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Sample records for human cirrhotic liver

  1. Elements in normal and cirrhotic human liver. Potassium, iron, copper, zinc and bromine measured by X-ray fluorescence spectrometry

    DEFF Research Database (Denmark)

    Laursen, J.; Milman, N.; Leth, Peter Mygind

    1990-01-01

    Various elements (K, Fe, Cu, Zn, Br) were measured by X-ray flourescence spectrometry in cellular and connective tissue fractions of normal and cirrhotic liver samples obtained at autopsy. Normal livers: 32 subjects (16 males, 16 females) median age 69 years. Cirrhotic livers: 14 subjects (13 mal...

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

    Science.gov (United States)

    2010-01-01

    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. PMID:21059220

  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. Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver

    International Nuclear Information System (INIS)

    Shankar, T.P.; Drake, S.; Solomon, S.S.

    1987-01-01

    Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of 125 I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t/sub 1/2/) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers. Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance

  5. Liver resection for non-cirrhotic hepatocellular carcinoma in south ...

    African Journals Online (AJOL)

    Background. We describe the clinicopathologic features and outcome of South African patients who have undergone hepatic resection for hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. Methods. We utilised the prospective liver resection database in the Surgical Gastroenterology Unit at Groote Schuur ...

  6. Hepatic regeneration after sublethal partial liver irradiation in cirrhotic rats

    International Nuclear Information System (INIS)

    Gu Ke; Lai Songtao; Ma Ningyi; Zhao Jiandong; Ren Zhigang; Wang Jian; Liu Jin; Jiang Guoliang

    2011-01-01

    Our previous animal study had demonstrated that partial liver irradiation (IR) could stimulate regeneration in the protected liver, which supported the measurements adopted in radiotherapy planning for hepatocellular carcinoma. The purpose of this present study is to investigate whether cirrhotic liver repopulation could be triggered by partial liver IR. The cirrhosis was induced by thioacetamide (TAA) in rats. After cirrhosis establishment, TAA was withdrawn. In Experiment 1, only right-half liver was irradiated with single doses of 5 Gy, 10 Gy and 15 Gy, respectively. In Experiment 2, right-half liver was irradiated to 15 Gy, and the left-half to 2.5 Gy, 5 Gy and 7.5 Gy, respectively. The regeneration endpoints, including liver index (LI); mitotic index (MI); liver proliferation index (LPI); proliferating cell nuclear antigen-labeling index (PCNA-LI); serum hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-α and interleukin (IL)-6, were evaluated on 0 day, 30-day, 60-day, 90-day, 120-day and 150-day after IR. Serum and in situ TGF-β1 were also measured. In both experimental groups, the IR injuries were sublethal, inducing no more than 9% animal deaths. Upon TAA withdrawal, hepatic regeneration decelerated in the controls. In Experiment 1 except for LI, all other regeneration parameters were significantly higher than those in controls for both right-half and left-half livers. In Experiment 2 all regeneration parameters were also higher compared with those in controls for both half livers. Serum HGF and VEGF were increased compared with that of controls. Both unirradiated and low dose-irradiated cirrhotic liver were able to regenerate triggered by sublethal partial liver IR and higher doses and IR to both halves liver triggered a more enhanced regeneration. (author)

  7. In vivo P-31 MR spectroscopic studies of liver in normal adults and cirrhotic patients

    International Nuclear Information System (INIS)

    Ban, N.; Moriyasu, F.; Tamada, T.

    1986-01-01

    The author performed in vivo P-31 MR spectroscopic studies of normal and diseased human liver using an experimental 2.0-T whole-body MR imager. Then normal adults and ten cirrhotic patients in the fasting state were studied. Spatially localized in vivo P-31 MR spectra of human liver were obtained in combination with the use of a surface coil and gradient magnetic field. Six spectral peaks were observed in both groups and were assigned, from left to right, to phosphomonoester, inorganic phosphate, phosophodiester, γ-ATP, α-ATP, and β-ATP, on the basis of the chemical shifts. There were no definite differences between the spectral patterns of normal adults and those of cirrhotic patients in the fasting state

  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. Safety and efficacy of endoscopic retrograde cholangiopancreatography for common bile duct stones in liver cirrhotic patients.

    Science.gov (United States)

    Li, De-min; Zhao, Jie; Zhao, Qiu; Qin, Hua; Wang, Bo; Li, Rong-xiang; Zhang, Min; Hu, Ji-fen; Yang, Min

    2014-08-01

    In order to investigate the safety and efficacy of endoscopic retrograde cholangiopancreatograpy (ERCP) in liver cirrhosis patients with common bile duct stones, we retrospectively analyzed data of 46 common bile duct stones patients with liver cirrhosis who underwent ERCP between 2000 and 2008. There were 12 cases of Child-Pugh A, 26 cases of Child-Pugh B, and 8 cases of Child-Pugh C. 100 common bile duct stones patients without liver cirrhosis were randomly selected. All the patients were subjected to ERCP for biliary stones extraction. The rates of bile duct clearance and complications were compared between cirrhotic and non-cirrhotic patients. The success rate of selective biliary cannulation was 95.6% in liver cirrhotic patients versus 97% in non-cirrhotic patients (P>0.05). The bile duct clearance rate was 87% in cirrhotic patients versus 96% in non-cirrhotic patients, but the difference was not statistically significant. Two liver cirrhotic patients (4.35%, 2/46) who were scored Child-Pugh C had hematemesis and melena 24 h after ERCP. The hemorrhage rate after ERCP in non-cirrhotic patients was 3%. The hemorrhage rate associated with ERCP in Child-Pugh C patients was significantly higher (25%, 2/8) than that (3%, 3/100) in non-cirrhotic patients (Pbile duct stones. Hemorrhage risk in ERCP is higher in Child-Pugh C patients.

  11. Hepatic enhancement on Gd-BOPTA-enhanced MR imaging: comparison between cirrhotic and normal livers

    International Nuclear Information System (INIS)

    Shin, Sang Soo; Jeong, Yong Yeon; Kang, Heoung Keun; Lim, Hyo Soon; Yoon, Woong; Seo, Jeong Jin; Park, Jin Gyoon

    2004-01-01

    To compare the enhancement features of hepatic parenchyma between cirrhotic and normal liver, using Gd-BOPTA-enhanced delayed MR imaging. The 60 patients (35 with cirrhotic and 25 with normal liver) included in our study underwent Gd-BOPTA-enhanced MR imaging using a 1.5T system with a phase-array multicoil. In all cases, T1-weighted in-phase and opposed-phase gradient-echo MR imaging was performed before and 60 minutes after intravenous administration of a bolus of Gd-BOPTA. All images were quantitatively analysed by comparing the signal-to-noise ratio (SNR) and signal enhancement (SE) of cirrhotic and normal liver before and after contrast enhancement, and in cirrhotic patients, SNR and SE were also compared in terms of the Child-Pugh classification. For qualitative analysis, the hepatic enhancement patterns of cirrhotic and normal liver were classified as homogeneous or heterogeneous according to the consensual findings of two radiologists. At contrast-enhanced imaging, both cirrhotic (p<0.001) and normal liver (p<0.001) showed substantially increased SNR relative to unenhanced images, and the SNR of cirrhotic liver was significantly lower than that of normal livers at both in-phase (p<0.001) and opposed-phase (p<0.001) imaging. The SE of cirrhotic liver was significantly lower than that of normal liver (in-phase:p=0.002; opposed phase:p=0.011). Both Child-Pugh class A (p<0.001) and B (p<0.001) cirrhotic liver showed a substantial increase in SNR at contrast-enhanced imaging relative to unenhanced imaging and the SNR of Child-Pugh class A was significantly higher than that of Child-Pugh class B at both in-phase (p<0.001) and opposed-phase (p=0.022) imaging. In addition, the SE of class A was significantly higher than that of class B at in-phase imaging (p=0.004). Cirrhotic liver showed heterogeneous enhancement in 20 of 35 patients (57%), whereas normal liver showed homogeneous enhancement in all patients. At Gd-BOPTA-enhanced delayed MR imaging, cirrhotic liver

  12. 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.

  13. Hepatic stellate cell and myofibroblast-like cell gene expression in the explanted cirrhotic livers of patients undergoing liver transplantation.

    Science.gov (United States)

    Estep, J Michael; O'Reilly, Linda; Grant, Geraldine; Piper, James; Jonsson, Johann; Afendy, Arian; Chandhoke, Vikas; Younossi, Zobair M

    2010-02-01

    Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling associated with an insult to the liver affects an HSC transdifferentiation to fibrogenic myofibroblast-like cells. To investigate the transcriptional expression distinguishing HSC and myofibroblast-like cells between livers with and without cirrhosis. Tissue from ten cirrhotic livers (undergoing transplant) and four non-cirrhotic livers from the National Disease Research Interchange underwent cell separation to extract HSC and myofibroblast-like cell populations. Separated cell types as well as LI-90 cells were subjected to microarray analysis. Selected microarray results were verified by quantitative real-time PCR. Differential expression of some genes, such as IL-1beta, IL-1alpha, and IL-6, was associated with both transdifferentiation and disease. Other genes, such as fatty acid 2-hydroxylase only show differential expression in association with disease. Functional analysis supported these findings, indicating some signal transduction pathways (IL-6) are involved in disease and activation, whereas retinoid X receptor signaling in HSC from cirrhotic and non-cirrhotic livers varies in scope and quality. These findings indicate distinct phenotypes for HSC from cirrhotic and non-cirrhotic livers. Furthermore, coordinated differential expression between genes involved in the same signal transduction pathways provides some insight into the mechanisms that may control the balance between fibrogenesis and fibrolysis.

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

    International Nuclear Information System (INIS)

    Seo, J.M.; Lee, S.J.; Kim, S.H.; Park, C.K.; Ha, S.Y.

    2012-01-01

    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.

  15. 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.

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

    Science.gov (United States)

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

    2011-02-01

    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 cirrhotic liver disease by this fast imaging method. 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. 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 value of HBF at the tumor

  17. Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats.

    Science.gov (United States)

    Vilaseca, Marina; García-Calderó, Héctor; Lafoz, Erica; Ruart, Maria; López-Sanjurjo, Cristina Isabel; Murphy, Michael P; Deulofeu, Ramon; Bosch, Jaume; Hernández-Gea, Virginia; Gracia-Sancho, Jordi; García-Pagán, Juan Carlos

    2017-07-01

    In cirrhosis, activated hepatic stellate cells (HSC) play a major role in increasing intrahepatic vascular resistance and developing portal hypertension. We have shown that cirrhotic livers have increased reactive oxygen species (ROS), and that antioxidant therapy decreases portal pressure. Considering that mitochondria produce many of these ROS, our aim was to assess the effects of the oral mitochondria-targeted antioxidant mitoquinone on hepatic oxidative stress, HSC phenotype, liver fibrosis and portal hypertension. Ex vivo: Hepatic stellate cells phenotype was analysed in human precision-cut liver slices in response to mitoquinone or vehicle. In vitro: Mitochondrial oxidative stress was analysed in different cell type of livers from control and cirrhotic rats. HSC phenotype, proliferation and viability were assessed in LX2, and in primary human and rat HSC treated with mitoquinone or vehicle. In vivo: CCl 4 - and thioacetamide-cirrhotic rats were treated with mitoquinone (5 mg/kg/day) or the vehicle compound, DecylTPP, for 2 weeks, followed by measurement of oxidative stress, systemic and hepatic haemodynamic, liver fibrosis, HSC phenotype and liver inflammation. Mitoquinone deactivated human and rat HSC, decreased their proliferation but with no effects on viability. In CCl 4 -cirrhotic rats, mitoquinone decreased hepatic oxidative stress, improved HSC phenotype, reduced intrahepatic vascular resistance and diminished liver fibrosis. These effects were associated with a significant reduction in portal pressure without changes in arterial pressure. These results were further confirmed in the thioacetamide-cirrhotic model. We propose mitochondria-targeted antioxidants as a novel treatment approach against portal hypertension and cirrhosis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. 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.

  19. Cardiac systolic function in cirrhotic patients’ candidate of liver trans-plantation compared with control group

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    Roya Sattarzadeh-Badkoubeh

    2017-02-01

    Full Text Available Background: We assessed different systolic cardiac indices to describe left and right ventricular dysfunction in cirrhotic patients before liver transplantation. Methods: In this case-control study, eighty-one consecutive individuals with the confirmed hepatic cirrhosis and candidate for liver transplantation in the Imam Khomeini Hospital between March 2008 and March 2010 were selected. Thirty-two age and gender cross-matched healthy volunteers were also selected as the control group. A detailed two-dimensional and Doppler echocardiography was obtained in all patients and controls performed by the same operator on the day of admission. Results: Dimensions of both left and right atriums as well as left ventricular end-diastolic volume and basal right ventricular dimension in the cirrhotic group were significantly higher than control group. Left ventricular end-systolic dimensions as well as aortic annulus diameter were not different between the two study groups. Left ventricular outflow tract velocity time integral, isovolumic pre-ejection time, isovolumic relaxation time, stroke volume, left ventricular ejection fraction, IVCT+IVRT+ET, systolic velocity of tricuspid annulus, systolic velocity of basal segment of RV free wall, systolic velocity of basal segment of septal wall, peak strain of septal margin (base, peak strain of septal margin (midpoint, peak strain of lateral margin (midpoint, strain rate of septal margin (base, strain rate of septal margin (midpoint, strain rate of lateral margin (base, strain rate of lateral margin (midpoint, Tei index (left and right ventricles, systolic time interval and tricuspid annular plane systolic excursion were higher in cirrhotic group, significantly, (P< 0.05. Left ventricular ejection time and systolic velocity of mid segment of lateral wall were lower in cirrhotic group, significantly, (P< 0.05. Conclusion: In this study, the effects of liver on heart were volume overload, hyperdynamic state and

  20. A slowly growing mass around a cirrhotic liver: Usefulness of the hepatobility phase in the diagnosis of ectopic liver

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    Kim, Soo Jung; Kim, Kyung Ah; Im, So Young [St. Vincent' s Hospital, College of Medicine, The Catholic University of Korea, Suwon (Korea, Republic of)

    2017-08-15

    An ectopic liver is a rare congenital abnormality that is difficult to detect before surgery due to its small size. A 53-year-old man had liver cirrhosis and received regular surveillance. An ovoid mass on the surface of the gallbladder separated from the liver proper was found on computed tomography (CT). The mass had grown slowly over five years of surveillance. Upon further evaluation, the mass exhibited iso-signal intensity compared to liver on T2-weighted images, precontrast T1-weighted images, and the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (MRI). Surgical resection was performed, and the mass was diagnosed as an ectopic liver with normal liver parenchyma without cirrhotic changes. This case demonstrates that ectopic liver with normal liver tissue can develop in a patient with liver cirrhosis and can grow in the absence of a tumor. MRI with gadoxetic acid is useful to identify this condition correctly.

  1. MR and magnetisation transfer imaging in cirrhotic and fatty livers

    International Nuclear Information System (INIS)

    Alanen, A.; Komu, M.; Leino, R.; Toikkanen, S.

    1998-01-01

    Purpose: To determine whether low-field MR fat/water separation and magnetisation transfer (MT) techniques are useful in studying the livers of patients with parenchymal liver diseases in vivo. Material and Methods: MR and MT imaging of the liver in 33 patients (14 with primary biliary cirrhosis, 15 with alcohol-induced liver disease, and 4 with fatty liver) was performed by means of the fat/water separation technique at 0.1 T. The relaxation time T1 and the MT contrast (MTC) parameter of liver and spleen tissue were measured, and the relative proton density fat content N(%) and MTC of the liver were calculated from the separate fat and water images. The value of N(%) was also compared with the percentage of fatty hepatocytes at histology. Results: The relaxation rate R1 of liver measured from the magnitude image, and the difference in the value of MTC measured form the water image compared with the one measured from the fat and water magnitude image, both depended linearly on the value of N(%). The value of N(%) correlated significantly with the percentage of the fatty hepatocytes. In in vivo fatty tissue, fat infiltration increased both the observed relaxation rate R1 and the measured magnetisation ratio (the steady state magnetisation M s divided by the equilibrium magnetisation M o , M s /M o ) and consequently decreased the MT efficiency measured in a magnitude MR image. The amount of liver fibrosis did not correlate with the value of MTC measured after fat separation. Conclusion: Our results in studying fatty livers with MR imaging and the MT method show that the fat/water separation gives more reliable parametric results. Characterisation of liver cirrhosis by means of the MTC parameter is not reliable, even after fat separation. (orig.)

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

    Science.gov (United States)

    Vasconcelos, José Olímpio Maia DE; Batista, Laécio Leitão; Pitta, Guilherme Benjamin Brandão; Lacerda, Cláudio Moura

    2016-01-01

    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). RESUMO Este estudo descreve duas importantes adaptações para o preparo de moldes de resina em fígado humano cirrótico, captado no momento do transplante: a primeira, é a maneira de fixação dos cateteres nos "óstios" das veias hepáticas e porta, através de uma "cerclagem" dos mesmos, de modo a evitar o deslocamento do cateter e/ou extravasamento da resina durante sua injeção, e a segunda, é o prolongamento do tempo de corrosão na solução de NaOH, atingindo a média de 6,8 dias, com a substituição diária da solução, até a remoção completa do tecido parenquimatoso. O método foi empregado em 14 fígados cirróticos com bom preenchimento e coloração dos territórios das veias porta e hepáticas, utilizando cores distintas. Isto permite um estudo anatômico desses vasos, capaz de complementar os conhecimentos da histopatologia em trabalhos de pesquisa, e planejar procedimentos terapêuticos como a derivação porto-sistêmica intra-hepática transjugular (TIPS - Transjugular Intrahepatic Postosystemic Shunt).

  3. Improved hepatocyte function of future liver remnant of cirrhotic rats after portal vein ligation: a bonus other than volume shifting.

    Science.gov (United States)

    Lin, Kun-Ju; Liao, Chien-Hung; Hsiao, Ing-Tsung; Yen, Tzu-Chen; Chen, Tse-Ching; Jan, Yi-Yin; Chen, Miin-Fu; Yeh, Ta-Sen

    2009-02-01

    Preoperative portal vein embolization is increasingly employed for those with hepatocellular carcinoma and cirrhosis to gain a volume-shifting effect. However, the alterations of histologic architecture and hepatocyte function of future liver remnant (FLR) remain unexplored. Portal vein ligation (PVL) was performed in cirrhotic and noncirrhotic rats. Regeneration indices that include the DNA synthesis index, restituted liver mass, and the redistributed volume ratio were measured. The indocyanine green 15' retention test (ICG-R15), histologic changes, total Knodell score, and activated hepatic stellate cells (HSCs) were measured before and after PVL. Tc-99m sulfur-colloid liver single photon emission computed tomography (SPECT) and diisopropyl iminoacetic acid (DISIDA) SPECT were conducted. The redistributed volume ratio of cirrhotic rats was less than noncirrhotic rats (63% vs 80%, P baseline (6.0 +/- 4.1% vs 15.8 +/- 4.6%, P baseline. The redistributed volume ratio of noncirrhotic and cirrhotic rats based on 99mTc sulfur-colloid SPECT were 79% and 64%, respectively. The clearance T(1/2) of FLR in cirrhotic rats based on DISIDA SPECT was decreased compared with baseline (5.2 +/- 1.9 min vs 8.6 +/- 3.1 min). The regenerated functional liver mass of cirrhotic rats after PVL is less than noncirrhotic rats, whereas the hepatocyte function of FLR in cirrhotic rats is improved relevant to tissue remodeling.

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

    International Nuclear Information System (INIS)

    Cheng, Yue; Huang, Li Xiang; Xie, Shuang

    2017-01-01

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  6. Glycogen content in hepatocytes is related with their size in normal rat liver but not in cirrhotic one.

    Science.gov (United States)

    Bezborodkina, Natalia N; Chestnova, Anna Yu; Vorobev, Mikhail L; Kudryavtsev, Boris N

    2016-04-01

    Hepatocytes differ from one another by the degree of the ploidy, size, position in the liver lobule, and level of the DNA-synthetic processes. It is believed, that the cell size exerts substantial influence on the metabolism of the hepatocytes and the glycogen content in them. The aim of the present study was to test this hypothesis. Dry weight of hepatocytes, their ploidy and glycogen content were determined in the normal and the cirrhotic rat liver. Liver cirrhosis in rats was produced by chronic inhalation of CCl4 vapours in the course of 6 months. A combined cytophotometric method was used. Dry weight of the cell, its glycogen and DNA content were successively measured on a mapped preparation. Hepatocytes of each ploidy class in the normal and the cirrhotic rat liver accumulated glycogen at the same rate. In the normal liver, there was a distinct correlation between the size of hepatocytes and glycogen content in them. This correlation was observed in each ploidy class, and was especially pronounced in the class of mononucleate tetraploid hepatocytes. In the cirrhotic liver, there was no correlation between the size of the cells and their glycogen content. The impairment of liver lobular structure probably explains the observed lack of correlation between hepatocyte size and their glycogen content in the cirrhotic liver. © 2016 International Society for Advancement of Cytometry. © 2016 International Society for Advancement of Cytometry.

  7. 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.

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

    International Nuclear Information System (INIS)

    Wang, Q.; Wang, L.X.; Zeng, J.P.; Liu, X.J.; Liang, X.M.; Zhou, Y.B.

    2013-01-01

    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

  9. 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....

  10. Usefulness of Ultrasound in the Evaluation of Morphologic Change of a Cirrhotic Liver During Respiration

    International Nuclear Information System (INIS)

    Byun, Joo Nam; Kim, Dong Hun; Suk, Eun Ha

    2010-01-01

    This study was designed to determine whether transabdominal ultrasound can detect different hepatic stiffness between patients with cirrhosis and control subjects. Sevent-three patients (Child-Pugh class A stage) with liver cirrhosis and 57 control subjects were included in this study. All patients were subdivided arbitrarily into two groups: early cirrhosis (n = 53) and overt cirrhosis (n = 20). Two sagittal images of the left lobe of the liver were obtained in the left hepatic vein level during the resting state and at full inspiration while pushing their belly out, by abdominal US (i.e., resting and stress image). The length between the inferior hepatic angle and the midpoint of the liver dome was measured in all images for the evaluation of liver distortion. The elongation was calculated by a formula: (L2-L1/L1) x 100(%): where L1 and L2 are the length of the liver for both the resting and stress image. The calculated elongated length (L2-L1, EL) and elongation rate were compared between cirrhotic patients and control subjects. For the control subjects, early cirrhosis, and overt cirrhosis groups, the mean ELs (elongation rate) were 2.34±0.98 cm (30.2±13.2%), 1.18±0.73 cm (14.9 ±9.5%) and 0.53±0.54 cm (6.3±6.6%), respectively. This difference among the three groups was statistically significant (p < 0.05). A possible best cut-off value of liver elongation rate is 17% for the prediction of cirrhosis (sensitivity: 90%, specificity: 75.3%). The liver of patients with liver cirrhosis is stiffer than that of control subjects. Calculation of the elongation rate in the left lobe of the liver during a respiratory maneuver may be used as an ancillary method of US for the evaluation of liver cirrhosis

  11. Usefulness of Ultrasound in the Evaluation of Morphologic Change of a Cirrhotic Liver During Respiration

    Energy Technology Data Exchange (ETDEWEB)

    Byun, Joo Nam [Chosun University Hospital, Gwangju (Korea, Republic of); Kim, Dong Hun [Soonchunhyang University Hospital Bucheon, Bucheon (Korea, Republic of); Suk, Eun Ha [Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2010-12-15

    This study was designed to determine whether transabdominal ultrasound can detect different hepatic stiffness between patients with cirrhosis and control subjects. Sevent-three patients (Child-Pugh class A stage) with liver cirrhosis and 57 control subjects were included in this study. All patients were subdivided arbitrarily into two groups: early cirrhosis (n = 53) and overt cirrhosis (n = 20). Two sagittal images of the left lobe of the liver were obtained in the left hepatic vein level during the resting state and at full inspiration while pushing their belly out, by abdominal US (i.e., resting and stress image). The length between the inferior hepatic angle and the midpoint of the liver dome was measured in all images for the evaluation of liver distortion. The elongation was calculated by a formula: (L2-L1/L1) x 100(%): where L1 and L2 are the length of the liver for both the resting and stress image. The calculated elongated length (L2-L1, EL) and elongation rate were compared between cirrhotic patients and control subjects. For the control subjects, early cirrhosis, and overt cirrhosis groups, the mean ELs (elongation rate) were 2.34{+-}0.98 cm (30.2{+-}13.2%), 1.18{+-}0.73 cm (14.9 {+-}9.5%) and 0.53{+-}0.54 cm (6.3{+-}6.6%), respectively. This difference among the three groups was statistically significant (p < 0.05). A possible best cut-off value of liver elongation rate is 17% for the prediction of cirrhosis (sensitivity: 90%, specificity: 75.3%). The liver of patients with liver cirrhosis is stiffer than that of control subjects. Calculation of the elongation rate in the left lobe of the liver during a respiratory maneuver may be used as an ancillary method of US for the evaluation of liver cirrhosis

  12. Assessment of serum level cholinesterase as a biomarker of liver cirrhosis in Egyptian cirrhotic patients

    Directory of Open Access Journals (Sweden)

    Mona A. Amin

    2017-09-01

    Full Text Available Serum cholinesterase levels are closely correlated with the severity of liver disease. The aim of the paper was to assess the value of serum cholinesterase in evaluating liver reserve function in cirrhotic patients. 90 patients with liver cirrhosis and thirty healthy control group were included. Liver cirrhosis patients were classified according to child score into three equal groups: Child A liver cirrhosis, Child B liver cirrhosis and Child C liver cirrhosis. Patients were subjected to clinical evaluation, laboratory analysis, abdominal U/S. Measuring serum cholinesterase, and Calculation of both Child and model of end stage liver disease (MELD scores. The level of serum cholinesterase was higher in control group than the three groups of liver cirrhosis with median (IQR 17,410 (12,111-21,774, 7528 (5200-9856, 6021 (4500-7542, 3828.5 (1541-6060, respectively P<0.001. And the level of serum cholinesterase was higher in Child A more than Child B and Child C and the level of serum cholinesterase was higher in Child B more than Child C with very strong negative correlation between serum Cholinesterase level and Child score (r=-0.9, P<0.001. Also strong negative correlation between serum Cholinesterase level and MELD score (r=- 0.85, P=0.001, and positive correlation with prothrombin concentration (r=0.554, P=0.009, and serum albumin levels (r=0.582, P=0.0002. Serum cholinesterase is a good biomarker of cirrhosis. Since it distinguishes decompensated from compensated cirrhosis well, low levels in cirrhosis may serve as a useful prognostic marker of advanced liver disease.

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

    Science.gov (United States)

    Klein, Sabine; Hinüber, Christian; Hittatiya, Kanishka; Schierwagen, Robert; Uschner, Frank Erhard; Strassburg, Christian P; Fischer, Hans-Peter; Spengler, Ulrich; Trebicka, Jonel

    2016-01-01

    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. 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 week after last embolization), hemodynamics were investigated, hepatic fibrosis and accumulation of myofibroblasts were analysed. General characteristics, laboratory analyses and liver histology were collected in patients with NCIPH. Weekly embolization induced a hyperdynamic circulation, with increased PP. The mesenteric flow and hepatic hydroxyproline content was significantly higher in weekly embolized compared to single embolized rats (mesenteric flow +54.1%, hydroxyproline +41.7%). Mesenteric blood flow and shunt volumes increased, whereas splanchnic vascular resistance was decreased in the weekly embolization group. Fibrotic markers αSMA and Desmin were upregulated in weekly embolized rats. This study establishes a model using repetitive embolization via portal veins, comparable with human NCIPH and may serve to test new therapies.

  14. 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.

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    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...... receptor level was elevated in the hepatic vein compared with the portal vein (0.57(interquartile range 0.31) vs 0.55(0.40) mg/L, P=.005). The soluble mannose receptor levels were similar in bacterial DNA-positive and -negative patients. The soluble mannose receptor level in the portal and hepatic veins...

  16. 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.

  17. Differential metabonomic profiles of primary hepatocellular carcinoma tumors from alcoholic liver disease, HBV-infected, and HCV-infected cirrhotic patients

    OpenAIRE

    Cao, Ding; Cai, Can; Ye, Mingxin; Gong, Junhua; Wang, Menghao; Li, Jinzheng; Gong, Jianping

    2017-01-01

    Our objective was to comparatively profile the metabolite composition of primary hepatocellular carcinoma (HCC) tumors from alcoholic liver disease (ALD), hepatitis B virus (HBV)-infected, and hepatitis C virus (HCV)-infected cirrhotic patients. Primary HCC tumors were collected from ALD, HBV-infected, and HCV-infected cirrhotic patients (n=20 each). High-resolution magic-angle spinning proton nuclear magnetic resonance spectroscopy and metabonomic data analysis were performed to compare HCC ...

  18. Transplantation of endothelial progenitor cells ameliorates vascular dysfunction and portal hypertension in carbon tetrachloride-induced rat liver cirrhotic model.

    Science.gov (United States)

    Sakamoto, Masaharu; Nakamura, Toru; Torimura, Takuji; Iwamoto, Hideki; Masuda, Hiroshi; Koga, Hironori; Abe, Mitsuhiko; Hashimoto, Osamu; Ueno, Takato; Sata, Michio

    2013-01-01

    In cirrhosis, sinusoidal endothelial cell injury results in increased endothelin-1 (ET-1) and decreased nitric oxide synthase (NOS) activity, leading to portal hypertension. However, the effects of transplanted endothelial progenitor cells (EPCs) on the cirrhotic liver have not yet been clarified. We investigated whether EPC transplantation reduces portal hypertension. Cirrhotic rats were created by the administration of carbon tetrachloride (CCl(4) ) twice weekly for 10 weeks. From week 7, rat bone marrow-derived EPCs were injected via the tail vein in this model once a week for 4 weeks. Endothelial NOS (eNOS), vascular endothelial growth factor (VEGF) and caveolin expressions were examined by Western blots. Hepatic tissue ET-1 was measured by a radioimmunoassay (RIA). Portal venous pressure, mean aortic pressure, and hepatic blood flow were measured. Endothelial progenitor cell transplantation reduced liver fibrosis, α-smooth muscle actin-positive cells, caveolin expression, ET-1 concentration and portal venous pressure. EPC transplantation increased hepatic blood flow, protein levels of eNOS and VEGF. Immunohistochemical analyses of eNOS and isolectin B4 demonstrated that the livers of EPC-transplanted animals had markedly increased vascular density, suggesting reconstitution of sinusoidal blood vessels with endothelium. Transplantation of EPCs ameliorates vascular dysfunction and portal hypertension, suggesting this treatment may provide a new approach in the therapy of portal hypertension with liver cirrhosis. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  19. Comparison of qtc duration on electrocardiogram between patients of liver cirrhosis and non cirrhotic controls

    International Nuclear Information System (INIS)

    Umair, M.; Nadeem, K.; Azam, M.N.; Mansoor, J.; Khan, H.

    2012-01-01

    Objective: To compare the QTc duration on electrocardiogram (ECG) of patients of cirrhosis (hep B and C origin) with non cirrhotic controls. Study Design: Case control study. Place and duration of study: The study was carried out at the Department of Medicine, Military Hospital, Rawalpindi, from 8th Feb 2009 to 8th Aug 2009. Material and Method: After meeting the exclusion and inclusion criteria, 80 cirrhotic patients were enrolled in group-I and equal number of non cirrhotic controls were enrolled in group-II. Three 12 lead ECG recording were taken for each patient, 5 minutes apart, and QTc value was calculated for each ECG and then mean of the three was used for the analysis. A QTc value more than 0.44 seconds was taken as prolonged. Results: The mean QTc interval on electrocardiogram in group-I i.e. cirrhotic was 0.4603 seconds (SD+-0.1312) and mean QTc interval on electrocardiogram in group-II i.e. noncirrhotic was 0.407 seconds (SD+-0.029). These findings were statistically significant (p value < 0.001). Conclusion: Cirrhotic patients have prolonged QTc interval as compared to noncirrhotic controls. (author)

  20. Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis.

    Science.gov (United States)

    Deng, Wensheng; Zhu, Yiming; Lin, Jiayun; Zheng, Lei; Zhang, Chihao; Luo, Meng

    2017-07-01

    Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. 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.)

  2. Evaluation of liver hemodynamics using SPIO-enhanced dynamic MRI. Comparison between cirrhotic liver and normal liver

    International Nuclear Information System (INIS)

    Shimada, Kotaro; Kobayashi, Hisato; Furuta, Akihiro; Nunoura, T.; Takahashi, Takahiro; Ogasawara, Nobuhiko; Akuta, Keizo

    2006-01-01

    SPIO, ferucarbotran (Resovist), which enables rapid bolus injection is well suited for the evaluation of liver hemodynamics. Our study aimed to assess the difference of hemodynamics associated with progression of chronic liver disease using SPIO-enhanced dynamic MRI. Ten patients with normal liver function, 10 patients with chronic hepatitis, and 16 patients with liver cirrhosis were examined. The MR perfusion studies were performed by 1.5T MR system with a single-shot GRE-EPI with spectral presaturation inversion recovery (SPIR) and sensitivity encoding (SENSE) technique. After the bolus injection of SPIO (0.016 ml/kg) followed by a 20 ml saline flush, 30 sequential dynamic echo planar images were obtained under the condition of 30 seconds breath hold. From the ROI set in the right lobe of the liver, time-to-signal intensity curves (TICs) were obtained. TICs were converted to time-to-R2 * curves, and the slope at hepatic arterial phase (Sa) and at portal predominant phase (Sp) were calculated by the linear regression. Sp/Sa (portal/arterial ratio) of each group was analyzed statistically. (unpaired T-test) In comparing Sp/Sa of each group, there was a significant difference between normal liver and advanced liver cirrhosis. The decrease of Sp/Sa was seen in severe cirrhosis, but this change was unclear in chronic hepatitis and mild cirrhosis. In extremely severe cirrhosis, there was a bizarre phenomenon that Sp became minus number. In conclusion, SPIO-enhanced dynamic MRI was useful to assess the difference of liver hemodynamics associated with progression of chronic liver disease. (author)

  3. 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...

  4. The relationship between a model of end stage liver disease score (MELD score) and the occurrence of spontaneous bacterial peritonitis in liver cirrhotic patients.

    Science.gov (United States)

    Gayatri, A A Ayu Yuli; Suryadharma, I G A; Purwadi, N; Wibawa, I D N

    2007-01-01

    To determine relationship between MELD score and the occurrence of SBP, prevalence of SBP, pattern of bacterial culture and antibiotic susceptibility of causative bacteria of liver cirrhotic patients at Sanglah Hospital. Study design was a cross-sectional analytic study. The population in this study consists of liver cirrhotic patients admitted at Sanglah Hospital Denpasar from June 2005 to February 2006. This result confirmed that the MELD score is a reliable index of disease severity and that higher MELD scores had a significantly more frequent SBP prevalence in patients with a MELD score of 18 or more compared with that in patients with a MELD score of 17 or less (p=0.01; 95% CI = 1.379-15.537). Prevalence of SBP was 30.6%. Thirteen patients (68.4%) had monomicrobial positive culture of Aerob bacteria, consisting of Gram negative bacterias in 10 (77%), with Escherichia coli and Acinettobacter baumanii being the most frequent, and 3 (23%) had Gram positive bacteria. High sensitivity to Cefoperazone, Cefotaxim, Ceftazidime, Cefpirome, Ciprofloxacin, Fosfomicin, Meropenem, Streptomycin, Gentamycin, Trimethoprim/Sulphamethoxazole, were shown. Based on this study we concluded that severe liver cirrhosis with MELD score > or = 18 was associated with an increase risk of SBP, with a prevalence of 30.6%. Common causes of SBP mostly were Escherichia coli and Acinettobacter baumanii, which were sensitive to antibiotic treatment of Cefoperazone, Cefotaxime and Ciprofloxacin.

  5. 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 HCCguidelines 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 guidelines claim to be evidence based. Surprisingly, despite European guidelines, Germany and Italy use their own national guidelines which partially differ from the European. Possible solutions of the problems are discussed.

  6. 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...

  7. 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.

  8. Regulation of collagen production in freshly isolated cell populations from normal and cirrhotic rat liver: Effect of lactate

    International Nuclear Information System (INIS)

    Cerbon-Ambriz, J.; Cerbon-Solorzano, J.; Rojkind, M.

    1991-01-01

    Previous work has shown that lactic acid, and to a lesser extent pyruvic acid, is able to increase collagen synthesis significantly in liver slices of CCl4-treated rats but not normal rats. The purpose of this report is to document which cells in the cirrhotic liver are responsible for the lactate-stimulated increase in collagen synthesis. It was found that (a) incorporation of 3H-proline into protein-bound 3H-hydroxyproline is increased threefold to fourfold in hepatocytes from CCl4-treated rats as compared with normal rat hepatocytes; (b) neither the hepatocytes from normal nor those from CCl4-treated rats modify their collagen synthesizing capacity when 30 mmol/L lactic acid was added to the incubation medium; (c) nonparenchymal cells obtained from livers of CCl4-treated rats synthesize much less collagen than hepatocytes, but their synthesis is stimulated twofold by lactic acid; (d) from the different nonparenchymal cells, only fat-storing (Ito) cells increase collagen synthesis when lactic acid is present in the incubation medium. These results suggest that the increased lactic acid levels observed in patients with alcoholic hepatic cirrhosis may play an important role in the development of fibrosis by stimulating collagen production by fat-storing (Ito) cells

  9. Laparoscopic liver resection for hepatocellular carcinoma in cirrhotic patients. Feasibility of nonanatomic resection in difficult tumor locations

    Directory of Open Access Journals (Sweden)

    Marco Casaccia

    2011-01-01

    Full Text Available Background: Surgical resection for hepatocellular carcinoma (HCC in cirrhotic patients remains controversial because of high morbidity and recurrence rates. Laparoscopic resection of liver tumors has recently been developed and could reduce morbidity. The aim of this study was to evaluate retrospectively our results for laparoscopic liver resection (LLR for HCC including lesions in the posterosuperior segments of the liver in terms of feasibility, outcome, recurrence and survival. Materials and Methods: Between June 2005 and February 2009, we performed 20 LLR for HCC. Median age of the patients was 66 years. The underlying cirrhosis was staged as Child A in 17 cases and Child B in 3. Results: LLR included anatomic resection in six cases and nonanatomic resection in 14. Eleven procedures were associated in nine (45% patients. Median tumor size and surgical margins were 3.1 cm and 15 mm, respectively. A conversion to laparotomy occurred in one (5% patient for hemorrhage. Mortality and morbidity rates were 0% and 15% (3/20. Median hospital stay was 8 days (range: 5-16 days. Over a mean follow-up period of 26 months (range: 19-62 months, 10 (50% patients presented recurrence, mainly at distance from the surgical site. Treatment of recurrence was possible in all the patients, including orthotopic liver transplantation in three cases. Conclusions: LLR for HCC in selected patients is a safe procedure with good short-term results. It can also be proposed in tumor locations with a difficult surgical access maintaining a low morbidity rate and good oncological adequacy. This approach could have an impact on the therapeutic strategy of HCC complicating cirrhosis as a treatment with curative intent or as a bridge to liver transplantation.

  10. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).

    Science.gov (United States)

    Cordoba, Juan; Ventura-Cots, Meritxell; Simón-Talero, Macarena; Amorós, Àlex; Pavesi, Marco; Vilstrup, Hendrik; Angeli, Paolo; Domenicali, Marco; Ginés, Pere; Bernardi, Mauro; Arroyo, Vicente

    2014-02-01

    In spite of the high incidence of hepatic encephalopathy (HE) in cirrhosis, there are few observational studies. We performed an analysis to define the characteristics of HE and associated features using the database of the Canonic Study. Clinical, laboratory and survival data of 1348 consecutive cirrhotic patients admitted with an acute decompensation were compared according to the presence (n=406) or absence of HE and of acute-on-chronic liver failure (ACLF) (n=301). HE development was independently associated with previous HE episodes; survival probabilities worsen in relation to the presence and grade of HE. There were marked differences between HE associated (n=174) and not associated (n=286) to ACLF. HE not associated with ACLF occurred in older cirrhotics, inactive drinkers, without severe liver failure or systemic inflammatory reaction and in relation to diuretic use. In contrast, HE associated with ACLF occurred in younger cirrhotics, more frequently alcoholics, with severe liver failure and systemic inflammatory reaction, and in relation to bacterial infections, active alcoholism and/or dilutional hyponatremia. Prognosis was relatively preserved in the first and extremely poor in the second group. Independent risk factors of mortality in patients with HE were age, bilirubin, INR, creatinine, sodium, and HE grade. In cirrhosis, previous HE identifies a subgroup of patients that is especially vulnerable for developing new episodes of HE. The course of HE appears to be different according to the presence of ACLF. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  11. n-3 fatty acid-based parenteral nutrition improves postoperative recovery for cirrhotic patients with liver cancer: A randomized controlled clinical trial.

    Science.gov (United States)

    Zhang, Binhao; Wei, Gang; Li, Rui; Wang, Yanjun; Yu, Jie; Wang, Rui; Xiao, Hua; Wu, Chao; Leng, Chao; Zhang, Bixiang; Chen, Xiao-Ping

    2017-10-01

    A new lipid emulsion enriched in n-3 fatty acid has been reported to prevent hepatic inflammation in patients following major surgery. However, the role of n-3 fatty acid-based parenteral nutrition for postoperative patients with cirrhosis-related liver cancer is unclear. We investigated the safety and efficacy of n-3 fatty acid-based parenteral nutrition for cirrhotic patients with liver cancer followed hepatectomy. A prospective randomized controlled clinical trial (Registered under ClinicalTrials.gov Identifier no. NCT02321202) was conducted for cirrhotic patients with liver cancer that underwent hepatectomy between March 2010 and September 2013 in our institution. We compared isonitrogenous total parenteral nutrition with 20% Structolipid and 10% n-3 fatty acid (Omegaven, Fresenius-Kabi, Germany) (treatment group) to Structolipid alone (control group) for five days postoperatively, in the absence of enteral nutrition. We enrolled 320 patients, and 312 (97.5%) were included in analysis (155 in the control group and 157 in the treatment group). There was a significant reduction of morbidity and mortality in the treatment group, when compared with the control group (total complications 78 [50.32%] vs. 46 [29.30%]; P parenteral nutrition significantly improved postoperative recovery for cirrhotic patients with liver cancer following hepatectomy, with a significant reduction in overall mortality and length of hospital stay. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  12. 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.

  13. Liver transplantation in cirrhotic patients with diabetes mellitus: Midterm results, survival, and adverse events

    OpenAIRE

    Blanco, J.J. (Jose J.); Herrero, J.I. (José Ignacio); Quiroga, J. (Jorge); Sangro, B. (Bruno); Gomez-Manero, N. (Noemí); Pardo, F. (Fernando); Cienfuegos, J.A. (Javier A.)

    2001-01-01

    Liver cirrhosis is frequently associated with diabetes mellitus (DM), and this metabolic complication is also frequent after orthotopic liver transplantation (OLT). The aim of our study is to investigate which factors are associated with DM before and after OLT and their impact on post-OLT evolution. We evaluated the prevalence of DM among 115 liver transplant candidates with cirrhosis and assessed their evolution after OLT (median follow-up, 41 m...

  14. Transient elastography for predicting liver-related events in cirrhotic HIV-infected patients

    OpenAIRE

    Montes-Ramírez, M. L.; Berenguer, Juan; Miró, J. M.; Quereda, Carmen; Hernando Jeréz, María Asunción; Sanz, J.; Ortega, E.; Tural, Cristina; Wichmann, M. A.; Zamora, F. X.; González García, J. J.

    2017-01-01

    We assessed liver stiffness measurement (LSM) for the prediction of mortality and decompensation in HIVinfected patients with compensated liver cirrhosis. A prospective cohort study of HIV-infected patients with confirmed liver cirrhosis from 9 hospitals in Spain. LSM was undertaken for each patient; clinical events were collected prospectively after the baseline visit, and patients were followed until death or the censoring date. We used univariate/multivariate Cox proportional haz...

  15. 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.

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

    Science.gov (United States)

    An, Chansik; Park, Sumi; Choi, Yoon Jung

    2013-01-01

    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. Assessment of triple-phase CT findings for the differentiation of fat-deficient hepatic angiomyolipoma from hepatocellular carcinoma in non-cirrhotic liver

    International Nuclear Information System (INIS)

    Jeon, Tae Yeon; Kim, Seong Hyun; Lim, Hyo K.; Lee, Won Jae

    2010-01-01

    Background: To evaluate the triple-phase CT findings for the differentiation of fat-deficient angiomyolipoma from hepatocellular carcinoma in non-cirrhotic liver. Methods: We retrospectively reviewed contrast-enhanced triple-phase CT images of 10 patients with fat-deficient hepatic angiomyolipoma and 28 patients with 29 hepatocellular carcinomas in non-cirrhotic liver proved on histologic examination. The CT findings for the two types of tumors were compared using Fisher's exact test. Results: Early draining vein depicted on arterial or portal phases was seen in eight (80%) angiomyolipomas and two hepatocellular carcinomas (7%) (p < 0.001), in which the early draining vein was connected with tumoral vessels. The tumoral vessels in the angiomyolipoma were more prominent and ectatic, were distributed both centrally and peripherally, and were seen in smaller tumors than in the hepatocellular carcinoma. Tumor capsule enhancement was absent in all angiomyolipomas as compared with two (7%) hepatocellular carcinomas with no tumor capsule (p < 0.001). The other CT findings were not significantly different for the two different types of tumors. Conclusions: The presence of early draining vein connecting with prominent tumoral vessels and absent tumor capsule were useful CT findings for the differentiation of fat-deficient angiomyolipoma from hepatocellular carcinoma in non-cirrhotic liver.

  18. 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...... treatment with nucleoside or nucleotide analogs (NUCs) for CHB. Materials and methods. Patients with CHB and advanced fibrosis or cirrhosis prior to treatment with NUCs for at least 1 year were offered inclusion in the study. We measured liver stiffness using transient elastography (TE) at follow-up. TE cut...... duration was 50.5 months. Among patients with cirrhosis prior to treatment, 26 (49%) had liver stiffness below 11.0 kPa at follow-up, suggesting regression of cirrhosis. Among patients with advanced fibrosis (F3) prior to treatment, 10 (77%) had liver stiffness below 8.1 kPa after treatment, suggesting...

  19. Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid.

    Science.gov (United States)

    Lin, Liteng; Cai, Mingyue; Deng, Shaohui; Huang, Wensou; Huang, Jingjun; Huang, Xinghua; Huang, Mingsheng; Wang, Yong; Shuai, Xintao; Zhu, Kangshun

    2017-10-01

    Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A 2 (TXA 2 ), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA 2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Tissue specific MR contrast media role in the differential diagnosis of cirrhotic liver nodules.

    Science.gov (United States)

    Lupescu, Ioana Gabriela; Capsa, Razvan A; Gheorghe, Liana; Herlea, Vlad; Georgescu, Serban A

    2008-09-01

    State-of-the-art magnetic resonance (MR) imaging using tissue specific contrast media facilitates detection and characterization in most cases of hepatic nodules. According to the currently used nomenclature, in liver cirrhosis there are only two major types of hepatocellular nodular lesions: regenerative lesions and dysplastic or neoplastic lesions. The purpose of this clinical imaging review is to provide information on the properties of tissue-specific MR contrast agents and on their usefulness in the demonstration of the pathologic changes that take place at the level of the hepatobiliary and reticuloendothelial systems during the carcinogenesis in liver cirrhosis.

  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

    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...

  2. Effect of Buqi Huoxue decoction on hemodynamics and liver fibrosis indices in hepatitis B patients with cirrhotic portal hypertension

    Directory of Open Access Journals (Sweden)

    BAI Zhiqin

    2017-02-01

    Full Text Available ObjectiveTo investigate the effect of Buqi Huoxue decoction on hemodynamics and liver fibrosis indices in hepatitis B patients with cirrhotic portal hypertension. MethodsA total of 79 patients with hepatitis B cirrhosis who were admitted to The People′s Hospital of Qingyuan District from December 2013 to August 2015 were enrolled and randomly divided into study group (41 patients and control group (38 patients. The patients in both groups were given oral entecavir (0.5 mg, once a day and bicyclol tablets (25 mg, three times a day; the patients in the control group were given propranolol (10 mg, three times a day in addition, and those in the study group were given Buqi Huoxue decoction in addition. The course of treatment was 12 weeks for both groups. The hemodynamics and liver fibrosis indices were compared between the two groups before treatment and after 12 weeks of treatment. The t-test was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data between groups. ResultsAfter 12 weeks of treatment, both groups had significant reductions in diameter of the portal vein, diameter of the splenic vein, and portal vein flow and a significant increase in portal vein blood flow velocity (t=3.847, 4.672, 3.524, 5.237, 3.578, 3.829, 3.468, and 3.673, P=0.041, 0.036, 0.047, 0.032, 0.045, 0.042, 0.048, and 0.046, and the study group had significantly greater changes in these parameters compared with the control group (diameter of the portal vein: 12.86±2.34 mm vs 13.65±2.45 mm, t=3.725, P=0.044; diameter of the splenic vein: 9.50±1.26 mm vs 11.15±1.37 mm, t=-6.672, P=0.012; portal vein flow: 1.23±0.35 L/min vs 1.38±0.44 L/min, t=-3.521, P=0.047; portal vein blood flow velocity: 19.50±4.65 cm/s vs 17.57±2.40 cm/s, t=-6.225, P=0.024. After 12 weeks of treatment, both groups had reductions in the four liver fibrosis indices hyaluronic acid, laminin, procollagen type Ⅲ, and

  3. Esophageal varices in cirrhotics on dynamic computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Miyazaki, Masaru; Takahashi, Osamu; Shimura, Tadanori

    1985-07-01

    Dynamic CT was performed on fifteen cirrhotics. The cirrhotics with esophageal varices were compared with those without esophageal varices in regard to the enhanced capacity of the liver and the spleen and the declining ratio of the spleen following the enhancement. Both the liver and the spleen in cirrhotics were enhanced less than non-cirrhotics, especially in those with esophageal varices (p<0.01). Splenic declining ratio following splenic enhancement clearly distinguish cirrhotics with esophageal varices from those without esophageal varices (p<0.01). These parameters on dynamic CT could be useful for the diagnosis of portal hypertension in cirrhotics.

  4. Isolation of primary human hepatocytes from normal and diseased liver tissue: a one hundred liver experience.

    Directory of Open Access Journals (Sweden)

    Ricky H Bhogal

    2011-03-01

    Full Text Available Successful and consistent isolation of primary human hepatocytes remains a challenge for both cell-based therapeutics/transplantation and laboratory research. Several centres around the world have extensive experience in the isolation of human hepatocytes from non-diseased livers obtained from donor liver surplus to surgical requirement or at hepatic resection for tumours. These livers are an important but limited source of cells for therapy or research. The capacity to isolate cells from diseased liver tissue removed at transplantation would substantially increase availability of cells for research. However no studies comparing the outcome of human hepatocytes isolation from diseased and non-diseased livers presently exist. Here we report our experience isolating human hepatocytes from organ donors, non-diseased resected liver and cirrhotic tissue. We report the cell yields and functional qualities of cells isolated from the different types of liver and demonstrate that a single rigorous protocol allows the routine harvest of good quality primary hepatocytes from the most commonly accessible human liver tissue samples.

  5. in Human Liver Diseases

    Directory of Open Access Journals (Sweden)

    Minoru Fujimoto

    2010-01-01

    Full Text Available Toll-like receptor (TLR signaling pathways are strictly coordinated by several mechanisms to regulate adequate innate immune responses. Recent lines of evidence indicate that the suppressor of cytokine signaling (SOCS family proteins, originally identified as negative-feedback regulators in cytokine signaling, are involved in the regulation of TLR-mediated immune responses. SOCS1, a member of SOCS family, is strongly induced upon TLR stimulation. Cells lacking SOCS1 are hyperresponsive to TLR stimulation. Thus, SOCS1 is an important regulator for both cytokine and TLR-induced responses. As an immune organ, the liver contains various types of immune cells such as T cells, NK cells, NKT cells, and Kupffer cells and is continuously challenged with gut-derived bacterial and dietary antigens. SOCS1 may be implicated in pathophysiology of the liver. The studies using SOCS1-deficient mice revealed that endogenous SOCS1 is critical for the prevention of liver diseases such as hepatitis, cirrhosis, and cancers. Recent studies on humans suggest that SOCS1 is involved in the development of various liver disorders in humans. Thus, SOCS1 and other SOCS proteins are potential targets for the therapy of human liver diseases.

  6. Combinatorial gene therapy renders increased survival in cirrhotic rats

    Directory of Open Access Journals (Sweden)

    Armendáriz-Borunda Juan S

    2010-05-01

    Full Text Available Abstract Background Liver fibrosis ranks as the second cause of death in México's productive-age population. This pathology is characterized by acummulation of fibrillar proteins in hepatic parenchyma causing synthetic and metabolic disfunction. Remotion of excessive fibrous proteins might result in benefit for subjects increasing survival index. The goal of this work was to find whether the already known therapeutical effect of human urokinase Plasminogen Activator and human Matrix Metalloprotease 8 extends survival index in cirrhotic animals. Methods Wistar rats (80 g underwent chronic intoxication with CCl4: mineral oil for 8 weeks. Cirrhotic animals were injected with a combined dose of Ad-delta-huPA plus Ad-MMP8 (3 × 1011 and 1.5 × 1011 vp/Kg, respectively or with Ad-beta-Gal (4.5 × 1011 and were killed after 2, 4, 6, 8 and 10 days. Then, liver and serum were collected. An additional set of cirrhotic animals injected with combined gene therapy was also monitored for their probability of survival. Results Only the cirrhotic animals treated with therapeutical genes (Ad-delta-huPA+Ad-MMP-8 showed improvement in liver fibrosis. These results correlated with hydroxyproline determinations. A significant decrement in alpha-SMA and TGF-beta1 gene expression was also observed. Cirrhotic rats treated with Ad-delta-huPA plus Ad-MMP8 had a higher probability of survival at 60 days with respect to Ad-beta-Gal-injected animals. Conclusion A single administration of Ad-delta-huPA plus Ad-MMP-8 is efficient to induce fibrosis regression and increase survival in experimental liver fibrosis.

  7. 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.

  8. New insights into cirrhotic cardiomyopathy

    DEFF Research Database (Denmark)

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

    2013-01-01

    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...

  9. 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...... systems. As the disease progresses, the circulation becomes hyperdynamic, and signs of cardiac, pulmonary, and renal dysfunction are observed, in addition to reduced survival. Infections and an altered cardiac function known as cirrhotic cardiomyopathy may be precipitators for the development of other...

  10. 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...

