBO disappeared in many individuals of the probiotic therapy group, but none in the placebo (24 vs. 0%, P<0.05). General gastrointestinal symptoms also improved more in the probiotic group and improvement in intestinal permeability was slightly but not significantly more frequent in the probiotic arm than the placebo arm (50 vs. 31.3%, P=0.248). Numbers of lactobacilli in stool were correlated negatively with intestinal permeability (P for trend<0.05). Liver chemistry did not improve significantly in either group., Conclusions: We conclude that short-term probiotic administration in chronic liver disease is effective in alleviating SIBO and clinical symptoms, but ineffective in improving intestinal permeability and liver function.

Introduction: The factors involved in the progression of liver disease towards decompensated cirrhosis are not completely elucidated. It seems that bacterial translocation (BT) from the gut to the systemic blood flow has an important role in the disease progression, but literature data are controversial. Our objectives were to evaluate the presence of BT in patients with chronic HCV infection and to assess the correlation between BT and liver fibrosis stages and inflammatory state., Methods: We conducted a cross-sectional study on patients with chronic HCV infection in a tertiary care hospital between January and July 2013. Blood samples were collected for aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), total cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, platelets, lipopolysaccharide (LPS) and tumor necrosis-alpha (TNFα). Plasma LPS were measured by ELISA (Kamiya Biomedical Company Seattle, SUA) and TNFα by DIAsource ImmunoAssay (Louvain-la-Neuve, Belgium) kits. Liver fibrosis was evaluated by means of FibroMax (BioPredictive, Paris, France) in all patients., Results: We enrolled 116 patients with CHC, with a sex ratio M/F of 0.55 and a median age of 54 (45-61) years. Most of the patients (32) had compensated cirrhosis (F4). LPS levels were higher in patients with mild fibrosis--median value of 60.34 (32-91.7) ng/mL, than in cirrhotic patients--median value 40.39 (20.2-74.4) ng/mL (p = 0.051). We found no statistical correlation between LPS levels and fibrosis (p = 0.068) or TNFα levels (p = 0.097) CONCLUSIONS: There was BT in patients with CHC but it was not correlated with liver fibrosis stages or systemic inflammation. This may suggest that LPS evaluation may not be the best technique to assess baterial translocation, but further studies are needed.

Background: Using comparative glycoproteomics, we have previously identified a glycoprotein that is altered in both amount and glycosylation as a function of liver cirrhosis. The altered glycoprotein is an agalactosylated (G0) immunoglobulin G molecule (IgG) that recognizes the heterophilic alpha-gal epitope. Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease., Methods: The N-linked glycosylation of anti-gal IgG molecules from patients with fibrosis and cirrhosis was determined and the effector function of anti-bacterial antibodies from over 100 patients examined. In addition, markers of microbial exposure were determined., Results: Surprisingly, the subset of agalactosylated anti-gal antibodies described here, was impaired in their ability to mediate complement mediated lysis and inhibited the complement-mediated destruction of common gut bacteria. In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure., Conclusions: Anti-gal antibodies in patients with liver cirrhosis were reduced in their ability to mediate complement mediated lysis of target cells. As bacterial infection is a major complication in patients with cirrhosis and bacterial products such as LPS are thought to play a major role in the development and progression of liver fibrosis, this finding has many clinical implications in the etiology, prognosis and treatment of liver disease.

Objective: To review the literature regarding current strategies for the management of anemia associated with treatment for chronic viral hepatitis C (HCV) in adults., Data Sources: The MEDLINE/PubMed, EMBASE, and Cochrane databases were searched (January 1980-October 2012) for articles in English using the search terms anemia, ribavirin, dose reduction, erythropoietin stimulating agents, hepatitis C, HIV, liver transplant, telaprevir, and boceprevir., Study Selection and Data Extraction: All relevant original studies, meta-analyses, systematic reviews, guidelines, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search., Data Synthesis: Standard of care for patients infected with HCV genotype 1 now requires a triple therapy regimen including an HCV NS3 protease inhibitor. These regimens lead to significantly higher rates of anemia compared to prior dual therapy regimens. Development of an optimal management strategy should begin with risk stratification. Ribavirin dose reductions have been recommended in the package inserts for the pegylated interferon products and studies have demonstrated the need for maintenance of 80% of the initial ribavirin dose to achieve optimal sustained virologic response (SVR) with dual therapy. The use of erythropoietin-stimulating agents has been shown to be effective for anemia caused by peginterferon and ribavirin without compromising SVR rates. Limited data have been published regarding the management of anemia with triple therapy; however, efficacy studies for boceprevir and telaprevir have used ribavirin dose reduction and erythropoietin-stimulating agents to successfully manage anemia., Conclusions: Anemia is a common adverse event associated with the use of ribavirin, and, more recently, the new HCV protease inhibitors. Ribavirin dose reduction should continue to be used as an initial anemia management strategy, with the use of erythropoietin alfa 40,000 units once weekly reserved for patients whose hemoglobin does not adequately respond to initial management strategies.

