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Sample records for thioacetamide-induced liver fibrosis

  1. The heat shock protein 90 inhibitor, 17-AAG, attenuates thioacetamide induced liver fibrosis in mice.

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    Abu-Elsaad, Nashwa M; Serrya, Marwa S; El-Karef, Amr M; Ibrahim, Tarek M

    2016-04-01

    Heat shock protein 90 (Hsp90) is proposed to be involved in liver disorders. This study was conducted to test effect of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90, on attenuating thioacetamide induced liver fibrosis in vivo. Four groups of Swiss albino male mice (CD-1 strain) were used as follows: control group; thioacetamide group (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks); thioacetamide plus 17-AAG groups (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks plus 25 or 50mg/kg 17-AAG, ip injection, 5 days/week along the last 4 weeks). Fibrosis was quantified by measuring hydroxyproline level and by morphometry and oxidative stress biomarkers were assigned. Relative hepatic mRNA expressions of α-smooth muscle actin (α-SMA), collagen-1-alpha-1 (Col1A1) and tissue inhibitor metalloproteinase-1 (TIMP-1) mRNAs were measured by RT-PCR. Levels of the apoptotic markers caspase-3, factor related apoptosis (Fas) and Hsp-90 were assigned in tissue homogenate. 17-AAG (50mg/kg) significantly decreased fibrosis percentage significantly (pAAG (50mg/kg) compared to other groups. The Hsp90 inhibitor, 17-AAG, can attenuate thioacetamide hepatotoxicity through oxidative stress counterbalance, reducing stellate cells activity and inducing apoptosis. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  2. 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.

  3. Protective effect of Phellinus linteus polysaccharide extracts against thioacetamide-induced liver fibrosis in rats: a proteomics analysis

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    Wang, H.; Wu, G.; Park, H.J.; Jiang, P.P.; Sit, W.H.; Griensven, van L.J.L.D.; Wan, J.M.F.

    2012-01-01

    Background: The hepatoprotective potential of Phellinus linteus polysaccharide (PLP) extracts has been described. However, the molecular mechanism of PLP for the inhibition of liver fibrosis is unclear. This study aims to investigate the molecular protein signatures involved in the hepatoprotective

  4. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease.

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    Peter G Traber

    Full Text Available Galectin-3 protein is critical to the development of liver fibrosis because galectin-3 null mice have attenuated fibrosis after liver injury. Therefore, we examined the ability of novel complex carbohydrate galectin inhibitors to treat toxin-induced fibrosis and cirrhosis. Fibrosis was induced in rats by intraperitoneal injections with thioacetamide (TAA and groups were treated with vehicle, GR-MD-02 (galactoarabino-rhamnogalaturonan or GM-CT-01 (galactomannan. In initial experiments, 4 weeks of treatment with GR-MD-02 following completion of 8 weeks of TAA significantly reduced collagen content by almost 50% based on Sirius red staining. Rats were then exposed to more intense and longer TAA treatment, which included either GR-MD-02 or GM-CT-01 during weeks 8 through 11. TAA rats treated with vehicle developed extensive fibrosis and pathological stage 6 Ishak fibrosis, or cirrhosis. Treatment with either GR-MD-02 (90 mg/kg ip or GM-CT-01 (180 mg/kg ip given once weekly during weeks 8-11 led to marked reduction in fibrosis with reduction in portal and septal galectin-3 positive macrophages and reduction in portal pressure. Vehicle-treated animals had cirrhosis whereas in the treated animals the fibrosis stage was significantly reduced, with evidence of resolved or resolving cirrhosis and reduced portal inflammation and ballooning. In this model of toxin-induced liver fibrosis, treatment with two galectin protein inhibitors with different chemical compositions significantly reduced fibrosis, reversed cirrhosis, reduced galectin-3 expressing portal and septal macrophages, and reduced portal pressure. These findings suggest a potential role of these drugs in human liver fibrosis and cirrhosis.

  5. Hepatoprotective Role of Ethanolic Extract of Vitex negundo in Thioacetamide-Induced Liver Fibrosis in Male Rats

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    Farkaad A. Kadir

    2013-01-01

    Full Text Available 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.

  6. Modulation of thioacetamide-induced hepatic inflammations, angiogenesis and fibrosis by andrographolide in mice.

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    Lee, Tzung-Yan; Chang, Hen-Hong; Wen, Chorng-Kai; Huang, Tse-Hung; Chang, Ya-Shu

    2014-12-02

    Liver fibrosis is a complex disease in which several pathological processes, such as inflammation and angiogenesis, are closely integrated. We hypothesised that treatment with the pharmacological agent, andrographolide (AP), which has multiple mechanisms of action, will provide a greater understanding of the role of AP during the multiple pathological processes that occur in advanced liver disease. Liver fibrogenesis was induced in mice using thioacetamide (TAA), which was administrated for 6 weeks. Andrographolide (5, 20 or 100mg/kg) was then given once daily following TAA injection. Liver collagen was examined using hydroxyproline and α-SMA, while the inflammatory response was quantified by Western blot and RT-PCR assays. Liver angiogenesis, neutrophil infiltration and hypoxia were assessed using CD11b+, vWF and HIF-1α immunostaining. Mice with liver injuries that were treated with andrographolide showed improved inflammatory response and diminished angiogenesis and hepatic fibrosis. Andrographolide treatment inhibited liver neutrophil infiltration, while a decreased in TNF-α and COX-2 signalling indicated macrophage activation. Andrographolide decreased overall liver hypoxia, as shown by the downregulation of hypoxia-inducible cascade genes, such as VEGF. Andrographolide treatment resulted in a significant decrease in hepatic fibrogenesis, α-SMA abundance, and TGF-βR1 expression. The present results suggest that multi-targeted therapies directed against angiogenesis, inflammation, and fibrosis should be considered for the treatment of advanced liver injury. They further suggest that andrographolide treatment may be a novel therapeutic agent for the treatment of liver disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. Efficacy of Boesenbergia rotunda Treatment against Thioacetamide-Induced Liver Cirrhosis in a Rat Model

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    Suzy M. Salama

    2012-01-01

    Full Text Available Background. Experimental research in hepatology has focused on developing traditional medicines into potential pharmacological solutions aimed at protecting liver from cirrhosis. Along the same line, this study investigated the effects of ethanol-based extract from a traditional medicine plant Boesenbergia rotunda (BR on liver cirrhosis. Methodology/Results. The BR extract was tested for toxicity on 3 groups of rats subjected to vehicle (10% Tween 20, 5 mL/kg and 2g/kg and 5g/kg doses of the extract, respectively. Next, experiments were conducted on a rat model of cirrhosis induced by thioacetamide injection. The rats were divided into five groups and, respectively, administered orally with 10% Tween-20 (5 mL/kg (normal control group, 10% Tween-20 (5 mL/kg (cirrhosis control group, 50 mg/kg of silymarin (reference control group, and 250 mg/kg and 500 mg/kg of BR extract (experimental groups daily for 8 weeks. The rats in normal group were intraperitoneally injected with sterile distilled water (1 mL/kg 3 times/week, and those in the remaining groups were injected intraperitoneally with thioacetamide (200 mg/kg thrice weekly. At the end of the 8 weeks, the animals were sacrificed and samples were collected for comprehensive histopathological, coagulation profile and biochemical evaluations. Also, the antioxidant activity of the BR extract was determined and compared with that of silymarin. Data from the acute toxicity tests showed that the extract was safe to use. Histological analysis of the livers of the rats in cirrhosis control group revealed uniform coarse granules on their surfaces, hepatocytic necrosis, and lymphocytes infiltration. But, the surfaces morphologically looked much smoother and the cell damage was much lesser in those livers from the normal control, silymarin and BR-treated groups. In the high-dose BR treatment group, the livers of the rats exhibited nearly normal looking lobular architecture, minimal inflammation

  8. Ameliorative Effect of Curcumin-Encapsulated Hyaluronic Acid–PLA Nanoparticles on Thioacetamide-Induced Murine Hepatic Fibrosis

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    Yu-Nong Chen

    2016-12-01

    Full Text Available In this study, we developed curcumin-encapsulated hyaluronic acid–polylactide nanoparticles (CEHPNPs to be used for liver fibrosis amelioration. CD44, the hyaluronic acid (HA receptor, is upregulated on the surface of cancer cells and on activated hepatic stellate cells (aHSCs rather than normal cells. CEHPNPs could bind to CD44 and be internalized effectively through endocytosis to release curcumin, a poor water-soluble liver protective agent. Thus, CEHPNPs were potentially not only improving drug efficiency, but also targeting aHSCs. HA and polylactide (PLA were crosslinked by adipic acid dihydrazide (ADH. The synthesis of HA–PLA was monitored by Fourier-transform infrared (FTIR and Nuclear Magnetic Resonance (NMR. The average particle size was approximately 60–70 nm as determined by dynamic light scattering (DLS and scanning electron microscope (SEM. Zeta potential was around −30 mV, which suggested a good stability of the particles. This drug delivery system induced significant aHSC cell death without affecting quiescent HSCs, hepatic epithelial, and parenchymal cells. This system reduced drug dosage without sacrificing therapeutic efficacy. The cytotoxicity IC50 (inhibitory concentration at 50% value of CEHPNPs was approximately 1/30 to that of the free drug treated group in vitro. Additionally, the therapeutic effects of CEHPNPs were as effective as the group treated with the same curcumin dose intensity in vivo. CEHPNPs significantly reduced serum aspartate transaminase/alanine transaminase (ALT/AST significantly, and attenuated tissue collagen production and cell proliferation as revealed by liver biopsy. Conclusively, the advantages of superior biosafety and satisfactory therapeutic effect mean that CEHPNPs hold great potential for treating hepatic fibrosis.

  9. Melatonin mitigates thioacetamide-induced hepatic fibrosis via antioxidant activity and modulation of proinflammatory cytokines and fibrogenic genes.

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    Lebda, Mohamed A; Sadek, Kadry M; Abouzed, Tarek K; Tohamy, Hossam G; El-Sayed, Yasser S

    2018-01-01

    The potential antifibrotic effects of melatonin against induced hepatic fibrosis were explored. Rats were allocated into four groups: placebo; thioacetamide (TAA) (200mg/kg bwt, i.p twice weekly for two months); melatonin (5mg/kgbwt, i.p daily for a week before TAA and continued for an additional two months); and melatonin plus TAA. Hepatic fibrotic changes were evaluated biochemically and histopathologically. Hepatic oxidative/antioxidative indices were assessed. The expression of hepatic proinflammatory cytokines (tumor necrosis factor-α, and interleukin-1β), fibrogenic-related genes (transforming growth factor-1β, collagen I, collagen, III, laminin, and autotaxin) and an antioxidant-related gene (thioredoxin-1) were detected by qRT-PCR. In fibrotic rats, melatonin lowered serum aspartate aminotransferase, alanine aminotransferase, and autotaxin activities, bilirubin, hepatic hydroxyproline and plasma ammonia levels. Melatonin displayed hepatoprotective and antifibrotic potential as indicated by mild hydropic degeneration of some hepatocytes and mild fibroplasia. In addition, TAA induced the depletion of glutathione, glutathione s-transferase, glutathione peroxidase, superoxide dismutase, catalase, and paraoxonase-1 (PON-1), while inducing the accumulation of malondialdehyde, protein carbonyl (C=O) and nitric oxide (NO), and DNA fragmentation. These effects were restored by melatonin pretreatment. Furthermore, melatonin markedly attenuated the expression of proinflammatory cytokines and fibrogenic genes via the upregulation of thioredoxin-1 mRNA transcripts. Melatonin exhibits potent anti-inflammatory, antioxidant and fibrosuppressive activities against TAA-induced hepatic fibrogenesis via the suppression of oxidative stress, DNA damage, proinflammatory cytokines and fibrogenic gene transcripts. In addition, we demonstrate that the antifibrotic activity of melatonin is mediated by the induction of thioredoxin-1 with attenuation of autotaxin expressions

  10. Biomarkers for liver fibrosis

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

    2017-05-16

    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.

  11. The dimethylarginine (ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure: Modulation by histidine.

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    Milewski, Krzysztof; Hilgier, Wojciech; Albrecht, Jan; Zielińska, Magdalena

    2015-09-01

    Hepatic encephalopathy (HE) is related to variations in the nitric oxide (NO) synthesis and oxidative/nitrosative stress (ONS), and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases (NOSs). In the present study we compared the effects of acute liver failure (ALF) in the rat TAA model on ADMA concentration in plasma and cerebral cortex, and on the activity and expression of the ADMA degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), in brain and liver. ALF increased blood and brain ADMA, and the increase was correlated with decreased DDAH activity in both brain and liver. An i.p. administration of histidine (His), an amino acid reported to alleviate oxidative stress associated with HE (100 mg/kg b.w.), reversed the increase of brain ADMA, which was accompanied by the recovery of brain DDAH activity (determined ex vivo), and with an increase of the total NOS activity. His also activated DDAH ex vivo in brain homogenates derived from control and TAA rats. ALF in this model was also accompanied by increases of blood cyclooxygenase activity and blood and brain TNF-α content, markers of the inflammatory response in the periphery, but these changes were not affected by His, except for the reduction of TNF-α mRNA transcript in the brain. His increased the total antioxidant capacity of the brain cortex, but not of the blood, further documenting its direct neuroprotective power. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. ATTENUATING EFFECT OF UVARIA NARUM (DUNAL) WALL. LEAVES ON THIOACETAMIDE INDUCED HEPATIC INJURY

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    Patel Jagir R; Moses Samuel Rajan; Ashok Shenoy; Prima D’souza; K. Gunjan

    2013-01-01

    The objective of the present study was to evaluate the hepatoprotective potential of Uvaria narum leaf extract at two different doses (200 and 400 mg / kg b.w.) against thioacetamide induced Hepatic injury. Thioacetamide at dose of 100 mg / kg induced liver toxicity, which was assessed by quantifying the serum hepatic biomarkers like SGPT, SGOT, ALP, total and direct bilirubin, serum biochemical parameters like albumin, total protein, cholesterol, triglycerides, glucose and urea and oxidative...

  13. Serum markers of liver fibrosis

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    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......, a 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....

  14. Therapeutic targets in liver fibrosis.

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    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.

  15. Liver manifestations of cystic fibrosis

    International Nuclear Information System (INIS)

    Akata, Deniz; Akhan, Okan

    2007-01-01

    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

  16. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis.

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    Eric Lefebvre

    Full Text Available Interactions between C-C chemokine receptor types 2 (CCR2 and 5 (CCR5 and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC's anti-inflammatory and antifibrotic effects were evaluated in a range of preclinical models of inflammation and fibrosis.Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC's antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses.CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05. At these doses, CVC showed antifibrotic effects, with significant reductions in collagen deposition (p < 0.05, and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alcoholic fatty liver disease activity score (p < 0.05 vs. controls. CVC treatment had no notable effect on body or liver/kidney weight.CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further experimental studies are needed to clarify the underlying mechanisms of CVC's antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475.

  17. 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...... effort have been invested in finding alternative non-invasive approaches, these have not been sufficiently successful to replace biopsy assessment. AIM: To identify the extracellular matrix proteins of interest, that as protein degradation fragments produced during extracellular matrix metabolism neo......, a 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....

  18. Epigenetics and Liver FibrosisSummary

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    Eva Moran-Salvador

    2017-07-01

    Full Text Available Liver fibrosis arises because prolonged injury combined with excessive scar deposition within hepatic parenchyma arising from overactive wound healing response mediated by activated myofibroblasts. Fibrosis is the common end point for any type of chronic liver injury including alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, and cholestatic liver diseases. Although genetic influences are important, it is epigenetic mechanisms that have been shown to orchestrate many aspects of fibrogenesis in the liver. New discoveries in the field are leading toward the development of epigenetic biomarkers and targeted therapies. This review considers epigenetic mechanisms as well as recent advances in epigenetic programming in the context of hepatic fibrosis. Keywords: Liver Fibrosis, Epigenetics, DNA Methylation, Histone Modifications, Chronic Liver Disease

  19. Liver Transplantation for Cirrhosis in Cystic Fibrosis

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    T Lamireau

    2006-01-01

    Full Text Available BACKGROUND: Liver disease is the third most common cause of death in children with cystic fibrosis (CF. Liver transplantation is an effective treatment in children with hepatic failure.

  20. Noninvasive Biomarkers of Liver Fibrosis: An Overview

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    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.

  1. Pathological assessment of liver fibrosis regression

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    WANG Bingqiong

    2017-03-01

    Full Text Available Hepatic fibrosis is the common pathological outcome of chronic hepatic diseases. An accurate assessment of fibrosis degree provides an important reference for a definite diagnosis of diseases, treatment decision-making, treatment outcome monitoring, and prognostic evaluation. At present, many clinical studies have proven that regression of hepatic fibrosis and early-stage liver cirrhosis can be achieved by effective treatment, and a correct evaluation of fibrosis regression has become a hot topic in clinical research. Liver biopsy has long been regarded as the gold standard for the assessment of hepatic fibrosis, and thus it plays an important role in the evaluation of fibrosis regression. This article reviews the clinical application of current pathological staging systems in the evaluation of fibrosis regression from the perspectives of semi-quantitative scoring system, quantitative approach, and qualitative approach, in order to propose a better pathological evaluation system for the assessment of fibrosis regression.

  2. Liver Fibrosis: Current Principles of Diagnosis

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    A.K. Duda

    2014-09-01

    Full Text Available Liver fibrosis — a natural consequence of almost all liver diseases of any origin. We are faced with a number of standard stereotype processes that take place in the liver tissue. Mostly it is the processes of chronic inflammation, which oppose the processes of liver tissue regeneration. The basis of imbalance between the processes of fibrosis and regeneration is an accumulation of extracellular matrix. Liver fibrosis in its development leads to liver cirrhosis, hepatocellular carcinoma, and the increase in morbidity rate is observed worldwide. Furthermore, the process is genetically determined, but modifiable factors play an important role in the progression of this disease. Current data indicate the possibility of reversible liver fibrosis.

  3. Chronic hepatitis C and liver fibrosis.

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    Sebastiani, Giada; Gkouvatsos, Konstantinos; Pantopoulos, Kostas

    2014-08-28

    Chronic infection with hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide and predisposes to liver fibrosis and end-stage liver complications. Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, and is considered as a wound healing response to chronic liver injury. Its staging is critical for the management and prognosis of chronic hepatitis C (CHC) patients, whose number is expected to rise over the next decades, posing a major health care challenge. This review provides a brief update on HCV epidemiology, summarizes basic mechanistic concepts of HCV-dependent liver fibrogenesis, and discusses methods for assessment of liver fibrosis that are routinely used in clinical practice. Liver biopsy was until recently considered as the gold standard to diagnose and stage liver fibrosis. However, its invasiveness and drawbacks led to the development of non-invasive methods, which include serum biomarkers, transient elastography and combination algorithms. Clinical studies with CHC patients demonstrated that non-invasive methods are in most cases accurate for diagnosis and for monitoring liver disease complications. Moreover, they have a high prognostic value and are cost-effective. Non-invasive methods for assessment of liver fibrosis are gradually being incorporated into new guidelines and are becoming standard of care, which significantly reduces the need for liver biopsy.

  4. Nanoparticles for the treatment of liver fibrosis

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    Poilil Surendran S

    2017-09-01

    Full Text Available Suchithra Poilil Surendran, Reju George Thomas, Myeong Ju Moon, Yong Yeon Jeong Department of Radiology, BioMolecular Theranostics (BiT Lab, Chonnam National University Medical School, Chonnam National University Hwasun Hospital (CNUHH, South Korea Abstract: Chronic liver diseases represent a global health problem due to their high prevalence worldwide and the limited available curative treatment options. They can result from various causes, both infectious and noninfectious diseases. The application of nanoparticle (NP systems has emerged as a rapidly evolving area of interest for the safe delivery of various drugs and nucleic acids for chronic liver diseases. This review presents the pathogenesis, diagnosis and the emerging nanoparticulate systems used in the treatment of chronic liver diseases caused by liver fibrosis. Activated hepatic stellate cell (HSC is considered to be the main mechanism for liver fibrosis. Ultrasonography and magnetic resonance imaging techniques are widely used noninvasive diagnostic methods for hepatic fibrosis. A variety of nanoparticulate systems are mainly focused on targeting HSC in the treatment of hepatic fibrosis. As early liver fibrosis is reversible by current NP therapy, it is being studied in preclinical as well as clinical trials. Among various nanoparticulate systems, inorganic NPs, liposomes and nanomicelles have been widely studied due to their distinct properties to deliver drugs as well as other therapeutic moieties. Liposomal NPs in clinical trials is considered to be a milestone in the treatment of hepatic fibrosis. Currently, NP therapy for liver fibrosis is updating fast, and hopefully, it can be the future remedy for liver fibrosis. Keywords: liver fibrosis, inorganic nanoparticles, liposomes, micelles

  5. Transient elastography for liver fibrosis diagnosis

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    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...... to be a valuable diagnostic procedure and follow-up of patients with chronic liver diseases....

  6. Outcome in cystic fibrosis liver disease.

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    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.

  7. 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...

  8. Evaluation of hepatoprotective activity of Colocasia esculenta (L. Schott) leaves on thioacetamide-induced hepatotoxicity in rats.

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    Chinonyelum, Azubike Nkiruka; Uwadiegwu, Achukwu Peter; Nwachukwu, Okwuosa Chukwugozie; Emmanuel, Oduah

    2015-11-01

    The hepatoprotective effect of orally administered leaf aqueous extract of Colocasia esculenta (CCLE) in thioacetamide-induced liver toxicity in rats was investigated in this study. Adult male Wistar rats (weight range: 120-150g) were divided into 5 groups (n=5) and received no treatment (normal control), distilled water (negative control), 50mg/kg silymarin (positive control) and CCLE (250 and 500mg/kg) respectively once daily for 3 consecutive days. Thioacetamide (TAA) (150mg/kg b.w.) was administered intraperitoneally on the 4th day to rats in all groups except the normal control. Evaluations were made for serum levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphate (ALP) and serum albumin. Histopathological examination was performed on the excised liver tissues. TAA-induced hepatotoxicity increased ALT, AST, ALP and decreased serum albumin. Histopathological results revealed extensive disruption of the liver histoarchitecture when compared to the normal control liver sections. Pre-treatment with CCLE showed protective effects by normalizing the liver enzymes markers. These results were supported by the histopathological observations. The activity of the CCLE was comparable to that of the standard hepatoprotective drug, silymarin (50mg/kg). Overall findings suggest that CCLE possesses in vivo hepatoprotective activity against thioacetamide in rats.

  9. Clinical application of noninvasive diagnosis of liver fibrosis

    OpenAIRE

    ZHU Chuanlong

    2015-01-01

    Hepatic fibrosis is the common outcome of chronic liver diseases of various causes. At present, liver biopsy is the “gold standard” for the diagnosis of liver fibrosis, but it has limitations and is invasive, which leads to the development of noninvasive assessment of liver fibrosis. The article mainly introduces the technology and application of noninvasive diagnosis of liver fibrosis from the aspects of clinical manifestation, serology, and radiology. It has pointed out the clinical value o...

  10. Liver Disease in Cystic Fibrosis: an Update

    Science.gov (United States)

    Parisi, Giuseppe Fabio; Di Dio, Giovanna; Franzonello, Chiara; Gennaro, Alessia; Rotolo, Novella; Lionetti, Elena; Leonardi, Salvatore

    2013-01-01

    Context Cystic fibrosis (CF) is the most widespread autosomal recessive genetic disorder that limits life expectation amongst the Caucasian population. As the median survival has increased related to early multidisciplinary intervention, other manifestations of CF have emergedespecially for the broad spectrum of hepatobiliary involvement. The present study reviews the existing literature on liver disease in cystic fibrosis and describes the key issues for an adequate clinical evaluation and management of patients, with a focus on the pathogenetic, clinical and diagnostic-therapeutic aspects of liver disease in CF. Evidence Acquisition A literature search of electronic databases was undertaken for relevant studies published from 1990 about liver disease in cystic fibrosis. The databases searched were: EMBASE, PubMed and Cochrane Library. Results CF is due to mutations in the gene on chromosome 7 that encodes an amino acidic polypeptide named CFTR (cystic fibrosis transmembrane regulator). The hepatic manifestations include particular changes referring to the basic CFTR defect, iatrogenic lesions or consequences of the multisystem disease. Even though hepatobiliary disease is the most common non-pulmonary cause ofmortalityin CF (the third after pulmonary disease and transplant complications), only about the 33%ofCF patients presents clinically significant hepatobiliary disease. Conclusions Liver disease will have a growing impact on survival and quality of life of cystic fibrosis patients because a longer life expectancy and for this it is important its early recognition and a correct clinical management aimed atdelaying the onset of complications. This review could represent an opportunity to encourage researchers to better investigate genotype-phenotype correlation associated with the development of cystic fibrosis liver disease, especially for non-CFTR genetic polymorphisms, and detect predisposed individuals. Therapeutic trials are needed to find strategies of

  11. Clinical application of noninvasive diagnosis of liver fibrosis

    Directory of Open Access Journals (Sweden)

    ZHU Chuanlong

    2015-03-01

    Full Text Available Hepatic fibrosis is the common outcome of chronic liver diseases of various causes. At present, liver biopsy is the “gold standard” for the diagnosis of liver fibrosis, but it has limitations and is invasive, which leads to the development of noninvasive assessment of liver fibrosis. The article mainly introduces the technology and application of noninvasive diagnosis of liver fibrosis from the aspects of clinical manifestation, serology, and radiology. It has pointed out the clinical value of these noninvasive diagnosis techniques, and it discusses the progress in clinical research and its limitations for noninvasive diagnosis of liver fibrosis.

  12. Effect of coriander on thioacetamide-induced hepatotoxicity in rats.

    Science.gov (United States)

    Moustafa, Abdel Halim A; Ali, Ehab Mostafa M; Moselhey, Said S; Tousson, Ehab; El-Said, Karim S

    2014-08-01

    Thioacetamide (TAA) is a potent hepatotoxin that causes centrilobulal necrosis and nephrotoxic damage following acute administration. Prolonged exposure to TAA can result in bile duct proliferation and liver cirrhosis histologically similar to that caused due to viral hepatitis infection. Coriander in food increases the antioxidant content, acting as a natural antioxidant and inhibiting undesirable oxidation processes. The present study investigated the antioxidant activity of Coriandrum sativum on TAA-induced hepatotoxicity in the male rats. Phenolic content and antioxidant activity were evaluated in the coriander leaves and seeds. Forty-eight adult male rats were divided into four groups. Group I (control), group II (TAA injected rats), group III (TAA injected rats fed coriander leaves) and group IV (TAA injected rats fed coriander seeds). The results revealed that serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were significantly increased in the groups II, III and IV as compared to the normal control. Oxidative stress in the group II was manifested by a significant rise in nitric oxide (NO), thiobarbituric acid reactive substance (TBARS) levels and myloperoxidase (MPO) activities in the liver tissues as compared with the control group. Rats fed with coriander leaves and seeds showed a decrease in the serum ALT, AST and ALP activities and in the liver NO and TBARS levels as compared to the group II. Histopathological study revealed that coriander feeding attenuated TAA-induced hepatotoxicity in the rats. In conclusion, coriander leaves attenuate hepatotoxicity induced by TAA more than that of seeds due to the higher content of phenolic compounds and antioxidants in the leaves of coriander. Liver of rats intoxicated with TAA exhibited advanced CIRRHOSIS: in the form of macronodular and micronodular structure surrounded by fibrous tissue. Treatment with coriander leaves and seeds helps in improving

  13. Research advances in immune cellular pathogenesis in liver fibrosis

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    XIAO Chunyang

    2015-09-01

    Full Text Available Liver fibrosis is the common pathological consequence of all chronic liver diseases with various etiologies. The mechanism of liver fibrosis is associated with the activation and proliferation of hepatic stellate cells (HSCs. The interaction between immune cells and HSCs can regulate the production of extracellular matrix (ECM and lead to the excessive deposition of ECM and subsequent liver fibrosis and cirrhosis. This article reviews the current understanding of the effects and action mechanisms of immune cells in the development of liver fibrosis and summarizes the regulatory functions of the innate and adaptive immune systems in liver fibrosis. Further study of the interactions between immune cells, cytokines, and HSCs and the regulatory mechanisms of the immune system will provide novel opportunity for the treatment of liver fibrosis.

  14. Non invasive assessment of liver fibrosis in chronic hemodialysis ...

    African Journals Online (AJOL)

    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 ...

  15. Accuracy of FibroScan for diagnosing liver fibrosis

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    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.

  16. Addressing liver fibrosis with Liposomes targeted to hepatic stellate cells

    NARCIS (Netherlands)

    Adrian, Joanna E.; Poelstra, Klaas; Kamps, Jan A. A. M.

    2007-01-01

    Liver fibrosis is a chronic disease that results from hepatitis B and C infections, alcohol abuse or metabolic and genetic disorders. Ultimately, progression of fibrosis leads to cirrhosis, a stage of the disease characterized by failure of the normal liver functions. Currently, the treatment of

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

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    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.

  18. Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution.

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    Andrea Baiocchini

    Full Text Available Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis. Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies.

  19. Investigation of Therapeutic Effects of α-Mangostin on Thioacetamide-Induced Cirrhosis in Rats.

    Science.gov (United States)

    Supawadee, Sukseree; Thanet, Sophonnithiprasert; Wisut, Pradidarcheep; Somneuk, Nilbunga; Sirinun, Nilwarangoon; Ramida, Watanapokasin

    2015-10-01

    To determine the effects of alpha-mangostin on thioacetamide (TAA)-induced liver cirrhosis in rats. Male Wistar rats were divided into 3 groups and treated with intraperitoneal injections of TAA (200 mg/kg) 3 times per week for per week for 8, 12 and 16 weeks, respectively. One subgroup was left untreated whereas the other two were treated either with 100 mg/kg α-mangostin or vehicle alone (80% DMSO, 20% water), which were administered intraperitoneally 3 times per weekfor a total of4 weeks. The incidence offibrotic nodules on the liver and the serum levels of the liver enzymes aspartate transaminase (AST) and alanine transaminase (ALT) were measured. Moreover the liver cirrhosis-related genes expression and p53 protein level in liver were analyzed by quantitative reverse transcription PCR and Western blot analysis, respectively. Fibrotic nodules on the liver were formed upon treatment with TAA for 12 or 16 weeks. The nodules were then reduced by treatment with α-mangostin as compared to treatment with the vehicle DMSO. Moreover, the serum levels of the liver enzymes AST and ALT after treatment with α-mangostin decreased as compared to DMSO alone. The liver cirrhosis-related genes expression showed no significant differences, whereas the p53 protein level in liver showed that α-mangostin reduced risk of liver fibrosis through the decrease in p53 expression as compared to the TAA_DMSO treatment. The results suggest that α-mangostin has a beneficial therapeutic effect in the TAA liver cirrhosis model. Further investigations on mechanisms of α-mangostin as therapeutic agent should be determined.

  20. 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

  1. Optical methods in diagnostics of liver fibrosis via blood observation

    Science.gov (United States)

    Kruchinina, Margarita V.; Generalov, Vladimir M.; Atuchin, Victor V.; Kruchinin, Vladimir N.; Volodin, Vladimir A.; Gromov, Andrey A.; Rykhlitsky, Sergey V.

    2016-11-01

    A possible application of optical methods (dielectrophoresis, spectral and imaging ellipsometry, Fourier- transform infrared spectroscopy, Raman spectroscopy) for the early diagnostics in studies of red blood cells and serum in patients with the diffuse liver disease, with varying degrees of fibrosis, has been evaluated. As experimentally confirmed, the combined optical methods significantly improve the sensitivity, specificity and accuracy index in the diagnosis of both severe fibrosis and slight ulterior liver fibrosis. The identified optical methods diagnostic potential can be efficiently utilized in noninvasive screening evaluation of the stages of diffuse liver disease of various genesis.

  2. Evolving strategies for liver fibrosis staging: Non-invasive assessment.

    Science.gov (United States)

    Stasi, Cristina; Milani, Stefano

    2017-01-14

    Transient elastography and the acoustic radiation force impulse techniques may play a pivotal role in the study of liver fibrosis. Some studies have shown that elastography can detect both the progression and regression of fibrosis. Similarly, research results have been analysed and direct and indirect serum markers of hepatic fibrosis have shown high diagnostic accuracy for advanced fibrosis/cirrhosis. The prognosis of different stages of cirrhosis is well established and various staging systems have been proposed, largely based on clinical data. However, it is still unknown if either non-invasive markers of liver fibrosis or elastography may contribute to a more accurate staging of liver cirrhosis, in terms of prognosis and fibrosis regression after effective therapy. In fact, not enough studies have shown both the fibrosis regression in different cirrhosis stages and the point beyond which the prognosis does not change - even in the event of fibrosis regression. Therefore, future studies are needed to validate non-invasive methods in predicting the different phases of liver cirrhosis.

  3. Evaluation of liver fibrosis: "Something old, something new…".

    Science.gov (United States)

    Almpanis, Zannis; Demonakou, Maria; Tiniakos, Dina

    2016-01-01

    Hepatic fibrogenesis may gradually result to cirrhosis due to the accumulation of extracellular matrix components as a response to liver injury. Thus, therapeutic decisions in chronic liver disease, regardless of the cause, should first and foremost be guided by an accurate quantification of hepatic fibrosis. Detection and assessment of the extent of hepatic fibrosis represent a challenge in modern Hepatology. Although traditional histological staging systems remain the "best standard", they are not able to quantify liver fibrosis as a dynamic process and may not accurately substage cirrhosis. This review aims to compare the currently used non-invasive methods of measuring liver fibrosis and provide an update in current tissue-based digital techniques developed for this purpose, that may prove of value in daily clinical practice.

  4. The Protective Effect of Omega-3 Against Thioacetamide Induced Lipid and Renal Dysfunction in Male Rats

    Directory of Open Access Journals (Sweden)

    Davood Moghadamnia

    2016-10-01

    Full Text Available Background Thioacetamide causes lipid and kidney dysfunction.Omega-3 unsaturated fatty acids prevent the progression of renal diseases. Objectives This study aimed to assess the protective effects of omega-3 fish oil supplement on thioacetamide induced lipid and kidney dysfunction in male rats. Methods In this experimental study, 42 male rats were divided into 6 groups of 7: control group sham group which received 0.4 mL olive oil as a solvent, Thioacetamide group receiving thioacetamide at a dose of 150 mg/kg once as intraperitoneal injection, Experimental groups of 1, 2 and 3 which received omega-3 fish oil supplement at the doses of 100, 200, 300 mg/kg orally for 3 months respectively and then they received thioacetamide at the dose of 150 mg/kg intraperitoneally for once. The levels of serum creatinine, BUN, total cholesterol, LDL, HDL, FBS, triglyceride, sodium and potassium were measured. The pathological changes of tissue samples of the kidneys were studied after hematoxylin-eosin staining. The data were analyzed by SPSS-18 software and using one way ANOVA and Tukey as post hoc test. Significant level was considered to be P < 0.05. Results The mean serum levels of potassium in the second experimental group significantly decreased (5.26 ± 0.02 compared to the group receiving thioacetamide (6.50 ± 0. The mean serum sodium in all experimental groups decreased significantly compared to the group receiving thioacetamide. The mean serum levels of total cholesterol in experimental group 3 (66.80 ± 1.46 significantly decreased compared to the group receiving thioacetamide (84 ± 0.57. No significant changes were observed in the mean serum levels of FBS, BUN, HDL, LDL, triglycerides and creatinine in all experimental groups compared to the group receiving thioacetamide. All the experimental groups improved renal histological changes induced by thioacetamide and these protective effects were dose-dependent (P ≤ 0.05. Conclusions The results of

  5. Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance.

    Science.gov (United States)

    Stål, Per

    2015-10-21

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD.

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

    DEFF Research Database (Denmark)

    Thiele, Maja; Kjærgaard, Maria; Thielsen, Peter

    2017-01-01

    , 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...... results. Key factors that limit the applicability of liver stiffness measurements are as follows: liver vein congestion, cholestasis, a recent meal, inflammation, obesity, observer experience and ascites. The coming years will show whether elastography will be widely adapted in general care.......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...

  7. The Human Amnion Epithelial Cell Secretome Decreases Hepatic Fibrosis in Mice with Chronic Liver Fibrosis

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    Majid Alhomrani

    2017-10-01

    Full Text Available Background: Hepatic stellate cells (HSCs are the primary collagen-secreting cells in the liver. While HSCs are the major cell type involved in the pathogenesis of liver fibrosis, hepatic macrophages also play an important role in mediating fibrogenesis and fibrosis resolution. Previously, we observed a reduction in HSC activation, proliferation, and collagen synthesis following exposure to human amnion epithelial cells (hAEC and hAEC-conditioned media (hAEC-CM. This suggested that specific factors secreted by hAEC might be effective in ameliorating liver fibrosis. hAEC-derived extracellular vesicles (hAEC-EVs, which are nanosized (40–100 nm membrane bound vesicles, may act as novel cell–cell communicators. Accordingly, we evaluated the efficacy of hAEC-EV in modulating liver fibrosis in a mouse model of chronic liver fibrosis and in human HSC.Methods: The hAEC-EVs were isolated and characterized. C57BL/6 mice with CCl4-induced liver fibrosis were administered hAEC-EV, hAEC-CM, or hAEC-EV depleted medium (hAEC-EVDM. LX2 cells, a human HSC line, and bone marrow-derived mouse macrophages were exposed to hAEC-EV, hAEC-CM, and hAEC-EVDM. Mass spectrometry was used to examine the proteome profile of each preparation.Results: The extent of liver fibrosis and number of activated HSCs were reduced significantly in CCl4-treated mice given hAEC-EVs, hAEC-CM, and hAEC EVDM compared to untreated controls. Hepatic macrophages were significantly decreased in all treatment groups, where a predominant M2 phenotype was observed. Human HSCs cultured with hAEC-EV and hAEC-CM displayed a significant reduction in collagen synthesis and hAEC-EV, hAEC-CM, and hAEC-EVDM altered macrophage polarization in bone marrow-derived mouse macrophages. Proteome analysis showed that 164 proteins were unique to hAEC-EV in comparison to hAEC-CM and hAEC-EVDM, and 51 proteins were co-identified components with the hAEC-EV fraction.Conclusion: This study provides novel data

  8. The therapeutic effect of nano-encapsulated and nano-emulsion forms of carvacrol on experimental liver fibrosis.

    Science.gov (United States)

    Hussein, Jihan; El-Banna, Mona; Mahmoud, Khaled F; Morsy, Safaa; Abdel Latif, Yasmin; Medhat, Dalia; Refaat, Eman; Farrag, Abdel Razik; El-Daly, Sherien M

    2017-06-01

    The present study aimed to compare the therapeutic efficiency of nano-encapsulated and nano-emulsion carvacrol administration on liver injury in thioacetamide (TAA) treated rats. To fulfill our target, we used sixty male albino rats classified into six groups as follow: control, nano-encapsulated carvacrol, nano-emulsion carvacrol, thioacetamide, treated nano-encapsulated carvacrol and treated nano-emulsion carvacrol groups. Blood samples were collected from all groups and the separated serum was used for analysis of the following biochemical parameters; aspartate aminotransferase (AST), alanine aminotransferase (ALT), S100 B protein, alpha fetoprotein (AFP) and caspase-3. The levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), monocyte chemoattractant protein-1(MCP-1) and hydroxyproline content were all evaluated in liver tissue homogenate. Histopathological examinations for liver tissues were also performed. Thioacetamide induced hepatic damage in rats as revealed by the significant increase in the levels of serum ALT, AST and produced oxidative stress as displayed by the significant elevation in the levels of hepatic MDA and NO concomitant with a significant decrease in GSH. In addition, thioacetamide significantly increased serum S100B protein, alpha fetoprotein and caspase-3 along with hepatic MCP-1 and hydroxyproline; these results were confirmed by the histopathological investigation. In contrast, nano-encapsulated and nano-emulsion carvacrol were able to ameliorate these negative changes in the thioacetamide injected rats. However, the effect of the nano-encapsulated form of carvacrol was more prominent than the nano-emulsion form. Nano-encapsulated and nano-emulsion carvacrol can ameliorate thioacetamide induced liver injury. These results could be attributed to the potential anti-inflammatory, antioxidant, and anti-apoptotic activities of carvacrol in addition to the effectiveness of the encapsulation technique that can protect

  9. Hepatosplenic volumetric assessment at MDCT for staging liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Pickhardt, Perry J.; Malecki, Kyle; Hunt, Oliver F.; Beaumont, Claire; Kloke, John; Ziemlewicz, Timothy J.; Lubner, Meghan G. [University of Wisconsin School of Medicine and Public Health, Department of Radiology, Madison, WI (United States)

    2017-07-15

    To investigate hepatosplenic volumetry at MDCT for non-invasive prediction of hepatic fibrosis. Hepatosplenic volume analysis in 624 patients (mean age, 48.8 years; 311 M/313 F) at MDCT was performed using dedicated software and compared against pathological fibrosis stage (F0 = 374; F1 = 48; F2 = 40; F3 = 65; F4 = 97). The liver segmental volume ratio (LSVR) was defined by Couinaud segments I-III over segments IV-VIII. All pre-cirrhotic fibrosis stages (METAVIR F1-F3) were based on liver biopsy within 1 year of MDCT. LSVR and total splenic volumes increased with stage of fibrosis, with mean(±SD) values of: F0: 0.26 ± 0.06 and 215.1 ± 88.5 mm{sup 3}; F1: 0.25 ± 0.08 and 294.8 ± 153.4 mm{sup 3}; F2: 0.331 ± 0.12 and 291.6 ± 197.1 mm{sup 3}; F3: 0.39 ± 0.15 and 509.6 ± 402.6 mm{sup 3}; F4: 0.56 ± 0.30 and 790.7 ± 450.3 mm{sup 3}, respectively. Total hepatic volumes showed poor discrimination (F0: 1674 ± 320 mm{sup 3}; F4: 1631 ± 691 mm{sup 3}). For discriminating advanced fibrosis (≥F3), the ROC AUC values for LSVR, total liver volume, splenic volume and LSVR/spleen combined were 0.863, 0.506, 0.890 and 0.947, respectively. Relative changes in segmental liver volumes and total splenic volume allow for non-invasive staging of hepatic fibrosis, whereas total liver volume is a poor predictor. Unlike liver biopsy or elastography, these CT volumetric biomarkers can be obtained retrospectively on routine scans obtained for other indications. (orig.)

  10. Adverse outcome pathway development from protein alkylation to liver fibrosis.

    Science.gov (United States)

    Horvat, Tomislav; Landesmann, Brigitte; Lostia, Alfonso; Vinken, Mathieu; Munn, Sharon; Whelan, Maurice

    2017-04-01

    In modern toxicology, substantial efforts are undertaken to develop alternative solutions for in vivo toxicity testing. The adverse outcome pathway (AOP) concept could facilitate knowledge-based safety assessment of chemicals that does not rely exclusively on in vivo toxicity testing. The construction of an AOP is based on understanding toxicological processes at different levels of biological organisation. Here, we present the developed AOP for liver fibrosis and demonstrate a linkage between hepatic injury caused by chemical protein alkylation and the formation of liver fibrosis, supported by coherent and consistent scientific data. This long-term process, in which inflammation, tissue destruction, and repair occur simultaneously, results from the complex interplay between various hepatic cell types, receptors, and signalling pathways. Due to the complexity of the process, an adequate liver fibrosis cell model for in vitro evaluation of a chemical's fibrogenic potential is not yet available. Liver fibrosis poses an important human health issue that is also relevant for regulatory purposes. An AOP described with enough mechanistic detail might support chemical risk assessment by indicating early markers for downstream events and thus facilitating the development of an in vitro testing strategy. With this work, we demonstrate how the AOP framework can support the assembly and coherent display of distributed mechanistic information from the literature to support the use of alternative approaches for prediction of toxicity. This AOP was developed according to the guidance document on developing and assessing AOPs and its supplement, the users' handbook, issued by the Organisation for Economic Co-operation and Development.

  11. Impact of liver fibrosis and fatty liver on T1rho measurements: A prospective study

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Shuang Shuang; Li, Qing; Cheng, Yue; Shen, Wen [Dept. of Radiology, Tianjin First Center Hospital, Tianjin (China); Zhang, Yu; Zhuo, Zhi Zheng [Clinical Science, Philips Healthcare, Beijing (China); Zhao, Guiming [Dept. of Hepatology, Tianjin Second People' s Hospital, Tianjin (China)

    2017-11-15

    To investigate the liver T1rho values for detecting fibrosis, and the potential impact of fatty liver on T1rho measurements. This study included 18 healthy subjects, 18 patients with fatty liver, and 18 patients with liver fibrosis, who underwent T1rho MRI and mDIXON collections. Liver T1rho, proton density fat fraction (PDFF) and T2* values were measured and compared among the three groups. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the T1rho values for detecting liver fibrosis. Liver T1rho values were correlated with PDFF, T2* values and clinical data. Liver T1rho and PDFF values were significantly different (p < 0.001), whereas the T2* (p = 0.766) values were similar, among the three groups. Mean liver T1rho values in the fibrotic group (52.6 ± 6.8 ms) were significantly higher than those of healthy subjects (44.9 ± 2.8 ms, p < 0.001) and fatty liver group (45.0 ± 3.5 ms, p < 0.001). Mean liver T1rho values were similar between healthy subjects and fatty liver group (p = 0.999). PDFF values in the fatty liver group (16.07 ± 10.59%) were significantly higher than those of healthy subjects (1.43 ± 1.36%, p < 0.001) and fibrosis group (1.07 ± 1.06%, p < 0.001). PDFF values were similar in healthy subjects and fibrosis group (p = 0.984). Mean T1rho values performed well to detect fibrosis at a threshold of 49.5 ms (area under the ROC curve, 0.855), had a moderate correlation with liver stiffness (r = 0.671, p = 0.012), and no correlation with PDFF, T2* values, subject age, or body mass index (p > 0.05). T1rho MRI is useful for noninvasive detection of liver fibrosis, and may not be affected with the presence of fatty liver.

  12. Impact of liver fibrosis and fatty liver on T1rho measurements: A prospective study

    International Nuclear Information System (INIS)

    Xie, Shuang Shuang; Li, Qing; Cheng, Yue; Shen, Wen; Zhang, Yu; Zhuo, Zhi Zheng; Zhao, Guiming

    2017-01-01

    To investigate the liver T1rho values for detecting fibrosis, and the potential impact of fatty liver on T1rho measurements. This study included 18 healthy subjects, 18 patients with fatty liver, and 18 patients with liver fibrosis, who underwent T1rho MRI and mDIXON collections. Liver T1rho, proton density fat fraction (PDFF) and T2* values were measured and compared among the three groups. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the T1rho values for detecting liver fibrosis. Liver T1rho values were correlated with PDFF, T2* values and clinical data. Liver T1rho and PDFF values were significantly different (p < 0.001), whereas the T2* (p = 0.766) values were similar, among the three groups. Mean liver T1rho values in the fibrotic group (52.6 ± 6.8 ms) were significantly higher than those of healthy subjects (44.9 ± 2.8 ms, p < 0.001) and fatty liver group (45.0 ± 3.5 ms, p < 0.001). Mean liver T1rho values were similar between healthy subjects and fatty liver group (p = 0.999). PDFF values in the fatty liver group (16.07 ± 10.59%) were significantly higher than those of healthy subjects (1.43 ± 1.36%, p < 0.001) and fibrosis group (1.07 ± 1.06%, p < 0.001). PDFF values were similar in healthy subjects and fibrosis group (p = 0.984). Mean T1rho values performed well to detect fibrosis at a threshold of 49.5 ms (area under the ROC curve, 0.855), had a moderate correlation with liver stiffness (r = 0.671, p = 0.012), and no correlation with PDFF, T2* values, subject age, or body mass index (p > 0.05). T1rho MRI is useful for noninvasive detection of liver fibrosis, and may not be affected with the presence of fatty liver

  13. Can acoustic radiation force impulse elastography be a substitute for liver biopsy in predicting liver fibrosis?

    International Nuclear Information System (INIS)

    Jain, V.; Dixit, R.; Chowdhury, V.; Puri, A.S.; Gondal, R.

    2016-01-01

    Aim: To evaluate the clinical feasibility and accuracy of acoustic radiation force impulse (ARFI) elastography for the detection of liver fibrosis in patients with chronic viral hepatitis. Materials and methods: ARFI-based ultrasound elastography was performed in 69 patients with chronic liver disease (CLD) of viral aetiology and 36 healthy volunteers. Fifty-eight patients with CLD also underwent liver biopsy. Results: ARFI was feasible in all 36 healthy volunteers and all 69 CLD patients, while valid measurements were obtained in 65 patients (95.6%) and all healthy volunteers. The mean shear-wave velocity (SWV) in healthy volunteers was 1.12±0.2 m/s. A gradual increase in mean SWV was noted from fibrosis of Grade F0 to F6 (Ishak's score) and a high positive correlation was found between the mean SWV on ARFI and fibrosis scores at liver biopsy (rho=0.789). The difference between the mild (F1 and F2) versus significant fibrosis (F3 and F4) was also statistically significant (p<0.001). The difference in the SWV measurements obtained from consecutive groups (i.e., F1 versus F2, F2 versus F3, and F3 versus F4) was not statistically significant. Using the area under the receiver operating characteristic curve (AUROC), the best calculated cut-off SWVs for the presence of fibrosis (≥F1), significant fibrosis (≥F3), severe fibrosis (≥F4), and cirrhosis (F6) were found to be 1.207, 1.347, 1.513, and 1.92 m/s, respectively. ARFI values were significantly higher in cirrhotic patients than in other patients (p<0.001). Conclusions: ARFI elastography allows valid non-invasive evaluation of liver stiffness and may help to distinguish between no/mild fibrosis and significant fibrosis and guide management decisions. - Highlights: • Our study included healthy volunteer with 28 males and 8 females in a ratio of 3:1 with mean SWV of 1.2±0.20m/s. • A high positive correlation was found between the SWV on ARFI and fibrosis scores. • There was a significantly higher

  14. Current research status of mechanisms of the development and progression of liver fibrosis

    Directory of Open Access Journals (Sweden)

    XU Mingcui

    2016-09-01

    Full Text Available Liver fibrosis is the intermediate process in the progression of various chronic liver diseases to liver cirrhosis, and its serious complications affect the prognosis of patients with chronic liver diseases. However, so far, there remain no effective drugs for the treatment of liver fibrosis. This article investigates the development and progression of liver fibrosis from the aspects of signaling pathways and molecular mechanisms and briefly introduces the latest research advances in the roles of signaling pathways, including transforming growth factor-β/Smad pathway, platelet-derived growth factor pathway, leptin signaling pathway, and connective tissue growth factor pathway, chemokines, neuroendocrine factors, and angiogenesis in the development of liver fibrosis, so as to enhance the knowledge of the development of liver fibrosis and provide a theoretical basis for the research on molecular-targeted drugs based on the pathogenesis of liver fibrosis.

  15. Cystic fibrosis liver disease - from diagnosis to risk factors.

    Science.gov (United States)

    Ciucă, Ioana Mihaiela; Pop, Liviu; Tămaş, Liviu; Tăban, Sorina

    2014-01-01

    Cystic fibrosis (CF) is the most frequent monogenic genetic disease, autosomal recessive transmitted, characterized by an impressive clinical polymorphism and appreciative fatal prospective. Liver disease is the second non-pulmonary cause of death in cystic fibrosis, which, with increasing life expectancy, became an important management problem. Predisposing factors like male gender, pancreatic insufficiency, meconium ileus and severe mutation are incriminated to influence the occurrence of cystic fibrosis associated liver disease (CFLD). Our study included 174 patients with CF, monitored in the National Cystic Fibrosis Centre, Timisoara, Romania. They were routinely followed-up by clinical assessment, liver biochemical tests, ultrasound examinations and other methods like transient elastography, biopsy, in selected cases. Sixty-six patients, with median age at diagnosis 4.33 years, diagnosed with CFLD, without significant gender gap. CFLD was frequent in patients aged over eight years, with meconium ileus history, carriers of severe mutations (p=0.002). Pancreatic insufficiency, although present in 75% of patients with CFLD was not confirmed as risk factor, not male gender, in our study. CF children older than eight years, carriers of a severe genotype, with a positive history of meconium ileus, were more likely predisposed to CFLD.

  16. Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis.

    Science.gov (United States)

    Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

    2016-12-14

    To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. Liver stiffness was measured in sixty-eight rabbits with CCl 4 -induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. LSM by ElastPQ was significantly correlated with histologic fibrosis stage ( r = 0.85, P splenectomy (especially F1) may delay liver fibrosis progression. ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl 4 -induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy.

  17. Ursodeoxycholic acid treatment is associated with improvement of liver stiffness in cystic fibrosis patients

    NARCIS (Netherlands)

    van der Feen, Cathelijne; van der Doef, Hubert P. J.; van der Ent, Cornelis K.; Houwen, Roderick H. J.

    2016-01-01

    Background: Ursodeoxycholic acid (UDCA) might prevent progression of cystic fibrosis liver disease, but objective parameters for its effect are lacking. Methods: We used liver stiffness measurements to evaluate the effect of Ursodeoxycholic acid. Results: Paired measurements of liver stiffness were

  18. Colchicine for alcoholic and non-alcoholic liver fibrosis or cirrhosis

    DEFF Research Database (Denmark)

    Rambaldi, A; Gluud, C

    2001-01-01

    Colchicine is an anti-inflammatory and anti-fibrotic drug. Several randomized clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic as well as non-alcoholic fibrosis and cirrhosis. The objectives were to assess the efficacy of colchicine...... evaluated in randomized trials on mortality, liver related mortality, liver related complications, liver fibrosis markers, liver histology, alcohol consumption, quality of life, and health economics in patients with alcoholic and non-alcoholic fibrosis or cirrhosis....

  19. Accuracy of the Enhanced Liver Fibrosis Test vs Fibrotest, Elastography and Indirect Markers in Detection of Advanced Fibrosis in Patients with Alcoholic Liver Disease

    DEFF Research Database (Denmark)

    Thiele, Maja; Madsen, Bjørn Stæhr; Hansen, Janne Fuglsang

    2018-01-01

    -dimensional shear-wave elastography), and 6 indirect marker tests in detection of advanced liver fibrosis (Kleiner stage ≥F3). METHODS: We performed a prospective study of 10 liver fibrosis markers (patented and not), all performed on the same day. Patients were recruited from primary centers (municipal...... alcohol rehabilitation, n=128; 6% with advanced fibrosis) and secondary healthcare centers (hospital outpatient clinics, n=161; 36% with advanced fibrosis) in the Region of Southern Denmark from 2013 through 2016. Biopsy-verified fibrosis stage was used as the reference standard. The primary aim...... was to validate ELF in detection of advanced fibrosis in patients with alcoholic liver disease recruited from primary and secondary healthcare centers, using the literature-based cut-off value of 10.5. Secondary aims were to assess the diagnostic accuracy of ELF for significant fibrosis and cirrhosis...

  20. Molecular Cues Guiding Matrix Stiffness in Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Takaoki Saneyasu

    2016-01-01

    Full Text Available Tissue and matrix stiffness affect cell properties during morphogenesis, cell growth, differentiation, and migration and are altered in the tissue remodeling following injury and the pathological progression. However, detailed molecular mechanisms underlying alterations of stiffness in vivo are still poorly understood. Recent engineering technologies have developed powerful techniques to characterize the mechanical properties of cell and matrix at nanoscale levels. Extracellular matrix (ECM influences mechanical tension and activation of pathogenic signaling during the development of chronic fibrotic diseases. In this short review, we will focus on the present knowledge of the mechanisms of how ECM stiffness is regulated during the development of liver fibrosis and the molecules involved in ECM stiffness as a potential therapeutic target for liver fibrosis.

  1. Short-term effects of splenectomy on serum fibrosis indexes in liver cirrhosis patients.

    Science.gov (United States)

    Kong, Degang; Chen, Xiuli; Lu, Shichun; Guo, Qingliang; Lai, Wei; Wu, Jushan; Lin, Dongdong; Zeng, Daobing; Duan, Binwei; Jiang, Tao; Cao, Jilei

    2015-01-01

    To determine the changing patterns of 4 liver fibrosis markers pre and post splenectomy (combined with pericardial devascularization [PCDV]) and to examine the short-term effects of splenectomy on liver fibrosis. Four liver fibrosis markers of 39 liver cirrhosis patients were examined pre, immediately post, 2 days post, and 1 week post (15 cases) splenectomy (combined with PCDV). The laminin (LN) level decreased immediately post surgery compared with the preoperative LN level (P splenectomy showed characteristic changes, splenectomy may transiently initiate the degradation process of liver fibrosis.

  2. Discovery of novel biomarker candidates for liver fibrosis in hepatitis C patients: a preliminary study.

    Directory of Open Access Journals (Sweden)

    Bevin Gangadharan

    Full Text Available Liver biopsy is the reference standard for assessing liver fibrosis and no reliable non-invasive diagnostic approach is available to discriminate between the intermediate stages of fibrosis. Therefore suitable serological biomarkers of liver fibrosis are urgently needed. We used proteomics to identify novel fibrosis biomarkers in hepatitis C patients with different degrees of liver fibrosis.Proteins in plasma samples from healthy control individuals and patients with hepatitis C virus (HCV induced cirrhosis were analysed using a proteomics technique: two dimensional gel electrophoresis (2-DE. This technique separated the proteins in plasma samples of control and cirrhotic patients and by visualizing the separated proteins we were able to identify proteins which were increasing or decreasing in hepatic cirrhosis. Identified markers were validated across all Ishak fibrosis stages and compared to the markers used in FibroTest, Enhanced Liver Fibrosis (ELF test, Hepascore and FIBROSpect by Western blotting. Forty four candidate biomarkers for hepatic fibrosis were identified of which 20 were novel biomarkers of liver fibrosis. Western blot validation of all candidate markers using plasma samples from patients across all Ishak fibrosis scores showed that the markers which changed with increasing fibrosis most consistently included lipid transfer inhibitor protein, complement C3d, corticosteroid-binding globulin, apolipoprotein J and apolipoprotein L1. These five novel fibrosis markers which are secreted in blood showed a promising consistent change with increasing fibrosis stage when compared to the markers used for the FibroTest, ELF test, Hepascore and FIBROSpect. These markers will be further validated using a large clinical cohort.This study identifies 20 novel fibrosis biomarker candidates. The proteins identified may help to assess hepatic fibrosis and eliminate the need for invasive liver biopsies.

  3. [Combination of NAFLD Fibrosis Score and liver stiffness measurement for identification of moderate fibrosis stages (II & III) in non-alcoholic fatty liver disease].

    Science.gov (United States)

    Drolz, Andreas; Wehmeyer, Malte; Diedrich, Tom; Piecha, Felix; Schulze Zur Wiesch, Julian; Kluwe, Johannes

    2018-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent causes of chronic liver disease. Currently, therapeutic options for NAFLD patients are limited, but new pharmacologic agents are being investigated in the course of clinical trials. Because most of these studies are focusing on patients with fibrosis stages II and III (according to Kleiner), non-invasive identification of patients with intermediate fibrosis stages (II and III) is of increasing interest. Evaluation of NAFLD Fibrosis Score (NFS) and liver stiffness measurement (LSM) for prediction of fibrosis stages II/III. Patients with histologically confirmed NAFLD diagnosis were included in the study. All patients underwent a clinical and laboratory examination as well as a LSM prior to liver biopsy. Predictive value of NFS and LSM with respect to identification of fibrosis stages II/III was assessed. 134 NAFLD patients were included and analyzed. Median age was 53 (IQR 36 - 60) years, 55 patients (41 %) were female. 82 % of our patients were overweight/obese with typical aspects of metabolic syndrome. 84 patients (66 %) had liver fibrosis, 42 (50 %) advanced fibrosis. LSM and NFS correlated with fibrosis stage (r = 0.696 and r = 0.685, respectively; p stages II/III. If both criteria were met, probability of fibrosis stage II/III was 61 %. If none of the two criteria was met, chance for fibrosis stage II/III was only 6 % (negative predictive value 94 %). Combination of LSM and NFS enables identification of patients with significant probability of fibrosis stage II/III. Accordingly, these tests, especially in combination, may be a suitable screening tool for fibrosis stages II/III in NAFLD. The use of these non-invasive methods might also help to avoid unnecessary biopsies. © Georg Thieme Verlag KG Stuttgart · New York.

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

    Directory of Open Access Journals (Sweden)

    Jian-Xia Liu

    2016-03-01

    Full Text Available 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.

  5. 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.

  6. Role of Kupffer Cells in Thioacetamide-Induced Cell Cycle Dysfunction

    Directory of Open Access Journals (Sweden)

    Mirandeli Bautista

    2011-09-01

    Full Text Available It is well known that gadolinium chloride (GD attenuates drug-induced hepatotoxicity by selectively inactivating Kupffer cells. In the present study the effect of GD in reference to cell cycle and postnecrotic liver regeneration induced by thioacetamide (TA in rats was studied. Two months male rats, intraveously pretreated with a single dose of GD (0.1 mmol/Kg, were intraperitoneally injected with TA (6.6 mmol/Kg. Samples of blood and liver were obtained from rats at 0, 12, 24, 48, 72 and 96 h following TA intoxication. Parameters related to liver damage were determined in blood. In order to evaluate the mechanisms involved in the post-necrotic regenerative state, the levels of cyclin D and cyclin E as well as protein p27 and Proliferating Cell Nuclear Antigen (PCNA were determined in liver extracts because of their roles in the control of cell cycle check-points. The results showed that GD significantly reduced the extent of necrosis. Noticeable changes were detected in the levels of cyclin D1, cyclin E, p27 and PCNA when compared to those induced by thioacetamide. Thus GD pre-treatment reduced TA-induced liver injury and accelerated the postnecrotic liver regeneration. These results demonstrate that Kupffer cells are involved in TA-induced liver and also in the postnecrotic proliferative liver states.