  11. In vivo hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells: Therapeutic effect on liver fibrosis/cirrhosis

    OpenAIRE

    Zhang, Guo-Zun; Sun, Hui-Cong; Zheng, Li-Bo; Guo, Jin-Bo; Zhang, Xiao-Lan

    2017-01-01

    AIM To investigate the hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and to evaluate their therapeutic effect on liver fibrosis/cirrhosis. METHODS A CCl4-induced liver fibrotic/cirrhotic rat model was used to assess the effect of hUC-MSCs. Histopathology was assessed by hematoxylin and eosin (H&E), Masson trichrome and Sirius red staining. The liver biochemical profile was measured using a Beckman Coulter analyzer. Expression analysis was ...

  12. Diastolic dysfunction characterizes cirrhotic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Piyush O. Somani

    2014-11-01

    Conclusions: Present study shows that although diastolic dysfunction is a frequent event in cirrhosis, it is usually of mild degree and does not correlate with severity of liver dysfunction. There are no significant differences in echocardiographic parameters between alcoholic and non-alcoholic cirrhosis. HRS is not correlated to diastolic dysfunction in cirrhotic patients. There is no difference in survival at one year between patients with or without diastolic dysfunction. Diastolic dysfunction in cirrhosis is unrelated to circulatory dysfunction, ascites and HRS.

  13. Serum and ascitic fluid serotonin levels and 5-hydroxyindoleacetic acid urine excretion in the liver of cirrhotic patients with encephalopathy.

    Science.gov (United States)

    Chojnacki, C; Walecka-Kapica, E; Stepien, A; Pawlowicz, M; Wachowska-Kelly, P; Chojnacki, J

    2013-01-01

    The excess and deficit of serotonin can be the cause of somatic and mental disorders. The aim of this study was to evaluate serotonin levels in blood and ascitic fluid as well as excretion of 5-hydroxyindoleacetic acid (5-HIAA) in urine in patients with hepatic encephalopathy (HE). The study included 75 alcoholic cirrhotic patients divided into 3 groups (HE1, HE2, HE3), 25 patients each, with grade 1, 2 and 3 of hepatic encephalopathy according to West-Haven classification. The control group (C) included 25 clinically healthy volunteers. Venous blood and ascitic fluid were collected in fasting. On the same day a 24-hour urine collection was performed. Immunoenzymatic method was used to determine the serotonin level in serum and ascitic fluid, and 5-HIAA in urine (IBL-RE-59121, RE-59131). In the control group, mean serum serotonin level (ng/ml) was 155.5 ± 38.1 and in the 3 study groups: HE1 - 175.2 ± 32.4 (NS), HE2 - 137.2 ± 28.6 (NS), HE3 - 108.3 ± 46.3 (pencephalopathy. In patients with severe hepatic encephalopathy serotonin concentration in blood is decreased which can affect some clinical manifestation of this disease.

  14. The Time Course of Dynamic Computed Tomographic Appearance of Radiation Injury to the Cirrhotic Liver Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Tomoki Kimura

    Full Text Available This study aimed to evaluate the dynamic computed tomographic (CT appearance of focal radiation injury to cirrhotic liver tissue around the tumor following stereotactic body radiation therapy (SBRT for hepatocellular carcinoma (HCC. Seventy-seven patients with 92 HCCs were observed for >6 months. Sixty-four and 13 patients belonged to Child-Pugh class A and B, respectively. The median SBRT dose was 48 Gy/4fr. Dynamic CT scans were performed in non-enhanced, arterial, portal, and venous phases. The median follow-up period was 18 months. Dynamic CT appearances were classified into 3 types: type 1, hyperdensity in all enhanced phases; type 2, hypodensity in arterial and portal phases; type 3, isodensity in all enhanced phases. Half of the type 2 or 3 appearances significantly changed to type 1, particularly in patients belonging to Child-Pugh class A. After 3-6 months, Child-Pugh class B was a significant factor in type 3 patients. Thus, dynamic CT appearances were classified into 3 patterns and significantly changed over time into the enhancement group (type 1 in most patients belonging to Child-Pugh class A. Child-Pugh class B was a significant factor in the non-enhancement group (type 3.

  15. 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.

    Science.gov (United States)

    Laursen, Jens; Milman, Nils; Pind, Niels; Pedersen, Henrik; Mulvad, Gert

    2014-01-01

    Meta-analysis of previous studies evaluating associations between content of elements sulphur (S), chlorine (Cl), potassium (K), iron (Fe), copper (Cu), zinc (Zn) and bromine (Br) in normal and cirrhotic autopsy liver tissue samples. Normal liver samples from 45 Greenlandic Inuit, median age 60 years and from 71 Danes, median age 61 years. Cirrhotic liver samples from 27 Danes, median age 71 years. Element content was measured using X-ray fluorescence spectrometry. Dual hierarchical clustering analysis, creating a dual dendrogram, one clustering element contents according to calculated similarities, one clustering elements according to correlation coefficients between the element contents, both using Euclidian distance and Ward Procedure. 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, Br and Zn; Cl with S and Br; K with S, Br and Zn; Cu with Br. Zn with S and K. Br with S, Cl, K and Cu. Fe did not show significant associations with any other element. In contrast to simple statistical methods, which analyses content of elements separately one by one, dual hierarchical clustering analysis incorporates all elements at the same time and can be used to examine the linkage and interplay between multiple elements in tissue samples. Copyright © 2013 Elsevier GmbH. All rights reserved.

  16. 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.

  17. Identifying changes in the synaptic proteome of cirrhotic alcoholic superior frontal gyrus.

    Science.gov (United States)

    Etheridge, N; Mayfield, R D; Harris, R A; Dodd, P R

    2011-03-01

    Hepatic complications are a common side-effect of alcoholism. Without the detoxification capabilities of the liver, alcohol misuse induces changes in gene and protein expression throughout the body. A global proteomics approach was used to identify these protein changes in the brain. We utilised human autopsy tissue from the superior frontal gyrus (SFG) of six cirrhotic alcoholics, six alcoholics without comorbid disease, and six non-alcoholic non-cirrhotic controls. Synaptic proteins were isolated and used in two-dimensional differential in-gel electrophoresis coupled with mass spectrometry. Many expression differences were confined to one or other alcoholic sub-group. Cirrhotic alcoholics showed 99 differences in protein expression levels from controls, of which half also differed from non-comorbid alcoholics. This may reflect differences in disease severity between the sub-groups of alcoholics, or differences in patterns of harmful drinking. Alternatively, the protein profiles may result from differences between cirrhotic and non-comorbid alcoholics in subjects' responses to alcohol misuse. Ten proteins were identified in at least two spots on the 2D gel; they were involved in basal energy metabolism, synaptic vesicle recycling, and chaperoning. These post-translationally modified isoforms were differentially regulated in cirrhotic alcoholics, indicating a level of epigenetic control not previously observed in this disorder.

  18. The utility of the macro-aggregated albumin lung perfusion scan in the diagnosis and prognosis of hepatopulmonary syndrome in cirrhotic patients candidates for liver transplantation

    Directory of Open Access Journals (Sweden)

    Israel Grilo

    Full Text Available Background: The macro-aggregated albumin lung perfusion scan (99mTc-MAA is a diagnostic method for hepatopulmonary syndrome (HPS. Aim: To determine the sensitivity of 99mTc-MAA in diagnosing HPS, to establish the utility of 99mTc-MAA in determining the influence of HPS on hypoxemia in patients with concomitant pulmonary disease and to determine the correlation between 99mTc-MAA values and other respiratory parameters. Methods: Data from 115 cirrhotic patients who were eligible for liver transplantation (LT were prospectively analyzed. A transthoracic contrast echocardiography and 99mTc-MAA were performed in 85 patients, and 74 patients were diagnosed with HPS. Results: The overall sensitivity of 99mTc-MAA for the diagnosis of HPS was 18.9% (14/74 in all of the HPS cases and 66.7% (4/6 in the severe to very severe cases. In HPS patients who did not have lung disease, the degree of brain uptake of 99mTc-MAA was correlated with the alveolar-arterial oxygen gradient (A-a PO2 (r = 0.32, p < 0.05 and estimated oxygen shunt (r = 0.41, p < 0.05 and inversely correlated with partial pressure of arterial oxygen (PaO2 while breathing 100% O2 (r = -0.43, p < 0.05. The 99mTc-MAA was positive in 20.6% (7/36 of the patients with HPS and lung disease. The brain uptake of 99mTc-MAA was not associated with mortality and normalized in all cases six months after LT. Conclusions: The 99mTc-MAA is a low sensitivity test for the diagnosis of HPS that can be useful in patients who have concomitant lung disease and in severe to very severe cases of HPS. It was not related to mortality, and brain uptake normalized after LT.

  19. 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

  20. Prevalence and severity of hepatopulmonary syndrome and its influence on survival in cirrhotic patients evaluated for liver transplantation.

    Science.gov (United States)

    Pascasio, J M; Grilo, I; López-Pardo, F J; Ortega-Ruiz, F; Tirado, J L; Sousa, J M; Rodriguez-Puras, M J; Ferrer, M T; Sayago, M; Gómez-Bravo, M A; Grilo, A

    2014-06-01

    The prevalence of hepatopulmonary syndrome (HPS) and its influence on survival before and after liver transplantation (LT) remain controversial. Additionally, the chronology of post-LT reversibility is unclear. This study prospectively analyzed 316 patients with cirrhosis who were evaluated for LT in 2002-2007; 177 underwent LT at a single reference hospital. HPS was defined by a partial pressure of arterial oxygen (PaO2 ) position and positive contrast echocardiography. The prevalence of HPS was 25.6% (81/316 patients), and most patients (92.6%) had mild or moderate HPS. High Child-Pugh scores and the presence of ascites were independently associated with HPS. Patients with and without HPS did not significantly differ in LT waiting list survival (mean 34.6 months vs. 41.6 months, respectively; log-rank, p = 0.13) or post-LT survival (mean 45 months vs. 47.6 months, respectively; log-rank, p = 0.62). HPS was reversed in all cases within 1 year after LT. One-fourth of the patients with cirrhosis who were evaluated for LT had HPS (mostly mild to moderate); the presence of HPS did not affect LT waiting list survival. HPS was always reversed after LT, and patient prognosis did not worsen. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

  1. 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

  2. A morphometric study on regeneration of the human liver following hepatectomy by computed tomography

    International Nuclear Information System (INIS)

    Okamoto, Eizo; Yamanaka, Naoki

    1983-01-01

    A morphometric study has been carried out on the restoration of remnant hepatic volume (RHV) after various extent of hepatectomy in humans by serial computed tomography in 15 non-cirrhotics, 14 cirrhotics and 7 hepatic failures. Restoration of RHV has been observed only in patients with more than 10 % hepatectomy. In non-cirrhotics with major hepatectomy (RHV less than 600 cm 3 ), an early rapid increasing phase was followed by a subsequent decreasing phase and then a slow increasing phase. Decreasing phase was absent in most non-cirrhotics with moderate hepatectomy (RHV 600-1000 cm 3 ) and cirrhotics. Daily increase rate of RHV during the first posthepatectomy month was inversely proportional to the RHV at operation restoring invariably to 800-900 cm 3 at the end of this month. Termination of regeneration was within 6 months in non-cirrhotics with moderate hepatectomy and from 6 to 12 months in those with major hepatectomy. It was delayed in cirrhotics. RHV has finally attained to an average of 90 % of preoperative hepatic volume in non-cirrhotics and 81 % in cirrhotics. The restoration of RHV was extremely poor in hepatic failures. (author)

  3. Increased diacylglycerols characterize hepatic lipid changes in progression of human nonalcoholic fatty liver disease; comparison to a murine model.

    Science.gov (United States)

    Gorden, D Lee; Ivanova, Pavlina T; Myers, David S; McIntyre, J Oliver; VanSaun, Michael N; Wright, J Kelly; Matrisian, Lynn M; Brown, H Alex

    2011-01-01

    The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and progression to cirrhosis. While differences in liver lipids between disease states have been reported, precise composition of phospholipids and diacylglycerols (DAG) at a lipid species level has not been previously described. The goal of this study was to characterize changes in lipid species through progression of human NAFLD using advanced lipidomic technology and compare this with a murine model of early and advanced NAFLD. Utilizing mass spectrometry lipidomics, over 250 phospholipid and diacylglycerol species (DAGs) were identified in normal and diseased human and murine liver extracts. Significant differences between phospholipid composition of normal and diseased livers were demonstrated, notably among DAG species, consistent with previous reports that DAG transferases are involved in the progression of NAFLD and liver fibrosis. In addition, a novel phospholipid species (ether linked phosphatidylinositol) was identified in human cirrhotic liver extracts. Using parallel lipidomics analysis of murine and human liver tissues it was determined that mice maintained on a high-fat diet provide a reproducible model of NAFLD in regards to specificity of lipid species in the liver. These studies demonstrated that novel lipid species may serve as markers of advanced liver disease and importantly, marked increases in DAG species are a hallmark of NAFLD. Elevated DAGs may contribute to altered triglyceride, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) levels characteristic of the disease and specific DAG species might be important lipid signaling molecules in the progression of NAFLD.

  4. Pentose pathway in human liver

    International Nuclear Information System (INIS)

    Magnusson, I.; Chandramouli, V.; Schumann, W.C.; Kumaran, K.; Wahren, J.; Landau, B.R.

    1988-01-01

    [1- 14 C]Ribose and [1- 14 C]glucose were given to normal subjects along with glucose loads (1 g per kg of body weight) after administration of diflunisal and acetaminophen, drugs that are excreted in urine as glucuronides. Distributions of 14 C were determined in the carbons of the excreted glucoronides and in the glucose from blood samples drawn from hepatic veins before and after glucagon administration. Eighty percent or more of the 14 C from [1- 14 C]ribose incorporated into the glucuronic acid moiety of the glucuronides was in carbons 1 and 3, with less than 8% in carbon 2. In glucuronic acid from glucuronide excreted when [2- 14 C]glucose was given, 3.5-8.1% of the 14 C was in carbon 1, 2.5-4.3% in carbon 3, and more than 70% in carbon 2. These distributions are in accord with the glucuronides sampling the glucose unit of the glucose 6-phosphate pool that is a component of the pentose pathway and is intermediate in glycogen formation. It is concluded that the glucuronic acid conjugates of the drugs can serve as a noninvasive means of sampling hepatic glucose 6-phosphate. In human liver, as in animal liver, the classical pentose pathway functions, not the L-type pathway, and only a small percentage of the glucose is metabolized via the pathway

  5. Human immunodeficiency virus infection and the liver.

    Science.gov (United States)

    Crane, Megan; Iser, David; Lewin, Sharon R

    2012-03-27

    Liver disease in human immunodeficiency virus (HIV)-infected individuals encompasses the spectrum from abnormal liver function tests, liver decompensation, with and without evidence of cirrhosis on biopsy, to non-alcoholic liver disease and its more severe form, non-alcoholic steatohepatitis and hepatocellular cancer. HIV can infect multiple cells in the liver, leading to enhanced intrahepatic apoptosis, activation and fibrosis. HIV can also alter gastro-intestinal tract permeability, leading to increased levels of circulating lipopolysaccharide that may have an impact on liver function. This review focuses on recent changes in the epidemiology, pathogenesis and clinical presentation of liver disease in HIV-infected patients, in the absence of co-infection with hepatitis B virus or hepatitis C virus, with a specific focus on issues relevant to low and middle income countries.

  6. 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.

  7. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes

    International Nuclear Information System (INIS)

    Parkinson, Andrew; Mudra, Daniel R.; Johnson, Cory; Dwyer, Anne; Carroll, Kathleen M.

    2004-01-01

    hepatocytes isolated from cirrhotic liver was comparable to that in normal hepatocytes, which supports the 'healthy hepatocyte, sick environment' hypothesis of liver cirrhosis. This review summarizes these findings and discusses their implications for the use of human liver microsomes and hepatocytes for in vitro studies of drug metabolism and enzyme induction, which play a key role in drug development

  8. Dynamic-contrast-enhanced magnetic resonance imaging of cirrhotic liver parenchyma: A comparison between gadolinium–diethylenetriamine pentaacetic acid and gadolinium–ethoxybenzyl–diethylenetriamine pentaacetic acid

    Directory of Open Access Journals (Sweden)

    Chun-Yi Lin

    2015-11-01

    Conclusion: The enhancement effect of the liver parenchyma using both MRI contrast agents was not affected by the degree of liver cirrhosis or abnormal liver function. However, it was affected by the serum-bilirubin levels in the Gd–EOB–DTPA-enhanced MRIs. Furthermore, enhancement of the liver was higher when using Gd–EOB–DTPA in the VP, DP, and HP. This knowledge is helpful when performing dynamic MRIs to diagnose focal hepatic lesions in the heterogeneous liver parenchyma.

  9. 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.

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

    International Nuclear Information System (INIS)

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

    2004-01-01

    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. 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

  12. Relevance of plasma malondialdehyde level and severity of portal hypertension in cirrhotic patients.

    Science.gov (United States)

    Wang, Sheng-Lan; Zhu, Xin-Yan; Zhang, Dong-Wei; Zhang, Zhao-Jie; Gao, Heng-Jun; Yang, Chang-Qing

    2015-01-01

    Portal hypertension is one of the death reasons for the liver cirrhosis patients. The oxidative stress is related to the occurrence and development of portal hypertension in cirrhosis. Malondialdehyde (MDA), one of the lipid peroxides, increases substantially in cirrhotic patients. To evaluate the relevance between the MDA level and portal hypertension in cirrhotic patients. 60 liver cirrhotic patients and 30 healthy controls were enrolled. The plasma MDA level and general blood tests including ALT, AST, ALB, total bilirubin, and platelet were measured. All people enrolled accepted endoscopic examination and B-Ultrasound check to evaluate the severity of portal hypertension. The MDA plasma level of cirrhotic patients was significantly higher than the controls (Pportal hypertension (Pportal vein (r=0.652, Pportal hypertension. Plasma MDA level may correlate with the severity of portal hypertension in cirrhotic patients.

  13. Mass spectrometric characterization of human serum albumin dimer: A new potential biomarker in chronic liver diseases.

    Science.gov (United States)

    Naldi, Marina; Baldassarre, Maurizio; Nati, Marina; Laggetta, Maristella; Giannone, Ferdinando Antonino; Domenicali, Marco; Bernardi, Mauro; Caraceni, Paolo; Bertucci, Carlo

    2015-08-10

    Human serum albumin (HSA) undergoes several structural alterations affecting its properties in pro-oxidant and pro-inflammatory environments, as it occurs during liver cirrhosis. These modifications include the formation of albumin dimers. Although HSA dimers were reported to be an oxidative stress biomarker, to date nothing is known about their role in liver cirrhosis and related complications. Additionally, no high sensitive analytical method was available for HSA dimers assessment in clinical settings. Thus the HSA dimeric form in human plasma was characterized by mass spectrometry using liquid chromatography tandem mass spectrometry (LC-ESI-Q-TOF) and matrix assisted laser desorption time of flight (MALDI-TOF) techniques. N-terminal and C-terminal truncated HSA, as well as the native HSA, undergo dimerization by binding another HSA molecule. This study demonstrated the presence of both homo- and hetero-dimeric forms of HSA. The dimerization site was proved to be at Cys-34, forming a disulphide bridge between two albumin molecules, as determined by LC-MS analysis after tryptic digestion. Interestingly, when plasma samples from cirrhotic subjects were analysed, the dimer/monomer ratio resulted significantly increased when compared to that of healthy subjects. These isoforms could represent promising biomarkers for liver disease. Additionally, this analytical approach leads to the relative quantification of the residual native HSA, with fully preserved structural integrity. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. [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.

  15. Metformin reduces intrahepatic fibrosis and intrapulmonary shunts in biliary cirrhotic rats

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    Mu-Tzu Ko

    2017-08-01

    Conclusion: Metformin reduced liver injury and improved hepatic fibrosis in cirrhotic rats. It also attenuated the intrapulmonary shunts. However, the effects of metformin on pulmonary angiogenesis and hypoxia were insignificant.

  16. 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.

  17. Idiopathic non-cirrhotic portal hypertension: a review

    NARCIS (Netherlands)

    Schouten, Jeoffrey N. L.; Verheij, Joanne; Seijo, Susana

    2015-01-01

    Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disease characterized of intrahepatic portal hypertension in the absence of cirrhosis or other causes of liver disease and splanchnic venous thrombosis. The etiology of INCPH can be classified in five categories: 1) immunological

  18. Dynamic-contrast-enhanced magnetic resonance imaging of cirrhotic liver parenchyma: A comparison between gadolinium–diethylenetriamine pentaacetic acid and gadolinium–ethoxybenzyl–diethylenetriamine pentaacetic acid

    OpenAIRE

    Lin, Chun-Yi; Chang, Wei-Chou; Chou, Chen-Te; Chen, Ran-Chou

    2015-01-01

    Background: The newly developed magnetic-resonance-imaging (MRI) hepatocyte-specific contrast agent, gadolinium–ethoxybenzyl–diethylenetriamine pentaacetic acid (Gd–EOB–DTPA), has different excretion pathways from the conventional MRI contrast agent, gadolinium–diethylenetriamine pentaacetic acid (Gd–DTPA). In this study, we compare the enhancement effect of the liver and renal parenchyma between these two contrast agents for patients with liver cirrhosis. Methods: We retrospectively inclu...

  19. Continuous high expression of XBP1 and GRP78 is important for the survival of bone marrow cells in CCl4-treated cirrhotic liver

    International Nuclear Information System (INIS)

    Marumoto, Yoshio; Terai, Shuji; Urata, Yohei; Matsumoto, Toshihiko; Mizunaga, Yuko; Yamamoto, Naoki; Jin, Haiyan; Fujisawa, Koichi; Murata, Tomoaki; Shinoda, Koh; Nishina, Hiroshi; Sakaida, Isao

    2008-01-01

    We have previously shown that infusion of bone marrow cells (BMC) improves CCl 4 -induced cirrhosis. However, it is unclear why the injected BMC are resistant to CCl 4 damage and subsequently improve the local microenvironment in damaged liver. To analyze the cellular phenomena involved in this process, we studied the damaged liver using electron microscopy. We found that CCl 4 caused rough endoplasmic reticula to swell in hepatocytes. To analyze the gene expression patterns associated with this process, we conducted PCR-selected suppressive subtractive hybridization. We found that expression levels of HSP84, HSP40, and XBP1 differed markedly between control liver and liver infused with BMC. Immunohistochemical staining revealed that expression levels of HSP84 and HSP40 were markedly higher in the early phase of differentiation immediately after BMC infusion, but decreased over time. XBP1 expression remained high during the late phase, and GRP78 expression increased with XBP1 activation. We also found that GFP-positive BMC expressed XBP1 and GRP78. XBP1 and GRP78 are associated with ER stress. Thus, continuous high XBP1 and GRP78 expression might be essential for the survival and proliferation of BMC in a CCl 4 -induced persistent liver damage environment

  20. 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

    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....

  1. Pathology of idiopathic non-cirrhotic portal hypertension.

    Science.gov (United States)

    Guido, Maria; Sarcognato, Samantha; Sacchi, Diana; Colloredo, Guido

    2018-04-12

    Idiopathic non-cirrhotic portal hypertension is an under-recognized vascular liver disease of unknown etiology, characterized by clinical signs of portal hypertension in the absence of cirrhosis. By definition, any disorder known to cause portal hypertension in the absence of cirrhosis and any cause of chronic liver disease must be excluded to make a diagnosis of idiopathic non-cirrhotic portal hypertension. However, the diagnosis is often difficult because the disease resembles cirrhosis and there is no gold standard test. Liver biopsy is an essential tool: it is able to exclude cirrhosis and other causes of portal hypertension and it allows the identification of the characteristic lesions. Nonetheless, the histological diagnosis of idiopathic non-cirrhotic portal hypertension is not always straightforward, in particular by needle biopsy samples, because there is no pathognomonic lesion, but rather a variety of vascular changes which are unevenly distributed, very subtle, and not all necessarily identified in a single specimen. Pathologists should be able to recognize several patterns of injury, involving portal/periportal areas as well as parenchymal structures.The histological features of idiopathic non-cirrhotic portal hypertension are described in this review, focusing on their interpretation in needle biopsy specimens.

  2. The use of human albumin for the treatment of ascites in patients with liver cirrhosis: item of safety, facts, controversies and perspectives.

    Science.gov (United States)

    Facciorusso, Antonio; Nacchiero, Maurizio Cosimo; Rosania, Rosa; Laonigro, Giulio; Longo, Nunzio; Panella, Carmine; Ierardi, Enzo

    2011-09-01

    Albumin constitutes approximately one half of the proteins in the plasma and plays a pivotal role in modulating the distribution of fluid between body compartments. Hence it is commonly employed in cirrhotic patients in association with diuretics for the treatment of ascites. Nevertheless, its usefulness is controversial in this condition and well-stated only in some circumstances. The item of safety of the drug appears to be convincing due to the accurate cautions in the course of its preparation. Side effects are described in literature only as sporadic events. Indeed, albumin administration is effective to prevent the circulatory dysfunctions after large-volume paracentesis and renal failure and after Spontaneous Bacterial Peritonitis (SBP). Finally albumin represents, associated with vasoconstrictors, the therapeutic gold standard for the hepatorenal-syndrome (HRS). Physiopathological bases of the therapeutic use of albumin in hepatic cirrhosis consist in both hypoalbuminemia and portal hypertension consequences. In fact, cirrhotic patient with ascites, in spite of hydrosaline retention, shows an effective hypovolemia with peripheral arterial vasodilatation and increase in heart rate. Therefore the effectiveness of albumin administration in the treatment of ascites is due to its plasma volume expander property as well as its efficacy in restoring plasmatic oncotic pressure. Trials are in progress in order to define the effectiveness of the prolonged home-administration of human albumin in the treatment and prevention of ascites. Finally, it has been recently demonstrated that the binding, transport and detoxification capacities of human albumin are severely reduced in cirrhotics and this impairment correlates with the degree of liver failure. Therefore, the next challenge will be to determine whether the alterations of non-oncotic properties of albumin are able to forecast mortality in cirrhotics with ascites and exogenous albumin chronic administration will be

  3. Dataset of protein species from human liver

    Directory of Open Access Journals (Sweden)

    Stanislav Naryzhny

    2017-06-01

    Full Text Available This article contains data related to the research article entitled “Zipf׳s law in proteomics” (Naryzhny et al., 2017 [1]. The protein composition in the human liver or hepatocarcinoma (HepG2 cells extracts was estimated using a filter-aided sample preparation (FASP protocol. The protein species/proteoform composition in the human liver was determined by two-dimensional electrophoresis (2-DE followed by Electrospray Ionization Liquid Chromatography-Tandem Mass Spectrometry (ESI LC-MS/MS. In the case of two-dimensional electrophoresis (2-DE, the gel was stained with Coomassie Brilliant Blue R350, and image analysis was performed with ImageMaster 2D Platinum software (GE Healthcare. The 96 sections in the 2D gel were selected and cut for subsequent ESI LC-MS/MS and protein identification. If the same protein was detected in different sections, it was considered to exist as different protein species/proteoforms. A list of human liver proteoforms detected in this way is presented.

  4. The long-term outcomes of cirrhotic patients with pleural effusion.

    Science.gov (United States)

    Hung, Tsung-Hsing; Tseng, Chih-Wei; Tsai, Chih-Chun; Tsai, Chen-Chi; Tseng, Kuo-Chih; Hsieh, Yu-Hsi

    2018-01-01

    A pleural effusion is an abnormal collection of fluid in the pleural space and may cause related morbidity or mortality in cirrhotic patients. Currently, there are insufficient data to support the long-term prognosis for cirrhotic patients with pleural effusion. In this study, we investigated the short- and long-term effects of pleural effusion on mortality in cirrhotic patients and evaluated the benefit of liver transplantation in these patients. The National Health Insurance Database, derived from the Taiwan National Health Insurance Program, was used to identify 3,487 cirrhotic patients with pleural effusion requiring drainage between January 1, 2007 and December 31, 2010. The proportional hazards Cox regression model was used to control for possible confounding factors. The 30-day, 90-day, 1-year, and 3-year mortalities were 20.1%, 40.2%, 59.1%, and 75.9%, respectively, in the cirrhotic patients with pleural effusion. After Cox proportional hazard regression analysis adjusted by patient gender, age, complications of cirrhosis and comorbid disorders, old age, esophageal variceal bleeding, hepatocellular carcinoma, hepatic encephalopathy, pneumonia, renal function impairment, and without liver transplantation conferred higher risks for 3-year mortality in the cirrhotic patients with pleura effusion. Liver transplantation is the most important factor to determine the 3-year mortalities (HR: 0.17, 95% CI 0.11- 0.26, P pleural effusion predicts poor long-term outcomes. Liver transplantation could dramatically improve the survival and should be suggested as soon as possible.

  5. 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.

  6. Intrarenal octreotide treatment prevents sodium retention in liver cirrhotic rats: evidence for direct effects within the thick ascending limb of Henle's loop

    DEFF Research Database (Denmark)

    Jonassen, Thomas; Christensen, Sten; Marcussen, Niels

    2006-01-01

    not affect the abundance of NCKK2 within the outer medulla. Together with the histological findings, these results indicate that IROA reduces the total number of NKCC2 within the outer medulla. In conclusion, the results indicate a direct intrarenal effect of octreotide on TAL function and morphology......We have previously shown that systemic treatment with the somatostatin analog octreotide has marked beneficial effects on renal function in rats with liver cirrhosis induced by common bile duct ligation (CBL; Jonassen TEN, Christensen S, Sørensen AM, Marcussen N, Flyvbjerg A, Andreasen F......, and Petersen JS. Hepatology 29: 1387-1395, 1999). In the present study, we tested the hypothesis that octreotide has a direct effect on renal tubular function. Rats (CBL or Sham-CBL) were intrarenally treated with low-dose octreotide in a long-acting release formulation, which had no systemic actions (100...

  7. HUMAN LIVER SLICES EXPRESS THE SAME LIDOCAINE BIOTRANSFORMATION RATE AS ISOLATED HUMAN HEPATOCYTES

    NARCIS (Netherlands)

    OLINGA, P; MEIJER, DKF; SLOOFF, MJH; GROOTHUIS, GMM; Merema, M.T.

    1993-01-01

    In order to investigate whether liver slices are a valuable tool for the assessment of drug metabolism in human liver, we compared the phase I metabolism of lidocaine in human liver slices and hepatocytes prepared from three human livers. Lidocaine is mainly metabolised to monoethylglycinexylidide

  8. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis.

    Directory of Open Access Journals (Sweden)

    Henning W Zimmermann

    Full Text Available BACKGROUND: Monocyte-derived macrophages critically perpetuate inflammatory responses after liver injury as a prerequisite for organ fibrosis. Experimental murine models identified an essential role for the CCR2-dependent infiltration of classical Gr1/Ly6C(+ monocytes in hepatic fibrosis. Moreover, the monocyte-related chemokine receptors CCR1 and CCR5 were recently recognized as important fibrosis modulators in mice. In humans, monocytes consist of classical CD14(+CD16(- and non-classical CD14(+CD16(+ cells. We aimed at investigating the relevance of monocyte subpopulations for human liver fibrosis, and hypothesized that 'non-classical' monocytes critically exert inflammatory as well as profibrogenic functions in patients during liver disease progression. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed circulating monocyte subsets from freshly drawn blood samples of 226 patients with chronic liver disease (CLD and 184 healthy controls by FACS analysis. Circulating monocytes were significantly expanded in CLD-patients compared to controls with a marked increase of the non-classical CD14(+CD16(+ subset that showed an activated phenotype in patients and correlated with proinflammatory cytokines and clinical progression. Correspondingly, CD14(+CD16(+ macrophages massively accumulated in fibrotic/cirrhotic livers, as evidenced by immunofluorescence and FACS. Ligands of monocyte-related chemokine receptors CCR2, CCR1 and CCR5 were expressed at higher levels in fibrotic and cirrhotic livers, while CCL3 and CCL4 were also systemically elevated in CLD-patients. Isolated monocyte/macrophage subpopulations were functionally characterized regarding cytokine/chemokine expression and interactions with primary human hepatic stellate cells (HSC in vitro. CD14(+CD16(+ monocytes released abundant proinflammatory cytokines. Furthermore, CD14(+CD16(+, but not CD14(+CD16(- monocytes could directly activate collagen-producing HSC. CONCLUSIONS/SIGNIFICANCE: Our data

  9. Radiological evaluation of a liver simulator in comparison to a human real liver

    International Nuclear Information System (INIS)

    Toledo, Janine M.; Campos, Tarcisio P.R. de

    2009-01-01

    The present study evaluates the radiological features of a human real healthy liver reproducing its characteristics on a developed liver simulator. The radiological evaluation will be performed through radiological methods such as CT and X-ray images, density and weight measurements, as well as representation of the coloration and texture. According to literature, the liver is the highest weight organ and gland of the body, weighing approximately 1,5 kg. On the liver, the nutrients are absorbed from the digestive tract and are prosecuted and stored for future use by other organs. Also the liver is responsible for the neutralization and elimination of various toxic substances. Thus, it is an interface between the digestive system and the blood. Besides, this organ is the principal source of plasmatic proteins like the albumin, transport of graxos oily acids. Due to its proprieties, the liver holds a large amount of radionuclides on any uptake from external source. The liver simulator was designed to have the same density, weight and corresponding shape. The radiographic image was produced by conventional X-rays machine, in which the radiographic applied parameters were the same applied to abdomen. The result of the radiographic and CT images demonstrates radiological equivalence between the simulator and human real liver. Hounsfield number of the synthetic liver tissue was found on the range of human livers. Therefore, due to its similar shape, chemical composition, radiological response, the liver simulator can be used to investigate ionizing radiation procedures during radiation therapy intervention. (author)

  10. 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.

  11. In vivo hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells: Therapeutic effect on liver fibrosis/cirrhosis.

    Science.gov (United States)

    Zhang, Guo-Zun; Sun, Hui-Cong; Zheng, Li-Bo; Guo, Jin-Bo; Zhang, Xiao-Lan

    2017-12-14

    To investigate the hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and to evaluate their therapeutic effect on liver fibrosis/cirrhosis. A CCl 4 -induced liver fibrotic/cirrhotic rat model was used to assess the effect of hUC-MSCs. Histopathology was assessed by hematoxylin and eosin (H&E), Masson trichrome and Sirius red staining. The liver biochemical profile was measured using a Beckman Coulter analyzer. Expression analysis was performed using immunofluorescent staining, immunohistochemistry, Western blot, and real-time PCR. We demonstrated that the infused hUC-MSCs could differentiate into hepatocytes in vivo . Functionally, the transplantation of hUC-MSCs to CCl 4 -treated rats improved liver transaminases and synthetic function, reduced liver histopathology and reversed hepatobiliary fibrosis. The reversal of hepatobiliary fibrosis was likely due to the reduced activation state of hepatic stellate cells, decreased collagen deposition, and enhanced extracellular matrix remodeling via the up-regulation of MMP-13 and down-regulation of TIMP-1. Transplanted hUC-MSCs could differentiate into functional hepatocytes that improved both the biochemical and histopathologic changes in a CCl 4 -induced rat liver fibrosis model. hUC-MSCs may offer therapeutic opportunities for treating hepatobiliary diseases, including cirrhosis.

  12. Comparison of vitamin D deficiency and magnitude of severity of vitamin D deficiency in cirrhotic and non-cirrhotic patients with chronic hepatitis C in a tertiary care hospital Rawalpindi, Pakistan

    International Nuclear Information System (INIS)

    Hamid, S.; Faheem, M.; Ambreen, S.; Tirmizi, A.; Umar, M.

    2017-01-01

    Objective: To determine Vitamin D deficiency in both cirrhotic and non-cirrhotic patients with chronic hepatitis C (CHC). Methodology: We conducted a cross-sectional study at Centre for Liver and Digestive Diseases (CLD), Holy Family Hospital, Rawalpindi, Pakistan from August 2015 to February 2016 and included 120 Patients with CHC with or without cirrhosis. Two groups were formed and vitamin D levels were measured and level of severity was assessed. Results: Out of 120 patients, 94(78.3%) patients had Vitamin D deficiency. 63(100%) cirrhotic patients and 31 54.4%) non cirrhotic patients had Vitamin D deficiency. In cirrhotic patients, 26(41.3%) had mild and 36(58.7%) had moderate Vitamin D deficiency while in non-cirrhotic patients 25(43.9%) had mild and 6(10.5%) had moderate deficiency. No patient with severe Vitamin D deficiency was observed. Conclusion: Most of the patients infected with CHC suffer from vitamin D deficiency. This was observed more in cirrhotic patients than non-cirrhotic patients. Moreover, positive correlation was observed among vitamin D deficiency and stage of fibrosis. (author)

  13. Interaction of rocuronium with human liver cytochromes P450

    OpenAIRE

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

    2015-01-01

    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 micro...

  14. Recellularization of rat liver: An in vitro model for assessing human drug metabolism and liver biology.

    Directory of Open Access Journals (Sweden)

    Matthew J Robertson

    Full Text Available Liver-like organoids that recapitulate the complex functions of the whole liver by combining cells, scaffolds, and mechanical or chemical cues are becoming important models for studying liver biology and drug metabolism. The advantages of growing cells in three-dimensional constructs include enhanced cell-cell and cell-extracellular matrix interactions and preserved cellular phenotype including, prevention of de-differentiation. In the current study, biomimetic liver constructs were made via perfusion decellularization of rat liver, with the goal of maintaining the native composition and structure of the extracellular matrix. We optimized our decellularization process to produce liver scaffolds in which immunogenic residual DNA was removed but glycosaminoglycans were maintained. When the constructs were recellularized with rat or human liver cells, the cells remained viable, capable of proliferation, and functional for 28 days. Specifically, the cells continued to express cytochrome P450 genes and maintained their ability to metabolize a model drug, midazolam. Microarray analysis showed an upregulation of genes involved in liver regeneration and fibrosis. In conclusion, these liver constructs have the potential to be used as test beds for studying liver biology and drug metabolism.

  15. Short-term outcome of total clipless laparoscopic cholecystectomy for complicated gallbladder stones in cirrhotic patients.

    Science.gov (United States)

    Kassem, Mohamed I; Hassouna, Ehab M

    2018-03-01

    Cirrhotic patients have been known to be more affected with gallstones than their non-cirrhotic counterparts; since laparoscopy was introduced, it has been generally approved as the standard approach for cholecystectomies with the exception of end-stage cirrhosis. The purpose of this study was to evaluate the safety and efficacy of clipless laparoscopic cholecystectomy using the harmonic scalpel in complicated cholelithiasis in cirrhotic patients. This prospective study was conducted on 62 cirrhotic patients presenting to the Gastrointestinal Surgery Unit in Alexandria Main University Hospital with complicated gallstones between March 2013 and March 2016. Both intraoperative time and blood loss were calculated in addition to rates of conversion to open cholecystectomy, morbidity and mortality. Most of our cases were females with a ratio of 1.7:1, with a mean age of 45.21 years, ranging from 25 to 65 years. The most common cause of cirrhotic liver was hepatitis C in 45.1% of patients. Among the 62 patients included in the study, 56 patients (90.3%) were presenting with acute cholecystitis and six patients were operated at the onset of acute biliary pancreatitis. The mean operative time was 72.9 min with mean blood loss 45.45 mL. The study concluded safety of total clipless laparoscopic cholecystectomy using a harmonic scalpel in Child A and B type cirrhotic patients, who presented with complicated gallstones. © 2017 Royal Australasian College of Surgeons.

  16. Fraction from human and rat liver which is inhibitory for proliferation of liver cells.

    Science.gov (United States)

    Chen, T S; Ottenweller, J; Luke, A; Santos, S; Keeting, P; Cuy, R; Lea, M A

    1989-01-01

    A comparative study was undertaken with human and rat liver of a fraction reported to have growth inhibitory activity when prepared from rat liver. Fractions which were soluble in 70% ethanol and insoluble in 87% ethanol were prepared from liver cytosols. Electrophoretic analysis under denaturing conditions indicated that there were several quantitative or qualitative differences in the fractions from the two species. Fractions from both human and rat liver were found to be inhibitory for the incorporation of 3H-thymidine into DNA of foetal chick hepatocytes. Under conditions in which the rat fraction inhibited precursor incorporation into DNA of rat liver epithelial cells there was not a significant inhibitory effect with the fraction from human liver. DNA synthesis in a rat hepatoma cell line was not significantly inhibited by preparations from either species. The data suggested that corresponding fractions from both rat and human liver could have inhibitory effects on precursor incorporation into DNA but the magnitude of the effects and target cell specificity may differ.

  17. Assessment of emerging biomarkers of liver injury in human subjects.

    Science.gov (United States)

    Schomaker, Shelli; Warner, Roscoe; Bock, Jeff; Johnson, Kent; Potter, David; Van Winkle, Joyce; Aubrecht, Jiri

    2013-04-01

    Hepatotoxicity remains a major challenge in drug development. Although alanine aminotransferase (ALT) remains the gold standard biomarker of liver injury, alternative biomarker strategies to better predict the potential for severe drug-induced liver injury (DILI) are essential. In this study, we evaluated the utility of glutamate dehydrogenase (GLDH), purine nucleoside phosphorylase (PNP), malate dehydrogenase (MDH), and paraxonase 1 (PON1) as indicators of liver injury in cohorts of human subjects, including healthy subjects across age and gender, subjects with a variety of liver impairments, and several cases of acetaminophen poisoning. In the healthy subjects, levels of GLDH and MDH were not affected by age or gender. Reference ranges for GLDH and MDH in healthy subjects were 1-10 and 79-176U/L, respectively. In contrast, the levels of PON1 and PNP were not consistent across cohorts of healthy subjects. Furthermore, GLDH and MDH had a strong correlation with elevated ALT levels and possessed a high predictive power for liver injury, as determined by ROC analysis. In contrast, PON1 and PNP did not detect liver injury in our study. Finally, evaluation of patients with acetaminophen-induced liver injury provided evidence that both GLDH and MDH might have utility as biomarkers of DILI in humans. This study is the first to evaluate GLDH, MDH, PON1, and PNP in a large number of human subjects and, and it provides an impetus for prospective clinical studies to fully evaluate the diagnostic value of GLDH and MDH for detection of liver injury.

  18. The long-term outcomes of cirrhotic patients with pleural effusion

    Science.gov (United States)

    Hung, Tsung-Hsing; Tseng, Chih-Wei; Tsai, Chih-Chun; Tsai, Chen-Chi; Tseng, Kuo-Chih; Hsieh, Yu-Hsi

    2018-01-01

    Background/Aim: A pleural effusion is an abnormal collection of fluid in the pleural space and may cause related morbidity or mortality in cirrhotic patients. Currently, there are insufficient data to support the long-term prognosis for cirrhotic patients with pleural effusion. In this study, we investigated the short- and long-term effects of pleural effusion on mortality in cirrhotic patients and evaluated the benefit of liver transplantation in these patients. Patients and Methods: The National Health Insurance Database, derived from the Taiwan National Health Insurance Program, was used to identify 3,487 cirrhotic patients with pleural effusion requiring drainage between January 1, 2007 and December 31, 2010. The proportional hazards Cox regression model was used to control for possible confounding factors. Results: The 30-day, 90-day, 1-year, and 3-year mortalities were 20.1%, 40.2%, 59.1%, and 75.9%, respectively, in the cirrhotic patients with pleural effusion. After Cox proportional hazard regression analysis adjusted by patient gender, age, complications of cirrhosis and comorbid disorders, old age, esophageal variceal bleeding, hepatocellular carcinoma, hepatic encephalopathy, pneumonia, renal function impairment, and without liver transplantation conferred higher risks for 3-year mortality in the cirrhotic patients with pleura effusion. Liver transplantation is the most important factor to determine the 3-year mortalities (HR: 0.17, 95% CI 0.11- 0.26, P effusion predicts poor long-term outcomes. Liver transplantation could dramatically improve the survival and should be suggested as soon as possible. PMID:29451184

  19. Study of pulmonary dysfunctions in liver cirrhosis

    Directory of Open Access Journals (Sweden)

    Amr M. Helmy

    2014-10-01

    Conclusion: Liver cirrhosis is associated with unique pulmonary complications. The early identification of pulmonary dysfunctions in cirrhotic patients is crucial as it affects the prognosis and guides the future management by speeding up orthotopic liver transplantation (OLT recommendations.

  20. Merlin, the product of NF2 gene, is associated with aromatase expression and estrogen formation in human liver tissues and liver cancer cells.

    Science.gov (United States)

    Cocciadiferro, Letizia; Miceli, Vitale; Granata, Orazia M; Carruba, Giuseppe

    2017-09-01

    The product of neurofibromatosis type 2 (NF2) gene, also known as Merlin/neurofibromin 2, homeostatically regulates liver stem cells by controlling abundance and signaling of epidermal growth factor receptor (EGFR), with a mechanism independent of the Hippo pathway. We have reported that locally elevated estrogen formation, driven by abnormally high expression and function of aromatase, may be implicated in development and progression of human hepatocellular carcinoma (HCC) through activation of a rapid signaling pathway mediated by amphiregulin (AREG) and EGFR. We have recently presented a model by which the aromatase-estrogen-amphiregulin-EGFR axis is activated in response to tissue injury and/or inflammatory disease, with its alteration eventually leading to development of major human tumors (liver, breast, prostate) and other chronic diseases (diabetes, obesity, Alzheimer's and heart disease). In this study, we investigated NF2 expression in liver cancer cells and tissues in relation to aromatase expression/function, estrogen receptor (ER) status and amphiregulin. Our data indicate that NF2 expression is associated with aromatase and AREG expression, being elevated in HCC tissues and HepG2 cells, intermediate in cirrhotic tissues and Huh7 cells, and lower in nontumoral liver and HA22T cells. In addition, NF2 expression is inversely related to wild type hERα66 and proportional to the expression of the membrane-associated hERα36 splice variant, as measured by exon-specific RT-PCR analysis, both in vivo and in vitro. Furthermore, incubation with estradiol induced a significant decrease of NF2 expression in both HA22T and Huh7 cells (over 54% and 22%, respectively), while no change could be observed in HepG2 cells, this effect being inversely related to aromatase expression and activity in HCC cell lines. Based on the above combined evidence, we hypothesize that NF2 behaves as a protein sensing tissue damage and aromatase-driven local estrogen formation

  1. Research advances in non-cirrhotic portal hypertension

    Directory of Open Access Journals (Sweden)

    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.

  2. 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.

  3. Hepatic cholesterol ester hydrolase in human liver disease.

    Science.gov (United States)

    Simon, J B; Poon, R W

    1978-09-01

    Human liver contains an acid cholesterol ester hydrolase (CEH) of presumed lysosomal origin, but its significance is unknown. We developed a modified CEH radioassay suitable for needle biopsy specimens and measured hepatic activity of this enzyme in 69 patients undergoing percutaneous liver biopsy. Histologically normal livers hydrolyzed 5.80 +/- 0.78 SEM mumoles of cholesterol ester per hr per g of liver protein (n, 10). Values were similar in alcoholic liver disease (n, 17), obstructive jaundice (n, 9), and miscellaneous hepatic disorders (n, 21). In contrast, mean hepatic CEH activity was more than 3-fold elevated in 12 patients with acute hepatitis, 21.05 +/- 2.45 SEM mumoles per hr per g of protein (P less than 0.01). In 2 patients studied serially, CEH returned to normal as hepatitis resolved. CEH activity in all patients paralleled SGOT levels (r, 0.84; P less than 0.01). There was no correlation with serum levels of free or esterified cholesterol nor with serum activity of lecithin-cholesterol acyltransferase, the enzyme responsible for cholesterol esterification in plasma. These studies confirm the presence of CEH activity in human liver and show markedly increased activity in acute hepatitis. The pathogenesis and clinical significance of altered hepatic CEH activity in liver disease require further study.

  4. A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Lay Teng Ang

    2018-02-01

    Full Text Available How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs. Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines are restricted during liver commitment. Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses. However, these signaling combinations were temporally re-interpreted: cellular competence to respond to retinoid, WNT, TGF-β, and other signals sharply changed within 24 hr. Consequently, temporally dynamic manipulation of extracellular signals was imperative to suppress the production of unwanted cell fates across six consecutive developmental junctures. This efficiently generated 94.1% ± 7.35% TBX3+HNF4A+ human liver bud progenitors and 81.5% ± 3.2% FAH+ hepatocyte-like cells by days 6 and 18 of hPSC differentiation, respectively; the latter improved short-term survival in the Fah−/−Rag2−/−Il2rg−/− mouse model of liver failure.

  5. 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

    Directory of Open Access Journals (Sweden)

    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

  6. 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.

  7. In vitro metabolism of [14C]-toluene by human and rat liver microsomes and liver slices

    International Nuclear Information System (INIS)

    Chapman, D.E.; Moore, T.J.; Michener, S.R.; Powis, G.

    1990-01-01

    Toluene metabolites produced by liver microsomes from six human donors included benzylalcohol (Balc), benzaldehyde (Bald) and benzoic acid (Bacid). Microsomes from only one human donor metabolized toluene to p-cresol and o-cresol. Human liver microsomes also metabolized Balc to Bald. Balc metabolism required NADPH, was inhibited by carbon monoxide, and was decreased at a buffer pH of 10. Balc metabolism was not inhibited by ADP-ribose or sodium azide. These results suggest that cytochrome P450 is responsible for the in vitro metabolism of Balc by human liver microsomes. Toluene metabolites formed by human liver slices and released into the incubation media included hippuric acid, and Bacid. Cresols or cresol-conjugates were not detected in liver slice incubation media from any human donor. Toluene metabolism by human liver was compared to metabolism by comparable liver preparations from male Fischer F344 rats. Rates of toluene metabolism by human liver microsomes and liver slices were 9-fold and 1.3-fold greater than for rat liver, respectively. Covalent binding of toluene to human liver microsomes and liver slices was 21-fold and 4-fold greater than for comparable rat liver preparations. Covalent binding of toluene to human microsomes required NADPH, was significantly decreased by coincubation with 4 mM cysteine or 4 mM glutathione, and radioactivity associated with microsomes was decreased by subsequent digestion of microsomes with protease. These results suggest that toluene metabolism and covalent binding of toluene are underestimated if the male Fischer 344 rat is used as a model for human toluene metabolism

  8. Characteristic risk factors in cirrhotic patients for posthepatectomy complications: comparison with noncirrhotic patients.

    Science.gov (United States)

    Itoh, Shinji; Uchiyama, Hideaki; Kawanaka, Hirofumi; Higashi, Takahiro; Egashira, Akinori; Eguchi, Daihiko; Okuyama, Toshiro; Tateishi, Masahiro; Korenaga, Daisuke; Takenaka, Kenji

    2014-02-01

    There seemed to be characteristic risk factors in cirrhotic patients for posthepatectomy complications because these patients have less hepatic reserve as compared with noncirrhotic patients. The aim of the current study was to identify these characteristic risk factors in cirrhotic patients. We performed 419 primary hepatectomies for hepatocellular carcinoma. The patients were divided into the cirrhotic group (n = 198) and the noncirrhotic group (n = 221), and the risk factors for posthepatectomy complications were compared between the groups. Thirty-six cirrhotic patients (18.2%) experienced Clavien's Grade III or more complications. Tumor size, intraoperative blood loss, duration of operation, major hepatectomy (two or more segments), and necessity of blood transfusion were found to be significant risk factors in univariate analyses. Multivariate analysis revealed that major hepatectomy and intraoperative blood loss were independent risk factors for posthepatectomy complications in patients with cirrhosis. On the other hand, the duration of operation was only an independent risk factor for posthepatectomy complication in noncirrhotic patients. Cirrhotic patients should avoid a major hepatectomy and undergo a limited resection preserving as much liver tissue as possible and meticulous surgical procedures to lessen intraoperative blood loss are mandatory to prevent major posthepatectomy complications.

  9. Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis

    International Nuclear Information System (INIS)

    Ilowski, Maren; Kleespies, Axel; Toni, Enrico N. de; Donabauer, Barbara; Jauch, Karl-Walter; Hengstler, Jan G.; Thasler, Wolfgang E.

    2011-01-01

    Research highlights: → ALR decreases cytochrome c release from mitochondria. → ALR protects hepatocytes against apoptosis induction by ethanol, TRAIL, anti-Apo, TGF-β and actinomycin D. → ALR exerts a liver-specific anti-apoptotic effect. → A possible medical usage of ALR regarding protection of liver cells during apoptosis inducing therapies. -- Abstract: Augmenter of liver regeneration (ALR) is known to support liver regeneration and to stimulate proliferation of hepatocytes. However, it is not known if ALR exerts anti-apoptotic effects in human hepatocytes and whether this protective effect is cell type specific. This is relevant, because compounds that protect the liver against apoptosis without undesired effects, such as protection of metastatic tumour cells, would be appreciated in several clinical settings. Primary human hepatocytes (phH) and organotypic cancer cell lines were exposed to different concentrations of apoptosis inducers (ethanol, TRAIL, anti-Apo, TGF-β, actinomycin D) and cultured with or without recombinant human ALR (rhALR). Apoptosis was evaluated by the release of cytochrome c from mitochondria and by FACS with propidium iodide (PI) staining. ALR significantly decreased apoptosis induced by ethanol, TRAIL, anti-Apo, TGF-β and actinomycin D. Further, the anti-apoptotic effect of ALR was observed in primary human hepatocytes and in HepG2 cells but not in bronchial (BC1), colonic (SW480), gastric (GC1) and pancreatic (L3.6PL) cell lines. Therefore, the hepatotrophic growth factor ALR acts in a liver specific manner with regards to both its mitogenic and its anti-apoptotic effect. Unlike the growth factors HGF and EGF, rhALR acts in a liver specific manner. Therefore, ALR is a promising candidate for further evaluation as a possible hepatoprotective factor in clinical settings.

