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Sample records for human cirrhotic liver

  1. Discoidin domain receptor 1: isoform expression and potential functions in cirrhotic human liver.

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    Song, Sunmi; Shackel, Nicholas A; Wang, Xin M; Ajami, Katerina; McCaughan, Geoffrey W; Gorrell, Mark D

    2011-03-01

    Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and is activated by collagens. Transcriptional profiling of cirrhosis in human liver using a DNA array and quantitative PCR detected elevated mRNA expression of DDR1 compared with that in nondiseased liver. The present study characterized DDR1 expression in cirrhotic and nondiseased human liver and examined the cellular effects of DDR1 expression. mRNA expression of all five isoforms of DDR1 was detected in human liver, whereas DDR1a demonstrated differential expression in liver with hepatitis C virus and primary biliary cirrhosis compared with nondiseased liver. In addition, immunoblot analysis detected shed fragments of DDR1 more readily in cirrhotic liver than in nondiseased liver. Inasmuch as DDR1 is subject to protease-mediated cleavage after prolonged interaction with collagen, this differential expression may indicate more intense activation of DDR1 protein in cirrhotic compared with nondiseased liver. In situ hybridization and immunofluorescence localized intense DDR1 mRNA and protein expression to epithelial cells including hepatocytes at the portal-parenchymal interface and the luminal aspect of the biliary epithelium. Overexpression of DDR1a altered hepatocyte behavior including increased adhesion and less migration on extracelular matrix substrates. DDR1a regulated extracellular expression of matrix metalloproteinases 1 and 2. These data elucidate DDR1 function pertinent to cirrhosis and indicate the importance of epithelial cell-collagen interactions in chronic liver injury.

  2. Hepatocyte differentiation of human fibroblasts from cirrhotic liver in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    Yu-Ling Sun; Sheng-Yong Yin; Lin Zhou; Hai-Yang Xie; Feng Zhang; Li-Ming Wu; Shu-Sen Zheng

    2011-01-01

    BACKGROUND: Mesenchymal stem cells (MSCs) and fibro-blasts have intimate relationships, and the phenotypic homology between fibroblasts and MSCs has been recently described. The aim of this study was to investigate the hepatic differentiating potentialofhumanfibroblastsincirrhoticliver. METHODS: The phenotypes of fibroblasts in cirrhotic liver were labeled by biological methods. After that, the differentiation potential of these fibroblasts in vitro was characterized in terms of liver-specific gene and protein expression. Finally, an animal model of hepatocyte regeneration in severe combined immunodeficient (SCID) mice was created by retrorsine injection and partial hepatectomy, and the expression of human hepatocyte proteins in SCID mouse livers was checked by immunohistochemicalanalysisafterfibroblastadministration. RESULTS: Surface immunophenotyping revealed that a minority of fibroblasts expressed markers of MSCs and hepatic epithelial cytokeratins as well as alpha-smooth muscle actin, but homogeneously expressed vimentin, desmin, prolyl 4-hydroxylase and fibronectin. These fibroblasts presented the characteristics of hepatocytes in vitro and differentiated directly into functional hepatocytes in the liver of hepatecto-mized SCID mice. CONCLUSIONS: This study demonstrated that fibroblasts in cirrhotic liver have the potential to differentiate into hepatocyte-like cells in vitro and in vivo. Our findings infer that hepatic differentiation of fibroblasts may serve as a new target for reversion of liver fibrosis and a cell source for tissue engineering.

  3. Lymphatic marker podoplanin/D2-40 in human advanced cirrhotic liver- Re-evaluations of microlymphatic abnormalities

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    Yoshimura Kazunori

    2010-11-01

    Full Text Available Abstract Background From the morphological appearance, it was impossible to distinguish terminal portal venules from small lymphatic vessels in the portal tract even using histochemical microscopic techniques. Recently, D2-40 was found to be expressed at a high level in lymphatic endothelial cells (LECs. This study was undertaken to elucidate hepatic lymphatic vessels during progression of cirrhosis by examining the expression of D2-40 in LECs. Methods Surgical wedge biopsy specimens were obtained from non-cirrhotic portions of human livers (normal control and from cirrhotic livers (LC (Child A-LC and Child C-LC. Immunohistochemical (IHC, Western blot, and immunoelectron microscopic studies were conducted using D2-40 as markers for lymphatic vessels, as well as CD34 for capillary blood vessels. Results Imunostaining of D2-40 produced a strong reaction in lymphatic vessels only, especially in Child C-LC. It was possible to distinguish the portal venules from the small lymphatic vessels using D-40. Immunoelectron microscopy revealed strong D2-40 expression along the luminal and abluminal portions of the cell membrane of LECs in Child C-LC tissue. Conclusion It is possible to distinguish portal venules from small lymphatic vessels using D2-40 as marker. D2-40- labeling in lymphatic capillary endothelial cells is related to the degree of fibrosis in cirrhotic liver.

  4. Triple Staining Including FOXA2 Identifies Stem Cell Lineages Undergoing Hepatic and Biliary Differentiation in Cirrhotic Human Liver.

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    Rogler, Charles E; Bebawee, Remon; Matarlo, Joe; Locker, Joseph; Pattamanuch, Nicole; Gupta, Sanjeev; Rogler, Leslie E

    2017-01-01

    Recent investigations have reported many markers associated with human liver stem/progenitor cells, "oval cells," and identified "niches" in diseased livers where stem cells occur. However, there has remained a need to identify entire lineages of stem cells as they differentiate into bile ducts or hepatocytes. We have used combined immunohistochemical staining for a marker of hepatic commitment and specification (FOXA2 [Forkhead box A2]), hepatocyte maturation (Albumin and HepPar1), and features of bile ducts (CK19 [cytokeratin 19]) to identify lineages of stem cells differentiating toward the hepatocytic or bile ductular compartments of end-stage cirrhotic human liver. We identified large clusters of disorganized, FOXA2 expressing, oval cells in localized liver regions surrounded by fibrotic matrix, designated as "micro-niches." Specific FOXA2-positive cells within the micro-niches organize into primitive duct structures that support both hepatocytic and bile ductular differentiation enabling identification of entire lineages of cells forming the two types of structures. We also detected expression of hsa-miR-122 in primitive ductular reactions expected for hepatocytic differentiation and hsa-miR-23b cluster expression that drives liver cell fate decisions in cells undergoing lineage commitment. Our data establish the foundation for a mechanistic hypothesis on how stem cell lineages progress in specialized micro-niches in cirrhotic end-stage liver disease.

  5. VEGF in hepatocellular carcinoma and surrounding cirrhotic liver tissues

    Institute of Scientific and Technical Information of China (English)

    Muriel Mathonnet; Bernard Descottes; Denis Valleix; Francois Labrousse; Yves Denizot

    2006-01-01

    @@ TO THE EDITOR We read with a great interest the recent work of Deli and colleagues.[1] in the World Journal of Gastroenterology reporting vascular endothelial growth factor (VEGF) expression in hepatocellular carcinoma (HCC) and cirrhotic liver tissues.

  6. Platelet-activating factor in cirrhotic liver and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Muriel Mathonnet; Bernard Descottes; Denis Valleix; Véronique Truffinet; Francois Labrousse; Yves Denizot

    2006-01-01

    AIM: Platelet-activating factor (PAF) is a pro-inflammatory and angiogenic lipid mediator. Here we aimed to investigate levels of PAF, lyso-PAF (the PAF precursor),phospholipase A2 (PLA2, the enzymatic activity generating lyso-PAF), acetylhydrolase activity (AHA, the PAF degrading enzyme) and PAF receptor (PAF-R) transcripts in cirrhotic liver and hepatocellular carcinoma (HCC).METHODS: Twenty-nine patients with HCC were ehrolled in this study. Cirrhosis was present in fourteen patients and seven had no liver disease. Tissue PAF levels were investigated by a platelet-aggregation assay. LysoPAF was assessed after its chemical acetylation into PAF.AHA was determined by degradation of [3H]-PAF. PLA2 levels were assessed by EIA. PAF-R transcripts were investigated using RT-PCR.RESULTS: Elevated amounts of PAF and PAF-R transcripts 1 (leukocyte-type) were found in cirrhotic tissues as compared with non-cirrhotic ones. Higher amounts of PAF and PAF-R transcripts 1 and 2 (tissue-type) were found in HCC tissues as compared with non-tumor tissues. PLA2, lyso-PAF and AHA levels were not changed in cirrhotic tissues and HCC.CONCLUSION: While the role of PAF is currently unknown in liver physiology, this study suggests its potential involvement in the inflammatory network found in the cirrhotic liver and in the angiogenic response during HCC.

  7. Hepatocellular carcinoma (HCC) in non-cirrhotic liver: clinical, radiological and pathological findings

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    Di Martino, Michele; Di Miscio, Rossella; Lombardo, Concetta Valentina; Catalano, Carlo [University of Rome ' ' Sapienza' ' , Department of Radiological Sciences, Oncology and Anatomical Pathology, Rome (Italy); Saba, Luca; Piga, Mario [Department of Radiology Azienda Ospedaliera Universitaria (A.O.U.), Monserrato (Italy); Bosco, Sandro [University of Rome ' ' Sapienza' ' , Department of Molecular Medicine, Rome (Italy); Rossi, Massimo [University of Rome ' ' Sapienza' ' , Department of General Surgery, Division of Organ Transplantation, Rome (Italy); Miles, Kirchin A. [Worldwide Medical and Regulatory Affairs, Milan (Italy); Tamponi, Elisabetta [Azienda Ospedaliera Universitaria (A.O.U.), Department of Anatomical Pathology, Monserrato (Italy)

    2014-07-15

    Our aim was to evaluate the clinical and pathological findings, mutidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI) appearances, treatment and 1-year survival of patients with HCC in non-cirrhotic liver. Histopathological and laboratory findings of 30 non-cirrhotic patients with 32 HCCs were reviewed retrospectively. MDCT and gadobenate dimeglumine-enhanced MR images were evaluated in consensus by two radiologists in terms of HCC size, presence of tumour capsule, necrosis, haemorrhage, fat and calcification, and vascular involvement. Imaging patterns were compared directly with HCC findings in a matched group of cirrhotic patients. No differences between non-cirrhotic and cirrhotic patients were noted in terms of serum α-fetoprotein levels (elevated in 11 [36.7 %] and 21 [35 %] patients, respectively). The imaging appearance at CT and contrast-enhanced MRI was typical in 27 (84.3 %) and 28 (87.5 %) cases respectively. Most lesions presented as a well-differentiated large solitary mass, with well-defined margins, areas of necrosis and peripheral capsule. No significant differences in HCC pattern were observed between cirrhotic and non-cirrhotic liver. In non-cirrhotic patients, HCC is more likely to manifest as an asymptomatic mass with elevation of serum tumour markers similar to that seen in cirrhotic patients. HCC in cirrhotic and non-cirrhotic livers show similar enhancement patterns. (orig.)

  8. Prevalence of simple liver cysts and hemangiomas in cirrhotic and non-cirrhotic patients submitted to magnetic resonance imaging

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    Breno Victor Tomaz Galvao

    2013-07-01

    Full Text Available Objective To determine the prevalence of liver cysts and hemangiomas in the general population and in cirrhotic patients. Materials and Methods Retrospective, observational, and cross-sectional study selecting consecutive magnetic resonance imaging studies performed in the period from February to July 2011. A total of 303 patients (187 women and 116 men with mean age of 53.3 years were included in the present study. Patients with previously known liver lesions were excluded. The images were consensually analyzed by two observers in the search for simple liver cysts and typical liver hemangiomas, according to universally accepted imaging criteria. Lesions prevalence, diameters and location were determined in both cirrhotic and non-cirrhotic individuals. Results The authors observed prevalence of 8.6% for hemangiomas and 14.5% for simple cysts. No statistically significant difference was observed in relation to prevalence of hemangiomas and cysts among cirrhotic and non-cirrhotic patients (p = 0.954; p = 0.472. Conclusion In the present study, the prevalence of cysts and hemangiomas was higher than the prevalence reported by autopsy series. No influence of cirrhosis was observed on the prevalence and appearance of such incidental lesions.

  9. Modified technique for preparation of venous circulation resin casts in the cirrhotic liver

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    JOSÉ OLÍMPIO MAIA DE VASCONCELOS FILHO

    Full Text Available ABSTRACT This study describes two major adaptations for the preparation of resin casts in human cirrhotic liver, harvested at the time of transplantation. The first is the way of fixing the catheter in the ostia of the hepatic and portal veins through a cerclage, so as to prevent displacement of the catheter and / or leakage of the resin during its injection. The second is the extension of corrosion time in the NaOH solution, averaging 6.8 days, with daily replacement the solution until complete removal of parenchymal tissue. We applied the method in 14 cirrhotic livers, with good filling and coloring of the portal and hepatic vein territories, using different colors. This allows an anatomical study of these vessels, able to complement the knowledge of the histopathology in research work, and the planning of therapeutic procedures, such as the Trans-Jugular Intrahepatic Port-Systemic Shunt (TIPS.

  10. Differential distribution of age and HBV serological markers in liver cirrhosis and non-cirrhotic patients with primary liver cancer

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    XU Xiuhua

    2013-03-01

    Full Text Available ObjectiveTo compare the age distributions and presence of hepatitis B virus (HBV serological markers between primary hepatic cancer (PHC patients with and without liver cirrhosis. MethodsA total of 547 PHC cases were analyzed retrospectively. After dividing into two groups according to liver cirrhosis status, the between-group differences in age and HBV serological markers, such as hepatitis B e antigen (HBeAg status, were statistically compared using the Chi-squared test. ResultsThe number of cirrhotic and non-cirrhotic PHC patients was 265 and 282, respectively. HBV infection was present in 221 cirrhotic PHC patients and 256 non-cirrhotic PHC patients (834% vs. 90.8%. There was a substantial bias in the proportion of males to females in the cirrhotic PHC patients (7.83∶1. The number of PHC patients <60 years old was similar between the cirrhotic and non-cirrhotic groups, but the non-cirrhotic group had significantly more patients >60 years old (P<0.005. In cirrhotic PHC patients, the HBV infection rate was highest in the <40 years old age group (96.7% and the HBeAg serological conversion rate was highest in the 40-60 years old age group (89.5%. In non-cirrhotic PHC patients, the 40-60 years old age group showed the highest HBV infection rate (90.3% but the lowest HBeAg serological conversion rate (80.0%. ConclusionPHC with liver cirrhosis mainly occurred in males, with the HBV infection rate being higher in individuals <60 years old. Non-cirrhotic PHC patients were more often >60 years old. Many of the HBV-infected PHC patients with cirrhosis had high HBeAg serological conversion rate.

  11. Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver

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    Seo, J.M. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lee, S.J., E-mail: lucia@skku.edu [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Kim, S.H. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Park, C.K.; Ha, S.Y. [Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-04-15

    Hepatocellular adenoma (HCA) is a rare, benign proliferation of hepatocytes that occurs mostly in a normal liver and in extreme rare cases, occurs in a cirrhotic liver. Hepatocellular carcinomas (HCC) arising within HCA through malignant transformation is rare. The specific incidence and mechanism of malignant transformation has not been established, but the long term use of oral contraceptives is considered a causative agent. We report a case of HCC arising from HCA detected in a hepatitis B-related cirrhotic liver with serial radiologic images.

  12. Hepatic venous oxygen content in alcoholic cirrhosis and non-cirrhotic alcoholic liver disease

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    Bendtsen, F; Henriksen, Jens Henrik Sahl; Widding, A

    1987-01-01

    Blood gas analyses and hepatic blood flow were determined during hepatic vein catheterization in order to establish a possible hypoxic component in alcoholic liver disease. Fifty-six patients (9 non-cirrhotic liver disease, 14 cirrhosis Child-Turcotte class A, 23 class B, 10 class C) and 10 control...

  13. Increase of Serum gamma-Glutamyltransferase Associated With Development of Cirrhotic Cystic Fibrosis Liver Disease

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    Bodewes, Frank A. J. A.; van der Doef, Hubert P. J.; Houwen, Roderick H. J.; Verkade, Henkjan J.

    2015-01-01

    Background:Identification of patients at risk for developing cirrhotic cystic fibrosis liver disease (CCFLD) is essential for targeting potentially preventive treatment. We studied the evolution of serum liver enzymes and thrombocyte counts as predictors of CCFLD development.Methods:For this study,

  14. Significance of hepatic arterial responsiveness for adequate tissue oxygenation upon portal vein occlusion in cirrhotic livers.

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    Mücke, I; Richter, S; Menger, M D; Vollmar, B

    2000-11-01

    We investigated sinusoidal blood flow and hepatic tissue oxygenation during portal vein occlusion in cirrhotic rat livers to examine the effect of cirrhosis on the properties of hepatic microvascular blood flow regulation. After 8 weeks of CCl4/phenobarbital sodium treatment to induce cirrhosis Sprague-Dawley rats were prepared surgically to allow assessment of portal venous and hepatic arterial inflow using miniaturized flow probes with simultaneous analysis of hepatic microcirculation and tissue oxygenation by fluorescence microscopy and polarographic oxymetry. Age-matched noncirrhotic animals served as controls. Upon portal vein occlusion in cirrhotic livers (flow reduction to portal vein occlusion did not cause a deterioration in hepatic tissue pO2 (11 +/- 3 vs. 10 +/- 3 mmHg at baseline). Sinusoidal diameters were found unchanged, disproving a major role of the sinusoidal tone in the regulation of HABR. Microvascular response of cirrhotic livers did not generally differ from that in noncirrhotic livers upon portal inflow restriction. We conclude that HABR in cirrhotic livers operates sufficiently to meet the liver tissue oxygen demand, most probably by an increased relative contribution of arterial perfusion of hepatic sinusoids.

  15. HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver.

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    Schoedel, Karen E; Tyner, Valerie Zajac; Kim, Tae-Hyoung; Michalopoulos, George K; Mars, Wendy M

    2003-01-01

    Fibrolamellar variant is an uncommon subcategory of hepatocellular carcinoma with a better prognostic outcome. Proteinases and growth factors that are involved in the remodeling of extracellular matrix may influence the behavior of cancers. To determine whether these factors contribute to the distinct etiologies of fibrolamellar hepatocellular carcinoma and traditional hepatocellular carcinoma, we assayed hepatocyte growth factor, the hepatocyte growth factor receptor, and two hepatocyte growth factor activators, hepatocyte growth factor activator and urokinase-type plasminogen activator, in hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, cirrhotic liver and normal liver. In addition, we examined the urokinase-type plasminogen activator receptor, the type 1 plasminogen activator inhibitor, plasmin, fibrinogen, and the type IV matrix metalloproteinases. Eighteen hepatocellular carcinomas and 11 fibrolamellar hepatocellular carcinomas were obtained as paraffin embedded sections from the University of Pittsburgh Department of Pathology. Frozen tissues from a subset of cases (9 hepatocellular carcinomas, 4 fibrolamellar hepatocellular carcinomas, 12 cirrhotic livers and 2 normal livers) were also available for analysis. Antibodies against urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, hepatocyte growth factor and hepatocyte growth factor receptor were used to analyze immunoperoxidase stained slides from the paraffin blocks. Western blot analyses using antibodies against hepatocyte growth factor, hepatocyte growth factor receptor, phosphotyrosine, hepatocyte growth factor activator, urokinase-type plasminogen activator receptor, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, fibrinogen and plasmin were performed on membrane-enriched fractions from the frozen tissue, as was collagen zymography for matrix metalloproteinase-2 and matrix metalloproteinase-9. The most notable findings are as

  16. The soluble mannose receptor is released from the liver in cirrhotic patients, but is not associated with bacterial translocation

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    Laursen, Tea L; Rødgaard-Hansen, Sidsel; Møller, Holger J

    2016-01-01

    BACKGROUND & AIMS: Intestinal bacterial translocation is involved in activation of liver macrophages in cirrhotic patients. Macrophages play a key role in liver inflammation and are involved in the pathogenesis of cirrhosis and complications. Bacterial translocation may be determined by presence ...

  17. Assessment of tumor vascularization with functional computed tomography perfusion imaging in patients with cirrhotic liver disease

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    Jin-Ping Li; De-Li Zhao; Hui-Jie Jiang; Ya-Hua Huang; Da-Qing Li; Yong Wan; Xin-Ding Liu; Jin-E Wang

    2011-01-01

    BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and early diagnosis is critical for patient outcome. In patients with HCC, it is mostly based on liver cirrhosis, developing from benign regenerative nodules and dysplastic nodules to HCC lesions, and a better understanding of its vascular supply and the hemodynamic changes may lead to early tumor detection. Angiogenesis is essential for the growth of primary and metastatic tumors due to changes in vascular perfusion, blood volume and permeability. These hemodynamic and physiological properties can be measured serially using functional computed tomography perfusion (CTP) imaging and can be used to assess the growth of HCC. This study aimed to clarify the physiological characteristics of tumor angiogenesis in cirrhoticliverdiseasebythisfastimagingmethod. METHODS: CTP was performed in 30 volunteers without liver disease (control subjects) and 49 patients with liver disease (experimental subjects: 27 with HCC and 22 with cirrhosis). All subjects were also evaluated by physical examination, laboratory screening and Doppler ultrasonography of the liver. The diagnosis of HCC was made according to the EASL criteria. All patients underwent contrast-enhanced ultrasonography, pre- and post-contrast triple-phase CT and CTP study. A mathematical deconvolution model was applied to provide hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS), hepatic arterial index (HAI), hepatic arterial perfusion (HAP) and hepatic portal perfusion (HPP) data. The Mann-Whitney U test was used to determine differences in perfusion parameters between the background cirrhotic liver parenchyma and HCC and between the cirrhotic liver parenchyma with HCC and that without HCC. RESULTS: In normal liver, the HAP/HVP ratio was about 1/4. HCC had significantly higher HAP and HAI and lower HPP than background liver parenchyma adjacent to the HCC. The

  18. RASSF1A and DOK1 Promoter Methylation Levels in Hepatocellular Carcinoma, Cirrhotic and Non-Cirrhotic Liver, and Correlation with Liver Cancer in Brazilian Patients

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    Araújo, Oscar C.; Rosa, Agatha S.; Fernandes, Arlete; Niel, Christian; Villela-Nogueira, Cristiane A.; Pannain, Vera; Araujo, Natalia M.

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide. Most cases of HCC are associated with cirrhosis related to chronic hepatitis B virus or hepatitis C virus infections. Hypermethylation of promoter regions is the main epigenetic mechanism of gene silencing and has been involved in HCC development. The aim of this study was to determine whether aberrant methylation of RASSF1A and DOK1 gene promoters is associated with the progression of liver disease in Brazilian patients. Methylation levels were measured by pyrosequencing in 41 (20 HCC, 9 cirrhotic, and 12 non-cirrhotic) liver tissue samples. Mean rates of methylation in RASSF1A and DOK1 were 16.2% and 12.0% in non-cirrhotic, 26.1% and 19.6% in cirrhotic, and 59.1% and 56.0% in HCC tissues, respectively, showing a gradual increase according to the progression of the disease, with significantly higher levels in tumor tissues. In addition, hypermethylation of RASSF1A and DOK1 was found in the vast majority (88%) of the HCC cases. Interestingly, DOK1 methylation levels in HCC samples were significantly higher in the group of younger (<40 years) patients, and higher in moderately differentiated than in poorly differentiated tumors (p < 0.05). Our results reinforce the hypothesis that hypermethylation of RASSF1A and DOK1 contributes to hepatocarcinogenesis and is associated to clinicopathological characteristics. RASSF1A and DOK1 promoter hypermethylation may be a valuable biomarker for early diagnosis of HCC and a potential molecular target for epigenetic-based therapy. PMID:27078152

  19. EXHALED AND PLASMA NITRITE: a comparative study among healthy, cirrhotic and liver transplant patients

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    Viviane S AUGUSTO

    2014-03-01

    Full Text Available Context There is a relative lack of studies about exhaled nitrite (NO2- concentrations in cirrhotic and transplanted patients. Objective Verify possible differences and correlations between the levels of NO2-, measured in plasma and exhaled breath condensate collected from patients with cirrhosis and liver transplant. Method Sixty adult male patients, aged between 27 and 67 years, were subdivided into three groups: a control group comprised of 15 healthy volunteers, a cirrhosis group composed of 15 volunteers, and a transplant group comprised of 30 volunteers. The NO2- concentrations were measured by chemiluminescence. Results 1 The analysis of plasma NO2- held among the three groups showed no statistical significance. 2 The comparison between cirrhotic and control groups, control and transplanted and cirrhotic and transplanted was not statistically significant. 3 The measurements performed on of NO2- exhaled breath condensate among the three groups showed no statistical difference. 4 When comparing the control group samples and cirrhotic, control and transplanted and cirrhotic and transplanted, there was no significant changes in the concentrations of NO2-. Conclusion No correlations were found between plasma and exhaled NO2-, suggesting that the exhaled NO2- is more reflective of local respiratory NO release than the systemic circulation.

  20. Activity of glycogen synthase and glycogen phosphorylase in normal and cirrhotic rat liver during glycogen synthesis from glucose or fructose.

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    Bezborodkina, Natalia N; Chestnova, Anna Yu; Okovity, Sergey V; Kudryavtsev, Boris N

    2014-03-01

    Cirrhotic patients often demonstrate glucose intolerance, one of the possible causes being a decreased glycogen-synthesizing capacity of the liver. At the same time, information about the rates of glycogen synthesis in the cirrhotic liver is scanty and contradictory. We studied the dynamics of glycogen accumulation and the activity of glycogen synthase (GS) and glycogen phosphorylase (GP) in the course of 120min after per os administration of glucose or fructose to fasted rats with CCl4-cirrhosis or fasted normal rats. Blood serum and liver pieces were sampled for examinations. In the normal rat liver administration of glucose/fructose initiated a fast accumulation of glycogen, while in the cirrhotic liver glycogen was accumulated with a 20min delay and at a lower rate. In the normal liver GS activity rose sharply and GPa activity dropped in the beginning of glycogen synthesis, but 60min later a high synthesis rate was sustained at the background of a high GS and GPa activity. Contrariwise, in the cirrhotic liver glycogen was accumulated at the background of a decreased GS activity and a low GPa activity. Refeeding with fructose resulted in a faster increase in the GS activity in both the normal and the cirrhotic liver than refeeding with glucose. To conclude, the rate of glycogen synthesis in the cirrhotic liver is lower than in the normal one, the difference being probably associated with a low GS activity.

  1. Doppler study of hepatic vein in cirrhotic patients: Correlation with liver dysfunction and hepatic hemodynamics

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    KC Sudhamshu; Shoiichi Matsutani; Hitoshi Maruyama; Taro Akiike; Hiromitsu Saisho

    2006-01-01

    AIM: To elucidate the significance of Doppler measurements of hepatic vein in cirrhotic patients and to correlate with liver dysfunction and hepatic hemodynamics.METHODS: One hundred patients with liver cirrhosis and 60 non-cirrhotic controls were studied. Doppler waveforms were obtained from right hepatic vein and flow velocity measured during quiet respiration. Doppler measurements were also obtained from portal trunk,right portal vein and proper hepatic artery.RESULTS: Hepatic vein waveforms were classified into three classical patterns. Flat waveform was uncommon.Mean hepatic vein velocity was significantly higher in cirrhotic patients (12.7 ± 6.4 vs 5.1 ± 2.1 and 6.2 ± 3.2 cm/s; P < 0.0001). The poorer the grade of cirrhosis,the higher was the mean velocity. Maximum forward velocity was never greater than 40 cm/s in controls.Degree of ascites was found to be highly correlated with mean velocity. "Very high" group (≥ 20 cm/s) presented clinically with moderate to massive ascites. Correlations between right portal flow and mean velocity was significant (P < 0.0001, r = 0.687).CONCLUSION: Doppler waveforms of hepatic vein,which is independent of liver dysfunction, should be obtained during normal respiration. Mean hepatic vein velocity reflects the change in hepatic circulation associated with progression of liver cirrhosis. It can be used as a new parameter in the assessment of liver cirrhosis.

  2. [Guidelines for diagnosis and management of cirrhotic ascites and its complications. The Israeli Association for the Study of the Liver].

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    Sikuler, Emanuel; Ackerman, Zvi; Braun, Marius; Baruch, Yaakov; Bruck, Refael; Safadi, Rifaat; Shlomai, Amir; Ben-Ari, Ziv

    2012-12-01

    Ascites is the most common manifestation of decompensated liver cirrhosis. The life expectancy of cirrhotic patients developing uncomplicated ascites is 50% for 3 years. Refractory ascites, electrolyte imbalance, hepato-renal syndrome and spontaneous bacterial peritonitis may develop. Successful treatment can improve symptoms and outcomes. This article summarizes the Israeli Association for the Study of the Liver guidelines for diagnosis and management of cirrhotic ascites and its complications.

  3. Novel approaches to assessing renal function in cirrhotic liver disease.

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    Portal, Andrew J; Austin, Mark; Heneghan, Michael A

    2007-09-01

    Renal dysfunction is common in patients with end-stage liver disease. Etiological factors include conditions as diverse as acute tubular necrosis, immunoglobulin A nephropathy and hepatorenal syndrome. Current standard tests of renal function, such as measurement of serum urea and creatinine levels, are inaccurate as the synthesis of these markers is affected by the native liver pathology. This article reviews novel markers of renal function and their potential use in patients with liver disease.

  4. Cirrhotic cardiomyopathy

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    Wiese, Signe; Hove, Jens D; Bendtsen, Flemming

    2014-01-01

    Cirrhosis is known to cause alterations in the systemic haemodynamic system. Cirrhotic cardiomyopathy designates a cardiac dysfunction that includes impaired cardiac contractility with systolic and diastolic dysfunction, as well as electromechanical abnormalities in the absence of other known...... biomarkers could improve the diagnostic assessm+ent. Cirrhotic cardiomyopathy contributes to various complications in cirrhosis, especially as an important factor in the development of hepatic nephropathy. Additionally, cirrhotic cardiomyopathy seems to be associated with the development of heart failure...... in relation to invasive procedures such as shunt insertion and liver transplantation. Current pharmacological treatment is nonspecific and directed towards left ventricular failure, and liver transplantation is currently the only proven treatment with specific effect on cirrhotic cardiomyopathy....

  5. New concepts in liver cirrhosis: clinical significance of sarcopenia in cirrhotic patients.

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    Montano-Loza, A J

    2013-06-01

    The natural history of cirrhotic patients is highly variable due to several factors including hepatic synthetic function, presence and degree of portal hypertension, the cause of cirrhosis, the possibility of resolution of the underlying damaging process, and the occurrence of liver cancer. Currently, D'Amico stage classification and Child-Pugh and Model for End-Stage Liver Disease (MELD) scores constitute the best tools to predict mortality in patients with cirrhosis; however, one of their main limitations is the lack of evaluation of the nutritional and functional status. Most widely recognized complications in cirrhotic patients include ascites, hepatic encephalopathy, variceal bleeding, kidney dysfunction, and hepatocellular carcinoma; however, sarcopenia or severe muscle wasting is one of the most common and frequently hidden complications which negatively impact survival, quality of life, and response to stressor, such as infection and surgery. In this review, we discuss the current accepted and new methods to evaluate prognosis in cirrhosis, and also analyze the current knowledge regarding incidence and clinical impact of malnutrition and sarcopenia in cirrhosis and their impact after liver transplantation. We also discuss existing and potential novel therapeutic strategies for malnutrition in cirrhosis, emphasizing the recognition of sarcopenia in cirrhosis in an effort to improve survival and reduced morbidity related to cirrhosis. Finally, we propose that future studies including sarcopenia with the MELD score may allow better prediction of mortality among cirrhotic patients waiting for liver transplantation; however, due to the worldwide shortage of organs for transplants, one of the vital clinical questions is the feasibility to treat sarcopenia in cirrhosis without the need of liver transplant.

  6. Longitudinal intrinsic brain activity changes in cirrhotic patients before and one month after liver transplantation

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    Cheng, Yue; Huang, Li Xiang; Xie, Shuang [Dept. of Radiology, Tianjin First Central Hospital, Tianjin (China); and others

    2017-04-15

    To evaluate the spontaneous brain activity alterations in liver transplantation (LT) recipients using resting-state functional MRI. Twenty cirrhotic patients as transplant candidates and 25 healthy controls (HCs) were included in this study. All patients repeated the MRI study one month after LT. Amplitude of low-frequency fluctuation (ALFF) values were compared between cirrhotic patients (both pre- and post-LT) and HCs as well as between the pre- and post-LT groups. The relationship between ALFF changes and venous blood ammonia levels and neuropsychological tests were investigated using Pearson's correlation analysis. In the cirrhotic patients, decreased ALFF in the vision-related regions (left lingual gyrus and calcarine), sensorimotor-related regions (left postcentral gyrus and middle cingulate cortex), and the default-mode network (bilateral precuneus and left inferior parietal lobule) were restored, and the increased ALFF in the temporal and frontal lobe improved in the early period after LT. The ALFF decreases persisted in the right supplementary motor area, inferior parietal lobule, and calcarine. The ALFF changes in the right precuneus were negatively correlated with changes in number connection test-A scores (r = 0.507, p < 0.05). LT improved spontaneous brain activity and the results for associated cognition tests. However, decreased ALFF in some areas persisted, and new-onset abnormal ALFF were possible, indicating that complete cognitive function recovery may need more time.

  7. Cirrhotic cardiomyopathy: a pathophysiological review of circulatory dysfunction in liver disease

    DEFF Research Database (Denmark)

    Møller, Søren; Henriksen, Jens Henrik

    2002-01-01

    The systemic circulation in patients with cirrhosis is hyperdynamic with an increased cardiac output and heart rate and a reduced systemic vascular resistance as the most pronounced alterations. The concomitant cardiac dysfunction has recently been termed "cirrhotic cardiomyopathy", which...... stress the heart such as shunt implantation and liver transplantation....... is an entity different from that seen in alcoholic heart muscle disease. Clinically, these patients present with sodium fluid retention and strain often unmasks the presence of latent heart failure. No specific treatment can yet be recommended but caution should be used with respect to procedures that may...

  8. Cirrhotic cardiomyopathy: a pathophysiological review of circulatory dysfunction in liver disease

    DEFF Research Database (Denmark)

    Møller, Søren; Henriksen, Jens Henrik

    2002-01-01

    is an entity different from that seen in alcoholic heart muscle disease. Clinically, these patients present with sodium fluid retention and strain often unmasks the presence of latent heart failure. No specific treatment can yet be recommended but caution should be used with respect to procedures that may......The systemic circulation in patients with cirrhosis is hyperdynamic with an increased cardiac output and heart rate and a reduced systemic vascular resistance as the most pronounced alterations. The concomitant cardiac dysfunction has recently been termed "cirrhotic cardiomyopathy", which...... stress the heart such as shunt implantation and liver transplantation....

  9. Histone demethylase retinoblastoma binding protein 2 regulates the expression of α-smooth muscle actin and vimentin in cirrhotic livers

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Q. [Department of Microbiology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Medicine, Shandong University, Jinan (China); Wang, L.X. [Department of Pharmacology, School of Medicine, Shandong University, Jinan (China); Zeng, J.P. [Department of Biochemistry, School of Medicine, Shandong University, Jinan (China); Liu, X.J.; Liang, X.M.; Zhou, Y.B. [Department of Microbiology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Medicine, Shandong University, Jinan (China)

    2013-09-06

    Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of α-smooth muscle actin (α-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased α-SMA and vimentin levels. Treatment with transforming growth factor β (TGF-β) upregulated the expression of RBP2, α-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-β-mediated upregulation of α-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of α-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis.

  10. Novel Rat Model of Repetitive Portal Venous Embolization Mimicking Human Non-Cirrhotic Idiopathic Portal Hypertension

    DEFF Research Database (Denmark)

    Klein, Sabine; Hinüber, Christian; Hittatiya, Kanishka

    2016-01-01

    BACKGROUND: Non-cirrhotic idiopathic portal hypertension (NCIPH) is characterized by splenomegaly, anemia and portal hypertension, while liver function is preserved. However, no animal models have been established yet. This study assessed a rat model of NCIPH and characterized the hemodynamics......, and compared it to human NCIPH. METHODS: Portal pressure (PP) was measured invasively and coloured microspheres were injected in the ileocecal vein in rats. This procedure was performed weekly for 3 weeks (weekly embolization). Rats without and with single embolization served as controls. After four weeks (one...... in the weekly embolization group. Fibrotic markers αSMA and Desmin were upregulated in weekly embolized rats. DISCUSSION: This study establishes a model using repetitive embolization via portal veins, comparable with human NCIPH and may serve to test new therapies....

  11. Pulmonary Complications in Cirrhotic Candidates for Liver Transplantation

    Directory of Open Access Journals (Sweden)

    Seiyed Mohammad Ali Ghayumi

    2010-04-01

    Full Text Available Background and Aims: The determination of the prevalence of cardiopulmonary complications at a liver transplant center in Iran.Methods: Ninety-nine patients (61 male and 38 female with a mean age of 36.5 (15-66 years with proven cirrhosis were enrolled in this study. Patients with primary cardiac disease, current smokers, those with sepsis, hepatocellular carcinoma, recently ruptured esophageal varices and chronic pulmonary or renal diseases were excluded from the study. Sixty-nine patients had ascites. Forty-four patients had grade C Child-Pugh classification. All patients were evaluated for respiratory function by chest X-ray (CXR, room air arterial blood gas, simultaneous pulse oximetry, cardiac echocardiography and spirometry. Results: Sixty-one patients (66.1% had a widened alveolar-arterial O2 difference ( > 20 mmHg; 14 (14.1% had hy- poxemia; 6 (6.1% had mean pulmonary arterial pressure (MPAP = 25-40 mmHg; 12 (12.1% had tricuspid regurgita- tion; pleural effusion and lung restriction were detected in 4 (4% and 50 (50.5%, respectively. P(A-aO2 was nega- tively associated with pulmonary hypertension (P < 0.03 and tricuspid regurgitation (P < 0.005. Portal hypertension and portal vein thrombosis were detected in 91 and 8 patients, respectively. Conclusions: A widened alveolar-arterial oxygen difference was common in our patients, but hypoxemia occurred in 14% of patients. Portopulmonary hypertension was preponderant in those patients of male gender.

  12. Hepatocellular adenoma with malignant transformation in male patients with non-cirrhotic livers

    Institute of Scientific and Technical Information of China (English)

    Song-Lin An; Jian-Xiong Wu; Li-Ming Wang; Wei-Qi Rong; Fan Wu; Wei Sun; Wei-Bo Yu; Li Feng; Fa-Qiang Liu; Fei Tian

    2015-01-01

    Introduction:Hepatocellular adenomas (HCAs), with a risk of malignant transformation into hepatocellular carcinoma (HCC), classically develop in young women who are taking oral contraceptives. It is now clear that HCAs may also occur in men. However, it is rarely reported that HCAs with malignant transformation occur in male patients with non-cirrhotic livers. This study aimed to characterize the malignancy of HCAs occurring in male patients. Methods:Al patients with HCAs with malignant transformation who underwent hepatectomy at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Col ege between January 1, 1999 and December 31, 2011 were enrolled in the study. The clinical characteristics as well as radiologic and pathologic data were reviewed. Results:HCAs with malignant transformation were observed in 5 male patients with non-cirrhotic livers, but not in female patients. The alpha-fetoprotein (AFP) levels were higher in patients with HCAs with malignant transformation than in patients with HCAs without malignant transformation. The diameters of the tumors with malignant transformation were larger than 5 cm in 3 cases and smaller than 5 cm in 2 cases. The 5 patients were all alive without recurrence by the end of the study period. The disease-free survival times of the 5 patients were 26, 48, 69, 69, and 92 months. Conclusion:Our results indicate that resection would be advised even if the presumptive diagnosis is adenoma smaller than 5 cm in diameter, especially in male patients.

  13. Safe upper limit of intermittent hepatic inflow occlusion for liver resection in cirrhotic rats

    Institute of Scientific and Technical Information of China (English)

    Dao-Xiong Lei; Cheng-Hong Peng; Shu-You Peng; Xian-Chuan Jiang; Yu-Lian Wu; Hong-Wei Shen

    2001-01-01

    AIM To evaluate the effects of varying ischemic durations on cirrhotic liver and to determine the safe upper limit of repeated intermittent hepatic inflow occlusion.``METHODS Hepatic ischemia in cirrhotic rats was induced by clamping the common pedicle of left and median lobes after non-ischemic lobes resection. The cirrhotic rats were divided into six groups according to the duration and form of vascular clamping: sham occlusion (SO),intermittent occlusion for 10 (IO-10), 15(IO-15). 20(IO-20)and 30(IO-30) minutes with 5 minutes of refiow andcontinuous occlusion for 60 minutes (CO-60). All animals received a total duration of 60 minutes of hepatic inflow occlusion. Liver viability was investigated in relation of hepatic adenylate energy charge ( EC ).Triphenyltetrazollum chloride (TTC) reduction activities were assayed to qualitatively evaluate the degree of irreversible hepatocellular injury. The biochemical and morphological changes were also assessed and a 7-day mortality was observed.``RESULTS At 60 minutes after reperfusion following atotal of 60 minutes of hepatic inflow occlusion, EC values in lO-L0 (0.749±:0.012) and IO-15 (0.699 ±0.002) groups were rapidly restored to that in SO group (0. 748± 0.016).TTC reduction activities remained in high levels (0. 144 ±0.002 mg/mg protein, 0. 139 + 0.003 mg/mg protein and 0.121 ± 0.003 mg/mg protein in SO, IO-10 and IO-15groups, respectively). But in IO-20 and IO-30 groups, EC levels were partly restored (0.457 ± 0.023 and 0.534 ±0.027) accompanying with a significantly decreased TTCreduction activities (0.070 ± 0.005 mg/mg protein and 0.061 ±0.003 rng/mg protein). No recovery in EC values , i).228 ± 0.004) and a progressive decrease in TTC reduction activities ( 0.03.3 ± 0.002 mg/mg protein) were shown in CO-60 group. Although not significantly different, the activities of the serum aspartate aminotransferase (AST) on the third postoperative day (POD3 ) and POD7 and of the serum alanineaminotransferase

  14. Magnetic resonance imaging of the cirrhotic liver: diagnosis of hepatocellular carcinoma and evaluation of response to treatment - Part 1

    Science.gov (United States)

    Ramalho, Miguel; Matos, António P.; AlObaidy, Mamdoh; Velloni, Fernanda; Altun, Ersan; Semelka, Richard C.

    2017-01-01

    Magnetic resonance imaging (MRI) is the modern gold standard for the noninvasive evaluation of the cirrhotic liver. The combination of arterial phase hyperenhancement and delayed wash-out allows a definitive diagnosis of hepatocellular carcinoma (HCC) in patients with liver cirrhosis or chronic liver disease, without the requirement for confirmatory biopsy. That pattern is highly specific and has been endorsed in Western and Asian diagnostic guidelines. However, the sensitivity of the combination is relatively low for small HCCs. In this two-part review paper, we will address MRI of the cirrhotic liver. In this first part, we provide a brief background on liver cirrhosis and HCC, followed by descriptions of imaging surveillance of liver cirrhosis and the diagnostic performance of the different imaging modalities used in clinical settings. We then describe some of the requirements for the basic MRI technique, as well as the standard MRI protocol, and provide a detailed description of the appearance of various types of hepatocellular nodules encountered in the setting of the carcinogenic pathway in the cirrhotic liver, ranging from regenerative nodules to HCC. PMID:28298731

  15. Systemic chemotherapy for hepatocellular carcinoma in non-cirrhotic liver: A retrospective study

    Institute of Scientific and Technical Information of China (English)

    Julien Edeline; Jean-Luc Raoul; Elodie Vauleon; Anne Guillygomac'h; Karim Boudjema; Eveline Boucher

    2009-01-01

    AIM: To investigate the efficacy and toxicity of systemic chemotherapy in a retrospective study of patients with hepatocellular carcinoma (HCC) occurring in normal or fibrotic liver without cirrhosis. METHODS: Twenty-four patients with metastatic or locally advanced HCC in a normal or a fibrotic liver were given systemic chemotherapy (epirubicin, cisplatin and 5-fluorouracil or epirubicin, cisplatin and capecitabine regimens). Tumor response, time to progression, survival, and toxicity were evaluated. RESULTS: There were 7 women and 17 men, mean 6 had a fibrotic liver (F1/F2 on biopsy). Mean tumor size was 14 cm, 5 patients had portal vein thrombosis and 7 had metastasis. Patients received a median of 4 chemotherapy sessions. Overall tolerance was good. There were 5 partial responses (objective response rate = 22%), and tumor control rate was 52%. Second line surgical resection was possible in two patients. Median survival was 11 mo, and 1- and 2-year overall survival rates were 50% ± 10% and 32% ± 11%, respectively. ``CONCLUSION: In patients with HCC in a non-cirrhotic liver, chemotherapy was well tolerated and associated with an objective response rate of 22%, including two patients who underwent secondary surgical resection.

  16. [Nutritional assessment of alcoholic liver cirrhotic patients treated in the liver Clinic of the Mexico's General Hospital].

    Science.gov (United States)

    Landa-Galván, H V; Milke-García, Ma P; León-Oviedo, C; Gutiérrez-Reyes, G; Higuera-de la Tijera, F; Pérez-Hernández, J L; Serralde-Zúñiga, A E

    2012-01-01

    Malnutrition in the cirrhotic patient is associated to a higher morbidity and mortality rate; however, the diagnosis is complex, so the study objective was to assess the nutritional status using different methods. Adult patients with alcoholic liver cirrhosis treated in the Liver Clinic of the Mexico's General Hospital were evaluated. Anthropometric measurements and a 24 hours recall were made; screening tools (Malnutrition Universal Screening Tool, Nutritional Risk Screening-2002) and a method for assessing nutritional status specifically in cirrhotic patients (Royal Free Hospital Global Assessment) were used. We included 62 patients, 51.6% of them were men. Malnutrition by arm muscle area was 31.3% in men and 10% in women, and by arm fat area was 23.3% in women and 3.1% in men (p malnutrition risk were 43.5% and 54.8% respectively, vs. 1.6% identified as "low weight" with the Body Mass Index. With the Royal Free Hospital Global Assessment tool the percentage of malnutrition was 45.2%. Patients with malnutrition had an energy and protein intake significantly lower than the well-nourished: 19.7 kcal/kg and 0.89 g/kg vs 30 kcal/kg and 1.25 g/kg (p Malnutrition is a common complication in patients with liver cirrhosis. Men have higher depletion of muscle mass and women a higher loss of body fat. The Body Mass Index is not a reliable tool for assessing malnutrition. It's advisable to use tools with indicators of body composition such as the Royal Free Hospital Global Assessment.

  17. Hepatocellular carcinoma in cirrhotic patients with portal hypertension: Is liver resection always contraindicated?

    Institute of Scientific and Technical Information of China (English)

    Andrea Ruzzenente; Alessandro Valdegamberi; Tommaso Campagnaro; Simone Conci; Silvia Pachera; Calogero Iacono,; Alfredo Guglielmi

    2011-01-01

    AIM: To analyze the outcome of hepatocellular carcinoma (HCC) resection in cirrhosis patients, related to presence of portal hypertension (PH) and extent of hepatectomy. METHODS: A retrospective analysis of 135 patients with HCC on a background of cirrhosis was submitted to curative liver resection. RESULTS: PH was present in 44 (32.5%) patients. Overall mortality and morbidity were 2.2% and 33.7%, respectively. Median survival time in patients with or without PH was 31.6 and 65.1 mo, respectively (P = 0.047); in the subgroup with Child-Pugh class A cirrhosis, median survival was 65.1 mo and 60.5 mo, respectively (P = 0.257). Survival for patients submitted to limited liver resection was not significantly different in presence or absence of PH. Conversely, median survival for patients after resection of 2 or more segments with or without PH was 64.4 mo and 163.9 mo, respectively (P = 0.035). CONCLUSION: PH is not an absolute contraindication to liver resection in Child-Pugh class A cirrhotic patients, but resection of 2 or more segments should not be recommended in patients with PH.

  18. Impact of future remnant liver volume on post-hepatectomy regeneration in non-cirrhotic livers

    Directory of Open Access Journals (Sweden)

    Duilio ePagano

    2014-04-01

    Full Text Available Objective: The purpose of the study is to detect if some parameters can be considered as predictors of liver regeneration in two different patient populations composed of in living donors for adult to adult living donor liver transplant and patients with hepatic malignancies within a single institution.Summary Background Data: Preoperative multi-detector computed tomography volumetry is an essential tool to assess the volume of the remnant liver. Methods: a retrospective analysis from an ongoing clinical study on 100 liver resections, between 2004 and 2010. 70 patients were right lobe living donors for liver transplantation and 30 patients were resected for treatment of tumors. Pre-surgical factors such as age, weight, height, body mass index (BMI, original liver volume, future remnant liver volume (FRLV, spleen volume, liver function tests, creatinine, platelet count, steatosis, portal vein embolization (PVE and number of resected segments were analyzed to evidence potential markers for liver regeneration. Results: Follow-up period did not influence the amount of liver regenerated: the linear regression evidenced that there is no correlation between percentage of liver regeneration and time of follow-up (p=0.88. The pre-surgical variables that resulted markers of liver regeneration include higher preoperative values of BMI (p=0.01, bilirubin(p=0.04, glucose (p=0.05 and GGT (p=0.014; the most important association was revealed regarding the lower FRLV (pConclusions: Liver regeneration follows similar pathway in living donor and in patients resected for cancer. Small FRLV tends to regenerate more and faster, confirming that a larger resections may lead to a greater promotion of liver regeneration in patients with optimal conditions in terms of body habitus, preoperative liver function tests and glucose level.

  19. Classification tool for the systematic histological assessment of hepatocellular carcinoma, macroregenerative nodules, and dysplastic nodules in cirrhotic liver

    Institute of Scientific and Technical Information of China (English)

    A Quaglia; MA Jutand; A Dhillon; A Godfrey; R Togni; P Bioulac-Sage; C Balabaud; M Winnock; AP Dhillon

    2005-01-01

    AIM: To design a classification tool for the histological assessment of hepatocellular carcinoma (HCC), dysplastic nodules (DN), and macroregenerative nodules (MRN) in cirrhotic liver.METHODS: Two hundred and twelve hepatocellular nodules (106 HCC;74 MRN;32 DN) were assessed systematically, quantitatively, and semiquantitatively as appropriate for 10 histological features that have been described as helpful in distinguishing small HCC, DN, and MRN in cirrhotic livers. The data were analyzed by multiple correspondence analysis (MCA).RESULTS: MCA distributed HCC, DN, and MRN as defined by traditional histological evaluation as well as the individual histological variables, in a "malignancy scale".Based on the MCA data representation, we created a classification tool, which categorizes an individual nodular lesion as MRN, DN, or HCC based on the balance of all histological features (i.e., vascular invasion, capsular invasion, tumor necrosis, tumor heterogeneity, reticulin loss,capillarization of sinusoids, trabecular thickness, nuclear atypia, and mitotic activity). The classification tool dassified most (83%) of a validation set of 47 nodules in the same way as the routine histological assessment. No discrepandes were present for DN and MRN between the routine histological assignment and the classification tool. Of 25 HCC assigned by routine assessment in the validation set, 8were assigned to the DN category by the classification tool.CONCLUSION: We have designed a classification tool for the histological assessment of HCC and its putative precursors in cirrhotic liver. Application of this tool systematically records histological features of diagnostic importance in the evaluation of small HCC.

  20. Prevalence of hepatitis A and B markers and vaccine indication in cirrhotic patients evaluated for liver transplantation in Spain.

    Science.gov (United States)

    Aoufi, S; Pascasio, J M; Sousa, J M; Sayago, M; Ferrer, M T; Gómez-Delgado, E; De la Cruz, M D; Alamo, J M; Gómez-Bravo, M A; Bernardos, A; Márquez, J L

    2008-11-01

    Vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) is generally recommended for patients with chronic liver disease and those evaluated for liver transplantation in the absence of immunity. HAV and HBV infections after liver transplantation are frequent and associated with a worse prognosis. The data suggest that the number of patients with chronic liver disease without naturally acquired immunity against HAV and HBV is substantial, and that new vaccination strategies are needed. The aim of this study was to determine the level of immunity from hepatitis A and B infections and the need for HBV and HAV vaccination among cirrhotic patients evaluated for liver transplantation. We studied HBV and HAV serological markers (HbsAg, anti-HBc, anti-HBs, IgG anti-HAV) in 451 cirrhotic patients evaluated for liver transplantation to investigate the association with gender, age, and etiology of cirrhosis. Negative HBV markers were observed in 57% of patients with 43% displaying one positive HBV marker: HBsAg (+), 9.5%; anti-HBc (+)/anti-HBs (-), 11.5%; anti-HBc (-)/anti-HBs(+), 4.2%; anti-HBc(+)/anti-HBs(+), 17.7%. HBV vaccine indication established in 68.5% of patients was greater among women and hepatitis C virus-negative patients. No differences were observed in age or cause of cirrhosis. HAV vaccination indicated in 6.7% of patients (IgG anti-HVA-negative) was greater among patients with negative HBV markers (9.3% vs 3.3%, P = .018) and younger patients (25.3% of patients cirrhotic patients evaluated for liver transplantation, as is time for HAV vaccine, especially among patients younger than 45 years of age.

  1. Liver angiogenesis as a risk factor for hepatocellular carcinoma development in hepatitis C virus cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To evaluate the predictive value of hepatocyte proliferation and hepatic angiogenesis for the occurrence of Hepatocellular carcinoma (HCC) in hepatitis C virus(HCV) cirrhotic patients.METHODS: One hundred-five patients (69 males,36 females; age range, 51-90 year; median 66 year)with biopsy proven HCV cirrhosis were prospectively monitored for HCC occurrence for a median time of 64 mo. Angiogenesis was assessed by using microvessel density (MVD), hepatocyte turnover by MIB1 and PCNA indexes at inclusion in liver biopsies.RESULTS: Forty six patients (43.8%) developed HCC after a median time of 55 (6-120) mo while 59 (56.2%)did not. Patients were divided into two groups according to the median value of each index. The difference between patients with low (median MVD = 3; range 0-20) and high (median MVD = 7; range 1-24) MVD was statistically significant (χ2 = 22.06; P < 0.0001) which was not the case for MIB1 or PCNA (MIB-1: χ2 = 1.41;P = 0.2351; PCNA: χ2 = 1.27; P = 0.2589). The median MVD was higher in patients who developed HCC than in those who did not. HCC-free interval was significantly longer in patients with the MVD ≤ 4 (P = 0.0006).No relationship was found between MIB1 or PCNA and MVD (MIB-1 r2 = 0.00007116, P = 0.9281; PCNA: r2 =0.001950; P = 0.6692). MVD only was able to predict the occurrence of HCC in these patients. Among other known risk factors for HCC, only male sex was statistically associated with an increased risk.CONCLUSION: Liver angiogenesis has a role for in HCVrelated liver carcinogenesis and for defining patients at higher risk.

  2. Liver stiffness measurement in cirrhotic patient — Implications of disease activity and treatment efficacy

    Directory of Open Access Journals (Sweden)

    Huang-Wei Xu

    2012-12-01

    Full Text Available Liver stiffness measurement (LSM is a noninvasive method for the diagnosis of hepatic fibrosis. The aim of this study was to evaluate the effects of hepatitis activity and antiviral therapy on LSM in cirrhotic patients. Consecutive patients with compensated hepatic cirrhosis were enrolled for LSM. The medical records of hepatitis activity and antiviral therapy before enrollment were reviewed. Patients were stratified into inactive, fluctuating, and active groups by serial change of alanine transaminase level. For chronic hepatitis C, patients were stratified into sustained virological response (SVR and non-SVR (NSVR by effect of antiviral treatment. LSM results were compared among different groups. A total of 163 patients (mean age = 57.2 ± 11.0 years were enrolled. The median (range LSM values were 9.6 (4.2–20.6, 10.25 (3.9–49.6, and 15.75 (4.8–61.5 kPa in the inactive, fluctuating, and active groups, respectively. Patients in the active group had significantly higher LSM values. For chronic hepatitis C, median (range LSM values were 16.6 (8.1–61.5, 22.9 (11.1–37.4, and 11.2 (3.9–27.0 kPa in patients without antiviral therapy, in NSVR, and in SVR groups, respectively. Patients with SVR had significantly lower LSM values. For chronic hepatitis B, median (range LSM values were 11.8 (5.1–46.6, 16.85 (4.2–48, and 10.6 (4.3–46.4 kPa kPa in patients without oral nucleos(tide analogue (NA therapy, with NA < 12, and ≧12 months, respectively. There was a significantly lower LSM value in patients with NA therapy≧12 months. There were low LSM values in cirrhotic patients without hepatitis activity, as well as with SVR in chronic hepatitis C and long-term NA therapy in chronic hepatitis B.

  3. Changes in systemic and splanchnic hemodynamics after orthotopic liver transplantation in cirrhotic rats

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective To investigate early changes in systemic and splanchnic hemodynamics after orthotopic liver transplantation (OLT) in normal and cirrhotic rats. Methods Male Sprague-Dawley rats were divided into 4 groups:normal controls (NL,n=10),intrahepatic portal hypertension (IHPH, n=10) induced by injection of CCl4, normal rats with OLT (NL-OLT,n=9) and IHPH rats with OLT (IHPH-OLT,n=16). IHPH-OLT rots were divided into 2 subgroups: 3 days (Group A, n=9) and 7 days (Group B, n=7) after OLT. OLT was pedormed in rats using cuffs for the anastomosis of the suprahepatic inferior vena cava,infrahepatic vena cava and portal vein. Two weeks after production of IHPH rots, 7 days after NL-OLT rats, 3 days and 7 days after IHPH-OLT rats, radicective microspheres were used in a hemodynamic study. Results There were no significant differences in hemodynamic changes between NL-OLT and NL rets, except mean arterial blood pressure (MAP).The characteristies of systemic and splanchnic hyperdynamic circulatory slate,including increased cardiac output and splanchnic blood flow, decreased mean acterial blood pressure, total peripheral vascular resistance and splanchnic vascular resistance were ibserved in IHPH, IHPH-OLT A, and IHPH-OLT B rats,The magnitude of hyperhemodynamics was in the order of IHPH>IHPH-OLT A>IHPH-OLT B rats. Moreover, the derangement of splanchnic hyper hemodynamice was more significant than that of systemic hyperhemodynamics. Conclusioos The present study demonstrates that the persistence of early systemic and splanchnic hyperkinetic circulation after OLT may be the consequence of factors which maintain hyperhemo dynamics in liver cirrhosis, where portal hypertension is not completely eliminated. Hyperhemodynamics is not induced by OLT per se.

  4. [Enzyme levels and morphological picture of normal and cirrhotic rat livers following portal vein ligation and subcutaneous transposition of the spleen].

    Science.gov (United States)

    Zelder, O; Dorn, R; Bürcklein, H H; Bode, Ch; Bode, J C; Jerusalem, C R

    1975-01-01

    The effect of portal vein ligation after subcutaneous transposition of the spleen is investigated on enzyme-activities. and morphological pattern of the normal and cirrhotic rat-liver. The increase of glycolytic enzyme-activities and the decrease of enzyme-activities of oxidative metabolic pathways can be explained by adaptation on throttled blood supply of the liver. Significant decrease of arginase-activity (urea-cycle) can not be explained by reduced protein content of food (pair-fed-animals). Diminished substrate (ammonia)-level (NH3/t/hepatocytes) may be an explanation. Histological pattern of normal and cirrhotic rat liver is nearly unchanged after portal vein ligation.

  5. Endothelin 1 and transforming growth factor-β1 correlate with liver function and portal pressure in cirrhotic patients.

    Science.gov (United States)

    Wereszczynka-Siemiatkowska, Urszula; Swidnicka-Siergiejko, Agnieszka; Siemiatkowski, Andrzej; Bondyra, Zofia; Wasielica-Berger, Justyna; Mroczko, Barbara; Janica, Jacek; Dabrowski, Andrzej

    2015-12-01

    The invasive measurement of hepatic venous pressure gradient is the recommended method for the assessment of portal hypertension. We assessed if the mediators that regulate portal hypertension may be used as noninvasive markers of portal hypertension and liver insufficiency. We explored in prospective, observational study the concentration of endothelin-1, nitric oxide, and transforming growth factor-β1/2 in peripheral and hepatic venous blood; their relationship with the values of portal hypertension and liver insufficiency; and their level changes 4-6 months after non-selective beta-blocker therapy in cirrhotic patients with non-bleeding esophageal varices. (1) Cirrhotics have significantly increased peripheral endothelin 1 and decreased transforming growth factor-β1 levels; (2) peripheral levels of all factors correlated significantly with their hepatic levels; (3) after therapy, peripheral endothelin-1 levels significantly increased, but transforming growth factor-β2 levels decreased and were lower in patients with pressure gradient value normalization; (4) before and after therapy, peripheral and hepatic endothelin-1, transforming growth factor-β1/2 levels correlated significantly with liver failure indicators (laboratory parameters, Child-Pough and MELD scores) and pressure gradient values. Peripheral endothelin-1 and transforming growth factor-β1 levels, which strongly correlate with their hepatic levels, reflect the stage of portal hypertension and liver insufficiency in cirrhosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Stability of cirrhotic systemic hemodynamics ensures sufficient splanchnic blood flow after living-donor liver transplantation in adult recipients with liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the correlation between systemic hemodynamics and splanchnic circulation in recipients with cirrhosis undergoing living-donor liver transplantation (LDLT), and to clarify how systemic hemodynamics impact on local graft circulation after LDLT.METHODS: Systemic hemodynamics, indocyanine green (ICG) elimination rate (KICG) and splanchnic circulation were simultaneously and non-invasively investigated by pulse dye densitometry (PDD) and ultrasound. Accurate estimators of optimal systemic hyperdynamics after LDLT [i.e., balance of cardiac output (CO) to blood volume (BV) and mean transit time (MTT), defined as the time required for half the administered ICG to pass through an attached PDD sensor in the first circulation] were also measured. Thirty recipients with cirrhosis were divided into two groups based on clinical outcomes corresponding to postoperative qraft function.RESULTS: Cirrhotic systemic hyperdynamics characterized by high CO, expanded BV and low total peripheral resistance (TPR) were observed before LDLT. TPR reflecting cirrhotic vascular alterations was slowly restored after LDLT in both groups. Although no significant temporal differences in TPR were detected between the two groups, CO/BV and MTT differed significantly. Recipients with good outcomes showed persistent cirrhotic systemic hyperdynamics after LDLT, whereas recipients with poor outcomes presented with unstable cirrhotic systemic hyperdynamics and severely decreased KICG. Systemic hyperdynamic disorders after LDLT impacted on portal venous flow but not hepatic arterial flow.CONCLUSION: We conclude that subtle systemic hyperdynamics disorders impact on splanchnic circulation, and that an imbalance between CO and BV decreases portal venous flow, which results in critical outcomes.

  7. Arterio-portal shunts in the cirrhotic liver: perfusion computed tomography for distinction of arterialized pseudolesions from hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, Michael A. [University Hospital Zurich, Department of Diagnostic and Interventional Radiology, Zurich (Switzerland); Karolinska Institutet, Division of Medical Imaging and Technology. Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden); Marquez, Herman P.; Gordic, Sonja; Alkadhi, Hatem [University Hospital Zurich, Department of Diagnostic and Interventional Radiology, Zurich (Switzerland); Leidner, Bertil; Aspelin, Peter; Brismar, Torkel B. [Karolinska Institutet, Division of Medical Imaging and Technology. Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden); Klotz, Ernst [Computed Tomography and Radiation Oncology, Siemens Healthcare, Forchheim (Germany)

    2017-03-15

    To determine perfusion computed tomography (P-CT) findings for distinction of arterial pseudolesions (APL) from hepatocellular carcinoma (HCC) in the cirrhotic liver. 32 APL and 21 HCC in 20 cirrhotic patients (15 men; 65 ± 10 years), who underwent P-CT for evaluation of HCC pre- (N = 9) or post- (N = 11) transarterial chemoembolization, were retrospectively included using CT follow-up as the standard of reference. All 53 lesions were qualitatively (visual) and quantitatively (perfusion parameters) analysed according to their shape (wedge, irregular, nodular), location (not-/adjunct to a fistula), arterial liver perfusion (ALP), portal venous liver perfusion (PLP), hepatic perfusion index (HPI). Accuracy for diagnosis of HCC was determined using receiver operating characteristics. 18/32 (56 %) APL were wedge shaped, 10/32 (31 %) irregular and 4/32 (12 %) nodular, while 11/21 (52 %) HCC were nodular or 10/21 (48 %) irregular, but never wedge shaped. Significant difference between APL and HCC was seen for lesion shape in pretreated lesions (P < 0.001), and for PLP and HPI in both pre- and post-treated lesions (all, P < 0.001). Diagnostic accuracy for HCC was best for combined assessment of lesion configuration and PLP showing an area under the curve of 0.901. Combined assessment of lesion configuration and portal venous perfusion derived from P-CT allows best to discriminate APL from HCC with high diagnostic accuracy. (orig.)

  8. Predictive Value of the Model of End-Stage Liver Disease in Cirrhotic Patients with and without Spontaneous Bacterial Peritonitis

    Directory of Open Access Journals (Sweden)

    Bledar Kraja

    2012-01-01

    Full Text Available Objective. We aimed to assess the predictive value of the model of end-stage liver disease (MELD in hospitalized cirrhotic patients with and without spontaneous bacterial peritonitis (SBP and fatal outcome. Methods. A cross-sectional study included 256 consecutive patients (199 men and 57 women diagnosed with cirrhosis and ascites who were hospitalized at the University Hospital Center in Tirana from January 2008 to December 2009. SBP was defined as a neutrophil count of ≥250 cells/mm3 in ascitic fluid. MELD score was based on laboratory parameters determined by UNOS Internet site MELD calculator. Results. In multivariable-adjusted logistic regression models controlling for age, sex, diabetes, and etiology, there was evidence of a positive association of SBP with MELD score: the odds ratio (OR for SBP for one unit increment of MELD score was 1.06 (95% Cl = 1.02–1.09. MELD score was significantly higher in fatal cases than nonfatal patients (mean age-adjusted score was 32.7 versus 18.4 overall; 34.8 versus 18.0 in SBP patients, and 32.0 versus 18.5 in non-SBP patients; all P<0.001. Conclusions. In this Albanian sample of hospitalized cirrhotic patients, MELD score was confirmed as a significant predictor of both SBP and fatal outcome.

  9. Management of cirrhotic ascites

    DEFF Research Database (Denmark)

    Pedersen, Julie Steen; Bendtsen, Flemming; Møller, Søren

    2015-01-01

    The most common complication to chronic liver failure is ascites. The formation of ascites in the cirrhotic patient is caused by a complex chain of pathophysiological events involving portal hypertension and progressive vascular dysfunction. Since ascites formation represents a hallmark in the na......The most common complication to chronic liver failure is ascites. The formation of ascites in the cirrhotic patient is caused by a complex chain of pathophysiological events involving portal hypertension and progressive vascular dysfunction. Since ascites formation represents a hallmark...... in the natural history of chronic liver failure it predicts a poor outcome with a 50% mortality rate within 3 years. Patients with ascites are at high risk of developing complications such as spontaneous bacterial peritonitis, hyponatremia and progressive renal impairment. Adequate management of cirrhotic...

  10. Novel bioimaging techniques of metals by laser ablation inductively coupled plasma mass spectrometry for diagnosis of fibrotic and cirrhotic liver disorders.

    Directory of Open Access Journals (Sweden)

    Pornwilard M-M

    Full Text Available BACKGROUND AND AIMS: Hereditary disorders associated with metal overload or unwanted toxic accumulation of heavy metals can lead to morbidity and mortality. Patients with hereditary hemochromatosis or Wilson disease for example may develop severe hepatic pathology including fibrosis, cirrhosis or hepatocellular carcinoma. While relevant disease genes are identified and genetic testing is applicable, liver biopsy in combination with metal detecting techniques such as energy-dispersive X-ray spectroscopy (EDX is still applied for accurate diagnosis of metals. Vice versa, several metals are needed in trace amounts for carrying out vital functions and their deficiency due to rapid growth, pregnancy, excessive blood loss, and insufficient nutritional or digestive uptake results in organic and systemic shortcomings. Established in situ techniques, such as EDX-ray spectroscopy, are not sensitive enough to analyze trace metal distribution and the quantification of metal images is difficult. METHODS: In this study, we developed a quantitative biometal imaging technique of human liver tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS in order to compare the distribution of selected metals in cryo-sections of healthy and fibrotic/cirrhotic livers. RESULTS: Most of the metals are homogeneous distributed within the normal tissue, while they are redirected within fibrotic livers resulting in significant metal deposits. Moreover, total iron and copper concentrations in diseased liver were found about 3-5 times higher than in normal liver samples. CONCLUSIONS: Biometal imaging via LA-ICP-MS is a sensitive innovative diagnostic tool that will impact clinical practice in identification and evaluation of hepatic metal disorders and to detect subtle metal variations during ongoing hepatic fibrogenesis.

  11. Biopsychosocial functioning among cirrhotic patients in various stages of transplant process in comparison to liver transplant recipients

    Directory of Open Access Journals (Sweden)

    Agustín Martín-Rodríguez

    2014-01-01

    Full Text Available Background: Although assessment of pre and posttransplant quality of life is a current scientific target; it has not yet been carried out throughout the entire transplant process. Aims: 1 To analyze differences in mental health and quality of life at prewaiting list study, waiting list, and post transplant phases; 2 to analyze correlation between these quality of life and affective variables and Model for End Stage Liver Disease (MELD scores. Methods: Two liver patient groups were recruited: 51 cirrhotic patients, who were assessed at two different stages (at pre waiting list study and waiting list phases, and 51 cadaveric liver transplant recipients; groups were homogeneous in gender and age variables by matching. Anxiety depressive symptomatology and quality of life were assessed by HADS and SF-36 Health Survey, respectively. Results: Pre waiting list study patients self perceived their global health status much worse than transplant recipients. Waiting list patients displayed much higher anxiety, more role limitations due to physical problems, worse physical functioning, as well as perceiving their global health status much worse than transplant recipients. Statistically significant correlations were only found in waiting list patients between MELD-Anxiety and MELD-Social Functioning subscales. Conclusions: Waiting list patients displayed the worst biopsychosocial well being status; liver transplant recipients enjoyed the best status instead.

  12. Laparoscopic versus Open Liver Resection: Differences in Intraoperative and Early Postoperative Outcome among Cirrhotic Patients with Hepatocellular Carcinoma—A Retrospective Observational Study

    Directory of Open Access Journals (Sweden)

    Antonio Siniscalchi

    2014-01-01

    Full Text Available Introduction. Laparoscopic liver resection is considered risky in cirrhotic patients, even if minor surgical trauma of laparoscopy could be useful to prevent deterioration of a compromised liver function. This study aimed to identify the differences in terms of perioperative complications and early outcome in cirrhotic patients undergoing minor hepatic resection for hepatocellular carcinoma with open or laparoscopic technique. Methods. In this retrospective study, 156 cirrhotic patients undergoing liver resection for hepatocellular carcinoma were divided into two groups according to type of surgical approach: laparoscopy (LS group: 23 patients or laparotomy (LT group: 133 patients. Perioperative data, mortality, and length of hospital stay were recorded. Results. Groups were matched for type of resection, median number of nodules, and median diameter of largest lesions. Groups were also homogeneous for preoperative liver and renal function tests. Intraoperative haemoglobin decrease and transfusions of red blood cells and fresh frozen plasma were significantly lower in LS group. MELD score lasted stable after laparoscopic resection, while it increased in laparotomic group. Postoperative liver and renal failure and mortality were all lower in LS group. Conclusions. Lower morbidity and mortality, maintenance of liver function, and shorter hospital stay suggest the safety and benefit of laparoscopic approach.

  13. Cirrhotic cardiomyopathy

    DEFF Research Database (Denmark)

    Møller, Søren; Henriksen, Jens H

    2010-01-01

    and electrophysiological abnormalities. This syndrome is termed cirrhotic cardiomyopathy. Results of experimental studies indicate the involvement of several mechanisms in the pathophysiology, such as reduced beta-adrenergic receptor signal transduction, altered transmembrane currents and electromechanical coupling...... of the cirrhotic patients and it may be normalised by beta-blockers. No specific therapy for cirrhotic cardiomyopathy can be recommended, but treatment should be supportive and directed against the cardiac dysfunction. Future research should better describe the prevalence, impact on morbidity and survival...

  14. Is there a standard for surgical therapy of hepatocellular carcinoma in healthy and cirrhotic liver? A comparison of eight guidelines.

    Science.gov (United States)

    Manzini, Giulia; Henne-Bruns, Doris; Porzsolt, Franz; Kremer, Michael

    2017-01-01

    Liver resection (LR) and transplantation are the most reliable treatments for hepatocellular carcinoma (HCC). Aim was to compare different guidelines regarding indication for resection and transplantation because of HCC with and without underlying cirrhosis. We compared the following guidelines published after 1 January 2010: American (American Association for the Study of Liver Diseases (AASLD)), Spanish (Sociedad Espanola de Oncologia Medica (SEOM)), European (European Association for the study of liver-European Organization for Research and Treatment of Cancer (EASL-EORTC) and European Society for Medical Oncology-European Society of Digestive Oncology (ESMO-ESDO)), Asian (Asian Pacific Association for the Study of Liver (APASL)), Japanese (Japan Society of Hepatology (JSH)), Italian (Associazione Italiana Oncologia Medica (AIOM)) and German (S3) guidelines. All guidelines recommend resection as therapy of choice in healthy liver. Guidelines based on the Barcelona Clinic Liver Cancer staging system recommend resection for single HCC<2 cm and Child-Pugh A cirrhosis and for HCC≤5 cm with normal bilirubin and portal pressure, whereas transplantation is recommended for multiple tumours between Milan criteria and for single tumours ≤5 cm and advanced liver dysfunction. Patients with HCC and Child-Pugh C cirrhosis are not candidates for transplantation. JSH guidelines recommend LR for patients with Child-Pugh A/B with HCC without tumour size restriction; APASL guidelines in general exclude patients with Child-Pugh A from transplantation. In patients with Child-Pugh B, transplantation is the second-line therapy, if resection is not possible for patients within Milan criteria. German and Italian guidelines recommend transplantation for all patients within Milan criteria. Whereas resection is the standard therapy of HCC in healthy liver, a standard regarding the indication for LR and transplantation for HCC in cirrhotic liver does not exist, although nearly all

  15. Focal masses in a non-cirrhotic liver: The additional benefit of CEUS over baseline imaging

    Energy Technology Data Exchange (ETDEWEB)

    Chiorean, L., E-mail: lilichiorean@yahoo.com [Sino-German Research Center of Ultrasound in Medicine, The First Affiliated Hospital of Zhengzhou University (China); Med. Klinik 2, Caritas Krankenhaus Bad Mergentheim, Uhlandstr. 7, D-97980 Bad Mergentheim (Germany); Département d’imagerie médicale, Clinique des Cévennes, 07100 Annonay (France); Cantisani, V., E-mail: vito.cantisani@uniroma1.it [Dipartimento di Scienze Radiologiche, Oncologiche, Anatomo-patologiche, Policlinico Umberto I, Univ. Sapienza, Roma (Italy); Jenssen, C., E-mail: C.Jenssen@khmol.de [Innere Medizin, Krankenhaus Märkisch Oderland, Prötzeler Chaussee 5, 15433 Strausberg (Germany); Sidhu, P.S., E-mail: paulsidhu@nhs.net [Department of Radiology, King' s College Hospital, Denmark Hill, London SE5 9RS, England (United Kingdom); Baum, U., E-mail: Ulrich.Baum@ckbm.de [Department of Radiology, Caritas Krankenhaus Bad Mergentheim, Uhlandstr. 7, D-97980 Bad Mergentheim (Germany); Dietrich, C.F., E-mail: christoph.dietrich@ckbm.de [Sino-German Research Center of Ultrasound in Medicine, The First Affiliated Hospital of Zhengzhou University (China); Med. Klinik 2, Caritas Krankenhaus Bad Mergentheim, Uhlandstr. 7, D-97980 Bad Mergentheim (Germany)

    2015-09-15

    Highlights: • Contrast-enhanced ultrasound in detection of focal liver lesions. • Contrast-enhanced ultrasound in characterization of focal liver lesions. • Contrast-enhanced ultrasound in differential diagnosis of focal liver lesions. • Contrast-enhanced ultrasound in final diagnosis of focal liver lesions. • Contrast-enhanced ultrasound in liver metastases screening. • Roles of cross-sectional imaging techniques for focal liver lesions assessment. • Advantages of contrast-enhanced ultrasound over other imaging procedures. - Abstract: Incidentally detected focal liver lesions are commonly encountered in clinical practice presenting a challenge in the daily department work flow. Guidelines for the management of incidental focal liver lesions have been published but comments, illustrations and recommendations regarding practical issues are crucial. The unique features of contrast-enhanced ultrasound in non-invasive assessment of focal liver lesion enhancement throughout the vascular phases in real-time has allowed an impressive improvement in the diagnostic accuracy of ultrasound. We highlight the additional benefit of contrast-enhanced ultrasound over conventional B-mode ultrasound imaging in detection, characterization, differential and final diagnosis of focal liver lesions, as well as for liver metastases screening. The current roles of cross-sectional imaging are explained in detail, with indications and limitations for each procedure. The advantages of CEUS, such as non-ionizing radiation exposure, cost benefits, non-iodinate contrast agents, and repeatability are also described ultimately improving patient management.

