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Sample records for attenuates liver fibrosis

  1. Liver fibrosis

    OpenAIRE

    Bataller, Ramón; Brenner, David A.

    2005-01-01

    Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major ...

  2. Oleoylethanolamide, an endogenous PPAR-α ligand, attenuates liver fibrosis targeting hepatic stellate cells.

    Science.gov (United States)

    Chen, Ling; Li, Long; Chen, Junde; Li, Lei; Zheng, Zihan; Ren, Jie; Qiu, Yan

    2015-12-15

    Oleoylethanolamide (OEA), an endocannabinoid-like molecule, was revealed to modulate lipid metabolism through a peroxisome proliferator-activated receptor-α (PPAR-α) mediated mechanism. In present study, we further investigated the activities and mechanisms of OEA in ameliorating hepatic fibrosis in Sv/129 mice induced by a methionine choline-deficient (MCD) diet or thioacetamide (TAA) treatment. Liver fibrosis development was assessed by Hematoxylin-eosin and Sirius red staining. Treatment with OEA (5 mg/kg/day, intraperitoneal injection, i.p.) significantly attenuated the progress of liver fibrosis in both two experimental animal models by blocking the activation of hepatic stellate cells (HSCs). Gene expression analysis of hepatic tissues indicated that OEA inhibited the expression of α-smooth muscle action (α-SMA) and collagen matrix, fibrosis markers, and genes involved in inflammation and extracellular matrix remodeling. In vitro studies showed that OEA inhibited transforming growth factor β1-stimulated HSCs activation through suppressing Smad2/3 phosphorylation, α-SMA expression and myofibroblast transformation. These improvements could not be observed in PPAR-α knockout mice models with OEA administration, which suggested all the anti-fibrotic effects of OEA in vivo and in vitro were mediated by PPAR-α activation. Collectively, our results suggested that OEA exerted a pharmacological effect on modulating hepatic fibrosis development through the inhibition of HSCs activation in liver and therefore may be a potential therapeutic agent for liver fibrosis. PMID:26729705

  3. Triplex Forming Oligonucleotides against Type α 1(I) Collagen attenuates Liver Fibrosis induced by Bile Duct ligation

    OpenAIRE

    Panakanti, Ravikiran; Pratap, Akshay; Yang, Ningning; JACKSON, JOHN S.; Mahato, Ram I.

    2010-01-01

    Liver fibrosis is a consequence of chronic liver disorders which lead to the accumulation of extracellular matrix (ECM). Particularly, there is an increased accumulation of collagen in the fibrotic liver. We have therefore used a triplex forming oligonucleotide (TFO) against the type α 1 (I) collagen and evaluated, whether it can attenuate liver fibrosis induced by common bile duct ligation (CBDL) in rats. There was a significant decrease in hydroxyproline levels and Masson’s trichrome staini...

  4. MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis

    OpenAIRE

    Csak, Timea; Bala, Shashi; Lippai, Dora; Kodys, Karen; Catalano, Donna; Iracheta-Vellve, Arvin; Szabo, Gyongyi

    2015-01-01

    Background & Aim MicroRNAs (miRs) regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis. Methods Wild type (WT) and miR-155-deficient (KO) mice were fed methionine-choline-deficient (MCD) or -supplemented (MCS) control diet for 5 weeks. Liver injury, inflammation, steatosis and fibrosis were assessed. Re...

  5. The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice.

    Science.gov (United States)

    Rehman, Hasibur; Liu, Qinlong; Krishnasamy, Yasodha; Shi, Zengdun; Ramshesh, Venkat K; Haque, Khujista; Schnellmann, Rick G; Murphy, Michael P; Lemasters, John J; Rockey, Don C; Zhong, Zhi

    2016-01-01

    Oxidative stress plays an essential role in liver fibrosis. This study investigated whether MitoQ, an orally active mitochondrial antioxidant, decreases liver fibrosis. Mice were injected with corn oil or carbon tetrachloride (CCl4, 1:3 dilution in corn oil; 1 µl/g, ip) once every 3 days for up to 6 weeks. 4-Hydroxynonenal adducts increased markedly after CCl4 treatment, indicating oxidative stress. MitoQ attenuated oxidative stress after CCl4. Collagen 1α1 mRNA and hydroxyproline increased markedly after CCl4 treatment, indicating increased collagen formation and deposition. CCl4 caused overt pericentral fibrosis as revealed by both the sirius red staining and second harmonic generation microscopy. MitoQ blunted fibrosis after CCl4. Profibrotic transforming growth factor-β1 (TGF-β1) mRNA and expression of smooth muscle α-actin, an indicator of hepatic stellate cell (HSC) activation, increased markedly after CCl4 treatment. Smad 2/3, the major mediator of TGF-β fibrogenic effects, was also activated after CCl4 treatment. MitoQ blunted HSC activation, TGF-β expression, and Smad2/3 activation after CCl4 treatment. MitoQ also decreased necrosis, apoptosis and inflammation after CCl4 treatment. In cultured HSCs, MitoQ decreased oxidative stress, inhibited HSC activation, TGF-β1 expression, Smad2/3 activation, and extracellular signal-regulated protein kinase activation. Taken together, these data indicate that mitochondrial reactive oxygen species play an important role in liver fibrosis and that mitochondria-targeted antioxidants are promising potential therapies for prevention and treatment of liver fibrosis. PMID:27186319

  6. Ghrelin Attenuates Liver Fibrosis through Regulation of TGF-β1 Expression and Autophagy

    Directory of Open Access Journals (Sweden)

    Yuqing Mao

    2015-09-01

    and maintaining the balance between MMP2 and TIMP1. Our results demonstrated that ghrelin attenuates liver fibrosis via inhibition of the TGF-β1/Smad3 and NF-κB signaling pathways, as well as autophagy suppression.

  7. Isorhamnetin attenuates liver fibrosis by inhibiting TGF-β/Smad signaling and relieving oxidative stress.

    Science.gov (United States)

    Yang, Ji Hye; Kim, Sang Chan; Kim, Kyu Min; Jang, Chang Ho; Cho, Sam Seok; Kim, Seung Jung; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

    2016-07-15

    Hepatic fibrosis is considered integral to the progression of chronic liver diseases, leading to the development of cirrhosis and hepatocellular carcinoma. Activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. We investigated the ability of isorhamnetin, the 3'-O-methylated metabolite of quercetin, to protect against hepatic fibrosis in vitro and in vivo. Isorhamnetin inhibited transforming growth factor (TGF)-β1-induced expression of α-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and collagen in primary murine HSCs and LX-2 cells. The TGF-β1- or Smad-induced luciferase reporter activity of Smad binding elements was significantly decreased by isorhamnetin with a concomitant decrease in Smad2/3 phosphorylation. Isorhamnetin increased the nuclear translocation of Nrf2 in HSCs and increased antioxidant response element reporter gene activity. Furthermore, isorhamnetin blocked TGF-β1-induced reactive oxygen species production. The specific role of Nrf2 in isorhamnetin-mediated suppression of PAI-1 and phosphorylated Smad3 was verified using a siRNA against Nrf2. To examine the anti-fibrotic effect of isorhamnetin in vivo, liver fibrosis was induced by CCl4 in mice. Isorhamnetin significantly prevented CCl4-induced increases in serum alanine transaminase and aspartate transaminase levels, and caused histopathological changes characterized by decreases in hepatic degeneration, inflammatory cell infiltration, and collagen accumulation. Moreover, isorhamnetin markedly decreased the expression of phosphorylated Smad3, TGF-β1, α-SMA, and PAI-1. Isorhamnetin attenuated the CCl4-induced increase in the number of 4-hydroxynonenal and nitrotyrosine-positive cells, and prevented glutathione depletion. We propose that isorhamnetin inhibits the TGF-β/Smad signaling pathway and relieves oxidative stress, thus inhibiting HSC activation and preventing liver fibrosis. PMID:27151496

  8. Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice.

    Science.gov (United States)

    Motiño, Omar; Agra, Noelia; Brea Contreras, Rocío; Domínguez-Moreno, Marina; García-Monzón, Carmelo; Vargas-Castrillón, Javier; Carnovale, Cristina E; Boscá, Lisardo; Casado, Marta; Mayoral, Rafael; Valdecantos, M Pilar; Valverde, Ángela M; Francés, Daniel E; Martín-Sanz, Paloma

    2016-09-01

    Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression. PMID:27321932

  9. Biomarkers for liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Jacobs, Jon M.; Burnum-Johnson, Kristin E.; Baker, Erin M.; Smith, Richard D.; Gritsenko, Marina A.; Orton, Daniel

    2015-09-15

    Methods and systems for diagnosing or prognosing liver fibrosis in a subject are provided. In some examples, such methods and systems can include detecting liver fibrosis-related molecules in a sample obtained from the subject, comparing expression of the molecules in the sample to controls representing expression values expected in a subject who does not have liver fibrosis or who has non-progressing fibrosis, and diagnosing or prognosing liver fibrosis in the subject when differential expression of the molecules between the sample and the controls is detected. Kits for the diagnosis or prognosis of liver fibrosis in a subject are also provided which include reagents for detecting liver fibrosis related molecules.

  10. MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis.

    Directory of Open Access Journals (Sweden)

    Timea Csak

    Full Text Available MicroRNAs (miRs regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis.Wild type (WT and miR-155-deficient (KO mice were fed methionine-choline-deficient (MCD or -supplemented (MCS control diet for 5 weeks. Liver injury, inflammation, steatosis and fibrosis were assessed.MCD diet resulted in steatohepatitis and increased miR-155 expression in total liver, hepatocytes and Kupffer cells. Steatosis and expression of genes involved in fatty acid metabolism were attenuated in miR-155 KO mice after MCD feeding. In contrast, miR-155 deficiency failed to attenuate inflammatory cell infiltration, nuclear factor κ beta (NF-κB activation and enhanced the expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα and monocyte chemoattractant protein-1 (MCP1 in MCD diet-fed mice. We found a significant attenuation of apoptosis (cleaved caspase-3 and reduction in collagen and α smooth muscle actin (αSMA levels in miR-155 KO mice compared to WTs on MCD diet. In addition, we found attenuation of platelet derived growth factor (PDGF, a pro-fibrotic cytokine; SMAD family member 3 (Smad3, a protein involved in transforming growth factor-β (TGFβ signal transduction and vimentin, a mesenchymal marker and indirect indicator of epithelial-to-mesenchymal transition (EMT in miR-155 KO mice. Nuclear binding of CCAAT enhancer binding protein β (C/EBPβ a miR-155 target involved in EMT was significantly increased in miR-155 KO compared to WT mice.Our novel data demonstrate that miR-155 deficiency can reduce steatosis and fibrosis without decreasing inflammation in steatohepatitis.

  11. Ginseng extract and ginsenoside Rb1 attenuate carbon tetrachloride-induced liver fibrosis in rats

    OpenAIRE

    Hou, Ya-Ling; Tsai, Ya-Hui; Lin, Yun-Ho; Chao, Jane C-J

    2014-01-01

    Background Ginsenosides, the major bioactive compounds in ginseng root, have been found to have antioxidant, immunomodulatory and anti-inflammatory activities. This study investigated the effects of ginsenosides on carbon tetrachloride (CCl4)-induced hepatitis and liver fibrosis in rats. Methods Male Sprague–Dawley rats were randomly divided into four groups: control, CCl4, CCl4 + 0.5 g/kg Panax ginseng extract and CCl4 + 0.05 g/kg ginsenoside Rb1 groups. The treated groups were orally given ...

  12. Angiogenesis and liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Gülsüm ?zlem Elpek

    2015-01-01

    Recent data indicate that hepatic angiogenesis,regardless of the etiology, takes place in chronic liverdiseases (CLDs) that are characterized by inflammationand progressive fibrosis. Because antiangiogenictherapy has been found to be efficient inthe prevention of fibrosis in experimental models ofCLDs, it is suggested that blocking angiogenesis couldbe a promising therapeutic option in patients withadvanced fibrosis. Consequently, efforts are beingdirected to revealing the mechanisms involved inangiogenesis during the progression of liver fibrosis.Literature evidences indicate that hepatic angiogenesisand fibrosis are closely related in both clinical andexperimental conditions. Hypoxia is a major inducer ofangiogenesis together with inflammation and hepaticstellate cells. These profibrogenic cells stand at theintersection between inflammation, angiogenesis andfibrosis and play also a pivotal role in angiogenesis.This review mainly focuses to give a clear view on therelevant features that communicate angiogenesis withprogression of fibrosis in CLDs towards the-end point ofcirrhosis that may be translated into future therapies.The pathogenesis of hepatic angiogenesis associatedwith portal hypertension, viral hepatitis, non-alcoholicfatty liver disease and alcoholic liver disease are alsodiscussed to emphasize the various mechanisms involvedin angiogenesis during liver fibrogenesis.

  13. Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831 a novel NOX4/NOX1 inhibitor in vivo

    OpenAIRE

    Jiang, Joy X.; Chen, Xiangling; Serizawa, Nobuko; Szyndralewiez, Cedric; Page, Patrick; Schröder, Katrin; Brandes, Ralf P.; Devaraj, Sridevi; Török, Natalie J.

    2012-01-01

    Reactive oxygen species (ROS) play a key role in chronic liver injury and fibrosis. Homologues of NADPH oxidases (NOXs) are major sources of ROS, but the exact role of the individual homologues in liver disease is unknown. Our goal was to determine the role of NOX4 in liver fibrosis induced by bile duct ligation (BDL) with the aid of the pharmacological inhibitor GKT137831, and genetic deletion of NOX4 in mice. GKT136731 was either applied for the full term of BDL (preventive arm), or startin...

  14. S-nitroso-N-acetylcysteine attenuates liver fibrosis in experimental nonalcoholic steatohepatitis

    Directory of Open Access Journals (Sweden)

    Mazo DF

    2013-06-01

    Full Text Available Daniel FC Mazo,1 Marcelo G de Oliveira,2 Isabel VA Pereira,1 Bruno Cogliati,3 José T Stefano,1 Gabriela FP de Souza,2 Fabíola Rabelo,1 Fabiana R Lima,4 Venâncio A Ferreira Alves,4 Flair J Carrilho,1 Claudia PMS de Oliveira1 1University of São Paulo School of Medicine, Department of Gastroenterology, Clinical Division, Hepatology Branch (LIM-07, Sao Paulo, Brazil; 2Institute of Chemistry, University of Campinas, Campinas, Sao Paulo, Brazil; 3University of Sao Paulo School of Veterinary Medicine and Animal Science, Department of Pathology, Sao Paulo, Brazil; 4University of São Paulo School of Medicine, Department of Pathology (LIM14, São Paulo, Brazil Abstract: S-Nitroso-N-acetylcysteine (SNAC is a water soluble primary S-nitrosothiol capable of transferring and releasing nitric oxide and inducing several biochemical activities, including modulation of hepatic stellate cell activation. In this study, we evaluated the antifibrotic activity of SNAC in an animal model of nonalcoholic steatohepatitis (NASH induced in Sprague-Dawley rats fed with a choline-deficient, high trans fat diet and exposed to diethylnitrosamine for 8 weeks. The rats were divided into three groups: SNAC, which received oral SNAC solution daily; NASH, which received the vehicle; and control, which received standard diet and vehicle. Genes related to fibrosis (matrix metalloproteinases [MMP]-13, -9, and -2, transforming growth factor ß-1 [TGFß-1], collagen-1a, and tissue inhibitors of metalloproteinase [TIMP-1 and -2] and oxidative stress (heat-shock proteins [HSP]-60 and -90 were evaluated. SNAC led to a 34.4% reduction in the collagen occupied area associated with upregulation of MMP-13 and -9 and downregulation of HSP-60, TIMP-2, TGFß-1, and collagen-1α. These results indicate that oral SNAC administration may represent a potential antifibrotic treatment for NASH. Keywords: nitric oxide, S-nitroso-N-acetylcysteine, fibrogenesis, NASH, diethylnitrosamine

  15. Serum markers of liver fibrosis

    DEFF Research Database (Denmark)

    Veidal, Sanne Skovgård; Bay-Jensen, Anne-Christine; Tougas, Gervais;

    2010-01-01

    BACKGROUND: Fibrosis is a central histological feature of chronic liver diseases and is characterized by the accumulation and reorganization of the extracellular matrix. The gold standard for assessment of fibrosis is histological evaluation of a percutaneous liver biopsy. Albeit a considerable......-epitopes, may be targeted for novel biochemical marker development in fibrosis. We used the recently proposed BIPED system (Burden of disease, Investigative, Prognostic, Efficacy and Diagnostic) to characterise present serological markers. METHODS: Pubmed was search for keywords; Liver fibrosis, neo...... systematic use of the neo-epitope approach, i.e. the quantification of peptide epitopes generated from enzymatic cleavage of proteins during extracellular remodeling, may prove productive in the quest to find new markers of liver fibrosis....

  16. Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis.

    Science.gov (United States)

    Jeftic, Ilija; Jovicic, Nemanja; Pantic, Jelena; Arsenijevic, Nebojsa; Lukic, Miodrag L; Pejnovic, Nada

    2015-01-01

    The importance of Galectin-3 (Gal-3) in obesity-associated liver pathology is incompletely defined. To dissect the role of Gal-3 in fibrotic nonalcoholic steatohepatitis (NASH), Gal-3-deficient (LGALS3(-/-)) and wild-type (LGALS3(+/+)) C57Bl/6 mice were placed on an obesogenic high fat diet (HFD, 60% kcal fat) or standard chow diet for 12 and 24 wks. Compared to WT mice, HFD-fed LGALS3(-/-) mice developed, in addition to increased visceral adiposity and diabetes, marked liver steatosis, which was accompanied with higher expression of hepatic PPAR-γ, Cd36, Abca-1 and FAS. However, as opposed to LGALS3(-/-) mice, hepatocellular damage, inflammation and fibrosis were more extensive in WT mice which had an elevated number of mature myeloid dendritic cells, proinflammatory CD11b(+)Ly6C(hi) monocytes/macrophages in liver, peripheral blood and bone marrow, and increased hepatic CCL2, F4/80, CD11c, TLR4, CD14, NLRP3 inflammasome, IL-1β and NADPH-oxidase enzymes mRNA expression. Thus, obesity-driven greater steatosis was uncoupled with attenuated fibrotic NASH in Gal-3-deficient mice. HFD-fed WT mice had a higher number of hepatocytes that strongly expressed IL-33 and hepatic CD11b(+)IL-13(+) cells, increased levels of IL-33 and IL-13 and up-regulated IL-33, ST2 and IL-13 mRNA in liver compared with LGALS3(-/-) mice. IL-33 failed to induce ST2 upregulation and IL-13 production by LGALS3(-/-) peritoneal macrophages in vitro. Administration of IL-33 in vivo enhanced liver fibrosis in HFD-fed mice in both genotypes, albeit to a significantly lower extent in LGALS3(-/-) mice, which was associated with less numerous hepatic IL-13-expressing CD11b(+) cells. The present study provides evidence of a novel role for Gal-3 in regulating IL-33-dependent liver fibrosis. PMID:26018806

  17. Potent effects of dioscin against liver fibrosis

    Science.gov (United States)

    Zhang, Xiaoling; Han, Xu; Yin, Lianhong; Xu, Lina; Qi, Yan; Xu, Youwei; Sun, Huijun; Lin, Yuan; Liu, Kexin; Peng, Jinyong

    2015-01-01

    We previously reported the promising effects of dioscin against liver injury, but its effect on liver fibrosis remains unknown. The present work investigated the activities of dioscin against liver fibrosis and the underlying molecular mechanisms. Dioscin effectively inhibited the cell viabilities of HSC-T6, LX-2 and primary rat hepatic stellate cells (HSCs), but not hepatocytes. Furthermore, dioscin markedly increased peroxisome proliferator activated receptor-γ (PPAR-γ) expression and significantly reduced a-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), collagen α1 (I) (COL1A1) and collagen α1 (III) (COL3A1) levels in vitro. Notably, dioscin inhibited HSCs activation and induced apoptosis in activated HSCs. In vivo, dioscin significantly improved body weight and hydroxylproline, laminin, α-SMA, TGF-β1, COL1A1 and COL3A1 levels, which were confirmed by histopathological assays. Dioscin facilitated matrix degradation, and exhibited hepatoprotective effects through the attenuation of oxidative stress and inflammation, in addition to exerting anti-fibrotic effects through the modulation of the TGF-β1/Smad, Wnt/β-catenin, mitogen-activated protein kinase (MAPK) and mitochondrial signaling pathways, which triggered the senescence of activated HSCs. In conclusion, dioscin exhibited potent effects against liver fibrosis through the modulation of multiple targets and signaling pathways and should be developed as a novel candidate for the treatment of liver fibrosis in the future. PMID:25853178

  18. Dioscin alleviates alcoholic liver fibrosis by attenuating hepatic stellate cell activation via the TLR4/MyD88/NF-κB signaling pathway

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    Liu, Min; Xu, Youwei; Han, Xu; Yin, Lianhong; Xu, Lina; Qi, Yan; Zhao, Yanyan; Liu, Kexin; Peng, Jinyong

    2015-01-01

    The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). In vivo liver fibrosis in mice was induced by an alcoholic liquid diet, and in vitro studies were performed on activated HSC-T6 and LX2 cells treated with lipopolysaccharide. Our results showed that dioscin significantly attenuated hepatic stellate cells (HSCs) activation, improved collagen accumulation, and attenuated inflammation through down-regulating the levels of myeloid differentiation factor 88 (MyD88), nuclear factor κB (NF-κB), interleukin (IL)-1, IL-6 and tumour necrosis factor-α by decreasing Toll-like receptor (TLR)4 expression both in vivo and in vitro. TLR4 overexpression was also decreased by dioscin, leading to the markedly down-regulated levels of MyD88, NF-κB, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) in cultured HSCs. Suppression of cellular MyD88 by ST2825 or abrogation of NF-κB by pyrrolidine dithiocarbamate eliminated the inhibitory effects of dioscin on the levels of TGF-β1, α-SMA and COL1A1. In a word, dioscin exhibited potent effects against ALF via altering TLR4/MyD88/NF-κB signaling pathway, which provided novel insights into the mechanisms of this compound as an antifibrogenic candidate for the treatment of ALF in the future. PMID:26655640

  19. Therapeutic targets in liver fibrosis.

    Science.gov (United States)

    Fallowfield, Jonathan A

    2011-05-01

    Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points. PMID:21233278

  20. Doxazosin Treatment Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Hamsters through a Decrease in Transforming Growth Factor β Secretion

    Science.gov (United States)

    Muñoz-Ortega, Martin Humberto; Llamas-Ramírez, Raúl Wiliberto; Romero-Delgadillo, Norma Isabel; Elías-Flores, Tania Guadalupe; de Jesus Tavares-Rodríguez, Edgar; del Rosario Campos-Esparza, María; Cervantes-García, Daniel; Muñoz-Fernández, Luis; Gerardo-Rodríguez, Martin; Ventura-Juárez, Javier

    2016-01-01

    Background/Aims The development of therapeutic strategies for the treatment of cirrhosis has become an important focus for basic and clinical researchers. Adrenergic receptor antagonists have been evaluated as antifibrotic drugs in rodent models of carbon tetrachloride (CCl4)-induced cirrhosis. The aim of the present study was to evaluate the effects of carvedilol and doxazosin on fibrosis/cirrhosis in a hamster animal model. Methods Cirrhotic-induced hamsters were treated by daily administration of carvedilol and doxazosin for 6 weeks. Hepatic function and histological evaluation were conducted by measuring biochemical markers, including total bilirubin, aspartate aminotransferase, alanine aminotransferase and albumin, and liver tissue slices. Additionally, transforming growth factor β (TGF-β) immunohistochemistry was analyzed. Results Biochemical markers revealed that hepatic function was restored after treatment with doxazosin and carvedilol. Histological evaluation showed a decrease in collagen type I deposits and TGF-β-secreting cells. Conclusions Taken together, these results suggest that the decrease in collagen type I following treatment with doxazosin or carvedilol is achieved by decreasing the profibrotic activities of TGF-β via the blockage of α1- and β-adrenergic receptor. Consequently, a diminution of fibrotic tissue in the CCl4-induced model of cirrhosis is achieved. PMID:26573293

  1. Dendritic Cells and Liver Fibrosis

    OpenAIRE

    Rahman, Adeeb H.; Aloman, Costica

    2013-01-01

    Dendritic cells are a relative rare population of specialized antigen presenting cells that are distributed through most lymphoid and non-lymphoid tissues and play a critical role in linking the innate and adaptive arms of the immune system. The liver contains a heterogeneous population of dendritic cells that may contribute to liver inflammation and fibrosis through a number of mechanisms. This review summarizes current knowledge on the development and characterization of liver dendritic cel...

  2. Liver manifestations of cystic fibrosis

    International Nuclear Information System (INIS)

    Chronic liver disease is one of the major complications of cystic fibrosis (CF). Significant liver disease is seen in 13-25% of children with CF. Improved life expectancy and prolonged follow-up have favored better characterization of the hepatic manifestations of CF and allowed direct observation of an increasing number of liver-related events. Liver disease typically develops in the first decade of life, with the incidence dropping rapidly after the age of 10 years. The wide spectrum of liver disease ranging from asymptomatic gallbladder abnormalities to biliary cirrhosis will be reviewed in this article

  3. [Non-invasive assessment of liver fibrosis].

    Science.gov (United States)

    Cohen-Ezra, Oranit; Ben-Ari, Ziv

    2015-03-01

    Chronic liver diseases represent a major public health problem, accounting for significant morbidity and mortality worldwide. Prognosis and management of chronic liver diseases depend on the amount of liver fibrosis. Liver biopsy has long remained the gold standard for assessment of liver fibrosis. Liver biopsy is an invasive procedure with associated morbidity, it is rarely the cause for mortality, and has a few limitations. During the past two decades, in an attempt to overcome the limitations of liver biopsy, non-invasive methods for the evaluation of liver fibrosis have been developed, mainly in the field of viral hepatitis. This review will focus on different methods available for non-invasive evaluation of liver fibrosis including a biological approach which quantifies serum levels of biomarkers of fibrosis and physical techniques which measure liver stiffness by transient elastography, ultrasound or magnetic resonance based elastography, their accuracy, advantages and disadvantages. PMID:25962254

  4. BIOCONJUGATION OF OLIGONUCLEOTIDES FOR TREATING LIVER FIBROSIS

    OpenAIRE

    Ye, Zhaoyang; Hajj Houssein, Houssam S.; Mahato, Ram I.

    2007-01-01

    Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductul...

  5. Noninvasive Biomarkers of Liver Fibrosis: An Overview

    Directory of Open Access Journals (Sweden)

    Hind I. Fallatah

    2014-01-01

    Full Text Available Chronic liver diseases of differing etiologies are among the leading causes of mortality and morbidity worldwide. Establishing accurate staging of liver disease is very important for enabling both therapeutic decisions and prognostic evaluations. A liver biopsy is considered the gold standard for assessing the stage of hepatic fibrosis, but it has many limitations. During the last decade, several noninvasive markers for assessing the stage of hepatic fibrosis have been developed. Some have been well validated and are comparable to liver biopsy. This paper will focus on the various noninvasive biochemical markers used to stage liver fibrosis.

  6. Noninvasive Markers to Assess Liver Fibrosis.

    Science.gov (United States)

    Czul, Frank; Bhamidimarri, Kalyan R

    2016-07-01

    Chronic liver disease represents a major public health problem, accounting for significant morbidity and mortality worldwide. Their prognosis and management greatly depends on the amount and progression of liver fibrosis with time and the risk of development of cirrhosis. Historically, liver biopsy was considered to be the gold standard for the detection of fibrosis. Nevertheless, liver biopsy is an invasive procedure that has limitations in terms of patient acceptance, risk-benefit ratio, cost-effectiveness, and its availability in various geographic regions. Moreover, it is a questionable gold standard due to significant sampling error and intraobserver and interobserver variability. These limitations have led to the development of noninvasive techniques for assessing the presence and the degree of liver fibrosis. This review aims to revise the most recent data from the literature about noninvasive methods useful in the evaluation of liver fibrosis. PMID:27105176

  7. HIV Infection Accelerates Hepatitis C-Related Liver Fibrosis

    Science.gov (United States)

    ... HIV Infection Accelerates Hepatitis C–Related Liver Fibrosis HIV Infection Accelerates Hepatitis C–Related Liver Fibrosis Email ... the progression of other chronic diseases as well. HIV and Fibrosis Dr. Kirk and his team tapped ...

  8. Transient elastography for liver fibrosis diagnosis

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Christensen, Peer Brehm; Weis, Nina

    2008-01-01

    Liver biopsy is considered the "golden standard" for assessment of hepatic fibrosis. However, the procedure has limitations because of inconvenience and rare but serious complications as bleeding. Furthermore, sampling errors are frequent, and interobserver variability often poses problems....... Recently, a modified ultrasound scanner (transient elastography) has been developed to assess fibrosis. The device measures liver elasticity, which correlates well with the degree of fibrosis. Studies have shown that transient elastography is more accurate in diagnosing cirrhosis than minor to moderate...... fibrosis. Most of the studies have been conducted on patients with chronic hepatitis but a few studies have also covered fibrosis and cirrhosis due to other etiologies, and they also demonstrate the high sensitivity and specificity. Transient elastography for assessment of fibrosis may turn out to be a...

  9. Transient elastography for liver fibrosis diagnosis

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Christensen, Peer Brehm; Weis, Nina

    2009-01-01

    Liver biopsy is considered the "golden standard" for assessment of hepatic fibrosis. However, the procedure has limitations because of inconvenience and rare but serious complications as bleeding. Furthermore, sampling errors are frequent, and interobserver variability often poses problems....... Recently, a modified ultrasound scanner (transient elastography) has been developed to assess fibrosis. The device measures liver elasticity, which correlates well with the degree of fibrosis. Studies have shown that transient elastography is more accurate in diagnosing cirrhosis than minor to moderate...... fibrosis. Most of the studies have been conducted on patients with chronic hepatitis but a few studies have also covered fibrosis and cirrhosis due to other etiologies, and they also demonstrate the high sensitivity and specificity. Transient elastography for assessment of fibrosis may turn out to be a...

  10. Outcome in cystic fibrosis liver disease.

    LENUS (Irish Health Repository)

    Rowland, Marion

    2011-01-01

    Evidence suggests that cystic fibrosis liver disease (CFLD) does not affect mortality or morbidity in patients with cystic fibrosis (CF). The importance of gender and age in outcome in CF makes selection of an appropriate comparison group central to the interpretation of any differences in mortality and morbidity in patients with CFLD.

  11. Targeting the PDGF-B/PDGFR-β Interface with Destruxin A5 to Selectively Block PDGF-BB/PDGFR-ββ Signaling and Attenuate Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Xingqi Wang

    2016-05-01

    Full Text Available PDGF-BB/PDGFR-ββ signaling plays very crucial roles in the process of many diseases such as liver fibrosis. However, drug candidates with selective affinities for PDGF-B/PDGFR-β remain deficient. Here, we identified a natural cyclopeptide termed destruxin A5 that effectively inhibits PDGF-BB-induced PDGFR-β signaling. Interestingly and importantly, the inhibitory mechanism is distinct from the mechanism of tyrosine kinase inhibitors because destruxin A5 does not have the ability to bind to the ATP-binding pocket of PDGFR-β. Using Biacore T200 technology, thermal shift technology, microscale thermophoresis technology and computational analysis, we confirmed that destruxin A5 selectively targets the PDGF-B/PDGFR-β interaction interface to block this signaling. Additionally, the inhibitory effect of destruxin A5 on PDGF-BB/PDGFR-ββ signaling was verified using in vitro, ex vivo and in vivo models, in which the extent of liver fibrosis was effectively alleviated by destruxin A5. In summary, destruxin A5 may represent an efficacious and more selective inhibitor of PDGF-BB/PDGFR-ββ signaling.

  12. Doxycycline Attenuated Pulmonary Fibrosis Induced by Bleomycin in Mice

    OpenAIRE

    Fujita, Masaki; Ye, Qing; Ouchi, Hiroshi; Harada, Eiji; Inoshima, Ichiro; Kuwano, Kazuyoshi; Nakanishi, Yoichi

    2006-01-01

    The administration of doxycycline prior to bleomycin in mice attenuated pulmonary fibrosis. Bronchoalveolar neutrophil influx and gelatinase activity, but not caseinolytic activity, were attenuated by doxycycline. Established fibrosis was not affected by doxycycline. Thus, doxycycline might be useful for slowing down pulmonary fibrosis by biological activity other than antibacterial activity.

  13. Role of NADPH Oxidases in Liver Fibrosis

    OpenAIRE

    Paik, Yong-Han; Kim, Jonghwa; Aoyama, Tomonori; De Minicis, Samuele; Bataller, Ramon; Brenner, David A

    2014-01-01

    Significance: Hepatic fibrosis is the common pathophysiologic process resulting from chronic liver injury, characterized by the accumulation of an excessive extracellular matrix. Multiple lines of evidence indicate that oxidative stress plays a pivotal role in the pathogenesis of liver fibrosis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is a multicomponent enzyme complex that generates reactive oxygen species (ROS) in response to a wide range of stimuli. In addition to...

  14. Correlation between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models

    Institute of Scientific and Technical Information of China (English)

    Qing-He Nie; Ya-Fei Zhang; Yu-Mei Xie; Xin-Dong Luo; Bin Shao; Jun Li; Yong-Xing Zhou

    2006-01-01

    AIM: To evaluate serum TIMP-1 level and the correlation between TIMP-1 expression and liver fibrosis in immuneinduced and CCL4-induced liver fibrosis models in rats.METHODS: Immune-induced and CCL4-induced liver fibrosis models were established by dexamethasone (0.01 mg) and CCL4 respectively. Serum TIMP-1 level was detected with ELISA, while histopathological grade of liver biopsy was evaluated. Spearman rankcorrelation test was used to analyse the difference of the correlation between the TIMP-1 expression and hepatic fibrosis in the two fibrosis models. Furthermore,in situ hybridization was used to determine the expression difference of TIMP-1 mRNA in the two models.RESULTS: Positive correlation existed between serum TIMP-1 level of immune induced group and the histopathological stages of fibrosis liver of corresponding rats (Spearman rank-correlation test, rs = 0.812, P < 0.05), and the positivein situ hybridization signal of TIMP-1 mRNA was strong. In CCL4-induced liver fibrosis model, the correlation between the serum TIMP-1 level and the severity of hepatic fibrosis was not statistically significant(Spearman rank-correlation test, rs = 0.229, P > 0.05). And compared with immune-induced model,the positive in situ hybridization signal of TIMP-1 mRNA was weaker, while the expression variation was higher in hepatic fibrosis of the same severity.CONCLUSION: The correlations between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models are different. In immune-induced model, serum TIMP-1 level could reflect the severity of liver fibrosis,while in CCL4-induced model, the correlation between the serum TIMP-1 level and the severity of hepatic fibrosis was not statistically significant.

  15. Bioconjugation of oligonucleotides for treating liver fibrosis.

    Science.gov (United States)

    Ye, Zhaoyang; Houssein, Houssam S Hajj; Mahato, Ram I

    2007-01-01

    Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is urgently needed to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remain the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of alpha1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in-depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed. PMID:18154454

  16. Hepatic inflammation and progressive liver fibrosis in chronic liver disease

    OpenAIRE

    Czaja, Albert J

    2014-01-01

    Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to ...

  17. Geranylgeranylacetone attenuates hepatic fibrosis by increasing the expression of heat shock protein 70.

    Science.gov (United States)

    He, Wei; Zhuang, Yun; Wang, Liangzhi; Qi, Lei; Chen, Binfang; Wang, Mei; Shao, Dong; Chen, Jianping

    2015-10-01

    Increasing evidence has demonstrated that the heat shock protein 70 (HSP70) gene may be closely associated with tissue fibrosis; however, the association between HSP70 and liver fibrosis remains to be fully elucidated. The present study hypothesized that geranylgeranylacetone (GGA) exerts beneficial effects on liver fibrosis though upregulation of the expression of HSP70. Liver fibrosis was induced in rats using carbon tetrachloride (CCl4). The rats were subsequently divided into three groups: Control group, CCl4 model group and CCl4 model + GGA group. Liver fibrosis in the rats was evaluated using hematoxylin and eosin staining, Masson's trichrome staining and Sirius red staining. The levels of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin were determined using an automated biochemistry analyzer. The levels of total hepatic hydroxyproline were also determined. The expression levels of α‑smooth muscle actin (α‑SMA) and transforming growth factor‑β1 (TGF‑β1) were determined using immunofluorescence staining and western blotting, and the protein expression levels of HSP70 were determined using western blotting. The CCl4‑induced rats exhibited liver fibrosis, increased hydroxyproline content, impaired liver function, upregulated expression levels of the α‑SMA and TGF‑β1 pro‑fibrogenic proteins, and increased expression of HSP70, compared with the control group. These changes were attenuated by treatment with GGA. These results demonstrated that GGA exerted beneficial effects in CCl4‑induced liver fibrosis via upregulating the expression of HSP70. PMID:26165998

  18. Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

    Institute of Scientific and Technical Information of China (English)

    En-tong YI; Rui-xia LIU; Yan WEN; Cheng-hong YIN

    2012-01-01

    Aim: To evaluate the antifibrotic effect of telmisartan,an angiotensin Ⅱ receptor blocker,in bile duct-ligated rats.Methods: Adult Sprague-Dawley rats were allocated to 3 groups: sham-operated rats,model rats underwent common bile duct ligation (BDL),and BDL rats treated with telmisartan (8 mg/kg,po,for 4 weeks).The animals were sacrificed on d 29,and liver histology was examined,the Knodell and Ishak scores were assigned,and the expression of angiotensin-converting enzyme (ACE) and ACE2 was evaluated with immunohistochemical staining.The mRNAs and proteins associated with liver fibrosis were evaluated using RTQ-PCR and Western blot,respectively.Results: The mean fibrosis score of BDL rats treated with telmisartan was significantly lower than that of the model rats (1.66±0.87 vs 2.13±0.35,P=0.015).However,there was no significant difference in inflammation between the two groups,both of which showed moderate inflammation.Histologically,treatment with telmisartan significantly ameliorated BDL-caused the hepatic fibrosis.Treatment with telmisartan significantly upregulated the mRNA levels of ACE2 and MAS,and decreased the mRNA levels of ACE,angiotensin Ⅱ type 1 receptor (AT1-R),collagen type Ⅲ,and transforming growth factor β1 (TGF-β1).Moreover,treatment with telmisartan significantly increased the expression levels of ACE2 and MAS proteins,and inhibited the expression levels of ACE and AT1-R protein.Conclusion: Telmisartan attenuates liver fibrosis in bile duct-ligated rats via increasing ACE2 expression level.

  19. Mouse models of liver fibrosis mimic human liver fibrosis of different etiologies.

    Science.gov (United States)

    Martínez, Allyson K; Maroni, Luca; Marzioni, Marco; Ahmed, Syed T; Milad, Mena; Ray, Debolina; Alpini, Gianfranco; Glaser, Shannon S

    2014-12-01

    The liver has the amazing capacity to repair itself after injury; however, the same processes that are involved in liver regeneration after acute injury can cause serious consequences during chronic liver injury. In an effort to repair damage, activated hepatic stellate cells trigger a cascade of events that lead to deposition and accumulation of extracellular matrix components causing the progressive replacement of the liver parenchyma by scar tissue, thus resulting in fibrosis. Although fibrosis occurs as a result of many chronic liver diseases, the molecular mechanisms involved depend on the underlying etiology. Since studying liver fibrosis in human subjects is complicated by many factors, mouse models of liver fibrosis that mimic the human conditions fill this void. This review summarizes the general mouse models of liver fibrosis and mouse models that mimic specific human disease conditions that result in liver fibrosis. Additionally, recent progress that has been made in understanding the molecular mechanisms involved in the fibrogenic processes of each of the human disease conditions is highlighted. PMID:25396098

  20. Serum parameters of liver fibrosis

    OpenAIRE

    Zanten, R. A A

    1991-01-01

    textabstractChronic liver disease is often associated with deposition of fibrous tissue, a process which together with the destruction of normal liver and liver cell regeneration, leads to the condition called cirrhosis. Cirrhosis is known to be associated with a reduction in life expectancy. In recent years there has been an increasing interest in the pathogenesis of cirrhosis and in the possibilities reversing the process of fibrogenesis. Liver biopsy is the present "gold standard" for dete...

  1. Serum parameters of liver fibrosis

    NARCIS (Netherlands)

    R.A.A. van Zanten

    1991-01-01

    textabstractChronic liver disease is often associated with deposition of fibrous tissue, a process which together with the destruction of normal liver and liver cell regeneration, leads to the condition called cirrhosis. Cirrhosis is known to be associated with a reduction in life expectancy. In rec

  2. Assessment of liver fibrosis: Noninvasive means

    Directory of Open Access Journals (Sweden)

    Poynard Thierry

    2008-01-01

    Full Text Available Liver biopsy, owing to its limitations and risks, is an imperfect gold standard for assessing the severity of the most frequent chronic liver diseases chronic hepatitis C (HCV, B (HBV non alcoholic (NAFLD and alcoholic (ALD fatty liver diseases. This review summarizes the advantages and the limits of the available biomarkers of liver fibrosis. Among a total of 2,237 references, a total of 14 validated serum biomarkers have been identified between 1991 and 2008. Nine were not patented and five were patented. Two alternatives to liver biopsy were the most evaluated FibroTest and Fibroscan. For FibroTest, there was a total of 38 different populations including 7,985 subjects with both FibroTest and biopsy (4,600 HCV, 1,580 HBV, 267 NAFLD, 524 ALD, and 1014 mixed. For Fibroscan, there was a total of 11 published studies including 2,260 subjects (1,466 HCV, 95 cholestatic liver disease, and 699 mixed. For FibroTest, the mean diagnostic value for the diagnosis of advanced fibrosis assessed using standardized area under the ROC curves was 0.84 (95% confidence interval 0.83-0.86, without a significant difference between the causes of liver disease, hepatitis C, hepatitis B, and alcoholic or non alcoholic fatty liver disease. High-risk profiles of false negative/false positive of FibroTest, mainly Gilbert syndrome, hemolysis and acute inflammation, are present in 3% of the populations. In case of discordance between biopsy and FibroTest, half of the failures can be due to biopsy; the prognostic value of FibroTest is at least similar to that of biopsy in HCV, HBV and ALD. In conclusion this overview of evidence-based data suggests that biomarkers could be used as an alternative to liver biopsy for the first line assessment of fibrosis stage in the four most common chronic liver diseases, namely HCV, HBV, NAFLD and ALD. Neither biomarkers nor biopsy alone is sufficient for taking a definite decision in a given patient; all the clinical and biological data

  3. Biopsy-controlled liver fibrosis staging using the enhanced liver fibrosis (ELF score compared to transient elastography.

    Directory of Open Access Journals (Sweden)

    Kristin Wahl

    Full Text Available BACKGROUND AND AIMS: Chronic liver diseases are characterized by inflammatory and fibrotic liver injuries that often result in liver cirrhosis with its associated complications such as portal hypertension and hepatocellular carcinoma. Liver biopsy still represents the reference standard for fibrosis staging, although transient elastography is increasingly used for non-invasive monitoring of fibrosis progression. However, this method is not generally available and is associated with technical limitations emphasizing the need for serological biomarkers staging of liver fibrosis. The enhanced liver fibrosis (ELF score was shown to accurately predict significant liver fibrosis in different liver diseases, although extracellular matrix components detected by this score may not only mirror the extent of liver fibrosis but also inflammatory processes. METHODS: In this prospective biopsy-controlled study we evaluated the utility of the ELF score in comparison to transient elastography to predict different stages of fibrosis in 102 patients with chronic liver diseases. RESULTS: Both techniques revealed similar area under receiver operating characteristic curve values for prediction of advanced fibrosis stages. Compared to transient elastography, the ELF score showed a broader overlap between low and moderate fibrosis stages and a stronger correlation with inflammatory liver injury. CONCLUSIONS: Both the ELF score as well as transient elastography allowed for high quality fibrosis staging. However, the ELF score was less discriminative in low and moderate fibrosis stages and appeared more strongly influenced by inflammatory liver injury. This should be considered when making clinical interpretations on the basis of ELF score values.

  4. Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection

    Directory of Open Access Journals (Sweden)

    Lindsey J. Reese

    2012-01-01

    Full Text Available Background. Liver fibrosis is accelerated in HIV and hepatitis C coinfection, mediated by profibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is attenuate liver fibrosis in coinfection. Methods. A retrospective review of 156 coinfected subjects was conducted to analyze the association between exposure to ACE-Is and liver fibrosis. Noninvasive indices of liver fibrosis (APRI, FIB-4, Forns indices were compared between subjects who had taken ACE-Is and controls who had not taken them. Linear regression was used to evaluate ACE-I use as an independent predictor of fibrosis. Results. Subjects taking ACE-Is for three years were no different than controls on the APRI and the FIB-4 but had significantly higher scores than controls on the Forns index, indicating more advanced fibrosis. The use of ACE-Is for three years remained independently associated with an elevated Forns score when adjusted for age, race, and HIV viral load (P<0.001. There were significant associations between all of the indices and significant fibrosis, as determined clinically and radiologically. Conclusions. There was not a protective association between angiotensin inhibition and liver fibrosis in coinfection. These noninvasive indices may be useful for ruling out significant fibrosis in coinfection.

  5. Promising Therapy Candidates for Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Ping eWang

    2016-02-01

    Full Text Available Liver fibrosis is a wound-healing process in response to repeated and chronic injury to hepatocytes and/or cholangiocytes. Ongoing hepatocyte apoptosis or necrosis lead to increase in ROS production and decrease in antioxidant activity, which recruits inflammatory cells from the blood and activate hepatic stellate cells changing to myofibroblasts. Injury to cholangiocytes also recruits inflammatory cells to the liver and activates portal fibroblasts in the portal area, which release molecules to activate and amplify cholangiocytes. No matter what origin of myofibroblasts, either hepatic stellate cells or portal fibroblasts, they share similar characteristics, including being positive for -smooth muscle actin and sproducing extra cellular matrix. Based on the extensive pathogenesis knowledge of liver fibrosis, therapeutic strategies have been designed to target each step of this process, including hepatocyte apoptosis, cholangiocyte proliferation, inflammation, and activation of myofibroblasts to deposit extracellular matrix, yet the current therapies are still in early-phase clinical development. There is an urgent need to translate the molecular mechanism of liver fibrosis to effective and potent reagents or therapies in human.

  6. Natural Killer cells and liver fibrosis

    Directory of Open Access Journals (Sweden)

    Frank eFasbender

    2016-01-01

    Full Text Available In the 40 years since the discovery of Natural Killer (NK cells it has been well established that these innate lymphocytes are important for early and effective immune responses against transformed cells and infections with different pathogens. In addition to these classical functions of NK cells, we now know that they are part of a larger family of innate lymphoid cells and that they can even mediate memory-like responses. Additionally, tissue resident NK cells with distinct phenotypical and functional characteristics have been identified. Here we focus on the phenotype of different NK cell subpopulations that can be found in the liver and summarize the current knowledge about the functional role of these cells with a special emphasis on liver fibrosis. NK cell cytotoxicity can contribute to liver damage in different forms of liver disease. However, NK cells can limit liver fibrosis by killing hepatic stellate cell-derived myofibroblasts, which play a key role in this pathogenic process. Therefore, liver NK cells need to be tightly regulated in order to balance these beneficial and pathological effects.

  7. Computed tomography findings in liver fibrosis and cirrhosis

    OpenAIRE

    Huber, Adrian Thomas; Ebner, Lukas Michael; Montani, Matteo; Semmo, Nasser; Roy, Choudhury; Heverhagen, Johannes; Christe, Andreas

    2014-01-01

    Abstract PRINCIPLES: Computed tomography (CT) is inferior to the fibroscan and laboratory testing in the noninvasive diagnosis of liver fibrosis. On the other hand, CT is a frequently used diagnostic tool in modern medicine. The auxiliary finding of clinically occult liver fibrosis in CT scans could result in an earlier diagnosis. The aim of this study was to analyse quantifiable direct signs of liver remodelling in CT scans to depict liver fibrosis in a precirrhotic stage. METHO...

  8. Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

    Science.gov (United States)

    Liu, Ziyi; Cao, Zongxian; Jourdan, Tony; Erdelyi, Katalin; Godlewski, Grzegorz; Szanda, Gergő; Liu, Jie; Park, Joshua K.; Mukhopadhyay, Bani; Rosenberg, Avi Z.; Liow, Jeih-San; Lorenz, Robin G.; Pacher, Pal; Innis, Robert B.; Kunos, George

    2016-01-01

    Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases. Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group. In mouse models of fibrosis induced by CCl4 or bile duct ligation, the hybrid CB1R/iNOS antagonist surpassed the antifibrotic efficacy of the CB1R antagonist rimonabant or the iNOS inhibitor 1400W, without inducing anxiety-like behaviors or CB1R occupancy in the CNS. The hybrid inhibitor also targeted CB1R-independent, iNOS-mediated profibrotic pathways, including increased PDGF, Nlrp3/Asc3, and integrin αvβ6 signaling, as judged by its ability to inhibit these pathways in cnr1−/− but not in nos2−/− mice. Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

  9. Liver Fibrosis: From Pathogenesis to Novel Therapies.

    Science.gov (United States)

    Weiskirchen, Ralf; Tacke, Frank

    2016-01-01

    Chronic liver injury is accompanied by a dysbalanced scarring process, termed fibrosis. This process is mainly driven by chronic inflammation and an altered activity of a multitude of different chemokines and cytokines, resulting in the infiltration by immune cells (especially macrophages) and increase of matrix-expressing cell types. These processes might lead to cirrhosis representing the end-stage of fibrosis. Recent clinical studies comprising patients successfully treated for viral hepatitis showed that liver fibrogenesis and even cirrhosis may be reverted. The hepatic capacity to remodel scar tissue and to revert into a normal liver follows specific mechanistic principles that include the termination of chronic tissue damage, shifting the cellular bias from inflammation to resolution, initiation of myofibroblast apoptosis or senescence and, finally, fibrinolysis of excess scar tissue. The plurality of molecular and cellular triggers involved in initiation, progression and resolution of hepatic fibrogenesis offers an infinite number of therapeutic possibilities. For instance, inflammatory macrophages can be targeted via inhibition of chemokine CCL2 or its receptor CCR2 (e.g., by cenicriviroc) as well as by transfer of restorative macrophage subsets. Another target is galectin-3 that acts at various stages along the continuum from acute to chronic inflammation. Profibrogenic cytokines (e.g., transforming growth factor-β), matricellular proteins (e.g., CCN1/CYR61) or signaling pathways involved in fibrogenesis offer further possible targets. Other options are the application of therapeutic antibodies directed against components involved in biogenesis or remodeling of connective tissue such as lysyl oxidase-like-2 or synthetic bile acids like obeticholic acid that activate the farnesoid X receptor and was antifibrotic in a phase 2 study (FLINT trial). Factors affecting the gut barrier function or the intestinal microbiome further expanded the repertoire of drug

  10. Taurine attenuates radiation-induced lung fibrosis in C57/Bl6 fibrosis prone mice.

    LENUS (Irish Health Repository)

    Robb, W B

    2010-03-01

    The amino acid taurine has an established role in attenuating lung fibrosis secondary to bleomycin-induced injury. This study evaluates taurine\\'s effect on TGF-beta1 expression and the development of lung fibrosis after single-dose thoracic radiotherapy.

  11. Liver fibrosis caused by choledocholith to regress after biliary drainage

    Institute of Scientific and Technical Information of China (English)

    Zuo-Bing Chen; Shu-Sen Zheng; Guo-Zhi Hu; Yuan Gao; Chen-Yan Ding; Yun Zhang; Xue-Hong Zhao; Lin-Mei Ni

    2005-01-01

    AIM: To study the correlation between liver fibrosis severity and biliary drainage in patients with choledocholith.METHODS: A follow-up study on seven patients with liver fibrosis due to choledocholith was made. The data, including biochemical tests (aspartate aminotransferase, alanine aminotransferase) and liver histological features before and after biliary drainage, were collected and studied. The fibrosis severity was scored on a scale from 0 to 3, with 0 denoting none, 1 portal and periportal fibrosis, 2 the presence of numerous fiber septa, and 3 cirrhosis. The average liver fibrosis severity scores of the first and second biopsy were compared with statistical method.RESULTS: The first, second liver fibrosis severity scores of these seven patients were 2,1; 2,1; 1,0; 1,1; 2,1; 2,1;1,0 respectively. The results showed that the average liver fibrosis severity score of the second liver biopsy decreased significantly compared with the first liver biopsy (n = 7, t = 4.25, P<0.05).CONCLUSION: Liver fibrosis due to choledocholith may regress after biliary drainage.

  12. Accuracy of FibroScan for diagnosing liver fibrosis

    Directory of Open Access Journals (Sweden)

    Jian ZHANG

    2011-11-01

    Full Text Available Objective To evaluate the accuracy of transient elastometry(FibroScan for the detection of liver fibrosis.Methods A total of 323 patients diagnosed with chronic liver disease based on pathological examination in the 302 Hospital of the People’s Liberation Army from April to December of 2009 were involved in the current study.Among them,141 patients were subjected to liver biopsy.Their liver function,coagulant index,B-ultrasound and blood cell count were examined clinically.Four examinations related to liver fibrosis were done on some of the patients.Meanwhile,FibroScan was used for liver stiffness measurement(LSM of every patient.The correlation between liver stiffness and the serologic index and liver fibrosis degree was analyzed.The Receive Operating Characteristic(ROC curve was adopted to analyze the accuracy of FibroScan for diagnosing liver fibrosis.Results Each serologic index was significantly correlated with liver stiffness(P < 0.001,and liver stiffness was closely related to the stage of liver fibrosis(r=0.74,P < 0.001.The statistical results of the 141 patients who underwent pathologic examination show that the areas under the ROC curve were 0.97(0.94,1.00 for patients with portal fibrosis(F1,0.96(0.93,0.99 for patients with significant fibrosis(F2,0.99(0.98,1.00 for patients with severe fibrosis(F3,and 0.97(0.94,0.99 for patients with cirrhosis(F4.The cutoff values were 4.4KPa,6.8KPa,9.7KPa,and 10.0KPa,respectively.Conclusion FibroScan is valuable for the diagnosis of liver fibrosis.It can be used as the basis for follow-up and management of patients with chronic liver diseases.

  13. Update of liver fibrosis and steatosis with transient elastography (Fibroscan)

    OpenAIRE

    Wong, Grace Lai-Hung

    2013-01-01

    Background: Assessment of liver fibrosis and steatosis is now almost indispensable in most of the chronic liver diseases in order to determine prognosis and need for treatment, and to monitor disease progression and response to treatment. Liver biopsy is limited by its invasiveness and patient acceptability. Transient elastography (TE; Fibroscan) is a non-invasive tool with satisfactory accuracy and reproducibility to estimate liver fibrosis. Aims & Methods: To review the existing evidence co...

  14. Liver fibrosis in vitro : Cell culture models and precision-cut liver slices

    NARCIS (Netherlands)

    de Bovenkamp, M. Van; Groothuis, G. M. M.; Meijer, D. K. F.; Olinga, P.

    2007-01-01

    Chronic liver injury of various etiologies can cause liver fibrosis, which is characterized by the progressive accumulation of connective tissue in the liver. As no effective treatment for liver fibrosis is available yet, extensive research is ongoing to further study the mechanisms underlying the d

  15. Assessment of liver fibrosis by Fibroscan as compared to liver biopsy in biliary atresia

    OpenAIRE

    Shen, Qiu-Long; Chen, Ya-Jun; Wang, Zeng-Meng; Zhang, Ting-Chong; Pang, Wen-Bo; Shu, Jun; Peng, Chun-Hui

    2015-01-01

    AIM: To evaluate liver stiffness measurement (LSM) using non-invasive transient elastography (Fibroscan) in comparison with liver biopsy for assessment of liver fibrosis in children with biliary atresia (BA).

  16. Dynamics of allograft fibrosis in pediatric liver transplantation.

    Science.gov (United States)

    Venturi, C; Sempoux, C; Quinones, J A; Bourdeaux, C; Hoyos, S P; Sokal, E; Reding, R

    2014-07-01

    Progressive liver allograft fibrosis (LAF) is well known to occur long term, as shown by its high prevalence in late posttransplant liver biopsies (LBs). To evaluate the influence of clinical variables and immunosuppression on LAF progression, LAF dynamic was assessed in 54 pediatric liver transplantation (LT) recipients at 6 months, 3 and 7 years post-LT, reviewing clinical, biochemical data and protocol LBs using METAVIR and the liver allograft fibrosis score, previously designed and validated specifically for LAF assessment. Scoring evaluations were correlated with fibrosis quantification by morphometric analysis. Progressive LAF was found in 74% of long-term patients, 70% of whom had unaltered liver enzymes. Deceased grafts showed more fibrosis than living-related grafts (p = 0.0001). Portal fibrosis was observed in correlation with prolonged ischemia time, deceased grafts and lymphoproliferative disease (p = 0.001, 0.006 and 0.012, respectively). Sinusoidal fibrosis was correlated with biliary complications (p = 0.01). Centrilobular fibrosis was associated with vascular complications (p = 0.044), positive autoantibodies (p = 0.017) and high gamma-globulins levels (p = 0.028). Steroid therapy was not associated with reduced fibrosis (p = 0.83). LAF could be viewed as a dynamic process with mostly progression along the time. Peri- and post-LT-associated factors may condition fibrosis development in a specific area of the liver parenchyma. PMID:24934832

  17. The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis

    OpenAIRE

    Jung, Gwon-Soo; Kim, Mi-Kyung; Choe, Mi Sun; Lee, Kyeong-Min; Kim, Hye-Soon; Park, Young Joo; Choi, Hueng-Sik; Lee, Ki-Up; Park, Keun-Gyu; Lee, In-Kyu

    2009-01-01

    The accumulation of extracellular matrix proteins is a common feature of fibrotic kidney diseases. Accumulating evidence suggests that TGF-β and plasminogen activator inhibitor type 1 (PAI-1) promote the development of renal fibrosis by stimulating the generation and inhibiting the removal of matrix proteins. The small heterodimer partner (SHP) represses PAI-1 expression in the liver by inhibiting TGF-β signaling, but whether SHP inhibits renal fibrosis is unknown. Here, unilateral ureteral o...

  18. Contemporary use of elastography in liver fibrosis and portal hypertension

    DEFF Research Database (Denmark)

    Thiele, Maja; Kjærgaard, Maria; Thielsen, Peter;

    2016-01-01

    The risk and speed of progression from fibrosis to compensated and decompensated cirrhosis define the prognosis in liver diseases. Therefore, early detection and preventive strategies affect outcomes. Patients with liver disease have traditionally been diagnosed at an advanced stage of disease, in...... part due to lack of non-invasive markers. Ultrasound elastography to measure liver stiffness can potentially change this paradigm. The purpose of this review was therefore to summarize advances in the field of ultrasound elastography with focus on diagnosis of liver fibrosis, cirrhosis and clinically....... That said, the role of elastography in other aetiologies such as alcoholic- and non-alcoholic liver fibrosis still needs clarification. Although elastography can be used to diagnose liver fibrosis and cirrhosis, its true potential lies in the possibility of multiple, repeated measurements that allow...

  19. Liver Hemangioma Might Lead to overestimation of Liver Fibrosis by Fibroscan; A Missed Issue in Two Cases

    OpenAIRE

    Seyed Hossein Aalaei-Andabili; Leila Mehrnoush; Shima Salimi; Mustafa Shafiei; Seyed Moayed Alavian

    2012-01-01

    Background: The assessment of liver fibrosis is an important way for prediction of liver disease progression and patient’s prognosis. Liver stiffness measurement (LSM) is strongly associated with stage of liver diseases. Overestimation of liver fibrosis in heart failure has been reported. We would like to introduce a new leading cause of liver fibrosis overestimation by presentation of two cases.Case Presentation: One case with right lobe hemangioma has an overestimation of liver fibrosis. Th...

  20. Endothelial Dysfunction Correlates with Liver Fibrosis in Chronic HCV Infection

    OpenAIRE

    Michele Barone; Maria Teresa Viggiani; Annabianca Amoruso; Serafina Schiraldi; Annapaola Zito; Fiorella Devito; Francesca Cortese; Michele Gesualdo; Natale Brunetti; Alfredo Di Leo; Pietro Scicchitano; Marco Matteo Ciccone

    2015-01-01

    Background. Hepatitis C virus (HCV) infection can exert proatherogenic activities due to its direct action on vessel walls and/or via the chronic inflammatory process involving the liver. Aims. To clarify the role of HCV in atherosclerosis development in monoinfected HCV patients at different degrees of liver fibrosis and with no risk factors for coronary artery disease. Methods. Forty-five patients were included. Clinical, serological, and anthropometric parameters, liver fibrosis (transient...

  1. Fibrosis Assessment in Nonalcoholic Fatty Liver Disease (NAFLD) in 2016.

    Science.gov (United States)

    Kaswala, Dharmesh H; Lai, Michelle; Afdhal, Nezam H

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver pathologies characterized by hepatic steatosis with a history of little to no alcohol consumption or secondary causes of hepatic steatosis. The prevalence of NAFLD is 20-25 % of the general population in the Western countries and is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. The spectrum of disease ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis. Advanced fibrosis is the most significant predictor of mortality in NAFLD. It is crucial to assess for the presence and degree of hepatic fibrosis in order to make therapeutic decisions and predict clinical outcomes. Liver biopsy, the current gold standard to assess the liver fibrosis, has a number of drawbacks such as invasiveness, sampling error, cost, and inter-/intra-observer variability. There are currently available a number of noninvasive tests as an alternative to liver biopsy for fibrosis staging. These noninvasive fibrosis tests are increasingly used to rule out advanced fibrosis and help guide disease management. While these noninvasive tests perform relatively well for ruling out advanced fibrosis, they also have limitations. Understanding the strengths and limitations of liver biopsy and the noninvasive tests is necessary for deciding when to use the appropriate tests in the evaluation of patients with NAFLD. PMID:27017224

  2. The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Pietrobattista Andrea

    2009-05-01

    Full Text Available Abstract Background Liver fibrosis is a stage of non-alcoholic fatty liver disease (NAFLD which is responsible for liver-related morbidity and mortality in adults. Accordingly, the search for non-invasive markers of liver fibrosis has been the subject of intensive efforts in adults with NAFLD. Here, we developed a simple algorithm for the prediction of liver fibrosis in children with NAFLD followed at a tertiary care center. Methods The study included 136 male and 67 female children with NAFLD aged 3.3 to 18.0 years; 141 (69% of them had fibrosis at liver biopsy. On the basis of biological plausibility, readily availability and evidence from adult studies, we evaluated the following potential predictors of liver fibrosis at bootstrapped stepwise logistic regression: gender, age, body mass index, waist circumference, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase, albumin, prothrombin time, glucose, insulin, triglycerides and cholesterol. A final model was developed using bootstrapped logistic regression with bias-correction. We used this model to develop the 'pediatric NAFLD fibrosis index' (PNFI, which varies between 0 and 10. Results The final model was based on age, waist circumference and triglycerides and had a area under the receiver operating characteristic curve of 0.85 (95% bootstrapped confidence interval (CI with bias correction 0.80 to 0.90 for the prediction of liver fibrosis. A PNFI ≥ 9 (positive likelihood ratio = 28.6, 95% CI 4.0 to 201.0; positive predictive value = 98.5, 95% CI 91.8 to 100.0 could be used to rule in liver fibrosis without performing liver biopsy. Conclusion PNFI may help clinicians to predict liver fibrosis in children with NAFLD, but external validation is needed before it can be employed for this purpose.

  3. Current Strategies for Quantitating Fibrosis in Liver Biopsy

    Directory of Open Access Journals (Sweden)

    Yan Wang

    2015-01-01

    Full Text Available Objective: The present mini-review updated the progress in methodologies based on using liver biopsy. Data Sources: Articles for study of liver fibrosis, liver biopsy or fibrosis assessment published on high impact peer review journals from 1980 to 2014. Study Selection: Key articles were selected mainly according to their levels of relevance to this topic and citations. Results: With the recently mounting progress in chronic liver disease therapeutics, comes by a pressing need for precise, accurate, and dynamic assessment of hepatic fibrosis and cirrhosis in individual patients. Histopathological information is recognized as the most valuable data for fibrosis assessment. Conventional histology categorical systems describe the changes of fibrosis patterns in liver tissue; but the simplified ordinal digits assigned by these systems cannot reflect the fibrosis dynamics with sufficient precision and reproducibility. Morphometric assessment by computer assist digital image analysis, such as collagen proportionate area (CPA, detects change of fibrosis amount in tissue section in a continuous variable, and has shown its independent diagnostic value for assessment of advanced or late-stage of fibrosis. Due to its evident sensitivity to sampling variances, morphometric measurement is feasible to be taken as a reliable statistical parameter for the study of a large cohort. Combining state-of-art imaging technology and fundamental principle in Tissue Engineering, structure-based quantitation was recently initiated with a novel proof-of-concept tool, qFibrosis. qFibrosis showed not only the superior performance to CPA in accurately and reproducibly differentiating adjacent stages of fibrosis, but also the possibility for facilitating analysis of fibrotic regression and cirrhosis sub-staging. Conclusions: With input from multidisciplinary innovation, liver biopsy assessment as a new "gold standard" is anticipated to substantially support the accelerated

  4. Current Strategies for Quantitating Fibrosis in Liver Biopsy

    Institute of Scientific and Technical Information of China (English)

    Yan Wang; Jin-Lin Hou

    2015-01-01

    Objective:The present mini-review updated the progress in methodologies based on using liver biopsy.Data Sources:Articles for study of liver fibrosis,liver biopsy or fibrosis assessment published on high impact peer review journals from 1980 to 2014.Study Selection:Key articles were selected mainly according to their levels of relevance to this topic and citations.Results:With the recently mounting progress in chronic liver disease therapeutics,comes by a pressing need for precise,accurate,and dynamic assessment of hepatic fibrosis and cirrhosis in individual patients.Histopathological information is recognized as the most valuable data for fibrosis assessment.Conventional histology categorical systems describe the changes of fibrosis patterns in liver tissue; but the simplified ordinal digits assigned by these systems cannot reflect the fibrosis dynamics with sufficient precision and reproducibility.Morphometric assessment by computer assist digital image analysis,such as collagen proportionate area (CPA),detects change of fibrosis amount in tissue section in a continuous variable,and has shown its independent diagnostic value for assessment of advanced or late-stage of fibrosis.Due to its evident sensitivity to sampling variances,morphometric measurement is feasible to be taken as a reliable statistical parameter for the study of a large cohort.Combining state-of-art imaging technology and fundamental principle in Tissue Engineering,structure-based quantitation was recently initiated with a novel proof-of-concept tool,qFibrosis.qFibrosis showed not only the superior performance to CPA in accurately and reproducibly differentiating adjacent stages of fibrosis,but also the possibility for facilitating analysis of fibrotic regression and cirrhosis sub-staging.Conclusions:With input from multidisciplinary innovation,liver biopsy assessment as a new "gold standard" is anticipated to substantially support the accelerated progress of Hepatology medicine.

  5. Fibroscan ® : A noninvasive test of liver fibrosis assessment

    Directory of Open Access Journals (Sweden)

    Al-Ghamdi Abdullah

    2007-01-01

    Full Text Available Determination of the extent of progress of hepatic fibrosis is important in clinical practice, where it may reflect the severity of liver disease and predict response to treatment. Percutaneous liver biopsy is the gold standard for grading and staging of liver disease. However, liver biopsy is an invasive procedure with certain unavoidable risks and complications. Several methods have been studied in an attempt to reach a diagnosis of cirrhosis by noninvasive means. Fibroscan ® has been designed to quantify liver fibrosis by means of elastography and found to have reasonably good sensitivity and specificity patterns, especially in patients with advanced fibrosis and can be used as an alternative to liver biopsy.

  6. Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating against TGF-β1.

    Directory of Open Access Journals (Sweden)

    Xiaobao Fan

    Full Text Available Transforming growth factor β1 (TGF-β1 is the pivotal pro-fibrogenic cytokine in hepatic fibrosis. Reducing the over-produced expression of TGF-β1 or blocking its signaling pathways is considered to be a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the feasibility of attenuating hepatic fibrosis by vaccination against TGF-β1 with TGF-β1 kinoids. Two TGF-β1 kinoid vaccines were prepared by cross-linking TGF-β1-derived polypeptides (TGF-β1(25-[41-65] and TGF-β1(30-[83-112] to keyhole limpet hemocyanin (KLH. Immunization with the two TGF-β1 kinoids efficiently elicited the production of high-levels of TGF-β1-specific antibodies against in BALB/c mice as tested by enzyme-linked immunosorbent assay (ELISA and Western blotting. The antisera neutralized TGF-β1-induced growth-inhibition on mink lung epithelial cells (Mv1Lu and attenuated TGF-β1-induced Smad2/3 phosphorylation, α-SMA, collagen type 1 alpha 2 (COL1A2, plasminogen activator inhibitor-1 (PAI-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1 expression in the rat hepatic stellate cell (HSC line, HSC-T6. Vaccination against TGF-β1 with the kinoids significantly suppressed CCl4-induced collagen deposition and the expression of α-SMA and desmin, attenuated hepatocyte apoptosis and accelerated hepatocyte proliferation in BALB/c mice. These results demonstrated that immunization with the TGF-β1 kinoids efficiently attenuated CCl4-induced hepatic fibrosis and liver injury. Our study suggests that vaccination against TGF-β1 might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases.

  7. Preventive effect of halofuginone on concanavalin A-induced liver fibrosis.

    Directory of Open Access Journals (Sweden)

    Jie Liang

    Full Text Available Halofuginone (HF is an active component of extracts derived from the plant alkaloid febrifugine and has shown therapeutic promise in animal models of fibrotic disease. Our main objectives were to clarify the suppressive effect of HF on concanavalin A (ConA-induced liver fibrosis. ConA injection into the tail vein caused a great increase in the serum aspartate aminotransferase (AST and alanine aminotransferase (ALT levels, while orally administration of HF significantly decreased the levels of the transaminases. In addition, the levels of hyaluronic acid (HA, procollagen III (PCIII and TGF-β1 in the serum and collagen I, α-SMA, tissue inhibitors of metalloproteinase 2 (TIMP2 and Smad3 in the liver tissue were significantly lowered with the treatment of HF. Histological examination also demonstrated that HF significantly reduced the severity of liver fibrosis. Since ConA-induced liver fibrosis is caused by the repeated activation of T cells, immunomodulatory substances might be responsible for the suppressive effect of HF. We found that the production of nuclear factor (NF-kB in the serum was increased in ConA-treated group, while decreased significantly with the treatment of HF. The changes of inflammatory cytokines tumor necrosis factor (TNF-α, IL-6 and IL-1β in the serum followed the same rhythm. All together, our findings indicate that orally administration HF (10ppm would attenuate the liver fibrosis by suppressing the synthesis of collagen I and inflammation-mediated liver injury.

  8. Increased liver stiffness in alcoholic liver disease: Differentiating fibrosis from steatohepatitis

    OpenAIRE

    Mueller, Sebastian; Millonig, Gunda; Sarovska, Lucie; Friedrich, Stefanie; Reimann, Frank M; Pritsch, Maria; Eisele, Silke; Stickel, Felix; Longerich, Thomas; Schirmacher, Peter; Seitz, Helmut Karl

    2010-01-01

    AIM: To test if inflammation also interferes with liver stiffness (LS) assessment in alcoholic liver disease (ALD) and to provide a clinical algorithm for reliable fibrosis assessment in ALD by FibroScan® (FS).