The association between HCV infection and myocardial disorders remains unclear. This study aimed to assess whether or not HCV infection influences myocardial dysfunction by the use of NT-proBNP, a sensitive marker of myocardial dysfunction. A total of 198 participants [99 patients with chronic HCV infection (aged 46-68 years) and 99 anti-HCV-negative sex and age matched controls] were examined. Serum HCV-RNA level and HCV genotype were tested and liver biopsy was done only for the patient group. The NT-proBNP concentration of the HCV patients (mean 71.6 ± 79.1 pg/ml; median 46.0 pg/ml, range 5.0-400.0) was significantly higher than that of the controls (mean 39.8 ± 24.4 pg/ml; median 35.8 pg/ml, range 7.0-108.0) (P < 0.05). 20.0 % of the HCV patients and 0.6 % of the controls had high NT-proBNP (higher than 125 pg/ml; the single cut off point for patients under 75 years of age) (P < 0.05). Stepwise multiple regression analysis revealed that chronic HCV infection was independently correlated with NT-proBNP level after adjustment for parameters that might influence NT-proBNP (P = 0.005). Our data suggest that chronic HCV infection is associated with increased NT-proBNP, indicating that chronic HCV infection might induce myocardial dysfunction.

We carried out a cross-sectional study to explore whether bacterial 16S ribosomal DNA (bactDNA) shows association with severity of liver disease among human immunodeficiency virus/hepatitis C virus coinfected patients. Patients with advanced fibrosis (F3/F4), moderate activity grade (A2/A3), and high fibrosis progression rate (FPR > 0.15) had higher values of plasma bactDNA levels than did patients without these markers of liver disease (P < 0.05). The chance of having a fibrosis stage or activity grade increased was 1.20 [95% confidence interval (CI) = 1.0 to 1.44, P = 0.045] and 1.22 (95% CI = 1.1 to 1.45, P = 0.029) times greater for every 100 copies per microliter of plasma bactDNA. Likewise, the odds of having values of FPR > 0.15 was 1.18 (95% CI = 0.98 to 1.42, P = 0.089). In addition, patients with high bactDNA levels (≥175 copies per microliter) had the highest odds of having high values of Metavir score and FPR (P < 0.05). Our data show that bacterial translocation is associated with severe liver disease among human immunodeficiency virus-infected patients with chronic hepatitis C.

The mammalian intestinal tract is colonized by trillions of beneficial commensal bacteria that are anatomically restricted to specific niches. However, the mechanisms that regulate anatomical containment remain unclear. Here, we show that interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) are present in intestinal tissues of healthy mammals. Depletion of ILCs resulted in peripheral dissemination of commensal bacteria and systemic inflammation, which was prevented by administration of IL-22. Disseminating bacteria were identified as Alcaligenes species originating from host lymphoid tissues. Alcaligenes was sufficient to promote systemic inflammation after ILC depletion in mice, and Alcaligenes-specific systemic immune responses were associated with Crohn's disease and progressive hepatitis C virus infection in patients. Collectively, these data indicate that ILCs regulate selective containment of lymphoid-resident bacteria to prevent systemic inflammation associated with chronic diseases.

Background & Aims: Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes., Methods: In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein, and interleukin-6 by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment., Results: Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, intestinal fatty acid binding protein (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and interleukin-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for aspartate aminotransferase, P=.002 for ferritin) and fibrosis (P<.0001 for γ-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for α-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively)., Conclusions: LPS-induced local and systemic inflammation is associated with cirrhosis and predicts progression to end-stage liver disease in patients with HBV or HCV infection., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Human immunodeficiency virus (HIV)-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation., Methods: We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized., Results: HIV-related CD4(+) lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS-binding protein, soluble CD14, and fucose-binding lectin (AAL) reactive to immunoglobulin G specific for the alpha-galactose epitope and suppressed levels of endotoxin core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), eg, LPS, odds ratio, 19.0 (P = .002); AAL, odds ratio, 27.8 (P < .0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis., Conclusions: Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease.