  16. Diffusion weighted MRI in intrahepatic bile duct adenoma arising from the cirrhotic liver

    Energy Technology Data Exchange (ETDEWEB)

    An, Chansik [Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Park, Sumi; Choi, Yoon Jung [National Health Insurance Corporation Ilsan Hospital, Goyang (Korea, Republic of)

    2013-10-15

    A 64-year-old male patient with liver cirrhosis underwent a CT study for hepatocellular carcinoma surveillance, which demonstrated a 1.4-cm hypervascular subcapsular tumor in the liver. On gadoxetic acid-enhanced MRI, the tumor showed brisk arterial enhancement and persistent hyperenhancement in the portal phase, but hypointensity in the hepatobiliary phase. On diffusion-weighted MRI, the tumor showed an apparent diffusion coefficient twofold greater than that of the background liver parenchyma, which suggested that the lesion was benign. The histologic diagnosis was intrahepatic bile duct adenoma with alcoholic liver cirrhosis.

  17. Prevalence of hepatitis B and A virus markers and vaccination indication in cirrhotic patients evaluated for liver transplantation in Spain.

    Science.gov (United States)

    Gutiérrez Domingo, I; Pascasio Acevedo, J M; Alcalde Vargas, A; Ramos Cuadra, A; Ferrer Ríos, M T; Sousa Martín, J M; Sayago Mota, M; Giráldez Gallego, A; Suárez Artacho, G

    2012-01-01

    In the absence of immunity, vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended for patients with chronic liver disease and those evaluated for liver transplantation (OLT) HAV and HBV infections after OLT which are frequent in this setting, are associated with a worse prognosis. The aim of this study was to estimate the need for vaccination against HBV and HAV among cirrhotic patients who were candidates for OLT and associations with gender, age, and etiologic factors. HBV and HAV serological markers HBsAg, anti-HBc, antiHBs, immunoglobulin G (IgG)-anti-HAV were investigated among 568 patients, including 75% men. The overall mean age was 53.6 ± 8.9 years range 17-69, and 20% were diabetic. This etiologies were alcohol (68%), hepatitis C virus (35%) or other causes (10.4%). Child-Pugh classes were: A (26%), B (44%), and C (30%). In contrast with 359 patients (63.2%) who had negative HBV markers, 209 (36.8%) were positive: HBsAg (+), 43 (7.6%), isolated anti-HBc (+), 57 (10%), isolated anti-HBs (+), 19 (3.3%), anti-HBc (+)/anti-HBs (+), 90 (15.8%). HBV vaccine indication was performed in 416 patients (73.2%) who either had negative HBV markers or isolated anti-HBc (+). It was more frequently performed in women (82.3% versus 70.3%, P = .005), albeit with no differences according to age or etiology. There were only 8.2% (44/538) IgG-anti-HAV-negative, an indication for vaccination against HAV, which was more frequent affecting patients who were younger [≤ 45 years (27.6%), 46-55 (7.2%), >55 (2.6%); P < .0001)]; nondiabetic (9.5% versus 2.8%, P = .023); nonalcoholic (11.4% versus 6.6%, P = .056); and displayed negative HBV markers (10.2% versus 4.6%, P = .023). Only three patients with IgG-anti- HAV (-) were over 60 years. In conclusion, there is a frequent indication for HBV vaccination among cirrhotic and especially HAV vaccine for under 45 year old patients undergoing evaluation for OLT.

  18. Downregulation of sulfotransferase expression and activity in diseased human livers.

    Science.gov (United States)

    Yalcin, Emine B; More, Vijay; Neira, Karissa L; Lu, Zhenqiang James; Cherrington, Nathan J; Slitt, Angela L; King, Roberta S

    2013-09-01

    Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe substrates. However, it is not well known if sulfotransferase activity changes in metabolic and liver disease, such as diabetes, steatosis, or cirrhosis. Sulfotransferases have significant roles in the regulation of hormones and excretion of xenobiotics. In the present study of normal subjects with nonfatty livers and patients with steatosis, diabetic cirrhosis, and alcoholic cirrhosis, we sought to determine SULT1A1, SULT2A1, SULT1E1, and SULT1A3 activity and mRNA and protein expression in human liver tissue. In general, sulfotransferase activity decreased significantly with severity of liver disease from steatosis to cirrhosis. Specifically, SULT1A1 and SULT1A3 activities were lower in disease states relative to nonfatty tissues. Alcoholic cirrhotic tissues further contained lower SULT1A1 and 1A3 activities than those affected by either of the two other disease states. SULT2A1, on the other hand, was only reduced in alcoholic cirrhotic tissues. SULT1E1 was reduced both in diabetic cirrhosis and in alcoholic cirrhosis tissues, relative to nonfatty liver tissues. In conclusion, the reduced levels of sulfotransferase expression and activity in diseased versus nondiseased liver tissue may alter the metabolism and disposition of xenobiotics and affect homeostasis of endobiotic sulfotransferase substrates.

  19. Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension.

    Science.gov (United States)

    Uschner, Frank E; Ranabhat, Ganesh; Choi, Steve S; Granzow, Michaela; Klein, Sabine; Schierwagen, Robert; Raskopf, Esther; Gautsch, Sebastian; van der Ven, Peter F M; Fürst, Dieter O; Strassburg, Christian P; Sauerbruch, Tilman; Diehl, Anna Mae; Trebicka, Jonel

    2015-09-28

    Liver cirrhosis but also portal vein obstruction cause portal hypertension (PHT) and angiogenesis. This study investigated the differences of angiogenesis in cirrhotic and non-cirrhotic PHT with special emphasis on the canonical (Shh/Gli) and non-canonical (Shh/RhoA) hedgehog pathway. Cirrhotic (bile duct ligation/BDL; CCl4 intoxication) and non-cirrhotic (partial portal vein ligation/PPVL) rats received either atorvastatin (15 mg/kg; 7d) or control chow before sacrifice. Invasive hemodynamic measurement and Matrigel implantation assessed angiogenesis in vivo. Angiogenesis in vitro was analysed using migration and tube formation assay. In liver and vessel samples from animals and humans, transcript expression was analyzed using RT-PCR and protein expression using Western blot. Atorvastatin decreased portal pressure, shunt flow and angiogenesis in cirrhosis, whereas atorvastatin increased these parameters in PPVL rats. Non-canonical Hh was upregulated in experimental and human liver cirrhosis and was blunted by atorvastatin. Moreover, atorvastatin blocked the non-canonical Hh-pathway RhoA dependently in activated hepatic steallate cells (HSCs). Interestingly, hepatic and extrahepatic Hh-pathway was enhanced in PPVL rats, which resulted in increased angiogenesis. In summary, statins caused contrary effects in cirrhotic and non-cirrhotic portal hypertension. Atorvastatin inhibited the non-canonical Hh-pathway and angiogenesis in cirrhosis. In portal vein obstruction, statins enhanced the canonical Hh-pathway and aggravated PHT and angiogenesis.

  20. Low liver stiffness among cirrhotic patients with hepatitis B after prolonged treatment with nucleoside analogs

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Weiland, Ola; Leutscher, Peter

    2011-01-01

    Case reports and short-term clinical trials have suggested that treatment for chronic hepatitis B (CHB) may lead to improvement of cirrhosis. The aim of the present study was to measure liver stiffness in patients diagnosed with advanced fibrosis or cirrhosis prior to prolonged treatment...

  1. Low liver stiffness among cirrhotic patients with hepatitis B after prolonged treatment with nucleoside analogs

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Weiland, Ola; Leutscher, Peter

    2011-01-01

    Abstract Objective. Case reports and short-term clinical trials have suggested that treatment for chronic hepatitis B (CHB) may lead to improvement of cirrhosis. The aim of the present study was to measure liver stiffness in patients diagnosed with advanced fibrosis or cirrhosis prior to prolonged...

  2. EVALUATION OF CIRRHOTIC LIVER WITH PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING: A PRELIMINARY EXPERIMENTAL STUDY IN ANIMAL MODELS WITH HALF-LIVER CIRRHOSIS

    Institute of Scientific and Technical Information of China (English)

    Zheng-han Yang; Xiao-hua Ye; Ye Tan; Min Zhang; Ming-zhu Zhou; Jing-xia Xie; Min Chen; Cheng Zhou

    2006-01-01

    Objective To investigate the role of perfusion-weighted magnetic resonance imaging (MRI) in evaluation of cirrhotic liver.Methods With a 4F catheter,1% diluted carbon tetrachloride (1 ml/kg) was selectively injected into right or left hepatic artery of 12 dogs fortnightly.The half liver into which carbon tetrachloride was injected was called as study side (SS),while the other half liver without carbon tetrachloride injection was called as study control side (SCS).Conventional and perfusion-weighted MRI were performed in every 4 weeks.Via a 4F catheter,5ml gadolinium diethylentriamine pentaaceti acid (Gd-DTPA) dilution was injected into superior mesenteric artery at the 5th scan.The signal intensity-time curves of SS,SCS,and portal vein were completed in MR workstation.The maximal relative signal increase (MRSI),peak time (tp),and slope of the curves were measured.Results On conventional MR images,no abnormalities of externality and signal intensity were observed in both SS and SCS of liver at each stage.The mean tp,MRSI,and slope of intensity-time curves in normal liver were 10.56 seconds,1.01,and 10.23 arbitrary unit (au)/s,respectively.Three parameters of curves didn't show obvious change in SCS of liver at every stage.Abnormal perfusion curves occurred in SS of liver at the 12th week after the 1st injection.The abnormality of perfusion curve in SS was more and more serious as the times of injection increased.The mean tp,MRSI,and slope intensity-time curves in SS of liver were 19.45 seconds,0.43,and 3.60 au/s respectively at the 24th week.Conclusion Perfusion-weighted imaging can potentially provide information about portal perfusion of hepatic parenchyma,and to some degree,reflect the severity of cirrhosis.

  3. Expression of glyoxalase-I is reduced in cirrhotic livers: A possible mechanism in the development of cirrhosis

    Science.gov (United States)

    Hollenbach, Marcus; Thonig, Antje; Pohl, Sabine; Ripoll, Cristina; Michel, Maurice; Zipprich, Alexander

    2017-01-01

    Background High concentrations of methylglyoxal (MGO) cause cytotoxiticy via formation of advanced glycation endproducts (AGEs) and inflammation. MGO is detoxificated enzymatically by glyoxalase-I (Glo-I). The aim of this study was to analyze the role of Glo-I during the development of cirrhosis. Methods In primary hepatocytes, hepatic stellate cells (pHSC) and sinusoidal endothelial cells (pLSEC) from rats with early (CCl4 8wk) and advanced cirrhosis (CCl4 12wk) expression and activity of Glo-I were determined and compared to control. LPS stimulation (24h; 100ng/ml) of HSC was conducted in absence or presence of the partial Glo-I inhibitor ethyl pyruvate (EP) and the specific Glo-I inhibitor BrBzGSHCp2. MGO, inflammatory and fibrotic markers were measured by ELISA and Western blot. Additional rats were treated with CCl4 ± EP 40mg/kg b.w. i.p. from wk 8–12 and analyzed with sirius red staining and Western blot. Results Expression of Glo-I was significantly reduced in cirrhosis in whole liver and primary liver cells accompanied by elevated levels of MGO. Activity of Glo-I was reduced in cirrhotic pHSC and pLSEC. LPS induced increases of TNF-α, Nrf2, collagen-I, α-SMA, NF-kB and pERK of HSC were blunted by EP and BrBzGSHCp2. Treatment with EP during development of cirrhosis significantly decreased the amount of fibrosis (12wk CCl4: 33.3±7.3%; EP wk 8–12: 20.7±6.2%; p<0.001) as well as levels of α-SMA, TGF-β and NF-κB in vivo. Conclusions Our results show the importance of Glo-I as major detoxifying enzyme for MGO in cirrhosis. The reduced expression of Glo-I in cirrhosis demonstrates a possible explanation for increased inflammatory injury and suggests a “vicious circle” in liver disease. Blunting of the Glo-I activity decrease the amount of fibrosis in established cirrhosis and constitutes a novel target for antifibrotic therapy. PMID:28231326

  4. Role of diffusion-weighted imaging, apparent diffusion coefficient and correlation with hepatobiliary phase findings in the differentiation of hepatocellular carcinoma from dysplastic nodules in cirrhotic liver.

    Science.gov (United States)

    Inchingolo, Riccardo; De Gaetano, Anna Maria; Curione, Davide; Ciresa, Marzia; Miele, Luca; Pompili, Maurizio; Vecchio, Fabio Maria; Giuliante, Felice; Bonomo, Lorenzo

    2015-04-01

    To investigate the utility of diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) and the correlation with hepatobiliary phase (delayed phase imaging, DPI) findings in the differentiation of cirrhotic hepatocellular nodules. Forty-three patients with 53 pathology-proven nodules (29 hepatocellular carcinomas (HCCs), 13 high-grade (HGDNs) and 11 low-grade dysplastic nodules (LGDNs); mean size 2.17 cm, range 1-4 cm), who underwent liver MRI with DWI and DPI sequences, were retrospectively reviewed. Lesions were classified as hypointense, isointense, or hyperintense relative to the adjacent liver parenchyma. ADC of each nodule, of the surrounding parenchyma, and lesion-to-liver ratio were calculated. Hyperintensity versus iso/hypointensity on DWI, hypointensity versus iso/hyperintensity on DPI, and the mean lesion-to-liver ratio showed a statistically significant difference both between HCCs versus DNs and between "HCCs + HGDNs" versus LGDNs (p Correlation of DWI with DPI improves differential diagnosis of cirrhotic nodules. • Characterization of atypically enhancing lesions becomes more confident.

  5. Large ({>=}2 cm) non-hypervascular nodules depicted on MRI in the cirrhotic liver: fate and implications

    Energy Technology Data Exchange (ETDEWEB)

    Yu, J.S. [Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine, YongDong Severance Hospital, Seoul (Korea, Republic of)], E-mail: yjsrad97@yuhs.ac; Chung, J.J.; Kim, J.H.; Kim, K.W. [Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine, YongDong Severance Hospital, Seoul (Korea, Republic of)

    2008-10-15

    Aim: To determine the fate and clinical implication of large ({>=}2 cm), non-hypervascular nodules depicted on magnetic resonance imaging (MRI) in the cirrhotic liver. Materials and methods: In 21 patients with cirrhosis (14 hepatitis B, two ethanol abuse, four cryptogenic, one Wilson's disease), 25 large ({>=}2 cm in the longest dimension) non-hypervascular nodules were identified on dynamic MRI. The implications for diagnosis of the initial size, contour, and signal characteristics on MRI in addition to patients' age and cause of cirrhosis were assessed in our analysis. Results: Twelve (75%) out of 16 lesions were malignant or potentially-malignant from 14 hepatitis B patients, while seven (78%) of the nine lesions from other patients were benign (p = 0.016). The mean age of the patients who had malignant or potentially malignant lesions (57 years) was older than that for the other patients (47 years; p = 0.039). The ratio of the short-to-long diameter was higher in malignant or potentially malignant lesions (mean 0.86) than in benign lesions (mean 0.69; p = 0.008). There was no discriminative signal intensity characteristic (p > 0.2 for all factors) that indicated the malignant potential for each non-hypervascular nodule. For all 10 lesions in the hepatitis B patients who were older than 52 years with a short-to-long diameter ratio of more than 0.75, the positive predictive value for malignant potential based on these three combined factors was 100%. Conclusion: In older patients with cirrhosis from hepatitits B, large ({>=}2 cm), non-hypervascular nodules with a spherical contour have a high malignant potential.

  6. Spontaneous bacterial peritonitis: The clinical challenge ofa leaky gut and a cirrhotic liver

    Institute of Scientific and Technical Information of China (English)

    Philipp Lutz; Hans Dieter Nischalke; Christian P Strassburg; Ulrich Spengler

    2015-01-01

    Spontaneous bacterial peritonitis (SBP) is a frequent,life-threatening bacterial infection in patients withliver cirrhosis and ascites. Portal hypertension leadsto increased bacterial translocation from the intestine.Failure to eliminate invading pathogens due to immunedefects associated with advanced liver disease on thebackground of genetic predisposition may result in SBP.The efficacy of antibiotic treatment and prophylaxis hasdeclined due to the spread of multi-resistant bacteria.Patients with nosocomial SBP and with prior antibiotictreatment are at a particularly high risk for infectionwith resistant bacteria. Therefore, it is important toadapt empirical treatment to these risk factors and tothe local resistance profile. Rifaximin, an oral, nonabsorbableantibiotic, has been proposed to preventSBP, but may be useful only in a subset of patients.Since novel antibiotic classes are lacking, we have todevelop prophylactic strategies which do not inducebacterial resistance. Farnesoid X receptor agonistsmay be a candidate, but so far, clinical studies are notavailable. New diagnostic tests which can be carriedout quickly at the patient's site and provide additionalprognostic information would be helpful. Furthermore,we need tools to predict antibiotic resistance in orderto tailor first-line antibiotic treatment of spontaneousbacterial peritonitis to the individual patient and toreduce mortality.

  7. Role of Chymase in the Development of Liver Cirrhosis and Its Complications: Experimental and Human Data

    Science.gov (United States)

    Sansoè, Giovanni; Aragno, Manuela; Mastrocola, Raffaella; Mengozzi, Giulio; Novo, Erica; Parola, Maurizio

    2016-01-01

    Background Tissue Angiotensin II (Ang-II), produced through local non ACE-dependent pathways, stimulates liver fibrogenesis, renal vasoconstriction and sodium retention. Aim To highlight chymase-dependent pathway of Ang-II production in liver and kidney during cirrhosis development. Methods Liver histology, portal pressure, liver and kidney function, and hormonal status were investigated in rat liver cirrhosis induced through 13 weeks of CCl4, with or without chymase inhibitor SF2809E, administered between 4th and 13th CCl4 weeks; liver and kidney chymase immunolocation and Ang-II content were assessed. Chymase immunohistochemistry was also assessed in normal and cirrhotic human liver, and chymase mRNA transcripts were measured in human HepG2 cells and activated hepatic stellate cells (HSC/MFs) in vitro. Results Rats receiving both CCl4 and SF2809E showed liver fibrotic septa focally linking portal tracts but no cirrhosis, as compared to ascitic cirrhotic rats receiving CCl4. SF2809E reduced portal pressure, plasma bilirubin, tissue content of Ang-II, plasma renin activity, norepinephrine and vasopressin, and increased glomerular filtration rate, water clearance, urinary sodium excretion. Chymase tissue content was increased and detected in α-SMA-positive liver myofibroblasts and in kidney tubular cells of cirrhotic rats. In human cirrhosis, chymase was located in hepatocytes of regenerative nodules. Human HepG2 cells and HSC/MFs responded to TGF-β1 by up-regulating chymase mRNA transcription. Conclusions Chymase, through synthesis of Ang-II and other mediators, plays a role in the derangement of liver and kidney function in chronic liver diseases. In human cirrhosis, chymase is well-represented and apt to become a future target of pharmacological treatment. PMID:27637026

  8. Generic and disease-specific health related quality of life in non-cirrhotic, cirrhotic and transplanted liver patients: a cross-sectional study.

    NARCIS (Netherlands)

    S.M. van der Plas (Simone); B.E. Hansen (Bettina); J.B. de Boer (Josien); Th. Stijnen (Theo); J. Passchier (Jan); R.A. de Man (Robert); S.W. Schalm (Solko)

    2003-01-01

    textabstractBACKGROUND: Studies on Health Related Quality of Life (HRQoL) of chronic liver patients were performed in clinical populations. These studies included various disease stages but small variations in aetiology and no transplanted patients. We performed a large HRQoL study

  9. Recent advances in cirrhotic cardiomyopathy.

    Science.gov (United States)

    Karagiannakis, Dimitrios S; Papatheodoridis, George; Vlachogiannakos, Jiannis

    2015-05-01

    Cirrhotic cardiomyopathy, a cardiac dysfunction presented in patients with cirrhosis, represents a recently recognized clinical entity. It is characterized by altered diastolic relaxation, impaired contractility, and electrophysiological abnormalities, in particular prolongation of the QT interval. Several mechanisms seem to be involved in the pathogenesis of cirrhotic cardiomyopathy, including impaired function of beta-receptors, altered transmembrane currents, and overproduction of cardiodepressant factors, like nitric oxide, tumor necrosis factor α, and endogenous cannabinoids. Diastolic dysfunction is the first manifestation of cirrhotic cardiomyopathy and reflects the increased stiffness of the cardiac mass, which leads to delayed left ventricular filling. On the other hand, systolic incompetence is presented later, is usually unmasked during pharmacological or physical stress, and predisposes to the development of hepatorenal syndrome. The prolongation of QT is found in about 50 % of cirrhotic patients, but rarely leads to fatal arrhythmias. Cirrhotics with blunted cardiac function seem to have poorer survival rates compared to those without, and the risk is particularly increased during the insertion of transjugular intrahepatic portosystemic shunt or liver transplantation. Till now, there is no specific treatment for the management of cirrhotic cardiomyopathy. New agents, targeting to its pathogenetical mechanisms, may play some role as future therapeutic options.

  10. Pressure profile in liver sinusoids. A model of localization of sinusoidal resistance in the normal and cirrhotic liver

    DEFF Research Database (Denmark)

    Henriksen, J H; Lassen, N A

    1988-01-01

    A model of pressure profile along the sinusoids in the liver is presented. The major prerequisite is a converging sinusoidal flow pattern through a network of tubes with almost equal diameter. In this case the main hemodynamic resistance is located downstream at the outlet. Different geometric...... configurations (sphere, cylinder, and sections of these) are considered, and it is concluded that the precise shape of the microcirculatory unit is not crucial. The applicability in cirrhosis is considered in relation to a decreased diameter and number of the sinusoids in this condition. Estimated pressure...... profiles along the sinusoids indicate a steep downstream pressure fall in cirrhosis, implying that the spatial average of sinusoidal pressure is close to that of the inlet, i.e. portal pressure. Another prediction is an increased blood flow rate (flow rate per vessel) in the region near the outlet...

  11. Pressure profile in liver sinusoids. A model of localization of sinusoidal resistance in the normal and cirrhotic liver

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Lassen, N A

    1988-01-01

    profiles along the sinusoids indicate a steep downstream pressure fall in cirrhosis, implying that the spatial average of sinusoidal pressure is close to that of the inlet, i.e. portal pressure. Another prediction is an increased blood flow rate (flow rate per vessel) in the region near the outlet......A model of pressure profile along the sinusoids in the liver is presented. The major prerequisite is a converging sinusoidal flow pattern through a network of tubes with almost equal diameter. In this case the main hemodynamic resistance is located downstream at the outlet. Different geometric...... configurations (sphere, cylinder, and sections of these) are considered, and it is concluded that the precise shape of the microcirculatory unit is not crucial. The applicability in cirrhosis is considered in relation to a decreased diameter and number of the sinusoids in this condition. Estimated pressure...

  12. Role of diffusion-weighted imaging, apparent diffusion coefficient and correlation with hepatobiliary phase findings in the differentiation of hepatocellular carcinoma from dysplastic nodules in cirrhotic liver

    Energy Technology Data Exchange (ETDEWEB)

    Inchingolo, Riccardo; De Gaetano, Anna Maria; Curione, Davide; Ciresa, Marzia; Bonomo, Lorenzo [Catholic University of the Sacred Heart, Department of Bioimaging and Radiological Sciences, Institute of Radiology, ' ' Agostino Gemelli' ' Hospital, Rome (Italy); Miele, Luca; Pompili, Maurizio [Catholic University of the Sacred Heart, Department of Internal Medicine, ' ' Agostino Gemelli' ' Hospital, Rome (Italy); Vecchio, Fabio Maria [Catholic University of the Sacred Heart, Department of Anatomo-Pathology, ' ' Agostino Gemelli' ' Hospital, Rome (Italy); Giuliante, Felice [Catholic University of the Sacred Heart, Department of Surgery, ' ' Agostino Gemelli' ' Hospital, Rome (Italy)

    2015-04-01

    To investigate the utility of diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) and the correlation with hepatobiliary phase (delayed phase imaging, DPI) findings in the differentiation of cirrhotic hepatocellular nodules. Forty-three patients with 53 pathology-proven nodules (29 hepatocellular carcinomas (HCCs), 13 high-grade (HGDNs) and 11 low-grade dysplastic nodules (LGDNs); mean size 2.17 cm, range 1-4 cm), who underwent liver MRI with DWI and DPI sequences, were retrospectively reviewed. Lesions were classified as hypointense, isointense, or hyperintense relative to the adjacent liver parenchyma. ADC of each nodule, of the surrounding parenchyma, and lesion-to-liver ratio were calculated. Hyperintensity versus iso/hypointensity on DWI, hypointensity versus iso/hyperintensity on DPI, and the mean lesion-to-liver ratio showed a statistically significant difference both between HCCs versus DNs and between ''HCCs + HGDNs'' versus LGDNs (p < 0.05); sensitivity, specificity, and accuracy for the diagnosis of ''HCCs + HGDNs'' were 96.8 %, 100 %, 97.4 % respectively when combining hyperintensity on DWI and hypointensity on DPI, and 90.9 %, 81.0 %, 83.6 % respectively when lesion-to-liver ratio was <0.95. Hyperintensity on DWI, especially in association with hypointensity on DPI, and low lesion-to-liver ratios should raise the suspicion of HCC, or at least of HGDN, thus helping the characterization of atypically enhancing lesions. (orig.)

  13. MRI for characterization of primary tumors in the non-cirrhotic liver: Added value of Gd-EOB-DTPA enhanced hepatospecific phase

    Energy Technology Data Exchange (ETDEWEB)

    Donati, Olivio F.; Hunziker, Roger; Fischer, Michael A. [Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich (Switzerland); Raptis, Dimitri A.; Breitenstein, Stefan [Department of Visceral and Transplant Surgery, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich (Switzerland); Patak, Michael A., E-mail: Michael.Patak@hirslanden.ch [Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich (Switzerland); Clinic Hirslanden, Hirslanden Hospital Group, Zurich (Switzerland)

    2014-07-15

    Purpose: To evaluate the added value of hepatospecific phase in Gd-EOB-DTPA enhanced magnetic resonance imaging (MRI) in patients with primary tumors in non-cirrhotic liver. Methods: Twenty-nine patients (median, 39 years; range, 18–81 years; 11 male) underwent preoperative Gd-EOB-DTPA enhanced MRI including hepatospecific phase after 10 and 20 min of contrast injection at four institutions in Europe, North America and New Zealand. Images were evaluated by three different readers (R1–R3) who characterized liver tumors with and without consultation of the hepatospecific phase images. Confidence in diagnosis was scored on a visual analog scale from 1 to 10. Histopathology (adenoma, n = 5; focal nodular hyperplasia, n = 11 and hepatocellular carcinoma, n = 13) in all patients served as the standard of reference. Differences were evaluated using the McNemar and Wilcoxon signed rank test. Results: Without hepatospecific phase images available, 22 (76%), 19 (66%) and 19 (66%) of 29 tumors were characterized correctly by the three readers respectively. Mean confidence in diagnosis was 6.1, 5.7 and 5.8. With the hepatospecific phase included, characterization of liver tumors did not change significantly with 21 (72%), 23 (79%) and 19 (66%) of 29 tumors diagnosed correctly (p > 0.05). According confidence ratings increased to 6.3, 6.5 and 7.7, respectively. Increase in diagnostic confidence was significant for R2 and R3 (p < 0.05) and independent of reader's experience. Conclusion: The additional hepatospecific phase in Gd-EOB-DTPA enhanced MRI did not significantly increase diagnostic accuracy in characterization of primary tumors in the non-cirrhotic liver. However, 2/3 readers showed a significant increase in diagnostic confidence after consultation of the hepatospecific phase.

  14. Clinical value of susceptibility-weighted imaging for studying the multi-step hepatocarcinogenic process of cirrhotic liver nodules

    Directory of Open Access Journals (Sweden)

    ZENG Mengsu

    2013-01-01

    Full Text Available Early detection, diagnosis, and effective treatment markedly improves the 5-year survival rate of patients with hepatocellular carcinoma (HCC. Initiation of the multi-step hepatocarcinogenesis process often involves a cirrhotic nodule. After the regenerative nodule develops into a dysplastic nodule (DN, it continues to advance from a low degree DN to a high degree DN. The high degree DN may then further develop to early HCC/small HCC or even progressed/advanced HCC. Previous studies have shown that endogenous iron within the nodule can inhibit or resolve the hepatocarcinogenic process. This review discusses the clinical utility of magnetic resonance (MR susceptibility-weighted imaging for detecting and monitoring changes in nodular iron and the implications of this technology when combined with T2WI, diffusion weighted imaging, and dynamic contrast enhancement for improving clinical decision-making, thereby enhancing diagnostic efficacy for early HCC/small HCC in the cirrhotic background.

  15. New insights into cirrhotic cardiomyopathy

    DEFF Research Database (Denmark)

    Møller, Søren; Hove, Jens D; Dixen, Ulrik

    2013-01-01

    Cirrhotic cardiomyopathy designates a cardiac dysfunction, which includes reduced cardiac contractility with systolic and diastolic dysfunction, and presence of electrophysiological abnormalities in particular prolongation of the QT interval. Several pathophysiological mechanisms including reduced...... beta-receptor function seem involved in the autonomic and cardiac dysfunction. Cirrhotic cardiomyopathy can be revealed by tissue Doppler imaging but is best demasked by physical or pharmacological stress. Liver transplantation may revert cardiac dysfunction but surgery and shunt insertion may also...... aggravate the condition. Moreover, cirrhotic cardiomyopathy may contribute to heart failure after invasive procedures and to development of hepatic nephropathy as part of a cardiorenal syndrome. Whether beta-blockers have a deleterious effect in this clinical situation remains to be settled....

  16. Effect of oral testosterone treatment on serum concentrations of sex steroids gonadotrophins and prolactin in alcoholic cirrhotic men. Copenhagen Study Group for Liver Diseases

    DEFF Research Database (Denmark)

    Gluud, C; Bennett, Patrick; Svenstrup, Bo

    1988-01-01

    The aim of this study was to examine the serum concentrations of sex steroids and pituitary hormones in a randomly selected group of alcoholic cirrhotic men participating in a randomized, placebo-controlled study on the efficacy of oral testosterone treatment on the liver. Before treatment......, patients (n = 25) had median serum concentrations of testosterone, oestradiol, non-protein bound oestradiol, non-sex hormone binding globulin (SHBG) bound oestradiol and oestrone sulphate which did not differ significantly from those of healthy controls (n = 16), but the patients had significantly (P less...... than 0.01) higher median serum concentrations of oestrone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin. The patients were randomized to treatment with either oral micronized testosterone (200 mg t.d.s.) or placebo for a median duration of 1 year. In the placebo group (n...

  17. The Proper Scan Delay of the Hepatobiliary Phase of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging to Evaluate Small-Sized ({<=} 3 cm) Hepatocellular Carcinoma in Cirrhotic Liver

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Yong Yeon; Heo, Sook Hee; Kim, Jin Woong; Kang, Heoung Keun [Dept. of Radiology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun (Korea, Republic of); Lee, Ji Hyun; Shin, Sang Soo [Dept. of Radiology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju (Korea, Republic of)

    2013-04-15

    To assess the optimal scan delay of hepatobiliary phase of gadoxetic acid (GA)-enhanced magnetic resonance (MR) imaging for small-sized ({<=} 3 cm) hepatocellular carcinomas (HCCs) in cirrhotic liver. There were 71 HCCs included in this study, derived from 53 patients with liver cirrhosis. Hepatobiliary phase MR imaging was obtained at 10, 15 and 20 mins after GA injection. For quantitative analysis, 2 radiologists calculated signal to noise ratio (SNR), enhancement ratio (ER) of the tumor and liver parenchyma and contrast-to-noise ratio (CNR) at 10 min, 15 min, and 20 min images, respectively. For qualitative analysis, 3 radiologists independently reviewed the 3 different phase about HCC possibilities using a 5-point scale. For each observer, the diagnostic accuracy of different hepatobiliary phases was compared using the area under the alternative free-response receiver operating characteristic curve (Az). In addition, sensitivity and specificity were compared. No significant differences in SNR, ER and CNR at 10 min, 15 min, and 20 min were found. The Az values for HCC possibility were not significantly different. Sensitivity and specificity were also not significantly different. Hepatobiliary phase MR imaging were obtained at 10 min, 15 min and 20 min yield comparable diagnostic information, so that the choice of scan delay can be adapted according to the clinical routine needs.

  18. A STUDY OF CORRELATION OF ESOPHAGEAL VARICES IN CIRRHOTIC PATIENTS WITH PORTAL HAEMODYNAMICS WITH SPECIAL REFERENCE TO PORTAL VEIN DIAMETER, PORTAL VEIN VELOCITY, CONGESTION INDEX, LIVER VASCULAR INDEX

    Directory of Open Access Journals (Sweden)

    Arvind

    2014-12-01

    Full Text Available OBJECTIVE : Approximately two thirds of patients with decompensated cirrhosis and one third of those with compensated cirrhosis have varices at the time of diagnosis. Therefore , it is essential to identify and treat those patients at highest risk because each episode of variceal hemorrhage carries a 20% to 30% risk of death , and 70% of patients not receiving treatment will die within 1 year of the initial bleeding episode . (1 METH OD S: For this study , patients with cirrhosis with or without the evidence of any upper Gastrointestinal bleed , admitted in the department of medicine , JA Group of Hospitals , GR Medical College were taken. The study was conducted between September 2011 and November 2012 and cases were evaluated on the basis of clinical , haematological , ultrasonographic and endoscopic findings. Total number of cases were 100. RESULT : The prevalence of esophageal varices was 75% in cirrhotic patients out of which 28% had bleeding. The prevalence of gastric varices was 1.33%. The portal vein diameter correlated with the presence of varices while portal vein velocity , congestion index and liver vascular index had no significant correlation with esophageal varices. The Portal vein diameter more than 1.4 cm can predict varices with sensitivity 76 % (p<0.05 and Portal vein diameter more than 1.5 cm can detect bleeding varices in cirrhotic patients with sensitivity 55.56% and specificity 80.70% . CONCLUSION : This study showed tha t duration of illness , spleen size and tense ascitis on ultrasonography and portal vein diameter correlated with the presence of esophageal varices. The duration of illness and portal vein diameter are also correlated with bleeding manifestation

  19. Analysis of the survival of cirrhotic patients enlisted for liver transplantation in the pre- and post-MELD era in southern Brazil.

    Science.gov (United States)

    Mattos, Ângelo Zambam de; Mattos, Angelo Alves de; Sacco, Fernanda Karlinski Fernandes; Hoppe, Lísia; Oliveira, Denise Maria Sarti de

    2014-01-01

    Transplantation is the only cure for decompensated cirrhosis. Model for End-Stage Liver Disease (MELD) is used in liver allocation. Comparing survival of enlisted populations in pre- and post-MELD eras and estimating their long-term survival. This is a retrospective study of cirrhotics enlisted for transplantation during pre- and post-MELD eras. Survival curves were generated using Kaplan-Meier's model. Cox's model was used to determine risk factors for mortality. Exponential, Weibull's, normal-log and Gompertz's models were used to estimate long-term survival. The study included 162 patients enlisted in pre-MELD era and 184 in post-MELD period. Kaplan-Meier's survival curve of patients enlisted in post-MELD era was better than that of pre-MELD period (P = 0.009). This difference remained for long-term estimates, with a survival of 53.54% in 5 years and 44.64% in 10 years for patients enlisted in post-MELD era and of 43.17% and 41.75% for pre-MELD period. Era in which patients had been enlisted (P = 0.010) and MELD score at enlistment (Ptransplantation policy is superior to chronology-based one, promoting better survival for enlisted patients, even in long-term.

  20. Hemodynamic and morphologic changes of peripheral hepatic vasculature in cirrhotic liver disease: A preliminary study using contrast-enhanced coded phase inversion harmonic ultrasonography

    Institute of Scientific and Technical Information of China (English)

    Rong-Qin Zheng; Bo Zhang; Masatoshi Kudo; Yasuhiro Sakaguchi

    2005-01-01

    AIM: To provide the useful information for the diagnosis of liver cirrhosis by observing the morphology of peripheral hepatic vessels and the hemodynamics of microbubble arrival time in these vessels.METHODS: Twenty-one subjects including 5 normal volunteers and 16 patients (liver cirrhosis, n=10;chronic hepatitis, n=6) were studied by contrast-enhanced coded phase inversion harmonic sonography (GE LOGIQ9 series) using a 6-8 MHz convex-arrayed wide-band transducer. The images of peripheral hepatic artery,portal and hepatic vein were observed in real-time for about 2 min after intravenous injection of Levovist. The time when microbubbles appeared in the peripheral vessels (microbubble arrival time) was also recorded. The morphologic changes of peripheral hepatic vasculature were classified as marked, slight, and no changes based on the regularity in caliber, course, ramification, and the delineation of vessels compared to normal subjects.RESULTS: The microbubble arrival time at peripheral artery, portal, and hepatic vein was shorter in cirrhotic patients than in chronic hepatitis patients and normal subjects. The marked, slight and no morphologic changes of peripheral hepatic vasculature found in 5 (5/6,83.3%), 1 (1/6, 16.7% ), and 0 (0/6, 0%) liver cirrhosis patients, respectively, and in 1 (1/10, 10%), 6 (6/10,60%), and 3 (3/10, 30%) chronic hepatitis patients,respectively. There was a significant difference between the two groups (P<0.001).CONCLUSION: Evaluation of the hemodynamics and morphology of peripheral hepatic vasculature by contrast-enhanced coded pulse inversion harmonic sonography can provide useful information for the diagnosis of liver cirrhosis.

  1. Changes of nitric oxide and endothelin, thromboxane A2 and prostaglandin in cirrhotic patients undergoing liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Zi-Qing Hei; He-Qing Huang; Chen-Fang Luo; Shang-Rong Li; Gang-Jian Luo

    2006-01-01

    AIM: To investigate the perioperative changes of nitric oxide (NO) and endothelin (ET), thromboxane A2 (TXA2) and prostaglandin (PGI2) during liver transplantation in end-stage liver disease patients.METHODS: Twenty-seven patients with end-stage cirrhosis undergoing liver transplantation were enrolled in this prospective study. Blood samples were obtained from superior vena at five different surgical stages.Plasma concentrations of nitrate and nitrite were determined to reflect plasma NO levels. Plasma levels of ET-1,6-keto-PGF1 alpha and thromboxane B2 (TXB2),the latter two being stable metabolites of PGI2 and TXA2 respectively, were measured.RESULTS: The NO level decreased significantly after vascular cross-clamping and increased significantly at 30 min after reperfusion. While the ET levels at 30 min after clamping and after reperfusion were significantly elevated. The ratio of NO/ET decreased significantly at 30 min after vascular cross-clamping and at the end of surgery. The PGI2 level and the TXA2 during liver transplantation were significantly higher than the baseline level, but the ratio of TXA2/PGI2 decreased significantly at 30 min after clamping.CONCLUSION: NO/ET and TXA2/PGI2 change during liver transplantation. Although the precise mechanism remains unknown, they may play a role in the pathobiology of a variety of liver transplant-relevant processes.

  2. The association between content of the elements S, Cl, K, Fe, Cu, Zn and Br in normal and cirrhotic liver tissue from Danes and Greenlandic Inuit examined by dual hierarchical clustering analysis

    DEFF Research Database (Denmark)

    Laursen, Jens; Milman, Nils; Pind, N.;

    2014-01-01

    contents according to calculated similarities, one clustering elements according to correlation coefficients between the element contents, both using Euclidian distance and Ward Procedure. RESULTS: One dendrogram separated subjects in 7 clusters showing no differences in ethnicity, gender or age....... The analysis discriminated between elements in normal and cirrhotic livers. The other dendrogram clustered elements in four clusters: sulphur and chlorine; copper and bromine; potassium and zinc; iron. There were significant correlations between the elements in normal liver samples: S was associated with Cl, K...

  3. Iron, copper, zinc and bromine mapping in cirrhotic liver slices from patients with hemochromatosis studied by microscopic synchrotron radiation X-ray fluorescence analysis in continuous scanning mode

    Energy Technology Data Exchange (ETDEWEB)

    Osterode, W. [Medizinische Universitaet Wien, Univ. Klinik fuer Innere Medizin IV, Klinische Abteilung fuer Arbeitsmedizin, Waehringer Guertel 18-20, A-1090 Wien (Austria)], E-mail: wolf.osterode@meduniwien.ac.at; Falkenberg, G. [Hamburger Synchrotronstrahlungslabor HASYLAB, Deutsches Elektronen-Synchrotron DESY (Germany); Hoeftberger, R. [Medizinische Universitaet Wien, Klinisches Institut fuer Neurologie (Austria); Wrba, F. [Medizinische Universitaet Wien, Klinisches Institut fuer Klinische Pathologie (Austria)

    2007-07-15

    Iron (Fe) and copper (Cu) are essential metals in physiological cell metabolism. While Fe is easy to determine biochemically in histological slices, Cu and zinc (Zn) distribution is frequently critical in confirming the presence of an overload in disturbed Fe/Cu metabolism. To analyze Fe, Cu and Zn in a near histological resolution, energy dispersive microscopic synchrotron radiation X-ray fluorescence was applied. In normal liver tissue, after fixation and imbedding in paraffin, mean Fe, Cu and Zn concentrations were 152 {+-} 54, 20.1 {+-} 4.3 and 88.919.5 {mu}g/g sample weight, respectively. No substantial, characteristic differences in their distribution were found in the two-dimensional scans. In slices from patients with hemochromatosis mean Fe, Cu and Zn concentrations were 1102 {+-} 539, 35.9 {+-} 14.6 and 27.2 {+-} 6.7 {mu}g/g sample weight, respectively. Additionally, a significant decrease in phosphorus and sulphur concentrations existed. An increased Cu around cirrhotic regenerations nodules is mostly associated with a lymphocytic infiltration in this region. Analyzing concentrations of Fe in different regions of the samples show a clear negative dependency between Fe and Cu, Cu and Zn, but a positive one between Fe and Zn. Conclusion: With a focal beam size of 15 {mu}m in diameter a resolution of the elemental distribution was achieved which is widely comparable with stained histological slices (20x light microscope). The analysis of simultaneous determined elements reveals metabolic differences between Fe, Cu and Zn in liver tissue from patients with hemochromatosis.

  4. Iron, copper, zinc and bromine mapping in cirrhotic liver slices from patients with hemochromatosis studied by microscopic synchrotron radiation X-ray fluorescence analysis in continuous scanning mode

    Science.gov (United States)

    Osterode, W.; Falkenberg, G.; Höftberger, R.; Wrba, F.

    2007-07-01

    Iron (Fe) and copper (Cu) are essential metals in physiological cell metabolism. While Fe is easy to determine biochemically in histological slices, Cu and zinc (Zn) distribution is frequently critical in confirming the presence of an overload in disturbed Fe/Cu metabolism. To analyze Fe, Cu and Zn in a near histological resolution, energy dispersive microscopic synchrotron radiation X-ray fluorescence was applied. In normal liver tissue, after fixation and imbedding in paraffin, mean Fe, Cu and Zn concentrations were 152 ± 54, 20.1 ± 4.3 and 88.919.5 μg/g sample weight, respectively. No substantial, characteristic differences in their distribution were found in the two-dimensional scans. In slices from patients with hemochromatosis mean Fe, Cu and Zn concentrations were 1102 ± 539, 35.9 ± 14.6 and 27.2 ± 6.7 μg/g sample weight, respectively. Additionally, a significant decrease in phosphorus and sulphur concentrations existed. An increased Cu around cirrhotic regenerations nodules is mostly associated with a lymphocytic infiltration in this region. Analyzing concentrations of Fe in different regions of the samples show a clear negative dependency between Fe and Cu, Cu and Zn, but a positive one between Fe and Zn. Conclusion: With a focal beam size of 15 μm in diameter a resolution of the elemental distribution was achieved which is widely comparable with stained histological slices (20× light microscope). The analysis of simultaneous determined elements reveals metabolic differences between Fe, Cu and Zn in liver tissue from patients with hemochromatosis.

  5. Single-Lobe Living Donor Liver Transplant in a Morbidly Obese Cirrhotic Patient Preceded by Laparoscopic Sleeve Gastrectomy

    Science.gov (United States)

    Gupta, Subash; Wadhawan, Manav; Goyal, Neerav

    2013-01-01

    Nonalcoholic steatohepatitis (NASH) is a stage of nonalcoholic fatty liver disease (NAFLD), and, in most patients, it is associated with obesity and metabolic syndrome with progression to end-stage liver disease in about 20% of patients (McCullough (2004); Matteoni et al. (1999); Liou and Kowdley (2006)). It has been estimated that between 20 and 30% of patients with end-stage cirrhosis referred for liver transplantation (LT) evaluation and 30 to 70% of LT recipients exhibit some degree of obesity (Muñoz and ElGenaidi (2005)). Management of obesity in chronic liver disease patients is not only difficult but also preludes them from undergoing major bariatric surgery due to associated high morbidity and mortality. Here, we present a case report of a morbidly obese patient who underwent laparoscopic sleeve gastrectomy followed by single-lobe living donor liver transplantation (LDLT) with a successful outcome. We believe that this is the first report of successful LDLT following planned weight loss to facilitate LDLT. PMID:24386588

  6. A Single Center Study Comparing the Stainable Iron Depositions in 1000 Explanted Cirrhotic Livers of Different Causes

    Directory of Open Access Journals (Sweden)

    Geramizadeh

    2015-12-01

    Full Text Available Background There have been very few studies evaluating the close association between excess iron and cirrhosis; however, cirrhosis could be regarded as an iron-loading disorder. Objectives In this study, the goal was to show the levels of the iron content in the liver tissue in certain types of cirrhosis. Patients and Methods In this 7 year study (2008 - 2014, in 1000 explanted livers, the amount of iron was scored and compared according to the cause of the cirrhosis. The amount of iron in the liver was determined via the histochemical staining of the liver tissue, using Prussian-blue staining. Additionally, in each patient, the serum iron was determined and compared according to the cause of cirrhosis. Results The highest content of iron has been found in cirrhosis caused by chronic hepatitis (i.e. hepatitis B, C, and autoimmune hepatitis, as well as in alcoholic cirrhosis. The least amount of stainable iron has been shown in biliary cirrhosis. Conclusions The presence of high stainable iron in patients with cirrhosis, secondary to chronic viral hepatitis, autoimmune hepatitis, and alcoholic hepatitis, should not be considered indicative of the presence of hereditary hemochromatosis; however, in those patients with biliary cirrhosis, a high iron content is rare, and can be a sign of the presence of the high iron Fe (HFE gene mutation, or another type of hereditary hemochromatosis.

  7. Erythrocytes Membrane Alterations Reflecting Liver Damage in CCl₄-Induced Cirrhotic Rats: The Ameliorative Effect of Naltrexone

    Directory of Open Access Journals (Sweden)

    Fatemeh Sarhadi Kholari

    2016-11-01

    Full Text Available Cirrhosis is the consequence of chronic liver disease. Deleterious effects of oxidative stress on hepatocytes may be reflected in the erythrocyte membrane. Naltrexone (NTX has been shown to attenuate hepatocellular injury in fibrotic animal models. The aim of this study was to investigate the progressive effect of CCl4 on the liver and whether the improvement of liver cirrhosis can be monitored through alterations in the erythrocyte membrane. In this study, 84 male Wistar rats were divided into 4 groups and received reagents (i.p. as follows: 1- CCl₄, 2- NTX + CCl₄, 3- Mineral Oil (M, and 4- NTX + M. After 2, 6 and 8 weeks, the blood and liver tissue samples were collected. Plasma enzyme activities, the content of erythrocyte GSH and some membrane compositions, including protein carbonyl, protein sulfhydryl, and malondialdehyde were assessed. After 6 and 8 weeks, plasma enzyme activities and the content of protein carbonyl were higher in CCl4 group significantly, as compared to other groups (P<0.001. NTX significantly diminished protein carbonyl and plasma enzyme activities (P<0.001. GSH did not change until the 6th week. However, CCl4+NTX increased it significantly as compared to CCl₄ group (P<0.05. Protein sulfhydryl showed changes in NTX+CCl₄ group which indicated a significant increase in protein sulfhydryl content in a 6th week compared to CCl4 group (P<0.05. MDA did not show any significant alteration. CCl₄-induced cirrhosis is accompanied by increased content of oxidative stress markers, especially protein carbonyl of RBC membrane and plasma enzyme activities. This study shows that the progression of liver cirrhosis and the ameliorative effect of NTX can be followed through alterations of these markers.

  8. Hemoperitoneum in cirrhotic patients without abdominal trauma or tumor

    Institute of Scientific and Technical Information of China (English)

    Yuan-Ji Ma; En-Qiang Chen; Jia-Jie Lu; Ming-Zhen Tan; Hong Tang

    2011-01-01

    BACKGROUND: Hemoperitoneum is associated with several emergency conditions and is especially evident when it occurs in patients with liver cirrhosis. This study aimed to assess the clinical characteristics of cirrhotic patients who did not have abdominal trauma or tumor but who developed hemoperitoneum. METHODS: Wereviewedtheclinicalrecordsof1276consecutive cirrhotic patients with hemoperitoneum at our center between January 2007 and December 2009. Hemoperitoneum was confirmed by abdominal paracentesis. RESULTS: Of the 1276 cirrhotic patients, 19 were found to have hemoperitoneum, but only 6 did not have abdominal trauma or tumor. The occurrence of spontaneous hemoperitoneum in the cirrhotic patients was therefore 0.5%. Hemoperitoneum can occur spontaneously in severely decompensated cirrhotic patients with intra-abdominal collateral vessels and high scores on the model for end-stage liver disease and Child-Pugh-Turcotte test. Most patients presented with abdominal distension, abdominal pain, increased abdominal girth and hemodynamic instability with a significant drop in the hemoglobin level. Three patients died of hemorrhagic shock within 24 hours, and the other 3 died of hepatic encephalopathy or spontaneous bacterial peritonitis after 5 to 10 days because of further decompensation of the liver. CONCLUSIONS: Hemoperitoneum can occur in cirrhotic patients who do not have abdominal trauma or tumor. It mainly occurs in severely decompensated end-stage cirrhotic patients. Cirrhotic patients with hemoperitoneum have a poor prognosis.

  9. Intraoperative pulmonary hypertension occurred in an asymptomatic patient with pre-existent liver cirrhotic and portal hypertension

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Portopulmonary hypertension (PPH) is clinically defined as the development of pulmonary arterial hypertension complicated by portal hypertension, with or without advanced hepatic disease. Physical signs may be absent in mild to moderate PPH and only appear in a hyperdynamic circulatory state. Similar signs of advanced liver disease can be observed in severe PPH, with ascites and lower extremity edema. Pulmonary hypertension is usually diagnosed after anesthetic induction during liver transplantation (LT). We present intraoperative pulmonary hypertension in a 41-year-old male patient with hepatic cirrhosis. Since this patient had no preoperation laboratory data supporting the diagnosises of pulmonary hypertension and was asymptomatic for a number of years, it was necessary to send him to the intensive care unit after operation. Further study should be focued on the diagnosis and treatment of pulmonary arterial hypertension in order to reduce its mortality.

  10. Diagnostic performance of Baveno IV criteria in cirrhotic patients with upper gastrointestinal bleeding: analysis of the F7 liver-1288 study population.

    Science.gov (United States)

    Thabut, D; D'Amico, G; Tan, P; De Franchis, R; Fabricius, S; Lebrec, D; Bosch, J; Bendtsen, F

    2010-12-01

    The definition of failure to control bleeding agreed upon at the Baveno IV consensus meeting, included the Adjusted Blood Requirement Index [ABRI: number of blood units/(final-initial hematocrit+0.01)]. ABRI ≥0.75 denotes failure. However, timing for hematocrit measurements was not defined. The aims of this study were: (1) to assess the Baveno IV criteria performance to classify treatment success or failure to control bleeding at 5 days, (2) to determine the appropriate timing for hematocrit. Two hundred and forty-two cirrhotic patients with gastrointestinal bleeding were independently classified by three clinical experts according to the Baveno IV criteria, by analysis of the database of a randomized trial. ABRI was calculated by using the closest hematocrit to the 5 day time point from the first trial product administration (ABRI-1) or after the latest transfusion within the 5-day period (ABRI-2). The gold standard for success/failure for 5-day control of bleeding was the clinical judgment of the three independent observers based on all the clinical and follow-up data. Inter-observer agreement for the final outcome assessment was 0.82 and a final consensus was obtained in 236/242 patients. Inter-observer agreement on patient classification with Baveno IV criteria was 0.70 with ABRI-1 and 0.84 with ABRI-2. c-statistics for correct patients classification were 0.86 for ABRI-1, 0.84 for ABRI-2, and 0.88 for Baveno IV criteria without ABRI. ABRI-1 caused misclassification of 27 patients and ABRI-2 of 39. Baveno IV criteria are accurate to assess outcome of patients with variceal bleeding. There is a substantial observer variability linked to timing of hematocrits for ABRI calculation. With the current definition ABRI does not add to the performance of the other criteria. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  11. Grey scale enhancement by a new self-made contrast agent in early cirrhotic stage of rabbit liver

    Directory of Open Access Journals (Sweden)

    Zhang Yong

    2007-08-01

    Full Text Available Abstract Background The development of new ultrasound contrast agents (UCAs has become one of the most promising fields in ultrasound medicine. This paper evaluates a new self-made contrast agent enhancement effect developed to study the fibrotic stages of the liver in perfusion models in vivo. Methods We constructed experimental models of hepatic fibrosis involving five stages from F0 to F4 via administration of CCL4 (0.01 ml/kg BW every 3 days for 3 months. The intrahepatic circulatory time of the contrast agent was analyzed via an image and Cine-loop display. Calculations of the perfusion-related parameters including the peak signal intensity (PSI and peak signal intensity time (PIT of the portal vein and parenchyma were obtained from an analysis of the time-acoustic intensity curve. Results Hepatic artery to vein transmit time (HA-HVTT was significantly shorter at F4 stage (mean 5.1 seconds compared with those in other stages (mean 8.3 s, 7.5 s, 6.9 s, 6.6 s, P Conclusion These results indicate that the new self-made contrast agent is capable of indicating intrahepatic hemodynamic changes. HA-HVTT and the PSI difference of the microbubble perfusion in liver parenchyma and PV were considered to differentiate the degree of hepatic fibrosis between F4 and other early stages.

  12. Intravenous patient-controlled fentanyl with and without transversus abdominis plane block in cirrhotic patients post liver resection

    Directory of Open Access Journals (Sweden)

    Serag Eldin M

    2014-05-01

    Full Text Available Manar Serag Eldin,1 Fatma Mahmoud,1 Rabab El Hassan,2 Mohamed Abdel Raouf,1 Mohamed H Afifi,2 Khaled Yassen,1 Wesam Morad31Department of Anaesthesia, Liver Institute, 2Department of Anaesthesia, Faculty of Medicine, 3Department of Community Medicine and Public Health, Liver Institute, Menoufiya University, Shebin El-Kom, EgyptBackground: Coagulation changes can complicate liver resection, particularly in patients with cirrhosis. The aim of this prospective hospital-based comparative study was to compare the postoperative analgesic efficacy of intravenous fentanyl patient-controlled analgesia (IVPCA with and without transversus abdominis plane (TAP block.Methods: Fifty patients with Child’s A cirrhosis undergoing liver resection were randomly divided into two groups for postoperative analgesia, ie, an IVPCA group receiving a 10 µg/mL fentanyl bolus of 15 µg with a 10-minute lockout and a maximum hourly dose of 90 µg, and an IVPCA + TAP group that additionally received TAP block (15 mL of 0.375% bupivacaine on both sides via a posterior approach with ultrasound guidance before skin incision. Postoperatively, bolus injections of bupivacaine 0.375% were given every 8 hours through a TAP catheter inserted by the surgeon in the open space during closure of the inverted L-shaped right subcostal with midline extension (subcostal approach guided by the visual analog scale score (<3, 5 mL; 3 to <6, 10 mL; 6–10, 15–20 mL according to weight (maximum 2 mg/kg. The top-up dosage of local anesthetic could be omitted if the patient was not in pain. Coagulation was monitored using standard coagulation tests.Results: Age, weight, and sex were comparable between the groups (P<0.05. The visual analog scale score was significantly lower at 12, 18, 24, 48, and 72 hours (P<0.01 in IVPCA + TAP group. The Ramsay sedation score was lower only after 72 hours in the IVPCA + TAP group when compared with the IVPCA group (1.57±0.74 versus 2.2±0.41, respectively, P

  13. SOME THEORETICAL ASPECTS OF COMPLEX CLINICAL-PSYCHOLOGICAL INVESTIGATION OF PATIENTS WITH AUTOIMMUNE LIVER DISEASES IN CIRRHOTIC STAGE BEFORE LIVER TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    O. A. Gerasimova

    2010-01-01

    Full Text Available This article presents preliminary results of complex clinical-psychological investigation of patients with autoim- mune liver diseases with cirrhosis waiting for liver transplant. The data discussed defense role of anxiety com- bined with other emotional affective disorders, psychological mechanisms in combination with coping strategies of stress-overcoming behavior in the state of disease and their involvement in formation of the clinical picture of the disease. It considers the need for differential diagnosis of the pathology using modern experimental- psychological methods in connection with further building of psychological aid to patients with autoimmune liver diseases. 

  14. Ayurvedic management of cirrhotic ascites

    Directory of Open Access Journals (Sweden)

    G Aswathy

    2016-01-01

    Full Text Available Cirrhosis is the final stage of most of the chronic liver diseases and is most invariably complicated by portal hypertension resulting in ascites. A case of chronic liver disease with portal hypertension (cryptogenic cirrhosis, managed at Amrita School of Ayurveda is discussed in this paper. The clinical picture was that of an uncomplicated cirrhotic ascites. Snehapāna (therapeutic oral administration of lipids followed by virecana (purgation was done after an initial course of nityavirecana (daily purgation. Later Vardhamāna pippalī rasāyana [administration of single drug - pippalī (piper longum in a structured dose pattern] was administered with an intention of rejuvenating liver cells. Ascites and lower limb oedema were completely resolved after the therapy. No recurrence of ascites has been reported after a follow up period of one year.

  15. Experimental study of bioartificial liver with cultured human liver cells

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    AIM To establish an extracorporeal bioartificial liver support system (EBLSS) using cultured human liver cells and to study its support effect for fulminant hepatic failure (FHF).METHODS The liver support experiment of EBLSS consisting of aggregates cultured human liver cells, hollow fiber bioreactor, and circulation unit was carried out in dizhepatic dogs.RESULTS The viability of isolated hepatocytes and nonparenchymal liver cells reached 96%. These cells were successfully cultured as multicellular spheroids with synthetic technique. The typical morphological appearance was retained up to the end of the artificial liver experiment. Compared with the control dogs treated with EBLSS without liver cells, the survival time of artificial liver support dogs was significantly prolonged. The changes of blood pressure, heart rate and ECG were slow. Both serum ammonia and lactate levels were significantly lowered at the 3rd h and 5th h. In addition, a good viability of human liver cells was noted after 5 h experiment.CONCLUSION EBLSS playing a metabolic role of cultured human hepatocytes, is capable of compensating the function of the liver, and could provide effective artificial liver support and therapy for patients with FHF.

  16. 正常肝脏和肝硬化门静脉高压患者CT增强扫描参数研究%Study on protocol in spiral CT scanning:comparison between normal liver and cirrhotic liver

    Institute of Scientific and Technical Information of China (English)

    程明; 陈文军; 赵新宇; 王恩峰

    2015-01-01

    Objective:To study the effect of scanning protocol on image quality when the normal and cirrhotic livers were examined by contrast-enhanced MSCT. Methods:Sixty healthy volunteers were divided into group A and B,which had the conventional and high dose respectively. And ninty patients were divided into group C,D and E,which had the conventional dose,high dose and high dose and delay time respectively. The CT values of hepatic artery,portal vein,liver parenchyma,hepatic vein and the density difference values between portal vein and liver parenchyma were measured. The image quality was scored with double-blind method. Results:The CT values of hepatic artery,portal vein,hepatic vein and the density difference values between portal vein and liver parenchyma had obvious statistical differences between group A and B (P<0.05),and liver parenchyma had no statistical difference. The image quality score had no statistical difference between group A and B. The CT values of hepatic artery,portal vein,liver parenchyma,hepatic vein and the density difference values between portal vein and liver parenchyma had obvious statistical differences between group C and D (P<0.05). The CT values of hepatic artery and portal vein in group E were lower than those in group D,but had no statistical difference (P>0.05),while the CT values of hepatic vein and liver parenchyma in group E increased and the density difference values between portal vein and liver parenchyma decreased ,and they had significant differences to those in group D (P<0.05). The image quality scores had statistical differences in group C, D and E (P<0.05). Conclusions:When the livers are examined by contrast-enhanced MSCT with the injection rate of 3 mL/s, the optimal protocol for normal livers: contrast agent dose is 1.5 mL/kg,start time of hepatic arterial phase is 28 s,start time of portal vein phase is 60 s. The optimal protocol for cirrhotic livers: contrast agent dose is 2.0 mL/kg ,start time of hepatic

  17. Multi-organ perfusion CT in the abdomen using a 320-detector row CT scanner: Preliminary results of perfusion changes in the liver, spleen, and pancreas of cirrhotic patients

    Energy Technology Data Exchange (ETDEWEB)

    Motosugi, Utaroh, E-mail: utaroh-motosugi@nifty.com [Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi (Japan); Ichikawa, Tomoaki, E-mail: ichikawa@yamanashi.ac.jp [Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi (Japan); Sou, Hironobu, E-mail: fffun0300@yahoo.ac.jp [Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi (Japan); Morisaka, Hiroyuki, E-mail: morisakahiroyuki@hotmail.co.jp [Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi (Japan); Sano, Katsuhiro, E-mail: snkthr@yahoo.co.jp [Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi (Japan); Araki, Tsutomu, E-mail: arakit@yamanashi.ac.jp [Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi (Japan)

    2012-10-15

    Purpose: To utilize 320-detector row CT in perfusion CT of multiple abdominal organs and to compare the tissue perfusion between patients with and without liver cirrhosis. Materials and methods: This study included 21 patients with cirrhosis and 20 without cirrhosis. The 320-detector row CT scanner enabled multi-organ perfusion CT without requiring the scanner table to be moved. Perfusion was calculated using the maximum slope model for the aorta, the portal vein, the right and left lobes of the liver, the head and body of the pancreas, the spleen, and the corpus and antrum of the stomach. Perfusion in each organ of patients with and without cirrhosis was compared. Results: Portal venous perfusion of the right and left lobes of the liver in patients with cirrhosis (117 and 100 mL min{sup −1} 100 mL{sup −1}, respectively) was significantly less than that in patients without cirrhosis (213 and 174 mL min{sup −1} 100 mL{sup −1}, respectively; p = 0.0081 and 0.0294, respectively). Arterial perfusion of the spleen (111 mL min{sup −1} 100 mL{sup −1}) and the body of the pancreas (112 mL min{sup −1} 100 mL{sup −1}) in patients with cirrhosis was also significantly decreased compared with that in patients without cirrhosis (spleen, 162 mL min{sup −1} 100 mL{sup −1}, p = 0.0020; body of pancreas, 133 mL min{sup −1} 100 mL{sup −1}, p = 0.0405). Conclusion: The results of the perfusion CT suggest that arterial perfusion of the spleen and the body of the pancreas, as well as portal perfusion of the liver, in cirrhotic patients was decreased compared with that in non-cirrhotic patients.

  18. Liver regeneration.

    Science.gov (United States)

    Mao, Shennen A; Glorioso, Jaime M; Nyberg, Scott L

    2014-04-01

    The liver is unique in its ability to regenerate in response to injury. A number of evolutionary safeguards have allowed the liver to continue to perform its complex functions despite significant injury. Increased understanding of the regenerative process has significant benefit in the treatment of liver failure. Furthermore, understanding of liver regeneration may shed light on the development of cancer within the cirrhotic liver. This review provides an overview of the models of study currently used in liver regeneration, the molecular basis of liver regeneration, and the role of liver progenitor cells in regeneration of the liver. Specific focus is placed on clinical applications of current knowledge in liver regeneration, including small-for-size liver transplant. Furthermore, cutting-edge topics in liver regeneration, including in vivo animal models for xenogeneic human hepatocyte expansion and the use of decellularized liver matrices as a 3-dimensional scaffold for liver repopulation, are proposed. Unfortunately, despite 50 years of intense study, many gaps remain in the scientific understanding of liver regeneration.

  19. Mice with humanized liver endothelium

    NARCIS (Netherlands)

    el Filali, E.

    2014-01-01

    The only curative treatment option for a large proportion of patients suffering from a liver disorder is liver transplantation. The use of ex vivo genetically modified autologous liver cells instead of whole liver transplantation could overcome the problem of donor scarcity. Even though clinical

  20. Mice with humanized liver endothelium

    NARCIS (Netherlands)

    el Filali, E.

    2014-01-01

    The only curative treatment option for a large proportion of patients suffering from a liver disorder is liver transplantation. The use of ex vivo genetically modified autologous liver cells instead of whole liver transplantation could overcome the problem of donor scarcity. Even though clinical tri

  1. Comparison of homocysteine level between pre- and post- liver transplantation in cirrhotic patients%肝硬化患者肝移植术前后同型半胱氨酸水平对比分析

    Institute of Scientific and Technical Information of China (English)

    林建华; 周杰

    2011-01-01

    Objection To analyze the change of plasma homocysteine (Hey) of pre- and post-liver transplantation in cirrhotic patients. Methods The plasma concentrations of Hey were measured in 36 cases of cirrhotic patients before and three months after liver transplantation, and 40 healthy subjects (control group). Results were compared each other. Results The Hcy level was significantly decreased in patients post-operation compared with before operation (P <0.05), and also significantly decreased at three months post-operation. There was significant difference between pre- and three months post-operation (P <0.05). Conclusions It is demonstrated that the liver is the major site for the metabolism of Hcy.%目的 探讨肝硬化患者肝移植术前及术后血浆同型半胱氨酸(Hcy)水平变化的意义.方法 36例肝硬化行肝移植的患者于术前、术后3个月及40名健康人群进行血浆Hcy定量测定,比较各组之间的差别.结果 肝硬化肝移植患者术前Hcy水平较健康人群增高(P<0.05),术后3个月血浆Hcy水平明显下降,术前、术后相比较差异显著(P<0.05).结论 肝硬化肝移植患者术后血浆Hcy水平明显下降,提示肝脏是一个重要的Hcy代谢器官.

  2. Targeting naproxen coupled to human serum albumin to nonparenchymal cells reduces endotoxin-induced mortality in rats with biliary cirrhosis

    NARCIS (Netherlands)

    Albrecht, C.; Meijer, D.K F; Lebbe, C; Sägesser, H; Melgert, B.N; Poelstra, Klaas; Reichen, J

    1997-01-01

    Endotoxin is thought to play a major role in cirrhotic liver disease, Cyclo-oxygenase inhibitors were shown to be partially protective against endotoxin but cannot be used in cirrhotic patients because of renal side-effects, We argued that administration of naproxen (NAP) linked to human serum album

  3. Targeting naproxen coupled to human serum albumin to nonparenchymal cells reduces endotoxin-induced mortality in rats with biliary cirrhosis

    NARCIS (Netherlands)

    Albrecht, C.; Meijer, D.K F; Lebbe, C; Sägesser, H; Melgert, B.N; Poelstra, Klaas; Reichen, J

    1997-01-01

    Endotoxin is thought to play a major role in cirrhotic liver disease, Cyclo-oxygenase inhibitors were shown to be partially protective against endotoxin but cannot be used in cirrhotic patients because of renal side-effects, We argued that administration of naproxen (NAP) linked to human serum

  4. The secretion of high molecular weight cathepsin B from cultured human liver cancers.

    Directory of Open Access Journals (Sweden)

    Ohsawa,Toshiya

    1989-02-01

    Full Text Available The biochemical characteristics of cathepsin B secreted from cultured human liver cancer cells were examined. The enzyme activity of culture medium against a synthetic substrate, N-carbobenzoxy-L-arginyl-L-arginine-4-methyl-coumaryl-7-amide, was dependent on the addition of cysteine, and the optimal pH was found to be 6.0. No activity was observed when the enzyme source was fresh medium not used for culture. These results suggest that the enzyme released from liver cancer cells is the thiol-protease cathepsin B. The molecular weight of the enzyme with 90% of the total activity was 40,000. Two cathepsin B molecules were found in liver tissue from patients with hepatocellular carcinoma (HCC; one was equivalent in size to the secreted enzyme, and a smaller one was the same as normal liver cathepsin B (27,000, which was also obtained from HCC-bearing cirrhotic liver. These results demonstrate that two molecules of cathepsin B are synthesized in liver cancer, and that the larger one is released into the surrounding tissue.

  5. Ursodeoxycholic Acid Influences the Expression of p27kip1 but Not FoxO1 in Patients with Non-Cirrhotic Primary Biliary Cirrhosis

    Directory of Open Access Journals (Sweden)

    Malgorzata Milkiewicz

    2014-01-01

    Full Text Available Background. Enhanced expression of cell cycle inhibitor p27kip1 suppresses cell proliferation. Ursodeoxycholic acid (UDCA delays progression of primary biliary cirrhosis (PBC but its effect on p27kip1 expression is uncertain. Aims. To analyze the expression of p27kip1 and its transcription modulator FoxO1 in patients with PBC, and to assess the impact of UDCA on this pathway. Materials and Methods. The examined human tissue included explanted livers from patients with cirrhotic PBC (n=23, primary sclerosing cholangitis (PSC; n=9, alcoholic liver disease (ALD; n=9, and routine liver biopsies from patients with non-cirrhotic PBC (n=26. Healthy liver samples served as controls (n=19. Livers of FoxO-deficient mice were also studied. mRNA and protein expressions were analyzed by real-time PCR and Western blot. Results. p27kip1 expression was increased in cirrhotic and non-cirrhotic PBC. FoxO1 mRNA levels were increased in PBC (8.5-fold increase versus controls. FoxO1 protein expression in PBC was comparable to controls, but it was decreased in patients with PSC and ALD (63% and 70% reduction, respectively; both P<0.05 versus control. UDCA-treated non-cirrhotic patients with PBC showed decreased expression of p27kip1 mRNA. Conclusion. PBC progression is characterized by a FoxO1-independent increase of p27kip1 expression. In early PBC, UDCA may enhance liver regeneration via p27kip1-dependent mechanism.

  6. Evaluation of Echocardiographic Findings in Cirrhotic Patients

    Directory of Open Access Journals (Sweden)

    M Seidian

    2005-10-01

    Full Text Available Introduction: Cardiovascular abnormalities have been reported in liver cirrhosis (LC. In these patients, cardiac symptoms and physical signs occur as the liver functions worsen. Cirrhosis is associated with hyper dynamic circulation and beta-adrenergic system changes responsible for the cardiovascular abnormalities. The purpose of the present study was to explore the echocardiographic findings in cirrhotic patients. Methods: A total of 90 patients (63 men, 27 women with imaging or biopsy-proven cirrhosis of various etiologies without any known cardiac dysfunction were included in the study. Ninety healthy persons of the same age and sex were enrolled as the control group. Cirrhotic patients and controls were investigated by echocardiography. Left ventricle diastolic function (E/A ratio, systolic function (ejection fraction, and wall thickness (left ventricle posterior wall thickness + interventricular septum thickness along with left and right ventricular dimensions were evaluated. Results: Right & left atrium and ventricle diameters were enlarged in 3 cirrhotic patients and the E/A ratio was decreased in class C patients (0.9 ± 0.2 as compared to class B and A (1.3 ± 0.4 and controls (1.3± 1 (P value < 0.05. The left ventricular end diastolic volumes were increased in 3 cirrhotic patients(5.9+/- 0.3(normal 3.5-4.7 cm. The estimated ejection fraction was decreased in39 cirrhotic patients; 28 patients with ascites (35 -47% as compared to 11 patients without ascites (40-48% and controls (50-75% (P < 0.05. Conclusion: Liver cirrhosis is associated with enlarged left cardiac chambers, but wall thickness and right ventricle functions and diameters are normal. LV Diastolic dysfunction and decreased ejection fraction are evident in cirrhotic patients with ascites in class C children. This demonstration of diastolic dysfunction together with the dilated left cardiac chambers suggests that the patients indeed have cardiac abnormalities. Cardiovascular

  7. Coagulation abnormalities in the cirrhotic patient.

    Science.gov (United States)

    Muciño-Bermejo, Jimena; Carrillo-Esper, Raúl; Uribe, Misael; Méndez-Sánchez, Nahum

    2013-01-01

    The clotting process is a dynamic array of multiple processes which can be described in four phases: platelet plug initiation and formation, clotting process propagation by the coagulation cascade, clotting termination by antithrombotic mechanisms and clot removal by fibrinolysis. The liver plays a central role in each of these phases of clotting process, as it synthesizes the majority of coagulation factors and proteins involved in fibrinolysis as well as thrombopoeitin, which is responsible for platelet production from megakaryocytes. Many pathological processes associated with cirrhosis, such as portal hypertension and endothelial dysfunction, as well as co-morbid conditions, may also alter the coagulation process. Consequently, patients with liver disease have a disturbed balance of procoagulant and anti-coagulant factors which deviates from the normal coagulation cascade. This situation poses an additional problem in the diagnostic and therapeutic approach to this group of patients, since traditional coagulation test may not be reliable for assessing bleeding or thrombotic risk and traditional transfusional strategies may not be applicable in cirrhotic patients. In this article, we review the pathophysiological bases of coagulation abnormalities, in cirrhotic patients, the diagnostic therapeutic strategies to be followed and its impact on the clinical outcome in the cirrhotic patient.