  9. CUFA algorithm: assessment of liver fibrosis using routine laboratory data.

    Science.gov (United States)

    Shehab, H; Elattar, I; Elbaz, T; Mohey, M; Esmat, G

    2014-12-01

    Staging of liver fibrosis is an integral part of the management of HCV. Liver biopsy is hampered by its invasiveness and possibility of sampling error. Current noninvasive methods are disadvantaged by their cost and complexity. In this study, we aimed at developing a noninvasive method for the staging of liver fibrosis based only on routine laboratory tests and clinical data. Basic clinical and laboratory data and liver biopsies were collected from 994 patients presenting for the evaluation of HCV. Logistic regression was used to create a model predictive of fibrosis stages. A sequential test was then developed by combining our new model with APRI. In the training set (497) a model was created by logistic regression for the prediction of significant fibrosis (≥F2), it included platelets, AST and age (PLASA). The areas under the curve (AUC), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 0.753, 66.8, 71.4, 69.8, 68.4, respectively, while in the validation set (497), they were 0.777, 66.7, 72.8, 68.6 and 71, respectively. These were the best performance indicators when compared to APRI, FIB-4, King's score, platelets, fibrosis index, age-platelet index and Lok index in the same set of patients. A sequential test was then developed including APRI followed by PLASA [Cairo University Fibrosis Assessment (CUFA) algorithm], this allowed saving 20% and 34% of liver biopsies for patients being tested for significant fibrosis and cirrhosis, respectively. In conclusion, the CUFA algorithms at no cost allow saving a significant proportion of patients from performing a liver biopsy or a more complex costly test. These algorithms could be used as the first step in the assessment of liver fibrosis before embarking on the more costly advanced serum markers, Fibroscan or liver biopsy. PMID:24989248

  10. Liver fibrosis in chronic viral hepatitis: An ultrasonographic study

    Institute of Scientific and Technical Information of China (English)

    Rong-Qin Zheng; Qing-Hui Wang; Ming-De Lu; Shi-Bin Xie; Jie Ren; Zhong-Zhen Su; Yin-Ke Cai; Ji-Lu Yao

    2003-01-01

    AIM: To select valuable ultrasonographic predictors for the evaluation of hepatic inflammation and fibrosis degree in chronic hepatitis, and to study the value of ultrasonography in the evaluation of liver fibrosis and compensated liver cirrhosis in comparison with serology and histology.METHODS: Forty-four ultrasonographic variables were analyzed and screened using color Doppler ultrasound system in 225 patients with chronic viral hepatitis and compensated liver cirrhosis. The valuable ultrasonographic predictors were selected on the basis of a comparison with histopathological findings. The value of ultrasonography and serology in the evaluation of liver fibrosis degree and the diagnosis of compensated liver cirrhosis was also studied and compared. Meanwhile, the influencing factors on ultrasonographic diagnosis of compensated liver cirrhosis were also analyzed.RESULTS: By statistical analysis, the maximum velocity of portal vein and the degree of gall-bladder wall smoothness were selected as the valuable predictors for the inflammation grade (G), while liver surface, hepatic parenchymal echo pattern, and the wall thickness of gall-bladder were selected as the valuable predictors for the fibrosis stage (S). Three S-related independent ultrasonographyic predictors and three routine serum fibrosis markers (HA, HPCIII and CIV) were used to discriminate variables for the comparison of ultrasonography with serology. The diagnostic accuracy of ultrasonography in moderate fibrosis was higher than that of serology (P<0.01), while there were no significant differences in the general diagnostic accuracy of fibrosis as well as between mild and severe fibrosis (P<0.05). There were no significant differences between ultrasonography and serology in the diagnosis of compensated liver cirrhosis.However, the diagnostic accuracy of ultrasonography was higher in inactive liver cirrhosis and lower in active cirrhosis than that of serology (both P<0.05). False positive and false

  11. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    Energy Technology Data Exchange (ETDEWEB)

    Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G. [Radiotherapy Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy); Castiglione, F. [Department of Human Pathology and Oncology, University of Florence, Firenze (Italy); Vanzi, E.; Bottoncetti, A.; Pupi, A. [Nuclear Medicine Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy)

    2011-10-15

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  12. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    International Nuclear Information System (INIS)

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  13. Liver and spleen volume variations in patients with hepatic fibrosis

    Institute of Scientific and Technical Information of China (English)

    Peng Liu; Peng Li; Wen He; Li-in Zhao

    2009-01-01

    AIM: To study the liver and spleen volume variations in hepatic fibrosis patients at different histopathological stages.METHODS: Multidetector computed tomography (MDCT) scan was performed in 85 hepatic fibrosis patients. Liver volume (LV) and spleen volume (SV) were measured. Fifteen healthy individuals served as a control group (S0). The patients were divided into stage 1 (S1) group ( n = 34), stage 2 (S2) group ( n = 25), stage 3 (S3) group ( n = 16), and stage 4 (S4)group ( n = 10) according to their histopathological stage of liver fibrosis.RESULTS: The LV and standard LV(SLV)had a tendency to increase with the severity of fibrosis, but no statistical difference was observed in the 5 groups (LV: F = 0.245, P = 0.912; SLV: F = 1.902,P = 0.116). The SV was gradually increased with the severity of fibrosis, and a statistically significant difference in SV was observed among the 5 groups( P < 0.01). The LV/SV ratio and SLV/SV ratio were gradually decreased with the aggravation of hepatic fibrosis, and statistically significant differences in both LV/SV and SLV/SV were found among the 5 groups ( P< 0.01).CONCLUSION: The absence of obvious LV reduction in patients with chronic liver disease may be a morphological index of patients without liver cirrhosis. The SV is related to the severity of fibrosis, and the spleen of patients with advanced fibrosis is enlarged evidently. The LV/SV ratio and SLV/SV ratio are of a significant clinical value in the diagnosis of advanced liver fibrosis.

  14. Quantification of portal-bridging fibrosis area more accurately reflects fibrosis stage and liver stiffness than whole fibrosis or perisinusoidal fibrosis areas in chronic hepatitis C.

    Science.gov (United States)

    Sandrini, Jérémy; Boursier, Jérôme; Chaigneau, Julien; Sturm, Nathalie; Zarski, Jean-Pierre; Le Bail, Brigitte; de Ledinghen, Victor; Calès, Paul; Rousselet, Marie-Christine

    2014-07-01

    Morphometry provides an objective evaluation of fibrosis in liver diseases. We developed an image analysis algorithm using automated thresholding and segmentation to separately quantify the areas and the fractal dimensions of portal-bridging fibrosis and perisinusoidal fibrosis in chronic hepatitis C liver biopsies. We studied 427 digitized liver biopsies and compared the automated measures of the different fibrosis compartments with (1) the Metavir F (fibrosis) and A (activity) histological scores, (2) the digitally assessed area of steatosis, and (3) the liver stiffness measured by elastography (Fibroscan). The perisinusoidal fibrosis area was higher than that of portal fibrosis in stages ≤F2; it reached its highest value in F2 stage and stabilized thereafter. The F3 stage was characterized by equal proportions of portal-bridging and perisinusoidal fibrosis, whereas portal-bridging area was predominant in cirrhosis. Measurement of portal-bridging fibrosis showed highly significantly different values between contiguous F stages; the ratio of portal-bridging fibrosis/perisinusoidal fibrosis displayed less overlap between Metavir stages than did the whole fibrosis area values. Fractal dimension showed that portal-bridging fibrosis tended to display a homogeneous surface-like spatial organization, whereas perisinusoidal fibrosis appeared more heterogeneous according to stage and curvilinear. The portal-bridging fibrosis area was low in cases with low Metavir activity and little steatosis, and became predominant with increasing activity and steatosis. Using stepwise multiple linear regression analysis, the liver stiffness was independently correlated to the portal-bridging fibrosis area (first step, P<0.001), the steatosis area (second step, P<0.001), and the Metavir A grade (third step, P=0.001), but not to the perisinusoidal fibrosis area. Automated quantification in a large cohort of chronic hepatitis C showed that perisinusoidal fibrosis progressively grew in

  15. Imaging Based Methods of Liver Fibrosis Assessment in Viral Hepatitis: A Practical Approach

    OpenAIRE

    Hicham Khallafi; Kamran Qureshi

    2015-01-01

    Liver fibrosis represents the repair mechanism in liver injury and is a feature of most chronic liver diseases. The degree of liver fibrosis in chronic viral hepatitis infections has major clinical implications and presence of advanced fibrosis or cirrhosis determines prognosis. Treatment initiation for viral hepatitis is indicated in most cases of advanced liver fibrosis and diagnosis of cirrhosis entails hepatology evaluation for specialized clinical care. Liver biopsy is an invasive techni...

  16. Non-Invasive Evaluation of Cystic Fibrosis Related Liver Disease in Adults with ARFI, Transient Elastography and Different Fibrosis Scores

    OpenAIRE

    Karlas, Thomas; Neuschulz, Marie; Oltmanns, Annett; Güttler, Andrea; Petroff, David; Wirtz, Hubert; Mainz, Jochen G.; Mössner, Joachim; Berg, Thomas; Tröltzsch, Michael; Keim, Volker; Wiegand, Johannes

    2012-01-01

    Background Cystic fibrosis-related liver disease (CFLD) is present in up to 30% of cystic fibrosis patients and can result in progressive liver failure. Diagnosis of CFLD is challenging. Non-invasive methods for staging of liver fibrosis display an interesting diagnostic approach for CFLD detection. Aim We evaluated transient elastography (TE), acoustic radiation force impulse imaging (ARFI), and fibrosis indices for CFLD detection. Methods TE and ARFI were performed in 55 adult CF patients. ...

  17. Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis.

    Science.gov (United States)

    Kang, Jung-Woo; Hong, Jeong-Min; Lee, Sun-Mee

    2016-05-01

    Liver fibrosis leads to liver cirrhosis and failure, and no effective treatment is currently available. Growing evidence supports a link between mitochondrial dysfunction and liver fibrogenesis and mitochondrial quality control-based therapy has emerged as a new therapeutic target. We investigated the protective mechanisms of melatonin against mitochondrial dysfunction-involved liver fibrosis, focusing on mitophagy and mitochondrial biogenesis. Rats were treated with carbon tetrachloride (CCl4 ) dissolved in olive oil (0.5 mL/kg, twice a week, i.p.) for 8 wk. Melatonin was administered orally at 2.5, 5, and 10 mg/kg once a day. Chronic CCl4 exposure induced collagen deposition, hepatocellular damage, and oxidative stress, and melatonin attenuated these increases. Increases in mRNA and protein expression levels of transforming growth factor β1 and α-smooth muscle actin in response to CCl4 were attenuated by melatonin. Melatonin attenuated hallmarks of mitochondrial dysfunction, such as mitochondrial swelling and glutamate dehydrogenase release. Chronic CCl4 exposure impaired mitophagy and mitochondrial biogenesis, and melatonin attenuated this impairment, as indicated by increases in mitochondrial DNA and in protein levels of PTEN-induced putative kinase 1 (PINK1); Parkin; peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α); nuclear respiratory factor 1 (NRF1); and transcription factor A, mitochondrial (TFAM). CCl4 -mediated decreases in mitochondrial fission- and fusion-related proteins, such as dynamin-related protein 1 (DRP1) and mitofusin 2, were also attenuated by melatonin. Moreover, melatonin induced AMP-activated protein kinase (AMPK) phosphorylation. These results suggest that melatonin protects against liver fibrosis via upregulation of mitophagy and mitochondrial biogenesis, and may be useful as an anti-fibrotic treatment. PMID:26882442

  18. Protection effect of kallistatin on carbon tetrachloride-induced liver fibrosis in rats via antioxidative stress.

    Directory of Open Access Journals (Sweden)

    Xiaoping Huang

    Full Text Available Prolonged inflammation and oxidative stress are emerging as key causes of pathological wound healing and the development of liver fibrosis. We have investigated the effects of recombinant human kallistatin, produced in Pichia. pastoris, on preventing carbon tetrachloride (CCl4-induced liver fibrosis in rats. Daily administration of kallistatin prevented development of CCl4-induced liver fibrosis, which was evidenced by histological study. In all kallistatin treated rats, activation of hepatic stellate cells (HSC as assessed by s-smooth muscle actin staining was attenuated, TGF- β1 expression was inhibited, class I serum biomarkers associated with the process of fibrogenesis, such as hyaluronic acid, laminin, and procollagen III, were lowered, compared with that in the model control group. Furthermore, residual hepatic functional reserve was improved by kallistatin treatment. CCl4 induced elevation of malondialdehyde level and reduced superoxide dismutase activity in the liver, while kallistatin reduced these oxidative parameters. We also investigated the effects of kallistatin on rat primary HSC and LX-2, the human HSC cell line. Kallistatin scavenged H2O2-induced ROS in the LX-2 cells, and suppressed the activation of primary HSC. These results suggest recombinant human kallistatin might be a promising drug candidate for therapeutic intervention of liver fibrosis.

  19. Protection Effect of Kallistatin on Carbon Tetrachloride-Induced Liver Fibrosis in Rats via Antioxidative Stress

    Science.gov (United States)

    Huang, Xiaoping; Wang, Xiao; Lv, Yinghui; Xu, Luli; Lin, Junsheng; Diao, Yong

    2014-01-01

    Prolonged inflammation and oxidative stress are emerging as key causes of pathological wound healing and the development of liver fibrosis. We have investigated the effects of recombinant human kallistatin, produced in Pichia. pastoris, on preventing carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Daily administration of kallistatin prevented development of CCl4-induced liver fibrosis, which was evidenced by histological study. In all kallistatin treated rats, activation of hepatic stellate cells (HSC) as assessed by s-smooth muscle actin staining was attenuated, TGF- β1 expression was inhibited, class I serum biomarkers associated with the process of fibrogenesis, such as hyaluronic acid, laminin, and procollagen III, were lowered, compared with that in the model control group. Furthermore, residual hepatic functional reserve was improved by kallistatin treatment. CCl4 induced elevation of malondialdehyde level and reduced superoxide dismutase activity in the liver, while kallistatin reduced these oxidative parameters. We also investigated the effects of kallistatin on rat primary HSC and LX-2, the human HSC cell line. Kallistatin scavenged H2O2-induced ROS in the LX-2 cells, and suppressed the activation of primary HSC. These results suggest recombinant human kallistatin might be a promising drug candidate for therapeutic intervention of liver fibrosis. PMID:24558397

  20. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Hiroshi Sakugawa; Fukunori Kinjo; Atsushi Saito; Tomofumi Nakayoshi; Kasen Kobashigawa; Tsuyoshi Yamashiro; Tatsuji Maeshiro; Satoru Miyagi; Joji Shiroma; Akiyo Toyama; Tomokuni Nakayoshi

    2005-01-01

    AIM: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and progresses to the end stage of liver disease. Biochemical markers of liver fibrosis are strongly associated with the degree of histological liver fibrosis in patients with chronic liver disease.However, data are few on the usefulness of markers in NAFLD patients. The aim of this study was to identify better noninvasive predictors of hepatic fibrosis, with special focus on markers of liver fibrosis, type Ⅵ collagen 7S domain and hyaluronic acid.METHODS: One hundred and twelve patients with histologically proven NAFLD were studied.RESULTS: The histological stage of NAFLD correlated with several clinical and biochemical variables, the extent of hepatic fibrosis and the markers of liver fibrosis were relatively strong associated. The best cutoff values to detect NASH were assessed by using receiver operating characteristic analysis: type Ⅵ collagen 7S domain ≥5.0 ng/mL, hyaluronic acid ≥43 ng/mL. Both markers had a high positive predictive value: type Ⅵ collagen 7S domain, 86% and hyaluronic acid,92%. Diagnostic accuracies of these markers were evaluated to detect severe fibrosis. Both markers showed high negative predictive values: type Ⅵ collagen 7S domain (≥5.0 ng/mL),84% and hyaluronic acid (≥50 ng/mL), 78%, and were significantly and independently associated with the presence of NASH or severe fibrosis by logistic regression analysis.CONCLUSION: Both markers of liver fibrosis are useful in discriminating NASH from fatty liver alone or patients with severe fibrosis from patients with non-severe fibrosis.

  1. Autophagy: A new therapeutic target for liver fibrosis.

    Science.gov (United States)

    Mao, Yu-Qing; Fan, Xiao-Ming

    2015-08-01

    Hepatic fibrosis is a wound-healing response to liver injury and the result of imbalance of extracellular matrix (ECM) accumulation and degradation. The relentless production and progressive accumulation of ECM can lead to end-stage liver disease. Although significant progress has been achieved in elucidating the mechanisms of fibrogenesis, effective anti-fibrotic strategies are still lacking. Autophagy is an intracellular process of self-digestion of defective organelles to provide material recycling or energy for cell survival. Autophagy has been implicated in the pathophysiology of many human disorders including hepatic fibrosis. However, the exact relationships between autophagy and hepatic fibrosis are not totally clear and need further investigations. A new therapeutic target for liver fibrosis could be developed with a better understanding of autophagy. PMID:26261688

  2. CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis.

    Directory of Open Access Journals (Sweden)

    Po-Yin Chu

    Full Text Available Heart failure (HF is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice or type II diabetes (Israeli Sand-rats and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.

  3. Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation

    Institute of Scientific and Technical Information of China (English)

    Wen-ying CHOU; Cheng-nan LU; Tsung-hsing LEE; Chia-ling WU; Kung-sheng HUNG; Allan M CONCEJERO; Bruno JAWAN; Cheng-haung WANG

    2006-01-01

    Aim:Liver fibrosis represents a process of healing and scarring in response to chronic liver injury.Effective therapies for liver fibrosis are lacking.Interleukin-10 (IL-10) is a cytokine that downregulates pro-inflammatory responses and has a modulatory effect on hepatic fibrogenesis.The aim of this study was to investigate whether electroporative IL-10 gene therapy has an hepatic fibrolytic effect on mice.Methods:Hepatic fibrosis was induced by administering carbon tetrachloride (CCl4) for 10 weeks in mice.The human IL-10 expression plasmid was delivered via electroporation after hepatic fibrosis was established.Histopathology,reverse transcription polymerase chain reaction (RT-PCR) ,immunoblotting,and gelatin zymography were used to investigate the possible mechanisms of action of IL-10.Results:Human IL-10 gene therapy reversed CCl4-induced liver fibrosis in mice.RT-PCR revealed that IL-10 gene therapy attenuated liver TGF-β1,collagen αl,fibronectin,and cell adhesion molecule mRNA upregulation.Following gene transfer,both the activation of α-smooth muscle actin and cyclooxygenase-2 were significantly attenuated.Furthermore.IL-10 significantly inhibited matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of matrix metalloproteinase (TIMP) activation after CCl4 intoxication.Conclusions:We demonstrated that IL-10 gene therapy attenuated CCl4-induced liver fibrosis in mice.IL-10 prevented upregulated fibrogenic and pro-inflammatory gene responses.Its collagenolytic effect may be attributed to MMP and TIMP modulation.IL-10 gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

  4. New Effective Treatment of Liver Fibrosis by Chinese Herbal Medicine

    Institute of Scientific and Technical Information of China (English)

    张国梁

    2002-01-01

    @@ Liver fibrosis is an abnormal proliferation pathologic process of intrahepatic fibrous connective tissue that occurs after liver cells have been necrotized and stimulated by inflammatory factors. It is called fibrosis when the pathological change is mild, and liver cirrhosis when the change becomes so severe as to reconstruct the liver lobuli to form pseudolobuli and nodule(1). Liver fibrosis is an important pathological characteristic of chronic hepatopathy and the chief intermediate link to further develop of liver cirrhosis. No ideal remedy for treatment of chronic hepatitic cirrhosis has been found so far. Although some drugs, such as colchicine and penicillamine, had been reported to have the effect of fibrosis inhibition, their clinical application is still limited for the rather severe toxic-side effects. Certain progress have been made from the clinical and experimental studies on anti-fibrosis treatment by traditional Chinese medicine (TCM) carried out widely in China in recent ten years. And here is a general review of the drugs used.

  5. Th2-Associated Alternative Kupffer Cell Activation Promotes Liver Fibrosis without Inducing Local Inflammation

    Directory of Open Access Journals (Sweden)

    Giuliana López-Navarrete, Espiridión Ramos-Martínez, Karina Suárez-Álvarez, Jesús Aguirre-García, Yadira Ledezma-Soto, Sonia León-Cabrera, Marco Gudiño-Zayas, Carolina Guzmán, Gabriela Gutiérrez-Reyes

    2011-01-01

    Full Text Available Cirrhosis is the final outcome of liver fibrosis. Kupffer cell-mediated hepatic inflammation is considered to aggravate liver injury and fibrosis. Alternatively-activated macrophages are able to control chronic inflammatory events and trigger wound healing processes. Nevertheless, the role of alternative Kupffer cell activation in liver harm is largely unclear. Thus, we evaluated the participation of alternatively-activated Kupffer cells during liver inflammation and fibrosis in the murine model of carbon tetrachloride-induced hepatic damage. To stimulate alternative activation in Kupffer cells, 20 Taenia crassiceps (Tc larvae were inoculated into BALBc/AnN female mice. Six weeks post-inoculation, carbon tetrachloride or olive oil were orally administered to Tc-inoculated and non-inoculated mice twice per week during other six weeks. The initial exposure of animals to T. crassiceps resulted in high serum concentrations of IL-4 accompanied by a significant increase in the hepatic mRNA levels of Ym-1, with no alteration in iNOS expression. In response to carbon tetrachloride, recruitment of inflammatory cell populations into the hepatic parenchyma was 5-fold higher in non-inoculated animals than Tc-inoculated mice. In contrast, carbon tetrachloride-induced liver fibrosis was significantly less in non-inoculated animals than in the Tc-inoculated group. The latter showed elevated IL-4 serum levels and low IFN-γ concentrations during the whole experiment, associated with hepatic expression of IL-4, TGF-β, desmin and α-sma, as well as increased mRNA levels of Arg-1, Ym-1, FIZZ-1 and MMR in Kupffer cells. These results suggest that alternative Kupffer cell activation is favored in a Th2 microenvironment, whereby such liver resident macrophages could exhibit a dichotomic role during chronic hepatic damage, being involved in attenuation of the inflammatory response but at the same time exacerbation of liver fibrosis.

  6. Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation.

    Directory of Open Access Journals (Sweden)

    Tian Lan

    Full Text Available Reactive oxygen species (ROS produced by nicotinamide adenine dinucleotide phosphate oxidase (NOX play a key role in liver injury and fibrosis. Previous studies demonstrated that GKT137831, a dual NOX1/4 inhibitor, attenuated liver fibrosis in mice as well as pro-fibrotic genes in hepatic stellate cells (HSCs as well as hepatocyte apoptosis. The effect of NOX1 and NOX4 deficiency in liver fibrosis is unclear, and has never been directly compared. HSCs are the primary myofibroblasts in the pathogenesis of liver fibrosis. Therefore, we aimed to determine the role of NOX1 and NOX4 in liver fibrosis, and investigated whether NOX1 and NOX4 signaling mediates liver fibrosis by regulating HSC activation. Mice were treated with carbon tetrachloride (CCl4 to induce liver fibrosis. Deficiency of either NOX1 or NOX4 attenuates liver injury, inflammation, and fibrosis after CCl4 compared to wild-type mice. NOX1 or NOX4 deficiency reduced lipid peroxidation and ROS production in mice with liver fibrosis. NOX1 and NOX4 deficiency are approximately equally effective in preventing liver injury in the mice. The NOX1/4 dual inhibitor GKT137831 suppressed ROS production as well as inflammatory and proliferative genes induced by lipopolysaccharide (LPS, platelet-derived growth factor (PDGF, or sonic hedgehog (Shh in primary mouse HSCs. Furthermore, the mRNAs of proliferative and pro-fibrotic genes were downregulated in NOX1 and NOX4 knock-out activated HSCs (cultured on plastic for 5 days. Finally, NOX1 and NOX4 protein levels were increased in human livers with cirrhosis compared with normal controls. Thus, NOX1 and NOX4 signaling mediates the pathogenesis of liver fibrosis, including the direct activation of HSC.

  7. Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience.

    Science.gov (United States)

    Sivam, S; Al-Hindawi, Y; Di Michiel, J; Moriarty, C; Spratt, P; Jansz, P; Malouf, M; Plit, M; Pleass, H; Havryk, A; Bowen, D; Haber, P; Glanville, A R; Bye, P T P

    2016-07-01

    Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation. PMID:27405894

  8. Antifibrotic effect of heparin on liver fibrosis model in rats

    Institute of Scientific and Technical Information of China (English)

    Binita; Shah; Gaurang; Shah

    2012-01-01

    AIM: To evaluate the effect of chronic thrombin inhibition by heparin on experimentally induced chronic liver injury (liver fibrosis) in rats. METHODS: Chronic liver injury (liver fibrosis) was induced in Wistar rats by oral administration of carbon tetrachloride (CCl 4 ) for 7 wk, an animal model with persistent severe hepatic fibrosis. Intravenous administration of the thrombin antagonist (heparin) started 1 wk after the start of CCl 4 intoxication for 6 wk. After completion of treatment (7 wk), markers of hepatic dysfunction were measured and changes evaluated histopathologically. RESULTS: Higher serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total, direct and indirect bilirubin levels, as well as lower fibrinogen levels, were found in CCl 4 intoxicated rats. Heparin, silymarin and combination of drug (heparin and silymarin) treatment for 6 wk prevented a rise in SGOT, SGPT, ALP, total, direct and indirect bilirubin levels and improved fibrinogen levels. Deterioration in hepatic function determined by the fibrosis area was retarded, as evident from hepatic histopathology. Total protein levels were not changed in all groups.CONCLUSION: Heparin, a thrombin antagonist, preserved hepatic function and reduced severity of hepatic dysfunction/fibrogenesis. Combination of heparin and silymarin produced additional benefits on liver fibrosis.

  9. Liver fibrosis in primary intestinal lymphangiectasia: An undervalued topic

    Institute of Scientific and Technical Information of China (English)

    Raffaele; Licinio; Mariabeatrice; Principi; Enzo; Ierardi; Alfredo; Di; Leo

    2014-01-01

    The relationship between primary intestinal lymphangiectasia(PIL) and liver fibrosis is an emerging topic with many obscure aspects due to the rarity of the disorder.A recent paper reported that a six-month lowfat diet improved liver fibrosis.We report the case of a 17-year-old girl affected by PIL whose hepatic fibrosis progressively worsened within one year,despite dietetic support.This and the previous case report describe extraordinary events,which do not allow clear-cut clinical aspects to be established.Nevertheless,both cases suggest that in patients with PIL,it is necessary to closely monitor liver morphology with in-depth investigations including not only ultrasonography,but also elastography.

  10. Simultaneous liver-pancreas transplantation for cystic fibrosis-related liver disease : A multicenter experience

    NARCIS (Netherlands)

    Bandsma, R. H. J.; Bozic, M. A.; Fridell, J. A.; Crull, M. H.; Molleston, J.; Avitzur, Y.; Mozer-Glassberg, Y.; Gonzalez-Peralta, R. P.; Hodik, M.; Fecteau, A.; de Angelis, M.; Durie, P.; Ng, V. L.

    2014-01-01

    Background: Diabetes is associated with increased morbidity and mortality in patients with cystic fibrosis (CF). While liver transplantation is well established for CF-related liver disease (CFLD), the role of simultaneous liver pancreas transplantation is less understood. Methods: We polled 81 pedi

  11. Prediction of Liver-Related Events Using Fibroscan in Chronic Hepatitis B Patients Showing Advanced Liver Fibrosis

    OpenAIRE

    Kim, Seung Up; Lee, Ji Hoon; Kim, Do Young; Ahn, Sang Hoon; Jung, Kyu Sik; Choi, Eun Hee; Park, Young Nyun; Han, Kwang-Hyub; Chon, Chae Yoon; Park, Jun Yong

    2012-01-01

    Background Liver stiffness measurement (LSM) using transient elastography (FibroScan®) can assess liver fibrosis noninvasively. This study investigated whether LSM can predict the development of liver-related events (LREs) in chronic hepatitis B (CHB) patients showing histologically advanced liver fibrosis. Methods Between March 2006 and April 2010, 128 CHB patients with who underwent LSM and liver biopsy (LB) before starting nucleot(s)ide analogues and showed histologically advanced fibrosis...

  12. Transplantation of fetal liver epithelial progenitor cells ameliorates experimental liver fibrosis in mice

    Institute of Scientific and Technical Information of China (English)

    Jin-Fang Zheng; Li-Jian Liang; Chang-Xiong Wu; Jin-Song Chen; Zhen-Sheng Zhang

    2006-01-01

    AIM: To investigate the effect of transplanted fetal liver epithelial progenitor (FLEP) cells on liver fibrosis in mice.METHODS: FLEP cells were isolated from embryonal day (ED) 14 BALB/c mice and transplanted into female syngenic BALB/c mice (n = 60). After partial hepatectomy (PH), diethylnitrosamine (DEN) was administered to induce liver fibrosis. Controls received FLEP cells and non-supplemented drinking water, the model group received DEN-spiked water, and the experimental group received FLEP cells and DEN.Mice were killed after 1, 2, and 3 mo, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), and laminin (LN) in serum,and hydroxyproline (Hyp) content in liver were assessed.Alpha-smooth muscle actin (α-SMA) of liver was tested by immunohistochemistry. Transplanted male mice FLEP cells were identified by immunocytochemistry for sry (sex determination region for Y chromosome) protein.RESULTS: Serum ALT, AST, HA, and LN were markedly reduced by transplanted FLEP cells. Liver Hyp content and α-SMA staining in mice receiving FLEP cells were lower than that of the model group, which was consistent with altered liver pathology. Transplanted cells proliferated and differentiated into hepatocytes and bile duct epithelial cells with 30%-50% repopulation in the liver fibrosis induced by DEN after 3 mo.CONCLUSION: Transplanted FLEP cells proliferate and differentiate into hepatocytes and bile duct epithelial cells with high repopulation capacity in the fiberized liver induced by DEN, which restores liver function and reduces liver fibrosis.

  13. Accuracy of FibroScan for diagnosing liver fibrosis

    OpenAIRE

    Zhang, Jian; Han, Ping; SHAO, QING; Ji, Dong; Song-hai CHEN; Wang, Chun-Yan; Chen, Guo-Feng

    2011-01-01

    Objective To evaluate the accuracy of transient elastometry(FibroScan) for the detection of liver fibrosis.Methods A total of 323 patients diagnosed with chronic liver disease based on pathological examination in the 302 Hospital of the People’s Liberation Army from April to December of 2009 were involved in the current study.Among them,141 patients were subjected to liver biopsy.Their liver function,coagulant index,B-ultrasound and blood cell count were examined clinically.Four examinations ...

  14. Advance in quantitatively diagnosing and staging liver fibrosis with magnetic resonance imaging

    International Nuclear Information System (INIS)

    Liver fibrosis is the common characteristic of all kinds of chronic liver diseases, and early quantitative diagnosis of the fibrosis is of great significance for the choice of therapeutic methods and the promotion of this disease inversion. Liver biopsy is the gold standard for the diagnosis of liver fibrosis, but it is limited in clinical application due to its invasive nature. As a non-invasive examination method, magnetic resonance quantitative technique has progressed greatly in assessment of liver fibrosis in recent years. We will review the progress in the study on quantitatively diagnosing and staging liver fibrosis with magnetic resonance imaging. (authors)

  15. Broad-spectrum matrix metalloproteinase inhibition curbs inflammation and liver injury but aggravates experimental liver fibrosis in mice.

    Directory of Open Access Journals (Sweden)

    Vincent E de Meijer

    Full Text Available BACKGROUND: Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs. The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF-alpha-converting enzyme (TACE. We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury. METHODOLOGY/PRINCIPAL FINDINGS: Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4 administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4 was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-alpha receptors. Liver injury was quantified by alanine aminotransferase (ALT levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-alpha receptors exhibited an 80% reduction of serum ALT

  16. Relevance of activated hepatic stellate cells in predicting the development of pediatric liver allograft fibrosis.

    Science.gov (United States)

    Venturi, Carla; Reding, Raymond; Quinones, Jorge Abarca; Sokal, Etienne; Rahier, Jacques; Bueno, Javier; Sempoux, Christine

    2016-06-01

    Activated hepatic stellate cells (HSCs) are the main collagen-producing cells in liver fibrogenesis. With the purpose of analyzing their presence and relevance in predicting liver allograft fibrosis development, 162 liver biopsies of 54 pediatric liver transplantation (LT) recipients were assessed at 6 months, 3 years, and 7 years after LT. The proportion of activated HSCs, identified by α-smooth muscle actin (ASMA) immunostaining, and the amount of fibrosis, identified by picrosirius red (PSR%) staining, were determined by computer-based morphometric analysis. Fibrosis was also staged by using the semiquantitative liver allograft fibrosis score (LAFSc), specifically designed to score fibrosis in the pediatric LT population. Liver allograft fibrosis displayed progression over time by PSR% (P evolution with respect to fibrosis (P evolution with respect to fibrosis in the long term. Liver Transplantation 22 822-829 2016 AASLD. PMID:26851053

  17. Color correction for automatic fibrosis quantification in liver biopsy specimens

    OpenAIRE

    Yuri Murakami; Tokiya Abe; Akinori Hashiguchi; Masahiro Yamaguchi; Akira Saito; Michiie Sakamoto

    2013-01-01

    Context: For a precise and objective quantification of liver fibrosis, quantitative evaluations through image analysis have been utilized. However, manual operations are required in most cases for extracting fiber areas because of color variation included in digital pathology images. Aims: The purpose of this research is to propose a color correction method for whole slide images (WSIs) of Elastica van Gieson (EVG) stained liver biopsy tissue specimens and to realize automated operation of im...

  18. Prognostic Value of Liver Fibrosis Biomarkers: A Meta-Analysis

    OpenAIRE

    Poynard, Thierry; Ngo, Yen; Perazzo, Hugo; Munteanu, Mona; Lebray, Pascal; Moussalli, Joseph; Thabut, Dominique; Benhamou, Yves; Ratziu, Vlad

    2011-01-01

    Aims and Methods: Several serum biomarkers such as FibroTest, aspartate transaminase-platelet ratio index (APRI), FIB-4, and liver stiffness measurement by FibroScan have been validated as alternatives to biopsy for the diagnosis of fibrosis in patients with chronic liver disease. This paper aims to assess the 5-year prognostic values of these biomarkers. A meta-analysis combined all published prognostic studies. Baseline biopsy and APRI data were used as references. Results: Only 3 biomarker...

  19. Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis

    OpenAIRE

    Canbay, Ali; Guicciardi, Maria Eugenia; Higuchi, Hajime; Feldstein, Ariel; Bronk, Steven F.; Rydzewski, Robert; Tanai, Makiko; Gores, Gregory J.

    2004-01-01

    Although a lysosomal, cathepsin B–dependent (Ctsb-dependent) pathway of apoptosis has been described, the contribution of this pathway to tissue damage remains unclear. Our aim was to ascertain if Ctsb inactivation attenuates liver injury, inflammation, and fibrogenesis after bile duct ligation (BDL). In 3-day BDL mice, hepatocyte apoptosis, mitochondrial cytochrome c release, and serum alanine aminotransferase (ALT) values were reduced in Ctsb–/– versus Ctsb+/+ animals. Likewise, R-3032 (a C...

  20. Endothelial dysfunction correlates with liver fibrosis in chronic HCV infection.

    Science.gov (United States)

    Barone, Michele; Viggiani, Maria Teresa; Amoruso, Annabianca; Schiraldi, Serafina; Zito, Annapaola; Devito, Fiorella; Cortese, Francesca; Gesualdo, Michele; Brunetti, Natale; Di Leo, Alfredo; Scicchitano, Pietro; Ciccone, Marco Matteo

    2015-01-01

    Background. Hepatitis C virus (HCV) infection can exert proatherogenic activities due to its direct action on vessel walls and/or via the chronic inflammatory process involving the liver. Aims. To clarify the role of HCV in atherosclerosis development in monoinfected HCV patients at different degrees of liver fibrosis and with no risk factors for coronary artery disease. Methods. Forty-five patients were included. Clinical, serological, and anthropometric parameters, liver fibrosis (transient liver elastometry (fibroscan) and aspartate aminotransferase to platelet ratio index (APRI)), carotid intima-media thickness (c-IMT), and brachial artery flow-mediated vasodilatation (FMD) were assessed. Patients were divided into 3 tertiles according to fibroscan values. Results. Patients in the third tertile (fibroscan value >11.5 KPa) showed FMD values were significantly lower than second and first tertiles (4.7 ± 1.7% versus 7.1 ± 2.8%, p = 0.03). FMD values were inversely related to liver elastomeric values. c-IMT values were normal. The risk for endothelial dysfunction development in the third tertile (p = 0.02) was 6.9 higher than the first tertile. A fibroscan value >11.5 KPa had a positive predictive power equal to 79% for endothelial dysfunction. Conclusions. HCV advanced liver fibrosis promotes atherosclerosis by inducing endothelial dysfunction independently of common cardiovascular risk factors. PMID:26000012

  1. Autophagy: A new therapeutic target for liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Hepatic fibrosis is a wound-healing response to liverinjury and the result of imbalance of extracellular matrix(ECM) accumulation and degradation. The relentless production and progressive accumulation of ECM canlead to end-stage liver disease. Although significantprogress has been achieved in elucidating the mechanismsof fibrogenesis, effective anti-fibrotic strategiesare still lacking. Autophagy is an intracellular process ofself-digestion of defective organelles to provide materialrecycling or energy for cell survival. Autophagy hasbeen implicated in the pathophysiology of many humandisorders including hepatic fibrosis. However, the exactrelationships between autophagy and hepatic fibrosisare not totally clear and need further investigations.A new therapeutic target for liver fibrosis could bedeveloped with a better understanding of autophagy.

  2. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease.

    OpenAIRE

    Zeybel, Müjdat; Hardy, Timothy; Robinson, Stuart M.; Fox, Christopher; Anstee, Quentin M.; Ness, Thomas; Masson, Steven; Masson, Steven; French, Jeremy; White, Steve; Mann, Jelena

    2015-01-01

    Background: Chronic liver injury can lead to the development of liver fibrosis and cirrhosis but only in a minority of patients. Currently, it is not clear which factors determine progression to fibrosis. We investigated whether DNA\\methylation profile as determined by pyrosequencing can distinguish patients with mild from those with advanced/severe fibrosis in non-alcoholic liver disease (NAFLD) and alcoholic liver disease (ALD). To this end, paraffin-embedded liverbiopsies were collected fr...

  3. Color correction for automatic fibrosis quantification in liver biopsy specimens

    Directory of Open Access Journals (Sweden)

    Yuri Murakami

    2013-01-01

    Full Text Available Context: For a precise and objective quantification of liver fibrosis, quantitative evaluations through image analysis have been utilized. However, manual operations are required in most cases for extracting fiber areas because of color variation included in digital pathology images. Aims: The purpose of this research is to propose a color correction method for whole slide images (WSIs of Elastica van Gieson (EVG stained liver biopsy tissue specimens and to realize automated operation of image analysis for fibrosis quantification. Materials and Methods: Our experimental dataset consisted of 38 WSIs of liver biopsy specimens collected from 38 chronic viral hepatitis patients from multiple medical facilities, stained with EVG and scanned at ×20 using a Nano Zoomer 2.0 HT (Hamamatsu Photonics K.K., Hamamatsu, Japan. Color correction was performed by modifying the color distribution of a target WSI so as to fit to the reference, where the color distribution was modeled by a set of two triangle pyramids. Using color corrected WSIs; fibrosis quantification was performed based on tissue classification analysis. Statistical Analysis Used: Spearman′s rank correlation coefficients were calculated between liver stiffness measured by transient elastography and median area ratio of collagen fibers calculated based on tissue classification results. Results: Statistical analysis results showed a significant correlation r = 0.61-0.68 even when tissue classifiers were trained by using a subset of WSIs, while the correlation coefficients were reduced to r = 0.40-0.50 without color correction. Conclusions: Fibrosis quantification accompanied with the proposed color correction method could provide an objective evaluation tool for liver fibrosis, which complements semi-quantitative histologic evaluation systems.

  4. Prediction of Post-Operative Liver Dysfunction by Serum Markers of Liver Fibrosis in Hepatocellular Carcinoma

    Science.gov (United States)

    Shen, Yinghao; Shi, Guoming; Huang, Cheng; Zhu, Xiaodong; Chen, Si; Sun, Huichuan; Zhou, Jian; Fan, Jia

    2015-01-01

    Aim To investigate the role of biomarkers in predicting postoperative liver dysfunction in patients with hepatocellular carcinoma (HCC). Methods A total of 200 patients operated from July 2009 to June 2010 at Zhongshan Hospital, Fudan University for pathologically confirmed HCC were retrospectively analyzed for clinical data, HBD DNA level and serum biochemical markers for liver fibrosis. The patients were followed up to observersation end point. Correlation of the monitored parameters with postoperative liver dysfunction and patient survival was statistically analyzed. Results Preoperative hepatitis B virus (HBV) DNA level, serum prealbumin (PA) hyaluronic acid (HA), and laminin (LN) levels correlated with postoperative liver dysfunction. A predictive model was generated using these 4 parameters and validated in 89 HCC patients with sensitivity and specificity of 0.625 and 0.912, respectively. However, no correlation was identified between postoperative liver function and overall survival. Conclusion Liver fibrosis markers could be preoperatively used in predicting postoperative liver dysfunction in HCC patients. PMID:26501145

  5. Staging of liver fibrosis or cirrhosis: The role of hepaticvenous pressure gradient measurement

    Institute of Scientific and Technical Information of China (English)

    Ki Tae Suk; Dong Joon Kim

    2015-01-01

    Liver fibrosis is a common histological change ofchronic liver injury and it is closely related with portalhypertension which is hemodynamic complication ofchronic liver disease. Currently, liver fibrosis has beenknown as a reversible dynamic process in previousliteratures. Although liver biopsy is a gold standardfor assessing the stage of liver fibrosis, it may notcompletely represent the stage of liver fibrosis becauseof sampling error or semi-quantative measurement.Recent evidences suggested that histologic, clinical,hemodynamic, and biologic features are closelyassociated in patients with chronic liver disease. Hepaticvenous pressure gradient (HVPG) measurement has beenknown as a modality to evaluate the portal pressure.The HVPG measurement has been used clinicallyfor fibrosis diagnosis, risk stratification, preoperativescreening for liver resection, monitoring the efficacy ofmedical treatments, and assessing the prognosis of liverfibrosis. Therefore, the HVPG measurement can be usedto monitor areas the chronic liver disease but also otherimportant areas of chronic liver disease.

  6. Effective Prevention of Liver Fibrosis by Liver-targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in a Rat Liver Fibrosis Model.

    Science.gov (United States)

    Abe, Hiroyuki; Kamimura, Kenya; Kobayashi, Yuji; Ohtsuka, Masato; Miura, Hiromi; Ohashi, Riuko; Yokoo, Takeshi; Kanefuji, Tsutomu; Suda, Takeshi; Tsuchida, Masanori; Aoyagi, Yutaka; Zhang, Guisheng; Liu, Dexi; Terai, Shuji

    2016-01-01

    Liver fibrosis is the final stage of liver diseases that lead to liver failure and cancer. While various diagnostic methods, including the use of serum marker, have been established, no standard therapy has been developed. The objective of this study was to assess the approach of overexpressing matrix metalloproteinase-13 gene (MMP13) in rat liver to prevent liver fibrosis progression. A rat liver fibrosis model was established by ligating the bile duct, followed by liver-targeted hydrodynamic gene delivery of a MMP13 expression vector, containing a CAG promoter-MMP13-IRES-tdTomato-polyA cassette. After 14 days, the serum level of MMP13 peaked at 71.7 pg/ml in MMP13-treated group, whereas the nontreated group only showed a level of ~5 pg/ml (P sirius red showed a statistically larger volume of fibrotic tissue in the nontreated group compared to that of MMP13-treated rats (P < 0.05). These results suggest that the liver-targeted hydrodynamic delivery of MMP13 gene could be effective in the prevention of liver fibrosis. PMID:26730813

  7. Non-invasive assessment of liver fibrosis in chronic liver diseases: Implementation in clinical practice and decisional algorithms

    Institute of Scientific and Technical Information of China (English)

    Giada Sebastiani

    2009-01-01

    Chronic hepatitis B and C together with alcoholic and non-alcoholic fatty liver diseases represent the major causes of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications, including decompensation, bleeding and liver cancer. Formation and accumulation of fibrosis in the liver is the common pathway that leads to an evolutive liver disease. Precise definition of liver fibrosis stage is essential for management of the patient in clinical practice since the presence of bridging fibrosis represents a strong indication for antiviral therapy for chronic viral hepatitis, while cirrhosis requires a specific follow-up including screening for esophageal varices and hepatocellular carcinoma. Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis but it has some limitations being invasive, costly and prone to sampling errors. Recently, blood markers and instrumental methods have been proposed for the non-invasive assessment of liver fibrosis. However, there are still some doubts as to their implementation in clinical practice and a real consensus on how and when to use them is not still available. This is due to an unsatisfactory accuracy for some of them, and to an incomplete validation for others. Some studies suggest that performance of non-invasive methods for liver fibrosis assessment may increase when they re combined. Combination algorithms of non-invasive methods for assessing liver fibrosis may represent a rational and reliable approach to implement noninvasive assessment of liver fibrosis in clinical practice and to reduce rather than abolish liver biopsies.

  8. Physicians’ practices for diagnosing liver fibrosis in chronic liver diseases: A nationwide, Canadian survey

    OpenAIRE

    Sebastiani, Giada; Ghali, Peter; Wong, Philip; Klein, Marina B; Deschenes, Marc; Myers, Robert P

    2014-01-01

    OBJECTIVE: To determine practices among physicians in Canada for the assessment of liver fibrosis in patients with chronic liver diseases.METHODS: Hepatologists, gastroenterologists, infectious diseases specialists, members of the Canadian Gastroenterology Association and/or the Canadian HIV Trials Network who manage patients with liver diseases were invited to participate in a web-based, national survey.RESULTS: Of the 237 physicians invited, 104 (43.9%) completed the survey. Routine assessm...

  9. Liver fibrosis can be assessed by non-invasive ultrasound elastography

    DEFF Research Database (Denmark)

    Thielsen, Peter; Wilkens, Rune; Rafaelsen, Søren Rafael;

    2014-01-01

    Diagnosis and assessment of liver fibrosis is of great importance for initiating treatment and starting hepatocellular carcinoma surveillance in patients with established cirrhosis. Liver biopsy is still considered the gold standard for liver fibrosis staging, however; it is far from perfect. Non......-invasive assessment of liver fibrosis is becoming more available and is well tolerated. This review describes the feasibility and reliability of two elastography methods: transient elastography and Acoustic Radiation Force Impulse-elastography....

  10. Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice

    International Nuclear Information System (INIS)

    Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl4)-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl4-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl4-treated group relative to the Control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl4-treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-(4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy)-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl4, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress. - Highlights: • We administer an inhibitor of sEH in a CCl4 murine model. • sEH inhibition reduces liver collagen deposition and pro-fibrotic gene expression. • sEH inhibition induces MMP-1a activity

  11. The Dimethylnitrosamine Induced Liver Fibrosis Model in the Rat.

    Science.gov (United States)

    Chooi, Kum Fai; Kuppan Rajendran, Dinesh Babu; Phang, Siew Siang Gary; Toh, Han Hui Alden

    2016-01-01

    Four to six week old, male Wistar rats were used to produce animal models of liver fibrosis. The process requires four weeks of administration of 10 mg/kg dimethylnitrosamine (DMN), given intraperitoneally for three consecutive days per week. Intraperitoneal injections were performed in the fume hood as DMN is a known hepatoxin and carcinogen. The model has several advantages. Firstly, liver changes can be studied sequentially or at particular stages of interest. Secondly, the stage of liver disease can be monitored by measurement of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. Thirdly, the severity of liver damage at different stages can be confirmed by sacrifice of animals at designated time points, followed by histological examination of Masson's Trichome stained liver tissues. After four weeks of DMN dosing, the typical fibrosis score is 5 to 6 on the Ishak scale. The model can be reproduced consistently and has been widely used to assess the efficacy of potential anti-fibrotic agents. PMID:27340889

  12. The relationship between the degree of liver fibrosis and serum markers in patient with hepatic diseases

    International Nuclear Information System (INIS)

    To study the relationship between the degree of liver fibrosis and serum markers in patients with hepatic diseases, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (GGT), total bilirubin (TBIL), albumin (ALB), globulin (GLO), platelet (PLT), prothrombin time (PT), procollagen type III (PIIINP), hyaluronic acid (HA), laminin (LN) and collagen type IV in 114 patients with different causes hepatic disease were determined. The liver puncture biopsy was also carried out to determine the stages of liver fibrosis. The results showed that the serum albumin, globulin, platelet, prothrombin time, PIIINP, HA, collagen type IV had significant difference in different stages of liver fibrosis. The serum platelets and albumin levels were negatively correlated with the degree of liver fibrosis. The serum PT and GLO levels were positively correlated with time course of liver fibrosis. The serum PIIINP, HA and collagen type IV levels were positively correlated with degree of liver fibrosis. The serum albumin, globulin, prothrombin time, platelets, PIIINP, HA, collagen type IV were correlated with the progress of the liver fibrosis. The prothrombin time and platelets have directive significance in the diagnosis of liver cirrhosis and also used to judge the stage of liver fibrosis in some extent. The serum PIIINP, HA and collagen type IV levels may better reflect the process of liver fibrosis. (authors)

  13. Systems level analysis and identification of pathways and networks associated with liver fibrosis.

    Directory of Open Access Journals (Sweden)

    Mohamed Diwan M AbdulHameed

    Full Text Available Toxic liver injury causes necrosis and fibrosis, which may lead to cirrhosis and liver failure. Despite recent progress in understanding the mechanism of liver fibrosis, our knowledge of the molecular-level details of this disease is still incomplete. The elucidation of networks and pathways associated with liver fibrosis can provide insight into the underlying molecular mechanisms of the disease, as well as identify potential diagnostic or prognostic biomarkers. Towards this end, we analyzed rat gene expression data from a range of chemical exposures that produced observable periportal liver fibrosis as documented in DrugMatrix, a publicly available toxicogenomics database. We identified genes relevant to liver fibrosis using standard differential expression and co-expression analyses, and then used these genes in pathway enrichment and protein-protein interaction (PPI network analyses. We identified a PPI network module associated with liver fibrosis that includes known liver fibrosis-relevant genes, such as tissue inhibitor of metalloproteinase-1, galectin-3, connective tissue growth factor, and lipocalin-2. We also identified several new genes, such as perilipin-3, legumain, and myocilin, which were associated with liver fibrosis. We further analyzed the expression pattern of the genes in the PPI network module across a wide range of 640 chemical exposure conditions in DrugMatrix and identified early indications of liver fibrosis for carbon tetrachloride and lipopolysaccharide exposures. Although it is well known that carbon tetrachloride and lipopolysaccharide can cause liver fibrosis, our network analysis was able to link these compounds to potential fibrotic damage before histopathological changes associated with liver fibrosis appeared. These results demonstrated that our approach is capable of identifying early-stage indicators of liver fibrosis and underscore its potential to aid in predictive toxicity, biomarker identification, and to

  14. Correlation of serum liver fibrosis markers with severity of liver dysfunction in liver cirrhosis: a retrospective cross-sectional study

    OpenAIRE

    Zhu, Cuihong; Qi, Xingshun; Li, Hongyu; Peng, Ying; Dai, Junna; Chen, Jiang; Xia, Chunlian; Hou, Yue; Zhang, Wenwen; Guo, Xiaozhong

    2015-01-01

    Hyaluronic acid (HA), laminin (LN), amino-terminal pro-peptide of type III pro-collagen (PIIINP), and collagen IV (CIV) are four major serum markers of liver fibrosis. This retrospective cross-sectional study aimed to evaluate the correlations of the four serum markers with the severity of liver dysfunction in cirrhotic patients. Between January 2013 and June 2014, a total of 228 patients with a clinical diagnosis with liver cirrhosis and without malignancy underwent the tests of HA, LN, PIII...

  15. A comparison of MR elastography and 31P MR spectroscopy with histological staging of liver fibrosis

    International Nuclear Information System (INIS)

    Conventional imaging techniques are insensitive to liver fibrosis. This study assesses the diagnostic accuracy of MR elastography (MRE) stiffness values and the ratio of phosphomonoesters (PME)/phosphodiesters (PDE) measured using 31P spectroscopy against histological fibrosis staging. The local research ethics committee approved this prospective, blinded study. A total of 77 consecutive patients (55 male, aged 49 ± 11.5 years) with a clinical suspicion of liver fibrosis underwent an MR examination with a liver biopsy later the same day. Patients underwent MRE and 31P spectroscopy on a 1.5 T whole body system. The liver biopsies were staged using an Ishak score for chronic hepatitis or a modified NAS fibrosis score for fatty liver disease. MRE increased with and was positively associated with fibrosis stage (Spearman's rank = 0.622, P 31P MR spectroscopy and fibrosis stage. circle Magnetic resonance elastography (MRE) and MR spectroscopy can both assess the liver. (orig.)

  16. Cystic fibrosis-related liver disease: a single-center experience

    OpenAIRE

    Paula Catarino Costa; Celeste Canha Barreto; Luisa Pereira; Maria Luisa Lobo; Maria Adília Costa; Ana Isabel Gouveia Lopes

    2011-01-01

    Prospective studies concerning liver disease in pediatric cystic fibrosis patients are scarce. The present study aimed to describe the prevalence and clinical expression of cystic fibrosis - related liver disease, in a cohort of 62 pediatric patients. Descriptive study, resulting from the prospective evaluation, between 1994 and 2009, of 62 pediatric patients (age <18 years) with cystic fibrosis. The follow-up protocol included a clinical assessment every 2 months, liver function tests eve...

  17. Loss of Matrix Metalloproteinase-13 Attenuates Murine Radiation-Induced Pulmonary Fibrosis

    International Nuclear Information System (INIS)

    Purpose: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMP13 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. Methods and Materials: We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57Bl/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. Results: We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Conclusions: Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis.

  18. FEASIBILITY OF DIAGNOSING AND STAGING LIVER FIBROSIS WITH DIFFUSION WEIGHTED IMAGING

    Institute of Scientific and Technical Information of China (English)

    Nai-yi Zhu; Ke-min Chen; Wei-min Chai; Wei-xia Li; Lian-jun Du

    2008-01-01

    Objective To assess the clinical feasibility of diagnosing and staging liver fibrosis by apparent diffusion coefficient (ADC). Methods Totally, 43 patients (mean age 29.3 years) with chronic hepatitis by liver biopsy and 7 healthy controls (mean age 39.9 years) underwent liver diffusion weighted imaging (DWI) with four b values: 0, 200, 500, and 1000 s/mm2 respectively. The liver fibrosis was staged according to Ishak fibrosis stage. The ADC value of liver fibrosis patients and healthy controls was compared. The correlation of ADC value and liver fibrosis staging was analyzed.Result The histological staging showed 8 stage 1 patients, 10 stage 2 patients, 6 stage 3 patients, 9 stage 4 patients, 8 stage 5 patients and 2 stage 6 patients. The mean ADC value of liver fibrosis patients was significantly lower than that of healthy controls except for stage 1 group (P < 0.05). There was a negative correlation between liver fibrosis staging and ADC value (r = -0.697 with b=500 s/mm2, P < 0.01). Receiver operating characteristic (ROC) curve of ADC value of advanced liver fibrosis (Ishak stage F3 and higher) showed that area under curve = 0.913, 0.825, and 0.794 with b=500, 1000, and 200 s/mm2, respectively (95% confidence interval: 83.6%-99.0%, 70.7%-94.3%, 66.50%-92.4%; P < 0.05). When b value was 500 s/mm2, the sensitivity (84%) and specificity (800%) of DWI for diagnosis of advanced liver fibrosis were the highest.Conclusion DWI is proved to be a useful clinical tool in the quantitative evaluation of liver fibrosis and in the prediction of the process of liver fibrosis with the recommendable b value (500 s/mm2).

  19. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.

    Directory of Open Access Journals (Sweden)

    George M Philips

    Full Text Available OBJECTIVE: Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3 develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/- mice to investigate the hypothesis that activation of the hedgehog (Hh signaling pathway promotes development of both liver fibrosis and HCC. METHODS: Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/- mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. RESULTS: Unlike controls, Mdr2(-/- mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. CONCLUSIONS: Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.

  20. Correlation between ultrasound imaging and serum markers of liver fibrosis in patients with chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Jian-Xia Liu

    2016-01-01

    Objective:To investigate the clinical value of ultrasonic imaging in the assessment of liver fibrosis in patients with chronic hepatitis B. Methods:A total of 20 cases of liver biopsy in chronic hepatitis B, according to the degree of hepatic fibrosis were divided into mild hepatic fibrosis group, moderate fibrosis group, severe fibrosis group, the other selected healthy volunteers as control group, using color Doppler ultrasound, the use of imaging technology and automatic tracking. Strengthen the quantitative analysis, using the second generation microbubble contrast agent SonoVue contrast analysis, contrast agent reach the portal time (PVAT), hepatic artery time (HAAT), hepatic vein (HVVT), the calculation time of hepatic arteriovenous transit time (VAT) and hepatic portal vein transit time (VVT), using chemiluminescence detection of serum liver fiber hyaluronic acid (HA), laminin (LN) and collagen type IV (CIV) index. Results:there was no significant difference in HAAT, PVAT, VAT, VVT and HVAT in all groups, and there was no significant difference, mild, moderate and severe liver fibrosis group, and HA, LN and C levels were significantly higher than those in control group. Conclusion:serum liver fibrosis indexes can guide the degree of liver fibrosis. The ultrasound contrast can reflect the changes of liver blood flow dynamics, and it has a certain guiding significance to the assessment of the degree of liver fibrosis, the monitoring of the disease and the clinical treatment.

  1. Hepatocellular carcinoma complicating cystic fibrosis related liver disease.

    LENUS (Irish Health Repository)

    O'Donnell, D H

    2012-02-01

    Early diagnosis and treatment of the respiratory and gastrointestinal complications of cystic fibrosis (CF) have led to improved survival with many patients living beyond the fourth decade. Along with this increased life expectancy is the risk of further disease associated with the chronic manifestations of their condition. We report a patient with documented CF related liver disease for which he was under routine surveillance that presented with histologically proven hepatocellular carcinoma (HCC). It is important that physicians are aware of this association as increased vigilance may lead to earlier diagnosis and perhaps, a better outcome.

  2. Long non-coding RNA APTR promotes the activation of hepatic stellate cells and the progression of liver fibrosis

    International Nuclear Information System (INIS)

    In this study, we aimed at assessing a role of Alu-mediated p21 transcriptional regulator (APTR) in hepatofibrogenesis. APTR was upregulated in fibrotic liver samples and activated hepatic stellate cells (HSCs). Knockdown of APTR inhibited the activation of HSCs in vitro and mitigated the accumulation of collagen in vivo. Importantly, APTR silencing could abrogate TGF-β1-induced upregulation of α-SMA in HSCs. In addition, inhibition of cell cycle and cell proliferation by APTR knockdown was attenuated by p21 siRNA1 in primary HSCs. Finally, serum APTR levels were increased in patients with liver cirrhosis, indicating a potential biomarker for liver cirrhosis. Collectively, evidence is proposed for a new biological role of APTR in hepatofibrogenesis. - Highlights: • APTR is upregulated in fibrotic liver tissues and activated HSCs. • APTR silencing inhibits HSC activation and the progression of liver fibrosis. • Antifibrotic effect of APTR silencing is achieved by increasing p21

  3. The role of relaxin in the regulation of human liver and kidney fibrosis

    OpenAIRE

    Hayden, Annette Louise

    2009-01-01

    Liver fibrosis has a range of aetiologies and is a global cause of mortality. A critical effect of liver fibrosis which also increases mortality is portal hypertension. The hepatic stellate cell is accepted as a major progenitor of liver myofibroblasts, which have been shown to be a major source of collagen and extracellular matrix proteins that disrupt liver architecture and function. Relaxin is a hormone involved in remodelling of extracellular matrix in the uterus and cer...

  4. Liver Hemangioma Might Lead to overestimation of Liver Fibrosis by Fibroscan; A Missed Issue in Two Cases

    Directory of Open Access Journals (Sweden)

    Seyed Hossein Aalaei-Andabili

    2012-06-01

    Full Text Available Background: The assessment of liver fibrosis is an important way for prediction of liver disease progression and patient’s prognosis. Liver stiffness measurement (LSM is strongly associated with stage of liver diseases. Overestimation of liver fibrosis in heart failure has been reported. We would like to introduce a new leading cause of liver fibrosis overestimation by presentation of two cases.Case Presentation: One case with right lobe hemangioma has an overestimation of liver fibrosis. The result completely changed when Fibroscan was performed in patient’s left lobe. Interestingly, another case with left lobe hemangioma had overestimation of fibrosis in her left lobe but, right lob Fibroscan was normal.Conclusions: We found that liver hemangioma may leads to overestimation of liver stiffness and the correct inspection of liver echogenicity before any interpretation of high liver stiffness is recommended. We suggest that patient with higher level of Fibroscan score repeat it in other sides of the liver. Also, they should be evaluated by sonography for ruling out of possible confounders such as hepatic hemangioma..

  5. Imaging Based Methods of Liver Fibrosis Assessment in Viral Hepatitis: A Practical Approach

    Directory of Open Access Journals (Sweden)

    Hicham Khallafi

    2015-01-01

    Full Text Available Liver fibrosis represents the repair mechanism in liver injury and is a feature of most chronic liver diseases. The degree of liver fibrosis in chronic viral hepatitis infections has major clinical implications and presence of advanced fibrosis or cirrhosis determines prognosis. Treatment initiation for viral hepatitis is indicated in most cases of advanced liver fibrosis and diagnosis of cirrhosis entails hepatology evaluation for specialized clinical care. Liver biopsy is an invasive technique and has been the standard of care of fibrosis assessment for years; however, it has several limitations and procedure related complications. Recently, several methods of noninvasive assessment of liver fibrosis have been developed which require either serologic testing or imaging of liver. Imaging based noninvasive techniques are reviewed here and their clinical use is described. Some of the imaging based tests are becoming widely available, and collectively they are shown to be superior to liver biopsy in important aspects. Clinical utilization of these methods requires understanding of performance and quality related parameters which can affect the results and provide wrong assessment of the extent of liver fibrosis. Familiarity with the strengths and weaknesses of each modality is needed to correctly interpret the results in appropriate clinical context.

  6. Effects of glycyrrhetinic acid on collagen metabolism of hepatic stellate cells at different stages of liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Ji Yao Wang; Qi Sheng Zhang; Ji Sheng Guo; Mei Yu Hu

    2001-01-01

    @@ INTRODUCTIONLiver fibrosis is a dynamic course leading tocirrhosis from a various chronic liver diseases. Thepathological basis of fibrosis is the disturbance ofproduction and degradation of the extracellularmatrix (ECM), which causes accumulation of ECMin the liver[1,2].

  7. BM-derived fibrocytes contribute to liver fibrosis

    Science.gov (United States)

    2016-01-01

    Chronic liver injury often leads to hepatic fibrosis, a condition associated with increased levels of circulating TGF-β1 and lipopolysaccharide (LPS), activation of myofibroblasts, and extensive deposition of extracellular matrix, mostly collagen type I. Hepatic stellate cells (HSCs) are considered to be the major [1] but not the only source of myofibroblasts in the injured liver [2]. Hepatic myofibroblasts may also originate from portal fibroblasts, mesenchymal cells and fibrocytes [3]. Since the discovery of fibrocytes in 1994 by Dr. Bucala and colleagues, these bone marrow (BM)-derived collagen Type I-producing CD45+ cells remain the most fascinating cells of the hematopoietic system. Due to the ability to differentiate into collagen Type I producing cells/myofibroblasts, fibrocytes were implicated in the pathogenesis of liver, skin, lung, and kidney fibrosis. However, studies of different organs often contain controversial results on the number of fibrocytes recruited to the site of injury, and their biological function. Furthermore, fibrocytes were implicated in pathogenesis of sepsis, and were shown to possess anti-microbial activity. Finally, in response to specific stimuli, fibrocytes can give rise to fully differentiated macrophages, suggesting that in concurrence with high plasticity of hematopoietic cells, fibrocytes exhibit progenitor properties. Here we summarize our current understanding of the role of CD45+Collagen Type I+ BM-derived cells in response to fibrogenic liver injury and septicemia and discuss the most recent evidence supporting the critical role of fibrocytes in the mediation of pro-fibrogenic and/or pro-inflammatory responses. PMID:25966982

  8. The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies.

    Directory of Open Access Journals (Sweden)

    JunXu

    2014-07-01

    Full Text Available Liver fibrosis results from dysregulation of normal wound healing, inflammation, activation of myofibroblasts and deposition of extracellular matrix (ECM. Chronic liver injury causes death of hepatocytes and formation of apoptotic bodies, which in turn, release factors that recruit inflammatory cells (neutrophils, monocytes, macrophages, and lymphocytes to the injured liver. Hepatic macrophages (Kupffer cells produce TGF1 and other inflammatory cytokines that activate Collagen Type I producing myofibroblasts, which are not present in the normal liver. Secretion of TGF1 and activation of myofibroblasts play a critical role in the pathogenesis of liver fibrosis of different etiologies. Although the composition of fibrogenic myofibroblasts varies dependent on etiology of liver injury, liver resident Hepatic Stellate Cells (HSCs and Portal Fibroblasts (PFs are the major source of myofibroblasts in fibrotic liver in both experimental models of liver fibrosis and in patients with liver disease. Several studies have demonstrated that hepatic fibrosis can reverse upon cessation of liver injury. Regression of liver fibrosis is accompanied by the disappearance of fibrogenic myofibroblasts followed by resorption of the fibrous scar. Myofibroblasts either apoptose or inactivate into a quiescent-like state (e.g. stop collagen production and partially restore expression of lypogenic genes. Resolution of liver fibrosis is associated with recruitment of macrophages that secrete matrix-degrading enzymes (matrix metalloproteinase, collagenases and are responsible for fibrosis resolution. However, prolonged/repeated liver injury may cause irreversible crosslinking of ECM and formation of uncleavable collagen fibers. Advanced fibrosis progresses to cirrhosis and hepatocellular carcinoma (HCC. The current review will summarize the role and contribution of different cell types to populations of fibrogenic myofibroblasts in fibrotic liver.

  9. Role of histone deacetylases(HDACs) in progression and reversal of liver fibrosis.

    Science.gov (United States)

    Li, Xing; Wu, Xiao-Qin; Xu, Tao; Li, Xiao-Feng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun

    2016-09-01

    Liver fibrosis refers to a reversible wound healing process response to chronic liver injuries. Activation of hepatic stellate cells (HSCs) is closely correlated with the development of liver fibrosis. Histone deacetylases(HDACs) determine the acetylation levels of core histones to modulate expression of genes. To demonstrate the link between HDACs and liver fibrosis, CCl4-induced mouse liver fibrosis model and its spontaneous reversal model were established. Results of the current study demonstrated that deregulation of liver HDACs may involved in the development of liver fibrosis. Among 11 HDACs tested in our study (Class I, II, and IV HDACs), expression of HDAC2 was maximally increased in CCl4-induced fibrotic livers but decreased after spontaneous recovery. Moreover, expression of HDAC2 was elevated in human liver fibrotic tissues. In this regard, the potential role of HDAC2 in liver fibrosis was further evaluated. Our results showed that administration of HSC-T6 cells with transforming growth factor-beta1 (TGF-β1) resulted in an increase of HDAC2 protein expression in dose- and time-dependent manners. Moreover, HDAC2 deficiency inhibited HSC-T6 cell proliferation and activation induced by TGF-β1. More importantly, the present study showed HDAC2 may regulate HSCs activation by suppressing expression of Smad7, which is a negative modulator in HSCs activation and liver fibrosis. Collectively, these observations revealed that HDAC2 may play a pivotal role in HSCs activation and liver fibrosis while deregulation of HDACs may serve as a novel mechanism underlying liver fibrosis. PMID:27396813

  10. Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells

    Directory of Open Access Journals (Sweden)

    Xiang Y. Kong

    2014-03-01

    Full Text Available Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1gt/gt mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1gt/gt liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1gt/gt Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1gt/gt mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage.

  11. The pattern of fibrosis in the acinar zone 3 areas in early alcoholic liver disease

    DEFF Research Database (Denmark)

    Junge, Jette; Horn, T; Vyberg, M;

    1991-01-01

    The degree of fibrosis and the pattern of collagen distribution in the acinar zone 3, as well as the thickness of the terminal hepatic vein walls (THV) were analyzed in 48 consecutive liver needle biopsies from 48 alcoholics with preserved liver architecture. The fibrosis occurred to more or less...

  12. Hyaluronic acid as a biomarker of fibrosis in chronic liver diseases of different etiologies

    Science.gov (United States)

    ORASAN, OLGA HILDA; CIULEI, GEORGE; COZMA, ANGELA; SAVA, MADALINA; DUMITRASCU, DAN LUCIAN

    2016-01-01

    Chronic liver diseases represent a significant public health problem worldwide. The degree of liver fibrosis secondary to these diseases is important, because it is the main predictor of their evolution and prognosis. Hyaluronic acid is studied as a non-invasive marker of liver fibrosis in chronic liver diseases, in an attempt to avoid the complications of liver puncture biopsy, considered the gold standard in the evaluation of fibrosis. We review the advantages and limitations of hyaluronc acid, a biomarker, used to manage patients with chronic viral hepatitis B or C infection, non-alcoholic fatty liver disease, HIV-HCV coinfection, alcoholic liver disease, primary biliary cirrhosis, biliary atresia, hereditary hemochromatosis and cystic fibrosis. PMID:27004022

  13. Contribution of bone marrow-derived fibrocytes to liver fibrosis.

    Science.gov (United States)

    Xu, Jun; Cong, Min; Park, Tae Jun; Scholten, David; Brenner, David A; Kisseleva, Tatiana

    2015-02-01

    Since the discovery of fibrocytes in 1994 by Dr. Bucala and colleagues, these bone marrow (BM)-derived collagen Type I producing CD45(+) cells remain the most fascinating cells of the hematopoietic system. Despite recent reports on the emerging contribution of fibrocytes to fibrosis of parenchymal and non-parenchymal organs and tissues, fibrocytes remain the most understudied pro-fibrogenic cellular population. In the past years fibrocytes were implicated in the pathogenesis of liver, skin, lung, and kidney fibrosis by giving rise to collagen type I producing cells/myofibroblasts. Hence, the role of fibrocytes in fibrosis is not well defined since different studies often contain controversial results on the number of fibrocytes recruited to the site of injury versus the number of fibrocyte-derived myofibroblasts in the same fibrotic organ. Furthermore, many studies were based on the in vitro characterization of fibrocytes formed after outgrowth of BM and/or peripheral blood cultures. Therefore, the fibrocyte function(s) still remain(s) lack of understanding, mostly due to (I) the lack of mouse models that can provide complimentary in vivo real-time and cell fate mapping studies of the dynamic differentiation of fibrocytes and their progeny into collagen type I producing cells (and/or possibly, other cell types of the hematopoietic system); (II) the complexity of hematopoietic cell differentiation pathways in response to various stimuli; (III) the high plasticity of hematopoietic cells. Here we summarize the current understanding of the role of CD45(+) collagen type I(+) BM-derived cells in the pathogenesis of liver injury. Based on data obtained from various organs undergoing fibrogenesis or other type of chronic injury, here we also discuss the most recent evidence supporting the critical role of fibrocytes in the mediation of pro-fibrogenic and/or pro-inflammatory responses. PMID:25713803

  14. Lack of hepcidin expression attenuates steatosis and causesfibrosis in the liver

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    AIM To investigate the role of key iron-regulatoryprotein, hepcidin in non-alcoholic fatty liver disease(NAFLD).METHODS: Hepcidin (Hamp1 ) knockout and floxedcontrol mice were administered a high fat and highsucrose (HFS) or a regular control diet for 3 or 7 mo.Steatosis, triglycerides, fibrosis, protein and gene expressionin mice livers were determined by histologicaland biochemical techniques, western blotting and realtimepolymerase chain reaction.RESULTS: Knockout mice exhibited hepatic ironaccumulation. Despite similar weight gains, HFS feedinginduced hepatomegaly in floxed, but not knockout,mice. The livers of floxed mice exhibited higher levelsof steatosis, triglycerides and c-Jun N-terminal kinase(JNK) phosphorylation than knockout mice. In contrast,a significant increase in fibrosis was observed inknockout mice livers within 3 mo of HFS administration.The hepatic gene expression levels of sterol regulatory element-binding protein-1c and fat-specific protein-27,but not peroxisome proliferator-activated receptoralphaor microsomal triglyceride transfer protein, wereattenuated in HFS-fed knockout mice. Knockout micefed with regular diet displayed increased carnitinepalmitoyltransferase-1a and phosphoenolpyruvatecarboxykinase-1 but decreased glucose-6-phosphataseexpression in the liver. In summary, attenuated steatosiscorrelated with decreased expression of lipogenic andlipid storage genes, and JNK phosphorylation. Deletionof Hamp1 alleles per se modulated hepatic expressionof beta-oxidation and gluconeogenic genes.CONCLUSION: Lack of hepcidin expression inhibitshepatic lipid accumulation and induces early developmentof fibrosis following high fat intake. Hepcidinand iron may play a role in the regulation of metabolicpathways in the liver, which has implications for NAFLDpathogenesis.