Helicobacter DNA has been reported in hepatocellular carcinoma tissues in several studies from varying geographic locations, raising the possibility that Helicobacter infection may contribute to the pathogenesis of hepatocellular carcinoma. Other known risk factors for hepatocellular carcinoma show significant geographic variability, but whether the same holds for Helicobacter is unknown. We studied the prevalence of Helicobacter DNA in a US cohort of hepatocellular carcinoma, where the prevalence of Helicobacter infection is low in the general population. Liver tissues from 57 individuals were examined. Thirty-five individuals had paired tumor/nontumor samples, including 21 cases of hepatocellular carcinoma, for a total of 92 samples studied. Both Helicobacter genus and Helicobacter pylori species-specific polymerase chain reaction was performed. Helicobacter DNA was detected in 5 (9%) of 57 cases, all in nonneoplastic cirrhotic liver tissues from individuals with hepatitis C infection (n = 4) or alcohol liver disease (n = 1). Tissues from 22 hepatocellular carcinomas and 10 cholangiocarcinomas were all negative as were tissues from 8 benign primary hepatic tumors. In conclusion, Helicobacter DNA was detectable in 9% of liver tissues in this cohort but was not found in primary benign or malignant liver tumors. These findings indicate that Helicobacter infection is unlikely to be etiologically associated with hepatocellular carcinoma in this cohort. If Helicobacter infection does contribute to the development of hepatocellular carcinoma in general, then significant regional variability must exist.

Bacteremia has rarely been reported in patients receiving treatment for hepatitis C virus (HCV) infection. We describe the features and investigation of four cases of Staphylococcus aureus bacteremia occurring between 3 November 2004 and 10 January 2005 in patients on therapy for chronic HCV infection. The unusual occurrence of S. aureus bacteremia in a series of patients led to an epidemiologic investigation and molecular typing methods were employed to assess the relatedness of cases. The mean time of bacteremia onset was week 10 of HCV treatment. No patient had neutropenia previously. The average duration of bacteremia was 2.6 days and complications included acute renal failure (2/4), disseminated intravascular coagulopathy (DIC) with sepsis syndrome (1/4), septic arthritis (1/4), spinal epidural abscess (1/4) and endocarditis (1/4). Two patients were in the same weight class for dosing, but no other epidemiologic links were found. One patient admitted to intravenous drug use (IVDU) and a second was suspected of IVDU. The two other patients were cirrhotic, but had no further identifiable risk factors. All bacterial isolates were methicillin-susceptible. By pulsed-field gel electrophoresis, two cases were found to have identical bacterial strains. However, fluorescent-based amplified fragment-length polymorphism analysis demonstrated distinct band patterns in all four cases. The epidemiologic data and molecular analysis of this cluster of S. aureus bacteremia cases among patients receiving combination therapy for treatment of chronic HCV infection suggest that these cases were not related. Additionally, IVDU and cirrhosis, but not neutropenia, are identified as potential risk factors for this uncommon complication of HCV therapy.

We sought to clarify the incidence and role of Helicobacter pylori (H. pylori) seropositivity in patients with hepatitis C virus (HCV) infection and the effect of coinfection on interferon-alpha and ribavirin therapy. The presence of H. pylori was tested using a commercially available enzyme immunoassay in serum samples from 93 patients with chronic hepatitis C. Clinical features, HCV markers and response of HCV to interferon-alpha and ribavirin were compared between H. pylori-positive and H. pylori-negative patients. Anti-H. pylori antibody was detected in 45 (48%) of the 93 patients, whose median HCV-RNA level (495 vs 760 kIU/mL; P = 0.013) and platelet count (128 vs 158 x 10(3)/microL; P = 0.009) were significantly lower than in patients with HCV infection alone. Anti-H. pylori antibody levels were found to be significantly correlated with fibrosis score (P = 0.0083, r = 0.33) but inversely related to platelet count (P = 0.0037, r = -0.34). The sustained response rate for HCV clearance following interferon-alpha and ribavirin treatment did not differ between patients with and without anti-H. pylori seropositivity. The presence of H. pylori [odds ratio (OR) 8.61; 95% confidence interval (CI) 1.59-46.70] and fibrosis score (OR 30.13; 95% CI 5.44-166.78) were found by multivariate analysis to be associated with the decrease of platelet count during therapy. Coexistent H. pylori infection does not demonstrably influence the clinical course of chronic hepatitis C. A possible connection between H. pylori coinfection and thrombocytopenia was found during the treatment course, suggesting that preemptive eradication of H. pylori may facilitate completion of treatment and increased sustained virological response.