  7. Graft Fibrosis After Pediatric Liver Transplantation : Ten Years of Follow-up

    NARCIS (Netherlands)

    Scheenstra, Rene; Peeters, Paul M. G. J.; Verkade, Henkjan J.; Gouw, Annette S. H.

    Previously we reported the presence of portal fibrosis in 31% (n = 84) of the grafts in protocol biopsies I year after pediatric liver transplantation (LTx). To assess the natural history of graft fibrosis after pediatric liver transplantation, we extended the analysis of graft histology in

  8. Association of Fasciola hepatica Infection with Liver Fibrosis, Cirrhosis, and Cancer: A Systematic Review.

    Science.gov (United States)

    Machicado, Claudia; Machicado, Jorge D; Maco, Vicente; Terashima, Angelica; Marcos, Luis A

    2016-09-01

    Fascioliasis has been sporadically associated with chronic liver disease on previous studies. In order to describe the current evidence, we carried out a systematic review to assess the association between fascioliasis with liver fibrosis, cirrhosis and cancer. A systematic search of electronic databases (PubMed, LILACS, Scopus, Embase, Cochrane, and Scielo) was conducted from June to July 2015 and yielded 1,557 published studies. Among 21 studies that met inclusion and exclusion criteria, 12 studies explored the association of F. hepatica with liver fibrosis, 4 with liver cirrhosis, and 5 with cancer. Globally these studies suggested the ability of F. hepatica to promote liver fibrosis and cirrhosis. The role of F. hepatica in cancer is unknown. Given the heterogeneity of the studies, a meta-analysis could not be performed. Future high-quality studies are needed to determine the role of F. hepatica on the development of liver fibrosis, liver cirrhosis, and cancer in humans.

  9. 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 ASMA expression decreased in the long term, with inverse evolution with respect to fibrosis (P ASMA-positive HSCs area ≥ 8% at 6 months (n = 20) developed a higher fibrosis proportion compared to those with ASMA-positive HSCs area ≤ 8% (n = 34) at the same period of time and in the long term (P = 0.03 and P ASMA expression ≥ 8% at 6 months was found to be an independent risk factor for 7-year fibrosis development by PSR% (r(2) = 0.5; P ASMA expression ≥ 8% at 3 years showed an association with the development of fibrosis at 7 years (P = 0.02). In conclusion, there is a high proportion of activated HSCs in pediatric LT recipients. ASMA ≥ 8% at 6 months seems to be a risk factor for early and longterm fibrosis development. In addition, activated HSCs showed inverse evolution with respect to fibrosis in the long term. Liver Transplantation 22 822-829 2016 AASLD. © 2016 American Association for the Study of Liver Diseases.

  10. Non-invasive diagnosis of liver fibrosis and cirrhosis

    Science.gov (United States)

    Lurie, Yoav; Webb, Muriel; Cytter-Kuint, Ruth; Shteingart, Shimon; Lederkremer, Gerardo Z

    2015-01-01

    The evaluation and follow up of liver fibrosis and cirrhosis have been traditionally performed by liver biopsy. However, during the last 20 years, it has become evident that this “gold-standard” is imperfect; even according to its proponents, it is only “the best” among available methods. Attempts at uncovering non-invasive diagnostic tools have yielded multiple scores, formulae, and imaging modalities. All are better tolerated, safer, more acceptable to the patient, and can be repeated essentially as often as required. Most are much less expensive than liver biopsy. Consequently, their use is growing, and in some countries the number of biopsies performed, at least for routine evaluation of hepatitis B and C, has declined sharply. However, the accuracy and diagnostic value of most, if not all, of these methods remains controversial. In this review for the practicing physician, we analyze established and novel biomarkers and physical techniques. We may be witnessing in recent years the beginning of the end of the first phase for the development of non-invasive markers. Early evidence suggests that they might be at least as good as liver biopsy. Novel experimental markers and imaging techniques could produce a dramatic change in diagnosis in the near future. PMID:26556987

  11. [Laparoscopic surgical treatment for schistosomiasis liver fibrosis portal hypertension combined with calculous cholecystitis].

    Science.gov (United States)

    Zhang, Lan; Liu, Xiong; Zhang, Hua-ming; Wang, Qing-shan

    2014-04-01

    To evaluate the curative effect of laparoscopic cholecystectomy (LC) in the treatment of schistosomiasis liver fibrosis portal hypertension combined with calculous cholecystitis. The clinical data of 196 cases of schistosomiasis liver fibrosis portal hypertension combined with calculous cholecystitis (Child A 160 cases, Child B 36 cases) treated with LC were collected and analyzed from June 2006 to June 2013. Among the 196 cases, there were 154 cases of schistosomiasis liver fibrosis portal hypertension combined with chronic calculous cholecystitis, and 42 cases of schistosomiasis liver fibrosis portal hypertension combined with acute calculous cholecystitis. Totally 189 patients underwent LC successfully, but 7 were transited to the general operation because of LC failure, including 3 cases of adhesion around gallbladder and ambiguous dissection of gallbladder triangle, and 4 cases of intraoperative bleeding and the bleeding was difficult to stop under the laparoscopy. All the 196 patients were cured. LC is effective and safe in the treatment of schistosomiasis liver fibrosis portal hypertension combined with calculous cholecystitis.

  12. 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.)

  13. Assessment of liver fibrosis in primary biliary cholangitis: Comparison between indirect serum markers and fibrosis morphometry.

    Science.gov (United States)

    Stasi, Cristina; Leoncini, Luisa; Biagini, Maria Rosa; Arena, Umberto; Madiai, Stefania; Laffi, Giacomo; Marra, Fabio; Milani, Stefano

    2016-03-01

    The accuracy of non-invasive methods for the quantification of liver fibrosis in primary biliary cholangitis (PBC) is still debated. To determine the histo-morphometric measurement of fibrotic tissue and to explore the possible association between indirect markers (APRI, FORNS, FIB-4, and Lok) and morphometry. Retrospective analysis of medical data from patients with PBC, on whom needle liver biopsy was performed as part of the diagnostic assessment. One section of each biopsy stained with Sirius red was used for calculating the percentage of collagen. Quantitative measure of fibrotic tissue (fibrosis morphometry) was calculated as a percentage of collagen content by digital image analysis. Morphometry results were divided into four groups reflecting Ludwig's staging and compared with values for indirect serum markers. 50 PBC patients were enrolled (86% females, mean age 57 ± 12.30 years), 19 were Ludwig's stage I (38%), 14 stage II (28%), 12 stage III (24%), and five stage IV (10%). Morphometry results were significantly different among Ludwig stages (p<0.05). No significant differences were found for indirect serum markers. A significant correlation was found between morphometry results and indirect serum markers tested (p<0.05). In our cohort, the histo-morphometric values of fibrotic tissue increased progressively with Ludwig's stages of PBC, while non-invasive markers did not. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  14. A prediction model for the grade of liver fibrosis using magnetic resonance elastography.

    Science.gov (United States)

    Mitsuka, Yusuke; Midorikawa, Yutaka; Abe, Hayato; Matsumoto, Naoki; Moriyama, Mitsuhiko; Haradome, Hiroki; Sugitani, Masahiko; Tsuji, Shingo; Takayama, Tadatoshi

    2017-11-28

    Liver stiffness measurement (LSM) has recently become available for assessment of liver fibrosis. We aimed to develop a prediction model for liver fibrosis using clinical variables, including LSM. We performed a prospective study to compare liver fibrosis grade with fibrosis score. LSM was measured using magnetic resonance elastography in 184 patients that underwent liver resection, and liver fibrosis grade was diagnosed histologically after surgery. Using the prediction model established in the training group, we validated the classification accuracy in the independent test group. First, we determined a cut-off value for stratifying fibrosis grade using LSM in 122 patients in the training group, and correctly diagnosed fibrosis grades of 62 patients in the test group with a total accuracy of 69.3%. Next, on least absolute shrinkage and selection operator analysis in the training group, LSM (r = 0.687, P prediction model. This prediction model applied to the test group correctly diagnosed 32 of 36 (88.8%) Grade I (F0 and F1) patients, 13 of 18 (72.2%) Grade II (F2 and F3) patients, and 7 of 8 (87.5%) Grade III (F4) patients in the test group, with a total accuracy of 83.8%. The prediction model based on LSM, ICGR15, and platelet count can accurately and reproducibly predict liver fibrosis grade.

  15. 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.

  16. 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.

  17. Ipomoea aquatica Extract Shows Protective Action Against Thioacetamide-Induced Hepatotoxicity

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    A. Hamid A. Hadi

    2012-05-01

    Full Text Available In the Indian system of traditional medicine (Ayurveda it is recommended to consume Ipomoea aquatica to mitigate disorders like jaundice. In this study, the protective effects of ethanol extract of I. aquatica against liver damage were evaluated in thioacetamide (TAA-induced chronic hepatotoxicity in rats. There was no sign of toxicity in the acute toxicity study, in which Sprague-Dawley (SD rats were orally fed with I. aquatica (250 and 500 mg/kg for two months along with administration of TAA (i.p injection 200 mg/kg three times a week for two months. The results showed that the treatment of I. aquatica significantly lowered the TAA-induced serum levels of hepatic enzyme markers (ALP, ALT, AST, protein, albumin, bilirubin and prothrombin time. The hepatic content of activities and expressions SOD and CAT that were reduced by TAA were brought back to control levels by the plant extract supplement. Meanwhile, the rise in MDA level in the TAA receiving groups also were significantly reduced by I. aquatica treatment. Histopathology of hepatic tissues by H&E and Masson trichrome stains displayed that I. aquatica has reduced the incidence of liver lesions, including hepatic cells cloudy swelling, infiltration, hepatic necrosis, and fibrous connective tissue proliferation induced by TAA in rats. Therefore, the results of this study show that the protective effect of I. aquatica in TAA-induced liver damage might be contributed to its modulation on detoxification enzymes and its antioxidant and free radical scavenger effects. Moreover, it confirms a scientific basis for the traditional use of I. aquatica for the treatment of liver disorders.

  18. Twelve potential fibrosis markers to differentiate mild liver fibrosis from cirrhosis in patients infected with chronic hepatitis C genotype 1

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Ruhwald, M; Moessner, B

    2011-01-01

    Information about the stage of liver fibrosis is important for managing patients with chronic hepatitis C (CHC). The aim of this study was to evaluate 12 plasma markers for differentiating no/mild liver fibrosis from cirrhosis among patients with CHC genotype 1. Transient elastography was used...... to assess the stage of fibrosis for the patients included in the study. Forty patients were included (21 cirrhotic). Plasma levels of tumor necrosis factor-a (TNF-a), interleukin 8 (IL-8), interferon-¿ inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), soluble urokinase-type plasminogen....... In conclusion, several of the investigated markers showed promise for differentiating cirrhosis from no/mild fibrosis among patients with CHC genotype 1....

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

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    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.

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

    NARCIS (Netherlands)

    Westra, Inge M.; Oosterhuis, Dorenda; Groothuis, Geny M. M.; Olinga, Peter

    2014-01-01

    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

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

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    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.)

  2. Recent research findings on non-invasive diagnosis of liver fibrosis

    Directory of Open Access Journals (Sweden)

    WU Qiong

    2015-02-01

    Full Text Available Early diagnosis of liver fibrosis and dynamic monitoring of relevant changes have great implications for the treatment and prognosis improvement of chronic liver diseases. So far, liver biopsy remains the “golden standard” for the diagnosis and staging of liver fibrosis. However, due to its inherent limitations, a great effort has been made to develop more accurate non-invasive diagnostic methods, including serum fibrosis markers and mathematical models, ultrasound, contrast-enhanced ultrasonography, ultrasonic elastography, computed tomography, magnetic resonance imaging, and nuclear medicine. The advantages and disadvantages of relevant methods are discussed. Furthermore, proper selection of the non-invasive diagnostic methods for clinical application and the means for mutual verification are analyzed. As for the future direction, it is expected to employ the above methods for combined analysis and comprehensive assessment, in order to enhance the clinical value of non-invasive liver fibrosis diagnosis.

  3. Contrast-enhanced ultrasonography for the evaluation of liver fibrosis after biliary obstruction.

    Science.gov (United States)

    Shin, Hyun Joo; Chang, Eun Young; Lee, Hye Sun; Hong, Jung Hwa; Park, Gyuri; Kim, Hyun Gi; Kim, Myung-Joon; Lee, Mi-Jung

    2015-03-07

    To investigate perfusion change in contrast-enhanced ultrasonography (CEUS) to evaluate liver fibrosis based on biliary obstruction using an animal model. New Zealand white rabbits (3-4 kg) underwent bile duct ligation to form a biliary obstruction model. We performed liver CEUS and laboratory tests on the day before the operation (day 0) and every 7 postoperative days until the rabbits were sacrificed. After CEUS, signal intensity of liver parenchyma with a time-intensity curve was analyzed. Perfusion parameters were automatically calculated from region-of-interests, including peak signal intensity, mean transit time, area under the curve and time to peak. Histological grades of liver fibrosis were assessed according to the Metavir score system immediately after sacrifice. Generalized estimating equations were used to analyze the association between liver fibrosis grades and perfusion parameters for statistical analysis. The perfusion parameters were measured on the last day and the difference between day 0 and the last day were evaluated. From the nine rabbits, histological grades of liver fibrosis were grade 1 in one rabbit, grade 2 and 3 in three rabbits each, and grade 4 in two rabbits. Among the four CEUS parameters, only the peak signal intensity measured on the last day demonstrated a significant association with liver fibrosis grades (OR = 1.392, 95%CI: 1.114-1.741, P = 0.004). The difference in peak signal intensity between day 0 and the last day also demonstrated an association with liver fibrosis (OR = 1.191, 95%CI: 0.999-1.419, P = 0.051). The other parameters tested, including mean transit time, area under the curve, and time to peak, showed no significant correlation with liver fibrosis grades. This animal study demonstrates that CEUS can be used to evaluate liver fibrosis from biliary obstruction using peak signal intensity as a parameter.

  4. Usefulness of virtual touch quantification for staging liver fibrosis in patients with hepatitis C, and factors affecting liver stiffness measurement failure compared with liver biopsy.

    Science.gov (United States)

    Tsukano, Natsumi; Miyase, Shiho; Saeki, Tatsuhiko; Mizobe, Keiko; Iwashita, Hirofumi; Arima, Nobuyuki; Fujiyama, Shigetoshi

    2017-12-11

    The assessment of liver fibrosis in patients with hepatitis C is important to predict carcinogenesis. In this study, we evaluated the usefulness of virtual touch quantification (VTQ) for staging liver fibrosis, and investigated factors causing discrepancies between the estimated fibrosis stage using VTQ and the pathological fibrosis stage. Patients with hepatitis C (n = 302) were assessed using VTQ and underwent pathological liver investigation within 1 week before and after VTQ. A receiver operator characteristic (ROC) curve was obtained for VTQ, fibrosis-4 (FIB-4) index, and aspartate aminotransferase-to-platelet ratio index (APRI), and each area under the ROC curve (AUROC) was compared to predict fibrosis stage. We used univariate and multivariate analyses to investigate the factors related to the discrepancy between the estimated fibrosis stage using VTQ and the pathological fibrosis stage. At any stage, VTQ was the most accurate for staging liver fibrosis. The VTQ cut-off values were 1.33 m/s (AUROC = 0.822) for ≥F2, 1.51 m/s (AUROC = 0.836) for ≥F3, and 1.92 m/s (AUROC = 0.890) for F4. Skin liver capsule distance (SCD) was the most relevant factor for the discrepancy between the estimated fibrosis stage using VTQ and the pathological fibrosis stage. The SCD cut-off value was 17.5 mm. Virtual touch quantification is a non-invasive, simple method that is more accurate for staging liver fibrosis than the FIB-4 index and APRI. However, when the SCD is longer than 17.5 mm, there may be measurement failures. © 2017 The Japan Society of Hepatology.

  5. microRNA changes in liver tissue associated with fibrosis progression in patients with hepatitis C.

    Science.gov (United States)

    Van Keuren-Jensen, Kendall R; Malenica, Ivana; Courtright, Amanda L; Ghaffari, Layla T; Starr, Alex P; Metpally, Raghu P; Beecroft, Taylor A; Carlson, Elizabeth W J; Kiefer, Jeffrey A; Pockros, Paul J; Rakela, Jorge

    2016-03-01

    Accumulating evidence indicates that microRNAs play a role in a number of disease processes including the pathogenesis of liver fibrosis in hepatitis C infection. Our goal is to add to the accruing information regarding microRNA deregulation in liver fibrosis to increase our understanding of the underlying mechanisms of pathology and progression. We used next generation sequencing to profile all detectable microRNAs in liver tissue and serum from patients with hepatitis C, stages F1-F4 of fibrosis. We found altered expression of several microRNAs, in particular, miR-182, miR199a-5p, miR-200a-5p and miR-183 were found to be significantly upregulated in tissue from liver biopsies of hepatitis C patients with advanced fibrosis, stage F3 and F4, when compared with liver biopsies from patients with early fibrosis, stages F1 and F2. We also found miR-148-5p, miR-1260b, miR-122-3p and miR-378i among the microRNAs most significantly down-regulated from early to advanced fibrosis of the liver. We also sequenced the serum microRNAs; however, we were not able to detect significant changes in circulating microRNAs associated with fibrosis stage after adjusting for multiple tests. Adding measurements of tissue microRNAs acquired during routine biopsies will continue to increase our knowledge of underlying mechanisms of fibrosis. Our goal is that these data, in combination with studies from other researchers and future long-term studies, could be used to enhance the staging accuracy of liver biopsies and expand the surveillance of patients at increased risk for cancer and progression to advanced fibrosis. © 2015 The Authors. Liver International Published by John Wiley & Sons Ltd.

  6. Impact of Helicobacter pylori infection on liver fibrosis in Egyptian patients with chronic hepatitis C

    Directory of Open Access Journals (Sweden)

    Mustafa M. Ragheb

    2012-07-01

    Full Text Available Both Helicobacter pylori (HP and hepatitis C virus (HCV infections are endemic in Egypt. This work aimed to investigate the presence of HP in the liver of patients with chronic hepatitis C (CHC and explore the relation between HP infection, liver histopathology and HCV viral load. The study included 60 patients with CHC. Virological, biochemical, liver biopsy and testing for anti-Hp and anti-schistosomal antibodies in serum were done. Liver tissues were examined for histopathological and presence of Hp by detection of HP 16S rRNA gene by PCR and sequence analysis. Anti-schistosomal and anti HP antibody was found in 45% and 61.7%, respectively. Low stages of fibrosis (F0–F3 were found in 73.3% and advanced fibrosis (F4–F6 in 26.7%. HP DNA was found in 10% of the liver specimens. Although the frequency HP antibodies was equally high in patients with advanced and low fibrosis (68.8% and 59.1%, P > 0.05, the HP DNA in liver tissue was significantly more frequent in patients with advanced fibrosis (31.25% vs. 2.7%, P = 0.004. Meanwhile, the median viral load of HCV was higher in patients with HP DNA in liver tissue compared to patients with no HP DNA in liver tissue (337.000 vs. 165.000, P = 0.3491. HCV RNA titer, fibrosis score and history of blood transfusion, are independent factors associated with HP DNA in liver tissue. In conclusion, the presence of HP in liver tissue of patients with advanced fibrosis suggests a potential relation between HP infection and progression of liver fibrosis due to HCV.

  7. Dietary Supplementation of Blueberry Juice Enhances Hepatic Expression of Metallothionein and Attenuates Liver Fibrosis in Rats

    Science.gov (United States)

    Wang, Yuping; Cheng, Mingliang; Zhang, Baofang; Nie, Fei; Jiang, Hongmei

    2013-01-01

    Aim To investigate the effect of blueberry juice intake on rat liver fibrosis and its influence on hepatic antioxidant defense. Methods Rabbiteye blueberry was used to prepare fresh juice to feed rats by daily gastric gavage. Dan-shao-hua-xian capsule (DSHX) was used as a positive control for liver fibrosis protection. Liver fibrosis was induced in male Sprague-Dawley rats by subcutaneous injection of CCl4 and feeding a high-lipid/low-protein diet for 8 weeks. Hepatic fibrosis was evaluated by Masson staining. The expression of α-smooth muscle actin (α-SMA) and collagen III (Col III) were determined by immunohistochemical techniques. The activities of superoxide dismutase (SOD) and malondialdehyde (MDA) in liver homogenates were determined. Metallothionein (MT) expression was detected by real-time RT-PCR and immunohistochemical techniques. Results Blueberry juice consumption significantly attenuates CCl4-induced rat hepatic fibrosis, which was associated with elevated expression of metallothionein (MT), increased SOD activity, reduced oxidative stress, and decreased levels of α-SMA and Col III in the liver. Conclusion Our study suggests that dietary supplementation of blueberry juice can augment antioxidative capability of the liver presumably via stimulating MT expression and SOD activity, which in turn promotes HSC inactivation and thus decreases extracellular matrix collagen accumulation in the liver, and thereby alleviating hepatic fibrosis. PMID:23554912

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

    International Nuclear Information System (INIS)

    Abdel-Mageed, M.E.A.

    2010-01-01

    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.

  9. 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.

  10. Association between noninvasive fibrosis markers and chronic kidney disease among adults with nonalcoholic fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Giorgio Sesti

    Full Text Available Evidence suggests that nonalcoholic fatty liver disease (NAFLD and non-alcoholic steatohepatitis (NASH are associated with an increased risk of chronic kidney disease (CKD. In this study we aimed to evaluate whether the severity of liver fibrosis estimated by NAFLD fibrosis score is associated with higher prevalence of CKD in individuals with NAFLD. To this end NAFLD fibrosis score and estimated glomerular filtration rate (eGFR were assessed in 570 White individuals with ultrasonography-diagnosed NAFLD. As compared with subjects at low probability of liver fibrosis, individuals at high and intermediate probability showed an unfavorable cardio-metabolic risk profile having significantly higher values of waist circumference, insulin resistance, high sensitivity C-reactive protein, fibrinogen, uric acid and lower insulin-like growth factor-1 levels. Individuals at high and intermediate probability of liver fibrosis have lower eGFR after adjustment for gender, smoking, glucose tolerance status, homeostasis model assessment index of insulin resistance (HOMA-IR index, diagnosis of metabolic syndrome, statin therapy, anti-diabetes and anti-hypertensive treatments (P = 0.001. Individuals at high probability of liver fibrosis had a 5.1-fold increased risk of having CKD (OR 5.13, 95%CI 1.13-23.28; P = 0.03 as compared with individuals at low probability after adjustment for age, gender, and BMI. After adjustment for glucose tolerance status, statin therapy, and anti-hypertensive treatment in addition to gender, individuals at high probability of liver fibrosis had a 3.9-fold increased risk of CKD (OR 3.94, 95%CI 1.11-14.05; P = 0.03 as compared with individuals at low probability. In conclusion, advanced liver fibrosis, determined by noninvasive fibrosis markers, is associated with CKD independently from other known factors.

  11. Diffusion-weighted MRI for the assessment of liver fibrosis: principles and applications.

    Science.gov (United States)

    Palmucci, Stefano; Cappello, Giuseppina; 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.

  12. 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

    . No relationship was found between TTHV and PSF. The results were compared to similar data obtained in liver biopsies from 117 non-alcoholics with normal morphology or slight non-specific changes. No significant difference concerning TTHV and THV diameter was found between alcoholic and non-alcoholic patients......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....... The results suggest that the initial liver fibrosis in alcoholics is slightly asymmetrical distributed in each acinar zone 3 area. With progression, the fibrosis tends to be more uniformly distributed and septa appear, eventually linking THV with portal tracts. Apparently, thickening of the THV walls does...

  13.  High prevalence of undiagnosed liver cirrhosis and advanced fibrosis in type 2 diabetic patients.

    Science.gov (United States)

    Arab, Juan P; Barrera, Francisco; Gallego, Consuelo; Valderas, Juan P; Uribe, Sergio; Tejos, Cristian; Serrano, Cristóbal; Serrano, Cristóbal; Huete, Álvaro; Liberona, Jessica; Labbé, Pilar; Quiroga, Teresa; Benítez, Carlos; Irarrázaval, Pablo; Riquelme, Arnoldo; Arrese, Marco

    2016-01-01

     Background. Patients with type 2 diabetes mellitus (T2DM) are at risk for developing end-stage liver disease due to nonalcoholic steatohepatitis (NASH), the aggressive form of non-alcoholic fatty liver disease (NAFLD). Data on prevalence of advanced fibrosis among T2DM patients is scarce. To evaluate prevalence of steatosis, advanced fibrosis and cirrhosis using non-invasive methods in T2DM patients. 145 consecutive T2DM patients (> 55 years-old) were prospectively recruited. Presence of cirrhosis and advanced fibrosis was evaluated by magnetic resonance imaging (MRI) and NAFLD fibrosis score (NFS) respectively. Exclusion criteria included significant alcohol consumption, markers of viral hepatitis infection or other liver diseases. Results are expressed in percentage or median (interquartile range). 52.6% of patients were women, the median age was 60 years old (57-64), mean BMI was 29.6 ± 4.7 kg/m2 and diabetes duration was 7.6 ± 6.9 years. A high prevalence of liver steatosis (63.9%), advanced fibrosis assessed by NFS (12.8%) and evidence of liver cirrhosis in MRI (6.0%) was observed. In a multivariate analysis GGT > 82 IU/L (P = 0.004) and no alcohol intake (P = 0.032) were independently associated to advanced fibrosis. A high frequency of undiagnosed advanced fibrosis and cirrhosis was observed in non-selected T2DM patients. Screening of these conditions may be warranted in this patient population.

  14. Human precision-cut liver slices as a model to test antifibrotic drugs in the early onset of liver fibrosis

    NARCIS (Netherlands)

    Westra, Inge M.; Mutsaers, Henricus A. M.; Luangmonkong, Theerut; Hadi, Mackenzie; Oosterhuis, Dorenda; de Jong, Koert P.; Groothuis, Geny M. M.; Olinga, Peter

    Liver fibrosis is the progressive accumulation of connective tissue ultimately resulting in loss of organ function. Currently, no effective antifibrotics are available due to a lack of reliable human models. Here we investigated the fibrotic process in human precision-cut liver slices (PCLS) and

  15. Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens

    OpenAIRE

    Tsai, Meng-Tsz; Chen, Ching-Yi; Pan, Yu-Hui; Wang, Siou-Huei; Mersmann, Harry J.; Ding, Shih-Torng

    2015-01-01

    Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4-) induced fibrosis for studying antifibrotic effect of betaine in vivo and in vitro. Two-week-old male chicks were supplemented with betaine (1%, w/v) in drinking water for 2 weeks prior to th...

  16. Digital quantification of fibrosis in liver biopsy sections: description of a new method by Photoshop software.

    Science.gov (United States)

    Dahab, Gamal M; Kheriza, Mohamed M; El-Beltagi, Hussien M; Fouda, Abdel-Motaal M; El-Din, Osama A Sharaf

    2004-01-01

    The precise quantification of fibrous tissue in liver biopsy sections is extremely important in the classification, diagnosis and grading of chronic liver disease, as well as in evaluating the response to antifibrotic therapy. Because the recently described methods of digital image analysis of fibrosis in liver biopsy sections have major flaws, including the use of out-dated techniques in image processing, inadequate precision and inability to detect and quantify perisinusoidal fibrosis, we developed a new technique in computerized image analysis of liver biopsy sections based on Adobe Photoshop software. We prepared an experimental model of liver fibrosis involving treatment of rats with oral CCl4 for 6 weeks. After staining liver sections with Masson's trichrome, a series of computer operations were performed including (i) reconstitution of seamless widefield images from a number of acquired fields of liver sections; (ii) image size and solution adjustment; (iii) color correction; (iv) digital selection of a specified color range representing all fibrous tissue in the image and; (v) extraction and calculation. This technique is fully computerized with no manual interference at any step, and thus could be very reliable for objectively quantifying any pattern of fibrosis in liver biopsy sections and in assessing the response to antifibrotic therapy. It could also be a valuable tool in the precise assessment of antifibrotic therapy to other tissue regardless of the pattern of tissue or fibrosis.

  17. Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis

    Science.gov (United States)

    Liu, Longwei; You, Zhifeng; Yu, Hongsheng; Zhou, Lyu; Zhao, Hui; Yan, Xiaojun; Li, Dulei; Wang, Bingjie; Zhu, Lu; Xu, Yuzhou; Xia, Tie; Shi, Yan; Huang, Chenyu; Hou, Wei; Du, Yanan

    2017-12-01

    The role of pathological angiogenesis on liver fibrogenesis is still unknown. Here, we developed fibrotic microniches (FμNs) that recapitulate the interaction of liver sinusoid endothelial cells (LSECs) and hepatic stellate cells (HSCs). We investigated how the mechanical properties of their substrates affect the formation of capillary-like structures and how they relate to the progression of angiogenesis during liver fibrosis. Differences in cell response in the FμNs were synonymous of the early and late stages of liver fibrosis. The stiffness of the early-stage FμNs was significantly elevated due to condensation of collagen fibrils induced by angiogenesis, and led to activation of HSCs by LSECs. We utilized these FμNs to understand the response to anti-angiogenic drugs, and it was evident that these drugs were effective only for early-stage liver fibrosis in vitro and in an in vivo mouse model of liver fibrosis. Late-stage liver fibrosis was not reversed following treatment with anti-angiogenic drugs but rather with inhibitors of collagen condensation. Our work reveals stage-specific angiogenesis-induced liver fibrogenesis via a previously unrevealed mechanotransduction mechanism which may offer precise intervention strategies targeting stage-specific disease progression.

  18. Ultrasound Elastography Is Useful for Evaluation of Liver Fibrosis in Children

    DEFF Research Database (Denmark)

    Andersen, Sofie Bech; Ewertsen, Caroline; Carlsen, Jonathan Frederik

    2016-01-01

    OBJECTIVES: Adult studies have proven ultrasound elastography as a validated measure of liver fibrosis. The present study aimed to review the available literature on ultrasound elastography in children to evaluate the ability of the method to distinguish healthy from fibrotic liver tissue...... and investigate whether cutoff values for liver fibrosis in children have been established. METHODS: A literature search was performed in MEDLINE, EMBASE, the Cochrane Library, and Web of Science to identify studies on ultrasound elastography of the liver in children. Only original research articles in English...

  19. Multifaceted Therapeutic Benefits of Factors Derived From Dental Pulp Stem Cells for Mouse Liver Fibrosis

    OpenAIRE

    Hirata, Marina; Ishigami, Masatoshi; Matsushita, Yoshihiro; Ito, Takanori; Hattori, Hisashi; Hibi, Hideharu; Goto, Hidemi; Ueda, Minoru; Yamamoto, Akihito

    2016-01-01

    Chronic liver injury from various causes often results in liver fibrosis (LF). Although the liver possesses endogenous tissue-repairing activities, these can be overcome by sustained inflammation and excessive fibrotic scar formation. Advanced LF leads to irreversible cirrhosis and subsequent liver failure and/or hepatic cancer. Here, using the mouse carbon tetrachloride (CCl4)-induced LF model, we showed that a single intravenous administration of stem cells derived from human exfoliated dec...

  20. 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.

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

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    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. Digital image analysis in liver fibrosis: basic requirements and clinical implementation

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    Ender Gunes Yegin

    2016-07-01

    Full Text Available Accurate assessment of liver fibrosis is a critical aspect of diagnosis, prognosis prediction, surveillance strategies, therapeutic planning and monitoring, and also for validation of non-invasive surrogates of fibrosis. Traditional histopathological stagings depend on subjective visual interpretation process of architectural changes of fibrosis without providing quantification as continuous numerical data, but rather in the form of discrete staging. This makes high level reproducibility practically impossible in its application, which should be minimized in scientific research. In the light of increasing demand for an objective method, digital image analysis (DIA technology has been increasingly implemented for liver fibrosis assessment. Potential advantages and applications of reproducible quantitative fibrosis ratio measurements with DIA include performing broader scale of statistical analysis and comparison between studies, monitoring minor but potentially important quantity changes during fibrosis regression or progression (especially in the context of therapeutic trials, and to be a better histological reference standard for validity and accuracy of surrogates of fibrosis. DIA may also have a potential role within the new perspective of redefining and sub-classifying cirrhosis. Since DIA algorithm covers multiple domains of hepatopathology and engineering, it may seem to be complicated to a researcher. This review provides an understanding of all basic steps, techniques, clinical applications of computerized image analysis for the particular purpose of liver fibrosis aiming its better implementation in hepatology research. Further work is required for standardization of all stages of pre-imaging, digital image acquisition and digital image processing steps for generation of reproducible outputs.

  3. Immunological basis of septal fibrosis of the liver in Capillaria hepatica-infected rats

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    Lemos Q.T.

    2003-01-01

    Full Text Available Rats infected with the helminth Capillaria hepatica regularly develop septal fibrosis of the liver similar to that induced by repeated ip injections of pig serum. Fibrosis starts when the focal parasitic lesions begin to show signs of resorption, thus suggesting an immunologically mediated pathogenesis of this fibrosis. To explore this possibility, the development of C. hepatica-related hepatic fibrosis was observed in rats exposed to worm antigens from the first neonatal day onward. Wistar rats (150 g were either injected ip with an extract of C. hepatica eggs (protein concentration: 1 mg/ml or received immature eggs by gavage from the first neonatal day until adult life and were then infected with 500 embryonated eggs. Changes were monitored on the basis of serum levels of anti-worm antibodies and hepatic histopathology. Rats submitted to immunological oral tolerance markedly suppressed C. hepatica-related serum antibodies and septal fibrosis of the liver when infected with the helminth later on. Tolerance trials with ip injections of worm antigens gave essentially negative results. The partial suppression of septal fibrosis of the liver after the induction of immunological tolerance to C. hepatica antigens in rats indicates an immunological basis for the fibrosis and emphasizes the importance of immunological factors in the pathogenesis of hepatic fibrosis.

  4. In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.

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    Pascal Trouvé

    Full Text Available Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

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

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    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.

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

    NARCIS (Netherlands)

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

    2010-01-01

    Introduction Activation of the coagulation cascade during liver fibrosis: a puzzling paradox Protease-activated receptors: the link between coagulation cascade activation and liver fibrosis Expression and distribution of human PAR-2 in normal and pathological liver tissue FXa signalling on PAR-2

  7. Hepatic fibrosis in nonalcoholic fatty liver disease and its quantitative assessment

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    WANG Yan

    2017-12-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is becoming a primary etiology underlying the chronic liver injury-related fibrogenesis among general population. Histologic fibrosis has been demonstrated as the most important independent predictor for the major outcomes of NAFLD patients. NAFLD-related fibrosis has distinct characteristics through the disease course, which is largely attributed to its "metabolic" pathophysiology: The progression of fibrosis is correlated to the factors including obesity, metabolic syndrome components, aging, etc.; and the patterns of histologic distribution and evolution as well as the association with the other histological features are remarkably different from those of the other chronic liver diseases. Based on the criteria of current standard histology, accurate quantitative assessment of NAFLD fibrosis could be relevant in terms of research and utilization to stratifying the disease risk, monitoring the therapeutic response, as well as to facilitating the development of new diagnostic tools.

  8. Prevalence and risk factors for significant liver fibrosis among HIV-monoinfected patients

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    Localio Russell

    2010-05-01

    Full Text Available Abstract Background HIV-monoinfected patients may be at risk for significant liver fibrosis, but its prevalence and determinants in these patients are unknown. Since HIV-monoinfected patients do not routinely undergo liver biopsy, we evaluated the prevalence and risk factors of significant hepatic fibrosis in this group using the aspartate aminotransferase (AST-to-platelet ratio index (APRI. Methods We conducted a cross-sectional study among HIV-infected patients negative for hepatitis B surface antigen and hepatitis C antibody in the Penn Center for AIDS Research Adult/Adolescent Database. Clinical and laboratory data were collected from the database at enrollment. Hypothesized determinants of significant fibrosis were modifiable risk factors associated with liver disease progression, hepatic fibrosis, or hepatotoxicity, including immune dysfunction (i.e., CD4 T lymphocyte count 3, HIV viremia, diseases associated with hepatic steatosis (e.g., obesity, diabetes mellitus, and use of antiretroviral therapy. The primary outcome was an APRI score >1.5, which suggests significant hepatic fibrosis. Multivariable logistic regression identified independent risk factors for significant fibrosis by APRI. Results Among 432 HIV-monoinfected patients enrolled in the CFAR Database between November 1999 and May 2008, significant fibrosis by APRI was identified in 36 (8.3%; 95% CI, 5.9 - 11.4% patients. After controlling for all other hypothesized risk factors as well as active alcohol use and site, detectable HIV viremia (adjusted OR, 2.56; 95% CI, 1.02 - 8.87 and diabetes mellitus (adjusted OR, 3.15; 95% CI, 1.12 - 10.10 remained associated with significant fibrosis by APRI. Conclusions Significant fibrosis by APRI score was found in 8% of HIV-monoinfected patients. Detectable HIV viremia and diabetes mellitus were associated with significant fibrosis. Future studies should explore mechanisms for fibrosis in HIV-monoinfected patients.

  9. Prediction of liver-related events using fibroscan in chronic hepatitis B patients showing advanced liver fibrosis.

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    Seung Up Kim

    Full Text Available 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.Between March 2006 and April 2010, 128 CHB patients with who underwent LSM and liver biopsy (LB before starting nucleot(side analogues and showed histologically advanced fibrosis (≥F3 with a high viral loads [HBV DNA ≥2,000 IU/mL] were enrolled. All patients were followed regularly to detect LRE development, including hepatic decompensation (variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome and hepatocellular carcinoma (HCC.The mean age of the patient (72 men, 56 women was 52.2 years. During the median follow-up period [median 27.8 (12.6-61.6 months], LREs developed in 19 (14.8% patients (five with hepatic decompensation, 13 with HCC, one with both. Together with age, multivariate analysis identified LSM as an independent predictor of LRE development [P19 kPa were at significantly greater risk than those with LSM≤19 kPa for LRE development (HR, 7.176; 95% CI, 2.257-22.812; P = 0.001.LSM can be a useful predictor of LRE development in CHB patients showing histologically advanced liver fibrosis.

  10. A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression

    International Nuclear Information System (INIS)

    Dutta-Moscato, Joyeeta; Solovyev, Alexey; Mi, Qi; Nishikawa, Taichiro; Soto-Gutierrez, Alejandro; Fox, Ira J.; Vodovotz, Yoram

    2014-01-01

    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 histopathological 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 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 histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl 4 ). 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 CCl 4 -treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl 4 -injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into

  11. A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression

    Energy Technology Data Exchange (ETDEWEB)

    Dutta-Moscato, Joyeeta [Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA (United States); Department of Surgery, University of Pittsburgh, Pittsburgh, PA (United States); Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Solovyev, Alexey [Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Mathematics, University of Pittsburgh, Pittsburgh, PA (United States); Mi, Qi [Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, PA (United States); Nishikawa, Taichiro [McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA (United States); Soto-Gutierrez, Alejandro [McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Pathology, University of Pittsburgh, Pittsburgh, PA (United States); Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA (United States); Fox, Ira J. [McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA (United States); Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA (United States); Vodovotz, Yoram, E-mail: vodovotzy@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA (United States); Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States)

    2014-05-30

    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 histopathological 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 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 histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl{sub 4}). 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 CCl{sub 4}-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl{sub 4}-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant

  12. Glucocorticoids Have Opposing Effects on Liver Fibrosis in Hepatic Stellate and Immune Cells.

    Science.gov (United States)

    Kim, Kang Ho; Lee, Jae Man; Zhou, Ying; Harpavat, Sanjiv; Moore, David D

    2016-08-01

    Liver fibrosis is a reversible wound-healing process that is protective in the short term, but prolonged fibrotic responses lead to excessive accumulation of extracellular matrix components that suppresses hepatocyte regeneration, resulting in permanent liver damage. Upon liver damage, nonparenchymal cells including immune cells and hepatic stellate cells (HSCs) have crucial roles in the progression and regression of liver fibrosis. Here, we report differential roles of the glucocorticoid receptor (GR), acting in immune cells and HSCs, in liver fibrosis. In the carbon tetrachloride hepatotoxin-induced fibrosis model, both steroidal and nonsteroidal GR ligands suppressed expression of fibrotic genes and decreased extracellular matrix deposition but also inhibited immune cell infiltration and exacerbated liver injury. These counteracting effects of GR ligands were dissociated in mice with conditional GR knockout in immune cells (GR(LysM)) or HSC (GR(hGFAP)): the impacts of dexamethasone on immune cell infiltration and liver injury were totally blunted in GR(LysM) mice, whereas the suppression of fibrotic gene expression was diminished in GR(hGFAP) mice. The effect of GR activation in HSC was further confirmed in the LX-2 HSC cell line, in which antifibrotic effects were mediated by GR ligand inhibition of Sma and mad-related protein 3 (SMAD3) expression. We conclude that GR has differential roles in immune cells and HSCs to modulate liver injury and liver fibrosis. Specific activation of HSC-GR without alteration of GR activity in immune cells provides a potential therapeutic approach to treatment of hepatic fibrosis.

  13. Inflammation-adapted liver stiffness values for improved fibrosis staging in patients with hepatitis C virus and alcoholic liver disease.

    Science.gov (United States)

    Mueller, Sebastian; Englert, Stefan; Seitz, Helmut K; Badea, Radu I; Erhardt, Andreas; Bozaari, Bita; Beaugrand, Michel; Lupșor-Platon, Monica

    2015-12-01

    It is well known that inflammation increases liver stiffness (LS) in patients with chronic hepatitis C (HCV) and alcoholic liver disease (ALD) independent of fibrosis stage, but no inflammation-adapted cut-off values have been settled so far. An early identification of rapid fibrosers, however, is essential to decide whom to treat first with the novel but expensive antiviral drugs. Liver stiffness, biopsy-proven fibrosis stages F0-F4 (METAVIR or Kleiner score) and routine laboratory parameters were studied in 2068 patients with HCV (n = 1391) and ALD (n = 677). Among the routine parameters for liver damage, AST correlated best with LS (HCV: r = 0.54, P liver diseases. Especially in HCV, they could help to decide whom to treat first with the novel but expensive antiviral drugs. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Risk factors of accelerated liver fibrosis in HIV-HCV coinfection: a ...

    African Journals Online (AJOL)

    Introduction: Chronic liver diseases have become a significant cause of mortality in HIV patients. Few reports have assessed risk factors for HCV disease progression in HIV infected patients. Objectives: The aim of our study was to compare the progression rate of liver fibrosis in HIV-HCV coinfected patients with that of ...

  15. 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...

  16. mTOR Overactivation in Mesenchymal cells Aggravates CCl4- Induced liver Fibrosis.

    Science.gov (United States)

    Shan, Lanlan; Ding, Yan; Fu, You; Zhou, Ling; Dong, Xiaoying; Chen, Shunzhi; Wu, Hongyuan; Nai, Wenqing; Zheng, Hang; Xu, Wanfu; Bai, Xiaochun; Jia, Chunhong; Dai, Meng

    2016-11-07

    Hepatic stellate cells are of mesenchymal cell type located in the space of Disse. Upon liver injury, HSCs transactivate into myofibroblasts with increase in expression of fibrillar collagen, especially collagen I and III, leading to liver fibrosis. Previous studies have shown mTOR signaling is activated during liver fibrosis. However, there is no direct evidence in vivo. The aim of this study is to examine the effects of conditional deletion of TSC1 in mesenchymal on pathogenesis of liver fibrosis. Crossing mice bearing the floxed TSC1 gene with mice harboring Col1α2-Cre-ER(T) successfully generated progeny with a conditional knockout of TSC1 (TSC1 CKO) in collagen I expressing mesenchymal cells. TSC1 CKO and WT mice were subjected to CCl 4 , oil or CCl 4 + rapamycin treatment for 8 weeks. TSC1 CKO mice developed pronounced liver fibrosis relative to WT mice, as examined by ALT, hydroxyproline, histopathology, and profibrogenic gene. Absence of TSC1 in mesenchymal cells induced proliferation and prevented apoptosis in activated HSCs. However, there were no significant differences in oil-treated TSC1 CKO and WT mice. Rapamycin, restored these phenotypic changes by preventing myofibroblasts proliferation and enhancing their apoptosis. These findings revealed mTOR overactivation in mesenchymal cells aggravates CCl 4 - induced liver fibrosis and the rapamycin prevent its occurance.

  17. Transient elastography for diagnosis of stages of hepatic fibrosis and cirrhosis in people with alcoholic liver disease

    DEFF Research Database (Denmark)

    Pavlov, Chavdar S; Casazza, Giovanni; Nikolova, Dimitrinka

    2015-01-01

    of the diagnosis of alcoholic liver disease was not provided in one study and was not clearly defined in two studies, but it was clear in the remaining 11 studies. The study authors used different liver stiffness cut-off values of transient elastography for the hepatic fibrosis stages.There was only one study (103......BACKGROUND: The presence and progression of hepatic (liver) fibrosis into cirrhosis is a prognostic variable having impact on survival in people with alcoholic liver disease. Liver biopsy, although an invasive method, is the recommended 'reference standard' for diagnosis and staging of hepatic...... fibrosis in people with liver diseases. Transient elastography is a non-invasive method for assessing and staging hepatic fibrosis. OBJECTIVES: To determine the diagnostic accuracy of transient elastography for diagnosis and staging hepatic fibrosis in people with alcoholic liver disease when compared...

  18. Association of genetic variants with rapid fibrosis: progression after liver transplantation for hepatitis C.

    Science.gov (United States)

    Layden, Jennifer E; Tayo, Bamidele O; Cotler, Scott J; Clark, Nina M; Baraoidan, Kristine; Friedman, Scott L; Cooper, Richard S

    2014-05-27

    Recurrence of hepatitis C, the main indication for liver transplantation in the United States, leads to rapid fibrosis progression and worse outcomes compared to other indications. While clinical variables play a role, they are insufficient to explain all inter-patient variability in posttransplant fibrosis progression. Genetic factors associated with hepatitis C virus (HCV) outcomes have been identified, but limited studies have been conducted in the context of HCV-related liver transplantation. Therefore, the purpose of this study was to examine candidate genes related to the immune response and rate of fibrosis in subjects undergoing liver transplantation for HCV. One hundred twelve recipients with detailed posttransplant fibrosis and clinical information were genotyped using 25 single nucleotide variants (SNVs), including five SNVs within the IL28B gene region. Associations between SNVs and rapid fibrosis progression were performed controlling for pertinent clinical variables and haplotype analyses for the IL28B gene were completed. Significant multivariable associations were found for rs8099917 (IL28B), rs1991401 (DDX5), rs4969168 (SOC3), and rs7976497 (MLEC). The minor allele was protective against rapid fibrosis progression for the IL28B SNV (G allele), MLEC SNV (T allele), and DDX5 SNV (G allele). For the SOC3 SNV, the minor allele (A) increased the risk for rapid fibrosis progression. Additionally, two recipient haplotype structures for IL28B were significantly associated with rapid fibrosis progression. These findings indicate that recipient genetic factors play a role in posttransplant HCV-related fibrosis progression. Molecular studies of these pathways may elucidate the pathogenesis of posttransplant fibrosis progression and provide risk prediction markers.

  19. 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.

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    Wafaa M. Ezzat

    2013-12-01

    Full Text Available 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 2: fibrosis score: 4, 5, 6.The mean values of ATX in all studied patients with chronic HCV infection was 63.02 ± 36.29 while that of healthy controls was 65.31 ± 12.24 without any significant difference. Surprisingly, mean values of ATX were higher among patients with group 1 but it did not reach the significant level. In each group of them, the differences between mean values of ATX among different grades of liver fibrosis were insignificant. It was also noticed that the mean values of ATX were higher among men than in women .It was concluded that Autotoxin might not be used as a useful diagnostic marker for liver fibrosis in Egyptian chronic HCV patients.

  2. Potentials of the elevated circulating miR-185 level as a biomarker for early diagnosis of HBV-related liver fibrosis

    OpenAIRE

    Bin-bin Li; Dong-liang Li; Chao Chen; Bao-hai Liu; Chun-yan Xia; Han-jun Wu; Chao-qun Wu; Guo-qin Ji; Su Liu; Wu Ni; Ding-kang Yao; Zhi-yu Zeng; Da-gui Chen; Bao-dong Qin; Xuan Xin

    2016-01-01

    Early diagnosis of liver fibrosis is critical for early intervention and prognosis of various chronic liver diseases. Conventional repeated histological assessment is impractical due to the associated invasiveness. In the current study, we evaluated circulating miR-185 as a potential biomarker to predict initiation and progression of liver fibrosis. We found that miR-185 was significantly up-regulated in blood specimens from patients with HBV-liver fibrosis and rats with liver fibrosis, the m...

  3. Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis

    Directory of Open Access Journals (Sweden)

    Cuiyuan Huang

    2017-07-01

    Full Text Available Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble–mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.

  4. Chronic Hepatitis E Viral Infection After Liver Transplantation: A Regression of Fibrosis After Antiviral Therapy.

    Science.gov (United States)

    Mazzola, Alessandra; Tran Minh, Margherita; Charlotte, Frédéric; Hdiji, Aisha; Bernard, Denis; Wendum, Dominique; Calmus, Yvon; Conti, Filomena

    2017-09-01

    Hepatitis E virus (HEV) infection is increasingly being reported in immunocompromised patients and particularly organ transplant recipients. In this context, HEV infection frequently evolves to chronic infection with a rapid progression of fibrosis to cirrhosis. Ribavirin monotherapy and a minimization of immunosuppression represent the treatment of choice, with a good response rate. However, no data are available on whether treatment can achieve a regression of liver fibrosis in chronic HEV patients. A 57-year-old male patient received a liver transplant for alcoholic cirrhosis and, 6 years later, developed biopsy-proven chronic HEV infection. The patient received different antiviral therapy regimens (pegylated interferon alpha 2b and ribavirin different dosages, and long-term treatment with ribavirin monotherapy still ongoing) but without achieving a sustained virological response. Liver function parameters normalized after 1 month of treatment but without the clearance of HEV. Hepatitis E virus RNA levels also remained detectable in the serum and stools throughout ribavirin monotherapy. No serious adverse events were reported. A gradual regression of liver fibrosis was reported (Metavir A0/F1 in 2015 versus A3/F4 in 2008). Long-term treatment with ribavirin is safe in liver transplant recipients, without achieving HEV sustained virological response, and may induce a biopsy-proven regression of liver fibrosis in a liver transplant recipient with cirrhosis after chronic HEV infection.

  5. 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 method was applied, combining support vector machine and multivariate generalized linear models to assess the early and late stages of fibrosis, respectively, based on these parameters. The verification cohort was used to verify the scoring method, and the area under the receiver operating characteristic curve was >0.82 for liver cirrhosis detection. Since no subjective gradings are needed, interobserver discrepancies could be avoided using this fully automated method.

  6. Liver shear-wave velocity and serum fibrosis markers to diagnose hepatic fibrosis in patients with chronic viral hepatitis B

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jian Xue; Ji, Yong Hao; Zhao Junzhi; Zhang, Yao Ren; Dun, Guo Liang; Ning, Bo [Dept. of Ultrasonography, Baoji Central Hospital, Baoji (China); Ai, Hong [Dept. of Ultrasonography, The First Affiliated Hospital of Medical College, Xi' an Jiaotong University, Xi' an (China)

    2016-06-15

    To compare several noninvasive indices of fibrosis in chronic viral hepatitis B, including liver shear-wave velocity (SWV), hyaluronic acid (HA), collagen type IV (CIV), procollagen type III (PCIII), and laminin (LN). Acoustic radiation force impulse (ARFI) was performed in 157 patients with chronic viral hepatitis B and in 30 healthy volunteers to measure hepatic SWV (m/s) in a prospective study. Serum markers were acquired on the morning of the same day of the ARFI evaluation. Receiver operating characteristic (ROC) analysis was performed to evaluate and compare the accuracies of SWV and serum markers using METAVIR scoring from liver biopsy as a reference standard. The most accurate test for diagnosing fibrosis F ≥ 1 was SWV with the area under the ROC curve (AUC) of 0.913, followed by LN (0.744), HA (0.701), CIV (0.690), and PCIII (0.524). The best test for diagnosing F ≥ 2 was SWV (AUC of 0.851), followed by CIV (0.671), HA (0.668), LN (0.562), and PCIII (0.550). The best test for diagnosing F ≥ 3 was SWV (0.854), followed by CIV (0.693), HA (0.675), PCIII (0.591), and LN (0.548). The best test for diagnosing F = 4 was SWV (0.965), followed by CIV (0.804), PCIII (0.752), HA (0.744), and LN (0.662). SWV combined with HA and CIV did not improve diagnostic accuracy (AUC = 0.931 for F ≥ 1, 0.863 for F ≥ 2, 0.855 for F ≥ 3, 0.960 for F = 4). The performance of SWV in diagnosing liver fibrosis is superior to that of serum markers. However, the combination of SWV, HA, and CIV does not increase the accuracy of diagnosing liver fibrosis and cirrhosis.

  7. Serum γ-glutamyl transferase levels, insulin resistance and liver fibrosis in patients with chronic liver diseases.

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    Salvatore Petta

    Full Text Available BACKGROUND AND AIMS: Serum levels of γ-glutamyl-transpeptidase(γ-GT were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD, genotype 1 chronic hepatitis C (G1CHC and chronic hepatitis B (CHB, we assessed the link between liver fibrosis and γ-GT serum levels, and we evaluated if normal or high γ-GT serum levels affect the association between insulin resistance (IR and severity of liver fibrosis. METHODS: 843 consecutive patients with chronic liver disease (CLD(193 NAFLD, 481 G1CHC, 169 CHB were evaluated by liver biopsy (Kleiner and Scheuer scores and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum γ-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of γ-GT. RESULTS: By multivariate logistic regression analysis, abnormal γ-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120-6.564,p = 0.02, G1CHC (OR3.461,CI2.138-5.603,p80%. Interestingly, among patients with high or normal γ-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal γ-GT values only (OR4.150,CI1.079-15.970,p = 0.03 for NAFLD; OR2.250,CI1.211-4.181,p = 0.01 for G1CHC; OR3.096,CI2.050-34.220,p = 0.01 for CHB. CONCLUSIONS: In patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal γ-GT values, without differences according to liver disease etiology, and suggesting a role of γ-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and pharmacologic management of patients with CLD.

  8. 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

    ±12 ng/mL, P2 (362 ±25 PMMP degraded vimentin in an animal model of liver fibrosis and in early fibrosis associated with HCV and NAFLD patients. These data......)-treated rats, mean systemic VICM levels increased 31% at week 12 (176 ng/mL, P2% at weeks 20 (200 ng/ml, P....75, P2 (628 ng/mL ±59, p

  9. The effect of a liver-X-receptor ligand on bleomycin induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Shi, Ying; Chen, Qiongju; Yan, Haijun; Gu, Wei

    2016-12-01

    The liver-X-receptors have shown anti-fibrosis ability in several animal models. Our purpose was to investigate the effect of LXRs in bleomycin induced lung fibrosis in mice. Bleomycin was intratracheally delivered to mice. Some mice were administered a LXR agonist, T0901317. Then mice were evaluated for the development of lung inflammation and fibrosis. T0901317 was able to attenuate the inflammation and fibrosis induced by bleomycin. T0901317 treatment evidently abolished the high level of TGF-β1 and inhibited NF-κB DNA-binding activity in lung. So LXRs may attenuate the progressing of lung fibrosis, providing a potential treatment of IPF. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. 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.

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

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    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.

  12. Value of 3 Tesla diffusion-weighted magnetic resonance imaging for assessing liver fibrosis.

    Science.gov (United States)

    Papalavrentios, Lavrentios; Sinakos, Emmanouil; Chourmouzi, Danai; Hytiroglou, Prodromos; Drevelegas, Konstantinos; Constantinides, Manos; Drevelegas, Antonios; Talwalkar, Jayant; Akriviadis, Evangelos

    2015-01-01

    Limited data are available regarding the role of magnetic resonance imaging (MRI), particularly the new generation 3 Tesla technology, and especially diffusion-weighted imaging (DWI) in predicting liver fibrosis. The aim of our pilot study was to assess the clinical performance of the apparent diffusion coefficient (ADC) of liver parenchyma for the assessment of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). 18 patients with biopsy-proven NAFLD underwent DWI with 3 Tesla MRI. DWI was performed with single-shot echo-planar technique at b values of 0-500 and 0-1000 s/mm 2 . ADC was measured in four locations in the liver and the mean ADC value was used for analysis. Staging of fibrosis was performed according to the METAVIR system. The median age of patients was 52 years (range 23-73). The distribution of patients in different fibrosis stages was: 0 (n=1), 1 (n=7), 2 (n=1), 3 (n=5), 4 (n=4). Fibrosis stage was poorly associated with ADC at b value of 0-500 s/mm 2 (r= -0.30, P=0.27). However it was significantly associated with ADC at b value of 0-1000 s/mm 2 (r= -0.57, P=0.01). For this b value (0-1000 s/mm 2 ) the area under receiver-operating characteristic curve was 0.93 for fibrosis stage ≥3 and the optimal ADC cut-off value was 1.16 ×10 -3 mm 2 /s. 3 Tesla DWI can possibly predict the presence of advanced fibrosis in patients with NAFLD.

  13. Role of Hedgehog signaling pathway in progression of non-alcoholic fatty liver fibrosis

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    AN Baiquan

    2015-03-01

    Full Text Available Obesity and related metabolic syndromes are prevalent on the global scale. Thus far, non-alcoholic fatty liver (NAFL disease has caused wide attention from domestic and overseas scholars. NAFL cirrhosis is considered to be the central part and inevitable stage of liver cirrhosis developed from simple fatty liver and non-alcoholic steatohepatitis. The effect of Hedgehog signaling pathway on hepatocytes in the progression of NAFL fibrosis was elucidated and investigated by a population study. Results showed that abnormal activation of the Hedgehog signaling pathway promoted the progression of NAFL fibrosis. In-depth study on the Hedgehog signaling pathway may provide a new approach for the treatment of NAFL fibrosis.

  14. FOXA2 alleviates CCl4-induced liver fibrosis by protecting hepatocytes in mice.

    Science.gov (United States)

    Wang, Wei; Yao, Li-Jia; Shen, Weifeng; Ding, Kai; Shi, Pei-Mei; Chen, Fei; He, Jin; Ding, Jin; Zhang, Xin; Xie, Wei-Fen

    2017-11-14

    The liver-enriched transcription factor Forkhead Box A2 (FOXA2) has been reported to be involved in bile acid homeostasis and bile duct development. However, the role of FOXA2 in liver fibrogenesis remains undefined. In this study, we found that the abundance of FOXA2 was significantly lower in fibrotic livers of patients and mice treated with CCl 4 than in controls. Interestingly, the expression level of FOXA2 decreased in hepatocytes, whereas FOXA2 was elevated in hepatic stellate cells (HSCs) of mouse fibrotic livers. Hepatocyte-specific ablation of FOXA2 in adult mice exacerbated liver fibrosis induced by CCl 4 . Either lentivirus LV-CMV-FOXA2 mediated FOXA2 overexpression in the liver or adeno-associated virus AAV8-TBG-FOXA2-mediated hepatocyte-specific upregulation of FOXA2 alleviated hepatic fibrosis. Overexpression of FOXA2 in HSCs did not obviously affect hepatic fibrogenesis. Additionally, FOXA2 knockout in hepatocytes resulted in aberrant transcription of metabolic genes. Furthermore, hepatocyte-specific knockout of FOXA2 enhanced endoplasmic reticulum stress (ER stress) and the apoptosis of hepatocytes, whereas FOXA2 overexpression in hepatocytes suppressed ER stress and hepatocyte apoptosis in mouse fibrotic livers. In conclusion, our findings suggested that FOXA2-mediated hepatocyte protection has a therapeutic role in hepatic fibrosis, and thus may be a new, promising anti-fibrotic option for treating chronic liver diseases.

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

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    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.

  16. [The diagnostic significance of ultrasound elastometry in evaluation of fibrosis in chronic diffuse liver diseases].

    Science.gov (United States)

    Lazebnik, L B; Vinnitskaia, E V; Shaposhnikova, N A; Khomeriki, S G; Nikanorov, A V; Terekhin, A A; Vorob'eva, N N; Golovanova, E V

    2010-01-01

    Determination of the diagnostic value of ultrasound elastometry of liver (UEL) in the assessment of liver fibrosis in patients with chronic diffuse liver diseases (CDLD). The study involved 316 patients with various etiologies of the CDLD, with the underwent both liver biopsy, the UEL, and evaluation of fibrosis (F) according to the Metavir classification. The maximum diagnostic accuracy of the UEL was obtained in determining of the 4-th stage of fibrosis according to the Metavir. The accuracy of the method was 91% with a sensitivity of 100%. The lowest sensitivity of the UEL determined in patients with nonalcoholic fatty liver disease (NAFLD): F1 - 25%, F2 - 33%, F3 and F4 - 50%. The High body mass index (BMI = 30,1 +/- 3,8 kg/m2) is a factor which is limiting the use of elastometry for patients NAFLD. The low sensitivity for F1 and F2 - 14,3% and 10%, respectively, 100% for F4, with a BMI = 24,4 +/- 5,1 kg/m2 was obtained in primary biliary cirrhosis (PBC). In the alcoholic liver disease (ALD) obtained high sensitivity (100%) for F2 and F4. In the CDLD of viral etiology the sensitivity of UEL was 33-71,4% in the early stages of fibrosis (F1 and F2) with high specificity - 100% and 93.5% respectively. The use of the UEL allows the diagnosis of fibrosis in chronic liver diseases of different etiologies as an alternative to needle biopsy of the liver.