  15. Viscoelasticity-based magnetic resonance elastography for the assessment of liver fibrosis in hepatitis C patients after liver transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Kamphues, C.; Bova, R.; Yahyazadeh, A.; Bahra, M.; Neuhaus, P. [Charite, Campus Virchow Klinikum, Berlin (Germany). Klinik fuer Allgemein-, Viszeral- und Transplantationschirurgie; Klatt, D.; Braun, J.; Sack, I.; Asbach, P. [Charite - Universitaetsmedizin, Berlin (Germany). Klinik fuer Radiologie; Klauschen, F. [Charite - Universitaetsmedizin, Berlin (Germany). Inst. fuer Pathologie

    2012-11-15

    Purpose: Despite advantages in antiviral therapy of hepatitis C (HCV) in recent years, progressing liver fibrosis remains a major problem for patients suffering from hepatitis C after liver transplantation. Therefore, effective non-invasive methods for the assessment of liver fibrosis are needed in order to guide treatment decisions and predict prognosis in these patients. The aim of this study was to prospectively assess the diagnostic accuracy of viscoelasticity-based magnetic resonance (MR) elastography for the assessment of liver fibrosis in HCV patients after liver transplantation. Materials and Methods: After IRB approval, a total of 25 patients, who had received a liver graft due to chronic hepatitis C underwent both liver biopsy and MR elastography. Two viscoelastic constants, the shear elasticity {mu} and the powerlaw exponent {alpha} were calculated by fitting the frequency function of the complex shear modulus with the viscoelastic springpot-model. Results: A strong positive correlation between shear elasticity {mu} and the stage of fibrosis could be found (R = 0.486, p = 0.0136). The area under the receiver operating curve (AUROC) of MR elastography based on {mu} for diagnosis of severe fibrosis (F {>=} 3) was 0.87 and 0.65 for diagnosis of significant fibrosis (F {>=} 2). The powerlaw exponent {alpha} did not correlate with the stage of fibrosis. Conclusion: MR elastography represents a promising non-invasive procedure for the assessment of higher grades of fibrosis in HCV patients after liver transplantation. The poor correlation for lower grades of fibrosis suggests unknown mechanical interactions in the transplanted liver. (orig.)

  16. Viscoelasticity-based magnetic resonance elastography for the assessment of liver fibrosis in hepatitis C patients after liver transplantation

    International Nuclear Information System (INIS)

    Purpose: Despite advantages in antiviral therapy of hepatitis C (HCV) in recent years, progressing liver fibrosis remains a major problem for patients suffering from hepatitis C after liver transplantation. Therefore, effective non-invasive methods for the assessment of liver fibrosis are needed in order to guide treatment decisions and predict prognosis in these patients. The aim of this study was to prospectively assess the diagnostic accuracy of viscoelasticity-based magnetic resonance (MR) elastography for the assessment of liver fibrosis in HCV patients after liver transplantation. Materials and Methods: After IRB approval, a total of 25 patients, who had received a liver graft due to chronic hepatitis C underwent both liver biopsy and MR elastography. Two viscoelastic constants, the shear elasticity μ and the powerlaw exponent α were calculated by fitting the frequency function of the complex shear modulus with the viscoelastic springpot-model. Results: A strong positive correlation between shear elasticity μ and the stage of fibrosis could be found (R = 0.486, p = 0.0136). The area under the receiver operating curve (AUROC) of MR elastography based on μ for diagnosis of severe fibrosis (F ≥ 3) was 0.87 and 0.65 for diagnosis of significant fibrosis (F ≥ 2). The powerlaw exponent α did not correlate with the stage of fibrosis. Conclusion: MR elastography represents a promising non-invasive procedure for the assessment of higher grades of fibrosis in HCV patients after liver transplantation. The poor correlation for lower grades of fibrosis suggests unknown mechanical interactions in the transplanted liver. (orig.)

  17. Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy

    Institute of Scientific and Technical Information of China (English)

    Giada Sebastiani; Alfredo Alberti

    2006-01-01

    Chronic liver diseases are very common worldwide,particularly those linked to viral hepatitis and to alcoholic and non-alcoholic fatty liver. Their natural history is variable and long-term evolution differs in individual patients. Optimised clinical management of compensated chronic liver diseases requires precise definition of the stage of liver fibrosis, the main determinant of prognosis and of most therapeutic decisions. Liver biopsy is the gold standard for assessment of hepatic fibrosis.However, it is invasive with possible complications,costly and prone to sampling errors. Many non-invasive markers of liver fibrosis have been recently proposed and assessed in the clinical setting as surrogates of liver biopsy. Direct markers are based on biochemical parameters directly linked to fibrogenesis while indirect markers use simple or more sophisticated parameters that correlate with liver fibrosis stages. Non-invasive markers of liver fibrosis have been tested in different forms of chronic liver disease and showed variable diagnostic performance, but accuracy rarely was above 75%-80%. Better results were obtained when markers were combined. On this line, we have recently proposed a set of algorithms that combine sequentially indirectnon-invasive markers of liver fibrosis, reaching 90%-95%diagnostic accuracy with significant reduction in the need for liver biopsy. Based on available evidence, it can be anticipated that non-invasive markers of liver fibrosis and their combined use will soon become a most useful tool in the clinical management of many forms of chronic liver disease. However, their implementation is expected to reduce, but not to completely eliminate, the need for liver biopsy.

  18. Global analysis of DNA methylation in early-stage liver fibrosis

    Directory of Open Access Journals (Sweden)

    Komatsu Yoko

    2012-01-01

    Full Text Available Abstract Background Liver fibrosis is caused by chemicals or viral infection. The progression of liver fibrosis results in hepatocellular carcinogenesis in later stages. Recent studies have revealed the importance of DNA hypermethylation in the progression of liver fibrosis to hepatocellular carcinoma (HCC. However, the importance of DNA methylation in the early-stage liver fibrosis remains unclear. Methods To address this issue, we used a pathological mouse model of early-stage liver fibrosis that was induced by treatment with carbon tetrachloride (CCl4 for 2 weeks and performed a genome-wide analysis of DNA methylation status. This global analysis of DNA methylation was performed using a combination of methyl-binding protein (MBP-based high throughput sequencing (MBP-seq and bioinformatic tools, IPA and Oncomine. To confirm functional aspect of MBP-seq data, we complementary used biochemical methods, such as bisulfite modification and in-vitro-methylation assays. Results The genome-wide analysis revealed that DNA methylation status was reduced throughout the genome because of CCl4 treatment in the early-stage liver fibrosis. Bioinformatic and biochemical analyses revealed that a gene associated with fibrosis, secreted phosphoprotein 1 (Spp1, which induces inflammation, was hypomethylated and its expression was up-regulated. These results suggest that DNA hypomethylation of the genes responsible for fibrosis may precede the onset of liver fibrosis. Moreover, Spp1 is also known to enhance tumor development. Using the web-based database, we revealed that Spp1 expression is increased in HCC. Conclusions Our study suggests that hypomethylation is crucial for the onset of and in the progression of liver fibrosis to HCC. The elucidation of this change in methylation status from the onset of fibrosis and subsequent progression to HCC may lead to a new clinical diagnosis.

  19. The Role of Butylidenephthalide in Targeting Microenvironment Contributes to the Ameliorate of Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Hong-Meng eChuang

    2016-04-01

    Full Text Available The treatment of liver fibrosis has clinical limitations because of its multiple etiologies, such as epithelial–mesenchymal transition (EMT promotion, cell regeneration and remodeling dysfunction, inflammatory cell activation, and scar tissue deposition. These factors might be considered as a new target for the fibrotic microenvironment, leading to increased fibrogenesis and liver fibrosis. Here, we investigate a small molecule named butylidenephthalide (BP and its multiple effects on liver fibrosis treatment. Thioacetamide was used in vivo to induce chronic liver fibrosis. BP was administered orally in rats for a period of 2 weeks and 4 weeks, which resulted in a significantly reduced fibrosis score (p<0.05 and (p<0.001, respectively. The inflammatory reaction of macrophage infiltration were reduced in the administration of BP, which led to the decrease in the transaminase levels. Moreover, we also found liver functions recovering (due to the increased serum albumin and reduced prothrombin time where liver cells regenerated, which can be seen in the increase of Ki-67 on Oval cell. In addition, the fibrotic scar was also reduced, along with the expression of matrix metalloprotease by hepatic stellate cell. Furthermore, regarding the mechanism/study of EMT reduced by BP, the knockdown of BMP-7, which could reduce α-SMA expression, was mediated by the regulation of TGF-β, which implies its major role on EMT. Finally, in the in vivo study, BP treatment of liver fibrosis was reduced by Bmp7 knockdown in zebrafish, suggesting that BP leads to the reduction of liver fibrosis, which also depends on BMP-7 induction. These results suggest that BP had multiple targets for treating liver fibrosis in the following ways: reduction of EMT, decreasing inflammatory reaction, and liver cell proliferation. This multiple targets approach provided a new mechanism to treat liver injury and fibrosis.

  20. Increased liver stiffness in alcoholic liver disease:Differentiating fibrosis from steatohepatitis

    Institute of Scientific and Technical Information of China (English)

    Sebastian; Mueller; Gunda; Millonig; Lucie; Sarovska; Stefanie; Friedrich; Frank; M; Reimann; Maria; Pritsch; Silke; Eisele; Felix; Stickel; Thomas; Longerich; Peter; Schirmacher; Helmut; Karl; Seitz

    2010-01-01

    AIM:To test if inflammation also interferes with liver stiffness (LS) assessment in alcoholic liver disease (ALD) and to provide a clinical algorithm for reliable fibrosis assessment in ALD by FibroScan (FS).METHODS:We first performed sequential LS analysis before and after normalization of serum transaminases in a learning cohort of 50 patients with ALD admitted for alcohol detoxification. LS decreased in almost all patients within a mean observation interval of 5.3 d. Six patients (12%) would have been m...

  1. [Diagnostic accuracy for alcoholic liver disease with controlled Attenuation Parameter (CAP) measured by transient elastography for the non-invasive assessment of liver steatosis].

    Science.gov (United States)

    Kikuchi, Masahiro; Umeda, Rumiko; Tsuruya, Kota; Shiozawa, Hirokazu; Matsushima, Masashi; Abe, Keiichiro; Kikuchi, Miho; Takahashi, Masahiko; Yamagishi, Yoshiyuki; Nishizaki, Hiroyasu; Horie, Yoshinori; Kanai, Takanori

    2015-10-01

    Along with the development of interferon and therapeutic medication, the incidence of viral hepatitis constituting the largest part of liver disease decreased, and the main target in the field of liver disease is now shifting from viral hepatitis to alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) as metabolic liver disease. Although these diseases tend.to. be gathered as non-viral liver disease because the similar specific liver tissue, the natural history and etiology are considerably different between them. We need to distinguish both of them to do appropriate treatment intervention. Questioning of amount of drinking is needed, but we experience some difficult cases to understand drinking history because of a too little declaration of amount of drinking. A new ultrasonic image analyses using propagation speed in the organization of the pulse vibration wave was developed as Fibroscan by Echosens company in recent years. Fibroscan is a non-invasive test to quantify liver fibrosis as Liver Stiffness Measurement (LSM). It also detects and quantifies steatosis simultaneously using the Controlled Attenuation Parameter (CAP). CAP is a measurement of the ultrasound attenuation. We measured liver steatosis of patients using Fibroscan, and other blood tests. 63 cases of ALD, 177 cases of NAFLD, 57 cases of Virus and 271 cases of Normal were enrolled. CAP value were significantly lower in the ALD group compared with NAFLD group. (P Fibroscan for ALD patients, comparing the results of them to those of virus patients and NAFLD patients. PMID:26946784

  2. Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice

    Energy Technology Data Exchange (ETDEWEB)

    Harris, Todd R. [Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616 (United States); Bettaieb, Ahmed [Department of Nutrition, University of California, Davis, CA 95616 (United States); Kodani, Sean; Dong, Hua [Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616 (United States); Myers, Richard; Chiamvimonvat, Nipavan [Department of Internal Medicine: Cardiovascular, University of California, Davis, CA 95616 (United States); Haj, Fawaz G. [Department of Nutrition, University of California, Davis, CA 95616 (United States); Department of Internal Medicine: Endocrinology, Diabetes and Metabolism, University of California, Davis, CA 95616 (United States); Hammock, Bruce D., E-mail: bdhammock@ucdavis.edu [Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616 (United States)

    2015-07-15

    Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl{sub 4})-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl{sub 4}-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl{sub 4}-treated group relative to the Control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl{sub 4}-treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-(4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy)-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl{sub 4}, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress. - Highlights: • We administer an inhibitor of sEH in a CCl4 murine model. • sEH inhibition reduces liver collagen deposition and pro-fibrotic gene expression. • sEH inhibition induces MMP-1a activity.

  3. Liver fibrosis and regeneration in dogs and cats : An immunohistochemical approach

    OpenAIRE

    Ijzer, J

    2008-01-01

    In this thesis we focus on liver tissue repair processes in canine and feline hepatitis, on formalin fixed paraffin embedded archival liver specimens. Hepatitis was diagnosed using histological standard criteria, and always includes hepatocellular cell death and an inflammatory infiltrate. Subsequently, the liver may react with regeneration and fibrosis (a detectable deposit of extracellular matrix). Fibrosis can develop into cirrhosis, which has a poor prognosis. Based on a better understand...

  4. Non invasive assessment of liver fibrosis in chronic hemodialysis patients with viral hepatitis C

    OpenAIRE

    Arrayhani, Mohamed; Sqalli, Tarik; Tazi, Nada; El Youbi, Randa; Chaouch, Safae; Aqodad, Nourdin; Ibrahimi, Sidi Adil

    2015-01-01

    The liver biopsy has long been the "gold standard" for assessing liver fibrosis in patients with hepatitis C. It's an invasive procedure which is associated with an elevated bleeding, especially in chronic hemodialysis patients. Main goal is to assess liver fibrosis in chronic hemodialysis with HCV by Fibroscan and by biological scores (APRI, Forns and Fib-4), and to measure the correlation between these tests. Cross-sectional study including all chronic hemodialysis patients with hepatitis C...

  5. Non-invasive evaluation of cystic fibrosis related liver disease in adults with ARFI, transient elastography and different fibrosis scores.

    Directory of Open Access Journals (Sweden)

    Thomas Karlas

    Full Text Available BACKGROUND: Cystic fibrosis-related liver disease (CFLD is present in up to 30% of cystic fibrosis patients and can result in progressive liver failure. Diagnosis of CFLD is challenging. Non-invasive methods for staging of liver fibrosis display an interesting diagnostic approach for CFLD detection. AIM: We evaluated transient elastography (TE, acoustic radiation force impulse imaging (ARFI, and fibrosis indices for CFLD detection. METHODS: TE and ARFI were performed in 55 adult CF patients. In addition, AST/Platelets-Ratio-Index (APRI, and Forns' score were calculated. Healthy probands and patients with alcoholic liver cirrhosis served as controls. RESULTS: Fourteen CF patients met CFLD criteria, six had liver cirrhosis. Elastography acquisition was successful in >89% of cases. Non-cirrhotic CFLD individuals showed elastography values similar to CF patients without liver involvement. Cases with liver cirrhosis differed significantly from other CFLD patients (ARFI: 1.49 vs. 1.13 m/s; p = 0.031; TE: 7.95 vs. 4.16 kPa; p = 0.020 and had significantly lower results than individuals with alcoholic liver cirrhosis (ARFI: 1.49 vs. 2.99 m/s; p = 0.002. APRI showed the best diagnostic performance for CFLD detection (AUROC 0.815; sensitivity 85.7%, specificity 70.7%. CONCLUSIONS: ARFI, TE, and laboratory based fibrosis indices correlate with each other and reliably detect CFLD related liver cirrhosis in adult CF patients. CF specific cut-off values for cirrhosis in adults are lower than in alcoholic cirrhosis.

  6. Effect of Fuzheng Huayu formula and its actions against liver fibrosis

    Directory of Open Access Journals (Sweden)

    Xu Lieming

    2009-06-01

    Full Text Available Abstract Liver fibrosis is a common histological process to develop into cirrhosis in various chronic liver diseases including chronic hepatitis and fatty liver. Therefore anti-liver fibrosis is very important strategy to treat chronic liver diseases. Fuzheng Huayu (FZHY, a preparation containing herbs such as Radix Salvia Miltiorrhizae, Cordyceps, Semen Persicae, was formulated on the basis of Chinese medicine theory in treating liver fibrosis and was approved. Pharmacological studies and clinical trials demonstrate that FZHY has a significant effect against liver fibrosis and that many of the pharmacological actions are attributable to the effect. This article reviews the effects and actions of FZHY, in particular the effects observed from clinical trials in treating liver fibrosis caused by chronic hepatitis B and the actions on inhibition of hepatic stellate cell activation, protection of hepatocytes and inhibition of hepatic sinusoidal capillarization. This article also reviews the coordinated effects of the constituent herbs of FZHY and the actions of their active compounds such as salvianonic acid B (SA-B on liver fibrosis.

  7. Chlorogenic acid reduces liver inflammation and fibrosis through inhibition of toll-like receptor 4 signaling pathway

    International Nuclear Information System (INIS)

    Highlights: ► Chlorogenic acid decreased serum transaminase level and increased albumin level. ► Chlorogenic acid attenuated CCl4-induced liver collagen deposition. ► Chlorogenic acid ameliorated CCl4-induced inflammatory response. ► Chlorogenic acid inhibited the activation of TLR4/NF-κB signaling in liver. -- Abstract: Chlorogenic acid (CGA) is a type of polyphenol with anti-inflammatory, antioxidant activities. Our previous studies showed CGA could efficiently inhibit carbon tetrachloride (CCl4)-induced liver fibrosis in rats. However, the specific underlying mechanism remains unclear. The aim of this study is to investigate the effects of CGA on liver inflammation and fibrosis induced by CCl4 and whether they are related to inhibition of toll-like receptor 4 (TLR4) signaling pathway. Male Sprague-Dawley (SD) rats were administrated CCl4 together with or without CGA for 8 weeks. Histopathological and biochemical analyses were carried out. The mRNA and protein expression levels of proinflammatory and profibrotic mediators were detected by RT-PCR and Western blot, respectively. The levels of serum proinflammatory cytokines were detected by ELISA. CGA significantly attenuated CCl4-induced liver damage and symptoms of liver fibrosis, accompanied by reduced serum transaminase levels, collagen I and α-smooth muscle actin (α-SMA) expression. As compared with the CCl4-treated group, the expression levels of TLR4, myeloid differentiation factor 88 (MyD88), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were reduced in the treatment group of CCl4 and CGA, whereas bone morphogenetic protein and activin membrane-bound inhibitor (Bambi) expression was increased. CGA also suppressed CCl4 induced nuclear factor-κB (NF-κB) activation. Moreover, the hepatic mRNA expression and serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were significantly increased in CCl4-treated rats and attenuated by co

  8. Acoustic radiation force imaging sonoelastography for noninvasive staging of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Carmen Fierbinteanu-Braticevici; Dan Andronescu; Radu Usvat; Dragos Cretoiu; Cristian Baicus; Gabriela Marinoschi

    2009-01-01

    AIM: To investigate the diagnostic accuracy of acoustic radiation force impulse (ARFI) imaging as a noninvasive method for the assessment of liver fibrosis in chronic hepatitis C (CHC) patients.METHODS: We performed a prospective blind comparison of ARFI elastography, APRI index and FibroMax in a consecutive series of patients who underwent liver biopsy for CHC in University Hospital Bucharest. Histopathological staging of liver fibrosis according to the METAVIR scoring system served as the reference. A total of 74 patients underwent ARFI elastography, APRI index, FibroMax and successful liver biopsy.RESULTS: The noninvasive tests had a good correlation with the liver biopsy results. The most powerful test in predicting fibrosis was ARFI elastography. The diagnostic accuracy of ARFI elastography, expressed as area under receiver operating characteristic curve (AUROC) had a validity of 90.2% (95% CI AUROC =0.831-0.972, P < 0.001) for the diagnosis of significant fibrosis (F ≥ 2). ARFI sonoelastography predicted even better F3 or F4 fibrosis (AUROC = 0.993, 95% CI =0.979-1).CONCLUSION: ARFI elastography had very good accuracy for the assessment of liver fibrosis and was superior to other noninvasive methods (APRI Index,FibroMax) for staging liver fibrosis.

  9. Effects of Guiyuanfang and autologous transplantation of bone marrow stem cells on rats with liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Li-Mao Wu; Lian-Da Li; Hong Liu; Ke-Yong Ning; Yi-Kui Li

    2005-01-01

    AIM: To investigate the therapeutic effects of Guiyuanfang and bone marrow stem cells (BMSCs) on rats with liver fibrosis.METHODS: Liver fibrosis model was induced by carbon tetrachloride, ethanol, high lipid and assessed biochemically and histologically. Liver function and hydroxyproline contents of liver tissue were determined.Serum hyaluronic acid (HA) level and procollagen Ⅲ level were performed by radioimmunoassay. The VG staining was used to evaluate the collagen deposit in the liver.Immunohistochemical SABC methods were used to detect transplanted BMSCs and expression of urokinase plasminogen activator (uPA).RESULTS: Serum transaminase level and liver fibrosis in rats were markedly reduced by Guiyuanfang and BMSCs. HA level and procollagen Ⅲ level were also reduced obviously,compared to model rats (HA: 47.18±10.97 ng/mL,48.96±14.79 ng/mL; PCⅢ: 22.48±5.46 ng/mL, 26.90±3.35ng/mL; P<0.05).Hydroxyproline contents of liver tissue in both BMSCs group and Guiyuanfang group were far lower than that of model group (1 227.2±43.1 μg/g liver tissue, 1390.8±156.3 μg/g liver tissue; P<0.01). After treatment fibrosis scores were also reduced. Both Guiyuanfang and BMSCs could increase the expression of uPA. The transplanted BMSCs could engraft, survive, and proliferate in the liver.CONCLUSION: Guiyuanfang protects against liver fibrosis.Transplanted BMSCs may engraft, survive, and proliferate in the fibrosis livers indefinitely. Guiyuanfang may synergize with BMSCs to improve recovery from liver fibrosis.

  10. MR elastography of the liver at 3.0 T in diagnosing liver fibrosis grades; preliminary clinical experience

    International Nuclear Information System (INIS)

    To clarify the usefulness of 3.0-T MR elastography (MRE) in diagnosing the histological grades of liver fibrosis using preliminary clinical data. Between November 2012 and March 2014, MRE was applied to all patients who underwent liver MR study at a 3.0-T clinical unit. Among them, those who had pathological evaluation of liver tissue within 3 months from MR examinations were retrospectively recruited, and the liver stiffness measured by MRE was correlated with histological results. Institutional review board approved this study, waiving informed consent. There were 70 patients who met the inclusion criteria. Liver stiffness showed significant correlation with the pathological grades of liver fibrosis (rho = 0.89, p < 0.0001, Spearman's rank correlation). Areas under the receiver operating characteristic curve were 0.93, 0.95, 0.99 and 0.95 for fibrosis score greater than or equal to F1, F2, F3 and F4, with cut-off values of 3.13, 3.85, 4.28 and 5.38 kPa, respectively. Multivariate analysis suggested that grades of necroinflammation also affected liver stiffness, but to a significantly lesser degree as compared to fibrosis. 3.0-T clinical MRE was suggested to be sufficiently useful in assessing the grades of liver fibrosis. (orig.)

  11. MR elastography of the liver at 3.0 T in diagnosing liver fibrosis grades; preliminary clinical experience

    Energy Technology Data Exchange (ETDEWEB)

    Yoshimitsu, Kengo; Mitsufuji, Toshimichi; Shinagawa, Yoshinobu; Fujimitsu, Ritsuko; Morita, Ayako; Urakawa, Hiroshi; Takano, Koichi [Fukuoka University, Department of Radiology, Fukuoka (Japan); Hayashi, Hiroyuki [Fukuoka University, Department of Pathology, Faculty of Medicine, Fukuoka (Japan)

    2016-03-15

    To clarify the usefulness of 3.0-T MR elastography (MRE) in diagnosing the histological grades of liver fibrosis using preliminary clinical data. Between November 2012 and March 2014, MRE was applied to all patients who underwent liver MR study at a 3.0-T clinical unit. Among them, those who had pathological evaluation of liver tissue within 3 months from MR examinations were retrospectively recruited, and the liver stiffness measured by MRE was correlated with histological results. Institutional review board approved this study, waiving informed consent. There were 70 patients who met the inclusion criteria. Liver stiffness showed significant correlation with the pathological grades of liver fibrosis (rho = 0.89, p < 0.0001, Spearman's rank correlation). Areas under the receiver operating characteristic curve were 0.93, 0.95, 0.99 and 0.95 for fibrosis score greater than or equal to F1, F2, F3 and F4, with cut-off values of 3.13, 3.85, 4.28 and 5.38 kPa, respectively. Multivariate analysis suggested that grades of necroinflammation also affected liver stiffness, but to a significantly lesser degree as compared to fibrosis. 3.0-T clinical MRE was suggested to be sufficiently useful in assessing the grades of liver fibrosis. (orig.)

  12. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease

    OpenAIRE

    Zeybel, Müjdat; Hardy, Timothy; Robinson, Stuart M.; Fox, Christopher; Anstee, Quentin M.; Ness, Thomas; Masson, Steven; Masson, Steven; French, Jeremy; White, Steve; Mann, Jelena

    2015-01-01

    RESEARCH Open Access Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease Müjdat Zeybel1, Timothy Hardy1, Stuart M Robinson1, Christopher Fox1, Quentin M Anstee1, Thomas Ness2, Steven Masson1, John C Mathers1, Jeremy French1, Steve White1 and Jelena Mann1* Abstract Background: Chronic liver injury can lead to the development of liver fibrosis and cirrhosis but only in a minority of patie...

  13. Glutamine inhibits CCl4 induced liver fibrosis in mice and TGF-β1 mediated epithelial-mesenchymal transition in mouse hepatocytes.

    Science.gov (United States)

    Shrestha, Nirajan; Chand, Lokendra; Han, Myung Kwan; Lee, Seung Ok; Kim, Chan Young; Jeong, Yeon Jun

    2016-07-01

    Glutamine, traditionally a non-essential amino acid, now has been considered as essential in serious illness and injury. It is a major precursor for glutathione synthesis. However, the anti-fibrotic effect of glutamine and its molecular mechanism in experimental liver fibrosis have not been explored. In the present study we aimed to examine the potential role of glutamine in carbon tetrachloride (CCl4) induced liver fibrosis and TGF-β1 mediated epithelial mesenchymal transition (EMT) and apoptosis in mouse hepatocytes. Liver fibrosis was induced by intraperitoneal injection of CCl4 three times a week for 10 weeks. Glutamine treatment effectively attenuated liver injury and oxidative stress. Collagen content was significantly decreased in liver sections of glutamine treated mice compared to CCl4 model mice. Furthermore, glutamine decreased expression level of α-SMA and TGF-β in liver tissue. Our in vitro study showed that TGF-β1 treatment in hepatocytes resulted in loss of E-cadherin and increased expression of mesenchymal markers and EMT related transcription factor. In addition, TGF-β1 increased the expression of apoptotic markers. However, glutamine interestingly suppressed TGF-β1 mediated EMT and apoptosis. In conclusion, our results suggest that glutamine ameliorates CCl4 induced liver fibrosis and suppresses TGF-β1 induced EMT progression and apoptosis. PMID:27137983

  14. Prevention of Liver Fibrosis by Triple Helix-Forming Oligodeoxyribonucleotides Targeted to the Promoter Region of Type I Collagen Gene

    OpenAIRE

    Koilan, Subramaniyan; Hamilton, David; Baburyan, Narina; Padala, Mythili K.; Weber, Karl T.; Guntaka, Ramareddy V.

    2010-01-01

    Hepatic fibrosis leading to cirrhosis remains a global health problem. The most common etiologies are alcoholism and viral infections. Liver fibrosis is associated with major changes in both quantity and composition of extracellular matix and leads to disorganization of the liver architecture and irreversible damage to the liver function. As of now there is no effective therapy to control fibrosis. The end product of fibrosis is abnormal synthesis and accumulation of type I collagen in the ex...

  15. Baseline prevalence and predictors of liver fibrosis among HIV-positive individuals

    DEFF Research Database (Denmark)

    Matthews, G V; Neuhaus, J; Bhagani, S;

    2015-01-01

    OBJECTIVES: Liver disease is increasingly recognized in HIV-positive individuals, even among those without viral hepatitis, partly as a result of the recent availability of noninvasive methods of liver fibrosis assessment. The objective of this substudy is to compare the effects of early versus...... deferred antiretroviral therapy (ART) on liver fibrosis progression. METHODS: Sites in the Strategic Timing of AntiRetroviral Treatment (START) study with access to FibroScan® were invited to participate in the Liver Fibrosis Progression Substudy. All substudy participants underwent FibroScan® at baseline...... valid transient elastography (TE) result. The median TE score was 4.9 kPa [interquartile range (IQR) 4.3-6.0 kPa]. Seventeen patients (7.8%) [95% confidence interval (CI) 5.1-12.1%] had a TE score of > 7.2 kPa, indicating significant liver fibrosis. Baseline factors associated with higher TE scores in...

  16. Liver fibrosis grading using multiresolution histogram information in real-time elastography

    Science.gov (United States)

    Albouy-Kissi, A.; Sarry, L.; Massoulier, S.; Bonny, C.; Randl, K.; Abergel, A.

    2010-03-01

    Despites many limitations, liver biopsy remains the gold standard method for grading and staging liver biopsy. Several modalities have been developed for a non invasive assessment of liver diseases. Real-time elastography may constitute a true alternative to liver biopsy by providing an image of tissular elasticity distribution correlated to the fibrosis grade. In this paper, we investigate a new approach for the assessment of liver fibrosis by the classification of fibrosis morphometry. Multiresolution histogram, based on a combination of intensity and texture features, has been tested as feature space. Thus, the ability of such multiresolution histograms to discriminate fibrosis grade has been proven. The results have been tested on seventeen patients that underwent a real time elastography and FibroScan examination.

  17. Platycodin D attenuates bile duct ligation-induced hepatic injury and fibrosis in mice.

    Science.gov (United States)

    Kim, Tae-Won; Lee, Hong-Ki; Song, In-Bae; Lim, Jong-Hwan; Cho, Eun-Sang; Son, Hwa-Young; Jung, Ju-Young; Yun, Hyo-In

    2013-01-01

    Platycodin D (PD) is the major triterpene saponin in the root of Platycodon grandiflorum. The aim of the present study was to evaluate the protective effects of PD on bile duct ligation (BDL)-induced cholestasis in mice. Mice were allocated to five groups: sham, BDL alone, and BDL with PD treatment at 1, 2, and 4mg/kg. PD was administered to the mice for 28 consecutive days after the BDL operation. PD treatment of BDL-operated mice decreased serum alanine aminotransferase, serum aspartate aminotransferase, and total bilirubin levels by up to 37%, 31%, and 41%, respectively, in comparison with the levels in mice that underwent BDL alone. PD treatment attenuated oxidative stress, as evidenced by an increase in anti-oxidative enzyme levels glutathione and superoxide dismutase together with a decrease in lipid peroxidation and oxidative stress indices levels of malondialdehyde and nitric oxide. Histopathological studies further confirmed the protective effects of PD on cholestasis-induced hepatic injury and liver fibrosis in mice. In addition, nuclear factor-kappa B and inducible nitric oxide synthase levels significantly decreased after PD treatment, as did the levels of hepatocyte apoptosis. Taken together, these results suggest that PD treatment might be beneficial in cholestasis-induced hepatotoxicity. PMID:23116642

  18. Effect of Sea buckthorn on liver fibrosis: A clinical study

    Institute of Scientific and Technical Information of China (English)

    Ze-Li Gao; Xiao-Hong Gu; Feng-Tao Cheng; Fo-Hu Jiang

    2003-01-01

    AIM: To appraise the effect of sea buckthorn (Hippophae rhamnoides) on cirrhotic patients.METHODS: Fifty cirrhotic patients of Child-Pugh grade A and B were randomly divided into two groups: Group A as the treated group (n=30), taking orally the sea buckthom extract, 15 g 3 times a day for 6 months. Group B as the control group (n=18), taking vitamin B complex one tablet,3 times a day for 6 months. The following tests were performed before and after the treatment in both groups to determine LN, HA, collagens types Ⅲ and IV, cytokines IL6 and TNFα, liver serum albumin, total bile acid, ALT, AST and prothrombin time.RESULTS: The serum levels of TNFα, IL-6, laminin and type IV collagen in group A were significantly higher than those in the control group. After a course of sea buckthorn treatment, the serum levels of LN, HA, collagen types Ⅲand IV, total bile acid (TBA) decreased significantly as compared with those before and after treatment in the control group. The sea buckthorn notably shortened the duration for normalization of aminotransferases.CONCLUSION: Sea buckthom may be a hopeful drug for prevention and treatment of liver fibrosis.

  19. Non-invasive detection of liver fibrosis: Is superparamagnetic iron oxide particle-enhanced MR imaging a contributive technique?

    International Nuclear Information System (INIS)

    The purpose of our study was to evaluate the ability of superparamagnetic iron oxide (SPIO)-enhanced MR imaging to detect liver fibrosis in patients with chronic liver disease and to compare the findings with histopathological data. Sixty-seven patients with chronic hepatitis (n=58) or focal nodular hyperplasia (FNH; n=9) were studied using a 1.5-T MR system. The protocol included proton density-weighted, T2-weighted spin-echo (SE) and fast SE (FSE) sequences before and after SPIO administration and T2*-weighted gradient-recalled-echo (GRE) sequences after SPIO. Pre- and post-contrast T2-weighted and T2*-weighted sequences were retrospectively evaluated by three independent observers for evidence of non-tumor hypersignal intensities. Three liver patterns were considered: thick reticulations; thin reticulations; and/or multiple areas of hypersignal intensities. Unenhanced or enhanced patterns were compared with histopathological specimens, which had been obtained by percutaneous biopsy of the right lobe within a maximum of 12 months of MR examination. Liver fibrosis was histologically graded using a five-level scale (F0-F4), according to the METAVIR classification. Histopathology demonstrated significant fibrosis (F2-F4) in 57 patients, non-significant fibrosis in 1 patient (F1), and normal liver surrounding FNH in 9 patients (F0). After SPIO administration, at least one pattern of non-tumor hypersignal intensities was seen in 43 (76%) of the 57 patients with F≥2 with good agreement (kappa=0.68) compared with 2 (20%) of the 10 F0/1 patients (p<0.01). Attenuated non-homogeneous liver-signal intensities with persistent thick reticulations, thin reticulations, or multiple areas of hypersignals were observed in, respectively, 30, 52, and 56% of patients with F≥2 with moderate agreement (kappa=0.51). Before SPIO, MR images were positive in 21 of 57 (37%) F≥2 and zero F0/1 patients. Post-contrast proton-density-weighted and T2*-weighted GRE were the most sensitive

  20. Adenovirus-mediated over-expression of Septin4 ameliorates hepatic fibrosis in mouse livers infected with Schistosoma japonicum.

    Science.gov (United States)

    He, Xue; Bao, Jing; Chen, Jinling; Sun, Xiaolei; Wang, Jianxin; Zhu, Dandan; Song, Ke; Peng, Wenxia; Xu, Tianhua; Duan, Yinong

    2015-12-01

    Septin4 (Sept4) belongs to Septin family and may be involved in apoptosis, vesicle trafficking and other cell processes. In this study, we attempted to investigate the effect of Sept4 in hepatic fibrosis induced by Schistosoma japonicum. ICR mice infected with S. japonicum for 12weeks were treated with PBS, Ad-ctr and Ad-Sept4, respectively. All mice were killed at 2weeks after injection, and the changes in the fibrotic livers were detected via H&E staining, Sirius red staining, qRT-PCR, western blot and TUNEL analysis. In addition, pcDNA3.1-Sept4 plasmid was transfected into LX-2 cells to observe the effect of Sept4 on apoptosis of HSCs in vitro. Ad-Sept4 could ameliorate liver fibrosis, as detected by H&E staining and Sirius red staining. The number of TUNEL-positive cells was increased in the Ad-Sept4 treated group. The expression of Sept4 and cleaved-caspase-3 were all augmented, while the expression of α-SMA, Col1α1 and IL-13 were reduced in the Ad-Sept4 treated group, compared with that expressed in the Ad-ctr group. Over-expression of Sept4 in LX-2 cells could promote apoptosis of LX-2 cells in vitro. In conclusion, Ad-Sept4 can attenuate the development of liver fibrosis induced by S. japonicum through apoptosis. PMID:26190030

  1. Biochemical and radio-immunological studies on HCV-induced liver fibrosis

    International Nuclear Information System (INIS)

    Hepatitis C virus infection is now becoming a common health problem in Egypt. Liver biopsy is the gold standard for this diagnosis. However, liver biopsy is invasive and is associated with complications with chronic hepatitis C patients. There is a clinical need for noninvasive measurement of liver fibrosis. Noninvasive bio markers such as Collagen III was identified in serum samples of patients with HCV induced liver fibrosis at 70 kDa using SDS-PAGE and western blot, measured by ELISA and purified using electro elution . Hyaluronic acid also can be used to differentiate between liver fibrosis patients and healthy individuals using radioimmunoassay .we have developed noninvasive diagnosis that can be applied to patients who either have contraindications or refuse liver biopsy for the management of their HCV infection.

  2. Usefulness of non-invasive serum markers for predicting liver fibrosis in Egyptian patients with chronic HCV infection.

    Science.gov (United States)

    El Guesiry, Dalal; Moez, Pacinte; Hossam, Nermine; Kassem, Mohamed

    2011-01-01

    Accurate monitoring of liver fibrosis changes in patients with hepatitis C virus (HCV) infection would be helpful in defining the need to intervene, implement the appropriate response in treatment and to minimize the use of liver biopsy. We aimed to evaluate the diagnostic utility of the different serum markers and indices in detecting liver fibrosis in study patients. Initial liver biopsy, routine liver function tests, estimation of hyaluronic acid, MMP-1, and PIIINP levels was performed for 30 Egyptian patients with HCV and 15 controls. Marker algorithms based on common laboratory such APRI score, Fibrotest and Actitest. PIIINP and MMP-1 serum markers were combined and entered into a stepwise logistic regression analysis with formulation of a score equation for fibrosis staging. Combined PIIINP and MMP-1 yielded different cut off scores to estimate two clinically relevant fibrosis stages: "significant fibrosis" versus "extensive fibrosis. Apri score also showed AUC of 1.0 with 100 % sensitivity and specificity to exclude the presence of cirrhosis and was significantly correlated to Metavair fibrosis stage in early fibrosis. On the other hand, PIIINP, Fibrotest and acti test were significantly correlated to Metavair fibrosis stage in both early and late fibrosis. In conclusion, integrating PIIINP/MMP-1 score was able to provide reliable information about the degree of liver fibrosis in chronic hepatitis C patients using different cut-offs values. A combination of liver markers as well as its related indices is an emerging tool to differentiate early from advanced liver fibrosis in HCV patients. PMID:23082465

  3. State-of-the-art imaging of liver fibrosis and cirrhosis: A comprehensive review of current applications and future perspectives

    Directory of Open Access Journals (Sweden)

    Adrian Huber

    2015-01-01

    Conclusion: MR elastography (MRE appears to be the most reliable method for grading liver fibrosis, although the CT fibrosis score derived from the combination of caudate-to-right-lobe ratio and the diameters of the liver veins significantly correlates with the stage of fibrosis.

  4. Nanoencapsulated curcumin and praziquantel treatment reduces periductal fibrosis and attenuates bile canalicular abnormalities in Opisthorchis viverrini-infected hamsters.

    Science.gov (United States)

    Charoensuk, Lakhanawan; Pinlaor, Porntip; Wanichwecharungruang, Supason; Intuyod, Kitti; Vaeteewoottacharn, Kulthida; Chaidee, Apisit; Yongvanit, Puangrat; Pairojkul, Chawalit; Suwannateep, Natthakitta; Pinlaor, Somchai

    2016-01-01

    This study investigated the effects of nanoencapsulated curcumin (NEC) and praziquantel (PZQ) treatment on the resolution of periductal fibrosis (PDF) and bile canalicular (BC) abnormalities in Opisthorchis viverrini infected hamsters. Chronic O. viverrini infection (OV) was initially treated with either PZQ (OP) and subsequently treated with NEC (OP+NEC), curcumin (OP+Cur) or unloaded carriers (OP+carrier) daily for one month. OP+NEC treatment reduced the PDF by suppression of fibrotic markers (hydroxyproline content, α-SMA, CTGF, fibronectin, collagen I and III), cytokines (TGF-β and TNF-α) and TIMP-1, 2, 3 expression and upregulation of MMP-7, 13 genes. Higher activity of NEC in reducing fibrosis compared to curcumin was also demonstrated in in vitro studies. Moreover, OP+NEC also prevented BC abnormalities and upregulated several genes involved in bile acid metabolism. These results demonstrate that NEC and PZQ treatment reduces PDF and attenuates BC defect in experimental opisthorchiasis. From the Clinical Editor: Infection by Opisthorchis viverrini leads to liver fibrosis and affects population in SE Asia. Currently, praziquantel (PZQ) is the drug of choice but this drug has significant side effects. In this study, the authors combined curcumin (NEC) and praziquantel in a nanocarrier to test the anti-oxidative effect of curcumin in an animal model. The encouraging results may pave a way for better treatment in the future. PMID:26542278

  5. Influence of heme oxygenase-1 expression on immune liver fibrosis induced by cobalt protoporphyrin in rats

    Institute of Scientific and Technical Information of China (English)

    Fei Wang; Zhi-Jun Duan; Ying-Jie Sun

    2009-01-01

    AIM: To investigate the effect of heme oxygenase-1 (HO-1) expression on immune liver fibrosis induced by cobalt protoporphyrin (CoPP) in rats. METHODS: An immune liver fibrosis model of rat was established by administering human serum albumin (HSA). The rats were divided into CoPP, liver fibrosis and normal control groups. Rats in the CoPP group received intraperitoneal CoPP concurrently with HSA. Expression of HO-1 protein was observed by Western blotting and immunohistochemistry. Hematoxylin and eosin (HE) staining was performed to assess fibrosis proliferation and distribution, proliferation extent of fibroblasts, and alterations in hepatocytes and inflammatory cells. Type Ⅰ and Ⅲ collagens were detected with Van Gieson's (VG) staining and Foot's reticular fiber staining, respectively. In addition, spindle-shaped cells existing at perisinusoidal locations beyond portal and septa areas were investigated with HE staining.RESULTS: Western blotting and immunohistochemistry showed that the expression of HO-1 protein was higher in the CoPP group than in the liver fibrosis group (P < 0.05). Compared with the liver fibrosis group, the serological index of hepatic fibrosis in the CoPP group decreased significantly (P < 0.05). HE, VG and Foot's staining revealed that administration of CoPP reduced the extent of hepatic fibrosis. The levels of serological indicators and the number of spindle-shaped cells at perisinuous locations beyond the portal and septa areas were reduced in the CoPP group. Only a few inflammatory cells were seen around the portal areas and central veins in the CoPP group. CONCLUSION: Increased endogenous HO-1 may suppress liver fibrosis by protecting liver cells,inhibiting inflammatory cell infiltration and hepatic stellate cell transformation.

  6. Diffusion-Weighted MRI for the Assessment of Liver Fibrosis: Principles and Applications

    Science.gov (United States)

    Attinà, Giancarlo; Fuccio Sanzà, Giovanni; Foti, Pietro Valerio; Ettorre, Giovanni Carlo; Milone, Pietro

    2015-01-01

    The importance of an early identification of hepatic fibrosis has been emphasized, in order to start therapy and obtain fibrosis regression. Biopsy is the gold-standard method for the assessment of liver fibrosis in chronic liver diseases, but it is limited by complications, interobserver variability, and sampling errors. Several noninvasive methods have been recently introduced into clinical routine, in order to detect liver fibrosis early. One of the most diffuse approaches is represented by diffusion-weighted liver MRI. In this review, the main technical principles are briefly reported in order to explain the rationale for clinical applications. In addition, roles of apparent diffusion coefficient, intravoxel incoherent motion, and relative apparent diffusion coefficient are also reported, showing their advantages and limits. PMID:25866819

  7. Diffusion-Weighted MRI for the Assessment of Liver Fibrosis: Principles and Applications

    Directory of Open Access Journals (Sweden)

    Stefano Palmucci

    2015-01-01

    Full Text Available The importance of an early identification of hepatic fibrosis has been emphasized, in order to start therapy and obtain fibrosis regression. Biopsy is the gold-standard method for the assessment of liver fibrosis in chronic liver diseases, but it is limited by complications, interobserver variability, and sampling errors. Several noninvasive methods have been recently introduced into clinical routine, in order to detect liver fibrosis early. One of the most diffuse approaches is represented by diffusion-weighted liver MRI. In this review, the main technical principles are briefly reported in order to explain the rationale for clinical applications. In addition, roles of apparent diffusion coefficient, intravoxel incoherent motion, and relative apparent diffusion coefficient are also reported, showing their advantages and limits.

  8. [Clinical Application of Non-invasive Diagnostic Tests for Liver Fibrosis].

    Science.gov (United States)

    Shin, Jung Woo; Park, Neung Hwa

    2016-07-25

    The diagnostic assessment of liver fibrosis is an important step in the management of patients with chronic liver diseases. Liver biopsy is considered the gold standard to assess necroinflammation and fibrosis. However, recent technical advances have introduced numerous serum biomarkers and imaging tools using elastography as noninvasive alternatives to biopsy. Serum markers can be direct or indirect markers of the fibrosis process. The elastography-based studies include transient elastography, acoustic radiation force imaging, supersonic shear wave imaging and magnetic resonance elastography. As accumulation of clinical data shows that noninvasive tests provide prognostic information of clinical relevance, non-invasive diagnostic tools have been incorporated into clinical guidelines and practice. Here, the authors review noninvasive tests for the diagnosis of liver fibrosis. PMID:27443617

  9. Acoustic radiation force impulse imaging for assessing liver fibrosis in alcoholic liver disease

    Science.gov (United States)

    Kiani, Anita; Brun, Vanessa; Lainé, Fabrice; Turlin, Bruno; Morcet, Jeff; Michalak, Sophie; Le Gruyer, Antonia; Legros, Ludivine; Bardou-Jacquet, Edouard; Gandon, Yves; Moirand, Romain

    2016-01-01

    AIM: To evaluate the performance of elastography by ultrasound with acoustic radiation force impulse (ARFI) in determining fibrosis stage in patients with alcoholic liver disease (ALD) undergoing alcoholic detoxification in relation to biopsy. METHODS: Eighty-three patients with ALD undergoing detoxification were prospectively enrolled. Each patient underwent ARFI imaging and a liver biopsy on the same day. Fibrosis was staged according to the METAVIR scoring system. The median of 10 valid ARFI measurements was calculated for each patient. RESULTS: Sixty-nine males and thirteen females (one patient excluded due to insufficient biopsy size) were assessed with a mean alcohol consumption of 132.4 ± 128.8 standard drinks per week and mean cumulative year duration of 17.6 ± 9.5 years. Sensitivity and specificity were respectively 82.4% (0.70-0.95) and 83.3% (0.73-0.94) (AUROC = 0.87) for F ≥ 2 with a cut-off value of 1.63m/s; 82.4% (0.64-1.00) and 78.5% (0.69-0.89) (AUROC = 0.86) for F ≥ 3 with a cut-off value of 1.84m/s; and 92.3% (0.78-1.00] and 81.6% (0.72-0.90) (AUROC = 0.89) for F = 4 with a cut-off value of 1.94 m/s. CONCLUSION: ARFI is an accurate, non-invasive and easy method for assessing liver fibrosis in patients with ALD undergoing alcoholic detoxification. PMID:27239119

  10. Utility of diffusion-weighted imaging in the evaluation of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Bakan, Ayse Ahsen; Inci, Ercan; Cimilli, Tan [Istanbul Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of Radiology, Istanbul (Turkey); Bakan, Selim [Istanbul University, Faculty of Medicine, Deparment of Radiology, Istanbul (Turkey); Gokturk, Suut [Istanbul University, Faculty of Medicine, Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul (Turkey)

    2012-03-15

    To evaluate the usefulness of diffusion- weighted MRI (DWI) in the detection and staging of liver fibrosis and inflammation. DWI was performed with b-factors of 0, 500 and 1000 s/mm{sup 2}. ADC values were obtained by placing circular regions of interest in four segments of the liver. Differences between the study (n = 34) and control groups' (n = 25) ADC values were examined. Further, this study investigated if and how ADC values were related to fibrosis stages and histological activity index (HAI) scores. The mean ADC value of the liver was smaller in the study group compared with the control group (P < 0.001). Spearman rho correlation analyses showed lower ADC values were associated with higher fibrosis and HAI scores (P < 0.01). There were statistically significant differences in liver ADC values between each combination of fibrosis stages (e.g. stages 0 and 1, 0 and 2) except for stages 1 and 2. ADC values prove to be a valuable technique for the diagnosis of liver fibrosis and inflammation. They can also be useful in fibrosis staging, particularly in distinguishing later stages of fibrosis from intermediate and early stages. (orig.)

  11. Antifibrotic effects of green tea on in vitro and in vivo models of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Hye Kyung Kim; Taik-Hoon Yang; Hong-Yon Cho

    2009-01-01

    AIM: To examine the protective effect of green tea extract (GT) on hepatic fibrosis in vitro and in vivo in dimethylnitrosamine (DMN)-induced rats. METHODS: HSC-T6, a rat hepatic stellate cell line, was used as an in vitro assay system. Cell proliferation,collagen content, and type 1 collagen expression were examined in activated HSC-T6 cells. Collagen was determined by estimating the hydroxyproline content.In rats with DMN-induced hepatic fibrosis, serum aspartate aminotransferase and alanine aminotransferase concentrations, liver hydroxyproline and lipid peroxides were determined. Pathologic changes were examined by hematoxylin & eosin staining.RESULTS: GT administration prevented the development of hepatic fibrosis in the rat model of DMN-induced liver fibrosis. These results were confirmed both by liver histology and by quantitative measurement of hepatic hydroxyproline content, a marker of liver collagen deposition. Accordingly, inhibition of proliferation, reduced collagen deposition, and type 1 collagen expression were observed in activated HSC-T6 cells following GT treatment. These results imply that GT reduced the proliferation of activated HSC and down regulated the collagen content and expression of collagen type 1, thereby ameliorating hepatic fibrosis. tea administration can effectively improve liver fibrosis caused by DMN, and may be used as a therapeutic option and preventive measure against hepatic fibrosis.

  12. Non invasive assessment of liver fibrosis in chronic hemodialysis patients with viral hepatitis C.

    Science.gov (United States)

    Arrayhani, Mohamed; Sqalli, Tarik; Tazi, Nada; El Youbi, Randa; Chaouch, Safae; Aqodad, Nourdin; Ibrahimi, Sidi Adil

    2015-01-01

    The liver biopsy has long been the "gold standard" for assessing liver fibrosis in patients with hepatitis C. It's an invasive procedure which is associated with an elevated bleeding, especially in chronic hemodialysis patients. Main goal is to assess liver fibrosis in chronic hemodialysis with HCV by Fibroscan and by biological scores (APRI, Forns and Fib-4), and to measure the correlation between these tests. Cross-sectional study including all chronic hemodialysis patients with hepatitis C virus, in two public hemodialysis centers of Fez. All patients were evaluated for liver fibrosis using noninvasive methods (FibroScan and laboratory tests). Subsequently, the correlation between different tests has been measured. 95 chronic hemodialysis were studied, twenty nine patients (30.5%) with chronic hepatitis C. The average age was 52.38 ± 16.8 years. Nine liver fibrosis cases have been concluded by forns score. Fibroscan has objectified significant fibrosis in 6 cases. On the other side APRI has objectified sgnifivant fibrosis only in 3 cases. The Fib-4 showed severe fibrosis in five cases. The results have been most consistent between APRI and Fib-4, followed by Fibroscan and Forns, then APRI and FibroScan. PMID:26958136

  13. Relationship Between Serum GGT Levels and Liver Fibrosis in Chronic Hepatitis B Patients

    OpenAIRE

    AYGÜN, Cem; Gözel, Nevzat; DEMİREL, Ulvi; Yalniz, Mehmet; ÖZERCAN, İbrahim Hanifi; BAHCECİOĞLU, İbrahim Halil

    2010-01-01

    Objective: The aim of this study was to evaluate the relationship between serum GGT levels and liver fibrosis among patients with chronic hepatitis B in Fırat University Medical School. Materials and Methods: In Gastroenterology Clinics of Fırat University Medical School, data regarding 140 chronic hepatitis B patients and laboratory results were analysed retrospectively. All patients had undergone liver biopsies and according to histopathological stages of fibrosis (Knodell's classificatio...

  14. Heme oxygenase-1 prevents liver fibrosis in rats by regulating the expression of PPARγ and NF-κB

    Institute of Scientific and Technical Information of China (English)

    Hui Yang; Long-Feng Zhao; Zhong-Fu Zhao; Yan Wang; JingJing Zhao; Li Zhang

    2012-01-01

    AIM:To investigate the effects of heme oxygenase (HO)-1 on liver fibrosis and the expression of peroxisome proliferator-activated receptor gamma (PPARγ)and nuclear factor-kappa B (NF-κB) in rats.METHODS:Sixty Wistar rats were used to construct liver fibrosis models and were randomly divided into 5 groups:group A (normal,untreated),group B (model for 4 wk,untreated),group C (model for 6 wk,untreated),group D [model for 6 wk,treated with zinc protoporphyrin Ⅸ (ZnPP-Ⅸ) from week 4 to week 6],group E (model for 6 wk,treated with hemin from week 4 to week 6).Next,liver injury was assessed by measuring serum alanine aminotransferase (ALT),aspartate aminotransferase (AST) and albumin levels.The degree of hepatic fibrosis was evaluated by measuring serum hyaluronate acid (HA),type Ⅳ collagen (IV-C) and by histological examination.Hydroxyproline (Hyp) content in the liver homogenate was determined.The expression levels of alpha-smooth muscle actin (α-SMA) in liver tissue were measured by real-time quantitative polymerase chain reaction (RT-PCR).The expression levels of PPARγ,and NF-KB were determined by RT-PCR and Western blotting.RESULTS:The expression of HO-1 increased with the development of fibrosis.Induction of HO-1 by hemin significantly attenuated the severity of liver injury and the levels of liver fibrosis as compared with inhibition of HO-1 by ZnPP-Ⅸ.The concentrations of serum ALT,AST,HA and IV-C in group E decreased compared with group C and group D (P < 0.01).Amount of Hyp and α-SMA in the liver tissues in group E decreased compared with group C (0.62 ± 0.14 vs 0.84 ± 0.07,1.42 ±0.17 vs 1.84 ± 0.17,respectively,P < 0.01) and group D (0.62-0.14 vs 1.11 ± 0.16,1.42 ± 0.17 vs 2.56 ±0.37,respectively,P < 0.01).The expression of PPARγ at levels of transcription and translation decreased with the development of fibrosis especially in group D; and it increased in group E compared with groups C and D (0.88 ± 0.15 vs 0.56 ± 0.19,0.88 ± 0

  15. Protective effects of curcumin against liver fibrosis through modulating DNA methylation.

    Science.gov (United States)

    Wu, Peng; Huang, Rui; Xiong, Ya-Li; Wu, Chao

    2016-04-01

    Recent research has demonstrated that advanced liver fibrosis in patients could be reversed, but no approved agents are available for the treatment and prevention of liver fibrosis in humans. Curcumin (CUR) is the principal curcuminoid of turmeric. Inhibitory effects of CUR and its underlying mechanisms in liver fibrogenesis have been explored. In the present study, we hypothesized that epigenetic mechanisms contribute to the protective effects of CUR against liver fibrosis. We used CCl4-induced liver injury in BALB/c mice and the rat hepatic stellate cell line HSC-T6 as experimental models. Genomic DNA methylation was analyzed by MeDIP-chip and verified by real-time PCR on MeDIP-enriched DNA. The mRNA and protein expressions of DNMT1, α-SMA, and Col1α1 were determined by real-time PCR and Western blotting, respectively. The methylation statuses of FGFR3, FZD10, Gpx4, and Hoxd3 were further confirmed by quantitative methylation-specific PCR (qMSP). Our results showed that CUR treatment reversed liver injury in vivo and in vitro, possibly through down regulation of DNMT1, α-SMA, and Col1α1 and by demethylation of the key genes. In conclusion, aberrant methylation is closely associated with liver fibrosis and CUR treatment may reverse liver fibrosis by epigenetic mechanisms. PMID:27114312

  16. Umbilical cord-derived mesenchymal stem cells alleviate liver fibrosis in rats

    Science.gov (United States)

    Chai, Ning-Li; Zhang, Xiao-Bin; Chen, Si-Wen; Fan, Ke-Xing; Linghu, En-Qiang

    2016-01-01

    AIM: To evaluate the efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation in the treatment of liver fibrosis. METHODS: Cultured human UC-MSCs were isolated and transfused into rats with liver fibrosis induced by dimethylnitrosamine (DMN). The effects of UC-MSCs transfusion on liver fibrosis were then evaluated by histopathology; serum interleukin (IL)-4 and IL-10 levels were also measured. Furthermore, Kupffer cells (KCs) in fibrotic livers were isolated and cultured to analyze their phenotype. Moreover, UC-MSCs were co-cultured with KCs in vitro to assess the effects of UC-MSCs on KCs’ phenotype, and IL-4 and IL-10 levels were measured in cell culture supernatants. Finally, UC-MSCs and KCs were cultured in the presence of IL-4 antibodies to block the effects of this cytokine, followed by phenotypical analysis of KCs. RESULTS: UC-MSCs transfused into rats were recruited by the injured liver and alleviated liver fibrosis, increasing serum IL-4 and IL-10 levels. Interestingly, UC-MSCs promoted mobilization of KCs not only in fibrotic livers, but also in vitro. Co-culture of UC-MSCs with KCs resulted in increased production of IL-4 and IL-10. The addition of IL-4 antibodies into the co-culture system resulted in decreased KC mobilization. CONCLUSION: UC-MSCs could increase IL-4 and promote mobilization of KCs both in vitro and in vivo, subsequently alleviating the liver fibrosis induced by DMN.

  17. Dynamic change of hepcidin in liver fibrosis induced by CCl4 among mice

    Directory of Open Access Journals (Sweden)

    PANG Guojin

    2015-03-01

    Full Text Available ObjectiveTo investigate the dynamic change of hepcidin in liver fibrosis induced by CCl4 among mice. MethodsC57BL/6 mice were given CCl4 by intragastric administration to establish a liver fibrosis model. The degree of liver injury and fibrosis was evaluated by HE and Masson staining. Prussian blue staining was used to detect liver iron deposition in the progression of liver fibrosis. Primary hepatocytes, hepatic stellate cells, and Kupffer cells were isolated from C57BL/6 mice by two-step in situ collagenase perfusion and density gradient centrifugation. The mRNA levels of tumor necrosis factor alpha (TNFα, interleukin-6 (IL-6, interleukin-1β (IL-1β, and hepcidin were measured by quantitative real-time PCR (qRT-PCR. Continuous data were expressed as mean±SD, and comparison of continuous data between the two groups was made by t test. ResultsThe HE and Masson staining of liver tissues showed that the degree of liver fibrosis gradually increased as CCl4 was given, and hepatic fibrosis was reversed after the administration of CCl4 was stopped. Prussian blue staining showed that liver iron deposition increased as CCl4 was given; the area of liver iron deposition was significantly increased compared with that of the normal control group at week 4 of administration (t=4.772, P<0.05, but no significant increase was seen from week 4 to week 6; the area of liver iron deposition at week 6 was still higher than that of the normal control group (t=10.32, P<0.05; liver iron deposition decreased in the spontaneous reversal after the administration was stopped. The mRNA levels of TNFα, IL-1β, and IL-6 assessed by qRT-PCR continuously increased in model mice, reaching the peak levels at week 6, and significant differences were observed between the model mice and normal controls (t=4.322, 9.707, and 5.678, P<0.05 for all. The expression of hepcidin in the liver increased in the early stage of model establishment and reached the peak level at week 4

  18. Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis.

    OpenAIRE

    Elena Turola; Salvatore Petta; Ester Vanni; Fabiola Milosa; Luca Valenti; Rosina Critelli; Luca Miele; Livia Maccio; Vincenza Calvaruso; Fracanzani, Anna L.; Marcello Bianchini; Nazarena Raos; Elisabetta Bugianesi; Serena Mercorella; Marisa Di Giovanni

    2015-01-01

    ABSTRACT Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and m...

  19. Cystic fibrosis-related liver disease: a single-center experience

    Directory of Open Access Journals (Sweden)

    Paula Catarino Costa

    2011-10-01

    Full Text Available Prospective studies concerning liver disease in pediatric cystic fibrosis patients are scarce. The present study aimed to describe the prevalence and clinical expression of cystic fibrosis - related liver disease, in a cohort of 62 pediatric patients. Descriptive study, resulting from the prospective evaluation, between 1994 and 2009, of 62 pediatric patients (age <18 years with cystic fibrosis. The follow-up protocol included a clinical assessment every 2 months, liver function tests every 6 months and annual liver ultrasonography. The cumulative prevalence of liver disease was 11.2% (7/62 cases. All patients had ΔF508 mutation and pancreatic insufficiency, none had meconium ileus. The liver involvement became clinically evident at a mean age of 8 years (3-15 years, revealed by hepatomegaly or hepatosplenomegaly (3 cases and/ or abnormalities of liver function tests (3 cases changes of liver ultrasound (7 cases with evidence of portal hypertension (2 cases. Four patients were submitted to liver biopsy; biliary fibrosis was documented in one case, focal biliary cirrhosis in 2 cases and multilobular cirrhosis in another case. Within a median 11.6 years follow-up period (all patients under UDCA therapy after liver disease diagnosis, progression of liver disease was observed in 2 patients; one patient developed refractory variceal bleeding and progressive hepatic failure, requiring liver transplant. The results of the present study agree with those of previous pediatric studies, further documenting clinical expression of liver disease in CF patients, which is usually detected in the first decade of life and emphasize the contribution of ultrasound to early diagnosis of liver involvement. Moreover, although advanced liver disease is a relatively rare event, early isolated liver transplantation may have to be considered at this age group.

  20. Fibroscan ® : A noninvasive test of liver fibrosis assessment

    OpenAIRE

    Al-Ghamdi Abdullah

    2007-01-01

    Determination of the extent of progress of hepatic fibrosis is important in clinical practice, where it may reflect the severity of liver disease and predict response to treatment. Percutaneous liver biopsy is the gold standard for grading and staging of liver disease. However, liver biopsy is an invasive procedure with certain unavoidable risks and complications. Several methods have been studied in an attempt to reach a diagnosis of cirrhosis by noninvasive means. Fibroscan ® has bee...

  1. Liver fibrosis progression in HIV/hepatitis C virus coinfected patients with normal aminotransferases levels

    Directory of Open Access Journals (Sweden)

    Fábio Heleno de Lima Pace

    2012-08-01

    Full Text Available INTRODUCTION: Approximately 30% of hepatitis C virus (HCV monoinfected patients present persistently normal alanine aminotransferase (ALT levels. Most of these patients have a slow progression of liver fibrosis. Studies have demonstrated the rate of liver fibrosis progression in hepatitis C virus-human immunodeficiency virus (HCV-HIV coinfected patients is faster than in patients infected only by HCV. Few studies have evaluated the histological features of chronic hepatitis C in HIV-infected patients with normal ALT levels. METHODS: HCV-HIV coinfected patients (HCV-RNA and anti-HIV positive with known time of HCV infection (intravenous drugs users were selected. Patients with hepatitis B surface antigen (HBsAg positive or hepatitis C treatment before liver biopsy were excluded. Patients were considered to have a normal ALT levels if they had at least 3 normal determinations in the previous 6 months prior to liver biopsy. All patients were submitted to liver biopsy and METAVIR scale was used. RESULTS: Of 50 studied patients 40 (80% were males. All patients were treated with antiretroviral therapy. The ALT levels were normal in 13 (26% patients. HCV-HIV co-infected patients with normal ALT levels had presented means of the liver fibrosis stages (0.77±0.44 versus 1.86±1.38; p<0.001 periportal inflammatory activity (0.62±0.77 versus 2.24±1.35; p<0.001 and liver fibrosis progression rate (0.058±0.043 fibrosis unit/year versus 0.118±0.102 fibrosis unit/year significantly lower as compared to those with elevated ALT. CONCLUSIONS: HCV-HIV coinfected patients with persistently normal ALTs showed slower progression of liver fibrosis. In these patients the development of liver cirrhosis is improbable.

  2. A pilot study on the use of optical spectroscopy to detection of liver fibrosis

    International Nuclear Information System (INIS)

    In this paper we present the preliminary study to evaluate the use of optical spectroscopy as a tool to detect liver fibrosis. In vivo fluorescence and diffuse reflectance spectra were acquired from male rats in which fibrosis were induced by means of carbon tetrachloride. Spectral measurements were obtained using a portable system with an excitation source of 365 nm and a fiber-optic probe. The livers from rats with fibrosis showed an increase in fluorescence and diffuse reflectance intensity when compared to normal liver tissue. A support vector machine discrimination algorithm based on fluorescence and diffuse reflectance intensities at 493 and 365 nm was developed. This algorithm yields a sensitivity and specificity of 88% and 94%, respectively, in differentiating fibrotic liver from normal liver tissue. the results obtained in this study suggest that optical spectroscopy could be worthy of further exploration in patients. (Author)

  3. Validity of Autotaxin as a Novel Diagnostic Marker for Liver Fibrosis in Egyptian Chronic HCV Patients

    OpenAIRE

    Ezzat, Wafaa M.; Halla M. Ragab; Nabila Abd El Maksoud; Nour A. Abdulla; Yasser A. Elhosary

    2013-01-01

    We aimed to detect the validity of serum ATX as a diagnostic marker for liver fibrosis. Forty-eight males and 16 females were enrolled in the current study. Their ages ranged from 29-57 years with mean of 45.09, all were chronically HCV infected. Laboratory assessment was done for all subjects in form of complete blood picture; liver function test; lipid profile and serum detection of ATX. Patients were grouped according to the stage of fibrosis into group 1: fibrosis score 0, 1, 2, 3; group ...

  4. The utility of thrombopoietin in predicting liver fibrosis in chronic hepatitis B

    OpenAIRE

    Yilmaz, Baris; Basar, Ömer; Altınbas, Akif; Ekiz, Fuat; Aktas, Bora; Öztürk, Gülfer; Ginis, Zeynep; Coban, Sahin; Ucar, Engin; Erarslan, Elife; Coskun, Yusuf; Yüksel, İlhami; Tuna, Yasar; Yüksel, Osman

    2014-01-01

    Many noninvasive serum markers have been studied to determine the liver fibrosis score (LFS). In this study, we aimed to investigate the association between thrombopoietin (TPO) levels and the stage of liver fibrosis in patients with chronic hepatitis B (CHB). Seventy-seven patients (64 active and 13 inactive) with CHB were included in this cross-sectional study. Patients were divided into three groups: In group 1, patients with mild or no fibrosis (F0, F1); in group 2, patients with signific...

  5. Gene expression profiles of hepatic cell-type specific marker genes in progression of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Yoshiyuki Takahara; Mitsuo Takahashi; Hiroki Wagatsuma; Fumihiko Yokoya; Qing-Wei Zhang; Mutsuyo Yamaguchi; Hiroyuki Aburatani; Norifumi Kawada

    2006-01-01

    AIM: To determine the gene expression profile data for the whole liver during development of dimethylnitrosamine (DMN)-induced hepatic fibrosis.METHODS: Marker genes were identified for different types of hepatic cells, including hepatic stellate cells (HSCs), Kupffer cells (including other inflammatory cells),and hepatocytes, using independent temporal DNA microarray data obtained from isolated hepatic cells.RESULTS: The cell-type analysis of gene expression gave several key results and led to formation of three hypotheses: (1) changes in the expression of HSCspecific marker genes during fibrosis were similar to gene expression data in in vitro cultured HSCs, suggesting a major role of the self-activating characteristics of HSCs in formation of fibrosis; (2) expression of mast cell-specific marker genes reached a peak during liver fibrosis,suggesting a possible role of mast cells in formation of fibrosis; and (3) abnormal expression of hepatocytespecific marker genes was found across several metabolic pathways during fibrosis, including sulfur-containing amino acid metabolism, fatty acid metabolism, and drug metabolism, suggesting a mechanistic relationship between these abnormalities and symptoms of liver fibrosis.CONCLUSION: Analysis of marker genes for specific hepatic cell types can identify the key aspects of fibrogenesis. Sequential activation of inflammatory cells and the self-supporting properties of HSCs play an important role in development of fibrosis.