Goal: Iron may play a role in the pathogenesis of chronic hepatitis C. Helicobacter pylori (Hp) infection was recently associated with iron-deficiency anemia. We examined the influence of Hp infection on hepatic iron accumulation in hepatitis C., Methods: Ninety-five hepatitis C virus (HCV)-RNA-positive patients, including 60 chronic hepatitis, 17 cirrhosis and 18 hepatocellular carcinoma as well as 95 age- and sex-matched normal subjects without HCV infection as control, were studied. Liver biopsies were also obtained from 44 HCV-infected patients. Serum Hp antibodies were measured by an enzyme-linked immunosorbent assay and clinical data, including iron parameters and histological findings, were compared between Hp-positive and -negative HCV-infected patients., Results: The percentage of serum Hp antibodies was lower in HCV-infected patients than in controls (52/95 (54.7%) vs. 68/95 (71.6%); P<0.05). HCV-infected patients had higher serum ferritin levels than controls (120 [2.8-1700] vs. 58 [2.2-420] ng/ml; P<0.0001). In HCV-infected patients, the serum ferritin levels (medians and [ranges]) in Hp-positive patients were significantly lower than those of Hp-negative patients (99 [8.5-770] vs. 150 [2.8-1700] ng/ml; P<0.05). The grades of hepatic iron deposit in Hp-positive patients were significantly lower than those in Hp-negative patients (P<0.01)., Conclusions: Hp infection may at least partly affect hepatic iron accumulation in HCV-related liver diseases.

Aim: Intrahepatic bile ducts are the targets for inflammation in primary biliary cirrhosis (PBC), but their pathogenesis is not known. Gram-positive bacterial DNA was detected recently in gallbladder bile of PBC patients. In the present study, we assessed the possible pathological role of lipoteichoic acid (LTA), the gram-positive bacterial cell wall component, in PBC., Methods: Liver samples, obtained from 20 patients with PBC (stage 1-2 with CNSDC: stage 3-4 with loss of bile ducts = 10:10) and from 13 patients with chronic hepatitis due to hepatitis C virus (CH-C) with lymphocytic cholangitis, were subjected to immunohistochemical staining with polyclonal rabbit anti-LTA as the primary antibody. Serum reactivities to LTA were studied by ELISA. After 1 microg of purified LTA was placed in a 96-well microplate as an antigen, an antibody capture assay was carried out using serum samples from PBC (n = 20), CH-C (n = 13) and healthy subjects (n = 11)., Results: LTA was localized around the sites of chronic non-suppurative destructive cholangitis (CNSDC) in the portal area in stage 1-2 PBC but was not detected in the portal area in CH-C. In stage 3-4 PBC, LTA was localized around sites of ductular proliferation at the periphery of portal tracts. IgM class anti-LTA serum titers were significantly higher in PBC than in CH-C. IgA class anti-LTA serum titers were significantly higher in PBC than in healthy subjects., Conclusions: In the PBC livers, the profile of immunoreactivity to LTA changed markedly as the disease progressed. Sera from PBC showed higher levels of anti-LTA titers than CH-C (IgM) or from healthy subjects (IgA). The LTA-mediated immune system might affect the initiation and/or progression of PBC.