  17. 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.)

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

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    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

  19. Application of magnetic resonance elastography as a non-invasive technique for diagnosis of liver fibrosis

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    YANG Minglei

    2016-03-01

    Full Text Available At present, liver biopsy is the gold standard for the diagnosis and grading of liver fibrosis, but its limitations have been widely acknowledged. The non-invasive detection methods are needed in clinical practice, and at present, magnetic resonance elastography (MRE is a hot research topic. This article reviews the advances in the clinical application of MRE in related fields, and studies have shown that MRE has a high diagnostic value due to its high sensitivity and specificity in the diagnosis and grading of liver fibrosis and an area under the receiver operating characteristic curve as high as 0.95. Compared with serological and other imaging diagnostic methods, MRE can determine fibrosis stage more accurately and has good reproducibility and objectivity. MRE can be widely applied in all patients except those with hemochromatosis, with special advantages in the diagnosis for patients with obesity and ascites, and can make up for the disadvantages of other methods. This article points out that MRE may become the best non-invasive method for the assessment of liver fibrosis, especially advanced fibrosis.

  20. 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.

  1. 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.

  2. Diagnostic value of real-time tissue elastography for liver fibrosis in patients with chronic hepatitis B

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    ZHANG Guosheng

    2014-07-01

    Full Text Available ObjectiveTo investigate the diagnostic value of real-time tissue elastography (RTE in evaluating liver fibrosis in patients with chronic hepatitis B (CHB. MethodsEighty-six patients with CHB, who visited Beijing Tiantan Hospital and Beijing You′an Hospital from March to August, 2013, were grouped according to the pathological stages of liver fibrosis. They were examined by RTE, biochemical tests, and liver biopsy. Then, liver fibrosis index (LFI and aspartate aminotransferase-to-platelet ratio index (APRI were calculated. Comparison between groups was made by one-way analysis of variance, followed by LSD t-test for multiple comparisons. The correlation between LFI and pathological stage of liver fibrosis was analyzed by Spearman correlation test. The sensitivity and specificity of LFI for the diagnosis of liver fibrosis were calculated. Regarding S≥2 (significant liver fibrosis and S≥4 (early liver cirrhosis as the positive standards, the receiver operating characteristic (ROC curve was drawn and compared with APRI. ResultsLFI differed significantly across the groups (P=0.000, except the comparison between S0 and S1 (P=0.298. LFI was significantly correlated with pathological stage (r=0.831, P<0.001. The areas under the ROC curve of LFI in diagnosing significant liver fibrosis and early liver cirrhosis were 0873 (P<0.001 and 0.923 (P=0002, respectively; the diagnostic thresholds were 2.74 and 3.61, respectively; the sensitivity and specificity were 0.766/0.872 and 0.833/0.878, respectively. LFI was significantly superior to APRI. ConclusionRTE has high diagnostic values for significant liver fibrosis and early liver cirrhosis and is an important noninvasive diagnostic method for liver fibrosis in patients with CHB.

  3. [Aspartate aminotransferase (AST) more than alanine aminotransferase (ALT) levels predict the progression of liver fibrosis in chronic HCV infection].

    Science.gov (United States)

    Stránský, J; Ryzlová, M; Striteský, J; Horák, J

    2002-10-01

    The development and severity of liver fibrosis in patients with chronic HCV infection can be evaluated best according to the staging of fibrosis in blind liver biopsy. So far there is however no biochemical indicator suggesting advanced fibrosis or progression of fibrosis in chronic HCV infection. In 1997 - 1999 60 adult out-patients (32 women) with chronic HCV infection were examined by blind liver biopsy. The grading of hepatitis was scored according to Knodell and staging of fibrosis according to Desmet. All patients were anti-HCV positive, assessed by the ELISA-3 method and 48/60 had positive HCV RNA in serum. The main risk factor of HCV infection was blood transfusion (67%). Of 27 examined patients 20 (74%) had serotype HCV 1. Staging of fibrosis: histologically confirmed fibrosis was not recorded in 11 patients (18.3%), mild and medium fibrosis was recorded in 25 (42%), severe fibrosis in 14 (23%) and cirrhosis in 10 (17%). With confirmed fibrosis correlated more closely AST serum activity (p < 0.002) than ALT activity (p < 0.03). Steatosis of the liver was found in 25 (42%) patients. The mean age of patients with steatosis was significantly higher than that of patients without steatosis (p < 0.0008). Steatosis was more frequent in patients with fibrosis (p < 0.04), in particularin the age group above 60 years. The development of fibrosis in patients with chronic HCV infection is suggested by permanently elevated activity of both transaminases whereby AST has a higher predictive value than ALT activity. A total of 40% histologically tested patients had the highest staging of fibrosis (3 - 4). Steatosis is in chronic HCV infection a very frequent finding (42%), in particular in patients above 60 years and those with serious fibrosis. The finding of fibrosis should stimulate the initiation of antiviral treatment which can lead to regression of fibrosis and improvement of the histological finding.

  4. Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition.

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    Pauta, Montse; Ribera, Jordi; Melgar-Lesmes, Pedro; Casals, Gregori; Rodríguez-Vita, Juan; Reichenbach, Vedrana; Fernandez-Varo, Guillermo; Morales-Romero, Blai; Bataller, Ramon; Michelena, Javier; Altamirano, Jose; Jiménez, Wladimiro; Morales-Ruiz, Manuel

    2015-04-01

    Studies in experimental models of cirrhosis showed that anti-angiogenic treatments may be effective for the treatment of liver fibrosis. In this context, angiopoietins are potential therapeutic targets as they are involved in the maintenance and stabilization of newly formed blood vessels. In addition, angiopoietin-2 is expressed in fibrotic livers and its inhibition in tumours results in vessel stability. Therefore, our study was aimed to assess the therapeutic utility of inhibiting angiopoietin-2. Circulating levels of angiopoietin-1 and angiopoietin-2 were quantified by ELISA in CCl4 -treated rats and in patients with cirrhosis. In vivo blockade of angiopoietin-2 in rats with liver fibrosis was performed with a chemically programmed antibody, CVX-060. High levels of angiopoietin-2 were found in the systemic and suprahepatic circulation of cirrhotic patients and the ratio angiopoietin-1/angiopoietin-2 inversely correlated with prognostic models for alcoholic liver disease. Chronic treatment of CCl4 -treated rats with CVX-060 was associated with a significant decrease in inflammatory infiltrate, normalization of the hepatic microvasculature and reduction in VCAM-1 vascular expression. The anti-angiopoietin-2 treatment was also associated with less liver fibrosis and with lower levels of circulating transaminases. CVX-060 treatment was not associated with either vascular pruning in healthy tissue or compensatory overexpression of VEGF. Inhibition of angiopoietin-2 is an effective and safe treatment for liver fibrosis in CCl4 -treated rats, acting mainly through the induction of vessel normalization and the attenuation of hepatic inflammatory infiltrate. Therefore, inhibition of angiopoietin-2 offers a therapeutic alternative for liver fibrosis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Sara Crespo Yanguas

    2018-03-01

    Full Text Available Although a plethora of signaling pathways are known to drive the activation of hepatic stellate cells in liver fibrosis, the involvement of connexin-based communication in this process remains elusive. Connexin43 expression is enhanced in activated hepatic stellate cells and constitutes the molecular building stone of hemichannels and gap junctions. While gap junctions support intercellular communication, and hence the maintenance of liver homeostasis, hemichannels provide a circuit for extracellular communication and are typically opened by pathological stimuli, such as oxidative stress and inflammation. The present study was set up to investigate the effects of inhibition of connexin43-based hemichannels and gap junctions on liver fibrosis in mice. Liver fibrosis was induced by administration of thioacetamide to Balb/c mice for eight weeks. Thereafter, mice were treated for two weeks with TAT-Gap19, a specific connexin43 hemichannel inhibitor, or carbenoxolone, a general hemichannel and gap junction inhibitor. Subsequently, histopathological analysis was performed and markers of hepatic damage and functionality, oxidative stress, hepatic stellate cell activation and inflammation were evaluated. Connexin43 hemichannel specificity of TAT-Gap19 was confirmed in vitro by fluorescence recovery after photobleaching analysis and the measurement of extracellular release of adenosine-5′-triphosphate. Upon administration to animals, both TAT-Gap19 and carbenoxolone lowered the degree of liver fibrosis accompanied by superoxide dismutase overactivation and reduced production of inflammatory proteins, respectively. These results support a role of connexin-based signaling in the resolution of liver fibrosis, and simultaneously demonstrate the therapeutic potential of TAT-Gap19 and carbenoxolone in the treatment of this type of chronic liver disease.

  6. 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.

  7. Liver fibrosis assessment by FibroScan compared with pathological findings of liver resection specimen in hepatitis C infection.

    Science.gov (United States)

    Nakamura, Yuki; Aikata, Hiroshi; Fukuhara, Takayuki; Honda, Fumi; Morio, Kei; Morio, Reona; Hatooka, Masahiro; Kobayashi, Tomoki; Nagaoki, Yuko; Kawaoka, Tomokazu; Tsuge, Masataka; Hiramatsu, Akira; Imamura, Michio; Kawakami, Yoshiiku; Ochi, Hidenori; Kobayashi, Tsuyoshi; Ohdan, Hideki; Shiroma, Noriyuki; Arihiro, Koji; Chayama, Kazuaki

    2017-07-01

    FibroScan is a tool for the non-invasive diagnosis of hepatic fibrosis. Previous studies have compared liver stiffness to percutaneous liver biopsy findings, but no study has compared liver stiffness to liver resection specimen findings. The aim of this study was to compare FibroScan measurements to resected liver specimen findings. From April 2011 to November 2015, a total of 114 patients with liver tumor and hepatitis C were enrolled. We divided them into two groups, the training set and validation set. Liver stiffness was measured by FibroScan before surgery, and specimens obtained by liver resection were evaluated according to the METAVIR system. Using Spearman's rank correlation analysis, a positive correlation between liver stiffness measurement and liver fibrosis stage was observed (r = 0.786, P ≤ 0.0001). In the training set, the area under receiver operating curves for diagnosis of F ≥ 2 was 0.971 (95% confidence interval, 0.928-1.000; cut-off value, 5.9), for diagnosis of F ≥ 3 was 0.911 (0.825-0.997, 9.8), and for diagnosis of F = 4 was 0.917 (0.849-0.985, 15.5). In the validation set, at a cut-off value of 5.9 kPa, sensitivity, specificity, positive predictive values, and negative predictive values for F ≥ 2 were 95.7%, 0.0%, 97.8%, and 0.0%, respectively, of 9.8 kPa for F ≥ 3 were 86.2%, 52.6%, 73.5%, and 71.4%, and of 15.5 kPa for F = 4 were 100%, 71.8%, 45.0%, and 100%. The stage of stiffness graded by FibroScan has a good correlation with the liver fibrosis of resected liver specimens. It has the ability to diagnose fibrosis stage non-invasively. © 2016 The Japan Society of Hepatology.

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

    International Nuclear Information System (INIS)

    Westra, Inge M.; Oosterhuis, Dorenda; Groothuis, Geny M.M.; Olinga, Peter

    2014-01-01

    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

  10. Effects of Liver Fibrosis Progression on Tissue Relaxation Times in Different Mouse Models Assessed by Ultrahigh Field Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Andreas Müller

    2017-01-01

    Full Text Available Recently, clinical studies demonstrated that magnetic resonance relaxometry with determination of relaxation times T1 and T2⁎ may aid in staging and management of liver fibrosis in patients suffering from viral hepatitis and steatohepatitis. In the present study we investigated T1 and T2⁎ in different models of liver fibrosis to compare alternate pathophysiologies in their effects on relaxation times and to further develop noninvasive quantification methods of liver fibrosis. MRI was performed with a fast spin echo sequence for measurement of T1 and a multigradient echo sequence for determination of T2⁎. Toxic liver fibrosis was induced by injections of carbon tetrachloride (1.4 mL CCl4 per kg bodyweight and week, for 3 or 6 weeks in BALB/cJ mice. Chronic sclerosing cholangitis was mimicked using the ATP-binding cassette transporter B4 knockout (Abcb4 -/- mouse model. Untreated BALB/cJ mice served as controls. To assess hepatic fibrosis, we ascertained collagen contents and fibrosis scores after Sirius red staining. T1 and T2⁎ correlate differently to disease severity and etiology of liver fibrosis. T2⁎ shows significant decrease correlating with fibrosis in CCl4 treated animals, while demonstrating significant increase with disease severity in Abcb4 -/- mice. Measurements of T1 and T2⁎ may therefore facilitate discrimination between different stages and causes of liver fibrosis.

  11. Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions

    OpenAIRE

    Hung, Yu-Ping; Lee, Chun-Lin

    2017-01-01

    Deep ocean water (DOW) has been shown to enhance the functional components of fungi, resulting in increased health benefits. Therefore, using DOW for culturing fungi can enhance the cordycepin and adenosine of Cordyceps militaris (CM) and its protective effects on the liver. In this study, the antiliver fibrosis effects and mechanisms of ultrapure water-cultured CM (UCM), DOW-cultured CM (DCM), synthetic water-cultured CM, DOW, cordycepin, and adenosine were compared in the liver fibrosis mic...

  12. Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease.

    Directory of Open Access Journals (Sweden)

    Omar A Mesarwi

    Full Text Available Obstructive sleep apnea (OSA is associated with the progression of non-alcoholic fatty liver disease (NAFLD to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing α subunit of hypoxia inducible factor-1 (HIF-1, a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis.Wild-type mice and mice with hepatocyte-specific HIF-1α knockout (Hif1a-/-hep were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2 or normoxia (16% O2 for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking.Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 μg collagen/mg liver tissue, versus 1.23 μg collagen/mg liver tissue, p = 0.03, which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia.Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver

  13. Hepatitis B virus sequencing and liver fibrosis evaluation in HIV/HBV co-infected Nigerians.

    Science.gov (United States)

    Grant, Jennifer; Agbaji, Oche; Kramvis, Anna; Yousif, Mukhlid; Auwal, Mu'azu; Penugonda, Sudhir; Ugoagwu, Placid; Murphy, Robert; Hawkins, Claudia

    2017-06-01

    Molecular characteristics of hepatitis B virus (HBV), such as genotype and genomic mutations, may contribute to liver-related morbidity and mortality. The association of these characteristics with liver fibrosis severity in sub-Saharan Africa is uncertain. We aimed to characterise molecular HBV features in human immunodeficiency virus (HIV)/HBV co-infected Nigerians and evaluate associations between these characteristics and liver fibrosis severity before and after antiretroviral therapy (ART) initiation. HIV/HBV co-infected Nigerians underwent liver fibrosis estimation by transient elastography (TE) prior to and 36 months after ART initiation. Basal core promoter/precore (BCP/PC) and preS1/preS2/S regions of HBV were sequenced from baseline plasma samples. We evaluated associations between HBV mutations and liver fibrosis severity by univariate and multivariable regression. At baseline, 94 patients underwent TE with median liver stiffness of 6.4 (IQR 4.7-8.7) kPa. Patients were predominantly infected with HBV genotype E (45/46) and HBe-antigen negative (75/94, 79.8%). We identified BCP A1762T/G1764A in 15/35 (43%), PC G1896A in 20/35 (57%), 'a' determinant mutations in 12/45 (26.7%) and preS2 deletions in 6/16 (37.5%). PreS2 mutations were associated with advanced fibrosis in multivariable analysis. At follow-up, median liver stiffness was 5.2 (IQR 4.1-6.6) kPa. No HBV molecular characteristics were associated with lack of fibrosis regression, although HIV virologic control, body mass index (BMI) and baseline CD4+ T-cell count were associated with a decline in fibrosis stage. Frequent BCP/PC and preS1/preS2/S mutations were found in ART-naïve HIV/HBV co-infected Nigerians. Median liver stiffness declined after initiation of ART, regardless of pre-ART HBV mutational pattern or virologic characteristics. © 2017 John Wiley & Sons Ltd.

  14. Evaluating the Significance of Viscoelasticity in Diagnosing Early-Stage Liver Fibrosis with Transient Elastography

    Science.gov (United States)

    Cheng, Jun; He, Qiong; Luo, Jianwen; Yang, Xueping; Shao, Jinhua; Xing, Huichun

    2017-01-01

    Transient elastography quantifies the propagation of a mechanically generated shear wave within a soft tissue, which can be used to characterize the elasticity and viscosity parameters of the tissue. The aim of our study was to combine numerical simulation and clinical assessment to define a viscoelastic index of liver tissue to improve the quality of early diagnosis of liver fibrosis. This is clinically relevant, as early fibrosis is reversible. We developed an idealized two-dimensional axisymmetric finite element model of the liver to evaluate the effects of different viscoelastic values on the propagation characteristics of the shear wave. The diagnostic value of the identified viscoelastic index was verified against the clinical data of 99 patients who had undergone biopsy and routine blood tests for staging of liver disease resulting from chronic hepatitis B infection. Liver stiffness measurement (LSM) and the shear wave attenuation fitting coefficient (AFC) were calculated from the ultrasound data obtained by performing transient elastography. Receiver operating curve analysis was used to evaluate the reliability and diagnostic accuracy of LSM and AFC. Compared to LSM, the AFC provided a higher diagnostic accuracy to differentiate early stages of liver fibrosis, namely F1 and F2 stages, with an overall specificity of 81.48%, sensitivity of 83.33% and diagnostic accuracy of 81.82%. AFC was influenced by the level of LSM, ALT. However, there are no correlation between AFC and Age, BMI, TBIL or DBIL. Quantification of the viscoelasticity of liver tissue provides reliable measurement to identify and differentiate early stages of liver fibrosis. PMID:28107385

  15. Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease.

    Science.gov (United States)

    McPherson, Stuart; Henderson, Elsbeth; Burt, Alastair D; Day, Christopher P; Anstee, Quentin M

    2014-05-01

    A third of the population are estimated to have NAFLD of varying severity. Serum immunoglobulins are frequently elevated in patients with chronic liver disease, but little is known about serum immunoglobulin levels in patients with NAFLD. Aim of this study was to evaluate serum immunoglobulin levels (IgA, IgG, and IgM) in a large cohort of patients with biopsy-proven NAFLD and determine if immunoglobulin levels are associated with clinical or histological features. Patients seen in a tertiary fatty liver clinic between 1999 and 2009 were included. Liver biopsies were assessed using the Kleiner score. Immunoglobulin levels and other blood tests were taken at time of biopsy. 285 patients (110 simple steatosis and 175 NASH) had serum immunoglobulins measured within 6months of liver biopsy. 130 (46%) patients had elevated (>1× upper limit of normal) serum IgA levels, 28 (10%) patients had elevated IgG and 22 (8%) raised IgM. Serum IgA levels were elevated more frequently in patients with NASH compared with subjects with simple steatosis (55% vs. 31%, p<0.001). Overall, 55 (19%) patients had advanced liver fibrosis (Kleiner stage 3-4). There was a significant positive association between serum IgA levels and the stage of fibrosis (p<0.001). Serum IgA, age, platelets, AST/ALT ratio and BMI were all independently with advanced fibrosis following multivariate analysis. A model constructed from these independent predictors accurately predicted advanced fibrosis (AUROC 0.87). The serum IgA level was frequently elevated in patients with NAFLD and was an independent predictor of advanced fibrosis. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  16. 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

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

    International Nuclear Information System (INIS)

    Marginean, Cristina Oana; Marginean, Claudiu

    2012-01-01

    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

  18. 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: 2.868, year: 2015

  19. Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens.

    Science.gov (United States)

    Tsai, Meng-Tsz; Chen, Ching-Yi; Pan, Yu-Hui; Wang, Siou-Huei; Mersmann, Harry J; Ding, Shih-Torng

    2015-01-01

    Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4-) induced fibrosis for studying antifibrotic effect of betaine in vivo and in vitro. Two-week-old male chicks were supplemented with betaine (1%, w/v) in drinking water for 2 weeks prior to the initiation of CCl4 treatment (i.p.) until sacrifice. Primary chicken hepatocytes were treated with CCl4 and betaine to mimic the in vivo supplementation. The supplementation of betaine significantly alleviated liver fibrosis development along with the inhibition of lipid peroxidation, hepatic inflammation cytokine, and transforming growth factor-β1 expression levels. These inhibitive effects were also accompanied with the attenuation of hepatic stellate cell activation. Furthermore, our in vitro studies confirmed that betaine provides antioxidant capacity for attenuating the hepatocyte necrosis by CCl4. Altogether, our results highlight the antioxidant ability of betaine, which alleviates CCl4-induced fibrogenesis process along with the suppression of hepatic stellate cells activation. Since betaine is a natural compound without toxicity, we suggest betaine can be used as a potent nutritional or therapeutic factor for reducing liver fibrosis.

  20. Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens

    Directory of Open Access Journals (Sweden)

    Meng-Tsz Tsai

    2015-01-01

    Full Text Available Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4- induced fibrosis for studying antifibrotic effect of betaine in vivo and in vitro. Two-week-old male chicks were supplemented with betaine (1%, w/v in drinking water for 2 weeks prior to the initiation of CCl4 treatment (i.p. until sacrifice. Primary chicken hepatocytes were treated with CCl4 and betaine to mimic the in vivo supplementation. The supplementation of betaine significantly alleviated liver fibrosis development along with the inhibition of lipid peroxidation, hepatic inflammation cytokine, and transforming growth factor-β1 expression levels. These inhibitive effects were also accompanied with the attenuation of hepatic stellate cell activation. Furthermore, our in vitro studies confirmed that betaine provides antioxidant capacity for attenuating the hepatocyte necrosis by CCl4. Altogether, our results highlight the antioxidant ability of betaine, which alleviates CCl4-induced fibrogenesis process along with the suppression of hepatic stellate cells activation. Since betaine is a natural compound without toxicity, we suggest betaine can be used as a potent nutritional or therapeutic factor for reducing liver fibrosis.

  1. Diagnosis, follow-up and treatment of cystic fibrosis-related liver disease

    NARCIS (Netherlands)

    van de Peppel, Ivo P; Bertolini, Anna; Jonker, Johan W; Bodewes, Frank A J A; Verkade, Henkjan J

    2017-01-01

    Purpose of review To provide an insight and overview of the challenges in the diagnosis, follow-up and treatment of cystic fibrosis-related liver disease (CFLD). Recent findings The variable pathophysiology of CFLD complicates its diagnosis and treatment. A 'gold standard' for CFLD diagnosis is

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

    Science.gov (United States)

    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

  3. Proteomic and transcriptomic studies of HBV-associated liver fibrosis of an AAV-HBV-infected mouse model.

    Science.gov (United States)

    Kan, Fangming; Ye, Lei; Yan, Tao; Cao, Jiaqi; Zheng, Jianhua; Li, Wuping

    2017-08-22

    Human hepatitis B virus (HBV) infection is an important public health issue in the Asia-Pacific region and is associated with chronic hepatitis, liver fibrosis, cirrhosis and even liver cancer. However, the underlying mechanisms of HBV-associated liver fibrosis remain incompletely understood. In the present study, proteomic and transcriptomic approaches as well as biological network analyses were performed to investigate the differentially expressed molecular signature and key regulatory networks that were associated with HBV-mediated liver fibrosis. RNA sequencing and 2DE-MALDI-TOF/TOF were performed on liver tissue samples obtained from HBV-infected C57BL/6 mouse generated via AAV8-HBV virus. The results showed that 322 genes and 173 proteins were differentially expressed, and 28 HBV-specific proteins were identified by comprehensive proteomic and transcriptomic analysis. GO analysis indicated that the differentially expressed proteins were predominantly involved in oxidative stress, which plays a key role in HBV-related liver fibrosis. Importantly, CAT, PRDX1, GSTP1, NXN and BLVRB were shown to be associated with oxidative stress among the differentially expressed proteins. The most striking results were validated by Western blot and RT-qPCR. The RIG-I like receptor signaling pathway was found to be the major signal pathway that changed during HBV-related fibrosis. This study provides novel insights into HBV-associated liver fibrosis and reveals the significant role of oxidative stress in liver fibrosis. Furthermore, CAT, BLVRB, NXN, PRDX1, and IDH1 may be candidates for detection of liver fibrosis or therapeutic targets for the treatment of liver fibrosis.

  4. Racial differences in fibrosis progression after HCV-related liver transplantation.

    Science.gov (United States)

    Layden, Jennifer E; Cotler, Scott; Brown, Kimberly A; Lucey, Michael R; Te, Helen S; Eswaran, Sheila; Fimmel, Claus; Layden, Thomas J; Clark, Nina M

    2012-07-27

    Black recipients undergoing liver transplantation (LT) for hepatitis C virus (HCV) have decreased patient and graft survival compared with white recipients, a finding that is primarily limited to black recipients of livers from white donors. The cause(s) for these discrepant outcomes are unclear but may be related to HCV disease recurrence. The rates of HCV-related disease recurrence and liver fibrosis progression among black and white liver transplant recipients have not been investigated. In this study, we compared liver fibrosis progression between 105 black and 364 white recipients after HCV-related LT in a multisite cohort study and assessed the impact of donor race. At 6, 12, and 24 months after LT, there was a significantly higher percentage in the black recipient/white donor (B/W) group with severe fibrosis, defined as stage 3 or 4 (F3/F4), compared with all other recipient/donor race combinations. The adjusted odds ratio of developing F3/F4 for the B/W group was 2.54 (1.49-4.69; reference group, white recipient/white donor). Black recipients with black donors demonstrated a similar rate of progression to F3/F4 as white recipients. Patient survival was also decreased in the B/W group compared with other recipient/donor race combinations. African American recipients with white donors have more severe fibrosis progression after HCV-related LT. The mechanisms responsible for accelerating fibrosis progression in this high-risk race-mismatched group need to be investigated.

  5. Effect of acid-sensing ion channel 1a on the process of liver fibrosis under hyperglycemia

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Huan, E-mail: wanghuan7@126.com [School of Pharmacy, Anhui Medical University, Hefei, 230032 (China); Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Medical University, Hefei, 230032 (China); Wang, Ying-hong; Yang, Feng; Li, Xiao-feng; Tian, Yuan-yao; Ni, Ming-ming; Zuo, Long-quan; Meng, Xiao-Ming [School of Pharmacy, Anhui Medical University, Hefei, 230032 (China); Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Medical University, Hefei, 230032 (China); Huang, Yan, E-mail: aydhy@126.com [School of Pharmacy, Anhui Medical University, Hefei, 230032 (China); Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Medical University, Hefei, 230032 (China)

    2015-12-25

    Metabolic syndrome characterized by hyperglycemia contributes to nonalcoholic steatohepatitis-associated liver fibrosis. This study was to investigate the effects of Acid-sensing ion Channel 1a (ASIC1a) on the process of liver fibrosis under hyperglycemia. Results showed that high glucose significantly worsen the pathology of liver fibrosis in vivo. In vitro, high glucose stimulated proliferation, activation and extracellular matrix (ECM) production in HSCs, and enhanced the effect of PDGF-BB on the activation and proliferation of HSCs. These effects could be attenuated by ASIC1a specific inhibitor Psalmotoxin-1(PcTx1) or specific ShRNA for ASIC1a through Notch1/Hes-1 pathways. These data indicate that ASIC1a plays an important role in diabetes complication liver fibrosis. - Highlights: • Hyperglycemia is a risk factor for the process of liver fibrosis. • ASIC1a may be a key factor linking between high glucose and liver fibrosis. • Notch1/Hes-1 may involve to the process of liver fibrosis under hyperglycemia.

  6. Evaluation of methanolic extract of Phragmites karka on carbon tetrachloride-induced liver fibrosis in rat

    Directory of Open Access Journals (Sweden)

    Atta ur Rehman

    2017-07-01

    Full Text Available Phragmites karka has been reported for its anti-inflammatory and analgesic activities. Here, extracts of leaf and rhizome of the plant were individually investigated in CCl4-induced hepatofibrosis in male Wistar rats by administering CCl4 intraperitoneally biweekly for 6 weeks. Afterwards the animals were investigated for liver fibrosis at biochemical, molecular and histological levels, and it showed a profound increase (p<0.001 in elevation of serum levels of transaminases, γ-glutamyl transpeptidase, mRNA expression of α smooth muscle actin, collagen and transforming growth factor beta (TGFβ, and extracellular matrix deposition and perilobular necrosis. Both extracts markedly (p<0.001 decreased the elevated levels of these markers. Histopathological investigations also substantiated the above results by exhibiting a decreased in extracellular matrix deposition in post-treatment animals. In conclusion, both extracts had substantially modified the biochemical and molecular markers of liver fibrosis, in addition to histological improvement in architecture of liver.

  7. 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.

  8. Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease.

    Science.gov (United States)

    Alazawi, William; Bernabe, Eduardo; Tai, David; Janicki, Tomasz; Kemos, Polychronis; Samsuddin, Salma; Syn, Wing-Kin; Gillam, David; Turner, Wendy

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) has a bidirectional association with metabolic syndrome. It affects up to 30% of the general population, 70% of individuals with diabetes and 90% with obesity. The main histological hallmark of progressive NAFLD is fibrosis. There is a bidirectional epidemiological link between periodontitis and metabolic syndrome. NAFLD, periodontitis and diabetes share common risk factors, are characterised by inflammation and associated with changes in commensal bacteria. Therefore we tested the hypothesis that periodontitis is associated with NAFLD and with significant fibrosis in two study groups. We analyzed data from a population-based survey and a patient-based study. NHANES III participants with abdominal ultrasound and sociodemographic, clinical, and oral examination data were extracted and appropriate weighting applied. In a separate patient-based study, consenting patients with biopsy-proved NAFLD (or with liver indices too mild to justify biopsy) underwent dental examination. Basic Periodontal Examination score was recorded. In NHANES, periodontitis was significantly associated with steatosis in 8172 adults even after adjusting for sociodemographic factors. However, associations were fully explained after accounting for features of metabolic syndrome. In the patient-based study, periodontitis was significantly more common in patients with biopsy-proven NASH and any fibrosis (F0-F4) than without NASH (p = 0.009). Periodontitis was more common in patients with NASH and significant fibrosis (F2-4) than mild or no fibrosis (F0-1, p = 0.04). Complementary evidence from an epidemiological survey and a clinical study show that NAFLD is associated with periodontitis and that the association is stronger with significant liver fibrosis.

  9. Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease.

    Directory of Open Access Journals (Sweden)

    William Alazawi

    Full Text Available Non-alcoholic fatty liver disease (NAFLD has a bidirectional association with metabolic syndrome. It affects up to 30% of the general population, 70% of individuals with diabetes and 90% with obesity. The main histological hallmark of progressive NAFLD is fibrosis. There is a bidirectional epidemiological link between periodontitis and metabolic syndrome. NAFLD, periodontitis and diabetes share common risk factors, are characterised by inflammation and associated with changes in commensal bacteria. Therefore we tested the hypothesis that periodontitis is associated with NAFLD and with significant fibrosis in two study groups.We analyzed data from a population-based survey and a patient-based study. NHANES III participants with abdominal ultrasound and sociodemographic, clinical, and oral examination data were extracted and appropriate weighting applied. In a separate patient-based study, consenting patients with biopsy-proved NAFLD (or with liver indices too mild to justify biopsy underwent dental examination. Basic Periodontal Examination score was recorded.In NHANES, periodontitis was significantly associated with steatosis in 8172 adults even after adjusting for sociodemographic factors. However, associations were fully explained after accounting for features of metabolic syndrome. In the patient-based study, periodontitis was significantly more common in patients with biopsy-proven NASH and any fibrosis (F0-F4 than without NASH (p = 0.009. Periodontitis was more common in patients with NASH and significant fibrosis (F2-4 than mild or no fibrosis (F0-1, p = 0.04.Complementary evidence from an epidemiological survey and a clinical study show that NAFLD is associated with periodontitis and that the association is stronger with significant liver fibrosis.

  10. MR elastography of liver fibrosis: preliminary results comparing spin-echo and echo-planar imaging

    Energy Technology Data Exchange (ETDEWEB)

    Huwart, Laurent; Salameh, Najat; Peeters, Frank; Beers, Bernard E. van [Universite Catholique de Louvain, St-Luc University Hospital, Diagnostic Radiology Unit, Brussels (Belgium); Beek, Leon ter [Philips Medical Systems, Best (Netherlands); Vicaut, Eric [Universite Paris Diderot, Hopital Lariboisiere, Paris (France); Sinkus, Ralph [Universite Paris Diderot, Laboratoire Ondes et Acoustique, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris, Paris (France)

    2008-11-15

    The purpose of this study was to prospectively compare the performance of magnetic resonance (MR) elastography using echo-planar and spin-echo imaging for staging of hepatic fibrosis. Twenty-four patients who had liver biopsy for suspicion of chronic liver disease had MR elastography performed with both spin-echo and echo-planar sequences. At histology, the fibrosis stage was assessed according to METAVIR. The data acquisition time was about 20 min using spin-echo, and only 2 min using echo-planar imaging. The hepatic signal-to-noise ratios were similar on both images (22.51 {+-} 5.37 for spin-echo versus 21.02 {+-} 4.76 for echo-planar, p = 0.33). The elasticity measurements and the fibrosis stages were strongly correlated. The Spearman correlation coefficients were r = 0.91 (p < 0.01) with spin-echo and r = 0.84 (p < 0.01) with echo-planar sequences. These correlation coefficients did not differ significantly (p = 0.17). A strong correlation was also observed between spin-echo and echo-planar elasticity (r = 0.83, p < 0.001), without systematic bias. The results of our study showed that echo-planar imaging substantially decreased the data acquisition time of MR elastography, while maintaining the image quality and diagnostic performance for staging of liver fibrosis. This suggests that echo-planar MR elastography could replace spin-echo MR elastography in clinical practice. (orig.)

  11. Advanced non-alcoholic fatty liver disease and adipose tissue fibrosis in patients with Alström syndrome.

    Science.gov (United States)

    Gathercole, Laura L; Hazlehurst, Jonathan M; Armstrong, Matthew J; Crowley, Rachel; Boocock, Sarah; O'Reilly, Michael W; Round, Maria; Brown, Rachel; Bolton, Shaun; Cramb, Robert; Newsome, Phillip N; Semple, Robert K; Paisey, Richard; Tomlinson, Jeremy W; Geberhiwot, Tarekegn

    2016-11-01

    Alström syndrome (AS) is a recessive monogenic syndrome characterized by obesity, extreme insulin resistance and multi-organ fibrosis. Despite phenotypically being high risk of non-alcoholic fatty liver disease (NAFLD), there is a lack of data on the extent of fibrosis in the liver and its close links to adipose in patients with AS. Our aim was to characterize the hepatic and adipose phenotype in patients with AS. Observational cohort study with comprehensive assessment of metabolic liver phenotype including liver elastography (Fibroscan ® ), serum Enhanced Liver Fibrosis (ELF) Panel and liver histology. In addition, abdominal adipose histology and gene expression was assessed. We recruited 30 patients from the UK national AS clinic. A subset of six patients underwent adipose biopsies which was compared with control tissue from nine healthy participants. Patients were overweight/obese (BMI 29.3 (25.95-34.05) kg/m 2 ). A total of 80% (24/30) were diabetic; 74% (20/27) had liver ultrasound scanning suggestive of NAFLD. As judged by the ELF panel, 96% (24/25) were categorized as having fibrosis and 10/21 (48%) had liver elastography consistent with advanced liver fibrosis/cirrhosis. In 7/8 selected cases, there was evidence of advanced NAFLD on liver histology. Adipose tissue histology showed marked fibrosis as well as disordered pro-inflammatory and fibrotic gene expression profiles. NAFLD and adipose dysfunction are common in patients with AS. The severity of liver disease in our cohort supports the need for screening of liver fibrosis in AS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. [Effect of cordyceps polysaccharide on lipid peroxidation of rats with dimethylnitrosamine-induced liver fibrosis].

    Science.gov (United States)

    Peng, Jing-Hua; Li, Xue-Mei; Hu, Yi-Yang; Feng, Qin

    2013-02-01

    To observe the pharmacological effect of Cordyceps polysaccharide on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. DMN rat liver fibrosis model was established and divided into the normal group (N, n = 6), the model group (M, n = 11), the Cordyceps polysaccharide group (C, n = 8) and the colchicine group (Q, n = 9). During the modeling for four weeks, Cordyceps polysaccharide (60 mg x kg(-1)) and colchicine (0.1 mg x kg(-1)) were orally administered for three weeks, while the model and normal groups were given disinfected water of the same amount. serum ALT, AST, GGT and Alb, TBil content; content of hydroxyproline (Hyp) in liver tissues; liver pathology and collagen staining; SOD activity and MDA, GSH, GSH-Px in liver tissues; protein expression of proliferating cell nuclear antigen (PCNA) in liver tissues. Serum ALT, AST, GGT, TBil significantly increased, and A1b decreased significantly in the model group. Hepatic Hyp significantly increased in the model group, whereas the index remarkably decreased in the Cordyceps polysaccharide group and the colchicine group. HE staining: the structure of normal hepatic lobules was damaged, with hepatocytes tumefaction and proliferation of connective tissues in portal tracts in the model group, while the Cordyceps polysaccharide group and the colchicine group recorded notable reduction in above pathological changes. Collagen staining: the model group showed hepatic lobule fibrous septum and many intact pseudolobules; while the Cordyceps polysaccharide group and the colchicine group witnessed decrease in collagen deposition. The model group showed significant decrease in SOD, GSH-Px and GSH and increase in MDA, whereas the Cordyceps polysaccharide group and the colchicine group recorded notable growth in GSH and GSH-Px. The model group showed significant decrease in protein expression of PCNA in liver tissues, while the Cordyceps polysaccharide group and the colchicine group showed significant reduction. Cordyceps

  13. GOLGA2 loss causes fibrosis with autophagy in the mouse lung and liver.

    Science.gov (United States)

    Park, Sungjin; Kim, Sanghwa; Kim, Min Jung; Hong, Youngeun; Lee, Ah Young; Lee, Hyunji; Tran, Quangdon; Kim, Minhee; Cho, Hyeonjeong; Park, Jisoo; Kim, Kwang Pyo; Park, Jongsun; Cho, Myung-Haing

    2018-01-01

    Autophagy is a biological recycling process via the self-digestion of organelles, proteins, and lipids for energy-consuming differentiation and homeostasis. The Golgi serves as a donor of the double-membraned phagophore for autophagosome assembly. In addition, recent studies have demonstrated that pulmonary and hepatic fibrosis is accompanied by autophagy. However, the relationships among Golgi function, autophagy, and fibrosis are unclear. Here, we show that the deletion of GOLGA2, encoding a cis-Golgi protein, induces autophagy with Golgi disruption. The induction of autophagy leads to fibrosis along with the reduction of subcellular lipid storage (lipid droplets and lamellar bodies) by autophagy in the lung and liver. GOLGA2 knockout mice clearly demonstrated fibrosis features such as autophagy-activated cells, densely packed hepatocytes, increase of alveolar macrophages, and decrease of alveolar surfactant lipids (dipalmitoylphosphatidylcholine). Therefore, we confirmed the associations among Golgi function, fibrosis, and autophagy. Moreover, GOLGA2 knockout mice may be a potentially valuable animal model for studying autophagy-induced fibrosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. 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.

  15. Separation of advanced from mild fibrosis in diffuse liver disease using 31P magnetic resonance spectroscopy

    International Nuclear Information System (INIS)

    Noren, Bengt; Dahlqvist, Olof; Lundberg, Peter; Almer, Sven; Kechagias, Stergios; Ekstedt, Mattias; Franzen, Lennart; Wirell, Staffan; Smedby, Orjan

    2008-01-01

    31 P-MRS using DRESS was used to compare absolute liver metabolite concentrations (PME, Pi, PDE, γATP, αATP, βATP) in two distinct groups of patients with chronic diffuse liver disorders, one group with steatosis (NAFLD) and none to moderate inflammation (n = 13), and one group with severe fibrosis or cirrhosis (n = 16). All patients underwent liver biopsy and extensive biochemical evaluation. A control group (n = 13) was also included. Absolute concentrations and the anabolic charge, AC = {PME}/({PME} + {PDE}), were calculated. Comparing the control and cirrhosis groups, lower concentrations of PDE (p = 0.025) and a higher AC (p < 0.001) were found in the cirrhosis group. Also compared to the NAFLD group, the cirrhosis group had lower concentrations of PDE (p = 0.01) and a higher AC (p = 0.009). No significant differences were found between the control and NAFLD group. When the MRS findings were related to the fibrosis stage obtained at biopsy, there were significant differences in PDE between stage F0-1 and stage F4 and in AC between stage F0-1 and stage F2-3. Using a PDE concentration of 10.5 mM as a cut-off value to discriminate between mild, F0-2, and advanced, F3-4, fibrosis the sensitivity and specificity were 81% and 69%, respectively. An AC cut-off value of 0.27 showed a sensitivity of 93% and a specificity of 54%. In conclusion, the results suggest that PDE is a marker of liver fibrosis, and that AC is a potentially clinically useful parameter in discriminating mild fibrosis from advanced

  16. Liver and blood cytokine microenvironment in HCV patients is associated to liver fibrosis score: a proinflammatory cytokine ensemble orchestrated by TNF and tuned by IL-10.

    Science.gov (United States)

    de Souza-Cruz, Soriane; Victória, Marilú Barbieri; Tarragô, Andréa Monteiro; da Costa, Allyson Guimarães; Pimentel, João Paulo Diniz; Pires, Ericka Florêncio; Araújo, Lorene de Paula; Coelho-dos-Reis, Jordana Grazziela; Gomes, Matheus de Souza; Amaral, Laurence Rodrigues; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Victória, Flamir da Silva; Malheiro, Adriana

    2016-01-07

    In this study, we have evaluated the immunological status of hepatitis C virus (HCV)-infected patients aiming at identifying putative biomarkers associated with distinct degrees of liver fibrosis. Peripheral blood and tissue T-cells as well as cytokine levels were quantified by flow cytometry. Data analysis demonstrated higher frequency of circulating CD8(+) T-cells and Tregs along with a mixed proinflammatory/IL-10-modulated cytokine pattern in HCV patients. Patients with severe liver fibrosis presented lower frequency of circulating CD8(+) T-cells, higher levels of proinflammatory cytokines, but lower levels of IL-10, in addition to the higher viral load. Despite the lower frequency of intrahepatic T-cells and scarce frequency of Tregs, patients with severe liver fibrosis showed higher levels of proinflammatory cytokines (TNF and IFN-γ). The tissue proinflammatory cytokine pattern supported further studies of serum cytokines as relevant biomarkers associated with different liver fibrosis scores. Serum cytokine signature showed that mild liver fibrosis is associated with higher IL-10 serum levels as compared to severe liver disease. There was a clear positive connection of IL-10 with the TNF node in patients with mild liver fibrosis, whereas there is an evident inverse correlation between IL-10 with all other cytokine nodes. These results suggest the absence of modulatory events in patients with severe liver damage as opposed to mild fibrosis. Machine-learning data mining pointed out TNF and IL-10 as major attributes to differentiate HCV patients from non-infected individuals with highest performance. In conclusion, our findings demonstrated that HCV infection triggers a local and systemic cytokine ensemble orchestrated by TNF and tuned by IL-10 in such a manner that mirrors the liver fibrosis score, which highly suggests the relevance of these set of biomarkers for clinical investigations.

  17. TLR4 Deficiency Protects against Hepatic Fibrosis and Diethylnitrosamine-Induced Pre-Carcinogenic Liver Injury in Fibrotic Liver.

    Directory of Open Access Journals (Sweden)

    Susanne Nicole Weber

    Full Text Available The development of hepatocellular carcinoma (HCC is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN, with HCC formation depending amongst others on interleukin (IL 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver. The aim of this study was to investigate DEN-induced liver injury in TLR4-deficient mice with biliary fibrosis.ABCB4-deficient mice on the FVB/NJ genetic background were crossed to two distinct genetic backgrounds (TLR4-sufficient C3H/HeN and TLR4-deficient C3H/HeJ for more than 10 generations. The two congenic knockout and the two corresponding wild-type mouse lines were treated with a single dose of DEN for 48 hours. Phenotypic differences were assessed by measuring hepatic collagen contents, inflammatory markers (ALT, CRP, IL6 as well as hepatic apoptosis (TUNEL and proliferation (Ki67 rates.Hepatic collagen accumulation is significantly reduced in ABCB4-/-:TLR4-/-double-deficient mice. After DEN challenge, apoptosis, proliferation and inflammatory markers are decreased in TLR4-deficient in comparison to TLR4-sufficient mice. When combining ABCB4 and TLR4 deficiency with DEN treatment, hepatic IL6 expression and proliferation rates are lowest in fibrotic livers from the double-deficient line. Consistent with these effects, selective digestive tract decontamination in ABCB4-/- mice also led to reduced tumor size and number after DEN.This study demonstrates that liver injury upon DEN challenge

  18. Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan®.

    Science.gov (United States)

    Cassinotto, Christophe; Lapuyade, Bruno; Mouries, Amaury; Hiriart, Jean-Baptiste; Vergniol, Julien; Gaye, Delphine; Castain, Claire; Le Bail, Brigitte; Chermak, Faiza; Foucher, Juliette; Laurent, François; Montaudon, Michel; De Ledinghen, Victor

    2014-09-01

    Non-invasive assessment of liver fibrosis by elastography is a rapidly developing field with frequent technological innovations. The aim of this study was to assess the diagnostic performances of Supersonic Shear Imaging (SSI) for the diagnosis of liver fibrosis in chronic liver disease. A total of 349 consecutive patients with chronic liver diseases who underwent liver biopsy from November 2011 to October 2013 were prospectively enrolled. For each patient, liver stiffness was assessed by SSI, ARFI, FibroScan® (M probe for patients with BMI liver biopsy. Areas under the receiver operating curves (AUROCs) were performed and compared for each degree of liver fibrosis. SSI, FibroScan®, and ARFI correlated significantly with histological fibrosis score (r=0.79, pliver fibrosis in chronic liver diseases, comparing favourably to FibroScan® and ARFI. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  19. Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions.

    Science.gov (United States)

    Hung, Yu-Ping; Lee, Chun-Lin

    2017-06-08

    Deep ocean water (DOW) has been shown to enhance the functional components of fungi, resulting in increased health benefits. Therefore, using DOW for culturing fungi can enhance the cordycepin and adenosine of Cordyceps militaris (CM) and its protective effects on the liver. In this study, the antiliver fibrosis effects and mechanisms of ultrapure water-cultured CM (UCM), DOW-cultured CM (DCM), synthetic water-cultured CM, DOW, cordycepin, and adenosine were compared in the liver fibrosis mice induced by intraperitoneal injections of thioacetamide (TAA). The results indicated that DCM exhibited superior performance in reducing liver collagen accumulation, mitigating liver injuries, inhibiting proinflammatory factors and fibrosis-related factor (TGF-β1, Smad2/3, α-SMA, COL1A1) expression compared with UCM. DOW, cordycepin, and adenosine also performed antiliver fibrosis effect. Therefore, because DCM is rich in DOW and functional components, it can achieve anti-liver fibrosis effects through multiple pathways. These ameliorative effects are considerably superior to those of UCM.

  20. Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions

    Directory of Open Access Journals (Sweden)

    Yu-Ping Hung

    2017-06-01

    Full Text Available Deep ocean water (DOW has been shown to enhance the functional components of fungi, resulting in increased health benefits. Therefore, using DOW for culturing fungi can enhance the cordycepin and adenosine of Cordyceps militaris (CM and its protective effects on the liver. In this study, the antiliver fibrosis effects and mechanisms of ultrapure water-cultured CM (UCM, DOW-cultured CM (DCM, synthetic water-cultured CM, DOW, cordycepin, and adenosine were compared in the liver fibrosis mice induced by intraperitoneal injections of thioacetamide (TAA. The results indicated that DCM exhibited superior performance in reducing liver collagen accumulation, mitigating liver injuries, inhibiting proinflammatory factors and fibrosis-related factor (TGF-β1, Smad2/3, α-SMA, COL1A1 expression compared with UCM. DOW, cordycepin, and adenosine also performed antiliver fibrosis effect. Therefore, because DCM is rich in DOW and functional components, it can achieve anti-liver fibrosis effects through multiple pathways. These ameliorative effects are considerably superior to those of UCM.

  1. Sparse Logistic Regression for Diagnosis of Liver Fibrosis in Rat by Using SCAD-Penalized Likelihood

    Directory of Open Access Journals (Sweden)

    Fang-Rong Yan

    2011-01-01

    Full Text Available The objective of the present study is to find out the quantitative relationship between progression of liver fibrosis and the levels of certain serum markers using mathematic model. We provide the sparse logistic regression by using smoothly clipped absolute deviation (SCAD penalized function to diagnose the liver fibrosis in rats. Not only does it give a sparse solution with high accuracy, it also provides the users with the precise probabilities of classification with the class information. In the simulative case and the experiment case, the proposed method is comparable to the stepwise linear discriminant analysis (SLDA and the sparse logistic regression with least absolute shrinkage and selection operator (LASSO penalty, by using receiver operating characteristic (ROC with bayesian bootstrap estimating area under the curve (AUC diagnostic sensitivity for selected variable. Results show that the new approach provides a good correlation between the serum marker levels and the liver fibrosis induced by thioacetamide (TAA in rats. Meanwhile, this approach might also be used in predicting the development of liver cirrhosis.

  2. SENP1 attenuates the liver fibrosis through down-regulating the expression of SMAD2.

    Science.gov (United States)

    Wu, Linshi; Qiu, Weiqing; Sun, Jianhua; Wang, Jian

    2018-01-01

    To investigate whether SENP1 could play a regulating role in the liver fibrosis process, the Sprague-Dawley (SD) rats were used to establish the liver fibrosis rat models by intraperitoneally injecting with 1 ml/kg of 10% CCl 4 , while the control normal rats were injected with olive oil. Then confirmation experiments to verify the successful establishment of these models were conducted by detecting the cellular and lobular architecture, and liver function indexes using hematoxylin-eosin staining, Masson's trichrome staining and microplate method, respectively. In addition, the expression levels of fibrosis markers including collagen I, collagen III, α-SMA and TGF-β1 were inspected using quantitative real-time PCR (qRT-PCR), as well as SMAD2. Subsequently, the relative mRNA and protein level of SENP1 was also determined via qRT-PCR and western blot analysis. Next, the HSC-T6 cells of SENP1 knock-down were constructed and used to test the relative protein expression levels of α-SMA and SMAD2 in these cells. The results of hematoxylin-eosin staining, Masson's trichrome staining and microplate method turned out that the rat liver fibrosis models were constructed successfully, which was further confirmed by the increased expression of collagen I, collagen III, α-SMA and TGF-β1 in mRNA and protein level, as well as SMAD2. Then the expression of SENP1 was overexpressed in the rat liver fibrosis models induced by CCl 4 and the TGF-β1 treatment could increase the protein expression level of collagen I, collagen III and α-SMA. Lastly, the SENP1 knockdown HSC-T6 cells were successfully constructed, while the silence of SENP1 down-regulated the protein expression of α-SMA and SMAD2. In conclusion, this study provided a new regulation mechanism about the liver fibrosis process. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. 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.

  4. Vitamin K status in cystic fibrosis patients with liver cirrhosis.

    Science.gov (United States)

    Krzyżanowska, Patrycja; Drzymała-Czyż, Sławomira; Pogorzelski, Andrzej; Duś-Żuchowska, Monika; Skorupa, Wojciech; Bober, Lyudmyla; Sapiejka, Ewa; Oralewska, Beata; Rohovyk, Nataliya; Moczko, Jerzy; Nowak, Jan; Wenska-Chyży, Ewa; Rachel, Marta; Lisowska, Aleksandra; Walkowiak, Jarosław

    2017-06-01

    The available data on the influence of liver cirrhosis on vitamin K status in CF patients is scarce. Therefore, the aims of the present study were to assess the prevalence of vitamin K deficiency in cirrhotic CF subjects and to determine whether it correlates with liver cirrhosis. The study group comprised of 27 CF patients with and 63 without liver cirrhosis. Vitamin K status was assessed using prothrombin induced by vitamin K absence (PIVKA-II) and the percentage of undercarboxylated osteocalcin (u-OC). PIVKA-II concentrations were higher in cirrhotic than in non-cirrhotic CF patients (median [1st-3rd quartile]: 3.2ng/ml [1.0-10.0] vs. 1.3ng/ml [0.2-2.6], p=0.0029). However, the differences in u-OC percentages between the studied groups did not reach the level of significance (49.4% [7.0-73.8] vs. 8.0% [2.6-59.1], p=0.0501). Based on multiple linear regression analysis the dose of vitamin K and F508del mutation were potentially defined as determinants of vitamin K deficiency. Liver cirrhosis was not documented to be an independent risk factor. In CF patients with liver cirrhosis vitamin K deficiency is not only more frequent, but also more severe. However, not liver cirrhosis, but the presence of a F508del CFTR mutation constitutes an independent risk factor for vitamin K deficiency. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  5. Role of stellate cells in alcoholic liver fibrosis

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    Krzysztof Plewka

    2009-07-01

    Full Text Available Many different diseases and toxins can cause liver damage, which is diffi cult to treat and often leads to the development of liver fi brosis or even cirrhosis. The key event in this process is the activation of hepatic stellate cells (HSCs. During such activation, HSCs undergo a dramatic transformation in morphology and behavior, changing from a neuronal-like to a fi broblast-like morphology. After activation, HSCs increase their proliferation rate and extracellular matrix (ECM production. Overproduction of ECM, which contains mainly collagen type I, is a direct cause of liver disruption. HSCs also produce substances which inhibit protease activities, such as TIMPs, which enhance ECM deposition in the liver. On the molecular level, HSCs are activated by cytokines, growth factors, and oxidative stress, which are abundant in affl icted liver. These factors induce intracellular signals transmitted by many kinases, the most important of which are JNK, ERK1/2, p38, TAK-1, PKC, FAK, and P3IK. Signals transmitted via these pathways change the activities of transcription factors such as Smad, AP-1, and NF-κβ. This in turn causes changes In gene transcription and ultimately alters the whole cell’s behavior and morphology. The cell begins the production collagen type I, TIMP-1, and aSMA. Activated HSCs can sustain their own activation by producing growth factors such as PDGF and TGF-β. Despite the vast knowledge about the mechanisms causing liver fi brosis and cirrhosis, there is still no effective cure. Further studies are therefore needed to solve this problem.

  6. VAP score as a novel non-invasive liver fibrosis model in patients with chronic hepatitis C.

    Science.gov (United States)

    Ahmed Hassan, Elham; Sharaf El-Din Abd El-Rehim, Abeer; Ahmed Sayed, Zain El-Abdeen; Farah Mohamed Kholef, Emad; Sabry, Abeer; Abd El-Rehim Abo Elhagag, Noha

    2017-12-01

    Assessment of liver fibrosis in chronic hepatitis C (CHC) patients is necessary before antiviral treatment. This study aimed to evaluate the effectiveness of eight non-invasive models (aspartate aminotransferase [AST]/alanine transaminase ratio [AAR], AST/platelet ratio index [APRI], fibrosis-cirrhosis index [FCI], fibrosis index [FI], fibrosis-4 [FIB-4] score, fibrosis quotient [FibroQ], King, and von Willebrand factor antigen (vWF-Ag)/thrombocyte ratio [VITRO] scores) for predicting fibrosis compared with liver biopsy and to create a new score for predicting different fibrosis stages with increased accuracy. We prospectively studied 127 treatment-naive CHC patients who underwent liver biopsy. The AAR, APRI, FCI, FI, FIB-4, FibroQ, King and VITRO scores were calculated and correlated with fibrosis stages. A new score (VAP) was derived from vWF-Ag, AST, and platelets: [VAP = (AST (U/L) × vWF-Ag)/platelets (10 9 /L)]. Apart from AAR, readily available scores were correlated with liver fibrosis stages. VITRO (r = 0.62) and APRI (r = 0.46) showed the closest correlation. Our new (VAP) score significantly correlated with fibrosis stages (r = 0.702, P 1, VAP had 75.2% sensitivity and 100% positive predictive value for predicting mild fibrosis. At a cut-off value >2.3 for predicting cirrhosis, VAP had 73% sensitivity and 81.7% positive predictive value. The VAP score is a novel model that had higher diagnostic performance to predict different fibrosis stages and subclinical cirrhosis among CHC patients compared to the other studied scores and hence may offer a useful strategy to stratify patients who would benefit from direct-acting antivirals. © 2017 The Japan Society of Hepatology.

  7. Doppler ultrasonography combined with transient elastography improves the non-invasive assessment of fibrosis in patients with chronic liver diseases.

    Science.gov (United States)

    Alempijevic, Tamara; Zec, Simon; Nikolic, Vladimir; Veljkovic, Aleksandar; Stojanovic, Zoran; Matovic, Vera; Milosavljevic, Tomica

    2017-01-31

    Accurate clinical assessment of liver fibrosis is essential and the aim of our study was to compare and combine hemodynamic Doppler ultrasonography, liver stiffness by transient elastography, and non-invasive serum biomarkers with the degree of fibrosis confirmed by liver biopsy, and thereby to determine the value of combining non-invasive method in the prediction significant liver fibrosis. We included 102 patients with chronic liver disease of various etiology. Each patient was evaluated using Doppler ultrasonography measurements of the velocity and flow pattern at portal trunk, hepatic and splenic artery, serum fibrosis biomarkers, and transient elastography. These parameters were then input into a multilayer perceptron artificial neural network with two hidden layers, and used to create models for predicting significant fibrosis. According to METAVIR score, clinically significant fibrosis (≥F2) was detected in 57.8% of patients. A model based only on Doppler parameters (hepatic artery diameter, hepatic artery systolic and diastolic velocity, splenic artery systolic velocity and splenic artery Resistance Index), predicted significant liver fibrosis with a sensitivity and specificity of75.0% and 60.0%. The addition of unrelated non-invasive tests improved the diagnostic accuracy of Doppler examination. The best model for prediction of significant fibrosis was obtained by combining Doppler parameters, non-invasive markers (APRI, ASPRI, and FIB-4) and transient elastography, with a sensitivity and specificity of 88.9% and 100%. Doppler parameters alone predict the presence of ≥F2 fibrosis with fair accuracy. Better prediction rates are achieved by combining Doppler variables with non-invasive markers and liver stiffness by transient elastography.

  8. Reversal of Liver Fibrosis in Chronic Murine Schistosomiasis ...

    African Journals Online (AJOL)

    Purpose: To evaluate the safety, pharmacological effect and mechanism of action of an antifibrotic compound, safironil (SAF)/praziquantel (PZQ) combination on reversal of liver fibrogenesis in chronic murine Schistosomiasis mansoni. Methods: The antifibrotic effect of 0.5, 1 and 2 mg/ml of SAF was evaluated in vitro ...

  9. Hepatic stellate cell-derived PDGFRα-enriched extracellular vesicles promote liver fibrosis in mice through SHP2.

    Science.gov (United States)

    Kostallari, Enis; Hirsova, Petra; Prasnicka, Alena; Verma, Vikas K; Yaqoob, Usman; Wongjarupong, Nicha; Roberts, Lewis R; Shah, Vijay H

    2018-01-23

    Liver fibrosis is characterized by the activation and migration of hepatic stellate cells (HSCs) followed by matrix deposition. Recently, several studies have shown the importance of extracellular vesicles (EVs) derived from liver cells, such as hepatocytes and endothelial cells, in liver pathobiology. While most of the studies describe how liver cells modulate HSC behavior, an important gap exists in the understanding of HSC-derived signals and more specifically HSC-derived EVs in liver fibrosis. Here, we investigated the molecules released through HSC-derived EVs, the mechanism of their release and the role of these EVs in fibrosis. Mass spectrometry analysis showed that platelet-derived growth factor (PDGF) receptor α (PDGFRα) was enriched in EVs derived from PDGF-BB-treated HSCs. Moreover, patients with liver fibrosis had increased PDGFRα levels in serum EVs compared to healthy individuals. Mechanistically, in vitro tyrosine720-to-phenylalanine mutation (Y720F) on PDGFRα sequence abolished enrichment of PDGFRα in EVs and redirected the receptor towards degradation. Congruently, the inhibition of Src homology 2 domain tyrosine phosphatase 2 (SHP2), the regulatory binding partner of phosphorylated Y720, also inhibited PDGFRα enrichment in EVs. EVs derived from PDGFRα-overexpressing cells promoted in vitro HSC migration and in vivo liver fibrosis. Finally, administration of SHP2 inhibitor, SHP099, to carbon tetrachloride-administered mice inhibited PDGFRα enrichment in serum EVs and reduced liver fibrosis. PDGFRα is enriched in EVs derived from PDGF-BB-treated HSCs in an SHP2-dependent manner and these PDGFRα-enriched EVs participate in development of liver fibrosis. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

  10. Ethanol and High Cholesterol Diet Causes Severe Steatohepatitis and Early Liver Fibrosis in Mice.

    Directory of Open Access Journals (Sweden)

    Yasodha Krishnasamy

    Full Text Available Because ethanol consumption is commonly associated with a high cholesterol diet, we examined whether combined consumption of ethanol and high cholesterol increases liver injury and fibrosis.Male C57BL/6J mice were fed diets containing: 1 35% of calories from corn oil (CTR, 2 CTR plus 0.5% (w/v cholesterol (Chol, 3 CTR plus ethanol (27% of calories (EtOH, or 4 EtOH+Chol for 3 months.In mice fed Chol or EtOH alone, ALT increased to ~160 U/L, moderate hepatic steatosis occurred, and leukocyte infiltration, necrosis, and apoptosis increased modestly, but no observable fibrosis developed. By contrast in mice fed EtOH+Chol, ALT increased to ~270 U/L, steatosis was more extensive and mostly macrovesicular, and expression of proinflammatory molecules (HMGB-1, TLR4, TNFα, ICAM-1 and leukocyte infiltration increased substantially. Necrosis and apoptosis also increased. Trichrome staining and second harmonic generation microscopy revealed hepatic fibrosis. Fibrosis was mostly sinusoidal and/or perivenular, but in some mice bridging fibrosis occurred. Expression of smooth muscle α-actin and TGF-β1 increased slightly by Chol, moderately by EtOH, and markedly by EtOH+Chol. TGF-β pseudoreceptor BAMBI increased slightly by Chol, remained unchanged by EtOH and decreased by EtOH+Chol. MicroRNA-33a, which enhances TGF-β fibrotic effects, and phospho-Smad2/3, the down-stream signal of TGF-β, also increased more greatly by EtOH+Chol than Chol or EtOH. Metalloproteinase-2 and -9 were decreased only by EtOH+Chol.High dietary cholesterol and chronic ethanol consumption synergistically increase liver injury, inflammation, and profibrotic responses and suppress antifibrotic responses, leading to severe steatohepatitis and early fibrosis in mice.

