Elevated serum f erritin is an independent predictor of severe liver fibrosis, steatosis, and treatment failure in chronic hepatitis C

Background: Infection with the hepatitis C virus (HCV) i s associatedwith hepatic iron accumulation. We performed a comprehensive analysisof serum ferritin levels and of their genetic determinants in thepathogenesis and treatment of patients with chronic hepatitis C enrolledin the Swiss Hepatitis C Cohort Study (SCCS).Methods: Serum ferritin levels at baseline o f therapy with p egylatedinterferon-α ( PEG-IFN-α) and ribavirin or b efore liver biopsy werecorrelated with clinical features of c hronic HCV infection, includingnecroinflammatory activity (N=970), fibrosis (N=980), steatosis (N=886)and response to treatment (N=876). The association b etween highferritin levels (> median) and the endpoints w as assessed b y logisticregression. In addition, a candidate gene analysis as well as a genomewideassociation study (GWAS) of serum ferritin levels were performed.Results: S erum ferritin > sex-specific median was one of the strongestpre-treatment predictors of failure to achieve SVR (P<0.0001, OR=0.46,95% CI=0.34-0.60). This association remained highly significant in amultivariate analysis (P=0.0001, OR=0.32, 95% CI=0.18-0.57), with anodds ratio c omparable to that of IL28B g enotype, and persisted afteradjustment for duration of infection. Additional independent predictors ofnonresponse were viral load, HCV genotype, presence of diabetes, andliver fibrosis stage. Higher serum ferritin levels were also independentlyassociated with severe liver fibrosis (P<0.0001, OR=2.67, 95% CI=1.66-4.28) a nd steatosis (P=0.0034, OR=2.34, 95% CI=1.33-4.12), but n otwith necroinflammatory a ctivity (P=0.3). No significant g eneticdeterminants of serum ferritin levels were identified.Conclusions: Elevated serum ferritin levels are associated withadvanced liver fibrosis, hepatic steatosis, and poor r esponse to IFN-α-based therapy in c hronic hepatitis C, i ndependently from IL28Bgenotype.

Imaging techniques and histology in the evaluation of liver fibrosis in hepatosplenic schistosomiasis mansoni in Brazil: a comparative study

Few publications have compared ultrasound (US) to histology in diagnosing schistosomiasis-induced liver fibrosis (LF); none has used magnetic resonance (MR). The aim of this study was to evaluate schistosomal LF using these three methods. Fourteen patients with hepatosplenic schistosomiasis admitted to hospital for surgical treatment of variceal bleeding were investigated. They were submitted to upper digestive endoscopy, US, MR and wedge liver biopsy. The World Health Organization protocol for US in schistosomiasis was used. Hepatic fibrosis was classified as absent, slight, moderate or intense. Histology and MR confirmed Symmers' fibrosis in all cases. US failed to detect it in one patient. Moderate agreement was found comparing US to MR; poor agreement was found when US or MR were compared to histology. Re-classifying LF as only slight or intense created moderate agreement between imaging techniques and histology. Histomorphometry did not separate slight from intense LF. Two patients with advanced hepatosplenic schistosomiasis presented slight LF. Our data suggest that the presence of the characteristic periportal fibrosis, diagnosed by US, MR or histology, associated with a sign of portal hypertension, defines the severity of the disease. We conclude that imaging techniques are reliable to define the presence of LF but fail in grading its intensity.

Serum hyaluronan and collagen IV as non-invasive markers of liver fibrosis in patients from an endemic area for schistosomiasis mansoni: a field-based study in Brazil