  10. Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Ilowski, Maren [Liver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Kleespies, Axel [Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Toni, Enrico N. de [Department of Medicine II, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Donabauer, Barbara [Liver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Jauch, Karl-Walter [Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Hengstler, Jan G. [Leibniz Research Centre for Working Environment and Human Factors, Technical University, Dortmund (Germany); Thasler, Wolfgang E., E-mail: wolfgang.thasler@med.uni-muenchen.de [Liver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany)

    2011-01-07

    Research highlights: {yields} ALR decreases cytochrome c release from mitochondria. {yields} ALR protects hepatocytes against apoptosis induction by ethanol, TRAIL, anti-Apo, TGF-{beta} and actinomycin D. {yields} ALR exerts a liver-specific anti-apoptotic effect. {yields} A possible medical usage of ALR regarding protection of liver cells during apoptosis inducing therapies. -- Abstract: Augmenter of liver regeneration (ALR) is known to support liver regeneration and to stimulate proliferation of hepatocytes. However, it is not known if ALR exerts anti-apoptotic effects in human hepatocytes and whether this protective effect is cell type specific. This is relevant, because compounds that protect the liver against apoptosis without undesired effects, such as protection of metastatic tumour cells, would be appreciated in several clinical settings. Primary human hepatocytes (phH) and organotypic cancer cell lines were exposed to different concentrations of apoptosis inducers (ethanol, TRAIL, anti-Apo, TGF-{beta}, actinomycin D) and cultured with or without recombinant human ALR (rhALR). Apoptosis was evaluated by the release of cytochrome c from mitochondria and by FACS with propidium iodide (PI) staining. ALR significantly decreased apoptosis induced by ethanol, TRAIL, anti-Apo, TGF-{beta} and actinomycin D. Further, the anti-apoptotic effect of ALR was observed in primary human hepatocytes and in HepG2 cells but not in bronchial (BC1), colonic (SW480), gastric (GC1) and pancreatic (L3.6PL) cell lines. Therefore, the hepatotrophic growth factor ALR acts in a liver specific manner with regards to both its mitogenic and its anti-apoptotic effect. Unlike the growth factors HGF and EGF, rhALR acts in a liver specific manner. Therefore, ALR is a promising candidate for further evaluation as a possible hepatoprotective factor in clinical settings.

  11. Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.

    Science.gov (United States)

    Bacalini, Maria Giulia; Franceschi, Claudio; Gentilini, Davide; Ravaioli, Francesco; Zhou, Xiaoyuan; Remondini, Daniel; Pirazzini, Chiara; Giuliani, Cristina; Marasco, Elena; Gensous, Noémie; Di Blasio, Anna Maria; Ellis, Ewa; Gramignoli, Roberto; Castellani, Gastone; Capri, Miriam; Strom, Stephen; Nardini, Christine; Cescon, Matteo; Grazi, Gian Luca; Garagnani, Paolo

    2018-03-15

    The feasibility of liver transplantation from old healthy donors suggests that this organ is able to preserve its functionality during aging. To explore the biological basis of this phenomenon, we characterized the epigenetic profile of liver biopsies collected from 45 healthy liver donors ranging from 13 to 90 years old using the Infinium HumanMethylation450 BeadChip. The analysis indicates that a large remodeling in DNA methylation patterns occurs, with 8823 age-associated differentially methylated CpG probes. Notably, these age-associated changes tended to level off after the age of 60, as confirmed by Horvath's clock. Using stringent selection criteria we further identified a DNA methylation signature of aging liver including 75 genomic regions. We demonstrated that this signature is specific for liver compared to other tissues and that it is able to detect biological age-acceleration effects associated with obesity. Finally we combined DNA methylation measurements with available expression data. Although the intersection between the two omic characterizations was low, both approaches suggested a previously unappreciated role of epithelial-mesenchymal transition and Wnt signaling pathways in the aging of human liver.

  12. Human germline hedgehog pathway mutations predispose to fatty liver.

    Science.gov (United States)

    Guillen-Sacoto, Maria J; Martinez, Ariel F; Abe, Yu; Kruszka, Paul; Weiss, Karin; Everson, Joshua L; Bataller, Ramon; Kleiner, David E; Ward, Jerrold M; Sulik, Kathleen K; Lipinski, Robert J; Solomon, Benjamin D; Muenke, Maximilian

    2017-10-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway. Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2 +/- ) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2 +/- mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2 +/- mice exposed to a high-fat diet. Our results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous

  13. Isolation and characterization of adult human liver progenitors from ischemic liver tissue derived from therapeutic hepatectomies.

    Science.gov (United States)

    Stachelscheid, Harald; Urbaniak, Thomas; Ring, Alexander; Spengler, Berlind; Gerlach, Jörg C; Zeilinger, Katrin

    2009-07-01

    Recent evidence suggests that progenitor cells in adult tissues and embryonic stem cells share a high resistance to hypoxia and ischemic stress. To study the ischemic resistance of adult liver progenitors, we characterized remaining viable cells in human liver tissue after cold ischemic treatment for 24-168 h, applied to the tissue before cell isolation. In vitro cultures of isolated cells showed a rapid decline of the number of different cell types with increasing ischemia length. After all ischemic periods, liver progenitor-like cells could be observed. The comparably small cells exhibited a low cytoplasm-to-nucleus ratio, formed densely packed colonies, and showed a hepatobiliary marker profile. The cells expressed epithelial cell adhesion molecule, epithelial-specific (CK8/18) and biliary-specific (CK7/19) cytokeratins, albumin, alpha-1-antitrypsin, cytochrome-P450 enzymes, as well as weak levels of hepatocyte nuclear factor-4 and gamma-glutamyl transferase, but not alpha-fetoprotein or Thy-1. In vitro survival and expansion was facilitated by coculture with mouse embryonic fibroblasts. Hepatic progenitor-like cells exhibit a high resistance to ischemic stress and can be isolated from human liver tissue after up to 7 days of ischemia. Ischemic liver tissue from various sources, thought to be unsuitable for cell isolation, may be considered as a prospective source of hepatic progenitor cells.

  14. 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.

  15. Morphology and some biomechanical properties of human liver and spleen

    Czech Academy of Sciences Publication Activity Database

    Stingl, J.; Bača, V.; Čech, V.; Kovanda, J.; Kovandová, H.; Mandys, Václav; Rejmontová, J.; Sosna, B.

    2002-01-01

    Roč. 24, - (2002), s. 285-289 ISSN 0930-1038 Institutional research plan: CEZ:AV0Z5039906 Keywords : Human liver and spleen Subject RIV: FE - Other Internal Medicine Disciplines Impact factor: 0.252, year: 2002

  16. A low muscle mass increases mortality in compensated cirrhotic patients with sepsis.

    Science.gov (United States)

    Lucidi, Cristina; Lattanzi, Barbara; Di Gregorio, Vincenza; Incicco, Simone; D'Ambrosio, Daria; Venditti, Mario; Riggio, Oliviero; Merli, Manuela

    2018-05-01

    Severe infections and muscle wasting are both associated to poor outcome in cirrhosis. A possible synergic effect of these two entities in cirrhotic patients has not been previously investigated. We aimed at analysing if a low muscle mass may deteriorate the outcome of cirrhotic patients with sepsis. Consecutive cirrhotic patients hospitalized for sepsis were enrolled in the study. Patients were classified for the severity of liver impairment (Child-Pugh class) and for the presence of "low muscle mass" (mid-arm muscle circumferencelow muscle mass. In patients with and without low muscle mass, severity of liver disease and characteristics of infections were similar. Mortality tended to be higher in patients with low muscle mass (47% vs 26%, P = .06). A multivariate analysis selected low muscle mass (P low muscle mass compared with those without (50% vs 16%; P = .01). The mortality rate and the incidence of complications in malnourished patients classified in Child-Pugh A-B were similar to those Child-Pugh C. Low muscle mass worsen prognosis in cirrhotic patients with severe infections. This is particularly evident in patients with Child A-B cirrhosis in whom the coexistence of low muscle mass and sepsis caused a negative impact on mortality similar to that observable in all Child C patients with sepsis. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. 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.

  19. PVA matches human liver in needle-tissue interaction.

    Science.gov (United States)

    de Jong, Tonke L; Pluymen, Loes H; van Gerwen, Dennis J; Kleinrensink, Gert-Jan; Dankelman, Jenny; van den Dobbelsteen, John J

    2017-05-01

    Medical phantoms can be used to study needle-tissue interaction and to train medical residents. The purpose of this research is to study the suitability of polyvinyl alcohol (PVA) as a liver tissue mimicking material in terms of needle-tissue interaction. Insertions into ex-vivo human livers were used for reference. Six PVA samples were created by varying the mass percentage of PVA to water (4m% and 7m%) and the number of freeze-thaw cycles (1, 2 and 3 cycles, 16hours of freezing at -19°C, 8hours of thawing). The inner needle of an 18 Gauge trocar needle with triangular tip was inserted 13 times into each of the samples, using an insertion velocity of 5 mm/s. In addition, 39 insertions were performed in two ex-vivo human livers. Axial forces on the needle were captured during insertion and retraction and characterized by friction along the needle shaft, peak forces, and number of peak forces per unit length. The concentration of PVA and the number of freeze-thaw cycles both influenced the mechanical interaction between needle and specimen. Insertions into 4m% PVA phantoms with 2 freeze-thaw cycles were comparable to human liver in terms of estimated friction along the needle shaft and the number of peak forces. Therefore, these phantoms are considered to be suitable liver mimicking materials for image-guided needle interventions. The mechanical properties of PVA hydrogels can be influenced in a controlled manner by varying the concentration of PVA and the number of freeze-thaw cycles, to mimic liver tissue characteristics. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    African Journals Online (AJOL)

    In schistosomiasis, healing of parasite egg- induced liver ... greater in liver than in other tissues. It has been reported that ..... biology, diseases, and potentials for therapy. Annul Rev Biochem ... regeneration in cirrhotic rats. J Hepatol, 2002;.

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

    NARCIS (Netherlands)

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

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

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

    International Nuclear Information System (INIS)

    Tao, Ran; Zhang, Jiuquan; You, Zhonglan; Wei, Luqing; Fan, Yi; Cui, Jinguo; Wang, Jian

    2013-01-01

    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

  3. 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.

  4. Pancreatic α- and β-Cell Function and Metabolic Changes during Oral L-Alanine and Glucose Administration: Comparative Studies between Normal, Diabetic and Cirrhotic Subjects

    OpenAIRE

    HATTORI, TADAKAZU; HOTTA, NIGISHI; OHARA, KIYOJI; SHINODA, HIROSHI; KUNIEDA, TAKEHIDE; NOMURA, TAKAHIDE; KAKUTA, HIRONOBU; TAMAGAWA, TATSUO; SAKAMOTO, NOBUO

    1989-01-01

    The present study investigated whether or not, in addition to the oral glucose tolerance test, oral alanine loading was a useful diagnostic tool for hormonal and metabolic diseases. Fifty g of L-alanine was administered orally in 14 normal, 12 diabetic, and 8 liver cirrhotic subjects. The influence of oral alanine loading on hormones and metabolites was compared with the results of 100g oral glucose loading. The results obtained were as follows: 1) In the normal subjects and cirrhotics, lacta...

  5. Phosphorus-31 spectroscopic imaging of the human liver

    International Nuclear Information System (INIS)

    Biran, M.; Raffard, G.; Canioni, P.; Kien, P.

    1993-01-01

    During the last decade, progresses in the field of nuclear magnetic resonance spectroscopy (M.R.S.), have allowed the metabolic studies of complex biological systems. Since the coming out of whole body magnets, clinical applications are possible; they utilize magnetic field gradients coupled with selective pulse sequences. Study of the phosphorylated metabolism of human liver can be performed with sequences as ISIS, FROGS or 1D-CSI. But they present some disadvantages (for instance contamination by phosphocreatine from muscle). In the present work, we have studied the human liver in vivo by 31 P spectroscopic imaging. Several spectra could be acquired with only one acquisition. This study has needed the building of radiofrequency coils (surface coils), specially designed for liver observation (15 cm diameter 31 P coil and 19 cm diameter proton coil, both transmitter and receiver coils). Preliminary studies have been done on a phantom followed by in vivo measurements on healthy subject livers. We have obtained localized 31 P N.M.R. spectra corresponding to different voxels within the hepatic tissue. The conditions of acquisition of spectra and the problems related to the saturation of phosphorylated metabolite signals (in particular phosphodiesters) are discussed. (author). 5 figs., 15 refs

  6. Analysis of iron storage proteins in chicken liver and spleen tissues in comparison with human liver ferritin by Moessbauer spectroscopy

    International Nuclear Information System (INIS)

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

    2006-01-01

    Characterization of iron storage proteins in liver and spleen from normal chicken and chicken with lymphoid leukemia in comparison with human liver ferritin were considered by Moessbauer spectroscopy (preliminary results). Small differences in Moessbauer hyperfine parameters for both normal and lymphoid leukemia chicken liver and spleen were observed. The value of quadrupole splitting for human liver ferritin was higher than those for chicken tissues. A decrease of iron content in lymphoid leukemia chicken tissues was also found, however, the reason of this fact (pathology or feeding) was not clear yet. (author)

  7. Indeterminate solid hepatic lesions identified on non-diagnostic contrast-enhanced computed tomography: Assessment of the additional diagnostic value of contrast-enhanced ultrasound in the non-cirrhotic liver

    International Nuclear Information System (INIS)

    Quaia, Emilio; De Paoli, Luca; Angileri, Roberta; Cabibbo, Biagio; Cova, Maria Assunta

    2014-01-01

    Objective: To assess the additional diagnostic value of contrast-enhanced ultrasound (CEUS) in the characterization of indeterminate solid hepatic lesions identified on non-diagnostic contrast-enhanced computed tomography (CT). Methods: Fifty-five solid hepatic lesions (1–4 cm in diameter) in 46 non-cirrhotic patients (26 female, 20 male; age ± SD, 55 ± 10 years) underwent CEUS after being detected on contrast-enhanced CT which was considered as non-diagnostic after on-site analysis. Two blinded independent readers assessed CT and CEUS scans and were asked to classify retrospectively each lesion as a malignant or benign based on reference diagnostic criteria for the different hepatic lesion histotypes. Diagnostic accuracy and confidence (area – A z – under ROC curve) were assessed by using gadobenate dimeglumine-enhanced magnetic resonance (MR) imaging (n = 30 lesions), histology (n = 7 lesions), or US follow-up (n = 18 lesions) as the reference standards. Results: Final diagnoses included 29 hemangiomas, 3 focal nodular hyperplasias, 1 hepatocellular adenoma, and 22 metastases. The additional review of CEUS after CT images improved significantly (P < .05) the diagnostic accuracy (before vs after CEUS review = 49% [20/55] vs 89% [49/55] – reader 1 and 43% [24/55] vs 92% [51/55] – reader 2) and confidence (A z , 95% Confidence Intervals before vs after CEUS review = .773 [.652–.895] vs .997 [.987–1] – reader 1 and .831 [.724–.938] vs .998 [.992–1] – reader 2). Conclusions: CEUS improved the characterization of indeterminate solid hepatic lesions identified on non-diagnostic contrast-enhanced CT by identifying some specific contrast enhancement patterns.

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

    Directory of Open Access Journals (Sweden)

    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. Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

    Science.gov (United States)

    Ushijima, Kentarou; Tsuruoka, Shu-ichi; Tsuda, Hidetoshi; Hasegawa, Gohki; Obi, Yuri; Kaneda, Tae; Takahashi, Masaki; Maekawa, Tomohiro; Sasaki, Tomohiro; Koshimizu, Taka-aki; Fujimura, Akio

    2009-01-01

    AIM To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9. METHODS The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics. RESULTS Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects. CONCLUSIONS Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations. PMID:19694738

  10. A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension

    NARCIS (Netherlands)

    Koot, Bart G. P.; Alders, Marielle; Verheij, Joanne; Beuers, Ulrich; Cobben, Jan M.

    2016-01-01

    Non-cirrhotic portal hypertension is characterized by histopathological abnormalities in the liver, mostly affecting small intrahepatic portal veins that cause portal hypertension in the absence of cirrhosis. It can be secondary to coagulation disorders or toxic agents. However, most cases are

  11. Evaluation of renal resistive index in cirrhotic patients for predicting the hepatirenal syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Baek, Seung Yon; Kim, Hyae young; Yi, Sun Young [Ewha WoMans Univ. Mokdong Hospital, Seoul (Korea, Republic of)

    1996-04-01

    To evaluate the usefulness of renal resistive index(RI) in patients with liver cirrhosis as an indicator for predicting hepatorenal syndrome. Renal RIs of thirty cirrhotic patients were analyzed using the gray-scale and Doppler ultrasonograms. As a control group, eight normal subjects were included. Renal RIs were measured at three sites of interlobar or arcuate arteries of both kidneys. The patients were divided into three groups (A, B, or C) according to the Child-Turcotte-Pugh classification and their serum BUN and creatinine levels were compared. We determined whether RIs of normal controls differed from those of cirrhotic patients or whether RIs of cirrhotic patients correlated with the Child-Turcotte-Pugh classification or BUN and creatinine levels. Mean RIs(0.63 {+-}0.33) of normal subjects were statistically different from those(0.67 {+-} 0.05) of cirrhotic patients(P=0.009). RIs of group A(n=6), B(n=9) and C(n=15) were 0.65 {+-} 0.03, 0.65 {+-} 0.04 and 0.70 {+-} 0.04, respectively. The ANOVA test revealed statistically significant differences between the three groups(F ratio=4.472, P=0.021). RIs did not correlate with BUN or creatinine levels. RI could be used as an index for predicting hepatorenal syndrome before the renal function becomes impaired.

  12. Evaluation of renal resistive index in cirrhotic patients for predicting the hepatirenal syndrome

    International Nuclear Information System (INIS)

    Baek, Seung Yon; Kim, Hyae young; Yi, Sun Young

    1996-01-01

    To evaluate the usefulness of renal resistive index(RI) in patients with liver cirrhosis as an indicator for predicting hepatorenal syndrome. Renal RIs of thirty cirrhotic patients were analyzed using the gray-scale and Doppler ultrasonograms. As a control group, eight normal subjects were included. Renal RIs were measured at three sites of interlobar or arcuate arteries of both kidneys. The patients were divided into three groups (A, B, or C) according to the Child-Turcotte-Pugh classification and their serum BUN and creatinine levels were compared. We determined whether RIs of normal controls differed from those of cirrhotic patients or whether RIs of cirrhotic patients correlated with the Child-Turcotte-Pugh classification or BUN and creatinine levels. Mean RIs(0.63 ±0.33) of normal subjects were statistically different from those(0.67 ± 0.05) of cirrhotic patients(P=0.009). RIs of group A(n=6), B(n=9) and C(n=15) were 0.65 ± 0.03, 0.65 ± 0.04 and 0.70 ± 0.04, respectively. The ANOVA test revealed statistically significant differences between the three groups(F ratio=4.472, P=0.021). RIs did not correlate with BUN or creatinine levels. RI could be used as an index for predicting hepatorenal syndrome before the renal function becomes impaired

  13. Low Molecular Weight Heparin in Portal Vein Thrombosis of Cirrhotic Patients: Only Therapeutic Purposes?

    Directory of Open Access Journals (Sweden)

    Raffaele Licinio

    2014-01-01

    Full Text Available Cirrhosis has always been regarded as hemorrhagic coagulopathy caused by the reduction in the hepatic synthesis of procoagulant proteins. However, with the progression of liver disease, the cirrhotic patient undergoes a high rate of thrombotic phenomena in the portal venous system. Although the progression of liver failure produces a reduction in the synthesis of anticoagulant molecules, a test able to detect the patients with hemostatic balance shifting towards hypercoagulability has not yet been elaborated. The need of treatment and/or prophylaxis of cirrhotic patients is demonstrated by the increased mortality, the risk of bleeding from esophageal varices, and the mortality of liver transplantation, when portal vein thrombosis (PVT occurs even if current guidelines do not give indications about PVT treatment in cirrhosis. In view of the general feeling that the majority of cirrhotic patients at an advanced stage may be in a procoagulant condition (suggested by the sharp increase in the prevalence of PVT, it is presumable that a prophylaxis of this population could be of benefit. The safety and the efficacy of prophylaxis and treatment with enoxaparin in patients with cirrhosis demonstrated by a single paper suggest this option only in controlled trials and, currently, there are no sufficient evidences for a recommendation in the clinical practice.

  14. 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.

  15. Repeated courses of transarterial embolization with polyvinyl alcohol particles: 'long life elixir' in a cirrhotic patient with unresectable hepatocellular carcinoma.

    Science.gov (United States)

    Marelli, Laura; Shusang, Vibhakorn; Senzolo, Marco; Cholongitas, Evangelos; Goode, Antony; Yu, Dominic; Patch, David W; Burroughs, Andrew K

    2007-04-01

    Chemoembolization improves survival in selected cirrhotic patients with hepatocellular carcinoma, but prolonged survival is unusual. In this study, a 70-year-old cirrhotic patient, who had a histologically proven hepatocellular carcinoma of 5 cm diameter, embolization with polyvinyl alcohol particles alone, without chemotherapeutic agent, has resulted in continued survival, of 5 years to date, with virtual elimination of residual hypervascularity following 10 sessions of embolization, and with continued patency of the injected branch of the hepatic artery. Provided liver function is maintained, embolization alone appears a feasible long term and effective therapy for unresectable hepatocellular carcinoma.

  16. Hepatocellular Carcinoma Surveillance Among Cirrhotic Patients With Commercial Health Insurance.

    Science.gov (United States)

    Goldberg, David S; Valderrama, Adriana; Kamalakar, Rajesh; Sansgiry, Sujit S; Babajanyan, Svetlana; Lewis, James D

    2016-03-01

    To evaluate hepatocellular carcinoma (HCC) surveillance rates among commercially insured patients, and evaluate factors associated with compliance with surveillance recommendations. Most HCC occurs in patients with cirrhosis. American Association for the Study of Liver Diseases and European Association for the Study of the Liver guidelines each recommend biannual HCC surveillance for cirrhotic patients to diagnose HCC at an early, curable stage. However, compliance with these guidelines in commercially insured patients is unknown. We used the Truven Health Analytics databases from 2006 to 2010, using January 1, 2006 as the anchor date for evaluating outcomes. The primary outcome was continuous surveillance measure, defined as the proportion of time "up-to-date" with surveillance (PTUDS), with the 6-month interval immediately following each ultrasound categorized as "up-to-date." During a median follow-up of 22.9 (interquartile range, 16.3 to 33.9) months among 8916 cirrhotic patients, the mean PTUDS was 0.34 (SD, 0.29), and the median was 0.31 (interquartile range, 0.03 to 0.52). These values increased only modestly with inclusion of serum alpha-fetoprotein testing, contrast-enhanced abdominal computed tomographic scans or magnetic resonance imagings, and/or extension of up-to-date time to 12 months. Being diagnosed by a nongastroenterology provider and increasing age were significantly associated with decreased HCC surveillance (Psurveillance (Psurveillance rates remained low. HCC surveillance rates in commercially insured at-risk patients remain poor despite formalized guidelines, highlighting the need to develop interventions to improve surveillance rates.

  17. Radionuclide imaging of the liver in human fascioliasis

    International Nuclear Information System (INIS)

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

    1984-01-01

    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

  18. 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.

  19. ALTERATION OF TASTE BUDS IN EXPERIMENTAL CIRRHOSIS. Is there correlation with human hypogeusia?

    Directory of Open Access Journals (Sweden)

    Sabrina Alves FERNANDES

    Full Text Available ABSTRACT Background The inherent complications of cirrhosis include protein-calorie malnutrition and micronutrient deficiencies.Changes in taste are detrimental to the nutritional status, and the mechanism to explain these changes is not well documented in the cirrhotic patients. Objective To evaluate the taste buds of cirrhotic rats. Methods Fourteen male Wistar rats were evaluated. After 16 weeks, the liver was removed to histologically diagnose cirrhosis, and blood was collected to perform liver integrity tests. The tongue was removed for histological examination and immunohistochemistry using antibodies against protein gene product PGP 9.5 and the sweet taste receptors T1R2 and T1R3. Morphological changes were determined by scanning electron microscopy. Serum zinc levels were measured. Results The cirrhotic animals, but not the control animals, exhibited zinc deficiency. In both groups, there was positive immunoreactivity for type II and III cells and T1R2 receptors. The cirrhotic animals had no immunoreactivity for T1R3 receptors. Scanning electron microscopy analysis of the cirrhotic group revealed a uniform tapering of the gustatory papillae. Conclusion In conclusion the experimental cirrhosis model mimicked the biochemical and histological parameters of human cirrhosis, therefore enabling a study of the gustatory papillae and taste buds.

  20. ALTERATION OF TASTE BUDS IN EXPERIMENTAL CIRRHOSIS. Is there correlation with human hypogeusia?

    Science.gov (United States)

    Fernandes, Sabrina Alves; Bona, Silvia; Cerski, Carlos Thadeu Schmidt; Marroni, Norma Possa; Marroni, Claudio Augusto

    2016-01-01

    The inherent complications of cirrhosis include protein-calorie malnutrition and micronutrient deficiencies.Changes in taste are detrimental to the nutritional status, and the mechanism to explain these changes is not well documented in the cirrhotic patients. To evaluate the taste buds of cirrhotic rats. Fourteen male Wistar rats were evaluated. After 16 weeks, the liver was removed to histologically diagnose cirrhosis, and blood was collected to perform liver integrity tests. The tongue was removed for histological examination and immunohistochemistry using antibodies against protein gene product PGP 9.5 and the sweet taste receptors T1R2 and T1R3. Morphological changes were determined by scanning electron microscopy. Serum zinc levels were measured. The cirrhotic animals, but not the control animals, exhibited zinc deficiency. In both groups, there was positive immunoreactivity for type II and III cells and T1R2 receptors. The cirrhotic animals had no immunoreactivity for T1R3 receptors. Scanning electron microscopy analysis of the cirrhotic group revealed a uniform tapering of the gustatory papillae. In conclusion the experimental cirrhosis model mimicked the biochemical and histological parameters of human cirrhosis, therefore enabling a study of the gustatory papillae and taste buds.

  1. Non-cirrhotic portal hypertension in HIV mono-infected patients.

    Science.gov (United States)

    Jackson, Belinda D; Doyle, Joseph S; Hoy, Jennifer F; Roberts, Stuart K; Colman, John; Hellard, Margaret E; Sasadeusz, Joseph J; Iser, David M

    2012-09-01

    Unexplained liver injury including fibrosis and portal hypertension has rarely been reported among patients with HIV in the absence of co-infection with hepatitis B (HBV) or hepatitis C (HCV). We describe a series of HIV mono-infected patients with evidence of non-cirrhotic portal hypertension. HIV-infected patients with evidence of portal hypertension who were anti-HBV and anti-HCV negative and HBV and HCV RNA polymerase chain reaction (PCR) negative were identified from patients managed by the Victorian statewide HIV referral service located at The Alfred Hospital, Melbourne. Portal hypertension was defined as either radiological or endoscopic evidence of varices, portal vein flow obstruction, or elevated hepatic venous pressure gradient (HPVG). Five patients were found to have portal hypertension. These patients were male, aged 41 to 65 years, with known duration of HIV infection between 11 to 25 years. All had been treated with antiretroviral therapy, including didanosine. Tests for metabolic, autoimmune, and hereditary causes of liver disease failed to establish an etiology for the liver injury. All had radiological or endoscopic findings of varices, and four patients had radiological features of portal vein obstruction or flow reversal. Only one patient underwent HPVG measurement, which was elevated. Non-invasive fibrosis assessment revealed increased liver stiffness in three (out of four) patients, and no cirrhotic features were found on those who underwent liver biopsy. To our knowledge, this is the largest published series of non-cirrhotic portal hypertension in HIV mono-infected patients in Australia. Further research is needed to understand what relationship, if any, HIV or its treatments might have on liver injury over time. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

  2. Extended normothermic extracorporeal perfusion of isolated human liver after warm ischaemia: a preliminary report.

    Science.gov (United States)

    Bellomo, Rinaldo; Marino, Bruno; Starkey, Graeme; Fink, Michael; Wang, Bao Zhong; Eastwood, Glenn M; Peck, Leah; Young, Helen; Houston, Shane; Skene, Alison; Opdam, Helen; Jones, Robert

    2014-09-01

    Donation after circulatory death (DCD) livers are at markedly increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to transplant DCD livers and may allow their use for artificial extracorporeal liver support of patients with fulminant liver failure. We conducted two proof-of-concept experiments using human livers after DCD to assess the feasibility and functional efficacy of NELP over an extended period. We applied extracorporeal membrane oxygenation, parenteral nutrition, separate hepatic artery and portal vein perfusion and physiological perfusion pressures to two livers obtained after DCD. We achieved NELP and evidence of liver function (bile production, paracetamol removal and maintenance of normal lactate levels) in both livers; one for 24 hours and the other for 43 hours. Histological examination showed areas of patchy ischaemia but preserved biliary ducts and canaliculi. Our experiments justify further investigations of the feasibility and efficacy of extended DCD liver preservation by ex-vivo perfusion.

  3. Single photon emission computed tomography and statistical parametric mapping analysis in cirrhotic patients with and without minimal hepatic encephalopathy

    International Nuclear Information System (INIS)

    Nakagawa, Yuri; Matsumura, Kaname; Iwasa, Motoh; Kaito, Masahiko; Adachi, Yukihiko; Takeda, Kan

    2004-01-01

    The early diagnosis and treatment of cognitive impairment in cirrhotic patients is needed to improve the patients' daily living. In this study, alterations of regional cerebral blood flow (rCBF) were evaluated in cirrhotic patients using statistical parametric mapping (SPM). The relationships between rCBF and neuropsychological test, severity of disease and biochemical data were also assessed. 99m Tc-ethyl cysteinate dimer single photon emission computed tomography was performed in 20 patients with non-alcoholic liver cirrhosis without overt hepatic encephalopathy (HE) and in 20 age-matched healthy subjects. Neuropsychological tests were performed in 16 patients; of these 7 had minimal HE. Regional CBF images were also analyzed in these groups using SPM. On SPM analysis, cirrhotic patients showed regions of significant hypoperfusion in the superior and middle frontal gyri, and inferior parietal lobules compared with the control group. These areas included parts of the premotor and parietal associated areas of the cortex. Among the cirrhotic patients, those with minimal HE had regions of significant hypoperfusion in the cingulate gyri bilaterally as compared with those without minimal HE. Abnormal function in the above regions may account for the relatively selective neuropsychological deficits in the cognitive status of patients with cirrhosis. These findings may be important in the identification and management of cirrhotic patients with minimal HE. (author)

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

    International Nuclear Information System (INIS)

    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. The 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. - Highlights: • Present study demonstrates that hepatic SULT 1A1/1A3 are primarily sulfonate BPA in mouse and human. • Hepatic BPA sulfonation is profoundly reduced steatosis, diabetes and cirrhosis. • With BPA-S detectable in urine under low or common exposures, these findings are novel and important.

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

    Energy Technology Data Exchange (ETDEWEB)

    Yalcin, Emine B.; Kulkarni, Supriya R.; Slitt, Angela L., E-mail: angela_slitt@uri.edu; King, Roberta, E-mail: rking@uri.edu

    2016-02-01

    Background: Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. The 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. - Highlights: • Present study demonstrates that hepatic SULT 1A1/1A3 are primarily sulfonate BPA in mouse and human. • Hepatic BPA sulfonation is profoundly reduced steatosis, diabetes and cirrhosis. • With BPA-S detectable in urine under low or common exposures, these findings are novel and important.

  6. The liver taxis of receptor mediated lactosaminated human growth hormone

    International Nuclear Information System (INIS)

    Chen Zelian; Shi Lin; Li Tongling; Pang Qijie; He Juying; Guan Changtian

    2002-01-01

    Radiography imaging is used to assess liver taxis mechanism of anti-dwarfism drug lactosaminated human growth hormone (L-rhGH). Both L-rhGH and rhGH labelled with 131 I are used to study their biodistribution in animals (including rabbits, cocks and rats). The results show that L-rhGH is of specific hepatic targeting property, and the maximum hepatic concentration rate is 76.8%, which is two times of rhGH. Its hepatic binding is receptor mediated

  7. Nucleic acid metabolism in human chronic liver disease by in vitro autoradiography. I. Altered RNA metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Yoshida, T [Okayama Univ. (Japan). School of Medicine

    1976-06-01

    Biopsy liver specimens from healthy control subjects (N=5) and patients with various liver diseases (N=43) were investigated by the vitro autoradiography. The Leevy technique of adding /sup 3/H-5-uridine (/sup 3/H-U) to the incubation medium was used. In healthy subjects labeling with /sup 3/H-U was observed mostly in hepatocytes and Kupffer cells and the frequency of /sup 3/H-U labeled cells was extremely high. Higher frequencies of labeled fibrocytes and endothelial cells of the blood vessel were found in acute hepatitis than in control subjects. In the active form of chronic hepatitis, significantly higher counts of labeled fibrocytes, ductular cells and lymphocytes were found. In patients with acute hepatitis or the inactive form of chronic hepatitis, only a few labeled lymphocytes were observed. Larger numbers of labeled fibrocytes were found in patients with chronic hepatitis with sublobular hepatic necrosis, than in patients with the active form of chronic hepatitis. In cirrhotic livers, marked increases of labeled ductular cells, fibrocytes and bile duct cells were found. No significant labeling differences were observed in the hepatocytes of various liver diseases. In chronic hepatitis with sublobular hepatic necrosis, a more significant decrease of labeled Kupffer cells was present than in the inactive form of chronic hepatitis. Labeled ductular cells and fibrocytes increased as the disease progressed from acute hepatitis to liver cirrhosis. The labeling index of rosettes cells was intermediate between the hepatocytes and ductular cells. The ratio of labeled parenchymal to non-parenchymal cells decreased proportionally from chronic hepatitis to cirrhosis.

  8. APTR is a prognostic marker in cirrhotic patients with portal hypertension during TIPS procedure.

    Science.gov (United States)

    Yu, Shanshan; Qi, Yanhua; Jiang, Jue; Wang, Hua; Zhou, Qi

    2018-03-01

    Portal hypertension is a major cause of mortality and morbidity in cirrhotic patients. In this study, we aimed to analyze the clinical characteristics of Alu-mediated p21 transcriptional regulator (APTR) during transjugular intrahepatic portosystemic shunt (TIPS) procedure. Portal and hepatic venous blood was drawn from 84 patients with liver cirrhosis and portal hypertension before and after TIPS treatment. Then, we detected biochemical, hemodynamic parameters and APTR expression before and after TIPS treatment. Indeed, TIPS treatment could markedly ameliorate the serum blood urea nitrogen (BUN) level and portal vein hemodynamics in cirrhotic patients. We found that portal venous levels of APTR was significantly decreased after TIPS treatment and its aberrant expression levels were positively correlated with Model for End Stage Liver Disease (MELD), portal hepatic venous pressure gradient (PHPG) in patients. Higher APTR expression in portal vein was associated with poor prognosis. APTR level in portal vein was an independent predictors of mortality. Our data indicated that APTR may serve as a novel biomarker for cirrhotic patients with portal hypertension before and after receiving TIPS. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

    NARCIS (Netherlands)

    Geuken, Erwin; Visser, Dorien; Kuipers, Folkert; Blokzijl, Hans; Leuvenink, Henri G. D.; de Jong, Koert P.; Peeters, Paul M. J. G.; Jansen, Peter L. M.; Slooff, Maarten J. H.; Gouw, Annette S. H.; Porte, Robert J.

    2004-01-01

    BACKGROUND/AIMS: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. METHODS: In 28 liver transplant recipients, bile samples were collected daily

  10. Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

    NARCIS (Netherlands)

    Geuken, E; Visser, D; Kuipers, F; Blokzijl, H; Leuvenink, HGD; de Jong, KP; Peeters, PMJG; Jansen, PLM; Slooff, MJH; Gouw, ASH; Porte, RJ

    2004-01-01

    Background/Aims: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. Methods: In 28 liver transplant recipients, bile samples were collected daily

  11. Clinical usefulness of Tc-99M pertechnetate per-rectal portal scintigraphy in evaluation the severity of portal hypertension in cirrhotic patients

    International Nuclear Information System (INIS)

    Namwongprom, S.; Ekmahachai, M.; Boonyaprapa, S.; Vilasdechanon, N.; Taya, P.; Chankaew, N.; Chitapanarux, T.

    2004-01-01

    Objectives: Variceal hemorrhage is a potentially life-threatening complication in cirrhotic patients. Identification of patients at high risk for bleeding is particularly important. The aim of this study was to determine the clinical usefulness of per-rectal portal scintigraphy in evaluation the severity of portal hypertension in cirrhotic patients in terms of correlation between cirrhosis and classic indicators of hepatic functional reserve and identifying the difference of the portal shunt index (PSI) of the bleeding esophageal varices group and non-bleeding esophageal varices group. Material and methods: Portal circulations in 15 healthy volunteer's and in 67 patients with cirrhosis were evaluated by Tc-99m pertechnetate per-rectal p. ortal scintigraphy. Tc-99m pertechnetate (550 MBq) was instilled into the upper rectum, and dynamic images were taken. Radioactivity curves of the liver and the heart were generated sequentially. Through the analysis of these curves, the PSI was determined by calculating the ratio of counts of the liver to counts of the heart integrated for 24 seconds immediately after the appearance of the liver time-activity curve. Results: The results, expressed as PSI were: 13.63 +/- 6.28 % in healthy subjects and 66.32+/-22.80 % in cirrhotic patients. Of these, the PSIs were 56036 +/- 27.14 % in 31 cirrhotic patients without esophageal varices, and 74.89 +/- 13.62 % in 36 cirrhotic patients with esophageal varices. The PSI was significantly lower in cirrhotic patients without bleeding esophageal vances (BEV) than those with BEV (p=0.001). The PSI calculated with this method was correlated with the serum albumin, the serum bilirubin and the Child-Pugh's score. Conclusion: The Tc-99m pertechnetate per-rectal portal scintigraphy has clinical usefulness as a relatively non-invasive method of choice for quantitative evaluating the severity of portal hypertension in cirrhotic patients. (authors)

  12. 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.

  13. Three-dimensional reconstructions of intrahepatic bile duct tubulogenesis in human liver

    DEFF Research Database (Denmark)

    Vestentoft, Peter S; Jelnes, Peter; Hopkinson, Branden M

    2011-01-01

    BACKGROUND: During liver development, intrahepatic bile ducts are thought to arise by a unique asymmetric mode of cholangiocyte tubulogenesis characterized by a series of remodeling stages. Moreover, in liver diseases, cells lining the Canals of Hering can proliferate and generate new hepatic...... in normal liver and in the extensive ductular reactions originating from intrahepatic bile ducts and branching into the parenchyma of the acetaminophen intoxicated liver. In the developing human liver, three-dimensional reconstructions using multiple marker proteins confirmed that the human intrahepatic...

  14. [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.

  15. Human Precision-Cut Liver Slices as an ex Vivo Model to Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge M.; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, M.T.; Groothuis, Geny M. M.

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Because of the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict

  16. Human precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, Maja; Groothuis, Genoveva

    2013-01-01

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Due to the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict and to

  17. A novel canine model of portal vein stenosis plus thioacetamide administration-induced cirrhotic portal hypertension with hypersplenism.

    Science.gov (United States)

    Lin, Dexin; Wu, Xianbin; Ji, Xiaoke; Zhang, Qiyu; Lin, YuanWei; Chen, WeiJian; Jin, Wangxun; Deng, Liming; Chen, Yunzhi; Chen, Bicheng; Li, Jianmin

    2012-01-01

    Current large animal models that could closely resemble the typical features of cirrhotic portal hypertension in human have not been well established. Thus, we aimed to develop and describe a reliable and reproducible canine cirrhosis model of portal hypertension. A total of 30 mongrel dogs were randomly divided into four groups: 1 (control; n = 5), 2 (portal vein stenosis [PVS]; n = 5], 3 (thioacetamide [TAA]; n = 5), and 4 (PVS plus TAA; n = 15). After 4-months modeling period, liver and spleen CT perfusion, abdominal CT scans, portal hemodynamics, gastroscopy, hepatic function, blood routine, the bone marrow, liver, and spleen histology were studied. The animals in group 2 (PVS) developed extrahepatic portosystemic collateral circulation, particularly esophageal varices, without hepatic cirrhosis and portal hypertension. Animals from group 3 (TAA) presented mild cirrhosis and portal hypertension without significant symptoms of esophageal varices and hypersplenism. In contrast, animals from group 4 (PVS + TAA) showed well-developed micronodular and macronodular cirrhosis, associated with significant portal hypertension and hypersplenism. The combination of PVS and TAA represents a novel, reliable, and reproducible canine cirrhosis model of portal hypertension, which is associated with the typical characteristics of portal hypertension, including hypersplenism.

  18. 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.

  19. Liver surgery in cirrhosis and portal hypertension.

    Science.gov (United States)

    Hackl, Christina; Schlitt, Hans J; Renner, Philipp; Lang, Sven A

    2016-03-07

    The prevalence of hepatic cirrhosis in Europe and the United States, currently 250 patients per 100000 inhabitants, is steadily increasing. Thus, we observe a significant increase in patients with cirrhosis and portal hypertension needing liver resections for primary or metastatic lesions. However, extended liver resections in patients with underlying hepatic cirrhosis and portal hypertension still represent a medical challenge in regard to perioperative morbidity, surgical management and postoperative outcome. The Barcelona Clinic Liver Cancer classification recommends to restrict curative liver resections for hepatocellular carcinoma in cirrhotic patients to early tumor stages in patients with Child A cirrhosis not showing portal hypertension. However, during the last two decades, relevant improvements in preoperative diagnostic, perioperative hepatologic and intensive care management as well as in surgical techniques during hepatic resections have rendered even extended liver resections in higher-degree cirrhotic patients with portal hypertension possible. However, there are few standard indications for hepatic resections in cirrhotic patients and risk stratifications have to be performed in an interdisciplinary setting for each individual patient. We here review the indications, the preoperative risk-stratifications, the morbidity and the mortality of extended resections for primary and metastatic lesions in cirrhotic livers. Furthermore, we provide a review of literature on perioperative management in cirrhotic patients needing extrahepatic abdominal surgery and an overview of surgical options in the treatment of hepatic cirrhosis.

  20. Liver

    International Nuclear Information System (INIS)

    Bernardino, M.E.; Sones, P.J. Jr.; Barton Price, R.; Berkman, W.A.

    1984-01-01

    Evaluation of the liver for focal lesions is extremely important because the liver is one of the most common sites for metastatic disease. Most patients with metastatic deposits to the liver have a survival rate of about 6 months. Thus, metastatic disease to the liver has an extremely grave prognosis. In the past patients with hepatic lesions had no therapeutic recourse. However, with recent aggressive surgical advances (such as partial hepatectomies) and hepatic artery embolization, survival of patients with hepatic metastases has increased. Thus it is important for noninvasive imaging not only to detect lesions early in their course, but also to give their true hepatic involvement and the extent of the neoplastic process elsewhere in the body. Recent advances in imaging have been rapidly changing over the past 5 years. These changes have been more rapid in computed tomography (CT) and ultrasound than in radionuclide imaging. Thus, the question addressed in this chapter is: What is the relationship of hepatic ultrasound to the other current diagnostic modalities in detecting metastatic liver disease and other focal liver lesions? Also, what is its possible future relationship to nuclear magnetic resonance?

  1. 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.

  2. 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.

  3. Laparoscopic cholecystectomy in cirrhotic patients: the role of subtotal cholecystectomy and its variants.

    Science.gov (United States)

    Palanivelu, Chinnasamy; Rajan, Pidigu Seshiyer; Jani, Kalpesh; Shetty, Alangar Roshan; Sendhilkumar, Karuppasamy; Senthilnathan, Palanisamy; Parthasarthi, Ramakrishnan

    2006-08-01

    Open cholecystectomy is associated with considerable morbidity and mortality in cirrhotic patients. Laparoscopic cholecystectomy may offer a better option because of the magnification available and the availability of newer instruments like the ultrasonic shears. We present our experience of 265 laparoscopic cholecystectomies and attempt to identify the difficulties encountered in this group of patients. Between 1991 and 2005, 265 cirrhotic patients of Child-Pugh Classification A and B, with symptomatic gallstones, were subjected to laparoscopic cholecystectomy. We describe here our tailored approach and our techniques of subtotal cholecystectomy. Features of acute cholecystitis were present in 35.1% of the patients, and 64.9% presented with chronic cholecystitis. In 81.5% of the patients, the diagnosis of cirrhosis was established preoperatively. In 8.3% of the patients, a fundus first method was adopted when the hilum could not be approached despite additional ports. Modified subtotal cholecystectomy was performed in a total of 206 patients. Mean operative time in the subtotal cholecystectomy group was 72 minutes; in the standard group, it was 41 minutes. There was no mortality. In 15% of patients, postoperative deterioration in liver function occurred. Worsening of ascites, port site infection, port site bleeding, intraoperative hemorrhage, bilious drainage, and stone formation in the remnant were the other complications encountered. Laparoscopic cholecystectomy is a safe and effective treatment for calculous cholecystitis in cirrhotic patients. Appropriate modification of subtotal cholecystectomy should be practiced, depending on the risk factors present, to avoid complications.

  4. [An analysis of clinical characteristic and related risk factors in 208 cirrhotic patients complicated with infections].

    Science.gov (United States)

    Zhang, G H; Wang, M; Wang, L; Wang, X M; Wang, Y; Ou, X J; Jia, J D

    2018-02-01

    Objective: To analyze the clinical features and risk factors of cirrhotic patients complicated with infections. Methods: The clinical and laboratory characteristics of cirrhotic patients complicated with infections hospitalized from April 2014 to June 2017 were retrospectively analyzed. Relevant risk factors for infection and mortality were explored. Results: The overall incidence of infections was 17.6% in 1 670 hospitalized cirrhotic patients. Among the recruited 208 patients in this study, alcoholic, viral hepatitis B or C and autoimmune liver diseases accounted for 29.8% (62/208), 26.0% (54/208), and 22.1% (46/208), respectively. The most common infection site was respiratory tract (70.2%), followed by urinary tract, intestinal and intra-abdomen. Forty-six pathogens were isolated from 32 patients, including 22 (47.8%) Gram negative bacteria, 16 (34.8%) Gram positive bacteria and 2(4.3%) mycobacterium tuberculosis, 5 (10.9%) fungi and 1 (2.2%) mycoplasma. The mortality in patients with nosocomial infections (16.7%,7/42) was higher than that in patients with community-acquired infections (6.0%,10/166, P =0.025). All 17 deaths occurred in decompensated cirrhosis. Multivariate analysis demonstrated that hepatic encephalopathy and prothrombin time were independent risk factors of mortality. Conclusions: Patients with decompensated cirrhosis are more susceptible to infections. Hepatic encephalopathy and prothrombin time are independent risk factors for death.

  5. Liver slices in in vitro pharmacotoxicology with special reference to the use of human liver tissue

    NARCIS (Netherlands)

    Olinga, Peter; Meijer, D.K F; Slooff, M.JH; Groothuis, Geny

    In the early years of research in in vitro pharmacotoxicology liver slices have been used. After a decline in the application of slices in favour of the use of isolated hepatocytes and the isolated perfused liver preparation, the development of the Krumdieck slicer in the 1980s led to a 'comeback'

  6. Current status of prediction of drug disposition and toxicity in humans using chimeric mice with humanized liver.

    Science.gov (United States)

    Kitamura, Shigeyuki; Sugihara, Kazumi

    2014-01-01

    1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.

  7. Can the tyrosine kinase inhibitors trigger metabolic encephalopathy in cirrhotic patients?

    Science.gov (United States)

    Brandi, Giovanni; de Rosa, Francesco; Calzà, Laura; Girolamo, Stefania Di; Tufoni, Manuel; Ricci, Carmen Serena; Cirignotta, Fabio; Caraceni, Paolo; Biasco, Guido

    2013-03-01

    Sorafenib is the standard treatment of advanced hepatocarcinoma (HCC) in cirrhotic patients with preserved liver function. It shares many adverse effects with other tyrosine-kinase (TK) inhibitors and antiangiogenic drugs. TK inhibitors could have a direct toxicity on CNS, both by interfering with TK-related pathways and by inhibiting angiogenesis. The aim of this study was to investigate whether sorafenib administration can be associated to metabolic encephalopathy in patients with cirrhosis. We retrospectively reviewed medical records of all cirrhotic patients treated with sorafenib for HCC afferent at our Department from January 2009 to December 2011. Among 62 patients, we identified 10 patients with clinically significant cognitive impairment. Seven of these were clearly diagnosed with overt hepatic encephalopathy (HE), one with brain metastases and two with drug-related toxic-metabolic encephalopathy. These last two cases were characterized by severe cognitive impairment, mood alteration and memory deficit. Clinical exam, blood tests and brain CT excluded organic causes of encephalopathy and precipitating factors of HE. Sorafenib discontinuation was associated with complete reversal of the syndrome, which recurred on drug re-administration in one case. Our study suggests that sorafenib may be a precipitating factor of metabolic encephalopathy in cirrhotic patients with advanced HCC. This neurological syndrome appears to be not responsive to the conventional treatment for HE, but it is fully reversible by drug discontinuation. It can be speculated that the potential direct neuronal action of sorafenib may represent a trigger for the onset of metabolic encephalopathy in a subset of cirrhotic patients. © 2012 John Wiley & Sons A/S.

  8. Ghrelin, leptin and insulin in cirrhotic children and adolescents: relationship with cirrhosis severity and nutritional status.

    Science.gov (United States)

    Dornelles, Cristina T L; Goldani, Helena A S; Wilasco, Maria Inês A; Maurer, Rafael L; Kieling, Carlos O; Porowski, Marilene; Ferreira, Cristina T; Santos, Jorge L; Vieira, Sandra M G; Silveira, Themis R

    2013-01-10

    Ghrelin, leptin, and insulin concentrations are involved in the control of food intake and they seem to be associated with anorexia-cachexia in cirrhotic patients. The present study aimed to investigate the relationship between the nutritional status and fasting ghrelin, leptin and insulin concentrations in pediatric cirrhotic patients. Thirty-nine patients with cirrhosis and 39 healthy controls aged 0-15 years matched by sex and age were enrolled. Severity of liver disease was assessed by Child-Pugh classification, and Pediatric for End Stage Liver Disease (PELD) or Model for End-stage Liver Disease (MELD) scores. Blood samples were collected from patients and controls to assay total ghrelin, acyl ghrelin, leptin and insulin by using a commercial ELISA kit. Anthropometry parameters used were standard deviation score of height-for-age and triceps skinfold thickness-for-age ratio. A multiple linear regression analysis was used to determine the correlation between dependent and independent variables. Acyl ghrelin was significantly lower in cirrhotic patients than in controls [142 (93-278) pg/mL vs 275 (208-481) pg/mL, P=0.001]. After multiple linear regression analysis, total ghrelin and acyl ghrelin showed an inverse correlation with age; acyl ghrelin was associated with the severity of cirrhosis and des-acyl ghrelin with PELD or MELD scores ≥15. Leptin was positively correlated with gender and anthropometric parameters. Insulin was not associated with any variable. Low acyl ghrelin and high des-acyl ghrelin concentrations were associated with cirrhosis severity, whereas low leptin concentration was associated with undernourishment in children and adolescents with cirrhosis. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. 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, R.|info:eu-repo/dai/nl/155644033; Groothuis, Geny M M; Russel, Frans G M

    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

  10. 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...... up time was 16.7 (0.2-21.9) years in the non-alcoholic and 9.2 (0.6-23.1) years in the alcoholic group. Systematic data collection was carried out by review of all medical records. All members of the study cohort were linked through their unique personal identification number to the National Registry...

  11. Hepatoprotective Effects of Chinese Medicine Herbs Decoction on Liver Cirrhosis in Rats

    Directory of Open Access Journals (Sweden)

    Nor Aziyah Mat-Rahim

    2017-01-01

    Full Text Available Hepatoprotective and curative activities of aqueous extract of decoction containing 10 Chinese medicinal herbs (HPE-XA-08 were evaluated in Sprague–Dawley albino rats with liver damage induced by thioacetamide (TAA. These activities were assessed by investigating the liver enzymes level and also histopathology investigation. Increases in alkaline phosphatase (ALP and gamma-glutamyl transferase (GGT levels were observed in rats with cirrhotic liver. No significant alterations of the liver enzymes were observed following treatment with HPE-XA-08. Histopathology examination of rats treated with HPE-XA-08 at 250 mg/kg body weight, however, exhibited moderate liver protective effects. Reduced extracellular matrix (ECM proteins within the hepatocytes were noted in comparison to the cirrhotic liver. The curative effects of HPE-XA-08 were observed with marked decrease in the level of ALP (more than 3x and level of GGT (more than 2x in cirrhotic rat treated with 600 mg/kg body weight HPE-XA-08 in comparison to cirrhotic rat treated with just water diluent. Reversion of cirrhotic liver to normal liver condition in rats treated with HPE-XA-08 was observed. Results from the present study suggest that HPE-XA-08 treatment assisted in the protection from liver cirrhosis and improved the recovery of cirrhotic liver.

  12. Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats.

    Science.gov (United States)

    Gao, Jin-Hang; Wen, Shi-Lei; Feng, Shi; Yang, Wen-Juan; Lu, Yao-Yao; Tong, Huan; Liu, Rui; Tang, Shi-Hang; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Xie, Hui-Qi; Tang, Cheng-Wei

    2016-10-01

    Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway.

  13. [Role of splenectomy in the treatment of non-cirrhotic portal hypertension: about 3 cases].

    Science.gov (United States)

    Belhamidi, Mohamed Said; Hammi, Salah Eddine; Bouzroud, Mohamed; Benmoussa, Mustapha; Ali, Abdelmounaim Ait; Bounaim, Ahmed

    2017-01-01

    Non-cirrhotic portal hypertension was first described by Guido BANTI in 1898 as a condition characterized by the association of portal hypertension with splenomegaly, anemia and healthy liver. The diagnosis was based on abdominal ultrasound, splenoportography and liver biopsy. Our study aimed to evaluate the role of splenectomy in non-cirrhotic portal hypertension. We conducted a retrospective study of 3 patients (2 women and 1 man) treated by our staff over the period January 2010 -September 2016. The diagnosis of idiopathic portal hypertension was based on the following criteria: portal hypertension, the presence of oesophageal varices associated with splenomegaly, the absence of cirrhosis or of other liver disorders responsible of portal hypertension. All patients underwent splenectomy. Outcome after splenectomy was marked by the standardization of clinical, radiological and biological signs of this disease associated with the absence of oesophageal varices recurrence. Splenectomy associated with ligation of oesophageal varices may be sufficient to treat this syndrome and especially its consequences without using splenorenal bypass.

  14. 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.

  15. Liver lipase and high-density lipoprotein. Lipoprotein changes after incubation of human serum with rat liver lipase.

    Science.gov (United States)

    Groot, P H; Scheek, L M; Jansen, H

    1983-05-16

    Human sera were incubated with rat liver lipase after inactivation of lecithin:cholesterol acyltransferase, and the changes in serum lipoprotein composition were measured. In the presence of liver lipase serum triacylglycerol and phosphatidylcholine were hydrolyzed. The main changes in the concentrations of these lipids were found in the high-density lipoprotein fraction. Subfractionation of high-density lipoprotein by rate-zonal ultracentrifugation showed a prominent decrease in all constituents of high-density lipoprotein2, a smaller decrease in the 'light' high-density lipoprotein3 and an increase in the 'heavy' high-density lipoprotein3. These data support a concept in which liver lipase is involved in high-density lipoprotein2 phospholipid and triacylglycerol catabolism and suggest that as a result of this action high-density lipoprotein2 is converted into high-density lipoprotein3.