  11. Mechanisms of accelerated liver fibrosis in HIV-HCV coinfection.

    Science.gov (United States)

    Chrysanthidis, Theofilos; Loli, Georgia; Metallidis, Simeon; Germanidis, Georgios

    2017-01-01

    Although there is evidence that HCV progresses rapidly in HIV/HCV coinfected patients in comparison with HCV monoinfected, the HIV-, HCV- and host/genetic-related factors, as well as the exact mechanisms implicated in this process are not fully elucidated. Furthermore, cure of HCV in those coinfected seems possible with the new antiviral drugs, but high cost as well as insufficient identification, linkage with care and treatment hamper the achievement of this goal. Research on the subject, could reveal an important prognostic marker for the effectiveness of persuasion of patients with HIV/HCV coinfection with a predicted accelerated fibrosis course, in order to facilitate and prioritize, not in terms of guidelines but in the real life situation, their treatment with a medically just framework.

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

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    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.

  13. Novel biomarkers predict liver fibrosis in hepatitis C patients: alpha 2 macroglobulin, vitamin D binding protein and apolipoprotein AI

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    Lee Jing-Ying

    2010-07-01

    Full Text Available Abstract Background The gold standard of assessing liver fibrosis is liver biopsy, which is invasive and not without risk. Therefore, searching for noninvasive serologic biomarkers for liver fibrosis is an importantly clinical issue. Methods A total of 16 healthy volunteers and 45 patients with chronic hepatitis C virus (HCV were enrolled (F0: n = 16, F1: n = 7, F2: n = 17, F3: n = 8 and F4: n = 13, according to the METAVIR classification. Three serum samples of each fibrotic stage were analyzed by two-dimension difference gel electrophoresis (2D-DIGE. The differential proteins were identified by the cooperation of MALDI-TOF/TOF and MASCOT; then western blotting and Bio-Plex Suspension Array were used to quantify the protein levels. Results Three prominent candidate biomarkers were identified: alpha 2 macroglobulin (A2M is up regulated; vitamin D binding protein (VDBP and apolipoprotein AI (ApoAI are down regulated. The serum concentration of A2M was significantly different among normal, mild (F1/F2 and advanced fibrosis (F3/F4 (p p Conclusions This study not only reveals three putative biomarkers of liver fibrosis (A2M, VDBP and ApoAI but also proves the differential expressions of those markers in different stages of fibrosis. We expect that combination of these novel biomarkers could be applied clinically to predict the stage of liver fibrosis without the need of liver biopsy.

  14. Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography

    DEFF Research Database (Denmark)

    Herrmann, Eva; de Lédinghen, Victor; Cassinotto, Christophe

    2018-01-01

    sites, as well as on successful transient elastography (TE) in 665 patients. Most patients had chronic hepatitis C (HCV, n = 379), hepatitis B (HBV, n = 400) or non-alcoholic fatty liver disease (NAFLD, n = 156). AUROCs of 2D-SWE in patients with HCV, HBV and NAFLD were 86.3%, 90.6% and 85...... was strongest in HBV patients. CONCLUSION: 2D-SWE has good to excellent performance for the non-invasive staging of liver fibrosis in patients with hepatitis B. Further prospective studies are needed for head to head comparison between 2D SWE and other imaging modalities to establish disease...

  15. Persistent abnormal liver fibrosis after weaning off parenteral nutrition in pediatric intestinal failure.

    Science.gov (United States)

    Mutanen, Annika; Lohi, Jouko; Heikkilä, Päivi; Koivusalo, Antti I; Rintala, Risto J; Pakarinen, Mikko P

    2013-08-01

    The aim of this study was to evaluate the long-term effects of pediatric intestinal failure (IF) on liver histology. Altogether, 38 IF patients (median age: 7.2 years; range, 0.2-27) underwent liver biopsy, gastroscopy, abdominal ultrasound, and laboratory tests. Sixteen patients were on parenteral nutrition (PN) after 74 PN months (range, 2.5-204). Twenty-two had weaned off PN 8.8 years (range, 0.3-27) earlier, after 35 PN months (range, 0.7-250). Fifteen transplant donor livers served as controls. Abnormal liver histology was found in 94% of patients on PN and 77% of patients weaned off PN (P = 0.370). During PN, liver histology weighted with cholestasis (38% of patients on PN versus 0% of patients weaned off PN; P = 0.003) and portal inflammation (38% versus 9%; P = 0.050) were found. Fibrosis (88% versus 64%; P = 0.143; Metavir stage: 1.6 [range, 0-4] versus 1.1 [range, 0-2]; P = 0.089) and steatosis (50% versus 45%; P = 1.000) were equally common during and after weaning off PN. Plasma alanine aminotransferase (78 U/L [range, 19-204] versus 34 [range, 9-129]; P = 0.009) and conjugated bilirubin (43 μmol/L [range, 1-215] versus 4 [range, 1-23]; P = 0.037) were significantly higher during than after weaning off PN. Esophageal varices were encountered in 1 patient after weaning off PN. Metavir stage was associated with small bowel length (r = -0.486; P = 0.002) and number of septic episodes (r = 0.480; P = 0.002). In a multivariate analysis, age-adjusted small bowel length (ß = -0.533; P = 0.001), portal inflammation (ß = 0.291; P = 0.030), and absence of an ileocecal valve (ß = 0.267; P = 0.048) were predictive for fibrosis stage. Despite resolution of cholestasis and portal inflammation, significant liver fibrosis and steatosis persist after weaning off PN. Extensive small intestinal resection was the major predictor for liver fibrosis stage. Copyright © 2013 American Association for the Study of Liver Diseases.

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

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    Yuqing Mao

    2015-09-01

    Full Text Available Ghrelin is a stomach-derived growth hormone secretagogue that promotes various physiological effects, including energy metabolism and amelioration of inflammation. The purpose of this study was to investigate the protective mechanism of ghrelin against liver fibrosis. Liver fibrosis was induced in C57BL/6 mice by intraperitoneal injection of CCl4 (2.0 mL/kg of 10% CCl4 v/v solution in peanut oil two times per week for eight weeks. Ghrelin (10 μg/kg was intraperitoneally injected two times per week for eight weeks. A second murine liver fibrosis model was induced by bile duct ligation (BDL and concurrent ghrelin administration for four weeks. Hematoxylin eosin (H&E, and Masson’s trichrome were used to detect pathological changes to liver tissue. Western blotting was used to detect protein levels of transforming growth factor (TGF-β1, phosphorylated Smad3 (p-Smad3, I-collage, α-smooth muscle actin (α-SMA, matrix metalloproteinases (MMPs 2, tissue inhibitor of matrix metalloproteinases (TIMPs 1, phosphorylated NF-κB (p-NF-κB, and microtubule-associated protein light chain 3 (LC3. In addition, qRT-PCR was used to detect mRNA levels of TGF-β1, I-collage, α-SMA, MMP2, TIMP1 and LC3, while levels of TGF-β1, p-Smad3, I-collage, α-SMA, and LC3 were detected immunohistochemically. Levels of aspartate aminotransferase and alanine aminotransferase were significantly decreased by ghrelin treatment. Ghrelin administration also significantly reduced the extent of pathological changes in both murine liver fibrosis models. Expression levels of I-collage and α-SMA in both models were clearly reduced by ghrelin administration. Furthermore, ghrelin treatment decreased protein expression of TGF-β1 and p-Smad3. The protein levels of NF-κB and LC3 were increased in the CCl4- and BDL-treatment groups but were significantly reduced following ghrelin treatment. In addition, ghrelin inhibited extracellular matrix formation by decreasing NF-κB expression

  17. Repeatability of shear wave elastography in liver fibrosis phantoms—Evaluation of five different systems

    Science.gov (United States)

    2018-01-01

    This study aimed to assess and validate the repeatability and agreement of quantitative elastography of novel shear wave methods on four individual tissue-mimicking liver fibrosis phantoms with different known Young’s modulus. We used GE Logiq E9 2D-SWE, Philips iU22 ARFI (pSWE), Samsung TS80A SWE (pSWE), Hitachi Ascendus (SWM) and Transient Elastography (TE). Two individual investigators performed all measurements non-continued and in parallel. The methods were evaluated for inter- and intraobserver variability by intraclass correlation, coefficient of variation and limits of agreement using the median elastography value. All systems used in this study provided high repeatability in quantitative measurements in a liver fibrosis phantom and excellent inter- and intraclass correlations. All four elastography platforms showed excellent intra-and interobserver agreement (interclass correlation 0.981–1.000 and intraclass correlation 0.987–1.000) and no significant difference in mean elasticity measurements for all systems, except for TE on phantom 4. All four liver fibrosis phantoms could be differentiated by quantitative elastography, by all platforms (pphantoms with higher Young’s modulus. All platforms had a coefficient of variation in the range 0.00–0.21 for all four phantoms, equivalent to low variance and high repeatability. PMID:29293527

  18. Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus.

    Science.gov (United States)

    Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

    2016-09-14

    The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully.

  19. Risk of end-stage liver disease, hepatocellular carcinoma, and liver-related death by fibrosis stage in the hepatitis C Alaska Cohort.

    Science.gov (United States)

    Bruden, Dana J T; McMahon, Brian J; Townshend-Bulson, Lisa; Gounder, Prabhu; Gove, Jim; Plotnik, Julia; Homan, Chriss; Hewitt, Annette; Barbour, Youssef; Spradling, Philip R; Simons, Brenna C; McArdle, Susan; Bruce, Michael

    2017-07-01

    Long-term prospective studies of the outcomes associated with hepatitis C virus (HCV) infection are rare and critical for assessing the potential impact of HCV treatment. Using liver biopsy as a starting point, we analyzed the development of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC), and liver-related death (LRD) according to fibrosis stage among a cohort of American Indian/Alaska Native persons in Alaska. Persons were classified as having no/mild (Ishak = 0,1), moderate (Ishak = 2), or severe (Ishak = 3,4) fibrosis or cirrhosis (Ishak = 5,6). We examined time until development of ESLD, HCC, and LRD and report survival probabilities at 3, 5, 7, and 10 years. Of 407 persons, 39% (n = 150) had no/mild fibrosis, 32% (n = 131) had moderate fibrosis, 22% (n = 88) had severe fibrosis, and 9% (n = 38) had cirrhosis. The average time of follow-up was 7.3 years. Within 5 years of biopsy, 1.7% (95% confidence interval [CI]: 0.4-6.8) of persons with no/mild fibrosis developed ESLD compared with 7.9% (95% CI, 4.0-15.2), 16.4% (95% CI, 9.6-27.2), and 49.0% (95% CI, 33.0-67.7) with moderate, severe fibrosis, and cirrhosis, respectively (P Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

  20. Increased Expression of TGF-β1 in Correlation with Liver Fibrosis during Echinococcus granulosus Infection in Mice.

    Science.gov (United States)

    Liu, Yumei; Abudounnasier, Gulizhaer; Zhang, Taochun; Liu, Xuelei; Wang, Qian; Yan, Yi; Ding, Jianbing; Wen, Hao; Yimiti, Delixiati; Ma, Xiumin

    2016-08-01

    To investigate the potential role of transforming growth factor (TGF)-β1 in liver fibrosis during Echinococcus granulosus infection, 96 BALB/c mice were randomly divided into 2 groups, experimental group infected by intraperitoneal injection with a metacestode suspension and control group given sterile physiological saline. The liver and blood samples were collected at days 2, 8, 30, 90, 180, and 270 post infection (PI), and the expression of TGF-β1 mRNA and protein was determined by real-time quantitative RT-PCR and ELISA, respectively. We also evaluated the pathological changes in the liver during the infection using hematoxylin and eosin (H-E) and Masson staining of the liver sections. Pathological analysis of H-E stained infected liver sections revealed liver cell edema, bile duct proliferation, and structural damages of the liver as evidenced by not clearly visible lobular architecture of the infected liver, degeneration of liver cell vacuoles, and infiltration of lymphocytes at late stages of infection. The liver tissue sections from control mice remained normal. Masson staining showed worsening of liver fibrosis at the end stages of the infection. The levels of TGF-β1 did not show significant changes at the early stages of infection, but there were significant increases in the levels of TGF-β1 at the middle and late stages of infection (Pgranulosus infection may play a significant role in liver fibrosis associated with E. granulosus infection.

  1. Biomarkers of fibrosis and impaired liver function in chronic hepatitis C: how well do they predict clinical outcomes?

    DEFF Research Database (Denmark)

    Peters, L.; Rockstroh, J.K.

    2010-01-01

    PURPOSE OF REVIEW: To review the recent literature on the prognostic value of biomarkers of liver fibrosis and impaired liver function in patients with chronic hepatitis C with or without HIV coinfection. RECENT FINDINGS: A combination of standard blood tests seems to be useful in identifying...... levels of the fibrosis marker hyaluronic acid are a strong predictor of clinical complications. A smaller study found hyaluronic acid and two other fibrosis tests, aspartate aminotransferase-to-platelet ratio index (APRI) and Fib-4, to be independent predictors of mortality when included in models...

  2. 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.

  3. A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

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    Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhiro; Uehara, Takeki; Kato, Yuki; Kono, Hiroshi; Bataller, Ramon; Rusyn, Ivan

    2016-01-01

    Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl 4 )-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl 4 (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day for 3 weeks) and with continued CCl 4 . We observed that combined treatment with CCl 4 and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis

  4. Diagnostic values of FibroScan and FibroTouch for liver fibrosis: a comparative analysis

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    WU Na

    2014-07-01

    Full Text Available ObjectiveTo compare the diagnostic values of FibroScan and FibroTouch for liver fibrosis. MethodsA total of 962 patients who visited Department of Hepatology, The First Hospital of Jilin University from September 2013 to March 2014 were enrolled. FibroScan and FibroTouch were performed among these patients. Thirty-three cases underwent liver biopsy, and Aspartate aminotransferase-to-platelet ratio index (APRI was calculated in 66 patients (chronic hepatitis B (CHB: 53 cases; chronic hepatitis C (CHC: 13 cases. Spearman rank correlation test was used to analyze the correlation between the results measured by FibroScan and FibroTouch. The diagnostic values of FibroScan and FibroTouch for liver fibrosis were analyzed and compared by receiver operating characteristic (ROC curve. ResultsThe analysis of liver stiffness measured by FibroScan and FibroTouch among all patients showed that the correlation coefficient between FibroScan and FibroTouch was 0.866 (P<0.05, n=962. FibroScan and FibroTouch were significantly correlated with APRI (r=0.58 and 0.63, P<0.05, n=66 and pathological stage determined by liver biopsy (r=0.67 and 0.74, P<0.05, n=33. Among patients with CHB, for the diagnosis of APRI ≥2 (liver cirrhosis, the areas under the ROC curve (AUCs of FibroScan and FibroTouch were 0.761 vs 0.728 (P=0.61; among patients with CHC, for the diagnosis of APRI ≥1 (liver cirrhosis, the AUCs of FibroScan and FibroTouch were 0.810 vs 0.893 (P=0.38. For pathological stages ≥S1, ≥S2, ≥S3, and ≥S4, the AUCs of FibroScan and FibroTouch were 0.830 vs 0.889 (P=0.15, 0.841 vs 0.835 (P=0.90, 0.888 vs 0.920 (P=0.43, and 0.964 vs 0.979 (P=0.45, respectively. ConclusionFibroScan and FibroTouch have comparable diagnostic values for liver fibrosis. However, the number of cases undergoing liver biopsy in this study was relatively small, and investigation of more cases is needed to make further confirmation.

  5. Progressive Fibrosis Is Driven by Genetic Predisposition, Allo-immunity, and Inflammation in Pediatric Liver Transplant Recipients.

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    Varma, S; Ambroise, J; Komuta, M; Latinne, D; Baldin, P; Reding, R; Smets, F; Stephenne, X; Sokal, E M

    2016-07-01

    To determine predisposing factors of idiopathic allograft fibrosis among pediatric liver transplant recipients. Protocol biopsies (PB) from stable liver transplant (LT) recipient children frequently exhibit idiopathic fibrosis. The relation between allograft inflammation, humoral immune response and fibrosis is uncertain. Also the role of HLA-DRB1 genotype has not been evaluated, though it's associated with fibrosis in autoimmune hepatitis. This observational study, included 89 stable LT recipient transplanted between 2004-2012 with mean follow-up of 4.3years, 281 serial PBs (3.1 biopsy/child) and human leukocyte antigen (HLA) antibody data. PBs were taken 1-2, 2-3, 3-5, 5-7, and 7-10years post-LT, and evaluated for inflammation and fibrosis using liver allograft fibrosis score (LAFSc). The evolution of fibrosis, inflammation and related predisposing factors were analysed. HLA-DRB1*03/04 allele and Class II DSA were significantly associated with portal fibrosis (p=0.03; p=0.03, respectively). Portal inflammation was predisposed by Class II DSA (p=0.02) and non-HLA antibody presence (p=0.01). Non-portal fibrosis wasn't predisposed by inflammation. Lobular inflammation was associated with non-HLA antibodies. We conclusively demonstrated that allograft inflammation results in fibrosis and is associated with post-LT Class II DSA and non-HLA antibodies. The HLA-DRB1*03/04 allele caused genetic predisposition for fibrosis. None. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Is there an association between vitamin D and liver fibrosis in patients with chronic hepatitis C?

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    Kalinca da Silva OLIVEIRA

    Full Text Available ABSTRACT BACKGROUND Vitamin D is known for its immunomodulatory, anti-inflammatory and antifibrotic properties, which are quite relevant in the pathogenesis and treatment of many causes of chronic liver disease. OBJECTIVE This study aimed to evaluate the association between serum vitamin D levels and the histopathological findings in patients with chronic hepatitis C virus infection. METHODS Cross-sectional study composed of patients with chronic hepatitis C. All patients underwent vitamin D 25 dosage and anthropometric data analysis. Liver biopsy was performed in a maximum 36-month period before inclusion in the study. RESULTS Of the 74 patients included in the study, 45 (60.8% were women, mean age was 57.03±9.24 years, and 63 (85.1% were white. No association was observed between the serum levels of vitamin D and inflammatory activity (P=0.699 nor with the degree of liver fibrosis (P=0.269. CONCLUSION In this study, no association was observed between vitamin D and inflammatory activity, as well as the degree of liver fibrosis, in patients with chronic hepatitis C.

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

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    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

  8. Non-invasive assessment of liver fibrosis: Between prediction/prevention of outcomes and cost-effectiveness.

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    Stasi, Cristina; Milani, Stefano

    2016-01-28

    The assessment of the fibrotic evolution of chronic hepatitis has always been a challenge for the clinical hepatologist. Over the past decade, various non-invasive methods have been proposed to detect the presence of fibrosis, including the elastometric measure of stiffness, panels of clinical and biochemical parameters, and combinations of both methods. The aim of this review is to analyse the most recent data on non-invasive techniques for the evaluation of hepatic fibrosis with particular attention to cost-effectiveness. We searched for relevant studies published in English using the PubMed database from 2009 to the present. A large number of studies have suggested that elastography and serum markers are useful techniques for diagnosing severe fibrosis and cirrhosis and for excluding significant fibrosis in hepatitis C virus patients. In addition, hepatic stiffness may also help to prognosticate treatment response to antiviral therapy. It has also been shown that magnetic resonance elastography has a high accuracy for staging and differentiating liver fibrosis. Finally, studies have shown that non-invasive methods are becoming increasingly precise in either positively identifying or excluding liver fibrosis, thus reducing the need for liver biopsy. However, both serum markers and transient elastography still have "grey area" values of lower accuracy. In this case, liver biopsy is still required to properly assess liver fibrosis. Recently, the guidelines produced by the World Health Organization have suggested that the AST-to-platelet ratio index or FIB-4 test could be utilised for the evaluation of liver fibrosis rather than other, more expensive non-invasive tests, such as elastography or FibroTest.

  9. Value of five noninvasive diagnostic techniques and their combinations in diagnosis of liver fibrosis in patients with chronic hepatitis B

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    ZHANG Xu

    2016-10-01

    Full Text Available Objective To investigate the correlation of aspartate aminotransferase to platelet ratio index (APRI, FIB-4, Forns index, S index, and FibroScan with the degree of liver fibrosis, the diagnostic value of these techniques used alone or in combination, and the clinical value of these noninvasive techniques in the assessment of the degree of liver fibrosis in patients with chronic hepatitis B (CHB. Methods A retrospective analysis was performed for the clinical data of 91 patients with pathologically confirmed CHB who visited General Hospital of Ningxia Medical University and underwent liver biopsy from January 2009 to April 2015. According to the Scheuer pathological stage and liver fibrosis stage (S, the patients were divided into non-liver fibrosis group (a liver fibrosis stage of S0, 32 patients, mild liver fibrosis group (a liver fibrosis stage of <S2, 30 patients, and marked liver fibrosis group (a liver fibrosis stage of ≥S2, 29 patients. The APRI, FIB-4, Forns index, and S index were calculated, and liver stiffness was measured by FibroScan. An analysis of variance was used for the comparison of normally distributed continuous data between three groups, and the Dunnett t-test was used for further comparison between any two groups. The Spearman correlation analysis was also performed. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC were used to evaluate the value of these noninvasive techniques in the diagnosis of liver fibrosis. Results There were significant differences in age, albumin, aspartate aminotransferase, alanine aminotransferase, and platelet count between the three groups (F=3.552, 4.035, 4.374, and 5.992, all P<0.05, and there were significant differences in these parameters between the non-liver fibrosis group and the mild and marked liver fibrosis groups (P<0.05. There were significant differences in APRI, FIB-4, Forns index, S index, and FibroScan between the three groups (F

  10. Overexpression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Mediates Liver Fibrosis in Transgenic Mice.

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    Guo, Yongze; Ding, Qian; Chen, Lei; Ji, Chenguang; Hao, Huiyao; Wang, Jia; Qi, Wei; Xie, Xiaoli; Ma, Junji; Li, Aidi; Jiang, Xiaoyu; Li, Xiaotian; Jiang, Huiqing

    2017-08-01

    The role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in liver fibrosis is not clear and is sometimes even contradictory. To clarify this role, a HB-EGF transgenic (Tg) mouse model was, for the first time, used to evaluate the functions of HB-EGF in liver fibrosis. For the in vivo study, carbon tetrachloride injection and bile duct ligation treatment were used to induce liver fibrosis in HB-EGF Tg mice and wild-type (WT) mice, respectively. Primary hepatic satellite cells (HSCs) were isolated from HB-EGF Tg and WT mice for the in vitro study. Compared with the WT mice, HB-EGF Tg mice were shown to develop more severe liver fibrosis when treated with carbon tetrachloride or bile duct ligation, with increased matrix metalloproteinases 13 activity and enhanced expression of fibrogenic genes including α-smooth muscle actin and collagen I. HB-EGF gene transfer led to an increase in proliferation and a decrease in apoptosis in primary HSCs. The ERK signaling pathway was more highly activated in primary HSCs from HB-EGF Tg mice than in those from WT mice. Our investigation confirmed the profibrotic effect of HB-EGF on the liver using a Tg mouse model. This result may contribute to the elucidation of HB-EGF as a therapeutic target in liver fibrosis. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  11. Assessment of liver fibrosis stage influence on clinical course of periodontal diseases in patients with chronic hepatitis C

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    О. М. Slaba

    2017-08-01

    Full Text Available The aim. To assess the influence of liver fibrosis stage on the clinical course of periodontal diseases in patients with chronic hepatitis C. Material and Methods. 122 patients with chronic hepatitis C, treated at the 7th department ofLvivRegionalInfectiousDiseasesHospital during 2013 – 2015 were included into dental investigation. The periodontal disease was diagnosed in accordance with the classification of M. F. Danilevsky (1994. The clinical condition of periodontium was assessed by the papillary marginal alveolar index (PMA in the modification ofParma, by the periodontal index – PI (AL Russel, 1956, by the Muhlemann and Son index – the degree of bleeding in the region of the gingival papilla (PBI. The stage of liver fibrosis was determined according to the medical history. The significance of the difference between two or more relative indicators was calculated using the Fisher test with the Metropolis algorithm. The correlation dependence between the clinical condition of periodontal tissues and the stage of liver fibrosis in patients with viral hepatitis C was studied using the Spearman rank correlation coefficient. Results. The highest percentage of patients with stage of liver fibrosis F0 (70.00 ± 15.28 % was registered in patients with healthy periodont, the lowest - in patients with generalized periodontitis of the third stage (7.89 ± 4.37 %. The highest frequency of patients with the stage of liver fibrosis F3 (73.68 ± 7.14 % was also observed in persons suffering from generalized periodontitis stage III (73.68 ± 7.14 %. Conclusions. The distribution of periodontal lesion severity statistically significant (p < 0.001 depended on the stage of liver fibrosis in patients with chronic hepatitis C. Direct (R = 0.70; p < 0.001 strong correlation between the clinical state of periodontal tissues and the stage of liver fibrosis in patients with chronic hepatitis C (using the Spearman rank correlation coefficient has been determined

  12. Attenuating Effect of Ginkgo biloba Leaves Extract on Liver Fibrosis Induced by Thioacetamide in Mice

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    Al-Attar, Atef M.

    2012-01-01

    The purpose of this study is to investigate the effect of Ginkgo biloba leaves extract on experimental liver fibrosis induced by thioacetamide (TAA) in male albino mice. The experimental mice were divided into four groups. The mice of the first group were served as control. The experimental animals of the second group were given 150 mg/kg body weight of TAA by intraperitoneal injection, twice weekly, for 9 weeks. The mice of the third group were exposed to TAA and supplemented with G. biloba leaves extract. The animals of the fourth group were supplemented with G. biloba leaves extract. The levels of plasma alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, triglycerides, cholesterol, and low-density lipoprotein cholesterol were statistically increased while the levels of plasma total protein, albumin, glucose, and high-density lipoprotein cholesterol were significantly decreased. The levels of liver superoxide dismutase, glutathione, glycogen and total protein were notably declined, whereas the level of total lipid was increased in mice of the second group. Furthermore, microscopic examination of liver sections from mice treated with TAA showed an abnormal morphology characterized by nodular transformations in liver parenchyma which surrounded by fibrous septa. Administration of G. biloba leaves extract reduced extent and development of fibrous septa, liver cells change, and biochemical alterations in mice exposed to TAA. This study showed that G. biloba leaves extract has a potential activity against TAA-induced liver fibrosis and suggested that the chemical constituents of G. biloba are effective in modulation of oxidative stress induced by TAA. PMID:23091357

  13. Assessment of hepatic fibrosis with superb microvascular imaging in hepatitis C virus-associated chronic liver diseases.

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    Koyama, Nobuko; Hata, Jiro; Sato, Tokeshi; Tomiyama, Yasuyuki; Hino, Keisuke

    2017-05-01

    Superb microvascular imaging (SMI) is an ultrasound Doppler technique using a unique algorithm that allows visualization of minute vessels with slow velocity and minimal motion artifacts. The aim of this preliminary study was to investigate whether SMI could predict liver fibrosis by visualizing the vessels present in the vicinity of the liver surface because the morphology of the peripheral hepatic vasculature is affected by the progression of liver fibrosis. We recruited 29 patients with biopsy-proven chronic hepatitis C or liver cirrhosis C, and 36 patients without liver disease as controls. Using an Aplio 500 ultrasound system with a 7-MHz or 12-MHz linear probe, we assessed the vascular shapes and the bifurcation angles of five randomly selected vessels in the vicinity of the liver surface. The vascular shape was scored based on the number of winding and/or irregular vessels. The mean vascular score and the mean bifurcation angle were significantly greater in patients with advanced liver fibrosis (3.5 ± 1.1 and 90.5 ± 14.3) than in those with mild-to-moderate liver fibrosis (1.3 ± 1.4 and 68.0 ± 16.1) and controls (0.6 ± 0.7 and 62.2 ± 10.5). The area under the receiver-operating curve of the vascular score and the bifurcation angle were 0.88 with 76.5% sensitivity and 83.3% specificity, and 0.87 with 94.1% sensitivity and 75.0% specificity, respectively. The present results indicate that SMI potentially predicts the extent of liver fibrosis by detecting small vessels present in the vicinity of the liver surface. © 2016 The Japan Society of Hepatology.

  14. Paraoxonase-1 is related to inflammation, fibrosis and PPAR delta in experimental liver disease

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    Mackness Michael

    2009-01-01

    Full Text Available Abstract Background Paraoxonase-1 (PON1 is an antioxidant enzyme synthesized by the liver. It protects against liver impairment and attenuates the production of the pro-inflammatory monocyte chemoattractant protein-1 (MCP-1. We investigated the relationships between hepatic PON1 and MCP-1 expression in rats with liver disease and explored the possible molecular mechanisms involved. Methods CCl4 was administered for up to 12 weeks to induce liver damage. Serum and hepatic levels of PON1 and MCP-1, their gene and protein expression, nuclear transcription factors, and histological and biochemical markers of liver impairment were measured. Results High levels of PON1 and MCP-1 expression were observed at 12th week in the hepatocytes surrounding the fibrous septa and inflammatory areas. CCl4-administered rats had an increased hepatic PON1 concentration that was related to decreased gene transcription and inhibited protein degradation. Decreased PON1 gene transcription was associated with PPARδ expression. These changes were accompanied by increased hepatic MCP-1 concentration and gene expression. There were significant direct relationships between hepatic PON1 and MCP-1 concentrations (P = 0.005 and between PON1 and the amount of activated stellate cells (P = 0.001. Conclusion Our results from this experimental model suggest a hepato-protective role for PON1 against inflammation, fibrosis and liver disease mediated by MCP-1.

  15. Ameliorative Effect of Camel's Milk and Nigella Sativa Oil against Thioacetamide-induced Hepatorenal Damage in Rats.

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    Ahmad, Aftab; Al-Abbasi, Fahad A; Sadath, Saida; Ali, Soad Shaker; Abuzinadah, Mohammed F; Alhadrami, Hani A; Mohammad Alghamdi, Anwar Ali; Aseeri, Ali H; Khan, Shah Alam; Husain, Asif

    2018-01-01

    Camel milk (CM) and Nigella sativa (NS) have been traditionally claimed to cure wide range of diseases and used as medicine in different part of world, particularly in Saudi Arabia. Several research studies have been published that proved beneficial effects of CM and NS. This study was undertaken to investigate the antihepatotxic potential of CM and NS oil (NSO) against thioacetamide (TAA)-induced hepato and nephrotoxicity in rats. Thirty female Albino Wistar rats were randomly divided in to six groups having five rats in each group. A single subcutaneous injection of TAA (100 mg/kg b. w.) was administered to all the rats in Group-II to VI on 1 st day to induce hepatorenal damage. Group I served as a normal control while Group II served as toxic control for comparison purpose. Experimental animals in Group III, IV, and V were supplemented with fresh CM, (250 mL/24 h/cage), NSO (2 mL/kg/day p. o.), and NSO + fresh CM, respectively. Group VI was treated with a polyherbal hepatoprotective Unani medicine Jigreen (2 mL/kg/day p. o.) for 21 days. TAA-induced hepatorenal damage and protective effects of CM and NSO were assessed by analyzing liver and kidney function tests in the serum. Histopathology of liver and kidney tissues was also carried out to corroborate the findings of biochemical investigation. The results indicated that the TAA intoxicated rats showed significant increase in the alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, lipid profile, urea, creatinine, uric acid, sodium, and potassium levels in serum. Treatment of rats with CM, NSO, and CM plus NSO combination and Jigreen significantly reversed the damage and brought down the serum biochemical parameters and lipid profile toward the normal levels. The histopathological studies also support the hepato and nephroprotective effects of CM and NSO. This study demonstrated the ameliorative effects of CM, NSO, and CM plus NSO combination against TAA

  16. Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages.

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    Yiannis N Kallis

    Full Text Available Liver fibrosis results from the co-ordinated actions of myofibroblasts and macrophages, a proportion of which are of bone marrow origin. The functional effect of such bone marrow-derived cells on liver fibrosis is unclear. We examine whether changing bone marrow genotype can down-regulate the liver's fibrotic response to injury and investigate mechanisms involved. Proteinase activated receptor 1 (PAR1 is up-regulated in fibrotic liver disease in humans, and deficiency of PAR1 is associated with reduced liver fibrosis in rodent models. In this study, recipient mice received bone marrow transplantation from PAR1-deficient or wild-type donors prior to carbon tetrachloride-induced liver fibrosis. Bone marrow transplantation alone from PAR1-deficient mice was able to confer significant reductions in hepatic collagen content and activated myofibroblast expansion on wild-type recipients. This effect was associated with a decrease in hepatic scar-associated macrophages and a reduction in macrophage recruitment from the bone marrow. In vitro, PAR1 signalling on bone marrow-derived macrophages directly induced their chemotaxis but did not stimulate proliferation. These data suggest that the bone marrow can modulate the fibrotic response of the liver to recurrent injury. PAR1 signalling can contribute to this response by mechanisms that include the regulation of macrophage recruitment.

  17. Prospective comparison among transient elastography, supersonic shear imaging, and ARFI imaging for predicting fibrosis in nonalcoholic fatty liver disease.

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    Myoung Seok Lee

    Full Text Available The diagnostic performance of supersonic shear imaging (SSI in comparison with those of transient elastography (TE and acoustic radiation force impulse imaging (ARFI for staging fibrosis in nonalcoholic fatty liver disease (NAFLD patients has not been fully assessed, especially in Asian populations with relatively lean NAFLD compared to white populations. Thus, we focused on comparing the diagnostic performances of TE, ARFI, and SSI for staging fibrosis in a head-to-head manner, and identifying the clinical, anthropometric, biochemical, and histological features which might affect liver stiffness measurement (LSM in our prospective biopsy-proven NAFLD cohort. In this study, ninety-four patients with biopsy-proven NAFLD were included prospectively. Liver stiffness was measured using TE, SSI, and ARFI within 1 month of liver biopsy. The diagnostic performance for staging fibrosis was assessed using receiver operating characteristic (ROC analysis. Anthropometric data were evaluated as covariates influencing LSM by regression analyses. Liver stiffness correlated with fibrosis stage (p < 0.05; the area under the ROC curve of TE (kPa, SSI (kPa, and ARFI (m/s were as follows: 0.757, 0.759, and 0.657 for significant fibrosis and 0.870, 0.809, and 0.873 for advanced fibrosis. Anthropometric traits were significant confounders affecting SSI, while serum liver injury markers significantly confounded TE and ARFI. In conclusion, the LSM methods had similar diagnostic performance for staging fibrosis in patients with NAFLD. Pre-LSM anthropometric evaluation may help predict the reliability of SSI.

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

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    Miao Shen

    2014-01-01

    Full Text Available 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, 40, and 80 mg/kg. Pathological results indicated that astaxanthin significantly improved the pathological lesions of liver fibrosis. The levels of alanine aminotransferase aspartate aminotransferase and hydroxyproline were also significantly decreased by astaxanthin. The same results were confirmed in bile duct liagtion, (BDL model. In addition, astaxanthin inhibited hepatic stellate cells (HSCs activation and formation of extracellular matrix (ECM by decreasing the expression of NF-κB and TGF-β1 and maintaining the balance between MMP2 and TIMP1. In addition, astaxanthin reduced energy production in HSCs by downregulating the level of autophagy. These results were simultaneously confirmed in vivo and in vitro. In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors.

  19. ADAR1 deletion induces NFκB and interferon signaling dependent liver inflammation and fibrosis.

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    Ben-Shoshan, Shirley Oren; Kagan, Polina; Sultan, Maya; Barabash, Zohar; Dor, Chen; Jacob-Hirsch, Jasmine; Harmelin, Alon; Pappo, Orit; Marcu-Malina, Victoria; Ben-Ari, Ziv; Amariglio, Ninette; Rechavi, Gideon; Goldstein, Itamar; Safran, Michal

    2017-05-04

    Adenosine deaminase acting on RNA (ADAR) 1 binds and edits double-stranded (ds) RNA secondary structures found mainly within untranslated regions of many transcripts. In the current research, our aim was to study the role of ADAR1 in liver homeostasis. As previous studies show a conserved immunoregulatory function for ADAR1 in mammalians, we focused on its role in preventing chronic hepatic inflammation and the associated activation of hepatic stellate cells to produce extracellular matrix and promote fibrosis. We show that hepatocytes specific ADAR1 knock out (KO) mice display massive liver damage with multifocal inflammation and fibrogenesis. The bioinformatics analysis of the microarray gene-expression datasets of ADAR1 KO livers reveled a type-I interferons signature and an enrichment for immune response genes compared to control littermate livers. Furthermore, we found that in vitro silencing of ADAR1 expression in HepG2 cells leads to enhanced transcription of NFκB target genes, foremost of the pro-inflammatory cytokines IL6 and IL8. We also discovered immune cell-independent paracrine signaling among ADAR1-depleted HepG2 cells and hepatic stellate cells, leading to the activation of the latter cell type to adopt a profibrogenic phenotype. This paracrine communication dependent mainly on the production and secretion of the cytokine IL6 induced by ADAR1 silencing in hepatocytes. Thus, our findings shed a new light on the vital regulatory role of ADAR1 in hepatic immune homeostasis, chiefly its inhibitory function on the crosstalk between the NFκB and type-I interferons signaling cascades, restraining the development of liver inflammation and fibrosis.

  20. microRNA are central players in anti- and profibrotic gene regulation during liver fibrosis.

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    Andrea eNoetel

    2012-03-01

    Full Text Available miRNA are small noncoding RNA molecules that posttranscriptionally effect mRNA stability and translation by targeting the 3´-untranslated region (3`-UTR of various transcripts. Thus, dysregulation of miRNA affects a wide range of cellular processes such as cell proliferation and differentiation involved in organ remodelling processes. Divergent miRNA patterns wereobserved during chronic liver diseases of various etiologies. Chronic liver diseases result in uncontrolled scar formation ending up in liver fibrosis or even cirrhosis. Since it has been shown that miR-29 dysregulation is involved in synthesis of extracellular matrix (ECM proteins, miR-29 is of special interest. The importance of miR-29 in hepatic collagen homeostasis is underlined by in vivo data showing that experimental severe fibrosis is associated with a prominent miR-29 decrease. The loss of miR-29 is due to the response of hepatic stellate cells to exposure to the profibrogenic mediators TGF-β and PDGF-BB. Several putative binding sites for the Smad proteins and the Ap-1 complex are located in the miR-29 promoter, which are suggested to mediate miR-29 decrease in fibrosis. Other miRNA are highly increased after profibrogenic stimulation, such as miR-21. miR-21 is transcriptionally upregulated in response to Smad-3 rather than Smad-2 activation after TGF-β stimulation. In addition, TGF-β promotes miR-21 expression by formation of a microprocessor complex containing Smad proteins. Elevated miR-21 may then act as a profibrogenic miRNA by its repression of the TGF-β inhibitory Smad-7 protein.

  1. Gene expression profiling of HCV genotype 3a initial liver fibrosis and cirrhosis patients using microarray

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    Ahmad Waqar

    2012-03-01

    Full Text Available Abstract Background Hepatitis C virus (HCV causes liver fibrosis that may lead to liver cirrhosis or hepatocellular carcinoma (HCC, and may partially depend on infecting viral genotype. HCV genotype 3a is being more common in Asian population, especially Pakistan; the detail mechanism of infection still needs to be explored. In this study, we investigated and compared the gene expression profile between initial fibrosis stage and cirrhotic 3a genotype patients. Methods Gene expression profiling of human liver tissues was performed containing more than 22000 known genes. Using Oparray protocol, preparation and hybridization of slides was carried out and followed by scanning with GeneTAC integrator 4.0 software. Normalization of the data was obtained using MIDAS software and Significant Microarray Analysis (SAM was performed to obtain differentially expressed candidate genes. Results Out of 22000 genes studied, 219 differentially regulated genes found with P ≤ 0.05 between both groups; 107 among those were up-regulated and 112 were down-regulated. These genes were classified into 31 categories according to their biological functions. The main categories included: apoptosis, immune response, cell signaling, kinase activity, lipid metabolism, protein metabolism, protein modulation, metabolism, vision, cell structure, cytoskeleton, nervous system, protein metabolism, protein modulation, signal transduction, transcriptional regulation and transport activity. Conclusion This is the first study on gene expression profiling in patients associated with genotype 3a using microarray analysis. These findings represent a broad portrait of genomic changes in early HCV associated fibrosis and cirrhosis. We hope that identified genes in this study will help in future to act as prognostic and diagnostic markers to differentiate fibrotic patients from cirrhotic ones.

  2. Association between novel MRI-estimated pancreatic fat and liver histology-determined steatosis and fibrosis in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Patel, N S; Peterson, M R; Brenner, D A; Heba, E; Sirlin, C; Loomba, R

    2013-03-01

    Ectopic fat deposition in the pancreas and its association with hepatic steatosis have not previously been examined in patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD). To quantify pancreatic fat using a novel magnetic resonance imaging (MRI) technique and determine whether it is associated with hepatic steatosis and/or fibrosis in patients with NAFLD. This is a cross-sectional study including 43 adult patients with biopsy-proven NAFLD who underwent clinical evaluation, biochemical testing and MRI. The liver biopsy assessment was performed using the NASH-CRN histological scoring system, and liver and pancreas fat quantification was performed using a novel, validated MRI biomarker; the proton density fat fraction. The average MRI-determined pancreatic fat in patients with NAFLD was 8.5% and did not vary significantly between head, body, and tail of the pancreas. MRI-determined pancreatic fat content increased significantly with increasing histology-determined hepatic steatosis grade; 4.6% in grade 1; 7.7% in grade 2; 13.0% in grade 3 (P = 0.004) respectively. Pancreatic fat content was lower in patients with histology-determined liver fibrosis than in those without fibrosis (11.2% in stage 0 fibrosis vs. 5.8% in stage 1-2 fibrosis, and 6.9% in stage 3-4 fibrosis, P = 0.013). Pancreatic fat did not correlate with age, body mass index or diabetes status. In patients with NAFLD, increased pancreatic fat is associated with hepatic steatosis. However, liver fibrosis is inversely associated with pancreatic fat content. Further studies are needed to determine underlying mechanisms to understand if pancreatic steatosis affects progression of NAFLD. © 2013 Blackwell Publishing Ltd.

  3. Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Arndt, Stephanie; Wacker, Eva; Dorn, Christoph; Koch, Andreas; Saugspier, Michael; Thasler, Wolfgang E; Hartmann, Arndt; Bosserhoff, Anja Katrin; Hellerbrand, Claus

    2015-06-01

    Bone morphogenetic protein 6 (BMP6) has been identified as crucial regulator of iron homeostasis. However, its further role in liver pathology including non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) is elusive. The aim of this study was to investigate the expression and function of BMP6 in chronic liver disease. BMP6 was analysed in hepatic samples from murine models of chronic liver injury and patients with chronic liver diseases. Furthermore, a tissue microarray comprising 110 human liver tissues with different degree of steatosis and inflammation was assessed. BMP6-deficient (BMP6(-/-)) and wild-type mice were compared in two dietary NASH-models, that is, methionine choline-deficient (MCD) and high-fat (HF) diets. BMP6 was solely upregulated in NAFLD but not in other murine liver injury models or diseased human livers. In NAFLD, BMP6 expression correlated with hepatic steatosis but not with inflammation or hepatocellular damage. Also, in vitro cellular lipid accumulation in primary human hepatocytes induced increased BMP6 expression. MCD and HF diets caused more hepatic inflammation and fibrosis in BMP6(-/-) compared with wild-type mice. However, only in the MCD and not in the HF diet model BMP6(-/-) mice developed marked hepatic iron overload, suggesting that further mechanisms are responsible for protective BMP6 effect. In vitro analysis revealed that recombinant BMP6 inhibited the activation of hepatic stellate cells (HSCs) and reduced proinflammatory and profibrogenic gene expression in already activated HSCs. Steatosis-induced upregulation of BMP6 in NAFLD is hepatoprotective. Induction of BMP6-signalling may be a promising antifibrogenic strategy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  4. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis

    DEFF Research Database (Denmark)

    Karsdal, Morten A; Manon-Jensen, Tina; Genovese, Federica

    2015-01-01

    the essential information needed for maintenance of a sophisticated structure anchoring the cells and sustaining normal function of tissues. Therefore, the matrix itself may be considered as a paracrine/endocrine entity, with more complex functions than previously appreciated. The aims of this review are to 1......) explore key structural and functional components of the ECM as exemplified by monogenetic disorders leading to severe pathologies, 2) discuss selected pathological posttranslational modifications of ECM proteins resulting in altered functional (signaling) properties from the original structural proteins...... homeostasis. These properties should be exploited to establish novel biochemical markers and antifibrotic treatment strategies for liver fibrosis as well as other fibrotic diseases....

  5. 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 - others: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

  6. Clinical effect of Mongolian medicine Qinggan Jiuwei powder in treatment of alcoholic liver fibrosis

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    GE Hongyan

    2017-12-01

    Full Text Available ObjectiveTo observe the clinical effect of Mongolian medicine Qinggan Jiuwei powder in the treatment of alcoholic liver fibrosis by observing the improvement in imaging indices. MethodsA total of 104 patients with alcoholic liver fibrosis who visited Department of Gastroenterology in Horqin District First People′s Hospital in Tongliao from October 2015 to January 2017 were enrolled and randomly divided into experimental group and control group, with 52 patients in each group. The patients in the experimental group were given Mongolian medicine Qinggan Jiuwei powder, while those in the control group were given reduced glutathione tablets. Liver function parameters, liver-spleen ultrasound findings, and liver stiffness measurement (LSM determined by FibroScan were observed before and after treatment. The independent samples t-test was used for comparison of normally distributed continuous data between groups, and the paired samples t-test was used for comparison within each group; the Wilcoxon rank sum test was used for comparison of non-normally distributed continuous data between groups. ResultsBoth groups had varying degrees of improvements in clinical symptoms and signs. Both groups had significant changes in alanine aminotransferase, aspartate aminotransferase (AST, gamma-glutamyl transpeptidase (GGT, and LSM after treatment (experimental group: Z=-3.09, -7.19, and -8.27, t=7.13, P=0.002, <0.001, <0.001, and <0.001; control group: Z=-3.28, -4.60, and -5.06, t=8.54. P=0.001, <0.001, <0.001, and <0.001. There were significant differences in AST and GGT after treatment between the two groups (Z=-2.02 and -2.15, P=0.04 and 0.03. Both groups had significant changes in oblique diameter of the right liver lobe, diameter of the portal vein, blood flow rate of the portal vein, spleen thickness, and diameter of the splenic vein after treatment (experimental group: t=6.48,11.02,2.20,3.30 and 5.30, P<0.001, <0.001, =0.030, <0

  7. Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion

    International Nuclear Information System (INIS)

    Wu, Yuting; Liu, Xuejiao; Zhou, Qun; Huang, Cheng; Meng, Xiaoming; Xu, Fengyun; Li, Jun

    2015-01-01

    SIRT1 (silent information regulator 1), a conserved NAD +-dependent histone deacetylase, is closely related with various biological processes. Moreover, the important role of SIRT1 in alcoholic liver disease, nonalcoholic fatty liver and HCC had been widely reported. Recently, a novel role of SIRT1 was uncovered in organ fibrosis diseases. Here, we investigated the inhibitory effect of SIRT1 in liver fibrogenesis. SIRT1 protein was dramatically decreased in CCl4-treated mice livers. Stimulation of LX-2 cells with TGF-β1 also resulted in a significant suppression of SIRT1 protein. Nevertheless, TGF-β1-induced LX-2 cell activation was inhibited by SIRT1 plasmid, and this was accompanied by up-regulation of cell apoptosis-related proteins. Overexpression of SIRT1 also attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and COL1a. However, the important characteristic of the recovery of liver fibrosis is not only the apoptosis of activated stellate cells but also the reversal of the myofibroblast-like phenotype to a quiescent-like phenotype. Restoration of SIRT1 protein was observed in the in vivo spontaneously liver fibrosis reversion model and in vitro MDI (isobutylmethylxanthine, dexamethasone, and insulin)-induced reversed stellate cells, and forced expression of SIRT1 also promoted the reversal of activated stellate cells. Furthermore, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was increased in liver fibrosis. RNAi-mediated suppression of MALAT1 resulted in a decrease of myofibroblast markers and restoration of SIRT1 protein. These observations suggested that SIRT1 contributed to apoptosis and reversion of activated LX-2 cells and SIRT1 might be regulated by MALAT1 in liver fibrosis. Therefore, SIRT1 could be considered as a valuable therapeutic target for translational studies of liver fibrosis. - Highlights: • This is the first report of SIRT1 expression and function in liver fibrogenesis and reversion.

  8. Non-invasive quantification of liver fibrosis regression following successful treatment of chronic hepatitis C with direct acting antivirals

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    Nițescu Maria

    2017-10-01

    Full Text Available Introduction. The past years have revolutionized the treatment of hepatitis C virus (HCV infection, with high rates of sustained virologic response (SVR. Furthermore, liver fibrosis has recently been redefined as a dynamic, reversible process. Methods. We performed a prospective cohort study to assess the role of laboratory evaluations and non-invasive measurement of liver stiffness in establishing the right time for starting treatment and in assessing the regression of liver fibrosis in Romanian patients treated with direct acting antivirals (DAA for genotype 1b chronic hepatitis C. Results. We present the results for 102 patients, with a mean age of 58.5 years, and a rate of SVR of 100%. Our study has ruled out older age (p=0.628, IL28B non-CC genotype (p=0.693, baseline viral load above the cutoff of 600,000 IU/mL (p=0.353, and the presence of diabetes mellitus (p=0.272 or baseline steatosis (p=0.706 as factors potentially influencing the regression of liver fibrosis following DAA treatment of HCV infection with the 3D regimen. The quantitative regression of liver stiffness was inversely correlated with the duration of HCV infection (p=0.017, suggesting that timely treatment might associate better outcomes in terms of liver fibrosis. Conclusion. Our study’s results point towards the need to start DAA treatment earlier in patients with HCV infection.

  9. A prognostic model for development of significant liver fibrosis in HIV-hepatitis C co-infection.

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    Nasheed Moqueet

    Full Text Available Liver fibrosis progresses rapidly in HIV-Hepatitis C virus (HCV co-infected individuals partially due to heightened inflammation. Immune markers targeting stages of fibrogenesis could aid in prognosis of fibrosis.A case-cohort study was nested in the prospective Canadian Co-infection Cohort (n = 1119. HCV RNA positive individuals without fibrosis, end-stage liver disease or chronic Hepatitis B at baseline (n = 679 were eligible. A random subcohort (n = 236 was selected from those eligible. Pro-fibrogenic markers and Interferon Lambda (IFNL rs8099917 genotype were measured from first available sample in all fibrosis cases (APRI ≥ 1.5 during follow-up and the subcohort. We used Cox proportional hazards and compared Model 1 (selected clinical predictors only to Model 2 (Model 1 plus selected markers for predicting 3-year risk of liver fibrosis using weighted Harrell's C and Net Reclassification Improvement indices.113 individuals developed significant liver fibrosis over 1300 person-years (8.63 per 100 person-years 95% CI: 7.08, 10.60. Model 1 (age, sex, current alcohol use, HIV RNA, baseline APRI, HCV genotype was nested in model 2, which also included IFNL genotype and IL-8, sICAM-1, RANTES, hsCRP, and sCD14. The C indexes (95% CI for model 1 vs. model 2 were 0.720 (0.649, 0.791 and 0.756 (0.688, 0.825, respectively. Model 2 classified risk more appropriately (overall net reclassification improvement, p<0.05.Including IFNL genotype and inflammatory markers IL-8, sICAM-1, RANTES, hs-CRP, and sCD14 enabled better prediction of the 3-year risk of significant liver fibrosis over clinical predictors alone. Whether this modest improvement in prediction justifies their additional cost requires further cost-benefit analyses.

  10. Quantification of liver viscoelasticity with acoustic radiation force: a study of hepatic fibrosis in a rat model.

    Science.gov (United States)

    Chen, Xin; Shen, Yuanyuan; Zheng, Yi; Lin, Haoming; Guo, Yanrong; Zhu, Ying; Zhang, Xinyu; Wang, Tianfu; Chen, Siping

    2013-11-01

    Ultrasound elastography, based on shear wave propagation, enables the quantitative and non-invasive assessment of liver mechanical properties such as stiffness and has been found to be feasible for and useful in the diagnosis of hepatic fibrosis. Most ultrasound elastographic methods use a purely elastic model to describe liver mechanical properties. However, to describe tissue that is dispersive and to obtain an accurate measure of tissue elasticity, the viscoelasticity of the tissue should be examined. The objective of this study was to investigate the shear viscoelastic characteristics, as measured by ultrasound elastography, of liver fibrosis in a rat model and to evaluate the diagnostic accuracy of viscoelasticity for staging liver fibrosis. Liver fibrosis was induced in 37 rats using carbon tetrachloride (CCl4); 6 rats served as controls. Liver viscoelasticity was measured in vitro using shear waves induced by acoustic radiation force. The measured mean values of liver elasticity and viscosity ranged from 0.84 to 3.45 kPa and from 1.12 to 2.06 Pa·s for fibrosis stages F0-F4, respectively. Spearman correlation coefficients indicated that stage of fibrosis was well correlated with elasticity (0.88) and moderately correlated with viscosity (0.66). The areas under receiver operating characteristic curves were 0.97 (≥F2), 0.91 (≥F3) and 1.00 (F4) for elasticity and 0.91 (≥F2), 0.79 (≥F3) and 0.74 (F4) for viscosity, respectively. The results confirmed that shear wave velocity was dispersive in frequency, suggesting a viscoelastic model to describe liver fibrosis. The study finds that although viscosity is not as good as elasticity for staging fibrosis, it is important to consider viscosity to make an accurate estimation of elasticity; it may also provide other mechanical insights into liver tissues. Copyright © 2013 World Federation for Ultrasound in Medicine & Biology. All rights reserved.

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

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    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.

  12. Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population.

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    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. Characterization of the properties of a selective, orally bioavailable autotaxin inhibitor in preclinical models of advanced stages of liver fibrosis.

    Science.gov (United States)

    Baader, Manuel; Bretschneider, Tom; Broermann, Andre; Rippmann, Joerg F; Stierstorfer, Birgit; Kuttruff, Christian A; Mark, Michael

    2018-02-01

    Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non-alcoholic steatohepatitis (NASH) remains unclear. The relevance of ATX in the pathogenesis of liver fibrosis was investigated by oral administration of Ex_31, a selective ATX inhibitor, in a 10 week model of carbon tetrachloride-induced liver injury and in a 14 week model of choline-deficient amino acid-defined diet-induced liver injury in rats. Oral administration of Ex_31, a selective ATX inhibitor, at 15 mg·kg -1 twice daily in therapeutic intervention mode resulted in efficient ATX inhibition and more than 95% reduction in plasma LPA levels in both studies. Treatment with Ex_31 had no effect on biomarkers of liver function, inflammation, or fibrosis and did not result in histological improvements in diseased animals. Our findings question the role of ATX in the pathogenesis of hepatic fibrosis and the potential of small molecule ATX inhibitors for the treatment of patients with NASH and advanced stages of liver fibrosis. © 2017 The British Pharmacological Society.

  14. Spleen dynamic contrast-enhanced magnetic resonance imaging as a new method for staging liver fibrosis in a piglet model.

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    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.

  15. The diagnostic performance of shear-wave elastography for liver fibrosis in children and adolescents: A systematic review and diagnostic meta-analysis.

    Science.gov (United States)

    Kim, Jeong Rye; Suh, Chong Hyun; Yoon, Hee Mang; Lee, Jin Seong; Cho, Young Ah; Jung, Ah Young

    2018-03-01

    To assess the diagnostic performance of shear-wave elastography for determining the severity of liver fibrosis in children and adolescents. An electronic literature search of PubMed and EMBASE was conducted. Bivariate modelling and hierarchical summary receiver-operating-characteristic modelling were performed to evaluate the diagnostic performance of shear-wave elastography. Meta-regression and subgroup analyses according to the modality of shear-wave imaging and the degree of liver fibrosis were also performed. Twelve eligible studies with 550 patients were included. Shear-wave elastography showed a summary sensitivity of 81 % (95 % CI: 71-88) and a specificity of 91 % (95 % CI: 83-96) for the prediction of significant liver fibrosis. The number of measurements of shear-wave elastography performed was a significant factor influencing study heterogeneity. Subgroup analysis revealed shear-wave elastography to have an excellent diagnostic performance according to each degree of liver fibrosis. Supersonic shear imaging (SSI) had a higher sensitivity (pwave elastography is an excellent modality for the evaluation of the severity of liver fibrosis in children and adolescents. Compared with ARFI, SSI showed better diagnostic performance for prediction of significant liver fibrosis. • Shear-wave elastography is beneficial for determining liver fibrosis severity in children. • Shear-wave elastography showed summary sensitivity of 81 %, specificity of 91 %. • SSI showed better diagnostic performance than ARFI for significant liver fibrosis.