  8. The role of glucocorticoids in sodium retention in cirrhotic patients

    DEFF Research Database (Denmark)

    Hansen, Martin Højmark; Kristensen, Steffen Skott; Schaffalitzky de Muckadell, Ove B

    2012-01-01

    Abstract Objective. Cirrhotic patients have an increased ratio of urinary cortisol to cortisone metabolites, indicating decreased renal 11-β-hydroxysteroid dehydrogenase type-2 activity. This suggests that cortisol - by activation of the mineralocorticoid receptor - may contribute to the abnormal...... sodium retention evident in cirrhosis. The aim was to elucidate the role of glucocorticoids in sodium retention in decompensated cirrhotic patients. Methods. A randomized, double-blind, placebo-controlled, crossover study was performed in nine patients with alcoholic cirrhosis of the liver. A washout....... Conclusion. These results indicate that endogenous glucocorticoids contribute to the sodium retention in patients with alcoholic cirrhosis of the liver....

  9. Melatonin protects the liver and erythrocytes against oxidative stress in cirrhotic rats Melatonina protege o fígado e eritrócitos do estresse oxidativo em ratos cirróticos

    Directory of Open Access Journals (Sweden)

    Darlan Pase da Rosa

    2010-03-01

    Full Text Available CONTEXT: Cirrhosis is a progressive chronic hepatopathy which constitutes an irreversible stage of liver dysfunction. OBJECTIVES: To evaluate the oxidative stress in the blood of cirrhotic rats treated with the antioxidant melatonin. METHODS: Cirrhosis was induced through inhalation of carbon tetrachloride. Liver integrity was evaluated by measuring serum enzymes, oxidative damage measured by lipoperoxidation, and antioxidant enzyme activity in erythrocytes. Lipoperoxidation, total nitrates, collagen, and histology by picrosirius staining were evaluated in the livers of these animals (n = 15, which were divided in three groups: control, carbon tetrachloride, and carbon tetrachloride + melatonin. Melatonin (20 mg/kg was administered intraperitoneal from week 10 of carbon tetrachloride inhalation. In order to shorten the cirrhosis induction time, phenobarbital (0.3 g/L was added to the animals' drinking water. RESULTS: A significant impairment in the liver integrity of melatonin-treated animals as compared to cirrhotic animals was observed. In rat erythrocytes and liver, lipoperoxidation was significantly increased in the cirrhotic rats as compared to controls, as measured through thiobarbituric acid reactive substances, and significantly decreased in melatonin-treated animals as compared to cirrhotic ones. In blood, a decrease in superoxide dismutase and glutathione peroxidase enzymes was detected in the cirrhotic group as compared to the control group, with increased superoxide dismutase activity when melatonin was administered. A reduction in the levels of total nitrates was detected in the hepatic tissue of the animals in the carbon tetrachloride group as compared to the control group and an increase of these levels in the carbon tetrachloride + melatonin group. As for hepatic collagen, we found a significant increase in the carbon tetrachloride group as compared to the controls and a regression of these values in the treated group. In

  10. Comparative Study of Human Liver Ferritin and Chicken Liver by Moessbauer Spectroscopy. Preliminary Results

    Energy Technology Data Exchange (ETDEWEB)

    Oshtrakh, M. I. [Ural State Technical University - UPI, Division of Applied Biophysics, Faculty of Physical Techniques and Devices for Quality Control (Russian Federation); Milder, O. B.; Semionkin, V. A. [Ural State Technical University - UPI, Faculty of Experimental Physics (Russian Federation); Prokopenko, P. G. [Russian State Medical University, Faculty of Biochemistry (Russian Federation); Malakheeva, L. I. [Simbio Holding, Science Consultation Department (Russian Federation)

    2004-12-15

    A comparative study of normal human liver ferritin and livers from normal chicken and chicken with Marek disease was made by Moessbauer spectroscopy. Small differences of quadrupole splitting and isomer shift were found for human liver ferritin and chicken liver. Moessbauer parameters for liver from normal chicken and chicken with Marek disease were the same.

  11. Comparative Study of Human Liver Ferritin and Chicken Liver by Mössbauer Spectroscopy. Preliminary Results

    Science.gov (United States)

    Oshtrakh, M. I.; Milder, O. B.; Semionkin, V. A.; Prokopenko, P. G.; Malakheeva, L. I.

    2004-12-01

    A comparative study of normal human liver ferritin and livers from normal chicken and chicken with Marek disease was made by Mössbauer spectroscopy. Small differences of quadrupole splitting and isomer shift were found for human liver ferritin and chicken liver. Mössbauer parameters for liver from normal chicken and chicken with Marek disease were the same.

  12. AGE WISE HISTOMORPHOLOGICAL CHANGES IN HUMAN LIVER

    Directory of Open Access Journals (Sweden)

    Tribeni

    2015-11-01

    Full Text Available CONTEXT: Hepato cellular carcinoma (HCC results in between 2.5 lakhs to 1million deaths globally per annum. Liver transplantation nowadays is a well accepted treatment option for end-stage liver disease and acute liver failure. AIMS: Keeping this concept in view, a study was conducted in the Guwahati Zone of Northeast India, to compare the histomorphological features of the human liver in different age groups. SETTING AND DESIGN: Apparently healthy livers were obtained from 21 subjects on whom medicolegal post-mortems had been performed. Their ages varied from newborn to 90 years. Subjects were divided into 3 groups. 7 specimens were taken from each group. (1 Pediatric (2 Adult (3 Old age. METHODS AND MATERIALS: In all the above age groups, immediately after removal of the livers, they were washed in normal saline, dried with blotting paper and weighed in an electronic weighing machine. Sections of liver were fixed, processed, cut and stained with Harris Haematoxylin and Eosin stain. RESULTS: The liver loses weight from 50 years onwards. There appears to be racial and environmental differences in the change in liver weight in old age. Autopsy studies show a diminution of nearly 46% in liver weight between the 3rd and 10th decades of life. The liver decreases in size with age. The hepatocytes are radially disposed in the liver lobule. They are piled up, forming a layer one cell thick (except in young children in a fashion similar to the bricks of a wall. These plates are directed from the periphery of the lobule to its centre and anastomose freely forming a complex labyrinthine and sponge-like structure. CONCLUSIONS: From the findings in the present study it can be concluded that: 1. Nowadays, the measurement of liver volume has gained practical use in relation to liver transplantation. 2. We have compared the histomorphology of adult liver with a child. The findings in both the groups are very similar. This feature is important, since in

  13. [Evaluation and treatment of the critically ill cirrhotic patient].

    Science.gov (United States)

    Fernández, Javier; Aracil, Carles; Solà, Elsa; Soriano, Germán; Cinta Cardona, Maria; Coll, Susanna; Genescà, Joan; Hombrados, Manoli; Morillas, Rosa; Martín-Llahí, Marta; Pardo, Albert; Sánchez, Jordi; Vargas, Victor; Xiol, Xavier; Ginès, Pere

    2016-11-01

    Cirrhotic patients often develop severe complications requiring ICU admission. Grade III-IV hepatic encephalopathy, septic shock, acute-on-chronic liver failure and variceal bleeding are clinical decompensations that need a specific therapeutic approach in cirrhosis. The increased effectiveness of the treatments currently used in this setting and the spread of liver transplantation programs have substantially improved the prognosis of critically ill cirrhotic patients, which has facilitated their admission to critical care units. However, gastroenterologists and intensivists have limited knowledge of the pathogenesis, diagnosis and treatment of these complications and of the prognostic evaluation of critically ill cirrhotic patients. Cirrhotic patients present alterations in systemic and splanchnic hemodynamics, coagulation and immune dysfunction what further increase the complexity of the treatment, the risk of developing new complications and mortality in comparison with the general population. These differential characteristics have important diagnostic and therapeutic implications that must be known by general intensivists. In this context, the Catalan Society of Gastroenterology and Hepatology requested a group of experts to draft a position paper on the assessment and treatment of critically ill cirrhotic patients. This article describes the recommendations agreed upon at the consensus meetings and their main conclusions. Copyright © 2015 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

  14. Liver immune-pathogenesis and therapy of human liver tropic virus infection in humanized mouse models.

    Science.gov (United States)

    Bility, Moses T; Li, Feng; Cheng, Liang; Su, Lishan

    2013-08-01

    Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect and replicate primarily in human hepatocytes. Few reliable and easy accessible animal models are available for studying the immune system's contribution to the liver disease progression during hepatitis virus infection. Humanized mouse models reconstituted with human hematopoietic stem cells (HSCs) have been developed to study human immunology, human immunodeficiency virus 1 infection, and immunopathogenesis. However, a humanized mouse model engrafted with both human immune and human liver cells is needed to study infection and immunopathogenesis of HBV/HCV infection in vivo. We have recently developed the humanized mouse model with both human immune and human liver cells (AFC8-hu HSC/Hep) to study immunopathogenesis and therapy of HCV infection in vivo. In this review, we summarize the current models of HBV/HCV infection and their limitations in immunopathogenesis. We will then present our recent findings of HCV infection and immunopathogenesis in the AFC8-hu HSC/Hep mouse, which supports HCV infection, human T-cell response and associated liver pathogenesis. Inoculation of humanized mice with primary HCV isolates resulted in long-term HCV infection. HCV infection induced elevated infiltration of human immune cells in the livers of HCV-infected humanized mice. HCV infection also induced HCV-specific T-cell immune response in lymphoid tissues of humanized mice. Additionally, HCV infection induced liver fibrosis in humanized mice. Anti-human alpha smooth muscle actin (αSMA) staining showed elevated human hepatic stellate cell activation in HCV-infected humanized mice. We discuss the limitation and future improvements of the AFC8-hu HSC/Hep mouse model and its application in evaluating novel therapeutics, as well as studying both HCV and HBV infection, human immune responses, and associated human liver fibrosis and cancer.

  15. Cytoglobin is expressed in hepatic stellate cells, but not in myofibroblasts, in normal and fibrotic human liver.

    Science.gov (United States)

    Motoyama, Hiroyuki; Komiya, Tohru; Thuy, Le Thi Thanh; Tamori, Akihiro; Enomoto, Masaru; Morikawa, Hiroyasu; Iwai, Shuji; Uchida-Kobayashi, Sawako; Fujii, Hideki; Hagihara, Atsushi; Kawamura, Etsushi; Murakami, Yoshiki; Yoshizato, Katsutoshi; Kawada, Norifumi

    2014-02-01

    Cytoglobin (CYGB) is ubiquitously expressed in the cytoplasm of fibroblastic cells in many organs, including hepatic stellate cells. As yet, there is no specific marker with which to distinguish stellate cells from myofibroblasts in the human liver. To investigate whether CYGB can be utilized to distinguish hepatic stellate cells from myofibroblasts in normal and fibrotic human liver, human liver tissues damaged by infection with hepatitis C virus (HCV) and at different stages of fibrosis were obtained by liver biopsy. Immunohistochemistry was performed on histological sections of liver tissues using antibodies against CYGB, cellular retinol-binding protein-1 (CRBP-1), α-smooth muscle actin (α-SMA), thymocyte differentiation antigen 1 (Thy-1), and fibulin-2 (FBLN2). CYGB- and CRBP-1-positive cells were counted around fibrotic portal tracts in histological sections of the samples. The expression of several of the proteins listed above was examined in cultured mouse stellate cells. Quiescent stellate cells, but not portal myofibroblasts, expressed both CYGB and CRBP-1 in normal livers. In fibrotic and cirrhotic livers, stellate cells expressed both CYGB and α-SMA, whereas myofibroblasts around the portal vein expressed α-SMA, Thy-1, and FBLN2, but not CYGB. Development of the fibrotic stage was positively correlated with increases in Sirius red-stained, α-SMA-positive, and Thy-1-positive areas, whereas the number of CYGB- and CRBP-1-positive cells decreased with fibrosis development. Primary cultured mouse stellate cells expressed cytoplasmic CYGB at day 1, whereas they began to express α-SMA at the cellular margins at day 4. Thy-1 was undetectable throughout the culture period. In human liver tissues, quiescent stellate cells are CYGB positive. When activated, they also become α-SMA positive; however, they are negative for Thy-1 and FBLN2. Thus, CYGB is a useful marker with which to distinguish stellate cells from portal myofibroblasts in the damaged human

  16. Hepatocellular Carcinoma Mimicking Liver Abscesses in a Cirrhotic Patient with Severe Septic Shock as a Result of Salmonella O9 HG Infection

    Directory of Open Access Journals (Sweden)

    Shuichi Hagiwara

    2009-04-01

    Full Text Available We describe a case of severe Salmonella O9 HG sepsis with a mass in the liver, which was diagnosed as hepatocellular carcinoma (HCC by autopsy of the liver. The patient was a 67-year-old man with chronic high blood pressure. In addition, he was an alcoholic and had been drinking every day for many years. He had had a dinner of ‘sukiyaki’ with a raw egg two days before admission. The next morning, he had developed vomiting, diarrhea, and abdominal pain. Salmonella O9 HG was found in the blood and stool cultures. In the computed tomography (CT finding of the liver, there was a 2 cm early-enhanced mass with a multilocular structure, with ringed enhancement and daughter nodes. Since we thought that the mass was a liver abscess, we performed needle aspiration from the liver mass and were able to withdraw blood. Despite adequate antibiotic treatment, the patient died as a result of complications on the 55th day after admission. After the patient’s death, we conducted an autopsy. There were two HCC masses, a moderately-differentiated and a well-differentiated mass, as a result of alcoholic cirrhosis of the liver. As the HCC had multilocular cyst-like structures, which were fiber- and necrosis-rich, CT images of the liver masses resembled abscesses.

  17. The incidence of venous thromboembolism and practice of deep venous thrombosis prophylaxis in hospitalized cirrhotic patients

    Directory of Open Access Journals (Sweden)

    Alqahtani Saad

    2011-01-01

    Full Text Available Abstract Background Cirrhotic patients are characterized by a decreased synthesis of coagulation and anticoagulation factors. The coagulopathy of cirrhotic patients is considered to be auto-anticoagulation. Our aim was to determine the incidence and predictors of venous thromboembolism (VTE and examine the practice of deep venous thrombosis (DVT prophylaxis among hospitalized cirrhotic patients. Methods A retrospective cohort study was performed in a tertiary teaching hospital. We included all adult patients admitted to the hospital with a diagnosis of liver cirrhosis from January 1, 2009 to December 31, 2009. We grouped our cohort patients in two groups, cirrhotic patients without VTE and cirrhotic with VTE. Results Over one year, we included 226 cirrhotic patients, and the characteristics of both groups were similar regarding their clinical and laboratory parameters and their outcomes. Six patients (2.7% developed VTE, and all of the VTEs were DVT. Hepatitis C was the most common (51% underlying cause of liver cirrhosis, followed by hepatitis B (22%; 76% of the cirrhotic patients received neither pharmacological nor mechanical DVT prophylaxis. Conclusion Cirrhotic patients are at risk for developing VTE. The utilization of DVT prophylaxis was suboptimal.

  18. Clinical Significance of a Myeloperoxidase Gene Polymorphism and Inducible Nitric Oxide Synthase Expression in Cirrhotic Patients with Hepatopulmonary Syndrome

    Institute of Scientific and Technical Information of China (English)

    王燕颖; 王文多; 张艳霞; 赵欣; 杨东亮

    2010-01-01

    The clinical significance of a myeloperoxidase (MPO) gene polymorphism and inducible nitric oxide synthase (iNOS) expression in cirrhotic patients with hepatopulmonary syndrome (HPS) was explored. Enrolled subjects were divided into three groups according to their disease/health conditions: the HPS group (cirrhotic patients with HPS; n=63), the non-HPS group (cirrhotic patients without HPS; n=182), and the control group (healthy subjects without liver disease; n=35). The distribution of the MPO-463 G/A geno...

  19. Postoperative day one serum alanine amino-transferase does not predict patient morbidity and mortality after elective liver resection in non-cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    RickY Harminder Bhogal; Amit Nair; Davide Papis; Zaed Hamady; Jawad Ahmad; For Tai Lam; Saboor Khan; Gabriele Marangoni

    2016-01-01

    Serum aminotransferases have been used as sur-rogate markers for liver ischemia-reperfusion injury that fol-lows liver surgery. Some studies have suggested that rises in serum alanine aminotransferase (ALT) correlate with patient outcome after liver resection. We assessed whether postopera-tive day 1 (POD 1) ALT could be used to predict patient mor-bidity and mortality following liver resection. We reviewed our prospectively held database and included consecutive adult patients undergoing elective liver resection in our in-stitution between January 2013 and December 2014. Primary outcome assessed was correlation of POD 1 ALT with patient’s morbidity and mortality. We also assessed whether concurrent radiofrequency ablation, neoadjuvant chemotherapy and use of the Pringle maneuver signiifcantly affected the level of POD 1 ALT. A total of 110 liver resections were included in the study. The overall in-hospital patient morbidity and mortality were 31.8% and 0.9%, respectively. The median level of POD 1 ALT was 275 IU/L. No correlation was found between POD 1 serum ALT levels and patient morbidity after elective liver resection, whilst correlation with mortality was not possible because of the low number of mortalities. Patients undergoing concur-rent radiofrequency ablation were noted to have an increased level of POD 1 serum ALT but not those given neoadjuvant chemotherapy and those in whom the Pringle maneuver was used. Our study demonstrates POD 1 serum ALT does not cor-relate with patient morbidity after elective liver resection.

  20. Human Ex-Vivo Liver Model for Acetaminophen-induced Liver Damage

    Science.gov (United States)

    Schreiter, Thomas; Sowa, Jan-Peter; Schlattjan, Martin; Treckmann, Jürgen; Paul, Andreas; Strucksberg, Karl-Heinz; Baba, Hideo A.; Odenthal, Margarete; Gieseler, Robert K.; Gerken, Guido; Arteel, Gavin E.; Canbay, Ali

    2016-01-01

    Reliable test systems to identify hepatotoxicity are essential to predict unexpected drug-related liver injury. Here we present a human ex-vivo liver model to investigate acetaminophen-induced liver injury. Human liver tissue was perfused over a 30 hour period with hourly sampling from the perfusate for measurement of general metabolism and clinical parameters. Liver function was assessed by clearance of indocyanine green (ICG) at 4, 20 and 28 hours. Six pieces of untreated human liver specimen maintained stable liver function over the entire perfusion period. Three liver sections incubated with low-dose acetaminophen revealed strong damage, with ICG half-lives significantly higher than in non-treated livers. In addition, the release of microRNA-122 was significantly higher in acetaminophen-treated than in non-treated livers. Thus, this model allows for investigation of hepatotoxicity in human liver tissue upon applying drug concentrations relevant in patients. PMID:27550092

  1. Obesity accelerates epigenetic aging of human liver.

    Science.gov (United States)

    Horvath, Steve; Erhart, Wiebke; Brosch, Mario; Ammerpohl, Ole; von Schönfels, Witigo; Ahrens, Markus; Heits, Nils; Bell, Jordana T; Tsai, Pei-Chien; Spector, Tim D; Deloukas, Panos; Siebert, Reiner; Sipos, Bence; Becker, Thomas; Röcken, Christoph; Schafmayer, Clemens; Hampe, Jochen

    2014-10-28

    Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an "epigenetic clock") to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 × 10(-4) in dataset 1 and r = 0.42, P = 1.2 × 10(-4) in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10(-9)) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.

  2. Quercetin Treatment Ameliorates Systemic Oxidative Stress in Cirrhotic Rats

    Science.gov (United States)

    Vieira, Emanuelle Kerber; Bona, Silvia; Di Naso, Fábio Cangeri; Porawski, Marilene; Tieppo, Juliana; Marroni, Norma Possa

    2011-01-01

    Our aim was to investigate whether the antioxidant quercetin protects against liver injury and ameliorates the systemic oxidative stress in rats with common bile duct ligation. Secondary biliary cirrhosis was induced through 28 days of bile duct obstruction. Animals received quercetin (Q) after 14 days of obstruction. Groups of control (CO) and cirrhotic (CBDL) animals received a daily 50 mg/kg body weight i.p. injection of quercetin (CO + Q; CBDL + Q) or vehicle (CO; CBDL). Quercetin corrected the reduction in superoxide dismutase (SOD), catalase CAT, and glutathione peroxidase GPx activities and prevented the increase of thiobarbituric acid reactive substances (TBARS), aminotransferases, and alkaline phosphatase in cirrhotic animals. Quercetin administration also corrected the reduced total nitrate concentration in the liver and prevented liver fibrosis and necrosis. These effects suggest that quercetin might be a useful agent to preserve liver function and prevent systemic oxidative stress. PMID:21991520

  3. Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

    Directory of Open Access Journals (Sweden)

    Alison E. M. Vickers

    2017-03-01

    Full Text Available Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM, diclofenac (DCF, 1 mM and etomoxir (ETM, 100 μM. Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM and cyclosporin A (CSA, 10 μM, while GSH was affected more than ATP by methimazole (MMI, 500 μM, terbinafine (TBF, 100 μM, and carbamazepine (CBZ 100 μM. Oxidative stress genes were affected by TBF (18%, CBZ, APAP, and ETM (12%–11%, and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%–6%. Apoptosis genes were affected by DCF (14%, while apoptosis plus necrosis were altered by APAP and ETM (15%. Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%, ETM (66%, DCF, TBF, MMI (61%–60%, APAP, CBZ (57%–56%, and DTL (48%. Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%, CBZ and ETM (44%–43%, APAP and DCF (40%–38%, MMI, TBF and CSA (37%–35%. This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects.

  4. Liver Effects of Clinical Drugs Differentiated in Human Liver Slices.

    Science.gov (United States)

    Vickers, Alison E M; Ulyanov, Anatoly V; Fisher, Robyn L

    2017-03-07

    Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM), diclofenac (DCF, 1 mM) and etomoxir (ETM, 100 μM). Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM) and cyclosporin A (CSA, 10 μM), while GSH was affected more than ATP by methimazole (MMI, 500 μM), terbinafine (TBF, 100 μM), and carbamazepine (CBZ 100 μM). Oxidative stress genes were affected by TBF (18%), CBZ, APAP, and ETM (12%-11%), and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%-6%). Apoptosis genes were affected by DCF (14%), while apoptosis plus necrosis were altered by APAP and ETM (15%). Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%), ETM (66%), DCF, TBF, MMI (61%-60%), APAP, CBZ (57%-56%), and DTL (48%). Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%), CBZ and ETM (44%-43%), APAP and DCF (40%-38%), MMI, TBF and CSA (37%-35%). This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects.

  5. Liver immune-pathogenesis and therapy of human liver tropic virus infection in humanized mouse models

    OpenAIRE

    Bility, Moses T.; Li, Feng; Cheng, Liang; Su, Lishan

    2013-01-01

    Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect and replicate primarily in human hepatocytes. Few reliable and easy accessible animal models are available for studying the immune system’s contribution to the liver disease progression during hepatitis virus infection. Humanized mouse models reconstituted with human hematopoietic stem cells (HSCs) have been developed to study human immunology, human immunodeficiency virus 1 infection, and immunopathogenesis. However, a humanized mous...

  6. Stem cell differentiation and human liver disease

    Institute of Scientific and Technical Information of China (English)

    Wen-Li Zhou; Claire N Medine; Liang Zhu; David C Hay

    2012-01-01

    Human stem cells are scalable cell populations capable of cellular differentiation.This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells.Such an approach has the potential to improve our understanding of human biology and treating disease.In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases.In recent years,efficient hepatic differentiation from human stem cells has been achieved by several research groups including our own.In this review we provide an overview of the field and discuss the future potential and limitations of stem cell technology.

  7. Human herpesvirus 6 infections after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Rima Camille Abdel Massih; Raymund R Razonable

    2009-01-01

    Human herpesvirus 6 (HHV-6) infections occur in > 95% of humans. Primary infection, which occurs in early childhood as an asymptomatic illness or manifested clinically as roseola infantum, leads to a state of subclinical viral persistence and latency. Reactivation of latent HHV-6 is common after liver transplantation, possibly induced and facilitated by allograft rejection and immunosuppressive therapy. Since the vast majority of humans harbor the virus in a latent state, HHV-6 infections after liver transplantation are believed to be mostly due to endogenous reactivation or superinfection (reactivation in the transplanted organ). In a minority of cases, however,primary HHV-6 infection may occur when an HHV-6 negative individual receives a liver allograft from an HHV-6 positive donor. The vast majority of documented HHV-6 infections after liver transplantation are asymptomatic. In a minority of cases, HHV-6 has been implicated as a cause of febrile illness with rash and myelosuppression, hepatitis, pneumonitis, and encephalitis after liver transplantation. In addition,HHV-6 has been associated with a variety of indirect effects such as allograft rejection, and increased predisposition and severity of other infections including cytomegalovirus (CMV), hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6- specific approach to prevention. However, ganciclovir and valganciclovir, which are primarily intended for the prevention of CMV disease, are also active against HHV-6 and may prevent its reactivation after transplantation. The treatment of established HHV-6 disease is usually with intravenous ganciclovir, cidofovir,or foscarnet, complemented by reduction in the degree of immunosuppression. This article reviews the current advances in the pathogenesis, clinical diagnosis, and therapeutic modalities against HHV6 in the setting of liver transplantation.

  8. [A case of hepatic sarcoidosis presenting with cirrhotic symptoms].

    Science.gov (United States)

    Kaji, Kiichiro; Ogino, Hidero; Hirai, Satoshi; Shimatani, Akiyoshi; Horita, Yosuke; Matsuda, Kouichiro; Hiramatsu, Katsushi; Matsuda, Mitsuru; Shimizu, Koichi; Nakanishi, Yuko; Noda, Yatsugi

    2014-03-01

    A man in 40s with skin sarcoidosis presented with signs and symptoms of liver injury and thrombocytopenia. Enhanced computed tomography and magnetic resonance imaging revealed cholecystolithiasis, hepatic deformation, and giant splenomegaly. Gastrointestinal endoscopy showed esophageal varices. Cholecystectomy, splenectomy, and wedge biopsy of the liver were performed. Histopathology of the liver revealed many granulomas and severe periportal fibrosis without lobular reconstruction. These findings were compatible with hepatic sarcoidosis, but not liver cirrhosis. Here we report a rare case of hepatic sarcoidosis presenting with cirrhotic symptoms.

  9. Compliance with the clinical practice guidelines for the management of hepatitis B and C virus-related chronic liver disease: a survey based on hospitalized cirrhotic patients

    Directory of Open Access Journals (Sweden)

    Emanuele La Spada

    2013-04-01

    Full Text Available In recent years, significant progress has been made in furthering our knowledge of chronic liver disease (CLD and evaluating the therapeutic approaches. These have been updated in the form of recommendations by international scientific societies. Through a retrospective analysis, this study aimed to verify whether these recommendations have been applied in real practice. The study design included data gathered from all patients consecutively hospitalized for decompensated liver cirrhosis during one year. A pre-made master form was used to record data on the patients’ past knowledge of the etiology and management of their liver disease. As expected, hepatitis C virus (HCV was the most frequent cause of CLD, while 41 cases were cryptogenic. In 69 of 263 patients with HCV infection, viral genotyping had been performed, although only 39 of these cases had been treated. Only 3 of 44 patients suffering from hepatitis B virus (HBV-related liver cirrhosis had been treated in the past, while 11 patients were still being treated. Among the remaining patients, 15 were not aware that they had CLD and 15 had never been considered for antiviral treatment. In 81 cases, the disease had progressed to hepatocellular carcinoma, but only 19 patients had discovered the tumor following regular ultrasound screening. Thirty-seven patients were receiving specific treatment consistent with the stage of their disease. The management of HBV- and HCV-related CLD in Sicily is far from optimal, and although the natural history and management practices of these diseases are well known, this knowledge is a long way from being applied in our daily practice.

  10. Nitric oxide synthase and heme oxygenase expressions in human liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Beatrice J Goh; Bee Tee Tan; Wei Min Hon; Kang Hoe Lee; Hoon Eng Khoo

    2006-01-01

    AIM: Portal hypertension is a common complication of liver cirrhosis. Intrahepatic pressure can be elevated in several ways. Abnormal architecture affecting the vasculature, an increase in vasoconstrictors and increased circulation from the splanchnic viscera into the portal system may all contribute. It follows that endogenous vasodilators may be able to alleviate the hypertension. We therefore aimed to investigate the levels of endogenous vasodilators, nitric oxide (NO) and carbon monoxide (CO) through the expression of nitric oxide synthase (NOS) and heme oxygenase (HO).METHOD: Cirrhotic (n= 20) and non-cirrhotic (n = 20) livers were obtained from patients who had undergone surgery. The mRNA and protein expressions of the various isoforms of NOS and HO were examined using competitive PCR, Western Blot and immunohistochemistry.RESULTS: There was no significant change in either inducible NOS (iNOS) or neuronal NOS (nNOS) expressions while endothelial NOS (eNOS) was upregulated in cirrhotic livers. Concomitantly, caveolin-1, an established down-regulator of eNOS, was up-regulated.Inducible HO-1 and constitutive HO-2 were found to show increased expression in cirrhotic livers albeit in different localizations.CONCLUSION: The differences of NOS expression might be due to their differing roles in maintaining liver homeostasis and/or involvement in the pathology of cirrhosis. Sheer stress within the hypertensive liver may induce increased expression of eNOS. In turn, caveolin-1 is also increased. Whether this serves as a defense mechanism against further cirrhosis or is a consequence of cirrhosis, is yet unknown. The elevated expression of HO-1 and HO-2 suggest that CO may compensate in its role as a vasodilator albeit weakly. It is possible that CO and NO have parallel or coordinated functions within the liver and may work antagonistically in the pathophysiology of portal hypertension.

  11. Nutritional assessment in cirrhotic patients with hepaticencephalopathy

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Hepatic encephalopathy (HE) is one of the worstcomplications of liver disease and can be greatly influencedby nutritional status. Ammonia metabolism, inflammationand muscle wasting are relevant processes inHE pathophysiology. Malnutrition worsens the prognosisin HE, requiring early assessment of nutritional statusof these patients. Body composition changes inducedby liver disease and limitations superimposed by HEhamper the proper accomplishment of exams in thispopulation, but evidence is growing that assessmentof muscle mass and muscle function is mandatory dueto the role of skeletal muscles in ammonia metabolism.In this review, we present the pathophysiologicalaspects involved in HE to support further discussionabout advantages and drawbacks of some methods forevaluating the nutritional status of cirrhotic patients withHE, focusing on body composition.

  12. Towards a Humanized Mouse Model of Liver Stage Malaria Using Ectopic Artificial Livers

    Science.gov (United States)

    Ng, Shengyong; March, Sandra; Galstian, Ani; Gural, Nil; Stevens, Kelly R.; Mota, Maria M.; Bhatia, Sangeeta N.

    2017-01-01

    The malaria liver stage is an attractive target for antimalarial development, and preclinical malaria models are essential for testing such candidates. Given ethical concerns and costs associated with non‐human primate models, humanized mouse models containing chimeric human livers offer a valuable alternative as small animal models of liver stage human malaria. The best available human liver chimeric mice rely on cellular transplantation into mice with genetically engineered liver injury, but these systems involve a long and variable humanization process, are expensive, and require the use of breeding-challenged mouse strains which are not widely accessible. We previously incorporated primary human hepatocytes into engineered polyethylene glycol (PEG)-based nanoporous human ectopic artificial livers (HEALs), implanted them in mice without liver injury, and rapidly generated human liver chimeric mice in a reproducible and scalable fashion. By re-designing the PEG scaffold to be macroporous, we demonstrate the facile fabrication of implantable porous HEALs that support liver stage human malaria (P. falciparum) infection in vitro, and also after implantation in mice with normal liver function, 60% of the time. This proof-of-concept study demonstrates the feasibility of applying a tissue engineering strategy towards the development of scalable preclinical models of liver stage malaria infection for future applications. PMID:28361899

  13. Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.

    Science.gov (United States)

    Tripathi, Dinesh M; Erice, Eva; Lafoz, Erica; García-Calderó, Héctor; Sarin, Shiv K; Bosch, Jaime; Gracia-Sancho, Jordi; García-Pagán, Juan Carlos

    2015-09-01

    Increased hepatic vascular resistance is the primary factor in the development of portal hypertension. Metformin ameliorates vascular cells function in several vascular beds. Our study was aimed at evaluating the effects, and the underlying mechanisms, of metformin on hepatic and systemic hemodynamics in cirrhotic rats and its possible interaction with the effects of propranolol (Prop), the current standard treatment for portal hypertension. CCl4-cirrhotic rats received by gavage metformin 300 mg/kg or its vehicle once a day for 1 wk, before mean arterial pressure (MAP), portal pressure (PP), portal blood flow (PBF), hepatic vascular resistance, and putative molecular/cellular mechanisms were measured. In a subgroup of cirrhotic rats, the hemodynamic response to acute Prop (5 mg/kg iv) was assessed. Effects of metformin ± Prop on PP and MAP were validated in common bile duct ligated-cirrhotic rats. Metformin-treated CCl4-cirrhotic rats had lower PP and hepatic vascular resistance than vehicle-treated rats, without significant changes in MAP or PBF. Metformin caused a significant reduction in liver fibrosis (Sirius red), hepatic stellate cell activation (α-smooth muscle actin, platelet-derived growth factor receptor β polypeptide, transforming growth factor-βR1, and Rho kinase), hepatic inflammation (CD68 and CD163), superoxide (dihydroethidium staining), and nitric oxide scavenging (protein nitrotyrosination). Prop, by decreasing PBF, further reduced PP. Similar findings were observed in common bile duct ligated-cirrhotic rats. Metformin administration reduces PP by decreasing the structural and functional components of the elevated hepatic resistance of cirrhosis. This effect is additive to that of Prop. The potential impact of this pharmacological combination, otherwise commonly used in patients with cirrhosis and diabetes, needs clinical evaluation.

  14. No effect of oral testosterone treatment on sexual dysfunction in alcoholic cirrhotic men

    DEFF Research Database (Denmark)

    Gluud, C; Wantzin, P; Eriksen, J

    1988-01-01

    The prevalence and course of sexual dysfunction was evaluated in 221 alcoholic cirrhotic men participating in a double-blind, placebo-controlled study on the effect of oral testosterone treatment on liver disease. At entry, 67% (95% confidence limits, 61%-74%) complained of sexual dysfunction....... In conclusion, oral testosterone treatment does not significantly influence the type or course of sexual dysfunction in alcoholic cirrhotic men. However, sexual function improved after reduction of ethanol consumption in these patients....

  15. The effects of Helicobacter pylori infection on hyperammonaemia and hepatic encephalopathy in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    王良静

    2006-01-01

    Objective To evaluate the relationship among Helicobacter pylori (Hp) infection, blood ammonia concentrations , and hepatic encephalopathy (HE) status, and to investigate the effect of Hp eradication on blood ammonia levels and hepatic encephalopathy status in cirrhotic patients. Methods From July 2003 to Jan 2005, cirrhotic patients in 5 regions of Zhejiang Province were enrolled. Patients were evaluated for the demographic checklists, number connection test, Hp infection, liver impairment level, blood ammonia concentrations and he-

  16. Molecular Structure of Human-Liver Glycogen.

    Directory of Open Access Journals (Sweden)

    Bin Deng

    Full Text Available Glycogen is a highly branched glucose polymer which is involved in maintaining blood-sugar homeostasis. Liver glycogen contains large composite α particles made up of linked β particles. Previous studies have shown that the binding which links β particles into α particles is impaired in diabetic mice. The present study reports the first molecular structural characterization of human-liver glycogen from non-diabetic patients, using transmission electron microscopy for morphology and size-exclusion chromatography for the molecular size distribution; the latter is also studied as a function of time during acid hydrolysis in vitro, which is sensitive to certain structural features, particularly glycosidic vs. proteinaceous linkages. The results are compared with those seen in mice and pigs. The molecular structural change during acid hydrolysis is similar in each case, and indicates that the linkage of β into α particles is not glycosidic. This result, and the similar morphology in each case, together imply that human liver glycogen has similar molecular structure to those of mice and pigs. This knowledge will be useful for future diabetes drug targets.

  17. Molecular Structure of Human-Liver Glycogen

    Science.gov (United States)

    Deng, Bin; Sullivan, Mitchell A.; Chen, Cheng; Li, Jialun; Powell, Prudence O.; Hu, Zhenxia; Gilbert, Robert G.

    2016-01-01

    Glycogen is a highly branched glucose polymer which is involved in maintaining blood-sugar homeostasis. Liver glycogen contains large composite α particles made up of linked β particles. Previous studies have shown that the binding which links β particles into α particles is impaired in diabetic mice. The present study reports the first molecular structural characterization of human-liver glycogen from non-diabetic patients, using transmission electron microscopy for morphology and size-exclusion chromatography for the molecular size distribution; the latter is also studied as a function of time during acid hydrolysis in vitro, which is sensitive to certain structural features, particularly glycosidic vs. proteinaceous linkages. The results are compared with those seen in mice and pigs. The molecular structural change during acid hydrolysis is similar in each case, and indicates that the linkage of β into α particles is not glycosidic. This result, and the similar morphology in each case, together imply that human liver glycogen has similar molecular structure to those of mice and pigs. This knowledge will be useful for future diabetes drug targets. PMID:26934359

  18. The effect of oral testosterone on serum TBG levels in alcoholic cirrhotic men

    DEFF Research Database (Denmark)

    Becker, U; Gluud, C; Bennett, Patrick

    1988-01-01

    , it is demonstrated that testosterone treatment significantly reduced TBG concentrations in cirrhotic men with preserved liver function, like normal men, but not in patients with moderate liver dysfunction. The lack of effect of testosterone in patients with more advanced cirrhosis may be due to a decreased function...

  19. Cirrhotic Multiorgan Syndrome

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming

    2015-01-01

    Patients with cirrhosis and portal hypertension are at an increased risk of the development of circulatory dysfunction that may potentially result in multiple organ failure. Apart from the liver, this may involve the heart, lungs, kidneys, the immune system, the adrenal glands, and other organ...... complications such as hepatorenal syndrome. In patients with chronic organ dysfunction, various precipitating events may induce an acute-on-chronic renal failure and acute-on-chronic liver failure that negatively affect the prognosis. Future research on the pathophysiologic mechanisms of the complications...

  20. Safety of frozen liver for human consumption

    Directory of Open Access Journals (Sweden)

    Ghada A.K. Kirrella

    2017-07-01

    Full Text Available The objective of this study was to ensure and evaluate the safety of imported frozen beef liver traded in supermarkets of Kafr El-Sheikh Governorate, Egypt, through detection of Salmonella typhimurium, Salmonella enteritidies, Escherichia coli O157:H7, antibiotic residues, and aflatoxin B1 residue. Fifty samples of imported frozen liver were randomly collected from different shops at Kafr El-Sheikh Governorate for isolation of S. typhimurium, S. enteritidies, and E. coli O157:H7. The results revealed that for both microorganisms 4% of the examined samples presumed to contain Salmonella and E. coli O157:H7 organisms, according to the colonial character on Harlequin Salmonella ABC agar media and Harlequin SMAC-BCIG agar media. According to biochemical and serological identifications, both organisms could not be detected in the examined samples. A total of 29 (58% samples were positive for antibiotic residues, using the Premi test (a broad-spectrum screening test for the detection of antibiotic residues in meat at or below the maximum residue limits. In addition, aflatoxin B1 was detected in one (2% samples with a concentration of 1.1 μg/kg. The results reflect that there was good hygiene practice for handling and preparation of frozen liver while selling to consumers. However, a high percentage of antibiotic residues reflect ignorance of withdrawal time before slaughtering of animals as well as misuse of antibiotics in veterinary fields. Furthermore, aflatoxin B1 residue was detected in examined frozen liver samples at a concentration below the maximum residual level, which is not enough to cause threat to humans, but it is enough to cause problem if it is eaten regularly reflect contamination of animal feed with aflatoxins.

  1. Beneficial effect of hyperbaric oxygenation on liver regeneration in cirrhosis.

    Science.gov (United States)

    Ozdogan, Mehmet; Ersoy, Eren; Dundar, Kadir; Albayrak, Levent; Devay, Seda; Gundogdu, Haldun

    2005-12-01

    Underlying hepatic injury and cirrhosis are leading factors that interfere with the post-operative liver regeneration and function. Hyperbaric oxygenation (HBO) has been reported to ameliorate the ischemia-reperfusion injury of the liver, to induce compensatory hypertrophy of the predicted remnant liver in rats after portal vein ligation and to augment liver regeneration after hepatectomy in non-cirrhotic rats. Our aim was to determine the effect of HBO treatment on liver regeneration after partial hepatectomy in normal and cirrhotic mice in this experimental study. The effect of HBO on liver regeneration was studied in a mice model combining carbon tetrachloride induced cirrhosis and partial hepatectomy. Mice were divided into four groups: Control, cirrhotic, non-cirrhotic HBO-treated, and cirrhotic HBO-treated. All animals underwent 40% hepatectomy. Liver regeneration was evaluated by the proliferating cell nuclear antigen-labeling index. Serum aspartate aminotransferase and alanine aminotransferase levels were measured to evaluate liver injury. Serum alanine aminotransferase and aspartate aminotransferase levels were significantly decreased in HBO-treated cirrhotic group compared to cirrhosis group after hepatectomy (P = 0.001 and P = 0.014, respectively). The proliferating cell nuclear antigen labeling index was significantly higher in HBO treated cirrhotic group than in cirrhotic group after hepatectomy (P = 0.022). Our results suggest that HBO treatment improves liver functions and augments hepatocyte regeneration in cirrhotic mice after hepatectomy. Post-operative HBO treatment may have a beneficial effect on post-operative liver function and regeneration in cirrhotic patients.

  2. Unusual cause of gastrointestinal bleeding in a cirrhotic patient:hepatocellular carcinoma with gastric invasion

    Institute of Scientific and Technical Information of China (English)

    Marcos Vinicius Perini; Paulo Herman; Rodrigo Pessoa; Willian Abraao Saad

    2009-01-01

    BACKGROUND: Upper gastrointestinal (GI) bleeding is a common complication of portal hypertension in cirrhotic patients, and hepatocellular carcinoma (HCC) is the most common tumor in cirrhotic livers. Bleeding from tumor erosion into the GI tract is very rare. A patient with HCC and gastric tumor invasion was described and the previously reported cases were reviewed. METHOD: A patient with upper GI bleeding was treated in a tertiary hospital. RESULTS: A cirrhotic patient with a HCC invading the stomach leading to upper GI bleeding was treated by left lateral segmentectomy and sub-total gastrectomy. The bleeding was controlled and a good surgical outcome was achieved. CONCLUSIONS: HCC with gastric invasion should be differentially diagnosed from upper GI bleeding in cirrhotic patients. Bleeding can be controlled and symptomatic relief marked in selected cases.

  3. Detection of novel biomarkers of liver cirrhosis by proteomic analysis

    DEFF Research Database (Denmark)

    Mölleken, Christian; Sitek, Barbara; Henkel, Corinna;

    2009-01-01

    liver biopsy allows a reliable evaluation of the course of hepatitis C by grading inflammation and staging fibrosis, and thus serum biomarkers for hepatic fibrosis with high sensitivity and specificity are needed. To identify new candidate biomarkers for hepatic fibrosis, we performed a proteomic......Hepatic cirrhosis is a life-threatening disease arising from different chronic liver disorders. One major cause for hepatic cirrhosis is chronic hepatitis C. Chronic hepatitis C is characterized by a highly variable clinical course, with at least 20% developing liver cirrhosis within 40 years. Only...... approach of microdissected cirrhotic septa and liver parenchyma cells. In cirrhotic septa, we detected an increasing expression of cell structure associated proteins, including actin, prolyl 4-hydroxylase, tropomyosin, calponin, transgelin, and human microfibril-associated protein 4 (MFAP-4). Tropomyosin...

  4. Short-Term, Low-Dose Use of Tolvaptan as a Bridge Therapy to Expedite Liver Transplant for Severe Hyponatremic, Cirrhotic Patients With High Model for End-Stage Liver Disease Scores.

    Science.gov (United States)

    Lenci, Ilaria; Milana, Martina; Angelico, Mario; Baiocchi, Leonardo

    2015-11-17

    For patients on liver transplant waiting lists, hyponatremia is associated with increased mortality before transplant and complications during the early posttransplant period. Conventional therapies, such as fluid restriction or hypertonic saline infusion, are of limited value. We describe 2 patients with high Model for End-Stage Liver Disease scores (> 30) who were referred to our unit for expedited liver transplant. While on waiting lists, these patients developed severe hyponatremia (therapies. Low-dose, short-term tolvaptan therapy (15 mg/d for 5 d) was then administered, as a bridge therapy to transplant, resulting in prompt restoration of serum sodium levels without any major clinical event. One patient died a few days later as no suitable grafts were available. The other received a liver transplant, and the outcome was uneventful. In conclusion, our report demonstrates that a short-term, low-dose tolvaptan-based strategy promptly resolves hyponatremia in patients who are on expedited waiting lists for liver transplant, allowing surgery with improved sodium levels and possibly limiting peritransplant complications.

  5. Umbilical hernia in cirrhotic patients: outcome of elective repair.

    Science.gov (United States)

    Lasheen, Adel; Naser, Hatem M; Abohassan, Ahmed

    2013-12-01

    Cirrhotic patients with umbilical hernia have an increased likelihood of complications following repair. The aim of this study was to assess the outcomes of elective umbilical hernia repair in cirrhotic patients. Fifty patients having uncomplicated umbilical hernia with a cirrhotic liver were studied prospectively. These patients divided into three groups' according to Child-Turcotte-Pugh (CTP) classification. After management of coagulopathy, correction of hypoalbuminaemia and electrolytes imbalance, and control of ascites, all patients underwent elective hernia repair under regional anesthesia. A comparison was made between the three groups as regard the size of the defect in the linea Alba, operative time, postoperative morbidity and mortality, length of hospital stay, time of return to daily life and postoperative changes in liver function tests (LFTs) in relation to the regional anesthesia applied. hernioplasty was done under spinal anesthesia in 13 patients (26%), under epidural anesthesia in 10 patients (20%), under intercostal nerve block in 7 patients (14%), and under local anesthesia in 20 patients (40%). There was an increased safety (less changes in LFTs) in cases done under local anesthesia and intercostal nerve block. The overall complications rate was 30%. There was an increased complications rate towards the decompensated cases. The differences in the mean length of hospital stay and mean time of return to daily life are statistically significant between the three groups. Umbilical hernia recurrence rate was 2% and no mortality was reported in the study groups.

  6. Long term prognosis of fatty liver: risk of chronic liver disease and death

    DEFF Research Database (Denmark)

    Dam-Larsen, S; Franzmann, M; Andersen, I B;

    2004-01-01

    BACKGROUND AND AIMS: Fatty liver is a common histological finding in human liver biopsy specimens. It affects 10-24% of the general population and is believed to be a marker of risk of later chronic liver disease. The present study examined the risk of development of cirrhotic liver disease...... and the risk of death in a cohort diagnosed with pure fatty liver without inflammation. METHODS: A total of 215 patients who had a liver biopsy performed during the period 1976-1987 were included in the study. The population consisted of 109 non-alcoholic and 106 alcoholic fatty liver patients. Median follow...... of Patients and the nationwide Registry of Causes of Death, and all admissions, discharge diagnoses, and causes of death were obtained. RESULTS: In the non-alcoholic fatty liver group, one patient developed cirrhosis during the follow up period compared with 22 patients in the alcoholic group. Survival...

  7. Prevalence of subclinical hepatic encephalopathy in cirrhotic patients in China

    Institute of Scientific and Technical Information of China (English)

    Yu-Yuan Li; Yu-Qiang Nie; Wei-Hong Sha; Zheng Zeng; Fu-Ying Yang; Li Ping; Lin Jia

    2004-01-01

    AIM: Subclinical hepatic encephalopathy (SHE) is a common complication of liver diseases. The aim of this study was to find out the normal value of psychometric test and to investigate the prevalence of SHE in Chinese patients with stabilized hepatic cirrhosis.METHODS: Four hundred and nine consecutive cirrhotic patients without overt clinical encephalopathy were screened for SHE by using number connection test part A (NCT-A) and symbol digit test (SDT). SHE was defined as presence of at least one abnormal psychometric test. The age-corrected normal values were defined as the mean±2times standard deviation (2SD), and developed in 356 healthy persons as normal controls. Four hundred and sixteen patients with chronic viral hepatitis were tested as negative controls to assess the diagnostic validity of this test battery.RESULTS: There was no significant difference in NCT scores and SDT quotients between healthy controls and chronic hepatitis group (P>0.05). In all age subgroups,the NCT and SDT measurements of cirrhotic patients differed significantly from those of the controls (P<0.05).When mean±2SD of SDT and NCT measurements from healthy control group was set as the normal range, 119cirrhotic patients (29.1%) were found to have abnormal NCT-A and SDT tests, 53 (13.0%) were abnormal only in SDT and 36 (8.8%) only in NCT-A. Taken together, SHE was diagnosed in 208 (50.9%) cirrhotic patients by this test battery. The prevalence of SHE increased from 39.9%and 55.2% in Child-Pugh's grade A and B groups to 71.8%in Child-Pugh's grade C group (P<0.05). After the adjustment of age and residential areas required from the tests, no correlation was found in the rate of SHE and causes of cirrhosis, education level and smoking habit.CONCLUSION: Psychometric tests are simple and reliable indicators for screening SHE among Chinese cirrhotic patients. By using a NCT and SDT battery, SHE could be found in 50.9% of cirrhotic patients without overt clinical encephalopathy. The

  8. [Liver resection by water jet].

    Science.gov (United States)

    Horie, T

    1989-01-01

    Major problem in resecting liver parenchyma is how to control the bleeding. Recently, resection of the liver by water jet has been reported. So, experimental and clinical studies were performed to investigate the usefulness of the water jet equipment. Ten pigs weighing around 17kg were used. The optimal pressure to resect the porcine liver was 7 to 15kg/cm2. By 4 weeks the cut surface was covered with fibrous capsule. Portal angiography showed no abnormality in the resected area. The water jet was also used in 30 human operations. The optimal pressure was 12 to 18kg/cm2 for non cirrhotic liver and 15 to 20kg/cm2 for cirrhotic liver. The surface immediately after jet cutting was more smooth than that of CUSA and histologically there was slight bleeding and necrosis. The volume of blood loss during dissection was not different between water jet group and CUSA group. No significant changes were found in the laboratory data. These results suggest that water jet is as useful as CUSA for cutting the liver parenchyma.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Omega-3 polyunsaturated fatty acids prevent progression of liver fibrosis and promote liver regeneration after partial hepatectomy in cirrhotic rats%ω-3多不饱和脂肪酸对肝硬化大鼠肝切除术后肝细胞再生及肝纤维化程度的影响

    Institute of Scientific and Technical Information of China (English)

    杨跃; 段飞; 蔡浩; 陈靓; 林建宇; 仇毓东

    2013-01-01

    Objective:To evaluate the effect of omega-3 polyunsaturated fatty acids (ω-3 PUFA) on liver regeneration after hepatectomy and antifibrosis under the condition of liver cirrhosis in rats. Methods:Seventy precent hepatectomy was carried out in rats,which were subsequently divided into 4 groups: ①normal and hepatectomy group(PH) ,②liver cirrhosis and hepatectomy group(LC + PH) , ③liver cirrhosis,n-3 PUFA (1 ml/kg) and hepatectomy group (LC +n-3 PUFA[S] +PH) ,④liver cirrhosis , n-3 PUFA (2 ml/kg) and hepatectomy group (LC + n-3PUFA[ L] + PH). Body/liver weight ratios , Serum parameters, histopathological examination, immunostaining and quantification of mRNA expression were also investigated. Results:Liver regeneration in LC + PH group was significantly delayed compared with PH group 7 days after hepatectomy. On the other hand,liver regeneration in LC + n-3 PUFA[L] +PH group increased significantly. The liver fibrosis was significantly lower in the groups with use of n-3 PUFA. Conclusion: The n-3 PUFA can reduce liver fibrosis and promote liver regeneration, even under cirrhotic conditions.%目的:观察ω-3多不饱和脂肪酸(ω-3PUFA)对肝硬化大鼠70%肝切除术后肝细胞再生及肝纤维化程度的影响. 方法:将96只大鼠随机分为四组,即正常对照组(仅行70%肝切除);肝硬化对照组(肝硬化大鼠行70%肝切除);肝硬化小剂量组(肝硬化大鼠行70%肝切除后静脉注射ω-3PUFA 1 ml/kg);肝硬化大剂量组(肝硬化大鼠行70%肝切除后静脉注射ω-3PUFA 2 ml/kg).观察大鼠术后第1、3、5和7天肝细胞再生的情况,肝功能指标,残肝肝纤维化程度的变化等. 结果:与肝硬化对照组比,肝硬化大剂量组大鼠术后肝有明显的再生(P<0.05);术后第1和第3天ALT和AST有明显降低(P<0.05).术后第7天,肝硬化小剂量组和肝硬化大剂量组肝纤维化程度有明显减轻(P<0.05). 结论:ω-3PUFA不仅能促进肝硬化大鼠术后肝细胞再

  11. Effect of sorafenib on liver regeneration after partial hepatoectomy in liver cirrhotic rats%索拉菲尼对肝硬化大鼠部分肝切除术后肝脏再生的影响

    Institute of Scientific and Technical Information of China (English)

    周小虎; 张红卫; 万云乐

    2012-01-01

    AIM:To sludy lhe effecl of sorafenib on lhe liver regeneration afler parlial hepaleclomy (PH) in cirrholic rals. METHODS: Thirly Wislar rals wilh liver cirrhosis induced successfully wilh dielhylnilrosamine (DEN) un-derwenl 30% PH and lhen were randomly divided inlo 2 groups ( n = 15 ). The rals in experimental group were fed wilh sorafenib al dose of 30 mg ? Kg-1·d-1 from lhe lsl day lo lhe l0th day afler PH, while ihose in conlrol group were fed wilh vehicle by gavage. The blood and liver lissues of lhe rals were collected afler PH and al lhe end of lhe experimenl. Liver regeneralion rale (LRR) and proliferating cell nuclear anligen (PCNA) expression were assessed for determining lhe hepatocyle proliferation. The conlent of alanine Iransaminase (ALT) , albumin (ALB) , tolal bilirubin (TBIL) , direct bili-rubin (DBIL) , angiogenesis relaled factors including vascular endolhelial growth faclor ( VEGF) , vascular endothelial growlh factor receplor 2 ( VEGFR - 2) , platelel - derived growth faclor receptor (3 ( PDGFR - (3 ) and micro - vessel densily ( MVD) were measured in both groups. RESULTS: LRRs on day 10 afler PH were 45.43% ±3.36% and 44.21% ±2.77% in experimental group and conlrol group, respectively (P>0. 05) , and lhe expression of PCNA in hepatic lissues of the rals was not found by lhe method of immunohislochemistry in bolh groups. Liver function index had no significant difference between lhe 2 groups (P >0. 05) . However, other lhan VEGF, sorafenib resulted in inhibilion of VEGFR -2 and PDGFR - (3 expression and reduction of MVD in experimenl group, and significant difference belween the 2 groups was observed (P0.05);(2)免疫组织化学(IHC)没有检测到PCNA;(3)2组的生化指标无显著差异(P>0.05);(4)实验组VEGFR-2和PDGFR-β的表达受到抑制,MVD降低,并且实验组与对照组差异有统计学意义(P<0.01).结论:索拉菲尼虽然对肝硬化血管再生相关因子有抑制作用,但是对肝细胞再生和肝功能没有明显影响.

  12. Phenotypic changes of human cells in human-rat liver during partial hepatectomy-induced regeneration

    Institute of Scientific and Technical Information of China (English)

    Yan Sun; Dong Xiao; Hong-An Li; Jin-Fang Jiang; Qing Li; Ruo-Shuang Zhang; Xi-Gu Chen

    2009-01-01

    AIM: To examine the human hepatic parenchymal and stromal components in rat liver and the phenotypic changes of human cells in liver of human-rat chimera (HRC) generated by in utero transplantation of human cells during partial hepatectomy (PHx)-induced liver regeneration. METHODS: Human hepatic parenchymal and stromal components and phenotypic changes of human cells during liver regeneration were examined by flow cytometry, in situ hybridization and immunohistochemistry. RESULTS: ISH analysis demonstrated human Alupositive cells in hepatic parenchyma and stroma of recipient liver. Functional human hepatocytes generated in this model potentially constituted human hepatic functional units with the presence of donor-derived human endothelial and biliary duct cells in host liver. Alpha fetoprotein (AFP)+, CD34+ and CD45+ cells were observed in the chimeric liver on day 10 after PHxinduced liver regeneration and then disappeared in PHx group, but not in non-PHx group, suggesting that dynamic phenotypic changes of human cells expressing AFP, CD34 and CD45 cells may occur during the chimeric liver regeneration. Additionally, immunostaining for human proliferating cell nuclear antigen (PCNA) showed that the number of PCNA-positive cells in the chimeric liver of PHx group was markedly increased, as compared to that of control group, indicating that donor-derived human cells are actively proliferated during PHx-induced regeneration of HRC liver.

  13. Adrenomedullin in cirrhotic and non-cirrhotic portal hypertension

    Institute of Scientific and Technical Information of China (English)

    V Tahan; C Kalayci; A Okten; N Tozun; E Avsar; C Karaca; E Uslu; F Eren; S Aydin; H Uzun; HO Hamzaoglu; F Besisik

    2003-01-01

    AIM:Adrenomedullin (ADM) is a potent vasodilator peptide.ADM and nitric oxide (NO) are produced in vascular endothelial cells. Increased ADM level has been linked to hyperdynamic circulation and arterial vasodilatation in cirrhotic portal hypertension (CPH). The role of ADM in non-cirrhotic portal hypertension (NCPH) is unknown, plasma ADM levels were studied in patients with NCPH, compensated and decompensated cirrhosis in order to determine its contribution to portal hypertension (PH) in these groups.METHODS: There were 4 groups of subjects. Group 1consisted of 27 patients (F/M: 12/15) with NCPH due to portal and/or splenic vein thrombosis (mean age: 41±12years), group 2 consisted of 14 patients (F/M: 6/8) with compensated (Child-Pugh A) cirrhosis (mean age: 46±4),group 3 consisted of 16 patients (F/M: 6/10) with decompensated (Child-Pugh C) cirrhosis (mean age: 47±12).Fourteen healthy subjects (F/M: 6/8) (mean age: 44±8) were used as controls in Group 4. ADM level was measured by ELISA. NO was determined as nitrite/nitrate level by chemoluminescence.RESULTS: Adl level in Group 11 (236±61.4 pg/mL) was significantly higher than that in group 2 (108.4±28.3 pg/mL)and group 4 (84.1±31.5 pg/mL) (both P<0.0001) but was lower than that in Group3 (324±93.7 pg/mL) (P=0.002). NO level in group 1 (27±1.4 μmol/L) was significantly higher than that in group 2 (19.8±2.8 μmol/L) and group 4 (16.9±1.6μmol/L) but was lower than that in Group 3 (39±3.6 μmol/L)(for all three P<0.0001). A strong correlation was observed between ADM and NO levels (r=0.827, P<0.0001).CONCLUSION: Adrenomedullin and NO levels were high in both non-cirrhotic and cirrhotic portal hypertension and were closely correlated, Adrenomedullin and NO levels increased proportionally with the severity of cirrhosis, and were significantly higher than those in patients with NCPH.Portal hypertension plays an important role in the increase of ADM and NO. Parenchymal damage in cirrhosis may

  14. Chimeric mice with a humanized liver as an animal model of troglitazone-induced liver injury.

    Science.gov (United States)

    Kakuni, Masakazu; Morita, Mayu; Matsuo, Kentaro; Katoh, Yumiko; Nakajima, Miki; Tateno, Chise; Yokoi, Tsuyoshi

    2012-10-02

    Troglitazone (Tro) is a thiazolidinedione antidiabetic drug that was withdrawn from the market due to its association with idiosyncratic severe liver injury. Tro has never induced liver injury in experimental animals in vivo. It was assumed that the species differences between human and experimental animals in the pharmaco- or toxicokinetics of Tro might be associated with these observations. In this study, we investigated whether a chimeric mouse with a humanized liver that we previously established, whose replacement index with human hepatocytes is up to 92% can reproduce Tro-induced liver injury. When the chimeric mice were orally administered Tro for 14 or 23 days (1000mg/kg/day), serum alanine aminotransferase (ALT) was significantly increased by 2.1- and 3.6-fold, respectively. Co-administration of l-buthionine sulfoximine (10mM in drinking water), an inhibitor of glutathione (GSH) synthesis, unexpectedly prevented the Tro-dependent increase of ALT, which suggests that the GSH scavenging pathway will not be involved in Tro-induced liver injury. To elucidate the mechanism of the onset of liver injury, hepatic GSH content, the level of oxidative stress markers and phase I and phase II drug metabolizing enzymes were determined. However, these factors were not associated with Tro-induced liver injury. An immune-mediated reaction may be associated with Tro-induced liver toxicity in vivo, because the chimeric mouse is derived from an immunodeficient SCID mouse. In conclusion, we successfully reproduced Tro-induced liver injury using chimeric mice with a humanized liver, which provides a new animal model for studying idiosyncratic drug-induced liver injury. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  15. Evaluación del estado nutricional de pacientes con cirrosis hepática alcohólica atendidos en la Clínica de Hígado del Hospital General de México Nutritional assessment of alcoholic liver cirrhotic patients treated in the liver Clinic of the Mexico's General Hospital

    Directory of Open Access Journals (Sweden)

    H. V. Landa-Galván

    2012-12-01

    Full Text Available La desnutrición en el paciente cirrótico se asocia a mayor morbi-mortalidad; sin embargo, su diagnóstico es complejo por lo que el objetivo del estudio fue evaluar el estado nutricional empleando distintos métodos. Se evaluaron pacientes adultos con cirrosis hepática de origen alcohólico que acudieron a la Clínica de Hígado del Hospital General de México. Se aplicó un recordatorio de 24 horas y antropometría, herramientas de tamizaje (Malnutrition Universal Screening Tool, Nutritional Risk Screening-2002 y de diagnóstico nutricional específica para pacientes con cirrosis hepática (Royal Free Hospital Global Assessment. Se incluyeron 62 pacientes y 51,6% fueron hombres. La desnutrición por área muscular de brazo fue de 31,3% en hombres y de 10% en mujeres, y por área grasa de brazo fue de 23,3% en mujeres y 3,1% en hombres (p Malnutrition in the cirrhotic patient is associated to a higher morbidity and mortality rate; however, the diagnosis is complex, so the study objective was to assess the nutritional status using different methods. Adult patients with alcoholic liver cirrhosis treated in the Liver Clinic of the Mexico's General Hospital were evaluated. Anthropometric measurements and a 24 hours recall were made; screening tools (Malnutrition Universal Screening Tool, Nutritional Risk Screening-2002 and a method for assessing nutritional status specifically in cirrhotic patients (Royal Free Hospital Global Assessment were used. We included 62 patients, 51.6% of them were men. Malnutrition by arm muscle area was 31.3% in men and 10% in women, and by arm fat area was 23.3% in women and 3.1% in men (p < 0.05. With the screening tools the percentages of malnutrition risk were 43.5% and 54.8% respectively, vs. 1.6% identified as "low weight" with the Body Mass Index. With the Royal Free Hospital Global Assessment tool the percentage of malnutrition was 45.2%. Patients with malnutrition had an energy and protein intake significantly

  16. Changes in serum ammonia concentration in cirrhotic patients with Helicobacter pylori infection

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective To study whether liver cirrhosis associated with Helicopacter pylori (H. pylori)infection will induce increased serum ammonia and whether the peripheral serum ammonia reflects the level of portal vein serum ammonia. Methods Blood was taken from the portal vein and the cubital vein in cirrhotic patients with and without H.pylori infection and non-cirrhotic patients (splenic rupiure) with and without H. pylori infection, and the serum ammonia was measured. Results The mean levels of serum ammonia in the group of cirrhotic patients with H. pylori infection were 167.82±8.97 μmol/L (pertal vein) and 142.2±13.35 μmol/L (cubital vein). They were increased significantly as compared with cirrhotic patients without H.pyiori infection(47.68±12.03 μmol/L portal vein and 37.23±7.04 μmol/L cubital vein),and also compared with the groups of splenic rupture patients with and without H. pylori infection (P<0.0t).There was no significant difference between the serum ammonia level of the cubital vein and pertal vein(P>0.05). Conclusions H.pylori intection can induce an increase in serum ammonia in patients with liver dysfunction,and the peripheral serum ammonia measurement may replace the portal vein serum ammania as a monitoring method. Eradication of H.pylori in cirrhotic patients may prevent hepatic encephalopathy(HE).

  17. Human liver microsomal metabolism of (+)-discodermolide.

    Science.gov (United States)

    Fan, Yun; Schreiber, Emanuel M; Day, Billy W

    2009-10-01

    The polyketide natural product (+)-discodermolide is a potent microtubule stabilizer that has generated considerable interest in its synthetic, medicinal, and biological chemistry. It progressed to early clinical oncology trials, where it showed some efficacy in terms of disease stabilization but also some indications of causing pneumotoxicity. Remarkably, there are no reports of its metabolism. Here, we examined its fate in mixed human liver microsomes. Due to limited availability of the agent, we chose a nanoflow liquid chromatography-electrospray ionization-mass spectrometry analytical approach employing quadrupolar ion trap and quadrupole-quadrupole-time-of-flight instruments for these studies. (+)-Discodermolide was rapidly converted to eight metabolites, with the left-side lactone (net oxidation) and the right-side diene (epoxidation followed by hydrolysis, along with an oxygen insertion product) being the most metabolically labile sites. Other sites of metabolism were the allylic and pendant methyl moieties in the C12-C14 region of the molecule. The results provide information on the metabolic soft spots of the molecule and can be used in further medicinal chemistry efforts to optimize discodermolide analogues.

  18. Bacterial infections in patients with liver cirrhosis

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    Giacomo Zaccherini

    2011-07-01

    Full Text Available Bacterial infections represent a frequent complication of liver cirrhosis carrying a significantly greater risk of morbidity and mortality as compared to that observed in non-cirrhotic patients. Such unfavourable prognosis is related to the systemic complications (liver and renal failure, shock, coagulopathy, multiple organ failure induced by a series of pro-inflammatory and immunological systems which are activated by bacteria and their pathogenetic products.The epidemiology of bacterial infections in cirrhosis has changed in the last years with a marked increase of Gram+ infections and the emergence of multi-resistant bacteria.The severity of liver disease represents the major clinical factor predisposing to bacterial infections, which are asymptomatic or paucisymptomatic at presentation in almost half of the cases. Aim of this review is to summarise the clinical and therapeutic aspects of bacterial infections in cirrhotic patients. The most common sites of infection are the urinary tract, ascites, blood, lungs and soft tissues.Beside antibiotics, it has been proposed the administration of human albumin to prevent the development of renal failure in patients with spontaneous bacterial peritonitis and, more recently, the use of hydrocortisone to treat cirrhotic patients with septic shock.

  19. Enantioselective Metabolism of Flufiprole in Rat and Human Liver Microsomes.

    Science.gov (United States)

    Lin, Chunmian; Miao, Yelong; Qian, Mingrong; Wang, Qiang; Zhang, Hu

    2016-03-23

    The enantioselective metabolism of flufiprole in rat and human liver microsomes in vitro was investigated in this study. The separation and determination were performed using a liquid chromatography system equipped with a triple-quadrupole mass spectrometer and a Lux Cellulose-2 chiral column. The enantioselective metabolism of rac-flufiprole was dramatically different in rat and human liver microsomes in the presence of the β-nicotinamide adenine dinucleotide phosphate regenerating system. The half-lives (t1/2) of flufiprole in rat and human liver microsomes were 7.22 and 21.00 min, respectively, for R-(+)-flufiprole, whereas the values were 11.75 and 17.75 min, respectively, for S-(-)-flufiprole. In addition, the Vmax of R-(+)-flufiprole was about 3-fold that of S-(-)-flufiprole in rat liver microsomes, whereas its value in the case of S-(-)-flufiprole was about 2-fold that of R-(+)-flufiprole in human liver microsomes. The CLint of rac-flufiprole also showed opposite enantioselectivy in rat and human liver microsomes. The different compositions and contents of metabolizing enzyme in the two liver microsomes might be the reasons for the difference in the metabolic behavior of the two enantiomers.

  20. Inactivation of extrahepatic vascular Akt improves systemic hemodynamics and sodium excretion in cirrhotic rats.

    Science.gov (United States)

    Fernández-Varo, G; Melgar-Lesmes, P; Casals, G; Pauta, M; Arroyo, V; Morales-Ruiz, M; Ros, J; Jiménez, W

    2010-12-01

    Increased activity of the vascular Akt/eNOS signaling pathway is involved in the hemodynamic and renal complications developed by patients and rats with cirrhosis and ascites. This occurs in the setting of impaired Akt/eNOS activity within the cirrhotic liver. Here we assessed the feasibility of selectively inhibiting vascular eNOS without further impairing the intrahepatic activity of this enzyme. Ultimately, we sought to determine whether endothelial transduction of a constitutively inactive mutant of Akt (AA-Akt) improves circulatory function and sodium excretion in cirrhotic rats with ascites. First, we administered recombinant adenoviruses that encode the β-galactosidase gene (β-gal) to 5 control rats and 5 cirrhotic rats with ascites and analyzed their tissue distribution by chemiluminescence. Next, urine samples were obtained from 18 cirrhotic rats with ascites and then the animal randomly received saline or adenoviruses containing the β-gal or the AA-Akt genes. Following a 24-h urine collection period, hemodynamic studies were performed and tissue samples were obtained to analyze Akt and eNOS expressions. No β-gal activity was detected in the liver of cirrhotic rats compared to that of controls. This was paralleled by increased β-gal activity in other territories such as the thoracic aorta. AA-Akt transduction improved systemic hemodynamics, splanchnic perfusion pressure and renal excretory function in comparison with cirrhotic rats transduced with β-gal adenoviruses or receiving saline. Moreover, the AA-Akt transgene did not modify portal pressure. Inactivation of extrahepatic vascular Akt and the concomitant decrease in nitric oxide expression ameliorate systemic hemodynamics and renal excretory function in experimental cirrhosis. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  1. Differences in viral kinetics between genotypes 1 and 3 of hepatitis C virus and between cirrhotic and non-cirrhotic patients during antiviral therapy

    Institute of Scientific and Technical Information of China (English)

    José Eymard Medeiros-Filho; Isabel Maria Vicente Guedes de Carvalho Mello; Jo(a)o Renato Rebello Pinho; Avidan U Neumann; Fernanda de Mello Malta; Luiz Caetano da Silva; Flair José Carrilho

    2006-01-01

    AIM: To evaluate the impact of hepatitis C virus (HCV)infection with genotype 1 or 3 and the presence or absence of liver cirrhosis (LC) in the early viral kinetics response to treatment.METHODS: Naive patients (n = 46) treated with interferon-α (IFN-α) and ribavirin and followed up with frequent early HCV-RNA determinations were analysed.Patients were infected with genotype 1 (n = 28, 7 with LC) or 3 (n = 18, 5 with LC).RESULTS: The first phase decline was larger in genotype 3 patients than in genotype 1 patients (1.72 vs 0.95log IU/mL, P < 0.001). The second phase slope decline was also larger in genotype 3 patients than in genotype 1 patients (0.87 vs 0.15 log/wk, P < 0.001). Differences were found in both cirrhotic and non-cirrhotic patients.Genotype 1 cirrhotic patients had a slower 2nd phase slope than non-cirrhotic patients (0.06 vs 0.18 log/wk, P< 0,02). None of genotype 1 cirrhotic patients had a 1stphase decline larger than 1 log (non-cirrhotic patients:55%, P < 0.02). A similar trend toward a slower 2ndphase slope was observed in genotype 3 cirrhotic patients but the 1st phase slope decline was not different.Sustained viral response was higher in genotype 3 patients than in genotype 1 patients ,(72% vs14%, P <0.001) and in genotype 1 non-cirrhotic patients than in genotype 1 cirrhotic patients (19% vs 0%). A second phase decline slower than 0.3 log per week was predictive of non-response in all groups.CONCLUSION: Genotype 3 has faster early viral decline than genotype 1. Cirrhosis correlates with a slower 2nd phase decline and possibly with a lower 1st phase slope decline in genotype 1 patients.

  2. Research advances in non-cirrhotic portal hypertension

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    ZHANG Bojing

    2016-02-01

    Full Text Available Although liver cirrhosis is the most common cause of portal hypertension (PH, about 20% of PH cases are caused by non-cirrhotic reasons, which are referred to as non-cirrhotic portal hypertension (NCPH, with a high incidence rate in developing countries. NCPH is a group of heterogeneous hepatic vascular diseases, including idiopathic portal hypertension (IPH and extrahepatic portal vein obstruction (EHPVO, as well as the rare diseases in clinical practice such as Budd-Chiari syndrome, congenital hepatic fibrosis, and nodular regenerative hyperplasia. The patients with NCPH usually have the symptoms of portal hypertension, such as recurrent variceal bleeding and splenomegaly, but liver function is well preserved in these patients. At present, the diagnosis of NCPH lacks a universally accepted standard and remains a challenge. In clinical practice, the method of exclusion is usually applied for the diagnosis of HCPH, and liver biopsy is performed when necessary to make a confirmed diagnosis. This paper introduces the pathogenesis and pathological manifestations of IPH and EHPVO, as well as the selection of diagnostic methods and therapeutic strategies. If upper gastrointestinal bleeding can be effectively controlled, NCPH is considered to have a relatively good prognosis.