  6. Liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfection: Diagnostic methods and clinical impact

    Institute of Scientific and Technical Information of China (English)

    Caterina; Sagnelli; Salvatore; Martini; Mariantonietta; Pisaturo; Giuseppe; Pasquale; Margherita; Macera; Rosa; Zampino; Nicola; Coppola; Evangelista; Sagnelli

    2015-01-01

    Several non-invasive surrogate methods have recently challenged the main role of liver biopsy in assessing liver fibrosis in hepatitis C virus(HCV)-monoinfected and human immunodeficiency virus(HIV)/HCV-coinfected patients, applied to avoid the well-known side effects of liver puncture. Serological tests involve the determination of biochemical markers of synthesis or degradation of fibrosis, tests not readily available in clinical practice, or combinations of routine tests used in chronic hepatitis and HIV/HCV coinfection. Several radiologic techniques have also been proposed, some of which commonly used in clinical practice. The studies performed to compare the prognostic value of noninvasive surrogate methods with that of the degree of liver fibrosis assessed on liver tissue have not as yet provided conclusive results. Each surrogate technique has shown some limitations, including the risk of over- or under-estimating the extent of liver fibrosis. The current knowledge on liver fibrosis in HIV/HCVcoinfected patients will be summarized in this review article, which is addressed in particular to physicians involved in this setting in their clinical practice.

  7. Bone marrow cells ameliorate liver fibrosis and express albumin after transplantation in CCl 4 -induced fibrotic liver

    Directory of Open Access Journals (Sweden)

    Gibran Ali

    2012-01-01

    Full Text Available Background/Aim: We investigated the effect of bone marrow-derived stem cell (BMSC transplantation on carbon tetrachloride (CCl 4 -induced liver fibrosis. Patients and Methods: BMSCs of green fluorescent protein (GFP mice were transplanted into 4-week CCl 4 -treated C57BL/6 mice directly to the liver, and the mice were treated for 4 more weeks with CCl 4 (total, 8 weeks. After sacrificing the animals, quantitative data of percentage fibrosis area and the number of cells expressing albumin was obtained. One-way analysis of variance was applied to calculate the significance of the data. Results: GFP expressing cells clearly indicated migrated BMSCs with strong expression of albumin after 28 days post-transplantation shown by anti-albumin antibody. Double fluorescent immunohistochemistry showed reduced expression of αSMA on GFP-positive cells. Four weeks after BMSC transplantation, mice had significantly reduced liver fibrosis as compared with that of mice treated with CCl 4 assessed by Sirius red staining. Conclusion: Mice with BMSC transplantation with continuous CCl 4 injection had reduced liver fibrosis and a significantly improved expression of albumin compared with mice treated with CCl 4 alone. These findings strengthen the concept of cellular therapy in liver fibrosis.

  8. Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

    Directory of Open Access Journals (Sweden)

    Shu Li

    2012-01-01

    Full Text Available The renin-angiotensin system (RAS plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B, one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN- induced rat fibrotic model in vivo and Ang-II stimulated hepatic stellate cells (HSCs in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I and α-smooth muscle actin (α-SMA production in vitro, reduced the gene expression of transforming growth factor beta (TGF-β, and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation.

  9. Cannabinoid receptors are involved in the protective effect of a novel curcumin derivative C66 against CCl4-induced liver fibrosis.

    Science.gov (United States)

    Huang, Si-Si; Chen, Da-Zhi; Wu, He; Chen, Rui-Cong; Du, Shan-Jie; Dong, Jia-Jia; Liang, Guang; Xu, Lan-Man; Wang, Xiao-Dong; Yang, Yong-Ping; Yu, Zhen-Ping; Feng, Wen-Ke; Chen, Yong-Ping

    2016-05-15

    Liver fibrosis is one of the major causes of morbidity and mortality worldwide and lacks efficient therapy. Recent studies suggest the curcumin protects liver from fibrosis. However, curcumin itself is in low bioavailable concentration when administered orally, and the protective mechanism remains poorly understood. The current study aimed to investigate whether a more stable derivative of curcumin, C66, protects against CCl4-inudced liver fibrosis and examine the underlying mechanism involving cannabinoid receptor (CB receptor). At a dose lower than curcumin itself, C66 displayed a superior anti-fibrotic effect. C66 significantly reduced collagen deposition, pro-inflammatory cytokine expression, and liver enzyme activities. Mechanistic study revealed that C66 treatment decreased CCl4-induced cannabinoid receptor 1 (CB1 receptor) expression and increased cannabinoid receptor 2 (CB2 receptor) expression, along with an inhibition of JNK/NF-κB-mediated inflammatory signaling. In conclusion, this curcumin derivative attenuates liver fibrosis likely involving a CB/JNK/NF-κB-mediated pathway. PMID:26945822

  10. Chikusetsusaponin V attenuates lipopolysaccharide-induced liver injury in mice.

    Science.gov (United States)

    Dai, Yan Wen; Zhang, Chang Cheng; Zhao, Hai Xia; Wan, Jing Zhi; Deng, Li Li; Zhou, Zhi Yong; Dun, Yao Yan; Liu, Chao Qi; Yuan, Ding; Wang, Ting

    2016-06-01

    Chikusetsusaponin V (CsV), a saponin from Panax japonicus, has been reported to inhibit inflammatory responses in lipopolysaccharide (LPS)-induced macrophage cells. However, whether CsV could alleviate LPS-induced liver injury in vivo and the potential mechanisms involved remain unclear. In the present study, we investigated the anti-inflammatory effects of CsV on LPS-induced acute liver injury in mice and further explored the potential mechanisms involved. Our results showed that CsV significantly attenuated elevation of alanine transaminase (ALT) and aspartate aminotransferase (AST) levels and improved liver histopathological changes in LPS-induced mice. In addition, CsV decreased serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels and inhibited mRNA expressions of inducible nitric oxide synthase (iNOS), TNF-α and IL-1β in LPS challenged mice. Furthermore, CsV inhibited nuclear factor kappa B (NF-κB) activation by downregulating phosphorylated NF-κB, IκB-α, ERK, c-Jun N-terminal kinase (JNK) and p38 levels in the liver tissue, which ultimately decreased nucleus NF-κB protein level. In conclusion, our data suggested that CsV could be a promising drug for preventing LPS challenged liver injury since it attenuated LPS-induced inflammatory responses, partly via inhibiting NF-κB and MAPK signaling pathways. PMID:26981791

  11. Unani Treatment Decreased Fibrosis and Improved Liver Functions in Decompensated Cirrhosis of Liver: A Case Series

    Directory of Open Access Journals (Sweden)

    Akhtar Siddiqui

    2016-03-01

    Full Text Available At present, liver transplantation remains the only curative option for the patients with cirrhosis and end-stage liver diseases. The survival rate and recurrent diseases remain the major issues in the patient post-transplantation. Unani medicine is one of the oldest traditional systems of medicine which has been treating chronic liver diseases and cirrhosis (Talayyaful-Kabid for centuries. The current study aimed to assess the impact of Unani treatment on decompensated cirrhosis and collect data to warrant further clinical trials. Authors conducted a case series on five patients with decompensated cirrhosis and portal hypertension. The disease was confirmed through FibroScan and ultrasound and treated with Unani treatment orally for seven months. Results were evaluated based on FibroScan, liver function test (LFT, EuroQol-5D (EQ5D, Child-Pugh and TTO-TIME (trade-off question. Significant improvements in LFT, fibrosis and quality of life were achieved in the studied patients. The literature related to the herbal constituents of chief medicines used to treat in this case was reviewed. The herbs proved their potential anti-oxidative, anti-inflammatory, hepato-protective, immuno-modulator and antiviral activities, suggesting plausible mechanisms of action in the cases. The preliminary findings indicated the potential therapeutic role of Unani treatment in decompensated cirrhosis. Clinical trials should be conducted to explore further therapeutic potential of Unani treatment in decompensated cirrhosis.

  12. Progress of Targeting Transforming Growth Factor-β1 Small Interfering RNA in Liver Fibrosis

    Institute of Scientific and Technical Information of China (English)

    Xuan Zhou; Xue-feng Yang

    2014-01-01

    Liver fibrosis is a common pathological consequence of a variety of chronic stimuli, including viral, autoimmune, drug-induced, cholestatic and metabolic diseases. Fibrosis is driven by a dynamic process involving increased synthesis of matrix components and a failure of physiological mechanisms of matrix turnover. Activation of hepatic stellate cells (HSCs) remains a central event in fibrosis. HSCs are the main source of extracellular matrix (ECM). Transforming growth factor-beta (TGF-β), which is the fibrogenic master cytokine, can induce the activation of HSCs to produce a large amount of ECM, and is capable of inducing apoptosis of liver cells. RNA interference (RNAi) is a novel gene disruption technology. Studies have shown that small interfering RNA (siRNA) targeting TGF-β1 may inhibit the activation and proliferation of HSCs, suppress ECM synthesis and block liver fibrosis. TGF-β1 siRNA-mediated gene silencing therapy provides a new avenue for liver fibrosis. This review summarizes recent progresses in research on HSCs, TGF-β1 and TGF-β1 siRNA in liver fibrosis.

  13. Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis.

    Science.gov (United States)

    Lua, Ingrid; Li, Yuchang; Pappoe, Lamioko S; Asahina, Kinji

    2015-12-01

    Mesothelial cells (MCs) form a single epithelial layer and line the surface of body cavities and internal organs. Patients who undergo peritoneal dialysis often develop peritoneal fibrosis that is characterized by the accumulation of myofibroblasts in connective tissue. Although MCs are believed to be the source of myofibroblasts, their contribution has remained obscure. We determined the contribution of peritoneal MCs to myofibroblasts in chlorhexidine gluconate (CG)-induced fibrosis compared with that of phenotypic changes of liver MCs. CG injections resulted in disappearance of MCs from the body wall and the accumulation of myofibroblasts in the connective tissue. Conditional linage tracing with Wilms tumor 1 (Wt1)-CreERT2 and Rosa26 reporter mice found that 17% of myofibroblasts were derived from MCs in peritoneal fibrosis. Conditional deletion of transforming growth factor-β type II receptor in Wt1(+) MCs substantially reduced peritoneal fibrosis. The CG treatment also induced myofibroblastic conversion of MCs in the liver. Lineage tracing with Mesp1-Cre mice revealed that Mesp1(+) mesoderm gave rise to liver MCs but not peritoneal MCs. During recovery from peritoneal fibrosis, peritoneal MCs, but not liver MCs, contribute to the regeneration of the peritoneal mesothelium, indicating an inherent difference between parietal and visceral MCs. In conclusion, MCs partially contribute to myofibroblasts in peritoneal and liver fibrosis, and protection of the MC layer leads to reduced development of fibrous tissue. PMID:26598235

  14. The Progression of Liver Fibrosis Is Related with Overexpression of the miR-199 and 200 Families

    OpenAIRE

    Murakami, Yoshiki; Toyoda, Hidenori; Tanaka, Masami; Kuroda, Masahiko; Harada, Yoshinori; Matsuda, Fumihiko; Tajima, Atsushi; Kosaka, Nobuyoshi; Ochiya, Takahiro; Shimotohno, Kunitada

    2011-01-01

    Background Chronic hepatitis C (CH) can develop into liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Liver fibrosis and HCC development are strongly correlated, but there is no effective treatment against fibrosis because the critical mechanism of progression of liver fibrosis is not fully understood. microRNAs (miRNAs) are now essential to the molecular mechanisms of several biological processes. In order to clarify how the aberrant expression of miRNAs participates in development o...

  15. Protective Effect of Astaxanthin on Liver Fibrosis through Modulation of TGF-β1 Expression and Autophagy

    OpenAIRE

    Shen, Miao; CHEN, KAN; Lu, Jie; Cheng, Ping; Ling XU; Dai, Weiqi; Wang, Fan; He, Lei; Yan ZHANG; Chengfen, Wang; Li, Jingjing; Yang, Jing; Zhu, Rong; Zhang, Huawei; Zheng, Yuanyuan

    2014-01-01

    Liver fibrosis is a common pathway leading to cirrhosis and a worldwide clinical issue. Astaxanthin is a red carotenoid pigment with antioxidant, anticancer, and anti-inflammatory properties. The aim of this study was to investigate the effect of astaxanthin on liver fibrosis and its potential protective mechanisms. Liver fibrosis was induced in a mouse model using CCL4 (intraperitoneal injection, three times a week for 8 weeks), and astaxanthin was administered everyday at three doses (20, 4...

  16. Circulating levels of citrullinated and MMP-degraded vimentin (VICM) in liver fibrosis related pathology

    DEFF Research Database (Denmark)

    Vassiliadis, E.; Oliveira, C. P.; Alvares-da-Silva, M. R.;

    2012-01-01

    -citrulline (VICM) was developed and evaluated in a carbon tetrachloride (CCl4) (n=52 + 28 controls) rat model of liver fibrosis and two clinical cohorts of adult patients with hepatitis C (HCV) (n=92) and non-alcoholic fatty liver disease (NAFLD) (n=62), and compared to healthy controls. Results: In CCl4-treated...

  17. Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis. Protocol for a Cochrane Review

    DEFF Research Database (Denmark)

    Rambaldi, A; Gluud, C

    2000-01-01

    The majority of liver fibrosis and liver cirrhosis cases in the Western World is caused by alcohol and hepatotoxic viruses. Colchicine is an anti-inflammatory and anti-fibrotic medication. Several randomised clinical trials have addressed the question whether colchicine has any efficacy in patients...

  18. Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study

    OpenAIRE

    Ryder, S. D.

    2004-01-01

    Background: The natural history of hepatitis C virus (HCV) infection remains uncertain. Previous data concerning rates of progression are from studies using estimated dates of infection and single liver biopsy scores. We prospectively studied the rate of progression of fibrosis in HCV infected patients by repeat liver biopsies without intervening treatment.

  19. Ginkgo biloba extract reverses CCl4-induced liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Yan-Jun Luo; Jie-Ping Yu; Zhao-Hong Shi; Li Wang

    2004-01-01

    AIM: To study the reversing effect of Ginkgo biloba extract (GbE) on established liver fibrosis in rats.METHODS: Following confirmation of CCl4-induced liver fibrosis, GbE or saline was administrated to the rats for 4 weeks. The remaining rats received neither CCl4 nor GbE as normal control. The four groups were compared in terms of serum enzymes, tissue damage, expression of αSMA and tissue inhibitor-1 of metalloproteinase (TIMP-1) and metalloproteinase-1 (MMP-1).RESULTS: Compared with saline-treated group, liver fibrosis rats treated with GbE had decreased serum total bilirubin (P<0.01) and aminotransferase levels (P<0.01) and increased levels of serum albumin (P<0.01). Microscopic studies revealed that the livers of rats receiving GbE showed allieviation in fibrosis (P<0.05) as well as expression of αSMA (P<0.01). The liver collagen and reticulum contents were lower in rats treated with GbE than saline-treated group (P<0.01). RT-PCR revealed that the level of TIMP-1 decreased while the level of MMP-1 increased in GbE group.CONCLUSION: Administration of GbE improved CCl4-induced liver fibrosis. It is possibly attributed to its effect of inhibiting the expression of TIMP-1 and promoting the apoptosis of hepatic stellate cells.

  20. Effect of Chinese herbal compound on liver fibrosis in rabbits with schistosomiasis by B-ultrasound

    Institute of Scientific and Technical Information of China (English)

    Xiao-Lu Liang; Jia-Ying Yuan

    2013-01-01

    Objective:To explore the value of B-ultrasound on the evaluation of the effects of traditional Chinese medicine compound of Radix astragali, Salvia miltiorrhiza and Angelica sinensis, and TCM +praziquantel on liver fibrosis in rabbits with schistosomiasis. Methods: The hepatic fibrosis model in rabbits with schistosomiasis was established. The experimental animals (24 rabbits) were randomly divided into four groups (group A, B, C and D, n=6). Group A (control group) was only treated by praziquantel; Group B was treated by mixture of Radix astragali and Salvia miltiorrhiza +praziquantel; Group C was treated by mixture of Radix astragali and Angelica sinensis +praziquantel; Group D was treated by mixture of Radix astragali, Salvia miltiorrhiza and Angelica sinensis +praziquantel. Then B-ultrasonogram was used to evaluate the effects. Results: Each group showed certain curative effect on liver fibrosis in rabbits with schistosomiasis. The efficacy of group B, C and D was better than group A, and that of group D was the best. The differences in long diameter, thickness diameter, transverse diameter and portal vein inner diameter of liver before and after treatment were statistically significant (P<0.05). The liver function indexes and liver fibrosis indexes were significantly improved after treatment (P<0.05). Conclusions:The mixture of Radix astragali, Salvia miltiorrhiza and Angelica sinensis combined with Western medicine treatment can obviously improve the efficacy on liver fibrosis of schistosomiasis.

  1. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis

    Science.gov (United States)

    Dadrich, Monika; Nicolay, Nils H.; Flechsig, Paul; Bickelhaupt, Sebastian; Hoeltgen, Line; Roeder, Falk; Hauser, Kai; Tietz, Alexandra; Jenne, Jürgen; Lopez, Ramon; Roehrich, Manuel; Wirkner, Ute; Lahn, Michael; Huber, Peter E.

    2016-01-01

    ABSTRACT Background: Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods: C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results: Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion: Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement: RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined

  2. L -Carnitine and Melatonin Reverse CCl4 Induced Liver Fibrosis In Rats (Histological and Histochemical Studies

    Directory of Open Access Journals (Sweden)

    Fatma, A. Morsy, Abdel Razik, H. Farrag and Sonya, L. El-Sharkawy

    2004-12-01

    Full Text Available Carbontetrachloride (CCl4 is closely related chemically to chloroform and likewise in hepatic poisons. This study was designed to evaluate the effects of carbon tetrachloride on liver of male rats and the reversing effects of L-carnitine and melatonin on established liver fibrosis. A total of 72 adult male albino rats were used in this study. The animals were divided into six groups. Group (1 animals of the first group were kept as control andtreated with paraffin oil twice weekly for eight weeks. Group (2 rats of the second group were injected with CCl4 intraperitoneally at 0.15 ml per rats (diluted 1:1 in liquid paraffin twice weekly for eight weeks to produced liver fibrosis. Group (3 following establishment with CCl4 which induced liver fibrosis, the rats were treated with L-carnitine at a dose level of 50 mg/kg for four weeks. Group (4 rats with liver fibrosis were injected intraperitoneally with melatonin at dose level of 10 mg/kg for four weeks. The fifth and sixth groups were given L-carnitine and/or melatonin at dose levels of 50 mg/kg and 10 mg/kg respectively for four weeks. Histological changes in the liver of rats treated with CCl4 including liver fibrosis, architecture distortion and appearance of many pseudolobule. The fibrous tissues run in septa between the nodules. The liver damage varied from one area to another and varied from moderate fibrosis to cirrhosis. Quantitative measurement of the severity of liver fibrosis (area damage was achieved by using computerized image analysis (Leica image showed that highly significant increase in area of fibrosis was recorded in the case of rats treated with CCl4 only. Quantitative DNA image analysis showed that 3% of aneuploid cells could be noticed in liver of rats treated with CCl4 only. Histochemical results of rats treated with CCl4 showed highly significant increase in grey level of mucopolysaccharides and protein levels. No histological and histochemical changes could be noticed in

  3. Chop Deficiency Protects Mice Against Bleomycin-induced Pulmonary Fibrosis by Attenuating M2 Macrophage Production.

    Science.gov (United States)

    Yao, Yingying; Wang, Yi; Zhang, Zhijun; He, Long; Zhu, Jianghui; Zhang, Meng; He, Xiaoyu; Cheng, Zhenshun; Ao, Qilin; Cao, Yong; Yang, Ping; Su, Yunchao; Zhao, Jianping; Zhang, Shu; Yu, Qilin; Ning, Qin; Xiang, Xudong; Xiong, Weining; Wang, Cong-Yi; Xu, Yongjian

    2016-05-01

    C/EBP homologous protein (Chop) has been shown to have altered expression in patients with idiopathic pulmonary fibrosis (IPF), but its exact role in IPF pathoaetiology has not been fully addressed. Studies conducted in patients with IPF and Chop(-/-) mice have dissected the role of Chop and endoplasmic reticulum (ER) stress in pulmonary fibrosis pathogenesis. The effect of Chop deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis were affected by the altered Chop expression and ER stress. In particular, Chop deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of Chop significantly attenuated transforming growth factor β (TGF-β) production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that Chop deficiency repressed the M2 program in macrophages, which then attenuated TGF-β secretion. Specifically, loss of Chop promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which Chop deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that Chop and ER stress are implicated in IPF pathoaetiology, involving at least the induction and differentiation of M2 macrophages. PMID:26883801

  4. Serum Liver Fibrosis Markers in the Prognosis of Liver Cirrhosis: A Prospective Observational Study.

    Science.gov (United States)

    Qi, Xingshun; Liu, Xu; Zhang, Yongguo; Hou, Yue; Ren, Linan; Wu, Chunyan; Chen, Jiang; Xia, Chunlian; Zhao, Jiajun; Wang, Di; Zhang, Yanlin; Zhang, Xia; Lin, Hao; Wang, Hezhi; Wang, Jinling; Cui, Zhongmin; Li, Xueyan; Deng, Han; Hou, Feifei; Peng, Ying; Wang, Xueying; Shao, Xiaodong; Li, Hongyu; Guo, Xiaozhong

    2016-01-01

    BACKGROUND The prognostic role of serum liver fibrosis markers in cirrhotic patients remains unclear. We performed a prospective observational study to evaluate the effect of amino-terminal pro-peptide of type III pro-collagen (PIIINP), collagen IV (CIV), laminin (LN), and hyaluronic acid (HA) on the prognosis of liver cirrhosis. MATERIAL AND METHODS All patients who were diagnosed with liver cirrhosis and admitted to our department were prospectively enrolled. PIIINP, CIV, LN, and HA levels were tested. RESULTS Overall, 108 cirrhotic patients were included. Correlation analysis demonstrated that CIV (coefficient r: 0.658, p<0.001; coefficient r: 0.368, p<0.001), LN (coefficient r: 0.450, p<0.001; coefficient r: 0.343, p<0.001), and HA (coefficient r: 0.325, p=0.001; coefficient r: 0.282, p=0.004) levels, but not PIIINP level (coefficient r: 0.081, p=0.414; coefficient r: 0.090, p=0.363), significantly correlated with Child-Pugh and MELD scores. Logistic regression analysis demonstrated that HA (odds ratio=1.00003, 95% confidence interval [CI]=1.000004-1.000056, p=0.022) was significantly associated with the 6-month mortality. Receiver operating characteristics analysis demonstrated that the area under the curve (AUC) of HA for predicting the 6-month mortality was 0.612 (95%CI=0.508-0.709, p=0.1531). CONCLUSIONS CIV, LN, and HA levels were significantly associated with the severity of liver dysfunction, but might be inappropriate for the prognostic assessment of liver cirrhosis. PMID:27480906

  5. Correlation between ultrasonographic and pathologic diagnosis of liver fibrosis due to chronic virus hepatitis

    Institute of Scientific and Technical Information of China (English)

    Lei Shen; Ji-Qiang Li; Min-De Zeng; Lun-Gen Lu; Si-Tao Fan; Han Bao

    2006-01-01

    AIM: To evaluate the validity of ultrasonographic and pathologic diagnosis of liver fibrosis in patients with chronic viral hepatitis.METHODS: The liver fibrosis status in 324 patients was evaluated by both needle biopsy and ultrasonography.Liver fibrosis was divided into S0 -S4 stages. S4 stage was designated as definite cirrhosis. The ultrasonographic examination included qualitative variables, description of liver surface and parenchyma, and quantitative parameters, such as diameter of vessels, blood flow velocity and spleen size.RESULTS: Ultrasonographic qualitative description of liver surface and parenchyma was related with the severity of fibrosis. Among the quantitative ultrasonographic parameters, cut-off value of spleen length (12.1 cm) had a sensitivity of 0.600 and a specificity of 0.753 for diagnosis of liver cirrhosis. The diameters of spleen (8 mm) and portal vein (12 mm) had a diagnostic sensitivity of 0.600and 0.767, and a diagnostic specificity of 0.781 and 0.446,respectively. The diagnostic accuracy for liver cirrhosis was moderately satisfactory, and the negative predictive values of these parameters reached near 0.95.CONCLUSION: Ultrasonography can predict the degree of liver fibrosis or cirrhosis. A single ultrasonographic parameter is limited in sensitivity and specificity for the diagnosis of early cirrhosis. The presence or absence of liver cirrhosis in patients with chronic virus hepatitis can be detected using 2 or 3 quantitative and qualitative parameters, especially the length of spleen, the diameter of spleen vein and echo pattern of liver surface.

  6. Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice.

    Science.gov (United States)

    Tabet, Elise; Genet, Valentine; Tiaho, François; Lucas-Clerc, Catherine; Gelu-Simeon, Moana; Piquet-Pellorce, Claire; Samson, Michel

    2016-07-25

    Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s. It is not itself hepatotoxic, but its metabolism in the liver triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone is now banned, but it persists in soil and water, resulting in an ongoing public health problem in the Caribbean area. We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury. PMID:26853152

  7. The application of artificial neural network model in the non-invasive diagnosis of liver fibrosis

    Directory of Open Access Journals (Sweden)

    Bo LI

    2012-12-01

    Full Text Available Objective  To construct and evaluate an artificial neural network (ANN model as a new non-invasive diagnostic method for clinical assessment of liver fibrosis at early stage. Methods  The model was set up and tested among 683 chronic hepatitis B (CHB patients, with authentic positive clinical biopsy results, proved to have liver fibrosis or cirrhosis, admitted to 302 Hospital of PLA from May 2008 to March 2011. Among 683 samples, 504 samples were diagnosed as cirrhosis as a result of CHB, and 179 liver fibrosis due to other liver diseases. 134 out of 683 patients were included in training group by stratified sampling, and the others for verification. Six items (age, AST, PTS, PLT, GGT and DBil were selected as input layer indexes to set up the model for evaluation. Results  The ANN model for diagnosis of liver fibrosis was set up. The diagnostic accuracy was 77.4%, sensitivity was 76.8%, and specificity was 77.8%. Its Kappa concordance tests showed the diagnosis result of the model was consistent with biopsy result (Kappa index=0.534. The accuracy, sensitivity and specificity of CHB patients were 80.4%, 79.9% and 80.7% (Kappa index=0.598 respectively, and those for other liver diseases were 67.9%, 64.3% and 69.7% (Kappa index=0.316. Conclusion  The artificial neural network model established by the authors demonstrates its high sensitivity and specificity as a new non-invasive diagnostic method for liver fibrosis induced by HBV infection. However, it shows limited diagnostic reliability to fibrosis as a result of other liver diseases.

  8. A multiscale agent-based in silico model of liver fibrosis progression

    Directory of Open Access Journals (Sweden)

    Joyeeta eDutta-Moscato

    2014-05-01

    Full Text Available Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM of liver tissue in order to computationally examine the consequence of liver inflammation. Our Liver Fibrosis ABM (LFABM is comprised of literature-derived rules describing molecular and histopathologic aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern (DAMP molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathologic features observed in liver sections from rats treated with carbon tetrachloride (CCl4. An in silico tension test for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing TNF-a vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathologic and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into live fibrosis.

  9. Vitamin D Receptor Attenuates Renal Fibrosis by Suppressing the Renin-Angiotensin System

    OpenAIRE

    Zhang, Yan; Kong, Juan; Dilip K. Deb; Chang, Anthony; Li, Yan Chun

    2010-01-01

    Analogs of vitamin D attenuate renal injury in several models of kidney disease, but the mechanism underlying this renoprotective effect is unknown. To address the role of the vitamin D receptor (VDR) in renal fibrogenesis, we subjected VDR-null mice to unilateral ureteral obstruction for 7 days. Compared with wild-type mice, VDR-null mice developed more severe renal damage in the obstructed kidney, with marked tubular atrophy and interstitial fibrosis. Significant induction of extracellular ...

  10. PDW Index - A Simple Model for the Prediction of Liver Fibrosis in Chronic Viral Hepatitis

    International Nuclear Information System (INIS)

    Objectives: To assess the accuracy of platelets, platelet morphological parameters, mean platelet volume(MPV) and platelet distribution width, (PDW) to diagnose advanced fibrosis. Study Design: Validation study. Place and Duration of Study: Combined Military Hospital, Malir, from Jun 2008 to Jun 2009. Patients and Methods: Simple laboratory tests, aspartate aminotransferase (AST) alanine aminotransferase (ALT) platelet count and platelet morphological parameters were measured in 91 chronic viral hepatitis patients. All patients had liver biopsy performed. A new index, PDW index was derived to detect the opposing effects of liver fibrosis on platelet count, MPV, and PDW. The predictive value of the index for advanced fibrosis (F3-F4) was assessed through descriptive statistics and area under the ROC curves. Results: Two cut-offs were chosen to qualify different stages of fibrosis. A value of > 8.00 predicted advanced fibrosis, F3-F4, with a specificity of 94% and positive predictive value of 78%. A value of < 6.00 ruled out advanced fibrosis with a negative predictive value of 93% and a sensitivity of 82%. The area under the ROC curve for advanced fibrosis was 0.840. PDW Index values outside of these cut-offs correctly classified 60% of patients. Conclusion: A simple index comprising platelet as only parameters have high diagnostic value for the advanced stages of fibrosis. (author)

  11. Garlic attenuates histological and histochemical alterations in livers of Schistosoma mansoni infected mice.

    Science.gov (United States)

    Mahmoud, Y I; Riad, N H; Taha, H

    2016-08-01

    Interest in screening for new anti-schistosomal agents is growing because of increased concerns about resistance to and safety of praziquantel. We investigated the anti-schistosomal action of prophylactic and therapeutic doses of garlic on the histological and histochemical alterations caused by Schistosoma mansoni infection. Livers of infected mice were characterized by granulomas, periportal inflammation and fibrosis, hepatocyte vacuolation, fatty degeneration and necrosis, and hypertrophy and pigmentation of Kupffer cells. Significant depletion of carbohydrates and increased lipid vacuoles also were observed. All garlic regimens caused suppression of granuloma formation and amelioration of histological and histochemical changes; the continuous treatment protocol produced the best results. Garlic appears to be a safe and economical anti-schistosomal adjuvant for attenuating the pathogenicity of schistosomiasis. PMID:27045197

  12. Effect of Anluohuaxian Tablet Combined with y-IFN on Schistosomal Liver Fibrosis

    Institute of Scientific and Technical Information of China (English)

    Jiaquan HUANG; Haiyan HUANG; Yuntao JIAO; Guo AI; Tiejun HUANG; Lan LI; Haijing YU; Ke MA; Fei XLAO

    2009-01-01

    The therapeutic effects of anluohuaxian tablet combined with γ-IFN on schistosomal liver fibrosis and its mechanism were studied in a murine model and clinical cases of schistosomal liver fibrosis.Fifty Kunming mice were randomly divided into 5 groups:normal control group,infection control group,anluohuaxian tablet-treated group,γ-IFN-treated group and combined treatment (anluohuaian tablet+γ-IFN) group.Pathologic changes in liver,including hepatic pigmentation and the size of schistosomal egg granuloma,were observed by HE staining after treatment for 8 weeks.The expression of the type Ⅰ and Ⅲ collagen,and TIMP-1 was detected by immunohistochemistry.TGF-β1 mRNA expression was examined by real-time fluorescent quantitative PCR.Sixty patients with schistosomal liver fibrosis were divided into treatment group and control group.The patients in treatment group were treated with anluohuaxian tablet in combination with γ-IFN for 6 months.Be-fore and after treatment,the changes of symptoms and signs,liver function,serum liver fibrosis in-dexes and imaging indexes were observed.The results showed that as compared with infection con-trol group,all forms of treatments relieved the hepatic pathological injury with apparently diminished size of schistosomal egg nodules and decreased percentage of pigmentation (P<0.05).Furthermore,the expression of collagen Ⅰ and Ⅲ,TIMP-Ⅰ,and TGF-β1 mRNA in combined treatment group was significantly decreased as compared with anluohuaxian tablet-treated and γ-IFN-treated groups (P<0.05).In the clinical observation,the serum liver fibrosis indexes,the portal vein width as well as the spleen thickness was significantly reduced in treatment group as compared with control group (P<0.05).It was concluded that the combined use of anluohuaxian tablet with γ-IFN in schistosomal liver fibrosis could protect liver function,alleviate liver fibrosis,and could be used as a choice in treating patients with schiatosomal liver fibrosis.

  13. Regulatory T Cells Prevent Liver Fibrosis During HIV Type 1 Infection in a Humanized Mouse Model

    OpenAIRE

    Nunoya, Jun-ichi; Washburn, Michael L.; Kovalev, Grigoriy I; Su, Lishan

    2013-01-01

    Human immunodeficiency virus type 1 (HIV-1) disease is associated with aberrant immune activation, and coinfection with hepatitis C virus (HCV) exacerbates hepatic inflammation and fibrosis. However, the role of HIV-1 infection or host immune modulation in liver pathogenesis is not clearly defined. Here, we report that regulatory T (Treg) cells prevent liver immunopathogenesis during HIV-1 infection in a humanized mouse model. In the absence of Treg cells, HIV-1 infection induced liver fibros...

  14. Blockade of advanced glycation end product formation attenuates bleomycin-induced pulmonary fibrosis in rats

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    Liu Dai-Shun

    2009-06-01

    Full Text Available Abstract Background Advanced glycation end products (AGEs have been proposed to be involved in pulmonary fibrosis, but its role in this process has not been fully understood. To investigate the role of AGE formation in pulmonary fibrosis, we used a bleomycin (BLM-stimulated rat model treated with aminoguanidine (AG, a crosslink inhibitor of AGE formation. Methods Rats were intratracheally instilled with BLM (5 mg/kg and orally administered with AG (40, 80, 120 mg/kg once daily for two weeks. AGEs level in lung tissue was determined by ELISA and pulmonary fibrosis was evaluated by Ashcroft score and hydroxyproline assay. The expression of heat shock protein 47 (HSP47, a collagen specific molecular chaperone, was measured with RT-PCR and Western blot. Moreover, TGFβ1 and its downstream Smad proteins were analyzed by Western blot. Results AGEs level in rat lungs, as well as lung hydroxyproline content and Ashcroft score, was significantly enhanced by BLM stimulation, which was abrogated by AG treatment. BLM significantly increased the expression of HSP47 mRNA and protein in lung tissues, and AG treatment markedly decreased BLM-induced HSP47 expression in a dose-dependent manner (p Conclusion These findings suggest AGE formation may participate in the process of BLM-induced pulmonary fibrosis, and blockade of AGE formation by AG treatment attenuates BLM-induced pulmonary fibrosis in rats, which is implicated in inhibition of HSP47 expression and TGFβ/Smads signaling.

  15. Liver Fibrosis progression using Fibroscan in HIV/HCV coinfected patients with undetectable HIV viral load

    OpenAIRE

    Laura Perez-Martinez; Isabel Sanjoaquin; Maria Rivero; Desiré Gil-Pérez; Santiago Letona; Carmen Irigoyen Olaiz; Piedad Arazo; Jose Ramón Blanco

    2014-01-01

    Introduction: Several factors such as duration of infection, age, male gender, consumption of alcohol, HIV infection and low CD4 count have been associated with fibrosis progression rate. However, it is relatively scarce, the knowledge about the liver fibrosis progression rate in HIV-infected patients with undetectable HIV viral load (VL). For this reason, we performed the present study. Materials and Methods: Observational and multicenter study (2008–2012) conducted in four hospitals of the ...

  16. Clusterin/apolipoprotein J attenuates angiotensin II-induced renal fibrosis.

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    Gwon-Soo Jung

    Full Text Available The blockade of angiotensin II (Ang II is a major therapeutic strategy for diabetic nephropathy. The main roles of Ang II in renal disease are mediated via the Ang type 1 receptor (AT1R. Upregulation of clusterin/apolipoprotein J has been reported in nephropathy models, suggesting it has a protective role in nephropathogenesis. Here, we studied how clusterin acts against Ang II-induced renal fibrosis. Levels of AT1R and fibrotic markers in clusterin-/- mice and Ang II infused rats transfected with an adenovirus encoding clusterin were evaluated by immunoblot analysis, real time RT-PCR, and immunohistochemical staining. The effect of clusterin on renal fibrosis was evaluated in NRK-52E cells, a cultured renal tubular epithelial cell line, using immunoblot analysis and real time RT-PCR. Nuclear localization of NF-κB was evaluated using immunofluorecence and co-immunoprecipitation. Renal fibrosis and expression of AT1R was higher in the kidneys of clusterin-/- mice than in those of wild-type mice. Furthermore, loss of clusterin accelerated Ang II-stimulated renal fibrosis and AT1R expression. Overexpression of clusterin in proximal tubular epithelial cells decreased the levels of Ang II-stimulated fibrotic markers and AT1R. Moreover, intrarenal delivery of clusterin attenuated Ang II-mediated expression of fibrotic markers and AT1R in rats. Fluorescence microscopy and co-immunoprecipitation in conjunction with western blot revealed that clusterin inhibited Ang II-stimulated nuclear localization of p-NF-κB via a direct physical interaction and subsequently decreased the AT1R level in proximal tubular epithelial cells. These data suggest that clusterin attenuates Ang II-induced renal fibrosis by inhibition of NF-κB activation and subsequent downregulation of AT1R. This study raises the possibility that clusterin could be used as a therapeutic target for Ang II-induced renal diseases.

  17. Expression of exogenous rat collagenase in vitro and in a rat model of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Ji-Yao Wang; Jin-Sheng Guo; Chang-Qing Yang

    2002-01-01

    AIM: The present study was conducted to test thehypothesis that the introduction of the collagenase geneinto tissue culture cells and into a rat model of liver fibrosiswould result in the expression of enzymatically active product.METHODS: FLAG-tagged full-length rat collagenase cDNAwas PCR amplified and cloned into a mammalian expressionvector. NIH3T3 cells were then transiently transfected withthis construct. Expression of exogenous collagenase mRNAwas assessed by RT-PCR, and the exogenous collagenasedetected by Western blotting using anti-FLAG monoclonalantibodyEnzymatic activity was detected by gelatinzymography. To determine the effects of exogenouscollagenase production in vivo, the construct was boundto glycosyl-poly-L-lysine and then transduced into rats thathad developed liver fibrosis as a result of CCI4 plus ethanoltreatment. The hepatic expression of the construct and itseffect on the formation of liver fibrosis were demonstratedusing RT-PCR and immunohistochemistry.RESULTS: It was found that exogenously expressed ratcollagenase mRNA could be detected in NTH3T3 cellsfollowing transfection. Enzymatic ally active collagenase couldalso be detected in the culture medium. The recombinantplasmid was also expressed in rat liver after in vivo genetransfer. Expression of exogenous rat collagenase correlatedwith decreased deposition of collagen types I and Ⅲ in thelivers of rats with experimentally induced liver fibrosis.CONCLUSION: The expression of active exogenous ratcollagenase could be achieved in vitro and in vivo. It wassuggested that in vivo expression of active exogenouscollagenase may have therapeutic effects on the formationof liver fibrosis.

  18. ASSOCIATION OF CAFFEINE INTAKE AND LIVER FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS C

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    Kalinca da Silva OLIVEIRA

    2015-03-01

    Full Text Available Background Caffeine consumption has been associated to decreased levels of liver enzymes and lower risk of fibrosis in patients with hepatitis C virus. Objectives This study aimed to evaluate the association between caffeine consumption and inflammatory activity or degree of liver fibrosis in patients with hepatitis C virus infection. Methods A cross-sectional study of patients with chronic hepatitis C virus infection treated in an outpatient Gastroenterology Unit of Santa Casa Hospital (Porto Alegre - Brasil. Patients were interviewed regarding the consumption of caffeine and anthropometric assessment was performed. Liver biopsy was performed in a maximum period of 36 months before inclusion in the study Results There were 113 patients, 67 (59.3% females, 48 (42.5% were aged between 52 and 62 years, and 101 (89.4% were white. The average caffeine consumption was 251.41 ± 232.32 mg/day, and 70 (62% patients consumed up to 250 mg/day of caffeine. There was no association between caffeine consumption and inflammatory activity on liver biopsy. On the other hand, when evaluating the caffeine consumption liver fibrosis an inverse association was observed. Conclusions The greater consumption of caffeine was associated with lower liver fibrosis. There was no association between caffeine consumption and inflammatory activity.

  19. The severity of liver fibrosis is associated with high leptin levels in chronic hepatitis C.

    Science.gov (United States)

    Piche, T; Vandenbos, F; Abakar-Mahamat, A; Vanbiervliet, G; Barjoan, E M; Calle, G; Giudicelli, J; Ferrua, B; Laffont, C; Benzaken, S; Tran, A

    2004-01-01

    Recent attention has focused on the liver profibrogenic role of leptin in animal models. The purpose of this study was to evaluate the role of leptin and TNF-alpha in the severity of liver fibrosis in patients with chronic hepatitis C (CHC). We used a radioimmunoassay to determine serum leptin concentrations in 77 consecutive patients with CHC and 22 healthy controls. Leptin was correlated with liver histological (METAVIR) and metabolic indices. Sixty five patients had none to moderate liver fibrosis (F0-F2) and twelve severe fibrosis (F3-F4). Steatosis was observed in all but 27 patients. Leptin was significantly increased in patients compared with controls and was significantly more elevated in females both in patients and controls. The age, age at infection, prothrombin index, body mass index (BMI), triglycerides, glycaemia, ferritin, leptin and TNF-alpha, were associated with severe fibrosis. Steatosis was significantly more pronounced in patients with severe than those without or moderate fibrosis (P = 0.04). Only leptin was significantly and independently associated with severe fibrosis (OR = 1.2, CI 95%: 1.1-1.4, P = 0.03). Leptin was significantly associated with BMI (r = 0.64, P < 0.001) and glycaemia (r = 0.43, P < 0.001). Significant correlations were found between steatosis and BMI (r = 0.30, P < 0.01) and glycaemia (r = 0.30, P < 0.01). In patients with CHC and higher BMI and glycaemia levels, the severity of liver fibrosis is associated with serum leptin. TNF-alpha is a putative candidate involved in the mechanism. PMID:14738564

  20. Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis

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    Elena Turola

    2015-09-01

    Full Text Available Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD. Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and metabolic features, including menopausal status (self-reported; liver biopsy was scored according to ‘The Pathology Committee of the NASH Clinical Research Network’. Young and old male and female zebrafish were fed for 24 weeks with a high-calorie diet. Weekly body mass index (BMI, histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender [odds ratio (OR: 1.408, 95% confidence interval (95% CI: 0.779-2.542, P=0.25] vs women at reproductive age was not associated with F2-F4 fibrosis, whereas a trend was observed for menopause (OR: 1.752, 95% CI: 0.956-3.208, P=0.06. In women, menopause (OR: 2.717, 95% CI: 1.020-7.237, P=0.04 was independently associated with F2-F4 fibrosis. Similarly, in overfed zebrafish, old female fish with failing ovarian function [as demonstrated by extremely low circulating estradiol levels (1.4±0.1 pg/µl and prevailing presence of atretic follicles in the ovaries] developed massive steatosis and substantial fibrosis (comparable with that occurring in males, whereas young female fish developed less steatosis and were totally protected from the development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis.

  1. Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis

    Science.gov (United States)

    Turola, Elena; Petta, Salvatore; Vanni, Ester; Milosa, Fabiola; Valenti, Luca; Critelli, Rosina; Miele, Luca; Maccio, Livia; Calvaruso, Vincenza; Fracanzani, Anna L.; Bianchini, Marcello; Raos, Nazarena; Bugianesi, Elisabetta; Mercorella, Serena; Di Giovanni, Marisa; Craxì, Antonio; Fargion, Silvia; Grieco, Antonio; Cammà, Calogero; Cotelli, Franco; Villa, Erica

    2015-01-01

    ABSTRACT Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and metabolic features, including menopausal status (self-reported); liver biopsy was scored according to ‘The Pathology Committee of the NASH Clinical Research Network’. Young and old male and female zebrafish were fed for 24 weeks with a high-calorie diet. Weekly body mass index (BMI), histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender [odds ratio (OR): 1.408, 95% confidence interval (95% CI): 0.779-2.542, P=0.25] vs women at reproductive age was not associated with F2-F4 fibrosis, whereas a trend was observed for menopause (OR: 1.752, 95% CI: 0.956-3.208, P=0.06). In women, menopause (OR: 2.717, 95% CI: 1.020-7.237, P=0.04) was independently associated with F2-F4 fibrosis. Similarly, in overfed zebrafish, old female fish with failing ovarian function [as demonstrated by extremely low circulating estradiol levels (1.4±0.1 pg/µl) and prevailing presence of atretic follicles in the ovaries] developed massive steatosis and substantial fibrosis (comparable with that occurring in males), whereas young female fish developed less steatosis and were totally protected from the development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis. PMID:26183212

  2. Supersonic shearwave elastography in the assessment of liver fibrosis for postoperative patients with biliary atresia

    Science.gov (United States)

    Chen, Shuling; Liao, Bing; Zhong, Zhihai; Zheng, Yanling; Liu, Baoxian; Shan, Quanyuan; Xie, Xiaoyan; Zhou, Luyao

    2016-01-01

    To explore an effective noninvasive tool for monitoring liver fibrosis of children with biliary atresia (BA) is important but evidences are limited. This study is to investigate the predictive accuracy of supersonic shearwave elastography (SSWE) in liver fibrosis for postoperative patients with BA and to compare it with aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4). 24 patients with BA received SSWE and laboratory tests before scheduled for liver biopsy. Spearman rank coefficient and receiver operating characteristic (ROC) were used to analyze data. Metavir scores were F0 in 3, F1 in 2, F2 in 4, F3 in 7 and F4 in 8 patients. FIB-4 failed to correlate with fibrosis stage. The areas under the ROC curves of SSWE, APRI and their combination were 0.79, 0.65 and 0.78 for significant fibrosis, 0.81, 0.64 and 0.76 for advanced fibrosis, 0.82, 0.56 and 0.84 for cirrhosis. SSWE values at biopsy was correlated with platelet count (r = −0.426, P = 0.038), serum albumin (r = −0.670, P < 0.001), total bilirubin (r = 0.419, P = 0.041) and direct bilirubin levels (r = 0.518, P = 0.010) measured at 6 months after liver biopsy. Our results indicate that SSWE is a more promising tool to assess liver fibrosis than APRI and FIB-4 in children with BA. PMID:27511435

  3. Long non-coding RNA APTR promotes the activation of hepatic stellate cells and the progression of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Fujun [Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai, 201508 (China); Zheng, Jianjian [Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 (China); Mao, Yuqing [Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai, 201508 (China); Dong, Peihong [Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 (China); Li, Guojun [Department of Hepatology, Ningbo Yinzhou Second Hospital, Ningbo, 315000 (China); Lu, Zhongqiu [Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 (China); Guo, Chuanyong; Liu, Zhanju [Department of Gastroenterology, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai, 200072 (China); Fan, Xiaoming, E-mail: ktsqdph@163.com [Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai, 201508 (China)

    2015-08-07

    In this study, we aimed at assessing a role of Alu-mediated p21 transcriptional regulator (APTR) in hepatofibrogenesis. APTR was upregulated in fibrotic liver samples and activated hepatic stellate cells (HSCs). Knockdown of APTR inhibited the activation of HSCs in vitro and mitigated the accumulation of collagen in vivo. Importantly, APTR silencing could abrogate TGF-β{sub 1}-induced upregulation of α-SMA in HSCs. In addition, inhibition of cell cycle and cell proliferation by APTR knockdown was attenuated by p21 siRNA1 in primary HSCs. Finally, serum APTR levels were increased in patients with liver cirrhosis, indicating a potential biomarker for liver cirrhosis. Collectively, evidence is proposed for a new biological role of APTR in hepatofibrogenesis. - Highlights: • APTR is upregulated in fibrotic liver tissues and activated HSCs. • APTR silencing inhibits HSC activation and the progression of liver fibrosis. • Antifibrotic effect of APTR silencing is achieved by increasing p21.

  4. Present Situation in Preventing and Treating Liver Fibrosis with TCM Drugs

    Institute of Scientific and Technical Information of China (English)

    杜斌; 尤松鑫

    2001-01-01

    @@Liver fibrosis is a gradual process of increased secretion and decreased degradation of extracellular materials (ECM). Most author hold that the process is initiated by the damage of hepatic cells (HCs), which leads to activation and secretion of multiple cellular factors of Kupffer cells. These factors, along with the cellular factors secreted by damaged HCs, thrombocytes and endothelial cells of the hepatic sinusoid, and some chemical mediators are activators of hepatic stellate cells (HSCs). Being activated, HSCs differentiate into myofibroblasts, and, via self-secretion and parasecretion, proliferate and synthesize a massive amount of extracellular materials which gradually accumulate and lead to formation of liver fibrosis.1 Since fibrosis is a common course in a variety of chronic liver diseases, prevention against its formation is of great importance. The following are the recent achievements of traditional Chinese medicine (TCM) in this field.

  5. The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Paloma Almeda-Valdes

    2015-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance.

  6. A comparison of MR elastography and {sup 31}P MR spectroscopy with histological staging of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Godfrey, Edmund M. [St James' Hospital, Leeds (United Kingdom); St James' Hospital, Department of Radiology, Leeds (United Kingdom); Patterson, Andrew J.; Priest, Andrew N.; Davies, Susan E.; Joubert, Ilse; Krishnan, Anant S.; Shaw, Ashley S.; Alexander, Graeme J.; Allison, Michael E.; Griffiths, William J.H.; Gimson, Alexander E.S. [Addenbrooke' s Hospital, Cambridge (United Kingdom); Griffin, Nyree [St Thomas' s Hospital, London (United Kingdom); Lomas, David J. [University of Cambridge, Department of Radiology, Cambridge (United Kingdom)

    2012-12-15

    Conventional imaging techniques are insensitive to liver fibrosis. This study assesses the diagnostic accuracy of MR elastography (MRE) stiffness values and the ratio of phosphomonoesters (PME)/phosphodiesters (PDE) measured using {sup 31}P spectroscopy against histological fibrosis staging. The local research ethics committee approved this prospective, blinded study. A total of 77 consecutive patients (55 male, aged 49 {+-} 11.5 years) with a clinical suspicion of liver fibrosis underwent an MR examination with a liver biopsy later the same day. Patients underwent MRE and {sup 31}P spectroscopy on a 1.5 T whole body system. The liver biopsies were staged using an Ishak score for chronic hepatitis or a modified NAS fibrosis score for fatty liver disease. MRE increased with and was positively associated with fibrosis stage (Spearman's rank = 0.622, P < 0.001). PME/PDE was not associated with fibrosis stage (Spearman's rank = -0.041, p = 0.741). Area under receiver operating curves for MRE stiffness values were high (range 0.75-0.97). The diagnostic utility of PME/PDE was no better than chance (range 0.44-0.58). MRE-estimated liver stiffness increases with fibrosis stage and is able to dichotomise fibrosis stage groupings. We did not find a relationship between {sup 31}P MR spectroscopy and fibrosis stage. circle Magnetic resonance elastography (MRE) and MR spectroscopy can both assess the liver. (orig.)

  7. Metabolic Profile Changes of CCl₄-Liver Fibrosis and Inhibitory Effects of Jiaqi Ganxian Granule.

    Science.gov (United States)

    Wang, Ge; Li, Zehao; Li, Hao; Li, Lidan; Li, Jian; Yu, Changyuan

    2016-01-01

    Jiaqi Ganxian Granule (JGG) is a famous traditional Chinese medicine, which has been long used in clinical practice for treating liver fibrosis. However, the mechanism underlying its anti-hepatic fibrosis is still not clear. In this study, an Ultra-Performance Liquid Chromatography-Time-Of-Flight Mass Spectrometry (UPLC-TOF-MS)-based metabolomics strategy was used to profile the metabolic characteristic of serum obtained from a carbon tetrachloride (CCl₄)-induced hepatic fibrosis model in Sprague-Dawley (SD) rats with JGG treatment. Through Principal Component Analysis (PCA) and Partial Least Square Discriminant Analysis (PLS-DA), it was shown that metabolic perturbations induced by CCl₄ were inhibited after treatment of JGG, for 17 different metabolites related to CCl₄. Among these compounds, the change tendency of eight potential drug targets was restored after the intervention with JGG. The current study indicates that JGG has a significant anti-fibrosis effect on CCl₄-induced liver fibrosis in rats, which might be by regulating the dysfunction of sphingolipid metabolism, glycerophospholipid metabolism, N-acylethanolamine biosynthesis, fat digestion and absorption, while glycerophospholipid metabolism played vital roles in the inhibitory effects of JGG on hepatic fibrosis according to Metabolic Pathway Analysis (MetPA). Our findings indicated that the metabolomics approach may provide a useful tool for exploring potential biomarkers involved in hepatic fibrosis and elucidate the mechanisms underlying the action of therapies used in traditional Chinese medicine. PMID:27248993

  8. Analysis of the efficiency of FibroScan combined with serologic markers for diagnosing liver fibrosis

    Directory of Open Access Journals (Sweden)

    Dong JI

    2011-11-01

    Full Text Available Objective To determine the usefulness of transient elastography(FibroScan combined with other serologic markers in diagnosing liver fibrosis.Methods The study enrolled 313 patients with hepatitis B virus(HBV infection for routine biochemical examination,FibroScan,and liver biopsy.A Receive Operating Characteristic(ROC curve was drawn and the area under the curve was analyzed to determine the cutoff value,sensitivity,specificity,positive predictive value,and negative predictive value of FibroScan,APRI,and FIB-4 for diagnosing different stages of liver fibrosis.Results FibroScan,APRI,and FIB-4 were used to diagnose moderate liver fibrosis.The areas under the curve(AUROC were 0.791,0.792,and 0.796;the cutoff values were 9.3,0.65,and 1.15 kPa;the sensitivities were 55.1%,62.3%,and 69.1%;and specificities were 94.8%,88.3%,and 89.7%,respectively.For diagnosing liver cirrhosis,the AUROC were 0.947,0.911,and 0.953;the cutoff values were 15.4,1.14,and 2.96 kPa;the sensitivities were 90.0%,96.0%,and 88.0%;and the specificities were 87.8%,79.8%,and 92.8%,respectively.FibroScan combined with APRI or FIB-4 was used to diagnose moderate liver fibrosis,and the AUROC was 0.836,which is obviously higher than the AUROC(0.791,P < 0.05 obtained using FibroScan alone.Conclusion The combination of FibroScan with APRI or FIB-4 significantly improves the sensitivity of diagnosing moderate liver fibrosis without significantly reducing the specificity.It can be used as an alternative of liver biopsy,and in determining whether patients with transaminase levels less than twice the normal value need antiviral treatment or not.

  9. Cystamine ameliorates liver fibrosis induced by carbon tetrachloride via inhibition of tissue transglutaminase

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the anti-fibrosis effect of the tissue transglutaminase (tTG) specific inhibitor cystamine on liver fibrosis.METHODS: Sixty-eight male Sprague Dawley rats were divided into three groups: normal control, liver fibrosis control and cystamine-treated group. Liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl4), and Cystamine was administrated by intraperitoneal injection starting 2 d before the first administration of CCl4. Animals in each group were further divided into 2 subgroups according to two time points of 4 wk and 8 wk after treatment. Hepatic function, pathological evaluation (semi-quantitative scoring system, SSS) and liver hydroxyproline (Hyp)content were examined. Real-time PCR was used to detect the expression of tTG, smooth muscle alpha actin (α-SMA), tissue inhibitor of metalloproteinase 1 (TIMP-1)and collagen-1 mRNA. The expressions of tTG and α-SMA protein were detected by Western Blotting.RESULTS: Eight weeks after treatment, the SSS score of liver was significantly less in the cystamine group than that in the fibrosis control group (P < 0.01). The levels of alanine aminotransferase (ALT) and total bile acid (TBA)at the 4 wk and 8 wk time points were decreased in the cystamine group compared with those in fibrosis controls (P < 0.01). Liver hydroxyproline content at the 4 wk and 8 wk time points showed a substantial reduction in the cystamine group compared to fibrosis controls (P < 0.01).The expression of tTG, α-SMA, collagen-1, TIMP-1 mRNA and tTG, as well as α-SMA protein was downregulated in the cystamine group compared to fibrosis controls.CONCLUSION: Cystamine can ameliorate CCl4 induced liver fibrosis and protect hepatic function. The possible mechanism is related to the reduced synthesis of the extracellular matrix (ECM) caused by the inhibition of hepatic stellate cell activation and decreased expression of TIMP-1.

  10. Non-invasive index of liver fibrosis induced by alcohol, thioacetamide and schistosomal infection in mice

    Directory of Open Access Journals (Sweden)

    El-Beltagy Doha M

    2010-06-01

    Full Text Available Abstract Background Non invasive approaches will likely be increasing utilized to assess liver fibrosis. This work provides a new non invasive index to predict liver fibrosis induced in mice. Methods Fibrosis was generated by thioacetamide (TAA, chronic intake of ethanol, or infection with S. mansoni in 240 mice. Both progression and regression of fibrosis (after treatment with silymarin and/or praziquantel were monitored. The following methods were employed: (i The METAVIR system was utilized to grade and stage liver inflammation and fibosis; (ii Determination of hepatic hydroxyproline and collagen; and (iii Derivation of a new hepatic fibrosis index from the induced changes, and its prospective validation in a group of 70 mice. Results The index is composed of 4 serum variable including total proteins, γ-GT, bilirubin and reduced glutathione (GSH, measured in diseased, treated and normal mice. These parameters were highly correlated with both the histological stage and the grade. They were combined in a logarithmic formula, which non-invasively scores the severity of liver fibrosis through a range (0 to 2, starting with healthy liver (corresponding to stage 0 to advanced fibrosis (corresponding stage 3.Receiver operating characteristic curves (ROC for the accuracy of the index to predict the histological stages demonstrated that the areas under the curve (AUC were 0.954, 0.979 and 0.99 for index values corresponding to histological stages 1, 2 and 3, respectively. Also, the index was correlated with stage and grade, (0.947 and 0.859, respectively. The cut off values that cover the range between stages 0-1, 1-2 and 2-3 are 0.4, 1.12 and 1.79, respectively. The results in the validation group confirmed the accuracy of the test. The AUROC was 0.869 and there was good correlation with the stage of fibrosis and grade of inflammation. Conclusion The index fulfils the basic criteria of non-invasive marker of liver fibrosis since it is liver

  11. Staging of liver fibrosis in chronic hepatitis B patients with a composite predictive model:A comparative study

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To evaluate the efficacy of 6 noninvasive liver fibrosis models and to identify the most valuable model for the prediction of liver fibrosis stage in chronic hepatitis B(CHB) patients.METHODS:Seventy-eight CHB patients were consecutively enrolled in this study.Liver biopsy was performed and blood serum was obtained at admission.Histological diagnosis was made according to the METAVIR system.Significant fibrosis was defined as stage score ≥ 2,severe fibrosis as stage score ≥ 3.The diagnostic accuracy of ...

  12. Effects of a plasmid expressing antisense tissue inhibitor of metalloproteinase-1 on liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    JIANG Wei; WANG Ji-yao; YANG Chang-qing; LIU Wen-bin; WANG Yi-qing; HE Bo-ming

    2005-01-01

    Background No efficient therapy for liver fibrosis has been available. This study was aimed to provide evidence that the introduction of a plasmid expressing antisense tissue inhibitor of metalloproteinase-1 (TIMP-1) into a rat model of immunologically induced liver fibrosis can result in the increased activity of interstitial collagenase, thus enhancing the degradation of collagen.Methods Real-time nested polymerase chain reaction (RT-Nested-PCR) and gene recombination techniques were used to construct a rat antisense TIMP-1 recombinant plasmid that can be expressed in eukaryotic cells. Both the recombinant plasmid and an empty vector (pcDNA3) were encapsulated with glycosyl-poly-L-lysine and injected into rats suffering from pig serum-induced liver fibrosis. The expression of exogenous transfected plasmid was assessed by Northern blot, RT-PCR, and Western blot. Hepatic interstitial collagenase activity was detected using fluorescinisothiocyanate (FITC)-labeled type Ⅰ collagen. In addition to hepatic hydroxyproline content, hepatic collagen types Ⅰ and Ⅲ were detected by immunohistochemical staining, and the stages of liver fibrosis by Van Gieson staining.Results Exogenous antisense TIMP-1 was successfully expressed in vivo and could block the gene and protein expression of TIMP-1. Active and latent hepatic interstitial collagenase activities were elevated (P<0.01), hepatic hydroxyproline content and the accumulation of collagen types Ⅰ and Ⅲ were lowered, and liver fibrosis was alleviated in the antisense TIMP-1 group (P<0.01) as compared with the model group. Conclusion The results demonstrate that antisense TIMP-1 recombinant plasmids have some inhibitory effect on liver fibrosis.

  13. Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children

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    Yasser E Nassef

    2013-11-01

    Full Text Available The aim of the present study was to identify specific markers that mirror liver fibrosis progression as an alternative to biopsy when biopsy is contraindicated, especially in children. After liver biopsies were performed, serum samples from 30 hepatitis C virus (HCV paediatric patients (8-14 years were analysed and compared with samples from 30 healthy subjects. All subjects were tested for the presence of serum anti-HCV antibodies. Direct biomarkers for liver fibrosis, including transforming growth factor-β1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1, hyaluronic acid (HA, procollagen type III amino-terminal peptide (PIIINP and osteopontin (OPN, were measured. The indirect biomarkers aspartate and alanine aminotransferases, albumin and bilirubin were also tested. The results revealed a significant increase in the serum marker levels in HCV-infected children compared with the healthy group, whereas albumin levels exhibited a significant decrease. Significantly higher levels of PIIINP, TIMP-1, OPN and HA were detected in HCV-infected children with moderate to severe fibrosis compared with children with mild fibrosis (p < 0.05. The diagnostic accuracy of these direct biomarkers, represented by sensitivity, specificity and positive predictive value, emphasises the utility of PIIINP, TIMP-1, OPN and HA as indicators of liver fibrosis among HCV-infected children.

  14. Automatic scale-independent morphology-based quantification of liver fibrosis

    Science.gov (United States)

    Coatelen, J.; Albouy-Kissi, A.; Albouy-Kissi, B.; Coton, J.-.; Sifre, L.; Dechelotte, P.; Abergel, A.

    2014-03-01

    The pathologists have an expert knowledge of the classification of fibrosis. However, the differentiation of intermediate grades (ex: F2-F3) may cause significant inter-expert variability. A quantitative morphological marker is presented in this paper, introducing a local-based image analysis on human liver tissue slides. Having defined hotspots in slides, the liver collagen is segmented with a color deconvolution technique. After removing the regions of interstitial fibrosis, the fractal dimension of the fibrosis regions is computed by using the boxcounting algorithm. As a result, a quantitative index provides information about the grade of the fibrosis regions and thus about the tissue damage. The index does not take account of the pathological status of the patient but it allows to discriminate accurately and objectively the intermediate grades for which the expert evaluation is partially based on the fibrosis development. This method was used on twelve human liver biopsies (from six different patients) using constant conditions of preparation, acquisition (same image resolution, magnification x20) and box-counting parameters. The liver tissue slides were labeled by a pathologist using METAVIR scores. A reasonably good correlation is observed between the METAVIR scores and the proposed morphological index (p-value < 0:001). Furthermore, the method is reproducible and scale independent which is appropriate for biological high resolution images. Nevertheless, further work is needed to define reference values for this index in such a way that METAVIR subdomains will be well delimited.

  15. Fibrosis assessment: impact on current management of chronic liver disease and application of quantitative invasive tools.

    Science.gov (United States)

    Wang, Yan; Hou, Jin-Lin

    2016-05-01

    Fibrosis, a common pathogenic pathway of chronic liver disease (CLD), has long been indicated to be significantly and most importantly associated with severe prognosis. Nowadays, with remarkable advances in understanding and/or treatment of major CLDs such as hepatitis C, B, and nonalcoholic fatty liver disease, there is an unprecedented requirement for the diagnosis and assessment of liver fibrosis or cirrhosis in various clinical settings. Among the available approaches, liver biopsy remains the one which possibly provides the most direct and reliable information regarding fibrosis patterns and changes in the parenchyma at different clinical stages and with different etiologies. Thus, many endeavors have been undertaken for developing methodologies based on the strategy of quantitation for the invasive assessment. Here, we analyze the impact of fibrosis assessment on the CLD patient care based on the data of recent clinical studies. We discuss and update the current invasive tools regarding their technological features and potentials for the particular clinical applications. Furthermore, we propose the potential resolutions with application of quantitative invasive tools for some major issues in fibrosis assessment, which appear to be obstacles against the nowadays rapid progress in CLD medicine. PMID:26742762

  16. A Novel Fibrosis Index Comprising a Non-Cholesterol Sterol Accurately Predicts HCV-Related Liver Cirrhosis

    DEFF Research Database (Denmark)

    Ydreborg, Magdalena; Lisovskaja, Vera; Lagging, Martin;

    2014-01-01

    significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5-6, as the outcome variable. A new index, referred to...

  17. Real-time elastography with a novel quantitative technology for assessment of liver fibrosis in chronic hepatitis B

    International Nuclear Information System (INIS)

    Background: The accurate evaluation of liver fibrosis stage is important in determining the treatment strategy. The limitations of percutaneous liver biopsy as the gold standard are obvious for invasion. Real-time elastography with conventional ultrasound probes and a new quantitative technology for diffuse histological lesion is a novel approach for staging of liver fibrosis. Purpose: This study aimed to evaluate the value of real-time tissue elastography with a new quantitative technology for the assessment of liver fibrosis stage. Materials and methods: Real-time elastography was performed in 55 patients with liver fibrosis and chronic hepatitis B and in 20 healthy volunteers. Eleven parameters for every patient in colorcode image obtained from the real-time elastography were analyzed with principal components analysis. We analyzed the correlation between elasticity index and liver fibrosis stage and the accuracy of real-time elastography for liver fibrosis staging. Additionally, aspartate transaminase-to-platelet ratio index was also included in the analysis. Results: The Spearman's correlation coefficient between the elasticity index and the histologic fibrosis stage was 0.81, which is highly significant (p 0.05), respectively. Conclusions: Real-time elastography with a new quantitative technology for diffuse histological lesion is a new and promising sonography-based noninvasive method for the assessment of liver fibrosis in patients with chronic hepatitis B.

  18. Diffusion-weighted MRI versus transient elastography in quantification of liver fibrosis in patients with chronic cholestatic liver diseases

    Energy Technology Data Exchange (ETDEWEB)

    Kovač, Jelena Djokić, E-mail: jelenadjokic2003@yahoo.co.uk [Center for Radiology and Magnetic Resonance Imaging, Clinical Center of Serbia, Pasterova 2, 11000 Belgrade (Serbia); Daković, Marko [Center for Radiology and Magnetic Resonance Imaging, Clinical Center of Serbia, Faculty of Physical Chemistry, University of Belgrade, Pasterova 2, 11000 Belgrade (Serbia); Stanisavljević, Dejana [Institute for Statistics, Faculty of Medicine, University of Belgrade, Dr. Subotica 8, 11000 Belgrade (Serbia); Alempijević, Tamara; Ješić, Rada [Clinic for Gastroenterohepatology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Pasterova 2, 11000 Belgrade (Serbia); Seferović, Petar [Institute for Cardiovascular Diseases, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Pasterova 2, 11000 Belgrade (Serbia); Maksimović, Ružica [Center for Radiology and Magnetic Resonance Imaging, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade (Serbia)

    2012-10-15

    Purpose: To evaluate the diagnostic value of diffusion-weighted magnetic resonance imaging (DWMRI) and transient elastography (TE) in quantification of liver fibrosis in patients with chronic cholestatic liver diseases. Materials and methods: Forty-five patients underwent DWMRI, TE, and liver biopsy for staging of liver fibrosis. Apparent diffusion coefficient (ADC) was calculated for six locations in the liver for combination of five diffusion sensitivity values b = 0, 50, 200, 400 and 800 s/mm{sup 2}. A receiver operating characteristic (ROC) analysis was performed to determine the diagnostic performance of DWMRI and TE. Segmental ADC variations were evaluated by means of coefficient of variation. Results: The mean ADCs (×10{sup −3} mm{sup 2}/s; b = 0–800 s/mm{sup 2}) were significantly different at stage F1 versus F ≥ 2 (p < 0.05) and F2 versus F4. However, no significant difference was found between F2 and F3. For prediction of F ≥ 2 and F ≥ 3 areas under the ROC curves were 0.868 and 0.906 for DWMRI, and 0.966 and 0.960 for TE, respectively. The sensitivity and specificity were 90.9% and 89.3% for F ≥ 2 (ADC ≤ 1.65), and 92.3% and 92.1% for F ≥ 3 (ADC ≤ 1.63). Segmental ADC variation was lowest for F4 (CV = 9.54 ± 6.3%). Conclusion: DWMRI and TE could be used for assessment of liver fibrosis with TE having higher diagnostic accuracy and DWMRI providing insight into liver fibrosis distribution.

  19. Diffusion-weighted MRI versus transient elastography in quantification of liver fibrosis in patients with chronic cholestatic liver diseases

    International Nuclear Information System (INIS)

    Purpose: To evaluate the diagnostic value of diffusion-weighted magnetic resonance imaging (DWMRI) and transient elastography (TE) in quantification of liver fibrosis in patients with chronic cholestatic liver diseases. Materials and methods: Forty-five patients underwent DWMRI, TE, and liver biopsy for staging of liver fibrosis. Apparent diffusion coefficient (ADC) was calculated for six locations in the liver for combination of five diffusion sensitivity values b = 0, 50, 200, 400 and 800 s/mm2. A receiver operating characteristic (ROC) analysis was performed to determine the diagnostic performance of DWMRI and TE. Segmental ADC variations were evaluated by means of coefficient of variation. Results: The mean ADCs (×10−3 mm2/s; b = 0–800 s/mm2) were significantly different at stage F1 versus F ≥ 2 (p < 0.05) and F2 versus F4. However, no significant difference was found between F2 and F3. For prediction of F ≥ 2 and F ≥ 3 areas under the ROC curves were 0.868 and 0.906 for DWMRI, and 0.966 and 0.960 for TE, respectively. The sensitivity and specificity were 90.9% and 89.3% for F ≥ 2 (ADC ≤ 1.65), and 92.3% and 92.1% for F ≥ 3 (ADC ≤ 1.63). Segmental ADC variation was lowest for F4 (CV = 9.54 ± 6.3%). Conclusion: DWMRI and TE could be used for assessment of liver fibrosis with TE having higher diagnostic accuracy and DWMRI providing insight into liver fibrosis distribution

  20. Comparison of ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis

    OpenAIRE

    Friedrich-Rust Mireen; Rosenberg William; Parkes Julie; Herrmann Eva; Zeuzem Stefan; Sarrazin Christoph

    2010-01-01

    Abstract Background FibroTest (FT) is the most frequently used serum fibrosis marker and consists of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoproteinA1, haptoglobin, GGT, bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of an algorithm of three fibrosis markers (hyaluronic acid, amino-terminal propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1). While a systematic review has shown comparable results for both individual markers, ...