  16. Aerobic exercise training in the treatment of non‐alcoholic fatty liver disease related fibrosis

    Science.gov (United States)

    Linden, Melissa A.; Sheldon, Ryan D.; Meers, Grace M.; Ortinau, Laura C.; Morris, E. Matthew; Booth, Frank W.; Kanaley, Jill A.; Vieira‐Potter, Victoria J.; Sowers, James R.; Ibdah, Jamal A.; Thyfault, John P.; Laughlin, M. Harold

    2016-01-01

    Key points Physiologically relevant rodent models of non‐alcoholic steatohepatitis (NASH) that resemble the human condition are limited.Exercise training and energy restriction are first‐line recommendations for the treatment of NASH.Hyperphagic Otsuka Long–Evans Tokushima fatty rats fed a western diet high in fat, sucrose and cholesterol for 24 weeks developed a severe NASH with fibrosis phenotype.Moderate intensity exercise training and modest energy restriction provided some improvement in the histological features of NASH that coincided with alterations in markers of hepatic stellate cell activation and extracellular matrix remodelling.The present study highlights the importance of lifestyle modification, including exercise training and energy restriction, in the regulation of advanced liver disease. Abstract The incidence of non‐alcoholic steatohepatitis (NASH) is rising but the efficacy of lifestyle modifications to improve NASH‐related outcomes remain unclear. We hypothesized that a western diet (WD) would induce NASH in the Otsuka Long–Evans Tokushima Fatty (OLETF) rat and that lifestyle modification would improve this condition. Eight‐week‐old Long–Evans Tokushima Otsuka (L) and OLETF (O) rats consumed a control diet (10% kcal fat, 3.5% sucrose) or a WD (45% kcal fat, 17% sucrose, 1% cholesterol) for 24 weeks. At 20 weeks of age, additional WD‐fed OLETFs were randomized to sedentary (O‐SED), food restriction (O‐FR; ∼25% kcal reduction vs. O‐SED) or exercise training (O‐EX; treadmill running 20 m min–1 with a 15% incline, 60 min day–1, 5 days week–1) conditions for 12 weeks. WD induced a NASH phenotype in OLETFs characterized by hepatic fibrosis (collagen 1α1 mRNA and hydroxyproline content), as well as elevated inflammation and non‐alcoholic fatty liver disease activity scores, and hepatic stellate cell activation (α‐smooth muscle actin) compared to Long–Evans Tokushima Otsuka rats. FR and EX modestly

  17. Second Harmonic Generation Reveals Subtle Fibrosis Differences in Adult and Pediatric Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Liu, Feng; Zhao, Jing-Min; Rao, Hui-Ying; Yu, Wei-Miao; Zhang, Wei; Theise, Neil D; Wee, Aileen; Wei, Lai

    2017-11-20

    Investigate subtle fibrosis similarities and differences in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using second harmonic generation (SHG). SHG/two-photon excitation fluorescence imaging quantified 100 collagen parameters and determined qFibrosis values by using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system in 62 adult and 36 pediatric NAFLD liver specimens. Six distinct parameters identified differences among the NASH CRN stages with high accuracy (area under the curve, 0835-0.982 vs 0.885-0.981, adult and pediatric). All portal region parameters showed similar changes across early stages 0, 1C, and 2, in both groups. Parameter values decreased in adults with progression from stage 1A/B to 2 in the central vein region. In children, aggregated collagen parameters decreased, but nearly all distributed collagen parameters increased from stage 1A/B to 2. SHG analysis accurately reproduces NASH CRN staging in NAFLD, as well as reveals differences and similarities between adult and pediatric collagen deposition not captured by currently available quantitative methods. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  18. Pathomorphology of liver fibrosis in trepanobioptates of patients with steatohepatitis: main types, sources of development, features of progression

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    V. A. Tumanskiy

    2017-12-01

    Full Text Available Until recently, among the pathologists, hepatologists and gastroenterologists, a discussion continues on the morphogenesis and gradation of liver fibrosis in non-alcoholic patients (NASH and alcoholic steatohepatitis (ASH. Purpose of the study. Studying the main types and sources of liver fibrosis in patients with nonalcoholic and alcoholic steatohepatitis, justifying the gradation of its severity, taking into account the quantitative dynamics of fibrogenic producer cells, the relative area of fibrosis and the deposition of type I, III and IV collagen in the liver. Material and methods. Histological and histochemical examination of liver fibrosis was performed in 198 patients with NASH of 18-79 years and in 79 patients with ASH of 47-63 years. Immunohistochemical study with measurement of the area of expression of activated αSMA + perisinusoidal stellate cells and αSMA + portal myofibroblasts with F1 (mild, F2 (moderate, F3 (severe fibrosis and F4 fibrosis / cirrhosis was performed in 80 trepanobioptates of patients with NASH (20 cases in each group, electron microscopic examination of the liver – in 10 deceased patients suffering from NASH. Results. In patients with NASH and ASH, there are two major types of liver fibrosis progress: the perisinusoidal pericellular and portal-Z3 perisinusoidal fibrosis, the development of which is the new generation of αSMA + star cells and αSMA + portal myofibroblasts of the fibrogenic immunophenotype, with co-expression of fascin and vimentin and absence of desmine expression. As the perisinusoidal pericellular fibrosis progresses from the mild F1 degree, to the severe F3 fibrosis and to the extremely severe F4 fibrosis / cirrhosis of the pericellular type, the area of the Masson-positive extracellular molecular-fibrous matrix (H = 88,70 р = 0,05 and the area of αSMA + collagen-producing stellate cells of perisinusoidal-pericellular localization (H = 45,12, p = 0,05. According to the data of

  19. The histological quantification of alpha-smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients.

    Science.gov (United States)

    Varma, Sharat; Stéphenne, Xavier; Komuta, Mina; Bouzin, Caroline; Ambroise, Jerome; Smets, Françoise; Reding, Raymond; Sokal, Etienne M

    2017-02-01

    Activated hepatic stellate cells express cytoplasmic ASMA prior to secreting collagen and consequent liver fibrosis. We hypothesized that quantifying ASMA could predict severity of future fibrosis after LT. For this, 32 pairs of protocol biopsies, that is, "baseline" and "follow-up" biopsies taken at 1- to 2-year intervals from 18 stable pediatric LT recipients, transplanted between 2006 and 2012 were selected. Morphometric quantification of "ASMA-positive area percentage" was performed on the baseline biopsy. Histological and fibrosis assessment using Metavir and LAFSc was performed on all biopsies. The difference of fibrosis severity between the "baseline" and "follow-up" was termed "prospective change in fibrosis." Significant association was seen between extent of ASMA positivity on baseline biopsy and "prospective change in fibrosis" using Metavir (P=.02), cumulative LAFSc (P=.02), and portal LAFSc (P=.01) values. ASMA-positive area percentage >1.05 predicted increased fibrosis on next biopsy with 90.0% specificity. Additionally, an association was observed between extent of ASMA positivity and concomitant ductular reaction (P=.06), but not with histological inflammation in the portal tract or lobular area. Hence, ASMA quantification can predict the future course of fibrosis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation.

    Science.gov (United States)

    Wang, Qiu-Ming; Du, Jian-Ling; Duan, Zhi-Jun; Guo, Shi-Bin; Sun, Xiao-Yu; Liu, Zhen

    2013-05-21

    To investigate the effects of the heme oxygenase (HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation (BDL). Male Sprague-Dawley rats were divided randomly into a Sham group, BDL group, Fe group, deferoxamine (DFX) group, zinc protoporphyrin (ZnPP) group and cobalt protoporphyrin (CoPP) group. The levels of HO-1 were detected using different methods. The serum carboxyhemoglobin (COHb), iron, and portal vein pressure (PVP) were also quantified. The plasma and mRNA levels of hepcidin were measured. Hepatic fibrosis and its main pathway were assessed using Van Gieson's stain, hydroxyproline, transforming growth factor-β1 (TGF-β1), nuclear factor-E2-related factor 2 (Nrf2), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Serum COHb and protein and mRNA expression levels of HO-1 and Nrf2 were increased in the BDL group compared with the Sham group and were much higher in the CoPP group. The ZnPP group showed lower expression of HO-1 and Nrf2 and lower COHb. The levels of iron and PVP were enhanced in the BDL group but were lower in the ZnPP and DFX groups and were higher in the CoPP and Fe groups. Hepcidin levels were higher, whereas superoxide dismutase levels were increased and malonaldehyde levels were decreased in the ZnPP and DFX groups. The ZnPP group also showed inhibited TGF-β1 expression and regulated TIMP-1/MMP-2 expression, as well as obviously attenuated liver fibrosis. Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the Nrf2/Keap pathway could be helpful in improving hepatic fibrosis and regulating PVP.

  1. Comparison of AI techniques for prediction of liver fibrosis in hepatitis patients.

    Science.gov (United States)

    Keltch, Brian; Lin, Yuan; Bayrak, Coskun

    2014-08-01

    Globally one in twelve people have the Hepatitis B or Hepatitis C virus. Diagnosis and treatment of this disease is guided by liver biopsies where a small amount of tissue is removed by a surgeon and examined by a pathologist to determine the fibrosis stage from F(0) (no damage) to F(4) (cirrhosis). Biopsies are costly and carry some risk for the patient. Non-invasive techniques for determining fibrosis stage have been developed and evaluated since 2003. Non-invasive methods have utilized serum markers, imaging test, and genetic studies. The accuracy of these non-invasive techniques has not achieved sufficient acceptance and so the invasive biopsy is still considered the gold standard.Clinical decision support systems (CDSS) use decision support system theory and technology to assist clinicians in the evaluation and treatment process. Using historical clinical data and the relationship processed by Artificial Intelligence (AI) techniques to aid physicians in their decision making process is the goal of CDSS. The CDSS provides a large number of medical support functions to help clinicians make the most reasonable diagnosis and choose the best treatment measures.This paper applies four artificial intelligence predictive techniques to publicly available data on 424 Hepatitis B and Hepatitis C patients. Demographic and standard serum markers are utilized to predict fibrosis stage and compare these predictions to known biopsy results. A final decision tree evaluation is applied to make a final prediction. We have also developed a publically available web application that can be used as a prototype for presenting AI predictive results in a CDSS environment based on these models. This technique along with others could mitigate the need for some liver biopsies in the more than 500 million Hepatitis B and C patients worldwide with additional validation and verification.

  2. 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

  3. Comparative evaluation of GPR versus APRI and FIB-4 in predicting different levels of liver fibrosis of chronic hepatitis B.

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    Liu, D-P; Lu, W; Zhang, Z-Q; Wang, Y-B; Ding, R-R; Zhou, X-L; Huang, D; Li, X-F

    2017-12-12

    It is of great significance to develop and evaluate noninvasive indexes predicting the level of liver fibrosis. The aim of this study was to comparatively evaluate gamma-glutamyl transpeptidase-to-platelet ratio (GPR) versus aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on 4 factors (FIB-4) in predicting different levels of liver fibrosis of chronic hepatitis B (CHB) within the framework of HBeAg-positive and HBeAg-negative patients. A total of 1157 HBeAg-positive and 859 HBeAg-negative CHB patients were enrolled, among whom the pathological stage ≥S2, ≥S3, ≥S4 were defined as significant fibrosis, extensive fibrosis and cirrhosis, respectively. Receiver operating characteristic (ROC) curves were used to evaluate the performance of GPR, APRI and FIB-4 in predicting different levels of liver fibrosis. In HBeAg-positive patients, the area under ROC curves (AUROCs) of GPR in predicting extensive fibrosis and cirrhosis were both significantly larger than those of APRI (P = .0001 and P GPR in predicting significant fibrosis and cirrhosis were significantly larger than those of FIB-4 (P = .0006 and P = .0041). The AUROC of GPR in predicting extensive fibrosis was significantly larger than that of APRI and FIB-4 (P = .0320 and P = .0018). Using a cut-off of GPR > 0.500 as standard, the sensitivities and specificities of GPR in predicting significant fibrosis in HBeAg-positive patients were 59.6% and 81.2%, and for cirrhosis 80.9% and 63.8%, respectively; and those of HBeAg-negative patients were 60.3% and 78.3%, 84.5% and 66.1%, respectively. Regardless of HBeAg-positive or HBeAg-negative status, GPR had the best performance in predicting different levels of liver fibrosis. © 2017 John Wiley & Sons Ltd.

  4. Regression of liver fibrosis by taurine in rats fed alcohol: effects on collagen accumulation, selected cytokines and stellate cell activation.

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    Devi, Shanmugam Lakshmi; Viswanathan, Periyaswamy; Anuradha, Carani V

    2010-11-25

    The antifibrogenic effect of taurine in experimental liver fibrosis has been shown. The role of taurine to abate fibrogenic mediators and collagen deposition during liver fibrosis induced by simultaneous administration of iron carbonyl (0.5% w/w) and alcohol (6 g/kg/day) was investigated in this study. Liver histology, the levels of inflammatory cytokines, stellate cell activation, oxidative stress and collagen content were assessed. Liver fibrosis and a rise in collagen content in ethanol plus iron-fed rat were evident from van Gieson and Masson's trichrome staining respectively. Hepatic myeloperoxidase activity and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were markedly elevated. This was associated with an imbalance in the oxidant-antioxidant system, increased expression of transforming growth factor-β(1) (TGF-β(1)) and stellate cell activation suggested by α-smooth muscle actin (α-SMA) localization. This condition was protected in the presence of taurine. Taurine lowered the levels of IL-6, TNF-α and peroxidation products and the expression of α-SMA, desmin and TGF-β(1) and improved the antioxidant status. A positive relationship between hepatic collagen with iron and lipid peroxides and an inverse relationship between collagen and glutathione were noted. It is concluded that taurine reduces iron-potentiated alcoholic liver fibrosis by curtailing oxidative stress, production of inflammatory and fibrogenic mediators and activation of stellate cells. Copyright © 2010. Published by Elsevier B.V.

  5. Heterogenic transplantation of bone marrow-derived rhesus macaque mesenchymal stem cells ameliorates liver fibrosis induced by carbon tetrachloride in mouse

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    Xufeng Fu

    2018-02-01

    Full Text Available Liver fibrosis is a disease that causes high morbidity and has become a major health problem. Liver fibrosis can lead to the end stage of liver diseases (livercirrhosisand hepatocellularcarcinoma. Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, the shortage of organ donors, high cost of medical surgery, immunological rejection and transplantation complications severely hamper liver transplantation therapy. Mesenchymal stem cells (MSCs have been regarded as promising cells for clinical applications in stem cell therapy in the treatment of liver diseases due to their unique multipotent differentiation capacity, immunoregulation and paracrine effects. Although liver fibrosis improvements by MSC transplantation in preclinical experiments as well as clinical trials have been reported, the in vivo fate of MSCs after transportation and their therapeutic mechanisms remain unclear. In this present study, we isolated MSCs from the bone marrow of rhesus macaques. The cells exhibited typical MSC markers and could differentiate into chondrocytes, osteocytes, and adipocytes, which were not affected by labeling with enhanced green fluorescent protein (EGFP. The harvested MSCs respond to interferon-γ stimulation and have the ability to inhibit lymphocyte proliferation in vitro. EGFP-labeled MSCs (1 × 106 cells were transplanted into mice with carbon tetrachloride-induced liver fibrosis via tail vein injection. The ability of the heterogenic MSC infusion to ameliorate liver fibrosis in mice was evaluated by a blood plasma chemistry index, pathological examination and liver fibrosis-associated gene expression. Additionally, a small number of MSCs that homed and engrafted in the mouse liver tissues were evaluated by immunofluorescence analysis. Our results showed that the transplantation of heterogenic MSCs derived from monkey bone marrow can be used to treat liver fibrosis in the mouse model and that the

  6. Tumor necrosis factor-α promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells.

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    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.

  7. Preventative effects of prostaglandin E1 in combination with iodized olive oil on liver fibrosis after transcatheter arterial chemoembolization in a rabbit model of CCl4-induced liver fibrosis.

    Science.gov (United States)

    Jin, Shuqiang; Cao, Haili; Wang, Kaibing; Li, Ying; Bai, Bin

    2015-06-01

    To explore the preventative effects of prostaglandin E1 (PGE1) on a rabbit model of CCl4-induced liver fibrosis after transcatheter arterial chemoembolization (TACE), we generated a rabbit model of CCl4-induced liver fibrosis by treatment with 40% CCl4 in iodized olive oil for 16 weeks. Body mass and serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), albumin:globulin ratio (A:G), total bilirubin (TBIL), and direct bilirubin (DBIL) were measured. After TACE, the levels of hyaluronic acid (HA), procollagen III (PC III), laminin (LN), and collagen IV (IV-C) were measured, and the severity of liver fibrosis as well as the morphology of liver tissues were determined. Body mass in the model group was significantly decreased from 10 to 16 weeks, and the serum levels of ALT, AST, TP, TBIL, and DBIL levels were significantly increased while the model was being generated; the levels of ALB and A:G were significantly decreased. After TACE, serum levels of HA, PC III, and LN in the group injected with 1.0 mL iodized olive oil (Group B) were higher than in the group that were injected with 1.0 mL iodized olive oil + 0.2 mL PGE1 (Group C), whereas the serum levels of IV-C were lower. The severity of liver fibrosis was ameliorated in Group C. The combination of PGE1 and iodized olive oil prevented the development of liver fibrosis following TACE.

  8. Chloroquine upregulates TRAIL/TRAILR2 expression and potentiates doxorubicin anti-tumor activity in thioacetamide-induced hepatocellular carcinoma model.

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    Helmy, Sahar A; El-Mesery, Mohamed; El-Karef, Amro; Eissa, Laila A; El Gayar, Amal M

    2018-01-05

    Impaired apoptosis and systemic toxicity of chemotherapeutic drugs make cancer treatment suboptimal. Thus, there is urgency for drug repurposing which facilitates discovery of safe and effective combination therapy. This study aimed to evaluate chloroquine's (CQ) ability to trigger TRAIL/TRAILR2 apoptotic pathway in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) either alone or in combination with doxorubicin (DOX). Moreover, its ability to attenuate DOX-induced cardiotoxicity was investigated. TAA was injected in male Sprague Dawely rats (200 mg/kg; ip; 2 times/week) for 16 weeks. After the 16th week, rats were further divided into different groups (n = 10) and treated for 7 weeks. CQ group (received CQ 25 mg/kg/day; orally), DOX group (received DOX 1 mg/kg; ip; 2 times/week) and CQ/DOX group. Liver function biomarkers, AFP, hepatic levels of MDA and GSH, serum CK-MB and LDH enzymes activity were measured. Quantitative, Real-Time PCR was used to measure TRAIL, TRAILR2, caspase-8, caspase-9, caspase-3, BCL-2 and TGF-β1 genes expression levels. Necroinflammation and fibrosis were scored by histopathological examination. CQ improved liver functions, reduced AFP level and attenuated HCC progression. CQ induced apoptosis via upregulation of TRAIL/TRAILR2, caspase-8, caspase-3 and caspase-8 genes and downregulation of BCL-2 gene. Moreover, CQ/DOX showed marked decrease in hepatic MDA level, serum CK-MB, LDH enzymes activity, as well as marked increase in hepatic GSH level. In conclusion, this work assess the in vivo efficacy of CQ/DOX combination therapy in this HCC model that not only has enhanced anti-tumor activity but it also protects against DOX-induced cardiotoxicity. Nevertheless, more studies should be performed to illustrate the molecular mechanism of CQ's cardioprotective effect. Copyright © 2017. Published by Elsevier B.V.

  9. Routine Laboratory Blood Tests May Diagnose Significant Fibrosis in Liver Transplant Recipients with Chronic Hepatitis C: A 10 Year Experience.

    Science.gov (United States)

    Sheen, Victoria; Nguyen, Heajung; Jimenez, Melissa; Agopian, Vatche; Vangala, Sitaram; Elashoff, David; Saab, Sammy

    2016-03-28

    The aims of our study were to determine whether routine blood tests, the aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) and Fibrosis 4 (Fib-4) scores, were associated with advanced fibrosis and to create a novel model in liver transplant recipients with chronic hepatitis C virus (HCV). We performed a cross sectional study of patients at The University of California at Los Angeles (UCLA) Medical Center who underwent liver transplantation for HCV. We used linear mixed effects models to analyze association between fibrosis severity and individual biochemical markers and mixed effects logistic regression to construct diagnostic models for advanced fibrosis (METAVIR F3-4). Cross-validation was used to estimate a receiving operator characteristic (ROC) curve for the prediction models and to estimate the area under the curve (AUC). The mean (± standard deviation [SD]) age of our cohort was 55 (±7.7) years, and almost three quarter were male. The mean (±SD) time from transplant to liver biopsy was 19.9 (±17.1) months. The mean (±SD) APRI and Fib-4 scores were 3 (±12) and 7 (±14), respectively. Increased fibrosis was associated with lower platelet count and alanine aminotransferase (ALT) values and higher total bilirubin and Fib-4 scores. We developed a model that takes into account age, gender, platelet count, ALT, and total bilirubin, and this model outperformed APRI and Fib-4 with an AUC of 0.68 (p < 0.001). Our novel prediction model diagnosed the presence of advanced fibrosis more reliably than APRI and Fib-4 scores. This noninvasive calculation may be used clinically to identify liver transplant recipients with HCV with significant liver damage.

  10. Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice

    International Nuclear Information System (INIS)

    Ghatak, Subhadip; Biswas, Ayan; Dhali, Gopal Krishna; Chowdhury, Abhijit; Boyer, James L.; Santra, Amal

    2011-01-01

    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.

  11. Effect of Qianggan capsules on insulin resistance index and liver fibrosis score in patients with nonalcoholic fatty liver disease

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    OU Qiang

    2016-10-01

    Full Text Available Objective To investigate the effect of Qianggan capsules on liver fibrosis score and insulin resistance index in patients with nonalcoholic fatty liver disease (NAFLD. Methods A total of 85 NAFLD patients who were treated in the Eighth People′s Hospital of Shanghai from August 2014 to July 2015 were enrolled and randomly divided into treatment group (45 patients and control group (40 patients. The patients in the treatment group were given Qianggan capsules, and those in the control group were given polyene phosphatidylcholine capsules. The course of treatment was 24 weeks for both groups. The changes in serum aminotransferases [aspartate aminotransferase (AST and alanine aminotransferase (ALT], homeostasis model assessment of insulin resistance (HOMA-IR, and NAFLD fibrosis score (NAFLDFS after treatment were observed in both groups. The t-test was used for comparison of continuous data between groups, before-after comparison within each group was made by paired t-test; and the chi-square test was used for comparison of categorical data between groups. Results Both groups showed significant improvements in ALT and AST levels after treatment (all P<0.01. After treatment the treatment group showed significant reductions in HOMA-IR and NAFLDFS (3.58±0.85 vs 2.48±078,t=6.40,P<0.01; -1.78±1.24 vs -2.35±0.98,t=2.40,P<0.01 and the treatment group had significantly lower HOMA-IR and NAFLDFS than the control group(12.48±0.78 vs 3.09±0.89, t=3.36, P<0.01; -2.35±0.98 vs -1.48±1.08, t=3.80, P<0.01. No serious adverse events were observed during the course of treatment. Conclusion Qianggan capsules not only reduce the levels of serum aminotransferases, but also improve insulin resistance and reduce fibrosis degree in NAFLD patients.

  12. Assessment of Liver Fibrosis by Transient Elastography Should Be Done After Hemodialysis in End Stage Renal Disease Patients with Liver Disease.

    Science.gov (United States)

    Taneja, Sunil; Borkakoty, Amritangsu; Rathi, Sahaj; Kumar, Vivek; Duseja, Ajay; Dhiman, Radha K; Gupta, Krishan L; Chawla, Yogesh

    2017-11-01

    The patients with end stage renal disease (ESRD) are at greater risk of acquiring chronic hepatitis B or C and subsequently development of liver disease. The aim of the study was to assess liver fibrosis by transient elastography (TE) and look for factors associated with change in liver stiffness measurement (LSM) with one session of hemodialysis (HD). Consecutive ESRD patients on maintenance hemodialysis (MHD) with suspected liver disease were enrolled. They underwent LSM by TE before and after one session of HD. Bioelectric impedance analysis was done to evaluate the volume status at the time of TE. Sixty-eight patients with mean age of 40 ± 14 years were included. There was a significant reduction in LSM after HD (18.5 [95% CI 14.8-23.1] vs. 11.2 [95% CI 8.8-13.7] kPa, p  or  2.5 L (8.6 [95% CI 5.7-11.5] vs. 5.1 [95% CI 2.9-7.5], p = 0.05). In 18 patients who underwent liver biopsy, LSM after HD performed better at detecting significant fibrosis, with area under receiver operating characteristics curve 0.71 [95% CI 0.46-0.97], versus 0.64 [95% CI 0.38-0.90], respectively. An LSM value of 12.2 kPa after HD was 71% sensitive and 74% specific for detection of significant fibrosis (≥ F2), while values less than 9 kPa ruled out significant fibrosis with a sensitivity and specificity of 37 and 100%, respectively. LSM by TE decreases significantly after HD in patients with ESRD on long-term MHD. Hence, TE should be done after HD for accurate assessment of liver fibrosis.

  13. Splenectomy attenuates murine liver fibrosis with hypersplenism stimulating hepatic accumulation of Ly-6C(lo) macrophages.

    Science.gov (United States)

    Yada, Akito; Iimuro, Yuji; Uyama, Naoki; Uda, Yugo; Okada, Toshihiro; Fujimoto, Jiro

    2015-10-01

    Splenectomy in cirrhotic patients has been reported to improve liver function; however the underlying mechanism remains obscure. In the present study, we investigated the mechanism using a murine model, which represents well the compensated liver cirrhosis. C57BL/6 male mice were allowed to drink water including thioacetamide (TAA: 300 mg/L) ad libitum for 32 weeks. After splenectomy at 32 weeks, mice were sacrificed on days one, seven, and 28, respectively, while TAA-administration was continued. Perioperative changes in peripheral blood and liver tissues were analyzed. TAA treatment of mice for 32 weeks reproducibly achieved advanced liver fibrosis with splenomegaly, thrombocytopenia, and leukocytopenia. After splenectomy, liver fibrosis was attenuated, and macrophages/monocytes were significantly increased in peripheral blood, as well as in the liver. Progenitor-like cells expressing CK-19, EpCAM, or CD-133 appeared in the liver after TAA treatment, and gradually disappeared after splenectomy. Macrophages/monocytes accumulated in the liver, most of which were negative for Ly-6C, were adjacent to the hepatic progenitor-like cells, and quantitative RT-PCR indicated increased canonical Wnt and decreased Notch signals. As a result, a significant amount of β-catenin accumulated in the progenitor-like cells. Moreover, relatively small Ki67-positive hepatic cells were significantly increased. Protein expression of MMP-9, to which Ly-6G-positive neutrophils contributed, was also increased in the liver after splenectomy. The hepatic accumulation of macrophages/monocytes, most of which are Ly-6C(lo), the reduction of fibrosis, and the gradual disappearance of hepatic progenitor-like cells possibly play significant roles in the tissue remodeling process in cirrhotic livers after splenectomy. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  14. Accuracy of transient elastography in assessing liver fibrosis in chronic viral hepatitis: A multicentre, retrospective study.

    Science.gov (United States)

    Seo, Yeon Seok; Kim, Moon Young; Kim, Seung Up; Hyun, Bae Si; Jang, Jae Young; Lee, Jin Woo; Lee, Jung Il; Suh, Sang Jun; Park, Soo Young; Park, Hana; Jung, Eun Uk; Kim, Byung Seok; Kim, In Hee; Lee, Tae Hee; Um, Soon Ho; Han, Kwang-Hyub; Kim, Sang Gyune; Paik, Soon Koo; Choi, Jong Young; Jeong, Soung Won; Jin, Young Joo; Lee, Kwan Sik; Yim, Hyung Joon; Tak, Won Young; Hwang, Seong Gyu; Lee, Youn Jae; Lee, Chang Hyeong; Kim, Dae-Ghon; Kang, Young Woo; Kim, Young Seok

    2015-10-01

    Transient elastography (TE) has become an alternative to liver biopsy (LB). This study investigated the diagnostic performance of liver stiffness (LS) measurement using TE in Korean patients with chronic hepatitis B and C (CHB and CHC). From April 2006 to June 2014, 916 patients (567 CHB and 349 CHC) who underwent LB and TE at 15 centres were analyzed. The Batts and Ludwig scoring system was used for histologic assessment. Aspartate aminotransferase (AST)-to-platelet ratio indexes (APRI) were calculated. Area under the receiver operating characteristic curve (AUROC) was used. The median age, LS value, and APRI score were 45 years, 8.8 kPa, and 0.61, respectively, in CHB patients vs. 51 years, 6.8 kPa and 0.55, respectively, in CHC patients. TE was significantly superior to APRI in CHB patients (AUROC 0.774 vs. 0.72 for ≥F2, 0.849 vs. 0.812 for ≥F3, and 0.902 vs. 0.707 for F4, respectively; all P 0.05) in CHC patients. In CHB patients, optimal cut-off LS values were 7.8 kPa for ≥F2, 8.2 kPa for ≥ F3, and 11.6 kPa for F4, vs. 6.8 kPa, 8.6 kPa, and 14.5 kPa, respectively, in CHC patients. TE can accurately assess the degree of liver fibrosis in Korean patients with CVH. TE was superior to APRI for predicting each fibrosis stage. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. 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.

  16. Effect of host-related factors on the intensity of liver fibrosis in patients with chronic hepatitis C virus infection

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    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.

  17. Prospective validation of FibroTest in comparison with liver stiffness for predicting liver fibrosis in Asian subjects with chronic hepatitis B.

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    Beom Kyung Kim

    Full Text Available Diagnostic values of FibroTest (FT for hepatic fibrosis have rarely been assessed in Asian chronic hepatitis B (CHB patients. We aimed to validate its diagnostic performances in comparison with liver stiffness (LS.From 2008 to 2010, 194 CHB patients who underwent liver biopsies along with FT and transient elastography were prospectively enrolled. Fibrosis stage was assessed according to the Batts and Ludwig system.To predict significant fibrosis (F≥2, advanced fibrosis (F≥3, and cirrhosis (F = 4, areas under receiver operating characteristic curves (AUROCs of FT were 0.903, 0.907, and 0.866, comparable to those of LS (0.873, 0.897, and 0.910, respectively. Optimized cutoffs of FT to maximize sum of sensitivity and specificity were 0.32, 0.52, and 0.68 for F≥2, F≥3, and F = 4, while those of LS were 8.8, 10.2, and 14.1 kPa, respectively. According to FT and LS cutoffs, 123 (63.4% and 124 (63.9% patients were correctly classified consistent with histological fibrosis (F1, F2, F3, and F4, respectively. Overall concordance between each fibrosis stage estimated by FT and LS was observed in 111 patients, where 88 were correctly classified with histological results. A combination formula adding LS to FT (LS+FT showed similar AUROC levels (0.885, 0.905, and 0.915, while another multiplying LS by FT (LS×FT showed the best AUROCs (0.941, 0.931, and 0.929 for F≥2, F≥3, and F4, respectively.FT provides good fibrosis prediction, with comparable outcomes to LS in Asian CHB patients. FT substantially reduces need for liver biopsy, especially when used in combination with LS.

  18. Non-invasive assessment of liver fibrosis in patients with HBV-related chronic liver disease undergoing antiviral treatment: A preliminary study.

    Science.gov (United States)

    Stasi, Cristina; Salomoni, Elena; Arena, Umberto; Corti, Giampaolo; Montalto, Paolo; Bartalesi, Filippo; Marra, Fabio; Laffi, Giacomo; Milani, Stefano; Zignego, Anna Linda; Pinzani, Massimo

    2017-07-05

    In chronic hepatitis B (CHB) patients, fibrosis assessment during antiviral treatment is a key step in the clinical management. Aim of this study was to evaluate the performance of elastography in assessing fibrosis stage in CHB before and after two years of nucleoside/nucleotide analogues (NUC) treatment in comparison with indirect serum markers. CHB diagnosis was made according to standard criteria. A clinical and virological evaluation was performed at baseline and again at 3, 6, 9, 12 18, and 24 months during treatment. Fibrosis was evaluated by liver biopsy, elastography and indirect serum markers. Of 75 patients, 50 had CHB, HBeAg negative and were deemed eligible for this study. Of these, 22 underwent liver biopsy. Mean histo-morphometric values of fibrotic tissue differed significantly in the stage < S3 vs. stage ≥S3: 2.01±2.62% vs. 12.85±7.31% (p=0.03), respectively. At 18 and 24 months, stiffness values were statistically reduced from those previously observed (P=0.03 and P<0.001). At 24 months the values of APRI, FIB-4 and LOK were not different from baseline values, while the value of FORNS score at 24 months was the only one statistically reduced. In two patients with fibrosis stage S3 and S6, respectively, fibrosis regressed to stage S2 and S5. In conclusion, the results of the present study show that liver histology, stiffness and FORNS score improve significantly during a long-term follow-up of HBV patients successfully treated with NUC. These results strongly suggest that the non-invasive evaluation of liver fibrosis represents a key step in the management and treatment of chronic HBV hepatitis. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Liver fibrosis in type I Gaucher disease: magnetic resonance imaging, transient elastography and parameters of iron storage.

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    Anneloes E Bohte

    Full Text Available Long term liver-related complications of type-1 Gaucher disease (GD, a lysosomal storage disorder, include fibrosis and an increased incidence of hepatocellular carcinoma. Splenectomy has been implicated as a risk factor for the development of liver pathology in GD. High ferritin concentrations are a feature of GD and iron storage in Gaucher cells has been described, but iron storage in the liver in relation to liver fibrosis has not been studied. Alternatively, iron storage in GD may be the result of iron supplementation therapy or regular blood transfusions in patients with severe cytopenia. In this pilot study, comprising 14 type-1 GD patients (7 splenectomized, 7 non-splenectomized and 7 healthy controls, we demonstrate that liver stiffness values, measured by Transient Elastography and MR-Elastography, are significantly higher in splenectomized GD patients when compared with non-splenectomized GD patients (p = 0.03 and p = 0.01, respectively. Liver iron concentration was elevated (>60±30 µmol/g in 4 GD patients of whom 3 were splenectomized. No relationship was found between liver stiffness and liver iron concentration. HFE gene mutations were more frequent in splenectomized (6/7 than in non-splenectomized (2/7 participants (p = 0.10. Liver disease appeared more advanced in splenectomized than in non-splenectomized patients. We hypothesize a relationship with excessive hepatic iron accumulation in splenectomized patients. We recommend that all splenectomized patients, especially those with evidence of substantial liver fibrosis undergo regular screening for HCC, according to current guidelines.

  20. Multifaceted Therapeutic Benefits of Factors Derived From Dental Pulp Stem Cells for Mouse Liver Fibrosis.

    Science.gov (United States)

    Hirata, Marina; Ishigami, Masatoshi; Matsushita, Yoshihiro; Ito, Takanori; Hattori, Hisashi; Hibi, Hideharu; Goto, Hidemi; Ueda, Minoru; Yamamoto, Akihito

    2016-10-01

    : Chronic liver injury from various causes often results in liver fibrosis (LF). Although the liver possesses endogenous tissue-repairing activities, these can be overcome by sustained inflammation and excessive fibrotic scar formation. Advanced LF leads to irreversible cirrhosis and subsequent liver failure and/or hepatic cancer. Here, using the mouse carbon tetrachloride (CCl 4 )-induced LF model, we showed that a single intravenous administration of stem cells derived from human exfoliated deciduous teeth (SHEDs) or of SHED-derived serum-free conditioned medium (SHED-CM) resulted in fibrotic scar resolution. SHED-CM suppressed the gene expression of proinflammatory mediators, such as TNF-α, IL-1β, and iNOS, and eliminated activated hepatic stellate cells by inducing their apoptosis, but protected parenchymal hepatocytes from undergoing apoptosis. In addition, SHED-CM induced tissue-repairing macrophages that expressed high levels of the profibrinolytic factor, matrix metalloproteinase 13. Furthermore, SHED-CM suppressed the CCl 4 -induced apoptosis of primary cultured hepatocytes. SHED-CM contained a high level of hepatocyte growth factor (HGF). Notably, HGF-depleted SHED-CM (dHGF-CM) did not suppress the proinflammatory response or resolve fibrotic scarring. Furthermore, SHED-CM, but not dHGF-CM, inhibited CCl 4 -induced hepatocyte apoptosis. These results suggest that HGF plays a central role in the SHED-CM-mediated resolution of LF. Taken together, our findings suggest that SHED-CM provides multifaceted therapeutic benefits for the treatment of LF. This study demonstrated that a single intravenous administration of stem cells from human exfoliated deciduous teeth (SHEDs) or of the serum-free conditioned medium (CM) derived from SHEDs markedly improved mouse liver fibrosis (LF). SHED-CM suppressed chronic inflammation, eliminated activated hepatic stellate cells by inducing their apoptosis, protected hepatocytes from undergoing apoptosis, and induced

  1. Serum Metabolomic Characterization of Liver Fibrosis in Rats and Anti-Fibrotic Effects of Yin-Chen-Hao-Tang.

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    Zhang, Hongyang; Wang, Xiaoning; Hu, Ping; Zhou, Wenjun; Zhang, Min; Liu, Jia; Wang, Yuerong; Liu, Ping; Luo, Guoan

    2016-01-21

    Yin-Chen-Hao-Tang (YCHT) is a famous Chinese medicine formula which has long been used in clinical practice for treating various liver diseases, such as liver fibrosis. However, to date, the mechanism for its anti-fibrotic effects remains unclear. In this paper, an ultra-performance liquid chromatography-time-of-flight mass spectrometry (UPLC-TOF-MS)-based metabolomic study was performed to characterize dimethylnitrosamine (DMN)-induced liver fibrosis in rats and evaluate the therapeutic effects of YCHT. Partial least squares-discriminant analysis (PLS-DA) showed that the model group was well separated from the control group, whereas the YCHT-treated group exhibited a tendency to restore to the controls. Seven significantly changed fibrosis-related metabolites, including unsaturated fatty acids and lysophosphatidylcholines (Lyso-PCs), were identified. Moreover, statistical analysis demonstrated that YCHT treatment could reverse the levels of most metabolites close to the normal levels. These results, along with histological and biochemical examinations, indicate that YCHT has anti-fibrotic effects, which may be due to the suppression of oxidative stress and resulting lipid peroxidation involved in hepatic fibrogenesis. This study offers new opportunities to improve our understanding of liver fibrosis and the anti-fibrotic mechanisms of YCHT.

  2. Serum Metabolomic Characterization of Liver Fibrosis in Rats and Anti-Fibrotic Effects of Yin-Chen-Hao-Tang

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    Hongyang Zhang

    2016-01-01

    Full Text Available Yin-Chen-Hao-Tang (YCHT is a famous Chinese medicine formula which has long been used in clinical practice for treating various liver diseases, such as liver fibrosis. However, to date, the mechanism for its anti-fibrotic effects remains unclear. In this paper, an ultra-performance liquid chromatography-time-of-flight mass spectrometry (UPLC-TOF-MS-based metabolomic study was performed to characterize dimethylnitrosamine (DMN-induced liver fibrosis in rats and evaluate the therapeutic effects of YCHT. Partial least squares-discriminant analysis (PLS-DA showed that the model group was well separated from the control group, whereas the YCHT-treated group exhibited a tendency to restore to the controls. Seven significantly changed fibrosis-related metabolites, including unsaturated fatty acids and lysophosphatidylcholines (Lyso-PCs, were identified. Moreover, statistical analysis demonstrated that YCHT treatment could reverse the levels of most metabolites close to the normal levels. These results, along with histological and biochemical examinations, indicate that YCHT has anti-fibrotic effects, which may be due to the suppression of oxidative stress and resulting lipid peroxidation involved in hepatic fibrogenesis. This study offers new opportunities to improve our understanding of liver fibrosis and the anti-fibrotic mechanisms of YCHT.

  3. Including osteoprotegerin and collagen IV in a score-based blood test for liver fibrosis increases diagnostic accuracy.

    Science.gov (United States)

    Bosselut, Nelly; Taibi, Ludmia; Guéchot, Jérôme; Zarski, Jean-Pierre; Sturm, Nathalie; Gelineau, Marie-Christine; Poggi, Bernard; Thoret, Sophie; Lasnier, Elisabeth; Baudin, Bruno; Housset, Chantal; Vaubourdolle, Michel

    2013-01-16

    Noninvasive methods for liver fibrosis evaluation in chronic liver diseases have been recently developed, i.e. transient elastography (Fibroscan™) and blood tests (Fibrometer®, Fibrotest®, and Hepascore®). In this study, we aimed to design a new score in chronic hepatitis C (CHC) by selecting blood markers in a large panel and we compared its diagnostic performance with those of other noninvasive methods. Sixteen blood tests were performed in 306 untreated CHC patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using METAVIR histological fibrosis stage as reference. The new score was constructed by non linear regression using the most accurate biomarkers. Five markers (alpha-2-macroglobulin, apolipoprotein-A1, AST, collagen IV and osteoprotegerin) were included in the new function called Coopscore©. Using the Obuchowski Index, Coopscore© shows higher diagnostic performances than for Fibrometer®, Fibrotest®, Hepascore® and Fibroscan™ in CHC. Association between Fibroscan™ and Coopscore© might avoid 68% of liver biopsies for the diagnosis of significant fibrosis. Coopscore© provides higher accuracy than other noninvasive methods for the diagnosis of liver fibrosis in CHC. The association of Coopscore© with Fibroscan™ increases its predictive value. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Modified citrus pectin stops progression of liver fibrosis by inhibiting galectin-3 and inducing apoptosis of stellate cells.

    Science.gov (United States)

    Abu-Elsaad, Nashwa M; Elkashef, Wagdi Fawzi

    2016-05-01

    Modified citrus pectin (MCP) is a pH modified form of the dietary soluble citrus peel fiber known as pectin. The current study aims at testing its effect on liver fibrosis progression. Rats were injected with CCl4 (1 mL/kg, 40% v/v, i.p., twice a week for 8 weeks). Concurrently, MCP (400 or 1200 mg/kg) was administered daily in drinking water from the first week in groups I and II (prophylactic model) and in the beginning of week 5 in groups III and IV (therapeutic model). Liver function biomarkers (ATL, AST, and ALP), fibrosis markers (laminin and hyaluronic acid), and antioxidant biomarkers (reduced glutathione (GSH) and superoxide dismutase (SOD)) were measured. Stained liver sections were scored for fibrosis and necroinflammation. Additionally, expression of galectin-3 (Gal-3), α-smooth muscle actin (SMA), tissue inhibitor metalloproteinase (TIMP)-1, collagen (Col)1A1, caspase (Cas)-3, and apoptosis related factor (FAS) were assigned. Modified pectin late administration significantly (p liver fibrosis through an antioxidant effect, inhibition of Gal-3 mediated hepatic stellate cells activation, and induction of apoptosis.

  5. 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.

  6. 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].

  7. Placental Growth Factor Contributes to Liver Inflammation, Angiogenesis, Fibrosis in Mice by Promoting Hepatic Macrophage Recruitment and Activation

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    Xi Li

    2017-07-01

    Full Text Available Placental growth factor (PlGF, a member of the vascular endothelial growth factor (VEGF family, mediates wound healing and inflammatory responses, exerting an effect on liver fibrosis and angiogenesis; however, the precise mechanism remains unclear. The aims of this study are to identify the role of PlGF in liver inflammation and fibrosis induced by bile duct ligation (BDL in mice and to reveal the underlying molecular mechanism. PlGF small interfering RNA (siRNA or non-targeting control siRNA was injected by tail vein starting 2 days after BDL. Liver inflammation, fibrosis, angiogenesis, macrophage infiltration, and hepatic stellate cells (HSCs activation were examined. Our results showed that PlGF was highly expressed in fibrotic livers and mainly distributed in activated HSCs and macrophages. Furthermore, PlGF silencing strongly reduced the severity of liver inflammation and fibrosis, and inhibited the activation of HSCs. Remarkably, PlGF silencing also attenuated BDL-induced hepatic angiogenesis, as evidenced by attenuated liver endothelial cell markers CD31 and von Willebrand factor immunostaining and genes or protein expression. Interestingly, these pathological ameliorations by PlGF silencing were due to a marked reduction in the numbers of intrahepatic F4/80+, CD68+, and Ly6C+ cell populations, which were reflected by a lower expression of these macrophage marker molecules in fibrotic livers. In addition, knockdown of PlGF by siRNA inhibited macrophages activation and substantially suppressed the expression of pro-inflammatory cytokines and chemokines in fibrotic livers. Mechanistically, evaluation of cultured RAW 264.7 cells revealed that VEGF receptor 1 (VEGFR1 mainly involved in mediating the role of PlGF in macrophages recruitment and activation, since using VEGFR1 neutralizing antibody blocking PlGF/VEGFR1 signaling axis significantly inhibited macrophages migration and inflammatory responses. Together, these findings indicate

  8. The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice

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    Xi Li

    2018-02-01

    Full Text Available At present, there are no effective antifibrotic drugs for patients with chronic liver disease; hence, the development of antifibrotic therapies is urgently needed. Here, we performed an experimental and translational study to investigate the potential and underlying mechanism of quercetin treatment in liver fibrosis, mainly focusing on the impact of quercetin on macrophages activation and polarization. BALB/c mice were induced liver fibrosis by carbon tetrachloride (CCl4 for 8 weeks and concomitantly treated with quercetin (50 mg/kg or vehicle by daily gavage. Liver inflammation, fibrosis, and hepatic stellate cells (HSCs activation were examined. Moreover, massive macrophages accumulation, M1 macrophages and their related markers, such as tumor necrosis factor (TNF-α, interleukin (IL-1β, IL-6, and monocyte chemotactic protein-1 (MCP-1 in livers were analyzed. In vitro, we used Raw 264.7 cells to examine the effect of quercetin on M1-polarized macrophages activation. Our results showed that quercetin dramatically ameliorated liver inflammation, fibrosis, and inhibited HSCs activation. These results were attributed to the reductive recruitment of macrophages (F4/80+ and CD68+ into the liver in quercetin-treated fibrotic mice confirmed by immunostaining and expression levels of marker molecules. Importantly, quercetin strongly inhibited M1 polarization and M1-related inflammatory cytokines in fibrotic livers when compared with vehicle-treated mice. In vitro, studies further revealed that quercetin efficiently inhibited macrophages activation and M1 polarization, as well as decreased the mRNA expression of M1 macrophage markers such as TNF-α, IL-1β, IL-6, and nitric oxide synthase 2. Mechanistically, the inhibition of M1 macrophages by quercetin was associated with the decreased levels of Notch1 expression on macrophages both in vivo and in vitro. Taken together, our data indicated that quercetin attenuated CCl4-induced liver inflammation and

  9. Association of MICA gene polymorphisms with liver fibrosis in schistosomiasis patients in the Dongting Lake region

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    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.

  10. Association of MICA gene polymorphisms with liver fibrosis in schistosomiasis patients in the Dongting Lake region

    International Nuclear Information System (INIS)

    Gong, Zheng; Luo, Qi-Zhi; Lin, Lin; Su, Yu-Ping; Peng, Hai-Bo; Du, Kun; Yu, Ping; Wang, Shi-Ping

    2012-01-01

    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

  11. Utility of shear-wave elastography to differentiate low from advanced degrees of liver fibrosis in patients with hepatitis C virus infection of native and transplant livers.

    Science.gov (United States)

    Rattansingh, Anand; Amooshahi, Hosein; Menezes, Ravi J; Wong, Florence; Fischer, Sandra; Kirsch, Richard; Atri, Mostafa

    2018-03-06

    To determine the accuracy of shear-wave elastography (SWE) to differentiate low from advanced degrees of liver fibrosis in hepatitis C patients. Consented native/transplant hepatitis C patients underwent SWE using a C1-6 MHz transducer before ultrasound (US)-guided liver biopsy. Five interpretable SWE samples were obtained from the right lobe of the liver immediately before US-guided random biopsy of the right lobe. Average kilopascal (kPa) values were compared to the meta-analysis of histological data in viral hepatitis (METAVIR) fibrosis grading. SWE values were correlated with the degree of inflammation and fatty infiltration. Study population consisted of 115 patients (63 with transplant, and 52 with native liver) including 29 women and 86 men, with a mean ± SD age of 56 ± 8.7 years. Mean ± SD SWE values were 7.9 ± 3 kPa in 83 patients with METAVIR scores of 0-2 and 13.2 ± 5.9 kPa in 32 patients with METAVIR scores of 3 or 4 (P  .05). for kPa threshold of SWE value of 10.67 kPa to differentiate advanced from low degree of fibrosis had a sensitivity of 59% (CI: 41%-76%) and specificity of 90% (CI: 82%-96%). Liver stiffness evaluated by SWE can differentiate low from advanced liver fibrosis. © 2018 Wiley Periodicals, Inc.

  12. Comparison of Histochemical Stainings in Evaluation of Liver Fibrosis and Correlation with Transient Elastography in Chronic Hepatitis

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    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.

  13. Utility of Aminotransferase/Platelet Ratio Index to Predict Liver Fibrosis in Intestinal Failure-Associated Liver Disease in Pediatric Patients.

    Science.gov (United States)

    Rumbo, Carolina; Martinez, María Inés; Cabanne, Ana; Trentadue, Julio; Fernández, Adriana; Gondolesi, Gabriel

    2017-07-01

    Intestinal failure-associated liver disease (IFALD) is a frequent indication for intestinal transplantation. Liver biopsy (LBX) is the gold standard test for its diagnosis. Identifying noninvasive markers of fibrosis progression would be of considerable clinical use. Aspartate aminotransferase/platelet ratio index (APRI) has a good correlation in adult patients with chronic liver disease; few studies have been performed in children with IFALD. To evaluate APRI in a cohort of children with IFALD. Retrospective analysis of a prospective database of patients failure and at least 1 LBX, registered in our unit from March 2006 to December 2014. Forty-nine LBX were done on 36 patients: 20 were male, and 31 had short gut. Fibrosis was found in 71% of LBX. Biopsies were grouped according to the fibrosis stage (METAVIR [M]): (1) group 1 (G1) LBX with M 0, 1, 2 (n = 33) and (2) group 2 (G2) LBX with M 3, 4 (n = 16). The median APRI score was 0.92 (interquartile range [IQR] 0.63-1.50) for G1 and 2.50 (IQR 1.81-5.82) for G2 ( P = .001) The c statistic of the receiving operating characteristic curve was 0.79 (95% CI 0.64-0.94; P 1.6 correlates with advanced fibrosis.

  14. Smoking is associated with severity of liver fibrosis but not with histological severity in nonalcoholic fatty liver disease. Results from a cross-sectional study.

    Science.gov (United States)

    Munsterman, Isabelle D; Smits, Mark M; Andriessen, Rene; van Nieuwkerk, Carin M J; Bloemena, Elisabeth; Mulder, Chris J J; Tjwa, Eric T T L; van Geenen, Erwin J M

    2017-08-01

    To assess the influence of smoking on histological disease severity and fibrosis in real-world NAFLD patients. Consecutive NAFLD patients were identified with liver biopsies performed between 2008 and 2015. Characteristics such as smoking status and total number of pack years were collected. Biopsies were revised and BRUNT fibrosis and NAFLD activity score (NAS) determined. Patients with a high NAS (≥5) were compared to patients with a low NAS (smoking (current or past smoker) were defined ever smokers. Fifty-six patients were included (mean age 49 ± 14.3, 68.9% males and 39.3% history of smoking). Ever smokers had a higher fibrosis score than never smokers; two (IQR 0-3) versus one (IQR 1-1.5) (p = .040). Patients with advanced fibrosis smoked significantly more pack years than patients with no-early fibrosis; 10.6 (IQR 0-25.8) versus 0 (IQR 0-7) (p = .011). There is a weak to moderate correlation between fibrosis stage and number of pack years (Spearman's Rho = 0.341, p = .012). There was no difference in NAS between never and ever smokers; 2.8 ± 1.5 versus 3.3 ± 1.4 (p = .205). Patients with NAS Smoking is associated with severity of NAFLD-related liver fibrosis but not with histological disease severity. This supports the recommendation to cease smoking for NAFLD patients.

  15. Effect of Angelica Sinensis on liver fibrosis after radiotherapy combined with transarterial chemoembolization for rabbits with VX 2 tumor

    International Nuclear Information System (INIS)

    Long Qingyun; Zhou Yunfeng; Hu Jinxiang; Zhou Jun; Le Tao

    2008-01-01

    Objective: To evaluate the effect of Angelica Sinensis on liver fibrosis after radiotherapy (RT) combined with transarterial chemoembolization(TACE) for rabbits with VX 2 tumor, and the mechanism of anti-hepatic fibrosis. Methods: Fifty New Zealand white rabbits were divided randomly into three groups: Control group (n=10) was given saline 2 ml by gastroduodenal artery, model group (n=10) was given pingyangmycin 1 mg and iodized oil 0.2 ml, and exposed to single fraction of 20 Gy, Angelica group (n=30) undergoing RT combined with TACE was given Angelica Sinensis injection. According to different doses of Angelica Sinensis, Angelica group was divided into low-dose group (4 ml/kg), middle dose group (6 ml/kg) and high-dose group (8 ml/kg), twice per week for 4 weeks. Serum levels of HA, LN, PCIII, CIV and liver specimens were obtained at the end of 6th week after RT combined with TACE. The histological changes were determined by HE, VG staining and TGF-β1 immunohistochemistry staining. Results: Stages of liver fibrosis in the model group were mostly stages II and III, and stages of liver fibrosis in the Angelica group were mostly stages I, there was significant difference between the model group and the Angelica group, and stages of liver fibrosis were associated with Angelica intercention treatment (r=0.7631, P<0.01). Serum HA, LN, PCIII and CIV in the model group were higher than those in the control group(P<0.01), TGF-β1 expression in the Angelica group was significantly reduced compared with the wodel group and different doses of Angelica group showed dose-effect (r=0.4427, P<0.01). Conclusions: Angelica Sinensis injection has inhibitive effect on liver fibrosis after RT combined with TACE for rabbits with VX 2 tumor, the mechanism of anti-hepatic fibrosis might possibly be associated with down-regulating TGF-β1. (authors)

  16. The Role of Ultrasound Imaging in the Definition of the Stage of Liver Fibrosis in Patients with Chronic Hepatitis C

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    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.

  17. Fibroscan Compared to FIB-4, APRI, and AST/ALT Ratio for Assessment of Liver Fibrosis in Saudi Patients With Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Fallatah, Hind I; Akbar, Hisham O; Fallatah, Alyaa M

    2016-07-01

    Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as a cause of chronic liver disease. It has also been associated with devastating outcomes such as decompensated liver cirrhosis and hepatocellular carcinoma, as well as diabetes and metabolic syndrome. This study was conducted in order to assess liver fibrosis using Fibroscan, and to compare these results to the use of Fibrosis-4 (FIB-4) scores, AST platelet ratio index (APRI scores), and the AST/ALT ratios on NAFLD patients. A cross sectional study was conducted on NAFLD patients who underwent Fibroscan examinations between September 1, 2011 and June 30, 2014. Demographic data was collected, including sex, age, and nationality; serum alanine aminotransferase levels (ALT, 30 - 65 U/L), serum aspartate aminotransferase levels (AST, 15 - 37 U/L), and platelet counts (150 - 400 k/μL) were also determined. The stages of fibrosis (F0 1 - 6, F1 6.1 - 7, F2 7 - 9, F3 9.1 - 10.3, and F4 ≥ 10.4) were defined in kPa. For each patient, the AST/ALT ratio was also measured. The results of APRI and FIB-4 were compared with the Fibroscan fibrosis scores. The results of 122 patients were analyzed, including 65 (53.3%) males with a mean age of 50.2 years (SD: 13.7; range: 18 - 86). The males were significantly younger than the females (48.7 years (SD: 16.03) versus 51.8 years (SD: 10.3 P = 0.05), respectively). The mean stiffness score was 12.02 (SD: 12.7) kPa. Forty-four patients (36%) had advanced fibrosis. The mean platelet and serum ALT levels were normal. There was a significant positive correlation between the Fibroscan results and the AST/ALT ratios, the APRI scores, and the FIB-4 results. Similarly, there was a significant positive correlation between age and fibrosis score, and a significant negative correlation between platelet count and stiffness score. The data showed that more than one-third of the cohort exhibited advanced fibrosis, demonstrating the need for the early diagnosis and

  18. Quantitative imaging: quantification of liver shape on CT using the statistical shape model to evaluate hepatic fibrosis.

    Science.gov (United States)

    Hori, Masatoshi; Okada, Toshiyuki; Higashiura, Keisuke; Sato, Yoshinobu; Chen, Yen-Wei; Kim, Tonsok; Onishi, Hiromitsu; Eguchi, Hidetoshi; Nagano, Hiroaki; Umeshita, Koji; Wakasa, Kenichi; Tomiyama, Noriyuki

    2015-03-01

    To investigate the usefulness of the statistical shape model (SSM) for the quantification of liver shape to evaluate hepatic fibrosis. Ninety-one subjects (45 men and 46 women; age range, 20-75 years) were included in this retrospective study: 54 potential liver donors and 37 patients with chronic liver disease. The subjects were classified histopathologically according to the fibrosis stage as follows: F0 (n = 55); F1 (n = 6); F2 (3); F3 (n = 1); and F4 (n = 26). Each subject underwent contrast-enhanced computed tomography (CT) using a 64-channel scanner (0.625-mm slice thickness). An abdominal radiologist manually traced the liver boundaries on every CT section using an image workstation; the boundaries were used for subsequent analyses. An SSM was constructed by the principal component analysis of the subject data set, which defined a parametric model of the liver shapes. The shape parameters were calculated by fitting SSM to the segmented liver shape of each subject and were used for the training of a linear support vector regression (SVR), which classifies the liver fibrosis stage to maximize the area under the receiver operating characteristic curve (AUC). SSM/SVR models were constructed and were validated in a leave-one-out manner. The performance of our technique was compared to those of two previously reported types of caudate-right lobe ratios (C/RL-m and C/RL-r). In our SSM/SVR models, the AUC values for the classification of liver fibrosis were 0.96 (F0 vs. F1-4), 0.95 (F0-1 vs. F2-4), 0.96 (F0-2 vs. F3-4), and 0.95 (F0-3 vs. F4). These values were significantly superior to AUC values using the C/RL-m or C/RL-r ratios (P < .005). SSM was useful for estimating the stage of hepatic fibrosis by quantifying liver shape. Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.

  19. 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.

  20. MHC II-, but not MHC II+, hepatic Stellate cells contribute to liver fibrosis of mice in infection with Schistosoma japonicum.

    Science.gov (United States)

    Zhou, Chun-Lei; Kong, De-Long; Liu, Jin-Feng; Lu, Zhong-Kui; Guo, Hong-Fei; Wang, Wei; Qiu, Jing-Fan; Liu, Xin-Jian; Wang, Yong

    2017-07-01

    Hepatic stellate cells (HSCs) are considered as the main effector cells in vitamin A metabolism and liver fibrosis, as well as in hepatic immune regulation. Recently, researches have revealed that HSCs have plasticity and heterogeneity, which depend on their lobular location and whether liver is normal or injured. This research aimed to explore the biological characteristics and heterogeneity of HSCs in mice with Schistosoma japonicum (S. japonicum) infection, and determine the subpopulation of HSCs in pathogenesis of hepatic fibrosis caused by S. japonicum infection. Results revealed that HSCs significantly increased the expressions of MHC II and fibrogenic genes after S. japonicum infection, and could be classified into MHC II + HSCs and MHC II - HSCs subsets. Both two HSCs populations suppressed the proliferation of activated CD4 + T cells, whereas only MHC II - HSCs displayed a myofibroblast-like phenotype. In response to IFN-γ, HSCs up-regulated the expressions of MHC II and CIITA, while down-regulated the expression of fibrogenic gene Col1. In addition, praziquantel treatment decreased the expressions of fibrogenic genes in MHC II - HSCs. These results confirmed that HSCs from S. japonicum-infected mice have heterogeneity. The MHC II - α-SMA + HSCs were major subsets of HSCs contributing to liver fibrosis and could be considered as a potential target of praziquantel anti-fibrosis treatment. Copyright © 2017. Published by Elsevier B.V.

  1. Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Young Eun Chon

    Full Text Available Transient elastography (TE, a non-invasive tool that measures liver stiffness, has been evaluated in meta-analyses for effectiveness in assessing liver fibrosis in European populations with chronic hepatitis C (CHC. However, these data cannot be extrapolated to populations in Asian countries, where chronic hepatitis B (CHB is more prevalent. In this study, we performed a meta-analysis to assess the overall performance of TE for assessing liver fibrosis in patients with CHB.Studies from the literature and international conference abstracts which enrolled only patients with CHB or performed a subgroup analysis of such patients were enrolled. Combined effects were calculated using area under the receiver operating characteristic curves (AUROC and diagnostic accuracy values of each study.A total of 18 studies comprising 2,772 patients were analyzed. The mean AUROCs for the diagnosis of significant fibrosis (F2, severe fibrosis (F3, and cirrhosis (F4 were 0.859 (95% confidence interval [CI], 0.857-0.860, 0.887 (95% CI, 0.886-0.887, and 0.929 (95% CI, 0.928-0.929, respectively. The estimated cutoff for F2 was 7.9 (range, 6.1-11.8 kPa, with a sensitivity of 74.3% and specificity of 78.3%. For F3, the cutoff value was determined to be 8.8 (range, 8.1-9.7 kPa, with a sensitivity of 74.0% and specificity of 63.8%. The cutoff value for F4 was 11.7 (range, 7.3-17.5 kPa, with a sensitivity of 84.6% and specificity of 81.5%.TE can be performed with good diagnostic accuracy for quantifying liver fibrosis in patients with CHB.

  2. A Simple Diet- and Chemical-Induced Murine NASH Model with Rapid Progression of Steatohepatitis, Fibrosis and Liver Cancer.

    Science.gov (United States)

    Tsuchida, Takuma; Lee, Youngmin A; Fujiwara, Naoto; Ybanez, Maria; Allen, Brittany; Martins, Sebastiao; Fiel, M Isabel; Goossens, Nicolas; Chou, Hsin-I; Hoshida, Yujin; Friedman, Scott L

    2018-03-20

    Although the majority of patients with nonalcoholic fatty liver disease (NAFLD) have only steatosis without progression, a sizable fraction develop non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis and hepatocellular carcinoma (HCC). Many established diet-induced mouse models for NASH require 24-52 weeks, which makes testing for drug response costly and time consuming. We have sought to establish a murine NASH model with rapid progression of extensive fibrosis and HCC by using a western diet (WD), which is high-fat, high-fructose and high-cholesterol, combined with low dose weekly intraperitoneal carbon tetrachloride (CCl 4 ), which served as an accelerator. C57BL/6J mice were fed a normal chow diet (ND) ± CCl 4 or WD ± CCl 4 for 12 and 24 weeks. Addition of CCl 4 exacerbated histological features of NASH, fibrosis, and tumor development induced by WD, which resulted in stage 3 fibrosis at 12 weeks and HCC development at 24 weeks. Furthermore, whole liver transcriptomic analysis indicated that dysregulated molecular pathways in WD/CCl 4 mice and immunologic features were closely similar to those of human NASH. Our mouse NASH model exhibits rapid progression of advanced fibrosis and HCC, and mimics histological, immunological and transcriptomic features of human NASH, suggesting that it will be a useful experimental tool for preclinical drug testing. A carefully characterized model has been developed in mice that recapitulates the progressive stages of human fatty liver disease, from simple steatosis, to inflammation, fibrosis and cancer. The functional pathways of gene expression and immune abnormalities in this model closely resemble human disease. The ease and reproducibility of this model makes it ideal to study disease pathogenesis and test new treatments. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  3. Enhanced liver fibrosis test in patients with psoriasis, psoriatic arthritis and rheumatoid arthritis : A cross-sectional comparison with procollagen-3 N-terminal peptide (P3NP)

    NARCIS (Netherlands)

    E.A.M. van der Voort (Ella); M. Wakkee (Marlies); P. Veldt-Kok; S. Darwish Murad (Sarwa); T.E.C. Nijsten (Tamar)

    2016-01-01

    markdownabstractBackground: The enhanced liver fibrosis (ELF) test has been introduced to screen, diagnose and/or monitor liver conditions in large groups of patients with liver diseases. It has not been used in inflammatory skin or joint diseases. Objectives: To evaluate the distribution of the

  4. The acitretin and methotrexate combination therapy for psoriasis vulgaris achieves higher effectiveness and less liver fibrosis.