  3. Bisphenol A sulfonation is impaired in metabolic and liver disease

    Science.gov (United States)

    Yalcin, Emine B.; Kulkarni, Supriya R.; Slitt, Angela L.; King, Roberta

    2016-01-01

    Background Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. Liver metabolizes and facilitates BPA excretion through glucuronidation and sulfonation. The sulfotransferase enzymes contributing to BPA sulfonation (detected in human and rodents) is poorly understood. Objectives To determine the impact of metabolic and liver disease on BPA sulfonation in human and mouse livers. Methods The capacity for BPA sulfonation was determined in human liver samples that were categorized into different stages of metabolic and liver disease (including obesity, diabetes, steatosis, and cirrhosis) and in livers from ob/ob mice. Results In human liver tissues, BPA sulfonation was substantially lower in livers from subjects with steatosis (23%), diabetes cirrhosis (16%), and cirrhosis (18%), relative to healthy individuals with non-fatty livers (100%). In livers of obese mice (ob/ob), BPA sulfonation was lower (23%) than in livers from lean wild-type controls (100%). In addition to BPA sulfonation activity, Sult1a1 protein expression decreased by 97% in obese mouse livers. Conclusion Taken together these findings establish a profoundly reduced capacity of BPA elimination via sulfonation in obese or diabetic individuals and in those with fatty or cirrhotic livers versus individuals with healthy livers. PMID:26712468

  4. Effect of liver ischemic preconditioning in cirrhotic rats submitted to hepatic ischemia/reperfusion injury Efeito do pré-condicionamento isquêmico hepático submetidos a lesão de isquemia/reperfusão do fígado

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    Eduardo Garcia Pacheco

    2006-01-01

    Full Text Available PURPOSE: The main aim of this study was to determine the influence of ischemic preconditioning (IPC on rat liver cirrhosis. METHODS: Cirrhosis was induced in Wistar rats by occlusion of the hepatic duct. The animals were divided into four groups of six animals each: non-cirrhotic group (simulated operation only, cirrhotic control group (simulated operation in cirrhotic rats, I/R group (40-minute ischemia without IPC, and IPC group (cirrhotic rats with ischemia, previously submitted to IPC. The IPC procedure consisted of partial hepatic ischemia for five minutes, followed by 10 minutes of reperfusion. In the case of the IPC group, the animals were submitted to liver ischemia for 40 minutes after the preconditioning procedure, followed by 2 hours of reperfusion. Blood samples were collected for measurement of serum aminotransferases (ALT and AST. The respiratory control ratio (RCR, the mitochondrial membrane potential (MMP, and malondialdehyde (MDA values in the hepatic tissue were analyzed. Nonparametric statistical analysis was used and a value of pOBJETIVO: O objetivo deste estudo foi determinar a influência do pré-condicionamento isquêmico (IPC em fígados de ratos cirróticos. MÉTODOS: A cirrose hepática foi induzida em ratos Wistar machos (250 a 300g por oclusão, durante 30 dias, do ducto hepático comum.A seguir, os animais cirróticos foram divididos em três grupos de seis; Grupo controle cirrótico (operação simulada para isquemia/reperfusão/pré-condicionamento, Grupo I/R, isquemia de 40 minutos sem pré-condicionamento (IPC e grupo IPC com isquemia precedida por IPC. O IPC consistiu de uma isquemia parcial por cinco minutos, seguida por 10 minutos de reperfusão. No grupo IPC, após o pré-condicionamento, os animais foram submetidos à isquemia hepática de 40 minutos seguida de 2 horas de reperfusão. Foram colhidas amostras de sangue para dosagem sérica de aminotransferases (ALT e AST. Razão de controle respiratório (RCR

  5. Pituitary glycoprotein hormone a-subunit secretion by cirrhotic patients

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    Oliveira M.C.

    1999-01-01

    Full Text Available Secretion of the a-subunit of pituitary glycoprotein hormones usually follows the secretion of intact gonadotropins and is increased in gonadal failure and decreased in isolated gonadotropin deficiency. The aim of the present study was to determine the levels of the a-subunit in the serum of patients with cirrhosis of the liver and to compare the results obtained for eugonadal cirrhotic patients with those obtained for cirrhotic patients with hypogonadotropic hypogonadism. Forty-seven of 63 patients with cirrhosis (74.6% presented hypogonadism (which was central in 45 cases and primary in 2, 7 were eugonadal, and 9 women were in normal menopause. The serum a-subunit was measured by the fluorimetric method using monoclonal antibodies. Cross-reactivity with LH, TSH, FSH and hCG was 6.5, 1.2, 4.3 and 1.1%, respectively, with an intra-assay coefficient of variation (CV of less than 5% and an interassay CV of 5%, and sensitivity limit of 4 ng/l. The serum a-subunit concentration ranged from 36 to 6253 ng/l, with a median of 273 ng/l. The median was 251 ng/l for patients with central hypogonadism and 198 ng/l for eugonadal patients. The correlation between the a-subunit and basal LH levels was significant both in the total sample (r = 0.48, P<0.01 and in the cirrhotic patients with central hypogonadism (r = 0.33, P = 0.02. Among men with central hypogonadism there was a negative correlation between a-subunit levels and total testosterone levels (r = 0.54, P<0.01 as well as free testosterone levels (r = -0.53, P<0.01. In conclusion, although the a-subunit levels are correlated with LH levels, at present they cannot be used as markers for hypogonadism in patients with cirrhosis of the liver.

  6. A microfluidically perfused three dimensional human liver model.

    Science.gov (United States)

    Rennert, Knut; Steinborn, Sandra; Gröger, Marko; Ungerböck, Birgit; Jank, Anne-Marie; Ehgartner, Josef; Nietzsche, Sandor; Dinger, Julia; Kiehntopf, Michael; Funke, Harald; Peters, Frank T; Lupp, Amelie; Gärtner, Claudia; Mayr, Torsten; Bauer, Michael; Huber, Otmar; Mosig, Alexander S

    2015-12-01

    Within the liver, non-parenchymal cells (NPCs) are critically involved in the regulation of hepatocyte polarization and maintenance of metabolic function. We here report the establishment of a liver organoid that integrates NPCs in a vascular layer composed of endothelial cells and tissue macrophages and a hepatic layer comprising stellate cells co-cultured with hepatocytes. The three-dimensional liver organoid is embedded in a microfluidically perfused biochip that enables sufficient nutrition supply and resembles morphological aspects of the human liver sinusoid. It utilizes a suspended membrane as a cell substrate mimicking the space of Disse. Luminescence-based sensor spots were integrated into the chip to allow online measurement of cellular oxygen consumption. Application of microfluidic flow induces defined expression of ZO-1, transferrin, ASGPR-1 along with an increased expression of MRP-2 transporter protein within the liver organoids. Moreover, perfusion was accompanied by an increased hepatobiliary secretion of 5(6)-carboxy-2',7'-dichlorofluorescein and an enhanced formation of hepatocyte microvilli. From this we conclude that the perfused liver organoid shares relevant morphological and functional characteristics with the human liver and represents a new in vitro research tool to study human hepatocellular physiology at the cellular level under conditions close to the physiological situation.

  7. Human augmenter of liver regeneration: molecular cloning, biological activity and roles in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    杨晓明; 谢玲; 邱兆华; 吴祖泽; 贺福初

    1997-01-01

    The complete amino acid sequence of human augmenter of liver regeneration (hALR) was reported by deduction from nucleotide sequence of its complementary DNA . The cDNA for hALR was isolated by screening a human fetal liver cDNA library and the sequencing of this insert revealed an open reading frame encoding a protein with 125aa and highly homologous (87% ) with rat ALR encoding sequence. The recombinant hALR expressed from its cDNA in transient expression experiments in cos-7 cells could stimulate DNA synthesis of HTC hepatoma cell in the dose-dependent and heat-resistant way. Northern blot analysis with rat ALR cDNA as probe confirmed that ALR mRNA was expressed in the normal rat liver at low level and that dramatically increased in the regenerating liver after partial hepatectomied rat. This size of hALR mRNA is 1.4 kb long and expressed in human fetal liver, kidney and testis. These findings indicated that liver itself may be the resource of ALR and suggested that ALR seems to be an im-portant parac

  8. In-hospital mortality among a cohort of cirrhotic patients admitted to a Tertiary Hospital

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    Mohammad A Alsultan

    2011-01-01

    Full Text Available Background/Aim : To determine the mortality rate in a cohort of hospitalized patients with cirrhosis and examine their resuscitation status at admission. Materials and Methods : A retrospective chart review was conducted of patients with cirrhosis who were admitted to a tertiary care hospital in Riyadh, Saudi Arabia, from January 1, 2009, to December 31, 2009. Results: We reviewed 226 cirrhotic patients during the study period. The hospital mortality rate was 35%. A univariate analysis revealed that worse outcomes were seen in patients with advanced age or who had worse child-turcotte-pugh (CPT scores, worse model for end-stage liver disease (MELD scores, low albumin and high serum creatinine. Using a multivariate analysis, we found that advanced age (P=0.004 and high MELD (P=0.001 scores were independent risk factors for the mortality of cirrhotic patients. The end-of-life decision were made in 34% of cirrhotic patients, and the majority of deceased patients were "no resuscitation" status (90% vs. 4%, P<0.001. Conclusions : The relatively high mortality in cirrhotic patients admitted for care in a tertiary hospital, Saudi Arabia was comparable to that reported in the literature. Furthermore, end-of-life discussions should be addressed early in the hospitalization of cirrhotic patients.

  9. The Role of Serum Cytokines in the Pathogenesis of Hepatic Osteodystrophy in Male Cirrhotic Patients

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    Ali Riza Soylu

    2012-01-01

    Full Text Available Objective. In this study, we aimed to investigate the possible role of serum cytokines in the development of hepatic osteodystrophy. Matherial and Methods. 44 consecutive male cirrhotic patients (17 alcoholic, 20 hepatitis B, 7 hepatitis C, 15 age- and sex-matched chronic alcoholics without liver disease, and 17 age- and sex-matched healthy controls were included in the study during one year period. Bone mineral density was measured by dual X-ray absorptiometry in the lumbar vertebrate and femoral neck. Serum interleukin levels were measured by ELISA method. Results. Although osteopenia frequency between our cirrhotic patients was 20%, there was no difference in T-scores among the controls and other groups. Serum interleukin-1, interleukin-8, and tumor necrosis factor-alpha levels were not different between all groups. Serum interleukin-2 and interleukin-6 levels were higher in the cirrhotics than controls (P<0.001. However, there were no significant difference between osteopenic and nonosteopenic cirrhotics. Conclusion. According to the results of the study in this small population of 44 male cirrhotic patients, frequency of hepatic osteopenia is small and serum interleukins 1, 2, 6, 8, and tumor necrosis factor-alpha may not play a role in the pathogenesis of hepatic osteodystrophy. Further studies in which large number of patients involved are necessary in this field.

  10. Peritoneal Dialysis is Associated With A Better Survival in Cirrhotic Patients With Chronic Kidney Disease.

    Science.gov (United States)

    Chou, Che-Yi; Wang, Shu-Ming; Liang, Chih-Chia; Chang, Chiz-Tzung; Liu, Jiung-Hsiun; Wang, I-Kuan; Hsiao, Lien-Cheng; Muo, Chih-Hsin; Chung, Chi-Jung; Huang, Chiu-Ching

    2016-01-01

    Peritoneal dialysis (PD) can be an ideal treatment in cirrhotic patients with ascites and chronic kidney disease stage 5 (CKD 5D) who require dialysis. The survival of cirrhotic patients with CKD 5D on PD, however, is not clear. We compared the survival of cirrhotic patients with CKD 5D on PD and the survival of those on HD. Two datasets including a cohort study of China Medical University Hospital (CMUH) from 2004 to 2013 and the Longitudinal National Health Insurance Database for Catastrophic Illness Patients (LHID-CIP) of Taiwan from 1996 to 2011 were analyzed. The survival of cirrhotic patients on PD and the propensity score matched cirrhotic patients on HD were analyzed using Cox proportional hazards regression. In CMUH cohort of 85 PD and 340 HD patients, the all-cause mortality was lower in PD patients compared to it in HD patients (hazard ratio [HR]: 0.48, 95% confidence interval [CI]: 0.31-0.74, P model for end-stage liver disease (MELD) score, however, was not associated with all-cause mortality. In the LHID-CIP cohort of 285 PD and 1140 HD patients, the HR of all-cause mortality in PD patients was 0.61 (95% CI: 0.47 - 0.79, P < 0.01), as compared with HD patients. PD in cirrhotic patients who need dialysis is associated with lower all-cause mortality than HD is. This association is independent of patients' comorbidity, severity of liver cirrhosis, and serum albumin levels.

  11. Human platelets inhibit liver fibrosis in severe combined immunodeficiency mice

    Science.gov (United States)

    Takahashi, Kazuhiro; Murata, Soichiro; Fukunaga, Kiyoshi; Ohkohchi, Nobuhiro

    2013-01-01

    AIM: To investigate the role of human platelets in liver fibrosis. METHODS: Severe combined immunodeficiency (SCID) mice were administered CCl4 and either phosphate-buffered saline (PBS group) or human platelet transfusions (hPLT group). Concentrations of hepatocyte growth factor (HGF), matrix metallopeptidases (MMP)-9, and transforming growth factor-β (TGF-β) in the liver tissue were compared between the PBS and the hPLT groups by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The effects of a human platelet transfusion on liver fibrosis included the fibrotic area, hydroxyproline content, and α-smooth muscle actin (α-SMA) expression, which were evaluated by picrosirius red staining, ELISA, and immunohistochemical staining using an anti-mouse α-SMA antibody, respectively. Phosphorylations of mesenchymal-epithelial transition factor (Met) and SMAD3, downstream signals of HGF and TGF-β, were compared between the two groups by Western blotting and were quantified using densitometry. Hepatocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Furthermore, the accumulation of human platelets in the liver 2 h after platelet transfusion was compared between normal and fibrotic livers by immunohistochemical staining using an anti-human CD41 antibody. RESULTS: The fibrotic area and hydroxyproline content in the liver were both significantly lower in the hPLT group when compared to the PBS group (fibrotic area, 1.7% ± 0.6% vs 2.5% ± 0.6%, P = 0.03; hydroxyproline content, 121 ± 26 ng/g liver vs 156 ± 47 ng/g liver, P = 0.04). There was less α-smooth muscle actin staining in the hPLT group than in the PBS group (0.5% ± 0.1% vs 0.8% ± 0.3%, P = 0.02). Hepatic expression levels of mouse HGF and MMP-9 were significantly higher in the hPLT group than in the PBS group (HGF, 109 ± 13 ng/g liver vs 88 ± 22 ng/g liver, P = 0.03; MMP-9, 113% ± 7%/GAPDH vs 92% ± 11%/GAPDH, P = 0.04). In contrast, the

  12. MANAGEMENT OF PORTAL VEIN THROMBOSIS IN CIRRHOTIC PATIENTS

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    Lucio Amitrano

    2009-11-01

    Full Text Available Portal vein thrombosis (PVT not associated with hepatocellular carcinoma is considered a frequent complication of liver cirrhosis but, unlike PVT occurring in non-cirrhotic patients, very few data are available on its natural history and management.  The reduced portal blood flow velocity is the main determinant of PVT but, as in other venous thromboses, multiple factors local and systemic, inherited or acquired often can concur with. PVT has a variety of clinical presentations ranging from asymptomatic to life-threatening diseases like gastroesophageal bleeding or acute intestinal ischemia. It is usually diagnosed by Doppler ultrasound but computed tomography and magnetic resonance imaging are useful to study the extent of thrombosis and the involvement of the abdominal organs. The risk of bleeding mainly determined by the presence of gastroesophageal varices and clotting alterations causes concern for the treatment of PVT in cirrhotic patients. To date, anticoagulant therapy seems to be indicated only in patients awaiting liver transplantation. This review focuses on the definition of the subgroups of patients with cirrhosis that might benefit from treatment of PVT and examines the pros and cons of the available treatments in terms of efficacy, monitoring and safety, providing also perspectives for future studies.

  13. MANAGEMENT OF PORTAL VEIN THROMBOSIS IN CIRRHOTIC PATIENTS

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    Maria Anna Guardascione

    2009-11-01

    Full Text Available

    Portal vein thrombosis (PVT not associated with hepatocellular carcinoma is considered a frequent complication of liver cirrhosis but, unlike PVT occurring in non-cirrhotic patients, very few data are available on its natural history and management.  The reduced portal blood flow velocity is the main determinant of PVT but, as in other venous thromboses, multiple factors local and systemic, inherited or acquired often can concur with. PVT has a variety of clinical presentations ranging from asymptomatic to life-threatening diseases like gastroesophageal bleeding or acute intestinal ischemia. It is usually diagnosed by Doppler ultrasound but computed tomography and magnetic resonance imaging are useful to study the extent of thrombosis and the involvement of the abdominal organs. The risk of bleeding mainly determined by the presence of gastroesophageal varices and clotting alterations causes concern for the treatment of PVT in cirrhotic patients. To date, anticoagulant therapy seems to be indicated only in patients awaiting liver transplantation. This review focuses on the definition of the subgroups of patients with cirrhosis that might benefit from treatment of PVT and examines the pros and cons of the available treatments in terms of efficacy, monitoring and safety, providing also perspectives for future studies.

  14. A study of human liver ferritin and chicken liver and spleen using Moessbauer spectroscopy with high velocity resolution

    Energy Technology Data Exchange (ETDEWEB)

    Oshtrakh, M. I., E-mail: oshtrakh@mail.utnet.ru [Ural State Technical University-UPI, Faculty of Physical Techniques and Devices for Quality Control (Russian Federation); Milder, O. B.; Semionkin, V. A. [Ural State Technical University-UPI, Faculty of Experimental Physics (Russian Federation)

    2008-01-15

    Lyophilized samples of human liver ferritin and chicken liver and spleen were measured at room temperature using Moessbauer spectroscopy with high velocity resolution. An increase in the velocity resolution of Moessbauer spectroscopy permitted us to increase accuracy and decrease experimental error in determining the hyperfine parameters of human liver ferritin and chicken liver and spleen. Moessbauer spectroscopy with high velocity resolution may be very useful for revealing small differences in hyperfine parameters during biomedical research.

  15. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients.

    Science.gov (United States)

    Zhang, Zheng; Lin, Hu; Shi, Ming; Xu, Ruonan; Fu, Junliang; Lv, Jiyun; Chen, Liming; Lv, Sa; Li, Yuanyuan; Yu, Shuangjie; Geng, Hua; Jin, Lei; Lau, George K K; Wang, Fu-Sheng

    2012-03-01

    Decompensated liver cirrhosis (LC), a life-threatening complication of chronic liver disease, is one of the major indications for liver transplantation. Recently, mesenchymal stem cell (MSC) transfusion has been shown to lead to the regression of liver fibrosis in mice and humans. This study examined the safety and efficacy of umbilical cord-derived MSC (UC-MSC) in patients with decompensated LC. A total of 45 chronic hepatitis B patients with decompensated LC, including 30 patients receiving UC-MSC transfusion, and 15 patients receiving saline as the control, were recruited; clinical parameters were detected during a 1-year follow-up period. No significant side-effects and complications were observed in either group. There was a significant reduction in the volume of ascites in patients treated with UC-MSC transfusion compared with controls (P decompensated LC. UC-MSC transfusion, therefore, might present a novel therapeutic approach for patients with decompensated LC.

  16. Study of apoptosis in human liver cancers

    Institute of Scientific and Technical Information of China (English)

    Chang-Min Shan; Juan Li

    2002-01-01

    AIM: To investigate the action of apoptosis in occurrence ofliver cacinornas in vivo and the biological effect of Solanumlyratum Thumb on BEL-7404 cell line inducing apoptosis invitro.METHODS: The apoptosis in the liver carcinoma wasdetected with terminal deoxynucl neotidyl transferasemediated dUTP nick end labelling (TUNEL); the cancer cellscultured in DMED medium were treated with extract ofSolanum lyratum Thumb and observed under microscope,and their DNA was assayed by gel electrophoresis.RESULTS: In vivo apoptotic cells in the cancer adjacenttissues inceased; in vitro treatment of liver cancers withextract of Solanum lyratum Thumb could induce the cells tomanifest a typical apoptotic morphology. Their DNA wasfractured and a characteristic ladder pattem could be foundusing electrophoresis.CONCLUSION: In vivo the apoptosis of carcinomas waslower; maybe the cells divided quickly and then the cancersoccurred. In the cancer adjacent tissues, the apoptosispricked up, and in vitro Solarium lyratum Thumb couldinduce the apoptosis of BEL-7404 cells.

  17. Micro-RNA profiling in human serum reveals compartment-specific roles of miR-571 and miR-652 in liver cirrhosis.

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    Christoph Roderburg

    Full Text Available BACKGROUND AND AIMS: Micro-RNAs (miRNAs have recently emerged as crucial modulators of molecular processes involved in chronic liver diseases. The few miRNAs with previously proposed roles in liver cirrhosis were identified in screening approaches on liver parenchyma, mostly in rodent models. Therefore, in the present study we performed a systematic screening approach in order to identify miRNAs with altered levels in the serum of patients with chronic liver disease and liver cirrhosis. METHODS: We performed a systematic, array-based miRNA expression analysis on serum samples from patients with liver cirrhosis. In functional experiments we evaluated the relationship between alterations of miRNA serum levels and their role in distinct cellular compartments involved in hepatic cirrhosis. RESULTS: The array analysis and the subsequent confirmation by qPCR in a larger patient cohort identified significant alterations in serum levels of miR-513-3p, miR-571 and miR-652, three previously uncharacterized miRNAs, in patients with alcoholic or hepatitis C induced liver cirrhosis. Of these, miR-571 serum levels closely correlated with disease stages, thus revealing potential as a novel biomarker for hepatic cirrhosis. Further analysis revealed that up-regulation of miR-571 in serum reflected a concordant regulation in cirrhotic liver tissue. In isolated primary human liver cells, miR-571 was up-regulated in human hepatocytes and hepatic stellate cells in response to the pro-fibrogenic cytokine TGF-β. In contrast, alterations in serum levels of miR-652 were stage-independent, reflecting a concordant down-regulation of this miRNA in circulating monocytes of patients with liver cirrhosis, which was inducible by proinflammatory stimuli like bacterial lipopolysaccharide. CONCLUSION: Alterations of miR571 and miR-652 serum levels in patients with chronic liver disease reflect their putative roles in the mediation of fibrogenic and inflammatory processes in

  18. Magnetic resonance imaging of the cirrhotic liver: Anupdate

    Institute of Scientific and Technical Information of China (English)

    Agnes Watanabe; Miguel Ramalho; Mamdoh AlObaidy; Hye Jin Kim; Fernanda G Velloni; Richard C Semelka

    2015-01-01

    Noninvasive imaging has become the standard forhepatocellular carcinoma (HCC) diagnosis in cirrhoticlivers. In this review paper, we go over the basics ofMR imaging in cirrhotic livers and describe the imagingappearance of a spectrum of hepatic nodules markingthe progression from regenerative nodules to low- andhigh-grade dysplastic nodules, and ultimately to HCCs.We detail and illustrate the typical imaging appearancesof different types of HCC including focal, multifocal,massive, diffuse/infiltrative, and intra-hepaticmetastases; with emphasis on the diagnostic value ofMR in imaging these lesions. We also shed some lighton liver imaging reporting and data system, and therole of different magnetic resonance imaging (MRI)contrast agents and future MRI techniques includingthe use of advanced MR pulse sequences and utilizationof hepatocyte-specific MRI contrast agents, and howthey might contribute to improving the diagnosticperformance of MRI in early stage HCC diagnosis.

  19. Glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes.

    Science.gov (United States)

    Yamanaka, Hiroyuki; Nakajima, Miki; Katoh, Miki; Yokoi, Tsuyoshi

    2007-09-01

    Glucuronidation of thyroxine is a major metabolic pathway facilitating its excretion. In this study, we characterized the glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes, and identified human UDP-glucuronosyltransferase (UGT) isoforms involved in the activity. Human jejunum microsomes showed a lower K(m) value (24.2 microM) than human liver (85.9 microM) and kidney (53.3 microM) microsomes did. Human kidney microsomes showed a lower V(max) value (22.6 pmol/min/mg) than human liver (133.4 pmol/min/mg) and jejunum (184.6 pmol/min/mg) microsomes did. By scaling-up, the in vivo clearances in liver, intestine, and kidney were estimated to be 1440, 702, and 79 microl/min/kg body weight, respectively. Recombinant human UGT1A8 (108.7 pmol/min/unit), UGT1A3 (91.6 pmol/min/unit), and UGT1A10 (47.3 pmol/min/unit) showed high, and UGT1A1 (26.0 pmol/min/unit) showed moderate thyroxine glucuronosyltransferase activity. The thyroxine glucuronosyltransferase activity in microsomes from 12 human livers was significantly correlated with bilirubin O-glucuronosyltransferase (r = 0.855, p microsomes was mainly catalyzed by UGT1A8 and UGT1A10 and to a lesser extent by UGT1A1, and the activity in human kidney microsomes was mainly catalyzed by UGT1A7, UGT1A9, and UGT1A10. The changes of activities of these UGT1A isoforms via inhibition and induction by administered drugs as well as genetic polymorphisms may be a causal factor of interindividual differences in the plasma thyroxine concentration.

  20. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?

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    A.L. Chagas

    2009-10-01

    Full Text Available Non-alcoholic steatohepatitis (NASH has been associated with hepatocellular carcinoma (HCC often arising in histologically advanced disease when steatohepatitis is not active (cryptogenic cirrhosis. Our objective was to characterize patients with HCC and active, histologically defined steatohepatitis. Among 394 patients with HCC detected by ultrasound imaging over 8 years and staged by the Barcelona Clinic Liver Cancer (BCLC criteria, we identified 7 cases (1.7% with HCC occurring in the setting of active biopsy-proven NASH. All were negative for other liver diseases such as hepatitis C, hepatitis B, autoimmune hepatitis, Wilson disease, and hemochromatosis. The patients (4 males and 3 females, age 63 ± 13 years were either overweight (4 or obese (3; 57% were diabetic and 28.5% had dyslipidemia. Cirrhosis was present in 6 of 7 patients, but 1 patient had well-differentiated HCC in the setting of NASH without cirrhosis (fibrosis stage 1 based on repeated liver biopsies, the absence of portal hypertension by clinical and radiographic evaluations and by direct surgical inspection. Among the cirrhotic patients, 71.4% were clinically staged as Child A and 14.2% as Child B. Tumor size ranged from 1.0 to 5.2 cm and 5 of 7 patients were classified as early stage; 46% of all nodules were hyper-echoic and 57% were <3 cm. HCC was well differentiated in 1/6 and moderately differentiated in 5/6. Alpha-fetoprotein was <100 ng/mL in all patients. HCC in patients with active steatohepatitis is often multifocal, may precede clinically advanced disease and occurs without diagnostic levels of alpha-fetoprotein. Importantly, HCC may occur in NASH in the absence of cirrhosis. More aggressive screening of NASH patients may be warranted.

  1. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?

    Directory of Open Access Journals (Sweden)

    A.L. Chagas

    Full Text Available Non-alcoholic steatohepatitis (NASH has been associated with hepatocellular carcinoma (HCC often arising in histologically advanced disease when steatohepatitis is not active (cryptogenic cirrhosis. Our objective was to characterize patients with HCC and active, histologically defined steatohepatitis. Among 394 patients with HCC detected by ultrasound imaging over 8 years and staged by the Barcelona Clinic Liver Cancer (BCLC criteria, we identified 7 cases (1.7% with HCC occurring in the setting of active biopsy-proven NASH. All were negative for other liver diseases such as hepatitis C, hepatitis B, autoimmune hepatitis, Wilson disease, and hemochromatosis. The patients (4 males and 3 females, age 63 ± 13 years were either overweight (4 or obese (3; 57% were diabetic and 28.5% had dyslipidemia. Cirrhosis was present in 6 of 7 patients, but 1 patient had well-differentiated HCC in the setting of NASH without cirrhosis (fibrosis stage 1 based on repeated liver biopsies, the absence of portal hypertension by clinical and radiographic evaluations and by direct surgical inspection. Among the cirrhotic patients, 71.4% were clinically staged as Child A and 14.2% as Child B. Tumor size ranged from 1.0 to 5.2 cm and 5 of 7 patients were classified as early stage; 46% of all nodules were hyper-echoic and 57% were <3 cm. HCC was well differentiated in 1/6 and moderately differentiated in 5/6. Alpha-fetoprotein was <100 ng/mL in all patients. HCC in patients with active steatohepatitis is often multifocal, may precede clinically advanced disease and occurs without diagnostic levels of alpha-fetoprotein. Importantly, HCC may occur in NASH in the absence of cirrhosis. More aggressive screening of NASH patients may be warranted.

  2. Synchrotron refractive-index microradiography of human liver cancer tissue

    Institute of Scientific and Technical Information of China (English)

    TONG Yongpeng; ZHANG Guilin; LI Yan; HWU Yeukuang; TSAI Wenli; JE Jung Ho; Margaritondo G.; YUAN Dong

    2005-01-01

    Three human liver tissue samples (~5 mm × 40 mm × 20 mm) were excised from a cancer patient's liver during surgery. The microradiology analysis was performed with a non-standard approach on a synchrotron. High-resolution refractive-index edge-enhanced microradiographs that cover a larger volume of the liver tissue sample were obtained. The cancer tissue and normal tissue could be clearly identified and distinguished based on their different textures. Furthermore, new blood vessel hyperplasia was found near the cancer area. Blood vessels with a diameter smaller than 20 μm could be identified. These findings were fully consistent with the histopathological examination of the same area. Microradiographs of the newly formed blood vessels at different angles were also obtained. This result shows that it is possible to further develop this approach into a technique of microradiographic imaging for clinic diagnosis of liver cancer at the early stage.

  3. Effect of human liver source on the functionality of isolated hepatocytes and liver slices

    NARCIS (Netherlands)

    Olinga, Peter; Hof, I.H; de Jong, Kurt; Slooff, M.JH; Meijer, D.K F; Groothuis, Geny; Merema, M.T.

    1998-01-01

    In vitro experiments using human liver tissue to study drug metabolism and transport are usually performed and interpreted without real consideration of the differences in procurement of the tissue, if it is obtained from different sources. Therefore, in this study the functionality of isolated hepa

  4. The thalamus in cirrhotic patients with and without hepatic encephalopathy: A volumetric MRI study

    Energy Technology Data Exchange (ETDEWEB)

    Tao, Ran, E-mail: taoran1648@yahoo.cn [Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Department of Radiology, Bethune International Peace Hospital of People' s Liberty Army, Shijiazhuang 050082, Hebei Province (China); Zhang, Jiuquan, E-mail: jiuquanzhang@yahoo.com [Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); You, Zhonglan, E-mail: you_zhonglan@163.com [Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Wei, Luqing, E-mail: weiluqing@foxmail.com [Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Fan, Yi, E-mail: fanyi1978@yahoo.cn [Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Cui, Jinguo, E-mail: cuijinguo2005@163.com [Department of Radiology, Bethune International Peace Hospital of People' s Liberty Army, Shijiazhuang 050082, Hebei Province (China); Wang, Jian, E-mail: wangjian_811@yahoo.com [Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China)

    2013-11-01

    Background and aims: The thalamus is a major relay and filter station in the central neural system. Some previous studies have suggested that the thalamus maybe implicated in the pathogenesis of hepatic encephalopathy. The aim of our study was to investigate changing thalamic volumes in cirrhotic patients with and without hepatic encephalopathy. Methods: Neuropsychological tests and structural MR scanning were performed on 24 cirrhotic patients, 23 cirrhotic patients with minimal hepatic encephalopathy, 24 cirrhotic patients during their first episode of overt hepatic encephalopathy, and 33 healthy controls. Voxel-based morphometry analysis was performed to detect gray matter morphological changes. The thalamus and whole brain volume were extrapolated. A receiver operating characteristic curve analysis of thalamic volumes was used to discriminate patients with minimal hepatic encephalopathy from those with hepatic cirrhosis. Results: Thalamic volume increased in a stepwise manner in patients with progressively worse stages of hepatic encephalopathy compared to healthy subjects. Additionally, a comparison of gray matter morphometry between patients with Child–Pugh grades A, B, or C and controls revealed a progression in thalamic volumes in parallel with the degree of liver failure. Moreover, thalamic volume was significantly correlated with the number connection test A time and digit-symbol test score in cirrhotic patients with minimal hepatic encephalopathy (r = 0.659, P = 0.001; r = −0.577, P = 0.004; respectively). The area under the receiver operating characteristic curve was 0.827 (P = 0.001). Conclusions: A significantly increased thalamic volume may be provide an objective imaging measure for predicting seizures due to minimal hepatic encephalopathy in cirrhotic patients.

  5. What we should know about portal vein thrombosis in cirrhotic patients: A changing perspective

    Institute of Scientific and Technical Information of China (English)

    Francesca Romana Ponziani; Maria Assunta Zocco; Matteo Garcovich; Francesca D'Aversa; Davide Roccarina; Antonio Gasbarrini

    2012-01-01

    Portal vein thrombosis (PVT) is one of the most common complications occurring during the natural course of liver cirrhosis.Even though PVT is often asymptomatic,the worsening of liver function,an unexpected episode of gastrointestinal bleeding or ascitic decompensation may be landmarks of PVT development.Beyond these clinical manifestations,it is debated whether PVT really has an impact on liver cirrhosis natural history or rather represents only one of its consequences.Probably PVT development should not only be considered as a matter of impaired blood flow or pro-coagulation tendency.On one hand,PVT seems a consequence of the worsening in portal vein outflow due to the increased hepatic resistance in cirrhotic livers.On the other hand,vascular microthrombosis secondary to necroinflammation may cause liver ischemia and infarction,with loss of hepatic tissue (parenchymal extinction) which is replaced by fibrotic tissue.Therefore,PVT might also be considered as the overt manifestation of the liver fibrosing process evolution and anticoagulant therapy may thus have microscopic indirect effects also on the progression of liver disease.At present,a connection between PVT development and the progression of liver fibrosis/cirrhosis has not yet been demonstrated.Nevertheless,it is not clear if PVT development may worsen cirrhotic patients' outcome by itself.Some authors tried to assess liver transplant benefit in PVT cirrhotic patients but data are contrasting.In this review,we will try to answer these questions,providing a critical analysis of data reported in literature.

  6. Increased survival of cirrhotic patients with septic shock.

    Science.gov (United States)

    Sauneuf, Bertrand; Champigneulle, Benoit; Soummer, Alexis; Mongardon, Nicolas; Charpentier, Julien; Cariou, Alain; Chiche, Jean-Daniel; Mallet, Vincent; Mira, Jean-Paul; Pène, Frédéric

    2013-04-19

    The overall outcome of septic shock has been recently improved. We sought to determine whether this survival gain extends to the high-risk subgroup of patients with cirrhosis. Cirrhotic patients with septic shock admitted to a medical intensive care unit (ICU) during two consecutive periods (1997-2004 and 2005-2010) were retrospectively studied. Forty-seven and 42 cirrhotic patients presented with septic shock in 1997-2004 and 2005-2010, respectively. The recent period differed from the previous one by implementation of adjuvant treatments of septic shock including albumin infusion as fluid volume therapy, low-dose glucocorticoids, and intensive insulin therapy. ICU and hospital survival markedly improved over time (40% in 2005-2010 vs. 17% in 1997-2004, P = 0.02 and 29% in 2005-2010 vs. 6% in 1997-2004, P = 0.009, respectively). Furthermore, this survival gain in the latter period was sustained for 6 months (survival rate 24% in 2005-2010 vs. 6% in 1997-2004, P = 0.06). After adjustment with age, the liver disease stage (Child-Pugh score), and the critical illness severity score (SOFA score), ICU admission between 2005 and 2010 remained an independent favorable prognostic factor (odds ratio (OR) 0.09, 95% confidence interval (CI) 0.02-0.4, P = 0.004). The stage of the underlying liver disease was also independently associated with hospital mortality (Child-Pugh score: OR 1.42 per point, 95% CI 1.06-1.9, P = 0.018). In the light of advances in management of both cirrhosis and septic shock, survival of such patients substantially increased over recent years. The stage of the underlying liver disease and the related therapeutic options should be included in the decision-making process for ICU admission.

  7. Repair pathways evident in human liver organ slices

    NARCIS (Netherlands)

    Vickers, Alison E. M.; Fisher, Robyn; Olinga, Peter; Dial, Sharon

    2011-01-01

    The extension of human liver slice culture viability for several days broadens the potential of this ex vivo model for characterizing pathways of organ injury and repair, and allows for the multiple dosing of compounds. Extended viability is demonstrated by continued synthesis of GSH and ATP, and ma

  8. Pharmacokinetic Study of Frusemide in Healthy and Cirrhotic Indian Subjects

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    Dr. Yuvrajsing Dhunnoo

    2008-01-01

    Full Text Available Liver cirrhosis is associated with various complications such as ascites and fluid retention, progressing to development of hepatorenal syndrome, further compromising fluid elimination. Frusemide, a loop diuretic is normally administered to relieve fluid retentions. The kinetics of frusemide has not been conclusively reported in the three types of cirrhosis and among Indian subjects. The aim of the current study was to evaluate the kinetics of frusemide among healthy and Child’s A, B and C cirrhosis and compare with earlier data. 24 cirrhotic were selected and classified according to the Child’s-Pugh classification. 12 healthy male volunteers were screened and included in the study. 40 mg of frusemide was administered orally to both groups and blood samples were withdrawn at various intervals of time for a duration of 8 hrs. The amount of frusemide present in plasma was analyzed using HPLC. The volumes of distribution (Vd, area under curve (AUC, systemic clearance (CL, maximum concentration (Cmax, time for maximum concentration (tmax in healthy volunteers were respectively 4.56 ± 0.15 L, 2258 ± 530.7, 4.97 ± 1.67 L/h, 892 ± 49.4 ng/ml, 85.20± 7.49 mins. Corresponding values in Group A were 5.00 ± 0.31 L, 2471 ± 228.6, 6.60 ± 2.90L/h, 1021 ± 47.97 ng/ml and 88.25 V 2.12 mins; in Group B 7.73 ± 1.10 L, 4038 ± 154.7, 8.84 ± 0.45 L/h, 1448 ± 43.20 ng/ml and 120 ± 1.89 mins; In group C cirrhosis 9.69 ± 1.32 L, 4085 ± 131.75, 3.49 ± 1.40 L/h, 1551± 59.02 ng/ml and 185.7 ± 2.68 mins respectively. Significant differences at 1% and 5% were observed among the cirrhotic groups and between healthy v/s cirrhotic patients. Data from current study do not correlate with earlier reports, carried mainly in Western population, due to possibly differences in instrumentation, etc but a possible genetic interplay should not be ruled out. Data from cirrhotic patients could not be effectively compared with earlier studies as kinetics of frusemide

  9. Strong correlation by ultrasonography of hepatomegaly and the presence of co-infection in HIV/HCV cirrhotic patients

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    Denise Cerqueira Paranaguá Vezozzo

    2013-04-01

    Full Text Available OBJECTIVES: Progression of hepatic fibrosis is accelerated in patients co-infected with human immunodeficiency virus and hepatitis C virus compared to hepatitis C virus mono-infected patients. This study aimed to compare ultrasound features and selected clinical and biochemical variables between patients with human immunodeficiency virus/hepatitis C virus co-infection (n = 16 versus hepatitis C virus mono-infection (n = 16. METHODS: Each patient underwent abdominal ultrasound, and a specific evaluation was performed in order to detect findings consistent with chronic liver disease. Characterization of spleen size, liver structural pattern, diameter of the portal, spleen, and mesenteric veins was based on classical ultrasound parameters. Propensity score was used for control of selection bias and performed using binary logistic regression to generate a score for each patient. The Fisher and Mann-Whitney tests were used to evaluate categorical variables and continuous variables, respectively. RESULTS: On univariate analysis right hepatic lobe size was larger in human immunodeficiency virus/hepatitis C virus patients (157.06 ± 17.56 mm compared to hepatitis C virus mono-infected patients (134.94 ± 16.95 mm (p = 0.0011. The left hepatic lobe was also significantly larger in human immunodeficiency virus/hepatitis C virus patients Cirrhosis (115.88 ±22.69 mm versus hepatitis C virus mono-infected patients (95.06 ±24.18 mm (p= 0.0177. Also, there was a strong correlation between hepatomegaly and co-infection (p=0.005. CONCLUSION: Human immunodeficiency virus infection was the primary variable influencing liver enlargement in this population. Hepatomegaly on ultrasound was more common among cirrhotic human immunodeficiency virus/hepatitis C virus co-infected patients than among cirrhotic hepatitis C virus mono-infected patients. This aspect is very important in the management of human immunodeficiency virus/hepatitis C virus co-infected patients

  10. Perivascular mesenchymal progenitors in human fetal and adult liver.

    Science.gov (United States)

    Gerlach, Jörg C; Over, Patrick; Turner, Morris E; Thompson, Robert L; Foka, Hubert G; Chen, William C W; Péault, Bruno; Gridelli, Bruno; Schmelzer, Eva

    2012-12-10

    The presence of mesenchymal stem cells (MSCs) has been described in various organs. Pericytes possess a multilineage differentiation potential and have been suggested to be one of the developmental sources for MSCs. In human liver, pericytes have not been defined. Here, we describe the identification, purification, and characterization of pericytes in human adult and fetal liver. Flow cytometry sorting revealed that human adult and fetal liver contains 0.56%±0.81% and 0.45%±0.39% of CD146(+)CD45(-)CD56(-)CD34(-) pericytes, respectively. Of these, 41% (adult) and 30% (fetal) were alkaline phosphatase-positive (ALP(+)). In situ, pericytes were localized around periportal blood vessels and were positive for NG2 and vimentin. Purified pericytes could be cultured extensively and had low population doubling times. Immunofluorescence of cultures demonstrated that cells were positive for pericyte and mesenchymal cell markers CD146, NG2, CD90, CD140b, and vimentin, and negative for endothelial, hematopoietic, stellate, muscle, or liver epithelial cell markers von Willebrand factor, CD31, CD34, CD45, CD144, CD326, CK19, albumin, α-fetoprotein, CYP3A7, glial fibrillary acid protein, MYF5, and Pax7 by gene expression; myogenin and alpha-smooth muscle actin expression were variable. Fluorescence-activated cell sorting analysis of cultures confirmed surface expression of CD146, CD73, CD90, CD10, CD13, CD44, CD105, and ALP and absence of human leukocyte antigen-DR. In vitro differentiation assays demonstrated that cells possessed robust osteogenic and myogenic, but low adipogenic and low chondrogenic differentiation potentials. In functional in vitro assays, cells had typical mesenchymal strong migratory and invasive activity. In conclusion, human adult and fetal livers harbor pericytes that are similar to those found in other organs and are distinct from hepatic stellate cells.

  11. Evaluation of Zinc Plasma Level in Iranian Cirrhotic Patients due to Hepatitis B and Hepatitis C

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    Mohammad Reza Zali

    2010-01-01

    Full Text Available Background and Aims: Zinc (Zn has various significant roles in physiological functions of the liver. Furthermore, it has been reported that the administration of zinc has an important role in pharmacotherapy of viral hepatitis. Cirrhotic patients with decrease in plasma zinc level have been covered in previous studies. It is seemingly necessary to assess the zinc level, in Iranian cirrhotic patients, as a distinct population, Because of the large phytate amounts in Iranians diet. Regarding to etiology, disease progress, and treatment, there are some differences in the 2 most common causes of cirrhosis in the Iranian population (hepatitis B and hepatitis C and it is possible that the zinc level may be different between the two. This study was done to shadow some lights on the subject. Methods: Between April 2008 and November 2008, plasma zinc level was determined, by atomic absorption method, in 60 cirrhotic inpatients treated due to hepatitis B or hepatitis C in Talighani hospital (a referral center for gastrointestinal and liver diseases in Tehran, Iran. Results: Mean ± standard deviation (SD plasma zinc levels determined 0.34±0.22 mg/L and 0.37±0.22 mg/L in hepatitis B and hepatitis C patients respectively. Analysis of t-test showed there is no significant difference between 2 groups regarding to plasma zinc level (P = 0.745.Conclusions: It is concluded that zinc level of studied cirrhotic patients is less than half of the normal range. Moreover, there is no difference in plasma zinc level between cirrhotic patients due to hepatitis B or hepatitis C. Regarding to this result, supplementation with complementary zinc, may be recommended in both groups in order to optimize the nutritional support and probably better the treatment response.

  12. Survey of serum procalcitonin in cirrhotic patients.

    Science.gov (United States)

    Rahimkhani, Monireh; Einollahi, Nahid; Khavari Daneshvar, Hossein; Dashti, Nasrin

    2013-04-06

    Procalcitonin (PCT) is a prohormone that has been used as a marker for the diagnosis of bacterial infections. The aim of this study was to survey PCT levels in patients with cirrhosis. Sixty-four patients with hepatic cirrhosis and 32 healthy blood donors were enrolled in this study. Serum PCT levels was detected using immunoluminometric assay. The rate of positive PCT was higher in patients with hepatitis C cirrhosis (92.8%) than the other groups. Among other cirrhotic patients, positive PCT levels were 77% for hepatitis B, 70% for cancer and 53.3% for unknown groups respectively. Serum procalcitonin levels were significantly higher in cirrhotic patients with bacterial infection (2.65±1.11 ng/ml) than those without infection (0.59±0.16 ng/ml, P=0.0001). PCT assay in cirrhotic patients may help diagnosis of sepsis and reduce unnecessary antibiotic use.

  13. Survey of Serum Procalcitonin in Cirrhotic Patients

    Directory of Open Access Journals (Sweden)

    Monireh Rahimkhani

    2013-03-01

    Full Text Available Procalcitonin (PCT is a prohormone that has been used as a marker for the diagnosis of bacterial infections. The aim of this study was to survey PCT levels in patients with cirrhosis. Sixty-four patients with hepatic cirrhosis and 32 healthy blood donors were enrolled in this study. Serum PCT levels was detected using immunoluminometric assay. The rate of positive PCT was higher in patients with hepatitis C cirrhosis (92.8% than the other groups. Among other cirrhotic patients, positive PCT levels were 77% for hepatitis B, 70% for cancer and 53.3% for unknown groups respectively. Serum procalcitonin levels were significantly higher in cirrhotic patients with bacterial infection (2.65±1.11 ng/ml than those without infection (0.59±0.16 ng/ml, P=0.0001. PCT assay in cirrhotic patients may help diagnosis of sepsis and reduce unnecessary antibiotic use

  14. A novel form of the human manganese superoxide dismutase protects rat and human livers undergoing ischaemia and reperfusion injury

    National Research Council Canada - National Science Library

    Hide, Diana; Ortega-Ribera, Martí; Fernández-Iglesias, Anabel; Fondevila, Constantino; Salvadó, M Josepa; Arola, Lluís; García-Pagán, Juan Carlos; Mancini, Aldo; Bosch, Jaime; Gracia-Sancho, Jordi

    2014-01-01

    ...), liver grafts from healthy and steatotic rats, and human liver samples, we aimed to characterize the effects of a new recombinant form of human manganese superoxide dismutase (rMnSOD) on hepatic CS+WR injury. After CS...

  15. Methods of Liver Stem Cell Therapy in Rodents as Models of Human Liver Regeneration in Hepatic Failure.

    Science.gov (United States)

    Hashemi Goradel, Nasser; Darabi, Masoud; Shamsasenjan, Karim; Ejtehadifar, Mostafa; Zahedi, Sarah

    2015-09-01

    Cell therapy is a promising intervention for treating liver diseases and liver failure. Different animal models of human liver cell therapy have been developed in recent years. Rats and mice are the most commonly used liver failure models. In fact, rodent models of hepatic failure have shown significant improvement in liver function after cell infusion. With the advent of stem-cell technologies, it is now possible to re-programme adult somatic cells such as skin or hair-follicle cells from individual patients to stem-like cells and differentiate them into liver cells. Such regenerative stem cells are highly promising in the personalization of cell therapy. The present review article will summarize current approaches to liver stem cell therapy with rodent models. In addition, we discuss common cell tracking techniques and how tracking data help to direct liver cell therapy research in animal models of hepatic failure.

  16. 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

    2016-01-01

    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 stu

  17. PLASMID DNA DAMAGE CAUSED BY METHYLATED ARSENICALS, ASCORBIC ACID AND HUMAN LIVER FERRITIN

    Science.gov (United States)

    PLASMID DNA DAMAGE CAOUSED BY METHYLATED ARSENICALS, ASCORBIC ACID AND HUMAN LIVER FERRITINABSTRACT Both dimethylarsinic acid (DMA(V)) and dimethylarsinous acid (DMA(III)) release iron from human liver ferritin (HLF) with or without the presence of ascorbic acid. ...

  18. Activated hepatic stellate cells in liver cirrhosis. A morphologic and morphometrical study.

    Science.gov (United States)

    Carpino, Guido; Franchitto, Antonio; Morini, Sergio; Corradini, Stefano Ginanni; Merli, Manuela; Gaudio, Eugenio

    2004-01-01

    Hepatic stellate cells have been considered the most important cell-type involved in hepatic fibrogenesis. Proliferation and differentiation of hepatic stellate cells into myofibroblast-like cells has been related to the development of liver fibrosis. The alpha-actin expressed by hepatic stellate cells was considered a marker of their activation to myofibroblast-like cell. The aim of this study is to evaluate the changes in morphology, distribution, percentage and alpha-smooth muscle actin expression of hepatic stellate cells in normal and cirrhotic livers, and to correlate activated hepatic stellate cells with the progression of fibrosis. Human liver biopsies (n=121) were divided in five groups: 1) normal livers (controls); 2) cirrhosis post-HCV hepatitis; 3) cirrhosis post-HBV hepatitis; 4) non viral related cirrhosis; 5) recurrent HCV hepatitis after orthotopic liver transplantation. Samples immunostained with anti alpha-smooth muscle actin antibody by immunoperoxidase method were semi-quantitatively evaluated. Liver fibrosis was quantified by computer image analysis on specimens stained with Masson's trichrome. In normal adult livers stellate cells were very rarely stained for alpha-smooth muscle actin. In cirrhotic livers, a strongly enhanced percentage of stellate cells expressing alpha-smooth muscle actin was detected in cirrhotic fragments with respect to the control group, with a significant correlation between alpha-smooth muscle actin positive stellate cells and the volume fraction of fibrosis. Moreover, liver biopsies of recurrent hepatitis revealed an increased number of activated stellate cells compared to normal livers, and intermediate volume fraction of fibrosis. These results confirmed that a direct correlation existed between activated stellate cells and the progression of fibrosis. Alpha-smooth muscle actin confirmed to be a reliable marker of hepatic stellate cells activation also in precocious stages of the disease.

  19. Effects of lactulose on intestinal endotoxin and bacterial translocation in cirrhotic rats

    Institute of Scientific and Technical Information of China (English)

    张顺财; 王唯; 任卫英; 戴茜; 贺伯明; 周康

    2003-01-01

    Objective To investigate the effects of lactulose on intestinal bacterial overgrowth (IBO), bacterial translocation (BT), intestinal transit and permeability in cirrhotic rats. Methods BT in all animals was assessed by bacterial culture of mesenteric lymph node (MLN), liver and spleen, and IBO was assessed by a jejunal bacterial count of the specific organism. Intestinal permeability was determined by the 24-hour urinary 99mTc-diethylenetriaminepentaacetate (99mTc-DTPA) excretion, and intestinal transit was determined by measuring the distribution of 51 Cr in the intestine. Results BT and IBO were found in 48% and 80% of the cirrhotic rats, respectively, while not in the control rats. Cirrhotic rats with IBO had significantly higher levels of intestinal endotoxin higher rates of bacterial translocation, shorter intestinal transit time and higher intestinal permeability than those without IBO. It was also found that BT was closely associated with IBO and injury of the intestinal barrier. Compared with the placebo group, lactulose-treated rats had lower rates of BT and IBO, which was closely associated with increased intestinal transit and improved intestinal permeability by lactulose. Conclusions Our study indicate that endotoxin and bacterial translocation in cirrhotic rats may attribute to IBO and increased intestinal permeability. Lactulose that accelerates intestinal transit and improves intestinal permeability might be helpful in preventing intestinal bacterial and endotoxin translocation.

  20. [Fatal pulmonary mycosis in a diabetic and cirrhotic patient].

    Science.gov (United States)

    Ayadi-Kaddour, Aïda; Braham, Emna; Marghli, Adel; Ismail, Olfa; Helal, Imen; Mlika, Mona; Kilani, Tarak; El Mezni, Faouzi

    2015-04-01

    Pulmonary mucormycosis is a rare, devastating, opportunistic fungal infection, caused by the ubiquitous filamentous fungi of the Mucorales order of the class of Zygomycetes. This infection occurs principally in some particular conditions, specially in diabetic patients and immunocompromised host, and rarely in cirrhotic patients. The diagnosis of mucormycosis can only be confirmed by pathological and mycological examination of biopsy specimens. We report a case of pulmonary mucormycosis in a 68-year-old woman with underlying liver cirrhosis and diabetes mellitus. Endoscopic and radiologic findings supported the diagnosis of hydatid cyst of the lung. The patient underwent surgical resection and was started on amphotericin B, after pathological examination. Unfortunately, she succumbed to the infection within one month of surgery.

  1. Obesity accelerates epigenetic aging of human liver

    OpenAIRE

    Horvath, S; Erhart, W.; Brosch, M; Ammerpohl, O.; von Schonfels, W.; Ahrens, M.; Heits, N.; Bell, J.T.; Tsai, P.-C.; Spector, T D; Deloukas, P.; Siebert, R.; Sipos, B.; Becker, T.; Rocken, C.

    2014-01-01

    Because obese people are at an increased risk of many age-related diseases, it is a plausible hypothesis that obesity increases the biological age of some tissues and cell types. However, it has been difficult to detect such an accelerated aging effect because it is unclear how to measure tissue age. Here we use a recently developed biomarker of aging (known as “epigenetic clock”) to study the relationship between epigenetic age and obesity in several human tissues. We report an unexpectedly ...

  2. Portal Vein Thrombosis in non cirrhotic patients

    NARCIS (Netherlands)

    M.C.W. Spaander (Manon)

    2010-01-01

    textabstractExtrahepatic portal vein thrombosis (EPVT) is the most common cause of portal hypertension in non- cirrhotic patients. EPVT has been defined as an obstruction of the extrahepatic portal vein with or without involvement of the intrahepatic portal veins. Although the portal vein accounts f

  3. 不同病因肝硬化患者肝实时剪切波弹性成像测值范围比较%Comparison of the liver Young's modulus value range of cirrhotic patients with different etiologies by real-time ;shear wave elastography

    Institute of Scientific and Technical Information of China (English)

    汪惠鹏; 韩秀梅; 王学梅

    2015-01-01

    目的:分析不同病因的肝硬化患者肝杨氏模量值是否有差异。方法收集经临床确诊的肝硬化失代偿期患者199例,其中乙型肝炎后肝硬化患者139例,丙型肝炎后肝硬化患者26例,酒精性肝硬化患者34例。选择同期50名健康志愿者作为健康对照组。所有受试者均进行肝实时剪切波弹性成像检查,测量并记录肝组织的杨氏模量值,分析比较各组受试者肝组织的杨氏模量值差异。结果健康对照组的肝组织杨氏模量值最低,为(4.81±0.9)kPa。乙肝后肝硬化组、丙肝后肝硬化组、酒精性肝硬化组的肝组织杨氏模量值依次增高,分别为(16.3±8.9)kPa、(17.8±4.8)kPa、(30.6±12.3)kPa,组间差异有统计学意义(F =27.95,P <0.01)。结论实时剪切波弹性成像技术测量的不同病因肝硬化患者的肝组织杨氏模量值有一定的差异。%Objective To analyze the difference of Young's modulus between cirrhotic patients with different etiologies.Methods There were 1 99 patients with decompensated cirrhosis enrolled in this study, all of them had been diagnosed clinically.There were 139 cases of hepatitis B patients with cirrhosis,26 cases of hepatitis C patients with liver cirrhosis,34 cases of patients with alcoholic cirrhosis,and selected 50 healthy volunteers as control group in the same period.All subj ects underwent liver shear wave elastography examination,measured and recorded the Young's modulus,and compared the difference between each groups.Results The Young's modulus of liver in the healthy control group was (4.81±0.9)kPa,which was lowest in all groups.The Young's modulus of hepatitis B cirrhosis,hepatitis C cirrhosis,alcoholic cirrhosis increased successively,which was (16.3±8.9)kPa,(17.8±4.8)kPa,(30.6±12.3)kPa,respectively,and the difference between the groups was statistically significant(F =27.95,P <0.01).Conclusions There were some differences of the Young's modulus of cirrhotic patients with

  4. Isolation of human liver angiotensin-converting enzyme by chromatofocusing.

    Science.gov (United States)

    Sakharov IYu; Danilov, S M; Sukhova, N V

    1987-10-01

    Angiotensin-converting enzyme (EC 3.4.15.1) has been isolated from human liver by chromatofocusing. The isolation procedure permitted us to obtain a 9000-fold purified enzyme with a 22% yield. Specific activity of the angiotensin-converting enzyme was 10 units/mg of protein. The molecular mass of enzyme determined by polyacrylamide gel electrophoresis under denaturing conditions was 150,000. The isoelectric point (4.2-4.3) was also determined by chromatofocusing. The Km values of the enzyme for hippuryl-L-histidyl-L-leucine and N-benzyloxycarbonyl-L-phenylalanyl-L-histidyl-L-leucine are 5000 and 125 microM, respectively. The human liver angiotensin-converting enzyme is inhibited by bradykinin-potentiating factor SQ 20881 (IC50 = 18 nM).

  5. [Metabolism of mitomycin C by human liver microsomes in vitro].

    Science.gov (United States)

    Hao, Fu-rong; Yan, Min-fen; Hu, Zhuo-han; Jin, Yi-zun

    2007-02-01

    To provide the profiles of metabolism of mitomycin C (MMC) by human liver microsomes in vitro, MMC was incubated with human liver microsomes, then the supernatant component was isolated and detected by HPLC. Types of metabolic enzymes were estimated by the effect of NADPH or dicumarol (DIC) on metabolism of MMC. Standard, reaction, background control (microsomes was inactivated), negative control (no NADPH), and inhibitor group (adding DIC) were assigned, the results were analyzed by Graphpad Prism 4. 0 software. Reaction group compared with background control and negative control groups, 3 NADPH-dependent absorption peaks were additionally isolated by HPLC after MMC were incubated with human liver microsomes. Their retention times were 10. 0, 14. 0, 14. 8 min ( named as Ml, M2, M3) , respectively. Their formation was kept as Sigmoidal dose-response and their Km were 0. 52 (95% CI, 0. 40 - 0.67) mmol x L(-1), 0. 81 (95% CI, 0. 59 - 1. 10) mmol x L(-1), 0. 54 (95% CI, 0. 41 -0. 71) mmol x L(-1) , respectively. The data indicated that the three absorption peaks isolated by HPLC were metabolites of MMC. DIC can inhibit formation of M2, it' s dose-effect fitted to Sigmoidal curve and it' s IC50 was 59. 68 (95% CI, 40. 66 - 87. 61) micromol x L(-1) , which indicated DT-diaphorase could take part in the formation of M2. MMC can be metabolized by human liver microsomes in vitro, and at least three metabolites of MMC could be isolated by HPLC in the experiment, further study showed DT-diaphorase participated in the formation of M2.

  6. Influência do grau de insuficiência hepática e do índice de congestão portal na recidiva hemorrágica de cirróticos submetidos a cirurgia de Teixeira-Warren Role of liver function and portal vein congestion index on rebleeding in cirrhotics after distal splenorenal shunt

    Directory of Open Access Journals (Sweden)

    Fabio Gonçalves Ferreira

    2007-06-01

    distal em relação aos Child-Pugh A.BACKGROUND: Bleeding from esophagogastric varices is the worst and most lethal complication of cirrhotic portal hypertension. Distal splenorenal shunt (Warren’s surgery is used in the therapeutic of this patients, Child A and B, with rebleeding after clinical endoscopic therapy. The portal vein congestion index is elevated in cirrhotic portal hypertension and could predict rebleeding after Warren’s surgery in these patients. AIM: To verify if the portal vein congestion index or liver function (Child-Pugh at preoperative are predictive factors of rebleeding after Warren’s surgery. METHODS: Sixty-two cirrhotic patients were submitted to Warren’s surgery at "Santa Casa" Medical School and Hospital - Liver and Portal Hypertension Unit, São Paulo, SP, Brazil. Fifty-eight were analyzed for Child-Pugh class and 36 for portal vein congestion index, divided in two groups: with or without rebleeding and statistical analysis was performed. RESULTS: In the rebleeding group, 69% were Child B, with portal vein congestion index = 0.09. The group without rebleeding show us 62% patients Child A with portal vein congestion index = 0.076. The difference was significant for Child-Pugh class but not to portal vein congestion index. CONCLUSION: Portal vein congestion index was not predictive of rebleeding after Warren’s surgery, but cirrhotics Child B have more chance to rebleed after this surgery than Child A.

  7. Cloning and expression of special F protein from human liver

    Institute of Scientific and Technical Information of China (English)

    Shu-Ye Liu; Xin-Da Yu; Chun-Juan Song; Wei Lu; Jian-Dong Zhang; Xin-Rong Shi; Ying Duan; Ju Zhang

    2007-01-01

    AIM:To clone human liver special F protein and to express it in a prokaryotic system.METHODS:Total RNA was isolated from human liver tissue and first-strand cDNA was reverse transcribed using the PCR reverse primer. Following this,cDNA of the F protein was ligated into the clone vector pUCm-T. The segment of F protein's cDNA was subcloned into the expression vector pET-15b and transformed into E coli BL21 (DEB) pLyss. Isopropy-β-D-thiogalactoside (IPTG) was then used to induce expression of the target protein.RESULTS:The cDNA clone of human liver special F protein (1134bp) was successfully produced,with the cDNA sequence being published in Gene-bank:DQ188836. We confirmed the expression of F protein by Western blot with a molecular weight of 43 kDa. The expressed protein accounted for 40% of the total protein extracted.CONCLUSION:F protein expresses cDNA clone in a proKaryotic system,which offers a relatively simple way of producing sufficient quantities of F protein and contributes to understanding the principal biological functions of this protein.

  8. Serum cystatin C level is an excellent predictor of mortality in patients with cirrhotic ascites.

    Science.gov (United States)

    Seo, Yeon Seok; Park, Soo Young; Kim, Moon Young; Kim, Sang Gyune; Park, Jun Yong; Yim, Hyung Joon; Jang, Byoung Kuk; Park, Seung Ha; Kim, Ji Hoon; Suk, Ki Tae; Kim, Jin Dong; Kim, Tae Yeob; Cho, Eun Young; Lee, Jun Sung; Jung, Soung Won; Jang, Jae Young; An, Hyonggin; Tak, Won Young; Baik, Soon Koo; Hwang, Jae Seok; Kim, Young Seok; Sohn, Joo Hyun; Um, Soon Ho

    2017-09-14

    Although serum cystatin C level is considered a more accurate marker of renal function in patients with liver cirrhosis, its prognostic efficacy remains uncertain. This study aimed to evaluate the prognostic efficacy of serum cystatin C level in patients with cirrhotic ascites. Patients with cirrhotic ascites from 15 hospitals were prospectively enrolled between September 2009 and March 2013. Cox regression analyses were performed to identify independent predictive factors of mortality and development of type 1 hepatorenal syndrome (HRS-1). In total, 350 patients were enrolled in this study. The mean age was 55.4 ± 10.8 years, and 267 patients (76.3%) were men. The leading cause of liver cirrhosis was alcoholic liver disease (64.3%), followed by chronic viral hepatitis (29.7%). Serum creatinine and cystatin C levels were 0.9 ± 0.4 mg/dL and 1.1 ± 0.5 mg/L, respectively. Multivariate analyses revealed that international normalized ratio (INR) and serum bilirubin, sodium, and cystatin C levels were independent predictors of mortality and INR and serum sodium and cystatin C levels were independent predictors of the development of HRS-1. Serum creatinine level was not significantly associated with mortality and development of HRS-1 on multivariate analysis. Serum cystatin C level was an independent predictor of mortality and development of HRS-1 in patients with cirrhotic ascites, while serum creatinine level was not. Predictive models based on serum cystatin C level instead of serum creatinine level would be more helpful in the assessment of the condition and prognosis of patients with cirrhotic ascites. This article is protected by copyright. All rights reserved.

  9. Renal failure after upper-gastrointestinal bleeding among cirrhotic patients in Upper Egypt.

    Science.gov (United States)

    Makhlouf, Nahed A; Morsy, Khairy H

    2012-09-01

    Renal dysfunction is a common and serious problem in patients with advanced liver disease. The study aims to assess the incidence, risk factors and short-term prognosis of renal failure after upper-gastrointestinal bleeding among cirrhotic patients in Upper Egypt. We recruited 159 cirrhotic patients with 168 episodes of upper-gastrointestinal bleeding from Tropical Medicine and Gastroenterology Department, Assiut University Hospital. For all participants, the following were conducted: clinical evaluation, abdominal ultrasonography (US) examination, laboratory investigations and upper endoscopy. Risk factors of renal failure were identified using univariate, then multivariate analysis. The incidence of renal failure among bleeding episodes was 28%. Higher risk of renal failure among cirrhotic patients with upper-gastrointestinal bleeding was observed with shock (odds ratio (OR) 0.171, 95% confidence interval (CI) 0.047:0.624), bacterial infection (OR 0.310, 95% CI 107:897), Child-Pugh class C (OR 2.79, 95% CI 1.018:7.62), higher serum bilirubin (OR 0.122, 95% CI 0.000:0.002), lower serum albumin (OR -0.188, 95% CI -0.288:-0.056) and raised baseline blood urea (OR 0.181, 95% CI 0.003:0.017) and serum creatinine (OR 0.533, 95% CI 0.002:0.004). Mortality among patients with renal failure was 31.9%. Renal failure is a frequent event among cirrhotic patients with upper-gastrointestinal bleeding and there are many contributing factors for its development. Mortality is relatively high among patients with renal failure in cirrhotics with upper-gastrointestinal bleeding. Copyright © 2012 Arab Journal of Gastroenterology. Published by Elsevier Ltd. All rights reserved.

  10. Expression of ATP7B in normal human liver

    Directory of Open Access Journals (Sweden)

    D Fanni

    2009-06-01

    Full Text Available ATP7B is a copper transporting P-type ATPase, also known as Wilson disease protein, which plays a key role in copper distribution inside cells. Recent experimental data in cell culture have shown that ATP7B putatively serves a dual function in hepatocytes: when localized to the Golgi apparatus, it has a biosynthetic role, delivering copper atoms to apoceruloplasmin; when the hepatocytes are under copper stress, ATP7B translocates to the biliary pole to transport excess copper out of the cell and into the bile canaliculus for subsequent excretion from the body via the bile. The above data on ATP7B localization have been mainly obtained in tumor cell systems in vitro. The aim of the present work was to assess the presence and localization of the Wilson disease protein in the human liver. We tested immunoreactivity for ATP7B in 10 human liver biopsies, in which no significant pathological lesion was found using a polyclonal antiserum specific for ATP7B. In the normal liver, immunoreactivity for ATP7B was observed in hepatocytes and in biliary cells. In the hepatocytes, immunoreactivity for ATP7B was observed close to the plasma membrane, both at the sinusoidal and at the biliary pole. In the biliary cells, ATP7B was localized close to the cell membrane, mainly concentrated at the basal pole of the cells. The data suggest that, in human liver, ATP7B is localized to the plasma membrane of both hepatocytes and biliary epithelial cells.

  11. Interaction of rocuronium with human liver cytochromes P450.

    Science.gov (United States)

    Anzenbacherova, Eva; Spicakova, Alena; Jourova, Lenka; Ulrichova, Jitka; Adamus, Milan; Bachleda, Petr; Anzenbacher, Pavel

    2015-02-01

    Rocuronium is a neuromuscular blocking agent acting as a competitive antagonist of acetylcholine. Results of an inhibition of eight individual liver microsomal cytochromes P450 (CYP) are presented. As the patients are routinely premedicated with diazepam, possible interaction of diazepam with rocuronium has been also studied. Results indicated that rocuronium interacts with human liver microsomal CYPs by binding to the substrate site. Next, concentration dependent inhibition of liver microsomal CYP3A4 down to 42% (at rocuronium concentration 189 μM) was found. This effect has been confirmed with two CYP3A4 substrates, testosterone (formation of 6β-hydroxytestosterone) and diazepam (temazepam formation). CYP2C9 and CYP2C19 activities were inhibited down to 75-80% (at the same rocuronium concentration). Activities of other microsomal CYPs have not been inhibited by rocuronium. To prove the possibility of rocuronium interaction with other drugs (diazepam), the effect of rocuronium on formation of main diazepam metabolites, temazepam (by CYP3A4) and desmethyldiazepam, (also known as nordiazepam; formed by CYP2C19) in primary culture of human hepatocytes has been examined. Rocuronium has caused inhibition of both reactions by 20 and 15%, respectively. The results open a possibility that interactions of rocuronium with drugs metabolized by CYP3A4 (and possibly also CYP2C19) may be observed. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  12. Radionuclide imaging of the liver in human fascioliasis

    Energy Technology Data Exchange (ETDEWEB)

    Rivera, J.V.; Bermudez, R.H.

    1984-08-01

    The clinical, laboratory, and scintigraphic findings in four cases of human fascioliasis are described. Acute onset of fever, abdominal pain, and weight loss in a person who has ingested watercress constitutes the clinical syndrome often seen. Eosinophilia and alteration in liver function tests, particularly alkaline phosphatase are frequent. Tc-99m sulfur colloid images showed hepatomegaly in four patients, focal defects in two, splenomegaly in three, and increased splenic uptake in two. Gallium citrate (Ga 67) images show increased uptake in the focal lesions in two of two. Sonographic imaging showed focal lucent abnormality in one of three. Liver biopsy findings were nonspecific. The differential diagnosis from other invasive parasitic diseases is discussed. A possible role of hepatic imaging in the evaluation of fascioliasis is suggested.

  13. Three-dimensional reconstruction of digitized human liver: based on Chinese Visible Human

    Institute of Scientific and Technical Information of China (English)

    CHEN Gang; DONG Jia-hong; LI Xue-cheng; WU Guo-qing; ZHANG Shao-xiang; XIONG Xiao-feng; TAN Li-wen; YANG Ri-gao; LI Kai; YANG Shi-zhong

    2010-01-01

    Background Comparing with two dimensional (2D) imaging, both in diagnosis and treatment, three dimensional (3D) imaging has many advantages in clinical medicine. 3D reconstruction makes the target easier to identify and reveals the volume and shape of the organ much better than 2D imaging. A 3D digitized visible model of the liver was built to provide anatomical structure for planing of hepatic operation and for realizing accurate simulation of the liver on the computer.Methods Transverse sections of abdomen were chosen from the Chinese Visible Human dataset. And Amira software was selected to segment and reconstruct the structures of the liver. The liver was reconstructed in three-dimensions with both surface and volume rendering reconstruction.Results Accurately segmented images of the main structures of the liver were completed. The reconstructed structures can be displayed singly, in small groups or as a whole and can be continuously rotated in 3D space at different velocities. Conclusions The reconstructed liver is realistic, which demonstrates the natural shape and exact position of liver structures. It provides an accurate model for the automated segmentation algorithmic study and a digitized anatomical mode of viewing the liver.

  14. Assessment of indicators of vitamin A status in non-cirrhotic chronic hepatitis C patients.

    Science.gov (United States)

    Santana, R C; Machado, A A; Martinelli, A L C; Jordão, A A; Ramalho, L N Z; Vannucchi, H

    2016-01-01

    Subjects with chronic liver disease are susceptible to hypovitaminosis A due to several factors. Therefore, identifying patients with vitamin deficiency and a requirement for vitamin supplementation is important. Most studies assessing vitamin A in the context of hepatic disorders are conducted using cirrhotic patients. A cross-sectional study was conducted in 43 non-cirrhotic patients with chronic hepatitis C to evaluate markers of vitamin A status represented by serum retinol, liver retinol, and serum retinol-binding protein levels. We also performed the relative dose-response test, which provides an indirect estimate of hepatic vitamin A reserves. These vitamin A indicators were assessed according to the stage of liver fibrosis using the METAVIR score and the body mass index. The sample study was predominantly composed of male subjects (63%) with mild liver fibrosis (F1). The relative dose-response test was retinol levels than those with a normal body mass index (2.6 and 1.9 µmol/L, respectively; Plevels of serum retinol (1.9 vs 2.5 µmol/L, P=0.01) and retinol-binding protein levels compared with those with mild fibrosis (F1) (46.3 vs 67.7 µg/mL, Pretinol levels. Furthermore, more advanced stages of liver fibrosis were related to a decrease in serum vitamin A levels.

  15. Tumorigenicity, Motility and Liver Metastasis of Human Gastric Carcinoma Lines with High Metastatic Potential in the Liver of Nude Mice

    OpenAIRE

    1995-01-01

    To analyze the human gastric carcinoma metastasis to the liver, a human gastric carcinoma line, AZ521 was injected into the spleens of nude mice. Cells from the few liver metastatic foci of injected AZ521 were expanded in vitro and subsequently injected into the spleens of nude mice. By repeating these proce-dures five times, we were able to obtain a cell line, designated AZ-H5c, with high metastatic potential in nude mice. It was observed that animals had liver metastasis in 10 of 12 (83%) c...