  1. Texture analysis of liver fibrosis microscopic images: a study on the effect of biomarkers

    Institute of Scientific and Technical Information of China (English)

    Amr Amin; Doaa Mahmoud-Ghoneim

    2011-01-01

    Chronic hepatic injury results in liver fibrosis with eventual progression to irreversible cirrhosis. Liver fibrogenesis involves the activation of the quiescent hepatic stellate cell into an activated myofibroblast that is characterized by α-smooth muscle actin (α-SMA) expression and the production of collagens (types Ⅰ and Ⅲ). In the present study,rats were randomly divided into three groups: (i) control group, where rats were only treated with a vehicle; (ii) fibrosis group, where rats were treated with carbon tetrachloride (CCl4) to induce liver fibrosis; and (iii) silymarin group,where rats were protected with silymarin during CCl4 treatment. Rats were sacrificed and sections of liver tissue were counterstained with hematoxylin and eosin and Masson's trichrome. Other sections were immunostained using collagens and α-SMA primary antibodies. Fibrosis was confirmed using serum marker measurements. Microscopic images of the stained sections were acquired and digitized.The Biomarker Index of Fibrosis (BIF) was calculated from the images by quantifying the percentage of stained fibers.Statistical methods of texture analysis (TA), namely cooccurrence and run-length matrices, were applied on the digital images followed by classification using agglomerative hierarchical clustering and linear discriminant analysis with cross validation. TA applied on different biomarkers was successful in discriminating between the groups,showing 100% sensitivity and specificity for classification between the control and fibrosis groups using any biomarker. Some classification attempts showed dependence on the biomarker used, especially for classification between the silymarin and fibrosis groups, which showed optimal results using Masson's trichrome. TA results were consistent with both BIF and serum marker measurements.

  2. Automated biphasic morphological assessment of hepatitis B-related liver fibrosis using second harmonic generation microscopy

    Science.gov (United States)

    Wang, Tong-Hong; Chen, Tse-Ching; Teng, Xiao; Liang, Kung-Hao; Yeh, Chau-Ting

    2015-08-01

    Liver fibrosis assessment by biopsy and conventional staining scores is based on histopathological criteria. Variations in sample preparation and the use of semi-quantitative histopathological methods commonly result in discrepancies between medical centers. Thus, minor changes in liver fibrosis might be overlooked in multi-center clinical trials, leading to statistically non-significant data. Here, we developed a computer-assisted, fully automated, staining-free method for hepatitis B-related liver fibrosis assessment. In total, 175 liver biopsies were divided into training (n = 105) and verification (n = 70) cohorts. Collagen was observed using second harmonic generation (SHG) microscopy without prior staining, and hepatocyte morphology was recorded using two-photon excitation fluorescence (TPEF) microscopy. The training cohort was utilized to establish a quantification algorithm. Eleven of 19 computer-recognizable SHG/TPEF microscopic morphological features were significantly correlated with the ISHAK fibrosis stages (P 0.82 for liver cirrhosis detection. Since no subjective gradings are needed, interobserver discrepancies could be avoided using this fully automated method.

  3. Liver fibrosis and Gd-EOB-DTPA-enhanced MRI: A histopathologic correlation.

    Science.gov (United States)

    Verloh, Niklas; Utpatel, Kirsten; Haimerl, Michael; Zeman, Florian; Fellner, Claudia; Fichtner-Feigl, Stefan; Teufel, Andreas; Stroszczynski, Christian; Evert, Matthias; Wiggermann, Philipp

    2015-01-01

    Gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) is a hepatocyte-specific MRI contrast agent. Because the hepatic uptake of Gd-EOB-DTPA depends on the integrity of the hepatocyte mass, this uptake can be quantified to assess liver function. We report the relationship between the extent of Gd-EOB-DTPA uptake and the degree of liver fibrosis. T1-weighted volume-interpolated breath-hold examination (VIBE) sequences with fat suppression were acquired before and 20 minutes after contrast injection. Strong correlations of the uptake characteristics of Gd-EOB-DTPA with the relative enhancement (RE) of the liver parenchyma and the grade of fibrosis/cirrhosis, classified using the Ishak scoring system, were observed. The subdivisions between the grades of liver fibrosis based on RE were highly significant for all combinations, and a ROC revealed sensitivities ≥82% and specificities ≥87% for all combinations. MR imaging is a satisfactorily sensitive method for the assessment of liver fibrosis/cirrhosis. PMID:26478097

  4. Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

    International Nuclear Information System (INIS)

    Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH

  5. Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

    Energy Technology Data Exchange (ETDEWEB)

    Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Coelho, A.M.M. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Xerfan, M.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Cogliati, B. [Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); Barbeiro, D.F. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Mazo, D.F.C. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Kubrusly, M.S.; D' Albuquerque, L.A.C. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Souza, H.P. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Carrilho, F.J.; Oliveira, C.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2015-02-24

    Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg{sup -1}·day{sup -1} by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

  6. Liver Fibrosis progression using Fibroscan in HIV/HCV coinfected patients with undetectable HIV viral load

    Directory of Open Access Journals (Sweden)

    Laura Perez-Martinez

    2014-11-01

    Full Text Available Introduction: Several factors such as duration of infection, age, male gender, consumption of alcohol, HIV infection and low CD4 count have been associated with fibrosis progression rate. However, it is relatively scarce, the knowledge about the liver fibrosis progression rate in HIV-infected patients with undetectable HIV viral load (VL. For this reason, we performed the present study. Materials and Methods: Observational and multicenter study (2008–2012 conducted in four hospitals of the northern Spain. HIV/HCV (hepatitis c virus coinfected patients ≥18 years on stable combination antiretroviral therapy (cART (≥6 months and with a HIV VL <50 copies/mL were selected to analyze their liver fibrosis progression. Fibrosis progression was assessed using a Fibroscan® (502 STEP 3 model and measuring a basal test and a second one at least 12 months apart from baseline. This evolution was compared with different variables such as duration of HIV/HCV coinfection, gender, age, previous treatment for HCV, HCV genotype, CD4 lymphocyte counts and the cART employed at the basal test. Results: A total of 608 patients were included (median age 29.4 years, 71.7% men. Of these, 463 patients met the inclusion criteria. In these patients, the liver fibrosis progression was nearly flat and the only variables related to a higher liver fibrosis progression were the increasing age of the patients (p=0.02 and the duration of the coinfection (p=0.001. CD4 lymphocyte counts showed a tendency to improved liver fibrosis (p=0.056. Conclusions: In HIV/HCV coinfected patients on stable cART and HIV undetectable VL, the increase in liver fibrosis rate progression was nearly flat, although it was significantly associated with the duration of the coinfection and the age of the patient. The beneficial effects of the cART were independent of the antiretroviral drug employed. A tendency to a lower fibrosis progression was observed in those patients with a higher CD4 count.

  7. Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs

    International Nuclear Information System (INIS)

    Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48 h, viability was assessed by ATP and gene expression of PDGF-B and TGF-β1 and the fibrosis markers Hsp47, αSma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGFβ-pathway inhibitors, were determined. After 48 h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-β1 was not changed. Hsp47, αSma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48 h, which was further increased by PDGF-BB and TGF-β1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGFβ-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevated TGF-β1 gene expression and the limited effect of the TGFβ-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway. - Highlights: • During culture, fibrosis markers increased in precision-cut liver slices (PCLS). • Gene expression of PDGF-β was increased, while TGFβ was not changed in rat PCLS. • PDGF-pathway inhibitors down-regulated this increase of fibrosis markers. • TGFβ-pathway inhibitors had only

  8. Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Westra, Inge M. [Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen (Netherlands); Oosterhuis, Dorenda [Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen (Netherlands); Groothuis, Geny M.M. [Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen (Netherlands); Olinga, Peter, E-mail: p.olinga@rug.nl [Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen (Netherlands)

    2014-01-15

    Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48 h, viability was assessed by ATP and gene expression of PDGF-B and TGF-β1 and the fibrosis markers Hsp47, αSma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGFβ-pathway inhibitors, were determined. After 48 h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-β1 was not changed. Hsp47, αSma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48 h, which was further increased by PDGF-BB and TGF-β1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGFβ-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevated TGF-β1 gene expression and the limited effect of the TGFβ-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway. - Highlights: • During culture, fibrosis markers increased in precision-cut liver slices (PCLS). • Gene expression of PDGF-β was increased, while TGFβ was not changed in rat PCLS. • PDGF-pathway inhibitors down-regulated this increase of fibrosis markers. • TGFβ-pathway inhibitors had only

  9. Fuzheng Huayu Recipe Ameliorates Liver Fibrosis by Restoring Balance between Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Hepatic Stellate Cells.

    Science.gov (United States)

    Pan, Qin; Wang, Yu-Qin; Li, Guang-Ming; Duan, Xiao-Yan; Fan, Jian-Gao

    2015-01-01

    Activation of hepatic stellate cells (HSCs) depending on epithelial-to-mesenchymal transition (EMT) reflects the key event of liver fibrosis. Contrastively, mesenchymal-to-epithelial transition (MET) of HSCs facilitates the fibrosis resolution. Here we investigated the effect of Fuzheng Huayu (FZHY) recipe, a Chinese herbal decoction made of Radix Salviae Miltiorrhizae, Semen Persicae, Cordyceps sinensis, Pollen Pini, and Gynostemma pentaphyllum, on liver fibrosis concerning the balance of EMT and MET in HSCs. In contrast to the increased TGF-β 1/BMP-7 ratio in activated HSCs, FZHY administration induced significant upregulation of BMP-7 and downregulation of TGF-β 1 at both transcription and translation levels. Restoration of TGF-β 1/BMP-7 ratio inhibited the expression of p38 MAPK and phosphorylated p38 MAPK, resulting in the reversal of epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) as characterized by the abolishment of EMT markers (α-SMA and desmin) and reoccurrence of MET marker (E-cadherin). In vivo treatment of FZHY recipe also demonstrated the statistical reduction of activated HSCs with EMT phenotype, which attenuated the carbon tetrachloride- (CCl4-) induced liver fibrosis in a dose-dependent manner. These findings may highlight a novel antifibrotic role of FZHY recipe on the basis of rebalancing EMT and MET in HSCs. PMID:26881209

  10. Fuzheng Huayu Recipe Ameliorates Liver Fibrosis by Restoring Balance between Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Hepatic Stellate Cells

    Directory of Open Access Journals (Sweden)

    Qin Pan

    2015-01-01

    Full Text Available Activation of hepatic stellate cells (HSCs depending on epithelial-to-mesenchymal transition (EMT reflects the key event of liver fibrosis. Contrastively, mesenchymal-to-epithelial transition (MET of HSCs facilitates the fibrosis resolution. Here we investigated the effect of Fuzheng Huayu (FZHY recipe, a Chinese herbal decoction made of Radix Salviae Miltiorrhizae, Semen Persicae, Cordyceps sinensis, Pollen Pini, and Gynostemma pentaphyllum, on liver fibrosis concerning the balance of EMT and MET in HSCs. In contrast to the increased TGF-β1/BMP-7 ratio in activated HSCs, FZHY administration induced significant upregulation of BMP-7 and downregulation of TGF-β1 at both transcription and translation levels. Restoration of TGF-β1/BMP-7 ratio inhibited the expression of p38 MAPK and phosphorylated p38 MAPK, resulting in the reversal of epithelial-to-mesenchymal transition (EMT to mesenchymal-to-epithelial transition (MET as characterized by the abolishment of EMT markers (α-SMA and desmin and reoccurrence of MET marker (E-cadherin. In vivo treatment of FZHY recipe also demonstrated the statistical reduction of activated HSCs with EMT phenotype, which attenuated the carbon tetrachloride- (CCl4- induced liver fibrosis in a dose-dependent manner. These findings may highlight a novel antifibrotic role of FZHY recipe on the basis of rebalancing EMT and MET in HSCs.

  11. Protective Effect of the Total Saponins from Rosa laevigata Michx Fruit against Carbon Tetrachloride-Induced Liver Fibrosis in Rats

    Directory of Open Access Journals (Sweden)

    Deshi Dong

    2015-06-01

    Full Text Available In this study, the protective effect of the total saponins from Rosa laevigata Michx (RLTS against liver fibrosis induced by carbon tetrachloride (CCl4 in rats was evaluated. The results showed that RLTS significantly rehabilitated the levels of alanine aminotransferase, aspartate aminotransferase, malondialdehyde, glutathione, glutathione peroxidase, catalase, superoxide dismutase, hydroxyproline, α-smooth muscle actin, collagen I, collagen III and fibronectin, which were confirmed using H&E, Sirius Red and Masson histopathological assays. Further research indicated that RLTS markedly reduced cytochrome P450 2E1 activity, attenuated oxidative stress, and suppressed inflammation. In addition, RLTS facilitated matrix degradation through down-regulation of matrix metalloproteinase2, matrix metalloproteinase 9 and metalloproteinases1, and exerted the anti-fibrotic effects through affecting transforming growth factor β/Smad, focal adhesion kinase/phosphatidylinositol-3-kinase/amino kinase terminal/70-kDa ribosomal S6 Kinase (FAK-PI3K-Akt-p70S6K and mitogen-activated protein kinase (MAPK signaling pathways. Taken together, our data indicate that RLTS can be applied as one effective candidate for the treatment of liver fibrosis in the future.

  12. Liver fibrosis and tissue architectural change measurement using fractal-rectified metrics and Hurst's exponent

    Institute of Scientific and Technical Information of China (English)

    Nicola Dioguardi; Fabio Grizzi; Barbara Franceschini; Paola Bossi; Carlo Russo

    2006-01-01

    AIM: To provide the accurate alternative metrical means of monitoring the effects of new antiviral drugs on the reversal of newly formed collagen.METHODS: Digitized histological biopsy sections taken from 209 patients with chronic C virus hepatitis with different grade of fibrosis or cirrhosis, were measured by means of a new, rapid, user-friendly, fully computeraided method based on the international system meter rectified using fractal principles.RESULTS: The following were described: geometric perimeter, area and wrinkledness of fibrosis; the collation of the Knodell, Sheuer, Ishak and METAVIR scores with fractal-rectified metric measurements; the meaning of the physical composition of fibrosis in relation to the magnitude of collagen islets; the intra- and inter-biopsy sample variability of these parameters; the "staging"of biopsy sections indicating the pathway covered by fibrosis formation towards its maximum known value;the quantitative liver tissue architectural changes with the Hurst exponent.CONCLUSION: Our model provides the first metrical evaluations of the geometric properties of fibrosis and the quantitative architectural changes of the liver tissue.The representativeness of histological sections of the whole liver is also discussed in the light of the results obtained with the Hurst coefficient.

  13. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects

    OpenAIRE

    Liedtke, Christian; Luedde, Tom; Sauerbruch, Tilman; Scholten, David; Streetz, Konrad; Tacke, Frank; Tolba, René; Trautwein, Christian; Trebicka, Jonel; Weiskirchen, Ralf

    2013-01-01

    Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between matrix-producing hepatic stellate cells and an abundance of liver-resident and infiltrating cells. Investigation of these processes requires in vitro and in vivo experimental work in animals. However, the use of animals in translational research will be increasingly challenged, at least in countries of the European Union, because of the adoption of new animal welfare rules in 20...

  14. Protective effect of the ω-3 polyunsaturated fatty acids on the schistosomiasis liver fibrosis in mice

    OpenAIRE

    Wu, Yuan; Liang, Yu; Zhu, Yi; Gao, Yongqiang; Chen, Hu; Zhang, Yukuai; Yin, Weiguo; Li, Yingju; Wang, Kegeng; Xiao, Jianhua

    2015-01-01

    This study aims to observe the effect of ω-3 polyunsaturated fatty acids on initiation and elimination of the schistosomiasis inflammatory response and liver fibrosis. The mice infected with the cercariae of Schistosoma japonicum (20 ± cercarie per mice) were separated randomly into several groups. After 60 days, liver tissue samples of all mice were sectioned. Hematoxylin-eosin (HE) staining, Masson staining, the enzyme-linked immunosorbent assay (ELISA), and flow cytometry (FCM) were perfor...

  15. Analysis of the efficiency of FibroScan combined with serologic markers for diagnosing liver fibrosis

    OpenAIRE

    Ji, Dong; SHAO, QING; Han, Ping; Zhang, Jian; Xiao-xia NIU; Li, Bing; Li, Fan; Chen, Guo-Feng

    2011-01-01

    Objective To determine the usefulness of transient elastography(FibroScan) combined with other serologic markers in diagnosing liver fibrosis.Methods The study enrolled 313 patients with hepatitis B virus(HBV) infection for routine biochemical examination,FibroScan,and liver biopsy.A Receive Operating Characteristic(ROC) curve was drawn and the area under the curve was analyzed to determine the cutoff value,sensitivity,specificity,positive predictive value,and negative predictive value of Fib...

  16. Angiogenic factor with G patch and FHA domains 1 (Aggf1) regulates liver fibrosis by modulating TGF-β signaling.

    Science.gov (United States)

    Zhou, Bisheng; Zeng, Sheng; Li, Luyuang; Fan, Zhiwen; Tian, Wenfang; Li, Min; Xu, Huihui; Wu, Xiaoyan; Fang, Mingming; Xu, Yong

    2016-06-01

    Fibrosis is a common pathophysiological process following liver injury and can lead to, if left unattended to, irreversible end-stage liver disease such as cirrhosis. Hepatic stellate cells (HSCs) are a major contributor to liver fibrosis. Here we investigated the involvement of angiogenic factor with G patch and FHA domains 1 (Aggf1) in HSC activation and the underlying mechanisms. Aggf1 expression was down-regulated in the livers in three different mouse models of liver fibrosis following injury. Aggf1 expression was also suppressed in activated HSCs when compared to quiescent HSCs. Over-expression of Aggf1 alleviated liver fibrosis in mice and in cultured HSCs. RNA-sequencing (RNA-seq) analysis performed in HSCs revealed that Aggf1-dependent transcription regulates several key fibrogenic pathways. Mechanistically, Aggf1 regulated liver fibrogenesis by forming a complex with the inhibitor SMAD protein (SMAD7) thereby leading to diminished SMAD3 binding to the pro-fibrogenic gene promoters. On the contrary, SMAD7 knockdown abrogated the effect of Aggf1 and rescued HSC activation. Aggf1 expression was silenced during HSC activation/liver fibrogenesis as a result of DNA methylation. Treatment with a DNA methyltransferase inhibitor (5-Azacytidine) restored Aggf1 expression and repressed liver fibrosis in an Aggf1-dependent manner. In conclusion, our data illustrate a previously unknown role for Aggf1 and shed light on the development of novel therapeutic solutions against liver fibrosis. PMID:26850475

  17. Iron deposition and fat accumulation in dimethylnitrosamine-induced liver fibrosis in rat

    Institute of Scientific and Technical Information of China (English)

    Jin-Yang He; Wen-Hua Ge; Yuan Chen

    2007-01-01

    AIM: To investigate if iron deposition and fat accumulation in the liver play a pathogenetic role in dimethylnitrosamine (DMN)-induced liver fibrosis in rat.METHODS: Thirty rats were treated with DMN at does consecutive days of 10 μL/kg daily, i.p., for 3 consecutive day each week for 4 wk. Rats (n = 30) were sacrificed on the first day (model group A) and 21st d (model group B) after cessation of DMN injection. The control group (n = 10) received an equivalent amount of saline. Liver tissues were stained with hematoxylin & eosin (HE) and Masson and Prussian blue assay and oberserved under electron microscopy. Serum alanine aminotransferase (ALT)and liver tissue hydroxyproline (Hyp) content were tested.RESULTS: The liver fibrosis did not automaticallyreverse, which was similar to previous reports, the perilobular deposition of iron accompanied with collagen showed marked characteristics at both the first and 21st d after cessation of DMN injection. However, fat accumulation in hepatocytes occurred only at the 21st d after cessation of DMN injection.CONCLUSION: Iron deposition and fat accumulation may play important roles in pathological changes in DMN-induced rat liver fibrosis. The detailed mechanisms of these characteristics need further research.

  18. Routine blood tests to predict liver fibrosis in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Yung-Yu Hsieh; Shui-Yi Tung; Kamfai Lee; Cheng-Shyong Wu; Kuo-Liang Wei; Chien-Heng Shen; Te-Sheng Chang; Yi-Hsiung Lin

    2012-01-01

    AIM:To verify the usefulness of FibroQ for predicting fibrosis in patients with chronic hepatitis C,compared with other noninvasive tests.METHODS:This retrospective cohort study included 237 consecutive patients with chronic hepatitis C who had undergone percutaneous liver biopsy before treatment.FibroQ,aspartate aminotransferase (AST)/alanine aminotransferase ratio (AAR),AST to platelet ratio index,cirrhosis discriminant score,age-platelet index (API),Pohl score,FIB-4 index,and Lok's model were calculated and compared.RESULTS:FibroQ,FIB-4,AAR,API and Lok's model results increased significantly as fibrosis advanced (analysis of variance test:P < 0.001).FibroQ trended to be superior in predicting significant fibrosis score in chronic hepatitis C compared with other noninvasive tests.CONCLUSION:FibroQ is a simple and useful test for predicting significant fibrosis in patients with chronic hepatitis C.

  19. Elastographic assessment of liver fibrosis in children: A prospective single center experience

    Energy Technology Data Exchange (ETDEWEB)

    Marginean, Cristina Oana, E-mail: marginean.oana@gmail.com [Department of Paediatrics, University of Medicine and Pharmacy of Tg. Mures (Romania); Marginean, Claudiu, E-mail: marginean.claudiu@gmail.com [Department of Obstetrics and Gynecology, University of Medicine and Pharmacy of Tg. Mures (Romania)

    2012-08-15

    Background: The assessment of liver damage in various disease states relies on a combination of clinical findings, biochemical parameters and invasive tests such as liver biopsy. The ultrasound elastography has emerged as a potential alternative test, providing quantifiable information on the elasticity/stiffness of the examined-tissues. We assessed the performance of ultrasound elastography using real-time Acoustic Radiation Force Imaging (ARFI) technology in evaluating the degree of liver fibrosis in children with and without liver disease. Methods: Children aged 0-18 years, hospitalized in the Emergency Clinical County Hospital Tg. Mures, Romania, between September 15, 2010 and January 15, 2011, were eligible for the study. Four groups were recruited as follow: patients with liver disease in the setting of various malignant disorders, children with non-malignant liver disease, overweight and obese children and healthy controls. The liver tissue elasticity was assessed in each individual using Shear Wave Velocity (SWV). Biochemical tests included transaminase levels. 19 children with chronic liver disease underwent biopsies. SWV was measured globally and separately for the liver-segments 1 and 8. Correlations between the SWV and laboratory test were established using non-parametric Spearman correlation test. Results: A total of 103 children underwent liver ultrasound elastographic assessments. Of these, 39 had malignancies, 19 had various chronic liver diseases, 13 had nonalcoholic fatty liver disease (NAFLD), and 32 were healthy controls. The transaminase values differed significantly between children with liver diseases and controls. In normal controls SWV values in the 1st segment were significantly lower compared to those in the in 8th segment of the liver (p = 0.0216). In the group with hepatic steatosis, the SWV values were statistically higher compared to those in healthy controls. Positive statistical correlations have been established between AST and SWV

  20. Elastographic assessment of liver fibrosis in children: A prospective single center experience

    International Nuclear Information System (INIS)

    Background: The assessment of liver damage in various disease states relies on a combination of clinical findings, biochemical parameters and invasive tests such as liver biopsy. The ultrasound elastography has emerged as a potential alternative test, providing quantifiable information on the elasticity/stiffness of the examined-tissues. We assessed the performance of ultrasound elastography using real-time Acoustic Radiation Force Imaging (ARFI) technology in evaluating the degree of liver fibrosis in children with and without liver disease. Methods: Children aged 0–18 years, hospitalized in the Emergency Clinical County Hospital Tg. Mures, Romania, between September 15, 2010 and January 15, 2011, were eligible for the study. Four groups were recruited as follow: patients with liver disease in the setting of various malignant disorders, children with non-malignant liver disease, overweight and obese children and healthy controls. The liver tissue elasticity was assessed in each individual using Shear Wave Velocity (SWV). Biochemical tests included transaminase levels. 19 children with chronic liver disease underwent biopsies. SWV was measured globally and separately for the liver-segments 1 and 8. Correlations between the SWV and laboratory test were established using non-parametric Spearman correlation test. Results: A total of 103 children underwent liver ultrasound elastographic assessments. Of these, 39 had malignancies, 19 had various chronic liver diseases, 13 had nonalcoholic fatty liver disease (NAFLD), and 32 were healthy controls. The transaminase values differed significantly between children with liver diseases and controls. In normal controls SWV values in the 1st segment were significantly lower compared to those in the in 8th segment of the liver (p = 0.0216). In the group with hepatic steatosis, the SWV values were statistically higher compared to those in healthy controls. Positive statistical correlations have been established between AST and

  1. Comparison on Efficacy between Astragalus-Polygonum Anti-Fibrosis Decoction and Jinshuibao (金水宝) Capsule in Treating Liver Fibrosis of Chronic Hepatitis B

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To observe the efficacy of Astragalus-Polygonum Anti-Fibrosis decoction (APAFD)and Jinshuibao capsule (JSBC) in treating liver fibrosis of chronic hepatitis B. Methods: Ninety-two cases of liver fibrosis of chronic hepatitis B were randomly divided into group A and group B. Patients in group A received APAFD for 48 weeks, and in group B, they received JSBC for 48 weeks. The effects on the level change of hyaluronic acid (HA), laminin (LN), pro-collagen Ⅲ (PCⅢ) and collagen Ⅳ (CⅣ) as well as liver functional tests and liver biochemical parameters before and after treatment were observed.Results: Level of serum HA, LN, PCⅢ and CⅣ in group A declined more obviously than that of group B, the difference was significant (P<0.01). The liver functional tests such as total bilirubin (TB), alanine aminotransferase (ALT), albumin/globulin (A/G) ratio, hepatitis related serum biochemical parameters such as cholylglycine (CG), serum ferritin (SF), prealbumin (PC) of group A were all improved more significantly than that of group B (P<0.01).Conclusion: APAFD is more effective than JSBC in treating liver fibrosis of chronic hepatitis B and in the inhibition of hepatic inflammation, hence it is a good composite Chinese herbal preparation against liver fibrosis.

  2. Berberine Inhibition of Fibrogenesis in a Rat Model of Liver Fibrosis and in Hepatic Stellate Cells

    Directory of Open Access Journals (Sweden)

    Ning Wang

    2016-01-01

    Full Text Available Aim. To examine the effect of berberine (BBR on liver fibrosis and its possible mechanisms through direct effects on hepatic stellate cells (HSC. Methods. The antifibrotic effect of BBR was determined in a rat model of bile duct ligation- (BDL- induced liver fibrosis. Multiple cellular and molecular approaches were introduced to examine the effects of BBR on HSC. Results. BBR potently inhibited hepatic fibrosis induced by BDL in rats. It exhibited cytotoxicity to activated HSC at doses nontoxic to hepatocytes. High doses of BBR induced apoptosis of activated HSC, which was mediated by loss of mitochondrial membrane potential and Bcl-2/Bax imbalance. Low doses of BBR suppressed activation of HSC as evidenced by the inhibition of α-smooth muscle actin (α-SMA expression and cell motility. BBR did not affect Smad2/3 phosphorylation but significantly activated 5′ AMP-activated protein kinase (AMPK signalling, which was responsible for the transcriptional inhibition by BBR of profibrogenic factors α-SMA and collagen in HSC. Conclusion. BBR is a promising agent for treating liver fibrosis through multiple mechanisms, at least partially by directly targeting HSC and by inhibiting the AMPK pathway. Its value as an antifibrotic drug in patients with liver disease deserves further investigation.

  3. Morphometric alterations, steatosis, fibrosis and active caspase-3 detection in carbamate bendiocarb treated rabbit liver

    Czech Academy of Sciences Publication Activity Database

    Petrovová, E.; Purzyc, H.; Mazenský, D.; Luptáková, L.; Torma, N.; Sopoliga, I.; Sedmera, David

    2015-01-01

    Roč. 30, č. 2 (2015), s. 212-222. ISSN 1520-4081 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : bendiocarb * caspase-3 activity * fibrosis * toxicity * rabbit * liver Subject RIV: EA - Cell Biology Impact factor: 3.197, year: 2014

  4. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects.

    Science.gov (United States)

    Liedtke, Christian; Luedde, Tom; Sauerbruch, Tilman; Scholten, David; Streetz, Konrad; Tacke, Frank; Tolba, René; Trautwein, Christian; Trebicka, Jonel; Weiskirchen, Ralf

    2013-01-01

    Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between matrix-producing hepatic stellate cells and an abundance of liver-resident and infiltrating cells. Investigation of these processes requires in vitro and in vivo experimental work in animals. However, the use of animals in translational research will be increasingly challenged, at least in countries of the European Union, because of the adoption of new animal welfare rules in 2013. These rules will create an urgent need for optimized standard operating procedures regarding animal experimentation and improved international communication in the liver fibrosis community. This review gives an update on current animal models, techniques and underlying pathomechanisms with the aim of fostering a critical discussion of the limitations and potential of up-to-date animal experimentation. We discuss potential complications in experimental liver fibrosis and provide examples of how the findings of studies in which these models are used can be translated to human disease and therapy. In this review, we want to motivate the international community to design more standardized animal models which might help to address the legally requested replacement, refinement and reduction of animals in fibrosis research. PMID:24274743

  5. Assessment of liver fibrosis by a noninvasive method of transient elastography and biochemical markers

    OpenAIRE

    Kawamoto, Masaki; Mizuguchi, Toru; Katsuramaki, Tadashi; Nagayama, Minoru; Oshima, Hideki; Kawasaki, Hiroyuki; Nobuoka, Takayuki; Kimura, Yasutoshi; Hirata, Koichi

    2006-01-01

    AIM: To assess the correlation between the fibrotic area (FA) as calculated by a digital image analysis (DIA), and to compare the diagnostic accuracy of FibroScan to the other existing Liver fibrosis (LF) markers using the receiver operating curve analysis.

  6. The effects of Maraviroc on liver fibrosis in HIV/HCV co-infected patients

    Directory of Open Access Journals (Sweden)

    Enrique Ortega Gonzalez

    2014-11-01

    .62% showed regression of liver fibrosis in one stage. Conclusions: The data above shows a benefit over fibrosis progression with MVC, expressed by fibrosis serum marker tests in HIV/HCV co-infected patients with CCR5 tropism. The prolong treatment with MVC (over two years has a better effect on liver fibrosis.

  7. Intravenous injection of mesenchymal stem cells is effective in treating liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Wei Zhao; Jun-Jie Li; Da-Yong Cao; Xiao Li; Lin-Ying Zhang; Yong He; Shu-Qiang Yue

    2012-01-01

    AIM:To compare the influence of different transplant sites in bone marrow mesenchymal stem cell (MSC)-based therapy for liver fibrosis.METHODS:MSCs isolated from Sprague Dawley (SD) rats were induced into hepatocyte-like cells.Liver fibrosis in SD rats was induced with carbon tetrachloride.Following hepatocyte induction in vitro,4',6-diamidino2-phenylindole (DAPI)-labeled MSCs were transplanted by intravenous,intrahepatic,and intraperitoneal injection.Histopathological staining,immunohistochemistry,and biochemical analysis were used to compare the morphological and functional liver regeneration among different MSC injection modalities.The expression di-ferences of interleukins,growth factor,extracellular matrix,matrix metalloproteinases,and tissue inhibitor of metalloproteinase were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA).RESULTS:Four days after exposure to hepatocyte differentiation medium,MSCs that did not express hepatocyte markers could express α-fetoprotein,albumin,and cytokeratin 18.The results of histopathological staining,immunohistochemistry,and biochemical analysis indicated that intravenous injection is more effective at rescuing liver failure than other injection modalities.DAPI-labeled cells were found around liver lobules in all three injection site groups,but the intravenous group had the highest number of cells.PCR and ELISA analysis indicated that interleukin-10 (IL-10)was highest in the intravenous group,whereas il1β,il6,tnfα and tgfβ,which can be regulated by IL10 and are promoters of liver fibrosis,were significantly lower than in the other groups.CONCLUSION:MSC administration is able to protect against liver fibrosis.Intravenous injection is the most favorable treatment modality through promotion of IL10 expression.

  8. Liver Fibrosis Can Be Induced by High Salt Intake through Excess Reactive Oxygen Species (ROS) Production.

    Science.gov (United States)

    Wang, Guang; Yeung, Cheung-kwan; Wong, Wing-Yan; Zhang, Nuan; Wei, Yi-fan; Zhang, Jing-li; Yan, Yu; Wong, Ching-yee; Tang, Jun-jie; Chuai, Manli; Lee, Kenneth Ka Ho; Wang, Li-jing; Yang, Xuesong

    2016-02-24

    High salt intake has been known to cause hypertension and other side effects. However, it is still unclear whether it also affects fibrosis in the mature or developing liver. This study demonstrates that high salt exposure in mice (4% NaCl in drinking water) and chick embryo (calculated final osmolality of the egg was 300 mosm/L) could lead to derangement of the hepatic cords and liver fibrosis using H&E, PAS, Masson, and Sirius red staining. Meanwhile, Desmin immunofluorescent staining of mouse and chick embryo livers indicated that hepatic stellate cells were activated after the high salt exposure. pHIS3 and BrdU immunohistological staining of mouse and chick embryo livers indicated that cell proliferation decreased; as well, TUNEL analyses indicated that cell apoptosis increased in the presence of high salt exposure. Next, dihydroethidium staining on the cultured chick hepatocytes indicated the excess ROS was generated following high salt exposure. Furthermore, AAPH (a known inducer of ROS production) treatment also induced the liver fibrosis in chick embryo. Positive Nrf2 and Keap1 immunohistological staining on mouse liver suggested that Nrf2/Keap1 signaling was involved in high salt induced ROS production. Finally, the CCK8 assay was used to determine whether or not the growth inhibitory effect induced by high salt exposure can be rescued by antioxidant vitamin C. Meanwhile, the RT-PCR result indicated that the Nrf2/Keap1 downsteam genes including HO-1, NQO-1, and SOD2 were involved in this process. In sum, these experiments suggest that high salt intake would lead to high risk of liver damage and fibrosis in both adults and developing embryos. The pathological mechanism may be the result from an imbalance between oxidative stress and the antioxidant system. PMID:26843032

  9. Endocannabinoids Anandamide and Its Cannabinoid Receptors in Liver Fibrosis after Murine Schistosomiasis

    Institute of Scientific and Technical Information of China (English)

    Hongyan LIU; Xiao GAO; Ruixian DUAN; Qiao YANG; Yaowen ZHANG; Yongwei CHENG; Yan GUO; Wangxian TANG

    2009-01-01

    This study examined endogenous cannabinoid (ECB)-anandamide (AEA) and its can-nabinoid receptors (CBR) in mice liver with the development of schistosomajaponicum.Mice were infected with schistosoma by means of pasting the cercaria onto their abdomens.Liver fibrosis was pathologically confirmed nine weeks after the infection.High performance liquid chromatography (HPLC) was employed to determine the concentration of AEA in the plasma of mice.Immunofluorescence was used to detect the expression of CBR 1 and CBR2 in liver tissue.Morphological examination showed typical pathological changes,with worm tubercles of schistosoma deposited in the liver tissue,fibrosis around the worm tubercles and infiltration or soakage ofinfiammatory cells.Also,CBRI and CBR2 were present in hepatocytes and hepatic sinusoids of the two groups,but they were obviously enhanced in the schistosoma-infected mice.However,the average optical density of CBR1 in the negative control and fibrosis group was 13.28±7.32 and 30.55±7.78,and CBR2 were 28.13±6.42 and 52.29±4.24 (P<0.05).The levels of AEA in the fibrosis group were significantly increased as compared with those of the control group.The concentrations of AEA were (0.37±0.07) and (5.67±1.34) ng/mL (P<0.05).It is concluded that the expression of endocannabinoids AEA and its cannabinoid receptor CBR were significantly increased in schistosoma-infected mice.Endogenous endocannabinoids may be involved in the development of schistosoma-induced liver fibrosis.

  10. Changes in fibrosis and oxygen metabolism index during perioperative period of patients with laparoscopic liver resection

    Institute of Scientific and Technical Information of China (English)

    Ya-Qi Jiang

    2016-01-01

    Objective:To observe the changes in fibrosis and oxygen metabolism index during perioperative period of patients with laparoscopic liver resection, and to explore the advantages of laparoscopic liver resection in the treatment of liver cancer.Methods:According to the inclusion criteria, 53 patients who processed with liver resection from February 2013 to March 2015 in our hospital were randomly divided into control group (open operation group, n=25) and study group (laparoscopic liver resection group,n=28). Then the operation and postoperative recovery of two groups were compared, and the fibrosis and oxygen metabolism indexes of two groups were compared too.Results:There was no significant difference in operation time, bleeding volume, tumor resection margin and liver resection volume between the two groups. The postoperative activity time, the first time for dieting post operation and time of postoperative hospital stay in study group were significantly shorter than the control group. After operation in 3, 7, 14 d, the serum levels of AST, ALT and CRP in study group were significantly lower than the control group. During perioperative period, there was no obvious change in the oxygen metabolism index in the study group, while which showed significantly change in the control group. After operation in the 3rd, 7th, 14th days, the levels of fibrosis related indexes HA, PCⅢ and Ⅳ C in study group were significantly lower than the control group.Conclusion:The efficacy of laparoscopic liver resection for the treatment of liver cancer is consistent with the open surgery, while the laparoscopic surgery has the advantages of less trauma, less liver damage and rapid recovery.

  11. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease

    DEFF Research Database (Denmark)

    Angulo, Paul; Kleiner, David E; Dam-Larsen, Sanne;

    2015-01-01

    transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination. RESULTS: Over a...... median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2...... activity score, had shorter survival times than patients without fibrosis. CONCLUSIONS: In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver...

  12. Noninvasive estimation of liver fibrosis and response to interferon therapy by a serum fibrogenesis marker, YKL-40, in patients with HCV-associated liver disease

    Institute of Scientific and Technical Information of China (English)

    Yukiko Saitou; Katsuya Shiraki; Yutaka Yamanaka; Yumi Yamaguchi; Tomoyuki Kawakita; Norihiko Yamamoto; Kazushi Sugimoto; Kazumoto Murata; Takeshi Nakano

    2005-01-01

    AIM: To evaluate the clinical utility of serum fibrosis markers,including YKL-40, in patients with HCV-associated liver disease.METHODS: A total of 109 patients with HCV-associated liver disease were enrolled. We measured serum type Ⅳ collagen, amino-terminal peptide of type Ⅲ procollagen (PⅢP),hyaluronic acid (HA), YKL-40 levels and biochemical.Parameters by RIA or ELISA. Eighty-eight patients underwent liver biopsy, and 67 of 109 patients received interferon (IFN)therapy. We also investigated the relationship between the concentrations of serum fibrosis markers and histological fibrosis scores (METAVIR), and evaluated the changes of the levels of fibrosis markers before and after the IFN therapy.RESULTS: The increase in serum levels of all markers,particularly HA, was correlated with the progression of liver fibrosis (for type Ⅳ collagen, F= 9.076, P<0.0001; for PⅢP,F= 9.636, P<0.0001; for HA, F= 13.128, P<0.0001; and for YKL-40, F= 8.016, P<0.0001). YKL-40 had strong correlation with HA (r= 0.536, P<0.0001). Based on the receiver operating curve (ROC), the ability of serum HA exceeded the abilities of other serum markers to determine fibrosis score 4 from fibrosis score 0-3 (AUC = 0.854). While YKL-40 was superior to other fibrosis markers for predicting severe fibrosis (F2-F4) from mild fibrosis (F0-F1) (YKL-40, AUC = 0.809;HA, AUC = 0.805). After IFN therapy, only YKL-40 values significantly decreased not only in the responder group,but also in the nonresponder group (P = 0.03).CONCLUSION: YKL-40 may be a useful non-invasive serum marker to estimate the degree of liver fibrosis and to evaluate the efficacy of IFN therapies in patients with HCV-associated liver disease.

  13. Advances in mesenchymal stem cells combined with traditional Chinese medicine therapy for liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Shu Dong; Shi-bing Su

    2014-01-01

    Liver fibrosis is a primary cause of liver cirrhosis, and even hepatocarcinoma. Recently, the usage of mesenchymal stem cells (MSCs) has been investigated to improve liver ifbrosis. It has been reported that the differentiation, proliferation and migration of MSCs can be regulated by traditional Chinese medicine treatment;however, the mechanisms are still unclear. In this article, the authors review the characteristics of MSCs such as multidirectional differentiation and homing, and its application in animal experiments and clinical trials. The authors also list areas that need further investigation, and look at the future prospects of clinical application of MSCs.

  14. Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights.

    Science.gov (United States)

    Greuter, Thomas; Shah, Vijay H

    2016-06-01

    Changes of hepatic sinusoids are crucial in the pathogenesis of liver cirrhosis and portal hypertension. Liver injury leads to distinct morphological abnormalities such as loss of sinusoidal fenestration, vasoconstriction, and angiogenesis as well as molecular changes. Communication between the two key cells in this hepatic microenvironment-hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC)-has been studied for many years and several canonical pathways have been elucidated, such as decreased eNOS activity or increased PDGF and TGF-β production leading to activation and migration of HSC. In recent studies, alternative pathways of intercellular communication in liver diseases have been described such as cell-derived extracellular vesicles called exosomes, which deliver cell compounds to their target cells. Moreover, such extracellular vesicles may link injury to inflammation in alcoholic hepatitis. While inflammation leading to liver fibrosis has been studied in detail, in some circumstances pathways other than the known canonical inflammatory pathways may contribute to hepatic fibrogenesis. For example, in congestive hepatopathy, sinusoidal dilatation and fibrosis have been shown to be mediated by non-inflammatory mechanisms and associated with sinusoidal thrombi. A recently developed murine model further enables experimental studies of this disease entity. Increasing knowledge about these alternative disease pathways in liver injury, inflammation, and fibrosis may reveal possible target molecules for future therapies. This article builds upon a seminar given at the recent 3rd JSGE International Topic Conference in Sendai, Japan, and reviews the areas outlined above. PMID:26939970

  15. Data Mining Visualization to Support Biochemical Markers for Liver Fibrosis in Patients With Chronic Hepatitis C Virus

    Directory of Open Access Journals (Sweden)

    Ayman Khedr & Samir Sabry.

    2011-08-01

    Full Text Available The reference diagnostic test to detect fibrosis is liver biopsy (LB, a procedure subject to variouslimitations, including risk of patient injury and sampling error. FibroTest (FT and ActiTest (AT arebiochemical markers (noninvasive tests used in determining the level of fibrosis and the degreeof necroinflammatory activity in the liver [1]. The objective of this work is to discover thedifferences in the temporal patterns between noninvasive tests and liver biopsy by visualizationtools, which made it easier to understand the relations of the complicated rules. This Study warefocused on the major serum fibrosis markers (FT/AT. The test uses a combination of serumbiochemical markers with visualization technique to evaluate whether biochemical markers canbe used to estimate the stage of liver fibrosis and necro-inflammatory activity in the liver.

  16. Pegylated interferon-alpha plus taurine in treatment of rat liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Ilker Tasci; Cihan Yurdaydin; Hakan Bozkaya; Ozden Uzunalimoglu; Ahmet Turan Isik; Harun M Said; Mehmet Refik Mas; Sevil Atalay Vural; Salih Deveci; Bilgin Comert; Gunay Alcigir; Nuket Mas; Cemal Akay; Mithat Bozdayi

    2007-01-01

    AIM: To investigate the antifibrotic effects of peginterferonalpha 2b and taurine on oxidative stress markers and hepatocellular apoptosis.METHODS: Sixty rats with CCl4-induced liver fibrosis were divided into 4 groups (n=15). Group 1 was left for spontaneous recovery (SR). Groups 2-4 received peginterferon-alpha 2b, taurine, and their combination,respectively, for four weeks. Histological fibrosis scores,histomorphometric analysis, tissue hydroxyproline, tissue MDA, GPx and SOD activities were determined. Activated stellate cells and hepatocellular apoptosis were also evaluated.RESULTS: The degree of fibrosis decreased in all treatment groups compared to spontaneous recovery group. Taurine alone and in combination with peginterferon-alpha 2b reduced oxidative stress markers,but peginterferon-alpha 2b alone did not. Apoptotic hepatocytes and activated stellate cells were higher in groups 2-4 than in group 1. Combined taurine and peginterferon-alpha 2b further reduced fibrosis and increased activated stellate cell apoptosis, but could not improve oxidative stress more than taurine alone.CONCLUSION: Peginterferon-alpha 2b exerts antifibrotic effects on rat liver fibrosis. It seems ineffective against oxidative stress in vivo. Peginterferon-alpha 2b in combination with taurine seems to be an antifibrotic strategy.

  17. Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine N-methyltransferase-deficient mice.

    Science.gov (United States)

    van der Veen, Jelske N; Lingrell, Susanne; Gao, Xia; Quiroga, Ariel D; Takawale, Abhijit; Armstrong, Edward A; Yager, Jerome Y; Kassiri, Zamaneh; Lehner, Richard; Vance, Dennis E; Jacobs, René L

    2016-04-01

    Phosphatidylethanolamine N-methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Pemt(-/-) mice are protected against high-fat diet (HFD)-induced obesity and insulin resistance; however, these mice develop nonalcoholic fatty liver disease (NAFLD). We hypothesized that peroxisomal proliferator-activated receptor-γ (PPARγ) activation by pioglitazone might stimulate adipocyte proliferation, thereby directing lipids from the liver toward white adipose tissue. Pioglitazone might also act directly on PPARγ in the liver to improve NAFLD. Pemt(+/+) and Pemt(-/-) mice were fed a HFD with or without pioglitazone (20 mg·kg(-1)·day(-1)) for 10 wk. Pemt(-/-) mice were protected from HFD-induced obesity but developed NAFLD. Treatment with pioglitazone caused an increase in body weight gain in Pemt(-/-) mice that was mainly due to increased adiposity. Moreover, pioglitazone improved NAFLD in Pemt(-/-) mice, as indicated by a 35% reduction in liver weight and a 57% decrease in plasma alanine transaminase levels. Livers from HFD-fed Pemt(-/-) mice were steatotic, inflamed, and fibrotic. Hepatic steatosis was still evident in pioglitazone-treated Pemt(-/-) mice; however, treatment with pioglitazone reduced hepatic fibrosis, as evidenced by reduced Sirius red staining and lowered mRNA levels of collagen type Iα1 (Col1a1), tissue inhibitor of metalloproteinases 1 (Timp1), α-smooth muscle actin (Acta2), and transforming growth factor-β (Tgf-β). Similarly, oxidative stress and inflammation were reduced in livers from Pemt(-/-) mice upon treatment with pioglitazone. Together, these data show that activation of PPARγ in HFD-fed Pemt(-/-) mice improved liver function, while these mice were still protected against diet-induced obesity and insulin resistance. PMID:26797396

  18. Liver-protecting and fibrosis-resisting effect of Ganxianning on rats withspleen deficiency and stagnation of Liver-qi

    Institute of Scientific and Technical Information of China (English)

    Zhen Qiu Guo; Xiao Wei Zhao; Xin Yu Chen

    2000-01-01

    AIM To study the liver-protecting and fibrosis-resisting effect of Ganxianning (GXN) and its mechanism.METHODS Model of carbon tetrachloride hepatic injury fibrosis rats was reproduced. In the experimentthere were six groups, the treatment groups with GXN's large, moderate and small dose (GXNb, GXNm andGXNs), the treatment group with colchicine, the blank model group and normal control group. The course of treatment was 30 days, then the rats were killed with their blood and liver tested.RESULTS In treatment groups, alanine aminotransferase (ALT) was lower than that in the model group(P<0.01), and albumin (Alb) higher than that in the model (P<0.01). Hydroxylproline (Hyp) and redcell membrane C3B receptor garland in GXNb's and GXNm's groups were lower and circulation complex(CIC) was slightly higher. Fibrinogen (Fb) in both colchicine and model groups was higher than that innormal group and the difference was significant (P<0.05, P<0.01). Compared with model group, acid-α-naphthyl acetate esterase (ANAE) increased in GXNb's and GXNm's groups (P<0.05, P<0.01). Underlight and electron microscopes, level of hepatic fibrosis of GXN groups was much lower than that of themodel group, P<0.01, and their difference was very significant. In GXNms group, liver cell was normal onthe whole and its chromatin was more than the model group and its nucleolus was evident.CONCLUSION GXN has rather good functions of protecting liver and resisting fibrosis, and thesefunctions are related to the increase of ANAE and C3b, decrease of CIC and Fb. and improvement of bodyimmunity function.

  19. Oxidized low-density-lipoprotein accumulation is associated with liver fibrosis in experimental cholestasis

    Directory of Open Access Journals (Sweden)

    Güldeniz Karadeniz

    2008-01-01

    Full Text Available OBJECTIVE: The aim of the present study was to examine the probable relationship between the accumulation of oxLDL and hepatic fibrogenesis in cholestatic rats. INTRODUCTION: There is growing evidence to support the current theories on how oxidative stress that results in lipid peroxidation is involved in the pathogenesis of cholestatic liver injury and fibrogenesis. One of the major and early lipid peroxidation products, OxLDL, is thought to play complex roles in various immuno-inflammatory mechanisms. METHODS: A prolonged (21-day experimental bile duct ligation was performed on Wistar-albino rats. Biochemical analysis of blood, histopathologic evaluation of liver, measurement of the concentration of malondialdehyde (MDA and superoxide-dismutase (SOD in liver tissue homogenates, and immunofluorescent staining for oxLDL in liver tissue was conducted in bile-duct ligated (n = 8 and sham-operated rats (n = 8. RESULTS: Significantly higher levels of MDA and lower concentrations of SOD were detected in jaundiced rats than in the sham-operated rats. Positive oxLDL staining was also observed in liver tissue sections of jaundiced rats. Histopathological examination demonstrated that neither fibrosis nor other indications of hepatocellular injury were found in the sham-operated group, while features of severe hepatocellular injury, particularly fibrosis, were found in jaundiced rats. CONCLUSION: Our results support the finding that either oxLDLs are produced as an intermediate agent during exacerbated oxidative stress or they otherwise contribute to the various pathomechanisms underlying the process of liver fibrosis. Whatever the mechanism, it is clear that an association exists between elevated oxLDL levels and hepatocellular injury, particularly with fibrosis. Further studies are needed to evaluate the potential effects of oxLDLs on the progression of secondary biliary cirrhosis.

  20. Preventive effect of Qianggan-Rongxian Decoction on rat liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Chun-Hui Li; Li-Hui Pan; Zong-Wei Yang; Chun-Yu Li; Wen-Xie Xu

    2008-01-01

    AIM: To study the preventive effects of Qianggan-Rongxian Decoction on liver fibrosis induced by dimethylnitrosamine (DMN) in rats.METHODS: Male Wistar rats were randomly divided into hepatic fibrosis model group, control group and 3 treatment groups (12 rats in each group). Except for the normal control group, all the rats received 1% DMN (10μL/kg body weight, I. P), 3 times a week for 4wk. The rats in the 3 treatment groups including a high-dose DMN group (10mL/kg), a medium-dose DMN group (7 mL/kg), and a low-dose DMN group (4mL/kg) were daily gavaged with Qianggan-Rongxian Decoction, and the rats in the model and normal control groups were given saline vehicle. Enzyme-linked immunosorbent assay (ELISA) was used to determine the changes in serum hyaluronic acid (HA), laminin (LN), and type Ⅳ collagen levels. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured using routine laboratory methods. Pathologic changes, particularly fibrosis, were examined by hematoxylin and eosin (HE) and Sirius red staining. Hepatic stellate cells (HSC) were examined by transmission electron microscopy.RESULTS: Compared with the model control group, the serum levels of HA, LN, type Ⅳ collagen, ALT and AST were decreased markedly in the other groups after treatment with Qianggan-Rongxian Decoction, especially in the medium-dose DMN group (P<0.05). Moreover, the area-density percentage of collagen fibrosis was lower in the Qianggan-Rongxian Decoction treatment groups than in the model group, and a more significant drop was observed in the medium-dose DMN group (P<0.05).CONCLUSION: Qianggan-Rongxian Decoction can inhibit hepatic fibrosis due to chronic liver injury, delay the development of cirrhosis, and notably ameliorate liver function. It may be used as a safe and effective thera-peutic drug for patients with fibrosis.

  1. Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Dong-Chang Zhao; Jun-Xia Lei; Rui Chen; Wei-Hua Yu; Xiu-Ming Zhang; Shu-Nong Li; Peng Xiang

    2005-01-01

    AIM: Recent reports have shown the capacity of mesenchymal stem cells (MSCs) to differentiate into hepatocytes in vitro and in vivo. MSCs administration could repair injured liver, lung, or heart through reducing inflammation, collagen deposition, and remodeling. These results provide a clue to treatment of liver fibrosis. The aim of this study was to investigate the effect of infusion of bone marrow (BM)-derived MSCs on the experimental liver fibrosis in rats.METHODS: MSCs isolated from BM in male Fischer 344 rats were infused to female Wistar rats induced with carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN).There were two random groups on the 42nd d of CCl4:CCl4/MSCs, to infuse a dose of MSCs alone; CCl4/saline,to infuse the same volume of saline as control. There were another three random groups after exposure to DMN: DMN10/MSCs, to infuse the same dose of MSCs on d 10; DMN10/saline, to infuse the same volume of saline on d 10; DMN20/MSCs, to infuse the same dose of MSCson d 20. The morphological and behavioral changes ofrats were monitored everyday. After 4-6 wk of MSCs administration, all rats were killed and fibrosis index were assessed by histopathology and radioimmunoassay. Smooth muscle alpha-actin (alpha-SMA) of liver were tested by immunohistochemistry and quantified by IBAS 2.5 software. Male rats sex determination region on the Y chromosome (sry) gene were explored by PCR.RESULTS: Compared to controls, infusion of MSCsreduced the mortality rates of incidence in CCl4-induced model (10% vs 20%) and in DMN-induced model (2040% vs 90%).The amount of collagen deposition and alpha-SMA staining was about 40-50% lower in liver of rats with MSCs than that of rats without MSCs. The similar results were observed in fibrosis index. And the effect of the inhibition of fibrogenesis was greater in DMN10/MSCs than in DMN20/MSCs. The sry gene was positive in the liver of rats with MSCs treatment by PCR.CONCLUSION: MSCs treatment can protect against

  2. Multicenter clinical study on Fuzhenghuayu capsule against liver fibrosis due to chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Ping Liu; Mo-Bin Wan; Xiong Cai; Zhi-Qing Zhang; Jun Ye; Ren-Xing Zhou; Jia He; Bao-Zhang Tang; Yi-Yang Hu; Cheng Liu; Lie-Ming Xu; Cheng-Hai Liu; Ke-Wei Sun; De-Chang Hu; You-Kuan Yin; Xia-Qiu Zhou

    2005-01-01

    AIM: To study the efficacy and safety of Fuzhenghuayu capsule (FZHY capsule, a capsule for strengthening body resistance to remove blood stasis) against liver fibrosis due to chronic hepatitis B. METHODS: Multicenter, randomized, double blinded and parallel control experiment was conducted in patients (aged from 18 to 65 years) with liver fibrosis due to chronic hepatitis B. Hepatic histologic changes and HBV markers were examined at wk 0 and 24 during treatment. Serologic parameters (HA, LM, P-Ⅲ-P, Ⅳ-C) were determined and B ultrasound examination of the spleen and liver was performed at wk 0, 12 and 24. Liver function (liver function and serologic parameters for liver fibrosis) was observedat wk 0, 6, 12, 18 and 24. Blood and urine routine test, renal function and ECG were examined before and after treatment. RESULTS: There was no significant difference between experimental group (110 cases) and control group (106 cases) in demographic features, vital signs, course of illness, history for drug anaphylaxis and previous therapy, liver function, serologic parameters for liver fibrosis, liver histologic examination (99 cases in experimental group, 96 cases in control group), HBV markers, and renal function. According to the criteria for liver fibrosis staging, meanscore of fibrotic stage(s) in experimental group after treatment (1.80) decreased significantly compared to the previous treatment (2.33, P<0.05), but there was no significant difference in mean score of fibrotic stage(s) (2.11 and 2.14 respectively). There was a significant difference in reverse rate between experimental group (52%) and control group (23.3%) in liver biopsy. With marked effect on decreasing the mean value of inflammatory activity and score of inflammation (P<0.05), Fuzhenghuayu capsule had rather good effects on inhibiting inflammatory activity and was superior to that of Heluoshugan capsule. Compared to that of pretreatment, there was a significant decrease in HA, LM, P-Ⅲ-P and

  3. IkB kinase-beta inhibitor attenuates hepatic fibrosis in mice

    Institute of Scientific and Technical Information of China (English)

    Jue Wei; Min Shi; Wei Qi Wu; Ting Wang; Na Wang; Jia-Li Ma; Yu-Gang Wang

    2011-01-01

    AIM: To investigate the anti-fibrosis effect of IκkB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin- 6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κkB (NF-κkB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeⅠand type Ⅲ collagen proteins and mRNA. RESULTS: A mouse model of liver injury was successfully established, and IMD decreased nuclear translocation translocation of NF-κkB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeⅠcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type Ⅲ collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05).CONCLUSION: IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver

  4. Effects of liver inflammation on FibroScan diagnosis of hepatic fibrosis in patients with chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    刘志权

    2013-01-01

    Objective To investigate the influence of liver inflammation on the ability of the FibroScan non-invasive elastrography scanner to diagnose hepatic fibrosis in patients with chronic hepatitis B (CHB) .Methods A total of 124 CHB patients who received liver biopsy and concomitant liver stiffness measurement (LSM) by FibroScan

  5. Cystic Fibrosis Related Liver Disease—Another Black Box in Hepatology

    Directory of Open Access Journals (Sweden)

    Katharina Staufer

    2014-08-01

    Full Text Available Due to improved medical care, life expectancy in patients with cystic fibrosis (CF has veritably improved over the last decades. Importantly, cystic fibrosis related liver disease (CFLD has become one of the leading causes of morbidity and mortality in CF patients. However, CFLD might be largely underdiagnosed and diagnostic criteria need to be refined. The underlying pathomechanisms are largely unknown, and treatment strategies with proven efficacy are lacking. This review focuses on current invasive and non-invasive diagnostic standards, the current knowledge on the pathophysiology of CFLD, treatment strategies, and possible future developments.

  6. Assessment of Liver Fibrosis Using Fast Strain-Encoded (FSENC) MRI Driven by Inherent Cardiac Motion

    Science.gov (United States)

    Harouni, Ahmed A.; Gharib, Ahmed M.; Osman, Nael F.; Morse, Caryn; Heller, Theo; Abd-Elmoniem, Khaled Z.

    2014-01-01

    Purpose An external driver-free MRI method for assessment of liver fibrosis offers a promising non-invasive tool for diagnosis and monitoring of liver disease. Lately, the heart’s intrinsic motion and MR tagging have been utilized for the quantification of liver strain. However, MR tagging requires multiple breath-hold acquisitions and substantial post-processing. This work proposes a fast strain-encoded (FSENC) MRI methodology to measure the peak strain (Sp) in the liver’s left lobe, which is in close proximity and caudal to the heart. Additionally, a new method is introduced to measure heart-induced shear wave velocity (SWV) inside the liver. Methods Phantom and in-vivo experiments (11 healthy subjects, and 11 patients with liver fibrosis) were conducted. Reproducibility experiments were performed in seven healthy subjects. Results Peak liver strain Sp significantly decreased in fibrotic liver compared healthy liver (6.46%±2.27% vs. 12.49%±1.76%, P<0.05). Heart-induced SWV significantly increased in patients compared to healthy subjects (0.15±0.04 m/s vs. 0.63±0.32 m/s, P<0.05). Reproducibility analysis yielded no significant difference in Sp (P=0.47) or SWV (P=0.56). Conclusion Accelerated external driver-free noninvasive assessment of left liver lobe strain and shear wave velocity is feasible using strain-encoded MRI. The two measures significantly separate healthy subjects from patients with fibrotic liver. PMID:25081734

  7. PASS-Predicted Hepatoprotective Activity of Caesalpinia sappan in Thioacetamide-Induced Liver Fibrosis in Rats

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    Farkaad A. Kadir

    2014-01-01

    Full Text Available The antifibrotic effects of traditional medicinal herb Caesalpinia sappan (CS extract on liver fibrosis induced by thioacetamide (TAA and the expression of transforming growth factor β1 (TGF-β1, α-smooth muscle actin (αSMA, and proliferating cell nuclear antigen (PCNA in rats were studied. A computer-aided prediction of antioxidant and hepatoprotective activities was primarily performed with the Prediction Activity Spectra of the Substance (PASS Program. Liver fibrosis was induced in male Sprague Dawley rats by TAA administration (0.03% w/v in drinking water for a period of 12 weeks. Rats were divided into seven groups: control, TAA, Silymarin (SY, and CS 300 mg/kg body weight and 100 mg/kg groups. The effect of CS on liver fibrogenesis was determined by Masson’s trichrome staining, immunohistochemical analysis, and western blotting. In vivo determination of hepatic antioxidant activities, cytochrome P450 2E1 (CYP2E1, and matrix metalloproteinases (MPPS was employed. CS treatment had significantly increased hepatic antioxidant enzymes activity in the TAA-treated rats. Liver fibrosis was greatly alleviated in rats when treated with CS extract. CS treatment was noted to normalize the expression of TGF-β1, αSMA, PCNA, MMPs, and TIMP1 proteins. PASS-predicted plant activity could efficiently guide in selecting a promising pharmaceutical lead with high accuracy and required antioxidant and hepatoprotective properties.

  8. LIVER FIBROSIS IN COMBINED COURSE OF CHRONIC HEPATITIS C AND HIV INFECTION.

    Science.gov (United States)

    Sarsekeyeva, N; Kosherova, B; Tabagari-Bregvadze, N

    2015-11-01

    The urgency of the problem connected with HIV infection and parenteral forms of viral hepatitis largely stems from common epidemiological, social and economic indices. HIV infection accelerates progression of liver disease associated with HCV infection, especially in patients with more severe immunodeficiency. The aim of the study was to compare results of liver elastometry in patients co-infected with HIV/CHC and those monoinfected with CHC. Verification of the diagnosis was carried out on the basis of clinical-anamnestic data, by taking into account the epidemiological history of patients and confirming the results of enzyme immunoassay with the definition of markers of hepatitis C in paired sera and polymerase chain reaction with the detection of RNA virus in blood plasma. The degree of liver fibrosis was measured on a scale of METAVIR by means of FibroScan apparatus. The article presents the results of the comparative assessment of liver fibrosis in patients co-infected with HIV/CHC and those monoinfected with CHC. It suggests that patients co-infected with HIV/CHC are at a higher risk of severe fibrosis and cirrhosis. PMID:26656547

  9. The Impact of PNPLA3 rs738409 SNP on Liver Fibrosis Progression, Portal Hypertension and Hepatic Steatosis in HIV/HCV Coinfection.

    Directory of Open Access Journals (Sweden)

    Bernhard Scheiner

    Full Text Available Faster fibrosis progression and hepatic steatosis are hallmarks of HIV/HCV coinfection. A single nucleotide polymorphism (SNP of the PNPLA3-gene is associated with development of non-alcoholic steatohepatitis and a worse outcome in alcoholic liver disease. However, the role of PNPLA3 rs738409 SNP on liver fibrosis and steatosis, portal hypertension, and virological response in HIV/HCV coinfection remains unclear.In this cross-sectional study PNPLA3 (rs738409 and IL28B (rs12979860 SNPs were determined in 177 HIV/HCV coinfected patients. Liver fibrosis and steatosis-staged by liver biopsy and transient elastography using the Controlled Attenuation Parameter (CAP-and portal hypertension (hepatic venous pressure gradient, HVPG were compared across PNPLA3 genotypes.75 (42.4% patients tested positive for a PNPLA3 minor/major risk allele (G/C:66; G/G:9 showed comparable fibrosis stages (median F2 vs. F2; p = 0.292 and similar amounts of hepatic steatosis (CAP: 203.5 ± 41.9 vs. 215.5 ± 59.7 dB/m; p = 0.563 as compared to patients without a PNPLA3 risk allele. Advanced liver fibrosis was neither associated with PNPLA3 (p = 0.253 nor IL28B-genotype (p = 0.628, but with HCV-GT3 (p = 0.003, higher BMI (p = 0.008 and higher age (p = 0.007. Fibrosis progression rate (0.27 ± 0.41 vs. 0.20 ± 0.26 units/year; p = 0.984 and HVPG (3.9 ± 2.6 vs. 4.4 ± 3.0 mmHg; p = 0.472 were similar in patients with and without PNPLA3 risk alleles. SVR rates to PEGIFN/RBV therapy were similar across PNPLA3 genotypes.The presence of a PNPLA3 risk allele had no independent impact on liver disease or virological response rates to PEGIFN/RBV therapy in our cohort of HIV/HCV coinfected patients.

  10. Prevention of liver fibrosis by triple helix-forming oligodeoxyribonucleotides targeted to the promoter region of type I collagen gene.

    Science.gov (United States)

    Koilan, Subramaniyan; Hamilton, David; Baburyan, Narina; Padala, Mythili K; Weber, Karl T; Guntaka, Ramareddy V

    2010-10-01

    Hepatic fibrosis leading to cirrhosis remains a global health problem. The most common etiologies are alcoholism and viral infections. Liver fibrosis is associated with major changes in both quantity and composition of extracellular matix and leads to disorganization of the liver architecture and irreversible damage to the liver function. As of now there is no effective therapy to control fibrosis. The end product of fibrosis is abnormal synthesis and accumulation of type I collagen in the extracellular matrix, which is produced by activated stellate or Ito cells in the damaged liver. Therefore, inhibition of transcription of type I collagen should in principle inhibit its production and accumulation in liver. Normally, DNA exists in a duplex form. However, under some circumstances, DNA can assume triple helical (triplex) structures. Intermolecular triplexes, formed by the addition of a sequence-specific third strand to the major groove of the duplex DNA, have the potential to serve as selective gene regulators. Earlier, we demonstrated efficient triplex formation between the exogenously added triplex-forming oligodeoxyribonucleotides (TFOs) and a specific sequence in the promoter region of the COL1A1 gene. In this study we used a rat model of liver fibrosis, induced by dimethylnitrosamine, to test whether these TFOs prevent liver fibrosis. Our results indicate that both the 25-mer and 18-mer TFOs, specific for the upstream nucleotide sequence from -141 to -165 (relative to the transcription start site) in the 5' end of collagen gene promoter, effectively prevented accumulation of liver collagen and fibrosis. We also observed improvement in liver function tests. However, mutations in the TFO that eliminated formation of triplexes are ineffective in preventing fibrosis. We believe that these TFOs can be used as potential antifibrotic therapeutic molecules. PMID:20818932

  11. Interaction Between Alcohol Consumption Patterns, Antiretroviral Therapy Type, and Liver Fibrosis in Persons Living with HIV.

    Science.gov (United States)

    Bilal, Usama; Lau, Bryan; Lazo, Mariana; McCaul, Mary E; Hutton, Heidi E; Sulkowski, Mark S; Moore, Richard D; Chander, Geetanjali

    2016-05-01

    We examined the longitudinal association between alcohol use and liver fibrosis, measured by FIB-4 Score, among HIV-infected individuals by (1) antiretroviral therapy (ART) class, and (2) the presence of hepatitis C (HCV) co-infection. This was a prospective cohort study of 550 individuals in the Johns Hopkins HIV Clinical Cohort initiating ART between 2000 and 2012. The relationship between alcohol consumption (defined using NIAAA categories of non-, moderate, and hazardous drinkers) and liver fibrosis (FIB-4 score) by ART class was assessed using linear mixed effects models. Additionally, we examined whether the presence of HCV modified and whether viral load mediated the relationship between alcohol use and liver fibrosis. Overall, FIB-4 levels were 15.6% higher in hazardous drinkers compared to moderate drinkers (p = 0.025) after adjusting by age, sex, and race. Hazardous drinkers on PI-based regimens had FIB-4 scores 26.9% higher than moderate drinkers (p = 0.015). However, there was no difference in FIB-4 levels between hazardous drinkers on non-PI-based regimens compared to moderate drinkers (1.83% versus moderate drinkers, p = 0.848). There was no significant difference in FIB-4 between nondrinkers and moderate drinkers, irrespective of ART regimen. These associations were not modified by HCV status or mediated by viral load changes. Individuals with hazardous alcohol consumption and on PI-based regimens had significantly increased liver fibrosis, as measured by the FIB-4. These data suggest that providers should consider level of alcohol consumption when choosing an ART regimen to minimize detrimental effects on the liver. PMID:27158847

  12. Interleukin-13 is involved in the formation of liver fibrosis in Clonorchis sinensis-infected mice.

    Science.gov (United States)

    Xu, Yanquan; Liang, Pei; Bian, Meng; Chen, Wenjun; Wang, Xiaoyun; Lin, Jinsi; Shang, Mei; Qu, Hongling; Wu, Zhongdao; Huang, Yan; Yu, Xinbing

    2016-07-01

    Clonorchiasis is a chronic infection disease often accompanied by formation of liver fibrosis. Previous study has identified that Clonorchis sinensis (C. sinensis, Cs) infection and CsRNASET2 (a member of CsESPs) immunization can drive Th2 immune response. IL-13, a multifunctional Th2 cytokine, has been widely confirmed to be profibrotic mediator. We want to determine whether IL-13 is involved in the generation of liver fibrosis during C. sinensis infection. A part of mice were infected with C. sinensis or immunized with CsRNASET2, respectively. Another part of mice were intravenously injected with rIL-13. Liver tissues of C. sinensis-infected mice were stained with hematoxylin-eosin and Masson's trichrome, respectively. The transcriptional levels of collagen-I, collagen-III, α-SMA, and TIMP-1 in the livers of infected mice and rIL-13-treated mice were measured by quantitative RT-PCR. Besides, splenocytes of C. sinensis-infected and CsRNASET2-immunized mice were isolated, respectively. The levels of IL-13 in splenocytes were detected by ELISA. Our results displayed that the livers of C. sinensis-infected mice had serious chronic inflammation and collagen deposition. The transcriptional levels of collagen-I, collagen-III, α-SMA, and TIMP-1 in the livers of C. sinensis-infected mice were obviously increased. Splenocytes from both C. sinensis-infected and CsRNASET2-immunized mice expressed high levels of IL-13. Moreover, rIL-13 treatment markedly promoted the transcriptional levels of collagen-I, collagen-III, α-SMA, and TIMP-1. These data implied that hepatic fibrosis was formed in the livers of C. sinensis-infected mice, and IL-13 induced by C. sinensis infection and CsRNASET2 immunization might favor this progression. PMID:26993324

  13. The coagulation factor Xa/protease activated receptor-2 axis in the progression of liver fibrosis: a multifaceted paradigm

    OpenAIRE

    Borensztajn, Keren; von der Thüsen, Jan H.; Peppelenbosch, Maikel P.; Spek, C Arnold

    2009-01-01

    Abstract Hepatic fibrosis is a common response to virtually all forms of chronic liver injury independent of the etiologic agent. Despite the relatively large population of patients suffering from hepatic fibrosis and cirrhosis, no efficient and well-tolerated drugs are available for the treatment of this disorder. The lack of efficient treatment options is at least partly because the underlying cellular mechanisms leading to hepatic fibrosis are only partly understood. It is thus of pivotal ...

  14. Comparison of accuracy of fibrosis degree classifications by liver biopsy and non-invasive tests in chronic hepatitis C

    OpenAIRE

    Boursier Jérôme; Bertrais Sandrine; Oberti Frédéric; Gallois Yves; Fouchard-Hubert Isabelle; Rousselet Marie-Christine; Zarski Jean-Pierre; Calès Paul

    2011-01-01

    Abstract Background Non-invasive tests have been constructed and evaluated mainly for binary diagnoses such as significant fibrosis. Recently, detailed fibrosis classifications for several non-invasive tests have been developed, but their accuracy has not been thoroughly evaluated in comparison to liver biopsy, especially in clinical practice and for Fibroscan. Therefore, the main aim of the present study was to evaluate the accuracy of detailed fibrosis classifications available for non-inva...