Non-invasive markers of fibrosis have been used to diagnose liver fibrosis in a variety of diseases. Hyaluronic acid (HA) and collagen IV (C-IV) levels were measured in the sera of patients from an endemic area for schistosomiasis in Brazil to diagnose and to rank the intensity of liver fibrosis. Seventy-nine adult patients with schistosomiasis, in the age range of 21-82 years (49 ± 13.4) were submitted to clinical and ultrasonographic examinations. Ultrasound was employed to diagnose and categorise liver fibrosis according to World Health Organization patterns. Serum HA and C-IV levels were measured using commercial ELISA kits. Ultrasound revealed six patients with intense liver fibrosis, 21 with moderate, 23 with light and 29 without. Serum HA was able to separate individuals with fibrosis from those without (p < 0.001) and light from intense fibrosis (p = 0.029), but C-IV was not (p = 0.692). The HA diagnostic accuracy for fibrosis was 0.89. The 115.4 ng/mL cut-off level diagnosed patients with fibrosis (sensitivity 0.98, specificity 0.64). HA correlated positively with portal hypertension. Periportal fibrosis (subjective evaluation), age and collateral circulation predicted HA increase. In conclusion, we propose that serum HA can be used to identify patients with liver fibrosis in an endemic area for schistosomiasis mansoni in Brazil.

A non-interventional phase IV Belgian survey to assess the antiviral effectiveness of pegylated interferon-alpha-2b and ribavirin treatment according to the stage of liver fibrosis in previously untreated patients with genotype 1/4/5/6 chronic hepatitis C (PRACTICE).

BACKGROUND AND STUDY AIMS: This was an observational, non-interventional, multicenter, phase IV study, in patients with genotype 1/4/5/6 chronic hepatitis C (CHC). The primary objectives were to evaluate SVR in patients with no or minimal fibrosis (METAVIR F0-F1) versus well established fibrosis (F2-F4), and to estimate response on Weeks 12, 24 and 48 on treatment in previously untreated patients with genotypes 1/4/5/6 CHC. PATIENTS AND METHODS: 538 patients treated with pegylated interferon alfa 2b 1.5 mcg/kg in combination with ribavirin 800-1200 mg/day were enrolled in 55 sites in Belgium and Luxembourg, 505 being considered for the analysis. 40% of the patients were female and 60% male, the average age was 47.5 years, 10.5% were 65 or older. RESULTS: SVR was observed in 35% of the patients, EVR in 68%, of which pEVR in 33% and cEVR in 35%. SVR was observed in 43% of the low fibrosis group (F0, F1) and 30% of the high fibrosis group (F2, F3, F4) (p = 0.005). SVR rates were 34% for genotype 1, 37% for genotype 4, and 47% for genotype 5 (NS). Multivariate analysis showed that EVR and baseline METAVIR score are independent prognostic factors for SVR. CONCLUSIONS: This trial confirms that fibrosis stage and early viral response are the most important key-factors to predict sustained response, suggesting that the earlier patients are treated, the better the outcome. Non-invasive techniques enable us to closely monitor progression of fibrosis, allowing a better selection of patients for antiviral treatment in the DAA-era.

Role of hepatitis C virus genotype 3 in liver fibrosis progression: a systematic review and meta-analysis.

The progression of liver fibrosis in chronic hepatitis C has long been considered to be independent from viral genotypes. However, recent studies suggest an association between Hepatitis C virus (HCV) genotype 3 and accelerated liver disease progression. We completed a systematic review and meta-analysis of studies evaluating the association between HCV genotypes and fibrosis progression. PubMed, Embase and ISI Web of Knowledge databases were searched for cohort, cross-sectional and case-control studies on treatment-naïve HCV-infected adults in which liver fibrosis progression rate (FPR) was assessed by the ratio of fibrosis stage in one single biopsy to the duration of infection (single-biopsy studies) or from the change in fibrosis stage between two biopsies (paired biopsies studies). A random effect model was used to derive FPR among different HCV genotypes. Eight single-biopsy studies (3182 patients, mean/median duration of infection ranging from 9 to 21 years) and eight paired biopsies studies (mean interval between biopsies 2-12 years) met the selection criteria. The odds ratio for the association of genotype 3 with accelerated fibrosis progression was 1.52 (95% CI 1.12-2.07, P = 0.007) in single-biopsy studies and 1.37 (95% CI 0.87-2.17, P = 0.17) in paired biopsy studies. In conclusion, viral genotype 3 was associated with faster fibrosis progression in single-biopsy studies. This observation may have important consequences on the clinical management of genotype 3-infected patients. The association was not significant in paired biopsies studies, although the latter may be limited by important indication bias, short observation time and small sample size.