  16. Effect of H pylori infection and its eradication on hyperammo-nemia and hepatic encephalopathy in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Shu-Jie Chen; Liang-Jing Wang; Qin Zhu; Jian-Ting Cai; Tao Chen; Jian-Min Si

    2008-01-01

    AIM: To investigate the relationship between H pylori infection, blood ammonia concentration and hepatic encephalopathy (HE), and the effect of H pylori eradication in cirrhotic patients.METHODS: From July 2003 to January 2005, 457 cirrhotic patients in five regions of Zhejiang Province were enrolled. Patients were evaluated for demographics, number connection test, H pylori infection, liver impairment, blood ammonia concentration and HE. Patients with H pylori infection were given 1 wk therapy with omeprazole plus clarithromycin and tinidazole. 14C urea breath test was performed and mental symptoms and blood ammonia level were reassessed after bacterium eradication.RESULTS: Overall H pylori infection rate was 60.6%, and HE occurred in 47.5% of cirrhotic patients. Subclinical HE (SHE) was detected in 55 of 117 cirrhotic patients. Blood ammonia concentration in H pylori negative (n = 180) and positive (n = 277) cirrhotic patients was 53.8 ± 51.4 and 78.4 ± 63.6 nmol/L, respectively (P < 0.01), which was significantly reduced to 53.5 ± 37.7 nmol/L after bacterium eradication (n = 126) (P < 0.01). Blood ammonia was 97.5 ± 81.0 nmol/L in H py/ori-positive cirrhotic patients, and this did not significantly change in those with persistent infection after H pylori eradication (n = 11). HE was more frequently observed in patients with H pylori infection than in those without (58.5% vs 30.6%, P < 0.01). HE rate significantly dropped to 34.1% after H pylori eradiation (P < 0.01). H pylori prevalence significantly differed among cirrhotic patients with HE (74.4%), SHE (69.1%), and those without HE (53.2%) (P < 0.05). Blood ammonia level was significantly different among cirrhotic patients with HE (94.5 ± 75.6 nmol/L), SHE (59.9 ± 49.2 nmol/L), and without HE (47.3 ± 33.5 nmol/L) (P < 0.05). Logistic regression analysis showed that blood ammonia concentration, Child-Pugh stage, upper gastrointestinal bleeding, electrolyte disturbance, and urea nitrogen were risk factors

  17. Human Liver Infection in a Dish: Easy-To-Build 3D Liver Models for Studying Microbial Infection.

    Directory of Open Access Journals (Sweden)

    Debora B Petropolis

    Full Text Available Human liver infection is a major cause of death worldwide, but fundamental studies on infectious diseases affecting humans have been hampered by the lack of robust experimental models that accurately reproduce pathogen-host interactions in an environment relevant for the human disease. In the case of liver infection, one consequence of this absence of relevant models is a lack of understanding of how pathogens cross the sinusoidal endothelial barrier and parenchyma. To fill that gap we elaborated human 3D liver in vitro models, composed of human liver sinusoidal endothelial cells (LSEC and Huh-7 hepatoma cells as hepatocyte model, layered in a structure mimicking the hepatic sinusoid, which enable studies of key features of early steps of hepatic infection. Built with established cell lines and scaffold, these models provide a reproducible and easy-to-build cell culture approach of reduced complexity compared to animal models, while preserving higher physiological relevance compared to standard 2D systems. For proof-of-principle we challenged the models with two hepatotropic pathogens: the parasitic amoeba Entamoeba histolytica and hepatitis B virus (HBV. We constructed four distinct setups dedicated to investigating specific aspects of hepatic invasion: 1 pathogen 3D migration towards hepatocytes, 2 hepatocyte barrier crossing, 3 LSEC and subsequent hepatocyte crossing, and 4 quantification of human hepatic virus replication (HBV. Our methods comprise automated quantification of E. histolytica migration and hepatic cells layer crossing in the 3D liver models. Moreover, replication of HBV virus occurs in our virus infection 3D liver model, indicating that routine in vitro assays using HBV or others viruses can be performed in this easy-to-build but more physiological hepatic environment. These results illustrate that our new 3D liver infection models are simple but effective, enabling new investigations on infectious disease mechanisms. The

  18. Avaliação da ressecção hepática em pacientes cirróticos com carcinoma hepatocelular Evaluation of hepatic resection for hepatocellular carcinoma on cirrhotic livers

    Directory of Open Access Journals (Sweden)

    Maurício Silva

    2008-06-01

    Full Text Available RACIONAL: O carcinoma hepatocelular é uma complicação que acomete pacientes que apresentam cirrose hepática. A ressecção hepática, o transplante ortotópico de fígado e a ablação percutânea constituem opções terapêuticas com o intuito curativo. OBJETIVO: Avaliar os resultados da ressecção hepática para o tratamento do carcinoma hepatocelular, em fígados cirróticos, em um hospital geral. MÉTODOS: Foram avaliadas as características clínicas, laboratoriais, endoscópicas e histopatológicas de 22 pacientes submetidos a ressecção hepática entre os anos de 1996 e 2005, com o intuito de se avaliar a sobrevida, a identificação de fatores prognósticos e a incidência de recidiva tumoral. Para tanto, especial atenção foi dada aos níveis séricos de bilirrubinas e alfa-fetoproteína, grau de disfunção hepatocelular (avaliado pelas classificações Child-Pugh-Turcotte e " Model for End-Stage Liver Disease" - MELD, tamanho e número de tumores, invasão microvascular e presença de lesões satélites. O nível de significância utilizado foi de 95% na análise estatística. RESULTADOS: A média de idade dos pacientes estudados foi de 62,09 anos, sendo 17 do sexo masculino. Em 10 casos a cirrose hepática esteve associada à infecção crônica pelo vírus da hepatite C, em 4 à combinação do uso crônico do etanol e vírus da hepatite C, em 3 ao vírus da hepatite B, em 2 ao uso do etanol isoladamente, em 1 com uso de medicamentos e, em 2 casos, não foi identificada a causa. Dezoito pacientes apresentaram tumor único, sendo que em 11 o tumor media menos que 5 cm. A sobrevida variou entre 10 dias e 120 meses, com média de 33,5 meses. No final do 1º, 3º e 5º anos, identificou-se sobrevida de 61,90%, 16,67% e 11,11%, respectivamente. Houve três óbitos nos primeiros 3 meses posteriores à ressecção hepática. Treze óbitos foram identificados após os primeiros 3 meses, sendo que 12 casos foram relacionados

  19. Mapping the genetic architecture of gene expression in human liver.

    Directory of Open Access Journals (Sweden)

    Eric E Schadt

    2008-05-01

    Full Text Available Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large

  20. 支链氨基酸强化的肠内肠外营养对肝硬化大鼠术后肝功能及血浆氨基酸谱的影响%Effects of branched-chain amino acids-enriched early parenteral and enteral nutrition on the liver function and serum aminograms in cirrhotic rats after partial hepatectomy

    Institute of Scientific and Technical Information of China (English)

    赖佳明; 胡文杰; 王恕同; 华赟鹏; 郝元涛; 罗时敏; 赖英荣; 梁力建

    2010-01-01

    -chain amino acids-enriched early parenteral and enteral nutrition on the liver function and serum aminograms in cirrhotic rats after partial hepatectomy. Methods In this prospective randomized controlled study, 24 cirrhotic rats, induced by thioacetamide, were randomized into three groups: enteral nutrition (EN) group, EN + branched-chain amino acid (BCAA) group, and parenteral nutrition (PN) + BCAA group. After receiving partial hepatectomy, rats in all three groups were nutritionally supported with equal amount of calorie and nitrogen contents from the 1st postoperative day ( PO day 1 ) to PO day 5. On PO day 6, parameters including body weight, liver functions, prealbumin, transferring, and serum aminograms were measured or determined, and the level of liver albumin mRNA was detected by reversal transcription-polymerase chain reaction and morphological examinations such as HE staining and immunohistochemical staining, which were assessed by index of Ki67 protein index. Results Body weight was significantly decreased in all three groups on PO day 6 (P <0.05 ). Compared with EN + BCAA group, serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase after partial hepatectomy were significantly higher in PN + BCAA group (P <0.05 ). Serum alkaline phosphatase level was significantly higher in PN + BCAA group than in EN group ( P <0. 05). The level of prealbumin was significantly lower in PN + BCAA group when compared with EN group or EN +BCAA group ( both P < 0. 05 ), although no such significant difference was noted in terms of transferrin ( P >0. 05 ). The levels of leucine and isoleucine elevated while those of tyrosine, phenylalanine, arginine and tryptophan declined in PN + BCAA group or EN + BCAA group when compared with EN group ( P < 0. 05 ). Aminograms were not significantly different between EN + BCAA group and PN + BCAA group ( P > 0. 05 ). Levels of total amino acid and aromatic amino acid (AAA) were significantly lower while

  1. In vivo liver regeneration potential of human induced pluripotent stem cells from diverse origins.

    Science.gov (United States)

    Liu, Hua; Kim, Yonghak; Sharkis, Saul; Marchionni, Luigi; Jang, Yoon-Young

    2011-05-11

    Human induced pluripotent stem cells (iPSCs) are a potential source of hepatocytes for liver transplantation to treat end-stage liver disease. In vitro differentiation of human iPSCs into hepatic cells has been achieved using a multistage differentiation protocol, but whether these cells are functional and capable of engrafting and regenerating diseased liver tissue is not clear. We show that human iPSC-derived hepatic cells at various differentiation stages can engraft the liver in a mouse transplantation model. Using the same differentiation and transplantation protocols, we also assessed the ability of human iPSCs derived from each of the three developmental germ layer tissues (that is, ectoderm, mesoderm, and endoderm) to regenerate mouse liver. These iPSC lines, with similar but distinct global DNA methylation patterns, differentiated into multistage hepatic cells with an efficiency similar to that of human embryonic stem cells. Human hepatic cells at various differentiation stages derived from iPSC lines of different origins successfully repopulated the liver tissue of mice with liver cirrhosis. They also secreted human-specific liver proteins into mouse blood at concentrations comparable to that of proteins secreted by human primary hepatocytes. Our results demonstrate the engraftment and liver regenerative capabilities of human iPSC-derived multistage hepatic cells in vivo and suggest that human iPSCs of distinct origins and regardless of their parental epigenetic memory can efficiently differentiate along the hepatic lineage.

  2. Trefoil factor-3 expression in human colon cancer liver metastasis.

    Science.gov (United States)

    Babyatsky, Mark; Lin, Jing; Yio, Xianyang; Chen, Anli; Zhang, Jie-yu; Zheng, Yan; Twyman, Christina; Bao, Xiuliang; Schwartz, Myron; Thung, Swan; Lawrence Werther, J; Itzkowitz, Steven

    2009-01-01

    Deaths from colorectal cancer are often due to liver metastasis. Trefoil factor-3 (TFF3) is expressed by normal intestinal epithelial cells and its expression is maintained throughout the colon adenoma-carcinoma sequence. Our previous work demonstrated a correlation between TFF3 expression and metastatic potential in an animal model of colon cancer. The aim of this study was to determine whether TFF3 is expressed in human colon cancer liver metastasis (CCLM) and whether inhibiting TFF3 expression in colon cancer cells would alter their invasive potential in vitro. Human CCLMs were analyzed at the mRNA and protein level for TFF3 expression. Two highly metastatic rat colon cancer cell lines that either natively express TFF3 (LN cells) or were transfected with TFF3 (LPCRI-2 cells), were treated with two rat TFF3 siRNA constructs (si78 and si365), and analyzed in an in vitro invasion assay. At the mRNA and protein level, TFF3 was expressed in 17/17 (100%) CCLMs and 10/11 (91%) primary colon cancers, but not in normal liver tissue. By real time PCR, TFF3 expression was markedly inhibited by both siRNA constructs in LN and LPCRI-2 cells. The si365 and si78 constructs inhibited invasion by 44% and 53%, respectively, in LN cells, and by 74% and 50%, respectively, in LPCRI-2 cells. These results provide further evidence that TFF3 contributes to the malignant behavior of colon cancer cells. These observations may have relevance for designing new diagnostic and treatment approaches to colorectal cancer.

  3. Antiviral therapy in hepatitis C virus cirrhotic patients in compensated and decompensated condition

    Institute of Scientific and Technical Information of China (English)

    Angelo Iacobellis; Antonio Ippolito; Angelo Andriulli

    2008-01-01

    The main goals of treating cirrhotic patients with antiviral therapy are to attain sustained viral clearance (SVR), halt disease progression, and prevent re-infection of the liver graft. However, while the medical need is great, the use of interferon and ribavirin might expose these patients to severe treated-related side effects as a large proportion of them have pre-existing hematological cytopenias. We have reviewed potential benefits and risks associated with antiviral drugs in patients with liver cirrhosis, due to hepatitis C virus (HCV) infection. In cases presenting with bridging fibrosis or cirrhosis, current regimens of antiviral therapy have attained a 44%-48% rate of SVR. In cirrhotic patients with portal hypertension, the SVR rate was 22% overall, 12.5% in patients with genotype 1, and 66.7% in those with genotypes 2 and 3 following therapy with low doses of either Peg-IFN alpha-2b and of ribavirin. In patients with decompensated cirrhosis, full dosages of Peg-IFN alpha-2b and of ribavirin produced a SVR rate of 35% overall, 16% in patients with genotype 1 and 4, and 59% in those with genotype 2 and 3. Use of hematological cytokines will either ensure full course of treatment to be accomplished with and prevent development of treatment-associated side effects. Major benefits after HCV eradication were partial recovery of liver metabolic activity, prevention of hepatitis C recurrence after transplantation, and removal of some patients from the waiting list for liver transplant. Several observations highlighted that therapy is inadvisable for individuals with poor hepatic reserve (ChUd-Pugh-Turcotte score ≥ 10). Although SVR rates are low in decompensated cirrhotics due to hepatitis C, these patients have the most to gain as successful antiviral therapy is potentially lifesaving. C 2008 The W.1G Press. All dghts reserved.

  4. Con A affinity glycoproteomics of normal human liver tissue

    Institute of Scientific and Technical Information of China (English)

    SUN QiangLing; LU HaoJie; LIU YinKun; LU WenJing; CHENG Gang; ZHOU HaiJun; ZHOU XinWen; WEI LiMing; DAI Zhi; GUO Kun

    2007-01-01

    In order to establish the novel high throughput, high efficiency and Iow cost technological platform for the research of N-glycoproteomics, to resolve the significance of characteristic expression profile of glycoprotein and to find the proteins with biological functional importance, the glycoproteins with high-mannose core and the two antennary types were purified and enriched by the Con A affinity chromatography. Con A affinity protein expression profiles of normal human liver tissue were generated by using SDS-PAGE, two-dimensional electrophoresis (2-DE) followed by fast fluorescence staining based on multiplexed proteomics (MP) technology. 301 visible protein spots on the gel were detected and 85 of glycoproteins were further successfully identified via peptide mass fingerprinting (PMF) by a matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS/MS) and annotated to IPI databases. Identified glycoproteins definitely take part in the regulation of cell cycle and metabolic processes. The glycosylation sites were predicted with NetNGlyc 1.0 and NetOGlyc 3.1 software, meanwhile they were classified according to the geneontology methods. The construction of Con A affinity glycoprotein database of normal human liver tissue would contribute to the subsequent research.

  5. Con A affinity glycoproteomics of normal human liver tissue

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In order to establish the novel high throughput, high efficiency and low cost technological platform for the research of N-glycoproteomics, to resolve the significance of characteristic expression profile of glycoprotein and to find the proteins with biological functional importance, the glycoproteins with high-mannose core and the two antennary types were purified and enriched by the Con A affinity chromatography. Con A affinity protein expression profiles of normal human liver tissue were gener- ated by using SDS-PAGE, two-dimensional electrophoresis (2-DE) followed by fast fluorescence stain- ing based on multiplexed proteomics (MP) technology. 301 visible protein spots on the gel were de- tected and 85 of glycoproteins were further successfully identified via peptide mass fingerprinting (PMF) by a matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF- MS/MS) and annotated to IPI databases. Identified glycoproteins definitely take part in the regulation of cell cycle and metabolic processes. The glycosylation sites were predicted with NetNGlyc 1.0 and NetOGlyc 3.1 software, meanwhile they were classified according to the geneontology methods. The construction of Con A affinity glycoprotein database of normal human liver tissue would contribute to the subsequent research.

  6. Adult human liver mesenchymal progenitor cells express phenylalanine hydroxylase.

    Science.gov (United States)

    Baruteau, Julien; Nyabi, Omar; Najimi, Mustapha; Fauvart, Maarten; Sokal, Etienne

    2014-09-01

    Phenylketonuria (PKU) is one of the most prevalent inherited metabolic diseases and is accountable for a severe encephalopathy by progressive intoxication of the brain by phenylalanine. This results from an ineffective L-phenylalanine hydroxylase enzyme (PAH) due to a mutated phenylalanine hydroxylase (PAH) gene. Neonatal screening programs allow an early dietetic treatment with restrictive phenylalanine intake. This diet prevents most of the neuropsychological disabilities but remains challenging for lifelong compliance. Adult-derived human liver progenitor cells (ADHLPC) are a pool of precursors that can differentiate into hepatocytes. We aim to study PAH expression and PAH activity in a differenciated ADHLPC. ADHLPC were isolated from human hepatocyte primary culture of two different donors and differenciated under specific culture conditions. We demonstrated the high expression of PAH and a large increase of PAH activity in differenciated LPC. The age of the donor, the cellular viability after liver digestion and cryopreservation affects PAH activity. ADHLPC might therefore be considered as a suitable source for cell therapy in PKU.

  7. Experimental models for induction of liver cirrhosis in animals: a review

    Directory of Open Access Journals (Sweden)

    Cristiane Carlin Passos

    2010-06-01

    Full Text Available The liver plays a key role in the homeostatic balance of many biological processes. Cirrhosis is a syndrome in which chronic liver diseases converge, leading to hepatocellular injury, the exacerbated deposition of fibrous tissue, and eventually the disruption of the tissue architecture. The liver is subject to potential injury by a large quantity of pharmacological agents, toxic and/or microbiological. For the study of possible treatments for cirrhosis, it is necessary to establish animal models of induction of cirrhosis, especially in laboratory rodents which mimic the cirrhotic process found in animals and humans, that have high reproducibility and uniformity, with a low mortality rate. Thus, the induction of liver cirrhosis becomes essential to the investigation of chronic liver diseases, as well as to test possible therapeutic treatments for subsequent use in human and veterinary clinics. Currently, experimental studies have been conducted to collect data about the various hepatotoxic drug effects. Carbon tetrachloride -CCl4, Thioacetamide –TAA and dimethylnitrosamine -DMN were the drugs of choice for cirrhosis induction in experimental models in this study. The model using cirrhotic TAA seems to be the best model for the reason that it produces a histological pattern closest to that of human cirrhosis, leading to lower mortality with higher reproducibility and security, despite the longer period of induction (14 weeks.

  8. [Diabetes in liver cirrhosis].

    Science.gov (United States)

    García-Compeán, Diego; Jáquez-Quintana, Joel O; González-González, José A; Lavalle-González, Fernando J; Villarreal-Pérez, Jesús Z; Maldonado-Garza, Hector J

    2013-01-01

    The prevalence of overt diabetes mellitus (DM) in liver cirrhosis is about 30%. However, DM or impaired glucose tolerance can be observed in 90% after an oral glucose tolerance test in patients with normal fasting plasma glucose. Type 2 DM may produce cirrhosis, whereas DM may be a complication of cirrhosis. The latter is known as «hepatogenous diabetes». Overt and subclinical DM is associated with liver complications and death in cirrhotic patients. Treating diabetes is difficult in cirrhotic patients because of the metabolic impairments due to liver disease and because the most appropriate pharmacologic treatment has not been defined. It is also unknown if glycemic control with hypoglycemic agents has any impact on the course of the liver disease. Copyright © 2013 Elsevier España, S.L. y AEEH y AEG. All rights reserved.

  9. Adiponectin and its receptors in rodent models of fatty liver disease and liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Markus Neumeier; Jürgen Sch(o)lmerich; Christa Buechler; Claus Hellerbrand; Erwin G(a)bele; Roland Buettner; Cornelius Bollheimer; Johanna Weigert; Andreas Sch(a)ffler; Thomas S Weiss; Monika Lichtenauer

    2006-01-01

    AIM: To determine circulating and hepatic adiponectin in rodents with fatty liver disease or liver cirrhosis and investigate expression of the adiponectin receptors AdipoR1 on the mRNA and protein level and AdipoR2 on the mRNA level.METHODS: Fat fed rats were used as a model for fatty liver disease and bile duct ligation in mice to investigate cirrhotic liver. Expression of AdipoR1 and AdipoR2 mRNA was determined by real time RT-PCR. AdipoR1 protein was analysed by immunoblot. Adiponectin was measured by ELISA.RESULTS: Systemic adiponectin is reduced in fat fed rats but is elevated in mice after bile duct ligation (BDL). Hepatic adiponectin protein is lower in steatotic liver but not in the liver of BDL-mice when compared to controls. Adiponectin mRNA was not detected in human liver samples or primary human hepatocytes nor in rat liver but recombinant adiponectin is taken up by isolated hepatocytes in-vitro. AdipoR1 mRNA and AdipoR1 protein levels are similar in the liver tissue of control and fat fed animals whereas AdipoR2 mRNA is induced. AdipoR2 mRNA and AdipoR1 mRNA and protein is suppressed in the liver of BDL-mice.CONCLUSION: Our studies show reduced circulating adiponectin in a rat model of fatty liver disease whereas circulating adiponectin is elevated in a mouse model of cirrhosis and similar findings have been described in humans. Diminished hepatic expression of adiponectin receptors was only found in liver cirrhosis.

  10. Application of chimeric mice with humanized liver for study of human-specific drug metabolism.

    Science.gov (United States)

    Bateman, Thomas J; Reddy, Vijay G B; Kakuni, Masakazu; Morikawa, Yoshio; Kumar, Sanjeev

    2014-06-01

    Human-specific or disproportionately abundant human metabolites of drug candidates that are not adequately formed and qualified in preclinical safety assessment species pose an important drug development challenge. Furthermore, the overall metabolic profile of drug candidates in humans is an important determinant of their drug-drug interaction susceptibility. These risks can be effectively assessed and/or mitigated if human metabolic profile of the drug candidate could reliably be determined in early development. However, currently available in vitro human models (e.g., liver microsomes, hepatocytes) are often inadequate in this regard. Furthermore, the conduct of definitive radiolabeled human ADME studies is an expensive and time-consuming endeavor that is more suited for later in development when the risk of failure has been reduced. We evaluated a recently developed chimeric mouse model with humanized liver on uPA/SCID background for its ability to predict human disposition of four model drugs (lamotrigine, diclofenac, MRK-A, and propafenone) that are known to exhibit human-specific metabolism. The results from these studies demonstrate that chimeric mice were able to reproduce the human-specific metabolite profile for lamotrigine, diclofenac, and MRK-A. In the case of propafenone, however, the human-specific metabolism was not detected as a predominant pathway, and the metabolite profiles in native and humanized mice were similar; this was attributed to the presence of residual highly active propafenone-metabolizing mouse enzymes in chimeric mice. Overall, the data indicate that the chimeric mice with humanized liver have the potential to be a useful tool for the prediction of human-specific metabolism of xenobiotics and warrant further investigation.

  11. Diabetes: one of few remarkable differences in clinicopathologic features between cirrhotic and noncirrhotic Swedes with hepatocellular carcinoma.

    Science.gov (United States)

    Kaczynski, Jerzy; Hansson, Göran; Wallerstedt, Sven

    2006-04-01

    The prognosis of hepatocellular carcinoma (HCC) is usually very poor, so increased knowledge of clinicopathologic characteristics and etiologic factors may improve the clinical handling. Because HCC in many patients is unrecognized before death, it is of particular interest to study cases from a period with a high autopsy frequency. The records and liver biopsies from all patients with a diagnosis of primary liver cancer in Göteborg, Sweden, during a 22-year period were scrutinized. Only patients with evaluable non-neoplastic liver tissue were included in the final analysis. The majority (95%) of 478 HCC cases were autopsied and cirrhosis of the liver could be established in 71%. At presentation, general paramalignant symptoms such as malaise, weight loss, anorexia, and hepatomegaly (84%) were common irrespective of cirrhosis. Alcoholism and diabetes mellitus were each significantly more common among cirrhotics (29% and 20%, respectively; P diabetes and cirrhosis was independent of reported alcoholism. In an unselected population in a low HCC incidence area, there are few differences in clinicopathologic features between cirrhotic and noncirrhotic patients. Diabetes mellitus seems to play an etiologic role in HCC in cirrhotics, and cholelithiasis in noncirrhotics.

  12. Vascular endothelial growth factor attenuates hepatic sinusoidal capillarization in thioacetamide-induced cirrhotic rats

    Institute of Scientific and Technical Information of China (English)

    Hao Xu; Bao-Min Shi; Xiao-Fei Lu; Feng Liang; Xing Jin; Tai-Huang Wu; Jian Xu

    2008-01-01

    AIM: To investigate the effect of vascular endothelial growth factor (VEGF) transfection on hepatic sinusoidal capillarization.MEthODS: Enhanced green fluorescent protein (EGFP)/VEGF transfection was confirmed by immunofluorescencemicroscopy and immunohistoche-mistry both in primaryhepatocytes and in normal liven Cirrhotic rats weregenerated by thioacetamide (TAA) administration andthen divided into a treatment group, which receivedinjections of 400 μg of plasmid DNA encoding an EGFP-VEGF fusion protein, and a blank group, which receivedan equal amount of normal saline through the portalvein. The portal vein pressure was measured in the normal and cirrhotic state, in treated and blank groups.The average number of fenestrae per hepatic sinusoidwas determined using transmission electron microscopy(TEM), while the relative abundance of VEGF transcriptswas examined by Gene array.RESULTS: Green fluorescent protein was observed in the cytoplasms of liver cells under immunofluorescence microscopy 24 h after transfection with EGFP/VEGFplasmid in vitro. Staining with polyclonal antibodies against VEGF illustrated that hepatocytes expressed immunodetectable VEGF both in vitro and in vitro. There were significant differences in the number of fenestrae and portal vein pressures between normal and cirrhotic rats (7.40±1.71 vs 2.30± 2.26 and 9.32± 0.85 cmH2Ovs 27.92± 0.90 cmH2O1, P < 0.02), between cirrhotic and treated rats (2.30 + 1.16 cmH2O vs 4.60± 1.65 and 17.92± 0.90 cmH2O vs 15.52±0.93 cmH20, P < 0.05)and between the treatment group and the blank group (4.60±1.65 cmH20 vs 2.10 ± 1.10 cmH20 and 25.52 +0.93 cmH20 vs 17.26 ± 1.80 cmH20, P < 0.05). Gene-array analysis revealed that the relative abundance oftranscripts of VEGF family members decreased in the cirrhotic state and increased after transfection. CONCLUSION: Injection of a plasmid encoding VEGFthrough the portal vein is an effective method toinduce the formation of fenestrae and decrease portalvein

  13. Role of the heme oxygenases in abnormalities of the mesenteric circulation in cirrhotic rats.

    Science.gov (United States)

    Sacerdoti, David; Abraham, Nader G; Oyekan, Adebayo O; Yang, Liming; Gatta, Angelo; McGiff, John C

    2004-02-01

    Carbon monoxide (CO), a product of heme metabolism by heme-oxygenase (HO), has biological actions similar to those of nitric oxide (NO). The role of CO in decreasing vascular responses to constrictor agents produced by experimental cirrhosis induced by carbon tetrachloride was evaluated before and after inhibition of HO with tin-mesoporphyrin (SnMP) in the perfused superior mesenteric vasculature (SMV) of cirrhotic and normal rats and in normal rats transfected with the human HO-1 (HHO-1) gene. Perfusion pressure and vasoconstrictor responses of the SMV to KCl, phenylephrine (PE), and endothelin-1 (ET-1) were decreased in cirrhotic rats. SnMP increased SMV perfusion pressure and restored the constrictor responses of the SMV to KCl, PE, and ET-1 in cirrhotic rats. The relative roles of NO and CO in producing hyporeactivity of the SMV to PE in cirrhotic rats were examined. Vasoconstrictor responses to PE were successively augmented by stepwise inhibition of CO and NO production, suggesting a complementary role for these gases in the regulation of reactivity of the SMV. Expression of constitutive but not of inducible HO (HO-1) was increased in the SMV of cirrhotic rats as was HO activity. Administration of adenovirus containing HHO-1 gene produced detection of HHO-1 RNA and increased HO activity in the SMV within 7 days. Rats transfected with HO-1 demonstrated reduction in both perfusion pressure and vasoconstrictor responses to PE in the SMV. We propose that HO is an essential component in mechanisms that modulate reactivity of the mesenteric circulation in experimental hepatic cirrhosis in rats.

  14. Per rectal portal scintigraphy as a useful tool for predicting esophageal variceal bleeding in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Taned Chitapanarux; Ong-ard Praisontarangkul; Satawat Thongsawat; Pises Pisespongsa; Apinya Leerapun

    2007-01-01

    AIM: To investigate potential roles of per rectal portal scintigraphy in diagnosis of esophageal varices and predicting the risk of bleeding.METHODS: Fifteen normal subjects and fifty cirrhotic patients with endoscopically confirmed esophageal varices were included. Patients were categorized into bleeder and non-bleeder groups according to history of variceal bleeding. All had completed per rectal portal scintigraphy using 99mTechnetium pertechnetate.The shunt index was calculated from the ratio of 99mTechnetium pertechnetate in the heart and the liver.Data were analyzed using Student's t-test and receiver operating characteristics.RESULTS: Cirrhotic patients showed a higher shunt index than normal subjects (63.80 ± 25.21 vs 13.54 ± 6.46, P < 0.01). Patients with variceal bleeding showed a higher shunt index than those without bleeding (78.45 ± 9.40 vs 49.35 ± 27.72, P < 0.01). A shunt index of over 20% indicated the presence of varices and that of over 60% indicated the risk of variceal bleeding.CONCLUSION: In cirrhotic patients, per rectal portal scintigraphy is a clinically useful test for identifying esophageal varices and risk of variceal bleeding.

  15. Autoimmune thrombocytopenia in response to splenectomy in cirrhotic patients with accompanying hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Tetsuro Sekiguchi; Takeaki Nagamine; Hitoshi Takagi; Masatomo Mori

    2006-01-01

    AIM: To estimate the contribution of autoimmune thrombocytopenia to hepatitis C virus-related liver cirrhosis (type C cirrhosis), we evaluated the influence of splenectomy upon platelet-associated immunoglobulin G (PAIgG) levels and platelet numbers.METHODS: PAIgG titers and immune markers were determined in 24 type C cirrhotic patients with an intact spleen, 17 type C cirrhotic patients submitted to splenectomy, and 21 non-C cirrhosis with an intact spleen.RESULTS: Thrombocytopenia (PLT<15×104/μL) in type C cirrhosis was diagnosed in all patients with an intact spleen, 8 patients submitted to splenectomy, and in 19 non-C cirrhosis with intact spleen. Elevated titers of PAIgG at more than 25.0 ng/107 cells were detected in all cirrhotic patients except for one splenectomized patient.PAIgG titers (ng/107 cells) were significantly higher in the type C cirrhosis with an intact spleen (247.9 ± 197.0)compared with the splenectomized patients (125.6±87.8)or non-C cirrhosis (152.4± 127.4). PAIgG titers were negatively correlated with platelet counts in type C cirrhotic patients with an intact spleen. In comparison with the type C cirrhosis with an intact spleen, the splenectomized patients had a reduced CD4/CD8 ratio and serum neopterin levels. The spleen index (cm2) was negatively correlated with platelet counts in the non-C cirrhosis, but not in the type C cirrhosis.CONCLUSION: Our data indicate that the autoimmune mechanism plays an important role in thrombocytosis complicated by HCV-positive cirrhosis. In addition,splenectomy may impair T ceils function through, at least in part, a reduction of CD4/CD8 ratio, consequently suppressing PAIgG production.

  16. Malabsorption in cirrhosis of the liver

    Directory of Open Access Journals (Sweden)

    Patwardhan R

    1977-01-01

    Full Text Available Gastrointestinal function of absorption has been studied in twenty biopsy proved cases of cirrhosis of the liver. The gastro-intestinal function was assessed by means of glucose and lactose tolerance tests and by fecal fat, d-Xylose and Co 57 B 12 excretion tests. Steatorrhoea and lactose intolerance are common in cir-rhotics. The etiopathogenesis of this malabsorption in cirrhotics is discussed and appears multifactorial in origin.

  17. Expression of local renin and angiotensinogen mRNA in cirrhotic portal hypertensive patient

    Institute of Scientific and Technical Information of China (English)

    Li Zhang; Zhen Yang; Bao-Min Shi; Da-Peng Li; Chong-Yun Fang; Fa-Zu Qiu

    2003-01-01

    AIM: To investigate the expression of local renin and angiotensinogen mRNA in cirrhotic portal hypertensive patients.METHODS: The expression of local renin and angiotensinogen mRNA in the liver, splenic artery and vein of PH patients was detected by RT-PCR analysis.RESULTS: Expression of local renin mRNA in the liver of control group was (0.19±0.11), significantly lower than that in splenic artery(0.45±0.17)or splenic vein(0.39±0.12)respectively, (P<0.05). Expression of local angiotensinogen mRNA in the liver was (0.64±0.21), significantly higher than that in splenic artery(0.41±0.15) or in splenic vein (0.35±0.18)respectively, (P<0.05). Expression of local renin mRNA in the liver, splenic artery and vein of PH group was (0.78±0.28),(0.86±0.35) and (0.81±0.22) respectively, significantly higher than that in the control group, (P<0.05). Expression of local angiotensinogen mRNA in the liver, splenic artery and vein of PH group was (0.96±0.25), (0.83±0.18) and (0.79±0.23)respectively, significantly higher than that in the control group,(P<0.05). There was no significant difference between the liver, splenic artery and vein in the expression of local renin or local angiotensinogen mRNA in PH group, (P<0.05).CONCLUSION: In normal subjects the expression of local renin and angiotensinogen mRNA was organ specific, but with increase of the expression of LRAS, the organ-specificity became lost in cirrhotic patients. LRAS may contribute to increased resistance of portal vein with liver and formation of splanchnic vasculopathy.

  18. Hepatic progenitor cells in human liver tumor development

    Institute of Scientific and Technical Information of China (English)

    Louis Libbrecht

    2006-01-01

    In recent years, the results of several studies suggest that human liver tumors can be derived from hepatic progenitor cells rather than from mature cell types.The available data indeed strongly suggest that most combined hepatocellular-cholangiocarcinomas arise from hepatic progenitor cells that retained their potential to differentiate into the hepatocytic and biliary lineages.Hepatic progenitor cells could also be the basis for some hepatocellular carcinomas and hepatocellular adenomas, although it is very difficult to determine the origin of an individual hepatocellular carcinoma. There is currently not enough data to make statements regarding a hepatic progenitor cell origin of cholangiocarcinoma.The presence of hepatic progenitor cell markers and the presence and extent of the cholangiocellular component are factors that are related to the prognosis of hepatocellular carcinomas and combined hepatocellularcholangiocarcinomas, respectively.

  19. Is administrating branched-chain amino acid-enriched nutrition achieved symptom-free in malnourished cirrhotic patients?

    OpenAIRE

    Tsuda, Yasuhiro; Fukui, Hideo; Sujishi, Tetsuya; Ohama, Hideko; Tsuchimoto, Yusuke; Asai, Akira; Fukunisi, Shinya; Higuchi, Kazuhide

    2013-01-01

    Administration of branched-chain amino acids (BCAA) has been reported to improve liver function, quality of life (QOL). However, in some malnourished patients, serum albumin levels do not improve in response to BCAA granules. In this study, we examined the effects of BCAA-enriched enteral nutrition in patients unresponsive to BCAA granules. Thirty-two decompensated cirrhotic patients at Osaka Medical College were enrolled in this study. Since all patients showed no improvement in serum albumi...

  20. PARTIAL PORTOSYSTEMIC SHUNTING BY CARBON-COATED ePTFE GRAFTS FOR PORTAL HYPERTENSION IN CIRRHOTIC PATIENTS

    Directory of Open Access Journals (Sweden)

    I. A. Porshennikov

    2010-01-01

    Full Text Available We present our first experience gained in use of polytetrafluoroethylene carbon-coated grafts for partial portosystemic shunting in three cirrhotic patients. The results obtained indicate that these grafts in mesocaval position can function as a long-term «bridge» to hepatic transplantation in patients with uncontrolled gastroesophageal varices. The different options of portal hypertension treatment and the current role of shunting procedures in the era of liver transplantation are discussed in short literature review. 

  1. Effect of the Human Amniotic Membrane on Liver Regeneration in Rats

    Science.gov (United States)

    Sipahi, Mesut; Şahin, Sevinç; Arslan, Ergin; Börekci, Hasan; Metin, Bayram; Cantürk, Nuh Zafer

    2015-01-01

    Introduction. Operations are performed for broader liver surgery indications for a better understanding of hepatic anatomy/physiology and developments in operation technology. Surgery can cure some patients with liver metastasis of some tumors. Nevertheless, postoperative liver failure is the most feared complication causing mortality in patients who have undergone excision of a large liver mass. The human amniotic membrane has regenerative effects. Thus, we investigated the effects of the human amniotic membrane on regeneration of the resected liver. Methods. Twenty female Wistar albino rats were divided into control and experimental groups and underwent a 70% hepatectomy. The human amniotic membrane was placed over the residual liver in the experimental group. Relative liver weight, histopathological features, and biochemical parameters were assessed on postoperative day 3. Results. Total protein and albumin levels were significantly lower in the experimental group than in the control group. No difference in relative liver weight was observed between the groups. Hepatocyte mitotic count was significantly higher in the experimental group than in the control group. Hepatic steatosis was detected in the experimental group. Conclusion. Applying the amniotic membrane to residual liver adversely affected liver regeneration. However, mesenchymal stem cell research has the potential to accelerate liver regeneration investigations. PMID:26457000

  2. Effect of the Human Amniotic Membrane on Liver Regeneration in Rats

    Directory of Open Access Journals (Sweden)

    Mesut Sipahi

    2015-01-01

    Full Text Available Introduction. Operations are performed for broader liver surgery indications for a better understanding of hepatic anatomy/physiology and developments in operation technology. Surgery can cure some patients with liver metastasis of some tumors. Nevertheless, postoperative liver failure is the most feared complication causing mortality in patients who have undergone excision of a large liver mass. The human amniotic membrane has regenerative effects. Thus, we investigated the effects of the human amniotic membrane on regeneration of the resected liver. Methods. Twenty female Wistar albino rats were divided into control and experimental groups and underwent a 70% hepatectomy. The human amniotic membrane was placed over the residual liver in the experimental group. Relative liver weight, histopathological features, and biochemical parameters were assessed on postoperative day 3. Results. Total protein and albumin levels were significantly lower in the experimental group than in the control group. No difference in relative liver weight was observed between the groups. Hepatocyte mitotic count was significantly higher in the experimental group than in the control group. Hepatic steatosis was detected in the experimental group. Conclusion. Applying the amniotic membrane to residual liver adversely affected liver regeneration. However, mesenchymal stem cell research has the potential to accelerate liver regeneration investigations.

  3. Endotoxemia, encephalopathy, and mortality in cirrhotic patients.

    Science.gov (United States)

    Bigatello, L M; Broitman, S A; Fattori, L; Di Paoli, M; Pontello, M; Bevilacqua, G; Nespoli, A

    1987-01-01

    Endotoxemia without sepsis was detected with a chromogenic Limulus assay in 36 of 39 (92.3%) cirrhotic patients and was absent in seven healthy volunteers. In 11 patients who underwent elective portasystemic shunt, portal vein endotoxemia was higher than inferior vena caval: p less than 0.05, systemic endotoxin levels did not change, compared to preoperative levels, on the 1st, 2nd, and 3rd postoperative days, attendant to an uneventful recovery. In 21 patients in hepatic encephalopathy after esophagogastric hemorrhage, systemic endotoxemia was higher than in well-compensated cirrhotics: p less than 0.001; it was higher in deep than in light coma: p less than 0.05; it was higher in those who died than in those who survived: p less than 0.001. Endotoxin levels showed a positive correlation with serum bilirubin: r = 0.59, p less than 0.001, and a negative correlation with prothrombin activity: r = -0.59, p less than 0.001. These data show endotoxemia without sepsis is a constant finding in cirrhosis and increasing levels of endotoxemia are associated with hepatic failure, encephalopathy, and death.

  4. [Cardiomyopathy in liver cirrhosis--an undiagnosed entity?].

    Science.gov (United States)

    Burcă, Paula; Mihai, B; Mihai, Cătălina; Drug, V L; Dranga, Mihaela; Lăcătuşu, Cristina; Prelipcean, Cristina Cijevschi

    2010-01-01

    Cirrhotic cardiomyopathy is a condition recently known in liver cirrhosis consisting of systolic dysfunction to stress factors, diastolic dysfunction and electrophysiological abnormalities in the absence of cardiac disease. The prevalence of cirrhotic cardiomyopathy remains unknown until now. It can be diagnosed by using a combination of electrocardiograph, 2-dimensional echocardiography, and various serum markers (brain natriuretic factor--BNP, proBNP, TnI). Pathogenic mechanisms underlying cirrhotic cardiomyopathy development include abnormal signaling betaadrenergic, cardiomyocites membrane fluidity changes, interstitial fibrosis, myocardial hypertrophy, altered transmembrane ion channels as intervention with negative inotropic effect of different substances whose concentration is increased in cirrhosis. Major stresses on the cardiovasculary system such as liver transplantations, infections, insertion of transjugular portosystemic stent-shunt (TIPSS) have been demonstrated to put in evidence the presence of cirrhotic cardiomyopathy. Heart failure is a significant cause of mortality after liver transplantation but the improvement of liver function determines cardiac abnormalities reversal. Current management recommendations include empirical, nonspecific and mainly supportive measures, no specific treatment can be recommended, and cardiac failure should be treated as in non-cirrhotic patients with sodium restriction, diuretics, and oxygen therapy when necessary. The exact prognosis remains unclear. The extent of cirrhotic cardiomyopathy generally correlates to the degree of liver insufficiency. Reversibility is possible (either pharmacological or after liver transplantation), but further studies are needed.

  5. Motor vehicle accidents: How should cirrhotic patients be managed?

    Science.gov (United States)

    Kawaguchi, Takumi; Taniguchi, Eitaro; Sata, Michio

    2012-01-01

    Motor vehicle accidents (MVAs) are serious social issues worldwide and driver illness is an important cause of MVAs. Minimal hepatic encephalopathy (MHE) is a complex cognitive dysfunction with attention deficit, which frequently occurs in cirrhotic patients independent of severity of liver disease. Although MHE is known as a risk factor for MVAs, the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown. Recently, Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test (ICT), and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs. Besides the ICT and lactulose, there are various diagnostic tools and therapeutic strategies for MHE. In this commentary, we discussed a current issue of diagnostic tools for MHE, including neuropsychological tests. We also discussed the advantages of the other therapeutic strategies for MHE, such as intake of a regular breakfast and coffee, and supplementation with zinc and branched chain amino acids, on the MVA-related societal costs. PMID:22690067

  6. Motor vehicle accidents: How should cirrhotic patients be managed?

    Institute of Scientific and Technical Information of China (English)

    Takumi Kawaguchi; Eitaro Taniguchi; Michio Sata

    2012-01-01

    Motor vehicle accidents (MVAs) are serious social issues worldwide and driver illness is an important cause of MVAs.Minimal hepatic encephalopathy (MHE) is a complex cognitive dysfunction with attention deficit,which frequently occurs in cirrhotic patients independent of severity of liver disease.Although MHE is known as a risk factor for MVAs,the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown.Recently,Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test (ICT),and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs,Besides the ICT and lactulose,there are various diagnostic tools and therapeutic strategies for MHE.In this commentary,we discussed a current issue of diagnostic tools for MHE,including neuropsychological tests.We also discussed the advantages of the other therapeutic strategies for MHE,such as intake of a regular breakfast and coffee,and supplementation with zinc and branched chain amino acids,on the MVA-related societal costs.

  7. The role and regulation of the peroxisome proliferator activated receptor alpha in human liver.

    Science.gov (United States)

    Kersten, Sander; Stienstra, Rinke

    2017-05-01

    The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is abundantly expressed in liver. PPARα is activated by fatty acids and various other lipid species, as well as by a class of chemicals referred to as peroxisome proliferators. Studies in mice have shown that PPARα serves as the master regulator of hepatic lipid metabolism during fasting. In addition, PPARα suppresses inflammation and the acute phase response. Comparatively little is known about PPARα in human liver. Here, an overview is provided of the role and regulation of PPARα in human liver. The main outcomes are: 1) the level of PPARA mRNA expression in human and mouse liver is similar. 2) Expression of PPARA in human liver is reduced in patients with non-alcoholic steatohepatitis or infected with the hepatitis C virus. 3) PPARα in human liver is able to effectively induce the expression of numerous genes involved in numerous lipid metabolic pathways, including microsomal, peroxisomal and mitochondrial fatty acid oxidation, fatty acid binding and activation, fatty acid elongation and desaturation, synthesis and breakdown of triglycerides and lipid droplets, lipoprotein metabolism, gluconeogenesis, bile acid metabolism, and various other metabolic pathways and genes. 4) PPARα activation in human liver causes the down-regulation of a large number of genes involved in various immunity-related pathways. 5) Peroxisome proliferators do not promote tumour formation in human liver as opposed to mouse liver because of structural and functional differences between human and mouse PPARα. 6) In addition to helping to correct dyslipidemia, PPARα agonists may hold promise as a therapy for patients with cholestatic liver diseases, non-alcoholic fatty liver disease, and/or type 2 diabetes. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  8. Photoacoustic physio-chemical analysis of liver conditions in animal and human subjects

    Science.gov (United States)

    Wang, Xueding; Xu, Guan; Tian, Chao; Wan, Shanshan; Welling, Theodore H.; Lok, Anna S. F.; Rubin, Jonathan M.

    2016-03-01

    Non-alcoholic fatty liver disease (NAFLD) is a common liver disease affecting 30% of the population in the United States. Biopsy is the gold standard for diagnosing NAFLD. Liver histology assesses the amount of fat, and determines type and extent of cell injury, inflammation and fibrosis. However, liver biopsy is invasive and is limited by sampling error. Current radiological diagnostic modalities can evaluate the 'physical' morphology in liver by quantifying the backscattered US signals, but cannot interrogate the 'histochemical' components forming these backscatterers. For example, ultrasound (US) imaging can detect the presence of fat but cannot differentiate steatosis alone from steatohepatitis. Our previous study of photoacoustic physiochemical analysis (PAPCA) has demonstrated that this method can characterize the histological changes in livers during the progression of NAFLD in animal models. In this study, we will further validate PAPCA with human livers. Ex vivo human liver samples with steatosis, fibrosis and cirrhosis will be scanned using optical illumination at wavelengths of 680-1700 nm and compared to histology results. In vivo study on human subjects with confirmed steatosis is planned using our PA-ultrasound (US) parallel imaging system based on Verasonic US imaging flatform with an L7-4 probe. 10 mJ/cm2 per pulse optical energy at 755 nm will be delivered to the skin surface, which is under the safety limit of American National Standard Institute. Preliminary study with ex vivo human tissue has demonstrated the potential of the proposed approach in differentiating human liver conditions.

  9. Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats Papel da N-acetilcisteína na fibrose e estresse oxidativo em ratos cirróticos

    Directory of Open Access Journals (Sweden)

    Gustavo Pereira-Filho

    2008-06-01

    Full Text Available BACKGROUND: Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis which is the main response to the liver injury. The inhalatory carbon tetrachloride is an effective experimental model that triggers cirrhosis and allows to obtain histological and physiological modifications similar to the one seen in humans. AIM: To investigate the effects of N-acetylcysteine (NAC on the fibrosis and oxidative stress in the liver of cirrhotic rats, analyzing liver function tests, lipoperoxidation, activity of glutathione peroxidase enzyme, collagen quantification, histopathology, as well as the nitric oxide role. METHODS: The animals were randomly in three experimentals groups: control (CO; cirrhotic (CCl4 and CCl4 + NAC. Evaluate the lipid peroxidation, the glutathione peroxidase enzyme, the collagen and the expression of inducible nitric oxide synthase (iNOS. RESULTS: The cirrhotic group treated with N-acetylcysteine showed trough the histological analysis and collagen quantification lower degrees of fibrosis. This group has also shown less damage to the cellular membranes, less decrease on the glutathione peroxidase levels and less expression of inducible nitric oxide synthase when matched with the cirrhotic group without treatment. CONCLUSION: N-acetylcysteine seams to offer protection against hepatic fibrosis and oxidative stress in cirrhotic rat livers.RACIONAL: A cirrose é o estágio final da disfunção hepática, sendo caracterizada por fibrose difusa, que compõe a resposta principal do organismo ao dano hepático. O tetracloreto de carbono inalatório é um modelo experimental efetivo, que desencadeia a cirrose e permite obter modificações histológicas e fisiológicas similares às vistas em humanos. OBJETIVO: Investigar os efeitos da N-acetilcisteina (NAC sobre a fibrose e o estresse oxidativo no fígado de ratos cirróticos, analisando as provas hepáticas, a lipoperoxidação, a atividade da enzima

  10. Assessment of indicators of vitamin A status in non-cirrhotic chronic hepatitis C patients

    Directory of Open Access Journals (Sweden)

    R.C. Santana

    2016-01-01

    Full Text Available Subjects with chronic liver disease are susceptible to hypovitaminosis A due to several factors. Therefore, identifying patients with vitamin deficiency and a requirement for vitamin supplementation is important. Most studies assessing vitamin A in the context of hepatic disorders are conducted using cirrhotic patients. A cross-sectional study was conducted in 43 non-cirrhotic patients with chronic hepatitis C to evaluate markers of vitamin A status represented by serum retinol, liver retinol, and serum retinol-binding protein levels. We also performed the relative dose-response test, which provides an indirect estimate of hepatic vitamin A reserves. These vitamin A indicators were assessed according to the stage of liver fibrosis using the METAVIR score and the body mass index. The sample study was predominantly composed of male subjects (63% with mild liver fibrosis (F1. The relative dose-response test was <20% in all subjects, indicating vitamin A sufficiency. Overweight or obese patients had higher serum retinol levels than those with a normal body mass index (2.6 and 1.9 µmol/L, respectively; P<0.01. Subjects with moderate liver fibrosis (F2 showed lower levels of serum retinol (1.9 vs 2.5 µmol/L, P=0.01 and retinol-binding protein levels compared with those with mild fibrosis (F1 (46.3 vs 67.7 µg/mL, P<0.01. These results suggested an effect of being overweight on serum retinol levels. Furthermore, more advanced stages of liver fibrosis were related to a decrease in serum vitamin A levels.

  11. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Hadi, Mackenzie; Laarakkers, Coby M. M.; Masereeuw, Rosalinde; Groothuis, Geny M. M.; Russel, Frans G. M.

    2014-01-01

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker ide

  12. The heart and the liver

    DEFF Research Database (Denmark)

    Møller, Søren; Dümcke, Christine Winkler; Krag, Aleksander

    2009-01-01

    against the heart failure. Transjugular intrahepatic portosystemic shunt insertion and liver transplantation affect cardiac function in portal hypertensive patients and cause stress to the cirrhotic heart, with a risk of perioperative heart failure. The risk and prevalence of coronary artery disease......Cardiac failure affects the liver and liver dysfunction affects the heart. Chronic and acute heart failure can lead to cardiac cirrhosis and cardiogenic ischemic hepatitis. These conditions may impair liver function and treatment should be directed towards the primary heart disease and seek...... are increasing in cirrhotic patients and since perioperative mortality is high, careful evaluation of such patients with dobutamine stress echocardiography, coronary angiography and myocardial perfusion imaging is required prior to liver transplantation. Future research should focus on beneficial effects...

  13. Quality of life in cirrhotic patients and liver transplant recipients

    OpenAIRE

    Pantiga Alonso, Carmen; López Álvarez, Laudino; Pérez Álvarez, Marino; Rodríguez, Manuel; Linares Rodríguez, Antonio; Diéguez, Luisa G.; Alonso,Pilar; Hernández Mejía, Radhamés; Rodrigo, Luis

    2005-01-01

    Este estudio analiza la calidad de vida relacionada con la salud en pacientes diagnosticados de cirrosis hepática (CH) en los tres estadios Child-Pugh (A, B y C) y en pacientes trasplantados (OLT). La calidad de vida ha sido cuantificada por la prueba psicométrica multidimensional PLC (Siegrits, Boer and Junge, 1996). En general, los pacientes CH y OLT presentaron peores puntuaciones que el grupo control en las dimensiones de Capacidad física, Función física, Ánimo positivo, Ánimo negativo y ...

  14. Portal vein thrombosis: Etiology and clinical outcome of cirrhosis and malignancy-related non-cirrhotic, non-tumoral extrahepatic portal venous obstruction

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The etiology and pathogenesis of portal vein thrombosis are unclear. Portal venous thrombosis presentation differs in cirrhotic and tumor-related versus non-cirrhotic and non-tumoral extrahepatic portal venous obstruction (EHPVO). Non-cirrhotic and non-tumoral EHPVO patients are young and present with well tolerated bleeding.Cirrhosis and tumor-related portal vein thrombosis patients are older and have a grim prognosis. Among the 118 patients with portal vein thrombosis, 15.3% had cirrhosis, 42.4% had liver malignancy (primary or metastatic), 6% had pancreatitis (acute or chronic), 5% had hypercoagulable state and 31.3% had idiopathy,12% had hypercoagulable state in the EHPVO group.

  15. PSYCHOMETRIC PROPERTY OF FATIGUE SEVERITY SCALE AND CORRELATION WITH DEPRESSION AND QUALITY OF LIFE IN CIRRHOTICS

    Directory of Open Access Journals (Sweden)

    Danusa ROSSI

    2017-10-01

    Full Text Available ABSTRACT BACKGROUND: Fatigue is a common complaint in cirrhotic patients and may be considered a debilitating symptom with negative impact on quality of life. Research on its etiology and treatment has been hampered by the lack of relevant and reproducible measures of fatigue. OBJECTIVE: To evaluate the psychometric properties of the Fatigue Severity Scale (FSS in cirrhotic patients and to correlate with depressive symptomatology and quality of life. METHODS: Cross-sectional study with a convenience sample of 106 cirrhotic patients, aged between 18 and 70 years, both genders, literate, pre and post liver transplantation in outpatient follow-up. Internal consistency, reproducibility, discriminant validity, criterion validity, construct validity, responsiveness criterion, depressive symptomatology and quality of life were evaluated through questionnaires between January and October 2015. RESULTS: The mean age was 54.75±9.9 years, 65.1% male and 32.1% of the sample had cirrhosis due to hepatitis C virus. The mean FSS score was 4.74±1.64. Cronbach’s alpha was 0.93, and the Intraclass Correlation Coefficient was 0.905 (95% CI: 0.813-0.952. For discriminant validity, FSS differentiated scores from different groups (P=0.009 and presented a correlation with the Modified Fatigue Impact Scale (r=0.606, P=0.002. FSS correlated significantly and positively with depressive symptomatology and correlated negatively with the SF-36 domains for construct validity. For responsiveness, no significant changes were observed in the fatigue scores in the pre and post-liver transplantation periods (P=0.327. CONCLUSION: FSS showed good psychometric performance in the evaluation of fatigue in patients with cirrhosis. Fatigue presented a strong correlation with depressive symptomatology and quality of life.

  16. Cholecystolithotomy Combined Armillarisin A versus Cholecystectomy in Cirrhotic Portal Hypertension Patients with Symptomatic Cholelithiasis.

    Science.gov (United States)

    Fei, Yang; Li, Wei-Qin; Zong, Guang-Quan; Chen, Jian; Wang, Wei

    2017-01-01

    To discover whether cirrhotic portal hypertension patients with symptomatic cholelithiasis would benefit from cholecystolithotomy combined with Armillarisin A in the authors hospital. Methods: Sixty-one patients with cirrhotic portal hypertension and symptomatic gallstone disease who underwent either cholecystolithotomy combined with Armillarisin A (group A) or cholecystectomy (group B) for cholelithiasis from Feb 2007 to March 2011 were retrospectively reviewed. These patients were undergoing simultaneous procedure for esophageal varices. The operation-relevant information, change of laboratory examination data, postoperative complications and symptoms were analyzed. Results: There were no significant differences between group A and group B in mean operative time, intraoperative blood loss, time to resume diet postoperatively and length of hospital stay (P 0.05). The hepatic function biochemical profile and Child-Pugh'™s score at 2 weeks and 1 month after operations were both altered significantly less in group A than in group B (ALT, 0.008, 0.011; AST, 0.006, 0.003; Child-Pugh'™s score, 0.010, 0.016, respectively). However, at 6 months postoperatively, the changes were not significant (P 0.05). Except for gallstone recurrence and wound infection, occurrences or development of postoperative complications including biliary fistula, liver failure and subphrenic infection showed significant differences between the two groups (P = 0.037, P = 0.041, P = 0.019, respectively). After a mean follow-up of 4.2 years, all patients remain alive. Twenty-seven patients in group A (93%) are free of biliary symptoms. Cholecystolithotomy combined with using Armillarisin A is a useful treatment for symptomatic gallstones in patients with cirrhotic portal hypertension who are at high risk for cholecystectomy. It preserves gallbladder function and reduces the possibility of liver failure; moreover the rate of recurrent gallstones are relatively low. Celsius.

  17. Effects of raloxifene on portal hypertension and hepatic encephalopathy in cirrhotic rats.

    Science.gov (United States)

    Chang, Ching-Chih; Lee, Wen-Shin; Chuang, Chiao-Lin; Hsin, I-Fang; Hsu, Shao-Jung; Chang, Ting; Huang, Hui-Chun; Lee, Fa-Yauh; Lee, Shou-Dong

    2017-05-05

    Raloxifene, a selective estrogen receptor modulator, has been used extensively for osteoporosis. In addition to the effect of osteoporosis treatment, emerging evidences show that raloxifene affects the vascular function in different tissues. Cirrhosis is characterized with portal hypertension and complicated with hepatic encephalopathy. Portal hypertension affects portal-systemic shunt which leads to hepatic encephalopathy that the vascular modulation might influence severity of hepatic encephalopathy. Herein, we evaluated the impact of raloxifene on bile duct ligation (BDL)-induced cirrhotic rats. The female Sprague-Dawley rats received BDL plus ovariectomy or sham-operation. Four weeks later, rats were divided into 2 subgroups respectively to receive of raloxifene (10mg/kg/day) or saline (vehicle) for 14 days. On the 43th day, motor activities and hemodynamic parameters were measured. Hepatic and vascular mRNA and protein expressions were determined. The histopathological change of liver was examined. We found that the liver biochemistry, ammonia level and motor activity were similar between cirrhotic rats with or without raloxifene administration. The hemodynamic parameters were not significantly different except that raloxifene reduced portal venous inflow. Raloxifene exacerbated hepatic fibrosis and up-regulated hepatic endothelin-1 and cyclooxygenase 2 protein expressions. In addition, raloxifene modulated the mRNA expressions of endothelial nitric oxide synthase, cyclooxygenase and endothelin-1 in the superior mesenteric artery and collateral vessel. In conclusion, raloxifene aggravates hepatic fibrosis and decreases portal venous inflow in cirrhotic rats without adversely affecting portal hypertension and hepatic encephalopathy. The modulation of hepatic and vascular endothelin-1, endothelial nitric oxide synthase and cyclooxygenase expressions may play a role in the mechanism.

  18. Liver transplantation in patients with hepatocellular carcinoma

    NARCIS (Netherlands)

    Polak, Wojciech G.; Soyama, Akihiko; Slooff, Maarten J. H.

    2008-01-01

    Liver transplantation has a definitive place in the treatment of patients with hepatocellular carcinoma (HCC) in a cirrhotic liver. Patients with a tumor load within the Milan criteria have excellent survival comparable to survival in patients with benign indications. When tumor load exceeds the Mil

  19. Vigorous, but differential mononuclear cell response of cirrhotic patients to bacterial ligands

    Institute of Scientific and Technical Information of China (English)

    Varenka J Barbero-Becerra; María Concepción Gutiérrez-Ruiz; Carmen Maldonado-Bernal; Félix I Téllez-Avila; Roberto Alfaro-Lara; Florencia Vargas-Vorácková

    2011-01-01

    AIM: To study the role of gram-positive and gram-negative bacteria in the pathogenesis of liver injury, specifically the activation of inflammatory mediators. METHODS: Peripheral blood mononuclear cells of 20 out-patients were studied, 10 of them with cirrhosis. Peripheral blood mononuclear cells were isolated and exposed to lipopolysaccharide or lipoteichoic acid. CD14, Toll-like receptor 2 and 4 expression was determined by flow cytometry, and tumor necrosis factor (TNF) α, interleukin (IL)-1β, IL-6, IL-12 and IL-10 secretion in supernatants was determined by ELISA. RESULTS: Higher CD14, Toll-like receptor 2 and 4 expression was observed in peripheral blood mononuclear cells from cirrhotic patients, (P < 0.01, P < 0.006, P < 0.111) respectively. Lipopolysaccharide and lipoteichoic acid induced a further increase in CD14 expression (P < 0.111 lipopolysaccharide, P < 0.013 lipoteichoic acid), and a decrease in Toll-like receptor 2 (P < 0.008 lipopolysaccharide, P < 0.008 lipoteichoic acid) and Toll-like receptor 4 (P < 0.008 lipopolysaccharide, P < 0.028 lipoteichoic acid) expression. With the exception of TNFα, absolute cytokine secretion of peripheral blood mononuclear cells was lower in cirrhotic patients under nonexposure conditions (P < 0.070 IL-6, P < 0.009 IL-1β, P < 0.022 IL-12). Once exposed to lipopolysaccharide or lipoteichoic acid, absolute cytokine secretion of peripheral blood mononuclear cells was similar in cirrhotic and non-cirrhotic patients, determining a more vigorous response in the former (P < 0.005 TNFα, IL-1β, IL-6, IL-2 and IL-10 lipopolysaccharide; P < 0.037 TNFα; P < 0.006 IL-1β; P < 0.005 IL-6; P < 0.007 IL-12; P < 0.014 IL-10 lipoteichoic acid). Response of peripheral blood mononuclear cells was more intense after lipopolysaccharide than after lipoteichoic acid exposure. CONCLUSION: Peripheral blood mononuclear cells of cirrhotic patients are able to respond to a sudden bacterial ligand exposure, particularly lipopolysaccharide

  20. Serum zinc concentrations in two cohorts of 153 healthy subjects and 100 cirrhotic patients from Mexico City.

    Science.gov (United States)

    Poo, J L; Rosas-Romero, R; Rodríguez, F; Silencio, J L; Muñoz, R; Bourges, H; Uribe, M

    1995-01-01

    The aim of this study was to assess serum zinc levels in a cohort of healthy subjects and cirrhotic patients from Mexico City. A total of 153 healthy subjects and 100 cirrhotic patients, males and females aged 18-65, were studied. Inclusion criteria for healthy subjects were (1) Mexican-born with first and second generation relatives born in Mexico, and (2) somatometric (body mass index under 30) and clinical evaluation establishing that they had no underlying disease. Entry criteria for cirrhotic patients were (1) clinical and histological proven cirrhosis, (2) compensated liver disease (absence of coma, bleeding hemorrhage or refractory ascitis), and (3) cirrhosis of any cause. Zinc serum levels were measured with atomic absorption spectrophotometry. In healthy subjects, mean serum levels were 77.4 +/- 4.2 micrograms/dl (range 42.9-105.2 micrograms/dl). In cirrhotic patients zinc serum levels (58.9 +/- 16.1 micrograms/dl, range 22-88 micrograms/dl) were significantly lower than in healthy subjects (p < 0.05). A stepwise decline in serum zinc with worsening Child class (A, 73.4 +/- 13; B, 64.4 +/- 12; C, 55.8 +/- 15.6; p < 0.05 by ANOVA test) was found. In conclusion, this study confirms that zinc serum levels are significantly lower in cirrhotic patients and shows that zinc serum levels in a cohort of 153 healthy subjects from Mexico City were unexpectedly lower compared to those found in other countries. This last finding might be explained by different dietetic patterns and deserves further investigation.

  1. Ultrasonic characterization of porcine liver tissue at frequency between 25 to 55 MHz

    Institute of Scientific and Technical Information of China (English)

    Xiao-Zhou Liu; Xiu-Fen Gong; Dong Zhang; Shi-Gong Ye; Bing Rui

    2006-01-01

    AIM: To study the relation between acoustic parameters and histological structure of biological tissue and to provide the basis for high-resolution image of biological tissues and quantitative ultrasonic diagnosis of liver disease.METHODS: Ultrasonic imaging and tissue characterization of four normal porcine liver and five cirrhotic liver tissue samples were performed using a high frequency imaging system.RESULTS: The acoustic parameters of cirrhotic liver tissue were larger than those of normal liver tissue. The sound velocity was 1577 m/s in normal liver tissue and 1631 m/s in cirrhotic liver tissue. At 35 MHz, the attenuation coefficient was 3.0 dB/mm in normal liver tissue and 4.1 dB/mm in cirrhotic liver tissue. The backscatter coefficient was 0.00431 dB/Srmm in cirrhotic liver tissue and 0.00303 dB/Srmm in normal liver tissue. The backscatter coefficient increased with the frequency. The high frequency images coincided with their histological features.CONCLUSION: The acoustic parameters, especially the sound backscatter coefficient, are sensitive to the changes of liver tissues and can be used to differentiate between the normal and pathological liver tissues.High frequency image system is a useful device for high-resolution image and tissue characterization.

  2. Current concepts in hepatic resection for hepatocellular carcinoma in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Alessandro Cucchetti; Matteo Cescon; Franco Trevisani; Antonio Daniele Pinna

    2012-01-01

    Hepatocellular carcinoma (HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with liver cirrhosis.Liver resection is considered the most potentially curative therapy for HCC patients when liver transplantation is not an option or is not immediately accessible.This review is aimed at investigating the current concepts that drive the surgical choice in the treatment of HCC in cirrhotic patients;Eastern and Western perspectives are highlighted.An extensive literature review of the last two decades was performed,on topics covering various aspects of hepatic resection.Early post-operative and long-term outcome measures adopted were firstly analyzed in an attempt to define an optimal standardization useful for research comparison.The need to avoid the development of post-hepatectomy liver failure represents the "conditio sine qua non" of surgical choice and the role of the current tools available for the assessment of liver function reserve were investigated.Results of hepatic resection in relationship with tumor burden were compared with those of available competing strategies,namely,radiofrequency ablation for early stages,and trans-arterial chemoembolization for intermediate and advanced stages.Finally,the choice for anatomical versus non-anatomical,as well as the role of laparoscopic approach,was overviewed.The literature review suggests that partial hepatectomy for HCC should be considered in the context of multi-disciplinary evaluation of cirrhotic patients.Scientific research on HCC has moved,in recent years,from surgical therapy toward non-surgical approaches and most of the literature regarding topics debated in the present review is represented by observational studies,whereas very few well-designed randomized controlled trials are currently available; thus,no robust recommendations can be derived.

  3. Human Fetal Liver: An In Vitro Model of Erythropoiesis

    Directory of Open Access Journals (Sweden)

    Guillaume Pourcher

    2011-01-01

    Full Text Available We previously described the large-scale production of RBCs from hematopoietic stem cells (HSCs of diverse sources. Our present efforts are focused to produce RBCs thanks to an unlimited source of stem cells. Human embryonic stem (ES cells or induced pluripotent stem cell (iPS are the natural candidates. Even if the proof of RBCs production from these sources has been done, their amplification ability is to date not sufficient for a transfusion application. In this work, our protocol of RBC production was applied to HSC isolated from fetal liver (FL as an intermediate source between embryonic and adult stem cells. We studied the erythroid potential of FL-derived CD34+ cells. In this in vitro model, maturation that is enucleation reaches a lower level compared to adult sources as observed for embryonic or iP, but, interestingly, they (i displayed a dramatic in vitro expansion (100-fold more when compared to CB CD34+ and (ii 100% cloning efficiency in hematopoietic progenitor assays after 3 days of erythroid induction, as compared to 10–15% cloning efficiency for adult CD34+ cells. This work supports the idea that FL remains a model of study and is not a candidate for ex vivo RBCS production for blood transfusion as a direct source of stem cells but could be helpful to understand and enhance proliferation abilities for primitive cells such as ES cells or iPS.

  4. Bile salt recognition by human liver fatty acid binding protein.

    Science.gov (United States)

    Favretto, Filippo; Santambrogio, Carlo; D'Onofrio, Mariapina; Molinari, Henriette; Grandori, Rita; Assfalg, Michael

    2015-04-01

    Fatty acid binding proteins (FABPs) act as intracellular carriers of lipid molecules, and play a role in global metabolism regulation. Liver FABP (L-FABP) is prominent among FABPs for its wide ligand repertoire, which includes long-chain fatty acids as well as bile acids (BAs). In this work, we performed a detailed molecular- and atomic-level analysis of the interactions established by human L-FABP with nine BAs to understand the binding specificity for this important class of cholesterol-derived metabolites. Protein-ligand complex formation was monitored using heteronuclear NMR, steady-state fluorescence spectroscopy, and mass spectrometry. BAs were found to interact with L-FABP with dissociation constants in the narrow range of 0.6-7 μm; however, the diverse substitution patterns of the sterol nucleus and the presence of side-chain conjugation resulted in complexes endowed with various degrees of conformational heterogeneity. Trihydroxylated BAs formed monomeric complexes in which single ligand molecules occupied similar internal binding sites, based on chemical-shift perturbation data. Analysis of NMR line shapes upon progressive addition of taurocholate indicated that the binding mechanism departed from a simple binary association equilibrium, and instead involved intermediates along the binding path. The co-linear chemical shift behavior observed for L-FABP complexes with cholate derivatives added insight into conformational dynamics in the presence of ligands. The observed spectroscopic features of L-FABP/BA complexes, discussed in relation to ligand chemistry, suggest possible molecular determinants of recognition, with implications regarding intracellular BA transport. Our findings suggest that human L-FABP is a poorly selective, universal BA binder.

  5. Incidence and clinical presentation of portal vein thrombosis in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Yasir Furkan Cagin; Yahya Atayan; Mehmet Ali Erdogan; Firat Dagtekin; Cemil Colak

    2016-01-01

    BACKGROUND: Portal vein thrombosis (PVT) is due to many risk factors, but its pathogenesis is still not clearly understood. To identify the risk factors for PVT, we analyzed the clinical characteristics and complications associated with PVT in cir-rhotic patients. METHODS: We studied patients with liver cirrhosis who were admitted to our unit from April 2009 to December 2014. The patients were divided into the PVT and non-PVT groups, and were compared by variables including gender, age, the etiology of cirrhosis, stage of cirrhosis, complications, imaging, and treatment. RESULTS: PVT was found in 45 (9.8%) of 461 cirrhotic pa-tients admitted to our hospital. Most patients (45.9%) had hepatitis B virus (HBV)-related cirrhosis, with a similar dis-tribution of etiologies between the groups. However, there was no positive relationship between PVT and etiologies of cirrhosis. Most patients (71.5%) were in the stage of hepatic decompensation. No statistically signiifcant differences were found in complications including esophageal varices, ascites, and hepatic encephalopathy between the groups. However, there was a signiifcant positive correlation between hepatocel-lular carcinoma (HCC) and PVT (P CONCLUSIONS: The incidence of PVT was 9.8%, mainly in patients with HBV-related cirrhosis. The development of PVT was associated with the severity of liver disease and HCC.

  6. Rifaximin, but not growth factor 1, reduces brain edema in cirrhotic rats

    Institute of Scientific and Technical Information of China (English)

    Gemma (ò)dena; Mireia Miquel; Anna Serafín; Amparo Galan; Rosa Morillas; Ramon Planas; Ramon Bartolí

    2012-01-01

    AIM:To compare rifaximin and insulin-like growth factor (IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS:Rats with CCl4-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups:Cirrhosis; Cirrhosis + IGF-1;Cirrhosis + rifaximin; Controls; Controls + IGF-1; and Controls + rifaximin.An oral glutamine-challenge test was performed,and plasma and cerebral ammonia,glucose,bilirubin,transaminases,endotoxemia,brain water content and ileocecal cultures were measured and liver histology was assessed.RESULTS:Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups,and improved some liver function parameters (bilirubin,alanine aminotransferase and aspartate aminotransferase).These effects were associated with a significant reduction in cerebral water content.Blood and cerebral ammonia levels,and area-underthe-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals.By contrast,IGF-1 administration failed to improve most alterations observed in cirrhosis.CONCLUSION:By reducing gut bacterial overgrowth,only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema,alterations associated with hepatic encephalopathy.

  7. Advances in gene therapy of liver cirrhosis: a review

    Institute of Scientific and Technical Information of China (English)

    Wen Jie Dai; Hong Chi Jiang

    2001-01-01

    @@ INTRODUCTION Liver fibrosis or cirrhosis is a common progressively pathological lesion of chronic liver diseases in response to various liver-damaging factors. The main mechanisms of fibrotic or cirrhotic initiation and progression at the level of cellular and molecular events have been elucidated in the past two decades[1,2].

  8. Identification of CYP isozymes involved in benzbromarone metabolism in human liver microsomes.

    Science.gov (United States)

    Kobayashi, Kaoru; Kajiwara, Eri; Ishikawa, Masayuki; Oka, Hidenobu; Chiba, Kan

    2012-11-01

    Benzbromarone (BBR) is metabolized to 1'-hydroxy BBR and 6-hydroxy BBR in the liver. 6-Hydroxy BBR is further metabolized to 5,6-dihydroxy BBR. The aim of this study was to identify the CYP isozymes involved in the metabolism of BBR to 1'-hydroxy BBR and 6-hydroxy BBR and in the metabolism of 6-hydroxy BBR to 5,6-dihydroxy BBR in human liver microsomes. Among 11 recombinant P450 isozymes examined, CYP3A4 showed the highest formation rate of 1'-hydroxy BBR. The formation rate of 1'-hydroxy BBR significantly correlated with testosterone 6β-hydroxylation activity in a panel of 12 human liver microsomes. The formation of 1'-hydroxy BBR was completely inhibited by ketoconazole in pooled human liver microsomes. On the other hand, the highest formation rate of 6-hydroxy BBR was found in recombinant CYP2C9. The highest correlation was observed between the formation rate of 6-hydroxy BBR and diclofenac 4'-hydroxylation activity in 12 human liver microsomes. The formation of 6-hydroxy BBR was inhibited by tienilic acid in pooled human liver microsomes. The formation of 5,6-dihydroxy BBR from 6-hydroxy BBR was catalysed by recombinant CYP2C9 and CYP1A2. The formation rate of 5,6-dihydroxy BBR was significantly correlated with diclofenac 4'-hydroxylation activity and phenacetin O-deethylation activity in 12 human liver microsomes. The formation of 5,6-dihydroxy BBR was inhibited with either tienilic acid or α-naphthoflavone in human liver microsomes. These results suggest that (i) the formation of 1'-hydroxy BBR and 6-hydroxy BBR is mainly catalysed by CYP3A4 and CYP2C9, respectively, and (ii) the formation of 5,6-dihydroxy BBR is catalysed by CYP2C9 and CYP1A2 in human liver microsomes.

  9. Long-term culture of genome-stable bipotent stem cells from adult human liver

    NARCIS (Netherlands)

    Huch, Meritxell; Gehart, Helmuth; van Boxtel, Ruben; Hamer, Karien; Blokzijl, Francis; Verstegen, Monique M A; Ellis, Ewa; van Wenum, Martien; Fuchs, Sabine A; de Ligt, Joep; van de Wetering, Marc; Sasaki, Nobuo; Boers, Susanne J; Kemperman, Hans; de Jonge, Jeroen; Ijzermans, Jan N M; Nieuwenhuis, Edward E S; Hoekstra, Ruurdtje; Strom, Stephen; Vries, Robert R G; van der Laan, Luc J W; Cuppen, Edwin; Clevers, Hans

    2015-01-01

    Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be

  10. Long-term culture of genome-stable bipotent stem cells from adult human liver

    NARCIS (Netherlands)

    M. Huch (Meritxell); H. Gehart (Helmuth); R. Van Boxtel (Ruben); K. Hamer (Karien); F. Blokzijl (Francis); M.M.A. Verstegen (Monique); E. Ellis (Ewa); M. Van Wenum (Martien); S.A. Fuchs (Sabine A.); J. de Ligt (Joep); M. van de Wetering (M.); N. Sasaki (Nobuo); S.J. Boers (Susanne J.); H. Kemperman (Hans); J. de Jonge (Jeroen); J.N.M. IJzermans (Jan); E.E.S. Nieuwenhuis (Edward); R. Hoekstra (Ruurdtje); S. Strom (Stephen); R.R.G. Vries (Robert R.G.); L.J.W. van der Laan (Luc); E. Cuppen (Edwin); H.C. Clevers (Hans)

    2015-01-01

    textabstractDespite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro

  11. Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

    NARCIS (Netherlands)

    Huch, Meritxell; Gehart, Helmuth; van Boxtel, Ruben; Hamer, Karien; Blokzijl, Francis; Verstegen, Monique M. A.; Ellis, Ewa; van Wenum, Martien; Fuchs, Sabine A.; de Ligt, Joep; van de Wetering, Marc; Sasaki, Nobuo; Boers, Susanne J.; Kemperman, Hans; de Jonge, Jeroen; Ijzermans, Jan N. M.; Nieuwenhuis, Edward E. S.; Hoekstra, Ruurdtje; Strom, Stephen; Vries, Robert R. G.; van der Laan, Luc J. W.; Cuppen, Edwin; Clevers, Hans

    2015-01-01

    Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be

  12. Cell sources for in vitro human liver cell culture models.

    Science.gov (United States)

    Zeilinger, Katrin; Freyer, Nora; Damm, Georg; Seehofer, Daniel; Knöspel, Fanny

    2016-09-01

    In vitro liver cell culture models are gaining increasing importance in pharmacological and toxicological research. The source of cells used is critical for the relevance and the predictive value of such models. Primary human hepatocytes (PHH) are currently considered to be the gold standard for hepatic in vitro culture models, since they directly reflect the specific metabolism and functionality of the human liver; however, the scarcity and difficult logistics of PHH have driven researchers to explore alternative cell sources, including liver cell lines and pluripotent stem cells. Liver cell lines generated from hepatomas or by genetic manipulation are widely used due to their good availability, but they are generally altered in certain metabolic functions. For the past few years, adult and pluripotent stem cells have been attracting increasing attention, due their ability to proliferate and to differentiate into hepatocyte-like cells in vitro However, controlling the differentiation of these cells is still a challenge. This review gives an overview of the major human cell sources under investigation for in vitro liver cell culture models, including primary human liver cells, liver cell lines, and stem cells. The promises and challenges of different cell types are discussed with a focus on the complex 2D and 3D culture approaches under investigation for improving liver cell functionality in vitro Finally, the specific application options of individual cell sources in pharmacological research or disease modeling are described.