We evaluated, employing a logistic regression model, the association between Helicobacter pylori infection and cirrhosis in a cohort of 106 patients (57 males; mean age, 52.9 years; range, 20-78 years) with chronic hepatitis C virus (HCV) from Rosario, Argentina. HCV was confirmed by ELISA and PCR. H. pylori status was determined by ELISA. Of the 106 patients evaluated, 47 (44.3%) had cirrhosis. A total of 70.2% (33/47) of cirrhotic patients and 47.5% (28/59) of noncirrhotic patients were H. pylori-positive. In univariate analyses, cirrhosis was associated with age (P = 0.016) and H. pylori-positive status (P = 0.019) but not with gender (P = 0.28) or length of infection (P = 0.35). In multivariate analysis, H. pylori infection (P = 0.037; OR = 2.42; 95% CI = 1.06-5.53) and age (P = 0.033; OR = 1.04; 95% CI = 1.00-1.07) of patients remained significant and independently associated with cirrhosis. In conclusion, our results demonstrate an association between H. pylori infection and cirrhosis in patients with hepatitis C virus.

Purpose of Review: Chronic liver disease due to hepatitis B virus or hepatitis C virus infection results in cirrhosis and hepatocellular carcinoma. Successful eradication or suppression of viral replication may lead to clinical improvement and better prognosis. Important discoveries have been made in recent years on the management of these diseases. This article aims at reviewing important publications of the past year that contribute to better understanding and treatment of chronic viral hepatitis., Recent Findings: The effect of virus genotype on the natural history continued to be an important topic of research. Landmark studies on the use of pegylated interferon in chronic hepatitis B and benefit of antiviral treatment in patients with advanced fibrosis or cirrhosis have been published. New antiviral agents were evaluated with encouraging results. In chronic hepatitis C, several treatment trials using pegylated interferon on HIV-coinfected patients have been published. Treatment in specific groups of patients, including those with normal alanine transaminase or posttransplantation recurrence, has also been investigated., Summary: Major progress has been made in the treatment of chronic hepatitis B and pegylated interferon is likely to become one of the first-line therapeutic options in the near future. Combined pegylated interferon and ribavirin will be the standard treatment regimen for hepatitis C and HIV coinfection. Future challenges include treatment of hepatitis B and HIV coinfection and discovery of more potent antiviral agents.

To test whether Helicobacter species play a role in the enhancement of liver necro-inflammation and fibrosis and in the development of hepatocellular carcinoma (HCC), we sought DNA sequences of Helicobacter species in liver specimens from patients with viral-related chronic hepatitis, HCC or metastatic liver carcinoma. We enrolled 28 consecutive patients with ultrasound evidence of hepatic nodule(s) on their first liver biopsy: 21 had histological evidence of HCC (Group I) and 7 of metastatic liver carcinoma (Group II). In the same period we observed 27 consecutive patients with chronic hepatitis on their first liver biopsy (Group III). Helicobacter sequences were sought by PCR using primers for the 16S rDNA of Helicobacter spp, designed to amplify a 400 base-pair fragment, and detected by 2% agarose gel and hybridization with a specific biotinylated probe. We used, as positive controls for the DNA extraction from liver tissue, hepatic biopsy sections in which HBV infection was confirmed by HBcAg positivity and in which we amplified HBV-DNA by specific primers; positive controls for the amplification of Helicobacter spp were obtained from gastric biopsy sections in which Helicobacter pylori infection was confirmed by biochemical and histochemical tests. HBV-DNA was found in all five HBcAg positive liver biopsies. Helicobacter spp 16S rDNA was detected in all five biopsy specimens of gastric mucosa and in none of liver specimens from patients in any group. Our data suggest that Helicobacter species were not involved in the pathogenesis of virus-related HCC, chronic hepatitis or liver carcinoma metastasis.

Background: Infection by Helicobacter hepaticus causes chronic hepatitis and hepatocellular carcinoma (HCC) in mice, and Helicobacter pylori (H. pylori) genomic sequences have been demonstrated in the liver of patients with HCC. H. pylori infection reportedly occurs with high frequency in patients with cirrhosis but none of the studies has investigated it in subjects with cirrhosis and superimposed HCC. In this case-control study, we searched for the seroprevalence of H. pylori infection in patients with HCC., Patients and Method: Forty-six patients (30 males, 16 females, mean age 69 years) with HCC and hepatitis C virus (HCV)-related cirrhosis were compared to 46 sex and age (+/-1 year) matched patients presenting consecutively to the Emergency Department of Molinette Hospital of Torino. All subjects were tested for presence in serum of IgG antibodies against H. pylori and the result was analyzed using the chi-square test., Results: H. pylori seropositivity was more prevalent among patients with HCC (36/46, 78.2%) than in controls (25/46, 54%) (P<0.05) (OR 3.02, 95% confidence interval ). Twenty-five out of 30 (83.3%) male patients showed seropositivity at a variance with 16/30 (53%) in the controls (P<0.05); 11 out of 16 (68.7%) female patients were seropositive versus 9 out of 16 (56.2%) control subjects (P=n.s.)., Conclusion: Seroprevalence of antibodies to H. pylori was found to be higher in patients with HCC than in controls.