    Science.gov (United States)

    An, Jingang; Zhang, Dingwei; Wu, Jiawen; Li, Jiong; Teng, Xiu; Gao, Xiaomin; Li, Ruilian; Wang, Xiuying; Xia, Linlin; Xia, Yumin

    2017-07-01

    Both acitretin and methotrexate are effective in ameliorating psoriatic lesion. However, their combination has been seldom reported in the treatment of psoriasis because of the warning regarding the potential hepatotoxicity of the drug interactions. This study was designed to investigate the effectiveness of such combination therapy for psoriasis vulgaris, and the potential benefit as well as side effect during the treatment. Thirty-nine patients with psoriasis vulgaris were treated with acitretin, methotrexate or their combination or as control. Similarly, K14-VEGF transgenic psoriasis-like mice were treated with these drugs. Human primary keratinocytes and hepatic stellate cells were used for analyzing their effect in vitro. The results showed that the combination therapy exhibited higher effectiveness in remitting skin lesion, but did not significantly affect the liver function of both patients and mice. Moreover, the combination groups showed less elevation of profibrotic factors in sera when compared with methotrexate alone groups accordingly. Furthermore, primary keratinocytes expressed more involucrin as well as loricrin and proliferated more slowly on the combined stimulation. Interestingly, such combination treatment induced lower expression of profibrotic factors in hepatic stellate cells. In conclusion, the acitretin-methotrexate combination therapy for psoriasis vulgaris can achieve higher effectiveness and result in less liver fibrosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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

    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......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 collagen-proportionate area were used as reference. METHODS: We performed a prospective study of 199 consecutive patients with ongoing or prior alcohol abuse, but without known liver disease. One group of patients had a high pretest probability of cirrhosis because they were identified at hospital liver...

  7. Development of a non-invasive model to improve the accuracy of determining liver fibrosis stage in nonalcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Yu.M. Stepanov

    2017-11-01

    Full Text Available Background. The differentiation of mild (F1-F2 and advanced fibrosis (F3-F4, as well as the exclusion of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD, are extremely important for prediction of the disease course. Integrative analyses of serum markers have been proposed as promising alternatives to biopsy method. Our study was targeted to develop a new model for determining the stage of fibrosis based on a more efficient combination of serological markers and to compare it with well-established algorithms. Materials and methods. Sixty patients with biopsy-proven NAFLD, including 26 (43 % men and 34 (57 % women, with average age of 37.10 ± 12.4 and 44.30 ± 7.25 years, respectively, were recruited for the study. Particularly, advanced fibrosis was diagnosed in 8 patients, 28 had mild fibrosis and 24 didn’t have any fibrosis according to morphological study. The following fibrosis markers were calculated: aspartate aminotransferase and alanine aminotransferase ratio (AAR, aspartate aminotransferase to platelet ratio index (APRI, fibrosis index based on the 4 factor (FIB-4. Among many variables, hyaluronic acid, α2-macroglobulin, apolipoprotein A1, fibronectin, and haptoglobin were included in comprehensive study. Integrative model have been built up to determine the stage of fibrosis. The models were compared with the area under the receiver operating characteristic (AUROC curves. Results. The ROC analysis showed that the FIB-4 demonstrated the largest AUROC, for the F2 — 0.72, F3 — 0.8, F4 — 0.82, respectively. Obtained results of the APRI were significantly higher for mild and advanced fibrosis (F2 — 0.74, F3 — 0.82. The AAR values were reliable only for liver cirrhosis (AUROC 0.89. A strong direct correlation was determined between the stage of fibrosis and the level of hyaluronic acid, α2-macroglobulin and fibronectin (r = 0.72, 0.93 and 0.71, p < 0.05, respectively. Whereas, we observed a moderate negative

  8. The influence of hepatic steatosis on the evaluation of fibrosis with non-alcoholic fatty liver disease by acoustic radiation force impulse.

    Science.gov (United States)

    Yanrong Guo; Haoming Lin; Xinyu Zhang; Huiying Wen; Siping Chen; Xin Chen

    2017-07-01

    Acoustic radiation force impulse (ARFI) elastography is a non-invasive method for the assessment of liver by measuring liver stiffness. The aim of this study is to evaluate the accuracy of ARFI for the diagnosis of liver fibrosis and to assess impact of steatosis on liver fibrosis stiffness measurement, in rats model of non-alcoholic fatty liver disease (NAFLD). The rat models were conducted in 59 rats. The right liver lobe was processed and embedded in a fabricated gelatin solution. Liver mechanics were measured using shear wave velocity (SWV) induced by acoustic radiation force. In rats with NAFLD, the diagnostic performance of ARFI elastography in predicting severe fibrosis (F ≥ 3) and cirrhosis (F ≥ 4) had the areas under the receiver operating characteristic curves (AUROC) of 0.993 and 0.985. Among rats mean SWV values were significantly higher in rats with severe steatosis by histology compared to those mild or without steatosis for F0-F2 fibrosis stages (3.07 versus 2.51 m/s, P = 0.01). ARFI elastography is a promising method for staging hepatic fibrosis with NAFLD in rat models. The presence of severe steatosis is a significant factor for assessing the lower stage of fibrosis.

  9. The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin.

    Directory of Open Access Journals (Sweden)

    Jessica L Feig

    Full Text Available Fibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection. Belonging to the class of acyclic nucleoside phosphonates, tenofovir is an analogue of AMP. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis.Thioacetamide (100mg/kg IP-treated mice were treated with vehicle, or tenofovir (75mg/kg, SubQ (n = 5-10. Bleomycin (0.25U, SubQ-treated mice were treated with vehicle or tenofovir (75mg/kg, IP (n = 5-10. Adenosine levels were determined by HPLC, and ATP release was quantitated as luciferase-dependent bioluminescence. Skin breaking strength was analysed and H&E and picrosirus red-stained slides were imaged. Pannexin-1expression was knocked down following retroviral-mediated expression of of Pannexin-1-specific or scrambled siRNA.Treatment of mice with tenofovir diminished adenosine release from the skin of bleomycin-treated mice and the liver of thioacetamide-treated mice, models of diffuse skin fibrosis and hepatic cirrhosis, respectively. More importantly, tenofovir treatment diminished skin and liver fibrosis in these models. Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1.These studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases.

  10. 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

    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 pres......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...... 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...... 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....

  11. Liver fibrosis changes in HIV-HBV-coinfected patients: clinical, biochemical and histological effect of long-term tenofovir disoproxil fumarate use.

    Science.gov (United States)

    Boyd, Anders; Lasnier, Elisabeth; Molina, Jean Michel; Lascoux-Combe, Caroline; Bonnard, Philippe; Miailhes, Patrick; Wendum, Dominique; Meynard, Jean-Luc; Girard, Pierre-Marie; Lacombe, Karine

    2010-01-01

    Data on liver fibrosis evolution in HIV-HBV-coinfected patients treated with tenofovir disoproxil fumarate (TDF) are scarce. The effect of TDF on liver fibrosis in 148 HIV-HBV-coinfected patients was prospectively evaluated using Fibrometer∆ scores and liver biopsies in a subset of patients. The mean change from baseline (Δ) in Fibrometer score was modelled using a generalized estimating equation. Homogeneous continuous-time Markov models were used to study risk factors for regression or progression of liver fibrosis. Median follow-up of patients treated with TDF was 29.5 months (25th-75th percentile 20.9-38.1). The distribution of scored fibrosis at TDF initiation was F0-F1 n=65, F2 n=37 and F3-F4 n=46. In patients with a baseline fibrosis score of F3-F4, Fibrometer score decreased with a triphasic shape (Fibrometer Δ at 12, 24 and 36 months after TDF initiation was -0.079, -0.069 and -0.102, respectively). Despite duration on TDF, higher fibrosis scores were noted in F3-F4 patients with high HBV viral load and HDV coinfection, and in F0-F2 patients who had high HBV viral load and low CD4(+) T-cell count. Progression in fibrosis score over time was influenced by age, alcohol consumption, low CD4(+) T-cell count and HCV coinfection, whereas HDV coinfection and longer duration of HBV infection prevented fibrosis regression. No influence of antiretrovirals other than TDF was found. The use of TDF in HIV-HBV-coinfected patients led to a decrease in liver fibrosis score in patients with advanced fibrosis or cirrhosis. Sustainability of its direct antiviral and indirect antifibrotic effects on the liver need to be studied further.

  12. Mucosal-associated invariant T-cell frequency and function in blood and liver of HCV mono- and HCV/HIV co-infected patients with advanced fibrosis.

    Science.gov (United States)

    Beudeker, Boris J B; van Oord, Gertine W; Arends, Joop E; Schulze Zur Wiesch, Julian; van der Heide, Marieke S; de Knegt, Robert J; Verbon, Annelies; Boonstra, Andre; Claassen, Mark A A

    2018-03-01

    Mucosal-associated invariant T (MAIT) cells are important innate T cells with antimicrobial and immunoregulatory activity, recently found to be depleted in blood of patients with HIV and HCV mono-infections. In this study, we assessed the impact of HIV, HCV and HCV/HIV co-infection on circulating and intrahepatic MAIT-cells and correlations with liver fibrosis. In this cross-sectional study, nine healthy subjects, nine HIV, 20 HCV and 22 HCV/HIV co-infected patients were included. Blood and liver fine needle aspirate biopsies were studied using flowcytometry for CD3 + CD161 + Vα7.2 + MAIT-cell frequency, phenotype and function in HCV mono-infected and HCV/HIV co-infected patients without or with mild fibrosis (Metavir-score F0-F1) or severe fibrosis to cirrhosis (Metavir-score F3-F4). Circulating MAIT-cells were decreased in blood of HCV, HIV and HCV/HIV patients with F0-F1. In HCV/HIV co-infected individuals with severe fibrosis to cirrhosis, the frequency of circulating MAIT-cells was even further depleted, whereas their function was comparable to HCV/HIV co-infected patients with low or absent fibrosis. In contrast, in HCV mono-infected patients, MAIT-cell frequencies were not related to fibrosis severity; however, MAIT-cell function was impaired in mono-infected patients with more fibrosis. More advanced liver fibrosis in HCV or HCV/HIV-infected patients was not reflected by increased accumulation of MAIT-cells in the affected liver. Severe liver fibrosis is associated with dysfunctional MAIT-cells in blood of HCV mono-infected patients, and lower MAIT frequencies in blood of HCV/HIV co-infected patients, without evidence for accumulation in the liver. © 2017 The Authors. Liver International Published by John Wiley & Sons Ltd.

  13. Role of the Aspartate Transaminase and Platelet Ratio Index in Assessing Hepatic Fibrosis and Liver Inflammation in Adolescent Patients with HBeAg-Positive Chronic Hepatitis B

    Directory of Open Access Journals (Sweden)

    Yu Zhijian

    2015-01-01

    Full Text Available This study described an index of aspartate aminotransferase-to-platelet ratio index (APRI to assess hepatic fibrosis with limited expense and widespread availability compared to the liver biopsy in adolescent patients with CHB.

  14. Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis

    DEFF Research Database (Denmark)

    Veidal, Sanne S.; Karsdal, Morten A.; Nawrocki, Arkadiusz

    2011-01-01

    Collagen deposition and an altered matrix metalloproteinase (MMP) expression profile are hallmarks of fibrosis. Type IV collagen is the most abundant structural basement membrane component of tissue, which increases 14-fold during fibrogenesis in the liver. Proteolytic degradation of collagens...

  15. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury.

    Science.gov (United States)

    Moustafa, Tarek; Fickert, Peter; Magnes, Christoph; Guelly, Christian; Thueringer, Andrea; Frank, Sasa; Kratky, Dagmar; Sattler, Wolfgang; Reicher, Helga; Sinner, Frank; Gumhold, Judith; Silbert, Dagmar; Fauler, Günter; Höfler, Gerald; Lass, Achim; Zechner, Rudolf; Trauner, Michael

    2012-01-01

    The liver controls central processes of lipid and bile acid homeostasis. We aimed to investigate whether alterations in lipid metabolism contribute to the pathogenesis of chronic cholestatic liver disease in mice. We used microarray and metabolic profiling analyses to identify alterations in systemic and hepatic lipid metabolism in mice with disruption of the gene ATP-binding cassette sub-family B member 4 (Abcb4(-/-) mice), a model of inflammation-induced cholestatic liver injury, fibrosis, and cancer. Alterations in Abcb4(-/-) mice, compared with wild-type mice, included deregulation of genes that control lipid synthesis, storage, and oxidation; decreased serum levels of cholesterol and phospholipids; and reduced hepatic long-chain fatty acyl-CoAs (LCA-CoA). Feeding Abcb4(-/-) mice the side chain-modified bile acid 24-norursodeoxycholic acid (norUDCA) reversed their liver injury and fibrosis, increased serum levels of lipids, lowered phospholipase and triglyceride hydrolase activities, and restored hepatic LCA-CoA and triglyceride levels. Additional genetic and nutritional studies indicated that lipid metabolism contributed to chronic cholestatic liver injury; crossing peroxisome proliferator-activated receptor (PPAR)-α-deficient mice with Abcb4(-/-) mice (to create double knockouts) or placing Abcb4(-/-) mice on a high-fat diet protected against liver injury, with features similar to those involved in the response to norUDCA. Placing pregnant Abcb4(-/-) mice on high-fat diets prevented liver injury in their offspring. However, fenofibrate, an activator of PPARα, aggravated liver injury in Abcb4(-/-) mice. Alterations in lipid metabolism contribute to the pathogenesis and progression of cholestatic liver disease in mice. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Drug-induced Liver Fibrosis: Testing Nevirapine in a Viral-like Liver Setting Using Histopathology, MALDI IMS, and Gene Expression.

    Science.gov (United States)

    Brown, H Roger; Castellino, Stephen; Groseclose, M Reid; Elangbam, Chandikumar S; Mellon-Kusibab, Kathryn; Yoon, Lawrence W; Gates, Lisa D; Krull, David L; Cariello, Neal F; Arrington-Brown, Leigh; Tillman, Tony; Fowler, Serita; Shah, Vishal; Bailey, David; Miller, Richard T

    2016-01-01

    Nevirapine (NVP) is associated with hepatotoxicity in 1-5% of patients. In rodent studies, NVP has been shown to cause hepatic enzyme induction, centrilobular hypertrophy, and skin rash in various rat strains but not liver toxicity. In an effort to understand whether NVP is metabolized differently in a transiently inflamed liver and whether a heightened immune response alters NVP-induced hepatic responses, female brown Norway rats were dosed with either vehicle or NVP alone (75 mg/kg/day for 15 days) or galactosamine alone (single intraperitoneal [ip] injection on day 7 to mimic viral hepatitis) or a combination of NVP (75/100/150 mg/kg/day for 15 days) and galactosamine (single 750 mg/kg ip on day 7). Livers were collected at necropsy for histopathology, matrix-assisted laser desorption/ionization imaging mass spectrometry and gene expression. Eight days after galactosamine, hepatic fibrosis was noted in rats dosed with the combination of NVP and galactosamine. No fibrosis occurred with NVP alone or galactosamine alone. Gene expression data suggested a viral-like response initiated by galactosamine via RNA sensors leading to apoptosis, toll-like receptor, and dendritic cell responses. These were exacerbated by NVP-induced growth factor, retinol, apoptosis, and periostin effects. This finding supports clinical reports warning against exacerbation of fibrosis by NVP in patients with hepatitis C. © The Author(s) 2016.

  17. Pentraxin 3 Is a Predictor for Fibrosis and Arterial Stiffness in Patients with Nonalcoholic Fatty Liver Disease

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    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.

  18. Diagnostic value of FIB-4 for liver fibrosis in patients with hepatitis B: a meta-analysis of diagnostic test.

    Science.gov (United States)

    Yin, Zhi; Zou, Jin; Li, Qiongxuan; Chen, Lizhang

    2017-04-04

    This study is aimed at evaluating the diagnostic value of FIB-4 for liver fibrosis in patients with hepatitis B through a meta-analysis of diagnostic test. We conducted a comprehensive search in the Pubmed, Embase, Web of Science, and Chinese National Knowledge Infrastructure before October 31, 2016. Stata 14.0 software was used for calculation and statistical analyses. We used the sensitivity, specificity, positive and negative likelihood ratio (PLR, NLR), diagnostic odds ratio (DOR) and 95% confidence intervals (CIs) to evaluate the diagnostic value of FIB-4 for liver fibrosis in patients with hepatitis B. Twenty-six studies were included in the final analyses, with a total of 8274 individuals. The pooled parameters are calculated from all studies: sensitivity of 0.69 (95%CI:0.63-0.75), specificity of 0.81 (95%CI: 0.73-0.87), PLR of 3.63 (95%CI:2.66-4.94), NLR of 0.38 (95%CI:0.32-0.44), DOR of 9.57 (95%CI: 6.67-13.74), and area under the curve (AUC) of 0.80 (95%CI: 0.76-0.83). We also conducted subgroup based on the range of cut-off values. Results from subgroup analysis showed that cut-off was the source of heterogeneity in the present study. The sensitivity and specificity of cut-off>2 were 0.69 and 0.95 with the AUC of 0.90 (95%CI: 0.87-0.92). The overall diagnostic value of FIB-4 is not very high for liver fibrosis in patients with hepatitis B. However, the diagnostic value is affected by the cut-off value. FIB-4 has relatively high diagnostic value for detecting liver fibrosis in patients with hepatitis B when the diagnostic threshold value is more than 2.0.

  19. Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD).

    Science.gov (United States)

    Verma, Siddharth; Jensen, Donald; Hart, John; Mohanty, Smruti R

    2013-10-01

    Non-alcoholic fatty liver disease (NAFLD) patients with elevated serum alanine aminotransferase (ALT) generally undergo a liver biopsy to evaluate for possible non-alcoholic steatohepatitis (NASH) or advanced fibrosis. However, patients with normal ALT could also have advanced stages of NAFLD. To determine ALT value that will accurately predict NASH and advanced fibrosis using area under the receiver operating characteristics curve (AUROC) analysis. Demographic, clinical and laboratory data of an ethnically diverse cohort of biopsy proven NAFLD patients were retrospectively analysed under univariate and multivariate analyses. Liver biopsies were scored using NASH clinical research network (NASH CRN) system. AUROC were performed for NAFLD Activity Score ≥5 (NASH) and fibrosis score ≥2 (advanced fibrosis). Two hundred and twenty-two patients were analysed. Fifty six (23%) had normal ALT. There was no difference in the rate of advanced fibrosis between normal and elevated ALT (26.8% vs. 18.1%, P = 0.19). However, significantly lower percentage of normal ALT group had NASH compared with elevated ALT group (10.7% vs. 28.9%, P ALT group had NASH or advanced fibrosis, whereas 53% of elevated ALT had no NASH or advanced fibrosis. Higher ALT values correlated with higher specificity, but lower sensitivity for both NASH and advanced fibrosis. AUROC for ALT level correlating NASH and advanced fibrosis were 0.62 and 0.46 respectively. There is no optimal ALT level to predict NASH and advanced fibrosis. Metabolic risk factors should be evaluated to select patients for a liver biopsy to confirm NASH and advanced fibrosis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Andrographolide Ameliorates Liver Fibrosis in Mice: Involvement of TLR4/NF-κB and TGF-β1/Smad2 Signaling Pathways

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    Liteng Lin

    2018-01-01

    Full Text Available Liver fibrosis is characterized by activated hepatic stellate cells (HSC and extracellular matrix accumulation. Blocking the activation of HSC and the inflammation response are two major effective therapeutic strategies for liver fibrosis. In addition to the long history of using andrographolide (Andro for inflammatory disorders, we aimed at elucidating the pharmacological effects and potential mechanism of Andro on liver fibrosis. In this study, liver fibrosis was induced by carbon tetrachloride (CCl4 and the mice were intraperitoneally injected with Andro for 6 weeks. HSC cell line (LX-2 and primary HSC were also treated with Andro in vitro. Treatment of CCl4-induced mice with Andro decreased the levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST, Sirius red staining as well as the expression of α smooth muscle actin (α-SMA and transforming growth factor- (TGF- β1. Furthermore, the expression of Toll-like receptor (TLR4 and NF-κB p50 was also inhibited by Andro. Additionally, in vitro data confirmed that Andro treatment not only attenuated the expression of profibrotic and proinflammatory factors but also blocked the TGF-β1/Smad2 and TLR4/NF-κB p50 pathways. These results demonstrate that Andro prevents liver inflammation and fibrosis, which is in correlation with the inhibition of the TGF-β1/Smad2 and TLR4/NF-κB p50 pathways, highlighting Andro as a potential therapeutic strategy for liver fibrosis.

  1. Long-chain PUFA in Granulocytes, Mononuclear Cells, and RBC in Patients With Cystic Fibrosis: Relation to Liver Disease

    DEFF Research Database (Denmark)

    Jorgensen, Marianne H.; Ott, Peter; Michaelsen, Kim F.

    2012-01-01

    -related liver disease were matched with 20 CF patients without. Blood samples were analysed for liver biochemistry and haematology. Granulocytes, mononuclear cells, and RBC were separated by density gradient centrifugation, and fatty acid composition was measured by gas chromatography. Hepatic ultrasound......Background and Aim: Patients with cystic fibrosis (CF) have low levels of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) in plasma or red blood cells (RBC), as also seen in other chronic and acute liver diseases. The differences may be more pronounced in CF transmembrane conductance...... of liver disease was negatively associated with LCPUFA n-3 levels in CFTR-expressing white blood cells but unrelated to those levels in CFTR-negative RBC....

  2. Effect of “treating liver by nourishing spleen” on gut microbiota in rats with liver fibrosis based on Xiaoyao powder and its separated recipe

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    CHEN Bin

    2016-04-01

    Full Text Available ObjectiveTo investigate the possible mechanism of “treating liver by nourishing spleen” in the treatment of liver fibrosis with reference to the effect of Xiaoyao powder and its separated recipe on gut microbiota and the level of portal endotoxins. MethodsA total of 70 healthy Wistar rats were randomly divided into blank group (10 rats, model group (20 rats, experimental group (20 rats, and control group (20 rats, and tail vein injection of bovine serum albumin was performed for 8 weeks to establish a rat model of immune liver fibrosis. The rats in the experimental group were given Xiaoyao granules by gavage, and those in the control group were given Xiaoyao granules without the spleen-strengthening traditional Chinese medicines Atractylodes macrocephala Koidz., Poria cocos, ginger, and Radix Glycyrrhizae Preparata by gavage. Serum aminotransferases, liver pathology, portal endotoxins, and the enterobacterial repetitive intergenic consensus (ERIC-PCR fingerprint of gut microbiota were observed in each group. The analysis of variance was applied for comparison of continuous data with homogeneity of variance between multiple groups, and the least significant difference t-test was used for further comparison between any two groups; the Tamhane’s method was applied for data with heterogeneity of variance; the Pearson correlation analysis was used for correlation analysis. ResultsCompared with the blank group, the model group showed changes in the diversity and structure of gut microbiota and an increase in the level of portal endotoxins (0.421±0.170 EU/ml vs 0.784±0.180 EU/ml, which showed significant differences between these two groups (P<0.01, and the level of portal endotoxins was positively correlated with collagen area percentage in liver tissue(r=0736,P<001. Compared with the model group, the experimental group had significantly reduced levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST, and portal

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

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    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.

  4. Non-Invasive Assessment of Hepatic Fibrosis by Elastic Measurement of Liver Using Magnetic Resonance Tagging Images

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    Xuejun Zhang

    2018-03-01

    Full Text Available To date, the measurement of the stiffness of liver requires a special vibrational tool that limits its application in many hospitals. In this study, we developed a novel method for automatically assessing the elasticity of the liver without any use of contrast agents or mechanical devices. By calculating the non-rigid deformation of the liver from magnetic resonance (MR tagging images, the stiffness was quantified as the displacement of grids on the liver image during a forced exhalation cycle. Our methods include two major processes: (1 quantification of the non-rigid deformation as the bending energy (BE based on the thin-plate spline method in the spatial domain and (2 calculation of the difference in the power spectrum from the tagging images, by using fast Fourier transform in the frequency domain. By considering 34 cases (17 normal and 17 abnormal liver cases, a remarkable difference between the two groups was found by both methods. The elasticity of the liver was finally analyzed by combining the bending energy and power spectral features obtained through MR tagging images. The result showed that only one abnormal case was misclassified in our dataset, which implied our method for non-invasive assessment of liver fibrosis has the potential to reduce the traditional liver biopsy.

  5. Cytokines, hepatic cell profiling and cell interactions during bone marrow cell therapy for liver fibrosis in cholestatic mice.

    Directory of Open Access Journals (Sweden)

    Daphne Pinheiro

    Full Text Available Bone marrow cells (BMC migrate to the injured liver after transplantation, contributing to regeneration through multiple pathways, but mechanisms involved are unclear. This work aimed to study BMC migration, characterize cytokine profile, cell populations and proliferation in mice with liver fibrosis transplanted with GFP+ BMC. Confocal microscopy analysis showed GFP+ BMC near regions expressing HGF and SDF-1 in the fibrotic liver. Impaired liver cell proliferation in fibrotic groups was restored after BMC transplantation. Regarding total cell populations, there was a significant reduction in CD68+ cells and increased Ly6G+ cells in transplanted fibrotic group. BMC contributed to the total populations of CD144, CD11b and Ly6G cells in the fibrotic liver, related to an increment of anti-fibrotic cytokines (IL-10, IL-13, IFN-γ and HGF and reduction of pro-inflammatory cytokines (IL-17A and IL-6. Therefore, HGF and SDF-1 may represent important chemoattractants for transplanted BMC in the injured liver, where these cells can give rise to populations of extrahepatic macrophages, neutrophils and endothelial progenitor cells that can interact synergistically with other liver cells towards the modulation of an anti-fibrotic cytokine profile promoting the onset of liver regeneration.

  6. Liver fibrosis in treatment-naïve HIV-infected and HIV/HBV co-infected patients: Zambia and Switzerland compared.

    Science.gov (United States)

    Wandeler, Gilles; Mulenga, Lloyd; Vinikoor, Michael J; Kovari, Helen; Battegay, Manuel; Calmy, Alexandra; Cavassini, Matthias; Bernasconi, Enos; Schmid, Patrick; Bolton-Moore, Carolyn; Sinkala, Edford; Chi, Benjamin H; Egger, Matthias; Rauch, Andri

    2016-10-01

    To examine the association between hepatitis B virus (HBV) infection and liver fibrosis in HIV-infected patients in Zambia and Switzerland. HIV-infected adults starting antiretroviral therapy in two clinics in Zambia and Switzerland were included. Liver fibrosis was evaluated using the aspartate aminotransferase-to-platelet-ratio index (APRI), with a ratio >1.5 defining significant fibrosis and a ratio >2.0 indicating cirrhosis. The association between hepatitis B surface antigen (HBsAg) positivity, HBV replication, and liver fibrosis was examined using logistic regression. In Zambia, 96 (13.0%) of 739 patients were HBsAg-positive compared to 93 (4.5%) of 2058 in Switzerland. HBsAg-positive patients were more likely to have significant liver fibrosis than HBsAg-negative ones: the adjusted odds ratio (aOR) was 3.25 (95% confidence interval (CI) 1.44-7.33) in Zambia and 2.50 (95% CI 1.19-5.25) in Switzerland. Patients with a high HBV viral load (≥20000 IU/ml) were more likely to have significant liver fibrosis compared to HBsAg-negative patients or patients with an undetectable viral load: aOR 3.85 (95% CI 1.29-11.44) in Zambia and 4.20 (95% CI 1.64-10.76) in Switzerland. In both settings, male sex was a strong risk factor for significant liver fibrosis. Despite the differences in HBV natural history between Sub-Saharan Africa and Europe, the degree of liver fibrosis and the association with important risk factors were similar. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  7. Liver Fibrosis in Treatment-naïve HIV-infected and HIV/HBV-coinfected Patients: Zambia and Switzerland Compared

    Science.gov (United States)

    Wandeler, Gilles; Mulenga, Lloyd; Vinikoor, Michael J.; Kovari, Helen; Battegay, Manuel; Calmy, Alexandra; Cavassini, Matthias; Bernasconi, Enos; Schmid, Patrick; Bolton-Moore, Carolyn; Sinkala, Edford; Chi, Benjamin H.; Egger, Matthias; Rauch, Andri

    2016-01-01

    Objective To examine the association between HBV infection and liver fibrosis in HIV-infected patients in Zambia and Switzerland. Design and Methods We included HIV-infected adults starting antiretroviral therapy in two clinics in Zambia and Switzerland. Liver fibrosis was evaluated using the AST-to-Platelet-Ratio Index (APRI), with a ratio >1.5 defining significant fibrosis and >2.0 cirrhosis. The association between HBsAg-positivity, HBV replication and liver fibrosis was examined using logistic regression. Results In Zambia 96 (13.0%) of 739 patients were HBsAg-positive compared to 93 (4.5%) of 2,058 in Switzerland. HBsAg-positive patients were more likely to have significant liver fibrosis than HBsAg-negative ones: the adjusted odds ratio (aOR) was 3.25 (95% CI 1.44-7.33) in Zambia and 2.50 (1.19-5.25) in Switzerland. Patients with high HBV viral load (≥20,000 UI/mL) were more likely to have significant liver fibrosis compared to HBsAg-negative patients or patients with undetectable viral load: aOR 3.85 (1.29-11.44) in Zambia and 4.20 (1.64-10.76) in Switzerland. In both settings male sex was a strong risk factor for significant liver fibrosis. Conclusions Despite the differences in HBV natural history between sub-Saharan Africa and Europe, the degree of liver fibrosis and the association with important risk factors were similar. PMID:27596685

  8. Diethylcarbamazine Reduces Chronic Inflammation and Fibrosis in Carbon Tetrachloride- (CCl4- Induced Liver Injury in Mice

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    Sura Wanessa Santos Rocha

    2014-01-01

    Full Text Available This study investigated the anti-inflammatory effects of DEC on the CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation was induced by i.p. administration of CCl4 0.5 μL/g of body weight through two injections a week for 6 weeks. DEC (50 mg/kg was administered by gavage for 12 days before finishing the CCl4 induction. Histological analyses of the DEC-treated group exhibited reduced inflammatory process and prevented liver necrosis and fibrosis. Immunohistochemical and immunofluorescence analyses of the DEC-treated group showed reduced COX-2, IL1β, MDA, TGF-β, and αSMA immunopositivity, besides exhibiting decreased IL1β, COX-2, NFκB, IFNγ, and TGFβ expressions in the western blot analysis. The DEC group enhanced significantly the IL-10 expression. The reduction of hepatic injury in the DEC-treated group was confirmed by the COX-2 and iNOS mRNA expression levels. Based on the results of the present study, DEC can be used as a potential anti-inflammatory drug for chronic hepatic inflammation.

  9. In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis.

    Science.gov (United States)

    Africa, Jonathan A; Behling, Cynthia A; Brunt, Elizabeth M; Zhang, Nan; Luo, Yunjun; Wells, Alan; Hou, Jiayi; Belt, Patricia H; Kohil, Rohit; Lavine, Joel E; Molleston, Jean P; Newton, Kimberly P; Whitington, Peter F; Schwimmer, Jeffrey B

    2018-03-01

    Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. We performed a cross-sectional study of baseline data from 813 children (age Zone 1 steatosis was present in 18% of children with NAFLD (n = 146) and zone 3 steatosis was present in 32% (n = 244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P 51%; P zone 3 steatosis. In contrast, children with zone 3 steatosis were significantly more likely to have steatohepatitis (30% vs 6% in children with zone 1 steatosis; P zone 1 or zone 3 distribution of steatosis have an important subphenotype of pediatric NAFLD. Children with zone 1 steatosis are more likely to have advanced fibrosis and children with zone 3 steatosis are more likely to have steatohepatitis. To achieve a comprehensive understanding of pediatric NAFLD, studies of pathophysiology, natural history, and response to treatment should account for the zonality of steatosis. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

  10. Management of pancreatic, gastrointestinal and liver complications in adult cystic fibrosis.

    Science.gov (United States)

    Munck, A; Languepin, J; Debray, D; Lamireau, T; Abely, M; Huet, F; Maudinas, R; Michaud, L; Mas, E

    2015-06-01

    The gastrointestinal tract is a major source of morbidity in adults with cystic fibrosis (CF), with a wide range of complications, some of them being specific to the underlying disease. Abnormal CFTR function, with reduced bicarbonate and other ion transport levels through the apical surface of epithelial cells, affects the intestinal tract including the pancreas and the liver. Similarly to what is observed in the respiratory tract, gastrointestinal CFTR dysfunction leads to mucus accumulation, dysmotility, small bowel bacterial overgrowth and inflammation with alteration of innate immune responses, all of which being likely to be interrelated. In developed countries, almost half of patients with CF are adults followed in multidisciplinary CF care centres by pneumologists who often have to manage gastrointestinal complications. It therefore appears essential that adult gastroenterologists develop the expertise needed for managing CF gastrointestinal complications in close collaboration with multidisciplinary CF care centre teams to improve the quality of life of adults with CF. Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  11. The use of DWI to assess spleen and liver quantitative ADC changes in the detection of liver fibrosis stages in chronic viral hepatitis

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    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.

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

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    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.

  13. Evolutionary-driven support vector machines for determining the degree of liver fibrosis in chronic hepatitis C.

    Science.gov (United States)

    Stoean, Ruxandra; Stoean, Catalin; Lupsor, Monica; Stefanescu, Horia; Badea, Radu

    2011-01-01

    Hepatic fibrosis, the principal pointer to the development of a liver disease within chronic hepatitis C, can be measured through several stages. The correct evaluation of its degree, based on recent different non-invasive procedures, is of current major concern. The latest methodology for assessing it is the Fibroscan and the effect of its employment is impressive. However, the complex interaction between its stiffness indicator and the other biochemical and clinical examinations towards a respective degree of liver fibrosis is hard to be manually discovered. In this respect, the novel, well-performing evolutionary-powered support vector machines are proposed towards an automated learning of the relationship between medical attributes and fibrosis levels. The traditional support vector machines have been an often choice for addressing hepatic fibrosis, while the evolutionary option has been validated on many real-world tasks and proven flexibility and good performance. The evolutionary approach is simple and direct, resulting from the hybridization of the learning component within support vector machines and the optimization engine of evolutionary algorithms. It discovers the optimal coefficients of surfaces that separate instances of distinct classes. Apart from a detached manner of establishing the fibrosis degree for new cases, a resulting formula also offers insight upon the correspondence between the medical factors and the respective outcome. What is more, a feature selection genetic algorithm can be further embedded into the method structure, in order to dynamically concentrate search only on the most relevant attributes. The data set refers 722 patients with chronic hepatitis C infection and 24 indicators. The five possible degrees of fibrosis range from F0 (no fibrosis) to F4 (cirrhosis). Since the standard support vector machines are among the most frequently used methods in recent artificial intelligence studies for hepatic fibrosis staging, the

  14. Prevalence and Profile of Fibrosis in Diabetic Patients with Non-alcoholic Fatty Liver Disease and the Associated Factors.

    Science.gov (United States)

    Prasetya, Ignatius Bima; Hasan, Irsan; Wisnu, Wismandari; Rumende, Cleopas Martin

    2017-04-01

    the risk of Non-Alcoholic Fatty Liver Disease (NAFLD) is increasing in patients with type-2 diabetes. Prevalence and factors related to the increased risk of NAFLD in diabetic patients in Indonesia has never been studied before. Data regarding the profile of fibrosis in the population has also been unknown. This study aimed to identify the difference on the profile of diabetic patients with and without NAFLD as well as the degree of fibrosis. the study was conducted using a cross-sectional method in type-2 diabetic patients who were treated at the outpatient clinic of endocrinology and metabolic division in Cipto Mangunkusumo Hospital. Sampling was done consecutively. Collected data comprised of age, duration of diabetes, body mass index (BMI), waist circumference, HDL, triglyceride, and HbA1C levels. Abdominal ultrasonography was conducted for all patients to determine the presence of NAFLD. Patients with NAFLD were subsequently underwent transient elastography in order to assess their degree of liver fibrosis. Chi-square or Fisher's-Exact tests were used for bivariate analysis and logistic regression was used for multivariate analysis. as many as 186 patients were analyzed in the study and 84 patients (45.2%) were demonstrated to have NAFLD. Transient elastography examinations were carried out in 68 patients and 17 patients (25.0%) were found with severe fibrosis. Univariate analysis showed significant differences on BMI (PR=1.878; 95%CI= 1.296-2.721; pdiabetic patients in Cipto Mangunkusumo Hospital has reached 45.2% and 25.0% among them had severe fibrosis. BMI is the only factor found to be associated with the occurrence of NAFLD.

  15. 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.

  16. Intestinal flora imbalance promotes alcohol-induced liver fibrosis by the TGFβ/smad signaling pathway in mice.

    Science.gov (United States)

    Zhang, Dong; Hao, Xiuxian; Xu, Lili; Cui, Jing; Xue, Li; Tian, Zibin

    2017-10-01

    Intestinal flora performs a crucial role in human health and its imbalance may cause numerous pathological changes. The liver can also affect the intestinal function through bile secretion via the enterohepatic cycle. The pathophysiological association between the gut and the liver is described as the gut-liver axis. The present study investigated the role of intestinal flora in alcohol-induced liver fibrosis. A total of 36 C57 mice were randomly and equally divided into 3 different dietary regimes: Group I (alcohol injury; received alcohol); group II (alcohol injury with flora imbalance; received alcohol plus lincomycin hydrochloride) and group III (alcohol injury with corrected flora imbalance; received alcohol, lincomycin hydrochloride and extra probiotics). The present study then investigated several indicators of liver damage. Alkaline phosphatase (ALP) levels, aspartate aminotransferase (AST) levels and alanine aminotransferase (ALT) levels in mice serum were studied. Masson staining and Annexin V-fluorescein isothiocyanate/propidium iodide double staining was also performed, and the expression of mothers against decapentaplegic homolog (smad) 3 and smad4 proteins in hepatic stellate cells (HSCs) of the mice was examined using western blot analysis. The levels of serum ALP, AST and ALT were the highest in group II mice, and all 3 levels decreased in group III mice compared with those from group II. The degree of liver fibrosis was aggravated in group II mice compared with group I mice. The apoptosis of HSCs was significantly inhibited in group II mice, but was increased in group III mice. The HSCs in group II mice exhibited higher expression of smad3 and smad4, whilst group III mice (with corrected intestinal flora imbalance) exhibited downregulated expression of smad3 and smad4. The present data indicates that the intestinal flora perform a significant role in maintaining liver homeostasis. Furthermore, an imbalance of intestinal flora can exacerbate alcohol

  17. Effects of gentiana scabra bage on expression of hepatic type I, III collagen proteins in Paragonimus skrjabini rats with liver fibrosis.

    Science.gov (United States)

    Qu, Zhao-Xia; Li, Fang; Ma, Chao-Dong; Liu, Jun; Li, Shu-De; Wang, Wen-Lin

    2015-01-01

    To explore the effects of gentiana scabra bage on the expression of hepatic collagen proteins in Paragonimus skrjabini rats with liver fibrosis. 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. Comparing with the model group, changes of hepatic type I and type III collagen proteins in gentiana scabra bage treated group were significantly weakened. 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. Copyright © 2015 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

  18. AST/ALT ratio is not an index of liver fibrosis in chronic hepatitis C when aminotransferase activities are determinate according to the international recommendations.

    Science.gov (United States)

    Guéchot, Jérôme; Boisson, Renée Claude; Zarski, Jean-Pierre; Sturm, Nathalie; Calès, Paul; Lasnier, Elisabeth

    2013-11-01

    The aspartate aminotransferase activity (AST)/alanine aminotransferase activity (ALT) ratio is used as liver fibrosis index whereas the reported data are conflicting. In chronic hepatitis C (CHC), reported diagnostic accuracies range from none to good for significant fibrosis and to excellent for cirrhosis. Assuming that AST/ALT increases are mainly due to vitamin B6 defects since pyridoxal phosphate (PLP), active form of B6, acts as coenzyme in transamination reactions, we evaluated the diagnostic accuracy of the AST/ALT ratio using standardized methods for AST and ALT activities, with PLP addition as recommended, in a prospective multicenter cohort of CHC patients. ALT and AST activities were measured using the recommended IFCC methods with addition of pyridoxal 5'-phosphate. We evaluated the AST/ALT ratio for the diagnosis of liver fibrosis or cirrhosis in a cohort of CHC patients included in a multicenter prospective study. A liver biopsy was performed in each patient and reviewed by two independent pathologists in order to determine the fibrosis stage according to Metavir classification which was the reference standard. AST/ALT ratio significantly increased with histological stage of liver fibrosis and there was a significant correlation between Metavir fibrosis stage and AST/ALT ratio (r=0.129, PALT ratio does not discriminate significant fibrosis (F≥2) (AUROC=0.531) and had only very poor diagnostic accuracies for severe fibrosis (F≥3) (AUROC=0.584) or cirrhosis (F4) (AUROC=0.626). AST/ALT ratio is not a good and discriminative index of liver fibrosis in CHC when aminotransferase activities are determinate according to the international recommendations. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  19. MicroRNA-122 associates with serum apolipoprotein B but not liver fibrosis markers in CHC genotype 1 infection.

    Science.gov (United States)

    Lee, Tzu-Hao; Matta, Bassem; King, Bernard D; Hodges, Michael R; Tillmann, Hans L; Patel, Keyur

    2015-10-01

    miR-122 is the predominant liver miRNA that regulates hepatic lipid metabolism and inflammation. Hepatitis C virus (HCV) modulates host intracellular lipid metabolism. HCV stability and propagation also depend on an interaction between virus and miR-122. Our aims were to examine the associations between miR-122, apolipoproteins, and serum makers of fibrosis in chronic hepatitis C (CHC) patients. We evaluated baseline sera from 36 CHC genotype 1 patients who completed the Phase IIa study of miravirsen (LNA oligonucleotide targeting miR-122). Samples were assessed for liver transaminases, IL 28B genotype, IP-10, and lipid profiles. The noninvasive markers of liver fibrosis, APRI, and FIB-4, were calculated using standard formulae. miR-122 levels were measured using RT-PCR and expressed as fold-change compared to normal healthy controls. CHC patients were mostly male (61%) with mean age 47.5 ± 11.6 years. Patients with higher ApoB (ApoB/ULN ≥ 0.5) has significantly lower miR-122 levels in compared to patients with lower ApoB (ApoB/ULN HCV RNA and lipoproteins. There were no differences in miR-122 levels between patients with different stages of fibrosis determined by APRI or FIB-4. Patients with lower ApoB had higher serum miR-122 levels. However, we cannot identify significant association between miR-122, ApoA-1, or fibrosis markers in this small cohort of CHC genotype 1 patients. The mechanism of HCV dyslipidemia is complex and could partly relate to the effect of miR-122 on lipid metabolism which requires further evaluation in a larger study. © 2015 Wiley Periodicals, Inc.

  20. Visceral adiposity index is associated with significant fibrosis in patients with non-alcoholic fatty liver disease.

    Science.gov (United States)

    Petta, S; Amato, M C; Di Marco, V; Cammà, C; Pizzolanti, G; Barcellona, M R; Cabibi, D; Galluzzo, A; Sinagra, D; Giordano, C; Craxì, A

    2012-01-01

    Metabolic factors have been associated with liver damage in patients with non-alcoholic fatty liver disease (NAFLD). To test a new marker of adipose dysfunction, the visceral adiposity index (VAI), in NAFLD patients to assess whether or not it is associated with host factors, and to investigate a potential correlation with histological findings. One hundred and forty-two consecutive NAFLD patients were evaluated by liver biopsy, and clinical and metabolic measurements, including insulin resistance with the homeostasis model assessment (HOMA), and VAI by using waist circumference, body mass index, triglycerides and HDL. Serum levels of TNFα, IL-6, adiponectin and leptin were also assessed. All biopsies were scored for NAFLD activity score (NAS) and its components, and for staging (Kleiner). By multiple linear regression analysis, VAI was independently associated with higher HOMA (P = 0.04), and fibrosis (P = 0.04). In addition, an independent association was found between higher VAI and lower adiponectin levels (P = 0.002). Higher HOMA (OR 1.149, 95% CI 1.003-1.316, P = 0.04), higher VAI (OR 1.446, 95% CI 1.023-2.043, P = 0.03), lobular inflammation (OR 3.777, 95% CI 1.771-8.051, P = 0.001), and ballooning (OR 2.884, 95% CI 1.231-6.757, P = 0.01) were correlated with significant fibrosis (F2-F4) on multiple logistic regression analysis. In particular, the prevalence of significant fibrosis progressively increased from patients with a VAI ≤ 2.1 and HOMA ≤ 3.4 (26%) to those with a VAI > 2.1 and HOMA > 3.4 (83%). In NAFLD patients, visceral adiposity index is an expression of both qualitative and quantitative adipose tissue dysfunction and, together with insulin resistance, is independently correlated with significant fibrosis. © 2011 Blackwell Publishing Ltd.

  1. Hepatitis C Genotypes in Libya: Correlation with Patients’ Characteristics, Level of Viremia, and Degree of Liver Fibrosis

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    Abdel-Naser Elzuoki

    2017-09-01

    Full Text Available Objectives: Our study sought to determine the distribution of hepatitis C virus (HCV-genotypes among patients attending two tertiary care hospitals in Benghazi and Tripoli, Libya, and correlate this with patient’s characteristics, viral load, and degree of fibrosis. Methods: We conducted a retrospective study of 286 HCV-RNA positive Libyan patients referred from different health care facilities in east and west Libya for specific HCV treatment. HCV genotyping was carried out by gene amplification. Liver histology was graded by Metavir score according to the stage of fibrosis. Results: HCV genotypes 1, 2, 3, and 4 were found in 24.1%, 10.8%, 3.4%, and 61.5% of the patients, respectively. Genotype 4 was detected more frequently in patients from east Libya (Benghazi compared to west Libya (Tripoli (75.9% vs. 41.6%, p = 0.245. Genotype 1 was more frequent in patients from west Libya compared to east Libya (34.1% vs. 16.8%, p = 0.657. There was a significant correlation between HCV genotype distribution and viral load. Patients with genotype 4 exhibited a higher degree of liver fibrosis (p < 0.001. Conclusions: HCV genotype 4 is the predominant genotype in Libya followed by genotype 1. However, as we go from the east to the west of the country, genotype 1 increases. Genotype 4 was associated with higher level of viremia and higher stage of liver fibrosis. It is important to note that both genotypes 1 and 4 are associated with a poor response to pegylated interferon and ribavirin combination therapy. The findings emphasize the need to develop improved strategies in Libya for the successful treatment of HCV infection with novel newly available antiviral drugs.

  2. The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Kurowska-Stolarska, Mariola; Hasoo, Manhl K; Welsh, David J; Stewart, Lynn; McIntyre, Donna; Morton, Brian E; Johnstone, Steven; Miller, Ashley M; Asquith, Darren L; Millar, Neal L; Millar, Ann B; Feghali-Bostwick, Carol A; Hirani, Nikhil; Crick, Peter J; Wang, Yuqin; Griffiths, William J; McInnes, Iain B; McSharry, Charles

    2017-06-01

    Idiopathic pulmonary fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF; therefore, microRNAs may reveal novel pathogenic pathways. We sought to determine the regulatory role of microRNA (miR)-155 in the profibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts, and its contribution to experimental pulmonary fibrosis. Bleomycin-induced lung fibrosis in wild-type and miR-155 -/- mice was analyzed by histology, collagen, and profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors. miR-155 -/- mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-β production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the profibrotic phenotype of IPF and miR-155 -/- fibroblasts. We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. 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)

    Takemura, Takayo; Yoshida, Yuichi; Kiso, Shinichi; Kizu, Takashi; Furuta, Kunimaro; Ezaki, Hisao; Hamano, Mina; Egawa, Mayumi; Chatani, Norihiro; Kamada, Yoshihiro; Imai, Yasuharu; Higashiyama, Shigeki; Iwamoto, Ryo; Mekada, Eisuke; Takehara, Tetsuo

    2013-01-01

    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

  4. Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice

    Energy Technology Data Exchange (ETDEWEB)

    Takemura, Takayo; Yoshida, Yuichi [Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Osaka (Japan); Kiso, Shinichi, E-mail: kiso@gh.med.osaka-u.ac.jp [Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Osaka (Japan); Kizu, Takashi; Furuta, Kunimaro; Ezaki, Hisao; Hamano, Mina; Egawa, Mayumi; Chatani, Norihiro; Kamada, Yoshihiro [Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Osaka (Japan); Imai, Yasuharu [Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Osaka (Japan); Higashiyama, Shigeki [Department of Biochemistry and Molecular Genetics, Ehime University, Graduate School of Medicine and Department of Cell Growth and Tumor Regulation, Proteo-Medicine Research Center (ProMRes), Ehime University, Shitsukawa, Toon, Ehime (Japan); Iwamoto, Ryo; Mekada, Eisuke [Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); Takehara, Tetsuo [Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Osaka (Japan)

    2013-07-26

    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.

  5. Chronic administration of ethanol with high vitamin A supplementation in a liquid diet to rats does not cause liver fibrosis. 2. Biochemical observations

    NARCIS (Netherlands)

    Seifert, W. F.; Bosma, A.; Hendriks, H. F.; Blaner, W. S.; van Leeuwen, R. E.; van Thiel-de Ruiter, G. C.; Wilson, J. H.; Knook, D. L.; Brouwer, A.

    1991-01-01

    The inability of the 'ethanol/high vitamin A Lieber-DeCarli diet' to induce liver fibrosis in two different rat strains was further evaluated by determining changes in parameters of liver cell damage and of retinoid and lipid metabolism. In the ethanol/vitamin A-treated group, slight but constant

  6. Genetic prevention of hepatitis C virus-induced liver fibrosis by allele-specific downregulation of MERTK.

    Science.gov (United States)

    Cavalli, Marco; Pan, Gang; Nord, Helena; Wallén Arzt, Emelie; Wallerman, Ola; Wadelius, Claes

    2017-07-01

    Infection by hepatitis C virus (HCV) can result in the development of liver fibrosis and may eventually progress into cirrhosis and hepatocellular carcinoma. However, the molecular mechanisms for this process are not fully known. Several genome-wide association studies have been carried out to pinpoint causative variants in HCV-infected patient cohorts, but these variants are usually not the functional ones. The aim of this study was to identify the regulatory single nucleotide polymorphism associated with the risk of HCV-induced liver fibrosis and elucidate its molecular mechanism. We utilized a bioinformatics approach to identify a non-coding regulatory variant, located in an intron of the MERTK gene, based on differential transcription factor binding between the alleles. We validated the results using expression reporter assays and electrophoresis mobility shift assays. Chromatin immunoprecipitation sequencing indicated that transcription factor(s) bind stronger to the A allele of rs6726639. Electrophoresis mobility shift assays supported these findings and suggested that the transcription factor is interferon regulatory factor 1 (IRF1). Luciferase report assays showed lower enhancer activity from the A allele and that IRF1 may act as a repressor. Treatment of hepatitis C with interferon-α results in increased IRF1 levels and our data suggest that this leads to an allele-specific downregulation of MERTK mediated by an allelic effect on the regulatory element containing the functional rs6726639. This variant also shows the hallmarks for being the driver of the genome-wide association studies for reduced risk of liver fibrosis and non-alcoholic fatty liver disease at MERTK. © 2016 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.

  7. Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice.

    Science.gov (United States)

    Kim, In Hee; Xu, Jun; Liu, Xiao; Koyama, Yukinori; Ma, Hsiao-Yen; Diggle, Karin; You, Young-Hyun; Schilling, Jan M; Jeste, Dilip; Sharma, Kumar; Brenner, David A; Kisseleva, Tatiana

    2016-08-01

    We aimed to investigate whether aging increases the susceptibility of hepatic and renal inflammation or fibrosis in response to high-fat diet (HFD) and explore the underlying genetic alterations. Middle (10 months old) and old (20 months old) aged, male C57BL/6N mice were fed either a low-fat diet (4 % fat) or HFD (60 % fat) for 4 months. Young (3 months old) aged mice were included as control group. HFD-induced liver and kidney injuries were analyzed by serum and urine assay, histologic staining, immunohistochemistry, and reverse-transcription real-time quantitative polymerase chain reaction. Total RNA sequencing with next-generation technology was done with RNA extracted from liver tissues. With HFD feeding, aged was associated with higher serum alanine aminotransferase levels, marked infiltration of hepatic macrophages, and increased expression of inflammatory cytokines (MCP1, TNF-α, IL-1β, IL-6, IL-12, IL-17A). Importantly, aged mice showed more advanced hepatic fibrosis and increased expression of fibrogenic markers (Col-I-α1, αSMA, TGF-β1, TGF-β2, TGFβRII, PDGF, PDGFRβII, TIMP1) in response to HFD. Aged mice fed on HFD also showed increased oxidative stress and TLR4 expression. In the total RNA seq and gene ontology analysis of liver, old-aged HFD group showed significant up-regulation of genes linked to innate immune response, immune response, defense response, inflammatory response compared to middle-aged HFD group. Meanwhile, aging and HFD feeding showed significant increase in glomerular size and mesangial area, higher urine albumin/creatinine ratio, and advanced renal inflammation or fibrosis. However, the difference of HFD-induced renal injury between old-aged group and middle-aged group was not significant. The susceptibility of hepatic fibrosis as well as hepatic inflammation in response to HFD was significantly increased with aging. In addition, aging was associated with glomerular alterations and increased renal inflammation or

  8. Gadoxetate-enhanced MR imaging and compartmental modelling to assess hepatocyte bidirectional transport function in rats with advanced liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Giraudeau, Celine; Leporq, Benjamin; Doblas, Sabrina [University Paris Diderot, Sorbonne Paris Cite, Hopital Beaujon, Laboratory of Imaging Biomarkers, UMR1149 Inserm, Clichy (France); Lagadec, Matthieu; Daire, Jean-Luc; Van Beers, Bernard E. [University Paris Diderot, Sorbonne Paris Cite, Hopital Beaujon, Laboratory of Imaging Biomarkers, UMR1149 Inserm, Clichy (France); Beaujon University Hospital Paris Nord, Department of Radiology, Clichy (France); Pastor, Catherine M. [University Paris Diderot, Sorbonne Paris Cite, Hopital Beaujon, Laboratory of Imaging Biomarkers, UMR1149 Inserm, Clichy (France); Hopitaux Universitaires de Geneve, Departement d' Imagerie et des Sciences de l' Information Medicale, Geneva (Switzerland)

    2017-05-15

    Changes in the expression of hepatocyte membrane transporters in advanced fibrosis decrease the hepatic transport function of organic anions. The aim of our study was to assess if these changes can be evaluated with pharmacokinetic analysis of the hepatobiliary transport of the MR contrast agent gadoxetate. Dynamic gadoxetate-enhanced MRI was performed in 17 rats with advanced fibrosis and 8 normal rats. After deconvolution, hepatocyte three-compartmental analysis was performed to calculate the hepatocyte influx, biliary efflux and sinusoidal backflux rates. The expression of Oatp1a1, Mrp2 and Mrp3 organic anion membrane transporters was assessed with reverse transcription polymerase chain reaction. In the rats with advanced fibrosis, the influx and efflux rates of gadoxetate decreased and the backflux rate increased significantly (p = 0.003, 0.041 and 0.010, respectively). Significant correlations were found between influx and Oatp1a1 expression (r = 0.78, p < 0.001), biliary efflux and Mrp2 (r = 0.50, p = 0.016) and sinusoidal backflux and Mrp3 (r = 0.61, p = 0.002). These results show that changes in the bidirectional organic anion hepatocyte transport function in rats with advanced liver fibrosis can be assessed with compartmental analysis of gadoxetate-enhanced MRI. (orig.)

  9. Phosphodiesterase inhibition mediates matrix metalloproteinase activity and the level of collagen degradation fragments in a liver fibrosis ex vivo rat model

    Directory of Open Access Journals (Sweden)

    Veidal Sanne Skovgård

    2012-12-01

    Full Text Available Abstract Background Accumulation of extracellular matrix (ECM and increased matrix metalloproteinase (MMP activity are hallmarks of liver fibrosis. The aim of the present study was to develop a model of liver fibrosis combining ex vivo tissue culture of livers from CCl4 treated animals with an ELISA detecting a fragment of type III collagen generated in vitro by MMP-9 (C3M, known to be associated with liver fibrosis and to investigate cAMP modulation of MMP activity and liver tissue turnover in this model. Findings In vivo: Rats were treated for 8 weeks with CCl4/Intralipid. Liver slices were cultured for 48 hours. Levels of C3M were determined in the supernatants of slices cultured without treatment, treated with GM6001 (positive control or treated with IBMX (phosphodiesterase inhibitor. Enzymatic activity of MMP-2 and MMP-9 were studied by gelatin zymography. Ex vivo: The levels of serum C3M increased 77% in the CCl4-treated rats at week 8 (p 4-treated animals had highly increased MMP-9, but not MMP-2 activity, compared to slices derived from control animals. Conclusions We have combined an ex vivo model of liver fibrosis with measurement of a biochemical marker of collagen degradation in the condition medium. This technology may be used to evaluate the molecular process leading to structural fibrotic changes, as collagen species are the predominant structural part of fibrosis. These data suggest that modulation of cAMP may play a role in regulation of collagen degradation associated with liver fibrosis.

  10. Discordance between liver biopsy and Fibroscan® in assessing liver fibrosis in chronic hepatitis b: risk factors and influence of necroinflammation.

    Directory of Open Access Journals (Sweden)

    Seung Up Kim

    Full Text Available BACKGROUND: Few studies have investigated predictors of discordance between liver biopsy (LB and liver stiffness measurement (LSM using FibroScan®. We assessed predictors of discordance between LB and LSM in chronic hepatitis B (CHB and investigated the effects of necroinflammatory activity. METHODS: In total, 150 patients (107 men, 43 women were prospectively enrolled. Only LSM with ≥ 10 valid measurements was considered reliable. Liver fibrosis was evaluated using the Laennec system. LB specimens <15 mm in length were considered ineligible. Reference cutoff LSM values to determine discordance were calculated from our cohort (6.0 kPa for ≥ F2, 7.5 kPa for ≥ F3, and 9.4 kPa for F4. RESULTS: A discordance, defined as a discordance of at least two stages between LB and LSM, was identified in 21 (14.0% patients. In multivariate analyses, fibrosis stages F3-4 and F4 showed independent negative associations with discordance (P = 0.002; hazard ratio [HR], 0.073; 95% confidence interval [CI], 0.014-0.390 for F3-4 and P = 0.014; HR, 0.067; 95% CI, 0.008-0.574 for F4. LSM values were not significantly different between maximal activity grades 1-2 and 3-4 in F1 and F2 fibrosis stages, whereas LSM values were significantly higher in maximal activity grade 3-4 than 1-2 in F3 and F4 fibrosis stage (median 8.6 vs. 11.3 kPa in F3, P = 0.049; median 11.9 vs. 19.2 kPa in F4, P = 0.009. CONCLUSION: Advanced fibrosis stage (F3-4 or cirrhosis (F4 showed a negative correlation with discordance between LB and LSM in patients with CHB, and maximal activity grade 3-4 significantly influenced LSM values in F3 and F4.

  11. A comparative study on the hepatoprotective action of bear bile and Coptidis Rhizoma aqueous extract on experimental liver fibrosis in rats.

    Science.gov (United States)

    Wang, Ning; Feng, Yibin; Cheung, Fan; Chow, Oi-Yee; Wang, Xuanbin; Su, Weiwei; Tong, Yao

    2012-11-29

    Bear bile and Coptidis Rhizoma have been used in Chinese medicine with a long tradition in treating heat-diseases. Both bear bile and Coptidis Rhizoma are used to treat liver diseases in clinical practice of Chinese Medicine. Since bears are currently endangered, it raises the question whether the use of bear bile is ethical. To look for substitute for bear bile, the aim of this study is to compare the anti-fibrotic effects of Coptidis Rhizoma and its major component berberine with the actions of bear bile and its major compound tauroursodeoxycholic acid on experimental liver fibrosis in rats. Quality assessment was conducted with high performance liquid chromatography. The experimental liver fibrosis in rats was induced by carbon tetrachloride, alcohol, and bile duct ligation respectively. The biochemical criteria in the blood and tissue samples were measured to evaluate the anti-fibrotic properties and underlying mechanisms of the drugs. Coptidis Rhizoma Aqueous Extract (CRAE), berberine, and bear bile exerted anti-fibrotic properties on various liver fibrosis models in rats. CRAE and berberine significantly reduced the peroxidative stress in liver through increasing the superoxide dismutase enzyme activity. CRAE and berberine were able to excrete bilirubin products from the liver and protect hepatocytes from cholestatic damage. The effect of CRAE and berberine are comparable to that of bear bile. Instead of using bear bile, CRAE and berberine can be potential substitutes in treating liver fibrosis.

  12. Significant burden of nonalcoholic fatty liver disease with advanced fibrosis in the US: a cross-sectional analysis of 2011-2014 National Health and Nutrition Examination Survey.