  16. 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

  17. Extracellular Vesicles from Human Liver Stem Cells Reduce Injury in an Ex Vivo Normothermic Hypoxic Rat Liver Perfusion Model.

    Science.gov (United States)

    Rigo, Federica; De Stefano, Nicola; Navarro-Tableros, Victor; David, Ezio; Rizza, Giorgia; Catalano, Giorgia; Gilbo, Nicholas; Maione, Francesca; Gonella, Federica; Roggio, Dorotea; Martini, Silvia; Patrono, Damiano; Salizzoni, Mauro; Camussi, Giovanni; Romagnoli, Renato

    2018-05-01

    The gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. Here, we aimed to explore the feasibility of a pharmacological intervention on isolated rat livers by using a combination of NMP and human liver stem cells-derived extracellular vesicles (HLSC-EV). We established an ex vivo murine model of NMP capable to maintain liver function despite an ongoing hypoxic injury induced by hemodilution. Livers were perfused for 4 hours without (control group, n = 10) or with HLSC-EV (treated group, n = 9). Bile production was quantified; perfusate samples were collected hourly to measure metabolic (pH, pO2, pCO2) and cytolysis parameters (AST, alanine aminotransferase, lactate dehydrogenase). At the end of perfusion, we assessed HLSC-EV engraftment by immunofluorescence, tissue injury by histology, apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, tissue hypoxia-inducible factor 1-α, and transforming growth factor-beta 1 RNA expression by quantitative reverse transcription-polymerase chain reaction. During hypoxic NMP, livers were able to maintain homeostasis and produce bile. In the treated group, AST (P = 0.018) and lactate dehydrogenase (P = 0.032) levels were significantly lower than those of the control group at 3 hours of perfusion, and AST levels persisted lower at 4 hours (P = 0.003). By the end of NMP, HLSC-EV had been uptaken by hepatocytes, and EV treatment significantly reduced histological damage (P = 0.030), apoptosis (P = 0.049), and RNA overexpression of hypoxia-inducible factor 1-α (P < 0.0001) and transforming growth factor-beta 1 (P = 0.014). HLSC-EV treatment, even in a short-duration model, was feasible and effectively reduced liver injury during hypoxic NMP.

  18. A rapid and simple method for cryopreservation of human liver slices

    NARCIS (Netherlands)

    de Kanter, R; Olinga, Peter; Hof, I.H; de Jager, M.H; Verwillegen, W.A; Slooff, M.JH; Meijer, D.K F; Groothuis, Geny; Koster, H

    1. Precision-cut liver slices represent a suitable and convenient in vitro preparation for studying metabolism and toxicity mechanisms of drugs and toxic chemicals. Particularly in the case of human liver slices, cryopreservation would enable more efficient utilization of this scarce and irregularly

  19. Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Takanori Takebe

    2017-12-01

    Full Text Available Summary: Organoid technology provides a revolutionary paradigm toward therapy but has yet to be applied in humans, mainly because of reproducibility and scalability challenges. Here, we overcome these limitations by evolving a scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC. By conducting massive “reverse” screen experiments, we identified three progenitor populations that can effectively generate liver buds in a highly reproducible manner: hepatic endoderm, endothelium, and septum mesenchyme. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass producing homogeneous and miniaturized liver buds on a clinically relevant large scale (>108. Vascularized and functional liver tissues generated entirely from iPSCs significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacturing platform for multicellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations. : With the goal of clinical translation of liver bud transplant therapy, Takebe et al. established a massive organoid production platform from endoderm, endothelial, and mesenchymal progenitor populations specified entirely from human iPSCs, reproducibly demonstrating functionality both in vitro and in vivo. Keywords: iPSC, liver bud, organoid, transplantation, self-organization, endothelial, mesenchymal, liver failure, clinical grade

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

    Science.gov (United States)

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

    2016-01-01

    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. PMID:27385595

  1. Metabolism of styrene in the human liver in vitro: interindividual variation and enantioselectivity

    NARCIS (Netherlands)

    Wenker, M. A.; Kezić, S.; Monster, A. C.; de Wolff, F. A.

    2001-01-01

    1. The interindividual variation and enantioselectivity of the in vitro styrene oxidation by cytochrome P450 have been investigated in 20 human microsomal liver samples. Liver samples were genotyped for the CYP2E1*6 and CYP2E1*5B alleles. 2. Kinetic analysis indicated the presence of at least two

  2. Volumetric Growth of the Liver in the Human Fetus: An Anatomical, Hydrostatic, and Statistical Study

    Directory of Open Access Journals (Sweden)

    Michał Szpinda

    2015-01-01

    Full Text Available Using anatomical, hydrostatic, and statistical methods, liver volumes were assessed in 69 human fetuses of both sexes aged 18–30 weeks. No sex differences were found. The median of liver volume achieved by hydrostatic measurements increased from 6.57 cm3 at 18–21 weeks through 14.36 cm3 at 22–25 weeks to 20.77 cm3 at 26–30 weeks, according to the following regression: y = −26.95 + 1.74 × age ± Z  × (−3.15 + 0.27 × age. The median of liver volume calculated indirectly according to the formula liver volume = 0.55 × liver length × liver transverse diameter × liver sagittal diameter increased from 12.41 cm3 at 18–21 weeks through 28.21 cm3 at 22–25 weeks to 49.69 cm3 at 26–30 weeks. There was a strong relationship (r=0.91, p<0.001 between the liver volumes achieved by hydrostatic (x and indirect (y methods, expressed by y = −0.05 + 2.16x  ± 7.26. The liver volume should be calculated as follows liver volume = 0.26 × liver length × liver transverse diameter × liver sagittal diameter. The age-specific liver volumes are of great relevance in the evaluation of the normal hepatic growth and the early diagnosis of fetal micro- and macrosomias.

  3. Long-term culture of human liver tissue with advanced hepatic functions.

    Science.gov (United States)

    Ng, Soon Seng; Xiong, Anming; Nguyen, Khanh; Masek, Marilyn; No, Da Yoon; Elazar, Menashe; Shteyer, Eyal; Winters, Mark A; Voedisch, Amy; Shaw, Kate; Rashid, Sheikh Tamir; Frank, Curtis W; Cho, Nam Joon; Glenn, Jeffrey S

    2017-06-02

    A major challenge for studying authentic liver cell function and cell replacement therapies is that primary human hepatocytes rapidly lose their advanced function in conventional, 2-dimensional culture platforms. Here, we describe the fabrication of 3-dimensional hexagonally arrayed lobular human liver tissues inspired by the liver's natural architecture. The engineered liver tissues exhibit key features of advanced differentiation, such as human-specific cytochrome P450-mediated drug metabolism and the ability to support efficient infection with patient-derived inoculums of hepatitis C virus. The tissues permit the assessment of antiviral agents and maintain their advanced functions for over 5 months in culture. This extended functionality enabled the prediction of a fatal human-specific hepatotoxicity caused by fialuridine (FIAU), which had escaped detection by preclinical models and short-term clinical studies. The results obtained with the engineered human liver tissue in this study provide proof-of-concept determination of human-specific drug metabolism, demonstrate the ability to support infection with human hepatitis virus derived from an infected patient and subsequent antiviral drug testing against said infection, and facilitate detection of human-specific drug hepatotoxicity associated with late-onset liver failure. Looking forward, the scalability and biocompatibility of the scaffold are also ideal for future cell replacement therapeutic strategies.

  4. 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.

  5. 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. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Transjugular Intrahepatic Portosystemic Shunt before Abdominal Surgery in Cirrhotic Patients: A Retrospective, Comparative Study

    Directory of Open Access Journals (Sweden)

    Evelyne Vinet

    2006-01-01

    Full Text Available Surgery in cirrhotic patients is associated with high morbidity and mortality related to portal hypertension and liver insufficiency. Therefore, preoperative portal decompression is a logical approach to facilitate abdominal surgery and hopefully to improve postoperative survival. The present study evaluated the clinical outcomes of 18 patients (mean age 58 years with cirrhosis (seven alcoholics and 11 nonalcoholics who underwent transjugular intrahepatic portosystemic shunt (TIPS placement before antrectomy (n=5, colectomy (n=10, small-bowel resection (n=1, pancreatectomy (n=1 and nephrectomy (n=1. TIPS was performed a mean (± SD of 72±21 days before surgery and induced a marked mean decrease in portohepatic gradient from 21.4±3.9 mmHg to 8.4±3.4 mmHg. Cirrhotic patients (n=17 who underwent elective abdominal surgery without preoperative TIPS placement were used as the control group. Both groups were matched for age, etiology of cirrhosis, indications for surgery, type of surgery and coagulation parameters. The mean Pugh score was significantly higher in the TIPS group (7.7 versus 6.2. No significant differences were observed for operative blood loss, postoperative complications, duration of hospitalization and one-month (83% versus 88% or one-year (54% versus 63% cumulative survival rate. Analysis using the Cox proportional hazards model showed that neither TIPS placement nor preoperative Pugh score were independent predictors for survival. The present study suggests that preoperative TIPS placement does not improve postoperative evolution after abdominal surgery in cirrhotic patients with good or moderately impaired liver function.

  7. Child-Pugh classification dependent alterations in serum leptin levels among cirrhotic patients: a case controlled study

    Directory of Open Access Journals (Sweden)

    Zeyrek Fadile

    2004-09-01

    Full Text Available Abstract Background As anorexia and hypermetabolism are common in cirrhosis, leptin levels may be increased in this disease. In this study, we investigated the relation between the severity of disease and serum leptin levels in post-hepatitis cirrhosis and the role of body composition, gender and viral aetiology of cirrhosis in this association. Methods Thirty-five cases with post-hepatitis cirrhosis and 15 healthy controls were enrolled in this study. Body composition including body mass index, body fat percentage and body fat mass were determined. Serum leptin levels were assayed. Results Leptin levels were significantly higher among cirrhotic patients independent of sex compared to controls (p = 0.001. Female patients in both groups have had higher leptin levels than males (in cirrhotics p = 0.029, in controls p = 0.02. Cirrhotic patients in each of A, B and C subgroups according to the Child- Pugh classification revealed significantly different levels compared to controls (p = 0.046, p = 0.004, p = 0.0001, respectively. Male cirrhotics in Child-Pugh Class B and C subgroups had significantly higher leptin levels compared to male controls (p = 0.006, p = 0.008. On the other hand, female patients only in Child Pugh class C subgroup have had higher levels of serum leptin compared to controls (p = 0.022. Child-Pugh classification has been found to be the sole discriminator in determination of leptin levels in cirrhotics by linear regression (beta: 0.435 p = 0.015. Conclusion Serum leptin levels increase in advanced liver disease independently of gender, body composition in posthepatitic cirrhosis. The increase is more abundant among patients that belong to C subgroup according to the Child- Pugh classification.

  8. 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...

  9. Volumetric Growth of the Liver in the Human Fetus: An Anatomical, Hydrostatic, and Statistical Study

    Science.gov (United States)

    Szpinda, Michał; Paruszewska-Achtel, Monika; Mila-Kierzenkowska, Celestyna; Elminowska-Wenda, Gabriela; Dombek, Małgorzata; Szpinda, Anna; Badura, Mateusz

    2015-01-01

    Using anatomical, hydrostatic, and statistical methods, liver volumes were assessed in 69 human fetuses of both sexes aged 18–30 weeks. No sex differences were found. The median of liver volume achieved by hydrostatic measurements increased from 6.57 cm3 at 18–21 weeks through 14.36 cm3 at 22–25 weeks to 20.77 cm3 at 26–30 weeks, according to the following regression: y = −26.95 + 1.74 × age ± Z  × (−3.15 + 0.27 × age). The median of liver volume calculated indirectly according to the formula liver volume = 0.55 × liver length × liver transverse diameter × liver sagittal diameter increased from 12.41 cm3 at 18–21 weeks through 28.21 cm3 at 22–25 weeks to 49.69 cm3 at 26–30 weeks. There was a strong relationship (r = 0.91, p hydrostatic (x) and indirect (y) methods, expressed by y = −0.05 + 2.16x  ± 7.26. The liver volume should be calculated as follows liver volume = 0.26 × liver length × liver transverse diameter × liver sagittal diameter. The age-specific liver volumes are of great relevance in the evaluation of the normal hepatic growth and the early diagnosis of fetal micro- and macrosomias. PMID:26413551

  10. The evaluation of the right inferior phrenic artery diameter in cirrhotic patients.

    Science.gov (United States)

    Esen, Kaan; Balci, Yuksel; Tok, Sermin; Ucbilek, Enver; Kara, Engin; Kaya, Omer

    2017-09-01

    The purpose of this study is to evaluate the relationship between right inferior phrenic artery diameter and portal hypertension in cirrhotic patients. CT examinations of 38 patients with chronic liver disease (patient group) and 40 patients without any liver disease (control group) were evaluated. The right inferior phrenic artery diameter of the patient and control group were measured. CT findings of portal hypertension, which were accepted as ascites, collaterals, splenomegaly and portal vein diameter greater than 13 mm, were determined and scored in the patient group. Patients obtained scores between one and four with respect to portal hypertension findings, and the scores were compared with phrenic artery diameters. Child-Pugh and MELD scores of the patients were also calculated. The mean diameter of the right inferior phrenic artery in the patient group was larger than that in the control group (p phrenic artery diameter of the patients with score 1 was significantly different from those with score 2 (p = 0.028), score 3 (p = 0.001) and score 4 (p = 0.005). We found a linear and moderate relationship between phrenic artery diameter values and Child-Pugh scores (p = 0.012, r = 0.405). Dilatation of the right inferior phrenic artery in cirrhotic patients may be a nonspecific sign of developing portal hypertension.

  11. Osteodystrophy in liver cirrhosis

    International Nuclear Information System (INIS)

    Sezai, Shu-ichi; Ishizawa, Suguru; Yoshino, Katsumasa

    1987-01-01

    In order to investigate the osteodystrophy in liver cirrhosis, 21 liver cirrhotic patients having no malignancy and normal renal function were examined by 99m Tc Methylene Diphosphonate (MDP) bone scintigraphy. The cirrhotic subjects consisted of 14 males and 7 females. Their age was 31 - 80, average 55.7 years. The causes of their cirrhotic damage were 1 primary biliary cirrhosis, 9 alcoholic, 2 HB viral and 9 cryptogenic. The contents of their illness showed 9 cases in A, 4 in B and 8 in C of Child's classification. Abnormal hot spot(s) on bone in the cirrhotics could be observed very frequently in 99m Tc MDP bone scintigraphy (47.6 %; 10/21 cases). Those spots were seen more frequently in female and advanced stage of cirrhosis. The number of spot(s) increased also in advanced liver cirrhosis. Serum Ca, P and PTH were in normal range. All of three vitamin D 3 fractions decreased and especially 1,25 (OH) 2 D 3 was depressed more in scinti-positive cases. Metacarpal bone X-p with an alumimum step wedge as a reference was analyzed by a microdensitometry (MD) method (Inoue T et al) and the pattern of osteopathy (i.e. porosis, malacia and poromalacia) was examined according to Sumi Y et al. MD method was not known yet if there was any definite correlation with bone scintigraphy and the osteopathic pattern belonged to border categories. In conclusion, more attension on hepatic osteodystrophy will be significantly necessary due to the fact that it has been found very frequently in liver cirrhosis. 99m Tc MDP bone scintigraphy is a good means for detection of the hepatic osteodystrophy. (author)

  12. Methods of measuring metabolism during surgery in humans: focus on the liver-brain relationship.

    Science.gov (United States)

    Battezzati, Alberto; Bertoli, Simona

    2004-09-01

    The purpose of this work is to review recent advances in setting methods and models for measuring metabolism during surgery in humans. Surgery, especially solid organ transplantation, may offer unique experimental models in which it is ethically acceptable to gain information on difficult problems of amino acid and protein metabolism. Two areas are reviewed: the metabolic study of the anhepatic phase during liver transplantation and brain microdialysis during cerebral surgery. The first model offers an innovative approach to understand the relative role of liver and extrahepatic organs in gluconeogenesis, and to evaluate whether other organs can perform functions believed to be exclusively or almost exclusively performed by the liver. The second model offers an insight to intracerebral metabolism that is closely bound to that of the liver. The recent advances in metabolic research during surgery provide knowledge immediately useful for perioperative patient management and for a better control of surgical stress. The studies during the anhepatic phase of liver transplantation have showed that gluconeogenesis and glutamine metabolism are very active processes outside the liver. One of the critical organs for extrahepatic glutamine metabolism is the brain. Microdialysis studies helped to prove that in humans there is an intense trafficking of glutamine, glutamate and alanine among neurons and astrocytes. This delicate network is influenced by systemic amino acid metabolism. The metabolic dialogue between the liver and the brain is beginning to be understood in this light in order to explain the metabolic events of brain damage during liver failure.

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

    International Nuclear Information System (INIS)

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-01-01

    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

  14. 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.

  15. 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

  16. Bibliographical review of tomographic characterisation of hepatic masses in cirrhotic patients: Servicio de Radiologia e Imagenes Medicas: Hospital Dr. R. A. Calderon Guardia

    International Nuclear Information System (INIS)

    Urena Urena, Andrea

    2014-01-01

    Liver cirrhosis has constituted one of the major health problems in the world and in Costa Rica, due to its high mortality, and this has been a very frequent pathology in radiological daily practice. This has forced to know very well the morphological changes caused by this pathology, and to always think about the possibility of a hepatocellular carcinoma. Early detection of liver mass has been crucial to improve prognosis and patient survival. A literature review is made and an exhaustive analysis is performed of the various differential diagnosis of liver mass in a cirrhotic patient, in order to make an early and accurate diagnosis, as well as global standards are showed in terms of screening in cirrhotic patients and the protocol for the management of hepatocellular carcinoma [es

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

    International Nuclear Information System (INIS)

    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 λ gt11 were screened using isolated rat arginase cDNA as a probe. Two of the positive clones, designated λ hARG6 and λ 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 λ 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

  18. Metabolism of ethylbenzene by human liver microsomes and recombinant human cytochrome P450s (CYP).

    Science.gov (United States)

    Sams, Craig; Loizou, George D; Cocker, John; Lennard, Martin S

    2004-03-07

    The enzyme kinetics of the initial hydroxylation of ethylbenzene to form 1-phenylethanol were determined in human liver microsomes. The individual cytochrome P450 (CYP) forms catalysing this reaction were identified using selective inhibitors and recombinant preparations of hepatic CYPs. Production of 1-phenylethanol in hepatic microsomes exhibited biphasic kinetics with a high affinity, low Km, component (mean Km = 8 microM; V(max) = 689 pmol/min/mg protein; n = 6 livers) and a low affinity, high Km, component (Km = 391 microM; V(max) = 3039 pmol/min/mg protein; n = 6). The high-affinity component was inhibited 79%-95% (mean 86%) by diethyldithiocarbamate, and recombinant CYP2E1 was shown to metabolise ethylbenzene with low Km (35 microM), but also low (max) (7 pmol/min/pmol P450), indicating that this isoform catalysed the high-affinity component. Recombinant CYP1A2 and CYP2B6 exhibited high V(max) (88 and 71 pmol/min/pmol P450, respectively) and high Km (502 and 219 microM, respectively), suggesting their involvement in catalysing the low-affinity component. This study has demonstrated that CYP2E1 is the major enzyme responsible for high-affinity side chain hydroxylation of ethylbenzene in human liver microsomes. Activity of this enzyme in the population is highly variable due to induction or inhibition by physiological factors, chemicals in the diet or some pharmaceuticals. This variability can be incorporated into the risk assessment process to improve the setting of occupational exposure limits and guidance values for biological monitoring.

  19. Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.

    Science.gov (United States)

    Shimizu, Makiko; Suemizu, Hiroshi; Mitsui, Marina; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

    2017-10-01

    1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity - attributable to metabolites formed by cytochrome P450 enzymes - but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs. 2. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice. 3. Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans. 4. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized-liver mice and that control and humanized-liver mice mediated pomalidomide 5-hydroxylation in vivo. Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized-liver mice.

  20. 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

    -binding globulin-bound testosterone concentrations disappeared, however, when age, ethanol consumption, and severity of liver disease were included as covariates in the analysis. During follow-up (median 30 mo, range 1-48 mo) sexual dysfunction improved significantly (p less than 0.05) at 6, 12, and 24 mo......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....... Sexual dysfunction was significantly (p less than 0.05) associated with lower serum concentrations of testosterone, non-protein-bound testosterone, and non-sex hormone-binding globulin-bound testosterone. The significant associations between sexual dysfunction and non-protein-bound and non-sex hormone...

  1. High mortality in cirrhotic patients following hemorrhagic stroke.

    Science.gov (United States)

    Hung, Tsung-Hsing; Hsieh, Yu-Hsi; Tseng, Kuo-Chih; Tseng, Chih-Wei; Lee, Hsing-Feng; Tsai, Chih-Chun; Tsai, Chen-Chi

    2015-06-01

    The impact of hemorrhagic stroke (HS) on the mortality of cirrhotic patients is unknown. To evaluate the morality risk of HS in cirrhotic patients, we used the Taiwan National Health Insurance Database to evaluate cirrhotic patients with HS who were discharged between 1 January and 31 December 2007. In total, there were 321 cirrhotic patients with HS. We randomly selected 3210 cirrhotic patients without HS as a comparison group. The 30 and 90 day mortality rates were 29.6% and 43.0% in the HS group, and 9.1% and 17.7% in the comparison group, respectively (pmortality in the HS group was 3.89 (95% confidence interval [CI] 3.20-4.71, pmortality in the subarachnoid hemorrhage and other HS groups were 7.93 (95% CI 5.23-12.0, pmortality risk in cirrhotic patients, in whom subarachnoid hemorrhage can also increase the risk of mortality eight-fold. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Nakagawa, Shin-ichiro; Hirata, Yuichi; Kameyama, Takeshi; Tokunaga, Yuko; Nishito, Yasumasa; Hirabayashi, Kazuko; Yano, Junichi; Ochiya, Takahiro; Tateno, Chise; Tanaka, Yasuhito; Mizokami, Masashi; Tsukiyama-Kohara, Kyoko; Inoue, Kazuaki; Yoshiba, Makoto; Takaoka, Akinori; Kohara, Michinori

    2013-01-01

    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). 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. 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. 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.

  3. 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.

  4. Research advances in computed tomography and magnetic resonance imaging findings of cirrhotic portal hypertension

    Directory of Open Access Journals (Sweden)

    YAN Fuhua

    2016-06-01

    Full Text Available Portal hypertension is the most common complication of liver cirrhosis. Noninvasive radiological examinations have important values in evaluating liver parenchyma, collateral circulation, and esophagogastric variceal bleeding in liver cirrhosis. Computed tomography (CT and magnetic resonance imaging (MRI can reflect the changes in liver morphology, the density and signals of liver parenchyma, and hemodynamics and have important values in disease diagnosis and prognostic evaluation. CT and functional MRI, such as perfusion-weighted imaging, MR elastography, and MR diffusion-weighted imaging, can provide quantitative information and can be applied in the diagnosis of hepatic fibrosis and early-stage liver cirrhosis in clinical practice. CT angiography and MR angiography, especially unenhanced MR angiography, can show the condition of the branches of portal vein, which helps to evaluate the risk of esophagogastric variceal bleeding and detect the markers for early warning. A combination of CT and MRI and evaluation of their potential in clinical application can give full play to the role of radiological examinations in the diagnosis, evaluation, and prognostic analysis of cirrhotic portal hypertension.

  5. Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery.

    Science.gov (United States)

    Naritomi, Yoichi; Sanoh, Seigo; Ohta, Shigeru

    2018-02-01

    Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans; therefore, these mice are useful for predicting human drug metabolism and PK. In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  6. 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

  7. Comparative Metabolism Study of Five Protoberberine Alkaloids in Liver Microsomes from Rat, Rhesus Monkey, and Human.

    Science.gov (United States)

    Li, Yan; Zhou, Yanyan; Si, Nan; Han, Lingyu; Ren, Wei; Xin, Shaokun; Wang, Hongjie; Zuo, Ran; Wei, Xiaolu; Yang, Jian; Zhao, Haiyu; Bian, Baolin

    2017-11-01

    Protoberberine alkaloids including berberine, palmatine, jatrorrhizine, coptisine, and epiberberine are major components in many medicinal plants. They have been widely used for the treatment of cancer, inflammation, diabetes, depression, hypertension, and various infectious areas. However, the metabolism of five protoberberine alkaloids among different species has not been clarified previously. In order to elaborate on the in vitro metabolism of them, a comparative analysis of their metabolic profile in rat, rhesus monkey, and human liver microsomes was carried out using ultrahigh-performance liquid chromatography coupled with a high-resolution linear trap quadrupole-Orbitrap mass spectrometer (UHPLC-electrospray ionization-Orbitrap MS) for the first time. Each metabolite was identified and semiquantified by its accurate mass data and peak area. Fifteen metabolites were characterized based on accurate MS/MS spectra and the proposed MS/MS fragmentation pathways including demethylation, hydroxylation, and methyl reduction. Among them, the content of berberine metabolites in human liver microsomes was similar with those in rhesus monkey liver microsomes, whereas berberine in rat liver microsomes showed no demethylation metabolites and the content of metabolites showed significant differences with that in human liver microsomes. On the contrary, the metabolism of palmatine in rat liver microsomes resembled that in human liver microsomes. The content of jatrorrhizine metabolites presented obvious differences in all species. The HR-ESI-MS/MS fragmentation behavior of protoberberine alkaloids and their metabolic profile in rat, rhesus monkey, and human liver microsomes were investigated for the first time. The results demonstrated that the biotransformation characteristics of protoberberine alkaloids among different species had similarities as well differences that would be beneficial for us to better understand the pharmacological activities of protoberberine alkaloids

  8. 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.

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

    Science.gov (United States)

    Ramachandran, Sarada Devi; Schirmer, Katharina; Münst, Bernhard; Heinz, Stefan; Ghafoory, Shahrouz; Wölfl, Stefan; Simon-Keller, Katja; Marx, Alexander; Øie, Cristina Ionica; Ebert, Matthias P; Walles, Heike; Braspenning, Joris; Breitkopf-Heinlein, Katja

    2015-01-01

    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.

  10. Detection of driver metabolites in the human liver metabolic network using structural controllability analysis

    Science.gov (United States)

    2014-01-01

    Background Abnormal states in human liver metabolism are major causes of human liver diseases ranging from hepatitis to hepatic tumor. The accumulation in relevant data makes it feasible to derive a large-scale human liver metabolic network (HLMN) and to discover important biological principles or drug-targets based on network analysis. Some studies have shown that interesting biological phenomenon and drug-targets could be discovered by applying structural controllability analysis (which is a newly prevailed concept in networks) to biological networks. The exploration on the connections between structural controllability theory and the HLMN could be used to uncover valuable information on the human liver metabolism from a fresh perspective. Results We applied structural controllability analysis to the HLMN and detected driver metabolites. The driver metabolites tend to have strong ability to influence the states of other metabolites and weak susceptibility to be influenced by the states of others. In addition, the metabolites were classified into three classes: critical, high-frequency and low-frequency driver metabolites. Among the identified 36 critical driver metabolites, 27 metabolites were found to be essential; the high-frequency driver metabolites tend to participate in different metabolic pathways, which are important in regulating the whole metabolic systems. Moreover, we explored some other possible connections between the structural controllability theory and the HLMN, and find that transport reactions and the environment play important roles in the human liver metabolism. Conclusion There are interesting connections between the structural controllability theory and the human liver metabolism: driver metabolites have essential biological functions; the crucial role of extracellular metabolites and transport reactions in controlling the HLMN highlights the importance of the environment in the health of human liver metabolism. PMID:24885538

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

    International Nuclear Information System (INIS)

    Valletta, Daniela; Czech, Barbara; Thasler, Wolfgang E.; Müller, Martina; Bosserhoff, Anja-Katrin; Hellerbrand, Claus

    2012-01-01

    Highlights: ► The expression of the atypical cadherin FAT1 is increased in chronic liver disease. ► FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). ► Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. ► FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. ► 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 cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NFκB activity. This

  12. 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

  13. A microscale human liver platform that supports the hepatic stages of Plasmodium falciparum and vivax.

    Science.gov (United States)

    March, Sandra; Ng, Shengyong; Velmurugan, Soundarapandian; Galstian, Ani; Shan, Jing; Logan, David J; Carpenter, Anne E; Thomas, David; Sim, B Kim Lee; Mota, Maria M; Hoffman, Stephen L; Bhatia, Sangeeta N

    2013-07-17

    The Plasmodium liver stage is an attractive target for the development of antimalarial drugs and vaccines, as it provides an opportunity to interrupt the life cycle of the parasite at a critical early stage. However, targeting the liver stage has been difficult. Undoubtedly, a major barrier has been the lack of robust, reliable, and reproducible in vitro liver-stage cultures. Here, we establish the liver stages for both Plasmodium falciparum and Plasmodium vivax in a microscale human liver platform composed of cryopreserved, micropatterned human primary hepatocytes surrounded by supportive stromal cells. Using this system, we have successfully recapitulated the full liver stage of P. falciparum, including the release of infected merozoites and infection of overlaid erythrocytes, as well as the establishment of small forms in late liver stages of P. vivax. Finally, we validate the potential of this platform as a tool for medium-throughput antimalarial drug screening and vaccine development. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. 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.

  15. Determination of cobalt in human liver by atomic absorption spectrometry with electrothermal atomization

    International Nuclear Information System (INIS)

    Caldas, E.D.; Gine-Rosias, M.F.; Dorea, J.G.

    1991-01-01

    A detailed study of the use of electrothermal atomic absorption spectrometry for the determination of cobalt in human liver is described. Comparisons of sample digestion using nitric acid or nitric acid plus perchloric acid, atomization procedures and the application of palladium and magnesium nitrate chemical modifiers were studied using NBS SRM 1577a Bovine Liver. The best results were achieved with sample decomposition in nitric acid, atomization from the tube wall and no chemical modifier. Cobalt was determined in 90 samples of livers from foetuses and deceased newborns using the standard addition method with an average recovery of 99.8%. (author). 30 refs.; 4 figs.; 2 tabs

  16. 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.

  17. AMC-Bio-Artificial Liver culturing enhances mitochondrial biogenesis in human liver cell lines: The role of oxygen, medium perfusion and 3D configuration

    NARCIS (Netherlands)

    Adam, Aziza A. A.; van Wenum, Martien; van der Mark, Vincent A.; Jongejan, Aldo; Moerland, Perry D.; Houtkooper, Riekelt H.; Wanders, Ronald J. A.; Oude Elferink, Ronald P.; Chamuleau, Robert A. F. M.; Hoekstra, Ruurdtje

    2017-01-01

    Human liver cell lines, like HepaRG and C3A, acquire higher functionality when cultured in the AMC-Bio-Artificial Liver (AMC-BAL). The three main differences between BAL and monolayer culture are the oxygenation (40% vs 20%O2), dynamic vs absent medium perfusion and 3D vs 2D configuration. Here, we

  18. Dipeptidyl peptidase-4 greatly contributes to the hydrolysis of vildagliptin in human liver.

    Science.gov (United States)

    Asakura, Mitsutoshi; Fujii, Hideaki; Atsuda, Koichiro; Itoh, Tomoo; Fujiwara, Ryoichi

    2015-04-01

    The major metabolic pathway of vildagliptin in mice, rats, dogs, and humans is hydrolysis at the cyano group to produce a carboxylic acid metabolite M20.7 (LAY151), whereas the major metabolic enzyme of vildagliptin has not been identified. In the present study, we determined the contribution rate of dipeptidyl peptidase-4 (DPP-4) to the hydrolysis of vildagliptin in the liver. We performed hydrolysis assay of the cyano group of vildagliptin using mouse, rat, and human liver samples. Additionally, DPP-4 activities in each liver sample were assessed by DPP-4 activity assay using the synthetic substrate H-glycyl-prolyl-7-amino-4-methylcoumarin (Gly-Pro-AMC). M20.7 formation rates in liver microsomes were higher than those in liver cytosol. M20.7 formation rate was significantly positively correlated with the DPP-4 activity using Gly-Pro-AMC in liver samples (r = 0.917, P vildagliptin hydrolysis in the liver. Additionally, we established stable single expression systems of human DPP-4 and its R623Q mutant, which is the nonsynonymous single-nucleotide polymorphism of human DPP-4, in human embryonic kidney 293 (HEK293) cells to investigate the effect of R623Q mutant on vildagliptin-hydrolyzing activity. M20.7 formation rate in HEK293 cells expressing human DPP-4 was significantly higher than that in control HEK293 cells. Interestingly, R623Q mutation resulted in a decrease of the vildagliptin-hydrolyzing activity. Our findings might be useful for the prediction of interindividual variability in vildagliptin pharmacokinetics. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  19. The heart and the liver

    DEFF Research Database (Denmark)

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

    2009-01-01

    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...... 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...

  20. Anti-liver-kidney microsome antibody type 1 recognizes human cytochrome P450 db1.

    Science.gov (United States)

    Gueguen, M; Yamamoto, A M; Bernard, O; Alvarez, F

    1989-03-15

    Anti-liver-kidney microsome antibody type 1 (LKM1), present in the sera of a group of children with autoimmune hepatitis, was recently shown to recognize a 50 kDa protein identified as rat liver cytochromes P450 db1 and db2. High homology between these two members of the rat P450 IID subfamily and human P450 db1 suggested that anti-LKM1 antibody is directed against this human protein. To test this hypothesis, a human liver cDNA expression library in phage lambda GT-11 was screened using rat P450 db1 cDNA as a probe. Two human cDNA clones were found to be identical to human P450 db1 by restriction mapping. Immunoblot analysis using as antigen, the purified fusion protein from one of the human cDNA clones showed that only anti-LKM1 with anti-50 kDa reactivity recognized the fusion protein. This fusion protein was further used to develop an ELISA test that was shown to be specific for sera of children with this disease. These results: 1) identify the human liver antigen recognized by anti-LKM1 auto-antibodies as cytochrome P450 db1, 2) allow to speculate that mutation on the human P450 db1 gene could alter its expression in the hepatocyte and make it auto-antigenic, 3) provide a simple and specific diagnostic test for this disease.

  1. Cell Pleomorphism and Cytoskeleton Disorganization in Human Liver Cancer.

    Science.gov (United States)

    Cheng, Chiung-Chi; Lai, Yen-Chang Clark; Lai, Yih-Shyong; Chao, Wei-Ting; Tseng, Yu-Hui; Hsu, Yung-Hsiang; Chen, You-Yin; Liu, Yi-Hsiang

    Nucleoskeleton maintains the framework of a cell nucleus that is required for a variety of nuclear functions. However, the nature of nucleoskeleton structure has not been yet clearly elucidated due to microscopy visualization limitations. Plectin, a nuclear pore-permeable component of cytoskeleton, exhibits a role of cross-linking between cytoplasmic intermediate filaments and nuclear lamins. Presumably, plectin is also a part of nucleoskeleton. Previously, we demonstrated that pleomorphism of hepatoma cells is the consequence of cytoskeletal changes mediated by plectin deficiency. In this study, we applied a variety of technologies to detect the cytoskeletons in liver cells. The images of confocal microscopy did not show the existence of plectin, intermediate filaments, microfilaments and microtubules in hepatic nuclei. However, in the isolated nuclear preparation, immunohistochemical staining revealed positive results for plectin and cytoskeletal proteins that may contribute to the contamination derived from cytoplasmic residues. Therefore, confocal microscopy provides a simple and effective technology to observe the framework of nucleoskeleton. Accordingly, we verified that cytoskeletons are not found in hepatic cell nuclei. Furthermore, the siRNA-mediated knockdown of plectin in liver cells leads to collapsed cytoskeleton, cell transformation and pleomorphic nuclei. Plectin and cytoskeletons were not detected in the nuclei of liver cells compared to the results of confocal microscopy. Despite the absence of nuclear plectin and cytoskeletal filaments, the evidence provided support that nuclear pleomorphism of cancer cells is correlated with the cytoplasmic disorganization of cytoskeleton. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. 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.

  3. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    International Nuclear Information System (INIS)

    Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro; Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro

    2014-01-01

    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

  4. 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.

  5. Differentiation of cirrhotic vs idiopathic portal hypertension using /sup 99m/Tc-Sn colloid dynamic and static scintigraphy

    International Nuclear Information System (INIS)

    Qureshi, H.; Zuberi, S.J.; Alam, S.E.; Kamal, S.; Khan, R.A.

    1991-01-01

    Thirty seven cases of portal hypertension with endoscopically proven oesophageal varices underwent liver biopsy to determine the etiology hypertension. Of the total, 19 had idiopathic hypertension (IPH). Later all these patients udnderwent Tc/sup 99m/Sn colloid, static and dynamic scintigraphy of the liver and spleen. Ratios of the area and of the integral and slope of the integral for liver and spleen were calculated to see if any of these ratios can differentiate cirrhotics from IPH. Significant difference was noted in the ratio of the area (L/S) in both patients and controls, but the ratios of the integral and the slope of the integral were not only significantly different in the patients and controls but also in the two groups of patients (cirrosis and IPH). The sensitivity of this test when compared with the histology was 58% for both cirrosis and IPH but when compared with clinical diagnosis it was 76% for cirrosis and 62% for idiophatic group. Therefore by adding the above mentioned test in the routine study of liver scintigraphy in patients with portal hypertension, further differentiation of cirrhotic group can be done from idiophatic group. (author)

  6. All-In-One: Advanced preparation of Human Parenchymal and Non-Parenchymal Liver Cells.

    Directory of Open Access Journals (Sweden)

    Melanie Werner

    Full Text Available Liver cells are key players in innate immunity. Thus, studying primary isolated liver cells is necessary for determining their role in liver physiology and pathophysiology. In particular, the quantity and quality of isolated cells are crucial to their function. Our aim was to isolate a large quantity of high-quality human parenchymal and non-parenchymal cells from a single liver specimen.Hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and stellate cells were isolated from liver tissues by collagenase perfusion in combination with low-speed centrifugation, density gradient centrifugation, and magnetic-activated cell sorting. The purity and functionality of cultured cell populations were controlled by determining their morphology, discriminative cell marker expression, and functional activity.Cell preparation yielded the following cell counts per gram of liver tissue: 2.0 ± 0.4 × 10(7 hepatocytes, 1.8 ± 0.5 × 10(6 Kupffer cells, 4.3 ± 1.9 × 10(5 liver sinusoidal endothelial cells, and 3.2 ± 0.5 × 10(5 stellate cells. Hepatocytes were identified by albumin (95.5 ± 1.7% and exhibited time-dependent activity of cytochrome P450 enzymes. Kupffer cells expressed CD68 (94.5 ± 1.2% and exhibited phagocytic activity, as determined with 1 μm latex beads. Endothelial cells were CD146(+ (97.8 ± 1.1% and exhibited efficient uptake of acetylated low-density lipoprotein. Hepatic stellate cells were identified by the expression of α-smooth muscle actin (97.1 ± 1.5%. These cells further exhibited retinol (vitamin A-mediated autofluorescence.Our isolation procedure for primary parenchymal and non-parenchymal liver cells resulted in cell populations of high purity and quality, with retained physiological functionality in vitro. Thus, this system may provide a valuable tool for determining liver function and disease.

  7. [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.

  8. Changes in cardiac output and incidence of volume overload in cirrhotics receiving 20% albumin infusion.

    Science.gov (United States)

    Shasthry, Saggere M; Kumar, Manoj; Khumuckham, Jelen S; Sarin, Shiv Kumar

    2017-08-01

    Patients with cirrhosis are prone to develop volume over load, have increased capillary permeability and latent or overt cardiomyopathy. Whether albumin infusion causes volume overload in cirrhotics has not been adequately studied. Ninety nine consecutive cirrhotic patients receiving 1gm per kg albumin infusion were evaluated for development of volume overload. Clinical, echocardiographic and haemodynamic changes were closely monitored during and after albumin infusion. Thirty (30.30%) patients developed volume overload. Patients with higher BMI (P=.003), lower CTP (P=.01) and MELD (P=.034) were more often associated with the development of volume overload. Though baseline diastolic dysfunction was present in 82.8% of the patients, it did not influence the development of volume overload or changes in the cardiac output. The cardiac output increased significantly after albumin infusion (4.9±1.554 L/min to 5.86±1.85 L/min, Palbumin infusion develop volume overload, specially, those with higher BMI and lower severity of liver disease. Cardiac output increases after albumin infusion, and, baseline diastolic dysfunction has little effect on the development of volume overload or changes in cardiac output. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Efficacy of CT portography in the evaluation of cirrhotic patients for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Oliver, J.H. III; Baron, R.L.; Dodd, G.D. III; Carr, B.I.; Van Thiel, D.

    1991-01-01

    CT portography (CTAP) is sensitive in the detection of liver neoplasms. However, this paper reports on a high technical failure rate in cirrhotic patients and the authors review the usefulness of CTAP in these patients at risk for hepatoma. To date, the authors have evaluated 43 cirrhotic patients with CTAP with use of 120-150 mL of 60% iodinated contrast material at 1.0-1.5 mL/sec. Scans were evaluated for the presence and enhancement of collateral vessels. Lover parenchyma enhancement was evaluated as homogeneous or heterogeneous. The degree of enhancement was categorized as poor, moderate, or good based on maximal postcontrast attenuation. A determination of the presence and location of flow artifacts simulating thrombus in the portal vein was made. Twenty of 43 examination were technical failures, with 6 portosystemic shunts and large varices siphoning contrast material in 7. In 7 of the failures, no varices or shunts were present. Twenty-three of 43 examinations had acceptable enhancement, but 9 had heterogeneous regions of decreased enhancement, not due to tumor, that could obscure or be confused with small tumor foci

  10. 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.

  11. Screening of 110 cirrhotic patients for hepatitis B and C at Saidu Teaching Hospital, Saidu Sharif, Swat

    International Nuclear Information System (INIS)

    Khan, P.; Ahmad, A.; Ahmad, B.; Khan, T.M.

    2009-01-01

    Cirrhosis liver is amongst the commonest clinical conditions in Pakistan. Besides other causes, it is mostly related to previous viral infection, in this part of the world. The main objective of this study was to find the frequency of HBsAg and anti HCV in cirrhotic patients of Swat district. This Prospective Study was conducted in the Medical unit of Saidu Teaching Hospital, Saidu Sharif from January 2006 to December 2006. One hundred and ten Cirrhotic Patients, 62 Male and 48 Female aged from 14 to 75 years were included in this study. Sera were tested by third generation Elisa method. Fifty-nine out of 110 (53.6%) patients were positive for anti HCV antibodies. Twenty-four (21.81%) Patients were positive for HBsAg. Eleven (10%) patients were positive for both HBsAg and anti HCV anti bodies. Sixteen (14.54%) were negative for both sero maker of hepatitis B and C. It is evident from this study that Hepatitis C, is a leading cause of cirrhosis in District Swat followed by HBV. Both the viruses account for at least three fourths of the total Cirrhotic. (Author)

  12. Circulating levels of 3-hydroxymyristate, a direct quantification of endotoxemia in non-infected cirrhotic patients.

    Science.gov (United States)

    Weil, Delphine; Pais de Barros, Jean-Paul; Mourey, Guillaume; Laheurte, Caroline; Cypriani, Benoit; Badet, Nicolas; Delabrousse, Eric; Grandclément, Emilie; Di Martino, Vincent; Saas, Philippe; Lagrost, Laurent; Thévenot, Thierry

    2018-06-22

    The quantification of lipopolysaccharide (LPS) in biological fluids is challenging. We aimed to measure plasma LPS concentration using a new method of direct quantification of 3-hydroxymyristate (3-HM), a lipid component of LPS, and to evaluate correlations between 3-HM and markers of liver function, endothelial activation, portal hypertension and enterocyte damage. Plasma from 90 non-infected cirrhotic patients (30 Child-Pugh [CP]-A, 30 CP-B, 30 CP-C) was prospectively collected. The concentration of 3-HM was determined by High Performance Liquid Chromatography coupled with Mass Spectrometry. 3-HM levels were higher in CP-C patients (CP-A/CP-B/CP-C: 68/70/103 ng/mL, p=0.005). Patients with severe acute alcoholic hepatitis (n=16; 113 vs 74 ng/mL,p=0.012), diabetic patients (n=22; 99 vs 70 ng/mL, p=0.028) and those not receiving beta-blockers (n=44; 98 vs 72 ng/mL, p=0.034) had higher levels of 3-HM. We observed a trend towards higher baseline levels of 3-HM in patients with hepatic encephalopathy (n=7; 144 vs 76 ng/mL, p=0.45) or SIRS (n=10; 106 vs 75 ng/mL, p=0.114). In multivariate analysis, high levels of 3-HM were associated with CP (OR=4.39; 95%CI=1.79-10.76) or MELD (OR=8.24; 95%CI=3.19-21.32) scores. Patients dying from liver insufficiency (n=6) during a 12-month follow-up had higher baseline levels of 3-HM (106 vs 75 ng/mL, p=0.089). In non-infected cirrhotic patients, 3-HM arises more frequently with impairment of liver function, heavy alcohol consumption, diabetic status, non-use of beta-blockers, and a trend towards poorer outcome is also observed. The direct mass-measurement of LPS using 3-HM appears reliable to detect transient endotoxemia and promising to manage the follow-up of cirrhotic patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  13. Effect of ultrasound frequency on the Nakagami statistics of human liver tissues.

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    Po-Hsiang Tsui

    Full Text Available 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 < 0.0001. However, the effect of ultrasound frequency on the 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. Intranasal desmopressin versus blood transfusion in cirrhotic patients with coagulopathy undergoing dental extraction: a randomized controlled trial.

    Science.gov (United States)

    Stanca, Carmen M; Montazem, Andre H; Lawal, Adeyemi; Zhang, Jin X; Schiano, Thomas D

    2010-01-01

    Cirrhotic patients waiting for liver transplantation who need dental extractions are given fresh frozen plasma and/or platelets to correct coagulopathy. This is costly and may be associated with transfusion reactions and fluid overload. We evaluated the efficacy of intranasal desmopressin as an alternative to transfusion to correct the coagulopathy of cirrhotic patients undergoing dental extraction. Cirrhotic patients with platelet counts of 30,000 to 50,000/microL and/or international normalized ratio (INR) 2.0 to 3.0 were enrolled in a prospective, controlled, randomized clinical trial. Blood transfusion (fresh frozen plasma 10 mL/kg and/or 1 unit of single donor platelets, respectively) or intranasal desmopressin (300 microg) were given before dental extraction. A standard oral and maxillofacial surgical treatment protocol was performed by the same surgeon. Patients were followed for postextraction bleeding and side-effects over the next 24 to 48 hours. No significant differences were noted between the 2 groups in gender, age, INR, platelet count, creatinine, total bilirubin, ALT, albumin, MELD score, or number of teeth removed (median 3 vs 4). The number of teeth removed ranged between 1 and 31 in the desmopressin group and 1 and 22 in the transfusion group. No patients in desmopressin group required rescue blood transfusion after extraction. One patient in the transfusion group had bleeding after the procedure and required an additional transfusion. Another patient experienced an allergic reaction at the end of transfusion, which was effectively treated with diphenhydramine. Treatment associated average costs were lower for desmopressin ($700/patient) compared with transfusion ($1,173/patient). Intranasal desmopressin was as effective as blood transfusion in achieving hemostasis in cirrhotic patients with moderate coagulopathy undergoing dental extraction. Intranasal desmopressin was much more convenient, less expensive, and well tolerated.

  15. Alloxan-Induced Diabetes Causes Morphological and Ultrastructural Changes in Rat Liver that Resemble the Natural History of Chronic Fatty Liver Disease in Humans

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    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.

  16. The Use of an Acellular Oxygen Carrier in a Human Liver Model of Normothermic Machine Perfusion.

    Science.gov (United States)

    Laing, Richard W; Bhogal, Ricky H; Wallace, Lorraine; Boteon, Yuri; Neil, Desley A H; Smith, Amanda; Stephenson, Barney T F; Schlegel, Andrea; Hübscher, Stefan G; Mirza, Darius F; Afford, Simon C; Mergental, Hynek

    2017-11-01

    Normothermic machine perfusion of the liver (NMP-L) is a novel technique that preserves liver grafts under near-physiological conditions while maintaining their normal metabolic activity. This process requires an adequate oxygen supply, typically delivered by packed red blood cells (RBC). We present the first experience using an acellular hemoglobin-based oxygen carrier (HBOC) Hemopure in a human model of NMP-L. Five discarded high-risk human livers were perfused with HBOC-based perfusion fluid and matched to 5 RBC-perfused livers. Perfusion parameters, oxygen extraction, metabolic activity, and histological features were compared during 6 hours of NMP-L. The cytotoxicity of Hemopure was also tested on human hepatic primary cell line cultures using an in vitro model of ischemia reperfusion injury. The vascular flow parameters and the perfusate lactate clearance were similar in both groups. The HBOC-perfused livers extracted more oxygen than those perfused with RBCs (O2 extraction ratio 13.75 vs 9.43 % ×10 per gram of tissue, P = 0.001). In vitro exposure to Hemopure did not alter intracellular levels of reactive oxygen species, and there was no increase in apoptosis or necrosis observed in any of the tested cell lines. Histological findings were comparable between groups. There was no evidence of histological damage caused by Hemopure. Hemopure can be used as an alternative oxygen carrier to packed red cells in NMP-L perfusion fluid.

  17. Proton MR spectroscopic features of the human liver: in-vivo application to the normal condition

    International Nuclear Information System (INIS)

    Cho, Soon Gu; Kim, Mi Young; Kim, Young Soo; Choi, Won; Shin, Seok Hwan; Ok, Chul Soo; Suh, Chang Hae

    1999-01-01

    To determine the feasibility of MR spectroscopy in the living human liver, and to evaluate the corresponding proton MR spectroscopic features. In fifteen normal volunteers with neither previous nor present liver disease, the proton MR spectroscopic findings were reviewed. Twelve subjects were male and three were female ; they were aged between 28 and 32 (mean, 30) years. MR spectroscopy involved the use of a 1.5T GE Signa Horizon system with body coil(GE Medical System, Milwaukee, U.S.A). We used STEAM (Stimulated Echo-Acquisition Mode) with 3000/30 msec of TR/TE for signal acquisition, and the prone position without respiratory interruption. Mean and standard deviation of the ratios of glutamate+glutamine/lipids, phosphomonoesters/lipids, and glycogen+glucose/lipids were calculated from the area of their peaks. The proton MR spectroscopic findings of normal human livers showed four distinctive peaks, i.e. lipids, glutamate and glutamine complex, phosphomonoesters, and glycogen and glucose complex. The mean and standard deviation of the ratios of glutamate+glutamine/lipids, phosphomonoesters/lipids, and glycogen+glucose/lipids were 0.02±0.01, 0.01±0.01, and 0.04±0.03, respectively. In living normal human livers, MR spectroscopy can be successfully applied. When applied to a liver whose condition is pathologic, the findings can be used as a standard

  18. Human Liver Cells Expressing Albumin and Mesenchymal Characteristics Give Rise to Insulin-Producing Cells

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    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. Gene discovery for the carcinogenic human liver fluke, Opisthorchis viverrini

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    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

  20. Control of oxygen tension recapitulates zone-specific functions in human liver microphysiology systems.

    Science.gov (United States)

    Lee-Montiel, Felipe T; George, Subin M; Gough, Albert H; Sharma, Anup D; Wu, Juanfang; DeBiasio, Richard; Vernetti, Lawrence A; Taylor, D Lansing

    2017-10-01

    This article describes our next generation human Liver Acinus MicroPhysiology System (LAMPS). The key demonstration of this study was that Zone 1 and Zone 3 microenvironments can be established by controlling the oxygen tension in individual devices over the range of ca. 3 to 13%. The oxygen tension was computationally modeled using input on the microfluidic device dimensions, numbers of cells, oxygen consumption rates of hepatocytes, the diffusion coefficients of oxygen in different materials and the flow rate of media in the MicroPhysiology System (MPS). In addition, the oxygen tension was measured using a ratiometric imaging method with the oxygen sensitive dye, Tris(2,2'-bipyridyl) dichlororuthenium(II) hexahydrate (RTDP) and the oxygen insensitive dye, Alexa 488. The Zone 1 biased functions of oxidative phosphorylation, albumin and urea secretion and Zone 3 biased functions of glycolysis, α1AT secretion, Cyp2E1 expression and acetaminophen toxicity were demonstrated in the respective Zone 1 and Zone 3 MicroPhysiology System. Further improvements in the Liver Acinus MicroPhysiology System included improved performance of selected nonparenchymal cells, the inclusion of a porcine liver extracellular matrix to model the Space of Disse, as well as an improved media to support both hepatocytes and non-parenchymal cells. In its current form, the Liver Acinus MicroPhysiology System is most amenable to low to medium throughput, acute through chronic studies, including liver disease models, prioritizing compounds for preclinical studies, optimizing chemistry in structure activity relationship (SAR) projects, as well as in rising dose studies for initial dose ranging. Impact statement Oxygen zonation is a critical aspect of liver functions. A human microphysiology system is needed to investigate the impact of zonation on a wide range of liver functions that can be experimentally manipulated. Because oxygen zonation has such diverse physiological effects in the liver, we

  1. Liver transplantation for NASH cirrhosis is not performed at the expense of major post-operative morbidity

    NARCIS (Netherlands)

    van den Berg, Eline H.; Douwes, Rianne M.; de Meijer, Vincent E.; Schreuder, Tim C. M. A.; Blokzijl, Hans

    Background: Non-alcoholic steatohepatitis (NASH) is an emerging indication for liver transplantation (LT) and coexists with multiple comorbidities. Obese and cirrhotic patients experience more perioperative complications. Limited data exist about short-term complications after LT for NASH cirrhosis.

  2. Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors

    International Nuclear Information System (INIS)

    Pasquinelli, C.; Garreau, F.; Bougueleret, L.; Cariani, E.; Thiers, V.; Croissant, O.; Hadchouel, M.; Tiollais, P.; Brechot, C.; Grzeschik, K.H.