  13. ADENOSINE-TRIPHOSPHATE DEPENDENT TAUROCHOLATE TRANSPORT IN HUMAN LIVER PLASMA-MEMBRANES

    NARCIS (Netherlands)

    WOLTERS, H; KUIPERS, F; SLOOFF, MJH; VONK, RJ

    1992-01-01

    Transport systems involved in uptake and biliary secretion of bile salts have been extensively studied in rat liver; however, little is known about these systems in the human liver. In this study, we investigated taurocholate (TC) transport in canalicular and basolateral plasma membrane vesicles iso

  14. The impact of PPARalpha activation on whole genome gene expression in human precision cut liver slices

    NARCIS (Netherlands)

    Janssen, A.W.H.; Betzel, B; Stoopen, G.; Berends, F.J.; Janssen, I.M.C.; Peijnenburg, A.A.; Kersten, S.

    2015-01-01

    BACKGROUND: Studies in mice have shown that PPARalpha is an important regulator of lipid metabolism in liver and key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPARalpha in human liver. METHODS: Here we set out to study the functi

  15. Expression kinetics of hepatic progenitor markers in cellular models of human liver development recapitulating hepatocyte and biliary cell fate commitment.

    Science.gov (United States)

    Chaudhari, Pooja; Tian, Lipeng; Deshmukh, Abhijeet; Jang, Yoon-Young

    2016-09-01

    Due to the limitations of research using human embryos and the lack of a biological model of human liver development, the roles of the various markers associated with liver stem or progenitor cell potential in humans are largely speculative, and based on studies utilizing animal models and certain patient tissues. Human pluripotent stem cell-based in vitro multistage hepatic differentiation systems may serve as good surrogate models for mimicking normal human liver development, pathogenesis and injury/regeneration studies. Here, we describe the implications of various liver stem or progenitor cell markers and their bipotency (i.e. hepatocytic- and biliary-epithelial cell differentiation), based on the pluripotent stem cell-derived model of human liver development. Future studies using the human cellular model(s) of liver and biliary development will provide more human relevant biological and/or pathological roles of distinct markers expressed in heterogeneous liver stem/progenitor cell populations.

  16. Sciatic Hernia Mimicking Perianal Abscess in a Cirrhotic Patient

    Directory of Open Access Journals (Sweden)

    Wellington Andraus

    2012-01-01

    Full Text Available Abdominal hernias are very frequent in cirrhotic patients with ascites. The hernias usually present as umbilical, inguinal, incisional, or femoral. However, these patients can also develop uncommon hernias such as pelvic hernias because of pelvic floor weakness and high abdominal pressure due to ascites. We present the first case of a cirrhotic patient with ascites that developed a giant sciatic hernia mimicking a perianal abscess.

  17. Evaluation of the protective effects of quercetin in biliary cirrhotic rats

    Directory of Open Access Journals (Sweden)

    Derakhshanian H

    2013-04-01

    Full Text Available Background: Biliary cirrhosis is a chronic disease marked by the progressive destruct-tion of liver. There is no known cure for this disease; however, medications may slow its progression. The present study was designed to investigate the effect of quercetin as a plant derived flavonoid on the hepatic injury reduction of biliary cirrhotic rats.Methods: Thirty male Sprague-Dawley rats aged 6-7 months were randomized into three groups of ten each. One group served as control (sham operated, while the other two groups underwent a complete bile-duct ligation (BDL. Four weeks after the opera-tion, serum bilirubin, alkaline phosphatase (ALP, alanine amino-transferase (ALT, and aspartate amino-transferase (AST were measured in two BDL groups to confirm the occurrence of cirrhosis. Then one of the BDL groups received placebo and the other one injected intraperitoneally with 50mg/kg of quercetin once a day for a period of four weeks. At the end of the study, hepatic enzymes and serum bilirubin were measured again. Liver species were tested for histological characteristics.Results: Quercetin could decrease serum level of bilirubin (7.4±0.9 vs. 8.9±1.6 mg/dL; P<0.05, ALP (1387±76.9 vs. 2273±65.3 IU/L; P<0.001 and ALT (601.9±38.1 vs. 644.8±37.4 IU/L; P<0.05 compared to cirrhotic group. AST was higher in cirrhotic groups compared to control both in the 4th and 8th week. However, the difference between BDL and BDL+Q groups was not statistically significant. Quercetin decreased ALT/AST ratio, as an indicator of liver damage. No significant histological changes were observed in quercetin group.Conclusion: These data suggest that although quercetin did not change histological characteristics of liver, it could significantly decrease bilirubin, alkaline phosphatase and alanine amino-transferase, indicating less liver injury.

  18. Trace elements and chronic liver diseases

    Energy Technology Data Exchange (ETDEWEB)

    Loguercio, C.; De Girolamo, V.; Federico A., A.; Del Vecchio Blanco, C. [Seconda Universita di Napoli, Naples (Italy). Cattedra di Gastroenterologia; Feng, S.L.; Gialanella, G. [Naples Univ. (Italy). Dipt. di Scienze Fisiche; Cataldi, V. [Naples Univ. (Italy). Prima Medicina Ospedale Ascalesi

    1997-12-31

    The relationships between chronic liver diseases and trace element (TE) contents are debated. Particularly, no defined data are available about the TE levels in viral liver disease patients with or without malnutrition. In this study we evaluated blood and plasma levels of various trace elements in patients with HCV-related chronic liver disease, at different stages of liver damage (8 patients with chronic hepatitis and 32 with liver cirrhosis) with or without malnutrition. We also studied 10 healthy volunteers as control group. We found that cirrhotic subjects had a significant decrease of blood levels of Zn and Se, independently on the nutritional status, whereas plasma levels of Fe were significantly reduced only in malnourished cirrhotic patients. Our data indicate that liver impairment is the main cause of the blood decrease of Se and Zn levels in patients with non alcoholic liver disease, whereas the malnutrition affects Fe levels only. (orig.)

  19. WJH 6th Anniversary Special Issues(1): Management of hepatocellular carcinoma Management of “very early” hepatocellular carcinoma on cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Gonzalo; Sapisochin; Elena; Fernandez; de; Sevilla; Juan; Echeverri; Ramón; Charco

    2014-01-01

    Due to the advances in screening of cirrhotic patients, hepatocellular carcinoma(HCC) is being diagnosed in earlier stages. For this reason the number of patients diagnosed of very early HCC(single tumors ≤ 2 cm) is continuously increasing. Once a patient has been diagnosed with this condition, treatment strategies include liver resection, local therapies or liver transplantation. The decision on which therapy should the patient undergo depends on the general patients performance status and liver disease. Anyway, even in patients with similar conditions, the best treatment offer is debatable. In this review we analyze the state of the art on the management of very early HCC on cirrhotic patients to address the best treatment strategy for this patient population.

  20. The human liver-specific proteome defined by transcriptomics and antibody-based profiling.

    Science.gov (United States)

    Kampf, Caroline; Mardinoglu, Adil; Fagerberg, Linn; Hallström, Björn M; Edlund, Karolina; Lundberg, Emma; Pontén, Fredrik; Nielsen, Jens; Uhlen, Mathias

    2014-07-01

    Human liver physiology and the genetic etiology of the liver diseases can potentially be elucidated through the identification of proteins with enriched expression in the liver. Here, we combined data from RNA sequencing (RNA-Seq) and antibody-based immunohistochemistry across all major human tissues to explore the human liver proteome with enriched expression, as well as the cell type-enriched expression in hepatocyte and bile duct cells. We identified in total 477 protein-coding genes with elevated expression in the liver: 179 genes have higher expression as compared to all the other analyzed tissues; 164 genes have elevated transcript levels in the liver shared with at least one other tissue type; and an additional 134 genes have a mild level of increased expression in the liver. We identified the precise localization of these proteins through antibody-based protein profiling and the subcellular localization of these proteins through immunofluorescent-based profiling. We also identified the biological processes and metabolic functions associated with these proteins, investigated their contribution in the occurrence of liver diseases, and identified potential targets for their treatment. Our study demonstrates the use of RNA-Seq and antibody-based immunohistochemistry for characterizing the human liver proteome, as well as the use of tissue-specific proteins in identification of novel drug targets and discovery of biomarkers.-Kampf, C., Mardinoglu, A., Fagerberg, L., Hallström, B. M., Edlund, K., Lundberg, E., Pontén, F., Nielsen, J., Uhlen, M. The human liver-specific proteome defined by transcriptomics and antibody-based profiling. © FASEB.

  1. Sequential metabolism of sesamin by cytochrome P450 and UDP-glucuronosyltransferase in human liver.

    Science.gov (United States)

    Yasuda, Kaori; Ikushiro, Shinichi; Kamakura, Masaki; Munetsuna, Eiji; Ohta, Miho; Sakaki, Toshiyuki

    2011-09-01

    Our previous study revealed that CYP2C9 played a central role in sesamin monocatecholization. In this study, we focused on the metabolism of sesamin monocatechol that was further converted into the dicatechol form by cytochrome P450 (P450) or the glucuronide by UDP-glucuronosyltransferase (UGT). Catecholization of sesamin monocatechol enhances its antioxidant activity, whereas glucuronidation strongly reduces its antioxidant activity. In human liver microsomes, the glucuronidation activity was much higher than the catecholization activity toward sesamin monocatechol. In contrast, in rat liver microsomes, catecholization is predominant over glucuronidation. In addition, rat liver produced two isomers of the glucuronide, whereas human liver produced only one glucuronide. These results suggest a significant species-based difference in the metabolism of sesamin between humans and rats. Kinetic studies using recombinant human UGT isoforms identified UGT2B7 as the most important UGT isoform for glucuronidation of sesamin monocatechol. In addition, a good correlation was observed between the glucuronidation activity and UGT2B7-specific activity in in vitro studies using 10 individual human liver microsomes. These results strongly suggest that UGT2B7 plays an important role in glucuronidation of sesamin monocatechol. Interindividual difference among the 10 human liver microsomes is approximately 2-fold. These results, together with our previous results on the metabolism of sesamin by human P450, suggest a small interindividual difference in sesamin metabolism. We observed the methylation activity toward sesamin monocatechol by catechol O-methyl transferase (COMT) in human liver cytosol. On the basis of these results, we concluded that CYP2C9, UGT2B7, and COMT played essential roles in the metabolism of sesamin in the human liver.

  2. Portal hemodynamics as predictors of high risk esophageal varices in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Mohammad K Tarzamni; Mohammad H Somi; Sara Farhang; Morteza Jalilvand

    2008-01-01

    AIM: To evaluate portal hypertension parameters in liver cirrhosis patients with and without esophageal varices (EV).METHODS: A cohort of patients with biopsy confirmed liver cirrhosis was investigated endoscopically and with color Doppler ultrasonography as a possible non-invasive predictive tool. The relationship between portal hemodynamics and the presence and size of EV was evaluated using uni- and multivariate approaches.RESULTS: Eighty five consecutive cirrhotic patients (43 men and 42 women) were enrolled. Mean age (± SD) was 47.5 (± 15.9). Portal vein diameter (13.88 ± 2.42 vs 12.00 ± 1.69, P 2.08 and spleen size > 15.05 cm. These factors may help identifying patients with a low probability of LEV who may not need upper gastrointestinal endoscopy.

  3. Fractionation of human liver mitochondria: enzymic and morphological characterization of the inner and outer membranes as compared to rat liver mitochondria.

    Science.gov (United States)

    Benga, G; Hodarnau, A; Tilinca, R; Porutiu, D; Dancea, S; Pop, V; Wrigglesworth, J

    1979-02-01

    The fractionation of human liver mitochondria into inner membrane, outer membrane and matrix material is reported. Compared with rat, human liver mitochondria are more fragile. Fractionation can be achieved in only 2 steps, a digitonin treatment for removal of the outer membrane and centrifugation of the inner membrane plus matrix particles through a linear sucrose gradient resulting in purified inner membranes and matrix.

  4. Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: First North American results.

    Science.gov (United States)

    Selzner, Markus; Goldaracena, Nicolas; Echeverri, Juan; Kaths, Johan M; Linares, Ivan; Selzner, Nazia; Serrick, Cyril; Marquez, Max; Sapisochin, Gonzalo; Renner, Eberhard L; Bhat, Mamatha; McGilvray, Ian D; Lilly, Leslie; Greig, Paul D; Tsien, Cynthia; Cattral, Mark S; Ghanekar, Anand; Grant, David R

    2016-11-01

    The European trial investigating normothermic ex vivo liver perfusion (NEVLP) as a preservation technique for liver transplantation (LT) uses gelofusine, a non-US Food and Drug Administration-approved, bovine-derived, gelatin-based perfusion solution. We report a safety and feasibility clinical NEVLP trial with human albumin-based Steen solution. Transplant outcomes of 10 human liver grafts that were perfused on the Metra device at 37 °C with Steen solution, plus 3 units of erythrocytes were compared with a matched historical control group of 30 grafts using cold storage (CS) as the preservation technique. Ten liver grafts were perfused for 480 minutes (340-580 minutes). All livers cleared lactate (final lactate 1.46 mmol/L; 0.56-1.74 mmol/L) and produced bile (61 mL; 14-146 mL) during perfusion. No technical problems occurred during perfusion, and all NEVLP-preserved grafts functioned well after LT. NEVLP versus CS had lower aspartate aminotransferase and alanine aminotransferase values on postoperative days 1-3 without reaching significance. No difference in postoperative graft function between NEVLP and CS grafts was detected as measured by day 7 international normalized ratio (1.1 [1-1.56] versus 1.1 [1-1.3]; P = 0.5) and bilirubin (1.5; 1-7.7 mg/dL versus 2.78; 0.4-15 mg/dL; P = 0.5). No difference was found in the duration of intensive care unit stay (median, 1 versus 2 days; range, 0-8 versus 0-23 days; P = 0.5) and posttransplant hospital stay (median, 11 versus 13 days; range, 8-17 versus 7-89 days; P = 0.23). Major complications (Dindo-Clavien ≥ 3b) occurred in 1 patient in the NEVLP group (10%) compared with 7 (23%) patients in the CS group (P = 0.5). No graft loss or patient death was observed in either group. Liver preservation with normothermic ex vivo perfusion with the Metra device using Steen solution is safe and results in comparable outcomes to CS after LT. Using US Food and Drug Administration-approved Steen

  5. Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes.

    Science.gov (United States)

    Slovak, J E; Mealey, K; Court, M H

    2017-04-01

    Use of the immunosuppressant mycophenolic acid (MPA) in cats is limited because MPA elimination depends on glucuronidation, which is deficient in cats. We evaluated formation of major (phenol glucuronide) and minor (acyl glucuronide, phenol glucoside, and acyl glucoside) MPA metabolites using liver microsomes from 16 cats, 26 dogs, and 48 humans. All MPA metabolites were formed by human liver microsomes, while dog and cat liver microsomes formed both MPA glucuronides, but only one MPA glucoside (phenol glucoside). Intrinsic clearance (CLint) of MPA for phenol glucuronidation by cat liver microsomes was only 15-17% that of dog and human liver microsomes. However, CLint for acyl glucuronide and phenol glucoside formation in cat liver microsomes was similar to or greater than that for dog and human liver microsomes. While total MPA conjugation CLint was generally similar for cat liver microsomes compared with dog and human liver microsomes, relative contributions of each pathway varied between species with phenol glucuronidation predominating in dog and human liver microsomes and phenol glucosidation predominating in cat liver microsomes. MPA conjugation variation between cat liver microsomes was threefold for total conjugation and for phenol glucosidation, sixfold for phenol glucuronidation, and 11-fold for acyl glucuronidation. Our results indicate that total MPA conjugation is quantitatively similar between liver microsomes from cats, dogs, and humans despite large differences in the conjugation pathways that are utilized by these species.

  6. Characterization of triptolide hydroxylation by cytochrome P450 in human and rat liver microsomes.

    Science.gov (United States)

    Li, W; Liu, Y; He, Y-Q; Zhang, J-W; Gao, Y; Ge, G-B; Liu, H-X; Huo, H; Liu, H-T; Wang, L-M; Sun, J; Wang, Q; Yang, L

    2008-12-01

    Triptolide, the primary active component of a traditional Chinese medicine Tripterygium wilfordii Hook F, has a wide range of pharmacological activities. In the present study, the metabolism of triptolide by cytochrome P450s was investigated in human and rat liver microsomes. Triptolide was converted to four metabolites (M-1, M-2, M-3, and M-4) in rat liver microsomes and three (M-2, M-3, and M-4) in human liver microsomes. All the products were identified as mono-hydroxylated triptolides by liquid chromatography-mass spectrometry (LC-MS). The studies with chemical selective inhibitors, complementary DNA-expressed human cytochrome P450s, correlation analysis, and enzyme kinetics were also conducted. The results demonstrate that CYP3A4 and CYP2C19 could be involved in the metabolism of triptolide in human liver, and that CYP3A4 was the primary isoform responsible for its hydroxylation.

  7. The sinusoidal lining cells in "normal" human liver. A scanning electron microscopic investigation

    DEFF Research Database (Denmark)

    Horn, T; Henriksen, Jens Henrik Sahl; Christoffersen, P

    1986-01-01

    The scanning electron microscopic was used to study the fenestrations of human liver sinusoids. Thirteen biopsies, where light microscopy and transmission electron microscopy revealed normal sinusoidal architecture, were investigated. The number of fenestrae was calculated in acinar zone 3...

  8. Up-regulation of NAD(P)H quinone oxidoreductase 1 during human liver injury

    Institute of Scientific and Technical Information of China (English)

    Lauren M Aleksunes; Michael Goedken; José E Manautou

    2006-01-01

    AIM: To investigate the expression and activity of NAD(P)H quinone oxidoreductase 1 (NQO1) in human liver specimens obtained from patients with liver damage due to acetaminophen (APAP) overdose or primary biliary cirrhosis (PBC).METHODS: NQO1 activity was determined in cytosol from normal, APAP and PBC liver specimens. Western blot and immunohistochemical staining were used to determine patterns of NQO1 expression using a specific antibody against NQO1.RESULTS: NQO1 protein was very low in normal human livers. In both APAP and PBC livers, there was strong induction of NQO1 protein levels on Western blot.Correspondingly, significant up-regulation of enzyme activity (16- and 22-fold, P< 0.05) was also observed in APAP and PBC livers, respectively. Immunohistochemical analysis highlighted injury-specific patterns of NQO1 staining in both APAP and PBC livers.CONCLUSION: These data demonstrate that NQO1 protein and activity are markedly induced in human livers during both APAP overdose and PBC. Up-regulation of this cytoprotective enzyme may represent an adaptive stress response to limit further disease progression by detoxifying reactive species.

  9. HEMOGLOBIN PRODUCTION FACTORS IN THE HUMAN LIVER : ANEMIAS, HYPOPROTEINEMIA, CIRRHOSIS, PIGMENT ABNORMALITIES, AND PREGANCY.

    Science.gov (United States)

    Whipple, G H; Robscheit-Robbins, F S

    1942-09-01

    Human liver tissue has been assayed to determine the amount of hemoglobin production factors in normal and abnormal states. Standardized dogs made anemic by blood removal have been used in this biological assay. Normal animal liver as control is rated as 100 per cent. Normal human liver tissue as compared with the normal animal control contains more of these hemoglobin production factors-a biological assay ratio of 120 to 160 per cent. Infections, acute and chronic, do not appear to modify these values, the concentration of hemoglobin-producing factors falling within the normal range. Pernicious anemia and aplastic anemia both show large liver stores of hemoglobin-producing factors-a biological assay ratio of 200 to 240 per cent. Therapy in pernicious anemia reduces these liver stores as new red cells are formed. Secondary anemia presents a low normal or subnormal liver store of hemoglobin-producing factors-an assay of 60 to 130 per cent. Hemochromatosis, erythroblastic anemia, and hemolytic icterus in spite of large iron deposits in the liver usually show a biological assay which is normal or close to normal. Polycythemia shows low reserve stores of hemoglobin-producing factors. Leukemias present a wide range of values discussed above. Hypoproteinemia almost always is associated with low reserve stores of hemoglobin-producing factors in the liver-biological assays of 60 to 80 per cent. Hypoproteinemia means a depletion of body protein reserve stores including the labile protein liver reserves-a strong indication that the prehemoglobin material (or globin) is related to these liver stores. Pregnancy, eclampsia, and lactation all may present subnormal liver stores of hemoglobin-producing factors. Exhaustion of protein stores lowers the barrier to infection and renders the liver very susceptible to many toxic substances. It should not be difficult to correct hypoproteinemia under these conditions and thus relieve the patient of a real hazard.

  10. Portal hypertensive colopathy is associated with portal hypertension severity in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Antonio Diaz-Sanchez; Oscar Nu(n)ez-Martinez; Cecilia Gonzalez-Asanza; Ana Matilla; Beatriz Merino; Diego Rincon; Inmaculada Beceiro; Maria Vega Catalina; Magdalena Salcedo; Rafael Ba(n)ares; Gerardo Clemente

    2009-01-01

    AIM: To assess the prevalence of portal hypertension (PH) related colorectal lesions in liver transplant candidates, and to evaluate its association with the severity of PH.METHODS: Between October 2004 and December 2005, colonoscopy was performed in 92 cirrhotic liver transplant candidates. We described the lesions resulting from colorectal PH and their association with the grade of PH in 77 patients who underwent measurement of hepatic venous pressure gradient (HVPG). RESULTS: Mean age was 55 years and 80.7% of patients were men. The main etiology of cirrhosis was alcoholism (45.5%). Portal hypertensive colopathy (PHC) was found in 23.9%, colonic varices in 7.6% and polyps in 38% of patients (adenomatous type 65.2%). One asymptomatic patient had a well-differentiated adenocarcinoma. The manifestations of colorectal PH were not associated with the etiology of liver disease or with the Child-Pugh grade. Ninety percent of patients with colopathy presented with gastroesophageal varices (GEV), and 27.5% of patients with GEV presented with colopathy ( P = 0.12). A relationship between higher values of HVPG and presence of colopathy was observed (19.9 ± 6.2 mmHg vs 16.8 ± 5.4 mmHg, P = 0.045), but not with the grade of colopathy ( P = 0.13). Preneoplastic polyps and neoplasm ( P = 0.02) and spontaneous bacterial peritonitis ( P = 0.006) were more prevalent in patients with colopathy. We did not observe any association between previous β-blocker therapy and the presence of colorectal portal hypertensive vasculopathy. CONCLUSION: PHC is common in cirrhotic liver transplant candidates and is associated with higher portal pressure.

  11. Comparative study of bacterial infection prevalence between cirrhotic patients with and without upper gastrointestinal bleeding

    Directory of Open Access Journals (Sweden)

    Delvone Almeida

    Full Text Available Bacterial infection is a frequent complication in patients with chronic liver disease, mainly during the advanced stages. There is evidence that the main factors that contribute to a predisposition to infection in cirrhotic patients are related to hepatic failure with consequent immunodeficiency. Invasive procedures (diagnostic or therapeutic can predispose to bacterial infections, and upper gastrointestinal bleeding (UGB is considered a potentially important risk factor. A group of cirrhotic patients (child B and C Pugh groups were evaluated retrospectively by chart reviews regarding the prevalence of bacterial infection during hospitalization to determine whether UGB was a risk factor. An infection was considered present if a specific organ system was identified or if fever (>38ºC persisted for more than 24 hours with associated leukocytosis. Spontaneous bacterial peritonitis was based on classical criteria. Eighty-nine patients were evaluated. Fourty-six patients presented with UGB, and 43 patients had no UGB (control. There were infections recorded in 25/46 (54% patients with UGB, and 15/43 (35% in those without UGB (p=0.065. The ratio of the number of infections/admitted patients, was significantly larger in the group with UGB (0.78 ± 0.89 vs. 0.39 ± 0.62; p=0.028 since patients had more than one infection. In the UGB group compared to non UGB group, ascites was more frequent (67% vs. 42%; p=0.027; they were more likely to have undergone endoscopic procedures (p<0.001 and the mean ± SD for platelets count was smaller (96,114 ± 57,563 vs. 145,674 ± 104,083; p=0.007. The results show that UGB is an important contribution to bacterial infection among Child B and C cirrhotic patients.

  12. Comparative study of bacterial infection prevalence between cirrhotic patients with and without upper gastrointestinal bleeding

    Directory of Open Access Journals (Sweden)

    Delvone Almeida

    2001-06-01

    Full Text Available Bacterial infection is a frequent complication in patients with chronic liver disease, mainly during the advanced stages. There is evidence that the main factors that contribute to a predisposition to infection in cirrhotic patients are related to hepatic failure with consequent immunodeficiency. Invasive procedures (diagnostic or therapeutic can predispose to bacterial infections, and upper gastrointestinal bleeding (UGB is considered a potentially important risk factor. A group of cirrhotic patients (child B and C Pugh groups were evaluated retrospectively by chart reviews regarding the prevalence of bacterial infection during hospitalization to determine whether UGB was a risk factor. An infection was considered present if a specific organ system was identified or if fever (>38ºC persisted for more than 24 hours with associated leukocytosis. Spontaneous bacterial peritonitis was based on classical criteria. Eighty-nine patients were evaluated. Fourty-six patients presented with UGB, and 43 patients had no UGB (control. There were infections recorded in 25/46 (54% patients with UGB, and 15/43 (35% in those without UGB (p=0.065. The ratio of the number of infections/admitted patients, was significantly larger in the group with UGB (0.78 ± 0.89 vs. 0.39 ± 0.62; p=0.028 since patients had more than one infection. In the UGB group compared to non UGB group, ascites was more frequent (67% vs. 42%; p=0.027; they were more likely to have undergone endoscopic procedures (p<0.001 and the mean ± SD for platelets count was smaller (96,114 ± 57,563 vs. 145,674 ± 104,083; p=0.007. The results show that UGB is an important contribution to bacterial infection among Child B and C cirrhotic patients.

  13. Prognostic Value of a New Marker of Ventricular Repolarization in Cirrhotic Patients

    Science.gov (United States)

    Salgado, Angelo Antunes; Barbosa, Paulo Roberto Benchimol; Ferreira, Alinne Gimenez; Reis, Camila Aparecida de Souza Segrégio; Terra, Carlos

    2016-01-01

    Background There is still debate about the relationship between changes in ventricular repolarization on the surface electrocardiogram and cirrhosis severity. Objective To study the relationship between variables related to ventricular repolarization and the clinical severity of the cirrhotic disease. Methods We selected 79 individuals with hepatic cirrhosis, classified according to the Child-Pugh-Turcotte criteria (Child A, B, and C). We measured the QT and corrected QT (QTc) intervals, and the interval between the peak and the end of the T wave (TpTe), and we identified their minimum, maximum, and mean values in the 12-lead electrocardiogram. We also calculated the dispersion of the QT (DQT) and QTc (DQTc) intervals. Results In 12 months of clinical follow-up, nine subjects underwent hepatic transplantation (Child A: 0 [0%]; Child B: 6 [23.1%]; Child C: 3 [18.8%]; p = 0.04) and 12 died (Child A: 3 [12.0%]; Child B: 4 [15.4%]; Child C: 5 [31.3%]; p = 0.002). No significant differences were observed between the cirrhotic groups related to the minimum, maximum, and mean values for the QT, QTc, TpTe, DQT, and DQTc intervals. A minimum TpTe interval ≤ 50 ms was a predictor for the composite endpoints of death or liver transplantation with a sensitivity of 90% and a specificity of 57% (p = 0.005). In the Cox multivariate analysis, the Child groups and a minimum TpTe of ≤ 50 ms were independent predictors of the composite endpoints. Conclusion The intervals QT, QTc, DQT, DQTc, and TpTe have similar distributions between different severity stages in cirrhotic disease. The TpTe interval proved to be a prognostic marker in subjects with cirrhosis, regardless of disease severity (NCT01433848).

  14. HNF1α inhibition triggers epithelial-mesenchymal transition in human liver cancer cell lines

    Directory of Open Access Journals (Sweden)

    Vignjevic Danijela

    2011-10-01

    Full Text Available Abstract Background Hepatocyte Nuclear Factor 1α (HNF1α is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA, rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA. Methods We transfected hepatoma cell lines HepG2 and Hep3B with siRNA targeting HNF1α and obtained a strong inhibition of HNF1α expression. We then looked at the phenotypic changes by microscopy and studied changes in gene expression using qRT-PCR and Western Blot. Results Hepatocytes transfected with HNF1α siRNA underwent severe phenotypic changes with loss of cell-cell contacts and development of migration structures. In HNF1α-inhibited cells, hepatocyte and epithelial markers were diminished and mesenchymal markers were over-expressed. This epithelial-mesenchymal transition (EMT was related to the up regulation of several EMT transcription factors, in particular SNAIL and SLUG. We also found an overexpression of TGFβ1, an EMT initiator, in both cells transfected with HNF1α siRNA and H-HCA. Moreover, TGFβ1 expression is strongly correlated to HNF1α expression in cell models, suggesting regulation of TGFβ1 expression by HNF1α. Conclusion Our results suggest that HNF1α is not only important for hepatocyte differentiation, but has also a role in the maintenance of epithelial phenotype in hepatocytes.

  15. Glucuronidation of drugs in humanized UDP-glucuronosyltransferase 1 mice: Similarity with glucuronidation in human liver microsomes.

    Science.gov (United States)

    Kutsuno, Yuki; Sumida, Kyohei; Itoh, Tomoo; Tukey, Robert H; Fujiwara, Ryoichi

    2013-10-01

    Uridine 5'-diphosphate-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various endogenous and exogenous substrates. Among 19 functional human UGTs, UGT1A family enzymes largely contribute to the metabolism of clinically used drugs. While the UGT1A locus is conserved in mammals such as humans, mice, and rats, species differences in drug glucuronidation have been reported. Recently, humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) have been developed. To evaluate the usefulness of hUGT1 mice to predict human glucuronidation of drugs, UGT activities, and inhibitory effects on UGTs were examined in liver microsomes of hUGT1 mice as well as in those of wild-type mice and humans. Furosemide acyl-glucuronidation was sigmoidal and best fitted to the Hill equation in hUGT1 mice and human liver microsomes, while it was fitted to the substrate inhibition equation in mouse liver microsomes. Kinetic parameters of furosemide glucuronidation were very similar between hUGT1 mice and human liver microsomes. The kinetics of S-naproxen acyl-glucuronidation and inhibitory effects of compounds on furosemide glucuronidation in hUGT1 liver microsomes were also slightly, but similar to those in human liver microsomes, rather than in wild-type mice. While wild-type mice lack imipramine and trifluoperazine N-glucuronidation potential, hUGT1 mice showed comparable N-glucuronidation activity to that of humans. Our data indicate that hUGT1 mice are promising tools to predict not only in vivo human drug glucuronidation but also potential drug-drug interactions.

  16. Idiopathic non-cirrhotic portal hypertension

    Directory of Open Access Journals (Sweden)

    CHEN Jie

    2013-07-01

    Full Text Available The pathogenesis of idiopathic non-cirrhotic portal hypertension (INCPH remains unknown and the disease is diagnosed by the absence of recognized clinical indicators of cirrhosis and of any other known etiologies of portal hypertension. To promote understanding of this disease, a comprehensive overview of potential etiologies, clinical manifestations, histopathological features, methods of diagnosis and potential differential diagnoses, and outcome of clinical management is presented in this review. In particular, we discuss the findings from INCPH studies and their implications in regards to each of the above-mentioned categories. For example, associations with various comorbidities have suggested a possible immune system component to INCPH development and/or progression. In addition, the common clinical characteristics of patients upon presentation can not only help to recognize disease suspects but may also provide insights into the pathogenesis and prognosis. Finally, prognosis following the various intervention strategies appears to depend mainly on severity of the portal hypertension, as well as its various accompanying complications.

  17. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Lake, April D. [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States); Novak, Petr [Biology Centre ASCR, Institute of Plant Molecular Biology, Ceske Budejovice 37001 (Czech Republic); Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Lu, Zhenqiang [The Arizona Statistical Consulting Laboratory, University of Arizona, Tucson, AZ 85721 (United States); Lehman-McKeeman, Lois D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Cherrington, Nathan J., E-mail: cherrington@pharmacy.arizona.edu [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States)

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  18. Expression pattern of thymosin beta 4 in the adult human liver

    Science.gov (United States)

    Nemolato, S.; Van Eyken, P.; Cabras, T.; Cau, F.; Fanari, M.U.; Locci, A.; Fanni, D.; Gerosa, C.; Messana, I.; Castagnola, M.; Faa, G.

    2011-01-01

    Thymosin beta-4 (Tβ4) is a member of beta-thymosins, a family of small peptides involved in polymerization of G-actin, and in many critical biological processes including apoptosis, cell migration, angiogenesis, and fibrosis. Previous studies in the newborn liver did not reveal any significant reactivity for Tβ4 during the intrauterine life. The aim of the present study was to investigate by immunohistochemistry Tβ4 expression in the adult normal liver. Thirty-five human liver samples, including 11 needle liver biopsies and 24 liver specimens obtained at autopsy, in which no pathological change was detected at the histological examination, were immunostained utilizing an anti-Tβ4 commercial antibody. Tβ4 was detected in the hepatocytes of all adult normal livers examined. A zonation of Tβ4 expression was evident in the vast majority of cases. Immunostaining was preferentially detected in zone 3, while a minor degree of reactivity was detected in periportal hepatocytes (zone 1). At higher power, Tβ4-reactive granules appeared mainly localized at the biliary pole of hepatocytes. In cases with a strong immunostaining, even perinuclear areas and the sinusoidal pole of hepatocytes appeared interested by immunoreactivity for Tβ4. The current work first evidences a strong diffuse expression of Tβ4 in the adult human liver, and adds hepatocytes to the list of human cells able to synthesize large amounts of Tβ4 in adulthood. Moreover, Tβ4 should be added to the liver proteins characterized by a zonate expression pattern, in a descending gradient from the terminal vein to the periportal areas of the liver acinus. Identifying the intimate role played by this peptide intracellularly and extracellularly, in physiology and in different liver diseases, is a major challenge for future research focusing on Tβ4. PMID:22073372

  19. Expression pattern of thymosin beta 4 in the adult human liver

    Directory of Open Access Journals (Sweden)

    S. Nemolato

    2011-09-01

    Full Text Available Thymosin beta-4 (Tβ4 is a member of beta-thymosins, a family of small peptides involved in polymerization of G-actin, and in many critical biological processes including apoptosis, cell migration, angiogenesis, and fibrosis. Previous studies in the newborn liver did not reveal any significant reactivity for Tβ4 during the intrauterine life. The aim of the present study was to investigate by immunohistochemistry Tβ4 expression in the adult normal liver. Thirty-five human liver samples, including 11 needle liver biopsies and 24 liver specimens obtained at autopsy, in which no pathological change was detected at the histological examination, were immunostained utilizing an anti-Tβ4 commercial antibody. Tβ4 was detected in the hepatocytes of all adult normal livers examined. A zonation of Tβ4 expression was evident in the vast majority of cases. Immunostaining was preferentially detected in zone 3, while a minor degree of reactivity was detected in periportal hepatocytes (zone 1. At higher power, Tβ4-reactive granules appeared mainly localized at the biliary pole of hepatocytes. In cases with a strong immunostaining, even perinuclear areas and the sinusoidal pole of hepatocytes appeared interested by immunoreactivity for Tβ4. The current work first evidences a strong diffuse expression of Tβ4 in the adult human liver, and adds hepatocytes to the list of human cells able to synthesize large amounts of Tβ4 in adulthood. Moreover, Tβ4 should be added to the liver proteins characterized by a zonate expression pattern, in a descending gradient from the terminal vein to the periportal areas of the liver acinus. Identifying the intimate role played by this peptide intracellularly and extracellularly, in physiology and in different liver diseases, is a major challenge for future research focusing on Tβ4.

  20. Molecular cloning and nucleotide sequence of cDNA for human liver arginase

    Energy Technology Data Exchange (ETDEWEB)

    Haraguchi, Y.; Takiguchi, M.; Amaya, Y.; Kawamoto, S.; Matsuda, I.; Mori, M.

    1987-01-01

    Arginase (EC3.5.3.1) catalyzes the last step of the urea cycle in the liver of ureotelic animals. Inherited deficiency of the enzyme results in argininemia, an autosomal recessive disorder characterized by hyperammonemia. To facilitate investigation of the enzyme and gene structures and to elucidate the nature of the mutation in argininemia, the authors isolated cDNA clones for human liver arginase. Oligo(dT)-primed and random primer human liver cDNA libraries in lambda gt11 were screened using isolated rat arginase cDNA as a probe. Two of the positive clones, designated lambda hARG6 and lambda hARG109, contained an overlapping cDNA sequence with an open reading frame encoding a polypeptide of 322 amino acid residues (predicted M/sub r/, 34,732), a 5'-untranslated sequence of 56 base pairs, a 3'-untranslated sequence of 423 base pairs, and a poly(A) segment. Arginase activity was detected in Escherichia coli cells transformed with the plasmid carrying lambda hARG6 cDNA insert. RNA gel blot analysis of human liver RNA showed a single mRNA of 1.6 kilobases. The predicted amino acid sequence of human liver arginase is 87% and 41% identical with those of the rat liver and yeast enzymes, respectively. There are several highly conserved segments among the human, rat, and yeast enzymes.

  1. Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.

    Directory of Open Access Journals (Sweden)

    Shin-ichiro Nakagawa

    Full Text Available BACKGROUND & AIMS: The interferon (IFN system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV and hepatitis B virus (HBV. METHODS: This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC. Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs in the livers and sera of these humanized chimeric mice. RESULTS: Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1, suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. CONCLUSIONS: These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

  2. [Extracellular fluid, plasma and interstitial volume in cirrhotic patients without clinical edema or ascites].

    Science.gov (United States)

    Noguera Viñas, E C; Hames, W; Mothe, G; Barrionuevo, M P

    1989-01-01

    Extracellular fluid volume (E.C.F.) and plasma volume (P.V.), were measured with sodium sulfate labeled with 35I and 131I human serum albumin, respectively, by the dilution technique in control subjects and in cirrhotic patients without clinical ascites or edema, renal or hepatic failure, gastrointestinal bleeding or diuretics. Results are expressed as mean +/- DS in both ml/m2 and ml/kg. In normal subjects E.C.F. (n = 8) was 7,533 +/- 817 ml/m2 (201.3 +/- 182 ml/kg), P.V. (n = 11) 1,767 +/- 337 ml/m2 (47.2 +/- 9.3 ml/kg), and interstitial fluid (I.S.F.) (n = 7) 5,758 +/- 851 ml/m2 (Table 2). In cirrhotic patients E.C.F. (n = 11) was 10,318 +/- 2,980 ml/m2 (261.7 +/- 76.8 ml/kg), P.V. (n = 12) 2,649 +/- 558 ml/m2 (67.7 +/- 15.6 ml/kg) and I.S.F. (n = 11) 7,866 +/- 2,987 ml/m2 (Table 3). Cirrhotic patients compared with normal subjects have hypervolemia due to a significant E.C.F. and P.V. expansion (p less than 0.02 and less than 0.001 respectively) (Fig. 1). Reasons for E.C.F. and P.V. abnormalities in cirrhotic patients may reflect urinary sodium retention related to portal hipertension which stimulates aldosterone release or enhanced renal tubular sensitivity to the hormone. However, it is also possible that these patients, in the presence of hypoalbuminemia (Table 1), have no clinical edema or ascites due to increased glomerular filtration, suppressed release of vasopressin, increased natriuretic factor, and urinary prostaglandin excretion, in response to the intravascular expansion, all of which increased solute and water delivery to the distal nephron and improved renal water excretion. We conclude that in our clinical experience cirrhotic patients without ascites or edema have hypervolemia because of a disturbance in E.C.F.

  3. Butylbenzyl phthalate hydrolysis in liver microsomes of humans, monkeys, dogs, rats and mice.

    Science.gov (United States)

    Takahara, Yuka; Kinashi, Yu; Takahara, Yuusuke; Hichiya, Hiroyuki; Okada, Kenji; Murata, Mikio; Shigeyama, Masato; Hanioka, Nobumitsu

    2014-01-01

    Butylbenzyl phthalate (BBzP) is used as a plasticizer to import flexibility to polyvinylchloride plastics. In this study, hydrolysis of BBzP to monobutyl phthalate (MBP) and monobenzyl phthalate (MBzP) in liver microsomes of humans, monkeys, dogs, rats and mice was examined. The kinetics for MBP formation by human, dog and mouse liver microsomes followed the Michaelis-Menten model, whereas the kinetics by monkey and rat liver microsomes fitted the Hill model. The kinetics for MBzP formation fitted the Hill model for all liver microsomes. The Vmax and in vitro clearance (CLint or CLmax) ratios of MBP/MBzP formation varied among animal species, although the Km for MBP and MBzP formation in each liver microsomes were generally comparable. The hydrolysis of BBzP to monoester phthalates in mammalian liver microsomes could be classified into two types: MBzP>MBP type for humans and dogs, and MBP>MBzP type for monkeys, rats and mice. These findings suggest that the formation profile of MBzP and MBP from BBzP by liver microsomes differs extensively among animal species.

  4. Expression and function of the atypical cadherin FAT1 in chronic liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Valletta, Daniela; Czech, Barbara [Department of Internal Medicine I, University Hospital Regensburg, Regensburg (Germany); Thasler, Wolfgang E. [Grosshadern Tissue Bank and Center for Liver Cell Research, Department of Surgery, Ludwig-Maximilians-University Munich (Germany); Mueller, Martina [Department of Internal Medicine I, University Hospital Regensburg, Regensburg (Germany); Bosserhoff, Anja-Katrin [Institute of Pathology, University of Regensburg, Regensburg (Germany); Hellerbrand, Claus, E-mail: claus.hellerbrand@ukr.de [Department of Internal Medicine I, University Hospital Regensburg, Regensburg (Germany)

    2012-09-28

    Highlights: Black-Right-Pointing-Pointer The expression of the atypical cadherin FAT1 is increased in chronic liver disease. Black-Right-Pointing-Pointer FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. Black-Right-Pointing-Pointer FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. Black-Right-Pointing-Pointer FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. -- Abstract: Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these

  5. Expression, purification and bioactivity of human augmenter of liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Yang-De Zhang; Jian Zhou; Jin-Feng Zhao; Jian Peng; Xiao-Dong Liu; Xin-Sheng Liu; Ze-Ming Jia

    2006-01-01

    AIM: To construct the expression vectors for prokaryotic and eukaryotic human augmenter of liver regeneration (hALR) and to study their biological activity.METHODS: hALRcDNA clone was obtained from plasmid pGEM-T-hALR, and cDNA was subcloned into the prokatyotic expression vector pGEX-4T-2.The recombinant vector and pGEX-4T-2hALR were identified by enzyme digestion and DNA sequencing and transformed into E coli JM109. The positively selected clone was induced by the expression of GST-hALR fusion protein with IPTG, then the fusion protein was purified by glutathine s-transferase (GST) sepharose 4B affinity chromatography, cleaved by thrombin and the hALR monomer was obtained and detected by measuring H thymidine incorporation.RESULTS: The product of PCR from plasmid pGEM-ThALR was examined by 1.5% sepharose electrophoresis.The specific strap was coincident with the theoretical one. The sequence was accurate and pGEX-4T-hALP digested by enzymes was coincident with the theoretical one. The sequence was accurate and the fragment was inserted in the positive direction. The recombinant vector was transformed into E coli JM109. SDS-PAGE proved that the induced expressive fusion protein showed a single band with a molecular weight of 41 kDa. The product was purified and cleaved. The molecular weights of GST and hALR were 26 kDa, 15 kDa respectively. The recombinant fusion protein accounted for 31% of the total soluble protein of bacterial lysate. HALR added to the culture medium of adult rat hepatocytes in primary culture and HepG2 cell line could significantly enhance the rate of DNA synthesis compared to the relevant control groups (P < 0.01).CONCLUSION: Purified hALR has the ability to stimulate DNA synthesis of adult rat hepatocytes in primary culture and HepG2 cells in vitro, and can provide evidence for its clinical application.

  6. Recognition rate of the MDCT imaging features of hepatocellular carcinoma in cirrhotic liver:based on LI-RADS(v2014)defi-nition%肝硬化背景下肝细胞癌的CT动态增强表现:LI-RADS(2014版)定义征象的出现率

    Institute of Scientific and Technical Information of China (English)

    郭小超; 王鹤; 王可; 陆健; 刘爱连; 缪小芬; 汪禾青; 杨学东; 王霄英

    2016-01-01

    目的:分析肝硬化背景下肝细胞肝癌(HCC)的 CT 动态增强表现,探讨2014版肝脏影像报告及数据系统(LI-RADS)所定义的各种征象在图像中的出现率。方法:2008年12月-2014年8月共51例乙肝肝硬化患者行CT动态增强检查、且经病理证实有54个 HCC病灶。两位阅片者采用盲法独立进行阅片,根据LI-RADS标准,分析所有入组病例的动态增强CT图像,对每个病灶的主要征象(动脉期高强化、"廓清"表现、包膜)和次要征象(马赛克征、出血等)进行评估并计算其出现率。通过Kappa检验来分析两位阅片者所评估的各种征象的出现率的一致性。结果:对54个 HCC病灶的动脉期高强化、“廓清”表现和包膜这3个主要征象的出现率,两位阅片者的评估结果分别为:77.8%和75.9%、81.5%和81.5%、14.8%和18.5%,阅片者间的一致性(Kappa值)分别为0.636、0.755和0.468。所有次要征象的出现率均较低,以马赛克征的出现率最高,两位阅片者的评估结果分别为25.9%和11.1%,阅片者间的一致性(Kappa 值)为0.289。结论:基于LI-RADS的诊断标准,动态增强CT图像对乙肝肝硬化背景下的 HCC的主要征象显示较好,阅片者间的一致性较高;但其它征象的出现率较低及/或诊断一致性欠佳。%Objective:To evaluate the recognition rate of imaging features of hepatocellular carcinoma (HCC)in cir-rhotic liver due to HBV based on criteria of LI-RADS (v2014).Methods:From November 2008 to August 2014,totally 54 HCC foci proved by pathology were found in 5 1 patients with liver cirrhosis due to HBV and undergone multiphase contrast enhanced-CT (CECT)examination.The CECT images were retrospectively analyzed by two experienced radiologists inde-pendently.The imaging features of each HCC focus were analyzed and categorized based on LI-RADS.The recognition rate was

  7. Reconstruction and analysis of human liver-specific metabolic network based on CNHLPP data.

    Science.gov (United States)

    Zhao, Jing; Geng, Chao; Tao, Lin; Zhang, Duanfeng; Jiang, Ying; Tang, Kailin; Zhu, Ruixin; Yu, Hong; Zhang, Weidong; He, Fuchu; Li, Yixue; Cao, Zhiwei

    2010-04-05

    Liver is the largest internal organ in the body that takes central roles in metabolic homeostasis, detoxification of various substances, as well as in the synthesis and storage of nutrients. To fulfill these complex tasks, thousands of biochemical reactions are going on in liver to cope with a wide range of foods and environmental variations, which are densely interconnected into an intricate metabolic network. Here, the first human liver-specific metabolic network was reconstructed according to proteomics data from Chinese Human Liver Proteome Project (CNHLPP), and then investigated in the context of the genome-scale metabolic network of Homo sapiens. Topological analysis shows that this organ-specific metabolic network exhibits similar features as organism-specific networks, such as power-law degree distribution, small-world property, and bow-tie structure. Furthermore, the structure of liver network exhibits a modular organization where the modules are formed around precursors from primary metabolism or hub metabolites from derivative metabolism, respectively. Most of the modules are dominated by one major category of metabolisms, while enzymes within same modules have a tendency of being expressed concertedly at protein level. Network decomposition and comparison suggest that the liver network overlays a predominant area in the global metabolic network of H. sapiens genome; meanwhile the human network may develop extra modules to gain more specialized functionality out of liver. The results of this study would permit a high-level interpretation of the metabolite information flow in human liver and provide a basis for modeling the physiological and pathological metabolic states of liver.

  8. Fixation methods for electron microscopy of human and other liver

    Institute of Scientific and Technical Information of China (English)

    Eddie; Wisse; Filip; Braet; Hans; Duimel; Celien; Vreuls; Ger; Koek; Steven; WM; Olde; Damink; Maartje; AJ; van; den; Broek; Bart; De; Geest; Cees; HC; Dejong; Chise; Tateno; Peter; Frederik

    2010-01-01

    For an electron microscopic study of the liver,expertise and complicated,time-consuming processing of hepatic tissues and cells is needed.The interpretation of electron microscopy(EM) images requires knowledge of the liver fine structure and experience with the numerous artifacts in fixation,embedding,sectioning,contrast staining and microscopic imaging.Hence,the aim of this paper is to present a detailed summary of different methods for the preparation of hepatic cells and tissue,for the purpose of preserv...

  9. Increased Expression of Endothelin Receptors in Human Cirrhosis——Relationship with Spl anchnic Hemodynamics

    Institute of Scientific and Technical Information of China (English)

    邓小荣; 杨镇

    2002-01-01

    The purpose of the present study was to assess the correlation that likely exists among increased portal pressure (Pp), portal blood flow quantity (Qp) and ETA and ETB receptor mRNA expression in human cirrhosis. In situ hybridization and reverse-transcription polymerase chain reactions (RT-PCR) were performed to determine the expression of ETA and ETB receptor mRNA in liver tissues from traumatic subjects (n= 10) and cirrhotic patients (n= 15) in whom hepatic hemodynamic values were measured. The expression of the two transcripts was significantly higher in liver samples of cirrhotic patients than in those obtained from traumatic subjects. It has shown that ETA receptor mRNA predominantly located in hepatic stellate cells (HSCs) and vascular smooth muscle cells of intrahepatic arteries and portal veins, ETB receptor mRNA in HSCs, sinusoidal endothelial cells and Kuppfer cells. There was a highly significant direct relationship between ETA and ETB receptor mRNA and Pp and Qp in cirrhotic patients. It suggests that liver paracrine endothelin system may be overactivated in human cirrhosis accompanied with increased expression of ETA and ETB receptor mRNA which may play an important role in the pathogenesis and maintenance of splanchnic hyperdynamics.

  10. Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice.

    Science.gov (United States)

    Van Steenkiste, Christophe; Ribera, Jordi; Geerts, Anja; Pauta, Montse; Tugues, Sònia; Casteleyn, Christophe; Libbrecht, Louis; Olievier, Kim; Schroyen, Ben; Reynaert, Hendrik; van Grunsven, Leo A; Blomme, Bram; Coulon, Stephanie; Heindryckx, Femke; De Vos, Martine; Stassen, Jean Marie; Vinckier, Stefan; Altamirano, Jose; Bataller, Ramón; Carmeliet, Peter; Van Vlierberghe, Hans; Colle, Isabelle; Morales-Ruiz, Manuel

    2011-05-01

    Placental growth factor (PlGF) is associated selectively with pathological angiogenesis, and PlGF blockade does not affect the healthy vasculature. Anti-PlGF is therefore currently being clinically evaluated for the treatment of cancer patients. In cirrhosis, hepatic fibrogenesis is accompanied by extensive angiogenesis. In this paper, we evaluated the pathophysiological role of PlGF and the therapeutic potential of anti-PlGF in liver cirrhosis. PlGF was significantly up-regulated in the CCl(4) -induced rodent model of liver cirrhosis as well as in cirrhotic patients. Compared with wild-type animals, cirrhotic PlGF(-/-) mice showed a significant reduction in angiogenesis, arteriogenesis, inflammation, fibrosis, and portal hypertension. Importantly, pharmacological inhibition with anti-PlGF antibodies yielded similar results as genetic loss of PlGF. Notably, PlGF treatment of activated hepatic stellate cells induced sustained extracellular signal-regulated kinase 1/2 phosphorylation, as well as chemotaxis and proliferation, indicating a previously unrecognized profibrogenic role of PlGF. PlGF is a disease-candidate gene in liver cirrhosis, and inhibition of PlGF offers a therapeutic alternative with an attractive safety profile. Copyright © 2011 American Association for the Study of Liver Diseases.

  11. [Digestive tract hemorrhages of cirrhotic patients. Relation between hepatic insufficiency and the hemorrhagic lesion].

    Science.gov (United States)

    Franco, D; Deporte, A; Darragon, T; Bismuth, H

    1975-12-06

    The cause of upper gastrointestinal bleeding was studied in 85 cirrhotic patients by emergency endoscopy. In every patient, one or several lesions were observed and the site of bleeding was ascertained in 59. The two main causes were oesophago-gastric varices (46 p.cent) and acute mucosal lesions(42 p.cent). The source of bleeding appeared to be related to the degree of liver function impairment. In patients with no or moderate liver function impariment, bleeding usually originated from varices or from drug-associated mucosal erosions. Patients with severe impairment of liver function most often bled from spontaneous acute oeso-gastro-duodenal ulcerations. These ulcerations resembled what has been described in "stress" hemorrhage. Because of the relationship between liver function and the cause of hemorrhage, mortality was lower in variceal bleeders (29 p.cent) than in patients with spontaneous ulcerations (83 p.cent). In patients with severely impaired liver function, portacaval shunt was rarely indicated since hemorrhage was generally due to acute mucosal ulcerations.

  12. Idiopathic non-cirrhotic intrahepatic portal hypertension: common cause of cryptogenic intrahepatic portal hypertension in a Southern Indian tertiary hospital.

    Science.gov (United States)

    Madhu, Kadiyala; Avinash, Balekuduru; Ramakrishna, Banumathi; Eapen, C E; Shyamkumar, N K; Zachariah, Uday; Chandy, George; Kurian, George

    2009-01-01

    Patients with intrahepatic portal hypertension and negative etiological work-up for liver disease are often labeled as having cryptogenic cirrhosis. The aim of this study was to evaluate causes of liver disease in patients with unexplained intrahepatic portal hypertension. We retrospectively analyzed cause of liver disease in all patients with cryptogenic intrahepatic portal hypertension who underwent liver biopsies between June 2005 to June 2007 in our center. Five hundred and seventeen patients underwent liver biopsies of whom 227 had portal hypertension. Of these, the cause of liver disease could not be detected prior to liver biopsy in 62 patients. Causes of liver disease identified after liver biopsy in these 62 patients were: idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) (30 patients, 48%), cirrhosis (14), fatty liver disease (7) and other causes (11). Initial presentations in idiopathic NCIPH patients were splenomegaly and anemia (18 patients), variceal bleed (9) and ascites (3). Median age (range) of patients at first presentation was 32 (15-57) years, and 19 were male. Majority (90%) were in Child's class A. Hepatic vein pressure gradient was <5 mmHg in 2 of 7 NCIPH patients tested. We identified 30 patients with idiopathic NCIPH at our center over the 2 year study period. The clinical presentation and investigations of NCIPH closely mimic cryptogenic cirrhosis. Idiopathic NCIPH should be considered as a differential diagnosis of cryptogenic cirrhosis in India.

  13. Features of Hemodialysis in Cirrhotic Patients: Single Center Experience

    Directory of Open Access Journals (Sweden)

    Süleyman KÖZ

    2015-09-01

    Full Text Available OBJECTIVE: End-stage kidney disease and advanced cirrhosis are sometimes seen concomitantly. Our purpose was to compare hemodialysis (HD sessions in critically ill cirrhotic patients from ICU versus stable cirrhotic patients from outpatient clinic, and observe endurance of both stable and acutely ill cirrhotic patients to intermittent HD. MATERIAL and METHODS: All of the Child-Pugh class B or C cirrhotic patients requiring renal replacement therapy during a period of three years were included in the study. If hypotension, arrhythmia, bleeding, or any other health problems were present during dialysis, the dialysis session was regarded as a troubled session. RESULTS: There were two groups of patients. All of the stable patients lived more than three months, whereas all patients in the ICU group died within a month. Mean ultrafiltration volume per session was 1786±210 ml in ICU and 1616±266 ml in stable patients (p>0.05. The number of the troubled sessions was 24 in ICU and 1 in stable patients (p<0.0001. Bleeding was a problem in a minority of the patients. CONCLUSION: Intermittent HD may be an acceptable choice for stable cirrhotic dialysis patients. Hypotension is a frequent complication of intermittent HD in ICU patients.

  14. In Vitro Generation of Functional Liver Organoid-Like Structures Using Adult Human Cells.

    Directory of Open Access Journals (Sweden)

    Sarada Devi Ramachandran

    Full Text Available In this study we used differentiated adult human upcyte® cells for the in vitro generation of liver organoids. Upcyte® cells are genetically engineered cell strains derived from primary human cells by lenti-viral transduction of genes or gene combinations inducing transient proliferation capacity (upcyte® process. Proliferating upcyte® cells undergo a finite number of cell divisions, i.e., 20 to 40 population doublings, but upon withdrawal of proliferation stimulating factors, they regain most of the cell specific characteristics of primary cells. When a defined mixture of differentiated human upcyte® cells (hepatocytes, liver sinusoidal endothelial cells (LSECs and mesenchymal stem cells (MSCs was cultured in vitro on a thick layer of Matrigel™, they self-organized to form liver organoid-like structures within 24 hours. When further cultured for 10 days in a bioreactor, these liver organoids show typical functional characteristics of liver parenchyma including activity of cytochromes P450, CYP3A4, CYP2B6 and CYP2C9 as well as mRNA expression of several marker genes and other enzymes. In summary, we hereby describe that 3D functional hepatic structures composed of primary human cell strains can be generated in vitro. They can be cultured for a prolonged period of time and are potentially useful ex vivo models to study liver functions.

  15. Cloning and characterization of human liver cytosolic beta-glycosidase

    NARCIS (Netherlands)

    De Graaf, M; Van Veen, IC; Van Der Meulen-Muileman, IH; Gerritsen, WR; Pinedo, HM; Haisma, HJ

    2001-01-01

    Cytosolic beta -glucosidase (EC 3.2.1.21) from mammalian liver is a member of the family 1 glycoside hydrolases and is known for its ability to hydrolyse a range of beta -D-glycosides. including beta -D-glucoside acid beta -D-galactoside. We therefore refer to this enzyme as cytosolic beta

  16. Effect of early propranolol administration on portal hypertensive gastropathy in cirrhotic rats

    Institute of Scientific and Technical Information of China (English)

    Savas Rafailidis; Charalampos Demertzidis; Konstantinos Ballas; Michail Alatsakis; Nikolaos Symeonidis; Theodoros Pavlidis; Kyriakos Psarras; Valentini Tzioufa-Asimakopoulou; Athanassios Sakadamis

    2009-01-01

    AIM: To investigate any protective effect of early propranolol administration in the development of portal hypertensive gastropathy in cirrhotic rats. METHODS: For the development of liver cirrhosis and portal hypertensive gastropathy, 60 rats underwent ligation of the left adrenal vein and complete devascularization of the left renal vein, followed by phenobarbital and carbon tetrachloride (CCl4) administration. After two weeks of CCl4 administration, the rats were randomly separated into two groups. In group A, propranolol was continuously administered intragastrically throughout the study, whereas in group B normal saline (placebo) was administered instead. Hemodynamic studies and vascular morphometric analysis of gastric sections were performed after complete induction of cirrhosis. RESULTS: Vascular morphometric studies showed higher numbers of vessels in all mucosal layers in the control group. Statistical analysis revealed a significantly higher total vascular surface in the control group compared to the propranolol group, but with no statistically significant difference between the mean vascular surfaces between the groups. Our study clearly shows that the increased mucosal blood flow is manifested by a marked increase of vessel count. CONCLUSION: Early propranolol's administration in portal hypertensive cirrhotic rats seems to prevent intense gastric vascular congestion that characterizes portal hypertensive gastropathy.

  17. Hepatocellular carcinoma in cirrhotic patients: prospective comparison of US, CT and MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Di Martino, Michele; De Filippis, Gianmaria; Geiger, Daniel; Del Monte, Maurizio; Lombardo, Concetta Valentina; Catalano, Carlo [University of Rome ' ' Sapienza' ' , Department of Radiological Sciences, Oncology and Anatomical Pathology, Rome (Italy); De Santis, Adriano; Corradini, Stefano Ginanni [University of Rome ' ' Sapienza' ' , Department of Clinical Medicine, Division of Gastroenterology, Rome (Italy); Rossi, Massimo; Mennini, Gianluca [University of Rome ' ' Sapienza' ' , Department of General Surgery, Division of Organ Transplantation, Rome (Italy)

    2013-04-15

    To prospectively compare the diagnostic performance of ultrasound (US), multidetector computed tomography (MDCT) and contrast-enhanced magnetic resonance imaging (MRI) in cirrhotic patients who were candidates for liver transplantation. One hundred and forty consecutive patients with 163 hepatocellular carcinoma (HCC) nodules underwent US, MRI and MDCT. Diagnosis of HCC was based on pathological findings or substantial growth at 12-month follow-up. Four different image datasets were evaluated: US, MDCT, MRI unenhanced and dynamic phases, MRI unenhanced dynamic and hepatobiliary phase. Diagnostic accuracy, sensitivity, specificity, PPV and NPV, with corresponding 95 % confidence intervals, were determined. Statistical analysis was performed for all lesions and for three lesion subgroups (<1 cm, 1-2 cm, >2 cm). Significantly higher diagnostic accuracy, sensitivity and NPV was achieved on dynamic + hepatobiliary phase MRI compared with US, MDCT and dynamic phase MRI alone. The specificity and PPV of US was significantly lower than that of MDCT, dynamic phase MRI and dynamic + hepatobiliary phase MRI. Similar results were obtained for all sub-group analyses, with particular benefit for the diagnosis of smaller lesions between 1 and 2 cm. Dynamic + hepatobiliary phase MRI improved detection and characterisation of HCC in cirrhotic patients. The greatest benefit is for diagnosing lesions between 1 and 2 cm. (orig.)

  18. Studies on adenosine triphosphate transphosphorylases. Human isoenzymes of adenylate kinase: isolation and physicochemical comparison of the crystalline human ATP-AMP transphosphorylases from muscle and liver.

    Science.gov (United States)

    Kuby, S A; Fleming, G; Frischat, A; Cress, M C; Hamada, M

    1983-02-10

    Procedures are described for the isolation, in crystalline form, of the adenylate kinases from autopsy samples of human muscle and from human liver. Weight average molecular weights were determined by sedimentation equilibrium to be 22,000 (+/- 700) and 25,450 (+/- 160) for the human muscle and liver isoenzymes, respectively. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis, their molecular weights were estimated to be 21,700 and 26,500 for the muscle and liver enzymes, respectively. Both isoenzymes are accordingly monomeric proteins in their native state. Amino acid analyses are reported here for the normal human liver, calf liver, and rabbit liver adenylate kinases and compared with the normal human muscle, calf muscle, and rabbit muscle myokinases. The liver types as a group and the muscle types as a group show a great deal of homology, but some distinct differences are evident between the liver and muscle enzyme groups, especially in the number of residues of His, Pro, half-cystine, and the presence of tryptophan in the liver enzymes. The normal human liver adenylate kinase, as isolated in this report, has proved to be similar in its properties, if not identical, to the adenylate kinase isolated directly from human liver mitochondria (Hamada, M., Sumida, M., Okuda, H., Watanabe, T., Nojima, M., and Kuby, S. A. (1982) J. Biol. Chem. 257, 13120-13128). Therefore, the liver-type adenylate kinase may be considered a mitochondrial type.

  19. Proteomic analysis of tyrosine phosphorylation during human liver transplantation

    Directory of Open Access Journals (Sweden)

    Boutros Tarek

    2007-01-01

    Full Text Available Abstract Background Ischemia-reperfusion (I/R causes a dramatic reprogramming of cell metabolism during liver transplantation and can be linked to an alteration of the phosphorylation level of several cellular proteins. Over the past two decades, it became clear that tyrosine phosphorylation plays a pivotal role in a variety of important signalling pathways and was linked to a wide spectrum of diseases. Functional profiling of the tyrosine phosphoproteome during liver transplantation is therefore of great biological significance and is likely to lead to the identification of novel targets for drug discovery and provide a basis for novel therapeutic strategies. Results Using liver biopsies collected during the early phases of organ procurement and transplantation, we aimed at characterizing the global patterns of tyrosine phosphorylation during hepatic I/R. A proteomic approach, based on the purification of tyrosine phosphorylated proteins followed by their identification using mass spectrometry, allowed us to identify Nck-1, a SH2/SH3 adaptor, as a potential regulator of I/R injury. Using immunoblot, cell fractionation and immunohistochemistry, we demonstrate that Nck-1 phosphorylation, expression and localization were affected in liver tissue upon I/R. In addition, mass spectrometry identification of Nck-1 binding partners during the course of the transplantation also suggested a dynamic interaction between Nck-1 and actin during I/R. Conclusion Taken together, our data suggest that Nck-1 may play a role in I/R-induced actin reorganization, which was previously reported to be detrimental for the hepatocytes of the transplanted graft. Nck-1 could therefore represent a target of choice for the design of new organ preservation strategies, which could consequently help to reduce post-reperfusion liver damages and improve transplantation outcomes.

  20. Cirrhotic patients have good insight into their daily functional impairment despite prior hepatic encephalopathy: comparison with PROMIS norms.

    Science.gov (United States)

    Bajaj, Jasmohan S; White, Melanie B; Unser, Ariel B; Ganapathy, Dinesh; Fagan, Andrew; Gavis, Edith A; Sterling, Richard K; Heuman, Douglas M; Matherly, Scott; Puri, Puneet; Sanyal, Arun J; Luketic, Velimir; Fuchs, Michael; Siddiqui, Muhammad S; Stravitz, R Todd; John, Binu; Thacker, Leroy R; Wade, James B

    2016-10-01

    Health-related quality of life (HRQOL) is an important determinant of prognosis in cirrhosis and hepatic encephalopathy (HE). However due to inherent cognitive dysfunction, insight into HRQOL severity in patients with liver disease may be impaired. To assess insight into HRQOL using PROMIS tools compared to norms in cirrhotic patients. PROMIS tools are validated HRQOL instruments that test the domains of anger, anxiety, depression, physical function, pain behavior/impact, sleep disturbances/impairment, and social activities/roles, compared to US-norms. Patients were administered the PROMIS tools, the results of which were reviewed using a visual comparison with thed norms. Then two Likert scales from 0 to 10 per domain were administered that inquired about (1) Surprise Intensity: 0-4: not surprised, 5-10: surprised; and (2) Expectancies: 0-4: results better than expected, 5:10: as/worse than expected. Comparisons between HE/no-HE were also performed. 203 cirrhotic patients (57 yrs., 62 % men, MELD 12, 83 HE) were included. All HE patients were controlled on therapy. Prior HE patients were significantly impaired on all PROMIS domains (p PROMIS results were better than expected. Prior HE status did not significantly impact expectations or surprise based on placement with the norms. The majority of cirrhotic patients, regardless of prior HE, have good insight regarding their HRQOL issues.

  1. Is administrating branched-chain amino acid-enriched nutrition achieved symptom-free in malnourished cirrhotic patients?

    Science.gov (United States)

    Tsuda, Yasuhiro; Fukui, Hideo; Sujishi, Tetsuya; Ohama, Hideko; Tsuchimoto, Yusuke; Asai, Akira; Fukunisi, Shinya; Higuchi, Kazuhide

    2014-01-01

    Administration of branched-chain amino acids (BCAA) has been reported to improve liver function, quality of life (QOL). However, in some malnourished patients, serum albumin levels do not improve in response to BCAA granules. In this study, we examined the effects of BCAA-enriched enteral nutrition in patients unresponsive to BCAA granules. Thirty-two decompensated cirrhotic patients at Osaka Medical College were enrolled in this study. Since all patients showed no improvement in serum albumin levels despite 3 months of BCAA granule administration, they were administered 50 g of a flavored BCAA-enriched enteral nutrient twice daily, i.e., during the daytime and late evening. Serum albumin levels and major cirrhotic symptoms were examined 1, 3, and 5 months after treatment initiation. Serum albumin levels improved significantly 3 months after treatment initiation (3.14 ± 0.32 g/dl vs 3.5 ± 0.31 g/dl, pBCAA-enriched nutrients improves QOL of cirrhotic patients unresponsive to BCAA granules.

  2. Effects of recombinant human growth hormone on remnant liver after hepatectomy in hepatocellular carcinoma with cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Shi-Min Luo; Li-Jian Liang; Jia-Ming Lai

    2004-01-01

    AIM: To explore the effects of recombinant human growth hormone (rhGH) on the remnant liver after hepatectomy in hepatocellular carcinoma with liver cirrhosis.METHODS: Twenty-four patients with hepatocellular carcinoma who underwent hepatectomy were randomly divided into 2groups: parenteral nutrition (PN) group (n=12) and rhGH+PN group (n=12). Liver function, blood glucose, AFP, serum prealbumin and transferrin were detected before operation,at post-operative d 1 and d 6. Albumin (ALB) mRNA in liver biopsy specimens was detected by RT-PCR at post-operative d 6. Liver Ki67 immunohistochemical staining was studied.RESULTS: On post-operative d 6, compared with PN group,the levels of blood glucose, serum prealbumin, transferrin,the expression of hepatic ALB mRNA and liver Ki67 labeling index were higher in rhGH+PN group.CONCLUSION: rhGH can improve protein synthesis and liver regeneration after hepatectomy in hepatocellular carcinoma with liver cirrhosis.

  3. Human Adipose Tissue Derived Stem Cells Promote Liver Regeneration in a Rat Model of Toxic Injury

    Directory of Open Access Journals (Sweden)

    Eva Koellensperger

    2013-01-01

    Full Text Available In the light of the persisting lack of donor organs and the risks of allotransplantations, the possibility of liver regeneration with autologous stem cells from adipose tissue (ADSC is an intriguing alternative. Using a model of a toxic liver damage in Sprague Dawley rats, generated by repetitive intraperitoneal application of retrorsine and allyl alcohol, the ability of human ADSC to support the restoration of liver function was investigated. A two-thirds hepatectomy was performed, and human ADSC were injected into one remaining liver lobe in group 1 (n = 20. Injection of cell culture medium performed in group 2 (n = 20 served as control. Cyclosporine was applied to achieve immunotolerance. Blood samples were drawn weekly after surgery to determine liver-correlated blood values. Six and twelve weeks after surgery, animals were sacrificed and histological sections were analyzed. ADSC significantly raised postoperative albumin (P < 0.017, total protein (P < 0.031, glutamic oxaloacetic transaminase (P < 0.001, and lactate dehydrogenase (P < 0.04 levels compared to injection of cell culture medium alone. Transplanted cells could be found up to twelve weeks after surgery in histological sections. This study points towards ADSC being a promising alternative to hepatocyte or liver organ transplantation in patients with severe liver failure.

  4. Human liver morphine UDP-glucuronyl transferase enantioselectivity and inhibition by opioid congeners and oxazepam.

    OpenAIRE

    Wahlström, A; Pacifici, G. M.; Lindström, B; Hammar, L.; Rane, A.

    1988-01-01

    1. Morphine uridine diphosphate glucuronyl transferase (UDP-GT) was studied in human liver microsomes. The (-)- and (+)-morphine enantiomers were used as substrates and inhibitors, such as oxazepam and various opioid congeners were employed to characterize the different glucuronidation pathways. The kinetics of the oxazepam inhibition were studied in the rat liver. 2. The overall glucuronidation of (+)-morphine was higher than that of (-)-morphine. The morphine congeners tested, potently inhi...

  5. In Vitro Generation of Functional Liver Organoid-Like Structures Using Adult Human Cells

    NARCIS (Netherlands)

    Ramachandran, S.D.; Schirmer, K.; Munst, B.; Heinz, S.; Ghafoory, S.; Wolfl, S.; Simon-Keller, K.; Marx, A.; Oie, C.I.; Ebert, M.P.; Walles, H.; Braspenning, J.C.; Breitkopf-Heinlein, K.

    2015-01-01

    In this study we used differentiated adult human upcyte(R) cells for the in vitro generation of liver organoids. Upcyte(R) cells are genetically engineered cell strains derived from primary human cells by lenti-viral transduction of genes or gene combinations inducing transient proliferation capacit

  6. A new human 3D-liver model unravels the role of galectins in liver infection by the parasite Entamoeba histolytica.

    Directory of Open Access Journals (Sweden)

    Debora B Petropolis

    2014-09-01

    Full Text Available Investigations of human parasitic diseases depend on the availability of appropriate in vivo animal models and ex vivo experimental systems, and are particularly difficult for pathogens whose exclusive natural hosts are humans, such as Entamoeba histolytica, the protozoan parasite responsible for amoebiasis. This common infectious human disease affects the intestine and liver. In the liver sinusoids E. histolytica crosses the endothelium and penetrates into the parenchyma, with the concomitant initiation of inflammatory foci and subsequent abscess formation. Studying factors responsible for human liver infection is hampered by the complexity of the hepatic environment and by the restrictions inherent to the use of human samples. Therefore, we built a human 3D-liver in vitro model composed of cultured liver sinusoidal endothelial cells and hepatocytes in a 3D collagen-I matrix sandwich. We determined the presence of important hepatic markers and demonstrated that the cell layers function as a biological barrier. E. histolytica invasion was assessed using wild-type strains and amoebae with altered virulence or different adhesive properties. We showed for the first time the dependence of endothelium crossing upon amoebic Gal/GalNAc lectin. The 3D-liver model enabled the molecular analysis of human cell responses, suggesting for the first time a crucial role of human galectins in parasite adhesion to the endothelial cells, which was confirmed by siRNA knockdown of galectin-1. Levels of several pro-inflammatory cytokines, including galectin-1 and -3, were highly increased upon contact of E. histolytica with the 3D-liver model. The presence of galectin-1 and -3 in the extracellular medium stimulated pro-inflammatory cytokine release, suggesting a further role for human galectins in the onset of the hepatic inflammatory response. These new findings are relevant for a better understanding of human liver infection by E. histolytica.