Role of hepatitis C virus genotype 3 in liver fibrosis progression : a systematic review and meta-analysis ; et, Impact of nurse vaccination program on hepatitis B immunity in a Swiss HIV clinic

Rôle du génotype 3 du virus de l'hépatite C dans la progression de la fibrose hépatique, une revue systématique avec méta-analyse. On estime à 170 millions le nombre de personnes atteintes d'hépatite C chronique dans le monde. La principale conséquence de cette maladie est la fibrose du foie, qui évolue plus ou moins rapidement, pour aboutir au développement d'une cirrhose et/ou d'un hépatocarcinome. Certains des facteurs accélérateurs de la fibrose, comme l'âge avancé au moment de l'infection, le sexe masculin, la consommation d'alcool, sont bien connus. On a longtemps considéré que les six différents génotypes viraux n'influençaient pas la progression de la fibrose. Des études récentes ont cependant suggéré que certains génotypes, en particulier ie génotype 3, pouvaient entraîner une fibrose plus rapide. Le but de ce travail de thèse était de déterminer à l'aide d'une méta-analyse le rôle du génotype viral dans la progression de la fibrose dans l'infection chronique au virus de l'hépatite C. Les études ont été sélectionnées dans la littérature médicale à partir d'une série de mots-clés. Le degré de fibrose a été estimé par biopsie, en utilisant le score Metavir. Deux types d'études ont décrits de manière différente la durée d'infection. Les premières ont calculé la progression de la fibrose depuis le moment estimée de l'infection (« études avec une biopsie »), les secondes ont exprimés cette durée comme étant l'intervalle entre deux biopsies (« études avec deux biopsies »). L'analyse a permis d'identifier 8 études avec une biopsie pour un collectif total de 3182 patients ainsi que 8 études avec deux biopsies pour un collectif de 896 patients. Dans une méta-analyse de type « random effect », le rapport de cote pour l'association du génotype 3 avec une fibrose accélérée est de 1.52 (95% IC 1.12-2.07, p=0.007) pour les études à une biopsie. Pour les études à deux biopsies, le rapport de cote pour cette association est de 1.37 (95% IC 0.87-2.17, P=0.17). Cette étude montre que les patients avec une hépatite C chronique due au génotype 3 ont une progression de fibrose plus rapide que ceux qui sont infectés par les autres génotypes. Alors que la méta-analyse des études avec une biopsie est clairement significative, celle des études avec deux biopsies est au-dessous du seuil de significativité. Les études à deux biopsies peuvent être limitées par plusieurs facteurs, comprenant un « biais d'indication » (seuls les patients évoluant rapidement vers la cirrhose ont plus de risque d'avoir une deuxième biopsie), une durée d'observation très courte (5 années comparée à 13 années pour les études à 2 biopsies), et un nombre de patient limité (896 pour le études à 2 biopsies comparé à 3182 pour les études à 1 biopsie). Impact d'un programme de vaccination sur l'immunité contre l'hépatite Β dans une clinique suisse du VIH Le virus de l'hépatite Β cause une infection aigûe dont la symptomatologie varie d'une présentation subclinique à une progression fulminante. Dans une minorité de cas, l'infection aigiie est suivie d'une infection chronique pouvant évoluer vers une cirrhose hépatique et/ou un hépatocarcinome. La prévalence de l'hépatite Β aiguë et chronique chez les personnes vivant avec le virus d'immunodéficience humaine (VIH) est supérieure à celle de la population générale. Par ailleurs la co-infection avec le virus du VIH entraine une progression plus rapide de l'hépatite B. Dès lors, l'immunité pour le virus de l'hépatite Β représente un facteur primordial de prévention dans la population infectée par le virus de l'HIV. Bien que l'administration d'un vaccin contre l'hépatite Β soit particulièrement recommandée chez tous les individus infectés par le VIH, la couverture vaccinale dans cette population est souvent insuffisante. Le but de cette étude était de déterminer l'état d'immunisation contre le virus de l'hépatite Β dans la population infectée par le VIH de la cohorte Suisse HIV et d'analyser l'efficacité d'un programme de vaccination administré par le personnel soignant. L'immunité avant et après intervention dans notre centre a été comparée aux autres centres de la cohorte HIV en Suisse. L'immunité pour le centre d'intervention a passé de 32% avant intervention à 76% après intervention alors que pour les autres centres, l'immunité n'a progressé que de 33% à 39% dans le même laps de temps (n=2712, P=0.001). Cette étude montre qu'un contrôle systématique de l'immunité par du personnel soignant augmente de manière significative l'immunité pour le vaccin de l'hépatite Β dans la population HIV.

Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.

NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.

A role for the NADPH oxidases NOX1 and NOX2 in liver fibrosis has been proposed, but the implication of NOX4 is poorly understood yet. The aim of this work was to study the functional role of NOX4 in different cell populations implicated in liver fibrosis: hepatic stellate cells (HSC), myofibroblats (MFBs) and hepatocytes. Two different mice models that develop spontaneous fibrosis (Mdr2−/−/p19ARF−/−, Stat3Δhc/Mdr2−/−) and a model of experimental induced fibrosis (CCl4) were used. In addition, gene expression in biopsies from chronic hepatitis C virus (HCV) patients or non-fibrotic liver samples was analyzed. Results have indicated that NOX4 expression was increased in the livers of all animal models, concomitantly with fibrosis development and TGF-β pathway activation. In vitro TGF-β-treated HSC increased NOX4 expression correlating with transdifferentiation to MFBs. Knockdown experiments revealed that NOX4 downstream TGF-β is necessary for HSC activation as well as for the maintenance of the MFB phenotype. NOX4 was not necessary for TGF-β-induced epithelial-mesenchymal transition (EMT), but was required for TGF-β-induced apoptosis in hepatocytes. Finally, NOX4 expression was elevated in patients with hepatitis C virus (HCV)-derived fibrosis, increasing along the fibrosis degree. In summary, fibrosis progression both in vitro and in vivo (animal models and patients) is accompanied by increased NOX4 expression, which mediates acquisition and maintenance of the MFB phenotype, as well as TGF-β-induced death of hepatocytes.

Homocysteine induces oxidative stress, inflammatory infiltration, fibrosis and reduces glycogen/glycoprotein content in liver of rats

Hyperhomocysteinemia has been related to various diseases, including homocystinuria, neurodegenerative and hepatic diseases. In the present study we initially investigated the effect of chronic homocysteine administration on some parameters of oxidative stress, named total radical-trapping antioxidant potential, total antioxidant reactivity, catalase activity, chemiluminescence, thiobarbituric acid-reactive substances, and total thiol content in liver of rats. We also performed histological analysis, evaluating steatosis, inflammatory infiltration, fibrosis, and glycogen/glycoprotein content in liver tissue sections from hyperhomocysteinemic rats. Finally, we evaluated the activities of aminotransferases in liver and plasma of hyperhomocysteinemic rats. Wistar rats received daily subcutaneous injection of Hcy from their 6th to their 28th day of life. Twelve hours after the last injection the rats were sacrificed, liver and plasma were collected. Hyperhomocysteinemia decreased antioxidant defenses and total thiol content, and increased lipid peroxidation in liver of rats, characterizing a reliable oxidative stress. Histological analysis indicated the presence of inflammatory infiltrate, fibrosis and reduced content of glycogen/glycoprotein in liver tissue sections from hyperhomocysteinemic rats. Aminotransferases activities were not altered by homocysteine. Our data showed a consistent profile of liver injury elicited by homocysteine, which could contribute to explain, at least in part, the mechanisms involved in human liver diseases associated to hyperhomocysteinemia. (C) 2009 ISDN. Published by Elsevier Ltd. All rights reserved.