    1988-01-01

    Hepatitis B virus (HBV) DNA integration has been shown to occur frequently in human hepatocellular carcinomas. The authors have investigated whether common cellular DNA domains might be rearranged, possibly by HBV integration, in human primary liver tumors. Unique cellular DNA sequences adjacent to an HBV integration site were isolated from a patient with hepatitis B surface antigen-positive hepatocellular carcinoma. These probes detected rearrangement of this cellular region of chromosomal DNA in 3 of 50 additional primary liver tumors studied. Of these three tumor samples, two contained HBV DNA, without an apparent link between the viral DNA and the rearranged allele; HBV DNA sequences were not detected in the third tumor sample. By use of a panel of somatic cell hybrids, these unique cellular DNA sequences were shown to be located on chromosome 4. Therefore, this region of chromosomal DNA might be implicated in the formation of different tumors at one step of liver cell transformation, possible related to HBV integration

  3. Hepatic ADC value correlates with cirrhotic severity of patients with biliary atresia

    International Nuclear Information System (INIS)

    Mo, Yuan Heng; Jaw, Fu Shan; Ho, Ming Chih; Wang, Yung Cheng; Peng, Steven Shinn Forng

    2011-01-01

    Introduction: At least 40% of survivors of biliary atresia have progressive cirrhosis even after undergoing Kasai operation. The values of hepatic apparent diffusion coefficient and apparent-diffusion-coefficient-related indices were applied to biliary atresia patients and correlated with cirrhotic severity scores of model for end-stage liver disease or pediatric end-stage liver disease model, Child-Turcotte, and Child-Pugh systems. Materials and methods: Thirty-three biliary atresia patents (mean = 1140, 61–4314 days of age) received magnetic resonance image examinations due to complications of biliary atresia from April 2008 to August 2009. Two non-breath-hold diffusion weighted imaging sequences were performed with motion-probing gradients in three directions with two b values: 0/100 and 0/500 s/mm 2 ; 1000 ms/61.1 ms, time to repeat/time to echo; number of excitation, 1.0; 8 mm section thickness; 40 cm × 40 cm field of view; 128 × 256 matrix in all biliary atresia patients and 18 control subjects. We used the Spearman rank correlation test to analyze the relationship among the scores of model for end-stage liver disease or pediatric end-stage liver disease model, Child-Turcotte and Child-Pugh scores and right hepatic apparent diffusion coefficients, apparent diffusion coefficient using b factor of 500-albumin product and alanine transaminase/apparent diffusion coefficient with b factor of 500 ratio. Results: The right hepatic apparent diffusion coefficient using b factor of 100, apparent diffusion coefficient with b factor of 500 and product of apparent diffusion coefficient with b factor of 500-albumin level were significantly negatively correlated (p ≤ 0.0125) with model for end-stage liver disease or pediatric end-stage liver disease model, Child-Turcotte, and Child-Pugh scores of biliary atresia patients. The ratio of alanine transaminase level/right hepatic apparent diffusion coefficient with b factor of 500 was also significantly (p ≤ 0

  4. Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery.

    Science.gov (United States)

    Kizawa, Hideki; Nagao, Eri; Shimamura, Mitsuru; Zhang, Guangyuan; Torii, Hitoshi

    2017-07-01

    The liver plays a central role in metabolism. Although many studies have described in vitro liver models for drug discovery, to date, no model has been described that can stably maintain liver function. Here, we used a unique, scaffold-free 3D bio-printing technology to construct a small portion of liver tissue that could stably maintain drug, glucose, and lipid metabolism, in addition to bile acid secretion. This bio-printed normal human liver tissue maintained expression of several kinds of hepatic drug transporters and metabolic enzymes that functioned for several weeks. The bio-printed liver tissue displayed glucose production via cAMP/protein kinase A signaling, which could be suppressed with insulin. Bile acid secretion was also observed from the printed liver tissue, and it accumulated in the culture medium over time. We observed both bile duct and sinusoid-like structures in the bio-printed liver tissue, which suggested that bile acid secretion occurred via a sinusoid-hepatocyte-bile duct route. These results demonstrated that our bio-printed liver tissue was unique, because it exerted diverse liver metabolic functions for several weeks. In future, we expect our bio-printed liver tissue to be applied to developing new models that can be used to improve preclinical predictions of long-term toxicity in humans, generate novel targets for metabolic liver disease, and evaluate biliary excretion in drug development.

  5. Transplant of Hepatocytes, Undifferentiated Mesenchymal Stem Cells, and In Vitro Hepatocyte-Differentiated Mesenchymal Stem Cells in a Chronic Liver Failure Experimental Model: A Comparative Study.

    Science.gov (United States)

    El Baz, Hanan; Demerdash, Zeinab; Kamel, Manal; Atta, Shimaa; Salah, Faten; Hassan, Salwa; Hammam, Olfat; Khalil, Heba; Meshaal, Safa; Raafat, Inas

    2018-02-01

    Liver transplant is the cornerstone line of treatment for chronic liver diseases; however, the long list of complications and obstacles stand against this operation. Searching for new modalities for treatment of chronic liver illness is a must. In the present research, we aimed to compare the effects of transplant of undifferentiated human mesenchymal stem cells, in vitro differentiated mesenchymal stem cells, and adult hepatocytes in an experimental model of chronic liver failure. Undifferentiated human cord blood mesenchymal stem cells were isolated, pro-pagated, and characterized by morphology, gene expression analysis, and flow cytometry of surface markers and in vitro differentiated into hepatocyte-like cells. Rat hepatocytes were isolated by double perfusion technique. An animal model of chronic liver failure was developed, and undifferentiated human cord blood mesenchymal stem cells, in vitro hepato-genically differentiated mesenchymal stem cells, or freshly isolated rat hepatocytes were transplanted into a CCL4 cirrhotic experimental model. Animals were killed 3 months after transplant, and liver functions and histopathology were assessed. Compared with the cirrhotic control group, the 3 cell-treated groups showed improved alanine aminotransferase, aspartate aminotransferase, albumin, and bilirubin levels, with best results shown in the hepatocyte-treated group. Histopathologic examination of the treated groups showed improved fibrosis, with best results obtained in the undifferentiated mesenchymal stem cell-treated group. Both adult hepatocytes and cord blood mesenchymal stem cells proved to be promising candidates for cell-based therapy in liver regeneration on an experimental level. Improved liver function was evident in the hepatocyte-treated group, and fibrosis control was more evident in the undifferentiated mesenchymal stem cell-treated group.

  6. Suppression of Human Liver Cancer Cell Migration and Invasion via the GABAA Receptor

    International Nuclear Information System (INIS)

    Chen, Zhi-ao; Bao, Mei-yan; Xu, Yong-fen; Zha, Ruo-peng; Shi, Hai-bing; Chen, Tao-yang; He, Xiang-huo

    2012-01-01

    To investigate the roles of the γ-aminobutyric acid (GABA) in the metastasis of hepatocellular carcinoma (HCC) and to explore the potential of a novel therapeutic approach for the treatment of HCC. The expression levels of GABA receptor subunit genes in various HCC cell lines and patients‘ tissues were detected by quantitative real-time polymerase chain reaction and Western blot analysis. Transwell cell migration and invasion assays were carried out for functional analysis. The effects of GABA on liver cancer cell cytoskeletal were determined by immunofluorescence staining. And the effects of GABA on HCC metastasis in nude mice were evaluated using an in vivo orthotopic model of liver cancer. The mRNA level of GABA receptor subunits varied between the primary hepatocellular carcinoma tissue and the adjacent non-tumor liver tissue. GABA inhibited human liver cancer cell migration and invasion via the ionotropic GABA A receptor as a result of the induction of liver cancer cell cytoskeletal reorganization. Pretreatment with GABA also significantly reduced intrahepatic liver metastasis and primary tumor formation in vivo. These findings introduce a potential and novel therapeutic approach for the treatment of cancer patients based on the modulation of the GABAergic system

  7. 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...

  8. Detection of titanium particles in human liver and spleen and possible health implications

    NARCIS (Netherlands)

    Heringa, M.B.; Peters, R.J.B.; Bleys, R.L.A.W.; Lee, van der M.K.; Tromp, P.C.; Kesteren, van P.C.E.; Eijkeren, van J.C.H.; Undas, A.K.; Oomen, A.G.; Bouwmeester, H.

    2018-01-01

    Background: Titanium dioxide (TiO2) is produced at high volumes and applied in many consumer and food products. Recent toxicokinetic modelling indicated the potential of TiO2 to accumulate in human liver and spleen upon daily oral exposure, which is not routinely investigated in chronic animal

  9. Microsomal UDP-glucuronyltransferase-catalyzed bilirubin diglucuronide formation in human liver

    NARCIS (Netherlands)

    Peters, W. H.; Jansen, P. L.

    1986-01-01

    Human liver microsomal bilirubin UDP-glucuronyltransferase catalyzes formation of bilirubin mono- and diglucuronide. KmUDPGA and Vmax of the enzyme are 0.6 mM and 1.69 nmol/mg protein X min. In vitro, bilirubin readily dissolves in the microsomal lipid phase. Taking this into account a Kmbilirubin

  10. MicroRNA-mediated suppression of oncolytic adenovirus replication in human liver.

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    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.

  11. The draft genome of the carcinogenic human liver fluke Clonorchis sinensis

    Science.gov (United States)

    2011-01-01

    Background Clonorchis sinensis is a carcinogenic human liver fluke that is widespread in Asian countries. Increasing infection rates of this neglected tropical disease are leading to negative economic and public health consequences in affected regions. Experimental and epidemiological studies have shown a strong association between the incidence of cholangiocarcinoma and the infection rate of C. sinensis. To aid research into this organism, we have sequenced its genome. Results We combined de novo sequencing with computational techniques to provide new information about the biology of this liver fluke. The assembled genome has a total size of 516 Mb with a scaffold N50 length of 42 kb. Approximately 16,000 reliable protein-coding gene models were predicted. Genes for the complete pathways for glycolysis, the Krebs cycle and fatty acid metabolism were found, but key genes involved in fatty acid biosynthesis are missing from the genome, reflecting the parasitic lifestyle of a liver fluke that receives lipids from the bile of its host. We also identified pathogenic molecules that may contribute to liver fluke-induced hepatobiliary diseases. Large proteins such as multifunctional secreted proteases and tegumental proteins were identified as potential targets for the development of drugs and vaccines. Conclusions This study provides valuable genomic information about the human liver fluke C. sinensis and adds to our knowledge on the biology of the parasite. The draft genome will serve as a platform to develop new strategies for parasite control. PMID:22023798

  12. 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

  13. Human liver cell trafficking mutants: characterization and whole exome sequencing.

    Directory of Open Access Journals (Sweden)

    Fei Yuan

    Full Text Available The HuH7 liver cell mutant Trf1 is defective in membrane trafficking and is complemented by the casein kinase 2α subunit CK2α''. Here we identify characteristic morphologies, trafficking and mutational changes in six additional HuH7 mutants Trf2-Trf7. Trf1 cells were previously shown to be severely defective in gap junction functions. Using a Lucifer yellow transfer assay, remarkable attenuation of gap junction communication was revealed in each of the mutants Trf2-Trf7. Electron microscopy and light microscopy of thiamine pyrophosphatase showed that several mutants exhibited fragmented Golgi apparatus cisternae compared to parental HuH7 cells. Intracellular trafficking was investigated using assays of transferrin endocytosis and recycling and VSV G secretion. Surface binding of transferrin was reduced in all six Trf2-Trf7 mutants, which generally correlated with the degree of reduced expression of the transferrin receptor at the cell surface. The mutants displayed the same transferrin influx rates as HuH7, and for efflux rate, only Trf6 differed, having a slower transferrin efflux rate than HuH7. The kinetics of VSV G transport along the exocytic pathway were altered in Trf2 and Trf5 mutants. Genetic changes unique to particular Trf mutants were identified by exome sequencing, and one was investigated in depth. The novel mutation Ile34Phe in the GTPase RAB22A was identified in Trf4. RNA interference knockdown of RAB22A or overexpression of RAB22AI34F in HuH7 cells caused phenotypic changes characteristic of the Trf4 mutant. In addition, the Ile34Phe mutation reduced both guanine nucleotide binding and hydrolysis activities of RAB22A. Thus, the RAB22A Ile34Phe mutation appears to contribute to the Trf4 mutant phenotype.

  14. 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.

  15. Development of Murine Cyp3a Knockout Chimeric Mice with Humanized Liver.

    Science.gov (United States)

    Kato, Kota; Ohbuchi, Masato; Hamamura, Satoko; Ohshita, Hiroki; Kazuki, Yasuhiro; Oshimura, Mitsuo; Sato, Koya; Nakada, Naoyuki; Kawamura, Akio; Usui, Takashi; Kamimura, Hidetaka; Tateno, Chise

    2015-08-01

    We developed murine CYP3A knockout ko chimeric mice with humanized liver expressing human P450S similar to those in humans and whose livers and small intestines do not express murine CYP3A this: approach may overcome effects of residual mouse metabolic enzymes like Cyp3a in conventional chimeric mice with humanized liver, such as PXB-mice [urokinase plasminogen activator/severe combined immunodeficiency (uPA/SCID) mice repopulated with over 70% human hepatocytes] to improve the prediction of drug metabolism and pharmacokinetics in humans. After human hepatocytes were transplanted into Cyp3a KO/uPA/SCID host mice, human albumin levels logarithmically increased until approximately 60 days after transplantation, findings similar to those in PXB-mice. Quantitative real-time-polymerase chain reaction analyses showed that hepatic human P450s, UGTs, SULTs, and transporters mRNA expression levels in Cyp3a KO chimeric mice were also similar to those in PXB-mice and confirmed the absence of Cyp3a11 mRNA expression in mouse liver and intestine. Findings for midazolam and triazolam metabolic activities in liver microsomes were comparable between Cyp3a KO chimeric mice and PXB-mice. In contrast, these activities in the intestine of Cyp3a KO chimeric mice were attenuated compared with PXB-mice. Owing to the knockout of murine Cyp3a, hepatic Cyp2b10 and 2c55 mRNA levels in Cyp3a KO/uPA/SCID mice (without hepatocyte transplants) were 8.4- and 61-fold upregulated compared with PXB-mice, respectively. However, human hepatocyte transplantation successfully restored Cyp2b10 level nearly fully and Cyp2c55 level partly (still 13-fold upregulated) compared with those in PXB-mice. Intestinal Cyp2b10 and 2c55 were also repressed by human hepatocyte transplantation in Cyp3a KO chimeric mice. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  16. 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.

  17. Metabolism of 5-fluorouracil in human liver: an in vivo 19F NMR study

    International Nuclear Information System (INIS)

    Mohankrishnan, P.; Sprigg, J.; Cardwell, D.; Komoroski, R.A.; Hutchins, L.; Nauke, S.; Williamson, M.R.; Jagannathan, N.R.

    1999-01-01

    In vivo fluorine-19 nuclear magnetic resonance ( 19 F NMR) spectroscopy was used to study the metabolism and pharmacokinetics of 5-fluorouracil (5-FU) in human liver. Nine patients received 5-FU, and additional chemotherapeutic agents (methotrexate, leucovorin, or levamisole) either prophylactically after breast cancer surgery or for colorectal cancer. The time constant for the disappearance of 5-FU from the liver in vivo varied from 5 to 17 min, while the time constant for the appearance of α-fluoro-β-alanine (the major catabolite of 5 FU) varied from 7 to 86 min. The modulators of 5-FU metabolism did not appear to affect the time constant for the disappearance of 5-FU from the liver or for the appearance of α-fluoro-β-alanine. Results obtained indicate that the pharmacokinetics of 5-FU and α-fluoro-β-alanine may vary substantially at different times in a given individual. (author)

  18. The Role of Serum Leptin and IL-6 Levels in Post Viral Hepatitis Cirrhotic patients

    International Nuclear Information System (INIS)

    Mohamed, S.K.

    2010-01-01

    Chronic liver disease is characterized by numerous metabolic alterations resulting in the clinical picture of malnutrition or even cachexia and contributing to complications such as hepatic encephalopathy and ascites. Leptin is a hormone that plays an important role in regulating energy intake and expenditure including appetite and metabolism. Interleukin-6 (IL-6), on the other hand, is generally considered to be one of the important cytokines that regulate immunologic and metabolic actions. The aim of the present study was to investigate serum leptin and IL-6 levels in liver cirrhosis, as well as to determine their levels in relation to liver functions and lipid profile. This study was conducted on 25 patients with post- viral hepatic cirrhosis compared to 20 healthy matched individuals served as controls with the same age and sex. The severity of the disease assessed with Child-Pugh criteria yielded 8 patients (3 women, 5 men) with stage A, 10 patients (4 women, 6 men) with stage B and 7 patients (2 women, 5 men) with stage C. Compared to controls, body mass index (BMI) was decreased and reached statistical significance in group C liver cirrhosis (P< 0.05). Also, serum leptin level was highly significantly decreased in the three groups, while IL-6 level showed highly significant increase. Leptin level negatively correlated with aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin and positively correlated with serum albumin, triglycerides (TG), cholesterol and low density lipoprotein (LDL). In contrast, serum IL-6 level positively correlated with parameters of liver functions and negatively correlated with parameters of lipid profile. Additionally, there was highly significant negative correlation between serum leptin and IL-6 levels (P < 0.001) in post-hepatic cirrhotic patients. We concluded that leptin and IL-6 have important role in diagnosis and prognosis of patients with post-hepatic liver cirrhosis

  19. The Role of Serum Leptin and IL-6 Levels in Post Viral Hepatitis Cirrhotic patients

    Energy Technology Data Exchange (ETDEWEB)

    Mohamed, S.K., E-mail: Safaa-K-mohamed@hotmail.co [Health Radiation Research Department, National Center for Radiation Research and Technology, P. O. Box:29 Nasr City, Cairo (Egypt)

    2010-07-01

    Chronic liver disease is characterized by numerous metabolic alterations resulting in the clinical picture of malnutrition or even cachexia and contributing to complications such as hepatic encephalopathy and ascites. Leptin is a hormone that plays an important role in regulating energy intake and expenditure including appetite and metabolism. Interleukin-6 (IL-6), on the other hand, is generally considered to be one of the important cytokines that regulate immunologic and metabolic actions. The aim of the present study was to investigate serum leptin and IL-6 levels in liver cirrhosis, as well as to determine their levels in relation to liver functions and lipid profile. This study was conducted on 25 patients with post- viral hepatic cirrhosis compared to 20 healthy matched individuals served as controls with the same age and sex. The severity of the disease assessed with Child-Pugh criteria yielded 8 patients (3 women, 5 men) with stage A, 10 patients (4 women, 6 men) with stage B and 7 patients (2 women, 5 men) with stage C. Compared to controls, body mass index (BMI) was decreased and reached statistical significance in group C liver cirrhosis (P< 0.05). Also, serum leptin level was highly significantly decreased in the three groups, while IL-6 level showed highly significant increase. Leptin level negatively correlated with aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin and positively correlated with serum albumin, triglycerides (TG), cholesterol and low density lipoprotein (LDL). In contrast, serum IL-6 level positively correlated with parameters of liver functions and negatively correlated with parameters of lipid profile. Additionally, there was highly significant negative correlation between serum leptin and IL-6 levels (P < 0.001) in post-hepatic cirrhotic patients. We concluded that leptin and IL-6 have important role in diagnosis and prognosis of patients with post-hepatic liver cirrhosis

  20. In vivo time-harmonic multifrequency elastography of the human liver

    International Nuclear Information System (INIS)

    Tzschätzsch, Heiko; Guo, Jing; Streitberger, Kaspar-Josche; Fischer, Thomas; Sack, Ingolf; Ipek-Ugay, Selcan; Braun, Jürgen; Gentz, Enno; Klaua, Robert; Schultz, Michael

    2014-01-01

    Elastography is capable of noninvasively detecting hepatic fibrosis by imposing mechanical stress and measuring the viscoelastic response in the liver. Magnetic resonance elastography (MRE) relies on time-harmonic vibrations, while most dynamic ultrasound elastography methods employ transient stimulation methods. This study attempts to benefit from the advantages of time-harmonic tissue stimulation, i.e. relative insensitivity to obesity and ascites and mechanical approachability of the entire liver, and the advantages of ultrasound, i.e. time efficiency, low costs, and wide availability, by introducing in vivo time-harmonic elastography (THE) of the human liver using ultrasound and a broad range of harmonic stimulation frequencies. THE employs continuous harmonic shear vibrations at 7 frequencies from 30 to 60 Hz in a single examination and determines the elasticity and the viscosity of the liver from the dispersion of the shear wave speed within the applied frequency range. The feasibility of the method is demonstrated in the livers of eight healthy volunteers and a patient with cirrhosis. Multifrequency MRE at the same drive frequencies was used as elastographic reference method. Similar values of shear modulus and shear viscosity according the Kelvin–Voigt model were obtained by MRE and THE, indicating that the new method is suitable for in vivo quantification of the shear viscoelastic properties of the liver, however, in real-time and at a fraction of the costs of MRE. In conclusion, THE may provide a useful tool for fast assessment of the viscoelastic properties of the liver at low costs and without limitations in obesity, ascites or hemochromatosis. (paper)

  1. Portal hypertension and liver cirrhosis in rats: effect of the β3-adrenoceptor agonist SR58611A

    Science.gov (United States)

    Vasina, Valentina; Giannone, Ferdinando; Domenicali, Marco; Latorre, Rocco; Berzigotti, Annalisa; Caraceni, Paolo; Zoli, Marco; De Ponti, Fabrizio; Bernardi, Mauro

    2012-01-01

    BACKGROUND AND PURPOSE β3-Adrenoceptors participate in the regulation of vascular tone in physiological and pathological conditions. We aimed to assess the effect of pharmacological modulation of β3-adrenoceptors on portal pressure (PP) and systemic haemodynamics and their expression in the liver and mesenteric vessels of cirrhotic rats. EXPERIMENTAL APPROACH PP, central venous pressure (CVP) and systemic haemodynamics were invasively assessed in control and CCl4-treated cirrhotic rats before and during infusion of the selective β3-adrenoceptor agonist, SR58611A. Tissue samples were also collected from liver, heart, portal vein and mesenteric artery for immunohistochemistry and molecular biology analysis. The effect of SR58611A on isolated portal vein was assessed. KEY RESULTS At baseline, cirrhotic rats showed portal hypertension, reduced CVP and hyperdynamic circulation. SR58611A induced a significant, dose-dependent decrease in PP in cirrhotic rats, but not in controls. Although both groups manifested a dose-dependent reduction in mean arterial pressure, this effect was associated with decreased cardiac index (CI) and unchanged indicized peripheral vascular resistance (PVRI) in cirrhotic rats and increased CI and decreased PVRI in control animals. Pretreatment with the selective β3-adrenoceptor antagonist SR59230 prevented all SR58611A-induced changes in cirrhotic rats. SR58611A concentration-dependently relaxed portal vein in cirrhotic rats to a significantly greater extent than in healthy rats; pretreatment with SR59230A completely prevented SR58611A-induced cirrhotic portal vein relaxation. Finally, β3-adrenoceptors were identified in the liver, heart and portal vein of cirrhotic and control animals; their expression was increased in cirrhotic rats. CONCLUSIONS AND IMPLICATIONS β3-Adrenoceptors are altered in portal hypertension of experimental cirrhosis and may represent a novel therapeutic target. PMID:22708587

  2. 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.

  3. 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

  4. Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells

    International Nuclear Information System (INIS)

    Soeda, Junpei; Morgan, Maelle; McKee, Chad; Mouralidarane, Angelina; Lin, ChingI; Roskams, Tania; Oben, Jude A.

    2012-01-01

    Highlights: ► Cigarette smoke may induce liver fibrosis via nicotine receptors. ► Nicotine induces proliferation of hepatic stellate cells (HSCs). ► Nicotine activates hepatic fibrogenic pathways. ► Nicotine receptor antagonists attenuate HSC proliferation. ► 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-α2 and the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-β1) 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 (α1, β1, delta and epsilon) and neuronal type (α3, α6, α7, β2 and β4) nAChR subunits at the mRNA level. Among these subunits, α3, α7, β1 and ε were predominantly expressed as confirmed by Western blotting. Nicotine induced hHSC proliferation was attenuated by mecamylamine (p < 0.05). Additionally, collagen1-α2 and TGF-β1 mRNA expression were significantly upregulated by nicotine and inhibited by mecamylamine. α1 and α3-nAChR mRNA expression was significantly upregulated in NASH fibrosis compared to normal livers. Conclusion: Nicotine at levels in smokers’ blood is pro-fibrogenic, through

  5. Lack of cilia and differentiation defects in the liver of human foetuses with the Meckel syndrome.

    Science.gov (United States)

    Clotman, Frédéric; Libbrecht, Louis; Killingsworth, Murray C; Loo, Christine C K; Roskams, Tania; Lemaigre, Frédéric P

    2008-03-01

    Meckel syndrome is an autosomal-recessive disease characterized by a combination of renal cysts, anomalies of the central nervous system, polydactyly and ductal plate malformations (DPM), which are hepatic anomalies consisting of excessive and abnormal foetal biliary structures. Among the genomic loci associated with Meckel syndrome, mutations in four genes were recently identified. These genes code for proteins associated with primary cilia and are possibly involved in cell differentiation. The aim of the present work was to investigate the formation of the primary cilia and the differentiation of the hepatic cells in foetuses with Meckel syndrome. Sections of livers from human foetuses with Meckel syndrome were analysed by immunofluorescence, immunohistochemistry and electron microscopy. The primary cilia of the biliary cells were absent in some Meckel foetuses, but were present in others. In addition, defects in hepatic differentiation were observed in Meckel livers, as evidenced by the presence of hybrid cells co-expressing hepatocytic and biliary markers. Defects in cilia formation occur in some Meckel livers, and most cases show DPM associated with abnormal hepatic cell differentiation. Because differentiation precedes the formation of the cilia during liver development, we propose that defective differentiation may constitute the initial defect in the liver of Meckel syndrome foetuses.

  6. The ADOPT-LC score: a novel predictive index of in-hospital mortality of cirrhotic patients following surgical procedures, based on a national survey.

    Science.gov (United States)

    Sato, Masaya; Tateishi, Ryosuke; Yasunaga, Hideo; Horiguchi, Hiromasa; Matsui, Hiroki; Yoshida, Haruhiko; Fushimi, Kiyohide; Koike, Kazuhiko

    2017-03-01

    We aimed to develop a model for predicting in-hospital mortality of cirrhotic patients following major surgical procedures using a large sample of patients derived from a Japanese nationwide administrative database. We enrolled 2197 cirrhotic patients who underwent elective (n = 1973) or emergency (n = 224) surgery. We analyzed the risk factors for postoperative mortality and established a scoring system for predicting postoperative mortality in cirrhotic patients using a split-sample method. In-hospital mortality rates following elective or emergency surgery were 4.7% and 20.5%, respectively. In multivariate analysis, patient age, Child-Pugh (CP) class, Charlson Comorbidity Index (CCI), and duration of anesthesia in elective surgery were significantly associated with in-hospital mortality. In emergency surgery, CP class and duration of anesthesia were significant factors. Based on multivariate analysis in the training set (n = 987), the Adequate Operative Treatment for Liver Cirrhosis (ADOPT-LC) score that used patient age, CP class, CCI, and duration of anesthesia to predict in-hospital mortality following elective surgery was developed. This scoring system was validated in the testing set (n = 986) and produced an area under the curve of 0.881. We also developed iOS/Android apps to calculate ADOPT-LC scores to allow easy access to the current evidence in daily clinical practice. Patient age, CP class, CCI, and duration of anesthesia were identified as important risk factors for predicting postoperative mortality in cirrhotic patients. The ADOPT-LC score effectively predicts in-hospital mortality following elective surgery and may assist decisions regarding surgical procedures in cirrhotic patients based on a quantitative risk assessment. © 2016 The Authors Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.

  7. 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.

  8. Expression and kinetic properties of a recombinant 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzyme of human liver.

    Science.gov (United States)

    Deyashiki, Y; Tamada, Y; Miyabe, Y; Nakanishi, M; Matsuura, K; Hara, A

    1995-08-01

    Human liver cytosol contains multiple forms of 3 alpha-hydroxysteroid dehydrogenase and dihydrodiol dehydrogenase with hydroxysteroid dehydrogenase activity, and multiple cDNAs for the enzymes have been cloned from human liver cDNA libraries. To understand the relationship of the multiple enzyme froms to the genes, a cDNA, which has been reported to code for an isoenzyme of human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase, was expressed in Escherichia coli. The recombinant enzyme showed structural and functional properties almost identical to those of the isoenzyme purified from human liver. In addition, the recombinant isoenzyme efficiently reduced 5 alpha-dihydrotestosterone and 5 beta-dihydrocortisone, the known substrates of human liver 3 alpha-hydroxysteroid dehydrogenase and chlordecone reductase previously purified, which suggests that these human liver enzymes are identical. Furthermore, the steady-state kinetic data for NADP(+)-linked (S)-1-indanol oxidation by the recombinant isoenzyme were consistent with a sequential ordered mechanism in which NADP+ binds first. Phenolphthalein inhibited this isoenzyme much more potently than it did the other human liver dihydrodiol dehydrogenases, and was a competitive inhibitor (Ki = 20 nM) that bound to the enzyme-NADP+ complex.

  9. 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. Copyright © 2015. Published by Elsevier B.V.

  10. Potential genotoxic and cytotoxicity of emamectin benzoate in human normal liver cells.

    Science.gov (United States)

    Zhang, Zhijie; Zhao, Xinyu; Qin, Xiaosong

    2017-10-10

    Pesticide residue inducing cancer-related health problems draw people more attention recently. Emamectin benzoate (EMB) has been widely used in agriculture around the world based on its specificity targets. Although potential risk and the molecular mechanism of EMB toxicity to human liver has not been well-characterized. Unlike well-reported toxicity upon central nervous system, potential genotoxic and cytotoxicity of EMB in human liver cell was ignored and very limited. In this study, we identify genotoxicity and cytotoxicity of EMB to human normal liver cells (QSG7701 cell line) in vitro . We demonstrate that EMB inhibited the viability of QSG7701 cells and induced the DNA damage. Established assays of cytotoxicity were performed to characterize the mechanism of EMB toxicity on QSG7701 cells. Typical chromatin condensation and DNA fragmentation indicated the apoptosis of QSG7701 cells induced by EMB. And the intracellular biochemical results demonstrated that EMB-enhanced apoptosis of QSG7701 cells concurrent with generated ROS, a loss of mitochondrial membrane potential, the cytochrome-c release, up regulate the Bax/Bcl-2 and the activation of caspase-9/-3. Our results of EMB induces the death of QSG7701 cells maybe via mitochondrial-mediated intrinsic apoptotic pathways would contribute to promote the awareness of EMB as an extensive used pesticide to human being effects and reveal the underlying mechanisms of potential genotoxic.

  11. Purification and characterization of glutaryl-CoA dehydrogenase from porcine and human liver

    International Nuclear Information System (INIS)

    Lenich, A.C.

    1985-01-01

    Glutaryl-CoA dehydrogenase (GCDH) was purified from porcine liver mitochondria by pH and ammonium sulfate fractionations followed by a series of column chromatographies. The purified porcine enzyme was found by sodium dodecyl-sulfate polyacrylamide gel electrophoresis to have a subunit molecular weight of 47,800 and by gradient polyacrylamide gel electrophoresis (PAGE) to have a native molecular weight of approximately 186,000. The product of the GCDH reaction with its primary substrate, glutaryl-CoA, was investigated by radio-gas chromatography and found to be crotonyl-CoA. Alternate substrates as well as crotonyl-CoA, the glutaryl-CoA reaction end product, demonstrated competitive inhibition when incubated with (1,5- 14 C)-glutaryl-CoA in the presence of porcine GCDH. Kinetic parameters for the interaction of both ETF and glutaryl-CoA with porcine GCDH were determined. Purified porcine GCDH was used to produce an antiserum which cross-reacted with human liver GCDH with a reaction of partial identity, but proved too insensitive to detect GCDH in control human fibroblasts. As a result of these negative findings, GCDH was purified by a series of column chromatographies from human liver. The purified human enzyme was found by SDS-PAGE and gel filtration to have subunit and native molecular weights of 58,800 and 256,000 respectively

  12. Mice with chimeric livers are an improved model for human lipoprotein metabolism.

    Science.gov (United States)

    Ellis, Ewa C S; Naugler, Willscott Edward; Nauglers, Scott; Parini, Paolo; Mörk, Lisa-Mari; Jorns, Carl; Zemack, Helen; Sandblom, Anita Lövgren; Björkhem, Ingemar; Ericzon, Bo-Göran; Wilson, Elizabeth M; Strom, Stephen C; Grompe, Markus

    2013-01-01

    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. 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. 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. 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.

  13. Intrahepatic upregulation of MRTF-A signaling contributes to increased hepatic vascular resistance in cirrhotic rats with portal hypertension.

    Science.gov (United States)

    Zheng, Lei; Qin, Jun; Sun, Longci; Gui, Liang; Zhang, Chihao; Huang, Yijun; Deng, Wensheng; Huang, An; Sun, Dong; Luo, Meng

    2017-06-01

    Portal hypertension in cirrhosis is mediated, in part, by increased intrahepatic resistance, reflecting massive structural changes associated with fibrosis and intrahepatic vasoconstriction. Activation of the Rho/MRTF/SRF signaling pathway is essential for the cellular regulatory network of fibrogenesis. The aim of this study was to investigate MRTF-A-mediated regulation of intrahepatic fibrogenesis in cirrhotic rats. Portal hypertension was induced in rats via an injection of CCl 4 oil. Hemodynamic measurements were obtained using a polyethylene PE-50 catheter and pressure transducers. Expression of hepatic fibrogenesis was measured using histological staining. Expression of protein was measured using western blotting. Upregulation of MRTF-A protein expression in the livers of rats with CCl 4 -induced cirrhosis was relevant to intrahepatic resistance and hepatic fibrogenesis in portal hypertensive rats with increased modeling time. Inhibition of MRTF-A by CCG-1423 decelerated hepatic fibrosis, decreased intrahepatic resistance and portal pressure, and alleviated portal hypertension. Increased intrahepatic resistance in rats with CCl 4 -induced portal hypertension is associated with an upregulation of MRTF-A signaling. Inhibition of this pathway in the liver can decrease hepatic fibrosis and intrahepatic resistance, as well as reduce portal pressure in cirrhotic rats with CCl 4 -induced portal hypertension. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  14. A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension.

    Science.gov (United States)

    Koot, Bart G P; Alders, Marielle; Verheij, Joanne; Beuers, Ulrich; Cobben, Jan M

    2016-04-01

    Non-cirrhotic portal hypertension is characterized by histopathological abnormalities in the liver, mostly affecting small intrahepatic portal veins that cause portal hypertension in the absence of cirrhosis. It can be secondary to coagulation disorders or toxic agents. However, most cases are idiopathic non-cirrhotic portal hypertension (INCPH) and familial cases are rare. We report a family in which a father and three of his four children conceived with three different mothers are affected by INCPH. Whole exome and Sanger sequencing showed the father to have a de novo single nucleotide substitution c.1348G>C in the KCNN3 gene that was transmitted to all three of his affected offspring. The KCNN3 gene encodes small conductance calcium-activated potassium (SK) channel 3. SK channels are involved in the regulation of arterial and venous vascular tone by causing smooth muscle relaxation on activation. No data exist on the expression and function of SK channels in portal veins. The autosomal dominant inheritance in this unique pedigree and the single de novo mutation identified, strongly suggests that KCNN3 mutations have a pathogenetic role in INCPH. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  15. Adipokines in Liver Cirrhosis.

    Science.gov (United States)

    Buechler, Christa; Haberl, Elisabeth M; Rein-Fischboeck, Lisa; Aslanidis, Charalampos

    2017-06-29

    Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively.

  16. [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.

  17. 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

  18. Postprandial hepatic volume change: spiral CT evaluation in case of liver cirrhosis

    International Nuclear Information System (INIS)

    Rho, Kwang Suk; Moon, Jang Il; Ko, Myong Kwan; Byun, Joo Nam; Kim, Young Suk; Kim, Young Chol; Oh, Jae Hee

    1999-01-01

    To investigate the usefulness of evaluating liver cirrhosis through the measurement of liver volume. In a control group(20 normal subjects) and 20 cirrhotic patients, variations in liver volume before and after a meal were obtained. A case-control study was conducted between the two groups. In the control group, the range of increased liver volume after the meal was 67-186ml. Mean increased liver volume was 119.3ml, the range of percentage increase was 6-12.4% and the mean percentage increase was 9.89%. In cirrhotic patients, the range of increased liver volume after the meal was 1-20ml. Mean increase liver volume was 6.9ml, the range of percentage increase was 0-1.9% and the mean percentage increase was 0.65%. Compared with the control group, cirrhotic patients showed a much smaller increase in liver volume(p<0.01). Difference in variation of liver volume between a control group and cirrhotic patients before and after a meal can be used for the evaluation of liver cirrhosis

  19. Low density in liver of idiopathic portal hypertension

    International Nuclear Information System (INIS)

    Ishito, Hiroyuki

    1988-01-01

    In order to evaluate the diagnostic value of low density in liver on computed tomography (CT), CT scans of 11 patients with idiopathic portal hypertension (IPH) were compared with those from 22 cirrhotic patients, two patients with scarred liver and 16 normal subjects. Low densities on plain CT scans in patients with IPH were distinctly different from those observed in normal liver. Some of the low densities had irregular shape with unclear margin and were scattered near the liver surface, and others had vessel-like structures with unclear margin and extended as far as near the liver surface. Ten of the 11 patients with IPH had low densities mentioned above, while none of the 22 cirrhotic patients had such low densities. The present results suggest that the presence of low densities in liver on plain CT scan is clinically beneficial in diagnosis of IPH. (author)

  20. CULTIVATION OF HUMAN LIVER CELLS AND ADIPOSE-DERIVED MESENCHYMAL STROMAL CELLS IN PERFUSION BIOREACTOR

    Directory of Open Access Journals (Sweden)

    Yu. В. Basok

    2018-01-01

    Full Text Available Aim: to show the progress of the experiment of cultivation of human liver cells and adipose-derived mesenchymal stromal cells in perfusion bioreactor.Materials and methods. The cultivation of a cell-engineered construct, consisting of a biopolymer microstructured collagen-containing hydrogel, human liver cells, adipose-derived mesenchymal stromal cells, and William’s E Medium, was performed in a perfusion bioreactor.Results. On the 7th day large cells with hepatocyte morphology – of a polygonal shape and a centrally located round nucleus, – were present in the culture chambers of the bioreactor. The metabolic activity of hepatocytes in cell-engineered constructs was confi rmed by the presence of urea in the culture medium on the seventh day of cultivation in the bioreactor and by the resorption of a biopolymer microstructured collagen-containing hydrogel.

  1. 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

  2. Expression and Regulation of the Bile Acid Transporter, OST alpha-OST beta in Rat and Human Intestine and Liver

    NARCIS (Netherlands)

    Khan, Ansar A.; Chow, Edwin C. Y.; Porte, Robert J.; Pang, K. Sandy; Groothuis, Geny M. M.

    The regulation of the OST alpha and OST beta expression was studied in the rat jejunum, ileum, colon and liver and in human ileum and liver by ligands for the farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR) and glucocorticoid receptor (GR) using precision cut tissue

  3. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study

    NARCIS (Netherlands)

    Weber, Rainer; Sabin, Caroline A.; Friis-Møller, Nina; Reiss, Peter; El-Sadr, Wafaa M.; Kirk, Ole; Dabis, Francois; Law, Matthew G.; Pradier, Christian; de Wit, Stephane; Akerlund, Börje; Calvo, Gonzalo; D'Arminio Monforte, Antonella; Rickenbach, Martin; Ledergerber, Bruno; Phillips, Andrew N.; Lundgren, Jens D.

    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

  4. Rapid production of human liver scaffolds for functional tissue engineering by high shear stress oscillation-decellularization

    NARCIS (Netherlands)

    Mazza, G. (Giuseppe); Al-Akkad, W. (Walid); Telese, A. (Andrea); Longato, L. (Lisa); Urbani, L. (Luca); Robinson, B. (Benjamin); Hall, A. (Andrew); Kong, K. (Kenny); Frenguelli, L. (Luca); Marrone, G. (Giusi); Willacy, O. (Oliver); Shaeri, M. (Mohsen); A.J. Burns (Alan); Malago, M. (Massimo); Gilbertson, J. (Janet); Rendell, N. (Nigel); Moore, K. (Kevin); Hughes, D. (David); Notingher, I. (Ioan); Jell, G. (Gavin); Del Rio Hernandez, A. (Armando); P. de Coppi (Paolo); Rombouts, K. (Krista); Pinzani, M. (Massimo)

    2017-01-01

    textabstractThe development of human liver scaffolds retaining their 3-dimensional structure and extra-cellular matrix (ECM) composition is essential for the advancement of liver tissue engineering. We report the design and validation of a new methodology for the rapid and accurate production of

  5. Percutaneous laser ablation of hepatocellular carcinoma in patients with liver cirrhosis awaiting liver transplantation

    International Nuclear Information System (INIS)

    Pompili, Maurizio; Pacella, Claudio Maurizio; Francica, Giampiero; Angelico, Mario; Tisone, Giuseppe; Craboledda, Paolo; Nicolardi, Erica; Rapaccini, Gian Ludovico; Gasbarrini, Giovanni

    2010-01-01

    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.

  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. 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.

  8. A search for losses of chromium and other trace elements during lyophilization of human liver tissue

    International Nuclear Information System (INIS)

    Goeij, J.J.M. de; Volkers, K.J.; Tjioe, P.S.

    1979-01-01

    Human liver tissues were investigated for possible trace-element losses during lyophilization by comparison of concentrations of lyophilized and untreated (wet) samples. When destructive neutron activation analysis (n.a.a.) was used, no significant losses were observed for As, Br, Cd, Co, Cr, Cu, Fe, Hg, Mo, Sb, Se, and Zn. The advantages of n.a.a. over radio-tracer techniques for studies of trace-element volatility are discussed. (Auth.)

  9. CHARACTERIZATION OF HUMAN LIVER MICROSOMAL UDP-GLYCOSYLTRANSFERASES USING PHOTOAFFINITY ANALOGS

    NARCIS (Netherlands)

    LITTLE, JM; DRAKE, RR; VONK, R; KUIPERS, F; LESTER, R; RADOMINSKA, A

    The photoaffinity analogs [beta-P-32]5-azido-UDP-glucuronic acid ([P-32]5N3UDP-GlcUA) and [beta-P-32]5-azido-UDP-glucose ([P-32]5N(3)UDP-Glc) were used to characterize UDP-glycosyl-transferases of microsomes prepared from human liver. Photoincorporation of both probes into proteins in the 50- to

  10. [Molecular detection of hepatitis E virus in pig livers destined for human consumption in the state of Nuevo Leon, Mexico].

    Science.gov (United States)

    Cantú-Martínez, Marco Antonio; Roig-Sagués, Artur Xavier; Cedillo-Rosales, Sibilina; Zamora-Ávila, Diana Elisa; Avalos-Ramírez, Ramiro

    2013-04-01

    Molecular detection of HEV in pig livers destined for human consumption in Nuevo Leon, Mexico. 87 livers were collected from pigs slaughtered in TIF and 40 livers from butchers. A 212 pb fragment of HEV ORF2 gene was amplified by semi-nested RT-PCR. 19.54% (17) of tif's and 22.5% (9) of butcher's livers were positive for HEV. Sequencing of the amplified products showed a 94%-95% homology with the sequences reported for genotype 3. Our results indicate that HEV is circulating in swine herds in the state, constituting a probable source of contamination of pig meat products.

  11. Sinusoidal obstruction syndrome (SOS): A light and electron microscopy study in human liver.

    Science.gov (United States)

    Vreuls, C P H; Driessen, A; Olde Damink, S W M; Koek, G H; Duimel, H; van den Broek, M A J; Dejong, C H C; Braet, F; Wisse, E

    2016-05-01

    Oxaliplatin is an important chemotherapeutic agent, used in the treatment of hepatic colorectal metastases, and known to induce the sinusoidal obstruction syndrome (SOS). Pathophysiological knowledge concerning SOS is based on a rat model. Therefore, the aim was to perform a comprehensive study of the features of human SOS, using both light microscopy (LM) and electron microscopy (EM). Included were all patients of whom wedge liver biopsies were collected during a partial hepatectomy for colorectal liver metastases, in a 4-year period. The wedge biopsy were perfusion fixated and processed for LM and EM. The SOS lesions were selected by LM and details were studied using EM. Material was available of 30 patients, of whom 28 patients received neo-adjuvant oxaliplatin. Eighteen (64%) of the 28 patients showed SOS lesions, based on microscopy. The lesions consisted of sinusoidal endothelial cell detachment from the space of Disse on EM. In the enlarged space of Disse a variable amount of erythrocytes were located. Sinusoidal endothelial cell detachment was present in human SOS, accompanied by enlargement of the space of Disse and erythrocytes in this area. These findings, originally described in a rat model, were now for the first time confirmed in human livers under clinically relevant settings. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Systemic thrombolysis of portal vein thrombosis in cirrhotic patients: a pilot study.

    Science.gov (United States)

    De Santis, Adriano; Moscatelli, Rosanna; Catalano, Carlo; Iannetti, Antonio; Gigliotti, Francesca; Cristofari, Francesca; Trapani, Silvia; Attili, Adolfo F

    2010-06-01

    Portal vein thrombosis is a frequent complication in liver cirrhosis. Encouraging reports of systemic thrombolysis in non-cirrhotic patients suffering from acute portal vein thrombosis led us to start a pilot study on the efficacy and safety of systemic low dose recombinant tissue plasminogen activator (Actilyse, Boheringer Ingelheim, Florence, Italy). Nine cirrhotic patients (6 males and 3 females) with recent portal vein thrombosis were enrolled. Exclusion criteria were portal cavernomatosis, recent (30 days) surgery, active bleeding, hepatocellular carcinoma and cancer in other sites. All cases were treated for a maximum of 7 days by continuous i.v. infusion of 0.25mg/kg/die of r-tPA plus subcutaneous low molecular weight heparin. Efficacy was evaluated by colour doppler sonography monitoring and confirmed by contrast enhanced computerized tomography. The combined r-tPA/LMWH treatment was well tolerated without clinically significant side effects. Complete resolution of thrombosis occurred in 4 cases, partial regression in 4 and none in 1. Retreatment of a complete recurrence in 1 patient was successful. Variceal pressure dropped from 30.7+/-4.5 mmHg to 21.2+/-6.6 mmHg (p=0.012). Our preliminary data demonstrate that thrombolytic treatment of recent portal vein thrombosis with i.v. r-tPA and LMWH in patients with cirrhosis appears to be safe and effective and can significantly reduce pressure in oesophageal varices. Copyright 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  13. [Esophageal motor disorders in cirrhotic patients with esophageal varices non-submitted to endoscopic treatment].

    Science.gov (United States)

    Flores, Priscila Pollo; Lemme, Eponina Maria de Oliveira; Coelho, Henrique Sérgio Moraes

    2005-01-01

    The hepatic cirrhosis has as one of the main morbid-mortality causes, the portal hypertension with the development of esophageal varices, the possibility of a digestive hemorrhage and worsening of hepatic insufficiency. It is important to identify causal predictive or aggravating factors and if possible to prevent them. In the last years, it has been observed the association of esophageal motor disorders and gastro-esophageal reflux in cirrhotic patients with esophageal varices. To study the prevalence of the esophageal motility disorders and among them, the ineffective esophageal motility, in patients with hepatic cirrhosis and esophageal varices, without previous endoscopic therapeutic and the predictive factors. Prospectively, it has been evaluate 74 patients suffering from liver cirrhosis and esophagic varices, without previous endoscopic treatment. All of them were submitted to a clinical protocol, esophageal manometry and 55 patients also held the ambulatory esophageal pHmetry. Esophageal motility disorders have been found in 44 patients (60%). The most prevalent was the ineffective esophageal motility, observed in 28%. The abnormal reflux disease was diagnosed through the pHmetry in 35% of the patients. There were no correlation between the manometrical abnormality in general and the ineffective esophageal motility in particular and the esophageal or gastroesophageal reflux disease symptoms, the abnormal reflux, the disease seriousness, the ascites presence and the gauge of the varices. The majority of cirrhotic patients with non-treated esophageal varices present esophageal motor disorders. No predictive factor was found. The clinical relevance of these findings need more researches in the scope to define the real meaning of theses abnormalities.

  14. FOOD CONSUMPTION OF CIRRHOTIC PATIENTS, COMPARISON WITH THE NUTRITIONAL STATUS AND DISEASE STAGING

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    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.

  15. Protocol for Isolation of Primary Human Hepatocytes and Corresponding Major Populations of Non-parenchymal Liver Cells

    Science.gov (United States)

    Pfeiffer, Elisa; Zeilinger, Katrin; Seehofer, Daniel; Damm, Georg

    2016-01-01

    Beside parenchymal hepatocytes, the liver consists of non-parenchymal cells (NPC) namely Kupffer cells (KC), liver endothelial cells (LEC) and hepatic Stellate cells (HSC). Two-dimensional (2D) culture of primary human hepatocyte (PHH) is still considered as the "gold standard" for in vitro testing of drug metabolism and hepatotoxicity. It is well-known that the 2D monoculture of PHH suffers from dedifferentiation and loss of function. Recently it was shown that hepatic NPC play a central role in liver (patho-) physiology and the maintenance of PHH functions. Current research focuses on the reconstruction of in vivo tissue architecture by 3D- and co-culture models to overcome the limitations of 2D monocultures. Previously we published a method to isolate human liver cells and investigated the suitability of these cells for their use in cell cultures in Experimental Biology and Medicine1. Based on the broad interest in this technique the aim of this article was to provide a more detailed protocol for the liver cell isolation process including a video, which will allow an easy reproduction of this technique. Human liver cells were isolated from human liver tissue samples of surgical interventions by a two-step EGTA/collagenase P perfusion technique. PHH were separated from the NPC by an initial centrifugation at 50 x g. Density gradient centrifugation steps were used for removal of dead cells. Individual liver cell populations were isolated from the enriched NPC fraction using specific cell properties and cell sorting procedures. Beside the PHH isolation we were able to separate KC, LEC and HSC for further cultivation. Taken together, the presented protocol allows the isolation of PHH and NPC in high quality and quantity from one donor tissue sample. The access to purified liver cell populations could allow the creation of in vivo like human liver models. PMID:27077489

  16. Hepatic Differentiation of Human Induced Pluripotent Stem Cells in a Perfused 3D Porous Polymer Scaffold for Liver Tissue Engineering

    DEFF Research Database (Denmark)

    Hemmingsen, Mette; Muhammad, Haseena Bashir; Mohanty, Soumyaranjan

    A huge shortage of liver organs for transplantation has motivated the research field of tissue engineering to develop bioartificial liver tissue and even a whole liver. The goal of NanoBio4Trans is to create a vascularized bioartificial liver tissue, initially as a liver-support system. Due...... to limitations of primary hepatocytes regarding availability and maintenance of functionality, stem cells and especially human induced pluripotent stem cells (hIPS cells) are an attractive cell source for liver tissue engineering. The aim of this part of NanoBio4Trans is to optimize culture and hepatic...... differentiation of hIPS-derived definitive endoderm (DE) cells in a 3D porous polymer scaffold built-in a perfusable bioreactor. The use of a microfluidic bioreactor array enables the culture of 16 independent tissues in one experimental run and thereby an optimization study to be performed....

  17. Plasmodium falciparum full life cycle and Plasmodium ovale liver stages in humanized mice.

    Science.gov (United States)

    Soulard, Valérie; Bosson-Vanga, Henriette; Lorthiois, Audrey; Roucher, Clémentine; Franetich, Jean-François; Zanghi, Gigliola; Bordessoulles, Mallaury; Tefit, Maurel; Thellier, Marc; Morosan, Serban; Le Naour, Gilles; Capron, Frédérique; Suemizu, Hiroshi; Snounou, Georges; Moreno-Sabater, Alicia; Mazier, Dominique

    2015-07-24

    Experimental studies of Plasmodium parasites that infect humans are restricted by their host specificity. Humanized mice offer a means to overcome this and further provide the opportunity to observe the parasites in vivo. Here we improve on previous protocols to achieve efficient double engraftment of TK-NOG mice by human primary hepatocytes and red blood cells. Thus, we obtain the complete hepatic development of P. falciparum, the transition to the erythrocytic stages, their subsequent multiplication, and the appearance of mature gametocytes over an extended period of observation. Furthermore, using sporozoites derived from two P. ovale-infected patients, we show that human hepatocytes engrafted in TK-NOG mice sustain maturation of the liver stages, and the presence of late-developing schizonts indicate the eventual activation of quiescent parasites. Thus, TK-NOG mice are highly suited for in vivo observations on the Plasmodium species of humans.

  18. Preoperative assessment of congestive liver dysfunction using technetium-99m galactosyl human Serum albumin liver scintigraphy in patients with severe valvular heart disease

    International Nuclear Information System (INIS)

    Nishi, Hiroyuki; Matsumiya, Goro; Takano, Hiroshi; Ichikawa, Hajime; Miyagawa, Shigeru; Sawa, Yoshiki; Takahashi, Toshiki

    2007-01-01

    Severe valvular heart disease is often complicated by congestive liver dysfunction, which greatly compromises the operative results. We evaluated congestive liver dysfunction by a novel approach using technetium-99m galactosyl human serum albumin ( 99m Tc-GSA) with liver scintigraphy. Between 1998 and 2004, we performed scintigraphy accompanied by 99m Tc-GSA in 28 patients who had valvular heart disease with moderate-to-severe tricuspid regurgitation and who showed symptoms of right heart failure. Based on the results, we calculated a receptor index (LHL15) and an index of blood clearance (HH15) and assessed the correlation between these factors and postoperative liver dysfunction, defined as the maximum serum total bilirubin level (max T-bil) as >2.0 mg/dl. Nineteen patients, including four who died in hospital, had postoperative liver dysfunction. The level of HH15 was significantly higher and the level of cholinesterase was significantly lower (P 99m Tc-GSA is a clinically useful predictor of postoperative liver dysfunction in patients with severe valvular disease. (author)

  19. Human liver segments: role of cryptic liver lobes and vascular physiology in the development of liver veins and left-right asymmetry

    NARCIS (Netherlands)

    Hikspoors, Jill P. J. M.; Peeters, Mathijs M. J. P.; Kruepunga, Nutmethee; Mekonen, Hayelom K.; Mommen, Greet M. C.; Köhler, S. Eleonore; Lamers, Wouter H.

    2017-01-01

    Couinaud based his well-known subdivision of the liver into (surgical) segments on the branching order of portal veins and the location of hepatic veins. However, both segment boundaries and number remain controversial due to an incomplete understanding of the role of liver lobes and vascular

  20. Laser Capture and Deep Sequencing Reveals the Transcriptomic Programmes Regulating the Onset of Pancreas and Liver Differentiation in Human Embryos

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    Rachel E. Jennings

    2017-11-01

    Full Text Available To interrogate the alternative fates of pancreas and liver in the earliest stages of human organogenesis, we developed laser capture, RNA amplification, and computational analysis of deep sequencing. Pancreas-enriched gene expression was less conserved between human and mouse than for liver. The dorsal pancreatic bud was enriched for components of Notch, Wnt, BMP, and FGF signaling, almost all genes known to cause pancreatic agenesis or hypoplasia, and over 30 unexplored transcription factors. SOX9 and RORA were imputed as key regulators in pancreas compared with EP300, HNF4A, and FOXA family members in liver. Analyses implied that current in vitro human stem cell differentiation follows a dorsal rather than a ventral pancreatic program and pointed to additional factors for hepatic differentiation. In summary, we provide the transcriptional codes regulating the start of human liver and pancreas development to facilitate stem cell research and clinical interpretation without inter-species extrapolation.