  7. A new human 3D-liver model unravels the role of galectins in liver infection by the parasite Entamoeba histolytica.

    Science.gov (United States)

    Petropolis, Debora B; Faust, Daniela M; Deep Jhingan, Gagan; Guillen, Nancy

    2014-09-01

    Investigations of human parasitic diseases depend on the availability of appropriate in vivo animal models and ex vivo experimental systems, and are particularly difficult for pathogens whose exclusive natural hosts are humans, such as Entamoeba histolytica, the protozoan parasite responsible for amoebiasis. This common infectious human disease affects the intestine and liver. In the liver sinusoids E. histolytica crosses the endothelium and penetrates into the parenchyma, with the concomitant initiation of inflammatory foci and subsequent abscess formation. Studying factors responsible for human liver infection is hampered by the complexity of the hepatic environment and by the restrictions inherent to the use of human samples. Therefore, we built a human 3D-liver in vitro model composed of cultured liver sinusoidal endothelial cells and hepatocytes in a 3D collagen-I matrix sandwich. We determined the presence of important hepatic markers and demonstrated that the cell layers function as a biological barrier. E. histolytica invasion was assessed using wild-type strains and amoebae with altered virulence or different adhesive properties. We showed for the first time the dependence of endothelium crossing upon amoebic Gal/GalNAc lectin. The 3D-liver model enabled the molecular analysis of human cell responses, suggesting for the first time a crucial role of human galectins in parasite adhesion to the endothelial cells, which was confirmed by siRNA knockdown of galectin-1. Levels of several pro-inflammatory cytokines, including galectin-1 and -3, were highly increased upon contact of E. histolytica with the 3D-liver model. The presence of galectin-1 and -3 in the extracellular medium stimulated pro-inflammatory cytokine release, suggesting a further role for human galectins in the onset of the hepatic inflammatory response. These new findings are relevant for a better understanding of human liver infection by E. histolytica.

  8. [Liver damage caused by drugs].

    Science.gov (United States)

    Strohmeyer, G; Weik, C

    1999-05-01

    The liver has a central role in the metabolism of many drugs, since this organ is the main site of biotransformation of endo- and xenobiotics. Water-soluble drugs have a small volume of distribution and can be eliminated unchanged in the urine. By contrast, lipid-soluble drugs have a larger volume of distribution and require conversion to water-soluble metabolites for their elimination in urine or bile. The liver with its specific receptors, transporters and enzymes is responsible for the uptake, transformation and excretion of the lipophilic drugs. While most of the drugs are transformed into stable metabolites, other drugs form reactive, potentially toxic, metabolites producing liver cell damage. Liver injury caused by drugs may mimic almost any kind of liver disease. Clinical findings are gastrointestinal symptoms with nausea, vomiting and abdominal pain, cholestatic liver injury with jaundice and pruritus of severe inflammatory and cirrhotic liver damage with signs of liver failure, encephalopathy and cerebral edema. The morphological changes vary from hepatitis, cholestasis, fatty liver, granulomatous hepatitis, peri-/portal inflammation, to fibrosis with cirrhotic alterations and vascular lesions and tumors. The most commonly used drugs causing severe liver injury are discussed in detail. These are anabolics, oral contraceptives, antituberculous and antifungal agents, nonsteroidal anti-inflammatory drugs, ring substituted amphetamins ("designer drugs"), antiarrhythmics and antibiotics.

  9. Propofol versus midazolam for upper gastrointestinal endoscopy in cirrhotic patients: a meta-analysis of randomized controlled trials.

    Directory of Open Access Journals (Sweden)

    Hsiao-Chien Tsai

    Full Text Available Sedation during gastrointestinal endoscopy is often achieved using propofol or midazolam in general population. However, impaired protein synthesis, altered drug metabolism, and compromised hepatic blood flow in patients with liver cirrhosis might affect the pharmacokinetics of sedatives, placing cirrhotic patients undergoing endoscopy at a greater risk of adverse events. The objective of this study was to assess comparative efficacies and safety of propofol and midazolam in cirrhotic patients undergoing endoscopy.Randomized, controlled trials comparing propofol with midazolam in cirrhotic patients undergoing gastrointestinal endoscopy were selected. We performed the meta-analysis, using a random-effect model, the Review Manager, Version 5.2, statistical software package (Cochrane Collaboration, Oxford, UK according to the PRISMA guidelines.Five studies between 2003 and 2012, including 433 patients, were included. Propofol provided a shorter time to sedation (weight mean difference: -2.76 min, 95% confidence interval: -3.00 to -2.51 and a shorter recovery time (weight mean difference -6.17 min, 95% confidence interval: -6.81 to -5.54 than midazolam did. No intergroup difference in the incidence of hypotension, bradycardia, or hypoxemia was observed. Midazolam was associated with the deterioration of psychometric scores for a longer period than propofol.This meta-analysis suggests that Propofol sedation for endoscopy provides more rapid sedation and recovery than midazolam does. The risk of sedation-related side effects for propofol does not differ significantly from that of midazolam. The efficacy of propofol in cirrhotic patients undergoing endoscopy is superior to those of midazolam.

  10. Propofol versus Midazolam for Upper Gastrointestinal Endoscopy in Cirrhotic Patients: A Meta-Analysis of Randomized Controlled Trials

    Science.gov (United States)

    Tsai, Hsiao-Chien; Lin, Yu-Cih; Ko, Ching-Lung; Lou, Horng-Yuan; Chen, Ta-Liang; Tam, Ka-Wai; Chen, Chien-Yu

    2015-01-01

    Background Sedation during gastrointestinal endoscopy is often achieved using propofol or midazolam in general population. However, impaired protein synthesis, altered drug metabolism, and compromised hepatic blood flow in patients with liver cirrhosis might affect the pharmacokinetics of sedatives, placing cirrhotic patients undergoing endoscopy at a greater risk of adverse events. The objective of this study was to assess comparative efficacies and safety of propofol and midazolam in cirrhotic patients undergoing endoscopy. Methods Randomized, controlled trials comparing propofol with midazolam in cirrhotic patients undergoing gastrointestinal endoscopy were selected. We performed the meta-analysis, using a random-effect model, the Review Manager, Version 5.2, statistical software package (Cochrane Collaboration, Oxford, UK) according to the PRISMA guidelines. Results Five studies between 2003 and 2012, including 433 patients, were included. Propofol provided a shorter time to sedation (weight mean difference: -2.76 min, 95% confidence interval: -3.00 to -2.51) and a shorter recovery time (weight mean difference -6.17 min, 95% confidence interval: -6.81 to -5.54) than midazolam did. No intergroup difference in the incidence of hypotension, bradycardia, or hypoxemia was observed. Midazolam was associated with the deterioration of psychometric scores for a longer period than propofol. Conclusion This meta-analysis suggests that Propofol sedation for endoscopy provides more rapid sedation and recovery than midazolam does. The risk of sedation-related side effects for propofol does not differ significantly from that of midazolam. The efficacy of propofol in cirrhotic patients undergoing endoscopy is superior to those of midazolam. PMID:25646815

  11. [Endotoxinaemia in liver cirrhosis (author's transl)].

    Science.gov (United States)

    Nilius, R; Bernhardt, H; Zipprich, B; Knoke, M

    1980-01-01

    23 patients with liver cirrhosis of diverse etiology and of different activity levels and grades of compensation of the portal circulation were examined with regard to the systemic endotoxinaemia. The endotoxin was determined using the Limulus-Amoebocyte-Lysat-test. Endotoxin was traceable in the venous blood of 7 out of 23 patients (= 30,4%). No relation was found between endotoxaemia and the activity or grade of severity of liver cirrhosis; nor were there any accumulation of endotoxinaemia in patients with collateral circulation or portal decompensation. Consequently, as a result of our findings, the prognostic value of the symptom endotoxinaemia remains debatable, then endotoxinaemia does not always mean endotoxicosis. Particularly high immunoglobulin concentration and low albumin values in serum of endotoxin-positive cirrhotics indicate a "spillovet" of antigen substances and also of endotoxines in the body circulation resulting from insufficiency of the liver-RHS. Parallel analysis of microbian small bowel flora in 10 patients indicate that coli-dysbiosis appears to play a role in the development of systemic endoxinaemia, although the latter was also traceable in borderline cases of eubiosis/dysbiosis. Our findings strengthen the view that it is not possible to simply translate the findings in animals on to human liver diseases. Quite a number of the mechanisms being discussed are still with uncleared details and they give only a blurred picture of the pathophysiology of endotoxinaemia.

  12. Opisthorchis viverrini:The carcinogenic human liver fluke

    Institute of Scientific and Technical Information of China (English)

    Natthawut Kaewpitoon; Soraya J Kaewpitoon; Prasit Pengsaa; Banchob Sripa

    2008-01-01

    Opisthorchiasis caused by Opisthorchis viverrini remains a major public health problem in many parts of Southeast Asia,including Thailand,Lao PDR,Vietnam and Cambodia.The infection is associated with a number of hepatobiliary diseases,including cholangitis,obstructive jaundice,hepatomegaly,cholecystitis and cholelithiasis.Multi-factorial etiology of cholangiocarcinoma,mechanical damage,parasite secretions,and immunopathology may enhance cholangiocarcinogenesis.Moreover,both experimental and epidemiological evidences strongly implicate liver fluke infection as the major risk factor in cholangiocarcinoma,cancer of the bile ducts.The liver fluke infection is induced by eating raw or uncooked fish products that is the tradition and popular in the northeastern and northern region,particularly in rural areas,of Thailand.The health education programs to prevent and control opisthorchiasis are still required in the high-risk areas.

  13. Involvement of CYP2B6 in the biotransformation of propofol by human liver microsomes

    Institute of Scientific and Technical Information of China (English)

    TANG Bing; WANG Jun-ke; FENG Wan-yu

    2008-01-01

    Objective To determine whether the cytochrome P4502B6 (CYP2B6) is involved in the oxidation of propofol by human liver microsomes. Methods The change of propofol concentration in an incubation mixture with human liver microsomes was monitored by the high performance liquid chromatography (HPLC), in order to calculate the rate constants of metabolism of propofol. The correlation between the rate constants and the rate of metabolism of CYP2B6 selective substrate bupropion, and the effect of two different CYP2B6 specific inhibitors on the propofol metabolism were examined. Results The mean rate constant of propofol metabolism by liver microsomes obtained from twelve individuals was 3.9 (95 % confidence intervals 3.3, 4.5) nmol·min-1·mg-1 protein. The rate constants of propofol metabolism by liver microsomes were significantly correlated with bupropion hydroxylation (r=0.888, P<0.001). Both selective chemical inhibitors of CYP2B6, orphenadrine and N, N′, N″-triethylenethiophosphoramide (thioTEPA), reduced the rate constants of propofol metabolism by 37.596 (P<0.001) and 42.796 (P<0.001)in liver microsomes, respectively. Conclusions CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes.

  14. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    Energy Technology Data Exchange (ETDEWEB)

    Yannam, Govardhana Rao [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Han, Bing [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an, Shaanxi (China); Setoyama, Kentaro [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamamoto, Toshiyuki [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Ito, Ryotaro; Brooks, Jenna M. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Guzman-Lepe, Jorge [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Galambos, Csaba [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Fong, Jason V. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Deutsch, Melvin; Quader, Mubina A. [Department of Radiation Oncology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamanouchi, Kosho [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kabarriti, Rafi; Mehta, Keyur [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Soto-Gutierrez, Alejandro [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

  15. CONCENTRATION AND HEMODYNAMICS PATTERN CHANGES IN CIRRHOTIC RATS

    Institute of Scientific and Technical Information of China (English)

    黄颖秋; 萧树东; 莫剑忠; 张德中

    2000-01-01

    Objective To investigate the effects of hemoglobin (Hb) on serum nitric oxide (NO) concentration and hemodynamics pattern changes in rats with cirrhosis. Methods Cirrhosis model was induced in male SD rats by injection of 60% CCl4 oily solution subcutaneously. Cirrhotic rats were treated with erythropoietin (l00U/kg) injected subcutaneously for 2 weeks. Mean arterial pressure (MAP), cardiac output (CO), cardiac index (CI), splanchnic vascular resistance (SVR), splanchnic blood flow (SBF) and serum NO concentration were determined in erythropoietin - treated, erythropoietin - untreated cirrhotic rats and controls by using 57Co- labelled microsphere technique and a fluorometric assay, respectively. In addition, blood Hb levels were also measured in the 3 groups. Results Untreated cirrhotic rats had significantly lower MAP, SVR, Hb and higher CO, CI, SBF and NO concentration than those of the controls (P<0.01). In treated cirrhotic rats, erythropoietin significantly attenuated the increase of CO, CI, SBF, NO concentration and the decrease of MAP and SVR. In cirrhotic rats,epoetin beta in subcutaneous dose of 100U· kg-1· d-1 induced a markedly increment of blood Hb levels and decrement of NO concentration in comparison with untreated cirrhotic rats (181±11g/L vs 120±15g/L;1.14±0.62μmol/L vs 4.20±1.25μmol/L). Conclusion The endogenous NO may play an important role in the changes of hemodynamics pattern in cirrhosis, and hyperdynamic circulatory status in rats with cirrhosis might be ameliorated by inactivation of overproduced NO by increasing hemoglobin with erythropoietin.

  16. Functional Integrity of the Chimeric (Humanized) Mouse Liver: Enzyme Zonation, Physiologic Spaces, and Hepatic Enzymes and Transporters.

    Science.gov (United States)

    Chow, Edwin C Y; Wang, Jason Z Ya; Quach, Holly P; Tang, Hui; Evans, David C; Li, Albert P; Silva, Jose; Pang, K Sandy

    2016-09-01

    Chimeric mouse liver models are useful in vivo tools for human drug metabolism studies; however, liver integrity and the microcirculation remain largely uninvestigated. Hence, we conducted liver perfusion studies to examine these attributes in FRGN [Fah(-/-), Rag2(-/-), and Il2rg(-/-), NOD strain] livers (control) and chimeric livers repopulated with mouse (mFRGN) or human (hFRGN) hepatocytes. In single-pass perfusion studies (2.5 ml/min), outflow dilution profiles of noneliminated reference indicators ((51)Cr-RBC, (125)I-albumin, (14)C-sucrose, and (3)H-water) revealed preservation of flow-limited distribution and reduced water and albumin spaces in hFRGN livers compared with FRGN livers, a view supported microscopically by tightly packed sinusoids. With prograde and retrograde perfusion of harmol (50 µM) in FRGN livers, an anterior sulfation (Sult1a1) over the posterior distribution of glucuronidation (Ugt1a1) activity was preserved, evidenced by the 42% lower sulfation-to-glucuronidation ratio (HS/HG) and 14% higher harmol extraction ratio (E) upon switching from prograde to retrograde flow. By contrast, zonation was lost in mFRGN and hFRGN livers, with HS/HG and E for both flows remaining unchanged. Remnant mouse genes persisted in hFRGN livers (10%-300% those of FRGN). When hFRGN livers were compared with human liver tissue, higher UGT1A1 and MRP2, lower MRP3, and unchanged SULT1A1 and MRP4 mRNA expression were observed. Total Sult1a1/SULT1A1 protein expression in hFRGN livers was higher than that of FRGN livers, consistent with higher harmol sulfate formation. The composite data on humanized livers suggest a loss of zonation, lack of complete liver humanization, and persistence of murine hepatocyte activities leading to higher sulfation.

  17. Estimation of the Functional Reserve of Human Liver

    Science.gov (United States)

    Moody, Frank G.; Rikkers, Layton F.; Aldrete, Joaquin S.

    1974-01-01

    Functional hepatic reserve was determined in 32 patients with known liver or biliary tract disease employing kinetic analysis of hepatic removal of indocyanine green (ICG). The initial removal rates of incremental doses of ICG (0.5, 1.0 and 5.0 mg/kg body weight) were plotted as a reciprocal against the inverse of dose (Lineweaver-Burk plot) to provide a means of determining maximal removal rate from submaximal doses (Rmax). This function equalled 3.40 mg/kg/min in ten patients with normal livers, but was only .24 mg/kg/min in eight patients with alcoholic cirrhosis. Portasystemic shunting did not further influence Rmax. Infiltrative liver disease had only a mild depressive effect on this function. The results show that hepatic function can be precisely quantitated by classical enzyme kinetics (Michaelis-Menten). If Rmax is an estimate of protein receptor mass for organic anions, then the technique may allow an indirect means for quantitating hepatocytes even in the presence of changes in blood flow or hepatic function. The profound depression in Rmax observed in patients with alcoholic cirrhosis is consistent with the progressive loss in hepatic mass associated with this disease. PMID:4413286

  18. Reelin expression in human liver of patients with chronic hepatitis C infection

    Directory of Open Access Journals (Sweden)

    Simone Carotti

    2017-03-01

    Full Text Available Reelin is a secreted extracellular glycoprotein that plays a critical role during brain development. Several studies have described Reelin expression in hepatic stellate cells of the human liver. In order to investigate the possible role of Reelin in the process of hepatic fibrogenesis, in this study we investigated Reelin expression in the liver tissue of patients infected with the Hepatitis C Virus (HCV. On this basis, Reelin expression was analysed by immunohistochemistry during liver biopsies of 81 patients with HCV-related chronic hepatitis. A Knodell score was used to stage liver fibrosis. Hepatic stellate cells/myofibroblast immunohistochemical markers (CRBP-1, alpha-SMA were also evaluated. As further confirmed by co-localization experiments (Reelin +CRBP-1, Reelin protein was expressed by hepatic stellate cells/myofibroblasts, and a significant positive correlation was found between Reelin expression and the stage of liver fibrosis (P=0.002. Moreover, Reelin correlated with CRBP-1 positive cells (P=0.002, but not with alpha-SMA, suggesting that Reelin should not be regarded as a marker of hepatic stellate cells/myofibroblasts differentiation but rather as a functional protein expressed during some phases of liver fibrosis. Furthermore, Disabled-1 (Dab1, a Reelin adaptor protein, was expressed in cells of ductular reaction suggesting a paracrine role for Reelin with regards these elements. In conclusion, Reelin was expressed by human hepatic stellate cells/myofibroblasts and the number of these cells increased significantly in the lobule as the liver fibrosis progressed, suggesting a role for Reelin in the activation of hepatic stellate cells/myofibroblasts during liver injury. Reelin may potentially be incorporated into liver injury evaluations in combination with other histological data.

  19. Reelin Expression in Human Liver of Patients with Chronic Hepatitis C Infection

    Science.gov (United States)

    Carotti, Simone; Perrone, Giuseppe; Amato, Michelina; Gentilucci, Umberto Vespasiani; Righi, Daniela; Francesconi, Maria; Pellegrini, Claudio; Zalfa, Francesca; Zingariello, Maria; Picardi, Antonio; Muda, Andrea Onetti; Morini, Sergio

    2017-01-01

    Reelin is a secreted extracellular glyco-protein that plays a critical role during brain development. Several studies have described Reelin expression in hepatic stellate cells of the human liver. In order to investigate the possible role of Reelin in the process of hepatic fibrogenesis, in this study we investigated Reelin expression in the liver tissue of patients infected with the Hepatitis C Virus (HCV). On this basis, Reelin expression was analysed by immunohistochemistry during liver biopsies of 81 patients with HCV-related chronic hepatitis. A Knodell score was used to stage liver fibrosis. Hepatic stellate cells/myofibroblast immunohistochemical markers (CRBP-1, alpha-SMA) were also evaluated. As further confirmed by colocalization experiments (Reelin +CRBP-1), Reelin protein was expressed by hepatic stellate cells/myofibroblasts, and a significant positive correlation was found between Reelin expression and the stage of liver fibrosis (P=0.002). Moreover, Reelin correlated with CRBP-1 positive cells (P=0.002), but not with alpha-SMA, suggesting that Reelin should not be regarded as a marker of hepatic stellate cells/myofibroblasts differentiation but rather as a functional protein expressed during some phases of liver fibrosis. Furthermore, Disabled-1 (Dab1), a Reelin adaptor protein, was expressed in cells of ductular reaction suggesting a paracrine role for Reelin with regards these elements. In conclusion, Reelin was expressed by human hepatic stellate cells/myofibroblasts and the number of these cells increased significantly in the lobule as the liver fibrosis progressed, suggesting a role for Reelin in the activation of hepatic stellate cells/myofibroblasts during liver injury. Reelin may potentially be incorporated into liver injury evaluations in combination with other histological data. PMID:28348420

  20. Human fetal liver stromal cells expressing erythropoietin promote hematopoietic development from human embryonic stem cells.

    Science.gov (United States)

    Yang, Chao; Ji, Lei; Yue, Wen; Shi, Shuang-Shuang; Wang, Ruo-Yong; Li, Yan-Hua; Xie, Xiao-Yan; Xi, Jia-Fei; He, Li-Juan; Nan, Xue; Pei, Xue-Tao

    2012-02-01

    Blood cells transfusion and hematopoietic stem cells (HSCs) transplantation are important methods for cell therapy. They are widely used in the treatment of incurable hematological disorder, infectious diseases, genetic diseases, and immunologic deficiency. However, their availability is limited by quantity, capacity of proliferation and the risk of blood transfusion complications. Recently, human embryonic stem cells (hESCs) have been shown to be an alternative resource for the generation of hematopoietic cells. In the current study, we describe a novel method for the efficient production of hematopoietic cells from hESCs. The stable human fetal liver stromal cell lines (hFLSCs) expressing erythropoietin (EPO) were established using the lentiviral system. We observed that the supernatant from the EPO transfected hFLSCs could induce the hESCs differentiation into hematopoietic cells, especially erythroid cells. They not only expressed fetal and embryonic globins but also expressed the adult-globin chain on further maturation. In addition, these hESCs-derived erythroid cells possess oxygen-transporting capacity, which indicated hESCs could generate terminally mature progenies. This should be useful for ultimately developing an animal-free culture system to generate large numbers of erythroid cells from hESCs and provide an experimental model to study early human erythropoiesis.

  1. Automated low-flow ascites pump for the treatment of cirrhotic patients with refractory ascites

    Science.gov (United States)

    Stirnimann, Guido; Banz, Vanessa; Storni, Federico; De Gottardi, Andrea

    2017-01-01

    Cirrhotic patients with refractory ascites (RA) can be treated with repeated large volume paracentesis (LVP), with the insertion of a transjugular intrahepatic portosystemic shunt (TIPS) or with liver transplantation. However, side effects and complications of these therapeutic options, as well as organ shortage, warrant the development of novel treatments. The automated low-flow ascites pump (alfapump®) is a subcutaneously-implanted novel battery-driven device that pumps ascitic fluid from the peritoneal cavity into the urinary bladder. Ascites can therefore be aspirated in a time- and volume-controlled mode and evacuated by urination. Here we review the currently available data about patient selection, efficacy and safety of the alfapump and provide recommendations for the management of patients treated with this new method. PMID:28203285

  2. Non-invasive measurement of hepatic oxygenation by an oxygen electrode in human orthotopic liver transplantation.

    Science.gov (United States)

    Seifalian, A M; Mallett, S; Piasecki, C; Rolles, K; Davidson, B R

    2000-06-01

    Precise evaluation of graft reperfusion is difficult in clinical liver transplantation. The oxygen electrode (OE) is a novel technique to detect blood flow indirectly by measuring the quantity of oxygen which can diffuse from the hepatic tissue to the surface electrode. Application of the surface OE does not influence the liver blood flow or parenchymal perfusion. Adequate graft oxygenation is essential to the outcome of organ transplantation and has not previously been analysed intra-operatively in liver transplant recipients. The OE was applied to the surface of the graft intra-operatively in 22 human liver grafts after restoring portal vein and hepatic artery inflow. OE readings were compared with liver blood flow using an electromagnetic flowmeter (EMF). Intra-operative haemodynamics and donor organ parameters known to influence graft function were correlated with the OE readings. There was a significant correlation (r=0.89; poxygenation using the OE and total liver blood flow measured by EMF. The tissue oxygenation measurements were reproducible with a coefficient of variation of 5%. The hepatic tissue oxygenation increased significantly from baseline following venous reperfusion of the graft (282+/-23 vs 3107+/-288 (+/-SE) nA, poxygen perfusion. There was significant negative correlation (r=0.80, poxygenation. The OE provides a reliable, cheap and non-invasive method of monitoring liver graft oxygenation and perfusion during transplantation.

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

    Institute of Scientific and Technical Information of China (English)

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

    2015-01-01

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

  4. Successful transplantation of human hepatic stem cells with restricted localization to liver using hyaluronan grafts.

    Science.gov (United States)

    Turner, Rachael A; Wauthier, Eliane; Lozoya, Oswaldo; McClelland, Randall; Bowsher, James E; Barbier, Claire; Prestwich, Glenn; Hsu, Edward; Gerber, David A; Reid, Lola M

    2013-02-01

    Cell therapies are potential alternatives to organ transplantation for liver failure or dysfunction but are compromised by inefficient engraftment, cell dispersal to ectopic sites, and emboli formation. Grafting strategies have been devised for transplantation of human hepatic stem cells (hHpSCs) embedded into a mix of soluble signals and extracellular matrix biomaterials (hyaluronans, type III collagen, laminin) found in stem cell niches. The hHpSCs maintain a stable stem cell phenotype under the graft conditions. The grafts were transplanted into the livers of immunocompromised murine hosts with and without carbon tetrachloride treatment to assess the effects of quiescent versus injured liver conditions. Grafted cells remained localized to the livers, resulting in a larger bolus of engrafted cells in the host livers under quiescent conditions and with potential for more rapid expansion under injured liver conditions. By contrast, transplantation by direct injection or via a vascular route resulted in inefficient engraftment and cell dispersal to ectopic sites. Transplantation by grafting is proposed as a preferred strategy for cell therapies for solid organs such as the liver.

  5. Human liver tumors in relation to steroidal usage.

    Science.gov (United States)

    Barrows, G H; Christopherson, W M

    1983-01-01

    Since 1973 a number of investigators have reported an association between liver neoplasia and steroid usage. Through referral material we have examined the histology of over 250 cases of hepatic neoplasia, most in patients receiving steroid medications. The majority have been benign, predominantly focal nodular hyperplasia (55%) and hepatocellular adenoma (39%). The average age was 31.4 years; 83% had significant steroid exposure with an average duration of 71 months for focal nodular hyperplasia and 79.6 months for hepatocellular adenoma. The type of estrogenic agent was predominantly mestranol; however, during the period mestranol was the most frequently used synthetic steroid. A distinct clinical entity of life threatening hemorrhage from the lesion occurred in 31% of patients with hepatocellular adenoma and 9% of patients with focal nodular hyperplasia. Recurrence of benign tumors has occurred in some patients who continued using steroids and regression has been observed in patients who had incomplete tumor removal but discontinued steroid medication. Medial and intimal vascular changes have been present in a large number of the benign tumors. The relationship of these vascular changes to oncogenesis is unclear, but similar lesions have been described in the peripheral vasculature associated with steroid administration. A number of hepatocellular carcinomas have also been seen. Of significance is the young age of these patients and lack of abnormal histology in adjacent nonneoplastic liver. A striking number of the malignant hepatocellular tumors have been of the uncommon type described as "eosinophilic hepatocellular carcinoma with lamellar fibrosis." The epidemiology of liver lesions within this series is difficult to assess, since the material has been referred from very diverse locations. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. PMID:6307679

  6. Hydration of arene and alkene oxides by epoxide hydrase in human liver microsomes.

    Science.gov (United States)

    Kapitulnik, J; Levin, W; Morecki, R; Dansette, P M; Jerina, D M; Conney, A H

    1977-02-01

    The comparative hydration of styrene 7,8-oxide, octene 1,2-oxide, naphthalene 1,2-oxide, phenanthrene 9,10-oxide, benzo[a]anthracene 5,6-oxide, 3-methylcholanthrene 11,12-oxide, dibenzo[a,h]anthracene 5,6-oxide, and benzo[a, 7,8-, 9,10-, and 11,12-oxides to their respective dihydrodiols was investigated in microsomes from nine human autopsy livers. The substrate specificity of the epoxide hydrase in human liver microsomes was very similar to that of the epoxide hydrase in rat liver microsomes. Phenanthrene 9,10-oxide was the best substrate for the human and rat epoxide hydrases and dibenzo[a,h]anthracene 5,6-oxide and benzo[a-a)pyrene 11, 12-oxide were the poorest substrates. Plotting epoxide hydrase activity obtained with one substrate against epoxide hydrase activity for another substrate for each of the nine human livers revealed excellent correlations for all combinations of the 11 substrates studied (r = 0.87 to 0.99). The data suggest the presence in human liver of a single epoxide hydrase with broad substrate specificity. However, the results do not exclude the possible presence in human liver of several epoxide hydrases that are under similar regulatory control. These results suggest the need for further investigation to determine whether there is a safe epoxide of a drug whose in vivo metabolism is predictive of the capacity of different individuals to metabolize a wide variety of epoxides of drugs and environmental chemicals.

  7. Prediction of Drug-Induced Liver Injury in HepG2 Cells Cultured with Human Liver Microsomes.

    Science.gov (United States)

    Choi, Jong Min; Oh, Soo Jin; Lee, Ji-Yoon; Jeon, Jang Su; Ryu, Chang Seon; Kim, Young-Mi; Lee, Kiho; Kim, Sang Kyum

    2015-05-18

    Drug-induced liver injury (DILI) via metabolic activation by drug-metabolizing enzymes, especially cytochrome P450 (CYP), is a major cause of drug failure and drug withdrawal. In this study, an in vitro model using HepG2 cells in combination with human liver microsomes was developed for the prediction of DILI. The cytotoxicity of cyclophosphamide, a model drug for bioactivation, was augmented in HepG2 cells cultured with microsomes in a manner dependent on exposure time, microsomal protein concentration, and NADPH. Experiments using pan- or isoform-selective CYP inhibitors showed that CYP2B6 and CYP3A4 are responsible for the bioactivation of cyclophosphamide. In a metabolite identification study employing LC-ESI-QTrap and LC-ESI-QTOF, cyclophosphamide metabolites including phosphoramide mustard, a toxic metabolite, were detected in HepG2 cells cultured with microsomes, but not without microsomes. The cytotoxic effects of acetaminophen and diclofenac were also potentiated by microsomes. The potentiation of acetaminophen cytotoxicity was dependent on CYP-dependent metabolism, and the augmentation of diclofenac cytotoxicity was not mediated by either CYP- or UDP-glucuronosyltransferase-dependent metabolism. The cytotoxic effects of leflunomide, nefazodone, and bakuchiol were attenuated by microsomes. The detoxication of leflunomide by microsomes was attributed to mainly CYP3A4-dependent metabolism. The protective effect of microsomes against nefazodone cytotoxicity was dependent on both CYP-mediated metabolism and nonspecific protein binding. Nonspecific protein binding but not CYP-dependent metabolism played a critical role in the attenuation of bakuchiol cytotoxicity. The present study suggests that HepG2 cells cultured with human liver microsomes can be a reliable model in which to predict DILI via bioactivation by drug metabolizing enzymes.

  8. Three-dimensional perfusion bioreactor culture supports differentiation of human fetal liver cells.

    Science.gov (United States)

    Schmelzer, Eva; Triolo, Fabio; Turner, Morris E; Thompson, Robert L; Zeilinger, Katrin; Reid, Lola M; Gridelli, Bruno; Gerlach, Jörg C

    2010-06-01

    The ability of human fetal liver cells to survive, expand, and form functional tissue in vitro is of high interest for the development of bioartificial extracorporeal liver support systems, liver cell transplantation therapies, and pharmacologic models. Conventional static two-dimensional culture models seem to be inadequate tools. We focus on dynamic three-dimensional perfusion technologies and developed a scaled-down bioreactor, providing decentralized mass exchange with integral oxygenation. Human fetal liver cells were embedded in a hyaluronan hydrogel within the capillary system to mimic an in vivo matrix and perfusion environment. Metabolic performance was monitored daily, including glucose consumption, lactate dehydrogenase activity, and secretion of alpha-fetoprotein and albumin. At culture termination cells were analyzed for proliferation and liver-specific lineage-dependent cytochrome P450 (CYP3A4/3A7) gene expression. Occurrence of hepatic differentiation in bioreactor cultures was demonstrated by a strong increase in CYP3A4/3A7 gene expression ratio, lower alpha-fetoprotein, and higher albumin secretion than in conventional Petri dish controls. Cells in bioreactors formed three-dimensional structures. Viability of cells was higher in bioreactors than in control cultures. In conclusion, the culture model implementing three-dimensionality, constant perfusion, and integral oxygenation in combination with a hyaluronan hydrogel provides superior conditions for liver cell survival and differentiation compared to conventional culture.

  9. Long Term Maintenance of a Microfluidic 3-D Human Liver Sinusoid

    OpenAIRE

    Prodanov, Ljupcho; Jindal, Rohit; Bale, Shyam Sundhar; Hegde, Manjunath; McCarty, William J.; Golberg, Inna; Bhushan, Abhinav; Yarmush, Martin L.; Usta, O. Berk

    2015-01-01

    The development of long-term human organotypic liver-on-a-chip models for successful prediction of toxic response is one of the most important and urgent goals of the NIH/DARPA’s initiative to replicate and replace chronic and acute drug testing in animals. For this purpose we developed a microfluidic chip that consists of two microfluidic chambers separated by a porous membrane. The aim of this communication is to demonstrate the recapitulation of a liver sinusoid-on-a-chip using human cells...

  10. Differentiation of human embryonic stem cells along a hepatocyte lineage and its application in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Hepatocyte transplantation and bioartificial liver(BAL)as alternatives to liver transplantation offer the possibility of effective treatment for many inherited and acquired hepatic disorders.Unfortunately,the limited availability of donated livers and the variability of their derived hepatocytes make it difficult to obtain enough viable human hepatocytes for the hepatocyte-based therapies.Embryonic stem cells (ESCs),which could be isolated directly from the blastocyst inner cell mass,have permanent self-renewal capability and developmental pluripotency and therefore might be an ideal cell source in the treatment of hepatic discords.However,differentiation of hESCS into hepatocytes with significant numbers remains a challenge.This review updates our current understanding of differentiation of ESCs into hepatic lineage cells,their future therapeutic uses and problems in liver regeneration.

  11. Nutritional assessment and treatment of patients with liver cirrhosis.

    Science.gov (United States)

    Moctezuma-Velázquez, Carlos; García-Juárez, Ignacio; Soto-Solís, Rodrigo; Hernández-Cortés, Juan; Torre, Aldo

    2013-01-01

    Prevalence of chronic liver diseases, including liver cirrhosis, is increasing worldwide. The nutritional state assessment in these patients is complicated, and besides anthropometry is based on several other tools in order to be more accurate. Specific dietary recommendations are needed in patients with chronic liver diseases in order to help prevent and treat liver decompensation because malnutrition is an independent predictor of mortality. This review focuses on essential aspects in the nutritional assessment of cirrhotic patients and some general recommendations for their treatment.

  12. Transcriptional networks implicated in human nonalcoholic fatty liver disease.

    Science.gov (United States)

    Ye, Hua; Liu, Wei

    2015-10-01

    The transcriptome of nonalcoholic fatty liver disease (NAFLD) was investigated in several studies. However, the implications of transcriptional networks in progressive NAFLD are not clear and mechanisms inducing transition from nonalcoholic simple fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) are still elusive. The aims of this study were to (1) construct networks for progressive NAFLD, (2) identify hub genes and functional modules in these networks and (3) infer potential linkages among hub genes, transcription factors and microRNAs (miRNA) for NAFLD progression. A systems biology approach by combining differential expression analysis and weighted gene co-expression network analysis (WGCNA) was utilized to dissect transcriptional profiles in 19 normal, 10 NAFL and 16 NASH patients. Based on this framework, 3 modules related to chromosome organization, proteasomal ubiquitin-dependent protein degradation and immune response were identified in NASH network. Furthermore, 9 modules of co-expressed genes associated with NAFL/NASH transition were found. Further characterization of these modules defined 13 highly connected hub genes in NAFLD progression network. Interestingly, 11 significantly changed miRNAs were predicted to target 10 of the 13 hub genes. Characterization of modules and hub genes that may be regulated by miRNAs could facilitate the identification of candidate genes and pathways responsible for NAFL/NASH transition and lead to a better understanding of NAFLD pathogenesis. The identified modules and hub genes may point to potential targets for therapeutic interventions.

  13. Effect of ultrasound frequency on the Nakagami statistics of human liver tissues.

    Science.gov (United States)

    Tsui, Po-Hsiang; Zhou, Zhuhuang; Lin, Ying-Hsiu; Hung, Chieh-Ming; Chung, Shih-Jou; Wan, Yung-Liang

    2017-01-01

    The analysis of the backscattered statistics using the Nakagami parameter is an emerging ultrasound technique for assessing hepatic steatosis and fibrosis. Previous studies indicated that the echo amplitude distribution of a normal liver follows the Rayleigh distribution (the Nakagami parameter m is close to 1). However, using different frequencies may change the backscattered statistics of normal livers. This study explored the frequency dependence of the backscattered statistics in human livers and then discussed the sources of ultrasound scattering in the liver. A total of 30 healthy participants were enrolled to undergo a standard care ultrasound examination on the liver, which is a natural model containing diffuse and coherent scatterers. The liver of each volunteer was scanned from the right intercostal view to obtain image raw data at different central frequencies ranging from 2 to 3.5 MHz. Phantoms with diffuse scatterers only were also made to perform ultrasound scanning using the same protocol for comparisons with clinical data. The Nakagami parameter-frequency correlation was evaluated using Pearson correlation analysis. The median and interquartile range of the Nakagami parameter obtained from livers was 1.00 (0.98-1.05) for 2 MHz, 0.93 (0.89-0.98) for 2.3 MHz, 0.87 (0.84-0.92) for 2.5 MHz, 0.82 (0.77-0.88) for 3.3 MHz, and 0.81 (0.76-0.88) for 3.5 MHz. The Nakagami parameter decreased with the increasing central frequency (r = -0.67, p statistical distribution of the backscattered envelopes was not found in the phantom results (r = -0.147, p = 0.0727). The current results demonstrated that the backscattered statistics of normal livers is frequency-dependent. Moreover, the coherent scatterers may be the primary factor to dominate the frequency dependence of the backscattered statistics in a liver.

  14. Human hepatocyte growth factor (hHGF-modified hepatic oval cells improve liver transplant survival.

    Directory of Open Access Journals (Sweden)

    Zhu Li

    Full Text Available Despite progress in the field of immunosuppression, acute rejection is still a common postoperative complication following liver transplantation. This study aims to investigate the capacity of the human hepatocyte growth factor (hHGF in modifying hepatic oval cells (HOCs administered simultaneously with orthotopic liver transplantation as a means of improving graft survival. HOCs were activated and isolated using a modified 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH model in male Lewis rats. A HOC line stably expressing the HGF gene was established following stable transfection of the pBLAST2-hHGF plasmid. Our results demonstrated that hHGF-modified HOCs could efficiently differentiate into hepatocytes and bile duct epithelial cells in vitro. Administration of HOCs at the time of liver transplantation induced a wider distribution of SRY-positive donor cells in liver tissues. Administration of hHGF-HOC at the time of transplantation remarkably prolonged the median survival time and improved liver function for recipients compared to these parameters in the other treatment groups (P<0.05. Moreover, hHGF-HOC administration at the time of liver transplantation significantly suppressed elevation of interleukin-2 (IL-2, tumor necrosis factor-α (TNF-α and interferon-γ (IFN-γ levels while increasing the production of IL-10 and TGF-β1 (P<0.05. HOC or hHGF-HOC administration promoted cell proliferation, reduced cell apoptosis, and decreased liver allograft rejection rates. Furthermore, hHGF-modified HOCs more efficiently reduced acute allograft rejection (P<0.05 versus HOC transplantation only. Our results indicate that the combination of hHGF-modified HOCs with liver transplantation decreased host anti-graft immune responses resulting in a reduction of allograft rejection rates and prolonging graft survival in recipient rats. This suggests that HOC-based cell transplantation therapies can be developed as a means of treating severe liver

  15. Adenosine receptor blockade reduces splanchnic hyperemia in cirrhotic rats.

    Science.gov (United States)

    Lee, S S; Chilton, E L; Pak, J M

    1992-06-01

    To explore a possible role for adenosine in the pathogenesis of the splanchnic hyperemia of cirrhosis, we administered 8-phenyltheophylline, a specific adenosine receptor antagonist, to rats with biliary cirrhosis caused by bile duct ligation and to control sham-operated rats. Micro-Doppler flow studies showed that a 10-mumol/kg dose of 8-phenyltheophylline completely abolished the superior mesenteric hyperemic response to infusions of exogenous adenosine in both cirrhotic and control rats. Analysis of regional blood flows by radioactive microspheres demonstrated that this dose of 8-phenyltheophylline in cirrhotic rats significantly increased portal tributary vascular resistance by 60% and decreased portal tributary blood flow by 26%. This decrease was entirely the result of a 42% reduction in the intestinal blood flow. 8-phenyltheophylline did not affect cardiac output, arterial pressure or any other extrasplanchnic hemodynamic variables in cirrhotic rats. No detectable effect of 8-phenyltheophylline was seen in sham-operated rats. These results suggest that adenosine may be involved in the genesis of splanchnic hyperemia in cirrhotic rats.

  16. Species and sex differences in propofol glucuronidation in liver microsomes of humans, monkeys, rats and mice.

    Science.gov (United States)

    Mukai, M; Isobe, T; Okada, K; Murata, M; Shigeyama, M; Hanioka, N

    2015-07-01

    Propofol (2,6-diisopropylphenol) is a short-acting anesthetic commonly used in clinical practice, and is rapidly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT). In the present study, propofol glucuronidation was examined in the liver microsomes of male and female humans, monkeys, rats, and mice. The kinetics of propofol glucuronidation by liver microsomes fit the substrate inhibition model for humans and mice, the Hill model for monkeys, and the isoenzyme (biphasic) model for rats. The K(m), V(max), and CL(int) values of human liver microsomes were 50 μM, 5.6 nmol/min/mg protein, and 110 μL/min/mg protein, respectively, for males, and 46 μM, 6.0 nmol/min/mg protein, and 130 μL/min/mg protein, respectively, for females. The rank order of the CL(int) or CL(max) (in vitro clearance) values of liver microsomes was mice humans > monkeys > rats (high-affinity phase) rats (low-affinity phase) in both males and females. Although no significant sex differences were observed in the values of kinetic parameters in any animal species, the in vitro clearance values of liver microsomes were males females in monkeys, rats (high-affinity phase), and mice. These results demonstrated that the kinetic profile of propofol glucuronidation by liver microsomes markedly differed among humans, monkeys, rats, and mice, and suggest that species and sex differences exist in the roles of UGT isoform(s), including UGT1A9, involved in its metabolism.

  17. Identification of CYP3A7 for Glyburide Metabolism in Human Fetal Livers

    Science.gov (United States)

    Shuster, Diana L.; Risler, Linda J.; Prasad, Bhagwat; Calamia, Justina C.; Voellinger, Jenna L.; Kelly, Edward J.; Unadkat, Jashvant D.; Hebert, Mary F.; Shen, Danny D.; Thummel, Kenneth E.; Mao, Qingcheng

    2014-01-01

    Glyburide is commonly prescribed for the treatment of gestational diabetes mellitus; however, fetal exposure to glyburide is not well understood and may have short- and long-term consequences for the health of the child. Glyburide can cross the placenta; fetal concentrations at term are nearly comparable to maternal levels. Whether or not glyburide is metabolized in the fetus and by what mechanisms has yet to be determined. In this study, we determined the kinetic parameters for glyburide depletion by CYP3A isoenzymes; characterized glyburide metabolism by human fetal liver tissues collected during the first or early second trimester of pregnancy; and identified the major enzyme responsible for glyburide metabolism in human fetal livers. CYP3A4 had the highest metabolic capacity towards glyburide, followed by CYP3A7 and CYP3A5 (Clint,u = 37.1, 13.0, and 8.7 ml/min/nmol P450, respectively). M5 was the predominant metabolite generated by CYP3A7 and human fetal liver microsomes (HFLMs) with approximately 96% relative abundance. M5 was also the dominant metabolite generated by CYP3A4, CYP3A5, and adult liver microsomes; however, M1-M4 were also present, with up to 15% relative abundance. CYP3A7 protein levels in HFLMs were highly correlated with glyburide Clint, 16α-OH DHEA formation, and 4′-OH midazolam formation. Likewise, glyburide Clint was highly correlated with 16α-OH DHEA formation. Fetal demographics as well as CYP3A5 and CYP3A7 genotype did not alter CYP3A7 protein levels or glyburide Clint. These results indicate that human fetal livers metabolize glyburide predominantly to M5 and that CYP3A7 is the major enzyme responsible for glyburide metabolism in human fetal livers. PMID:25450675

  18. Human Liver Cells Expressing Albumin and Mesenchymal Characteristics Give Rise to Insulin-Producing Cells

    Directory of Open Access Journals (Sweden)

    Irit Meivar-Levy

    2011-01-01

    Full Text Available Activation of the pancreatic lineage in the liver has been suggested as a potential autologous cell replacement therapy for diabetic patients. Transcription factors-induced liver-to-pancreas reprogramming has been demonstrated in numerous species both in vivo and in vitro. However, human-derived liver cells capable of acquiring the alternate pancreatic repertoire have never been characterized. It is yet unknown whether hepatic-like stem cells or rather adult liver cells give rise to insulin-producing cells. Using an in vitro experimental system, we demonstrate that proliferating adherent human liver cells acquire mesenchymal-like characteristics and a considerable level of cellular plasticity. However, using a lineage-tracing approach, we demonstrate that insulin-producing cells are primarily generated in cells enriched for adult hepatic markers that coexpress both albumin and mesenchymal markers. Taken together, our data suggest that adult human hepatic tissue retains a substantial level of developmental plasticity, which could be exploited in regenerative medicine approaches.

  19. Alpha-2A Adrenoceptor Agonist Guanfacine Restores Diuretic Efficiency in Experimental Cirrhotic Ascites: Comparison with Clonidine.

    Directory of Open Access Journals (Sweden)

    Giovanni Sansoè

    Full Text Available In human cirrhosis, adrenergic hyperfunction causes proximal tubular fluid retention and contributes to diuretic-resistant ascites, and clonidine, a sympatholytic drug, improves natriuresis in difficult-to-treat ascites.To compare clonidine (aspecific α2-adrenoceptor agonist to SSP-002021R (prodrug of guanfacine, specific α2A-receptor agonist, both associated with diuretics, in experimental cirrhotic ascites.Six groups of 12 rats were studied: controls (G1; controls receiving furosemide and potassium canrenoate (G2; rats with ascitic cirrhosis due to 14-week CCl4 treatment (G3; cirrhotic rats treated (over the 11th-14th CCl4 weeks with furosemide and canrenoate (G4, furosemide, canrenoate and clonidine (G5, or diuretics and SSP002021R (G6. Three rats of each group had their hormonal status and renal function assessed at the end of 11th, 12th, 13th, and 14th weeks of respective treatments.Cirrhotic rats in G3 and G4 gained weight over the 12th-14th CCl4 weeks. In G4, brief increase in sodium excretion over the 11th-12th weeks preceded worsening of inulin clearance and natriuresis (diuretic resistance. In comparison with G4, the addition of clonidine (G5 or guanfacine (G6 to diuretics improved, respectively, sodium excretion over the 11th-12th CCl4 weeks, or GFR and electrolytes excretion over the 13th-14th CCl4 weeks. Natriuretic responses in G5 and G6 were accompanied by reduced catecholamine serum levels.α2A-receptor agonists restore glomerular filtration rate and natriuresis, and delay diuretic-resistant ascites in experimental advanced cirrhosis. Clonidine ameliorates diuretic-dependent natriuresis just for a short time.

  20. Prognostic indicators in alcoholic cirrhotic men

    DEFF Research Database (Denmark)

    Gluud, C; Henriksen, J H; Nielsen, G

    1988-01-01

    The relationships between portal pressure, liver function and clinical variables on one hand and development of variceal hemorrhage and death on the other were investigated in 58 men with newly diagnosed alcoholic cirrhosis. Portal pressure was determined during hepatic vein catheterization as we...

  1. Differential selectivity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes

    Science.gov (United States)

    Eagling, Victoria A; Tjia, John F; Back, David J

    1998-01-01

    Aims Chemical inhibitors of cytochrome P450 (CYP) are a useful tool in defining the role of individual CYPs involved in drug metabolism. The aim of the present study was to evaluate the selectivity and rank the order of potency of a range of isoform-selective CYP inhibitors and to compare directly the effects of these inhibitors in human and rat hepatic microsomes. Methods Four chemical inhibitors of human cytochrome P450 isoforms, furafylline (CYP1A2), sulphaphenazole (CYP2C9), diethyldithiocarbamate (CYP2E1), and ketoconazole (CYP3A4) were screened for their inhibitory specificity towards CYP-mediated reactions in both human and rat liver microsomal preparations. Phenacetin O-deethylation, tolbutamide 4-hydroxylation, chlorzoxazone 6-hydroxylation and testosterone 6β-hydroxylation were monitored for enzyme activity. Results Furafylline was a potent, selective inhibitor of phenacetin O-deethylation (CYP1A2-mediated) in human liver microsomes (IC50 = 0.48 μm), but inhibited both phenacetin O-deethylation and tolbutamide 4-hydroxylation (CYP2C9-mediated) at equimolar concentrations in rat liver microsomes (IC50 = 20.8 and 24.0 μm respectively). Sulphaphenazole demonstrated selective inhibition of tolbutamide hydroxylation in human liver microsomes but failed to inhibit this reaction in rat liver microsomes. DDC demonstrated a low level of selectivity as an inhibitory probe for chlorzoxazone 6-hydroxylation (CYP2E1-mediated). DDC also inhibited testosterone 6β-hydroxylation (CYP3A-mediated) in man and rat, and tolbutamide 4-hydroxylase activity in rat. Ketoconazole was a very potent, selective inhibitor of CYP3A4 activity in human liver (IC50 = 0.04 μm). Although inhibiting CYP3A in rat liver it also inhibited all other reactions at concentrations ≤5 μm. Conclusions It is evident that CYP inhibitors do not exhibit the same selectivity in human and rat liver microsomes. This is due to differential selectivity of the inhibitors and/or differences in the CYP

  2. Alloxan-Induced Diabetes Causes Morphological and Ultrastructural Changes in Rat Liver that Resemble the Natural History of Chronic Fatty Liver Disease in Humans

    Directory of Open Access Journals (Sweden)

    Amanda Natália Lucchesi

    2015-01-01

    Full Text Available Purpose. This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. Methods. Thirty nondiabetic control rats (NC and 30 untreated diabetic (UD rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed. Results. UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed. Conclusion. Alloxan-induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis.

  3. Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion.

    Directory of Open Access Journals (Sweden)

    Michael E Sutton

    Full Text Available Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37 °C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1 steadily increasing bile production, resulting in a cumulative output of ≥ 30 g after 6 h (high bile output group, and (2 a cumulative bile production <20 g in 6 h (low bile output group. Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial.

  4. A shift in paradigm towards human biology-based systems for cholestatic-liver diseases.

    Science.gov (United States)

    Noor, Fozia

    2015-12-01

    Cholestatic-liver diseases (CLDs) arise from diverse causes ranging from genetic factors to drug-induced cholestasis. The so-called diseases of civilization (obesity, diabetes, metabolic disorders, non-alcoholic liver disease, cardiovascular diseases, etc.) are intricately implicated in liver and gall bladder diseases. Although CLDs have been extensively studied, there seem to be important gaps in the understanding of human disease. Despite the fact that many animal models exist and substantial clinical data are available, translation of this knowledge towards therapy has been disappointingly limited. Recent advances in liver cell culture such as in vivo-like 3D cultivation of human primary hepatic cells, human induced pluripotent stem cell-derived hepatocytes; and cutting-edge analytical techniques such as 'omics' technologies and high-content screenings could play a decisive role in deeper mechanistic understanding of CLDs. This Topical Review proposes a roadmap to human biology-based research using omics technologies providing quantitative information on mechanisms in an adverse outcome/disease pathway framework. With modern sensitive tools, a shift in paradigm in human disease research seems timely and even inevitable to overcome species barriers in translation.

  5. CYP3A4 mediated in vitro metabolism of vinflunine in human liver microsomes

    Institute of Scientific and Technical Information of China (English)

    Xiao-ping ZHAO; Jiao ZHONG; Xiao-quan LIU; Guang-ji WANG

    2007-01-01

    Aim: To study the metabolism of vinflunine and the effects of selective cyto-chrome P-450 (CYP450) inhibitors on the metabolism of vinflunine in human liver microsomes. Methods: Individual selective CYP450 inhibitors were used to inves-tigate their effects on the metabolism of vinflunine and the principal CYP450 isoform involved in the formation of metabolites M1 and M2 in human liver microsomes.Results: Vinflunine was rapidly metabolized to 2 metabolites: M1 and M2 in human liver microsomes. M1 and M2 were tentatively presumed to be the N-oxide metabo-lite or hydroxylated metabolite and epoxide metabolite of vinflunine, respectively. Ketoconazole uncompetitively inhibited the formation of M1, and competitively inhibited the formation of M2, while α-naphthoflavone, sulfaphenazole, diethyl dithiocarbamate, tranylcypromine and quinidine had little or no inhibitory effect on the formation of M1 and M2. Conclusion: Vinflunine is rapidly metabolized in human liver microsomes, and CYP3A4 is the major human CYP450 involved in the metabolism of vinflunine.

  6. Chronic Liver Disease and the Detection of Hepatocellular Carcinoma by [18F]fluorocholine PET/CT

    Directory of Open Access Journals (Sweden)

    Sandi A. Kwee

    2015-05-01

    Full Text Available Positron emission tomography (PET using the radiopharmaceutical tracer fluorine-18 fluorocholine (FCh can elucidate tumors based on differences in choline phospholipid metabolism between tumor and surrounding tissue. The feasibility of detecting hepatocellular carcinoma (HCC using FCh PET has been shown despite constitutively high parenchymal choline metabolism in the liver. Since HCC frequently develops in the setting of chronic liver disease, we comparatively evaluated FCh PET/CT between cirrhotic and non-cirrhotic patients with HCC to investigate the effects of hepatic dysfunction on tumor detection and the tumor-to-background ratio (TBR of FCh uptake. FCh PET/CT was performed prospectively in 22 consecutive patients with HCC (7 newly diagnosed, 15 previously treated. Of these 22 patients, 14 were cirrhotic and 8 non-cirrhotic. Standardized uptake value (SUV measurements were obtained by region of interest analysis of the PET images. Tumor FCh uptake and the TBR were compared between cirrhotic and non-cirrhotic patients. Liver lesions were confirmed to be HCC by biopsy in 10 patients and by Barcelona criteria in 4 patients. There was correspondingly increased liver tumor FCh uptake in 13/14 of those patients, and iso-intense tumor FCh uptake (TBR 0.94 in one non-cirrhotic patient with newly diagnosed HCC. FCh PET/CT also showed metastatic disease without local tumor recurrence in 2 previously treated patients, and was negative in 6 treated patients without tumor recurrence by radiographic and clinical follow-up. Tumor maximum SUV ranged from 6.4 to 15.3 (mean 12.1 and liver TBR ranged from 0.94 to 2.1 (mean 1.6, with no significant differences between cirrhotic and non-cirrhotic patients (SUVmax 11.9 vs. 12.2, p = 0.83; TBR 1.71 vs. 1.51, p = 0.29. Liver parenchyma mean SUV was significantly lower in cirrhotic patients (6.4 vs. 8.7, p < 0.05. This pilot study supports the general feasibility of HCC detection by FCh PET/CT. However, a broad

  7. Isolation and characterization of cloned cDNAs as encoding human liver chlordecone reductase

    Energy Technology Data Exchange (ETDEWEB)

    Winters, C.J.; Molowa, D.T.; Guzelian, P.S. (Medical College of Virginia, Richmond (USA))

    1990-01-30

    Chlordecone (Kepone), a toxic organochlorine pesticide, undergoes bioreduction to chlorodecone alcohol in human liver. This reaction is controlled by a cytosolic enzyme, chlordecone reductase (CDR), which may be of the aldo-keto reductase family of xenobiotic metabolizing enzymes. To further investigate the primary structure and expression of CDR, the authors screened a library of human liver cDNAs cloned in the expression vector {lambda}gt11 and isolated an 800 bp cDNA that directed synthesis of a fusion protein recognized by polyclonal anti-CDR antibodies. Using this cDNA as a probe, they screened two human liver cDNA libraries and found several 1.2-kb cDNAs which would code for polypeptide with 308 residues (35.8 kDa). However, a similar full-length cDNA, possibly the transcript of a pseudogene, contained an in-frame nonsense codon. The deduced protein sequence of CDR showed 65% similarity to the primary structure of human liver aldehyde reductase and 66% similarity to the inferred protein sequence of rat lens aldose reductase. A search of GenBank revealed significant nucleotide similarity to a cDNA coding for bovine lung prostaglandin f synthase and to a partial cDNA coding for frog lens {rho}-crystallin. RNA from adult but not fetal human liver, and from the human hepatoma cell-line Hep G2, contained major (1.6 kb) and minor (2.8 kb) species hybridizable to a CDR cDNA. The relative amounts of these RNAs varied markedly among nine subjects. From this initial description of the nucleotide sequence for a human carbonyl reductase, they conclude that CDR and several related enzymes are part of a novel multigene family involved in the metabolism of such xenobiotics as chlordecone and possibly endogenous substrates.

  8. Ultrastructural characteristics of novel epithelial cell types identified in human pathologic liver specimens with chronic ductular reaction.

    OpenAIRE

    De Vos, R; Desmet, V

    1992-01-01

    Previous immunohistochemical studies on human liver biopsies with chronic ductular reaction revealed the presence of "small cells" with bile-duct type cytokeratin profile in the periportal area. This study identified similar cells by electron microscopy. The authors studied 13 human liver specimens with various liver diseases, but all characterized by chronic ductular reaction. In all specimens, variable numbers of "small cells" with common epithelial characteristics were identified in the pe...

  9. Gene discovery for the carcinogenic human liver fluke, Opisthorchis viverrini

    Directory of Open Access Journals (Sweden)

    Gasser Robin B

    2007-06-01

    Full Text Available Abstract Background Cholangiocarcinoma (CCA – cancer of the bile ducts – is associated with chronic infection with the liver fluke, Opisthorchis viverrini. Despite being the only eukaryote that is designated as a 'class I carcinogen' by the International Agency for Research on Cancer, little is known about its genome. Results Approximately 5,000 randomly selected cDNAs from the adult stage of O. viverrini were characterized and accounted for 1,932 contigs, representing ~14% of the entire transcriptome, and, presently, the largest sequence dataset for any species of liver fluke. Twenty percent of contigs were assigned GO classifications. Abundantly represented protein families included those involved in physiological functions that are essential to parasitism, such as anaerobic respiration, reproduction, detoxification, surface maintenance and feeding. GO assignments were well conserved in relation to other parasitic flukes, however, some categories were over-represented in O. viverrini, such as structural and motor proteins. An assessment of evolutionary relationships showed that O. viverrini was more similar to other parasitic (Clonorchis sinensis and Schistosoma japonicum than to free-living (Schmidtea mediterranea flatworms, and 105 sequences had close homologues in both parasitic species but not in S. mediterranea. A total of 164 O. viverrini contigs contained ORFs with signal sequences, many of which were platyhelminth-specific. Examples of convergent evolution between host and parasite secreted/membrane proteins were identified as were homologues of vaccine antigens from other helminths. Finally, ORFs representing secreted proteins with known roles in tumorigenesis were identified, and these might play roles in the pathogenesis of O. viverrini-induced CCA. Conclusion This gene discovery effort for O. viverrini should expedite molecular studies of cholangiocarcinogenesis and accelerate research focused on developing new interventions

  10. Characterization of hepatic progenitors from human fetal liver using CD34 as a hepatic progenitor marker

    Institute of Scientific and Technical Information of China (English)

    Parveen Nyamath; Ayesha AM; Aejaz Habeeb; Sanjeev Khosla; Aleem A Khan; CM Habibullah

    2007-01-01

    AIM: To enrich putative hepatic progenitors from the developing human fetal liver using CD34 as a marker.METHODS: Aborted fetuses of 13-20 wk were used for the isolation of liver cells. The cells were labeled with anti CD34; a marker used for isolating progenitor population and the cells were sorted using magnetic cell sorting. The positive fractions of cells were assessed for specific hepatic markers. Further, these cells were cultured in vitro for long term investigation.RESULTS: Flow cytometric and immunocytochemical analysis for alphafetoprotein (AFP) showed that the majority of the enriched CD34 positive cells were positive for AFP. Furthermore, these enriched cells proliferated in the long term and maintained hepatic characteristics in in vitro culture.CONCLUSION: The study shows that aborted human fetal liver is a potential source for isolation of hepatic progenitors for clinical applications. The study also demonstrates that CD34 can be a good marker for the enrichment of progenitor populations.

  11. Dataset on force measurements of needle insertions into two ex-vivo human livers.

    Science.gov (United States)

    de Jong, Tonke L; Dankelman, Jenny; van den Dobbelsteen, John J

    2017-04-01

    A needle-tissue interaction experiment has been carried out, by inserting the inner needle of a trocar needle into two ex-vivo human livers. The dataset contains the forces that act on the needle during insertion and retraction into the livers. In addition, a MATLAB code file is included that provides base-level analysis of the data and generates force-position diagrams of the needle insertions. The dataset is available on Mendeley Data (do1i:10.17632/94s7xd9mzt.2), and is made publicly available to enable other researchers to use it for their own research purposes. For further interpretation and discussion of the data, one is referred to the associated research article entitled "PVA matches human liver in needle-tissue interaction" de Jong et al., 2017.

  12. Incidence of bacteremia in cirrhotic patients undergoing upper endoscopic ultrasonography.

    Science.gov (United States)

    Fernández-Esparrach, Gloria; Sendino, Oriol; Araujo, Isis; Pellisé, Maria; Almela, Manel; González-Suárez, Begoña; López-Cerón, María; Córdova, Henry; Sanabria, Erwin; Uchima, Hugo; Llach, Josep; Ginès, Àngels

    2014-01-01

    The incidence of bacteremia after endoscopic ultrasonography (EUS) or EUS-guided fine-needle aspiration (EUS-FNA) is between 0% and 4%, but there are no data on this topic in cirrhotic patients. To prospectively assess the incidence of bacteremia in cirrhotic patients undergoing EUS and EUS-FNA. We enrolled 41 cirrhotic patients. Of these, 16 (39%) also underwent EUS-FNA. Blood cultures were obtained before and at 5 and 30 min after the procedure. When EUS-FNA was used, an extra blood culture was obtained after the conclusion of radial EUS and before the introduction of the sectorial echoendoscope. All patients were clinically followed up for 7 days for signs of infection. Blood cultures were positive in 16 patients. In 10 patients, blood cultures grew coagulase-negative Staphylococcus, Corynebacterium species, Propionibacterium species or Acinetobacterium Lwoffii, which were considered contaminants (contamination rate 9.8%, 95% CI: 5.7-16%). The remaining 6 patients had true positive blood cultures and were considered to have had true bacteremia (15%, 95% CI: 4-26%). Blood cultures were positive after diagnostic EUS in five patients but were positive after EUS-FNA in only one patient. Thus, the frequency of bacteremia after EUS and EUS-FNA was 12% and 6%, respectively (95% CI: 2-22% and 0.2-30%, respectively). Only one of the patients who developed bacteremia after EUS had a self-limiting fever with no other signs of infection. Asymptomatic Gram-positive bacteremia developed in cirrhotic patients after EUS and EUS-FNA at a rate higher than in non-cirrhotic patients. However, this finding was not associated with any clinically significant infections. Copyright © 2013 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

  13. Differential genomic effects of six different TiO2 nanomaterials on human liver HepG2 cells

    Science.gov (United States)

    Engineered nanoparticles are reported to cause liver toxicity in vivo. To better assess the mechanism of the in vivo liver toxicity, we used the human hepatocarcinoma cells (HepG2) as a model system. Human HepG2 cells were exposed to 6 TiO2 nanomaterials (with dry primary partic...

  14. Open-Porous Hydroxyapatite Scaffolds for Three-Dimensional Culture of Human Adult Liver Cells

    Directory of Open Access Journals (Sweden)

    Anthony Finoli

    2016-01-01

    Full Text Available Liver cell culture within three-dimensional structures provides an improved culture system for various applications in basic research, pharmacological screening, and implantable or extracorporeal liver support. Biodegradable calcium-based scaffolds in such systems could enhance liver cell functionality by providing endothelial and hepatic cell support through locally elevated calcium levels, increased surface area for cell attachment, and allowing three-dimensional tissue restructuring. Open-porous hydroxyapatite scaffolds were fabricated and seeded with primary adult human liver cells, which were embedded within or without gels of extracellular matrix protein collagen-1 or hyaluronan. Metabolic functions were assessed after 5, 15, and 28 days. Longer-term cultures exhibited highest cell numbers and liver specific gene expression when cultured on hydroxyapatite scaffolds in collagen-1. Endothelial gene expression was induced in cells cultured on scaffolds without extracellular matrix proteins. Hydroxyapatite induced gene expression for cytokeratin-19 when cells were cultured in collagen-1 gel while culture in hyaluronan increased cytokeratin-19 gene expression independent of the use of scaffold in long-term culture. The implementation of hydroxyapatite composites with extracellular matrices affected liver cell cultures and cell differentiation depending on the type of matrix protein and the presence of a scaffold. The hydroxyapatite scaffolds enable scale-up of hepatic three-dimensional culture models for regenerative medicine applications.

  15. Open-Porous Hydroxyapatite Scaffolds for Three-Dimensional Culture of Human Adult Liver Cells.

    Science.gov (United States)

    Finoli, Anthony; Schmelzer, Eva; Over, Patrick; Nettleship, Ian; Gerlach, Joerg C

    2016-01-01

    Liver cell culture within three-dimensional structures provides an improved culture system for various applications in basic research, pharmacological screening, and implantable or extracorporeal liver support. Biodegradable calcium-based scaffolds in such systems could enhance liver cell functionality by providing endothelial and hepatic cell support through locally elevated calcium levels, increased surface area for cell attachment, and allowing three-dimensional tissue restructuring. Open-porous hydroxyapatite scaffolds were fabricated and seeded with primary adult human liver cells, which were embedded within or without gels of extracellular matrix protein collagen-1 or hyaluronan. Metabolic functions were assessed after 5, 15, and 28 days. Longer-term cultures exhibited highest cell numbers and liver specific gene expression when cultured on hydroxyapatite scaffolds in collagen-1. Endothelial gene expression was induced in cells cultured on scaffolds without extracellular matrix proteins. Hydroxyapatite induced gene expression for cytokeratin-19 when cells were cultured in collagen-1 gel while culture in hyaluronan increased cytokeratin-19 gene expression independent of the use of scaffold in long-term culture. The implementation of hydroxyapatite composites with extracellular matrices affected liver cell cultures and cell differentiation depending on the type of matrix protein and the presence of a scaffold. The hydroxyapatite scaffolds enable scale-up of hepatic three-dimensional culture models for regenerative medicine applications.

  16. Hepatitis B and C infection and liver disease trends among human immunodeficiency virus-infected individuals

    Institute of Scientific and Technical Information of China (English)

    Susan E Buskin; Elizabeth A Barash; John D Scott; David M Aboulafia; Robert W Wood

    2011-01-01

    AIM: To examine trends in and correlates of liver disease and viral hepatitis in an human immunodeficiency virus (HIV)-infected cohort.METHODS: The multi-site adult/adolescent spectrum of HIV-related diseases (ASD) followed 29 490 HIVinfected individuals receiving medical care in 11 U.S.metropolitan areas for an average of 2.4 years, and a total of 69 487 person-years, between 1998 and 2004.ASD collected data on the presentation, treatment, and outcomes of HIV, including liver disease, hepatitis screening, and hepatitis diagnoses.RESULTS: Incident liver disease, chronic hepatitis B virus (HBV), and hepatitis C virus (HCV) were diagnosed in 0.9, 1.8, and 4.7 per 100 person-years.HBV and HCV screening increased from fewer than 20% to over 60% during this period of observation (P < 0.001).Deaths occurred in 57% of those diagnosed with liver disease relative to 15% overall (P < 0.001).Overall 10% of deaths occurred among individuals with a diagnosis of liver disease.Despite care guidelines promoting screening and vaccination for HBV and screening for HCV, screening and vaccination were not universally conducted or, if conducted, not documented.CONCLUSION: Due to high rates of incident liver disease, viral hepatitis screening, vaccination, and treatment among HIV-infected individuals should be a priority.

  17. METABOLISM OF MYCLOBUTANIL AND TRIADIMEFON BY HUMAN AND RAT CYTOCHROME P450 ENZYMES AND LIVER MICROSOMES.

    Science.gov (United States)

    Metabolism of two triazole-containing antifungal azoles was studied using expressed human and rat cytochrome P450s (CYP) and liver microsomes. Substrate depletion methods were used due to the complex array of metabolites produced from myclobutanil and triadimefon. Myclobutanil wa...

  18. An attempt to eliminate fibroblast-like cells from primary cultures of fetal human livers.

    Directory of Open Access Journals (Sweden)

    Tokiwa,Takayoshi

    1986-04-01

    Full Text Available The elimination of fibroblast-like cells from primary cultures of fetal human livers was studied. A fibroblast-like cell line (HuF, which was obtained by subculturing fetal human liver cells 4 or more times, was briefly treated with hydrocortisone (HC or putrescine (PUT. The growth of HuF cells was inhibited by HC at a concentration of 10(-2 M and by PUT at a concentration higher than 10(-3 M. Long-term treatment of HuF cells with 10(-3 M HC inhibited the growth of the cells. Primary cultures of fetal human livers were made in medium containing HC or PUT, and morphological and functional examinations were made. The cultures were predominantly composed of epithelial-like cells, with few fibroblast-like cells, when the HC concentration was 10(-5M to 10(-3 M. A high amount of albumin was secreted at these concentrations of HC. On the other hand, at 10(-3 M PUT, many epithelial-like cells were seen, but albumin was undetectable. The present results indicate that albumin-producing epithelial-like cells can be selectively maintained in medium containing HC, in primary cultures of fetal human livers.

  19. Apolipoprotein B synthesis in humans: liver synthesizes only apolipoprotein B-100

    Energy Technology Data Exchange (ETDEWEB)

    Edge, S.B.; Hoeg, J.M.; Schneider, P.D.; Brewer, H.B. Jr.

    1985-08-01

    Apolipoprotein (apo) B-100 and B-48 are prominent apolipoproteins in VLDL, IDL, and chylomicrons. Organ cultures of normal adult human liver were established to ascertain the form of apo B synthesized by hepatocytes in humans. Human liver was minced and incubated in 15 mL methionine-free RPMI-1640 medium with 10% dialyzed fetal calf serum plus 250 microCi /sup 35/S-methionine for eight hours at 37 degrees C. Lipoproteins secreted by the liver were isolated by ultracentrifugation and the content of newly synthesized apo B determined by quantitation of radioactivity in the apoB-100 and apoB-48 bands after separation by 3% NaDodSO/sub 4/ gel electrophoresis. In the eight-hour period, 2.5% to 3.2% of added /sup 35/S-methionine was secreted in TCA-precipitable protein of which 0.34% was apo B. Ninety-nine percent of the apo B in VLDL, IDL, and LDL was in the apo B-100 electrophoretic band. No significant radioactivity was detected in the apo B-48 electrophoretic band. Eighty-nine percent of the total radioactivity of apo B-100 was in VLDL with 3% and 8% in IDL and LDL, respectively. These results establish that adult human liver in organ culture synthesizes apo B-100 but not apo B-48.

  20. Risk assessment of paracetamol-induced liver toxicity based on human in vitro data.

    NARCIS (Netherlands)

    Groothuis, Geny; Mafirakureva, Nyashadzaishe; Proost, Johannes; Jetten, M; Kleinjans, Jos; Lommen, A; Peijnenburg, A; Vredenburg, G; Vermeulen, N; Russel, Frans G. M.

    2014-01-01

    Currently risk assessment is based on animal experiments with limited success. The aim of this study was to explore the feasibility to replace the use of animals in risk assessment for drug-induced liver injury, by hazard identification and kinetic modeling based on human in vitro data for metabolis

  1. MicroRNA-mediated suppression of oncolytic adenovirus replication in human liver.

    Science.gov (United States)

    Ylösmäki, Erkko; Lavilla-Alonso, Sergio; Jäämaa, Sari; Vähä-Koskela, Markus; af Hällström, Taija; Hemminki, Akseli; Arola, Johanna; Mäkisalo, Heikki; Saksela, Kalle

    2013-01-01

    MicroRNAs (miRNAs) are important and ubiquitous regulators of gene expression that can suppress their target genes by translational inhibition as well as mRNA destruction. Cell type-specific miRNA expression patterns have been successfully exploited for targeting the expression of experimental and therapeutic gene constructs, for example to reduce pathogenic effects of cancer virotherapy in normal tissues. In order to avoid liver damage associated with systemic or intrahepatic delivery of oncolytic adenoviruses we have introduced the concept of suppressing adenovirus replication in hepatic cells by inserting target elements for the liver-specific miR122 into the viral genome. Here we show using ex vivo cultured tissue specimens that six perfectly complementary miR122 target sites in the 3' untranslated region of the viral E1A gene are sufficient in the absence of any other genetic modifications to prevent productive replication of serotype 5 adenovirus (Ad5) in normal human liver. This modification did not compromise the replicative capacity of the modified virus in cancer tissue derived from a colon carcinoma liver metastasis or its oncolytic potency in a human lung cancer xenograft mouse model. Unlike wild-type Ad5, the modified virus did not result in increased serum levels of liver enzymes in infected mice. These results provide a strong preclinical proof of concept for the use of miR122 target sites for reducing the risk of liver damage caused by oncolytic adenoviruses, and suggest that ectopic miR122 target elements should be considered as an additional safety measure included in any therapeutic virus or viral vector posing potential hazard to the liver.

  2. MicroRNA-mediated suppression of oncolytic adenovirus replication in human liver.

    Directory of Open Access Journals (Sweden)

    Erkko Ylösmäki

    Full Text Available MicroRNAs (miRNAs are important and ubiquitous regulators of gene expression that can suppress their target genes by translational inhibition as well as mRNA destruction. Cell type-specific miRNA expression patterns have been successfully exploited for targeting the expression of experimental and therapeutic gene constructs, for example to reduce pathogenic effects of cancer virotherapy in normal tissues. In order to avoid liver damage associated with systemic or intrahepatic delivery of oncolytic adenoviruses we have introduced the concept of suppressing adenovirus replication in hepatic cells by inserting target elements for the liver-specific miR122 into the viral genome. Here we show using ex vivo cultured tissue specimens that six perfectly complementary miR122 target sites in the 3' untranslated region of the viral E1A gene are sufficient in the absence of any other genetic modifications to prevent productive replication of serotype 5 adenovirus (Ad5 in normal human liver. This modification did not compromise the replicative capacity of the modified virus in cancer tissue derived from a colon carcinoma liver metastasis or its oncolytic potency in a human lung cancer xenograft mouse model. Unlike wild-type Ad5, the modified virus did not result in increased serum levels of liver enzymes in infected mice. These results provide a strong preclinical proof of concept for the use of miR122 target sites for reducing the risk of liver damage caused by oncolytic adenoviruses, and suggest that ectopic miR122 target elements should be considered as an additional safety measure included in any therapeutic virus or viral vector posing potential hazard to the liver.

  3. Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action.

    Science.gov (United States)

    de Mello, Vanessa D; Matte, Ashok; Perfilyev, Alexander; Männistö, Ville; Rönn, Tina; Nilsson, Emma; Käkelä, Pirjo; Ling, Charlotte; Pihlajamäki, Jussi

    2017-04-03

    Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 ± 7.7 years, BMI: 43 ± 5.7 kg/m(2), type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q liver. These epigenetic alterations in NASH are linked with insulin metabolism.