  15. Detection of Hepatic Fibrosis in Ex Vivo Liver Samples Using an Open-Photoacoustic-Cell Method: Feasibility Study

    Science.gov (United States)

    Stolik, S.; Fabila, D. A.; de la Rosa, J. M.; Escobedo, G.; Suárez-Álvarez, K.; Tomás, S. A.

    2015-09-01

    Design of non-invasive and accurate novel methods for liver fibrosis diagnosis has gained growing interest. Different stages of liver fibrosis were induced in Wistar rats by intraperitoneally administering different doses of carbon tetrachloride. The liver fibrosis degree was conventionally determined by means of histological examination. An open-photoacoustic-cell (OPC) technique for the assessment of liver fibrosis was developed and is reported here. The OPC technique is based on the fact that the thermal diffusivity can be accurately measured by photoacoustics taking into consideration the photoacoustic signal amplitude versus the modulation frequency. This technique measures directly the heat generated in a sample, due to non-radiative de-excitation processes, following the absorption of light. The thermal diffusivity was measured with a home-made open-photoacoustic-cell system that was specially designed to perform the measurement from ex vivo liver samples. The human liver tissue showed a significant increase in the thermal diffusivity depending on the fibrosis stage. Specifically, liver samples from rats exhibiting hepatic fibrosis showed a significantly higher value of the thermal diffusivity than for control animals.

  16. The relationship between serum thrombopoietin (TPO) levels and hepatic fibrosis markers in patients with chronic liver diseases

    International Nuclear Information System (INIS)

    Objective: This study evaluated the relationship between thrombopoietin (TPO) levels and Hepatic Fibrosis Markers with chronic liver diseases. Methods: Serum thrombopoietin levels was detected in patients with chronic liver disease and healthy controls with ELISA method, Hepatic Fibrosis Markers were measured with RIA. Results: TPO levels was no significance among chronic hepatits (120.41 ± 39.73) pg/ml vary stage, liver cirrhosis (125.84 ± 44.40) pg/ml and healthy controls (143.62 ± 47.97) pg/ml (P>0.05), serum TPO levels is correlated with Type IV Collagen in liver cirrhosis (r=0.517, P<0.05). Conclusion: Serum TPO levels is not associated with severity degree in chronic liver disease, and there is relative to hepatic fibrosis degree in liver cirrhosis. (authors)

  17. A specific gene-expression signature quantifies the degree of hepatic fibrosis in patients with chronic liver disease

    Institute of Scientific and Technical Information of China (English)

    Tohru Utsunomiya; Hiroshi Inoue; Graham F Barnard; Masaki Mori; Masahiro Okamoto; Shigeki Wakiyama; Masaji Hashimoto; Kengo Fukuzawa; Takahiro Ezaki; Shinichi Aishima; Yasuji Yoshikawa; Taizo Hanai

    2007-01-01

    AIM: To study a more accurate quantification of hepatic fibrosis which would provide clinically useful information for monitoring the progression of chronic liver disease.METHODS: Using a cDNA microarray containing over 22000 clones, we analyzed the gene-expression profiles of non-cancerous liver in 74 patients who underwent hepatic resection. We calculated the ratio of azan stained: total area, and determined the morphologic fibrosis index (MFI), as a mean of 9 section-images. We used the MFI as a reference standard to evaluate our method for assessing liver fibrosis.RESULTS: We identified 39 genes that collectively showed a good correlation (r>0.50) between geneexpression and the severity of liver fibrosis. Many of the identified genes were involved in immune responses and cell signaling. To quantify the extent of liver fibrosis,we developed a new genetic fibrosis index (GFI) based on gene-expression profiling of 4 clones using a linear support vector regression analysis. This technique, based on a supervised learning analysis, correctly quantified the various degrees of fibrosis in both 74 training samples (r= 0.76, 2.2% VS 2.8%, P<0.0001) and 12 independent additional test samples (r = 0.75, 9.8% vs 8.6%, P<0.005). It was far better in assessing liver fibrosis than blood markers such as prothrombin time (r= -0.53),type Ⅳ collagen 7s (r = 0.48), hyaluronic acid (r = 0.41),and aspartate aminotransferase to platelets ratio index(APRI) (r= 0.38).CONCLUSION: Our cDNA microarray-based strategy may help clinicians to precisely and objectively monitor the severity of liver fibrosis.

  18. Traditional herbal medicine use associated with liver fibrosis in rural Rakai, Uganda.

    Directory of Open Access Journals (Sweden)

    Brandon J Auerbach

    Full Text Available BACKGROUND: Traditional herbal medicines are commonly used in sub-Saharan Africa and some herbs are known to be hepatotoxic. However little is known about the effect of herbal medicines on liver disease in sub-Saharan Africa. METHODS: 500 HIV-infected participants in a rural HIV care program in Rakai, Uganda, were frequency matched to 500 HIV-uninfected participants. Participants were asked about traditional herbal medicine use and assessed for other potential risk factors for liver disease. All participants underwent transient elastography (FibroScan® to quantify liver fibrosis. The association between herb use and significant liver fibrosis was measured with adjusted prevalence risk ratios (adjPRR and 95% confidence intervals (CI using modified Poisson multivariable logistic regression. RESULTS: 19 unique herbs from 13 plant families were used by 42/1000 of all participants, including 9/500 HIV-infected participants. The three most-used plant families were Asteraceae, Fabaceae, and Lamiaceae. Among all participants, use of any herb (adjPRR = 2.2, 95% CI 1.3-3.5, p = 0.002, herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 2.9-8.7, p<0.001, and herbs from the Lamiaceae family (adjPRR = 3.4, 95% CI 1.2-9.2, p = 0.017 were associated with significant liver fibrosis. Among HIV infected participants, use of any herb (adjPRR = 2.3, 95% CI 1.0-5.0, p = 0.044 and use of herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 1.7-14.7, p = 0.004 were associated with increased liver fibrosis. CONCLUSIONS: Traditional herbal medicine use was independently associated with a substantial increase in significant liver fibrosis in both HIV-infected and HIV-uninfected study participants. Pharmacokinetic and prospective clinical studies are needed to inform herb safety recommendations in sub-Saharan Africa. Counseling about herb use should be part of routine health counseling and counseling of HIV-infected persons in Uganda.

  19. Expression of Basic Fibroblast Growth Factor in Rat Liver Fibrosis and Hepatic Stellate Cells

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The expression of basic fibroblast growth factor (bFGF) in rat liver fibrosis and hepatic stellate cells (HSCs) and the relationship between the expression of bFGF and rat liver fibrogenesis were studied. Sixty male SD rats (230-260 g) were divided into 4 groups randomly (the 0 week group, 1 week group, 4 week group and 8 week group). Liver fibrosis was induced by subcutaneous injection of carbon tetrachloride. The sections of rats' liver in each group were tested by VanGieson (V-G) staining and immunohistochemistry. The expression of bFGF mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR). HSCs were isolated by the combined methods of collagenase Ⅳ perfusion and density gradient centrifugation. The expression of bFGF protein in cultured HSCs was detected by Western blot. Images of immunohistochemistry detec tion, agarose gel electrophoresis of RT-PCR and SDS-polyacrylamide gel electrophoresis of Western blot were analyzed semiquantitatively by image-analyzing system. The results were analyzed by statistics. The results showed that the fibers were gradually increased in the sections of rat liver with the prolongation of the model induction. At the end of the 8th weeks, liver fibrosis was formed.The expression of bFGF detected by immunohistochemistry showed a similar tendency of gradual increase. At the end of the 8th weeks, the bFGF expression could be observed in many regions in sections and the strongest expression was in interstitial cells including HSCs and some hepatocytes in regions around the portal area and central veins. Also there was moderate expression widely in extracellular matrix (ECM). In RT-PCR detection and Western blot detection of HSCs cultured in vitro, the similar tendency of gradual increase was evident either. It is suggested that bFGF is related with liver fibrosis of rats closely and may be a fibrogenesis factor of liver. bFGF possibly regulates liver fibrogenesis through regulating metabolism of extracellular

  20. In vivo quantification of liver stiffness in a rat model of hepatic fibrosis with acoustic radiation force.

    Science.gov (United States)

    Wang, Michael H; Palmeri, Mark L; Guy, Cynthia D; Yang, Liu; Hedlund, Laurence W; Diehl, Anna Mae; Nightingale, Kathryn R

    2009-10-01

    Liver fibrosis is currently staged using needle biopsy, a highly invasive procedure with a number of disadvantages. Measurement of liver stiffness changes that accompany progression of the disease may provide a quantitative and noninvasive method to assess the health of the liver. The purpose of this study is to investigate the correlation between liver stiffness measured by radiation force induced shear waves and disease related changes in the liver. An additional aim is to present initial findings on the effects of liver viscosity on radiation force induced shear wave morphology. Liver fibrosis was induced in 10 rats using carbon tetrachloride (CCl(4)), while five rats acted as controls. Liver stiffness was measured in vivo in all rats after a treatment period of 8 weeks using a modified Siemens SONOLINE Antares scanner (Siemens Medical Solutions USA, Ultrasound Division, Issaquah, WA, USA). The spatial coherence of radiation force induced shear waves propagating in the viscoelastic rat liver decreased significantly with propagation distance, compared with shear waves in an elastic phantom and a finite element model of a purely elastic medium. Animals were sacrificed after imaging and liver samples were taken for histopathologic analysis and collagen quantification using picrosirius red staining and hydroxyproline assay. At the end of the treatment period, five rats had healthy livers (stage F0), while six had severe fibrosis (F3) and the rest had light to moderate fibrosis (F1 and F2). The measured liver stiffness for the F0 group was 1.5+/-0.1 kPa (mean+/-95% confidence interval) and for F3 livers was 1.8+/-0.2 kPa. In this study, liver stiffness was found to be linearly correlated with the amount of collagen in the liver measured by picrosirius red staining (r(2)=0.43, p=0.008). In addition, stiffness spatial heterogeneity was also linearly correlated with liver collagen content (r(2)=0.58, p=0.001) by picrosirius red staining. These results are consistent

  1. Liver fibrosis in guinea pigs experimentally induced by combined copper and aflatoxin application.

    Science.gov (United States)

    Schiller, F; Lippold, U; Heinze, R; Hoffmann, A; Seffner, W

    1998-09-01

    Aflatoxin B1 alone (0.05 mg resp. 0.037 mg/kg/d), copper alone (6.6 mg/kg/d or 200 mg/l drinking water) or a combination of both was administrated orally for 6 months to young guinea pigs from the first/second day of life. In the copper group there were no pathomorphological changes. For the aflatoxin B1 group liver damage was established. In the combined group liver injury was more frequent and more severe compared to the aflatoxin B1 group. Compared with the copper group biliary copper excretion was diminished and the kidney copper content was elevated in the Afl. B1 + Cu group. While copper concentrations in bile and kidney correlated with other parameters, notably the pathological lesions of the liver, no such correlation was found for liver copper. Therefore in this experiment the degree of Cu accumulation was not decisive for the liver lesions. The livers' capacity for excreting Cu by bile seems to be a much more important factor. Histologically only the livers of the combined group exhibited degeneration, atrophy and steatosis of liver cells, and a fibrosis more or less pronounced. For childhood cirrhosis (ICC and ICT), a combined etiology--a liver damaging agent plus elevated alimentary copper--is a plausible hypothesis. PMID:9784033

  2. Hepatic and Splenic Acoustic Radiation Force Impulse Shear Wave Velocity Elastography in Children with Liver Disease Associated with Cystic Fibrosis

    OpenAIRE

    Teresa Cañas; Araceli Maciá; Rosa Ana Muñoz-Codoceo; Teresa Fontanilla; Patricia González-Rios; María Miralles; Gloria Gómez-Mardones

    2015-01-01

    Background. Liver disease associated with cystic fibrosis (CFLD) is the second cause of mortality in these patients. The diagnosis is difficult because none of the available tests are specific enough. Noninvasive elastographic techniques have been proven to be useful to diagnose hepatic fibrosis. Acoustic radiation force impulse (ARFI) imaging is an elastography imaging system. The purpose of the work was to study the utility of liver and spleen ARFI Imaging in the detection of CFLD. Method. ...

  3. Clinical Observation on Effect of Ruangan Granule (软肝颗粒剂 ) in Treating Chronic Hepatitic Liver Fibrosis

    Institute of Scientific and Technical Information of China (English)

    李秀惠; 赵春惠; 金荣华; 黄春

    2002-01-01

    Objective: To observe the clinical effect of Ruangan granule (RGG) in treating liver fibrosis.Methods: One hundred and twenty patients of chronic viral hepatitis B were randomly divided into two groups, 60 patients in the treated group and 60 patients in the control group. They were treated with RGG or composite Biejia Ruangan tablet (复方鳖甲软肝片) respectively for three months. The changes of liver function, liver fibrosis indices, including fibronectin (FN), laminin (LN) and hyaluronic acid (HA), as well as liver morphology by B-ultrasonic examination were observed after treatment. A three-month follow-up study was also conducted. Results: In the treated group, the markedly effective rate was 50.0% and effective rate was 41.7%, while in the control group, the corresponding rates were 26.7% and 55.0% respectively. Comparison of the markedly effective rate between the two groups showed significant difference (P<0.01). The serum levels of FN, LN, HA as well as splenomegaly and portal vein widening in the treated group after treatment were significantly improved (P<0.05), as compared with those in the control group after treatment; significant difference was shown in comparison of serum FN, LN and HA. Conclusion: RGG could improve effectively serum liver fibrosis indices and liver function in patients of chronic hepatitic fibrosis. It is helpful in alleviating and inhibiting the genesis and development of liver fibrosis so as to block the progression of liver cirrhosis.

  4. Distribution of hepatic stellate cells and their role in the development of parasitic fibrosis and liver cirrhosis in domestic animals

    Directory of Open Access Journals (Sweden)

    Kukolj Vladimir

    2015-01-01

    Full Text Available Increasing of the extracellular matrix in rats, as well as in humans, occurs as a consequence of hepatic stellate cells (HSCs activity. The objective of this work was to investigation the role of these cells in the development of fibrosis and liver cirrhosis which occurs as a consequence of infection of sheep and goats with large (Fasciola hepatica and small (Dicrocoelium dendriticum fluke. Liver samples taken from 12 cattle and 10 sheep infected under natural conditions with large and small fluke were fixed in formalin and embedded in paraffin. Paraffin clips were stained with hematoxylin- eosin and masson trichrome method, and immunohistochemical method for α-smooth muscle actin (α-SMA. All tested samples were divided into three groups according to histological criteria: livers of infected animals with the first degree of fibrosis, livers of infected animals with the second degree of fibrosis, and livers of infected animals with cirrhosis. Distribution of HSCs depended on the degree of liver fibrosis. Immunohistochemically reactive HSCs were predominantly placed in perisinusoidal space. In liver samples with cirrhosis, HSCs were placed on the periphery of pseudolobulus. Cells of a different shape and size were positive to α-SMA. HSCs play an important role in synthesis of components of extracellular matrix during the development of parasitic fibrosis and liver cirrhosis in domestic animals.

  5. Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis.

    Science.gov (United States)

    Ziogas, Dimitrios C; Gras-Miralles, Beatriz; Mustafa, Sarah; Geiger, Brenda M; Najarian, Robert M; Nagel, Jutta M; Flier, Sarah N; Popov, Yury; Tseng, Yu-Hua; Kokkotou, Efi

    2013-05-15

    Fibrosis represents a major complication of several chronic diseases, including inflammatory bowel disease (IBD). Treatment of IBD remains a clinical challenge despite several recent therapeutic advances. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide shown to regulate appetite and energy balance. However, accumulating evidence suggests that MCH has additional biological effects, including modulation of inflammation. In the present study, we examined the efficacy of an MCH-blocking antibody in treating established, dextran sodium sulfate-induced experimental colitis. Histological and molecular analysis of mouse tissues revealed that mice receiving anti-MCH had accelerated mucosal restitution and lower colonic expression of several proinflammatory cytokines, as well as fibrogenic genes, including COL1A1. In parallel, they spared collagen deposits seen in the untreated mice, suggesting attenuated fibrosis. These findings raised the possibility of perhaps direct effects of MCH on myofibroblasts. Indeed, in biopsies from patients with IBD, we demonstrate expression of the MCH receptor MCHR1 in α-smooth muscle actin(+) subepithelial cells. CCD-18Co cells, a primary human colonic myofibroblast cell line, were also positive for MCHR1. In these cells, MCH acted as a profibrotic modulator by potentiating the effects of IGF-1 and TGF-β on proliferation and collagen production. Thus, by virtue of combined anti-inflammatory and anti-fibrotic effects, blocking MCH might represent a compelling approach for treating IBD. PMID:23538494

  6. PATHOPHYSIOLOGIC BASIS OF LIVER DISEASE IN CYSTIC FIBROSIS EMPLOYING A ΔF508 MOUSE MODEL

    OpenAIRE

    Freudenberg, Folke; BRODERICK, ANNEMARIE L.; Yu, Bian B.; Leonard, Monika R.; Glickman, Jonathan N.; CAREY, MARTIN C.

    2008-01-01

    The molecular pathogenesis of cystic fibrosis (CF) liver disease is unknown. This study investigates its earliest pathophysiologic manifestations employing a mouse model carrying ΔF508, the commonest human CF mutation. We hypothesized that, if increased bile salt spillage into the colon occurs as in the human disease, this should lead to a hydrophobic bile salt profile and to “hyperbilirubinbilia” because of induced enterohepatic cycling of unconjugated bilirubin. Hyperbilirubinbilia may then...

  7. Compression Elastography in Endosonography as an Early Differential Diagnostic Technique of Liver Fibrosis Stages

    OpenAIRE

    2014-01-01

    The aim of the investigation was to study the capabilities of compression elastography used in endosonography to estimate the stage of fibrosis process in liver parenchyma. Materials and Methods. We examined 67 patients with hepatic diseases including 29 patients (43.3%) with steatosis, 23 (34.3%) — with hepatitis, 15 (22.4%) — with cirrhosis. All patients underwent hepatic sonography, transient elastography, fibrogastroduodenoscopy, compression elastography in the course of endosonograp...

  8. Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.

    OpenAIRE

    Rath, Timo; Hage, Lisa; Kügler, Marion; Menendez Menendez, Katrin; Zachoval, Reinhart; Naehrlich, Lutz; Schulz, Richard; Roderfeld, Martin; Roeb, Elke

    2013-01-01

    Background and Aims Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. Methods 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting...

  9. Feasibility of histogram analysis of susceptibility-weighted MRI for staging of liver fibrosis

    Science.gov (United States)

    Yang, Zhao-Xia; Liang, He-Yue; Hu, Xin-Xing; Huang, Ya-Qin; Ding, Ying; Yang, Shan; Zeng, Meng-Su; Rao, Sheng-Xiang

    2016-01-01

    PURPOSE We aimed to evaluate whether histogram analysis of susceptibility-weighted imaging (SWI) could quantify liver fibrosis grade in patients with chronic liver disease (CLD). METHODS Fifty-three patients with CLD who underwent multi-echo SWI (TEs of 2.5, 5, and 10 ms) were included. Histogram analysis of SWI images were performed and mean, variance, skewness, kurtosis, and the 1st, 10th, 50th, 90th, and 99th percentiles were derived. Quantitative histogram parameters were compared. For significant parameters, further receiver operating characteristic (ROC) analyses were performed to evaluate the potential diagnostic performance for differentiating liver fibrosis stages. RESULTS The number of patients in each pathologic fibrosis grade was 7, 3, 5, 5, and 33 for F0, F1, F2, F3, and F4, respectively. The results of variance (TE: 10 ms), 90th percentile (TE: 10 ms), and 99th percentile (TE: 10 and 5 ms) in F0–F3 group were significantly lower than in F4 group, with areas under the ROC curves (AUCs) of 0.84 for variance and 0.70–0.73 for the 90th and 99th percentiles, respectively. The results of variance (TE: 10 and 5 ms), 99th percentile (TE: 10 ms), and skewness (TE: 2.5 and 5 ms) in F0–F2 group were smaller than those of F3/F4 group, with AUCs of 0.88 and 0.69 for variance (TE: 10 and 5 ms, respectively), 0.68 for 99th percentile (TE: 10 ms), and 0.73 and 0.68 for skewness (TE: 2.5 and 5 ms, respectively). CONCLUSION Magnetic resonance histogram analysis of SWI, particularly the variance, is promising for predicting advanced liver fibrosis and cirrhosis. PMID:27113421

  10. Losartan may inhibit the progression of liver fibrosis in chronic HCV patients

    Science.gov (United States)

    Salama, Zakaria A.; Sadek, Ahmed; Abdelhady, Ahmed M.; Morsy, Shereif Ahmed; Esmat, Gamal

    2016-01-01

    Background Abundant experimental evidence indicates overproduction of angiotensin II in the injured liver, and a role in stimulation of hepatic stellate cell (HSC) activation and fibrogenesis thereby, representing an attractive antifibrotic target. The aim of this study was to examine the antifibrotic effect of losartan on histopathologic level in chronic HCV patients. Methods A prospective study on fifty patients with chronic HCV and liver fibrosis proved by liver biopsy was conducted. They included patients who did not respond (n=36) or comply (n=2) or receive therapy due to established cirrhosis (n=10), or refused to receive (n=2) combined interferon and ribavirin therapy. They were divided randomly into 2 groups. The 1st group (n=25) was given losartan 50 mg OD for 1 year and the 2nd group (25 patients) was given silymarin, 140 mg t.i.d., (silymarin group). Liver biopsy was done at baseline and 1 year from the onset of treatment (end of study). Results In the second liver biopsy after 1 year, the decrease in fibrosis stage was significantly different between losartan group and silymarin group (a decrease of 1.88±0.96 (50.9%) vs. 0.45±0.93 (11.7%), respectively; Pfibrosis stage was observed in 14/16 patients vs. 2/11 in silymarin group (Pfibrosis stage but had no effect on the grade of inflammation.

  11. Impact of OAS1 Exon 7 rs10774671 Genetic Variation on Liver Fibrosis Progression in Egyptian HCV Genotype 4 Patients.

    Science.gov (United States)

    Bader El Din, Noha G; Anany, Mohamed A; Dawood, Reham M; Ibrahim, Marwa K; El-Shenawy, Reem; El Abd, Yasmin S; El Awady, Mostafa K

    2015-11-01

    The aim of this study was to assess the impact of genetic variants of oligoadenylate synthetase 1 (OAS1) single-nucleotide polymorphism (SNP) rs10774671 at the exon 7 splice acceptor site on liver fibrosis progression and hepatitis C virus (HCV) outcome in Egyptian HCV genotype 4 patients. In this study, 195 subjects were enrolled; 60 controls and 135 chronic HCV genotype 4 patients with different fibrosis grades. All subjects were genotyped for OAS1 SNP rs10774671 polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. There was an increasing trend of liver fibrosis progression as 52.9% GG, 73.6% GA, and 83.3% AA genotypes were detected in late fibrosis patients (p = 0.025). The AA genotype was higher in the late fibrosis group than in the early fibrosis group (83.3% vs. 16.7%) (p = 0.001). The A allele was significantly affecting the liver fibrosis progression rate, more than the G allele (p = 0.001). The multivariate analysis showed that the OAS1 GA and AA genotypes were independent factors associated with liver progression (p = 0.009, odds ratio [OR] 3.467, 95% confidence interval [CI] 1.273-7.584). In addition, the A allele was associated with liver fibrosis progression (p = 0.014, OR 2.525, 95% CI 1.157-4.545). The polymorphism at OAS1 exon 7 rs3741981 might be a potential genetic marker and can be useful in the assessment of liver fibrosis progression and disease outcome in HCV-infected patients. PMID:26505957

  12. The diagnostic efficacy of quantitative liver MR imaging with diffusion-weighted, SWI, and hepato-specific contrast-enhanced sequences in staging liver fibrosis - a multiparametric approach

    Energy Technology Data Exchange (ETDEWEB)

    Feier, Diana [Medical University of Vienna, General Hospital of Vienna (AKH), Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Emergency County Hospital, Department of Radiology, Cluj-Napoca (Romania); Balassy, Csilla; Bastati, Nina; Fragner, Romana; Ba-Ssalamah, Ahmed [Medical University of Vienna, General Hospital of Vienna (AKH), Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Wrba, Friedrich [Medical University of Vienna, General Hospital of Vienna (AKH), Department of Pathology, Vienna (Austria)

    2016-02-15

    To assess the diagnostic efficacy of multiparametric MRI using quantitative measurements of the apparent diffusion coefficient (ADC) of the liver parenchyma on diffusion-weighted imaging (DWI), signal intensity (SI) on susceptibility-weighted imaging (SWI), and gadoxetic acid-enhanced T1-weighted imaging during the hepatobiliary phase for the staging of liver fibrosis. Seventy-seven patients underwent a 3T MRI examination, including DWI/SWI sequences and gadoxetic acid-enhanced T1-weighted MRI. Liver fibrosis according to liver biopsy was staged using the Metavir fibrosis score: F0 (n = 21, 27.3 %); F1 (n = 7, 9.1 %); F2 (n = 8, 10.4 %); F3 (n = 12, 15.6 %); and F4 (n = 29, 37.7 %). SI of the liver was defined using region-of-interest measurements to calculate the ADC values, the relative enhancement (RE) in the hepatobiliary phase, and the liver-to-muscle ratio (LMR) measurements for SWI. The values of RE, LMR, and ADC measurements were statistically significantly different among the five fibrosis stages (p < 0.004). Combining the three parameters in a multiparametric approach, the AUC for detecting F1 stage or greater (≥ F1) was 94 %, for F2 or greater (≥F2) was 95 %, for F3 or greater (≥F3) was 90 %, and for stage F4 was 93 %. Multiparametric MRI is an efficient non-invasive diagnostic tool for the staging of liver fibrosis. (orig.)

  13. The diagnostic efficacy of quantitative liver MR imaging with diffusion-weighted, SWI, and hepato-specific contrast-enhanced sequences in staging liver fibrosis - a multiparametric approach

    International Nuclear Information System (INIS)

    To assess the diagnostic efficacy of multiparametric MRI using quantitative measurements of the apparent diffusion coefficient (ADC) of the liver parenchyma on diffusion-weighted imaging (DWI), signal intensity (SI) on susceptibility-weighted imaging (SWI), and gadoxetic acid-enhanced T1-weighted imaging during the hepatobiliary phase for the staging of liver fibrosis. Seventy-seven patients underwent a 3T MRI examination, including DWI/SWI sequences and gadoxetic acid-enhanced T1-weighted MRI. Liver fibrosis according to liver biopsy was staged using the Metavir fibrosis score: F0 (n = 21, 27.3 %); F1 (n = 7, 9.1 %); F2 (n = 8, 10.4 %); F3 (n = 12, 15.6 %); and F4 (n = 29, 37.7 %). SI of the liver was defined using region-of-interest measurements to calculate the ADC values, the relative enhancement (RE) in the hepatobiliary phase, and the liver-to-muscle ratio (LMR) measurements for SWI. The values of RE, LMR, and ADC measurements were statistically significantly different among the five fibrosis stages (p < 0.004). Combining the three parameters in a multiparametric approach, the AUC for detecting F1 stage or greater (≥ F1) was 94 %, for F2 or greater (≥F2) was 95 %, for F3 or greater (≥F3) was 90 %, and for stage F4 was 93 %. Multiparametric MRI is an efficient non-invasive diagnostic tool for the staging of liver fibrosis. (orig.)

  14. Circulating levels of citrullinated and MMP-degraded vimentin (VICM) in liver fibrosis related pathology

    DEFF Research Database (Denmark)

    Vassiliadis, Efstathios; Oliveira, Claudia P; Alvares-da-Silva, Mario R;

    2012-01-01

    AIM: To investigate whether increased levels of vimentin citrullinated peptides identified by MS in articular cartilage can be measured in pathologies other than rheumatoid arthritis and be utilised for diagnostic purposes. METHODS: A monoclonal antibody against the sequence RLRSSVPGV-citrulline ......AIM: To investigate whether increased levels of vimentin citrullinated peptides identified by MS in articular cartilage can be measured in pathologies other than rheumatoid arthritis and be utilised for diagnostic purposes. METHODS: A monoclonal antibody against the sequence RLRSSVPGV......-citrulline (VICM) was developed and evaluated in a carbon tetrachloride (CCl(4)) (n=52 + 28 controls) rat model of liver fibrosis and two clinical cohorts of adult patients with hepatitis C (HCV) (n=92) and non-alcoholic fatty liver disease (NAFLD) (n=62), and compared to healthy controls. RESULTS: In CCl(4...... ±12 ng/mL, P<0.05), 23.8% in F1 (348 ±12 ng/mL, P<0.05) and 28.8% in F2 (362 ±25 P<0.05). CONCLUSION: We demonstrated increased serological levels of citrullinated and MMP degraded vimentin in an animal model of liver fibrosis and in early fibrosis associated with HCV and NAFLD patients. These data...

  15. Mueller matrix microscope: a quantitative tool to facilitate detections and fibrosis scorings of liver cirrhosis and cancer tissues

    Science.gov (United States)

    Wang, Ye; He, Honghui; Chang, Jintao; He, Chao; Liu, Shaoxiong; Li, Migao; Zeng, Nan; Wu, Jian; Ma, Hui

    2016-07-01

    Today the increasing cancer incidence rate is becoming one of the biggest threats to human health. Among all types of cancers, liver cancer ranks in the top five in both frequency and mortality rate all over the world. During the development of liver cancer, fibrosis often evolves as part of a healing process in response to liver damage, resulting in cirrhosis of liver tissues. In a previous study, we applied the Mueller matrix microscope to pathological liver tissue samples and found that both the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters are closely related to the fibrous microstructures. In this paper, we take this one step further to quantitatively facilitate the fibrosis detections and scorings of pathological liver tissue samples in different stages from cirrhosis to cancer using the Mueller matrix microscope. The experimental results of MMPD and MMT parameters for the fibrotic liver tissue samples in different stages are measured and analyzed. We also conduct Monte Carlo simulations based on the sphere birefringence model to examine in detail the influence of structural changes in different fibrosis stages on the imaging parameters. Both the experimental and simulated results indicate that the polarized light microscope and transformed Mueller matrix parameters can provide additional quantitative information helpful for fibrosis detections and scorings of liver cirrhosis and cancers. Therefore, the polarized light microscope and transformed Mueller matrix parameters have a good application prospect in liver cancer diagnosis.

  16. Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection

    International Nuclear Information System (INIS)

    The molecular mechanisms of acute hepatitis C virus (HCV) infection, end-stage hepatitis (cirrhosis), and hepatocellular carcinoma have been extensively studied, but little is known of the changes in liver gene expression during the early stages of liver fibrosis associated with chronic HCV infection, that is, the transition from normal liver (NL) of uninfected patients to the first stage of liver fibrosis (F1-CH-C). To obtain insight into the molecular pathogenesis of F1-CH-C, we used real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to study the mRNA expression of 240 selected genes in liver tissue with F1-CH-C, in comparison with NL. The expression of 54 (22.5%) of the 240 genes was significantly different between F1-CH-C and NL; 46 genes were upregulated and 8 were downregulated in F1-CH-C. The most noteworthy changes in gene expression mainly affected the transcriptional network regulated by interferons (IFNs), including both IFN-α/β-inducible genes (STAT1, STAT2, ISGF3G/IRF9, IFI27, G1P3, G1P2, OAS2, MX1) and IFN-γ-inducible genes (CXCL9, CXCL10, CXCL11). Interesting, upregulation of IFN-α/β-inducible genes (but not IFN-γ-inducible genes) was independent of histological scores (grade and stage of fibrosis) and HCV characteristics (hepatic HCV mRNA levels and the HCV genotype), and was specific to HCV (as compared to hepatitis B virus (HBV)). Other genes dysregulated in F1-CH-C, albeit less markedly than IFN-α/β- and IFN-γ-inducible genes, were mainly involved in the activation of lymphocytes infiltrating the liver (IFNG, TNF, CXCL6, IL6, CCL8, CXCR3, CXCR4, CCR2), cell proliferation (p16/CDKN2A, MKI67, p14/ARF), extracellular matrix remodeling (MMP9, ITGA2), lymphangiogenesis (XLKD1/LYVE), oxidative stress (CYP2E1), and cytoskeleton microtubule organization (STMN2/SCG10). Thus, a limited number of signaling pathways, and particularly the transcriptional network regulated by interferons, are dysregulated in the first

  17. Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.

    Directory of Open Access Journals (Sweden)

    Timo Rath

    Full Text Available BACKGROUND AND AIMS: Cystic Fibrosis associated liver disease (CFLD develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. METHODS: 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. RESULTS: 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. CONCLUSIONS: Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD.

  18. Serum Proteome Profiling Identifies Novel and Powerful Markers of Cystic Fibrosis Liver Disease

    Science.gov (United States)

    Kügler, Marion; Menendez Menendez, Katrin; Zachoval, Reinhart; Naehrlich, Lutz; Schulz, Richard; Roderfeld, Martin; Roeb, Elke

    2013-01-01

    Background and Aims Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. Methods 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. Results 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. Conclusions Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD. PMID:23516586

  19. Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats

    Institute of Scientific and Technical Information of China (English)

    Ali Riza Soylu; Huseyin Baloglu; Mevlut Ture; Kemal Kutlu; Kadir Kaymak; Nurettin Aydogdu; Umit Nusret Basaran; Semsi Altaner; Orhan Tarcin; Nursal Gedik; Hasan Umit; Ahmet Tezel; Gulbin Dokmeci

    2006-01-01

    AIM:To investigate whether antioxidants vitamin E and C can retard development of hepatic fibrosis in the biliary-obstructed rats.METHODS: Fifty Wistar albino rats were randomly assigned to 5 groups (10 rats in each). Bile duct was ligated in 40 rats and they were treated as follows: group vitC, vitamin C 10 rog/kg sc daily; group vitE, vitamin E 15 mg/kg sc daily; group vitEC, both of the vitamins; bile duct-ligated (BDL, control) group, physiological saline sc. The fifth group was assigned to sham operation. At the end of fourth week, the rats were decapitated, and hepatic tissue biochemical collagen content and collagen surface area were measured. Hepatic tissue specimens were histopathologically evaluated according to Scheuer system. Serum hyaluronate levels were measured by ELTSA method.RESULTS: Despite being higher than sham group, hepatic collagen level was significantly decreased in each of the vitC, vitE and vitEC groups (32.7 ± 1.2, 33.8 ±2.9, 36.7 ± 0.5 μg collagen/mg protein, respectively)compared to BDL (48.3 ± 0.6 mg collagen/g protein) (P< 0.001 for each vitamin group). Each isolated vitamin C, isolated vitamin E and combined vitamin E/C supplementation prevented the increase in hepatic collagen surface density (7.0% ± 1.1%, 6.2% ± 1.7%, 12.3% ±2.0%, respectively) compared to BDL (17.4% ± 5.6%) (P< 0.05 for each). The same beneficial effect of vitamin C,vitamin E and combined vitamin E/C treatment was also observed on the decrease of serum hyaluronate levels compared to BDL group (P < 0.001). The relative liver and spleen weights, serum transaminases, cholestatic enzymes, bilirubins and histopathological inflammation scores were not different between the antioxidant treatment groups and the control. However, fibrosis staging scores were obviously reduced only in the vitamin E/C combination group (vit EC: 2.4 ± 0.8 vs BDL: 3.1 ± 0.7;P < 0.05).CONCLUSION: Each antioxidant vitamin E, vitamin C and their combination retard hepatic

  20. [Role of simple noninvasive markers of liver fibrosis in qualification to treatment in patients with chronic hepatitis C].

    Science.gov (United States)

    Gietka, Jan Andrzej

    2011-01-01

    Assessment of liver fibrosis in patients with chronic hepatitis C (CHC) is essential for determination of prognosis, monitoring of the disease and guiding therapeutic decisions. Current gold standard for diagnosis of hepatic fibrosis is liver biopsy. Since it has several limitations and risks there is ongoing development of alternative means to assess fibrosis. In recent years intensive research in the field of noninvasive assessment of liver fibrosis allowed to establish few laboratory markers, that answer some questions about severity of the disease. Among these methods there are direct indices using parameters reflecting processes of fibrogenesis and fibrolysis as well as indirect indices using widely available laboratory parameters. This review presents 9 different simple markers with an overview of their statistical performance in determining liver fibrosis and their potential role in management of patients with CHC. Despite conducting many validating studies many questions remain about their indications, accuracy and a need of validation before they are put into widespread use. Further evaluation of noninvasive methods of liver fibrosis prediction is a priority in clinical hepatology research. PMID:21735832

  1. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes

    Energy Technology Data Exchange (ETDEWEB)

    Queisser, Nina; Happ, Kathrin; Link, Samuel [Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg (Germany); Jahn, Daniel [Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg (Germany); Zimnol, Anna [Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg (Germany); Geier, Andreas [Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg (Germany); Schupp, Nicole, E-mail: schupp@uni-duesseldorf.de [Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg (Germany)

    2014-11-01

    Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague–Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased. - Highlights: • Aldosterone has direct profibrotic effects on the liver independent of blood pressure. • Fibrosis is mediated by the mineralocorticoid receptor and

  2. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes

    International Nuclear Information System (INIS)

    Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague–Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased. - Highlights: • Aldosterone has direct profibrotic effects on the liver independent of blood pressure. • Fibrosis is mediated by the mineralocorticoid receptor and

  3. Is it better to use two elastographic methods for liver fibro-sis assessment?

    Institute of Scientific and Technical Information of China (English)

    Ioan Sporea; Roxana (S)irli; Alina Popescu; Simona Bota; Radu Badea; Monica Lup(s)or; Mircea Foc(s)a; Mirela D(a)nil(a)

    2011-01-01

    AIM: To find out if by combining 2 ultrasound based elastographic methods: acoustic radiation force impulse (ARFI) elastography and transient elastography (TE), we can improve the prediction of fibrosis in patients with chronic hepatitis C.METHODS: Our study included 197 patients with chronic hepatitis C. In each patient, we performed, in the same session, liver stiffness (LS) measurements by means of TE and ARFI, respectively, and liver biopsy (LB), assessed according to the Metavir score. 10 LS measurements were performed both by TE and ARFI; median values were calculated and expressed in kilopascals (kPa) and meters/second (m/s), respectively. Only TE and ARFI measurements with IQR < 30% and SR ≥ 60% were considered reliable. RESULTS: On LB 13 (6.6%) patients had F0, 32 (16.2%) had F1, 52 (26.4%) had F2, 47 (23.9%) had F3, and 53 (26.9%) had F4. A direct, strong correlation was found between TE measurements and fibrosis (r = 0.741), between ARFI and fibrosis (r = 0.730) and also between TE and ARFI (r = 0.675). For predicting significant fibrosis (F ≥ 2), for a cut-off of 6.7 kPa, TE had 77.5% sensitivity (Se) and 86.5% specificity (Sp) [area under the receiver operating characteristic curve (AUROC) 0.87] and for a cut-off of 1.2 m/s, ARFI had 76.9% Se and 86.7% Sp (AUROC 0.84). For predicting cirrhosis (F = 4), for a cut-off of 12.2 kPa, TE had 96.2% Se and 89.6% Sp (AUROC 0.97) and for a cut-off of 1.8 m/s, ARFI had 90.4% Se and 85.6% Sp (AUROC 0.91). When both elastographic methods were taken into consideration, for predicting significant fibrosis (F ≥ 2), (TE ≥ 6.7 kPa and ARFI ≥ 1.2 m/s) we obtained 60.5% Se, 93.3% Sp, 96.8% positive predictive value (PPV), 41.4% negative predictive value (NPV) and 68% accuracy, while for predicting cirrhosis (TE ≥ 12.2 kPa and ARFI ≥ 1.8 m/s) we obtained 84.9% Se, 94.4% Sp, 84.9% PPV, 94.4% NPV and 91.8% accuracy.CONCLUSION: TE used in combination with ARFI is highly specific for predicting significant

  4. Effects of heparin on liver fibrosis in patients with chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Jun Shi; Jing-Hua Hao; Wan-Hua Ren; Ju-Ren Zhu

    2003-01-01

    AIM: To evaluate the effects of heparin on liver fibrosis in patients with chronic hepatitis B.METHODS: Fifty-two cases under study were divided into two groups, group A and group B. The two groups were given regular treatment and heparin/low molecular weight heparin (LMWH) treatment respectively. Hepatic functions,serum hyaluronic acid (HA) and type IV collagen levels were measured before and after the treatment, and six caseswere taken liver biopsy twice.RESULTS: After treatment, hepatic functions became significantly better in both groups. Serum HA and type IV collagen levels in group B compared with group A, decreased significantly after treatment. Collagen proliferation also decreased in group B after treatment.CONCLUSION: Heparin/LMWH can inhibit collagen proliferation in liver tissues with hepatitis B.

  5. Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Gallego-Durán, Rocío; Cerro-Salido, Pablo; Gomez-Gonzalez, Emilio; Pareja, María Jesús; Ampuero, Javier; Rico, María Carmen; Aznar, Rafael; Vilar-Gomez, Eduardo; Bugianesi, Elisabetta; Crespo, Javier; González-Sánchez, Francisco José; Aparcero, Reyes; Moreno, Inmaculada; Soto, Susana; Arias-Loste, María Teresa; Abad, Javier; Ranchal, Isidora; Andrade, Raúl Jesús; Calleja, Jose Luis; Pastrana, Miguel; Iacono, Oreste Lo; Romero-Gómez, Manuel

    2016-01-01

    There is a need, in NAFLD management, to develop non-invasive methods to detect steatohepatitis (NASH) and to predict advanced fibrosis stages. We evaluated a tool based on optical analysis of liver magnetic resonance images (MRI) as biomarkers for NASH and fibrosis detection by investigating patients with biopsy-proven NAFLD who underwent magnetic resonance (MR) protocols using 1.5T General Electric (GE) or Philips devices. Two imaging biomarkers (NASHMRI and FibroMRI) were developed, standardised and validated using area under the receiver operating characteristic curve (AUROC) analysis. The results indicated NASHMRI diagnostic accuracy for steatohepatitis detection was 0.83 (95% CI: 0.73-0.93) and FibroMRI diagnostic accuracy for significant fibrosis determination was 0.85 (95% CI: 0.77-0.94). These findings were independent of the MR system used. We conclude that optical analysis of MRI has high potential to define non-invasive imaging biomarkers for the detection of steatohepatitis (NASHMRI) and the prediction of significant fibrosis (FibroMRI) in NAFLD patients. PMID:27514671

  6. MicroRNA-17-5p-activated Wnt/β-catenin pathway contributes to the progression of liver fibrosis

    OpenAIRE

    Yu, Fujun; Lu, Zhongqiu; HUANG, KATE; Wang, Xiaodong; Xu, Ziqiang; Chen, Bicheng; Dong, Peihong; Zheng, Jianjian

    2015-01-01

    Aberrant Wnt/β-catenin pathway contributes to the development of liver fibrosis. MicroRNAs (MiRNAs) are found to act as regulators of the activation of hepatic stellate cell (HSC) in liver fibrosis. However, whether miRNAs activate Wnt/β-catenin pathway in activated HSCs during liver fibrosis is largely unknown. In this study, we found that Salvianolic acid B (Sal B) treatment significantly inhibited liver fibrosis in CCl4-treated rats, HSC-T6 cells and rat primary HSCs, resulting in the supp...

  7. Invasive and non-invasive methods for the assessment of fibrosis and disease progression in chronic liver disease.

    Science.gov (United States)

    Castera, Laurent

    2011-04-01

    Chronic liver diseases represent a major public health problem, accounting for significant morbidity and mortality worldwide. Their prognosis and management greatly depend on the amount and progression of liver fibrosis with the risk of developing cirrhosis. Liver biopsy, traditionally considered as the reference standard for staging of fibrosis, has been challenged over the past decade by the development of novel non invasive methodologies. These methods rely on two distinct but complementary approaches: i) a 'biological' approach based on the dosage of serum biomarkers of fibrosis; ii) a 'physical' approach based on the measurement of liver stiffness using transient elastography (TE). Non invasive methods have been initially studied and validated in chronic hepatitis C but are now increasingly used in other chronic liver diseases, resulting in a significant decrease in the need for liver biopsy. However, they will likely not completely abolish the need for liver biopsy and they should rather be employed as an integrated system with liver biopsy. This review is aimed at discussing the advantages and inconveniences of non invasive methods in comparison with liver biopsy for the management of patients with chronic liver diseases. PMID:21497746

  8. Effects of six months losartan administration on liver fibrosis in chronic hepatitis C patients: A pilot study

    Institute of Scientific and Technical Information of China (English)

    Silvia Sookoian; Maria Alejandra Fernández; Gustavo Casta(n)o

    2005-01-01

    AIM: To evaluate the safety and efficacy of chronic administration of losartan on hepatic fibrosis in chronic hepatitis C patients.METHODS: Fourteen patients with chronic hepatitis C non-responders (n = 10), with contraindications (n = 2)or lack of compliance (n = 2) to interferon plus ribavirin therapy and liver fibrosis were enrolled. Liver and renal function test, clinical evaluation, and liver biopsies were performed at baseline and after losartan administration at a dose of 50 mg/d during the 6 mo. The control group composed of nine patients with the same inclusion criteria and paired liver biopsies (interval 6-14 mo).Histological activity index (HAI) with fibrosis stage was assessed under blind conditions by means of Ishak's score. Subendothelial fibrosis was evaluated by digital image analyses.RESULTS: The changes in the fibrosis stage were significantly different between losartan group (decrease of 0.5±1.3) and controls (increase of 0.89±1.27;P<0.03). In the treated patients, a decrease in fibrosis stage was observed in 7/14 patients vs 1/9 control patients (P<0.04). A decrease in sub-endothelial fibrosis was observed in the losartan group. No differences were found in HAI after losartan administration. Acute and chronic decreases in systolic arterial pressures (P<0.05)were observed after the losartan administration, without changes in mean arterial pressure or renal function.CONCLUSION: Chronic AT-Ⅱ type 1 receptor (AT1R)blockade may reduce liver fibrosis in patients with chronic hepatitis C.

  9. Dynamic changes of capillarization and peri-sinusoid fibrosis in alcoholic liver diseases

    Institute of Scientific and Technical Information of China (English)

    Guang-Fu Xu; Xin-Yue Wang; Gui-Ling Ge; Peng-Tao Li; Xu Jia; De-Lu Tian; Liang-Duo Jiang; Jin-Xiang Yang

    2004-01-01

    AIM: To investigate the dynamic changes of capillarization and peri-sinusoid fibrosis in an alcoholic liver disease model induced by a new method.METHODS: Male SD rats were randomly divided into 6 groups, namely normal, 4 d, 2 w, 4 w, 9 w and 11 w groups.The animals were fed with a mixture of alcohol for designated days and then decollated, and their livers were harvested to examine the pathological changes of hepatocytes, hepatic stellate cells, sinusoidal endothelial cells, sinusoid, peri-sinusoid. The generation of three kinds of extra cellular matrix was also observed.RESULTS: The injury of hepatocytes became severer as modeling going on. Under electronic microscope, fatty vesicles and swollen mitochondria in hepatocytes, activated hepatic stellate cells with fibrils could been seen near or around it. Fenestrae of sinusoidal endothelial cells were decreased or disappeared, sinusoidal basement was formed.Under light microscopy typical peri-sinusoid fibrosis, gridding-like fibrosis, broaden portal areas, hepatocyte's fatty and balloon denaturation, iron sediment, dot necrosis,congregated lymphatic cells and leukocytes were observed.Type Ⅰ collagen showed an increasing trend as modeling going on, slightly recovered when modeling stopped for 2 weeks. Meanwhile, type Ⅳ collagen decreased rapidly when modeling began and recovered after modeling stopped for 2 weeks. Laminin increased as soon as modeling began and did not recover when modeling stopped for 2 weeks.CONCLUSION: The pathological changes of the model were similar to that of human ALD, but mild in degree. It had typical peri-sinusoid fibrosis; however, capillarization seemed to be instable. It may be related with the reduction of type Ⅳ collagen in the basement of sinusoid during modeling.

  10. Roles of Oxidized Diacylglycerol for Carbon Tetrachloride-induced Liver Injury and Fibrosis in Mouse

    International Nuclear Information System (INIS)

    Since there is a report that an inhibitor of protein kinase C (PKC) effectively suppresses the development of hepatic fibrosis, it is suggested that the PKC signaling pathway plays an important role in the pathogenesis of hepatic fibrosis. We reported that oxidized diacylglycerol (DAG), which is an activator of PKC, had a remarkably stronger PKC-activating action than un-oxidized DAG. In the present study, we explored the roles of oxidized DAG in hepatic fibrogenesis using mice, the livers of which developed fibrosis by long-term administration of carbon tetrachloride (CCl4). Liver fibrosis models were created by 4- or 8-week repetitive subcutaneous injections of CCl4 to the backs of C57BL/6J mice. The amount of oxidized DAG was significantly increased in the CCl4-treated group. Moreover, it was found that PKCα, βI, βII and δ were activated. In the CCl4-treated group, phosphorylation of ERK and JNK, which are downstream signal transmitters in the PKC pathway, was increased. It was also found in this group that there was an increase in TIMP-1, which is a fibrogenesis-promoting factor whose expression is enhanced by activated JNK, and of TNF-α, an inflammatory cytokine. Analysis by quantitative real-time RT-PCR showed that expressions of αSMA, collagen I, TNF-α and IL-10 were remarkably increased in the 8-week CCl4-treated group. The above results strongly suggested that oxidized DAG, which is increased by augmented oxidative stress, activated PKCα, βI, βII and δ molecular species and that these molecular species in turn stimulated the phosphorylation of MAP kinases including ERK and JNK, resulting in enhancement of hepatic fibrogenesis

  11. Assessment of liver fibrosis with 2-D shear wave elastography in comparison to transient elastography and acoustic radiation force impulse imaging in patients with chronic liver disease.

    Science.gov (United States)

    Gerber, Ludmila; Kasper, Daniela; Fitting, Daniel; Knop, Viola; Vermehren, Annika; Sprinzl, Kathrin; Hansmann, Martin L; Herrmann, Eva; Bojunga, Joerg; Albert, Joerg; Sarrazin, Christoph; Zeuzem, Stefan; Friedrich-Rust, Mireen

    2015-09-01

    Two-dimensional shear wave elastography (2-D SWE) is an ultrasound-based elastography method integrated into a conventional ultrasound machine. It can evaluate larger regions of interest and, therefore, might be better at determining the overall fibrosis distribution. The aim of this prospective study was to compare 2-D SWE with the two best evaluated liver elastography methods, transient elastography and acoustic radiation force impulse (point SWE using acoustic radiation force impulse) imaging, in the same population group. The study included 132 patients with chronic hepatopathies, in which liver stiffness was evaluated using transient elastography, acoustic radiation force impulse imaging and 2-D SWE. The reference methods were liver biopsy for the assessment of liver fibrosis (n = 101) and magnetic resonance imaging/computed tomography for the diagnosis of liver cirrhosis (n = 31). No significant difference in diagnostic accuracy, assessed as the area under the receiver operating characteristic curve (AUROC), was found between the three elastography methods (2-D SWE, transient elastography, acoustic radiation force impulse imaging) for the diagnosis of significant and advanced fibrosis and liver cirrhosis in the "per protocol" (AUROCs for fibrosis stages ≥2: 0.90, 0.95 and 0.91; for fibrosis stage [F] ≥3: 0.93, 0.95 and 0.94; for F = 4: 0.92, 0.96 and 0.92) and "intention to diagnose" cohort (AUROCs for F ≥2: 0.87, 0.92 and 0.91; for F ≥3: 0.91, 0.93 and 0.94; for F = 4: 0.88, 0.90 and 0.89). Therefore, 2-D SWE, ARFI imaging and transient elastography seem to be comparably good methods for non-invasive assessment of liver fibrosis. PMID:26116161

  12. A case of infantile Dubin-Johnson syndrome with high CT attenuation in the liver

    International Nuclear Information System (INIS)

    We report a case of Dubin-Johnson syndrome (DJS) with severe infantile cholestasis and elevated computed tomography (CT) attenuation of the liver. Increased levels of urinary coproporphyrin I were found as well as pigment granules in the hepatocytes and hepatosteatosis. The CT attenuation was markedly higher in the liver of this patient at the ages of 3 and 7 months than in the spleen or kidneys. This high attenuation may be a finding specific to infantile DJS and, therefore, abdominal CT may be helpful in the diagnosis. (orig.). With 3 figs

  13. Initial study of biexponential model of intravoxel incoherent motion magnetic resonance imaging in evaluation of the liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Chen Cuiyun; Wang Bin; Shi Dapeng; Fu Fangfang; Zhang Jiliang; Wen Zejun; Zhu Shaocheng

    2014-01-01

    Background The diagnosis of liver fibrosis is a difficult task at any time using conventional clinical imaging.Intravoxel incoherent motion (IVIM) can be used to investigate both diffusion and perfusion changes in tissues.This study was designed to determine the value of IVIM in the diagnosis and staging of liver fibrosis.Methods IVIM examinations were performed on a GE 3.0T MR scanner in 25 patients with liver fibrosis and 25 healthy volunteers as the control group.Patients with liver fibrosis diagnosis were confirmed by pathology and staged on a scale of F0-4.The standard ADC values and the values of a biexponential model (slow ADC (Dslow),fast ADC (Dfast) and fraction of fast ADC (FF)) were measured in three liver regions per person.The mean standard ADC values,Dslow values,Dfast values and FF values from the study group were compared among the right posterior hepatic lobe,right anterior hepatic lobe and medial segment of the left lobe.Receiver Operating Characteristic (ROC) curves and independent-samples t-tests were used to calculate the mean standard ADC values,Dslow values,Dfast values and FF values from the study group and the control group.Spearman rho correlation analysis was used for the stage of liver fibrosis.The liver fibrosis stages between the groups F0-1 and F2-4,the groups F0-2 and F3-4 were compared.Results Among the liver fibrosis,there was no significant difference in the mean standard ADC values,Dslow values,Dfast values,and FF values obtained from the right posterior hepatic lobe,right anterior hepatic lobe and medial segment of the left lobe.Using ROC analysis,the Area Under the Curve (AUC) values of standard ADC,Dslow,Dfast,FF were all between 0.7 to 0.9.The mean standard ADC values,Dslow values,Dfast values and FF values of the liver in the study group were significantly lower than the values in the control group (P <0.05).As the stage of the fibrosis increased,the values decreased by Spearman rho correlation analysis.The mean values

  14. MR diffusion weighted imaging for quantification of liver fibrosis in patients with chronic viral hepatitis

    International Nuclear Information System (INIS)

    Objective: The study was to evaluate DWI for quantifying liver fibrosis. Methods: A total of 12 volunteers, 47 patients who had chronic HBV or HCV hepatitis and underwent liver biopsy [Scheuer score for fibrosis(S) and inflammation(G)] were enrolled in this study. They were scanned using a 1.5 T MR unit with b value of 0,250,500,750, 1000 s/mm2. ADCs at b250-1000 and b500-1000 were the average ADCs of b=250, 500, 750, 1000 s/mm2 and b=500, 750, 1000 s/mm2. The studied the correlation between Scbeuer scores and ADC values, and conducted Mann-Whitney U test and Logistic regression to evaluate ADC for prediction of fibrosis scores. Results: The average ADCs were (1.41± 0.11), (1.37 ±0.09), (1.27 ± 0.05), (1.26 ± 0.04), (1.22 ± 0.06) mm2/s respectively from SO to S4, stage at b=750 s/mm2 (F=18.31, P250-1000 (r=-0.727, P750 and the two combined b values, the found significantly lower ADCs in S2 or greater versus S1 or less and in S3 or greater versus S2 or less fibrosis (P750 with the largest AUC of 0.909, sensitivity of 85.7%, and specificity of 100.0% (ADC ≤ 1.35 x 10-3 mm2/s). The best predictor for S3 or greater was b250-1000 with the largest AUC of 0.864, sensitivity of 69.6%, and specificity of 95.8% (ADC ≤ 1.53 x 10-3 mm2/s). Conclusion: DWI can be a good predictor for scoring liver fibrosis for S2 or S3 stage above, while b750 and the combined b values are suitable for evaluation. (authors)

  15. Epigallocatechin-3-gallate attenuates cadmium-induced chronic renal injury and fibrosis.

    Science.gov (United States)

    Chen, Jinglou; Du, Lifen; Li, Jingjing; Song, Hongping

    2016-10-01

    Cadmium (Cd) pollution is a serious environmental problem. Kidney is a main target organ of Cd toxicity. This study was undertaken to investigate the potential protective effects of epigallocatechin-3-gallate (EGCG) against chronic renal injury and fibrosis induced by CdCl2. Rat model was induced by exposing to 250 mg/L CdCl2 through drinking water. The renal function was evaluated by detecting the levels of blood urea nitrogen (BUN) and serum creatinine (SCR). The oxidative stress was measured by detecting the levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione/oxidized glutathione (GSH/GSSG) and renal enzymatic antioxidant status. Additionally, the renal levels of transforming growth factor-β1 (TGF-β1), Smad3, phosphorylation-Smad3 (pp-Smad3), α-smooth muscle actin (α-SMA), vimentin and E-cadherin were measured by western blot assay. Renal levels of microRNA-21 (miR-21), miR-29a/b/c and miR-192 were measured by quantitative RT-PCR. It was found that EGCG ameliorated the CdCl2-induced renal injury, inhibited the level of oxidative stress, normalized renal enzymatic antioxidant status and E-cadherin level, as well as attenuated the over generation of TGF-β1, pp-Smad3, vimentin and α-SMA. EGCG also decreased the production of miR-21 and miR-192, and enhanced the levels of miR-29a/b/c. These results showed that EGCG could attenuate Cd induced chronic renal injury. PMID:27474435

  16. Diagnostic performance of conventional diffusion weighted imaging and diffusion tensor imaging for the liver fibrosis and inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Tosun, Mesude, E-mail: mesude.tosun@kocaeli.edu.tr [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Inan, Nagihan, E-mail: inannagihan@ekolay.net [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Sarisoy, Hasan Tahsin, E-mail: htssarisoy@yahoo.com [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Akansel, Gur, E-mail: gakansel@gmail.com [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Gumustas, Sevtap, E-mail: svtgumustas@hotmail.com [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Gürbüz, Yeşim, E-mail: yesimgurbuz2002@yahoo.com [Department of Pathology, School of Medicine, University of Kocaeli (Turkey); Demirci, Ali, E-mail: alidemirci@kocaeli.edu.tr [Department of Radiology, School of Medicine, University of Kocaeli (Turkey)

    2013-02-15

    Objective: To evaluate the diagnostic accuracy of liver apparent diffusion coefficient (ADC) measured with conventional diffusion-weighted imaging (CDI) and diffusion tensor imaging (DTI) for the diagnosis of liver fibrosis and inflammation. Materials and methods: Thirty-seven patients with histologic diagnosis of chronic viral hepatitis and 34 healthy volunteers were included in this prospective study. All patients and healthy volunteers were examined by 3 T MRI. CDI and DTI were performed using a breath-hold single-shot echo-planar spin echo sequence with b factors of 0 and 1000 s/mm{sup 2}. ADCs were obtained with CDI and DTI. Histopathologically, fibrosis of the liver parenchyma was classified with the use of a 5-point scale (0–4) and inflammation was classified with use of a 4-point scale (0–3) in accordance with the METAVIR score. Quantitatively, signal intensity and the ADCs of the liver parenchyma were compared between patients stratified by fibrosis stage and inflammation grade. Results: With a b factor of 1000 s/mm{sup 2}, the signal intensity of the cirrhotic livers was significantly higher than those of the normal volunteers. In addition, ADCs reconstructed from CDI and DTI of the patients were significantly lower than those of the normal volunteers. Liver ADC values inversely correlated with fibrosis and inflammation but there was only statistically significant for inflammatory grading. CDI performed better than DTI for the diagnosis of fibrosis and inflammation. Conclusion: ADC values measured with CDI and DTI may help in the detection of liver fibrosis. They may also give contributory to the inflammatory grading, particularly in distinguishing high from low grade.

  17. Diagnostic performance of conventional diffusion weighted imaging and diffusion tensor imaging for the liver fibrosis and inflammation

    International Nuclear Information System (INIS)

    Objective: To evaluate the diagnostic accuracy of liver apparent diffusion coefficient (ADC) measured with conventional diffusion-weighted imaging (CDI) and diffusion tensor imaging (DTI) for the diagnosis of liver fibrosis and inflammation. Materials and methods: Thirty-seven patients with histologic diagnosis of chronic viral hepatitis and 34 healthy volunteers were included in this prospective study. All patients and healthy volunteers were examined by 3 T MRI. CDI and DTI were performed using a breath-hold single-shot echo-planar spin echo sequence with b factors of 0 and 1000 s/mm2. ADCs were obtained with CDI and DTI. Histopathologically, fibrosis of the liver parenchyma was classified with the use of a 5-point scale (0–4) and inflammation was classified with use of a 4-point scale (0–3) in accordance with the METAVIR score. Quantitatively, signal intensity and the ADCs of the liver parenchyma were compared between patients stratified by fibrosis stage and inflammation grade. Results: With a b factor of 1000 s/mm2, the signal intensity of the cirrhotic livers was significantly higher than those of the normal volunteers. In addition, ADCs reconstructed from CDI and DTI of the patients were significantly lower than those of the normal volunteers. Liver ADC values inversely correlated with fibrosis and inflammation but there was only statistically significant for inflammatory grading. CDI performed better than DTI for the diagnosis of fibrosis and inflammation. Conclusion: ADC values measured with CDI and DTI may help in the detection of liver fibrosis. They may also give contributory to the inflammatory grading, particularly in distinguishing high from low grade

  18. Herbal medicine Gan‑fu‑kang downregulates Wnt/Ca2+ signaling to attenuate liver fibrogenesis in vitro and in vivo.

    Science.gov (United States)

    Jia, Yujie; Yuan, Lijun; Xu, Tingting; Li, Hanshu; Yang, Guang; Jiang, Miaona; Zhang, Caihua; Li, Cong

    2016-06-01

    The present study was designed to verify the effect of the Chinese prescription Gan‑fu‑kang (GFK) on the treatment of liver fibrosis, and to investigate its underlying mechanisms. Liver fibrosis was established in rats by the subcutaneous administration of 0.5 mg/kg carbon tetrachloride (CCl4) twice a week for 8 weeks. Subsequently, the rats were divided into four CCl4 groups, which were treated daily with vehicle and GFK (31.25, 312.5 and 3,125 mg/kg/day) orally between weeks 9 and 20. The inhibitory action of GFK‑medicated serum on platelet‑derived growth factor (PDGF)‑stimulated HSC‑T6 cells was also investigated. Biochemical parameters, hydroxyproline (Hyp) content and histological changes to the liver were measured. Reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry were used to examine the expression of α‑smooth muscle actin (α‑SMA), PDGF‑BB, PDGF receptor β, collagen type I and II, and the Wnt/Ca2+ signaling pathway. The results showed that GFK significantly alleviated the histological changes, decreased the content of Hyp in the liver and improved liver function in rats. In addition, GFK and GFK‑medicated serum effectively inhibited collagen deposition, reduced the expression of α‑SMA and downregulated the Wnt/Ca2+ signaling pathway in vivo and in vitro, respectively, as well as cell viability (P<0.05). These results indicated that GFK was effective in attenuating liver injury and fibrosis through downregulation of the Wnt/Ca2+ signaling pathway. PMID:27082862

  19. Ameliorative effect of Ganoderma lucidum on carbon tetrachloride-induced liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Wen-Chuan Lin; Wei-Lii Lin

    2006-01-01

    AIM: To investigate the effects of Reishi mushroom,Ganoderma lucidum extract (GLE), on liver fibrosis induced by carbon tetrachloride (CCl4) in rats.METHODS: Rat hepatic fibrosis was induced by CCl4.Forty Wistar rats were divided randomly into 4 groups:control, CCl4, and two GLE groups. Except for rats in control group, all rats were administered orally with CCl4(20%, 0.2 mL/100 g body weight) twice a week for 8weeks. Rats in GLE groups were treated daily with GLE (1 600 or 600 mg/kg) via gastrogavage throughout the whole experimental period. Liver function parameters,such as ALT, AST, albumin, and albumin/globulin (A/G)ratio, spleen weight and hepatic amounts of protein,malondiladehyde (MDA) and hydroxyproline (HP) were determined. Histochemical staining of Sirius red was performed. Expression of transforming growth factor β1(TGF-β1), methionine adenosyltransferase (MAT1) 1A and MAT2A mRNA were detected by using RT-PCR.RESULTS: CCl4 caused liver fibrosis, featuring increase in plasma transaminases, hepatic MDA and HP contents,and spleen weight; and decrease in plasma albumin,A/G ratio and hepatic protein level. Compared with CCl4group, GLE (600, 1 600 mg/kg) treatment significantly increased plasma albumin level and A/G ratio (P< 0.05)and reduced the hepatic HP content (P<0.01). GLE (1600 mg/kg) treatment markedly decreased the activities of transaminases (P< 0.05), spleen weight (P< 0.05) and hepatic MDA content (P<0.05); but increased hepatic protein level (P<0.05). Liver histology in the GLE (1600 mg/kg)-treated rats was also improved (P<0.01).RT-PCR analysis showed that GLE treatment decreased the expression of TGF-β1 (P< 0.05-0.001) and changed the expression of MAT1A (P<0.05-0.01) and MAT2A (P< 0.05-0.001).CONCLUSION: Oral administration of GLE significantly reduces CCl4-induced hepatic fibrosis in rats, probably by exerting a protective effect against hepatocellular necrosis by its free-radical scavenging ability.

  20. Hepatoprotective effect of MMP-19 deficiency in a mouse model of chronic liver fibrosis

    Czech Academy of Sciences Publication Activity Database

    Jiroušková, Markéta; Žbodáková, Olga; Gregor, Martin; Chalupský, Karel; Sarnová, Lenka; Hajduch, M.; Ehrmann, J.; Jirkovska, M.; Sedláček, Radislav

    2012-01-01

    Roč. 7, č. 10 (2012), e46271. E-ISSN 1932-6203 R&D Projects: GA AV ČR IAA500520812; GA ČR GAP303/10/2044 Grant ostatní: MŠMT(CZ) CZ.1.05/1.1.00/02.0109; MŠMT(CZ) CZ.1.05/2.1.00/01.0030 Institutional support: RVO:68378050 Keywords : matrix metalloproteinase * liver * fibrosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.730, year: 2012

  1. The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis.

    Directory of Open Access Journals (Sweden)

    Abdulaleem Alnajar

    Full Text Available Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2 is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

  2. The LIM-Only Protein FHL2 Attenuates Lung Inflammation during Bleomycin-Induced Fibrosis

    Science.gov (United States)

    Schied, Tanja; Chiquet-Ehrismann, Ruth; Loser, Karin; Vogl, Thomas; Ludwig, Stephan; Wixler, Viktor

    2013-01-01

    Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2) is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages. PMID:24260575

  3. Validation of Ten Noninvasive Diagnostic Models for Prediction of Liver Fibrosis in Patients with Chronic Hepatitis B

    OpenAIRE

    Cheng, Jieyao; Hou, Jinlin; Ding, Huiguo; Chen, Guofeng; Xie, Qing; Wang, Yuming; Zeng, Minde; Ou, Xiaojuan; Ma, Hong; Jia, Jidong

    2015-01-01

    Background and Aims Noninvasive models have been developed for fibrosis assessment in patients with chronic hepatitis B. However, the sensitivity, specificity and diagnostic accuracy in evaluating liver fibrosis of these methods have not been validated and compared in the same group of patients. The aim of this study was to verify the diagnostic performance and reproducibility of ten reported noninvasive models in a large cohort of Asian CHB patients. Methods The diagnostic performance of ten...

  4. Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest

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    Bismut Françoise

    2010-04-01

    Full Text Available Abstract Background FibroTest and elastography have been validated as biomarkers of liver fibrosis in the most frequent chronic liver diseases and in the fibrosis screening of patients with diabetes. One challenge was to use them for estimating the prevalence of fibrosis, identifying independent risk factors and to propose screening strategies in the general population. Methods We prospectively studied 7,463 consecutive subjects aged 40 years or older. Subjects with presumed advanced fibrosis (FibroTest greater than 0.48 were re-investigated in a tertiary center. Results The sample characteristics were similar to those of the French population. FibroTest was interpretable in 99.6%. The prevalence of presumed fibrosis was 2.8%, (209/7,463, including cirrhosis in 0.3% (25/7,463; 105/209 (50% subjects with presumed fibrosis accepted re-investigation. Fibrosis was confirmed in 50, still suspected in 27, indeterminate in 25 and not confirmed with false positive FibroTest or false negative elastography in 3 subjects. False negative rate of FibroTest estimated using elastography was 0.4% (3/766. The attributable causes for confirmed fibrosis were both alcoholic and nonalcoholic fatty liver disease (NAFLD in 66%, NAFLD in 13%, alcohol in 9%, HCV in 6%, and other in 6%. Factors independently associated (all P Conclusions Biomarkers have permitted to estimate prevalence of advanced fibrosis around 2.8% in a general population aged 40 years or older, and several risk factors which may be used for the validation of selective or non-selective screening strategies.

  5. Protective effects of garcinol on dimethylnitrosamine-induced liver fibrosis in rats.

    Science.gov (United States)

    Hung, Wei-Lun; Tsai, Mei-Ling; Sun, Pei-Pei; Tsai, Chen-Yu; Yang, Chin-Chou; Ho, Chi-Tang; Cheng, An-Chin; Pan, Min-Hsiung

    2014-11-01

    Garcinol, a polyisoprenylated benzophenone derivative, mainly isolated from Garcinia indica fruit rind, has been suggested to exhibit many biological benefits including antioxidative, anti-inflammatory, and anti-tumor activities. The aim of this study is to evaluate the protective effects of garcinol on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. The administration of DMN for six consecutive weeks resulted in the decrease of body weights, the elevation of serum aminotransferases, as well as histological lesions in livers. However, oral administration of garcinol remarkably inhibited the elevation of aspartate transaminase (AST) and relieved liver damage induced by DMN. Furthermore, our results revealed that garcinol not only effectively reduced the accumulation of extracellular matrix (ECM) components but also inhibited the expression of α-smooth muscle actin (α-SMA) in livers. The expression of transforming growth factor-β1 (TGF-β1) and the phosphorylation of Smad 2 and Smad 3 were also suppressed by garcinol supplementation. In conclusion, our current study suggested that garcinol exerted hepatoprotective and anti-fibrotic effects against DMN-induced liver injury in rats. PMID:25183344

  6. Probability image of tissue characteristics for liver fibrosis using multi-Rayleigh model with removal of nonspeckle signals

    Science.gov (United States)

    Mori, Shohei; Hirata, Shinnosuke; Yamaguchi, Tadashi; Hachiya, Hiroyuki

    2015-07-01

    We have been developing a quantitative diagnostic method for liver fibrosis using an ultrasound image. In our previous study, we proposed a multi-Rayleigh model to express a probability density function of the echo amplitude from liver fibrosis and proposed a probability imaging method of tissue characteristics on the basis of the multi-Rayleigh model. In an evaluation using the multi-Rayleigh model, we found that a modeling error of the multi-Rayleigh model was increased by the effect of nonspeckle signals. In this paper, we proposed a method of removing nonspeckle signals using the modeling error of the multi-Rayleigh model and evaluated the probability image of tissue characteristics after removing the nonspeckle signals. By removing nonspeckle signals, the modeling error of the multi-Rayleigh model was decreased. A correct probability image of tissue characteristics was obtained by removing nonspeckle signals. We concluded that the removal of nonspeckle signals is important for evaluating liver fibrosis quantitatively.