  1. Purification of nonspecific lipid transfer protein (sterol carrier protein 2) from human liver and its deficiency in livers from patients with cerebro-hepato-renal (Zellweger) syndrome

    NARCIS (Netherlands)

    Amerongen, A. van; Helms, J.B.; Krift, T.P. van der; Schutgens, R.B.H.; Wirtz, K.W.A.

    1987-01-01

    The nonspecific lipid transfer protein (i.e., sterol carrier protein 2) from human liver was purified to homogeneity using ammonium sulfate precipitation, CM-cellulose chromatography, molecular sieve chromatography and fast protein liquid chromatography. Its amino acid composition was determined and

  2. Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology.

    Directory of Open Access Journals (Sweden)

    Wen Liang

    Full Text Available The recently developed histological scoring system for non-alcoholic fatty liver disease (NAFLD by the NASH Clinical Research Network (NASH-CRN has been widely used in clinical settings, but is increasingly employed in preclinical research as well. However, it has not been systematically analyzed whether the human scoring system can directly be converted to preclinical rodent models. To analyze this, we systematically compared human NAFLD liver pathology, using human liver biopsies, with liver pathology of several NAFLD mouse models. Based upon the features pertaining to mouse NAFLD, we aimed at establishing a modified generic scoring system that is applicable to broad spectrum of rodent models.The histopathology of NAFLD was analyzed in several different mouse models of NAFLD to define generic criteria for histological assessment (preclinical scoring system. For validation of this scoring system, 36 slides of mouse livers, covering the whole spectrum of NAFLD, were blindly analyzed by ten observers. Additionally, the livers were blindly scored by one observer during two separate assessments longer than 3 months apart.The criteria macrovesicular steatosis, microvesicular steatosis, hepatocellular hypertrophy, inflammation and fibrosis were generally applicable to rodent NAFLD. The inter-observer reproducibility (evaluated using the Intraclass Correlation Coefficient between the ten observers was high for the analysis of macrovesicular steatosis and microvesicular steatosis (ICC = 0.784 and 0.776, all p<0.001, respectively and moderate for the analysis of hypertrophy and inflammation (ICC = 0.685 and 0.650, all p<0.001, respectively. The intra-observer reproducibility between the different observations of one observer was high for the analysis of macrovesicular steatosis, microvesicular steatosis and hypertrophy (ICC = 0.871, 0.871 and 0.896, all p<0.001, respectively and very high for the analysis of inflammation (ICC = 0.931, p

  3. Low dose perfluorooctanoate exposure promotes cell proliferation in a human non-tumor liver cell line

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Hongxia; Cui, Ruina [Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101 (China); Guo, Xuejiang [State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029 (China); Hu, Jiayue [Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101 (China); Dai, Jiayin, E-mail: daijy@ioz.ac.cn [Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101 (China)

    2016-08-05

    Highlights: • Differential expression of proteins induced by PFOA in HL-7702 was identified. • Most of the differentially expressed proteins are related to cell proliferation. • A low dose of PFOA stimulates HL-7702 cell proliferation. • A high dose of PFOA inhibits HL-7702 cell proliferation. - Abstract: Perfluorooctanoate (PFOA) is a well-known persistent organic pollutant widely found in the environment, wildlife and humans. Medical surveillance and experimental studies have investigated the potential effects of PFOA on human livers, but the hepatotoxicity of PFOA on humans and its underlying mechanism remain to be clarified. We exposed a human liver cell line (HL-7702) to 50 μM PFOA for 48 h and 96 h, and identified 111 significantly differentially expressed proteins by iTRAQ analysis. A total of 46 proteins were related to cell proliferation and apoptosis. Through further analysis of the cell cycle, apoptosis and their related proteins, we found that low doses of PFOA (50–100 μM) promoted cell proliferation and numbers by promoting cells from the G1 to S phases, whereas high doses of PFOA (200–400 μM) led to reduced HL-7702 cell numbers compared with that of the control mainly due to cell cycle arrest in the G0/G1 phase. To our knowledge, this is the first report on the promotion of cell cycle progression in human cells following PFOA exposure.

  4. Low dose perfluorooctanoate exposure promotes cell proliferation in a human non-tumor liver cell line

    International Nuclear Information System (INIS)

    Zhang, Hongxia; Cui, Ruina; Guo, Xuejiang; Hu, Jiayue; Dai, Jiayin

    2016-01-01

    Highlights: • Differential expression of proteins induced by PFOA in HL-7702 was identified. • Most of the differentially expressed proteins are related to cell proliferation. • A low dose of PFOA stimulates HL-7702 cell proliferation. • A high dose of PFOA inhibits HL-7702 cell proliferation. - Abstract: Perfluorooctanoate (PFOA) is a well-known persistent organic pollutant widely found in the environment, wildlife and humans. Medical surveillance and experimental studies have investigated the potential effects of PFOA on human livers, but the hepatotoxicity of PFOA on humans and its underlying mechanism remain to be clarified. We exposed a human liver cell line (HL-7702) to 50 μM PFOA for 48 h and 96 h, and identified 111 significantly differentially expressed proteins by iTRAQ analysis. A total of 46 proteins were related to cell proliferation and apoptosis. Through further analysis of the cell cycle, apoptosis and their related proteins, we found that low doses of PFOA (50–100 μM) promoted cell proliferation and numbers by promoting cells from the G1 to S phases, whereas high doses of PFOA (200–400 μM) led to reduced HL-7702 cell numbers compared with that of the control mainly due to cell cycle arrest in the G0/G1 phase. To our knowledge, this is the first report on the promotion of cell cycle progression in human cells following PFOA exposure.

  5. Three-Dimensional Culture of Human Embryonic Stem Cell Derived Hepatic Endoderm and Its Role in Bioartificial Liver Construction

    Directory of Open Access Journals (Sweden)

    Ruchi Sharma

    2010-01-01

    Full Text Available The liver carries out a range of functions essential for bodily homeostasis. The impairment of liver functions has serious implications and is responsible for high rates of patient morbidity and mortality. Presently, liver transplantation remains the only effective treatment, but donor availability is a major limitation. Therefore, artificial and bioartificial liver devices have been developed to bridge patients to liver transplantation. Existing support devices improve hepatic encephalopathy to a certain extent; however their usage is associated with side effects. The major hindrance in the development of bioartificial liver devices and cellular therapies is the limited availability of human hepatocytes. Moreover, primary hepatocytes are difficult to maintain and lose hepatic identity and function over time even with sophisticated tissue culture media. To overcome this limitation, renewable cell sources are being explored. Human embryonic stem cells are one such cellular resource and have been shown to generate a reliable and reproducible supply of human hepatic endoderm. Therefore, the use of human embryonic stem cell-derived hepatic endoderm in combination with tissue engineering has the potential to pave the way for the development of novel bioartificial liver devices and predictive drug toxicity assays.

  6. Liver afferents contribute to water drinking-induced sympathetic activation in human subjects: a clinical trial.

    Directory of Open Access Journals (Sweden)

    Marcus May

    Full Text Available Water drinking acutely increases sympathetic activity in human subjects. In animals, the response appears to be mediated through transient receptor potential channel TRPV4 activation on osmosensitive hepatic spinal afferents, described as osmopressor response. We hypothesized that hepatic denervation attenuates water drinking-induced sympathetic activation. We studied 20 liver transplant recipients (44±2.6 years, 1.2±0.1 years post transplant as model of hepatic denervation and 20 kidney transplant recipients (43±2.6 years, 0.8±0.1 years post transplant as immunosuppressive drug matched control group. Before and after 500 ml water ingestion, we obtained venous blood samples for catecholamine analysis. We also monitored brachial and finger blood pressure, ECG, and thoracic bioimpedance. Plasma norepinephrine concentration had changed by 0.01±0.07 nmol/l in liver and by 0.21±0.07 nmol/l in kidney transplant recipients (p<0.05 between groups after 30-40 minutes of water drinking. While blood pressure and systemic vascular resistance increased in both groups, the responses tended to be attenuated in liver transplant recipients. Our findings support the idea that osmosensitive hepatic afferents are involved in water drinking-induced sympathetic activation in human subjects.ClinicalTrials.gov NCT01237431.

  7. Dengue Virus Capsid Protein Binds Core Histones and Inhibits Nucleosome Formation in Human Liver Cells

    Science.gov (United States)

    Colpitts, Tonya M.; Barthel, Sebastian; Wang, Penghua; Fikrig, Erol

    2011-01-01

    Dengue virus (DENV) is a member of the Flaviviridae and a globally (re)emerging pathogen that causes serious human disease. There is no specific antiviral or vaccine for dengue virus infection. Flavivirus capsid (C) is a structural protein responsible for gathering the viral RNA into a nucleocapsid that forms the core of a mature virus particle. Flaviviral replication is known to occur in the cytoplasm yet a large portion of capsid protein localizes to the nucleus during infection. The reasons for the nuclear presences of capsid are not completely understood. Here, we expressed mature DENV C in a tandem affinity purification assay to identify potential binding partners in human liver cells. DENV C targeted the four core histones, H2A, H2B, H3 and H4. DENV C bound recombinant histones in solution and colocalized with histones in the nucleus and cytoplasm of liver cells during DENV infection. We show that DENV C acts as a histone mimic, forming heterodimers with core histones, binding DNA and disrupting nucleosome formation. We also demonstrate that DENV infection increases the amounts of core histones in livers cells, which may be a cellular response to C binding away the histone proteins. Infection with DENV additionally alters levels of H2A phosphorylation in a time-dependent manner. The interactions of C and histones add an interesting new role for the presence of C in the nucleus during DENV infection. PMID:21909430

  8. Liver Afferents Contribute to Water Drinking-Induced Sympathetic Activation in Human Subjects: A Clinical Trial

    Science.gov (United States)

    May, Marcus; Gueler, Faikah; Barg-Hock, Hannelore; Heiringhoff, Karl-Heinz; Engeli, Stefan; Heusser, Karsten; Diedrich, André; Brandt, André; Strassburg, Christian P.; Tank, Jens; Sweep, Fred C. G. J.; Jordan, Jens

    2011-01-01

    Water drinking acutely increases sympathetic activity in human subjects. In animals, the response appears to be mediated through transient receptor potential channel TRPV4 activation on osmosensitive hepatic spinal afferents, described as osmopressor response. We hypothesized that hepatic denervation attenuates water drinking-induced sympathetic activation. We studied 20 liver transplant recipients (44±2.6 years, 1.2±0.1 years post transplant) as model of hepatic denervation and 20 kidney transplant recipients (43±2.6 years, 0.8±0.1 years post transplant) as immunosuppressive drug matched control group. Before and after 500 ml water ingestion, we obtained venous blood samples for catecholamine analysis. We also monitored brachial and finger blood pressure, ECG, and thoracic bioimpedance. Plasma norepinephrine concentration had changed by 0.01±0.07 nmol/l in liver and by 0.21±0.07 nmol/l in kidney transplant recipients (pwater drinking. While blood pressure and systemic vascular resistance increased in both groups, the responses tended to be attenuated in liver transplant recipients. Our findings support the idea that osmosensitive hepatic afferents are involved in water drinking-induced sympathetic activation in human subjects. Trial Registration ClinicalTrials.gov NCT01237431 PMID:22016786

  9. Critical concentrations of cadmium in human liver and kidney measured by prompt-gamma neutron activation

    International Nuclear Information System (INIS)

    Cohn, S.H.; Vartsky, D.; Yasumura, S.; Zanzi, I.; Ellis, K.J.

    1979-01-01

    Few data exist on Cd metabolism in human beings. In particular, data are needed on the role of parameters such as age, sex, weight, diet, smoking habits, and state of health. Prompt-gamma neutron activation analysis (PGNAA) provides the only currently available means for measuring in vivo levels of liver and kidney Cd. The method employs an 85 Ci, 235 Pu,Be neutron source and a gamma ray detection system consisting of two Ge(Li) detector. The dose delivered to the liver and left kidney is 666 mrem (detection limit is 1.4 μg/g Cd in the liver and 2.0 mg Cd for one kidney). Absolute levels of Cd in the kidney and concentrations of Cd in the liver were measured in vivo in twenty healthy adult males using 238 Pu,Be neutron sources. Organ Cd levels of smokers were significantly elevated above those of nonsmokers. Biological half-time for Cd in the body was estimated to be 15.7 yr. Cigarette smoking was estimated to result in the absorption of 1.9 μg of Cd per pack. No relationship was bound between body stores of Cd (liver and kidney) and Cd or β-microglobulin levels in urine and blood. Currently the above neutron activation facility is being mounted on a 34-ft mobile trailer unit. This unit will be used to monitor levels of Cd in industrial workers. It is anticipated that critically important data, particularly on industrially exposed workers, will provide a better basis for determining critical concentrations and for the setting or revision of standards for industrial and environmental Cd pollution

  10. Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids.

    Directory of Open Access Journals (Sweden)

    Cyrill Géraud

    Full Text Available Liver sinusoidal endothelium is strategically positioned to control access of fluids, macromolecules and cells to the liver parenchyma and to serve clearance functions upstream of the hepatocytes. While clearance of macromolecular debris from the peripheral blood is performed by liver sinusoidal endothelial cells (LSECs using a delicate endocytic receptor system featuring stabilin-1 and -2, the mannose receptor and CD32b, vascular permeability and cell trafficking are controlled by transcellular pores, i.e. the fenestrae, and by intercellular junctional complexes. In contrast to blood vascular and lymphatic endothelial cells in other organs, the junctional complexes of LSECs have not yet been consistently characterized in molecular terms. In a comprehensive analysis, we here show that LSECs express the typical proteins found in endothelial adherens junctions (AJ, i.e. VE-cadherin as well as α-, β-, p120-catenin and plakoglobin. Tight junction (TJ transmembrane proteins typical of endothelial cells, i.e. claudin-5 and occludin, were not expressed by rat LSECs while heterogenous immunreactivity for claudin-5 was detected in human LSECs. In contrast, junctional molecules preferentially associating with TJ such as JAM-A, B and C and zonula occludens proteins ZO-1 and ZO-2 were readily detected in LSECs. Remarkably, among the JAMs JAM-C was considerably over-expressed in LSECs as compared to lung microvascular endothelial cells. In conclusion, we show here that LSECs form a special kind of mixed-type intercellular junctions characterized by co-occurrence of endothelial AJ proteins, and of ZO-1 and -2, and JAMs. The distinct molecular architecture of the intercellular junctional complexes of LSECs corroborates previous ultrastructural findings and provides the molecular basis for further analyses of the endothelial barrier function of liver sinusoids under pathologic conditions ranging from hepatic inflammation to formation of liver metastasis.

  11. Systemic mastocytosis: A rare cause of non-cirrhotic portal hypertension.

    Science.gov (United States)

    Martins, Cláudio; Teixeira, Cristina; Ribeiro, Suzane; Trabulo, Daniel; Cardoso, Cláudia; Mangualde, João; Freire, Ricardo; Gamito, Élia; Alves, Ana Luísa; Cremers, Isabelle; Alves, Cecília; Neves, Anabela; Oliveira, Ana Paula

    2016-07-28

    Mastocytosis is a clonal neoplastic disorder of the mast cells (MC) that can be limited to the skin (cutaneous mastocytosis) or involve one or more extracutaneous organs (systemic mastocytosis). The clinical manifestations of mastocytosis are heterogeneous ranging from indolent disease with a long-term survival to a highly aggressive neoplasm with survival of about 6 mo. Although liver involvement in aggressive systemic mastocytosis (ASM) is relatively common, the development of portal hypertension with or without cirrhosis is rare. We report a case of ASM without skin involvement in a 72-year-old caucasian male who presented with non-cirrhotic portal hypertension based on clinical, analytical, imagiological and endoscopic findings. Given the hematological picture, the correct diagnosis was established based on ancillary tests for MC using bone marrow aspirates and biopsy. Extensive involvement of the liver and gastrointestinal tract was histologically documented. The disease progressed rapidly and severe pancytopenia and recurrent upper gastrointestinal bleeding became the dominant problem. This case illustrates the challenge in establishing a diagnosis of ASM especially when the clinical picture is atypical and without skin involvement. Gastroenterologists should consider infiltrative disease, particularly systemic mastocytosis, as a differential diagnosis in a clinical case of portal hypertension of unknown etiology.

  12. IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats.

    Science.gov (United States)

    Zhao, Tian-Yu; Su, Li-Ping; Ma, Chun-Ye; Zhai, Xiao-Han; Duan, Zhi-Jun; Zhu, Ying; Zhao, Gang; Li, Chun-Yan; Wang, Li-Xia; Yang, Dong

    2015-07-08

    Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines. We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings. Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells. Tight junction dysfunction develops during the

  13. Nitro-oxidative stress, VEGF and MMP-9 in patients with cirrhotic and non-cirrhotic portal hypertension.

    Science.gov (United States)

    Muti, Leon Adrian; Pârvu, Alina Elena; Crăciun, Alexandra M; Miron, Nicolae; Acalovschi, Monica

    2015-01-01

    Nitro-oxidative stress may have pathophysiological consequences. The study aimed to assess the nitro-oxidative stress, the vascular growth factor, and metalloproteinase-9 levels in patients with noncirrohic and cirrhotic portal hypertension. Patients with noncirrhotic portal hypertension (n=50) and cirrhotic portal hypertension (n=50) from the 3rd Medical Clinic in Cluj-Napoca Romania were prospectively enrolled between October 2004 and October 2006. A control group of healthy volunteers (n=50) was also evaluated. Nitro-oxidative stress was assessed by measuring serum concentration of nitrites and nitrate, 3-nitrotyrosine, total oxidative status, total antioxidant reactivity, and oxidative stress index. Serum vascular growth factor and matrix metalloproteinase-9 were also determined. Serum nitrites and nitrate levels significantly increased in both noncirrhotic (pportal hypertension (p=0.057). 3-nitrotyrosine also increased in noncirrhotic (p=0.001) and cirrhotic portal hypertension patients (p=0.014). Total oxidative status showed a significant increase in noncirrhotic (pportal hypertension (pportal hypertension (pportal hypertension a significant systemic nitro-oxidative stress was found, correlated with an increase of VEGF. MMP-9 decreased in noncirrhotic portal hypertension.

  14. Liver Immunology

    Science.gov (United States)

    Bogdanos, Dimitrios P.; Gao, Bin; Gershwin, M. Eric

    2014-01-01

    The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity. PMID:23720323

  15. From the Cover: Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells

    Science.gov (United States)

    Sapir, Tamar; Shternhall, Keren; Meivar-Levy, Irit; Blumenfeld, Tamar; Cohen, Hamutal; Skutelsky, Ehud; Eventov-Friedman, Smadar; Barshack, Iris; Goldberg, Iris; Pri-Chen, Sarah; Ben-Dor, Lya; Polak-Charcon, Sylvie; Karasik, Avraham; Shimon, Ilan; Mor, Eytan; Ferber, Sarah

    2005-05-01

    Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of adult human liver cells into functional insulin-producing cells. PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner. When transplanted under the renal capsule of diabetic, immunodeficient mice, the cells ameliorated hyperglycemia for prolonged periods of time. Inducing developmental redirection of adult liver offers the potential of a cell-replacement therapy for diabetics by allowing the patient to be the donor of his own insulin-producing tissue. pancreas | transdifferentiation

  16. Safety and efficacy of Mangafodipir trisodium in patients with liver lesions and cirrhosis

    International Nuclear Information System (INIS)

    Marti-Bonmati, Luis; Fog, Amura F.; de Beeck, Bart Op; Kane, Pauline; Fagertun, Hans

    2003-01-01

    Mangafodipir trisodium (Mn-DPDP, Teslascan) is a well-tolerated liver contrast agent. Although the enhancement characteristics of the cirrhotic liver after Mangafodipir trisodium administration have been studied, at present there is no published data on the impact that cirrhosis might have on the safety and efficacy profiles of this agent. Our objective is to evaluate by means of a retrospective comparison the safety and efficacy of Mangafodipir trisodium in patients with underlying cirrhosis who were examined for suspicion of focal liver lesions. A total of 923 patients received Mangafodipir trisodium (5 μmol/kg) in 11 prospective randomized European clinical trials. Adverse events and discomfort were recorded and graded in all patients. The efficacy analyses were performed on the subsets consisting of 617 patients with independent lesion counts (detection), and on the subset with 399 patients with independent and onsite final lesion diagnosis (characterization). Of the 399 patients, 149 had histologic confirmation. One hundred eighty of 923 patients (19.5%) had cirrhosis. There were no main differences between cirrhotic and non-cirrhotic patients. Adverse events were observed in 64 patients (6.9%), 6.7% in the cirrhotic group and 7.0% in the non-cirrhotic group, a non-significant difference. Adverse events in most patients were mild or moderate. The presence and intensity of the events did not differ between groups. Discomfort was recorded in 79 patients (8.6%), equally distributed in cirrhotic (6.1%) and non-cirrhotic (9.2%) patients. Regarding lesion count, significantly more lesions were found in the post- than in the precontrast images in both the cirrhotic and non-cirrhotic groups (p<0.0001). This increase was not influenced by the presence of liver cirrhosis (p=0.94). Lesion characterization was significantly improved in cirrhotic patients after administration of Mangafodipir trisodium (p=0.002) but not in non-cirrhotic patients (p=0.13). Mangafodipir

  17. Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients

    Science.gov (United States)

    Shi, Ming; Zhang, Zheng; Xu, Ruonan; Lin, Hu; Fu, Junliang; Zou, Zhengsheng; Zhang, Aimin; Shi, Jianfei; Chen, Liming; Lv, Sa; He, Weiping; Geng, Hua; Jin, Lei; Liu, Zhenwen

    2012-01-01

    Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cord-derived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients. PMID:23197664

  18. An Experimental Study to Measure the Mechanical Properties of the Human Liver.

    Science.gov (United States)

    Karimi, Alireza; Shojaei, Ahmad

    2018-01-01

    Since the liver is one of the most important organs of the body that can be injured during trauma, that is, during accidents like car crashes, understanding its mechanical properties is of great interest. Experimental data is needed to address the mechanical properties of the liver to be used for a variety of applications, such as the numerical simulations for medical purposes, including the virtual reality simulators, trauma research, diagnosis objectives, as well as injury biomechanics. However, the data on the mechanical properties of the liver capsule is limited to the animal models or confined to the tensile/compressive loading under single direction. Therefore, this study was aimed at experimentally measuring the axial and transversal mechanical properties of the human liver capsule under both the tensile and compressive loadings. To do that, 20 human cadavers were autopsied and their liver capsules were excised and histologically analyzed to extract the mean angle of a large fibers population (bundle of the fine collagen fibers). Thereafter, the samples were cut and subjected to a series of axial and transversal tensile/compressive loadings. The results revealed the tensile elastic modulus of 12.16 ± 1.20 (mean ± SD) and 7.17 ± 0.85 kPa under the axial and transversal loadings respectively. Correspondingly, the compressive elastic modulus of 196.54 ± 13.15 and 112.41 ± 8.98 kPa were observed under the axial and transversal loadings respectively. The compressive axial and transversal maximum/failure stress of the capsule were 32.54 and 37.30 times higher than that of the tensile ones respectively. The capsule showed a stiffer behavior under the compressive load compared to the tensile one. In addition, the axial elastic modulus of the capsule was found to be higher than that of the transversal one. The findings of the current study have implications not only for understanding the mechanical properties of the human capsule tissue under tensile

  19. A proteomic strategy to identify novel serum biomarkers for liver cirrhosis and hepatocellular cancer in individuals with fatty liver disease

    Directory of Open Access Journals (Sweden)

    Stewart Stephen

    2009-08-01

    Full Text Available Abstract Background Non-alcoholic fatty liver disease (NAFLD has a prevalence of over 20% in Western societies. Affected individuals are at risk of developing both cirrhosis and hepatocellular cancer (HCC. Presently there is no cost effective population based means of identifying cirrhotic individuals and even if there were, our ability to perform HCC surveillance in the at risk group is inadequate. We have performed a pilot proteomic study to assess this as a strategy for serum biomarker detection. Methods 2D Gel electrophoresis was performed on immune depleted sera from 3 groups of patients, namely those with (1 pre-cirrhotic NAFLD (2 cirrhotic NAFLD and (3 cirrhotic NAFLD with co-existing HCC. Five spots differentiating at least one of these three groups were characterised by mass spectroscopy. An ELISA assay was optimised and a cross sectional study assessing one of these serum spots was performed on serum from 45 patients with steatohepatitis related cirrhosis and HCC and compared to 77 patients with histologically staged steatohepatitis. Results Four of the spots identified were apolipoprotein isoforms, the pattern of which was able to differentiate the three groups. The 5th spot, seen in the serum of cirrhotic individuals and more markedly in those with HCC, was identified as CD5 antigen like (CD5L. By ELISA assay, although CD5L was markedly elevated in a number of cirrhotic individuals with HCC, its overall ability to distinguish non-cancer from cancer individuals as determined by AUC ROC analysis was poor. However, serum CD5L was dramatically increased, independently of age, sex, and the presence of necroinflammation, in the serum of individuals with NAFLD cirrhosis relative to those with pre-cirrhotic disease. Conclusion This novel proteomic strategy has identified a number of candidate biomarkers which may have benefit in the surveillance and diagnosis of individuals with chronic liver disease and/or HCC.

  20. Dynamic PET of human liver inflammation: impact of kinetic modeling with optimization-derived dual-blood input function.

    Science.gov (United States)

    Wang, Guobao; Corwin, Michael T; Olson, Kristin A; Badawi, Ramsey D; Sarkar, Souvik

    2018-05-30

    The hallmark of nonalcoholic steatohepatitis is hepatocellular inflammation and injury in the setting of hepatic steatosis. Recent work has indicated that dynamic 18F-FDG PET with kinetic modeling has the potential to assess hepatic inflammation noninvasively, while static FDG-PET did not show a promise. Because the liver has dual blood supplies, kinetic modeling of dynamic liver PET data is challenging in human studies. The objective of this study is to evaluate and identify a dual-input kinetic modeling approach for dynamic FDG-PET of human liver inflammation. Fourteen human patients with nonalcoholic fatty liver disease were included in the study. Each patient underwent one-hour dynamic FDG-PET/CT scan and had liver biopsy within six weeks. Three models were tested for kinetic analysis: traditional two-tissue compartmental model with an image-derived single-blood input function (SBIF), model with population-based dual-blood input function (DBIF), and modified model with optimization-derived DBIF through a joint estimation framework. The three models were compared using Akaike information criterion (AIC), F test and histopathologic inflammation reference. The results showed that the optimization-derived DBIF model improved the fitting of liver time activity curves and achieved lower AIC values and higher F values than the SBIF and population-based DBIF models in all patients. The optimization-derived model significantly increased FDG K1 estimates by 101% and 27% as compared with traditional SBIF and population-based DBIF. K1 by the optimization-derived model was significantly associated with histopathologic grades of liver inflammation while the other two models did not provide a statistical significance. In conclusion, modeling of DBIF is critical for kinetic analysis of dynamic liver FDG-PET data in human studies. The optimization-derived DBIF model is more appropriate than SBIF and population-based DBIF for dynamic FDG-PET of liver inflammation. © 2018

  1. Demonstration of Hepatitis C Virus RNA with In Situ Hybridization Employing a Locked Nucleic Acid Probe in Humanized Liver of Infected Chimeric Mice and in Needle-Biopsied Human Liver

    Directory of Open Access Journals (Sweden)

    Kazuya Shiogama

    2013-01-01

    Full Text Available Background. In situ hybridization (ISH with high sensitivity has been requested to demonstrate hepatitis C virus (HCV RNA in formalin-fixed, paraffin-embedded (FFPE sections of the liver. Methods. ISH employing a locked-nucleic-acid- (LNA-modified oligonucleotide probe and biotin-free catalyzed signal amplification system (CSAII was applied to HCV-RNA detection in the liver tissue. Nested reverse-transcription polymerase chain reaction (RT-PCR was performed for HCV genotyping using total RNA extracted from FFPE sections. The target tissues included FFPE tissue sections of humanized livers in HCV-infected chimeric mice (HCV genotypes 1a, 1b, and 2a and noninfected and of needle-biopsied livers from HCV-infected patients. Results. HCV-RNA was demonstrated with the ISH technique in HCV-infected liver tissues from both chimeric mice and 9 (82% of 11 patients with HCV infection. The HCV signals were sensitive to RNase. Nested RT-PCR confirmed the genotype in 8 (73% of 11 livers (type 1b: 6 lesions and type 2a: 2 lesions. HCV-RNA was not identified in chronic hepatitis B lesions, fatty liver, autoimmune hepatitis, and hepatocellular carcinoma. Conclusion. ISH using the LNA-modified oligonucleotide probe and CSAII was applicable to detecting HCV-RNA in routinely prepared FFPE liver specimens.

  2. Regulation of coagulation factor XI expression by microRNAs in the human liver.

    Directory of Open Access Journals (Sweden)

    Salam Salloum-Asfar

    Full Text Available High levels of factor XI (FXI increase the risk of thromboembolic disease. However, the genetic and environmental factors regulating FXI expression are still largely unknown. The aim of our study was to evaluate the regulation of FXI by microRNAs (miRNAs in the human liver. In silico prediction yielded four miRNA candidates that might regulate FXI expression. HepG2 cells were transfected with miR-181a-5p, miR-23a-3p, miR-16-5p and miR-195-5p. We used mir-494, which was not predicted to bind to F11, as a negative control. Only miR-181a-5p caused a significant decrease both in FXI protein and F11 mRNA levels. In addition, transfection with a miR-181a-5p inhibitor in PLC/PRF/5 hepatic cells increased both the levels of F11 mRNA and extracellular FXI. Luciferase assays in human colon cancer cells deficient for Dicer (HCT-DK demonstrated a direct interaction between miR-181a-5p and 3'untranslated region of F11. Additionally, F11 mRNA levels were inversely and significantly correlated with miR-181a-5p levels in 114 healthy livers, but not with miR-494. This study demonstrates that FXI expression is directly regulated by a specific miRNA, miR-181a-5p, in the human liver. Future studies are necessary to further investigate the potential consequences of miRNA dysregulation in pathologies involving FXI.

  3. Metabolism of ginger component [6]-shogaol in liver microsomes from mouse, rat, dog, monkey, and human.

    Science.gov (United States)

    Chen, Huadong; Soroka, Dominique; Zhu, Yingdong; Sang, Shengmin

    2013-05-01

    There are limited data on the metabolism of [6]-shogaol (6S), a major bioactive component of ginger. This study demonstrates metabolism of 6S in liver microsomes from mouse, rat, dog, monkey, and human. The in vitro metabolism of 6S was compared among five species using liver microsomes from mouse, rat, dog, monkey, and human. Following incubations with 6S, three major reductive metabolites 1-(4'-hydroxy-3'-methoxyphenyl)-4-decen-3-ol (M6), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9), and 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11), as well as two new oxidative metabolites (1E,4E)-1-(4'-hydroxy-3'-methoxyphenyl)-deca-1,4-dien-3-one (M14) and (E)-1-(4'-hydroxy-3'-methoxyphenyl)-dec-1-en-3-one (M15) were found in all species. The kinetic parameters of M6 in liver microsomes from each respective species were quantified using Michaelis-Menten theory. A broad CYP-450 inhibitor, 1-aminobenzotriazole, precluded the formation of oxidative metabolites, M14 and M15, and 18β-glycyrrhetinic acid, an aldo-keto reductase inhibitor, eradicated the formation of the reductive metabolites M6, M9, and M11 in all species. Metabolites M14 and M15 were tested for cancer cell growth inhibition and induction of apoptosis and both showed substantial activity, with M14 displaying greater potency than 6S. We conclude that 6S is metabolized extensively in mammalian species mouse, rat, dog, monkey, and human, and that there are significant interspecies differences to consider when planning preclinical trials toward 6S chemoprevention. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Featured Article: Isolation, characterization, and cultivation of human hepatocytes and non-parenchymal liver cells

    Science.gov (United States)

    Pfeiffer, Elisa; Kegel, Victoria; Zeilinger, Katrin; Hengstler, Jan G; Nüssler, Andreas K; Seehofer, Daniel

    2015-01-01

    Primary human hepatocytes (PHH) are considered to be the gold standard for in vitro testing of xenobiotic metabolism and hepatotoxicity. However, PHH cultivation in 2D mono-cultures leads to dedifferentiation and a loss of function. It is well known that hepatic non-parenchymal cells (NPC), such as Kupffer cells (KC), liver endothelial cells (LEC), and hepatic stellate cells (HSC), play a central role in the maintenance of PHH functions. The aims of the present study were to establish a protocol for the simultaneous isolation of human PHH and NPC from the same tissue specimen and to test their suitability for in vitro co-culture. Human PHH and NPC were isolated from tissue obtained by partial liver resection by a two-step EDTA/collagenase perfusion technique. The obtained cell fractions were purified by Percoll density gradient centrifugation. KC, LEC, and HSC contained in the NPC fraction were separated using specific adherence properties and magnetic activated cell sorting (MACS®). Identified NPC revealed a yield of 1.9 × 106 KC, 2.7 × 105 LEC and 4.7 × 105 HSC per gram liver tissue, showing viabilities >90%. Characterization of these NPC showed that all populations went through an activation process, which influenced the cell fate. The activation of KC strongly depended on the tissue quality and donor anamnesis. KC became activated in culture in association with a loss of viability within 4–5 days. LEC lost specific features during culture, while HSC went through a transformation process into myofibroblasts. The testing of different culture conditions for HSC demonstrated that they can attenuate, but not prevent dedifferentiation in vitro. In conclusion, the method described allows the isolation and separation of PHH and NPC in high quality and quantity from the same donor. PMID:25394621

  5. Detection of human leukocyte antigen compatibility and antibodies in liver transplantation in China

    Institute of Scientific and Technical Information of China (English)

    Xue-Qin Meng; Xuan Zhang; Jun Fan; Lin Zhou; Bing Hao; Xiao-Ming Chen; Wei-Hang Ma; Shu-Sen Zheng

    2009-01-01

    BACKGROUND: The exact roles of human leukocyte antigen (HLA) compatibility, HLA antibodies and underlying diseases in acute rejection of liver transplants are not clear. Moreover, cytomegalovirus (CMV) infection, one of the most common infections after transplantation, is related to HLA genotype and the incidence of acute rejection. METHODS: Since there are controversial reports, we analyzed the impact of HLA matching, HLA antibodies and underlying diseases in 38 liver transplant recipients in China, and assessed the association of CMV infection and HLA compatibility. RESULTS: The frequency of no HLA compatibility was high in patients without antigenemia (P=0.019). All 17 patients with HLA-A matching developed antigenemia (P0.05). In patients with acute rejection, no differences were found in the incidence of acute rejection in transplants for hepatitis B, tumors, or combined hepatitis B and tumors (P>0.05).CONCLUSIONS: There are fewer acute rejections in transplants with more HLA compatibilities. Speciifc investigations of underlying diseases and HLA typing may be necessary in liver transplantation. The mechanisms of CMV infection and HLA matching should be further studied. HLA before transplantation should be examined for the prevention of acute rejection and CMV infection.

  6. Extracellular vesicles from human liver stem cells restore argininosuccinate synthase deficiency.

    Science.gov (United States)

    Herrera Sanchez, Maria Beatriz; Previdi, Sara; Bruno, Stefania; Fonsato, Valentina; Deregibus, Maria Chiara; Kholia, Sharad; Petrillo, Sara; Tolosano, Emanuela; Critelli, Rossana; Spada, Marco; Romagnoli, Renato; Salizzoni, Mauro; Tetta, Ciro; Camussi, Giovanni

    2017-07-27

    Argininosuccinate synthase (ASS)1 is a urea cycle enzyme that catalyzes the conversion of citrulline and aspartate to argininosuccinate. Mutations in the ASS1 gene cause citrullinemia type I, a rare autosomal recessive disorder characterized by neonatal hyperammonemia, elevated citrulline levels, and early neonatal death. Treatment for this disease is currently restricted to liver transplantation; however, due to limited organ availability, substitute therapies are required. Recently, extracellular vesicles (EVs) have been reported to act as intercellular transporters carrying genetic information responsible for cell reprogramming. In previous studies, we isolated a population of stem cell-like cells known as human liver stem cells (HLSCs) from healthy liver tissue. Moreover, EVs derived from HLSCs were reported to exhibit regenerative effects on the liver parenchyma in models of acute liver injury. The aim of this study was to evaluate whether EVs derived from normal HLSCs restored ASS1 enzymatic activity and urea production in hepatocytes differentiated from HLSCs derived from a patient with type I citrullinemia. HLSCs were isolated from the liver of a patient with type I citrullinemia (ASS1-HLSCs) and characterized by fluorescence-activated cell sorting (FACS), immunofluorescence, and DNA sequencing analysis. Furthermore, their differentiation capabilities in vitro were also assessed. Hepatocytes differentiated from ASS1-HLSCs were evaluated by the production of urea and ASS enzymatic activity. EVs derived from normal HLSCs were purified by differential ultracentrifugation followed by floating density gradient. The EV content was analyzed to identify the presence of ASS1 protein, mRNA, and ASS1 gene. In order to obtain ASS1-depleted EVs, a knockdown of the ASS1 gene in HLSCs was performed followed by EV isolation from these cells. Treating ASS1-HLSCs with EVs from HLSCs restored both ASS1 activity and urea production mainly through the transfer of ASS1 enzyme

  7. Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24

    Energy Technology Data Exchange (ETDEWEB)

    Oda, Yuki; Nakajima, Miki; Mohri, Takuya [Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Takamiya, Masataka; Aoki, Yasuhiro [Department of Legal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka 020-8505 (Japan); Fukami, Tatsuki [Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@kenroku.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan)

    2012-05-01

    Aryl hydrocarbon receptor nuclear translocator (ARNT) forms a heterodimer with aryl hydrocarbon receptor or hypoxia inducible factor 1α to mediate biological responses to xenobiotic exposure and hypoxia. Although the regulation mechanism of the ARNT expression is largely unknown, earlier studies reported that the human ARNT protein level was decreased by hydrogen peroxide or reactive oxygen species. These stimuli increase the miR-24 level in various human cell lines. In silico analysis predicts that some microRNAs including miR-16 and miR-23b may bind to ARNT mRNA. This background prompted us to investigate whether human ARNT is regulated by microRNAs. Overexpression of miR-24 into HuH-7 and HepG2 cells significantly decreased the ARNT protein level, but not the ARNT mRNA level, indicating translational repression. However, overexpression of miR-16 or miR-23b caused no change in the ARNT expression. The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. Luciferase assay was performed to determine the element on the ARNT mRNA to which miR-24 binds. Finally, it was demonstrated that the miR-24 levels in a panel of 26 human livers were inversely correlated with the protein levels or the translational efficiency of ARNT. Taken together, we found that miR-24 negatively regulates ARNT expression in human liver, affecting the expression of its downstream genes. miR-24 would be one of the factors underlying the mechanisms by which ARNT protein is decreased by reactive oxygen species. -- Highlights: ► Overexpression of miR-24 into human cell lines decreased the ARNT protein level. ► miR-24-dependent down-regulation of ARNT affected the expression of CYP1A1 and CA IX. ► Luciferase assay was performed to identify functional MREs for miR-24 in ARNT mRNA. ► The miR-24 levels inversely correlated with the ARNT protein levels in human liver.

  8. Argininosuccinate synthetase as a plasma biomarker of liver injury after acetaminophen overdose in rodents and humans

    Science.gov (United States)

    McGill, Mitchell R.; Cao, Mengde; Svetlov, Archie; Sharpe, Matthew R.; Williams, C. David; Curry, Steven C.; Farhood, Anwar; Jaeschke, Hartmut; Svetlov, Stanislav I.

    2014-01-01

    Context New biomarkers are needed in acetaminophen (APAP) hepatotoxicity. Plasma argininosuccinate synthetase (ASS) is a promising candidate. Objective Characterize ASS in APAP hepatotoxicity. Methods ASS was measured in plasma from rodents and humans with APAP hepatotoxicity. Results In mice, ASS increased before injury, peaked before ALT, and decreased rapidly. Fischer rats had a greater increase in ASS relative to ALT. Patients with abnormal liver test results had very high ASS compared to controls. ASS appeared to increase early in some patients, and declined rapidly in all. Conclusions : ASS may be a useful biomarker of acute cell death in APAP hepatotoxicity. PMID:24597531

  9. Development and evaluation of a technique for in vivo monitoring of 60Co in human liver

    Science.gov (United States)

    Gomes, GH; Silva, MC; Mello, JQ; Dantas, ALA; Dantas, BM

    2018-03-01

    60Co is an artificial radioactive metal produced by activation of iron with neutrons. It decays by beta particles and gamma radiation and represents a risk of internal exposure of workers involved in the maintenance of nuclear power reactors. Intakes can be quantified through in vivo monitoring. This work describes the development of a technique for the quantification of 60Co in human liver. The sensitivity of the method is evaluated based on the minimum detectable effective doses. The results allow to state that the technique is suitable either for monitoring of occupational exposures or evaluation of accidental intakes.

  10. Potent inhibition of cytochrome P450 2B6 by sibutramine in human liver microsomes.

    Science.gov (United States)

    Bae, Soo Hyeon; Kwon, Min Jo; Choi, Eu Jin; Zheng, Yu Fen; Yoon, Kee Dong; Liu, Kwang-Hyeon; Bae, Soo Kyung

    2013-09-05

    The present study was performed to evaluate the potency and specificity of sibutramine as an inhibitor of the activities of nine human CYP isoforms in liver microsomes. Using a cocktail assay, the effects of sibutramine on specific marker reactions of the nine CYP isoforms were measured in human liver microsomes. Sibutramine showed potent inhibition of CYP2B6-mediated bupropion 6-hydroxylation with an IC50 value of 1.61μM and Ki value of 0.466μM in a competitive manner at microsomal protein concentrations of 0.25mg/ml; this was 3.49-fold more potent than the typical CYP2B6 inhibitor thio-TEPA (Ki=1.59μM). In addition, sibutramine slightly inhibited CYP2C19 activity (Ki=16.6μM, noncompetitive inhibition) and CYP2D6 activity (Ki=15.7μM, noncompetitive inhibition). These observations indicated 35.6- and 33.7-fold decreases in inhibition potency, respectively, compared with that of CYP2B6 by sibutramine. However, no inhibition of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, or CYP2E1 activities was observed. In addition, the CYP2B6 inhibitory potential of sibutramine was enhanced at a lower microsomal protein concentration of 0.05mg/ml. After 30min preincubation of human liver microsomes with sibutramine in the presence of NADPH, no shift in IC50 was observed in terms of inhibition of the activities of the nine CYPs, suggesting that sibutramine is not a time-dependent inactivator. These observations suggest that sibutramine is a selective and potent inhibitor of CYP2B6 in vitro, whereas inhibition of other CYPs is substantially lower. These in vitro data support the use of sibutramine as a well-known inhibitor of CYP2B6 for routine screening of P450 reversible inhibition when human liver microsomes are used as the enzyme source. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Production of factor VIII by human liver sinusoidal endothelial cells transplanted in immunodeficient uPA mice.

    Directory of Open Access Journals (Sweden)

    Marina E Fomin

    Full Text Available Liver sinusoidal endothelial cells (LSECs form a semi-permeable barrier between parenchymal hepatocytes and the blood. LSECs participate in liver metabolism, clearance of pathological agents, immunological responses, architectural maintenance of the liver and synthesis of growth factors and cytokines. LSECs also play an important role in coagulation through the synthesis of Factor VIII (FVIII. Herein, we phenotypically define human LSECs isolated from fetal liver using flow cytometry and immunofluorescence microscopy. Isolated LSECs were cultured and shown to express endothelial markers and markers specific for the LSEC lineage. LSECs were also shown to engraft the liver when human fetal liver cells were transplanted into immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA transgene (uPA-NOG mice. Engrafted cells expressed human Factor VIII at levels approaching those found in human plasma. We also demonstrate engraftment of adult LSECs, as well as hepatocytes, transplanted into uPA-NOG mice. We propose that overexpression of uPA provides beneficial conditions for LSEC engraftment due to elevated expression of the angiogenic cytokine, vascular endothelial growth factor. This work provides a detailed characterization of human midgestation LSECs, thereby providing the means for their purification and culture based on their expression of CD14 and CD32 as well as a lack of CD45 expression. The uPA-NOG mouse is shown to be a permissive host for human LSECs and adult hepatocytes, but not fetal hepatoblasts. Thus, these mice provide a useful model system to study these cell types in vivo. Demonstration of human FVIII production by transplanted LSECs encourages further pursuit of LSEC transplantation as a cellular therapy for the treatment of hemophilia A.

  12. Insulin Radioimmunoassay for Clinical Research in Psychiatric, Pancreatic, Cirrhotic and Irradiated Patients

    Energy Technology Data Exchange (ETDEWEB)

    Czerniak, P.; Chlebowski, J.; Kulcar, S.; Boruchowski, Sabina [Department Of Radiotherapy and Isotopes and Department of Psychiatry, Tel-Aviv University Medical School (Israel); Faculty for Continuing Medical Education, Tel-Hashomer Hospital, Tel-Hashomer (Israel)

    1970-02-15

    A modified Hales-Randle method for insulin radioimmunoassay is described. An insulin response curve was established in normal cases after glucose loading. Pathological changes were then investigated in patients and animals before and after therapeutic, operative and radiological procedures. Four representative groups of this material will be illustrated. (1) Psychotic patients (acute and chronic schizophrenics, neurotics and depressives) were examined with the aim of learning about the variable effects produced by insulin shock-therapy, as well as for biochemical diagnosis purposes in psychotics. Highest insulin response curves were found in chronic schizophrenics with improvement after insulin therapy. Schizophrenics without improvement presented different curves. Lowest insulin values were found in acute schizophrenia. Depressives and anxiety neurotics showed insulin tolerance curves similar to those of non-psychotic patients. (2) Pancreatic patients. Special attention was paid to pancreatic carcinoma (insulinoma excepted). In most cases of pancreatic carcinoma a very low and flat insulin tolerance curve was found. The above findings may be of a diagnostic importance in this condition, which is clinically hardly recognized. (3) Liver cirrhotic patients. A special group of shunt operated patients was investigated. The study was performed on eight liver cirrhotics before and after porto-caval or reno-splenal shunt operation. The plasma insulin level was examined in the vena cava, renal and cubital blood. The influence of tolbutamide was analysed. The normally occurring retention of insulin by normal hepatic tissue was found to be considerably disturbed. Other interesting changes were observed. (4) The plasma insulin level in the radiologically exposed. Experimental and clinical studies were performed, with insulin doses before and after radiation. Whole body X-ray exposure (300 rads) to rats resulted in a rapid lowering of insulin or its disappearance. Recovery was

  13. [Related factors to re-bleeding and mortality in cirrhotic patients with acute variceal bleeding at Hipolito Unanue Hospital, Lima, Peru].

    Science.gov (United States)

    Parra Pérez, Víctor Felipe; Raymundo Cajo, Roxana Magali; Gutiérrez de Aranguren, Constantino Fernando

    2013-01-01

    To determine related factors to 5 days re-bleeding and 6 week-mortality of an episode of variceal bleeding in cirrhotic patients. Observational, descriptive, co relational, retrospective study. In this study were included the cirrhotic patients who entered to Hipolito Unanue Hospital, Lima, Peru, between January 2006 and February 2012 with suspicion of variceal bleeding. Were excluded patients who bled from nonvariceal origin, or that did not have the data in clinical history to calculate the Child Pugh score, the Model for terminal diseases of the liver (MELD), or the endoscopic report detailing the bleeding source and the presence of esophageal and/or gastric varices. We include 63 patients, 35 (55.6%) were men. The median of age was of 64 years. 26 of them (41.3%) were Child Pugh C, where as the median of MELD score was 9. The multivariate analysis found that the Child Pugh score was related to 6 weeks-mortality (p=0,003), where as the presence of active bleeding during endoscopy (p=0.012) and the value of creatinine (p=0.012) were related to 5 days re-bleeding. The Child Pugh score was related to 6 weeks-mortality in cirrhotic patients with variceal bleeding. Active bleeding during endoscopy and the value of creatinine were related to 5 days re-bleeding.

  14. Transjugular portal vein recanalization with creation of intrahepatic portosystemic shunt (PVR-TIPS) in patients with chronic non-cirrhotic, non-malignant portal vein thrombosis.

    Science.gov (United States)

    Klinger, Christoph; Riecken, Bettina; Schmidt, Arthur; De Gottardi, Andrea; Meier, Benjamin; Bosch, Jaime; Caca, Karel

    2018-03-01

    To determine safety and efficacy of transjugular portal vein recanalization with creation of intrahepatic portosystemic shunt (PVR-TIPS) in patients with chronic non-cirrhotic, non-malignant portal vein thrombosis (PVT). This retrospective study includes 17 consecutive patients with chronic non-cirrhotic PVT (cavernous transformation n = 15). PVR-TIPS was indicated because of variceal bleeding (n = 13), refractory ascites (n = 2), portal biliopathy with recurrent cholangitis (n = 1), or abdominal pain (n = 1). Treatment consisted of a combination of transjugular balloon angioplasty, mechanical thrombectomy, and-depending on extent of residual thrombosis-transjugular intrahepatic portosystemic shunt and additional stenting of the portal venous system. Recanalization was successful in 76.5 % of patients despite cavernous transformation in 88.2 %. Both 1- and 2-year secondary PV and TIPS patency rates were 69.5 %. Procedure-related bleeding complications occurred in 2 patients (intraperitoneal bleeding due to capsule perforation, n = 1; liver hematoma, n = 1) and resolved spontaneously. However, 1 patient died due to subsequent nosocomial pneumonia. During follow-up, 3 patients with TIPS occlusion and PVT recurrence experienced portal hypertensive complications. PVR-TIPS is safe and effective in selected patients with chronic non-cirrhotic PVT. Due to technical complexity and possible complications, it should be performed only in specialized centers with high experience in TIPS procedures. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Initial prevalence of anal human papilloma virus infection in liver transplant recipients.

    Science.gov (United States)

    Grąt, Michał; Grąt, Karolina; Hołówko, Wacław; Malejczyk, Magdalena; Walter de Walthoffen, Szymon; Lewandowski, Zbigniew; Kobryń, Konrad; Patkowski, Waldemar; Majewski, Sławomir; Młynarczyk, Grażyna; Krawczyk, Marek

    2014-08-01

    Although liver transplant recipients are at increased risk of human papilloma virus (HPV)-related anal cancer, limited data are available regarding the initial prevalence of anal HPV infection in this population. Anal swabs collected from 50 liver transplant recipients within the first three postoperative weeks were subjected to real-time polymerase chain reaction for detection of the four HPV genotypes: 6, 11, 16, and 18. Predictors of any, low-risk, and high-risk anal HPV infection were evaluated. Overall, the prevalence of any anal HPV infection was 18.0%, with the corresponding rates for high- and low-risk HPV genotypes being 8.0% and 10.0%, respectively. Infection with any type of anal HPV was higher in patients with hepatitis B virus (HBV) infection (P = 0.027), ≥3 sexual partners (P = 0.031), and alcoholic liver disease (P = 0.063). HBV infection was the only factor significantly associated with high-risk HPV infection (P = 0.038). Male sex (P = 0.050), age ≥52 years (P = 0.016), ≥30 sexual partners (P = 0.003), age at first intercourse ≤18 years (P = 0.045), and time since first intercourse ≥38 years (P = 0.012) were identified as predictors of low-risk HPV infection. These results indicate that HPV vaccination of liver transplant candidates and screening for anal HPV infection in high-risk groups should be considered. © 2014 Steunstichting ESOT.

  16. Human fetal liver stromal cells that overexpress bFGF support growth and maintenance of human embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Jiafei Xi

    Full Text Available In guiding hES cell technology toward the clinic, one key issue to be addressed is to culture and maintain hES cells much more safely and economically in large scale. In order to avoid using mouse embryonic fibroblasts (MEFs we isolated human fetal liver stromal cells (hFLSCs from 14 weeks human fetal liver as new human feeder cells. hFLSCs feeders could maintain hES cells for 15 passages (about 100 days. Basic fibroblast growth factor (bFGF is known to play an important role in promoting self-renewal of human embryonic stem (hES cells. So, we established transgenic hFLSCs that stably express bFGF by lentiviral vectors. These transgenic human feeder cells--bFGF-hFLSCs maintained the properties of H9 hES cells without supplementing with any exogenous growth factors. H9 hES cells culturing under these conditions maintained all hES cell features after prolonged culture, including the developmental potential to differentiate into representative tissues of all three embryonic germ layers, unlimited and undifferentiated proliferative ability, and maintenance of normal karyotype. Our results demonstrated that bFGF-hFLSCs feeder cells were central to establishing the signaling network among bFGF, insulin-like growth factor 2 (IGF-2, and transforming growth factor β (TGF-β, thereby providing the framework in which hES cells were instructed to self-renew or to differentiate. We also found that the conditioned medium of bFGF-hFLSCs could maintain the H9 hES cells under feeder-free conditions without supplementing with bFGF. Taken together, bFGF-hFLSCs had great potential as feeders for maintaining pluripotent hES cell lines more safely and economically.

  17. 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...... carcinomas (up to 3- and 6-fold, respectively) and liver metastases from colonic carcinomas (up to 40- and 60-fold, respectively). The up-regulation of both ADAM9 and ADAM12 was correlated with an increase in matrix metalloproteinase 2 expression and activity. In conclusion, in liver cancers ADAM9 and ADAM12......-PCR, cDNA encoding sequences for ADAM9 and ADAM12 were identified in human activated hepatic stellate cells (HSCs). Northern blot analyses showed that HSCs, but not hepatocytes, expressed transcripts for ADAM9 messenger RNA (mRNA) and both the long and short forms of ADAM12. This expression...