  4. New evidence for the therapeutic potential of curcumin to treat nonalcoholic fatty liver disease in humans

    Science.gov (United States)

    Inzaugarat, María Eugenia; De Matteo, Elena; Baz, Placida; Lucero, Diego; García, Cecilia Claudia; Gonzalez Ballerga, Esteban; Daruich, Jorge; Sorda, Juan Antonio; Wald, Miriam Ruth

    2017-01-01

    Introduction The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties. Aims This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model. Results The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages. Conclusion Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research. PMID:28257515

  5. Apelin mediates the induction of profibrogenic genes in human hepatic stellate cells.

    Science.gov (United States)

    Melgar-Lesmes, Pedro; Casals, Gregori; Pauta, Montserrat; Ros, Josefa; Reichenbach, Vedrana; Bataller, Ramon; Morales-Ruiz, Manuel; Jimenez, Wladimiro

    2010-11-01

    Apelin is a peptide with relevant functions in angiogenesis and inflammation. Recent studies have demonstrated that apelin is overexpressed in hepatic stellate cells (HSCs) of cirrhotic rats. Moreover, patients with cirrhosis show high circulating levels of this peptide. We evaluated the role of endogenous apelin system in fibrogenesis-related gene induction in human HSCs. Messenger expression and immunolocalization of apelin were analyzed in human cirrhotic liver and in control samples. Apelin expression was analyzed in a human HSC line (LX-2) under hypoxic conditions or in the presence of proinflammatory or profibrogenic stimuli. LX-2 cells were stimulated with apelin, and a selected profile of fibrogenesis-related genes was quantified. In vivo inactivation of apelin was analyzed in the liver of fibrotic rats after administrating specific blockers of the molecules triggering apelin induction. Apelin was overexpressed in HSCs from human cirrhotic liver. Neither hypoxia nor proinflammatory substances induced the expression of apelin in LX-2. By contrast, both profibrogenic molecules angiotensin II (AII) and endothelin-1 (ET-1) enhanced apelin expression in these cells. Apelin increased the synthesis of collagen-I and platelet-derived growth factor receptor β (PDGFRβ) in LX-2. AII and ET-1 stimulated collagen-I and PDGFRβ expression, and this induction was drastically reduced when apelin receptor was blocked in these cells. In accordance, AII or ET-1 receptor antagonists reduced the hepatic synthesis of apelin, collagen-I, and PDGFRβ in fibrotic rats. apelin mediates some of the fibrogenic effects triggered by AII and ET-1, thus suggesting that apelin could be an important mediator of fibrogenesis in human liver disease.

  6. Association between polycyclic aromatic hydrocarbons and human rectal tumor or liver cancer

    Institute of Scientific and Technical Information of China (English)

    Guohong Jiang; Limin Lun; Liyuan Cong

    2012-01-01

    Objective: The aim of this study was to investigate the effect of polycyclic aromatic hydrocarbons (PAHs) in rectal carcinoma and hepatocarcinoma genesis. Methods: The PAHs in the human rectal cancer and liver cancer tissues, the adjacent tissues and homologous tissues without rectal cancer or liver cancer were extracted by ultrasonic wave. The extracts were then cleaned up and enriched by solid phase extraction, analyzed by high performance liquid chromatography (HPLC) with fluorescence spectroscopy. Results: Four kinds of PAHs were detected in human rectal and hepatic tissues. The contents of pyrene, 2-methylanthracene and benzo (a) pyrene in both rectal cancer tissues and adjacent homologous tissues were higher than rectal tissues without rectal cancer, the differences were statistically significant (P 0.05). The differences of the content of each PAHs between rectal cancer and adjacent tissue were not significant (P > 0.05). The contents of the four PAHs in the three kinds of liver tis-sues were not statistically significant (P > 0.05). Conclusion: PAHs are found in human rectal tissues or hepatic tissues. The contents of PAHs in human rectal tissue may have an effect on the occurrence of human rectal cancer while the contents of PAHs in human hepatic tissues may have not ones.

  7. Obstructive jaundice leads to accumulation of oxidized low density lipoprotein in human liver tissue

    Institute of Scientific and Technical Information of China (English)

    Mustafa Comert; Yucel Ustundag; Ishak Ozel Tekin; Banu Dogan Gun; Figen Barut

    2006-01-01

    Oxidized low density lipoprotein (ox-LDL) molecule is one of the most important modified lipoproteins produced during the oxidative stress. Modified lipoproteins have been defined as being part of the immune inflammatory mechanisms in association with oxidant stress. We have reported the accumulation of ox-LDL in Balb/c mice liver after bile duct ligation previously. Here, we investigated this finding in human beings with obstructive jaundice.Our study demonstrates that obstructive jaundice results in tremendous accumulation of ox-LDL in the liver tissue of patients.

  8. Association of human cytomegalovirus viremia with human leukocyte antigens in liver transplantation recipients

    Institute of Scientific and Technical Information of China (English)

    Jianhua Hu; Jun Fan; Xueqin Meng; Hong Zhao; Xuan Zhang; Hainv Gao; Meifang Yang; Yadan Ma; Minhuan Li; Weihang Ma

    2011-01-01

    Human cytomegalovirus (HCMV) reactivation is a common complication after liver transplantation (LT).Here, we investigated whether human leukocyte antigen (HLA)-matching was related to HCMV infection and subsequent graft failure after LT for hepatitis B virus cirrhosis. This retrospective study reviewed 91 LT recipients.All the patients were grouped according to HLA-A, HLA-B, and HLA-DR locus matching. Clinical data were collected, including complete HLA-typing, HCMV viremia, graft failure, and the time of HCMV viremia.HLA typing was performed using a sequence-specific primer-polymerase chain reaction kit. HCMV was detected by pp65 antigenemia using a commercial kit.The incidence of HCMV infection post-LT was 81.32%.Graft failure was observed in 16 of 91 (17.6%) patients during the 4-year study. The incidence of HCMV viremia was 100% (5/5), 91.4% (32/35), and 72.5% (37/51) in HLA-A two locus, one locus, and zero locus compatibility,respectively. Nevertheless, the degree of the HLA-A,HLA-B, or HLA-DR match did not influence the time of HCMV viremia, graft failure, or the time of graft failure after a diagnosis of HCMV viremia (all P> 0.05). An interesting discovery was that the risk of HCMV viremia tended to be higher in patients with better HLA-A compatibility. Graft failure, time of HCMV viremia, and graft failure after a diagnosis of HCMV viremia appear to be independent of HLA allele compatibility.

  9. Production of human liver prolidase by Saccharomyces cerevisiae as host cells

    Institute of Scientific and Technical Information of China (English)

    Shu-hao WANG; Min LIU; Mu-gen CHI; Qing-ding WANG; Man-ji SUN

    2004-01-01

    AIM: To clone and express the recombinant human liver prolidase in yeast and explore the activities of both dipeptidase and organophosphoric acid anhydrolase (OPAA). METHODS: The cDNA encoding human liver prolidase derived from healthy adult liver was cloned into the pYES2, an expression vector of S cerevisiae, and then transformed into S cerevisiae INVScl by electroporation. The transformant with the highest enzymatic activity was induced by galactose for expression. The optimal induction conditions (temperature, induction time, and the initial amount of inoculation cells) were estimated by orthogonal experimental design. The recombinant prolidase and OPAA activities were assayed by spectrocolorimetric methods. RESULTS: The recombinant enzyme catalyzed the hydrolysis of organophosphorous compound soman as well as the hydrolysis of dipeptide Gly-Pro. Under the optimal induction conditions (20 h, 25 ℃, initial OD600=0.4), the maximum activities of prolidase and OPAA came to enzyme in disrupted cell supernatants showed a molecular weight of 56 kDa. Intensity scanning of the SDS-PAGE gel revealed that the enzyme accounted for 3.16 % of the total protein in the supernatant. One liter incubation medium produced 7 g of wet yeast cell containing 4.56 mg of the recombination protein. CONCLUSION: The recombinant human liver prolidase produced by yeast cell (S cerevisiae) exhibited both dipeptidase and OPAA activities.

  10. In vitro Phase I and Phase II metabolism of α-pyrrolidinovalerophenone (α-PVP), methylenedioxypyrovalerone (MDPV) and methedrone by human liver microsomes and human liver cytosol.

    Science.gov (United States)

    Negreira, Noelia; Erratico, Claudio; Kosjek, Tina; van Nuijs, Alexander L N; Heath, Ester; Neels, Hugo; Covaci, Adrian

    2015-07-01

    The aim of the present study was to identify the in vitro Phase I and Phase II metabolites of three new psychoactive substances: α-pyrrolidinovalerophenone (α-PVP), methylenedioxypyrovalerone (MDPV), and methedrone, using human liver microsomes and human liver cytosol. Accurate-mass spectra of metabolites were obtained using liquid chromatography-quadrupole time-of-flight mass spectrometry. Six Phase I metabolites of α-PVP were identified, which were formed involving reduction, hydroxylation, and pyrrolidine ring opening reactions. The lactam compound was the major metabolite observed for α-PVP. Two glucuronidated metabolites of α-PVP, not reported in previous in vitro studies, were further identified. MDPV was transformed into 10 Phase I metabolites involving reduction, hydroxylation, and loss of the pyrrolidine ring. Also, six glucuronidated and two sulphated metabolites were detected. The major metabolite of MDPV was the catechol metabolite. Methedrone was transformed into five Phase I metabolites, involving N- and O-demethylation, hydroxylation, and reduction of the ketone group. Three metabolites of methedrone are reported for the first time. In addition, the contribution of individual human CYP enzymes in the formation of the detected metabolites was investigated.

  11. The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease.

    Science.gov (United States)

    Lake, April D; Novak, Petr; Hardwick, Rhiannon N; Flores-Keown, Brieanna; Zhao, Fei; Klimecki, Walter T; Cherrington, Nathan J

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) may progress from simple steatosis to severe, nonalcoholic steatohepatitis (NASH) in 7%-14% of the U.S. population through a second "hit" in the form of increased oxidative stress and inflammation. Endoplasmic reticulum (ER) stress signaling and the unfolded protein response (UPR) are triggered when high levels of lipids and misfolded proteins alter ER homeostasis creating a lipotoxic environment within NAFLD livers. The objective of this study was to determine the coordinate regulation of ER stress-associated genes in the progressive stages of human NAFLD. Human liver samples categorized as normal, steatosis, NASH (Fatty), and NASH (Not Fatty) were analyzed by individual Affymetrix GeneChip Human 1.0 ST microarrays, immunoblots, and immunohistochemistry. A gene set enrichment analysis was performed on autophagy, apoptosis, lipogenesis, and ER stress/UPR gene categories. An enrichment of downregulated genes in the ER stress-associated lipogenesis and ER stress/UPR gene categories was observed in NASH. Conversely, an enrichment of upregulated ER stress-associated genes for autophagy and apoptosis gene categories was observed in NASH. Protein expression of the adaptive liver response protein STC2 and the transcription factor X-box binding protein 1 spliced (XBP-1s) were significantly elevated among NASH samples, whereas other downstream ER stress proteins including CHOP, ATF4, and phosphorylated JNK and eIF2α were not significantly changed in disease progression. Increased nuclear accumulation of total XBP-1 protein was observed in steatosis and NASH livers. The findings reveal the presence of a coordinated, adaptive transcriptional response to hepatic ER stress in human NAFLD.

  12. The microcell mediated transfer of human chromosome 8 into highly metastatic rat liver cancer cell line C5F

    Institute of Scientific and Technical Information of China (English)

    Hu Liu; Sheng-Long Ye; Jiong Yang; Zhao-You Tang; Yin-Kun Liu; Lun-Xiu Qin; Shuang-Jian Qiu; Rui-Xia Sun

    2003-01-01

    AIM: Our previous research on the surgical samples of primary liver cancer with CGH showed that the loss of human chromosome 8p had correlation with the metastatic phenotype of liver cancer. In order to seek the functional evidence that there could be a metastatsis suppressor gene (s) for liver cancer on human chromosome 8, we tried to transfer normal human chromosome 8 into rat liver cancer cell line C5F, which had high metastatic potential to lung.METHODS: Human chromosome 8 randomly marked with neo gene was introduced into C5F cell line by MMCT and positive microcell hybrids were screened by double selections of G418 and HAT. Single cell isolation cloning was applied to clone microcell hybrids. Finally, STS-PCR and WCP-FISH were used to confirm the introduction.RESULTS: Microcell hybrids resistant to HAT and G418 were obtained and 15 clones were obtained by single-cell isolation cloning. STS-PCR and WCP-FISH proved that human chromosome 8 had been successfully introduced into rat liver cancer cell line C5F. STS-PCR detected a random loss in the chromosome introduced and WCP-FISH found a consistent recombination of the introduced human chromosome with the rat chromosome.CONCLUSION: The successful introduction of human chromosome 8 into highly metastatic rat liver cancer cell line builds the basis for seeking functional evidence of a metastasis suppressor gene for liver cancer harboring on human chromosome 8 and its subsequent cloning.

  13. Comparative metabolism of chloroacetamide herbicides and selected metabolites in human and rat liver microsomes.

    Science.gov (United States)

    Coleman, S; Linderman, R; Hodgson, E; Rose, R L

    2000-01-01

    Acetochlor [2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methyl-phenyl)-acetamide], alachlor [N-(methoxymethyl)-2-chloro-N-(2, 6-diethyl-phenyl)acetamide], butachlor [N-(butoxymethyl)-2-chloro-N-(2,6-diethyl-phenyl)acetamide], and metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamide] are pre-emergent herbicides used in the production of agricultural crops. These herbicides are carcinogenic in rats: acetochlor and alachlor cause tumors in the nasal turbinates, butachlor causes stomach tumors, and metolachlor causes liver tumors. It has been suggested that the carcinogenicity of these compounds involves a complex metabolic activation pathway leading to a DNA-reactive dialkylbenzoquinone imine. Important intermediates in this pathway are 2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA) produced from alachlor and butachlor and 2-chloro-N-(2-methyl-6-ethylphenyl)acetamide (CMEPA) produced from acetochlor and metolachlor. Subsequent metabolism of CDEPA and CMEPA produces 2,6-diethylaniline (DEA) and 2-methyl-6-ethylaniline (MEA), which are bioactivated through para-hydroxylation and subsequent oxidation to the proposed carcinogenic product dialkylbenzoquinone imine. The current study extends our earlier studies with alachlor and demonstrates that rat liver microsomes metabolize acetochlor and metolachlor to CMEPA (0.065 nmol/min/mg and 0.0133 nmol/min/mg, respectively), whereas human liver microsomes can metabolize only acetochlor to CMEPA (0.023 nmol/min/mg). Butachlor is metabolized to CDEPA to a much greater extent by rat liver microsomes (0.045 nmol/min/mg) than by human liver microsomes (< 0.001 nmol/min/mg). We have determined that both rat and human livers metabolize both CMEPA to MEA (0.308 nmol/min/mg and 0.541 nmol/min/mg, respectively) and CDEPA to DEA (0.350 nmol/min/mg and 0.841 nmol/min/mg, respectively). We have shown that both rat and human liver microsomes metabolize MEA (0.035 nmol/min/mg and 0.069 nmol/min/mg, respectively

  14. Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Walkiria Wingester Vilas-Boas; Ant(o)nio Ribeiro-Oliveira Jr; Renata da Cunha Ribeiro; Renata Lúcia Pereira Vieira; Jerusa Almeida; Ana Paula Nadu; Ana Cristina Sim(o)es e Silva; Robson Augusto Souza Santos

    2008-01-01

    AIM: To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS: Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) Ⅰ, Ang Ⅱ, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components.RESULTS: PRA, Ang Ⅰ, Ang Ⅱ and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang Ⅰ levels and between Ang Ⅱ and Ang Ⅰ were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang Ⅱ remained unchanged in splanchnic and peripheral circulation in patients under 13-blockade, whereas the relationship between Ang Ⅱ and Ang Ⅰ was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup.CONCLUSION: In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang Ⅱ in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio.

  15. Alpha-1-antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model for the development of liver pathology in human.

    Science.gov (United States)

    Giovannoni, Isabella; Callea, Francesco; Stefanelli, Marta; Mariani, Riccardo; Santorelli, Filippo M; Francalanci, Paola

    2015-01-01

    Homozygous individuals with alpha-1-antitrypsin deficiency (AATD) type PiZ have an increased risk of chronic liver disease and hepatocellular carcinoma (HCC). It is noteworthy that HCCs are composed by hepatocytes without accumulation of AAT, but the reason for this remains unclear. The aim of this study was to determine liver pathology in PiZ mice, focusing the attention on the distribution of AAT globules in normal liver, regenerative foci and neoplastic nodules. Liver of 79 PiZ mice and 18 wild type (Wt) was histologically analysed for steatosis, clear cell foci, hyperplasia and neoplasia. The expression of human-AAT transgene and murine AAT, in non-neoplastic liver and in hyperplastic/neoplastic nodules was tested by qPCR and qRT-PCR. RT-PCR was used to study expression of hepatic markers: albumin, α-foetoprotein, transthyretin, AAT, glucose-6-phospate, tyrosine aminotransferase. Liver pathology was seen more frequently in PiZ (47/79) than in Wt (5/18) and its development was age related. In older PiZ mice (18-24 m), livers showed malignant tumours (HCC and angiosarcoma) (17/50), hyperplastic nodules (28/50), non-specific changes (33/50), whereas only 9/50 were normal. Both human-AATZ DNA and mRNA showed no differences between tumours/nodules and normal liver, while murine-AAT mRNA was reduced in tumours/nodules. Accumulation of AAT is associated with an increased risk of liver nodules. The presence of globule-devoid hepatocytes and the reduced expression of murine-AAT mRNA in hyperplastic and neoplastic nodules suggest that these hepatic lesions in AATD could originate from proliferating dedifferentiated cells, lacking AAT storage and becoming capable of AFP re-expression. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Arrhythmia risk in liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Ioana Mozos

    2015-01-01

    Interactions between the functioning of the heart andthe liver have been described, with heart diseasesaffecting the liver, liver diseases affecting the heart,and conditions that simultaneously affect both. Theheart is one of the most adversely affected organs inpatients with liver cirrhosis. For example, arrhythmiasand electrocardiographic changes are observed inpatients with liver cirrhosis. The risk for arrhythmia isinfluenced by factors such as cirrhotic cardiomyopathy,cardiac ion channel remodeling, electrolyte imbalances,impaired autonomic function, hepatorenal syndrome, metabolic abnormalities, advanced age, inflammatory syndrome, stressful events, impaired drug metabolism and comorbidities. Close monitoring of cirrhotic patients is needed for arrhythmias, particularly when QT intervalprolonging drugs are given, or if electrolyte imbalances or hepatorenal syndrome appear. Arrhythmia risk may persist after liver transplantation due to possible QT interval prolongation, persistence of the parasympathetic impairment, post-transplant reperfusion and chronic immunosuppression, as well as consideration of the fact that the transplant itself is a stressful event for the cardiovascular system. The aims of the present article were to provide a review of the most important data regarding the epidemiology, pathophysiology, and biomarkers of arrhythmia risk in patients with liver cirrhosis, to elucidate the association with long-term outcome, and to propose future research directions.

  17. Identification of UDP-glucuronosyltransferase isoforms responsible for leonurine glucuronidation in human liver and intestinal microsomes.

    Science.gov (United States)

    Tan, Bo; Cai, Weimin; Zhang, Jinlian; Zhou, Ning; Ma, Guo; Yang, Ping; Zhu, Qing; Zhu, Yizhun

    2014-09-01

    Leonurine is a potent component of herbal medicine Herba leonuri. The detail information on leonurine metabolism in human has not been revealed so far. Two primary metabolites, leonurine O-glucuronide and demethylated leonurine, were observed and identified in pooled human liver microsomes (HLMs) and O-glucuronide is the predominant one. Among 12 recombinant human UDP-glucuronosyltransferases (UGTs), UGT1A1, UGT1A8, UGT1A9, and UGT1A10 showed catalyzing activity toward leonurine glucuronidation. The intrinsic clearance (CLint) of UGT1A1 was approximately 15-to 20-fold higher than that of UGT1A8, UGT1A9, and UGT1A10, respectively. Both chemical inhibition study and correlation study demonstrated that leonurine glucuronidation activities in HLMs had significant relationship with UGT1A1 activities. Leonurine glucuronide was the major metabolite in human liver microsomes. UGT1A1 was principal enzyme that responsible for leonurine glucuronidation in human liver and intestine microsomes.

  18. Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells

    Energy Technology Data Exchange (ETDEWEB)

    Soeda, Junpei; Morgan, Maelle; McKee, Chad; Mouralidarane, Angelina; Lin, ChingI [University College London, Centre for Hepatology, Royal Free Hospital, London NW3 2PF (United Kingdom); Roskams, Tania [Department of Morphology and Molecular Pathology, University of Leuven (Belgium); Oben, Jude A., E-mail: j.oben@ucl.ac.uk [University College London, Centre for Hepatology, Royal Free Hospital, London NW3 2PF (United Kingdom); Department of Gastroenterology and Hepatology, Guy' s and St Thomas' Hospital, London SE1 7EH (United Kingdom)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Cigarette smoke may induce liver fibrosis via nicotine receptors. Black-Right-Pointing-Pointer Nicotine induces proliferation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Nicotine activates hepatic fibrogenic pathways. Black-Right-Pointing-Pointer Nicotine receptor antagonists attenuate HSC proliferation. Black-Right-Pointing-Pointer Nicotinic receptor antagonists may have utility as novel anti-fibrotic agents. -- Abstract: Background and aims: Cigarette smoke (CS) may cause liver fibrosis but possible involved mechanisms are unclear. Among the many chemicals in CS is nicotine - which affects cells through nicotinic acetylcholine receptors (nAChR). We studied the effects of nicotine, and involved pathways, on human primary hepatic stellate cells (hHSCs), the principal fibrogenic cells in the liver. We then determined possible disease relevance by assaying nAChR in liver samples from human non-alcoholic steatohepatitis (NASH). Methods: hHSC were isolated from healthy human livers and nAChR expression analyzed - RT-PCR and Western blotting. Nicotine induction of hHSC proliferation, upregulation of collagen1-{alpha}2 and the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-{beta}1) was determined along with involved intracellular signaling pathways. nAChR mRNA expression was finally analyzed in whole liver biopsies obtained from patients diagnosed with non-alcoholic steatohepatitis (NASH). Results: hHSCs express muscle type ({alpha}1, {beta}1, delta and epsilon) and neuronal type ({alpha}3, {alpha}6, {alpha}7, {beta}2 and {beta}4) nAChR subunits at the mRNA level. Among these subunits, {alpha}3, {alpha}7, {beta}1 and {epsilon} were predominantly expressed as confirmed by Western blotting. Nicotine induced hHSC proliferation was attenuated by mecamylamine (p < 0.05). Additionally, collagen1-{alpha}2 and TGF-{beta}1 mRNA expression were significantly upregulated by nicotine and inhibited by

  19. Proteomic Profiling of Human Liver Biopsies: Hepatitis C Virus-Induced Fibrosis and Mitochondrial Dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Diamond, Deborah L.; Jacobs, Jon M.; Paeper, Bryan; Proll, Sean; Gritsenko, Marina A.; Carithers, Jr., Robert L.; Larson , Anne M.; Yeh, Matthew M.; Camp, David G.; Smith, Richard D.; Katze, Michael G.

    2007-09-01

    Liver biopsies from HCV-infected patients offer the unique opportunity to study human liver biology and disease in vivo. However, the low protein yields associated with these small samples present a significant challenge for proteomic analysis. In this study we describe the application of an ultra-sensitive proteomics platform for performing robust quantitative proteomic studies on microgram amounts of HCV-infected human liver tissue from 15 patients at different stages of fibrosis. A high quality liver protein data base containing 5,920 unique protein identifications supported high throughput quantitative studies using 16O:18O stable isotope labeling in combination with the accurate mass and time (AMT) tag approach. A total of 1,641 liver biopsy proteins were quantified and ANOVA identified 210 proteins exhibiting statistically significant differences associated with fibrosis stage. Hierarchical clustering revealed that biopsies representative of later fibrosis stages (e.g. Batts-Ludwig stages 3-4) exhibited a distinct protein expression profile indicating an apparent down-regulation of many proteins when compared to samples from earlier fibrosis stages (e.g. Batts-Ludwig stages 0-2). Functional analysis of these signature proteins suggests that impairment of key mitochondrial processes including fatty acid oxidation and oxidative phosphorylation, and response to oxidative stress and reactive oxygen species occurs during advanced stage 3-4 fibrosis. In conclusion, the results reported here represent a significant advancement in clinical proteomics providing to our knowledge, the first demonstration of global proteomic alterations accompanying liver disease progression in patients chronically infected with HCV. Our findings contribute to a generally emerging theme associating oxidative stress and hepatic mitochondrial dysfunction with HCV pathogenesis.

  20. FOOD CONSUMPTION OF CIRRHOTIC PATIENTS, COMPARISON WITH THE NUTRITIONAL STATUS AND DISEASE STAGING

    Directory of Open Access Journals (Sweden)

    Flavia Feijó NUNES

    Full Text Available ABSTRACT Background Patients with liver disease often present protein-energy malnutrition. The assessment of food intake is very important in the investigation regarding the "health-disease" process. Objective To assess dietary intake of cirrhotic patients through food record during 3 days, correlating it with the nutritional status of the patient and the stage of the disease. Methods Cirrhotic outpatients from the Santa Casa de Misericórdia Hospital, RS, Brazil, were assessed. Nutritional assessment was performed by anthropometry; non-dominating handgrip strength; adductor pollicis muscle thickness; phase angle by bioelectrical impedance analysis; and Subjective Global Assessment. For analysis of food consumption we used the food records of 3 days using scales for weighing of all foods. Results We evaluated 25 (68% patients, in which there was a prevalence of cirrhosis by hepatitis C virus. The upper arm circumference, handgrip strength and phase angle by bioelectrical impedance analysis diagnosed 56% of malnourished. Phase angle by bioelectrical impedance analysis and upper arm circumference were associated with Child-Pugh score (P<0.05. The average consumption of calories, carbohydrates, proteins and lipids were within the recommended. However, sodium was above the recommendations, 106±57.2 mEq, and was inversely associated with Child-Pugh score (rs=-0.410; P=0.042. Conclusion Food intake did not have a significant difference between the Child-Pugh scores and nutritional status. In addition, food intake did not vary neither according to the stage of the disease, nor to the nutritional assessment, by the phase angle by bioelectrical impedance analysis.

  1. Dose requirements of continuous infusion of rocuronium and atracurium throughout orthotopic liver transplantation in humans

    Institute of Scientific and Technical Information of China (English)

    WENG Xiao-chuan; ZHOU Liang; FU Yin-yan; ZHU Sheng-mei; HE Hui-liang; WU Jian

    2005-01-01

    Objective: To compare the dose requirements of continuous infusion of rocuronium and atracurium throughout orthotopic liver transplantation (OLT) in humans. Methods: Twenty male patients undergoing liver transplantation were randomly assigned to two comparable groups of 10 patients each to receive a continuous infusion of rocuronium or atracurium under itravenous balanced anesthesia. The response of adductor pollicis to train-of-four (TOF) stimulation of unlar nerve was monitored.The infusion rates of rocuronium and atracurium were adjusted to maintain T1/Tc ratio of 2%~10%. The total dose of each drug given during each of the three phases of OLT was recorded. Results: Rocuronium requirement, which were (0.468±0.167)unchanged during orthotopic liver transplantation. Conclusions: This study showed that the exclusion of the liver from the circulation results in the significantly reduced requirement of rocuronium while the requirement of atracurium was not changed,which suggests that the liver is of major importance in the clearance of rocuronium. A continuous infusion of atracurium with constant rate can provide stable neuromuscular blockade during the three stages of OLT.

  2. Thermal neutron irradiation field design for boron neutron capture therapy of human explanted liver.

    Science.gov (United States)

    Bortolussi, S; Altieri, S

    2007-12-01

    The selective uptake of boron by tumors compared to that by healthy tissue makes boron neutron capture therapy (BNCT) an extremely advantageous technique for the treatment of tumors that affect a whole vital organ. An example is represented by colon adenocarcinoma metastases invading the liver, often resulting in a fatal outcome, even if surgical resection of the primary tumor is successful. BNCT can be performed by irradiating the explanted organ in a suitable neutron field. In the thermal column of the Triga Mark II reactor at Pavia University, a facility was created for this purpose and used for the irradiation of explanted human livers. The neutron field distribution inside the organ was studied both experimentally and by means of the Monte Carlo N-particle transport code (MCNP). The liver was modeled as a spherical segment in MCNP and a hepatic-equivalent solution was used as an experimental phantom. In the as-built facility, the ratio between maximum and minimum flux values inside the phantom ((phi(max)/phi(min)) was 3.8; this value can be lowered to 2.3 by rotating the liver during the irradiation. In this study, the authors proposed a new facility configuration to achieve a uniform thermal neutron flux distribution in the liver. They showed that a phi(max)/phi(min) ratio of 1.4 could be obtained without the need for organ rotation. Flux distributions and dose volume histograms were reported for different graphite configurations.

  3. Transplantation of human stem cell-derived hepatocytes in an animal model of acute liver failure.

    Science.gov (United States)

    Ramanathan, Rajesh; Pettinato, Giuseppe; Beeston, John T; Lee, David D; Wen, Xuejun; Mangino, Martin J; Fisher, Robert A

    2015-08-01

    Hepatocyte cell transplantation can be life-saving in patients with acute liver failure (ALF); however, primary human hepatocyte transplantation is limited by the scarcity of donor hepatocytes. We investigated the effect of stem cell-derived, hepatocyte-like cells in an animal xenotransplant model of ALF. Intraperitoneal d-galactosamine was used to develop a lethal model of ALF in the rat. Human induced pluripotent stem cells (iPSC), human mesenchymal stem cells, and human iPSC combined with human endothelial cells (iPSC + EC) were differentiated into hepatocyte-like cells and transplanted into the spleens of athymic nude rats with ALF. A reproducible lethal model of ALF was achieved with nearly 90% death within 3 days. Compared with negative controls, rats transplanted with stem cell-derived, hepatocyte-like cells were associated with increased survival. Human albumin was detected in the rat serum 3 days after transplantation in more than one-half the animals transplanted with hepatocyte-like cells. Only animals transplanted with iPSC + EC-derived hepatocytes had serum human albumin at 14 days posttransplant. Transplanted hepatocyte-like cells homed to the injured rat liver, whereas the ECs were only detected in the spleen. Transplantation of stem cell-derived, hepatocyte-like cells improved survival with evidence of in vivo human albumin production. Combining ECs may prolong cell function after transplantation. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Umbilical paracentesis for acute hernia reduction in cirrhotic patients

    OpenAIRE

    2013-01-01

    Emergent repair of umbilical hernias in cirrhotic patients is associated with a high risk for morbidity and mortality. We propose a new technique, umbilical paracentesis, for reduction of incarcerated hernias in the patient with ascites. Under ultrasound guidance, removal of ascitic fluid from the umbilical hernia sac can reduce the local pressure and thereby allow for easy hernia reduction, thus avoiding the need for an emergent operation.

  5. Umbilical paracentesis for acute hernia reduction in cirrhotic patients.

    Science.gov (United States)

    Russell, Katie W; Mone, Mary C; Scaife, Courtney L

    2013-10-16

    Emergent repair of umbilical hernias in cirrhotic patients is associated with a high risk for morbidity and mortality. We propose a new technique, umbilical paracentesis, for reduction of incarcerated hernias in the patient with ascites. Under ultrasound guidance, removal of ascitic fluid from the umbilical hernia sac can reduce the local pressure and thereby allow for easy hernia reduction, thus avoiding the need for an emergent operation.

  6. The serum nT-proBnP in Patients with Cirrhosis:Relationship to Cardiac dysfunction and liver Function

    Institute of Scientific and Technical Information of China (English)

    2013-01-01

    Objective To detect the values of NT-proBNP and evaluate its relationship with liver function, cardiac structure, and cardiac function which was evaluated by echocardiography in patients with liver cirrhosis. Methods A total of 50 liver cirrhotic patients and 11 healthy controls were studied by two dimensional Doppler echocardiography. Liver cirrhotic patients were divided into group A, B and C according to the Child-Pugh score. Cardiac dimensions and left and right ventricular functions were also evaluated. At the same time, the serum NT-proBNP of liver cirrhotic patients and healthy controls were detected, respectively. Results By Comparison between two groups, we found that the values of LVd, LAs, LVPW, AAO, A Wave, RVOTs, PV and NT-proBNP in liver cirrhosis group were higher than those in control group, whereas the value of E/A decreased. As for the value of LAs and serum NT-proBNP, A and B group were all lower than C group. With LAs>35 mm, the number of cases in liver cirrhosis group was higher than that in control group. So did that With E/A Conclusions The cardiac dysfunction confirmed the existence of cirrhotic cardiomyopathy. More clinical implications were found in liver cirrhotic patients with increased values of serum NT-proBNP.

  7. Biotransformation of chlorpyrifos and diazinon by human liver microsomes and recombinant human cytochrome P450s (CYP).

    Science.gov (United States)

    Sams, C; Cocker, J; Lennard, M S

    2004-10-01

    The cytochrome P450 (CYP)-mediated biotransformation of the organophosphorothioate insecticides chlorpyrifos and diazinon was investigated. Rates of desulphuration to the active oxon metabolite (chlorpyrifos-oxon and diazinon-oxon) and dearylation to non-toxic hydrolysis products were determined in human liver microsome preparations from five individual donors and in recombinant CYP enzymes. Chlorpyrifos and diazinon underwent desulphuration in human liver microsome with mean Km = 30 and 45 microM and V(max) = 353 and 766 pmol min(-1) mg(-1), respectively. Dearylation of these compounds by human liver microsome proceeded with Km = 12 and 28 microM and V(max) = 653 and 1186 pmol min(-1) mg(-1), respectively. The apparent intrinsic clearance (V(max)/Km) of dearylation was 4.5- and 2.5-fold greater than desulphuration for chlorpyrifos and diazinon, respectively. Recombinant human CYP2B6 possessed the highest desulphuration activity for chlorpyrifos, whereas CYP2C19 had the highest dearylation activity. In contrast, both desulphuration and dearylation of diazinon were catalysed at similar rates, in the rank order CYP2C19 > CYP1A2 > CYP2B6 > CYP3A4. Both organophosphorothioates were more readily detoxified (dearylation) than bioactivated (desulphuration) in all human liver microsome preparations. However, the role of individual CYP enzymes in these two biotransformation pathways varied according to the structure of the organophosphorothioate, which was reflected in different activation/detoxification ratios for chlorpyrifos and diazinon. Variability in activity of individual CYP enzymes may influence interindividual sensitivity to the toxic effects of chlorpyrifos and diazinon.

  8. Reestablishing brain networks in patients without overt hepatic encephalopathy after liver transplantation

    OpenAIRE

    Lin, Wei-Che; Hsu, Tun-Wei; Chen, Chao-Long; Lu, Cheng-Hsien; Chen, Hsiu-Ling; Cheng, Yu-Fan; Lin, Ching-Po

    2014-01-01

    Cirrhotic patients without overt hepatic encephalopathy (HE) have associated with widespread neuro-psychological impairment. Liver transplantation can restore metabolic abnormalities but the mechanisms are unclear. We investigate brain functional networks after transplantation using resting-state funtional magnetic resonance imaging (MRI). Twenty-six cirrhotic patients without overt HE completed neuro-psychological assessment before and 6 to 12 months after transplantation, and compared with ...

  9. Percutaneous laser ablation of hepatocellular carcinoma in patients with liver cirrhosis awaiting liver transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Pompili, Maurizio, E-mail: mpompili@rm.unicatt.i [Department of Internal Medicine, Universita Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma (Italy); Pacella, Claudio Maurizio, E-mail: claudiomauriziopacella@gmail.co [Department of Diagnostic Imaging and Interventional Radiology, Ospedale Regina Apostolorum, Via S. Francesco D' Assisi, 50, 00041 Albano Laziale (RM) (Italy); Francica, Giampiero, E-mail: giampierofrancica@tin.i [Department of Interventional Ultrasound, Presidio Ospedaliero Camilliani, S. Maria della Pieta, Via S. Rocco, 9, 80026 Casoria (Namibia) (Italy); Angelico, Mario, E-mail: angelico@med.uniroma2.i [Hepatology Unit, Universita di Tor Vergata, Viale Oxford, 81, 00133 Rome (Italy); Tisone, Giuseppe, E-mail: tisone@med.uniroma2.i [Transplant and General Surgery Unit, Universita di Tor Vergata, Ospedale S. Eugenio, Piazzale dell' Umanesimo 10-00144 Rome (Italy); Craboledda, Paolo, E-mail: paolo.craboledda@virgilio.i [Department of Pathology, Ospedale S. Eugenio, Piazzale dell' Umanesimo, 10-00144 Rome (Italy); Nicolardi, Erica; Rapaccini, Gian Ludovico; Gasbarrini, Giovanni [Department of Internal Medicine, Universita Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma (Italy)

    2010-06-15

    Objective: The aim of this study was to determine the effectiveness and safety of percutaneous laser ablation for the treatment of cirrhotic patients with hepatocellular carcinoma awaiting liver transplantation. Materials and methods: The data of 9 male cirrhotic patients (mean age 50 years, range 45-60 years) with 12 biopsy proven nodules of hepatocellular carcinoma (mean diameter 2.0 cm, range 1.0-3.0 cm) treated by laser ablation before liver transplantation between June 2000 and January 2006 were retrospectively reviewed. Laser ablation was carried out by inserting 300 nm optical fibers through 21-Gauge needles (from two to four) positioned under ultrasound guidance into the target lesions. A continuous wave Neodymium:Yttrium Aluminium Garnet laser was used. Transarterial chemoembolization prior to liver transplantation was performed in two incompletely ablated tumors. Results: No procedure-related major complications were recorded. During the waiting time to liver transplantation local tumor progression after ablation occurred in 3 nodules (25%). At histological examination of the explanted livers complete necrosis was found in 8 nodules (66.7%, all treated exclusively with laser ablation), partial necrosis >50% in 3 nodules (25%), and partial necrosis <50% in 1 nodule. Conclusion: In patients with cirrhotic livers awaiting liver transplantation, percutaneous laser ablation is safe and effective for the management of small hepatocellular carcinoma.

  10. Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

    Science.gov (United States)

    Maschmeyer, Ilka; Hasenberg, Tobias; Jaenicke, Annika; Lindner, Marcus; Lorenz, Alexandra Katharina; Zech, Julie; Garbe, Leif-Alexander; Sonntag, Frank; Hayden, Patrick; Ayehunie, Seyoum; Lauster, Roland; Marx, Uwe; Materne, Eva-Maria

    2015-09-01

    Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called "human-on-a-chip" concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air-liquid interface for the skin model during their co-culture with the liver equivalents respectively at (1)/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver-skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance - troglitazone - to the chip-based co-cultures.

  11. Hepatic progenitor cells in human liver cirrhosis:Immunohistochemical,electron microscopic and immunofluorencence confocal microscopic findings

    Institute of Scientific and Technical Information of China (English)

    Jia-Cheng Xiao; Xiao-Long Jin; Peter Ruck; Anne Adam; Edwin Kaiserling

    2004-01-01

    AIM: To investigate whether hepatic progenitor cells (HPC),that reveal the features of oval cells in rodents and small epithelial cells (SEC) in certain human liver disease, were also found in human liver cirrhosis (HLC).METHODS: Surgical liver specimens from 20 cases of hepatitis B virus-positive HLC (15 cases containing hepatocellular carcinoma) were investigated by light microscopic immunohistochemistry (LM-IHC). Among them specimens from 15 cases were investigated by electron microscopy (EM)and those from 5 cases by immunofluorencence confocal laser scanning microscopy (ICLSM). Antibodies against cytokeratin 7 and albumin were used and single and/or double labelling were performed respectively.RESULTS: LM-IHC showed that at the margins of regenerating nodules and in the fibrous septae, a small number of cells in the proliferating bile ductules were positive for CK7 and albumin. At the EM level these HPC were morphologically similar to the SEC described previously, and also similar to the oval cells seen in experimental hepatocarcinogenesis.They were characterized by their small size, oval shape, a high nucleus/cytoplasm ratio, a low organelle content in cytoplasm, and existence of tonofilaments and intercellular junctions. ICLSM revealed that HPC expressed both cytokeratin 7 and albumin.CONCLUSION: HPC with ultrastructural and immunophenotypical features of oval cells, i.e., hepatic stem cell-like cells as noted in other liver diseases, were found in HLC. These findings further support the hypothesis that bipotent hepatic stem cells, that may give rise to biliary epithelial cells and hepatocytes, exist in human livers.

  12. Mechanism of action of novel piperazine containing a toxicant against human liver cancer cells

    Science.gov (United States)

    Kanthimathi, MS; Haerian, Batoul Sadat

    2016-01-01

    The purpose of this study was to assess the cytotoxic potential of a novel piperazine derivative (PCC) against human liver cancer cells. SNU-475 and 423 human liver cancer cell lines were used to determine the IC50 of PCC using the standard MTT assay. PCC displayed a strong suppressive effect on liver cancer cells with an IC50 value of 6.98 ± 0.11 µM and 7.76 ± 0.45 µM against SNU-475 and SNU-423 respectively after 24 h of treatment. Significant dipping in the mitochondrial membrane potential and elevation in the released of cytochrome c from the mitochondria indicated the induction of the intrinsic apoptosis pathway by PCC. Activation of this pathway was further evidenced by significant activation of caspase 3/7 and 9. PCC was also shown to activate the extrinsic pathways of apoptosis via activation of caspase-8 which is linked to the suppression of NF-κB translocation to the nucleus. Cell cycle arrest in the G1 phase was confirmed by flow cytometry and up-regulation of glutathione reductase expression was quantified by qPCR. Results of this study suggest that PCC is a potent anti-cancer agent inducing both intrinsic and extrinsic pathways of apoptosis in liver cancer cell lines. PMID:27019772

  13. A red wine polyphenolic extract reduces the activation phenotype of cultured human liver myofibroblasts

    Institute of Scientific and Technical Information of China (English)

    Véronique Neaud; Jean Rosenbaum

    2008-01-01

    AIM: To test the effect of a standardized red wine polyphenolic extract (RWPE) on the phenotype of human liver myofibroblasts in culture.METHODS: Human myofibroblasts grown from liver explants were used in this study. Cell proliferation was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Signaling events were analyzed by western blot with phosphospecific antibodies. Matrix-metalloproteinase activity was measured with gel zymography.RESULTS: We found that cell proliferation was dosedependently decreased by up to 90% by RWPE while cell viability was not affected. Exposure to RWPE also greatly decreased the phosphorylation of ERK1/ERK2 and Akt in response to stimulation by the mitogenic factor platelet-derived growth factor BB (PDGF-BB).Finally, RWPE affected extracellular matrix remodeling by decreasing the secretion by myofibroblasts of matrixmetalloproteinase-2 and of tissue inhibitor of matrixmetalloproteinases-1.CONCLUSION: Altogether, RWPE decreases the activation state of liver myofibroblasts. The identification of the active compounds in RWPE could offer new therapeutic strategies against liver fibrosis.

  14. Mice with chimeric livers are an improved model for human lipoprotein metabolism.

    Directory of Open Access Journals (Sweden)

    Ewa C S Ellis

    Full Text Available OBJECTIVE: Rodents are poor model for human hyperlipidemias because total cholesterol and low density lipoprotein levels are very low on a normal diet. Lipoprotein metabolism is primarily regulated by hepatocytes and we therefore assessed whether chimeric mice extensively repopulated with human cells can model human lipid and bile acid metabolism. DESIGN: FRG [ F ah(-/- R ag2(-/-Il2r g (-/-] mice were repopulated with primary human hepatocytes. Serum lipoprotein lipid composition and distribution (VLDL, LDL, and HDL was analyzed by size exclusion chromatography. Bile was analyzed by LC-MS or by GC-MS. RNA expression levels were measured by quantitative RT-PCR. RESULTS: Chimeric mice displayed increased LDL and VLDL fractions and a lower HDL fraction compared to wild type, thus significantly shifting the ratio of LDL/HDL towards a human profile. Bile acid analysis revealed a human-like pattern with high amounts of cholic acid and deoxycholic acid (DCA. Control mice had only taurine-conjugated bile acids as expcted, but highly repopulated mice had glycine-conjugated cholic acid as found in human bile. RNA levels of human genes involved in bile acid synthesis including CYP7A1, and CYP27A1 were significantly upregulated as compared to human control liver. However, administration of recombinant hFGF19 restored human CYP7A1 levels to normal. CONCLUSION: Humanized-liver mice showed a typical human lipoprotein profile with LDL as the predominant lipoprotein fraction even on a normal diet. The bile acid profile confirmed presence of an intact enterohepatic circulation. Although bile acid synthesis was deregulated in this model, this could be fully normalized by FGF19 administration. Taken together these data indicate that chimeric FRG-mice are a useful new model for human lipoprotein and bile-acid metabolism.

  15. Efficacy of entecavir combined with alprostadil in treatment of hepatitis B-related cirrhotic ascites

    Directory of Open Access Journals (Sweden)

    LI Huili

    2016-02-01

    Full Text Available ObjectiveTo investigate the efficacy of entecavir combined with alprostadil in the treatment of hepatitis B-related cirrhotic ascites. MethodsA total of 100 patients with hepatitis B-related cirrhotic ascites who were admitted to Dezhou Hospital of Traditional Chinese Medicine from May 2012 to February 2014 were selected and randomly divided into treatment group and control group, with 50 patients in each group. The patients in both groups received the liver-protecting treatment, diuretic treatment, and intermittent supplementation of albumin(Alb. Additionally, the patients in the treatment group received oral entecavir 0.5 mg once a day, combined with intravenous infusion of alprostadil 20 μg+5% glucose injection 100 ml once a day, and those in the observation group only received oral entecavir 0.5 mg once a day. The patients were hospitalized and treated for 4 weeks. Ascites regression, changes in the levels of alanine aminotransferase (ALT, total bilirubin (TBil, Alb, blood urea nitrogen (BUN, creatinine (Cr, and hepatitis B virus (HBV DNA, and prothrombin activity (PTA were observed in both groups. After discharge, the patients in both groups continued to take oral entecavir 0.5 mg once a day, and the long-term therapeutic effect was observed through follow-up for 3 months. The t-test was applied for comparison of continuous data between groups, and the chi-square test was applied for comparison of categorical data between groups. ResultsThe patients in both groups had varying degrees of reduction in the amount of ascites after treatment, and the treatment group had a significantly higher overall response rate than the control group (χ2=6.018, P<0.05. The patients in both groups had varying degrees of improvement in each index of liver and renal function (ALT, TBil, Alb, BUN, and Cr and PTA after treatment; the treatment group had a better treatment outcome than the control group, and there were significant differences in each index

  16. Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases.

    Science.gov (United States)

    Shekhawat, Prem; Bennett, Michael J; Sadovsky, Yoel; Nelson, D Michael; Rakheja, Dinesh; Strauss, Arnold W

    2003-06-01

    The role of fat metabolism during human pregnancy and in placental growth and function is poorly understood. Mitochondrial fatty acid oxidation disorders in an affected fetus are associated with maternal diseases of pregnancy, including preeclampsia, acute fatty liver of pregnancy, and the hemolysis, elevated liver enzymes, and low platelets syndrome called HELLP. We have investigated the developmental expression and activity of six fatty acid beta-oxidation enzymes at various gestational-age human placentas. Placental specimens exhibited abundant expression of all six enzymes, as assessed by immunohistochemical and immunoblot analyses, with greater staining in syncytiotrophoblasts compared with other placental cell types. beta-Oxidation enzyme activities in placental tissues were higher early in gestation and lower near term. Trophoblast cells in culture oxidized tritium-labeled palmitate and myristate in substantial amounts, indicating that the human placenta utilizes fatty acids as a significant metabolic fuel. Thus human placenta derives energy from fatty acid oxidation, providing a potential explanation for the association of fetal fatty acid oxidation disorders with maternal liver diseases in pregnancy.

  17. Metabolism of sesamin by cytochrome P450 in human liver microsomes.

    Science.gov (United States)

    Yasuda, Kaori; Ikushiro, Shinichi; Kamakura, Masaki; Ohta, Miho; Sakaki, Toshiyuki

    2010-12-01

    Metabolism of sesamin by cytochrome P450 (P450) was examined using yeast expression system and human liver microsomes. Saccharomyces cerevisiae cells expressing each of human P450 isoforms (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) were cultivated with sesamin, and monocatechol metabolite was observed in most of P450s. Kinetic analysis using the microsomal fractions of the recombinant S. cerevisiae cells revealed that CYP2C19 had the largest k(cat)/K(m) value. Based on the kinetic data and average contents of the P450 isoforms in the human liver, the putative contribution of P450s for sesamin metabolism was large in the order of CYP2C9, 1A2, 2C19, and 2D6. A good correlation was observed between sesamin catecholization activity and CYP2C9-specific activity in in vitro studies using 10 individual human liver microsomes, strongly suggesting that CYP2C9 is the most important P450 isoform for sesamin catecholization in human liver. Inhibition studies using each anti-P450 isoform-specific antibody confirmed that CYP2C9 was the most important, and the secondary most important P450 was CYP1A2. We also examined the inhibitory effect of sesamin for P450 isoform-specific activities and found a mechanism-based inhibition of CYP2C9 by sesamin. In contrast, no mechanism-based inhibition by sesamin was observed in CYP1A2-specific activity. Our findings strongly suggest that further studies are needed to reveal the interaction between sesamin and therapeutic drugs mainly metabolized by CYP2C9.

  18. [Detection of human parvovirus B19, human bocavirus and human parvovirus 4 infections in blood samples among 95 patients with liver disease in Nanjing by nested PCR].

    Science.gov (United States)

    Tong, Rui; Zhou, Wei-Min; Liu, Xi-Jun; Wang, Yue; Lou, Yong-Liang; Tan, Wen-Jie

    2013-04-01

    To analyze the infection of human parvovirus B19, human bocavirus (HBoV) and human parvovirus 4 (PARV4) in blood samples among patients with liver disease in Nanjing by molecular detection. Nested PCR assays were designed and validated to detect B19, HBoV and PARV4, respectively. The assays were used to screen three parvoviruses in blood samples from 95 patients with different liver disease in Nanjing. The parvovirus infection was analyzed statistically. The detection limits were 10 copies of genomic DNA equivalents per reaction for each assays and the good specificity were observed. The frequency of B19 and HBoV were 2/95 (2.1%) and 9/95 (9.5%) in blood samples respectively. No PARV4 was detected. HBoV was detected in 3/5 patients with drug-induced hepatitis. Both B19 and HBoV infection were detected in blood from patients with liver disease.

  19. Definition of the transcription initiation site of human plasminogen gene in liver and non hepatic cell lines.

    Science.gov (United States)

    Malgaretti, N; Bruno, L; Pontoglio, M; Candiani, G; Meroni, G; Ottolenghi, S; Taramelli, R

    1990-12-31

    We have mapped the cap site of the human plasminogen mRNA by primer extension and PCR techniques and found that it is located at position -161 relative to the first ATG, 97 bases upstream to the 5' end of the previously isolated cDNA clone. Seven human hepatic and non hepatic cell lines and fresh liver cells were tested for human plasminogen mRNA expression: the liver and the liver derived HepG2 cell line represent the major site of plasminogen RNA synthesis while the other cell lines (Hep3B, HeLa, IMR, 293 CaCo and SW626) show much lower levels.

  20. In vitro biotransformation of tris(2-butoxyethyl) phosphate (TBOEP) in human liver and serum

    Energy Technology Data Exchange (ETDEWEB)

    Van den Eede, Nele, E-mail: nele.vandeneede@uantwerpen.be [Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp (Belgium); Erratico, Claudio [Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp (Belgium); Exarchou, Vassiliki [Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp (Belgium); Maho, Walid; Neels, Hugo [Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp (Belgium); Covaci, Adrian, E-mail: adrian.covaci@uantwerpen.be [Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp (Belgium)

    2015-04-15

    Tris(2-butoxyethyl) phosphate (TBOEP) is a plasticizer present in indoor dust, reaching levels of several micrograms per gram. Such levels could lead to significant daily exposure of adults and children. Currently, no toxicokinetic data are available to estimate TBOEP clearance in humans after uptake and therefore, one objective of this study was to investigate intrinsic clearance of TBOEP by human liver microsome (HLM) and serum enzymes. Another objective was to generate information to identify and prioritize several metabolites of TBOEP for investigation of human exposure by biomonitoring. 1D and 2D-NMR methodologies were successfully applied on a mixture of the metabolites to confirm the structure of 3-HO-TBOEP (bis(2-butoxyethyl) 3-hydroxyl-2-butoxyethyl phosphate) and to tentatively assign structures to 1-HO-TBOEP and 2-HO-TBOEP. HO-TBOEP isomers and bis(2-butoxyethyl) phosphate (BBOEP), bis(2-butoxyethyl) hydroxyethyl phosphate (BBOEHEP) were further monitored by liquid chromatography–tandem mass spectrometry. Rates of formation of BBOEHEP and HO-TBOEP metabolites by liver enzymes were best described by the Michaelis–Menten model. Apparent K{sub m} values for BBOEHEP, 3-HO-TBOEP, and sum of 1- and 2-HO-TBOEP isomer formation were 152, 197 and 148 μM, respectively. Apparent V{sub max} values for the formation of BBOEHEP, 3-HO-TBOEP, and the sum of 1- and 2-HO-TBOEP isomers were 2560, 643, and 254 pmol/min/mg protein, respectively. No detectable formation of BBOEP occurred with liver or serum enzymes. Our findings indicate that intrinsic clearance of TBOEP is mainly catalyzed by oxidative enzymes in the liver and that its major in vitro metabolite is BBOEHEP. These findings can be applied in human biomonitoring studies and risk assessment. - Highlights: • First steps in the elucidation of TBOEP toxicokinetics • Quantification of TBOEP metabolites in human serum and liver microsomes • No detectable formation of BBOEP occurred with liver or serum

  1. Thiamethoxam induced mouse liver tumors and their relevance to humans. Part 2: species differences in response.

    Science.gov (United States)

    Green, Trevor; Toghill, Alison; Lee, Robert; Waechter, Felix; Weber, Edgar; Peffer, Richard; Noakes, James; Robinson, Mervyn

    2005-07-01

    Thiamethoxam is a neonicotinoid insecticide that is not a mutagen, but it did cause a significant increase in liver cancer in mice, but not rats, in chronic dietary feeding studies. Previous studies in mice have characterized a carcinogenicity mode of action that involved depletion of plasma cholesterol, cell death, both as single cell necrosis and as apoptosis, and sustained increases in cell replication rates. In a study reported in this article, female rats have been exposed to thiamethoxam in their diet at concentrations of 0, 1000, and 3000 ppm for 50 weeks, a study design directly comparable to the mouse study in which the mode of action changes were characterized. In rats, thiamethoxam had no adverse effects on either the biochemistry or histopathology of the liver at any time point during the study. Cell replication rates were not increased, in fact they were significantly decreased at several time points. The lack of effect on the rat liver is entirely consistent with the lack of liver tumor formation in the two-year cancer bioassay. Comparisons of the metabolism of thiamethoxam in rats and mice have shown that concentrations of the parent chemical were either similar or higher in rat blood than in mouse blood in both single dose and the dietary studies strongly indicating that thiamethoxam itself is unlikely to play a role in the development of liver tumors. In contrast, the concentrations of the two metabolites, CGA265307 and CGA330050, shown to play a role in the development of liver damage in the mouse, were 140- (CGA265307) and 15- (CGA330050) fold lower in rats than in mice following either a single oral dose, or dietary administration of thiamethoxam for up to 50 weeks. Comparisons of the major metabolic pathways of thiamethoxam in vitro using mouse, rat, and human liver fractions have shown that metabolic rates in humans are lower than those in the rat suggesting that thiamethoxam is unlikely to pose a hazard to humans exposed to this chemical at

  2. ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling

    DEFF Research Database (Denmark)

    Le Pabic, Hélène; Bonnier, Dominique; Wewer, Ulla M

    2003-01-01

    "A disintegrin and metalloproteinases" (ADAMs) form a family of cell-surface glycoproteins with potential protease and cell-adhesion activities. We have investigated ADAM expression in human liver cancers and their regulation by several cytokines involved in liver injury. Using degenerative RT-PC...

  3. Gene expression analysis of precision-cut human liver slices indicate stable expression of hepatotoxicity related genes

    NARCIS (Netherlands)

    Elferink, Maria; Olinga, Peter; van Leeuwen, E. M.; Bauerschmidt, S.; Polman, J.; Schoonen, W. G.; Heisterkamp, S. H.; Groothuis, Genoveva

    2011-01-01

    In the process of drug development it is of high importance to test the safety of new drugs with predictive value for human toxicity. A promising approach of toxicity testing is based on changes in the gene expression profile of the liver. Toxicity screening based on animal liver cells cannot be dir

  4. Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes

    NARCIS (Netherlands)

    Elferink, M. G. L.; Olinga, P.; van Leeuwen, E. M.; Bauerschmidt, S.; Polman, J.; Schoonen, W. G.; Heisterkamp, S. H.; Groothuis, G. M. M.

    2011-01-01

    In the process of drug development it is of high importance to test the safety of new drugs with predictive value for human toxicity. A promising approach of toxicity testing is based on shifts in gene expression profiling of the liver. Toxicity screening based on animal liver cells cannot be direct

  5. Liver-related deaths among persons infected with the human immunodeficiency virus: The D:A:D Study

    DEFF Research Database (Denmark)

    Weber, R; Sabin, CA; Friis-Møller, Nina;

    2006-01-01

    BACKGROUND: An increasing proportion of deaths among human immunodeficiency virus (HIV)-infected persons with access to combination antiretroviral therapy (cART) are due to complications of liver diseases. METHODS: We investigated the frequency of and risk factors associated with liver-related de...

  6. Completion of hepatitis C virus replication cycle in heterokaryons excludes dominant restrictions in human non-liver and mouse liver cell lines.

    Directory of Open Access Journals (Sweden)

    Anne Frentzen

    2011-04-01

    Full Text Available Hepatitis C virus (HCV is hepatotropic and only infects humans and chimpanzees. Consequently, an immunocompetent small animal model is lacking. The restricted tropism of HCV likely reflects specific host factor requirements. We investigated if dominant restriction factors expressed in non-liver or non-human cell lines inhibit HCV propagation thus rendering these cells non-permissive. To this end we explored if HCV completes its replication cycle in heterokaryons between human liver cell lines and non-permissive cell lines from human non-liver or mouse liver origin. Despite functional viral pattern recognition pathways and responsiveness to interferon, virus production was observed in all fused cells and was only ablated when cells were treated with exogenous interferon. These results exclude that constitutive or virus-induced expression of dominant restriction factors prevents propagation of HCV in these cell types, which has important implications for HCV tissue and species tropism. In turn, these data strongly advocate transgenic approaches of crucial human HCV cofactors to establish an immunocompetent small animal model.

  7. Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach.

    Science.gov (United States)

    Wei, Xiao; Yan, Xiabei; Zou, Dayang; Yang, Zhan; Wang, Xuesong; Liu, Wei; Wang, Simiao; Li, Xuelian; Han, Juqiang; Huang, Liuyu; Yuan, Jing

    2013-12-26

    Assessment and characterization of human colon microbiota is now a major research area in human diseases, including in patients with hepatitis B liver cirrhosis (HBLC). We recruited 120 patients with HBLC and 120 healthy controls. The fecal microbial community and functions in the two groups were analyzed using high-throughput Solexa sequencing of the complete metagenomic DNA and bioinformatics methods. Community and metabolism-wide changes of the fecal microbiota in 20 HBLC patients and 20 healthy controls were observed and compared. A negative correlation was observed between the Child-Turcotte-Pugh scores and Bacteroidetes (P microbiota samples demonstrated that these intestinal microbial markers might be useful for distinguishing liver cirrhosis microbiota samples from normal ones. The functional diversity was significantly reduced in the fecal microbiota of cirrhotic patients compared with in the controls. At the module or pathway levels, the fecal microbiota of the HBLC patients showed enrichment in the metabolism of glutathione, gluconeogenesis, branched-chain amino acid, nitrogen, and lipid (P microbiota community and metabolic potential were detected in the fecal microbiota of cirrhotic patients. The intestinal microbial community may act as an independent organ to regulate the body's metabolic balance, which may affect the prognosis for HBLC patients.

  8. Effect of New Water-Soluble Dendritic Phthalocyanines on Human Colorectal and Liver Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Ebru YABAŞ

    2017-08-01

    Full Text Available Human hepatocellular carcinoma (HepG2 cells and colorectal adenocarcinoma (DLD-1 cells were treated with the synthesized water soluble phthalocyanine derivatives to understand the effect of the compounds both on colorectal and liver cancer cells. The compounds inhibited cell proliferation and displayed cytotoxic effect on these cancer cell lines however; the effect of the compounds on healthy control fibroblast cell line was comparatively lower. The compounds can be employed for cancer treatment as anticancer agents.

  9. In vitro biotransformation of tris(2-butoxyethyl) phosphate (TBOEP) in human liver and serum.

    Science.gov (United States)

    Van den Eede, Nele; Erratico, Claudio; Exarchou, Vassiliki; Maho, Walid; Neels, Hugo; Covaci, Adrian

    2015-04-15

    Tris(2-butoxyethyl) phosphate (TBOEP) is a plasticizer present in indoor dust, reaching levels of several micrograms per gram. Such levels could lead to significant daily exposure of adults and children. Currently, no toxicokinetic data are available to estimate TBOEP clearance in humans after uptake and therefore, one objective of this study was to investigate intrinsic clearance of TBOEP by human liver microsome (HLM) and serum enzymes. Another objective was to generate information to identify and prioritize several metabolites of TBOEP for investigation of human exposure by biomonitoring. 1D and 2D-NMR methodologies were successfully applied on a mixture of the metabolites to confirm the structure of 3-HO-TBOEP (bis(2-butoxyethyl) 3-hydroxyl-2-butoxyethyl phosphate) and to tentatively assign structures to 1-HO-TBOEP and 2-HO-TBOEP. HO-TBOEP isomers and bis(2-butoxyethyl) phosphate (BBOEP), bis(2-butoxyethyl) hydroxyethyl phosphate (BBOEHEP) were further monitored by liquid chromatography-tandem mass spectrometry. Rates of formation of BBOEHEP and HO-TBOEP metabolites by liver enzymes were best described by the Michaelis-Menten model. Apparent Km values for BBOEHEP, 3-HO-TBOEP, and sum of 1- and 2-HO-TBOEP isomer formation were 152, 197 and 148μM, respectively. Apparent Vmax values for the formation of BBOEHEP, 3-HO-TBOEP, and the sum of 1- and 2-HO-TBOEP isomers were 2560, 643, and 254pmol/min/mg protein, respectively. No detectable formation of BBOEP occurred with liver or serum enzymes. Our findings indicate that intrinsic clearance of TBOEP is mainly catalyzed by oxidative enzymes in the liver and that its major in vitro metabolite is BBOEHEP. These findings can be applied in human biomonitoring studies and risk assessment.

  10. Serum levels of soluble Fas, nitric oxide and cytokines in acute decompensated cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Christoph Elsing; Sabine Harenberg; Wolfgang Stremmel; Thomas Herrmann

    2007-01-01

    AIM: To evaluate plasma levels of nitrite/nitrate (NOx),soluble Fas (sFas) antigen, tumor necrosis factor alpha(TNF-α) and interleukin-6 (TL-6) in patients with compensated and acute decompensated cirrhosis and to evaluate mediators causing acute decompensation in liver cirrhosis.METHODS: This prospective study was conducted in the medical intensive care unit of an academic tertiary center. Fifty-five patients with acute decompensation (gastrointestinal hemorrhage, encephalopathy, hydropic decompensation) and twenty-five patients with compensated liver cirrhosis were included. Blood samples were taken for analyses of sfas, Nox, TL-6, TNF-α. Liver enzymes and kidney functions were also tested.RESULTS: In patients with acute decompensation, plasma sfas levels were higher than in non-decompensated patients (15305±4646 vs 12458 ± 4322 pg/mL, P <0.05). This was also true for the subgroup of patients with alcoholic liver cirrhosis (P < 0.05). The other mediators were not different and none of the parameters predicted survival, except for ALT (alanine-aminotransferase). In patients with portal-hypertension-induced acute hemorrhage, NOx levels were significantly lower than in patients with other forms of decompensation (70.8 ±48.3 vs 112.9 ± 74.9 pg/mL, P < 0.05). When NOx levels were normalized to creatinine levels, the difference disappeared. IL-6, TNF-α and sfas were not different between bleeders and non-bleeders. In decompensated patients sfas, IL-6 and NOx levels correlated positively with creatinine levels, while IL-6 levels were dependent on Child class.CONCLUSION: In acute decompensated cirrhotic patients sFas is increased, suggesting a role of apoptosis in this process and patients with acute bleeding have lower NOx levels. However, in this acute complex clinical situation, kidney function seems to have a predominant influence on mediator levels.

  11. Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis.

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    Gil-Farina, Irene; Di Scala, Marianna; Salido, Eduardo; López-Franco, Esperanza; Rodríguez-García, Estefania; Blasi, Mercedes; Merino, Juana; Aldabe, Rafael; Prieto, Jesús; Gonzalez-Aseguinolaza, Gloria

    2016-09-15

    The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL/6 mice were i.v. injected with adeno-associated viral vectors encoding murine IL-12 or luciferase under the control of a liver-specific promoter. Organ histology, response to immunosuppressive therapy, and biochemical and immunological parameters, including Ag-specific humoral and cellular response, were analyzed. Mechanistic studies were carried out using genetically modified mice and depletion of lymphocyte subpopulations. Adeno-associated virus IL-12-treated mice developed histological, biochemical, and immunological changes resembling type 1 AIH, including marked and persistent liver mononuclear cell infiltration, hepatic fibrosis, hypergammaglobulinemia, anti-nuclear and anti-smooth muscle actin Abs, and disease remission with immunosuppressive drugs. Interestingly, transgenic IL-12 was short-lived, but endogenous IL-12 expression was induced, and both IL-12 and IFN-γ remained elevated during the entire study period. IFN-γ was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury. Furthermore, both MHC class I and MHC class II expression was upregulated at the hepatocellular membrane, and induction of autoreactive liver-specific T cells was detected. Remarkably, although immunoregulatory mechanisms were activated, they only partially mitigated liver damage. Thus, low and transient expression of transgenic IL-12 in hepatocytes causes loss of tolerance to hepatocellular Ags, leading to chronic hepatitis resembling human AIH type 1. This model provides a practical tool to explore AIH pathogenesis and novel therapies.

  12. Rapamycin ameliorates inflammation and fibrosis in the early phase of cirrhotic portal hypertension in rats through inhibition of mTORC1 but not mTORC2.

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    Weijie Wang

    Full Text Available OBJECTIVE: Hepatic stellate cells (HSCs transdifferentiation and subsequent inflammation are important pathological processes involved in the formation of cirrhotic portal hypertension. This study characterizes the pathogenetic mechanisms leading to cholestatic liver fibrosis and portal hypertension, and focuses on mammalian target of rapamycin (mTOR pathway as a potential modulator in the early phase of cirrhotic portal hypertension. METHODS: Early cirrhotic portal hypertension was induced by bile duct ligation (BDL for three weeks. One week after operation, sham-operated (SHAM and BDL rats received rapamycin (2 mg/kg/day by intraperitoneal injection for fourteen days. Vehicle-treated SHAM and BDL rats served as controls. Fibrosis, inflammation, and portal pressure were evaluated by histology, morphometry, and hemodynamics. Expressions of pro-fibrogenic and pro-inflammatory genes in liver were measured by RT-PCR; alpha smooth muscle actin (α-SMA and antigen Ki67 were detected by immunohistochemistry; expressions of AKT/mTOR signaling molecules, extracellular-signal-regulated kinase 1/2 (ERK1/2, p-ERK1/2, and interleukin-1 beta (IL-1β were assessed by western blot. RESULTS: The AKT/mTOR signaling pathway was markedly activated in the early phase of cirrhotic portal hypertension induced by BDL in rats. mTOR blockade by rapamycin profoundly improved liver function by limiting inflammation, fibrosis and portal pressure. Rapamycin significantly inhibited the expressions of phosphorylated 70KD ribosomal protein S6 kinase (p-P70S6K and phosphorylated ribosomal protein S6 (p-S6 but not p-AKT Ser473 relative to their total proteins in BDL-Ra rats. Those results suggested that mTOR Complex 1 (mTORC1 rather than mTORC2 was inhibited by rapamycin. Interestingly, we also found that the level of p-ERK1/2 to ERK1/2 was significantly increased in BDL rats, which was little affected by rapamycin. CONCLUSIONS: The AKT/mTOR signaling pathway played an important

  13. In Vitro Metabolism Studies of Polybrominated Diphenyl Ethers Using Rat and Human Liver Microsomes

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    Shun W. Cheng

    2008-01-01

    Full Text Available A number of studies have recently reported the bioaccumulation of the commonly used fire retardants, Polybrominated Diphenyl Ethers (PBDEs, in humans and wildlife. Exposure of animals to PBDEs has been shown to result in developmental neurological, reproductive abnormalities and the disruption of endocrine function. Thyroid hormone equilibria was also shown to be altered by PBDE exposure. There is evidence that hydroxylated metabolites of PBDEs are directly involved in some of these adverse effects. Although metabolites of PBDEs have been isolated and characterized during in vivo studies, the identification of metabolites from an in vitro system has been problematic. We investigated the in vitro metabolism of four PBDEs, with varying numbers of bromine atoms, in rat and human liver microsomes. The addition of small amounts of a nonionic surfactant to the reaction mixture was necessary to obtain measurable amounts of metabolites due to the low aqueous solubility of the PBDEs. Using gas chromatography/mass spectroscopy, mono and/or dihydroxylated metabolites were identified from three of the four PBDEs with phenobarbitol- and β-naphthoflavone-induced rat liver microsomes. When using uninduced rat or human liver microsomes, metabolites were found with only one of the PBDEs. The ease of PBDE metabolism appears to be inversely related to the number of bromine atoms on the parent compound.

  14. Diazinon is activated by CYP2C19 in human liver.

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    Kappers, W A; Edwards, R J; Murray, S; Boobis, A R

    2001-11-15

    Phosphorothioate compounds are used throughout the world as agricultural and domestic pesticides. Here, the activation of the phosphorothioate diazinon to diazoxon in human liver is described. In an initial study using three human liver microsomal samples, K(m) for diazoxon formation varied markedly (31, 208, and 660 microM; V(max) 1125, 685, and 1028 pmol/min/mg protein, respectively), suggesting the involvement of more than one P450 enzyme. A wide variation in activity was found using 50 microM diazinon as substrate, (11-648 pmol/min/mg protein, n = 15), whereas, with 500 microM, variation was less (164-978 pmol/min/mg protein). Among eight P450-catalyzed reactions, the putative high-affinity component (50 microM diazinon) correlated with S-mephenytoin 4'-hydroxylase activity (r = 0.686, p diazinon) correlated with both S-mephenytoin 4'-hydroxylase (r = 0.714; p diazinon (500 microM) at the fastest rate, followed by CYP3A4, CYP1A2, and CYP2C9. Both hepatic microsomal S-mephenytoin 4'-hydroxylase and high-affinity phenacetin O-deethylase activities were strongly inhibited by diazinon (IC50 diazinon activation in human liver, while other enzymes including CYP1A2 may play a more minor role.

  15. PDEs1-5 activity and expression in tissues of cirrhotic rats reveal a role for aortic PDE3 in NO desensitization.

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    Tahseldar-Roumieh, Rima; Keravis, Thérèse; Maarouf, Suha; Justiniano, Hélène; Sabra, Ramzi; Lugnier, Claire

    2009-12-01

    Liver cirrhosis is associated with increased nitric oxide (NO) production in the vasculature. We have previously demonstrated that aorta from rats with liver cirrhosis have a reduced relaxant response to NO donors that is corrected by DMPPO, a PDE5-specific inhibitor. Vasodilator responses to DMPPO itself were also reduced in rings from cirrhotic rats. These results supported previous suggestions that upregulation of PDE5 in liver cirrhosis might contribute to renal sodium retention, and consequently modulate vascular reactivity in the context of increased NO production (Tahseldar-Roumieh et al. in Am. J. Physiol. Heart Circ. Physiol. 290, H481-H488, 2006). Here, we investigated the possible alteration in activity and expression of cyclic nucleotide phosphodiesterase PDE1-PDE5 in kidney and vascular tissues in rats 4 weeks after bile duct ligation. The kidney of rats with cirrhosis had increased activity of PDE1 and PDE4 but not PDE5, and increased expression of PDE1A. Unexpectedly and interestingly, there was no change in cirrhotic aorta PDE5, but an increase in PDE3 and PDE4 activity associated with increased expression of PDE3A and PDE3B. Cilostamide, a specific PDE3 inhibitor, corrected the decreased response to an NO donor in isolated aorta from cirrhotic rats, suggesting that the difference in response to NO donors was due to differences in PDE3-induced hydrolysis of cGMP or to cGMP-induced inhibition of PDE3, rather than to differences in PDE5 contribution. In conclusion, these changes in PDE isozymes could greatly contribute to NO desensitization and to the regulation of vascular and renal function in liver cirrhosis.

  16. Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis.

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    Giannelli, Valerio; Di Gregorio, Vincenza; Iebba, Valerio; Giusto, Michela; Schippa, Serena; Merli, Manuela; Thalheimer, Ulrich

    2014-12-07

    Liver disease is associated with qualitative and quantitative changes in the intestinal microbiota. In cirrhotic patients the alteration in gut microbiota is characterized by an overgrowth of potentially pathogenic bacteria (i.e., gram negative species) and a decrease in autochthonous familiae. Here we summarize the available literature on the risk of gut dysbiosis in liver cirrhosis and its clinical consequences. We therefore described the features of the complex interaction between gut microbiota and cirrhotic host, the so called "gut-liver axis", with a particular attention to the acquired risk of bacterial translocation, systemic inflammation and the relationship with systemic infections in the cirrhotic patient. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of gut dysbiosis and its complication in liver cirrhosis.

  17. Investigation on Hepatopoietin and Other Novel Genes from Human Fetal Liver

    Institute of Scientific and Technical Information of China (English)

    He Fuchu; Zhang Chenggang; Li Yong; Lu Chengrong; Zhang Lingqiang

    2007-01-01

    The aim of this study is to discover the molecular mechanism of the 22-week gestated human fetal liver( HFL ) which rarely displays both hematopoietic and hepatic functions. Based on large-scale cDNA library sequencing and bioinformatic analysis, the largest gene expression profile of human fetal liver in the world was successfully established. A set of gene clusters functionally related to the liver development, hepatocarcinogenesis and hematopoiesis have been identified. This is for the first time that we could panoramically understand the molecular mechanism of the dual functions of human fetal liver. Moreover, 201 unrecorded human homologous genes and 609 novel genes have been identified and annotated, which accounting for more than 7% of the known human genes in 2001. In the recent human genome annotation map (