  7. AST-to-platelet ratio index in non-invasive assessment of long-term graft fibrosis following pediatric liver transplantation.

    Science.gov (United States)

    D'Souza, Rashmi S; Neves Souza, Lara; Isted, Alexander; Fitzpatrick, Emer; Vimalesvaran, Sunitha; Cotoi, Corina; Amin, Saista; Heaton, Nigel; Quaglia, Alberto; Dhawan, Anil

    2016-03-01

    Long-term graft fibrosis occurs in the majority of pediatric liver transplant recipients. Serial biopsies to monitor graft health are impractical and invasive. The APRI has been evaluated in pediatric liver disease, but not in the context of post-transplantation fibrosis. We aimed to investigate the validity of APRI as a predictor of long-term graft fibrosis in pediatric liver transplant recipients. This was a retrospective, observational study of a cohort of children who underwent liver transplantation at King's College Hospital between 1989 and 2003, with a relevant dataset available. Protocol liver biopsies were performed at 10-yr follow-up and fibrosis was graded using the Ishak scoring system, with S3-6 denoting "significant fibrosis." APRI was calculated concurrently with biopsy. A total of 39 asymptomatic patients (20 males; median age at transplant, 1.43 yr) underwent protocol liver biopsies at a median of 10.39 yr post-transplantation. APRI was associated with significant fibrosis (p = 0.012). AUROC for APRI as a predictor of significant fibrosis was 0.74 (p = 0.013). The optimal cutoff APRI value for significant fibrosis was 0.45 (sensitivity = 0.67; specificity = 0.79; PPV = 0.67; NPV = 0.79). APRI appears to be a useful non-invasive adjunct in the assessment of significant graft fibrosis in the long-term follow-up of pediatric liver transplant survivors. PMID:26806646

  8. Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver?

    Energy Technology Data Exchange (ETDEWEB)

    Duran, Rafael, E-mail: rafael.duran@chuv.ch [Centre Hospitalier Universitaire Vaudois, University of Lausanne, Diagnostic and Interventional Radiology, Lausanne (Switzerland); Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); Ronot, Maxime, E-mail: Maxime.ronot@bjn.aphp.fr [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); University Paris Diderot, Sorbonne Paris Cité, INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3 Paris (France); Di Renzo, Sara, E-mail: Direnzo.sara@gmail.com [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); Gregoli, Bettina, E-mail: Bettinagregoli@yahoo.it [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); Van Beers, Bernard E., E-mail: Bernard.van-beers@bjn.aphp.fr [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); Vilgrain, Valérie, E-mail: Valerie.vilgrain@bjn.aphp.fr [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); University Paris Diderot, Sorbonne Paris Cité, INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3 Paris (France)

    2015-05-15

    Highlights: • Hemangiomas were similar in patients with or without chronic liver disease on MRI. • Decrease in size & number of hemangiomas could start before the onset of cirrhosis. • T2 shine-through effect was less frequently observed in cirrhosis. - Abstract: Purpose: To compare qualitative and quantitative magnetic resonance (MR) imaging characteristics of hepatic hemangiomas in patients with normal, fibrotic and cirrhotic livers. Materials and methods: Retrospective, institutional review board approved study (waiver of informed consent). Eighty-nine consecutive patients with 231 hepatic hemangiomas who underwent liver MR imaging for lesion characterization were included. Lesions were classified into three groups according to the patients’ liver condition: no underlying liver disease (group 1), fibrosis (group 2) and cirrhosis (group 3). Qualitative and quantitative characteristics (number, size, signal intensities on T1-, T2-, and DW MR images, T2 shine-through effect, enhancement patterns (classical, rapidly filling, delayed filling), and ADC values) were compared. Results: There were 160 (69%), 45 (20%), and 26 (11%) hemangiomas in groups 1, 2 and 3, respectively. Lesions were larger in patients with normal liver (group 1 vs. groups 2 and 3; P = .009). No difference was found between the groups on T2-weighted images (fat-suppressed fast spin-echo (P = .82) and single-shot (P = .25)) and in enhancement patterns (P = .56). Mean ADC values of hemangiomas were similar between groups 1, 2 and 3 (2.11 ± .52 × 10{sup −3} mm{sup 2}/s, 2.1 ± .53 × 10{sup −3} mm{sup 2}/s and 2.14 ± .44 × 10{sup −3} mm{sup 2}/s, P = 87, respectively). T2 shine-through effect was less frequently observed in cirrhosis (P = .02). Conclusion: MR imaging characteristics of hepatic hemangioma were similar in patients with normal compared to fibrotic and cirrhotic livers. Smaller lesion size was observed with liver disease and less T2 shine-through effect was seen in

  9. Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver?

    International Nuclear Information System (INIS)

    Highlights: • Hemangiomas were similar in patients with or without chronic liver disease on MRI. • Decrease in size & number of hemangiomas could start before the onset of cirrhosis. • T2 shine-through effect was less frequently observed in cirrhosis. - Abstract: Purpose: To compare qualitative and quantitative magnetic resonance (MR) imaging characteristics of hepatic hemangiomas in patients with normal, fibrotic and cirrhotic livers. Materials and methods: Retrospective, institutional review board approved study (waiver of informed consent). Eighty-nine consecutive patients with 231 hepatic hemangiomas who underwent liver MR imaging for lesion characterization were included. Lesions were classified into three groups according to the patients’ liver condition: no underlying liver disease (group 1), fibrosis (group 2) and cirrhosis (group 3). Qualitative and quantitative characteristics (number, size, signal intensities on T1-, T2-, and DW MR images, T2 shine-through effect, enhancement patterns (classical, rapidly filling, delayed filling), and ADC values) were compared. Results: There were 160 (69%), 45 (20%), and 26 (11%) hemangiomas in groups 1, 2 and 3, respectively. Lesions were larger in patients with normal liver (group 1 vs. groups 2 and 3; P = .009). No difference was found between the groups on T2-weighted images (fat-suppressed fast spin-echo (P = .82) and single-shot (P = .25)) and in enhancement patterns (P = .56). Mean ADC values of hemangiomas were similar between groups 1, 2 and 3 (2.11 ± .52 × 10−3 mm2/s, 2.1 ± .53 × 10−3 mm2/s and 2.14 ± .44 × 10−3 mm2/s, P = 87, respectively). T2 shine-through effect was less frequently observed in cirrhosis (P = .02). Conclusion: MR imaging characteristics of hepatic hemangioma were similar in patients with normal compared to fibrotic and cirrhotic livers. Smaller lesion size was observed with liver disease and less T2 shine-through effect was seen in hemangiomas developed on cirrhosis, the

  10. Spleen dynamic contrast-enhanced magnetic resonance imaging as a new method for staging liver fibrosis in a piglet model.

    Directory of Open Access Journals (Sweden)

    Li Zhou

    Full Text Available OBJECTIVE: To explore spleen hemodynamic alteration in liver fibrosis with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI, and to determine how to stage liver fibrosis with spleen DCE-MRI parameters. MATERIALS AND METHODS: Sixteen piglets were prospectively used to model liver fibrosis staged by liver biopsy, and underwent spleen DCE-MRI on 0, 5th, 9th, 16th and 21st weekend after modeling this disease. DCE-MRI parameters including time to peak (TTP, positive enhancement integral (PEI, maximum slope of increase (MSI and maximum slope of decrease (MSD of spleen were measured, and statistically analyzed to stage this disease. RESULTS: Spearman's rank correlation tests showed that TTP tended to increase with increasing stages of liver fibrosis (r = 0.647, P0.05, and decreased from stage 2 to 4 (P0.05. Mann-Whitney tests demonstrated that TTP and PEI could classify fibrosis between stage 0 and 1-4, between 0-1 and 2-4, between 0-2 and 3-4, or between 0-3 and 4 (all P<0.01. MSD could discriminate between 0-2 and 3-4 (P = 0.006, or between 0-3 and 4 (P = 0.012. MSI could not differentiate between any two stages. Receiver operating characteristic analysis illustrated that area under receiver operating characteristic curve (AUC of TTP was larger than of PEI for classifying stage ≥1 and ≥2 (AUC = 0.851 and 0.783, respectively. PEI could best classify stage ≥3 and 4 (AUC = 0.903 and 0.96, respectively. CONCLUSION: Spleen DCE-MRI has potential to monitor spleen hemodynamic alteration and classify liver fibrosis stages.

  11. Sequential algorithms combining non-invasive markers and biopsy for the assessment of liver fibrosis in chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Giada Sebastiani; Alessandro Vario; Maria Guido; Alfredo Alberti

    2007-01-01

    AIM: To assess the performance of several noninvasive markers and of our recently proposed stepwise combination algorithms to diagnose significant fibrosis (F ≥ 2 by METAVIR) and cirrhosis (F4 by METAVIR) in chronic hepatitis B (CHB).METHODS: One hundred and ten consecutive patients (80 males, 30 females, mean age: 42.6 ± 11.3) with CHB undergoing diagnostic liver biopsy were included. ASTto-Platelet ratio (APRI), Forns' index, AST-to-ALT Ratio,Goteborg University Cirrhosis Index (GUCI), Hui's model and Fibrotest were measured on the day of liver biopsy.The performance of these methods and of sequential algorithms combining Fibrotest, APRI and biopsy was defined by positive (PPV) and negative (NPV) predictive values, accuracy and area under the curve (AUC).RESULTS: PPV for significant fibrosis was excellent (100%) with Forns and high (> 92%) with APRI, GUCI,Fibrotest and Hui. However, significant fibrosis could not be excluded by any marker (NPV < 65%). Fibrotest had the best PPV and NPV for cirrhosis (87% and 90%, respectively). Fibrotest showed the best AUC for both significant fibrosis and cirrhosis (0.85 and 0.76,respectively). Stepwise combination algorithms of APRI,Fibrotest and biopsy showed excellent performance (0.96 AUC, 100% NPV) for significant fibrosis and 0.95 AUC,98% NPV for cirrhosis, with 50%-80% reduced need for liver biopsy.CONCLUSION: In CHB sequential combination of APRI,Fibrotest and liver biopsy greatly improves the diagnostic performance of the single non-invasive markers. Need for liver biopsy is reduced by 50%-80% but cannot be completely avoided. Non-invasive markers and biopsy should be considered as agonists and not antagonists towards the common goal of estimating liver fibrosis.

  12. Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population.

    Directory of Open Access Journals (Sweden)

    Rabea A Hall

    Full Text Available The progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine 'genetic reference panel' of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury.

  13. Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population.

    Science.gov (United States)

    Hall, Rabea A; Liebe, Roman; Hochrath, Katrin; Kazakov, Andrey; Alberts, Rudi; Laufs, Ulrich; Böhm, Michael; Fischer, Hans-Peter; Williams, Robert W; Schughart, Klaus; Weber, Susanne N; Lammert, Frank

    2014-01-01

    The progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine 'genetic reference panel' of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL) analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs) with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury. PMID:24586654

  14. Angiotensin-converting enzyme inhibitor prevents oxidative stress, inflammation, and fibrosis in carbon tetrachloride-treated rat liver.

    Science.gov (United States)

    Reza, Hasan Mahmud; Tabassum, Nabila; Sagor, Md Abu Taher; Chowdhury, Mohammed Riaz Hasan; Rahman, Mahbubur; Jain, Preeti; Alam, Md Ashraful

    2016-01-01

    Hepatic fibrosis is a common feature of chronic liver injury, and the involvement of angiotensin II in such process has been studied earlier. We hypothesized that anti-angiotensin II agents may be effective in preventing hepatic fibrosis. In this study, Long Evans female rats were used and divided into four groups such as Group-I, Control; Group-II, Control + ramipril; Group-III, CCl4; and Group-IV, CCl4 + ramipril. Group II and IV are treated with ramipril for 14 d. At the end of treatment, the livers were removed, and the level of hepatic marker enzymes (aspartate aminotransferase, Alanine aminotransferase, and alkaline phosphatase), nitric oxide, advanced protein oxidation product , catalase activity, and lipid peroxidation were determined. The degree of fibrosis was evaluated through histopathological staining with Sirius red and trichrome milligan staining. Carbon-tetrachloride (CCl4) administration in rats developed hepatic dysfunction and raised the hepatic marker enzymes activities significantly. CCl4 administration in rats also produced oxidative stress, inflammation, and fibrosis in liver. Furthermore, angiotensinogen-inhibitor ramipril normalized the hepatic enzymes activities and improved the antioxidant enzyme catalase activity. Moreover, ramipril treatment ameliorated lipid peroxidation and hepatic inflammation in CCl4-treated rats. Ramipril treatment also significantly reduced hepatic fibrosis in CCl4-administered rats. In conclusion, our investigation suggests that the antifibrotic effect of ramipril may be attributed to inhibition of angiotensin-II mediated oxidative stress and inflammation in liver CCl4-administered rats. PMID:26862777

  15. Fuzheng Huayu Recipe Ameliorates Liver Fibrosis by Restoring Balance between Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Hepatic Stellate Cells

    OpenAIRE

    Qin Pan; Yu-Qin Wang; Guang-Ming Li; Xiao-Yan Duan; Jian-Gao Fan

    2015-01-01

    Activation of hepatic stellate cells (HSCs) depending on epithelial-to-mesenchymal transition (EMT) reflects the key event of liver fibrosis. Contrastively, mesenchymal-to-epithelial transition (MET) of HSCs facilitates the fibrosis resolution. Here we investigated the effect of Fuzheng Huayu (FZHY) recipe, a Chinese herbal decoction made of Radix Salviae Miltiorrhizae, Semen Persicae, Cordyceps sinensis, Pollen Pini, and Gynostemma pentaphyllum, on liver fibrosis concerning the balance of EM...

  16. Immunological tolerance to pig-serum partially inhibits the formation of septal fibrosis of the liver in Capillaria hepatica-infected rats

    OpenAIRE

    Rodrigo Guimarães Andrade; Bruna Magalhães Gotardo; Bárbara Cristina A Assis; José Mengel; Zilton A. Andrade

    2004-01-01

    Systhematized septal fibrosis of the liver can be induced in rats either by repeated intraperitoneal injections of pig-serum or by Capillaria hepatica infection. The relationship between these two etiological factors, as far as hepatic fibrosis is concerned, is not known, and present investigation attempts to investigate it. C. hepatica-induced septal fibrosis of the liver was considerably inhibited in rats previously rendered tolerant to pig-serum. Pig-serum-tolerant rats developed antibodie...

  17. The role of the replication of hepatitis B virus in the progress of liver fibrosis

    International Nuclear Information System (INIS)

    This article is to investigate the role of the replication of hepatitis B virus in the progress of liver fibrosis, 173 patients with hepatitis B virus were divided into six groups: chronic hepatitis B(CHB)-mild, -middle, -severe groups, Child-Pugh (CP)-A, -B, -C groups, and every group was again divided into two sub-groups according to HBV-DNA. The serum IL-6, IL-8, P III P, c-IV in the patient s were measured by RIA. The results were compared between HBV-DNA(+) and HBV-DNA(-) sub-groups. Except the case in CHB-mild and CP-C groups (P>0.05), the serum levels of IL-6, IL-8, P III P, c-IV were significantly higher in HBV-DNA positive sub-group than that in HBV-DNA negative sub-group (P<0.05), especially in CHB-severe and CP-A groups (P<0.01). The results suggest that hepatitis B virus may activate the hepatic starlike cell and make this progress continue , so the active replication of hepatitis B virus play an important role in the beginning stage and the progress stage of liver fibrosis

  18. The relationship between resistin and ghrelin levels with fibrosis in nonalcoholic fatty liver disease

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    Ahmet Tarık Eminler

    2014-01-01

    Full Text Available Background: Nonalcoholic fatty liver disease (NAFLD is one of the most common causes of chronic liver disease. It is generally accepted that insulin resistance is a pathophysiological factor in the development of NAFLD. In the present study, the aim was to determine the relationship between resistin and ghrelin levels, which were found to be closely related to insulin resistance and fibrosis scores in NAFLD. Materials and Methods : A total of 40 (21 male, 19 female NAFLD patients whose diagnosis was confirmed with biopsy and 40 (18 male, 22 female healthy controls were included in the study. Results: In the comparison of resistin and ghrelin levels, only resistin values were found to be significantly higher in NAFLD group while there was no significant difference in ghrelin values (respectively P < 0.05; P = 0.078. In according to the fibrosis groups there was no difference about fasting plasma glucose, insulin values, Homeostatic Measurement Assessment-Insulin Resistance measurements and also resistin and ghrelin levels. Conclusion: It has been understood that insulin resistance plays an important part in NAFLD. Larger studies are required that investigate the gene expression of hormones influencing insulin resistance, particularly resistin and ghrelin in order to determine their role in NAFLD.

  19. The therapeutic effect of the neuropeptide hormone somatostatin on Schistosoma mansoni caused liver fibrosis

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    Peeters Theo

    2005-06-01

    Full Text Available Abstract Background The neuropeptide somatostatin is one of the major regulatory peptides in the central nervous system and the digestive tract. Our recent work has delineated an association between fibrosis and low levels of endogenous somatostatin plasma levels in Schistosoma mansoni infected subjects. Based on these results this paper explores the therapeutic potential of somatostatin in a mouse model of hepatic fibrosis associated with S. mansoni infections. Methods Groups of outbred Swiss mice were infected with 100 S. mansoni cercariae, infection maintained till weeks 10 or 14, and then somatostatin therapy delivered in two regimens – Either a one or a two-day treatment. All animals were sacrificed one week after therapy and controlled for liver, spleen and total body weight. Circulating somatostatin levels in mice plasma were measured at the time of sacrifice by means of a radio-immuno assay. GraphPad Prism® was used for statistical calculations. Results Somatostatin administration showed little toxicity, probably due to its short half-life. Total liver and spleen weights of S. mansoni infected animals increased over time, with no changes observed due to somatostatin therapy. Total body weights were decreased after infection but were not affected by somatostatin therapy. Snap frozen liver sections were stained with haematoxylin-eosin or Masson's trichrome to study parasite count, hepatocyte status, granuloma size and cellularity. After somatostatin treatment mean egg counts per liver section (43.76 ± 3.56 were significantly reduced as compared to the egg counts in untreated mice after 10 weeks of infection (56.01 ± 3.34 (P = 0.03. Similar significant reduction in parasite egg counts were also observed after somatostatin treatment at 14 weeks of infection (56.62 ± 3.02 as compared to untreated animals (69.82 ± 2.77(P = 0.006. Fibrosis was assessed from the spectrophotometric determination of tissue hydroxyproline. Infection with S

  20. Accurate Prediction of Advanced Liver Fibrosis Using the Decision Tree Learning Algorithm in Chronic Hepatitis C Egyptian Patients

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    Somaya Hashem

    2016-01-01

    Full Text Available Background/Aim. Respectively with the prevalence of chronic hepatitis C in the world, using noninvasive methods as an alternative method in staging chronic liver diseases for avoiding the drawbacks of biopsy is significantly increasing. The aim of this study is to combine the serum biomarkers and clinical information to develop a classification model that can predict advanced liver fibrosis. Methods. 39,567 patients with chronic hepatitis C were included and randomly divided into two separate sets. Liver fibrosis was assessed via METAVIR score; patients were categorized as mild to moderate (F0–F2 or advanced (F3-F4 fibrosis stages. Two models were developed using alternating decision tree algorithm. Model 1 uses six parameters, while model 2 uses four, which are similar to FIB-4 features except alpha-fetoprotein instead of alanine aminotransferase. Sensitivity and receiver operating characteristic curve were performed to evaluate the performance of the proposed models. Results. The best model achieved 86.2% negative predictive value and 0.78 ROC with 84.8% accuracy which is better than FIB-4. Conclusions. The risk of advanced liver fibrosis, due to chronic hepatitis C, could be predicted with high accuracy using decision tree learning algorithm that could be used to reduce the need to assess the liver biopsy.

  1. Accurate Prediction of Advanced Liver Fibrosis Using the Decision Tree Learning Algorithm in Chronic Hepatitis C Egyptian Patients.

    Science.gov (United States)

    Hashem, Somaya; Esmat, Gamal; Elakel, Wafaa; Habashy, Shahira; Abdel Raouf, Safaa; Darweesh, Samar; Soliman, Mohamad; Elhefnawi, Mohamed; El-Adawy, Mohamed; ElHefnawi, Mahmoud

    2016-01-01

    Background/Aim. Respectively with the prevalence of chronic hepatitis C in the world, using noninvasive methods as an alternative method in staging chronic liver diseases for avoiding the drawbacks of biopsy is significantly increasing. The aim of this study is to combine the serum biomarkers and clinical information to develop a classification model that can predict advanced liver fibrosis. Methods. 39,567 patients with chronic hepatitis C were included and randomly divided into two separate sets. Liver fibrosis was assessed via METAVIR score; patients were categorized as mild to moderate (F0-F2) or advanced (F3-F4) fibrosis stages. Two models were developed using alternating decision tree algorithm. Model 1 uses six parameters, while model 2 uses four, which are similar to FIB-4 features except alpha-fetoprotein instead of alanine aminotransferase. Sensitivity and receiver operating characteristic curve were performed to evaluate the performance of the proposed models. Results. The best model achieved 86.2% negative predictive value and 0.78 ROC with 84.8% accuracy which is better than FIB-4. Conclusions. The risk of advanced liver fibrosis, due to chronic hepatitis C, could be predicted with high accuracy using decision tree learning algorithm that could be used to reduce the need to assess the liver biopsy. PMID:26880886

  2. Cordyceps sinensis attenuates renal fibrosis and suppresses BAG3 induction in obstructed rat kidney

    OpenAIRE

    Du, Feng; Li, Si; Wang, Tian; Zhang, Hai-Yan; Zong, Zhi-Hong; Du, Zhen-Xian; Li, De-Tian; Wang, Hua-Qin; Liu, Bo; Miao, Jia-Ning; Bian, Xiao-Hui

    2015-01-01

    BAG3 regulates a number of cellular processes, including cell proliferation, apoptosis, adhesion and migration, and epithelial-mesenchymal transition (EMT). However, the role of BAG3 in renal tubular EMT and renal interstitial fibrosis remains elusive. This study aimed to examine the dynamic expression of BAG3 during renal fibrosis, and to investigate the efficacy of Cordyceps sinensis (C. sinensis) on renal fibrosis. A rat model of unilateral ureteral obstruction (UUO) was established, and t...

  3. High-attenuation mucus plugs on MDCT in a child with cystic fibrosis: potential cause and differential diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Morozov, Andrey; Brown, Shanaree [Indiana University Medical School, Indianapolis, IN (United States); Applegate, Kimberly E. [Riley Hospital for Children, Department of Radiology, Indiana University Medical Center, Indianapolis, IN (United States); Howenstine, Michelle [Riley Hospital for Children, Department of Pulmonology, Indiana University Medical Center, Indianapolis, IN (United States)

    2007-06-15

    High-attenuation mucus plugging is a rare finding in both adults and children. When it occurs, the field of differential diagnoses is typically quite small and includes acute hemorrhage, aspiration of radiodense material, and allergic bronchopulmonary aspergillosis (ABPA). The last of these three diagnoses is the most difficult to make, although ABPA is more commonly seen in children with cystic fibrosis (CF) or asthma. ABPA is radiographically characterized by recurrent mucus plugging, atelectasis, and central bronchiectasis. Thus far, high-attenuation mucus plugs have only been reported in adults. We report a rare case of a child with CF who had high-attenuation mucus plugs and atelectasis that raised the possibility of ABPA. We discuss the differential diagnoses of this finding and the role of multidetector CT in these children. (orig.)

  4. High-attenuation mucus plugs on MDCT in a child with cystic fibrosis: potential cause and differential diagnosis

    International Nuclear Information System (INIS)

    High-attenuation mucus plugging is a rare finding in both adults and children. When it occurs, the field of differential diagnoses is typically quite small and includes acute hemorrhage, aspiration of radiodense material, and allergic bronchopulmonary aspergillosis (ABPA). The last of these three diagnoses is the most difficult to make, although ABPA is more commonly seen in children with cystic fibrosis (CF) or asthma. ABPA is radiographically characterized by recurrent mucus plugging, atelectasis, and central bronchiectasis. Thus far, high-attenuation mucus plugs have only been reported in adults. We report a rare case of a child with CF who had high-attenuation mucus plugs and atelectasis that raised the possibility of ABPA. We discuss the differential diagnoses of this finding and the role of multidetector CT in these children. (orig.)

  5. Tumor necrosis factor-α promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells.

    Directory of Open Access Journals (Sweden)

    Yosuke Osawa

    Full Text Available Tumor necrosis factor (TNF-α, which is a mediator of hepatotoxicity, has been implicated in liver fibrosis. However, the roles of TNF-α on hepatic stellate cell (HSC activation and liver fibrosis are complicated and remain controversial. To explore this issue, the role of TNF-α in cholestasis-induced liver fibrosis was examined by comparing between TNF-α(-/- mice and TNF-α(+/+ mice after bile duct ligation (BDL. Serum TNF-α levels in mice were increased by common BDL combined with cystic duct ligation (CBDL+CDL. TNF-α deficiency reduced liver fibrosis without affecting liver injury, inflammatory cell infiltration, and liver regeneration after CBDL+CDL. Increased expression levels of collagen α1(I mRNA, transforming growth factor (TGF-β mRNA, and α-smooth muscle actin (αSMA protein by CBDL+CDL in the livers of TNF-α(-/- mice were comparable to those in TNF-α(+/+ mice. Exogenous administration of TNF-α decreased collagen α1(I mRNA expression in isolated rat HSCs. These results suggest that the reduced fibrosis in TNF-α(-/- mice is regulated in post-transcriptional level. Tissue inhibitor of metalloproteinase (TIMP-1 plays a crucial role in the pathogenesis of liver fibrosis. TIMP-1 expression in HSCs in the liver was increased by CBDL+CDL, and the induction was lower in TNF-α(-/- mice than in TNF-α(+/+ mice. Fibrosis in the lobe of TIMP-1(-/- mice with partial BDL was also reduced. These findings indicate that TNF-α produced by cholestasis can promote liver fibrosis via TIMP-1 production from HSCs. Thus, targeting TNF-α and TIMP-1 may become a new therapeutic strategy for treating liver fibrosis in cholestatic liver injury.

  6. Aqueous garlic extract alleviates liver fibrosis and renal dysfunction in bile-duct-ligated rats.

    Science.gov (United States)

    Mahmoud, Mona F; Zakaria, Sara; Fahmy, Ahmed

    2014-01-01

    There is accumulating evidence that the renin-angiotensin system (RAS) is involved in hepatic inflammation and fibrogenesis. Garlic was found to lower the activity of the angiotensin converting enzyme (ACE) in the serum of rats in a diabetic model. We examined the effect of an aqueous garlic extract (AGE) on the ACE activity, cholestasis-induced liver fibrosis, and associated renal dysfunction in comparison with the effect of the standard drug enalapril. Both AGE and enalapril were administered orally for six weeks starting from the third day after bile duct ligation (BDL). BDL significantly increased the serum activities of liver enzymes, serum lactate dehydrogenase (LDH) activity, an indicator of liver cell death, serum total bilirubin (TB) level, liver myeloperoxidase (MPO) activity, and liver malondialdehyde (MDA) content. BDL was associated with elevation of serum urea and creatinine levels indicating renal dysfunction. BDL also caused an increase in the transcript levels of the genes coding for tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta-1 (TGF-beta1), and matrix metalloproteinase-13 (MMP-13), a collagenase, in liver tissues. A significant decrease in hepatic reduced glutathione (GSH) was observed in BDL rats, while serum ACE activity was increased. Both AGE and enalapril counteracted all these deleterious changes, with the exception that only AGE reduced the MPO activity. These findings suggest that AGE possesses hepato- and renoprotective properties, similar to enalapril, probably by modulating the levels of proteins such as TNF-alpha, TGF-beta1 and MMP-13, and involving a reduction of ACE and of oxidative stress. PMID:24873034

  7. Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice

    International Nuclear Information System (INIS)

    Arsenic is an environmental toxicant and carcinogen. Exposure to arsenic is associated with development of liver fibrosis and portal hypertension through ill defined mechanisms. We evaluated hepatic fibrogenesis after long term arsenic exposure in a murine model. BALB/c mice were exposed to arsenic by daily gavages of 6 μg/gm body weight for 1 year and were evaluated for markers of hepatic oxidative stress and fibrosis, as well as pro-inflammatory, pro-apoptotic and pro-fibrogenic factors at 9 and 12 months. Hepatic NADPH oxidase activity progressively increased in arsenic exposure with concomitant development of hepatic oxidative stress. Hepatic steatosis with occasional collection of mononuclear inflammatory cells and mild portal fibrosis were the predominant liver lesion observed after 9 months of arsenic exposure, while at 12 months, the changes included mild hepatic steatosis, inflammation, necrosis and significant fibrosis in periportal areas. The pathologic changes in the liver were associated with markers of hepatic stellate cells (HSCs) activation, matrix reorganization and fibrosis including α-smooth muscle actin, transforming growth factor-β1, PDGF-Rβ, pro-inflammatory cytokines and enhanced expression of tissue inhibitor of metalloproteinase-1 and pro(α) collagen type I. Moreover, pro-apoptotic protein Bax was dominantly expressed and Bcl-2 was down-regulated along with increased number of TUNEL positive hepatocytes in liver of arsenic exposed mice. Furthermore, HSCs activation due to increased hepatic oxidative stress observed after in vivo arsenic exposure was recapitulated in co-culture model of isolated HSCs and hepatocytes exposed to arsenic. These findings have implications not only for the understanding of the pathology of arsenic related liver fibrosis but also for the design of preventive strategies in chronic arsenicosis.

  8. Fenofibrate Attenuates Neutrophilic Inflammation in Airway Epithelia: Potential Drug Repurposing for Cystic Fibrosis.

    Science.gov (United States)

    Stolarz, Amanda J; Farris, Ryan A; Wiley, Charla A; O'Brien, Catherine E; Price, Elvin T

    2015-12-01

    A hallmark of cystic fibrosis (CF) lung disease is neutrophilic airway inflammation. Elevated neutrophil counts have been associated with decreased forced expiratory volume in 1 second and poor clinical measures in patients with CF. Interleukin 8 (IL-8), epithelial neutrophil activating protein 78 (ENA-78), tumor necrosis factor alpha (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) contribute to neutrophil activation and disease pathogenesis in the airways of patients with CF. Drugs that modify the production of these chemokines in the airways could potentially benefit CF patients. Thus, we determined the effects of fenofibrate on their production in cell populations obtained from the airways. Human small airway epithelial cells and CF bronchial epithelial cells were treated with IL-1β to induce inflammation. We cotreated the cells with fenofibrate at concentrations ranging from 10 to 50 μM to determine if this drug could attenuate the inflammation. IL-8, ENA-78, TNF-α, GM-CSF, and G-CSF production were measured from the cell culture supernates by ELISA. ANOVA statistical testing was conducted using SPSS 17.0. IL-1β increased the production of each of the chemokines by several fold. Fenofibrate reduced IL-1β induced production of each of these neutrophilic chemokines at the concentrations used. IL-1β increases the production of neutrophilic chemokines in airway epithelial cells. Cotreatment with fenofibrate blunts these processes. Fenofibrate should be explored as a therapeutic option to modulate the abundant neutrophilic inflammation observed in CF. PMID:26258991

  9. Excess body weight, liver steatosis, and early fibrosis progression due to hepatitis C recurrence after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Pierluigi Toniutto; Carlo Fabris; Claudio Avellini; Rosalba Minisini; Davide Bitetto; Elisabetta Rossi; Carlo Smirne; Mario Pirisi

    2005-01-01

    AIM: To investigate how weight gain after OLT affects the speed of fibrosis progression (SFP) during recurrent hepatitis C virus (HCV) infection of the graft.METHODS: Ninety consecutive patients (63 males,median age 53 years; 55 with HCV-related liver disease),transplanted at a single institution, were studied. All were followed for at least 2 years after OLT and had at least one follow-up graft biopsy, performed not earlier than 1 year after the transplant operation. For each biopsy, a single,experienced pathologist gave an estimate of both the staging according to Ishak and the degree of hepatic steatosis.The SFP was quantified in fibrosis units/month (FU/mo).The lipid metabolism status of patients was summarized by the plasma triglycerides/cholesterol (T/C) ratio. Body mass index (BMI) was measured before OLT, and 1 and 2 years after it.RESULTS: In the HCV positive group, the highest SFP was observed in the first post-OLT year. At that time point,a SFP ≤0.100 FU/mo was observed more frequently among recipients who had received their graft from a young donor and had a pre-transplant BMI value >26.0 kg/m2. At completion of the first post-transplant year, a BMI value >26.5 kg/m2 was associated with a T/C ratio ≤1. The proportion of patients with SFP >0.100 FU/mo descended in the following order: female recipients with a high T/C ratio, male recipients with high T/C ratio, and recipients of either gender with low T/C ratio. Hepatic steatosis was observed more frequently in recipients who, in the first post-transplant year, had increased their BMI ≥1.5 kg/m2 in comparison to the pre-transplant value. Hepatic steatosis was inversely associated with the staging score.CONCLUSION: Among HCV positive recipients, excessweight gain post-OLT does not represent a factor favoring early liver fibrosis development and might even be protective against it.

  10. Noninvasive assessment of liver fibrosis: Serum markers and transient elastography (FibroScan) Evaluación no invasiva de fibrosis hepática: Marcadores séricos y elastografía transitoria (FibroScan)

    OpenAIRE

    J. C. Marín-Gabriel; J. A. Solís-Herruzo

    2009-01-01

    Both the prognosis and potential treatment of chronic liver disease greatly depend on the progression of liver fibrosis, which is the ultimate outcome of chronic liver damage. Historically, liver biopsy has been instrumental in adequately assessing patients with chronic liver disease. Histological assessment allows clinicians both to obtain diagnostic information and initiate adequate therapy. However, the technique is not exempt of deleterious effects. Multiple diagnostic tests have been dev...

  11. Hepatectomy After Yttrium-90 (Y90) Radioembolization-Induced Liver Fibrosis.

    Science.gov (United States)

    Maker, Ajay V; August, Carey; Maker, Vijay K; Weisenberg, Elliot

    2016-04-01

    survival in patients with neuroendocrine liver metastases; however, hepatectomy after radioembolization is unique and carries increased morbidity/mortality, likely due to Y90-induced liver fibrosis. We demonstrate images of fibrotic yttrium-90 radiation-affected liver and histological sections of radioembolic microbeads in blood vessels and distributed around resected tumors. PMID:26847353

  12. Effect of host-related factors on the intensity of liver fibrosis in patients with chronic hepatitis C virus infection

    Directory of Open Access Journals (Sweden)

    Costa Luciano Bello

    2002-01-01

    Full Text Available There is increasing interest in the identification of factors associated with liver disease progression in patients infected with hepatitis C virus (HCV. We assessed host-related factors associated with a histologically advanced stage of this disease and determined the rate of liver fibrosis progression in HCV-infected patients. We included patients submitted to liver biopsy, who were anti-HCV and HCV RNA positive, who showed a parenteral risk factor (blood transfusion or intravenous drug use, and who gave information about alcohol consumption.Patients were divided into two groups for analysis: group 1 - grades 0 to 2; group 2 - grades 3 to 4. The groups were compared in terms of sex, age at the time of infection, estimated duration of infection and alcoholism. The rate of fibrosis progression (index of fibrosis was determined based on the relationship between disease stage and duration of infection (years. Logistic regression analysis revealed that age at the time of infection (P or = 40 years (median = 0.47. The main factors associated with a more rapid fibrosis progression were age at the time of infection and the estimated duration of infection. Patients who acquired HCV after 40 years of age showed a higher rate of fibrosis progression.

  13. Accurate Prediction of Advanced Liver Fibrosis Using the Decision Tree Learning Algorithm in Chronic Hepatitis C Egyptian Patients

    OpenAIRE

    Somaya Hashem; Gamal Esmat; Wafaa Elakel; Shahira Habashy; Safaa Abdel Raouf; Samar Darweesh; Mohamad Soliman; Mohamed Elhefnawi; Mohamed El-Adawy; Mahmoud ElHefnawi

    2016-01-01

    Background/Aim. Respectively with the prevalence of chronic hepatitis C in the world, using noninvasive methods as an alternative method in staging chronic liver diseases for avoiding the drawbacks of biopsy is significantly increasing. The aim of this study is to combine the serum biomarkers and clinical information to develop a classification model that can predict advanced liver fibrosis. Methods. 39,567 patients with chronic hepatitis C were included and randomly divided into two separate...

  14. Distribution of hepatic stellate cells and their role in the development of parasitic fibrosis and liver cirrhosis in domestic animals

    OpenAIRE

    Kukolj Vladimir; Nešić Slađan; Vučićević Ivana

    2015-01-01

    Increasing of the extracellular matrix in rats, as well as in humans, occurs as a consequence of hepatic stellate cells (HSCs) activity. The objective of this work was to investigation the role of these cells in the development of fibrosis and liver cirrhosis which occurs as a consequence of infection of sheep and goats with large (Fasciola hepatica) and small (Dicrocoelium dendriticum) fluke. Liver samples taken from 12 cattle and 10 sheep infected under n...

  15. Evaluation of Histological and non-Invasive Methods for the Detection of Liver Fibrosis: The Values of Histological and Digital Morphometric Analysis, Liver Stiffness Measurement and APRI Score.

    Science.gov (United States)

    Halász, Tünde; Horváth, Gábor; Kiss, András; Pár, Gabriella; Szombati, Andrea; Gelley, Fanni; Nemes, Balázs; Kenessey, István; Piurkó, Violetta; Schaff, Zsuzsa

    2016-01-01

    Prognosis and treatment of liver diseases mainly depend on the precise evaluation of the fibrosis. Comparisons were made between the results of Metavir fibrosis scores and digital morphometric analyses (DMA), liver stiffness (LS) values and aminotransferase-platelet ratio (APRI) scores, respectively. Liver biopsy specimens stained with Sirius red and analysed by morphometry, LS and APRI measurements were taken from 96 patients with chronic liver diseases (56 cases of viral hepatitis, 22 cases of autoimmune- and 18 of mixed origin). The strongest correlation was observed between Metavir score and DMA (r = 0.75 p < 0.05), followed in decreasing order by LS and Metavir (r = 0.61), LS and DMA (r = 0.47) LS and APRI (r = 0.35) and Metavir and APRI (r = 0.24), respectively. DMA is a helpful additional tool for the histopathological evaluation of fibrosis, even when the sample size is small and especially in case of advanced fibrosis. The non-invasive methods showed good correlation with the histopathological methods; LS proved to be more accurate than APRI. The stronger correlation between LS values and Metavir scores, as well as the results of DMA in case of appropriate sample size were remarkable. PMID:26189126

  16. Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model.

    Science.gov (United States)

    Karthikeyan, Swathi; Potter, James J; Geschwind, Jean-Francois; Sur, Surojit; Hamilton, James P; Vogelstein, Bert; Kinzler, Kenneth W; Mezey, Esteban; Ganapathy-Kanniappan, Shanmugasundaram

    2016-01-15

    Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis. PMID:26525850

  17. Heat Killed Lactobacillus reuteri GMNL-263 Reduces Fibrosis Effects on the Liver and Heart in High Fat Diet-Hamsters via TGF-β Suppression

    Directory of Open Access Journals (Sweden)

    Wei-Jen Ting

    2015-10-01

    Full Text Available Obesity is one of the major risk factors for nonalcoholic fatty liver disease (NAFLD, and NAFLD is highly associated with an increased risk of cardiovascular disease (CVD. Scholars have suggested that certain probiotics may significantly impact cardiovascular health, particularly certain Lactobacillus species, such as Lactobacillus reuteri GMNL-263 (Lr263 probiotics, which have been shown to reduce obesity and arteriosclerosis in vivo. In the present study, we examined the potential of heat-killed bacteria to attenuate high fat diet (HFD-induced hepatic and cardiac damages and the possible underlying mechanism of the positive effects of heat-killed Lr263 oral supplements. Heat-killed Lr263 treatments (625 and 3125 mg/kg-hamster/day were provided as a daily supplement by oral gavage to HFD-fed hamsters for eight weeks. The results show that heat-killed Lr263 treatments reduce fatty liver syndrome. Moreover, heat-killed Lactobacillus reuteri GMNL-263 supplementation in HFD hamsters also reduced fibrosis in the liver and heart by reducing transforming growth factor β (TGF-β expression levels. In conclusion, heat-killed Lr263 can reduce lipid metabolic stress in HFD hamsters and decrease the risk of fatty liver and cardiovascular disease.

  18. Characteristics of liver tissue for attenuate the gamma radiation

    International Nuclear Information System (INIS)

    It was determined the lineal attenuation coefficient of hepatic tissue before gamma radiation of a source of 137 Cs. When exposing organic material before X or gamma radiation fields, part of the energy of the photons is absorbed by the material, while another part crosses it without producing any effect. The quantity of energy that is absorbed is a measure of the dose that receives the material. The three main mechanisms by means of which the gamma rays interacting with the matter are: The Photoelectric Effect, the Compton dispersion and the Even production; the sum of these three processes is translated in the attenuation coefficient of the radiation. In this work we have used hepatic tissue of bovine, as substitute of the human hepatic tissue, and we have measured the lineal attenuation coefficient for photons of 0.662 MeV. Through a series of calculations we have determined the lineal attenuation coefficient for photons from 10-3 to 10-5 MeV and the measured coefficient was compared with the one calculated. (Author)

  19. Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats

    OpenAIRE

    B. Tang; Qiao, H.; Meng, F.; Sun, X.

    2007-01-01

    Massive hepatectomy associated with infection induces liver dysfunction, or even multiple organ failure and death. Glycyrrhizin has been shown to exhibit anti-oxidant and anti-inflammatory activities. The aim of the present study was to investigate whether glycyrrhizin could attenuate endotoxin-induced acute liver injury after partial hepatectomy. Male Wistar rats (6 to 8 weeks old, weighing 200-250 g) were randomly assigned to three groups of 24 rats each: sham, saline and glycyrrhizin. Rats...

  20. Study on the relationship between levels of serum thrombopoietin (TPO) and hepatic fibrosis markers in patients with chronic liver diseases

    International Nuclear Information System (INIS)

    Objective: To study the relationship between serum thrombopoietin (TPO) and hepatic fibrosis markers levels in patients with chronic liver disease. Methods: Serum thrombopoietin levels were detected and hepatic fibrosis markers with ELISA (HA, LN, PCIII, IVC) in 114 patients with various types of chronic hepatitis and 30 controls. Results: The serum TPO levels in patients with different types of chronic hepatitis inducing cirrhosis were not significantly different from those in controls (P>0.05). Serum TPO levels were correlated with the levels of IVC in the 18 patients with cirrhosis (r=0.517, P<0.05), but not with only hepatic fibrosis marker in any other group of patients. Conclusion: Serum TPO levels was not correlated with the severity of chronic hepatitis but was somewhat correlated with the degree of fibrosis in patients with cirrhosis. (authors)

  1. Association between thrombotic risk factors and extent of fibrosis in patients with non-alcoholic fatty liver diseases

    Institute of Scientific and Technical Information of China (English)

    N Assy; I Bekirov; Y Mejritsky; L Solomon; S Szvalb; O Hussein

    2005-01-01

    AIM: To evaluate the prevalence of genetic and acquired prothrombotic risk factors and their association with the extent of fibrosis and fatty infiltration in patients with non-alcoholic fatty liver disease (NAFLD).METHODS: Forty-four patients with chronic hepatitis (28 men and 16 women, with mean age of 45±11 and 49±12 years, respectively) constituted the patient population of this study. The groups were divided as follows: 15 patients with fatty liver (FL); 15 with non-alcoholic steatohepatitis (NASH); 14 with chronic viral hepatitis (CH) diagnosed by histology and liver technetium scan or ultrasound; and 10 healthy individuals. Thrombophilic, coagulation factors and genetic mutations were diagnosed by standard hemostatic and molecular coagulation assays.RESULTS: Activated protein C (APC) resistance and protein S were the most prevalent thrombotic risk factors (6% and 10% in NAFLD vs 21% and 14% in CH; P<0.01 and P<0.05, respectively). One thrombotic risk factor was identified in 41% of patients (23% mild fibrosis, 18% severe fibrosis) and two thrombotic risk factors in 6% of patients with NAFLD and severe fibrosis. While no differences in APC ratio, lupus anticoagulant, fibrinogen, factor V Leiden,prothrombin, and MTHFR mutation were found. Protein S levels were significantly lower in NASH patients than in patients with FL alone (92±19 vs106±2, P<0.01). Protein C levels were markedly higher in patients with NAFLD and mild or severe fibrosis as compared to the patients with CH, respectively (128±40 vs96±14, P<0.001 or 129±36 vs 88±13, P<0.01).CONCLUSION: Up to 46% of patients with NAFLD may have thrombotic risk factors, and the presence of thrombotic risk factors is correlated with the extent of hepatic fibrosis,suggesting a crucial role of the coagulation system in the pathogenesis of hepatic fibrosis.

  2. Diagnostic Value of Conventional and Doppler Ultrasound Findings in Liver Fibrosis in Patients with Chronic Viral Hepatitis

    Directory of Open Access Journals (Sweden)

    Yasmin Davoudi

    2015-09-01

    Conclusion: Based on these findings, one can conclude that US may be an accurate, noninvasive alternative modality for the diagnosis of liver fibrosis, with fewer side effects than biopsy. It may be especially useful for repetitive follow-up of patients.

  3. Effects of augmentation of liver regeneration recombinant plasmid on rat hepatic fibrosis

    Institute of Scientific and Technical Information of China (English)

    Qing Li; Dian-Wu Liu; Li-Mei Zhang; Bing Zhu; Yu-Tong He; Yong-Hong Xiao

    2005-01-01

    AIM: To investigate the effects of eukaryotic expression of plasmid on augmentation of liver regeneration (ALR) in rat hepatic fibrosis and to explore their mechanisms. METHODS: Ten rats were randomly selected from 50Wistar rats as normal control group. The rest were administered intraperitoneally with porcine serum twice weekly. After 8 wk, they were randomly divided into:model control group, colchicine group (Col), first ALR group (ALR1), second ALR group (ALR2). Then colchicine ALR recombinant plasmid were used to treat them respectively. At the end of the 4th wk, rats were killed.Serum indicators were detected and histopathological changes were graded. Expression of type Ⅰ, Ⅲ, collagen and TIMP-1 were detected by immunohisto-chemistry and expression of TIMP-1 mRNA was detected by semiquantified RT-PCR.RESULTS: The histologic examination showed that the degree of the rat hepatic fibrosis in two ALR groups was lower than those in model control group. Compared with model group, ALR significantly reduced the serum levels of ALT,AST, HA, LN, PCⅢ and Ⅳ (P<0.05). Immunohistochemical staining showed that expression of type Ⅰ, Ⅲ, collagen and TIMP-1 in two ALR groups was ameliorated dramatically compared with model group (Ⅰ collagen: 6.94±1.42, 5.80±1.66and 10.83±3.58 in ALR1, ALR2 and model groups, respectively;Ⅲ collagen: 7.18±1.95, 4.50±1.67 and 10.25±2.61,respectively; TIMP-1: 0.39±0.05, 0.20±0.06 and 0.53±0.12,respectively, P<0.05 or P<0.01). The expression level of TIMP-1 mRNA in the liver tissues was markedly decreased in two ALR groups compared with model group (TIMP-1mRNA/β-actin: 0.89±0.08, 0.65±0.11 and 1.36±0.11 in ALR1, ALR2 and model groups respectively, P<0.01).CONCLUSION: ALR recombinant plasmid has beneficial effects on rat hepatic fibrosis by enhancing regeneration of injured liver cells and inhibiting TIMP-1 expressions.

  4. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Weibin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China); Zhu, Bo; Peng, Xiaomin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhou, Meiling, E-mail: meilingzhou2012@gmail.com [Department of Radiology, Zhongshan Hospital of Fudan University and Shanghai Institute of Medical Imaging, Shanghai 200032 (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China)

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

  5. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    International Nuclear Information System (INIS)

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients

  6. Fibroscan versus simple noninvasive screening tools in predicting fibrosis in high-risk nonalcoholic fatty liver disease patients from Western India

    OpenAIRE

    Pathik, Parikh; Ravindra, Surude; Ajay, Choksey; Prasad, Bhate; Jatin, Patel; Prabha, Sawant

    2015-01-01

    Background The aim of the study was to determine the efficacy of Fibroscan versus noninvasive markers, i.e. nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS); Aspartate-aminotransferase (AST)/platelet ratio (APRI); and AST/Alanine-aminotransferase (AAR) as a screening tool in NAFLD patients with high risk of liver fibrosis. Methods This is a single-center study carried out in patients attending the outpatient department for dyspepsia and diagnosed with fatty liver on ultrasound. L...

  7. Treatment of pig serum-induced rat liver fibrosis with Boschniakia rossica, oxymatrine and interferon-α

    Institute of Scientific and Technical Information of China (English)

    Chun-Song Wu; Xi-Xu Piao; Dong-Ming Piao; Yong-Ri Jin; Cheng-Hao Li

    2005-01-01

    AIM: To investigate the effect of Boschniakia rossica (BR),oxymatrine (OM) and interferon-alpha (IFN-α) 1b on the therapy of rat liver fibrosis and its mechanism.METHODS: By establishing a rat model of pig serum-induced liver fibrosis, liver/weight index and serum alanine transaminase (ALT) were observed to investigate the therapeutic effect of BR, OM and IFN-α. Radioimmunoassay was utilized to measure procollagen type Ⅲ (PCⅢ) and collagen type Ⅳ (CIV). RT-PCR was used to assay the expression of liver transforming growth factor- beta 1 (TGF-β1) mRNA. Immunohistochemistry of alpha-smooth muscle actin (α-SMA) and pathologic changes of liver tissues were also under investigation.RESULTS: Serum PCⅢ and CIV in BR, OM and IFN-α groups were significantly declined compared with those in model group, and their RT-PCR revealed that TGF-β1 mRNA expression was also reduced more than that in model group. Immunohistochemistry demonstrated that α-SMA also declined more than that in model group. Serum ALT in IFN-α, control and model groups was within normal level.Serum ALT in BR group had no significant difference from those of IFN-α, control and model groups. Serum ALT in OM group was significantly higher than those in BR, IFN-α,model, and control groups.CONCLUSION: BR, OM and IFN-α can prevent pig seruminduced liver rat fibrosis by inhibiting the activation of hepatic stellate cells and synthesizing collagen. OM has hepatotoxicity to rat liver fibrosis induced by pig serum.

  8. Liver Steatosis and Fibrosis in OSA patients After Long-term CPAP Treatment: A Preliminary Ultrasound Study.

    Science.gov (United States)

    Buttacavoli, Maria; Gruttad'Auria, Claudia I; Olivo, Mirko; Virdone, Roberto; Castrogiovanni, Alessandra; Mazzuca, Emilia; Marotta, Anna Maria; Marrone, Oreste; Madonia, Salvatore; Bonsignore, Maria R

    2016-01-01

    In cases of morbid obesity, obstructive sleep apnea (OSA) was associated with biopsy-proven liver damage. The role of non-invasive techniques to monitor liver changes during OSA treatment with continuous positive airway pressure (CPAP) is unknown. We used non-invasive ultrasound techniques to assess liver steatosis and fibrosis in severe OSA patients at diagnosis and during long-term CPAP treatment. Fifteen consecutive patients with severe OSA (apnea hypopnea index 52.5 ± 19.1/h) were studied by liver ultrasound and elastography (Fibroscan) at 6-mo (n = 3) or 1-y (n = 12) follow-up. Mean age was 49.3 ± 11.9 y, body mass index (BMI) was 35.4 ± 6.4 kg/m(2). Adherence to CPAP was ≥5 h/night. At baseline, most patients had severe liver steatosis independent of BMI; at follow-up, liver steatosis was not statistically different, but a relationship between severity of steatosis and BMI became apparent (Spearman's rho: 0.53, p = 0.03). Significant fibrosis as assessed by Fibroscan was absent at diagnosis or follow-up (failure or unreliable measurements in four markedly obese patients). Therefore, ultrasound liver assessment is feasible in most OSA patients, and CPAP treatment may positively affect liver steatosis. PMID:26385053

  9. microRNA-222 modulates liver fibrosis in a murine model of biliary atresia

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Wen-jun; Dong, Rui; Chen, Gong, E-mail: chengongzlp@hotmail.com; Zheng, Shan

    2014-03-28

    Highlights: • The RRV infected group showed cholestasis, retardation and extrahepatic biliary atresia. • miR-222 was highly expressed, and PPP2R2A was inhibited in the murine biliary atresia model. • miR-222 profoundly modulated the process of fibrosis in the murine biliary atresia model. • miR-222 might represent a potential target for improving biliary atresia prognosis. - Abstract: microRNA-222 (miR-222) has been shown to initiate the activation of hepatic stellate cells, which plays an important role in the pathogenesis of liver fibrosis. The aim of our study was to evaluate the role of miR-22 in a mouse model of biliary atresia (BA) induced by Rhesus Rotavirus (RRV) infection. New-born Balb/c mice were randomized into control and RRV infected groups. The extrahepatic bile ducts were evaluated. The experimental group was divided into BA group and negative group based on histology. The expression of miR-222, protein phosphatase 2 regulatory subunit B alpha (PPP2R2A), proliferating cell nuclear antigen (PCNA) and phospho-Akt were detected. We found that the experimental group showed signs of cholestasis, retardation and extrahepatic biliary atresia. No abnormalities were found in the control group. In the BA group, miR-222, PCNA and Akt were highly expressed, and PPP2R2A expression was significantly inhibited. Our findings suggest that miR-222 profoundly modulated the process of fibrosis in the murine BA model, which might represent a potential target for improving BA prognosis.

  10. microRNA-222 modulates liver fibrosis in a murine model of biliary atresia

    International Nuclear Information System (INIS)

    Highlights: • The RRV infected group showed cholestasis, retardation and extrahepatic biliary atresia. • miR-222 was highly expressed, and PPP2R2A was inhibited in the murine biliary atresia model. • miR-222 profoundly modulated the process of fibrosis in the murine biliary atresia model. • miR-222 might represent a potential target for improving biliary atresia prognosis. - Abstract: microRNA-222 (miR-222) has been shown to initiate the activation of hepatic stellate cells, which plays an important role in the pathogenesis of liver fibrosis. The aim of our study was to evaluate the role of miR-22 in a mouse model of biliary atresia (BA) induced by Rhesus Rotavirus (RRV) infection. New-born Balb/c mice were randomized into control and RRV infected groups. The extrahepatic bile ducts were evaluated. The experimental group was divided into BA group and negative group based on histology. The expression of miR-222, protein phosphatase 2 regulatory subunit B alpha (PPP2R2A), proliferating cell nuclear antigen (PCNA) and phospho-Akt were detected. We found that the experimental group showed signs of cholestasis, retardation and extrahepatic biliary atresia. No abnormalities were found in the control group. In the BA group, miR-222, PCNA and Akt were highly expressed, and PPP2R2A expression was significantly inhibited. Our findings suggest that miR-222 profoundly modulated the process of fibrosis in the murine BA model, which might represent a potential target for improving BA prognosis

  11. Non-invasive assessment of liver fibrosis using real-time tissue elastography in patients with chronic hepatitis B

    International Nuclear Information System (INIS)

    Aim: To evaluate the utility of the elastic ratio calculated using real-time tissue elastography for assessing liver fibrosis in patients with chronic hepatitis B (CHB). Materials and methods: Ninety-six patients with CHB were enrolled between September 2012 and August 2013. The elastic ratio of the liver for the intrahepatic venous small vessel was calculated to measure liver stiffness. Diagnostic performance of the elastic ratio and aminotransferase–to–platelet ratio index (APRI) were compared with histological fibrosis stage at liver biopsy. In addition, 45 healthy adult volunteers were participated in intra- and interobserver reliability studies. Results: There was no significant influence of hepatitis B e antigen (HBeAg) status or hepatitis B virus DNA levels on the elastic ratio measurements in CHB patients. The elastic ratio was significantly correlated with histological fibrosis stage (r = 0.873, p < 0.001). Cut-off values were 2.62 for stage 2 and over (S ≥ 2), 3.20 for state 3 and over, and 3.86 for stage 4, respectively. The areas under the receiver operating characteristic (ROC) curves for elastic ratio and APRI diagnosis of significant fibrosis (S ≥ 2) was 0.91 (95% CI: 0.84–0.98) and 0.71 (95% CI: 0.57–0.86), and 0.94 (95% CI: 0.89–0.99) and 0.81 (95% CI: 0.71–0.91) for cirrhosis (S = 4), respectively. The elastic ratio measurements had good reproducibility: 0.838 for intra-observer reliability and 0.805 for inter-observer reliability, respectively (p < 0.001). Conclusion: Elastic ratio determined using real-time tissue elastography was an accurate and reproducible method for evaluating liver fibrosis in patients with CHB

  12. Noninvasive assessment of liver fibrosis: Serum markers and transient elastography (FibroScan Evaluación no invasiva de fibrosis hepática: Marcadores séricos y elastografía transitoria (FibroScan

    Directory of Open Access Journals (Sweden)

    J. C. Marín-Gabriel

    2009-11-01

    Full Text Available Both the prognosis and potential treatment of chronic liver disease greatly depend on the progression of liver fibrosis, which is the ultimate outcome of chronic liver damage. Historically, liver biopsy has been instrumental in adequately assessing patients with chronic liver disease. Histological assessment allows clinicians both to obtain diagnostic information and initiate adequate therapy. However, the technique is not exempt of deleterious effects. Multiple diagnostic tests have been developed for the staging of fibrosis using noninvasive methods, most of them in the setting of chronic hepatitis C. The goal of this paper is to review available data on the staging and assessment of liver fibrosis with two methods: serum markers and transient elastography (FibroScan®.

  13. Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    Fin Stolze Larsen; Ben Vainer; Martin Eefsen; Peter Nissen Bjerring; Bent Adel Hansen

    2007-01-01

    AIM: To determine the efficacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis(AIH).METHODS: Retrospectively, clinical parameters,biochemistry and histology were obtained from patient records.RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P=0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P=0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P=0.032),respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P=0.016), while the degree of fibrosis tended to decrease (P=0.049).CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of fibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantialreduction of prednisone dose.

  14. Effects of Da Ding Feng Zhu Decoction in 30 Cases of Liver Fibrosis

    Institute of Scientific and Technical Information of China (English)

    李伟林; 王才党; 张君利

    2003-01-01

    To study the clinical effects of Da Ding Feng Zhu (大定风珠) Decoction on liver fibrosis. 56 patients withliver fibrosis due to chronic hepatitis B were randomly divided into a treatment group (30 cases treatedwith Da Ding Feng Zhu Decoction) and a control group (26 cases treated with colchicine). The serumlevels of hyaluronic acid (HA), procollagen Ⅲ (PC-Ⅲ), Ⅳ collagen (Ⅳ-C) and Laminin (LN) of thepatients were determined, compared and analyzed before treatment and after 3-month treatment in the twogroups. The results showed that in the treatment group, the levels of HA, PC-Ⅲ, Ⅳ-C and LN after3-month treatment were significantly lowered as compared to that before treatment (P<0.01). In thecontrol group, only the HA level was obviously lowered (P<0.05). There was an significant difference(P<0.05) in PC-Ⅲ and Ⅳ-C and a very significant difference (P<0.01) in HA after treatment between thetwo groups. It is therefore concluded that Da Ding Feng Zhu Decoction can lower serum indexes of liverfibrosis.

  15. Advancing the High Throughput Identification of Liver Fibrosis Protein Signatures Using Multiplexed Ion Mobility Spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Baker, Erin Shammel; Burnum-Johnson, Kristin E.; Jacobs, Jon M.; Diamond, Deborah L.; Brown, Roslyn N.; Ibrahim, Yehia M.; Orton, Daniel J.; Piehowski, Paul D.; Purdy, David E.; Moore, Ronald J.; Danielson, William F.; Monroe, Matthew E.; Crowell, Kevin L.; Slysz, Gordon W.; Gritsenko, Marina A.; Sandoval, John D.; Lamarche, Brian L.; Matzke, Melissa M.; Webb-Robertson, Bobbie-Jo M.; Simons, Brenna C.; McMahon, Brian J.; Bhattacharya, Renuka; Perkins, James D.; Carithers, Robert L.; Strom, Susan; Self, Steven; Katze, Michael G.; Anderson, Gordon A.; Smith, Richard D.

    2014-04-01

    Rapid diagnosis of disease states using less invasive, safer, and more clinically acceptable approaches than presently employed is an imperative goal for the field of medicine. While mass spectrometry (MS)-based proteomics approaches have attempted to meet these objectives, challenges such as the enormous dynamic range of protein concentrations in clinically relevant biofluid samples coupled with the need to address human biodiversity have slowed their employment. Herein, we report on the use of a new platform that addresses these challenges by coupling technical advances in rapid gas phase multiplexed ion mobility spectrometry (IMS) separations [1, 2] with liquid chromatography (LC) and MS to dramatically increase measurement sensitivity and throughput, further enabling future MS-based clinical applications. An initial application of the LC-IMS-MS platform for the analysis of blood serum samples from stratified post-liver transplant patients with recurrent fibrosis progression illustrates its potential utility for disease characterization and use in personalized medicine [3, 4].

  16. "Liverscore" is predictive of both liver fibrosis and activity in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Shoukat Ali Arain; Qamar Jamal; Amir Omair

    2011-01-01

    AIM: To formulate a noninvasive index predictive of severity of liver fibrosis and activity in chronic hepatitis C.METHODS: This cross sectional study was conducted on polymerase chain reaction positive, treatment na(i)ve patients. Fibrosis was staged on a five point scale from F0-F4 and activity was graded on a four point scale from A0-A3, according to the METAVIR system. Patients were divided into two overall severity groups, minimal disease (< F2 and < A2) and significant disease (≥ F2 or ≥ A2). Eleven markers were measured in blood. Statistically, the primary outcome variable was identification of minimal and significant overall disease. Indices were formulated using β regression values of different combinations of nine statistically significant factors.Diagnostic performance of these indices was assessed through receiver-operating characteristic curve analysis.RESULTS: A total of 98 patients were included and of these 46 had an overall clinically significant disease. Our final six marker index, Liverscore for Hepatitis C, consisted of age, alanine transaminase, gamma-glutamyl transpeptidase, apolipoprotein A-1, alpha-2 macroglobulin and hyaluronic acid. The area under the curve was found to be 0.813. On a 0-1 scale, negative predictive value at a cutoff level of ≤ 0.40 was 83%, while positive predictive value at ≥ 0.80 remained 89%. Altogether,61% of the patients had these discriminative scores.CONCLUSION: This index is discriminative of minimal and significant overall liver disease in a majority of chronic hepatitis C patients and can help in clinical decision making.

  17. Association of MICA gene polymorphisms with liver fibrosis in schistosomiasis patients in the Dongting Lake region

    Energy Technology Data Exchange (ETDEWEB)

    Gong, Zheng; Luo, Qi-Zhi; Lin, Lin [Department of Immunology, College of Basic Medical Sciences, Central South University, Changsha, Hunan Province (China); Su, Yu-Ping; Peng, Hai-Bo [Central Blood Bank in Yueyang, Yueyang, Hunan Province (China); Du, Kun; Yu, Ping [Department of Immunology, College of Basic Medical Sciences, Central South University, Changsha, Hunan Province (China); Wang, Shi-Ping [Key Laboratory of Schistosomiasis in Hunan, Department of Parasitology, College of Basic Medical Sciences, Central South University, Changsha, Hunan Province (China)

    2012-03-02

    Major histocompatibility complex class I chain-related A (MICA) is a highly polymorphic gene located within the MHC class I region of the human genome. Expressed as a cell surface glycoprotein, MICA modulates immune surveillance by binding to its cognate receptor on natural killer cells, NKG2D, and its genetic polymorphisms have been recently associated with susceptibility to some infectious diseases. We determined whether MICA polymorphisms were associated with the high rate of Schistosoma parasitic worm infection or severity of disease outcome in the Dongting Lake region of Hunan Province, China. Polymerase chain reaction-sequence specific priming (PCR-SSP) and sequencing-based typing (SBT) were applied for high-resolution allele typing of schistosomiasis cases (N = 103, age range = 36.2-80.5 years, 64 males and 39 females) and healthy controls (N = 141, age range = 28.6-73.3 years, 73 males and 68 females). Fourteen MICA alleles and five short-tandem repeat (STR) alleles were identified among the two populations. Three (MICA*012:01/02, MICA*017 and MICA*027) showed a higher frequency in healthy controls than in schistosomiasis patients, but the difference was not significantly correlated with susceptibility to S. japonicum infection (Pc > 0.05). In contrast, higher MICA*A5 allele frequency was significantly correlated with advanced liver fibrosis (Pc < 0.05). Furthermore, the distribution profile of MICA alleles in this Hunan Han population was significantly different from those published for Korean, Thai, American-Caucasian, and Afro-American populations (P < 0.01), but similar to other Han populations within China (P > 0.05). This study provides the initial evidence that MICA genetic polymorphisms may underlie the severity of liver fibrosis occurring in schistosomiasis patients from the Dongting Lake region.

  18. Association of MICA gene polymorphisms with liver fibrosis in schistosomiasis patients in the Dongting Lake region

    International Nuclear Information System (INIS)

    Major histocompatibility complex class I chain-related A (MICA) is a highly polymorphic gene located within the MHC class I region of the human genome. Expressed as a cell surface glycoprotein, MICA modulates immune surveillance by binding to its cognate receptor on natural killer cells, NKG2D, and its genetic polymorphisms have been recently associated with susceptibility to some infectious diseases. We determined whether MICA polymorphisms were associated with the high rate of Schistosoma parasitic worm infection or severity of disease outcome in the Dongting Lake region of Hunan Province, China. Polymerase chain reaction-sequence specific priming (PCR-SSP) and sequencing-based typing (SBT) were applied for high-resolution allele typing of schistosomiasis cases (N = 103, age range = 36.2-80.5 years, 64 males and 39 females) and healthy controls (N = 141, age range = 28.6-73.3 years, 73 males and 68 females). Fourteen MICA alleles and five short-tandem repeat (STR) alleles were identified among the two populations. Three (MICA*012:01/02, MICA*017 and MICA*027) showed a higher frequency in healthy controls than in schistosomiasis patients, but the difference was not significantly correlated with susceptibility to S. japonicum infection (Pc > 0.05). In contrast, higher MICA*A5 allele frequency was significantly correlated with advanced liver fibrosis (Pc < 0.05). Furthermore, the distribution profile of MICA alleles in this Hunan Han population was significantly different from those published for Korean, Thai, American-Caucasian, and Afro-American populations (P < 0.01), but similar to other Han populations within China (P > 0.05). This study provides the initial evidence that MICA genetic polymorphisms may underlie the severity of liver fibrosis occurring in schistosomiasis patients from the Dongting Lake region

  19. Comparison of Histochemical Stainings in Evaluation of Liver Fibrosis and Correlation with Transient Elastography in Chronic Hepatitis

    Directory of Open Access Journals (Sweden)

    Daniela Cabibi

    2015-01-01

    Full Text Available Background and Aim. The best staining to evaluate liver fibrosis in liver hepatitis is still a debated topic. This study aimed to compare Masson’s trichrome (MT, Sirius Red (SR, and orcein stainings in evaluating liver fibrosis in chronic HCV hepatitis (CHC with semiquantitative and quantitative methods (Collagen Proportionate Area (CPA by Digital Image Analysis (DIA and correlate them with transient elastography (TE. Methods. Liver stiffness evaluation of 111 consecutive patients with CHC was performed by TE. Semiquantitative staging by Metavir score system and CPA by DIA were assessed on liver biopsy stained with MT, SR, and orcein. Results. MT, SR, and orcein staining showed concordant results in 89.6% of cases in staging CHC, without significant difference in both semiquantitative and quantitative evaluations of fibrosis. TE values were concordant with orcein levels in 86.5% of the cases and with MT/RS in 77.5% (P<0.001. No significant correlation between the grade of necroinflammatory activity and TE values was found. Conclusion. In CHC, SR/MT and orcein stainings are almost concordant and when discordant, orcein staining is better related to TE values than MT/RS. This suggests that elastic fibers play a more important role than reticular or collagenous ones in determining stiffness values in CHC.

  20. Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice.

    Science.gov (United States)

    Peppler, Willem T; Anderson, Zachary G; Sutton, Charles D; Rector, R Scott; Wright, David C

    2016-05-15

    Sepsis induces an acute inflammatory response in the liver, which can lead to organ failure and death. Given the anti-inflammatory effects of exercise, we hypothesized that habitual physical activity could protect against acute sepsis-induced liver inflammation via mechanisms, including heat shock protein (HSP) 70/72. Male C57BL/6J mice (n = 80, ∼8 wk of age) engaged in physical activity via voluntary wheel running (VWR) or cage control (SED) for 10 wk. To induce sepsis, we injected (2 mg/kg ip) LPS or sterile saline (SAL), and liver was harvested 6 or 12 h later. VWR attenuated increases in body and epididymal adipose tissue mass, improved glucose tolerance, and increased liver protein content of PEPCK (P challenges. This study provides novel evidence that physical activity protects against the inflammatory cascade induced by LPS in the liver and that these effects may be mediated via HSP70/72. PMID:26887432

  1. Study on the Anti-Liver Fibrosis Effect of Benefit Liver Granule (益肝冲剂) and Its Mechanism in Rats

    Institute of Scientific and Technical Information of China (English)

    姚希贤; 崔东来; 孙玉凤; 冯丽英; 孙泽民; 宋梅

    2002-01-01

    Objective:To explore the effect of Benefit Liver Granule (BLG), a traditional Chinese medical preparation, in antagonizing liver fibrosis and its possible mechanism. Methods:Carbon tetrachloride was used to establish the experimental liver fibrosis model of rat. The model rats were randomly divided into 4 groups and BLG, Astragalus (As), Salvia (Sa) and normal saline (for control) respectively were given to them by gastrogavage. Changes of serum alanine transaminase (ALT), aspartate aminotransferase (AST), transforming growth factor α(TGF-α), interleukine-6 (IL-6), liver content of hydroxyproline (Hyp), superoxide dismutase (SOD), malonyldialdehyde (MDA) as well as liver pathology after treatment were observed. A normal control group was also established for control.Results: Pathological examination showed that in the saline group, the structure of normal hepatic lobuli was destroyed with swelled liver cells, focal necrosis, extensive fatty degeneration, and focal inflammatory cell infiltration. Small amounts of proliferated fiber tissue were found in the intra-lobular area, peri-central vein area, portal area and limiting plate area, and formation of pseudolobuli was also seen. In the 3 treated groups, the serum ALT, AST, TGF-α and IL-6 as well as liver content of Hyp, and MDA were lower and SOD were higher than those in the control group significantly, P<0.05 or P<0.01.Conclusion: BLG, As and Sa have the action of anti-liver fibrosis, while BLG has the best effect. The mechanisms are probably related to their effects in regulating TGF-α and IL-6, reducing collagen fiber synthesis, promoting free radical scavenge and anti-lipid peroxidation.