Possible role of gram-negative bacteria in the genesis of hepatic damage during chronic viral hepatitis B and C was studied. Histological activity, hepatocyte proliferative activity, and expression of alpha-smooth muscle actin were compared with the severity of endotoxemia in patients with chronic hepatitis B and C. The study revealed a correlation between the degree of intralobular necroses, hepatocyte proliferation, and myofibroblast transdifferentiation of Ito cells with endotoxin concentration in the blood.

In chronic viral hepatitis B and C the development of intestinal dysbacteriosis and high occurrence of concomitant diseases of the gastrointestinal tract were observed. In cases of increased dysbacteriosis degree and in the presence of concomitant diseases the blood plasma of patients exhibited higher activity in reaction with the of amebocytes lysate obtained from crabs of the genus Limulus. A suggestion was made that the endotoxin of Gram negative intestinal microflora could probably play some role in the development of pathological processes in chronic viral hepatitis B and C.

Background: Recently, in vitro and in vivo studies demonstrated that non-steroidal anti-inflammatory drugs are able to enhance the activity of interferon alpha., Aim: To evaluate the efficacy and tolerability of ketoprofen (a non-steroidal anti-inflammatory drug) plus interferon alpha (group B) compared to interferon alpha plus ribavirin (group C) and interferon alpha alone (group A) in chronic hepatitis C non-responders after a 5-month course with interferon alpha., Patients and Methods: Without stopping interferon alpha, 49 patients were randomized to receive one of the three treatment regimens for 4 months., Results: Three patients discontinued the therapy. One out of 16 patients in group A, 6/16 in group B and 5/14 in group C, alanine aminotransferase returned to normal at the end of the therapies (B vs A: p=0.04); serum hepatitis C virus-RNA became negative in 1 patient in group A and in 4 patients in both group B and group C. Six months after treatment, normal alanine transferase and negative hepatitis C virus-RNA were observed in 3 patients in group B and 2 in group C. In these patients, liver histology significantly improved., Conclusions: These results indicate that a certain number of non-responder patients to interferon alpha can benefit from a combination therapy of interferon alpha plus ketoprofen that is at least as effective as the combination interferon alpha plus ribavirin.

Various genera of sulphate reducing bacteria (SRB) have been found in the human digestive tract. It is suggested that some of SRB species may be responsible for the development of the clinical symptoms of ulcerative colitis and other disease of large intestine. Sulphasalazine (salicyl-azo-sulphapyridine, SAS) is commonly used to treat patients with ulcerative colitis and Crohn disease. Above 30 samples of faeces or biopsy specimens from 25 patients (age 45 +/- 14 years; M/F, 13/12) suffering from gastrointestinal disorders were used for isolation of Desulfovibrio desulfuricans species. The morphological, physiological and biochemical characteristics of isolated strains and also their susceptibility to SAS was determined. D. desulfuricans isolates were obtained from 5 amongst all patients assayed. Some abnormal, cigar-shaped cells were detected as accompanying the cells represented by rods, curved rods and vibrios. After strains purification, two types of colonies were present on the solid Postgate's medium B (containing lactate as a carbon source and sulphate for energy conservation): the black colonies growing in bulk of agar medium and the transparent, surface-growing mucous colonies. These two types of D. desulfuricans colonies may be a result of different iron availability for bacterial cells. High metabolic activity of strain was not always accompanied by the presence of H2S gas lock in the test tube, although the H2S odor was perceptible. All tested strains multiplied inconsiderably slowly in the presence of SAS at concentrations 10, 20, 40 and 60 mg/cm3. The growing concentrations of SAS did not cause a proportional decrease of the bacterial cells number. Taking into account the positive results of using SAS to treat patients with some colonic diseases and the indicated resistance to SAS of intestinal D. desulfuricans strains, it appears probable, that this SRB species isn't responsible for the development of mentioned diseases.