    Science.gov (United States)

    Wong, R J; Liu, B; Bhuket, T

    2017-11-01

    Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease in the US. Understanding the epidemiology of NAFLD, with specific focus on individuals with hepatic fibrosis is important to guide healthcare resource planning. To evaluate prevalence and predictors of hepatic fibrosis among US adults with NAFLD. We performed a cross-sectional study using data from the updated 2011-2014 National Health and Nutrition Examination Survey, a national, stratified, multistage sampling survey of non-institutionalised US adults age ≥ 20. METAVIR F2 or greater fibrosis among individuals with NAFLD was assessed using AST to Platelet Ratio Index (APRI) score > 0.7. METAVIR F3 or greater fibrosis was assessed using NAFLD fibrosis score (NFS) > 0.676 and FIB-4 score > 3.25. Multivariate logistic regression models evaluated for predictors of fibrosis among individuals with NAFLD. Overall prevalence of NAFLD among US adults was 21.9% (95% CI 20.6-23.3), representing 51.6 million adults. Among individuals with NAFLD, we observed a 23.8% prevalence of ≥F2 fibrosis, representing 12.2 million individuals, and we observed a 2.3%-9.7% prevalence of ≥F3 fibrosis, representing as many as 5.0 million adults. On multivariate regression analyses, increasing age, obesity and concurrent diabetes mellitus were associated with increased risk of ≥F3 fibrosis. NAFLD represents a major healthcare burden among US adults with as many as 5 million adults estimated to have NAFLD with ≥F3 fibrosis. Age and the components of the metabolic syndrome are independently associated with higher risk of fibrosis. © 2017 John Wiley & Sons Ltd.

  13. Risk factors for hepatic steatosis in adults with cystic fibrosis: Similarities to non-alcoholic fatty liver disease.

    Science.gov (United States)

    Ayoub, Fares; Trillo-Alvarez, Cesar; Morelli, Giuseppe; Lascano, Jorge

    2018-01-27

    To investigate the clinical, biochemical and imaging characteristics of adult cystic fibrosis (CF) patients with hepatic steatosis as compared to normal CF controls. We performed a retrospective review of adult CF patients in an academic outpatient setting during 2016. Baseline characteristics, genetic mutation analysis as well as laboratory values were collected. Abdominal imaging (ultrasound, computed tomography, magnetic resonance) was used to determine presence of hepatic steatosis. We compare patients with hepatic steatosis to normal controls. Data was collected on 114 patients meeting inclusion criteria. Seventeen patients (14.9%) were found to have hepatic steatosis on imaging. Being overweight (BMI > 25) ( P = 0.019) and having a higher ppFEV1 (75 vs 53, P = 0.037) were significantly associated with hepatic steatosis. Patients with hepatic steatosis had a significantly higher median alanine aminotransferase level (27 vs 19, P = 0.048). None of the hepatic steatosis patients had frank CF liver disease, cirrhosis or portal hypertension. We found no significant association with pancreatic insufficiency or CF related diabetes. Hepatic steatosis appears to be a clinically and phenotypically distinct entity from CF liver disease. The lack of association with malnourishment and the significant association with higher BMI and higher ppFEV1 demonstrate similarities with non-alcoholic fatty liver disease. Long term prospective studies are needed to ascertain whether CF hepatic steatosis progresses to fibrosis and cirrhosis.

  14. Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats

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    Wang Yu

    2012-06-01

    Full Text Available Abstract Introduction Adipose derived mesenchymal stem cells (ADMSCs, carrying the similar characteristics to bone marrow mesenchymal stem cells, only much more abundant and easier to obtain, may be a promising treatment for liver fibrosis. We aim to investigate the therapeutic potential of ADMSCs transplantation in liver fibrosis caused by carbon tetrachloride (CCl4 in rats as well as its underlying mechanism, and to further explore the appropriate infusion pathway. Methods ADMSCs were isolated, cultured and identified. Placebo and ADMSCs were transplanted via portal vein and tail vein respectively into carbon tetrachloride (CCl4-induced liver fibrosis rats. Computed tomography (CT perfusion scan and microvessel counts were performed to measure the alteration of liver microcirculation after therapy. Liver function tests and histological findings were estimated. Results CT perfusion scan shown significant decrease of hepatic arterial perfusion index, significant increased portal vein perfusion, total liver perfusion in rats receiving ADMSCs from portal vein, and Factor VIII (FVIII immunohistochemical staining shown significant decrease of microvessels in rats receiving ADMSCs from portal vein, indicating microcirculation improvement in portal vein group. Vascular endothelial growth Factor (VEGF was significantly up-regulated in fibrosis models, and decreased after ADMSCs intraportal transplantation. A significant improvement of liver functional test and histological findings in portal vein group were observed. No significance was found in rats receiving ADMSCs from tail vein. Conclusions ADMSCs have a therapeutic effect against CCl4-mediated liver fibrosis. ADMSCs may benefit the fibrotic liver through alteration of microcirculation, evidenced by CT perfusion scan and down-regulation of VEGF. Intraportal transplantation is a better pathway than tail vein transplantation.

  15. Study of the therapeutic effects of Lactobacillus and α-lipoic acid against dimethylnitrosamine-induced liver fibrosis in rats

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    Khairy M.A. Zoheir

    2014-12-01

    Full Text Available Lactobacillus (LB and α-lipoic acid (ALA were investigated to compare their protective effects against dimethylnitrosamine (DMN-induced liver fibrosis in rats. Animals were either injected intraperitoneally with DMN to induce hepatic fibrosis, or were left untreated (negative control. For the DMN + LB and DMN + ALA treatment groups, at two weeks of DMN treatment LB or ALA was added to the feed and supplementation continued until the experimental endpoint at sixty days. At the study endpoint, expression of IL-1β, IL-6, IL-10, TNF-α, IFN-γ, TGF-β1, COL1-α1 genes and the concentration of glutathione and malondialdehyde were measured in liver tissues, while GOT, GPT, and ALP concentrations were measured in blood. Body weights remained higher in NC and DMN + LB groups compared to DMN and DMN + ALA groups, while activity of GOT and GPT in serum was lower in DMN + LB and DMN + ALA groups compared to the DMN group. Compared to other treatment groups, in the DMN group expression of both TGF-β1 and, COL1-α1 mRNAs and pro-inflammatory cytokines increased, while that of 1L-10 decreased. Furthermore, LB and ALA treatments increased antioxidant activity of glutathione and decreased malondialdehyde in comparison to the DMN group. Between LB and ALA treatments, glutathione concentration was higher in the DMN + LB group, while malondialdehyde was lower. Our results indicate that both LB and ALA exert hepatoprotective effects against DMN-induced liver fibrosis. Their beneficial effects may be partly associated with down-regulation of both TGF-β1 and COL1-α1 signaling, which may be accounted for reduction of increased oxidative stress and TNF-α production.

  16. Evolution of hepatic steatosis to fibrosis and adenoma formation in liver specific growth hormone receptor knockout (GHRLD mice

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    Yong eFan

    2014-12-01

    Full Text Available Background: Non-alcoholic fatty liver disease (NAFLD is one of the most common forms of chronic liver diseases closely associated with obesity and insulin resistance; deficient growth hormone (GH action in liver has been implicated as a mechanism. Here, we investigated the evolution of NAFLD in aged mice with liver-specific GHR deletion. Methods: We examined glucose tolerance, insulin responsiveness and lipid profiles in aged male mice (44-50 weeks with GHRLD. We performed proteomics analysis, pathway-based Superarray assay, as well as quantitative RT-PCR to gain molecular insight into the mechanism(s of GHR-deficiency mediated NAFLD. In addition, we examined the pathological changes of livers of aged GHRLD male mice. Results: The biochemical profile was consistent with that of the metabolic syndrome: abnormal glucose tolerance, impaired insulin secretion, and hyperlipidemia. RT-qPCR analysis of key markers of inflammation revealed a 3-5 fold increase in TNFα and CCL3, confirming the presence of inflammation. Expression of fibrotic markers (e.g., Col1A2 and Col3A1 was significantly increased, together with a 2-3 fold increase in TGFβ transcripts. Proteomics analyses showed a marked decrease of Mup1 and Selenbp2. In addition, pathway-analysis showed that the expression of cell cycle and growth relevant genes (i.e., Ccnd1, Socs2, Socs3 and Egfr were markedly affected in GHRLD liver. Microscopic analyses (H&E of GHRLD livers revealed the presence of hepatic adenomas of different stages of malignancy. Conclusion: Abrogation of GH-signaling in male liver leads to metabolic syndrome, hepatic steatosis, increased inflammation and fibrosis, and development of hepatic tumor. Since obesity, a common precursor of NAFLD, is a state of deficient GH secretion and action, the GHRLD model could be used to unravel the contribution of compromised hepatic GH-signaling in these pathological processes, and help to identify potential targets for intervention.

  17. Impact of Antiretroviral Therapy on Liver Fibrosis Among Human Immunodeficiency Virus-Infected Adults With and Without HBV Coinfection in Zambia.

    Science.gov (United States)

    Vinikoor, Michael J; Sinkala, Edford; Chilengi, Roma; Mulenga, Lloyd B; Chi, Benjamin H; Zyambo, Zude; Hoffmann, Christopher J; Saag, Michael S; Davies, Mary-Ann; Egger, Matthias; Wandeler, Gilles

    2017-05-15

    We investigated changes in hepatic fibrosis, based on transient elastography (TE), among human immunodeficiency virus (HIV)-infected patients with and without hepatitis B virus (HBV) coinfection on antiretroviral therapy (ART) in Zambia. Patients' liver stiffness measurements (LSM; kiloPascals [kPa]) at ART initiation were categorized as no or minimal fibrosis (equivalent to Metavir F0-F1), significant fibrosis (F2-F3), and cirrhosis (F4). TE was repeated following 1 year of ART. Stratified by HBV coinfection status (hepatitis B surface antigen positive at baseline), we described LSM change and the proportion with an increase/decrease in fibrosis category. Using multivariable logistic regression, we assessed correlates of significant fibrosis/cirrhosis at 1 year on ART. Among 463 patients analyzed (61 with HBV coinfection), median age was 35 years, 53.7% were women, and median baseline CD4+ count was 240 cells/mm3. Nearly all (97.6%) patients received tenofovir disoproxil fumarate-containing ART, in line with nationally recommended first-line treatment. The median LSM change was -0.70 kPa (95% confidence interval, -3.0 to +1.7) and was similar with and without HBV coinfection. Significant fibrosis/cirrhosis decreased in frequency from 14.0% to 6.7% (P < .001). Increased age, male sex, and HBV coinfection predicted significant fibrosis/cirrhosis at 1 year (all P < .05). The percentage of HIV-infected Zambian adults with elevated liver stiffness suggestive of significant fibrosis/cirrhosis decreased following ART initiation-regardless of HBV status. This suggests that HIV infection plays a role in liver inflammation. HBV-coinfected patients were more likely to have significant fibrosis/cirrhosis at 1 year on ART. NCT02060162. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  18. Nonlinear microscopy of lipid storage and fibrosis in muscle and liver tissues of mice fed high-fat diets

    Science.gov (United States)

    Brackmann, Christian; Gabrielsson, Britt; Svedberg, Fredrik; Holmäng, Agneta; Sandberg, Ann-Sofie; Enejder, Annika

    2010-11-01

    Hallmarks of high-fat Western diet intake, such as excessive lipid accumulation in skeletal muscle and liver as well as liver fibrosis, are investigated in tissues from mice using nonlinear microscopy, second harmonic generation (SHG), and coherent anti-Stokes Raman scattering (CARS), supported by conventional analysis methods. Two aspects are presented; intake of standard chow versus Western diet, and a comparison between two high-fat Western diets of different polyunsaturated lipid content. CARS microscopy images of intramyocellular lipid droplets in muscle tissue show an increased amount for Western diet compared to standard diet samples. Even stronger diet impact is found for liver samples, where combined CARS and SHG microscopy visualize clear differences in lipid content and collagen fiber development, the latter indicating nonalcoholic fatty liver disease (NAFLD) and steatohepatitis induced at a relatively early stage for Western diet. Characteristic for NAFLD, the fibrous tissue-containing lipids accumulate in larger structures. This is also observed in CARS images of liver samples from two Western-type diets of different polyunsaturated lipid contents. In summary, nonlinear microscopy has strong potential (further promoted by technical advances toward clinical use) for detection and characterization of steatohepatitis already in its early stages.

  19. The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis

    DEFF Research Database (Denmark)

    Sandahl, T D; McGrail, R; Møller, H J

    2016-01-01

    analyses improved the AUROC to 0.91 in the estimation cohort and 0.90 in the validation cohort. Furthermore, a high value of the combined score was associated with a high short-term mortality. CONCLUSIONS: The combination of the macrophage activation marker sCD163 and the fibrosis markers predicted......BACKGROUND: Noninvasive identification of significant portal hypertension in patients with cirrhosis is needed in hepatology practice. AIM: To investigate whether the combination of sCD163 as a hepatic inflammation marker and the fibrosis markers of the Enhanced Liver Fibrosis score (ELF) can...

  20. A novel assay for extracellular matrix remodeling associated with liver fibrosis

    DEFF Research Database (Denmark)

    Barascuk, N; Veidal, S S; Larsen, L

    2010-01-01

    Accumulation of extracellular matrix (ECM) components and increased matrix-metalloprotease (MMPs) activity are hallmarks of fibrosis. We developed an ELISA for quantification of MMP-9 derived collagen type III (CO3) degradation....

  1. MMP Mediated Degradation of Type VI Collagen Is Highly Associated with Liver Fibrosis - Identification and Validation of a Novel Biochemical Marker Assay

    DEFF Research Database (Denmark)

    Veidal, Sanne Skovgard; Karsdal, Morten Asser; Vassiliadis, Efstathios

    2011-01-01

    Background and Aims: During fibrogenesis, in which excessive remodeling of the extracellular matrix occurs, both the quantity of type VI collagen and levels of matrix metalloproteinases, including MMP-2 and MMP-9, increase significantly. Proteolytic degradation of type VI collagen into small...... fragments, so-called neo-epitopes, may be specific biochemical marker of liver fibrosis. The aim of this study was to develop an ELISA detecting a fragment of type VI collagen generated by MMP-2 and MMP-9, and evaluate this assay in two preclinical models of liver fibrosis. Methods: Mass spectrometric...... analysis of cleaved type VI collagen revealed a large number of protease-generated neo-epitopes. A fragment unique to type VI collagen generated by MMP-2 and MMP-9 was selected for ELISA development. The CO6-MMP assay was evaluated in two rat models of liver fibrosis: bile duct ligation (BDL) and carbon...

  2. Morin ameliorates chemically induced liver fibrosis in vivo and inhibits stellate cell proliferation in vitro by suppressing Wnt/β-catenin signaling

    Energy Technology Data Exchange (ETDEWEB)

    MadanKumar, Perumal; NaveenKumar, Perumal; Manikandan, Samidurai [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu (India); Devaraj, Halagowder [Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu (India); NiranjaliDevaraj, Sivasithamparam, E-mail: niranjali@yahoo.com [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu (India)

    2014-06-01

    The anti-fibrotic effect of morin was examined in LX-2 cells (culture-activated human hepatic stellate cells) and in diethylnitrosamine induced rat model of liver fibrosis. The in vitro study was designed to determine whether morin affects the survival of cultured LX-2 cells, while the in vivo study was designed to evaluate the antioxidant and anti-fibrotic efficacy of morin on diethylnitrosamine induced liver fibrosis in male albino Wistar rat. The activities of liver function enzymes in serum, liver lipid peroxide levels, activities of serum antioxidant enzymes and liver architecture were monitored to cast light on the antioxidant and hepatoprotective nature of morin. To establish the anti-fibrotic effects of morin, the levels of key Wnt signaling molecules which are strongly associated with the signal transduction pathway of HSC activation were measured. Overall, from the in vitro results, it was observed that morin at 50 μM concentration inhibited the proliferation of cultured LX-2 cells, inhibited Wnt signaling and induced G1 cell cycle arrest. The in vivo results further confirmed that morin by downregulating the expressions of GSK-3β, β-catenin and cyclin D1 ameliorated DEN-induced liver fibrosis. Hence morin could be employed as a promising chemopreventive natural supplement for liver fibrosis. - Highlights: • In vivo and in vitro results revealed the active participation of Wnt signaling. • Morin at 50 μM inhibited LX-2 cell proliferation by suppressing Wnt signaling. • Morin exhibited hepatoprotective effects against DEN induced liver fibrosis. • Morin inhibited HSC activation in vivo by downregulating Wnt/β-catenin signaling.

  3. Melatonin promotes hepatic differentiation of human dental pulp stem cells: clinical implications for the prevention of liver fibrosis.

    Science.gov (United States)

    Cho, Young-Ah; Noh, Kwantae; Jue, Seong-Suk; Lee, So-Youn; Kim, Eun-Cheol

    2015-01-01

    Melatonin's effect on hepatic differentiation of stem cells remains unclear. The aim of this study was to investigate the action of melatonin on hepatic differentiation as well as its related signaling pathways of human dental pulp stem cells (hDPSCs) and to examine the therapeutic effects of a combination of melatonin and hDPSC transplantation on carbon tetrachloride (CCl4 )-induced liver fibrosis in mice. In vitro hepatic differentiation was assessed by periodic acid-Schiff (PAS) staining and mRNA expression for hepatocyte markers. Liver fibrosis model was established by injecting 0.5 mL/kg CCl4 followed by treatment with melatonin (5 mg/kg, twice a week) and hDPSCs. In vivo therapeutic effects were evaluated by histopathology and by means of liver function tests including measurement of alanine transaminase (ALT), aspartate transaminase (AST), and ammonia levels. Melatonin promoted hepatic differentiation based on mRNA expression of differentiation markers and PAS-stained glycogen-laden cells. In addition, melatonin increased bone morphogenic protein (BMP)-2 expression and Smad1/5/8 phosphorylation, which was blocked by the BMP antagonist noggin. Furthermore, melatonin activated p38, extracellular signal-regulated kinase (ERK), and nuclear factor-κB (NF-κB) in hDPSCs. Melatonin-induced hepatic differentiation was attenuated by inhibitors of BMP, p38, ERK, and NF-κB. Compared to treatment of CCl4 -injured mice with either melatonin or hDPSC transplantation alone, the combination of melatonin and hDPSC significantly suppressed liver fibrosis and restored ALT, AST, and ammonia levels. For the first time, this study demonstrates that melatonin promotes hepatic differentiation of hDPSCs by modulating the BMP, p38, ERK, and NF-κB pathway. Combined treatment of grafted hDPSCs and melatonin could be a viable approach for the treatment of liver cirrhosis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Retrospective evaluation of serum markers APRI and AST/ALT for assessing liver fibrosis and cirrhosis in chronic hepatitis B and C patients with hepatocellular carcinoma.

    Science.gov (United States)

    Lin, Chen-Sheng; Chang, Chi-Sen; Yang, Sheng-Shun; Yeh, Hong-Zen; Lin, Cheng-Wen

    2008-01-01

    Aspartate aminotransferase-to-platelet ratio index (APRI), aspartate aminotransferase-to-alanine aminotransferase (AST/ALT) ratio, platelet count, AST, albumin, bilirubin and alkaline phosphatase were retrospectively evaluated for the prediction of advanced liver fibrosis and cirrhosis in patients with resectable hepatocellular carcinoma in this study. In total, the 97 selected patients consisted of 9 (9.3%) patients with non-B, non-C chronic hepatitis, 48 (49.5%) patients with chronic hepatitis B (CHB) and 40 (41.2%) patients with chronic hepatitis C (CHC). The APRI, but not AST/ALT or other serum markers, showed a significant correlation with advanced liver fibrosis and cirrhosis (p<0.05). The area under receiver operating characteristic curves (AUROC) for predicting advanced fibrosis was 0.69 in CHB patients and 0.87 in CHC patients, whereas AUROC for predicting cirrhosis was 0.75 in CHB patients and 0.84 in CHC patients. In addition, the sensitivity and specificity of APRI were greater than 80% for predicting advanced fibrosis and cirrhosis in the CHC patients. APRI is a simple and non-invasive biochemical marker of liver fibrosis and cirrhosis, particularly in CHC patients. APRI potentially could be used to decrease the number of liver biopsies.

  5. Prevalence and Profile of Fibrosis in Diabetic Patients with Non-alcoholic Fatty Liver Disease and the Associated Factors

    Directory of Open Access Journals (Sweden)

    Ignatius Bima Prasetya

    2017-04-01

    Full Text Available Background: the risk of Non-Alcoholic Fatty Liver Disease (NAFLD is increasing in patients with type-2 diabetes. Prevalence and factors related to the increased risk of NAFLD in diabetic patients in Indonesia has never been studied before. Data regarding the profile of fibrosis in the population has also been unknown. This study aimed to identify the difference on the profile of diabetic patients with and without NAFLD as well as the degree of fibrosis. Methods: the study was conducted using a cross-sectional method in type-2 diabetic patients who were treated at the outpatient clinic of endocrinology and metabolic division in Cipto Mangunkusumo Hospital. Sampling was done consecutively. Collected data comprised of age, duration of diabetes, body mass index (BMI, waist circumference, HDL, triglyceride, and HbA1C levels. Abdominal ultrasonography was conducted for all patients to determine the presence of NAFLD. Patients with NAFLD were subsequently underwent transient elastography in order to assess their degree of liver fibrosis. Chi-square or Fisher’s-Exact tests were used for bivariate analysis and logistic regression was used for multivariate analysis. Results: as many as 186 patients were analyzed in the study and 84 patients (45.2% were demonstrated to have NAFLD. Transient elastography examinations were carried out in 68 patients and 17 patients (25.0% were found with severe fibrosis. Univariate analysis showed significant differences on BMI (PR=1.878; 95%CI= 1.296-2.721; p<0.001 and waist circumference (PR=2.368; 95%CI= 1.117-5.017; p=0.018 between patients with and without NAFLD. However, the multivariate test showed that BMI was the only factor that had a significance difference between both groups (OR=2.989; 95%CI=1.625-5.499; p<0.001. Conclusion: prevalence of NAFLD among type-2 diabetic patients in Cipto Mangunkusumo Hospital has reached 45.2% and 25.0% among them had severe fibrosis. BMI is the only factor found to be associated

  6. Ginkgo biloba extract mitigates liver fibrosis and apoptosis by regulating p38 MAPK, NF-κB/IκBα, and Bcl-2/Bax signaling

    Directory of Open Access Journals (Sweden)

    Wang YY

    2015-12-01

    Full Text Available Yuanyuan Wang, Rong Wang, Yujie Wang, Ruqin Peng, Yan Wu, Yongfang Yuan Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China Background: Liver fibrosis is the consequence of diverse liver injuries and can eventually develop into liver cirrhosis. Ginkgo biloba extract (GBE is an extract from dried ginkgo leaves that has many pharmacological effects because of its various ingredients and has been shown to be hepatoprotective. Purpose and methods: Aimed to investigate the underlying protective mechanisms of GBE on carbon tetrachloride (CCl4-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly divided into four groups: control group (C, model group (M, low-dose group (L, and high-dose group (H. Liver fibrosis was induced by CCl4 groups M, L, and H: group C was administered saline. In addition, GBE at different doses was used to treat groups L and H. Results: The results of hematoxylin and eosin staining, Masson’s trichrome staining, a liver function index, and a liver fibrosis index showed that GBE application noticeably mitigated fibrosis and improved the function of the liver. The western blotting and immunohistochemistry analyses indicated that GBE reduced liver fibrosis not only by inhibiting p38 MAPK and NF-κBp65 via inhibition of IκBα degradation but also by inhibiting hepatocyte apoptosis via downregulation of Bax, upregulation of Bcl-2, and subsequent inhibition of caspase-3 activation. Inflammation-associated factors and hepatic stellate cell (HSC-activation markers further demonstrated that GBE could effectively inhibit HSC activation and inflammation as a result of its regulation of p38 MAPK and nuclear factor-kappa B/IκBα signaling. Conclusion: Our findings indicated a novel role for GBE in the treatment of liver fibrosis. The potential mechanisms may be associated with the following signaling pathways: 1 the p38 MAPK

  7. Mechanisms of liver fibrosis associated with experimental Fasciola hepatica infection: roles of Fas2 proteinase and hepatic stellate cell activation.

    Science.gov (United States)

    Marcos, Luis A; Terashima, Angélica; Yi, Pedro; Andrade, Roy; Cubero, Francisco J; Albanis, Efsevia; Gotuzzo, Eduardo; Espinoza, Jose R; Friedman, Scott L

    2011-02-01

    We have evaluated the possible mechanisms of liver fibrosis caused by Fasciola hepatica in an animal model and in culture using immortalized human stellate cells. Liver biopsies of F. hepatica-infected rats were performed at wk 8 and 16. Serum-starved LX-2 cells, a human stellate cell line, were exposed to increasing concentrations of Fas2 antigen. The expression of key fibrosis-related genes was evaluated by qRT-PCR. There was a significant correlation between fibrogenic gene expression and both intensity and duration of infection. LX-2 cells exposed to Fas2 showed progressively increased expression of mRNAs for Collagen I, alpha-smooth muscle-actin, platelet-derived growth factor beta receptor, and tissue inhibitor of metalloproteinase II; inhibition of Fas2 cysteine proteinase activity by E-64 abrogated these increases, suggesting that the protease activity of Fas2 is involved in fibrogenic stimulation. In summary, F. hepatica infection is associated with up-regulation of mRNAs associated with hepatic fibrogenesis in vivo and in activated hepatic stellate cells.

  8. A pilot study of the characterization of hepatic tissue strain in children with cystic-fibrosis-associated liver disease (CFLD) by acoustic radiation force impulse imaging

    International Nuclear Information System (INIS)

    Behrens, Christopher B.; Langholz, Juliane H.; Eiler, Jessika; Jenewein, Raphael; Fuchs, Konstantin; Alzen, Gerhard F.P.; Naehrlich, Lutz; Harth, Sebastian; Krombach, Gabriele A.

    2013-01-01

    Progressive fibrotic alterations of liver tissue represent a major complication in children with cystic fibrosis. Correct assessment of cystic-fibrosis-associated liver disease (CFLD) in clinical routine is a challenging issue. Sonographic elastography based on acoustic radiation force impulse imaging (ARFI) is a new noninvasive approach for quantitatively assessing in vivo elasticity of biological tissues in many organs. To characterize ARFI elastography as a diagnostic tool to assess alteration of liver tissue elasticity related to cystic fibrosis in children. ARFI elastography and B-mode US imaging were performed in 36 children with cystic fibrosis. The children's clinical history and laboratory parameters were documented. According to the findings on conventional US, children were assigned to distinct groups indicating severity of hepatic tissue alterations. The relationship between US findings and respective elastography values was assessed. Additionally, differences between ARFI elastography values of each US group were statistically tested. Children with sonomorphologic characteristics of fibrotic tissue remodeling presented significantly increased values for tissue elasticity. Children with normal B-mode US or discrete signs of hepatic tissue alterations showed a tendency toward increased tissue stiffness indicating early tissue remodeling. Assessment of children with CFLD by means of ARFI elastography yields adequate results when compared to conventional US. For detection of early stages of liver disease with mild fibrotic reactions of hepatic tissue, ARFI elastography might offer diagnostic advantages over conventional US. Thus, liver stiffness measured by means of elastography might represent a valuable biological parameter for evaluation and follow-up of CFLD. (orig.)

  9. A pilot study of the characterization of hepatic tissue strain in children with cystic-fibrosis-associated liver disease (CFLD) by acoustic radiation force impulse imaging

    Energy Technology Data Exchange (ETDEWEB)

    Behrens, Christopher B.; Langholz, Juliane H.; Eiler, Jessika; Jenewein, Raphael; Fuchs, Konstantin; Alzen, Gerhard F.P. [University Hospital Giessen, Department of Pediatric Radiology, Giessen (Germany); Naehrlich, Lutz [University Hospital Giessen, Department of Pediatrics, Giessen (Germany); Harth, Sebastian; Krombach, Gabriele A. [University Hospital Giessen, Department of Radiology, Giessen (Germany)

    2013-03-15

    Progressive fibrotic alterations of liver tissue represent a major complication in children with cystic fibrosis. Correct assessment of cystic-fibrosis-associated liver disease (CFLD) in clinical routine is a challenging issue. Sonographic elastography based on acoustic radiation force impulse imaging (ARFI) is a new noninvasive approach for quantitatively assessing in vivo elasticity of biological tissues in many organs. To characterize ARFI elastography as a diagnostic tool to assess alteration of liver tissue elasticity related to cystic fibrosis in children. ARFI elastography and B-mode US imaging were performed in 36 children with cystic fibrosis. The children's clinical history and laboratory parameters were documented. According to the findings on conventional US, children were assigned to distinct groups indicating severity of hepatic tissue alterations. The relationship between US findings and respective elastography values was assessed. Additionally, differences between ARFI elastography values of each US group were statistically tested. Children with sonomorphologic characteristics of fibrotic tissue remodeling presented significantly increased values for tissue elasticity. Children with normal B-mode US or discrete signs of hepatic tissue alterations showed a tendency toward increased tissue stiffness indicating early tissue remodeling. Assessment of children with CFLD by means of ARFI elastography yields adequate results when compared to conventional US. For detection of early stages of liver disease with mild fibrotic reactions of hepatic tissue, ARFI elastography might offer diagnostic advantages over conventional US. Thus, liver stiffness measured by means of elastography might represent a valuable biological parameter for evaluation and follow-up of CFLD. (orig.)

  10. Levels of hepatic Th17 cells and regulatory T cells upregulated by hepatic stellate cells in advanced HBV-related liver fibrosis.

    Science.gov (United States)

    Li, Xiaoyan; Su, Yujie; Hua, Xuefeng; Xie, Chan; Liu, Jing; Huang, Yuehua; Zhou, Liang; Zhang, Min; Li, Xu; Gao, Zhiliang

    2017-04-11

    Liver fibrosis which mainly occurs upon chronic hepatitis virus infection potentially leads to portal hypertension, hepatic failure and hepatocellular carcinoma. However, the immune status of Th17 and Treg cells in liver fibrosis is controversial and the exact mechanisms remain largely elusive. Liver tissues and peripheral blood were obtained simultaneously from 32 hepatitis B virus infected patients undergoing surgery for hepatocellular carcinoma at the medical center of Sun Yat-sen University. Liver tissues at least 3 cm away from the tumor site were used for the analyses. Levels of Th17 cells and regulatory T cells were detected by flow cytometry analysis and immunohistochemistry. In vitro experiment, we adopted magnetic cell sorting to investigate how hepatic stellate cells regulate the levels of Th17 cells and regulatory T cells. We found that hepatic Th17 cells and regulatory T cells were increased in patients with advanced stage HBV-related liver fibrosis. Hepatic stellate cells upregulated the levels of Th17 cells and regulatory T cells via PGE2/EP2 and EP4 pathway. We found that the increased levels of Th17 cells and regulatory T cells were upregulated by hepatic stellate cells. These results may provide insight into the role of hepatic stellate cells and Th17 cells and regulatory T cells in the persistence of fibrosis and into the occurrence of hepatocellular carcinoma following cirrhosis.

  11. Three-dimensional visualization of the microvasculature of bile duct ligation-induced liver fibrosis in rats by x-ray phase-contrast imaging computed tomography

    Science.gov (United States)

    Xuan, Ruijiao; Zhao, Xinyan; Hu, Doudou; Jian, Jianbo; Wang, Tailing; Hu, Chunhong

    2015-07-01

    X-ray phase-contrast imaging (PCI) can substantially enhance contrast, and is particularly useful in differentiating biological soft tissues with small density differences. Combined with computed tomography (CT), PCI-CT enables the acquisition of accurate microstructures inside biological samples. In this study, liver microvasculature was visualized without contrast agents in vitro with PCI-CT using liver fibrosis samples induced by bile duct ligation (BDL) in rats. The histological section examination confirmed the correspondence of CT images with the microvascular morphology of the samples. By means of the PCI-CT and three-dimensional (3D) visualization technique, 3D microvascular structures in samples from different stages of liver fibrosis were clearly revealed. Different types of blood vessels, including portal veins and hepatic veins, in addition to ductular proliferation and bile ducts, could be distinguished with good sensitivity, excellent specificity and excellent accuracy. The study showed that PCI-CT could assess the morphological changes in liver microvasculature that result from fibrosis and allow characterization of the anatomical and pathological features of the microvasculature. With further development of PCI-CT technique, it may become a novel noninvasive imaging technique for the auxiliary analysis of liver fibrosis.

  12. Hepatic steatosis progresses faster in HIV mono-infected than HIV/HCV co-infected patients and is associated with liver fibrosis.

    Science.gov (United States)

    Pembroke, Thomas; Deschenes, Marc; Lebouché, Bertrand; Benmassaoud, Amine; Sewitch, Maida; Ghali, Peter; Wong, Philip; Halme, Alex; Vuille-Lessard, Elise; Pexos, Costa; Klein, Marina B; Sebastiani, Giada

    2017-10-01

    Hepatic steatosis (HS) seems common in patients infected with human immunodeficiency virus (HIV). However, the relative effect of HIV, as well as hepatitis C virus (HCV) in those co-infected, and the influence of HS on liver fibrosis progression are unclear. The LIVEr disease in HIV (LIVEHIV) is a Canadian prospective cohort study using transient elastography and associated controlled attenuation parameter (CAP) to screen for HS and liver fibrosis, in unselected HIV-infected adults. HS progression was defined as development of any grade HS (CAP ⩾248dB/m), or transition to severe HS (CAP >292dB/m), for those with any grade HS at baseline. Fibrosis progression was defined as development of significant liver fibrosis (liver stiffness measurement [LSM] >7.1kPa), or transition to cirrhosis (LSM >12.5kPa) for those with significant liver fibrosis at baseline. Cox regression analysis was used to assess predictors of HS and fibrosis progression. A prospective cohort study was conducted, which included 726 HIV-infected patients (22.7% HCV co-infected). Prevalence of any grade HS did not differ between HIV mono-infected and HIV/HCV co-infected patients (36.1% vs. 38.6%, respectively). 313 patients were followed for a median of 15.4 (interquartile range 8.5-23.0) months. The rate of HS progression was 37.8 (95% confidence interval [CI] 29.2-49.0) and 21.9 (95% CI 15.6-30.7) per 100 person-years in HIV mono-infection and HIV/HCV co-infection, respectively. HCV co-infection was an independent negative predictor of HS progression (adjusted hazard ratio [aHR] 0.50, 95% CI 0.28-0.89). HS predicted liver fibrosis progression in HIV mono-infection (aHR 4.18, 95% CI 1.21-14.5), but not in HIV/HCV co-infection. HS progresses faster and is associated with liver fibrosis progression in HIV mono-infection but not in HIV/HCV co-infection. Lay summary: Fatty liver is the most frequent liver disease in Western countries. People living with HIV seem at high risk of fatty liver due to

  13. Noninvasive assessments of liver fibrosis with transient elastography and Hui index predict survival in patients with chronic hepatitis B.

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    Wong, Grace Lai-Hung; Chan, Henry Lik-Yuen; Yu, Zhuo; Wong, Catherine Ka-Yan; Leung, Calvin; Ho, Patricia Po-Lai; Chan, Candace Yim; Chung, Vivian Chi-Yee; Chan, Zhan Cham-Yan; Tse, Yee-Kit; Chim, Angel Mei-Ling; Lau, Tina Kit-Ting; Chan, Hoi-Yun; Tse, Chi-Hang; Wong, Vincent Wai-Sun

    2015-03-01

    The prognostic role of noninvasive assessments of liver fibrosis has been evolving. Our aim was to investigate the prognostic value of liver stiffness measurement (LSM) with transient elastography and serum-based Hui index to predict hepatic events and deaths in chronic hepatitis B (CHB) patients. The main prospective cohort included 1555 consecutive CHB patients referred for transient elastography examination; a subgroup of 980 patients underwent follow-up assessments at least 3 years later formed the serial cohort. Cox proportional hazard model was performed to determine the relationship of LSM, Hui index and other clinical variables with hepatic events and deaths. During a mean follow-up of 69 ± 9 months, 119 patients (7.6%) developed hepatic events or deaths. Hepatic event-free survival was significantly decreased with increasing stages of LSM and Hui index. The 5-year cumulative probability of hepatic event-free survival of patients of Stage 1-7 of LSM were 99.3%, 98.8%, 95.7%, 90.9%, 89.6%, 74.6%, and 50.0%, respectively; that of Stage 1 to 3 of Hui index were 98.2%, 93.1%, and 77.5%, respectively. Independent predictors of hepatic event-free survival were age, baseline LSM, and follow-up Hui index. Serum ALT and body mass index affected the accuracy of prediction by LSM. Patients remained early stages of LSM or Hui index at follow-up visit had better survival compared to those remained at late stages. Baseline and change in noninvasive parameters of liver fibrosis, LSM and Hui index, are accurate to predict hepatic event-free survival in CHB patients. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  14. [Clinical efficacy of AST/ALT ratio and platelet counts as predictors of degree of fibrosis in HBV infected patients without clinically evident liver cirrhosis].

    Science.gov (United States)

    Park, Soo Young; Kang, Kyung Hee; Park, Jee Hyun; Lee, Jong Hyup; Cho, Chang Min; Tak, Won Young; Kweon, Young Oh; Kim, Sung Kook; Choi, Yong Hwan

    2004-04-01

    Hepatic fibrosis is an important prognostic factor in chronic hepatitis B. Liver biopsy is a gold standard diagnostic tool but an invasive procedure, so it cannot be done on all patients. We evaluated the clinical efficacy of AST/ALT ratio and platelet counts as predictors of fibrosis in chronic hepatitis B. We reviewed retrospectively clinical records of 323 patients, who visited Kyungpook National University Hospital for chronic hepatitis B and underwent liver biopsy from September 1998 to May 2002. Correlation with laboratory parameters with hepatic fibrosis stage was identified. Of 323 patients, there were 278 male patients with mean age 27 (9~59). Platelet counts showed a significant correlation (r=-0.343, p=0.000), and AST/ALT ratio showed a weak but significant correlation (r=0.137, p=0.013) with fibrosis stage. Patients with severe fibrosis or cirrhosis (stage 3 and 4) can be identified to have AST/ALT ratio > 1 and platelet counts 1 in combination with platelet counts. However, its sensitivity is too low to replace liver biopsy.

  15. Spironolactone lowers portal hypertension by inhibiting liver fibrosis, ROCK-2 activity and activating NO/PKG pathway in the bile-duct-ligated rat.

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    Wei Luo

    Full Text Available OBJECTIVE: Aldosterone, one of the main peptides in renin angiotensin aldosterone system (RAAS, has been suggested to mediate liver fibrosis and portal hypertension. Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice. However, the mechanisms remain unclear. The present study aimed to investigate the role of spionolactone on liver cirrhosis and portal hypertension. METHODS: Liver cirrhosis was induced by bile duct ligation (BDL. Spironolactone was administered orally (20 mg/kg/d after bile duct ligation was performed. Liver fibrosis was assessed by histology, Masson's trichrome staining, and the measurement of hydroxyproline and type I collagen content. The activation of HSC was determined by analysis of alpha smooth muscle actin (α-SMA expression. Protein expressions and protein phosphorylation were determined by immunohistochemical staining and Western blot analysis, Messenger RNA levels by quantitative real time polymerase chain reaction (Q-PCR. Portal pressure and intrahepatic resistance were examined in vivo. RESULTS: Treatment with spironolactone significantly lowered portal pressure. This was associated with attenuation of liver fibrosis, intrahepatic resistance and inhibition of HSC activation. In BDL rat liver, spironolactone suppressed up-regulation of proinflammatory cytokines (TNFα and IL-6. Additionally, spironolactone significantly decreased ROCK-2 activity without affecting expression of RhoA and Ras. Moreover, spironolactone markedly increased the levels of endothelial nitric oxide synthase (eNOS, phosphorylated eNOS and the activity of NO effector-protein kinase G (PKG in the liver. CONCLUSION: Spironolactone lowers portal hypertension by improvement of liver fibrosis and inhibition of intrahepatic vasoconstriction via down-regulating ROCK-2 activity and activating NO/PKG pathway. Thus, early spironolactone therapy might be the optional therapy in cirrhosis and

  16. An Increased Ratio of Glycated Albumin to HbA1c Is Associated with the Degree of Liver Fibrosis in Hepatitis B Virus-Positive Patients

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    Hirayuki Enomoto

    2014-01-01

    Full Text Available Background. In hepatitis B virus- (HBV- positive patients, the relationship between the metabolic variables and histological degree of liver fibrosis has been poorly investigated. Methods. A total of 176 HBV-positive patients were assessed in whom the ratios of glycated albumin-to-glycated hemoglobin (GA/HbA1c were calculated in order to investigate the relationship with the degree of liver fibrosis. Results. The GA/HbA1c ratio increased in association with the severity of fibrosis (METAVIR scores: F0-1: 2.61 ± 0.24, F2: 2.65 ± 0.24, F3: 2.74 ± 0.38, and F4: 2.91 ± 0.63. The GA/HbA1c ratios were inversely correlated with four variables of liver function: the prothrombin time (PT percentage (P<0.0001, platelet count (P<0.0001, albumin value (P<0.0001, and cholinesterase value (P<0.0001. The GA/HbA1c ratio was positively correlated with two well-known markers of liver fibrosis, FIB-4 (P<0.0001 and the AST-to-platelet ratio index (APRI (P<0.0001. Furthermore, the GA/HbA1c showed better correlations with two variables of liver function (PT percentage and cholinesterase value than did FIB-4 and with all four variables than did the APRI. Conclusion. The GA/HbA1c ratio is associated with the degree of liver fibrosis in HBV-positive patients.

  17. High Prevalence of Liver Fibrosis in Patients with Human Immunodeficiency Virus Monoinfection and Human Immunodeficiency Virus Hepatitis-B Co-infection as Assessed by Shear Wave Elastography: Study at a Teaching Hospital in Kenya

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    Samuel Nguku Gitau

    2016-01-01

    Full Text Available Objectives: The aim of this study was to determine the prevalence of liver fibrosis in patients with human immunodeficiency virus (HIV monoinfection versus those with HIV hepatitis-B virus (HBV co-infection as assessed with shear wave elastography (SWE in a tertiary sub-Saharan Africa hospital. Materials and Methods: A total of 105 consecutive patients, 70 with HIV monoinfection and 35 with HIV-HBV co-infection, had liver elastography obtained using SWE to assess for the presence of liver fibrosis the cutoff of which was 5.6 kPa. Assessment of aspartate aminotransferase-to-platelet ratio index (APRI score (a noninvasive serum biomarker of liver fibrosis in these patients was also done. Results: The prevalence of liver fibrosis was significantly higher (P < 0.0001 in patients with HIV-HBV co-infection, 25.7%, compared to those with HIV monoinfection, 7.1%. APRI score was greater in patients with HIV-HBV co-infection than those with HIV monoinfection. HIV co-infection with HBV accelerates progression to liver fibrosis. Association of a low cluster of differentiation 4 (CD-4 count with advanced fibrosis supports earlier starting of antiretroviral therapy to prevent rapid progression of liver disease in HIV-positive patients. Conclusion: In view of the high prevalence of liver fibrosis in patients with HIV-HBV co-infection, regular monitoring of the disease progression is recommended.

  18. Black blood T1rho MR imaging may diagnose early stage liver fibrosis: a proof-of-principle study with rat biliary duct ligation model.

    Science.gov (United States)

    Koon, Chi-Man; Zhang, Xin; Chen, Weitian; Chu, Eagle Siu Hong; San Lau, Clara Bik; Wáng, Yì-Xiáng J

    2016-08-01

    To explore black blood T1rho (T1ρ) liver imaging and investigate the earliest stage when biliary duct ligation (BDL) induced liver fibrosis can be diagnosed. MR was performed at 3 Tesla. A T1ρ prepared 2D fast spin echo (FSE) sequence with acquisition of four spin lock times (TSLs: 1, 10, 30, and 50 msec) and spin-lock frequency of 500 Hz was applied. Inherent black blood effect of FSE and double inversion recovery (DIR) achieved blood signal suppression, and 3 axial sections per liver were obtained. Male Sprague-Dawley rats were scanned at baseline (n=32), and on day-3 (n=13), day-5 (n=11), day-7 (n=10), day-10 (n=4) respectively after BDL. Hematoxylin-eosin (HE) and picrosirius red staining liver histology was obtained at these time points. The physiological liver parenchyma T1ρ was 38.38±1.53 msec (range, 36.05-41.53 msec). Liver T1ρ value elevated progressively after BDL. On day-10 after BDL all experimental animals can be separated from normal liver based on T1ρ measurement with lowest value being 42.82 msec. Day-7 and day-10 liver resembled METAVIR stage-F1/F2 fibrosis, and fibrous area counted for 0.22%±0.13% and 0.38%±0.44% of liver parenchyma area, respectively. This study provides the first proof-of-principle that T1ρ might diagnose early stage liver fibrosis.

  19. Intra-Individual Comparison between 2-D Shear Wave Elastography (GE System) and Virtual Touch Tissue Quantification (Siemens System) in Grading Liver Fibrosis.

    Science.gov (United States)

    Sigrist, Rosa M S; El Kaffas, Ahmed; Jeffrey, R Brooke; Rosenberg, Jarrett; Willmann, Jürgen K

    2017-12-01

    Ultrasound-based shear wave elastography (SWE) has recently gained substantial attention for non-invasive assessment of liver fibrosis. The purpose of this study was to perform an intra-individual comparison between 2-D shear wave elastography (2-D-SWE with a GE system) and Virtual Touch Tissue Quantification (VTTQ with a Siemens system) to assess whether these can be used interchangeably to grade fibrosis. Ninety-three patients (51 men, 42 women; mean age, 54 y) with liver disease of various etiologies (hepatitis B virus = 47, hepatitis C virus = 22; alcohol = 6, non-alcoholic steatohepatitis = 5, other = 13) were included. Using published system-specific shear wave speed cutoff values, liver fibrosis was classified into clinically non-significant (F0/F1) and significant (≥F2) fibrosis. Results indicated that intra-modality repeatability was excellent for both techniques (GE 2-D-SWE: intra-class correlation coefficient = 0.89 [0.84-0.93]; VTTQ: intra-class correlation coefficient = 0.90 [0.86-0.93]). Intra-modality classification agreement for fibrosis grading was good to excellent (GE 2-D-SWE: κ = 0.65, VTTQ: κ = 0.82). However, inter-modality agreement for fibrosis grading was only fair (κ = 0.31) using published system-specific shear wave speed cutoff values of fibrosis. In conclusion, although both GE 2-D-SWE and Siemens VTTQ exhibit good to excellent intra-modality repeatability, inter-modality agreement is only fair, suggesting that these should not be used interchangeably. Copyright © 2017 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.

  20. Effects of a new bioactive lipid-based drug carrier on cultured hepatic stellate cells and liver fibrosis in bile duct-ligated rats

    NARCIS (Netherlands)

    Adrian, Joanna E.; Poelstra, Klaas; Scherphof, Gerrit L.; Meijer, Dirk K. F.; van Loenen - Weemaes, Anne-miek; Reker-Smit, Catharina; Morselt, Henriette W. M.; Zwiers, Peter; Kamps, Jan A. A. M.

    In the fibrotic liver, hepatic stellate cells ( HSC) produce large amounts of collagen and secrete variety of mediators that promote development of fibrosis in this organ. Therefore, these cells are considered an attractive target for antifibrotic therapies. We incorporated the bioactive lipid

  1. Prevalence of non-alcoholic fatty liver disease and fibrosis in a large population cohort in the north of the Netherlands: A lifelines cohort study

    NARCIS (Netherlands)

    Van Den Berg, E.H.; Amini, M.; Schreuder, T.C.M.A.; Dullaart, R.P.F.; Faber, K.N.; Alizadeh, B.Z.; Blokzijl, H.

    2016-01-01

    Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is an increasing health issue, being part of the worldwide epidemic of obesity. The aim of this study was to investigate the prevalence of NAFLD and fibrosis and analyze biochemical characteristics in a large population-based cohort

  2. Transient elastography discloses identical distribution of liver fibrosis in chronic hepatitis C between HIV-negative and HIV-positive patients on HAART

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    Grünhage F

    2010-04-01

    Full Text Available Abstract Objective Progressive immunodeficiency associated with HIV-infection leads to a progressive course of liver disease in HIV/HCV-co-infected patients. Highly active antiretroviral therapy (HAART efficiently restores and preserves immune functions and has recently been demonstrated to also result in reduced liver-related mortality in HIV/HCV-co-infected patients. Methods To analyse differences in current liver fibrosis as a possible effect of HAART on fibrosis progression we assessed hepatic fibrosis by transient elastography in a cross-sectional comparison between HCV-mono-infected and HIV/HCV-co-infected patients presenting at our outpatient department in 2007. Results Overall, we did not find any difference in the distribution of liver stiffness between mono- (n = 84 and double-infected (n = 57 patients (14.4 kPa (10.8 - 18.2 versus 12.4 kPa (9.1 - 16.1, mean (95%-CI. However, in the 8 HIV+ patients with CD4 counts Conclusions These findings are in line with other data that show an improved prognosis of chronic hepatitis C in HIV+ patients under effective HAART, and may be a hint that fibrosis progression in well-treated HIV+ patients will no longer be different from that in HCV-mono-infected patients.

  3. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: assessment of non-invasive indices predicting hepatic steatosis and fibrosis.

    Science.gov (United States)

    Polyzos, Stergios A; Goulis, Dimitrios G; Kountouras, Jannis; Mintziori, Gesthimani; Chatzis, Panagiotis; Papadakis, Efstathios; Katsikis, Ilias; Panidis, Dimitrios

    2014-01-01

    Insulin resistance contributes to the pathogenesis of both polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD). The main aim of the present study was the evaluation of non-invasive indices of hepatic steatosis and fibrosis in PCOS women with or without metabolic syndrome (MetS). In this cross-sectional study, three non-invasive indices for hepatic steatosis [NAFLD liver fat score, lipid accumulation product (LAP) and hepatic steatosis index (HIS)] and four for fibrosis [FIB-4, aspartate aminotransferase (AST)-to-Platelet Ratio Index (APRI), body mass index (BMI)-Age-Alanine aminotransferase (ALT)-Triglycerides (BAAT) and BMI AST/ALT Ratio Diabetes (BARD)] were calculated in 314 PCOS women (77 with, 237 without MetS) and 78 controls. All steatosis indices were significantly higher in the PCOS than the control group (NAFLD liver fat score: -0.139 ± 0.117 vs. -0.976 ± 0.159, psteatosis indices were significantly higher in PCOS women with than without MetS (NAFLD liver fat score: 1.874 ± 0.258 vs. -0.793 ± 0.099, phepatic steatosis were significantly higher in PCOS, especially in the presence of MetS, whereas indices of hepatic fibrosis yielded controversial results. Further studies are warranted to evaluate the long-term outcomes of hepatic steatosis and fibrosis indices in PCOS women.

  4. The long-term safety of chronic azithromycin use in patients with cystic fibrosis regarding the condition of the kidney, liver and heart

    NARCIS (Netherlands)

    Möhlmann, J.E.; Majoor, C.J.; Van Der Vaart, H.; Touw, D.

    2016-01-01

    Background: Azithromycin is a widely used macrolide antibiotic in cystic fibrosis (CF), but little is known about the safety of long-term use. Reported side effects only apply to short-term use. The aim of this study is to investigate possible azithromycin-induced toxicity of the kidney, liver and

  5. Peptide-Modified Albumin Carrier Explored as a Novel Strategy for a Cell-Specific Delivery of Interferon Gamma To Treat Liver Fibrosis

    NARCIS (Netherlands)

    Barisal, Ruchi; Prakash, Jai; de Ruijter, Marieke; Beljaars, Leonie; Poelstra, Klaas

    2011-01-01

    Excessive accumulation of the extracellular matrix proteins primarily produced by activated hepatic stellate cells (HSC) leads to liver fibrosis. To date, no successful therapeutic intervention is available for the treatment of this disease. Platelet derived growth factor beta receptor (PDGF beta R)

  6. Could viral load combined with indirect serum markers be an option for predicting the degree of liver fibrosis in treatment-naïve chronic hepatitis B patients?

    Science.gov (United States)

    Afyon, Murat

    2017-02-01

    In a recent issue of the Revista Española de Enfermedades Digestivas, we read with interest the article by Coskun et al. "The diagnostic value of a globulin/platelet model for evaluating liver fibrosis in chronic hepatitis B patients". However, we wanted to emphasize some points about the article.

  7. Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2

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    Ritu S. Sharma

    2018-01-01

    Conclusions: Pharmacologic activation of Nrf2 in mice that had already been rendered obese and insulin resistant reversed insulin resistance, suppressed hepatic steatosis, and mitigated against NASH and liver fibrosis, effects that we principally attribute to inhibition of ER, inflammatory, and oxidative stress.

  8. Ultrasound evaluation of liver disease in cystic fibrosis as part of an annual assessment clinic: A 9-year review

    International Nuclear Information System (INIS)

    Williams, Stuart M.; Goodman, Robin; Thomson, Anne; McHugh, Kieran; Lindsell, David R.M.

    2002-01-01

    AIM: To review 9 years of annual assessment data in cystic fibrosis (CF) and evaluate the frequency of hepatobiliary abnormalities and the correlation between ultrasound and biochemical findings. MATERIALS AND METHODS: Over a 9-year period (1990-99), 168 children (age range 1-18 years) with CF have undergone an annual assessment which has included clinical, biochemical and ultrasonographic evaluation of the hepatobiliary system. We have retrospectively reviewed the sequential ultrasound reports and correlated them with the contemporaneous biochemical results. RESULTS: A total of 725 ultrasound examinations were performed over the review period. Sixty patients had at least one examination showing an abnormality of liver echo texture and in 39 patients this was a persisting finding. Seven patients (4.2%) developed frank cirrhotic change on ultrasound criteria, while 15 patients (8.9%) had evidence of persistent splenomegaly. Gall-bladder calculi were present in 4.8%. In 176 examinations (24%) there was disparity between the ultrasound findings and aspartate aminotransferase (AST) levels. In 3.0% of cases (five patients) there were persisting abnormalities of liver echo texure and persisting splenomegaly with a normal range AST value. CONCLUSION: No perfect method of assessing hepatobiliary involvement in CF is currently available. Ultrasonographic and biochemical assessment may reflect different aspects of disease progression. Routine use of ultrasound in annual assessment allows identification of a minority of patients with liver changes but with normal biochemistry. Williams, S.M. et al. (2002)

  9. Serum platelet-derived growth factor BB levels: a potential biomarker for the assessment of liver fibrosis in patients with chronic hepatitis B.

    Science.gov (United States)

    Zhou, Jiyuan; Deng, Yongqiong; Yan, Linlin; Zhao, Hong; Wang, Guiqiang

    2016-08-01

    Few studies have investigated serum levels of platelet-derived growth factor (PDGF) in patients with chronic hepatitis B (CHB). The present study aimed to determine whether PDGF-BB could serve as a potential biomarker for the detection of liver fibrosis. From October 2013 to August 2015, 465 patients with CHB were enrolled prospectively in this study. All patients underwent liver biopsy and staging based on the Ishak system. The serum PDGF-BB level was measured quantitatively by ELISA. The serum PDGF-BB level was negatively correlated with fibrosis stage in all patients (p = 0.003, Spearman's rho=-0.16) and was significantly different between fibrosis stages. The areas under the receiver operating characteristics curves (AUROCs) for serum PDGF-BB level and PGT score (a combination of PDGF-BB, gamma-glutamyl transpeptidase, and platelet levels) were 0.667 and 0.831, respectively, for patients with significant fibrosis and normal alanine aminotransferase (ALT) levels. The AUROCs for aspartate aminotransferase-to-platelet ratio (APRI) and fibrosis index based on four factors (FIB-4) were 0.823 and 0.821, respectively. Importantly, a cut-off value of 1.05 and 1.43, respectively, resulted in a sensitivity of 0.95 and 0.52, a specificity of 0.29 and 0.95, a positive predictive value of 0.30 and 0.79, and a negative predictive value of 0.96 and 0.86. The rate of correct diagnosis was up to 88.4% when using cut-offs of 1.05 and 1.43 for the absence or presence of significant fibrosis, respectively. Serum PDGF-BB decreased remarkably as fibrosis progressed, and this could be used as a non-invasive biomarker for the assessment of fibrosis stage in patients with CHB. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. The predictive values of three noninvasive indices in diagnosis of liver fibrosis in patients with chronic hepatitis B: a comparative study

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    ZHUANG Xiaofang

    2016-08-01

    Full Text Available ObjectiveTo investigate the values of FibroTouch, FIB-4 index, and aspartate aminotransferase-to-platelet ratio index (APRI in the diagnosis of liver fibrosis in patients with chronic hepatitis B (CHB. MethodsA total of 148 patients with CHB who visited Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region and underwent liver biopsy from September 2013 to May 2015 were enrolled and divided into groups according to fibrosis stage. All the patients underwent blood biochemical examination, routine blood tests, and FibroTouch measurement. Then FIB-4 and APRI were calculated, and liver stiffness was recorded. The receiver operating characteristic (ROC curve was used to calculate the area under the ROC curve (AUC and determine the cut-off value, sensitivity, and specificity. Chi-square test was used for comparison between two groups, and the Pearson rank correlation analysis was also performed. ResultsFibroTouch, APRI, and FIB-4 were well correlated with fibrosis stage (r=0.628, 0.486, and 0482, respectively, all P<0.01. In the marked liver fibrosis (≥S2 group and liver cirrhosis (S4 group, FibroTouch had the best diagnostic performance, with AUCs of 0.84 and 0.93, respectively, followed by APRI, which had AUCs of 0.79 and 0.87, respectively; FIB-4 index had the worst diagnostic performance, with AUCs of 0.77 and 0.84, respectively. In patients with a fibrosis stage of ≥S2 or S4, FibroTouch had a better diagnostic value than APRI and FIB-4 (Z=21.589, P<0.001; Z=18.896, P<0.001; Z=11.192, P=0.001; Z=16.891, P<0.001, and APRI had a better diagnostic value than FIB-4 (Z=46.918, P<0.001; Z=35.334, P<0.001. ConclusionFibroTouch can accurately evaluate the presence of liver fibrosis and fibrosis degree and help most patients avoid invasive liver biopsy.

  11. Late Graft Hepatitis and Fibrosis in Pediatric Liver Allograft Recipients : Current Concepts and Future Developments

    NARCIS (Netherlands)

    Kelly, Deirdre; Verkade, Henkjan J.; Rajanayagam, Jeremy; McKiernan, Patrick; Mazariegos, George; Hubscher, Stefan

    2016-01-01

    Liver transplantation (LT) in children now has a 20-year survival of >80%, but the longterm outcome of these grafts remains uncertain. Serial protocol liver biopsies after transplantation from several pediatric centres have demonstrated the gradual development of unexplained graft inflammation

  12. Thioacetamide-induced cirrhosis in selenium-adequate mice displays rapid and persistent abnormity of hepatic selenoenzymes which are mute to selenium supplementation

    International Nuclear Information System (INIS)

    Zhang Jinsong; Wang Huali; Yu Hanqing

    2007-01-01

    Selenium reduction in cirrhosis is frequently reported. The known beneficial effect of selenium supplementation on cirrhosis is probably obtained from nutritionally selenium-deficient subjects. Whether selenium supplementation truly improves cirrhosis in general needs additional experimental investigation. Thioacetamide was used to induce cirrhosis in selenium-adequate and -deficient mice. Selenoenzyme activity and selenium content were measured and the influence of selenium supplementation was evaluated. In Se-adequate mice, thioacetamide-mediated rapid onset of hepatic oxidative stress resulted in an increase in thioredoxin reductase activity and a decrease in both glutathione peroxidase activity and selenium content. The inverse activity of selenoenzymes (i.e. TrxR activity goes up and GPx activity goes down) was persistent and mute to selenium supplementation during the progress of cirrhosis; accordingly, cirrhosis was not improved by selenium supplementation in any period. On the other hand, selenium supplementation to selenium-deficient mice always more efficiently increased hepatic glutathione peroxidase activity and selenium content compared with those treated with thioacetamide, indicating that thioacetamide impairs the liver bioavailability of selenium. Although thioacetamide profoundly affects hepatic selenium status in selenium-adequate mice, selenium supplementation does not modify the changes. Selenium supplementation to cirrhotic subjects with a background of nutritional selenium deficiency can improve selenium status but cannot restore hepatic glutathione peroxidase and selenium to normal levels

  13. Study of liquid scintillator in detecting the PMN-CL, Ly-CL and extracellular matrix in liver fibrosis

    International Nuclear Information System (INIS)

    Li Tianxing; Cao Rui; Liang Qizhong; Zou Xiaowei

    1997-01-01

    Chemiluminescence (CL) of polymorphonuclear (PMN) and lymphocyte(Ly) in blood of patients with cirrhosis has two peaks. Basic peak value of PMN-CL and Ly-CL is increased, the maximal peak values of Zym-PMN and PHA-Ly are decreased, phagolyosis and opsonic function is also decreased, extracellular matrix (ECM) is all increased, HA is positively correlated with 'child' sort (r = 0.96, A>B>C). It suggests that OR is produced and released during CL and superoxide phosphatides is produced by OR in ECM of cirrhosis. It injures the membrane of cells and tissue. Analysis of CL is aided to study the development mechanism of liver fibrosis

  14. Viral eradication reduces all-cause mortality, including non-liver-related disease, in patients with progressive hepatitis C virus-related fibrosis.