Role of hepatitis C virus genotype 3 in liver fibrosis progression - a systematic review and meta-analysis

The progression of liver fibrosis in chronic hepatitis C has long been considered to be independent from viral genotypes. However, recent studies suggest an association between Hepatitis C virus (HCV) genotype 3 and accelerated liver disease progression. We completed a systematic review and meta-analysis of studies evaluating the association between HCV genotypes and fibrosis progression. PubMed, Embase and ISI Web of Knowledge databases were searched for cohort, cross-sectional and case-control studies on treatment-naïve HCV-infected adults in which liver fibrosis progression rate (FPR) was assessed by the ratio of fibrosis stage in one single biopsy to the duration of infection (single-biopsy studies) or from the change in fibrosis stage between two biopsies (paired biopsies studies). A random effect model was used to derive FPR among different HCV genotypes. Eight single-biopsy studies (3182 patients, mean/median duration of infection ranging from 9 to 21 years) and eight paired biopsies studies (mean interval between biopsies 2-12 years) met the selection criteria. The odds ratio for the association of genotype 3 with accelerated fibrosis progression was 1.52 (95% CI 1.12-2.07, P = 0.007) in single-biopsy studies and 1.37 (95% CI 0.87-2.17, P = 0.17) in paired biopsy studies. In conclusion, viral genotype 3 was associated with faster fibrosis progression in single-biopsy studies. This observation may have important consequences on the clinical management of genotype 3-infected patients. The association was not significant in paired biopsies studies, although the latter may be limited by important indication bias, short observation time and small sample size.

Potent antifibrotic activity of mTOR inhibitors sirolimus and everolimus but not of cyclosporine A and tacrolimus in experimental liver fibrosis

Recurrence of chronic hepatitis C and progressive fibrosis in liver transplants is frequent and impairs both graft and patient survival. Whether or not the choice of immunosuppression affects progression of fibrosis remains unclear. The aim of the present study was to compare the potential of the commonly used immunosuppressants to halt experimental liver fibrosis progression.

Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice

Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice.

Unhealthy alcohol use, HIV infection and risk of liver fibrosis in drug users with hepatitis C

Aim To analyze alcohol use, clinical data and laboratory parameters that may affect FIB-4, an index for measuring liver fibrosis, in HCV-monoinfected and HCV/HIV-coinfected drug users. Patients and Methods Patients admitted for substance abuse treatment between 1994 and 2006 were studied. Socio-demographic data, alcohol and drug use characteristics and clinical variables were obtained through hospital records. Blood samples for biochemistry, liver function tests, CD4 cell count, and serology of HIV and HCV infection were collected at admission. Multivariate linear regression was used to analyze the predictors of FIB-4 increase. Results A total of 472 (83% M, 17% F) patients were eligible. The median age at admission was 31 years (Interquartile range (IQR) 27–35 years), and the median duration of drug use was 10 years (IQR 5.5–15 years). Unhealthy drinking (>50 grams/day) was reported in 32% of the patients. The FIB-4 scores were significantly greater in the HCV/HIV-coinfected patients (1.14, IQR 0.76–1.87) than in the HCV-monoinfected patients (0.75, IQR 0.56–1.11) (p<0.001). In the multivariate analysis, unhealthy drinking (p = 0.034), lower total cholesterol (p = 0.042), serum albumin (p<0.001), higher GGT (p<0.001) and a longer duration of addiction (p = 0.005) were independently associated with higher FIB-4 scores in the HCV-monoinfected drug users. The effect of unhealthy drinking on FIB-4 scores disappeared in the HCV/HIV-coinfected patients, whereas lower serum albumin (p<0.001), a lower CD4 cell count (p = 0.006), higher total bilirubin (p<0.001) and a longer drug addiction duration (p<0.001) were significantly associated with higher FIB-4 values. Conclusions Unhealthy alcohol use in the HCV-monoinfected patients and HIV-related immunodeficiency in the HCV/HIV-coinfected patients are important risk factors associated with liver fibrosis in the respective populations.