  18. Mass spectrometry-based proteomic analysis of human liver cytochrome(s) P450

    Energy Technology Data Exchange (ETDEWEB)

    Shrivas, Kamlesh; Mindaye, Samuel T.; Getie-Kebtie, Melkamu; Alterman, Michail A., E-mail: Michail.Alterman@fda.hhs.gov

    2013-02-15

    The major objective of personalized medicine is to select optimized drug therapies and to a large degree such mission is determined by the expression profiles of cytochrome(s) P450 (CYP). Accordingly, a proteomic case study in personalized medicine is provided by the superfamily of cytochromes P450. Our knowledge about CYP isozyme expression on a protein level is very limited and based exclusively on DNA/mRNA derived data. Such information is not sufficient because transcription and translation events do not lead to correlated levels of expressed proteins. Here we report expression profiles of CYPs in human liver obtained by mass spectrometry (MS)-based proteomic approach. We analyzed 32 samples of human liver microsomes (HLM) of different sexes, ages and ethnicity along with samples of recombinant human CYPs. We have experimentally confirmed that each CYP isozyme can be effectively differentiated by their unique isozyme-specific tryptic peptide(s). Trypsin digestion patterns for almost 30 human CYP isozymes were established. Those findings should assist in selecting tryptic peptides suitable for MS-based quantitation. The data obtained demonstrate remarkable differences in CYP expression profiles. CYP2E1, CYP2C8 and CYP4A11 were the only isozymes found in all HLM samples. Female and pediatric HLM samples revealed much more diverse spectrum of expressed CYPs isozymes compared to male HLM. We have confirmed expression of a number of “rare” CYP (CYP2J2, CYP4B1, CYP4V2, CYP4F3, CYP4F11, CYP8B1, CYP19A1, CYP24A1 and CYP27A1) and obtained first direct experimental data showing expression of such CYPs as CYP2F1, CYP2S1, CYP2W1, CYP4A22, CYP4X1, and CYP26A1 on a protein level. - Highlights: ► First detailed proteomic analysis of CYP isozymes expression in human liver ► Trypsin digestion patterns for almost 30 human CYP isozymes established ► The data obtained demonstrate remarkable differences in CYP expression profiles. ► Female HLM samples revealed more

  19. Mass spectrometry-based proteomic analysis of human liver cytochrome(s) P450

    International Nuclear Information System (INIS)

    Shrivas, Kamlesh; Mindaye, Samuel T.; Getie-Kebtie, Melkamu; Alterman, Michail A.

    2013-01-01

    The major objective of personalized medicine is to select optimized drug therapies and to a large degree such mission is determined by the expression profiles of cytochrome(s) P450 (CYP). Accordingly, a proteomic case study in personalized medicine is provided by the superfamily of cytochromes P450. Our knowledge about CYP isozyme expression on a protein level is very limited and based exclusively on DNA/mRNA derived data. Such information is not sufficient because transcription and translation events do not lead to correlated levels of expressed proteins. Here we report expression profiles of CYPs in human liver obtained by mass spectrometry (MS)-based proteomic approach. We analyzed 32 samples of human liver microsomes (HLM) of different sexes, ages and ethnicity along with samples of recombinant human CYPs. We have experimentally confirmed that each CYP isozyme can be effectively differentiated by their unique isozyme-specific tryptic peptide(s). Trypsin digestion patterns for almost 30 human CYP isozymes were established. Those findings should assist in selecting tryptic peptides suitable for MS-based quantitation. The data obtained demonstrate remarkable differences in CYP expression profiles. CYP2E1, CYP2C8 and CYP4A11 were the only isozymes found in all HLM samples. Female and pediatric HLM samples revealed much more diverse spectrum of expressed CYPs isozymes compared to male HLM. We have confirmed expression of a number of “rare” CYP (CYP2J2, CYP4B1, CYP4V2, CYP4F3, CYP4F11, CYP8B1, CYP19A1, CYP24A1 and CYP27A1) and obtained first direct experimental data showing expression of such CYPs as CYP2F1, CYP2S1, CYP2W1, CYP4A22, CYP4X1, and CYP26A1 on a protein level. - Highlights: ► First detailed proteomic analysis of CYP isozymes expression in human liver ► Trypsin digestion patterns for almost 30 human CYP isozymes established ► The data obtained demonstrate remarkable differences in CYP expression profiles. ► Female HLM samples revealed more

  20. Therapeutic efficacy of human hepatocyte transplantation in a SCID/uPA mouse model with inducible liver disease.

    Directory of Open Access Journals (Sweden)

    Donna N Douglas

    2010-02-01

    Full Text Available Severe Combined Immune Deficient (SCID/Urokinase-type Plasminogen Activator (uPA mice undergo liver failure and are useful hosts for the propagation of transplanted human hepatocytes (HH which must compete with recipient-derived hepatocytes for replacement of the diseased liver parenchyma. While partial replacement by HH has proven useful for studies with Hepatitis C virus, complete replacement of SCID/uPA mouse liver by HH has never been achieved and limits the broader application of these mice for other areas of biomedical research. The herpes simplex virus type-1 thymidine kinase (HSVtk/ganciclovir (GCV system is a powerful tool for cell-specific ablation in transgenic animals. The aim of this study was to selectively eliminate murine-derived parenchymal liver cells from humanized SCID/uPA mouse liver in order to achieve mice with completely humanized liver parenchyma. Thus, we reproduced the HSVtk (vTK/GCV system of hepatic failure in SCID/uPA mice.In vitro experiments demonstrated efficient killing of vTK expressing hepatoma cells after GCV treatment. For in vivo experiments, expression of vTK was targeted to the livers of FVB/N and SCID/uPA mice. Hepatic sensitivity to GCV was first established in FVB/N mice since these mice do not undergo liver failure inherent to SCID/uPA mice. Hepatic vTK expression was found to be an integral component of GCV-induced pathologic and biochemical alterations and caused death due to liver dysfunction in vTK transgenic FVB/N and non-transplanted SCID/uPA mice. In SCID/uPA mice with humanized liver, vTK/GCV caused death despite extensive replacement of the mouse liver parenchyma with HH (ranging from 32-87%. Surprisingly, vTK/GCV-dependent apoptosis and mitochondrial aberrations were also localized to bystander vTK-negative HH.Extensive replacement of mouse liver parenchyma by HH does not provide a secure therapeutic advantage against vTK/GCV-induced cytotoxicity targeted to residual mouse hepatocytes

  1. Early rebleeding and death at 6 weeks in alcoholic cirrhotic patients ...

    African Journals Online (AJOL)

    Background. This study evaluated the incidence of rebleeding and death at 6 weeks after a first episode of acute variceal haemorrhage (AVH) treated by emergency endoscopic sclerotherapy in a large cohort of alcoholic cirrhotic patients. Methods. From January 1984 to December 2006, 310 alcoholic cirrhotic patients (242 ...

  2. Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes

    International Nuclear Information System (INIS)

    Arino, J.; Woon, Chee Wai; Brautigan, D.L.; Miller, T.B. Jr.; Johnson, G.L.

    1988-01-01

    Two cDNA clones were isolated from a human liver library that encode two phosphatase 2A catalytic subunits. The two cDNAs differed in eight amino acids (97% identity) with three nonconservative substitutions. All of the amino acid substitutions were clustered in the amino-terminal domain of the protein. Amino acid sequence of one human liver clone (HL-14) was identical to the rabbit skeletal muscle phosphatase 2A cDNA (with 97% nucleotide identity). The second human liver clone (HL-1) is encoded by a separate gene, and RNA gel blot analysis indicates that both mRNAs are expressed similarly in several human clonal cell lines. Sequence comparison with phosphatase 1 and 2A indicates highly divergent amino acid sequences at the amino and carboxyl termini of the proteins and identifies six highly conserved regions between the two proteins that are predicted to be important for phosphatase enzymatic activity

  3. Human plasma metabolic profiles of benzydamine, a flavin-containing monooxygenase probe substrate, simulated with pharmacokinetic data from control and humanized-liver mice.

    Science.gov (United States)

    Yamazaki-Nishioka, Miho; Shimizu, Makiko; Suemizu, Hiroshi; Nishiwaki, Megumi; Mitsui, Marina; Yamazaki, Hiroshi

    2018-02-01

    1. Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir. 2. Following oral administration of benzydamine (10 mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine. In contrast, in control and ganciclovir-treated TK-NOG mice, concentrations of demethyl benzydamine were slightly higher than those of benzydamine N-oxide. 3. Simulations of human plasma concentrations of benzydamine and its N-oxide were achieved using simplified physiologically based pharmacokinetic models based on data from control TK-NOG mice and from reported benzydamine concentrations after low-dose administration in humans. Estimated clearance rates based on data from humanized-liver and ganciclovir-treated TK-NOG mice were two orders magnitude high. 4. The pharmacokinetic profiles of benzydamine were different for control and humanized-liver TK-NOG mice. Humanized-liver mice are generally accepted human models; however, drug oxidation in mouse kidney might need to be considered when probe substrates undergo FMO-dependent drug oxidation in mouse liver and kidney.

  4. Graft versus host disease in the bone marrow, liver and thymus humanized mouse model.

    Directory of Open Access Journals (Sweden)

    Matthew B Greenblatt

    Full Text Available Mice bearing a "humanized" immune system are valuable tools to experimentally manipulate human cells in vivo and facilitate disease models not normally possible in laboratory animals. Here we describe a form of GVHD that develops in NOD/SCID mice reconstituted with human fetal bone marrow, liver and thymus (NS BLT mice. The skin, lungs, gastrointestinal tract and parotid glands are affected with progressive inflammation and sclerosis. Although all mice showed involvement of at least one organ site, the incidence of overt clinical disease was approximately 35% by 22 weeks after reconstitution. The use of hosts lacking the IL2 common gamma chain (NOD/SCID/γc(-/- delayed the onset of disease, but ultimately did not affect incidence. Genetic analysis revealed that particular donor HLA class I alleles influenced the risk for the development of GVHD. At a cellular level, GVHD is associated with the infiltration of human CD4+ T cells into the skin and a shift towards Th1 cytokine production. GVHD also induced a mixed M1/M2 polarization phenotype in a dermal murine CD11b+, MHC class II+ macrophage population. The presence of xenogenic GVHD in BLT mice both presents a major obstacle in the use of humanized mice and an opportunity to conduct preclinical studies on GVHD in a humanized model.

  5. Splenic embolization in cirrhotic patients with portal hypertension

    International Nuclear Information System (INIS)

    Falappa, P.G.; Cotroneo, A.R.; De Cinque, M.; Maresca, G.; Patane', D.

    1988-01-01

    Over the last four years the authors performed transcatheter embolization of the splenic artery by Gianturco coils in 32 consecutive cirrhotic patients with portal hypertension, splenomegaly, cytopenia and gastro-esophageal varices endoscopically proved. This procedure was especially useful for treatement of splenomegaly and cytopenia because a constant reduction of spleen dimensions and increase in platelet count were registered. The effectiveness of transcatheter embolization and follow-up are based on clinic, hematologic and sonographic findings. Sonographic monitoring is believed to be very useful both to evaluate splenomegaly and signs of portal hypertension and to reveal splenic complications (abscesses). Severe complications have been never registered

  6. Splenic embolization in cirrhotic patients with portal hypertension. US findings

    Energy Technology Data Exchange (ETDEWEB)

    Falappa, P G; Cotroneo, A R; De Cinque, M; Maresca, G; Patane' , D

    1988-01-01

    Over the last four years the authors performed transcatheter embolization of the splenic artery by Gianturco coils in 32 consecutive cirrhotic patients with portal hypertension, splenomegaly, cytopenia and gastro-esophageal varices endoscopically proved. This procedure was especially useful for treatement of splenomegaly and cytopenia because a constant reduction of spleen dimensions and increase in platelet count were registered. The effectiveness of transcatheter embolization and follow-up are based on clinic, hematologic and sonographic findings. Sonographic monitoring is believed to be very useful both to evaluate splenomegaly and signs of portal hypertension and to reveal splenic complications (abscesses). Severe complications have been never registered. 21 refs.

  7. Human amnion epithelial cells expressing HLA-G as novel cell-based treatment for liver disease.

    Science.gov (United States)

    Strom, Stephen C; Gramignoli, Roberto

    2016-09-01

    Despite routine liver transplantation and supporting medical therapies, thousands of patients currently wait for an organ and there is an unmet need for more refined and widely available regenerative strategies to treat liver diseases. Cell transplants attempt to maximize the potential for repair and/or regeneration in liver and other organs. Over 40years of laboratory pre-clinical research and 25years of clinical procedures have shown that certain liver diseases can be treated by the infusion of isolated cells (hepatocyte transplant). However, like organ transplants, hepatocyte transplant suffers from a paucity of tissues useful for cell production. Alternative sources have been investigated, yet with limited success. The tumorigenic potential of pluripotent stem cells together with their primitive level of hepatic differentiation, have limited the use of stem cell populations. Stem cell sources from human placenta, and the amnion tissue in particular are receiving renewed interest in the field of regenerative medicine. Unlike pluripotent stem cells, human amnion epithelial (AE) cells are easily available without ethical or religious concerns; they do not express telomerase and are not immortal or tumorigenic when transplanted. In addition, AE cells have been reported to express genes normally expressed in mature liver, when transplanted into the liver. Moreover, because of the possibility of an immune-privileged status related to their expression of HLA-G, it might be possible to transplant human AE cells without immunosuppression of the recipient. Copyright © 2016. Published by Elsevier Inc.

  8. Menopausal age and sex hormones in postmenopausal women with alcoholic and non-alcoholic liver disease

    DEFF Research Database (Denmark)

    Becker, U; Gluud, C; Farholt, S

    1991-01-01

    In order to evaluate age at menopause and serum sex hormone profiles in postmenopausal women with stable chronic liver disease, six non-cirrhotic alcoholics, 13 with alcoholic cirrhosis, eight with non-alcoholic cirrhosis, and 46 healthy controls were studied. In all three groups, patients were...... and dehydroepiandrosterone sulphate (DHAS) (p less than 0.05). The observed changes may be a consequence of liver disease since similar changes were observed in patients with alcoholic and non-alcoholic liver disease, but an additional effect of alcohol cannot be excluded....... significantly (p less than 0.05) younger at the time of natural menopause than controls. Compared to controls, non-cirrhotic alcoholic women had significantly (p less than 0.05) reduced levels of DHAS, significantly (p less than 0.05) more alcoholic cirrhotic women had detectable oestradiol concentrations...

  9. Proliferative human cell sources applied as biocomponent in bioartificial livers: a review

    NARCIS (Netherlands)

    Nibourg, Geert A. A.; Chamuleau, Robert A. F. M.; van Gulik, Thomas M.; Hoekstra, Ruurdtje

    2012-01-01

    Introduction: Bioartificial livers (BALs) are urgently needed to bridge severe liver failure patients to liver transplantation or liver regeneration. When based on primary hepatocytes, their efficacy has been shown in animal experiments and their safety was confirmed in clinical trials. However, a

  10. Two insulin-like growth factor I messenger RNAs are expressed in human liver

    International Nuclear Information System (INIS)

    Rotwein, P.

    1986-01-01

    Through use of a synthetic radiolabelled oligonucleotide probe, human insulin-like growth factor I (IGF-I) cDNA clones were isolated from a liver library. Two types of cDNAs were defined by restriction enzyme analysis and DNA sequencing. Both encode IGF-I precursors of either 195 or 153 amino acids. The two predicted protein precursors are identical from their amino terminus to a lysine residue 16 codons beyond the IGF-I sequence, and then they diverge. Both cDNAs predict additional unique carboxyl-terminal extension peptides. Since there is only one IGF-I gene in the human genome, the finding of two different cDNAs suggests that alternative RNA processing plays a role in IGF-I gene expression. The functions of the different extension peptides remain to be elucidates

  11. Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice

    Directory of Open Access Journals (Sweden)

    Shanzheng Lu

    2016-10-01

    Full Text Available Abstract Background The endometrial regenerative cell (ERC is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl4–induced acute liver injury (ALI. Methods An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl4. Transplanted ERCs were intravenously injected (1 million/mouse into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl4 induction. Results ERC treatment effectively decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT and aspartate aminotransferase (AST activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA was increased after ERC treatment. Furthermore, the frequency of CD4+ and CD8+ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4+CD25+FOXP3+ regulatory T cells (Tregs was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1β, IL-6, and TNF-α but higher level of IL-10 in both serum and liver. Conclusions Human ERCs protect the liver from acute injury

  12. Environmental Toxin Screening Using Human-Derived 3D Bioengineered Liver and Cardiac Organoids

    Directory of Open Access Journals (Sweden)

    Steven D. Forsythe

    2018-04-01

    Full Text Available IntroductionEnvironmental toxins, such as lead and other heavy metals, pesticides, and other compounds, represent a significant health concern within the USA and around the world. Even in the twenty-first century, a plethora of cities and towns in the U.S. have suffered from exposures to lead in drinking water or other heavy metals in food or the earth, while there is a high possibility of further places to suffer such exposures in the near future.MethodsWe employed bioengineered 3D human liver and cardiac organoids to screen a panel of environmental toxins (lead, mercury, thallium, and glyphosate, and charted the response of the organoids to these compounds. Liver and cardiac organoids were exposed to lead (10 µM–10 mM, mercury (200 nM–200 µM, thallium (10 nM–10 µM, or glyphosate (25 µM–25 mM for a duration of 48 h. The impacts of toxin exposure were then assessed by LIVE/DEAD viability and cytotoxicity staining, measuring ATP activity and determining IC50 values, and determining changes in cardiac organoid beating activity.ResultsAs expected, all of the toxins induced toxicity in the organoids. Both ATP and LIVE/DEAD assays showed toxicity in both liver and cardiac organoids. In particular, thallium was the most toxic, with IC50 values of 13.5 and 1.35 µM in liver and cardiac organoids, respectively. Conversely, glyphosate was the least toxic of the four compounds, with IC50 values of 10.53 and 10.85 mM in liver and cardiac organoids, respectively. Additionally, toxins had a negative influence on cardiac organoid beating activity as well. Thallium resulting in the most significant decreases in beating rate, followed by mercury, then glyphosate, and finally, lead. These results suggest that the 3D organoids have significant utility to be deployed in additional toxicity screening applications, and future development of treatments to mitigate exposures.Conclusion3D organoids have significant utility to be

  13. The diminished expression of proangiogenic growth factors and their receptors in gastric ulcers of cirrhotic patients.

    Science.gov (United States)

    Luo, Jiing-Chyuan; Peng, Yen-Ling; Hou, Ming-Chih; Huang, Kuang-Wei; Huang, Hui-Chun; Wang, Ying-Wen; Lin, Han-Chieh; Lee, Fa-Yauh; Lu, Ching-Liang

    2013-01-01

    The pathogenesis of the higher occurrence of peptic ulcer disease in cirrhotic patients is complex. Platelets can stimulate angiogenesis and promote gastric ulcer healing. We compared the expressions of proangiogenic growth factors and their receptors in the gastric ulcer margin between cirrhotic patients with thrombocytopenia and those of non-cirrhotic patients to elucidate possible mechanisms. Eligible cirrhotic patients (n = 55) and non-cirrhotic patients (n = 55) who had gastric ulcers were enrolled. Mucosa from the gastric ulcer margin and non-ulcer areas were sampled and the mRNA expressions of the proangiogenic growth factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], basic fibroblast growth factor [bFGF]) and their receptors (VEGFR1, VEGFR2, PDGFRA, PDGFRB, FGFR1, FGFR2) were measured and compared. Platelet count and the expressions of these growth factors and their receptors were correlated with each other. The two groups were comparable in terms of gender, ulcer size and infection rate of Helicobacter pylori. However, the cirrhotic group were younger in age, had a lower platelet count than those in the non-cirrhotic group (pexpressions of PDGFB, VEGFR2, FGFR1, and FGFR2 in gastric ulcer margin when compared with those of the non-cirrhotic patients (pexpressions of PDGFB and VEGFR2, FGFR1, and FGFR2 were well correlated with the degree of thrombocytopenia in these cirrhotic patients (ρ>0.5, pimplied that diminished activity of proangiogenic factors and their receptors may contribute to the pathogenesis of gastric ulcers in cirrhotic patients.

  14. Long-term outcomes of liver transplant patients with human immunodeficiency virus infection and end-stage-liver-disease: single center experience

    Directory of Open Access Journals (Sweden)

    Vernadakis S

    2011-08-01

    Full Text Available Abstract Objective Orthotopic-liver-transplantation (OLT in patients with Human-Immunodeficiency-Virus infection (HIV and end-stage-liver-disease (ESDL is rarely reported. The purpose of this study is to describe our institutional experience on OLT for HIV positive patients. Material and methods This is a retrospective study of all HIV-infected patients who underwent OLT at the University Hospital of Essen, from January 1996 to December 2009. Age, sex, HIV transmission-way, CDC-stage, etiology of ESDL, concomitant liver disease, last CD4cell count and HIV-viral load prior to OLT were collected and analysed. Standard calcineurin-inhibitors-based immunosuppression was applied. All patients received anti-fungal and anti-pneumocystis carinii pneumonia prophylaxis post-OLT. Results Eight transplanted HIV-infected patients with a median age of 46 years (range 35-61 years were included. OLT indications were HCV (n = 5, HBV (n = 2, HCV/HBV/HDV-related cirrhosis (n = 1 and acute liver-failure (n = 1. At OLT, CD4 cell-counts ranged from 113-621 cells/μl, and HIV viral-loads from Conclusions OLT in HIV-infected patients and ESLD is an acceptable therapeutic option in selected patients. Long-term survival can be achieved without HIV disease-progression under antiretroviral therapy and management of the viral hepatitis co-infection.

  15. Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance.

    Science.gov (United States)

    Li, Xiao-Feng; Chen, Cheng; Xiang, Dai-Min; Qu, Le; Sun, Wen; Lu, Xin-Yuan; Zhou, Teng-Fei; Chen, Shu-Zhen; Ning, Bei-Fang; Cheng, Zhuo; Xia, Ming-Yang; Shen, Wei-Feng; Yang, Wen; Wen, Wen; Lee, Terence Kin Wah; Cong, Wen-Ming; Wang, Hong-Yang; Ding, Jin

    2017-12-01

    The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6-positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted tumor necrosis factor-α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self-renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6-positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. Our results not only clarify the cellular and molecular mechanisms underlying the inflammation-mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (Hepatology 2017;66:1934-1951). © 2017 by the American Association for the Study of Liver Diseases.

  16. ESGAR consensus statement on liver MR imaging and clinical use of liver-specific contrast agents

    Energy Technology Data Exchange (ETDEWEB)

    Neri, E.; Boraschi, P.; Bartolozzi, C. [University of Pisa, Department of Diagnostic and Interventional Radiology, Pisa (Italy); Bali, M.A.; Matos, C. [Hopital Erasme, MRI Clinics, Department of Radiology, Bruxelles (Belgium); Ba-Ssalamah, A. [The General Hospital of the Medical University of Vienna, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Brancatelli, G. [University of Palermo, Department of Radiology, Palermo (Italy); Alves, F.C. [University Hospital of Coimbra, Medical Imaging Department and Faculty of Medicine, Coimbra (Portugal); Grazioli, L. [Spedali Civili di Brescia, Department of Radiology, Brescia (Italy); Helmberger, T. [Academic Teaching Hospital of the Technical University, Department of Diagnostic and Interventional Radiology and Nuclear Medicine, Klinikum Bogenhausen, Munich (Germany); Lee, J.M. [Seoul National University College of Medicine, Division of Abdominal Imaging, Department of Radiology, Seoul (Korea, Republic of); Manfredi, R. [University of Verona, Department of Radiology, Verona (Italy); Marti-Bonmati, L. [Hospital Universitario y Politecnico La Fe, Area Clinica de Imagen Medica, Valencia (Spain); Merkle, E.M. [Universitaetsspital Basel, Klinik fuer Radiologie und Nuklearmedizin, Basel (Switzerland); Op De Beeck, B. [Antwerp University Hospital, Department of Radiology, Edegem (Belgium); Schima, W. [KH Goettlicher Heiland, Krankenhaus der Barmherzigen Schwestern and Sankt Josef-Krankenhaus, Department of Diagnostic and Interventional Radiology, Vienna (Austria); Skehan, S. [St Vincent' s University Hospital, Department of Radiology, Dublin (Ireland); Vilgrain, V. [Assistance Publique-Hopitaux de Paris, APHP, Hopital Beaujon, Radiology Department, Clichy, Paris (France); Zech, C. [Universitaetsspital Basel, Abteilungsleiter Interventionelle Radiologie, Klinik fuer Radiologie und Nuklearmedizin, Basel (Switzerland)

    2016-04-15

    To develop a consensus and provide updated recommendations on liver MR imaging and the clinical use of liver-specific contrast agents. The European Society of Gastrointestinal and Abdominal Radiology (ESGAR) formed a multinational European panel of experts, selected on the basis of a literature review and their leadership in the field of liver MR imaging. A modified Delphi process was adopted to draft a list of statements. Descriptive and Cronbach's statistics were used to rate levels of agreement and internal reliability of the consensus. Three Delphi rounds were conducted and 76 statements composed on MR technique (n = 17), clinical application of liver-specific contrast agents in benign, focal liver lesions (n = 7), malignant liver lesions in non-cirrhotic (n = 9) and in cirrhotic patients (n = 18), diffuse and vascular liver diseases (n = 12), and bile ducts (n = 13). The overall mean score of agreement was 4.84 (SD ±0.17). Full consensus was reached in 22 % of all statements in all working groups, with no full consensus reached on diffuse and vascular diseases. The consensus provided updated recommendations on the methodology, and clinical indications, of MRI with liver specific contrast agents in the study of liver diseases. (orig.)

  17. Hydrolysis of pyrethroids by human and rat tissues: Examination of intestinal, liver and serum carboxylesterases

    International Nuclear Information System (INIS)

    Crow, J. Allen; Borazjani, Abdolsamad; Potter, Philip M.; Ross, Matthew K.

    2007-01-01

    Hydrolytic metabolism of pyrethroid insecticides in humans is one of the major catabolic pathways that clear these compounds from the body. Rodent models are often used to determine the disposition and clearance rates of these esterified compounds. In this study the distribution and activities of esterases that catalyze pyrethroid metabolism have been investigated in vitro using several human and rat tissues, including small intestine, liver and serum. The major esterase in human intestine is carboxylesterase 2 (hCE2). We found that the pyrethroid trans-permethrin is effectively hydrolyzed by a sample of pooled human intestinal microsomes (5 individuals), while deltamethrin and bioresmethrin are not. This result correlates well with the substrate specificity of recombinant hCE2 enzyme. In contrast, a sample of pooled rat intestinal microsomes (5 animals) hydrolyze trans-permethrin 4.5-fold slower than the sample of human intestinal microsomes. Furthermore, it is demonstrated that pooled samples of cytosol from human or rat liver are ∼ 2-fold less hydrolytically active (normalized per mg protein) than the corresponding microsomal fraction toward pyrethroid substrates; however, the cytosolic fractions do have significant amounts (∼ 40%) of the total esteratic activity. Moreover, a 6-fold interindividual variation in carboxylesterase 1 protein expression in human hepatic cytosols was observed. Human serum was shown to lack pyrethroid hydrolytic activity, but rat serum has hydrolytic activity that is attributed to a single CE isozyme. We purified the serum CE enzyme to homogeneity to determine its contribution to pyrethroid metabolism in the rat. Both trans-permethrin and bioresmethrin were effectively cleaved by this serum CE, but deltamethrin, esfenvalerate, alpha-cypermethrin and cis-permethrin were slowly hydrolyzed. Lastly, two model lipase enzymes were examined for their ability to hydrolyze pyrethroids. However, no hydrolysis products could be detected

  18. Comparison of predictability for human pharmacokinetics parameters among monkeys, rats, and chimeric mice with humanised liver.

    Science.gov (United States)

    Miyamoto, Maki; Iwasaki, Shinji; Chisaki, Ikumi; Nakagawa, Sayaka; Amano, Nobuyuki; Hirabayashi, Hideki

    2017-12-01

    1. The aim of the present study was to evaluate the usefulness of chimeric mice with humanised liver (PXB mice) for the prediction of clearance (CL t ) and volume of distribution at steady state (Vd ss ), in comparison with monkeys, which have been reported as a reliable model for human pharmacokinetics (PK) prediction, and with rats, as a conventional PK model. 2. CL t and Vd ss values in PXB mice, monkeys and rats were determined following intravenous administration of 30 compounds known to be mainly eliminated in humans via the hepatic metabolism by various drug-metabolising enzymes. Using single-species allometric scaling, human CL t and Vd ss values were predicted from the three animal models. 3. Predicted CL t values from PXB mice exhibited the highest predictability: 25 for PXB mice, 21 for monkeys and 14 for rats were predicted within a three-fold range of actual values among 30 compounds. For predicted human Vd ss values, the number of compounds falling within a three-fold range was 23 for PXB mice, 24 for monkeys, and 16 for rats among 29 compounds. PXB mice indicated a higher predictability for CL t and Vd ss values than the other animal models. 4. These results demonstrate the utility of PXB mice in predicting human PK parameters.

  19. Disease modeling using human induced pluripotent stem cells: lessons from the liver.

    Science.gov (United States)

    Gieseck, Richard L; Colquhoun, Jennifer; Hannan, Nicholas R F

    2015-01-01

    Human pluripotent stem cells (hPSCs) have the capacity to differentiate into any of the hundreds of distinct cell types that comprise the human body. This unique characteristic has resulted in considerable interest in the field of regenerative medicine, given the potential for these cells to be used to protect, repair, or replace diseased, injured, and aged cells within the human body. In addition to their potential in therapeutics, hPSCs can be used to study the earliest stages of human development and to provide a platform for both drug screening and disease modeling using human cells. Recently, the description of human induced pluripotent stem cells (hIPSCs) has allowed the field of disease modeling to become far more accessible and physiologically relevant, as pluripotent cells can be generated from patients of any genetic background. Disease models derived from hIPSCs that manifest cellular disease phenotypes have been established to study several monogenic diseases; furthermore, hIPSCs can be used for phenotype-based drug screens to investigate complex diseases for which the underlying genetic mechanism is unknown. As a result, the use of stem cells as research tools has seen an unprecedented growth within the last decade as researchers look for in vitro disease models which closely mimic in vivo responses in humans. Here, we discuss the beginnings of hPSCs, starting with isolation of human embryonic stem cells, moving into the development and optimization of hIPSC technology, and ending with the application of hIPSCs towards disease modeling and drug screening applications, with specific examples highlighting the modeling of inherited metabolic disorders of the liver. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

  20. Regional differences in prostaglandin E2 metabolism in human colorectal cancer liver metastases

    International Nuclear Information System (INIS)

    Young, Alastair L; Chalmers, Claire R; Hawcroft, Gillian; Perry, Sarah L; Treanor, Darren; Toogood, Giles J; Jones, Pamela F; Hull, Mark A

    2013-01-01

    Prostaglandin (PG) E 2 plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE 2 catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE 2 content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE 2 in human CRC cells in vitro. Tissue from the periphery and centre of 20 human CRCLM was analysed for PGE 2 levels, 15-PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) β. PGE 2 levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15-PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE 2 . Combined 15-PGDH expression and loss of membranous E-cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo. There is significant intra-tumoral heterogeneity in PGE 2 content, 15-PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE 2 metabolism should be targeted for novel treatment of advanced CRC

  1. Differentiation of human-induced pluripotent stem cell under flow conditions to mature hepatocytes for liver tissue engineering

    DEFF Research Database (Denmark)

    Starokozhko, Viktoriia; Hemmingsen, Mette; Larsen, Layla

    2018-01-01

    Hepatic differentiation of human-induced pluripotent stem cells (hiPSCs) under flow conditions in a 3D scaffold is expected to be a major step forward for construction of bioartificial livers. The aims of this study were to induce hepatic differentiation of hiPSCs under perfusion conditions...... and to perform functional comparisons with fresh human precision-cut liver slices (hPCLS), an excellent benchmark for the human liver in vivo. The majority of the mRNA expression of CYP isoenzymes and transporters and the tested CYP activities, Phase II metabolism, and albumin, urea, and bile acid synthesis...... in the hiPSC-derived cells reached values that overlap those of hPCLS, which indicates a higher degree of hepatic differentiation than observed until now. Differentiation under flow compared with static conditions had a strong inducing effect on Phase II metabolism and suppressed AFP expression but resulted...

  2. A human cytochrome P-450 is recognized by anti-liver/kidney microsome antibodies in autoimmune chronic hepatitis.

    Science.gov (United States)

    Kiffel, L; Loeper, J; Homberg, J C; Leroux, J P

    1989-02-28

    1- Anti-liver/kidney microsome autoantibodies type 1 (anti-LKM1), observed in some children with chronic active hepatitis, were used to isolate their antigen in human liver microsomes. A protein, called P-LKM1 was thus purified. This protein was recognized by a rabbit antiserum directed against the related human cytochromes P-450 bufI and P-450 bufII. 2- A human liver microsomal protein immunoprecipitated with anti-LKM1 sera was also recognized by anti cytochromes P-450 bufI/II antibodies. 3- Anti-LKM1 antibodies potently inhibited microsomal bufuralol 1'-hydroxylation. These results displayed the possible identity between cytochrome P-450 bufI/II and LKM1 antigen.

  3. Ascitic Fluid Culture In Cirrhotic Patients With Spontaneous Bacterial Peritonitis

    International Nuclear Information System (INIS)

    Sajjad, M.; Khan, Z.A.; Khan, M.S.

    2016-01-01

    Objective: To determine the frequency and compare the culture yield of bacterial isolation by conventional and blood culture BACTEC bottle techniques in cirrhotic patients with spontaneous bacterial peritonitis (SBP). Study Design: Cross-sectional comparative study. Place and Duration of Study: Pathology Department, Bannu Medical College, Bannu, KPK, from January 2012 to December 2013. Methodology: Paracentesis of 20 ml of ascitic fluid tapped from cirrhotic patients with SBP was carried out by a single technologist. The analysis included differential leukocyte count (DLC), while 5 ml each of the fluid was inoculated into conventional culture media and BACTEC blood culture bottle. All the data were analysed on (SPSS) version 16 to determine frequencies with percentages and mean values with standard deviation. Chi-square test was used for comparing the yield of conventional and blood culture bottle methods. P-value was considered significant if < 0.05. Results: In 105 cases of ascitic fluid analyses, 27 (25.72 percent) had positive ascitic fluid culture whereas 78 (74.28 percent) had negative ascitic fluid culture. Ascitic fluid culture was positive in 6 cases by conventional culture media and in 27 cases by BACTEC culture bottle media (p < 0.001). Bacterial isolation was obtained by both culture methods in 6 cases (p < 0.001). Conclusion: Direct bedside inoculation of ascitic fluid by BACTEC culture bottle method has better yield as compared to conventional culture method. (author)

  4. Laparoscopic cholecystectomy in cirrhotic patients: Feasibility in adeveloping country

    International Nuclear Information System (INIS)

    Tayeb, M.; Khan, Muhammad R.; Riaz, N.

    2008-01-01

    Although laparoscopic cholecystectomy (LC) has become the procedure ofchoice for cholelithiasis in the general population, many consider cirrhosisas a relative or absolute contraindication for laparoscopic surgery. The aimof this study was to confirm the safety of LC in cirrhotic patients in ourset-up. This is a retrospective case series including all patients withcirrhosis who underwent LC for gallstones from January 2000 to December2006at our institution. Data were analyzed for Child class, indication forsurgery, hospital stay and procedure-related morbidity and mortality. Resultsare given as +- standard deviation. Thirty patients, including 21 females(median age: 42 years) underwent LC during the study period. There was nooperative mortality. Twenty-four patients belonged to Child class A and 6belonged to Child class B. Mean operative time was 80+-26 min. There was noincident of bile duct injury, but two patients (6.7%) required conversion toopen procedure. Mean hospital stay was 3+-2.7 days. Postoperative morbiditywas observed in 7 patients, including postoperative deterioration of liverfunction in 2, worsening of ascites in 2 and pneumonia and port-siteinfection in 1. Two patients had significant in hemoglobin requiring bloodtransfusion. Cirrhosis is not a contraindication for LC and it can beperformed safely in compensated cirrhotic patients with acceptable morbidityand mortality. (author)

  5. Exacerbating effects of human parvovirus B19 NS1 on liver fibrosis in NZB/W F1 mice.

    Directory of Open Access Journals (Sweden)

    Tsai-Ching Hsu

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disorder with unknown etiology that impacts various organs including liver. Recently, human parvovirus B19 (B19 is recognized to exacerbate SLE. However, the effects of B19 on liver in SLE are still unclear. Herein we aimed to investigate the effects of B19 on liver in NZB/W F1 mice by injecting subcutaneously with PBS, recombinant B19 NS1, VP1u or VP2, respectively. Our experimental results revealed that B19 NS1 protein significantly enhanced the TGF-β/Smad fibrotic signaling by increasing the expressions of TGF-β, Smad2/3, phosphorylated Smad2/3, Smad4 and Sp1. The consequent fibrosis-related proteins, PAI-1 and α-SMA, were also significantly induced in livers of NZB/W F1 mice receiving B19 NS1 protein. Accordingly, markedly increased collagen deposition was also observed in livers of NZB/W F1 mice receiving B19 NS1 protein. However, no significant difference was observed in livers of NZB/W F1 mice receiving B19 VP1u or VP2 as compared to the controls. These findings indicate that B19 NS1 plays a crucial role in exacerbating liver fibrosis in NZB/W F1 mice through enhancing the TGF-â/Smad fibrotic signaling.

  6. Exacerbating Effects of Human Parvovirus B19 NS1 on Liver Fibrosis in NZB/W F1 Mice

    Science.gov (United States)

    Hsu, Tsai-Ching; Tsai, Chun-Chou; Chiu, Chun-Ching; Hsu, Jeng-Dong; Tzang, Bor-Show

    2013-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with unknown etiology that impacts various organs including liver. Recently, human parvovirus B19 (B19) is recognized to exacerbate SLE. However, the effects of B19 on liver in SLE are still unclear. Herein we aimed to investigate the effects of B19 on liver in NZB/W F1 mice by injecting subcutaneously with PBS, recombinant B19 NS1, VP1u or VP2, respectively. Our experimental results revealed that B19 NS1 protein significantly enhanced the TGF-β/Smad fibrotic signaling by increasing the expressions of TGF-β, Smad2/3, phosphorylated Smad2/3, Smad4 and Sp1. The consequent fibrosis-related proteins, PAI-1 and α-SMA, were also significantly induced in livers of NZB/W F1 mice receiving B19 NS1 protein. Accordingly, markedly increased collagen deposition was also observed in livers of NZB/W F1 mice receiving B19 NS1 protein. However, no significant difference was observed in livers of NZB/W F1 mice receiving B19 VP1u or VP2 as compared to the controls. These findings indicate that B19 NS1 plays a crucial role in exacerbating liver fibrosis in NZB/W F1 mice through enhancing the TGF-â/Smad fibrotic signaling. PMID:23840852

  7. Diagnostic value of Doppler assessment of the hepatic and portal vessels and ultrasound of the spleen in liver disease.

    Science.gov (United States)

    O'Donohue, John; Ng, Chaan; Catnach, Susan; Farrant, Patricia; Williams, Roger

    2004-02-01

    To investigate the clinical utility and the intra-observer and inter-observer variability of Doppler ultrasound assessment of the hepatic and portal vessels along with measurement of spleen size in the diagnosis of chronic liver disease and cirrhosis. Ultrasound measurements of portal vein diameter (PVD), portal vein velocity (PVV), hepatic arterial resistance index (HARI), hepatic vein profile (HVP), and spleen size were obtained in 49 controls and 45 patients with liver disease (23 with primary biliary cirrhosis, 22 with hepatitis C) by two experienced observers, who each performed three blinded measurements of each variable. Control values were derived from normal hospital workers. Percutaneous liver biopsies in 41 of the patients showed cirrhosis (14 patients), moderate/severe fibrosis (13 patients), and early disease (14 patients). Seventy-one percent of cirrhotic patients had splenomegaly (> 13.6 cm). The spleen size was significantly larger in cirrhotics (16.0 cm) than in non-cirrhotics (13.0 cm, P HVP was abnormal in 76.9% of cirrhotics, 57.7% of non-cirrhotics and 2.1% of controls (P HVP are useful predictors of chronic liver disease and cirrhosis, and both can be measured reliably and reproducibly. However, Doppler measurements of PVV, PVD and HARI are not useful in distinguishing patients with chronic liver disease from normal controls.

  8. Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients

    OpenAIRE

    Shi, Ming; Zhang, Zheng; Xu, Ruonan; Lin, Hu; Fu, Junliang; Zou, Zhengsheng; Zhang, Aimin; Shi, Jianfei; Chen, Liming; Lv, Sa; He, Weiping; Geng, Hua; Jin, Lei; Liu, Zhenwen; Wang, Fu-Sheng

    2012-01-01

    This study assessed the safety and initial efficacy of umbilical cord-derived mesenchymal stem cell (UC-MSC) transfusions for acute-on-chronic liver failure (ACLF) patients associated with hepatitis B virus (HBV) infection. No significant side effects were observed, and the UC-MSC transfusions significantly increased the survival rates in ACLF patients. It was found that UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients.

  9. Foxa1 reduces lipid accumulation in human hepatocytes and is down-regulated in nonalcoholic fatty liver.

    Directory of Open Access Journals (Sweden)

    Marta Moya

    Full Text Available Triglyceride accumulation in nonalcoholic fatty liver (NAFL results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2 however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB. Moreover, Foxa1 represses the fatty acid transporter protein FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing peroxisomal fatty acid β-oxidation and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolic pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance.

  10. Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis.

    Science.gov (United States)

    Gao, Jin-Hang; Wen, Shi-Lei; Yang, Wen-Juan; Lu, Yao-Yao; Tong, Huan; Huang, Zhi-Yin; Liu, Zhang-Xu; Tang, Cheng-Wei

    2013-01-01

    Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2) in the cirrhotic liver might be a potential target to ameliorate portal hypertension. To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and related signal molecules were quantitated. Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, pportal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, pprotein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1α (HIF-1α), and c-fos were also down-regulated after celecoxib treatment. Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its modulation on VEGF/VEGFR-2 through the down-regulation of integrated signal pathways involving PGE2- HIF-1α- VEGF and p-ERK- c-fos- VEGFR-2.

  11. The Metabolism of Separase Inhibitor Sepin-1 in Human, Mouse, and Rat Liver Microsomes

    Directory of Open Access Journals (Sweden)

    Feng Li

    2018-05-01

    Full Text Available Separase, a known oncogene, is widely overexpressed in numerous human tumors of breast, bone, brain, blood, and prostate. Separase is an emerging target for cancer therapy, and separase enzymatic inhibitors such as sepin-1 are currently being developed to treat separase-overexpressed tumors. Drug metabolism plays a critical role in the efficacy and safety of drug development, as well as possible drug–drug interactions. In this study, we investigated the in vitro metabolism of sepin-1 in human, mouse, and rat liver microsomes (RLM using metabolomic approaches. In human liver microsomes (HLM, we identified seven metabolites including one cysteine–sepin-1 adduct and one glutathione–sepin-1 adduct. All the sepin-1 metabolites in HLM were also found in both mouse and RLM. Using recombinant CYP450 isoenzymes, we demonstrated that multiple enzymes contributed to the metabolism of sepin-1, including CYP2D6 and CYP3A4 as the major metabolizing enzymes. Inhibitory effects of sepin-1 on seven major CYP450s were also evaluated using the corresponding substrates recommended by the US Food and Drug Administration. Our studies indicated that sepin-1 moderately inhibits CYP1A2, CYP2C19, and CYP3A4 with IC50 < 10 μM but weakly inhibits CYP2B6, CYP2C8/9, and CYP2D6 with IC50 > 10 μM. This information can be used to optimize the structures of sepin-1 for more suitable pharmacological properties and to predict the possible sepin-1 interactions with other chemotherapeutic drugs.

  12. Cadmium Chloride Induces DNA Damage and Apoptosis of Human Liver Carcinoma Cells via Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Anthony Skipper

    2016-01-01

    Full Text Available Cadmium is a heavy metal that has been shown to cause its toxicity in humans and animals. Many documented studies have shown that cadmium produces various genotoxic effects such as DNA damage and chromosomal aberrations. Ailments such as bone disease, renal damage, and several forms of cancer are attributed to overexposure to cadmium.  Although there have been numerous studies examining the effects of cadmium in animal models and a few case studies involving communities where cadmium contamination has occurred, its molecular mechanisms of action are not fully elucidated. In this research, we hypothesized that oxidative stress plays a key role in cadmium chloride-induced toxicity, DNA damage, and apoptosis of human liver carcinoma (HepG2 cells. To test our hypothesis, cell viability was determined by MTT assay. Lipid hydroperoxide content stress was estimated by lipid peroxidation assay. Genotoxic damage was tested by the means of alkaline single cell gel electrophoresis (Comet assay. Cell apoptosis was measured by flow cytometry assessment (Annexin-V/PI assay. The result of MTT assay indicated that cadmium chloride induces toxicity to HepG2 cells in a concentration-dependent manner, showing a 48 hr-LD50 of 3.6 µg/mL. Data generated from lipid peroxidation assay resulted in a significant (p < 0.05 increase of hydroperoxide production, specifically at the highest concentration tested. Data obtained from the Comet assay indicated that cadmium chloride causes DNA damage in HepG2 cells in a concentration-dependent manner. A strong concentration-response relationship (p < 0.05 was recorded between annexin V positive cells and cadmium chloride exposure. In summary, these in vitro studies provide clear evidence that cadmium chloride induces oxidative stress, DNA damage, and programmed cell death in human liver carcinoma (HepG2 cells.

  13. Stereoselective sulfate conjugation of racemic 4-hydroxypropranolol by human and rat liver cytosol

    Energy Technology Data Exchange (ETDEWEB)

    Walle, T.; Walle, U.K. (Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston (USA))

    1991-03-01

    The objective of this study was to determine the stereochemistry of sulfoconjugation of a chiral phenolic amine drug, 4-hydroxypropranolol (HOP), by the human liver. The reaction was catalyzed by the 100,000 g cytosol as the phenolsulfotransferase (PST) enzyme source with PAP35S as the co-substrate. The enantiomers of the intact sulfate conjugate formed, (+)-HOP35S and (-)-HOP35S, were separated by HPLC and measured by liquid scintillation spectrometry. Complex velocity vs. substrate concentration curves were obtained with two peaks of activity, one at 3 microM (high affinity) and one at 500 microM (low affinity). The high-affinity reaction demonstrated a high degree of stereoselectivity. Whereas the affinity of the enantiomers for this reaction was identical, with a very low apparent KM value of 0.59 microM, the apparent Vmax value for (+)-HOPS formation was 4.6-fold higher than for (-)-HOPS. In sharp contrast, the low-affinity reaction, with an apparent KM of 65 microM, was not stereoselective. Inhibition of the high-affinity reaction by elevated temperature, but not by dichloronitrophenol, indicated that this activity was due to a monoamine form of PST. Inhibition of the low-affinity reaction by dichloronitrophenol, but not by elevated temperature, indicated that this activity was due to a phenol form of PST. As a comparison, experiments with the rat liver cytosol demonstrated only one activity, with apparent KM values of 50 microM for both enantiomers and opposite stereoselectivity in maximum velocity compared to humans, {plus minus}-HOPS ratio 0.72. The results of this study demonstrate stereoselectivity in human hepatic sulfation of a chiral phenolic amine, with clear differences between PST isoenzymes.

  14. Quantification of human hepatic binding protein (HBP) via sup 99m Tc-galactosyl-neoglycoalbumin (NGA) liver scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Virgolini, I; Hoebart, J; Bergmann, H; Sinzinger, H [Vienna Univ. (Austria). Abt. fuer Nuklearmedizin; Mueller, C [Vienna Univ. (Austria). 2. Klinik fuer Gastroenterologie und Hepatologie; Angelberger, P [Oesterreichisches Forschungszentrum Seibersdorf GmbH (Austria). Inst. fuer Chemie

    1991-01-01

    {sup 99m}Tc-galactosyl-neoglycoalbumin ({sup 99m}Tc-NGA) was synthesized by covalent coupling of 2-imino-2-methoxyethyl-1-thio-{beta}-D-galactopyranoside to the primary amino groups of human serum albumin. Injections of {sup 99m}Tc-NGA (150 MBq; 3.5 mg (=50 nmol)/ml) demonstrated the liver to be the exclusive site of tracer-uptake. Simulation of {sup 99m}Tc-NGA-kinetics allowed quantification of binding to the hepatic binding protein (HBP). Using this model we studied 250 patients with various liver disease. In alcoholic liver cirrhosis such patients with Child B and Child C stage cirrhosis had a lower HBP-concentration in the liver compared to control individuals. The group with the most advanced cirrhosis had a significantly lower HBP-concentration (0.20-0.45 {mu}mol/l) than Child A patients (0.60-0.85 {mu}mol/l; p<0.01) and Child B patients (0.45-0.60 {mu}mol/l; p<0.05). In patients with biopsy proven liver fibrosis (0.80-1.22 {mu}mol/l) no difference in receptor concentration to normal individuals was estimated. Patients with recently diagnosed acute viral hepatitis underwent repeated {sup 99m}Tc-galactosyl-neoglycoalbumin (NGA) scanning of the liver during the course of the disease. Return of liver function tests to normal values was associated with an increased hepatic imaging size as well as increase in HBP-concentration. In patients exhibiting a prolonged course of the disease changes in NGA-kinetic data were borderline and the hepatic image size unchanged. The values obtained for HBP-concentration in the liver amounted to 0.30-0.50 {mu}mol/l liver for patients with hepatoma, to 0.40-0.60 {mu}mol/l in patients with liver metastasis and to 0.90-1.20 {mu}mol/l in cancer patients without liver malignancy. It is concluded that scintigraphic evaluation of functional hepatic cell mass using the new receptor-tracer {sup 99m}Tc-NGA provides an in vivo diagnostic mean allowing quantitative data on liver function beside assessment of liver morphology.

  15. Exogenous regucalcin suppresses the growth of human liver cancer HepG2 cells in vitro.

    Science.gov (United States)

    Yamaguchi, Masayoshi; Murata, Tomiyasu

    2018-04-05

    Regucalcin, which its gene is localized on the X chromosome, plays a pivotal role as a suppressor protein in signal transduction in various types of cells and tissues. Regucalcin gene expression has been demonstrated to be suppressed in various tumor tissues of animal and human subjects, suggesting a potential role of regucalcin in carcinogenesis. Regucalcin, which is produced from the tissues including liver, is found to be present in the serum of human subjects and animals. This study was undertaken to determine the effects of exogenous regucalcin on the proliferation in cloned human hepatoma HepG2 cells in vitro. Proliferation of HepG2 cells was suppressed after culture with addition of regucalcin (0.01 – 10 nM) into culture medium. Exogenous regucalcin did not reveal apoptotic cell death in HepG2 cells in vitro. Suppressive effects of regucalcin on cell proliferation were not enhanced in the presence of various signaling inhibitors including tumor necrosis factor-α (TNF-α), Bay K 8644, PD98059, staurosporine, worthomannin, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) or gemcitabine, which were found to suppress the proliferation. In addition, exogenous regucalcin suppressed the formation of colonies of cultured hepatoma cells in vitro. These findings demonstrated that exogenous regucalcin exhibits a suppressive effect on the growth of human hepatoma HepG2 cells, proposing a strategy with the gene therapy for cancer treatment.

  16. Critical role of c-Jun overexpression in liver metastasis of human breast cancer xenograft model

    International Nuclear Information System (INIS)

    Zhang, Yan; Hu, Meiru; Shen, Beifen; Guo, Ning; Pu, Xiaoyun; Shi, Ming; Chen, Liyong; Song, Yuhua; Qian, Lu; Yuan, Guogang; Zhang, Hao; Yu, Ming

    2007-01-01

    c-Jun/AP-1 has been linked to invasive properties of aggressive breast cancer. Recently, it has been reported that overexpression of c-Jun in breast cancer cell line MCF-7 resulted in increased AP-1 activity, motility and invasiveness of the cells in vitro and tumor formation in nude mice. However, the role of c-Jun in metastasis of human breast cancer in vivo is currently unknown. To further investigate the direct involvement of c-Jun in tumorigenesis and metastasis, in the present study, the effects of c-Jun overexpression were studied in both in vitro and in nude mice. Ectopic overexpression of c-Jun promoted the growth of MCF-7 cells and resulted in a significant increase in the percentage of cells in S phase and increased motility and invasiveness. Introduction of c-Jun gene alone into weakly invasive MCF-7 cells resulted in the transfected cells capable of metastasizing to the nude mouse liver following tail vein injection. The present study confirms that overexpression of c-Jun contributes to a more invasive phenotype in MCF-7 cells. It indicates an interesting relationship between c-Jun expression and increased property of adhesion, migration and in vivo liver metastasis of MCF-7/c-Jun cells. The results provide further evidence that c-Jun is involved in the metastasis of breast cancer. The finding also opens an opportunity for development of anti-c-Jun strategies in breast cancer therapy

  17. Genomic instability induced by 60Co γ ray radiation in normal human liver cells

    International Nuclear Information System (INIS)

    Gen Xiaohua; Guo Xianhua; Zuo Yahui; Wang Xiaoli; Wang Zhongwen

    2007-01-01

    Objective: To explore the genomic instability induced by 60 Co γ rays. Methods: The cloning efficiency and micronucleus efficiency of normal human liver cell irradiated by 60 Co γ rays were detected, and the method of single cell gel electrophoresis (SCGE) was carried out to measure DNA chains damage. The fast-growing cells were divided into different dose-groups and then irradiated by 60 Co γ rays. After 40 populations doubling, the progenies were secondly irradiated with 2 Gy 60 Co γ rays. Results: The cloning efficiency decreased with the increase of doses after the initial irradiation. After the survival cells were given second irradiation, both results of SCGE and micronucleus frequency showed that the second damage was correlated with the original irradiation doses. Conclusions: 60 Co γ rays can not only induce the immediate biological effects in liver cells, but also lead to the genomic instability in the descendants that leads to an enhanced frequency of genetic changes occurring among the progeny of the original irradiated cell. The expanding effect of second event helps to study the genomic instability. (authors)

  18. The interaction of bacterial magnetosomes and human liver cancer cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Pingping, E-mail: wangpp@mail.iee.ac.cn [Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190 (China); Chen, Chuanfang [Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190 (China); Chen, Changyou [Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Li, Yue; Pan, Weidong; Song, Tao [Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190 (China)

    2017-04-01

    As the biogenic magnetic nanomaterial, bacterial magnetic nanoparticles, namely magnetosomes, provide many advantages for potential biomedical applications. As such, interactions among magnetosomes and target cells should be elucidated to develop their bioapplications and evaluate their biocompatibilities. In this study, the interaction of magnetosomes and human liver cancer HepG2 cells was examined. Prussian blue staining revealed numerous stained particles in or on the cells. Intracellular iron concentrations, measured through inductively coupled plasma optical emission spectroscopy, increased with the increasing concentration of the magnetosomes. Transmission electron microscopy images showed that magnetosomes could be internalized in cells, mainly encapsulated in membrane vesicles, such as endosomes and lysosomes, and partly found as free particles in the cytosol. Some of the magnetosomes on cellular surfaces were encapsulated through cell membrane ruffling, which is the initiating process of endocytosis. Applying low temperature treatment and using specific endocytic inhibitors, we validated that macropinocytosis and clathrin-mediated endocytosis were involved in magnetosome uptake by HepG2 cells. Consequently, we revealed the interaction and intrinsic endocytic mechanisms of magnetosomes and HepG2 cells. This study provides a basis for the further research on bacterial magnetosome applications in liver diseases. - Highlights: • Bacterial magnetosomes interact with HepG2 cells in a dose-dependent manner. • Magnetosomes are wrapped by membrane ruffling on cell surface. • Internalized magnetosomes mainly localize in endosomes and lysosomes. • Macropinocytosis and CME are involved in the cellular uptake of magnetosomes.