    Science.gov (United States)

    Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori; Kiriyama, Seiki; Tanikawa, Makoto; Hisanaga, Yasuhiro; Kanamori, Akira; Kitabatake, Shusuke; Yama, Tsuyoki; Tanaka, Junko

    2017-03-01

    Eradication of hepatitis C virus (HCV) with interferon (IFN)-based therapy has been reported to reduce all-cause mortality in patients with chronic HCV infection. However, the impact of HCV eradication on non-liver-related mortality and causes of death has not been sufficiently investigated in patients with progressive HCV-related fibrosis. We enrolled 784 chronic HCV patients with progressive liver fibrosis (aspartate aminotransferase to platelet ratio index >1). Cause of death, incidence of hepatocellular carcinoma, and all-cause mortality including non-liver-related mortality were analyzed. Of these 784 patients, 170 achieved sustained virological response (SVR) (eradication of HCV) with IFN-based therapy (IFN-SVR), and 614 did not receive IFN-based therapy (non-IFN patients, chronic HCV infection). The median follow-up duration was 10.3 years. Two hundred seventy-three patients died during follow-up (liver-related death, n = 171; non-liver-related death, n = 102). The mortality rate from non-liver-related disease was 63.6% (7/11) in IFN-SVR patients and 36.3% (95/262) in non-IFN patients, respectively. In multivariate analysis, the eradication of HCV associated with not only hepatocellular carcinoma incidence (hazard ratio (HR), 0.162; 95% confidence interval (CI), 0.092-0.284), and all-cause mortality (HR, 0.094; 95% CI, 0.047-0.187), but non-liver-related mortality (HR, 0.286; 95% CI, 0.127-0.644) as well. Eradication of HCV reduced both liver-related and non-liver-related mortality in patients with progressive HCV-related fibrosis. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  15. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis.

    Directory of Open Access Journals (Sweden)

    Henning W Zimmermann

    Full Text Available BACKGROUND: Monocyte-derived macrophages critically perpetuate inflammatory responses after liver injury as a prerequisite for organ fibrosis. Experimental murine models identified an essential role for the CCR2-dependent infiltration of classical Gr1/Ly6C(+ monocytes in hepatic fibrosis. Moreover, the monocyte-related chemokine receptors CCR1 and CCR5 were recently recognized as important fibrosis modulators in mice. In humans, monocytes consist of classical CD14(+CD16(- and non-classical CD14(+CD16(+ cells. We aimed at investigating the relevance of monocyte subpopulations for human liver fibrosis, and hypothesized that 'non-classical' monocytes critically exert inflammatory as well as profibrogenic functions in patients during liver disease progression. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed circulating monocyte subsets from freshly drawn blood samples of 226 patients with chronic liver disease (CLD and 184 healthy controls by FACS analysis. Circulating monocytes were significantly expanded in CLD-patients compared to controls with a marked increase of the non-classical CD14(+CD16(+ subset that showed an activated phenotype in patients and correlated with proinflammatory cytokines and clinical progression. Correspondingly, CD14(+CD16(+ macrophages massively accumulated in fibrotic/cirrhotic livers, as evidenced by immunofluorescence and FACS. Ligands of monocyte-related chemokine receptors CCR2, CCR1 and CCR5 were expressed at higher levels in fibrotic and cirrhotic livers, while CCL3 and CCL4 were also systemically elevated in CLD-patients. Isolated monocyte/macrophage subpopulations were functionally characterized regarding cytokine/chemokine expression and interactions with primary human hepatic stellate cells (HSC in vitro. CD14(+CD16(+ monocytes released abundant proinflammatory cytokines. Furthermore, CD14(+CD16(+, but not CD14(+CD16(- monocytes could directly activate collagen-producing HSC. CONCLUSIONS/SIGNIFICANCE: Our data

  16. Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach

    Energy Technology Data Exchange (ETDEWEB)

    Abhilash, P.A.; Harikrishnan, R.; Indira, M., E-mail: indiramadambath@gmail.com

    2014-01-15

    Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4 g/kg b.wt for 90 days. After 90 days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250 mg/kg b.wt) and AA (250 mg/kg b.wt) supplemented groups and maintained for 30 days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKβ and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-β{sub 1} and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α{sub 1} (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKβ, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis. - Highlights: • Alcohol increases intestinal bacterial overgrowth and permeability of endotoxin. • Endotoxin mediated inflammation plays a major role in alcoholic liver fibrosis. • Ascorbic acid reduces endotoxemia, NF-κB activation and proinflammatory cytokines. • AA's action is by inhibition of SIBO, IKKβ and alteration of

  17. High biological variation of serum hyaluronic acid and Hepascore, a biochemical marker model for the prediction of liver fibrosis.

    Science.gov (United States)

    Rossi, Enrico; Adams, Leon A; Ching, Helena L; Bulsara, Max; MacQuillan, Gerry C; Jeffrey, Gary P

    2013-05-01

    Serum hyaluronic acid and biochemical models which require hyaluronic acid analysis are commonly used as predictors of liver fibrosis in patients with chronic liver disease, however biological variation data for hyaluronic acid are deficient. Four serial serum samples were obtained at weekly intervals from healthy volunteers and patients with chronic hepatitis B, chronic hepatitis C and non- alcoholic fatty liver disease (NAFLD; 20 in each group). The within-individual week-to-week variation (CVI) and reference change values for hyaluronic acid, α₂-macroglobulin and Hepascore were obtained. Hepascore is calculated from hyaluronic acid, α2-macroglobulin, bilirubin and γ-glutamyltransferase activity. Hyaluronic acid displayed large within-individual variation, the CVI values were 62% in healthy subjects, 38% in hepatitis C, 37% in hepatitis B and 36% in NAFLD patients. Hepascore CVIs were 43% in healthy subjects, 24% in hepatitis C, 28% in hepatitis B and 39% in NAFLD patients. α₂-Macroglobulin was much less variable with CVIs ranging from 4.4% to 7.6%. Bland-Altman plots of week-to-week variations showed rates of significant disagreement for samples collected in any 2 successive weeks varied from 5% in NAFLD patients to 8.3% in healthy subjects. When using non-fasting serum samples, hyaluronic acid and to a lesser extent, the Hepascore model display large within-individual variations in both health and chronic liver disease. This information is critical for interpreting the significance of both single measurements and changes in serial measurements.

  18. FOXA2 alleviates CCl4-induced liver fibrosis by protecting hepatocytes in mice

    OpenAIRE

    Wang, Wei; Yao, Li-Jia; Shen, Weifeng; Ding, Kai; Shi, Pei-Mei; Chen, Fei; He, Jin; Ding, Jin; Zhang, Xin; Xie, Wei-Fen

    2017-01-01

    The liver-enriched transcription factor Forkhead Box A2 (FOXA2) has been reported to be involved in bile acid homeostasis and bile duct development. However, the role of FOXA2 in liver fibrogenesis remains undefined. In this study, we found that the abundance of FOXA2 was significantly lower in fibrotic livers of patients and mice treated with CCl4 than in controls. Interestingly, the expression level of FOXA2 decreased in hepatocytes, whereas FOXA2 was elevated in hepatic stellate cells (HSC...

  19. Relationship between adiponectin and hepatic fibrosis markers expressions as well as insulin resistance index in patients with non-alcoholic fatty liver disease

    International Nuclear Information System (INIS)

    Cui Jianhe; Pan Feng; Zhou Chuanwen; Ren Jianguo; Li Donghai

    2009-01-01

    Objective: To investigate the retationship between expressions of adiponectin and hepatic fibrosis markers as well as insulin resistance index in patients with non-alcoholic fatty liver disease. Methods: Serum adiponectin, type III pro-collagen (PCIII), hyaluronic acid (HA), type IV collagen (CIV), laminin levels (with ELISA) and insulin resistance index (IRI) (calculated from homeostasis model assessment) were determined in 46 patients with non-alcoholic fatty liver disease (NAFLD) and 46 controls. Results The serum adiponectin levels in patients with NAFLD were significantly lower than those in controls while the serum hepatic fibrosis markers (PCIII, HA, CIV, LN) levels and IRI were significantly higher than those in controls (P<0.05). IRI was significantly positively correlated with the hepatic fibrosis markers levels (P<0.05). Serum adiponectin levels were significantly negatively correlated with WHR, RMI, HOMA-IRI and levels of FRG, TG, FINS hepatic fibrosis markers (P<0.05 or P<0.01). Conclusion: Serum adiponectin levels were greatly reduced in patients with NAFLD, which might play important role in the increase of insulin resistance and development of hepatic fibrosis. (authors)

  20. Molecular magnetic resonance imaging of activated hepatic stellate cells with ultrasmall superparamagnetic iron oxide targeting integrin αvβ3 for staging liver fibrosis in rat model

    Directory of Open Access Journals (Sweden)

    Zhang C

    2016-03-01

    Full Text Available Caiyuan Zhang,1,* Huanhuan Liu,1,* Yanfen Cui,1,* Xiaoming Li,1 Zhongyang Zhang,1 Yong Zhang,2 Dengbin Wang1 1Department of Radiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 2MR Advanced Application and Research Center, GE Healthcare China, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: To evaluate the expression level of integrin αvβ3 on activated hepatic stellate cells (HSCs at different stages of liver fibrosis induced by carbon tetrachloride (CCl4 in rat model and the feasibility to stage liver fibrosis by using molecular magnetic resonance imaging (MRI with arginine-glycine-aspartic acid (RGD peptide modified ultrasmall superparamagnetic iron oxide nanoparticle (USPIO specifically targeting integrin αvβ3.Materials and methods: All experiments received approval from our Institutional Animal Care and Use Committee. Thirty-six rats were randomly divided into three groups of 12 subjects each, and intraperitoneally injected with CCl4 for either 3, 6, or 9 weeks. Controls (n=10 received pure olive oil. The change in T2* relaxation rate (ΔR2* pre- and postintravenous administration of RGD-USPIO or naked USPIO was measured by 3.0T clinical MRI and compared by one-way analysis of variance or the Student’s t-test. The relationship between expression level of integrin αvβ3 and liver fibrotic degree was evaluated by Spearman’s ranked correlation.Results: Activated HSCs were confirmed to be the main cell types expressing integrin αvβ3 during liver fibrogenesis. The protein level of integrin αv and β3 subunit expressed on activated HSCs was upregulated and correlated well with the progression of liver fibrosis (r=0.954, P<0.001; r=0.931, P<0.001, respectively. After injection of RGD-USPIO, there is significant difference in ΔR2* among rats treated with 0, 3, 6, and 9 weeks of CCl4 (P<0.001. The accumulation of iron particles in fibrotic liver specimen is

  1. 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.

  2. Effect of Buqi Huoxue decoction on hemodynamics and liver fibrosis indices in hepatitis B patients with cirrhotic portal hypertension

    Directory of Open Access Journals (Sweden)

    BAI Zhiqin

    2017-02-01

    Full Text Available ObjectiveTo investigate the effect of Buqi Huoxue decoction on hemodynamics and liver fibrosis indices in hepatitis B patients with cirrhotic portal hypertension. MethodsA total of 79 patients with hepatitis B cirrhosis who were admitted to The People′s Hospital of Qingyuan District from December 2013 to August 2015 were enrolled and randomly divided into study group (41 patients and control group (38 patients. The patients in both groups were given oral entecavir (0.5 mg, once a day and bicyclol tablets (25 mg, three times a day; the patients in the control group were given propranolol (10 mg, three times a day in addition, and those in the study group were given Buqi Huoxue decoction in addition. The course of treatment was 12 weeks for both groups. The hemodynamics and liver fibrosis indices were compared between the two groups before treatment and after 12 weeks of treatment. The t-test was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data between groups. ResultsAfter 12 weeks of treatment, both groups had significant reductions in diameter of the portal vein, diameter of the splenic vein, and portal vein flow and a significant increase in portal vein blood flow velocity (t=3.847, 4.672, 3.524, 5.237, 3.578, 3.829, 3.468, and 3.673, P=0.041, 0.036, 0.047, 0.032, 0.045, 0.042, 0.048, and 0.046, and the study group had significantly greater changes in these parameters compared with the control group (diameter of the portal vein: 12.86±2.34 mm vs 13.65±2.45 mm, t=3.725, P=0.044; diameter of the splenic vein: 9.50±1.26 mm vs 11.15±1.37 mm, t=-6.672, P=0.012; portal vein flow: 1.23±0.35 L/min vs 1.38±0.44 L/min, t=-3.521, P=0.047; portal vein blood flow velocity: 19.50±4.65 cm/s vs 17.57±2.40 cm/s, t=-6.225, P=0.024. After 12 weeks of treatment, both groups had reductions in the four liver fibrosis indices hyaluronic acid, laminin, procollagen type Ⅲ, and

  3. Anti-fibrotic potential of human umbilical cord mononuclear cells and mouse bone marrow cells in CCl4- induced liver fibrosis in mice.

    Science.gov (United States)

    Elmahdy, Nageh Ahmed; Sokar, Samia Salem; Salem, Mohamed Labib; Sarhan, Naglaa Ibrahim; Abou-Elela, Sherin Hamed

    2017-05-01

    Liver fibrosis is the consequence of hepatocyte injury that leads to the activation of hepatic stellate cells (HSC). The treatment of choice is Liver transplantation; however, it has many problems such as surgery-related complications, immunological rejection and high costs associated with the procedure. Stem cell-based therapy would be a potential alternative, so the aim of this study is to investigate the therapeutic potential of human umbilical cord mononuclear cells (MNC) and mouse bone marrow cells (BMC) against carbon tetrachloride (CCl 4 ) induced liver fibrosis in mice and compare it with that of silymarin. In the present study, male albino mice (N=60) were divided into six groups (10 mice each), the first group served as the normal control group while the remaining five groups were rendered fibrotic by intraperitoneal injections of CCl 4 and being left for 6 weeks to develop hepatic fibrosis. Thereafter, the mice were divided into CCl 4 group, CCl 4 group receiving MNC or BMC or silymarin or MNC and silymarin combination. After the specified treatment period, animals were then euthanized, blood and tissue samples were collected for measurement of alanine aminotransferase(ALT), aspartate aminotransferase(AST), malondialdehyde(MDA), reduced glutathione(GSH), collagen, Laminin, transforming growth factor β1(TGFβ1), tumor necrosis factor alpha(TNFα). MNC, BMC, and the combination therapy showed a significant decrease in ALT, AST, MDA, collagen, Laminin, TGFβ1, and TNFα and a significant increase in GSH. The data displayed a similar regression of fibrosis with the histological and immunohistological parameters. In conclusion, MNC, BMC and the combination therapy showed a potential therapeutic effect against liver fibrosis via reducing oxidative stress, inflammatory mediators, and fibrogenic markers. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Which are the cut-off values of 2D-Shear Wave Elastography (2D-SWE) liver stiffness measurements predicting different stages of liver fibrosis, considering Transient Elastography (TE) as the reference method?

    Energy Technology Data Exchange (ETDEWEB)

    Sporea, Ioan, E-mail: isporea@umft.ro; Bota, Simona, E-mail: bota_simona1982@yahoo.com; Gradinaru-Taşcău, Oana, E-mail: bluonmyown@yahoo.com; Şirli, Roxana, E-mail: roxanasirli@gmail.com; Popescu, Alina, E-mail: alinamircea.popescu@gmail.com; Jurchiş, Ana, E-mail: ana.jurchis@yahoo.com

    2014-03-15

    Introduction: To identify liver stiffness (LS) cut-off values assessed by means of 2D-Shear Wave Elastography (2D-SWE) for predicting different stages of liver fibrosis, considering Transient Elastography (TE) as the reference method. Methods: Our prospective study included 383 consecutive subjects, with or without hepatopathies, in which LS was evaluated by means of TE and 2D-SWE. To discriminate between various stages of fibrosis by TE we used the following LS cut-offs (kPa): F1-6, F2-7.2, F3-9.6 and F4-14.5. Results: The rate of reliable LS measurements was similar for TE and 2D-SWE: 73.9% vs. 79.9%, p = 0.06. Older age and higher BMI were associated for both TE and 2D-SWE with the impossibility to obtain reliable LS measurements. Reliable LS measurements by both elastographic methods were obtained in 65.2% of patients. A significant correlation was found between TE and 2D-SWE measurements (r = 0.68). The best LS cut-off values assessed by 2D-SWE for predicting different stages of liver fibrosis were: F ≥ 1: >7.1 kPa (AUROC = 0.825); F ≥ 2: >7.8 kPa (AUROC = 0.859); F ≥ 3: >8 kPa (AUROC = 0.897) and for F = 4: >11.5 kPa (AUROC = 0.914). Conclusions: 2D-SWE is a reliable method for the non-invasive evaluation of liver fibrosis, considering TE as the reference method. The accuracy of 2D-SWE measurements increased with the severity of liver fibrosis.

  5. Liver tryptase-positive mast cells and fibrosis in children with hepatic echinococcosis

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    Gulubova Maya

    2005-01-01

    Full Text Available The hepatic echinococcosis in children is a serious surgical problem. The aim of this study is to investigate the participation of mast cells in liver inflammatory reactions triggered by echinococcal cysts. Liver biopsy samples were collected from the tissue surrounding the cysts from 16 sick children (11 boys and 5 girls in the course of abdominal surgery and from 5 controls. Light and ultrastructural immunocytochemistry was performed using monoclonal antibody against tryptase. Light microscopical immunocytochemistry revealed abundance of tryptase-positive (MCT mast cells in the capsules of the cysts (43.58 cells/mm2. There were also observed greatly increased numbers of mast cells in portal tracts surrounding the cyst, compared to those of control biopsies (26.49 vs. 1.78 cells/mm2, p=0.0009, Mann-Whitney U test. Based on the ultrastructural appearance of tryptase-positive mast cell granules, morphological sings of activation of most of the mast cells were distinguished. In conclusion, we suggest that the accumulated and activated tryptase-positive mast cells in liver tissues surrounding the echinococcal cysts play a crucial role in modulation of the inflammatory liver response and could induce chronic inflammation and fibrogenesis, resulting in serious liver injury such as nonspecific reactive hepatitis.

  6. Antioxidant, antiapoptotic and amino acid balance regulating activities of 1,7-dihydroxy-3,4,8-trimethoxyxanthone against dimethylnitrosamine-induced liver fibrosis.

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    Xi-Yuan Zheng

    Full Text Available Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injury which could be caused by viral, autoimmune, drugs, and so on. Unfortunately, there was no effective therapy available for liver fibrosis in clinic. In this study, we identified the anti-fibrotic effects of 1,7-dihydroxy-3,4,8-trimethoxyxanthone (ZYC-1 on the dimethylnitrosamine (DMN-induced rat model. ZYC-1 was isolated from Swertia punicea Hemsl and was administrated to DMN-induced rat model. ZYC decreased the hyaluronic acid (HA, type IV collagen (CIV and hydroxyproline (Hyp levels and inhibited the expression of α smooth muscle actin (α-SMA and transforming growth factor beta 1 (TGF-1β. The anti-fibrotic effect of ZYC-1 was also confirmed by Sirius Red staining. Finally, we identified 42 differentially expressed proteins by using proteomics analysis after ZYC-1 treatment, of which 17 were up-regulated and 25 were down-regulated. These Most of the 42 proteins are involved in the oxidative stress pathway, the mitochondrial-mediated apoptotic pathway and the amino acid metabolism pathway. Our study presented the first elucidated mechanisms of xanthone on liver fibrosis in vivo. This study pointed out that ZYC-1 may be used as a lead compound for hepatofibrosis treatment.

  7. Vaccine induced Hepatitis A and B protection in children at risk for cystic fibrosis associated liver disease.

    Science.gov (United States)

    Shapiro, Adam J; Esther, Charles R; Leigh, Margaret W; Dellon, Elisabeth P

    2013-01-30

    Hepatitis A (HAV) and Hepatitis B (HBV) infections can cause serious morbidity in patients with liver disease, including cystic fibrosis associated liver disease (CFALD). HAV and HBV vaccinations are recommended in CFALD, and maintenance of detectable antibody levels is also recommended with chronic liver disease. A better understanding of factors predicting low HAV and HBV antibodies may help physicians improve protection from these viruses in CFALD patients. We examined HAV and HBV vaccine protection in children at risk for CFALD. Clinical and vaccine histories were reviewed, and HAV and HBV antibody titers measured. Those with no vaccination history or low HAV or HBV titers received primary or booster vaccinations, and responses were measured. Thirty-four of 308 children were at risk for CFALD per project criteria. Ten had previous HAV vaccination, of which 90% had positive anti-HAV antibodies. Thirty-three of 34 had previously received primary HBV vaccination (most in infancy), but only 12 (35%) had adequate anti-HBs levels (≥10mIU/mL). Children with adequate anti-HBs levels were older at first HBV vaccine (median 2.3 vs. 0.1 years, p<0.01), and at final HBV vaccine (median 4.0 vs. 0.8 years, p=0.01). Fourteen of 19 (74%) responded to HBV boosters. Z-scores for BMI at HBV booster were significantly lower in booster non-responders (p=0.04). Children at increased risk of CFALD have inadequate HAV and HBV antibody levels, and HBV antibody protection can be enhanced through vaccine boosters. HBV antibody titers should be assessed in CFALD patients with a history of vaccination, particularly in those who received HBV vaccines in infancy or who are malnourished. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Comparison of the Treatment Efficiency of Bone Marrow-Derived Mesenchymal Stem Cell Transplantation via Tail and Portal Veins in CCl4-Induced Mouse Liver Fibrosis

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    Nhung Hai Truong

    2016-01-01

    Full Text Available Because of self-renewal, strong proliferation in vitro, abundant sources for isolation, and a high differentiation capacity, mesenchymal stem cells are suggested to be potentially therapeutic for liver fibrosis/cirrhosis. In this study, we evaluated the treatment effects of mouse bone marrow-derived mesenchymal stem cells (BM-MSCs on mouse liver cirrhosis induced by carbon tetrachloride. Portal and tail vein transplantations were examined to evaluate the effects of different injection routes on the liver cirrhosis model at 21 days after transplantation. BM-MSCs transplantation reduced aspartate aminotransferase/alanine aminotransferase levels at 21 days after injection. Furthermore, BM-MSCs induced positive changes in serum bilirubin and albumin and downregulated expression of integrins (600- to 7000-fold, transforming growth factor, and procollagen-α1 compared with the control group. Interestingly, both injection routes ameliorated inflammation and liver cirrhosis scores. All mice in treatment groups had reduced inflammation scores and no cirrhosis. In conclusion, transplantation of BM-MSCs via tail or portal veins ameliorates liver cirrhosis in mice. Notably, there were no differences in treatment effects between tail and portal vein administrations. In consideration of safety, we suggest transfusion of bone marrow-derived mesenchymal stem cells via a peripheral vein as a potential method for liver fibrosis treatment.

  9. Regression of fibrosis/cirrhosis by Glycine propionyl-l-carnitine treatment in d-Galactosamine induced chronic liver damage.

    Science.gov (United States)

    Ganai, Ajaz Ahmad; Ganaie, Ishfaq Ahmad; Verma, Nishika; Farooqi, Humaira

    2016-12-25

    Liver fibrosis and cirrhosis are leading causes of morbidity and mortality, with majority of preventable cases attributed to excessive alcohol consumption, viral hepatitis, or non-alcoholic fatty liver disease. We previously reported the hepatoprotective effect of Glycine propionyl-l-carnitine (GPLC) against the fulminant hepatic failure (FHF) induced by d-Galactosamine (D-GalN). In this study we evaluated the protective effect of GPLC against D-GalN induced chronic liver damage. Animals received D-GalN twice a week for 12 weeks at a dose of 250 mg/kg body weight (BW). GPLC was given daily for 12 weeks as co-treatment along with D-GalN at a dose of 35 mg/kg BW. D-GalN injection resulted in a considerable decrease in body weight, hepatocellular disintegration, necrosis and lipid peroxidation as evident from altered levels of SOD, CAT and MDA while GPLC significantly restored the reduced body weight and ameliorated hepatocellular damage and lipid peroxidation. D-GalN administration resulted in DNA damage as evident from TUNEL positive cells in disease control rats while; GPLC significantly alleviated the genotoxic effects of D-GalN. Further histopathological analysis revealed significant tissue and cellular damage, and increased collagen content in D-GalN challenged rats. GPLC however ameliorated the damage as evident from normal cellular and morphological architecture in GPLC co-treated rats. Hydroxyproline and nitrotyrosine (NTY) levels marked a significant decrease in GPLC co-treated rats relative to disease control. GPLC significantly blocked D-GalN induced pro-inflammatory cytokine (TNF-α, IL-6) production and at the same time inhibited the expression of α-smooth muscle actin (α-SMA), collagen-I (COL-I) and transforming growth factor-β (TGF-β) significantly. Our results demonstrate significant protective activity of GPLC in chronic liver damage and other complications related to it. This study is a novel study to demonstrate the hepatoprotective effect

  10. Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis

    DEFF Research Database (Denmark)

    Rambaldi, A; Gluud, C

    2005-01-01

    Alcohol and hepatotropic viruses cause the majority of liver cirrhosis cases in the Western World. Colchicine is an anti-inflammatory and anti-fibrotic medication. Several randomised clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic or non-alcoholic...

  11. PHP14 regulates hepatic stellate cells migration in liver fibrosis via mediating TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway.

    Science.gov (United States)

    Xu, Anjian; Li, Yanmeng; Zhao, Wenshan; Hou, Fei; Li, Xiaojin; Sun, Lan; Chen, Wei; Yang, Aiting; Wu, Shanna; Zhang, Bei; Yao, Jingyi; Wang, Huan; Huang, Jian

    2018-02-01

    Hepatic fibrosis is characterized by the activation of hepatic stellate cells (HSCs). Migration of the activated HSCs to the site of injury is one of the key characteristics during the wound healing process. We have previously demonstrated that 14 kDa phosphohistidine phosphatase (PHP14) is involved in migration and lamellipodia formation of HSCs. However, the role of PHP14 in liver fibrosis remains unknown. In this study, we first assessed PHP14 expression and distribution in liver fibrotic tissues using western blot, immunohistochemistry, and double immunofluorescence staining. Next, we investigated the role of PHP14 in liver fibrosis and, more specifically, the migration of HSCs by Transwell assay and 3D collagen matrices assay. Finally, we explored the possible molecular mechanisms of the effects of PHP14 on these processes. Our results show that the PHP14 expression is up-regulated in fibrotic liver and mainly in HSCs. Importantly, TGF-β1 can induce PHP14 expression in HSCs accompanied with the activation of HSCs. Consistent with the previous study, PHP14 promotes HSCs migration, especially, promotes 3D floating collagen matrices contraction but inhibits stressed-released matrices contraction. Mechanistically, the PI3Kγ/AKT/Rac1 pathway is involved in migration regulated by PHP14. Moreover, PHP14 specifically mediates the TGF-β1 signaling to PI3Kγ/AKT pathway and regulates HSC migration, and thus participates in liver fibrosis. Our study identified the role of PHP14 in liver fibrosis, particularly HSC migration, and suggested a novel mediator of transducting TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway. PHP14 is up-regulated in fibrotic liver and activated hepatic stellate cells. The expression of PHP14 is induced by TGF-β1. The migration of hepatic stellate cells is regulated by PHP14. PHP14 is a mediator of TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway in hepatic stellate cells.

  12. Naringenin prevents experimental liver fibrosis by blocking TGFβ-Smad3 and JNK-Smad3 pathways

    Science.gov (United States)

    Hernández-Aquino, Erika; Zarco, Natanael; Casas-Grajales, Sael; Ramos-Tovar, Erika; Flores-Beltrán, Rosa E; Arauz, Jonathan; Shibayama, Mineko; Favari, Liliana; Tsutsumi, Víctor; Segovia, José; Muriel, Pablo

    2017-01-01

    AIM To study the molecular mechanisms involved in the hepatoprotective effects of naringenin (NAR) on carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS Thirty-two male Wistar rats (120-150 g) were randomly divided into four groups: (1) a control group (n = 8) that received 0.7% carboxy methyl-cellulose (NAR vehicle) 1 mL/daily p.o.; (2) a CCl4 group (n = 8) that received 400 mg of CCl4/kg body weight i.p. 3 times a week for 8 wk; (3) a CCl4 + NAR (n = 8) group that received 400 mg of CCl4/kg body weight i.p. 3 times a week for 8 wk and 100 mg of NAR/kg body weight daily for 8 wk p.o.; and (4) an NAR group (n = 8) that received 100 mg of NAR/kg body weight daily for 8 wk p.o. After the experimental period, animals were sacrificed under ketamine and xylazine anesthesia. Liver damage markers such as alanine aminotransferase (ALT), alkaline phosphatase (AP), γ-glutamyl transpeptidase (γ-GTP), reduced glutathione (GSH), glycogen content, lipid peroxidation (LPO) and collagen content were measured. The enzymatic activity of glutathione peroxidase (GPx) was assessed. Liver histopathology was performed utilizing Masson’s trichrome and hematoxylin-eosin stains. Zymography assays for MMP-9 and MMP-2 were carried out. Hepatic TGF-β, α-SMA, CTGF, Col-I, MMP-13, NF-κB, IL-1, IL-10, Smad7, Smad3, pSmad3 and pJNK proteins were detected via western blot. RESULTS NAR administration prevented increases in ALT, AP, γ-GTP, and GPx enzymatic activity; depletion of GSH and glycogen; and increases in LPO and collagen produced by chronic CCl4 intoxication (P < 0.05). Liver histopathology showed a decrease in collagen deposition when rats received NAR in addition to CCl4. Although zymography assays showed that CCl4 produced an increase in MMP-9 and MMP-2 gelatinase activity; interestingly, NAR administration was associated with normal MMP-9 and MMP-2 activity (P < 0.05). The anti-inflammatory, antinecrotic and antifibrotic effects of NAR may be attributed to its ability

  13. Assessing risk of fibrosis progression and liver-related clinical outcomes among patients with both early stage and advanced chronic hepatitis C.

    Directory of Open Access Journals (Sweden)

    Monica A Konerman

    Full Text Available Assessing risk of adverse outcomes among patients with chronic liver disease has been challenging due to non-linear disease progression. We previously developed accurate prediction models for fibrosis progression and clinical outcomes among patients with advanced chronic hepatitis C (CHC. The primary aim of this study was to validate fibrosis progression and clinical outcomes models among a heterogeneous patient cohort.Adults with CHC with ≥3 years follow-up and without hepatic decompensation, hepatocellular carcinoma (HCC, liver transplant (LT, HBV or HIV co-infection at presentation were analyzed (N = 1007. Outcomes included: 1 fibrosis progression 2 hepatic decompensation 3 HCC and 4 LT-free survival. Predictors included longitudinal clinical and laboratory data. Machine learning methods were used to predict outcomes in 1 and 3 years.The external cohort had a median age of 49.4 years (IQR 44.3-54.3; 61% were male, 80% white, and 79% had genotype 1. At presentation, 73% were treatment naïve and 31% had cirrhosis. Fibrosis progression occurred in 34% over a median of 4.9 years (IQR 3.2-7.6. Clinical outcomes occurred in 22% over a median of 4.4 years (IQR 3.2-7.6. Model performance for fibrosis progression was limited due to small sample size. The area under the receiver operating characteristic curve (AUROC for 1 and 3-year risk of clinical outcomes was 0.78 (95% CI 0.73-0.83 and 0.76 (95% CI 0.69-0.81.Accurate assessments for risk of clinical outcomes can be obtained using routinely collected data across a heterogeneous cohort of patients with CHC. These methods can be applied to predict risk of progression in other chronic liver diseases.

  14. Protective effects of a polymethoxy flavonoids-rich Citrus aurantium peel extract on liver fibrosis induced by bile duct ligation in mice.

    Science.gov (United States)

    Lim, Seol-Wa; Lee, Dong-Ryung; Choi, Bong-Keun; Kim, Hong-Suk; Yang, Seung Hwan; Suh, Joo-Won; Kim, Kyung Soo

    2016-12-01

    To evaluate the possible protective effect of Citrus aurantium peel extract (CAE) against apoptosis in cholestatic liver fibrosis induced by bile duct ligation in mice. Male ICR mice were divided to 5 groups: 1) Control group (Sham-operated mice), 2) Cholestatic liver injury group induced by bile duct ligation (BDL), 3) BDL mice treated with silymarin (200 mg/kg) for 4 weeks, 4) BDL mice treated with 50 mg/kg CAE for 4 weeks, 5) BDL mice treated with 200 mg/kg CAE for 4 weeks. Mice were sacrificed and liver fibrosis was evaluated by serum and hepatic tissue biochemistry tests and liver histopathological examination. Effects of CAE on inflammation and apoptosis gene regulation were investigated through real-time PCR. CAE effect on lipid metabolism related signaling was determined by western blot analysis. In BDL mice, administration of CAE for 4 weeks markedly attenuated liver fibrosis based on histopathological alteration. Serum and hepatic tissue biochemistry results revealed that CAE (50 and 200 mg/kg) decreased the levels of alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, total bilirubin, nitric oxide, and thiobarbituric acid reactive substances. Real-time PCR and western blot analysis showed that CAE regulated inflammation, apoptosis, and lipid metabolism factors increased by BDL. Interleukin family, tumor necrosis factor α, and related apoptosis factors mRNA levels were increased by BDL treatment. However, these increases were suppressed by CAE administration. In addition, CAE effectively increased phosphorylation of AMP-activated protein kinase, nuclear factor E2-related factor 2, and related cytoprotective proteins. CAE can efficiently regulate BDL-induced liver injury with antioxidant, anti-inflammatory, and anti-apoptotic activities. Copyright © 2016 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

  15. Lack of a 5.9 kDa peptide C-terminal fragment of fibrinogen α chain precedes fibrosis progression in patients with liver disease.

    Directory of Open Access Journals (Sweden)

    Santiago Marfà

    Full Text Available Early detection of fibrosis progression is of major relevance for the diagnosis and management of patients with liver disease. This study was designed to find non-invasive biomarkers for fibrosis in a clinical context where this process occurs rapidly, HCV-positive patients who underwent liver transplantation (LT. We analyzed 93 LT patients with HCV recurrence, 41 non-LT patients with liver disease showing a fibrosis stage F≥1 and 9 patients without HCV recurrence who received antiviral treatment before LT, as control group. Blood obtained from 16 healthy subjects was also analyzed. Serum samples were fractionated by ion exchange chromatography and their proteomic profile was analyzed by SELDI-TOF-MS. Characterization of the peptide of interest was performed by ion chromatography and electrophoresis, followed by tandem mass spectrometry identification. Marked differences were observed between the serum proteome profile of LT patients with early fibrosis recurrence and non-recurrent LT patients. A robust peak intensity located at 5905 m/z was the distinguishing feature of non-recurrent LT patients. However, the same peak was barely detected in recurrent LT patients. Similar results were found when comparing samples of healthy subjects with those of non-LT fibrotic patients, indicating that our findings were not related to either LT or HCV infection. Using tandem mass-spectrometry, we identified the protein peak as a C-terminal fragment of the fibrinogen α chain. Cell culture experiments demonstrated that TGF-β reduces α-fibrinogen mRNA expression and 5905 m/z peak intensity in HepG2 cells, suggesting that TGF-β activity regulates the circulating levels of this protein fragment. In conclusion, we identified a 5.9 kDa C-terminal fragment of the fibrinogen α chain as an early serum biomarker of fibrogenic processes in patients with liver disease.

  16. Virtual Touch™ Quantification to Diagnose and Monitor Liver Fibrosis in Hepatitis B and Hepatitis C: A NICE Medical Technology Guidance.

    Science.gov (United States)

    Summers, Jennifer A; Radhakrishnan, Muralikrishnan; Morris, Elizabeth; Chalkidou, Anastasia; Rua, Tiago; Patel, Anita; McMillan, Viktoria; Douiri, Abdel; Wang, Yanzhong; Ayis, Salma; Higgins, Joanne; Keevil, Stephen; Lewis, Cornelius; Peacock, Janet

    2017-04-01

    Virtual Touch™ Quantification (VTq) is a software application used with Siemens Acuson ultrasound scanners to assess the stiffness of liver tissue. The National Institute for Health and Care Excellence (NICE) Medical Technologies Advisory Committee (MTAC) selected VTq for evaluation and invited the company to submit clinical and economic evidence. King's Technology Evaluation Centre, an External Assessment Centre (EAC) commissioned by NICE, independently assessed the evidence submitted. The EAC conducted its own systematic review, meta-analysis and economic analysis to supplement the company's submitted evidence. The meta-analyses comparing VTq and transient elastography (TE) with liver biopsy (LB) provided pooled estimates of liver stiffness and stage of fibrosis for the study populations (hepatitis B, hepatitis C or combined populations). When comparing significant fibrosis (Metavir score F ≥ 2) for both hepatitis B and C, VTq had slightly higher values for both sensitivity and specificity (77 and 81 %) than TE (76 and 71 %). The overall prevalence of cirrhosis (F4, combined populations) was similar with VTq and TE (23 vs. 23 %), and significant fibrosis (F ≥ 2) was lower for VTq than for TE (55 vs. 62 %). The EAC revised the company's de novo cost model, which resulted in a cost saving of £53 (against TE) and £434 (against LB). Following public consultation, taking into account submitted comments, NICE Medical Technology Guidance MTG27 was published in September 2015. This recommended the adoption of the VTq software to diagnose and monitor liver fibrosis in patients with hepatitis B or hepatitis C.

  17. Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Hagström, Hannes; Nasr, Patrik; Ekstedt, Mattias; Kechagias, Stergios; Önnerhag, Kristina; Nilsson, Emma; Rorsman, Fredrik; Sheikhi, Reza; Marschall, Hanns-Ulrich; Hultcrantz, Rolf; Stål, Per

    2017-02-01

    Moderate alcohol consumption has been associated with a lower risk of disease severity in non-alcoholic fatty liver disease (NAFLD). It is unclear if this reflects current or lifetime drinking, or can be attributed to confounders such as diet and exercise. We evaluated the impact of lifetime alcohol consumption on fibrosis severity in NAFLD. We prospectively enrolled 120 subjects with biopsy-proven NAFLD and through detailed questionnaires examined lifetime alcohol consumption, diet and physical activity. Main outcome measures were odds ratios (OR) for fibrosis stage, calculated through ordinal regression after adjustment for body mass index, diabetes mellitus type 2, smoking and age at biopsy. A biomarker for recent alcohol consumption, phosphatidyl ethanol (PEth) was sampled. An increase in median weekly alcohol consumption to a maximum of 13 drinks per week was associated with lower fibrosis stage (adjusted OR for each incremental unit, 0.86; 95% CI, 0.76-0.97; p = .017). The lowest risk for fibrosis was found with the lowes`t odds seen in the top quartile of alcohol consumption (aOR 0.23; 95% CI 0.08-0.66; p = .006). Adding soft drink and coffee consumptions, and physical activity to the model did not change the estimates. Subjects with PEth ≥0.3 μmol/L had higher ORs for a higher fibrosis stage (aOR 2.77; 95% CI 1.01-7.59; p = .047). Lifetime alcohol consumption with up to 13 units per week is associated with lower fibrosis stage in NAFLD. Elevated PEth is associated with higher stages of fibrosis.

  18. Diagnostic value of real-time elastography in the assessment of hepatic fibrosis in patients with liver iron overload

    Energy Technology Data Exchange (ETDEWEB)

    Paparo, Francesco [Department of Radiology, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Cevasco, Luca [School of Radiology, University of Genoa, Via Leon Battista Alberti 4, 16132 Genoa (Italy); Zefiro, Daniele [Medical Physics Department, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Biscaldi, Ennio; Bacigalupo, Lorenzo [Department of Radiology, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Balocco, Manuela [Unit of Microcitemia and Hereditary Anaemias, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Pongiglione, Marta; Banderali, Simone [Department of Radiology, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Forni, Gian Luca [Unit of Microcitemia and Hereditary Anaemias, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Rollandi, Gian Andrea, E-mail: gian.andrea.rollandi@galliera.it [Department of Radiology, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy)

    2013-12-01

    Objective: The objective of our prospective monocentric work was to determine the diagnostic value of real-time elastography (RTE) in the assessment of liver fibrosis in patients with iron overload, using transient elastography (TE) as reference standard. Methods: Sixty-seven consecutive patients with MRI detectable iron overload (T2* < 6.3 ms) were enrolled. TE and RTE were performed on the same day as MRI. Elastograms were acquired by an experienced operator and analyzed by calculating the elastic ratio between perihepatic soft tissues and liver parenchyma. An elliptical ROI of 1 cm{sup 2} (Z{sub 1}) was positioned in the liver parenchyma and a smaller elliptical ROI of 2 mm{sup 2} (Z{sub 2}) was positioned in a homogeneously soft (red) region of the diaphragm, which was considered as internal control to calculate the elastic ratio Z{sub 2}/Z{sub 1}. Results: Seven patients were excluded because of invalid TE or RTE examinations. The remaining 60 patients were 57% males and 43% females (mean age: 42 [21–76] years), including 37 homozygous-β-thalassemics, 13 patients with β-thalassemia intermedia, 6 with primary hemochromatosis, and 4 with myelodysplastic syndrome. Increasing elastic ratios were significantly correlated with increasing TE values (r = 0.645, 95% CI 0.468–0.772, P < 0.0001). The mean elastic ratios for each METAVIR group were as follows: F0/1 = 1.9 ± 0.4; F2 = 2.2 ± 0.4; F3 = 2.9 ± 0.5; F4 = 3.2 ± 0.4. The diagnostic accuracy of RTE for F ≥ 2 evaluated by AUC-ROC analysis was 0.798 (95% CI 0.674–0.890). The diagnostic accuracy of RTE for F ≥ 3 was 0.909 (95% CI 0.806–0.968). At a cut-off ≥ 2.75, RTE showed a sensitivity of 70% (95% CI 45.7–88.1) and a specificity of 97.5% (95% CI 86.8–99.9). Conclusions: In patients with MRI-detectable liver iron-overload RTE allows to discriminate between F0/1–F2 and F3–F4 with a reasonable diagnostic accuracy.

  19. Fibrogenesis assessed by serological type III collagen formation identifies patients with progressive liver fibrosis and responders to a potential antifibrotic therapy

    DEFF Research Database (Denmark)

    Karsdal, Morten A; Henriksen, Kim; Nielsen, Mette Juul

    2016-01-01

    trial of the glitazone farglitazar in patients with advanced hepatitis C, with matched follow-up liver biopsies, and from a phase III study of balaglitazone in patients with late-stage Type 2 diabetes (BALLET study) were analyzed for serological Pro-C3 levels in conjunction with other disease parameters....... In the farglitazar study, a predefined cutoff value for Pro-C3 as a selection criterion led to the identification of subjects who 1) progressed by histological scores and 2) responded to therapy, as documented by attenuated fibrosis in liver biopsies. In the BALLET trial, subjects with the highest tertile of Pro-C3...

  20. [Intervention of chronic hepatitis B liver fibrosis patients in different stages by syndrome typing and different activating blood removing stasis methods: a clinical study].

    Science.gov (United States)

    Liu, Shi-yi; Zhang, Yin-qiang; Liu, Yan-ling; Guo, Peng; Zhou, Chun-mei

    2013-11-01

    To observe the clinical efficacy of treating chronic hepatitis B liver fibrosis (CHBLF) in different stages by syndrome typing and different activating blood removing stasis methods (ABRSM). Totally 100 CHBLF patients of vital qi deficiency blood stasis syndrome (VQDBSS) treated at the Department of Liver Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences from July 2008 to December 2011, were randomly assigned to the treatment group and the control group, 50 in each group. Those in the treatment group were treated by self-formulated decoctions for activating blood nourishing blood (ABNB), activating blood removing stasis (ABRS), and activating blood softening hard mass (ABSHM) according to their stages of disease conditions (mild, moderate, and severe). Those in the control group were treated with Compound Biejia Ruangan Tablet (CBRT). Integrals of Chinese medical syndromes, liver functions [mainly including alanine aminotransferase (ALT), albumin/globulin (A/ G)], ultrasonographic examinations of liver (mainly including echoes of liver, width of spleens, width of portal vein), four indicators of serum hepatic fibrosis [including serum hyaluronic acid (HA), laminin (LN), type IV collagen (IV-C), type III collagen peptide (P-III-P)] were statistically analyzed. The therapeutic course was 6 months for all. Compared with before treatment in the same group, the integrals of Chinese medical syndromes both decreased after treatment in the two groups (P serum biochemical indicators.

  1. The antioxidant effect of β-caryophyllene protects rat liver from carbon tetrachloride-induced fibrosis by inhibiting hepatic stellate cell activation.

    Science.gov (United States)

    Calleja, Miguel Angel; Vieites, Jose María; Montero-Meléndez, Trinidad; Montero-Meterdez, Trinidad; Torres, María Isabel; Faus, María José; Gil, Angel; Suárez, Antonio

    2013-02-14

    Plant-based whole foods provide thousands of bioactive metabolites to the human diet that reduce the risk of developing chronic diseases. β-Caryophyllene (CAR) is a common constituent of the essential oil of numerous plants, vegetables, fruits and medicinal herbs, and has been used as a flavouring agent since the 1930 s. Here, we report the antioxidant activity of CAR, its protective effect on liver fibrosis and its inhibitory capacity on hepatic stellate cell (HSC) activation. CAR was tested for the inhibition of lipid peroxidation and as a free radical scavenger. CAR had higher inhibitory capacity on lipid peroxidation than probucol, α-humulene and α-tocopherol. Also, CAR showed high scavenging activities against hydroxyl radical and superoxide anion. The activity of 5-lipoxygenase, an enzyme that actively participates in fibrogenesis, was significantly inhibited by CAR. Carbon tetrachloride-treated rats received CAR at 2, 20 and 200 mg/kg. CAR significantly improved liver structure, and reduced fibrosis and the expression of Col1a1, Tgfb1 and Timp1 genes. Oxidative stress was used to establish a model of HSC activation with overproduction of extracellular matrix proteins. CAR (1 and 10 μm) increased cell viability and significantly reduced the expression of fibrotic marker genes. CAR, a sesquiterpene present in numerous plants and foods, is as a natural antioxidant that reduces carbon tetrachloride-mediated liver fibrosis and inhibits hepatic cell activation.

  2. The gamma-glutamyl transpeptidase to platelet ratio (GPR) predicts significant liver fibrosis and cirrhosis in patients with chronic HBV infection in West Africa.

    Science.gov (United States)

    Lemoine, Maud; Shimakawa, Yusuke; Nayagam, Shevanthi; Khalil, Mustapha; Suso, Penda; Lloyd, Jo; Goldin, Robert; Njai, Harr-Freeya; Ndow, Gibril; Taal, Makie; Cooke, Graham; D'Alessandro, Umberto; Vray, Muriel; Mbaye, Papa Saliou; Njie, Ramou; Mallet, Vincent; Thursz, Mark

    2016-08-01

    Simple and inexpensive non-invasive fibrosis tests are highly needed but have been poorly studied in sub-Saharan Africa. Using liver histology as a gold standard, we developed a novel index using routine laboratory tests to predict significant fibrosis in patients with chronic HBV infection in The Gambia, West Africa. We prospectively assessed the diagnostic accuracy of the novel index, Fibroscan, aspartate transaminase-to-platelet ratio index (APRI), and Fib-4 in Gambian patients with CHB (training set) and also in French and Senegalese CHB cohorts (validation sets). Of 135 consecutive treatment-naïve patients with CHB who had liver biopsy, 39% had significant fibrosis (Metavir fibrosis stage ≥F2) and 15% had cirrhosis (F4). In multivariable analysis, gamma-glutamyl transpeptidase (GGT) and platelet count were independent predictors of significant fibrosis. Consequently, GGT-to-platelet ratio (GPR) was developed. In The Gambia, the area under the receiver operating characteristic curve (AUROC) of the GPR was significantly higher than that of APRI and Fib-4 to predict ≥F2, ≥F3 and F4. In Senegal, the AUROC of GPR was significantly better than Fib-4 and APRI for ≥F2 (0.73, 95% CI 0.59 to 0.86) and better than Fib-4 and Fibroscan for ≥F3 (0.93, 0.87 to 0.99). In France, the AUROC of GPR to diagnose ≥F2 (0.72, 95% CI 0.59 to 0.85) and F4 (0.87, 0.76 to 0.98) was equivalent to that of APRI and Fib-4. The GPR is a more accurate routine laboratory marker than APRI and Fib-4 to stage liver fibrosis in patients with CHB in West Africa. The GPR represents a simple and inexpensive alternative to liver biopsy and Fibroscan in sub-Saharan Africa. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  3. Diagnostic value of the APRI index for liver fibrosis in a Chinese patients population with chronic hepatitis C acquired from blood transfusion

    Directory of Open Access Journals (Sweden)

    LEI Chengduo

    2013-05-01

    Full Text Available ObjectiveTo evaluate the diagnostic efficacy of various newly developed non-invasive fibrotic predictive models based on measurements of common biochemical indices in a group of ethnic Chinese patients with long-standing chronic hepatitis C (CHC infection acquired by transfusion. MethodsBetween July 2010 and June 2011, 120 of the monitored residents of Dingxi District of Gansu Province who had acquired hepatitis C infection via the regional practice of untested whole blood or plasma transfusion during the years of 1992-1995 were recruited for the current study. Each participant underwent liver biopsy for histological evaluation of liver fibrosis (S1-S4 progressive stages, from mild fibrosis to early cirrhosis. Each participant also provided serum samples for biochemical measurement of fibrotic indicators, including hyaluronic acid (HA, type Ⅲ procollagen protein (PCⅢ, laminin (LN, and type IV collagen (CⅣ. In addition, aspartate aminotransferase (AST, platelet count (PLT, alanine aminotransferase (ALT, prothrombin time (PT, and international normalized ratio (INR were measured to calculate the various non-invasive fibrotic predictive models: AST-to-PLT ratio index (APRI, the Sheth index (AST/ALT, the FibroQ index (10×[(age×AST×PT INR/(ALT×PLT], and the FIB-4 index ([age×AST/(PLT×ALT1/2]. Using the pathologic results as the reference standards, the diagnostic efficacies of these four non-invasive fibrotic predictive models were evaluated by Spearman’s rank correlation coefficient. Accuracies of the four were compared by constructing receiver operating characteristic (ROC curves and analyzing their sensitivities, specificities and area under the curves (AUCs. ResultsThe APRI, FibroQ and FIB-4 indexes, and the levels of PCⅢ, CⅣ, and HA increased in conjunction with progressive stages of liver fibrosis. However, only the APRI showed significant correlation to liver fibrosis stage (r=0.446, P<0.001. The APRI index also had

  4. 4Ps medicine of the fatty liver: the research model of predictive, preventive, personalized and participatory medicine-recommendations for facing obesity, fatty liver and fibrosis epidemics.

    Science.gov (United States)

    Trovato, Francesca Maria; Catalano, Daniela; Musumeci, Giuseppe; Trovato, Guglielmo M

    2014-01-01

    Relationship between adipose tissue and fatty liver, and its possible evolution in fibrosis, is supported by clinical and research experience. Given the multifactorial pathogenesis of non-alcoholic fatty liver disease (NAFLD), treatments for various contributory risk factors have been proposed; however, there is no single validated therapy or drug association recommended for all cases which can stand alone. Mechanisms, diagnostics, prevention and treatment of obesity, fatty liver and insulin resistance are displayed along with recommendations and position points. Evidences and practice can get sustainable and cost-benefit valuable outcomes by participatory interventions. These recommendations can be enhanced by comprehensive research projects, addressed to societal issues and innovation, market appeal and industry development, cultural acceptance and sustainability. The basis of participatory medicine is a greater widespread awareness of a condition which is both a disease and an easy documented and inclusive clue for associated diseases and unhealthy lifestyle. This model is suitable for addressing prevention and useful for monitoring improvement, worsening and adherence with non-invasive imaging tools which allow targeted approaches. The latter include health psychology and nutritional and physical exercise prescription expertise disseminated by continuous medical education but, more important, by concrete curricula for training undergraduate and postgraduate students. It is possible and recommended to do it by early formal teaching of ultrasound imaging procedures and of practical lifestyle intervention strategies, including approaches aimed to healthier fashion suggestions. Guidelines and requirements of research project funding calls should be addressed also to NAFLD and allied conditions and should encompass the goal of training by research and the inclusion of participatory medicine topics. A deeper awareness of ethics of competences in health professionals

  5. Widen NomoGram for multinomial logistic regression: an application to staging liver fibrosis in chronic hepatitis C patients.

    Science.gov (United States)

    Ardoino, Ilaria; Lanzoni, Monica; Marano, Giuseppe; Boracchi, Patrizia; Sagrini, Elisabetta; Gianstefani, Alice; Piscaglia, Fabio; Biganzoli, Elia M

    2017-04-01

    The interpretation of regression models results can often benefit from the generation of nomograms, 'user friendly' graphical devices especially useful for assisting the decision-making processes. However, in the case of multinomial regression models, whenever categorical responses with more than two classes are involved, nomograms cannot be drawn in the conventional way. Such a difficulty in managing and interpreting the outcome could often result in a limitation of the use of multinomial regression in decision-making support. In the present paper, we illustrate the derivation of a non-conventional nomogram for multinomial regression models, intended to overcome this issue. Although it may appear less straightforward at first sight, the proposed methodology allows an easy interpretation of the results of multinomial regression models and makes them more accessible for clinicians and general practitioners too. Development of prediction model based on multinomial logistic regression and of the pertinent graphical tool is illustrated by means of an example involving the prediction of the extent of liver fibrosis in hepatitis C patients by routinely available markers.

  6. Evolutionary strategy to develop learning-based decision systems. Application to breast cancer and liver fibrosis stadialization.

    Science.gov (United States)

    Gorunescu, Florin; Belciug, Smaranda

    2014-06-01

    The purpose of this paper is twofold: first, to propose an evolutionary-based method for building a decision model and, second, to assess and validate the model's performance using five different real-world medical datasets (breast cancer and liver fibrosis) by comparing it with state-of-the-art machine learning techniques. The evolutionary-inspired approach has been used to develop the learning-based decision model in the following manner: the hybridization of algorithms has been considered as "crossover", while the development of new variants which can be thought of as "mutation". An appropriate hierarchy of the component algorithms was established based on a statistically built fitness measure. A synergetic decision-making process, based on a weighted voting system, involved the collaboration between the selected algorithms in making the final decision. Well-established statistical performance measures and comparison tests have been extensively used to design and implement the model. Finally, the proposed method has been tested on five medical datasets, out of which four publicly available, and contrasted with state-of-the-art techniques, showing its efficiency in supporting the medical decision-making process. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Enhancing hepatic fibrosis in spontaneously hypertensive rats fed a choline-deficient diet: a follow-up report on long-term effects of oxidative stress in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Yamamoto, Hiroya; Kanno, Keishi; Ikuta, Takuya; Arihiro, Koji; Sugiyama, Akiko; Kishikawa, Nobusuke; Tazuma, Susumu

    2016-05-01

    We previously reported a model of non-alcoholic fatty liver disease (NAFLD) using spontaneously hypertensive rats (SHRs), fed a choline-deficient (CD) diet for 5 weeks, that hepatic steatosis but not fibrosis is developed through oxidative stress. To determine the relationship between hypertension and hepatic fibrosis in NAFLD, we examined whether long-term CD diet leads to hepatic fibrosis through oxidative stress. Eight-week-old male SHR and normotensive Wistar Kyoto rats (WKYs) were fed a CD diet for 5 or 20 weeks, then liver histology and hepatic expression of genes related to lipid metabolism, fibrosis, and oxidative stress were assessed. Oxidative stress was assessed by hepatic thiobarbituric acid reactive substance (TBARS) levels. After 5 weeks on CD diet, prominent hepatic steatosis and decrease in expression of genes for lipid metabolism were observed in SHRs as compared with WKYs. SHRs on a CD diet demonstrated a downregulated expression of genes for antioxidants, along with significant increases in hepatic TBARS. After 20 weeks on CD diet, SHRs demonstrated severe liver fibrosis and upregulated expressions of genes for fibrosis when compared with WKY. Hypertension precipitated hepatic steatosis, and further, acts as an enhancer in NAFLD progression to liver fibrosis through oxidative stress. © 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  8. Factors influencing the progression of fibrosis in patients with recurrent hepatitis C after liver transplantation under antiviral therapy: a retrospective analysis of 939 liver biopsies in a single center.

    Science.gov (United States)

    Walter, Thomas; Dumortier, Jérôme; Guillaud, Olivier; Hervieu, Valérie; Scoazec, Jean-Yves; Boillot, Olivier

    2007-02-01

    Recurrent hepatitis C after liver transplantation (LT) is a major problem, since up to 30% of patients develop cirrhosis only 5 years after LT in the absence of antiviral therapy. The aim of this study was to examine the rate of progression of fibrosis and its associated risk factors in patients submitted to an early antiviral treatment post-LT. Included in the study were 105 patients submitted to LT between September 1990 and December 2004, 70 of whom were treated with interferon and/or ribavirin. A total of 939 liver biopsies were studied. The median fibrosis stage was 0.8 after 1 year post-LT, 1.1 after 3 years, 1.3 after 5 years, and 1.5 after 10 years. LT recipients with fibrosis >2 (13% at 10 years) had a significantly reduced survival rate (63% vs. 87% at 10 years, P = 0.03). Univariate analysis disclosed that recipient male gender, antiviral therapy before LT, LT after 1998, induction immunosuppressive regimen including tacrolimus, induction immunosuppressive regimen including mycophenolate (or without azathioprine), and short duration of prednisolone (time and that occurrence of severe fibrosis is related to previously described factors related to immunosuppressive regimen or donor age and also to a past history of pre-LT antiviral therapy. (c) 2007 AASLD.

  9. Cost-Effectiveness Analysis: Risk Stratification of Nonalcoholic Fatty Liver Disease (NAFLD by the Primary Care Physician Using the NAFLD Fibrosis Score.

    Directory of Open Access Journals (Sweden)

    Elliot B Tapper

    Full Text Available The complications of Nonalcoholic Fatty Liver Disease (NAFLD are dependent on the presence of advanced fibrosis. Given the high prevalence of NAFLD in the US, the optimal evaluation of NAFLD likely involves triage by a primary care physician (PCP with advanced disease managed by gastroenterologists.We compared the cost-effectiveness of fibrosis risk-assessment strategies in a cohort of 10,000 simulated American patients with NAFLD performed in either PCP or referral clinics using a decision analytical microsimulation state-transition model. The strategies included use of vibration-controlled transient elastography (VCTE, the NAFLD fibrosis score (NFS, combination testing with NFS and VCTE, and liver biopsy (usual care by a specialist only. NFS and VCTE performance was obtained from a prospective cohort of 164 patients with NAFLD. Outcomes included cost per quality adjusted life year (QALY and correct classification of fibrosis.Risk-stratification by the PCP using the NFS alone costs $5,985 per QALY while usual care costs $7,229/QALY. In the microsimulation, at a willingness-to-pay threshold of $100,000, the NFS alone in PCP clinic was the most cost-effective strategy in 94.2% of samples, followed by combination NFS/VCTE in the PCP clinic (5.6% and usual care in 0.2%. The NFS based strategies yield the best biopsy-correct classification ratios (3.5 while the NFS/VCTE and usual care strategies yield more correct-classifications of advanced fibrosis at the cost of 3 and 37 additional biopsies per classification.Risk-stratification of patients with NAFLD primary care clinic is a cost-effective strategy that should be formally explored in clinical practice.

  10. 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

  11. Rapid fibrosis and significant histologic recurrence of hepatitis C after liver transplant is associated with higher tumor recurrence rates in hepatocellular carcinomas associated with hepatitis C virus-related liver disease: a single center retrospective analysis.

    Science.gov (United States)

    Vasavada, Bhavin B; Chan, Chao Long

    2015-02-01

    Hepatitis C virus recurrence after transplant is universal. Histologic recurrence is observed in > 50% hepatitis C virus-infected grafts within the first year. The primary aim of our study was to evaluate factors responsible for hepatocellular carcinoma recurrence and mortality including histologic markers. All patients who had undergone transplant for hepatocellular carcinoma associated with hepatitis C virus from 2002 to 2012 were evaluated retrospectively. There were 109 patients with hepatocellular carcinoma associated with hepatitis C virus that underwent living-donor liver transplant from July 2002 to June 2012. On univariate analysis, preoperative Model for End-Stage Liver Disease Score (P = .026), α-fetoprotein level (P = .020), rapid fibrosis (P = .008), and Hepatitis Activity Index ≥ 6 (P = .008) were associated with recurrence. On multivariate Cox proportional hazards regression model, Model for End-Stage Liver Disease score (P Hepatitis C virus recurrence on biopsy is a poor prognostic indicator and is associated with a higher risk of hepatocellular carcinoma recurrence after liver transplant. Rapid fibrosis after liver transplant independently predicts hepatocellular carcinoma recurrence.

  12. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: A meta-analysis.

    Science.gov (United States)

    Xiao, Guangqin; Zhu, Sixian; Xiao, Xiao; Yan, Lunan; Yang, Jiayin; Wu, Gang

    2017-11-01

    Many noninvasive methods for diagnosing liver fibrosis (LF) have been proposed. To determine the best method for diagnosing LF in nonalcoholic fatty liver disease (NAFLD), we conducted a systemic review and meta-analysis to compare the performance of aspartate aminotransferase to platelets ratio index (APRI), fibrosis-4 index (FIB-4), BARD score, NAFLD fibrosis score (NFS), FibroScan, shear wave elastography (SWE), and magnetic resonance elastography (MRE) for diagnosing LF in NAFLD. We compared the sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUROC) of these noninvasive methods for detecting significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis. Heterogeneity was explored using meta-regression. Sixty-four articles with a total of 13,046 NAFLD subjects were included.