  2. Transient and 2-Dimensional Shear-Wave Elastography Provide Comparable Assessment of Alcoholic Liver Fibrosis and Cirrhosis

    DEFF Research Database (Denmark)

    Thiele, Maja; Detlefsen, Sönke; Møller, Linda Maria Sevelsted;

    2016-01-01

    BACKGROUND & AIMS: Alcohol abuse causes half of all deaths from cirrhosis in the West, but few tools are available for noninvasive diagnosis of alcoholic liver disease. We evaluated 2 elastography techniques for diagnosis of alcoholic fibrosis and cirrhosis; liver biopsy with Ishak score and...... biopsy after an overnight fast. RESULTS: Transient elastography and 2-dimensional shear wave elastography identified subjects in each group with significant fibrosis (Ishak score ≥3) and cirrhosis (Ishak score ≥5) with high accuracy (area under the curve ≥0.92). There was no difference in diagnostic...... predictive value for cirrhosis was >66% in the high-risk group vs approximately 50% in the low-risk group. Evidence of alcohol-induced damage to cholangiocytes, but not ongoing alcohol abuse, affected liver stiffness. The collagen-proportionate area correlated with Ishak grades and accurately identified...

  3. The Role of Ultrasound Imaging in the Definition of the Stage of Liver Fibrosis in Patients with Chronic Hepatitis C

    Directory of Open Access Journals (Sweden)

    Dmitry Konstantinov

    2014-09-01

    Full Text Available The aim of this research was to develop a method for noninvasive staging of liver fibrosis (LF in patients with chronic hepatitis C (CHC based on ultrasound imaging (UI of the abdominal cavity. We examined 124 patients with CHC. The diagnosis was verified on the basis of clinical and epidemiological, serological and molecular biological data. Direct ultrasonic parameters of the structure and hemodynamics of liver and spleen were supplemented with estimated indicators: square of the expected cross-section of the lobes of the liver and spleen, as well as their ratio. On the basis of the discriminant analysis of the survey data of 82 patients, we developed an analytical model (with predictive value of 95.2% for interval estimation of the fibrosis degree in CHC patients. We have concluded that UI performed on modern equipment, including Doppler, is able to determine the degree of LF without resorting to histological verification.

  4. Immunological detection of the type V collagen propeptide fragment, PVCP-1230, in connective tissue remodeling associated with liver fibrosis

    DEFF Research Database (Denmark)

    Vassiliadis, Efstathios; Veidal, Sanne Skovgård; Simonsen, Henrik;

    2011-01-01

    AIM: Liver fibrosis involves excessive remodeling and deposition of fibrillar extracellular matrix (ECM) components, which leads to malfunction of the organ, causing significant morbidity and mortality. The aim of this study was to assess whether levels of a type V collagen fragment, the propeptide......) = 0.3305). CONCLUSIONS: Increased serum levels of CO5-1230 were associated with the extent of collagen deposition in two different models of fibrotic processes in the liver. The data indicate that formation of type V collagen may be of value as a disease-specific diagnostic biomarker that reflects the...... CO5-1230, indicate the amount of collagen deposited during liver fibrosis. METHODS: A specific competitive enzyme-linked immunosorbent assay (ELISA) was developed to measure CO5-1230 levels. The sequence TAALGDIMGH located at the start of the C-terminal propeptide between amino acid position 1230...

  5. Alpha-lipoic acid attenuates cardiac fibrosis in Otsuka Long-Evans Tokushima Fatty rats

    OpenAIRE

    Lee Jung Eun; Yi Chin-ok; Jeon Byeong Tak; Shin Hyun Joo; Kim Soo Kyoung; Jung Tae Sik; Choi Jun Young; Roh Gu Seob

    2012-01-01

    Abstract Background Hyperglycemia leads to cardiac oxidative stress and an imbalance in glucose homeostasis. Diabetic cardiomyopathy is characterised by cardiac hypertrophy and fibrosis. However, the underlying mechanisms of diabetic cardiomyopathy are not fully understood. This study aimed to investigate the effects of alpha-lipoic acid (ALA) on cardiac energy metabolism, antioxidant effect, and fibrosis in the hearts of Otsuka Long-Evans Tokushima fatty (OLETF) rats. Methods Animals were se...

  6. Cordyceps sinensis attenuates renal fibrosis and suppresses BAG3 induction in obstructed rat kidney.

    Science.gov (United States)

    Du, Feng; Li, Si; Wang, Tian; Zhang, Hai-Yan; Zong, Zhi-Hong; Du, Zhen-Xian; Li, De-Tian; Wang, Hua-Qin; Liu, Bo; Miao, Jia-Ning; Bian, Xiao-Hui

    2015-01-01

    BAG3 regulates a number of cellular processes, including cell proliferation, apoptosis, adhesion and migration, and epithelial-mesenchymal transition (EMT). However, the role of BAG3 in renal tubular EMT and renal interstitial fibrosis remains elusive. This study aimed to examine the dynamic expression of BAG3 during renal fibrosis, and to investigate the efficacy of Cordyceps sinensis (C. sinensis) on renal fibrosis. A rat model of unilateral ureteral obstruction (UUO) was established, and the expression of BAG3 and α-SMA, and the efficacy of C. sinensis on renal fibrosis induced by UUO were examined. The results showed that UUO led to collagen accumulation, which was significantly suppressed by C. sinensis. UUO increased the expression of BAG3 and α-SMA, a mesenchymal marker, while UUO induced BAG3 and α-SMA expression was significantly inhibited by C. sinensis. In addition, immunohistochemical staining demonstrated that BAG3 immunoreactivity was restricted to tubular epithelium. In conclusion, BAG3 is a potential target for the prevention and/or treatment of renal fibrosis, and C. Sinensis is a promising agent for renal fibrosis. PMID:26175854

  7. Genetically Attenuated Plasmodium berghei Liver Stages Persist and Elicit Sterile Protection Primarily via CD8 T Cells

    OpenAIRE

    Mueller, Ann-Kristin; Deckert, Martina; Heiss, Kirsten; Goetz, Kristin; Matuschewski, Kai; Schlüter, Dirk

    2007-01-01

    Live-attenuated Plasmodium liver stages remain the only experimental model that confers complete sterile protection against malaria. Irradiation-attenuated Plasmodium parasites mediate protection primarily by CD8 T cells. In contrast, it is unknown how genetically attenuated liver stage parasites provide protection. Here, we show that immunization with uis3(−) sporozoites does not cause breakthrough infection in T and B-cell-deficient rag1−/− and IFN-γ−/− mice. However, protection was abolish...

  8. Evaluation of Liver Fibrosis Using Texture Analysis on Combined-Contrast-Enhanced Magnetic Resonance Images at 3.0T

    Directory of Open Access Journals (Sweden)

    Takeshi Yokoo

    2015-01-01

    Full Text Available Purpose. To noninvasively assess liver fibrosis using combined-contrast-enhanced (CCE magnetic resonance imaging (MRI and texture analysis. Materials and Methods. In this IRB-approved, HIPAA-compliant prospective study, 46 adults with newly diagnosed HCV infection and recent liver biopsy underwent CCE liver MRI following intravenous administration of superparamagnetic iron oxides (ferumoxides and gadolinium DTPA (gadopentetate dimeglumine. The image texture of the liver was quantified in regions-of-interest by calculating 165 texture features. Liver biopsy specimens were stained with Masson trichrome and assessed qualitatively (METAVIR fibrosis score and quantitatively (% collagen stained area. Using L1 regularization path algorithm, two texture-based multivariate linear models were constructed, one for quantitative and the other for quantitative histology prediction. The prediction performance of each model was assessed using receiver operating characteristics (ROC and correlation analyses. Results. The texture-based predicted fibrosis score significantly correlated with qualitative (r=0.698, P<0.001 and quantitative (r=0.757, P<0.001 histology. The prediction model for qualitative histology had 0.814–0.976 areas under the curve (AUC, 0.659–1.000 sensitivity, 0.778–0.930 specificity, and 0.674–0.935 accuracy, depending on the binary classification threshold. The prediction model for quantitative histology had 0.742–0.950 AUC, 0.688–1.000 sensitivity, 0.679–0.857 specificity, and 0.696–0.848 accuracy, depending on the binary classification threshold. Conclusion. CCE MRI and texture analysis may permit noninvasive assessment of liver fibrosis.

  9. Accelerated CCl4-induced liver fibrosis in Hjv-/- mice, associated with an oxidative burst and precocious profibrogenic gene expression.

    Directory of Open Access Journals (Sweden)

    Giada Sebastiani

    Full Text Available Hereditary hemochromatosis is commonly associated with liver fibrosis. Likewise, hepatic iron overload secondary to chronic liver diseases aggravates liver injury. To uncover underlying molecular mechanisms, hemochromatotic hemojuvelin knockout (Hjv-/- mice and wild type (wt controls were intoxicated with CCl(4. Hjv-/- mice developed earlier (by 2-4 weeks and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF and, notably, the iron-regulatory hormone hepcidin. Hence, CCl4-induced liver fibrogenesis was exacerbated and progressed precociously in Hjv-/- animals. Even though livers of naïve Hjv-/- mice were devoid of apparent pathology, they exhibited oxidative stress and immunoreactivity towards α-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2-3 fold vs. wt, p<0.05 levels of α1-(I-collagen, TGF-β1, endothelin-1 and PDGF mRNAs, indicative of early fibrogenesis. Our data suggest that hepatic iron overload in parenchymal cells promotes oxidative stress and triggers premature profibrogenic gene expression, contributing to accelerated onset and precipitous progression of liver fibrogenesis.

  10. Exacerbating effects of human parvovirus B19 NS1 on liver fibrosis in NZB/W F1 mice.

    Directory of Open Access Journals (Sweden)

    Tsai-Ching Hsu

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disorder with unknown etiology that impacts various organs including liver. Recently, human parvovirus B19 (B19 is recognized to exacerbate SLE. However, the effects of B19 on liver in SLE are still unclear. Herein we aimed to investigate the effects of B19 on liver in NZB/W F1 mice by injecting subcutaneously with PBS, recombinant B19 NS1, VP1u or VP2, respectively. Our experimental results revealed that B19 NS1 protein significantly enhanced the TGF-β/Smad fibrotic signaling by increasing the expressions of TGF-β, Smad2/3, phosphorylated Smad2/3, Smad4 and Sp1. The consequent fibrosis-related proteins, PAI-1 and α-SMA, were also significantly induced in livers of NZB/W F1 mice receiving B19 NS1 protein. Accordingly, markedly increased collagen deposition was also observed in livers of NZB/W F1 mice receiving B19 NS1 protein. However, no significant difference was observed in livers of NZB/W F1 mice receiving B19 VP1u or VP2 as compared to the controls. These findings indicate that B19 NS1 plays a crucial role in exacerbating liver fibrosis in NZB/W F1 mice through enhancing the TGF-â/Smad fibrotic signaling.

  11. Magnetic resonance-based total liver volume and magnetic resonance-diffusion weighted imaging for staging liver fibrosis in mini-pigs

    Institute of Scientific and Technical Information of China (English)

    Hang Li; Tian-Wu Chen; Xiao-Li Chen; Xiao-Ming Zhang; Zhen-Lin Li; Nan-Lin Zeng; Li Zhou

    2012-01-01

    AIM:TO determine whether and how magnetic resonance imaging (MRI)-based total liver volume (TLV) and diffusion weighted imaging (DWI) could predict liver fibrosis.METHODS:Sixteen experimental mature mini-pigs (6 males,10 females),weighing between 20.0 and 24.0 kg were prospectively used to model liver fibrosis induced by intraperitoneal injection of 40% CCl4 dissolved in fat emulsion twice a week for 16 wk,and by feeding 40% CCl4 mixed with maize flour twice daily for the subsequent 5 wk.All the survival animals underwent percutaneous liver biopsy and DWI using b =300,500 and 800 s/mm2 followed by abdominal gadolinium-enhanced MRI at the 0,5th,9th,16th and 21st weekend after beginning of the modeling.TLV was obtained on enhanced MRI,and apparent diffusion coefficient (ADC) was obtained on DWI.Hepatic tissue specimens were stained with hematoxylin and Masson's trichrome staining for staging liver fibrosis.Pathological specimens were scored using the human METAVIR classification system.Statistical analyses were performed to determine whether and how the TLV and ADC could be used to predict the stage of liver fibrosis.RESULTS:TLV increased from stage 0 to 2 and decreased from stage 3 (r =0.211; P < 0.001).There was a difference in TLV between stage 0-1 and 2-4 (P =0.03) whereas no difference between stage 0-2 and 3-4 (P =0.71).TLV could predict stage ≥ 2 [area under receiver operating characteristic curve (AUC) =0.682].There was a decrease in ADC values with increasing stage of fibrosis for b =300,500 and 800s/mm2 (r =-0.418,-0.535 and-0.622,respectively;all P < 0.001).Differences were found between stage 0-1 and 2-4 in ADC values for b =300,500 and 800 s/mm2,and between stage 0-2 and 3-4 for b =500 or 800 s/mm2 (all P < 0.05).For predicting stage ≥ 2 and ≥ 3,AUC was 0.803 and 0.847 for b =500 s/mm2,and 0.848 and 0.887 for b =800 s/mm2,respectively.CONCLUSION:ADC for b =500 or 800 s/mm2 could be better than TLV and ADC for b =300 s/mm2 to predict

  12. Total Glucosides of Danggui Buxue Tang Attenuate BLM-Induced Pulmonary Fibrosis via Regulating Oxidative Stress by Inhibiting NOX4

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    Ping Zhao

    2015-01-01

    Full Text Available Pulmonary fibrosis (PF is a serious chronic lung disease with unknown pathogenesis. Researches have confirmed that oxidative stress which is regulated by NADPH oxidase-4 (NOX4, a main source of reactive oxygen species (ROS, is an important molecular mechanism underlying PF. Previous studies showed that total glucosides of Danggui Buxue Tang (DBTG, an extract from a classical traditional Chinese herbal formula, Danggui Buxue Tang (DBT, attenuated bleomycin-induced PF in rats. However, the mechanisms of DBTG are still not clear. We hypothesize that DBTG attenuates PF through regulating the level of oxidative stress by inhibiting NOX4. And we found that fibrosis indexes hydroxyproline (HYP and type I collagen (Col-I were lower in DBTG groups compared with the model group. In addition, the expression of transforming growth factor-β1 (TGF-β1 and expression of alpha smooth muscle actin (α-SMA were also much more decreased than the model group. For oxidative stress indicators, DBTG blunted the decrease of superoxide dismutase (SOD activity, total antioxidant capacity (T-AOC, and the increase in malondialdehyde (MDA, 8-iso-prostaglandin in lung homogenates. Treatment with DBTG restrained the expression of NOX4 compared to the model group. Present study confirms that DBTG inhibits BLM-induced PF by modulating the level of oxidative stress via suppressing NOX4.

  13. Comparison of ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis

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    Friedrich-Rust Mireen

    2010-09-01

    Full Text Available Abstract Background FibroTest (FT is the most frequently used serum fibrosis marker and consists of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoproteinA1, haptoglobin, GGT, bilirubin. The Enhanced Liver Fibrosis (ELF test consists of an algorithm of three fibrosis markers (hyaluronic acid, amino-terminal propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1. While a systematic review has shown comparable results for both individual markers, there has been no direct comparison of both markers. Methods In the present study, the ELF-test was analyzed retrospectively in patients with chronic liver disease, who received a liver biopsy, transient elastography (TE and the FibroTest using histology as the reference method. Histology was classified according to METAVIR and the Ludwig's classification (F0-F4 for patients with chronic hepatitis C and B virus (HCV, HBV infection and primary biliary cirrhosis (PBC, respectively. Results Seventy-four patients were analysed: 36 with HCV, 10 with HBV, and 28 with PBC. The accuracy (AUROC for the diagnosis of significant fibrosis (F≥2 for ELF and FibroTest was 0.78 (95%CI:0.67-0.89 and 0.69 (95%-CI:0.57-0.82, respectively (difference not statistically significant, n.s.. The AUROC for the diagnosis of liver cirrhosis was 0.92 (95%CI:0.83-1,00, and 0.91 (95%CI:0.83-0.99, respectively (n.s.. For 66 patients with reliable TE measurements the AUROC for the diagnosis of significant fibrosis (cirrhosis for TE, ELF and FT were 0.80 (0.94, 0.76 (0.92, and 0.67 (0.91, respectively (n.s.. Conclusion FibroTest and ELF can be performed with comparable diagnostic accuracy for the non-invasive staging of liver fibrosis. Serum tests are informative in a higher proportion of patients than transient elastography.

  14. Transforming growth factor β3 attenuates the development of radiation-induced pulmonary fibrosis in mice by decreasing fibrocyte recruitment and regulating IFN-γ/IL-4 balance.

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    Xu, Long; Xiong, Shanshan; Guo, Renfeng; Yang, Zhihua; Wang, Qianjun; Xiao, Fengjun; Wang, Haibao; Pan, Xiujie; Zhu, Maoxiang

    2014-11-01

    Radiation-induced pulmonary fibrosis is a frequently occurred complication from radiotherapy of thoracic tumors. The transforming growth factor-β (TGF-β) superfamily plays a key regulatory role in pulmonary fibrosis. As TGF-β3 showed the potential anti-fibrotic properties especially in scar-less wound healing as opposed to the fibrotic function of TGF-β1, we sought to explore the role of TGF-β3 in radiation-induced pulmonary fibrosis. A single thoracic irradiation of 20 Gy was applied in mice to establish the model of radiation-induced pulmonary fibrosis and the mice were treated by intraperitoneal injections of recombinant TGF-β3 weekly after irradiation. We found that TGF-β3 decelerated the progress of radiation-induced pulmonary fibrosis and hindered the recruitment of fibrocytes to lung. In addition, Th1 response was suppressed as shown by diminished IFN-γ in bronchoalveolar lavage fluid (BALF) after irradiation, and enhancement of Th2 response was marked by increased IL-4 in BALF. TGF-β3 administration significantly attenuated these effects and increased the percentage of Tregs in lung during the progression of pulmonary fibrosis. Taken together, these data suggest that TGF-β3 might be involved in the regulatory mechanism for attenuation of radiation-induced pulmonary fibrosis. PMID:24996042

  15. Experimental induction of liver fibrosis in young guinea pigs by combined application of copper sulphate and aflatoxin B1.

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    Seffner, W; Schiller, F; Lippold, U; Dieter, H H; Hoffmann, A

    1997-08-22

    Aflatoxin B1 alone (0.05 mg resp. 0.037 mg/kg/d), copper alone (6.6 mg/kg/d or 200 mg/l drinking water) or a combination of both was administered orally for 6 months to young guinea pigs from the first/second day of life. In the copper group there were no pathomorphological changes. For the aflatoxin B1 group, liver damage was established. In the combined group, liver injury was more frequent and more severe compared to the aflatoxin B1 group and biliary copper excretion was diminished compared with the copper group. Histologically, only the livers of this group exhibited degeneration, atrophy and steatosis of liver cells, inflammatory processes and a more or less prominent fibrosis. For childhood cirrhosis (ICC and ICT) a combined etiology--a liver damaging agent plus elevated alimentary copper--is a plausible hypothesis. PMID:9334826

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

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    Roberto Muga

    Full Text Available 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.

  17. Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway.

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    Liu, Qingmei; Chu, Haiyan; Ma, Yanyun; Wu, Ting; Qian, Feng; Ren, Xian; Tu, Wenzhen; Zhou, Xiaodong; Jin, Li; Wu, Wenyu; Wang, Jiucun

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis. PMID:27278104

  18. Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway

    Science.gov (United States)

    Liu, Qingmei; Chu, Haiyan; Ma, Yanyun; Wu, Ting; Qian, Feng; Ren, Xian; Tu, Wenzhen; Zhou, Xiaodong; Jin, Li; Wu, Wenyu; Wang, Jiucun

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis. PMID:27278104

  19. A novel fibrosis index comprising a non-cholesterol sterol accurately predicts HCV-related liver cirrhosis.

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    Magdalena Ydreborg

    Full Text Available Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5-6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI in the paper, was based on the model: Log-odds (predicting cirrhosis = -12.17+ (age × 0.11 + (BMI (kg/m(2 × 0.23 + (D7-lathosterol (μg/100 mg cholesterol×(-0.013 + (Platelet count (x10(9/L × (-0.018 + (Prothrombin-INR × 3.69. The area under the ROC curve (AUROC for prediction of cirrhosis was 0.91 (95% CI 0.86-0.96. The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82-0.98. In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection.

  20. A quantitative index measured on 99mTc GSA SPECT/CT 3D fused images to evaluate severe fibrosis in patients with chronic liver disease

    International Nuclear Information System (INIS)

    We compared quantitative indices estimated by use of technetium-99m galactosyl human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT)/computed tomography (CT) fused imaging and hepatic fibrosis in patients with chronic liver disease. On the basis of pathological findings we divided 161 patients into non-severe and severe fibrosis groups (n=81 and n=80, respectively). We measured 2 indices by 99mTc-GSA SPECT/CT fused imaging: liver uptake value (LUV) = [radioactivity (whole liver)/radioactivity (injected)] x 100/body surface area, and functional liver index (FLI)=[radioactivity (hepatocytes)/radioactivity (injected)] x 100/liver volume. We compared these indices with biochemical and histopathological results. Univariate and multivariate analyses showed that FLI, LUV, liver and heart ROIs at 15 min post-injection (LHL15), and prothrombin time were significant independent predictors of severe fibrosis. On the basis of receiver operating characteristics analysis, the areas under curve values of FLI, LUV, LHL15, and prothrombin time for predicting severe fibrosis were 0.83, 0.73, 0.69, and 0.68, respectively. Using an FLI value of 0.053, it was possible to predict severe fibrosis with 65% sensitivity, 88% specificity, and 76% accuracy. Assessment of functional hepatocytes by use of 99mTc-GSA SPECT/CT fused images is useful for identifying pathological liver fibrosis. (author)

  1. Peroxiredoxin 2: a potential biomarker for early diagnosis of Hepatitis B Virus related liver fibrosis identified by proteomic analysis of the plasma

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    Wang Haijian

    2010-10-01

    Full Text Available Abstract Background Liver fibrosis is a middle stage in the course of chronic Hepatitis B virus (HBV infection, which will develop into cirrhosis and eventually hepatocellular carcinoma (HCC if not treated at the early stage. Considering the limitations and patients' reluctance to undergo liver biopsy, a reliable, noninvasive diagnostic system to predict and assess treatment and prognosis of liver fibrosis is needed. The aim of this study was to identify biomarkers for early diagnosis of HBV related liver fibrosis. Method Plasma samples from 7 healthy volunteers and 27 HBV infected patients with different stages of fibrosis were selected for 2-DIGE proteomic screening. One-way ANOVA analysis was used to assess differences in protein expression among all groups. The alteration was further confirmed by western blotting. Plasma levels of 25 serological variables in 42 healthy volunteers and 68 patients were measured to establish a decision tree for the detection of various stages fibrosis. Result The up-regulated proteins along with fibrosis progress included fibrinogen, collagen, macroglobulin, hemopexin, antitrypsin, prealbumin and thioredoxin peroxidase. The down-regulated proteins included haptoglobin, serotransferrin, CD5 antigen like protein, clusterin, apolipoprotein and leucine-rich alpha-2-glycoprotein. For the discrimination of milder stage fibrosis, the area under curve for Prx II was the highest. Four variables (PT, Pre, HA and Prx II were selected from the 25 variables to construct the decision tree. In a training group, the correct prediction percentage for normal control, milder fibrosis, significant fibrosis and early cirrhosis was 100%, 88.9%, 95.2% and 100%, respectively, with an overall correct percent of 95.9%. Conclusion This study showed that 2-D DIGE-based proteomic analysis of the plasma was helpful in screening for new plasma biomarkers for liver disease. The significant up-expression of Prx II could be used in the early

  2. Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet

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    Sodhi, Komal; Puri, Nitin; Favero, Gaia; Stevens, Sarah; Meadows, Charles; Abraham, Nader G.; Rezzani, Rita; Ansinelli, Hayden; Lebovics, Edward; Shapiro, Joseph I.

    2015-01-01

    Background Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox. Hypothesis We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction. Methods and Results We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP. Conclusion Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the

  3. Vitamin D Attenuates Kidney Fibrosis via Reducing Fibroblast Expansion, Inflammation, and Epithelial Cell Apoptosis.

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    Arfian, Nur; Muflikhah, Khusnul; Soeyono, Sri Kadarsih; Sari, Dwi Cahyani Ratna; Tranggono, Untung; Anggorowati, Nungki; Romi, Muhammad Mansyur

    2016-01-01

    Kidney fibrosis is the common final pathway of chronic kidney diseases (CKD). It is characterized by myofibroblast formation, inflammation, and epithelial architecture damage. Vitamin D is known as a renoprotective agent, although the precise mechanism is not well understood. This study aimed to elucidate the effect of vitamin D in fibroblast expansion, inflammation, and apoptosis in kidney fibrosis. We performed unilateral ureteral obstruction (UUO) in male Swiss-Webster background mice (3 months, 30-40 grams) to induce kidney fibrosis. The mice (n=25) were divided into five groups: UUO, 3 groups treated with different oral vitamin D doses (0.125 µg/kg (UUO+VD1), 0.25 µg/kg (UUO+VD2), and 0.5 µg/kg (UUO+VD3), and a Sham operation (SO) group with ethanol 0.2% supplementation. We sacrificed the mice on day14 after the operation and harvested the kidney. We made paraffin sections for histological analysis. Tubular injury and fibrosis were quantified based on periodic acid-Schiff (PAS) and Sirius Red (SR) staining. Immunostaining was done for examination of myofibroblasts (αSMA), fibroblasts (PDGFRβ), TLR4, and apoptosis (TUNEL). We did RNA extraction and cDNA for Reverse transcriptase PCR (RT-PCR) experiment for measuring MCP-1, ICAM-1, TLR4, and collagen 1 expression. TGFβ1 level was quantified using ELISA. We observed a significantly lower levels of fibrosis (pexpression of collagen1, as well as inflammation-mediator expression (MCP-1, ICAM-1, TLR4) in the UUO+VD-1 group compared with the SO group. Vitamin D reduces kidney fibrosis through inhibition of fibroblast activation, and ameliorates epithelial cell architecture. PMID:27578035

  4. MicroRNA-21 is associated with fibrosis in a rat model of nonalcoholic steatohepatitis and serves as a plasma biomarker for fibrotic liver disease.

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    Takeuchi-Yorimoto, Ayano; Yamaura, Yu; Kanki, Masayuki; Ide, Tetsuya; Nakata, Ayumi; Noto, Takahisa; Matsumoto, Masahiro

    2016-09-01

    Evidence indicates that hepatic fibrosis is the initial lesion of cirrhosis or hepatocellular carcinoma in diseases such as nonalcoholic steatohepatitis (NASH). To induce NASH, we fed rats a choline-deficient and iron-supplemented L-amino acid-defined (CDAA) diet. Histopathological examination revealed that fibrosis appeared from week 4 and progressed to bridging fibrosis from week 12. Using qRT-PCR assays, we detected increased expression of miR-21, Mmp-9, and Timp-1 in liver that peaked during week 4, when fibrosis was first detected. The expression pattern of miR-21 in plasma paralleled that in liver. Fibrosis tended to be resolved within 12 weeks of a recovery period after 12 weeks of feeding, and the expression of miR-21, Timp-1, and Mmp-9 decreased in liver. Comprehensive analyses of miRNA and mRNA expression in the liver using samples acquired at week 4 detected 16 miRNAs and 11 mRNAs that are mutually-interacting fibrosis-related factors. We therefore conclude that miR-21 was closely associated with fibrosis in a rat model of NASH and has potential as a plasma biomarker for hepatic fibrosis. PMID:27320964

  5. The value of multi-slice spiral CT liver perfusion imaging to evaluate the chronic hepatic fibrosis and cirrhosis

    International Nuclear Information System (INIS)

    Objective: To investigate the value of the MSCT liver perfusion imaging parameters in the evaluation of the chronic hepatic fibrosis and cirrhosis. Methods: Liver CT perfusion (CTP) was performed in 107 participants,including 31 patients with mild hepatic fibrosis (S1, S2), 34 patients with severe hepatic fibrosis (S3, S4) and early stage of hepatic cirrhosis which conformed by liver pathologic biopsy, 42 patients with hepatic cirrhosis who had typical clinical and image signs, and 30 healthy subjects as control group. The data of CTP (HAP, PVP, LTP, HPI and TTP) at different stages were obtained with Body perfect CT-syngo CT2007A and control study with histopathologic stage. Compared the study index by the one-way ANOVA analysis. Used Spearman rank correlation to analysis the relationship between liver perfusion imaging parameters and the degrees of the chronic hepatic fibrosis. Used Logistic regression to analysis the maximum regression coefficient among the liver perfusion imaging parameters, which affected the histopathologic stage mostly. Results: In the subgroups of the chronic hepatic fibrosis S1, S2, S3, S4 to the hepatic cirrhosis,HAP values was (28.9 ±8.6), (24.6 ±2.4), (29.2 ±2.3) and (38.9 ± 7.0) ml · 100 ml-1 · min-1, respectively. HAP decreased firstly,then increased. Statistic analysis showed the difference of HAP between later-stage cirrhosis and other groups (F=40.26, P<0.01). PVP values of above subgroups was (111.3 ± 18.1), (92.9 ±5.3), (73.0 ±9.0) and (54.1 ± 13.8) ml · 100 ml-1 ·min-1, respectively. TLP values of above subgroups was (140.2 ± 25.9), (117.1 ± 4.5), (102.3 ± 8.7)and (93.0 ± 11.8) ml · 100 ml-1·min-1, respectively. The difference of PVP, TLP among each subgroup was significant (F=136.79, 67.40, respectively, P<0.01). HPI values of above subgroups was (20.4 ± 2.6)%, (21.0 ±2.1)%, (28.5 ±3.1)% and (42.6± 11.1)%, respectively. TTP values of above subgroups was (123.7±22.2), (137.1 ±27.1), (145.0 ±28.6) and

  6. Rapamycin ameliorates CCl4-induced liver fibrosis in mice through reciprocal regulation of the Th17/Treg cell balance.

    Science.gov (United States)

    Gu, Lei; Deng, Wen-Sheng; Sun, Xiao-Fei; Zhou, Hong; Xu, Qing

    2016-08-01

    Previous investigations have suggested that the activation of Th17 cells and/or deficiency of regulatory T cells (Tregs) are involved in the pathogenesis of liver fibrosis. The aim of the present study was to investigate the effect of rapamycin on immune responses in a carbon tetrachloride (CCl4)-induced murine liver fibrosis model. Liver fibrosis was induced by intraperitoneal administration with CCl4. Following injection of CCl4, the mice were treated intraperitoneally with rapamycin (1.25 mg/kg/day) for 8 weeks. Hematoxylin and eosin staining and Masson's trichrome staining were used for histological examination. The protein levels of forkhead/winged helix transcription factor P3, retinoic-acid-related orphan receptor (ROR)‑γt in liver tissue were determined by western blotting, the frequency of Th17 and Treg cells in the liver was evaluated by flow cytometry, and a suppression assay was measured by incorporating [3H]‑thymidine. In addition, to explore the effect of Tregs expanded with rapamycin on hepatic stellate cells (HSC), HSCs were co‑cultured with Tregs from rapamycin or phosphate‑buffered saline‑treated mice. It was found that rapamycin treatment led to a significant reduction in the number of Th17 cells and in the expression levels of ROR‑γt in the liver tissues. Simultaneously, the results of the present study showed a significant increase in the frequency of Tregs and a marked enhancement in the expression of forkhead/winged helix transcription factor P3 in the rapamycin‑treated mice. Furthermore, the Tregs in rapamycin‑treated mice had significantly higher suppressive effects, compared with the cells from mice treated with phospphate‑buffered saline. Consequently, rapamycin treatment prevented the development of CCl4-induced hepatic fibrosis, which was shown by its histological appearances. These results suggested that the immunosuppressive effect of rapamycin on liver fibrosis was associated with the suppression of hepatic

  7. Responder Interferon λ Genotypes Are Associated With Higher Risk of Liver Fibrosis in HIV–Hepatitis C Virus Coinfection

    Science.gov (United States)

    Moqueet, Nasheed; Cooper, Curtis; Gill, John; Hull, Mark; Platt, Robert W.; Klein, Marina B.

    2016-01-01

    Background. Liver fibrosis progresses faster in individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Interferon λ3 (IFN-λ3) has both antiviral and proinflammatory properties. Genotypes at IFNL single-nucleotide proteins (SNPs; rs12979860CC and rs8099917TT) are linked to higher HCV clearance, potentially via rs8103142. We examined the relationship between IFN-λ genotypes and significant liver fibrosis in HIV-HCV coinfection. Methods. From the prospective Canadian Co-infection Cohort (n = 1423), HCV RNA–positive participants in whom IFN-λ genotypes were detected and who were free of fibrosis, end-stage liver disease, and chronic hepatitis B at baseline (n = 485) were included. Time to significant fibrosis (defined as an aspartate transaminase level to platelet count ratio index [APRI] of ≥1.5) by IFN-λ genotypes was analyzed using Cox proportional hazards, with adjustment for age, sex, ethnicity, alcohol use, CD4+ T-cell count, HCV genotype, γ-glutamyl transferase level, and baseline APRI. Haplotype analysis was performed, with adjustment for ethnicity. Results. A total of 125 participants developed fibrosis over 1595 person-years (7.84 cases/100 person-years; 95% confidence interval [CI], 6.58–9.34 cases/100 person-years). Each genotype was associated with an increased fibrosis risk, with adjusted hazard ratios of 1.37 (95% CI, .94–2.02) for rs12979860CC, 1.34 (95% CI, .91–1.97) for rs8103142TT, and 1.79 (95% CI, 1.24–2.57) for rs8099917TT. Haplotype TCT was also linked with a higher risk (hazard ratio, 1.14 [95% CI, .73–1.77]). Conclusions. IFN-λ SNPs rs12979860, rs8099917, and rs81013142 were individually linked to higher rates of fibrosis in individuals with HIV-HCV coinfection. IFN-λ genotypes may be useful to target HCV treatments to people who are at higher risk of liver disease. PMID:26984148

  8. Efficacy of Chinese medicine Yi-gan-kang granule in prophylaxis and treatment of liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Xi-Xian Yao; Sbu-Lin Jiang; You-Wei Tang; Dong-Mei Yao; Xin Yao

    2005-01-01

    AIM: To investigate the efficacy of a Chinese medicine, Yi-gan-kang granule (granules for benefiting the liver), in prophylaxis and treatment of liver fibrosis in rats and its possible mechanism.METHODS: One hundred and forty Sprague-Dawley rats were randomly divided into seven groups (20 each): group 1, blank control group without any interference during the study; group 2, CCl4-induced liver fibrosis group; group 3, pig serum-induced liver fibrosis group; group 4, prophylaxis group of CCl4-induced liver fibrosis by Yi-gan-kang, group 5,prophylaxis group of pig serum-induced liver fibrosis by Yi-gan-kang, group 6, treatment group of CCl4-induced liver fibrosis by Yi-gan-kang, group 7, treatment group of CCl4-induced liver fibrosis by Yi-gan-kang. At wk 6, 10, 14 and 20(baseline for CCl4 or big serum induction), five rats in each group were anesthetized and their livers were removed for pathological studies including immunohistochemicalstudies for α-SMA, type Ⅰ collagen and in situ hybridization of tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA of hepatic stellate cells (HSCs). Anti-lipid peroxidation in isolated mitochondria and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay for proliferation and terminal deoxynucleotidyl transferasemedicated dUTP-biotin nick end-labeling (TUNEL), flow cytometry and electron microscopy for apoptosis in isolated HSCs were also studied.RESULTS: The mean number of pseudolobuli at wk 10,14 and 20 in the prophylaxis group was significantly less than that in the control group (P<0.05 or 0.01). The effectof prophylaxis at wk 14 in CCl4 rats and at wk 10 in pig serum-induced rats was much better than that of treatment group (P<0.01). The thickness (in μm) of fibers both in pig serum-induced prophylaxis and in treatment groups at wk 14 and. 20 was significantly less than that in control group (P<0.05). The number of fibers both in prophylaxis and in treatment groups from wk 10 or 14

  9. Diffusion weighted imaging for quantification of liver fibrosis in patients using normalized apparent diffusion coefficient values at 3.0 T MR

    International Nuclear Information System (INIS)

    Objective: The purpose of this study is to discuss the diagnostic accuracy of normalized liver ADC using the spleen and renal cortex as reference organs for the diagnosis of liver fibrosis. Methods: Forty three patients with liver disease (chronic liver disease group) at compensated stage and 10 healthy volunteers (control group) were retrospectively assessed with diffusion-weighted imaging at a 3.0 T MR unit. Liver ADC, spleen ADC, renal ADC and normalized ADC (defined as the ratio of liver ADC to spleen ADC or renal cortex ADC, S-ADC and R-ADC for short) were measured in patients stratified by fibrosis stage. Spearman analysis was used to see the correlation between fibrosis stages and ADC, one-way ANOVA was used to compare the ADCs in different fibrosis stages. Logistic regression analysis was used to determine the performance of ADC for prediction of liver fibrosis, and show the area under the curve (AUC), sensitivity and specificity choosing the optimal cutoff value that maximized the Youden index. Results: Ten volunteers belonged to S0 stage. From S0 to S4 stage, there were 2, 5, 9, 12 and 15 patients, correspondingly, liver ADC were (1.37±0.13) ×10-3, (1.33±0.16) ×10-3, (1.17±0.16) ×10-3, (1.23±0.14) ×10-3 and (1.12 ±0.11) × 10-3 mm2/s, S-ADC were 1.86 ±0.18, 1.68 ±0.12, 1.34 ±0.14, 1.48 ±0.15 and 1.34±0.10, R-ADC were 0.71 ±0.08, 0.68 ±0.12, 0.61 ±0.09, 0.64 ±0.11 and 0.60 ±0.08 respectively, and the differences among them were significant (F=6.48, 18.70 and 3.04, P<0.05). The correlation between fibrosis stage and S-ADC was stronger than between fibrosis stage and liver ADC, R-ADC (r=-0.71, -0.51, -0.41; P<0.01). S-ADC was superior to liver ADC and R-ADC for detection of S2, S3 and S4 fibrosis stage (Youden index: 0.91, 0.58, and 0.59). Conclusion: Spleen normalized liver ADC improves diagnostic accuracy for detection of liver fibrosis than liver ADC and renal normalized liver ADC. (authors)

  10. Pentraxin 3 Is a Predictor for Fibrosis and Arterial Stiffness in Patients with Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Kadir Ozturk

    2016-01-01

    Full Text Available Objective. The aim of the present study was to investigate whether pentraxin 3 (PTX3 can be a new noninvasive marker for prediction of liver fibrosis in patients with NAFLD. We also aimed to evaluate the relationship between PTX3 and atherosclerosis in patients with NAFLD. Method. Fifty-four male patients with biopsy-proven NAFLD and 20 apparently healthy male volunteers were included. PTX3 levels were determined, using an ELISA method (R&D Sysytems, Quantikine ELISA, USA. To detect the presence of subclinical atherosclerosis in NAFLD, measurements of CIMT, FMD, and cf-PWV levels were performed. Results. PTX3 levels in NAFLD patients with fibrosis were higher than both NAFLD patients without fibrosis and controls (P=0.032 and P=0.028, respectively, but there was no difference between controls and NAFLD patients without fibrosis in terms of PTX3 levels (P=0.903. PTX3 levels were strongly correlated with cf-PWV (r=0.359, P=0.003, whereas no significant correlation was found with other atherosclerosis markers, CIMT and FMD. Conclusion. Elevated plasma PTX3 levels are associated with the presence of fibrosis in patients with NAFLD, independently of metabolic syndrome components. This study demonstrated that for the first time there is a close association between elevated PTX3 levels and increased arterial stiffness in patients with NAFLD.

  11. Protective Effect of the Total Saponins from Rosa laevigata Michx Fruit against Carbon Tetrachloride-Induced Liver Fibrosis in Rats

    OpenAIRE

    Deshi Dong; Lianhong Yin; Yan Qi; Lina Xu; Jinyong Peng

    2015-01-01

    In this study, the protective effect of the total saponins from Rosa laevigata Michx (RLTS) against liver fibrosis induced by carbon tetrachloride (CCl4) in rats was evaluated. The results showed that RLTS significantly rehabilitated the levels of alanine aminotransferase, aspartate aminotransferase, malondialdehyde, glutathione, glutathione peroxidase, catalase, superoxide dismutase, hydroxyproline, α-smooth muscle actin, collagen I, collagen III and fibronectin, which were confirmed using ...

  12. A Study on the dynamic alterations of serum HA in rats with carbontetrachloride-induced liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Lan Ma; Li Sheng Zhao; Chun Hua Li; Qi Lu; Ren Kuan Li; Shuang Sheng Deng

    2000-01-01

    AIM To study the clinical significance of alterations of serum hyaluronic acid in rats with carbontetrachioride-induced liver fibrosis.METHODS Rat liver fibrosis model was induced by carbon tetrachloride (CC14). The rats were divided intofive groups; group 1 (control): 0 week with no CCl4-inducing; group 2, 3, 4 and 5: 3, 6, 9 and 12 weeksafter CCl4-induction respectively. Serum HA level was analysed among various liver fibrosis groups andcontrol, and then compared the HA findings with the hepatic histopathology.RESULTS During rat liver fibrosis, serum HA levels of the liver fibrosis groups (group 2: 7.98ng/mL;group 3: 20.10 ng/mL; group 4:229.73 ng/mL; group 5:324,74 ng/mL) were significantly higher thanthat of control group (group 1:0.21 ng/mL) (P<0.01), in which group 4 and group 5 are much higher1094 times (229.73ng/mL/0.21 ng/mL) and 1546 times (324.74 ng/mL/0.21 ng/mL) than group 1respectively. When compared with each other, the serum HA levels are 38 times (7.98ng/mL/0.21 ng/mL; P<0.01, group 2 vs group 1); 2.5 times (20.10ng/mL/7.98 ng/mL; P<0.01, group 3 vsgroup 2); 11.4 times (229.73 ng/mL/20.10 ng/mL; P<0.01, group 4 vs group 3); 1.4 times (324.74 ng/mL/229.73 ng/mL; P<0.01, group 5 vs group 4) respectively.CONCLUSION The results demonstrated that the dynamic alterations of serum HA play an important rolein the early clinical diagnosis and staging of liver cirrhosis.

  13. Hepatic and Splenic Acoustic Radiation Force Impulse Shear Wave Velocity Elastography in Children with Liver Disease Associated with Cystic Fibrosis

    Directory of Open Access Journals (Sweden)

    Teresa Cañas

    2015-01-01

    Full Text Available Background. Liver disease associated with cystic fibrosis (CFLD is the second cause of mortality in these patients. The diagnosis is difficult because none of the available tests are specific enough. Noninvasive elastographic techniques have been proven to be useful to diagnose hepatic fibrosis. Acoustic radiation force impulse (ARFI imaging is an elastography imaging system. The purpose of the work was to study the utility of liver and spleen ARFI Imaging in the detection of CFLD. Method. 72 patients with cystic fibrosis (CF were studied and received ARFI imaging in the liver and in the spleen. SWV values were compared with the values of 60 healthy controls. Results. Comparing the SWV values of CFLD with the control healthy group, values in the right lobe were higher in patients with CFLD. We found a SWV RHL cut-off value to detect CFLD of 1.27 m/s with a sensitivity of 56.5% and a specificity of 90.5%. CF patients were found to have higher SWC spleen values than the control group. Conclusions. ARFI shear wave elastography in the right hepatic lobe is a noninvasive technique useful to detect CFLD in our sample of patients. Splenic SWV values are higher in CF patients, without any clinical consequence.

  14. Inhibition of SIRT2 suppresses hepatic fibrosis.

    Science.gov (United States)

    Arteaga, Maribel; Shang, Na; Ding, Xianzhong; Yong, Sherri; Cotler, Scott J; Denning, Mitchell F; Shimamura, Takashi; Breslin, Peter; Lüscher, Bernhard; Qiu, Wei

    2016-06-01

    Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis. PMID:27125275

  15. Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet

    International Nuclear Information System (INIS)

    Rennin-angiotensin system is involved in liver fibrogenesis through activating hepatic stellate cells (HSCs). Telmisartan (Tel) is an angiotensin II type 1 receptor antagonist, could function as a selective peroxisome proliferator-activated receptor γ activator. Here we studied the effect of Tel on liver fibrosis, pre-neoplastic lesions in vivo and primary HSCs in vitro. In vivo study, we used the choline-deficient L-amino acid-defined (CDAA)-diet induced rat NASH model. The rats were fed the CDAA diet for 8 weeks to induce liver fibrosis and pre-neoplastic lesions, and then co-administrated with Tel for another 10 weeks. Tel prevented liver fibrogenesis and pre-neoplastic lesions by down-regulating TGFβ1 and TIMP-1, 2 and increasing MMP-13 expression. Tel inhibited HSCs activation and proliferation. These results suggested that Tel could be a promising drug for NASH related liver fibrosis

  16. Combining automated attenuation-based tube voltage selection and iterative reconstruction: a liver phantom study

    Energy Technology Data Exchange (ETDEWEB)

    Husarik, Daniela B.; Morsbach, Fabian; Chuck, Natalie; Alkadhi, Hatem [University Hospital Zurich, Institute for Diagnostic and Interventional Radiology, Zurich (Switzerland); Schindera, Sebastian T. [University Hospital Basel, Radiology and Nuclear Medicine, Basel (Switzerland); Seifert, Burkhardt [University of Zurich, Division of Biostatistics, Institute of Social and Preventive Medicine, Zuerich (Switzerland); Szucs-Farkas, Zsolt [Radiology, Hospital Centre Biel, Biel (Switzerland)

    2014-03-15

    To determine the value of combined automated attenuation-based tube-potential selection and iterative reconstructions (IRs) for optimising computed tomography (CT) imaging of hypodense liver lesions. A liver phantom containing hypodense lesions was imaged by CT with and without automated attenuation-based tube-potential selection (80, 100 and 120 kVp). Acquisitions were reconstructed with filtered back projection (FBP) and sinogram-affirmed IR. Image noise and contrast-to-noise ratio (CNR) were measured. Two readers marked lesion localisation and rated confidence, sharpness, noise and image quality on a five-point scale (1 = worst, 5 = best). Image noise was lower (31-52 %) and CNR higher (43-102 %) on IR than on FBP images at all tube voltages. On 100-kVp and 80-kVp IR images, confidence and sharpness were higher than on 120-kVp FBP images. Scores for image quality score and noise as well as sensitivity for 100-kVp IR were similar or higher than for 120-kVp FBP and lower for 80-kVp IR. Radiation dose was reduced by 26 % at 100 kVp and 56 % at 80 kVp. Compared with 120-kVp FBP images, the combination of automated attenuation-based tube-potential selection at 100 kVp and IR provides higher image quality and improved sensitivity for detecting hypodense liver lesions in vitro at a dose reduced by 26 %. (orig.)

  17. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages.

    Directory of Open Access Journals (Sweden)

    Lynne A Murray

    Full Text Available Macrophages promote tissue remodeling but few mechanisms exist to modulate their activity during tissue fibrosis. Serum amyloid P (SAP, a member of the pentraxin family of proteins, signals through Fcgamma receptors which are known to affect macrophage activation. We determined that IPF/UIP patients have increased protein levels of several alternatively activated pro-fibrotic (M2 macrophage-associated proteins in the lung and monocytes from these patients show skewing towards an M2 macrophage phenotype. SAP therapeutically inhibits established bleomycin-induced pulmonary fibrosis, when administered systemically or locally to the lungs. The reduction in aberrant collagen deposition was associated with a reduction in M2 macrophages in the lung and increased IP10/CXCL10. These data highlight the role of macrophages in fibrotic lung disease, and demonstrate a therapeutic action of SAP on macrophages which may extend to many fibrotic indications caused by over-exuberant pro-fibrotic macrophage responses.

  18. Dasatinib Attenuates Pressure Overload Induced Cardiac Fibrosis in a Murine Transverse Aortic Constriction Model.

    Directory of Open Access Journals (Sweden)

    Sundaravadivel Balasubramanian

    Full Text Available Reactive cardiac fibrosis resulting from chronic pressure overload (PO compromises ventricular function and contributes to congestive heart failure. We explored whether nonreceptor tyrosine kinases (NTKs play a key role in fibrosis by activating cardiac fibroblasts (CFb, and could potentially serve as a target to reduce PO-induced cardiac fibrosis. Our studies were carried out in PO mouse myocardium induced by transverse aortic constriction (TAC. Administration of a tyrosine kinase inhibitor, dasatinib, via an intraperitoneally implanted mini-osmotic pump at 0.44 mg/kg/day reduced PO-induced accumulation of extracellular matrix (ECM proteins and improved left ventricular geometry and function. Furthermore, dasatinib treatment inhibited NTK activation (primarily Pyk2 and Fak and reduced the level of FSP1 positive cells in the PO myocardium. In vitro studies using cultured mouse CFb showed that dasatinib treatment at 50 nM reduced: (i extracellular accumulation of both collagen and fibronectin, (ii both basal and PDGF-stimulated activation of Pyk2, (iii nuclear accumulation of Ki67, SKP2 and histone-H2B and (iv PDGF-stimulated CFb proliferation and migration. However, dasatinib did not affect cardiomyocyte morphologies in either the ventricular tissue after in vivo administration or in isolated cells after in vitro treatment. Mass spectrometric quantification of dasatinib in cultured cells indicated that the uptake of dasatinib by CFb was greater that that taken up by cardiomyocytes. Dasatinib treatment primarily suppressed PDGF but not insulin-stimulated signaling (Erk versus Akt activation in both CFb and cardiomyocytes. These data indicate that dasatinib treatment at lower doses than that used in chemotherapy has the capacity to reduce hypertrophy-associated fibrosis and improve ventricular function.

  19. Hirsutella sinensis mycelium attenuates bleomycin-induced pulmonary inflammation and fibrosis in vivo

    OpenAIRE

    Tsung-Teng Huang; Hsin-Chih Lai; Yun-Fei Ko; Ojcius, David M; Ying-Wei Lan; Jan Martel; Young, John D.; Kowit-Yu Chong

    2015-01-01

    Hirsutella sinensis mycelium (HSM), the anamorph of Cordyceps sinensis, is a traditional Chinese medicine that has been shown to possess various pharmacological properties. We previously reported that this fungus suppresses interleukin-1β and IL-18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages. However, whether HSM may be used to prevent lung fibrosis and the mechanism underlying this activity remain unclear. Our results show that pretreatment wit...

  20. Reduced angiotensinogen expression attenuates renal interstitial fibrosis in obstructive nephropathy in mice

    OpenAIRE

    Fern, Robert J.; Yesko, Christine M.; Thornhill, Barbara A.; Kim, Hyung-Suk; Smithies, Oliver; Chevalier, Robert L.

    1999-01-01

    A novel approach was employed to assess the contribution of the renin-angiotensin system (RAS) to obstructive nephropathy in neonatal mice having zero to four functional copies of the angiotensinogen gene (Agt). Two-day-old mice underwent unilateral ureteral obstruction (UUO) or sham operation; 28 days later, renal interstitial fibrosis and tubular atrophy were quantitated. In all Agt genotypes, UUO reduced ipsilateral renal mass and increased that of the opposite kidney. Renal interstitial c...

  1. Curcumin Attenuates Radiation-Induced Inflammation and Fibrosis in Rat Lungs

    OpenAIRE

    Cho, Yu Ji; Yi, Chin Ok; Jeon, Byeong Tak; Jeong, Yi Yeong; Kang, Gi Mun; Lee, Jung Eun; Roh, Gu Seob; Lee, Jong Deog

    2013-01-01

    A beneficial radioprotective agent has been used to treat the radiation-induced lung injury. This study was performed to investigate whether curcumin, which is known to have anti-inflammatory and antioxidant properties, could ameliorate radiation-induced pulmonary inflammation and fibrosis in irradiated lungs. Rats were given daily doses of intragastric curcumin (200 mg/kg) prior to a single irradiation and for 8 weeks after radiation. Histopathologic findings demonstrated that macrophage acc...

  2. The use of DWI to assess spleen and liver quantitative ADC changes in the detection of liver fibrosis stages in chronic viral hepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Cece, Hasan, E-mail: hasan_cece@yahoo.com [Harran University, Faculty of Medicine, Department of Radiology, Sanliurfa (Turkey); Ercan, Abdulbasit, E-mail: abdulbasitercan@hotmail.com [Harran University, Faculty of Medicine, Department of Radiology, Sanliurfa (Turkey); Yıldız, Sema, E-mail: drsemayildiz@yahoo.com [Harran University, Faculty of Medicine, Department of Radiology, Sanliurfa (Turkey); Karakas, Ekrem, E-mail: karakasekrem@yahoo.com [Harran University, Faculty of Medicine, Department of Radiology, Sanliurfa (Turkey); Karakas, Omer, E-mail: dromerkarakas@hotmail.com [Harran University, Faculty of Medicine, Department of Radiology, Sanliurfa (Turkey); Boyacı, Fatıma Nurefsan, E-mail: drnurefsan@yahoo.com [Harran University, Faculty of Medicine, Department of Radiology, Sanliurfa (Turkey); Aydogan, Timucin, E-mail: drtaydogan@yahoo.com.tr [Harran University, Faculty of Medicine, Department of Gastroenterology, Sanliurfa (Turkey); Karakas, Emel Yigit, E-mail: e.ygtkarakas@yahoo.com.tr [Sanliurfa Training and Research Hospital, Department of İnternal Medicine, Sanliurfa (Turkey); Cullu, Nesat, E-mail: nesatcullu77@gmail.com [Muğla Sıtkı Koçman University, Faculty of Medicine, Department of Radiology, Mugla (Turkey); Ulas, Turgay, E-mail: turgayulas@yahoo.com [Harran University, Faculty of Medicine, Department of İnternal Medicine, Sanliurfa (Turkey)

    2013-08-15

    This study aimed to evaluate the changes in spleen and liver diffusion-weighted magnetic resonance imaging (DWI) in chronic viral hepatitis patients. The study comprised 47 patients and 30 healthy volunteers. DWIs were obtained. Apparent Diffusion Coefficient (ADC) measurements were made by transferring the images to the workstation. The measurements of value b 1000 were made from a total of five points of the liver and three points of the spleen. Liver biopsy was performed on the 47 patients. The fibrosis stages of the patients were defined according to the METAVIR scoring system. Student's t-test was used in the comparison of mean ages, liver and spleen ADC values between the patient and the control group. Kruskal–Wallis followed by Mann–Whitney U Test with Bonferroni adjustment was performed in the comparison of mean ADC values of the patients at different stages and the control group. A statistically significant difference was determined between the patient and control group in respect of liver and spleen mean ADC values (P < 0.05). F3 group showed a significant difference compared to control and F1 and F4 group showed a significant difference compared to control, F1, F2 and F3 group in terms of the mean liver ADC value (P < 0.01). F3 and F4 group showed a significant difference compared to control and F1 group in terms of the mean spleen ADC value (P < 0.01). As a result we believe that the measurement of liver and spleen ADC values may be an indicator in the determination of the level of fibrosis.

  3. The use of DWI to assess spleen and liver quantitative ADC changes in the detection of liver fibrosis stages in chronic viral hepatitis

    International Nuclear Information System (INIS)

    This study aimed to evaluate the changes in spleen and liver diffusion-weighted magnetic resonance imaging (DWI) in chronic viral hepatitis patients. The study comprised 47 patients and 30 healthy volunteers. DWIs were obtained. Apparent Diffusion Coefficient (ADC) measurements were made by transferring the images to the workstation. The measurements of value b 1000 were made from a total of five points of the liver and three points of the spleen. Liver biopsy was performed on the 47 patients. The fibrosis stages of the patients were defined according to the METAVIR scoring system. Student's t-test was used in the comparison of mean ages, liver and spleen ADC values between the patient and the control group. Kruskal–Wallis followed by Mann–Whitney U Test with Bonferroni adjustment was performed in the comparison of mean ADC values of the patients at different stages and the control group. A statistically significant difference was determined between the patient and control group in respect of liver and spleen mean ADC values (P < 0.05). F3 group showed a significant difference compared to control and F1 and F4 group showed a significant difference compared to control, F1, F2 and F3 group in terms of the mean liver ADC value (P < 0.01). F3 and F4 group showed a significant difference compared to control and F1 group in terms of the mean spleen ADC value (P < 0.01). As a result we believe that the measurement of liver and spleen ADC values may be an indicator in the determination of the level of fibrosis

  4. Hirsutella sinensis mycelium attenuates bleomycin-induced pulmonary inflammation and fibrosis in vivo.

    Science.gov (United States)

    Huang, Tsung-Teng; Lai, Hsin-Chih; Ko, Yun-Fei; Ojcius, David M; Lan, Ying-Wei; Martel, Jan; Young, John D; Chong, Kowit-Yu

    2015-01-01

    Hirsutella sinensis mycelium (HSM), the anamorph of Cordyceps sinensis, is a traditional Chinese medicine that has been shown to possess various pharmacological properties. We previously reported that this fungus suppresses interleukin-1β and IL-18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages. However, whether HSM may be used to prevent lung fibrosis and the mechanism underlying this activity remain unclear. Our results show that pretreatment with HSM inhibits TGF-β1-induced expression of fibronectin and α-SMA in lung fibroblasts. HSM also restores superoxide dismutase expression in TGF-β1-treated lung fibroblasts and inhibits reactive oxygen species production in lung epithelial cells. Furthermore, HSM pretreatment markedly reduces bleomycin-induced lung injury and fibrosis in mice. Accordingly, HSM reduces inflammatory cell accumulation in bronchoalveolar lavage fluid and proinflammatory cytokines levels in lung tissues. The HSM extract also significantly reduces TGF-β1 in lung tissues, and this effect is accompanied by decreased collagen 3α1 and α-SMA levels. Moreover, HSM reduces expression of the NLRP3 inflammasome and P2X7R in lung tissues, whereas it enhances expression of superoxide dismutase. These findings suggest that HSM may be used for the treatment of pulmonary inflammation and fibrosis. PMID:26497260

  5. Tanshinone IIA Attenuates Renal Fibrosis after Acute Kidney Injury in a Mouse Model through Inhibition of Fibrocytes Recruitment

    Science.gov (United States)

    Jiang, Chunming; Shao, Qiuyuan; Jin, Bo; Zhang, Miao

    2015-01-01

    Acute kidney injury (AKI) is associated with an increased risk of developing advanced chronic kidney disease (CKD). Yet, effective interventions to prevent this conversion are unavailable for clinical practice. In this study, we examined the beneficial effects of Tanshinone IIA on renal fibrosis in a mouse model of folic acid induced AKI. We found that Tanshinone IIA treatment significantly attenuated the folic acid elicited kidney dysfunction on days 3, 14, and 28. This effect was concomitant with a much lessened accumulation of fibronectin and collagen in tubulointerstitium 28 days after folic acid injury, denoting an ameliorated renal fibrosis. The kidney protective and antifibrotic effect of Tanshinone IIA was likely attributable to an early inhibition of renal recruitment of fibrocytes positive for both CD45 and collagen I. Mechanistically, Tanshinone IIA treatment not only markedly diminished renal expression of chemoattractants for fibrocytes such as TGFβ1 and MCP-1, but also significantly reduced circulating fibrocytes at the acute phase of kidney injury. These data suggested that Tanshinone IIA might be a novel therapy for preventing progression of CKD after AKI. PMID:26885500

  6. Comparison of accuracy of fibrosis degree classifications by liver biopsy and non-invasive tests in chronic hepatitis C

    Directory of Open Access Journals (Sweden)

    Boursier Jérôme

    2011-11-01

    Full Text Available Abstract Background Non-invasive tests have been constructed and evaluated mainly for binary diagnoses such as significant fibrosis. Recently, detailed fibrosis classifications for several non-invasive tests have been developed, but their accuracy has not been thoroughly evaluated in comparison to liver biopsy, especially in clinical practice and for Fibroscan. Therefore, the main aim of the present study was to evaluate the accuracy of detailed fibrosis classifications available for non-invasive tests and liver biopsy. The secondary aim was to validate these accuracies in independent populations. Methods Four HCV populations provided 2,068 patients with liver biopsy, four different pathologist skill-levels and non-invasive tests. Results were expressed as percentages of correctly classified patients. Results In population #1 including 205 patients and comparing liver biopsy (reference: consensus reading by two experts and blood tests, Metavir fibrosis (FM stage accuracy was 64.4% in local pathologists vs. 82.2% (p -3 in single expert pathologist. Significant discrepancy (≥ 2FM vs reference histological result rates were: Fibrotest: 17.2%, FibroMeter2G: 5.6%, local pathologists: 4.9%, FibroMeter3G: 0.5%, expert pathologist: 0% (p -3. In population #2 including 1,056 patients and comparing blood tests, the discrepancy scores, taking into account the error magnitude, of detailed fibrosis classification were significantly different between FibroMeter2G (0.30 ± 0.55 and FibroMeter3G (0.14 ± 0.37, p -3 or Fibrotest (0.84 ± 0.80, p -3. In population #3 (and #4 including 458 (359 patients and comparing blood tests and Fibroscan, accuracies of detailed fibrosis classification were, respectively: Fibrotest: 42.5% (33.5%, Fibroscan: 64.9% (50.7%, FibroMeter2G: 68.7% (68.2%, FibroMeter3G: 77.1% (83.4%, p -3 (p -3. Significant discrepancy (≥ 2 FM rates were, respectively: Fibrotest: 21.3% (22.2%, Fibroscan: 12.9% (12.3%, FibroMeter2G: 5.7% (6

  7. Effects of gentiana scabra bage on expression of hepatic type Ⅰ,Ⅲ collagen proteins in Paragonimus skrjabini rats with liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Zhao-Xia; Qu; Fang; Li; Chao-Dong; Ma; Jun; Liu; Shu-De; Li; Wen-Lin; Wang

    2015-01-01

    Objective:To exploit- the effects of gentiana scabra bage on the expression of hepatic collagen proteins in Paragonimus skrjabini rats with liver fibrosis.Methods:Immunohistochemical technique was used to observe the changes of content of hepatic type Ⅰ,Ⅲ collagen proteins in Paragonimus skrjabini rats with Liver fibrosis before and after the gentiana scabra bage treatmeat.Results:Comparing with the model group,changes of hepatic tvpe Ⅰ and type Ⅲ collagen proteins in gentiana scabra bage treated group were significantly weakened.Conclusions:Gentiana scabra bage treatment can reduce the content of hepatic type Ⅲ and type Ⅰ collagen protein significantly in Paragonimus skrjabini rats with liver fibrosis,thereby,playing the role against hepatic fibrosis.

  8. Effects of gentiana scabra bage on expression of hepatic typeⅠ,Ⅱ collagen proteins inParagonimus skrjabini rats with liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Zhao-Xia Qu; Fang Li; Chao-Dong Ma; Jun Liu; Shu-De Li; Wen-Lin Wang

    2015-01-01

    Objective:To explore the effects of gentiana scabra bage on the expression of hepatic collagen proteins in Paragonimus skrjabinirats with liver fibrosis.Methods:Immunohistochemical technique was used to observe the changes of content of hepatic type Ⅰ, Ⅱ collagen proteins in Paragonimus skrjabinirats with liver fibrosis before and after the gentiana scabra bage treatmeat. Results:Comparing with the model group, changes of hepatic type Ⅰand type Ⅱ collagen proteins in gentiana scabra bage treated group were significantly weakened.Conclusions:Gentiana scabra bage treatment can reduce the content of hepatic type Ⅱ and typeⅠcollagen protein significantly in Paragonimus skrjabinirats with liver fibrosis, thereby, playing the role against hepatic fibrosis.

  9. Liver fibrosis is associated with cognitive impairment in HIV-positive patients

    Directory of Open Access Journals (Sweden)

    Nicoletta Ciccarelli

    2014-11-01

    Full Text Available Introduction: The aim of our study was to investigate the potential relationship between liver fibrosis (LF and cognitive performance in HIV+ patients. Materials and Methods: We performed a cross-sectional cohort study by consecutively enrolling HIV+ patients during routine outpatient visits at two clinical centres in Italy. Subjects with decompensated liver disease were excluded. All subjects underwent a comprehensive neuropsychological battery exploring memory, attention, psychomotor speed and language; cognitive impairment was defined as at least two abnormal [1.5 SD below the mean for appropriate norms] cognitive domains. LF was explored by calculating FIB4 index; in a subgroup of patients, LF was also assessed by transient elastography. Factors associated with cognitive impairment were investigated by logistic regression models. Results: A total of 413 patients [77% males, median age 46 (IQR 39–52, 17% with past AIDS-defining events, 19% past IDU, 3% with diabetes, 94% on cART, 90% with HIV RNA 3.25 and 14/129 (3% had liver stiffness >14KPa. Forty-seven patients (11% were diagnosed with cognitive impairment. At multivariate analyses patients with FIB4 >1.45 showed a higher risk of cognitive impairment in comparison with those with lower values (OR 2.19, 95% CI 1.02–4.72; p=0.044 after adjusting for education (OR 0.79, 95% CI 0.71–0.88; p14KPa in comparison with fibroscan score <7KPa (OR 285.07; 95% CI 2.42–33574.06; p=0.020 after adjusting for education (OR 0.54, 95% CI 0.31–0.92; p=0.024, age (for 10 years increase (OR 2.03, 95% CI 0.55–7.53; p=0.288, past IDU (OR 4.43, 95% CI 0.35–7.57; p=0.526, HIV RNA <50 copies/mL (OR 0.01, 95% CI 0.00–0.18; p=0.003, HIV history (for 1 year increase (OR 0.96, 95% CI 0.83–1.12; p=0.641, CD4 cells count at nadir (OR 1.10, 95% CI 0.56–2.16; p=0.779, and HCV co-infection (OR 0.06; 95% CI 0.00–1.93; p=0.113. Conclusions: In HIV-infected patients higher LF, estimated through non

  10. Liver Steatosis Assessed by Controlled Attenuation Parameter (CAP) Measured with the XL Probe of the FibroScan: A Pilot Study Assessing Diagnostic Accuracy.

    Science.gov (United States)

    Sasso, Magali; Audière, Stéphane; Kemgang, Astrid; Gaouar, Farid; Corpechot, Christophe; Chazouillères, Olivier; Fournier, Céline; Golsztejn, Olivier; Prince, Stéphane; Menu, Yves; Sandrin, Laurent; Miette, Véronique

    2016-01-01

    To assess liver steatosis, the controlled attenuation parameter (CAP; giving an estimate of ultrasound attenuation ∼3.5 MHz) is available with the M probe of the FibroScan. We report on the adaptation of the CAP for the FibroScan XL probe (center frequency 2.5 MHz) without modifying the range of values (100-400 dB/m). CAP validation was successfully performed on Field II simulations and on tissue-mimicking phantoms. In vivo performance was assessed in a cohort of 59 patients spanning the range of steatosis. In vivo reproducibility was good and similar with both probes. The area under receiver operative characteristic curve was equal to 0.83/0.84 and 0.92/0.91 for the M/XL probes to detect >2% and >16% liver fat, respectively, as assessed by magnetic resonance imaging. Patients can now be assessed simultaneously for steatosis and fibrosis using the FibroScan, regardless of their morphology. PMID:26386476

  11. Hepatoprotective Role of Ethanolic Extract of Vitex negundo in Thioacetamide-Induced Liver Fibrosis in Male Rats.

    Science.gov (United States)

    Kadir, Farkaad A; Kassim, Normadiah M; Abdulla, Mahmood A; Yehye, Wageeh A

    2013-01-01

    The hepatoprotective activity of ethanolic extract from the leaves of Vitex negundo (VN) was conducted against thioacetamide- (TAA-) induced hepatic injury in Sprague Dawley rats. The therapeutic effect of the extract was investigated on adult male rats. Rats were divided into seven groups: control, TAA, Silymarin (SY), and VN high dose and low dose groups. Rats were administered with VN extract at two different doses, 100 mg/kg and 300 mg/kg body weight. After 12 weeks, the rats administered with VN showed a significantly lower liver to body weight ratio. Their abnormal levels of biochemical parameters and liver malondialdehyde were restored closer to the normal levels and were comparable to the levels in animals treated with the standard drug, SY. Gross necropsy and histopathological examination further confirmed the results. Progression of liver fibrosis induced by TAA in rats was intervened by VN extract administration, and these effects were similar to those administered with SY. This is the first report on hepatoprotective effect of VN against TAA-induced liver fibrosis. PMID:23762157

  12. Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice

    International Nuclear Information System (INIS)

    Highlights: •HB-EGF expression was increased during the development of liver fibrosis. •Conditional HB-EGF knockout mouse showed enhanced experimental liver fibrosis. •HB-EGF antagonized TGF-β-induced activation of hepatic stellate cells. •We report a possible protective role of HB-EGF in cholestatic liver fibrosis. -- Abstract: Our aims were to evaluate the involvement of heparin-binding EGF-like growth factor (HB-EGF) in liver fibrogenesis of humans and mice and to elucidate the effect of HB-EGF deficiency on cholestatic liver fibrosis using conditional HB-EGF knockout (KO) mice. We first demonstrated that gene expression of HB-EGF had a positive significant correlation with that of collagen in human fibrotic livers, and was increased in bile duct ligation (BDL)-induced fibrotic livers in mouse. We then generated conditional HB-EGF knockout (KO) mice using the interferon inducible Mx-1 promoter driven Cre recombinase transgene and wild type (WT) and KO mice were subjected to BDL. After BDL, KO mice exhibited enhanced liver fibrosis with increased expression of collagen, compared with WT mice. Finally, we used mouse hepatic stellate cells (HSCs) to examine the role of HB-EGF in the activation of these cells and showed that HB-EGF antagonized TGF-β-induced gene expression of collagen in mouse primary HSCs. Interestingly, HB-EGF did not prevent the TGF-β-induced nuclear accumulation of Smad3, but did lead to stabilization of the Smad transcriptional co-repressor TG-interacting factor. In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis

  13. Role of TGF-β signaling in differentiation of mesothelial cells to vitamin A-poor hepatic stellate cells in liver fibrosis.

    Science.gov (United States)

    Li, Yuchang; Lua, Ingrid; French, Samuel W; Asahina, Kinji

    2016-02-15

    Mesothelial cells (MCs) form a single layer of the mesothelium and cover the liver surface. A previous study demonstrated that, upon liver injury, MCs migrate inward from the liver surface and give rise to hepatic stellate cells (HSCs) in biliary fibrosis induced by bile duct ligation (BDL) or myofibroblasts in CCl4-induced fibrosis. The present study analyzed the role of transforming growth factor-β (TGF-β) signaling in mesothelial-mesenchymal transition (MMT) and the fate of MCs during liver fibrosis and its regression. Deletion of TGF-β type II receptor (Tgfbr2) gene in cultured MCs suppressed TGF-β-mediated myofibroblastic conversion. Conditional deletion of Tgfbr2 gene in MCs reduced the differentiation of MCs to HSCs and myofibroblasts in the BDL and CCl4 models, respectively, indicating that the direct TGF-β signaling in MCs is responsible to MMT. After BDL and CCl4 treatment, MC-derived HSCs