  19. Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms.

    Science.gov (United States)

    Brill, Shirley S; Furimsky, Anna M; Ho, Mark N; Furniss, Michael J; Li, Yi; Green, Adam G; Bradford, Wallace W; Green, Carol E; Kapetanovic, Izet M; Iyer, Lalitha V

    2006-04-01

    Resveratrol (trans-resveratrol, trans-3,5,4'-trihydroxystilbene) is a naturally occurring stilbene analogue found in high concentrations in red wine. There is considerable research interest to determine the therapeutic potential of resveratrol, as it has been shown to have tumour inhibitory and antioxidant properties. This study was performed to investigate the glucuronidation of resveratrol and possible drug interactions via glucuronidation. Two glucuronide conjugates, resveratrol 3-O-glucuronide and resveratrol 4'-O-glucuronide, were formed by human liver and intestinal microsomes. UGT1A1 and UGT1A9 were predominantly responsible for the formation of the 3-O-glucuronide (Km = 149 microM) and 4'-O-glucuronide (Km = 365 microM), respectively. The glucuronide conjugates were formed at higher levels (up to 10-fold) by intestinal rather than liver microsomes. Resveratrol was co-incubated with substrates of UGT1A1 (bilirubin and 7-ethyl-10-hydroxycamptothecin (SN-38)) and UGT1A9 (7-hydroxytrifluoromethyl coumarin (7-HFC)). No major changes were noted in bilirubin glucuronidation in the presence of resveratrol. Resveratrol significantly inhibited the glucuronidation of SN-38 (Ki = 6.2 +/- 2.1 microM) and 7-HFC (Ki = 0.6 +/- 0.2 microM). Hence, resveratrol has the potential to inhibit the glucuronidation of concomitantly administered therapeutic drugs or dietary components that are substrates of UGT1A1 and UGT1A9.

  20. Cell Spheroids with Enhanced Aggressiveness to Mimic Human Liver Cancer In Vitro and In Vivo.

    Science.gov (United States)

    Jung, Hong-Ryul; Kang, Hyun Mi; Ryu, Jea-Woon; Kim, Dae-Soo; Noh, Kyung Hee; Kim, Eun-Su; Lee, Ho-Joon; Chung, Kyung-Sook; Cho, Hyun-Soo; Kim, Nam-Soon; Im, Dong-Soo; Lim, Jung Hwa; Jung, Cho-Rok

    2017-09-05

    We fabricated a spheroid-forming unit (SFU) for efficient and economic production of cell spheroids. We optimized the protocol for generating large and homogenous liver cancer cell spheroids using Huh7 hepatocellular carcinoma (HCC) cells. The large Huh7 spheroids showed apoptotic and proliferative signals in the centre and at the surface, respectively. In particular, hypoxia-induced factor-1 alpha (HIF-1α) and ERK signal activation were detected in the cell spheroids. To diminish core necrosis and increase the oncogenic character, we co-cultured spheroids with 2% human umbilical vein endothelial cells (HUVECs). HUVECs promoted proliferation and gene expression of HCC-related genes and cancer stem cell markers in the Huh7 spheroidsby activating cytokine signalling, mimicking gene expression in liver cancer. HUVECs induced angiogenesis and vessel maturation in Huh7 spheroids in vivo by activating epithelial-mesenchymal transition and angiogenic pathways. The large Huh7 cell spheroids containing HUVECs survived at higher concentrations of anti-cancer drugs (doxorubicin and sorafenib) than did monolayer cells. Our large cell spheroid provides a useful in vitro HCC model to enable intuitive observation for anti-cancer drug testing.

  1. Clonorchis sinensis, an oriental liver fluke, as a human biological agent of cholangiocarcinoma: a brief review.

    Science.gov (United States)

    Kim, Tong-Soo; Pak, Jhang Ho; Kim, Jong-Bo; Bahk, Young Yil

    2016-11-01

    Parasitic diseases remain an unarguable public health problem worldwide. Liver fluke Clonorchis sinensis is a high risk pathogenic parasitic helminth which is endemic predominantly in Asian countries, including Korea, China, Taiwan, Vietnam, and the far eastern parts of Russia, and is still actively transmitted. According to the earlier 8th National Survey on the Prevalence of Intestinal Parasitic Infections in 2012, C. sinensis was revealed as the parasite with highest prevalence of 1.86% in general population among all parasite species surveyed in Korea. This fluke is now classified under one of the definite Group 1 human biological agents (carcinogens) by International Agency of Research on Cancer (IARC) along with two other parasites, Opisthorchis viverrini and Schistosoma haematobium. C. sinensis infestation is mainly linked to liver and biliary disorders, especially cholangiocarcinoma (CCA). For the purposes of this mini-review, we will only focus on C. sinensis and review pathogenesis and carcinogenesis of clonorchiasis, disease condition by C. sinensis infestation, and association between C. sinensis infestation and CCA. In this presentation, we briefly consider the current scientific status for progression of CCA by heavy C. sinensis infestation from the food-borne trematode and development of CCA. [BMB Reports 2016; 49(11): 590-597].

  2. Electrical conductivity measurement of excised human metastatic liver tumours before and after thermal ablation.

    Science.gov (United States)

    Haemmerich, Dieter; Schutt, David J; Wright, Andrew W; Webster, John G; Mahvi, David M

    2009-05-01

    We measured the ex vivo electrical conductivity of eight human metastatic liver tumours and six normal liver tissue samples from six patients using the four electrode method over the frequency range 10 Hz to 1 MHz. In addition, in a single patient we measured the electrical conductivity before and after the thermal ablation of normal and tumour tissue. The average conductivity of tumour tissue was significantly higher than normal tissue over the entire frequency range (from 4.11 versus 0.75 mS cm(-1) at 10 Hz, to 5.33 versus 2.88 mS cm(-1) at 1 MHz). We found no significant correlation between tumour size and measured electrical conductivity. While before ablation tumour tissue had considerably higher conductivity than normal tissue, the two had similar conductivity throughout the frequency range after ablation. Tumour tissue conductivity changed by +25% and -7% at 10 Hz and 1 MHz after ablation (0.23-0.29 at 10 Hz, and 0.43-0.40 at 1 MHz), while normal tissue conductivity increased by +270% and +10% at 10 Hz and 1 MHz (0.09-0.32 at 10 Hz and 0.37-0.41 at 1 MHz). These data can potentially be used to differentiate tumour from normal tissue diagnostically.

  3. Induction of Morphological Changes in Human Embryo Liver Cells by the Pyrrolizidine Alkaloid Lasiocarpine

    Science.gov (United States)

    Armstrong, Sylvia J.; Zuckerman, A. J.; Bird, R. G.

    1972-01-01

    The pyrrolizidine alkaloids have been implicated in the aetiology of liver disease in man and in animals. Studies of the effects of lasiocarpine indicate that they have several and perhaps independent effects on human liver cells in culture. These may be summarized as follows: 1. Nuclear and nucleolar changes which are probably related to the alkylation of DNA and ensuing inhibition of nucleic acid and protein synthesis. 2. The induction of possible chromosomal damage and mutation. 3. A generalized reduction of the metabolic activities of the cells due to membrane and mitochondrial damage, and to alkylation and inactivation of cell enzymes and proteins. 4. A long-term inhibition of mitosis leading to the formation of giant cells (“megalocytes”). The morphological effects induced by a number of the pyrrolizidine alkaloids were very similar but the pattern of metabolic changes varied somewhat. It is believed that the hepatotoxic effects are not due to the pyrrolizidine alkaloids themselves but to metabolic derivatives formed by the cell. ImagesFigs. 3-5Figs. 1-2 PMID:5032090

  4. Identification and characterization of metabolites of ASP015K, a novel oral Janus kinase inhibitor, in rats, chimeric mice with humanized liver, and humans.

    Science.gov (United States)

    Nakada, Naoyuki; Oda, Kazuo

    2015-01-01

    1. Here, we elucidated the structure of metabolites of novel oral Janus kinase inhibitor ASP015K in rats and humans and evaluated the predictability of human metabolites using chimeric mice with humanized liver (PXB mice). 2. Rat biological samples collected after oral dosing of (14)C-labelled ASP015K were examined using a liquid chromatography-radiometric detector and mass spectrometer (LC-RAD/MS). The molecular weight of metabolites in human and the liver chimeric mouse biological samples collected after oral dosing of non-labelled ASP015K was also investigated via LC-MS. Metabolites were also isolated from rat bile samples and analyzed using nuclear magnetic resonance. 3. Metabolic pathways of ASP015K in rats and humans were found to be glucuronide conjugation, methyl conjugation, sulfate conjugation, glutathione conjugation, hydroxylation of the adamantane ring and N-oxidation of the 1H-pyrrolo[2,3-b]pyridine ring. The main metabolite of ASP015K in rats was the glucuronide conjugate, while the main metabolite in humans was the sulfate conjugate. Given that human metabolites were produced by human hepatocytes in chimeric mice with humanized liver, this human model mouse was believed to be useful in predicting the human metabolic profile of various drug candidates.

  5. Interactions of the heart and the liver

    DEFF Research Database (Denmark)

    Møller, Søren; Bernardi, Mauro

    2013-01-01

    There is a mutual interaction between the function of the heart and the liver and a broad spectrum of acute and chronic entities that affect both the heart and the liver. These can be classified into heart diseases affecting the liver, liver diseases affecting the heart, and conditions affecting...... the heart and the liver at the same time. In chronic and acute cardiac hepatopathy, owing to cardiac failure, a combination of reduced arterial perfusion and passive congestion leads to cardiac cirrhosis and cardiogenic hypoxic hepatitis. These conditions may impair the liver function and treatment should...... be directed towards the primary heart disease and seek to secure perfusion of vital organs. In patients with advanced cirrhosis, physical and/or pharmacological stress may reveal a reduced cardiac performance with systolic and diastolic dysfunction and electrophysical abnormalities termed cirrhotic...

  6. Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.

    Directory of Open Access Journals (Sweden)

    Dan Xu

    2014-04-01

    Full Text Available Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU] developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology

  7. Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.

    Science.gov (United States)

    Xu, Dan; Nishimura, Toshi; Nishimura, Sachiko; Zhang, Haili; Zheng, Ming; Guo, Ying-Ying; Masek, Marylin; Michie, Sara A; Glenn, Jeffrey; Peltz, Gary

    2014-04-01

    Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers. FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve

  8. Metabolism of lysergic acid diethylamide (LSD) to 2-oxo-3-hydroxy LSD (O-H-LSD) in human liver microsomes and cryopreserved human hepatocytes.

    Science.gov (United States)

    Klette, K L; Anderson, C J; Poch, G K; Nimrod, A C; ElSohly, M A

    2000-10-01

    The metabolism of lysergic acid diethylamide (LSD) to 2-oxo-3-hydroxy lysergic acid diethylamide (O-H-LSD) was investigated in liver microsomes and cyropreserved hepatocytes from humans. Previous studies have demonstrated that O-H-LSD is present in human urine at concentrations 16-43 times greater than LSD, the parent compound. Additionally, these studies have determined that O-H-LSD is not generated during the specimen extraction and analytical processes or due to parent compound degradation in aqueous urine samples. However, these studies have not been conclusive in demonstrating that O-H-LSD is uniquely produced during in vivo metabolism. Phase I drug metabolism was investigated by incubating human liver microsomes and cryopreserved human hepatocytes with LSD. The reaction was quenched at various time points, and the aliquots were extracted using liquid partitioning and analyzed by liquid chromatography-mass spectrometry. O-H-LSD was positively identified in all human liver microsomal and human hepatocyte fractions incubated with LSD. In addition, O-H-LSD was not detected in any microsomal or hepatocyte fraction not treated with LSD nor in LSD specimens devoid of microsomes or hepatocytes. This study provides definitive evidence that O-H-LSD is produced as a metabolic product following incubation of human liver microsomes and hepatocytes with LSD.

  9. Development of a prognostic nomogram for cirrhotic patients with upper gastrointestinal bleeding.

    Science.gov (United States)

    Zhou, Yu-Jie; Zheng, Ji-Na; Zhou, Yi-Fan; Han, Yi-Jing; Zou, Tian-Tian; Liu, Wen-Yue; Braddock, Martin; Shi, Ke-Qing; Wang, Xiao-Dong; Zheng, Ming-Hua

    2017-10-01

    Upper gastrointestinal bleeding (UGIB) is a complication with a high mortality rate in critically ill patients presenting with cirrhosis. Today, there exist few accurate scoring models specifically designed for mortality risk assessment in critically ill cirrhotic patients with upper gastrointestinal bleeding (CICGIB). Our aim was to develop and evaluate a novel nomogram-based model specific for CICGIB. Overall, 540 consecutive CICGIB patients were enrolled. On the basis of Cox regression analyses, the nomogram was constructed to estimate the probability of 30-day, 90-day, 270-day, and 1-year survival. An upper gastrointestinal bleeding-chronic liver failure-sequential organ failure assessment (UGIB-CLIF-SOFA) score was derived from the nomogram. Performance assessment and internal validation of the model were performed using Harrell's concordance index (C-index), calibration plot, and bootstrap sample procedures. UGIB-CLIF-SOFA was also compared with other prognostic models, such as CLIF-SOFA and model for end-stage liver disease, using C-indices. Eight independent factors derived from Cox analysis (including bilirubin, creatinine, international normalized ratio, sodium, albumin, mean artery pressure, vasopressin used, and hematocrit decrease>10%) were assembled into the nomogram and the UGIB-CLIF-SOFA score. The calibration plots showed optimal agreement between nomogram prediction and actual observation. The C-index of the nomogram using bootstrap (0.729; 95% confidence interval: 0.689-0.766) was higher than that of the other models for predicting survival of CICGIB. We have developed and internally validated a novel nomogram and an easy-to-use scoring system that accurately predicts the mortality probability of CICGIB on the basis of eight easy-to-obtain parameters. External validation is now warranted in future clinical studies.

  10. Low density in liver of idiopathic portal hypertension. A computed tomographic observation with possible diagnostic significance

    Energy Technology Data Exchange (ETDEWEB)

    Ishito, Hiroyuki

    1988-01-01

    In order to evaluate the diagnostic value of low density in liver on computed tomography (CT), CT scans of 11 patients with idiopathic portal hypertension (IPH) were compared with those from 22 cirrhotic patients, two patients with scarred liver and 16 normal subjects. Low densities on plain CT scans in patients with IPH were distinctly different from those observed in normal liver. Some of the low densities had irregular shape with unclear margin and were scattered near the liver surface, and others had vessel-like structures with unclear margin and extended as far as near the liver surface. Ten of the 11 patients with IPH had low densities mentioned above, while none of the 22 cirrhotic patients had such low densities. The present results suggest that the presence of low densities in liver on plain CT scan is clinically beneficial in diagnosis of IPH.

  11. Liver and Muscle Contribute Differently to the Plasma Acylcarnitine Pool During Fasting and Exercise in Humans

    DEFF Research Database (Denmark)

    Xu, G.; Hansen, J S; Zhao, Jian-xin

    2016-01-01

    BACKGROUND: Plasma acylcarnitine levels are elevated by physiological conditions such as fasting and exercise but also in states of insulin resistance and obesity. AIM: To elucidate the contribution of liver and skeletal muscle to plasma acylcarnitines in the fasting state and during exercise...... in humans. METHODS: In 2 independent studies, young healthy males were fasted overnight and performed an acute bout of exercise to investigate either acylcarnitines in skeletal muscle biopsies and arterial-to-venous plasma differences over the exercising and resting leg (n = 9) or the flux over the hepato......-splanchnic bed (n = 10). RESULTS: In the fasting state, a pronounced release of C2- and C3-carnitines from the hepato-splanchnic bed and an uptake of free carnitine by the legs were detected. Exercise further increased the release of C3-carnitine from the hepato-splanchnic bed and the uptake of free carnitine...

  12. Reference intervals for putative biomarkers of drug-induced liver injury and liver regeneration in healthy human volunteers.

    Science.gov (United States)

    Francis, Ben; Clarke, Joanna I; Walker, Lauren E; Brillant, Nathalie; Jorgensen, Andrea L; Park, B Kevin; Pirmohamed, Munir; Antoine, Daniel J

    2018-05-02

    The potential of mechanistic biomarkers to improve the prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration as well as to characterize their natural variability and impact of diurnal variation. Serum samples from 200 healthy volunteers were recruited as part of a cross sectional study; of these, 50 subjects had weekly serial sampling over 3 weeks, while 24 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), high mobility group box-1 (HMGB1), total keratin-18 (FL-K18), caspase cleaved keratin-18 (cc-K18), glutamate dehydrogenase (GLDH) and colony stimulating factor-1 (CSF-1) were assessed by validated assays. Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models (ALT 50 (41-50) U/l, miR-122 3548 (2912-4321) copies/µl, HMGB1 2.3 (2.2-2.4) ng/ml, FL-K18 475 (456-488) U/l, cc-K18 272 (256-291) U/l, GLDH 27 (26-30) U/l and CSF-1 2.4 (2.3-2.9) ng/ml). There was a small but significant intra-individual time random effect detected but no significant impact of diurnal variation was observed, with the exception of GLDH. Reference intervals for novel DILI biomarkers have been described for the first time. An upper limit of a reference range might represent the most appropriate method to utilize these data. Regulatory authorities have published letters of support encouraging further qualification of leading candidate biomarkers. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification. Drug-induced liver injury (DILI) has a big impact on patient health and the development of new medicines. Unfortunately, currently used blood-based tests to assess liver injury and recovery suffer from insufficiencies. Newer blood

  13. Peritransplant energy changes and their correlation to outcome after human liver transplantation

    NARCIS (Netherlands)

    Bruinsma, Bote G; Avruch, James H; Sridharan, Gautham V; Weeder, Pepijn D; Jacobs, Marie Louise; Crisalli, Kerry; Amundsen, Beth; Porte, Robert J; Markmann, James F; Uygun, Korkut; Yeh, Heidi

    BACKGROUND: The ongoing shortage of donor livers for transplantation and the increased use of marginal livers necessitate the development of accurate pretransplant tests of viability. Considering the importance energy status during transplantation, we aimed to correlate peritransplant energy

  14. The proteome of human liver peroxisomes: identification of five new peroxisomal constituents by a label-free quantitative proteomics survey.

    Directory of Open Access Journals (Sweden)

    Thomas Gronemeyer

    Full Text Available The peroxisome is a key organelle of low abundance that fulfils various functions essential for human cell metabolism. Severe genetic diseases in humans are caused by defects in peroxisome biogenesis or deficiencies in the function of single peroxisomal proteins. To improve our knowledge of this important cellular structure, we studied for the first time human liver peroxisomes by quantitative proteomics. Peroxisomes were isolated by differential and Nycodenz density gradient centrifugation. A label-free quantitative study of 314 proteins across the density gradient was accomplished using high resolution mass spectrometry. By pairing statistical data evaluation, cDNA cloning and in vivo colocalization studies, we report the association of five new proteins with human liver peroxisomes. Among these, isochorismatase domain containing 1 protein points to the existence of a new metabolic pathway and hydroxysteroid dehydrogenase like 2 protein is likely involved in the transport or β-oxidation of fatty acids in human peroxisomes. The detection of alcohol dehydrogenase 1A suggests the presence of an alternative alcohol-oxidizing system in hepatic peroxisomes. In addition, lactate dehydrogenase A and malate dehydrogenase 1 partially associate with human liver peroxisomes and enzyme activity profiles support the idea that NAD(+ becomes regenerated during fatty acid β-oxidation by alternative shuttling processes in human peroxisomes involving lactate dehydrogenase and/or malate dehydrogenase. Taken together, our data represent a valuable resource for future studies of peroxisome biochemistry that will advance research of human peroxisomes in health and disease.

  15. Quantification of human hepatic binding protein (HBP) via 99mTc-galactosyl-neoglycoalbumin (NGA) liver scintigraphy

    International Nuclear Information System (INIS)

    Virgolini, I.; Hoebart, J.; Bergmann, H.; Sinzinger, H.; Mueller, C.; Angelberger, P.

    1991-01-01

    99m Tc-galactosyl-neoglycoalbumin ( 99m Tc-NGA) was synthesized by covalent coupling of 2-imino-2-methoxyethyl-1-thio-β-D-galactopyranoside to the primary amino groups of human serum albumin. Injections of 99m Tc-NGA (150 MBq; 3.5 mg (=50 nmol)/ml) demonstrated the liver to be the exclusive site of tracer-uptake. Simulation of 99m Tc-NGA-kinetics allowed quantification of binding to the hepatic binding protein (HBP). Using this model we studied 250 patients with various liver disease. In alcoholic liver cirrhosis such patients with Child B and Child C stage cirrhosis had a lower HBP-concentration in the liver compared to control individuals (0.85-1.2 μmol/l). The group with the most advanced cirrhosis (Child C stage) had a significantly lower HBP-concentration (0.20-0.45 μmol/l) than Child A patients (0.60-0.85 μmol/l; p 99m Tc-galactosyl-neoglycoalbumin (NGA) scanning of the liver during the course of the disease. Return of liver function tests to normal values was associated with an increased hepatic imaging size as well as increase in HBP-concentration (up to a 3-fold of initial concentration). In patients exhibiting a prolonged course of the disease changes in NGA-kinetic data were borderline and the hepatic image size unchanged. The values obtained for HBP-concentration in the liver amounted to 0.30-0.50 μmol/l liver for patients with hepatoma, to 0.40-0.60 μmol/l in patients with liver metastasis and to 0.90-1.20 μmol/l in cancer patients without liver malignancy. It is concluded that scintigraphic evaluation of functional hepatic cell mass using the new receptor-tracer 99m Tc-NGA provides an in vivo diagnostic mean allowing quantitative data on liver function beside assessment of liver morphology. (Authors)

  16. Differentiation of human-induced pluripotent stem cell under flow conditions to mature hepatocytes for liver tissue engineering

    DEFF Research Database (Denmark)

    Starokozhko, Viktoriia; Hemmingsen, Mette; Larsen, Layla

    2018-01-01

    and to perform functional comparisons with fresh human precision-cut liver slices (hPCLS), an excellent benchmark for the human liver in vivo. The majority of the mRNA expression of CYP isoenzymes and transporters and the tested CYP activities, Phase II metabolism, and albumin, urea, and bile acid synthesis...... in the hiPSC-derived cells reached values that overlap those of hPCLS, which indicates a higher degree of hepatic differentiation than observed until now. Differentiation under flow compared with static conditions had a strong inducing effect on Phase II metabolism and suppressed AFP expression but resulted...... in slightly lower activity of some of the Phase I metabolism enzymes. Gene expression data indicate that hiPSCs differentiated into both hepatic and biliary directions. In conclusion, the hiPSC differentiated under flow conditions towards hepatocytes express a wide spectrum of liver functions at levels...

  17. Carboxylated nanodiamonds are neither cytotoxic nor genotoxic on liver, kidney, intestine and lung human cell lines.

    Science.gov (United States)

    Paget, V; Sergent, J A; Grall, R; Altmeyer-Morel, S; Girard, H A; Petit, T; Gesset, C; Mermoux, M; Bergonzo, P; Arnault, J C; Chevillard, S

    2014-08-01

    Although nanodiamonds (NDs) appear as one of the most promising nanocarbon materials available so far for biomedical applications, their risk for human health remains unknown. Our work was aimed at defining the cytotoxicity and genotoxicity of two sets of commercial carboxylated NDs with diameters below 20 and 100 nm, on six human cell lines chosen as representative of potential target organs: HepG2 and Hep3B (liver), Caki-1 and Hek-293 (kidney), HT29 (intestine) and A549 (lung). Cytotoxicity of NDs was assessed by measuring cell impedance (xCELLigence® system) and cell survival/death by flow cytometry while genotoxicity was assessed by γ-H2Ax foci detection, which is considered the most sensitive technique for studying DNA double-strand breaks. To validate and check the sensitivity of the techniques, aminated polystyrene nanobeads were used as positive control in all assays. Cell incorporation of NDs was also studied by flow cytometry and luminescent N-V center photoluminescence (confirmed by Raman microscopy), to ensure that nanoparticles entered the cells. Overall, we show that NDs effectively entered the cells but NDs do not induce any significant cytotoxic or genotoxic effects on the six cell lines up to an exposure dose of 250 µg/mL. Taken together these results strongly support the huge potential of NDs for human nanomedicine but also their potential as negative control in nanotoxicology studies.

  18. PEDIATRIC LIVER TRANSPLANTATION WITH EX-SITU LIVER TRANSECTION AND THE APPLICATION OF THE HUMAN FIBRINOGEN AND THROMBIN SPONGE IN THE WOUND AREA.

    Science.gov (United States)

    Vicentine, Fernando Pompeu Piza; Gonzalez, Adriano Miziara; Azevedo, Ramiro Anthero de; Benini, Barbara Burza; Linhares, Marcelo Moura; Lopes-Filho, Gaspar de Jesus; Martins, Jose Luiz; Salzedas-Netto, Alcides Augusto

    2016-01-01

    Surgical strategy to increase the number of liver transplants in the pediatric population is the ex-situ liver transection (reduction or split). However, it is associated with complications such as hemorrhage and leaks. The human fibrinogen and thrombin sponge is useful for improving hemostasis in liver surgery. Compare pediatric liver transplants with ex-situ liver transection (reduction or split) with or without the human fibrinogen and thrombin sponge. Was performed a prospective analysis of 21 patients submitted to liver transplantation with ex-situ liver transection with the application of the human fibrinogen and thrombin sponge in the wound area (group A) and retrospective analysis of 59 patients without the sponge (group B). The characteristics of recipients and donors were similar. There were fewer reoperations due to bleeding in the wound area in group A (14.2%) compared to group B (41.7%, p=0.029). There was no difference in relation to the biliary leak (group A: 17.6%, group B: 5.1%, p=0.14). There was a lower number of reoperations due to bleeding of the wound area of ​​the hepatic graft when the human fibrinogen and thrombin sponge were used. Estratégia cirúrgica para aumentar o número de transplantes hepáticos na população pediátrica é a transecção hepática ex-situ (redução ou split). No entanto, ela está associada com complicações, tais como hemorragia e fístulas. A esponja de fibrinogênio e trombina humana é útil para melhorar a hemostasia nas operações hepáticas. Comparar transplantes hepáticos pediátricos com transecção hepática ex-situ (redução ou split) com ou sem a esponja de fibrinogênio e trombina humana. Foi realizada análise prospectiva de 21 pacientes submetidos ao transplante de fígado com transecção hepática ex-situ com a aplicação da esponja de fibrinogênio e trombina humana na área cruenta (grupo A) e análise retrospectiva de 59 pacientes sem a esponja (grupo B). As características dos

  19. Idiopathic Non-Cirrhotic Intrahepatic Portal Hypertension (NCIPH)—Newer Insights into Pathogenesis and Emerging Newer Treatment Options

    Science.gov (United States)

    Goel, Ashish; Elias, Joshua E.; Eapen, Chundamannil E.; Ramakrishna, Banumathi; Elias, Elwyn

    2014-01-01

    Chronic microangiopathy of portal venules results in idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH). Recent data suggest a role for vasoactive factors of portal venous origin in the pathogenesis of this ‘pure’ vasculopathy of the liver. Enteropathies (often silent), are an important ‘driver’ of this disease. NCIPH is under-recognized and often mis-labeled as cryptogenic cirrhosis. Liver biopsy is needed to prove the diagnosis of NCIPH. In these patients, with advancing disease and increased porto-systemic shunting, the portal venous vasoactive factors bypass the liver filter and contribute to the development of pulmonary vascular endothelial disorders—porto-pulmonary hypertension and hepato-pulmonary syndrome as well as mesangiocapillary glomerulonephritis. Prognosis in NCIPH patients is determined by presence, recognition and management of associated disorders. With better understanding of the pathogenesis of NCIPH, newer treatment options are being explored. Imbalance in ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13): vWF (von-Willebrand factor) ratio is documented in NCIPH patients and may have a pathogenic role. Therapeutic interventions to correct this imbalance may prove to be important in the management of NCIPH. PMID:25755567

  20. Effects of Vitamin D Supplementation on Serum 25-Hydroxyvitamin D Concentrations in Cirrhotic Patients: A Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    Stefan Pilz

    2016-05-01

    Full Text Available Background: The liver is crucial for 25-hydroxyvitamin D (25(OHD metabolism, and vitamin D deficiency is highly prevalent in patients with cirrhosis and predicts adverse outcomes. We aimed to evaluate whether vitamin D supplementation in patients with cirrhosis is effective in increasing 25(OHD serum concentrations. Secondary outcome measures included liver function tests (aspartate aminotransferase (AST, alanine aminotransferase (ALT, gamma glutamyltransferase (GGT, and alkaline phosphatase (AP, albumin, International Normalized Ratio (INR, bilirubin, the liver fibrosis marker hyaluronic acid, and parameters of mineral metabolism including parathyroid hormone (PTH. Methods: This is a double-center, double-blind, placebo-controlled study conducted from December 2013 to May 2014 at the Medical University of Graz, and the hospital Hoergas-Enzenbach, Austria. We enrolled 36 consecutive patients with cirrhosis and 25(OHD concentrations below 30 ng/mL. Study participants were randomly allocated to receive either 2800 International Units of vitamin D3 per day as oily drops (n = 18 or placebo (n = 18 for 8 weeks. Results: Thirty-three study participants (mean (SD age: 60 (9 years; 21% females; 25(OHD: 15.6 (7.4 ng/mL completed the trial. The mean treatment effect (95% CI for 25(OHD was 15.2 (8.0 to 22.4 ng/mL (p < 0.001. There was no significant effect on any secondary outcome. Conclusions: In this randomized controlled trial, vitamin D supplementation increases 25(OHD serum concentrations, even in cirrhotic patients.

  1. Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tomasi, Maria Lauda [Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); The Southern California Research Center for Alcoholic and Pancreatic Diseases and Cirrhosis, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); Ryoo, Minjung; Skay, Anna [Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); Tomasi, Ivan; Giordano, Pasquale [Department of Colorectal Surgery, Whipps Cross University Hospital, London E11 1NR (United Kingdom); Mato, José M. [CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia (Spain); Lu, Shelly C., E-mail: shellylu@usc.edu [Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); The Southern California Research Center for Alcoholic and Pancreatic Diseases and Cirrhosis, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States)

    2013-07-15

    Methionine adenosyltransferase (MAT) is an essential enzyme that is responsible for the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and precursor of polyamines. MAT1A is expressed in normal liver and MAT2A is expressed in all extrahepatic tissues. MAT2A expression is increased in human colon cancer and in colon cancer cells treated with mitogens, whereas silencing MAT2A resulted in apoptosis. The aim of the current work was to examine the mechanism responsible for MAT2A-dependent growth and apoptosis. We found that in RKO (human adenocarcinoma cell line) cells, MAT2A siRNA treatment lowered cellular SAMe and putrescine levels by 70–75%, increased apoptosis and inhibited growth. Putrescine supplementation blunted significantly MAT2A siRNA-induced apoptosis and growth suppression. Putrescine treatment (100 pmol/L) raised MAT2A mRNA level to 4.3-fold of control, increased the expression of c-Jun and c-Fos and binding to an AP-1 site in the human MAT2A promoter and the promoter activity. In human colon cancer specimens, the expression levels of MAT2A, ornithine decarboxylase (ODC), c-Jun and c-Fos are all elevated as compared to adjacent non-tumorous tissues. Overexpression of ODC in RKO cells also raised MAT2A mRNA level and MAT2A promoter activity. ODC and MAT2A are also overexpressed in liver cancer and consistently, similar MAT2A-ODC-putrescine interactions and effects on growth and apoptosis were observed in HepG2 cells. In conclusion, there is a crosstalk between polyamines and MAT2A. Increased MAT2A expression provides more SAMe for polyamines biosynthesis; increased polyamine (putrescine in this case) can activate MAT2A at the transcriptional level. This along with increased ODC expression in cancer all feed forward to further enhance the proliferative capacity of the cancer cell. -- Highlights: • MAT2A knockdown depletes putrescine and leads to apoptosis. • Putrescine attenuates MAT2A knockdown-induced apoptosis and growth

  2. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans.

    Science.gov (United States)

    Sevastianova, Ksenia; Santos, Alexandre; Kotronen, Anna; Hakkarainen, Antti; Makkonen, Janne; Silander, Kaisa; Peltonen, Markku; Romeo, Stefano; Lundbom, Jesper; Lundbom, Nina; Olkkonen, Vesa M; Gylling, Helena; Fielding, Barbara A; Rissanen, Aila; Yki-Järvinen, Hannele

    2012-10-01

    Cross-sectional studies have identified a high intake of simple sugars as an important dietary factor predicting nonalcoholic fatty liver disease (NAFLD). We examined whether overfeeding overweight subjects with simple sugars increases liver fat and de novo lipogenesis (DNL) and whether this is reversible by weight loss. Sixteen subjects [BMI (kg/m²): 30.6 ± 1.2] were placed on a hypercaloric diet (>1000 kcal simple carbohydrates/d) for 3 wk and, thereafter, on a hypocaloric diet for 6 mo. The subjects were genotyped for rs739409 in the PNPLA3 gene. Before and after overfeeding and after hypocaloric diet, metabolic variables and liver fat (measured by proton magnetic resonance spectroscopy) were measured. The ratio of palmitate (16:0) to linoleate (18:2n-6) in serum and VLDL triglycerides was used as an index of DNL. Carbohydrate overfeeding increased weight (±SEM) by 2% (1.8 ± 0.3 kg; P fat by 27% from 9.2 ± 1.9% to 11.7 ± 1.9% (P = 0.005). DNL increased in proportion to the increase in liver fat and serum triglycerides in subjects with PNPLA3-148IIbut not PNPLA3-148MM. During the hypocaloric diet, the subjects lost 4% of their weight (3.2 ± 0.6 kg; P fat content (from 11.7 ± 1.9% to 8.8 ± 1.8%; P Carbohydrate overfeeding for 3 wk induced a >10-fold greater relative change in liver fat (27%) than in body weight (2%). The increase in liver fat was proportional to that in DNL. Weight loss restores liver fat to normal. These data indicate that the human fatty liver avidly accumulates fat during carbohydrate overfeeding and support a role for DNL in the pathogenesis of NAFLD. This trial was registered at www.hus.fi as 235780.

  3. Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days

    NARCIS (Netherlands)

    Starokozhko, Viktoriia; Vatakuti, Suresh; Schievink, Bauke; Merema, Marjolijn T.; Asplund, Annika; Synnergren, Jane; Aspegren, Anders; Groothuis, Geny M. M.

    Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and

  4. Nomenclature of the finer branches of the biliary tree : Canals, ductules, and ductular reactions in human livers

    NARCIS (Netherlands)

    Roskams, TA; Theise, ND; Balabaud, C; Bhagat, G; Bhathal, PS; Bioulac-Sage, P; Brunt, EM; Crawford, JM; Crosby, HA; Desmet, [No Value; Finegold, MJ; Geller, SA; Gouw, ASH; Hytiroglou, P; Knisely, AS; Kojiro, M; Letkowitch, JH; Nakanuma, Y; Olynyk, JK; Park, YN; Portmann, B; Saxena, R; Scheuer, PJ; Strain, AJ; Thung, SN; Wanless, IR; West, AB

    The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what

  5. Dynamics of the vascular profile of the finer branches of the biliary tree in normal and diseased human livers

    NARCIS (Netherlands)

    Gouw, Annette S. H.; van den Heuvel, Marius C.; Boot, Marcel; Slooff, Maarten J. H.; Poppema, Sibrand; de Jong, Koert P.

    Background/Aims: Results of our previous studies supported the concept that in the human liver, the smallest ramification of the biliary tree, the bile ductules, might contain hepatic progenitor cells. An insufficient proliferative response and loss of bile ductules preceded bile duct loss whereas

  6. Organ slices as an in vitro test system for drug metabolism in human liver, lung and kidney

    NARCIS (Netherlands)

    Olinga, Peter; de Jager, M.H; Meijer, D.K F; Groothuis, Geny; Merema, M.T.

    1999-01-01

    Metabolism of xenobiotics occurs mainly in the liver, but in addition, the lungs and kidneys may contribute considerably. The choice of the animal species during drug development as a predictive model for the human condition is often inadequate due to large interspecies differences. Therefore, a

  7. Phytanic acid alpha-oxidation: decarboxylation of 2-hydroxyphytanoyl-CoA to pristanic acid in human liver

    NARCIS (Netherlands)

    Verhoeven, N. M.; Wanders, R. J.; Schor, D. S.; Jansen, G. A.; Jakobs, C.

    1997-01-01

    The degradation of the first intermediate in the alpha-oxidation of phytanic acid, 2-hydroxyphytanoyl-CoA, was investigated. Human liver homogenates were incubated with 2-hydroxyphytanoyl-CoA or 2-hydroxyphytanic acid, after which formation of 2-ketophytanic acid and pristanic acid were studied.

  8. Hepatorenal Syndrome with Cirrhotic Cardiomyopathy: Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Luis Mocarzel

    2015-01-01

    Full Text Available The hepatorenal syndrome (HRS is defined as a potentially reversible kidney failure in patients with cirrhosis and ascites. An association of HRS and cirrhotic cardiomyopathy has been reported recently, but there are no result studies about the use of positive inotropes as part of the acute phase treatment. We report the case of a patient diagnosed with HRS, with high levels of NT pro-BNP, but with normal ejection fraction of the left ventricle, which showed abnormalities in systolic function through speckle tracking in echocardiography, reversible after the infusion of dobutamine. The patient showed clinical and laboratory improvement of his renal function after the infusion of dobutamine. Clinical studies are needed on HRS therapeutic approach taking into account the myocardial dysfunction as a major contributing factor to renal dysfunction.

  9. Systemic administration of a novel human umbilical cord mesenchymal stem cells population accelerates the resolution of acute liver injury

    Directory of Open Access Journals (Sweden)

    Burra Patrizia

    2012-07-01

    Full Text Available Abstract Background Hepatocytes and stem cells transplantation may be an alternative to liver transplantation in acute or chronic liver disease. We aimed to evaluate the therapeutic potential of mesenchymal stem cells from human umbilical cord (UCMSCs, a readily available source of mesenchymal stem cells, in the CCl4-induced acute liver injury model. Methods Mesenchymal stem cells profile was analyzed by flow cytometry. In order to evaluate the capability of our UCMSCs to differentiate in hepatocytes, cells were seeded on three different supports, untreated plastic support, MatrigelTM and human liver acellular matrix. Cells were analyzed by immunocitochemistry for alpha-fetoprotein and albumin expression, qPCR for hepatocyte markers gene expression, Periodic Acid-Schiff staining for glycogen storage, ELISA for albumin detection and colorimetric assay for urea secretion. To assess the effects of undifferentiated UCMSCs in hepatic regeneration after an acute liver injury, we transplanted them via tail vein in mice injected intraperitoneally with a single dose of CCl4. Livers were analyzed by histological evaluation for damage quantification, immunostaining for Kupffer and stellate cells/liver myofibroblasts activation and for UCMSCs homing. Pro- and anti-inflammatory cytokines gene expression was evaluated by qPCR analysis and antioxidant enzyme activity was measured by catalase quantification. Data were analyzed by Mann–Whitney U-test, Kruskal-Wallis test and Cuzick’s test followed by Bonferroni correction for multiple comparisons. Results We have standardized the isolation procedure to obtain a cell population with hepatogenic properties prior to in vivo transplantation. When subjected to hepatogenic differentiation on untreated plastic support, UCMSCs differentiated in hepatocyte-like cells as demonstrated by their morphology, progressive up-regulation of mature hepatocyte markers, glycogen storage, albumin and urea secretion. However

  10. Serum zinc level in patients with liver cirrhosis

    International Nuclear Information System (INIS)

    Soomro, A.A.; Devrajani, B.R.; Shaikh, K.; Shah, S.Z.A.; Devrajani, T.; Bibi, I.

    2009-01-01

    Objective: To determine the serum zinc level in patients with liver cirrhosis. Methodology: This descriptive cross sectional study was conducted at Liaquat University Hospital Hyderabad Sindh, Pakistan. All patients above 12 years of age, of either gender and known (diagnosed) cases of liver cirrhosis were further evaluated for their serum zinc level. The data was analyzed in statistical software (SPSS) and the p value <0.05 was considered as statistically significant. Result: One hundred twenty seven cirrhotic patients with means age 42.7559 +- 15.8894 were evaluated and assessed. The serum zinc was low in 69% patients. According to Child-Pugh classification 72% zinc deficient cirrhotic subjects were in class C, 16% in class B and 12% in class A. 94% subjects had hepatitis C virus infection, 4% had hepatitis B virus infection and 2% had history of alcoholism. Conclusion: The serum zinc level was low in patients with liver cirrhosis. (author)

  11. Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.

    Science.gov (United States)

    Ijssennagger, Noortje; Janssen, Aafke W F; Milona, Alexandra; Ramos Pittol, José M; Hollman, Danielle A A; Mokry, Michal; Betzel, Bark; Berends, Frits J; Janssen, Ignace M; van Mil, Saskia W C; Kersten, Sander

    2016-05-01

    The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA alters hepatic expression of many genes. However, no data are available on the effects of OCA in the human liver. Here we generated gene expression profiles in human precision cut liver slices (hPCLS) after treatment with OCA. hPCLS were incubated with OCA for 24 h. Wild-type or FXR(-/-) mice received OCA or vehicle by oral gavage for 7 days. Transcriptomic analysis showed that well-known FXR target genes, including NR0B2 (SHP), ABCB11 (BSEP), SLC51A (OSTα) and SLC51B (OSTβ), and ABCB4 (MDR3) are regulated by OCA in hPCLS. Ingenuity pathway analysis confirmed that 'FXR/RXR activation' is the most significantly changed pathway upon OCA treatment. Comparison of gene expression profiles in hPCLS and mouse livers identified 18 common potential FXR targets. ChIP-sequencing in mouse liver confirmed FXR binding to IR1 sequences of Akap13, Cgnl1, Dyrk3, Pdia5, Ppp1r3b and Tbx6. Our study shows that hPCLS respond to OCA treatment by upregulating well-known FXR target genes, demonstrating its suitability to study FXR-mediated gene regulation. We identified six novel bona-fide FXR target genes in both mouse and human liver. Finally, we discuss a possible explanation for changes in high or low density lipoprotein observed in NASH and primary biliary cholangitis patients treated with OCA based on the genomic expression profile in hPCLS. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  12. Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane x receptors.

    Science.gov (United States)

    Luisier, Raphaëlle; Lempiäinen, Harri; Scherbichler, Nina; Braeuning, Albert; Geissler, Miriam; Dubost, Valerie; Müller, Arne; Scheer, Nico; Chibout, Salah-Dine; Hara, Hisanori; Picard, Frank; Theil, Diethilde; Couttet, Philippe; Vitobello, Antonio; Grenet, Olivier; Grasl-Kraupp, Bettina; Ellinger-Ziegelbauer, Heidrun; Thomson, John P; Meehan, Richard R; Elcombe, Clifford R; Henderson, Colin J; Wolf, C Roland; Schwarz, Michael; Moulin, Pierre; Terranova, Rémi; Moggs, Jonathan G

    2014-06-01

    The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CAR(KO)-PXR(KO)), double humanized CAR and PXR (CAR(h)-PXR(h)), and wild-type C57BL/6 mice. Wild-type and CAR(h)-PXR(h) mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CAR(KO)-PXR(KO) mouse livers and largely reversible in wild-type and CAR(h)-PXR(h) mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CAR(h)-PXR(h) mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.

  13. Phosphodiester content measured in human liver by in vivo 31 P MR spectroscopy at 7 tesla.

    Science.gov (United States)

    Purvis, Lucian A B; Clarke, William T; Valkovič, Ladislav; Levick, Christina; Pavlides, Michael; Barnes, Eleanor; Cobbold, Jeremy F; Robson, Matthew D; Rodgers, Christopher T

    2017-12-01

    Phosphorus ( 31 P) metabolites are emerging liver disease biomarkers. Of particular interest are phosphomonoester and phosphodiester (PDE) "peaks" that comprise multiple overlapping resonances in 31 P spectra. This study investigates the effect of improved spectral resolution at 7 Tesla (T) on quantifying hepatic metabolites in cirrhosis. Five volunteers were scanned to determine metabolite T 1 s. Ten volunteers and 11 patients with liver cirrhosis were scanned at 7T. Liver spectra were acquired in 28 min using a 16-channel 31 P array and 3D chemical shift imaging. Concentrations were calculated using γ-adenosine-triphosphate (γ-ATP) = 2.65 mmol/L wet tissue. T 1 means ± standard deviations: phosphatidylcholine 1.05 ± 0.28 s, nicotinamide-adenine-dinucleotide (NAD + ) 2.0 ± 1.0 s, uridine-diphosphoglucose (UDPG) 3.3 ± 1.4 s. Concentrations in healthy volunteers: α-ATP 2.74 ± 0.11 mmol/L wet tissue, inorganic phosphate 2.23 ± 0.20 mmol/L wet tissue, glycerophosphocholine 2.34 ± 0.46 mmol/L wet tissue, glycerophosphoethanolamine 1.50 ± 0.28 mmol/L wet tissue, phosphocholine 1.06 ± 0.16 mmol/L wet tissue, phosphoethanolamine 0.77 ± 0.14 mmol/L wet tissue, NAD + 2.37 ± 0.14 mmol/L wet tissue, UDPG 2.00 ± 0.22 mmol/L wet tissue, phosphatidylcholine 1.38 ± 0.31 mmol/L wet tissue. Inorganic phosphate and phosphatidylcholine concentrations were significantly lower in patients; glycerophosphoethanolamine concentrations were significantly higher (P < 0.05). We report human in vivo hepatic T 1 s for phosphatidylcholine, NAD + , and UDPG for the first time at 7T. Our protocol allows high signal-to-noise, repeatable measurement of metabolite concentrations in human liver. The splitting of PDE into its constituent peaks at 7T may allow more insight into changes in metabolism. Magn Reson Med 78:2095-2105, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on

  14. Development of {sup 68}Ga-labelled DTPA galactosyl human serum albumin for liver function imaging

    Energy Technology Data Exchange (ETDEWEB)

    Haubner, Roland [Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck (Austria); Medizinische Universitaet Innsbruck, Universitaetsklinik fuer Nuklearmedizin, Innsbruck (Austria); Vera, David R.; Farshchi-Heydari, Salman [University of California, Department of Radiology, School of Medicine, and the UCSD Molecular Imaging Program, San Diego, CA (United States); Helbok, Anna; Rangger, Christine; Putzer, Daniel; Virgolini, Irene J. [Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck (Austria)

    2013-08-15

    The hepatic asialoglycoprotein receptor is responsible for degradation of desialylated glycoproteins through receptor-mediated endocytosis. It has been shown that imaging of the receptor density using [{sup 99m}Tc]diethylenetriamine pentaacetic acid (DTPA) galactosyl human serum albumin ([{sup 99m}Tc]GSA) allows non-invasive determination of functional hepatocellular mass. Here we present the synthesis and evaluation of [{sup 68}Ga]GSA for the potential use with positron emission tomography (PET). Labelling of GSA with {sup 68}Ga was carried out using a fractionated elution protocol. For quality control thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) and size exclusion chromatography (SEC) techniques were evaluated. Stability of [{sup 68}Ga]GSA was studied in phosphate-buffered saline (PBS) and human serum. For in vivo evaluation [{sup 68}Ga]GSA distribution in Lewis rats was compared with [{sup 99m}Tc]GSA by using a dual isotope protocol. PET and planar imaging studies were performed using the same scaled molar dose of [{sup 68}Ga]GSA and [{sup 99m}Tc]GSA. Time-activity curves (TAC) for heart and liver were generated and corresponding parameters calculated (t50, t90). [{sup 68}Ga]GSA can be produced with high radiochemical purity. The best TLC methods for determining potential free {sup 68}Ga include 0.1 M sodium citrate as eluent. None of the TLC methods tested were able to determine potential colloids. This can be achieved by SEC. HPLC confirmed high radiochemical purity (>98 %). Stability after 120 min incubation at 37 C was high in PBS (>95 % intact tracer) and low in human serum ({proportional_to}27 % intact tracer). Biodistribution studies simultaneously injecting both tracers showed comparable liver uptake, whereas activity concentration in blood was higher for [{sup 68}Ga]GSA compared to [{sup 99m}Tc]GSA. The [{sup 99m}Tc]GSA TACs exhibited a small degree of hepatic metabolism compared to the [{sup 68}Ga]GSA curves. The mean

  15. Molecular cloning of cDNAs of human liver and placenta NADH-cytochrome b5 reductase

    International Nuclear Information System (INIS)

    Yubisui, T.; Naitoh, Y.; Zenno, S.; Tamura, M.; Takeshita, M.; Sakaki, Y.

    1987-01-01

    A cDNA coding for human liver NADH-cytochrome b 5 reductase was cloned from a human liver cDNA library constructed in phage λgt11. The library was screened by using an affinity-purified rabbit antibody against NADH-cytochrome b 5 reductase of human erythrocytes. A cDNA about 1.3 kilobase pairs long was isolated. By using the cDNA as a probe, another cDNA (pb 5 R141) of 1817 base pairs was isolated that hybridized with a synthetic oligonucleotide encoding Pro-Asp-Ile-Lys-Tyr-Pro, derived from the amino acid sequence at the amino-terminal region of the enzyme from human erythrocytes. Furthermore, by using the pb 5 R141 as a probe, cDNA clones having more 5' sequence were isolated from a human placenta cDNA library. The amino acid sequences deduced from the nucleotide sequences of these cDNA clones overlapped each other and consisted of a sequence that completely coincides with that of human erythrocytes and a sequence of 19 amino acid residues extended at the amino-terminal side. The latter sequence closely resembles that of the membrane-binding domain of steer liver microsomal enzyme

  16. Natural history of patients with non cirrhotic portal hypertension: Comparison with patients with compensated cirrhosis.

    Science.gov (United States)

    Gioia, Stefania; Nardelli, Silvia; Pasquale, Chiara; Pentassuglio, Ilaria; Nicoletti, Valeria; Aprile, Francesca; Merli, Manuela; Riggio, Oliviero

    2018-01-31

    The knowledge of natural history of patients with portal hypertension (PH) not due to cirrhosis is less well known than that of cirrhotic patients. To describe the clinical presentation and the outcomes of 89 patients with non-cirrhotic PH (25 with non-cirrhotic portal hypertension, INCPH, and 64 with chronic portal vein thrombosis, PVT) in comparison with 77 patients with Child A cirrhosis. The patients were submitted to a standardized clinical, laboratory, ultrasonographic and endoscopic follow-up. Variceal progression, incidence of variceal bleeding, portal vein thrombosis, ascites and survival were recorded. At presentation, the prevalence of varices, variceal bleeding and ascites was similar in the 3 groups. During follow-up, the rate of progression to varices at risk of bleeding (p portal hypertension in these patients and cannot be simply derived by the observation of cirrhotic patients. Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  17. Association Between Proton Pump Inhibitor Use and Spontaneous Bacterial Peritonitis in Cirrhotic Patients with Ascites

    Directory of Open Access Journals (Sweden)

    Mélissa Ratelle

    2014-01-01

    Full Text Available BACKGROUND: There are data suggesting a link between proton pump inhibitor (PPI use and the development of spontaneous bacterial peritonitis (SBP in cirrhotic patients with ascites; however, these data are controversial.

  18. CT of the liver in cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Baert, A L; Wilms, G; Marchal, G; de Somer, F; de Maeyer, P; Ponette, E

    1980-07-01

    Of the diseases causing diffuse hepatic parenchyma alterations, CT will demonstrate most typically fatty replacement and hemochromatosis. Cirrhosis of the liver will be detected by CT in only a minority of the patients by virtue of changes in size and contour. Changes in attenuation coefficient in cirrhotic livers are described by some authors but not confirmed on a large scale until now. CT is useful for demonstrating associated anomalies such as signs of portal hypertension (splenomegaly, venous collaterals and ascites) and for studying the permeability of the portal vein.

  19. CT of the liver in cirrhosis

    International Nuclear Information System (INIS)

    Baert, A.L.; Wilms, G.; Marchal, G.; Somer, F. de; Maeyer, P. de; Ponette, E.

    1980-01-01

    Of the diseases causing diffuse hepatic parenchyma alterations, CT will demonstrate most typically fatty replacement and hemochromatosis. Cirrhosis of the liver will be detected by CT in only a minority of the patients by virtue of changes in size and contour. Changes in attenuation coefficient in cirrhotic livers are described by some authors but not confirmed on a large scale until now. CT is useful for demonstrating associated anomalies such as signs of portal hypertension (splenomegaly, venous collaterals and ascites) and for studying the permeability of the portal vein. (orig.) [de

  20. Bacterial infections in patients with liver cirrhosis: clinical characteristics and the role of C-reactive protein

    Science.gov (United States)

    Deutsch, Melanie; Manolakopoulos, Spilios; Andreadis, Ioannis; Giannaris, Markos; Kontos, George; Kranidioti, Hariklia; Pirounaki, Maria; Koskinas, John

    2018-01-01

    Background: The diagnosis of bacterial infection in cirrhotic patients may be difficult, because of the absence of classical signs such as fever and raised white blood cell count. The role of C-reactive protein (CRP) in this context has not been clearly defined. Methods: Clinical and laboratory characteristics of 210 consecutive cirrhotic patients with (n=100) or without (n=110) bacterial infection were compared with a control group of non-cirrhotic patients with infection (n=106). Results: Significantly fewer patients with cirrhosis had a body temperature ≥37°C when presenting with bacterial infection (56% cirrhotic vs. 85.5% non-cirrhotic patients, P=0.01). Mean leukocyte count was 6.92 × 103/mm3 in patients with cirrhosis and infection, 5.75 × 103/mm3 (P=0.02) in cirrhotic patients without infection, and 11.28 × 103/mm3 in non-cirrhotic patients with infection (P10 mg/L indicated the presence of infection with a sensitivity of 68%, a specificity of 84.5% and an area under the receiver operating characteristic curve of 0.8197. CRP cutoff level differed according to the severity of the liver disease: Child-Pugh score (CPS) A: 21.3 mg/L, B: 17 mg/L, and C: 5.78 mg/L. Conclusions: CRP at admission could help diagnose infection in cirrhotic patients. Since the severity of liver disease seems to affect the CRP values, lower CRP levels might indicate infection. Clinical suspicion is necessary to avoid delay in diagnosis and initiate antibiotic treatment. PMID:29333070